1

Drug Product DeveIopment in the

PharmaceuticaI Industry
Gurvi nder Si ngh Rekhi
Leon ShargeI
I. INTRODUCTION
A. Act i ve pharmaceut i caI i ngredi ent ( API )
1. A drug substance i s t he APÌ or component t hat pr oduces pharmacol ogi cal
act i vi t y.
2. The APÌ may be produced by chemi cal synt hesi s, r ecover y f r om a nat ur al
pr oduct , enzymat i c react i on, r ecombi nant DNA t echnol ogy, f er ment at i on, or a
combi nat i on of t hese processes. Furt her puri f i cat i on of t he APÌ may be needed
bef ore i t can be used i n a dr ug pr oduct .
3. A new chemi caI enti ty ( NCE) i s a drug subst ance wi t h unknown cl i ni cal ,
t oxi col ogi c, physi cal , and chemi cal pr oper t i es. Ì n addi t i on, t he U. S. Food and Drug
Admi ni st rat i on (FDA) consi ders an NCE as an APÌ t hat has not been appr oved f or
market i ng i n t he Uni t ed St at es.
4. The i denti t y, st rength, quaI i t y, and puri t y of a drug subst ance depend on
pr oper cont r ol of t he manuf act ur i ng and synt het i c process.
B. Drug product
1. A dr ug pr oduct i s t he f i ni shed dosage f orm (e. g. , capsul e, t abl et , i nj ect abl e)
t hat cont ai ns t he APÌ , gener al l y i n associ at i on wi t h ot her exci pi ent s, or i ner t
i ngredi ent s.
2. The exci pi ent s i n t he dr ug pr oduct may af f ect t he f unct i onal i t y and per f or mance
of t he dr ug pr oduct , i ncl udi ng modi f i cat i on of t he r at e of dr ug subst ance rel ease,
i mprovi ng drug st abi l i t y, and maski ng t he dr ug t ast e.
3. Di f f erent approaches ar e gener al l y used t o produce dr ug product s t hat cont ai n
NCEs, product l i ne ext ensi ons, generi c dr ug pr oduct s, and speci al t y drug pr oduct s.
C. New drug product deveI opment
Dr ug product s cont ai ni ng NCE are devel oped sequent i al l y i n t he f ol l owi ng phases.
1. PrecI i ni caI . Ani mal phar macol ogy and t oxi col ogy dat a ar e obt ai ned t o det er mi ne
t he saf et y and ef f i cacy of t he drug. Because l i t t l e i s known about t he human and t he
t her apeut i c/ t oxi col ogi c pot ent i al , many dr ug product s wi l l not r each t he mar ket pl ace.
No at t empt i s made t o devel op a f i nal f ormul at i on duri ng t he pr ecl i ni cal st age.
NoncI i ni caI st udi es ar e nonhuman st udi es t hat may cont i nue at any st age of
r esear ch t o obt ai n addi t i onal i nf ormat i on concerni ng t he phar macol ogy and
t oxi col ogy of t he dr ug.
2. Phase I
a. An I nvest i gat i onaI New Drug ( I ND) appl i cat i on f or human t est i ng i s submi t t ed t o
t he FDA. Cl i ni cal t est i ng t akes pl ace af t er t he Ì ND appl i cat i on i s submi t t ed.
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b. Heal t hy vol unt eers are used i n phase Ì cl i ni cal st udi es t o det er mi ne drug
t ol er ance and t oxi ci t y.
c. For or al dr ug admi ni st r at i on, a si mpl e har d gel at i n capsul e f or mul at i on cont ai ni ng
t he APÌ i s usual l y used f or Ì ND st udi es.
d. Toxi col ogi c st udi es÷i ncl udi ng acut e, chr oni c, subchroni c, and mut ageni ci t y÷and
ot her such st udi es i n vari ous ani mal speci es ar e pl anned dur i ng t hi s phase.
3. Phase I I
a. A l i mi t ed number of pat i ent s wi t h t he di sease or condi t i on f or whi ch t he dr ug was
devel oped are t reat ed under cl ose super vi si on.
b. Dose- response st udi es, bi oavai l abi l i t y, and phar macoki net i cs ar e per f or med t o
det ermi ne t he opt i mum dosage regi men f or t reat i ng t he di sease.
c. Saf et y i s measur ed by at t empt i ng t o det ermi ne t he t herapeuti c i ndex (r at i o of
t oxi c dose t o ef f ect i ve dose).
d. A dr ug f ormul at i on havi ng good physi co-chemi cal st abi l i t y i s devel oped.
e. Chroni c t oxi ci t y st udi es are st ar t ed i n t wo speci es; such st udi es normal l y l ast
mor e t han 2 years' dur at i on.
4. Phase I I I
a. Lar ge- scal e, muI ti cent er cI i ni caI st udi es ar e per f or med wi t h t he f i nal dosage
f or m devel oped i n phase Ì Ì . These st udi es ar e done t o det ermi ne t he saf et y and
ef f i cacy of t he drug pr oduct i n a l ar ge pat i ent popul at i on who have t he di sease or
condi t i on f or whi ch t he dr ug was devel oped.
b. Si de ef f ect s ar e moni t or ed. Ì n a l ar ge popul at i on, new t oxi c ef f ect s may occur
t hat wer e not evi dent i n pr evi ous cl i ni cal t r i al s.
5. Submi ssi on of a New Drug AppI i cati on ( NDA) . An NDA i s submi t t ed t o t he FDA
f or r evi ew and appr oval af t er t he compl et i on of cl i ni cal t ri al s t hat show t o t he
sat i sf act i on of t he medi cal communi t y t hat t he drug product i s ef f ect i ve by al l
par amet er s and i s reasonabl y saf e as demonst rat ed by ani mal and human st udi es.
6. Phase I V
a. Af t er t he NDA i s submi t t ed, and bef or e appr oval t o market t he pr oduct i s obt ai ned
f r om t he FDA, manuf act ur i ng scaI e-up act i vi t i es occur . Scal e-up i s t he i ncr ease i n
t he bat ch si ze f r om t he cl i ni cal bat ch, submi ssi on bat ch, or bot h t o t he f ul l - scal e
pr oduct i on bat ch si ze, usi ng t he f i ni shed, mar ket ed product .
b. The drug pr oduct may be i mpr oved as a r esul t of equi pment , r egul at or y, suppl y,
or mar ket demands.
c. Addi t i onal cl i ni cal st udi es may be per f ormed i n speci al popul at i ons, such as t he
el der l y, pedi at ri c, and renal -i mpai r ed, t o obt ai n i nf ormat i on on t he ef f i cacy of t he
dr ug i n t hese subj ect s.
d. Addi t i onal cl i ni cal st udi es may be per f ormed t o det ermi ne i f t he dr ug can be used
f or a new or addi t i onal l abel i ng i ndi cat i ons.
7. Phase V
a. Af t er t he FDA grant s market appr oval of t he dr ug, pr oduct devel opment may
cont i nue.
b. The drug f ormuI at i on may be modi f i ed sl i ght l y as a resul t of dat a obt ai ned
dur i ng t he manuf act uri ng scal e- up and val i dat i on pr ocesses.
c. Changes i n drug f ormuI ati on shoul d al ways be wi t hi n t he scal e- up and post -
approval change ( SUPAC) gui del i nes.
D. Product I i ne ext ensi ons ar e dosage f or ms i n whi ch t he physi cal f orm or
st r engt h, but not t he use or i ndi cat i on, of t he pr oduct changes. Product l i ne
ext ensi on i s usual l y perf or med dur i ng phase Ì Ì Ì , Ì V, or V.
1. Devel opi ng a t r ansdermal pat ch when onl y t abl et s have been avai l abl e, f or
exampl e:
• Pr ogest er one
• Ni cot i ne
• Est r adi ol
• Ni t r ogl yceri n
2. Addi t i onaI st rengt hs-as l ong as t hese st rengt hs are wi t hi n t he t ot al dai l y dose,
f or exampl e:
• Ì buprof en
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3. Cont roI I ed- reI ease or modi fi ed- reI ease dosage f or ms when onl y an i mmedi at e-
r el ease dosage f orm i s avai l abl e. Thi s i s an ongoi ng pr oj ect f or al l br and
compani es; al most ever y NCE has or wi l l event ual l y have a modi f i ed-r el ease dosage
f or m of t he i mmedi at e- r el ease pr oduct .
E. Bi oI ogi c product s
1. A bi ol ogi c product i s any vi r us, ser um, t oxi n, ant i t oxi n, vacci ne, bl ood, bl ood
component or deri vat i ve, al l er geni c pr oduct , or anal ogous pr oduct appl i cabl e t o t he
pr event i on, t reat ment , or cure of di seases or i nj ur i es.
2. Bi ol ogi c pr oduct s ar e a subset of dr ug product s, di st i ngui shed by t hei r
manuf act ur i ng processes ( bi ol ogi c vs. chemi cal ). Ì n general , t he t er m dr ugs i ncl udes
bi ol ogi c pr oduct s.
3. Bi oI ogi c I i cense appI i cat i on ( BLA) . Bi ol ogi c pr oduct s ar e appr oved f or
market i ng under t he provi si ons of t he Publ i c Heal t h Ser vi ce ( PHS) Act .
F. Generi c drug product s
1. Af t er pat ent expi rati on of t he APÌ and / or br and dr ug pr oduct , a generi c drug
pr oduct may be mar ket ed. A gener i c drug pr oduct i s t her apeut i cal l y equi val ent t o
t he br and name drug pr oduct and cont ai ns t he same amount of t he drug i n t he same
t ype of dosage f orm ( e. g. , t abl et , l i qui d, i nj ect abl e) .
2. A gener i c drug pr oduct must be bi oequi vaI ent ( i . e. , have t he same r at e and
ext ent of dr ug absor pt i on) t o t he brand dr ug pr oduct . Theref ore, a generi c drug
pr oduct i s expect ed t o gi ve t he same cl i ni cal r esponse ( Chapt er 7). These st udi es
ar e normal l y perf ormed wi t h heal t hy human vol unt eers.
3. Some gener i c pr oduct s are not absor bed; f or some ot hers bi oequi val ence i s not a
good mar ker . Under t hose condi t i ons, comparat i ve cI i ni caI t ri aI s or st udi es wi t h
pharmacodynami c end poi nts are consi der ed t o measur e t he equi val ence of t wo
pr oduct s. Ì nhal at i on pr oduct s and nonabsor bed dr ug pr oduct s f al l i nt o t hi s cat egor y.
4. The gener i c drug pr oduct may di f f er f r om t he br and pr oduct i n physi caI
appearance (i . e. , si ze, col or, shape) or i n t he amount and t ype of exci pi ent s used i n
t he f ormul at i on.
5. A gener i c drug pr oduct may not di f f er i n bot h t he qual i t at i ve and t he quant i t at i ve
composi t i ons f or l i qui ds, i nj ect abl es, semi sol i ds, t r ansder mal pat ches, i nhal at i on
pr oduct s, and opht hal mi c product s, unl ess adequat e saf et y st udi es have been
per f or med.
6. Bef or e a gener i c dr ug pr oduct i s market ed, t he manuf act ur er must submi t an
Abbrevi at ed New Drug AppI i cat i on ( ANDA) t o t he FDA f or appr oval . Because
pr ecl i ni cal saf et y and ef f i cacy st udi es have al r eady been per f ormed f or t he NDA-
approved br and product , human bi oequi val ence st udi es, i nst ead of cl i ni cal t r i al s,
ar e gener al l y r equi red f or t he ANDA. The chemi st r y, manuf act ur i ng, and cont r ol s
r equi r ement s f or t he gener i c drug pr oduct are si mi l ar t o t hose f or t he br and name
dr ug pr oduct .
G. Speci aI t y drug product s ar e exi st i ng pr oduct s devel oped as a new del i ver y
syst em or f or a new t herapeut i c i ndi cat i on. The saf et y and ef f i cacy of t he dr ug
pr oduct wer e est abl i shed i n t he i ni t i al NDA- approved dosage f orm. For exampl e, t he
ni t rogl ycer i n t ransdermal del i ver y syst em ( pat ch) was devel oped af t er exper i ence
wi t h ni t rogl yceri n subl i ngual t abl et s.
II. PRODUCT DEVELOPMENT.
For each drug, var i ous st udi es ar e r equi red t o devel op a saf e, ef f ect i ve, and st abl e
dosage f orm.
A. New chemi caI enti t i es
1. PreformuI at i on i s t he char act eri zat i on of t he physi cal and chemi cal proper t i es of
t he act i ve dr ug subst ance and dosage f orm. The t her apeut i c i ndi cat i on of t he dr ug
and t he r out e of admi ni st r at i on di ct at e t he t ype of dr ug product or dr ug del i ver y
syst em (e. g. , i mmedi at e r el ease, cont r ol l ed r el ease, supposi t or y, par ent eral ,
t r ansder mal ) t hat needs t o be devel oped.
a. Pr ef ormul at i on act i vi t i es ar e usual l y perf ormed duri ng t he precl i ni cal st age.
However , t hese act i vi t i es may cont i nue i nt o phases Ì and Ì Ì .
b. The f ol l owi ng i nf or mat i on i s obt ai ned dur i ng pref ormul at i on.
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( 1) Physi caI , i ncl udi ng par t i cl e si ze and shape, cr yst al l i ni t y, pol ymor phi sm, densi t y,
sur f ace area, hygr oscopi ci t y (abi l i t y t o t ake up and r et ai n moi st ure) , and powder
f l ow
( 2) SoI ubi I i t y, i ncl udi ng i nt ri nsi c di ssol ut i on, pH sol ubi l i t y pr of i l e, and gener al
sol ubi l i t y char act er i st i cs i n vari ous sol vent s
( 3) Chemi caI , i ncl udi ng sur f ace ener gy, pH st abi l i t y prof i l e, pKa, t emper at ur e
st abi l i t y ( dr y or under var i ous humi di t y condi t i ons) , and exci pi ent i nt eract i ons
( 4) AnaI yt i caI met hods devel opment , i ncl udi ng devel opment of a st abi l i t y i ndi cat i ng
met hod ( measur es bot h t he APÌ and t he rel at ed subst ances) , and cl eani ng met hods
2. FormuI at i on deveI opment i s a cont i nui ng pr ocess. Ì ni t i al dr ug f ormul at i ons ar e
devel oped f or ear l y cl i ni cal st udi es. When t he submi ssi on of an NDA i s consi der ed,
t he manuf act ur er at t empt s t o devel op t he f i nal (mar ket ed) dosage f orm. The dose of
t he dr ug and t he rout e of admi ni st r at i on are i mport ant i n det ermi ni ng t he
modi f i cat i ons needed.
a. I nj ectabI e
( 1) A f i nal i nj ect abl e dr ug pr oduct i s usual l y devel oped i n t he pr ecl i ni cal phase.
( 2) Maj or concerns i ncl ude t he st abi l i t y of t he drug i n sol ut i on and t he st er i l i t y of t he
pr oduct .
( 3) Because f ew exci pi ent s ar e al l owed i n i nj ect abl e product s, t he f ormul at or must
choose a f i nal pr oduct ear l y i n t he devel opment pr ocess.
( 4) Ì f t he f ormul at i on i s changed, bi oavai l abi l i t y st udi es ar e not r equi red f or
i nt ravenous sol ut i on i nj ect i ons because t he pr oduct i s i nj ect ed di r ect l y i nt o t he
body.
( 5) For mul at i on changes may requi r e acut e t oxi ci t y st udi es.
b. Topi caI ( for I ocaI appI i cat i on). Ì ncl udes ant i bact er i al s, ant i f ungal s,
cor t i cost er oi ds, and l ocal anest het i cs.
( 1) The f i nal dosage f orm f or a t opi cal dr ug product i s usual l y devel oped dur i ng
phase Ì st udi es because any maj or f ormul at i on changes may requi r e f ur t her cl i ni cal
t r i al s.
( 2) The rel ease of t he drug f rom t he mat ri x i s measured i n vi t r o wi t h var i ous
di f f usi on cel l model s.
( 3) Si gni f i cant probl ems encount ered wi t h l ocal l y act i ng t opi cal dr ug pr oduct s
i ncl ude l ocal i r ri t at i on, ski n seni st i zat i on and syst emi c dr ug absor pt i on.
c. Topi caI (f or syst emi c drug absorpt i on) . Ì ncl udes dr ug del i ver y t hrough t he ski n
( t r ansder mal ) , mucous membranes (i nt r anasal ) , and r ect al mucosa.
( 1) A pr ot ot ype f ormul at i on i s devel oped f or phase Ì .
( 2) A f i nal t opi cal dr ug pr oduct i s devel oped duri ng phase Ì Ì Ì af t er t he avai l abl e
t echnol ogy and desi red syst emi c l evel s ar e consi dered.
d. OraI
( 1) Pr ot ot ype dosage f orms ar e of t en devel oped dur i ng t he precI i ni caI phase t o
ensur e t hat t he dr ug i s opt i mal l y avai l abl e and t hat t he pr oduct di ssol ves i n t he
gast r oi nt est i nal t ract .
( 2) Ì n t he ear l y st ages of pr oduct devel opment , hard geI at i n capsuI e dosage f orms
ar e of t en devel oped f or phase I cl i ni cal t r i al s. Ì f t he dr ug shows ef f i cacy, t he same
dr ug f ormul at i on may be used i n phase Ì Ì st udi es.
( 3) Fi nal product devel opment begi ns when t he dr ug pr oceeds duri ng phase Ì Ì and
bef ore i ni t i at i ng phase Ì Ì Ì cl i ni cal st udi es.
3. Market ed Product . Consi der at i ons i n t he devel opment of a f i nal dosage f or m
i ncl ude t he f ol l owi ng:
a. Col or , shape, si ze, t ast e, vi scosi t y, sensi t i vi t y, ski n f eel , and physi cal
appear ance of t he dosage f orm
b. Si ze and shape of t he package or cont ai ner
c. Product i on equi pment
d. Pr oduct i on si t e
e. Count r y of ori gi n i n whi ch t he dr ug i s t o be manuf act ur ed
f . Count r y i n whi ch t he dr ug wi l l be mar ket ed
B. Product I i ne ext ensi ons ar e gener al l y def i ned as drug pr oduct s cont ai ni ng an
NDA- approved dr ug i n a di f f er ent dosage st r engt h or i n a di f f er ent dosage f orm
( e. g. , modi f i ed rel ease, or al l i qui d) .
1. OraI product I i ne extensi ons
a. The si mpl est dosage f or m t o devel op i s a di f f er ent dosage st r engt h of a dr ug i n a
t abl et or capsul e. Onl y bi oequi val ence st udi es are needed.
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b. A modi fi ed- reI ease dosage f orm i s more di f f i cul t t o devel op when onl y an
i mmedi at e- r el ease dosage f or m exi st s. Cl i ni cal t r i al s ar e normal l y r equi red.
c. Consi der at i ons i n devel opi ng t hese dosage f orms ar e si mi l ar t o t hose f or t he f i nal
dr ug pr oduct (see Ì Ì . A. 3).
d. Marketi ng has a r ol e i n t he choi ce of t he dosage f or m.
e. Because t he ori gi nal br and drug pr oduct i nf ormat i on cont ri but es t o t he body of
knowl edge about t he dr ug, no pref ormul at i on i s needed. Al l ot her f act ors consi dered
f or t he or i gi nal pr oduct ar e si mi l ar . Ì f t he rel at i on bet ween i n vi t ro di ssol ut i on and
i n vi vo bi oavai l abi l i t y i s known, t he i nnovat or can pr ogr ess t o a f i ni shed dosage
f or m r el at i vel y qui ckl y.
f . ReguI at or y approvaI i s based on t he f ol l owi ng:
( 1) Anal yt i cal and manuf act ur i ng cont r ol s
( 2) St abi l i t y i nf or mat i on
( 3) Bi oavai l abi l i t y and bi oequi val ence st udi es
( 4) Cl i ni cal t ri al s (i n t he case of modi f i ed- rel ease dosage f or ms)
g. A new t her apeut i c i ndi cat i on f or a dr ug r equi res new ef f i cacy st udi es and a new
NDA.
2. Li qui d product I i ne ext ensi ons
a. Ì f t he cur r ent market ed pr oduct i s a l i qui d prepar at i on, t hen t he same f act or s as
f or t he sol i d or al dosage f orms ar e consi der ed ( see Ì Ì . B. 1. a, b, c, d, e, f and g).
b. Ì f t he mar ket ed product i s a sol i d or al dosage f or m and t he pr oduct l i ne ext ensi on
i s a l i qui d, product devel opment must pr oceed wi t h caut i on because t he rat e and
ext ent of absor pt i on f or l i qui d and sol i d dosage f or ms may not be t he same.
c. ReguI at or y approvaI r equi r es
( 1) Anal yt i cal and manuf act ur i ng cont r ol s
( 2) St abi l i t y i nf or mat i on
( 3) Bi oavai l abi l i t y and bi oequi val ence st udi es
( 4) Saf et y st udi es (e. g. , dependi ng on t he drug subst ance, l ocal i r r i t at i on)
( 5) Cl i ni cal t ri al s, i f t he rat e and ext ent of drug absorpt i on ar e dr ast i cal l y al t er ed
f r om t he ori gi nal dosage f or m
C. Combi nat i on product s are made up of t wo or more r egul at ed component s ( e. g. ,
dr ug/ devi ce, bi ol ogi c/ devi ce, drug/ bi ol ogi c, or drug/ devi ce/ bi ol ogi c) t hat are
physi cal l y, chemi cal l y, or ot her wi se combi ned or mi xed and produced as a si ngl e
ent i t y.
1. These may be t wo or mor e separat e product s packaged t oget her i n a si ngl e
package or as a uni t and may be composed of drug and devi ce pr oduct s, devi ce and
bi ol ogi c pr oduct s, or bi ol ogi c and dr ug product s.
2. An exampI e i s an i nhal at i on st er oi d ( e. g. , becl omet hasone i nhal at i on aer osol ) i n
whi ch t he devi ce component i s i mpor t ant f or del i ver y of t he st eroi d.
III. PREAPPROVAL INSPECTIONS (PAIs)
A. The manuf act uri ng f aci l i t y i s i nspect ed by t he FDA af t er an NDA, abbr evi at ed
ant i bi ot i c dr ug appl i cat i on ( AADA) , or ANDA i s submi t t ed and bef or e t he appl i cat i on
i s approved.
B. A PAÌ may al so be i ni t i at ed i f a maj or change i s r epor t ed i n a suppl ement al
appl i cat i on t o an NDA, AADA, or ANDA.
C. Dur i ng t he PAÌ , t he FDA i nvest i gat or :
1. Performs a gener al cur r ent good manuf act uri ng pract i ce (cGMP) i nspect i on
r el at i ng speci f i cal l y t o t he dr ug pr oduct i nt ended f or t he market
2. Revi ews t he devel opment r epor t t o ver i f y t hat t he dr ug product has enough
suppor t i ng document at i on t o ensure a val i dat ed pr oduct and a rat i onal e f or t he
manuf act ur i ng di r ect i ons
3. ConsuI ts t he chemi st r y, manuf act ur i ng, and cont r ol ( CMC) sect i on of t he NDA,
AADA, or ANDA and det er mi nes t he capabi l i t y of t he manuf act ur er t o produce t he
dr ug pr oduct as descri bed
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4. Veri f i es t he t raceabi l i t y of t he i nf or mat i on submi t t ed i n t he CMC sect i on t o t he
or i gi nal l abor at or y not ebooks, el ect roni c i nf ormat i on, and bat ch recor ds
5. Veri f i es and ensures t hat al l t he qual i t y syst ems ar e i n pl ace t o manuf act ur e t he
pr oduct so i t r et ai ns t he i dent i t y, st rengt h, qual i t y, and pur i t y of t he dr ug pr oduct
t hat wer e appr oved by t he cent er .
6. Recommends approval f or t he manuf act ur e of t he dr ug product based on t he
st at us of t he i nspect i on
IV. SCALE-UP AND POSTAPPROVAL CHANGES
(SUPACs)
A. Purpose. These gui del i nes are i nt ended t o r educe t he number of manuf act uri ng
changes t hat r equi re pr e- approval by t he FDA. The gui del i nes ar e publ i shed by t he
FDA on t he Ì nt er net (ht t p: / / www. f da. gov/ cder / gui dance/ i ndex. ht m) .
B. Funct i on. These gui del i nes provi de r ecommendat i ons t o sponsor s of NDAs,
AADAs, and ANDAs duri ng t he post appr oval per i od when
1. Maki ng sl i ght changes i n t he amount of t he exci pi ent t o ai d i n t he pr ocessi ng of
t he pr oduct dur i ng scal e-up
2. Changi ng t he si t e of manuf act ur e
3. ScaI i ng up ( i ncreasi ng) or scaI i ng down ( decr easi ng) t he bat ch si ze of t he
f or mul at i on
4. Changi ng t he manuf act ur i ng process or equi pment
C. The FDA must be not i f i ed about a pr oposed change t o a dr ug pr oduct t hr ough
di f f er ent reguI ator y documentat i on, dependi ng on t he t ype of change proposed.
1. AnnuaI report . Changes t hat are unl i kel y t o have any det ect abl e ef f ect on
f or mul at i on qual i t y and per f ormance can be i nst i t ut ed wi t hout appr oval by t he FDA
and repor t ed annual l y. Exampl es of t hese changes i ncl ude:
a. CompI i ance wi t h an of f i ci al compendi um
b. LabeI descri pti on of t he dr ug product or how i t i s suppl i ed ( not i nvol vi ng dosage
st r engt h or dosage f orm)
c. Del et i on of an i ngredi ent t hat af f ect s onl y t he col or of t he pr oduct
d. Ext ensi on of t he expi rat i on date based on f ul l shel f -l i f e dat a obt ai ned f r om a
pr ot ocol approved i n t he appl i cat i on
e. Contai ner and cI osure syst em f or t he drug product (except a change i n
cont ai ner si ze f or nonsol i d dosage f orms) based on equi val ency t o t he appr oved
syst em under a pr ot ocol approved i n t he appl i cat i on or publ i shed i n an of f i ci al
compendi um
f . Addi t i on or del et i on of an aI t ernat e anaI yt i caI met hod
2. Changes bei ng ef fect ed ( CBE) suppI ement . Changes t hat pr obabl y woul d not
have any det ect abl e ef f ect but requi r e some val i dat i on ef f ort s r equi re speci f i c
document at i on, dependi ng on t he change. A suppl ement i s submi t t ed, and t he
change can be i mpl ement ed wi t hout pr evi ous appr oval ( CBE-0) by t he FDA or , i n
some cases, t he FDA has 30 days t o r evi ew t he change ( CBE-30) . FDA may r ej ect
t hi s suppl ement . Exampl es of reasons f or submi t t i ng a suppl ement i ncl ude
a. Addi t i on of a new speci f i cat i on or t est met hod or changes i n met hods, f aci l i t i es,
or cont rol s
b. LabeI change t o add or st r engt hen a cont r ai ndi cat i on, war ni ng, pr ecaut i on, or
adver se r eact i on
c. Use of a di f ferent f aci I i t y t o manuf act ur e t he dr ug subst ance and drug pr oduct
( t he manuf act ur i ng pr ocess i n t he new f aci l i t y does not di f f er mat eri al l y f rom t hat i n
t he f ormer f aci l i t y, and t he new f aci l i t y has r ecei ved a sat i sf act or y cGMP i nspect i on
wi t hi n t he pr evi ous 2 year s cover i ng t hat manuf act ur i ng pr ocess)
3. Pre-approvaI suppI ement . Changes t hat coul d have a si gni f i cant ef f ect on
f or mul at i on qual i t y and per f ormance r equi re speci f i c document at i on. Thi s
suppl ement must be appr oved bef ore t he pr oposed change i s i ni t i at ed. Appr opr i at e
exampl es f or pre- appr oval suppl ement ar e:
a. Addi t i on or del et i on of an i ngredi ent
b. Rel axat i on of t he l i mi t s f or a speci f i cat i on
P. 7


c. Est abl i shment of a new reguI ator y anaI yt i caI met hod
d. Del et i on of a speci f i cat i on or regul at or y anal yt i cal met hod
e. Change i n t he met hod of manufacture of t he dr ug pr oduct , i ncl udi ng changi ng or
r el axi ng an i n- pr ocess cont r ol
f . Ext ensi on of t he expi rat i on date of t he drug product based on dat a obt ai ned
under a new or revi sed st abi l i t y t est i ng pr ot ocol t hat was been approved i n t he
appl i cat i on
D. When any change t o a dr ug pr oduct i s proposed, t he manuf act ur er must show
t hat t he r esul t ant drug product i s bi oequi vaI ent and t herapeut i caI I y equi vaI ent t o
t he or i gi nal appr oved drug product ( see Chapt er 7) .
1. A mi nor change i s a change t hat has mi ni mal pot ent i al t o have an adver se ef f ect
on t he i dent i t y, st r engt h, qual i t y, puri t y, or pot ency of t he pr oduct as t hey may
r el at e t o t he saf et y or ef f ect i veness of t he product . Ì f t he proposed change i s
consi dered mi nor by t he FDA, bi oequi val ence may be demonst r at ed by comparat i ve
di ssol ut i on prof i l es f or t he ori gi nal and new f or mul at i ons.
2. A maj or change i s one t hat has subst ant i al pot ent i al t o have an adverse ef f ect
on t he i dent i t y, st r engt h, qual i t y, puri t y, or pot ency of a product as t hey may r el at e
t o t he saf et y or ef f ect i veness of t he pr oduct . Ì f t he pr oposed change i s consi dered
maj or by t he FDA, bi oequi val ence must be demonst rat ed by an i n vi vo
bi oequi val ence st udy compari ng t he or i gi nal and new f or mul at i ons.
V. GOOD MANUFACTURING PRACTICES (GMPs)
ar e regul at i ons devel oped by t he FDA. GMPs ar e mi ni mum r equi rement s t hat t he
i ndust r y must meet when manuf act ur i ng, pr ocessi ng, packi ng, or hol di ng human and
vet er i nar y drugs. These r egul at i ons, al so known as cGMPs, est abl i sh cri t er i a f or
per sonnel , f aci l i t i es, and manuf act ur i ng pr ocesses t o ensure t hat t he f i ni shed dr ug
pr oduct has t he corr ect i dent i t y, st r engt h, qual i t y, and pur i t y char act eri st i cs.
A. Good Manuf act uri ng Pr act i ces ar e descr i bed i n t he Code of Federal Regul at i ons
( CFR) , t i t l e 21, sect i ons 210 and 211.
B. QuaI i t y cont roI ( QC) i s t he gr oup wi t hi n t he manuf act ur er t hat i s r esponsi bl e f or
est abl i shi ng pr ocess and pr oduct speci f i cat i ons.
1. Speci fi cati ons are t he cri t eri a t o whi ch a drug pr oduct shoul d conf or m t o be
consi dered havi ng accept abl e qual i t y f or i t s i nt ended use.
2. The QC uni t t est s t he pr oduct and veri f i es t hat t he speci f i cat i ons are met . QC
t est i ng i ncl udes t he accept ance or rej ecti on of t he i ncomi ng r aw mat eri al s,
packagi ng component s, dr ug pr oduct s, wat er syst em, and envi r onment al condi t i ons
( e. g. , heat i ng, vent i l at i on, ai r - condi t i oni ng, ai r qual i t y, mi cr obi al l oad) t hat exi st
dur i ng t he manuf act uri ng pr ocess.
C. QuaI i t y assurance (QA) i s t he gr oup wi t hi n t he manuf act ur er t hat det er mi nes
t hat t he syst ems and f aci l i t i es ar e adequat e and t hat t he wr i t t en pr ocedures ar e
f ol l owed t o ensure t hat t he f i ni shed dr ug product meet s t he appl i cabl e speci f i cat i ons
f or qual i t y.
P. 8


STUDY QUESTIONS
Di rect i ons: Each st at ement i n t hi s sect i on can be cor r ect l y compl et ed by one or
more of t he suggest ed phr ases. Choose t he correct answer , A- E:
1. HeaI t hy human voI unt eers are used i n drug deveI opment f or
I . phase I test i ng af t er the submi ssi on of an i nvest i gat i onaI new drug ( I ND)
appI i cat i on.
I I . generi c drug deveI opment f or an abbrevi ated new drug appI i cat i on ( ANDA)
submi ssi on.
I I I . phase I I I test i ng j ust bef ore t he submi ssi on of a new drug appI i cat i on
( NDA) .
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I ar e cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 1. The answer i s C[ see] . 2. The requi red i nf ormat i on
cont ai ned i n a new drug appI i cat i on ( NDA) t hat i s not i ncI uded i n the
abbrevi ated new drug appI i cat i on ( ANDA) consi st s of
I . precI i ni caI ani maI t oxi ci t y st udi es.
I I . cI i ni caI ef f i cacy st udi es.
I I I . human saf et y and t oI erance st udi es.
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I ar e cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 2. The answer i s E[see] . 3. A product I i ne extensi on contai ns
t he new drug appI i cat i on ( NDA) approved drug i n a new
I . dosage f orm.
I I . dosage st rengt h.
I I I . therapeut i c i ndi cat i on.
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I ar e cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 3. The answer i s C[ see] . Di recti ons: Each st at ement i n t hi s
sect i on can be cor r ect l y compl et ed by one of t he suggest ed phr ases. Choose t he
best answer .
4. The reguI at i ons deveI oped by t he U. S. Food and Drug Admi ni st rat i on ( FDA)
f or t he pharmaceut i caI i ndust r y f or meet i ng t he mi ni mum requi rements i n the
manufacturi ng, processi ng, packi ng, or hoI di ng of human and veteri nar y drugs
are known as
( A) good manuf act ur i ng pr act i ces ( GMPs) .
( B) qual i t y assur ance ( QA) .
( C) qual i t y cont r ol ( QC) .
( D) pr e-appr oval i nspect i on ( PAÌ ) .
( E) scal e- up and post - appr oval changes ( SUPACs) .
Vi ew Answer 4. The answer i s A[ see] . 5. The uni t wi t hi n t he
pharmaceut i caI manuf act urer that ensures that t he fi ni shed dosage form has
met aI I the speci f i cat i ons f or i t s i nt ended use i s t he
( A) anal yt i cal met hods uni t .
( B) mar ket i ng and sal es uni t .
( C) pr e-appr oval i nspect i on ( PAÌ ) uni t .
( D) qual i t y assurance ( QA) uni t .
( E) qual i t y cont rol ( QC) uni t .
Vi ew Answer 5. The answer i s E[see] . 6. Manufact urers may make a change
i n t he f ormuI ati on af t er market approvaI . I f t he change i n the formuI ati on i s
consi dered a mi nor change, the manuf act urer needs t o report t he change to t he
FDA onI y i n t he
( A) annual r eport .
( B) pr e-appr oval suppl ement .
( C) i nvest i gat i onal new dr ug ( Ì ND) submi ssi on.
( D) changes bei ng ef f ect ed suppl ement , 30 days ( CBE- 30) .
( E) no r epor t i s r equi red f or a mi nor change.
Vi ew Answer 6. The answer i s A[ see] . P. 9


ANSWERS AND EXPLANATIONS
1. The answer i s C (Ì , Ì Ì ) [ see Ì . C. 2. b; Ì . F. 2] .
Phase Ì t est i ng i s t he f i rst set of human st udi es per f or med dur i ng new drug
devel opment . Phase Ì st udi es est abl i sh t he t ol erance and t oxi ci t y of t he dr ug i n
humans. Bi oequi val ence st udi es f or gener i c drug devel opment are most of t en
per f or med i n heal t hy human vol unt eer s. These st udi es est abl i sh t he bi oequi val ence
of t he gener i c drug pr oduct agai nst t he br and drug product . Phase Ì Ì Ì t est i ng ent ai l s
l ar ge- scal e, mul t i cent er cl i ni cal st udi es per f or med i n pat i ent s wi t h t he di sease or
condi t i on t o be t r eat ed. Phase Ì Ì Ì st udi es det er mi ne t he saf et y and ef f i cacy of t he
dr ug i n a l ar ge pat i ent popul at i on.
2. The answer i s E ( Ì , Ì Ì , and Ì Ì Ì ) [ see Ì . C. 5; Ì . F. 6] .
The devel opment of a new dr ug r equi res ext ensi ve t oxi ci t y and ef f i cacy t est i ng i n
ani mal s and humans. The NDA document s al l st udi es per f or med on t he drug. The
ANDA i s used f or gener i c drug pr oduct submi ssi ons. The gener i c drug product i s
si mi l ar t o t he or i gi nal brand dr ug product t hat has al r eady been market ed. Because
t he ef f i cacy, saf et y, and t oxi ci t y of t hi s dr ug product have been st udi ed and
document ed, f ur t her st udi es of t hi s nat ure are unnecessar y.
3. The answer i s C (Ì , Ì Ì ) [ see Ì . D] .
Pr oduct l i ne ext ensi ons ar e devel oped af t er f ur t her st udi es wi t h t he or i gi nal NDA-
approved dr ug pr oduct . Fr om t hese st udi es, t he manuf act ur er may devel op a new
dosage f orm (e. g. , cont rol l ed- rel ease product ) or a new dosage st rengt h. A new
t her apeut i c i ndi cat i on requi res an NDA.
4. The answer i s A [ see V] .
Qual i t y cont r ol and qual i t y assur ance f ol l ow GMP r egul at i ons t o ensur e t hat t he
f i ni shed pr oduct meet s al l appl i cabl e speci f i cat i ons f or qual i t y. The FDA may
i nspect a manuf act uri ng si t e ( PAÌ ) bef or e t he drug appl i cat i on i s appr oved. Ì n
addi t i on, t he FDA must be not i f i ed about any pr oposed changes t o an appr oved dr ug
pr oduct .
5. The answer i s E [ see V. B] .
The QC uni t per f orms t he appr opr i at e t est s on t he dosage f orm. PAÌ i s per f or med by
FDA compl i ance i nspect or s, who exami ne t he phar maceut i cal manuf act urer and
r evi ew t he pr ocedur es and r ecor ds f or manuf act ur i ng t he f i ni shed dosage f orm
bef ore t he admi ni st r at i on gr ant s mar ket approval . The anal yt i cal devel opment uni t
devel ops t he anal yt i cal met hods used i n t est i ng t he dr ug product .
6. The answer i s A [ see Ì V. C. 1] .
Al l changes i n t he f ormul at i on must be report ed t o t he FDA. A mi nor change i s a
change t hat has mi ni mal pot ent i al t o have an adver se ef f ect on t he i dent i t y,
st r engt h, qual i t y, puri t y, or pot ency of t he product as t hey may rel at e t o t he
pr oduct ' s saf et y or ef f ect i veness. Changes t hat are unl i kel y t o have any det ect abl e
ef f ect on f ormul at i on qual i t y and per f or mance can be i nst i t ut ed wi t hout appr oval by
t he FDA and need onl y t o be r epor t ed i n t he annual r epor t .

2
PharmaceuticaI CaIcuIations and
Statistics
Ri ccardo L. Boni
I. FUNDAMENTALS OF MEASUREMENT AND
CALCULATION.
The pharmaci st i s of t en requi r ed t o perf orm or eval uat e a var i et y of
cal cul at i ons i n hi s or her pr act i ce. Many of t hese cal cul at i ons i nvol ve t he
use of di rect or i nverse pr opor t i ons. Di mensi onaI ( or uni t ) anaI ysi s and
approxi mat i on can be usef ul i n sol vi ng t hese probl ems. Ì n di mensi onal
anal ysi s, di mensi ons ( or uni t s) ar e i ncl uded wi t h each number used i n t he
cal cul at i on. Uni t s common t o t he numer at or and denomi nat or may be
cancel ed and t he remai ni ng uni t s pr ovi de t he uni t s f or t he f i nal answer . Ì n
approxi mat i on, each number used i n t he cal cul at i on i s r ounded t o a si ngl e
si gni f i cant di gi t . Fact or s common t o t he numer at or and denomi nat or may be
cancel ed and t he answer t o t hi s approxi mat i on shoul d be r easonabl y cl ose
t o t he f i nal exact answer .
A. Rat i o and proport i on
1. Rat i o. The r el at i ve magni t ude of t wo l i ke quant i t i es i s a r at i o, whi ch i s
expr essed as a f r act i on. Cer t ai n basi c pr i nci pl es appl y t o t he r at i o, as t hey
do t o al l f r act i ons.
a. When t he t wo t erms of a rat i o are mul t i pl i ed or di vi ded by t he same
number , t he val ue of t he r at i o i s unchanged.

b. Two r at i os wi t h t he same val ue ar e equi val ent . Equi val ent rat i os have
equal cr oss pr oduct s and equal r eci pr ocal s. For exampl e:

and
1 × 6 = 3 × 2 = 6
Ì f t wo r at i os are equal , t hen t hei r reci pr ocal s ar e equal :

2. Proport i on. The expressi on of t he equal i t y of t wo r at i os i s a propor t i on.
The pr oduct of t he ext r emes i s equal t o t he pr oduct of t he means f or any
pr opor t i on. Furt hermore, t he numerat or of t he one f r act i on equal s t he
pr oduct of i t s denomi nat or and t he ot her f ract i on ( i . e. , one mi ssi ng t er m can
al ways be f ound gi ven t he ot her t hr ee t er ms) . Most pharmaceut i cal
cal cul at i ons can be per f or med by use of proport i on.
a. Proper rat i os. Some pharmaci st s use pr oper rat i os (i n whi ch si mi l ar
uni t s ar e used i n t he numer at or and denomi nat or of each rat i o) i n t hei r
pr opor t i on cal cul at i ons. Sever al exampl es f ol l ow.
( 1) Ì f 240 mL of a cough syr up cont ai ns 480 mg of dext r omet hor phan
hydr obromi de, t hen what mass of dr ug i s cont ai ned i n a chi l d' s dose, 1
t easpoonf ul (5 mL) of syr up?

P. 11


( 2) Ì f a chi l d' s dose ( 5 mL) of a cough syr up cont ai ns 10 mg of
dext r omet hor phan hydrobr omi de, what mass of dr ug i s cont ai ned i n 240
mL?

( 3) Ì f t he amount of dext r omet hor phan hydr obr omi de i n 240 mL of cough
syr up i s 480 mg, what woul d be t he vol ume r equi r ed f or a chi l d' s dose of 10
mg?

( 4) How many mi l l i grams of dext r omet horphan base (mol ecul ar wei ght =
271. 4) ar e equi val ent t o 10 mg of dext r omet horphan hydrobromi de
( mol ecul ar wei ght = 352. 3) ?

b. Mi xed rat i os. Some phar maci st s use mi xed r at i os ( i n whi ch di ssi mi l ar
uni t s ar e used i n t he numer at or and denomi nat or of each rat i o) i n t hei r
pr opor t i on cal cul at i ons. Such comput at i ons gener al l y gi ve cor rect answer s,
pr ovi di ng t he condi t i ons i n whi ch mi xed r at i os cannot be used ar e known. A
l at er exampl e shows mi xed r at i os l eadi ng t o f ai l ur e i n t he case of di l ut i on,
when i nverse pr opor t i ons are r equi r ed. For i nverse proport i ons, si mi l ar
uni t s must be used i n t he numerat or and denomi nat or of each r at i o.
Fol l owi ng i s an exampl e of a mi xed rat i o cal cul at i on usi ng t he pr evi ous
pr obl em.

The same answer i s obt ai ned i n t hi s exampl e whet her we use proper r at i os,
wi t h si mi l ar uni t s i n numer at or and denomi nat or , or mi xed r at i os. Thi s i s not
t he case when deal i ng wi t h i nverse pr opor t i ons.
3. I nverse proport i on. The most common exampl e of t he need f or i nverse
pr opor t i on f or t he phar maci st i s t he case of di I uti on. Whereas i n t he
pr evi ous exampl es of propor t i on t he rel at i onshi ps i nvol ved di rect
pr opor t i on, t he case of di l ut i on cal l s f or an i nverse pr oport i on ( i . e. , as
vol ume i ncreases, concent r at i on decreases) . The necessi t y of usi ng i nverse
pr opor t i ons f or di l ut i on pr obl ems i s shown i n t hi s exampl e.
I f 120 mL of a 10% st ock soI ut i on i s di I ut ed t o 240 mL, what i s the fi naI
concent rati on? Usi ng i nver se pr opor t i on,

As expect ed, t he f i nal concent r at i on i s one hal f t he ori gi nal concent r at i on
because t he vol ume i s doubl ed. However , i f t he pharmaci st at t empt s t o use
di r ect pr opor t i on and negl ect s t o est i mat e an appr opri at e answer , t he
r esul t i ng cal cul at i on woul d pr ovi de an answer of 20%, whi ch i s t wi ce t he
act ual concent r at i on.

P. 12


Li kewi se, t he pharmaci st usi ng mi xed r at i os f ai l s i n t hi s case.

and

B. AI i quot . A phar maci st r equi r es t he al i quot met hod of measur ement when
t he sensi t i vi t y ( t he smal l est quant i t y t hat can be measured wi t h t he
r equi r ed accur acy and preci si on) of t he measur i ng devi ce i s not great
enough f or t he r equi red measurement . Al i quot cal cul at i ons can be used f or
measurement of sol i ds or l i qui ds, al l owi ng t he phar maci st t o real i ze t he
r equi r ed preci si on t hrough a pr ocess of measur i ng a mul t i pl e of t he desi red
amount f ol l owed by di l ut i on and f i nal l y sel ect i on and measur ement of an
al i quot par t t hat cont ai ns t he desi red amount of mat eri al . Thi s exampl e
pr obl em i nvol ves wei ghi ng by t he al i quot met hod, usi ng a pr escr i pt i on
bal ance.
A pr escri pt i on bal ance has a sensi t i vi t y r equi r ement of 6 mg. How woul d
you wei gh 10 mg of dr ug wi t h an accuracy of ± 5%, usi ng a sui t abl e di l uent ?
1. Fi r st , cal cul at e t he l east wei ghabl e quant i t y f or t he bal ance wi t h a
sensi t i vi t y requi r ement of 6 mg, assumi ng ± 5% accur acy i s r equi red.
2. Now i t i s obvi ous t hat an al i quot cal cul at i on i s r equi r ed because 10 mg of
dr ug i s r equi red, wher eas t he l east wei ghabl e quant i t y i s 120 mg t o achi eve
t he requi r ed per cent age of er ror . Usi ng t he l east wei ghabl e quant i t y met hod
of al i quot measur ement , use t he smal l est quant i t y wei ghabl e on t he bal ance
at each st ep t o pr eser ve mat er i al s.
a. Wei gh 12 × 10 mg = 120 mg of dr ug.
b. Di l ut e t he 120 mg of dr ug ( f r om st ep a) wi t h a sui t abl e di l uent by
geomet ri cal di l ut i on t o achi eve a mi xt ur e t hat wi l l pr ovi de 10 mg of dr ug i n
each 120-mg al i quot . The amount of di l uent t o be used can be det er mi ned
t hr ough proporti on.

c. Wei gh 120 mg ( 1/ 12) of t he t ot al mi xt ur e, whi ch wi l l cont ai n t he requi r ed
10 mg of dr ug.
II. SYSTEMS OF MEASURE.
The pharmaci st must be f ami l i ar wi t h three syst ems of measure: t he met ri c
syst em and t wo common syst ems of measure ( t he avoi rdupoi s and
apot hecari es' syst ems). The pr i mar y syst em of measure i n pharmacy and
medi ci ne i s t he met r i c syst em. Most st udent s f i nd i t easi est t o conver t
measurement s i n t he common syst ems t o met ri c uni t s. A t abl e of conversi on
equi val ent s i s provi ded and shoul d be memor i zed by t he phar maci st (see
Appendi x A) . The met ri c syst em, because of i t s uni ver sal accept ance and
br oad use, wi l l not be revi ewed her e.
A. Apot hecari es' syst em of fI ui d measure. The apot hecari es' syst em of
f l ui d measure i s summari zed i n Appendi x A.
B. Apot hecari es' syst em f or measuri ng wei ght. The apot hecar i es' syst em
f or measuri ng wei ght i ncl udes uni t s of gr ai ns, scrupl es, dr ams, ounces, and
pounds ( see Appendi x A) .
C. Avoi rdupoi s syst em of measuri ng wei ght. The avoi r dupoi s ( AV)
syst em of measuri ng wei ght i ncl udes t he gr ai n, ounce, and pound. The
gr ai n i s a uni t common wi t h t he apot hecar i es' syst em and al l ows f or easy
conversi on bet ween t he syst ems. The avoi r dupoi s pound, however ,
P. 13

i s 16 AV ounces i n cont rast t o t he apot hecar i es' pound, whi ch i s 12
apot hecari es' ounces (see Appendi x A) .
D. Conversi on equi vaI ent s. See Appendi x A.
III. REDUCING AND ENLARGING FORMULAS.
The pharmaci st i s of t en requi r ed t o r educe or enl ar ge a reci pe. Pr obl ems of
t hi s t ype are sol ved t hrough pr opor t i on, or by mul t i pl i cat i on or di vi si on by
t he appropri at e f act or t o obt ai n t he r equi red amount of each i ngredi ent t hat
wi l l gi ve t he desi red t ot al mass or vol ume of t he f or mul a. Formul as can be
pr ovi ded i n amount s or i n part s.
A. FormuI as t hat i ndi cat e parts. When deal i ng wi t h f ormul as t hat speci f y
par t s, par t s by wei ght wi l l requi r e t he det ermi nat i on of wei ght s of
i ngredi ent s, whereas part s by vol ume war r ant t he cal cul at i on of vol umes of
i ngredi ent s. Al ways f i nd t he t ot al number of par t s i ndi cat ed i n t he f ormul a,
and equat e t hat t ot al wi t h t he t ot al mass or vol ume of t he desi red f or mul a i n
or der t o set up a pr opor t i on. Such a propor t i on wi l l al l ow cal cul at i on of t he
mass or vol ume of each i ngredi ent i n uni t s common t o t he t ot al mass or
vol ume.
What quant i t i es shouI d be used t o prepare 100 g of camphorat ed
parachI orophenoI ?
R
x
parachlorophenol 7 parts
camphor 13 parts
7 parts ¹ 13 parts ÷ 20 parts total


B. FormuI as t hat i ndi cat e quant i ti es. The pr evi ous pr escr i pt i on f or col d
cr eam pr ovi des a 100 g quant i t y.
What mass of each i ngredi ent i s requi red t o provi de 1 pound ( AV) of
cream?
R
x
white wax 12.5 g
mineral oil 60.0 g
lanolin 2.5 g
sodium borate 1.0 g
rose water 24.0 g

1 l b = 454 g
12.5 g × 4.54 ÷ 56.8 g oI white wax
60.0 g × 4.54 ÷ 272 g oI mineral oil
2.5 g × 4.54 ÷ 11.4 g oI lanolin
1.0 g × 4.54 ÷ 4.54 oI sodium borate
24.0 g × 4.54 ÷ 109 g oI rose water

IV. CALCULATING DOSES.
Cal cul at i on of doses gener al l y can be per f or med wi t h di mensi onal anal ysi s.
ProbI ems encount ered i n t he pharmacy i ncl ude cal cul at i on of t he number of
doses, quant i t i es i n a dose or t ot al mass/ vol ume, amount of act i ve or
i nact i ve i ngr edi ent s, and si ze of dose. Cal cul at i on of chi I dren' s doses i s
commonl y per f or med by t he pharmaci st . Dosage i s opt i mal l y cal cul at ed by
usi ng t he chi l d' s body wei ght or mass and t he appr opri at e dose i n
mi l l i gr ams per ki l ogr am (mg/ kg). Wi t hout t hese dat a, t he f ol l owi ng f or mul as
based on an adul t dose can be used.
A. Fri ed' s ruI e for i nfant s

P. 14


B. CI ark' s ruI e

C. Chi I d' s dosage based on body surf ace area ( BSA)
D. Young' s ruI e f or chi I dren 2 2 years oI d

E. Constant rat e i nt ravenous i nfusi ons. Some dr ugs ar e admi ni st er ed
i nt ravenousl y at a const ant ( zero- order ) r at e by usi ng a cont i nuous- dr i p
i nf usi on set or a const ant - r at e i nf usi on pump. The f l ow r at e ( vol ume per
uni t t i me) r equi red can be cal cul at ed f rom t he vol ume t o be admi ni st ered
and t he durat i on of t he i nf usi on. The r at e of dr ug admi ni st r at i on can be
cal cul at ed f r om t he concent r at i on of drug i n t he i nf used sol ut i on and t he
f l ow r at e of t he i nf usi on set or pump. Conversi on f act ors may be r equi red t o
obt ai n t he f i nal answer i n t he cor r ect uni t s ( drops per mi nut e or mi l l i l i t ers
per hour ).
A vancomyci n sol ut i on cont ai ni ng 1000 mg of vancomyci n hydr ochl or i de
di l ut ed t o 250 mL wi t h D5W i s t o be i nf used at a const ant rat e wi t h a
cont i nuous-dr i p i nt r avenous i nf usi on set t hat del i ver s 25 drops/ mL. What
f I ow rat e ( drops/ mi n) shouI d be used t o i nf use aI I 250 mL of t he
vancomyci n hydrochI ori de soI uti on i n 2 hr?

V. PERCENTAGE, RATIO STRENGTH, AND OTHER
CONCENTRATION EXPRESSIONS
A. Percent age wei ght i n voI ume (w/ v)
1. Def i ni t i on. Per cent age, i ndi cat i ng par t s per hundred, i s an i mpor t ant
means of expr essi ng concent r at i on i n pharmacy pr act i ce. Per cent age w/ v
i ndi cat es t he number of gr ams of a const i t uent per 100 mL of sol ut i on or
l i qui d f ormul at i on. The phar maci st may be r equi red t o per f orm three t ypes
of cal cul at i ons: det er mi ne t he wei ght of act i ve i ngr edi ent i n a cer t ai n
vol ume when gi ven t he per cent age st rengt h, det er mi ne t he percent age w/ v
when t he wei ght of subst ance and vol ume of l i qui d f ormul at i on are known,
and det er mi ne t he voI ume of l i qui d mi xt ur e when t he per cent age st r engt h
and amount of subst ance ar e known.
2. ToI u baI sam syrup. Tol u bal sam t i nct ur e cont ai ns 20% w/ v t ol u bal sam.
What i s the percent age concent rat i on of toI u baI sam i n t he syrup?
tolu balsam tincture 50 mL
magnesium carbonate 10 g
sucrose 820 g
puriIied water. qs ad 1000 mL

a. Fi r st , det ermi ne what t he amount of t ol u bal sam i s i n t he 50 mL quant i t y
of t i nct ure used f or t he syr up. Then, by propor t i on, cal cul at e t he
concent r at i on of t ol u bal sam i n t he syr up.
Ì n answer i ng t hi s one quest i on, t he f i r st t wo t ypes of probl ems l i st ed above
have been sol ved, whi l e exhi bi t i ng t wo met hods of sol vi ng per cent age
pr obl ems÷namel y, by di mensi onaI anaI ysi s and proport i on.
b. For an exampl e of t he t hi rd t ype of percent age w/ v pr obl em, det ermi ne
what vol ume of syr up coul d be pr epar ed i f we had onl y 8 g of magnesi um
car bonat e. Use proport i on t o f i nd t he t ot al vol ume of syr up t hat can be
made usi ng onl y 8 g of magnesi um
P. 15

car bonat e. Ì f we have 8 g of magnesi um car bonat e i n 1000 mL of sol ut i on,
t hen, accor di ng t o t he r eci pe, 800 mL of sol ut i on can be pr epared usi ng al l
8 g of t he dr ug.

B. Percent age voI ume i n voI ume ( v/ v) . Per cent age v/ v i ndi cat es t he
number of mi l l i l i t ers of a const i t uent i n 100 mL of l i qui d f or mul at i on. The
per cent age st r engt h of mi xt ur es of l i qui ds i n l i qui ds i s i ndi cat ed by percent
v/ v, whi ch i ndi cat es t he par t s by vol ume of a subst ance i n 100 par t s of t he
l i qui d pr eparat i on. The three t ypes of probl ems t hat ar e encount ered
i nvol ve cal cul at i ng percent age st rength, cal cul at i ng voI ume of i ngredi ent ,
and cal cul at i ng voI ume of t he I i qui d preparat i on. Usi ng t he same t ol u
bal sam syr up f ormul a f rom ear l i er , we' l l now wor k a per cent v/ v pr obl em.
What i s the percent age st rengt h v/ v of t he t oI u baI sam t i nct ure i n the
syrup preparat i on? By pr opor t i on, we can sol ve t he pr obl em i n one st ep.

C. Percent age wei ght i n wei ght (w/ w) . Per cent age w/ w i ndi cat es t he
number of gr ams of a const i t uent per 100 g of f ormul at i on ( sol i d or l i qui d).
Sol ut i on of probl ems i nvol vi ng per cent age w/ w i s st rai ght f or war d when t he
t ot al mass of t he mi xt ur e i s avai l abl e or when t he t ot al mass can be
det ermi ned f rom t he avai l abl e dat a. Ì n cal cul at i ons si mi l ar t o t hose f or
per cent age w/ v and v/ v, t he pharmaci st mi ght need t o sol ve several t ypes of
pr obl ems, i ncl udi ng det er mi nat i on of t he wei ght of a const i t uent , t he t ot al
wei ght of a mi xt ur e, or t he per cent age w/ w.
1. How many grams of drug substance shouI d be used to prepare 240 g
of a 5% w/ w soI uti on i n water?
a. The f i r st st ep i n any per cent age w/ w pr obl em i s t o at t empt i dent i f i cat i on
of t he t ot al mass of t he mi xt ur e. Ì n t hi s probl em, t he t ot al mass i s,
obvi ousl y, pr ovi ded ( 240 g) .
b. The probl em can be easi l y sol ved t hrough di mensi onaI anaI ysi s.

2. When t he t ot al mass of t he mi xt ur e i s unavai l abl e or cannot be
det ermi ned, an ext ra st ep i s r equi red i n t he cal cul at i ons. Because i t i s
usual l y i mpossi bl e t o know how much vol ume i s di spl aced by a sol i d
mat er i al , t he phar maci st i s unabl e t o pr epare a speci f i ed vol ume of a
sol ut i on gi ven t he per cent age w/ w.
How much drug shouI d be added t o 30 mL of wat er t o make a 10% w/ w
soI ut i on? The vol ume of wat er t hat i s di spl aced by t he dr ug i s unknown, so
t he f i nal vol ume i s unknown. Li kewi se, even t hough t he mass of sol vent i s
known ( 30 mL × 1 g/ mL = 30 g) , i t i s not known how much drug i s needed,
so t he t ot al mass i s unknown. The wat er r epr esent s 100% - 10% = 90% of
t he t ot al mi xt ur e. Then, by pr opor t i on, t he mass of drug t o be used can be
i dent i f i ed.
The common error t hat many st udent s make i n sol vi ng probl ems of t hi s
t ype i s t o assume t hat 30 g i s t he t ot al mass of t he mi xt ur e. Sol vi ng t he
pr obl em wi t h t hat assumpt i on gi ves t he f ol l owi ng i ncor r ect answer .
D. Rat i o st rengt h. Sol i d or l i qui d f ormul at i ons t hat cont ai n l ow
concent r at i ons of act i ve i ngredi ent s wi l l of t en have concent rat i on expr essed
i n rati o st rengt h. Rat i o st r engt h, as t he name i mpl i es, i s t he expr essi on of
concent r at i on by means of a r at i o. The numer at or and denomi nat or of t he
r at i o i ndi cat e gr ams ( g) or mi l l i l i t er s (mL) of a sol i d or l i qui d const i t uent i n
t he t ot al mass ( g) or vol ume ( mL) of a sol i d or l i qui d preparat i on. Because
percent age st rength i s
P. 16

essent i al l y a r at i o of part s per hundr ed, conversi on bet ween rat i o st r engt h
and percent age st r engt h i s easi l y accompl i shed by pr opor t i on.
1. Express 0. 1% w/ v as a rat i o st rengt h.
a. Rat i o st rengt hs are by convent i on expr essed i n r educed f or m, so i n
set t i ng up our propor t i on t o sol ve f or r at i o st rengt h, use t he numeral 1 i n
t he numer at or of t he r i ght hand r at i o as shown:
b. Li kewi se, conver si on f r om rat i o st r engt h t o percent age st r engt h by
pr opor t i on i s easy, as seen i n t he f ol l owi ng exampl e. Keep i n mi nd t he
def i ni t i on of per cent age st r engt h ( par t s per hundred) when set t i ng up t he
pr opor t i on.
2. Express 1:2500 as a percent age st rength.

E. Ot her concent rat i on expressi ons
1. MoI ari t y ( M) i s t he expr essi on of t he number of mol es of sol ut e di ssol ved
per l i t er of sol ut i on. Ì t i s cal cul at ed by di vi di ng t he mol es of sol ut e by t he
vol ume of sol ut i on i n l i t er s.

2. NormaI i t y. A conveni ent way of deal i ng wi t h aci ds, bases, and
el ect r ol yt es i nvol ves t he use of equi val ent s. One equi val ent of an aci d i s
t he quant i t y of t hat aci d t hat suppl i es or donat es 1 mol e of H
+
i ons. One
equi val ent of a base i s t he quant i t y t hat f urni shes 1 mol e of OH
-
i ons. One
equi val ent of aci d r eact s wi t h 1 equi val ent of base. Equi val ent wei ght can
be cal cul at ed f or at oms or mol ecul es.

The normaI i t y ( N) of a sol ut i on i s t he number of gr am- equi val ent wei ght s
( equi val ent s) of sol ut e per l i t er of sol ut i on. Normal i t y i s anal ogous t o
mol ar i t y; however , i t i s def i ned i n t erms of equi val ent s rat her t han mol es.

3. MoI aI i t y ( m) i s t he mol es of sol ut e di ssol ved per ki l ogr am of sol vent .
Mol al i t y i s cal cul at ed by di vi di ng t he number of mol es of sol ut e by t he
number of ki l ogr ams of sol vent . Mol al i t y of f er s an advant age over mol ari t y
because i t i s based on sol vent wei ght and avoi ds pr obl ems associ at ed wi t h
vol ume expansi on or cont r act i on owi ng t o t he addi t i on of sol ut es.

4. MoI e f racti on ( X) i s t he r at i o of t he number of mol es of one component
t o t he t ot al mol es of a mi xt ur e or sol ut i on.

VI. DILUTION AND CONCENTRATION.
Ì f t he amount of dr ug r emai ns const ant i n a di l ut i on or concent r at i on, t hen
any change i n t he mass or vol ume of a mi xt ur e i s i nversel y pr opor t i onal t o
t he concent rat i on.
A. Di I ut i on and concentrat i on probI ems can be soI ved by:
1. Ì nver se proport i on (as ment i oned ear l i er )
2. The equat i on quant i t y1 × concent r at i on1 = quant i t y2 × concent r at i on2
3. Det er mi ni ng t he amount of act i ve i ngr edi ent present i n t he i ni t i al mi xt ure
and, wi t h t he assumpt i on t hat t he i ni t i al quant i t y does not change,
cal cul at i ng of t he f i nal concent rat i on of t he new t ot al mass or vol ume
P. 17


4. AI I i gat i on medi aI . A met hod f or cal cul at i ng t he aver age concent rat i on of
a mi xt ur e of t wo or mor e subst ances
5. AI I i gat i on aI t ernat e. A met hod f or cal cul at i ng t he number of part s of t wo
or mor e component s of known concent rat i on t o be mi xed when t he f i nal
desi r ed concent r at i on i s known
B. Di I ut i on of aI cohoI s and aci ds
1. Di I ut i on of aI cohoI s. When al cohol and wat er ar e mi xed, a cont ract i on
of vol ume occur s. As a resul t , t he f i nal vol ume of sol ut i on cannot be
det ermi ned accur at el y. Nor can t he vol ume of wat er needed t o di l ut e t o a
cer t ai n per cent age v/ v be i dent i f i ed. Accordi ngl y, percent age w/ w i s of t en
used f or sol ut i ons of al cohol .
2. The percent age st rengt h of concent r at ed aci ds i s expr essed as
per cent age w/ w. The concent r at i on of di l ut ed aci ds i s expr essed as
per cent age w/ v. Det ermi ni ng t he vol ume of concent r at ed aci d t o be used i n
pr epar i ng a di l ut ed aci d r equi r es t he speci f i c gravi t y of t he concent rat ed
aci d.
C. Di I ut i on and concentrat i on of I i qui ds and soI i ds. Di l ut i on and
concent r at i on probl ems ar e of t en easi l y sol ved by i dent i f yi ng t he amount of
dr ug i nvol ved f ol l owed by use of an appropri at e pr opor t i on.
1. How many mi I I i I i t ers of a 1:50 st ock soI ut i on of ephedri ne suI f ate
shouI d be used i n compoundi ng the foI I owi ng prescri pt i on?
R
x
ephedrine sulIate 0.25°
rose water. ad 30 mL

2. How many mi I I i I i t ers of a 15% w/ v concent rat e of benzaI koni um
chI ori de shouI d be used i n prepari ng 300 mL of a stock soI ut i on such
t hat 15 mL di I uted to 1 L wi I I yi eI d a 1: 5000 soI ut i on?
a. Fi r st , det ermi ne t he amount of dr ug i n 1 L of a 1: 5000 sol ut i on.
b. Now, because 15 mL of t he st ock sol ut i on i s bei ng di l ut ed t o 1 L, a st ock
sol ut i on i s needed i n whi ch 15 mL cont ai n 0. 2 g of dr ug. The amount of
dr ug r equi red t o make 300 mL of t he st ock sol ut i on i s f ound by pr opor t i on.
c. Fi nal l y, t o det er mi ne t he amount of 15% concent r at e r equi r ed,

3. When t he r el at i ve amount of component s must be det ermi ned f or
pr epar at i on of a mi xt ur e of a desi red concent rat i on, t he pr obl em i s most
easi l y sol ved usi ng al l i gat i on al t er nat e.
How many grams of 2. 5% hydrocort i sone cream shouI d be mi xed wi th
360 g of 0. 25% cream to make a 1% hydrocort i sone cream?
The r el at i ve amount s of t he 2. 5% and 1% cr eams ar e 1 t o 2, r espect i vel y.
By pr opor t i on, t he mass of 2. 5% cream t o use can be det ermi ned. I f 2 part s
of 0. 25% cream i s represent ed by 360 g, t hen the t otaI mass ( 3 parts) i s
represent ed by what mass?

P. 18


Wi t h t he t ot al mass known, t he amount of 2. 5% cr eam can be i dent i f i ed. Ì f 3
par t s r epr esent t he t ot al mass of 540 g, t hen 1 par t r epr esent s t he mass of
2. 5% cream (x g = 180 g) .

VII. ELECTROLYTE SOLUTIONS.
El ect r ol yt e sol ut i ons cont ai n speci es (el ect rol yt es) t hat di ssoci at e i nt o i ons.
The mi I I i equi vaI ent ( mEq) i s t he uni t used t o expr ess t he concent r at i on of
el ect r ol yt es i n sol ut i on. Tabl e 2- 1 exhi bi t s some physi ol ogi cal l y i mpor t ant
i ons and t hei r pr oper t i es.
A. Mi I I i equi vaI ent s. The mi l l i equi val ent i s t he amount , i n mi l l i gr ams, of a
sol ut e equal t o 1/ 1000 of i t s gram-equi val ent wei ght . Conversi on of
concent r at i ons i n t he f orm of mi l l i equi val ent t o concent rat i ons i n per cent age
st r engt h, mi l l i gr ams per mi l l i l i t er s ( mg/ mL) or any ot her t er ms, begi ns wi t h
cal cul at i on of t he number of mi l l i equi val ent s of dr ug. The f ol l owi ng
exampl es demonst r at e t he comput at i on of mi l l i equi val ent s and mani pul at i on
of dat a f r om Tabl e 2- 1 t o per f or m t he r equi r ed cal cul at i ons f or prepar i ng
el ect r ol yt e sol ut i ons.
What i s the concent rati on, i n percent w/ v, of a soI uti on cont ai ni ng 2
mEq of pot assi um chI ori de per mi I I i I i t er?
Cal cul at i ons i nvol vi ng mi l l i equi val ent s are easi l y sol ved i f t he pr act i t i oner
f ol l ows a pr edef i ned procedur e t o det er mi ne t he mi l l i equi val ent wei ght . Thi s
i nvol ves t hr ee st eps.
1. Fi nd t he mol ecul ar wei ght ( mol wt ) .
Atomic wt K ÷ 39
Atomic wt Cl ÷ 35.5
39 ¹ 35.5 ÷ 74.5 g ÷ mol wt oI KCl

2. Cal cul at e t he equi val ent wei ght ( Eq wt ) of KCl .

3. Det er mi ne t he mi l l i equi val ent wei ght , whi ch i s of t he equi val ent wei ght .
mEq wt = 74. 5 g / 1000 = 0. 745 g or 74. 5 mg
Table 2-1. Valences. Atomic Weights. and Milliequivalent Weights of Selected
Ions
Ion Formula Valence
Atomic/Formula
Weight
Milliequivalent
Weight (mg)
Aluminum A
¹¹¹
3 27 9
Ammonium NH
4
¹
1 18 18
Calcium Ca
¹¹
2 40 20
Ferric Fe
¹¹¹
3 56 18.7
Ferrous Fe
¹¹
2 56 28
Lithium Li
¹
1 7 7
Magnesium Mg
¹¹
2 24 12
Bicarbonate HCO
3
-
1 61 61
Carbonate CO
3
-
1 60 30
Chloride Cl
-
1 35.5 35.5
Citrate C
6
H
5
O
7
---
3 189 63
Gluconate C
6
H
11
O
7
-
1 195 195
Lactate C
3
H
5
O
3
-
1 89 89
Phosphate H
2
PO
4
-
1 97 97
SulIate SO
4
--
2 96 48
Potassium K
¹
1 29 39
Sodium Na
¹
1 23 23
Acetate C
2
H
3
O
2
-
1 59 59

P. 19


Now t hat we know t he mi l l i equi val ent wei ght , we can cal cul at e by
di mensi onal anal ysi s and pr oport i on t he concent r at i on i n percent age i n a
f our t h st ep.
4. 0. 0745 g/ mEq × 2 mEq = 0. 149 g of dr ug

How many mi I I i equi vaI ent s of Na
+
wouI d be cont ai ned i n a 15-mL
voI ume of t he f oI I owi ng buf f er?
Na
2
HPO
4
·7H
2
O 180 g
NaH
2
PO
4
·H
2
O 480 g
PuriIied water ad 1000 mL

For each sal t , t he mass (and mi l l i equi val ent s) must be f ound i n a 15-mL
dose.
B. Mi I I i osmoI es ( mOsmoI ) . Osmot i c pressure i s di r ect l y pr opor t i onal t o t he
t ot al number of par t i cl es i n sol ut i on. The mi l l i osmol e i s t he uni t of measur e
f or osmot i c concent rat i on. For nonel ect r ol yt es, 1 mi l l i mol e r epresent s 1
mi l l i osmol e. However , f or el ect rol yt es, t he t ot al number of par t i cl es i n
sol ut i on i s det ermi ned by t he number of par t i cl es pr oduced i n sol ut i on and
i nf l uenced by t he degr ee of di ssoci at i on. Assumi ng compl et e di ssoci at i on, 1
mi l l i mol e of KCl r epr esent s 2 mi l l i osmol es of t ot al par t i cl es, 1 mi l l i mol e of
CaCl 2 repr esent s 3 mi l l i osmol es of t ot al par t i cl es, et c. The i deal osmol ar
concent r at i on can be cal cul at ed wi t h t he f ol l owi ng equat i on.
The pharmaci st shoul d recogni ze t he di f f er ence bet ween i deaI osmol ar
concent r at i on and act uaI osmol ari t y. As t he concent r at i on of sol ut e
i ncreases, i nt er act i on bet ween di ssol ved par t i cl es i ncreases, resul t i ng i n a
r educt i on of t he act ual osmol ar val ues.
C. I sotoni c soI ut i ons. An i sot oni c sol ut i on i s one t hat has t he same
osmot i c pr essur e as body f l ui ds. I sosmot i c f l ui ds are f l ui ds wi t h t he same
osmot i c pr essur e. Sol ut i ons t o be admi ni st ered t o pat i ent s shoul d be
i sosmot i c wi t h body f l ui ds. A hypot oni c sol ut i on i s one wi t h a l ower osmot i c
pr essure t han body f l ui ds, wher eas a hypert oni c sol ut i on has an osmot i c
pr essure t hat i s great er t han body f l ui ds.
1. Preparat i on of i sot oni c soI uti ons. Col l i gat i ve pr opert i es, i ncl udi ng
f r eezi ng poi nt depressi on, are r epr esent at i ve of t he number of par t i cl es i n
sol ut i on and consi der ed i n pr epar at i on of i sot oni c sol ut i ons.
a. When 1 g mol wt of any nonel ect r ol yt e i s di ssol ved i n 1000 g of wat er ,
t he f r eezi ng poi nt of t he sol ut i on i s depr essed by 1. 86°C. By proport i on, t he
wei ght of any nonel ect r ol yt e needed t o make t he sol ut i on i sot oni c wi t h body
f l ui d can be cal cul at ed.
P. 20


b. Bori c aci d ( H3BO3) has a mol wt of 61. 8 g. Thus 61. 8 g of H3BO3 i n 1000
g of wat er shoul d pr oduce a f r eezi ng poi nt of 1. 86°C. Ther ef or e, knowi ng
t hat t he f r eezi ng poi nt depr essi on of body f l ui ds i s -0. 52°C,

and 17. 3 g of H3BO3 i n 1000 g of wat er pr ovi des a sol ut i on t hat i s i sot oni c.
c. The degr ee of di ssoci at i on of el ect r ol yt es must be t aken i nt o account i n
such cal cul at i ons. For exampl e, NaCl i s appr oxi mat el y 80% di ssoci at ed i n
weak sol ut i ons, yi el di ng 180 par t i cl es i n sol ut i on f or each 100 mol ecul es of
NaCl . Theref ore,

i ndi cat i ng t hat 9. 09 g of NaCl i n 1000 g of wat er ( 0. 9% w/ v) shoul d make a
sol ut i on i sot oni c. Lacki ng any i nf or mat i on on t he degree of di ssoci at i on of
an el ect r ol yt e, t he f ol l owi ng di ssoci at i on vaI ues ( i ) may be used.
( 1) Subst ances t hat di ssoci at e i nt o t wo i ons: 1. 8
( 2) Subst ances t hat di ssoci at e i nt o t hr ee i ons: 2. 6
( 3) Subst ances t hat di ssoci at e i nt o f our i ons: 3. 4
( 4) Subst ances t hat di ssoci at e i nt o f i ve i ons: 4. 2
2. Sodi um chI ori de equi vaI ent s. The pharmaci st wi l l of t en be r equi red t o
pr epar e an i sot oni c sol ut i on by addi ng an appropri at e amount of anot her
subst ance (dr ug or i ner t el ect r ol yt e or nonel ect rol yt e) . Consi deri ng t hat
i sot oni c f l ui ds cont ai n t he equi val ent of 0. 9% NaCl , t he quest i on ar i ses,
How much of t he added i ngr edi ent i s r equi red t o make t he sol ut i on i sot oni c?
A common method f or comput i ng t he amount of added i ngredi ent t o use f or
r eachi ng i sot oni ci t y i nvol ves t he use of sodi um chI ori de equi vaI ent s.
a. Def i ni t i on. The sodi um chl or i de equi val ent repr esent s t he amount of
NaCl t hat i s equi val ent t o t he amount of par t i cul ar dr ug i n quest i on. For
ever y subst ance, t her e i s one quant i t y t hat shoul d have a const ant t oni c
ef f ect when di ssol ved i n 1000 g of wat er . Thi s i s 1 g mol wt of t he
subst ance di vi ded by i t s di ssoci at i on val ue ( i ).
b. ExampI es
( 1) Consi deri ng H3BO3, f r om t he l ast sect i on, 17. 3 g of H3BO3 i s equi val ent
t o 0. 52 g of NaCl i n t oni ci t y. Theref or e, t he r el at i ve quant i t y of NaCl t hat i s
equi val ent t o H3BO3 i n t oni ci t y ef f ect s i s det er mi ned as f ol l ows:

Appl yi ng t hi s met hod t o at r opi ne sul f at e, r ecal l t hat t he mol ecul ar wei ght of
NaCl and t he mol ecul ar wei ght of at r opi ne sul f at e ar e 58. 5 and 695 g,
r espect i vel y, and t hei r i val ues are 1. 8 and 2. 6, respect i vel y. Cal cul at e t he
mass of NaCl repr esent ed by 1 g of at r opi ne sul f at e ( Tabl e 2- 2).
Table 2-2. Sodium Chloride (NaCl) Equivalents
Substance NaCl Equivalent
Atropine sulIate (H
2
O) 0.12
Boric acid 0.52
Chlorobutanol 0.24
Dextrose (anhydrous) 0.18
Ephedrine hydrochloride 0.29
Phenacaine hydrochloride 0.20
Potassium chloride 0.78

P. 21


( 2) An exampl e of t he pract i cal use of sodi um chl or i de equi val ent s i s seen
i n t he f ol l owi ng pr obl em.
How many grams of bori c aci d shouI d be used i n compoundi ng the
f oI I owi ng prescri pt i on?
R
x
phenacaine hydrochloride 1°
chlorobutanol 0.5°
boric acid qs
puriIied water. ad 60.0 mL
make isotonic solution

The pr escri pt i on cal l s f or 0. 3 g of chl or obut anol and 0. 6 g of phenacai ne.
How much bori c aci d i s requi r ed t o pr epare t hi s pr escr i pt i on? The quest i on
i s best answer ed i n f our st eps.
( a) Fi nd t he mass of sodi um chl or i de r epresent ed by al l i ngr edi ent s.
0.20 ×
0.6
÷ 0.120
g
oI sodium chloride represented by phenacaine
hydrochloride
0.24 ×
0.3
÷ 0.072
g
oI sodium chloride represented by chlorobutanol

0.192
g
oI sodium chloride represented by the two active
ingredients

( b) Fi nd t he mass of sodi um chl ori de r equi r ed t o pr epar e an equal vol ume
of i sot oni c sol ut i on.

( c) Cal cul at e, by subt ract i on, t he amount of NaCl r equi r ed t o make t he
sol ut i on i sot oni c.
0.540 g NaCl required Ior isotonicity
0.192 g NaCl represented by ingredients
0.348 g NaCl required to make isotonic solution

( d) Because t he prescr i pt i on cal l s f or bor i c aci d t o be used, one l ast st ep i s
r equi r ed.
VIII. STATISTICS
A. I nt roduct i on. St at i st i cs can be used t o descr i be and compar e dat a
di st r i but i ons. Such f requency di st ri but i ons are const ruct ed by cl assi f yi ng
i ndi vi dual obser vat i ons i nt o cat egor i es cor respondi ng t o f i xed numer i c
i nt er val s and pl ot t i ng t he number of obser vat i ons i n each such cat egor y
( i . e. , i ntervaI f requency) ver sus t he cat egor y descri pt or ( e. g. , t he i nt er val
mean or r ange). Because of r andom er rors, r epeat ed obser vat i ons or
measurement s (of t he same val ue) are not i dent i cal . These obser vat i ons
have a normaI di st ri buti on. Nor mal l y di st r i but ed dat a are descr i bed by a
beI I -shaped ( Gaussi an) curve wi t h a maxi mum, µ ( popuI at i on mean) ,
cor respondi ng t o t he cent r al t endency of t he popul at i on and a spr ead
charact eri zed by t he popuI at i on st andard devi at i on ( o) . St at i st i cs der i ved
f r om a sampI e or subset of a popul at i on can be used as est i mat es of t he
popul at i on par amet er s.
B. Frequency di st ri but i on
1. Esti mates of popuI ati on mean. The popul at i on mean, µ, i s t he best
est i mat e of t he t r ue val ue.
a. The sampI e mean. For a f i ni t e number of obser vat i ons, t he ari t hmet i c
aver age or mean ( [ X wi t h bar above] ) i s t he best est i mat e of t he t r ue val ue,
µ.

wher e Zxi i s t he sum of al l ( n) obser vat i ons.
P. 22


( 1) Accuracy i s t he degree t o whi ch a measur ed val ue (X or [ X wi t h bar
above] ) agrees wi t h t he "t r ue¨ val ue ( µ) .
( 2) Error (or bi as) i s t he di f f er ence bet ween a measur ed val ue ( X or [ X wi t h
bar above] ) and t he "t r ue¨ val ue ( µ) .
b. Medi an. The medi an i s t he mi dmost val ue of a dat a di st r i but i on. When al l
t he val ues ar e ar r anged i n i ncr easi ng (or decreasi ng) or der , t he medi an i s
t he mi ddl e val ue f or an odd number of obser vat i ons. For an even number of
obser vat i ons, t he medi an i s t he ar i t hmet i c mean of t he t wo mi ddl e val ues.
For a normaI di st ri but i on, t he medi an equaI s t he mean. The medi an i s
l ess af f ect ed by " out l i er s¨ or by a skewed di st r i but i on.
c. Mode. The mode i s t he most f r equent l y occur ri ng val ue (or val ues) i n a
f r equency di st ri but i on. The mode i s usef ul f or non- normal di st r i but i ons,
especi al l y t hose t hat ar e bi modaI .
2. Esti mates of vari abi I i t y. For an i nf i ni t e number of obser vat i ons, t he
popuI at i on vari ance ( o
2
) can be used t o descr i be t he var i abi l i t y or
" spread¨ of obser vat i ons i n a dat a di st ri but i on. For a fi ni te number of
obser vat i ons, t he sampI e vari ance (s
2
) can be used t o descri be t he
var i abi l i t y or spread of obser vat i ons i n a dat a di st r i but i on.
a. SampI e vari ance (s
2
) i s est i mat ed by

wher e [ X wi t h bar above] i s t he mean and ( n - 1) i s t he number of degr ees
of f reedom ( df ).
b. Range. For a ver y smal l number of obser vat i ons, t he range ( w) can be
used t o descr i be t he vari abi l i t y i n t he dat a set :
w = | Xl ar ges t - Xs mal l es t |
c. The st andard devi at i on ( s or SD) , one of t he most commonl y
encount ered est i mat es of var i abi l i t y, i s equal t o t he squar e root of t he
var i ance.

or

d. Preci si on ( repr oduci bi l i t y) i s t he degr ee t o whi ch repl i cat e
measurement s "made i n exact l y t he same way¨ agr ee wi t h each ot her .
Preci si on i s of t en expr essed as t he reI at i ve standard devi at i on ( RSD or
%RSD) :

3. The st andard devi at i on of the mean (sm) , or st andard err or of t he mean
( SEM) , i s an est i mat e of t he vari abi I i t y or error i n t he mean obt ai ned f r om
n obser vat i ons. Ì t i s of t en used t o est abl i sh conf i dence i nt er val s f or
descr i bi ng t he mean of a dat a set or when compar i ng t he means of t wo dat a
set s.

P. 23


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 30: Each quest i on, st at ement , or i ncompl et e
st at ement i n t hi s sect i on can be cor r ect l y answer ed or compl et ed by one of
t he suggest ed answer s or phrases. Choose t he best answer .
1. I f a vi t ami n soI ut i on cont ai ns 0. 5 mg of f I uori de i on i n each mi I I i I i ter,
t hen how many mi I I i grams of f I uori de i on wouI d be provi ded by a
dropper t hat deI i vers 0. 6 mL?
( A) 0. 3 mg
( B) 0. 1 mg
( C) 1 mg
( D) 0. 83 mg
Vi ew Answer 1. The answer i s A[ see] . 2. How many
chI orampheni coI capsuI es, each cont ai ni ng 250 mg, are needed t o
provi de 25 mg per kg per day f or 7 days f or a person wei ghi ng 200 I b?
( A) 90 capsul es
( B) 64 capsul es
( C) 13 capsul es
( D) 25 capsul es
Vi ew Answer 2. The answer i s B[ see] . 3. I f 3. 17 kg of a drug i s
used t o make 50, 000 tabI et s, how many mi I I i grams wi I I 30 tabI et s
cont ai n?
( A) 1. 9 mg
( B) 1900 mg
( C) 0. 0019 mg
( D) 3. 2 mg
Vi ew Answer 3. The answer i s B[ see] . 4. A capsuI e cont ai ns 1/ 8 gr
of ephedri ne suI fat e, ¼ gr of t heophyI I i ne, and gr of phenobarbi taI .
What i s the t ot aI mass of t he acti ve i ngredi ents i n mi I I i grams?
( A) 20 mg
( B) 8 mg
( C) 28 mg
( D) 4 mg
Vi ew Answer 4. The answer i s C[ see] . 5. I f 1 f I ui d ounce of a cough
syrup cont ai ns 10 gr of sodi um ci t rate, how many mi I I i grams are
cont ai ned i n 10 mL?
( A) 650 mg
( B) 65 mg
( C) 217 mg
( D) 20 mg
Vi ew Answer 5. The answer i s C[ see] . 6. How many capsuI es, each
cont ai ni ng ¼ gr of phenobarbi t aI , can be manuf act ured i f a bot t I e
cont ai ni ng 2 avoi rdupoi s ounces of phenobarbi t aI i s avai I abI e?
( A) 771 capsul es
( B) 350 capsul es
( C) 3500 capsul es
( D) 1250 capsul es
Vi ew Answer 6. The answer i s C[ see] . 7. Usi ng the f ormuI a f or
caI ami ne I oti on, determi ne t he amount of caI ami ne ( i n grams)
necessar y t o prepare 240 mL of I oti on.
Calamine 80 g
Zinc oxide 80 g
Glycerin 20 mL
Bentonite magma 250 mL
Calcium hydroxide topical solution suIIicient quantity to make 1000 mL

( A) 19. 2 g
( B) 140 g
( C) 100 g
( D) 24 g
Vi ew Answer 7. The answer i s A[ see] . 8. From the f oI I owi ng
f ormuI a, caI cuI ate t he amount of whi t e wax requi red t o make 1 I b of
coI d cream. Det ermi ne t he mass i n grams.
Cetyl esters wax 12.5 parts
White wax 12.0 parts
Mineral oil 56.0 parts
Sodium borate 0.5 parts
PuriIied water 19.0 parts

( A) 56. 75 g
( B) 254. 24 g
( C) 54. 48 g
( D) 86. 26 g
Vi ew Answer 8. The answer i s C[ see] . 9. How many grams of aspi ri n
shouI d be used to prepare 1. 255 kg of the powder?
ASA 6 parts
Phenacetin 3 parts
CaIIeine 1 part

( A) 125 g
( B) 750 g
( C) 175 g
( D) 360 g
Vi ew Answer 9. The answer i s B[ see] . P. 24


10. A soI ut i on cont ai ns 1. 25 mg of a drug per mi I I i I i t er. At what rat e shouI d t he
soI ut i on be i nf used (drops/ mi n) i f t he drug i s t o be admi ni st ered at a rat e of 80
mg/ hr? ( 1 mL = 30 drops)
( A) 64 dr ops/ mi n
( B) 1. 06 dr ops/ mi n
( C) 32 dr ops/ mi n
( D) 20 dr ops/ mi n
Vi ew Answer 10. The answer i s C[ see] . 11. The recommended mai nt enance
dose of ami nophyI I i ne f or chi I dren i s 1. 0 mg/ kg/ hr by i nj ect i on. I f 10 mL of a 25-
mg/ mL soI ut i on of ami nophyI I i ne i s added t o a 100-mL bot t I e f or dext rose, what
shouI d be t he rate of deI i ver y i n mL/ hr f or a 40- I b chi I d?
( A) 2. 30 mL/ hr
( B) 8. 00 mL/ hr
( C) 18. 9 mL/ hr
( D) 18. 2 mL/ hr
Vi ew Answer 11. The answer i s B[ see] . 12. For chi I dren, st rept omyci n i s t o
be admi ni stered at a dose of 30 mg/ kg of body wei ght dai I y i n di vi ded doses
ever y 6- 12 hr . The dr y powder i s di ssoI ved by addi ng water f or i nj ecti on, USP
i n an amount t o yi eI d t he desi red concent rati on as i ndi cat ed i n the foI I owi ng
t abI e ( f or a 1-g vi aI ) .
Approximate
Concentration (mg/mL) Volume (mL)
200 4.2
250 3.2
400 1.8

Reconst i t uti ng at t he I owest possi bI e concent rat i on, what voI ume ( i n mL) wouI d
be wi t hdrawn t o obtai n one day' s dose f or a 50- I b chi I d?
( A) 3. 4 mL
( B) 22. 73 mL
( C) 2. 50 mL
( D) 2. 27 mL
Vi ew Answer 12. The answer i s A[ see] . 13. The atropi ne suI f at e i s
avai I abI e onI y i n t he form of 1/ 150 gr t abI ets. How many at ropi ne suI fat e tabI et s
wouI d you use t o compound the foI I owi ng prescri pt i on?
Atropine sulIate 1/200 gr
Codeine phosphate 1/4 gr
Aspirin 5 gr
d.t.d. #24 capsules
Sig: 1 capsule p.r.n.

( A) 3 t abl et s
( B) 6 t abl et s
( C) 12 t abl et s
( D) 18 t abl et s
Vi ew Answer 13. The answer i s D[ see] . 14. I n 25. 0 mL of a soI uti on for
i nj ect i on, t here are 4. 00 mg of t he drug. I f the dose t o be admi ni stered t o a
pat i ent i s 200 µg, what quanti t y ( i n mL) of t hi s soI ut i on shouI d be used?
( A) 1. 25 mL
( B) 125 mL
( C) 12. 0 mL
( D) None of t he above
Vi ew Answer 14. The answer i s A[ see] . 15. How many mi I I i grams of
papaveri ne wi I I t he pati ent recei ve each day?
R
x
papaverine 1.0 g
hydrochloride aqua 30.0 mL
syrup tolu. qs ad 90.0 mL
Sig: 1 teaspoon t.i.d.

( A) 56 mg
( B) 5. 6 mg
( C) 166 mg
( D) 2. 5 mg
Vi ew Answer 15. The answer i s C[ see] . 16. Consi deri ng t he f oI I owi ng
f ormuI a, how many grams of sodi um bromi de shouI d be used i n f i I I i ng t hi s
prescri pt i on?
R
x
sodium bromide 1.2 g
syrup tolu 2.0 mL
syrup wild cherry. qs ad 5.0 mL
d.t.d. #24

( A) 1. 2 g
( B) 1200 g
( C) 28. 8 g
( D) 220 g
Vi ew Answer 16. The answer i s C[ see] . 17. How many mi I I i I i t ers of a 7. 5%
st ock soI ut i on of KMnO4 shouI d be used t o obtai n t he KMnO needed?
KMnO4, qs
Di st i I I ed water, ad 1000
Si g: 2 t easpoons di I ut ed t o 500 mL yi eI d a 1:5000 soI ut i on
( A) 267 mL
( B) 133 mL
( C) 26. 7 mL
( D) 13. 3 mL
Vi ew Answer 17. The answer i s B[ see] . 18. The formuI a f or Ri nger' s
soI ut i on foI I ows. How much sodi um chI ori de i s needed t o make 120 mL?
R
x
sodium chloride 8.60 g
potassium chloride 0.30 g
calcium chloride 0.33 g
water Ior iniection. qs ad 1000 mL

( A) 120 g
( B) 1. 03 g
( C) 0. 12 g
( D) 103 g
Vi ew Answer 18. The answer i s B[ see] . P. 25


19. How many grams of t aI c shouI d be added to 1 I b of a powder contai ni ng 20
g of zi nc undecyI enat e per 100 g t o reduce t he concent rat i on of zi nc
undecyI enat e t o 3%?
( A) 3026. 7 g
( B) 2572. 7 g
( C) 17 g
( D) 257 g
Vi ew Answer 19. The answer i s B[ see] . 20. How many mi I I i I i t ers of a 0. 9%
aqueous soI ut i on can be made f rom 20. 0 g of sodi um chI ori de?
( A) 2222 mL
( B) 100 mL
( C) 222 mL
( D) 122 mL
Vi ew Answer 20. The answer i s A[ see] . 21. The bI ood of a reckI ess dri ver
cont ai ns 0. 1% aI cohoI . Express t he concent rati on of aI cohoI i n parts per
mi I I i on.
( A) 100 ppm
( B) 1000 ppm
( C) 1 ppm
( D) 250 ppm
Vi ew Answer 21. The answer i s B[ see] . 22. Syrup i s an 85% w/ v soI ut i on of
sucrose i n wat er. I t has a densi t y of 1. 313 g/ mL. How many mi I I i I i t ers of wat er
shouI d be used to make 125 mL of syrup?
( A) 106. 25 mL
( B) 164. 1 mL
( C) 57. 9 mL
( D) 25. 0 mL
Vi ew Answer 22. The answer i s C[ see] . 23. How many grams of
benzet honi um chI ori de shouI d be used i n prepari ng 5 gal . of a 0. 025% w/ v
soI ut i on?
( A) 189. 25 g
( B) 18. 9 g
( C) 4. 73 g
( D) 35 g
Vi ew Answer 23. The answer i s C[ see] . 24. How many grams of ment hoI
shouI d be used to prepare t hi s prescri pt i on?
R
x
menthol 0.8°
alcohol. qs ad 60.0 mL

( A) 0. 48 g
( B) 0. 8 g
( C) 4. 8 g
( D) 1. 48 g
Vi ew Answer 24. The answer i s A[ see] . 25. How many mi I I i I i t ers of a 1:1500
soI ut i on can be made by di ssoI vi ng 4. 8 g of cet yI pyr i di ni um chI ori de i n wat er?
( A) 7200 mL
( B) 7. 2 mL
( C) 48 mL
( D) 4. 8 mL
Vi ew Answer 25. The answer i s A[ see] . 26. The manuf act urer speci f i es that
one Domeboro t abI et di ssoI ved i n 1 pi nt of water makes a modi f i ed Burow' s
soI ut i on approxi mat eI y equi vaI ent to a 1:40 di I ut i on. How many t abI ets shouI d
be used i n prepari ng ½ gaI of a 1:10 di I ut i on?
( A) 16 t abl et s
( B) 189 t abl et s
( C) 12 t abl et s
( D) 45 t abl et s
Vi ew Answer 26. The answer i s A[ see] . 27. How many mi I I i osmoI es of
caI ci um chI ori de ( CaCI 2· 2H2O - moI wt = 147) are represented i n 147 mL of a
10% w/ v caI ci um chI ori de soI ut i on?
( A) 100 mOsmol
( B) 200 mOsmol
( C) 300 mOsmol
( D) 3 mOsmol
Vi ew Answer 27. The answer i s C[ see] . 28. How many grams of bori c aci d
shouI d be used i n compoundi ng the foI I owi ng prescri pt i on?
Phenacai ne HCI 1. 0% ( NaCI eq = 0. 17)
ChI orobutanoI 0. 5% ( NaCI eq = 0. 18)
Bori c aci d, qs ( NaCI eq = 0. 52)
Puri f i ed H2O, ad 30 mL
Make i sot oni c soI ut i on
Si g: 1 drop i n each eye
( A) 0. 37 g
( B) 0. 74 g
( C) 0. 27 g
( D) 0. 47 g
Vi ew Answer 28. The answer i s A[ see] . 29. A pharmaci st prepares 1 gaI of
KCI soI ut i on by mi xi ng 565 g of KCI ( vaI ence = 1) i n an appropri at e vehi cI e.
How many mi I I i equi vaI ent s of K
+
are i n 15 mL of t hi s soI ut i on? (at omi c wei ghts:
K = 30; CI = 35. 5)
( A) 7. 5 mEq
( B) 10 mEq
( C) 20 mEq
( D) 30 mEq
( E) 40 mEq
Vi ew Answer 29. The answer i s D[ see] . P. 26


30. A vancomyci n soI uti on cont ai ni ng 1000 mg of vancomyci n hydrochI ori de
di I ut ed t o 250 mL wi th D5W i s t o be i nf used at a constant rat e wi th an i nf usi on
pump i n 2 hr. What i s the rate of drug admi ni st rat i on?
( A) 2. 08 mg/ mi n
( B) 8. 33 mg/ mi n
( C) 4. 17 mg/ mi n
( D) 16. 7 mg/ mi n
( E) 5. 21 mg/ mi n
Vi ew Answer 30. The answer i s B[ see] . For questi ons 31-34: Fi ve i bupr of en
t abl et s wer e assayed f or dr ug cont ent , and t he f ol l owi ng r esul t s wer e obt ai ned by
hi gh- pr essur e l i qui d chromat ogr aphy ( HPLC) anal ysi s: 198. 2 mg, 199. 7 mg, 202. 5
mg, 201. 3 mg, 196. 4 mg.
31. What i s the mean i buprof en cont ent?
( A) 196. 9 mg
( B) 200. 2 mg
( C) 199. 6 mg
( D) 249. 5 mg
( E) 202. 5 mg
Vi ew Answer 31. The answer i s C[ see] . 32. What i s t he standard devi at i on
of i buprof en cont ent i n t he anaI yzed t abI et s?
( A) 2. 17 mg
( B) 3. 35 mg
( C) 2. 42 mg
( D) 3. 00 mg
( E) - 2. 17 mg
Vi ew Answer 32. The answer i s C[ see] . 33. What i s t he percent reI at i ve
st andard devi at i on ( %RSD) f or t hi s i buprofen tabI et anaI ysi s?
( A) 1. 69%
( B) 1. 21%
( C) 8. 25%
( D) 3. 35%
( E) 1. 50%
Vi ew Answer 33. The answer i s B[ see VI I I . B. 4] . 34. What i s t he standard
devi at i on of the mean drug cont ent of thi s sampI e?
( A) 0. 480 mg
( B) 0. 605 mg
( C) 1. 21 mg
( D) 1. 08 mg
( E) 0. 825 mg
Vi ew Answer 34. The answer i s D[ see VI I I . C] . P. 27


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see Ì . A. 2] .
2. The answer i s B [ see Ì Ì ] .
3. The answer i s B [ see Ì Ì ] .
4. The answer i s C [ see Ì Ì ] .
5. The answer i s C [ see Ì . A. 2] .
6. The answer i s C [ see Ì Ì ] .
7. The answer i s A [ see Ì Ì Ì ] .
8. The answer i s C [ see Ì Ì ; Ì Ì Ì . A] .
The f ormul a t el l s t he phar maci st t hat whi t e wax ( W.W. ) r epresent s 12 part s out of
t he t ot al 100 part s i n t he pr escri pt i on. What we wi sh t o det ermi ne i s t he mass of
whi t e wax r equi red t o prepare 454 g ( 1 l b) of t he r eci pe. Thi s can be easi l y sol ved
by pr opor t i on:

9. The answer i s B [ see Ì Ì Ì . A] .
10. The answer i s C [ see Ì V. E] .
11. The answer i s B [ see Ì Ì ; Ì V] .
12. The answer i s A [ see Ì V] .
13. The answer i s D [ see Ì Ì ; Ì Ì Ì . B] .
14. The answer i s A [ see Ì . A. 2; Ì Ì ] .
Di mensi onal anal ysi s i s of t en usef ul f or cal cul at i ng doses. Consi deri ng t hat 4 mg of
t he dr ug i s present i n each 25 mL of sol ut i on, we can easi l y cal cul at e t he number of
mi l l i l i t er s t o be used t o gi ve a dose of 0. 200 mg (200 µg) . Al ways i ncl ude uni t s i n
your cal cul at i ons.

15. The answer i s C [ see Ì Ì Ì . B] .
16. The answer i s C [ see Ì Ì Ì . B] .
17. The answer i s B [ see V. A; VÌ ] .
Fi r st , det er mi ne t he mass of drug i n t he f i nal di l ut ed sol ut i on.

Now, i f 0. 1 g of dr ug i s pr esent i n 500 mL of 1: 5000 sol ut i on, 2 t easpoonf ul s ( 10
mL) of t he pr escr i pt i on cont ai ns t he same amount of dr ug ( 0. 1 g) bef ore di l ut i on.
Fr om t hi s, t he amount of dr ug i n 1000 mL ( t he t ot al vol ume) of t he pr escri pt i on can
be det ermi ned:

Fi nal l y, t o obt ai n t he corr ect amount of drug t o f or mul at e t he prescr i pt i on ( 10 g) , we
ar e t o use a 7. 5% st ock sol ut i on. Recal l i ng t he def i ni t i on of percent age st r engt h
w/ v:

P. 28


18. The answer i s B [ see Ì Ì Ì . B] .
19. The answer i s B [ see V. C; VÌ . C] .
20. The answer i s A [ see Ì . A. 2; V. A] .
Usi ng di mensi onal anal ysi s

21. The answer i s B [ see V. D. 1] .
22. The answer i s C [ see Ì . A; V. A. 1] .
Usi ng t he densi t y, t he wei ght of 125 mL of syr up can be cal cul at ed:
125 mL × 1. 313g/ mL = 164. 125 g
Usi ng propor t i on and t he sucr ose concent rat i on i n w/ v, t he wei ght of sucrose i n 125
mL of syr up can be cal cul at ed:

Fi nal l y, t he wei ght of wat er i n 125 mL of syr up can be cal cul at ed:
164. 125 g - 106. 25 g = 57. 875 g
whi ch has a vol ume of 57. 9 mL.
23. The answer i s C [ see Ì ; Ì Ì ; V] .
24. The answer i s A [ see Ì ; V] .
25. The answer i s A [ see Ì ; V] .
The pr obl em i s easi l y sol ved by proport i on. The quest i on t o be answer ed i s, Ì f 1 g of
dr ug i s present i n 1500 mL of sol ut i on, what vol ume can be made wi t h 4. 8 g of
dr ug?

26. The answer i s A [ see Ì ; V] .
27. The answer i s C [ see VÌ Ì . B] .
Recal l i ng t he expr essi on f or i deal osmol ar concent r at i on:

28. The answer i s A [ see VÌ Ì . C] .
29. The answer i s D [ see VÌ Ì . A] .
30. The answer i s B [ see Ì V. E] .
Usi ng di mensi onal anayl si s:

31. The answer i s C [ see VÌ Ì Ì . B. 1] .
The mean i s cal cul at ed di r ect l y f r om t he equat i on:

P. 29


32. The answer i s C [ see VÌ Ì Ì . B. 3] .
The st andar d devi at i on can be cal cul at ed wi t h t he most commonl y used equat i on:
33. The answer i s B [ see VI I I . B. 4] .

34. The answer i s D [ see VI I I . C] .




























3
PharmaceuticaI PrincipIes and Drug
Dosage Forms
Lawrence H. BI ock
I. INTRODUCTION.
Phar maceut i cal pr i nci pl es are t he under l yi ng physi cochemi cal pri nci pl es
t hat al l ow a drug t o be i ncor por at ed i nt o a pharmaceut i cal dosage f orm
( e. g. , sol ut i on, capsul e) . These pr i nci pl es appl y whet her t he dr ug i s
ext empor aneousl y compounded by t he pharmaci st or manuf act ured f or
commer ci al di st ri but i on as a drug product .
A. The f i ni shed dosage f orm cont ai ns t he act i ve dr ug i ngr edi ent i n
associ at i on wi t h nondr ug ( usual l y i ner t ) i ngr edi ent s (exci pi ent s) t hat make
up t he vehi cI e, or f ormuI at i on mat ri x.
B. The drug deI i ver y syst em concept , whi ch has evol ved si nce t he 1960s,
i s a mor e hol i st i c concept . Ì t embr aces not onl y t he drug ( or pr odr ug) and
i t s f ormul at i on mat r i x, but al so t he dynami c i nt er act i ons among t he dr ug, i t s
f or mul at i on mat ri x, i t s cont ai ner , and t he physi ol ogi c mi l i eux of t he pat i ent .
These dynami c i nt eract i ons ar e t he subj ect of bi opharmaceut i cs (see
Chapt er 4).
II. INTERMOLECULAR FORCES OF ATTRACTION
A. I nt roduct i on. The appl i cat i on of phar maceut i cal pri nci pl es t o drug
dosage f orms i s i l l ust r at ed when dr ug dosage f orms ar e categori zed
accor di ng t o t hei r physi caI st ate, degree of heterogenei t y, and chemi caI
composi ti on. The usual r el evant st at es of mat t er ar e gases, I i qui ds, and
soI i ds. Ì nt er mol ecul ar f or ces of at t r act i on ar e weakest i n gases and
st r ongest i n sol i ds. Conver si ons f rom one physi cal st at e t o anot her can
i nvol ve si mpl y overcomi ng i nt ermol ecul ar f orces of at t r act i on by addi ng
energy ( heat ) . Chemi cal composi t i on can have a dr amat i c ef f ect on
physi cochemi cal pr oper t i es and behavi or. For t hi s r eason, i t i s necessar y t o
di st i ngui sh bet ween poI ymers, or macromoI ecuI es, and mor e convent i onal
( i . e. , smal l er ) mol ecul es, or mi cromoI ecuI es.
B. I nt ermoI ecuI ar f orces of at t ract i on. Because at oms var y i n t hei r
el ect r onegat i vi t y, el ect r on shar i ng bet ween di f f erent at oms i s l i kel y t o be
unequal . Thi s asymmet ri c el ect r on di st r i but i on causes a shi f t i n t he over al l
el ect r on cl oud i n t he mol ecul e. As a resul t , t he mol ecul e t ends t o behave as
a di poI e ( i . e. , as i f i t had a posi t i ve and a negat i ve pol e) . The di pol e
associ at ed wi t h each coval ent bond has a cor r espondi ng di poI e moment
( µ) def i ned as t he pr oduct of t he di st ance of charge separ at i on ( d) and t he
charge ( q) :
µ = q × d
The mol ecul ar di pol e moment may be vi ewed as t he vect or sum of t he
i ndi vi dual bond moment s.
1. NonpoI ar mol ecul es t hat have perf ect symmet r y ( e. g. , carbon
t et r achl ori de) have di pol e moment s of zer o ( Fi gur e 3-1) .
2. PoI ar mol ecul es ar e asymmet ri c and have nonzer o di pol e moment s.
3. When di poI ar mol ecul es approach one anot her cl ose enough÷"posi t i ve
t o posi t i ve¨ or "negat i ve t o negat i ve¨ ÷so t hat t hei r el ect r on cl ouds
i nt er penet rat e, i ntermoI ecuI ar repuI si ve forces ar i se. When t hese di pol ar
mol ecul es appr oach one anot her so t hat t he posi t i ve
P. 31

pol e of one i s cl ose t o t he negat i ve pol e of t he ot her , mol ecul ar at t racti on
occurs ( di poI edi poI e i nteract i on) . When t he i dent i cal l y char ged pol es of
t he t wo mol ecul es ar e cl oser, repuI si on occurs.

Figure 3-1. The carbon tetrachloride molecule.
C. Types of i nt ermoI ecuI ar f orces of at t ract i on i ncl ude t he f ol l owi ng:
1. Nonpol ar mol ecul es do not have per manent di pol es. However , t he
i nst ant aneous el ect ron di st ri but i on i n a mol ecul e can be asymmet r i c. The
r esul t ant t r ansi ent di pol e moment can i nduce a di pol e i n an adj acent
mol ecul e. Thi s i nduced di poI e- i nduced di poI e i nt eracti on ( London
di spersi on f orce) , wi t h a f orce of 0. 5-1 kcal / mol , i s suf f i ci ent t o f aci l i t at e
or der i n a mol ecul ar ar r ay. These rel at i vel y weak el ect r ost at i c f or ces ar e
r esponsi bl e f or t he l i quef act i on of nonpol ar gases.
2. The t ransi ent di pol e i nduced by a permanent di pol e, or di poI e-i nduced
di poI e i nt eract i on ( Debye i nduct i on f orce) , i s a st r onger i nt er act i on, wi t h
a f orce of 1- 3 kcal / mol .
3. Permanent di poI e i nteract i ons ( Keesom ori ent at i on f orces), wi t h a
f or ce of 1-7 kcal / mol , t oget her wi t h Debye and London f or ces, const i t ut e
van der WaaI s f orces. Col l ect i vel y, t hey are responsi bl e f or t he mor e
subst ant i ve st r uct ure and mol ecul ar or der i ng f ound i n l i qui ds.
4. Hydrogen bonds. Because t hey ar e smal l and have a l ar ge el ect r ost at i c
f i el d, hydr ogen at oms can appr oach hi ghl y el ect ronegat i ve at oms (e. g. ,
f l uor i ne, oxygen, ni t rogen, chl or i ne, sul f ur) and i nt er act el ect r ost at i cal l y t o
f or m a hydr ogen bond. Dependi ng on t he el ect r onegat i vi t y of t he second
at om and t he mol ecul ar envi r onment i n whi ch hydr ogen bondi ng occurs,
hydr ogen bond ener gy var i es f rom appr oxi mat el y 1 t o 8 kcal / mol .
5. I on- i on, i on- di poI e, and i on- i nduced di poI e forces. Posi t i ve- negat i ve
i on i nt eract i ons i n t he sol i d st at e i nvol ve f orces of 100- 200 kcal / mol . Ì oni c
i nt er act i ons are r educed consi derabl y i n l i qui d syst ems i n t he presence of
ot her el ect r ol yt es. I on- di poI e i nt er act i on, or di poI e i nducti on by an i on,
can al so af f ect mol ecul ar aggr egat i on, or or der i ng, i n a syst em.
III. STATES OF MATTER
A. Gases. Mol ecul es i n t he gaseous st at e can be pi ct ured as movi ng al ong
st r ai ght pat hs, i n al l di r ect i ons and at hi gh vel oci t i es ( e. g. , mean vel oci t y
f or H2O vapor : 587 m/ sec; f or O2: 440 m/ sec), unt i l t hey col l i de wi t h ot her
mol ecul es. As a resul t of t hese r andom col l i si ons, mol ecul ar vel oci t i es and
pat hs change, and t he mol ecul es cont i nue t o col l i de wi t h ot her mol ecul es
and wi t h t he boundari es of t he syst em (e. g. , t he wal l s of a cont ai ner hol di ng
t he gas) . Thi s process, repeat ed i ncessant l y, i s responsi bl e f or t he
pressure exhi bi t ed wi t hi n t he conf i nes of t he syst em.
1. The i nt er r el at i on among voI ume ( V), pressure ( P) , and t he absoI ut e
t emperat ure ( T) i s gi ven by t he i deaI gas I aw, whi ch i s t he equat i on of
st at e f or an i deal gas:
PV = nRT
PV = ( g/ M) RT
wher e n i s t he number of mol es of gas÷equi val ent t o t he number of gr ams
( g) of gas di vi ded by t he mol ecul ar wei ght of t he gas ( M) ÷and R i s t he
moI ar gas const ant ( 0. 08205 L at m/ mol e deg) .
2. Phar maceut i cal gases i ncl ude t he anest het i c gases ( e. g. , ni t r ous oxi de,
hal ot hane). Compressed gases i ncl ude oxygen ( f or t herapy) , ni t rogen, and
car bon di oxi de. Li quefi abI e gases, i ncl udi ng cert ai n haI ohydrocarbons
and hydrocarbons, are used as pr opel l ant s i n aerosoI product s
( pressuri zed packagi ng) , as are compr essed gases, such as ni t rous oxi de,
ni t rogen, and car bon di oxi de. Et hyl ene oxi de i s a gas used t o st er i l i ze or
di si nf ect heat -l abi l e obj ect s.
3. Ì n general , as t he t emper at ur e of a subst ance i ncr eases, i t s heat
cont ent , or ent haI py, i ncr eases as wel l .
a. Subst ances can undergo a change of st at e, or phase change, f r om t he
sol i d t o t he l i qui d st at e ( meI t i ng) or f rom t he l i qui d t o t he gaseous st at e
( vapori zat i on).
b. VoI at i I e I i qui ds (e. g. , et her , hal ot hane, met hoxyf l ur ane) are used as
i nhal at i on anest het i cs. Amyl ni t r i t e i s a vol at i l e l i qui d t hat i s i nhal ed f or i t s
vasodi l at i ng ef f ect i n acut e angi na.
c. SubI i mat i on occurs when a sol i d i s heat ed di rect l y t o t he gaseous, or
vapor , st at e wi t hout passi ng t hr ough t he l i qui d st at e (e. g. , camphor ,
i odi ne). Ì ce subl i mes at pr essures bel ow
P. 32

3 t or r. The pr ocess of f reeze- dr yi ng, or I yophi I i zat i on, i s a f or m of vacuum
dr yi ng i n whi ch wat er i s r emoved by subl i mat i on f r om t he f rozen pr oduct . Ì t
i s an especi al l y usef ul process f or dr yi ng aqueous sol ut i ons or di sper si ons
of heat - or oxygen- sensi t i ve dr ugs and bi ol ogi cal s ( e. g. , pr ot ei ns, pept i des) .
d. The r ever se process (i . e. , di r ect t ransi t i on f rom t he vapor st at e t o t he
sol i d st at e) i s al so r ef er red t o as subl i mat i on, but t he pr ef er red t er m i s
deposi t i on. Some f or ms of sul f ur and col l oi dal si l i con di oxi de ar e pr epared
i n t hi s way.
4. The i nt er mol ecul ar f orces of at t r act i on i n gases are vi r t ual l y nonexi st ent
at r oom t emper at ur e. Gases di spl ay l i t t l e or no order i ng.
B. Li qui ds. The i nt er mol ecul ar f orces of at t r act i on i n l i qui ds ( van der
WaaI s f orces) ar e suf f i ci ent t o i mpose some or der i ng, or r egul ar
ar r angement , among t he mol ecul es. Hydrogen bondi ng i ncreases t he
l i kel i hood of cohesi on i n l i qui ds and f ur t her af f ect s t hei r physi cochemi cal
behavi or . However , t hese f orces ar e much weaker t han covaI ent or i oni c
f or ces. Ther ef or e, l i qui ds t end t o di spl ay shor t -range r at her t han l ong- r ange
or der. Hypot het i cal l y, al t hough mol ecul es of a l i qui d woul d t end t o
aggregat e i n l ocal i zed cl ust er s, no def i ned st ruct ur i ng woul d be evi dent .
1. Surface and i nterf aci aI t ensi on
a. Mol ecul es i n t he bul k phase of a l i qui d ar e surr ounded by ot her
mol ecul es of t he same ki nd ( Fi gur e 3- 2A) . Mol ecul es at t he sur f ace of a
l i qui d ar e not compl et el y sur rounded by l i ke mol ecul es ( Fi gure 3-2B) . As a
r esul t , mol ecul es at or near t he surf ace of a l i qui d exper i ence a net i nward
pul l f rom mol ecul es i n t he i nt eri or of t he l i qui d. Because of t hi s net i nwar d
i nt er mol ecul ar at t ract i on, t he l i qui d surf ace t ends t o spont aneousl y
cont r act . Thus l i qui ds t end t o assume a spheri cal shape ( i . e. , a vol ume wi t h
t he mi ni mum sur f ace area) . Thi s conf i gur at i on has t he l east f r ee ener gy.
b. Any expansi on of t he sur f ace i ncreases t he f ree ener gy of t he syst em.
Thus surface f ree energy can be def i ned by t he wor k r equi r ed t o i ncrease
t he surf ace ar ea A of t he l i qui d by 1 ar ea uni t . Thi s val ue i s expr essed as
t he number of mi l l i - Newt ons ( mN) needed t o expand a 1-m2 sur f ace by 1
uni t :
wor k = v × AA
wher e AA i s t he i ncr ease i n surf ace ar ea and v i s t he surf ace tensi on, or
surf ace f ree energy, i n mN m
- 1
÷equi val ent t o cent i met er -gr am- second
( CGS) uni t s of dynes cm
- 1
. At 20°C. wat er has a sur f ace t ensi on of 72 mN
m
- 1
, wher eas n- oct anol has a sur f ace t ensi on of 27 mN m
- 1
. Thus mor e wor k
must be expended t o expand t he sur f ace of wat er t han t o expand t he
sur f ace of n-oct anol (i . e. , t o pr oceed f rom a gi ven vol ume of bul k l i qui d t o
t he cor respondi ng vol ume of smal l dr opl et s) .
c. At t he boundar y, or i nt erf ace, bet ween t wo i mmi sci bl e l i qui ds t hat are i n
cont act wi t h one anot her, t he cor r espondi ng i nterf aci aI t ensi on (i . e. , f ree
energy, or wor k r equi red t o expand t he i nt erf aci al ar ea) r ef l ect s t he ext ent
of t he i nt er mol ecul ar f orces of at t r act i on and r epul si on at t he i nt erf ace.
When t he i nt erf ace i s bet ween t wo l i qui ds, subst ant i al mol ecul ar i nt er act i on
occurs acr oss t he i nt erf ace bet ween t he t wo phases. Thi s i nt er act i on
P. 33

r educes t he i mbal ance i n f orces of at t r act i on wi t hi n each phase. The
i nt er f aci al t ensi on bet ween n-oct anol and wat er i s r educed t o 8. 5 mN m
- 1

f r om 72 mN m
- 1
(v ai r / wat er ) . Thi s reduct i on i ndi cat es, i n par t , t he
i nt er f aci al i nt er act i on bet ween n- oct anol and wat er .

Figure 3-2. A. Molecules in the bulk phase. B.
Molecules at the surIace oI a liquid.

Figure 3-3. Liquid Ilow.
2. The f l ow of a l i qui d acr oss a sol i d sur f ace can be exami ned i n t erms of
t he veI oci t y, or r at e of movement , of t he l i qui d rel at i ve t o t he sur f ace
acr oss whi ch i t f l ows. Mor e i nsi ght can be gai ned by vi sual i zi ng t he f l ow of
l i qui d as i nvol vi ng t he movement of numer ous par al l el l ayers of l i qui d
bet ween an upper , movabl e pl at e and a l ower , f i xed pl at e ( Fi gur e 3- 3) . The
appl i cat i on of a const ant f orce (F) t o t he upper pl at e causes bot h t hi s pl at e
and t he uppermost l ayer of l i qui d i n cont act wi t h i t t o move wi t h a vel oci t y
Ay/ Ax. The i nt er act i on bet ween t he f i xed bot t om pl at e and t he l i qui d l ayer
cl osest t o i t pr event s t he movement of t he bot t om l ayer of l i qui d. The
veI oci t y ( v) of t he r emai ni ng l ayer s of l i qui d bet ween t he t wo pl at es i s
pr opor t i onal t o t hei r di st ance f rom t he i mmovabl e pl at e ( i . e. , Ay/ Ax) . The
veI oci t y gradi ent l eads t o def ormat i on of t he l i qui d wi t h t i me. Thi s
def ormat i on i s t he rat e of shear, dv/ dx, or D. Newt on def i ned f l ow i n t erms
of t he rat i o of t he f or ce F appl i ed t o a pl at e of area A÷shear st ress (¡) ÷
di vi ded by t he vel oci t y gr adi ent ( D) i nduced by ¡:

or

The pr opor t i onal i t y const ant n i s t he coef f i ci ent of vi scosi t y. Ì t i ndi cat es
t he resi st ance t o f l ow of adj acent l ayers of f l ui d. The r eci procal of n i s
f I ui di t y. Uni t s of vi scosi t y i n t he CGS syst em ar e dynes cm
- 2
s
- 1
, or poi se.
Ì n t he SÌ syst em, t he uni t s ar e Newt ons m
- 2
s
- 1
, whi ch cor responds t o 10
poi se. The vi scosi t y of wat er at 20°C i s appr oxi mat el y 0. 01 poi se, or 1
cent i poi se (cps) , whi ch cor r esponds t o 1 mN m
- 2
s
- 1
.
a. Subst ances t hat f l ow i n accor dance wi t h t he equat i on i n Ì Ì Ì . B. 2 ( Newt on' s
l aw) ar e known as Newtoni an subst ances. Li qui ds t hat consi st of si mpl e
mol ecul es and di l ut e di sper si ons t end t o be Newt oni an. For a Newt oni an
f l ui d, a pl ot of shear st ress as a f unct i on of shear r at e ( a fI ow curve or
rheogram) yi el ds a st r ai ght l i ne wi t h a sl ope of n ( Fi gur e 3- 4, Curve 1) .
b. Non- Newtoni an subst ances do not obey Newt on' s equat i on of f l ow.
These subst ances t end t o exhi bi t shear- dependent or ti me- dependent
vi scosi t y. Ì n ei t her case, vi scosi t y i s more apt l y t er med apparent
vi scosi t y because Newt on' s l aw i s not st r i ct l y obeyed. Het erogeneous
l i qui ds and sol i ds ar e most l i kel y non- Newt oni an.
( 1) Shear- dependent vi scosi t y i nvol ves ei t her an i ncr ease i n appar ent
vi scosi t y ( i . e. , shear t hi ckeni ng, or di I at ancy) ( Fi gur e 3- 4, Cur ve 3) or a
decrease i n appar ent vi scosi t y (i . e. , shear t hi nni ng, or pseudo- pI ast i ci ty)
( Fi gur e 3- 4, Curve 2) wi t h an i ncr ease i n t he rat e of shear . Shear t hi ckeni ng
i s di spl ayed by suspensi ons t hat have a hi gh sol i ds cont ent of smal l ,
def l occul at ed par t i cl es. Shear t hi nni ng i s di spl ayed by pol ymer
P. 34

or macromol ecul e sol ut i ons. PI ast i c, or Bi ngham body, behavi or ( Fi gure 3-
4, Curve 4) i s exempl i f i ed by f l occul at ed par t i cl es i n concent r at ed
suspensi ons t hat show no apparent r esponse t o l ow- l evel st r ess. Fl ow
begi ns onl y af t er a l i mi t i ng yi el d st ress ( yi eI d vaI ue) i s exceeded.

Figure 3-4. Non-Newtonian Ilow curves.
( 2) Ti me- dependent vi scosi t y
( a) The yi el d val ue of pI ast i c syst ems may be t i me dependent ( i . e. , may
depend on t he t i me scal e i nvol ved i n t he appl i cat i on of f orce). Thi xot ropi c
syst ems di spl ay shear - t hi nni ng behavi or but do not i mmedi at el y r ecover
t hei r hi gher appar ent vi scosi t y when t he r at e of shear i s l ower ed. Ì n a
t hi xot r opi c syst em, st r uct ur al r ecover y i s rel at i vel y sl ow compar ed wi t h
st r uct ur al br eakdown.
( b) Thi xot ropy occurs wi t h het er ogeneous syst ems t hat i nvol ve a t hr ee-
di mensi onal st r uct ure or net wor k. When such a syst em i s at rest , i t appears
t o have a r el at i vel y r i gi d consi st ency. Under shear , t he st r uct ure br eaks
down and f l ui di t y i ncreases (i . e. , geI - soI t r ansf ormat i on).
( c) Rheopexy ( negat i ve t hi xot ropy, or ant i t hi xot ropy) occur s when t he
appar ent vi scosi t y of t he syst em cont i nues t o i ncrease wi t h cont i nued
appl i cat i on of shear up t o some equi l i br i um val ue at a gi ven shear rat e.
These syst ems di spl ay a soI - geI t r ansf or mat i on. One expl anat i on f or
ant i t hi xot r opi c behavi or i s t hat cont i nued shear i ncr eases t he f r equency of
par t i cl e or macromol ecul e i nt er act i ons and l eads t o i ncreased st r uct ure i n
t he syst em.
C. SoI i ds. Ì nt er mol ecul ar f orces of at t r act i on ar e st ronger i n sol i ds t han i n
l i qui ds or gases. Mol ecul ar ar rangement s i n sol i ds may be char act er i zed as
ei t her cr yst al l i ne or amor phous.
1. Cr yst aI I i ne soI i ds have t he f ol l owi ng at t r i but es:
a. Fi xed moI ecuI ar order ( i . e. , mol ecul es occupy set posi t i ons i n a speci f i c
ar r ay)
b. A di st i nct mel t i ng poi nt
c. Ani sot ropi ci t y ( i . e. , t hei r pr oper t i es ar e not t he same i n al l di rect i ons) ,
wi t h t he except i on of cubi c cr yst al s
2. Amorphous soI i ds have t he f ol l owi ng at t r i but es:
a. Randoml y ar r anged mol ecul es wi t h t he shor t - range order t ypi cal of
l i qui ds
b. No mel t i ng poi nt s
c. I sot ropi ci t y ( i . e. , proper t i es are t he same i n al l di r ect i ons)
P. 35


d. Less t hermodynami c st abi l i t y t han t he cor respondi ng cr yst al l i ne sol i d and
t her ef ore mor e apt t o exhi bi t chemi cal and physi cal i nst abi l i t y, i ncr eased
di ssol ut i on r at e, et c.
3. PoI ymorphi sm i s t he condi t i on wher ei n subst ances can exi st i n more
t han one cr yst al l i ne f orm. These poI ymorphs have di f f erent mol ecul ar
ar r angement s or cr yst al l at t i ce st ruct ur es. As a r esul t , t he di f f er ent
pol ymor phs of a drug sol i d can have di f f erent pr oper t i es. For exampl e, t he
mel t i ng poi nt , sol ubi l i t y, di ssol ut i on r at e, densi t y, and st abi l i t y can di f f er
consi derabl y among t he pol ymor phi c f or ms of a dr ug. Many dr ugs exhi bi t
pol ymor phi c behavi or . Fat t y ( t ri gl ycer i de) exci pi ent s ( e. g. , t heobr oma oi l ,
cocoa but t er ) ar e r ecogni zed f or t hei r pol ymor phi c behavi or .
4. The i ncor por at i on of sol vent mol ecul es i nt o t he cr yst al l at t i ce of a sol i d
r esul t s i n a mol ecul ar adduct known as a soI vate or hydrat e ( t he l at t er
t er m i s used when wat er i s t he sol vent ) . Ì n general , sol vat es or hydrat es
exhi bi t di f f er ent sol ubi l i t i es and di ssol ut i on rat es t han t hei r
unsol vat ed/ anhydrous count erpart s.
5. MeI t i ng poi nt and heat of fusi on. The mel t i ng poi nt of a sol i d i s t he
t emper at ure at whi ch t he sol i d i s t ransf ormed t o a l i qui d. When 1 g of a
sol i d i s heat ed and mel t s, t he heat absor bed i n t he pr ocess i s ref er red t o as
t he I at ent heat of f usi on.
D. Phase di agrams and phase equi I i bri a. A phase di agram r epr esent s t he
st at es of mat t er ( i . e. , sol i d, l i qui d, and gas) t hat exi st as t emper at ur e and
pr essure ar e vari ed ( Fi gur e 3- 5) . The dat a
P. 36

ar r ays separat i ng t he phases i n Fi gur e 3- 5 del i neat e t he t emper at ur es and
pr essures at whi ch t he phases can coexi st . Thus gas ( or vapor ) and l i qui d
coexi st al ong " cur ve¨ BC, sol i d and l i qui d coexi st al ong "cur ve¨ AB, and
sol i d and gas (or vapor ) coexi st al ong " cur ve¨ DB. Dependi ng on t he change
i n t emper at ure and pr essur e, evaporat i on or condensat i on occur al ong
cur ve BC, f usi on or meI t i ng al ong cur ve AB, and subI i mat i on or
deposi t i on al ong cur ve DB. The t hree " cur ves¨ i nt ersect at poi nt B. Onl y at
t hi s uni que t emperat ur e and pr essur e, known as t he t ri pI e poi nt , do al l
t hr ee phases exi st i n equi l i bri um. ( The t r i pl e poi nt f or wat er i s 0. 01°C and
6. 04 × 10
- 3
at m. ) Cont i nui ng al ong cur ve BC, t o hi gher t emperat ures and
pr essures, one ul t i mat el y r eaches poi nt C, known as t he cri t i caI poi nt,
above whi ch t here i s no di st i nct i on bet ween t he l i qui d and t he gas phases.
Subst ances t hat exi st above t hi s cri t i cal poi nt are known as supercri t i caI
f I ui ds. Supercr i t i cal f l ui ds such as car bon di oxi de ( cri t i cal poi nt , 30. 98°C
and 73. 8 at m) of t en exhi bi t markedl y al t ered physi cochemi cal proper t i es
( e. g. , densi t y, di f f usi vi t y, or sol ubi l i t y char act eri st i cs) t hat r ender t hem
usef ul as sol vent s and pr ocessi ng ai ds i n t he pr oduct i on of pharmaceut i cal s
and dr ug del i ver y syst ems.

Figure 3-5. Phase diagram Ior CO
2
showing the
variation oI the state oI matter as pressure and
temperature are varied. The solid state exists in
the region ABD, the liquid state. in the region
ABC, and the gas state. in the region to the right
oI curve CD. B corresponds to the triple point. the
pressure and temperature at which all three phases
coexist. C corresponds to the critical point. the
pressure and temperature above which the liquid
and gas phases are indistinguishable.
IV. PHYSICOCHEMICAL BEHAVIOR
A. Homogeneous syst ems
1. A soI uti on i s a homogeneous syst em i n whi ch a soI ut e i s mol ecul ar l y
di spersed, or di ssol ved, i n a soI vent . The sol vent i s t he predomi nant
speci es. Saturat ed soI ut i ons ar e sol ut i ons t hat , at a gi ven t emper at ur e
and pr essur e, cont ai n t he maxi mum amount of sol ut e t hat can be
accommodat ed by t he sol vent . Ì f t he sat ur at i on, or sol ubi l i t y, l i mi t i s
exceeded, a f r act i on of t he sol ut e can separ at e f rom t he sol ut i on and exi st
i n equi l i br i um wi t h i t .
a. SoI ut es can be gases, l i qui ds, or sol i ds, and nonel ect r ol yt es or
el ect r ol yt es.
( 1) NoneI ect roI yt es ar e subst ances t hat do not form i ons when di ssol ved
i n wat er . Exampl es ar e est r adi ol , gl ycer i n, ur ea, and sucr ose. Thei r
aqueous sol ut i ons do not conduct el ect r i c cur r ent .
( 2) EI ect roI yt es ar e subst ances t hat do f orm i ons i n sol ut i on. Exampl es
ar e sodi um chl or i de, hydr ochl ori c aci d, and at r opi ne. As a r esul t , t hei r
aqueous sol ut i ons conduct el ect ri c curr ent . El ect rol yt es are charact er i zed
as st rong or weak. St r ong el ect r ol yt es ( e. g. , sodi um chl ori de, hydr ochl or i c
aci d) ar e compI eteI y i oni zed i n wat er at al l concent r at i ons. Weak
el ect r ol yt es ( e. g. , aspi r i n, at r opi ne) are part i aI I y i oni zed i n wat er .
b. The coI I i gat i ve propert i es of a soI ut i on depend on t he t ot al number of
i oni c and noni oni c soI ut e moI ecuI es i n t he soI ut i on. These proper t i es
depend on i oni zat i on but ar e i ndependent of ot her chemi caI properti es of
t he soI ute.
2. CoI I i gat i ve propert i es i ncl ude t he f ol l owi ng:
a. Loweri ng of vapor pressure. The part i aI vapor pressure of each
vol at i l e component i n a sol ut i on i s equal t o t he product of t he mol f ract i on
of t he component i n t he sol ut i on and t he vapor pr essur e of t he pur e
component . Thi s i s RaouI t ' s I aw:

wher e pA i s t he par t i al vapor pr essur e above a sol ut i on i n whi ch t he mol
f r act i on of t he sol ut e A i s xA and i s t he vapor pressure of t he pur e
component A. The vapor pr essur e i s t he pressure at whi ch an equi l i br i um i s
est abl i shed bet ween t he mol ecul es of A i n t he l i qui d st at e and t he
mol ecul es of A i n t he gaseous ( vapor) st at e i n a cl osed, evacuat ed
cont ai ner . The vapor pressur e i s t emper at ur e dependent , but i ndependent
of t he amount of l i qui d and vapor . Raoul t ' s l aw hol ds f or i deal sol ut i ons of
nonel ect rol yt es. For a bi nar y soI ut i on ( i . e. , a sol ut i on of component B i n
component A)

The l ower i ng of t he vapor pr essur e of t he sol ut i on r el at i ve t o t he vapor
pr essure of t he pur e sol vent i s pr opor t i onal t o t he number of mol ecul es of
sol ut e i n t he sol ut i on. The act ual l ower i ng of t he vapor pr essur e by t he
sol ut e, ApA, i s gi ven by

b. EI evati on of t he boi I i ng poi nt . The boi I i ng poi nt i s t he t emper at ur e at
whi ch t he vapor
P. 37

pr essure of a l i qui d equal s an ext er nal pr essur e of 760 mm Hg. A sol ut i on
of a nonvol at i l e sol ut e has a hi gher boi l i ng poi nt t han a pur e sol vent
because t he sol ut e l ower s t he vapor pr essur e of t he sol vent . The amount of
el evat i on of t he boi l i ng poi nt ( ATb) depends on t he concent r at i on of t he
sol ut e:

wher e Kb i s t he mol al boi l i ng poi nt el evat i on const ant , R i s t he mol ar gas
const ant , T i s absol ut e t emper at ur e ( degr ees K) , M1 i s t he mol ecul ar wei ght
of t he sol ut e, m i s t he mol al i t y of t he sol ut i on, and AHv ap i s t he mol al
ent hal py of vapor i zat i on of t he sol vent .
c. Depressi on of the f reezi ng poi nt . The f reezi ng poi nt , or mel t i ng poi nt ,
of a pure compound i s t he t emper at ur e at whi ch t he sol i d and t he l i qui d
phases are i n equi l i br i um under a pr essur e of 1 at mosphere ( at m). The
f r eezi ng poi nt of a sol ut i on i s t he t emper at ur e at whi ch t he sol i d phase of
t he pur e sol vent and t he l i qui d phase of t he sol ut i on ar e i n equi l i bri um
under a pr essur e of 1 at m. The amount of depr essi on of t he f reezi ng poi nt
( ATf ) depends on t he mol al i t y of t he sol ut i on:

wher e Kf i s t he mol al f r eezi ng poi nt const ant and AHf usi on i s t he mol al heat
of f usi on.
d. Osmot i c pressure. Osmosi s i s t he process by whi ch sol vent mol ecul es
pass t hr ough a semi permeabl e membr ane (a barr i er t hr ough whi ch onl y
sol vent mol ecul es may pass) f rom a regi on of di l ut e sol ut i on t o one of mor e
concent r at ed sol ut i on. Sol vent mol ecul es t ransf er because of t he i nequal i t y
i n chemi cal pot ent i al on t he t wo si des of t he membr ane. Sol vent mol ecul es
i n a concent r at ed sol ut i on have a l ower chemi cal pot ent i al t han sol vent
mol ecul es i n a mor e di l ut e sol ut i on.
( 1) Osmot i c pressure i s t he pressure t hat must be appl i ed t o t he sol ut i on
t o prevent t he f l ow of pur e sol vent i nt o t he concent r at ed sol ut i on.
( 2) Sol vent mol ecul es move f r om a r egi on wher e t hei r escapi ng t endency
i s hi gh t o one wher e t hei r escapi ng t endency i s I ow. The pr esence of
di ssol ved sol ut e l ower s t he escapi ng t endency of t he sol vent i n proport i on
t o t he sol ut e concent r at i on.
( 3) The van' t Hof f equati on def i nes t he osmot i c pr essure ¬ as a f unct i on of
t he number of mol es of sol ut e n2 i n t he sol ut i on of vol ume V:
¬V = n2RT
3. EI ect roI yt e soI ut i ons and i oni c equi I i bri a
a. Aci d- base equi I i bri a
( 1) Accor di ng t o t he Arrheni us di ssoci at i on t heor y, an aci d i s a
subst ance t hat l i berat es H
+
i n aqueous sol ut i on. A base i s a subst ance t hat
l i ber at es hydr oxyl i ons (OH
-
) i n aqueous sol ut i on. Thi s def i ni t i on appl i es
onl y under aqueous condi t i ons.
( 2) The Lowr y- Brønst ed t heor y i s a mor e power f ul concept t hat appl i es t o
aqueous and nonaqueous syst ems. Ì t i s most commonl y used f or
pharmaceut i cal and bi ol ogi c syst ems because t hese syst ems ar e pr i mari l y
aqueous.
( a) Accor di ng t o t hi s def i ni t i on, an aci d i s a subst ance (charged or
uncharged) t hat i s capabl e of donat i ng a pr ot on. A base i s a subst ance
( char ged or unchar ged) t hat i s capabl e of accept i ng a pr ot on f r om an aci d.
The di ssoci at i on of an aci d ( HA) al ways pr oduces a base (A
-
) accordi ng t o
t he f ol l owi ng f ormul a:
HA ÷ H
+
+ A
-

( b) HA and A
-
are a conj ugat e aci d- base pai r ( an aci d and a base t hat
exi st i n equi l i bri um and di f f er i n st r uct ur e by a prot on). The pr ot on of an
aci d does not exi st f r ee i n sol ut i on, but combi nes wi t h t he sol vent . Ì n wat er ,
t hi s hydrat ed prot on i s a hydroni um i on ( H3O
+
).
( c) The rel at i ve st rengt hs of aci ds and bases are det er mi ned by t hei r
abi l i t y t o donat e or accept prot ons. For exampl e, i n wat er, HCl donat es a
pr ot on more r eadi l y t han does acet i c aci d. Thus HCl i s a st ronger aci d. Aci d
st r engt h i s al so det er mi ned by t he af f i ni t y of t he sol vent f or pr ot ons. For
exampl e, HCl may di ssoci at e compl et el y i n l i qui d ammoni a, but onl y ver y
sl i ght l y i n gl aci al acet i c aci d. Thus HCl i s a st rong aci d i n l i qui d ammoni a
and a weak aci d i n gl aci al acet i c aci d.
P. 38


( 3) The Lewi s theor y ext ends t he aci d-base concept t o r eact i ons t hat do
not i nvol ve pr ot ons. Ì t def i nes an aci d as a mol ecul e or i on t hat accept s an
el ect r on pai r f r om anot her at om and a base as a subst ance t hat donat es an
el ect r on pai r t o be shar ed wi t h anot her at om.
b. H
+
concent rat i on val ues ar e ver y smal l . Theref or e, t hey are expr essed
i n exponenti aI not at i on as pH. The pH i s t he l ogar i t hm of t he r eci procal of
t he H
+
concent rat i on

wher e [ H
+
] i s t he mol ar concent rat i on of H
+
. Because t he l ogari t hm of a
r eci pr ocal equal s t he negat i ve I ogari thm of t he number , t hi s equat i on may
be r ewr i t t en as:
pH = -l og [ H
+
]
or
[ H
+
] = 10
- pH

Thus t he pH val ue may be def i ned as t he negat i ve l ogari t hm of t he [ H
+
]
val ue. For exampl e, i f t he H
+
concent r at i on of a sol ut i on i s 5 × 10
- 6
, t he pH
val ue may be cal cul at ed as f ol l ows:
pH ÷ -log (5 × 10
-6
)
log 5 ÷ 0.699
log 10
-6
÷ -6.0
pH ÷ -(-6 ¹ 0.699)
÷ -(-5.301)
÷ 5.301

c. As pH decr eases, H
+
concent rati on i ncreases exponent i aI I y. When t he
pH decr eases f r om 6 t o 5, t he H
+
concent r at i on i ncr eases f r om 10
- 6
t o 10
- 5
,
or 10 t i mes i t s ori gi nal val ue. When t he pH f al l s f r om 5 t o 4. 7, t he H
+

concent r at i on i ncreases f r om 1 × 10
- 5
t o 2 × 10
- 5
, or doubl e i t s i ni t i al val ue.
d. Di ssoci at i on constant s. I oni zati on i s t he compl et e separat i on of t he
i ons i n a cr yst al l at t i ce when t he sal t i s di ssol ved. Di ssoci ati on i s t he
separ at i on of i ons i n sol ut i on when t he i ons ar e associ at ed by i nt eri oni c
at t r act i on.
( 1) For weak eI ect roI yt es, di ssoci at i on i s a reversi bl e pr ocess. The
equi l i br i um of t hi s pr ocess can be expr essed by t he l aw of mass act i on.
Thi s l aw st at es t hat t he rat e of t he chemi cal react i on i s pr oport i onal t o t he
pr oduct of t he concent r at i on of t he r eact i ng subst ances, each r ai sed t o a
power of t he number of mol es of t he subst ance i n sol ut i on.
( 2) For weak aci ds, di ssoci at i on i n wat er i s expr essed as:
HA ÷ H
+
+ A
-

The dynami c equi l i br i um bet ween t he si mul t aneous f or war d and rever se
r eact i ons i s i ndi cat ed by t he ar r ows. By t he l aw of mass act i on,
r at e of f or war d r eact i on = K1[ HA]
r at e of rever se r eact i on = K2[ H
+
] [ A
-
]
At equi l i bri um, t he f or war d and rever se r at es are equal . Theref or e,
K1[ HA] = K2[ H
+
] [ A
-
]
Thus t he equi I i bri um expressi on for t he di ssoci at i on of a weak aci d i s
wr i t t en as:

wher e Kar epr esent s t he aci d di ssoci at i on const ant . For a weak aci d, t he
aci d di ssoci at i on constant i s convent i onal l y expr essed as pKa, whi ch i s -
l og Ka. For exampl e, t he Ka of acet i c aci d at 25°C i s 1. 75 × 10
- 5
. The pKa i s
cal cul at ed as f ol l ows:
P. 39


pKa ÷ -log (1.75 × 10
-5
)
log 1.75 ÷ 0.243
log 10
-5
÷ -5
pH ÷ -(-5 ¹ 0.243)
÷ -(-4.757)
÷ 4.76

( 3) For weak bases, di ssoci at i on may al so be expr essed wi t h t he Ka
expr essi on f or t he conj ugat e aci d of t he base. Thi s aci d i s f or med when a
pr ot on react s wi t h t he base. For a base t hat does not cont ai n a hydroxyl
gr oup,
BH
+
÷ H
+
+ B
The di ssoci at i on constant f or t hi s r eact i on i s expr essed as:

However , a base di ssoci at i on const ant i s t r adi t i onal l y def i ned f or a weak
base wi t h t hi s expr essi on:
B + H2O ÷ OH
-
+ BH
+


wher e Kb r epr esent s t he di ssoci at i on const ant of a weak base. Thi s
di ssoci at i on const ant can be expr essed as pKb, as f ol l ows:
pKb = - l og Kb
( 4) Cert ai n compounds ( aci ds or bases) can accept or donat e more t han
one pr ot on. Consequent l y, t hey have more t han one di ssoci at i on
constant .
e. Henderson- HasseI baI ch equati ons descr i be t he r el at i on bet ween t he
i oni zed and t he uni oni zed speci es of a weak el ect r ol yt e.
( 1) For weak aci ds, t he Henderson- Hassel bal ch equat i on i s obt ai ned f r om
t he equi l i br i um r el at i on descr i bed i n Ì V. A. 3d. (2) :

( 2) Si mi l arl y, t he Henderson- Hassel bal ch equat i on f or weak bases i s as
f ol l ows:

wher e B i s t he uni oni zed weak base and BH
+
i s t he prot onat ed base.
f . The degree of i oni zati on ( o) , t he f ract i on of a weak el ect r ol yt e t hat i s
i oni zed i n sol ut i on, i s cal cul at ed f rom t he f ol l owi ng equat i on:

wher e [ Ì ] and [ U] represent t he concent r at i ons of t he i oni zed and uni oni zed
speci es, r espect i vel y. The degr ee of i oni zat i on depends sol el y on t he pH of
t he sol ut i on and t he pKa of t he weak el ect r ol yt e. When pH = pKa, t he
Henderson- Hassel bal ch equat i ons are, f or a weak aci d and a weak base,
r espect i vel y:

t hus

P. 40



t hus

Ì n ef f ect , when t he pH of t he sol ut i on i s numer i cal l y equi val ent t o t he pKa of
t he weak el ect r ol yt e, whet her a weak base or a weak aci d, [ Ì ] = [ U] and t he
degree of i oni zat i on q = 0. 5 (i . e. , 50% of t he sol ut e i s i oni zed) .
g. SoI ubi I i t y of a weak eI ect roI yt e var i es as a f unct i on of pH.
( 1) For a weak aci d, t he t ot al sol ubi l i t y Cs i s gi ven by t he expr essi on:
Cs = [ HA] + [ A
-
]
wher e [ HA] i s t he i nt r i nsi c sol ubi l i t y of t he uni oni zed weak aci d and i s
denot ed as C0, wher eas [ A
-
] i s t he concent r at i on of i t s ani on. Because [ A
-
]
can be expr essed i n t erms of C0 and t he di ssoci at i on const ant Ka,

Thus t he soI ubi I i t y of a weak aci d i ncreases wi t h i ncreasi ng pH ( i . e. ,
wi t h an i ncr easi ng degr ee of i oni zat i on, as t he ani on i s mor e pol ar and
t her ef ore mor e wat er sol ubl e t han t he uni oni zed weak aci d).
( 2) Si mi l arl y, f or weak bases,

Thus t he soI ubi I i t y decreases wi t h i ncreasi ng pH because mor e of t he
weak base i s i n t he unprot onat ed f or m. Thi s f orm i s l ess pol ar and t her ef or e
l ess wat er sol ubl e.
h. Buf fers and buf f er capaci t y
( 1) A buf f er i s a mi xt ur e of sal t wi t h aci d or base t hat r esi st s changes i n pH
when smal l quant i t i es of aci d or base ar e added. A buf f er can be a
combi nati on of a weak aci d and i t s conj ugat e base ( sal t ) or a combi nat i on
of a weak base and i t s conj ugat e aci d (sal t ) . However , buf f er sol ut i ons are
mor e commonI y prepared f rom weak aci ds and t hei r sal t s. They ar e not
or di nari l y prepared f r om weak bases and t hei r sal t s because weak bases
ar e of t en unst abl e and vol at i l e.
( a) For a weak aci d and i t s saI t, t he f ol l owi ng buf f er equat i on i s
sat i sf act or y f or cal cul at i ons wi t h a pH of 4-10. Ì t i s i mpor t ant i n t he
pr epar at i on of buf f ered phar maceut i cal sol ut i ons:

( b) For a weak base and i t s saI t , t he buf f er equat i on i s si mi l ar but al so
depends on t he di ssoci at i on const ant of wat er ( pKw) . The equat i on
becomes:

( 2) Buf fer act i on i s t he r esi st ance t o a change i n pH.
( 3) Buf fer capaci t y i s t he abi l i t y of a buf f er sol ut i on t o resi st changes i n
pH. The smaI I er the pH change caused by addi t i on of a gi ven amount of
aci d or base, t he great er t he buf f er capaci t y of t he sol ut i on.
( a) Buf f er capaci t y i s t he number of gr am equi val ent s of an aci d or base
t hat changes t he pH of 1 L of buf f er sol ut i on by 1 uni t .
( b) Buf f er capaci t y i s af f ect ed by t he concent r at i on of t he buf f er
const i t uent s. A hi gher concent r at i on pr ovi des a great er aci d or base
r eser ve. Buf f er capaci t y ( 8) i s r el at ed t o t ot al concent r at i on ( C) as f ol l ows:
P. 41



wher e C r epresent s t he mol ar concent r at i ons of t he aci d and t he sal t .
( c) Thus buf f er capaci t y depends on t he val ue of t he rat i o of t he sal t t o t he
aci d f or m. Ì t i ncr eases as t he rat i o appr oaches uni t y. Maxi mum buf f er
capaci t y occur s when pH = pKa, and i s r epresent ed by 8 = 0. 576C.
B. Het erogeneous ( di sperse) syst ems
1. I nt roduct i on
a. A suspensi on i s a t wo- phase syst em t hat i s composed of a sol i d mat er i al
di spersed i n an oi l y or aqueous l i qui d. The par t i cl e si ze of t he di sper sed
sol i d i s usual l y > 0. 5 µm.
b. An emuI si on i s a het er ogeneous syst em t hat consi st s of at l east one
i mmi sci bl e l i qui d t hat i s i nt i mat el y di spersed i n anot her i n t he f orm of
dr opl et s. The dr opl et di amet er usual l y exceeds 0. 1 µm. Emul si ons ar e
i nherent I y unst abI e because t he dr opl et s of t he di spersed l i qui d t end t o
coal esce t o f orm l arge dropl et s unt i l al l of t he di sper sed dr opl et s have
coal esced. The t hi r d component of t he syst em i s an emuI si f yi ng agent .
Thi s agent prevent s coal escence and mai nt ai ns t he i nt egr i t y of t he
i ndi vi dual dr opl et s.
2. Di spersi on st abi I i t y. Ì n an i deaI di spersi on, t he di spersed par t i cl es do
not i nt er act . The par t i cl es are uni f or m i n si ze and under go no change i n
posi t i on ot her t han t he random movement t hat r esul t s f r om Browni an
mot i on. Ì n cont rast , i n a reaI di spersi on, t he part i cl es are not uni f orml y
si zed ( i . e. , t hey ar e not monodi sperse). The part i cl es are subj ect t o
par t i cul at e aggregat i on, or cl umpi ng, and t he di sper si on becomes more
het erogeneous wi t h t i me. The rat e of set tI i ng ( separati ng, or creami ng) of
t he di spersed phase i n t he di spersi on medi um i s a f unct i on of t he par t i cl e
si ze, di sper si on phase vi scosi t y, and di f f er ence i n densi t y bet ween t he
di spersed phase and t he di spersi on medi um, i n accor dance wi t h Stokes' s
I aw:

wher e d i s t he part i cl e di amet er , g i s t he accel erat i on owi ng t o gr avi t y, n i s
t he vi scosi t y of t he di sper si on medi um, and ( p1 - p2) i s t he di f f erence
bet ween t he densi t y of t he par t i cl es ( p1) and t he densi t y of t he di spersi on
medi um ( p2) . Al t hough St okes' s l aw was der i ved t o det ermi ne t he set t l i ng,
or sedi ment at i on, of noni nt er act i ng spheri cal part i cl es, i t al so pr ovi des
gui dance f or det er mi ni ng t he st abi l i zat i on of di sper si on:
a. Parti cI e si ze shoul d be as smaI I as possi bl e. Smal l er part i cl es yi el d
sl ower sedi ment at i on, or f l ot at i on, r at es.
b. Hi gh parti cuI at e ( di spersed phase) concent rat i ons i ncrease t he r at e of
par t i cl e- par t i cl e col l i si ons and i nt er act i on. As a resul t , part i cl e aggr egat i on
occurs, and i nst abi l i t y i ncr eases as t he aggr egat es behave as l ar ger
par t i cl es. Ì n t he case of l i qui d- l i qui d di sper si ons, par t i cl e- par t i cl e col l i si ons
can l ead t o coal escence ( i . e. , l ar ger par t i cl es) and decr ease di spersi on
st abi l i t y.
c. Avoi dance of part i cI e- part i cI e i nteracti ons
( 1) Aggr egat i on can be pr event ed i f t he par t i cl es have a si mi l ar el ect r i cal
charge. Par t i cl es i n an aqueous syst em al ways have some el ect r i cal charge
because of i oni zat i on of chemi cal gr oups on t he par t i cl e sur f ace or
adsorpt i on of char ged mol ecul es or i ons at t he i nt er f ace. Ì f t he adsorbed
speci es i s an i oni c surfact ant ( e. g. , sodi um l auryl sul f at e) , t he char ge
associ at ed wi t h t he sur f act ant i on ( e. g. , l aur yl sul f at e ani on) wi l l
accumul at e at t he i nt er f ace. However , i f a rel at i vel y non- sur f ace- act i ve
el ect r ol yt e i s adsorbed, t he si gn of t he charge of t he adsor bed i on i s l ess
r eadi l y predi ct ed.
( 2) The magni t ude of t he charge i s t he di f f er ence i n el ect r i cal pot ent i al
bet ween t he char ged surf ace of t he par t i cl e and t he bul k of t he di spersi on
medi um. Thi s magni t ude i s appr oxi mat ed by t he eI ect roki net i c, or zet a,
pot enti aI ( ï) . The zet a pot ent i al i s measur ed f r om t he f i xed, avi dl y bound
l ayer s of i ons and sol vent mol ecul es on t he par t i cl e sur f ace. When c i s hi gh
( e. g. , < 25 mV) , i nt er par t i cul at e repuI si ve f orces exceed t he at t ract i ve
f or ces. As a resul t , t he di sper si on i s def I occuI ated and rel at i vel y st abl e t o
col l i si on and subsequent aggregat i on ( fI occuI at i on) . When c i s so l ow t hat
i nt er part i cul at e at t ract i ve f orces pr edomi nat e, l oose part i cl e aggr egat es,
or f I ocs, f orm (i . e. , f I occuI ati on occurs) .
d. Densi t y can be mani pul at ed t o decr ease t he rat e of di spersi on
i nst abi l i t y. The set t l i ng
P. 42

r at e decr eases as ( p1 - p2) appr oaches zer o. However , t he densi t y of t he
di spersi on medi um usual l y cannot be al t ered suf f i ci ent l y t o hal t t he set t l i ng
( or f l ot at i on) pr ocess. Ì n t he di spersed phase, t he densi t y of sol i d par t i cl es
i s not r eadi l y al t er ed; al t er i ng t he densi t y of l i qui d part i cl es woul d r equi r e
t he addi t i on of a mi sci bl e l i qui d of hi gher (or l ower ) densi t y. Al t eri ng t he
composi t i on of suspensi ons i s al so probl emat i c because most sol i d
par t i cl es are denser t han t he di sper si on medi um. Addi t i ves of hi gher ( or
l ower ) densi t y mi ght al t er t he bi opharmaceut i cal charact eri st i cs of t he
f or mul at i on (e. g. , r at e of dr ug r el ease, r esi dence t i me at t he si t e of
admi ni st rat i on, or absorpt i on) .
e. The sedi mentat i on, or f I ot at i on, rate i s i nversel y pr opor t i onal t o t he
vi scosi t y. An i ncrease i n t he vi scosi t y of t he di spersi on medi um
decreases t he rat e of set t l i ng, or f l ot at i on. However , al t hough t he rat e of
dest abi l i zat i on can be sl owed by an i ncr ease i n vi scosi t y, i t cannot be
hal t ed.
3. EmuI si on st abi I i t y. CoaI escence occur s i n emul si on syst ems when t he
l i qui d part i cl es of t he di sper sed phase mer ge t o f or m l arger par t i cl es.
Coal escence i s l ar gel y pr event ed by t he i nt erfaci aI f i I m of sur f act ant
ar ound t he dr opl et s. Thi s f i l m prevent s di r ect cont act of t he l i qui d phase of
t he dr opl et s. Coal escence of dr opl et s i n oi l i n wat er ( o/ w) emul si ons i s al so
i nhi bi t ed by t he eI ect rost at i c repuI si on of si mi l ar l y char ged par t i cl es.
Creami ng i s t he reversi bI e separ at i on of a l ayer of emul si f i ed part i cl es.
Because mi xi ng or shaki ng may be suf f i ci ent t o reconst i t ut e t he emul si on
syst em, cr eami ng i s not necessari l y unaccept abl e. However , cracki ng, or
i rreversi bI e phase separat i on, i s never accept abl e. Phase i nversi on, or
emul si on- t ype r eversal , i nvol ves t he r eversi on of an emul si on f r om an o/ w
t o a wat er i n oi l ( w/ o) f orm, or vi ce versa. Phase i nver si on can change t he
consi st ency or t ext ur e of t he emul si on or cause f ur t her det eri orat i on i n i t s
st abi l i t y.
V. CHEMICAL KINETICS AND DRUG STABILITY
A. I nt roduct i on. The stabi I i t y of t he act i ve component of a dr ug i s a
maj or cr i t er i on i n t he r at i onal desi gn and eval uat i on of drug dosage f or ms.
Pr obl ems wi t h st abi I i t y can det ermi ne whet her a gi ven f ormul at i on i s
accept ed or rej ect ed.
1. Ext ensi ve chemi cal degr adat i on of t he act i ve i ngr edi ent can cause
substant i aI I oss of act i ve i ngr edi ent f r om t he dosage f or m.
2. Chemi cal degradat i on can produce a toxi c product t hat has undesi r abl e
si de ef f ect s.
3. Ì nst abi l i t y of t he dr ug pr oduct can cause decreased bi oavai I abi I i t y. As a
r esul t , t he t her apeut i c ef f i cacy of t he dosage f orm may be subst ant i al l y
r educed.
B. Rat es and orders of react i ons
1. The rate of a reacti on, or degr adat i on r at e, i s t he vel oci t y wi t h whi ch t he
r eact i on occurs. Thi s r at e i s expr essed as dC/ dt ( t he change i n
concent r at i on, or C, wi t hi n a gi ven t i me i nt er val , or dt ).
a. React i on r at es depend on cer t ai n condi t i ons (e. g. , react ant
concent rati on, t emperat ure, pH, presence of soI vent s or addi t i ves).
Radi at i on and cat al yt i c agent s (e. g. , pol yval ent cat i ons) al so have an
ef f ect .
b. The ef f ect i ve st udy of r eact i on rat es i n t he body r equi r es appl i cat i on of
pharmacoki net i c pri nci pI es ( see Chapt er 6) .
2. The order of a reacti on i s t he way i n whi ch t he concent r at i on of t he drug
or r eact ant i n a chemi cal r eact i on af f ect s t he r at e. The r at e of a r eact i on,
dC/ dt , i s propor t i onal t o t he concent rat i on t o t he nt h power , wher e n i s t he
or der of t he r eact i on÷t hat i s,

The st udy of r eact i on order s i s a cruci al aspect of pharmacoki net i cs ( see
Chapt er 6). Usual l y, pharmaceut i caI degradat i on can be t reat ed as a
zero- order, fi rst - order, or hi gher- order react i on. The f i r st t wo ar e
summar i zed as f ol l ows.
a. Ì n a zero- order react i on, t he rat e i s i ndependent of t he concent rat i on
of t he react ants (i . e. , dC/ dt C
0
) (see Chapt er 6) . Ot her f act ors, such as
absor pt i on of l i ght i n cert ai n phot ochemi cal react i ons, det er mi ne t he r at e.
P. 43



Figure 3-6. Concentration (C) versus time (t) Ior
a zero-order reaction. The slope oI the line equals
-k
0
. The slope oI the line is not equal to the rate
constant because it includes the minus sign.
( 1) A zero-order reacti on can be expr essed as:
C = - k0t + C0
wher e C i s t he drug concent r at i on, k0 i s t he zer o-or der r at e const ant i n
uni t s of concent r at i on/ t i me, t i s t he t i me, and C0 i s t he i ni t i al concent r at i on.
( 2) When t hi s equat i on i s pl ot t ed wi t h C on t he ver t i cal axi s ( or di nat e)
agai nst t on t he hori zont al axi s (absci ssa), t he sI ope of t he I i ne i s equaI
t o - k0 ( Fi gure 3-6) . The negat i ve si gn i ndi cat es t hat t he sl ope i s
decreasi ng.
b. Ì n a fi rst - order react i on, t he rat e depends on t he fi rst power of t he
concent rati on of a si ngI e react ant ( i . e. , dC/ dt C
1
) .
( 1) Ì n a f i rst - order r eact i on, drug concent rat i on decreases exponenti aI I y
wi t h t i me, i n accordance wi t h t he equat i on
C = C0e
- k
1
t

wher e C i s t he concent r at i on of t he r eact i ng mat er i al , C0 i s t he i ni t i al
concent r at i on, k1 i s t he f i r st -or der r at e const ant i n uni t s of r eci pr ocal t i me,
and t i s t i me. A pl ot of t he l ogari t hm of concent r at i on agai nst t i me pr oduces
a st r ai ght l i ne wi t h a sl ope of -k/ 2. 303 ( Fi gure 3-7) .
( 2) The haI f - I i f e (t 1/ 2) of a r eact i on i s t he t i me requi red f or t he
concent r at i on of a dr ug t o decr ease by one hal f . For a f i rst -or der r eact i on,
hal f - l i f e i s expr essed by:

( 3) The t i me requi red for a drug t o degrade t o 90% of i t s or i gi nal
concent r at i on ( t 90%) i s al so i mpor t ant . Thi s t i me repr esent s a reasonabl e
l i mi t of degradat i on f or t he act i ve i ngr edi ent s. The t 90% can be cal cul at ed
as:

( a) Because
k1 = 0. 693 / t ½
( b) Then

P. 44



Figure 3-7. Logarithm oI concentration (log C)
versus time (t) Ior a Iirst-order reaction. The slope
oI the line equals -k/2.303.
( 4) Bot h t ½ and t 90% are concent rati on i ndependent . Thus, f or t ½, i t t akes
t he same amount of t i me t o reduce t he concent r at i on of t he drug f r om 100
mM t o 50 mM as i t does f r om 50 mM t o 25 mM.
C. Fact ors that af f ect react i on rat es. Fact or s ot her t han concent r at i on can
af f ect t he r eact i on r at e and st abi l i t y of a dr ug. These f act ors i ncl ude
t emper at ure, t he pr esence of a sol vent , pH, and t he pr esence of addi t i ves.
1. Temperat ure. An i ncrease i n t emperature causes an i ncr ease i n
r eact i on rat e, as expr essed i n t he equat i on f i rst suggest ed by Ar r heni us:
k = Ae
- Ea/ RT

or

wher e k i s t he speci f i c react i on r at e const ant , A i s a const ant known as t he
f r equency f act or , Ea i s t he energy of act i vat i on, R i s t he mol ar gas const ant
( 1. 987 cal / degr ee × mol e) , and T i s t he absol ut e t emper at ur e.
a. The constants A and Ea are obt ai ned by det ermi ni ng k at several
t emper at ures and t hen pl ot t i ng l og k agai nst 1/ T. The sl ope of t he r esul t i ng
l i ne equal s - Ea/ (2. 303 × R) . The i nt ercept on t he ver t i cal axi s equal s l og A.
b. The act i vat i on energy ( Ea) i s t he amount of ener gy r equi red t o put t he
mol ecul es i n an act i vated st ate. Mol ecul es must be act i vat ed t o r eact . As
t emperat ure i ncreases, more mol ecul es ar e act i vat ed, and t he react i on
rat e i ncreases.
2. Presence of soI vent . Many dosage f or ms requi r e t he i ncor porat i on of a
wat er - mi sci bl e sol vent ÷f or exampl e, l ow mol ecul ar wei ght al cohol s, such
as t he pol yet hyl ene gl ycol s ( PEGs) ÷t o st abi l i ze t he dr ug.
a. A change i n t he sol vent syst em aI t ers t he t ransi t i on st at e and t he
act i vi t y coef f i ci ents of t he react ant mol ecul es. Ì t can al so cause
si mul t aneous changes i n physi cochemi cal paramet ers, such as pKa, sur f ace
t ensi on, and vi scosi t y. These changes i ndi rect I y af f ect t he react i on rate.
b. Ì n some cases, addi t i onaI reacti on pathways ar e gener at ed. For
exampl e, wi t h an i ncreasi ng concent rat i on of et hanol i n an aqueous
sol ut i on, aspi ri n degr ades by an ext r a r out e and f or ms t he et hyl est er of
acet yl sal i cyl i c aci d. However , a change i n soI vent can aI so st abi I i ze the
drug.
P. 45


3. Change i n pH. The magni t ude of t he rat e of a hydr ol yt i c react i on
cat al yzed by H
+
and OH
-
can var y consi der abl y wi t h pH.
a. H
+
cat aI ysi s pr edomi nat es at I ower pH, whereas OH
-
cat aI ysi s operat es
at hi gher pH. At i ntermedi ate pH, t he r at e may be pH i ndependent or may
be cat al yzed by bot h H
+
and OH
-
. Rat e const ant s i n t he i nt ermedi at e pH
r ange are t ypi cal l y l ess t han t hose at hi gher or l ower pH.
b. To det ermi ne t he ef f ect of pH on degradati on ki net i cs, decomposi t i on
i s measur ed at several H
+
concent r at i ons. The pH of opti mum st abi I i t y can
be det ermi ned by pl ot t i ng t he l ogari t hm of t he r at e const ant (k) as a
f unct i on of pH ( Fi gure 3-8) . The poi nt of i nf I ect i on of t he pl ot i s t he pH of
opt i mum st abi l i t y. Thi s val ue i s usef ul i n t he devel opment of a st abl e dr ug
f or mul at i on.
4. Presence of addi t i ves
a. Buf fer saI t s must be added t o many dr ug sol ut i ons t o mai nt ai n t he
f or mul at i on at opt i mum pH. These sal t s can af f ect t he rat e of degradat i on,
pr i mar i l y as a r esul t of sal t i ncr easi ng t he i oni c st r engt h.
( 1) Ì ncr easi ng sal t concent r at i ons, part i cul ar l y f rom pol yel ect r ol yt es ( e. g. ,
ci t rat e, phosphat e), can substant i aI I y af f ect t he magni t ude of pKa. Ì n t hi s
way, t hey change t he rat e const ant .
( 2) Buf f er sal t s can al so promote drug degradat i on t hrough gener al aci d
or base cat al ysi s.
b. The addi t i on of surf act ants may accel erat e or decel er at e dr ug
degradat i on.
( 1) AcceI erat i on of degradat i on i s common and i s caused by mi cel l ar
cat al ysi s.
( 2) St abi I i zati on of a drug t hrough t he addi t i on of a sur f act ant i s l ess
common.
c. CompI exi ng agents can i mprove dr ug st abi l i t y. Ar omat i c est ers ( e. g. ,
benzocai ne, pr ocai ne, t et r acai ne) i ncrease i n haI f - I i f e i n t he presence of
caf f ei ne. Thi s i ncr eased st abi l i t y appear s t o r esul t f r om t he f ormat i on of a
l ess react i ve compl ex bet ween t he aromat i c est er and t he caf f ei ne.
D. Modes of pharmaceut i caI degradati on. The decomposi t i on of act i ve
i ngredi ent s i n a dosage f or m occurs t hr ough sever al pat hways (e. g. ,
hydr ol ysi s, oxi dat i on, phot ol ysi s; see Chapt er 12, Ì Ì . A) .
1. HydroI ysi s i s t he most common t ype of degradat i on because many
medi ci nal compounds are est ers, ami des, or l act ams.
a. H
+
and OH
-
ar e t he most common cat al yst s of hydr ol yt i c degradat i on i n
sol ut i on.
b. Esters usual l y under go hydr ol yt i c r eact i ons t hat cause dr ug i nst abi l i t y.
Because est er s ar e r api dl y degr aded i n aqueous sol ut i on, f or mul at ors are
r el uct ant t o i ncor por at e dr ugs t hat have est er f unct i onal gr oups i nt o l i qui d
dosage f orms.

Figure 3-8. Semilogarithmic plot oI the rate
constant (k) versus pH. This plot is used to
determine the pH oI optimum stability.
P. 46


2. Oxi dat i on i s usual l y medi at ed t hr ough r eact i on wi t h at mospheri c oxygen
under ambi ent condi t i ons ( aut o-oxi dat i on) .
a. Medi ci nal compounds t hat under go aut o-oxi dat i on at room t emper at ur e
ar e af f ect ed by oxygen di ssoI ved i n t he soI vent and i n t he head space of
t hei r packages. These compounds shoul d be packed i n an i nert
at mosphere ( e. g. , ni t r ogen) t o excl ude ai r f r om t hei r cont ai ner s.
b. Most oxi dat i on r eact i ons i nvol ve a f ree radi caI mechani sm and a chai n
react i on. Fr ee r adi cal s t end t o t ake el ect r ons f r om ot her compounds.
( 1) Ant i oxi dants i n t he f or mul at i on r eact wi t h t he f r ee r adi cal s by pr ovi di ng
el ect r ons and easi l y avai l abl e hydr ogen at oms. Ì n t hi s way, t hey pr event t he
pr opagat i on of chai n react i ons.
( 2) CommonI y used anti oxi dant s i ncl ude ascorbi c aci d, but yl at ed
hydr oxyani sol e ( BHA), but yl at ed hydr oxyt ol uene ( BHT) , pr opyl gal l at e,
sodi um bi sul f i t e, sodi um sul f i t e, and t he t ocopherol s.
3. Phot oI ysi s i s t he degr adat i on of drug mol ecul es by normal sunl i ght or
r oom l i ght .
a. Mol ecul es may absor b t he pr oper wavel engt h of l i ght and acqui re
suf f i ci ent energy t o undergo reacti on. Usual l y, phot ol yt i c degr adat i on
occurs on exposur e t o l i ght of wavel engt hs < 400 nm.
b. An amber gI ass bott I e or an opaque contai ner act s as a bar ri er t o t hi s
l i ght , t hereby prevent i ng or r et ardi ng phot ol ysi s. For exampl e, sodi um
ni t ropr ussi de i n aqueous sol ut i on has a shel f l i f e of onl y 4 hr i f exposed t o
nor mal r oom l i ght . When pr ot ect ed f r om l i ght , t he sol ut i on i s st abl e f or at
l east 1 year.
E. Det ermi nat i on of sheI f I i fe. The shel f l i f e of a dr ug preparat i on i s t he
amount of t i me t hat t he pr oduct can be st ored bef or e i t becomes unf i t f or
use, t hr ough ei t her chemi cal decomposi t i on or physi cal det er i or at i on.
1. St orage t emperature af f ect s shel f l i f e. Ì t i s gener al l y underst ood t o be
ambi ent t emper at ur e unl ess speci al st orage condi t i ons ar e speci f i ed.
2. I n generaI , a preparat i on i s consi dered f i t f or use i f i t vari es f rom the
nomi naI concent rat i on or dose by no more t han 10%, pr ovi ded t hat t he
decomposi t i on product s ar e not more t oxi c or harmf ul t han t he ori gi nal
mat er i al .
3. SheI f - I i f e test i ng ai ds i n det ermi ni ng t he st andar d shel f l i f e of a
f or mul at i on. a. Sampl es ar e st ored at 3- 5°C and at r oom t emper at ur e (20-
25°C) . The sampl es ar e t hen anal yzed at vari ous i nt er val s t o det ermi ne t he
rat e of decomposi t i on. Shel f l i f e i s cal cul at ed f rom t hi s rat e.
b. Because st or age t i me at t hese t emperat ures can r esul t i n an ext ended
t est i ng t i me, acceI erated t esti ng i s conduct ed as wel l , wi t h a range of
hi gher t emperat ures. The rat e const ant s obt ai ned f rom t hese sampl es ar e
used t o predi ct shel f l i f e at ambi ent or r ef ri ger at i on t emper at ur es.
Temperat ure- acceI erat ed st abi I i t y t est i ng i s not usef ul i f t emper at ur e
changes ar e accompani ed by changes i n t he react i on mechani sm or by
physi cal changes i n t he syst em (e. g. , change f r om t he sol i d t o t he l i qui d
phase) .
c. Stabi I i t y at room temperat ure can be pr edi ct ed f rom accel erat ed t est i ng
dat a by t he Ar rheni us equat i on:

wher e kT2 and kT1 are t he r at e const ant s at t he absol ut e t emper at ur es T2
and T1, respect i vel y; R i s t he mol ar gas const ant ; and Ea i s t he energy of
act i vat i on.
d. Al t er nat i vel y, an expr essi on of concent r at i on can be pl ot t ed as a l i near
f unct i on of t i me. Rat e const ant s (k) f or degradat i on at sever al t emper at ures
ar e obt ai ned. The l ogari t hm of t he rat e const ant (l og k) i s pl ot t ed agai nst
t he reci procal of absol ut e t emper at ur e (1/ T) t o obt ai n, by ext r apol at i on, t he
r at e const ant f or degr adat i on at r oom t emper at ure ( Fi gure 3-9) .
e. The I ength of t i me t hat t he drug wi I I mai nt ai n i t s requi red pot ency
can al so be pr edi ct ed by cal cul at i on of t he t 90% ( see V. B. 2. b. ( 3) ). Thi s
met hod appl i es t o chemi cal r eact i ons wi t h act i vat i on ener gi es of 10-30
kcal / mol , t he magni t ude of t he act i vat i on energy f or many pharmaceut i cal
degradat i ons t hat occur i n sol ut i on.
P. 47



Figure 3-9. Semilogarithmic plot oI the rate
constant (k) versus the reciprocal oI absolute
temperature (1/T). showing the temperature
dependency oI degradation rates.
VI. DRUG DOSAGE FORMS AND DELIVERY
SYSTEMS
A. OraI soI ut i ons. The Uni t ed St at es Pharmacopei a ( USP) 31/ Nat i onal
Formul ary ( NF) 26 cat egor i zes oraI soI uti ons as " l i qui d pr eparat i ons,
i nt ended f or or al admi ni st r at i on, t hat cont ai n one or mor e subst ances wi t h
or wi t hout f l avor i ng, sweet eni ng, or col or i ng agent s di ssol ved i n wat er or
cosol vent - wat er mi xt ur es. ¨ Or al sol ut i ons can cont ai n cer t ai n pol yol s ( e. g. ,
sor bi t ol , gl ycer i n) t o i nhi bi t cr yst al l i zat i on and t o modi f y sol ubi l i t y, t ast e,
mout h f eel , and ot her vehi cl e pr oper t i es. They can be " f ormul at ed f or di rect
or al admi ni st r at i on t o t he pat i ent or t hey may be di spensed i n a mor e
concent r at ed f orm t hat must be di l ut ed pri or t o admi ni st rat i on. ¨ Drugs i n
soI ut i on ar e more homogeneous and easi er t o swal l ow t han dr ugs i n sol i d
f or m. For drugs t hat have a sl ow di ssol ut i on r at e, onset of act i on and
bi oavai l abi l i t y ar e al so i mpr oved. However , dr ugs i n sol ut i on ar e bul ki er
dosage f orms, degrade mor e r api dl y, and ar e mor e l i kel y t o i nt eract wi t h
const i t uent s t han t hose i n sol i d f or m.
1. Wat er i s t he most commonI y used vehi cI e f or dr ug sol ut i ons. The USP
r ecogni zes seven t ypes of wat er f or t he pr epar at i on of dosage f orms:
a. Puri fi ed wat er USP i s wat er obt ai ned by di st i l l at i on, i on exchange,
r ever se osmosi s, or ot her sui t abl e t r eat ment . Ì t cannot cont ai n mor e t han
10 par t s per mi l l i on (ppm) of t ot al sol i d and shoul d have a pH bet ween 5
and 7. Pur i f i ed wat er i s used i n prescr i pt i ons and f i ni shed manuf act ur ed
pr oduct s except par ent eral and opht hal mi c product s.
b. Wat er f or i nj ect i on USP i s wat er obt ai ned by di st i l l at i on or by r everse
osmosi s. Ì t conf or ms t o t he st andards of puri f i ed wat er but i s al so f r ee of
pyr ogen. Wat er f or i nj ect i on i s used as a sol vent f or t he pr epar at i on of
par ent eral sol ut i ons.
c. Steri I e wat er for i nj ect i on USP i s wat er f or i nj ect i on t hat i s st er i l i zed
and packaged i n si ngl e-dose cont ai ners of t ype Ì and Ì Ì gl ass. These
cont ai ners do not exceed a capaci t y of 1 L. The l i mi t at i ons f or t ot al sol i ds
depend on t he si ze of t he cont ai ner .
d. Bact eri ost at i c water f or i nj ect i on USP i s st eri l e wat er f or i nj ect i on t hat
cont ai ns one or mor e sui t abl e ant i mi cr obi al agent s. Ì t i s al so packaged i n
si ngl e- or mul t i pl e- dose cont ai ners of t ype Ì or Ì Ì gl ass. These cont ai ners do
not exceed t he capaci t y of 30 mL.
e. St eri I e wat er f or i nhaI at i on USP i s wat er t hat i s puri f i ed by di st i l l at i on
or by r everse osmosi s (i . e. , wat er f or i nj ect i on) and r ender ed st er i l e. Ì t
cont ai ns no ant i mi cr obi al agent s, except when used i n humi di f i er s or si mi l ar
devi ces. Thi s t ype of wat er shoul d not be used f or parent er al admi ni st rat i on
or f or ot her st er i l e dosage f orms.
f . St eri I e water f or i rri gat i on USP i s wat er f or i nj ect i on t hat i s st er i l i zed
and sui t abl y packaged. Ì t cont ai ns no ant i mi cr obi al agent s or ot her added
subst ance.
P. 48


g. St eri I e puri f i ed water USP i s puri f i ed wat er st er i l i zed and sui t abl y
packaged. Ì t cont ai ns no ant i mi crobi al agent . Ì t i s not i nt ended f or use i n
par ent eral s.
2. OraI drug soI ut i ons i ncl ude syrups and eI i xi rs as wel l as ot her l ess
wi del y pr escri bed cl assi c ( gaI eni caI ) f ormul at i ons, such as aromat i c
waters, ti nctures, f I ui dext ract s, and spi ri t s.
a. Syrups ar e t r adi t i onal l y per or al sol ut i ons t hat cont ai n hi gh
concent r at i ons of sucr ose or ot her sugar s. Thr ough common usage, t he
t er m syr up has al so come t o i ncl ude any ot her l i qui d dosage f or m pr epared
i n a sweet , vi scous vehi cl e, i ncl udi ng per or al suspensi ons.
( 1) Syrup NF ( si mpI e syrup) i s a concent r at ed or nearl y sat urat ed aqueous
sol ut i on of sugar (85%; 65% w/ w) .
( 2) Syr ups have a I ow soI vent capaci t y f or water- soI ubI e drugs because
t he hydr ogen bondi ng bet ween sucrose and wat er i s ver y st rong. For t hi s
r eason, i t can be di f f i cul t or i mpossi bl e t o di ssol ve a dr ug i n a syr up. Of t en,
t he dr ug i s best di ssol ved i n a smal l quant i t y of wat er , and t he f l avori ng
syr up i s added.
( 3) The sucrose concent rat i on of syr up pl ays a cr uci al rol e i n t he cont r ol
of mi cr obi al growt h. Di l ut e sucrose sol ut i ons are excel l ent medi a f or
mi cr oor gani sms. As t he concent r at i on of sucrose approaches sat ur at i on, t he
syr up becomes sel f -pr eser vi ng ( i . e. , requi r es no addi t i onal preser vat i ve) .
However , a sat urat ed sol ut i on i s undesi r abl e because t emper at ur e
f l uct uat i ons may cause cr yst al l i zat i on. Syrup NF i s a sel f pr eser ved sol ut i on
wi t h a mi ni mal t endency t o undergo cr yst al l i zat i on.
b. EI i xi rs ar e t r adi t i onal l y per oral sol ut i ons t hat cont ai n al cohol as a
cosol vent . Many peror al sol ut i ons are not descri bed as el i xi r s but cont ai n
al cohol .
( 1) To be consi der ed an el i xi r , t he sol ut i on must cont ai n aI cohoI .
Tr adi t i onal l y, t he al cohol cont ent of el i xi r s has var i ed f r om 5% t o 40%. Most
el i xi r s become t ur bi d when moder at el y di l ut ed by aqueous l i qui ds. El i xi r s
ar e not t he pr ef er red vehi cl e f or sal t s because al cohol accent uat es sal i ne
t ast e. Sal t s al so have l i mi t ed sol ubi l i t y i n al cohol . Ther ef or e, t he al cohol i c
cont ent of sal t -cont ai ni ng el i xi r s must be l ow.
( 2) Aromat i c eI i xi r NF, pr epar ed i n par t f rom syrup, cont ai ns appr oxi mat el y
22% al cohol . The l i mi t ed usef ul ness of t hi s el i xi r as a sol vent f or drugs was
of f set by t he devel opment of i so- aI cohoI i c eI i xi r. Ì t i s a combi nat i on of
I ow-aI cohoI i c eI i xi r, an el i xi r wi t h l ow al cohol i c cont ent ( 8%- 10% al cohol ) ,
and hi gh-aI cohoI i c eI i xi r, an el i xi r wi t h hi gh al cohol i c cont ent (73%- 78%
al cohol ) . Mi xi ng appr opr i at e vol umes of t he t wo el i xi r s provi des an al cohol i c
cont ent suf f i ci ent t o di ssol ve t he dr ugs.
B. Mi sceI I aneous soI ut i ons
1. Aromat i c wat ers are cl ear , sat urat ed aqueous soI ut i ons of voI at i I e
oi I s or ot her aromat i c or vol at i l e subst ances. Ar omat i c wat ers may be used
as pl easant l y f l avor ed vehi cl es f or a wat er - sol ubl e dr ug or as an aqueous
phase i n an emul si on or suspensi on. Ì f a l ar ge amount of wat er -sol ubl e dr ug
i s added t o an ar omat i c wat er , t hen an i nsol ubl e l ayer may f or m at t he t op.
Thi s "saI t i ng out" i s a compet i t i ve pr ocess. The mol ecul es of wat er -sol ubl e
dr ugs have mor e at t r act i on f or t he sol vent mol ecul es of wat er t han t he " oi l ¨
mol ecul es. The associ at ed wat er mol ecul es ar e pul l ed away f r om t he oi l
mol ecul es, whi ch ar e no l onger hel d i n sol ut i on. Ar omat i c wat ers shoul d be
st ored i n t i ght , l i ght - resi st ant bot t l es t o r educe vol at i l i zat i on and
degradat i on f rom sunl i ght . Ar omat i c wat er s ar e usual l y prepar ed by one of
t he f ol l owi ng met hods:
a. Di sti I I at i on i s a uni ver sal met hod but i s not pract i cal or economi cal f or
most pr oduct s. Ì t i s t he onl y met hod, however , f or pr epar i ng st rong r ose
wat er and or ange f l ower wat er .
b. Wi t h t he soI ut i on method, t he vol at i l e, or aromat i c, subst ance i s
admi xed wi t h wat er , wi t h or wi t hout t he use of a di spersant ( e. g. , t al c) .
2. Spi ri t s, or essences, ar e al cohol i c or hydroal cohol i c sol ut i ons of vol at i l e
subst ances, t hat cont ai n 50%-90% al cohol . Thi s hi gh aI cohoI i c content
mai nt ai ns t he wat er -i nsol ubl e vol at i l e oi l s i n sol ut i on. Ì f wat er i s added t o a
spi ri t , t he oi l s separ at e. Some spi ri t s ar e medi ci naI (e. g. , aromat i c
ammoni a spi r i t ) . Many spi r i t s (e. g. , compound orange spi ri t , compound
car damom spi ri t ) ar e used as f l avor i ng agent s. Spi r i t s shoul d be st or ed i n
t i ght cont ai ners t o r educe l oss by evaporat i on.
3. Ti nct ures ar e al cohol i c or hydr oal cohol i c sol ut i ons of chemi cal s or
sol ubl e const i t uent s of veget abl e dr ugs. Al t hough t i nct ur es var y i n dr ug
concent r at i on ( > 50%), t hose prepar ed f r om pot ent drugs are usual l y 10% i n
st r engt h ( i . e. , 100 mL of t he t i nct ur e has t he act i vi t y of 10 g of t he drug).
Ti nct ures ar e usual l y consi dered st abl e. The al cohol cont ent of t he of f i ci al
t i nct ures var i es f r om 17% t o 21% f or opi um t i nct ur e USP and f r om 74% t o
80% f or compound benzoi n t i nct ur e USP. Most t i nct ur es are prepar ed by an
ext ract i on process of
P. 49

macer at i on or per col at i on. The sel ect i on of a soI vent , or menst r uum, i s
based on t he sol ubi l i t y of t he act i ve and i ner t const i t uent s of t he crude
dr ugs. Agi ng can cause pr eci pi t at i on of t he i nact i ve const i t uent s of
t i nct ures. Gl ycer i n may be added t o t he hydroal cohol i c sol vent t o i ncr ease
t he sol ubi l i t y of t he act i ve const i t uent and reduce pr eci pi t at i on on st orage.
Ti nct ures must be t i ght l y st opper ed and kept f rom excessi ve t emper at ur es.
Because many of t hei r const i t uent s under go a phot ochemi cal change when
exposed t o l i ght , t i nct ur es must be st ored i n l i ght -r esi st ant cont ai ner s.
4. FI ui dext ract s ar e l i qui d ext r act s of veget abl e dr ugs t hat cont ai n al cohol
as a sol vent , pr eser vat i ve, or bot h. Fl ui dext r act s ar e pr epar ed by
per col at i on so t hat each mi l l i l i t er cont ai ns t he t her apeut i c const i t uent s of 1
g of t he st andar d drug. Because of t hei r hi gh drug cont ent , f l ui dext r act s ar e
somet i mes ref er r ed t o as " 100% t i nct ures. ¨ Fl ui dext r act s of pot ent drugs ar e
usual l y 10 t i mes as concent r at ed, or pot ent , as t he cor r espondi ng t i nct ur e.
For exampl e, t he usual dose of t i nct ur e bel l adonna i s 0. 6 mL; t he
equi val ent dose of t he mor e pot ent f l ui dext r act i s 0. 06 mL. Many
f l ui dext r act s ar e consi der ed t oo pot ent f or sel f -admi ni st r at i on by pat i ent s,
so t hey are al most never pr escri bed. Ì n addi t i on, many f l ui dext r act s ar e
si mpl y t oo bi t t er . Today, most f l ui dext r act s ar e modi f i ed by ei t her f l avori ng
or sweet eni ng agent s.
5. NasaI , opht haI mi c, ot i c, and parent eraI soI ut i ons ar e cl assi f i ed
separ at el y because of t hei r speci f i c use and met hod of pr epar at i on.
6. Mout hwashes ar e sol ut i ons t hat ar e used t o cl eanse t he mout h or t r eat
di seases of t he oral mucous membr ane. They of t en cont ai n al cohol or
gl yceri n t o ai d i n di ssol vi ng t he vol at i l e i ngr edi ent s. Mout hwashes ar e more
of t en used cosmet i cal l y t han t herapeut i cal l y.
7. Ast ri ngent s ar e l ocal l y appl i ed sol ut i ons t hat pr eci pi t at e pr ot ei n. They
r educe cel l permeabi l i t y wi t hout causi ng i nj ur y. Ast r i ngent s cause
const ri ct i on, wi t h wr i nkl i ng and bl anchi ng of t he ski n. Because ast r i ngent s
reduce secret i ons, t hey can be used as ant i perspi r ant s.
a. AI umi num acetat e and aI umi num subacetat e soI uti ons are used as wet
dr essi ngs i n cont act dermat i t i s. The pr eci pi t at i on i s mi ni mi zed by t he
addi t i on of bor i c aci d.
b. CaI ci um hydroxi de soI ut i on i s a mi l d st r i ngent t hat i s used i n l ot i ons as
a r eact ant and an al kal i zer .
8. Ant i bacteri aI t opi caI soI ut i ons ( e. g. , benzal koni um chl ori de, st r ong
i odi ne, povi donei odi ne) ki l l bact eri a when appl i ed t o t he ski n or mucous
membr ane i n t he pr oper st r engt h and under appropr i at e condi t i ons.
C. Suspensi ons
1. Loti ons, magmas ( i . e. , suspensi ons of f i nel y di vi ded mat er i al i n a smal l
amount of wat er) , and mi xt ures are al l suspensi ons t hat have had of f i ci al
f or mul as f or some t i me (e. g. , cal ami ne l ot i on USP, kaol i n mi xt ur e wi t h
pect i n NF) . Of f i ci al f or mul as are gi ven i n t he USP/ NF.
a. A compI ete f ormuI a and a det ai I ed method of preparat i on ar e
avai l abl e f or some of f i ci al suspensi ons. For ot her s, onl y t he concent rat i on
of t he act i ve i ngredi ent s i s gi ven, and t he manuf act urer has consi der abl e
l at i t ude i n t he f ormul at i on.
b. Some dr ugs ar e packaged i n a dr y f orm t o ci rcumvent t he i nst abi l i t y of
aqueous di spersi ons. Wat er i s added at t he t i me of di spensi ng t o
r econst i t ut e t he suspensi on.
2. Purposes of suspensi on
a. Sust ai ni ng ef fect . For a sust ai ned- r el ease preparat i on, a suspensi on
necessi t at es dr ug di ssol ut i on bef ore absor pt i on.
b. St abi I i t y. Dr ug degradat i on i n suspensi on or sol i d dosage f or ms occur s
much more sl owl y t han degr adat i on i n sol ut i on f or m.
c. Taste. A dr ug wi t h an unpl easant t ast e can be convert ed i nt o an
i nsol ubl e f or m and t hen pr epar ed as a suspensi on.
d. Basi c soI ubi I i t y. When sui t abl e sol vent s ar e not avai l abl e, t he
suspensi on pr ovi des an al t er nat i ve. For exampl e, onl y wat er can be used as
a sol vent f or opht hal mi c pr epar at i ons because of t he possi bi l i t y of corneal
damage. Opht hal mi c suspensi ons provi de an al t er nat i ve t o opht hal mi c
sol ut i ons.
3. Suspendi ng agent s i ncl ude hydrophi l i c col l oi ds, cl ays, and a f ew ot her
agent s. Some ar e al so used as emuI si f yi ng agent s (see VÌ . D. 3) .
a. Hydrophi I i c coI I oi ds ( i . e. , hydrocoI I oi ds) i ncr ease t he vi scosi t y of
wat er by bi ndi ng wat er mol ecul es, t hus l i mi t i ng t hei r mobi l i t y, or f l ui di t y.
Vi scosi t y i s pr opor t i onal t o t he concent r at i on of t he hydrocol l oi d. These
agent s support the growt h of mi croorgani sms and requi r e a pr eser vat i ve.
They ar e most l y ani oni c, wi t h t he except i on of met hyl cel l ul ose
P. 50

( neut r al ) and chi t osan ( cat i oni c) . Thus t he ani oni c hydrocol l oi ds ar e
i ncompat i bl e wi t h quat ernar y ant i bact eri al agent s and ot her posi t i vel y
charged drugs. Chi t osan i s i ncompat i bl e wi t h negat i vel y char ged drugs and
exci pi ent s. Most hydrocol l oi ds are i nsoI ubI e i n aI cohoI i c soI ut i ons.
( 1) Acaci a i s usual l y used as a 35% di spersi on i n wat er ( muci l age) . Ì t s
vi scosi t y i s great est bet ween pH 5 and pH 9. Acaci a i s suscept i bl e t o
mi cr obi al decomposi t i on.
( 2) Tragacant h i s usual l y used as a 6% di sper si on i n wat er (muci l age) . One
advant age of t r agacant h over acaci a i s t hat l ess i s needed. Al so,
t r agacant h does not cont ai n t he oxi dase t hat i s present i n acaci a. Thi s
oxi dase cat al yzes t he decomposi t i on of organi c chemi cal s. The vi scosi t y of
t r agacant h i s great est at pH 5.
( 3) Met hyI ceI I uI ose i s a pol ymer t hat i s noni oni c and st abl e t o heat and
l i ght . Ì t i s avai l abl e i n sever al vi scosi t y grades. Because i t i s sol ubl e i n col d
wat er , but not i n hot wat er , di spersi ons are prepar ed by addi ng met hyl
cel l ul ose t o boi l i ng wat er and t hen cool i ng t he preparat i on unt i l t he mat eri al
di ssol ves.
( 4) Carboxymet hyI ceI I uI ose i s an ani oni c mat er i al t hat i s sol ubl e i n wat er .
Pr ol onged exposur e t o heat causes l oss of vi scosi t y.
b. CI ays ( e. g. , bent oni t e, Veegum) are si l i cat es t hat ar e ani oni c i n aqueous
di spersi ons. They are st rongl y hydr at ed and exhi bi t thi xot ropy ( t he
pr oper t y of f ormi ng a gel - l i ke st r uct ur e on st andi ng and becomi ng f l ui d on
agi t at i on).
( 1) The of f i ci al f orm of bent oni t e i s t he 5% magma.
( 2) Veegum i s hydrat ed t o a gr eat er degr ee t han bent oni t e. Thus i t i s mor e
vi scous at t he same concent r at i on.
c. Ot her agent s i ncl ude agar , chondr us (car rageenan) , gel at i n, pect i n, and
gel at i ni zed st ar ch. Thei r use i s l i mi t ed by t hei r suscept i bi l i t y t o bact eri al
at t ack, t hei r i ncompat i bi l i t i es, and t hei r cost . Xant han gum i s used i n many
moder n suspensi on f or mul at i ons because of i t s cosol vent compat i bi l i t y, i t s
st abi l i t y, and i t s sol ut i on' s hi gh vi scosi t y r el at i ve t o concent r at i on.
4. Preparat i on
a. SoI i ds are wet t ed i ni t i aI I y t o separat e i ndi vi dual par t i cl es and coat t hem
wi t h a l ayer of di spersi on medi um. Wet t i ng i s accompl i shed by I evi gat i on
( i . e. , addi t i on of a sui t abl e nonsol vent , or I evi gati ng agent, t o t he sol i d
mat er i al , f ol l owed by bl endi ng t o f or m a past e) , usi ng a gl ass mor t ar and
pest l e or an oi nt ment sl ab. A surf act ant can al so be used.
b. Suspendi ng agent s ar e t hen added as dr y powder al ong wi t h t he act i ve
i ngredi ent . For best r esul t s, t he suspendi ng agent i s added i n t he f or m of
i t s aqueous di spersi on.
( 1) The aqueous di spersi on i s added t o t he sol i d (or t he l evi gat ed sol i d) by
geomet ri c di I ut i on.
( 2) The pr epar at i on i s brought t o t he desi r ed vol ume by st i r r i ng i n t he
appropr i at e vehi cl e.
D. EmuI si ons
1. Purposes of emuI si ons
a. I ncreased drug soI ubi I i t y. Many dr ugs have l i mi t ed aqueous sol ubi l i t y
but have maxi mum sol ubi l i t y i n t he oi l phase of an emul si on. Dr ug
par t i t i oni ng f r om t he oi l phase t o t he wat er phase can mai nt ai n or enhance
act i vi t y.
b. I ncreased drug st abi I i t y. Many dr ugs ar e more st abl e when
i ncor por at ed i nt o an emul si on r at her t han an aqueous sol ut i on.
c. ProI onged drug act i on. Ì ncorporat i on of a drug i nt o an emul si on can
pr ol ong bi oavai l abi l i t y, as wi t h cer t ai n i nt r amuscul ar i nj ect i on prepar at i ons.
d. I mproved tast e. Dr ugs wi t h an unpl easant t ast e ar e mor e pal at abl e and
t hus mor e conveni ent l y admi ni st er ed i n emul si on f orm.
e. I mproved appearance. Oi l y mat er i al s i nt ended f or t opi cal appl i cat i on ar e
mor e appeal i ng i n an emul si f i ed f orm.
2. Phases of emuI si ons. Most emul si ons are consi dered two-phase
syst ems.
a. The I i qui d dropI et i s known as t he di spersed, i nt ernaI , or
di scont i nuous phase. The ot her l i qui d i s known as t he di spersi on
medi um, externaI phase, or cont i nuous phase.
b. Ì n phar maceut i cal appl i cat i ons, one phase i s usual l y an aqueous
soI ut i on. The ot her phase i s usual l y I i pi d or oi I y. The l i pi ds r ange f r om
veget abl e or hydr ocarbon oi l s t o semi sol i d hydrocar bons and waxes.
Emul si ons are usual l y descr i bed i n t erms of wat er and oi l . Oi l i s t he l i pi d, or
nonaqueous, phase, r egar dl ess of i t s composi t i on.
P. 51


( 1) Ì f wat er i s t he i nt ernaI phase, t he emul si on i s cl assi f i ed as w/ o.
( 2) Ì f wat er i s t he ext ernaI phase, t he emul si on i s cl assi f i ed as o/ w.
c. The t ype of emuI si on f ormed i s pri mar i l y det er mi ned by t he reI at i ve
phase voI umes and t he emuI si f yi ng agent used.
( 1) For an i deal emul si on, t he maxi mum concent r at i on of i nt ernal phase i s
74% (i . e. , t heor et i cal l y, an o/ w emul si on can be pr epar ed cont ai ni ng > 74%
oi l ).
( 2) The choi ce of an emul si f yi ng agent i s more i mport ant t han t he r el at i ve
phase vol umes i n det ermi ni ng t he f i nal emul si on t ype. Most agent s
pr ef er ent i al l y f or m one t ype of emul si on or t he ot her i f t he phase vol ume
per mi t s.
3. EmuI si f yi ng agents. Any compound t hat l ower s t he i nt er f aci al t ensi on
and f orms a f i l m at t he i nt er f ace can pot ent i al l y f unct i on as an emul si f yi ng
agent . The ef f ect i veness of t he emul si f yi ng agent depends on i t s chemi cal
st r uct ur e, concent rat i on, sol ubi l i t y, pH, physi cal pr oper t i es, and
el ect r ost at i c ef f ect . True emuI si f yi ng agent s ( pri mar y agent s) can f or m
and st abi l i ze emul si ons by t hemsel ves. Stabi I i zers ( auxi l i ar y agent s) do not
f or m accept abl e emul si ons when used al one, but assi st pr i mar y agent s i n
st abi l i zi ng t he product ( e. g. , i ncr ease vi scosi t y) . Emul si f yi ng agent s ar e
ei t her nat uraI or synt het i c.
a. NaturaI emuI si f yi ng agents:
( 1) Acaci a f orms a good, st abl e emul si on of l ow vi scosi t y. Ì t t ends t o cream
easi l y, i s aci di c, and i s st abl e at a pH r ange of 2-10. Li ke ot her gums, i t i s
negat i vel y char ged, dehydr at es easi l y, and usual l y r equi r es a preser vat i ve.
Ì t i s i ncompat i bl e wi t h Per uvi an bal sam, bi smut h sal t s, and carbonat es.
( 2) Tragacant h f orms a st abl e emul si on t hat i s coar ser t han acaci a
emul si on. Ì t i s ani oni c, i s di f f i cul t t o hydr at e, and i s used mai nl y f or i t s
ef f ect s on vi scosi t y. Less t han of t he amount used f or acaci a i s needed.
( 3) Agar i s an ani oni c gum t hat i s pr i mar i l y used t o i ncr ease vi scosi t y. Ì t s
st abi l i t y i s af f ect ed by heat i ng, dehydr at i on, and dest r uct i on of char ge. Ì t i s
al so suscept i bl e t o mi crobi al degr adat i on.
( 4) Pect i n i s a quasi - emul si f i er t hat i s used i n t he same proport i on as
t r agacant h.
( 5) GeI at i n pr ovi des good emul si on st abi l i zat i on i n a concent r at i on of 0. 5%-
1. 0%. Ì t may be ani oni c or cat i oni c, dependi ng on i t s i soel ect r i c poi nt . Type
A gel at i n ( +) , pr epar ed f rom an aci d- t reat ed pr ecur sor , i s used i n aci di c
medi a. Type B gel at i n ( - ), pr epared f r om an al kal i - t r eat ed pr ecursor, i s used
i n basi c medi a.
( 6) Met hyI ceI I uI ose i s noni oni c and i nduces vi scosi t y. Ì t i s used as a
pr i mar y emul si f i er wi t h mi ner al oi l and cod l i ver oi l , and yi el ds an o/ w
emul si on. Ì t i s usual l y used i n 2% concent r at i on.
( 7) Carboxymet hyI ceI I uI ose i s ani oni c and i s usual l y used t o i ncr ease
vi scosi t y. Ì t t ol er at es al cohol up t o 40%, f orms a basi c sol ut i on, and
pr eci pi t at es i n t he presence of f r ee aci ds.
b. Synt het i c emuI si f yi ng agent s ar e ani oni c, cat i oni c, or noni oni c.
Al t hough t hese sur f act ant s ar e amphi phi l i c mol ecul es, t hei r l i pophi l i c and
hydr ophi l i c r egi ons ar e sel dom i nverse equal s of each ot her: Some
sur f act ant mol ecul es t end t o be pr edomi nant l y l i pophi l i c, whereas ot hers
ar e pr edomi nant l y hydr ophi l i c. Thi s i mbal ance i s r ef l ect ed i n t he
hydr ophi l i c-l i pophi l i c bal ance ( HLB) scal e: The l ar ger t he HLB val ue, t he
mor e hydr ophi l i c t he mol ecul e. Tabl e 3- 1 l i st s HLB val ues f or sur f act ant s
and t hei r cor respondi ng uses.
Table 3-1. Hydrophilic-Lipophilic Balance (HLB)
HLB Value Range Surfactant Application
0-3 AntiIoaming agents
4-6 Water-in-oil emulsiIying agents
7-9 Wetting agents
8-18 Oil-in-water emulsiIying agents
13-15 Detergents
10-18 Solubilizing agents

P. 52


( 1) Ani oni c synt het i c agent s i ncl ude suI f uri c aci d esters (e. g. , sodi um
l aur yl sul f at e) , suI f oni c aci d deri vat i ves ( e. g. , di oct yl sodi um
sul f osucci nat e) , and soaps. Soaps ar e f or ext er nal use. They have a hi gh
pH and are, t heref ore, sensi t i ve t o t he addi t i on of aci ds and el ect rol yt es.
( a) AI kaI i soaps ar e hydr ophi l i c and f orm an o/ w emul si on.
( b) Met aI I i c soaps ar e wat er i nsol ubl e and f orm a w/ o emul si on.
( c) MonovaI ent soaps f or m an o/ w emul si on.
( d) PoI yvaI ent soaps f or m a w/ o emul si on.
( 2) Cat i oni c synt het i c agent s (e. g. , benzal koni um chl or i de) ar e used as
sur f ace- act i ve agent s i n 1% concent r at i on. They ar e i ncompat i bl e wi t h
soaps.
( 3) Noni oni c synt het i c agent s ar e resi st ant t o t he addi t i on of aci ds and
el ect r ol yt es.
( a) The sorbi tan est ers known as Spans ar e hydr ophobi c i n nat ur e and
f or m w/ o emul si ons. They have l ow hydr ophi l i c-l i pophi l i c bal ance val ues (1-
9) ( Tabl e 3-2) .
( b) The poI ysorbat es known as Tweens are hydrophi l i c and t end t o f or m
o/ w emul si ons. They may f or m compl exes wi t h phenol i c compounds. They
have hi gh hydr ophi l i c-l i pophi l i c bal ance val ues (11- 20).
4. Preparat i on. Var i ous met hods ar e used t o prepar e emul si ons, dependi ng
on t he t ype of emul si f yi ng agent .
a. Cl assi cal , acaci a- st abi l i zed emul si ons ar e pr epar ed by one of t he
f ol l owi ng f our met hods:
( 1) Wet gum ( EngI i sh) met hod. A pr i mar y emul si on of f i xed oi l , wat er , and
acaci a ( i n a 4: 2: 1 r at i o) i s prepar ed as f ol l ows:
( a) Two par t s of wat er are added al l at once t o one part of acaci a. The
mi xt ur e i s t r i t ur at ed unt i l a smoot h muci l age i s f or med.
( b) Oi l i s added i n smal l i ncrement s (1- 5 mL) , wi t h cont i nuous t ri t urat i on,
unt i l t he pr i mar y emul si on i s f or med.
( c) The mi xt ur e ( an o/ w emul si on) i s t ri t ur at ed f or anot her 5 mi n.
( d) The o/ w mi xt ur e can t hen be br ought t o vol ume wi t h wat er and mi xed t o
achi eve homogenei t y.
( 2) Dr y gum ( cont i nentaI ) met hod. A pr i mar y emul si on of t he f i xed oi l ,
wat er , and acaci a ( i n a 4: 2: 1 r at i o) i s pr epared as f ol l ows:
Table 3-2. Commonly Used Surfactants and Their Hydrophilic-Lipophilic
Balance (HLB) Values
Agent HLB Value
Sorbitan trioleate (Span 85. Arlacel 85) 1.8
Sorbitan tristearate (Span 65) 2.1
Propylene glycol monostearate (pure) 3.4
Sorbitan sesquioleate (Arlacel C) 3.7
Sorbitan monooleate (Span 80y) 4.3
Sorbitan monostearate (Arlacel 60) 4.7
Sorbitan monopalmitate (Span 40. Arlacel 40) 6.7
Sorbitan monolaurate (Span 20. Arlacel 20) 8.6
Glyceryl monostearate (Aldo 28. Tegin) 5.5
Gelatin 9.8
Triethanolamine oleate (Trolamine) 12.0
Polyoxyethylene alkyl phenol (Igepal CA-630) 12.8
Tragacanth 13.2
Polyoxyethylene sorbitan monolaurate (Tween 21) 13.3
Polyoxyethylene castor oil (Atlas G-1794) 13.3
Polyoxyethylene sorbitan monooleate (Tween 80) 15.0
Polyoxyethylene sorbitan monopalmitate (Tween 40) 15.6
Polyoxyethylene sorbitan monolaurate (Tween 20) 16.7
Polyoxyethylene lauryl ether (Brii 35) 16.9
Sodium oleate 18
Sodium lauryl sulIate 40

P. 53


( a) Oi l i s added t o t he acaci a, and t he mi xt ur e i s t r i t urat ed unt i l t he powder
i s di st r i but ed uni f orml y t hr oughout t he oi l . Wat er i s added al l at once,
f ol l owed by r api d t ri t urat i on t o f orm t he pr i mar y emul si on.
( b) Any r emai ni ng wat er and ot her i ngredi ent s are added t o f i ni sh t he
pr oduct .
( i ) EI ect roI yt es i n hi gh concent rati on t end t o crack an emul si on. They
shoul d be added l ast and i n as di l ut e a f or m as possi bl e.
( i i ) AI cohoI i c soI ut i ons t end t o dehydr at e and preci pi t at e hydr ocol l oi ds.
They shoul d be added i n as di l ut e a concent rat i on as possi bl e.
( 3) Bot t I e met hod ( a vari at i on of t he dr y gum met hod used f or vol at i l e oi l s) .
Oi l i s added t o t he acaci a i n a bot t l e. The r at i o of oi l , wat er , and acaci a
shoul d be 3: 2: 1 or 2: 1: 1. The l ow vi scosi t y of t he vol at i l e oi l requi r es a
hi gher pr opor t i on of acaci a.
( 4) Nascent soap met hod. A soap i s f ormed by mi xi ng r el at i vel y equal
vol umes of an oi l and an aqueous sol ut i on t hat cont ai ns a suf f i ci ent amount
of al kal i . The soap act s as an emul si f yi ng agent .
( a) Thi s met hod i s used t o f orm an o/ w or a w/ o emul si on, dependi ng on t he
soap f or med. For exampl e, ol i ve oi l , whi ch cont ai ns ol ei c aci d, i s mi xed wi t h
l i me wat er duri ng t he prepar at i on of cal ami ne l ot i on t o cal ci um ol eat e, an
emul si f yi ng agent .
( b) A 50: 50 r at i o of oi l t o wat er ensures suf f i ci ent emul si on, pr ovi ded t hat
t he oi l cont ai ns an adequat e amount of f ree f at t y aci d. Ol i ve oi l usual l y
does. Cot t onseed oi l , peanut oi l , and some ot her veget abl e oi l s do not .
( c) The addi t i on of an aci d dest r oys t he emul si f yi ng soap and causes t he
emul si on t o separat e.
b. Emul si ons st abi l i zed by synt het i c emul si f yi ng agent s ar e r eadi l y
pr epar ed by a t wo- phase pr ocedur e:
( 1) Oi l - mi sci bl e i ngr edi ent s and wat er - mi sci bl e i ngr edi ent s ar e separat el y
admi xed, usi ng heat i f necessar y t o ensure l i quef act i on and ease of mi xi ng
of each phase.
( a) Hi gh mel t i ng poi nt oi l - mi sci bl e i ngredi ent s (e. g. , waxes) ar e mel t ed
bef ore l ower mel t i ng poi nt i ngr edi ent s (e. g. , oi l s) ar e added.
( 2) The t wo phases are heat ed t o 70°- 80° and t hen combi ned wi t h st i r ri ng
unt i l t he resul t ant emul si on has cool ed.
( a) Ì n general , heat - l abi l e or vol at i l e i ngr edi ent s shoul d not be i ncor por at ed
i n t he separ at e phases but i n t he resul t ant emul si on af t er i t has cool ed t o
about 40°C. or l ess.
( 3) Fur t her mechani cal pr ocessi ng of t he emul si on by a hand homogeni zer ,
i mmersi on bl ender, or ot her equi pment may be war r ant ed t o i mpr ove t he
homogenei t y and st abi l i t y of t he product .
5. I ncorporat i on of medi ci naI agents. Medi ci nal agent s can be
i ncor por at ed i nt o an emul si on ei t her duri ng or af t er i t s f ormat i on.
a. Addi t i on of a drug duri ng emuI si on f ormat i on. Ì t i s best t o i ncor porat e
a dr ug i nt o a vehi cl e dur i ng emul si on f ormat i on, when i t can be
i ncor por at ed i n mol ecul ar f orm. Sol ubl e drugs shoul d be di ssol ved i n t he
appropr i at e phase ( e. g. , dr ugs t hat ar e sol ubl e i n t he ext er nal phase of t he
emul si on shoul d be added as a sol ut i on t o t he pri mar y emul si on) .
b. Addi t i on of a drug t o a preformed emuI si on can pr esent some
di f f i cul t y, dependi ng on t he t ype of emul si on and t he nat ur e of t he
emul si f i er ( Tabl e 3- 3) .
( 1) Addi t i on of oI eagi nous mat eri aI s t o a w/ o emuI si on present s no
pr obl em because of t he mi sci bi l i t y of t he addi t i ve wi t h t he ext er nal phase.
However , addi ti on of oI eagi nous mat eri aI s to an o/ w emuI si on can be
di f f i cul t af t er emul si on f or mat i on.
( a) Occasi onal l y, a smal l amount of oi l y mat eri al i s added i f excess
emul si f i er was used i n t he ori gi nal f ormat i on.
( b) A smal l amount of an oi l - sol ubl e drug can be added i f i t i s di ssol ved i n a
ver y smal l quant i t y of oi l wi t h geomet r i c di l ut i on t echni ques.
( 2) Addi t i on of water or an aqueous materi aI t o a w/ o emuI si on i s
ext r emel y di f f i cul t , unl ess enough emul si f i er has been i ncor porat ed i nt o t he
emul si on. However , addi t i on of aqueous mat eri aI s to an o/ w emuI si on
usual l y pr esent s no pr obl ems i f t he added mat eri al does not i nt er act wi t h
t he emul si f yi ng agent . Pot ent i al i nt er act i ons shoul d be expect ed wi t h
cat i oni c compounds and sal t s of weak bases.
( 3) Addi t i on of smaI I quant i t i es of aI cohoI i c soI ut i ons t o an o/ w
emuI si on i s possi bl e i f t he sol ut e i s compat i bl e or di sper si bl e i n t he
aqueous phase of t he emul si on. Ì f
P. 54

acaci a or anot her gum i s used as t he emul si f yi ng agent , t he al cohol i c
sol ut i on shoul d be di l ut ed wi t h wat er bef or e i t i s added. Tabl e 3- 3 l i st s
some commer ci al emul si on bases and t hei r general composi t i on.
Table 3-3. Selected Commercial Emulsion Bases: Emulsion Type and Emulsifier
Used
Commercial Base Emulsion Type Emulsifier Type
Allercreme skin lotion o/w Triethanolamine stearate
Almay emulsion base o/w Fatty acid glycol esters
Cetaphil o/w Sodium lauryl sulIate
Dermovan o/w Fatty acid amides
Eucerin w/o Wool wax alcohol
HEB base o/w Sodium lauryl sulIate
Keri lotion o/w Nonionic emulsiIiers
Lubriderm o/w Triethanolamine stearate
Neobase o/w Polyhydric alcohol esters
Neutrogena lotion o/w Triethanolamine lactate
Nivea cream w/o Wool wax alcohols
pHorsix o/w Polyoxyethylene emulsiIiers
Polysorb hydrate w/o Sodium sesquioleate
Velvachol o/w Sodium lauryl sulIate
o/w. oil in water; w/o. water in oil.

( 4) Addi t i on of cr yst aI I i ne drugs to a w/ o emuI si on occurs more easi l y i f
t he dr ugs ar e di ssol ved or di spersed i n a smal l quant i t y of oi l bef or e t hey
ar e added.
E. Oi nt ment s
1. I nt roduct i on. Oi ntment s are semi soI i d preparat i ons i ntended for
ext ernaI use. They ar e easi l y spr ead. Modi f yi ng t he f ormul at i on cont r ol s
t hei r pl ast i c vi scosi t y. Oi nt ment s are t ypi cal l y used as:
a. EmoI I i ent s t o make t he ski n more pl i abl e
b. Prot ect i ve barri ers t o pr event harmf ul subst ances f rom comi ng i n
cont act wi t h t he ski n
c. Vehi cI es i n whi ch t o i ncorporat e medi cat i on
2. Oi ntment bases
a. OI eagi nous bases are anhydr ous and i nsol ubl e i n wat er . They cannot
absor b or cont ai n wat er and ar e not washabl e i n wat er .
( 1) Pet roI at um i s a good base f or oi l -i nsol ubl e i ngr edi ent s. Ì t f orms an
occl usi ve f i l m on t he ski n, absor bs < 5% wat er under normal condi t i ons,
and does not become r anci d. Wax can be i ncor por at ed t o st i f f en t he base.
( 2) Synt het i c est ers are used as const i t uent s of ol eagi nous bases. These
est er s i ncl ude gl ycer yl monost ear at e, i sopr opyl myr i st at e, i sopropyl
pal mi t at e, but yl st ear at e, and but yl pal mi t at e. Long- chai n al cohol s ( e. g. ,
cet yl al cohol , st ear yl al cohol , PEG) can al so be used.
( 3) LanoI i n deri vat i ves ar e of t en used i n t opi cal and cosmet i c
pr epar at i ons. Exampl es ar e l anol i n oi l and hydrogenat ed l anol i n.
b. Absorpt i on bases are anhydr ous and wat er i nsol ubl e. Ther ef or e, t hey
ar e not washabl e i n wat er , al t hough t hey can absor b wat er . These bases
per mi t wat er -sol ubl e medi cament s t o be i ncl uded t hr ough pri or sol ut i on and
upt ake as t he i nt ernal phase.
( 1) WooI fat ( anhydrous l anol i n) cont ai ns a hi gh per cent age of chol est er ol
as wel l as est ers and al cohol t hat cont ai n f at t y aci ds. Ì t absorbs t wi ce i t s
wei ght i n wat er and mel t s bet ween 36°C and 42°C.
( 2) Hydrophi I i c pet roI atum i s a whi t e pet rol at um combi ned wi t h 8%
beeswax, 3% st ear yl al cohol , and 3% chol est er ol . These component s ar e
added t o a w/ o emul si f i er . Pr epar ed f or ms i ncl ude Aquaphor , whi ch uses
wool al cohol t o render whi t e pet r ol at um emul si f i abl e. Aquaphor i s superi or
i n i t s abi l i t y t o absorb wat er .
c. EmuI si on bases may be w/ o emul si ons, whi ch ar e wat er i nsol ubl e and
ar e not washabl e i n wat er . These emul si ons can absor b wat er because of
t hei r aqueous i nt ernal phase. Emul si on bases may al so be o/ w emul si ons,
whi ch are wat er i nsol ubl e but washabl e i n wat er . They can absorb wat er i n
t hei r aqueous ext er nal phase.
P. 55


( 1) Hydrous wooI fat (l anol i n) i s a w/ o emul si on t hat cont ai ns
approxi mat el y 25% wat er . Ì t act s as an emol l i ent and occl usi ve f i l m on t he
ski n, ef f ect i vel y pr event i ng epi dermal wat er l oss.
( 2) CoI d cream i s a w/ o emul si on t hat i s pr epared by mel t i ng whi t e wax,
spermacet i , and expr essed al mond oi l t oget her ; addi ng a hot aqueous
sol ut i on of sodi um bor at e; and st i r r i ng unt i l t he mi xt ur e i s cool .
( a) The use of mi neral oi l r at her t han al mond oi l makes a more st abl e col d
cr eam. However , col d cream pr epared wi t h al mond oi l makes a bet t er
emol l i ent base.
( b) Thi s oi nt ment shoul d be f r eshl y pr epar ed.
( 3) Hydrophi I i c oi ntment i s an o/ w emul si on t hat uses sodi um l aur yl
sul f at e as an emul si f yi ng agent . Ì t absor bs 30%-50% w/ w wi t hout l osi ng i t s
consi st ency. Ì t i s r eadi l y mi sci bl e wi t h wat er and i s removed f r om t he ski n
easi l y.
( 4) Vani shi ng cream i s an o/ w emul si on t hat cont ai ns a l ar ge per cent age of
wat er as wel l as humect ant (e. g. , gl yceri n, propyl ene gl ycol ) t hat ret ar ds
moi st ur e l oss. An excess of st ear i c aci d i n t he f ormul a hel ps f orm a t hi n
f i l m when t he wat er evapor at es.
( 5) Ot her emuI si on bases i ncl ude Der movan, a hypoal l ergeni c, greasel ess
emul si on base, and Uni base, a nongr easy emul si on base t hat absorbs
approxi mat el y 30% of i t s wei ght i n wat er and has a pH cl ose t o t hat of t he
ski n.
d. Wat er- soI ubI e bases may be anhydr ous or may cont ai n some wat er .
They ar e washabl e i n wat er and absor b wat er t o t he poi nt of sol ubi l i t y.
( 1) PEG oi nt ment i s a bl end of wat er -sol ubl e pol yet hyl ene gl ycol s t hat f or m
a semi sol i d base. Thi s base can sol ubi l i ze wat er -sol ubl e dr ugs and some
wat er - i nsol ubl e dr ugs. Ì t i s compat i bl e wi t h a wi de r ange of dr ugs.
( a) Thi s base cont ai ns 40% PEG 3350 and 60% PEG 400. Ì t i s prepared by
t he f usi on met hod (see VÌ . E. 3. b) .
( b) Onl y a smal l amount of l i qui d ( < 5%) can be i ncorporat ed wi t hout l oss of
vi scosi t y. Thi s base can be made st i f f er by i ncr easi ng t he amount of PEG
3350 t o 60%.
( c) Ì f 6% t o 25% of an aqueous sol ut i on i s t o be i ncor por at ed, 5 g of t he 40
g of PEG 3350 can be r epl aced wi t h an equal amount of st ear yl al cohol .
( 2) PropyI ene gI ycoI and propyI ene gI ycoI - et hanoI f or m a cl ear gel when
mi xed wi t h 2% hydroxypr opyl cel l ul ose. Thi s base i s a popul ar der mat ol ogi c
vehi cl e.
3. I ncorporat i on of medi ci naI agents. Medi ci nal subst ances may be
i ncor por at ed i nt o an oi nt ment base by I evi gat i on or by t he fusi on met hod.
Ì nsol ubl e subst ances shoul d be r educed t o t he f i nest possi bl e f orm and
l evi gat ed bef ore i ncor porat i on wi t h a smal l amount of compat i bl e l evi gat i ng
agent or wi t h t he base i t sel f .
a. Levi gat i on. The subst ance i s i ncor por at ed i nt o t he oi nt ment by
l evi gat i on on an oi nt ment sl ab.
( 1) A st ai nl ess-st eel spat ul a wi t h a l ong, br oad, f l exi bl e bl ade shoul d be
used. Ì f t he subst ance may i nt er act wi t h a met al spat ul a ( e. g. , when
i ncor por at i ng i odi ne and mercuri c sal t s) , t hen a har d rubber spat ul a can be
used.
( 2) Ì nsol ubl e subst ances shoul d be powder ed f i nel y i n a mort ar and mi xed
wi t h an equal quant i t y of base unt i l a smoot h, gri t - f r ee mi xt ur e i s obt ai ned.
The r est of t he base i s added i n i ncrement s.
( 3) Levi gat i on of powder s i nt o a smal l por t i on of base i s f aci l i t at ed by t he
use of a mel t ed base or a smal l quant i t y of compat i bl e l evi gat i on ai d ( e. g. ,
mi ner al oi l , gl ycer i n) .
( 4) Wat er -sol ubl e sal t s ar e i ncor porat ed by di ssol vi ng t hem i n t he smal l est
possi bl e amount of wat er and i ncor porat i ng t he aqueous sol ut i on di r ect l y
i nt o a compat i bl e base.
( a) Usual l y, organi c sol vent s ( e. g. , et her , chl orof or m, al cohol ) are not used
t o di ssol ve t he drug because t he dr ug may cr yst al l i ze as t he sol vent
evaporat es.
( b) Sol vent s are used as l evi gat i ng ai ds onl y i f t he sol i d wi l l become a f i ne
powder af t er t he sol vent evaporat es.
b. Fusi on met hod. Thi s met hod i s used when t he base cont ai ns sol i ds t hat
have hi gher mel t i ng poi nt s (e. g. , waxes, cet yl al cohol , gl ycer yl
monost earat e). Thi s met hod i s al so usef ul f or sol i d medi cament s, whi ch ar e
r eadi l y sol ubl e i n t he mel t ed base.
( 1) The oi l phase shoul d be mel t ed separat el y, st ar t i ng wi t h mat er i al s t hat
have t he hi ghest mel t i ng poi nt . Al l ot her oi l - sol ubl e i ngredi ent s ar e added i n
decreasi ng or der of mel t i ng poi nt .
( 2) The i ngredi ent s i n t he wat er phase ar e combi ned and heat ed separ at el y
t o a t emper at ur e t hat i s equal t o or sever al degrees above t hat of t he
mel t ed oi l phase.
P. 56


( 3) The t wo phases are combi ned. Ì f a w/ o syst em i s desi red, t hen t he hot
aqueous phase i s i ncorpor at ed i nt o t he hot oi l phase wi t h agi t at i on. Ì f an
o/ w syst em i s pr ef er r ed, t hen t he hot oi l phase i s i ncor por at ed i nt o t he hot
aqueous phase.
( 4) Vol at i l e mat eri al s ( e. g. , ment hol , camphor , i odi ne, al cohol , per f umes)
ar e added af t er t he mel t ed mi xt ur e cool s t o 40°C or l ess.
F. Supposi t ori es
1. I nt roduct i on. A supposi t or y i s a soI i d or semi soI i d mass i ntended t o
be i nsert ed i nt o a body ori f i ce (i . e. , r ect um, vagi na, uret hr a) . Af t er i t i s
i nser t ed, a supposi t or y ei t her mel t s at body t emper at ur e or di ssol ves ( or
di sperses) i nt o t he aqueous secret i ons of t he body cavi t y.
a. Supposi t ori es are of t en used f or l ocal ef f ect s (e. g. , r el i ef of hemor r hoi ds
or i nf ect i on) .
b. When used rect al l y, supposi t ori es can pr ovi de syst emi c medi cat i on. The
absor pt i on of a dr ug f r om a supposi t or y t hr ough t he rect al mucosa i nt o t he
ci rcul at i on i nvol ves t wo st eps:
( 1) The dr ug i s r el eased f r om a vehi cl e and par t i t i ons/ di f f uses t hr ough t he
mucosa.
( 2) The dr ug i s t r ansport ed t hr ough t he vei ns or l ymph vessel s i nt o
syst emi c f l ui ds or t i ssues. The f i rst - pass ef f ect i s avoi ded because t he
r ect al vei ns " bypass¨ t he l i ver .
c. Rect al supposi t or i es ar e usef ul when or al admi ni st r at i on i s i nappr opr i at e,
as wi t h i nf ant s, debi l i t at ed or comat ose pat i ent s, and pat i ent s who have
nausea, vomi t i ng, or gast r oi nt est i nal di st ur bances. Some drugs can cause
di st ur bances of t he gast roi nt est i nal t r act .
2. Types of supposi t ori es
a. Rect aI supposi t ori es ar e usual l y cyl i ndr i cal and t apered t o a poi nt ,
f or mi ng a bul l et - l i ke shape. As t he rect um cont r act s, a supposi t or y of t hi s
shape moves i nwar d r at her t han out war d. Supposi t ori es f or adul t s wei gh
approxi mat el y 2 g. Supposi t ori es f or i nf ant s and chi l dren ar e smal l er .
b. Vagi naI supposi t ori es ar e oval and t ypi cal l y wei gh appr oxi mat el y 5 g.
Dr ugs admi ni st ered by t hi s r out e ar e i nt ended t o have a l ocal ef f ect , but
syst emi c absor pt i on can occur . Ant i sept i cs, cont racept i ve agent s, and drugs
used t o t reat t r i chomonal , moni l i al , or bact eri al i nf ect i ons ar e of t en
f or mul at ed as vagi nal supposi t or i es.
c. UrethraI supposi t ori es are t ypi cal l y l ong and t aper ed. They are
approxi mat el y 60 mm l ong and 4-5 mm i n di amet er . They ar e admi ni st ered
f or a l ocal ef f ect and ar e most of t en used f or ant i - i nf ect i ve agent s.
Al pr ost adi l , or prost agl andi n E1 (PGE1) , when used t o t reat er ect i l e
dysf unct i on, i s avai l abl e f or uret hr al i nsert i on i n t he f or m of a mi cr opel l et ,
or mi crosupposi t or y, t hat i s onl y 3- 6 mm l ong and 1. 4 mm i n di amet er .
3. Supposi t or y bases
a. Cri t eri a for sati sfactor y supposi t or y bases. Supposi t or y bases shoul d
( 1) Remai n f i r m at r oom t emper at ure t o al l ow i nser t i on. The supposi t or y
shoul d not sof t en < 30°C t o avoi d mel t i ng duri ng st orage.
( 2) Have a nar r ow, or shar p, mel t i ng range
( 3) Yi el d a cl ear mel t j ust bel ow body t emperat ure or di ssol ve rapi dl y i n t he
cavi t y f l ui d
( 4) Be i ner t and compat i bl e wi t h a vari et y of drugs
( 5) Be noni r ri t at i ng and nonsensi t i zi ng
( 6) Have wet t i ng and emul si f yi ng proper t i es
( 7) Have an aci d val ue of < 0. 2, a saponi f i cat i on val ue of 200-245, and an
i odi ne val ue of < 7 i f t he base i s f at t y
b. SeI ecti ng a supposi tor y base. Li pi d- wat er sol ubi l i t y must be consi dered
because of i t s r el at i on t o t he dr ug- r el ease r at e.
( 1) Ì f an oi l - sol ubl e drug i s i ncor por at ed i nt o an oi l y base, t hen t he rat e of
absor pt i on i s somewhat l ess t han t hat achi eved wi t h a wat er -sol ubl e base.
The l i pi d-sol ubl e dr ug t ends t o r emai n di ssol ved i n t he oi l y pool f r om t he
supposi t or y. Ì t i s l ess l i kel y t o escape i nt o t he mucous secret i ons f r om
whi ch i t i s ul t i mat el y absor bed.
( 2) Conver sel y, a wat er -sol ubl e dr ug t ends t o pass more rapi dl y f rom t he oi l
phase t o t he aqueous phase. Ther ef or e, i f r api d onset of act i on i s desi red,
t he wat er -sol ubl e dr ug shoul d be i ncor por at ed i nt o t he oi l y base.
c. Bases t hat meI t i ncl ude cocoa but t er, ot her combi nat i ons of f ats and
waxes, Wi tepsoI bases, and Wecobee bases ( Tabl e 3-4) .
( 1) Cocoa but t er ( t heobr oma oi l ) i s t he most wi del y used supposi t or y base.
Ì t i s f i r m and sol i d up t o a t emper at ur e of 32°C, at whi ch poi nt i t begi ns t o
sof t en. At 34- 35°C, i t mel t s t o pr oduce a t hi n, bl and, oi l y l i qui d.
P. 57


Table 3-4. Composition. Melting Range. and Congealing Range of Selected Bases
That Melt
Base Composition
Melting
Range (°C)
Congealing
Range (°C)
Cocoa butter Mixed triglycerides oI oleic.
palmitic. and stearic acids
34-35 28 or less
Cotmar Partially hydrogenated
cottonseed oil
34-75
Dehydag Hydrogenated Iatty alcohols and
esters

Base I 33-36 32-33
Base 37-39 36-37
II

Base
III
9 ranges 9 ranges
Wecobee R Glycerides oI saturated Iatty
acids C
12
-C
18

33-35 31-32
Wecobee SS Triglycerides derived Irom
coconut oil
40-43 33-35
Witepsol Triglycerides oI saturated Iatty
acids C
12
-C
18
. with varied
portions oI the corresponding
partial glycerides

H-12 32-33 29-32
H-15 33-35 32-34
H-85 42-44 36-38

( a) Cocoa but t er i s a good base f or a rect aI supposi t or y, but i t i s l ess t han
i deal f or a vagi nal or ur et hr al supposi t or y.
( b) A mi xt ur e of t ri gl yceri des, cocoa but t er exhi bi t s pol ymor phi sm.
Dependi ng on t he f usi on t emperat ure, i t can cr yst al l i ze i nt o any one of f our
cr yst al f or ms.
( c) Maj or I i mi t at i ons of cocoa but t er. Because of t he f ol l owi ng l i mi t at i ons,
many combi nat i ons of f at s and waxes ar e used as subst i t ut es ( Tabl e 3- 4):
( i ) An i nabi I i t y t o absorb aqueous soI ut i ons. The addi t i on of noni oni c
sur f act ant s t o t he base amel i orat es t hi s probl em t o some ext ent . However ,
t he resul t ant supposi t ori es have poor st abi l i t y and may t ur n r anci d rapi dl y.
( i i ) The I oweri ng of the meI t i ng poi nt produced by cert ai n drugs (e. g. ,
chl or al hydrat e).
( 2) Wi tepsoI bases cont ai n nat ur al sat ur at ed f at t y aci d chai ns bet ween C12
and C18. Laur i c aci d i s t he maj or component . Al l 12 bases of t hi s seri es ar e
col or l ess and al most odor l ess. The drug- rel ease charact eri st i cs of Wi t epsol
H15 are si mi l ar t o t hose of cocoa but t er .
( a) Unl i ke cocoa but t er, Wi t epsol bases do not exhi bi t pol ymorphi sm when
heat ed and cool ed.
( b) The i nt er val bet ween sof t eni ng and mel t i ng t emperat ur es i s ver y smal l .
Because Wi t epsol bases sol i di f y r api dl y i n t he mol d, l ubr i cat i on of t he mol d
i s not necessar y.
( 3) Wecobee bases are der i ved f rom coconut oi l . Thei r act i on i s si mi l ar t o
t hat of Wi t epsol bases. Ì ncorporat i on of gl ycer yl monost earat e and
pr opyl ene gl ycol monost ear at e makes t hese bases emul si f i abl e.
d. Bases that di ssoI ve i ncl ude PEG pol ymer s wi t h a mol ecul ar wei ght of
400-6000.
( 1) At room t emper at ure, PEG 400 i s a l i qui d, PEG 1000 i s a semi sol i d,
PEG 1500 and 1600 are f ai rl y f i rm semi sol i ds, and PEG 3350 and 6000 are
f i r m wax- l i ke sol i ds.
( 2) These bases ar e wat er sol ubl e, but t he di ssol ut i on process i s ver y sl ow.
Ì n t he rect um and vagi na, wher e t he amount of f l ui d i s ver y smal l , t hey
di ssol ve ver y sl owl y, but t hey sof t en and spr ead.
( 3) PEGs compl ex wi t h sever al dr ugs and af f ect dr ug rel ease and
absor pt i on.
( 4) Mi xt ur es of PEG pol ymers i n var yi ng propor t i ons pr ovi de a base of
di f f er ent proper t i es ( Tabl e 3- 5) .
4. Preparat i on. Supposi t or i es ar e pr epar ed by t he f ol l owi ng t hree met hods:
a. Hand- roI I i ng i nvol ves mol di ng t he supposi t or y wi t h t he f i nger s af t er a
pl ast i c mass i s f or med.
( 1) A f i nel y powder ed drug i s mi xed wi t h t he gr at ed base i n a mor t ar and
pest l e, usi ng l evi gat i on and geomet r i c di l ut i on t echni ques. A smal l quant i t y
of f i xed oi l may be added t o f aci l i t at e pr epar at i on.
P. 58


Table 3-5. Mixtures of Polyethylene Glycol (PEG) Bases Providing Satisfactory
Room Temperature Stability and Dissolution Characteristics
Base Comments Components
Proportion
(º)
1 Provides a good general-purpose. water-
soluble suppository
PEG
6000
50

PEG
1540
30

PEG
400
20
2 Provides a good general-purpose base that
is slightly soIter than base 1 and dissolves
PEG
4000
60

more rapidly PEG
1500
30

PEG
400
10
3 Has a higher melting point than the other
bases. which is usually suIIicient to
compensate Ior the melting-point lowering
eIIect oI such drugs as chloral hydrate and
camphor
PEG
6000
30

PEG
1540
70

( 2) The uni f orml y mi xed semi pl ast i c mass i s kneaded f ur t her , r ol l ed i nt o a
cyl i nder , and di vi ded i nt o t he r equi si t e number of supposi t ori es. Each smal l
cyl i nder i s r ol l ed by hand unt i l a supposi t or y shape i s f ashi oned.
b. Compressi on i s gener al l y used when cocoa but t er i s used as a base.
( 1) A uni f orm mi xt ur e of dr ug and base i s prepared as f or t he hand- r ol l i ng
met hod.
( 2) The mi xt ur e i s pl aced i nt o a supposi t or y compr essi on devi ce. Pressure
i s appl i ed, and t he mi xt ur e i s f or ced i nt o l ubri cat ed compr essi on mol d
cavi t i es. The mol d i s t hen cool ed and t he supposi t ori es ej ect ed.
( 3) Thi s procedure general l y pr oduces a 2-g supposi t or y. However , a l ar ge
vol ume of t he act i ve i ngredi ent s can af f ect t he amount of cocoa but t er
r equi r ed f or an i ndi vi dual f ormul a.
( a) The amount of cocoa but t er needed i s det ermi ned by cal cul at i ng t he
t ot al amount of act i ve i ngr edi ent t o be used, di vi di ng t hi s number by t he
cocoa but t er densi t y f act or ( Tabl e 3-6) , and subt ract i ng t he r esul t i ng
number f r om t he t ot al amount of cocoa but t er r equi red f or t he desi red
number of supposi t or i es.
( b) For exampl e, suppose 12 supposi t ori es, each cont ai ni ng 300 mg aspi ri n,
ar e requi r ed. Each mol d cavi t y has a 2- g capaci t y. For 13 supposi t ori es
( cal cul at ed t o pr ovi de one ext r a) , 3. 9 g aspi r i n ( 13 × 0. 3 g = 3. 9 g) i s
r equi r ed. Thi s number i s di vi ded by t he densi t y f act or of aspi r i n ( 1. 1) ( Tabl e
3- 6) . Thus 3. 9 g of aspi r i n r epl aces 3. 55 g of cocoa but t er . The t ot al
amount of cocoa but t er needed f or 13 supposi t or i es of 2 g each equal s 26
g. The amount of cocoa but t er r equi r ed i s 26 g - 3. 55 g, or 22. 45 g.
c. The fusi on met hod i s t he pr i nci pal way t hat supposi t ori es are made
commer ci al l y. Thi s met hod i s used pr i mari l y f or supposi t ori es t hat cont ai n
cocoa but t er , PEG, and gl yceri ngel at i n
P. 59

bases. Mol ds made of al umi num, br ass, or ni ckel - copper al l oys ar e used
and can make 6- 50 supposi t ori es at one t i me.
Table 3-6. Cocoa Butter Density Factors of Drugs Commonly Used in
Suppositories
Drug
Cocoa Butter
Density Factor Drug
Cocoa Butter
Density Factor
Aloin 1.3 Dimenhydrinate 1.3
Aminophylline 1.1 Diphenhydramine
hydrochloride
1.3
Aminopyrine 1.3 Gallic acid 2.0
Aspirin 1.1 Morphine
hydrochloride
1.6
Barbital sodium 1.2 Pentobarbital 1.2
Belladonna
extract
1.3 Phenobarbital sodium 1.2
Bismuth
subgallate
2.7 Salicylic acid 1.3
Chloral hydrate 1.3 Secobarbital sodium 1.2
Codeine
phosphate
1.1 Tannic acid 1.6
Digitalis leaI 1.6

( 1) The capaci t y of t he moI ds i s det ermi ned by mel t i ng a suf f i ci ent
quant i t y of base over a st eam bat h, pour i ng i t i nt o t he mol ds, and al l owi ng
i t t o congeal . The "bl ank¨ supposi t ori es are t ri mmed, removed, and
wei ghed. Once t he wei ght i s known, t he dr ug- cont ai ni ng supposi t or i es are
pr epar ed.
( a) To prepare supposi t or i es, t he dr ug i s r educed t o a f i ne powder . A smal l
amount of gr at ed cocoa but t er i s l i quef i ed i n a sui t abl e cont ai ner pl aced i n
a wat er bat h at 33°C or l ess.
( b) The f i nel y powder ed dr ug i s mi xed wi t h mel t ed cocoa but t er wi t h
cont i nuous st i r r i ng.
( c) The remai nder of t he gr at ed cocoa but t er i s added wi t h st i r ri ng. The
t emper at ure i s mai nt ai ned at or bel ow 33°C. The l i qui d shoul d appear
cr eamy r at her t han cl ear.
( d) The mol d i s ver y l i ght l y l ubr i cat ed wi t h mi neral oi l , and t he cr eamy mel t
i s poured i nt o t he mol d at r oom t emperat ure. The mel t i s poured
cont i nuousl y t o avoi d l ayer i ng.
( e) Af t er t he supposi t ori es congeal , t hey ar e pl aced i n a ref r i gerat or t o
har den. Af t er 30 mi n, t hey ar e r emoved f rom t he ref r i ger at or , t r i mmed, and
unmol ded.
( 2) The f usi on process shoul d be used car ef ul l y wi t h t hermoI abi I e drugs
and i nsoI ubI e powders.
( a) Ì nsol ubl e powders i n t he mel t may set t l e or f l oat dur i ng pouri ng,
dependi ng on t hei r densi t y. They may al so col l ect at one end of t he
supposi t or y bef or e t he mel t congeal s, and cause a nonuni f or m dr ug
di st r i but i on.
( b) Har d cr yst al l i ne mat er i al s (e. g. , i odi ne, mer bromi n) can be i ncorporat ed
by di ssol vi ng t he cr yst al s i n a mi ni mum vol ume of sui t abl e sol vent bef ore
t hey are i ncor por at ed i nt o t he base.
( c) Veget abl e ext r act s can be i ncor por at ed by moi st eni ng wi t h a f ew dr ops
of al cohol and l evi gat i ng wi t h a smal l amount of mel t ed cocoa but t er .
G. Powders
1. I nt roduct i on. A pharmaceut i cal powder i s a mi xt ur e of f i nel y di vi ded
dr ugs or chemi cal s i n dry f or m. The powder may be used i nt ernal l y or
ext er nal l y.
a. Advant ages of powder s
( 1) Fl exi bi l i t y of compoundi ng
( 2) Good chemi cal st abi l i t y
( 3) Rapi d di sper si on of i ngr edi ent s because of t he smal l par t i cl e si ze
b. Di sadvant ages of powder s
( 1) Ti me- consumi ng prepar at i on
( 2) Ì naccuracy of dose
( 3) Unsui t abi l i t y f or many unpl easant - t ast i ng, hygr oscopi c, and del i quescent
dr ugs
c. Mi I I i ng i s t he mechani cal pr ocess of r educi ng t he par t i cl e si ze of sol i ds
( commi nuti on) bef or e mi xi ng wi t h ot her component s, f urt her processi ng, or
i ncor por at i on i nt o a f i nal pr oduct ( Tabl es 3- 7 and 3- 8) . The par t i cl e si ze of
a powder i s r el at ed t o t he pr oport i on of t he powder t hat can pass t hr ough
t he openi ng of st andard si eves of var i ous di mensi ons i n a speci f i ed amount
of t i me. Mi cromeri ti cs i s t he st udy of par t i cl es.
Table 3-7. United States Pharmacopeia Standards for Powders of Animal and
Vegetable Drugs
Type of Powder
Sieve Size All Particles
Pass Through
Sieve Size Percentage of
Particles Pass Through
Very coarse (#8) #20 sieve 20° through a #60 sieve
Coarse (#20) #20 sieve 40° through a #60 sieve
Moderately
coarse (#40)
#40 sieve 40° through a #80 sieve
Fine (#60) #60 sieve 40° through a #100 sieve
Very Iine (#80) #80 sieve No limit

P. 60


Table 3-8. United States Pharmacopeia Standards for Powders of Chemicals
Type of Powder
Sieve Size All Particles
Pass Through
Sieve Size Percentage of
Particles Pass Through
Coarse (#20) #20 sieve 60° through a #40 sieve
Moderately
coarse (#40)
#40 sieve 60° through a #60 sieve
Fine (#80) #80 sieve No limit
Very Iine (#120) #120 sieve No limit

( 1) Advant ages of mi l l i ng
( a) Ì ncr eases t he sur f ace ar ea, whi ch may i ncrease t he di ssol ut i on r at e as
wel l as bi oavai l abi l i t y ( e. g. , gr i seof ul vi n)
( b) Ì ncr eases ext r act i on, or l eachi ng, f r om ani mal gl ands ( e. g. , l i ver ,
pancr eas) and f rom cr ude veget abl e ext r act s
( c) Faci l i t at es dr yi ng of wet masses by i ncr easi ng t he sur f ace area and
r educi ng t he di st ance t hat moi st ur e must t r avel t o r each t he out er sur f ace.
Mi cr oni zat i on and subsequent dr yi ng, i n t urn, i ncr ease st abi l i t y as occl uded
sol vent i s r emoved.
( d) Ì mpr oves mi xi ng, or bl endi ng, of several sol i d i ngr edi ent s i f t hey ar e
r educed t o appr oxi mat el y t he same si ze; al so mi ni mi zes segr egat i on and
pr ovi des gr eat er dose uni f ormi t y
( e) Permi t s uni f orm di st r i but i on of col or i ng agent s i n ar t i f i ci al l y col or ed
sol i d phar maceut i cal s
( f ) Ì mpr oves t he f unct i on of l ubri cant s used t o coat t he sur f ace of t he
gr anul at i on or powder i n compr essed t abl et s and capsul es
( g) Ì mpr oves t he t ext ur e, appearance, and physi cal st abi l i t y of oi nt ment s,
cr eams, and past es
( 2) Di sadvant ages of mi l l i ng
( a) Can change t he pol ymor phi c f or m of t he act i ve i ngr edi ent , r enderi ng i t
l ess act i ve
( b) Can degr ade t he dr ug as a r esul t of heat bui l dup, oxi dat i on, or
adsor pt i on of unwant ed moi st ur e because of i ncreased surf ace ar ea
( c) Decr eases t he bul k densi t y of t he act i ve compound and exci pi ent s,
causi ng f l ow pr obl ems and segregat i on.
( d) Decr eases t he part i cl e si ze of t he r aw mat eri al s and may cr eat e
pr obl ems wi t h st at i c charge, whi ch may cause part i cl e aggregat i on and
decrease t he di ssol ut i on r at e
( e) Ì ncr eases sur f ace area, whi ch may promot e ai r adsor pt i on and i nhi bi t
wet t abi l i t y
( 3) Commi nut i on t echni ques. On a l ar ge scal e, var i ous mi l l s and
pul veri zer s ( e. g. , rot ar y cut t er , hammer , rol l er , f l ui d ener gy mi l l ) are used
dur i ng manuf act ur i ng. On a smal l scal e, t he pharmaci st usual l y uses one of
t he f ol l owi ng commi nut i on t echni ques:
( a) Tri turat i on. The subst ance i s r educed t o smal l part i cl es by r ubbi ng i t i n
a mor t ar wi t h a pest l e. Tr i t urat i on al so descri bes t he pr ocess by whi ch f i ne
powder s ar e i nt i mat el y mi xed i n a mort ar .
( b) PuI veri zat i on by i nt ervent i on. Subst ances ar e r educed and subdi vi ded
wi t h an addi t i onal mat er i al (i . e. , sol vent ) t hat i s easi l y r emoved af t er
pul veri zat i on. Thi s t echni que i s of t en used wi t h gummy subst ances t hat
r eaggl omerat e or resi st gr i ndi ng. For exampl e, camphor i s r eadi l y r educed
af t er a smal l amount of al cohol or ot her vol at i l e sol vent i s added. The
sol vent i s t hen per mi t t ed t o evaporat e.
( c) Levi gat i on. The par t i cl e si ze of t he subst ance i s r educed by addi ng a
sui t abl e nonsol vent ( l evi gat i ng agent ) t o f orm a past e. The past e i s t hen
r ubbed i n a mor t ar and pest l e or usi ng an oi nt ment sl ab and spat ul a. Thi s
met hod i s of t en used t o pr event a gr i t t y f eel when sol i ds ar e i ncor porat ed
i nt o dermat ol ogi c or opht hal mi c oi nt ment s and suspensi ons. Mi neral oi l i s a
common l evi gat i ng agent .
2. Mi xi ng powders. Powder s are mi xed, or bl ended, by t he f ol l owi ng f i ve
met hods:
a. Spat uI at i on. A spat ul a i s used t o bl end smal l amount s of powder s on a
sheet of paper or a pi l l t i l e.
( 1) Thi s met hod i s not sui t abl e f or l arge quant i t i es of powders or f or
powder s t hat cont ai n pot ent subst ances because homogeneous bl endi ng
may not occur .
P. 61


( 2) Thi s met hod i s part i cul arl y usef ul f or sol i d subst ances t hat l i quef y or
f or m eutect i c mi xt ures ( i . e. , mi xt ur es t hat mel t at a l ower t emper at ur e t han
any of t hei r i ngredi ent s) when i n cl ose, pr ol onged cont act wi t h one anot her
because l i t t l e compr essi on or compact i on resul t s.
( a) These subst ances i ncl ude phenol , camphor , ment hol , t hymol , aspi ri n,
phenyl sal i cyl at e, and phenacet i n.
( b) To di mi ni sh cont act , powder s pr epar ed f rom t hese subst ances ar e
commonl y mi xed wi t h an i ner t di l uent ( e. g. , l i ght magnesi um oxi de or
magnesi um carbonat e, kaol i n, st ar ch, bent oni t e).
( c) Si l i ci c aci d ( approxi mat el y 20%) prevent s eut exi a wi t h aspi r i n,
phenyl sal i cyl at e, and ot her t r oubl esome compounds.
b. Tri turat i on i s used bot h t o commi nut e and t o mi x powder s.
( 1) Ì f commi nut i on i s desi r ed, a porcel ai n or cer ami c mor t ar wi t h a r ough
i nner sur f ace i s pref er r ed t o a gl ass mor t ar wi t h a smoot h wor ki ng sur f ace.
( 2) A gl ass mor t ar i s pref er abl e f or chemi cal s t hat st ai n a porcel ai n or
cer ami c surf ace as wel l as f or si mpl e admi xt ur e of subst ances wi t hout
speci al need f or commi nut i on. A gl ass mor t ar cl eans mor e readi l y af t er use.
c. Geomet ri c di I ut i on i s used when pot ent subst ances must be mi xed wi t h
a l ar ge amount of di l uent .
( 1) The pot ent dr ug and an approxi mat el y equal vol ume of di l uent ar e
pl aced i n a mort ar and t hor oughl y mi xed by t r i t urat i on.
( 2) A second por t i on of di l uent , equal i n vol ume t o t he powder mi xt ur e i n
t he mort ar , i s added, and t r i t ur at i on i s repeat ed. The pr ocess i s cont i nued;
equal vol umes of di l uent ar e added t o t he powder mi xt ur e i n t he mor t ar unt i l
al l of t he di l uent i s i ncorpor at ed.
d. Si f ti ng. Powder s ar e mi xed by passi ng t hem t hr ough si f t ers si mi l ar t o
t hose used t o si f t f l our . Thi s process resul t s i n a l i ght , f l uf f y product .
Usual l y, i t i s not accept abl e f or i ncorpor at i ng pot ent dr ugs i nt o a di l uent
base.
e. TumbI i ng i s t he process of mi xi ng powder s i n a l ar ge cont ai ner r ot at ed
by a mot ori zed pr ocess. These bl ender s ar e wi del y used i n i ndust r y, as are
l ar ge- vol ume powder mi xer s t hat use mot or i zed bl ades t o bl end t he powder
i n a l ar ge mi xi ng vessel .
3. Use and packagi ng of powders. Dependi ng on t hei r i nt ended use,
powder s ar e packaged and di spensed by pharmaci st s as bul k powder s or
di vi ded powder s.
a. Bul k powders are di spensed by t he pharmaci st i n bul k cont ai ners. A
perf orated, or si f t er, can i s used f or ext er nal dust i ng, and an aerosoI
cont ai ner i s used f or spr ayi ng ont o ski n. A wi de- mout hed gI ass j ar
per mi t s easy removal of a spoonf ul of powder .
( 1) Powders commonl y di spensed i n bul k f orm
( a) Ant aci d and I axat i ve powders ar e used by mi xi ng t he di r ect ed amount
of powder ( usual l y approxi mat el y 1 t easpoon) i n a port i on of l i qui d, whi ch
t he pat i ent t hen dr i nks.
( b) Douche powders are di ssol ved i n war m wat er and appl i ed vagi nal l y.
( c) Medi cated and nonmedi cat ed powders f or ext ernaI use ar e usual l y
di spensed i n a si f t er f or conveni ent appl i cat i on t o t he ski n.
( d) Denti f ri ces, or dentaI cI eansi ng powders, ar e used f or oral hygi ene.
( e) Powders f or t he ear, nose, t hroat , toot h socket s, or vagi na ar e
admi ni st er ed wi t h an i nsuf f l at or, or powder bl ower .
( 2) Nonpot ent substances are usual l y di spensed i n bul k powder f or m.
Those i nt ended f or ext er nal use shoul d be cl ear l y l abel ed.
( 3) Hygroscopi c, deI i quescent , or voI ati I e powder s shoul d be packed i n
gl ass j ars rat her t han past eboard cont ai ners. Amber or green gl ass shoul d
be used i f needed t o pr event decomposi t i on of l i ght - sensi t i ve component s.
Al l powder s shoul d be st or ed i n t i ght l y cl osed cont ai ners.
b. Di vi ded powders ar e di spensed i n i ndi vi dual doses, usual l y i n f ol ded
papers ( i . e. , char t ul ae) . They may al so be di spensed i n met al f oi l , smal l
heat -seal ed or r eseal abl e pI ast i c bags, or ot her cont ai ners.
( 1) Af t er t he i ngr edi ent s ar e wei ghed, commi nut ed, and mi xed, t he powder s
must be accur at el y di vi ded i nt o t he prescr i bed number of doses.
( 2) Dependi ng on t he pot ency of t he dr ug subst ance, t he phar maci st
deci des whet her t o wei gh each port i on separ at el y bef ore packagi ng or t o
approxi mat e por t i ons by t he bI ock- and- di vi de met hod.
P. 62


( 3) Powder papers can be of any conveni ent si ze t hat f i t s t he requi r ed
dose. Four basi c t ypes ar e used:
( a) Veget abI e parchment i s a t hi n, semi opaque, moi st ur e- resi st ant paper.
( b) Whi t e bond i s an opaque paper t hat has no moi st ur e- resi st ant
pr oper t i es.
( c) GI assi ne i s a gl azed, t r anspar ent , moi st ur e- resi st ant paper .
( d) Waxed paper i s a t ranspar ent wat er proof paper .
( 4) Hygr oscopi c and vol at i l e drugs are best pr ot ect ed wi t h waxed paper t hat
i s doubl e wr apped and cover ed wi t h a bond paper t o i mpr ove t he
appear ance. Par chment and gl assi ne paper s ar e of l i mi t ed use f or t hese
dr ugs.
4. Speci aI probI ems. Vol at i l e subst ances, eut ect i c mi xt ur es, l i qui ds, and
hygr oscopi c or del i quescent subst ances present pr obl ems when t hey ar e
mi xed i nt o powder s t hat r equi r e speci al t r eat ment .
a. VoI at i I e substances (e. g. , camphor, ment hol , essent i al oi l s) can be l ost
by vol at i l i zat i on af t er t hey ar e i ncor por at ed i nt o powder s. Thi s pr ocess i s
pr event ed or ret arded by t he use of heat -seal ed pl ast i c bags or by doubl e
wr appi ng wi t h waxed or gl assi ne paper i nsi de whi t e bond paper .
b. Li qui ds are i ncor por at ed i nt o di vi ded powder s i n smal l amount s.
( 1) Magnesi um carbonat e, st arch, or l act ose can be added t o i ncrease t he
absor babi l i t y of t he powder s by i ncreasi ng t he sur f ace ar ea.
( 2) When t he l i qui d i s a sol vent f or a nonvol at i l e heat -st abl e compound, i t i s
evaporat ed gent l y i n a wat er bat h. Some f l ui dext r act s and t i nct ur es are
t r eat ed i n t hi s way.
c. Hygroscopi c and deI i quescent subst ances t hat become moi st because
of an af f i ni t y f or moi st ure i n t he ai r can be pr epar ed as di vi ded powder s by
addi ng i ner t di l uent s. Doubl e wr appi ng i s desi rabl e f or f urt her pr ot ect i on.
d. Eutect i c mi xt ures
H. CapsuI es
1. I nt roduct i on. Capsul es ar e sol i d dosage f orms i n whi ch one or mor e
medi ci nal or i ner t subst ances (as powder , compact , beads, or gr anul at i on)
ar e encl osed wi t hi n a smal l gel at i n shel l . Gel at i n capsul es may be hard or
sof t . Most capsul es are i nt ended t o be swal l owed whol e, but occasi onal l y,
t he cont ent s ar e r emoved f r om t he gel at i n shel l and used as a premeasured
dose.
2. Hard geI at i n capsuI es
a. Preparat i on of f i I I ed hard capsuI es i ncl udes pr epar i ng t he f ormul at i on,
sel ect i ng t he appropri at e capsul e, f i l l i ng t he capsul e shel l s, and cl eani ng
and pol i shi ng t he f i l l ed capsul es.
( 1) Empt y har d capsul e shel l s are manuf act ur ed f r om a mi xt ur e of gel at i n,
col or ant s, and somet i mes an opaci f yi ng agent (e. g. , t i t ani um di oxi de) . The
USP al so permi t s t he addi t i on of 0. 15% sul f ur di oxi de t o pr event
decomposi t i on of gel at i n duri ng manuf act ur e.
( 2) Gel at i n USP i s obt ai ned by par t i al hydrol ysi s of col l agen obt ai ned f r om
t he ski n, whi t e connect i ve t i ssue, and bones of ani mal s. Types A and B ar e
obt ai ned by aci d and al kal i pr ocessi ng, respect i vel y.
( 3) Capsul e shel l s ar e cast by di ppi ng col d met al l i c mol ds or pi ns i nt o
gel at i n sol ut i ons t hat ar e mai nt ai ned at a uni f or m t emper at ure and an exact
degree of f l ui di t y.
( a) Vari at i on i n t he vi scosi t y of t he gel at i n sol ut i on i ncr eases or decr eases
t he t hi ckness of t he capsul e wal l .
( b) Af t er t he pi ns ar e wi t hdr awn f r om t he gel at i n sol ut i on, t hey ar e r ot at ed
whi l e bei ng dri ed i n ki l ns. A st r ong bl ast of f i l t er ed ai r wi t h cont r ol l ed
humi di t y i s f or ced t hr ough t he ki l ns. Each capsul e i s t hen mechani cal l y
st r i pped, t r i mmed, and j oi ned.
b. St orage. Har d capsul es shoul d be st ored i n t i ght l y cl osed gl ass
cont ai ners and pr ot ect ed f r om dust and ext r emes of humi di t y and
t emper at ure.
( 1) These capsul es cont ai n 12%- 16% wat er , var yi ng wi t h st or age
condi t i ons. When humi di t y i s l ow, t he capsul es become br i t t l e. When
humi di t y i s hi gh, t he capsul es become f l acci d and shapel ess.
( 2) St or age at hi gh t emper at ur es al so af f ect s t he qual i t y of har d gel at i n
capsul es.
c. Si zes. Har d capsul es ar e avai l abl e i n a var i et y of si zes.
P. 63


( 1) Empt y capsul es are numbered f r om 000, whi ch i s t he l ar gest si ze t hat
can be swal l owed, t o 5, t he smal l est si ze. The appr oxi mat e capaci t y of
capsul es r anges f r om 600 t o 30 mg f or capsul es f r om 000 t o 5, respect i vel y.
The capaci t y var i es because of var yi ng densi t i es of powder ed dr ug
mat er i al s and t he degr ee of pr essur e used t o f i l l t he capsul es.
( 2) Lar ge capsul es ar e avai l abl e f or vet eri nar y medi ci ne.
( 3) SeI ecti ng capsuI es. Capsul e si ze shoul d be chosen car ef ul l y. A
pr oper l y f i l l ed capsul e shoul d have i t s body f i l l ed wi t h t he dr ug mi xt ur e and
i t s cap f ul l y ext ended down t he body. The cap i s meant t o encl ose t he
powder , not t o ret ai n addi t i onal powder . Typi cal l y, har d gel at i n capsul es ar e
used t o encapsul at e bet ween 65 mg and 1 g of powder ed mat er i al , i ncl udi ng
t he dr ug and any di l uent s needed.
( a) Ì f t he drug dose i s i nadequat e t o f i l l t he capsul e, a di l uent (e. g. ,
l act ose) i s added.
( b) Ì f t he amount of dr ug needed f or a usual dose i s t oo l ar ge t o pl ace i n a
si ngl e capsul e, t wo or mor e capsul es may be r equi r ed.
( c) Lubr i cant s such as magnesi um st earat e ( f r equent l y, 1%) are added t o
f aci l i t at e t he f l ow of t he powder when an aut omat i c capsul e-f i l l i ng machi ne
i s used.
( d) Wet t i ng agent s ( e. g. , sodi um l aur yl sul f at e) may be added t o capsul e
f or mul at i ons t o enhance dr ug di ssol ut i on.
d. Fi I I i ng capsuI es. Whet her on a l arge- or a smal l -pr oduct i on scal e, t he
cap i s f i r st separat ed f rom t he body of t he capsul e bef or e f i l l i ng t he capsul e
body wi t h t he f ormul at i on and t hen r eat t achi ng t he cap. Aut omat ed and
semi aut omat ed capsul e- f i l l i ng equi pment f i l l t he capsul e bodi es wi t h t he
f or mul at i on by gr avi t y f i l l , t ampi ng, or a screw- f eed ( i . e. , auger )
mechani sm. Ext emporaneousl y compounded capsul es ar e usual l y f i l l ed by
t he punch met hod.
( 1) The powder i s pl aced on paper and f l at t ened wi t h a spat ul a so t hat t he
l ayer of powder i s no mor e t han appr oxi mat el y one t hi r d t he l engt h of t he
capsul e. The paper i s hel d i n t he l ef t hand. The body of t he capsul e i s hel d
i n t he ri ght hand and repeat edl y pressed i nt o t he powder unt i l t he capsul e
i s f i l l ed. The cap i s r epl aced and t he capsul e wei ghed.
( 2) GranuI ar mat er i al t hat does not l end i t sel f wel l t o t he punch met hod can
be poured i nt o each capsul e f rom t he powder paper on whi ch i t was
wei ghed.
( 3) Cr yst aI I i ne mat eri al s, especi al l y t hose t hat consi st of a mass of
f i l ament -l i ke cr yst al s ( e. g. , qui ni ne sal t s) wi l l not f i t i nt o a capsul e easi l y
unl ess t hey are powder ed.
( 4) Af t er t hey are f i l l ed, capsul es must be cl eaned and pol i shed.
( a) On a smaI I scaI e, capsul es are cl eaned i ndi vi dual l y or i n smal l number s
by r ubbi ng t hem on a cl ean gauze or cl ot h.
( b) On a I arge scaI e, many capsul e- f i l l i ng machi nes have a cl eani ng
vacuum t hat r emoves any ext r aneous mat eri al as t he capsul es l eave t he
machi ne.
3. Sof t geI at i n capsuI es
a. Preparat i on
( 1) Sof t gel at i n capsul es ar e pr epar ed f rom gel at i n shel l s. Gl ycer i n or a
pol yhydri c al cohol ( e. g. , sor bi t ol ) i s added t o t hese shel l s t o make t hem
el ast i c or pl ast i c- l i ke.
( 2) These shel l s cont ai n pr eser vat i ves (e. g. , met hyl and pr opyl par abens,
sor bi c aci d) t o pr event t he growt h of f ungi .
b. Uses. Sof t gel at i n shel l s are obl ong, el l i pt i cal , or spher i cal . They ar e
used t o cont ai n l i qui ds, suspensi ons, past es, dr y powder s, or pel l et s.
( 1) Dr ugs t hat are commer ci al l y pr epared i n sof t capsul es i ncl ude
demecl ocycl i ne hydr ochl or i de ( Decl omyci n, Leder l e) , chl oral hydr at e,
di goxi n ( Lanoxi caps, Gl axoSmi t hKl i ne), vi t ami n A, and vi t ami n E.
( 2) Sof t gel at i n capsul es ar e usual l y prepared by t he pl at e pr ocess or by
t he rot ar y or r eci pr ocat i ng di e process.
4. Uni formi t y and di si ntegrat i on
a. The uni f ormi t y of dosage f orms can be demonst r at ed by ei t her wei ght
var i at i on or cont ent uni f or mi t y met hods. The of f i ci al compendi a shoul d be
consul t ed f or det ai l s of t hese procedur es.
b. Di si nt egrat i on t est s ar e not usual l y r equi red f or capsul es unl ess t hey
have been t r eat ed t o r esi st sol ut i on i n gast r i c f l ui d ( ent eri c coat ed) . Ì n t hi s
case, t hey must meet t he r equi rement s f or di si nt egr at i on of ent eri c-coat ed
t abl et s.
P. 64


I . TABLETS
1. I nt roduct i on
a. The oraI rout e i s t he most i mpor t ant met hod f or admi ni st er i ng drugs f or
syst emi c ef f ect . Or al dr ugs can be gi ven as sol i ds or l i qui ds.
( 1) Advant ages of soI i d dosage forms
( a) Accur at e dosage
( b) Easy shi ppi ng and handl i ng
( c) Less shel f space needed per dose t han f or l i qui d
( d) No pr eser vat i on r equi r ement s
( e) No t ast e-maski ng probl em
( f ) Gener al l y mor e st abl e t han l i qui ds, wi t h l onger expi r at i on dat es
( 2) Advant ages of I i qui d dosage f orms
( a) For some drugs ( e. g. , adsorbent s, ant aci ds) , gr eat er ef f ect i veness t han
sol i d f orm
( b) Usef ul f or pat i ent s who have t roubl e swal l owi ng sol i d dosage f or ms
b. TabI ets are t he most commonI y used soI i d dosage f orm.
( 1) Advant ages
( a) Pr eci si on and l ow cont ent var i abi l i t y of t he uni t dose
( b) Low manuf act uri ng cost
( c) Easy t o package and shi p
( d) Si mpl e t o i dent i f y
( e) Easy t o swal l ow
( f ) Appropri at e f or speci al - r el ease f orms
( g) Best sui t ed t o l ar ge-scal e pr oduct i on
( h) Most st abl e of al l oral dosage f orms
( i ) Essent i al l y t amperpr oof
( 2) Di sadvant ages
( a) Some dr ugs r esi st compr essi on i nt o t abl et s.
( b) Some dr ugs ( i . e. , t hose wi t h poor wet t i ng, sl ow di ssol ut i on proper t i es,
i nt er medi at e t o l arge doses, opt i mum absorpt i on hi gh i n t he gast r oi nt est i nal
t r act , or any combi nat i on of t hese f eat ur es) may be di f f i cul t t o f ormul at e t o
pr ovi de adequat e bi oavai l abi l i t y.
( c) Some dr ugs ( e. g. , t hose wi t h an obj ect i onabl e t ast e or odor , t hose
sensi t i ve t o oxygen or at mospher i c moi st ur e) r equi r e encapsul at i on or
ent r apment bef or e compr essi on. These dr ugs ar e more appropr i at e i n
capsul e f orm.
2. TabI et desi gn and f ormuI ati on
a. Characteri st i cs of i deaI tabI et s
( 1) Free of def ect s (e. g. , chi ps, cr acks, di scol or at i on, cont ami nat i on)
( 2) St rong enough t o wi t hst and t he mechani cal st r esses of product i on
( 3) Chemi cal l y and physi cal l y st abl e over t i me
( 4) Capabl e of rel easi ng medi ci nal agent s i n a predi ct abl e and repr oduci bl e
manner
b. TabI et exci pi ents. Tabl et s ar e manuf act ur ed by wet granuI at i on, dr y
granuI at i on, or di rect compressi on. Regardl ess of t he met hod of
manuf act ur e, t abl et s f or or al i ngest i on usual l y cont ai n exci pi ent s, whi ch ar e
component s added t o t he act i ve i ngr edi ent s t hat have speci al f unct i ons
( Tabl e 3- 9) .
( 1) Di I uents are f i l l er s desi gned t o make up t he requi r ed bul k of t he t abl et
when t he dr ug dosage amount i s i nadequat e. Di l uent s may al so i mprove
cohesi on, per mi t di rect compressi on, or pr omot e f l ow.
( a) Common di I uents i ncl ude kaol i n, l act ose, manni t ol , st arch,
mi cr ocr yst al l i ne cel l ul ose, powder ed sugar , and cal ci um phosphat e.
( b) SeI ect i on of t he di I uent i s based on t he exper i ence of t he
manuf act ur er as wel l as on t he cost of t he di l uent and i t s compat i bi l i t y wi t h
t he ot her t abl et i ngredi ent s. For exampl e, cal ci um sal t s cannot be used as
f i l l ers f or t et r acycl i ne product s because cal ci um i nt er f eres wi t h t he
absor pt i on of t et r acycl i ne f r om t he gast r oi nt est i nal t ract .
( 2) Bi nders and adhesi ves ar e added i n ei t her dr y or l i qui d f orm t o
pr omot e granul at i on or t o pr omot e cohesi ve compact s duri ng di r ect
compr essi on.
( a) Common bi ndi ng agent s i ncl ude a 10%-20% aqueous pr epar at i on of
cor nst ar ch, a 25%- 50% sol ut i on of gl ucose, mol asses, var i ous nat ur al gums
( e. g. , acaci a) , cel l ul ose der i vat i ves ( e. g. , met hyl cel l ul ose,
car boxymet hyl cel l ul ose, mi cr ocr yst al l i ne
P. 65

cel l ul ose) , gel at i ns, and povi done. The nat ural gums ar e var i abl e i n
composi t i on and ar e usual l y cont ami nat ed wi t h bact er i a.
Table 3-9. Some Common Tablet Excipients
Diluents
Calcium phosphate dihydrate NF (dibasic)
Calcium sulIate dihydrate NF
Cellulose NF (microcrystalline)
Cellulose derivatives
Dextrose
Lactose USP
Lactose USP (anhydrous)
Lactose USP (spray dried)
Mannitol USP
Starches (directly compressible)
Starches (hydrolyzed)
Sorbitol
Sucrose USP (powder)
Sucrose-based materials
Binders and adhesives
Acacia
Cellulose derivatives
Gelatin
Glucose
Povidone (PVP)
Sodium alginate and alginate derivatives
Sorbitol
Starch (paste)
Starch (pregelatinized)
Tragacanth
Disintegrants
Alginates
Cellulose
Cellulose derivatives
Clays
Crospovidone (cross-linked PVP)
Starch
Starch derivatives
Lubricants
PEGs
Stearic acid
Stearic acid salts
Stearic acid derivatives
SurIactants
Talc
Waxes
Glidants
Cornstarch
Silica derivatives
Talc
Colors. flavors. and sweeteners
FD&C and D&C dyes and lakes
Flavors available in two Iorms (spray dried. oil)
ArtiIicial sweeteners
Natural sweetener
D&C. drugs and cosmetics; FD&C. Iood. drugs. and cosmetics; NF.
National Formularv, PEG. polyethylene glycol; PJP. polyvinylpyrrolidone
(more commonly. povidone); USP. United States Pharmacopeia.

( b) Ì f t he drug subst ance i s adversel y af f ect ed by an aqueous bi nder, a
nonaqueous bi nder can be used or t he bi nder can be added dr y. The
bi ndi ng act i on i s usual l y mor e ef f ect i ve when t he bi nder i s mi xed i n l i qui d
f or m.
( c) The amount of bi nder or adhesi ve used depends on t he exper i ence of
t he manuf act ur er as wel l as on t he ot her t abl et i ngr edi ent s. Over wet t i ng
usual l y pr oduces granul es t hat are t oo har d t o al l ow pr oper t abl et i ng.
Under wet t i ng usual l y pr oduces t abl et s t hat are t oo sof t and t end t o cr umbl e.
( 3) Di si nt egrants are added t o t abl et f ormul at i ons t o f aci l i t at e
di si nt egrat i on when t he t abl et cont act s wat er i n t he gast r oi nt est i nal t ract .
Di si nt egr ant s f unct i on by dr awi ng wat er i nt o t he t abl et , swel l i ng, and
causi ng t he t abl et t o burst .
( a) Tabl et di si nt egrat i on may be cri t i cal t o t he subsequent di ssol ut i on of t he
dr ug and t o sat i sf act or y dr ug bi oavai l abi l i t y.
( b) Common di si nt egrant s i ncl ude cornst ar ch and pot at o st arch; st arch
der i vat i ves ( e. g. , sodi um st ar ch gl ycol at e) ; cel l ul ose deri vat i ves (e. g. ,
sodi um car boxymet hyl cel l ul ose, cr oscarmel l ose sodi um) ; cl ays ( e. g. ,
VEEGUM, bent oni t e) ; and cat i on exchange r esi ns.
( c) The t ot al amount of di si ntegrant i s not al ways added t o t he dr ug-
di l uent mi xt ur e. A por t i on can be added, wi t h t he l ubr i cant , t o t he pr epar ed
gr anul at i on of t he dr ug. Thi s appr oach causes doubl e di si nt egr at i on of t he
t abl et . The por t i on of di si nt egr ant t hat i s added l ast causes t he t abl et t o
br eak i nt o smal l pi eces, or chunks. The por t i on t hat i s added f i rst br eaks
t he pi eces of t abl et i nt o f i ne part i cl es.
( 4) Lubri cant s, anti adherent s, and gI i dant s have over l appi ng f unct i on.
( a) Lubri cant s r educe t he f r i ct i on t hat occurs bet ween t he wal l s of t he
t abl et and t he wal l s of t he di e cavi t y when t he t abl et i s ej ect ed. Tal c,
magnesi um st ear at e, and cal ci um st ear at e ar e commonl y used.
P. 66


( b) Ant i adherents r educe st i cki ng, or adhesi on, of t he t abl et gr anul at i on or
powder t o t he f aces of t he punches or t he di e wal l s.
( c) GI i dant s promot e t he f l ow of t he t abl et gr anul at i on or powder by
r educi ng f r i ct i on among par t i cl es.
( 5) CoI ors and dyes di sgui se of f -col or dr ugs, provi de pr oduct
i dent i f i cat i on, and pr oduce a mor e aest het i cal l y appeal i ng product . Food,
drug, and cosmeti c dyes ar e appl i ed as sol ut i ons. Lakes ar e dyes t hat
have been absorbed on a hydr ous oxi de. Lakes ar e t ypi cal l y used as dr y
powder s.
( 6) FI avori ng agent s are usual l y l i mi t ed t o chewabl e t abl et s or t abl et s t hat
ar e i nt ended t o di ssol ve i n t he mout h.
( a) Wat er -sol ubl e f l avor s usual l y have poor st abi l i t y. For t hi s r eason, f l avor
oi l s or dr y powder s ar e t ypi cal l y used.
( b) Fl avor oi l s may be added t o t abl et granul at i ons i n sol vent s, di spersed
on cl ays and ot her adsorbent s, or emul si f i ed i n aqueous granul at i ng agent s.
Usual l y, t he maxi mum amount of oi l t hat can be added t o a gr anul at i on
wi t hout af f ect i ng i t s t abl et charact er i st i cs i s 0. 5%- 0. 75%.
( 7) Art i f i ci aI sweet eners, l i ke f l avors, ar e t ypi cal l y used onl y wi t h
chewabl e t abl et s or t abl et s t hat are i nt ended t o di ssol ve i n t he mout h.
( a) Some sweetness may come f rom t he di l uent (e. g. , manni t ol , l act ose).
Ot her agent s ( e. g. , sacchar i n, aspar t ame) may al so be added.
( b) Sacchari n has an unpl easant af t er t ast e.
( c) Aspart ame i s not st abl e i n t he pr esence of moi st ur e and heat .
( 8) Adsorbent s (e. g. , magnesi um oxi de, magnesi um car bonat e, bent oni t e,
si l i con di oxi de) hol d quant i t i es of f l ui d i n an appar ent l y dr y st at e.
3. TabI et t ypes and cI asses. Tabl et s are cl assi f i ed accordi ng t o t hei r r out e
of admi ni st rat i on, dr ug del i ver y syst em, and f or m and met hod of
manuf act ur e ( Tabl e 3- 10) .
a. TabI ets f or oraI i ngest i on ar e desi gned t o be swal l owed i nt act , wi t h t he
except i on of chewabl e t abl et s. Tabl et s may be coat ed f or a number of
r easons: t o mask t he t ast e, col or , or odor of t he dr ug; t o cont rol dr ug
r el ease; t o prot ect t he drug f rom t he aci d envi r onment of t he st omach; t o
i ncor por at e anot her dr ug and pr ovi de sequent i al rel ease or avoi d
i ncompat i bi l i t y; or t o i mpr ove appear ance.
( 1) Compressed t abI et s ar e f ormed by compr essi on and have no speci al
coat i ng. They ar e made f r om powder ed, cr yst al l i ne, or gr anul ar mat er i al s,
al one or i n combi nat i on wi t h exci pi ent s such as bi nders, di si nt egrant s,
di l uent s, and col or ant s.
( 2) MuI t i pI e compressed t abI et s ar e l ayer ed or compr essi on- coat ed.
( a) Layered t abI ets ar e pr epar ed by compr essi ng a t abl et gr anul at i on
ar ound a previ ousl y compr essed granul at i on. The operat i on i s r epeat ed t o
pr oduce mul t i pl e l ayers.
( b) Compressi on-coat ed, or dr y- coat ed, t abI ets ar e prepared by f eedi ng
pr evi ousl y compressed t abl et s i nt o a speci al t abl et i ng machi ne. Thi s
machi ne compresses an out er shel l ar ound t he t abl et s. Thi s pr ocess appl i es
a t hi nner , more uni f orm coat i ng t han sugar coat i ng, and i t can be used
saf el y wi t h drugs t hat are sensi t i ve t o moi st ure. Thi s process can be used
t o separ at e i ncompat i bl e mat er i al s, t o
P. 67

pr oduce r epeat - act i on or pr ol onged-act i on pr oduct s or t o pr oduce t abl et s
wi t h a mul t i l ayer ed appear ance.
Table 3-10. Tablet Types and Classes
Tablets for oral ingestion
Compressed
Multiple compressed
Layered
Compression coated
Repeat-action
Delayed action and enteric coated
Sugar coated and chocolate coated
Film coated
Air suspension coated
Chewable
Tablets used in the oral cavity
Buccal
Sublingual
Troches. lozenges. and dental cones
Tablets used to prepare solutions
EIIervescent
Dispensing
Hypodermic
Triturates

( 3) Repeat -act i on tabI ets ar e l ayer ed or compressi on-coat ed t abl et s i n
whi ch t he out er l ayer or shel l r api dl y di si nt egr at es i n t he st omach ( e. g. ,
Repet abs, Scher i ng; Ext ent abs, Wyet h) . The component s of t he i nner l ayer
or i nner t abl et are i nsol ubl e i n gast ri c medi a but sol ubl e i n i nt est i nal medi a.
( 4) DeI ayed- act i on and ent eri c- coat ed t abI ets del ay t he r el ease of a drug
f r om a dosage f or m. Thi s del ay i s i nt ended t o prevent dest r uct i on of t he
dr ug by gast ri c j ui ces, t o pr event i rr i t at i on of t he st omach l i ni ng by t he
dr ug, or t o pr omot e absor pt i on, whi ch i s bet t er i n t he i nt est i ne t han i n t he
st omach.
( a) Enteri c-coated t abl et s ar e coat ed and remai n i nt act i n t he st omach, but
yi el d t hei r i ngredi ent s i n t he i nt est i nes ( e. g. , Ecot r i n, Gl axoSmi t hKl i ne).
Ent eri c-coat ed t abl et s are a f orm of del ayed- act i on t abl et . However , not al l
del ayed- act i on t abl et s are ent er i c or ar e i nt ended t o pr oduce an ent eri c
ef f ect .
( b) Agent s used t o coat t hese t abl et s i ncl ude f at s, f at t y aci ds, waxes,
shel l ac, and cel l ul ose acet at e pht hal at e.
( 5) Sugar- coat ed and chocoI at e-coated tabI et s ar e compressed t abl et s
t hat ar e coat ed f or vari ous reasons. The coat i ng may be added t o prot ect
t he dr ug f r om ai r and humi di t y, t o provi de a bar ri er t o a dr ug' s obj ect i onabl e
t ast e or smel l , or t o i mprove t he appear ance of t he t abl et .
( a) Tabl et s may be coat ed wi t h a col ored or an uncol or ed sugar . The
pr ocess i ncl udes seaI coat i ng ( wat er proof i ng) , subcoat i ng, syrup coati ng
( f or smoot hi ng and col ori ng) , and poI i shi ng. These st eps t ake pl ace i n a
ser i es of mechani cal l y oper at ed coat i ng pans.
( b) Di sadvant ages of sugar -coat ed t abl et s i ncl ude t he t i me and exper t i se
r equi r ed f or t he process and t he i ncr ease i n t abl et si ze and wei ght . Sugar-
coat ed t abl et s may be 50% l ar ger and heavi er t han t he or i gi nal t abl et s.
( c) Chocol at e-coat ed t abl et s are r ar e t oday.
( 6) Fi I m- coated tabI et s ar e compr essed t abl et s t hat ar e coat ed wi t h a t hi n
l ayer of a wat er - i nsol ubl e or wat er -sol ubl e pol ymer ( e. g. , hydr oxypr opyl
met hyl cel l ul ose, et hyl cel l ul ose, povi done, PEG) .
( a) The f i l m i s usual l y col or ed. Ì t i s more dur abl e, l ess bul ky, and l ess t i me-
consumi ng t o appl y t han sugar coat i ng. Al t hough t he f i l m t ypi cal l y i ncr eases
t abl et wei ght by onl y 2%- 3%, i t i ncr eases f ormul at i on ef f i ci ency, resi st ance
t o chi ppi ng, and out put .
( b) Fi l m- coat i ng sol ut i ons usual l y cont ai n a f i l m f or mer , an al l oyi ng
subst ance, a pl ast i ci zer, a sur f act ant , opaci f i ers, sweet eners, f l avors,
col or s, gl ossant s, and a vol at i l e sol vent .
( c) The vol at i l e sol vent s used i n t hese sol ut i ons ar e expensi ve and
pot ent i al l y t oxi c when rel eased i nt o t he at mospher e. Speci f i cal l y f or mul at ed
aqueous di spersi ons of pol ymers ( e. g. , et hyl cel l ul ose) ar e now avai l abl e
as al t er nat i ves t o organi c sol vent - based coat i ng sol ut i ons.
( 7) Ai r suspensi on-coated t abI ets are f ed i nt o a ver t i cal cyl i nder and
suppor t ed by a col umn of ai r t hat ent er s f r om t he bot t om of t he cyl i nder . As
t he coat i ng sol ut i on ent er s t he syst em, i t i s r api dl y appl i ed t o t he
suspended, rot at i ng sol i ds ( Wurster process) . Roundi ng coat s can be
appl i ed i n < 1 hr when bl ast s of war m ai r ar e rel eased i n t he chamber .
( 8) Chewabl e t abl et s di si nt egrat e smoot hl y and r api dl y when chewed or
al l owed t o di ssol ve i n t he mout h. These t abl et s cont ai n speci al l y col or ed
and f l avored manni t ol and yi el d a creamy base.
( a) Chewabl e t abl et s are especi al l y usef ul i n f ormul at i ons f or chi l dren.
( b) They ar e commonl y used f or mul t i vi t ami n t abl et s and are used f or some
ant aci ds and ant i bi ot i cs.
b. Tabl et s used i n t he oral cavi t y ar e al l owed t o di ssol ve i n t he mout h.
( 1) Buccal and subl i ngual t abl et s al l ow absor pt i on t hrough t he or al mucosa
af t er t hey di ssol ve i n t he buccal pouch ( buccal t abl et s) or bel ow t he t ongue
( subl i ngual t abl et s) . These f orms ar e usef ul f or dr ugs t hat ar e dest r oyed by
gast r i c j ui ce or poorl y absor bed f r om t he i nt est i nal t r act . Exampl es i ncl ude
subl i ngual ni t rogl yceri n t abl et s, whi ch di ssol ve pr ompt l y t o gi ve r api d dr ug
ef f ect s, and buccal pr ogest er one t abl et s, whi ch di ssol ve sl owl y.
P. 68


( 2) Tr oches, l ozenges, and dent al cones di ssol ve sl owl y i n t he mout h and
pr ovi de pri mar i l y l ocal ef f ect s.
c. Tabl et s used t o prepar e sol ut i ons are di ssol ved i n wat er bef ore
admi ni st rat i on.
( 1) Ef f er vescent t abl et s ar e pr epar ed by compr essi ng granul ar ef f er vescent
sal t s or ot her mat er i al s (e. g. , ci t r i c aci d, t ar t ar i c aci d, sodi um bi car bonat e)
t hat r el ease carbon di oxi de gas when t hey come i nt o cont act wi t h wat er.
Commerci al al kal i ni zi ng anal gesi c t abl et s are of t en made t o ef f er vesce t o
encourage r api d di ssol ut i on and absor pt i on ( e. g. , Al ka- Sel t zer , Bayer ) .
( 2) Ot her t abl et s used t o pr epar e sol ut i ons i ncl ude di spensi ng t abl et s,
hypoder mi c t abl et s, and t abl et t r i t ur at es.
4. Pr ocessi ng probl ems
a. Cappi ng i s t he par t i al or compl et e separ at i on of t he t op or bot t om cr own
f r om t he mai n body of t he t abl et . Lami nat i on i s separat i on of a t abl et i nt o
t wo or mor e di st i nct l ayer s. These pr obl ems are usual l y caused by
ent r apment of ai r duri ng pr ocessi ng.
b. Pi cki ng i s removal of t he sur f ace mat er i al of a t abl et by a punch. St i cki ng
i s adhesi on of t abl et mat er i al t o a di e wal l . These pr obl ems are caused by
excessi ve moi st ure or t he i ncl usi on of subst ances wi t h l ow mel t i ng
t emper at ures i n t he f ormul at i on.
c. Mot t l i ng i s unequal col or di st r i but i on, wi t h l i ght or dar k ar eas st andi ng
out on an ot her wi se uni f or m surf ace. Thi s pr obl em occur s when a dr ug has
a di f f erent col or t han t he t abl et exci pi ent s or when a dr ug has col or ed
degradat i on product s. Col orant s sol ve t he probl em but can creat e ot her
pr obl ems.
5. Tabl et eval uat i on and cont r ol
a. The gener al appear ance of t abl et s i s an i mpor t ant f act or i n consumer
accept ance. Ì t al so al l ows moni t ori ng of l ot - t o-l ot uni f or mi t y, t abl et -t o- t abl et
uni f or mi t y, and el ement s of t he manuf act ur i ng process. The appearance of
t he t abl et i ncl udes vi sual i dent i t y and overal l appear ance. The appearance
of t he t abl et i s cont rol l ed by measurement of at t r i but es such as si ze, shape,
col or , odor , t ast e, surf ace, t ext ur e, physi cal f l aws, consi st ency, and
l egi bi l i t y of marki ngs.
b. Hardness and r esi st ance t o f r i abi l i t y ar e necessar y f or t abl et s t o
wi t hst and t he mechani cal shocks of manuf act ure, packagi ng, and shi ppi ng,
and t o ensur e consumer accept ance. Har dness i nvol ves bot h t abl et
di si nt egrat i on and dr ug di ssol ut i on. Cert ai n t abl et s t hat are i nt ended t o
di ssol ve sl owl y ar e made hard. Ot her t abl et s t hat ar e i nt ended t o di ssol ve
r api dl y are made sof t . Fri abi l i t y i s t he t endency of t he t abl et t o cr umbl e.
( 1) Tabl et har dness t est er s measur e t he degr ee of f or ce r equi r ed t o br eak a
t abl et .
( 2) Fri abi l at ors det er mi ne f r i abi l i t y by al l owi ng t he t abl et t o r ol l and f al l
wi t hi n a r ot at i ng t umbl i ng apparat us. The t abl et s ar e wei ghed bef ore and
af t er a speci f i ed number of r ot at i ons, and t he wei ght l oss i s det ermi ned.
( a) Resi st ance t o wei ght l oss i ndi cat es t he abi l i t y of t he t abl et t o wi t hst and
abr asi on dur i ng handl i ng, packagi ng, and shi ppi ng. Compressed t abl et s t hat
l ose < 0. 5%- 1% of t hei r wei ght are usual l y consi der ed accept abl e.
( b) Some chewabl e t abl et s and most ef f er vescent t abl et s ar e hi ghl y f ri abl e
and requi r e speci al uni t packagi ng.
c. Tabl et s are r out i nel y wei ghed t o ensur e t hat t hey cont ai n t he proper
amount of dr ug.
( 1) The USP def i nes a wei ght var i at i on st andar d t o whi ch t abl et s must
conf orm.
( 2) These st andards appl y t o t abl et s t hat cont ai n 50 mg or mor e of dr ug
subst ance when t he dr ug subst ance i s 50% or mor e ( by wei ght ) of t he
dosage f orm uni t .
d. Cont ent uni f or mi t y i s eval uat ed t o ensure t hat each t abl et cont ai ns t he
desi r ed amount of dr ug subst ance, wi t h l i t t l e vari at i on among cont ent s
wi t hi n a bat ch. The USP def i nes cont ent uni f or mi t y t est s f or t abl et s t hat
cont ai n 50 mg or l ess of dr ug subst ance.
e. Di si nt egr at i on i s eval uat ed t o ensure t hat t he dr ug subst ance i s f ul l y
avai l abl e f or di ssol ut i on and absorpt i on f r om t he gast r oi nt est i nal t ract .
( 1) Al l USP t abl et s must pass an of f i ci al di si nt egrat i on t est t hat i s
conduct ed i n vi t ro wi t h speci al equi pment .
( a) Di si nt egr at i on t i mes f or uncoat ed USP t abl et s ar e as l ow as 2 mi n
( ni t rogl ycer i n) t o 5 mi n (aspi r i n) . Most have a maxi mum di si nt egr at i on t i me
of l ess t han 30 mi n.
( b) Buccal t abl et s must di si nt egrat e wi t hi n 4 hr .
( c) Ent er i c-coat ed t abl et s must show no evi dence of di si nt egr at i on af t er 1
hr i n si mul at ed gast ri c f l ui d. Ì n si mul at ed i nt est i nal f l ui d, t hey shoul d
di si nt egrat e i n 2 hr pl us t he t i me speci f i ed.
P. 69


( 2) Di ssol ut i on requi r ement s i n t he USP have repl aced ear l i er di si nt egrat i on
r equi r ement s f or many dr ugs.
f . Di ssol ut i on charact er i st i cs ar e t est ed t o det ermi ne drug absorpt i on and
physi ol ogi c avai l abi l i t y.
( 1) The USP gi ves st andar ds f or t abl et di ssol ut i on.
( 2) An i ncr eased emphasi s on t est i ng t abl et di ssol ut i on and det ermi ni ng
dr ug bi oavai l abi l i t y has i ncr eased t he use of sophi st i cat ed t est i ng syst ems.
J. Aerosol pr oduct s
1. Ì nt r oduct i on. Aer osol pr oduct s, or aer osol s, are pr essuri zed dosage
f or ms. They ar e desi gned t o del i ver dr ug syst emi cal l y or t opi cal l y wi t h t he
ai d of a l i quef i ed or pr opel l ed gas ( propel l ant ). Aer osol pr oduct s consi st of
a pr essuri zabl e cont ai ner ( t i n- pl at ed st eel , al umi num, gl ass, or pl ast i c); a
val ve t hat al l ows t he pr essur i zed pr oduct t o be expel l ed f rom t he cont ai ner
( ei t her cont i nuousl y or i nt er mi t t ent l y) when t he act uat or i s pr essed; and a
di p t ube t hat conveys t he f ormul at i on f r om t he bot t om of t he cont ai ner t o
t he val ve assembl y. Aerosol s ar e pr epared by speci al met hods ( col d f i l l i ng,
pr essure f i l l i ng) because of t he gaseous component s.
2. Syst emi c or pul monary dr ug del i ver y i s provi ded by aer osol drug del i ver y
syst ems, or met ered dose i nhal ers ( MDÌ s) . These devi ces al l ow a dr ug t o be
i nhal ed as a f i ne mi st of dr ug or dr ug-cont ai ni ng par t i cl es. MDÌ s use speci al
met er i ng val ves t o regul at e t he amount of f or mul at i on and dr ug t hat i s
di spensed wi t h each dose ( i . e. , each act uat i on of t he cont ai ner ) . Aer osol
pr oduct s ar e used f or t opi cal dr ug del i ver y. The f or mul at i ons r ange f r om
sol ut i ons t o di spersi ons. Met er i ng val ves may al so be used wi t h t opi cal
aer osol product s t o r egul at e t he amount of drug appl i ed per appl i cat i on.
3. Pr opel l ant s used i n aer osol pr oduct s
a. Compressed gases i ncl ude carbon di oxi de, ni t r ogen, and ni t r ous oxi de.
Aer osol pr oduct s t hat cont ai n compr essed gas t end t o l ose pressure over
t i me as t he pr oduct i s di spensed. The drop i n pressur e r ef l ect s t he
expansi on of t he head space i n t he cont ai ner ( i . e. , i ncr ease i n t he vol ume
t hat t he gas can occupy) as f ormul at i on i s wi t hdrawn f or use. For t hi s
r eason, hi gher i ni t i al pressur es are t ypi cal l y used wi t h compressed gas-
based syst ems t han wi t h l i quef i abl e gas- based f or mul at i ons.
b. Li quef i abl e gases i ncl ude sat ur at ed hydr ocarbons ( n-but ane, i sobut ane,
pr opane); chl or of l uor ocar bons ( CFCs) , i ncl udi ng t et r af l uor odi chl or oet hane
( pr opel l ant 114) , di chl orodi f l uor omet hane ( pr opel l ant 12) , and
t r i chl or of l uoromet hane (pr opel l ant 11); di met hyl et her; and
hydr of l uorocar bons, such as 1, 1, 1, 2- f l uor oet hane ( propel l ant 134a) and 1, 1-
di f l uoroet hane ( pr opel l ant 152a). The negat i ve ef f ect of ol der CFCs on
at mospheri c ozone and t he pot ent i al f or gl obal war mi ng l ed t o t he
wor l dwi de r educt i on i n CFC pr oduct i on under t he Mont r eal Prot ocol . Thi s
pl an cal l ed f or a gener al ban on CFC product i on i n i ndust ri al i zed count r i es
by Januar y 1996. As a resul t , t he use of CFCs i n pharmaceut i cal product s
i s bei ng phased out . Temporar y exempt i ons f or CFCs i n MDÌ s wi l l
event ual l y l apse ( i n 2008) as st abl e, saf e, and ef f ect i ve al t er nat i ve
f or mul at i ons are devel oped wi t h more accept abl e pr opel l ant s ( e. g. ,
hydr of l uorocar bons) .
4. Advant ages of aerosol pr oduct s i ncl ude t he conveni ence of push- but t on
di spensi ng of medi cat i on and t he st abi l i t y af f or ded by a cl osed, pr essur i zed
cont ai ner t hat mi ni mi zes t he l i kel i hood of t amper i ng and pr ot ect s t he
cont ent s f r om l i ght , moi st ur e, ai r ( oxygen) , and mi cr obi al cont ami nat i on.
Aer osol f ormul at i ons and packagi ng component s (val ves, act uat ors) per mi t
a wi de r ange of pr oduct s t o be di spensed as sprays, f oams, or semi sol i ds.
5. The pr i nci pal di sadvant age of aer osol pr oduct s i s envi r onment al (e. g. ,
di sposal of pr essur i zed packages, vent i ng of propel l ant s t o t he
at mosphere) .
K. Cont rol l ed-r el ease dosage f or ms
1. Ì nt r oduct i on. Cont rol l ed- r el ease dosage f or ms ar e al so known as
del ayed- r el ease, sust ai ned- act i on, prol onged- act i on, sust ai ned- r el ease,
pr ol onged- rel ease, t i med- r el ease, sl ow- r el ease, ext ended- act i on, and
ext ended- rel ease f or ms. They ar e desi gned t o rel ease drug subst ance
sl owl y t o pr ovi de pr ol onged act i on i n t he body.
P. 70


2. Advant ages of cont rol l ed- r el ease f orms
a. Fewer pr obl ems wi t h pat i ent compl i ance
b. Use of l ess t ot al drug
c. Fewer l ocal or syst emi c si de ef f ect s
d. Mi ni mal dr ug accumul at i on wi t h l ong- t er m dosage
e. Fewer pr obl ems wi t h pot ent i at i on or l oss of drug act i vi t y wi t h l ong-t erm
use
f . Ì mpr oved t reat ment ef f i ci ency
g. Mor e r api d cont r ol of t he pat i ent ' s condi t i on
h. Less f l uct uat i on i n dr ug l evel
i . Ì mpr oved bi oavai l abi l i t y f or some drugs
j . Ì mpr oved abi l i t y t o provi de speci al ef f ect s (e. g. , mor ni ng rel i ef of ar t hr i t i s
by bedt i me dosi ng)
k. Reduced cost
3. Sust ai ned- rel ease f orms can be grouped accor di ng t o t hei r
pharmaceut i cal mechani sm.
a. Coat ed beads or granul es ( e. g. , Spansul es, Gl axoSmi t hKl i ne; Sequel s,
Wyet h) pr oduce a bl ood l evel pr of i l e si mi l ar t o t hat obt ai ned wi t h mul t i pl e
dosi ng.
( 1) A sol ut i on of t he dr ug subst ance i n a nonaqueous sol vent (e. g. , al cohol )
i s coat ed ont o smal l , i ner t beads, or granul es, made of a combi nat i on of
sugar and st ar ch. When t he dr ug dose i s l ar ge, t he st art i ng granul es may
be composed of t he drug i t sel f .
( 2) Some of t he gr anul es ar e l ef t uncoat ed t o provi de i mmedi at e r el ease of
t he dr ug.
( 3) Coat s of a l i pi d mat er i al ( e. g. , beeswax) or a cel l ul osi c mat eri al ( e. g. ,
et hyl cel l ul ose) ar e appl i ed t o t he remai ni ng granul es. Some granul es
r ecei ve f ew coat s, and some r ecei ve many. The var i ous coat i ng t hi cknesses
pr oduce a sust ai ned- rel ease ef f ect .
b. Mi cr oencapsul at i on i s a process by whi ch sol i ds, l i qui ds, or gases ar e
encased i n mi cr oscopi c capsul es. Thi n coat i ngs of a " wal l ¨ mat er i al ar e
f or med ar ound t he subst ance t o be encapsul at ed.
( 1) Coacer vat i on i s t he most common met hod of mi cr oencapsul at i on. Ì t
occurs when a hydr ophi l i c subst ance i s added t o a col l oi dal dr ug di spersi on
and causes l ayeri ng and t he f ormat i on of mi crocapsul es.
( 2) Fi l m- f ormi ng subst ances t hat ar e used as t he coat i ng mat er i al i ncl ude a
var i et y of nat ural and synt het i c pol ymer s. These mat er i al s i ncl ude shel l acs,
waxes, gel at i n, st ar ches, cel l ul ose acet at e pht hal at e, and et hyl cel l ul ose.
Af t er t he coat i ng mat eri al di ssol ves, al l of t he drug i nsi de t he mi crocapsul e
i s i mmedi at el y avai l abl e f or di ssol ut i on and absorpt i on. The t hi ckness of t he
wal l can var y f rom 1 t o 200 mm, dependi ng on t he amount of coat i ng
mat er i al used (3%- 30% of t ot al wei ght ) .
c. Mat r i x t abl et s use i nsol ubl e pl ast i cs (e. g. , pol yet hyl ene, pol yvi nyl
acet at e, pol ymet hacr yl at e) , hydrophi l i c pol ymers ( e. g. , met hyl cel l ul ose,
hydr oxypr opyl met hyl cel l ul ose) , or f at t y compounds (e. g. , var i ous waxes,
gl ycer yl t r i st ear at e) . Exampl es i ncl ude Gr adumet ( Abbot t ) and Dospan
( Avent i s) .
( 1) The most common met hod of prepar at i on i s mi xi ng of t he dr ug wi t h t he
mat ri x mat eri al f ol l owed by compressi on of t he mat eri al i nt o t abl et s.
( 2) The pr i mar y dose, or t he por t i on of t he drug t o be rel eased i mmedi at el y,
i s pl aced on t he t abl et as a l ayer, or coat . The r est of t he dose i s rel eased
sl owl y f r om t he mat r i x.
d. Osmot i c syst ems i ncl ude t he Or os syst em ( Al za) , whi ch i s an oral
osmot i c pump composed of a cor e t abl et and a semi permeabl e coat i ng t hat
has a smal l hol e ( 0. 4 mm i n di amet er ) f or dr ug exi t . The hol e i s produced by
a l aser beam. Exampl es i ncl ude Gl ucot r ol XL ( gl i pi zi de ext ended- r el ease
t abl et s, Pf i zer ) and Pr ocar di a XL ( ni f edi pi ne ext ended- r el ease t abl et s,
Pf i zer ) .
( 1) Thi s syst em r equi r es onl y osmot i c pr essur e t o be ef f ect i ve. Ì t i s
essent i al l y i ndependent of pH changes i n t he envi r onment .
( 2) The dr ug- rel ease rat e can be changed by changi ng t he t abl et sur f ace
ar ea, t he nat ure of t he membrane, or t he di amet er of t he dr ug- r el ease
aper t ur e.
e. Ì on- exchange r esi ns can be compl exed wi t h drugs by passage of a
cat i oni c dr ug sol ut i on t hrough a col umn t hat cont ai ns t he resi n. The drug i s
compl exed t o t he resi n by r epl acement of hydr ogen at oms. Exampl es
i ncl ude Ì onami n capsul es ( Cel l t ech; resi n compl exes of phent er mi ne) and
t he Pennki net i c syst em (Cel l t ech) , whi ch i ncor porat es a pol ymer bar ri er
coat i ng and bead t echnol ogy i n addi t i on t o t he i on- exchange mechani sm.
P. 71


( 1) Af t er t he component s ar e compl exed, t he resi n- dr ug compl ex i s washed
and t abl et ed, encapsul at ed, or suspended i n an aqueous vehi cl e.
( 2) Rel ease of dr ug f r om t he compl ex depends on t he i oni c envi r onment
wi t hi n t he gast r oi nt est i nal t ract and on t he pr oper t i es of t he resi n. Usual l y,
r el ease i s gr eat er i n t he hi ghl y aci di c st omach t han i n t he l ess aci di c smal l
i nt est i ne.
f . Compl ex f or mat i on i s used f or cer t ai n dr ug subst ances t hat combi ne
chemi cal l y wi t h ot her agent s. For exampl e, hydr oxypr opyl - 8- cycl odext r i n
f or ms a chemi cal compl ex t hat can be onl y sl owl y sol ubl e f r om body f l ui ds,
dependi ng on t he pH of t he envi r onment . Tanni c aci d (i . e. , t annat es)
compl exes wi t h t he ami no gr oups of weak bases di ssol ve at a sl ow r at e i n
t he gast r oi nt est i nal t r act , t her eby pr ovi di ng f or a pr ol onged rel ease of dr ug.
Exampl es of t he l at t er i ncl ude br ompheni r ami ne t annat e ( Br ovex, At hl on)
and chl orpheni rami ne/ phenyl ephr i ne t annat es ( Rynat an, Wal l ace) .
P. 72


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 28: Each of t he quest i ons, st at ement s, or
i ncompl et e st at ement s i n t hi s sect i on can be cor rect l y answer ed or
compl et ed by one of t he suggest ed answer s or phr ases. Choose t he best
answer .
1. Whi ch subst ance i s cI assi f i ed as a weak eI ect roI yt e?
( A) gl ucose
( B) ur ea
( C) ephedri ne
( D) sodi um chl ori de
( E) sucrose
Vi ew Answer 1. The answer i s C[ see] . 2. The pH vaI ue i s caI cuI ated
mat hemati caI I y as t he
( A) l og of t he hydroxyl i on ( OH- ) concent r at i on.
( B) negat i ve l og of t he OH
-
concent r at i on.
( C) l og of t he hydrogen i on ( H
+
) concent rat i on.
( D) negat i ve l og of t he H
+
concent r at i on.
( E) r at i o of H
+
/ OH
-
concent r at i on.
Vi ew Answer 2. The answer i s D[ see] . 3. Whi ch propert y i s
cI assi f i ed as coI I i gati ve?
( A) sol ubi l i t y of a sol ut e
( B) osmot i c pressure
( C) hydr ogen i on ( H
+
) concent r at i on
( D) di ssoci at i on of a sol ut e
( E) mi sci bi l i t y of t he l i qui ds
Vi ew Answer 3. The answer i s B[ see] . 4. The coI I i gat i ve propert i es
of a soI uti on are reI ated t o t he
( A) pH of t he sol ut i on.
( B) number of i ons i n t he sol ut i on.
( C) t ot al number of sol ut e part i cl es i n t he sol ut i on.
( D) number of uni oni zed mol ecul es i n t he sol ut i on.
( E) pKa of t he sol ut i on.
Vi ew Answer 4. The answer i s C[ see] . 5. The pH of a buf fer syst em
can be caI cuI ated wi th t he
( A) Noyes-Whi t ney equat i on.
( B) Henderson- Hassel bal ch equat i on.
( C) Mi chael i s- Ment en equat i on.
( D) Young equat i on.
( E) St okes equat i on.
Vi ew Answer 5. The answer i s B[ see] . 6. Whi ch mechani sm i s most
of t en responsi bI e f or chemi caI degradati on?
( A) r acemi zat i on
( B) phot ol ysi s
( C) hydr ol ysi s
( D) decarboxyl at i on
( E) oxi dat i on
Vi ew Answer 6. The answer i s C[ see] . 7. Whi ch equati on i s used t o
predi ct t he stabi I i t y of a drug product at room t emperat ure f rom
experi ment s at acceI erat ed temperat ures?
( A) St okes equat i on
( B) Young equat i on
( C) Ar r heni us equat i on
( D) Mi chael i s- Ment en equat i on
( E) Hi xson- Cr owel l equat i on
Vi ew Answer 7. The answer i s C[ see] . kkk8. Based on t he reI at i on
between t he degree of i oni zat i on and t he soI ubi I i t y of a weak aci d, t he
drug aspi ri n ( pKa 3. 49) wi I I be most soI ubI e at
( A) pH 1. 0
( B) pH 2. 0
( C) pH 3. 0
( D) pH 4. 0
( E) pH 6. 0
Vi ew Answer 8. The answer i s E[see] . 9. Whi ch soI ut i on i s used as
an ast ri ngent ?
( A) st rong i odi ne sol ut i on USP
( B) al umi num acet at e t opi cal sol ut i on USP
( C) acet i c aci d NF
( D) ar omat i c ammoni a spi r i t USP
( E) benzal koni um chl or i de sol ut i on NF
Vi ew Answer 9. The answer i s B[ see] . 10. The part i cI e si ze of the
di spersed soI i d i n a suspensi on i s usuaI I y great er t han
( A) 0. 5 µm
( B) 0. 4 µm
( C) 0. 3 µm
( D) 0. 2 µm
( E) 0. 1 µm
Vi ew Answer 10. The answer i s A[ see] . 11. I n t he ext emporaneous
preparat i on of a suspensi on, I evi gat i on i s used t o
( A) r educe t he zet a pot ent i al .
( B) avoi d bact er i al gr owt h.
( C) r educe par t i cl e si ze.
( D) enhance vi scosi t y.
( E) r educe vi scosi t y.
Vi ew Answer 11. The answer i s C[ see] . 12. Whi ch compound i s a
nat uraI emuI si f yi ng agent ?
( A) acaci a
( B) l act ose
( C) pol ysorbat e 20
( D) pol ysorbat e 80
( E) sor bi t an monopal mi t at e
Vi ew Answer 12. The answer i s A[ see] . Acaci a, P. 73


13. Vani shi ng cream i s an oi nt ment that may be cI assi f i ed as
( A) a wat er -sol ubl e base.
( B) an ol eagi nous base.
( C) an absorpt i on base.
( D) an emul si on base.
( E) an ol ei c base.
Vi ew Answer 13. The answer i s D[ see] . 14. Rect aI supposi t ori es
i nt ended f or aduI t use usuaI I y wei gh approxi mat eI y
( A) 1 g.
( B) 2 g.
( C) 3 g.
( D) 4 g.
( E) 5 g.
Vi ew Answer 14. The answer i s B[ see] . 15. I n t he f usi on met hod of
maki ng cocoa but t er supposi t ori es, whi ch subst ance i s most I i keI y t o
be used to I ubri cat e the moI d?
( A) mi neral oi l
( B) pr opyl ene gl ycol
( C) cet yl al cohol
( D) st ear i c aci d
( E) magnesi um si l i cat e
Vi ew Answer 15. The answer i s A[ see] . 16. A very f i ne powdered
chemi caI i s defi ned as one that
( A) compl et el y passes t hr ough a #80 si eve.
( B) compl et el y passes t hr ough a #120 si eve.
( C) compl et el y passes t hr ough a #20 si eve.
( D) passes t hrough a #60 si eve and not mor e t han 40% t hr ough a
#100 si eve.
( E) passes t hrough a #40 si eve and not mor e t han 60% t hr ough a
#60 si eve.
Vi ew Answer 16. The answer i s B[ see] . 17. Whi ch t echni que i s
t ypi caI I y used t o mi I I camphor?
( A) t r i t ur at i on
( B) l evi gat i on
( C) pul ver i zat i on by i nt ervent i on
( D) geomet r i c di l ut i on
( E) at t ri t i on
Vi ew Answer 17. The answer i s C[ see] . 18. The di spensi ng
pharmaci st usuaI I y bI ends pot ent powders wi th a I arge amount of
di I uent by
( A) spat ul at i on.
( B) si f t i ng.
( C) t r i t ur at i on.
( D) geomet r i c di l ut i on.
( E) l evi gat i on.
Vi ew Answer 18. The answer i s D[ see] . 19. Whi ch t ype of paper
best prot ect s a di vi ded hygroscopi c powder?
( A) waxed paper
( B) gl assi ne
( C) whi t e bond
( D) bl ue bond
( E) veget abl e parchment
Vi ew Answer 19. The answer i s A[ see] . 20. Whi ch capsuI e si ze has
t he smaI I est capaci t y?
( A) 5
( B) 4
( C) 1
( D) 0
( E) 000
Vi ew Answer 20. The answer i s A[ see] . 21. The sheI I s of sof t
geI ati n capsuI es may be made eI ast i c or pI asti c- I i ke by t he addi t i on of
( A) sor bi t ol .
( B) povi done.
( C) pol yet hyl ene gl ycol (PEG) .
( D) l act ose.
( E) hydr oxypr opyl met hyl cel l ul ose.
Vi ew Answer 21. The answer i s A[ seeand] . 22. The Uni ted Stat es
Pharmacopei a ( USP) cont ent uni formi t y t est f or t abI et s i s used t o
ensure whi ch quaI i t y?
( A) bi oequi val ency
( B) di ssol ut i on
( C) pot ency
( D) puri t y
( E) t oxi ci t y
Vi ew Answer 22. The answer i s C[ see] . 23. AI I of t he f oI I owi ng
st at ements about chemi caI degradati on are t rue except
( A) as t emper at ur e i ncr eases, degr adat i on decr eases.
( B) most dr ugs degr ade by a f i r st - or der pr ocess.
( C) chemi cal degr adat i on may pr oduce a t oxi c product .
( D) chemi cal degr adat i on may r esul t i n a l oss of act i ve i ngr edi ent s.
( E) chemi cal degr adat i on may af f ect t he t her apeut i c act i vi t y of a
dr ug.
Vi ew Answer 23. The answer i s A[ seeand] . kAe
- Ea/ RT
kAEaRT24. AI I
of t he f oI I owi ng st atement s concerni ng zero-order degradat i on are t rue
except
( A) i t s r at e i s i ndependent of t he concent r at i on.
( B) a pl ot of concent r at i on ver sus t i me yi el ds a st r ai ght l i ne on
r ect i l i near paper .
( C) i t s hal f -l i f e i s a changi ng par amet er .
( D) i t s concent r at i on r emai ns unchanged wi t h r espect t o t i me.
( E) t he sl ope of a pl ot of concent rat i on versus t i me yi el ds a r at e
const ant .
Vi ew Answer 24. The answer i s D[ see] . Ct P. 74


25. AI I of t he f oI I owi ng st at ements about f i rst -order degradat i on are
t rue except
( A) i t s r at e i s dependent on t he concent rat i on.
( B) i t s hal f - l i f e i s a changi ng par amet er .
( C) a pl ot of t he l ogari t hm of concent r at i on ver sus t i me yi el ds a
st r ai ght l i ne.
( D) i t s t 90% i s i ndependent of t he concent r at i on.
( E) a pl ot of t he l ogari t hm of concent r at i on ver sus t i me al l ows t he
r at e const ant t o be det ermi ned.
Vi ew Answer 25. The answer i s B[ see] . t kt26. A sat i sfact or y
supposi t or y base must meet aI I of the foI I owi ng cri t eri a except
( A) i t shoul d have a nar row mel t i ng r ange.
( B) i t shoul d be noni r r i t at i ng and nonsensi t i zi ng.
( C) i t shoul d di ssol ve or di si nt egrat e r api dl y i n t he body cavi t y.
( D) i t shoul d mel t < 30°C.
( E) i t shoul d be i nert .
Vi ew Answer 26. The answer i s D[ see] . 27. Cocoa but t er
( t heobroma oi I ) exhi bi ts aI I of the foI I owi ng propert i es except
( A) i t mel t s at t emper at ur es bet ween 33°C and 35°C.
( B) i t i s a mi xt ur e of gl ycer i des.
( C) i t i s a pol ymor ph.
( D) i t i s usef ul i n f or mul at i ng r ect al supposi t or i es.
( E) i t i s sol ubl e i n wat er .
Vi ew Answer 27. The answer i s E[see] . Theobroma cacao. 28.
Uni t ed St at es Pharmacopei a ( USP) tests t o ensure the quaI i t y of drug
products i n t abI et f orm i ncI ude aI I of the foI I owi ng except
( A) di si nt egr at i on.
( B) di ssol ut i on.
( C) hardness and f ri abi l i t y.
( D) cont ent uni f ormi t y.
( E) wei ght vari at i on.
Vi ew Answer 28. The answer i s C[ see] . Di recti ons f or questi ons
29- 42: The quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be
cor rect l y answer ed or compl et ed by one or more of t he suggest ed answer s.
Choose t he answer , A- E.
29. Forms of water t hat are sui t abI e f or use i n parenteraI preparat i ons
i ncI ude
I . puri f i ed wat er USP.
I I . water f or i nj ect i on USP.
I I I . st eri I e water f or i nj ect i on USP.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 29. The answer i s D[ see] . 30. The part i cI es i n an i deaI
suspensi on shouI d sat i sf y whi ch of t he f oI I owi ng cri teri a?
I . Thei r si ze shouI d be uni f orm.
I I . They shouI d be st at i onar y or move randomI y.
I I I . They shouI d remai n di scret e.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 30. The answer i s E[see] . 31. The sedi ment ati on of
part i cI es i n a suspensi on can be mi ni mi zed by
I . addi ng sodi um benzoat e.
I I . i ncreasi ng t he vi scosi t y of t he suspensi on.
I I I . reduci ng t he part i cI e si ze of t he act i ve i ngredi ent .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 31. The answer i s D[ see] . 32. I ngredi ents t hat may be
used as suspendi ng agent s i ncI ude
I . met hyI ceI I uI ose.
I I . acaci a.
I I I . taI c.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 32. The answer i s C[ see] . 33. Mechani sms that are
t hought t o provi de st abI e emuI si f i cat i ons i ncI ude t he
I . f ormat i on of i nt erfaci aI f i I m.
I I . I oweri ng of i nt erf aci aI t ensi on.
I I I . presence of charge on t he i ons.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 33. The answer i s E[see] . 34. Noni oni c surf ace- act i ve
agents used as synt het i c emuI si f i ers i ncI ude
I . t ragacant h.
I I . sodi um I aur yI suI f ate.
I I I . sorbi tan est ers ( Spans) .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 34. The answer i s B[ see] . 35. Advant ages of syst emi c
drug admi ni st rat i on by rect aI supposi t ori es i ncI ude
I . avoi dance of f i rst -pass eff ects.
I I . sui t abi I i t y when t he oraI rout e i s not f easi bI e.
I I I . predi ct abI e drug reI ease and absorpti on.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 35. The answer i s C[ seeand] . 36. True stat ements
about t he mi I I i ng of powders i ncI ude
I . a fi ne part i cI e si ze i s essent i aI i f t he I ubri cant i s t o f unct i on
properI y.
I I . an i ncreased surface area may enhance the di ssoI ut i on rat e.
I I I . mi I I i ng may cause degradat i on of thermoI abi I e drugs.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 36. The answer i s E[see] . P. 75


37. Substances used t o i nsuI at e powder components t hat I i quef y when
mi xed i ncI ude
I . t aI c.
I I . kaoI i n.
I I I . I i ght magnesi um oxi de.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 37. The answer i s D[ see] . 38. A cerami c mortar may
be pref erabI e to a gI ass mortar when
I . a voI at i I e oi I i s added t o a powder mi xt ure.
I I . coI ored substances ( dyes) are mi xed i nt o a powder.
I I I . commi nut i on i s desi red i n addi t i on t o mi xi ng.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 38. The answer i s B[ see] . 39. Di vi ded powders may
be di spensed i n
I . i ndi vi duaI - dose packet s.
I I . a buI k cont ai ner.
I I I . a perforat ed, si f t er-t ype cont ai ner.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 39. The answer i s A[ seeand] . 40. True stat ements
about t he f unct i on of exci pi ents used i n tabI et f ormuI at i ons i ncI ude
I . bi nders promot e granuI at i on duri ng t he wet granuI at i on process.
I I . gI i dant s heI p promote t he f I ow of t he t abI et granuI at i on duri ng
manufacture.
I I I . I ubri cants heI p the pat i ent swaI I ow the tabI et s.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 40. The answer i s C[ see] . 41. Whi ch manuf acturi ng
vari abI es wouI d be I i keI y t o af f ect the di ssoI uti on of a predni sone
t abI et i n t he body?
I . t he amount and t ype of bi nder added
I I . t he amount and t ype of di si ntegrant added
I I I . the force of compressi on used duri ng t abI et i ng
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 41. The answer i s E[see VI . 2. b. (3)] . 42. Agents t hat
may be used t o coat ent eri c- coated tabI et s i ncI ude
I . hydroxypropyI met hyI ceI I uI ose.
I I . carboxymet hyI ceI I uI ose.
I I I . ceI I uI ose acetat e pht haI ate.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 42. The answer i s B[ see] . Di recti ons f or questi ons
43- 46: Each of t he f ol l owi ng t abl et -pr ocessi ng pr obl ems can be t he r esul t of
one t he f ol l owi ng r easons. The pr ocessi ng probl ems may be used more t han
once or not at al l . Choose t he best answer , A- E.
43. Pi cki ng
A excessi ve moi st ur e i n t he gr anul at i on
B ent rapment of ai r
C t abl et f r i abi l i t y
D degraded dr ug
E t abl et hardness
Vi ew Answer 43. The answer i s A[ see] . 44. Mot t I i ng
A excessi ve moi st ur e i n t he gr anul at i on
B ent rapment of ai r
C t abl et f r i abi l i t y
D degraded dr ug
E t abl et hardness
Vi ew Answer 44. The answer i s D[ see] . 45. Cappi ng
A excessi ve moi st ur e i n t he gr anul at i on
B ent rapment of ai r
C t abl et f r i abi l i t y
D degraded dr ug
E t abl et hardness
Vi ew Answer 45. The answer i s B[ see] . 46. St i cki ng
A excessi ve moi st ur e i n t he gr anul at i on
B ent rapment of ai r
C t abl et f r i abi l i t y
D degraded dr ug
E t abl et hardness
Vi ew Answer 46. The answer i s A[ see] . Di recti ons f or questi ons
47- 49: Each of t he f ol l owi ng pr ocesses can be descr i bed by one of t he
f ol l owi ng commi nut i on procedures. The processes may be used mor e t han
once or not at al l . Choose t he best answer , A- E.
47. Rubbi ng or gri ndi ng a substance i n a mortar t hat has a rough i nner
surf ace
A t r i t ur at i on
B spat ul at i on
C l evi gat i on
D pul veri zat i on by i nt er vent i on
E t umbl i ng
Vi ew Answer 47. The answer i s A[ see] . 48. Reduci ng and
subdi vi di ng a substance by addi ng an easi I y r emoved soI vent
A t r i t ur at i on
B spat ul at i on
C l evi gat i on
D pul veri zat i on by i nt er vent i on
E t umbl i ng
Vi ew Answer 48. The answer i s D[ see] . 49. Addi ng a sui t abI e agent to f orm
a past e and t hen rubbi ng or gri ndi ng the paste i n a mort ar
A t r i t ur at i on
B spat ul at i on
C l evi gat i on
D pul veri zat i on by i nt er vent i on
E t umbl i ng
Vi ew Answer 49. The answer i s C[ see] . P. 76


Di rect i ons for quest i ons 50-53: Each of t he f ol l owi ng cont rol l ed-r el ease dosage
f or ms i s represent ed by one of t he f ol l owi ng dr ug pr oduct s. The dosage f or ms may
be used mor e t han once or not at al l . Choose t he best answer , A- E.
50. I onami n capsuI es
A mat r i x f or mul at i ons
B i on-exchange resi n compl ex
C dr ug compl exes
D osmot i c syst em
E coat ed beads or granul es
Vi ew Answer 50. The answer i s B[ see] . 51. Thorazi ne SpansuI e capsuI es
A mat r i x f or mul at i ons
B i on-exchange resi n compl ex
C dr ug compl exes
D osmot i c syst em
E coat ed beads or granul es
Vi ew Answer 51. The answer i s E[see] . 52. Rynat an pedi at ri c suspensi on
A mat r i x f or mul at i ons
B i on-exchange resi n compl ex
C dr ug compl exes
D osmot i c syst em
E coat ed beads or granul es
Vi ew Answer 52. The answer i s C[ see] . 53. Procardi a XL
A mat r i x f or mul at i ons
B i on-exchange resi n compl ex
C dr ug compl exes
D osmot i c syst em
E coat ed beads or granul es
Vi ew Answer 53. The answer i s D[ see] . P. 77


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì V. A. 1. a; Ì V. A. 3. d] .
Gl ucose, urea, and sucrose ar e nonel ect r ol yt es. Sodi um chl ori de i s a st rong
el ect r ol yt e. El ect rol yt es ar e subst ances t hat f orm i ons when di ssol ved i n wat er .
Thus t hey can conduct an el ect r i c cur r ent t hr ough t he sol ut i on. Ì ons ar e par t i cl es
t hat bear el ect r i cal charges: Cat i ons ar e posi t i vel y char ged, and ani ons ar e
negat i vel y char ged. St r ong el ect r ol yt es are compl et el y i oni zed i n wat er at al l
concent r at i ons. Weak el ect rol yt es (e. g. , ephedr i ne) ar e onl y par t i al l y i oni zed at
most concent r at i ons. Because nonel ect r ol yt es do not f orm i ons when i n sol ut i on,
t hey are nonconduct ors.
2. The answer i s D [ see Ì V. A. 3. b] .
The pH i s a measur e of t he aci di t y, or hydr ogen i on concent r at i on, of an aqueous
sol ut i on. The pH i s t he l ogari t hm of t he reci pr ocal of t he hydr ogen i on ( H
+
)
concent r at i on expr essed i n mol es per l i t er . Because t he l ogari t hm of a r eci procal
equal s t he negat i ve l ogar i t hm of t he number , t he pH i s t he negat i ve l ogar i t hm of t he
H
+
concent r at i on. A pH of 7. 0 i ndi cat es neut r al i t y. As t he pH decreases, t he aci di t y
i ncreases. The pH of art er i al bl ood i s 7. 35- 7. 45; of uri ne, 4. 8- 7. 5; of gast r i c j ui ce,
approxi mat el y 1. 4; and of cer ebrospi nal f l ui d, 7. 35- 7. 40. The concept of pH was
i nt roduced by Sör ensen i n t he ear l y 1900s. Al kal i ni t y i s t he negat i ve l ogari t hm of
[ OH
-
] and i s i nversel y r el at ed t o aci di t y.
3. The answer i s B [ see Ì V. A. 2. d] .
Osmot i c pressure i s an exampl e of a col l i gat i ve pr opert y. The osmot i c pr essur e i s
t he magni t ude of pressure needed t o st op osmosi s acr oss a semi permeabl e
membr ane bet ween a sol ut i on and a pur e sol vent . The col l i gat i ve pr oper t i es of a
sol ut i on depend on t he t ot al number of di ssoci at ed and undi ssoci at ed sol ut e
par t i cl es. These pr oper t i es ar e i ndependent of t he si ze of t he sol ut e. Ot her
col l i gat i ve propert i es of sol ut es ar e reduct i on i n t he vapor pressure of t he sol ut i on,
el evat i on of i t s boi l i ng poi nt , and depressi on of i t s f reezi ng poi nt .
4. The answer i s C [ see Ì V. A. 1. b] .
The col l i gat i ve pr oper t i es of a sol ut i on are r el at ed t o t he t ot al number of sol ut e
par t i cl es t hat i t cont ai ns. Exampl es of col l i gat i ve pr oper t i es ar e t he osmot i c
pr essure, l ower i ng of t he vapor pr essur e, el evat i on of t he boi l i ng poi nt , and
depressi on of t he f r eezi ng, or mel t i ng, poi nt .
5. The answer i s B [ see Ì V. A. 3. e] .
The Hender son- Hassel bal ch equat i on f or a weak aci d and i t s sal t i s as f ol l ows:

wher e pKa i s t he negat i ve l og of t he di ssoci at i on const ant of a weak aci d and
[ sal t ] / [ aci d] i s t he rat i o of t he mol ar concent r at i on of sal t and aci d used t o pr epar e a
buf f er .
6. The answer i s C [ see V. D. 1] .
Al t hough al l of t he mechani sms l i st ed can be responsi bl e, t he chemi cal degr adat i on
of medi ci nal compounds, par t i cul ar l y est er s i n l i qui d f ormul at i ons, i s usual l y caused
by hydr ol ysi s. For t hi s r eason, dr ugs t hat have est er f unct i onal groups ar e
f or mul at ed i n dr y f or m whenever possi bl e. Oxi dat i on i s anot her common mode of
degradat i on and i s mi ni mi zed by i ncl udi ng ant i oxi dant s (e. g. , ascor bi c aci d) i n drug
f or mul at i ons. Phot ol ysi s i s reduced by packagi ng suscept i bl e product s i n amber or
opaque cont ai ner s. Decar boxyl at i on, whi ch i s t he r emoval of COOH gr oups, af f ect s
compounds t hat i ncl ude car boxyl i c aci d. Racemi zat i on neut ral i zes t he ef f ect s of an
opt i cal l y act i ve compound by conver t i ng hal f of i t s mol ecul es i nt o t hei r mi r r or - i mage
conf i gur at i on. As a r esul t , t he dext r or ot at or y and l evor ot at or y f orms cancel each
ot her out . Thi s t ype of degr adat i on af f ect s onl y dr ugs t hat ar e char act eri zed by
opt i cal i someri sm.
7. The answer i s C [ see V. E. 3. d] .
Test i ng of a dr ug f or mul at i on t o det ermi ne i t s shel f l i f e can be accel erat ed by
appl yi ng t he Ar r heni us equat i on t o dat a obt ai ned at hi gher t emperat ures. The
met hod i nvol ves det ermi ni ng t he r at e const ant ( k) val ues f or t he degr adat i on of a
dr ug at vari ous el evat ed t emper at ures. The l og of k i s pl ot t ed agai nst t he r eci pr ocal
of t he absol ut e t emperat ur e, and t he k val ue f or degradat i on at r oom t emper at ur e i s
obt ai ned by ext r apol at i on.
P. 78


8. The answer i s E [ see Ì V. A. 3. g] .
The sol ubi l i t y of a weak aci d var i es as a f unct i on of pH. Because pH and pKa ( t he
di ssoci at i on const ant ) are r el at ed, sol ubi l i t y i s al so rel at ed t o t he degr ee of
i oni zat i on. Aspi r i n i s a weak aci d t hat i s compl et el y i oni zed at a pH t hat i s 2 uni t s
gr eat er t han i t s pKa. Ther ef ore, i t i s most sol ubl e at pH 6. 0.
9. The answer i s B [ see VÌ . B. 7] .
Al umi num acet at e and al umi num subacet at e sol ut i ons are ast ri ngent s t hat ar e used
as ant i perspi r ant s and as wet dr essi ngs f or cont act dermat i t i s. St r ong i odi ne
sol ut i on and benzal koni um chl or i de ar e t opi cal ant i bact er i al sol ut i ons. Acet i c aci d i s
added t o product s as an aci di f i er. Ar omat i c ammoni a spi r i t i s a r espi r at or y
st i mul ant .
10. The answer i s A [ see Ì V. B. 1. a] .
A suspensi on i s a t wo- phase syst em t hat consi st s of a f i nel y powder ed sol i d
di spersed i n a l i qui d vehi cl e. The part i cl e si ze of t he suspended sol i d shoul d be as
smal l as possi bl e t o mi ni mi ze sedi ment at i on, but i t i s usual l y > 0. 5 µm.
11. The answer i s C [ see VÌ . E. 3. a] .
Levi gat i on i s t he pr ocess of bl endi ng and gri ndi ng a subst ance t o separ at e t he
par t i cl es, r educe t hei r si ze, and f or m a past e. Levi gat i on i s perf ormed by addi ng a
smal l amount of sui t abl e l evi gat i ng agent (e. g. , gl ycer i n) t o t he sol i d and bl endi ng
t he mi xt ur e wi t h a mor t ar and pest l e.
12. The answer i s A [ see VÌ . D. 3] .
Acaci a, or gum ar abi c, i s t he exudat e obt ai ned f rom t he st ems and br anches of
var i ous speci es of Acaci a, a woody pl ant nat i ve t o Af r i ca. Acaci a i s a nat ur al
emul si f yi ng agent t hat provi des a st abl e emul si on of l ow vi scosi t y. Emul si ons ar e
dr opl et s of one or mor e i mmi sci bl e l i qui ds di spersed i n anot her l i qui d. Emul si ons
ar e i nher ent l y unst abl e: t he dr opl et s t end t o coal esce i nt o l ar ger and l ar ger drops.
The pur pose of an emul si f yi ng agent i s t o keep t he dr opl et s di sper sed and pr event
t hem f rom coal esci ng. Pol ysorbat e 20, pol ysor bat e 80, and sorbi t an monopal mi t at e
ar e al so emul si f i ers, but ar e synt het i c, not nat ur al , subst ances.
13. The answer i s D [ see VÌ . E. 2] .
Oi nt ment s ar e t ypi cal l y used as emol l i ent s t o sof t en t he ski n, as prot ect i ve barr i ers,
or as vehi cl es f or medi cat i on. A var i et y of oi nt ment bases are avai l abl e. Vani shi ng
cr eam, an emul si on t ype of oi nt ment base, i s an oi l -i n- wat er emul si on t hat cont ai ns
a hi gh percent age of wat er . St eari c aci d i s used t o creat e a t hi n f i l m on t he ski n
when t he wat er evapor at es.
14. The answer i s B [ see VÌ . F. 2. a] .
By convent i on, a r ect al supposi t or y f or an adul t wei ghs appr oxi mat el y 2 g.
Supposi t ori es f or i nf ant s and chi l dr en are smal l er. Vagi nal supposi t or i es t ypi cal l y
wei gh appr oxi mat el y 5 g. Rect al supposi t ori es are usual l y shaped l i ke an el ongat ed
bul l et ( cyl i ndri cal and t aper ed at one end) . Vagi nal supposi t or i es ar e usual l y ovoi d.
15. The answer i s A [ see VÌ . F. 4. c] .
Ì n t he f usi on met hod of maki ng supposi t or i es, mol ds made of al umi num, br ass, or
ni ckel - copper al l oys ar e used. Fi nel y powder ed dr ug mi xed wi t h mel t ed cocoa but t er
i s poured i nt o a mol d t hat i s l ubr i cat ed ver y l i ght l y wi t h mi ner al oi l .
16. The answer i s B [ see VÌ . G; Tabl e 3- 8] .
The USP def i nes a ver y f i ne chemi cal powder as one t hat compl et el y passes
t hr ough a st andard #120 si eve, whi ch has 125- µm openi ngs. The USP cl assi f i cat i on
f or powder ed veget abl e and ani mal dr ugs di f f ers f r om t hat f or powder ed chemi cal s.
To be cl assi f i ed as ver y f i ne, powder ed veget abl e and ani mal drugs must pass
compl et el y t hrough a #80 si eve, whi ch has 180- µm openi ngs.
17. The answer i s C [ see VÌ . G. 1. c. ( 3. (b) ] .
Pul ver i zat i on by i nt er vent i on i s t he mi l l i ng t echni que t hat i s used f or drug
subst ances t hat ar e gummy and t end t o reaggl omer at e or r esi st gri ndi ng (e. g. ,
camphor , i odi ne) . Ì n t hi s sense, i nt er vent i on i s t he addi t i on of a smal l amount of
mat er i al t hat ai ds mi l l i ng and can be removed easi l y af t er pul ver i zat i on i s compl et e.
For exampl e, camphor can be r educed r eadi l y i f a smal l amount of vol at i l e sol vent
( e. g. , al cohol ) i s added. The sol vent i s t hen al l owed t o evapor at e.
P. 79


18. The answer i s D [ see VÌ . G. 2. c] .
The pharmaci st uses geomet r i c di l ut i on t o mi x pot ent subst ances wi t h a l ar ge
amount of di l uent . The pot ent drug and an equal amount of di l uent ar e f i rst mi xed i n
a mor t ar by t ri t urat i on. A vol ume of di l uent equal t o t he mi xt ur e i n t he mort ar i s
added, and t he mi x i s agai n t r i t ur at ed. The procedur e i s r epeat ed, and each t i me,
di l uent equal i n vol ume t o t he mi xt ur e t hen i n t he mort ar i s added, unt i l al l of t he
di l uent i s i ncor por at ed.
19. The answer i s A [ see VÌ . G. 3. b. (4) ] .
Hygr oscopi c and vol at i l e dr ugs ar e best pr ot ect ed by waxed paper , whi ch i s
wat er pr oof . The packet may be doubl e- wr apped wi t h a bond paper t o i mpr ove t he
appear ance of t he compl et ed powder .
20. The answer i s A [ see VÌ . H. 2. c. ( 1)] .
Har d capsul es are number ed f r om 000 (l argest ) t o 5 (smal l est ) . Thei r appr oxi mat e
capaci t y r anges f r om 600 t o 30 mg; however , t he capaci t y of t he capsul e depends
on t he densi t y of t he cont ent s.
21. The answer i s A [ see VÌ . H. 3. a and b] .
The shel l s of sof t gel at i n capsul es ar e pl ast i ci zed by t he addi t i on of a pol yhydr i c
al cohol (pol yol ) , such as gl ycer i n or sorbi t ol . An ant i f ungal preser vat i ve can al so be
added. Bot h hard and sof t gel at i n capsul es can be f i l l ed wi t h a powder or anot her
dr y subst ance. Sof t gel at i n capsul es are al so usef ul dosage f orms f or f l ui ds or
semi sol i ds.
22. The answer i s C [ see VÌ . H. 4. a] .
A cont ent uni f ormi t y t est i s a t est of pot ency. To ensur e t hat each t abl et or capsul e
cont ai ns t he i nt ended amount of dr ug subst ance, t he USP provi des t wo t est s: wei ght
var i at i on and cont ent uni f or mi t y. The cont ent uni f or mi t y t est can be used f or any
dosage uni t , but i s r equi r ed f or coat ed t abl et s, f or t abl et s i n whi ch t he act i ve
i ngredi ent makes up < 50% of t he t abl et , f or suspensi ons i n si ngl e-uni t cont ai ner s or
i n sof t capsul es, and f or many sol i ds t hat cont ai n added subst ances. The wei ght
var i at i on t est can be used f or l i qui d- f i l l ed sof t capsul es, f or any dosage f or m uni t
t hat cont ai ns at l east 50 mg of a si ngl e dr ug i f t he dr ug makes up at l east 50% of
t he bul k, f or sol i ds t hat do not cont ai n added subst ances, and f or f r eeze- dr i ed
sol ut i ons.
23. The answer i s A [ see V. A and V. B] .
The r eact i on vel oci t y, or degradat i on r at e, of a phar maceut i cal pr oduct i s af f ect ed
by several f act ors, i ncl udi ng t emper at ur e, sol vent s, and l i ght . The degradat i on r at e
i ncreases t wo t o t hree t i mes wi t h each 10° i ncrease i n t emper at ur e. The ef f ect of
t emper at ure on r eact i on r at e i s gi ven by t he Ar r heni us equat i on:
k = Ae
- Ea/ RT

wher e k i s t he r eact i on rat e const ant , A i s t he f r equency f act or , Ea i s t he energy of
act i vat i on, R i s t he gas const ant , and T i s t he absol ut e t emper at ure.
24. The answer i s D [ see V. B. 2. a] .
Ì n zer o-or der degradat i on, t he concent r at i on of a dr ug decr eases over t i me.
However , t he change of concent r at i on wi t h respect t o t i me i s unchanged. Ì n t he
equat i on:

t he f act t hat dC/ dt i s negat i ve si gni f i es t hat t he concent rat i on i s decr easi ng.
However , t he vel oci t y of t he concent rat i on change i s const ant .
25. The answer i s B [ see V. B. 2. b. ( 2) ] .
The hal f - l i f e ( t 1/ 2) i s t he t i me r equi r ed f or t he concent r at i on of a dr ug t o decr ease by
one hal f . For a f i r st - or der degr adat i on:

Because bot h k and 0. 693 ar e const ant s, t 1/ 2 i s a const ant .
P. 80


26. The answer i s D [ see VÌ . F. 3] .
A sat i sf act or y supposi t ory base shoul d r emai n f i rm at r oom t emperat ur e. Pr ef erabl y,
i t shoul d not mel t < 30°C t o avoi d pr emat ur e sof t eni ng dur i ng st or age and i nser t i on.
Ì t shoul d al so be i ner t , nonsensi t i zi ng, noni r r i t at i ng, and compat i bl e wi t h a var i et y of
dr ugs. Mor eover , i t shoul d mel t j ust bel ow body t emperat ur e and shoul d di ssol ve or
di si nt egrat e r api dl y i n t he f l ui d of t he body cavi t y i nt o whi ch i t i s i nser t ed.
27. The answer i s E [ see VÌ . F. 3. c. (1) ] .
Cocoa but t er i s a f at t hat i s obt ai ned f r om t he seed of Theobroma cacao.
Chemi cal l y, i t i s a mi xt ure of st eari n, pal mi t i n, and ot her gl ycer i des t hat ar e
i nsol ubl e i n wat er and f reel y sol ubl e i n et her and chl or of orm. Dependi ng on t he
f usi on t emper at ur e, cocoa but t er can cr yst al l i ze i nt o any one of f our cr yst al f or ms.
Cocoa but t er i s a good base f or r ect al supposi t or i es, al t hough i t i s l ess t han i deal
f or vagi nal or uret hral supposi t or i es.
28. The answer i s C [ see VÌ . Ì . 5] .
To sat i sf y t he USP st andar ds, t abl et s are r equi r ed t o pass one of t wo t est s. A
wei ght var i at i on t est i s used i f t he act i ve i ngr edi ent makes up t he bul k of t he t abl et .
A cont ent uni f ormi t y t est i s used i f t he t abl et i s coat ed or i f t he act i ve i ngr edi ent
makes up < 50% of t he bul k of t he t abl et . Many t abl et s f or or al admi ni st rat i on ar e
r equi r ed t o meet a di si nt egr at i on t est . Di si nt egr at i on t i mes are speci f i ed i n t he
i ndi vi dual monogr aphs. A di ssol ut i on t est may be r equi red i nst ead i f t he act i ve
component of t he t abl et has l i mi t ed wat er sol ubi l i t y. Har dness and f r i abi l i t y woul d
af f ect t he di si nt egr at i on and di ssol ut i on rat es, but hardness and f r i abi l i t y t est s ar e
i n- house qual i t y cont r ol t est s, not of f i ci al USP t est s.
29. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see VÌ . A. 1] .
Wat er f or i nj ect i on USP i s wat er t hat has been pur i f i ed by di st i l l at i on or by r ever se
osmosi s. Thi s wat er i s used t o pr epar e par ent er al sol ut i ons t hat ar e subj ect t o f i nal
st eri l i zat i on. For parent er al sol ut i ons t hat ar e pr epar ed asept i cal l y and not
subsequent l y st er i l i zed, st eri l e wat er f or i nj ect i on USP i s used. St er i l e wat er f or
i nj ect i on USP i s wat er f or i nj ect i on USP t hat has been st er i l i zed and sui t abl y
packaged. Thi s wat er meet s t he USP r equi r ement s f or st eri l i t y. Bact eri ost at i c wat er
f or i nj ect i on USP i s st er i l e wat er f or i nj ect i on USP t hat cont ai ns one or mor e
ant i mi cr obi al agent s. Ì t can be used i n par ent eral sol ut i ons i f t he ant i mi crobi al
addi t i ves are compat i bl e wi t h t he ot her i ngr edi ent s i n t he sol ut i on, but i t cannot be
used i n newbor ns. Puri f i ed wat er USP i s not used i n parent er al prepar at i ons.
30. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì V. B. 2] .
An i deal suspensi on woul d have par t i cl es of uni f or m si ze, mi ni mal sedi ment at i on,
and no i nt er act i on bet ween par t i cl es. Al t hough t hese i deal cri t er i a ar e r arel y met ,
t hey can be appr oxi mat ed by keepi ng t he par t i cl e si ze as smal l as possi bl e, t he
densi t i es of t he sol i d and t he di spersi on medi um as si mi l ar as possi bl e, and t he
di spersi on medi um as vi scous as possi bl e.
31. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see Ì V. B. 2] .
As St okes' s l aw i ndi cat es, t he sedi ment at i on r at e of a suspensi on i s sl owed by
r educi ng i t s densi t y, reduci ng t he si ze of t he suspended part i cl es, or i ncreasi ng i t s
vi scosi t y by i ncor porat i ng a t hi ckeni ng agent . Sodi um benzoat e i s an ant i f ungal
agent and woul d not reduce t he sedi ment at i on rat e of a suspensi on.
32. The answer i s C ( Ì , Ì Ì ) [ see VÌ . C. 3] .
Acaci a and met hyl cel l ul ose ar e common suspendi ng agent s. Acaci a i s a nat ur al
pr oduct , and met hyl cel l ul ose i s a synt het i c pol ymer . By i ncreasi ng t he vi scosi t y of
t he l i qui d, t hese agent s enabl e part i cl es t o remai n suspended f or a l onger peri od.
33. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see VÌ . D. 3] .
Emul si f yi ng agent s pr ovi de a mechani cal bar ri er t o coal escence. They al so r educe
t he nat ur al t endency of t he dropl et s i n t he i nt er nal phase (oi l or wat er ) of t he
emul si on t o coal esce. Thr ee mechani sms appear t o be i nvol ved. Some emul si f i ers
pr omot e st abi l i t y by f ormi ng st rong, pl i abl e i nt erf aci al f i l ms around t he dropl et s.
Emul si f yi ng agent s al so r educe i nt er f aci al t ensi on. Fi nal l y, i ons (f r om t he emul si f i er )
i n t he i nt er f aci al f i l m can l ead t o charge repul si on t hat causes dropl et s t o r epel one
anot her , t her eby pr event i ng coal escence.
34. The answer i s B ( Ì Ì Ì ) [ see VÌ . D. 3] .
Al l of t he subst ances l i st ed are emul si f yi ng agent s, but onl y sorbi t an est ers are
noni oni c synt het i c agent s. Tr agacant h, l i ke acaci a, i s a nat ural emul si f yi ng agent .
Sodi um l aur yl sul f at e i s an ani oni c sur f act ant . Sor bi t an est er s ( known col l oqui al l y
as Spans because of t hei r t r ade names) ar e hydrophobi c and f orm wat er -i n- oi l
emul si ons. The pol ysor bat es ( known col l oqui al l y as Tweens) ar e al so noni oni c,
synt het i c sor bi t an der i vat i ves. However , t hey ar e hydr ophi l i c and t her ef ore f orm oi l -
i n- wat er emul si ons. Sodi um l aur yl sul f at e, as an al kal i soap, i s al so hydr ophi l i c and
t hus f or ms oi l -i n- wat er emul si ons.
P. 81


35. The answer i s C ( Ì , Ì Ì ) [ see VÌ . F. 1 and 2] .
Rect al supposi t or i es ar e usef ul f or del i veri ng syst emi c medi cat i on under cer t ai n
ci rcumst ances. Absor pt i on of a dr ug f rom a rect al supposi t or y i nvol ves rel ease of
t he dr ug f r om t he supposi t or y vehi cl e, di f f usi on t hr ough t he r ect al mucosa, and
t r anspor t t o t he ci rcul at i on t hr ough t he r ect al vei ns. The r ect al vei ns bypass t he
l i ver , so t hi s r out e avoi ds r api d hepat i c degr adat i on of cer t ai n dr ugs ( f i rst - pass
ef f ect ) . The r ect al rout e i s al so usef ul when a drug cannot be gi ven or al l y ( e. g. ,
because of vomi t i ng) . However , t he ext ent of dr ug r el ease and absorpt i on i s
var i abl e. Ì t depends on t he proper t i es of t he dr ug, t he supposi t or y base, and t he
envi r onment i n t he r ect um.
36. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see VÌ . G. 1. c] .
Mi l l i ng i s t he process of mechani cal l y r educi ng t he part i cl e si ze of sol i ds bef ore
t hey are f or mul at ed i nt o a f i nal product . To wor k ef f ect i vel y, a l ubr i cant must coat
t he surf ace of t he gr anul at i on or powder . Hence f i ne par t i cl e si ze i s essent i al .
Decr easi ng t he par t i cl e si ze i ncr eases t he sur f ace ar ea and can enhance t he
di ssol ut i on r at e. Thermol abi l e dr ugs may under go degradat i on because of t he
bui l dup of heat duri ng mi l l i ng.
37. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see VÌ . G. 2. a. ( 2) ] .
Some sol i d subst ances (e. g. , aspi r i n, phenyl sal i cyl at e, phenacet i n, t hymol ,
camphor ) l i quef y or f or m eut ect i c mi xt ur es when i n cl ose, pr ol onged cont act wi t h
one anot her . These subst ances are best i nsul at ed by t he addi t i on of l i ght
magnesi um oxi de or magnesi um car bonat e. Ot her i ner t di l uent s t hat can be used ar e
kaol i n, st arch, and bent oni t e.
38. The answer i s B ( Ì Ì Ì ) [ see VÌ . G. 2. b] .
When powders are mi xed, i f commi nut i on i s especi al l y i mpor t ant , a porcel ai n or
cer ami c mort ar t hat has a r ough i nner surf ace i s pr ef er r ed over t he smoot h wor ki ng
sur f ace of a gl ass mor t ar. Because a gl ass mor t ar cl eans more easi l y af t er use, i t i s
pr ef er r ed f or chemi cal s t hat may st ai n a por cel ai n or cerami c mor t ar as wel l as f or
si mpl e mi xi ng of subst ances t hat do not r equi re commi nut i on.
39. The answer i s A ( Ì ) [ see VÌ . G. 3. a and b] .
Powder s f or oral use can be di spensed by t he phar maci st i n bul k f orm or di vi ded
i nt o pr emeasur ed doses ( di vi ded powder s). Di vi ded powder s ar e t r adi t i onal l y
di spensed i n f ol ded paper packet s (char t ul ae) made of parchment , bond paper ,
gl assi ne, or waxed paper . However , i ndi vi dual doses can be packaged i n met al f oi l
or smal l pl ast i c bags i f t he powder needs great er pr ot ect i on f rom humi di t y or
evaporat i on.
40. The answer i s C ( Ì , Ì Ì ) [ see VÌ . Ì . 2. b] .
Tabl et s f or oral i ngest i on usual l y cont ai n exci pi ent s t hat are added t o t he
f or mul at i on f or t hei r speci al f unct i ons. Bi nder s and adhesi ves ar e added t o promot e
gr anul at i on or compact i on. Di l uent s are f i l l er s t hat ar e added t o make up t he
r equi r ed t abl et bul k. They can al so ai d i n t he manuf act ur i ng pr ocess. Di si nt egrant s
ai d i n t abl et di si nt egr at i on i n gast roi nt est i nal f l ui ds. Lubri cant s, ant i adherent s, and
gl i dant s ai d i n r educi ng f r i ct i on or adhesi on bet ween par t i cl es or bet ween t abl et and
di e. For exampl e, l ubri cant s ar e used i n t he manuf act ur e of t abl et s t o reduce f r i ct i on
when t he t abl et i s ej ect ed f r om t he di e cavi t y. Lubr i cant s ar e usual l y hydrophobi c
subst ances t hat can af f ect t he di ssol ut i on rat e of t he act i ve i ngr edi ent .
41. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see VI . 2. b. (3) ] .
Di si nt egr ant s ar e added t o t abl et f or mul at i ons t o f aci l i t at e di si nt egrat i on i n
gast r oi nt est i nal f l ui ds. Di si nt egr at i on of t he t abl et i n t he body i s cr i t i cal t o i t s
di ssol ut i on and subsequent absor pt i on and bi oavai l abi l i t y. The bi nder and t he
compr essi on f or ce used dur i ng t abl et manuf act uri ng af f ect t he hardness of t he
t abl et as wel l as t abl et di si nt egr at i on and dr ug di ssol ut i on.
42. The answer i s B ( Ì Ì Ì ) [ see VÌ . Ì . 3. a. ( 4) ] .
An ent eri c-coat ed t abl et has a coat i ng t hat r emai ns i nt act i n t he st omach, but
di ssol ves i n t he i nt est i nes t o yi el d t he t abl et i ngredi ent s t her e. Ent er i c coat i ngs
i ncl ude vari ous f at s, f at t y aci ds, waxes, and shel l acs. Cel l ul ose acet at e pht hal at e
r emai ns i nt act i n t he st omach because i t di ssol ves onl y when t he pH > 6. Ot her
ent eri c- coat i ng mat eri al s i ncl ude povi done ( pol yvi nyl pyr r ol i done), pol yvi nyl acet at e
pht hal at e, and hydroxypr opyl met hyl cel l ul ose pht hal at e.
43. The answer i s A [ see VÌ . Ì . 4] .
44. The answer i s D [ see VÌ . Ì . 4] .
45. The answer i s B [ see VÌ . Ì . 4] .
P. 82


46. The answer i s A [ see VÌ . Ì . 4] .
St i cki ng i s adhesi on of t abl et mat er i al t o a di e wal l . Ì t may be caused by excessi ve
moi st ur e or by t he use of i ngr edi ent s t hat have l ow mel t i ng t emperat ures. Mot t l i ng i s
uneven col or di st ri but i on. Ì t i s most of t en caused by poor mi xi ng of t he t abl et
gr anul at i on but may al so occur when a degr aded dr ug pr oduces a col ored
met abol i t e. Cappi ng i s separat i on of t he t op or bot t om cr own of a t abl et f r om t he
mai n body. Cappi ng i mpl i es t hat compr essed powder i s not cohesi ve. Reasons f or
cappi ng i ncl ude excessi ve f orce of compressi on, use of i nsuf f i ci ent bi nder, wor n
t abl et t ool i ng equi pment , and ent r apment of ai r dur i ng processi ng. Pi cki ng i s
adher ence of t abl et sur f ace mat eri al t o a punch. Ì t can be caused by a granul at i on
t hat i s t oo damp, by a scr at ched punch, by st at i c charges on t he powder , and
par t i cul arl y by t he use of a punch t i p t hat i s engraved or embossed.
47. The answer i s A [ see VÌ . G. 1. c; VÌ . G. 2] .
48. The answer i s D [ see VÌ . G. 1. c; VÌ . G. 2] .
49. The answer i s C [ see VÌ . G. 1. c; VÌ . G. 2] .
Commi nut i on i s t he process of r educi ng t he par t i cl e si ze of a powder t o i ncr ease i t s
f i neness. Several commi nut i on t echni ques are sui t abl e f or smal l - scal e use i n a
pharmacy. Tr i t urat i on i s used bot h t o commi nut e and t o mi x dr y powder s. Ì f
commi nut i on i s desi r ed, t he subst ance i s r ubbed i n a mor t ar t hat has a rough i nner
sur f ace. Pul ver i zat i on by i nt er vent i on i s of t en used f or subst ances t hat t end t o
aggl omer at e or r esi st gr i ndi ng. A smal l amount of easi l y removed (e. g. , vol at i l e)
sol vent i s added. Af t er t he subst ance i s pul ver i zed, t he sol vent i s al l owed t o
evaporat e or i s ot her wi se r emoved. Levi gat i on i s of t en used t o prepar e past es or
oi nt ment s. The powder i s r educed by addi ng a sui t abl e nonsol vent (l evi gat i ng agent )
t o f or m a past e and t hen ei t her rubbi ng t he past e i n a mor t ar wi t h a pest l e or
r ubbi ng i t on an oi nt ment sl ab wi t h a spat ul a. Spat ul at i on and t umbl i ng are
t echni ques t hat are used t o mi x or bl end powder s, not t o r educe t hem. Spat ul at i on
i s bl endi ng smal l amount s of powders by st i r r i ng t hem wi t h a spat ul a on a sheet of
paper or a pi l l t i l e. Tumbl i ng i s bl endi ng l arge amount s of powder i n a l arge r ot at i ng
cont ai ner .
50. The answer i s B [ see VÌ . K. 3. e] .
51. The answer i s E [ see VÌ . K. 3. a] .
52. The answer i s C [ see VÌ . K. 3. f ] .
53. The answer i s D [ see VÌ . K. 3. d] .
Cont r ol l ed- rel ease dosage f or ms ar e desi gned t o r el ease a drug sl owl y f or
pr ol onged act i on i n t he body. A vari et y of pharmaceut i cal mechani sms are used t o
pr ovi de t he cont r ol l ed r el ease. Ì on- exchange resi ns may be compl exed t o dr ugs by
passi ng a cat i oni c dr ug sol ut i on t hr ough a col umn t hat cont ai ns t he r esi n. The dr ug
i s compl exed t o t he r esi n by r epl acement of hydrogen at oms. Rel ease of dr ug f r om
t he compl ex depends on t he i oni c envi ronment wi t hi n t he gast roi nt est i nal t r act and
on t he pr oper t i es of t he resi n. Coat ed beads ( e. g. , Thor azi ne Spansul e capsul es) or
gr anul es pr oduce bl ood l evel s si mi l ar t o t hose obt ai ned wi t h mul t i pl e dosi ng. The
var i ous coat i ng t hi cknesses produce a sust ai ned- r el ease ef f ect .
Mat r i x devi ces may use i nsol ubl e pl ast i cs, hydr ophi l i c pol ymers, or f at t y
compounds. These component s ar e mi xed wi t h t he dr ug and compressed i nt o a
t abl et . The pri mar y dose, or t he port i on of t he drug t o be r el eased i mmedi at el y, i s
pl aced on t he t abl et as a l ayer or coat . The remai nder of t he dose i s r el eased sl owl y
f r om t he mat ri x. Rel at i vel y i nsol ubl e t annat e- ami ne compl exes pr ovi de f or a
pr ol onged gast r oi nt est i nal absor pt i on phase and sust ai ned syst emi c concent r at i ons
of t he weak bases. Osmot i c syst ems empl oy osmot i c pressure t o cont rol t he r el ease
of t he act i ve i ngredi ent f r om t he f ormul at i on. Osmot i c t abl et f ormul at i ons pr ovi de a
semi per meabl e membr ane as a coat i ng t hat sur r ounds t he osmot i cal l y act i ve core.
The coat i ng al l ows wat er t o di f f use i nt o t he cor e but does not al l ow dr ug t o di f f use
out . As wat er f l ows i nt o t he t abl et , t he drug di ssol ves. The l aser -dr i l l ed hol e i n t he
coat i ng al l ows t he dr ug sol ut i on wi t hi n t he t abl et t o f l ow t o t he out si de at a r at e t hat
i s equi val ent t o t he r at e of wat er f l ow i nt o t he t abl et . The osmot i c pr essure gr adi ent
and a zer o-or der dr ug- rel ease rat e wi l l be mai nt ai ned as l ong as excess osmot i cal l y
act i ve sol ut e ( e. g. , el ect r ol yt e) r emai ns i n t he t abl et cor e.

4
Biopharmaceutics and Drug DeIivery Systems
Lawrence H. BI ock
I. INTRODUCTION
A. Bi opharmaceuti cs i s t he st udy of t he r el at i on of t he physi cal and chemi cal
pr oper t i es of a drug t o i t s bi oavai l abi l i t y, phar macoki net i cs, and phar macodynami c
and t oxi col ogi c ef f ect s.
1. A drug product i s t he f i ni shed dosage f orm ( e. g. , t abl et , capsul e, sol ut i on) t hat
cont ai ns t he act i ve dr ug i ngredi ent i n associ at i on wi t h nondr ug ( usual l y i nact i ve)
i ngredi ent s (exci pi ent s) t hat make up t he vehi cI e, or f ormuI at i on mat ri x.
2. The phr ase dr ug del i ver y syst em i s of t en used i nt er changeabl y wi t h t he t erms
dr ug pr oduct or dosage f or m. However , a drug deI i ver y syst em i s a more
compr ehensi ve concept , whi ch i ncl udes t he drug f or mul at i on and t he dynami c
i nt er act i ons among t he dr ug, i t s f or mul at i on mat ri x, i t s cont ai ner , and t he pat i ent .
3. Bi oavai I abi I i t y i s a measur ement of t he rat e and ext ent ( amount ) of syst emi c
absor pt i on of t he t her apeut i cal l y act i ve drug.
B. Pharmacoki net i cs i s t he st udy of t he t i me cour se of dr ug movement i n t he body
dur i ng absor pt i on, di st r i but i on, and el i mi nat i on (excr et i on and bi ot r ansf ormat i on).
C. Pharmacodynami cs i s t he st udy of t he r el at i on of t he drug concent rat i on or
amount at t he si t e of act i on ( recept or ) and i t s phar macol ogi c r esponse as a f unct i on
of t i me.
II. DRUG TRANSPORT AND ABSORPTION
A. Transport of drug moI ecuI es across ceI I membranes. Drug absorpt i on r equi r es
t he dr ug t o be t r anspor t ed acr oss vari ous cel l membr anes. Drug mol ecul es may
ent er t he bl oodst r eam and be t ransport ed t o t he t i ssues and organs of t he body.
Dr ug mol ecul es may cr oss addi t i onal membranes t o ent er cel l s. Dr ug mol ecul es may
al so cr oss an i nt r acel l ul ar membr ane, such as t he nucl ear membrane or
endopl asmi c ret i cul um, t o r each t he si t e of act i on. Fi gur e 4- 1 demonst r at es some of
t he key t ranspor t processes i nvol ved i n dr ug absor pt i on.

Figure 4-1. The key drug transport processes in
intestinal epithelial cells. 1. Transcellular passive
(diIIusion and partitioning); 2. paracellular
transport (diIIusion and convection); 3. carrier-
mediated transport; 4. P-glycoproteinmediated
eIIlux. |ModiIied Irom Brayden DJ. Pharm News
4(1);1997:11-15.|
P. 84


1. GeneraI pri nci pI es
a. A ceI I membrane i s a semi permeabl e st r uct ure composed pr i mari l y of l i pi ds and
pr ot ei ns.
b. Dr ugs may be t ranspor t ed by passi ve di f f usi on, parti t i oni ng, carri er-medi at ed
t ransport , paraceI I uI ar t ransport , or vesi cuI ar t ransport .
c. Usual l y, prot ei ns, drugs bound t o prot ei ns, and macromoI ecuI es do not easi l y
cr oss cel l membr anes.
d. NonpoI ar I i pi d- soI ubI e drugs t r averse cel l membranes more easi l y t han do
i oni c or poI ar wat er-soI ubI e drugs.
e. Low moI ecuI ar wei ght drugs di f f use acr oss a cel l membr ane mor e easi l y t han
do hi gh moI ecuI ar wei ght drugs.
2. Passi ve di f f usi on and part i ti oni ng
a. Wi thi n t he cyt opI asm or i n i nt ersti t i aI f I ui d, most dr ugs under go t r ansport by
si mpl e di f f usi on.
b. Fi ck' s I aw of di f f usi on. Si mpI e passi ve di f f usi on i nvol ves t he t r ansf er of dr ugs
f r om an ar ea of hi gh concent r at i on ( C1) t o an ar ea of l ower concent r at i on ( C2)
accor di ng t o Fi ck' s l aw of di f f usi on:

wher e dQ/ dt i s t he rat e of dr ug di f f usi on, D i s t he di f f usi on coef f i ci ent f or t he drug,
A i s t he sur f ace ar ea of t he pl ane across whi ch t ransf er occurs, h i s t he t hi ckness of
t he regi on t hrough whi ch di f f usi on occur s, and ( C1 - C2) i s t he di f f er ence bet ween
t he dr ug concent r at i on i n ar ea 1 and ar ea 2, respect i vel y.
c. Passi ve dr ug t r ansport acr oss cel l membranes i nvol ves t he successi ve
part i t i oni ng of a sol ut e bet ween aqueous and l i pi d phases as wel l as di f fusi on
wi t hi n t he respect i ve phases. Modi f yi ng Fi ck' s l aw of di f f usi on t o accommodat e t he
par t i t i oni ng of dr ug gi ves t he f ol l owi ng:

The r at e of dr ug di f f usi on, dQ/ dt , now r ef l ect s i t s di rect dependence on K, t he oi l t o
wat er par t i t i on coef f i ci ent of t he dr ug, as wel l as on A and ( C1 - C2) .
d. I oni zat i on of a weak eI ect roI yt e i s af f ect ed by t he pH of t he medi um i n whi ch
t he dr ug i s di ssol ved as wel l as by t he pKa of t he dr ug. The noni oni zed speci es i s
mor e l i pi d sol ubl e t han t he i oni zed speci es, and i t part i t i ons more r eadi l y acr oss cel l
membr anes.
3. Carri er- medi ated t ransport
a. Act i ve t ransport of t he dr ug acr oss a membr ane i s a car r i er -medi at ed pr ocess
t hat has t he f ol l owi ng char act eri st i cs.
( 1) The dr ug moves agai nst a concent r at i on gr adi ent .
( 2) The pr ocess requi r es energy.
( 3) The car ri er may be sel ect i ve f or cer t ai n t ypes of dr ugs t hat r esembl e nat ural
subst rat es or met abol i t es t hat ar e normal l y act i vel y t r anspor t ed.
( 4) The car ri er syst em may be sat ur at ed at a hi gh dr ug concent r at i on.
( 5) The pr ocess may be compet i t i ve ( i . e. , drugs wi t h si mi l ar st ruct ur es may compet e
f or t he same carr i er) .
b. Faci I i t at ed di f f usi on i s al so a car r i er -medi at ed t r anspor t syst em. However ,
f aci l i t at ed di f f usi on occur s wi t h (i . e. , i n t he di rect i on of ) a concent r at i on gr adi ent
and does not r equi re ener gy.
4. ParaceI I uI ar t ransport . Dr ug t r anspor t acr oss t i ght (nar row) j unct i ons bet ween
cel l s or t r ansendot hel i al channel s of cel l s i s known as paraceI I uI ar t ransport . Ì t
i nvol ves bot h di f f usi on and t he convecti ve ( bul k) f l ow of wat er and accompanyi ng
wat er - sol ubl e dr ug mol ecul es t hrough t he par acel l ul ar channel s.
5. Vesi cuI ar t ransport i s t he pr ocess of engul f i ng part i cl es or di ssol ved mat er i al s
by a cel l . Vesi cul ar t r anspor t i s t he onl y t r anspor t mechani sm t hat does not r equi re
a dr ug t o be i n an aqueous sol ut i on t o be absorbed. Pi nocyt osi s and phagocyt osi s
ar e f or ms of vesi cul ar t ranspor t .
a. Pi nocyt osi s i s t he engul f ment of smal l sol ut e or f l ui d vol umes.
P. 85


b. Phagocyt osi s i s t he engul f ment of l ar ger par t i cl es, or macromol ecul es, gener al l y
by macr ophages.
c. Endocyt osi s and exocyt osi s ar e t he movement of macromol ecul es i nt o and out
of t he cel l , respect i vel y.
6. Ot her t ransport mechani sms: t ransporter prot ei ns. Var i ous t ransport er
prot ei ns ( e. g. , P- gI ycoprot ei n) ar e embedded i n t he l i pi d bi l ayer of cel l membr anes
i n t andem i n q- hel i cal t ransmembrane r egi ons or domai ns. These prot ei ns are
adenosi ne t ri phosphat e- ( ATP; energy) dependent " pumps, ¨ whi ch can f aci l i t at e t he
ef f l ux of dr ug mol ecul es f r om t he cel l . Because t hese t r ansmembrane ef f l ux pumps
ar e of t en f ound i n conj unct i on wi t h met abol i zi ng enzymes such as cyt ochrome P450
3A4, t hei r net ef f ect i s t o subst ant i al l y reduce i nt r acel l ul ar drug concent rat i ons.
Thus t hey det ermi ne, t o a l ar ge ext ent , t he pharmacoki net i c di sposi t i on and
ci rcul at i ng pl asma concent r at i ons of dr ugs (e. g. , cycl ospor i n, ni f edi pi ne, di goxi n)
t hat ar e subst r at es f or t hese pr ot ei ns.
B. Rout es of drug admi ni st rati on
1. Parent eraI admi ni st rat i on
a. I nt ravenous boI us i nj ect i on. The dr ug i s i nj ect ed di r ect l y i nt o t he bl oodst r eam,
di st r i but es t hr oughout t he body, and act s rapi dl y. Any si de ef f ect s, i ncl udi ng an
i nt ense pharmacol ogi c response, anaphyl axi s, or over t t oxi ci t y, al so occur r api dl y.
b. I nt ra- art eri aI i nj ect i on. The drug i s i nj ect ed i nt o a speci f i c ar t er y t o achi eve a
hi gh drug concent rat i on i n a speci f i c t i ssue bef ore dr ug di st r i but i on occurs
t hr oughout t he body. Ì nt ra- ar t er i al i nj ect i on i s used f or di agnost i c agent s and
occasi onal l y f or chemot her apy.
c. I nt ravenous i nf usi on. The drug i s gi ven i nt r avenousl y at a const ant i nput rat e.
Const ant r at e i nt r avenous i nf usi on mai nt ai ns a r el at i vel y const ant pl asma dr ug
concent r at i on once t he i nf usi on r at e i s appr oxi mat el y equal t o t he dr ug' s el i mi nat i on
r at e f r om t he body (i . e. , once st eady st at e i s r eached) .
d. I nt ramuscuI ar i nj ect i on. The dr ug i s i nj ect ed deep i nt o a skel et al muscl e. The
r at e of absor pt i on depends on t he vascul ar i t y of t he muscl e si t e, t he l i pi d sol ubi l i t y
of t he dr ug, and t he f ormul at i on mat ri x.
e. Subcutaneous i nj ect i on. The dr ug i s i nj ect ed beneat h t he ski n. Because t he
subcut aneous regi on i s l ess vascul ar t han muscl e t i ssues, dr ug absorpt i on i s l ess
r api d. The f act ors t hat af f ect absorpt i on f r om i nt ramuscul ar depot s al so af f ect
subcut aneous absor pt i on.
f . Mi sceI I aneous parenteraI rout es
( 1) I nt ra- art i cuI ar i nj ecti on. The dr ug i s i nj ect ed i nt o a j oi nt .
( 2) I nt radermaI ( i nt racut aneous) i nj ect i on. The dr ug i s i nj ect ed i nt o t he dermi s
( i . e. , t he vascul ar r egi on of t he ski n bel ow t he epi dermi s) .
( 3) I nt rat hecaI i nj ecti on. The drug i s i nj ect ed i nt o t he spi nal f l ui d.
2. EnteraI admi ni st rat i on
a. BuccaI and subI i nguaI admi ni st rati on. A t abl et or l ozenge i s pl aced under t he
t ongue (subI i nguaI ) or i n cont act wi t h t he mucosal ( buccaI ) surf ace of t he cheek.
Thi s t ype of admi ni st r at i on al l ows a nonpol ar , l i pi d- sol ubl e dr ug t o be absor bed
acr oss t he epi t hel i al l i ni ng of t he mout h. Af t er buccal or subl i ngual admi ni st r at i on,
t he dr ug i s absor bed di rect l y i nt o t he syst emi c ci r cul at i on, bypassi ng t he l i ver and
any f i rst -pass ef f ect s.
b. PeroraI ( oraI ) drug admi ni st rat i on. The drug i s admi ni st ered or al l y, i s
swal l owed, and undergoes absor pt i on f rom t he gast roi nt est i nal t r act t hrough t he
mesent er i c ci rcul at i on t o t he hepat i c port al vei n i nt o t he l i ver and t hen t o t he
syst emi c ci rcul at i on. The per or al r out e i s t he most common r out e of admi ni st rat i on.
( 1) The per oral r out e i s t he most conveni ent and t he saf est r out e.
( 2) Di sadvant ages of t hi s r out e i ncl ude t he f ol l owi ng.
( a) The dr ug may not be absor bed f rom t he gast roi nt est i nal t r act consi st ent l y or
compl et el y.
( b) The drug may be di gest ed by gast r oi nt est i nal enzymes or decomposed by t he
aci d pH of t he st omach.
( c) The dr ug may i r r i t at e mucosal epi t hel i al cel l s or compl ex wi t h t he cont ent s of t he
gast r oi nt est i nal t ract .
( d) Some dr ugs may be i ncompl et el y absor bed because of f i rst - pass ef f ect s or
pr esyst emi c el i mi nat i on (e. g. , t he drug i s met abol i zed by t he l i ver bef or e syst emi c
absor pt i on occur s).
( e) The absor pt i on r at e may be er rat i c because of del ayed gast r i c empt yi ng or
changes i n i nt est i nal mot i l i t y.
P. 86


( 3) Most drugs are xenobi ot i cs or exogenous mol ecul es and, consequent l y, are
absor bed f rom t he gast roi nt est i nal t r act by passi ve di f f usi on and parti t i oni ng.
Carri er- medi ated t ransport , paraceI I uI ar t ransport , and vesi cuI ar t ransport pl ay
smal l er , but cri t i cal , rol es, par t i cul arl y f or endogenous mol ecul es.
( 4) Dr ug mol ecul es ar e absorbed t hroughout t he gast r oi nt est i nal t ract ; but t he
duodenaI regi on, whi ch has a l ar ge sur f ace area because of t he vi l l i and mi cr ovi l l i ,
i s t he pr i mar y absor pt i on si t e. The l arge bl ood suppl y provi ded by t he mesent er i c
vessel s al l ows t he dr ug t o be absorbed mor e ef f i ci ent l y ( see Ì Ì . A. 2) .
( 5) AI t ered gast ri c empt yi ng af f ect s ar r i val of t he drug i n t he duodenum f or
syst emi c absor pt i on. Gast ri c empt yi ng t i me i s af f ect ed by f ood cont ent , emot i onal
st at e, and dr ugs t hat al t er gast roi nt est i nal t ract mot i l i t y ( e. g. , ant i chol i ner gi cs,
nar cot i c anal gesi cs, pr oki net i c agent s) .
( 6) Normal i nt est i nal mot i l i t y f r om peri staI si s bri ngs t he drug i n cont act wi t h t he
i nt est i nal epi t hel i al cel l s. A suf f i ci ent per i od of cont act ( r esi dence t i me) i s needed t o
per mi t dr ug absor pt i on acr oss t he cel l membr anes f rom t he mucosal t o t he ser osal
sur f ace.
( 7) Some dr ugs, such as ci met i di ne and acet ami nophen, when gi ven i n an
i mmedi at e- r el ease per oral dosage f orm t o f ast ed subj ect s produce a syst emi c drug
concent r at i on t i me wi t h t wo peaks. Thi s doubI e- peak phenomenon i s at t r i but ed t o
var i abi l i t y i n st omach empt yi ng, var i abl e i nt est i nal mot i l i t y, and ent erohepat i c
cycl i ng.
c. Rect aI admi ni st rati on. The drug i n sol ut i on (enema) or supposi t or y f or m i s
pl aced i n t he r ect um. Drug di f f usi on f r om t he sol ut i on or r el ease f r om t he
supposi t or y l eads t o absor pt i on acr oss t he mucosal sur f ace of t he r ect um. Dr ug
absor bed i n t he l ower t wo t hi r ds of t he r ect um ent er s t he syst emi c ci rcul at i on
di r ect l y, bypassi ng t he l i ver and any f i rst - pass ef f ect s.
3. Respi rator y t ract admi ni st rat i on
a. I nt ranasaI admi ni st rat i on. The drug cont ai ned i n a sol ut i on or suspensi on i s
admi ni st er ed t o t he nasal mucosa, ei t her as a spray or as dr ops. The medi cat i on
may be used f or l ocal (e. g. , nasal decongest ant s, i nt ranasal st eroi ds) or syst emi c
ef f ect s.
b. PuI monar y i nhaI at i on. The drug, as l i qui d or sol i d par t i cl es, i s i nhal ed peror al l y
( wi t h a nebul i zer or a met er ed- dose aerosol ) i nt o t he pul monar y t ree. Ì n general ,
part i cI es > 60 µm ar e pri mari l y deposi t ed i n t he trachea. Part i cI es > 20 µm do not
r each t he br onchi ol es, and part i cI es < 0. 6 µm are not deposi t ed and are exhaI ed.
Par t i cl es bet ween 2 and 6 µm can r each t he aI veoI ar duct s, al t hough onl y par t i cl es
of 1-2 µm are ret ai ned i n t he aI veoI i .
4. TransdermaI and t opi caI admi ni st rat i on
a. TransdermaI ( percutaneous) dr ug absor pt i on i s t he pl acement of t he dr ug ( i n a
l ot i on, oi nt ment , cr eam, past e, or pat ch) on t he ski n sur f ace f or syst emi c
absor pt i on. An occl usi ve dr essi ng or f i l m i mpr oves syst emi c drug absorpt i on f rom
t he ski n. Smal l l i pi d- sol ubl e mol ecul es, such as ni t r ogl ycer i n, ni cot i ne, scopol ami ne,
cl oni di ne, f ent anyl , and st eroi ds (e. g. , 17- 8- est radi ol , t est ost er one) , ar e r eadi l y
absor bed f rom t he ski n.
b. Dr ugs (e. g. , ant i bact er i al s, l ocal anest het i c agent s) are appl i ed t opi caI I y t o t he
ski n f or a l ocal ef f ect .
5. Mi scel l aneous r out es of drug admi ni st r at i on i ncl ude ophthaI mi c, ot i c, uret hraI ,
and vagi naI admi ni st rat i on. These r out es of admi ni st r at i on are general l y used f or
l ocal t herapeut i c act i vi t y. However , some syst emi c drug absor pt i on may occur .
C. LocaI drug act i vi t y ver sus syst emi c drug absorpt i on. The r out e of
admi ni st rat i on, absor pt i on si t e, and bi oavai l abi l i t y of t he drug f r om t he dosage f or m
ar e maj or f act ors i n t he desi gn of a dr ug pr oduct .
1. Dr ugs i nt ended f or I ocaI act i vi t y, such as t opi cal ant i bi ot i cs, ant i -i nf ect i ves,
ant i f ungal agent s, and l ocal anest het i cs ar e f ormul at ed i n dosage f or ms t hat
mi ni mi ze syst emi c absorpt i on. The concent rat i on of t hese dr ugs at t he appl i cat i on
si t e af f ect s t hei r act i vi t y.
2. When syst emi c absorpt i on i s desi red, t he bi oavai l abi l i t y of t he dr ug f rom t he
dosage f orm at t he absor pt i on si t e must be consi der ed ( e. g. , a dr ug gi ven
i nt ravenousl y i s 100% bi oavai l abl e because al l of t he dr ug i s pl aced di r ect l y i nt o t he
syst emi c ci rcul at i on) . The amount , or dose, of drug i n t he dosage f or m i s based on
t he ext ent of dr ug absorpt i on and t he desi red syst emi c dr ug concent rat i on. The t ype
of dosage f orm (e. g. , i mmedi at e r el ease, cont r ol l ed r el ease) af f ect s t he rat e of dr ug
absor pt i on.
P. 87


III. BIOPHARMACEUTIC PRINCIPLES
A. Physi cochemi caI propert i es
1. Drug di ssoI ut i on. For most dr ugs wi t h l i mi t ed wat er sol ubi l i t y, t he rat e at whi ch
t he sol i d dr ug ent er s i nt o sol ut i on (i . e. , t he rat e of di ssol ut i on) i s of t en t he r at e-
l i mi t i ng st ep i n bi oavai l abi l i t y. The Noyes- Whi t ney equat i on descri bes t he di f f usi on-
cont r ol l ed r at e of dr ug di ssol ut i on ( dm/ dt ; i . e. , t he change i n t he amount of drug i n
sol ut i on wi t h r espect t o t i me):

wher e D i s t he di f f usi on coef f i ci ent of t he sol ut e, A i s t he sur f ace ar ea of t he sol i d
under goi ng di ssol ut i on, ô i s t he t hi ckness of t he di f f usi on l ayer, Cs i s t he
concent r at i on of t he sol vat e at sat ur at i on, and Cb i s t he concent r at i on of t he drug i n
t he bul k sol ut i on phase at t i me t .
2. Drug soI ubi I i t y i n a sat ur at ed sol ut i on (see Chapt er 3, Ì V) i s a st at i c
( equi l i br i um) propert y. The di ssol ut i on r at e of a dr ug i s a dynami c pr oper t y r el at ed
t o t he rat e of absor pt i on.
3. Parti cI e si ze and surface area ar e i nver sel y rel at ed. As sol i d drug part i cl e si ze
decreases, par t i cl e surf ace ar ea i ncr eases.
a. As descr i bed by t he Noyes-Whi t ney equat i on, t he di ssol ut i on r at e i s di rect l y
pr opor t i onal t o t he sur f ace ar ea. An i ncr ease i n sur f ace ar ea al l ows f or mor e
cont act bet ween t he sol i d dr ug par t i cl es and t he sol vent , r esul t i ng i n a f ast er
di ssol ut i on r at e (see Ì Ì Ì . A. 1) .
b. Wi t h cert ai n hydrophobi c drugs, excessi ve par t i cl e si ze r educt i on does not
al ways i ncr ease t he di ssol ut i on r at e. Smal l part i cl es t end t o reaggr egat e i nt o l ar ger
par t i cl es t o r educe t he hi gh sur f ace f ree energy pr oduced by par t i cl e si ze r educt i on.
c. To prevent t he f or mat i on of aggr egat es, smal l dr ug part i cl es ar e mol ecul arl y
di spersed i n pol yet hyl ene gl ycol ( PEG) , pol yvi nyl pyr r ol i done ( PVP; povi done) ,
dext r ose, or ot her agent s. For exampl e, a mol ecul ar di sper si on of gr i seof ul vi n i n a
wat er - sol ubl e car ri er such as PEG 4000 ( e. g. , Gri s- PEG) enhances i t s di ssol ut i on
and bi oavai l abi l i t y.
4. Parti t i on coef f i ci ent and ext ent of i oni zat i on
a. The part i t i on coef fi ci ent of a dr ug i s t he rat i o of t he sol ubi l i t y of t he dr ug, at
equi l i br i um, i n a nonaqueous sol vent (e. g. , n-oct anol ) t o t hat i n an aqueous sol vent
( e. g. , wat er ; pH 7. 4 buf f er sol ut i on) . Hydrophi l i c dr ugs wi t h hi gher wat er sol ubi l i t y
have a f ast er di ssol ut i on r at e t han do hydr ophobi c or l i pophi l i c drugs, whi ch have
poor wat er sol ubi l i t y.
b. Extent of i oni zat i on. Dr ugs t hat ar e weak el ect r ol yt es (aci ds or bases) exi st i n
bot h an i oni zed f orm and a noni oni zed f or m i n sol ut i on. The ext ent of i oni zat i on
depends on t he pKa of t he weak el ect rol yt e and t he pH of t he sol ut i on. The i oni zed
f or m i s mor e pol ar , and t her ef or e mor e wat er sol ubl e, t han t he noni oni zed f orm. The
Henderson- HasseI baI ch equat i on descr i bes t he r el at i on bet ween t he i oni zed and
t he noni oni zed f orms of a dr ug as a f unct i on of pH and pKa. When t he pH of t he
medi um equal s t he pKa of t he drug, 50% of t he drug i n sol ut i on i s noni oni zed and
50% i s i oni zed, as can be shown f r om t he f ol l owi ng equat i ons:
( 1) For weak aci ds:

( 2) For weak bases:

5. SaI t f ormat i on
a. The choi ce of sal t f orm f or a dr ug depends on t he desi red physi cal , chemi cal , or
pharmacol ogi c pr oper t i es. Cert ai n sal t s ar e desi gned t o pr ovi de sl ower di ssol ut i on,
sl ower bi oavai l abi l i t y, and l onger dur at i on of act i on. Ot her sal t s are sel ect ed f or
gr eat er st abi l i t y, l ess l ocal i r r i t at i on at t he absorpt i on si t e, or l ess syst emi c t oxi ci t y.
( 1) Some sol ubl e sal t f orms ar e l ess st abl e t han t he noni oni zed f orm. For exampl e,
sodi um aspi r i n i s l ess st abl e t han aspi ri n i n t he aci d f orm.
( 2) A sol i d dosage f orm cont ai ni ng buf f er i ng agent s may be f ormul at ed wi t h t he f r ee
aci d f or m of t he dr ug (e. g. , buf f er ed aspi r i n) .
P. 88


( a) The buf f er i ng agent f or ms an al kal i ne medi um i n t he gast roi nt est i nal t ract , and
t he dr ug di ssol ves i n si t u.
( b) The di ssol ved sal t f or m of t he dr ug di f f uses i nt o t he bul k f l ui d of t he
gast r oi nt est i nal t ract , f orms a f i ne preci pi t at e t hat r edi ssol ves rapi dl y, and becomes
avai l abl e f or absor pt i on.
b. Ef f ervescent granuI es or tabI et s cont ai ni ng t he aci d drug i n addi t i on t o sodi um
bi car bonat e, t ar t ar i c aci d, ci t ri c aci d, or ot her i ngr edi ent s ar e added t o wat er j ust
bef ore or al admi ni st r at i on. The excess sodi um bi car bonat e f orms an al kal i ne
sol ut i on i n whi ch t he dr ug di ssol ves. Car bon di oxi de i s al so f ormed by t he
decomposi t i on of car boni c aci d.
c. For weakl y aci di c dr ugs, pot assi um and sodi um sal t s are mor e sol ubl e t han
di val ent cat i on sal t s ( e. g. , cal ci um, magnesi um) or t r i val ent cat i on sal t s (e. g. ,
al umi num) .
d. For weak bases, common wat er - sol ubl e sal t s i ncl ude t he hydrochl or i de, sul f at e,
ci t rat e, and gl uconat e sal t s. The est ol at e, napsyl at e, and st earat e sal t s ar e l ess
wat er sol ubl e.
6. PoI ymorphi sm i s t he abi l i t y of a dr ug t o exi st i n mor e t han one cr yst al l i ne f orm.
a. Di f f erent pol ymorphs have di f f er ent physi cal pr opert i es, i ncl udi ng mel t i ng poi nt
and di ssol ut i on rat e.
b. Amorphous, or noncryst aI I i ne, f orms of a drug have f ast er di ssol ut i on r at es
t han do cr yst al l i ne f orms.
7. Chi raI i t y i s t he abi l i t y of a drug t o exi st as opti caI I y act i ve st ereoi somers or
enanti omers. Ì ndi vi dual enant i omer s may not have t he same phar macoki net i c and
pharmacodynami c act i vi t y. Because most chi r al dr ugs are used as r acemi c mi xt ur es,
t he resul t s of st udi es wi t h such mi xt ur es may be mi sl eadi ng because t he dr ug i s
assumed t o behave as a si ngl e ent i t y. For exampl e, i buprof en exi st s as t he R- and
S- enant i omer s; onl y t he S- enant i omer i s pharmacol ogi cal l y act i ve. When t he
r acemi c mi xt ur e of i buprof en i s t aken oral l y, t he R- enant i omer undergoes
pr esyst emi c i nver si on i n t he gut t o t he S- enant i omer . Because t he r at e and ext ent of
i nver si on are si t e speci f i c and f or mul at i on dependent , i buprof en act i vi t y may var y
consi derabl y.
8. Hydrat es. Dr ugs may exi st i n a hydrat ed, or soI vat ed, f orm or as an anhydrous
moI ecuI e. Di ssol ut i on rat es di f f er f or hydr at ed and anhydr ous f orms. For exampl e,
t he anhydrous f or m of ampi ci l l i n di ssol ves f ast er and i s mor e r api dl y absor bed t han
t he hydr at ed f orm.
9. CompI ex f ormat i on. A compI ex i s a speci es f or med by t he r eversi bl e or
i r r eversi bl e associ at i on of t wo or more i nt er act i ng mol ecul es or i ons. CheI at es are
compl exes t hat t ypi cal l y i nvol ve a r i ng-l i ke st ruct ur e f or med by t he i nt eract i on
bet ween a par t i al r i ng of at oms and a met al . Many bi ol ogi cal l y i mpor t ant mol ecul es
( e. g. , hemogl obi n, i nsul i n, cyanocobal ami n) ar e chel at es. Dr ugs such as t et r acycl i ne
f or m chel at es wi t h di val ent ( e. g. , Ca
++
, Mg
++
) and t r i val ent ( e. g. , Al
+++
, Bi
+++
) met al
i ons. Many dr ugs adsorb st rongl y on charcoal or cl ay (e. g. , kaol i n, bent oni t e)
par t i cl es by f or mi ng compl exes. Drug compl exes wi t h pr ot ei ns, such as al bumi n or
q1- aci d gl ycopr ot ei n, of t en occur .
a. Compl ex f or mat i on usual l y al t er s t he physi cal and chemi cal char act eri st i cs of t he
dr ug. For exampl e:
( 1) The chel at e of t et r acycl i ne wi t h cal ci um i s l ess wat er sol ubl e and i s poor l y
absor bed.
( 2) Theophyl l i ne compl exed wi t h et hyl enedi ami ne t o f orm ami nophyl l i ne i s mor e
wat er sol ubl e and i s used f or parent er al and rect al admi ni st r at i on.
( 3) Cycl odext r i ns are used t o f or m compl exes wi t h many drugs t o i ncrease t hei r
wat er sol ubi l i t y.
b. Lar ge dr ug compl exes, such as drug-pr ot ei n compl exes, do not cr oss cel l
membr anes easi l y. These compl exes must di ssoci at e t o f r ee t he dr ug f or absor pt i on
at t he absor pt i on si t e or t o per mi t t r anspor t across cel l membr anes or gl omer ul ar
f i l t rat i on bef or e t he drug i s excr et ed i nt o t he ur i ne.
B. Drug product and deI i ver y syst em f ormuI at i on
1. GeneraI consi derat i ons
a. Desi gn of the appropri at e dosage form or deI i ver y syst em depends on t he
( 1) Physi cal and chemi cal pr oper t i es of t he dr ug
( 2) Dose of t he dr ug
( 3) Rout e of admi ni st r at i on
( 4) Type of dr ug del i ver y syst em desi red
( 5) Desi red t herapeut i c ef f ect
( 6) Physi ol ogi c r el ease of t he drug f r om t he del i ver y syst em
( 7) Bi oavai l abi l i t y of t he dr ug at t he absorpt i on si t e
( 8) Phar macoki net i cs and phar macodynami cs of t he drug
P. 89


b. Bi oavai I abi I i t y. The mor e compl i cat ed t he f ormul at i on of t he f i ni shed dr ug
pr oduct ( e. g. , cont rol l ed-r el ease t abl et , ent er i c- coat ed t abl et , t r ansdermal pat ch) ,
t he gr eat er t he pot ent i al f or a bi oavai l abi l i t y probl em. For exampl e, t he reI ease of a
dr ug f r om a peror al dosage f or m and i t s subsequent bi oavai l abi l i t y depend on a
successi on of r at e pr ocesses (Fi gur e 4- 2) . These pr ocesses may i ncl ude t he
f ol l owi ng:
( 1) At t ri t i on, di si nt egrat i on, or di saggregat i on of t he dr ug pr oduct
( 2) Di ssoI ut i on of t he drug i n an aqueous envi r onment
( 3) Convecti on and di ffusi on of t he drug mol ecul es t o t he absor bi ng surf ace
( 4) Absorpt i on of t he drug acr oss cel l membr anes i nt o t he syst emi c ci rcul at i on
c. The rat e- I i mi ti ng st ep i n t he bi oavai l abi l i t y of a drug f r om a dr ug product i s t he
sl owest st ep i n a seri es of ki net i c pr ocesses.
( 1) For most convent i onal sol i d dr ug product s (e. g. , capsul es, t abl et s) , t he
di ssol ut i on r at e i s t he sl owest , or r at e- l i mi t i ng, st ep f or bi oavai l abi l i t y.
( 2) For a cont r ol l ed- or sust ai ned- rel ease drug product , t he r el ease of t he dr ug f r om
t he del i ver y syst em i s t he r at e- l i mi t i ng st ep.
2. SoI ut i ons ar e homogeneous mi xt ur es of one or mor e sol ut es di sper sed
mol ecul ar l y i n a di ssol vi ng medi um (sol vent ) .
a. Compar ed wi t h ot her or al and per oral dr ug f ormul at i ons, a drug di ssol ved i n an
aqueous sol ut i on i s i n t he most bi oavai l abl e and consi st ent f orm. Because t he drug
i s al ready i n
P. 90

sol ut i on, no di ssol ut i on st ep i s necessar y bef or e syst emi c absor pt i on occur s.
Per or al dr ug sol ut i ons are of t en used as t he r ef erence prepar at i on f or sol i d peror al
f or mul at i ons.

Figure 4-2. The processes involved in drug
release Irom peroral dosage Iorms. GI.
gastrointestinal.
b. A dr ug di ssol ved i n a hydr oal cohol i c sol ut i on (e. g. , el i xi r ) al so has good
bi oavai l abi l i t y. Al cohol ai ds dr ug sol ubi l i t y. However , when t he dr ug i s di l ut ed by
gast r oi nt est i nal t ract f l ui d and ot her gut cont ent s ( e. g. , f ood) , i t may f orm a f i nel y
di vi ded pr eci pi t at e i n t he l umen of t he gast roi nt est i nal t ract . Because of t he
ext ensi ve di spersi on and l arge sur f ace area of such f i nel y di vi ded preci pi t at es,
r edi ssol ut i on and subsequent absorpt i on occur r api dl y.
c. A vi scous dr ug sol ut i on ( e. g. , syr up) may i nt er f er e wi t h di l ut i on and mi xi ng wi t h
gast r oi nt est i nal t ract cont ent s. The sol ut i on decreases t he gast r i c empt yi ng r at e and
t he rat e of t r ansf er of drug sol ut i on t o t he duodenal r egi on, wher e absor pt i on i s
most ef f i ci ent .
3. Suspensi ons ar e di sper si ons of f i nel y di vi ded sol i d par t i cl es of a dr ug i n a l i qui d
medi um i n whi ch t he dr ug i s not readi l y sol ubl e. The l i qui d medi um of a suspensi on
compr i ses a sat urat ed sol ut i on of t he drug i n equi l i bri um wi t h t he sol i d dr ug.
a. The bi oavai l abi l i t y of t he drug f r om suspensi ons may be si mi l ar t o t hat of a
sol ut i on because t he f i nel y di vi ded par t i cl es ar e di spersed and pr ovi de a l ar ge
sur f ace area f or rapi d di ssol ut i on. On t he ot her hand, a sl ow di ssol ut i on rat e
decreases t he absor pt i on r at e.
b. Suspendi ng agent s ar e of t en hydr ophi l i c col l oi ds ( e. g. , cel l ul ose deri vat i ves,
acaci a, xant han gum) added t o suspensi ons t o i ncr ease vi scosi t y, i nhi bi t
aggl omer at i on, and decrease t he rat e at whi ch par t i cl es set t l e. Hi ghl y vi scous
suspensi ons may prol ong gast ri c empt yi ng t i me, sl ow dr ug di ssol ut i on, and
decrease t he absorpt i on r at e.
4. CapsuI es ar e sol i d dosage f or ms wi t h har d or sof t gel at i n shel l s t hat cont ai n
dr ugs, usual l y admi xed wi t h exci pi ent s. Coat i ng t he capsul e shel l or t he dr ug
par t i cl es wi t hi n t he capsul e can af f ect bi oavai l abi l i t y.
a. Hard geI at i n capsuI es ar e usual l y f i l l ed wi t h a powder bl end t hat cont ai ns t he
dr ug. Typi cal l y, t he powder bl end i s si mpl er and l ess compact ed t han t he bl end i n a
compr essed t abl et . Af t er i ngest i on, t he gel at i n sof t ens, swel l s, and begi ns t o
di ssol ve i n t he gast r oi nt est i nal t ract . Encapsul at ed drugs are rel eased rapi dl y and
di spersed easi l y, and bi oavai l abi l i t y i s good. Har d gel at i n capsul es are t he pr ef er r ed
dosage f orm f or ear l y cl i ni cal t r i al s of new dr ugs.
b. Sof t geI at i n capsuI es may cont ai n a nonaqueous sol ut i on, a powder , or a dr ug
suspensi on. The vehi cl e may be wat er mi sci bl e ( e. g. , PEG). The car di ac gl ycosi de
di goxi n, di sper sed i n a wat er -mi sci bl e vehi cl e ( Lanoxi caps) , has bet t er
bi oavai l abi l i t y t han a compr essed t abl et f or mul at i on ( Lanoxi n) . However , a sof t
gel at i n capsul e t hat cont ai ns t he dr ug di ssol ved i n a hydrophobi c vehi cl e ( e. g. ,
veget abl e oi l ) may have poorer bi oavai l abi l i t y t han a compressed t abl et f or mul at i on
of t he dr ug.
c. Agi ng and st orage condi t i ons can af f ect t he moi st ur e cont ent of t he gel at i n
component of t he capsul e shel l and t he bi oavai l abi l i t y of t he drug.
( 1) At l ow moi st ur e l evel s, t he capsul e shel l becomes bri t t l e and i s easi l y r upt ur ed.
( 2) At hi gh moi st ur e l evel s, t he capsul e shel l becomes moi st , sof t , and di st ort ed.
Moi st ur e may be t ransf err ed t o t he capsul e cont ent s, par t i cul ar l y i f t he cont ent s ar e
hygr oscopi c.
5. Compressed t abI et s ar e sol i d dosage f or ms i n whi ch hi gh pr essur e i s used t o
compr ess a powder bl end or gr anul at i on t hat cont ai ns t he dr ug and ot her
i ngredi ent s, or exci pi ent s, i nt o a sol i d mass.
a. Exci pi ents, i ncl udi ng di l uent s (f i l l ers) , bi nder s, di si nt egr ant s, l ubr i cant s,
gl i dant s, sur f act ant s, dye, and f l avori ng agent s, have t he f ol l owi ng pr oper t i es.
( 1) They permi t t he ef f i ci ent manuf act ur e of compr essed t abl et s.
( 2) They af f ect t he physi cal and chemi cal charact er i st i cs of t he dr ug.
( 3) They af f ect bi oavai l abi l i t y. The hi gher t he r at i o of exci pi ent t o act i ve dr ug, t he
gr eat er t he l i kel i hood t hat t he exci pi ent s af f ect bi oavai l abi l i t y.
b. ExampI es
( 1) Di si nt egrants ( e. g. , st arch, croscarmel l ose, sodi um st arch gl ycol at e) var y i n
act i on, dependi ng on t hei r concent r at i on, t he met hod by whi ch t hey ar e mi xed wi t h
t he powder f or mul at i on or gr anul at i on, and t he degr ee of t abl et compact i on.
Al t hough t abl et di si nt egrat i on i s usual l y not a pr obl em because i t of t en occurs mor e
r api dl y t han dr ug di ssol ut i on, i t i s necessar y f or di ssol ut i on i n i mmedi at e- rel ease
f or mul at i ons. Ì nabi l i t y t o di si nt egrat e may i nt er f ere wi t h bi oavai l abi l i t y.
P. 91


( 2) Lubri cant s ar e usual l y hydr ophobi c, wat er -i nsol ubl e subst ances such as st eari c
aci d, magnesi um st earat e, hydrogenat ed veget abl e oi l , and t al c. They may r educe
wet t i ng of t he surf ace of t he sol i d dr ug par t i cl es, sl owi ng t he di ssol ut i on and
bi oavai l abi l i t y r at es of t he dr ug. Wat er - sol ubl e l ubr i cant s, such as L-l euci ne, do not
i nt er f ere wi t h di ssol ut i on or bi oavai l abi l i t y.
( 3) GI i dant s ( e. g. , col l oi dal si l i con di oxi de) i mprove t he f l ow pr oper t i es of a dr y
powder bl end bef ore i t i s compressed. Rat her t han posi ng a pot ent i al pr obl em wi t h
bi oavai l abi l i t y, gl i dant s may r educe t abl et -t o- t abl et vari abi l i t y and i mpr ove pr oduct
ef f i cacy.
( 4) Surfact ant s enhance dr ug di ssol ut i on r at es and bi oavai l abi l i t y by r educi ng
i nt er f aci al t ensi on at t he boundar y bet ween sol i d dr ug and l i qui d and by i mpr ovi ng
t he wet t abi l i t y (cont act ) of sol i d dr ug par t i cl es by t he sol vent .
c. Coat ed compressed tabI ets have a sugar coat , a f i l m coat , or an ent eri c coat
wi t h t he f ol l owi ng pr opert i es:
( 1) Ì t pr ot ect s t he drug f rom moi st ur e, l i ght , and ai r .
( 2) Ì t masks t he t ast e or odor of t he dr ug.
( 3) Ì t i mpr oves t he appear ance of t he t abl et .
( 4) Ì t may af f ect t he r el ease r at e of t he drug.
d. Ì n addi t i on, ent eri c coat i ngs mi ni mi ze cont act bet ween t he drug and t he gast r i c
r egi on by r esi st i ng di ssol ut i on or at t ri t i on and pr event i ng cont act bet ween t he
under l yi ng drug and t he gast r i c cont ent s or gast r i c mucosa. Some ent eri c coat i ngs
mi ni mi ze gast r i c cont act because t hey ar e i nsol ubl e at aci di c pHs. Ot her coat i ngs
r esi st at t r i t i on and r emai n whol e l ong enough f or t he t abl et t o l eave t he gast ri c
ar ea. By r esi st i ng di ssol ut i on or at t r i t i on, ent eri c coat i ngs may decr ease
bi oavai l abi l i t y. Ent er i c coat i ngs are used t o
( 1) Mi ni mi ze i r ri t at i on of t he gast r i c mucosa by t he dr ug
( 2) Pr event i nact i vat i on or degr adat i on of t he drug i n t he st omach
( 3) Del ay r el ease of t he dr ug unt i l t he t abl et r eaches t he smal l i nt est i ne, wher e
condi t i ons f or absor pt i on may be opt i mal
6. Modi fi ed- reI ease dosage forms ar e dr ug pr oduct s t hat al t er t he r at e or t i mi ng of
dr ug r el ease. Because modi f i ed- r el ease dosage f or ms are mor e compl ex t han
convent i onal i mmedi at e-r el ease dosage f orms, mor e st r i ngent qual i t y cont r ol and
bi oavai l abi l i t y t est s ar e requi r ed. Dose dumpi ng, or t he abr upt , uncont r ol l ed
r el ease of a l arge amount of dr ug, i s a probl em.
a. Extended- reI ease dosage f orms i ncl ude controI I ed- reI ease, sust ai ned- act i on,
and I ong-acti ng drug deI i ver y syst ems. These del i ver y syst ems al l ow at l east a
t wof ol d reduct i on i n dosi ng f requency compar ed wi t h convent i onal i mmedi at e-
r el ease f or mul at i ons.
( 1) The ext ended, sl ow r el ease of cont rol l ed- rel ease dr ug product s pr oduces a
r el at i vel y f l at , sust ai ned pl asma drug concent rat i on t hat avoi ds t oxi ci t y ( f rom hi gh
dr ug concent rat i ons) or l ack of ef f i cacy (f r om l ow dr ug concent r at i ons) .
( 2) Ext ended- r el ease dosage f or ms pr ovi de an i mmedi at e ( i ni t i al ) r el ease of t he
dr ug, f ol l owed by a sl ower sust ai ned r el ease.
b. DeI ayed- reI ease dosage forms r el ease act i ve dr ug at a t i me ot her t han
i mmedi at el y af t er admi ni st r at i on at a desi red si t e i n t he gast roi nt est i nal t ract . For
exampl e, an ent er i c-coat ed drug pr oduct does not al l ow f or di ssol ut i on i n t he aci d
envi r onment of t he st omach but , rat her , i n t he l ess aci di c envi ronment of t he smal l
i nt est i ne.
7. TransdermaI drug deI i ver y syst ems, or pat ches, ar e cont rol l ed- rel ease devi ces
t hat cont ai n t he dr ug f or syst emi c absor pt i on af t er t opi cal appl i cat i on t o t he ski n
sur f ace. Tr ansder mal drug del i ver y syst ems ar e avai l abl e f or a number of dr ugs
( ni t rogl ycer i n, ni cot i ne, scopol ami ne, cl oni di ne, f ent anyl , 17- 8- est r adi ol , and
t est ost er one). Al t hough t he f or mul at i on mat ri ces of t hese del i ver y syst ems di f f er
somewhat , t hey al l di f f er f r om convent i onal t opi cal f or mul at i ons i n t he f ol l owi ng
ways:
a. They have an i mpermeabl e occI usi ve backi ng f i I m t hat pr event s i nsensi bl e
wat er l oss f r om t he ski n beneat h t he pat ch. Thi s f i l m causes i ncreased hydr at i on
and ski n t emper at ur e under t he pat ch and enhanced permeat i on of t he ski n by t he
dr ug.
b. The f or mul at i on mat ri x of t he pat ch mai nt ai ns t he dr ug concent r at i on gr adi ent
wi t hi n t he devi ce af t er appl i cat i on so t hat drug del i ver y t o t he i nt er f ace bet ween t he
pat ch and t he ski n i s sust ai ned. As a resul t , drug par t i t i oni ng and di f f usi on i nt o t he
ski n persi st , and syst emi c absor pt i on i s mai nt ai ned t hr oughout t he dosi ng i nt er val .
c. Tr ansder mal dr ug del i ver y syst ems are kept i n pl ace on t he ski n sur f ace by an
adhesi ve I ayer, ensuri ng dr ug cont act wi t h t he ski n and cont i nued drug del i ver y.
8. Target ed ( si t e-speci fi c) drug deI i ver y syst ems are dr ug car r i er syst ems t hat
pl ace t he dr ug at or near t he r ecept or si t e. Exampl es i ncl ude macr omol ecul ar dr ug
car ri ers ( prot ei n dr ug
P. 92

car ri ers) , par t i cul at e dr ug del i ver y syst ems ( e. g. , l i posomes, nanopar t i cl es) , and
monocl onal ant i bodi es. Wi t h t arget ed dr ug del i ver y, t he drug may be del i ver ed t o
a. The capi l l ar y bed of t he act i ve si t e
b. A speci al t ype of cel l ( e. g. , t umor cel l s) but not t o normal cel l s
c. A speci f i c or gan or t i ssue by compl exi ng wi t h a car r i er t hat recogni zes t he t arget
9. I nsert s, i mpI ant s, and devi ces ar e used t o cont r ol dr ug del i ver y f or l ocal i zed or
syst emi c dr ug ef f ect s. The drug i s i mpregnat ed i nt o a bi odegradabl e or
nonbi odegradabl e mat er i al and i s r el eased sl owl y. The i nser t s, i mpl ant s, and
devi ces ar e i nsert ed i nt o a var i et y of cavi t i es ( e. g. , vagi na, buccal cavi t y) or t i ssues
( e. g. , ski n) . For exampl e, t he l euprol i de acet at e i mpl ant , Vi adur , i s i nser t ed beneat h
t he ski n of t he upper arm. Ì t provi des pal l i at i ve t r eat ment of advanced prost at e
cancer f or 1 year .
P. 93


STUDY QUESTIONS
Di rect i ons: Each quest i on, st at ement , or i ncompl et e st at ement i n t hi s sect i on can
be cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. Whi ch st atement best descri bes bi oavai I abi I i t y?
( A) r el at i on bet ween t he physi cal and t he chemi cal pr oper t i es of a dr ug and i t s
syst emi c absor pt i on
( B) measur ement of t he r at e and amount of t herapeut i cal l y act i ve dr ug t hat r eaches
t he syst emi c ci r cul at i on
( C) movement of t he dr ug i nt o body t i ssues over t i me
( D) di ssol ut i on of t he dr ug i n t he gast r oi nt est i nal t r act
( E) amount of drug dest royed by t he l i ver bef or e syst emi c absor pt i on f rom t he
gast r oi nt est i nal t ract occur s
Vi ew Answer 1. The answer i s B[ see] . 2. The rout e of drug admi ni st rati on
t hat gi ves t he most rapi d onset of t he pharmacoI ogi c ef f ect i s
( A) i nt r amuscul ar i nj ect i on.
( B) i nt r avenous i nj ect i on.
( C) i nt r ader mal i nj ect i on.
( D) peror al admi ni st rat i on.
( E) subcut aneous i nj ect i on.
Vi ew Answer 2. The answer i s B[ see] . 3. The rout e of drug admi ni st rati on
t hat provi des compI ete ( 100%) bi oavai I abi I i t y i s
( A) i nt r amuscul ar i nj ect i on.
( B) i nt r avenous i nj ect i on.
( C) i nt r ader mal i nj ect i on.
( D) peror al admi ni st rat i on.
( E) subcut aneous i nj ect i on.
Vi ew Answer 3. The answer i s B[ see] . 4. Af t er peroraI admi ni st rat i on,
drugs generaI I y are absorbed best f rom t he
( A) buccal cavi t y.
( B) st omach.
( C) duodenum.
( D) i l eum.
( E) r ect um.
Vi ew Answer 4. The answer i s C[ see] . 5. The charact eri st i cs of an act i ve
t ransport process i ncI ude aI I of t he f oI I owi ng except f or whi ch one?
( A) Act i ve t ranspor t moves dr ug mol ecul es agai nst a concent r at i on gradi ent .
( B) Act i ve t ranspor t f ol l ows Fi ck' s l aw of di f f usi on.
( C) Act i ve t ransport i s a car ri er -medi at ed t r anspor t syst em.
( D) Act i ve t ransport r equi r es ener gy.
( E) Act i ve t ranspor t of drug mol ecul es may be sat ur at ed at hi gh drug
concent r at i ons.
Vi ew Answer 5. The answer i s B[ seeand] . 6. The passage of drug
moI ecuI es f rom a regi on of hi gh drug concentrat i on to a regi on of I ow drug
concent rati on i s known as
( A) act i ve t r anspor t .
( B) bi oavai l abi l i t y.
( C) bi ophar maceut i cs.
( D) si mpl e di f f usi on.
( E) pi nocyt osi s.
Vi ew Answer 6. The answer i s D[ see] . 7. Whi ch equati on descri bes the rat e
of drug di ssoI ut i on f rom a tabI et ?
( A) Fi ck' s l aw
( B) Henderson- Hassel bal ch equat i on
( C) Law of mass act i on
( D) Mi chael i s- Ment en equat i on
( E) Noyes-Whi t ney equat i on
Vi ew Answer 7. The answer i s E[see] . 8. Whi ch condi t i on usuaI I y i ncreases
t he rate of drug di ssoI ut i on f rom a t abI et ?
( A) i ncr ease i n t he par t i cl e si ze of t he dr ug
( B) decr ease i n t he sur f ace ar ea of t he drug
( C) use of t he f ree aci d or f r ee base f or m of t he dr ug
( D) use of t he i oni zed, or sal t , f orm of t he dr ug
( E) use of sugar coat i ng ar ound t he t abl et
Vi ew Answer 8. The answer i s D[ seeand] . 9. Dose dumpi ng i s a probI em i n
t he f ormuI at i on of
( A) compr essed t abl et s.
( B) modi f i ed- r el ease dr ug pr oduct s.
( C) hard gel at i n capsul es.
( D) sof t gel at i n capsul es.
( E) supposi t ori es.
Vi ew Answer 9. The answer i s B[ see] . 10. The rat e- I i mi t i ng st ep i n the
bi oavai I abi I i t y of a I i pi d- soI ubI e drug f ormuI at ed as an i mmedi ate- reI ease
compressed tabI et i s t he rat e of
( A) di si nt egr at i on of t he t abl et and r el ease of t he dr ug.
( B) di ssol ut i on of t he dr ug.
( C) t r anspor t of t he dr ug mol ecul es acr oss t he i nt est i nal mucosal cel l s.
( D) bl ood f l ow t o t he gast r oi nt est i nal t r act .
( E) bi ot r ansf ormat i on, or met abol i sm, of t he dr ug by t he l i ver bef or e syst emi c
absor pt i on occur s.
Vi ew Answer 10. The answer i s B[ see] . P. 94


11. The extent of i oni zat i on of a weak eI ect roI yt e drug depends on t he
( A) pH of t he medi a and pKa of t he drug.
( B) oi l t o wat er par t i t i on coef f i ci ent of t he dr ug.
( C) par t i cl e si ze and sur f ace ar ea of t he dr ug.
( D) Noyes-Whi t ney equat i on f or t he drug.
( E) pol ymorphi c f orm of t he drug.
Vi ew Answer 11. The answer i s A[ see] . 12. The rat e of drug bi oavai I abi I i t y
i s most rapi d when t he drug i s f ormuI ated as a
( A) cont rol l ed- rel ease product .
( B) hard gel at i n capsul e.
( C) compressed t abl et .
( D) sol ut i on.
( E) suspensi on.
Vi ew Answer 12. The answer i s D[ see] . 13. The amount of drug t hat a
t ransdermaI pat ch ( i . e. , t ransdermaI drug deI i ver y syst em) deI i vers wi t hi n a 24-
hr peri od depends on the
( A) pat ch composi t i on, whi ch i ncl udes an occl usi ve backi ng and an adhesi ve f i l m i n
cont act wi t h t he ski n.
( B) af f i ni t y of t he drug f or t he f ormul at i on mat r i x r el at i ve t o i t s af f i ni t y f or t he
st r at um cor neum.
( C) r at e of dr ug par t i t i oni ng and/ or di f f usi on t hr ough t he pat ch t o t he ski n surf ace.
( D) surf ace ar ea of t he pat ch.
( E) Al l of t he above
Vi ew Answer 13. The answer i s E[see] . P. 95


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì . A. 3] .
Bi oavai l abi l i t y i s t he measurement of t he r at e and ext ent (amount ) of t herapeut i cal l y
act i ve drug t hat r eaches t he syst emi c ci r cul at i on. The r el at i on of t he physi cal and
t he chemi cal pr oper t i es of a dr ug t o i t s syst emi c absor pt i on ( i . e. , bi oavai l abi l i t y) i s
known as i t s bi ophar maceut i cs. The movement of a dr ug i nt o body t i ssues i s an
aspect of phar macoki net i cs, whi ch i s t he st udy of dr ug movement i n t he body over
t i me. The di ssol ut i on of a dr ug i n t he gast r oi nt est i nal t ract i s a physi cochemi cal
pr ocess t hat af f ect s bi oavai l abi l i t y. Si gni f i cant dest r uct i on of a drug by t he l i ver
bef ore i t i s syst emi cal l y absor bed (known as t he f i r st - pass ef f ect because i t occurs
dur i ng t he f i rst passage of t he dr ug t hrough t he l i ver ) decr eases bi oavai l abi l i t y.
2. The answer i s B [ see Ì Ì . B. 1. a] .
When t he act i ve f orm of t he dr ug i s gi ven i nt ravenousl y, i t ent er s t he syst emi c
ci rcul at i on di rect l y. The dr ug i s del i vered rapi dl y t o al l t i ssues, i ncl udi ng t he drug
r ecept or si t es. For al l ot her rout es of dr ug admi ni st rat i on, except i nt ra- art er i al
i nj ect i on, t he dr ug must be syst emi cal l y absor bed bef or e i t i s di st r i but ed t o t he dr ug
r ecept or si t es. For t hi s reason, t he onset of pharmacol ogi c ef f ect s i s sl ower . Ì f t he
dr ug i s a pr odr ug t hat must be conver t ed t o an act i ve dr ug, or al admi ni st rat i on, not
i nt ravenous i nj ect i on, may not pr ovi de t he most rapi d onset of act i vi t y i f conver si on
t o t he act i ve f or m t akes pl ace i n t he gast roi nt est i nal t r act or l i ver .
3. The answer i s B [ see Ì Ì . C. 2] .
When a dr ug i s gi ven by i nt ravenous i nj ect i on, t he ent i r e dose ent ers t he syst emi c
ci rcul at i on. Wi t h ot her r out es of admi ni st rat i on, t he dr ug may be l ost bef ore i t
r eaches t he syst emi c ci rcul at i on. For exampl e, wi t h f i rst - pass ef f ect s, a por t i on of
an oral l y admi ni st ered drug i s el i mi nat ed, usual l y t hr ough degr adat i on by l i ver
enzymes, bef ore t he dr ug r eaches i t s recept or si t es.
4. The answer i s C [ see Ì Ì . B. 2. b. ( 4) ] .
Dr ugs gi ven oral l y ar e wel l absorbed f r om t he duodenum. The duodenum has a l ar ge
sur f ace area because of t he pr esence of vi l l i and mi cr ovi l l i . Ì n addi t i on, because t he
duodenum i s wel l per f used by t he mesent eri c bl ood vessel s, a concent r at i on
gr adi ent i s mai nt ai ned bet ween t he l umen of t he duodenum and t he bl ood.
5. The answer i s B [ see Ì Ì . A. 2 and 3] .
Fi ck' s l aw of di f f usi on descri bes passi ve di f f usi on of dr ug mol ecul es movi ng f rom a
hi gh concent r at i on t o a l ow concent r at i on. Thi s pr ocess i s not sat ur abl e and does
not requi r e ener gy.
6. The answer i s D [ see Ì Ì . A. 2] .
The t r anspor t of a drug acr oss a cel l membrane by passi ve di f f usi on f ol l ows Fi ck' s
l aw of di f f usi on: The drug moves wi t h a concent rat i on gradi ent ( i . e. , f r om an ar ea of
hi gh concent r at i on t o an ar ea of l ow concent rat i on) . Ì n cont rast , dr ugs t hat ar e
act i vel y t ransport ed move agai nst a concent rat i on gr adi ent .
7. The answer i s E [ see Ì Ì Ì . A. 1] .
The Noyes-Whi t ney equat i on descr i bes t he r at e at whi ch a sol i d dr ug di ssol ves.
Fi ck' s l aw i s si mi l ar t o t he Noyes-Whi t ney equat i on i n t hat bot h equat i ons descr i be
dr ug movement caused by a concent rat i on gr adi ent . Fi ck' s l aw gener al l y ref ers t o
passi ve di f f usi on, or passi ve t r anspor t , of dr ugs. The l aw of mass act i on descr i bes
t he rat e of a chemi cal r eact i on, t he Mi chael i s- Ment en equat i on i nvol ves enzyme
ki net i cs, and t he Henderson- Hassel bal ch equat i on gi ves t he pH of a buf f er sol ut i on.
8. The answer i s D [ see Ì Ì Ì . A. 1 and 3] .
The i oni zed, or sal t , f orm of a dr ug has a charge and i s gener al l y mor e wat er
sol ubl e and, t her ef or e, di ssol ves more r api dl y t han t he noni oni zed ( f r ee aci d or f r ee
base) f or m of t he drug. The di ssol ut i on r at e i s di rect l y pr opor t i onal t o t he sur f ace
ar ea and i nver sel y propor t i onal t o t he part i cl e si ze. An i ncr ease i n t he part i cl e si ze
or a decr ease i n t he sur f ace ar ea sl ows t he di ssol ut i on r at e.
9. The answer i s B [ see Ì Ì Ì . B. 6] .
A modi f i ed- r el ease, or cont r ol l ed- rel ease, dr ug pr oduct cont ai ns t wo or mor e
convent i onal doses of t he dr ug. An abr upt rel ease of t he drug, known as dose
dumpi ng, may cause i nt oxi cat i on.
P. 96


10. The answer i s B [ see Ì Ì Ì . B. 1. c] .
For l i pi d-sol ubl e dr ugs, t he r at e of di ssol ut i on i s t he sl owest ( i . e. , r at e- l i mi t i ng) st ep
i n dr ug absorpt i on and t hus i n bi oavai l abi l i t y. The di si nt egr at i on r at e of an
i mmedi at e- r el ease or convent i onal compressed t abl et i s usual l y mor e rapi d t han t he
r at e of dr ug di ssol ut i on. Because t he cel l membrane i s a l i poprot ei n st ruct ur e,
t r anspor t of a l i pi d- sol ubl e dr ug acr oss t he cel l membrane i s usual l y r api d.
11. The answer i s A [ see Ì Ì Ì . A. 4. b] .
The ext ent of i oni zat i on of a weak el ect r ol yt e i s descr i bed by t he Henderson-
Hassel bal ch equat i on, whi ch r el at es t he pH of t he sol ut i on t o t he pKa of t he drug.
12. The answer i s D [ see Ì Ì Ì . B. 2. a] .
Because a dr ug i n sol ut i on i s al r eady di ssol ved, no di ssol ut i on i s needed bef or e
absor pt i on. Consequent l y, compared wi t h ot her dr ug f or mul at i ons, a dr ug i n sol ut i on
has a hi gh r at e of bi oavai l abi l i t y. A dr ug i n aqueous sol ut i on has t he hi ghest
bi oavai l abi l i t y r at e and i s of t en used as t he r ef erence prepar at i on f or ot her
f or mul at i ons. Dr ugs i n hydr oal cohol i c sol ut i on ( e. g. , el i xi r s) al so have good
bi oavai l abi l i t y. The r at e of drug bi oavai l abi l i t y f r om a hard gel at i n capsul e,
compr essed t abl et , or suspensi on may be equal t o t hat of a sol ut i on i f an opt i mal
f or mul at i on i s manuf act ur ed and t he drug i s i nherent l y rapi dl y absor bed.
13. The answer i s E [ see Ì Ì Ì . B. 7] .
Dr ug del i ver y f r om a t r ansdermal dr ug del i ver y syst em depends on al l of t he f act or s
ci t ed÷t hat i s, on t he pr esence of an occl usi ve backi ng ( t o mai nt ai n ski n hydr at i on
and el evat e ski n t emperat ur e sl i ght l y) and an adhesi ve f i l m t o mai nt ai n cont act of
t he f ormul at i on mat r i x wi t h t he ski n t o enabl e dr ug t r ansf er f r om t he pat ch i nt o t he
ski n. Ì f t he dr ug' s af f i ni t y f or t he f or mul at i on mat r i x i s gr eat er t han i t s af f i ni t y f or t he
st r at um cor neum, t he drug' s escapi ng t endency f r om t he pat ch wi l l be reduced,
mi ni mi zi ng t he gr adi ent f or drug t r ansf er i nt o t he ski n. The mi crovi scosi t y of t he
f or mul at i on mat ri x, t he pr esence of a membr ane bet ween t he dr ug r eser voi r i n t he
pat ch and t he ski n sur f ace, and i nt eract i on of t he dr ug wi t h t he f ormul at i on mat ri x
af f ect t he r at e and ext ent of di f f usi on and/ or par t i t i oni ng of t he drug t hr ough t he
pat ch t o t he ski n sur f ace. Fi nal l y, t he ext ent of drug del i ver y f r om t he pat ch i s
di r ect l y pr opor t i onal t o t he sur f ace area of t he pat ch i n cont act wi t h t he ski n
sur f ace.

5
Extemporaneous Prescription Compounding
Loyd V. AI I en Jr.
I. INTRODUCTION
A. Def i ni t i ons
1. Compoundi ng vs manuf acturi ng
2. Ì t i s i mpor t ant , but of t ent i mes di f f i cul t , t o di st i ngui sh bet ween compoundi ng and
manuf act ur i ng.
3. Compoundi ng has been def i ned by t he Nat i onal Associ at i on of Boards of
Phar macy as t he preparat i on, mi xi ng, assembl i ng, packagi ng, or l abel i ng of a drug
or devi ce ( i ) as t he r esul t of a pract i t i oner ' s pr escr i pt i on dr ug or der or i ni t i at i ve
based on t he phar maci st / pat i ent / prescr i ber r el at i onshi p i n t he course of pr of essi onal
pr act i ce or (i i ) f or t he pur pose of , as an i nci dent t o r esear ch, t eachi ng, or chemi cal
anal ysi s and not f or sal e or di spensi ng. Compoundi ng al so i ncl udes t he preparat i on
of drugs and devi ces i n ant i ci pat i on of pr escr i pt i on drug or der s based on r out i ne,
r egul arl y obser ved pat t er ns.
4. Manufacturi ng has been def i ned as t he pr oduct i on, pr eparat i on, pr opagat i on,
conversi on or pr ocessi ng of a dr ug or devi ce, ei t her di r ect l y or i ndi r ect l y, by
ext r act i on f rom subst ances of nat ur al or i gi n or i ndependent l y by means of chemi cal
or bi ol ogi cal synt hesi s, and i ncl udes any packagi ng or r epackagi ng of t he
subst ance(s) or l abel i ng or r el abel i ng of i t s cont ai ner, and t he pr omot i on and
market i ng of such drugs or devi ces. Manuf act uri ng al so i ncl udes t he pr epar at i on
and pr omot i on of commer ci al l y avai l abl e pr oduct s f r om bul k compounds f or r esal e
by pharmaci es, pract i t i oner s, or ot her persons.
5. The pur pose of pharmaceut i cal compoundi ng i s t o prepare an i ndi vi dual i zed dr ug
t r eat ment f or a pat i ent based on an order f r om a dul y l i censed prescr i ber . The
f undament al di f f er ence bet ween compoundi ng and manuf act uri ng i s t he exi st ence of
a phar maci st / prescr i ber / pat i ent r el at i onshi p t hat cont r ol s t he compoundi ng of t he
dr ug pr eparat i on. Compounded dr ugs ar e not f or resal e but , r at her, are per sonal
and responsi ve t o t he pat i ent ' s i mmedi at e needs. They ar e pr epar ed and
admi ni st er ed by t he pat i ent , car egi ver or pat i ent ' s heal t hcar e pr of essi onal s, whi ch
al l ows f or t he moni t or i ng of pat i ent out comes. On t he ot her hand, dr ug
manuf act ur ers produce bat ches consi st i ng of t ens or hundr eds of t housands of
dosage uni t s, such as t abl et s or capsul es, f or resal e, usi ng many personnel and
l ar ge- scal e manuf act ur i ng equi pment . These product s are di st r i but ed t hr ough t he
nor mal channel s of i nt erst at e commer ce t o i ndi vi dual s unknown t o t he company.
Manuf act ur ers are not requi red t o, and do not , provi de over si ght of i ndi vi dual
pat i ent s. Ì t i s al so accept abl e and rout i ne pract i ce f or phar maci st s t o compound f or
" of f i ce use¨ t hose pr eparat i ons t hat ar e not commer ci al l y avai l abl e. These
pr epar at i ons ar e "For Of f i ce Use Onl y¨ and ar e not f or r esal e or t o be gi ven t o t he
pat i ent s t o t ake home; t hey ar e t o be admi ni st er ed at t he of f i ce.
6. The Uni t ed St at es Phar macopei a ( USP) uses t he t er m pr eparat i on t o ref er t o
compounded pr escri pt i ons and t he t erm pr oduct s t o ref er t o manuf act ur ed
pharmaceut i cal s. Al so, f or st abi l i t y purposes, compounded pr epar at i ons ar e
assi gned a "beyond- use¨ dat e and manuf act ur ed pr oduct s ar e assi gned an
" expi r at i on dat e. ¨
B. ReguI at i on
1. Current good manuf act uri ng pract i ces (cGMPs) are t he st andards of pr act i ce
used i n t he pharmaceut i cal i ndust r y and ar e regul at ed by t he Food and Drug
Admi ni st rat i on (FDA) .
P. 98


2. Good compoundi ng pract i ces ( GCPs) ar e t he st andar ds of pr act i ce det ai l ed i n
t he USP, chapt er <1075>. Communi t y phar maci st s must compl y wi t h st at e boar d of
pharmacy l aws, regul at i ons, and gui del i nes t o ensur e a qual i t y pr epar at i on, whi ch
i ncl udes usi ng pr oper mat eri al s, wei ghi ng equi pment , document ed t echni ques, and
di spensi ng and st or age i nst ruct i ons.
3. LegaI consi derat i ons
a. Ext empor aneous compoundi ng by t he phar maci st or a pr escr i pt i on order f r om a
l i censed pract i t i oner , as wi t h t he di spensi ng of any ot her prescr i pt i on, i s cont r ol l ed
by t he st at e boar ds of phar macy.
b. The l egal ri sk (l i abi l i t y) of compoundi ng i s no gr eat er t han t he ri sk of f i l l i ng a
pr escri pt i on f or a manuf act ur ed pr oduct because t he phar maci st must ensur e t hat
t he cor rect drug, dose, and di r ect i ons ar e pr ovi ded. The pharmaci st i s al so
r esponsi bl e f or pr epari ng a qual i t y pharmaceut i cal pr epar at i on, provi di ng pr oper
i nst r uct i ons r egardi ng i t s st or age, and advi si ng t he pat i ent of any adverse ef f ect s.
4. Food and Drug Admi ni st rati on. The FDA has devel oped a l i st of pr epar at i ons
t hat shoul d not be ext empor aneousl y compounded. Thi s l i st was devel oped pri mar i l y
f r om commerci al pr oduct s t hat have been r emoved f r om t he market owi ng t o saf et y
and/ or ef f i cacy concer ns. Thi s i s a l engt hy l i st and must be r ead caref ul l y because,
i n some cases, onl y cer t ai n dosage f or ms of a speci f i c drug ar e i ncl uded on t he l i st
and ot her s ar e not . The l i st i s t oo ext ensi ve t o i ncl ude here but can be accessed at
www. f da. gov/ cder / phar mcomp/ pcwd. t xt .
C. St abi I i t y and quaI i t y cont roI of compounded preparat i ons
1. Beyond- use dates. The assi gnment of a beyond- use dat e i s one of t he most
di f f i cul t t asks requi r ed of a compoundi ng phar maci st . Chapt ers <795> and <797> of
t he USP pr ovi de gui del i nes f or t hi s t ask. Chapt er <795> i nvol ves nonst eri l e
pr epar at i ons, and chapt er <797> i nvol ves st eri l e pr epar at i ons. For nonst er i l e
pr epar at i ons, cur r ent USP cr i t eri a f or nonaqueous l i qui ds and sol i d f ormul at i ons ( f or
whi ch a manuf act ur ed drug product i s t he sour ce of act i ve i ngr edi ent s) i ncl ude a
beyond- use dat e not l at er t han 25% of t he t i me remai ni ng unt i l t he pr oduct ' s
expi r at i on dat e or 6 mont hs, whi chever i s earl i er. When a USP or Nat i onal
For mul ar y ( NF) subst ance i s t he sour ce of act i ve i ngredi ent , t he beyond- use dat e i s
not l at er t han 6 mont hs. For wat er -cont ai ni ng f ormul at i ons ( pr epar ed f r om
i ngredi ent s i n sol i d f orm), t he beyond-use dat e i s not l at er t han 14 days when
st ored at col d t emperat ur es. For al l ot her f ormul at i ons, t he beyond-use dat e i s not
l at er t han t he i nt ended dur at i on of t herapy or 30 days, whi chever i s ear l i er . These
beyond- use dat es may be exceeded when t her e i s suppor t i ng val i d sci ent i f i c
st abi l i t y i nf ormat i on t hat i s di rect l y appl i cabl e t o t he speci f i c preparat i on.
For st eri l e preparat i ons, i f a st er i l i t y t est i ng program i s not i n pl ace, t he f ol l owi ng
can be used pr ovi ded t he pr eparat i on i s pr operl y packaged and st or ed.
Low- Ri sk Level Compounded St eri l e Pr eparat i ons: Not mor e t han 48 hours at
cont r ol l ed r oom t emper at ur e, not mor e t han 14 days at a col d t emperat ure
( r ef r i gerat or ) and f or 45 days f rozen at -20°C or col der .
Medi um- Ri sk Level Compounded St er i l e Preparat i ons: Not more t han 30 hours at
cont r ol l ed r oom t emper at ur e, not mor e t han 9 days at col d t emperat ure ( ref r i ger at or )
and f or 45 days f r ozen at - 20°C or col der .
Hi gh- Ri sk Level Compounded St eri l e Pr eparat i ons: Not mor e t han 24 hours at
cont r ol l ed r oom t emper at ur e, not mor e t han 3 days at col d t emperat ure ( ref r i ger at or )
and f or 45 days f r ozen at - 20°C or col der .
Ì f a st er i l i t y t est i ng program i s i n pl ace, t he beyond- use dat es f or nonst eri l e
pr epar at i ons appl y. As i n nonst er i l e compoundi ng, t hese beyond-use dat es f or
st eri l e compoundi ng may be exceeded when t here i s suppor t i ng val i d sci ent i f i c
st abi l i t y i nf ormat i on t hat i s di rect l y appl i cabl e t o t he speci f i c preparat i on.
2. QuaI i t y cont roI . Qual i t y cont rol i s becomi ng one of t he f ast est growi ng aspect s
of pharmacy compoundi ng. Phar maci st s ar e becomi ng mor e i nvol ved i n t he f i nal
t est i ng of compounded pr eparat i ons or ar e sendi ng t hem t o cont ract l abor at ori es f or
t est i ng. For exampl e, t he f ol l owi ng qual i t y cont r ol t est s can be consi dered f or t he
r espect i ve compounded dosage f orms:
P. 99


a. Oi ntments, creams, and geI s. Theoret i cal wei ght compared t o act ual wei ght , pH,
speci f i c gravi t y, act i ve dr ug assay, physi cal obser vat i ons (col or , cl ari t y, t ext ur e-
sur f ace, t ext ur e- spat ul a spr ead, appear ance, f eel ) , and r heol ogi cal pr opert i es.
b. Hard geI at i n capsuI es. Wei ght over al l , aver age wei ght , i ndi vi dual wei ght
var i at i on, di ssol ut i on of capsul e shel l , di si nt egrat i on of capsul e cont ent s, act i ve
dr ug assay, physi cal appear ance ( col or , uni f ormi t y, ext ent of f i l l , l ocked) , and
physi cal st abi l i t y ( di scol or at i on, changes i n appear ance).
c. Speci aI hard geI at i n capsuI es. Wei ght over al l , average wei ght , i ndi vi dual wei ght
var i at i on, di ssol ut i on of capsul e shel l , di si nt egrat i on of capsul e cont ent s, act i ve
dr ug assay, physi cal appear ance ( col or , uni f ormi t y of appear ance, uni f or mi t y of
ext ent of f i l l , cl osur es) , and physi cal st abi l i t y ( di scol orat i on or ot her changes).
d. Supposi t ori es, t roches, I oI I i pops, and st i cks. Wei ght , speci f i c gr avi t y, act i ve
dr ug assay, physi cal obser vat i ons ( col or , cl ar i t y, t ext ur e of surf ace, appear ance,
f eel ) , mel t i ng t est , di ssol ut i on t est , physi cal st abi l i t y.
e. OraI and t opi caI I i qui ds. Wei ght t o vol ume, pH, speci f i c gr avi t y, act i ve dr ug
assay, gl obul e si ze range, r heol ogi cal pr oper t i es/ pourabi l i t y, physi cal obser vat i ons
( col or , cl ar i t y) , and physi cal st abi l i t y ( di scol orat i on, f or ei gn mat eri al s, gas
f or mat i on, mol d gr owt h) .
f . Parent eraI preparati ons. Wei ght or vol ume, pH, speci f i c gr avi t y, osmol al i t y,
assay, physi cal obser vat i ons (col or , cl ar i t y) , par t i cul at e mat t er , st eri l i t y, and
pyr ogeni ci t y.
3. QuaI i t y cont roI test i ng. Pharmaci st s have t he opt i on of doi ng t est i ng i n- house or
out sourci ng i t t o l abor at or i es.
a. I n-house test i ng can i ncl ude measur ement s such as wei ght , vol ume, pH, speci f i c
gr avi t y, osmol al i t y, physi cal obser vat i ons, st eri l i t y and endot oxi ns.
b. Out - sourced t est i ng can i ncl ude st er i l i t y, endot oxi ns, pot ency, and di ssol ut i on.
c. Test resuI t s shoul d be kept on f i l e wi t h t he compoundi ng r ecords f or t he
i ndi vi dual compounded pr eparat i ons.
II. REQUIREMENTS FOR COMPOUNDING
A. Sources for chemi caI s and drugs. Pharmaci st s can obt ai n smal l quant i t i es of
t he appropri at e chemi cal s or dr ugs f r om whol esal er s or chemi cal suppl y houses.
These suppl i ers t hen may al so ser ve as compoundi ng consul t ant s t o t he
pharmaci st s t o ai d i n ensur i ng t hei r pr oduct ' s pur i t y and qual i t y.
B. Equi pment . The correct equi pment i s i mport ant when compoundi ng. Many st at e
boards of pharmacy have a requi r ed mi ni mum l i st of equi pment f or compoundi ng
pr escri pt i ons. Suggest ed equi pment , whi ch vari es accordi ng t o t he amount of
mat er i al needed and t he t ype of compounded pr escri pt i on ( e. g. , parent er al ) ,
i ncl udes t he f ol l owi ng:
1. El ect r oni c bal ance and/ or cl ass A pr escr i pt i on bal ance
2. Hot pl at e
3. Magnet i c st i r r er
4. El ect r i c mi xer
5. Speci al cont ai ner s f or packagi ng (e. g. , appl i cat or t i p bot t l es, i nsuf f l at ors)
6. Gr aduat ed cyl i nder s f rom 10 mL t o 1000 mL
7. Gl ass, Wedgwood, and porcel ai n mort ars and pest l es of vari ous si zes
8. Funnel s of var i ous si zes
9. Spat ul as of var i ous si zes, i ncl udi ng sever al pl ast i c spat ul as
10. Wei ghi ng and f i l t er papers
11. St i r ri ng r ods (gl ass)
12. Oi nt ment / pi l l t i l e
13. Capsul e- f i l l i ng machi ne
14. Oi nt ment - f i l l i ng machi ne
15. Aut ocl ave
16. Lami nar f l ow cl ean bench
17. Speci al supposi t or y, t r oche and medi cat i on- st i ck mol ds
P. 100


18. Recor d-keepi ng syst em (compoundi ng l og book)
19. Gl ass beakers f rom 50 mL t o 1000 mL
C. Locat i on of compoundi ng area. Many pharmaci es act i vel y i nvol ved i n
compoundi ng have dedi cat ed a separ at e ar ea i n t he pharmacy t o t hi s pr ocess. The
i deal l ocat i on i s away f r om heavy f oot t raf f i c and i s near a si nk wher e t here i s
suf f i ci ent space t o wor k and st or e al l chemi cal s and equi pment . For compoundi ng of
st eri l e preparat i ons, a l ami nar ai r - f l ow hood (mi ni mal ) and a cl ean room ar e cur r ent
pr act i ce, or i sol at i on barr i er t echnol ogy equi pment .
D. Sources of i nformati on
1. Li br ar y at a col l ege of pharmacy
2. References
a. Al l en Jr LV. The Ar t , Sci ence and Technol ogy of Phar maceut i cal Compoundi ng.
3r d ed. Washi ngt on, DC: Ameri can Pharmaceut i cal Associ at i on, 2008.
b. Anon. Remi ngt on: The Sci ence and Pr act i ce of Phar macy. 21st ed. Phi l adel phi a:
Li ppi ncot t Wi l l i ams & Wi l ki ns; 2006.
c. Smi t h A, Heckel man PE, O' Nei l M, Budavar i S, eds. Mer ck I ndex. 13t h ed.
Whi t ehouse St at i on, NJ: Mer ck & Co, 2001.
d. The USP Phar maci st s' Phar macopei a. 2nd Edi t i on Rockvi l l e, MD: U. S.
Phar macopei al Convent i on, Ì nc. , 2008.
e. Al l en LV Jr , Popovi ch NG, Ansel HC. Ansel ' s Phar maceut i cal Dosage For ms and
Dr ug Del i very Syst ems. 9t h Edi t i on Medi a, PA: Li ppi ncot t Wi l l i ams & Wi l ki ns, 2008.
3. JournaI s
a. I nt ernat i onal Jour nal of Phar maceut i cal Compoundi ng
b. U. S. Phar maci st
c. Phar macy Ti mes
d. Li ppi ncot t ' s Hospi t al Phar macy
e. Amer i can Journal of Heal t h- Syst em Phar maci st s
4. Manuf act urers' dr ug pr oduct i nf or mat i on i nser t s; compoundi ng speci al t y suppl i er s
5. Web si t es
a. Compoundi ng Today: www. Compoundi ngToday. com
b. I nt er nat i onal Jour nal of Phar maceut i cal Compoundi ng: www. i j pc. com
c. Paddock Labor at or i es, Ì nc. : www. paddockl abs. com
III. COMPOUNDING OF SOLUTIONS
A. Def i ni t i on. USP 30 def i nes soI ut i ons as l i qui d pr eparat i ons t hat cont ai n one or
mor e chemi cal subst ances di ssol ved ( i . e. , mol ecul arl y di sper sed) i n a sui t abl e
sol vent or mi xt ur e of mut ual l y mi sci bl e sol vent s. Al t hough t he uni f ormi t y of t he
dosage i n a sol ut i on can be assumed, t he st abi l i t y, pH, sol ubi l i t y of t he drug or
chemi cal s, t ast e ( f or oral sol ut i ons) , and packagi ng need t o be consi der ed.
B. Types of soI ut i ons
1. St eri I e parent eraI and ophthaI mi c soI ut i ons r equi r e speci al consi derat i on f or
t hei r preparat i on ( see XÌ ) .
2. Nonst eri I e soI uti ons i ncl ude or al , t opi cal , and ot i c sol ut i ons.
C. Preparat i on of soI ut i ons. Sol ut i ons are t he easi est of t he dosage f orms t o
compound ext empor aneousl y, as l ong as a f ew gener al r ul es are f ol l owed.
1. Each dr ug or chemi cal i s di ssol ved i n t he sol vent i n whi ch i t i s most sol ubl e. Thus
t he sol ubi l i t y char act er i st i cs of each drug or chemi cal must be known.
2. Ì f an al cohol i c sol ut i on of a poorl y wat er - sol ubl e dr ug i s used, t he aqueous
sol ut i on i s added t o t he al cohol i c sol ut i on t o mai nt ai n as hi gh an al cohol
concent r at i on as possi bl e.
P. 101


3. The sal t f or m of t he drug÷not t he f r ee-aci d or base f or m, whi ch bot h have poor
sol ubi l i t y÷i s used.
4. Fl avor i ng or sweet eni ng agent s ar e pr epared ahead of t i me.
5. When addi ng a sal t t o a syr up, di ssol ve t he sal t i n a f ew mi l l i l i t ers of wat er f i rst ;
t hen add t he syr up t o vol ume.
6. The pr oper vehi cl e (e. g. , syr up, el i xi r , ar omat i c wat er , puri f i ed wat er ) must be
sel ect ed.
D. ExampI es
1. ExampI e 1
a. Medi cat i on order
Triamcinolone acetonide 100 mg
Menthol 50 mg
Ethanol 10 mL
Propylene glycol 30 mL
Glycerin 20 mL
Sorbitol 70° solution. qs 100 mL
Sodium saccharin 100 mg
Sodium metabisulIite 20 mg
Disodium EDTA 100 mg
PuriIied water 5 mL

b. Compoundi ng procedure. Tr i amci nol one acet oni de 0. 1% mout hwash sol ut i on i s
pr epar ed by di ssol vi ng t he t ri amci nol one acet oni de and ment hol i n t he et hanol . Add
t he pr opyl ene gl ycol , gl ycer i n, and about 10 mL of t he 70% sorbi t ol and mi x wel l .
Di ssol ve t he sodi um sacchari n, sodi um met abi sul f i t e, and di sodi um EDTA i n t he
pur i f i ed wat er . Add t he aqueous sol ut i on t o t he drug mi xt ur e and mi x wel l . Add
suf f i ci ent 70% sor bi t ol sol ut i on t o vol ume and mi x wel l .
How much of the t ri amci noI one base i s present i n thi s prescri pti on? The
mol ecul ar wei ght of t r i amci nol one i s 394. 4 and t hat of t ri amci nol one acet oni de i s
434. 5.

2. ExampI e 2
a. Medi cat i on order
Potassium chloride 1 mEq/mL
Preserved Ilavored. oral vehicle. qs 100 mL

b. CaI cuI at i ons. The mol ecul ar wei ght of pot assi um chl or i de i s 74. 5 ( K = 39; Cl =
35. 5). One mi l l i equi val ent ( mEq) wei ghs 74. 5 mg.
100 mL × 74. 5 mg/ mL = 7450 mg or 7. 45 g of KCl r equi red
What i s the moI ar concent rat i on of t hi s prescri pt i on?
7. 45 g per 100 mL or 74. 5 g per 1000 mL
1 mol e of KCl wei ght s 74. 5 g
Ì t i s a 1 mol ar sol ut i on
c. Compoundi ng procedure. The sol ubi l i t y of pot assi um chl or i de i s 1 g i n 2. 8 mL
wat er . Ther ef or e, di ssol ve t he 7. 45 g KCl i n 21 mL of puri f i ed wat er. Add suf f i ci ent
pr eser ved f l avor ed or al vehi cl e t o vol ume and mi x wel l .
3. ExampI e 3
a. Medi cat i on order
Salicylic acid 2°
Lactic acid 6 mL
Flexible collodion. ad 30 mL

b. Compoundi ng procedure. Pharmaci st s must use caut i on when prepari ng t hi s
pr escri pt i on because f l exi bl e col l odi on i s ext r emel y f l ammabl e. A 1- oz. appl i cat or -
t i p bot t l e i s cal i br at ed, usi ng et hanol , whi ch i s pour ed out and any r emai ni ng al cohol
al l owed t o
P. 102

evaporat e, r esul t i ng i n a dr y bot t l e. Sal i cyl i c aci d ( 0. 6 g) i s added di r ect l y i nt o t he
bot t l e, t o whi ch i s added t he 6 mL of l act i c aci d. The bot t l e i s agi t at ed or a gl ass
st i r ri ng r od i s used t o di ssol ve t he sal i cyl i c aci d. Fl exi bl e col l odi on i s added up t o
t he cal i brat ed 30-mL mar k on t he appl i cat or - t i p bot t l e.
4. ExampI e 4
a. Medi cat i on order
Iodine 2°
Sodium iodide 2.4°
Alcohol. qs 30 mL

b. Compoundi ng procedure. Ì odi ne ( 0. 6 g) and sodi um i odi de ( 0. 72 g) ar e
di ssol ved i n t he al cohol , and t he f i nal sol ut i on i s pl aced i n an amber bot t l e. A
rubber or pI ast i c spat uI a i s used because i odi ne i s corrosi ve.
IV. COMPOUNDING OF SUSPENSIONS
A. Def i ni t i on. Suspensi ons ar e def i ned by USP 30 as l i qui d preparat i ons t hat
consi st of sol i d part i cl es di spersed t hr oughout a l i qui d phase i n whi ch t he par t i cl es
ar e not sol ubl e.
B. GeneraI charact eri sti cs
1. Some suspensi ons shoul d cont ai n an ant i mi crobi al agent as a preser vat i ve.
2. Part i cl es set t l e i n suspensi ons even when a suspendi ng agent i s added; t hus
suspensi ons must be wel l shaken bef or e use t o ensur e t he di st r i but i on of par t i cl es
f or a uni f orm dose.
3. Ti ght cont ai ners are necessar y t o ensure t he st abi l i t y of t he f i nal pr epar at i on.
4. Pr i nci pl es t o keep i n mi nd when compoundi ng i ncl ude t he f ol l owi ng:
a. Ì nsol ubl e powders shoul d be smal l and uni f orm i n si ze t o decr ease set t l i ng.
b. The suspensi on shoul d be vi scous.
c. Topi cal suspensi ons shoul d have a smoot h, i mpal pabl e t ext ur e.
d. Or al suspensi ons shoul d have a pl easant odor and t ast e.
C. Format i on of suspensi ons. Suspensi ons are easy t o compound; however ,
physi cal st abi l i t y af t er compoundi ng t he f i nal pr epar at i on i s pr obl emat i c. The
f ol l owi ng st eps may mi ni mi ze st abi l i t y pr obl ems.
1. The par t i cl e si ze of al l powder s used i n t he f ormul at i on shoul d be reduced.
2. A t hi ckeni ng ( suspendi ng) agent may be used t o i ncr ease vi scosi t y. Common
t hi ckeni ng agent s i ncl ude al gi ni c aci d, bent oni t e, VEEGUM, met hyl cel l ul ose, and
t r agacant h.
3. A l evi gat i ng agent may ai d i n t he i ni t i al di spersi on of i nsol ubl e par t i cl es. Common
l evi gat i ng agent s i ncl ude gl ycer i n, propyl ene gl ycol , al cohol , syr ups, and wat er .
4. Fl avor i ng agent s and pr eser vat i ves shoul d be sel ect ed and added i f t he
pr epar at i on i s i nt ended f or oral use. Common pr eser vat i ves i ncl ude met hyl paraben,
pr opyl par aben, benzoi c aci d, and sodi um benzoat e. Fl avori ng agent s may be any
f l avor ed syr up or f l avor concent r at e ( Tabl e 5- 1).
5. The sour ce of t he act i ve i ngredi ent s ( e. g. , bul k powder s ver sus t abl et s or
capsul es) must be consi der ed; i f commer ci al dosage f orms ar e used, t he i nact i ve
i ngredi ent s must be consi der ed and onl y i mmedi at e- r el ease t abl et s or capsul es
shoul d be used and not modi f i ed r el ease.
D. Preparat i on of suspensi ons
1. The i nsol ubl e powders are t ri t urat ed t o a f i ne powder .
2. A smal l por t i on of l i qui d i s used as a l evi gat i ng agent , and t he powder s ar e
t r i t urat ed unt i l a smoot h past e i s f ormed.
3. The vehi cl e cont ai ni ng t he suspendi ng agent i s added i n di vi ded por t i ons. A hi gh-
speed mi xer gr eat l y i ncreases t he di spersi on.
P. 103


Table 5-1. Selected Flavor Applications
Drug Category Preferred Flavors
Antibiotics Cherry. maple. pineapple. orange. raspberry. banana-
pineapple. banana-vanilla. butterscotch-maple.
coconut custard. strawberry. vanilla. lemon custard.
cherry custard. Iruit-cinnamon
Antihistamines Apricot. black currant. cherry. cinnamon. custard.
grape. honey. lime. loganberry. peach-orange. peach-
rum. raspberry. root beer. wild cherry
Barbiturates Banana-pineapple. banana-vanilla. black currant.
cinnamonpeppermint. grenadine-strawberry. lime.
orange. peach-orange. root beer
Decongestants
and expectorants
Anise. apricot. black currant. butterscotch. cherry.
coconut custard. custard mint-strawberry. grenadine-
peach. strawberry. lemon. coriander. orange-peach.
pineapple. raspberry. strawberry. tangerine
Electrolyte
solutions
Cherry. grape. lemon-lime. raspberry. wild cherry.
black currant. grenadine-strawberry. lime. Port wine.
Sherry wine. root beer. wild strawberry

4. The pr epar at i on i s br ought t o t he r equi red vol ume usi ng t he vehi cl e.
5. The f i nal mi xt ur e i s t ransf er red t o a " t i ght ¨ bot t l e f or di spensi ng t o t he pat i ent .
6. Al l suspensi ons ar e di spensed wi t h a "shake wel l ¨ l abel .
7. Suspensi ons ar e not f i l t ered.
8. The wat er -sol ubl e i ngredi ent s, i ncl udi ng f l avori ng agent s, are mi xed i n t he
vehi cl e bef or e mi xi ng wi t h t he i nsol ubl e i ngr edi ent s.
E. ExampI es
1. ExampI e 1
a. Medi cat i on order
Propranolol HCI 4 mg/mL
Disp 30 mL
Sig: 1 mL p.o. t.i.d.

b. CaI cuI at i ons. Propranol ol HCl : 4 mg/ mL × 30 mL = 120 mg. Pr opr anol ol HCl i s
avai l abl e as a powder or i n i mmedi at e- rel ease and ext ended- r el ease ( l ong- act i ng)
dosage f orms. Onl y t he powder or t he i mmedi at e- r el ease t abl et s are used f or
compoundi ng prescr i pt i ons; t her ef or e, some combi nat i on of propranol ol HCl t abl et s
t hat yi el ds 120 mg act i ve dr ug ( e. g. , 3 × 40 mg t abl et s) may be used.
c. Compoundi ng procedure. The pr opr anol ol t abl et s ar e reduced t o a f i ne powder
i n a mor t ar. The powder or t he commi nut ed t abl et s are l evi gat ed t o a smoot h past e,
usi ng a 2% met hyl cel l ul ose sol ut i on. To t hi s mi xt ur e, about 10 mL of a sui t abl e
f l avori ng agent i s added. The mi xt ur e i s t r ansf er red t o a cal i br at ed cont ai ner and
br ought t o t he f i nal vol ume wi t h puri f i ed wat er or sui t abl e suspendi ng vehi cl e. A
" shake wel l ¨ l abel i s at t ached t o t he prescri pt i on cont ai ner .
2. ExampI e 2
a. Medi cat i on order
Zinc oxide 10
Ppt sulIur 10
Bentonite 3.6
PuriIied water. ad 90 mL
Sig: Apply t.i.d.

b. Compoundi ng procedure. The powders are reduced t o a f i ne uni f or m mi xt ur e i n
a mor t ar. The powder s ar e mi xed t o f or m a smoot h past e usi ng wat er and
t r ansf er red t o
P. 104

a cal i br at ed bot t l e. The f i nal vol ume i s at t ai ned wi t h puri f i ed wat er . A "shake wel l ¨
l abel i s at t ached t o t he pr escr i pt i on cont ai ner.
3. ExampI e 3
a. Medi cat i on order
RiIampin suspension 20 mg/mL
Disp 120 mL
Sig: u.d.

b. CaI cuI at i ons. Ri f ampi n: 20 mg/ mL × 120 mL = 2400 mg. Ri f ampi n i s avai l abl e i n
150-mg and 300-mg capsul es. Hence, 8 capsul es cont ai ni ng 300 mg of ri f ampi n i n
each capsul e or 16 capsul es cont ai ni ng 150 mg of r i f ampi n per capsul e ar e needed.
c. Compoundi ng procedure. The cont ent s of t he appr opr i at e number of r i f ampi n
capsul es are empt i ed i nt o a mort ar and commi nut ed wi t h a pest l e. Thi s powder i s
l evi gat ed wi t h a smal l amount of 1% met hyl cel l ul ose sol ut i on. Then 20 mL of si mpl e
syr up ar e added and mi xed. The mi xt ur e i s br ought t o t he f i nal vol ume wi t h si mpl e
syr up. " Shake wel l ¨ and " r ef r i gerat e¨ l abel s ar e at t ached t o t he prescr i pt i on
cont ai ner .
V. EMULSIONS
A. Def i ni t i on. Emul si ons ar e two- phase syst ems i n whi ch one l i qui d i s di spersed
t hr oughout anot her l i qui d i n t he f or m of smal l dropl et s ( see Chapt er 3. VÌ . D) .
B. GeneraI charact eri sti cs. Emul si ons can be used externaI I y as l ot i ons and
cr eams or i nternaI I y t o mask t he t ast e of medi cat i ons.
1. The t wo l i qui ds i n an emul si on are i mmi sci bl e and requi r e t he use of an
emuI si f yi ng agent .
2. Emul si ons are cl assi f i ed as ei t her oi I - i n-wat er ( o/ w) or wat er- i n- oi I (w/ o) ; t her e
can al so be mul t i pl e emul si ons, such as oi I -i n-wat er- i n- oi I ( o/ w/ o) and wat er- i n-
oi I - i n-wat er (w/ o/ w) , as wel l as emul si on-gel s, i n whi ch t he ext er nal phase of an oi l
i n wat er emul si on i s t hi ckened wi t h a gel l i ng agent .
3. Emul si ons are unst abI e by nat ur e, and t he f ol l owi ng st eps shoul d be t aken t o
pr event t he t wo phases of an emul si on f r om separ at i ng i nt o t wo l ayer s af t er
pr epar at i on.
a. The cor rect proport i ons of oi l and wat er shoul d be used duri ng preparat i on. The
i nt er nal phase shoul d r epr esent 40%- 60% of t he t ot al vol ume.
b. An emul si f yi ng agent i s needed f or emul si on f or mat i on.
c. A hand homogeni zer, whi ch reduces t he si ze of gl obul es of t he i nt er nal phase,
may be used; i f smal l quant i t i es ar e compounded, t wo 60-mL syr i nges at t ached wi t h
a Leur - Lock adapt er can be used and t he mat eri al s pushed back and f or t h bet ween
t he t wo syr i nges.
d. Preservat i ves shoul d be added i f t he pr epar at i on i s i nt ended t o l ast l onger t han
a f ew days. Gener al l y, a combi nat i on of met hyl par aben ( 0. 2%) and propyl par aben
( 0. 02%) may be used.
e. A "shake weI I " I abeI shoul d be pl aced on t he f i nal pr epar at i on.
f . The prepar at i on shoul d be prot ect ed f rom l i ght and ext r eme t emper at ur e. Bot h
f r eezi ng and heat may have an ef f ect on st abi l i t y.
C. EmuI si f yi ng agent s
1. Gums, such as acaci a or t ragacant h, are used t o f or m o/ w emul si ons. These
emul si f yi ng agent s ar e f or general use, especi al l y f or emul si ons i nt ended f or
i nt er nal admi ni st rat i on (Tabl e 5- 2) .
a. Use 1 g of acaci a powder f or ever y 4 mL of f i xed oi l or 1 g t o 2 mL f or a vol at i l e
oi l .
b. Ì f usi ng t ragacant h i n pl ace of acaci a, 0. 1 g of t r agacant h i s used f or ever y 1 g of
acaci a.
2. Met hyI ceI I uI ose and carboxymet hyI ceI I uI ose ar e used f or o/ w emul si ons. The
concent r at i ons of t hese agent s var y, dependi ng on t he gr ade t hat i s used.
Met hyl cel l ul ose i s avai l abl e i n several vi scosi t y gr ades, rangi ng f rom 15 t o 4000 and
desi gnat ed by a cent i poi se number, whi ch i s a uni t of vi scosi t y.
P. 105


Table 5-2. Agents Used in Prescription Compounding
Ointments
Oleaginous or hydrocarbon bases Hydrous emulsion bases (w/o)
Anhydrous Hydrous
Nonhydrophilic Will absorb water
Insoluble in water Insoluble in water

Not water removable
(occlusive)
Not water removable
(occlusive)
Good vehicles Ior antibiotics Examples
Example Cold cream
Petrolatum Hydrous lanolin
Absorption bases Emulsion bases (o/w)
Anhydrous Hydrous
Will absorb water Hydrophilic
Insoluble in water Insoluble in water

Not water removable
(occlusive)
Water removable
Examples Can absorb 30-50° oI weight
Hydrophilic petrolatum Examples
Lanolin USP (anhydrous) Hydrophilic ointment USP
Acid mantle cream
Water soluble
Anhydrous or hydrous
Soluble in water
Water removable
Hydrophilic
Example
Polyethylene glycol ointment
Suspending Agents
Acacia 10° Methylcellulose 1°-7°
Alginic acid 1°-2° Sodium alginate 1°-2°
Bentonite 6° Tragacanth 1°-3°
Carboxymethylcellulose 1°-5° VEEGUM 6°
Preservatives
Methylparaben 0.02°-0.2° Propylparaben 0.01°-0.04°
Emulsifying Agents
Hydrophilic colloids SurIactants. nonionic
Acacia Concentrations used (1-30°)
Tragacanth Tweens (e.g.. polysorbate 80)
Pectin; Iavor o/w Spans
Carboxymethylcellulose
Methylcellulose
Proteins Soaps
Gelatin Triethanolamine
Egg whites; Iavor o/w Stearic acid
Inorganic gels and magmas Others
Milk oI magnesia Sodium lauryl sulIate
Bentonite; Iavor o/w Dioctyl sodium sulIosuccinate
Cetyl pyridinium chloride
o/w. oil-in-water; w/o. water-in-oil

P. 106


3. Soaps can be used t o pr epar e o/ w or w/ o emul si ons f or ext er nal pr eparat i ons.
4. Noni oni c emuI si f yi ng agent s can be used f or o/ w and w/ o emul si ons.
D. Format i on and preparat i on of emuI si ons. The pr ocedure f or prepar i ng an
emul si on depends on t he desi r ed emul si f yi ng agent i n t he f or mul at i on.
1. A mort ar and pest I e ar e f requent l y al l t he equi pment t hat i s needed.
a. A mor t ar wi t h a rough surf ace (e. g. , Wedgwood) shoul d be used. Thi s rough
sur f ace al l ows maxi mal di spersi on of gl obul es t o pr oduce a f i ne par t i cl e si ze.
b. A rapi d mot i on i s essent i al when t r i t urat i ng an emul si on usi ng a mor t ar and
pest l e.
c. The mort ar shoul d be abl e t o hol d at l east t hree t i mes t he quant i t y bei ng made.
Tr i t ur at i on sel dom r equi res more t han 5 mi n t o creat e t he emul si on.
2. EI ect ri c mi xers and hand homogeni zer s ar e usef ul f or pr oduci ng emul si ons af t er
t he coar se emul si on i s f or med i n t he mort ar .
3. The order of mi xi ng of i ngr edi ent s i n an emul si on depends on t he t ype of
emul si on bei ng prepar ed ( i . e. , o/ w or w/ o) as wel l as t he emul si f yi ng agent chosen.
Met hods used f or compoundi ng i ncl ude t he f ol l owi ng:
a. Dr y gum ( cont i nent al ) met hod i s used f or f or mi ng emul si ons usi ng nat ur al
emul si f yi ng agent s and requi r es a speci f i c or der of mi xi ng.
b. Wet gum ( Engl i sh) met hod i s used f or f or mi ng emul si ons usi ng nat ural
emul si f yi ng agent s and requi r es a speci f i c or der of mi xi ng.
c. Bot tI e met hod i s used f or f ormi ng emul si ons usi ng nat ur al emul si f yi ng agent s
and requi r es a speci f i c or der of mi xi ng.
d. Beaker met hod i s used t o prepar e emul si ons usi ng synt het i c emul si f yi ng agent s
and pr oduces a sat i sf act or y pr epar at i on r egardl ess of t he or der of mi xi ng.
4. Preservat i ves. Ì f t he emul si on i s kept f or an ext ended per i od of t i me,
r ef r i ger at i on i s usual l y suf f i ci ent . The prepar at i on shoul d not be f r ozen. Ì f a
pr eser vat i ve i s used, i t must be sol ubl e i n t he wat er phase t o be ef f ect i ve.
5. FI avori ng agent s. Ì f t he addi t i on of a f l avor i s needed t o mask t he t ast e of t he oi l
phase, t he f l avor shoul d be added t o t he ext er nal phase bef or e emul si f i cat i on ( Tabl e
5- 3) .
E. ExampI es
1. ExampI e 1
a. Medi cat i on order
Mineral oil 18 mL
Acacia qs
Distilled water. qs ad 90.0 mL
Sig: 1 tablespoon q.d.

b. Compoundi ng procedure. Wi t h t he dr y gum met hod, an i ni t i al emul si on ( pr i mar y
emul si on) i s f or med, usi ng 4 part s ( 18 mL) of oi l , 2 par t s ( 9 mL) of wat er , and 1 par t
( 4. 5 g) of powder ed acaci a. The mi neral oi l i s t ri t ur at ed wi t h t he acaci a i n a
Wedgwood mor t ar. The 9 mL of wat er i s added al l at once and, wi t h r api d t r i t urat i on,
f or m t he pri mar y emul si on, whi ch i s t ri t urat ed f or about 5 mi n. The r emai ni ng wat er
i s i ncor por at ed i n smal l amount s wi t h t r i t ur at i on. The emul si on i s t r ansf er red t o a
90- mL pr escri pt i on bot t l e, and a " shake wel l ¨ l abel i s at t ached t o t he cont ai ner.
Table 5-3. Flavor Selection Guide
Taste Masking Flavor
Salt Butterscotch. maple
Bitter Wild cherry. walnut. chocolate mint. licorice
Sweet Fruit. berry. vanilla
Acid Citrus

P. 107


2. ExampI e 2
a. Medi cat i on order
Olive oil 30 mL
Zinc oxide 8 g
Calamine 8 g
Lime water 30 mL

b. Compoundi ng procedure. The ol i ve oi l i s pl aced i n a sui t abl y si zed beaker .
Usi ng an el ect r i c mi xer , t he zi nc oxi de, t he cal ami ne, and t he l i me wat er ar e added
i n t hat or der . Thi s yi el ds a w/ o emul si on. Thi s procedure i s known as t he nascent
soap met hod. The ol i ve oi l r eact s wi t h t he cal ci um hydroxi de sol ut i on (l i me wat er )
and f orms a soap. For t hi s react i on t o occur , f r esh l i me wat er (cal ci um hydr oxi de
sol ut i on) i s r equi red. A smal l quant i t y of ol ei c aci d can al so be added t o f ur t her
st abi l i ze t he emul si on.
3. ExampI e 3
a. Medi cat i on order
Mineral oil 50 mL
Water. qs 100 mL
Sig: 2.5 mL p.o. h.s.

b. Compoundi ng procedure. Usi ng a combi nat i on of noni oni c emul si f yi ng agent s,
such as Span 40 and Tween 40, t he cor r ect hydrophi l i c- l i pophi l i c bal ance ( HLB) i s
obt ai ned. Next , t he mi ner al oi l i s war med i n a wat er bat h t o about 60°C, and t he
Span 40 i s di ssol ved i n t he heat ed mi neral oi l . The wat er i s war med t o about 65°C,
and t he Tween 40 i s di ssol ved i n t he heat ed wat er . Thi s mi xt ur e i s added t o t he
mi ner al oi l and di ssol ved Span 40 and st i r red unt i l cool ed. An "ext er nal use onl y¨
l abel i s added t o t he cont ai ner .
VI. POWDERED DOSAGE FORMS
A. Def i ni t i on. Powders ar e i nt i mat e mi xt ur es of dr y, f i nel y di vi ded dr ugs and/ or
chemi cal s t hat may be i nt ended f or i nt er nal (or al powder s) or ext er nal (t opi cal
powder s) use. The maj or t ypes ar e powder papers, bul k powder s, and i nsuf f l at i ons.
B. GeneraI charact eri sti cs
1. Powder dosage f or ms ar e used when drug st abi I i t y or soI ubi I i t y i s a concer n.
These dosage f or ms may al so be used when t he powder s ar e t oo bul ky t o make i nt o
capsul es and when t he pat i ent has di f f i cul t y swal l owi ng a capsul e.
2. Some di sadvant ages t o powder s i ncl ude unpl easant - t ast i ng medi cat i ons and,
occasi onal l y, t he rapi d det eri or at i on of powder s.
3. BI endi ng of powder s may be accompl i shed by usi ng t r i t ur at i on i n a mor t ar ,
st i r ri ng wi t h a spat ul a, and si f t i ng. Geomet r i c di l ut i on shoul d be used i f needed.
When heavy powder s are mi xed wi t h l i ght er ones, t he heavi er powder shoul d be
pl aced on t op of t he l i ght er one and t hen bl ended. When mi xi ng t wo or mor e
powder s, each powder shoul d be pul veri zed separ at el y t o about t he same part i cl e
si ze bef or e bl endi ng t oget her.
a. The mor t ar and pest l e met hod i s pr ef er r ed when puI veri zati on and a t hor ough
mi xi ng of i ngr edi ent s ar e desi r ed (geomet r i c di l ut i on) . A Wedgwood mort ar i s
pr ef er abl e, but gl ass or por cel ai n may al so be used.
b. Li ght powder s ar e mi xed best by usi ng t he si f ti ng met hod. The si f t i ng i s
r epeat ed t hr ee t o f our t i mes t o ensure t horough mi xi ng of t he powder s.
C. Preparat i on of powder dosage f orms
1. BuI k powders, whi ch may be used i nt ernal l y or t opi cal l y, i ncl ude dust i ng
powder s, douche powders, l axat i ves, ant aci ds, and i nsuf f l at i on powder s.
2. Af t er a bul k powder has been pul veri zed and bl ended, i t shoul d be di spensed i n
an appropr i at e cont ai ner.
a. Hygroscopi c or ef f ervescent sal t s shoul d al ways be pl aced i n a t i ght , wi de-
mout h j ar .
b. Dusti ng powders shoul d be pl aced i n a cont ai ner wi t h a si f t er t op.
P. 108


3. Eutect i c mi xt ures of powder s can cause pr obl ems because t hey may l i quef y.
One r emedy i s t o add an i ner t powder , such as magnesi um oxi de, t o separ at e t he
eut ect i c mat eri al s.
4. Powder papers ar e al so cal l ed di vi ded powders.
a. The ent i r e powder i s i ni t i al l y bl ended. Each dose i s t hen i ndi vi dual l y wei ghed.
b. The dosage shoul d be wei ghed, t hen t r ansf er red ont o a powder paper and f ol ded.
Thi s t echni que r equi res pr act i ce. Hygr oscopi c, del i quescent , and ef f er vescent
powder s requi r e t he use of gl assi ne paper as an i nsi de l i ni ng. Pl ast i c bags or
envel opes wi t h snap- and- seal cl osur es of f er a conveni ent al t er nat i ve t o powder
paper s.
c. The f ol ded papers ar e di spensed i n a powder box or ot her sui t abl e cont ai ner ;
however , t hese cont ai ner s are not chi l d r esi st ant .
D. ExampI es
1. ExampI e 1
a. Medi cat i on order
Camphor 100 mg
Menthol 200 mg
Zinc oxide 800 mg
Talc 1.9 g
M Ioot powder
Sig: Apply to Ieet b.i.d.

b. Compoundi ng procedure. The camphor and ment hol are t ri t ur at ed t oget her i n a
gl ass mor t ar, wher e a l i qui d eut ect i c i s f or med. The zi nc oxi de and t al c are bl ended
and mi xed wi t h t he eut ect i c, usi ng geomet r i c di l ut i on. Thi s mi xi ng r esul t s i n a dr y
powder , whi ch i s passed t hr ough a wi r e mesh si eve. The f i nal preparat i on i s
di spensed i n a cont ai ner wi t h a si f t er t op.
2. ExampI e 2
a. Medi cat i on order
Citric acid 0.3 g
Sodium bicarbonate 0.25
g
Psyllium mucilloid 2 g
Powdered Ilavor. qs
M. Ft d.t.d. charts v
Sig: Empty the contents oI one chart into a glass oI water and take
h.s.


b. CaI cuI at i ons. Cal cul at e f or one ext r a powder paper :
Citric acid 0.3 g × 6 doses ÷ 1.8 g
Sodium bicarbonate 0.25 g × 6 doses ÷ 1.5 g
Psyllium mucilloid 2 g × 6 doses ÷ 12 g
Total wight ÷ 15.3 g
15.3 g/6 doses ÷ 2.55 g/dose

Not e: Al so consi der t he wei ght of t he powder ed f l avor .
c. Compoundi ng procedure. The i ngr edi ent s are f i rst pul ver i zed and wei ghed. The
ci t ri c aci d and sodi um bi car bonat e ar e mi xed t oget her f i rst ; t he psyl l i um muci l l oi d i s
t hen added al ong wi t h t he powder ed f l avor , usi ng geomet r i c di l ut i on. Each dose
( 2. 55 g) of t he r esul t ant mi xt ur e i s wei ghed and pl aced i nt o a powder paper . Thi s
pr epar at i on i s an ef f er vescent powder . When di ssol ved i n wat er, t he ci t ri c aci d and
sodi um bi car bonat e react t o f orm car boni c aci d, whi ch yi el ds car bon di oxi de, maki ng
t he sol ut i on mor e pal at abl e.
VII. CAPSULES
A. Def i ni t i on. CapsuI es ar e sol i d dosage f orms i n whi ch t he drug i s encl osed wi t hi n
ei t her a har d or sof t sol ubl e cont ai ner or shel l . The shel l s are usual l y made f rom a
sui t abl e gel at i n. Har d gel at i n capsul es may be manual l y f i l l ed f or ext empor aneous
compoundi ng.
P. 109


Table 5-4. Approximate Amount of Powder Contained in Capsules
Capsule SizeRange of Powder Capacity (mg)
No. 5 60-130
No. 4 95-260
No. 3 130-390
No. 2 195-520
No. 1 225-650
No. 0 325-910
No. 00 390-1300
No. 000 650-2000

B. CapsuI e si zes
1. A l i st of capsul e si zes and t he appr oxi mat e amount of powder t hat may be
cont ai ned i n t he capsul e appear on t he si de of t he capsul e box ( Tabl e 5- 4) .
2. Capsul e si zes f or or al admi ni st r at i on i n humans r ange f r om no. 5, t he smal l est , t o
no. 000, t he l ar gest .
3. No. 0 i s usual l y t he l ar gest oral si ze sui t abl e f or human pat i ent s.
4. Capsul es f or vet er i nari ans are avai l abl e i n no. 10, no. 11, and no. 12, cont ai ni ng
approxi mat el y 30, 15, and 7. 5 g, r espect i vel y.
C. Preparat i on of hard and sof t capsuI es
1. As wi t h t he bul k powder s, al l i ngredi ent s ar e t ri t urat ed and bl ended, usi ng
geomet ri c di l ut i on.
2. The cor rect si ze capsul e must be det er mi ned by t r yi ng di f f erent capsul e si zes,
wei ghi ng t hem, and t hen choosi ng t he appropri at e si ze.
3. Bef or e f i l l i ng capsul es wi t h t he medi cat i on, t he body and cap of t he capsul e are
separ at ed. Fi l l i ng i s accompl i shed by usi ng t he "punch¨ met hod ( Al t ernat i vel y, smal l
capsul e machi nes ar e commonl y used t o prepar e up t o 300 capsul es at a t i me,
ext empor aneousl y) .
a. The powder f or mul at i on i s compr essed wi t h a spat ul a on a pi l l t i l e or paper sheet
wi t h a uni f or m dept h of appr oxi mat el y hal f t he l engt h of t he capsul e body.
b. The empt y capsul e body i s r epeat edl y pr essed i nt o t he powder unt i l f ul l .
c. The capsul e i s t hen wei ghed t o ensure an accur at e dose. An empt y t are capsul e
of t he same si ze i s pl aced on t he pan cont ai ni ng t he wei ght s.
4. For a l arge number of capsul es, capsul e-f i l l i ng machi nes can be used f or smal l -
scal e use t o save t i me. Most commonl y, capsul es machi nes are used capabl e of
pr epar i ng 100 t o 300 capsul es at a t i me.
5. The capsul e i s wi ped cl ean of any powder or oi l and di spensed i n a sui t abl e
pr escri pt i on vi al .
D. ExampI es
1. ExampI e 1
a. Medi cat i on order
RiIampin 100 mg
dtd #50
Sig: 1 cap p.o. q.d.

b. CaI cuI at i ons. Compound t hi s pr escri pt i on usi ng t he commer ci al l y avai l abl e 300-
mg capsul es as t he dr ug sour ce. Cal cul at e f or at l east one ext r a capsul e.
51 caps × 100 mg/cap ÷ 5100 mg riIampin
5100 mg riIampin 300 mg/cap ÷ 17 caps

P. 110


c. Compoundi ng procedure. Use 17 ri f ampi n capsul es, each cont ai ni ng 300 mg
r i f ampi n. The cont ent of each capsul e i s empt i ed, and t he powder i s wei ghed. The
powder equi val ent t o 100 mg r i f ampi n i s pl aced i n a capsul e ( e. g. , i f t he t ot al
cont ent s of one capsul e wei gh 360 mg; t hen 100/ 300 = x/ 360; x = 120 mg of act i ve
dr ug powder requi r ed f rom t he capsul e cont ent s t o pr ovi de 100 mg act i ve dr ug) and
suf f i ci ent l act ose added t o f i l l t he capsul e. The t ot al f i l l ed capsul e cont ent s wei gh
200 mg. The wei ght of t he act i ve dr ug powder i s subt r act ed f rom 200 mg t o obt ai n
t he amount of l act ose r equi red per capsul e, whi ch i s 200 mg - 120 mg = 80 mg. Thi s
i s mul t i pl i ed by 51 capsul es. Enough l act ose (51 capsul es × 80 mg/ cap = 4. 08 g) i s
added t o make a t ot al of 10. 2 g of powder . The powder s are combi ned, usi ng
geomet ri c di l ut i on, and 50 capsul es can be punched out . Each capsul e shoul d wei gh
200 mg ( 10. 2 g/ 51 caps).
2. ExampI e 2
a. Medi cat i on order. Thi s or der i s f or vet er i nar y use onl y.
Castor oil 8 mL
Disp 12 caps
Sig: 2 caps p.o. h.s.

b. CaI cuI at i ons. No cal cul at i ons ar e necessar y.
c. Compoundi ng procedure. A no. 11 vet eri nary capsul e i s used. Usi ng a
cal i brat ed dropper or a pi pet t e, 8 mL of t he oi l i s car ef ul l y added t o t he i nsi de of
each capsul e body. Next , t he l ower i nsi de por t i on of t he cap i s moi st ened, usi ng a
gl ass r od or br ush. The cap and body are j oi ned t oget her, usi ng a t wi st i ng mot i on,
t o f or m a t i ght seal . The capsul es are pl aced on a pi ece of f i l t er paper and checked
f or si gns of l eakage. The capsul es ar e di spensed i n t he appropri at e si ze and t ype of
pr escri pt i on vi al . They can be st ored i n a r ef r i gerat or i f desi r ed.
VIII. MOLDED TABLETS (TABLET TRITURATES)
A. Def i ni t i on. Tabl et t r i t ur at es ar e smal l , usual l y cyl i ndri cal mol ded or compr essed
t abl et s. They are made of powders creat ed by moi st eni ng t he powder mi xt ur e wi t h
al cohol and wat er or by t he process of si nt eri ng. They can be used f or compoundi ng
pot ent dr ugs i n smal l doses and f or pr epar at i on of a r api dl y di si nt egr at i ng/ di ssol vi ng
dosage f orm.
B. FormuI at i on and preparat i on of t abI et t ri t urat es usi ng moi stened powders
1. Tabl et t ri t ur at es ar e made i n speci al mol ds consi st i ng of a pegboar d and a
cor respondi ng per f or at ed pl at e.
2. Ì n addi t i on t o t he mol d, a di l uent , usual l y a mi xt ur e of l act ose and sucrose
( 80: 20) , and a moi st eni ng agent , usual l y a mi xt ur e of et hyl al cohol and wat er
( 60: 40) , ar e r equi red.
3. The di l uent i s t ri t ur at ed wi t h t he act i ve i ngr edi ent s.
4. A past e i s t hen made, usi ng t he al cohol and wat er mi xt ur e.
5. Thi s past e i s spread i nt o t he mol d; t he t abl et s ar e punched out and r emai n on t he
pegs unt i l dr y.
C. ExampI e
1. Medi cat i on order
Atropine sulIate 0.4 mg
Disp #500 TT
Sig: u.d.

2. CaI cuI at i ons. For 500 TT: 500 × 0. 4 mg = 200 mg at r opi ne sul f at e
3. Compoundi ng procedure. The mol d pr epares 70-mg t abl et s. The 200 mg of
at r opi ne sul f at e, 6. 8 g of sucr ose, and 28 g of l act ose are wei ghed and mi xed by
geomet ri c di l ut i on. The powder i s wet wi t h a mi xt ur e of 40% puri f i ed wat er and 60%
et hyl al cohol (95%) . The past e t hat i s f or med i s spr ead ont o t he t abl et t ri t ur at e
mol d; t he t abl et s ar e t hen punched out of t he mol d and al l owed t o dr y on t he pegs.
Thi s procedur e i s repeat ed unt i l t he requi r ed number of t abl et t ri t urat es has been
pr epar ed.
P. 111


D. FormuI at i on and preparat i on of t abI et t ri t urat es usi ng si nt eri ng
1. These t abl et t r i t ur at es ar e made i n speci al mol ds consi st i ng of mat eri al s t hat can
t ol er at e heat t o about 100°C.
2. Ì n addi t i on t o t he mol d, a di l uent , usual l y a mi xt ur e of act i ve dr ug and di l uent ,
whi ch make up approxi mat el y 65% of t he t abl et wei ght , ar e bl ended t oget her .
Manni t ol i s good t o use i n combi nat i on wi t h l act ose f or par t i cl e si zes of 60- 80 mesh
f r act i on.
3. The mi xt ur e i s t r i t ur at ed wi t h pol yet hyl ene gl ycol 3350 wi t h a par t i cl e si ze of 80-
100 mesh f r act i on.
4. The powder mi xt ur e i s pl aced i nt o appr opr i at e mol ds and l i ght l y t amped.
5. The mol ds cont ai ni ng t he powder are pl aced i n an oven at about 90°C f or 10- 20
mi n, r emoved and al l owed t o cool . Dependi ng on t he mol ds used, t he t abl et s can be
di spensed i n t he mol ds or r emoved f r om t he mol ds and packaged and l abel ed.
E. ExampI e
6. Medi cat i on order
Homatropine hydrobromide 300 mg
Mannitol 3.5 g
Lactose 3.47 g
Flavor (dry powder type). qs
Polyethylene glycol 3350 3.5 g

7. CaI cuI at i ons. As pr esent ed, t hi s f or mul a i s f or 100 r api d-di ssol vi ng t abl et
t r i t urat es.
8. Compoundi ng procedure. Bl end t he homat ropi ne hydrobr omi de, manni t ol ,
l act ose, and dr y f l avor t oget her unt i l f i ne and uni f or ml y mi xed. Separat el y, r educe
t he par t i cl e si ze of t he pol yet hyl ene gl ycol 3350 t o 100- 200 mesh f r act i on. Li ght l y
bl end i n t he pol yet hyl ene gl ycol 3350 i nt o t he previ ousl y bl ended powder s. Pl ace
100 mg of t he powder i nt o t he cavi t i es of a mol d (some bl i st er packs wor k wel l ;
ot her wi se, obt ai n a t abl et t r i t ur at e mol d or a speci al mol d f or pr epari ng t hese
t abl et s) . Pl ace t he mol d cont ai ni ng t he powder i n an oven at 80- 90°C f or 15- 20 mi n.
The t i me depends on t he mol d, f ormul at i on, oven, et c. Remove f r om t he oven and
pl ace i n a r ef r i ger at or f or appr oxi mat el y 5 mi n. Remove f r om t he ref ri gerat or and l et
set at room t emper at ur e. Package and l abel .
IX. OINTMENTS, CREAMS, PASTES, AND GELS
A. Def i ni t i ons
1. Oi ntments, creams, and pastes ar e semi sol i d dosage f orms i nt ended f or t opi cal
appl i cat i on t o t he ski n or mucous membranes. Oi nt ment s ar e char act eri zed as
bei ng ol eagi nous i n nat ur e; creams are gener al l y o/ w or w/ o emul si ons, and past es
ar e char act eri zed by t hei r hi gh cont ent of sol i ds ( about 25%) .
2. GeI s (somet i mes cal l ed j el l i es) are semi sol i d syst ems consi st i ng of suspensi ons
made up of ei t her smal l i nor gani c par t i cl es or l arge organi c mol ecul es
i nt er penet rat ed by a l i qui d.
B. GeneraI charact eri sti cs. These dosage f orms ar e semi sol i d preparat i ons
gener al l y appl i ed ext er nal l y. Semi sol i d dosage f or ms may cont ai n act i ve dr ugs
i nt ended t o:
1. Act sol el y on t he sur f ace of t he ski n t o produce a l ocal ef f ect ( e. g. , ant i f ungal
agent ; t opi cal s)
2. Rel ease t he medi cat i on, whi ch, i n t ur n, penet rat es i nt o t he ski n ( e. g. ,
hydr ocor t i sone cr eam)
3. Rel ease medi cat i on f or syst emi c absorpt i on t hrough t he ski n (e. g. , ni t r ogl yceri n;
t r ansder mal s)
C. Types of oi nt ment bases
1. Hydr ophobi c bases f eel gr easy and cont ai n mi xt ur es of f at s, oi l s, and waxes.
Hydr ophobi c bases cannot be washed of f usi ng wat er .
P. 112


2. Hydr ophi l i c bases ar e usual l y emul si on bases. The o/ w- t ype emul si on bases can
be easi l y washed of f wi t h wat er , but t he w/ o t ype i s sl i ght l y more di f f i cul t t o r emove.
D. Preparat i on of oi ntment s, creams, past es, and geI s
1. Mi xi ng can be done i n a mor t ar or on an oi nt ment sl ab or t i l e or usi ng an oi nt ment
mi l l .
2. Li qui ds are i ncor por at ed by gr adual l y addi ng t hem t o an absorpt i on- t ype base and
mi xi ng.
3. Ì nsol ubl e powders are r educed t o a f i ne powder and t hen added t o t he base,
usi ng geomet r i c di l ut i on.
4. Wat er -sol ubl e subst ances are di ssol ved wi t h wat er and t hen i ncor por at ed i nt o t he
base.
5. The f i nal pr epar at i on shoul d be smoot h ( i mpal pabl e) and f r ee of any abr asi ve
par t i cl es.
E. ExampI es
1. ExampI e 1
a. Medi cat i on order
SulIur
Salicylic acid. aa 600 mg
White petrolatum. ad 30 g
Sig: Apply t.i.d.

b. Compoundi ng procedure. The part i cl e si zes of t he sul f ur and sal i cyl i c aci d are
r educed separ at el y i n a Wedgwood mor t ar and t hen bl ended t oget her. Usi ng a pi l l
t i l e, t he powder mi xt ur e i s l evi gat ed wi t h t he base. Usi ng geomet r i c di l ut i on, t he
base and powder s ar e bl ended t o t he f i nal wei ght . An oi nt ment j ar or pl ast i c t ube i s
used f or di spensi ng, and an "ext er nal use onl y¨ l abel i s pl aced on t he cont ai ner .
c. AI t ernate met hod. Suppose you have sul f ur 5% i n whi t e pet rol at um oi nt ment and
a sal i cyl i c aci d 5% oi nt ment . How can you prepare t he prescri pti on usi ng t hese
and di I uti ng wi th whi te pet roI at um?

However , si nce we ar e usi ng t wo di f f er ent 5% oi nt ment s, 2 part s of each, t hi s
l eaves 1 part f or t he whi t e pet r ol at um. A t ot al of 5 par t s i s t o be used t o make 30 g
( 6 g per part ) : 2 par t s ( 12 g) of t he sul f ur 5%, 2 par t s ( 12 g) of t he sal i cyl i c aci d 5%,
and 1 par t (6 g) of t he whi t e pet r ol at um coul d be used. To check:
12 g × 0.05 ÷ 600 mg oI sulIur
12 g × 0.05 ÷ 600 mg oI salicylic acid
12 g ¹ 12 g ¹ 6 g ÷ 30 g

2. ExampI e 2
a. Medi cat i on order
Methylparaben 0.25 g
Propylparaben 0.15 g
Sodium lauryl sulIate 10 g
Propylene glycol 120 g
Stearyl alcohol 250 g
White petrolatum 250 g
PuriIied water 370 g
Disp 60 g
Sig: Apply u.d.

P. 113


b. CaI cuI at i ons. The quant i t y of each i ngr edi ent r equi r ed t o pr epare 60 g i s
obt ai ned as f ol l ows. The medi cat i on or der i s f or 1000 g; t her ef or e, t he mul t i pl i cat i on
f act or i s 60/ 1000 = 0. 06.
0.25 g × 0.06 ÷ 0.15 g methylparaben
0.15 g × 0.06 ÷ 0.009 g propylparaben
10 g × 0.06 ÷ 0.6 g sodium lauryl sulIate
120 g × 0.06 ÷ 7.2 g propylene glycol
250 g × 0.06 ÷ 15 g stearyl alcohol
250 g × 0.06 ÷ 15 g white petrolatum
370 g × 0.06 ÷ 22.2 g puriIied water

Si nce t he 0. 009 g of propyl paraben i s t oo smal l t o accur at el y wei gh, a di l ut i on can
be prepar ed as f ol l ows, assumi ng a mi ni mum wei ghabl e quant i t y of 120 mg. Wei gh
120 mg of pr opyl paraben and add t o 40 mL of propyl ene gl ycol , r esul t i ng i n a
pr opyl par aben concent r at i on of 3 mg/ mL. Take 3 mL of t hi s sol ut i on t o obt ai n t he
pr opyl par aben and subt ract t he 3 mL f r om t he quant i t y of pr opyl ene gl ycol r equi red
i n t he f ormul a.
c. Compoundi ng procedure. The st ear yl al cohol and t he whi t e pet r ol at um are
mel t ed on a st eam bat h and heat ed t o about 75°C. The ot her i ngr edi ent s, pr evi ousl y
di ssol ved i n puri f i ed wat er at about 78°C, are added. The mi xt ur e i s st i r red unt i l i t
congeal s. An oi nt ment j ar i s used f or di spensi ng, and an "ext er nal use onl y¨ l abel i s
pl aced on t he j ar .
3. ExampI e 3
a. Medi cat i on order
Scopolamine hydrobromide 0.25°
Soy lecithin 12 g
Isopropyl palmitate 12 g
Pluronic F-127 20° gel. qs 100 mL
Sig: Apply 0.1 mL t.i.d.

b. CaI cuI at i ons. The quant i t y of scopol ami ne hydr obromi de r equi red f or t he
pr escri pt i on wi l l be
0. 0025 × 100 mL = 0. 25 g or 250 mg
c. Compoundi ng procedure. Mi x t he soy l eci t hi n wi t h t he i sopr opyl pal mi t at e.
Di ssol ve t he scopol ami ne hydr obr omi de i n about 3 mL of pur i f i ed wat er and add t o
about 70 mL of t he Pl uroni c F- 127 gel . Add t he soy l eci t hi n-i sopropyl pal mi t at e
mi xt ur e, and mi x wel l . Add suf f i ci ent Pl ur oni c F-127 gel t o vol ume, and mi x wel l
usi ng a shear i ng t echni que. Package and l abel .
X. SUPPOSITORIES
A. GeneraI charact eri sti cs
1. Supposi t ori es are soI i d bodi es of vari ous wei ght s and shapes, adapt ed f or
i nt roduct i on i nt o t he rect al , vagi nal , or ur et hr al ori f i ces of t he human body. They ar e
used t o del i ver drugs f or t hei r l ocal or syst emi c ef f ect s.
2. Supposi t ori es di f f er i n si ze and shape and i ncl ude
a. Rect al
b. Vagi nal
c. Ur et hral
B. Common supposi tory bases
1. Cocoa but t er ( t heobroma oi l ) , whi ch mel t s at body t emper at ur e, i s a f at - sol ubl e
mi xt ur e of t ri gl ycer i des t hat i s most of t en used f or r ect al supposi t ori es. Wi t epsol i s
a synt het i c t r i gl ycer i de. Fat t y aci d bases i ncl ude Fat t i base.
2. PoI yet hyI ene gI ycoI ( PEG, carbowax) der i vat i ves are wat er -sol ubl e bases
sui t abl e f or vagi nal and rect al supposi t or i es. Pol ybase i s an exampl e.
3. GI yceri nat ed geI at i n i s a wat er -mi sci bl e base of t en used i n vagi nal and r ect al
supposi t or i es.
P. 114


C. Supposi tor y moI ds
1. Supposi t or y mol ds can be made of r ubber , pl ast i c, br ass, st ai nl ess st eel , or ot her
sui t abl e mat er i al .
2. The f or mul at i on and vol ume of t he base depend on t he si ze of t he mol d used,
l ess t he di spl acement caused by t he act i ve i ngredi ent .
D. Methods of prepari ng and di spensi ng supposi t ori es
1. MoI ded supposi tori es ar e prepared by f i rst mel t i ng t he base and t hen
i ncor por at i ng t he medi cat i ons uni f orml y i nt o t he base. Thi s mi xt ur e i s t hen poured
i nt o t he supposi t or y mol d ( f usi on met hod) .
2. Hand- roI I ed supposi tori es requi r e a speci al t echni que. Wi t h pr oper t echni que, i t
i s possi bl e t o make a preparat i on equal i n qual i t y t o t he mol ded supposi t or i es.
3. Contai ners for t he supposi t ori es ar e det er mi ned by t he met hod and base used
i n pr epar at i on. Hand- rol l ed and mol ded supposi t or i es shoul d be di spensed i n
speci al boxes t hat pr event t he supposi t or i es f r om comi ng i n cont act wi t h each ot her .
Supposi t ori es made usi ng pl ast i c st r i p mol ds ar e easi l y di spensed i n vari ous t ypes
of packages.
4. St orage condi t i ons. Ì f appr opr i at e, a " ref r i gerat e¨ l abel shoul d appear on t he
cont ai ner . Regar dl ess of t he base or medi cat i on used i n t he f ormul at i on, t he pat i ent
shoul d be i nst ruct ed t o st or e t he supposi t ori es i n a cool , dr y pl ace.
E. ExampI es
1. ExampI e 1
a. Medi cat i on order
Naproxen suppository 500 mg
Disp #12
Sig: Insert u.d. into rectum

b. CaI cuI at i ons. Each st andar d adul t supposi t or y shoul d wei gh 2 g, but i t depends
on t he mol d used and shoul d be cal i br at ed bef ore compoundi ng. Al so, t he
di spl acement must be det er mi ned f or t he added powder .
2 g (t ot al wei ght ) - 0. 540 g ( wei ght of base di spl aced by t he 500-mg t abl et ) per
supposi t or y
÷ 1.46 g cocoa butter per suppository × 13 suppositories
÷ 18.98 g cocoa butter

c. Compoundi ng procedure. The 13 napr oxen 500- mg t abl et s are t ri t urat ed t o a
f i ne powder , usi ng a Wedgwood or por cel ai n mort ar . The 18. 98 g cocoa but t er base
i s mel t ed i n a beaker , usi ng a wat er bat h. The t emperat ur e of t he wat er bat h shoul d
not exceed 36°C. The powder i s t hen added and st i r red unt i l mi xed. The mi xt ur e i s
poured i nt o an appr opr i at e r ect al supposi t or y mol d ( about 2 g per supposi t or y) and
pl aced i nt o a r ef r i ger at or unt i l t he supposi t ori es congeal . Any excess i s scr aped
f r om t he t op of t he mol d, and a supposi t or y box i s used f or di spensi ng. A
" r ef r i gerat e¨ l abel i s pl aced on t he box.
2. ExampI e 2
a. Medi cat i on order
Progesterone 50 mg
Disp #14
Sig: 1 per vagina once daily on days 14-28 oI cycle

b. CaI cuI at i ons. Tot al wei ght of each vagi nal supposi t or y i s 1. 9 g. Assumi ng 50 mg
pr ogest er one di spl aces 50 mg PEG base:
50 mg pr ogest er one/ supposi t or y × 15 = 750 mg pr ogest er one
1. 9 g ( t ot al wei ght ) - 0. 050 g pr ogest erone
= 1. 85 g PEG × 15 supposi t ori es
= 27. 75 g PEG t ot al
P. 115


c. Compoundi ng procedure. The PEG i s mel t ed t o 55- 57°C, and 750 mg
pr ogest er one i s added. Thi s mi xt ur e i s poured i nt o a vagi nal supposi t or y mol d,
al l owed t o cool , cl eaned, and di spensed.
XI. PARENTERAL PREPARATIONS
A. GeneraI requi rements. The ext empor aneous compoundi ng of st er i l e pr eparat i ons
occurs i n many pharmacy envi r onment s, i ncl udi ng communi t y, home heal t hcare,
hospi t al , and nucl ear . Mi ni mum r equi rement s i ncl ude
1. Pr oper equi pment and suppl i es
2. Pr oper f aci l i t i es, i ncl udi ng a l ami nar - f l ow cl ean bench and a cl ean room or
i sol at i on bar r i er t echnol ogy equi pment
3. Pr oper document at i on of al l pr eparat i ons made
4. Qual i t y cont r ol , i ncl udi ng bat ch st er i l i t y t est i ng
5. Pr oper st or age bot h at t he f aci l i t y and i n t r anspor t t o t he pat i ent ' s home
6. Pr oper l abel i ng of t he pr escri pt i on pr eparat i on
7. Knowl edge of pr oduct ' s/ prepar at i on' s st abi l i t y and i ncompat i bi l i t i es
8. Knowl edge of al l anci l l ar y equi pment i nvol ved i n compoundi ng or del i ver y of t he
medi cat i ons
B. Compoundi ng of parent eraI preparati ons
1. Compoundi ng of st eri l e pr eparat i ons, i ncl udi ng i nt ravenous admi xt ur es, r equi r es
speci al ski l l s and t rai ni ng. Compoundi ng par ent er al pr epar at i ons or pr ovi di ng t hi s
ser vi ce wi t hout pr oper t rai ni ng shoul d not be at t empt ed.
2. These pr epar at i ons must be compounded i n a cl ean envi ronment , usi ng asept i c
t echni que ( i . e. , wor ki ng under cont rol l ed condi t i ons t o mi ni mi ze cont ami nat i on) .
3. Dr y powders of par ent er al dr ugs f or r econst i t ut i on ar e used f or dr ug product s or
pr epar at i ons t hat are unst abl e as sol ut i ons. Ì t i s i mpor t ant t o know t he cor r ect
di l uent s t hat can be used t o yi el d a sol ut i on.
4. Sol ut i ons of dr ugs f or par ent eral admi ni st r at i on may al so be f ur t her di l ut ed bef or e
admi ni st rat i on. Ì f f ur t her di l ut i on i s r equi red, t hen t he phar maci st must know t he
st abi l i t y and compat i bi l i t y of t he drug i n t he di l uent .
C. Reconst i tut i on of a dr y powder f rom a vi aI
1. Wor k t akes pl ace i n a cl ean-ai r envi ronment , obser vi ng asept i c t echni que.
2. The manuf act ur er ' s i nst r uct i ons shoul d be checked t o det ermi ne t he r equi red
vol ume of di l uent .
3. The appropri at e needl e si ze and syr i nge ar e chosen, keepi ng i n mi nd t hat t he
capaci t y of t he syri nge shoul d be sl i ght l y l ar ger t han t he vol ume r equi red f or
r econst i t ut i on.
4. Usi ng t he cor rect di l uent , t he sur f ace of t he cont ai ner i s cl eaned, usi ng an
al cohol pr ep pad, af t er whi ch t he al cohol i s permi t t ed t o evaporat e.
5. The syr i nge i s f i l l ed wi t h t he di l uent t o t he pr oper vol ume.
6. The sur f ace of t he vi al cont ai ni ng t he st eri l e powder i s cl eaned, usi ng an al cohol
pr ep pad, af t er whi ch i t i s per mi t t ed t o dr y. The di l uent i s i nj ect ed i nt o t he vi al
cont ai ni ng t he dr y powder .
7. The vi al i s gent l y shaken or rol l ed, and t he powder i s al l owed t o di ssol ve.
8. Af t er t he powder has di ssol ved, t he vi al i s i nver t ed and t he desi r ed vol ume i s
wi t hdr awn.
9. The vehi cl e i s prepared by swabbi ng t he medi cat i on por t of t he bag or bot t l e wi t h
an al cohol pr ep pad.
P. 116


10. The sol ut i on i n t he syr i nge i s i nj ect ed i nt o t he vehi cl e. Ì f a pl ast i c cont ai ner i s
used, care must be t aken not t o punct ur e t he si de wal l s of t he cont ai ner wi t h t he t i p
of t he needl e.
11. The cont ai ner shoul d be shaken or kneaded or r ot at ed t o ensure t hor ough
mi xi ng of t he cont ent s.
12. The cont ent s of t he cont ai ner shoul d be checked f or part i cul at e mat t er .
13. A st er i l e seal or cap i s appl i ed over t he por t of t he cont ai ner.
14. Al l needl es and syr i nges shoul d be pr oper l y di scar ded.
15. The bag i s l abel ed.
D. Removi ng t he f I ui d cont ents f rom an ampuI e
1. The ampul e i s hel d upr i ght t o open i t , and t he t op i s t apped t o r emove any
sol ut i on t r apped i n t hi s ar ea.
2. The neck of t he ampul e i s swabbed wi t h an al cohol swab.
3. The ampul e i s gr asped on each si de of t he neck wi t h t he t humb and i ndex f i nger
of each hand and qui ckl y snapped open.
4. A 5- µm f i l t er needl e i s at t ached t o a syri nge of t he appr opr i at e si ze.
5. The ampul e i s t i l t ed, and t he needl e i s i nser t ed.
6. The needl e i s posi t i oned near t he neck of t he ampul e, and t he sol ut i on i s
wi t hdr awn f r om t he ampul e.
7. Ì f t he sol ut i on i s f or an i nt r avenous push ( bol us i nj ect i on), t he f i l t er needl e i s
r emoved f rom t he syr i nge and r epl aced wi t h a cap.
8. Ì f t he sol ut i on i s f or an i nt r avenous i nf usi on, t hen t he f i l t er needl e i s removed and
r epl aced wi t h a new needl e of t he appr opr i at e si ze. The drug i s i nj ect ed i nt o t he
appropr i at e vehi cl e.
9. Al l mat er i al s shoul d be di scar ded pr oper l y, and t he f i nal product or pr epar at i on
shoul d be l abel ed.
E. Removi ng drug soI uti on f rom a vi aI
1. The t ab ar ound t he r ubber cl osur e on t he vi al i s r emoved, and t hi s surf ace i s
swabbed wi t h an al cohol pr ep pad.
2. An equi val ent amount of st eri l e ai r i s i nj ect ed i nt o t he vi al t o pr event a negat i ve
vacuum f rom bei ng cr eat ed and t o al l ow t he dr ug t o be r emoved.
3. Usi ng t he appropr i at e needl e si ze and syr i nge, t he needl e i s i nser t ed i nt o t he
r ubber cl osure.
4. The pl unger i s pushed down, and ai r i s r el eased i nt o t he vi al ; when t he pl unger i s
pul l ed back, t he sol ut i on i s wi t hdr awn.
5. The sol ut i on i s t hen i nj ect ed i nt o t he appr opr i at e vehi cl e.
F. ExampI es
1. ExampI e 1
a. Medi cat i on order
Progesterone 5 g
Benzyl alcohol 10 mL
Sesame oil. qs 100 mL

b. Compoundi ng procedure. Di ssol ve t he progest erone i n t he benzyl al cohol . Add
suf f i ci ent sesame oi l t o make 100 mL. St er i l i ze by f i l t rat i on t hr ough a st eri l e 0. 2- µm
f i l t er or by dr y heat ( 170°C f or 1. 5 hr ) . Package i n st er i l e vi al s and l abel .
2. ExampI e 2
a. Medi cat i on order
Fentanyl (as the citrate) 2 mg
Bupivacaine hydrochloride 125 mg
0.9° sodium chloride iniection. qs 100 mL

P. 117


b. CaI cuI at i ons. Si nce 157 µg f ent anyl ci t r at e i s equi val ent t o 100 µg f ent anyl , t he
quant i t y of f ent anyl ci t r at e r equi r ed i s ( 157/ 100) × 2 mg = 3. 14 mg f ent anyl ci t r at e.
Thi s i s t he quant i t y of f ent anyl ci t r at e t hat woul d be r equi r ed i f compoundi ng as a
hi gh- r i sk pr eparat i on f r om bul k powder s. Ì t woul d al so requi r e 125 mg bupi vacai ne,
and t he r emai nder i s t he 0. 9% sodi um chl or i de i nj ect i on. However , commer ci al
pr oduct s ar e avai l abl e so we can cal cul at e how much of each mi ght be requi r ed
usi ng f ent anyl 50 µg/ mL i nj ect i on and bupi vacai ne hydr ochl ori de 0. 5% i nj ect i on.

Bupi vacai ne hydr ochl ori de 0. 5% i nj ect i on cont ai ns 500 mg/ 100 mL; t her ef or e,

Ì f 40 mL of f ent anyl i nj ect i on i s used, and 25 mL of bupi vacai ne hydr ochl or i de
i nj ect i on i s used, t hen 40 + 25 = 65 mL; t he quant i t y of 0. 9% sodi um chl or i de
i nj ect i on r equi r ed i s 100 mL - 65 mL = 35 mL. Not e: I f t he order i s to be fi I I ed i n a
20- mL pump wi t h deI i ver y f or 30 days, what i s t he deI i ver y rat e i n µL/ hr?

c. Compoundi ng procedure. Usi ng commer ci al l y avai l abl e i nj ect i ons, accur at el y
measure t he vol ume of each and f i l l i nt o a st eri l e ambul at or y pump reser voi r . An ai r
bubbl e can be i nj ect ed and used t o t hor oughl y mi x t he sol ut i on. Remove t he ai r f rom
t he reser voi r , and t i ght l y seal / cl ose t he out l et . Label .
3. ExampI e 3
a. Medi cat i on order
Morphine sulIate 5 g
Citric acid 100 mg
Sodium chloride. qs to isotonic
Methylparaben 150 mg
Sterile water Ior iniection. qs 100 mL

b. CaI cuI at i ons. Usi ng a sodi um chl or i de equi val ent of 0. 09 f or a 5% morphi ne
sul f at e sol ut i on, 0. 18 f or ci t r i c aci d, 1 f or sodi um chl or i de, and i gnori ng t he
met hyl paraben, t he cal cul at i ons can be made as f ol l ows:
5 g morphi ne sul f at e i s equi val ent t o 450 mg sodi um chl or i de ( 5 g × 0. 09 = 450 mg) .
100 mg ci t r i c aci d i s equi val ent t o 18 mg sodi um chl or i de (100 mg × 0. 18 = 18)
450 mg + 18 mg = 468 mg
To be i sot oni c, t he sol ut i on needs t he equi val ent of 900 mg of sodi um chl or i de i n
t he 100 mL: 900 mg - 468 mg = 432 mg sodi um chl ori de needs t o be added.
c. Compoundi ng procedure. Di ssol ve t he met hyl par aben i n about 90 mL of st er i l e
wat er f or i nj ect i on. A smal l amount of heat may be r equi red. Cool t he sol ut i on t o
r oom t emper at ur e; t hen add t he mor phi ne sul f at e, ci t r i c aci d, and sodi um chl or i de.
Add suf f i ci ent st eri l e wat er f or i nj ect i on t o vol ume and mi x wel l . St er i l i ze by
f i l t rat i on t hrough a st er i l e 0. 2- µm f i l t er i nt o a st er i l e vi al or reser voi r. Package and
l abel .
4. ExampI e 4
a. Medi cat i on order
MeIoxitin 1 g
Diluent to Iinal concentration oI 125 mg/mL

P. 118


b. CaI cuI at i ons. A 1- g vi al of Mef oxi n ( cef oxi t i n f or i nj ect i on) i s r econst i t ut ed wi t h
10 mL of di l uent t o provi de f or approxi mat e wi t hdr awal of 10. 5 mL and an
approxi mat e aver age concent r at i on of 95 mg/ mL. What quant i t y of di I uent shouI d
be added t o provi de an approxi mat e average concent rat i on of 125 mg/ mL?

c. Compoundi ng procedure. Asept i cal l y, wi t hdraw 7. 5 mL of di l uent and i nj ect i nt o
t he vi al t o be reconst i t ut ed, usi ng an appr opr i at e vent ed needl e. Gent l y swi r l unt i l
di ssol ved.
P. 119


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 3: Each quest i on or i ncompl et e st at ement i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one of t he suggest ed answer s or
phr ases. Choose t he best answer . The f ol l owi ng medi cat i on or der i s gi ven t o t he
pharmaci st by t he physi ci an.
Olive oil 60.0 mL
Vitamin A 60.000 units
Water 120.0 mL
Sig: 15 mL t.i.d.

1. The f i naI dosage f orm of thi s prescri pt i on wi I I be
( A) a sol ut i on.
( B) an el i xi r .
( C) an emul si on.
( D) a suspensi on.
( E) a l ot i on.
Vi ew Answer 1. The answer i s C[ see] . 2. When prepari ng t hi s prescri pt i on,
t he pharmaci st needs to add
( A) Tween 80.
( B) acaci a.
( C) gl ycer i n.
( D) al cohol .
( E) pr opyl ene gl ycol .
Vi ew Answer 2. The answer i s B[ see] . 3. Whi ch of t he f oI I owi ng caut i on
I abeI s shouI d t he pharmaci st af f i x t o the contai ner when di spensi ng t hi s
preparat i on?
( A) Do not ref ri gerat e.
( B) Shake wel l .
( C) For ext er nal use onl y.
( D) No preser vat i ves added.
Vi ew Answer 3. The answer i s B[ see] . For 1- 3: Di rect i ons for quest i ons 4- 9:
Each quest i on or st at ement i n t hi s sect i on can be cor r ect l y answer ed or compl et ed
by one or more of t he suggest ed answer s or phrases. Choose t he cor r ect answer ,
A- E:
4. Whi ch st atement s about t he f oI I owi ng prescri pt i on are correct ?
Morphine 1 mg/mL
Flavored vehicle. qs ad 120 mL
Sig: 5-20 mg p.o. q
3-4 hours prn pain

I . The amount of morphi ne needed i s 240 mg.
I I . Powdered morphi ne aI kaI oi d shouI d be used when compoundi ng thi s
prescri pt i on.
I I I . The fi naI dosage f orm of thi s prescri pt i on i s a soI uti on.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 4. The answer i s B[ see] . 5. When prepari ng t he f oI I owi ng
prescri pt i on, t he pharmaci st shouI d
Podophyllum 5°
Salicylic acid 10°
Acetone 20°
Flexible collodion. ad 30 mL
Sig: Apply q h.s.

I . t ri t urat e 1. 5 g of podophyI I um wi t h the 8 mL of acet one.
I I . add 3 g of saI i cyI i c aci d t o t he coI I odi on wi th t ri t urati on.
I I I . af f i x an "ext ernaI use onI y" I abeI t o the cont ai ner.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 5. The answer i s B[ see] . P. 120


6. Whi ch st atement s about t he f oI I owi ng prescri pt i on are correct ?
SulIur 6 g
PuriIied water
Camphor water. aa qs ad 60

I . Preci pi tat ed suI f ur can be used t o prepare thi s prescri pt i on.
I I . The suI f ur can be t ri t urat ed wi t h gI yceri n bef ore mi xi ng wi th other
i ngredi ents.
I I I . A "shake weI I " I abeI shouI d be af f i xed t o t he bot tI e.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 6. The answer i s E[seeand] . 7. Whi ch stat ements about t he
f oI I owi ng prescri pt i on are correct ?
Starch 10°
Menthol 1°
Camphor 2°
Calamine. qs ad 120

I . The powders shouI d be bI ended together i n a mortar, usi ng geometri c
di I ut i on.
I I . The prescri pt i on shouI d be prepared by di ssoI vi ng the camphor i n a
suf f i ci ent amount of 90% aI cohoI .
I I I . A eut ect i c mi xt ure shouI d be avoi ded.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 7. The answer i s A[ see] . 8. When prepari ng t he f oI I owi ng
prescri pt i on, t he pharmaci st shouI d
Salicylic acid 3 g
SulIur ppt 7 g
Lanolin 10 g
White petrolatum 10 g

I . reduce t he part i cI e si ze of t he powders, usi ng a mort ar and pest I e or usi ng
t he pi I I ti I e wi t h a spatuI a.
I I . pI ace on an oi ntment t i I e and I evi gat e the i ngredi ent s, usi ng geomet ri c
di I ut i on.
I I I . package t he oi nt ment i n an oi ntment j ar or t ube.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 8. The answer i s E[seeand] . 9. An equaI voI ume of ai r i s
i nj ect ed when removi ng drug soI ut i ons f rom
I . vi aI s.
I I . ampuI es.
I I I . syri nges.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 9. The answer i s A[ see] . P. 121


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see V. B. 1. ] .
2. The answer i s B [ see V. B. 2; V. C. 1] .
3. The answer i s B [ see V. B. 3] .
For 1-3: Because ol i ve oi l and wat er are t wo i mmi sci bl e l i qui ds, t hei r i ncor por at i on
r equi r es a t wo- phase syst em i n whi ch one l i qui d i s di spersed t hr oughout anot her
l i qui d i n t he f or m of smal l dropl et s. To accompl i sh t hi s, an emul si f yi ng agent i s
necessar y. Acaci a i s t he most sui t abl e emul si f yi ng agent when f or mi ng an oi l - i n-
wat er emul si on t hat i s i nt ended f or i nt er nal use.
Emul si ons are physi cal l y unst abl e, and t hey must be pr ot ect ed agai nst t he ef f ect s of
mi cr obi al cont ami nat i on and physi cal separ at i on. Shaki ng bef ore use r edi st r i but es
t he t wo l ayer s of emul si on. Because l i ght , ai r , and mi croorgani sms al so af f ect t he
st abi l i t y of an emul si on, pr eser vat i ves can be added.
4. The answer i s B (Ì Ì Ì ) [ see Ì Ì Ì . A. C. 3] .
The concent rat i on of mor phi ne needed f or t he prescr i pt i on descr i bed i n t he quest i on
i s 1 mg/ mL, and because 120 mL i s t he f i nal vol ume, 120 mg of mor phi ne i s needed
t o compound t hi s pr escri pt i on. Mor phi ne al kal oi d has poor sol ubi l i t y; t her ef or e, one
of t he sal t f or ms shoul d be used. Because morphi ne i s di ssol ved i n t he vehi cl e,
r esul t i ng i n a l i qui d prepar at i on, t he f i nal dosage f orm i s a sol ut i on.
5. The answer i s B (Ì Ì Ì ) [ see Ì Ì Ì . C. 1. ; Ì Ì Ì . C. 5; Ì Ì Ì . D. 3] .
Cal cul at i ng f or t he amount of each i ngr edi ent of t he prescri pt i on i n t he quest i on
r equi r es 1. 5 g of podophyl l um, 3 g of sal i cyl i c aci d, and 6 mL of acet one. The
cor rect pr ocedure woul d be t o t ri t urat e t he podophyl l um wi t h t he acet one, t hen add
t he t r i t ur at ed sal i cyl i c aci d t o a cal i br at ed bot t l e cont ai ni ng t he podophyl l um and
acet one. Fl exi bl e col l odi on i s t hen added up t o t he 30- mL cal i brat i on. An " ext er nal
use onl y¨ l abel shoul d be af f i xed t o t he cont ai ner .
6. The answer i s E ( Ì , Ì Ì , and Ì Ì Ì ) [ see Ì V. B. 2; Ì V. C. 5; Ì V. D. 1 and 2] .
Whi l e pr eci pi t at ed sul f ur can be used t o pr epare t he pr escri pt i on descr i bed i n t he
quest i on, i t i s di f f i cul t t o t r i t ur at e; t heref ore, i t must f i rst be l evi gat ed wi t h a sui t abl e
l evi gat i ng agent (e. g. , gl ycer i n) . Al l suspensi ons, owi ng t o t hei r i nst abi l i t y, r equi re
shaki ng bef or e use t o r edi st r i but e t he i nsol ubl e i ngr edi ent s.
7. The answer i s A ( Ì ) [ see VÌ . C. 3; VÌ . D. 1] .
The pr oper pr ocedur e f or compoundi ng t he pr escr i pt i on descr i bed i n t he quest i on i s
t o f i r st f orm a l i qui d eut ect i c. Thi s i s done by t r i t ur at i ng t he ment hol and camphor
t oget her i n a mort ar . Thi s eut ect i c i s t hen bl ended wi t h t he powder ed st arch and
cal ami ne, usi ng geomet ri c di l ut i on.
8. The answer i s E ( Ì , Ì Ì , and Ì Ì Ì ) [ see Ì X. D. 1 and 3; Ì X. E. 1] .
The pr oper pr ocedur e f or pr epar i ng t he prescr i pt i on gi ven i n t he quest i on i s t o
r educe t he part i cl e si ze of each powder and mi x t hem t oget her, usi ng geomet ri c
di l ut i on. Thi s ensures t he pr oper bl endi ng of t he powder s. Next , t hi s powder ed
mi xt ur e i s i ncor por at ed, geomet ri cal l y, wi t h t he pet r ol at um. Then, t he l anol i n i s
added geomet r i cal l y.
9. The answer i s A ( Ì ) [ see XÌ . E. 2] .
An equal vol ume of ai r must be i nj ect ed when removi ng a dr ug sol ut i on f rom a vi al .
Thi s i s done t o prevent t he f or mat i on of a vacuum wi t hi n t he vi al . Thi s probl em does
not occur wi t h ampul es and syr i nges cont ai ni ng dr ug sol ut i ons; t heref ore, i t i s
unnecessar y t o i nj ect any ai r when removi ng t hem.

6
Basic Pharmacokinetics
Ri ccardo L. Boni
Leon ShargeI
I. PHARMACOKINETICS
A. I NTRODUCTI ON
1. Pharmacoki net i cs i s t he quant i t at i ve measurement of drug absor pt i on,
di st r i but i on, and el i mi nat i on ( i . e. , excr et i on and met abol i sm) and i ncl udes
t he rat e pr ocesses f or drug movement i nt o t he body, wi t hi n t he body, and
out of t he body.
2. Commonl y used uni t s i n pharmacoki net i cs are t abul at ed i n Tabl e 6- 1.
3. Rates and orders of react i ons. The rate of a chemi cal react i on or
pharmacoki net i c pr ocess i s t he vel oci t y wi t h whi ch i t occur s. The order of a
r eact i on i s t he way i n whi ch t he concent r at i on of a dr ug or r eact ant i n a
chemi cal r eact i on af f ect s t he r at e.
a. Zero- order react i on. The dr ug concent r at i on changes wi t h r espect t o
t i me at a const ant r at e, accor di ng t o t he f ol l owi ng equat i on:

Table 6-1. Common Units in Pharmacokinetics
Pharmacokinetic
Parameter Abbreviation
Fundamental
Units Units Example
Area under the
curve
AUC Concentration
X time
µg X hr/mL
Total body
clearance
Cl
T
Volume/time Liters/hr
Renal clearance Cl
R
Volume/time Liters/hr
Hepatic clearance Cl
H
Volume/time Liters/hr
Apparent volume
oI distribution
V
D
Volume Liters
Volume oI
distribution at
Vss Volume Liters
steady state
Peak plasma drug
concentration
Cmax Concentration mg/L
Plasma drug
concentration
Cp Concentration mg/L
Steady-state drug
concentration
Css or Cav Concentration mg/L
Time Ior peak
drug concentration
Tmax Time hr
Dose Do Mass mg
Loading dose D
L
Mass mg
Maintenance dose D
M
Mass mg
Amount oI drug in
the body
D
B
Mass mg
Rate oI drug
inIusion
R Mass/time mg/hr
First order rate
constant Ior drug
absorption
ka 1/time 1/hr or hr
-1

Zero order rate
constant Ior drug
absorption
ko Mass/time mg/hr
First order rate
constant Ior drug
absorption
K (sometimes
reIerred to as
kel)
1/time 1/hr or hr
-1

Elimination halI-
liIe
t
½
Time hr
Fraction oI drug
absorbed
F (no units) Ranges
Irom 0 to 1
(0 to 100°)

P. 123


wher e C i s t he drug concent r at i on and k0 i s t he zero- order rat e const ant
expr essed i n uni t s of concent r at i on per t i me ( e. g. , mi l l i grams per mi l l i l i t er
per hour ). Ì nt egr at i on of t hi s equat i on yi el ds t he l i near (st r ai ght - l i ne)
equat i on:
C = - k0t + C0
wher e k0 i s t he sl ope of t he l i ne ( see Fi gur e 3- 5) and C0 i s t he y i nt er cept ,
or drug concent rat i on, when t i me (t ) equal s zer o. The negat i ve si gn
i ndi cat es t hat t he sl ope i s decreasi ng.
b. Fi rst - order react i on. The change i n drug concent r at i on wi t h respect t o
t i me equal s t he product of t he rat e const ant and t he concent rat i on of dr ug
r emai ni ng, accor di ng t o t he f ol l owi ng equat i on:

wher e k i s t he f i rst -or der r at e const ant , expr essed i n uni t s of r eci pr ocal
t i me, or t i me
- 1
( e. g. , 1/ hr or hr
- 1
) .
( 1) Ì nt egr at i on of t hi s equat i on yi el ds t he f ol l owi ng mat hemat i cal l y
equi val ent equat i ons:

( 2) A gr aph of t he equat i on i n Fi gur e 6- 1 shows t he l i near rel at i on of t he l og
of t he concent r at i on versus t i me. Ì n Fi gur e 6- 1, t he sl ope of t he l i ne i s
equal t o -k/ 2. 3, and t he y i nt ercept i s C0. The val ues f or C are pl ot t ed on
l ogar i t hmi c coor di nat es, and t he val ues f or t are shown on l i near
coordi nat es.
( 3) The haI f - I i f e (t ½) of a r eact i on or pr ocess i s t he t i me r equi r ed f or t he
concent r at i on of a dr ug t o decr ease by one hal f . For a f i rst -or der r eact i on
or process, t he hal f - l i f e i s a const ant and i s r el at ed t o t he f i r st - order rat e
const ant , accor di ng t o t he f ol l owi ng equat i on:

2. ModeI s and compartment s
a. A modeI i s a mat hemat i c descr i pt i on of a bi ol ogi c syst em and i s used t o
expr ess quant i t at i ve r el at i onshi ps.
b. A compart ment i s a gr oup of t i ssues wi t h si mi l ar bl ood f l ow and dr ug
af f i ni t y. A compar t ment i s not a r eal physi ol ogi c or anat omi c regi on.
3. Drug di st ri but i on
a. Dr ugs di st ri but e rapi dl y t o t i ssues wi t h hi gh bl ood f l ow and mor e sl owl y
t o t i ssues wi t h l ow bl ood f l ow.
b. Dr ugs rapi dl y cr oss capi l l ar y membranes i nt o t i ssues because of passi ve
di f f usi on and hydrost at i c pressure. Drug permeabi I i t y acr oss capi l l ar y
membr anes var i es.
( 1) Dr ugs easi l y cr oss t he capi l l ar i es of t he gl omer ul us of t he ki dney and
t he si nusoi ds of t he l i ver.
( 2) The capi l l ari es of t he br ai n ar e sur rounded by gl i al cel l s t hat creat e a
bI ood-brai n barri er, whi ch act s as a t hi ck l i pi d membrane. Pol ar and i oni c
hydr ophi l i c dr ugs cross t hi s barr i er sl owl y.
( 3) Ì n di sease st at es, membr anes may become mor e permeabl e t o dr ugs.
For exampl e, i n meni ngi t i s, t he bl ood brai n bar r i er becomes mor e
per meabl e t o t he penet rat i on of drugs i nt o br ai n.
c. Drugs may accumuI at e i n t i ssues as a r esul t of t hei r physi cochemi cal
charact eri st i cs or speci al af f i ni t y of t he t i ssue f or t he dr ug.
( 1) Li pi d- sol ubl e drugs may accumul at e i n adi pose ( f at ) t i ssue because of
par t i t i oni ng of t he dr ug.
( 2) Tet r acycl i ne may accumul at e i n bone because compl exes are f or med
wi t h cal ci um.
P. 124


d. PI asma protei n bi ndi ng of dr ugs af f ect s dr ug di st r i but i on.
( 1) A dr ug bound t o a prot ei n f or ms a compl ex t hat i s t oo l arge t o cr oss cel l
membr anes.
( 2) AI bumi n i s t he maj or pl asma pr ot ei n i nvol ved i n dr ug prot ei n bi ndi ng.
o1- GI ycoprot ei n, al so f ound i n pl asma, i s i mpor t ant f or t he bi ndi ng of such
basi c dr ugs as propr anol ol .
( 3) Pot ent drugs, such as phenyt oi n, t hat ar e hi ghl y bound ( > 90%) t o
pl asma prot ei ns may be di spl aced by ot her hi ghl y bound dr ugs. The
di spl acement of t he bound drug r esul t s i n more f r ee (nonbound) dr ug, whi ch
r api dl y r eaches t he dr ug r ecept or s and causes a mor e i nt ense
pharmacol ogi c r esponse.
( 4) A f ew hor monal dr ugs bi nd t o speci f i c pl asma pr ot ei ns. For exampl e,
pr edni sone bi ndi ng t o t ranscort i n ( and al bumi n) r esul t s i n dose- dependent
pharmacoki net i cs of predni sone. Thi s nonl i near pharmacoki net i cs i s due t o
sat ur abl e pr ot ei n bi ndi ng. Tr anscor t i n has hi gh af f i ni t y and l ow capaci t y
whi l e al bumi n has l ow af f i ni t y and a hi gh capaci t y.
B. One- compart ment modeI
1. I nt ravenous boI us i nj ect i on. The ent i r e drug dose ent ers t he body
r api dl y, and t he r at e of absorpt i on i s negl ect ed i n cal cul at i ons ( Fi gure 6-1) .
The ent i r e body act s as a si ngl e compar t ment , and t he dr ug r api dl y
equi l i br at es wi t h al l of t he t i ssues i n t he body.
a. Drug eI i mi nat i on i s a f i rst - order ki net i c process, accor di ng t o t he
equat i ons i n Ì . A. 1. b.
( 1) The f i r st - order el i mi nat i on r at e const ant ( k or kel ) i s t he sum of t he r at e
const ant s f or r emoval of dr ug f r om t he body, i ncl udi ng t he r at e const ant s
f or r enal excr et i on and met abol i sm ( bi ot ransf ormat i on) as descri bed by
t he f ol l owi ng equat i on:
k = ke + km
wher e ke i s t he r at e const ant f or r enal excr et i on and km i s t he r at e const ant
f or met abol i sm. Thi s equat i on assumes t hat al l r at es ar e f i rst -or der
pr ocesses.

Figure 6-1. Generalized pharmacokinetic model
Ior a drug administered by rapid intravenous
bolus iniection. . extrapolated drug concentration;
J
D
. apparent volume oI distribution; D
B
. amount
oI drug in the body; k. elimination rate constant;
t
1/2
. elimination halI-liIe. |Adapted with
permission Irom Gibaldi M. Perrier D.
Pharmacokinetics. 2nd ed. New York. Marcel
Dekker. Inc.. 1982. Copyright © 1982
Routledge/Taylor & Francis Group. LLC.|
P. 125


( 2) The eI i mi nati on haI f- I i f e (t 1/ 2) i s gi ven by t he f ol l owi ng equat i on:

b. Apparent voI ume of di st ri but i on ( VD) i s t he hypot het i cal vol ume of
body f l ui d i n whi ch t he dr ug i s di ssol ved. Thi s val ue i s not a t rue anat omi c
or physi cal vol ume.
( 1) VD i s needed t o est i mat e t he amount of dr ug i n t he body r el at i ve t o t he
concent r at i on of drug i n t he pl asma, as shown i n t he f ol l owi ng:
VD × Cp = DB
wher e VD ( l i t ers) i s t he apparent vol ume of di st r i but i on, Cp ( mg/ l i t er ) i s t he
pl asma drug concent rat i on, and DB ( mg) i s t he amount of dr ug i n t he body.
( 2) To cal cul at e t he VD af t er an i nt ravenous bol us i nj ect i on, t he equat i on i s
r ear r anged t o gi ve:

wher e i s t he dose ( DB) of dr ug gi ven by i nt r avenous bol us and i s t he
ext r apol at ed dr ug concent r at i on at zer o t i me on t he y axi s, af t er t he dr ug
equi l i br at es ( Fi gure 6-1) .
( 3) Accor di ng t o t he equat i on, VD i s i ncreased and i s decreased when t he
dr ug i s di st ri but ed mor e ext r avascul ar l y i nt o t he t i ssues. When mor e drug i s
cont ai ned i n t he vascul ar space or pl asma, i s i ncr eased and VD i s
decreased.
2. Si ngI e oraI dose. Ì f t he drug i s gi ven i n an oral dosage f orm (e. g. ,
t abl et , capsul e) , t he dr ug i s general l y absorbed by f i rst - order ki net i cs.
El i mi nat i on of t he dr ug al so f ol l ows t he pr i nci pl es of f i r st - order ki net i cs
( Fi gur e 6- 2) .
a. The f ol l owi ng equat i on descr i bes t he pharmacoki net i cs of f i rst - order
absorpt i on and eI i mi nat i on:

wher e kA i s t he f i rst - or der absorpt i on rat e const ant and F i s t he f r act i on of
dr ug bi oavai l abl e. Changes i n F, D0, VD, kA, and k af f ect t he pl asma drug
concent r at i on.
b. The t i me f or maxi mum, or peak, drug absorpt i on i s gi ven by t he
f ol l owi ng equat i ons:

wher e t ma x depends onl y on t he rat e const ant s kA and k, not on F, D0, or VD.

Figure 6-2. Generalized plot Ior a one-
compartment model showing Iirst-order drug
absorption and Iirst-order drug elimination.
|Adapted with permission Irom Shargel L. Wu-
Pong S. Yu ABC. Applied Biopharmaceutics and
Pharmacokinetics. 5th ed. New York. McGraw-
Hill. 2005.|
P. 126


c. Af t er t ma x i s obt ai ned, t he peak dr ug concent r at i on ( Cma x) i s cal cul at ed,
usi ng t he equat i on i n Ì . B. 2. a and subst i t ut i ng t max f or t .
d. The area under t he cur ve ( AUC) may be det ermi ned by i nt egrat i on of
CPdt usi ng t he t rapezoi dal rul e or by t he f ol l owi ng equat i on:

changes i n F, D0, k, and VD af f ect t he AUC. Mi nor changes i n kA do not
af f ect t he AUC.
e. To obt ai n , obt ai n t he [ AUC] f r om 0 t o t by t he t r apezoi dal rul e and add
on t he ext r apol at ed sect i on of AUC, whi ch i s t he l ast measur abl e dr ug
concent r at i on at t i me t di vi ded by t he sl ope of t he t ermi nal el i mi nat i on
cur ve, as shown i n t he f ol l owi ng equat i on:

f . Lag t i me occurs at t he begi nni ng of syst emi c dr ug absor pt i on. For some
i ndi vi dual s, syst emi c dr ug absorpt i on i s del ayed af t er or al dr ug
admi ni st rat i on because of del ayed st omach empt yi ng or ot her f act ors.
3. I nt ravenous i nf usi on
a. Ì nt r avenous i nf usi on i s an exampl e of zer o- or der absor pt i on and f i r st -
or der el i mi nat i on (Fi gur e 6- 3) .
b. A f ew or al cont r ol l ed- rel ease drug pr oduct s r el ease t he dr ug by zer o-
or der ki net i cs and have zero- order syst emi c absorpt i on.
c. The pl asma dr ug concent r at i on at any t i me af t er t he st ar t of an
i nt ravenous i nf usi on i s gi ven by t he f ol l owi ng equat i on:

wher e R i s t he zer o- or der r at e of i nf usi on gi ven i n uni t s as mi l l i gr ams per
hour or mi l l i gr ams per mi nut e.
d. Ì f t he i nt r avenous i nf usi on i s di scont i nued, t he pl asma dr ug
concent r at i on decl i nes by a f i rst -or der process. The el i mi nat i on hal f -l i f e, or
el i mi nat i on r at e const ant , k, may be obt ai ned f r om t he decl i ni ng pl asma
dr ug concent rat i on ver sus t i me cur ve.
e. As t he drug i s i nf used, t he pl asma drug concent r at i on i ncreases t o a
pl at eau, or steady- st at e concent rat i on ( CSS) .

Figure 6-3. Generalized semilogarithmic plot Ior
a drug showing zero-order absorption and Iirst-
order elimination. C
ss
. steady-state concentration;
k. elimination rate constant. |Adapted with
permission Irom Gibaldi M. Perrier D.
Pharmacokinetics. 2nd ed. New York. Marcel
Dekker. Inc.. 1982. Copyright © 1982
Routledge/Taylor & Francis Group. LLC.|
P. 127


( 1) Under st eady- st at e condi t i ons, t he f r act i on of dr ug absorbed equal s t he
f r act i on of drug el i mi nat ed f rom t he body.
( 2) The pl asma concent rat i on at st eady st at e ( Css ) i s gi ven by t he f ol l owi ng
equat i on:

Wher e, Cl T i s t ot al body cl ear ance ( see Sect i on Ì . E. )
( 3) The rat e of dr ug i nf usi on ( R) may be cal cul at ed f rom a rear rangement of
t he equat i on i f t he desi red Cs s , t he VD, and t he k ar e known. These val ues
can of t en be obt ai ned f rom t he dr ug l i t erat ur e. To cal cul at e t he r at e of
i nf usi on, t he f ol l owi ng equat i on i s used:
R = Cs s VDk = Cs s Cl T
wher e Cs s i s t he desi r ed ( t ar get ) pl asma dr ug concent r at i on and Cl T i s t ot al
body cl ear ance.
f . A I oadi ng dose ( DL) i s gi ven as an i ni t i al i nt ravenous bol us dose t o
pr oduce t he Cs s as r api dl y as possi bl e. The i nt ravenous i nf usi on i s st ar t ed
at t he same t i me as t he DL.
( 1) The t i me t o r each Cs s depends on t he el i mi nat i on hal f - l i f e of t he drug.
Reachi ng 90%, 95%, or 99% of t he Css wi t hout a DL t akes 3. 32, 4. 32, or
6. 65 hal f -l i ves, r espect i vel y. Thus, f or a dr ug wi t h an el i mi nat i on t 1/ 2 of 8 hr ,
i t wi l l t ake 3. 32 × 8 hr, or 26. 56 hr , t o reach 90% of Cs s i f no l oadi ng dose
i s gi ven.
( 2) The DL i s t he amount of dr ug t hat , when di ssol ved i n t he appar ent VD,
pr oduces t he desi red Cs s. Thus DL i s cal cul at ed by t he f ol l owi ng equat i on:

g. An i nt r avenous i nf usi on pr ovi des a r el at i vel y const ant pl asma drug
concent r at i on and i s part i cul arl y usef ul f or dr ugs t hat have a nar r ow
t her apeut i c range. The Ì V i nf usi on keeps t he pl asma drug concent rat i on
bet ween t he mi ni mum t oxi c concent r at i on ( MTC) and t he mi ni mum ef f ect i ve
concent r at i on ( MEC) .
4. I ntermi tt ent i nt ravenous i nf usi ons
a. Ì nt ermi t t ent i nt r avenous i nf usi ons ar e i nf usi ons i n whi ch t he drug i s
i nf used f or short per i ods t o pr event accumul at i on and t oxi ci t y.
b. Ì nt ermi t t ent i nt r avenous i nf usi ons ar e used f or a f ew dr ugs, such as t he
ami nogl ycosi des. For exampl e, gent ami ci n may be gi ven as a 1-hr i nf usi on
ever y 12 hr . Ì n t hi s case, st eady- st at e drug concent r at i ons ar e not
achi eved.
c. The peak dr ug concent r at i on i n t he pl asma f or a dr ug gi ven by
i nt er mi t t ent i nt ravenous i nf usi on may be cal cul at ed by t he f ol l owi ng
equat i on:

wher e Cp, n i s t he peak drug concent r at i on, R i s t he r at e of drug i nf usi on, Cl
i s t ot al body cl ear ance, k i s t he dosage i nt er val , n i s t he number of
i nf usi ons, t i s t he t i me f or t he i nf usi on, and ¡ i s t he dosage i nt er val .
5. MuI t i pI e doses. Many dr ugs ar e gi ven i nt ermi t t ent l y i n a mul t i pl e-dose
r egi men f or cont i nuous or pr ol onged t her apeut i c act i vi t y. Thi s r egi men i s
of t en used t o t r eat chroni c di sease.
a. Ì f dr ug doses ar e gi ven f r equent l y bef or e t he pr evi ous dose i s compl et el y
el i mi nat ed, t hen pl asma dr ug concent rat i ons accumul at e and i ncr ease t o a
st eady- st at e l evel .
b. At st eady st at e, pl asma dr ug concent r at i on f l uct uat es bet ween a
maxi mum ( ) and a mi ni mum ( ) val ue ( Fi gur e 6- 4) .
c. When a mul t i pl e- dose r egi men i s cal cul at ed, t he superposi t i on pri nci pI e
assumes t hat pr evi ous dr ug doses have no ef f ect on subsequent doses.
Thus t he pr edi ct ed pl asma dr ug concent r at i on i s t he t ot al pl asma dr ug
concent r at i on obt ai ned by addi ng t he r esi dual drug concent r at i ons f ound
af t er each pr evi ous dose.
d. When a mul t i pl e-dose r egi men i s desi gned, onl y t he dosi ng rat e ( D0/ ¡)
can be adj ust ed easi l y.
( 1) The dosi ng r at e i s based on t he si ze of the dose ( D0) and t he i nt ervaI
( t) between doses, or t he f requency of dosi ng.
P. 128



Figure 6-4. Generalized plot showing plasma
drug concentration levels aIter administration oI
multiple doses and levels oI accumulation when
equal doses are given at equal time intervals. t.
time interval between doses (t). or the Irequency
oI dosing. |Adapted with permission Irom Shargel
L. Wu-Pong S. Yu ABC. Applied
Biopharmaceutics and Pharmacokinetics. 5th ed.
New York. McGraw-Hill. 2005|
( 2) The dosi ng r at e i s gi ven by t he f ol l owi ng equat i on:

( 3) As l ong as t he dosi ng r at e i s t he same, t he expect ed average drug
concent rati on at st eady st at e ( ) i s t he same (Fi gure 6-4) .
( a) For exampl e, i f a 600- mg dose i s gi ven ever y 12 hr, t he dosi ng r at e i s
600 mg/ 12 hr , or 50 mg/ hr .
( b) A dose of 300 mg ever y 6 hr or 200 mg ever y 4 hr al so gi ves t he same
dosi ng r at e (50 mg/ hr ) , wi t h t he same expect ed . However , t he and val ues
wi l l be di f f erent .
( c) For a l arger dose gi ven over a l onger i nt er val ( e. g. , 600 mg ever y 12
hr ) , t he i s hi gher and t he l ower compar ed wi t h a smal l er dose gi ven mor e
f r equent l y ( e. g. , 200 mg ever y 4 hr ).
e. Cer t ai n ant i bi ot i cs ar e gi ven by muI t i pI e rapi d i nt ravenous boI us
i nj ect i ons.
( 1) The peak, or maxi mum, serum drug concentrat i on at st eady st at e may
be est i mat ed by t he f ol l owi ng equat i on:

( 2) The mi ni mum serum drug concent rat i on ( ) at st eady st at e i s t he dr ug
concent r at i on af t er t he dr ug decl i nes one dosage i nt er val . Thus i s
det ermi ned by t he f ol l owi ng equat i on:

( 3) The average drug concent rat i on ( ) at st eady st at e i s est i mat ed wi t h
t he equat i on used f or mul t i pl e or al doses:

For i nt r avenous bol us i nj ect i ons, F = 1.
P. 129


f . Or al l y admi ni st ered drugs gi ven i n i mmedi ate-reI ease dosage forms
( e. g. , sol ut i ons, convent i onal t abl et s, capsul es) by mul t i pl e or al doses ar e
usual l y r api dl y absor bed and sl owl y el i mi nat ed kA < k) . and f or t hese dr ugs
ar e approxi mat ed by t he equat i ons shown i n Ì . B. 5. e. ( 1) and (2) .
( 1) For mor e exact cal cul at i ons of and af t er mul t i pl e or al doses, t he
f ol l owi ng equat i ons are used:

( 2) The cal cul at i on of i s t he same as f or mul t i pl e i nt ravenous bol us
i nj ect i ons, usi ng t he equat i on shown i n Ì . B. 5. e. ( 3) .
( 3) The t er m 1/ (1 - e
- k¡
) i s known as t he accumuI at i on rat e.
( 4) The f ract i on of drug remai ni ng i n t he body ( f ) af t er a dosage i nt er val i s
gi ven by t he f ol l owi ng equat i on:
f = e
- k ¡

g. Loadi ng dose. An i ni t i al l oadi ng dose ( DL) i s gi ven t o obt ai n a
t her apeut i c st eady- st at e dr ug l evel qui ckl y.
( 1) For mul t i pl e or al doses, DL i s cal cul at ed by:

wher e DM i s t he mai nt enance dose.
( 2) Ì f DM i s gi ven at a dosage i nt er val equal t o t he el i mi nat i on hal f - l i f e of
t he dr ug, t hen DL equal s t wi ce t he mai nt enance dose.
C. MuI t i compart ment modeI s
1. Dr ugs t hat exhi bi t mul t i compar t ment pharmacoki net i cs di st r i but e i nt o
di f f er ent t i ssue groups at di f f erent r at es. Ti ssues wi t h hi gh bl ood f l ow
equi l i br at e wi t h a drug mor e rapi dl y t han t i ssues wi t h l ow bl ood f l ow. Dr ug
concent r at i on i n vari ous t i ssues depends on t he physi cal and chemi cal
charact eri st i cs of t he dr ug and t he nat ur e of t he t i ssue. For exampl e, hi ghl y
l i pi d-sol ubl e dr ugs accumul at e sl owl y i n f at (l i pi d) t i ssue.
2. Two-compart ment modeI (i nt ravenous boI us i nj ect i on)
a. Af t er an i nt ravenous bol us i nj ect i on, t he dr ug di st ri but es and equi l i br at es
r api dl y i nt o hi ghl y per f used t i ssues (cent raI compart ment ) and mor e sl owl y
i nt o peri pher al t i ssues ( ti ssue compart ment ) .

b. The i ni t i al r api d decl i ne i n pl asma drug concent r at i on i s known as t he
di st ri but i on phase. The sl ower r at e of decl i ne i n dr ug concent r at i on af t er
compl et e equi l i brat i on i s achi eved i s known as t he eI i mi nat i on phase
( Fi gur e 6- 5) .
P. 130



Figure 6-5. Generalized plot showing drug
distribution and equilibration Ior a two-
compartment model (intravenous bolus iniection).
The distribution phase is the initial rapid decline
in plasma drug concentration. The elimination
phase is the slower rate oI decline aIter complete
equilibration oI the drug is achieved. |Adapted
with permission Irom Shargel L. Wu-Pong S. Yu
ABC. Applied Biopharmaceutics and
Pharmacokinetics. 5th ed. New York. McGraw-
Hill. 2005.|
c. The pI asma drug concent rati on at any t i me i s t he sum of t wo f i r st - or der
pr ocesses, as gi ven i n t he f ol l owi ng equat i on:
Cp = Ae
- at
+ Be
- bt

wher e a and b are hybri d f i rst - order r at e const ant s and A and B ar e y
i nt er cept s.
( 1) The hybri d f i rst - order rat e const ant b i s obt ai ned f r om t he sl ope of
t he el i mi nat i on phase of t he cur ve ( Fi gur e 6-5) and r epr esent s t he f i rst -
or der el i mi nat i on of dr ug f r om t he body af t er t he dr ug equi l i brat es wi t h al l
t i ssues.
( 2) The hybri d f i rst - order rat e const ant a i s obt ai ned f rom t he sl ope of t he
r esi dual l i ne of t he di st r i but i on phase af t er t he el i mi nat i on phase i s
subt r act ed.
d. The apparent voI ume of di st ri but i on depends on t he t ype of
pharmacoki net i c cal cul at i on. Vol umes of di st ri but i on i ncl ude t he vol ume of
t he cent r al compart ment ( Vp) , t he vol ume of di st r i but i on at st eady st at e
( Vs s ) , and t he vol ume of t he t i ssue compart ment (Vt ) .
P. 131


3. Two-compart ment modeI (oraI drug admi ni st rat i on)
a. A dr ug wi t h a r api d di st r i but i on phase may not show t wo- compar t ment
charact eri st i cs af t er oral admi ni st r at i on. As t he dr ug i s absor bed, i t
equi l i br at es wi t h t he t i ssues so t hat t he el i mi nat i on hal f -l i f e of t he
el i mi nat i on port i on of t he cur ve equal s 0. 693/ b.
b. Two- compar t ment char act er i st i cs are seen i f t he drug i s absorbed r api dl y
and t he di st ri but i on phase i s sl ower .
4. ModeI s wi th addi t i onaI compart ment s
a. The addi t i on of each new compart ment t o t he model requi r es an
addi t i onal f i r st - or der pl ot .
b. The addi t i on of a t hi r d compar t ment suggest s t hat t he dr ug sl owl y
equi l i br at es i nt o a deep t i ssue space. Ì f t he dr ug i s gi ven at f requent
i nt er val s, t he dr ug begi ns t o accumul at e i nt o t he t hi rd compar t ment .
c. The t ermi nal l i near phase general l y repr esent s t he el i mi nat i on of t he
dr ug f r om t he body af t er equi l i br at i on occur s. The r at e const ant f rom t he
el i mi nat i on phase i s used t o cal cul at e dosage regi mens.
d. Adequat e phar macoki net i c descri pt i on of mul t i compart ment model s i s
of t en di f f i cul t and depends on pr oper pl asma sampl i ng and det er mi nat i on of
dr ug concent rat i ons.
5. EI i mi nat i on rate const ants
a. The el i mi nat i on r at e const ant , k, repr esent s drug el i mi nat i on f r om t he
cent r al compar t ment .
b. The t er mi nal el i mi nat i on r at e const ant ( / or b i n t he t wo- compar t ment
model ) r epresent s dr ug el i mi nat i on af t er dr ug di st r i but i on i s most l y
compl et ed.
D. NonI i near pharmacoki neti cs ar e al so known as capaci t y- l i mi t ed, dose-
dependent , or sat ur at i on pharmacoki net i cs. Nonl i near phar macoki net i cs do
not f ol l ow f i rst - order ki net i cs as t he dose i ncreases (Fi gur e 6- 6). Nonl i near
pharmacoki net i cs may r esul t f rom t he sat urat i on of an enzymeor carr i er-
medi at ed syst em.
1. Characteri st i cs of nonI i near pharmacoki neti cs i ncl ude
a. The AUC i s not proport i onal t o t he dose.
b. The amount of dr ug excr et ed i n t he ur i ne i s not pr opor t i onal t o t he dose.
c. The el i mi nat i on hal f -l i f e may i ncr ease at hi gh doses.
d. The r at i o of met abol i t es f ormed changes wi t h i ncr eased dose.
2. Mi chaeI i s-Menten ki net i cs descr i be t he vel oci t y of enzyme react i ons.
Mi chael i s- Ment en ki net i cs are used t o descr i be nonl i near pharmacoki net i cs.

Figure 6-6. Generalized plot showing plasma
drug concentration versus time Ior a drug with
Michaelis-Menten (nonlinear) elimination
kinetics. For this one-compartment model
(intravenous iniection). the doses are 1 mg. 10
mg. and 100 mg; and the apparent in vivo rate
constant (k
M
) is 10 mg. The maximum velocity oI
the reaction (J
max
) is 0.2 mg/min. |Adapted with
permission Irom Gibaldi M. Perrier D.
Pharmacokinetics. 2nd ed. New York. Marcel
Dekker. Inc.. 1982. Copyright © 1982
Routledge/Taylor & Francis Group. LLC.|
P. 132


a. The Mi chaeI i s-Ment en equat i on descr i bes t he r at e of change ( vel oci t y)
of pl asma drug concent rat i on af t er an i nt r avenous bol us i nj ect i on, as
f ol l ows:

wher e Vma x i s t he maxi mum vel oci t y of t he react i on, Cp i s t he subst rat e or
pl asma drug concent rat i on, and kM i s t he Mi chael i s const ant equal t o t he Cp
at 0. 5 Vmax.
b. At l ow Cp val ues, wher e Cp << kM, t hi s equat i on r educes t o a f i r st - order
r at e equat i on because bot h kM and Vmax ar e const ant s.

c. At hi gh Cp val ues, wher e Cp >> kM, t he Mi chael i s- Ment en equat i on i s a
zer o- or der rat e equat i on, as f ol l ows:

3. Dr ugs t hat f ol l ow nonl i near pharmacoki net i cs may show zer o- order
el i mi nat i on r at es at hi gh dr ug concent rat i ons, f r act i onal -or der el i mi nat i on
r at es at i nt ermedi at e dr ug concent r at i ons, and f i rst - order el i mi nat i on rat es
at l ow dr ug concent rat i ons (Fi gur e 6- 6).
E. CI earance i s a measur ement of dr ug el i mi nat i on f r om t he body. Uni t s f or
cl ear ance are vol ume per t i me (e. g. , l i t er s per hour ) .
1. TotaI body cI earance ( Cl T ) i s t he drug el i mi nat i on r at e di vi ded by t he
pl asma drug concent rat i on. Accor di ng t o t he concept of cl ear ance, t he body
cont ai ns an appar ent vol ume of di st ri but i on i n whi ch t he drug i s di ssol ved.
A const ant por t i on of t hi s vol ume i s cl ear ed, or removed, f rom t he body per
uni t t i me.
a. The f ol l owi ng equat i ons expr ess t he measur ement of t ot al body
cl ear ance:

b. For drugs t hat f ol l ow f i r st -or der (l i near ) phar macoki net i cs, t ot al body
cl ear ance i s t he sum of al l t he cl ear ances i n t he body, as shown i n t he
f ol l owi ng equat i on:
CLT = CLR + Cl NR
wher e CLR i s renal cl earance and Cl NR i s nonrenal cl ear ance. Nonr enal
cl ear ance, Cl NR, i s of t en equat ed wi t h hepat i c cl ear ance, Cl H.
c. The rel at i on bet ween Cl T and t 1/ 2 i s obt ai ned by subst i t ut i ng 0. 693/ t 1/ 2 f or
k i n t he equat i on i n Ì . E. 1 a t o obt ai n t he f ol l owi ng expr essi on:

wher e VD and Cl T ar e consi dered i ndependent var i abl es, and t 1/ 2 i s
consi dered a dependent var i abl e.
d. As cl earance decr eases (e. g. , i n renal di sease) , t ½ i ncr eases. Changes
i n VD al so cause proport i onal changes i n t ½.
2. RenaI drug excret i on i s t he maj or r out e of dr ug el i mi nat i on f or pol ar
dr ugs, wat er -sol ubl e dr ugs, dr ugs wi t h l ow mol ecul ar wei ght ( < 500), and
dr ugs t hat ar e bi ot r ansf or med sl owl y. The r el at i on bet ween t he dr ug
excr et i on r at e and t he pl asma dr ug concent r at i on i s shown
P. 133

i n Fi gur e 6- 7. Dr ugs ar e excr et ed t hr ough t he ki dney i nt o t he ur i ne by
gl omerul ar f i l t rat i on, t ubul ar r eabsor pt i on, and act i ve t ubul ar secr et i on.

Figure 6-7. Generalized plot showing the
excretion rate versus plasma drug concentration
Ior a drug with active tubular secretion and Ior a
drug secreted by glomerular Iiltration only.
|Adapted with permission Irom Shargel L. Wu-
Pong S. Yu ABC. Applied Biopharmaceutics and
Pharmacokinetics. 5th ed. New York. McGraw-
Hill. 2005.|
a. GI omeruI ar f i I t rat i on i s a passi ve pr ocess by whi ch smal l mol ecul es and
dr ugs ar e f i l t er ed t hr ough t he gl omer ul us of t he nephron.
( 1) Dr ugs bound t o pl asma pr ot ei ns ar e t oo l arge t o be f i l t ered at t he
gl omerul us.
( 2) Dr ugs such as creat i ni ne and i nuI i n ar e not act i vel y secret ed or
r eabsorbed. They are used t o measure t he gI omeruI ar fi I t rati on rat e
( GFR) .
b. TubuI ar reabsorpti on i s a passi ve process t hat f ol l ows Fi ck' s l aw of
di f f usi on.
( 1) Li pi d- sol ubl e drugs ar e r eabsor bed f r om t he l umen of t he nephr on back
i nt o t he syst emi c ci rcul at i on.
( 2) For weak el ect rol yt e dr ugs, ur i ne pH af f ect s t he r at i o of noni oni zed and
i oni zed dr ug.
( a) Ì f t he drug exi st s pr i mar i l y i n t he noni oni zed or l i pi d- sol ubl e f or m, t hen
i t i s reabsorbed mor e easi l y f r om t he l umen of t he nephron.
( b) Ì f t he drug exi st s pr i mar i l y i n t he i oni zed or wat er - sol ubl e f orm, t hen i t
i s excr et ed mor e easi l y i n t he uri ne.
( c) Dependi ng on t he pKa of t he dr ug, al t er at i on of uri ne pH al t er s t he r at i o
of i oni zed t o noni oni zed dr ug and af f ect s t he r at e of dr ug excr et i on. For
exampl e, al kal i ni zat i on of t he uri ne by t he admi ni st r at i on of sodi um
bi car bonat e i ncr eases t he excr et i on of sal i cyl at es ( weak aci ds) i nt o t he
ur i ne.
( 3) An i ncr ease i n uri ne f l ow caused by si mul t aneous admi ni st r at i on of a
di uret i c decr eases t he t i me f or dr ug r eabsor pt i on. Consequent l y, more drug
i s excr et ed i f gi ven wi t h a di ur et i c.
c. Act i ve t ubuI ar secreti on i s a car r i er -medi at ed act i ve t ranspor t syst em
t hat r equi res ener gy.
( 1) Two act i ve t ubul ar secr et i on pat hways exi st i n t he ki dney: one syst em
f or weak aci ds and one syst em f or weak bases.
( 2) The act i ve t ubul ar secr et i on syst em shows compet i t i on ef f ect s. For
exampl e, probeneci d (a weak aci d) compet es f or t he same syst em as
peni ci l l i n, decr easi ng t he r at e of peni ci l l i n excr et i on, r esul t i ng i n a l onger
peni ci l l i n t 1/ 2.
( 3) The renal cl ear ance of drugs t hat ar e act i vel y secr et ed, such as p-
ami nohi ppurate ( PAH) , i s used t o measure ef f ect i ve renaI bI ood fI ow
( ERBF) .
3. RenaI cI earance i s t he vol ume of dr ug cont ai ned i n t he pl asma t hat i s
r emoved by t he ki dney per uni t t i me. Uni t s f or renaI cI earance are
expr essed i n vol ume per t i me (e. g. , mi l l i l i t er s per mi nut e or l i t ers per hour) .
a. Renal cl earance may be measured by di vi di ng t he r at e of dr ug excr et i on
by t he pl asma dr ug concent r at i on, as shown i n t he f ol l owi ng equat i on:

P. 134


b. Measurement of renal cl ear ance may al so be expr essed by t he f ol l owi ng
equat i on:
Cl R = keVD
wher e ke i s t he f i r st - or der r enal excr et i on r at e const ant and

wher e i s t he t ot al amount of parent ( unchanged) dr ug excr et ed i n t he uri ne.
c. Renal cl ear ance i s measured wi t hout r egar d t o t he physi ol ogi c
mechani sm of renal dr ug excr et i on. The pr obabl e mechani sm f or r enal
cl ear ance i s obt ai ned wi t h a cI earance rati o, whi ch rel at es drug cl earance
t o i nul i n cl earance (a measure of GFR) .
( 1) Ì f t he cl ear ance r at i o i s < 1. 0, t he mechani sm f or dr ug cl ear ance may
r esul t f r om f i l t rat i on pl us r eabsor pt i on.
( 2) Ì f t he r at i o i s 1. 0, t he mechani sm may be f i l t rat i on onl y.
( 3) Ì f t he r at i o i s > 1. 0, t he mechani sm may be f i l t r at i on pl us act i ve t ubul ar
secr et i on.
4. Hepat i c cI earance i s t he vol ume of pl asma cont ai ni ng dr ug t hat i s
cl ear ed by t he l i ver per uni t t i me.
a. Measurement of hepat i c cI earance. Hepat i c cl ear ance i s usual l y
measured i ndi r ect l y, as t he di f f er ence bet ween t ot al body cl ear ance and
r enal cl ear ance, as shown i n t he f ol l owi ng equat i on:
Cl H = Cl T - Cl R
wher e Cl H i s t he hepat i c cl ear ance. Hepat i c cl earance i s gener al l y
consi dered t o be equi val ent t o Cl NR, or nonr enal dr ug cl earance. Hepat i c
cl ear ance can al so be cal cul at ed as t he product of t he I i ver bI ood f I ow
( Q) and t he ext racti on rat i o ( ER), as shown i n t he f ol l owi ng equat i on:
Cl H = Q( ER)
( 1) The ext ract i on rat i o i s t he f r act i on of dr ug t hat i s i r r eversi bl y r emoved
by an or gan or t i ssue as t he pl asma-cont ai ni ng drug per f uses t hat t i ssue.
( 2) The ext r act i on r at i o i s obt ai ned by measur i ng t he pl asma dr ug
concent r at i on ent eri ng t he l i ver and t he pl asma dr ug concent rat i on exi t i ng
t he l i ver :

wher e Ca i s t he ar t eri al pl asma drug concent rat i on ent eri ng t he l i ver and Cv
i s t he venous pl asma drug concent r at i on exi t i ng t he l i ver .
( 3) Val ues f or t he ER r ange f r om 0 t o 1. For exampl e, i f t he ER i s 0. 9, t hen
90% of t he i ncomi ng dr ug i s r emoved as t he pl asma per f uses t he l i ver . Ì f
t he ER i s 0, t hen no dr ug i s r emoved by t he l i ver.
b. BI ood f I ow, i nt ri nsi c cI earance, and prot ei n bi ndi ng af f ect hepat i c
cl ear ance.
( 1) BI ood f I ow t o t he l i ver i s approxi mat el y 1. 5 L/ mi n and may be al t er ed
by exer ci se, f ood, di sease, or dr ugs.
( a) Bl ood ent ers t he l i ver t hr ough t he hepat i c por t al vei n and hepat i c ar t ery
and l eaves t hr ough t he hepat i c vei n.
( b) Af t er oral dr ug admi ni st rat i on, t he drug i s absor bed f rom t he
gast r oi nt est i nal t ract i nt o t he mesent er i c vessel s and pr oceeds t o t he
hepat i c por t al vei n, l i ver , and syst emi c ci r cul at i on.
( 2) I nt ri nsi c cI earance, Cl i nt descr i bes t he abi l i t y of t he l i ver t o r emove t he
dr ug i ndependent l y of bl ood f l ow.
( a) Ì nt r i nsi c dr ug cl ear ance pr i mari l y occur s because of t he i nherent abi l i t y
of t he bi ot ransf ormat i on enzymes ( mi xed- f unct i on oxi dases) t o met abol i ze
t he dr ug as i t ent ers t he l i ver .
( b) Normal l y, basal l evel mi xed- f unct i on oxi dase enzymes bi ot ransf orm
dr ugs. Level s of t hese enzymes may be i ncr eased by var i ous drugs ( e. g. ,
phenobar bi t al ) and envi ronment al agent s ( e. g. , t obacco smoke). These
enzymes may be i nhi bi t ed by ot her dr ugs and envi r onment al agent s ( e. g. ,
ci met i di ne, acut e l ead poi soni ng).
P. 135


( 3) Protei n bi ndi ng. Dr ugs t hat are bound t o prot ei n ar e not easi l y cl ear ed
by t he l i ver or ki dney because onl y t he f r ee, or nonpl asma prot ei n- bound,
dr ug crosses t he cel l membr ane i nt o t he t i ssue.
( a) The f ree drug i s avai l abl e t o dr ug-met abol i zi ng enzymes f or
bi ot r ansf or mat i on.
( b) A sudden i ncrease i n f r ee-dr ug pl asma concent r at i on r esul t s i n mor e
avai l abl e drug at pharmacol ogi c recept or s, produci ng a mor e i nt ense ef f ect
i n t he or gans ( e. g. , ki dney, l i ver ) i nvol ved i n dr ug r emoval .
( c) BI ood f I ow ( Q) , i nt ri nsi c cI earance ( Cl i nt ) , and f ract i on of f r ee dr ug i n
pl asma ( f ) ar e r el at ed t o hepat i c cl ear ance as shown i n t he f ol l owi ng
equat i on:

( 1) The hepat i c cl ear ance of dr ugs t hat have hi gh ext r act i on r at i os and hi gh
Cl i nt val ues ( e. g. , propr anol ol ) i s most af f ect ed by changes i n bl ood f l ow
and i nhi bi t ors of t he dr ug met abol i sm enzymes.
( 2) The hepat i c cl ear ance of dr ugs t hat have l ow ext r act i on r at i os and l ow
Cl i nt val ues ( e. g. , t heophyl l i ne) i s most af f ect ed by changes i n Cl i nt and i s
af f ect ed onl y sl i ght l y by changes i n hepat i c bl ood f l ow.
( 3) Onl y dr ugs t hat are hi ghl y pl asma pr ot ei n bound (i . e. , > 95%) and have
a l ow i nt r i nsi c cl earance ( e. g. , phenyt oi n) ar e af f ect ed by a sudden shi f t i n
pr ot ei n bi ndi ng. Thi s shi f t causes an i ncr ease i n f r ee- drug pl asma
concent r at i on.
c. Bi I i ar y drug excret i on, an act i ve t r anspor t process, i s al so i ncl uded i n
hepat i c cl ear ance. Separat e act i ve secr et i on syst ems exi st f or weak aci ds
and weak bases.
( 1) Dr ugs t hat are excr et ed i n bi l e are usual l y hi gh mol ecul ar wei ght
compounds (i . e. , > 500) or pol ar dr ugs, such as reserpi ne, di goxi n, and
var i ous gl ucuroni de conj ugat es.
( 2) Dr ugs may be recycl ed by t he enterohepat i c ci rcuI at i on.
( a) Some dr ugs ar e absor bed f r om t he gast r oi nt est i nal t r act t hrough t he
mesent er i c and hepat i c por t al vei ns, proceedi ng t o t he l i ver . The l i ver may
secr et e some of t he dr ug ( unchanged or as a gl ucur oni de met abol i t e) i nt o
t he bi l e.
( b) The bi l e and dr ug are st or ed i n t he gal l bl adder and wi l l empt y i nt o t he
gast r oi nt est i nal t ract t hrough t he bi l e duct and t hen may be r eabsor bed.
( c) Ì f t he drug i s a gI ucuroni de metaboI i t e, bact er i a i n t he gast roi nt est i nal
t r act may hydr ol yze t he gl ucuroni de moi et y, al l owi ng t he r el eased drug t o
be r eabsorbed.
d. Fi rst - pass ef f ect s (presyst emi c eI i mi nati on) occur wi t h drugs gi ven
or al l y. A por t i on of t he dr ug i s el i mi nat ed bef or e syst emi c absor pt i on
occurs.
( 1) Fi r st - pass ef f ect s gener al l y r esul t f r om r api d dr ug bi ot r ansf ormat i on by
l i ver enzymes. Ot her mechani sms i ncl ude met abol i sm of t he drug by
gast r oi nt est i nal mucosal cel l s, i nt est i nal f l or a, and bi l i ar y secret i on.
( 2) Fi r st - pass ef f ect s ar e usual l y obser ved by measuri ng t he absoI ut e
bi oavai I abi I i t y ( F) of t he dr ug (see Chapt er 7) . Ì f F < 1, t hen some of t he
dr ug was el i mi nat ed bef or e syst emi c dr ug absorpt i on occur r ed.
( 3) Dr ugs t hat have a hi gh hepat i c ext ract i on rat i o, such as propr anol ol
and morphi ne, show f i rst - pass ef f ect s.
( 4) To obt ai n bet t er syst emi c absor pt i on of a dr ug t hat demonst r at es hi gh
f i r st - pass ef f ect s, t hen ei t her
( a) The dr ug dose coul d be i ncreased ( e. g. , pr opranol ol , peni ci l l i n)
( b) The drug coul d be gi ven by an al t ernat e r out e of admi ni st r at i on ( e. g. ,
ni t rogl ycer i n subl i ngual , i nsul i n subcut aneous, est r adi ol t r ansdermal )
( c) The dosage f orm coul d be modi f i ed as a del ayed- r el ease dr ug product
( e. g. , ent eri c-coat ed aspi r i n, mesal ami ne) so t hat t he dr ug may be absorbed
mor e di st al l y i n t he GÌ t ract
F. Noncompart ment met hods. Some phar macoki net i c paramet er s f or
absor pt i on, di st r i but i on, and el i mi nat i on may be est i mat ed wi t h
noncompart ment met hods. These met hods usual l y r equi r e compar i son of
t he ar eas under t he cur ve.
1. Mean resi dence t i me
a. Mean resi dence t i me ( MRT) i s t he average t i me f or t he dr ug mol ecul es
t o r esi de i n t he body. MRT i s al so known as t he mean t ransi t t i me and mean
soj ourn t i me.
b. The MRT depends on t he rout e of admi ni st rat i on and assumes t hat t he
dr ug i s el i mi nat ed f rom t he cent r al compar t ment .
P. 136


c. The MRT i s t he t ot al resi dence t i me f or al l mol ecul es i n t he body di vi ded
by t he t ot al number of mol ecul es i n t he body, as shown i n t he f ol l owi ng
equat i on:
d. MRT af ter I V boI us i nj ect i on
( 1) The MRT af t er a bol us i nt r avenous i nj ect i on i s cal cul at ed by t he
f ol l owi ng equat i on:

wher e AUMC i s t he ar ea under t he f i r st moment ver sus t i me cur ve f r om t =
0 t o t = i nf i ni t y and AUC0- × i s t he area under t he pl asma drug concent rat i on
ver sus t i me cur ve f rom t = 0 t o t = i nf i ni t y. AUC0- × i s al so known as t he zero
moment cur ve.
( 2) The MRTÌ V i s r el at ed t o t he el i mi nat i on r at e const ant by t he f ol l owi ng
expr essi on:
MRTÌ V = 1/ k
( 3) Duri ng MRTÌ V, 62. 3% of t he i nt ravenous bol us dose i s el i mi nat ed.
( 4) The MRT f or a drug gi ven by a noni nst ant aneous i nput i s l onger t han t he
MRTÌ V.
2. Mean absorpt i on ti me ( MAT) i s t he di f f er ence bet ween MRT and MRTÌ V
af t er an ext r avascul ar r out e i s used.
MAT = MRTev = MRTÌ V
When f i rst -or der absor pt i on occurs, MAT = 1/ ka.
3. CI earance i s t he vol ume of pl asma cl ear ed of dr ug per uni t t i me and may
be cal cul at ed wi t hout consi derat i on of t he compar t ment model .

Af t er an Ì V dose, F = 1.
4. St eady- st at e voI ume of di st ri buti on ( Vss)
a. The st eady- st at e vol ume of di st r i but i on i s t he r at i o of t he amount of drug
i n t he body at st eady st at e and t he aver age st eady- st at e drug
concent r at i on.
b. Af t er an i nt ravenous bol us i nj ect i on, Vs s i s cal cul at ed by t he f ol l owi ng
equat i on:

II. CIinicaI Pharmacokinetics
i s t he appl i cat i on of pharmacoki net i c pr i nci pl es f or t he r at i onal desi gn of an
i ndi vi dual i zed dosage r egi men. The t wo mai n obj ect i ves ar e mai nt enance
of an opt i mum drug concent rat i on at t he recept or si te t o produce t he
desi r ed t her apeut i c r esponse f or a speci f i c peri od and mi ni mi zat i on of any
adverse or t oxi c ef f ects of t he drug.
III. Toxicokinetics
i s t he appl i cat i on of pharmacoki net i c pr i nci pl es t o t he desi gn, conduct , and
i nt er pr et at i on of dr ug saf et y eval uat i on st udi es.
A. Toxi coki net i cs i s al so used t o val i dat e dose- rel at ed exposur e i n
ani mal s. Toxi coki net i c st udi es ar e perf ormed i n ani mal s dur i ng pr ecl i ni cal
dr ug devel opment t o ai d i n pr edi ct i on of human drug t oxi ci t y. Toxi coki net i c
( noncl i ni cal ) st udi es may cont i nue af t er t he dr ug has been t est ed i n
humans.
B. CI i ni caI t oxi coI ogy i s t he st udy of adverse ef f ect s of dr ugs and t oxi c
subst ances ( poi sons) i n t he human body. The phar macoki net i cs of a drug i n
an overmedi cat ed (i nt oxi cat ed) pat i ent may be ver y di f f er ent f rom t he
pharmacoki net i cs of t he same dr ug gi ven i n t her apeut i c doses. For
exampl e, a ver y hi gh t oxi c dose may show nonl i near pharmacoki net i cs due
t o sat ur at i on ki net i cs
P. 137

compared t o t he dr ug gi ven at l ower t herapeut i c doses i n whi ch t he dr ug l evel s
f ol l ow l i near pharmacoki net i cs.
IV. PopuIation Pharmacokinetics
i s t he st udy of sources and cor rel at es of var i abi l i t y i n dr ug concent r at i ons among
i ndi vi dual s who are t he t ar get pat i ent popul at i on. Popul at i on pharmacoki net i cs i s
most of t en appl i ed t o t he cl i ni cal pat i ent who i s r ecei vi ng r el evant doses of a dr ug
of i nt erest . Bot h phar macoki net i c and nonphar macoki net i c dat a may be consi dered,
i ncl udi ng gender , age, wei ght , cr eat i ni ne cl ear ance, and concomi t ant di sease.
P. 138


STUDY QUESTIONS
Di rect i ons: Each quest i on, st at ement or i ncompl et e st at ement i n t hi s sect i on can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. Creat i ni ne cI earance i s used as a measurement of
( A) r enal excr et i on rat e.
( B) gl omer ul ar f i l t r at i on rat e ( GFR).
( C) act i ve renal secr et i on.
( D) passi ve r enal absor pt i on.
( E) dr ug met abol i sm r at e.
Vi ew Answer 1. The answer i s B[ see] . For questi ons 2- 5: A new
cephal ospori n ant i bi ot i c was gi ven at a dose of 5 mg/ kg by a si ngl e i nt ravenous
bol us i nj ect i on t o a 58- year - ol d man who wei ghed 75 kg. The ant i bi ot i c f ol l ows t he
pharmacoki net i cs of a one- compar t ment model and has an el i mi nat i on hal f - l i f e of 2
hr . The appar ent vol ume of di st r i but i on i s 0. 28 L/ kg, and t he drug i s 35% bound t o
pl asma prot ei ns.
2. What i s t he i ni t i aI pI asma drug concent rat i on ( ) i n t hi s pat i ent ?
( A) 0. 24 mg/ L
( B) 1. 80 mg/ L
( C) 17. 9 mg/ L
( D) 56. 0 mg/ L
( E) 1339 mg/ L
Vi ew Answer 2. The answer i s C[ see] . 3. What i s t he predi ct ed pI asma drug
concent rati on ( Cp) at 8 hr af t er t he dose?
( A) 0. 73 mg/ L
( B) 1. 11 mg/ L
( C) 2. 64 mg/ L
( D) 4. 02 mg/ L
( E) 15. 10 mg/ L
Vi ew Answer 3. The answer i s B[ see I . A. 1. b. (1); ] . 4. How much drug
remai ns i n t he pat i ent ' s body ( DB) 8 hr af t er the dose?
( A) 15. 3 mg
( B) 23. 3 mg
( C) 84. 4 mg
( D) 100. 0 mg
( E) 112. 0 mg
Vi ew Answer 4. The answer i s B[ see] . 5. How I ong af ter t he dose i s exact I y
75% of t he drug eI i mi nat ed f rom the pat i ent ' s body?
( A) 2 hr
( B) 4 hr
( C) 6 hr
( D) 8 hr
( E) 10 hr
Vi ew Answer 5. The answer i s B[ see] . CDCVt For quest i ons 6-11: A 35- year -
ol d man who wei ghs 70 kg and has normal r enal f unct i on needs an i nt r avenous
i nf usi on of t he ant i bi ot i c car beni ci l l i n. The desi r ed st eady- st at e pl asma drug
concent r at i on i s 15 mg/ dL. The physi ci an want s t he ant i bi ot i c t o be i nf used i nt o t he
pat i ent f or 10 hr . Car beni ci l l i n has an el i mi nat i on hal f - l i f e (t 1/ 2) of 1 hr and an
appar ent vol ume di st ri but i on ( VD) of 9 L i n t hi s pat i ent .
6. Assumi ng that no I oadi ng dose was gi ven, what rat e of i nt ravenous i nf usi on
i s recommended for t hi s pati ent?
( A) 93. 6 mg/ hr
( B) 135. 0 mg/ hr
( C) 468. 0 mg/ hr
( D) 936. 0 mg/ hr
( E) 1350. 0 mg/ hr
Vi ew Answer 6. The answer i s D[ see] . 7. Assumi ng t hat no I oadi ng
i nt ravenous dose was gi ven, how I ong af ter the i ni t i ati on of t he i nt ravenous
i nf usi on wouI d the pI asma drug concent rati on reach 95% of t he t heoret i c
st eady- st at e drug concent rat i on?
( A) 1. 0 hr
( B) 3. 3 hr
( C) 4. 3 hr
( D) 6. 6 hr
( E) 10. 0 hr
Vi ew Answer 7. The answer i s C[ see] . P. 139


8. What i s t he recommended I oadi ng dose?
( A) 93. 6 mg
( B) 135. 0 mg
( C) 468. 0 mg
( D) 936. 0 mg
( E) 1350. 0 mg
Vi ew Answer 8. The answer i s E[see] . 9. To i nf use t he ant i bi ot i c as a
soI ut i on contai ni ng 10 g drug i n 500 mL 5% dext rose, how many mi I I i I i t ers per
hour of t he soI ut i on wouI d be i nf used i nt o the pat i ent ?
( A) 10. 0 mL/ hr
( B) 46. 8 mL/ hr
( C) 100. 0 mL/ hr
( D) 936. 0 mL/ hr
( E) 1141. 0 mL/ hr
Vi ew Answer 9. The answer i s B[ see] . 10. What i s t he t otaI body cI earance
rat e f or carbeni ci I I i n i n t hi s pat i ent ?
( A) 100 mL/ hr
( B) 936 mL/ hr
( C) 4862 mL/ hr
( D) 6237 mL/ hr
( E) 9000 mL/ hr
Vi ew Answer 10. The answer i s D[ see] . 11. I f t he pat i ent ' s renaI cI earance
f or carbeni ci I I i n i s 86 mL/ mi n, what i s the hepat i c cI earance f or carbeni ci I I i n?
( A) 108 mL/ hr
( B) 1077 mL/ hr
( C) 3840 mL/ hr
( D) 5160 mL/ hr
( E) 6844 mL/ hr
Vi ew Answer 11. The answer i s B[ see] . CRkVCCCCDCl Cl Cl Cl Cl Cl Cl Cl 12.
The earI i est evi dence that a drug i s st ored i n t i ssue i s
( A) an i ncr ease i n pl asma pr ot ei n bi ndi ng.
( B) a l ar ge appar ent vol ume of di st r i but i on ( VD) .
( C) a decrease i n t he r at e of f ormat i on of met abol i t es by t he l i ver .
( D) an i ncr ease i n t he number of si de ef f ect s pr oduced by t he dr ug.
( E) a decr ease i n t he amount of f r ee drug excr et ed i n t he uri ne.
Vi ew Answer 12. The answer i s B[ see] . V13. The i nt ensi t y of t he
pharmacoI ogi c act i on of a drug i s most dependent on t he
( A) concent rat i on of t he dr ug at t he r ecept or si t e.
( B) el i mi nat i on hal f - l i f e (t 1/ 2) of t he dr ug.
( C) onset t i me of t he dr ug af t er or al admi ni st rat i on.
( D) mi ni mum t oxi c concent r at i on ( MTC) of t he dr ug i n pl asma.
( E) mi ni mum ef f ect i ve concent r at i on ( MEC) of t he dr ug i n t he body.
Vi ew Answer 13. The answer i s A[ see] . 14. Drugs t hat show nonI i near
pharmacoki net i cs have whi ch propert y?
( A) A const ant rat i o of drug met abol i t es i s f or med as t he admi ni st er ed dose
i ncreases.
( B) The el i mi nat i on hal f - l i f e (t 1/ 2) i ncreases as t he admi ni st er ed dose i ncreases.
( C) The ar ea under t he pl asma dr ug concent r at i on ver sus t i me cur ve ( AUC)
i ncreases i n di r ect pr opor t i on t o an i ncr ease i n t he admi ni st ered dose.
( D) Bot h l ow and hi gh doses f ol l ow f i r st -or der el i mi nat i on ki net i cs.
( E) The st eady- st at e dr ug concent r at i on i ncr eases i n di r ect pr opor t i on t o t he dosi ng
r at e.
Vi ew Answer 14. The answer i s B[ see] . 15. The I oadi ng dose ( DL) of a drug
i s usuaI I y based on t he
( A) t ot al body cl earance ( Cl T) of t he dr ug.
( B) percent age of dr ug bound t o pl asma pr ot ei ns.
( C) f r act i on of dr ug excr et ed unchanged i n t he uri ne.
( D) appar ent vol ume of di st ri but i on ( VD) and desi red drug concent rat i on i n pl asma.
( E) ar ea under t he pl asma dr ug concent r at i on versus t i me cur ve ( AUC) .
Vi ew Answer 15. The answer i s D[ see] . DDV16. The renaI cI earance of
i nuI i n i s used as a measurement of
( A) ef f ect i ve renal bl ood f l ow.
( B) r at e of r enal dr ug excr et i on.
( C) i nt r i nsi c enzyme act i vi t y.
( D) act i ve renal secr et i on.
( E) gl omer ul ar f i l t r at i on rat e ( GFR).
Vi ew Answer 16. The answer i s E[see] . P. 140


17. AI I of t he f oI I owi ng st at ements about pI asma prot ei n bi ndi ng of a drug are
t rue except whi ch one?
( A) Di spl acement of a drug f rom pl asma pr ot ei n bi ndi ng si t es r esul t s i n a t r ansi ent
i ncreased vol ume of di st r i but i on ( VD) .
( B) Di spl acement of a drug f rom pl asma pr ot ei n bi ndi ng si t es makes mor e f r ee dr ug
avai l abl e f or gl omer ul ar f i l t rat i on.
( C) Di spl acement of a pot ent dr ug t hat i s normal l y > 95% bound may cause t oxi ci t y.
( D) Al bumi n i s t he maj or pr ot ei n i nvol ved i n pr ot ei n bi ndi ng of dr ugs.
( E) Dr ugs t hat ar e hi ghl y bound t o pl asma pr ot ei ns general l y have a great er VD
compared wi t h dr ugs t hat ar e hi ghl y bound t o t i ssue prot ei ns.
Vi ew Answer 17. The answer i s E[see] . V18. The onset t i me f or a drug
gi ven oraI I y i s t he ti me f or t he drug t o
( A) r each t he peak pl asma dr ug concent r at i on.
( B) r each t he mi ni mum ef f ect i ve concent rat i on ( MEC) .
( C) r each t he mi ni mum t oxi c concent rat i on ( MTC) .
( D) begi n t o be el i mi nat ed f r om t he body.
( E) begi n t o be absorbed f r om t he smal l i nt est i ne.
Vi ew Answer 18. The answer i s B[ see] . 19. The i ni t i aI di st ri but i on of a
drug i nt o t i ssue i s det ermi ned chi ef I y by t he
( A) r at e of bl ood f l ow t o t i ssue.
( B) gl omer ul ar f i l t r at i on rat e ( GFR).
( C) st omach empt yi ng t i me.
( D) af f i ni t y of t he dr ug f or t i ssue.
( E) pl asma pr ot ei n bi ndi ng of t he dr ug.
Vi ew Answer 19. The answer i s A[ see] . 20. Whi ch t i ssue has t he greatest
capaci t y t o bi ot ransf orm drugs?
( A) br ai n
( B) ki dney
( C) l i ver
( D) l ung
( E) ski n
Vi ew Answer 20. The answer i s C[ see] . 21. The pri nci pI e of superposi t i on
i n desi gni ng muI t i pI e- dose regi mens assumes t hat
( A) each dose af f ect s t he next subsequent dose, causi ng nonl i near el i mi nat i on.
( B) each dose of dr ug i s el i mi nat ed by zer o- order el i mi nat i on.
( C) st eady-st at e pl asma dr ug concent rat i ons ar e r eached at appr oxi mat el y 10 hal f -
l i ves.
( D) earl y doses of drug do not af f ect subsequent doses.
( E) t he f r act i on of dr ug absorbed i s equal t o t he f r act i on of dr ug el i mi nat ed.
Vi ew Answer 21. The answer i s D[ see] . Cl For quest i ons 22- 24: A new
car di ac gl ycosi de i s devel oped f or or al and i nt ravenous admi ni st rat i on. The drug
has an el i mi nat i on hal f - l i f e ( t 1/ 2) of 24 hr and an appar ent vol ume of di st ri but i on (VD)
of 3 L/ kg. The ef f ect i ve dr ug concent rat i on i s 1. 5 ng/ mL. Toxi c ef f ect s of t he drug
ar e obser ved at dr ug concent r at i ons > 4 ng/ mL. The dr ug i s bound t o pl asma
pr ot ei ns at approxi mat el y 25%. The drug i s 75% bi oavai l abl e af t er an or al dose.
22. What i s the oraI mai nt enance dose, i f gi ven once a day, f or a 68- year- oI d
man who wei ghs 65 kg and has congesti ve heart f ai I ure ( CHF) and normaI renaI
f unct i on?
( A) 0. 125 mg
( B) 0. 180 mg
( C) 0. 203 mg
( D) 0. 270 mg
( E) 0. 333 mg
Vi ew Answer 22. The answer i s D[ see] . 23. What i s t he I oadi ng dose ( DL)
f or t hi s pati ent?
( A) 0. 270 mg
( B) 0. 293 mg
( C) 0. 450 mg
( D) 0. 498 mg
( E) 0. 540 mg
Vi ew Answer 23. The answer i s E[see] 24. I f the drug i s avai I abI e i n t abI et s
of 0. 125 mg and 0. 250 mg, what i s t he pat i ent ' s pI asma drug concent rat i on i f he
has a dosage regi men of 0. 125 mg ever y 12 hr?
( A) 1. 39 ng/ mL
( B) 1. 85 ng/ mL
( C) 2. 78 ng/ mL
( D) 3. 18 ng/ mL
( E) 6. 94 ng/ mL
Vi ew Answer 24. The answer i s A[ see] . DFVkFkVDFDkVCCDP. 141


Di rect i ons for quest i on 25: The quest i on i n t hi s sect i on can be cor r ect l y answer ed
by one or more of t he suggest ed answer s. Choose t he corr ect answer , A- E.
25. Whi ch equati on i s true f or a zero- order react i on rat e of a drug?

A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 25. The answer i s A[ see ] . At kAkt AtP. 142


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì . E. 2. a] .
A subst ance t hat i s used t o measure t he GFR must be f i l t er ed but not reabsorbed or
act i vel y secret ed. Al t hough i nul i n cl earance gi ves an accurat e measur ement of GFR,
cr eat i ni ne cl ear ance i s general l y used because no exogenous dr ug must be gi ven.
However , cr eat i ni ne f ormat i on depends on muscl e mass and muscl e met abol i sm,
whi ch may change wi t h age and vari ous di sease condi t i ons.
2. The answer i s C [ see Ì . B. 1. b. (2) ] .
3. The answer i s B [ see I . A. 1. b. (1) ; Ì . B. 1] .
4. The answer i s B [ see Ì . B. 1. a. (2) ] .
5. The answer i s B [ see Ì . B. 1. a. (2) ] .
Subst i t ut i ng t he dat a f or t hi s pat i ent i n t he equat i on f or t he i ni t i al pl asma dr ug
concent r at i on ( ) gi ves

To obt ai n t he pat i ent ' s pl asma dr ug concent r at i on ( Cp) 8 hr af t er t he dose, t he
f ol l owi ng cal cul at i on i s per f ormed:

The amount of drug i n t he pat i ent ' s body at 8 hr i s cal cul at ed as f ol l ows:
DB = CpVD = ( 1. 11) ( 0. 28)( 75) = 23. 3 mg
For any f i rst -or der el i mi nat i on process, 50% of t he i ni t i al amount of drug i s
el i mi nat ed at t he end of t he f i rst hal f - l i f e, and 50% of t he r emai ni ng dr ug ( i . e. , 75%
of t he or i gi nal amount ) i s el i mi nat ed at t he end of t he second hal f -l i f e. Because t he
dr ug i n t he cur r ent case has an el i mi nat i on hal f - l i f e ( t ½) of 2 hr , 75% of t he dose i s
el i mi nat ed i n t wo hal f - l i ves, or 4 hr .
6. The answer i s D [ see Ì . B. 3. e. (3) ] .
7. The answer i s C [ see Ì . B. 3. c] .
8. The answer i s E [ see Ì . B. 3. f . (2) ] .
9. The answer i s B [ see Ì . B. 3. e. (3) ] .
10. The answer i s D [ see Ì . B. 3. e. ( 3) ; Ì . E. 1. a] .
11. The answer i s B [ see Ì . E. 4. a] .
The equat i on f or t he pl asma concent r at i on at st eady st at e ( Cs s ) pr ovi des t he f ormul a
f or cal cul at i ng t he r at e of an i nt r avenous i nf usi on ( R) . The equat i on i s

wher e k i s t he f i rst -or der el i mi nat i on r at e const ant and VD i s t he apparent vol ume of
di st r i but i on. Rear r angi ng t he equat i on and subst i t ut i ng t he dat a f or t hi s pat i ent gi ve
t he f ol l owi ng cal cul at i ons:

P. 143


The t i me i t t akes f or an i nf used dr ug t o r each t he Cs s depends on t he el i mi nat i on
hal f - l i f e of t he dr ug. The t i me requi r ed t o r each 95% of t he Cs s i s equal t o 4. 3 t i mes
t he hal f - l i f e, wher eas t he t i me requi r ed t o r each 99% of t he Cs s i s equal t o 6. 6 t i mes
t he hal f - l i f e. Because t he hal f -l i f e i n t he cur rent case i s 1 hr, t he t i me t o r each 95%
of t he Cs s i s 4. 3 × 1 hr, or 4. 3 hr.
The l oadi ng dose ( DL) i s cal cul at ed as f ol l ows:

The answer t o quest i on 6 shows t hat t he i nf usi on r at e shoul d be 936 mg/ hr .
Ther ef ore, i f a dr ug sol ut i on cont ai ni ng 10 g i n 500 mL i s used, t he r equi red i nf usi on
r at e i s

The pat i ent ' s t ot al body cl ear ance ( Cl T) i s cal cul at ed as f ol l ows:

The hepat i c cl ear ance (Cl H) i s t he di f f er ence bet ween t ot al cl ear ance ( Cl T) and renal
cl ear ance ( Cl R):
Cl H = Cl T - Cl R
Cl H = 6237 - (86 mL/ mi n × 60 mi n/ hr ) = 1077 mL/ hr
12. The answer i s B [ see Ì . B. 1. b. ( 1) ] .
A l arge appar ent vol ume of di st r i but i on ( VD) i s an earl y si gn t hat a dr ug i s not
concent r at ed i n t he pl asma, but i s di st r i but ed wi del y i n t i ssue. An i ncrease i n
pl asma prot ei n bi ndi ng suggest s t hat t he drug i s l ocat ed i n t he pl asma r at her t han i n
t i ssue. A decr ease i n hepat i c met abol i sm, an i ncr ease i n si de ef f ect s, or a decr ease
i n ur i nar y excr et i on of f ree drug i s caused by a decr ease i n drug el i mi nat i on.
13. The answer i s A [ see Ì . A. 3. d. ( 3) ] .
As mor e dr ug i s concent r at ed at t he r ecept or si t e, mor e recept or s i nt er act wi t h t he
dr ug t o pr oduce a pharmacol ogi c ef f ect . The i nt ensi t y of t he r esponse i ncr eases
unt i l i t r eaches a maxi mum. When al l of t he avai l abl e r ecept ors ar e occupi ed by
dr ug mol ecul es, addi t i onal dr ug does not pr oduce a mor e i nt ense r esponse.
14. The answer i s B [ see Ì . D] .
Nonl i near pharmacoki net i cs i s a t erm used t o i ndi cat e t hat f i rst - order el i mi nat i on of
a dr ug does not occur at al l drug concent rat i ons. Wi t h some drugs, such as
phenyt oi n, as t he pl asma dr ug concent r at i on i ncreases, t he el i mi nat i on pat hway f or
met abol i sm of t he drug becomes sat ur at ed and t he hal f -l i f e i ncreases. The ar ea
under t he pl asma drug concent rat i on versus t i me cur ve ( AUC) of t he drug i s not
pr opor t i onal t o t he dose; nei t her i s t he rat e of met abol i t e f or mat i on. The met abol i c
r at e i s r el at ed t o t he ef f ect s of t he drug.
15. The answer i s D [ see Ì . B. 1. b. ( 2) ; Ì . B. 5. g. ( 1)] .
A l oadi ng dose ( DL) of a dr ug i s gi ven t o obt ai n a t her apeut i c pl asma drug l evel as
r api dl y as possi bl e. The DL i s cal cul at ed on t he basi s of t he appar ent vol ume of
di st r i but i on ( VD) and t he desi r ed pl asma l evel of t he drug.
16. The answer i s E [ see Ì . E. 3. c] .
Ì nul i n i s nei t her reabsorbed nor act i vel y secr et ed. Ther ef or e, i t i s excr et ed by
gl omerul ar f i l t rat i on onl y. The i nul i n cl earance rat e i s used as a st andard measure
of t he GFR, a t est t hat i s usef ul bot h i n a cl i ni cal si t uat i on and i n t he devel opment
of new dr ugs.
17. The answer i s E [ see Ì . A. 3. d] .
Dr ugs t hat ar e hi ghl y bound t o pl asma pr ot ei ns di f f use poor l y i nt o t i ssue and have a
l ow appar ent vol ume of di st r i but i on ( VD) .
18. The answer i s B [ see Ì . B. 3. g] .
The onset t i me i s t he t i me f r om t he admi ni st r at i on of t he dr ug t o t he t i me when
absor bed dr ug r eaches
P. 144

t he MEC. The MEC i s t he dr ug concent r at i on i n t he pl asma t hat i s pr oport i onal , but
not necessar i l y equal , t o t he mi ni mum dr ug concent r at i on at t he recept or si t e t hat
el i ci t s a pharmacol ogi c response.
19. The answer i s A [ see Ì . A. 3. a] .
The i ni t i al di st r i but i on of a drug i s chi ef l y det ermi ned by bl ood f l ow, wher eas t he
af f i ni t y of t he dr ug f or t i ssue det ermi nes whet her t he dr ug concent r at es at t hat si t e.
The GFR af f ect s t he r enal cl ear ance of a dr ug, not i t s i ni t i al di st r i but i on. The gast r i c
empt yi ng t i me and degr ee of pl asma pr ot ei n bi ndi ng af f ect dr ug di st ri but i on but are
l ess i mpor t ant t han t he rat e of bl ood f l ow t o t i ssue.
20. The answer i s C [ see Ì . E. 4. b. ( 2) ] .
The ki dney, l ung, ski n, and i nt est i ne al l have some capaci t y t o bi ot r ansf orm, or
met abol i ze, dr ugs; but t he br ai n has l i t t l e capaci t y f or drug met abol i sm. The l i ver
has t he hi ghest capaci t y f or drug met abol i sm.
21. The answer i s D [ see Ì . B. 5. c] .
The super posi t i on pr i nci pl e, whi ch underl i es t he desi gn of mul t i pl e- dose regi mens,
assumes t hat ear l i er dr ug doses do not af f ect subsequent doses. Ì f t he el i mi nat i on
r at e const ant or t ot al body cl ear ance of t he dr ug changes duri ng mul t i pl e dosi ng,
t hen t he super posi t i on pr i nci pl e i s no l onger val i d. Changes i n t he t ot al body
cl ear ance ( Cl T) may be caused by enzyme i nduct i on, enzyme i nhi bi t i on, or
sat ur at i on of an el i mi nat i on pat hway. Any of t hese changes woul d cause nonl i near
pharmacoki net i cs.
22. The answer i s D [ see Ì . B. 5. e. ( 3) ] .
23. The answer i s E [ see Ì . B. 5. g. ( 1) ]
24. The answer i s A [ see Ì . B. 5. d. ( 2) ; Ì . B. 5. e. ( 3)] .
The or al mai nt enance dose ( Do) shoul d mai nt ai n t he pat i ent ' s average drug
concent r at i on at t he ef f ect i ve dr ug concent r at i on. The bi oavai l abi l i t y of t he dr ug ( F) ,
t he appar ent vol ume of di st ri but i on ( VD), t he dosage i nt er val (¡) , and t he excr et i on
r at e const ant ( k) must be consi der ed i n cal cul at i ng t he dose. The equat i on used i s

For t hi s drug, F = 0. 75, k = 0. 693/ 24 hr , VD = 3 L/ kg × 65 kg, ¡ = 24 hr , and = 1. 5
ng/ mL, or 1. 5 µg/ L. Theref or e, by subst i t ut i on, Do = 270 µg, or 0. 270 mg. When t he
mai nt enance dose i s gi ven at a dosage f requency equal t o t he hal f - l i f e, t hen t he
l oadi ng dose i s equal t o t wi ce t he mai nt enance dose, i n t hi s case 540 µg, or 0. 540
mg. To det er mi ne t he pl asma dr ug concent r at i on f or a dosage r egi men of 0. 125 mg
ever y 12 hr , t he f ormul a i s used. Thi s t i me, F = 0. 75, Do = 0. 125 mg, k = 0. 693/ 24
hr , VD = 3 L/ kg × 65 kg, and ¡ = 12 hr . Ther ef or e, = 1. 39 ng/ mL. For car di ac
gl ycosi des, t he peak ( Cmax) and t rough ( Cmi n) concent r at i ons ar e cal cul at ed, and
pl asma drug concent rat i ons ar e moni t or ed af t er dosi ng. The l oadi ng dose ( DL) may
be gi ven i n smal l i ncrement s over a speci f i ed peri od, accor di ng t o t he dosage
r egi men suggest ed by t he manuf act urer .
25. The answer i s A ( Ì ) [ see Ì . A. 1. a] .
The f i rst equat i on i n t he quest i on descri bes a zero- or der react i on (dA/ dt ) i n whi ch
t he react i on rat e i ncr eases or decreases at a const ant rat e (k) . A zer o-or der
r eact i on pr oduces a gr aph of a st r ai ght l i ne wi t h t he equat i on of A = - kt + Ao when
A i s pl ot t ed agai nst t i me ( t ) . The ot her equat i ons i n t he quest i on repr esent f i rst -
or der r eact i ons.

7
BioavaiIabiIity and BioequivaIence
Leon ShargeI
I. BACKGROUND
A. Bi oavai I abi I i t y and bi oequi vaI ence st udi es ar e i mpor t ant f or t he devel opment
of bot h new dr ug product s ( new dr ug appl i cat i on [ NDA] ) and generi c dr ug pr oduct s
( abbrevi at ed new dr ug appl i cat i on [ ANDA] )
B. Bi oavai I abi I i t y st udi es are used f or est abl i shi ng dosage regi mens of new dr ug
pr oduct s
C. Bi oequi vaI ence st udi es can be usef ul duri ng t he i nvest i gat i onal new dr ug ( Ì ND)
devel opment or NDA devel opment peri od t o est abl i sh l i nks bet ween
1. Earl y and l at e cl i ni cal t r i al f or mul at i ons
2. For mul at i ons used i n cl i ni cal t ri al and st abi l i t y st udi es, i f di f f erent
3. Cl i ni cal t ri al f or mul at i ons and t o- be-mar ket ed dr ug pr oduct
D. Bi oequi vaI ence st udi es ar e a cr i t i cal component of ANDA submi ssi ons
1. The pur pose of t hese st udi es i s t o demonst rat e bi oequi val ence bet ween a
pharmaceut i cal l y equi val ent gener i c dr ug pr oduct and t he cor r espondi ng ref er ence
l i st ed dr ug (usual l y t he br and dr ug product ).
2. Toget her wi t h t he det er mi nat i on of pharmaceut i cal equi val ence, est abl i shi ng
bi oequi val ence al l ows a r egul at or y concl usi on of t her apeut i c equi val ence.
E. Scal e- up and post - approval changes ( SUPAC) ÷Af t er market appr oval , a drug
pr oduct may make a manuf act uri ng change. A bi oequi val ence st udy may be needed
t o show t hat t he new f ormul at i on or new met hod of manuf act ure ( t est product ) and
t he pr i or f or mul at i on or met hod of manuf act ur e (r ef erence pr oduct ) are equi val ent .
II. DEFINITIONS
1

A. Bi oavai I abi I i t y i s a measur ement of t he rat e and ext ent ( amount ) t o whi ch t he
act i ve i ngr edi ent or act i ve moi et y becomes avai l abl e at t he si t e of act i on.
Bi oavai l abi l i t y i s al so consi dered a measure of t he r at e and ext ent of t herapeut i cal l y
act i ve drug t hat i s syst emi cal l y absorbed. For drug product s t hat are not i nt ended t o
be absor bed i nt o t he bl oodst r eam, bi oavai l abi l i t y may be assessed by
measurement s i nt ended t o r ef l ect t he r at e and ext ent t o whi ch t he act i ve i ngr edi ent
or act i ve moi et y becomes avai l abl e at t he si t e of act i on.
B. Bi oequi vaI ent drug products. A generi c dr ug pr oduct i s consi der ed
bi oequi val ent t o t he ref erence I i sted drug ( RDL) product i f bot h pr oduct s are
pharmaceut i cal equi val ent s and t he gener i c drug pr oduct ' s rat e and ext ent of
syst emi c dr ug absorpt i on ( bi oavai l abi l i t y) do not show a st at i st i cal l y si gni f i cant
di f f er ence when admi ni st er ed i n t he same mol ar dose of t he act i ve i ngr edi ent , i n t he
same chemi cal f or m, i n a si mi l ar dosage f orm, by t he same rout e of admi ni st r at i on,
and under t he same exper i ment al condi t i ons. The RDL i s gener al l y t he brand
pr oduct .
P. 146


C. Generi c drug product
1. The gener i c drug pr oduct r equi res an abbrevi at ed new drug appI i cat i on ( ANDA)
f or approval by t he U. S. Food and Dr ug Admi ni st rat i on ( FDA) and may be market ed
af t er pat ent expi r at i on of t he r ef er ence dr ug pr oduct ( see Chapt er 1) .
2. The gener i c drug pr oduct must be a t herapeuti c equi vaI ent t o t he ref er ence dr ug
pr oduct but may di f f er i n cert ai n charact er i st i cs, i ncl udi ng shape, scor i ng
conf i gur at i on, packagi ng, and exci pi ent s (such as col ors, f l avors, pr eser vat i ves,
expi r at i on dat e, and mi nor aspect s of l abel i ng) .
3. FDA bel i eves t hat pr oduct s cl assi f i ed as t herapeut i cal l y equi val ent can be
subst i t ut ed wi t h t he f ul l expect at i on t hat t he subst i t ut ed pr oduct wi l l pr oduce t he
same cl i ni cal ef f ect and saf et y pr of i l e as t he pr escr i bed pr oduct .
D. Pharmaceut i caI equi vaI ent s ar e dr ug product s t hat cont ai n t he same
t her apeut i cal l y act i ve drug i ngredi ent (s) ; cont ai n t he same sal t , est er, or chemi cal
f or m; are of t he same dosage f or m; and ar e i dent i cal i n st r engt h, concent rat i on, and
r out e of admi ni st r at i on. Phar maceut i cal equi val ent s may di f f er i n char act er i st i cs
such as shape, scor i ng conf i gurat i on, r el ease mechani sms, packagi ng, and
exci pi ent s ( i ncl udi ng col or s, f l avor i ng, and pr eser vat i ves).
E. The ref erence I i st ed drug product i s usual l y t he cur rent l y mar ket ed, br and-
name product wi t h a f ul l new drug appI i cat i on (NDA) appr oved by t he FDA. The
RLD i s t he r ef er ence dr ug pr oduct i dent i f i ed by FDA ( see " El ect r oni c Or ange Book¨
at www. f da. gov/ cder / ob/ def aul t . ht m) .
F. Therapeut i c equi vaI ent drug product s ar e phar maceut i cal equi val ent s t hat can
be expect ed t o have t he same cl i ni cal ef f ect and saf et y pr of i l e when admi ni st er ed t o
pat i ent s under t he same condi t i ons speci f i ed i n t he l abel i ng. Therapeut i c equi val ent
dr ug pr oduct s have t he f ol l owi ng cr i t er i a:
1. The pr oduct s ar e saf e and ef f ect i ve.
2. The pr oduct s ar e pharmaceut i cal equi val ent s t hat cont ai n t he same act i ve dr ug
i ngredi ent i n t he same dosage f orm, gi ven by t he same r out e of admi ni st rat i on; meet
compendi al or ot her appl i cabl e st andards of st rengt h, qual i t y, pur i t y, and i dent i t y;
and meet an accept abl e i n vi t ro st andard.
3. The dr ug pr oduct s are bi oequi val ent i n t hat t hey do not pr esent a known pot ent i al
pr obl em and ar e shown t o meet an appr opri at e bi oequi val ence st andar d.
4. The dr ug pr oduct s are adequat el y l abel ed.
5. The dr ug pr oduct s are manuf act ur ed i n compl i ance wi t h cur rent good
manuf act ur i ng pract i ce regul at i ons.
G. Pharmaceut i caI aI t ernat i ves ar e dr ug product s t hat cont ai n t he same
t her apeut i c moi et y but are di f f erent sal t s, est ers, or compl exes (e. g. , t et r acycl i ne
hydr ochl or i de versus t et racycl i ne phosphat e) or ar e di f f erent dosage f orms ( e. g. ,
t abl et versus capsul e; i mmedi at e- r el ease dosage f or m ver sus cont r ol l ed- rel ease
dosage f orm) or st r engt hs.
III. BIOAVAILABILITY AND BIOEQUIVALENCE.
These may be det ermi ned di r ect l y usi ng phar macoki net i c st udi es ( e. g. , pl asma dr ug
concent r at i on versus t i me pr of i l es, uri nar y dr ug excr et i on st udi es), measur ement s of
an acut e pharmacodynami c ef f ect , compar at i ve cl i ni cal st udi es, or i n vi t ro st udi es.
The choi ce of st udy used i s based on t he si t e of act i on of t he drug and t he abi l i t y of
t he st udy desi gn t o compar e dr ug del i ver ed t o t hat si t e by t he t wo product s.
A. Acut e pharmacodynami c ef fect s, such as changes i n hear t r at e, bl ood
pr essure, el ect rocar di ogr am ( ECG) , cl ot t i ng t i me, or f or ced expi r at or y vol ume i n 1
sec ( FEV1) can be used t o measur e bi oavai l abi l i t y when no assay f or pl asma dr ug
concent r at i on i s avai l abl e or when t he pl asma drug concent r at i on does not r el at e t o
t he pharmacol ogi cal r esponse (e. g. , a bronchodi l at or
P. 147

such as al but er ol gi ven by i nhal at i on) . Quant i t at i on of t he pharmacol ogi cal ef f ect
ver sus t i me prof i l e can be used as a measur e of bi oavai l abi l i t y and/ or
bi oequi val ence ( Fi gur e 7- 1) .

Figure 7-1. Generalized plasma drug
concentration versus time curve aIter oral drug
administration. MEC. minimum eIIective
concentration; MTC. minimum toxic
concentration. |Adapted with permission Irom
Shargel L. Wu-Pong S. Yu ABC: Applied
Biopharmaceutics and Pharmacokinetics. 5th ed.
New York. McGraw-Hill. 2005. p. 6.|
1. Onset t i me. As t he drug i s syst emi cal l y absorbed, t he drug concent rat i on at t he
r ecept or r i ses t o a mi ni mum ef f ect i ve concent rat i on ( MEC) and a pharmacol ogi cal
r esponse i s i ni t i at ed. The t i me f r om dr ug admi ni st r at i on t o t he MEC i s known as t he
onset t i me.
2. I ntensi t y. The i nt ensi t y of t he pharmacol ogi cal ef f ect i s pr opor t i onal t o t he
number of recept or s occupi ed by t he dr ug up t o a maxi mum phar macol ogi cal ef f ect .
The maxi mum pharmacol ogi cal ef f ect may occur bef ore, af t er , or at peak dr ug
absor pt i on.
3. Durati on of act i on. As l ong as t he drug concent r at i on r emai ns above t he MEC,
pharmacol ogi cal act i vi t y i s obser ved. The dur at i on of act i on i s t he t i me f or whi ch t he
dr ug concent rat i on r emai ns above t he MEC.
4. Therapeut i c wi ndow. As t he dr ug concent r at i on i ncreases, ot her r ecept ors may
combi ne wi t h t he drug t o exer t a t oxi c or adver se r esponse. Thi s drug concent r at i on
i s t he mi ni mum t oxi c concent rat i on ( MTC) . The dr ug concent rat i on r ange bet ween
t he MEC and t he MTC i s t he t her apeut i c wi ndow.
B. PI asma drug concent rat i on. The pl asma drug concent r at i on ver sus t i me cur ve i s
most of t en used t o measur e t he syst emi c bi oavai l abi l i t y of a dr ug f rom a dr ug
pr oduct ( Fi gure 7-2) .
1. Ti me for peak pI asma drug concent rat i on ( Tma x) r el at es t o t he r at e const ant s
f or syst emi c dr ug absorpt i on and el i mi nat i on. Ì f t wo or al dr ug pr oduct s cont ai n t he
same amount of act i ve dr ug but di f f er ent exci pi ent s, t he dosage f orm t hat yi el ds t he
f ast er rat e of dr ug absorpt i on has t he shor t er Tmax.
2. Peak pI asma drug concent rat i on ( Cmax) . The pl asma drug concent rat i on at Tmax
r el at es t o t he i nt ensi t y of t he pharmacol ogi cal response. Ì deal l y, Cmax shoul d be
wi t hi n t he t herapeut i c wi ndow.
3. Area under t he pI asma drug concent rati on versus t i me curve ( AUC) r el at es t o
t he amount or ext ent of dr ug absorpt i on. The amount of syst emi c dr ug absor pt i on i s
di r ect l y r el at ed t o t he AUC. The AUC i s usual l y cal cul at ed by t he t rapezoi daI ruI e
and i s expr essed i n uni t s of concent r at i on mul t i pl i ed by t i me (e. g. , ) .
C. Uri nar y drug excret i on. Measurement of ur i nar y dr ug excr et i on can det ermi ne
bi oavai l abi l i t y f r om a dr ug pr oduct . Thi s met hod i s most accur at e i f t he act i ve
t her apeut i c moi et y i s excr et ed unchanged i n si gni f i cant quant i t y i n t he uri ne ( Fi gur e
7- 3) .
P. 148



Figure 7-2. Generalized plasma drug
concentration versus time curve. showing peak
time and peak concentration. AUC. area under the
curve; MEC. minimum eIIective concentration;
MTC. minimum toxic concentration. |Adapted
with permission Irom Shargel L. Wu-Pong S. Yu
ABC: Applied Biopharmaceutics and
Pharmacokinetics. 5th ed. New York. McGraw-
Hill. 2005. p. 7.|

Figure 7-3. These corresponding plots show the
relationship oI the plasma drug concentration
versus time curve to the cumulative amount oI
drug in the urine versus time curve. |Adapted
with permission Irom Shargel L. Wu-Pong S. Yu
ABC: Applied Biopharmaceutics and
Pharmacokinetics. 5th ed. New York. McGraw-
Hill. 2005. p. 463.|
P. 149


1. The cumuI at i ve amount of acti ve drug excret ed i n t he uri ne () i s di r ect l y
r el at ed t o t he ext ent of syst emi c dr ug absor pt i on.
2. The rate of drug excret i on i n the uri ne ( dDU/ dt ) i s di r ect l y r el at ed t o t he r at e of
syst emi c dr ug absorpt i on.
3. The t i me for t he drug t o be compI et eI y excret ed ( t
×
) cor responds t o t he t ot al
t i me f or t he dr ug t o be syst emi cal l y absorbed and compl et el y excr et ed af t er
admi ni st rat i on.
D. Comparat i ve cI i ni caI t ri aI s t o a dr ug can be used t o measure bi oavai l abi l i t y
quant i t at i vel y. Cl i ni cal st udi es ar e hi ghl y vari abl e and l ess preci se t han ot her
met hods because of i ndi vi dual di f f er ences i n dr ug phar macodynami cs and subj ect i ve
measurement s.
E. I n vi t ro measurement s of bi oequi vaI ence. Bi oequi val ence may somet i mes be
demonst r at ed usi ng an i n vi t r o bi oequi val ence st andar d, especi al l y when such an i n
vi t r o t est has been cor r el at ed wi t h human i n vi vo bi oavai l abi l i t y dat a. For exampl e,
t he rat e of dr ug di ssol ut i on i n vi t ro f or cer t ai n dr ug pr oduct s cor r el at es wi t h dr ug
bi oavai l abi l i t y i n vi vo. Ì f t he di ssol ut i on t est i n vi t r o i s consi der ed st at i st i cal l y
adequat e t o predi ct dr ug bi oavai l abi l i t y, t hen, i n some cases, di ssol ut i on may be
used i n pl ace of an i n vi vo bi oavai l abi l i t y st udy.
IV. RELATIVE AND ABSOLUTE BIOAVAILABILITY
A. ReI at i ve bi oavai I abi I i t y ( RBA) i s t he syst emi c avai l abi l i t y of t he dr ug f r om a
dosage f orm as compar ed t o a ref erence st andard gi ven by t he same r out e of
admi ni st rat i on. Rel at i ve bi oavai l abi l i t y i s cal cul at ed as t he r at i o of t he AUC f or t he
dosage f orm t o t he AUC f or t he ref erence dosage f orm gi ven i n t he same dose. A
r el at i ve bi oavai l abi l i t y of 1 ( or 100%) i mpl i es t hat dr ug bi oavai l abi l i t y f rom bot h
dosage f orms i s t he same but does not i ndi cat e t he compl et eness of syst emi c dr ug
absor pt i on. The det er mi nat i on of rel at i ve bi oavai l abi l i t y i s i mpor t ant i n gener i c dr ug
st udi es (e. g. , bi oequi val ence st udi es) . Bi oequi val ence i s a rel at i ve bi oavai l abi l i t y
st udy.

B. AbsoI ut e bi oavai I abi I i t y ( F) i s t he f r act i on of dr ug syst emi cal l y absorbed f rom
t he dosage f or m. F i s cal cul at ed as t he rat i o of t he AUC f or t he dosage f orm gi ven
or al l y t o t he AUC obt ai ned af t er i nt r avenous ( Ì V) dr ug admi ni st rat i on (adj ust ed f or
dose) . A parent er al drug sol ut i on gi ven by Ì V admi ni st r at i on i s consi dered t o have
100% syst emi c absor pt i on ( i . e. , F = 1) . An F val ue of 0. 80 (or 80%) i ndi cat es t hat
onl y 80% of t he dr ug was syst emi cal l y avai l abl e f r om t he oral dosage f orm.

V. BIOEQUIVALENCE STUDIES FOR SOLID ORAL DRUG
PRODUCTS
A. Obj ect i ve of bi oequi vaI ence st udi es. The obj ect i ve of a bi oequi val ence st udy i s
t o measure and compar e f ormul at i on per f ormance bet ween t wo or more
pharmaceut i cal l y equi val ent dr ug product s.
B. Desi gn of bi oequi vaI ence st udi es
1. The FDA' s Di vi si on of Bi oequi val ence, Of f i ce of Generi c Dr ugs pr ovi des gui dance
f or t he per f or mance of i n vi t r o di ssol ut i on and i n vi vo bi oequi val ence st udi es. These
gui dances ar e avai l abl e at www. f da. gov/ cder / gui dances.
2. Fast i ng study. Bi oequi val ence st udi es ar e usual l y eval uat ed by a si ngl e- dose,
t wo- per i od, t wo- t r eat ment , t wo- sequence, open- l abel , r andomi zed crossover desi gn,
compari ng equal doses of t he t est (gener i c) and ref er ence ( br and) pr oduct s i n
f ast ed, adul t , heal t hy subj ect s.
a. Bot h men and women may be used i n t he st udy.
b. Bl ood sampl i ng i s perf or med j ust bef ore t he dose ( zero t i me) and at appr opri at e
i nt er val s af t er t he dose t o obt ai n an adequat e descri pt i on of t he pl asma dr ug
concent r at i on versus t i me pr of i l e.
P. 150


3. Food i nt ervent i on study. Ì f t he bi oavai l abi l i t y of t he act i ve dr ug i ngr edi ent i s
known t o be af f ect ed by f ood, t he gener i c drug manuf act ur er must i ncl ude a si ngl e-
dose, randomi zed, crossover , f ood ef f ect s st udy compari ng equal doses of t he t est
pr oduct and r ef erence product s gi ven i mmedi at el y af t er a st andard hi gh- f at - cont ent
br eakf ast .
4. Ot her st udy desi gns. Cr ossover st udi es may not be pr act i cal i n drugs wi t h a
l ong hal f -l i f e i n t he body, and a paral l el st udy desi gn may be used i nst ead.
Al t ernat e st udy met hods, such as i n vi t r o st udi es or equi val ence st udi es wi t h cl i ni cal
or pharmacodynami c end poi nt s, ar e used f or dr ug pr oduct s wher e pl asma
concent r at i ons ar e not usef ul t o det er mi ne del i ver y of t he drug subst ance t o t he si t e
of act i vi t y ( such as i nhal er s, nasal spr ays, and t opi cal pr oduct s appl i ed t o t he ski n) .
5. Wai ver of an i n vi vo bi oequi vaI ence st udy ( Bi owai ver)
a. A compar at i ve i n vi t ro di ssol ut i on ( dr ug-r el ease) st udy bet ween t he t est and t he
r ef erence pr oduct s may be used i n l i eu of an i n vi vo bi oequi val ence st udy f or some
i mmedi at e- r el ease ( convent i onal ) or al drug pr oduct s.
b. No bi oequi val ence st udy i s r equi red f or cer t ai n dr ug product s gi ven as a sol ut i on
such as or al , par ent eral , opht hal mi c, or ot her sol ut i ons because bi oequi val ence i s
sel f - evi dent . Ì n t hi s case, t he drug i s i n a pur e aqueous sol ut i on and t her e i s no
dr ug di ssol ut i on rat e consi der at i on.
c. Ì mmedi at e r el ease ( Ì R) sol i d oral dr ug product s t hat meet bi opharmaceut i c
cl assi f i cat i on ( BCS) syst em cl ass 1 dr ugs, i . e. , hi ghl y wat er sol ubl e, r api dl y
di ssol vi ng, and rapi d permeat i on of cel l ul ar membr anes may obt ai n a bi owai ver .
d. Dr ug product s cont ai ni ng a l ower dose st rengt h ( e. g. , 200 mg, 100 mg, and 50 mg
Ì R t abl et s) . The drug pr oduct must be i n t he same dosage f orm, l ower st rengt h, and
i s pr opor t i onat el y si mi l ar i n i t s act i ve and i nact i ve i ngr edi ent s.
B. Pharmacoki net i c evaI uat i on of t he data. Phar macoki net i c anal ysi s i ncl udes
cal cul at i on f or each subj ect of t he AUC t o t he l ast quant i f i abl e concent r at i on ( AUCO-
t ) and t o i nf i ni t y ( AUC0- ×) , Tmax, and Cma x. Ì n addi t i on, t he el i mi nat i on r at e const ant
( k) , t he el i mi nat i on hal f - l i f e (t 1\ 2), and ot her par amet er s may be est i mat ed.
C. St at i st i caI evaI uati on of t he dat a
1. The st at i st i cal met hodol ogy f or anal yzi ng bi oequi val ence st udi es i s cal l ed t he t wo
one-si ded t est pr ocedur e. Two si t uat i ons ar e t est ed wi t h t hi s st at i st i cal
met hodol ogy.
a. The f i r st of t he t wo one- si ded t est s det er mi nes whet her a generi c product ( t est ) ,
when subst i t ut ed f or a brand-name pr oduct ( r ef erence) i s si gni f i cant l y l ess
bi oavai l abl e.
b. The second of t he t wo one-si ded t est s det er mi nes whet her a br and- name pr oduct
( r ef erence) when subst i t ut ed f or a gener i c product ( t est ) i s si gni f i cant l y l ess
bi oavai l abl e.
c. Based on t he opi ni ons of FDA medi cal exper t s, a di f f er ence of > 20% f or each of
t he above t est s was det er mi ned t o be si gni f i cant and, t her ef or e, undesi rabl e f or al l
dr ug pr oduct s.
2. An anal ysi s of vari ance ( ANOVA) shoul d be per f or med on t he l og t ransf or med
AUC and Cmax val ues obt ai ned f rom each subj ect . The 90% conf i dence i nt er val s f or
bot h phar macoki net i c par amet ers, AUC and Cma x, must be ent i r el y wi t hi n t he 80% t o
125% boundar i es based on l og t r ansf or mat i on of t he dat a. The rat i o of t he means of
t he st udy dat a (t est t o r ef er ence) shoul d l i e i n t he cent er of t he 90% conf i dence
i nt er val , or cl ose t o 100% ( equi val ent t o a t est t o r ef er ence r at i o of 1) ( Tabl e 7-1) .
3. Di f f erent st at i st i cal cr i t er i a are somet i mes used when bi oequi val ence i s
demonst r at ed t hrough comparat i ve cl i ni cal t r i al s, pharmacodynami c st udi es, or
comparat i ve i n vi t r o met hodol ogy.
4. The bi oequi val ence met hodol ogy and cri t eri a descr i bed above si mul t aneousl y
cont r ol f or bot h di f f er ences i n t he aver age response bet ween t est and r ef er ence
pr oduct s as wel l as t he pr eci si on wi t h whi ch t he aver age r esponse i n t he popul at i on
i s est i mat ed. Thi s pr eci si on depends on t he wi t hi n- subj ect ( nor mal vol unt eer or
pat i ent ) var i abi l i t y i n t he pharmacoki net i c paramet ers ( AUC and Cmax) of t he t wo
pr oduct s and on t he number of subj ect s i n t he st udy. The wi dt h of t he 90%
conf i dence i nt er val i s a ref l ect i on i n part of t he wi t hi n- subj ect var i abi l i t y of t he t est
and ref er ence pr oduct s i n t he bi oequi val ence st udy.
P. 151


Table 7-1. Bioavailability Comparison of a Generic (TEST) and Brand
(Reference) Drug Product
LN-Transformed Data

90 º
Confide
nce

Geometric Mean Interval
PK
Variabl
e Units Test
Referenc
e
º
Ratio
T/R
(Lower
Limit.
Upper
Limit)
P-
values
for
Product
Effects
Power
of
ANOV
A
ANOVA
º CV
C
ma
x

ng/
mL
344.
79
356.
81
96.
6
(89.
5.
112
)
0.3
586
0.8
791
17.9
0°
AU
C
0-t

ng
hr/
mL
265
9.12
267
4.92
99.
4
(95.
1.
104
)
0.8
172
1.0
000
12.6
0°
AU
C
inf

ng
hr/
mL
270
8.63
271
8.52
99.
6
(95.
4.
103
)
0.8
865
1.0
000
12.2
0°
T
ma
x
hr 4.29 4.24
10
1

k
eli
m

1/h
r
0.09
61
0.09
80
98.
1

t
1/2
hr 8.47 8.33
10
1.7
AUC. area under the curve; C
max
. peak plasma drug concentration; T
max
. time
Ior peak plasma drug concentration.
The results were obtained Irom a two-way crossover. single-dose. Iasting
study in 36 healthy adult volunteers. Mean values are reported. No statistical
diIIerences were observed between AUC and Cmax values Ior the test and
reIerence products.

P. 152


VI. BIOEQUIVALENCE ISSUES
A. ProbI ems i n det ermi ni ng bi oequi vaI ence i ncl ude l ack of an adequat e st udy
desi gn; i nabi l i t y t o accurat el y measur e t he dr ug anal yt es, i ncl udi ng met abol i t es and
enant i omer s ( chi r al drugs) ; and l ack of syst emi c dr ug absorpt i on ( Tabl e 7- 2. )
B. Bi oequi vaI ence st udi es f or whi ch obj ect i ve bl ood drug concent rat i ons cannot be
obt ai ned requi r e ei t her a pharmacodynami c st udy, a cl i ni cal t ri al , or an i n vi t r o
st udy t hat has been cor rel at ed wi t h human i n vi vo bi oavai l abi l i t y dat a.
1. Phar macodynami c measurement s ar e more di f f i cul t t o obt ai n, and t he dat a t end
t o be var i abl e, requi r i ng a l ar ger number of subj ect s compar ed t o t he
bi oequi val ence st udi es f or syst emi cal l y absorbed dr ugs.
a. A bi oequi val ence st udy usi ng pharmacodynami c measurement s t ri es t o obt ai n a
pharmacodynami c ef f ect ver sus t i me prof i l e f or t he dr ug i n each subj ect .
b. The area under t he ef f ect ver sus t i me pr of i l e, peak ef f ect , and t i me f or peak
ef f ect ar e obt ai ned f or t he t est and r ef er ence product s and are t hen st at i st i cal l y
anal yzed.
2. Compar at i ve cl i ni cal t r i al s ar e more di f f i cul t t o r un, do not have easi l y
quant i f i abl e obser vat i ons, and ar e qui t e cost l y.
3. Ì n vi t r o st udi es may r equi re t he devel opment of a r el i abl e sur r ogat e marker t hat
may be cor r el at ed wi t h human i n vi vo bi oavai l abi l i t y dat a. For exampl e, t he
penet r at i on of drug i nt o l ayer s of ski n wi t h r espect t o t i me
( der mat ophar macoki net i cs) has been suggest ed as a met hod f or measur i ng t he
bi oequi val ence of t opi cal dr ug product s i nt ended f or l ocal act i vi t y.
VII. DRUG PRODUCTION SELECTION
A. Generi c drug subst i tut i on
1. Generi c drug subst i tut i on i s t he process of di spensi ng a generi c dr ug pr oduct i n
pl ace of t he pr escr i bed dr ug pr oduct ( e. g. , generi c product f or br and- name pr oduct ,
gener i c product f or anot her gener i c product , brand- name product f or gener i c
pr oduct ) . The subst i t ut ed pr oduct must be a t herapeut i c equi val ent t o t he pr escri bed
pr oduct .
2. Gener i c dr ug pr oduct s t hat are cl assi f i ed as t her apeut i c equi val ent s by t he FDA
ar e expect ed t o pr oduce t he same cl i ni cal ef f ect and saf et y prof i l e as t he pr escri bed
dr ug.
Table 7-2. Problem Issues in the Determination of Bioequivalence
Problem Issues Example
Drugs with highly variable
bioavailability
a

Propranolol. verapamil
Drugs with active metabolites Selegiline
Chiral drugs IbuproIen. albuterol
Drugs with nonlinear
pharmacokinetics
Phenytoin
Orally administered drugs that are
not systemically absorbed
Cholestyramine resin. sucralIate
Drugs with long elimination halI-
lives
Probucol
Variable-dosage Iorms Dyazide. coniugated estrogens
Nonoral drug delivery
Topical drugs Steroids. antiIungals
Transdermal delivery systems Estrogen patch

Drugs given by inhalation
aerosols
Bronchodilators. steroids
Intranasal drugs Intranasal steroids
Biotechnology derived drugs Erythropoietin. interIeron
Bioavailable drugs that should not
reach peak drug levels
Potassium supplements. hormone
replacement therapy
Target population used in the
bioequivalence studies
Pediatric patients; renal disease
a
These drugs have high intrasubiect variability.

P. 153


3. Prescri babi I i t y r ef er s t o t he measur ement of aver age bi oequi val ence i n whi ch
t he compar i son of popul at i on means of t he t est and r ef erence pr oduct s f al l s wi t hi n
accept abl e st at i st i cal cr i t er i a. Prescr i babi l i t y i s t he cur rent basi s f or FDA approval
of t her apeut i c equi val ent gener i c dr ug pr oduct s.
4. Swi t chabi I i t y r ef er s t o t he measurement of i ndi vi dual bi oequi val ence, whi ch
r equi r es knowl edge of i ndi vi dual var i abi l i t y (i nt rasubj ect vari abi l i t y) and subj ect -by-
f or mul at i on ef f ect s. Swi t chabi l i t y ensur es t hat t he subst i t ut ed gener i c drug pr oduct
pr oduces t he same r esponse i n t he i ndi vi dual pat i ent .
B. Therapeut i c subst i t ut i on
1. Ther apeut i c subst i t ut i on i s t he pr ocess of di spensi ng a t herapeut i c al t er nat i ve i n
pl ace of t he pr escr i bed dr ug pr oduct . For exampl e, amoxi ci l l i n i s di spensed f or
ampi ci l l i n.
2. The subst i t ut ed dr ug pr oduct i s usual l y i n t he same t herapeut i c cl ass (e. g. ,
cal ci um channel bl ocker) and i s expect ed t o have a si mi l ar cl i ni cal prof i l e.
C. FormuI ar y i ssues
1. A formuI ar y i s a l i st of dr ugs. A posi ti ve f ormul ar y l i st s al l t he dr ugs t hat may be
subst i t ut ed, wher eas a negat i ve f ormul ar y l i st s dr ugs f or whi ch t he pharmaci st may
not subst i t ut e. A rest ri cti ve f ormul ar y l i st s onl y t hose drugs t hat may be rei mbursed
wi t hout j ust i f i cat i on by t he prescri ber; f or drugs not l i st ed i n t he rest r i ct i ve
f or mul ar y, t he prescr i ber must j ust i f y t he need f or t he nonl i st ed dr ug.
2. Many st at es have l egal requi r ement s t hat addr ess t he i ssue of dr ug product
sel ect i on. St at es may provi de i nf or mat i on and gui dance i n drug pr oduct sel ect i on
t hr ough posi t i ve, negat i ve, or r est r i ct i ve f or mul ari es.
3. The FDA annual l y publ i shes Appr oved Dr ug Product s wi t h Ther apeut i c
Equi val ence Eval uat i ons ( t he " Or ange Book¨ ) . Thi s publ i cat i on i s al so r epr oduced i n
t he Uni t ed St at es Phar macopei a ( USP), DÌ Vol . Ì Ì Ì , Appr oved Dr ug Pr oduct s and
Legal Requi r ement s, publ i shed annual l y by t he USP Convent i on. The " El ect r oni c
Or ange Book¨ may be f ound at ht t p: / / www. f da. gov/ cder / ob/ def aul t . ht m.
a. The " Or ange Book¨ provi des t her apeut i c eval uat i on codes f or dr ug product s
( Tabl e 7- 3) .
Table 7-3. Therapeutic Equivalence Evaluation Codes
A
Codes
Drug products that are considered to be therapeutically equivalent
to other pharmaceutically equivalent products
AA Products in conventional dosage Iorms not presenting
bioequivalence problems
AB Products meeting bioequivalence requirements
AN Solutions and powders Ior aerosolization
AO Iniectable oil solutions
AP Iniectable aqueous solutions
AT Topical products
B
Codes
Drug products that the FDA does not at this time consider to be
therapeutically equivalent to other pharmaceutically equivalent
products
BC Extended-release tablets. extended-release capsules. and extended-
release iniectables
BD Active ingredients and dosage Iorms with documented
bioequivalence problems
BE Delayed-release oral dosage Iorms
BN Products in aerosol-nebulizer drug delivery systems
BP Active ingredients and dosage Iorms with potential bioequivalence
problems
BR Suppositories or enemas Ior systemic use
BS Products with drug standard deIiciencies
BT Topical products with bioequivalence issues
BX InsuIIicient data
FDA. U.S. Food and Drug Administration.

P. 154


( 1) " A- " rat ed¨ drug pr oduct s ar e drug pr oduct s t hat cont ai n act i ve i ngr edi ent s and
dosage f orms t hat ar e not r egarded as present i ng ei t her act ual or pot ent i al
bi oequi val ence probl ems or drug qual i t y st andar ds i ssues. However , al l oral dosage
f or ms must meet an appropr i at e i n vi t r o bi oequi val ence st andar d t hat i s accept abl e
t o t he FDA t o be appr oved as t herapeut i cal l y equi val ent and may be i nt er changed.
( 2) " B" - rat ed¨ drug pr oduct s ar e drug pr oduct s f or whi ch act ual or pot ent i al
bi oequi val ence probl ems have not been resol ved by adequat e evi dence of
bi oequi val ence. These pr oduct s of t en have speci f i c dosage f or m probl ems r at her
t han a pr obl em wi t h t he act i ve i ngr edi ent s (e. g. , t wo di f f er ent ni cot i ne pat ches) . " B-
" r at ed¨ drug pr oduct s are not consi der ed t her apeut i cal l y equi val ent t o ot her
pharmaceut i cal l y equi val ent pr oduct s and are not i nt er changeabl e.
( 3) Cer t ai n product s pr esent speci al si t uat i ons t hat deser ve a mor e compl et e
expl anat i on t han can be pr ovi ded by t he t wo- codes used i n t he " Orange Book. ¨
These dr ugs have par t i cul ar pr obl ems wi t h st andar ds of i dent i t y, anal yt i cal
met hodol ogy, or bi oequi val ence t hat are consi der ed i ndi vi dual l y. For t hese dr ugs,
consul t t he " Or ange Book. ¨
b. For some drug pr oduct s, bi oequi val ence has not been est abl i shed or no generi c
pr oduct i s cur r ent l y avai l abl e.
4. Vari ous hospi t al s, i nst i t ut i ons, i nsurance pl ans, heal t h mai nt enance or gani zat i ons
( HMOs) , and ot her t hi r d-par t y pl ans may have a f or mul ar y t hat pr ovi des gui dance
f or drug pr oduct subst i t ut i on.
P. 155


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 3: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. The paramet ers used t o descri be bi oavai I abi I i t y are
( A) Cma x, AUC0- t , and AUC0- ×.
( B) Cma x, AUC0- t , AUC0- ×, and Tmax.
( C) Cma x, AUC0- t , AUC0- ×, and t 1\ 2.
( D) Cma x and AUC0- t .
( E) Cma x, AUC0- t , AUC0- ×, and Tmax, and t 1\ 2.
Vi ew Answer 1. The answer i s B[ see] . CTt 2. To det ermi ne t he absoI ute
bi oavai I abi I i t y of a drug gi ven as an oraI ext ended- reI ease t abI et , t he
bi oavai I abi I i t y of t he drug must be compared to t he bi oavai I abi I i t y of t he drug
f rom
( A) an i mmedi at e- rel ease or al t abl et cont ai ni ng t he same amount of act i ve
i ngredi ent .
( B) an or al sol ut i on of t he dr ug i n t he same dose.
( C) a par ent eral sol ut i on of t he dr ug gi ven by i nt ravenous (Ì V) bol us or Ì V i nf usi on.
( D) a r ef erence (br and) ext ended- rel ease t abl et t hat i s a phar maceut i cal equi val ent .
( E) an i mmedi at e- rel ease hard gel at i n capsul e cont ai ni ng t he same amount of act i ve
dr ug and l act ose.
Vi ew Answer 2. The answer i s C[ see] . F3. A si ngI e- dose, two-way
crossover, f ast i ng, comparati ve bi oavai I abi I i ty st udy was perf ormed i n 24
heaI thy, aduI t maI e subj ect s. PI asma drug concent rati ons were obt ai ned for
each subj ect , and the resuI ts shown i n Tabl e 7- Q3 were obt ai ned. The reI at i ve
bi oavai I abi I i t y of t he drug f rom t he generi c t abI et compared t o t he reference
t abI et i s
Table 7-Q3
Drug Product Dose (mg) C
max
(µg/mL)1
max
(hr)AUC
0-·
(µg hr/mL)
IV bolus iniection 100 1714
Oral solution 200 21.3 1.2 3143
Generic tablet 200 17.0 2.1 2822
ReIerence tablet 200 16.5 1.9 2715
IJ. intravenous.

( A) 82. 3%.
( B) 69. 8%.
( C) 91. 7%.
( D) 96. 2%.
( E) 103. 9%
Vi ew Answer 3. The answer i s E[see] . Di rect i ons f or questi ons 4-6: The
quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
P. 156


4. For two drug product s, generi c ( test ) and brand ( ref erence) , t o be
consi dered bi oequi vaI ent
I . t here shouI d be no stat i st i caI di f ference between t he ext ent of bi oavai I abi I i t y
of t he drug f rom t he t est product compared t o t he ref erence product .
I I . t he 90% conf i dence i nt ervaI s about t he rat i o of t he means of t he Cmax and
AUC vaI ues for t he t est product t o ref erence product must be wi t hi n 80%- 125%
of t he ref erence product .
I I I . there shouI d be no st at i st i caI di f f erences between t he mean Cmax and AUC
vaI ues for t he t est product compared t o t he reference product.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 4. The answer i s E[see] . TC5. For whi ch of t he f oI I owi ng
products i s measuri ng pI asma drug concent rat i ons not appropri ate for
est i mat i ng bi oequi vaI ence?
I . met ered- dose i nhaI er contai ni ng a bronchodi I at or
I I . ant i f ungaI agent for t he t reat ment of a vagi naI i nf ect i on
I I I . ent eri c- coat ed t abI et contai ni ng a nonsteroi daI ant i -i nf I ammat or y agent
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 5. The answer i s C[ see] . 6. Bi oequi vaI ence studi es compare
t he bi oavai I abi I i t y
I . of the generi c drug product t o t he brand drug product .
I I . of a ref ormuI at ed brand drug product t o the ori gi naI f ormuI ati on of t he brand
product.
I I I . of a t o- be- marketed brand product t o t he drug product used i n t he cI i ni caI
t ri aI s.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 6. The answer i s E[seeand] . P. 157


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì Ì Ì . B] .
AUC r el at es t o t he ext ent of dr ug absor pt i on. Cma x and Tmax r el at e t o t he rat e of
dr ug absorpt i on. The el i mi nat i on t 1/ 2 of t he drug i s usual l y i ndependent of t he r out e
of drug admi ni st r at i on and i s not used as a measur e of bi oavai l abi l i t y. For t he FDA,
onl y t he Cmax and AUC par amet er s must meet 90% conf i dence i nt er val s of 80-125%
of t he ref erence (br and) pr oduct ( Tabl e 7. 1) .
2. The answer i s C [ see Ì V. B] .
Af t er an Ì V bol us i nj ect i on or Ì V i nf usi on, al l t he dose i s absor bed i nt o t he body. The
r at i o of t he AUC of t he dr ug gi ven or al l y t o t he AUC of t he dr ug gi ven by Ì V i nj ect i on
i s used t o obt ai n t he absol ut e bi oavai l abi l i t y ( F) of t he drug.
3. The answer i s E [ see Ì V. A] .
The r el at i ve bi oavai l abi l i t y i s det er mi ned f rom t he r at i o of t he AUC of t he gener i c
( t est ) product t o t he AUC of t he ref erence st andar d. Thus t he rel at i ve bi oavai l abi l i t y
can exceed 100%, whereas t he absol ut e bi oavai l abi l i t y cannot exceed 100%.
4. The answer i s E [ see V. C] .
Al t hough Tmax i s an i ndi cat i on of r at e of dr ug absor pt i on, i t i s a di scr et e
measurement and usual l y t oo vari abl e t o use f or st at i st i cal compari sons i n
bi oequi val ence st udi es. St at i st i cal compar i sons use AUC and Cmax val ues f rom t est
and ref er ence dr ug product s as t he basi s of bi oequi val ence.
5. The answer i s C [ see V. A] .
Al t hough some syst emi c absor pt i on may be demonst rat ed af t er admi ni st eri ng a
met er ed dose i nhal er cont ai ni ng a bronchodi l at or or a vagi nal ant i f ungal agent ,
bi oequi val ence can be det ermi ned onl y by usi ng a cl i ni cal r esponse measur ement .
6. The answer i s E [ see Ì . A, B, C, D and E] .
Bi oequi val ence st udi es compar e t he bi oavai l abi l i t y of a dr ug f r om one drug pr oduct
t o anot her dr ug product cont ai ni ng t he same act i ve i ngredi ent . Dr ug pr oduct s such
as capsul es t hat ar e used i n cl i ni cal t r i al s shoul d be bi oequi val ent t o t he market ed
dr ug pr oduct whi ch may be a t abl et . Gener i c dr ug pr oduct s and t he cor respondi ng
br and drug pr oduct must be bi oequi val ent . For any change a f ormul at i on, t he
manuf act ur er (br and or generi c) must demonst r at e t hat t he f ormul at i on change does
not af f ect t he bi oavai l abi l i t y compared t o t he or i gi nal pr oduct .





8
FunctionaI Group Chemistry and Biochemistry
Marc W. HarroI d
I. FUNCTIONAL GROUP CHEMISTRY
A. I nt roduct i on. Drug mol ecul es can be vi ewed as a col l ect i on of f unct i onal gr oups
( i . e. , groups of at oms present wi t hi n t he dr ug t hat conf er speci f i c chemi cal and
physi cal proper t i es [ Fi gur e 8-1] ) . Funct i onal gr oups det er mi ne such charact eri st i cs
as i oni zat i on, sol ubi l i t y i n aqueous and l i pi d envi r onment s (aka pol ar i t y) , r eact i vi t y,
chemi cal st abi l i t y, and i n vi vo met abol i c st abi l i t y. Addi t i onal l y, t hese f unct i onal
gr oups ar e capabI e of formi ng speci fi c bonds ( pr i mar i l y noncoval ent ) wi t h t hei r
r ecept or s and are t hus ext r emel y i mport ant i n drug act i vi t y and pot ency.
1. Funct i onal groups t hat i mpar t hydrophi I i ci t y ar e l i kel y t o i ncr ease t he dr ug' s
wat er sol ubi l i t y, whi l e f unct i onal gr oups t hat i mpar t I i pophi I i ci t y ( hydr ophobi ci t y)
ar e l i kel y t o i ncrease t he dr ug' s t endency t o cr oss cel l ul ar membranes t hrough
passi ve di f f usi on. See Chapt er 12 VÌ Ì Ì B 1 f or a f ur t her di scussi on of wat er and l i pi d
sol ubi l i t y.
a. Aci di c and basi c f unct i onal gr oups al l ow f or drug i oni zat i on and, i n most cases,
i mpar t enhanced wat er sol ubi l i t y t o t he mol ecul e. One not abl e except i on t o t hi s i s
seen i n amphot eri c drugs ( i . e. , t hose compounds possessi ng bot h aci di c and basi c
f unct i onal groups). As exempl i f i ed by ampi ci l l i n i n Fi gur e 8- 2, amphot er i c
compounds can f orm zwi t t eri ons, or i nternaI saI t s. Si nce t he zwi t t eri on f or m of
ampi ci l l i n has a net overal l char ge of zer o, i t has di f f i cul t y di ssol vi ng i n aqueous
envi r onment s such as t he gast roi nt est i nal ( GÌ ) t ract .
b. Neut r al f unct i onal groups ( i . e. , t hose t hat ar e i ncapabl e of i oni zat i on) can
enhance ei t her wat er or l i pi d sol ubi l i t y dependi ng on t hei r abi l i t y t o f orm hydrogen
bonds wi t h water. Hydrogen bondi ng i s t he pr i mar y mechani sm f or i ncreasi ng t he
wat er sol ubi l i t y of nonel ect rol yt es (i . e. , compounds t hat do not possess aci di c,
basi c, or quat ernar y ammoni um f unct i onal groups) .
2. Funct i onal group react i vi t y af f ect s drug sheI f I i f e, stabi I i t y, and storage. Ther e
ar e a number of f unct i onal gr oups t hat wi l l degr ade, pr i mari l y t hr ough ai r oxi dat i on
and hydr ol ysi s, under normaI envi ronment aI condi t i ons. Two exampl es of t hi s
l at t er concern are seen wi t h aspi r i n and ni t r ogl ycer i n. Bot h compounds ar e subj ect
t o r api d hydrol ysi s i f exposed t o moi st envi r onment s.
3. Funct i onal groups al so af f ect i n vi vo st abi I i t y and t he dur at i on of dr ug act i on.
The suscept i bi l i t y of a gi ven dr ug t o met abol i c bi ot r ansf or mat i on depends i n par t
upon t he f unct i onal groups t hat are present ( see Chapt er 17 Ì Ì , Ì Ì Ì ) .
a. Dr ugs t hat cont ai n a l ar ge number or percent age of hydrophi l i c f unct i onal gr oups
ar e of t en el i mi nat ed f rom t he body unchanged or wi t h mi ni mal met abol i sm.
b. Dr ugs t hat cont ai n a l ar ge number or percent age of l i pophi l i c f unct i onal groups
of t en r equi r e ext ensi ve met abol i sm.

Figure 8-1. IbuproIen. a nonsteroidal anti-
inIlammatory agent. is comprised oI an ionizable.
hydrophilic carboxylic acid and three
hydrophobic Iunctional groups: an isobutyl alkyl
chain. an ethyl alkyl group. and an aromatic ring.
P. 159



Figure 8-2. Ampicillin is an amphoteric
compound. It contains an acidic carboxylic acid
and a basic amine and exists in vivo as a
zwitterion. The proton Irom the carboxylic acid
binds to the basic amine. producing a molecule
with an overall net charge equal to zero.
B. Aci di c f unct i onaI groups
1. Types. Shown i n Fi gur e 8-3 are exampl es of t he si x most common aci di c
f unct i onal groups. Ì n gener al , car boxyl i c aci ds t end t o be mor e aci di c t han any of
t he ot her f i ve f unct i onal gr oups. The t et r azol e ri ng pr ovi des t he best charge
del ocal i zat i on si nce r esonance al l ows t he charge t o be equal l y shared among al l
f i ve at oms i n t he r i ng.
2. Common at t ri but es
a. Aci di c f unct i onal gr oups i mpar t hydrophi I i ci t y t o a drug mol ecul e due t o t hei r
pot ent i al f or i oni zat i on.
b. Aci di c f unct i onal gr oups can f orm i oni c, i on- di poI e, and hydrogen bonds wi t h
r ecept or s, enzymes, t r ansport prot ei ns, and ot her macr omol ecul es.
c. Aci di c f unct i onal groups can f orm saI ts when combi ned wi t h bases.
d. CarboxyI i c aci ds ar e of t en est eri f i ed f or t he pur poses of pr odr ug f ormat i on ( see
Chapt er 17, sect i on VÌ f or addi t i onal i nf or mat i on). They can al so undergo aci d- or
enzymecat al yzed decarboxyI at i on r eact i ons.
e. Met aboI i sm. Aci di c f unct i onal gr oups can under go conj ugat i on wi t h gl ucuroni c
aci d, gl yci ne, and gl ut ami ne.

Figure 8-3. Examples oI drugs that contain an
acidic Iunctional group as part oI their chemical
structure.
P. 160


C. Basi c f unct i onaI groups
1. Types
a. AI i phati c and aI i cycI i c ami nes are t he most common basi c f unct i onal gr oups. As
shown i n Fi gure 8-4, t hese ami nes can be pri mar y, secondar y, or t ert i ar y,
dependi ng on t he number of subst i t uent s at t ached t o t he ni t r ogen.
b. Aromat i c ami nes, such as t hat seen i n procai nami de ( Fi gure 8-4) , ar e much l ess
basi c and f or al l i nt ent s and purposes can be consi dered neut r al .
c. Aromat i c, het erocycI i c ni t rogens var y i n t hei r basi ci t y, but i n general ar e much
l ess basi c t han al i phat i c and al i cycl i c ami nes ( Fi gur e 8- 5) .
d. Addi t i onal basi c f unct i onal groups i ncl ude i mi nes, hydrazi nes, ami di nes, and
guani di nes (Fi gur e 8- 6). Ì mi nes t end t o be l ess basi c t han al i phat i c and al i cycl i c
ami nes, wher eas guani di nes t end t o be much more basi c. The basi ci t y of t he ot her
t wo f unct i onal groups l i es somewher e i n bet ween.
2. Common at t ri but es
a. Basi c f unct i onal gr oups i mpar t hydrophi I i ci t y t o a dr ug mol ecul e due t o t hei r
pot ent i al f or i oni zat i on and t hei r abi l i t y t o f orm hydr ogen bonds.
b. Basi c f unct i onal groups can f orm i oni c, i on- di poI e, and hydrogen bonds wi t h
r ecept or s, enzymes, t r ansport prot ei ns, and ot her macr omol ecul es.
c. Basi c f unct i onal gr oups can f orm saI t s when combi ned wi th aci ds.
d. Met aboI i sm. Common met abol i c pat hways f or pr i mar y ami nes are oxi dat i ve
deami nati on, acet yI at i on, and N- oxi dat i on. Common pat hways f or secondar y and
t er t i ar y ami nes ar e acetyI at i on ( secondar y ami nes onl y) , oxi dat i ve N-deaI kyI at i on,
and N-oxi dat i on. Aromat i c ami nes can be acet yI at ed, whi l e ar omat i c het er ocycl i c
ni t rogens can under go N- oxi dat i on or N- deaI kyI at i on. Ì mi ne, hydr azi ne, ami di ne,
and guani di ne groups can undergo si mi l ar react i ons as t hose l i st ed f or pr i mar y,
secondar y, and t er t i ar y ami nes. Addi t i onal l y, ami nes can be gI ucuroni dat ed,
suI f ated, and met hyI at ed by phase I I conj ugati on r eact i ons.
D. Addi t i onaI hydrophi I i c f unct i onaI groups
1. Si mi l ar t o ami nes, hydroxyI groups (or aI cohoI s) may be cl assi f i ed as pri mar y,
secondar y, or t ert i ar y, dependi ng on t he number of subst i t uent s at t ached t o t hei r
r espect i ve carbons. A good exampl e of t hi s i s seen wi t h t he gl ucocor t i coi d
f l udr ocor t i sone ( Fi gure 8- 7) .
a. Hydr oxyl gr oups can f or m i on- di poI e and hydrogen bonds wi t h recept or s,
enzymes, t ransport prot ei ns, and ot her macr omol ecul es.

Figure 8-4. Examples oI drugs that contain a
primary. secondary. tertiary. or aromatic amine as
part oI their chemical structure. Whenever an
amine is part oI a nonaromatic ring (e.g..
ticlopidine). it is reIerred to as an alicyclic amine.
Whenever an amine amino is part oI a side chain
or is attached to a nonaromatic ring. it is reIerred
to as an aliphatic or alkyl amine. Whenever an
amine is directly attached to an aromatic ring
(e.g.. procainamide). it is reIerred to as an
aromatic amine.
P. 161



Figure 8-5. Examples oI drugs that contain
aromatic. heterocyclic nitrogens as part oI their
chemical structure.
b. Hydr oxyl gr oups enhance water soI ubi I i t y due t o t hei r abi l i t y t o f or m hydr ogen
bonds wi t h wat er.
c. Hydr oxyl gr oups ar e of t en esteri f i ed i n or der t o pr oduce pr odr ugs. See Chapt er
17 VÌ f or addi t i onal i nf ormat i on on pr odr ugs.
d. Met aboI i sm. Pr i mar y hydr oxyl gr oups are i ni t i al l y oxi di zed t o aI dehydes and
t hen t o carboxyI i c aci ds. Secondar y hydr oxyl gr oups are oxi di zed t o ket ones,
whi l e t ert i ar y hydr oxyl groups are not usual l y oxi di zed. Hydr oxyl gr oups may al so
under go phase I I gI ucuroni de or suI f at e conj ugat i on.

Figure 8-6. Examples oI drugs that contain a
basic imine. hydrazine. amidine. or guanidine
Iunctional group as part oI their chemical
structure.
P. 162



Figure 8-7. Examples oI drugs that contain a
hydroxyl group. phenol. catechol. or quaternary
ammonium Iunctional group as part oI their
chemical structure. Fludrocortisone contains a
primary. secondary. and tertiary hydroxyl group.
This designation is similar to that used Ior amines
and depends on the number oI substituents
attached to the respective carbons. As illustrated
with levodopa. a catechol is simply two phenol
groups that are ortho to one another.
2. PhenoI s, as exempl i f i ed by est radi ol ( Fi gure 8- 7) , ar e hydr oxyl gr oups t hat ar e
di r ect l y at t ached t o an ar omat i c r i ng.
a. Due t o r esonance st abi l i zat i on of t he ar omat i c r i ng, phenol s can be i oni zed i n
basi c envi ronment s; however , most phenol s ar e pri mari I y uni oni zed at
physi ol ogi cal pH and as such shoul d be t reat ed as neut raI , noni oni zabl e f unct i onal
gr oups.
b. Si mi l ar t o al cohol s, phenol s pri mar i l y f orm i on- di poI e and hydrogen bonds.
They can al so enhance water soI ubi I i t y and be est er i f i ed t o f orm pr odrugs (see
Chapt er 17 VÌ ).
c. Dr ug mol ecul es cont ai ni ng phenol s or catechoI s (see I evodopa i n Fi gur e 8-7)
ar e suscept i bl e t o ai r oxi dat i on and t o oxi dat i on on cont act wi t h f erri c i ons.
d. Met aboI i sm. Phenol s under go suI f at i on, gI ucuroni dat i on, aromati c
hydroxyI at i on, and O- met hyI at i on.
3. Quaternar y ammoni um saI t s, as exempl i f i ed by i pr at r opi um br omi de (Fi gur e 8-
7) , are nei t her aci di c nor basi c but cont ai n a permanent posi ti ve charge.
a. These sal t s enhance water soI ubi I i t y; however , due t o t he permanence of t he
posi t i ve char ge, compounds cont ai ni ng t hi s f unct i onal gr oup of t en have di f f i cuI t y
passi ng through I i pi d membranes.
b. Si mi l ar t o ami nes, quat er nar y ammoni um sal t s can par t i ci pat e i n i oni c and i on-
di poI e bonds.
c. Quat ernar y ammoni um sal t s are general l y not met abol i zed; however , N-
deaI kyI at i on coul d occur i n some cases.
E. Funct i onaI groups wi t h i ntermedi ate poI ari ty
1. Ketones are l ess pr eval ent t han al cohol s and phenol s i n t he st ruct ur es of dr ug
mol ecul es. One exampl e i s seen i n t he oral hypogl ycemi c agent , acet ohexami de,
shown i n Fi gure 8-8.
a. Ket ones ar e pr i mar i l y l i pi d sol ubl e; however , t hey ar e abl e t o f orm hydrogen
bonds wi t h al cohol s and cert ai n ami nes. They can al so f orm i on- di poI e bonds.
P. 163



Figure 8-8. Examples oI drugs that contain a
ketone. ester. amide. lactone. or lactam as part oI
their chemical structure.
b. Met aboI i sm. Ket ones ar e ver y st abl e. Thei r pr i mar y r out e of met abol i sm i s
reducti on to an aI cohoI .
2. Compounds cont ai ni ng esters, ami des and t hei r respect i ve cycl i c f orms,
I act ones, and I act ams can be seen i n Fi gure 8- 8.
a. These f unct i onal gr oups ar e capabl e of f ormi ng hydrogen bonds wi t h r ecept or s,
enzymes, t ransport prot ei ns, ot her macromol ecul es, and wat er . Si mi l ar t o ket ones,
est er s and l act ones can f unct i on as hydrogen- bond accept ors, whi l e ami des and
l act ams can f unct i on as ei t her hydrogen- bond donors or accept ors.
b. Met aboI i sm. Enzymat i c hydroI ysi s i s t he pri mar y r out e of met abol i sm f or t hese
f unct i onal groups. Est ers and l act ones ar e hydr ol yzed t o al cohol s and carboxyl i c
aci ds, whi l e ami des and l act ams ar e hydr ol yzed t o ami nes and car boxyl i c aci ds.
Est ers and l act ones ar e mor e suscept i bl e t o hydrol ysi s t han are ami des and
l act ams. Addi t i onal l y, some l act ams may under go N- deaI kyI at i on pri or t o or i n pl ace
of hydrol yt i c cl eavage.
F. Li pophi I i c f unct i onaI groups
1. AI kyI groups are saturat ed hydrocarbon chai ns, I i nks, and ri ngs t hat can var y
i n si ze f r om si ngl e-carbon methyI and met hyI ene gr oups t o l arge chai ns. Si mi l ar t o
t he desi gnat i ons pr evi ousl y gi ven f or ami nes, t he desi gnat i on aI i cycI i c r ef er s t o
al kyl gr oups t hat ar e part of a nonar omat i c ri ng, whi l e t he desi gnat i on aI i phat i c
r ef ers t o t hose t hat ar e par t of a si de chai n or t hat f unct i on t o connect , or br i dge,
ot her f unct i onal groups. Exampl es of al kyl gr oups are i l l ust rat ed i n Fi gure 8- 9.
a. Al kyl gr oups can par t i ci pat e i n van der WaaI s i nt eract i ons (i . e. , i nduced di pol e-
i nduced di pol e bonds) and hydrophobi c bondi ng.
b. Met aboI i sm. Oxi dat i on i s t he maj or rout e of met abol i sm. Al kyl si de chai ns ar e
usual l y oxi di zed at ei t her t he t ermi naI ( o) or penuI t i mat e ( m- 1) carbon at oms.
2. AI kenes, al so known as oI ef i ns, ar e unsat urat ed anal ogs of al kyl gr oups (see
Fi gur e 8- 9) .
a. The bi ndi ng abi l i t y of al kenes i s si mi l ar t o t hat of sat ur at ed al kyl groups.
P. 164



Figure 8-9. Examples oI drugs that contain alkyl
groups and alkenes as part oI their chemical
structure. For the sake oI clarity. only certain
Iunctional groups have been highlighted.
b. Met aboI i sm. Al kenes ar e somewhat more r eact i ve t han al kyl gr oups and ar e
subj ect t o met abol i c hydrat i on, epoxi dat i on, peroxi dat i on, and reduct i on.
3. Most aromati c hydrocarbons ar e anal ogs of ei t her benzene or naphthaI ene
( see Fi gure 8-10 f or exampl es). When at t ached t o a dr ug mol ecul e, benzene i s
r ef er red t o as a phenyI group.
a. Si mi l ar t o al kyl groups and al kenes, ar omat i c hydr ocarbons can par t i ci pat e i n van
der WaaI s i nteracti ons and hydrophobi c bondi ng. Addi t i onal l y, aromat i c r i ngs can
par t i ci pat e i n charge- t ransf er i nt eract i ons. El ect r on- ri ch aromat i c ri ngs (i . e. , t hose
wi t h el ect ron- donat i ng groups) can f orm di pol e- l i ke i nt er act i ons wi t h el ect ron- poor
ar omat i c ri ngs (i . e. , t hose wi t h el ect r on- wi t hdrawi ng groups) .
b. Met aboI i sm. Oxi dat i on i s t he pr i mar y r out e of met abol i sm f or ar omat i c
hydr ocar bons, wi t h hydr oxyI at i on, epoxi dat i on, and di oI f ormat i on compr i si ng t he
t hr ee most common pat hways.
4. Et her f unct i onal groups cont ai n an oxygen at om bound on bot h si des by ei t her
al kyl or ar omat i c car bons. They can be pr esent as ei t her a t ermi nal f unct i onal
gr oup, such as t he methoxy group of napr oxen, or as par t of a cent ral
chai n/ backbone, such as t hat seen i n gemf i brozi l ( Fi gur e 8- 10) .
a. The cont r i but i on of et her s t o dr ug bi ndi ng i s mi ni mal ; however , t hese f unct i onal
gr oups can par t i ci pat e i n di poI e- i nduced di poI e i nt eract i ons and can ser ve as
hydrogen- bond accept ors.
b. Met aboI i sm. Met hyl and et hyl et her s can under go O- deaI kyI at i on, whi l e t hose
l ar ger do not gener al l y undergo met abol i sm. Whi l e et hers used as organi c sol vent s
( e. g. , di et hyl et her ) can f or m peroxi des and may expI ode, t hi s propert y i s general l y
not pr esent i n drug mol ecul es.
5. AI kyI and aromat i c haI i des ar e eI ect ron-wi thdrawi ng f unct i onal gr oups. They
ar e of t en used t o " l ock¨ a dr ug mol ecul e i n a desi r ed conf or mat i on and/ or t o
decrease ar omat i c oxi dat i on of t he drug. Fl uor i ne i s t he smal l est hal ogen, wi t h i t s
si ze ver y si mi l ar t o t hat of hydrogen. Chl ori ne i s t he second smal l est , f ol l owed by
br omi ne and i odi ne, r espect i vel y. See Fi gur e 8- 10 f or speci f i c exampl es.
P. 165



Figure 8-10. Examples oI drugs that contain an
aromatic hydrocarbon. ether. and/or alkyl or
aromatic halide as part oI their chemical structure.
For the sake oI clarity. only certain Iunctional
groups have been highlighted.
a. Wi t h t he except i on of f l uor i ne, whi ch can ser ve as a hydrogen- bond accept or,
hal i des do not di rect l y par t i ci pat e i n t he bi ndi ng of drugs t o t hei r r ecept ors or ot her
macr omol ecul es.
b. Met aboI i sm. Ar omat i c hal i des ar e not nor mal l y met abol i zed. Al kyl hal i des can
under go oxi dat i ve dehaI ogenat i on t o f orm al dehydes.
II. BIOCHEMISTRY
A. I nt roduct i on. Bi ochemi st r y i s t he st udy of chemi cal pri nci pl es t hat suppor t l i f e
pr ocesses. Ì t i nf l uences dr ug met abol i sm, t herapeut i c ef f ect i veness, and
bi ot r ansf or mat i on. Bi ochemi cal l y si gni f i cant mol ecul es i ncl ude ami no aci ds,
car bohydrat es, l i pi ds, pyr i mi di nes, pur i nes, and bi opol ymer s÷pr ot ei ns and
enzymes, whi ch are bui l t f r om ami no aci ds; pol ysacchari des, whi ch ar e bui l t f r om
car bohydrat es; and nucl ei c aci ds, whi ch ar e bui l t f r om pyr i mi di nes and pur i nes.
B. Ami no aci ds ar e t he monomer i c uni t s of pr ot ei ns and enzymes and have t he
f ol l owi ng gener al f ormul a:

1. Wi t h t he except i on of gl yci ne, nat ur al l y occur ri ng ami no aci ds are L, q-ami no
aci ds. Pr ot ei ns ar e made up of t he 20 di f f er ent ami no aci ds, whi ch di f f er i n t he si de
chai n ( R) at t ached t o
P. 166

t he q-car bon. The 20 di f f er ent si de chai ns var y i n si ze, shape, char ge, hydr ogen-
bondi ng capaci t y, and chemi cal r eact i vi t y. A prot ei n can be hydr ol yzed i nt o i t s
component q- ami no aci ds by aci ds, bases, or enzymes.
a. Ami no aci ds wi t h aci di c si de chai ns i ncl ude aspart i c aci d and gl ut ami c aci d.
b. Ami no aci ds wi t h basi c si de chai ns i ncl ude argi ni ne, l ysi ne, and hi st ami ne.
c. Ami no aci ds wi t h poI ar, noni oni c si de chai ns i ncl ude gl yci ne, ser i ne, cyst ei ne,
t hr eoni ne, t yr osi ne, aspar agi ne, and gl ut ami ne.
d. Ami no aci ds wi t h nonpoI ar, hydrophobi c si de chai ns i ncl ude al ani ne, val i ne,
l euci ne, i sol euci ne, phenyl al ani ne, met hi oni ne, prol i ne, and t r ypt ophan.
2. Ami no aci ds have a zwi t teri on st ruct ure, whi ch account s f or t hei r hi gh mel t i ng
poi nt and l ow wat er sol ubi l i t y. Ami no aci ds i n sol ut i on have t he f ol l owi ng gener al
f or mul a:

3. I oni zat i on of ami no aci ds t o t he zwi t t eri on f orm or ot her f orms depends on pH
( Fi gur e 8- 11) .
C. Carbohydrat es. These ar e pol yhydr oxy al dehydes or ket ones. Thr ee maj or
cl asses of car bohydr at es exi st .
1. Monosacchari des ( si mpl e sugar s), such as gl ucose or f r uct ose, consi st of a
si ngl e pol yhydr oxy al dehyde or ket one uni t .
a. AI dehydi c monosacchar i des ar e r educi ng sugar s.
b. Monosacchari des can be l i nked t oget her by gI ycosi di c bonds, whi ch are
hydr ol yzed by aci ds but not by bases.
2. OI i gosacchari des, such as sucr ose, mal t ose, and l act ose, consi st of shor t
chai ns of monosacchari des j oi ned coval ent l y.
a. Sucrose cannot be absor bed by t he i nt est i ne unt i l i t i s conver t ed by sucr ase i nt o
i t s component s, gl ucose and f r uct ose.
b. MaI t ose i s hydr ol yzed by mal t ase i nt o t wo mol ecul es of gl ucose.
c. Lact ose ( or mi l k sugar ) cannot be absor bed by t he i nt est i ne unt i l i t i s convert ed
by l act ase i nt o i t s component s, gal act ose and gl ucose.
3. PoI ysacchari des, such as ceI I uI ose and gI ycogen, consi st of l ong chai ns of
monosacchar i des.
D. Pyri mi di nes and puri nes. These are bases t hat , when bonded wi t h ri bose, f or m
nucl eosi des, whi ch when subsequent l y bonded t o phosphori c aci d f orm
nucl eot i des÷t he st r uct ural bui l di ng bl ocks of nucl ei c aci ds.
1. Pyri mi di ne bases i ncl ude:
a. Cyt osi ne ( C) , f ound i n deoxyr i bonucl ei c aci d (DNA) and r i bonucl ei c aci d ( RNA)
b. Uraci I ( U) , f ound i n RNA onl y
c. Thymi ne ( T) , f ound i n DNA onl y

Figure 8-11. Amino acid ionization in solution.
The carboxyl and amino groups are either in
ionized or unionized Iorm depending on the pH oI
the solution.
P. 167


2. Puri ne bases i ncl ude:
a. Adeni ne ( A) , f ound i n DNA and RNA
b. Guani ne ( G) , f ound i n DNA and RNA
3. Pyr i mi di nes and pur i nes exhi bi t taut omeri sm ( a f orm of st ereoi somer i sm) and
can exi st i n ei t her ket o (l act am) or enoI (l act i m) f or ms.
E. Bi opoI ymers
1. Protei ns are pol ymers of ami no aci ds t hat ar e l i nked t oget her by pept i de bonds
( i . e. , l i nks bet ween car bonyl car bons and ami no ni t rogens [ Fi gure 8-12] ). Pr ot ei ns
have f our st ruct ur al l evel s.
a. Pri mar y st r uct ur e r ef er s t o t he sequence of ami no aci ds and l ocat i on of di sul f i de
bonds i n t he pr ot ei n.
b. Secondar y st r uct ur e ref ers t o t he spat i al arr angement of sequenced ami no aci ds
( f or exampl e, q- conf ormat i on [ hel i cal coi l ] or 8-conf ormat i on [ pl eat ed sheet ] ) .
c. Tert i ar y st r uct ure ref er s t o t he t hr ee- di mensi onal st ruct ur e of a si ngl e pr ot ei n.
d. Quaternar y st r uct ure r ef ers t o t he ar r angement of i ndi vi dual subuni t chai ns i nt o
compl ex mol ecul es.
2. Enzymes ar e pr ot ei ns capabl e of act i ng as cat al yst s f or bi ol ogi c r eact i ons. They
may be si mpl e or compl ex and may r equi r e cof act or s or coenzymes f or bi ol ogi c
act i vi t y.
a. An enzyme enhances t he rat e of a speci f i c chemi cal r eact i on by l ower i ng t he
act i vat i on energy of t he r eact i on. Ì t does not change t he r eact i on' s equi l i br i um
poi nt , and i t i s not used up or per manent l y changed by t he r eact i on.
b. A cof act or may be an i norgani c component (usual l y a met al i on) or a
nonprotei n organi c moI ecuI e. A cof act or may be bi ol ogi cal l y i nact i ve wi t hout an
apoenzyme (t he pr ot ei n por t i on of a compl ex enzyme) . A cof act or f i rml y bound t o
t he apoenzyme i s cal l ed a prost het i c group. An or gani c cof act or t hat i s not f i r ml y
bound but i s act i vel y i nvol ved duri ng cat al ysi s i s cal l ed a coenzyme.
c. A compl et e, cat al yt i cal l y act i ve enzyme syst em i s r ef er r ed t o as a hoI oenzyme.
d. Enzymes f al l i nt o si x maj or cl asses.
( 1) Oxi doreduct ases ( e. g. , dehydrogenases, oxi dases, per oxi dases) ar e i mpor t ant
i n t he oxi dat i ve met abol i sm of dr ugs.
( 2) Transf erases cat al yze t he t r ansf er of groups, such as phosphat e and ami no
gr oups.
( 3) HydroI ases ( e. g. , prot eol yt i c enzymes, amyl ases, est er ases) hydr ol yze t hei r
subst rat es.
( 4) Lyases ( e. g. , decar boxyl ases, deami nases) cat al yze t he r emoval of f unct i onal
gr oups by means ot her t han hydr ol ysi s.
( 5) Li gases (e. g. , DNA l i gase, whi ch bi nds nucl eot i des t oget her duri ng DNA
synt hesi s) cat al yze t he coupl i ng of t wo mol ecul es.
( 6) I somerases cat al yze var i ous i somer i zat i ons, such as t he change f r om D t o L
f or ms or t he change f r om ci si somer s t o t r ansi somers.
3. PoI ysacchari des (al so cal l ed gl ycans) are l ong- chai n pol ymer s of carbohydr at es
and may be l i near or br anched. They ar e cl assi f i ed as homopol ysacchar i des or
het eropol ysacchar i des.
a. HomopoI ysacchari des ( e. g. , st ar ch, gl ycogen, cel l ul ose) cont ai n onl y one t ype
of monomer i c uni t .
( 1) St arch (a r eser ve f ood mat er i al of pl ant s) i s composed of t wo gl ucose
pol ymer s÷amyl ose (l i near and wat er sol ubl e) and amyl opect i n ( hi ghl y branched and
wat er i nsol ubl e) . Ì t yi el ds mai nl y mal t ose ( a gl ucose di sacchari de) af t er enzymat i c
hydr ol ysi s wi t h sal i var y or pancr eat i c amyl ase; onl y gl ucose af t er compl et e
hydr ol ysi s by st r ong aci ds.

Figure 8-12. Peptide bond Iormation occurs as a
result oI the condensation oI the carboxyl group
oI one amino acid with the amino group oI
another. Water is eliminated during this process.
P. 168


( 2) GI ycogen, l i ke amyl opect i n, i s a hi ghl y br anched, compact chai n of D- gl ucose.
The mai n st or age pol ysacchar i de of ani mal cel l s, i t i s f ound most l y i n l i ver and
muscl e and can be hydrol yzed by sal i var y or pancr eat i c amyl ase i nt o mal t ose and
D- gl ucose.
( 3) CeI I uI ose (a wat er -i nsol ubl e st r uct ur al pol ysacchar i de f ound i n pl ant cel l wal l s)
i s a l i near , unbr anched chai n of D- gl ucose. Ì t cannot be di gest ed by humans
because t he human i nt est i nal t ract secret es no enzyme capabl e of hydr ol yzi ng i t .
b. HeteropoI ysacchari des ( e. g. , hepari n, hyal uroni c aci d) cont ai n t wo or more
t ypes of monomer i c uni t s.
( 1) Hepari n (an aci d mucopol ysacchar i de) consi st s of sul f at e deri vat i ves of D-
gl ucuronat e, D-gl ucosami ne and L-i duronat e. Ì t can be i sol at ed f r om l ung t i ssue and
i s used medi cal l y t o pr event bl ood cl ot f ormat i on.
( 2) HyaI uroni c aci d, a component of bact eri al cel l wal l s as wel l as of t he vi t r eous
humor and synovi al f l ui d, consi st s of al t er nat i ng uni t s of N- acet yl - D- gl ucosami ne
and N-acet yl -mur ami c aci d.
4. NucI ei c aci ds are l i near pol ymer s of nucl eot i des÷pyr i mi di ne and pur i ne bases
l i nked t o r i bose or deoxyr i bose sugars (nucl eosi des) and bound t o phosphat e
gr oups. The backbone of t he nucl ei c aci d consi st s of al t ernat i ng phosphat e and
pent ose uni t s wi t h a pur i ne or pyr i mi di ne base at t ached t o each.
a. Nucl ei c aci ds ar e cl osel y associ at ed wi t h ceI I uI ar cat i ons and such basi c
pr ot ei ns as hi stones and protami nes.
b. The t wo mai n t ypes of nucl ei c aci ds ar e DNA and RNA. RNA exi st s i n t hr ee
f or ms.
( 1) Ri bosomaI RNA ( r RNA) f unct i ons as a f ramewor k t o bi nd bot h messenger and
t r ansf er RNA. Ì t i s compri sed of numer ous subuni t s wi t h t he 40S and 60S bei ng t he
most wel l known.
( 2) Messenger RNA (mRNA) ser ves as t he t empl at e f or pr ot ei n synt hesi s and
speci f i es a pol ypept i de' s ami no aci d sequence.
( 3) Transf er RNA ( t RNA) carr i es act i vat ed ami no aci ds t o t he r i bosomes, wher e t he
ami no aci ds are i ncor porat ed i nt o t he gr owi ng pol ypept i de chai n.
c. Ì n bot h DNA and RNA, t he successi ve nucl eot i des ar e j oi ned by phosphodi est er
bonds bet ween t he 5' - hydr oxy gr oup of one nucl eot i de' s pent ose and t he 3' - hydr oxy
gr oup of t he next nucl eot i de' s pent ose.
d. DNA di f f er s f r om RNA i n t hat i t I acks a hydroxyI group at t he pent ose' s C2'
posi t i on, and i t cont ai ns T r at her t han U.
e. DNA st r uct ur e consi st s of t wo q- hel i cal DNA st r ands coi l ed around t he same axi s
t o f or m a doubl e hel i x. The st r ands are ant i paral l el ÷t he 5' , 3' -i nt er nucl eot i de
phosphodi est er l i nks run i n opposi t e di rect i ons.
( 1) Hydrogen bondi ng bet ween speci f i c base pai r s A- T and C- G hol ds t he t wo DNA
st r ands t oget her. The st rands are compl ement ar y ( t he base sequence of one st r and
det ermi nes t he base sequence of t he ot her ) .
( 2) The hydrophobi c bases ar e on t he i nsi de of t he hel i x; t he hydr ophi l i c
deoxyr i bose- phosphat e backbone i s on t he out si de.
III. BIOCHEMICAL METABOLISM
A. Over vi ew. Bi ochemi cal met abol i sm i s t he revi ew of pat hways t hat l ead t o t he
synt hesi s or br eakdown of compounds i mpor t ant t o t he l i f e of an or gani sm.
1. Cont roI of met aboI i sm. Met abol i sm i s cont rol l ed by subst r at e concent r at i on,
enzymes ( const i t ut i ve or i nduced) , al l ost er i c ( r egul at or y) enzymes, hor mones, and
compart ment at i on.
2. CataboI i sm i s t he sum of degr adat i on r eact i ons t hat usual l y r el ease ener gy f or
usef ul wor k ( e. g. , mechani cal , osmot i c, bi osynt het i c).
3. AnaboI i sm i s t he sum of bi osynt het i c (bui l d-up) r eact i ons t hat consume energy t o
f or m new bi ochemi cal compounds (met abol i t es) .
4. Amphi boI i c pathways ar e t hose t hat may be used f or bot h cat abol i c as wel l as
anabol i c purposes. Krebs cycI e br eaks down met abol i t es pri mar i l y t o rel ease 90%
of t he t ot al energy of an or gani sm. Ì t al so dr aws of f met abol i t es t o f orm compounds
such as ami no aci ds (e. g. , aspar t i c, gl ut ami c, al ani ne) . Hemogl obi n has i t s heme
moi et y f or med f rom succi nyl coenzyme A (succi nyl CoA) and gl yci ne f ol l owed by a
compl ex set of r eact i ons.
P. 169


B. Bi oenergeti cs
1. Subst rate I eveI phosphor yI at i on ent ai l s t he f or mat i on of one uni t of adenosi ne
t r i phosphat e ( ATP) per uni t of met abol i t e t ransf ormed ( e. g. , succi nyl CoA t o
succi nat e, phosphoenol pyr uvat e t o pyr uvat e) . These r eact i ons do not need oxygen.
2. Oxi dat i ve phosphor yI at i on ent ai l s t he f or mat i on of one- and-a- hal f or t wo- and- a-
hal f uni t s of ATP per uni t of met abol i t e t r ansf or med by oxi dor educt ase enzymes
( e. g. , dehydr ogenases); t hese enzymes use f l avi n A di nucl eot i de ( FAD) f or med f rom
t he vi t ami n r i bof l avi n, or ni cot i nami de A di nucl eot i de ( NAD
+
) f rom t he vi t ami n
ni cot i nami de as cof act ors. The react i ons are coupl ed t o t he el ect r on t ransport
syst em, and t he energy rel eased i s used t o f or m ATP i n t he mi t ochondr i a.
C. Carbohydrat e met aboI i sm
1. CataboI i sm. Thi s process rel eases st or ed ener gy f r om carbohydrat es.
a. GI ycogenoI ysi s i s t he br eakdown of gl ycogen i nt o gl ucose phosphat e i n t he l i ver
and skel et al muscl e. Ì t i s cont r ol l ed by t he hormones gl ucagon and epi nephr i ne.
b. GI ycoI ysi s i s t he br eakdown of sugar phosphat es ( e. g. , gl ucose, f r uct ose,
gl ycerol ) i nt o pyr uvat e (aer obi cal l y) or l act at e (anaerobi cal l y) .
2. AnaboI i sm. Thi s pr ocess consumes ener gy t o bui l d up compl ex mol ecul es f r om
si mpl er mol ecul es.
a. GI ycogenesi s i s t he f or mat i on of gl ycogen i n t he l i ver and muscl es f r om gl ucose
consumed i n t he di et ; i t s synt hesi s i s cont rol l ed by t he pancr eat i c hormone i nsul i n.
b. GI uconeogenesi s i s t he f or mat i on of gl ucose f r om noncarbohydr at e sour ces,
such as l act at e, al ani ne, pyr uvat e, and Krebs cycl e met abol i t es; f at t y aci ds cannot
f or m gl ucose.
D. Krebs cycI e. Thi s pat hway i s al so known as t he ci t r i c aci d cycl e, ser ves bot h
br eakdown and synt het i c pur poses, and occurs i n t he mi t ochondri al compar t ment .
1. CataboI i sm. Thi s pat hway conver t s pyr uvat e ( gl ycol ysi s) , acet yl CoA ( f at t y aci d
degradat i on) , and ami no aci ds t o car bon di oxi de and wat er wi t h a r el ease of energy.
The cycl e i s st ri ct l y oxygen- dependent (aerobi c) . Mat ur e r ed bl ood cel l s l ack
mi t ochondr i a; hence, t her e i s no Kr ebs cycl e act i vi t y.
2. AnaboI i sm. Thi s pat hway f or ms ami no aci ds such as aspar t at e and gl ut amat e
f r om cycl e i nt er medi at es; al so, t he por phyr i n ri ng of heme (e. g. , hemogl obi n,
myogl obi n, cyt ochromes) i s f ormed f rom a cycl e i nt ermedi at e.
3. AnapI erot i c react i ons. Because met abol i t es ar e used t o make ami no aci ds or
heme ( e. g. , succi nyl CoA) , t he met abol i t e must be r epl aced by i nt er medi at es f rom
ot her sources ( e. g. , gl ut amat e f r om t he breakdown of pr ot ei n f or ms q- ket ogl ut arat e) .
4. EI ect ron t ransport . The el ect r on t ranspor t syst em accept s el ect r ons and
hydr ogen f rom t he oxi dat i on of Krebs cycl e met abol i t es and coupl es t he ener gy
r el eased t o synt hesi ze ATP i n t he mi t ochondr i a.
E. Li pi d met aboI i sm
1. CataboI i sm. Tri gI yceri des (t r i acyl gl ycer ol s) st or ed i n f at cel l s ( adi pocyt es) ar e
hydr ol yzed by hormone-sensi t i ve l i pases i nt o t hree f at t y aci ds and gl ycerol .
a. Fat t y aci ds ar e br oken down by bet a oxi dat i on t o acet yl CoA ( t wo carbon uni t s) ,
whi ch ent er t he Kr ebs cycl e t o compl et e t he oxi dat i on t o car bon di oxi de and wat er
wi t h r el ease of consi derabl e ener gy. Too r api d br eakdown of f at t y aci ds l eads t o
ket one bodi es (ket ogenesi s) as i n di abet es mel l i t us.
b. GI yceroI ent ers gl ycol ysi s and i s oxi di zed t o pyr uvat e and, vi a t he Krebs cycl e,
t o car bon di oxi de and wat er .
c. Steroi ds may be conver t ed t o ot her compounds such as bi l e aci ds, vi t ami n D, or
st eroi dal hormones ( e. g. , cor t i sone, est r ogens, andr ogens) ; t hey ar e not br oken
down compl et el y.
2. AnaboI i sm. Bi osynt hesi s f orms f at t y aci ds, st er oi ds, and ot her t erpene- r el at ed
met abol i t es.
a. Fat t y aci ds ar e f ormed i n t he cyt opl asm, and unsat urat i on occurs i n t he
mi t ochondr i a
P. 170

or endopl asmi c r et i cul um. Humans cannot make l i nol ei c aci d; t hus, i t i s i mport ant
t hat i t be i ncl uded i n t he di et ( essent i al f at t y aci d) .
b. Terpene compounds ar e der i ved f rom acet yl CoA vi a meval onat e and i ncl ude:
( 1) Chol est er ol and ot her st er oi ds
( 2) Fat - sol ubl e vi t ami ns ( i . e. , A, D, E, K)
( 3) Bi l e aci ds
c. Sphi ngoI i pi ds cont ai n sphi ngeni ne f ormed f r om pal mi t oyl CoA and seri ne.
Sphi ngeni ne f or ms a cerami de backbone when j oi ned t o f at t y aci ds. The addi t i on of
sugar s, si al i c aci d, or chol i ne phosphat e f or ms compounds such as cer ebr osi des,
gangl i osi des, or sphi ngomyel i n f ound i n ner ve t i ssues and membr anes.
d. Phosphat i dyI compounds, such as phosphat i dyl chol i ne ( l eci t hi n) , phosphat i dyl
ser i ne, or et hanol ami ne, ar e al so i mpor t ant par t s of membr anes.
F. Ni t rogen metaboI i sm. Ni t rogen met abol i sm i nvol ves ami no aci d met abol i sm and
nucl ei c aci d met abol i sm ( see Chapt er 9 f or a di scussi on of t he nucl ei c aci d r ol e i n
cel l act i vi t y) .
1. CataboI i sm
a. Ami no aci ds. The ami no gr oup i s r emoved by a t r ansami nase enzyme. The
car bon skel et on i s br oken down t o acet yl CoA (ket ogeni c ami no aci ds) or t o ci t ri c
aci d cycl e i nt ermedi at es ( gl ycogeni c ami no aci ds) and oxi di zed t o carbon di oxi de
and wat er f or ener gy. Gl ycogeni c ami no aci ds f orm gl ucose as needed vi a
gl uconeogenesi s; some ami no aci ds are bot h ket ogeni c and gl ycogeni c ( e. g. ,
t yr osi ne) .
b. Puri nes ar e sal vaged ( 90%) , and t he r emai ni ng 10% are degraded i n a sequence
t hat i ncl udes xant hi ne oxi dase f or mi ng uri c aci d i n humans.
c. Pyri mi di nes are cat abol i zed t o 8- al ani ne, ammoni a, and car bon di oxi de.
2. AnaboI i sm
a. Ami no aci ds ar e f or med f rom t he ci t ri c aci d cycl e i nt ermedi at es ( see Ì Ì Ì D 2) ;
ot hers must be eat en dai l y i n di et ar y prot ei ns. The l at t er ar e cal l ed essent i al ami no
aci ds ( phenyl al ani ne, val i ne, t r ypt ophan [ PVT] ; t hr eoni ne, i sol euci ne, met hi oni ne
[ TÌ M] ; hi st i di ne, ar gi ni ne i n i nf ant s, l ysi ne, l euci ne [ HALL] ) .
b. Puri nes ar e f ormed by compl ex r eact i ons usi ng car bamoyl phosphat e, aspar t at e,
gl ut ami ne, gl yci ne, car bon di oxi de, and f ormyl t et r ahydrof ol at e.
c. Pyri mi di nes are f or med f rom aspart at e and car bamoyl phosphat e i n a mul t i st ep
pr ocess.
G. Ni t rogen excreti on. Excess ni t r ogen must be el i mi nat ed because i t i s t oxi c.
Humans pr i mari l y excr et e ur ea but al so excr et e ur i c aci d.
1. Urea synt hesi s. The Krebs- HenseI ei t pat hway i s used t o f or m ur ea pr i nci pal l y
i n t he l i ver . The ammoni a i s r emoved f rom ami no aci ds by ami no aci d t r ansf er ases
( t r ansami nases) t hat use pyr i doxal phosphat e ( vi t ami n B6) as a coenzyme.
GI ut ami ne i s f ormed f rom gl ut amat e ( an i nt ermedi at e) and ammoni a; gl ut ami ne and
car bon di oxi de f orm carbamoyl phosphat e, whi ch ent ers t he ur ea cycl e and af t er
sever al st eps f orms ur ea.
2. Uri c aci d synt hesi s. Al t hough most pur i nes ar e sal vaged, humans excr et e t he
r emai ni ng puri nes as uri c aci d.
P. 171


STUDY QUESTIONS
Di rect i ons: Each of t he numbered i t ems or i ncompl et e st at ement s i n t hi s sect i on i s
f ol l owed by answer s or by compl et i ons of t he st at ement . Sel ect t he one l et t er ed
answer or compl et i on t hat i s best i n each case.
1. Whi ch of the foI I owi ng f unct i onaI groups can react wi th hydrochI ori c aci d t o
f orm a saI t ?
( A) Ter t i ar y ami nes
( B) Car boxyl i c aci ds
( C) Ami des
( D) Et her s
( E) Secondar y al cohol s
Vi ew Answer 1. The answer i s A[] . 2. The compound shown contai ns aI I of
t he f oI I owi ng f unct i onaI groups EXCEPT:

( A) a phenol
( B) a subst i t ut ed phenyl r i ng
( C) an est er
( D) an al i cycl i c ni t r ogen
( E) a ket one
Vi ew Answer 2. The answer i s C[] . 3. Whi ch of the f oI I owi ng f unct i onaI
groups i s most suscepti bI e to hydroI ysi s?
( A) R÷CO÷R
( B) R÷COOR
( C) R÷O÷R
( D) R÷NH÷CH3
( E) R÷COOH
Vi ew Answer 3. The answer i s B[] . 4. Monomer uni t s of prot ei ns are known
as
( A) monosacchari des
( B) pr ost het i c gr oups
( C) ami no aci ds
( D) puri nes
( E) nucl eosi des
Vi ew Answer 4. The answer i s C[] . 5. Whi ch of the f oI I owi ng f ormuI as
represent s t he zwi t teri on f orm of an ami no aci d?

Vi ew Answer 5. The answer i s D[] . 6. GI ucose i s a carbohydrat e t hat
cannot be hydroI yzed i nt o a si mpI er subst ance. I t i s best descri bed as
( A) a sugar
( B) a monosacchar i de
( C) a di sacchar i de
( D) a pol ysacchar i de
( E) an ol i gosacchari de
Vi ew Answer 6. The answer i s B[] . 7. AI I of t he foI I owi ng carbohydrat es
are consi dered t o be poI ysacchari des EXCEPT
( A) hepari n
( B) st ar ch
( C) gl ycogen
( D) mal t ose
( E) cel l ul ose
Vi ew Answer 7. The answer i s D[] . 8. Whi ch of the f oI I owi ng compounds
are consi dered t he bui I di ng bI ocks of nucI ei c aci ds?
( A) Nucl eot i des
( B) Nucl eosi des
( C) Monosacchar i des
( D) Pur i nes
( E) Ami no aci ds
Vi ew Answer 8. The answer i s A[] . P. 172


9. Whi ch of the foI I owi ng t erms best descri bes a cof act or that i s fi rmI y bound
t o an apoenzyme?
( A) Hol oenzyme
( B) Pr ost het i c gr oup
( C) Coenzyme
( D) Tr ansf er ase
( E) Het er opol ysacchar i de
Vi ew Answer 9. The answer i s B[ and] . O10. Enzymes t hat uncoupI e pept i de
I i nkages are best cI assi f i ed as
( A) hydr ol ases
( B) l i gases
( C) oxi dor educt ases
( D) t r ansf er ases
( E) i somer ases
Vi ew Answer 10. The answer i s A[] . 11. The sugar t hat i s i nherent i n t he
nucI ei c aci ds RNA and DNA i s
( A) gl ucose
( B) sucrose
( C) r i bose
( D) di gi t oxose
( E) mal t ose
Vi ew Answer 11. The answer i s C[] . Di recti ons: Each i t em bel ow cont ai ns
t hr ee suggest ed answer s of whi ch one or more i s cor rect . Choose t he answer .
12. Whi ch of t he f oI I owi ng f unct i onaI groups can f orm a hydrogen bond?
I . An aromat i c ami ne
I I . A t ert i ar y hydroxyI
I I I . An aromat i c hydrocarbon
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 12. The answer i s C[] . 13. Whi ch of t he f oI I owi ng f unct i onaI
groups commonI y undergoes conj ugat i on wi t h gI ucuroni c aci d?
I . A carboxyI i c aci d
I I . A pri mar y ami ne
I I I . A phenoI
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 13. The answer i s E[] . Questi ons 14- 16
The f ol l owi ng quest i ons r ef er t o t he dr ug mol ecul e shown bel ow.

14. The functi onaI groups t hat enhance t hi s compound' s abi I i t y t o cross ceI I
membranes i ncI ude:
I . t he phenyI ri ngs
I I . t he cent raI aI kyI chai n
I I I . the secondar y and t ert i ar y hydroxyI s
A i f I onI y i s correct
B i f I I I onI y i s correct
C i f I and I I are correct
D i f I I and I I I are correct
E i f I , I I , and I I I are correct
15. Based upon t he f unct i onaI groups present, t hi s drug wouI d be expect ed t o
be abI e to f orm:
I . van der WaaI s i nteract i ons
I I . i oni c bonds
I I I . hydrogen bonds
A i f I onI y i s correct
B i f I I I onI y i s correct
C i f I and I I are correct
D i f I I and I I I are correct
E i f I , I I , and I I I are correct
16. Possi bI e met aboI i c pat hways f or t hi s drug i ncI ude:
I . reduct i on of t he carboxyI i c aci d
I I . hydroI yt i c cI eavage
I I I . aromat i c oxi dat i on
A i f I onI y i s correct
B i f I I I onI y i s correct
C i f I and I I are correct
D i f I I and I I I are correct
E i f I , I I , and I I I are correct
Vi ew Answer 14-16. The answers are: 14- C[] , 15-E ( I , I I , and I I I )[ ] , 16- B
( I I I )[ ] . P. 173


ANSWERS AND EXPLANATIONS
1. The answer i s A [ Ì C 2 c] .
Subst ances t hat r eact wi t h aci ds t o f orm sal t s must be bases. Onl y or gani c
compounds t hat cont ai n t he ni t rogen-cont ai ni ng ami ne gr oup ar e bases. Whi l e
ami des cont ai n ni t r ogen, t he adj acent car bonyl group decr eases t he basi ci t y;
t her ef ore, t hey are essent i al l y neut r al .
2. The answer i s C [ Fi gur es 8-4, 8-7, 8- 8, 8-10] .
As shown i n Fi gure 8-8, est er s have a car bonyl at om di rect l y bonded t o an oxygen
at om. Thi s st r uct ur al f eat ur e i s not present i n t hi s compound. However , t he
compound does have t hree subst i t ut ed phenyl ri ngs, t wo phenol s, a t er t i ary al i cycl i c
ni t rogen, a ket one, and an et her.
3. The answer i s B [ Ì E 2 b] .
Hydr ol ysi s i s a doubl e decomposi t i on react i on i n whi ch wat er i s one of t he
r eact ant s. Est ers, par t i cul arl y si mpl e est ers, commonl y undergo hydr ol ysi s. Cert ai n
t ypes of et her s such as gl ycosi des al so undergo hydr ol ysi s, but t hey usual l y r equi re
st r ongl y al kal i ne condi t i ons or a cat al yst such as an enzyme. Ket ones, ami nes, or
car boxyl i c aci ds do not undergo hydr ol ysi s.
4. The answer i s C [ Ì Ì B 1, Ì Ì E 1] .
Pr ot ei ns are l ar ge mol ecul es wi t h mol ecul ar wei ght s r angi ng f rom 5000 t o more t han
1 mi l l i on dal t ons. Al l pr ot ei ns ar e composed of chai ns of ami no aci ds and can be
hydr ol yzed t o yi el d a mi xt ur e of t hei r r espect i ve ami no aci ds. Ther e ar e 20 q- ami no
aci ds, whi ch are commonl y f ound i n pr ot ei ns. Al l t he nat ur al l y occur r i ng ami no aci ds
i n pr ot ei ns ar e L- enant i omers, wi t h t he except i on of gl yci ne. Al l have at l east one
ami no gr oup and one carboxyl gr oup. The ami no aci ds ar e l i nked t oget her t hr ough
t he ami no gr oup of one ami no aci d and t he car boxyl gr oup of anot her ami no aci d
wi t h t he spl i t t i ng out of a wat er mol ecul e t o f or m an ami de l i nkage, whi ch i n a
pr ot ei n i s r ef er r ed t o as a pept i de. Monosacchari des ar e si mpl e, nonhydrol yzabl e
sugar s. Puri nes and pyr i mi di nes ar e or gani c bases, whi l e a prost het i c group i s a
cof act or t hat i s f i r ml y bound t o an apoenzyme.
5. The answer i s D [ Ì A 1 a, Ì Ì B 2, 3, Ì Ì E 1, Fi gur es 8-2, 8-11, 8-12] .
A zwi t t er i on i s a si ngl e speci es cont ai ni ng bot h negat i ve and posi t i ve char ges. Ì t
somet i mes i s r ef er r ed t o as an i nt er nal sal t . Ami no aci ds have an ami no gr oup and a
car boxyl gr oup i n t he same mol ecul e. The ami no gr oup, whi ch i s basi c, at t r act s t he
pr ot on f rom t he car boxyl gr oup and becomes posi t i vel y char ged, whi l e t he carboxyl
gr oup becomes negat i vel y charged when i t donat es i t s prot on t o t he ami no gr oup.
Ami no aci ds exi st as zwi t t er i ons at near neut r al pH such as occurs wi t hi n a cel l or i n
t he bl oodst r eam.
6. The answer i s B [ Ì Ì C 1] .
Whi l e gl ucose i s a sugar, i t i s mor e speci f i cal l y a si mpl e sugar t hat cannot be
hydr ol yzed i nt o mor e si mpl e sugar s÷t hus, i t i s cl assi f i ed as a monosacchari de.
Sugars may be si mpl e, such as gl ucose, or compl ex, such as sucrose, and ar e
cl assi f i ed as di sacchar i des or ol i gosacchar i des, respect i vel y. Pol ysacchari des
consi st of l ong chai ns of monosacchar i des such as cel l ul ose and gl ycogen.
7. The answer i s D [ Ì Ì C 2 b, 3, E 3 a, b] .
Pol ysacchari des ar e l ong- chai n pol ymer s of sugar s. As t he pr ef i x " pol y¨ i ndi cat es,
t her e are many sugar uni t s i n t he mol ecul e. Mal t ose i s composed of t wo mol ecul es
of gl ucose and i s cl assi f i ed as a di sacchar i de or an ol i gosacchar i de.
8. The answer i s A [ Ì Ì D, E 4] .
Nucl ei c aci ds ar e l i near pol ymer s of nucl eot i des t hat consi st of t hree di f f er ent
mol ecul es t hat are coval ent l y l i nked t o f or m one uni t : ( 1) an organi c base of ei t her a
pur i ne or a pyr i mi di ne; (2) a 5- car bon sugar (e. g. , pent ose); and (3) a phosphor i c
aci d group. A nucl eosi de consi st s of t he or gani c base and t he pent ose. A
monosacchar i de i s a si mpl e nonhydr ol yzabl e carbohydrat e, whi ch may be
consi dered a bui l di ng bl ock of pol ysacchari des. Pur i nes ar e het er ocycl i c bases.
Adeni ne and guani ne are t he t wo puri nes f ound i n deoxyr i bonucl ei c aci d (DNA) and
r i bonucl ei c aci d ( RNA) . Ami no aci ds ar e t he bui l di ng bl ocks of prot ei n.
P. 174


9. The answer i s B [ Ì Ì E 2 b, c and d] .
Compl ex, or conj ugat ed, enzymes cont ai n a nonpr ot ei n gr oup cal l ed a cof act or ,
whi ch i s requi r ed f or bi ol ogi c act i vi t y. Ì n many cases, t he cof act or i s qui t e f i rml y
bound t o t he pr ot ei n. Ì n ot hers, t he bi ndi ng occurs onl y dur i ng t he react i on t hat t he
enzyme cat al yzes. Cof act or s t hat are f i r ml y bound t o t he prot ei n ar e known as
pr ost het i c groups, wher eas t hose t hat are act i vel y bound t o t he prot ei n onl y duri ng
cat al ysi s ar e r ef er r ed t o as coenzymes.
A hol oenzyme i s a compl et e, cat al yt i cal l y act i ve enzyme syst em. A t r ansf er ase i s an
enzyme t hat cat al yzes t he t r ansf er of gr oups f r om one subst ance t o anot her , such
as cat echol - O- met hyl t r ansf er ase ( COMT) . A het er opol ysacchari de i s a
pol ysacchar i de t hat cont ai ns t wo or mor e di f f er ent monomeri c uni t s, such as
hepar i n.
10. The answer i s A [ Ì Ì E 2 d] .
A pept i de l i nkage i s an ami de f unct i onal group f ormed f r om t he l oss of a mol ecul e of
wat er f r om t wo ami no aci ds. Uncoupl i ng t hi s l i nkage i s t he r everse of t hi s r eact i on,
a hydr ol ysi s react i on. A hydr ol ase i s an enzyme t hat cat al yzes hydr ol ysi s r eact i ons.
Mor e speci f i c t erms f or an enzyme t hat cat al yzes t he hydr ol ysi s of prot ei ns are
ami dase or pept i dase. A l i gase cat al yzes t he coupl i ng of t wo mol ecul es. An
oxi dor educt ase cat al yzes oxi dat i on r eact i ons. A t r ansf erase cat al yzes t he t r ansf er
of groups f r om one subst ance t o anot her . An i somer ase cat al yzes t he
i nt er conver si on of one i somer t o anot her .
11. The answer i s C [ Ì Ì E 4] .
Nucl ei c aci ds ar e bi opol ymer s consi st i ng of l ong chai ns of nucl eot i des. Nucl eot i des
cont ai n a pent ose monosacchari de as one of t hei r t hr ee const i t uent s. RNA cont ai ns,
as t he name suggest s, t he monosacchar i de ri bose, wher eas DNA cont ai ns
deoxyr i bose. The onl y di f f er ence bet ween t hese t wo sugars i s t he absence of
oxygen i n t he 2 posi t i on of t he ri bose r i ng. Gl ucose, al so known as dext r ose, i s a
hexose. Di gi t oxose i s a deoxyhexose pr esent i n t he di gi t al i s gl ycosi des. Sucr ose
and mal t ose ar e di sacchar i des.
12. The answer i s C ( Ì , Ì Ì ) [ Ì C 2 b, D 1 a, F 3 a] .
Hydr ogen bonds are a speci al i zed t ype of di pol e bond i n whi ch a hydr ogen at om
ser ves as a bri dge bet ween t wo el ect ronegat i ve at oms. Hydr ogen-bond donors
i ncl ude hydr oxyl gr oups, phenol s, ami nes, and ami des. Hydr ogen-bond accept or s
i ncl ude hydr oxyl gr oups, phenol s, uni oni zed ni t r ogen at oms, ket ones, and et her s.
Hydr ocarbons, r egar dl ess i f t hey ar e al i phat i c, al i cycl i c, or ar omat i c, are not
capabl e of f or mi ng hydr ogen bonds.
13. The answer i s E ( Ì , Ì Ì , and Ì Ì Ì ) [ Ì B 2 e, C 2 d, D 2 d] .
Gl ucur oni de conj ugat i on i s t he most common phase Ì Ì met abol i c pat hway f or t wo
r easons: (1) The body has a r eadi l y avai l abl e suppl y of gl ucur oni c aci d, and (2)
t her e are a l arge number of f unct i onal gr oups t hat can react wi t h t hi s compound.
Ì ncl uded among t hese f unct i onal gr oups are car boxyl i c aci ds, pri mar y, secondar y
and t er t i ar y ami nes, and phenol s.
14- 16. The answers are: 14- C ( Ì , Ì Ì ) [ Ì A 1, D 1 b, F 1, 3] , 15- E ( I , I I , and I I I ) [ Ì B 2
b, C 2 b, D 1 a, F 1 a, 3 a] , 16- B ( I I I ) [ Ì B 2 e, E 2 b, F 3 b] .
Li pophi l i c f unct i onal gr oups i ncr ease a dr ug' s abi l i t y t o cr oss cel l membranes. The
t hr ee aromat i c phenyl r i ngs, as wel l as t he al i phat i c but yl chai n connect i ng t he
cent r al phenyl r i ng t o t he ni t r ogen of t he pi peradi ne r i ng, ar e al l l i pophi l i c ( i . e. ,
hydr ophobi c) and cont r i but e t o t he dr ug' s passage t hrough cel l membr anes. The
hydr oxyl gr oups, as wel l as t he aci di c carboxyl i c aci d and t he basi c al i cycl i c ami ne,
ar e al l hydr ophi l i c and enhance t he overal l wat er sol ubi l i t y of t he compound.
The phenyl r i ngs, as wel l as t he cent ral al kyl chai n and t he met hyl groups, ar e
capabl e of f or mi ng van der Waal s i nt eract i ons wi t h ar omat i c and al i phat i c
hydr ocar bon regi ons on r ecept or mol ecul es. The car boxyl i c aci d and t he basi c
ni t rogen are capabl e of f or mi ng bot h i oni c and hydr ogen bonds, whi l e t he hydr oxyl
gr oups ar e al so capabl e of f or mi ng hydr ogen bonds.
Of t he met abol i c pat hways l i st ed, ar omat i c oxi dat i on i s t he onl y pl ausi bl e choi ce.
The t wo unsubst i t ut ed phenyl ri ngs ar e ver y suscept i bl e t o hydr oxyl at i on,
epoxi dat i on, and/ or di ol f or mat i on. Car boxyl i c aci ds ar e not normal l y r educed, but
r at her conj ugat ed wi t h ei t her gl ucur oni c aci d, gl yci ne or gl ut ami ne. Est ers, ami des
and t hei r cycl i c deri vat i ves, l act ones and l act ams, ar e t he pri mar y f unct i onal gr oups
t hat under go hydrol ysi s. None of t hese f unct i onal gr oups ar e present i n t he
compound shown.

9
MicrobioIogy
Gai I Goodman- Sni tkof f
I. SCOPE OF MICROBIOLOGY.
Mi cr obi ol ogy i s t he st udy of or gani sms f rom t hree domai ns as wel l as acel l ul ar
ent i t i es t hat are not consi dered t o be l i vi ng i n t he bi ol ogi cal sense.
A. Domai ns of I i vi ng organi sms
1. Archaea i ncl ude prokar yot es wi t h cel l wal l s t hat are bi ochemi cal l y di f f er ent f r om
bact er i a and t hat i nhabi t ext r eme envi r onment s of heat , col d, pH, or sal t s. Ar chaea
ar e not a medi cal l y i mpor t ant domai n of mi cr oor gani sms.
2. Eukar ya cont ai ns some mi croorgani sms÷f or exampl e, f ungi ( yeast s and mol ds) ,
pr ot ozoa, and al gae÷al ong wi t h macr oscopi c or gani sms such as mushr ooms,
pl ant s, and ani mal s. Di morphi c f ungi are t hose t hat can exi st i n ei t her t he
uni cel l ul ar ( yeast ) or t he f i l ament ous (mol d) phase, dependi ng on t he i ncubat i on
t emper at ure ( e. g. , Hi st opl asma and Bl ast omyces) .
a. Fungi ar e cl assi f i ed i nt o phyl a based on t he t ype of r eproduct i ve st r uct ur es
obser ved or t he l ack of obser vabl e sexual r epr oduct i ve st r uct ures.
( 1) Ascomycot a ( ascus) ( e. g. , Candi da and Hi st opl asma)
( 2) Basi di omycot a ( basi di um) (e. g. , Crypt ococcus)
( 3) Zygomycot a ( zygot e) ( e. g. , Rhi zopus)
( 4) Deuteromycot a ( asexual , al so cal l ed f ungi i mper f ect i ) (e. g. , Cocci di oi des).
Recent l y, some sexual repr oduct i ve st at es have been i dent i f i ed i n f ungi cl assi f i ed
as bel ongi ng t o Deut er omycot a.
b. Prot ozoa, uni cel l ul ar , nonphot osynt het i c eukar yot es char act er i zed by mode of
mot i l i t y, i ncl ude t he f ol l owi ng:
( 1) Masti gophora (f l agel l at es) (e. g. , Gi ar di a)
( 2) Sarcodi na (amoebae) ( e. g. , Ent amoeba)
( 3) Ci I i ophora (ci l i at es) ( e. g. , Bal ant i di um)
( 4) Sporozoa (nonmot i l e) ( e. g. , Pl asmodi um)
3. Bact eri a cont ai n a wi de var i et y of prokar yot es, i ncl udi ng gr am- posi t i ve and gr am-
negat i ve bact eri a. Sect i ons Ì Ì - VÌ Ì char act er i ze bact eri a i n more det ai l .
B. NonI i vi ng, but medi caI I y si gni f i cant enti t i es ar e t he f ol l owi ng
1. Vi ruses ( see VÌ Ì Ì ) , whi ch ar e cl assi f i ed by:
a. Capsi d st ruct ure, whi ch i s t he pr ot ei n coat i ng ar ound t he nucl ei c aci d
b. Type and st randedness of nucI ei c aci d, whi ch coul d be DNA or RNA, ei t her
si ngl e or doubl e st r anded
c. Presence or absence of a I i pi d enveI ope sur roundi ng t he pr ot ei n capsi d
d. Pr esence of enzymes, whi ch may be ei t her i ncor porat ed i nt o t he l i pi d envel ope
or f ound i n t he capsi d near t he nucl ei c aci d
2. Pri ons, i nf ect i ous prot ei ns, ar e i mpl i cat ed i n some spongi f or m
encephal opat hi es ( e. g. , mad cow di sease, Creut zf el dt -Jakob di sease, and kur u) .
II. TAXONOMY AND NOMENCLATURE OF BACTERI A
A. Taxonomy i s cl assi f i cat i on or order i ng i nt o gr oups based on degr ee of
r el at edness. Bact eri a are prokar yot es t hat bel ong t o t he Bact er i a domai n and t he
Eubact eri a ki ngdom and ar e gr ouped and named pr i mar i l y by mor phol ogy,
bi ochemi cal and met abol i c di f f er ences, and i mmunol ogi c and genet i c r el at i onshi ps.
DNA t echnol ogy has l ed t o t he recl assi f i cat i on of some or gani sms based on DNA
sequences and homol ogy. Bact er i a are named usi ng t he Li nnaean or bi nomi aI
syst em as a genus and speci es ( e. g. , Homo sapi ens i s t he genus and speci es f or
humans) .
P. 176


B. MorphoI ogy i s t he cl assi f i cat i on of bact eri a by shape and st ruct ur e.
1. CuI turaI morphoI ogy i s based on t he si ze, shape, and t ext ur e of col oni es t hat
ar e gr own i n pure cul t ure on an agar pl at e. Each col ony or i gi nat es f rom a coI ony-
f ormi ng uni t ( CFU) , consi st i ng of a si ngl e cel l or gr oup of adher ent cel l s.
2. Mi croscopi c morphoI ogy descri bes bact eri a on t he basi s of t he si ze, shape, and
ar r angement of t he cel l s ( see Ì Ì . C and D) .
C. St ai ns. Because of t hei r smal l si ze and rel at i ve t r anspar ency, bact er i a must be
st ai ned t o be vi si bl e under t he l i ght mi cr oscope. St ai ni ng i s al so used as a
cl assi f i cat i on syst em. The maj or t ypes of st ai ni ng r eact i ons are t he f ol l owi ng:
1. Si mpI e stai n. A si ngl e dye (e. g. , Gent i an vi ol et , saf rani n) t hat col or s t he cel l s.
2. Gram st ai n. A di f f erent i al st ai ni ng pr ocedur e t hat di vi des bact er i al cel l s i nt o
ei t her gr am- posi t i ve (purpl e) or gr am- negat i ve (pi nk) .
3. Aci d- f ast stai n. A pr ocedur e t hat st ai ns cel l s t hat have an out er l ayer of a waxy
l i pi d (aci df ast ) but not cel l s t hat l ack t hat l ayer (non-aci d- f ast ) .
4. Spore stai n. A pr ocedur e t hat uses heat t o hel p dye ent er t he spore.
5. CapsuI e stai n. Two dyes are used t o st ai n t he cel l and t he background, al l owi ng
vi sual i zat i on of t he unst ai ned capsul ar mat eri al .
D. Bacteri aI ceI I shape and arrangement
1. Cocci ar e spheri cal and exi st i n chai ns (St r ept ococcus pyogenes), pai r s or
di pl ococci ( St rept ococcus pneumoni ae, Nei sser i a gonor r hoeae) , cl ust ers
( st aphyl ococci ) , and packet s of f our or ei ght (sarci nae) .
2. Baci I I i are cyl i ndr i cal and rod-shaped organi sms ( pseudomonads, Escher i chi a) .
3. Coccobaci I I i ar e short r ounded rods ( Br ucel l a).
4. Spi rochet es and spi ri I I a ar e hel i cal , l i ke a cor kscr ew ( Tr eponema pal l i dum) ;
spi ri l l a ar e r i gi d hel i ces, wher eas spi r ochet es are f l exi bl e hel i ces.
5. Fusobacteri a have t aper ed ends and ar e sl i ght l y cur ved (i . e. , f usi f orm;
Fusobact er i um mort i f er um) .
6. Fi I ament ous or gani sms ar e br anchi ng or gani sms and ar e associ at ed wi t h mol d-
l i ke bact er i a ( Act i nomyces bovi s) .
7. Vi bri os ar e comma shaped r ods (Vi bri o chol erae) .
8. PI eomorphi c organi sms exi st i n var i ed f orms ( Haemophi l us, Legi onel l a,
Cor ynebact er i a) .
E. Ot her cI assi f i cati on paramet ers
1. Presence or absence of
a. Spores used f or sur vi val ( Baci l l us ant hr aci s) .
b. CapsuI es or sI i me I ayers used f or adher ence. Capsul es are al so ant i phagocyt i c
( St r ept ococcus pneumoni ae, Nei sser i a meni ngi t i di s) .
2. Mot i I i t y and t he t ype of f I ageI I a
a. Monot ri chous. A si ngl e f l agel l um
b. Lophot ri chous. A t uf t of f l agel l a at one pol e
c. Amphi t ri chous. A f l agel l um at bot h pol es
d. Peri t ri chous. Fl agel l a di st ri but ed evenl y over t he ent i r e cel l
e. Axi aI fi I aments. Per i pl asmi c f l agel l a wr apped ar ound spi r ochet es
f . GI i di ng mot i I i t y. As demonst r at ed by sl i me mol ds
P. 177


III. STRUCTURE OF THE PROKARYOTIC CELL
A. Over vi ew. Prokar yot i c cel l s ( bact er i a) are smaI I and r el at i vel y si mpI e ( Fi gur e 9-
1) . They have t he f ol l owi ng charact er i st i cs:
1. Contai n no i nt ernaI membrane bound organeI I es but have compl ex cel l wal l
st r uct ur es
2. Lack a t r ue nucl eus, a nucl ear membr ane, and i nt racyt opl asmi c membr anous
or ganel l es ( e. g. , pl ast i ds, endopl asmi c r et i cul um, vacuol es)
3. Mul t i pl y asexual l y by bi nar y f i ssi on r at her t han by mi t osi s or mei osi s
4. Protei n synt hesi s i s medi at ed by 70s rat her t han by 80s ri bosomes.
5. Bact er i al genet i c i nf ormat i on i s ar ranged on a si ngl e super coi l ed ci rcul ar st r and
of doubl e-st randed DNA; t he nucI eoi d i s t he ar ea of t he cel l cont ai ni ng t he t i ght l y
coi l ed chr omosome.
6. Some bact er i a cont ai n st or age granul es, or i ncl usi on bodi es, t he st ai ni ng of t hese
gr anul es may al so be usef ul i n i dent i f yi ng t he bact eri a.
B. Ext ernaI st ructures
1. CapsuI e and sI i me I ayer
a. The capsuI e i s an adher ent , surf ace coat made up of l ong chai n r epeat s of
car bohydrat es or pept i des. The capsul e di f f ers i n composi t i on among bact er i a of
di f f er ent genus and speci es. Ant i geni c di f f er ences among capsul es can be used t o
i dent i f y st rai ns wi t hi n a si ngl e speci es of bact eri a ( St r ept ococcus pneumoni ae) .
Capsul es ar e usual l y pol ysacchar i de i n nat ure; however , t he capsul e of Baci l l us i s
pol ypept i de. The capsul e has several f unct i ons:
( 1) Ì ncr eases t he vi ruI ence (degr ee of or gani sm pat hogeni ci t y) of a mi croor gani sm
( 2) Pr event s phagocyt osi s of t he or gani sm by macr ophages and neut r ophi l s
( 3) Ai ds i n adherence of t he or gani sm t o host cel l s
b. Ì f t he pol ysacchari de i s nonadher ent , i t i s cal l ed a sI i me I ayer.

Figure 9-1. Structure oI a procaryote cell.
|Adapted with permission Irom Winn WC Jr.
Allen SD. Janda WM. et al. Koneman's Color
Atlas and Textbook oI Diagnostic Microbiology.
6th ed. Philadelphia: Lippincott Williams &
Wilkins. 2006.|
P. 178


c. Transformati on f r om smoot h t o r ough col oni es on medi a i ndi cat es capsuI e I oss.
Concur r ent l y, t here i s a l oss of vi r ul ence. Thi s capsul ar mat eri al i s i mmunogeni c,
t her eby i nduci ng t he pr oduct i on of ant i bodi es, whi ch act as opsoni ns t o enhance
phagocyt osi s ( opsoni zati on) .
2. FI ageI I a ar e pr ot ei naceous, hel i cal l y coi l ed or gans used f or movement t hat
ext end out war d f r om t he cyt opl asm t hr ough t he cel l wal l i nt o t he envi r onment
( Fi gur e 9- 2) . Fl agel l a r ot at e ei t her cl ockwi se or count er cl ockwi se, al l owi ng a seri es
of r uns and t umbl es i n response t o chemi cal s i n t he envi r onment . The di rect i on of
movement i s cont r ol l ed by a compl ex mechani sm i nvol vi ng chemor ecept or s and an
i nt racel l ul ar cascade of met hyl at i on and phosphor yl at i on react i ons, causi ng bact er i a
t o move t owar d nut r i ent chemoat t ract ant s and away f r om r epel l ant s.
a. St ruct ure
( 1) Fl agel l a ar e composed of f I ageI I i n, a prot ei n cal l ed Hanti gen, whi ch i s
ant i geni cal l y di st i nct f rom ot her f l agel l a i n eucaryot es.
( 2) Fl agel l a have t hree part s:
( a) BasaI body
( i ) At t aches t he f l agel l a t o t he cyt opl asmi c membrane and cel l wal l

Figure 9-2. Structure oI a procaryote Ilagella
Irom a Gram-negative organism. |Adapted with
permission Irom Winn WC Jr. Allen SD. Janda
WM. et al. Koneman's Color Atlas and Textbook
oI Diagnostic Microbiology. 6th ed. Philadelphia:
Lippincott Williams & Wilkins. 2006.|
P. 179


( i i ) The number of r i ngs t hat make up t he basal body di f f er i n gr am-posi t i ve ( t wo)
and gr am- negat i ve (f our) or gani sms. The L and P r i ngs ar e absent i n Gr am- posi t i ve
or gani sms.
( b) Hook
( c) Fi I ament
b. Peri pI asmi c f I ageI I a, al so cal l ed axi aI f i I ament s, occur i n spi r ochet es and ar e
embedded i nt o t he cel l wal l ' s out er membr ane. Because t hey cause a corkscrew
t ype of mot i on on cont r act i on, t hese or gani sms ar e not hi nder ed by t he vi scosi t y of
medi a.
3. Pi I i ( f i mbri ae) ar e pr ot ei naceous, hai r - l i ke ext ensi ons t hat are short er t han
f l agel l a and composed of r egul ar l y ar ranged pr ot ei n subuni t s cal l ed pi I i n or
f i mbri I i n. They ar e more common i n gr am- negat i ve or gani sms but can be f ound i n
gr am- posi t i ve or gani sms. Ther e ar e t wo morphol ogi cal and f unct i onal vari et i es:
a. Common ( at t achment ) pi l i
( 1) Appear i n great er numbers t han sex pi l i
( 2) Have adhesi ve proper t i es, whi ch ar e i mpor t ant i n t he f ormat i on of bi of i l ms
( 3) Ar e l ect i ns, whi ch are r esponsi bl e f or t rophi sm, t he abi l i t y of t he or gani sm t o
bi nd t o speci f i c r ecept ors on host cel l s
b. Sex ( conj ugat i ve or F) pi l i
( 1) Ar e l onger t han common pi l i
( 2) For m i n gr oups of < 10
( 3) Ar e i nvol ved i n t he t ranspor t of DNA bet ween donor and reci pi ent cel l s
C. The ceI I waI I , peri pI asmi c space, and cyt opI asmi c membrane
1. The ceI I waI I i s r i gi d. Al t hough i t provi des t he gener al shape of t he cel l , i t s
f unct i on i s t o pr ot ect t he cel l f r om osmot i c shock. Ì f t he cel l wal l i s dest r oyed, t he
bact er i al cel l s ar e suscept i bl e t o al t er at i ons i n t he t oni ci t y of t he envi r onment . The
wal l i s composed of a basi c pept i dogI ycan I ayer , whi ch i n t urn i s composed of
r epeat i ng di sacchar i de uni t s ( a pol ymer of N- acetyI gI ucosami ne and N-
acet yI murami c aci d), wi t h a f our - ami no- aci d si de chai n t hat i s coval ent l y l i nked t o
ami no aci ds f rom nei ghbor i ng di sacchar i de uni t s, f ormi ng a st abl e cr oss-l i nked
st r uct ur e. Most bact er i a ar e desi gnat ed as ei t her gr am- posi t i ve or gr am- negat i ve,
based on f undament al di f f er ences i n t he component s of t he cel l wal l . Owi ng t o t he
uni queness and t he i mpor t ance of t he cel l wal l t o bact er i al vi abi l i t y, i t i s t he t arget
of many ant i bi ot i c agent s.
a. Gram-posi t i ve organi sms have a t hi ck cel l wal l , whi ch i s 90% pept i dogl ycan,
wi t h ext ensi ve cr oss- l i nki ng t hat i s approxi mat el y 40 l ayers t hi ck and f orms a
l ayer ed net wor k around t he cyt opl asmi c membrane. Wi t hi n t he cel l wal l , a var i et y of
el ement s ser ve t o st abi l i ze t he cel l wal l , mai nt ai n i t s associ at i on wi t h t he
cyt opl asmi c membrane, and act as r ecept ors and ant i geni c det ermi nant s. These
el ement s i ncl ude prot ei ns, pol ysacchar i des and t ei choi c aci d (gl ycer ol or r i bi t ol
phosphodi est ers) .
( 1) Tei choi c aci ds (gl ycer ol or ri bi t ol phosphodi est er s)
( a) Membrane-associ ated t ei choi c aci ds (l i pot ei choi c aci d) ar e coval ent l y l i nked t o
gl ycol i pi ds of t he cyt opl asmi c membrane.
( b) WaI I - associ ated tei choi c aci ds ar e coval ent l y l i nked t o t he gl ycan chai n of
pept i dogl ycan.
b. Gram-negat i ve organi sms' cel l wal l s are mul t i l ayered wi t h a t hi n pept i dogl ycan
l ayer t hat has no t ei choi c aci ds. Ext er nal t o t hi s i s t he out er membrane, a compl ex
cel l wal l l ayer , whi ch i s l i nked t o t he pept i dogl ycan l ayer by t he I i poprotei n l ayer .
The out er membr ane act s as a hydr ophobi c di f f usi on bar r i er and consi st s of
( 1) PhosphoI i pi d, a bi l ayer si mi l ar t o t he cyt opl asmi c membr ane wi t h prot ei n
channel s, cal l ed pori ns, f or nut ri ent t ransport . The phosphol i pi d l ayer of t he out er
membr ane f aces t he cyt opl asmi c membr ane.
( 2) The I i popoI ysacchari de ( LPS) component proj ect s f rom t he cel l sur f ace and i s
bot h t oxi c and ant i geni c ( O ant i gen) . Ì n a gr am- negat i ve organi sm, t he LPS bI ocks
di f f usi on of l ow mol ecul ar wei ght subst ances i nt o t he cel l , so ant i bi ot i cs and
chemi cal s t hat at t ack t he cel l wal l ( e. g. , l ysozyme, peni ci l l i n) cannot easi l y pass
t hr ough. LPS, al so known as endot oxi n, i s t oxi c t o humans and i s composed of
t hr ee par t s:
( a) Li pi d A: t oxi c por t i on t hat can ei t her sl ough of f i nt act cel l s or be r el eased i nt o
ci rcul at i on upon l ysi s of t he cel l , causi ng nonspeci f i c i nf l ammat i on, i ncl udi ng
di ar rhea, f ever , and sept i c shock
P. 180


( b) Core poI ysacchari de: si mi l ar wi t hi n genera
( c) O- speci fi c si de chai n: speci es speci f i c
( 3) Protei n
2. The peri pI asmi c space, an ar ea bet ween t he cel l wal l and t he cyt opl asmi c
membr ane, cont ai ns a gel of sever al t ypes of mol ecul es (e. g. , hydr ol yt i c enzymes,
per i pl asmi c- bi ndi ng pr ot ei ns) t hat pr ocess mol ecul es bef ore t hey ent er t he
cyt opl asm. Ì t al so cont ai ns pr ot ei ns t hat act as chemor ecept ors f or chemot axi s,
ot hers t hat act as carr i ers of nut r i ent s (si mi l ar t o car ri ers i n t he cyt opl asmi c
membr ane), and ant i bi ot i c- i nact i vat i ng enzymes.
3. The cyt opI asmi c membrane i s a phosphol i pi d bi l ayer mat r i x of a f at t y aci d cor e
( hydr ophobi c) and gl ycerol phosphat e ( hydrophi l i c) . Ì n t he pr esence of prot ei ns
embedded i n t he mat r i x, t hese membranes ar e act i vel y and passi vel y engaged i n
sever al ceI I uI ar functi ons.
a. Transport at i on of nut r i ent s t hr ough
( 1) Passi ve di f f usi on
( 2) Faci l i t at ed di f f usi on
( 3) Act i ve t r anspor t (t hi s met hod i s t he onl y one t hat act i vel y uses energy because
mol ecul es ar e movi ng i nt o t he cel l agai nst a concent r at i on gr adi ent )
b. The si t e of respi rat i on prot ei ns used f or eI ect ron t ransport and energy
f or mat i on
c. Enzymes i nvol ved i n t he assembl y of t he cel l wal l component s
d. Secret i on of exot oxi ns and ot her subst ances f or t he br eakdown of
macr omol ecul es
D. I nt ernaI st ruct ures
1. St orage granuI es are i ncl usi on bodi es used f or f ood or ener gy st orage ( e. g. ,
pol yphosphat e compl exes, car bohydrat e).
2. Ri bosomes ar e cel l ul ar uni t s t hat synt hesi ze pr ot ei n by t he t ransl at i on of
messenger RNA (mRNA) base sequences i nt o ami no aci d pr ot ei n sequences. These
r i bosomes, unl i ke t hose i n eukar yot i c cel l s, are 70s uni t s and are not associ at ed
wi t h membranes such as mi t ochondr i a or r ough endopl asmi c r et i cul um.
3. The nucI ear regi on of bact er i a i s a condensed ar ea (a nucl eoi d) cont ai ni ng t he
bact er i al chr omosome, whi ch l acks a nucl ear membr ane and consi st s of a l ong,
doubl e-st randed, supercoi l ed, ci r cul ar DNA mol ecul e.
4. Some or gani sms cont ai n pI asmi ds, ci r cul ar doubl e-st r anded pi eces of DNA t hat
ar e f ound out si de of t he bact er i al chr omosome. These st r uct ur es are aut onomous
( not cont r ol l ed by t he bact eri al chr omosome) , cont ai n i nf or mat i on f or heavy met al
and ant i bi ot i c resi st ance, ar e conj unct i ve, and car r y genet i c el ement s cal l ed
t ransposons.
IV. MICROBI AL PHYSIOLOGY
A. Nut ri t i onaI t ypes
1. Aut ot rophs use carbon di oxi de as t hei r sol e or mai n carbon source.
a. Phot oaut ot rophs use l i ght as an ener gy source.
b. Chemoaut ot rophs oxi di ze or gani c or i norgani c compounds t o produce energy.
2. Heterot rophs use organi c compounds as t hei r mai n carbon source.
a. Phot ohet erot rophs use l i ght as an ener gy sour ce.
b. Chemohet erot rophs oxi di ze or gani c and i norgani c compounds t o pr oduce
energy.
3. Prot ot rophs are par ent cel l s t hat have no speci al nut ri t i onal r equi r ement s. They
r equi r e t he same nut r i ent s as t he maj or number of t he nat ural member s of t he
speci es.
4. Auxot rophs ar e mut at ed so t hat t hey cannot synt hesi ze t he same essent i al
nut ri ent s (usual l y ami no aci ds) as t hei r parent cel l .
5. Subsets
a. HoI ophyt i c. Or gani sms whose nut r i ent s must be i n a sol ubl e, di f f usi bl e f or m
b. HoI ozoi c. Organi sms t hat need compl ex nut r i ent s, of t en sol i d mat er i al s t hat are
i ngest ed and t hen br oken down
c. Saprophyt i c. Or gani sms whose nut ri ent s ar e obt ai ned f rom dead or decayi ng
or gani c mat t er
P. 181


d. Parasi t i c. Or gani sms whose nut r i ent s ar e obt ai ned f r om and at t he expense of a
l i vi ng organi sm (human pat hogens)
B. Nut ri t i onaI requi rement s. Bact eri a use a wi de var i et y of nut ri ent s t o obt ai n
energy and t o const r uct new cel l ul ar component s. The si x el ement s used as t he
mai n component s of carbohydrat es, l i pi ds, pr ot ei ns, and nucl ei c aci ds are carbon,
oxygen, hydr ogen, ni t r ogen, phosphor us, and sul f ur . Several mi nor and t race
el ement s as wel l as cat i ons pl ay var i ous r ol es i n t he mi croor gani sms.
C. Temperature reI at i ons
1. Psychrophi I e, an or gani sm t hat gr ows wel l at 0°C, has opt i mal gr owt h at 15°C or
l ess, and a maxi mum gr owt h t emper at ur e of 20°C
2. Mesophi I e: an or gani sm wi t h opt i mal gr owt h at 20°-45°C, mi ni mum gr owt h
t emper at ures bet ween 15° and 20°C, and a maxi mum growt h t emperat ur e of
approxi mat el y 45°C (human pat hogens)
3. Thermophi I e: an or gani sm t hat can gr ow at 55°C or great er , wi t h a mi ni mum
gr owt h t emper at ur e of appr oxi mat el y 45°C.
D. Oxygen requi rements. How or gani sms use oxygen can be a maj or f act or i n t hei r
cl assi f i cat i on.
1. Aerobes have t he abi l i t y t o gr ow i n t he pr esence of at mospheri c oxygen.
a. ObI i gat e aerobes depend compl et el y on oxygen f or gr owt h. Oxygen serves as
t er mi nal el ect ron accept or i n aer obi c r espi r at i on.
b. FacuI tat i ve aerobes have t he abi l i t y t o gr ow wi t h or wi t hout mol ecul ar oxygen.
2. Anaerobes have t he abi l i t y t o grow wi t hout oxygen.
a. ObI i gat e anaerobes do not t ol er at e oxygen at al l and di e i n i t s pr esence. Many
st r ai ns l ack cat al ase and super oxi de di smut ase, whi ch prot ect cel l s f rom t he
dest r uct i ve oxi di zi ng capabi l i t i es of hydr ogen peroxi de and superoxi de i ons, whi ch
ar e normal l y pr oduced under aerobi c condi t i ons.
b. FacuI tat i ve anaerobes do not r equi r e oxygen but gr ow bet t er i n i t s presence.
3. Mi croaerophi I es requi r e oxygen l evel s bel ow nor mal at mospher i c pr essur es f or
gr owt h ( e. g. , Hel i cobact er pyl or i )
4. Capnophi I es r equi r e hi gher l evel s of carbon di oxi de t han ar e f ound at nor mal
at mospheri c pr essur es f or growt h ( e. g. , Nei sseri a sp. and St r ept ococcus
pneumoni ae) .
E. Bacteri aI growt h curve. Bact er i al gr owt h i s def i ned as an i ncr ease i n t he
number of cel l s present . Because bact er i a r epr oduce by bi nar y f i ssi on, gr owt h can
be pl ot t ed as t he l og of t he cel l number versus t i me t o pr oduce a cur ve wi t h f our
di st i nct phases (Fi gur e 9- 3) .
1. Lag phase. A t r ansi t i on per i od dur i ng whi ch t he bact er i a ar e repl i cat i ng DNA and
t he enzymes needed f or t he new envi r onment ar e bei ng i nduced. The cel l s are
i ncreasi ng i n si ze but not i n number . Dur i ng t hi s phase of gr owt h, t he cel l s are most
per meabl e.
2. Logari thmi c ( I og) phase. Di vi si on occur s at const ant and maxi mal r at e, and t he
number of cel l s i ncreases i n a geomet r i c pr ogressi on. The gener at i on t i me, whi ch
var i es among speci es, i s usual l y 15-20 mi nut es (Escher i chi a), but may be hours
( Mycobact eri um) . Because t he cel l wal l i s bei ng synt hesi zed so rapi dl y, bact er i al
cel l s ar e most suscept i bl e t o cel l wal l i nhi bi t ors dur i ng t hi s phase.
3. St ati onar y phase. The gr owt h rat e t apers of f and gr owt h and deat h rat es ar e
nearl y equal . A f ai rl y const ant popul at i on of vi abl e cel l s r esul t s. Duri ng t hi s phase,
cel l ul ar met abol i t es are pol l ut i ng t he envi r onment .
4. Deat h phase. When t he concent r at i on of vi abl e cel l s decr eases because of t he
accumul at i on of t oxi c wast es and aut ol yt i c enzymes.
V. METABOLISM AND ENERGY PRODUCTION.
Mi cr oor gani sms der i ve ener gy f rom nut r i ent s by a ser i es of chemi cal react i ons by
whi ch t he energy st or ed i n chemi cal bonds i s t r ansf er red t o newl y f or med chemi cal
bonds t o pr ovi de energy st orage i n a usef ul f or m, such as adenosi ne t r i phosphat e
( ATP) .
P. 182



Figure 9-3. Growth curve oI bacterial culture.
|Reprinted with permission Irom Winn WC Jr.
Allen SD. Janda WM. et al. Koneman's Color
Atlas and Textbook oI Diagnostic Microbiology.
6th ed. Philadelphia: Lippincott Williams &
Wilkins. 2006.|
A. ATP generat i on
1. Subst rate- I eveI phosphor yI at i on r el eases ener gy t hrough di r ect t r ansf er of
hi gh- ener gy phosphat e gr oups f rom an i nt ermedi at e met abol i c compound t o
adenosi ne di phosphat e (ADP) . No mol ecul ar oxygen or ot her i nor gani c f i nal el ect ron
accept or i s r equi red.
2. Oxi dat i ve phosphor yI at i on r emoves el ect r ons f rom or gani c compounds and
passes t hese el ect rons t hr ough a ser i es of el ect ron accept ors al ong an el ect ron
t r anspor t chai n, wi t h mol ecul ar oxygen or some ot her i nor gani c compound as t he
f i nal accept or .
B. Ferment at i on r ef er s t o ener gy- produci ng oxi dat i ve sequences, i n whi ch or gani c
compounds ser ve as bot h el ect r on donors and accept ors. Thi s process occurs i n t he
absence of ext er nal el ect r on accept ors.
1. GI ycoI ysi s i s t he f i rst st ep i n f er ment at i on and r espi rat i on and causes t he
oxi dat i on of gl ucose t o pyr uvi c aci d wi t h a yi el d of t wo mol es of ATP. There ar e
di f f er ent pat hways f or pyr uvi c aci d pr oduct i on i n mi cr oor gani sms:
a. The Embden- Meyerhof ( gI ycoI yt i c) pat hway i s t he maj or pat hway.
b. The Entner- Doudoroff pat hway i s an al t er nat e.
c. The hexose monophosphate shunt used wi t h t he gl ycol yt i c pat hway i s an
al t er nat i ve.
2. Secondar y f erment ati on process. Many bact er i a use pyr uvat e t o oxi di ze
reduced ni coti nami de adeni ne di nucI eoti de ( NADH) , pr oduced i n gl ycol ysi s, t o
manuf act ur e a var i et y of f i nal pr oduct s.
a. Lact i c aci d ferment at i on. The si mpl est pr ocess, whi ch conver t s pyr uvat e t o
l act at e ( Lact obaci l l us, St r ept ococcus) .
b. AI cohoI f erment at i on. Pyr uvat e i s conver t ed t o et hanol and car bon di oxi de
( Sacchar omyces) .
c. Mi xed aci d f ermentati on. A combi nat i on of l act i c, f ormi c, and acet i c aci ds i s
pr oduced wi t h et hanol , hydr ogen, and carbon di oxi de ( Escheri chi a col i ).
d. But anedi oI ferment ati on. Pyr uvat e i s conver t ed t o acet oi n, whi ch i s reduced t o
2, 3- but anedi ol ( Ent erobact er ).
e. But yri c aci d f ermentat i on. But anol , i sopropanol , and acet one are produced
( Cl ost r i di um) .
P. 183


f . Propi oni c aci d ferment at i on. Pyr uvat e i s conver t ed t o oxal oacet at e wi t h t he
addi t i on of car bon di oxi de and t hen t o pr opi oni c aci d ( Propi oni bact er i um).
C. Respi rat i on r ef ers t o energy- pr oduci ng oxi dat i ve sequences, i n whi ch i nor gani c
compounds act as t he l ast el ect ron accept or i n a ser i es of r eact i ons. Thi s pr ocess
i ncl udes gI ycoI ysi s, t he t ri carboxyI i c aci d ( TCA) cycI e, and t he eI ect ron
t ransport syst em, whi ch yi el ds ATP when coupl ed wi t h oxi dat i ve phosphor yl at i on.
1. Aerobi c respi rat i on. Oxygen ser ves as t he f i nal el ect r on accept or .
a. Pyr uvat e i s convert ed t o acet yI coenzyme A and car bon di oxi de and wat er
t hr ough t he TCA cycI e.
b. The eI ect ron t ransport syst em pl ays a r ol e i n t he t r anspor t of el ect rons al ong a
ser i es of car r i er s f ound i n t he cyt opl asmi c membrane, each wi t h successi vel y hi gher
oxi dat i on pot ent i al s. Maj or component s of t he el ect r on t ransport syst em i ncl ude
( 1) Cyt ochr omes
( 2) Fl avoprot ei ns
( 3) Ubi qui nones
2. Anaerobi c respi rat i on. An i nor gani c el ect r on accept or ot her t han oxygen ( e. g. ,
ni t rat e, sul f at e, car bonat e) ser ves as t he f i nal el ect r on accept or .
VI. GENETICS
A. Def i ni t i on and t erms. Genet i cs i s t he st udy of what genes are, how t hey car r y
i nf or mat i on, and how t hey ar e r epl i cat ed and passed on.
1. Chromosomes are bodi es composed of DNA t hat cont ai n genet i c i nf ormat i on.
Bact er i a have onl y one chr omosome÷a si ngl e, cont i nuous ( cl osed) , doubl e-
st r anded, ci rcul ar pi ece of DNA.
a. DupI i cat i on occur s by semi conser vat i ve r epl i cat i on, i n whi ch t he t wo st r ands of
t he hel i x separat e ( ori gi n) and at t hi s poi nt ( two repI i cat i on f orks) new st r ands ar e
synt hesi zed, bi di r ect i onal l y, wi t h t he or i gi nal s servi ng as t empl at es.
b. St ruct ure. The cel l membrane i s at t ached t o t he chr omosome; as t he cel l gr ows,
i t separ at es t he daught er chromosomes. Ther ef or e, each daught er cel l has one
or i gi nal and one new st rand.
2. Genes ar e DNA segment s t hat ar e pr ocessed i n t wo st eps t o pr oduce var i ous
pr ot ei ns. A normal bact er i al cel l i s hapI oi d.
B. ReguI at i on and expressi on of genet i c i nf ormat i on
1. DNA has many f unct i ons.
a. Ì t i s dupI i cat ed f or t ransf er t o pr ogeny dur i ng cel l di vi si on.
b. Ì t i s t ranscri bed i nt o RNA, whi ch can be t ransl at ed i nt o a pr ot ei n.
c. Ì t cont ai ns cont roI si gnaI s, whi ch ul t i mat el y cont r ol t he synt hesi s of prot ei n.
d. Ì t can be mut ated t o al t er speci f i c char act er i st i cs encoded by genes.
e. Ì t can be dupl i cat ed and t ransf er red t o ot her bact eri aI ceI I s i n pr ocesses ot her
t han cel l di vi si on (e. g. , conj ugat i on) .
2. DNA repI i cat i on, t ranscri pt i on, and t ransI at i on af f ect cel l ul ar gr owt h and
devel opment .
a. Bact er i al repI i cat i on i nvol ves accur at e dupl i cat i on of chr omosomal DNA, whi ch
enabl es t he f ormat i on of t wo i dent i cal daught er cel l s.
b. Transcri pt i on of i nf ormat i on f r om DNA t o RNA i s t he f i rst of t wo st eps needed t o
pr oduce necessar y prot ei ns. One gene can be t ranscr i bed i nt o many copi es of RNA.
Si mpl i st i cal l y, RNA pol ymer ase l ocat es t he begi nni ng of t he gene ( pr omot or ) , and
t hi s area under goes l ocal i zed unwi ndi ng t o al l ow RNA pol ymer ase t o t ranscri be
RNA ( cal l ed mRNA) f r om t he DNA t empl at e. The RNA i s not pr ocessed, as i n
eukar yot es. Ther e ar e no i nt r ons and exons, no cappi ng of t he 5' end, and no
pol yadeni ne t ai l s added t o t he 3' end.
c. TransI at i on i s t he pr ocessi ng of genet i c i nf ormat i on t o synt hesi ze pr ot ei ns.
Bef ore t r anscri pt i on i s compl et ed, a ri bosome wi l l at t ach t o t he 5' end of t he
message. The 70s
P. 184

bact er i al ri bosome i s composed of t wo subuni t s, 30s and 50s. The r i bosome
t ransI at es t he message i nt o pr ot ei n by readi ng t he t ri pI et codon ( t hr ee
nucl eot i des) whi ch code f or a speci f i c ami no aci d. Thi s ami no aci d i s car ri ed t o t he
si t e by t ransfer RNA ( t RNA) and pai r s wi t h t he codon by an ant i codon. Ami no
aci ds ar e j oi ned, and t he r i bosome moves t o t he next codon. Thi s cont i nues unt i l t he
compl et e pr ot ei n i s synt hesi zed.
3. ReguI ati on. The product s of cel l ul ar gr owt h must be pr oduced i n cor r ect
pr opor t i ons f or t he cel l t o l i ve and f unct i on. The t wo most common mechani sms of
met abol i c and genet i c regul at i on ar e as f ol l ows:
a. Feedback i nhi bi ti on of enzyme act i vi t y ( met abol i c r egul at i on) i nhi bi t s t he
synt hesi s of t he cel l gr owt h pr oduct . The product bi nds wi t h an al l ost er i c si t e on t he
enzyme, t hereby i nact i vat i ng t he act i ve si t e.
b. Repressi on of enzyme act i vi t y (genet i c regul at i on) i nhi bi t s t he synt hesi s of t he
enzyme at t he t r anscr i pt i onal l evel .
c. I nduct i on of enzyme act i vi t y act i vat es t he synt hesi s of t he enzyme at t he
t r anscri pt i on l evel .
C. Ot her met hods of DNA t ransf er. Mi cr oorgani sms can change t hei r genet i c
const i t ut i on by t he t r ansf er of genet i c mat eri al f r om a donor chromosome t o a
r eci pi ent chr omosome ( recombi nat i on) . Recombi nat i on occurs bet ween homol ogous
segment s ( t hose t hat have si mi l ar nucl eot i de sequences) . There are t hr ee gener al
mechani sms:
1. Transf ormat i on i nvol ves t he r eci pi ent cel l t aki ng up cel l -f r ee, f ragment ed (i . e. ,
naked) DNA and r ecombi ni ng genet i c el ement s.
a. Thi s process i s pri mi ti ve and occur s nat ur al l y wi t hi n onl y a f ew gener a.
b. Requi rement s i ncl ude compet ent r eci pi ent cel l s ( exhi bi t i ng DNA recept or s) or a
"I eaky" bact eri aI ceI I waI I , so t hat DNA can be i nt r oduced i nt o t he cel l .
c. Ì t i s gener al l y associ at ed wi t h recombi nant DNA t echnoI ogy or cI oni ng, a
t echni que t o ampl i f y a speci f i c gene i n prepar at i on f or anal ysi s. Ì n t hi s pr ocess, t he
bact er i al cel l wal l s ar e made l eaky by chemi cal t reat ment .
( 1) Cl oni ng i nvol ves spl i ci ng a gene i nt o a pl asmi d DNA ( vector) . Al l vect or s shar e
sever al common char act er i st i cs:
( a) Typi cal l y smal l , wel l -charact eri zed mol ecul es of DNA
( b) Cont ai n at l east one r epl i con and can be repl i cat ed wi t hi n t he host even when
t he vect ors cont ai n f or ei gn DNA
( c) Code f or a phenot ypi c t rai t t hat can be used t o det ect t he pr esence of f or ei gn
DNA, whi ch can of t en be used t o di st i ngui sh par ent al f r om recombi nant vect ors
( 2) SeI ectabI e markers ar e used t o f i nd cel l s t hat cont ai n t hese vect or s.
( 3) PI asmi ds cannot mai nt ai n st abi l i t y unl ess t hey ar e benef i ci al t o t he host , so t he
pl asmi d shoul d cont ai n a gene essent i al f or cel l ul ar sur vi val ÷ei t her an enzyme
r equi r ed i n a met abol i c pat hway or a gene t hat r esi st s cer t ai n ant i bi ot i cs (see
Ì Ì Ì . D. 4) .
2. Conj ugat i on i s an i mpor t ant means of gene t ransf er , part i cul ar l y among gr am-
negat i ve or gani sms. Thi s process i nvol ves t wo mat i ng t ypes÷t he donor ( F
+
) and
r eci pi ent ( F
-
) cel l s÷and t he ext r achr omosomal pi ece known as t he sex or f er t i l i t y
f act or (F f act or) . The F f act or ( e. g. , F pl asmi d or epi some) i s not under t he cont rol
of t he chromosome and can r epl i cat e aut onomousl y. Pl asmi d-medi at ed exchange of
genet i c i nf ormat i on can occur onl y t hr ough t he expr essi on of t ransf er genes. The
genes encoded on t he pl asmi d r esul t i n t he t r ansf er of a si ngl e st r and of DNA
t hr ough t he sex pi l us i nt o t he r eci pi ent cel l . The F f act or has several genes t hat
code f or f or mat i on and ai d i n donor at t achment of sex pi l i . Dur i ng t hi s process, a
copy i s made, a si ngl e st r and i s t r ansf er red, and t he r eci pi ent becomes F
+
. R
pl asmi ds al so exi st , whi ch encode f or resi st ance t o cer t ai n ant i bi ot i cs or heavy
met al s. When an F pl asmi d i nt egr at es i nt o t he cel l ul ar chr omosome, t he bact er i al
st r ai n i s sai d t o be a hi gh- f requency recombi nat i on ( Hf r) st rai n. Duri ng t he
conj ugal t r ansf er i nvol vi ng an Hf r st rai n, dependi ng on t he amount of t i me, t he
whol e bact er i al chromosome may be t r ansf er r ed. Ant i bi ot i c- r esi st ance genes ar e
of t en par t s of t ransposons (see Ì Ì Ì . D. 4) , whi ch ar e r esponsi bl e f or addi t i ons,
del et i ons, and i nversi ons of l ar ge ( 4- 80 ki l obases) sequences. When di f f er ent
t r ansposons " j ump¨ i nt o t r ansf erabl e pl asmi ds, cont agi ous resi st ance t o mul t i pl e
ant i bi ot i cs can occur .
3. Transduct i on i s t he t ransf er of genet i c mat er i al by bact eri ophages ( vi ruses t hat
i nf ect bact er i a). Such vi ruses can be cl assi f i ed i nt o t wo gr oups:
P. 185


a. Lyt i c phages ent er t he cel l , r epl i cat e, and package t hei r DNA; t hey t hen l yse t he
cel l t o r el ease mat ure i nf ect i ve vi r i ons.
b. Lysogeni c ( t emperate) phages can al t er nat e bet ween t wo pat hways:
( 1) The l yt i c pat hway
( 2) The l ysogeni c pat hway- i nt egr at i ng i nt o t he host DNA and r emai ni ng dor mant
( a) The vi ral DNA does not r epl i cat e but i s i nt egrat ed i nt o t he host genome and i s
known as prophage.
( b) The prophage suppr esses t he l yt i c st at e by synt hesi zi ng a prot ei n known as a
r epr essor , whi ch pr ot ect s t he cel l f rom f urt her i nf ect i on by a vi r us.
( c) Some pr ophages can change t he cel l ' s phenot ype ( phage or I ysogeni c
conversi on) , whi ch al l ows t he organi sm t o el abor at e mat eri al s ( exot oxi ns or
vi r ul ence f act or s) t hat are det r i ment al t o t he human host . Lysogeni c conver si on
t her eby i ncr eases t he vi rul ence or t he sympt oms of a speci f i c pat hogen÷f or
exampl e, Corynebact eri um di pht heri ae ( di pht her i a t oxi n) , St r ept ococcus pyogenes
( er yt hr ogeni c t oxi n i n scar l et f ever) , and Cl ost r i di um t et ani ( t et anus t oxi n) .
VII. EXAMPLES OF UNIQUE BACTERIA
A. Chl amydi a ar e obl i gat e i nt r acel l ul ar parasi t es t hat
1. Lack t he abi I i t y t o generat e ATP; hence t hey must obt ai n i t f r om t he host cel l
2. Have a two- phase I i fe cycI e
a. The i nf ect i ous f orm, or eI ementar y body, i s a dense, nonr epl i cat i ng cel l t hat i s
r esi st ant t o dr yi ng i n t he envi r onment .
b. The reti cuI at e body f or ms f rom engul f ed el ement ar y body and undergoes bi nar y
f i ssi on. Af t er mul t i pl e di vi si ons, t he r et i cul at e bodi es become t he dense, el ement ar y
bodi es, whi ch are r el eased f rom t he host cel l ( e. g. , Chl amydi a t r achomat i s, whi ch
causes bl i ndness and sexual l y t r ansmi t t ed di seases) .
B. Ri cket t si a, obl i gat e i nt r acel l ul ar parasi t es t ransmi t t ed by ar t hr opods, appear t o
have t he abi l i t y t o generat e ATP, but i nst ead use t he host ceI I products, i ncI udi ng
ATP, ami no aci ds, ni cot i nami de adeni ne di nucI eot i de ( NAD) , and coenzyme A
( e. g. , Ri cket t si a r i cket t si i , whi ch causes Rocky Mount ai n spot t ed f ever ).
C. Mycopl asma, t he smal l est bact er i a, are uni que i n t hat
1. They I ack a ceI I waI I .
2. The pl asma membr ane cont ai ns st eroI s f or added st rengt h (e. g. , Mycopl asma
pneumoni a, whi ch causes an at ypi cal or wal ki ng pneumoni a) .
VIII. VIRUSES
A. Vi raI st ruct ure
1. The basi c st r uct ure of a vi r us i s t he vi ri on or nucI eocapsi d. Thi s st r uct ure i s
composed of a pr ot ei n coat , whi ch surr ounds t he vi r al genome. The shape of t he
nucl eocapsi d i s one component t hat det ermi nes t he cl assi f i cat i on of t he vi r us. As
not ed i n Ì . B. 1. b, t he vi r al genome i s composed of ei t her RNA or DNA and may be
si ngl e or doubl e st r anded. The nucl eocapsi d of vi r uses t hat i nf ect humans has t wo
basi c shapes.
a. I cosahedraI . A r egul ar geomet ri c st r uct ure wi t h 12 or mor e f aces; r esembl es a
soccer bal l
b. HeI i caI . The pr ot ei ns t hat make up t he st r uct ur e wr ap i n a hel i cal f ashi on. Hel i cal
capsi ds of t en have cone or bul l et shapes.
P. 186


Table 9-1. The Multiplication of Animal Viruses
Number Step Action(s)
1 Attachment
(adsorption)
Virus attaches to a protein or polysaccharide
molecule (receptor) on the surIace oI a cell
2 Penetration Entire virus enters the cell. in some cases
because it was phagocytized by the cell
3 Uncoating Viral nucleic acid escapes Irom the capsid
4 Biosynthesis Viral genes are expressed. resulting in the
production oI pieces or parts oI viruses (i.e..
viral DNA and viral proteins)
5 Assembly Viral pieces are assembled to create complete
virions
6 Release Complete virions escape Irom the bacterial
cell by lysis or budding
Reprinted by permission Irom Burton GRW. Engelkirk PG. Microbiology
Ior the Health Sciences. 7th ed. Philadelphia: Lippincott Williams &
Wilkins. 2004.

2. The vi ri on may have a I i pi d enveI ope, whi ch i s produced when t he vi rus buds
f r om t he host cel l . The envel ope i s composed of t he host cel l pl asma membr ane and
vi r al l y coded gl ycoprot ei ns.
B. Vi raI repI i cati on. Vi ruses ar e nonl i vi ng ent i t i es t hat must ent er a host cel l t o
repI i cat e. Once i n t he host cel l , t he vi r us i s abl e t o repl i cat e i t s genome and
pr oduce mor e vi r uses, whi ch wi l l i nf ect ot her cel l s. The st eps i n t he mul t i pl i cat i on of
ani mal vi r uses ar e out l i ned i n Tabl e 9- 1 and i nvol ve:
1. The vi rus at t aches ( att achment ) t o t he host cel l usi ng vi r al pr ot ei ns or
gl ycopr ot ei ns, whi ch bi nd t o r ecept ors on t he host cel l sur f ace.
2. The vi ri on t hen ent ers ( penet rat i on) t he host cel l . Ent r y may be accompl i shed by
f usi on of a vi ral envel ope wi t h t he cel l membr ane or by upt ake of t he vi ri on i nt o an
endocyt i c vesi cl e. Ì f t he vi r us ent er s t he cel l t hr ough an endocyt i c vesi cl e, t her e ar e
sever al ways f or i t t o l eave t he endocyt i c vesi cl e and ent er t he cyt opl asm of t he
host cel l .
3. Once i n t he host cel l , t he vi rus uncoats, and t he nucl ei c aci d i s r el eased f rom
t he capsi d. The f r ee nucl ei c aci d t hen i s abl e t o begi n t he process of reproduct i on.
4. Protei n synt hesi s occurs i n t wo st ages. EarI y prot ei ns ar e necessar y f or t he
synt hesi s of a new vi r al genome and ar e synt hesi zed i mmedi at el y af t er i nf ect i on.
Lat e prot ei ns ar e synt hesi zed af t er t he vi r al genome has been copi ed; t hese ar e
t he pr ot ei ns necessar y f or t he assembl y of t he capsi d, gl ycoprot ei ns f or t he
envel ope, and any enzymes i ncl uded i n t he nucl eocapsi d.
a. For vi r uses wi t h a si ngI e- st randed RNA genome, t he RNA may be a pl us ( +)
st r and or a mi nus ( -) st rand. Pl us-st r and RNA genomes ar e mRNAs and ar e
t r ansl at ed di r ect l y t o prot ei ns. Mi nus- st r and RNA genomes have an RNA-dependent
RNA pol ymer ase t hat copi es t he genome i nt o a st r and of mRNA f or t r anscr i pt i on.
b. DoubI e-st randed RNA genomes use an RNA-dependent RNA pol ymerase t o
t r anscri be t he mi nus st rand of RNA i nt o a message f or t r ansl at i on.
c. Some pl us- st rand RNA vi r uses ar e members of t he ret rovi rus f ami l y (e. g. , human
i mmunodef i ci ency vi rus). These vi r uses have an enzyme cal l ed r everse pol ymerase,
whi ch t ranscri bes t he RNA t o doubl e-st randed DNA. The doubl e-st r anded DNA i s
i nt egr at ed i nt o t he host cel l chr omosome ( a provi rus) and t hen t ranscri bed t o
mRNA usi ng host cel l enzymes. The vi r al mRNA i s t hen t r ansl at ed i nt o vi ral
pr ot ei ns.
d. Ì n vi r uses wi t h a DNA genome, t he DNA may be doubl e st randed or si ngl e
st r anded. Ì n ei t her case, t he DNA i s t ranscri bed t o mRNA and t hen t r ansl at ed i nt o
pr ot ei ns.
5. Af t er genome and pr ot ei n synt hesi s, t he vi rus i s assembI ed i nt o new vi r i ons.
6. Af t er assembl y, t he vi r i ons ar e reI eased f r om t he host cel l . For nonenvel oped
vi r uses, t he vi r i ons are rel eased when t he host cel l l yses. Envel oped vi r uses are
r el eased f r om t he host cel l s by buddi ng out of t he host cel l membrane.
P. 187


IX. TRANSMISSION OF INFECTIOUS AGENTS
A. Ì nf ect i ous agent s are f ound i n a number of di f f er ent envi r onment s, cal l ed
reservoi rs.
1. Humans are reservoi rs f or di seases t hat are obl i gat e human pat hogens, whi ch
i ncl ude al most al l vi r al i nf ect i ons and many bact er i al di seases. When humans ar e
t he reser voi r f or t he di sease, t hey ar e sai d t o be carri ers.
a. Asympt omat i c carri ers harbor an i nf ect i on but have no sympt oms. Some
asympt omat i c car r i er s car r y t he i nf ect i ous agent as part of t hei r normal f l or a
( St r ept ococcus pyogenes) .
b. Sympt omat i c carri ers have obvi ous si gns and sympt oms of di sease.
2. An ani maI reservoi r exi st s when t he pr i mar y host i s an ani mal . Such ani mal s
may be wi l d (e. g. , f oxes, r accoons) or domest i cat ed (l i vest ock and pet s).
3. Envi ronmentaI reservoi rs i ncl ude soi l , l akes, and pl ant s.
B. The t ransmi ssi on of i nf ecti ous agents depends on t he source of i nf ect i on. For
di seases wi t h human reser voi rs, t he mechani sms of t ransmi ssi on i ncl ude
1. Contact
a. Di rect cont act requi res physi cal cont act bet ween an i nf ect ed i ndi vi dual and a
suscept i bl e i ndi vi dual (sexual l y t r ansmi t t ed di seases) .
b. I ndi rect cont act i nvol ves a suscept i bl e i ndi vi dual comi ng i n cont act wi t h a
cont ami nat ed sur f ace ( many vi r uses and bact eri a) . Fomi t es are sur f aces t hat can
be and f r equent l y are cont ami nat ed wi t h mi cr oorgani sms ( door knobs, count ers and
ot her sur f aces, comput er keyboar ds, t oys).
2. DropI et t ransmi ssi on. Ì nf ect ed dr opl et s ar e f or med when an i nf ect ed i ndi vi dual
coughs or sneezes. The i nf ect ed dr opl et s t r ansmi t t he di sease t o a suscept i bl e
i ndi vi dual when t hey come i n cont act wi t h t he mucous membr anes of t he i ndi vi dual ' s
nose, mout h, or eyes ( measl es) .
3. Ai rborne t ransmi ssi on. When smal l cont ami nat ed dust par t i cl es or t he r esi due
f r om dr i ed dr opl et s ( dr opl et nucl ei ) remai n suspended i n t he ai r f or l ong per i ods of
t i me, t hey can t r ansmi t di sease ( i nf l uenza, pneumoni a, t ubercul osi s). These smal l
nucl ei can i nf ect bot h t he upper and t he l ower r espi rat or y t r act .
4. Food and wat er contami nat i on. Food or wat er cont ami nat ed wi t h bact er i a f r om
human or ani mal f eces l eads t o t ransmi ssi on of di sease t hr ough t he f ecal - or al rout e.
C. Vectors ar e ani mal s capabl e of t ransmi t t i ng di seases. The most common vect or
f or di sease i s t he mosqui t o (mal ari a) , but ot her i nsect s ( f l eas, t i cks and f l i es) ar e
al so vect ors ( Rocky Mount ai n spot t ed f ever) . Ì n addi t i on, mammal s ( dogs, mi ce and
r at s) can be vect ors f or di sease.
D. Ent r y i nt o a host . Bact eri a can ent er a host t hr ough i ngest i on of f ood or wat er ,
i nhal at i on of dropl et s or dust par t i cl es, i nj ect i on by an i nsect vect or , or by
cont ami nat i on of a wound.
X. MECHANISMS OF PATHOGENICITY
A. Mi cr oor gani sms cause di sease i n di f f er ent ways. Al t hough si gns and sympt oms of
t he di sease ar e of t en t he r esul t of t he host r esponse, mi cr oor gani sms can damage
t i ssue t hr ough t he pr oduct i on of exot oxi ns and endot oxi ns, and by di r ect ef f ect s. Ì n
addi t i on, mi cr obi al vi rul ence f act ors cont r i but e t o t he abi l i t y of a mi cr oor gani sm t o
i nf ect a host and cause di sease.
1. Vi ruI ence fact ors are t he char act er i st i cs of an or gani sm t hat al l ow i t t o ei t her
damage t he host or evade host def enses.
a. Exot oxi ns ar e t oxi ns t hat ar e secret ed by t he mi cr oor gani sm ei t her i nt o t he
envi r onment or af t er col oni zat i on of a host .
( 1) Exot oxi ns secret ed i nt o f ood or wat er t hat are t hen i ngest ed by a host cause
i nt oxi cat i on ( bot ul i sm and st aphyl ococcal f ood poi soni ng) .
( 2) Exot oxi ns pr oduced af t er i nf ect i on and col oni zat i on i nt er f er e wi t h cel l f unct i on or
physi cal l y damage t he cel l ( Bor det el l a per t ussi s, Cor ynebact er i um di pht her i ae,
Vi br i o chol era) .
P. 188


Table 9-2. Important Human Pathogens and Their Diseases
Infectious Agent Typical Infection
Bacteria
Gram-positive cocci

Staphvlococcus aureus Abscess. skin inIections. toxic
shock

Streptococcus pvogenes Strep throat. erysipelas.
rheumatic Iever
Streptococcus pneumoniae Pneumonia
Gram-positive rods
Bacillus Anthrax
Clostridium Gas gangrene. tetanus
Corvnebacterium Diphtheria
Acid-fast rods
Mvcobacterium tuberculosis Tuberculosis
Mvcobacterium leprae Leprosy
Nocardia Nocardiosis
Gram-negative cocci
Neisseria gonorrhoeae Gonorrhea
Neisseria meningitidis Meningitis
Gram-negative rods
Bordetella Pertussis
Brucella Brucellosis

Escherichia coli Sepsis. diarrhea. urinary tract
inIection
Haemophilus influenzae Meningitis
Legionella Legionnaires disease

Pseudomonas Opportunistic lung and burn
inIections
Salmonella Typhoid Iever. salmonellosis
Shigella Dysentery
Jibrio cholerae Cholera
Yersinia pestis Plague
Spirochetes
Borrelia Lyme disease
Treponema pallidum Syphilis
Mycoplasma Pneumonia. urinary inIections
Rickettsia Rocky Mountain spotted Iever
Chlamydia Urethritis. vaginitis
Fungi
Systemic mycoses
Aspergillus Aspergillosis
Blastomvces Blastomycosis
Candida albicans Candidiasis
Coccidioides immitis Valley Iever
Crvptococcus neoformans Cryptococcosis

Pneumocvstis (carinii)
iiroveci
Pneumonia (PCP)
Sporothrix schenckii Sporotrichosis
Protozoa
Entamoeba histolvtica Amoebiasis
Giardia lamblia Giardiasis
Plasmodium Malaria
Toxoplasma gondii Toxoplasmosis
Trichomonas vaginalis Trichomoniasis
Trvpanosoma brucei Sleeping sickness
Helminths
Ascaris Acariosis
Cestodes Tapeworm
Schistosoma Schistosomiasis
Various Iluke inIections

Various roundworm
inIections
Adapted with permission Irom Cowan MK. Talaro KP. Microbiology: A
Systems Approach. 1st ed.: McGraw-Hill. 2005. With permission oI The
McGraw-Hill Companies. Inc.

P. 189


Table 9-3. Important Human Virus Families and Their Diseases
Family Virus Disease
DNA viruses

Poxviridae Variola and
vaccinia
Smallpox. cowpox

Herpesviridae Herpes simplex 1
virus (HSV-1)
Fever blister. cold sores

Herpes simplex 2
virus (HSV-2)
Genital herpes

Varicella zoster
virus (VZV)
Chickenpox. shingles

Human
cytomegalovirus
(CMV)
CMV inIections

Adenoviridae Human
adenoviruses
Adenovirus inIection

Papovaviridae Human
papillomavirus
(HPV)
Several types oI warts

JC virus (JCV) Progressive multiIocal
leukoencephalopathy
(PML)

Hepadnaviridae Hepatitis B virus
(HBV; oI Dane
particle)
Serum hepatitis
Parvoviridae Parvovirus B19 Erythema inIectiosum
RNA viruses
Picornaviridae Poliovirus Poliomyelitis

Coxsackievirus Hand-Ioot-mouth
disease

Hepatitis A virus
(HAV)
Short-term hepatitis

Human rhinovirus Common cold.
bronchitis

Calciviridae Norwalk virus Viral diarrhea.
Norwalk virus
syndrome

Togaviridae Eastern equine
encephalitis virus
Eastern equine
encephalitis (EEE)

Western equine
encephalitis virus
Western equine
encephalitis (WEE)
Yellow Iever virus Yellow Iever

St. Louis
encephalitis virus
St. Louis encephalitis

Rubella virus Rubella (German
measles)
Flaviviridae Dengue Iever virus Dengue Iever

West Nile Iever
virus
West Nile Iever

Bunyaviridae Bunyamwera
viruses
CaliIornia encephalitis

Sin Nombre virus Respiratory distress
syndrom

RiIt Valley Iever
virus
RiIt Valley Iever

Crimean-Congo
hemorrhagic Iever
virus (CCHF)
Crimean-Congo
hemorrhagic Iever

Filoviridae Ebola. Marburg
virus
Ebola Iever

Reoviridae Colorado tick Iever
virus
Colorado tick Iever

Human rotavirus Rotavirus
gastroenteritis

Orthomyxoviridae InIluenza virus.
type A (Asian.
InIluenza. Ilu
Hong Kong.
swine)

Paramyxoviridae ParainIluenza
virus. types 1-5
ParainIluenza
Mumps virus Mumps
Measles virus Measles (red)

Respiratory
syncytial virus
(RSV)
Common cold
syndrome
Rhabdoviridae Rabies virus Rabies (hydrophobia)

Retroviridae Human T-cell
leukemia virus
(HTLV)
T-cell leukemia
HIV (1 and 2) AIDS
Arenaviridae Lassa virus Lassa Iever

Coronaviridae InIectious
bronchitis virus
(IBV)
Bronchitis

Enteric corona
virus
Coronavirus enteritis

SARS virus Severe acute
respiratory syndrome
Adapted with permission Irom Cowan MK. Talaro KP. Microbiology: A
Systems Approach. 1st ed.: McGraw-Hill. 2005. With permission oI The
McGraw-Hill Companies. Inc.

P. 190


b. Endot oxi ns ( see Ì Ì Ì . C. 1. b) ar e i nt egr al part s of t he out er membrane of gr am-
negat i ve bact eri a. Dur i ng an i nf ect i on, endot oxi ns are abl e t o i nduce f ever and
shock i n t he host .
c. CapsuI es ( see Ì Ì Ì . B. 1) ar e used f or adher ence t o host sur f aces and hel p t he
bact er i a evade phagocyt osi s by t he host cel l s.
2. Mechani sms of di sease. There are t hr ee mai n pat t er ns by whi ch mi cr oor gani sms
cause di sease:
a. I ntoxi cat i on [ see X. A. 1. a. ( 1) ]
b. I nfect i on i s suf f i ci ent t o cause di sease f or some mi cr oor gani sms, especi al l y f or
di seases such as pneumoni a, i n whi ch t he capsul e sur r oundi ng t he bact eri a
st i mul at es a st r ong i nf l ammat or y response. Thi s r esponse i s r esponsi bl e f or many of
t he sympt oms of t he di sease. Ì n some cases, i nf ect i on may be f ol l owed by t oxi n
pr oduct i on ( see X. A. 1. a. ( 2) ) , as i n di pht her i a.
c. I nvasi on of host t i ssues and t hen gr owt h i n t he t i ssue i s t he mechani sm of
di sease i nf ect i on by vi ruses and bact eri a such as Mycobact eri a. Some bact eri a
( e. g. , Shi gel l a sp. ) ar e abl e t o pr oduce t oxi ns af t er t he i nvasi on of host t i ssue.
XI. DISEASES CAUSED BY INFECTIOUS AGENTS
A. Di seases caused by bact eri a, f ungi , prot ozoa, and heI mi nt hs ( Tabl e 9- 2)
B. Di seases caused by vi ruses ( Tabl e 9- 3)
P. 191


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 12: Each quest i on, st at ement , or i ncompl et e st at ement
i n t hi s sect i on can be cor r ect l y answer ed or compl et ed by one of t he suggest ed
answer s or phr ases. Choose t he best answer .
1. CeI I waI I s of both gram- posi t i ve and gram- negat i ve bacteri a are composed of
compI ex macromoI ecuI es. Whi ch of t he f oI I owi ng stat ements descri bes both
t ypes of ceI I waI I s?
( A) They cont ai n si gni f i cant amount s of t ei choi c aci d.
( B) They cont ai n pores made f rom pr ot ei ns.
( C) Thei r ant i geni c speci f i ci t y i s det ermi ned by t he pol ysacchari de O ant i gen.
( D) They cont ai n pept i dogl ycan.
Vi ew Answer 1. The answer i s D[ see] . 2. Whi ch of t he f oI I owi ng
descri pt i ons best charact eri zes sex pi I i ?
( A) They enabl e DNA t ranspor t bet ween bact er i a dur i ng conj ugat i on.
( B) They pl ay a r ol e i n t he adhesi on of bact er i a t o t hei r t ar get cel l s.
( C) They ar e numer ous on t he bact er i al cel l surf ace.
( D) They ar e f ound onl y on gram- posi t i ve or gani sms.
Vi ew Answer 2. The answer i s A[ see] . 3. The mode of gene t ransf er i n
whi ch naked DNA i s t aken up i s caI I ed
( A) t r ansf or mat i on.
( B) t r ansduct i on.
( C) conj ugat i on.
( D) cel l f usi on.
Vi ew Answer 3. The answer i s A[ see] . 4. Bacteri a t hat make ei t her a
f ermentat i ve or respi rat or y set of enzymes are known as
( A) obl i gat e anaerobes.
( B) obl i gat e aer obes.
( C) mi cr oaerophi l es.
( D) f acul t at i ve organi sms.
Vi ew Answer 4. The answer i s D[ see] . 5. Whi ch of t he f oI I owi ng st atement s
descri bes pI asmi ds?
( A) They ar e si ngl e-st r anded DNA mol ecul es.
( B) They car r y opt i onal genes.
( C) They car r y genes essent i al f or growt h.
( D) They ar e al ways f ound i n l i near f orm.
Vi ew Answer 5. The answer i s B[ see] . 6. AI I of the f oI I owi ng stat ements
descri be the nucI ear body except whi ch one?
( A) Ì t i s r ef er r ed t o as nucl eoi d.
( B) Ì t i s f r ee of r i bosomes.
( C) Ì t i s composed of ri bosomes.
( D) Ì t l acks a nucl ear membr ane.
Vi ew Answer 6. The answer i s C[ seeand] . 7. Bact eri a that grow at
t emperat ures as hi gh as 55°C are known as
( A) psychr ophi l es.
( B) t her mophi l es.
( C) mesophi l es.
( D) auxot r ophs.
Vi ew Answer 7. The answer i s B[ seeand] . 8. Whi ch of t he f oI I owi ng
organi sms can use onI y moI ecuI ar oxygen as t he f i naI acceptor?
( A) obl i gat e anaerobes
( B) f acul t at i ve anaer obes
( C) obl i gat e aerobes
( D) st ri ct anaerobes
Vi ew Answer 8. The answer i s C[ seeand] . 9. Vi ruses are cI assi f i ed by aI I of
t he f oI I owi ng except by
( A) st ruct ur e of capsi d.
( B) t ype of nucl ei c aci d.
( C) oxygen r equi r ement s.
( D) pr esence of l i pi d envel ope.
Vi ew Answer 9. The answer i s C[ see] . 10. Prot ozoa are cI assi fi ed by
( A) shape.
( B) cel l wal l t ype.
( C) sexual reproduct i ve st r uct ur es.
( D) mode of mot i l i t y.
Vi ew Answer 10. The answer i s D[ see] . 11. Whi ch of t he f oI I owi ng i s not
part of t he vi ruse' s i nfect i ous cycI e?
( A) at t achment
( B) unwi ndi ng
( C) r epl i cat i on of t he genome
( D) pr ot ei n synt hesi s
( E) r el ease
Vi ew Answer 11. The answer i s B[ seeand] . P. 192


12. I nf ect i ous agents are t ransmi t ted to peopI e f rom reservoi rs. These
reservoi rs i ncI ude
( A) dr opl et s.
( B) ani mal s.
( C) f omi t es.
( D) cont ami nat ed f ood.
Vi ew Answer 12. The answer i s B[ seeand] . Di recti ons for questi ons 13- 20:
The quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed
or compl et ed by one or more of t he suggest ed answer s. Choose t he cor rect answer ,
A- D.
13. Gram- negat i ve and gram- posi ti ve ceI I waI I s share whi ch of t he f oI I owi ng
charact eri st i cs?
I . pept i de cross- I i nks between poI ysacchari des
I I . hydroI ysi s by I ysozyme
I I I . ri gi d poI ysacchari de f ramework
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I and I I I are cor r ect
Vi ew Answer 13. The answer i s E[seeand] . 14. A decI i ni ng growt h rat e
occurs duri ng whi ch of t he foI I owi ng phases of bacteri aI ceI I growt h?
I . I ag phase
I I . exponent i aI phase
I I I . death phase
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I and I I I are cor r ect
Vi ew Answer 14. The answer i s B[ seeand] . 15. The pept i dogI ycan
backbone of a bact eri aI ceI I cont ai ns
I . di pept i de chai ns.
I I . N- acet yI murami c aci d.
I I I . N-acet yI gI ucosami ne.
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I and I I I are cor r ect
Vi ew Answer 15. The answer i s D[ see] . NN16. Enti t i es t hat are aceI I uI ar do
not f i t t he cI assi caI defi ni t i on of I i vi ng thi ngs. They are
I . vi ruses.
I I . f ungi .
I I I . pri ons.
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I and I I I are cor r ect
Vi ew Answer 16. The answer i s C[ seeand] . 17. Di morphi c f ungi have
I . a yeast phase.
I I . a sexuaI phase.
I I I . a moI d phase.
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I and I I I are cor r ect
Vi ew Answer 17. The answer i s C[ seeand] . Bl astomyces,
Cocci di oi des, Hi st opl asma18. Transmi ssi on of an i nfecti ous di sease by
t he f ecaI - oraI rout e occurs when
I . i nfect i ous agent s are deposi t ed on surfaces such as door knobs.
I I . an i ndi vi duaI coughs or sneezes and dropI ets wi t h i nf ect i ous agents are
expeI I ed.
I I I . food or wat er i s cont ami nat ed wi t h human or ani maI f eces.
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I and I I I are cor r ect
Vi ew Answer 18. The answer i s B[ seeand] . 19. Vi ruI ence f act ors t hat
enhance mi crobi aI pat hogeni ci t y i ncI ude
I . capsuI es.
I I . endotoxi ns.
I I I . exotoxi ns.
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I and I I I are cor r ect
Vi ew Answer 19. The answer i s E[see] . 20. On Fri day, Januar y 13, a
number of pat rons of Mom' s Di ner became i I I 2- 6 hr af t er eat i ng at t he
rest aurant . The heaI t h department was caI I ed i n t o i nvest i gat e. Duri ng t he
i nvest i gat i on, i t was found t hat aI I the i ndi vi duaI s who became i I I had eaten
banana cream pi e, Mom' s speci aI i t y, but had not eaten anyt hi ng eI se i n
common. The i nvesti gat ors f ound no vi abI e pat hogens i n t he pi e, but t est s
i ndi cat ed t he presence of st aphyI ococcaI contami nat i on of the cream pi e.
I I I ness resuI t i ng f rom thi s cont ami nat i on wouI d be consi dered an
I . i nfect i on.
I I . i nvasi on.
I I I . i nt oxi cat i on.
A i f I onl y i s cor r ect
B i f I I I onl y i s cor rect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I and I I I are cor r ect
Vi ew Answer 20. The answer i s B[ see] . St aphyl ococcus aureusP. 193


ANSWERS AND EXPLANATIONS
1. The answer i s D [ see Ì Ì Ì . C. 1] .
The cel l wal l of gr am- posi t i ve bact er i a i s a t hi ck l ayer of pept i dogl ycan wi t h a l arge
amount of t ei choi c aci ds ( sur f ace ant i gens) . Gr am- negat i ve bact eri a have onl y a
smal l amount of pept i dogl ycan, no t ei choi c aci d, and an out er membr ane composed
of l i popr ot ei n and l i popol ysacchar i de, of whi ch t he pol ysacchari de makes up t he O
ant i gen.
2. The answer i s A [ see Ì Ì Ì . B. 3. b] .
Sex pi l i ar e f ound onl y on gr am-negat i ve or gani sms and i n ver y smal l numbers (<
10) . They act as f ragi l e t r ansport t ubes f or DNA exchange. Common pi l i are
adhesi ons.
3. The answer i s A [ see VÌ . C. 1] .
Of t he t hree met hods of DNA t r ansf er , onl y t ransf or mat i on t akes up DNA wi t hout an
i nt er medi ar y.
4. The answer i s D [ see Ì V. D. 1. b] .
Facul t at i ve or gani sms can gr ow wi t hout ai r and make ei t her a f erment at i ve or a
r espi r at or y set of enzymes, dependi ng on t he condi t i ons.
5. The answer i s B [ see Ì Ì Ì . D. 4; VÌ . C. 2] .
The chromosome car r i es al l of t he genes essent i al f or growt h, wher eas pl asmi ds ar e
ext r achr omosomal , doubl e- st r anded, ci rcul ar pi eces of DNA t hat car r y opt i onal
genes t hat add ext r a pr oper t i es.
6. The answer i s C [ see Ì Ì Ì . D. 2 and 3] .
Ri bosomes are f ound i n t he cyt opl asm, not i n t he nucl eoi d ( a l ong, ci r cul ar , doubl e-
st r anded DNA wi t hout a nucl ear membr ane) .
7. The answer i s B [ see Ì V. C. 1, 2 and 3] .
Ther mophi l es grow at 55°C and ar e f ound i n hot spr i ngs and compost pi l es.
Mesophi l es grow at approxi mat el y 37°C, psychr ophi l es grow at 15°C and l ower , and
auxot r ophs are mut ant or gani sms.
8. The answer i s C [ see Ì V. D. 1 and 2] .
Obl i gat e aerobes requi r e oxygen and l ack an al t er nat i ve f erment at i ve pat hway.
Obl i gat e anaer obes ar e st r i ct anaer obes t hat cannot l i ve i n t he pr esence of oxygen.
Facul t at i ve anaer obes can use oxygen as t he f i nal accept or or t o provi de an
al t er nat e f er ment at i ve pat hway.
9. The answer i s C [ see Ì . B. 1; VÌ Ì Ì . A] .
Vi r uses are cl assi f i ed by t he st ruct ur e of t he capsi d, t he t ype and st randedness of
t he nucl ei c aci d, t he presence of a l i pi d envel ope, and t he pr esence of enzymes.
Vi r uses do not gener at e t hei r own ener gy, hence t her e i s no need f or oxygen.
Vi r uses use t he ener gy i n t he host cel l .
10. The answer i s D [ see Ì . A. 2. b] .
Pr ot ozoa are uni cel l ul ar , nonphot osynt het i c eukar yot es t hat are cl assi f i ed by t hei r
mode of mot i l i t y or l ack of mot i l i t y. The t ypes of mot i l i t y ar e f l agel l a, ci l i a, and
amoeboi d movement .
11. The answer i s B [ see VÌ Ì Ì . B. 1, 2, 3, 4, 5 and 6] .
The vi r al i nf ect i ous cycl e consi st s of at t achment , ent r y, uncoat i ng ( not unwi ndi ng),
pr ot ei n synt hesi s, genome repl i cat i on, assembl y, and r el ease.
12. The answer i s B [ see Ì X. A. 1, 2 and 3] .
Ì nf ect i ous agent s can be f ound i n many di f f erent envi r onment s, i ncl udi ng peopl e,
ani mal s, and t he nat ur al envi r onment . Ani mal s are a resevoi r ; f omi t es, dropl et s and
cont ami nat ed f ood or wat er are mechani sms of t ransmi ssi on.
13. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì Ì Ì . C. 1 and 2] .
Pept i dogl ycan i s t he basi c l ayer of t he cel l wal l i n bot h gr am- posi t i ve and gr am-
negat i ve or gani sms. Ì t provi des a r i gi d f r amewor k t hat i s suscept i bl e t o t he act i on of
l ysozyme. Gr am-posi t i ve cel l s are def i ci ent i n l i pi ds; however , gram- negat i ve cel l s
ar e ri ch i n compl ex l i pi ds ( e. g. , l i popol ysacchar i de) . Bot h t ypes of cel l wal l s have
cr oss-l i nks bet ween pol ysacchar i des.
P. 194


14. The answer i s B ( Ì Ì Ì ) [ see Ì V. E. 1, 2, 3 and 4] .
Dur i ng t he l ag phase, t he cel l s pr epar e f or gr owt h, so t here i s no act ual gr owt h.
Gr owt h i s maxi mal dur i ng t he exponent i al phase and l evel s out duri ng t he st at i onar y
phase wi t h no net i ncrease i n cel l number. Ther e i s a decl i ne i n organi sm number
dur i ng t he deat h phase because t her e ar e mor e or gani sms dyi ng t han ar e bei ng
pr oduced.
15. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see Ì Ì Ì . C. 1] .
The cel l wal l of bot h gr am- posi t i ve and gr am-negat i ve or gani sms i s composed of
r epeat i ng di sacchar i de uni t s. These uni t s cont ai n N- acet yl gl ucosami ne and N-
acet yl mur ami c aci d, t o whi ch t et r apept i de chai ns ar e cr oss-l i nked. Onl y gram-
posi t i ve or gani sms have t ei choi c aci d.
16. The answer i s C ( Ì , Ì Ì Ì ) [ see Ì . B. 1 and 2] .
Vi r uses are basi cal l y pr ot ei ns and nucl ei c aci ds, wher eas pr i ons are prot ei ns,
nei t her of whi ch ar e cel l s. Bact er i a are prokar yot i c cel l s, and f ungi ar e eukar yot i c
cel l s.
17. The answer i s C ( Ì , Ì Ì Ì ) [ see Ì . A. 2. a. ( 1) , ( 2), (3) and (4) ] .
Di morphi c f ungi l i ke Bl ast omyces, Cocci di oi des, and Hi st opl asma can be gr own i n
ei t her a yeast (uni cel l ul ar ) or mol d (f i l ament ous) phase, dependi ng on t he
t emper at ure of i ncubat i on. Fungi are pl aced i n phyl a based on t he t ype of sexual
r epr oduct i on obser ved: ei t her ascus, basi di um, or zygot e. Fungi i mper f ect i consi st
of speci es wi t hout observabl e sexual reproduct i ve st r uct ures.
18. The answer i s B ( Ì Ì Ì ) [ see Ì X. B. 1, 2, 3 and 4] .
The f ecal -or al r out e of t ransmi ssi on i nvol ves cont ami nat i on of f ood or wat er wi t h
ani mal f eces.
19. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see X. A. 1] .
Capsul es act as vi r ul ence f act or s by i nhi bi t i ng phagocyt osi s and act i ng t o at t ach
mi cr oor gani sms t o host sur f aces. Exot oxi ns ar e secr et ed by mi cr oor gani sms and
ei t her al t er cel l f unct i ons or cause cel l deat h. Endot oxi ns i nduce shock i n
mammal i an host s t hrough t he l i pi d A component of t he mol ecul e. Pept i dogl ycan i s
t he backbone of t he bact er i al cel l wal l .
20. The answer i s B ( Ì Ì Ì ) [ see X. A. 1. a. ( 1) ; X. A. 2] .
St aphyl ococcus aur eus can produce an exot oxi n, whi ch r esul t s i n gast r oi nt est i nal
di sease. When t here i s di sease i n t he absence of i nf ect i on or i nvasi on of t he t i ssues
by a l i ve organi sm, t he di sease i s cal l ed an i nt oxi cat i on.

10
ImmunoIogy
Gai I Goodman- Sni tkof f
I. THE PHYSIOLOGY OF THE IMMUNE
SYSTEM
A. I mmunogens, ant i gens, and haptens
1. I mmunogens ar e chemi cal compounds t hat cause a speci f i c
i mmune r esponse.
2. Ant i gens are chemi cal compounds t hat bi nd t o pr oduct s of an
i mmune r esponse. When t he ant i gens are r ecogni zed by ant i body
or act i vat ed cel l s, t hey can be el i mi nat ed by a speci f i c i mmune
r esponse.
3. I mmunogen- anti gens. Compounds associ at ed wi t h or secr et ed
by par asi t i c bact er i a, pr ot ozoa, f ungi , and vi r uses and of mol ecul ar
wei ght (mol wt ) > 5000 dal t ons may act as bot h i mmunogens and
ant i gens.
a. Mol ecul ar compl exi t y i s as i mpor t ant as mol ecul ar wei ght i n
det ermi ni ng t he st at us of a compound as an i mmunogen. For a
mol ecul e t o be i mmunogeni c, i t must cont ai n pr ot ei n or pept i de.
Ther ef ore, pr ot ei ns, gl ycopr ot ei ns, l i popr ot ei ns, and nucl eopr ot ei ns
ar e t he most pot ent i mmunogen-ant i gens.
b. Dr ugs of suf f i ci ent mol ecul ar wei ght ( e. g. , i nsul i n) can act as
i mmunogen- ant i gens. The cel l s of anot her i ndi vi dual and t he cel l s
of one' s own body ( see Ì Ì Ì ) can act as i mmunogen- ant i gens.
Ì mmunogen- ant i gens can be cont act ed envi r onment al l y ( e. g. ,
pol l ens) .
4. Hapt ens are l ow mol ecul ar wei ght compounds t hat act as
i mmunogens af t er coval ent l y bi ndi ng t o a l arger mol ecul e or cel l
sur f ace. Af t er t hey st i mul at e t he i mmune syst em i n t hi s compl ex,
t hese compounds can act as ant i gens i n t he unbound or bound
st at e.
a. Hapt ens may be pr esent i n t he envi r onment ( e. g. ,
pent adecacat echol of poi son i vy) .
b. Several t ypes of dr ugs act as hapt ens (e. g. , peni ci l l i n) .
5. ToI erogens are chemi cal compounds t hat el i ci t speci f i c
nonresponsi veness. Thi s speci f i c nonresponsi veness may be
caused by t he abi l i t y of t he compound t o be br oken down by t he
body or by t he rout e of admi ni st r at i on of t he compound (e. g. , oral
admi ni st rat i on of t en causes speci f i c nonr esponsi veness) .
6. Ì n t hi s chapt er , t he t erm ant i gen i s used f or compounds and cel l s
t hat ar e bot h i mmunogens and ant i gens.
B. CeI I s of t he i mmune syst em
1. B I ymphocyt es and T I ymphocyt es ar e t he pri mar y cel l s of
speci f i c i mmune r esponses. Al l B and T l ymphocyt es ar e ant i gen
speci f i c because t hey have speci f i c ant i gen r ecept or s embedded i n
t hei r pl asma membr anes. Ì n t hi s chapt er , t he t erms B cel l and T
cel l ar e used i nst ead of B l ymphocyt e and T l ymphocyt e.
2. Ant i gen recept ors of B ceI I s ar e ant i body mol ecul es.
a. B cel l s have t housands of i dent i cal ant i bodi es i n t hei r
membr anes t hat al l ow t hem t o bi nd t o a smal l group of chemi cal l y
r el at ed ant i gens. Thi s group def i nes t he ant i gen speci f i ci t y of each
B cel l . Di f f er ent B cel l s have di f f er ent ant i gen speci f i ci t i es, but
each B cel l has onl y one speci f i ci t y. B cel l s t hat recogni ze speci f i c
ant i gens di vi de t o f or m new B cel l s ( memor y B ceI I s) and pI asma
ceI I s ( ant i body- f ormi ng ceI I s) , whi ch secr et e f ree, sol ubl e
( humor al ) ant i body mol ecul es i nt o ext r acel l ul ar f l ui ds ( Fi gur e 10- 1) .
b. Vi rgi n B cel l s have not r esponded t o an ant i gen si nce t hei r
r el ease i nt o t he ci r cul at i on f rom bone mar row. Thei r membr ane
ant i bodi es ar e of t he i mmunogl obul i n M ( Ì gM) and D ( Ì gD) cl asses
( see Ì . D) .
c. Memor y B cel l s are der i ved by cel l di vi si on f rom anot her B cel l
t hat has responded t o an ant i gen. Thei r membr ane ant i bodi es are
of i mmunogl obul i n cl asses A ( Ì gA), E (Ì gE) , or G ( Ì gG; see Ì . D) .
P. 196



Figure 10-1. B cells: antigen speciIicity and
activation.
3. Ant i gen recept ors of T ceI I s have t wo membrane pr ot ei ns ( q
and 8 or v and ô) , whi ch def i ne t he ant i gen speci f i ci t y of each T
cel l , and sever al ot her i nt egr al membrane pr ot ei ns known as CD3
compI ex. Ther ef or e, T cel l s ar e CD3
+
. Each T cel l has t housands
of i dent i cal ant i gen r ecept ors i n i t s membrane. Di f f erent T cel l s of
di f f er ent ant i gen speci f i ci t i es di f f er i n t he conf ormat i on of t hei r
ant i gen r ecept ors.
a. Maj or hi stocompati bi I i t y compI ex ( MHC) prot ei ns. The ant i gen
r ecept or s of T cel l s do not r ecogni ze ant i gens al one. Rat her , t hey
nor mal l y r ecogni ze pept i de epi t opes (f r agment s of ant i gen) t hat
ar e chemi cal l y combi ned wi t h MHC pr ot ei ns on t he sur f ace of ot her
body cel l s ( Fi gure 10- 2) . MHC pr ot ei ns are di vi ded i nt o two maj or
cI asses:
( 1) CI ass I protei ns, whi ch ar e pr esent on t he sur f aces of al most
al l body cel l s
( 2) CI ass I I prot ei ns, whi ch are pr esent onl y on t he surf aces of
speci al ant i gen-presenti ng ceI I s ( APCs)
b. Thymus gI and. T cel l s do not ent er t he ci rcul at i on di r ect l y f r om
bone mar r ow but f i rst ent er t he t hymus gl and t o mat ur e. Most
devel opi ng T cel l s di e i n t he t hymus. The cel l s t hat di e ei t her do
not recogni ze nor mal sel f - ant i gens or pr oduce a response agai nst
nor mal sel f -ant i gens.
( 1) T cel l s t hat ar e r el eased f r om t he t hymus i nt o t he ci r cul at i on
ar e vi rgi n T ceI I s.
( 2) T cel l s t hat or i gi nat e t hr ough cel l di vi si on f r om t he responses of
ot her T cel l s are memory T ceI I s or ef f ect or T ceI I s.
c. GI ycoprot ei ns. Most T cel l s can be cl assi f i ed by t he pr esence of
a membr ane gl ycopr ot ei n known as CD4÷t he heI per, or TH ceI I ÷or
t he pr esence of CD8÷t he cyt ot oxi c T I ymphocyt e ( CTL), or TC
ceI I .
( 1) TH ceI I s can be di vi ded i nt o t wo f unct i onal groups: TH1 and TH2.
These cel l s have di f f erent f unct i ons i n t he i mmune r esponse and
r egul at e i mmune r esponses t hrough t he pr oduct i on of i nt erl euki ns
( Ì L; al so cal l ed l ymphoki nes), whi ch are prot ei ns t hat act on cel l s i n
an aut ocr i ne, par acr i ne, or endocr i ne manner.
P. 197



Figure 10-2. Helper T cell (T
H
cell) antigen
recognition. MHC. maior histocompatibility
complex; APC. antigen-presenting cell.
( a) TH1 ceI I s act i vat e ot her cel l s, i ncl udi ng some TH cel l s, TC cel l s,
and macr ophages. Ì n addi t i on, t hey can decrease ant i body ( Ab)
pr oduct i on by i nhi bi t i ng t he f or mat i on of TH2 cel l s.
( b) TH2 ceI I s act i vat e B cel l s t o di vi de and pr oduce Ab. They can
al so i nhi bi t t he f or mat i on of TH1 cel l s.
( 2) TC ceI I s ar e abl e t o ki l l cel l s t hat ar e i nf ect ed by vi r uses. They
do t hi s t hr ough di rect bi ndi ng wi t h t he i nf ect ed cel l or t hr ough t he
r el ease of cyt ot oxi ns.
( 3) Tr ceI I s, or T r egul at or y cel l s, have recent l y been descr i bed.
Most of t hese cel l s are CD4
+
, al t hough t her e i s a CD8
+
subset as
wel l . Al l of t hese cel l s suppress i mmune r esponses t hr ough t he
secr et i on of Ì L-10 and t ransf ormi ng gr owt h f act or 8 ( TGF- 8) ; i n
addi t i on, cel l s desi gnat ed CD4
+
CD25
+
ar e al so abl e t o i nhi bi t ot her
T cel l s t hr ough di rect cont act .
( 4) Ì nt erl euki ns ar e part of a l arger net wor k of r egul at or y
cyt oki nes. Thi s net wor k i ncl udes secr et i ons of ot her cel l t ypes i n
addi t i on t o t hose of l ymphocyt es. Tabl e 10-1 l i st s t he sour ces and
act i ons of i mpor t ant cyt oki nes t hat regul at e t he i mmune syst em and
i nf l ammat i on.
4. NaturaI ki I I er ( NK) ceI I s ar e l ar ge, gr anul ar l ymphocyt es wi t hout
a speci f i c T or B cel l ant i gen r ecept or. Thei r cyt ot oxi ci t y i s si mi l ar
t o t hat of CTL ( TC) cel l s. NK cel l s recogni ze and dest r oy t umor s,
and ar e i mport ant f or cont r ol l i ng vi ral i nf ect i ons pr i or t o t he
devel opment of adapt i ve i mmuni t y.
5. APCs ar e essent i al f or most i mmune responses and ar e f ound i n
t he si t es at whi ch t hese r esponses ori gi nat e.
a. The best underst ood APCs are t he macrophages and dendri t i c
ceI I s of t he I ymph nodes, spI een, and ot her I ymphoi d t i ssue.
Most i mmune r esponses wi t hi n t hese or gans begi n when t hese cel l s
pr esent epi t opes bound t o t hei r surf ace MHC cl ass Ì Ì mol ecul es t o
TH cel l s and secr et e cyt oki nes as accessor y si gnal s ( Fi gure 10- 2) .
APCs, especi al l y macrophages, ar e abl e t o cont rol t he t ype of
i mmune r esponse generat ed. They do t hi s by secr et i ng di f f erent
cyt oki nes i n response t o di f f er ent t ypes of pat hogens ( e. g. ,
ext r acel l ul ar bact er i a, i nt r acel l ul ar bact er i a, vi r uses) .
P. 198


Table 10-1. Major Cytokines and Their Actions
Cytokine Sources of Secretion
a
Major Actions
IL-1 Macrophages. APCs.
others
T and B cell activation.
pyrogenic. proinIlammatory
TNF-u.
TNF-þ
Macrophages. T
H
1
cells. T
C
cells
Similar to IL-1. but including
cytotoxicity
IL-2 T
H
0 cells. T
H
1 cells T cell. B cell. and NK cell
activation
IFN-v T
H
1 cells Induction oI MHC. activation oI
macrophages and NK cells.
Iormation oI memory B cells.
antiviral
IFN-u.
IFN-þ
Leukocytes.
Iibroblasts
Induction oI MHC. antiviral. and
growth inhibition
IL-3 Macrophages. T
H

cells
ProliIeration oI multilineage
marrow stem cells
IL-4 T
H
2 cells B cell activation and memory B
cell Iormation. increased mast
cell precursors. activation oI
mast cells
IL-5 T
H
2 cells Memory B cell Iormation.
eosinophil production
IL-6 T
H
2 cell. other types Plasma cell maturation. others
similar to IL-1
IL-7 Bone marrow stroma Lymphocyte maturation
IL-8
(CXCL8)
Monocytes.
macrophages.
endothelial.
Iibroblasts cells
Chemokine. attraction and
activation oI neutrophils.
attraction oI T cells
IL-9 T
H
1 cells ProliIeration and diIIerentiation
oI bone marrow cells and
thymocytes
IL-10 Macrophages. T
H
2
cells CD8
¹
T cells. B
cells
Increased humoral (antibody)
immunity. decreased cell-
mediated immunity. mast cell
growth
IL-11 Bone marrow stroma ProliIeration and diIIerentiation
oI bone marrow cells and
thrombocytes
IL-12 Macrophages. B cells Promotion oI cell-mediated
immunity. activation oI T
C
and
NK cells. suppression oI
humoral immunity
IL-13 T
H
cells IL-4-like eIIects on B cells.
inhibition oI production oI
inIlammatory cytokines by
monocytes
IL-14 T
H
cells Important Ior the generation oI B
memory cells
IL-15 Endothelial cells.
epithelial monocytes.
muscle cells
IL-2-like eIIects
GM-CSF T
H
1 cells.
macrophages
Marrow proliIeration oI myeloid
precursors
G-CSF Fibroblasts.
endothelial cells
ProliIeration and survival oI
neutrophil precursors
M-CSF Fibroblasts.
endothelial cells
Survival oI monocyte
macrophages
APC. antigen-presenting cell; G-CSF. granulocyte colony-stimulating Iactor;
GM-CSF. granulocyte-macrophage colony-stimulating Iactor; IFN.
interIeron; IL. interleukin; M-CSF. macrophage colony-stimulating Iactor;
MHC. maior histocompatibility complex; NK cell. natural killer cell; T
C
cell.
T cytotoxic cell; T
H
cell. T helper cell; TNF. tumor necrosis Iactor.
a
Not all sources are listed.

b. Any cel l i n t he body can act as an APC f or i mmune r esponses
i nvol vi ng CTL cel l s. Nucl eat ed cel l s can pr esent f r agment s of
ant i gens bound t o t hei r sur f ace MHC cl ass Ì mol ecul es t o Tc ( CD8
+
)
l ymphocyt es.
c. Bot h T and B cel l s cont i nual l y ci r cul at e f r om t he bl ood t hr ough
t he l ymph nodes, spl een, and ot her secondar y l ymphoi d t i ssue and
t hen back i nt o t he bl ood. Ì f t her e i s ant i gen present i n t he
secondar y l ymphoi d t i ssue t hat bi nds speci f i cal l y t o t he recept or on
t he T or B cel l , t hen an i mmune r esponse can begi n.
P. 199


6. Neut rophi I s, macrophages, eosi nophi I s, basophi I s, pI ateI et s,
and mast ceI I s assi st i n el i mi nat i ng ant i gens f rom t he body. Thei r
f unct i ons may be phagocyt i c, pr oi nf l ammat or y, cyt ot oxi c,
r egul at or y, or a combi nat i on of t hese.
C. HumoraI i mmuni t y: pri mar y and memor y responses that
produce ant i bodi es
1. Overvi ew. Ì n most humor al i mmune responses, ant i gens are
r ecogni zed by ant i gen-speci f i c B cel l s and TH cel l s ( non- ant i gen-
speci f i c B and TH cel l s do not r espond). Ì ni t i al l y, B and TH2 cel l s
di vi de t o i ncr ease t hei r cel l number s. Respondi ng B cel l s pr oduce
bot h memor y B cel l s and pl asma cel l s, ai ded by cyt oki nes secret ed
by TH2 cel l s. T-i ndependent responses t o cer t ai n bact er i al
pol ysacchar i de ant i gens do not requi r e TH cel l s. Dur i ng T-
i ndependent responses, a subcl ass of B cel l s ( B1 B cel l s) responds
al one and pr oduces pl asma cel l s t hat secr et e Ì gM ant i bodi es, but
no memor y B cel l s are pr oduced.
2. Pri mar y i mmune response. The f i rst t i me a speci f i c ant i gen i s
encount ered, onl y vi rgi n B ceI I s and vi rgi n TH ceI I s ar e pr esent t o
r espond t o t he ant i gen. Ì ni t i al l y, t he TH cel l s become TH ef f ect or
cel l s, and t he B cel l s pr oduce pl asma cel l s t hat secr et e Ì gM
ant i body. Lat er i n t he i mmune r esponse, pl asma cel l s pr oduci ng
ot her cl asses of ant i body devel op. The pr i mar y i mmune r esponse i s
det ect ed i n t he serum af t er 4 days and peaks i n 7- 11 days. Ì n a
pr i mar y i mmune r esponse, Ì gM i s pr oduced f i rst and i s f ol l owed by
Ì gG. Memor y B and TH2 cel l s ar e al so produced. Memor y B cel l s
can al so be act i vat ed t o pr oduce t he ot her cl asses of ant i body i n
subsequent i mmune responses.
3. Memor y i mmune responses. The second or subsequent
encount er wi t h t he same ant i gen or a cl osel y r el at ed ant i gen
pr oduces responses by memor y B cel l s and memor y TH2 cel l s.
These responses ar e mor e r api d because memory cel l s r equi re l ess
ant i gen f or st i mul at i on and are of great er magni t ude because t her e
ar e more ant i gen-speci f i c B and T cel l s t o r espond. Most ser um
ant i body pr oduced i s Ì gG, wi t h smal l er amount s of Ì gA and Ì gE.
Si gni f i cant amount s of ant i bodi es are produced as r api dl y as 2-3
days af t er t he r eencount er wi t h ant i gen, and t he absol ut e amount
of ant i body (measur ed i n mi l l i gr ams per deci l i t er of ser um) i s
gr eat er t han i n pri mar y i mmune r esponses. The dur at i on of memor y
var i es among ant i gens and probabl y among i ndi vi dual s. Some, but
not al l , memor y i s l i f el ong.
4. Maj or roI es of ant i bodi es
a. The f i r st f unct i on of an ant i body i s t o act as an anti gen recept or
f or B cel l s so t hat t he B cel l s can recogni ze and r espond t o
ant i gens.
b. The second f unct i on of an ant i body i s t o ai d i n t he eI i mi nati on
of anti gen. El i mi nat i on occurs t hr ough nonspeci f i c f unct i ons, such
as phagocyt osi s or compl ement act i vat i on. The mechani sm of
el i mi nat i on depends on t he cl ass of ant i body i nvol ved.
c. The t hi rd f unct i on of an ant i body i s neut raI i zati on of t oxi ns.
Neut r al i zat i on occur s when an ant i body bi nds t o t he t oxi n and
pr event s i t f rom r eachi ng t he t arget cel l or recept or .
D. I mmunogI obuI i ns: ant i gen bi ndi ng and cI ass- speci f i c
f unct i ons. The t er ms ant i body and i mmunogl obul i n ar e used
i nt er changeabl y.
1. St ruct ure. The st andar d i mmunogl obul i n uni t has f our
pol ypept i de chai ns: t wo i dent i cal l i ght ( L) pol ypept i de chai ns and
t wo i dent i cal heavy ( H) pol ypept i de chai ns. The st r uct ur e i s
r epr esent ed as H2L2. Each chai n can be di vi ded i nt o a C- t ermi naI
constant regi on and an N- t ermi naI vari abI e regi on of ami no aci ds
( Fi gur e 10- 3) . The N-t ermi nal vari abl e r egi on f ormed f r om t he H
and L var i abl e domai ns i s r esponsi bl e f or ant i gen bi ndi ng by t he
i mmunogl obul i n. The C- t er mi nal const ant regi ons of t he H chai n
det ermi ne t he cl ass of t he i mmunogl obul i n.
2. CI ass. Ther e ar e f i ve gener al heavy- chai n, const ant - regi on
ami no aci d sequences. These det ermi ne t he f i ve generaI cI asses
of i mmunogI obuI i ns: I gM, I gG, I gE, I gA, and I gD. Wi t hi n some
cl asses, var i ant s of t he heavy- chai n sequence yi el d subcl asses:
Ì gM1- 2, Ì gG1-4, and Ì gA1- 2. The cl ass of an i mmunogl obul i n
def i nes i t s nonspeci f i c ant i gen el i mi nat i on or i nf l ammat or y f unct i on.
These f unct i ons are act i vat ed onl y af t er ant i gen-ant i body
compl exes ar e f ormed, not by unbound ant i bodi es.
a. I gM i s t he f i rst i mmunogl obul i n secret ed dur i ng pri mar y i mmune
r esponses. Ì t pl ays a mi nor rol e i n memor y r esponses. Ì t does not
l eave t he bl ood i n si gni f i cant amount s because of i t s pent amer i c
st r uct ur e and l arge si ze ( mol wt 900, 000 dal t ons). Ì t account s f or
approxi mat el y 20% of t he adul t ser um i mmunogl obul i n. Ì gM i s t he
most pot ent act i vat or of t he compI ement syst em ( see Ì . E. 2) . Ì t s
ser um hal f - l i f e i s 9-11 days.
P. 200



Figure 10-3. Immunoglobulin molecule. Fc.
Iragment. crystallizable.
b. I gG i s t he predomi nant ser um i mmunogl obul i n secr et ed at t he end of t he
pr i mar y i mmune r esponses and duri ng memor y r esponses. Ì t can di f f use
f r om bl ood i nt o ot her ext r acel l ul ar f l ui ds, part i cul ar l y i n i nf l amed
mi cr ovascul at ur e, and i t cr osses t he pl acent a t o ent er t he f et al ci r cul at i on.
Ì t account s f or appr oxi mat el y 70% of adul t ser um i mmunogl obul i n. Ì t
opsoni zes ant i gens f or phagocyt osi s and act i vat es t he compI ement
syst em. Ì t s ser um hal f - l i f e i s 25- 35 days.
c. I gE i s secr et ed duri ng memor y responses and may al so be secret ed l at e
dur i ng a pri mar y r esponse. Ì t normal l y account s f or < 1% of serum
i mmunogl obul i n. Ì t bi nds t o I gE recept ors I ocated on the ceI I surfaces of
bI ood basophi I s and on mucosaI and connect i ve t i ssue mast ceI I s t o
t r i gger t he secr et i on of i nf l ammat or y medi at ors f rom t hese cel l s i n t he
pr esence of speci f i c ant i gens. Ì gE medi at es al l ergi c r eact i ons. Ì t s ser um
hal f - l i f e i s 2- 3 days, but i t s mast cel l -bound hal f - l i f e i s sever al mont hs t o
year s.
d. I gA i s secret ed dur i ng memor y responses and may al so be secret ed l at e
dur i ng a pri mar y r esponse. Ì t account s f or 10% of serum i mmunogl obul i n.
However , i t i s secret ed i n I arge quant i t i es across mucosaI surfaces i nt o
gast roi nt est i naI , respi rat or y, I achr ymaI , mammar y, and geni t ouri nary
secreti ons, where i t prot ects mucosa f rom coI oni zat i on by bact er i a and
ot her mi croorgani sms. Ì t s ser um hal f - l i f e i s appr oxi mat el y 5 days.
e. I gD account s f or < 1% of serum i mmunogl obul i n and has no known
f unct i on as a secr et ed i mmunogl obul i n.
3. Speci fi ci t y. The speci f i ci t y of each i mmunogl obul i n f or ant i gen bi ndi ng
r esi des i n t he t wo i dent i cal ant i gen-bi ndi ng si t es, each f ormed by t he
combi nat i on of t he var i abl e r egi ons of heavy and l i ght chai ns. Ì gG, Ì gE, and
Ì gD as wel l as ser um Ì gA have t wo ant i gen- bi ndi ng si t es. Ì gM ant i bodi es
have 10 i dent i cal ant i gen- bi ndi ng si t es t hr ough t he combi nat i on of
P. 201

f i ve H2L2 uni t s wi t h a j oi ni ng pol ypept i de chai n t o f orm a pent amer .
Li kewi se, secret ed Ì gA t ypi cal l y exi st s as a di mer wi t h f our bi ndi ng si t es.
4. Quant i t ati on of i mmunogI obuI i n: ant i gen bi ndi ng and cross-
react i vi t y. Bet ween 10
8
and 10
11
uni que i mmunogl obul i ns wi t h di f f er ent
ant i gen- bi ndi ng speci f i ci t i es are f or med by t he i mmune syst em.
a. Each i mmunogl obul i n speci f i ci t y can bi nd t o sever al di f f er ent , but cl osel y
st r uct ur al l y r el at ed, ant i gens. Thi s abi l i t y i l l ust r at es t he phenomenon of
cr oss- react i vi t y of a si ngl e ant i body f or mul t i pl e ant i gens. Each
i mmunogl obul i n- ant i gen i nt er act i on i s quant i t at ed by i t s associ ati on
constant ( Ka) .
b. Cr oss-r eact i vi t y may al so occur t hr ough t he shar i ng of some, but not al l ,
ant i gens by t wo st rai ns of bact er i a, vi r uses, or ot her mi cr oor gani sms.
c. Because each mi cr oorgani sm has sever al ant i gens, each el i ci t s t he
pr oduct i on of mul t i pl e ant i bodi es wi t h uni que speci f i ci t i es by t he i mmune
syst em. Thi s response i s known as a poI ycI onaI response and r esul t s i n a
combi nat i on of ant i bodi es known as a poI ycI onaI ant i serum and def i nes
t he serot ype of t he i mmuni zi ng organi sm.
5. Fragment s of i mmunogI obuI i n f or cI i ni caI use. Ì mmunogl obul i ns can
be enzymat i cal l y cl eaved i nt o f r agment s÷f or exampl e, Fab and F(ab' )2
( ant i gen- bi ndi ng f r agment s), Fc ( cr yst al l i zabl e f ragment ), and Fv ( var i abl e
r egi on f r agment ) . Fab and F( ab' ) 2 f ragment s ar e cl i ni cal l y usef ul because
t hey r et ai n ant i gen speci f i ci t y, but not cl ass-speci f i c ( e. g. , i nf l ammat or y)
f unct i ons, and ar e r eadi l y excr et ed renal l y. Conver sel y, t hi s charact er i st i c
l i mi t s t hei r ef f ect i veness i n cert ai n si t uat i ons.
E. Ant i gen eI i mi nati on and acute i nfI ammator y mechani sms of humoraI
i mmuni t y
1. Opsoni zat i on i s t he pr eparat i on of any ext r acel l ul ar ant i gen f or
phagocyt osi s t hrough bi ndi ng of ant i body. Neut rophi l s and macr ophages
have a var i et y of recept or s f or t he const ant r egi on of Ì gG ant i bodi es (FCvR) ,
whi ch bi nd ant i gen-ant i body compl exes. When t he ant i gen i s sol ubl e, t he
i mmune compl exes must be suf f i ci ent l y l arge t o i nduce t hi s react i on. Thi s
bi ndi ng t ri gger s phagocyt osi s of t he ant i gen- ant i body compl ex and act i vat es
t he met abol i sm of t he phagocyt e, shi f t i ng i t t oward t he product i on of
bact er i ci dal oxygen r adi cal s ( e. g. , superoxi de ani on, hydr ogen peroxi de) .
2. CompI ement i s a gr oup of appr oxi mat el y 20 ser um prot ei ns t hat , when
act i vat ed, f or m a pr ot eol yt i c cascade si mi l ar t o t he cl ot t i ng and f i bri nol yt i c
sequence. Wi t hi n t hi s compl ex of pr ot ei ns, t her e ar e some t hat i nhi bi t
compl ement act i vat i on. Compl ement i s responsi bl e f or i ncr easi ng t he
i nf l ammat or y r esponse, phagocyt osi s of ant i gen, l ysi s of cel l s ( usual l y
pat hogens) , and cl earance of i mmune compl exes.
a. Ì n t he cI assi c acti vat i on pat hway, i mmune compl exes of Ì gM or Ì gG
ant i bodi es bound t o ant i gen bi nd subuni t s of compl ement component 1 (C1)
and t r i gger an i ni t i al ser i es of pr ot eol yt i c cl eavages.
b. Ì n t he aI t ernat i ve acti vat i on pat hway, t he cel l wal l s of cer t ai n
mi cr oor gani sms (e. g. , gram- negat i ve bact eri a) are abl e t o bi nd C3b and
ot her compl ement pr ot ei ns t hat i ni t i at e a di f f er ent sequence of prot eol yt i c
cl eavages, l eadi ng t o t he same end poi nt as t he cl assi c act i vat i on pat hway.
c. Ì n t he mannose- bi ndi ng pat hway, mannose- bi ndi ng pr ot ei n ( MBP) i s
pr oduced by t he l i ver duri ng t he acut e- phase r esponse. MBP bi nds t o
mannose on t he sur f ace of bact er i a and, i n conj unct i on wi t h associ at ed
ser um pr ot eases, t ri ggers prot eol yt i c cl eavages i dent i cal t o t hose seen i n
t he cl assi c pat hway of compl ement .
d. C3b, C4b, and associ at ed degr adat i on pr oduct s pr ovi de opsoni zat i on, vi a
compl ement r ecept ors on cel l s such as macrophages and neut r ophi l s, i n
addi t i on t o t hat pr ovi ded by Ì gG i n i mmune compl exes.
e. Proi nf I ammat or y f ragments of cer t ai n compl ement pr ot ei ns act bot h by
di rect acti vi t y on t he mi crovascuI at ure, pr omot i ng ar t er i ol e di l at i on and
i ncreased vascul ar permeabi l i t y, and by t r i ggeri ng t he r el ease of hi st ami ne
and ot her pr oi nf l ammat or y medi at or s f r om mast cel l s and basophi l s.
f . A compl ex of compl ement pr ot ei ns known as t he membrane at t ack
compI ex ( MAC) can i nser t i nt o any l i pi d bi l ayer membrane, f or mi ng a l arge
channel t hr ough whi ch i ons and wat er di f f use. Many bact eri a, envel oped
vi r uses, and some human or mammal i an cel l s are subj ect t o t hi s osmot i c
l ysi s.
P. 202


3. Ci rcuI ati ng basophi I s and connect i ve t i ssue mast ceI I s are mai nl y
pr oi nf l ammat or y cel l s t hat r api dl y i ni t i at e acut e i nf l ammat i on. Tr i gger s of
secr et i on i ncl ude mechani cal and t her mal t r auma and i mmunol ogi c t r i ggers,
compl ement , and Ì gE.
a. I gE anti bodi es, r egardl ess of ant i gen speci f i ci t y, equi l i brat e bet ween
ser um and bi ndi ng noncoval ent l y t o hi gh-af f i ni t y Ì gE r ecept ors on mast cel l
and basophi l sur f aces. Thi s act i vi t y ar ms t he mast cel l s and basophi l s, but
t he t r i ggeri ng of secr et i on by t hese cel l s r equi res t hat ant i gen bi nd t o and
cr oss-l i nk ant i gen-speci f i c Ì gE mol ecul es al ready af f i xed t o t hei r r ecept ors.
b. Mast cel l s and basophi l s, when t r i gger ed, i mmedi at el y secr et e t he
cont ent s of t hei r st orage gr anul es, i ncl udi ng hi st ami ne, t umor necr osi s
f act or q ( TNF- q) , pr ot eases, and chemot act i c prot ei ns f or neut r ophi l s and
eosi nophi l s. Ì n addi t i on, act i vat i on of phosphol i pase A2 rel eases
ar achi doni c aci d f r om membrane phosphol i pi ds and r esul t s i n t he synt hesi s
of var i ous l eukot ri enes, pr ost agl andi ns, and t hr omboxanes. The pr i mar y
ef f ect s of t hese medi at ors are
( 1) Vascul ar di l at i on
( 2) Ì ncr eased vascul ar per meabi l i t y
( 3) Cont r act i on of respi rat or y and gast r oi nt est i nal smoot h muscl e
( 4) Neut r ophi l and eosi nophi l chemot axi s
4. Ant i body- dependent ceI I -medi at ed cyt ot oxi ci t y i s medi at ed by cel l s
wi t h cyt ot oxi c pot ent i al as wel l as recept or s f or Ì gG. These cel l s, NK cel l s,
macr ophages, and some TC cel l s, bi nd t o and l yse t arget cel l s coat ed wi t h
Ì gG.
5. Acut e i nf I ammat i on al l ows i ncr eased ease of movement of cr uci al
component s of t he bl ood i nt o t he t i ssues, i ncl udi ng phagocyt es ( especi al l y
neut rophi l s) , Ì gG ant i bodi es, compl ement , cl ot t i ng pr ot ei ns, and ki ni ns. The
adapt i ve resul t i s t he i sol at i on and r emoval of i nvadi ng mi cr oor gani sms and
necrot i c t i ssues, f ol l owed by t i ssue r epai r and r egener at i on.
F. CeI I - medi ated i mmune r esponses ( ceI I - medi at ed i mmuni t y) ar e t hose
i n whi ch ant i body i s not i nvoI ved i n t he eI i mi nat i on of anti gen.
1. Nonvi raI i nt raceI I uI ar parasi t es of macrophages, such as Mycobact eri a,
Li st eri a, and cer t ai n pr ot ozoa, ar e pr i mari l y el i mi nat ed by T cel l -
macr ophage i mmuni t y. CD4
+
TH1 cel l s r ecogni ze i nf ect ed macrophages and
secr et e l ymphoki nes, par t i cul ar l y i nt erf er on v ( Ì FN- v) . These l ymphoki nes
act i vat e macr ophages t o pr oduce mor e bact er i ci dal oxygen r adi cal s (e. g. ,
super oxi de ani on, hydr ogen peroxi de) and al so t o i ncr ease t he secr et or y
f unct i on of t he macr ophages and i nhi bi t phagocyt osi s, enabl i ng t he
macr ophages t o ki l l t he par asi t es i n t he ext raceI I uI ar envi r onment .
2. Vi ruses must be el i mi nat ed f rom bot h ext r acel l ul ar si t es and i nf ect ed
cel l s.
a. Ant i bodi es opsoni ze vi r us par t i cl es i n bl ood and t i ssue f l ui ds f or
phagocyt osi s, but ant i bodi es are gener al l y i nef f ect i ve agai nst i nf ect ed cel l s.
b. CTL ceI I s recogni ze i nf ect ed cel l s and di r ect l y ki l l t hem i n an ant i gen-
speci f i c manner , secr et i ng l ymphoki nes, such as TNF- 8 as wel l as
gr anzymes and gr anul ysi ns. Ì n addi t i on, CTL can i nduce apopt osi s vi a FAS
l i gand bi ndi ng t o FAS on t he t arget cel l s. Of t en, t he cel l s ar e ki l l ed bef or e
i nf ect i ous vi rus part i cl es ar e assembl ed. When ki l l ed cel l s r el ease
i nf ect i ous vi ral par t i cl es, t hey may be opsoni zed by an ant i body. Cel l -
medi at ed i mmuni t y and humoral i mmuni t y must f unct i on i n concer t t o
pr ovi de opt i mal ant i vi ral def enses.
c. NK ceI I s ki l l i nf ect ed ( and t umor ) cel l s i n a non- ant i gen-speci f i c manner ,
bi ndi ng t o MHC- l i ke mol ecul es usi ng a var i et y of r ecept or s. NK cel l s ki l l
t hei r t arget cel l s usi ng mechani sms si mi l ar t o t hose used by CTLs.
d. I FN- v (secr et ed by CTL, NK, and TH1 cel l s) and I FN- o and I FN-ß
( secr et ed by f i br obl ast s and ot her cel l s) provi de addi t i onal ant i vi ral
i mmuni t y by bi ndi ng t o recept ors on ot her cel l s and i nduci ng synt hesi s of
ki nases and endonucl eases ( i . e. , ant i vi ral pr ot ei ns) , whi ch i nhi bi t vi ral and
cel l ul ar gr owt h. Ì nt erf erons al so upr egul at e cl ass Ì MHC pr ot ei ns, whi ch
make i nf ect ed cel l s mor e vi si bl e t o CTL cel l s.
3. Tumors ar e modi f i ed host cel l s and must be el i mi nat ed by t he i mmune
syst em, usual l y by cel l -medi at ed i mmuni t y.
a. NK ceI I s are pri mar i l y r esponsi bl e f or ki l l i ng t umor cel l s. They act by
r ecogni zi ng changes i n cel l -surf ace pr ot ei ns or by ant i body- dependent
ceI I -medi at ed cyt ot oxi ci t y.
P. 203


b. CTL ceI I s recogni ze t umor cel l s i n an ant i gen-speci f i c manner and ki l l
t hem by secr et i ng l ymphoki nes, such as TNF- 8, and by i nduci ng apopt osi s
t hr ough t he bi ndi ng of FAS and FAS-l i gand.
c. Macrophages al so ki l l t umor cel l s i n a nonspeci f i c manner , t hr ough t he
r el ease of TNF- q.
4. Graf t rej ect i on ( see V)
II. Hypersensitivity Reactions are exaggerated,
inappropriate, or proIonged immune responses
that cause damage to otherwise normaI tissue.
Four t ypes of hypersensi t i vi t y r eact i ons ar e r ecogni zed, pr i mar i l y on t he
basi s of t he mechani sms of pat hogenesi s ( Fi gur e 10- 4) . Many di f f er ent
di seases are i ncl uded wi t hi n each t ype. AI I ergens ar e broadl y def i ned as
ant i gens or hapt ens t hat i nduce hyper sensi t i vi t y r eact i ons, and t hey ar e
usual l y nonpat hogeni c, nont oxi c agent s.

Figure 10-4. The Iour main types oI
hypersensitivity reactions. RBC. red blood cell.
P. 204


A. I gE- medi at ed t ype I hypersensi t i vi t y react i on ( i mmedi ate
hypersensi t i vi t y)
1. A t ype Ì hypersensi t i vi t y r eact i on i s caused by i nappropri ate producti on
and hypersecret i on of I gE t o speci f i c al l er gens pl us auxi l i ar y f act or s, such
as i ncr eased mucosal per meabi l i t y t o i r r i t ant s (e. g. , SO2, NO2, di esel
f umes). The t endency t o hypersecrete I gE i s i nheri tabI e; a chi l d' s
pr obabi l i t y of bei ng a hyper secret or i s 50% i f one parent i s a hypersecr et or
and 75% i f bot h par ent s ar e hyper secr et or s. These i ndi vi dual s ar e
consi dered t o be at opi c.
a. Ì gE i s produced l ocal l y af t er nonsyst emi c exposur e t o an ant i gen.
( 1) Ì n nor mosecr et ors (1- 10 µg/ dL of Ì gE) , armi ng of l ocal mast cel l s occur s
( see Ì . B. 6) .
( 2) Ì n hypersecr et ors ( t ypi cal l y 100 µg- 1 mg/ dL of Ì gE), Ì gE spi l l over
occurs, ar mi ng basophi l s and nonl ocal mast cel l s and causi ng i ncr eased
occupancy of mast cel l and basophi l Ì gE r ecept ors by Ì gE.
b. Because t her e i s a l ag peri od f or Ì gE synt hesi s and cel l ar mi ng, a t ype Ì
r eact i on usual l y does not occur on t he f i r st ( or f i rst seasonal ) exposur e t o a
speci f i c al l ergen.
2. Common aI I ergens
a. Respi rator y aI I ergens i ncl ude pol l ens of var i ous pl ant s (e. g. , r agweed,
gr asses, t r ees) , f ungi , ani mal f ur , car pet mi t es, and ot her shed al l er gens.
b. Gast roi nt est i naI aI I ergens i ncl ude dai r y pr oduct s, shel l f i sh, t r ee nut s,
and peanut s.
c. Ski n and mouth aI I ergens i ncl ude t opi cal l y appl i ed dr ugs ( e. g. ,
pr ocai ne) .
d. I nt ravenous aI I ergens i ncl ude i nsect venoms and dr ugs t hat act as cel l
or pl asma prot ei n- bound hapt ens (e. g. , peni ci l l i n, cephal ospor i ns,
vacci nes) . These dr ugs may cause t ype Ì Ì or Ì Ì Ì hyper sensi t i vi t y r eact i ons i n
peopl e who do not hypersecr et e Ì gE i n r esponse t o t hese dr ugs.
3. Act i vat i on of mast ceI I and basophi I secret i on by an al l er gen r equi res
t wo or mor e recept or - bound Ì gE mol ecul es t o be cr oss-l i nked by a speci f i c
al l er gen. Hapt en-si ze drugs t hat pr ovoke t hi s r eact i on bot h sensi t i ze t he
i mmune syst em and t r i gger mast cel l s when t he dr ug i s bound t o a l ar ger
mol ecul e ( e. g. , a pr ot ei n) . Act i vat i on l eads t o a t ransi ent i ncrease i n t he
cycl i c adenosi ne monophosphat e (cAMP) l evel , f ol l owed by an i ncr ease i n
t he l evel of cycl i c guanosi ne monophosphat e (cGMP) r el at i ve t o cAMP. Thi s
i s f ol l owed by phosphol i pase C pr oduci ng second messengers, whi ch l ead
t o a r api d i ncr ease i n cyt opl asmi c cal ci um i ons ( Ca
++
) . Wi t h t he i ncr ease i n
cyt opl asmi c Ca
++
, t her e i s i mmedi at e f usi on of vesi cl es cont ai ni ng
i nf l ammat or y medi at or s wi t h t he cel l membrane and r el ease of t hese
medi at or s i nt o t he ext r acel l ul ar mi l i eu. Ì n addi t i on, af t er degranul at i on,
mast cel l s pr oduce addi t i onal cyt oki nes, l eukot r i enes, and pr ost agl andi ns.
These act i vat e t he l at e-phase r esponse, whi ch f ur t her act i vat es t he l ocal
i nf l ammat or y r esponse. Pr ol onged i ncr eases i n cAMP l evel s i nhi bi t mast
cel l act i vat i on.
4. Ef f ect s of medi at ors secreted f rom mast ceI I s and basophi I s
a. Vasodi l at i on and i ncreased capi l l ar y per meabi l i t y ar e caused by
hi st ami ne; t he l eukot r i enes C4, D4, and E4; and pr ost agl andi n D2 (PGD2)
secr et ed by mast cel l s.
b. Gast r oi nt est i nal and respi r at or y smoot h muscl e const r i ct i on i s caused
pr i mar i l y by hi st ami ne, t he l eukot ri enes C4, D4, and E4; PGD2; and
pl at el et - act i vat i ng f act or secr et ed by mast cel l s and ot her l eukocyt es.
c. Eosi nophi l and neut r ophi l i nf i l t r at i on i s caused by chemot act i c f act ors
secr et ed by mast cel l s.
5. LocaI sympt oms of pat hogenesi s i ncl ude i nf l ammat i on of t he upper
( r hi ni t i s) and l ower r espi r at or y t ract ( ast hma) , gast r oi nt est i nal t r act , and
ski n.
a. Common cl i ni cal sympt oms i ncl ude ur t i cari a, prur i t us (i t chi ng), nasal
congest i on, br onchoconst r i ct i on, mucus and l achrymal hypersecr et i on,
l ar yngeal edema, vomi t i ng, and di ar r hea.
b. Sympt oms may be conf i ned t o t he port al of al l er gen ent r y ( e. g. ,
r espi r at or y al l er gen: respi r at or y sympt oms) or may be more wi despr ead as
a r esul t of al l ergen spi l l over i nt o t he ci rcul at i on (e. g. , f ood al l er gen:
gast r oi nt est i nal , ski n, r espi rat or y sympt oms).
c. At opi c dermat i t i s t ypi cal l y i ncl udes sever e prur i t i c dermat i t i s, and may
al so i ncl ude rhi ni t i s or ast hma, f ood al l er gi es, and changes i n t he cel l -
medi at ed i mmune syst em.
d. The l ocal i nt r oduct i on of al l er gen somet i mes l eads t o anaphyl axi s.
e. Appr oxi mat el y 50% of pat i ent s wi t h ast hma hyper secret e Ì gE. Thi s
t endency i s probabl y cont r i but or y, but anci l l ar y, t o t he underl yi ng bronchi al
hyper r eact i vi t y present i n t hese pat i ent s (see Chapt er 48) .
P. 205


6. Syst emi c anaphyI act i c mani fest at i ons of pat hogenesi s. Ì n sensi t i zed
i ndi vi dual s, i nt ravenous i nj ect i on of an al l er gen ( e. g. , bee venom) or
absor pt i on acr oss t he mucous membr anes ( e. g. , peanut s) can cause
syst emi c edema and hypovol emi c shock, wi t h cardi ac arr hyt hmi a,
asphyxi at i on as a resul t of bronchoconst r i ct i on and mucous hyper secr et i on,
and ur t i car i a. Deat h usual l y occurs because of asphyxi at i on. Whi l e ot her
sensi t i zed i ndi vi dual s may have onl y mi l d l ocal sympt oms upon
encount eri ng t he al l ergen, t hese resul t s demonst r at e di f f er i ng host
r esponses t o i dent i cal prot ei ns.
7. Ti me course. Ì mmedi at e hypersensi t i vi t y react i ons have t wo phases. The
earI y react i on, r esul t i ng f r om medi at or secr et i on by mast cel l s, begi ns
wi t hi n 1-2 mi n af t er al l ergen cont act and peaks wi t hi n 1- 2 hr . The I at e-
phase react i on begi ns 6- 12 hr af t er cont act wi t h t he al l er gen and l ast s f or
sever al hours. The l at e-phase react i ons are i ni t i at ed by newl y synt hesi zed
l eukot ri enes and pr ost agl andi ns al ong wi t h cyt oki nes, chemoki nes, and
ot her i nf l ammat or y medi at ors. The l at e- phase react i on i s charact er i zed by
i ncreased numbers of eosi nophi l s and i s mai nt ai ned by t he pr oduct s of
t hese cel l s.
8. Di agnosi s. Ì n scr at ch t est s, a vari et y of al l er gens ar e i nj ect ed
i nt radermal l y t o scr een f or t he presence of a wheal and f l ar e (i . e. , edema
and er yt hema) r esponse i n t he ski n. Radi oaI I ergosorbent ( RAST) and
radi oi mmunosorbent ( RI ST) assays use r adi ol abel ed reagent s t o det ect
ser um Ì gE concent rat i ons. The resul t s of t hese assays do not al ways agree
wi t h each ot her or wi t h cl i ni cal mani f est at i ons of t ype Ì hypersensi t i vi t y.
9. ProphyI axi s
a. Ì dent i f yi ng and avoi di ng al l er gens i s t he most i mpor t ant f orm of
pr ophyl axi s.
b. Hyposensi ti zat i on ( desensi t i zati on) i s per f ormed by i nj ect i ng weekl y,
i ncreasi ng doses of al l ergen i nt ramuscul arl y t o el i ci t an al l er gen- speci f i c
Ì gG r esponse and decr ease t he al l ergen- speci f i c Ì gE. Once desensi t i zat i on
has been achi eved, mont hl y i nj ect i ons are used t o mai nt ai n t he Ì gG l evel s.
Ì gG i s abl e t o bi nd t o t he al l er gen and i nhi bi t i t s bi ndi ng t o t he mast - cel l
bound Ì gE.
10. Therapy
a. Compet i t i ve H1- ant agoni st s of hi st ami ne ar e usef ul i n l ocal f orms but do
not compl et el y r everse t he i nf l ammat i on because hi st ami ne i s not t he onl y
i nf l ammat or y medi at or i n t he r eact i on. Compet i t i ve H1- ant agoni st s have
l i t t l e ef f ect on anaphyl axi s.
b. Epi nephri ne r everses anaphyl axi s t hr ough i t s q- agoni st and 8-agoni st
ef f ect s. Pat i ent s wi t h syst emi c al l er gi es are gi ven epi nephri ne sel f -
admi ni st rat i on ki t s. 82- agoni st s (e. g. , al but erol ) ar e abl e t o promot e
br onchodi l at i on, and q1-agoni st s ( e. g. , phenyl propanol ami ne) decr ease
nasal congest i on.
c. CromoI yn sodi um (cromogl ycat e) i s a l ocal l y admi ni st er ed i nhi bi t or of
mast cel l degranul at i on. GI ucocort i coi ds ar e abl e t o bl ock t he l at e phase
of t he react i on but ar e l ess ef f ect i ve dur i ng t he ear l y phase.
Ant i I eukot ri ene t herapi es are al so abl e t o bl ock t he l at e phase of t he
r eact i on.
d. Topi caI steroi ds i nhi bi t i nf l ammat i on and i mmune r esponses. Topi cal
appl i cat i on vi a spray or i nhal er l i mi t s t he si de ef f ect s seen when
gl ucocor t i coi ds ar e admi ni st er ed syst emi cal l y. Ì n addi t i on t o usi ng t opi cal
st eroi ds al one, t hey ar e al so combi ned wi t h l ong-act i ng 82- agoni st s as
t her apy f or ast hma.
e. Ant i - I gE therapy i s composed of a hi gh-af f i ni t y monocl onal ant i body t o
t he Fc regi on of Ì gE. Ì t i s abl e t o bi nd Ì gE and prevent sensi t i zat i on of mast
cel l s and basophi l s. Thi s t herapy i s usef ul i n hi ghl y at opi c i ndi vi dual s and
i s used f or i ndi vi dual s wi t h sever e ast hma f or whom ot her t her api es have
pr oven i nef f ect i ve.
B. Non- I gE- medi ated t ype I hypersensi t i vi t y react i ons ar e pr obabl y t he
r esul t of several poorl y underst ood causes and are somet i mes cal l ed
anaphyI act oi d react i ons. The f ol l owi ng f act ors may cont ri but e t o and
exacer bat e non- Ì gE-medi at ed t ype Ì react i ons.
1. Respi r at or y 82- r ecept or unr esponsi veness, whi ch l eads t o a di mi ni shed
br onchodi l at or y ef f ect of t he sympat het i c ner vous syst em.
2. Hyper react i vi t y of mast cel l s t hr ough H2- r ecept or unr esponsi veness. Thi s
decreases t he negat i ve f eedback of hi st ami ne on t he act i vat i on of mast
cel l s.
P. 206


C. Type I I hypersensi t i vi t y react i ons
1. Pathogenesi s. Ant i body- medi at ed cyt ot oxi ci t y occurs t hr ough t he
pr oduct i on of Ì gM and Ì gG. These ant i bodi es ar e abl e t o bi nd t o speci f i c
al l er gens l ocat ed on cel l surf aces.
a. These al l er gens may be i nt ri nsi c t o t he cel l ( i . e. , nat ur al cel l -sur f ace
component s) or ext r i nsi c compounds ( i . e. , dr ugs) adsor bed t o t he cel l
sur f ace.
b. Cyt ot oxi ci t y may r esul t f r om act i vat i on of compl ement , phagocyt osi s of
t he Ì gG opsoni zed cel l , or bot h.
c. A t hi r d cyt ot oxi c mechani sm, known as ant i body- dependent , cel l -
medi at ed cyt ot oxi ci t y, i nvol ves t he di rect ki l l i ng of ant i body-coat ed cel l s by
NK cel l s, macr ophages, or eosi nophi l s.
d. Type Ì Ì react i ons may exhi bi t anaphyl act i c si gns and sympt oms i f enough
compl ement i s act i vat ed; however , t hey usual l y do not progress t o t hi s
st age.
2. Common aI I ergens. Type Ì Ì al l er gens are di ver se. Ì t i s t he pat hogeni c
mechani sm t hat i s common t o al l t he r eact i ons.
a. For ei gn bl ood sur f ace ant i gens may act as al l er gens t o produce
t ransf usi on mi smat ches or Rh di sease.
b. Dr ug al l ergens (or dr ug met abol i t e al l ergens) act i ng as hapt ens ar e t he
I eadi ng cause of hemoI yt i c anemi a.
( 1) These al l er gens may di r ect l y adsor b t o cel l sur f aces and be speci f i cal l y
bound by ant i bodi es ( e. g. , peni ci l l i ns, cephal ospor i ns, qui ni di ne) .
( 2) Al t er nat el y, t hey may f orm ser um- phase i mmune compl exes, whi ch
adsor b nonspeci f i cal l y t o bl ood cel l surf aces. Thi s makes t he cel l
suscept i bl e t o l ysi s owi ng t o t he " i nnocent byst ander ¨ ef f ect ( e. g. , ri f ampi n,
sul f onami des, chl orpr omazi ne) .
c. SeI f - ant i gens ar e t he al l er gen i n cer t ai n aut oi mmune di seases ( e. g.
myast heni a gr avi s, aut oi mmune hemol yt i c anemi a; see Ì Ì Ì ) Aut oi mmune
hemol yt i c anemi a i s somet i mes associ at ed wi t h admi ni st r at i on of q-
met hyl dopa, whi ch i nduces aut oant i bodi es agai nst t he r ed bl ood cel l
sur f ace.
d. Hyperacut e rej ect i on of t ranspl ant ed t i ssue (see V)
3. Chemi caI medi at ors. Compl ement prot ei ns produce cyt ot oxi ci t y and
i nf l ammat i on, whi ch st i mul at e macrophages and granuI ocyt es t o secr et e
cyt oki nes and enzymes, whi ch i n t ur n enhance i nf l ammat i on.
4. CI i ni caI sympt oms depend on t he t ype of ant i gen or al l ergen i nvol ved
( see Ì Ì . D. 2) . Hemol yt i c anemi a and t hrombocyt openi a are t he maj or cl i ni cal
si gns of t ype Ì Ì hyper sensi t i vi t y r eact i ons. Ì n hyper acut e gr af t rej ect i on, t he
t r anspl ant ed t i ssue does not successf ul l y per f use because of ant i body-
medi at ed cyt ot oxi ci t y t o t he t r anspl ant ed vascul at ur e.
5. Ti me course
a. Ì n t he f i r st sensi t i zat i on t o a dr ug al l er gen, t he bl ood cel l l ysi s and
i nf l ammat i on begi n 7- 10 days af t er i ni t i at i on of dr ug t her apy. The second
exposur e t o t he dr ug causes sympt oms wi t hi n 3 days.
b. Transf usi on mi smat ch. Hemol ysi s begi ns 1- 2 hr af t er t r ansf usi on. Peak
ef f ect s occur af t er appr oxi mat el y 12 hr.
c. Rh di sease does not occur i n t he f i rst RhD
+
pregnancy of an RhD
-

mot her . Mat er nal Ì gG i s pr oduced i n t he second and subsequent
pr egnanci es af t er t ranspl acent al mat er nal sensi t i zat i on t o t he RhD
+
f et al
r ed bl ood cel l s. Thi s sensi t i zat i on usual l y t akes pl ace i n t he t hi rd t ri mest er .
Mat er nal ant i - RhD Ì gG cr osses t he pl acent a, bi nds t o t he f et al red bl ood
cel l s, and act i vat es t he f et al compl ement syst em pr enat al l y, whi ch l eads t o
per i nat al hemol yt i c anemi a.
6. ProphyI axi s and t herapy. Ì n dr ug- i nduced hyper sensi t i vi t y r eact i ons,
wi t hdr awi ng t he dr ug usual l y r everses t he l ysi s. Pr event i ng r econt act i s t he
best prophyl axi s. Ì n Rh di sease, ant i - RhD i s admi ni st er ed dur i ng pr egnancy
and wi t hi n 72 hr post part um f or each Rh
+
pr egnancy. The si mpl est
expl anat i on f or t he ef f i cacy of ant i - RhD i s t hat t hi s passi ve i mmuni zat i on
( see VÌ . B. 2. d) bi nds t o f et al r ed bl ood cel l s i n t he mat ernal ci r cul at i on and
pr event s sensi t i zat i on of t he mat ernal i mmune syst em.
D. Type I I I hypersensi t i vi t y react i ons i nvol ve t he persi st ence of i mmune
compl exes i n t he ci r cul at i on or at l ocal t i ssue si t es when t hey are not
r emoved af t er pr oduct i on of speci f i c ant i bodi es and ant i gen- ant i body
compl exes. The subt ypes of t ype Ì Ì Ì hypersensi t i vi t y r eact i ons have di verse
causes, and onl y t he pat hogeni c mechani sm i s common t o t hem al l .
P. 207


1. Pathogenesi s. Ì mmune compl exes act i vat e compl ement , cause
i nf l ammat i on, and i nduce posi t i ve chemot axi s i n neut rophi l s. Persi st ence of
i mmune compl exes may be caused by t he f ol l owi ng:
a. A hi gh concent rat i on of ant i gen or ant i body, whi ch l eads t o a di spari t y
i n t he mol ar rat i o of ant i gen t o ant i body and t he pr oduct i on of smal l i mmune
compl exes.
b. Chroni c formati on of i mmune compI exes i n t he ci rcul at i on as a resul t
of persi stence of anti gen as wi t h some chroni c i nf ect i ons.
c. Ot her f act ors t hat cause i nsol ubl e i mmune compl exes t o f orm and
pr eci pi t at e i nt ravascul ar l y or on basement membranes.
2. Common aI I ergens
a. SeI f - anti gens i n most non-organ-speci f i c ( rheumat ol ogi c) aut oi mmune
di sorders (e. g. , syst emi c l upus er yt hemat osus, rheumat oi d ar t hr i t i s)
b. Bact eri aI or prot ozoan ant i gens i n persi st ent or chroni c i nf ecti ons
and i n t he i ni t i al st ages of vi r emi a f or cer t ai n vi ral i nf ect i ons (e. g. ,
pr odrome of hepat i t i s B vi r us i nf ect i on) .
c. Drugs ( e. g. , peni ci l l i n, sul f onami des, t hi our aci l ) .
d. Ant i sera f r om anot her speci es ( e. g. , hor se) , can cause ser um si ckness
when used f or passi ve i mmuni zat i on.
e. FungaI and bact eri aI spores i n t he l ocal r espi r at or y f orm of t he react i on
3. Chemi caI medi at ors. CompI ement protei ns cause i nf l ammat i on and
st i muI at e mast ceI I and basophi I secret i ons, whi ch enhance
i nf l ammat i on. The i ncr eased vascul ar permeabi l i t y al l ows i mmune
compl exes t o l eave t he ci r cul at i on and at t ach t o basement membranes,
whi ch underl ay t he endot hel i al l i ni ng of bl ood vessel s. The ki dney
gl omerul us and smal l ar t er i es ar e par t i cul ar l y suscept i bl e. Compl ement and
mast cel l pr ot ei ns at t r act neut r ophi l s; t hese cel l s can phagocyt i ze i mmune
compl exes and r el ease enzymes t hat damage l ocal t i ssue, t hus i nt ensi f yi ng
i nf l ammat i on. Ì n addi t i on, pl at el et aggr egat i on and mi crot hrombus f or mat i on
may occur .
4. CI i ni caI sympt oms depend on t he severi t y and syst emi c or l ocal nat ure
of i mmune compl ex deposi t i on and per si st ence.
a. The f i r st sympt oms of syst emi c react i ons are l ymphadenopat hy,
spl enomegal y, f ever, and r ash. These are common i n drug-i nduced and
vi r emi a- i nduced t ype Ì Ì Ì hyper sensi t i vi t y r eact i ons.
b. Mor e seri ous sympt oms i ncl ude vascul i t i s and gl omer ul onephr i t i s, bot h of
whi ch may become necrot i zi ng. These sympt oms of t en occur wi t h syst emi c
l upus er yt hemat osus ( SLE) . Ar t hr al gi a and ar t hri t i s occur i n bot h syst emi c
and l ocal r eact i ons.
c. The most common t ypes of l ocal t ype Ì Ì Ì hypersensi t i vi t y react i ons are
pneumoni t i s f r om i nhal ed f ungi and bact er i a t o whi ch t he pat i ent i s
occupat i onal l y exposed (e. g. , mol dy hay i n f armer' s I ung) and r eact i ons t o
spores borne i n aerosol mi cr odr opl et s f rom di r t y ul t rasoni c humi di f i er s
( e. g. , humi di f i er I ung) . The cause of t hese di seases i s not compl et el y
under st ood, but bot h Ì gE and Ì gG ar e i nvol ved. Ì gE causes t he i ni t i al
i nf l ammat i on and t r appi ng of ant i gen, and Ì gG i s r esponsi bl e f or t he l ong-
t er m ef f ect s. Sympt oms i ncl ude
( 1) Nasal congest i on and br onchoconst ri ct i on
( 2) Joi nt pai n and i nf l ammat i on of r heumat oi d ar t hr i t i s caused by j oi nt -
l ocal i zed i mmune compl exes i nvol vi ng rheumat oi d f act or and neut r ophi l
phagocyt osi s ( see Chapt er 49)
5. Ti me course
a. Syst emi c. Ì n pat i ent s wi t h no pr i or exposur e t o t he al l ergen, t he
sympt oms appear i n 1- 2 weeks (possi bl y l onger ) af t er exposure. Ì n pat i ent s
wi t h pr eexi st i ng ant i bodi es, sympt oms appear wi t hi n several hour s t o 1 day
af t er exposure. Sever e sympt oms, such as gl omer ul onephr i t i s, usual l y
r equi r e 2 weeks or mor e t o appear .
b. LocaI . Ì n pat i ent s wi t h pr eexi st i ng ant i bodi es, hypersensi t i vi t y
pneumoni t i s sympt oms appear 6-8 hr af t er exposur e t o t he ant i gen.
6. ProphyI axi s and t herapy. Ì n dr ug- i nduced r eact i ons, wi t hdrawi ng t he
drug usual l y rever ses t he r eact i on. Tr eat ment i ncl udes ant i hi st ami nes or
cor t i cost er oi ds. Tr ansi ent i nf ect i ous f orms r esol ve spont aneousl y as
i mmune compl exes ar e removed by phagocyt es.
E. Type I V hypersensi t i vi t y react i ons
1. Pathogenesi s. Type Ì V r eact i ons i ncl ude pr ol onged i nappr opr i at e and
appropr i at e i mmune r esponses medi at ed by ant i gen- speci f i c TH1 cel l s i n
concert wi t h act i vat ed macr ophages.
P. 208

The TH1 cel l s i nf i l t r at e t i ssues i n whi ch t he ant i gen i s pr esent ed and r ecrui t
and act i vat e macrophages. The r el ease of enzymes and cyt oki nes by t hese
cel l s r esul t s i n i nf l ammat i on and di srupt i on of t i ssue st r uct ur e i n t he
absence of ant i body.
a. React i ons to i nf ecti ons i nvol ve a TH1 r esponse agai nst speci f i c
i nt racel l ul ar bact er i al (e. g. , Mycobact eri a) and prot ozoan par asi t es. When
t he response i s prol onged and i nef f ect i ve, gr anul oma f ormat i on wi l l occur.
b. Contact dermat i t i s i s an i nappropr i at e ski n r eact i on t o hapt ens (e. g. ,
pent adecacat echol s of poi son i vy) , whi ch bi nd t o epi dermal cel l sur f aces
and el i ci t a CTL and TH1 cel l response.
c. TubercuI i n react i on i s obser ved i n t he dermi s and i s an appr opr i at e
r eact i on t o mycobact eri al ant i gens. Thi s react i on i ndi cat es a st at e of act i ve
TH1 i mmuni t y ( owi ng t o an act i ve i nf ect i on) or T cel l memor y t o t he
or gani sm. ( Ì n pat i ent s who had a posi t i ve t ubercul i n r eact i on, a subsequent
negat i ve react i on woul d i ndi cat e i mmunol ogi c aner gy or unr esponsi veness. )
2. Common anti gens
a. I nfecti ous agent s i ncl ude Mycobact er i um t uber cul osi s, M. l eprae,
Li st eri a monocyt ogenes, t r ypanosomes, and vi r uses.
b. Hapten aI I ergens, such as pent adecacat echol s f rom poi son i vy, poi son
oak, chr omat es, ni ckel i ons (l eached f r om wat ch backs and ot her j ewel r y) ,
acr yl at es, hai r dyes t hat cont ai n p-phenyl ene di ami ne, par a- ami nobenzoi c
aci d, and cer t ai n ant i bi ot i c oi nt ment s (e. g. , t opi cal neomyci n), may i nduce
cont act dermati t i s.
c. Ant i gens t hat i nduce a t uber cul i n react i on i ncl ude pur i f i ed prot ei n
der i vat i ve ( PPD), t ubercul i n ( Mant oux r eact i on) , Candi da, mumps, and ot her
ant i gens f r om mi cr oorgani sms.
3. Chemi caI medi at ors ar e i mpor t ant i n t ype Ì V r eact i ons. These medi at or s
ar e cyt oki nes pr oduced by act i vat ed TH1 cel l s. The cyt oki nes at t ract and
act i vat e macr ophages t o t he si t e(s) wher e t he pat hogen/ al l er gen i s l ocat ed.
Ì n t ur n, t he act i vat ed macr ophages secret e cyt oki nes, whi ch are r esponsi bl e
f or i nf l ammat i on and cyt ot oxi ci t y (e. g. , TNF- q) .
4. CI i ni caI sympt oms depend on t he subt ype of r eact i on.
a. Gr anul omas ar e l ocal aggregat i ons of TH1 cel l s, macr ophages, and gi ant
epi t hel i oi d cel l s ( der i ved f r om f usi on of act i vat ed macr ophages) . They occur
at si t es of chroni c i nf ect i on and ser ve t o r est r i ct t he spr ead of t he i nf ect i on.
b. Ì n cont act sensi t i vi t y, cel l ul ar i nf i l t r at i on of t he epi dermi s by CTL, TH1
cel l s, and macr ophages pr oduces mi cr ovesi cl e f or mat i on wi t h spongi osi s.
c. Tuber cul i n t est s cause er yt hema and i ndur at i on as a r esul t of cel l ul ar
i nf i l t rat i on of t he dermi s, but no epi dermal spongi osi s i s obser ved.
5. Ti me course
a. Gr anul omas f orm at var i ous t i mes af t er t he onset of a chr oni c i mmune
r esponse but general l y requi r e a mi ni mum of 2 weeks.
b. Cont act sensi t i vi t y may not occur wi t h t he f i rst t r ansi ent exposur e.
However , i n a sensi t i zed i ndi vi dual , ski n i nf l ammat i on wi l l appear 12-24 hr
af t er cont act wi t h t he ant i gen and peaks bet ween 48 and 72 hr af t er
exposur e.
c. Tuber cul i n r eact i ons f ol l ow t he same t i me course as cont act sensi t i vi t y.
Thi s r eact i on i s of t en cal l ed deI ayed cut aneous hypersensi t i vi t y, or
del ayed- t ype hyper sensi t i vi t y.
6. ProphyI axi s and t herapy. Tr eat ment of gr anul omas depends on t he
or gani sm i nvol ved. Pr oper t r eat ment t o r esol ve t he i nf ect i on wi l l al so ai d i n
r esol vi ng t he chr oni c i mmune r esponse. For cont act sensi t i vi t y, i t i s
necessar y t o i dent i f y t he ant i gen/ al l er gen i nvol ved. Removal and avoi dance
of t he al l er gen i s i mpor t ant f or pr ophyl axi s. For t r eat ment , t opi cal
cor t i cost er oi ds suppr ess T cel l and macr ophage f unct i on. Ì n sever e cases,
or al cor t i cost eroi d t her apy may be r equi r ed.
III. Autoimmunity
i s a t i ssue- damagi ng i mmune r esponse di rect ed speci f i cal l y and
i nappr opr i at el y agai nst one or mor e sel f - ant i gens.
A. The ori gi n of aut oreact i ve i mmune r esponses i s not gener al l y known, but
i t r equi r es l oss of sel f - t ol er ance and der egul at i on of t he cont r ol net wor ks
t hat normal l y prevent devel opment of aut oi mmune di sease. Such
der egul at i on may i ncl ude l ack of r egul at i on of TH and TC cel l s,
P. 209

cr oss- react i vi t y wi t h ant i gens f rom mi croor gani sms, l oss of sel f -t ol er ance or
f ai l ur e t o devel op t ol er ance, and aber rant present at i on of sel f -ant i gen on
speci f i c HLA mol ecul es.
B. Epi demi oI ogy
1. Fami I i aI cI ust eri ng i s evi dent f or many, i f not most , aut oi mmune
r eact i ons r epr esent i ng a compl ex i nheri t ed predi sposi t i on t owar d
aut oi mmuni t y. Ì n most cases, t hi s pr edi sposi t i on i s associ at ed wi t h speci f i c
MHC t ypes, usual l y cl ass Ì Ì mol ecul es ( e. g. , r heumat oi d art hri t i s wi t h t he
MHC cl ass Ì Ì mol ecul e HLA- DR4) .
2. These react i ons are mor e common i n women. The f emal e-t o-mal e rat i o i n
myast heni a gr avi s i s appr oxi mat el y 2: 1 and i n SLE i s appr oxi mat el y 10: 1. Ì n
cont r ast , Sj ögr en' s di sease and Goodpast ure syndr ome ar e more common
i n men t han i n women.
C. Pat hogenesi s
1. Overvi ew. In a speciIic autoimmune disorder. the primary pathogenic
mechanism may be humoral (mediated by antibodies with or without a
contribution by complement). T cell mediated. or involve both humoral and
cell-mediated components. These diseases are commonly associated with
exacerbation and remission oI the disease.
2. Envi ronmentaI fact ors ar e t hought t o cont r i but e t o pat hogenesi s.
However , speci f i c associ at i ons have been f ound i n onl y a f ew cases; t hese
i ncl ude St r ept ococcus group A phar yngi t i s, rheumat i c f ever , exposure t o
or gani c sol vent s, Goodpast ur e syndrome, ul t ravi ol et i r radi at i on, and SLE. Ì t
i s l i kel y t hat envi r onment al f act ors act i n concer t wi t h genet i c
pr edi sposi t i on t o i nduce di sease.
3. Organ-speci f i c and syst emi c ( non-organ- speci f i c) di sorders
a. Organ-speci f i c di sorders (e. g. , ant i t hyr oi d aut oi mmuni t y) are l i mi t ed t o
and di rect ed speci f i cal l y agai nst sel f - ant i gen i n a si ngl e organ. Lesi ons and
cl i ni cal sympt oms are l i mi t ed pr i mari l y t o t hat organ. Cel l ul ar damage may
be medi at ed t hr ough ant i body- medi at ed and compl ement -medi at ed
cyt ot oxi ci t y ( t ype Ì Ì hyper sensi t i vi t y) and/ or t hr ough cel l - medi at ed
cyt ot oxi ci t y ( t ype Ì V hyper sensi t i vi t y) .
b. Syst emi c di sorders (e. g. , SLE)
( 1) These di sor der s ar e al so known as connect i ve t i ssue, col l agen vascul ar ,
or r heumat ol ogi c di sor der s. Aut oant i bodi es ar e f or med agai nst ant i gens
f ound i n most or al l t i ssues, especi al l y t hose l ocat ed i n t he nucl ei of cel l s
and cont ai ni ng DNA, RNA, or nucl ear - associ at ed pr ot ei ns (ant i nucI ear
ant i bodi es) . Pat hol ogi c changes occur syst emat i cal l y, pri mar i l y i n t he
connect i ve t i ssue and are at l east par t i al l y caused by t ype Ì Ì Ì
hyper sensi t i vi t y r eact i ons. Sympt oms may be seen i n t he bl ood vessel s,
ki dney gl omerul i , ski n, j oi nt s, and ser ous membr anes.
( 2) Non- or gan-speci f i c di sor der s are somet i mes di f f i cul t t o di st i ngui sh f rom
one anot her because of t he si mi l ar i t i es i n aut oant i gens and pat hogenesi s.
For exampl e, most pat i ent s wi t h SLE have ci rcul at i ng ant i nucl ear
ant i bodi es; however , t hese al so occur i n 50-65% of pat i ent s wi t h Sj ögr en' s
syndr ome and r heumat oi d ar t hr i t i s as wel l as i n a smal l per cent age of
cl i ni cal l y nor mal i ndi vi dual s. By cont rast , rheumat oi d f act or ( ant i -Ì gG) i s
seen i n 75- 90% of pat i ent s wi t h rheumat oi d ar t hri t i s or Sj ögr en' s syndr ome
as wel l as i n 35% of pat i ent s wi t h SLE. The synovi t i s of rheumat oi d ar t hri t i s
i s of t en a cl i ni cal f i ndi ng i n SLE, and t he vascul i t i s of SLE i s f ound i n
r heumat oi d art hr i t i s (see Chapt er 49) .
D. Organ- speci f i c autoi mmuni t i es
1. Rheumat i c f ever i s not t echni cal l y an aut oi mmune r esponse because
ant i bodi es ar e pr oduced agai nst group A st r ept ococci and cross- r eact wi t h
car di ac muscl e f i ber s t hat are damaged by compl ement . Ì ncreased r i sk i s
r el at ed t o a st r ong i mmune r esponse t o st r ept ococcal M ant i gen.
2. Ant i t hyroi d aut oi mmuni t i es (see Chapt er 52). Aspect s of several
subt ypes may occur i n t he same pat i ent . Ì ncr eased r i sk i s associ at ed wi t h
MHC cl ass Ì Ì t ypes DR3 and DR5.
a. Pri mar y aut oi mmune myxedema. Ant i bodi es agai nst t he t hyr oi d-
st i mul at i ng hormone ( TSH) r ecept or on t hyr oi d f ol l i cl e cel l s act as
ant agoni st s t o t he st i mul at i on of growt h of t he f ol l i cl e cel l s normal l y
pr ovoked by TSH. The r esul t i s t hyr oi d at r ophy wi t h hypot hyr oi di sm.
P. 210


b. Hashi mot o' s t hyroi di t i s. Ant i bodi es agai nst t hyr oi d peroxi dase on
f ol l i cl e cel l s cause cyt ot oxi ci t y and i nf l ammat i on t hr ough t he act i vat i on of
compl ement . Ant i bodi es agai nst t hyr ogl obul i n (col l oi d) al so may be pr esent .
Cel l -medi at ed i mmuni t y may cause some cyt ot oxi c damage. The r esul t i ng
hypot hyr oi di sm i s t r eat ed wi t h synt het i c t hyr oi d hor mone.
c. Grave' s di sease. Ant i bodi es act as agoni st s of TSH, bi ndi ng t o t he TSH
r ecept or and st i mul at i ng hyper secret i on of t hyr oi d hormone ( t hyr oi d-
st i mul at i ng i mmunogl obul i ns) . The r esul t i s hypert hyr oi di sm, whi ch i s
t r eat ed by ant i t hyr oi d drugs ( e. g. , pr opyl t hi ouraci l ) or t hyr oi d abl at i on wi t h
sur ger y or r adi at i on.
3. Myast heni a gravi s
a. Pathogenesi s. Ant i bodi es agai nst t he ni cot i ni c acet yl chol i ne r ecept or on
skel et al muscl e pl asma membr ane at neuromuscul ar j unct i ons act as
compet i t i ve ant agoni st s of acet yI choI i ne bi ndi ng. Thi s act i vi t y causes
weakness and f at i gue i n skel et al muscl es. Ì n addi t i on t o t hi s di rect
bl ockage of neur omuscul ar t r ansmi ssi on, down r egul at i on of r ecept or s and
compl ement damage t o muscl e f i ber s occur. Many pat i ent s have swal l owi ng
and respi rat or y muscl e dysf unct i on t hat may be caused by peni ci l l ami ne
t her apy. Ì ncreased r i sk i s associ at ed wi t h MHC cl ass Ì t ype B8.
b. Therapy. Ant i chol i nest er ase t herapy ( e. g. , neost i gmi ne) i ncreases
acet yl chol i ne synapt i c concent rat i ons ( pr eser vat i on of endogenous
acet yl chol i ne) . Ì mmunosuppressi on wi t h cort i cost er oi ds i s used i n sever e
cases; pl asmapher esi s t o r emove aut or eact i ve ant i bodi es f r om t he bl ood i s
al so hel pf ul . Thymect omy hel ps many pat i ent s.
4. Aut oi mmune perni ci ous anemi a
a. Pathogenesi s. Ant i bodi es agai nst i nt r i nsi c f act or are secr et ed i nt o t he
st omach l umen, wher e t hey i nhi bi t t he associ at i on of i nt ri nsi c f act or wi t h
vi t ami n B12. Thus t he absor pt i on of vi t ami n B12 i s decr eased. Thi s condi t i on
al so can r esul t f rom ant i bodi es agai nst gast ri n recept ors on par i et al cel l s of
t he st omach mucosa t hat bl ock st i mul at i on of t he cel l s by gast ri n and
decrease t hei r secr et i on of i nt r i nsi c f act or .
b. Therapy i s i nt ramuscul ar i nj ect i on of cyanocobal ami n or oral
admi ni st rat i on of concent r at ed i nt r i nsi c f act or prepar at i ons.
5. Goodpast ure' s syndr ome
a. Pathogenesi s. Ant i bodi es agai nst gI omeruI ar capi I I ar y basement
membrane ( GBM) act i vat e compl ement and neut rophi l -medi at ed damage.
Thi s act i vat i on l eads t o gl omerul onephr i t i s, wi t h r api d det eri orat i on of renal
f unct i on. These ant i bodi es cr oss- r eact wi t h pul monar y capi l l ar y basement
membr ane, pr oduci ng pul monar y hemor r hage i n smokers. Ì ncreased r i sk i s
associ at ed wi t h MHC cl ass Ì Ì t ype DR2.
b. Therapy. Ì mmunosuppr essi ve t her apy i ncl udes cor t i cost er oi ds, wi t h
pl asmapher esi s t o r emove aut or eact i ve ant i bodi es.
6. Aut oi mmune hemoI yt i c anemi a ( red bI ood ceI I ) , t hrombocyt openi a
( pI at eI et ), neut ropeni a ( neut rophi I ), and I ymphopeni a ( I ymphocyt e)
a. Pathogenesi s. Ant i bodi es agai nst membr ane ant i gens of one or more of
t he i ndi cat ed cel l t ypes may act i vat e compl ement and opsoni ze t he cel l s f or
r api d spl eni c phagocyt osi s. Ì t may al so occur as par t of t he spect r um of
aut oi mmuni t y i n non-or gan- speci f i c di sorders, par t i cul ar l y SLE. These
aut oi mmune vari et i es must be di st i ngui shed f r om t hose pr eci pi t at ed by
r esponses t o ext er nal ant i gens ( e. g. , dr ugs) but t he cl i ni cal ef f ect s are
si mi l ar .
b. Therapy. These di sorder s are of t en acut e and sel f - l i mi t i ng, but t her apy
i s requi r ed when t hey are chr oni c. Ì n adul t s, t r eat ment begi ns wi t h
cor t i cost er oi ds. Addi t i onal opt i ons are cycl ophosphami de, chl orambuci l , and
i nt ravenous i mmune gl obul i n ( Ì VÌ G).
7. I nsuI i n- dependent di abet es meI I i t us ( Ì DDM; see Chapt er 51).
Pr ogr essi ve and ul t i mat el y compl et e dest ruct i on of pancr eat i c B- i sl et cel l s
occurs i n di abet es. Al t hough t hey ar e pr edi ct i vel y usef ul , ant i bodi es agai nst
i nsul i n and sur f ace cyt opl asmi c ant i gens of t he B-i sl et cel l ar e pr esent
bef ore cl i ni cal onset . The mai n cyt ot oxi c mechani sms appear t o be
medi at ed by T cel l s and macr ophages. Thi s vi ew i s support ed by t he
benef i ci al ef f ect s of cycl ospor i ne t herapy i n pat i ent s wi t h earl y- st age Ì DDM
at l evel s t hat have l i t t l e ef f ect on ant i body pr oduct i on. Ì ncr eased ri sk i s
associ at ed wi t h MHC cl ass Ì Ì t ypes DR3 and DR4, and DQ2 and DQ8.
8. MuI t i pI e scI erosi s (MS)
a. Pathogenesi s. T cel l s and macrophages, whi ch ar e t hought t o be
cyt oci dal f or ol i godendr ocyt es, i nf i l t r at e t he cent ral ner vous syst em ( CNS)
and at t ack the basi c prot ei n of
P. 211

myeI i n as an aut oant i gen. The i mmunol ogi c component may be secondary
t o ot her, unknown i ni t i at i ng agent s. CNS demyeI i nat i on wi t h scI erot i c
pI aques l eads t o spast i ci t y. Ì ncr eased ri sk i s associ at ed wi t h MHC cl ass Ì Ì
t ype DR2. Gui l l ai n- Bar r é syndrome i s a r el at ed condi t i on t hat i nvol ves
per i pheral ner vous syst em ( PNS) demyel i nat i on t hat , unl i ke MS, can be
acut e.
b. Therapy. Spast i ci t y i s t r eat ed wi t h bacI ofen wi t h vari abl e ef f ect i veness.
The peri pher al skel et al muscl e rel axant dant roI ene i s ef f ect i ve i n some
pat i ent s. Adrenocort i cot ropi c hormone ( ACTH), r at her t han
cor t i cost er oi ds, i s t he f avor ed i mmunosuppr essi ve t her apy. Recombi nant
Ì FN- 8- 1b ( Bet aser on) , Ì FN- 8- 1a, and gl at i r amer acet at e ar e appr oved by t he
U. S. Food and Dr ug Admi ni st rat i on (FDA) as a t r eat ment f or MS.
E. Non- organ-speci f i c aut oi mmuni t i es. The si mi l ar i t i es and di f f erences i n
t hi s cl ass of di sorders are shown by a compar i son of Sj ögr en' s syndr ome
and SLE. Rheumat oi d art hr i t i s i s di scussed i n Chapt er 48.
1. Sj ögren' s syndrome
a. Di agnosi s i s usual l y based on l ymphocyt i c i nf i l t rat i on and t he presence
of aut oant i bodi es agai nst sal i var y gl and ant i gens and exocr i ne gl ands of
t he eyes, gast roi nt est i nal and r espi r at or y syst ems, and vagi na.
Hyper gammagl obul i nemi a ( 50%) as a r esul t of hyper act i ve B cel l s,
ant i nucl ear ant i bodi es (50- 65%) , and r heumat oi d f act or s ( ant i -Ì gG; 75- 90%)
ar e pr esent i n t he i ndi cat ed percent ages of pat i ent s.
b. Pathogenesi s. Pr i mary sympt oms i ncl ude i nhi bi t i on of exocri ne gI and
secreti on, wi t h dr yness of t he eyes, mout h, and gast r oi nt est i nal ,
r espi r at or y, and vagi nal mucous membranes; and pai n and edema i n t he
sal i var y gl ands. Pat i ent s wi t h hypergammagl obul i nemi a of t en have t ype Ì Ì Ì
hyper sensi t i vi t y r eact i ons ( e. g. , vascul i t i s wi t h CNS i nvol vement and ki dney
di sease; see Ì Ì . D) .
c. Therapy. Mi l d cases ar e t r eat ed wi t h art i f i ci aI t ears and f r equent
dr i nki ng of wat er . For mor e seri ous cases ( e. g. , vascul i t i s) , t r eat ment i s
si mi l ar t o t hat f or SLE (syst emi c cort i costeroi ds) .
2. SLE ( Syst emi c Lupus Er yt hemat osus)
a. Di agnosi s i s compl i cat ed and depends on t he pr esence of 4 or mor e of
11 cr i t er i a. The most usef ul cr i t eri on i s a hi gh concent r at i on of ant i nucl ear
ant i bodi es di r ect ed agai nst doubl e- st r anded DNA and t he Smi t h ( Sm)
nucl ear ant i gen, bot h of whi ch are consi dered speci f i c f or SLE. Ot her
di agnost i c cr i t eri a i ncl ude t he presence of t he l upus er yt hemat osus cel l (a
neut rophi l t hat has phagocyt osed nucl ei ); a di scoi d er yt hemat ous f aci al
r ash; phot osensi t i vi t y; oral ul cer s; art hri t i s; persi st ent pr ot ei nur i a; and
ant i cardi ol i pi n, ant i er yt hr ocyt e, or ant i l eukocyt e ant i bodi es.
b. Pathogenesi s i s t hat of t ype I I I hypersensi t i vi t y. Pat i ent s have
hyperact i vi t y of B ceI I s of unknown ori gi n. Thi s hyper r eact i vi t y causes
hyper gammagl obul i nemi a, wi t h ci rcul at i ng i mmune compl exes of DNA and
ot her nucl ear ant i gens t hat pr eci pi t at e ont o vascul ar basement membr anes
and act i vat e compl ement .
( 1) Mi l d art hr i t i s, f ever , rash, and f at i gue occur .
( 2) Pr ogr essi ve necrot i zi ng vascul i t i s wi t h CNS i nvol vement and
gl omerul onephr i t i s are t he most ser i ous consequences, occur ri ng i n
approxi mat el y 50% of pat i ent s.
( 3) Hyper t ensi on may devel op secondar y t o ki dney di sease.
( 4) Hemol yt i c anemi a and t hrombocyt openi a are common.
( 5) Behavi oral changes occur i n approxi mat el y 25% of pat i ent s.
( 6) Several dr ugs (e. g. , procai nami de, hydraI azi ne, qui ni di ne,
met hyI dopa, i soni azi d, phenyt oi n, chI orpromazi ne) provoke a l upus- l i ke
syndr ome t hat usual l y r esol ves when t he dr ug i s wi t hdr awn. The basi s f or
t hi s syndr ome i s not under st ood. No r enal di sorder occur s i n dr ug- i nduced
SLE.
c. Therapy. Mi l d di sease ( e. g. , l ow- gr ade f ever, ar t hr i t i s) i s managed wi t h
nonst eroi dal ant i -i nf l ammat or y dr ugs ( NSAÌ Ds) . Ther apy f or pat i ent s wi t h
sever e sympt oms i s usual l y or al met hyl pr edni sol one. Cycl ophosphami de
may al so be used, and pl asmapher esi s t o r emove ci rcul at i ng i mmune
compl exes may be hel pf ul .
F. Prospects f or more speci fi c i mmunoI ogi c t herapi es. Cur r ent t herapi es
i nvol ve appr oaches t hat suppr ess al l i mmune r esponses; however , cur r ent
cl i ni cal t ri al s seek t o suppr ess onl y l ymphocyt es t hat ar e act i vat ed÷f or
exampl e:
1. Feedi ng aut oant i gens t o pat i ent s t o i nduce i mmunol ogi c suppr essi on
2. Vacci nat i on wi t h autoreacti ve T ceI I s t o i nduce i mmunol ogi c
suppr essi on
P. 212


3. Admi ni st r at i on of ant i - TH monocl onal ant i bodi es (par t i cul ar l y ant i - CD4) t o
el i mi nat e aut oreact i ve T cel l s
4. Admi ni st r at i on of conj ugat es of I L-2 and t oxi ns f rom pl ant s or bact er i a
t o el i mi nat e aut oreact i ve T cel l s wi t hout gener al i zed T cel l suppr essi on
IV. Immunodeficiency
i s ei t her pr i mar y or secondar y. Pri mar y i mmunodef i ci enci es are ei t her
heredi t ar y or congeni taI , and at l east one el ement basi c t o t he i mmune
syst em does not f unct i on pr oper l y or i s absent . Secondar y
i mmunodef i ci enci es are t he resuI t of anot her syst emi c di sor der or ar e
i at rogeni c i n pat i ent s gi ven i mmunosuppressi ve t herapy. They usual l y
devel op i n pat i ent s who pr evi ousl y showed normal i mmune f unct i on. The
expect ed cl i ni cal out come of an i mmunodef i ci ency i s gover ned by t he
speci f i c por t i on of t he i mmune syst em t hat i s af f ect ed ( e. g. , B and T cel l s,
phagocyt i c cel l s, and compl ement ).
A. Pri mar y i mmunodefi ci enci es are, wi t h one except i on, r are. Exampl es
ar e t he f ol l owi ng:
1. X- I i nked agammagI obuI i nemi a ( hypogammagl obul i nemi a) i s an i nher i t ed
def i ci ency i n ant i body product i on (humoral i mmuni t y) i n whi ch T cel l
f unct i on i s r el at i vel y normal , but B cel l s do not f ul l y mat ur e because of a
f ai l ur e of B cel l si gnal i ng. Ser um i mmunogl obul i n l evel s are l ow. Because
t hi s di sor der i s l i nked t o t he X chr omosome, i t occurs pri mar i l y i n men.
a. Pathogenesi s occurs 6- 9 mont hs af t er bi rt h and r epr esent s si t uat i ons i n
whi ch ant i body f unct i on i s def i ci ent but T- cel l f unct i on i s i nt act , such as
r ecur r ent i nf ect i ons wi t h ext r acel l ul ar pyogeni c bact er i a ( e. g. , st rept ococci ,
pneumococci , Haemophi l us) . Ì mmuni t y t o f ungi and most vi r uses i s
gener al l y f unct i onal .
b. CI i ni caI sympt oms i ncl ude pneumoni a, si nusi t i s, ot i t i s, meni ngi t i s, and
sept i cemi a.
c. Therapy i s passi ve i mmuni zat i on wi t h human i nt ravenous
i mmunogI obuI i n ( Ì VÌ G; see VÌ . B. 1. c) .
2. Common vari abI e i mmunodef i ci ency i s an acqui r ed def i ci ency of B cel l
mat ur at i on t o pl asma cel l s. Ì t can occur at any age and i n ei t her sex.
Sympt oms and t reat ment ar e si mi l ar t o t hose f or X- l i nked
agammagl obul i nemi a; t he pat hogenesi s and ori gi n var y si gni f i cant l y.
3. SeI ecti ve I gA def i ci ency i s t he most common pr i mar y i mmunodef i ci ency,
af f ect i ng appr oxi mat el y 0. 5% of t he U. S. popul at i on. Ì t appears t o be
i nher i t ed. The l ow secret or y Ì gA (sÌ gA) concent r at i on pr edi sposes pat i ent s
t o ext r acel l ul ar bact er i al i nf ect i ons of t he mucosal sur f aces, l eadi ng t o
r espi r at or y, ur ogeni t al , and gast r oi nt est i nal i nf ect i ons. Some af f ect ed
i ndi vi dual s are asympt omat i c f or unknown r easons. Cer t ai n aut oi mmuni t i es
may be mor e pr eval ent . Ther e i s no speci f i c i mmunol ogi c t her apy.
4. Di George syndrome resul t s f rom devel opment al f ai l ur e of t he t hymus
and parat hyr oi d gl ands, accompani ed by cardi ovascul ar and ot her
devel opment al anomal i es. Pat i ent s have a decr ease i n t ot al T cel l number s
but rel at i vel y normal i mmunogl obul i n l evel s.
a. Pathogenesi s i n sever e cases ( i . e. , l i t t l e f unct i onal t hymi c t i ssue)
r epr esent s condi t i ons i nvol vi ng T cel l def i ci ency, such as r ecur rent
i nf ect i ons of t he ski n, l ungs, geni t ouri nar y t r act , and bl ood wi t h
oppor t uni st i c pat hogens, par t i cul ar l y vi r uses (e. g. , her pes vi ruses) , f ungi
( e. g. , Candi da) , and prot ozoa ( e. g. , Pneumocyst i s car i ni i ) ; i ncr eased
i nci dence of cer t ai n cancer s; gr af t - versus- host ( GVH) di sease ( see V. C)
af t er t r ansf usi on of whol e bl ood; and deat h i n i nf ancy or ear l y chi l dhood.
b. Therapy f or sever e T cel l def i ci enci es i s bone mar row t r anspl ant at i on,
al t hough t hymus gr af t s may be at t empt ed i n Di Geor ge syndr ome ( see V. C) .
5. NezeI of syndrome i s pr obabl y i nher i t ed and causes l ymphopeni a and
t hymi c abnor mal i t i es but normal or el evat ed ser um i mmunogl obul i n l evel s.
Gr am- negat i ve sepsi s may occur i n addi t i on t o t he oppor t uni st i c i nf ect i ons
associ at ed wi t h T cel l def i ci ency.
6. Severe combi ned i mmunodef i ci ency di sorders ( SCI Ds) are a
het erogeneous group of i nher i t ed di sor ders wi t h def i ci enci es i n T cel l s, B
cel l s ( var i abl e) , and ser um i mmunogl obul i n. Ì nf ect i ons wi t h oppor t uni st i c
or gani sms occur i n t he f i r st f ew mont hs post nat al l y, and sur vi val f or l onger
t han 1 year i s rar e wi t hout successf ul bone mar row t r anspl ant at i on. Thr ee
f or ms i nvol ve f ai l ure of DNA bi osynt hesi s or repai r , and a f ourt h def ect i s
t he resul t of def i ci ency of t he v chai n of t he Ì L- 2 recept or.
P. 213


7. Chroni c granuI omat ous di sease ( CGD) i s a def ect i n t he abi l i t y of
phagocyt es t o ki l l bact eri a. The di sease i s caused by a genet i c def ect i n t he
pr oduct i on of oxygen r adi cal s t hat ar e i mpor t ant f or i nt r acel l ul ar and
ext r acel l ul ar ki l l i ng of bact eri a. The def ect can occur i n any of t he f our
pr ot ei ns essent i al f or produci ng oxygen r adi cal s, but t he most common
def ect i s X- l i nked. CGD i s charact er i zed by chroni c i nf ect i on wi t h or gani sms
such as St aphyl ococcus aur eus and i s usual l y f at al .
8. Leukocyt e adhesi on def i ci ency ( LAD) i s associ at ed wi t h a def ect i n t he
phagocyt i c cel l s. These cel l s l ack i nt ercel l ul ar adhesi on mol ecul es, t he
pr ot ei ns necessar y f or bi ndi ng t o t he endot hel i al cel l s of t he bl ood vessel s
and ot her cel l membr anes. Thi s def ect l eads t o an i nabi l i t y of phagocyt i c
cel l s t o exi t t he bl ood and ent er t he t i ssues. Ì n addi t i on, t he phagocyt es
have a decr eased abi l i t y t o bi nd t o act i vat ed component s of compl ement on
a bact er i al sur f ace, l eadi ng t o a decr ease i n phagocyt osi s. Pat i ent s have
sever e bact er i al i nf ect i ons, especi al l y i n t he mout h and gast r oi nt est i nal
t r act .
9. Chédi ak- Hi gashi syndrome i s a def i ci ency i n t he f usi on of l ysosomes
wi t h phagocyt i c vesi cl es. The cause i s unknown, but t hi s syndr ome l eads t o
bact er i al sur vi val i n t he phagocyt e, wi t h an i ncr ease i n bact er i al i nf ect i ons.
10. Def ects i n compI ement may be t he r esul t of def ect s i n t he act i vat i on
pat hways, membrane at t ack compl ex, or regul at or y pr ot ei ns. Def ect s i n t he
act i vat i on pat hways and i n t he membrane at t ack compl ex ar e associ at ed
wi t h i ncr eased i nf ect i ons owi ng t o pyogeni c bact er i a and wi t h i ncreased
r at es of i mmune compl ex di seases, such as SLE. Def ect s i n r egul at i on can
be obser ved as angi oneur ot i c edema and noct urnal paroxsysmal
hemogl obi nuri a.
B. Secondar y i mmunodef i ci enci es i nvol ve decreased i mmunol ogi c
r esponsi veness.
1. Cyt ot oxi c drugs pr event t he di vi si on of respondi ng l ymphocyt es,
suppr ess t he product i on of bl ood cel l s i n bone mar r ow, and may di rect l y ki l l
cel l s. Pat i ent s who r ecei ve chemot her apy and exhi bi t a si gni f i cant l oss of
neut rophi l s may be t reat ed wi t h f i l gr ast i m or r ecombi nant granul ocyt e
col ony- st i mul at i ng f act or ( G- CSF; Neupogen) , t o r est or e t he whi t e bl ood
cel l count t o normal l evel s. Tr eat ment t o i ncr ease neut r ophi l l evel s i n t hese
pat i ent s resul t s i n decr eased mor bi di t y r at es f r om bact er i al i nf ect i on.
Cor t i cost eroi ds br oadl y suppress i mmune syst em cel l s, i ncl udi ng decreased
di vi si on, cyt oki ne secret i on, and chemot axi s (emi gr at i on f r om t he bl ood i nt o
t i ssues) .
2. Leukemi as, I ymphomas, and myeI omas ar e associ at ed wi t h decr eased
i mmune r esponsi veness, at l east some of whi ch resul t s f rom dest r uct i on of
t he ar chi t ect ur e of l ymphoi d or gans ( e. g. , spl een, l ymph nodes) .
Mal i gnancy- r el at ed i mmunodef i ci ency al so occurs i n ot her cancers.
3. Protei n-caI ori e maI nut ri t i on si gni f i cant l y decr eases i mmune
compet ence, par t i cul ar l y i n chi l dr en.
4. Agi ng i s associ at ed wi t h decr eased i mmunol ogi c compet ence.
5. Acut e i nf ect i ons produce a t r ansi ent i mmunodef i ci ency.
6. AI DS i s a secondar y i mmunodef i ci ency t hat i s usual l y persi st ent and i s
an i ndi r ect consequence of i nf ect i on by HI V-1 or HI V- 2. HÌ V-1 i s t he mor e
common subt ype i n t he Uni t ed St at es and west er n Eur ope.
a. Pathogenesi s. The vi r al envel ope gl ycoprot ei n 120 ( gp120) has a st rong
af f i ni t y f or CD4 ( see Ì . B. 3. c), al l owi ng t he vi r us t o di r ect l y i nf ect TH cel l s.
Ì n addi t i on, t hese pr ot ei ns use one of t wo chemoki ne r ecept ors: CCR5 t o
gai n ent r y t o macrophages and dendri t i c cel l s and CXCR4 t o gai n ent r y i nt o
CD4
+
T cel l s. Because i t i s a ret r ovi rus, vi r al ent ry and uncoat i ng r el ease
t he vi ral RNA genome and t he associ at ed rever se t r anscr i pt ase enzyme,
whi ch synt hesi zes a doubl e-st randed DNA copy of t he genome ( pr ovi rus) .
The pr ovi ral copy i s i nt egr at ed i nt o t he genome of t he i nf ect ed cel l , and t he
vi r us ent er s a per i od of l at ency, dur i ng whi ch i t i s essent i al l y hi dden f r om
t he i mmune syst em.
( 1) Duri ng i ni ti aI i nfect i on, t her e may be an acut e i l l ness t hat l ast s an
aver age of 3 weeks and r esembl es mononucl eosi s; some i ndi vi dual s have
no sympt oms.
( 2) Seroconversi on (i . e. , t he appear ance of ant i vi r al ant i bodi es) occurs 3
weeks t o 6 mont hs af t er t he i ni t i al exposur e t o HÌ V- 1. A peri od of
asympt omat i c i nfecti on t ypi cal l y f ol l ows ser oconver si on.
P. 214


( 3) Ì nf ect ed TH cel l s are ki l l ed when vi raI genes are react i vat ed f rom
I at ency and vi r uses bud f r om t he cel l . Ì n addi t i on, i nf ect ed TH cel l s may
f use t o f orm syncyt i a. Thi s f usi on may hast en t he spread of vi r us t o
uni nf ect ed TH cel l s and cont ri but e t o cel l ki l l i ng. A progressi ve depI et i on
of TH cel l s occur s ( normal count : 800- 1000/ mm
3
). However , even bef or e an
obvi ous l oss of CD4
+
T cel l s occurs, t here i s evi dence of a def ect i n CD4
+
T
cel l f unct i on. The f unct i onal def ect i s a f ai l ur e of t hese cel l s t o r espond t o
ant i gens t o whi ch t hey wer e pr evi ousl y sensi t i zed ( e. g. , t et anus t oxoi d).
The def ect i n r esponsi veness may be a f unct i on of t he CD4
+
T cel l s, t he
APCs, or bot h.
( 4) Macr ophages may produce new vi r us wi t hout bei ng ki l l ed and may
spr ead t he vi r us t o uni nf ect ed TH cel l s and ot her cel l t ypes. CD4
+
cel l l i nes
t hat ar e suscept i bl e t o HÌ V i nf ect i on i ncl ude neurons, l i ver , and f i br obl ast s.
Ì n di r ect cel l - t o- cel l t ransf er of t he vi r us, mi ni mal exposur e t o t he
ext r acel l ul ar i mmune syst em ( e. g. , ant i body) may occur .
( 5) APCs ar e al so af f ect ed by t he i nf ect i on. There i s a l oss of f ol l i cul ar
dendr i t i c cel l s and i nt er di gi t at i ng cel l s i n t he l ymphoi d t i ssue. Thi s l oss
l eads t o decr eased ant i gen present at i on t o t he CD4
+
T cel l s. Ì n addi t i on,
t he cyt oki nes pr oduced by t he APCs may pr oduce CD4
+
T cel l s t hat
i ncrease B cel l act i vat i on but do not pr oduce t he appropri at e cyt oki nes f or T
cel l pr ol i f erat i on. Thi s act i vi t y changes t he TH cel l r at i os.
b. CI i ni caI sympt oms
( 1) Persi stent generaI i zed I ymphadenopat hy ( ext r ai ngui nal ) i s an
i ndi cat or of i mpendi ng progr essi on t o f ul l di sease. Unexpl ai ned f ever, ni ght
sweat s, di ar r hea, and ot her sympt oms known as AI DS- reI at ed compI ex
( ARC) may occur .
( 2) Pr ogr essi on t o f ul l -bl own AÌ DS may occur 8 year s or l onger af t er t he
i ni t i al i nf ect i on. Depl et i on of t he TH cel l l evel t o < 200/ mm
3
and oral
candi di asi s suggest i mmi nent di sease. Because CD8
+
T cel l s ar e not
si gni f i cant l y af f ect ed, t he r at i o of ci rcul at i ng CD4
+
t o CD8
+
cel l s i s i nvert ed.
Ì n addi t i on, t he number of vi r gi n TH cel l s r el at i ve t o memor y TH cel l s
i ncreases. TH cel l s ar e l ost , and memor y TH cel l s ar e l ost i n rel at i vel y
l ar ger numbers. There i s al so a shi f t i n t he t ype of TH cel l hel p bei ng
gener at ed.
( 3) A di agnosi s of AÌ DS i nvol ves t he occur r ence of opport uni st i c
i nf ecti ons or neopI asms as a resuI t of the progressi ve
i mmunodef i ci ency caused by severe depl et i on of TH cel l ( CD4) f unct i on.
Al so i ncl uded i n t hi s di agnosi s are t he HÌ V wast i ng syndr ome and
encephal opat hy.
( a) Oppor t uni st i c i nf ect i ons ar e t he maj or consequence of AÌ DS, par t i cul ar l y
by P. car i ni i ( as many as 80% of pat i ent s) , Candi da al bi cans,
Mycobact eri um avi um- i nt r acel l ul ar e, herpes si mpl ex vi r us ( HSV) ,
cyt omegal ovi rus ( CMV) , and ot her s. Tubercul osi s occurs as a r eact i vat i on
of a l at ent i nf ect i on i n car r i ers. Cumul at i vel y, these opport uni sti c
i nf ecti ons are t he pri mar y cause of deat h.
( b) Kaposi sarcoma, an ot her wi se rar e cancer , occur s i n f ewer t han one
hal f of pat i ent s wi t h AÌ DS. Non- Hodgki n l ymphoma i s al so mor e common i n
t hese i ndi vi dual s t han i n t he gener al popul at i on.
( 4) HI V-associ at ed dement i a compI ex ( HADC) af f ect s mor e t han one hal f
of pat i ent s wi t h AÌ DS. Ì n HADC, macrophages i nf i l t rat e t he br ai n and are
t he most pr oduct i vel y i nf ect ed cel l i n compar i son t o neur ons or gl i a. Some
pat i ent s show demyel i nat i on.
( 5) Ot her i mmune syst em abnormal i t i es i ncl ude pol ycl onal B cel l act i vat i on
and hypergammagl obul i nemi a wi t h a concomi t ant decreased abi l i t y t o mount
humor al i mmune r esponses t o speci f i c ant i gens. Chemot axi s, cyt oki ne
secr et i on, and cyt ot oxi c abi l i t y of monocyt e- macrophages ar e al l
di mi ni shed. These probl ems are consequences of i mpai r ed T cel l
r egul at i on.
c. Therapy
( 1) Cur rent t her apy i ncl udes pr ophyl act i c use of ant i bi ot i cs and ant i f ungal
agent s. Opt i mal ant i - HÌ V t herapy i s combi nat i on t her apy wi t h t hree
ant i r et rovi r al drugs. At pr esent , t her e ar e f our cl asses of ant i r et rovi r al
dr ugs approved by t he FDA. These ar e nucl eosi de r everse- t r anscr i pt ase
i nhi bi t ors ( NRTÌ s; e. g. , zi dovudi ne- AZT, l ami vudi ne, st avudi ne, zal ci t abi ne-
ddC, di danosi ne-ddÌ , and abacavi r ) , nonnucl eosi de r ever se- t r anscr i pt ase
i nhi bi t ors ( NNRTÌ s; e. g. , nevi r api ne, del avi r di ne, ef avi r enz) , prot ease
i nhi bi t ors ( e. g. , saqui navi r , i ndi navi r, r i t onavi r , nel f i navi r ) and i nt egrase
i nhi bi t ors ( e. g. , r al t egr avi r ) . Ì FN- q i s r ecommended f or t he t reat ment of
Kaposi sarcoma. Ot her dr ugs and i mmunomodul at or s ar e curr ent l y under
devel opment and t est i ng.
P. 215


( 2) An ef f ect i ve act i ve vacci ne i s necessar y t o l i mi t t he spr ead of HÌ V
i nf ect i on. Because of vi ral ant i geni c var i at i on, cel l - t o- cel l t r ansmi ssi on, and
t he uncer t ai n r ol e of ant i bodi es i n prot ect i on, t he pr ocess of vacci ne
devel opment i s di f f i cul t . A l i ve, at t enuat ed vacci ne ( see VÌ . C. 2) i s
consi dered t oo gr eat a r i sk. Tr i al s of subuni t vacci nes ar e under way.
V. GRAFT REJECTION
A. Over vi ew. Ì ndi vi dual di f f er ences i n t he mol ecul ar st ruct ur es of cel l s and
t i ssues occur, except i n i dent i cal t wi ns, because of t he genet i c vari at i on
i nher ent i n humans. Because of t hese mol ecul ar di f f er ences, t r anspl ant ed
t i ssues or or gans ( i . e. , gr af t s) are l i kel y t o be ant i geni cal l y di f f erent f r om
t he reci pi ent and t heref or e may st i mul at e an i mmune response.
1. Al t hough MHC cl ass Ì and Ì Ì gl ycopr ot ei ns pl ay an essent i al rol e i n al l T
cel l i mmune r esponses (see Ì . B. 3. a), t hese mol ecul es ar e part i cul ar l y
ant i geni c and vari ant i n st r uct ur e among di f f erent humans (pol ymorphi c) .
2. Each person' s set of MHC gl ycoprot ei ns i s cal l ed hi s or her human
I eukocyt e ant i gen ( HLA) , or hi stocompati bi I i t y t ype. Cl ass Ì
gl ycopr ot ei ns ar e known as HLA- A, - B, and - C ant i gens. Cl ass Ì Ì
gl ycopr ot ei ns ar e known as HLA- DR, - DP, and - DQ ant i gens. Each person
r ecei ves one set of genes ( a hapl ot ype) encodi ng t hese pr ot ei n ant i gens
f r om each parent .
3. Ì dent i cal t wi ns have t he same hi st ocompat i bi l i t y t ype. For ot her si bl i ngs,
t he pr obabi l i t y i s appr oxi mat el y 25% (0. 25) t hat t wo si bl i ngs wi t h t he same
par ent s ar e HLA i dent i cal , or mat ched, and appr oxi mat el y 50% t hat t hey ar e
one hal f HLA mat ched, or hapl oi dent i cal . Par ent s and chi l dr en are al most
al ways hapl oi dent i cal . Some t r anspl ant ed t i ssues are r ej ect ed because of
HLA i ncompat i bi l i t y. Ì n ot her cases, t he r eason f or r ej ect i on i s t he resul t of
mi nor hi st ocompat i bi l i t y ant i gens or i s unknown. HLA mat chi ng i s not
al ways a f act or i n rej ect i on.
B. Common soI i d- organ t ranspI ants ar e ki dney, heart , l i ver , hear t -l ung,
and pancreas. Or gans are obt ai ned f r om cadavers or l i vi ng donors. The
pr obabi l i t y of an exact HLA mat ch i n a cadaver gr af t i s appr oxi mat el y 1 i n
10 mi l l i on.
1. HLA mat chi ng
a. The pr i mar y probl em wi t h or gan donat i on i s rej ect i on of t he t ranspl ant ed
or gan by t he host ' s i mmune response. Donat i on of an organ by an HLA-
mat ched si bl i ng i s t he best way t o avoi d t hi s pr obl em.
b. Al t hough HLA- DR and HLA- B mat chi ng decr eases t he r ej ect i on r eact i on
i n renal and cardi ac gr af t s, rej ect i on does occur i n HLA-mat ched si t uat i ons.
HLA mat chi ng i s not i mpor t ant i n l i ver t ranspl ant at i on.
2. Types of rej ect i on of organ graf ts
a. Hyperacut e rej ect i on i s medi at ed by pr eexi st i ng ant i body i n t he
r eci pi ent , usual l y agai nst ABO mi smat ches. Compl ement i s act i vat ed,
cl ot t i ng occurs, and t he vascul at ur e of t he t r anspl ant ed or gan i s occl uded.
Rej ect i on occurs wi t hi n 2 days af t er t r anspl ant at i on. An ABO-mi smat ched
gr af t i s r arel y at t empt ed. Rej ect i on i s essent i al l y unt r eat abl e.
b. Acut e rej ecti on i s a T cel l -macr ophage-medi at ed at t ack on t he gr af t
based on HLA and ot her t i ssue ant i gen mi smat ches. T cel l s and
macr ophages i nf i l t r at e t he gr af t and, i n 10- 14 days, cause cel l ul ar necrosi s
and i nf l ammat i on peri vascul arl y. The ent i r e gr af t begi ns t o necrose i f
unt r eat ed.
c. Chroni c rej ect i on occurs sever al mont hs t o sever al year s af t er
t r anspl ant at i on. Ì t causes f i br osi s and occl usi on of smal l ar t er i es and
ar t eri ol es i n t he ki dneys and at her oscl erosi s i n t he hear t . Ì t i s cont rol l ed by
i mmunol ogi c i nj ur y and medi at ed pr i mari l y by ant i body and i ncl udes t he
r el ease of i nf l ammat or y cyt oki nes by macrophages. Despi t e t he hi gh
success r at e of MHC- mat ched, phar macol ogi cal l y t r eat ed gr af t s i n t he f i r st
year af t er t r anspl ant at i on ( 85- 90% ki dney graf t s), t he r ej ect i on rat e af t er 5
year s i s near l y 50%. Thi s f or m of rej ect i on i s r el at i vel y resi st ant t o t her apy,
al t hough t reat ment wi t h cor t i cost er oi ds can be hel pf ul .
C. Bone marrow t ranspI ant at i on i s somet i mes at t empt ed i n pat i ent s wi t h
i mmunodef i ci ency di seases, apl ast i c anemi as, some l eukemi as, and cer t ai n
genet i c di seases. The graf t cont ai ns a
P. 216

hi gh proport i on of donor l ymphocyt es t hat r espond t o t he host HLA and
ot her ant i gens. Thi s response causes graf t - ver sus- host ( GVH) di sease.
1. Gr af t T cel l recogni t i on of t he host i s i mpor t ant i n GVH di sease, as
shown by t he decr eased i nci dence of GVH di sease af t er pr ocedur es t hat
pur ge mat ur e T cel l s f r om t he donor mar r ow.
2. CI i ni caI sympt oms of GVH di sease ar e seen i n t he ski n (e. g. , r ash,
desquamat i on) , gast r oi nt est i nal t ract ( e. g. , pai n, vomi t i ng, i nt est i nal
bl eedi ng) , and l i ver (e. g. , necr osi s i ndi cat ed by i ncr eased serum bi l i rubi n
l evel s) . Deat h commonl y occurs.
3. HLA mat chi ng i s i mpor t ant i n bone marr ow t r anspl ant at i on, but t he f ai l ur e
r at e even of mat ched graf t s as a r esul t of GVH di sease i s hi gh.
4. Because t he r eci pi ent of t he mar row ( host ) i s i mmunosuppr essed, owi ng
t o pri mar y i mmunodef i ci ency or by dr ugs or r adi at i on, host rej ect i on of
t r anspl ant ed bone mar row i s l ess i mport ant .
D. ProphyI axi s and t reat ment of graf t rej ecti on
1. I mmunosuppressi on of t he graf t reci pi ent
a. Cort i costeroi ds (e. g. , met hyl pr edni sol one, predni sone) ar e admi ni st ered
j ust bef ore t ranspl ant at i on and rapi dl y t aper ed because of t hei r si de
ef f ect s. Cor t i cost eroi ds ar e used i n combi nat i on wi t h azat hi opri ne,
cycl ospor i ne, or ant i I ymphocyt e gI obuI i ns/ ant i thymocyt e gI obuI i ns
( ALGs/ ATGs) .
b. Azat hi opri ne i s gi ven bef or e t r anspl ant at i on. Mai nt enance doses ar e
gi ven af t er war d.
c. Met hot rexat e i s used pr i mar i l y f or bone mar row t r anspl ant at i on i n
combi nat i on wi t h ALG/ ATG. Ì t i s admi ni st ered ei t her a f ew days bef or e or at
t he t i me of t ranspl ant at i on.
2. Speci fi c suppressi on of T ceI I s
a. CycI ospori ne A ( cycl ospor i n) bi nds t o an i nt racel l ul ar prot ei n known as
cycl ophi l i n and bl ocks t he t r anscr i pt i on of cyt oki ne genes i n a T cel l t hat
has r ecogni zed ant i gens. Ì n t hi s way, i t i nhi bi t s TH cel l secr et i on of Ì L-2 and
pr oduct i on of t he hi gh- af f i ni t y Ì L-2 r ecept or and pr event s compl et e T cel l
act i vat i on. Ì t i s admi ni st er ed pr ophyl act i cal l y because i t i s more ef f ect i ve i f
i t i s pr esent bef ore r ej ect i on begi ns. Cycl ospor i ne A i s commonl y combi ned
wi t h ot her agent s. The maj or si de ef f ect i s nephr ot oxi ci t y.
b. TacroI i mus ( FK- 506) i s an i mmunosuppr essi ve agent t hat i nhi bi t s TH
cel l f unct i on i n t he same way as cycl ospori ne A. Bot h dr ugs f unct i on
t hr ough t he same pat hway and ar e not used t oget her .
c. Rapamyci n ( si r ol i mus) i nhi bi t s TH cel l response t o Ì L-2 and pr event s TH
cel l act i vat i on. Ì t wor ks t hr ough a di f f er ent pat hway t han ei t her cycl ospor i ne
or t acr ol i mus and i s especi al l y ef f ect i ve i n combi nat i on wi t h t he ot her
dr ugs.
d. ALG and ATG ar e ant i sera der i ved f rom ani mal s. They cont ai n a var i et y
of ant i body speci f i ci t i es agai nst T cel l ant i gens. They ar e used bot h
pr ophyl act i cal l y and t herapeut i cal l y i n bone mar row and organ
t r anspl ant at i on.
e. Muromonab- CD3 ( OKT3) i s a mouse monocl onal ant i body speci f i c f or t he
CD3 ant i gen, whi ch i s present on al l peri pher al T cel l s. OKT3 i s used
t her apeut i cal l y t o hal t and r everse acut e r ej ect i on as soon as i t i s
di agnosed.
( 1) Ì t s mai n act i on i s t he opsoni zat i on of T cel l s f or enhanced phagocyt osi s.
Ì t i s admi ni st er ed dai l y f or 10- 14 days. Onl y one course i s t ypi cal l y used
because i t causes an i mmune r esponse agai nst t he f or ei gn mouse ant i body.
( 2) Acut e si de ef f ect s are common, probabl y because of nonspeci f i c T cel l
act i vat i on t hat causes t he r el ease of cyt oki nes. Si de ef f ect s i ncl ude hi gh
f ever , chi l l s, bl ood pr essur e changes, vomi t i ng, di ar r hea, and r espi r at or y
di st r ess. OKT3 i s cont rai ndi cat ed i n pat i ent s who have f l ui d over l oad
because i t may cause f at al pul monar y edema.
( 3) OKT3 may al so be used i n vi t ro t o pur ge donor bone mar row of T cel l s
t o r educe t he r i sk of GVH di sease.
3. I nvest i gat i onaI agents bei ng t est ed t o prevent or rever se graf t r ej ect i on
i ncl ude ant i - T cel l i mmunot oxi ns ( see VÌ Ì . C. 1) , conj ugat es of Ì L-2 and a
t oxi n, and ot her monocl onal s t hat pr event T cel l s f r om adheri ng t o f or ei gn
gr af t cel l s. These agent s ar e admi ni st ered t o t he gr af t r eci pi ent . Ì n addi t i on,
monocl onal ant i bodi es ar e used t o mask HLA ant i gens on t he gr af t t i ssue
bef ore i t i s t r anspl ant ed i nt o t he r eci pi ent .
P. 217


VI. VACCINATION
A. Over vi ew
1. Passi ve vacci nat i on i s t he i nt r amuscul ar or i nt r avenous i nj ect i on of
ant i body pr epar at i ons t o enhance a pat i ent ' s i mmune compet ence.
Pr ot ect i on depends on t he ser um hal f - l i f e of t he i nj ect ed ant i body and i s
l i mi t ed t o sever al weeks t o sever al mont hs f or each admi ni st r at i on of human
ser a.
2. Act i ve vacci nat i on i s t he i nt r amuscul ar, subcut aneous, or or al
i nt roduct i on of one or mor e ant i gens desi gned t o st i mul at e t he i mmune
syst em t o pr oduce a speci f i c i mmune r esponse. Thi s r esponse gener at es
ant i body, act i vat ed T cel l s, and speci f i c memor y. Pr ot ect i on t hr ough
memor y var i es wi t h t he vacci ne, but i mmuni t y i s l ong l ast i ng.
B. Passi ve vacci nat i on ( Tabl e 10- 2)
1. Preparat i ons. Doses of i nt r amuscul ar prepar at i ons ar e somet i mes gi ven
i n uni t s per ki l ogr am and somet i mes i n mi l l i l i t ers per ki l ogram. The dose
var i es wi t h t he vacci ne and pat i ent popul at i on. Ì nt r avenous pr eparat i ons ar e
commonl y used i n hi gh doses.
a. St andard human serum i mmunogI obuI i n f or i nt ramuscuI ar
vacci nati on i s a pol ycl onal ant i ser um pr epar ed f r om pool ed pl asma of
donor s. Ì t cont ai ns 165 mg/ mL human i mmunogl obul i n,
P. 218

pr edomi nant l y t he f our subcl asses of Ì gG. Si de ef f ect s ar e r are, mi ni mal ,
and usual l y conf i ned t o mi nor i nf l ammat i on and pai n at t he si t e of i nj ect i on.
Thi s prepar at i on i s unsui t abl e f or i nt r avenous i nj ect i on because ant i body
aggregat es f orm and may act i vat e compl ement and pl at el et s.
Table 10-2. Passive Vaccines
Illness Vaccine Rationale
Intramuscular
Hepatitis B (HBV) Hepatitis B
immunoglobulin
(HBIG)
Prophylaxis
Hepatitis A (HAV) Immunoglobulin.
intramuscular
(IGIM)
Prophylaxis
Non-A. non-B hepatitis IGIM Prophylaxis. therapy
Measles IGIM Prophylaxis. therapy
Rabies Rabies
immunoglobulin
(RIG)
Prophylaxis
Rubella IGIM Fetal prophylaxis in
exposed mother
Varicella Varicella zoster
immunoglobulin
(VZIG)
Prophylaxis and
therapy in
immunocompromised
individual
Tetanus Tetanus
immunoglobulin
Prophylaxis
(TIG)
Hypogammaglobulinemia IGIM Therapy Ior antibody
deIiciency
Rh disease Rho (D)
immunoglobulin
(RhoGAM)
Prophylaxis during
pregnancy and aIter
delivery oI Rh
¹
Ietus
by Rh
-
mother
Botulism Botulism
antiserum
(equine)
Prophylaxis. therapy
Snakebite Polyvalent
antivenin
(equine)
Prophylaxis. therapy
Black widow bite Black widow
antivenin
(equine)
Prophylaxis. therapy
Intravenous
a

Hypogammaglobulinemia Intravenous
immunoglobulin
(IVIG)
Therapy Ior antibody
deIiciency
Idiopathic
thrombocytopenic
purpura (ITP)
IVIg Therapy
Chronic lymphocytic
leukemia
IVIg Therapy Ior antibody
deIiciency
Cytomegalovirus (CMV)
inIection
CMV IVIG Therapy in renal
transplant patients
Acute renal reiection Muromonab-CD3
(murine)
Reversal oI acute
reiection
a
U.S. Food and Drug Administration-approved uses; many others currently
in trials result Irom vaccine preparation in cells oI nonhuman origin. The
valence oI a vaccine indicates the number oI strains oI organism included
(e.g.. trivalent polio vaccine includes three strains oI poliovirus).

b. Speci aI i nt ramuscuI ar i mmunogI obuI i ns ( I GI Ms) ar e i ndi vi dual ser a
pr epar ed f r om pl asma l ot s of subj ect s act i vel y i mmuni zed agai nst or
r ecoveri ng f rom speci f i c di seases. Each ser um i s enri ched f or ant i bodi es of
t he desi r ed speci f i ci t y (e. g. , t et anus i mmunogl obul i n cont ai ns more
ant i bodi es agai nst t et anus t oxi n t han woul d be f ound i n Ì GÌ M) .
c. I VI Gs are pr epar ed f rom pool ed human ser um and modi f i ed t o mi ni mi ze
ant i body aggr egat i on. Chi l l s, nausea, and abdomi nal pai n occur i n
approxi mat el y 10% of pat i ent s. Si de ef f ect s ar e di mi ni shed by r educi ng t he
r at e of i nt ravenous i nf usi on. Premedi cat i on wi t h cor t i cost eroi ds i s
r ecommended, and i nt ravenous epi nephr i ne i s used i f anaphyl axi s occurs.
d. Ani maI ant i sera. Equi ne ( horse) ant i ser a are used i n cer t ai n si t uat i ons
( Tabl e 10- 2). Mouse monocl onal ant i body (mur omonab- CD3) i s used i n
acut e renal rej ect i on ( see V. D. 2. e) . The hal f -l i ves of ani mal ant i bodi es are
short er i n humans.
2. Rat i onaI es f or passi ve vacci nati on
a. ProphyI axi s of i nf ecti ous di sease. Ant i bodi es are gi ven
pr ophyl act i cal l y t o prevent cl i ni cal sympt oms of a vi r al or bact eri al
i nf ect i ous pr ocess, part i cul ar l y i n a pat i ent wi t hout previ ous exposur e and
t her ef ore wi t hout i mmunol ogi c memor y. The vacci ne pr ot ect s t he r eci pi ent
dur i ng t he i ncubat i on per i od f or i nf ect i on. For exampl e:
( 1) Cl ost ri di um t et ani i nf ect i on has an i ncubat i on peri od of appr oxi mat el y 5
days bef or e si gni f i cant quant i t i es of t et anus t oxi n ar e pr oduced. A pri mar y
i mmune r esponse of 7- 10 days i s t oo sl ow. Passi ve vacci nat i on wi t h t et anus
i mmunogl obul i n ( TÌ G) bi nds t he t oxi n and pr event s di sease.
( 2) Hepat i t i s B i mmunogI obuI i n ( HBI G) i s admi ni st er ed t o i ndi vi dual s as
soon as possi bl e af t er exposur e t o prevent vi r al i nf ect i on.
b. ProphyI axi s or t herapy pr event s or at t enuat es t he ef f ect s of i nf ect i on i n
speci al popul at i ons. Exampl es ar e t he use of vari ceI I a zoster
i mmunogI obuI i n ( VZI G) i n i mmunocompr omi sed pat i ent s and t he use of
Ì GÌ M i n pr egnant women who ar e exposed t o rubel l a and have not been
act i vel y vacci nat ed.
c. Treat ment of ant i body def i ci ency. Ì ndi vi dual s who ar e def i ci ent i n
ant i body pr oduct i on, ei t her because of pri mar y i mmunodef i ci ency (see Ì V)
or as a r esul t of chr oni c l ymphocyt i c l eukemi a, recei ve i nt r avenous
i mmunogl obul i n ( Ì VÌ G) or Ì GÌ M ever y 2- 4 weeks t o mai nt ai n humor al
i mmuni t y. Ì VÌ G i s pref erred.
d. Ot her si t uat i ons. Ì VÌ G i s used f or i di opat hi c (aut oi mmune)
t hr ombocyt openi a purpura. Ì nt r amuscul ar Rho( D) i mmunogl obul i n ( RhoGAM)
i s used pr ophyl act i cal l y f or Rh di sease ( see Ì Ì . C. 5. c). Mur omonab- CD3 (see
V. D. 2. e) i s used f or acut e r enal gr af t rej ect i on.
C. Act i ve vacci nati on (Tabl e 10- 3) i s used f or pr ophyl axi s.
1. Overvi ew
a. Contents. Act i ve vacci nes cont ai n one or mor e subuni t s of a pat hogen or
whol e pat hogeni c organi sms but may al so cont ai n pr eser vat i ves, l ow doses
of ant i bi ot i cs, and ot her compounds t hat do not af f ect t he i mmune
r esponse.
b. Admi ni st rat i on. Act i ve vacci nes are admi ni st er ed subcut aneousl y,
i nt ramuscul ar l y, i nt r adermal l y, oral l y, or i nt ranasal l y. Some are i nt roduced
adsor bed t o al umi num hydr oxi de or al umi num phosphat e adj uvant s. An
adj uvant i ncr eases t he ant i geni ci t y of t he vacci ne.
c. Seroconversi on. For most act i ve vacci nes, t he success of t he ser i es of
vacci nat i ons i s i ndi cat ed by seroconversi on of t he pat i ent . Ser oconver si on
i ndi cat es t hat a per son who pr evi ousl y di d not have speci f i c serum
ant i bodi es (i . e. , ser onegat i ve) now has t hese ant i bodi es (i . e. , ser oposi t i ve) .
Ser oconversi on does not i ndi cat e est abl i shed i mmuni t y f or cer t ai n vacci nes
( e. g. , baci l l us Cal met t e-Guér i n vacci ne f or t ubercul osi s).
d. A scheduI e of act i ve vacci nat i on i s r ecommended f or i nf ant s and
chi l dren ( Tabl e 10-3) . The f i rst vacci nat i on i s gi ven af t er t he i nf ant i s 6
weeks ol d because r esponses ar e normal l y i nadequat e i n newbor ns and
because mat er nal ant i bodi es r emai n i n t he newbor n ci rcul at i on; some
vacci nes (e. g. , hepat i t i s B vi r us; HBV) , however , may be gi ven i mmedi at el y
af t er bi rt h. Some vacci nes ar e i nt ended f or use pr i mar i l y i n noni nf ant
popul at i ons.
P. 219


P. 220


Table 10-3. Commonly Administered U.S. Food and Drug Administration-
Approved Active Vaccines
Vaccine
Target
Population
a

Number of
Vaccinations Schedule Notes
Live.
attenuate
d viral

Oral polio
(OPV;
trivalent)
InIants.
children.
healthcare and
daycare
workers
4 2. 4. 15-18
months; 1
at school
entry
Approxim
ately 1 in
2.6
million
risk oI
vaccinein
duced
paralysis;
no longer
recomme
nded
because
oI risks;
substitute
killed
vaccine
Measles.
mumps.
rubella
(MMR)
InIants.
children
2 15 months
(· 12
months iI
high risk);
1 at school
entry
Generally
aIIords
liIelong
immunity
Rubella Adolescent
girls not
previously
vaccinated
1 Postpubert
y
Protects
Iuture
Ietus Irom
congenital
rubella
iniury
Varicella Children.
other at-risk
individuals
1 (iI > 13
years old.
2)
1 between
12 and 18
months or
2-3 years;
aIter 13
years old.
Duration
oI
immunity
or eIIect
on
developm
2-4 weeks
apart
ent oI
shingles
unknown
InIluenza
(trivalent)
Individuals
between 5 and
59 years old at
risk Ior
inIection
1 per year Annually
Ior
maximum
protection
Administe
red
intranasall
y
Bacterial
BCG
tuberculos
is
Individuals
exposed to
sputum-
positive
tuberculosis
patients
Varies Depends
on success
or initial
vaccinatio
n
Unpredict
able
eIIectiven
ess;
induces
cell-
mediated
immunity
Killed.
inactivate
d viral or
viral
subunit

InIluenza
(trivalent
or
polyvalent
)
Geriatric
patients.
healthcare
workers.
individuals at
risk Ior
complications
1 per year Annually
Ior
maximum
protection
Variant
strains
may
appear
each year;
vaccine
must be
updated
annually
Hepatitis
B (HBV)
All 3 Between 1
and 2
months. 2
and 3
months.
Recombin
ant.
subunit
aIter 6
months
Inactivate
d polio
(IPV;
trivalent)
All children;
as booster in
healthcare and
day-care
workers
4 2. 4. 15-18
months; 1
at school
entry
No slgA;
thus
reduced
protection
; no
paralysis
risk
Killed.
inactivate
d viral or
viral
subunit

Rabies
(HDCV)
Animal-care
workers
4 or 5
b
.
with
boosters
7 days
apart;
boosters as
required to
maintain
immunogl
obulin
Two
doses to
exposed.
already
immune
individual
Bacterial.
subunit

Diphtheri
a. tetanus.
pertussis
(DTP)
InIants.
children
4. with
boosters
2.4. 15-18
months; 1
at school
entry
Tetanus
toxoid
(Td)
booster
every 10
years or
on
exposure
through a
wound
Tetanus
and
diphtheria
Children > 7
years old;
adults with no
3. with
boosters
Second
dose in 4-8
weeks;
Td
booster
every 10
toxoids
(Td)
vaccination third dose
6 months
later
years or
on
exposure
through a
wound iI
more than
10 years
or vaccine
history
unavailabl
e
Haemophi
lus b
(Hib)
InIants.
children. HIV-
inIected adults
Depends
on
Iormulati
on
Depends
on
Iormulatio
n
Polysacch
aride
capsule is
poor
antigen;
coniugate
vaccines
enhance
potency
Pneumoco
ccus
(polyvale
nt)
At-risk adults
or children >
2 years old
(e.g..
immunocompr
omised
patients.
geriatric
patients)
1 or 1 per
year
As
necessary
in at-risk
patients;
not given
during
active
inIection;
1 per year
in geriatric
patients
Poor
response
to
polysacch
aride
antigen in
children ·
5 years
old
Meningoc
occus
(quadrival
ent A. C
Y. W-
135)
College
Ireshmen
living in
dormitories;
high-risk
adults or
children > 2
years old.
including
individuals
1.
subcutane
ously
As
necessary
in at-risk
individuals
at 3- to 5-
year
intervals
Polysacch
aride
vaccine
give poor
response
in
children ·
2 years
old; does
not
with
complement
component
deIiciencies or
anatomic or
Iunctional
asplenia
protect
against
serotype
B. which
accounts
Ior 46°
oI cases
BCG. bacille Calmette-Guerin; HDCJ. human diploid cell vaccine; slgA.
secretory immunoglobulin A.
a
Entire target population is not listed in all cases.

b
Five doses to already exposed individuals.

P. 221


e. Most vacci nes r equi r e a seri es of vacci nat i ons; ot hers are ef f ect i ve
wi t h a si ngl e vacci nat i on. For t hose t hat requi r e a ser i es, i nt er val s bet ween
vacci nat i ons gr eat er t han t hose r ecommended do not general l y di mi ni sh
pr ot ect i on. The dur at i on of memor y var i es wi t h each vacci ne, and boost er
vacci nati ons are of t en necessar y.
f . Si de ef fects i ncl ude i nf l ammat i on at t he si t e of vacci nat i on, mal ai se, mi l d
f ever , chi l l s, headache, myal gi a, and art hral gi a. Mor e sever e si de ef f ect s
i ncl ude f ebri l e i l l ness, somnol ence, sei zur es, or anaphyl act i c
hyper sensi t i vi t y t o vacci ne ant i gens or accessory component s (e. g. ,
ant i bi ot i c, chi cken prot ei n) . Severe react i ons cont r ai ndi cat e cont i nuat i on of
a ser i es. A per son wi t h sever e f ebri l e i l l ness shoul d not be act i vel y
vacci nat ed unt i l t he i l l ness r esol ves.
2. Types of act i ve vacci nes
a. Li ve, at tenuat ed vacci nes consi st of whol e or gani sms ( usual l y vi ruses) .
These or gani sms mul t i pl y af t er vacci nat i on, but ar e at t enuat ed t o reduce
t hei r pat hogeni ci t y.
( 1) A smal l dose produces a st r ong i mmune response because t he ant i gen
concent r at i on i ncreases when t he or gani sm mul t i pl i es. Some vacci nes el i ci t
l i f el ong i mmuni t y i n t wo doses÷f or exampl e, t he measl es, mumps, r ubel l a
( MMR) vacci ne. Because of t hei r r el at i ve genet i c i nst abi l i t y, vi r uses can
r ever t t o vi r ul ence and cause t he di sease agai nst whi ch t he pat i ent i s
vacci nat ed. Thi s i s a part i cul ar probl em wi t h one of t he serot ypes of t he
or al pol i o vacci ne ( OPV).
( 2) Li ve, at t enuat ed vi r al vacci nes ar e not r ecommended f or pr egnant
women or t hose i nt endi ng t o become pr egnant wi t hi n 3 mont hs of
vacci nat i on. Li ve, at t enuat ed vi r al or bact eri al vacci nes ar e not gi ven t o
i mmunocompr omi sed i ndi vi dual s.
b. Ki I I ed, i nact i vat ed vacci nes may cont ai n whol e ki l l ed cel l s ( e. g. ,
phenol -ki l l ed Bor det el l a per t ussi s) or any ant i geni c f r act i on i sol at ed f r om
t he or gani sm. They are usual l y gi ven adsorbed t o adj uvant .
c. Some i sol at ed ant i gens ( subuni t vacci nes) may r equi r e i nact i vat i on
bef ore t hey are used i n a vacci ne ÷f or exampl e, f or mal dehyde- modi f i ed
t oxi n of Cl ost r i di um t et ani , known as tet anus t oxoi d (Td) af t er
modi f i cat i on. Ì nact i vat i on el i mi nat es pat hogeni ci t y, but pr eser ves some
ant i geni ci t y. Ot her subuni t vacci nes i ncl ude pr ot ei ns and gl ycopr ot ei ns of
an organi sm t hat are produced by r ecombi nant DNA t echnol ogy i n bact er i a,
yeast , or mammal i an cel l s and ar e t hen used as t he ant i gens f or
vacci nat i on. The HBV vacci ne cont ai ns pr ot ei ns pr oduced by r ecombi nant
genet i c t echnol ogi es and i s appr oved by t he FDA f or use i n humans.
( 1) Because no l i ve organi sms are present , r eversi on t o pat hogeni ci t y i s not
a pr obl em. However , doses of cel l s or ant i gens must be hi gher t han i n l i ve,
at t enuat ed vacci nes, and hypersensi t i vi t y r eact i ons t o vacci ne component s
ar e more common. Mi ni mum ef f ect i ve doses are usual l y measur ed i n
numbers of cel l s or mi crogr ams of ant i gen.
( 2) Vacci nes i n whi ch t he ant i geni c f r agment i s a pol ysacchar i de (e. g. ,
Haemophi l us b) ar e usual l y poor at el i ci t i ng i mmune r esponses and
memor y, pr obabl y because t hey do not evoke T cel l act i vat i on. These
vacci nes have been i mproved by conj ugat i ng t he pol ysacchar i de t o anot her
ant i geni c compound (e. g. , Td) . These ar e known as conj ugate vacci nes.
4. Experi mentaI vacci nes i ncl ude ot her subuni t vacci nes; pept i des
pr oduced by chemi cal , cel l -f r ee synt hesi s; recombi nant DNA vi r uses
cont ai ni ng genes f or t he ant i gens of mul t i pl e or gani sms; and ant i - i di ot ype
ant i bodi es used f or act i ve vacci nat i on.
5. Speci fi c vacci nes i n common use and recommended admi ni st rat i on
schedul es ar e l i st ed i n Tabl e 10- 3.
D. Si muI t aneous admi ni st rat i on of act i ve and passi ve vacci nes.
Somet i mes act i ve and passi ve vacci nes agai nst a pat hogeni c organi sm ar e
admi ni st er ed si mul t aneousl y t o maxi mi ze post exposur e pr ophyl axi s. The
i mmunogl obul i n of f ers i mmedi at e pr ot ect i on, and t he act i ve vacci ne
st i mul at es an i mmune response. These vacci nes ar e gi ven at separ at e si t es
t o prevent ant i body ( passi ve) and ant i gen ( act i ve) f r om r eact i ng and
i nact i vat i ng one anot her .
1. Ì nf ant s wi t h HBV who ar e bor n t o mot hers who have t he hepat i t i s B
sur f ace ant i gen ( HBsAg) ar e si gni f i cant l y prot ect ed f rom becomi ng chroni c
car ri ers by t hi s combi ned pr ophyl axi s.
2. Rabi es. Post exposur e pr ophyl axi s t ypi cal l y i ncl udes t he combi ned use of
act i ve and passi ve vacci nes because of t he l et hal nat ur e of t he unchecked
i nf ect i on. The except i on i s pat i ent s wi t h a pr evi ous act i ve vacci nat i on who
have suf f i ci ent exi st i ng ser um ant i body concent r at i on.
P. 222


3. Tet anus. Combi ned pr ophyl axi s i s somet i mes used, dependi ng on t he
t ype of wound and t he pat i ent ' s hi st or y of act i ve vacci nat i on. Recommended
gui del i nes ar e as f ol l ows:
a. A t et anus- prone wound i s one t hat produces anaer obi c condi t i ons ( e. g. ,
deep punct ur e) or one i n whi ch exposur e t o Cl ost r i di um or i t s spores i s
pr obabl e ( e. g. , cont ami nat ed wi t h ani mal f eces) . Ì f t he pat i ent ' s hi st or y of
act i ve vacci nat i on i s uncer t ai n or i ncl udes f ewer t han t hr ee doses, bot h TÌ G
and Td ar e admi ni st ered. The pat i ent ret ur ns t o compl et e t he t oxoi d ser i es.
( 1) Ì f t he wound i s t et anus- pr one but t he pat i ent r ecei ved a f ul l ser i es of
act i ve vacci nat i on, no t reat ment i s necessar y i f t he l ast Td dose was
r ecei ved wi t hi n t he l ast 5 years.
( 2) Ì f t he l ast dose was recei ved more t han 10 year s ago, Td, but not TÌ G,
i s gi ven t o boost memory i mmuni t y and ant i body pr oduct i on.
b. For a cI ean, mi nor wound, i f t he pat i ent ' s hi st or y of act i ve vacci nat i on
i s uncer t ai n or i ncl udes f ewer t han t hree doses, Td i s admi ni st er ed.
( 1) Ì f t he pat i ent r ecei ved a f ul l ser i es of act i ve vacci nat i ons, no t reat ment
i s necessar y i f t he l ast Td dose was r ecei ved wi t hi n 10 year s.
( 2) Ì f t he l ast dose was recei ved more t han 10 year s ago, Td, but not TÌ G,
i s gi ven t o boost memory i mmuni t y and ant i body pr oduct i on.
VII. PROSPECTS FOR IMMUNOMODULATION
A. Fab anti di goxi n anti body pr epar at i ons obt ai ned f r om sheep ar e
approved f or t he rever sal of t oxi ci t y associ at ed wi t h t oxi c di goxi n ser um
l evel s. The ant i body bi nds di goxi n and prevent s i t f rom bi ndi ng t o i t s normal
r ecept or si t e. The Fab-di goxi n compl ex i s excr et ed r enal l y.
B. MonocI onaI ant i bodi es are gener al l y produced t hrough t he i n vi t r o
f usi on of a cancerous pl asma cel l (myel oma) wi t h an act i vat ed mouse B
cel l . The r esul t i ng hybri doma secret es mur i ne (mouse) ant i bodi es of a
si ngl e def i ned speci f i ci t y and has t he i mmort al i t y charact eri st i c of t he
myel oma. Techni ques f or t he pr oduct i on of human monocl onal ant i bodi es
and a var i et y of hybri d mouse- human monocl onal ant i bodi es ar e al so
avai l abl e.
1. MonocI onaI ant i bodi es÷f or exampl e, whol e ant i bodi es or Fab or F(ab' ) 2
f r agment s÷ar e r out i nel y used f or i n vi t r o di agnost i c t est s ( e. g. , bl ood group
and t i ssue t ypi ng f or HLA) , scr eeni ng f or cancer -r el at ed ant i gens ( e. g. ,
carci noembr yoni c ant i gen; CEA) , ur i ne t est i ng f or dr ugs and met abol i t es,
and t est i ng f or HÌ V i nf ect i on. Ì n t hese and many ot her di agnost i c
appl i cat i ons, monocl onal ant i bodi es ar e of t en conj ugat ed t o enzymes,
r adi oi sot opes, or f l uor escent dyes.
2. Muromonab- CD3 i s used t o t r eat acut e gr af t rej ect i on. Ot her monocl onal
ant i bodi es ar e used f or t r eat ment of breast cancer and l eukemi a.
3. Ì n cl i ni cal t r i al s, t he use of monocI onaI ant i bodi es agai nst T ceI I s
causes i mpr ovement i n cer t ai n aut oi mmune di sorder s.
4. MonocI onaI ant i bodi es agai nst neopI asti c ceI I s show some success,
and ar e usef ul i n t reat i ng cer t ai n l eukemi as and l ymphomas, as wel l as
br east and col on cancers.
C. MonocI onaI ant i bodi es are conj ugat ed t o enzymes, drugs, prodrugs,
radi oi sot opes, or pI ant and bacteri aI t oxi ns t o pr ovi de speci f i c del i ver y
of t he conj ugat ed agent t o one or mor e f ocused i n vi vo si t es of act i on.
Sever al pr obl ems are associ at ed wi t h t he use of t hese agent s.
1. I mmunot oxi ns ar e usual l y pr oduced by t he conj ugat i on of a monocl onal
ant i body t o a bi ol ogi c pol ypept i de t oxi n ( e. g. , di pht heri a t oxi n) t hat i s
modi f i ed t o reduce nonspeci f i c t oxi ci t y.
2. Al t hough t hey ar e bei ng t est ed f or gr af t r ej ect i on and aut oi mmuni t y,
i mmunot oxi ns ar e pri mari l y used as ant i neopl ast i c agent s. Cl i ni cal t ri al s
show moderat e success i n t reat i ng l eukemi a and l ymphoma, wi t h l ower
success r at es agai nst t umors such as br east carci noma.
3. MonocI onaI ant i bodi es conj ugated t o radi oi sot opes (e. g. ,
90
Y) cause
r emi ssi ons i n pat i ent s wi t h Hodgki n di sease and acut e T cel l l eukemi a.
4. MonocI onaI ant i bodi es conj ugated t o enzymes t hat act i vat e a prodr ug
t o t he act i ve drug at a speci f i c t i ssue si t e ( e. g. , neopl ast i c cel l surf ace) ar e
i n human t r i al s.
P. 223


D. I mmunost i muI ati on has been at t empt ed wi t h a var i et y of compounds,
r angi ng f r om cyt oki nes t o bact er i al pr oduct s ( Tabl e 10-1) .
1. Ì FN- q has many subt ypes. Two ar e cur r ent l y FDA approved. Because i t
i nhi bi t s cel l gr owt h, i t i s used t o t reat hai r y cel l l eukemi a, Kaposi sarcoma
i n pat i ent s wi t h AÌ DS, and geni t al war t s. At l ow doses, i nt er f er ons st i mul at e
i mmune cel l ul ar f unct i on ( e. g. , T cel l s, NK cel l s, macr ophages) , but at hi gh
doses, t hey ar e i mmunosuppressi ve. The use of Ì FN- q agai nst ot her
cancers pr oduces var i abl e resul t s.
2. Ì FN-v pr ovi des gr eat er i mmunost i mul at i on i n t he i nt act i mmune syst em,
but i t s ef f ect s depend on dose and t i mi ng. The combi ned use of Ì FN- q and
Ì FN- v yi el ds bet t er resul t s. The most common si de ef f ect s of i nt er f er on
t her apy ar e i nf l uenza-l i ke sympt oms. Ì FN- v i s appr oved f or use as a
macr ophage- act i vat i ng f act or i n chr oni c granul omat ous di sease.
3. Several pr ot ocol s usi ng I L-2 show pr omi si ng resul t s, wi t h apparent l y
compl et e r emi ssi ons i n some pat i ent s wi t h mel anoma. Wi t h t hi s t echni que,
known as adopt i ve i mmunot her apy, a pat i ent ' s per i pher al bl ood
l ymphocyt es, or t umor - i nf i l t rat i ng l ymphocyt es, are r emoved. They are
cul t ur ed wi t h Ì L- 2 and r ei nf used wi t h addi t i onal Ì L- 2. These Ì L-2- r esponsi ve
cel l s ar e l i kel y T cel l s and NK cel l s. Severe capi l l ar y l eakage syndrome,
occasi onal l y l eadi ng t o deat h, i s a probl emat i c si de ef f ect .
4. Hormones of t he t hymus t hat i nduce T cel l mat ur at i on and ot her
f unct i ons are used t o i ncr ease cer t ai n cel l - medi at ed i mmune f unct i ons, wi t h
var i abl e resul t s.
5. Sul f ur- cont ai ni ng compounds, such as I evami soI e ( a phenyl i mi dot hi azol e
ant hel mi nt i c) and di et hyl di t hi ocarbamat e ( I mut hi oI ) , have
i mmunost i mul at or y act i vi t y. Thei r ef f ect i s gr eat er on cel l -medi at ed
i mmuni t y t han on humoral i mmuni t y. Levami sol e i s approved as an or al
agent f or use i n col on cancer i n combi nat i on wi t h f l uor ouraci l .
6. I nosi ne pranobex i s l i censed f or use i n many count r i es as an
i mmunost i mul ant . Ì t i nduces T cel l di f f er ent i at i on and augment s cel l -
medi at ed i mmune f unct i ons, wi t h mi ni mal t oxi ci t y.
7. As a component of mycobact er i al cel l wal l s, muramyI di pept i de ( MDP)
st i mul at es macr ophage act i vat i on and may be used as an adj uvant , gi ven
wi t h ant i gen (see Ì ) , or gi ven al one as an i mmunost i mul ant .
P. 224


STUDY QUESTIONS
Di rect i ons: Each quest i on, st at ement , or i t em or i ncompl et e st at ement i n
t hi s sect i on can be cor r ect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. A man has sympt oms of a vi raI i nf ect i on of about 4 days' durat i on.
To conf i rm t he di agnosi s, t he physi ci an draws a bI ood sampI e and
request s the ant i body t i t er ( I eveI ) f or t he suspect ed agent . The f i rst
bI ood sampI e shows a I ow ti t er of ant i body. A week I at er, anot her bI ood
sampI e i s drawn, and the t i ter agai nst t he vi rus i s much hi gher. Thi s
si t uati on i s an exampI e of
( A) an i nf l ammat or y r esponse t o t he vi r al i nf ect i on.
( B) a pr i mar y i mmune r esponse t o t he vi r al i nf ect i on.
( C) a secondar y i mmune r esponse t o t he vi r al i nf ect i on.
( D) a cel l ul ar response t o t he vi r al i nf ect i on.
Vi ew Answer 1. The answer i s B[ seeand] . 2. Whi ch cI ass of
ant i body has t he I ongest serum haI f -I i f e and opsoni zes ant i gens f or
phagocyt osi s t hrough two di f f erent pat hways?
( A) Ì mmunogl obul i n G (Ì gG)
( B) Ì mmunogl obul i n M ( Ì gM)
( C) Ì mmunogl obul i n A ( Ì gA)
( D) Ì mmunogl obul i n E ( Ì gE)
Vi ew Answer 2. The answer i s A[ see] . 3. Urti cari a t hat appears
rapi dI y af t er t he i ngest i on of food usuaI I y i ndi cat es whi ch t ype of
hypersensi t i vi t y react i on?
( A) Type Ì
( B) Type Ì Ì
( C) Type Ì Ì Ì
( D) Type Ì V
Vi ew Answer 3. The answer i s A[ seeand] . 4. I n whi ch aut oi mmune
di sorder i s t he mechani sm of pat hogenesi s cI assi fi ed as t ype I I
hypersensi t i vi t y?
( A) Syst emi c l upus er yt hemat osus ( SLE)
( B) Ì nsul i n-dependent di abet es mel l i t us (Ì DDM)
( C) Gr ave' s di sease
( D) Hashi mot o' s t hyr oi di t i s
Vi ew Answer 4. The answer i s C[ seeand] . 5. A pat i ent recei ves
I ong- term, hi gh- dose t herapy wi t h a suI f onami de. Af t er approxi mateI y 3
weeks of t herapy, t he pat i ent has a I ow- grade f ever, rash, and muscI e
and j oi nt pai n. Whi ch type of hypersensi t i vi t y accounts f or these
sympt oms?
( A) Type Ì
( B) Type Ì Ì
( C) Type Ì Ì Ì
( D) Type Ì V
Vi ew Answer 5. The answer i s C[ seeand] . 6. I n whi ch t ype I V
hypersensi t i vi t y react i on i s t he t i ssue-damagi ng di sorder consi dered
an i nappropri ate response by t he i mmune syst em?
( A) Poi son i vy der mat i t i s
( B) Chr oni c t ubercul osi s
( C) Acut e gr af t r ej ect i on
( D) Tuber cul i n t est
Vi ew Answer 6. The answer i s A[ see] . Mycobacteri um. 7. Whi ch
agent i s commonI y used t o t reat muI t i pI e scI erosi s ( MS)?
( A) Neost i gmi ne
( B) Cyanocobal ami n
( C) Ì FN- 8- 1b
( D) Pr opyl t hi ouraci l
Vi ew Answer 7. The answer i s C[ see] . 8. The t herapeut i c roI e of
muromonab- CD3 i n acut e renaI graf t rej ecti on i s probabI y based on
( A) act i vat i on of T cel l f unct i on and secr et i on of cyt oki nes.
( B) dest ruct i on of T cel l s by compl ement .
( C) opsoni zat i on of T cel l s f or phagocyt osi s.
( D) sel ect i ve i nhi bi t i on of TH cel l f unct i on.
Vi ew Answer 8. The answer i s C[ see] . 9. Whi ch i s a current cI i ni caI
appI i cat i on of i nt ravenous human i mmunogI obuI i n ( I VI G) ?
( A) Pr ophyl axi s af t er hepat i t i s B vi r us ( HBV) exposur e
( B) Tr eat ment of humoral i mmunodef i ci ency
( C) Pr ophyl act i c i nf ant i mmuni zat i on f or pol i o
( D) Pr ophyl axi s f or Rh di sease by i nf ant i mmuni zat i on
Vi ew Answer 9. The answer i s B[ see] . 10. Whi ch cyt oki ne i s
approved for t he t reatment of cert ai n f orms of cancer?
( A) Ì nt er l euki n 2 (Ì L- 2)
( B) Ì nt er f er on q ( Ì FN- q)
( C) Ì nt er f eron v (Ì FN- v)
( D) Ì mut hi ol
Vi ew Answer 10. The answer i s B[ see] . P. 225


For quest i ons 11 and 12: A 6- year - ol d chi l d has a deep punct ur e wound.
The par ent i s unsure of t he chi l d' s hi st or y of vacci nat i on.
11. I f no ot her i nformati on i s avai I abI e, what shouI d t he physi ci an
recommend?
( A) No vacci nat i on
( B) Tet anus i mmunogl obul i n ( TÌ G)
( C) Tet anus t oxoi d ( Td)
( D) Bot h TÌ G and Td at separat e si t es
Vi ew Answer 11. The answer i s D[ see] . 12. I f t he chi I d recei ved a
f uI I seri es of di pht heri a, pert ussi s, tet anus ( DPT) vacci nat i ons, t he I ast
at ent r y i nt o schooI , what shouI d t he physi ci an recommend?
( A) No vacci nat i on
( B) Tet anus i mmunogl obul i n ( TÌ G)
( C) Tet anus t oxoi d ( Td)
( D) Bot h TÌ G and Td at separat e si t es
Vi ew Answer 12. The answer i s A[ see] . 13. Persi st ent i nf ect i ons by
opport uni sti c pat hogens, such as Candi da al bi cans and Pneumocyst i s
cari ni i , couI d i ndi cat e aI I of t he f oI I owi ng except
( A) i nheri t ed T cel l i mmunodef i ci ency.
( B) humoral i mmunodef i ci ency.
( C) AÌ DS.
( D) combi ned i mmunodef i ci ency.
Vi ew Answer 13. The answer i s B[ see] . 14. Whi ch st atement about
HI V i nf ect i on i s not correct ?
( A) Ì ndi vi dual s who become i nf ect ed wi t h HÌ V- 1 al ways show over t
sympt oms shor t l y af t er i nf ect i on.
( B) Ser oconver si on t o posi t i ve st at us f or ant i - HÌ V- 1 ant i bodi es i s t he
pr i mar y cri t er i on f or di agnosi s of a vi ral car ri er .
( C) The i ncubat i on per i od f or t he pat hogenesi s of AÌ DS i s bel i eved
t o be 8 year s or l onger af t er t he i ni t i al i nf ect i on wi t h HÌ V.
( D) CD4
+
T cel l s and macr ophages may be abl e t o spr ead HÌ V t o
uni nf ect ed CD4
+
cel l s wi t hout r el easi ng any ext r acel l ul ar vi rus
par t i cl es.
Vi ew Answer 14. The answer i s A[ see] . Di recti ons: The quest i ons
and i ncompl et e st at ement s i n t hi s sect i on can be cor rect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer ,
A- E.
15. Whi ch stat ements about the currentI y approved sheep Fab f ragment
used t o counteract di goxi n overdose are t rue?
I . I t i s obt ai ned by t he i mmuni zat i on of sheep wi t h a di goxi n-prot ei n
conj ugate and subsequent prot eoI yt i c cI eavage of the coI I ected
ant i body.
I I . I t speci fi caI I y bi nds di goxi n, prevent i ng i ts act i vi t y.
I I I . I t has a serum haI f -I i f e of approxi mat eI y 3 weeks.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 15. The answer i s C[ see] . 16. CD4
+
T ceI I s
speci f i caI I y recogni ze ant i gens i n whi ch form?
I . Bound t o maj or hi st ocompat i bi I i t y ( MHC) cI ass I moI ecuI es on the
surf ace of any body ceI I
I I . I n f ree, soI ubI e form i n ext raceI I uI ar fI ui ds
I I I . Bound t o MHC cI ass I I moI ecuI es on t he surf ace of speci aI ant i gen-
present i ng ceI I s ( APCs)
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 16. The answer i s B[ see] . 17. What i s a normaI
out come of t he act i vat i on of the compI ement syst em by ei t her t he
cI assi c or aI t ernat i ve pat hway?
I . Acut e i nf I ammati on
I I . Opsoni zat i on of i mmune compI exes
I I I . Cyt oI yt i c act i on
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 17. The answer i s E[see] . 18. I n anti vi raI i mmuni t y,
what di rect I y recogni zes and ki I I s vi raI - i nfected ceI I s?
I . Cyt ot oxi c T ceI I s ( CTLs)
I I . Ant i vi raI ant i bodi es
I I I . I nt erferons
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 18. The answer i s A[ see] . P. 226


19. A pat i ent i s t reat ed wi t h peni ci I I i n and produces ant i bodi es agai nst
t he drug. They are st i I I most I y present . An emergency si t uat i on
requi res admi ni st rat i on of an i nt ravenous dose of peni ci I I i n. I f t he
pat i ent has a t ype I peni ci I I i n hypersensi t i vi t y react i on, whi ch
pat hoI ogi c consequence wouI d be expected, and wi t hi n what t i me
course of cI i ni caI onset ?
I . HemoI yt i c anemi a, wi t h an onset of 1-2 hr aft er t he i nt ravenous dose
I I . AnaphyI axi s, wi t h an onset of a few mi nut es af t er the i nt ravenous
dose
I I I . Cut aneous urt i cari a and pruri t us, wi th an onset of a f ew mi nutes
af t er t he i nt ravenous dose
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 19. The answer i s D[ seeand] . 20. Whi ch si t uat i on
occurs i n aI I t ype I V hypersensi t i vi t y react i ons?
I . I nfi I t rati on of t he aff ect ed ti ssue by mononucI ear ceI I s
I I . A deI ay of 12 hr or I onger i n t he onset of cI i ni caI sympt oms af ter
aI I ergen contact
I I I . Si gni fi cant benefi ci aI ef fect of the admi ni st rat i on of H1-antagoni sts
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 20. The answer i s C[ seeand] . 21. Whi ch i mmunoI ogi c
f i ndi ng i s not uni que t o syst emi c I upus er yt hemat osus (SLE) ?
I . HypergammagI obuI i nemi a
I I . The presence of ci rcuI at i ng ant i nucI ear ant i bodi es
I I I . The presence of ci rcuI ati ng rheumat oi d fact ors
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 21. The answer i s E[see] . 22. An organ donor who i s
human I eukocyt e ant i gen ( HLA) matched wi t h t he reci pi ent of a graf t i s
sought . Whi ch i ndi vi duaI i s at I east somewhat I i keI y t o provi de a t ot aI
HLA mat ch?
I . A si bI i ng of t he graf t reci pi ent
I I . A parent of the graf t reci pi ent
I I I . A cadaver
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 22. The answer i s A[ see] . 23. Graf t -versus- host ( GVH)
di sease i s associ at ed pri mari I y wi t h whi ch t ype of t ranspI antat i on?
I . Ki dney
I I . Heart
I I I . Bone marrow
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 23. The answer i s B[ see] . 24. The prophyI act i c use of
cycI ospori ne i n graf t rej ect i on i s probabI y based on i t s abi I i t y t o
I . i nhi bi t synt hesi s of ant i bodi es, t hereby prevent i ng hyperacut e
rej ecti on.
I I . i nhi bi t act i vat i on of T ceI I s, t hereby prevent i ng acute rej ect i on.
I I I . bI ock t ranscri pt i on of t he i nterI euki n 2 ( I L-2) gene and synt hesi s or
secreti on of I L- 2.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 24. The answer i s D[ see] . 25. Whi ch i s a vaI i d
compari son of I i ve, at tenuated and ki I I ed, i nact i vat ed acti ve vacci nes?
I . RepI i cat i on of the organi sms i n a I i ve, at tenuat ed vacci ne i ncreases
t he sti muI at i on of t he i mmune syst em and a I ower dose i s of t en
requi red.
I I . At t enuated vacci nes of t en requi re muI t i pI e doses.
I I I . A ki I I ed, i nact i vat ed vacci ne probabI y produces I i feI ong i mmuni t y i n
one or two doses.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 25. The answer i s A[ seeand] . 26. Whi ch act i ve
vacci ne i s recommended f or heaI thcare workers but i s not rout i neI y
gi ven t o i nf ant s?
I . MeasI es, mumps, rubeI I a ( MMR) vacci ne
I I . I nf I uenza poI yvaI ent
I I I . Tet anus t oxoi d (Td)
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 26. The answer i s D[ see] . 27. Whi ch st atement about
pneumococcus and meni ngococcus vacci nes i s t rue?
I . They are composed of puri f i ed poI ysacchari des.
I I . They are recommended f or chi I dren < 2 years of age.
I I I . The vacci nes prot ect agai nst aI I serot ypes of di sease causi ng
pneumococcus or meni ngococcus.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 27. The answer i s A[ see] . P. 227


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see 1. C. 2 and 3] .
A pr i mar y i mmune response t o an i nf ect i on i s char act eri zed by t he i ni t i al
pr oduct i on of Ì gM, begi nni ng about 4 days af t er ant i gen i s encount ered. A
swi t ch t o a di f f er ent i mmunogl obul i n i sot ype ( i . e. , Ì gG, Ì gE, or Ì gA) occurs
bef ore t he peak of ant i body pr oduct i on i s r eached. The peak pr i mar y
i mmune r esponse occurs 10- 14 days af t er t he ant i gen i s encount ered, and
t he serum cont ai ns bot h Ì gM and Ì gG.
2. The answer i s A [ see Ì . D. 2. b; Ì . E] .
Ì gG has a ser um hal f - l i f e of 25- 35 days, l onger t han t hat of any ot her cl ass,
al t hough mast cel l - bound Ì gE has t he l ongest hal f - l i f e. Ì n general , i mmune
compl exes cont ai ni ng Ì gG ar e opsoni zed f or phagocyt osi s t hr ough bi ndi ng
t o t he Ì gG r ecept ors on neut rophi l s and macrophages and addi t i onal l y
t hr ough t he act i vat i on of compl ement . Ì gM al so opsoni zes, but onl y t hr ough
t he act i vat i on of compl ement .
3. The answer i s A [ see Ì Ì . A. 5. a and b] .
Food al l ergi es ar e usual l y t ype Ì react i ons. Ì n a pat i ent wi t h pr eexi st i ng
hyper secret ed Ì gE speci f i c t o a f ood al l er gen and bound t o mast cel l s, t he
al l er gi c response usual l y occurs short l y af t er i ngest i on. Mast cel l secret i ons
l ead t o vomi t i ng. Syst emi c spi l l over of al l er gen i nt o t he ci rcul at i on may l ead
t o mi l der ef f ect s i n ot her t i ssues ( e. g. , ur t i car i a) .
4. The answer i s C [ see Ì Ì . C. 1 and 2. c; Ì Ì Ì . D. 2. b] .
Ì n Gr aves' di sease, an ant i body act i ng as a TSH agoni st hyper st i mul at es
t he t hyr oi d. Ì n SLE, per si st ent ci r cul at i ng i mmune compl exes are
r esponsi bl e f or much of t he pat hogenesi s ( t ype Ì Ì Ì ) . Ì n Ì DDM, T cel l
cyt ot oxi ci t y t o bet a i sl et cel l s i s probabl y responsi bl e f or t he maj or
pat hogenesi s ( t ype Ì V). Ì n Hashi mot o' s t hyr oi di t i s, ant i bodi es t o t hyr oi d
per oxi dase may i ni t i at e i nf l ammat i on but TH1 cel l s and macr ophages
i nf i l t rat e t he organ ( Type Ì V) .
5. The answer i s C [ see Ì Ì . D. 2. c; Ì Ì . D. 4. a and b; Ì Ì . D. 5. a] .
One of t he most common causes of t ype Ì Ì Ì hypersensi t i vi t y i s t he r esponse
t o drugs. Thi s t ype of r eact i on i s of t en seen af t er l ong- t er m, hi gh-dose
t her apy. The t reat ment of choi ce i s t o di scont i nue t r eat ment and subst i t ut e
an unr el at ed dr ug.
6. The answer i s A [ see Ì Ì . E. 1] .
Poi son i vy cont ai ns a hapt en, pent adecyl cat echol , whi ch i s not known t o be
t oxi c. Ther ef or e, i t s capaci t y t o el i ci t an i mmune r esponse i s i nappr opr i at e
because i t ser ves no usef ul f unct i on. Ì n chr oni c t ubercul osi s, t he i mmune
r esponse i s at t empt i ng, al t hough unsuccessf ul l y, t o el i mi nat e t he
mycobact eri al pat hogen. Acut e gr af t r ej ect i on i s al so appropr i at e, but
unf ort unat e, because i t i s a r esponse agai nst f orei gn t i ssue. A t uber cul i n
t est i s an appr opr i at e mani f est at i on of t he exi st ence of act i ve i mmuni t y or
memor y t o Mycobact er i um.
7. The answer i s C [ see Ì Ì Ì . D. 8. b] .
Tr eat ment wi t h Ì FN- 8- 1b l ower s t he f r equency of at t acks by 33-50% at 2
year s i n MS pat i ent s. Neost i gmi ne i s used as an ant i chol i nergi c agent i n
myast heni a gr avi s. Cyanocobal ami n i s admi ni st ered i n aut oi mmune
per ni ci ous anemi a t o r epl ace nonabsor bed vi t ami n B12. Pr opyl t hi ouraci l i s
used as an ant i t hyr oi d i n Gr aves' di sease.
8. The answer i s C [ see V. D. 2. e] .
Mur omonab- CD3 i s a mouse ant i - CD3 monocl onal ant i body t hat bi nds t o al l
T cel l s because CD3 i s a const ant part of t he ant i gen recept or of each T
cel l . The bi ndi ng of muromonab- CD3 opsoni zes t he T cel l s f or
phagocyt osi s. Ther ef or e, t he t ot al number of T cel l s i s r educed. Mouse
ant i bodi es ar e i nef f i ci ent at act i vat i ng human compl ement . Some T cel l
act i vat i on wi t h cyt oki ne secr et i on occur s, but i t i s an undesi rabl e si de ef f ect
of mur omonab- CD3 admi ni st r at i on.
9. The answer i s B [ see VÌ . B. 1. c; Tabl e 10- 2] .
Ì VÌ Gs ar e used t o r epl ace ant i body i n i mmunodef i ci ent i ndi vi dual s. Hepat i t i s
B i mmunogl obul i n ( HBÌ G) i s admi ni st ered i nt r amuscul arl y. Ant i - Rh ant i body
i s al so admi ni st er ed i nt ramuscul ar l y t o t he mot her i mmedi at el y post par t um
( somet i mes duri ng pregnancy) , but not t o t he i nf ant . Prophyl act i c i nf ant
i mmuni zat i on f or pol i o i s pr ovi ded t hrough act i ve, not passi ve, vacci nat i on.
P. 228


10. The answer i s B [ see VÌ Ì . D] .
Ì FN- q i s appr oved f or use i n pat i ent s wi t h hai r y cel l l eukemi a and i n
pat i ent s wi t h AÌ DS and Kaposi sarcoma. Some of i t s benef i ci al ef f ect s
pr obabl y der i ve f r om i t s abi l i t y t o i nhi bi t growt h. The ot her cyt oki nes ar e i n
var i ous st ages of cl i ni cal t r i al s as ant i neopl ast i c t her api es, al t hough Ì FN-v
i s approved f or use i n pat i ent s wi t h chr oni c granul omat ous di sease.
Ì mut hi ol i s not a cyt oki ne but a synt het i c dr ug.
11. The answer i s D [ see VÌ . D. 3. a; Tabl e 10- 3] .
A pat i ent wi t h an uncer t ai n hi st or y of vacci nat i on and a t et anus- pr one
wound r equi res bot h act i ve and passi ve vacci nat i on. TÌ G provi des
i mmedi at e prot ect i on i f t he i ndi vi dual does not have memor y. Td begi ns t he
ser i es t hat l eads t o t he est abl i shment of memor y. A t et anus-pr one wound i n
an i ndi vi dual wi t h a f ul l ser i es of act i ve vacci nat i ons requi r es no t reat ment
i f t he l ast vacci nat i on i n t he seri es was admi ni st er ed l ess t han 5 year s
ear l i er . These r ecommendat i ons are gener al gui del i nes.
12. The answer i s A [ see VÌ . D. 3. a; Tabl e 10- 3] .
13. The answer i s B [ see Ì V. A; Ì V. B. 6] .
Oppor t uni st i c i nf ect i ons by f ungi , vi r uses, and par asi t es ot her t han
ext r acel l ul ar pyogeni c bact er i a suggest a def i ci ency of T cel l f unct i on.
Ì nheri t ed T cel l i mmunodef i ci ency and AÌ DS ar e i nheri t ed and acqui red T
cel l def i ci enci es, r espect i vel y. Combi ned i mmunodef i ci ency i ncl udes bot h
humor al and T cel l def i ci ency. Onl y humor al i mmunodef i ci ency i s a pr i mar i l y
humor al def i ci ency i n whi ch t he expect ed si gns ar e r ecur rent i nf ect i ons by
ext r acel l ul ar pyogeni c bact er i a.
14. The answer i s A [ see Ì V. B. 6. a. ( 1)] .
Ì t i s not known what percent age of i ndi vi dual s shows over t sympt oms af t er
i ni t i al i nf ect i on. Those who do, however , general l y show mononucl eosi s-l i ke
sympt oms f or approxi mat el y 3 weeks. Some i ndi vi dual s di spl ay no over t
sympt oms.
15. The answer i s C ( Ì , Ì Ì ) [ see Ì . A. 4; Ì . D. 2; Ì . D. 5; VÌ Ì . A] .
Di goxi n i s a hapt en, a mol ecul e t hat i s t oo smal l t o st i mul at e r esponses (be
an i mmunogen) i n i t s f r ee f orm, but can be recogni zed by ant i bodi es. To
obt ai n sheep ant i di goxi n ant i bodi es, t he sheep i s i mmuni zed wi t h di goxi n
t hat has been coupl ed t o a l ar ger mol ecul e, i n t hi s case, a prot ei n. The
ant i bodi es obt ai ned f r om t he sheep are cl eaved wi t h pr ot eol yt i c enzymes t o
yi el d t he Fab f ragment . Thi s f ragment i s speci f i c t o and can bi nd di goxi n,
bl ocki ng i t s bi ol ogi c act i vi t y. Ani mal ant i bodi es have a shor t er ser um hal f -
l i f e when i nj ect ed i nt o humans, and al l Fab f ragment s, even human, have a
short hal f -l i f e compar ed t o compl et e ant i body mol ecul es. Onl y compl et e
human Ì gG has a hal f - l i f e of appr oxi mat el y 1 mont h.
16. The answer i s B ( Ì Ì Ì ) [ see Ì . B. 3; Ì . B. 5] .
CD4
+
, or hel per, T cel l s have r ecept ors t hat r ecogni ze f r agment s ( epi t opes)
of i mmuni zi ng ant i gens (i mmunogens) onl y when t he f r agment s are bound
t o an MHC cl ass Ì Ì mol ecul e on t he sur f ace of APCs. As a r esul t , T cel l s
cannot be act i vat ed i nappr opri at el y by sol ubl e ant i gens. CD8
+
T cel l s
r ecogni ze f r agment s bound t o MHC cl ass Ì mol ecul es.
17. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì . E. 2] .
When compl ement i s act i vat ed, di f f erent pr ot ei ns of t he compl ement
sequence have f unct i ons t hat l ead t o al l t hr ee act i ons. Acut e i nf l ammat i on
al l ows gr eat er movement of pl asma pr ot ei ns and phagocyt es f r om bl ood t o
t i ssue. Opsoni zat i on of i mmune compl exes enhances t hei r phagocyt osi s.
Cyt ol ysi s of mi croorgani sms of t en r esul t s i n t hei r ki l l i ng.
18. The answer i s A ( Ì ) [ see Ì . F. 2] .
Ant i vi ral ant i bodi es ar e pr obabl y most i mpor t ant i n ext r acel l ul ar i mmuni t y t o
vi r uses, bi ndi ng vi r us par t i cl es f or opsoni zat i on and prevent i ng addi t i onal
i nf ect i on of cel l s. Ì nt er f er ons are secret ed f rom vi r al -i nf ect ed and ot her
cel l s ( e. g. , macr ophages, T cel l s) and, af t er bi ndi ng t o r ecept ors, i nduce
t he appearance of ant i vi r al pr ot ei ns i n ot her cel l s. CTLs r ecogni ze vi ral -
i nf ect ed cel l s and cause di r ect cyt ot oxi ci t y.
P. 229


19. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see Ì Ì . A. 2. d; Ì Ì . A. 6 and 7; Ì Ì . C. 1. b; Ì Ì . C. 5] .
Ì f t he pat i ent pr oduced ant i bodi es t hat ar e st i l l present and t he
hyper sensi t i vi t y r eact i on i s t ype Ì , t hese ant i bodi es ar e Ì gE, most l y bound
t o mast cel l and basophi l Ì gE recept or s. Thei r hal f - l i f e i s several mont hs t o
year s. Ì nt ravenous i nt r oduct i on of peni ci l l i n causes r api d act i vat i on of and
secr et i on by bl ood basophi l s. Sympt oms of t ype Ì hypersensi t i vi t y occur
wi t hi n mi nut es. These sympt oms may be sever e (anaphyl axi s) or l ess
sever e ( cut aneous, gast roi nt est i nal , or respi rat ory) , dependi ng on t he
i ndi vi dual . Hemol yt i c anemi a i s an expect ed r esul t of a t ype Ì Ì
hyper sensi t i vi t y r eact i on t o peni ci l l i n, based on t he presence of Ì gM or Ì gG
ant i bodi es i n t he serum. The onset i s del ayed by a f ew hour s i n a pat i ent
wi t h pr eexi st i ng ant i bodi es.
20. The answer i s C ( Ì , Ì Ì ) [ see Ì Ì . E. 3, 4, 5 and 6] .
Type Ì V hypersensi t i vi t y r eact i ons ar e del ayed af t er t he i nt r oduct i on of
al l er gen because al l er gen- speci f i c T cel l s become act i vat ed and at t r act
ot her cel l s, such as macr ophages, t o t he si t e of al l er gen i nt roduct i on ( e. g. ,
t he epi dermi s of t he ski n i n cont act sensi t i vi t y, t he l ungs i n t ubercul osi s) .
These si t es ar e i nf i l t r at ed by mononucl ear cel l s. Ì nf l ammat i on i s pr i mar i l y
caused by t i ssue di srupt i on and necr osi s as wel l as by secr et i on of
cyt oki nes by t he i nf i l t r at i ng cel l s. Al t hough hi st ami ne secr et i on can al so
occur f r om l ocal mast cel l s, H1-ant agoni st s of hi st ami ne usual l y do not have
si gni f i cant ef f ect s because T cel l and macr ophage act i vat i on, mi gr at i on,
and secr et i on are not great l y af f ect ed by t hese dr ugs.
21. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì Ì Ì . C. 3. b] .
Al l t hr ee f i ndi ngs ar e common t o mor e t han one non-or gan- speci f i c
aut oi mmune di sorder , but t hey occur i n di f f erent per cent ages of pat i ent s
wi t h speci f i c di sor der s. For exampl e, ant i nucl ear ant i bodi es ar e pr obabl y
pr esent i n al l pat i ent s wi t h SLE but are f ound i n onl y a f r act i on of pat i ent s
wi t h r heumat oi d art hri t i s and Sj ögr en' s syndr ome. Rheumat oi d f act or s ar e
mor e common i n r heumat oi d ar t hr i t i s t han i n SLE or Sj ögren' s syndr ome,
and hypergammagl obul i nemi a i s more preval ent i n SLE t han i n Sj ögren' s
syndr ome.
22. The answer i s A ( Ì ) [ see V. A. 3; V. B] .
Par ent s and chi l dr en are r ar el y HLA mat ched but ar e usual l y hal f mat ched.
An HLA mat ch f r om a cadaver - der i ved organ i s unl i kel y. The probabi l i t y t hat
t wo si bl i ngs ar e HLA mat ched i s 25%; t he probabi l i t y t hat t hey ar e hal f
mat ched i s 50%.
23. The answer i s B ( Ì Ì Ì ) [ see V. C. 1] .
Ì n bone mar r ow t r anspl ant at i on, mar r ow cont ai ni ng compet ent l ymphocyt es
i s t r anspl ant ed t o a gener al l y i mmunosuppr essed host . The gr eat est
pr obl em i s an i mmune response by t he gr af t agai nst HLAs and ot her t i ssue
ant i gens of t he host . Ì n renal and cardi ac t r anspl ant at i on, t he gr eat est
pr obl em i s rej ect i on of t he f orei gn or gan by t he i mmune syst em of t he host
( HVG di sease) .
24. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see V. B. 2; V. D. 2. a] .
Cel l -medi at ed i mmune mechani sms ar e t hought t o be mor e i mpor t ant i n
acut e gr af t r ej ect i on, and t he i nhi bi t i on of T cel l act i vat i on appears t o be
t he key el ement i n i mmunosuppr essi on. Respondi ng T cel l s r equi re
si gnal i ng f rom Ì L-2 t o r each f ul l act i vat i on and pr ogr ess t o cel l di vi si on. Ì L- 2
i s pr oduced by act i vat ed T cel l s and can act i n an aut ocr i ne manner .
Cycl ospori ne bl ocks t ranscri pt i on of t he Ì L-2 gene duri ng T cel l act i vat i on,
i nhi bi t s t he synt hesi s of Ì L- 2, and prevent s f ul l T cel l act i vat i on and
di vi si on. Ì t s ef f ect s ar e l i mi t ed t o act i vat ed T cel l s. Because i t has no di rect
ef f ect on ant i body synt hesi s, i t i s not usef ul i n t he hyperacut e r ej ect i on
phenomena t hat ar e based on ant i body-medi at ed mechani sms. Hyper acut e
r ej ect i on i s essent i al l y unt r eat abl e because i t depends on t he pr esence of
ant i bodi es i n t he gr af t r eci pi ent .
25. The answer i s A ( Ì ) [ see VÌ . C. 2. a and b] .
Li ve, at t enuat ed vacci nes i nt r oduce or gani sms t hat are compet ent t o
r epl i cat e. Thi s r epl i cat i on st i mul at es t he i mmune r esponse. For t hi s and
pr obabl y ot her r easons, a l i ve, at t enuat ed vacci ne ( but not a ki l l ed,
i nact i vat ed vacci ne) pr obabl y pr ovi des l i f el ong i mmuni t y i n one or t wo
doses.
26. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see VÌ . C. 1. d; Tabl e 10- 3] .
The MMR vacci ne i s admi ni st er ed t o i nf ant s wi t hi n or shor t l y af t er t he 1st
year of l i f e. A second dose i s r ecommended at school ent r y. Ì nf l uenza
act i ve vacci ne i s t arget ed t owar d speci f i c adul t popul at i ons. Heal t hcar e
wor ker s ar e i ncl uded i n t hi s t arget popul at i on, as ar e i nf ant s and chi l dr en at
r i sk; however , t he vacci ne i s not rout i nel y admi ni st ered t o i nf ant s. Td i s not
r out i nel y admi ni st ered t o i nf ant s, who i nst ead recei ve DTP. Td i s used
pr i mar i l y f or i ni t i al vacci nat i ons i n adul t s who wer e not previ ousl y
vacci nat ed and f or 10- year boost er vacci nat i ons i n al l i ndi vi dual s, i ncl udi ng
heal t hcare wor kers.
P. 230


27. The answer i s A ( Ì ) [ see VÌ . C. 2; Tabl e 10-3] .
The pneumococcal and meni ngococcal vacci nes ar e mul t i val ent and cont ai n
pur i f i ed pol ysacchar i de f r om a number of di f f er ent ser ot ypes. However ,
t hese vacci nes do not cont ai n pol ysacchar i de f rom al l t he r el evant
i nf ect i ous agent s. Pur i f i ed pol ysacchari des do not st i mul at e i mmune
r esponses i n chi l dren younger t han 2 years of age. For pol ysacchar i de
vacci nes t o be ef f ect i ve i n young chi l dren, t he pol ysacchar i de must be
conj ugat ed t o a pr ot ei n as i n t he Hi b vacci ne.


11
Biotechnology Drug Products
Godwin W. Fong
Charles Lee
I. INTRODUCTION.
Advances in biotechnology have made many formerly unstable or difficult-to-produce
biologic products available for therapeutic use. Some life-threatening diseases are
now treated with biotechnology products.
A. Interferon (INF) is an example of a drug that was genetically engineered to inhibit
certain types of cancer cells and some viruses.
B. Cellular hormones known as interleukins, lymphotoxins, and tumor necrosis factor
are now used to treat cancer and immunodeficiency diseases.
C. Monoclonal antibodies (MAbs) can deliver toxins specifically to cancer cells and
destroy them. MAbs are also used with radioisotopes to diagnose and visualize cancer
cells. Monoclonal antibodies have been developed to target signaling pathways
associated with immune response and are being used to treat various immunological
disorders, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and
moderate to severe asthma.
D. Many biopharmaceutical products derived from the body tissues (through cell
lines) are now produced on a large scale. Modified natural products also may be
further improved.
E. A synthetic analogue of thyrotropin-releasing hormone prevents paralysis after
spinal cord injuries in animal studies.
F. Superoxide dismutase may be useful in preventing damage to tissues that are
deprived of oxygen.
G. New biotechnologic treatments have been developed for emphysema, congestive
heart failure, ulcers, atherosclerosis, and an increasing number of medical conditions.
Table 11-1 lists the biotechnology products that are approved for human use.
II. BASIC TERMINOLOGY
A. An antigen is a substance that stimulates the production of antibodies.
B. An antibody is an immunoglobulin produced by the body in response to
stimulation from an antigen.
C. Antisense DNA is a complementary strand of DNA that is specifically synthesized
to attach to the sense DNA and prevent genetic transcription. The sense DNA that
carries the information that affects the disease process is usually elucidated before an
antisense drug is designed.
D. Colony-stimulating factors (CSFs) are a class of glycoprotein hormones. CSFs
regulate the differentiation and formation of blood cells from precursor cells.
E. Cytokines are a group of special proteins (nonantibodies) released by cells to
trigger action in other cells.
F. DNA is the molecule that contains the genetic instructions of a cell. DNA consists
of deoxyribose, phosphate, and repeating bases as building blocks. The four bases are
adenine, guanine, thymine, and cytosine.
P.232


P.233


P.234


P.235


P.236


P.237


P.238


P.239


P.240


Table 11-1. Approved Recombinant Therapeutics and Vaccines
Drug (Trade Name) Indication(s) Company; Year
Introduced
Human insulin (Humulin) Diabetes Eli Lilly,
Genentech; 1982
Somatrem for injection
(Protropin)
Human growth hormone deficiency in
children
Genentech; 1985
InterIeron u-2a (Roferon-
A)
Hairy cell leukemia Hoffmann-La
Roche; 1986
InterIeron u-2b (Intron A) Hairy cell leukemia Schering-Plough,
Biogen; 1986

Extension of therapy for chronic
hepatitis C from 6 months to 18-24
months
1997

Follicular lymphoma in conjunction
with chemotherapy
1997
Hepatitis B vaccine
recombinant (Recombivax
HB)
Prevention of hepatitis B Merck, Chiron;
1986
Muromonab-CD3
(Orthoclone OKT3)
Reversal of acute kidney transplant
rejection
Ortho Biotech;
1986
Somatropin for injection
(Humatrope)
Human growth hormone deficiency in
children
Eli Lilly; 1987
Alteplase (Activase) Acute myocardial infarction Genentech; 1987
Acute pulmonary embolism 1990

Restoration of function to central
venous access devices (as assessed by
the ability to withdraw blood)
2001
InterIeron u-2a (Roferon-
A)
AIDS-related Kaposi sarcoma Hoffmann-La
Roche; 1988
InterIeron u-2b (Intron A) AIDS-related Kaposi sarcoma Schering-Plough,
Biogen; 1988
Genital warts
Hepatitis C 1991
Interferon n3 (Alferon N
injection)
Genital warts Interferon Sciences;
1989
Hepatitis B vaccine
(Engerix-B)
Hepatitis B prevention SmithKline
Beecham, Biogen;
1989
Chronic hepatitis C infection 1998
Erythropoietin (Epogen) Anemia associated with chronic renal
failure
Amgen, Johnson &
Johnson, Kirin;
1989
Erythropoietin (Procrit) Anemia associated with AIDS or
zidovudine administration
Amgen, Ortho
Biotech; 1990

Anemia associated with chronic renal
failure
1990

Chemotherapy-associated anemia in
patients with nonmyloid malignancy
1993

Anemia associated with cancer and
chemotherapy
1993
PEG-adenosine
(ADAGEN)
ADA-deficient severe combined
immunodeficiency
Enzon, Eastman
Kodak; 1990
InterIeron v-1b
(Actimmune)
Management of chronic granulomatous
disease
Genentech; 1990

Delaying time to disease progression in
patients with severe, malignant
osteopetrosis
InterMune
Pharmaceuticals
(2000)
CMV immunoglobulin
(CytoGam)
Prevention of CMV in kidney
transplant recipients
Medimmune; 1990
Filgrastim; G-CSF Chemotherapy-induced neutropenia Amgen; 1991
Acute myeloid leukemia 1998
Glucocerebrosidase
(Ceredase)
Type I Gaucher disease
a
Genzyme; 1991
Glucocerebrosidase
(Cerezyme)
Type I Gaucher disease
a
Genzyme; 1994
Sargramostim (GM-CSF)
(Prokine)
Autologous bone marrow
transplantation
Hoechst-Roussel,
Immunex; 1991
Sargramostim (GM-CSF)
(Leukine)
Neutrophil recovery after bone marrow
transplantation
Immunex, Hoechst-
Roussel; 1991
Antihemophilic factor
(Mononine)
Hemophilia B Armour; 1992
Antihemophilic factor
(Recombinate)
Hemophilia A Genetics Institute,
Baxter Healthcare;
1992
Interleukin 2 (Proleukin) Renal cell carcinoma Chiron; 1992
Metastatic melanoma 1998
111
Indium-labeled
antibody (OncoScint
CR103)
Detection, staging, and follow-up of
colorectal cancer
Cytogen, Knoll;
1992
111
Indium-labeled
antibody (OncoScint
OV103)
Detection, staging, and follow-up of
ovarian cancer
1992
InterIeron þ-1b
(Betaseron)
Relapsing/remitting multiple sclerosis Chiron, Berlex;
1993
DNase alfa (Pulmozyme) Cystic fibrosis Genentech; 1993
Factor VIII (Kogenate) Hemophilia A Genentech, Miles;
1993
Filgrastim (G-CSF)
(Neupogen)
Bone marrow transplant Amgen; 1994
PEG-l-asparaginase
(Oncaspar)
Refractory childhood acute
lymphoblastic leukemia
Enzon; 1994
Human growth hormone
(Nutropin)
Short stature caused by human growth
hormone deficiency
Genentech; 1994
Abciximab (ReoPro) Antiplatelet prevention of blood clots Centocor; 1994

Treatment of a broader range of
patients undergoing percutaneous
coronary intervention; revised dosage
and patient management to reduce
bleeding


Unstable angina that does not respond
to conventional medical therapy when
percutaneous coronary intervention is
planned within 24 hr

Live varicella virus
vaccine (Varivax)
Active immunization of persons 12
months of age and older
Merck; 1995
RSV immunoglobulin
(RespiGam)
Prevention of serious lower respiratory
tract infection in children younger than
24 months old
Massachusetts
Public Health
Biologic Labs;
1996
Inactivated hepatitis A
vaccine (Vaqta)
Immunization against hepatitis A in
children older than 6 years of age
Merck; 1996
InterIeron þ-1a (Avonex) Multiple sclerosis Biogen; 1996
Human antihemophilic
factor
Hemophilia A Centeon; 1996
Haemophilus b conjugate
(meningococcal protein
conjugate) and hepatitis B
(recombinant vaccine)
(Comvax)
Immunization of individuals 6 weeks
to 15 months of age born of HBsAg-
negative mothers
Merck; 1996
Cryoprecipitated
antihemophilic factor A
Control of bleeding associated with
Factor VIII deficiency
Blood Bank of the
Redwoods; 1996
Reteplase (Retavase) Acute myocardial infarction in adults Boehringer
Mannheim; 1996
DTaP vaccine (Infanrix) Primary and booster immunization of
infants and children except as a fifth
dose in children who previously
received four doses of DTaP
SmithKline
Beecham; 1997
Recombinant coagulation
Factor IX (BeneFix)
Control and prevention of hemorrhagic
episodes in patients with hemophilia B,
Genetics Institute;
1997
including perioperative management of
patients with hemophilia B who are
undergoing surgery
Autologous cultured
chondrocytes (Carticel
SM Service)
Repair of clinically significant,
symptomatic, cartilaginous defects of
the femoral condyle (medial, lateral, or
trochlear) caused by acute or repetitive
trauma
Genzyme Tissue
Repair; 1997
Interferon alfacon-1
(Infergen)
Treatment of chronic HCV infection in
patients 18 years of age or older who
have compensated liver disease and
anti-HCV serum antibodies or HCV
RNA
Amgen; 1997

Subsequent treatment of HCV-infected
patients who tolerated an initial course
of interferon therapy
1997
Rabies vaccine
(RabAvert)
Preexposure and postexposure
immunization of children and adults
Chiron; 1997
Oprelvekin (Neumega) Prevention of severe thrombocytopenia
and reduction of the need for platelet
transfusions after myelosuppressive
chemotherapy in patients with
nonmyeloid malignancies who are at
high risk for severe thrombocytopenia
Genetics Institute;
1997
Rituximab (Rituxan) Treatment of patients with relapsed or
refractory low-grade or follicular B cell
non-Hodgkin lymphoma
Genentech; 1997
Daclizumab (Zenapax) Prophylaxis of acute organ rejection in
patients receiving renal transplants;
part of an immunosuppressive regimen
that includes cyclosporine and
corticosteroids
Hoffman-La
Roche; 1997
Becaplermin (Regranex) Lower-extremity diabetic neuropathic
ulcers that extend into the
subcutaneous tissue or beyond and
have an adequate blood supply
OMJ
Pharmaceuticals;
1997
HTLV-I and -II
(Vironostika HTLV-I and
-II MicroELISA System)
Detection of antibodies to HTLV-I and
-II in human serum or plasma
Organon Teknika;
1998
Fibrin sealant (Tisseel VH
kit)
Adjunct to hemostasis in surgeries that
involve cardiopulmonary bypass
Osterreichisches
Institut fur
Haemoderivate;
1998

Treatment of splenic injuries caused by
blunt or penetrating trauma to the
abdomen when control of bleeding by
conventional surgical techniques,
including suture, ligature, and cautery,
is ineffective or impractical

Closure of colostomies
Pooled plasma, solvent
detergent treated
(VIPLAS/SD)
Documented deficiencies of
coagulation factors for which there are
no concentrate preparations available,
including congenital single-factor
deficiencies of Factors I, V, VII, XI,
and XIII and acquired multiple
coagulation factor deficiencies
V.I. Technologies;
1998
Reversals of warfarin effect

Thrombotic thrombocytopenic purpura

Basiliximab (Simulect) Prophylaxis of acute organ rejection in
patients undergoing renal
transplantation
Novartis; 1998

Part of an immunosuppressive regimen
that includes cyclosporine and
corticosteroids


Use in renal transplantation in
combination with triple
immunosuppressive therapy
2001
Use in pediatric renal transplantation

Use of an IV bolus injection

Palivizumab (Synagis) Prophylaxis of serious lower
respiratory tract disease caused by
RSV in pediatric patients at high risk
of RSV disease
Medimmune; 1998
Sacrosidase (Sucraid) Congenital sucrose isomaltase
deficiency
Orphan Medical;
1998
Eptifibatide (Integrilin) Acute coronary syndrome COR Therapeutics;
1998

Treatment of patients undergoing
percutaneous coronary intervention

Diphtheria and tetanus
toxoids and acellular
pertussis vaccine
adsorbed (Certiva)
Active immunization of individuals 6
weeks to 7 years of age (before the 7th
birthday)
North American
Vaccine; 1998
Infliximab (Remicade) Treatment of moderately to severely
active Crohn disease to reduce the
signs and symptoms in patients who
have an inadequate response to
conventional therapies
Centocor; 1998

Treatment of patients with fistulizing
Crohn disease to reduce the number of
draining enterocutaneous fistula(s)


For reduction in signs and symptoms
of rheumatoid arthritis in patients who
have had an inadequate response to
methotrexate
1999

Inhibition of progression of structural
damage in patients with rheumatoid
arthritis who have had an inadequate
response to methotrexate
2000

Improving physical function in patients
with moderately to severely active
rheumatoid arthritis who have had an
inadequate response to methotrexate
2002

Reducing signs and symptoms, and
inducing and maintaining clinical
remission in patients with moderately
to severely active Crohn disease who
have had an inadequate response to
conventional therapy
2002

Reducing the number of draining
enterocutaneous and rectovaginal
fistulas and maintaining fistula closure
in patients with fistulizing Crohn
disease
2003

Improving physical function in patients
with moderately to severely active
rheumatoid arthritis who have had an
inadequate response to methotrexate
2003
Rotavirus vaccine, live,
oral, tetravalent
(RotaShield)
Primary immunization of infants at 2,
4, and 6 months of age
Wyeth-Ayerst
Laboratories; 1998
Trastuzumab (Herceptin) Metastatic breast cancer in patients
whose tumors overexpress the HER-2
protein and who have received one or
more chemotherapy regimens for
metastatic disease
Genentech; 1998
Median survival 2001
(Etanercept) Enbrel Reduction in signs and symptoms of
moderately to severely active
rheumatoid arthritis in patients who
have had an inadequate response to one
or more DMARDs
Immunex; 1998

Reducing the signs and symptoms and
delaying structural damage in patients
with moderately to severely active
rheumatoid arthritis, including those
who have not previously failed
treatment with a DMARD
2000

Reducing signs and symptoms of
active arthritis in patients with psoriatic
arthritis
2002
Recombinant OspA
(LYMErix)
Active immunization against Lyme
disease in people 15-70 years old
SmithKline
Beecham; 1998
Vitravene (Fomivirsen) Local treatment of CMV retinitis in
patients with AIDS who are intolerant
of or have a contraindication to other
treatments for CMV retinitis or who
were insufficiently responsive to
previous treatments
Isis
Pharmaceuticals,
Ciba Vision; 1998
Antithymocyte globulin
(Thymoglobulin)
Acute rejection in renal transplant
patients
Pasteur-Mérieux
Serums et
Vaccines—France;
1998
Denileukin diftitox
(Ontak)
Treatment of patients with persistent or
recurrent cutaneous T cell lymphoma
whose malignant cells express the
CD25 component of the interleukin 2
receptor
Seragen; 1999
Hepatitis B
immunoglobulin (Nabi-
HB)
Treatment of acute exposure to
HBsAg, perinatal exposure of infants
born to HBsAg-positive mothers
Nabi; 1999

Sexual exposure to HBsAg-positive
individuals


Household exposure of infants to
people with acute hepatitis B virus
infection

Recombinant coagulation
factor VIIa (NovoSeven)
Treatment of bleeding episodes in
hemophilia A or B with inhibitors to
Factor VIII or Factor IX
Novo Nordisk
A/S— Denmark;
1999
InterIeron u-n1,
lymphoblastoid
(Wellferon)
Chronic HCV infection in patients 18
years of age or older who do not have
decompensated liver disease
GlaxoWellcome;
1999
Antihemophilic factor/von
Willebrand factor
complex (Humate-P)
Used in adult patients for treatment and
prevention of bleeding hemophilia A
(classic hemophilia)
Centeon Pharma—
Germany; 1999

Used in adult and pediatric patients for
treatment of spontaneous and trauma-
induced bleeding episodes in severe
von Willebrand disease


Used in mild and moderate von
Willebrand disease when use of
desmopressin is known or suspected to
be inadequate

Hetastarch (Hextend) Plasma volume expander for treatment
of hypovolemia during surgery
BioTime; 1999
Pneumococcal 7-valent
conjugate vaccine
(diphtheria CRM197
protein) (Prevnar)
Immunization of infants 2, 4, 6, and
12-15 months of age to prevent
invasive pneumococcal disease
Lederle
Laboratories
Division American
Cyanamid; 2000

Immunization of infants and toddlers
against otitis media caused by vaccine
serotypes
2002
Antihemophilic factor
(recombinant) (ReFacto)
Control and prevention of hemorrhagic
episodes and for short-term routine and
surgical prophylaxis in patients with
hemophilia A
Genetics Institute;
2000
BCG, live (PACIS) Treatment of CIS in the absence of
associated invasive cancer of the
bladder
BioChem
Pharma—Canada;
2000
Tenecteplase (TNKase) Reduction of mortality associated with
AMI
Genentech; 2000
Crotalidae polyvalent
immune Fab (ovine)
(CroFab)
Treatment of minimal and moderate
North American Crotalidae
envenomation
Protherics; 2000
Botulinum toxin type B
(MYOBLOC)
Treatment of cervical dystonia to
reduce the severity of abnormal head
position and neck pain
Elan
Pharmaceuticals;
2000
Botulinum toxin type A
(BOTOX or BOTOX
COSMETIC)
Treatment of cervical dystonia Allergan; 2002

Temporary improvement in the
appearance of moderate to severe
glabellar lines associated with
corrugator and/or procerus muscle
activity in adult patients > 65 years oI
age

PeginterIeron u-2b (PEG-
Intron)
Treatment of chronic hepatitis C in
patients not previously treated with
interferon-u who have compensated
liver disease and are at least 18 years of
age
Schering; 2001
Alemtuzumab (Campath) Treatment of patients with B cell
chronic lymphocytic leukemia who
have been treated with alkylating
agents and who have failed fludarabine
therapy
Millennium and
ILEX Partners;
2001
Hepatitis A inactivated
and hepatitis B
(recombinant) vaccine
(TWINRIX)
Active immunization of people 18
years of age or older against disease
caused by hepatitis A virus and
infection by all known subtypes of
hepatitis B virus
SmithKline
Beecham
Biologicals; 2001
Digoxin immune Fab
(ovine) (DigiFab)
Treatment of patients with life-
threatening or potentially life-
threatening digoxin toxicity or
overdose
Protherics; 2001
Darbepoetin u (Aranesp) Treatment of anemia associated with
chronic renal failure, including patients
on dialysis and patients not on dialysis
Amgen; 2001

Treatment of anemia in patients with
nonmyeloid malignancies when anemia
is the result of the effect of
concomitantly administered
chemotherapy
2002
Hepatitis B
immunoglobulin (human)
(Nabi-HB)
Treatment of acute exposure to HBsAg
after acute exposure to blood
containing HBsAg, perinatal exposure
of infants born to HBsAg-positive
mothers, sexual exposure to HBsAg-
positive persons, and household
Nabi; 2001
exposure of infants to people with
acute hepatitis B virus infection
Anakinra (Kineret) Reduction in signs and symptoms of
moderately to severely active
rheumatoid arthritis, in patients 18
years of age or older who have failed
one or more DMARD
Amgen; 2001
Drotrecogin u (activated)
(Xigris)
Reduction of mortality in adult patients
with severe sepsis (sepsis associated
with acute organ dysfunction) who
have a high risk of dying from sepsis,
as measured by a scoring system based
on their general health and the severity
of their illness (e.g., by APACHE II)
Eli Lilly; 2001
Pegfilgrastim (Neulasta) To decrease the incidence of infection,
as manifested by febrile neutropenia, in
patients with nonmyeloid malignancies
receiving myelosuppressive anticancer
drugs associated with a clinically
significant incidence of febrile
neutropenia
Amgen; 2002
Ibritumomab tiuxetan
(Zevalin)
Treatment of patients with relapsed or
refractory low-grade, follicular, or
transformed B-cell non-Hodgkin
lymphoma, including patients with
rituximab (Rituxan) refractory
follicular non-Hodgkin lymphoma
IDEC
Pharmaceuticals;
2002

The therapeutic regimen includes
rituximab,
111
indium ibritumomab
tiuxetan, and
90
yttrium ibritumomab
tiuxetan

InterIeron þ-1a (Rebif) Treatment of patients with relapsing
forms of multiple sclerosis to decrease
the frequency of clinical exacerbations
and delay the accumulation of physical
disability
Serono; 2002
DTaP vaccine adsorbed
(DAPTACEL)
Active immunization of infants and
toddlers at 2, 4, 6, and 17-20 months of
age against diphtheria, tetanus, and
pertussis
Aventis Pasteur—
Canada; 2002
Rasburicase (Elitek) Initial management of plasma uric acid
levels in pediatric patients with
leukemia, lymphoma, and solid tumor
malignancies who are receiving
anticancer therapy expected to result in
tumor lysis and subsequent elevation of
plasma uric acid
Sanofi-Synthelabo;
2002
PeginterIeron u-2a
(PEGASYS)
Treatment of adults with chronic
hepatitis C who have compensated
liver disease and who have not been
Hoffman-La
Roche; 2002
previously treated with interIeron u

Combination therapy with ribavirin,
USP (Copegus), for the treatment of
chronic HCV infection
2002
PeginterIeron u-2a co-
packaged with ribavirin
(Pegasys Copegus
Combination Pack)
Prefilled syringes of Pegasys
(peginterIeron u-2a) for the treatment
of chronic hepatitis C, as a
subcutaneous injection taken once a
week
2004
Urokinase (Abbokinase) For adults for the lysis of acute
massive pulmonary emboli, defined as
obstruction of blood flow to a lobe or
multiple segments
Abbott
Laboratories; 2001

For the lysis of pulmonary emboli
accompanied by unstable
hemodynamics (i.e., failure to maintain
blood pressure without supportive
measures)

Adalimumab (Humira) For reducing signs and symptoms and
inhibiting the progression of structural
damage in adult patients with
moderately to severely active
rheumatoid arthritis who have had an
inadequate response to one or more
DMARDs
Abbott
Laboratories; 2002

Can be used alone or in combination
with methotrexate (MTX) or other
DMARDs

Laronidase (Aldurazyme) For patients with Hurler and Hurler-
Scheie forms of MPS-I and for patients
with the Scheie form who have
moderate to severe symptoms
Biomarin
Pharmaceutical;
2003
Alefacept (Amevive) Treatment of adult patients with
moderate to severe chronic plaque
psoriasis who are candidates for
systemic therapy or phototherapy
Biogen; 2003
Agalsidase beta
(Fabrazyme)
For use in patients with Fabry disease
to reduce GL-3 deposition in capillary
endothelium of the kidney and certain
other cell types
Genzyme; 2003
Tositumomab and
131
iodine tositumomab
(Bexxar)
Treatment of patients with CD20
positive, follicular, non-Hodgkin
lymphoma, with and without
transformation, whose disease is
refractory to rituximab and has
relapsed after chemotherapy
Corixa; 2004
Omalizumab (Xolair) For adults and adolescents (> 12 years
of age) with moderate to severe
persistent asthma who have a positive
skin test or in vitro reactivity to a
Genentech; 2004
perennial aeroallergen and whose
symptoms are inadequately controlled
with inhaled corticosteroids
Bevacizumab (Avastin) First-line treatment for patients with
metastatic colorectal cancer
Genentech; 2004
Cetuximab (Erbitux) A monoclonal antibody that targets the
protein EGFR
Imclone Systems;
2004
99m
Technetium
fanolesomab
(NeutroSpec)
For scintigraphic imaging of patients
with equivocal signs and symptoms of
appendicitis aged 5 years or older
Palatin
Technologies; 2004
Natalizumab (Tysabri) Treatment of patients with relapsing
forms of multiple sclerosis to reduce
the frequency of clinical exacerbations
Biogen Idec; 2004
Palifermin (Kepivance) Decreases the incidence and duration
of severe oral mucositis in patients
with hematologic malignancies
receiving myelotoxic therapy requiring
hematopoietic stem cell support
Amgen; 2004
Galsufase (Naglazyme) Treatment of patients with MPS-VI Biomarin
Pharmaceuticals;
2005
Alglucosidase alpha
(Myozyme)
Infantile-onset Pompe disease (GAA
deficiency)
Genzyme; 2006
Ranibizumab injection
(Lucentis)
For the treatment of neovascular (wet)
age-related macular degeneration
(AMD)
Genentech; 2006
Panitumumab (Vectibix) For the treatment of patients with
EGFR-expressing colorectal carcinoma
with disease progression on or
following fluoropyrimidine-,
oxaliplatin-, and irinotecan-containing
chemotherapy regimens
Amgen; 2006
Eculizumab (Soliris) For the treatment of patients with
paroxysmal nocturnal hemoglobinuria
(PNH) to reduce hemolysis
Alexion
Pharmaceuticals;
2007
ADA, adenosine deaminase; AMI, acute myocardial infarction; CIS, carcinoma-in-situ;
CMV, cytomegalovirus; DMARD, disease-modifying antirheumatic drug; DTaP,
diphtheria and tetanus toxoids and acellular pertussis; EGFR, epidermal growth factor
receptor; G-CSF, granulocyte colony-stimulating factor; GL, globotriaosylceramide;
GM-CSF, granulocyte-macrophage colony-stimulating factor; HBsAg, hepatitis B
surface antigen; HCV, hepatitis C virus; HER-2, human epidural growth receptor 2;
HTLV, human T lymphotropic virus; MPS, mucopolysaccharidosis; PEG,
polyethylene glycol; RSV, respiratory syncytial virus.
a
Gaucher disease is an autosomal dominant or recessive disorder caused by an excess
of glucocerebroside in the reticuloendothelial cells because of the lack of the
metabolic enzyme cerebrosidase. Proliferation of abnormal cells leads to
splenomegaly, hepatomegaly, skeletal lesions, and other symptoms. Data from
Biotechnology in the U.S. Pharmaceutical Industry. Research Triangle Park, NC,
Institute for Biotechnology Information, 1995; and www.fda.gov.
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G. DNA ligase is an enzyme that seals single-stranded nicks between nucleotides in
double-stranded DNA. DNA ligase enables DNA fragments from different sources to
be joined.
H. DNA polymerase is an enzyme that catalyzes the synthesis of DNA. It uses a
single strand of DNA as the template and nucleotides as the substrates.
I. An enzyme is a protein that catalyzes a substrate during its conversion to a product.
J. A gene is a segment of DNA that codes for a specific polypeptide.
K. A genome is the genetic information content of a cell.
L. A hormone is an endogenous substance that is secreted by one type of cell and acts
on another type of cell.
M. A hybridoma is a hybrid cell produced by the fusion of a myeloma cell and a
specific antibodyproducing B lymphocyte. A single hybridoma produces a single type
of antibody.
N. Interferon (INF) is any of a class of glycoproteins produced by animal cells in
response to viral infection.
O. Interleukin is a group of proteins synthesized by macrophages and T lymphocytes
in response to antigen and other stimulation.
P. A lymphokine is any of a class of soluble proteins produced by some white blood
cells. These proteins stimulate other white blood cells as part of the immune response.
Q. A plasmid is a circular piece of duplex DNA that is not part of a chromosome and
can replicate independently. Plasmids are used as vectors for the transfer of DNA in
recombinant DNA technology.
R. RNA is a macromolecule that contains information for protein synthesis. The three
types of RNA are ribosomal (rRNA), transfer (tRNA), and messenger (mRNA). RNA
is also the genetic material of some viruses.
S. Recombinant DNA (rDNA) is a hybrid DNA that is formed when pieces of DNA
from different sources are joined. The process is also known as gene splicing.
T. A restriction endonuclease is an enzyme that cleaves DNA at sequence-specific
sites.
U. Tumor necrosis factor (TNF) is a lymphokine produced by macrophages. It can be
activated to kill tumor cells.
V. Reverse transcriptase is an enzyme present in RNA viruses that catalyzes the
formation of DNA from the viral RNA.
III. PROTEINS AND PEPTIDES.
Proteins and peptides play essential roles in all aspects of cellular function. Many
endogenous substances synthesized in the body are essential proteins. Many enzymes
that catalyze vital reactions in the body are proteins.
A. Hemoglobin (Hb) is a large protein involved in oxygen transport.
B. Globulins are special proteins in the plasma that are involved in immunogenic
response and antibody formation.
C. Albumin is a plasma protein that binds to many drugs and is used as a carrier for
new drugs.
D. Other well-known proteins include insulin and the enzymes involved in digestion.
P.242


Table 11-2. Immunoglobulin Applications
Gammaglobulinemia
Hepatitis A prophylaxis
Measles and rubella prophylaxis
Multiple myeloma with specific antibody deficiency
Prophylaxis in infants and children with HIV exposure
Chronic inflammatory demyelinating neuropathy
Acquired hemophilia
Orphan drug for the treatment of juvenile rheumatoid arthritis
Respiratory tract infections
Immune thrombocytopenic purpura
Orphan drug for the treatment of polymyositis and acute myocarditis
Acute exposure to hepatitis B surface antigen
Kawasaki disease in conjunction with high-dose aspirin
E. Protein is an important component of keratin in hair and myosin in muscles.
F. Albumin (human) 5% USP is used to reverse hypovolemia in shock patients, burn
patients, and those with chronic hypoalbuminemia.
IV. Immunoglobulin (Ig)
is an important class of globulin proteins involved in immunity and the allergic
response. IgG is used therapeutically to modulate or replace antibody in various
immunodeficiency and disease states. Intramuscular and intravenous preparations are
available from a variety of manufacturers (Tables 11-2 and 11-3). Most of these
products must be stored under refrigeration (2-8°C) and have a limited shelf life.
V. RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING
FACTOR (G-CSF)
A. CSFs are glycoproteins that regulate the production of many types of blood cells
and components in the body. These include macrophages, eosinophils, neutrophils,
basophils, and platelets. Natural and modified CSFs are used to treat a number of
congenital disorders and several forms of cancer.
B. Lenograstim is a recombinant human granulocyte CSF (rhG-CSF) derived from
Chinese hamster ovary cells. It is glycosylated at the same site as natural hG-CSF
(threonine-133) and consists of 174 amino acids.
C. Filgrastim is an Escherichia coli-derived glycoprotein. It is not glycosylated, and it
differs in structure from natural hG-CSF. Like natural hG-CSF and filgrastim,
lenograstim selectively promotes the proliferation, differentiation, and maturation of
blood cell precursors. Dose-related
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increases in blood neutrophil counts are observed after lenograstim administration.
Lenograstim reduces the duration of neutropenia and the severity of infection in
patients who are receiving cytotoxic chemotherapy for nonmyeloid malignancy.
Colony-forming assays show that lenograstim is approximately three times as potent
as filgrastim. These agents were similarly potent in cell-proliferation assays. Both
natural and recombinant G-CSF products stimulate the release of mature neutrophils
from hematopoietic tissue, prolong their survival, and enhance their phagocytic and
cytotoxic activity.
Table 11-3. Immunoglobulin Products
Gamimune-N Nabi-HB
Gammagard RespiGam
Polygram Sandoglobulin
Gammar Polygam
Iveegam Venoglobulin
D. Other actions of rhG-CSF include synergism with interleukin 3 (IL-3) to induce
megakaryocyte formation and with granulocyte-macrophage CSF (GM-CSF) to
stimulate granulocyte- macrophage colonies.
VI. GLYCOPROTEINS
A. Many special proteins acquire biologic activity as a result of their covalent linking
with a polymer of sugar or carbohydrate. The covalently linked protein-carbohydrate
molecule is a glycoprotein. Glycoproteins form natural structural membranes in the
cells of unicellular (e.g., bacteria) and multicellular (e.g., humans, animals)
organisms.
B. N-acetylglucosamine (NAG) forms the cell membrane in bacteria. It is an example
of a carbohydrate chain linked to a protein through a chain of amino acids. Bacterial
resistance to penicillin is linked to the integrity of NAG in the cell membrane.
C. The extent and site of glycosylation of a protein molecule may affect the
physicochemical properties, stability, and specificity of a surface receptor in a cell.
Glycoproteins on the surface of red blood cells are involved in recognizing the
specific blood type.
D. The charge at the site of a glycoprotein molecule may play a role in the orientation
and interaction of the receptor. The charge may be modified by sialic acid, sulfate,
and phosphate groups. The protein molecule presents potential sites for N-
glycosylation and O-glycosylation. Change in glycosylation is a powerful tool for use
in engineering the preferred configuration and stability when designing recombinant
glycoprotein for therapeutic use.
E. Carbohydrates contribute to activities in a number of ways, including recognition
of the terminal sialic acids of glycoproteins by various viruses and bacteria,
recognition of polylactosamines on erythrocytes by autoimmune antibodies, and
recognition of sialylated, fucosylated lactosaminoglycans on leukocytes by E-selectin
of endothelial cells.
VII. DNA
A. DNA is the genetic material of all organisms except some viruses, whose genetic
material is in the form of RNA. Most organisms have double-stranded DNA. Some
viruses contain single-stranded DNA. This type of virus replicates itself by entering a
host cell, where it makes a complementary copy of itself and temporarily forms a
double strand.
B. All DNA molecules consist of many covalently linked subunits called nucleotides.
The nucleotides consist of deoxyribose, phosphate, and one of the nitrogen-containing
bases (adenine, guanine, thymine, or cytosine). DNA encodes information to produce
all of the proteins needed by the organism. The DNA sequence may be modified or
recombined with new strands. This recombinant technology may be used to correct
genetic defects in living organisms.
VIII. ANTISENSE DRUGS
A. Many diseases occur because of genetic defects or errors in the gene involved in
producing essential enzymes or proteins. Genetic information resides in chromosomes
that house helical strands of DNA within the nucleus. The Human Genome Initiative
was created several years ago to study all human genes. This national effort is now
yielding information on many serious
P.244

diseases that involve congenital defects, cancer, infection, AIDS, and other disorders
of the immune system.
B. Strategies are now available to moderate many disease processes by altering or
blocking the transcription of DNA. If the DNA sequence is altered so that the
complementary strand is transcribed instead of the normal “sense” gene, then the
DNA cannot make a copy of the normal RNA that participates in protein synthesis.
The aberrant copies of RNA may pair up (hybridize) with other RNA strands that
complement it and thereby block protein synthesis. This technique involves targeting
DNA or RNA with antisense drugs.
C. Many oligonucleotides are designed to target viral disease and cancer cells. To
further stabilize the drug, phosphodiesters are chemically converted to
phosphothioates.
D. Antisense drugs against cytomegalovirus (CMV), HIV, and other viruses are in
various phases of clinical trials. The first antisense drug, Vitravene, was approved by
the U.S. Food and Drug Administration (FDA) in 1998. Vitravene is a potent
biotechnology drug that is indicated for the local treatment of CMV retinitis in
patients with AIDS who are intolerant of other treatments, who have a
contraindication to other treatments, or who were insufficiently responsive to previous
treatments. The recommended labeled dosage is an induction dose on days 1 and 15,
followed by a monthly intravitreal injection of 330 µg.
E. When the nucleotide base sequence of a gene that controls a specific body function
is known, the antisense DNA strand can be synthesized. If necessary, the DNA strand
can be modified to provide increased stability and potency. These strands can then be
introduced into cells, where they attach themselves to the complementary sense DNA
strands and depress transcription of these genes. This technique was performed
successfully in cell culture for the gene that produces human squamous cell carcinoma
of the larynx.
F. If a duplicate copy of a gene is inserted into a chromosome in reverse orientation to
the normal gene, then the antisense DNA strand of this gene is transcribed. This
process yields an antisense mRNA strand that is complementary to the mRNA strand
transcribed for the normal gene. The two complementary RNA strands bind to each
other, thereby preventing the translation of the normal RNA strand that may control
protein synthesis.
IX. GENE THERAPY.
The first example of human gene therapy is from 1990, when the FDA approved
PEG-ADA (Enzon) for adenosine deaminase deficiency. This rare, but serious,
genetic disorder weakens the immune system and causes increased susceptibility to
infection. Two girls were reinfused with their own genetically altered white blood
cells. The altered cells live and function normally, and the two girls were living a
relatively normal life after 5 years.
X. MISCELLANEOUS BIOTECHNOLOGIC PRODUCTS
A. Alteplase (Activase, Genentech) is a thrombolytic agent formerly known as tissue-
plasminogen activator. Intravenous alteplase effectively produces recanalization of
occluded coronary arteries after acute myocardial infarction. Intravenous alteplase is
also effective in the treatment of acute massive pulmonary embolism. Adverse effects,
including bleeding complications, reperfusion arrhythmias, and reinfarction, are the
primary concerns with this therapy. Systemic fibrinolysis is less than that seen with
streptokinase. The recommended dose to produce recanalization after myocardial
infarction is 100 mg in divided doses. The recommended dose to treat pulmonary
embolism is 100 mg infused intravenously over 2 hr.
B. Antithrombin III (heparin cofactor, human antithrombin III, ATnativ, Pharmacia)
is designated an orphan product. It is used as replacement therapy to prevent or treat
thromboembolic episodes in congenital deficiency states. The amount of intravenous
antithrombin III concentrate to be administered is based on antithrombin III levels. In
patients who have congenital or acquired antithrombin III deficiency, the goal is to
maintain levels between 80% and
P.245

120% of normal. Once-daily doses of antithrombin III should maintain serum levels
above 80% of normal. Levels should be monitored twice daily until they stabilize,
then daily thereafter immediately before the next dose is administered.
C. IL-3 is a hematopoietic growth factor used to treat patients with bone marrow
failure. Recombinant human IL-3 (rhIL-3) alone improves neutrophil and platelet
counts in patients who have chemotherapy-related bone marrow failure and
myelodysplastic syndromes. However, only minimal improvements in hematopoiesis
are seen in patients who have aplastic anemia. Enhanced responses are seen with the
sequential combined use of rhIL-3 and other hematopoietic growth factors (e.g., GM-
CSF). Recombinant human IL-3 is given subcutaneously or intravenously.
Intravenous doses range from 30 to 1000 µg/m2/day infused over 4 hr.
D. Aldesleukin, a lymphokine, is a hrIL-2 product that is used to treat metastatic renal
cell carcinoma. The starting dose is 0.037 mg/kg every 8 hr by a 15-min intravenous
infusion. Aldesleukin is absorbed erratically after intramuscular or subcutaneous
injection. It follows two-compartment pharmacokinetics. with an u-half-life of 13 min
and a þ-half-life of 85 min. It is eliminated renally. The principal side effects are
hypotension and flulike symptoms. Most adverse effects are dose related.
E. Abciximab (c7E3 Fab, ReoPro) is a chimeric monoclonal antibody Fab fragment
that is specific for platelet glycoprotein IIb-IIIa receptors. Abciximab is extremely
effective in reducing fatalities (> 50%) in subjects who have unstable angina after
they undergo angioplasty. The recommended dosage is an intravenous bolus of 0.25
mg/kg administered 10-60 min before the start of angioplasty, followed by a
continuous infusion of 10 µg/min for 12 hr. Platelet aggregation is almost completely
inhibited 2 hr after the initiation of abciximab therapy. The major complication of
abciximab infusion is dose-related bleeding.
F. Campath-1 is a MAb that targets human lymphocytes and monocytes. It is used for
immunosuppression in patients who undergo organ transplant. The intravenous dose
is 25 mg once or twice daily. Campath-1 is also used to treat refractory autoimmune
disorders, including rheumatoid arthritis. It is used experimentally to treat vasculitis.
Campath-1 antibodies are used to prevent graft-versus-host disease and to treat
lymphoid malignancy caused by immunosuppression in patients who undergo organ
transplant.
G. Edobacomab is an immunoglobulin directed against gram-negative bacterial
endotoxins. For septic shock, single doses of 2-15 mg/kg intravenously every 24 hr
are used. The volume of distribution ranges from 4 to 8 L. The elimination half-life is
10-18 hr. The main side effects are hypersensitivity reactions and antibody
production. The drug is also being investigated for the treatment of gram-negative
sepsis and septic shock.
H. Muromonab-CD3 is an immunosuppressive agent with specific targeting. It is
effective in reversing acute renal allograft rejection. The usual dose is 5 mg/day
intravenously for 10-14 days after the initial signs and symptoms of rejection. The
volume of distribution is approximately 6.5 L, and the half-life is 18 hr. Side effects
include flulike symptoms, which appear to be associated with the release of cytokines.
Symptoms may be self-limiting or severe and life threatening.
I. Nebacumab is an immunoglobulin directed against gram-negative bacterial
endotoxins. The drug is being investigated for the treatment of gram-negative sepsis
and septic shock. Signs and symptoms of septic shock usually resolve during the first
7 days after treatment. Its half-life is 15.9 hr, and the volume of distribution is 48.5
mL/kg.
J. Satumomab pendetide is an MAb conjugate produced from the murine MAb B72.3.
It requires radiolabeling to form
111
indium chloride satumomab pendetide. It is used
as a diagnostic imaging agent in the staging of patients with known colorectal and
ovarian carcinoma. The metabolic fate of this agent is unclear. The antibody
conjugate is cleared slowly. It has a terminal half-life of approximately 56 hr.
Approximately 10% of an administered dose appears in the urine.
K. Zolimomab aritox (Orthozyme-CD5, Xoma/Ortho Biotech) is an immunoconjugate
of monoclonal anti-CD5 murine IgG and the ricin A-chain toxin. Its primary use is in
the treatment
P.246

of steroid-resistant graft-versus-host disease after allogeneic bone marrow transplant
for hematopoietic neoplasms (e.g., acute myelogenous leukemia). Other potential uses
include the treatment of rheumatoid arthritis and insulin-dependent diabetes mellitus.
After therapeutic doses, peak serum levels range from 1 to 5 µg/mL. The serum half-
life is 1.5-4 hr. The dose varies, depending on the indications.
L. Betaseron (INF-þ. Berlex Laboratories) is a glycoprotein with antiviral.
antiproliferative, and immunomodulatory activity. Many of its effects are similar to
those of INF-u. Its uses include the treatment oI multiple sclerosis. AIDS. malignant
melanoma, herpesvirus, and papillomavirus infections. It is also recommended at a
dose of 8 million units subcutaneously every other day to reduce exacerbations in
patients who have relapsing-remitting multiple sclerosis. It is administered
intravenously, intramuscularly, subcutaneously, intrathecally, topically, or
intralesionally for a variety of indications. Its biologic activity is evident in the
absence of detectable serum levels. Serum concentrations are not consistently
detectable aIter subcutaneous or intramuscular administration. InterIeron þ may cross
the disrupted blood-brain barrier. The compound does not appear in urine after
systemic administration. Adverse effects include flulike symptoms, bone marrow
suppression, neurotoxic effects with high doses, anorexia and other gastrointestinal
symptoms, and elevations of liver enzymes and serum creatinine.
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STUDY QUESTIONS
Directions: Each of the questions, statements, or items or incomplete statements in
this section can be correctly answered or completed by one of the suggested answers
or phrases. Choose the best answer.
1. Which type of cell contains double-stranded DNA?
(A) Human cells
(B) Bacteria cells
(C) HIV cells
(D) Viruses
View Answer
1. The answer is A [see VII.A].
Human cells contain double-stranded DNA, whereas lower organisms (e.g., bacteria,
viruses) do not.
2. Which enzyme is used by the human immunodeficiency virus (HIV) to form DNA
in the host cell?
(A) Restrictive endonuclease
(B) DNA-directed polymerase
(C) Reverse transcriptase
(D) Both A and B
(E) None of the above
View Answer
2. The answer is C [see II.V].
Reverse transcriptase is the enzyme that a virus uses to assemble its DNA from RNA.
Unlike higher organisms, viral particles have genetic material in the RNA and need a
host cell for reproduction.
3. Gammaglobulin is considered to be
(A) DNA.
(B) RNA.
(C) a protein.
(D) None of the above
View Answer
3. The answer is C [see III.C; Table 11-2].
Gammaglobulin is a subclass of immunoglobulin protein involved in immunity and
allergic response.
4. Glycoprotein is considered to be a protein linked to
(A) a carbohydrate.
(B) a hormone.
(C) a lipid.
(D) DNA.
(E) None of the above
View Answer
4. The answer is A [see III.B; VI].
Glycoprotein consists of a carbohydrate linked to a protein.
5. An enzyme that cleaves DNA at a specific site is called a
(A) restriction endonuclease.
(B) restrictive ribonuclease.
(C) trypsin.
(D) None of the above
View Answer
5. The answer is A [see II.T].
A restriction endonuclease is an enzyme that specifically cleaves DNA molecules.
Ribonuclease will cleave RNA only, and trypsin is a digestive enzyme found in the
gastrointestinal tract.
6. An example of a cytokine is
(A) interleukin.
(B) insulin.
(C) gonadotropin.
(D) thyroxine.
(E) None of the above
View Answer
6. The answer is A [see II.O;, X.C].
Interleukin is a “messenger” substance synthesized by the cell (cytokine) to
communicate and trigger cellular response.
7. A common storage condition for most biotechnology products after reconstitution
is
(A) at room temperature.
(B) in a cool place.
(C) in a warm place.
(D) no excessive heat.
(E) in a freezer.
View Answer
7. The answer is B [see I].
Most biologic compounds are heat labile and must be stored at low temperature.
8. What drug is used to prevent embolism in the lung and during myocardial
infarction?
(A) Alteplase
(B) Human growth hormone
(C) Granulocyte-macrophage colony-stimulating factor (GM-CSF)
(D) Epogen (EPO)
(E) None of the above
View Answer
8. The answer is A [see X.A; Table 11-1].
Alteplase is a thrombolytic agent formerly known as tissue-plasminogen activator.
9. What base is found in DNA?
(A) Cytosine
(B) Adenine
(C) Guanine
(D) Thymine
(E) All of the above
View Answer
9. The answer is E [see VII.B].
All DNA molecules consist of nucleotides, which consist of deoxyribose, phosphate,
and one of the following nitrogen-containing bases: adenine, guanine, thymine, and
cytosine.
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ANSWERS AND EXPLANATIONS
1. The answer is A [see VII.A].
Human cells contain double-stranded DNA, whereas lower organisms (e.g., bacteria,
viruses) do not.
2. The answer is C [see II.V].
Reverse transcriptase is the enzyme that a virus uses to assemble its DNA from RNA.
Unlike higher organisms, viral particles have genetic material in the RNA and need a
host cell for reproduction.
3. The answer is C [see III.C; Table 11-2].
Gammaglobulin is a subclass of immunoglobulin protein involved in immunity and
allergic response.
4. The answer is A [see III.B; VI].
Glycoprotein consists of a carbohydrate linked to a protein.
5. The answer is A [see II.T].
A restriction endonuclease is an enzyme that specifically cleaves DNA molecules.
Ribonuclease will cleave RNA only, and trypsin is a digestive enzyme found in the
gastrointestinal tract.
6. The answer is A [see II.O;, X.C].
Interleukin is a “messenger” substance synthesized by the cell (cytokine) to
communicate and trigger cellular response.
7. The answer is B [see I].
Most biologic compounds are heat labile and must be stored at low temperature.
8. The answer is A [see X.A; Table 11-1].
Alteplase is a thrombolytic agent formerly known as tissue-plasminogen activator.
9. The answer is E [see VII.B].
All DNA molecules consist of nucleotides, which consist of deoxyribose, phosphate,
and one of the following nitrogen-containing bases: adenine, guanine, thymine, and
cytosine.

12
PrincipIes of Pharmacodynamics and MedicinaI
Chemistry
Marc W. HarroI d
NeI son S. Yee
I. INTRODUCTION.
Phar macodynami cs i s a br anch of pharmacol ogy t hat f ocuses on t he st udy of t he
bi ochemi cal and physi ol ogi cal ef f ect s of dr ugs and t he mechani sms by whi ch t hey
pr oduce such ef f ect s. Anal ysi s of dr ug act i on pr ovi des t he basi s f or rat i onal desi gn
of t her apeut i c agent s and pr ovi des i nsi ght i nt o t he r egul at i on of cel l ul ar f unct i ons.
II. EFFECTS OF DRUGS
A. Pert urbat i on of normaI physi oI ogi caI processes. The act i ons of drugs ar e t he
consequences of t he dynami c i nt er act i ons bet ween dr ug mol ecul es and cel l ul ar
component s. Such i nt er act i ons l ead t o al t er at i on i n t he f unct i ons of t hese
component s, cal l ed recept ors. The r esul t i ng bi ochemi cal and physi ol ogi c changes
f or m t he basi s of t he cel l ul ar r esponse t o t he drug. Dr ugs act by modul at i ng t he
ongoi ng processes i nsi de t he cel l s.
B. Agoni st s and antagoni st s
1. Pot ent i al l y, any macromol ecul ar component may act as a drug receptor. For
exampl e, c- Ki t t yrosi ne ki nase can be i nhi bi t ed by i mat i ni b mesyl at e ( Gl eevec) ,
cycl ooxygenase- 2 i s bl ocked by cel ecoxi b ( Cel ebr ex) , and chromosomal DNA i s
cr oss-l i nked by ci spl at i n ( Pl at i nol ) .
2. Cer t ai n drug recept ors nor mal l y ser ve as r ecept ors f or endogenous l i gands and
t hus are physi oI ogi caI receptors. For exampl e, adr ener gi c r ecept ors are
physi ol ogi cal r ecept ors f or cat echol ami nes; est r ogen recept or s f or est r adi ol .
3. Dr ugs whose responses resembl e t he ef f ect s of t he endogenous mol ecul es ar e
r ecept or agoni st s. For exampl e, bet hanechol di rect l y st i mul at es chol i nergi c
r ecept or s and i s t hus an agoni st .
4. PharmacoI ogi caI antagoni st s ar e dr ugs t hat l ack i nt ri nsi c acti vi t y and produce
ef f ect s by compet i t i veI y or noncompet i t i veI y i nhi bi t i ng t he act i on of t he
endogenous mol ecul es at t he r ecept or .
a. A compet i ti ve antagoni st act s by i nt er f er i ng wi t h bi ndi ng of t he endogenous
l i gand t o t he r ecept or i n a r eversi bl e manner . For exampl e, propanol ol compet es
wi t h cat echol ami nes f or bi ndi ng wi t h adr energi c 8- r ecept or s; t amoxi f en compet es
wi t h est rogen recept or s f or bi ndi ng wi t h est radi ol .
b. A noncompet i t i ve ant agoni st act s by i nt er act i ng wi t h t he nonl i gand bi ndi ng si t e
of t he recept or ( e. g. , t hrough coval ent modi f i cat i on) , such t hat nor mal bi ndi ng of t he
endogenous l i gand t o t he r ecept or i s i r rever si bl y i nhi bi t ed. For i nst ance, monoami ne
oxi dase ( MAO) i nhi bi t ors such as t r anyl cypromi ne ( Par nat e) i ni t i al l y i nt er act wi t h
MAO i n a rever si bl e manner but t hen f or m coval ent adduct s t hat i r r ever si bl y i nhi bi t
MAO.
5. Parti aI ant agoni st s i nhi bi t t he endogenous l i gand f r om bi ndi ng t he r ecept or but
possess some i nt r i nsi c act i vi t y. Nal or phi ne i s a par t i al ant agoni st f or t he opi at e
r ecept or .
6. Physi oI ogi caI antagoni sm occur s when t he drugs act i ndependent l y at di f f er ent
r ecept or si t es, of t en yi el di ng opposi ng act i ons. For exampl e, epi nephr i ne and
acet yl chol i ne act on t he sympat het i c and parasympat het i c aut onomi c nervous
syst em, r espect i vel y, and t hei r ef f ect s ar e ant agoni st i c t o each ot her.
P. 250


7. Neut raI i zi ng ant agoni sm occurs when t wo dr ugs bi nd wi t h each ot her t o f orm an
i nact i ve compound. For exampl e, di goxi n- bi ndi ng ant i body used i n di goxi n over dose
act s by sequest er i ng t he dr ug, r esul t i ng i n t he f ormat i on of an i nact i ve compl ex.
III. MECHANISMS OF DRUG ACTION
A. CeI I surf ace recept ors
1. Recept ors can be prot ei ns or gI ycoprot ei ns. For exampl e, cel l ul ar det er mi nant s
such as CD20 ant i gen on B l ymphocyt es can bi nd wi t h r i t uxi mab ( Ri t uxan) , a
chi meri c monocl onal ant i body t ar get ed agai nst t he CD20 ant i gen.
2. The bi ndi ng of drugs t o r ecept ors i s hi ghl y speci f i c and can i nvol ve a var i et y of
i nt er act i ons, i ncl udi ng hydr ophobi c i nt er act i ons and van der Waal s f orces wi t h i oni c,
hydr ogen, and coval ent bonds. The t ype of i nt eract i on and t he bi ndi ng af f i ni t y can
i nf l uence t he dur at i on and r eversi bi l i t y of t he drug act i on.
3. The i nt er act i on and bi ndi ng af f i ni t y ar e rel at ed t o t he chemi cal st ruct ure of bot h
t he dr ug and t he l i gand. Chemi cal modi f i cat i on of t he st ruct ur e of t he drug mol ecul e
can change t he phar macol ogi cal and pharmacoki net i c pr oper t i es of dr ugs.
4. Thr ough st ruct ur e-act i vi t y r el at i onshi p st udi es, synt het i c dr ug anal ogs can be
devel oped t o achi eve a hi gh sel ect i vi t y of drug act i on÷a desi r abl e rat i o of
t her apeut i c t o t oxi c ef f ect wi t h a bet t er - t ol er at ed si de ef f ect pr of i l e.
B. Si gnaI t ransduct i on by ceI I - surf ace recept ors
1. Cel l -sur f ace r ecept ors ar e composed of ext r acel l ul ar domai ns t hat bi nd t he
l i gands (dr ugs or physi ol ogi cal mol ecul es) . For exampl e, epi dermal growt h f act or
( EGF) r ecept or normal l y bi nds EGF and t ransf ormi ng gr owt h f act or q, and i t i s t he
t ar get of t he monocl onal ant i body cet uxi mab ( Er bi t ux) , whi ch compet i t i vel y bi nds t o
t he EGF r ecept or .
2. The l i gand bi ndi ng serves as a t r i gger i ng si gnal t hat can be propagat ed i n t he
t ar get cel l t hr ough i nt r acel l ul ar r egul at or y mol ecul es, known as second
messengers or eff ectors. For exampl e, i soprot er enol bi nds wi t h t he 8- adr energi c
r ecept or , whi ch i s f unct i onal l y coupl ed t o adenyl at e cycl ase vi a t he st i mul at or y G
pr ot ei n ( Gs ) . As a r esul t , adenyl at e cycl ase i s act i vat ed, and t he cycl i c adenosi ne
monophosphat e (cAMP) l evel i ncreases.
3. Li gand bi ndi ng of recept ors of t en l eads t o i nt eract i on of t he r ecept ors wi t h t he
cyt opl asmi c ef f ect or s, whi ch i n t ur n become act i vat ed. Ì nt egr at i on of t he mul t i pl e
si gnal t r ansduci ng event s al ong t he recept or - ef f ect or syst em mi ght change t he
cel l ul ar phenot ype or gene expr essi on, l eadi ng t o new pr ot ei n synt hesi s. For
exampl e, bi ndi ng of t he l i gands t o t he EGF recept or l eads t o act i vat i on of t he
t yr osi ne ki nase of t he i nt r acel l ul ar domai n of t he r ecept or , whi ch t hen act i vat es
downst r eam si gnal i ng pat hways t hat r esul t s i n cel l ul ar prol i f erat i on. The monocl onal
ant i body er l ot i ni b ( Tar ceva) bi nds t o t he adenosi ne t ri phosphat e ( ATP) pocket of t he
t yr osi ne ki nase of t he EGF r ecept or and i nhi bi t s nor mal ATP bi ndi ng, t hus i nhi bi t i ng
t he act i vi t y of t he t yr osi ne ki nase.
C. Si gnaI i ng medi at ed by i nt raceI I uI ar receptors. Thyr oi d hormone, st er oi d
hor mones, vi t ami n D, and t he r et i noi ds act t hrough bi ndi ng cyt opl asmi c recept ors,
whi ch t ransl ocat e i nt o t he nucl eus. These recept or s ar e sol ubl e, DNA- bi ndi ng
pr ot ei ns t hat r egul at e t he t r anscr i pt i on of speci f i c genes. For exampl e, al l - t r ans-
r et i noi c aci d ( ATRA; Vesanoi d) bi nds t o r et i noi c aci d r ecept or i n t he cyt osol ,
r esul t i ng i n up- regul at i on of t arget gene expr essi on and di f f er ent i at i on of l eukemi c
pr omyel ocyt es.
D. Target ceI I desensi t i zat i on and hypersensi t i zat i on
1. Cel l s have t he abi l i t y t o respond t o endogenous regul at or y mol ecul es or
exogenousl y added dr ugs over a wi de r ange of concent rat i ons. However , pr ot ect i ve
mechani sms ar e avai l abl e f or mai nt ai ni ng homeost at i c cont rol t o pr event
over st i mul at i on or underst i mul at i on of t he t arget cel l s.
2. Cel l reguI at i on can occur at di f f erent l evel s al ong t he si gnal t r ansduct i on
pat hway. Regul at i on can i nvol ve changes i n t he l evel of t he recept or s or al t er at i ons
i n t he downst ream ef f ect or mol ecul es.
P. 251


3. The expr essi on of recept ors i s normal l y under homeost at i c cont rol t hrough
r ecept or i nt ernal i zat i on, r ecycl i ng, and de novo synt hesi s.
4. Down- reguI at i on and desensi t i zat i on
a. Down- reguI at i on of recept ors i s caused by cont i nuous pr ol onged exposur e of
r ecept or s t o dr ugs t hat di sr upt t he homeost at i c equi l i bri um and r esul t i n al t ered
l evel s of t he recept or s. Thi s di srupt i on i nvol ves endocyt osi s of l i gand-bound
r ecept or s, r esul t i ng i n sequest r at i on of r ecept ors f r om t he cel l sur f ace and possi bl y
accel er at ed degr adat i on of t he recept or s or i nact i vat i on of t he r ecept ors.
b. Desensi t i zat i on i s t he r esul t of down- r egul at i on. The t arget cel l s become
desensi t i zed, and t he ef f ect of subsequent exposur e t o t he same concent rat i on of
t he dr ug i s r educed. Ther ef ore, an i ncr eased concent r at i on of t he drug i s r equi r ed t o
pr oduce an ef f ect of t he same magni t ude as t he i ni t i al exposure wi t h a smal l er drug
concent r at i on.
c. Repeat ed doses of bronchodi l at or such as al but er ol i nhal er f or t he t reat ment of
ast hma can l ead t o down- r egul at i on of 8- adrenergi c r ecept ors i n t he br onchi al cel l s.
The pat i ent devel ops t ol er ance and r equi res i ncreased dosage of t he dr ug t o
achi eve rel i ef of t he i ni t i al ext ent . Ì n t hi s case, t he t arget cel l s become desensi t i zed
onl y t o l i gands t hat bi nd t o t hose recept or s; t hi s i s cal l ed homoI ogous
desensi ti zat i on.
5. HeteroI ogous desensi t i zat i on. Some f orms of desensi t i zat i on i nvol ve al t er at i on
of component s i n t he si gnal i ng pat hway, such as a G pr ot ei n. When cul t ured
f i brobl ast s ar e exposed t o pr ost agl andi n E1 ( PGE1) , whi ch nor mal l y act i vat es
adenyl at e cycl ase t hrough a Gs , t he cel l s l ose responsi veness not onl y t o PGE1 but
al so t o ot her l i gands bi ndi ng t o ot her recept or s t hat act t hrough t he Gs -adenyl at e
cycl ase pat hway.
6. Hyperreact i vi t y or supersensi t i vi t y t o r ecept or agoni st s i s expect ed when t ar get
cel l s ar e subj ect t o l ong-t er m exposure t o r ecept or ant agoni st s f ol l owed by abr upt
cessat i on of admi ni st rat i on of t he dr ug. Thi s can i nvol ve recept or up- reguI at i on
t hr ough synt hesi s of new r ecept or s.
E. PharmacoI ogi caI ef fect s not medi at ed by recept ors. The ef f ect s of some dr ugs
do not i nvol ve bi ndi ng wi t h speci f i c r ecept ors because of i nt eract i on wi t h mol ecul es
or i ons, whi ch are not t ypi cal l y def i ned as recept or s.
1. CoI I i gat i ve drug ef f ect s ar e char act eri zed by a l ack of requi r ement f or hi ghl y
speci f i c chemi cal st r uct ur e.
a. Vol at i l e general anesthet i c agent s wi t h di verse st r uct ures ar e l i pophi l i c and
i nt er act wi t h t he l i pi d bi l ayer of cel l membr anes, r esul t i ng i n depr essed exci t abi l i t y.
Exampl es i ncl ude ni t r ous oxi de and desf l ur ane.
b. Cat hart i cs, such as magnesi um sul f at e and sor bi t ol , act by i ncr easi ng t he
osmol ar i t y of i nt est i nal f l ui ds and t hus changi ng t he di st r i but i on of wat er.
2. Met hot rexat e, cyt arabi ne, and 5- f l uor ouraci l are exampl es of ant i metaboI i t es.
Ant i met abol i t es are st r uct ur al anal ogs of endogenous mol ecul es and ar e
i ncor por at ed i nt o cel l ul ar component s t hat i nt er f er e wi t h t he normal cel l ul ar
f unct i ons.
3. Cer t ai n drugs i nt eract wi t h speci f i c i ons normal l y f ound i n body f l ui ds. For
exampl e, antaci ds such as al umi num hydroxi de, cal ci um car bonat e, and magnesi um
hydr oxi de act by neut r al i zi ng gast r i c aci d.
IV. RELATIONSHIP BETWEEN DRUG CONCENTRATION
AND EFFECT
A. Dose- response reI at i onshi p. Ì n gener al , t he l ar ger t he drug dose, t he hi gher t he
dr ug concent rat i on at i t s si t e of act i on and t he great er t he ef f ect of t he drug, up t o a
maxi mum ef f ect . Hi gher dr ug concent rat i ons (or doses) wi l l not pr oduce an ef f ect
gr eat er t han t he maxi mum ef f ect .
B. A quant aI dose- response curve descr i bes t he r el at i onshi p bet ween t he number
of pat i ent s exhi bi t i ng a def i ned response ( e. g. , a 50% i ncr ease i n peak f l ow) and t he
speci f i ed dose of t he drug ( e. g. , mi ni mum dose of al but erol f or 50% i ncrease i n
peak f l ow) . Thi s rel at i onshi p of t en f ol l ows a gaussi an ( bel l - shaped) di st ri but i on
( Fi gur es 12- 1 and 12-2) .
C. A graded dose- response curve descr i bes t he r el at i onshi p bet ween t he
magni t ude of t he ef f ect of a dr ug ( e. g. , r educt i on of bl ood pr essur e by ni f edi pi ne) i n
an i ndi vi dual and t he dose of t he dr ug ( Fi gure 12- 3) .
P. 252



Figure 12-1. Frequency distribution curve.
plotting the number oI patients showing a quantal
response to a drug against the minimum dose
needed to produce the response.

Figure 12-2. Quantal dose-response curve.
cumulating the data used to plot Figure 12-1.

Figure 12-3. Graded dose-response curves Ior
two drugs. A and B. D
A
and D
B
. amount (dose) oI
drug A and drug B. respectively. needed to
produce the drug eIIect. E
1
, E
max
. maximum
eIIect.
P. 253



Figure 12-4. Log dose-response curves Ior two
drugs. A and B. ED
50
. smallest dose showing an
eIIect that is 50° oI the maximum eIIect (E
max
).
1. Gener al l y, as t he dose of a dr ug i ncr eases, t he ef f ect produced wi l l r each a
maxi mum l evel .
2. Gr aded dose- response cur ves f or di f f erent dr ugs al l ow compari son of t hei r
ef f i caci es and pot enci es.
a. Ef f i cacy of a dr ug i s measured by i t s maxi mum ef f ect ( Emax) .
b. Potency of a dr ug i s a r el at i ve measur e t hat compar es t he di f f er ent doses ( mol ar
doses) of di f f erent dr ugs needed t o pr oduce t he same ef f ect . From a cl i ni cal
vi ewpoi nt , pot ency i s consi dered i n dr ug sel ect i on ( e. g. , t r i azol am i s pr ef er r ed f or
t he t r eat ment of i nsomni a i nst ead of di azepam) .
c. Ì n cl i ni cal si t uat i ons, a dr ug wi t h gr eat er ef f i cacy mi ght be needed t o achi eve t he
t her apeut i c out come (e. g. , hydromor phone i s pref er r ed t o acet ami nophen f or
cont r ol l i ng bone pai n i n a pat i ent wi t h met ast at i c br east cancer ) .
D. A I og dose- response curve descr i bes t he r el at i onshi p bet ween t he drug ef f ect
and t he l og of t he dose. Thi s cur ve f aci l i t at es compari son of pot ency and ef f i cacy
among di f f er ent dr ugs wi t h t he same mechani sm of act i on ( whi ch t hus have t he
same sl opes) (Fi gur e 12- 4) .
1. The ef f i cacy of a dr ug i s det ermi ned by t he hei ght of i t s l og dose- response cur ve
( Emax) ; t he hi gher t he cur ve, t he great er t he Emax and ef f i cacy.
2. The pot ency of t wo dr ugs can be compared by det er mi ni ng t hei r ED50. The ED50
i s t he dose of each drug pr oduci ng 50% of t he cor r espondi ng maxi mum ef f ect ( 50%
of Emax) . The smal l er t he ED50, t he gr eat er t he pot ency.
3. A compet i ti ve antagoni st shi f t s t he l og dose- response cur ve t o t he ri ght , and
t he shi f t i s paraI I eI . A great er concent r at i on of t he agoni st i s r equi r ed t o pr oduce
t he same response t han when t he compet i t i ve ant agoni st i s absent . Even i n t he
pr esence of t he ant agoni st , t he same Emax can be achi eved i f enough agoni st i s
added ( Fi gur e 12-5) .

Figure 12-5. ShiIt in the log dose-response curve
that occurs when an agonist is administered in the
presence oI a competitive antagonist. E
max
.
maximum eIIect.
P. 254



Figure 12-6. ShiIt in the log dose-response curve
and lowering oI the maximum eIIect (E
max
) that
occur when an agonist is given in the presence oI
a noncompetitive antagonist.
4. A noncompet i t i ve ant agoni st bi nds t o t he same recept or or bi nds t o anot her si t e
t hat pr event s t he agoni st f r om produci ng a r esponse. The shi f t of t he l og dose-
r esponse cur ve i s t o t he ri ght and nonparaI I eI , resul t i ng i n a I ower Emax. The
act i on of t he ant agoni st cannot be overcome even i f mor e agoni st i s pr esent (Fi gur e
12- 6).
V. ENHANCEMENT OF DRUG EFFECTS
A. Addi t i on occurs when t wo di f f erent dr ugs wi t h t he same ef f ect ar e gi ven
t oget her, r esul t i ng i n a dr ug ef f ect t hat i s equal i n magni t ude t o t he sum of t he
i ndi vi dual ef f ect s of t he t wo dr ugs. For exampl e, t r i met hopr i m and sul f amet hoxazol e
i nhi bi t di f f er ent st eps i n t he synt hesi s of f ol i c aci d, r esul t i ng i n t he suppressi on of
bact er i al gr owt h.
B. Synergi sm occur s when t wo drugs wi t h t he same ef f ect ar e gi ven t oget her ,
pr oduci ng a dr ug ef f ect t hat i s gr eat er i n magni t ude t han t he sum of t he i ndi vi dual
ef f ect s of t he t wo drugs. For exampl e, peni ci l l i n and gent ami ci n ar e synergi st i c i n
t hei r ant i pseudomonal act i vi t i es.
C. Pot ent i ati on occurs when one dr ug, l acki ng an ef f ect of i t s own, i ncreases t he
ef f ect of anot her dr ug t hat i s act i ve. For exampl e, car bi dopa i s an i nact i ve anal og of
dopa. When car bi dopa bl ocks t he degr adat i on of dopa and i s gi ven wi t h dopa, i t
pr ol ongs t he hal f - l i f e of dopa and t he durat i on of t he ant i - Par ki nsoni an ef f ect .
VI. SELECTIVITY OF DRUG ACTION
A. The t herapeut i c i ndex and t he margi n of safet y ar e t he r el at i onshi p (r at i o)
bet ween t he dose of a drug r equi r ed t o pr oduce undesi red ef f ect s ( t oxi c or l et hal )
and t he dose r equi red t o pr oduce t he desi r ed ef f ect s ( t herapeut i c) .
1. The t herapeut i c i ndex of a dr ug i s a rel at i ve measure of t he saf et y and
ef f ect i veness i n l aborat or y st udi es.
2. The t herapeut i c i ndex i s t he rat i o of t he mi ni mum dose t hat i s t oxi c f or 50% of
t he popul at i on (medi an toxi c dose; TD50) t o t he mi ni mum dose t hat i s ef f ect i ve f or
50% of t he popul at i on (medi an ef f ect i ve dose; ED50) .
B. Ì n gener al , t he gr eat er t he TD50 or t he smal l er t he ED50, t he great er t he
t her apeut i c i ndex and t hus t he saf er t he dr ug when used at t he ef f ect i ve dosage.
C. The margi n of saf et y i s a more pract i cal t erm t o descri be t he r el at i ve saf et y and
ef f ect i veness of a dr ug. The margi n of saf et y i s t he r at i o of t he mi ni mum t oxi c dose
f or 0. 1% of t he popul at i on ( mi ni maI t oxi c dose; TD0. 1) t o t he mi ni mum ef f ect i ve
dose f or 99. 9% of t he popul at i on (mi ni maI ef fecti ve dose; ED99. 9) .
P. 255


VII. DRUG SOURCES AND MAJOR CLASSES
A. Nat uraI products are dr ugs obt ai ned f r om pl ant and ani mal sources.
1. AI kaI oi ds ar e ni t r ogen- cont ai ni ng compounds obt ai ned pr i mari l y f r om pl ant s
t hr ough ext r act i on and pur i f i cat i on, whi ch possess pharmacol ogi cal act i vi t y. The
maj or i t y of al kal oi ds ar e basi c compounds ( e. g. , morphi ne, f r om t he opi um poppy;
at ropi ne, f r om t he bel l adonna pl ant ) ; al t hough some ar e neut r al ami des ( e. g. ,
coI chi ci ne, f r om t he aut umn crocus). Al l al kal oi ds end i n t he suf f i x - i ne; however , i t
i s i mpor t ant t o not e t hat not al l drugs t hat end i n - i ne ar e al kal oi ds ( e. g. ,
meper i di ne) .
2. Pept i des and poI ypept i des are pol ymer s of ami no aci ds, are obt ai ned f r om
ei t her human or ani mal sour ces and are smal l er t han prot ei ns. The ami no aci d
l engt h di st i nct i ons bet ween t hese t hr ee cl assi f i cat i ons ar e vague and of t en var y
f r om one source t o anot her . Nat ural l y occur ri ng pept i des have l i t t l e t o no or al
act i vi t y and short hal f -l i ves (e. g. , somat ostat i n, a 14-ami no aci d pept i de;
gI ucagon, a 29-ami no aci d pol ypept i de) .
3. St eroi ds are chemi cal deri vat i ves of cycl opent anoper hydrophenant hr ene and can
be obt ai ned f rom ei t her human or ani mal sources ( e. g. , est radi oI , test ost erone,
hydrocort i sone).
4. Hormones are chemi cal subst ances t hat ar e f or med i n one or gan or part of t he
body and car ri ed i n t he bl ood t o anot her or gan or par t . They are pri nci pal l y pr ot ei ns
or st er oi ds and can be obt ai ned ei t her synt het i cal l y, t hr ough recombi nant DNA
t echnol ogy (e. g. , i nsuI i n) , or f r om ani mal sources ( e. g. , t hyroi d hormones and
conj ugated est rogens).
5. GI ycosi des are organi c subst ances consi st i ng of a sugar moi et y bound t o a
nonsugar (agl ycone) moi et y by means of a gl ycosi di c bond ( i . e. , a bond bet ween t he
anomeri c carbon of t he sugar and a hydr oxy gr oup on t he agl ycone). They can be of
ei t her pl ant (e. g. , di gi t oxi n) or mi cr obi al ( e. g. , st rept omyci n, doxorubi ci n) ori gi n.
6. Vi tami ns ar e or gani c subst ances t hat ar e pr esent i n f oods and are essent i al t o
nor mal met abol i sm.
a. Wat er- soI ubI e vi t ami ns are t hi ami ne (B1) , r i bof l avi n ( B2) , ni aci n ( B3), pyr i doxi ne
( B6) , cyanocobal ami n ( B12) , ascorbi c aci d ( C) , f ol i c aci d, pant ot heni c aci d, and
bi ot i n ( H) .
b. Li pi d-soI ubI e vi tami ns are r et i nol ( A) , er gocal ci f er ol ( D) , q- t ocopherol ( E), and
phyt onadi one ( K) .
7. PoI ysacchari des ar e pol ymer s of sugars t hat can be obt ai ned f r om ei t her human
or ani mal sources. These compounds can be used ei t her di r ect l y (e. g. , hepari n) ,
af t er part i al depol ymer i zat i on ( e. g. , t i nzapari n, enoxapari n), or af t er st r uct ural
modi f i cat i on ( e. g. , sucraI f at e).
8. Ant i bi oti cs ar e chemi cal subst ances pr oduced by mi croor gani sms t hat ei t her
suppr ess or ki l l ot her mi cr oor gani sms (e. g. , peni ci I I i n, tet racycI i ne, doxorubi ci n) .
B. Synt het i c products ar e drugs synt hesi zed f rom organi c compounds.
1. Synt het i c pr oduct s can have chemi caI st ructures cI oseI y resembI i ng t hose of
act i ve nat uraI products ( e. g. , hydroxymorphone, whi ch r esembl es mor phi ne;
ampi ci I I i n, whi ch resembl es peni ci l l i n) .
2. Synt het i c pr oduct s can cont ai n si mi l ar spaci ng of f unct i onal gr oups but l ack t he
gener al st r uct ure of a nat ur al l y occur r i ng compound. Pept i domi meti cs are
mol ecul es wi t h no pept i de bonds, a mol ecul ar wei ght < 700, and act i vi t y si mi l ar t o
t he or i gi nal pept i de (e. g. , I osart an i s a pept i domi met i c and an angi ot ensi n Ì Ì
r ecept or ant agoni st ) .
3. Synt het i c pr oduct s al so can be compI eteI y new products, obt ai ned by scr eeni ng
synt hesi zed mat er i al s f or dr ug act i vi t y ( e. g. , barbi t urates, ant i bact eri aI
suI f onami des, t hi azi de di uret i cs, phenot hi azi ne anti psychot i cs, benzodi azepi ne
anxi oI yt i cs) .
C. Maj or chemi caI and pharmacoI ogi c cI asses of drugs ( Tabl e 12- 1; Fi gur es 12-
7, 12- 8, 12-9, 12- 10, and 12-11)
P. 256


P. 257


P. 258


Table 12-1. Major Chemical and Pharmacological Classes of Drugs
Classification
a

Acid/Base
Character
b
Example
c
(Structure)
1. Polyhalogenated ethers
and hydrocarbons
Nonelectrolyte IsoIlurane (1)
General anesthetics
2. Barbiturates Acidic Phenobarbital (2)

Sedative/hypotonics;
anticonvulsants

3. Benzodiazepines Basic Diazepam (3)

Anxiolytic agents;
sedative/hypnotics

4. Hydantoins Acidic Phenytoin (4)
Anticonvulsants
5. Succinimides Acidic or
nonelectrolyte
Methsuximide (5)
Anticonvulsants
6. Phenothiazines Basic Chlorpromazine
(6)

Antipsychotics;
antihistamines;
antiemetics

7. Thioxanthenes Basic Thiothixene (7)
Antipsychotics
8. Butyrophenones Basic Haloperidol (8)
Antipsychotics
9. Tricyclic antidepressants Basic Imipramine (9)
Antidepressant agents
10. Selective serotonin
reuptake inhibitors
Basic Fluoxetine (10)
Anxiolytic agents
11. Benzazepines Basic Olanzapine (11)
Atypical antipsychotics
12. Methylxanthines Basic (weak) Theophylline (12)

CNS stimulants;
bronchodilators

13. Opioids Basic Codeine (13)

Narcotic analgesics;
antitussives

14. 4-Phenylpiperidines Basic Meperidine (14)
Narcotic analgesics
15. Phenylpropylamines Basic Methadone (15)
Narcotic analgesics
16. Direct-acting
cholinergics
Quaternary
ammonium
salt
Bethanechol (16)

GI smooth-muscle
stimulant; cataract
therapy

17. Aminoalkyl esters Basic or
quaternary
ammonium
salt
Dicyclomine (17)
Anticholinergic agents
18. Aminoalkyl ethers Basic Benztropine (18)

Anticholinergic agents;
antihistamines (H
1
-
antagonists)

19. Aminoalcohols Basic or
quaternary
ammonium
salt
Biperiden (19)
Anticholinergic agents
20. Ethylenediamines Basic Tripelennamine
(20)

Antihistamines (H
1
-
antagonists)

21. Alkylamines
(propylamines)
Basic Chlorpheniramine
(21)

Antihistamines (H
1
-
antagonists)

22. Piperazines Basic Cyclizine (22)

Antihistamines (H
1
-
antagonists); antivertigo;
antiemetics

23. Mast cell degranulation
inhibitors
Acidic Cromolyn sodium
(23)
Antiallergenics
24. Phenylethylamines Basic Albuterol (24)

Sympathomimetics (u-
and þ-adrenergic
agonists)

25. Adrenergic u
2
-agonists Basic Guanabenz (25)
Antihypertensive agents
26. Adrenergic u
1
-agonists Basic Terazosin (26)
Antihypertensive agents
27. Aryloxypropanolamines Basic Propranolol (27)
þ-adrenergic blockers
28. Prostaglandins Acidic Misoprostol (28)
Eicosanoids
29. Salicylates Acidic Aspirin (29)
NSAIDs
30. Fenamates Acidic MeIenamic acid
(3)
NSAIDs
31. Pyrazolidinediones Acidic Phenylbutazone
(31)
NSAIDs
32. Arylacetic acids
(includes indoleacetic
acids. pyrrolacetic acids.
and propionic acids)
Acidic Tolmetin (32)
NSAIDs
33. Selective COX-2
inhibitors
Acidic (weak)
or
nonelectrolyte
Celecoxib (33)
NSAIDs
34. Triptans Basic Sumatriptan (34)
5-HT
1B/1D
agonists
35. Serotonin 5-HT
3

antagonists
Basic Ondansetron (35)
Antiemetic agents
36. Coumarins Acidic WarIarin (36)
Oral anticoagulants
37. SulIated polysaccharides Acidic Heparin (37)
Anticoagulants
38. Benzothiadiazides
(thiazides)
Acidic Chlorothiazide
(38)
Diuretics; saluretics
39. High-ceiling (loop)
diuretics
Acidic Furosemide (39)
Diuretics; saluretics
40. Organic nitrates Nonelectrolyte Isosorbide
dinitrate (40)
Antianginal agents
41. Dihydropyridines Basic (weak) NiIedipine (41)

Antihypertensives;
antianginal agents;
antiarrhythmics

42. Angiotensin II receptor
antagonists
Acidic Losartan (42)
Antihypertensive agents
43. ACE inhibitors Amphoteric Enalapril (43)
Antihypertensive agents
44. HMG-CoA reductase
inhibitors
Acidic Pravastatin (44)

Cholesterol-lowering
agents

45. Bile acid sequestrants Basic or
quaternary
ammonium
salt
Cholestyramine
(45)

Cholesterol-lowering
agents

46. Fibrates Acidic GemIibrozil (46)

Cholesterol- and
triglyceride-lowering
agents

47. Steroids Nonelectrolyte Dexamethasone
(47)

Estrogens; progestins;
androgens;
adrenocorticoids

48. Selective estrogen
receptor modulators
Basic RaloxiIene (48)

Estrogen receptor
agonists and antagonists

49. 5u-Reductase inhibitors Nonelectrolyte Finasteride (49)
Antiandrogen
50. Androgen receptor
antagonists
Nonelectrolyte Nilutamide (50)
Antiandrogen
51. SulIonylureas Acidic Tolbutamide (51)
Oral hypoglycemics
52. Meglitinides Acidic Repaglinide (52)
Oral hypoglycemics
53. Thiazolidinediones
(glitazones)
Amphoteric
(acid stronger
than base)
Pioglitazone (53)

Insulin sensitizers;
antidiabetic agents

54. u-Glucosidase inhibitors Basic Miglitol (54)
Antidiabetic agents
55. H
2
-receptor antagonists Basic Cimetidine (55)
Antiulcer agents
56. Proton pump inhibitors Basic Omeprazole (56)
Antiulcer agents
57. Nitrosoureas Nonelectrolyte Carmustine (57)
Antineoplastic agents
58. þ-Chloroethylamines
(nitrogen mustards)
Basic Mechlorethamine
(58)
Antineoplastic agents
59. Folate antimetabolites Amphoteric Methotrexate (59)

Antineoplastic agents;
antibacterial agents;
antiIungals

60. Purine antimetabolites Basic 6-Mercaptopurine
(60)

Antineoplastic agents;
Antiviral agents

61. Pyrimidine
antimetabolites
Basic Cytarabine (61)

Antineoplastic agents;
antiviral agents

62. Anthracyclines Basic Doxorubicin (62)
Antineoplastic agents
63. Topoisomerase
inhibitors
Basic Topotecan (63)
Antineoplastic agents
64. HIV protease inhibitors Basic Saquinavir (64)
Antiretroviral agents
65. SulIanilamides Acidic SulIamethoxazole
(65)
Antibacterial agents
66. Penicillins Acidic Ampicillin (66)
Antibacterial agents
67. Cephalosporins Acidic CeIoxitin (67)
Antibacterial agents
68. Tetracyclines Amphoteric Tetracycline (68)
Antibacterial agents
69. Aminoglycosides Basic Gentamicin (69)
Antibacterial agents
70. Macrolides Basic Erythromycin
(70)
Antibacterial agents
71. 4-Quinolones Amphoteric OIloxacin (71)
Antibacterial agents
72. Allylamines Basic TerbinaIine (72)
AntiIungal agents
73. Polyenes Amphoteric Amphotericin B
(73)
AntiIungal agents
74. Imidazoles Basic Oxiconazole (74)
AntiIungal agents
ACE. angiotensin-converting enzyme; COX. cyclooxygenase; 5-HT. 5-
hydroxytryptamine (serotonin). Gl. gastrointestinal; HMG-CoA. þ-hydroxy-
þ-methylglutaryl coenzyme A; NSAID. nonsteroidal anti-inIlammatory drug.
a
Organized according to chemical structure. Not an inclusive list; includes
only classiIications that contain multiple compounds with a similar structure.
In some instances (e.g.. direct-acting cholinergic agonists and H
2
-receptor
antagonists). drugs are chemically similar but are usually denoted only by
pharmacological classiIications.

b
A general notation; some speciIic singular agents Iall outside these general
notations (e.g.. ampicillin is amphoteric. whereas the penicillins are
generally acidic).

c
Structures are given in Figures 12-7. 12-8. 12-9. 12-10 and 12-11.

P. 259



Figure 12-7. Chemical structures (1-19)
representing the maior chemical classes oI drugs
listed in Table 12-1.
P. 260



Figure 12-8. Chemical structures (20-37)
representing the maior chemical classes oI drugs
listed in Table 12-1.
VIII. DRUG ACTION AND PHYSICOCHEMICAL
PROPERTIES
A. Drug act i on r esul t s f rom t he i nt er act i on of dr ug mol ecul es wi t h ei t her nor mal or
abnor mal physi ol ogi cal pr ocesses. Dr ugs normal l y i nt eract wi t h r ecept ors, whi ch can
be ei t her pr ot ei ns, enzymes, cel l l i pi ds, or pi eces of DNA or RNA.
P. 261



Figure 12-9. Chemical structures (38-53)
representing the maior chemical classes oI drugs
listed in Table 12-1.
1. Syst emi cal l y act i ve drugs must enter and be transported by body f I ui ds.
a. The dr ug must pass vari ous membrane barri ers, escape excessi ve
di st ri but i on i nt o si t es of l oss, and penet rat e to the act i ve si t e.
b. At t he act i ve si t e, t he dr ug mol ecul es must ori ent t hemsel ves and i nt eract wi t h
t he recept or s t o aI ter f unct i on.
P. 262



Figure 12-10. Chemical structures (54-68)
representing the maior chemical classes oI drugs
listed in Table 12-1.
c. The dr ug must be r emoved f rom t he act i ve si t e and metaboI i zed t o a f or m t hat i s
easi l y excreted by t he body.
2. Dr ug absor pt i on, met abol i sm, ut i l i zat i on, and excr et i on al l depend on t he drug' s
physi cochemi caI propert i es and t he host ' s physi oI ogi caI and bi ochemi caI
propert i es. A drug' s physi cochemi cal proper t i es can be al t er ed vi a t he synt hesi s of
chemi cal anal ogs, wher eas t he host ' s pr oper t i es usual l y cannot be al t ered.
P. 263



Figure 12-11. Chemical structures (69-74)
representing the maior chemical classes oI drugs
listed in Table 12-1.
B. Two of t he most i mpor t ant physi cochemi caI propert i es of a drug mol ecul e ar e
i t s pol ari t y and i t s aci d-base nat ur e.
1. Drug poI ari t y i s a rel at i ve measur e of a drug' s l i pi d and wat er sol ubi l i t y and i s
usual l y expr essed i n t erms of a part i t i on coef f i ci ent.
a. The par t i t i on coef f i ci ent ( P) of a drug i s def i ned as t he rat i o of t he sol ubi l i t y of
t he compound i n an organi c sol vent t o t he sol ubi l i t y of t he same compound i n an
aqueous envi r onment :

The par t i t i on coef f i ci ent i s of t en expr essed as a l og val ue.
b. Wat er soI ubi I i t y ( or hydrophi I i ci t y) depends pr i mar i l y on t wo f act ors: i oni c
charact er and hydr ogen-bondi ng capabi l i t i es. The pr esence of oxygen- and ni t r ogen-
cont ai ni ng f unct i onal gr oups usual l y enhances wat er sol ubi l i t y. Wat er sol ubi l i t y i s
r equi r ed f or:
( 1) Di ssol ut i on i n t he gast r oi nt est i nal ( GÌ ) t ract
( 2) Pr eparat i on of par ent er al sol ut i ons ( as opposed t o suspensi ons)
( 3) Pr eparat i on of opht hal mi c sol ut i ons
( 4) Adequat e ur i ne concent r at i ons ( per t ai ns pri mar i l y t o ant i bi ot i cs)
c. Li pi d soI ubi I i t y ( or I i pophi I i ci t y) i s enhanced by noni oni zabl e hydr ocar bon
chai ns and ri ng syst ems. Li pi d sol ubi l i t y i s requi r ed f or :
( 1) Penet rat i on t hr ough t he l i pi d bi l ayer i n t he Gl t r act
( 2) Penet rat i on t hr ough t he bl ood- brai n bar r i er
( 3) Pr eparat i on of i nt ramuscul ar ( Ì M) depot i nj ect abl e f ormul at i ons
( 4) Enhanced pul monar y absor pt i on wi t hi n t he respi rat or y t r act
( 5) Enhanced t opi cal pot ency (seen wi t h many t opi cal gl ucocor t i coi ds)
( 6) Enhanced pl asma prot ei n bi ndi ng
2. Ì oni zat i on of aci ds and bases pl ays a r ol e wi t h subst ances t hat di ssoci at e i nt o
i ons.
a. The i oni zat i on constant ( Ka) i ndi cat es t he r el at i ve st rengt h of t he aci d or base.
An aci d
P. 264

wi t h a Ka of 1 × 10
- 3
i s st r onger (mor e i oni zed) t han one wi t h a Ka of 1 × 10
- 5
,
wher eas a base wi t h a Ka of 1 × 10
- 7
i s weaker (l ess i oni zed) t han one wi t h a Ka of 1
× 10
- 9
.
b. The negati ve I og of t he i oni zat i on constant (pKa) al so i ndi cat es t he rel at i ve
st r engt h of t he aci d or base. An aci d wi t h a pKa of 5 ( Ka = 1 × 10
- 5
) i s weaker ( l ess
i oni zed) t han one wi t h a pKa of 3 ( Ka = 1 × 10
- 3
), wher eas a base wi t h a pKa of 9 ( Ka
= 1 × 10
- 9
) i s st r onger (mor e i oni zed) t han one wi t h a pKa of 7 ( Ka = 1 × 10
- 7
) .
c. St rong aci ds÷f or exampl e, hydrochI ori c aci d ( HCl ) , sul f uri c aci d ( H2SO4) , ni t r i c
aci d ( HNO3) , hydr obr omi c aci d ( HBr ) , i odi c aci d (HÌ O3) , and perchl or i c aci d
( HCl O4) ÷ar e compl et el y i oni zed. Al most al l ot her aci ds, i ncl udi ng organi c aci ds, ar e
weak. Organi c aci ds cont ai n one or more of t hese f unct i onal gr oups:
( 1) Carboxyl i c aci d group ( ÷COOH)
( 2) Phenol i c group ( Ar ÷OH)
( 3) Sul f oni c aci d group (÷SO3H)
( 4) Sul f onami de group (÷SO2NH÷R)
( 5) Ì mi de gr oup ( ÷CO÷NH÷CO÷)
( 6) 8- Carbonyl gr oup ( ÷CO÷CHR÷CO÷)
( 7) Tet r azol e ri ng ( f i ve-member CHN4 r i ng; see Fi gur e 12- 9, 42, f or exampl e)
d. St rong bases÷f or exampl e, sodi um hydr oxi de ( NaOH) , pot assi um hydroxi de
( KOH) , magnesi um hydroxi de ( Mg( OH) 2) , cal ci um hydroxi de ( Ca( OH) 2), bar i um
hydr oxi de ( Ba( OH) 2) , and quat ernar y ammoni um hydr oxi des÷ar e al so compl et el y
i oni zed. Al most al l ot her bases, i ncl udi ng organi c bases, are weak.
( 1) Organi c bases cont ai n a pri mar y, secondar y, or t ert i ar y al i phat i c or al i cycl i c
ami no gr oup ( ÷NH2, ÷NHR, or ÷NR2).
( 2) Most aromat i c or unsat ur at ed het erocycl i c ni t rogens ar e so weakl y basi c t hat
t hey do not r eadi l y f or m sal t s wi t h aci ds. Sat ur at ed het erocycl i c ni t rogens, i n
cont r ast , ar e si mi l ar t o al i phat i c ami nes.
( 3) Addi t i onal basi c f unct i onal gr oups i ncl ude i mi ne ni t r ogens ( ÷N=C÷) , hydr azi ne
ni t rogens ( ÷NH÷NH2) , ami di ne ni t rogens ( ÷NH÷C=N÷) , and guani di ne ni t rogens
( f our at om f unct i onal gr oup, CH4N3; see Fi gur e 12- 8, 25, f or exampl e) .
e. Weak aci ds. Ì oni zat i on of a weak aci d ( e. g. , acet i c aci d, whi ch has a pKa of 4. 76)
t akes pl ace as f ol l ows:

( 1) When a weak aci d ( such as acet i c aci d) i s pl aced i n an aci d medi um, t he
equi l i br i um shi f t s t o t he l ef t , suppressi ng i oni zat i on. Thi s decr ease i n i oni zat i on
conf orms t o Le Chat eI i er' s pri nci pI e, whi ch st at es t hat when a st ress i s pl aced on
an equi l i br i um r eact i on, t he r eact i on wi l l move i n t he di r ect i on t hat t ends t o r el i eve
t he st ress.
( 2) When a weak aci d i s pl aced i n an aI kaI i ne medi um, i oni zat i on i ncreases. The H
+

i ons f rom t he aci d and t he OH
-
i ons f rom t he al kal i ne medi um combi ne t o f or m
wat er , shi f t i ng t he equi l i br i um t o t he ri ght .
( 3) WeakI y aci di c drugs ar e l ess i oni zed i n aci d medi a t han i n al kal i ne medi a.
When t he pKa of an aci di c drug i s gr eat er t han t he pH of t he medi um i n whi ch i t
exi st s, i t wi l l be > 50% i n i t s noni oni zed (mol ecul ar ) f or m and t hus mor e l i kel y t o
cr oss l i pi d cel l ul ar membr anes.
f . Weak bases. Ì oni zat i on of a weak base i s t he opposi t e of t hat f or a weak aci d.
( 1) Weak bases ar e l ess i oni zed i n a basi c ( aI kaI i ne) medi um and mor e i oni zed i n
an aci d medi um.
( 2) WeakI y basi c drugs ar e l ess i oni zed i n al kal i ne medi a t han i n aci d medi a. When
t he pKa of a basi c dr ug i s l ess t han t he pH of t he medi um i n whi ch i t exi st s, i t wi l l be
> 50% i n i t s noni oni zed (mol ecul ar ) f or m and t hus more l i kel y t o cr oss l i pi d cel l ul ar
membr anes.
g. Percent i oni zat i on can be approxi mat ed by usi ng t he ruI e of ni nes. Ì f t he | pH -
pKa| = 1, t hen a 90: 10 rat i o (not e t hat t her e i s one ni ne i n t he r at i o) exi st s. Ì f t he
| pH - pKa| = 2, t he r at i o becomes 99: 1 ( t wo ni nes i n t he r at i o) , and i f t he | pH - pKa|
= 3, t he r at i o i s 99. 9: 0. 1 ( t hr ee ni nes i n t he r at i o). The predomi nant f or m, i oni zed or
uni oni zed, i n t hese rat i os can easi l y be det er mi ned (see VÌ Ì Ì . B. 2. e. (3) ;
VÌ Ì Ì . B. 2. f . ( 2) ) .
3. A saI t i s t he combi nat i on of an aci d and a base.
a. Wi t h a f ew mi nor except i ons ( mer cur i c and cadmi um hal i des and l ead acet at e),
aI I saI ts are st rong eI ect roI yt es.
P. 265


b. Because t he vast maj or i t y of drugs are organi c mol ecul es, dr ug sal t s can be
di vi ded i nt o t wo cl asses based on t he chemi cal nat ur e of t he subst ance f or mi ng t he
sal t .
( 1) I norgani c saI ts are made by combi ni ng dr ug mol ecul es wi t h i nor gani c aci ds and
bases, such as hydr ochl or i c aci d, sul f ur i c aci d, pot assi um hydroxi de, and sodi um
hydr oxi de. The sal t f or m of t he dr ug has i ncr eased wat er sol ubi l i t y i n compar i son
wi t h t he parent mol ecul e. Ì nor gani c sal t s ar e gener al l y used t o i ncr ease t he
aqueous di ssol ut i on of a compound.
( 2) Organi c saI ts are made by combi ni ng dr ug mol ecul es wi t h ei t her smaI I ,
hydrophi I i c organi c compounds ( e. g. , succi ni c aci d, ci t r i c aci d) or I i pophi I i c
or gani c compounds (e. g. , pr ocai ne) . Wat er- sol ubl e or gani c sal t s are used t o
i ncrease di ssol ut i on and bi oavai l abi l i t y as wel l as t o ai d i n t he preparat i on of
par ent eral and opht hal mi c f or mul at i ons ( e. g. , t i mol ol mal eat e) . Li pi d-sol ubl e or gani c
sal t s ar e pr i mari l y used t o make depot i nj ect i ons ( e. g. , procai ne peni ci l l i n) .
c. Amphoteri c compounds cont ai n bot h aci di c and basi c f unct i onal gr oups and ar e
capabl e of f or mi ng i nternaI saI ts, or zwi t t er i ons, whi ch of t en have di ssol ut i on
pr obl ems.
d. Di ssoI ut i on of saI ts can al t er t he pH of an aqueous medi um.
( 1) Sal t s of st rong aci ds ( e. g. , HCl , H2SO4) and basi c drugs ( e. g. , ci met i di ne)
di ssoci at e i n an aqueous medi um t o yi el d an aci di c soI ut i on.
( 2) Sal t s of st rong bases ( e. g. , NaOH, KOH) and aci di c drugs ( e. g. , phenobar bi t al )
di ssoci at e i n an aqueous medi um t o yi el d a basi c soI uti on.
( 3) Sal t s of weak aci ds and weak bases di ssoci at e i n an aqueous medi um t o yi el d
an aci di c, basi c, or neut raI soI ut i on, dependi ng on t he r espect i ve i oni zat i on
const ant s i nvol ved.
( 4) Sal t s of st rong aci ds and st rong bases (e. g. , NaCl ) do not si gni f i cant l y al t er
t he pH of an aqueous medi um.
4. A neut raI i zat i on react i on mi ght occur when an aci di c sol ut i on of an organi c sal t
( a sol ut i on of a sal t of a st r ong aci d and a weak base) i s mi xed wi t h a basi c sol ut i on
( a sol ut i on of a sal t of a weak aci d and a st rong base) . The noni oni zed organi c aci d
or t he noni oni zed or gani c base i s l i kel y t o preci pi t at e i n t hi s case. Thi s react i on i s
t he basi s f or many drug i ncompati bi I i t i es, par t i cul arl y when i nt r avenous sol ut i ons
ar e mi xed. Neut r al i zat i on r eact i ons can be avoi ded by knowi ng how t o predi ct t he
approxi mat e pH of t he aqueous sol ut i ons of common dr ug sal t s.
a. Gener al l y, a drug' s saI t f orm can be recogni zed when t he gener i c or t rade name
consi st s of t wo separat e wor ds, i ndi cat i ng a cati on and an ani on.
b. Dr ugs wi t h ni t rat e, suI f at e, or hydrochI ori de not at i ons ( e. g. , pi l ocar pi ne
ni t rat e, mor phi ne sul f at e, meperi di ne hydr ochl ori de) ar e sal t s of st rong aci ds. Thus
t hese dr ugs (e. g. , pi l ocar pi ne, morphi ne, meperi di ne) must be bases.
c. Dr ugs wi t h sodi um or pot assi um cat i ons (e. g. , war f ar i n sodi um, pot assi um
peni ci l l i n G) ar e sal t s of st rong bases. Thus t hese dr ugs ( e. g. , war f ar i n, peni ci l l i n
G) must be aci ds.
d. Dr ugs whose cat i on name ends wi t h t he suf f i x "- oni um" or "-i ni um" and whose
ani on i s a chl or i de, br omi de, i odi de, ni t r at e, or sul f at e ( e. g. , benzal koni um chl ori de,
cet yl pyr i di ni um chl ori de), ar e known as quat ernary ammoni um sal t s and f or m
neut raI aqueous soI uti ons.
IX. STRUCTURAL FEATURES AND PHARMACOLOGIC
ACTIVITY.
Dr ugs can be cl assi f i ed as st r uct ur al l y nonspeci f i c or st r uct ur al l y speci f i c.
A. St ruct uraI I y nonspeci f i c drugs are t hose f or whi ch t he dr ug' s i nt er act i on wi t h
t he cel l membrane depends mor e on t he dr ug mol ecul e' s physi cal charact er i st i cs
t han on i t s chemi cal st r uct ure. Usual l y, t he i nt er act i on i s based on t he ceI I
membrane' s I i pi d nature and t he drug' s I i pi d att ract i on. Most generaI
anesthet i cs, as wel l as some hypnot i cs and some bacteri ci daI agent s, act
t hr ough t hi s mechani sm.
B. St ruct uraI I y speci f i c drugs ar e t hose f or whi ch pharmacol ogi cal act i vi t y i s
det ermi ned by t he dr ug' s abi l i t y t o bi nd t o a speci f i c endogenous receptor.
1. Receptor- si te t heor y descri bes t he phar macol ogi cal act i vi t y of such dr ugs.
a. The I ock-and-key t heor y post ul at es a compl et el y compl ement ar y rel at i onshi p
bet ween t he dr ug mol ecul e and a speci f i c ar ea on t he sur f ace of t he r ecept or
mol ecul e ( i . e. , t he
P. 266

act i ve, or cat aI yt i c, si t e) . Thi s t heor y does not account f or conf or mat i onal changes
i n ei t her dr ug or recept or mol ecul es and i s an over si mpl i f i cat i on of a compl ex
pr ocess.
b. The i nduced- fi t t heory al so post ul at es a compl ement ar y r el at i onshi p bet ween
t he dr ug mol ecul e and i t s act i ve si t e; however , i t pr ovi des f or mutuaI
conf ormat i onaI changes bet ween t he dr ug and i t s recept or . Conf ormat i onal
changes i n t he r ecept or mol ecul e are t hen t r ansl at ed i nt o bi ol ogi cal r esponses. Thi s
t heor y expl ai ns many mor e phenomena ( e. g. , aI I ost eri c i nhi bi t ors) t han t he l ock-
and-key model .
c. The occupati onaI t heor y of response f ur t her post ul at es t hat , f or a st ruct ur al l y
speci f i c drug, t he i nt ensi t y of t he pharmacol ogi cal ef f ect i s di r ect l y pr oport i onal t o
t he number of r ecept ors occupi ed by t he dr ug.
2. Receptor- si te bi ndi ng. The abi I i t y t o bi nd t o a speci f i c recept or, al t hough not
i ndependent of t he dr ug' s physi cal charact er i st i cs, i s pr i mari l y det ermi ned by t he
dr ug' s chemi caI st ruct ure.
a. Ì n such an i nt eract i on, t he dr ug' s chemi caI react i vi t y pl ays an i mport ant r ol e,
r ef l ect ed i n i t s bondi ng abi I i t y and i n t he exactness of i ts f i t t o t he r ecept or .
b. Drug i nt eract i on wi t h a speci f i c r ecept or i s anal ogous t o t he f i t t i ng t oget her of
j i gsawpuzzl e pi eces. Onl y dr ugs of si mi l ar shape ( i . e. , si mi l ar chemi cal st ruct ur e)
can bi nd t o a speci f i c r ecept or and i ni t i at e a bi ol ogi cal r esponse.
c. Of t en, onl y a cri t i caI port i on of the drug moI ecuI e ( r at her t han t he whol e
mol ecul e) i s i nvol ved i n r ecept or - si t e bi ndi ng.
( 1) The f unct i onal gr oup maki ng up t hi s cri t i cal por t i on i s known as a
pharmacophore.
( 2) Dr ugs wi t h si mi I ar cri t i caI regi ons but di f f er ences i n ot her par t s may have
si mi l ar qual i t at i ve ( al t hough not necessar i l y quant i t at i ve) phar macol ogi cal act i vi t y.
d. Ì n general , t he bett er a drug f i t s t he r ecept or si t e, t he hi gher t he af fi ni t y
bet ween t he dr ug and t he r ecept or and t he greater t he obser ved bi ol ogi cal
r esponse. A drug t hat bi nds t o a recept or and el i ci t s a bi ol ogi cal r esponse i s cal l ed
an agoni st .
e. Some dr ugs, l acki ng t he speci f i c pharmacophor e f or a par t i cul ar r ecept or , can
nonet hel ess bi nd t o t hat r ecept or . Such a dr ug wi l l have l i t t l e or no pharmacol ogi cal
ef f ect and mi ght al so prevent a mol ecul e havi ng t he speci f i c pharmacophor e f r om
bi ndi ng, bl ocki ng t he expect ed bi ol ogi cal r esponse. A drug t hat bl ocks a nat ural
agoni st and pr event s i t f r om bi ndi ng t o i t s r ecept or i s cal l ed an antagoni st .
3. The st ereochemi st r y of bot h t he r ecept or -si t e sur f ace and t he dr ug mol ecul e
hel ps det er mi ne t he nat ur e and ef f i ci ency of t he dr ug- r ecept or i nt eract i on.
St er eoi somers can be di vi ded i nt o t hr ee mai n groups: opti caI i somers, geomet ri c
i somers, and conf ormati onaI i somers.
a. Opt i caI i somers cont ai n at l east one asymmet r i c, or chi r al , carbon at om ( i . e. , a
car bon at om t hat i s coval ent l y bonded t o f our di f f er ent subst i t uent s) . Each
asymmet ri c car bon at om can exi st i n one of t wo nonsuper i mposabl e i somer i c f orms
( Fi gur e 12- 12) .
( 1) Enant i omers are opt i cal i somers t hat are mi rr or i mages of one anot her .
Enant i omers have i dent i cal physi cal and chemi cal pr oper t i es except t hat one r ot at es
t he pl ane of pol ar i zed l i ght i n a cl ockwi se di rect i on ( dext rorotat or y; desi gnat ed D
or +) and t he ot her i n a count ercl ockwi se di rect i on ( I evorot at or y; desi gnat ed L or -
) .
( 2) An equal mi xt ur e of D and L enant i omer s i s cal l ed a racemi c mi xt ure and i s
opt i cal l y i nact i ve.
( 3) Enant i omers can have l ar ge di f f erences i n pot ency, r ecept or f i t , bi ol ogi cal
act i vi t y, t ransport , and met abol i sm. These di f f erences resul t when t he drug
mol ecul e has an asymmet r i c i nt eract i on wi t h a recept or, a t r anspor t pr ot ei n, or a
met abol i zi ng enzyme. For exampl e, I evorphanoI has narcot i c, anal gesi c, and
ant i t ussi ve propert i es, wher eas i t s mi r r or i mage, dext rorphanoI , has onl y
ant i t ussi ve act i vi t y.
( 4) Di ast ereomers are st er eoi somer s, whi ch are nei t her mi r r or i mages nor
super i mposabl e. A dr ug must have at l east t wo chi r al cent ers t o exi st i n
di ast ereomers. Unl i ke enant i omer s, i n whi ch al l st er eochemi cal cent ers are
opposi t e, di ast er eomer s have
P. 267

some st ereochemi cal cent ers t hat ar e i dent i cal and some t hat ar e opposi t e.
Di ast er eomer s possess di f f er ent physi cochemi cal propert i es and t hus di f f er i n
pr oper t i es such as sol ubi l i t y, vol at i l i t y, and mel t i ng poi nt .

Figure 12-12. The two enantiomers oI 2-
hydroxybutane. The chiral. or asymmetric. carbon
is bonded to Iour diIIerent groups: a methyl
group. an ethyl group. a hydroxy group. and a
hydrogen. The structures shown are mirror
images. which cannot be superimposed.

Figure 12-13. Epimerization oI tetracycline to 4-
epi-tetracycline. The stereochemistry oI the 4-
dimethylamino group is inverted; however. the
stereochemistry oI all other chiral centers remains
unchanged.
( 5) Epi mers ar e a speci al t ype of di ast ereomers because al l epi mers are al so
di ast ereomers; however , t he opposi t e i s not t r ue. Epi mers are compounds t hat are
st r uct ur al l y i dent i cal i n al l respect s except f or t he st er eochemi st r y of one chi ral
cent er . The process of epi meri zati on ( i n whi ch t he st ereochemi st r y of one chi r al
cent er i s i nvert ed) i s i mpor t ant i n drug degr adat i on and i nact i vat i on ( Fi gure 12-13).
b. Geomet ri c i somers (ci s- t rans i somers) occur as a resul t of rest r i ct ed r ot at i on
ar ound a chemi cal bond, owi ng t o doubl e bonds or r i gi d r i ng syst ems i n t he
mol ecul e.
( 1) Ci s-t rans i somers ar e not mi r ror i mages and have di f f er ent physi cochemi cal
pr oper t i es and pharmacol ogi c act i vi t y.
( 2) Because t he f unct i onal gr oups of t hese i somer s are separ at ed by di f f er ent
di st ances, t hey gener al l y do not f i t t he same r ecept or equal l y wel l . Ì f t hese
f unct i onal groups ar e phar macophor es, t he i somer s wi l l di f fer i n bi oI ogi caI
act i vi t y. For exampl e, ci s- di et hyl st i l -best r ol has onl y 7% of t he est rogeni c act i vi t y
of t rans- di et hyl st i l best r ol ( Fi gur e 12-14) .
c. Conf ormat i onaI i somers, al so known as rotamers or conf ormers, are
nonsuper i mposabl e ori ent at i ons of a mol ecul e t hat r esul t f r om t he r ot at i on of at oms
ar ound si ngl e bonds. Al most ever y dr ug can exi st i n more t han one conf or mat i on,
and t hi s abi l i t y al l ows many dr ugs t o bi nd t o mul t i pl e r ecept ors and r ecept or
subt ypes. For exampl e, t he t rans conf ormat i on of acet yl chol i ne bi nds t o t he
muscar i ni c r ecept or , wher eas t he gauche conf ormat i on bi nds t o t he ni cot i ni c
r ecept or ( Fi gure 12- 15) .
d. Bi oi sost eres are mol ecul es cont ai ni ng gr oups t hat are spat i al l y and
el ect r oni cal l y equi val ent and t hus ar e i nt er changeabl e wi t hout si gni f i cant l y al t er i ng
t he mol ecul es' physi cochemi cal proper t i es. I sosteri c repI acement of f unct i onal
gr oups can i ncrease pot ency,
P. 268

decrease si de ef f ect s, separat e bi ol ogi cal act i vi t i es, and i ncr ease t he durat i on of
act i on by al t eri ng met abol i sm. Ì n addi t i on, i sosteri c anaI ogs may act
ant agoni st i cal l y t o t he par ent mol ecul e.

Figure 12-14. The presence oI the double bond in
diethylstilbestrol allows Ior the Iormation oI cis
and trans geometric isomers. Only the trans
isomer has estrogenic activity.

Figure 12-15. The trans (A) and gauche (B)
conIormations oI acetylcholine occur as the result
oI rotation around the carbon-carbon single bond.
( 1) Procai nami de, an ami de, has a l onger dur at i on of act i on t han procai ne, an
est er , because of t he i sost eri c r epl acement of t he est er oxygen wi t h a ni t rogen at om
( Fi gur e 12- 16) .
( 2) AI I oxant hi ne i s an i nhi bi t or of xant hi ne oxi dase. Ì t i s al so an i sost er e of
xant hi ne, t he nor mal subst rat e f or t he enzyme (Fi gur e 12- 16) .
X. MECHANISMS OF DRUG ACTION
A. I nt eract i on wi th recept ors (see Ì X. B. 1 and 2)
1. Agoni sts i nt eract wi t h speci f i c cel l ul ar const i t uent s, known as recept ors, and
el i ci t an obser vabl e bi ol ogi cal r esponse. Agoni st s have bot h af f i ni t y f or t he
r ecept or and i nt ri nsi c act i vi t y.

Figure 12-16. Bioisosteric pairs
procainamide/procaine and alloxanthine/xanthine.
The isosteric replacements are boxed.
P. 269


2. Parti aI agoni sts i nt eract wi t h t he same r ecept or s as f ul l agoni st s but ar e unabl e
t o el i ci t t he same maxi mum response. Part i al agoni st s have l ower i nt ri nsi c act i vi t y
t han f ul l agoni st s; however , t hei r af f i ni t y f or t he recept or can be gr eat er t han, l ess
t han, or equal t o t hat of f ul l agoni st s.
3. Ant agoni st s i nhi bi t t he act i ons of agoni st s.
a. PharmacoI ogi caI antagoni st s bi nd t o t he same recept or as t he agoni st , ei t her at
t he same si t e or at an al l ost er i c si t e. They have af f i ni t y f or t he r ecept or but l ack
i nt ri nsi c act i vi t y. Phar macol ogi cal ant agoni st s can be subdi vi ded i nt o r ever si bl e,
i r r eversi bl e, compet i t i ve, and noncompet i t i ve cat egori es si mi l ar t o enzyme i nhi bi t or s
( see X. B. 2) .
b. Chemi caI ant agoni sts r eact wi t h one anot her, r esul t i ng i n t he i nact i vat i on of
bot h compounds.
( 1) The ant i coagul ant hepari n, an aci di c pol ysacchari de, i s chemi cal l y ant agoni zed
by prot ami ne, a basi c prot ei n, vi a an aci d- base i nt er act i on.
( 2) CheI at i ng agents can be used as anti dotes for metaI poi soni ng.
Et hyI enedi ami netet raacet i c aci d ( EDTA) chel at es cal ci um and l ead; peni ci I I ami ne
chel at es copper ; and di mercaproI chel at es mercur y, gol d, ant i mony, and arseni c.
c. Functi onaI ( or physi caI ) ant agoni st s pr oduce ant agoni st i c physi ol ogi cal act i ons
t hr ough bi ndi ng at separat e recept or s. The adr ener gi c and chol i nergi c nervous
syst ems f r equent l y pr oduce t hi s t ype of ant agoni sm. Acet yI choI i ne const r i ct s t he
pupi l by act i ng on r ecept or s t hat cont rol t he ci r cul ar muscl es of t he eye, wher eas
norepi nephri ne di l at es t he pupi l by act i ng on r ecept ors t hat cont rol ocul ar di l at or
muscl es.
B. I nt eract i on wi th enzymes
1. Act i vat i on, or i ncreased enzyme act i vi t y, can r esul t f rom i nduct i on of enzyme
pr ot ei n synt hesi s by such dr ugs as bar bi t urat es, phenyt oi n and ot her ant i epi l ept i cs,
r i f ampi n, ant i hi st ami nes, gr i seof ul vi n, and oral cont r acept i ves.
a. AI I ost eri c bi ndi ng. A dr ug can enhance enzyme act i vi t y by al l ost er i c bi ndi ng,
whi ch t ri gger s a conf ormat i onal change i n t he enzyme syst em and t hus al t er s i t s
af f i ni t y f or subst rat e bi ndi ng.
b. Coenzymes pl ay a r ol e i n opt i mi zi ng enzyme act i vi t y. Coenzymes i ncl ude
vi t ami ns ( par t i cul ar l y t he vi t ami n B compI ex) and cof act ors÷mai nl y met al l i c i ons
such as sodi um ( Na
+
) , pot assi um ( K
+
) , magnesi um ( Mg
++
) , cal ci um ( Ca
++
), zi nc
( Zn
++
) , and i r on ( Fe
++
) . Coenzymes act i vat e enzymes by compl exat i on and
st ereochemi cal i nt eract i on.
2. I nhi bi ti on, or decreased enzyme act i vi t y, can r esul t f rom dr ugs t hat i nt er act
wi t h t he apoenzyme, t he coenzyme, or even t he whol e enzyme compl ex. The dr ug
mi ght modi f y or dest roy t he apoenzyme' s pr ot ei n conf ormat i on, r eact wi t h t he
coenzyme ( t hus r educi ng t he enzyme syst em' s capaci t y t o f unct i on) , or bi nd wi t h t he
enzyme compl ex ( r enderi ng i t unabl e t o bi nd wi t h i t s subst r at e) .
a. Reversi bI e i nhi bi t i on r esul t s f r om a noncovaI ent i nt eract i on bet ween t he
enzyme and t he drug. The dr ug i s f r ee t o associ at e and di ssoci at e wi t h t he enzyme,
and an equi l i bri um exi st s bet ween bound and f ree dr ug.
b. I rreversi bI e i nhi bi t i on r esul t s f r om a st abl e, covaI ent i nteracti on bet ween t he
enzyme and t he drug. Once bound t o t he enzyme, t he dr ug i s not abl e t o di ssoci at e.
c. Competi t i ve i nhi bi t i on occur s when t her e i s mut uaI I y excI usi ve bi ndi ng of t he
subst rat e and t he i nhi bi t or . Whi l e i t i s possi bl e f or compet i t i ve i nhi bi t ors t o bi nd t o
al l ost er i c si t es, t hese i nhi bi t ors ar e usual l y st ruct ur al l y si mi l ar t o t he nat ur al
subst rat es and compet e wi t h t he subst r at es f or common bi ndi ng si t es. Compet i t i ve
i nhi bi t i on can be overcome by i ncr easi ng t he concent r at i on of t he subst rat e.
d. Noncompet i ti ve i nhi bi t i on occur s when a drug bi nds t o an aI I ost eri c si t e on t he
enzyme. Thi s bi ndi ng i nduces a conf or mat i onal change i n t he enzyme t hat i nhi bi t s
enzyme act i on, even i f a subst rat e i s bound t o t he enzyme. Ì ncreasi ng subst rat e
concent r at i on does not over come t hi s t ype of i nhi bi t i on.
C. I nt eract i on wi th DNA/ RNA f ormat i on and f unct i on
1. I nhi bi ti on of nucI eot i de bi osynt hesi s occur s when f ol at e, pur i ne, and
pyr i mi di ne ant i met aboI i tes i nt erf ere wi t h t he bi osynt hesi s of puri ne and pyr i mi di ne
bui l di ng bl ocks.
a. FoI i c aci d anaI ogs (e. g. , met hot r exat e, t ri met rexat e) i nhi bi t pur i ne and
t hymi dyl at e synt hesi s by i nhi bi t i ng di hydrof ol at e r educt ase.
P. 270


b. Puri ne anaI ogs ( e. g. , 6- mer capt opur i ne, t hi oguani ne) act as ant agoni st s i n t he
synt hesi s of pur i ne bases. These anal ogs do not act as act i ve i nhi bi t or s unt i l t hey
ar e convert ed t o t hei r respect i ve nucl eot i des.
c. Pyri mi di ne anaI ogs (e. g. , 5- f l uor our aci l ) i nhi bi t t he synt hesi s of t hymi dyl i c aci d
by i nhi bi t i ng t hymi di ne synt het ase. As wi t h pur i ne anal ogs, pyr i mi di ne anal ogs ar e
not act i ve unt i l t hey are convert ed t o t hei r respect i ve nucl eot i des.
2. I nhi bi ti on of DNA or RNA bi osynt hesi s occurs when dr ugs i nt er f ere wi t h nucl ei c
aci d synt hesi s. These drugs ar e used pr i mar i l y as ant i neopl ast i c agent s f or cancer
chemot herapy.
a. Dr ugs t hat i nt erf ere wi t h DNA r epl i cat i on and f unct i on i ncl ude i nt er cal at i ng
agent s ( e. g. , t he anthracycI i nes, dact i nomyci n) , al kyl at i ng agent s ( e. g. , ni t rogen
must ards, ni t rosoureas) , and ant i met abol i t es.
b. Dr ugs t hat can damage and dest r oy DNA i ncl ude compounds t hat produce f r ee
r adi cal s ( e. g. , bI eomyci n, t he ant hracycI i nes) and compounds t hat i nhi bi t
t opoi somer ases ( e. g. , epi podophyI I ot oxi ns, mi toxant rone, i ri not ecan,
t opot ecan).
c. Dr ugs t hat i nt er f ere wi t h mi cr ot ubul e assembl y i n t he met aphase of ceI I mi t osi s
i ncl ude t he vi nca aI kaI oi ds and pacI i t axeI .
D. I nhi bi t i on of protei n synt hesi s
1. Tet racycI i nes i nt er f ere wi t h prot ei n synt hesi s by i nhi bi t i ng t r ansf er RNA ( t RNA)
bi ndi ng t o t he ri bosome and bl ocki ng t he rel ease of compl et ed pept i des f rom t he
r i bosome.
2. ChI orampheni coI and er yt hromyci n ( whi ch compet e f or t he same bi ndi ng si t e)
bi nd t o t he r i bosome and i nhi bi t pept i dyl t r ansf erase, bl ocki ng f ormat i on of t he
pept i de bond and i nt er rupt i ng f or mat i on of t he pept i de chai n.
3. Ami nogI ycosi des decr ease t he f i del i t y of t r anscri pt i on by bi ndi ng t o t he
r i bosome, whi ch permi t s f or mat i on of an abnor mal i ni t i at i on compl ex and pr ohi bi t s
addi t i on of ami no aci ds t o t he pept i de chai n. Ì n addi t i on, ami nogl ycosi des cause
mi sr eadi ng of t he messenger RNA ( mRNA) t empl at e, so t hat i ncor r ect ami no aci ds
ar e i ncor por at ed i nt o t he gr owi ng pol ypept i de chai n.
4. Qui nupri st i n and daI f opri st i n, i n combi nat i on, const r i ct t he exi t channel on
r i bosomal RNA ( r RNA) . Thi s act i on pr event s newl y synt hesi zed pol ypept i des f r om
bei ng rel eased and i n t ur n i nhi bi t s f ur t her pr ot ei n synt hesi s.
E. I nteracti on wi th ceI I membranes
1. Di gi t aI i s gI ycosi des i nhi bi t t he cel l membr ane' s sodi um-pot assi um pump,
i nhi bi t i ng t he i nf l ux of K
+
and t he out f l ow of Na
+
.
2. Qui ni di ne af f ect s t he membr ane pot ent i al of myocar di al membr anes by
pr ol ongi ng bot h t he pol ar i zed and depol ar i zed st at es.
3. LocaI anest het i cs bl ock i mpul se conduct i on i n ner ve cel l membr anes by
i nt er f eri ng wi t h membr ane permeabi l i t y t o Na
+
and K
+
.
4. PoI yene ant i f ungaI drugs (e. g. , amphot er i ci n B, nyst at i n) af f ect cel l membrane
per meabi l i t y, causi ng l eakage of cel l ul ar const i t uent s.
5. Certai n ant i bi ot i cs (e. g. , pol ymyxi n B, col i st i n) af f ect cel l membr ane
per meabi l i t y t hr ough an unknown mechani sm.
6. Acet yI choI i ne i ncr eases membr ane permeabi l i t y t o cat i ons.
7. OmeprazoI e and I ansoprazoI e i nhi bi t t he H
+
/ K
+
pump (l ocat ed i n par i et al cel l
membr anes) , t hus decr easi ng t he ef f l ux of prot ons i nt o t he st omach.
8. Several ant i neopI ast i c agent s exer t t hei r act i ons by i ni t i al l y bi ndi ng t o ceI I uI ar
det ermi nant s ( CDs) expr essed by t umor cel l s.
a. Gemtuzumab ozogami ci n bi nds wi t h CD33 expr essed by l eukemi c cel l s and
i mmat ur e myel omonocyt i c cel l s.
b. AI emt uzumab, a monocl onal ant i body, bi nds t o t he CD52 ant i gen expr essed on B
l ymphocyt es, T l ymphocyt es, and var i ous ot her cel l s.
P. 271


F. Nonspeci f i c act i on
1. St ruct ur al l y nonspeci f i c drugs f or m a monomol ecul ar l ayer over ent i r e ar eas of
cer t ai n cel l s. Because t hey i nvol ve such l ar ge surf aces, t hese drugs are usual l y
gi ven i n rel at i vel y l arge doses.
2. Dr ugs t hat act by nonspeci f i c act i on i ncl ude t he voI at i I e generaI anesthet i c
gases ( e. g. , et her, ni t r ous oxi de) , some depressant s (e. g. , et hanol , chl oral
hydr at e) , and many ant i sept i c compounds ( e. g. , phenol , rubbi ng al cohol ) .
P. 272


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one of t he suggest ed answer s or
phr ases. Choose t he best answer .
1. A 40- year- oI d man compI ai ns of dysuri a and uri nar y urgency and i s
di agnosed t o have uncompI i cated gonococcaI uret hri ti s. He i s gi ven procai ne
peni ci I I i n G i nt ramuscuI arI y. I n addi t i on, probeneci d i s gi ven to proI ong t he
durat i on of acti on of peni ci I I i n. Thi s t ype of combi ned drug eff ect i s known as
( A) syner gi sm.
( B) compet i t i ve ant agoni sm.
( C) addi t i on.
( D) pot ent i at i on.
( E) noncompet i t i ve ant agoni sm.
Vi ew Answer 1. The answer i s D[ see] . 2. A 40- year- oI d t eacher was
prescri bed I ovastat i n for t he t reatment of hyperchoI esteroI emi a. She want ed t o
know t he mechani sm of t he drug bef ore t aki ng i t . Her pharmaci st expI ai ned t o
her t hat I ovast at i n act s by bI ocki ng t he subst rat e- bi ndi ng si t e of t he enzyme ß-
hydroxy- ß- met hyI gI ut aryI - coenzyme A ( HMG- CoA) reduct ase, whi ch cat aI yzes
t he rate- I i mi t i ng st ep i n choI esteroI bi osynt hesi s. Such drug ef f ect i s known as
( A) addi t i on.
( B) syner gi sm.
( C) noncompet i t i ve ant agoni sm.
( D) pot ent i at i on.
( E) compet i t i ve ant agoni sm.
Vi ew Answer 2. The answer i s E[see] . 3. A 70- year- oI d man had proI onged
bI eedi ng duri ng an eI ect i ve knee surger y. Subsequent I y, t he pat i ent admi t ted to
t he surgeon t hat he had been seI f -admi ni steri ng 81 mg aspi ri n dai I y. The
consuI t ant pharmaci st expI ai ned t o t he pati ent t hat , aI though aspi ri n has a
short pI asma haI f -I i f e, i t can i rreversi bI y i nhi bi t pI ateI et f unct i on by acet yI at i ng
t he nonsubst rat e- bi ndi ng si te of t he pI at eI et cycI ooxygenase, resuI t i ng i n
proI onged ef f ect on pI at eI et aggregati on. Thi s drug eff ect i s known as
( A) pot ent i at i on.
( B) compet i t i ve ant agoni sm.
( C) synergi sm.
( D) addi t i on.
( E) noncompet i t i ve ant agoni sm.
Vi ew Answer 3. The answer i s E[see] . 4. A 65- year- oI d woman wi t h
i nt ractabI e pai n secondar y t o bony met ast asi s of breast cancer had been
recei vi ng escaI at i ng doses of morphi ne suI fate i nt ravenousI y. At 10 A. M. , she
was f ound to be unresponsi ve, her respi rat or y rat e was 4 breaths per mi nute,
and her pupi I s were pi n- poi nted. NaI oxone, a competi t i ve ant agoni st of t he
opi ate receptor, was gi ven i nt ravenousI y and repeated once. She graduaI I y
became consci ous and began t o compI ai n of pai n unreI i eved by morphi ne gi ven
at t he previ ous dose. Thi s i s most I i keI y because
( A) nal oxone di r ect l y aggr avat es t he pai n caused by t he bony met ast asi s.
( B) nal oxone r educes t he Emax f or mor phi ne.
( C) nal oxone r educes t he ED50 f or mor phi ne.
( D) nal oxone i ncreases t he Emax f or mor phi ne.
( E) nal oxone i ncreases t he ED50 f or mor phi ne.
Vi ew Answer 4. The answer i s E[see] . 5. Whi ch of t he f oI I owi ng st atement s
regardi ng si gnaI t ransduct i on i s i ncorrect?
( A) Thyr oxi ne- bound recept ors act on DNA and regul at e speci f i c t r anscr i pt i on of
genes.
( B) Cycl i c adenosi ne monophosphat e can act as a second messenger .
( C) The l evel of drug recept ors at t he cel l surf ace i ncr eases wi t h chroni c st i mul at i on
by r ecept or agoni st s.
( D) Bi ndi ng of l i gand t o cel l - sur f ace r ecept ors can l ead t o synt hesi s of prot ei ns.
( E) Ant aci ds act by i nt eract i ng wi t h smal l i ons nor mal l y f ound i n t he gast roi nt est i nal
t r act .
Vi ew Answer 5. The answer i s C[ see] . 6. A pharmaci st i s consuI t ed about
seI ect i ng a drug t hat i s reI at i veI y saf e and ef fect i ve f or t reat i ng t he pat i ent. He
searches t he I i terat ure and obt ai ns the foI I owi ng dat a that may heI p gui de hi s
deci si on. The TD0. 1 and ED99. 9 f or drug A are 20 mg and 0. 4 mg, respect i veI y;
whereas t he TD0. 1 and ED99. 9 for drug B are 15 mg and 0. 2 mg, respecti veI y.
Whi ch of the foI I owi ng st at ements i s t rue?
( A) Dr ug A has a hi gher TD0. 1 and t hus shoul d be t he dr ug of choi ce.
( B) Bot h drugs have t he same margi n of saf et y, so mor e i nf or mat i on i s needed.
( C) Dr ug B has a hi gher mar gi n of saf et y and t hus i s pr ef er r ed t o dr ug A.
( D) Dr ug A i s pref err ed because i t has a great er mar gi n of saf et y t han drug B.
( E) The i nf ormat i on obt ai ned i s i r rel evant .
Vi ew Answer 6. The answer i s C[ see] . P. 273


7. Whi ch of the foI I owi ng stat ements concerni ng a drug recept or i s t rue?
( A) Ì t medi at es t he nonspeci f i c act i on of vol at i l e anest het i cs.
( B) Ì t s expr essi on i s i nduced onl y by exogenousl y added drugs.
( C) Ì t can bi nd endogenous l i gand t o pr oduce physi ol ogi cal act i vi t y.
( D) Ì t medi at es t he cat har t i c act i vi t y of magnesi um ci t rat e.
( E) Down- r egul at i on of recept or l evel can l ead t o sensi t i zat i on of t he t ar get cel l t o
t he recept or agoni st .
Vi ew Answer 7. The answer i s C[ seeand] . 8. Whi ch of t he f oI I owi ng
st at ements concerni ng morphi ne and hydromorphone i s t rue?
( A) Hydr omor phone i s a mor e ef f ect i ve anal gesi c because i t has a smal l er ED50 t han
mor phi ne.
( B) Mor phi ne and hydromor phone ar e equal l y pot ent because t hey have t he same
Emax.
( C) Mor phi ne has a great er ED50 and i s t hus a l ess ef f ect i ve anal gesi c t han
hydr omor phone.
( D) Hydr omor phone i s a mor e pot ent anal gesi c because i t has a great er Emax t han
mor phi ne.
( E) Hydr omor phone has a smal l er ED50 and t hus i s a mor e pot ent anal gesi c t han
mor phi ne.
Vi ew Answer 8. The answer i s E[seeand] . 9. A 72- year- oI d man wi t h
hypert ensi on has been t aki ng hi gh- dose propranoI oI f or 20 years. He I ef t home
f or a week and forgot to bri ng hi s medi cat i on wi t h hi m. One day, he was f ound
coI I apsed on t he f I oor and was brought t o t he emergency room. Hi s bI ood
pressure was 300/ 180, heart rat e was 180 beats per mi nut e, and ret i naI
hemorrhage was observed. Whi ch of t he f oI I owi ng best expI ai ns t hi s si t uat i on?
( A) The 8- adr ener gi c r ecept ors i n t he car di ac muscl es under went spont aneous
mut at i on and became hyper act i ve.
( B) Reduct i on i n t he chroni c ant agoni sm of t he 8- adr energi c r ecept or l ed t o down-
r egul at i on of t he 8- adr ener gi c recept or .
( C) The pr opr anol ol t hat he had pr evi ousl y i ngest ed r emai ned i n hi s body and act ed
as a r ecept or agoni st .
( D) Long- t er m admi ni st rat i on of propranol ol r esul t s i n desensi t i zat i on of car di ac
muscl es t o endogenous 8- adr ener gi c st i mul at i on.
( E) Reduct i on i n t he chroni c l evel of recept or bl ockade r esul t s i n supersensi t i vi t y t o
st i mul at i on wi t h endogenous cat echol ami nes.
Vi ew Answer 9. The answer i s E[see] . 10. A 42- year- oI d man wi t h chroni c
I ymphocyt i c I eukemi a undergoi ng therapy ment i oned t o hi s pharmaci st t hat hi s
doct or had prescri bed ri t uxi mab for t reat i ng hi s cancer. The pat i ent asked what
ri t uxi mab i s and how i t works. Hi s pharmaci st expI ai ned t o hi m t hat ri t uxi mab
i s a monocI onaI anti body t hat
( A) i nhi bi t s DNA synt hesi s.
( B) bl ocks cel l cycl e pr ogr essi on.
( C) bi nds t o cel l sur f ace mol ecul es.
( D) boost s t he i mmune response.
Vi ew Answer 10. The answer i s C[ see] . 11. A 65-year- oI d woman
experi enced angi naI pai n wi t h ST segment eI evat i on on EKG. She was t reated
wi t h I V hepari n, ni t rogI yceri n, and at enoI oI f or acute myocardi aI i nf arct i on.
Then 2 hr I ater, when her nurse repI aced her FoI ey bag, she not i ced frank
bI ood drai ni ng out of the FoI ey cat het er. The physi ci an checked t he pat i ent ' s
part i aI t hrombi n t i me whi ch was > 150 s. The pat i ent was t hen admi ni st ered
prot ami ne, whi ch act s by
( A) pr omot i ng t hr ombosi s.
( B) r eact i ng wi t h hepari n and t hus neut r al i zi ng t he ef f ect of hepari n.
( C) di rect l y i nhi bi t i ng bl eedi ng.
( D) enhanci ng secr et i on of procoagul ant s.
Vi ew Answer 11. The answer i s B[ see] . 12. A 45-year- oI d man wi th acute
promyeI ocyt i c I eukemi a i s bei ng t reat ed wi t h aI I - t rans- reti noi c aci d (ATRA) . He
asks t he pharmaci st i f ATRA works I i ke vi t ami n A as a heaI t h suppI ement . The
pharmaci st expI ai ned that ATRA i s a f orm of vi t ami n A t hat act s by
( A) i mpr ovi ng i mmune f unct i ons.
( B) i nhi bi t i ng l eukemi c cel l secr et i on.
( C) l i mi t i ng l eukemi c cel l gr owt h.
( D) i nduci ng di f f er ent i at i on of l eukemi c cel l s.
Vi ew Answer 12. The answer i s D[ see] . 13. A 55-year- oI d man wi th a
hi st or y of heavy smoki ng had been di agnosed wi th non- smaI I ceI I I ung cancer,
whi ch was t reat ed wi t h chemot herapy; hi s di sease progressed. He i s now
recei vi ng erI ot i ni b, and he asks hi s pharmaci st how erI ot i ni b works. The
pharmaci st expI ai ns t hat erI ot i ni b act s by
( A) i nhi bi t i ng pr ot ei n t yrosi ne ki nase act i vi t y of t umor cel l s.
( B) decr easi ng l evel of pr ot ei n t yr osi ne ki nase of t umor cel l s.
( C) i ncr easi ng l i gand bi ndi ng of pr ot ei n t yr osi ne ki nase of t umor cel l s.
( D) i nduci ng t umor cel l di f f erent i at i on.
Vi ew Answer 13. The answer i s A[ see] . P. 274


14. Whi ch of t he f oI I owi ng drug- acti on pai rs i nvoI ves speci f i c recept ors?
( A) Magnesi um sul f at e f or t r eat ment of const i pat i on.
( B) Cal ci um carbonat e f or r el i ef of hear t bur n.
( C) Desf l urane f or i nduci ng sedat i on.
( D) Tamoxi f en f or t herapy of breast cancer.
( E) Sor bi t ol f or reduci ng i nt racrani al hyper t ensi on.
Vi ew Answer 14. The answer i s D[ see] . 15. Whi ch of t he f oI I owi ng saI t s
wi I I most I i keI y yi eI d an aqueous soI ut i on wi th a pH < 7?
( A) Sodi um sal i cyl at e
( B) Pot assi um chl ori de
( C) Magnesi um sul f at e
( D) Pot assi um peni ci l l i n
( E) At r opi ne sul f at e
Vi ew Answer 15. The answer i s E[see] . 16. Whi ch of t he f oI I owi ng
chemi caI / pharmacoI ogi caI cI asses of agent s i s i ncorrectl y mat ched wi t h i t s
aci d-base nat ure?
( A) Adr energi c 82-agoni st s: basi c
( B) Pr ost agl andi ns: aci di c
( C) Or gani c ni t r at es: nonel ect r ol yt es
( D) Megl i t i ni des: aci di c
( E) 4- Qui nol ones: basi c
Vi ew Answer 16. The answer i s E[seeand] . 17. AI I of t he f oI I owi ng
medi ci naI agents are cI assi fi ed as naturaI product s except
( A) at ropi ne.
( B) di azepam.
( C) di gi t oxi n.
( D) peni ci l l i n.
( E) mor phi ne.
Vi ew Answer 17. The answer i s B[ seeand] . 18. AI I of t he f oI I owi ng
st at ements about a st ruct uraI I y speci f i c agoni st are t rue except whi ch one?
( A) Act i vi t y i s det er mi ned mor e by i t s chemi cal st r uct ur e t han by i t s physi cal
pr oper t i es.
( B) The ent i re mol ecul e i s i nvol ved i n bi ndi ng t o a speci f i c endogenous recept or.
( C) The dr ug cannot act unl ess i t i s f i r st bound t o a r ecept or.
( D) A mi nor st r uct ural change i n a phar macophore can pr oduce a l oss i n act i vi t y.
( E) The hi gher t he af f i ni t y bet ween t he dr ug and i t s recept or , t he gr eat er t he
bi ol ogi cal response.
Vi ew Answer 18. The answer i s B[ see] . 19. The dext ro ( D) f orm of ß-
met hachoI i ne ( st ruct ure shown) i s approxi mateI y 500 t i mes more acti ve t han
t he I evo ( L) enant i omer. The observed di f f erence i n pharmacoI ogi caI act i vi t y
between t he two i somers i s most I i keI y t he resuI t of di ff erences i n


( A) r ecept or sel ect i vi t y.
( B) di ssol ut i on.
( C) di st ri but i on.
( D) i nt er at omi c di st ance bet ween pharmacophor e gr oups.
( E) sol ubi l i t y.
Vi ew Answer 19. The answer i s A[ see] . enant i omer20. The compound
shown beI ow can be cI assi fi ed as a


( A) peni ci l l i n.
( B) t hi azi de.
( C) coumar i n.
( D) phenot hi azi ne.
( E) hydant oi n.
Vi ew Answer 20. The answer i s B[ seeand] . 21. Whi ch of t he f oI I owi ng aci ds
has the hi ghest degree of i oni zat i on i n an aqueous soI uti on?
( A) Aspi r i n; pKa = 3. 5
( B) Ì ndomet haci n; pKa = 4. 5
( C) War f ar i n; pKa = 5. 1
( D) Ì bupr of en; pKa = 5. 2
( E) Phenobar bi t al ; pKa = 7. 4
Vi ew Answer 21. The answer i s A[ see] . P. 275


22. Whi ch of t he f oI I owi ng stat ements concerni ng t he st ruct ure shown beI ow i s
not correct ?


( A) The compound i s an aci d.
( B) The compound can be used t o t r eat art hri t i s.
( C) The compound i s a f enamat e.
( D) The compound i ncr eases pr ost agl andi n pr oduct i on.
( E) The compound i s a nonst er oi dal ant i - i nf l ammat or y drug ( NSAÌ D) .
Vi ew Answer 22. The answer i s D[ see] . 23. AI I of t he f oI I owi ng cI asses of
drugs are used t o t reat hypert ensi on except
( A) ar yl oxypr opanol ami nes.
( B) t hi azi des.
( C) f i br at es.
( D) di hydr opyr i di nes.
( E) angi ot ensi n- conver t i ng enzyme ( ACE) i nhi bi t or s.
Vi ew Answer 23. The answer i s C[ see] . 24. FI urazepam has pKa of 8. 2.
What percent age of f I urazepam wi I I be i oni zed at a uri ne pH of 5. 2?
( A) 0. 1%
( B) 1%
( C) 50%
( D) 99%
( E) 99. 9%
Vi ew Answer 24. The answer i s E[seeand] . Di recti ons for questi ons 25- 29:
The quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed
or compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
25. Drugs that act syst emi caI I y must
I . undergo bi ot ransformat i on i nt o an act i ve form af ter reachi ng thei r act i ve
si t e.
I I . be i n a form capabI e of passage t hrough vari ous membrane barri ers.
I I I . be i n or be convert ed t o a f orm t hat i s readi I y excret ed f rom the body.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 25. The answer i s D[ seeand] . 26. ExampI es of st rong
eI ect roI yt es ( i . e. , compI et eI y di ssoci at ed i n an aqueous soI ut i on) i ncI ude
I . acet i c aci d.
I I . pent obarbi taI sodi um.
I I I . di phenhydrami ne hydrochI ori de.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 26. The answer i s D[ see] . pent obarbi t al
sodi umdi phenhydrami ne hydrochl ori de27. Preci pi tat i on may occur when
mi xi ng aqueous soI ut i ons of meperi di ne hydrochI ori de wi th whi ch of the
f oI I owi ng soI ut i ons?
I . Sodi um bi carbonat e i nj ecti on
I I . At ropi ne suI f at e i nj ect i on
I I I . Sodi um chI ori de i nj ect i on
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 27. The answer i s A[ seeand] . 28. Drugs cI assi f i ed as
ant i met aboI i tes i ncI ude whi ch of t he f oI I owi ng?
I . 5- fI uorouraci I
I I . suI f i soxazoI e
I I I . di goxi n
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 28. The answer i s C[ see] . 29. The excret i on of a weakI y
aci di c drug i s generaI I y more rapi d i n aI kaI i ne uri ne t han i n aci di c uri ne. Thi s
process occurs because
I . a weak aci d i n aI kaI i ne medi a wi I I exi st pri mari I y i n i t s i oni zed f orm, whi ch
cannot be reabsorbed easi I y.
I I . a weak aci d i n aI kaI i ne medi a wi I I exi st i n i ts I i pophi I i c f orm, whi ch cannot
be reabsorbed easi I y.
I I I . aI I drugs are excreted more rapi dI y i n an aI kaI i ne uri ne.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 29. The answer i s A[ see] . P. 276


Quest i ons 30- 33, ref er t o t he drug meperi di ne (st r uct ur e shown) .
30. Functi onaI groups present i n t he moI ecuI e shown i ncI ude
I . an ester.
I I . a t ert i ar y ami ne.
I I I . a carboxyI i c aci d.


Vi ew Answer 30. The answer i s C[ seeand] . 31. Meperi di ne i s cI assi fi ed as
a
I . weak aci d.
I I . saI t .
I I I . weak base.


Vi ew Answer 31. The answer i s B[ seeand] . 32. Assumi ng t hat meperi di ne
i s absorbed af t er oraI admi ni st rat i on and t hat a I arge percent age of the dose i s
excreted unchanged, t he ef fect of aI kaI i ni zati on of t he uri ne wi I I i ncrease i t s
I . durat i on of act i on.
I I . rate of excret i on.
I I I . i oni zati on i n t he gI omeruI ar f i I t rat e.


Vi ew Answer 32. The answer i s A[ seeand] . 33. The appropri at e chemi caI
cI assi f i cat i on for meperi di ne i s
I . phenyI propyI ami ne.
I I . pi perazi ne.
I I I . 4- phenyI pi peri di ne.


Vi ew Answer 33. The answer i s B[ seeand] . Di recti ons for questi ons 34- 38:
The r el at i onshi p of each pai r of st ruct ur es shown i n t hi s sect i on i s most cl osel y
associ at ed wi t h one of t he f ol l owi ng t er ms. The t er ms may be used mor e t han once
or not at al l . Choose t he best answer , A- E.
34.

A Geomet r i c i somer s
B Enant i omers
C Di ast ereomers
D Bi oi sost er es
E Conf or mat i onal i somers
Vi ew Answer 34. The answer i s C[ see] . 35.

A Geomet r i c i somer s
B Enant i omers
C Di ast ereomers
D Bi oi sost er es
E Conf or mat i onal i somers
Vi ew Answer 35. The answer i s B[ see] . P. 277


36.

A Geomet r i c i somer s
B Enant i omers
C Di ast ereomers
D Bi oi sost er es
E Conf or mat i onal i somers
Vi ew Answer 36. The answer i s A[ see] . 37.

A Geomet r i c i somer s
B Enant i omers
C Di ast ereomers
D Bi oi sost er es
E Conf or mat i onal i somers
Vi ew Answer 37. The answer i s D[ see] . 38.

A Geomet r i c i somer s
B Enant i omers
C Di ast ereomers
D Bi oi sost er es
E Conf or mat i onal i somers
Vi ew Answer 38. The answer i s E[see] . P. 278


ANSWERS AND EXPLANATIONS
1. The answer i s D [ see V. C] .
Pr obeneci d al one i s i nact i ve agai nst gonococci . However , i t can compet e wi t h
peni ci l l i n f or ur i nar y excret i on. Thus pr obeneci d can r educe t he el i mi nat i on r at e of
peni ci l l i n, whose durat i on of act i on becomes pr ol onged. Theref or e, pr obeneci d
pot ent i at es t he act i vi t y of peni ci l l i n when t he t wo ar e gi ven t oget her .
2. The answer i s E [ see Ì Ì . B. 4. a; Ì V. D. 3] .
Lovast at i n rever si bl y bi nds t o t he subst r at e- bi ndi ng si t e of t he enzyme HMG- CoA
r educt ase, whi ch cat al yzes t he r at e- l i mi t i ng st ep i n t he synt hesi s of chol est erol ,
t hus l ower i ng t he chol est er ol l evel . Theref ore, l ovast at i n i nhi bi t s t he enzyme by
compet i t i ve ant agoni sm.
3. The answer i s E [ see Ì Ì . B. 4. b; Ì V. D. 4] .
Aspi r i n can coval ent l y modi f y t he pl at el et cycl ooxygenase t hr ough acet yl at i on of t he
enzyme ot her t han t he subst r at e- bi ndi ng si t e, causi ng i r r eversi bl e i nhi bi t i on of
pl at el et aggregat i on. Ther ef or e, aspi ri n i nhi bi t s pl at el et f unct i on by noncompet i t i ve
ant agoni sm of cycl ooxygenase.
4. The answer i s E [ see Ì V. D. 3] .
Nal oxone i s a compet i t i ve ant agoni st of opi at e r ecept or . Ì f one compar es t he l og
dose- r esponse cur ve of bot h mor phi ne and nal oxone t o t hat of mor phi ne al one, t he
mor phi ne- nal oxone cur ve i s shi f t ed t o t he r i ght . As a r esul t , t he ED50 f or mor phi ne i s
i ncreased. Thi s means t hat a l ar ger t han pr evi ous dose of mor phi ne i s requi red f or
achi evi ng t he same anal gesi c ef f ect .
5. The answer i s C [ see Ì Ì Ì . D. 4] .
The l evel of dr ug r ecept or s at t he cel l surf ace usual l y decr eases when t he t arget
cel l s ar e chr oni cal l y st i mul at ed by r ecept or agoni st s. Down- r egul at i on of recept ors
i s a prot ect i ve mechani sm t hat can prevent t he t ar get cel l s f r om bei ng
over st i mul at ed.
6. The answer i s C [ see VÌ . C] .
The margi n of saf et y of t he t wo drugs can be hel pf ul i n gui di ng sel ect i on of a dr ug.
Mar gi n of saf et y i s t he rat i o of TD0. 1 t o ED99. 9. Thus t he mar gi n of saf et y f or drug A
i s 20 mg ÷ 0. 4 mg, or 50, wher eas t he mar gi n of saf et y f or dr ug B i s 15 mg ÷ 0. 2
mg, or 75. Because dr ug B has a great er mar gi n of saf et y t han dr ug A, drug B i s
r el at i vel y saf e at t he dosage gi ven t o pr oduce t he desi r ed ef f ect .
7. The answer i s C [ see Ì Ì . B. 2; Ì Ì Ì . D. 4; Ì Ì Ì . E. 1. a and b] .
A dr ug r ecept or, such as muscar i ni c chol i ner gi c recept or, whi ch can bi nd at r opi ne,
nor mal l y bi nds endogenous acet yl chol i ne t o produce t he physi ol ogi cal r esponses
cont r ol l ed by t he par asympat het i c aut onomi c nervous syst em. Vol at i l e anest het i cs
act col l i gat i vel y as sol ut es i n t he l i pi d bi l ayer of t he cel l membrane. Dr ug r ecept or s
ar e endogenousl y expr essed, but t hei r l evel can be modul at ed by exogenousl y
added dr ugs. The cat hart i c act i vi t y of magnesi um ci t r at e i s a consequence of
i ncrease i n t he osmol ari t y of t he gast r oi nt est i nal f l ui ds. Down- r egul at i on of r ecept or
l evel can l ead t o desensi t i zat i on, not sensi t i zat i on, of t he t ar get cel l t o t he r ecept or
agoni st .
8. The answer i s E [ see Ì V. D. 1 and 2] .
The ef f i cacy of a dr ug i s det ermi ned by i t s Ema x, wher eas i t s pot ency i s measur ed by
t he ED50. Hydromor phone has a smal l er ED50 and t hus i s a more pot ent anal gesi c
t han mor phi ne. Hydr omor phone and mor phi ne are bot h agoni st s f or opi at e
r ecept or s, and t hey have t he same anal gesi c ef f i cacy ( i . e. , t hey have t he same
Emax) i f suf f i ci ent amount s of bot h dr ugs ar e used.
9. The answer i s E [ see Ì Ì Ì . D. 6] .
A chroni c l evel of bl ocki ng t he 8-adr energi c r ecept ors by pr opranol ol r esul t s i n up-
r egul at i on of t he r ecept or l evel . When t he pat i ent ceased t aki ng t he drug, t he
car di ac muscl es became supersensi t i ve t o st i mul at i on wi t h endogenous
cat echol ami nes. Thi s resul t ed i n t he hyper t ensi ve cr i si s t hat caused cer ebr al
hemor r hage and l oss of consci ousness.
P. 279


10. The answer i s C [ see Ì Ì Ì . A. 1] .
Ri t uxi mab i s a monocl onal ant i body t hat speci f i cal l y bi nds t o CD20 ant i gen on
mal i gnant and normal B l ymphocyt es, l eadi ng t o t hei r dest ruct i on.
11. The answer i s B [ see X. A. 3. b. ( 1) ] .
Pr ot ami ne i s a chemi cal ant agoni st of hepari n t hat act s vi a an aci d-base i nt er act i on.
12. The answer i s D [ see Ì Ì Ì . C] .
ATRA bi nds t o r et i noi c aci d r ecept or on t he cel l membr ane, l eadi ng t o expr essi on of
t ar get genes and r esul t i ng i n di f f er ent i at i on of l eukemi c pr omyel ocyt es.
13. The answer i s A [ see Ì Ì Ì . B. 3] .
Er l ot i ni b bi nds t o t he ATP pocket of t he t yr osi ne ki nase of t he EGF recept or and
t hus i nhi bi t s t yrosi ne ki nase act i vi t y.
14. The answer i s D [ see Ì Ì . B. 4. a, Ì Ì Ì . E. ] .
Tamoxi f en and i t s met abol i t es bi nd t o est r ogen recept ors, and prevent t hem f r om
bi ndi ng est radi ol . Thi s r esul t s i n suppressi on of est r ogen- dependent growt h i n
br east cancer cel l s. The pharmacol ogi cal ef f ect s of t he ot her drugs are not
medi at ed by r ecept ors.
15. The answer i s E [ see VÌ Ì Ì . B. 3. d] .
The sol ut i on must cont ai n an aci di c subst ance t o have a pH < 7. At r opi ne sul f at e i s
a sal t of a weak base and a st rong aci d; t her ef ore, i t s aqueous sol ut i on i s aci di c.
Sodi um sal i cyl at e and pot assi um peni ci l l i n ar e bot h sal t s of st rong bases and weak
aci ds; t her ef or e, t hei r aqueous sol ut i ons ar e al kal i ne. Magnesi um sul f at e and
pot assi um chl or i de ar e sal t s of st r ong bases and st r ong aci ds; t heref ore, t hei r
aqueous sol ut i ons are neut r al .
16. The answer i s E [ see Tabl e 12-1; Fi gur es 12- 8, 12- 9, and 12- 11] .
4- Qui nol ones ar e amphot er i c compounds. Al l compounds i n t hi s chemi cal cl ass
cont ai n a car boxyl i c aci d as wel l as a basi c ni t rogen. Most 4- qui nol ones cont ai n a
basi c pi perazi ne r i ng and basi c het er ocycl i c r i ngs; however , some of t he ol der
compounds i n t hi s cl ass onl y have t he basi c het er ocycl i c r i ngs. Al l ot her compounds
ar e cor rect l y mat ched wi t h t hei r aci d-base nat ur e.
17. The answer i s B [ see VÌ Ì . A and B] .
Di azepam i s a benzodi azepi ne anxi ol yt i c, whi ch÷al t hough i t i s a het erocycl i c
ni t rogen- cont ai ni ng mol ecul e÷i s not an al kal oi d and i s pr epared synt het i cal l y.
Nat ur al pr oduct s ref er t o subst ances bi osynt hesi zed i n pl ant s or ani mal s. Nat ural
pr oduct s i ncl ude al kal oi ds, such as at r opi ne and mor phi ne; pept i des, such as
gl ucagon; st er oi ds, such as est r adi ol ; hormones, such as i nsul i n; gl ycosi des, such
as di gi t oxi n; vi t ami ns, such as ri bof l avi n; pol ysacchari des, such as hepar i n; and
ant i bi ot i cs, such as peni ci l l i n.
18. The answer i s B [ see Ì X. B] .
The bi ndi ng of a dr ug t o i t s r ecept or usual l y i nvol ves onl y speci f i c f unct i onal
gr oups. These groups make up what i s known as t he phar macophor e of t he drug
mol ecul e. Al t hough t he ent i re drug mol ecul e i s present at t he recept or si t e, onl y a
por t i on of i t , t he pharmacophore, i s requi r ed f or a bi ol ogi cal r esponse.
19. The answer i s A [ see Ì X. B. 3. a; Fi gure 12- 12] .
The t erm enant i omer and t he D and L i ndi cat e t hat t he 8-met hachol i ne has a chi r al
cent er and exhi bi t s opt i cal i someri sm. Because t he opt i cal i somers have di f f er ent
or i ent at i ons i n space, one ori ent at i on wi l l gi ve a bet t er f i t t han t he ot her and wi l l
most l i kel y have great er bi ol ogi cal act i vi t y t han t he ot her. Di ssol ut i on, di st r i but i on,
i nt er at omi c di st ances, and sol ubi l i t y ar e al l r el at ed t o t he physi cal and chemi cal
pr oper t i es of t he t wo compounds, whi ch ar e i dent i cal because t he compounds are
enant i omer s.
20. The answer i s B [ see Tabl e 12-1; Fi gur es 12- 7, 12- 8, 12- 9 and 12-10] .
Key st ruct ur al f eat ur es of a t hi azi de÷a benzot hi adi azi ne ri ng wi t h an el ect r on-
wi t hdr awi ng chl or i de at om and a sul f onyl gr oup on t he benzene r i ng÷i dent i f y t hi s
compound as a t hi azi de.
P. 280


21. The answer i s A [ see VÌ Ì Ì . B. 2. b] .
The pKa (t he negat i ve l og of t he aci d i oni zat i on const ant ) i ndi cat es t he rel at i ve
st r engt h of an aci di c drug. The l ower t he pKa of an aci di c dr ug, t he st ronger i t i s as
an aci d. A st rong aci d i s def i ned as one t hat i s compl et el y i oni zed or di ssoci at ed i n
an aqueous sol ut i on; t her ef ore, t he st ronger t he aci d, t he gr eat er t he i oni zat i on.
22. The answer i s D [ see Tabl e 12-1; Fi gur e 12-8] .
The carboxyl i c aci d i dent i f i es t hi s compound as an aci d. Ot her st r uct ur al f eat ures
i dent i f y i t as a f enamat e. Fenamat es are NSAÌ Ds t hat can be used f or i nf l ammat or y
di sor der s ( e. g. , ar t hr i t i s, bursi t i s). The mechani sm of act i on of NSAÌ Ds i s i nhi bi t i on
of cycl ooxygenase, whi ch r esul t s i n a decr ease i n t he product i on of pr ost agl andi ns.
23. The answer i s C [ see Tabl e 12-1] .
Fi brat es decrease chol est erol and t r i gl ycer i de l evel s. Al l of t he ot her chemi cal
cl asses can be used t o t r eat hyper t ensi on. Ar yl oxypr opanol ami nes are 8-bl ocker s,
t hi azi des are di uret i cs, di hydr opyr i di nes ar e cal ci um channel bl ockers, and ACE
i nhi bi t ors decrease t he synt hesi s of angi ot ensi n Ì Ì , a pot ent vasoconst r i ct or .
24. The answer i s E [ see VÌ Ì Ì . B. 2. f and g; Tabl e 12- 1] .
Fl urazepam ( t ake not e of t he suf f i x, whi ch hel ps cl assi f y t he compound) i s a
benzodi azepi ne and t hus a basi c compound. Because t he pH i s l ess t han t he pKa,
f l urazepam i s i n an aci di c envi r onment and, t her ef or e, exi st s pr i mar i l y i n t he i oni zed
f or m. The per cent i oni zed can be easi l y cal cul at ed by usi ng t he rul e of ni nes. The
| pH - pKa| i s 3, so t he r at i o i s 99. 9%: 0. 01% i n f avor of t he i oni zed f or m.
25. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see VÌ Ì Ì . A. 1 and 2] .
Gener al l y, dr ugs must be l i pophi l i c t o pass t hr ough l i popr ot ei n membr anes and
hydr ophi l i c t o be excr et ed by t he ki dney. Drugs do not have t o be conver t ed i nt o an
act i ve f or m at t hei r act i ve si t e, al t hough most drugs must be i n t hei r act i ve f orm
when t hey reach t hei r act i ve si t e. Many dr ugs ar e act i ve i n t he f orm i n whi ch t hey
ar e admi ni st er ed. Some dr ugs, usual l y r ef er r ed t o as prodr ugs, are bi ot r ansf or med
i nt o t hei r act i ve f orm af t er admi ni st rat i on. Theoret i cal l y, drugs t hat reach t hei r
act i ve si t e and t hen ar e met abol i cal l y act i vat ed shoul d be more speci f i c i n t hei r
act i on and have f ewer si de ef f ect s. Curr ent l y, resear ch ef f ort s ar e under way t o
devel op si t e- speci f i c del i ver y syst ems and processes.
26. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see VÌ Ì Ì . B. 2. c; VÌ Ì Ì . B. 3. a; VÌ Ì Ì . B. 4. a] .
Al most al l sal t s ( wi t h very f ew except i ons) ar e st rong el ect rol yt es, and t he
t er mi nol ogy pent obar bi t al sodi um and di phenhydrami ne hydr ochl or i de i ndi cat e t hat
each compound i s sal t . Acet i c aci d i s a weak aci d; t her ef or e, i t i s a weak
el ect r ol yt e.
27. The answer i s A ( Ì ) [ see VÌ Ì Ì . B. 3 and 4] .
When meperi di ne hydr ochl ori de sol ut i on i s mi xed wi t h t he al kal i ne sol ut i on of
sodi um bi car bonat e, a neut r al i zat i on r eact i on occur s wi t h t he possi bl e preci pi t at i on
of t he wat er -i nsol ubl e f ree base meper i di ne. A neut r al i zat i on r eact i on occurs when
aci di c sol ut i ons are mi xed wi t h basi c sol ut i ons, or conver sel y. No r eact i on, i n t erms
of aci d- base, occur s when sol ut i ons ar e mi xed wi t h ot her aci di c or neut ral sol ut i ons
or when basi c sol ut i ons ar e mi xed wi t h ot her basi c or neut ral sol ut i ons. Ther e
shoul d be no r eact i on, t hen, when t he meper i di ne hydr ochl or i de sol ut i on, whi ch i s
aci di c, i s mi xed wi t h t he aci di c sol ut i on of at r opi ne sul f at e or t he neut r al sol ut i on of
sodi um chl or i de.
28. The answer i s C ( Ì , Ì Ì ) [ see Ì X. B. 3. d; X. C. 1; X. E. 1] .
Bot h sul f i soxazol e and 5- f l uor ouraci l compet e wi t h and ant agoni ze i sost eri c normal
bi ol ogi cal mol ecul es and t hus ar e ant i met abol i t es. Di goxi n i s a dr ug t hat i s t hought
t o i nhi bi t Na
+
/ K
+
- ATPase or t o af f ect i nt racel l ul ar i nf l ux or use of cal ci um i on ( Ca
++
) .
Because di goxi n i s st er oi dal , i t i s not i sost eri c wi t h ei t her an enzyme, whi ch i s a
pr ot ei n, or an i on; t heref or e, i t i s not cl assi f i ed as an ant i met abol i t e.
29. The answer i s A ( Ì ) [ see VÌ Ì Ì . B. 1; VÌ Ì Ì . B. 2. e] .
A weakl y aci di c drug wi l l be more i oni zed i n an al kal i ne uri ne; t her ef or e, i t wi l l be
mor e pol ar and t hus more sol ubl e i n t he aqueous ur i ne. Ì t woul d al so be l ess
l i posol ubl e, l ess l i kel y t o under go t ubul ar reabsor pt i on, and t hus be more l i kel y t o
be excr et ed.
30. The answer i s C ( Ì , Ì Ì ) [ see VÌ Ì Ì . B. 2 and 3; Fi gur e 12-7] .
31. The answer i s B ( Ì Ì Ì ) [ see VÌ Ì Ì . B. 2 and 3; Fi gur e 12- 7] .
P. 281


32. The answer i s A ( l ) [ see VÌ Ì Ì . B. 2 and 3; Fi gure 12-7] .
33. The answer i s B ( Ì Ì Ì ) [ see VÌ Ì Ì . B. 2 and 3; Fi gur e 12- 7] .
The mol ecul e cont ai ns a basi c ni t r ogen, whi ch i s bonded t o t hr ee car bon at oms
( i . e. , a t er t i ar y ami ne), and an et hyl carboxyl at e, whi ch i s an est er gr oup. An est er
i s t he pr oduct of t he react i on of an al cohol wi t h a car boxyl i c aci d t hat f orms an al kyl
car boxyl at e. Ther e i s no f r ee carboxyl i c aci d present . However , i f t hi s mol ecul e i s
subj ect ed t o hydrol ysi s, i t f orms a carboxyl i c aci d and et hyl al cohol .
Because meper i di ne cont ai ns a t er t i ar y ami ne, i t i s cl assi f i ed as a base; because i t
i s an or gani c base, i t i s consi dered weak. The ni t r ogen i s not pr ot onat ed. Ì t i s not
i oni c and, t her ef ore, i s not a sal t .
Al kal i ni zat i on of t he uri ne decr eases t he i oni zat i on of meper i di ne, maki ng i t mor e
l i posol ubl e and t hus more l i kel y t o under go reabsor pt i on i n t he ki dney t ubul e. Thi s
r esul t s i n a decr eased rat e of excr et i on and an i ncr eased dur at i on of act i on. The
si x- member , nonaromat i c r i ng i s a pi per i di ne ri ng t hat i s subst i t ut ed at t he 4-
posi t i on (ni t r ogen i s posi t i on 1) wi t h a phenyl r i ng. The compound does not cont ai n
a pi perazi ne r i ng or a propyl group.
34. The answer i s C [ see Ì X. B. 3. a. 4; Fi gur e 12- 13] .
These mol ecul es ar e i somers t hat have t wo asymmet ri c car bon at oms. They ar e not
super i mposabl e and ar e not mi r ror i mages; t heref or e, t hey ar e known as
di ast ereomers.
35. The answer i s B [ see Ì X. B. 3. a. 1; Fi gur e 12- 12] .
These mol ecul es ar e i somers t hat have one asymmet r i c carbon at om. They ar e
nonsuper i mposabl e mi r ror i mages; t her ef or e, t hey ar e enant i omers.
36. The answer i s A [ see Ì X. B. 3. b; Fi gure 12- 14] .
These mol ecul es have di f f er ent spat i al ar r angement s; however , t hese mol ecul es do
not have an asymmet r i c cent er . The presence of t he doubl e bond, whi ch rest ri ct s
t he rot at i on of t he gr oups on each car bon at om i nvol ved i n t he doubl e bond,
charact eri zes t hi s t ype of i somer i sm as geomet ri c.
37. The answer i s D [ see Ì X. B. 3. d; Fi gure 12- 16] .
These mol ecul es ar e nei t her i somer s nor t he same compound because one cont ai ns
t hr ee oxygens, whereas t he ot her cont ai ns t wo oxygens and a sul f ur . Because
oxygen and sul f ur ar e i n t he same peri odi c f ami l y, t hey ar e i sost er i c and ar e known
as bi oi sost er es.
38. The answer i s E [ see Ì X. B. 3. c; Fi gur e 12- 15] .
These st r uct ur es are act ual l y t wo vi ews of t he same compound. Rot at i on ar ound t he
si de chai n si ngl e bonds connect i ng t he r i ng ni t rogen t o t he t er t i ar y ni t rogen
pr oduces t hese t wo di f f er ent conf ormat i ons. Thus t hese ar e conf or mat i onal i somers.

13
MedicinaI Chemistry and PharmacoIogy: Drugs
Affecting the Nervous System
Habi ba O. U. Vongtau
Ashi weI S. Undi eh
INTRODUCTION.
Dr ugs af f ect i ng t he ner vous syst em modul at e neur ot ransmi ssi on i n t he cent raI
nervous syst em ( CNS) , whi ch consi st s of t he brai n and t he spi nal cord, or i n t he
peri pheraI nervous syst em ( PNS), whi ch i ncl udes t he aut onomi c nervous syst em
( ANS) and t he somat i c syst em t hat i nner vat es t he skel et al muscl es. The ANS, i n
t ur n, consi st s of sympat het i c (or adr ener gi c) and par asympat het i c ( or chol i ner gi c)
br anches. Agent s act i ng i n t he ANS i ncl ude adr ener gi c agoni st s and ant agoni st s,
chol i ner gi c agoni st s and ant agoni st s, and i ndi r ect l y act i ng agent s t hat coul d af f ect
one or bot h ANS syst ems. Dr ugs af f ect i ng t he PNS ar e usef ul f or t reat i ng a vari et y
of ai l ment s i ncl udi ng bl ood pressure di st urbances, br onchi al ast hma, cardi ac
dysf unct i ons, anaphyl act i c react i ons, nasal congest i on, and skel et al muscl e
spast i ci t y. Dr ugs af f ect i ng t he CNS provi de anest hesi a and sedat i on, rel i eve pai n
and anxi et y, suppr ess movement di sor der s and epi l ept i c sei zur es, and t r eat
psychot i c and af f ect i ve di sorders. These dr ugs i ncl ude gener al and l ocal
anest het i cs, anxi ol yt i cs and sedat i ve- hypnot i cs, opi oi d anal gesi cs, ant i par ki nsoni an
agent s, ant i epi l ept i cs, ant i psychot i cs, and ant i depr essant s.
I. GENERAL MECHANISMS OF DRUG ACTION IN THE
NERVOUS SYSTEM.
Dr ugs act i ng i n t he ner vous syst em achi eve t hei r pharmacol ogi c ef f ect s by
modi f yi ng t he synapt i c concent rat i ons or r ecept or act i ons of neur ot ransmi t t ers.
Ot her dr ugs modul at e t he i nt r acel l ul ar r esponse pat hways by whi ch t he recept or
act i ons of t he t r ansmi t t er s are conveyed t o yi el d t he ul t i mat e physi ol ogi cal
r esponse. The maj or neur ot r ansmi t t ers i n t he nervous syst em, t hei r pr i mar y r ecept or
subt ypes, and t he pr edomi nant ef f ect s of recept or st i mul at i on on neurot r ansmi ssi on
ar e shown i n Tabl e 13- 1. Some general mechani sms by whi ch di verse dr ugs
modul at e t he act i vi t y of t he ner vous syst em ar e summar i zed i n Tabl e 13- 2, wi t h
exampl es drawn f r om t he adrener gi c and chol i ner gi c component s of t he PNS. Ì n
addi t i on, t here ar e vari ous cl asses of drugs t hat modul at e neur al f unct i on by
i nt er act i ng wi t h t he pores of i on channel s or by bi ndi ng t o al l ost eri c si t es on t he
pr ot ei n subuni t s t hat const i t ut e t he channel .
II. ADRENERGIC AGONISTS
A. Chemi st r y
1. Di rect - act i ng adrenergi c agoni st s i nt er act di r ect l y wi t h adr ener gi c r ecept ors t o
el i ci t a response. These agoni st s i ncl ude nor epi nephri ne and epi nephr i ne, whi ch ar e
endogenous or nat ural l y occur ri ng cat echol ami nes. The cat echol ami nes ar e
bi osynt hesi zed f r om t yr osi ne, an ami no aci d ( Fi gur e 13- 1). Exampl es of ot her di rect -
act i ng adrener gi c agoni st s i ncl ude naphazol i ne, t er but al i ne, and dobut ami ne ( Fi gur e
13- 2). The cl assi f i cat i on of adr ener gi c agoni st s and ant agoni st s shown i n Tabl e 13-
3 shoul d pr ovi de a broad perspect i ve on t he vari et y of agent s t hat act on t hi s
syst em t o pr oduce t hei r pharmacol ogi c and t her apeut i c ef f ect s.
a. The et hyl ami ne chai n common t o t hese agoni st s i s essent i al t o t hei r adrenergi c
act i vi t y.
b. N- subst i t ut i on al t ers dr ug act i vi t y. Smal l subst i t uent s ( e. g. , hydr ogen, q- met hyl
gr oup) produce q- r ecept or act i vi t y, as wi t h nor epi nephr i ne; l ar ger subst i t uent s (e. g. ,
i sopr opyl group) produce 8- r ecept or act i vi t y, as wi t h i sopr ot erenol .
c. Removal of t he par a (4) hydroxyl gr oup l eaves onl y q- recept or act i vi t y, as wi t h
phenyl ephr i ne.
P. 283


Table 13-1. Major Neurotransmitters in the Nervous System. Their Major
Postsynaptic Receptors. and Receptor Effects on Ionic Conductance and Second
Messenger (Signaling) Pathways
Neurotransmitter
Primary Receptor
Subtypes Effects of Receptor Stimulation
Acetylcholine Muscarinic M
1
(and
M
3
. M
5
)
Excitatory (|IP3/DAG)

Muscarinic M
2
(and
M
4
)
Inhibitory (|cAMP)

Nicotinic (N
1
and N
2
) Excitatory (|cation
conductance)
Dopamine D
1
(and D
5
) Excitatory (|cAMP;
|IP3/DAG)

D
2
(and D
3
. D
4
) Inhibitory (|cAMP; |K
¹

conductance)
GABA GABA
A
Inhibitory (|Cl
-
ion
conductance)

GABA
B
Mixed (cAMP modulation;
|Ca
2¹
; |K
¹
Iluxes)
Glutamate Ionotropic-NMDA Excitatory (|Ca
2¹
ion
conductance)

Ionotropic-
AMPA/Kainate
Excitatory (|cation
conductance)

Metabotropic Excitatory (|IP3/DAG;
modulate cAMP)
Histamine H
1
Excitatory (|IP3/DAG)
H
2
Excitatory (|cAMP)
Norepinephrine u
1
Excitatory (|IP3/DAG)
u
2
Inhibitory (|cAMP)
þ
1
Excitatory (|cAMP)
þ
2
Inhibitory in ANS (|cAMP)
þ
3
Excitatory (|cAMP)
Serotonin
(5HT)
5HT
1
Inhibitory (|cAMP)
5HT
2
Excitatory (|IP3/DAG)
5HT
(3/4/5/6/7)
Mixed (type 4.6.7 |cAMP)
Opioid peptides Mu (µ) Mixed (|cAMP; Ca
2¹
& K
¹

channel eIIects)

Delta (o) Mixed (|cAMP; Ca
2¹
& K
¹

channel eIIects)

Kappa (k) Mixed (|cAMP; Ca
2¹
& K
¹

channel eIIects)

Table 13-2. Some General Mechanisms of Drug Action in the Nervous System
Exemplified by the Adrenergic and Cholinergic Neurotransmitter Systems
Mechanism Adrenergic System Cholinergic System
1. Ganglionic
stimulation
Nicotine

2. Ganglionic blockade Hexamethonium.
trimethaphan

3. Inhibition oI
neurotransmitter
synthesis
Metyrosine.
carbidopa
Hemicholinium
4. Inhibition oI
neurotransmitter
release
Bretylium.
guanethidine
Botulinum toxin
5. Facilitation oI
neurotransmitter
release
Amphetamine.
tyramine
u-Iatrotoxin
6. Depletion oI
vesicular transmitter
storage
Reserpine Vesamicol
7. Blockade oI Cocaine. See note
a

neurotransmitter
reuptake
desipramine
8. Inhibition oI
neurotransmitter
metabolism
Clorgyline (inhibits
MAO-A)
b

Neostigmine and
other AChE
inhibitors

Selegiline (inhibits
MAO-B)


Tolcapone (inhibits
COMT)

9. Direct interaction
with postsynaptic
receptors
Adrenoceptor
agonists
Cholinergic
agonists

Adrenoceptor
antagonists
Cholinergic
antagonists
a
Reuptake is not a maior mechanism Ior termination oI acetylcholine's
action; most oI the released transmitter is metabolized by
acetylcholinesterase (AChE).

b
COMT (catechol-O-methyl transIerase); MAO-A. MAO-B (monoamine
oxidase-A. -B).

P. 284



Figure 13-1. Synthesis oI catecholamines Irom
the amino acid tyrosine. In the presence oI
tyrosine hydroxylase. (A) tyrosine is converted to
(B) dihydroxyphenylalanine (dopa). Further
substitutions permit the synthesis oI (C)
dopamine. (D) norepinephrine. and (E)
epinephrine.

Figure 13-2. Structural Iormulas oI representative
direct-acting sympathomimetic amines. (A)
Naphazoline. (B) terbutaline. (C) dobutamine.
P. 285


Table 13-3. Classification of Adrenoceptor Agonists and Antagonists*
Class Adrenoceptor Agonist Adrenoceptor Antagonist
A. Nonselective
A.1 Indirect-acting Tyramine
Ephedrine
Amphetamine
Cocaine
A.2 Direct-acting Norepinephrine Labetalol
Epinephrine Carvedilol
B. o-Receptor-Selective
B.1 Nonselective u Oxymetazoline Phenoxybenzamine
Xylometazoline
Tetrahydrozoline Phentolamine
B.2 Selective u
1
Phenylephrine Prazosin
Methoxamine Terazosin
Metaraminol Doxazosin
Indoramin
B.3 Selective u
2
Clonidine Rauwolscine
Guanabenz Yohimbine
GuanIacine Tolazoline
Rilmenidine
Moxonidine
u-Methyldopa
C. ß-Receptor-Selective
C.1 Nonselective þ Isoproterenol Propranolol
Nadolol
Pindolol
Carteolol
Timolol
Sotalol
Penbutolol
C.2 Selective þ
1
Xamoterol Acebutolol
Atenolol
Betaxolol
Celiprolol
Esmolol
Metoprolol
C.3 Selective þ
2
Metaproterenol Butoxamine
Fenoterol
Terbutaline

Albuterol
(Salbutamol)

Ritodrine
Salmeterol
Formoterol
Pirbuterol
Bitolterol
C.4 Selective þ
3
BRL37344;
CL316243
*
To describe the classiIication oI a particular drug. the receptor selectivity
class on the leIt is combined with the receptor activity descriptor on the top
oI the column; Ior example. tyramine is an indirect-acting adrenoceptor
agonist. and tolazoline is a selective u
2
-adrenoceptor antagonist.

P. 286


d. The met a ( 3) hydr oxyl gr oup i s essent i al f or di r ect q- and 8- act i vi t y. However ,
dr ugs i n whi ch t he met a hydr oxyl i s r epl aced by a met hoxy gr oup ( e. g. ,
met hoxami ne) r et ai n q- act i vi t y.
e. Cat echol ami nes ar e i nact i vat ed by met hyl at i on of t he met a hydroxyl gr oup
( cat al yzed by cat echol O- met hyl t r ansf er ase [ COMT] ) and by oxi dat i ve deami nat i on
( cat al yzed by monoami ne oxi dase [ MAO] ) .
2. I ndi rect - act i ng adrenergi c agoni sts are chemi cal l y r el at ed t o t he
cat echol ami nes, but t hey do not si gni f i cant l y i nt er act di rect l y wi t h adr energi c
r ecept or s. These most l y synt het i c compounds i nduce t hei r phar macol ogi cal ef f ect s
by enhanci ng t he rel ease of t he endogenous neur ot r ansmi t t ers. Physi ol ogi cal l y,
t her ef ore, t hey have ef f ect s si mi l ar t o t he cat echol ami ne neurot r ansmi t t ers, hence
t hei r ni ckname of sympat homi met i c ami nes. Exampl es i ncl ude amphet ami ne,
ephedr i ne, phenyl ephri ne, and t yrami ne ( Fi gure 13- 3).
a. Ì ndi rect - act i ng sympat homi met i c ami nes may have t wo, one, or no hydroxyl
gr oups. The f ewer t he hydr oxyl gr oups, t he hi gher t he l i pophi l i ci t y, and t he gr eat er
t he absor pt i on and t he dur at i on of act i vi t y af t er or al admi ni st r at i on. Fast er and
gr eat er absor pt i on al so i mpl i es l ess i nt est i nal dest r uct i on of t he dr ug.
b. Al kyl subst i t ut i on at t he q- car bon (adj acent t o t he ami no group) r et ar ds
dest r uct i on of phenol and phenyl compounds and i ncr eases l i pophi l i c charact er ,
cont r i but i ng t o pr ol onged act i vi t y.
c. N-subst i t ut i on wi t h bul ky gr oups i ncreases di r ect 8- recept or act i vi t y, as wi t h t he
di r ect act i ng agent s.
B. PharmacoI ogy
1. Adrenergi c peri pheraI responses ar e medi at ed by bot h q- and 8-adr enocept or s
( Tabl e 13- 4). Adrener gi c ( and ot her ANS) r ecept or s may be l ocat ed at t he cel l
membr anes of ner ve t ermi nal s ( pr ej unct i onal recept ors) or at t he membranes of
post j unct i onal cel l s whi ch r ecei ve t he neur al i nput f r om t he ner ve t ermi nal s.
Pr ej unct i onal and post j unct i onal recept or s are al so cal l ed presynapt i c and
post synapt i c recept or s, respect i vel y, wher e bot h t he prej unct i onal cel l and t he
post j unct i onal cel l are ner ve cel l s separ at ed by a synapt i c space.
a. o- Receptors f al l i nt o t wo mai n groups.
( 1) Post j unct i onaI o1- adrenergi c recept ors ar e f ound i n t he r adi al smoot h muscl e
of t he i r i s; i n t he ar t er i es, ar t er i ol es, and vei ns; i n t he pi l omot or smoot h muscl e of
hai r f ol l i cl es; i n t he heart ; and i n t he sphi nct er s of t he gast roi nt est i nal ( GÌ ) t r act .
Dr ugs t hat ar e o1-seI ecti ve agoni st s cause exci t at or y r esponses such as
vasoconst ri ct i on and smoot h muscl e cont ract i on, and i ncl ude phenyl ephri ne and
met hoxami ne.
( 2) Prej uncti onaI o2-adrenergi c receptors medi at e t he i nhi bi t i on of adrener gi c
neurot r ansmi t t er r el ease. Dr ugs t hat ar e o2- seI ect i ve agoni sts al so i nhi bi t l i pol ysi s
i n f at cel l s and pr omot e pl at el et aggregat i on. Exampl es of such drugs i ncl ude
cl oni di ne and guanabenz.

Figure 13-3. Chemical structures oI some
indirect-acting sympathomimetic amines. (A)
Hydroxyamphetamine (Paredrine). (B) ephedrine
or pseudoephedrine (SudaIed). (C)
methamphetamine (Methedrine). (D) tyramine.
P. 287


Table 13-4. Adrenoceptor-Mediated Responses to Adrenergic Agonists
Organ/Tissue
Receptor
Type Response
Heart þ
1
Increases conduction velocity (dromotropic)
þ
1
Increases contraction Iorce (inotropic)
þ
1
Increases contraction rate (chronotropic)
Arterioles u
1
Constricts cerebral arterioles
u
1
Constricts cutaneous arterioles
u
1
Constricts visceral arterioles
þ
2
Dilates skeletal muscle arterioles
Eye u
1
Contracts iris sphincter muscle. producing
mydriasis
Lung þ
2
Relaxes tracheal and bronchial muscles
Intestine u. þ Decreases peristalsis
u
1
Contracts sphincters
Urinary
bladder
u
1
Contracts trigone and sphincter muscles.
inhibiting micturition
Uterus þ
1
Relaxes detrusor muscle
u
1
Excites uterine contractions
þ
2
Inhibits uterine contractions
Adipose
tissue
þ
3
Causes adipolysis; mobilizes Iatty acids

b. ß- Recept ors f al l i nt o t hr ee mai n groups.
( 1) Post j unct i onaI ß1-adrenergi c recept ors ar e f ound mai nl y i n t he myocar di um,
wher e t hei r st i mul at i on i ncr eases myocari dal conduct i on speed (dr omot r opi c ef f ect )
and t he f orce ( i not r opi c ef f ect ) and r at e (chronot r opi c ef f ect ) of myocar di al
cont r act i on. Dr ugs t hat ar e ß1-seI ect i ve agoni sts i ncl ude xamot er ol and t o some
ext ent dobut ami ne.
( 2) Post j unct i onaI ß2-adrenergi c recept ors ar e f ound i n t he smoot h muscl e of t he
vascul at ur e, bronchi ol es, and ut er us; st i mul at i on of t hese recept or s causes smoot h-
muscl e rel axat i on. Drugs t hat are ß2-seI ecti ve agoni sts i ncl ude al but erol and
t er but al i ne.
( 3) Post j unct i onaI ß3-adrenergi c recept ors ar e expr essed on f at cel l s, and t hei r
st i mul at i on causes l i pol ysi s. A number of 83- agoni st s ar e under devel opment as
pot ent i al t r eat ment s f or obesi t y, non- i nsul i n- dependent di abet es mel l i t us, and
f r equent uri nat i on.
2. Di rect - act i ng adrenergi c agoni st s ( e. g. , norepi nephr i ne, phenyl ephr i ne,
cl oni di ne, t er but al i ne) produce t hei r ef f ect s pri mar i l y by di r ect st i mul at i on of
adr ener gi c r ecept ors. They may be r ecept or- sel ect i ve, as wi t h t he dr ugs l i st ed
pr evi ousl y, or t hey may be nonsel ect i ve. For exampl e, t he adrener gi c
neurot r ansmi t t er norepi nephri ne af f ect s al l adr ener gi c recept or s, especi al l y q1- , q2- ,
and 81- r ecept ors, wher eas t he adrenal medul l ar y hormone epi nephr i ne af f ect s q1-,
q2- , 81- , and 82- recept ors. Ì sopr ot er enol af f ect s bot h 81- and 82- r ecept ors but not q-
r ecept or s.
3. I ndi rect - act i ng adrenergi c agoni sts wor k t hrough ot her pr i mar y mechani sms,
whi ch ul t i mat el y l ead t o r ecept or ef f ect s. For exampl e, t yrami ne act s by rel easi ng
nor epi nephr i ne f rom st orage si t es i n adr ener gi c neur ons, whi l e cocai ne bl ocks t he
r eupt ake of nor epi nephri ne, t hereby i ncreasi ng t he durat i on and act i vi t y of t he
t r ansmi t t er at t he synapse.
4. Cer t ai n agoni st s ( e. g. , ephedri ne, met ar ami nol , mephent ermi ne) pr oduce t hei r
ef f ect s t hr ough bot h di r ect and i ndi r ect mechani sms.
C. Therapeut i c i ndi cati ons
1. Epi nephri ne, an q- and 8- adr ener gi c agoni st , i s i ndi cat ed t o t reat bronchospasm
and hypersensi t i vi t y react i ons and i s t he agent of choi ce f or anaphyl act i c react i ons.
Ì t i s used t o
P. 288

pr ol ong t he act i vi t y of l ocal anest het i c sol ut i ons and t o rest or e car di ac act i vi t y i n
car di ac ar r est . Epi nephr i ne i s al so used t opi cal l y i n t he t r eat ment of gl aucoma,
pr esumabl y decr easi ng i nt r aocul ar pr essur e by enhanci ng t he out f l ow of aqueous
humor and t hr ough vasoconst ri ct i on- i nduced decr ease i n pr oduct i on of aqueous
humor . Local appl i cat i on of epi nephr i ne i s used t o ar rest bl ood f l ow i n epi st axi s and
gi ngi val sur ger y.
2. PhenyI ephri ne, an q1- sel ect i ve agoni st , i s used t o pr ovi de pr essor act i vi t y i n
hypot ensi ve emergenci es, t o prol ong t he act i vi t y of l ocal anest het i c sol ut i ons, and
t o r el i eve par oxysmal at ri al t achycar di a. Phenyl ephr i ne or phenyl pr opanol ami ne i s
gi ven syst emi cal l y f or nasal decongest i on. Oxymet azol i ne and xyl omet azol i ne, al so
q- r ecept or agoni st s, ar e appl i ed l ocal l y t o rel i eve nasal congest i on.
3. CI oni di ne and reI ated o2- sel ect i ve agoni st s (e. g. , met hyl dopa, guanf aci ne,
guanabenz) are used as ant i hyper t ensi ves based on t hei r i nhi bi t i on of cent r al
sympat het i c out f l ow. Apracl oni di ne i s used t opi cal l y i n t he eye t o decr ease
i nt raocul ar pressure dur i ng sur ger y.
4. I soproterenoI , a 8- adr energi c agoni st , i s used as a br onchodi l at or and as a
car di ac st i mul ant i n shock and cardi ac ar r est .
5. Dobut ami ne, a r el at i vel y ß1-sel ect i ve agoni st , i s used t o i mpr ove myocar di al
f unct i on i n congest i ve hear t f ai l ure, especi al l y i n emer gency si t uat i ons.
6. Ter but al i ne and ot her ß2- sel ect i ve agoni st s ( e. g. , met aprot erenol , al but er ol ,
bi t ol t er ol , sal met er ol ) are used as syst emi c or l ocal br onchodi l at ors i n t he t r eat ment
of bronchospast i c condi t i ons such as ast hma.
7. The ß2- sel ect i ve agoni st s, especi al l y ri t odr i ne, may be used t o r el ax ut er i ne
smoot h muscl e i n t he t r eat ment of pr emat ur e l abor .
D. Adverse ef f ect s. Adrenergi c agoni st s may cause car di ac dysrhyt hmi as, cer ebr al
hemor r hage, pul monar y hyper t ensi on and edema, anxi et y, headache, and r ebound
nasal congest i on.
III. ADRENERGIC ANTAGONISTS
A. Chemi st r y
1. o- Adrenergi c ant agoni st s ( q- bl ockers) have var i ed st ruct ur es and bear l i t t l e
r esembl ance t o t he adr ener gi c agoni st s. Ant agoni st s i ncl ude t he er got al kal oi ds
( e. g. , ergot ami ne) , t he di benzami nes ( e. g. , phenoxybenzami ne) , t he benzol i nes
( e. g. , t ol azol i ne) , and t he qui nazol i nes ( e. g. , prazosi n) ( Fi gure 13- 4) .
2. ß- Adrenergi c ant agoni st s ( 8- bl ocker s) ar e st r uct ur al l y si mi l ar t o 8- agoni st s
( Fi gur e 13- 5) . The catechoI ri ng can be r epl aced by a vari et y of ot her r i ng syst ems
wi t hout l oss of ant agoni st i c act i vi t y. The l engt h of t he si de chai n i s i mpor t ant and
t he si de chai n hydr oxyl , as wel l as a pr opyl or ot her bul ky subst i t ut i on on t he chai n
ni t rogen, ar e essent i al f or i nt eract i on wi t h 8- recept ors.
B. PharmacoI ogy
1. Adrener gi c ant agoni st s i nhi bi t or bl ock adr energi c r ecept or -medi at ed r esponses.

Figure 13-4. The structural Iormulas oI (A)
phenoxybenzamine (Dibenzyline) and (B)
prazosin (Minipress). representative u-blockers.
P. 289



Figure 13-5. The structural Iormulas oI (A)
propranolol (Inderal); (B) pindolol (Visken); (C)
atenolol (Tenormin). and (D) timolol (Blocadren).
representative þ-blockers.
2. o- Adrenergi c ant agoni st s may be q1-sel ect i ve ( e. g. , pr azosi n) or nonsel ect i ve
( e. g. , phenoxybenzami ne) . Phenoxybenzami ne i s an i r rever si bl e ant agoni st because
i t f or ms coval ent bonds wi t h q- r ecept or s, t her eby i nact i vat i ng t he recept or s.
3. ß- Adrenergi c ant agoni st s may be 81- sel ect i ve ( e. g. , met oprol ol ) or nonsel ect i ve
( e. g. , propranol ol ) . Gener al l y, however , 81-sel ect i ve agent s may l ose t hei r
sel ect i vi t y at hi gher doses and t hus bl ock 82- recept ors as wel l ( a pot ent i al pr obl em
i n ast hmat i cs).
C. Therapeut i c i ndi cati ons
1. Prazosi n and r el at ed q1- sel ect i ve ant agoni st s ( e. g. , doxazosi n, t er azosi n,
t r i mazosi n, al f uzosi n) produce vasodi l at i on ( by bl ocki ng basal vascul ar t one
mai nt ai ned by ci rcul at i ng cat echol ami ne act i vat i on of vascul ar q1- recept ors) . They
ar e t hus i mpor t ant ant i hyper t ensi ve agent s. They ar e al so usef ul i n t he sympt omat i c
t r eat ment of beni gn pr ost at i c hyper pl asi a.
P. 290



Figure 13-6. The structural Iormula oI
acetylcholine.
2. Phenoxybenzami ne and phentoI ami ne ( nonsel ect i ve q- bl ocker s) can be used t o
r el i eve vasospasm i n Raynaud' s syndr ome and f or acut e hypert ensi ve emer genci es
r esul t i ng f r om pheochr omocyt oma or f r om i nt ake of MAO i nhi bi t or s or
sympat homi met i cs. Tol azol i ne, a si mi l ar agent , i s used t o t r eat persi st ent neonat al
pul monar y hyper t ensi on.
3. LabetaI oI , an agent t hat possesses bot h sel ect i ve q1- bl ocki ng act i vi t y and
nonsel ect i ve 8-bl ocki ng act i vi t y, i s used i n t he t reat ment of hypert ensi on.
4. PropranoI oI , a nonsel ect i ve 8- ant agoni st , i s used f or t he prophyl axi s of angi na
pect or i s, supr avent r i cul ar and vent ri cul ar dysr hyt hmi as, and mi gr ai ne headache. Ì t
i s al so used as an ant i hyper t ensi ve, a negat i ve i not r opi c agent i n hypert r ophi c
obst r uct i ve car di omyopat hy, and a negat i ve chr onot r opi c agent i n anxi et y and
hyper t hyr oi di sm.
5. 81- Sel ect i ve ant agoni st s ( e. g. , met opr ol ol , bet axol ol , at enol ol , acebut ol ol ) ar e
used i n t he t r eat ment of hyper t ensi on, t achyar r hyt hmi as, and angi na.
6. Bot h 81-sel ect i ve ( bet axol ol ) and nonsel ect i ve ( t i mol ol ) bl ockers decrease ci l i ar y
body product i on of aqueous humor and may be used i n t he t opi cal t reat ment of
gl aucoma.
D. Adverse ef f ect s
1. Prazosi n can cause sudden syncope wi t h t he f i r st dose, or t host at i c hypot ensi on,
di zzi ness, headache, dr owsi ness, pal pi t at i ons, f l ui d ret ent i on, and pri api sm.
2. Phenoxybenzami ne can cause or t host at i c hypot ensi on, t achycar di a, i nhi bi t i on of
ej acul at i on, mi osi s, and nasal congest i on.
3. PropranoI oI can cause br adycardi a and congest i ve hear t f ai l ur e, i ncreased
ai r way r esi st ance, i ncr eased ser um t ri gl ycer i des, decreased hi gh-densi t y l i popr ot ei n
chol est erol , bl ood dyscrasi as, psori asi s, depressi on, hal l uci nat i ons, and t r ansi ent
heari ng l oss. Sudden wi t hdr awal can be car di ot oxi c due t o rebound
sympat homi met i c act i vi t y.
4. Met oproI oI has adverse ef f ect s si mi l ar t o t hose of pr opr anol ol , except t hat i t i s
l ess l i kel y t o i ncr ease ai r way r esi st ance gi ven i t s 81- sel ect i vi t y.
IV. CHOLINERGIC AGONISTS
A. Chemi st r y
1. Acet yI choI i ne, t he nat ur al endogenous medi at or and t he most pot ent chol i nergi c
agoni st , i s an est er of acet i c aci d and chol i ne÷a quat er nar y ami no al cohol ( Fi gure
13- 6). Acet yl chol i ne i n t he bl ood i s unst abl e as i t i s qui ckl y i nact i vat ed t hr ough
hydr ol ysi s by acet yl chol i nest er ase. Thus, i t i s ext r emel y shor t act i ng and usual l y i s
not a sat i sf act or y t her apeut i c agent .
2. Therapeut i caI I y usef uI choI i nergi c agoni st s may be di r ect act i ng or i ndi rect
act i ng.
a. Di rect - act i ng agoni sts may be pr oduced by r epl aci ng t he acet yl gr oup of
acet yl chol i ne wi t h a car bamoyl gr oup or by subst i t ut i ng a met hyl group of t he 8-
car bon. These subst i t ut i ons pr oduce compounds t hat ar e mor e resi st ant to
acet yI choI i nesterase and t hus have l onger dur at i ons of act i on. Such st abl e
agoni st s i ncl ude met hachol i ne ( Pr ovochol i ne) and bet hanechol ( Urechol i ne) ( Fi gur e
13- 7).

Figure 13-7. Clinically useIul direct-acting
cholinergic agonists include (A) methacholine
chloride (Provocholine) and (B) bethanechol
chloride (Urecholine).
P. 291



Figure 13-8. The structural Iormula oI
neostigmine bromide (Prostigmin). a reversible
acetylcholinesterase inhibitor.
b. I ndi rect - acti ng agoni st s ar e gener al l y acet yl chol i nest er ase i nhi bi t ors and ar e
di vi ded i nt o t wo maj or cl asses.
( 1) Reversi bI e ( short- act i ng) agent s ar e pri nci pal l y carbamat es ( car bami c aci d
est er s), such as physost i gmi ne (Eser i ne) , neost i gmi ne, and ambenoni um (Met yl ase)
( Fi gur e 13- 8) .
( 2) I rreversi bI e ( I ong- act i ng) agent s ar e pri nci pal l y or ganophosphat e est ers, such
as echot hi ophat e ( Phosphol i ne) ( Fi gure 13- 9) .
B. PharmacoI ogy
1. ChoI i nergi c responses are medi at ed by bot h muscar i ni c and ni cot i ni c r ecept or s
( Tabl e 13- 5).
a. PNS muscari ni c recept ors ar e pr esent at parasympat het i c post j unct i onal
neuroef f ect or si t es.
b. PNS ni coti ni c receptors are present at t he gangl i a of bot h t he par asympat het i c
and sympat het i c br anches of t he ANS and al so at t he neur omuscul ar j unct i ons of
t he somat i c ner vous syst em.
2. ChoI i nergi c agoni sts act by mi mi cki ng the act i vi t y of endogenous
acet yI choI i ne at muscari ni c and ni cot i ni c recept or si t es.
a. Di rect - act i ng agoni sts i nt er act di rect l y wi t h t hese r ecept ors.
b. I ndi rect - acti ng agoni st s i nhi bi t or bl ock t he act i vi t y of chol i nest erase enzymes
( e. g. , acet yl chol i nest er ase, but yr yl chol i nest erase) , whi ch br eak down endogenous
acet yl chol i ne t o i nact i ve met abol i t es. Thus, f ol l owi ng physi ol ogi cal rel ease of
acet yl chol i ne f r om ner ve t ermi nal s, t hese agent s al l ow t he neurot r ansmi t t er t o
accumul at e at chol i nergi c synapses, t hereby enhanci ng chol i ner gi c recept or
st i mul at i on. Or ganophosphat e chol i nest erase i nhi bi t ors, such as cert ai n agr i cul t ur al
i nsect i ci des and t he so-cal l ed ner ve gases, can be ext r emel y t oxi c as t hey bi nd t o
t he enzyme t o f orm an i rr ever si bl e or l ong-l ast i ng enzyme i nhi bi t or compl ex.
C. Therapeut i c i ndi cati ons
1. Di rect - act i ng agoni sts ar e i ndi cat ed t o:
a. Ì ni t i at e mi ct uri t i on i n acut e nonobst r uct i ve uri nar y r et ent i on ( e. g. , bet hanechol )
b. Pr oduce mi osi s i n t he t r eat ment of gl aucoma (e. g. , pi l ocarpi ne)
2. Ì ndi rect - act i ng agoni st s are i ndi cat ed t o:
a. Pr oduce mi osi s i n t he t r eat ment of gl aucoma (e. g. , physost i gmi ne, echot hi ophat e)
b. Ai d i n t he di f f er ent i al di agnosi s of myast heni a gr avi s ( a di sease caused by
ni cot i ni c r ecept or hypof unct i on at t he neur omuscul ar j unct i on) and hyperchol i nergi c
cr i si s ( whi ch produces depol ar i zat i on bl ockade of t he neur omuscul ar j unct i on) .
Edr ophoni um i s used f or t hi s pur pose.
c. Tr eat myast heni a gr avi s (e. g. , ambenoni um, neost i gmi ne, pyr i dost i gmi ne)
d. Count eract i nt oxi cat i on or adverse ef f ect s f r om compounds wi t h ant i chol i nergi c
act i vi t y ( e. g. , physost i gmi ne)
e. Ì mprove cogni t i ve f unct i on i n Al zhei mer ' s di sease pat i ent s ( e. g. , t acr i ne,
donepezi l , gal ant ami ne, and ri vast i gmi ne)
f . Tr eat par al yt i c i l eus or cardi ac t archyar r yt hmi as ( e. g. , edrophoni um) .

Figure 13-9. The structural Iormula oI
isoIlurophate (Floropryl). an irreversible
acetylcholinesterase inhibitor.
P. 292


Table 13-5. Cholinoceptor-Mediated Responses to Cholinergic Agonists
Organ Response
Heart

Atrioventricular node Decreased conduction velocity
(negative dromotropy)

Atria. ventricles Decreased contraction Iorce
(negative inotropy)

Sinoatrial node Decreased contraction rate (negative
chronotropy)
Eye
Sphincter muscle Contraction. producing miosis

Ciliary muscle Contraction. accommodates Ior near
vision
Lung
Bronchial muscle Contraction (bronchoconstriction)
Bronchial glands Increased secretion
Gastrointestinal tract
Intestine Increased motility (peristalsis)
Sphincters Relaxation oI sphincters
Glands Increased secretions
Urinary bladder
Detrusor muscle Contraction
Trigone and sphincter Relaxation
Glands (sweat. salivary.
nasopharyngeal. lacrimal)
Increased glandular secretion

D. Adverse ef f ect s
1. Topi caI adverse ef f ect s i ncl ude congest ed conj unct i vae, myopi c accommodat i on,
and t r ansi ent l ent i cul ar opaci t y.
2. Syst emi c adverse ef fect s i ncl ude headache, syncope, nausea, vomi t i ng,
br adycar di a, hypot ensi on, bronchospasm, abdomi nal cr amps, di ar rhea, epi gast ri c
di st r ess, sal i vat i on, sweat i ng, l acr i mat i on, f l ushi ng, and t r emors.
V. CHOLINERGIC ANTAGONISTS
bl ock t he act i ons of acet yl chol i ne at muscar i ni c or ni cot i ni c chol i nocept ors.
A. Chemi st r y
1. At ropi ne, an al kal oi d ext r act ed f r om t he bel l adonna pl ant , i s t he pr ot ot ypi cal
chol i ner gi c ant agoni st ( ant i chol i ner gi c agent ). A por t i on of t he at ropi ne mol ecul e i s
st r uct ur al l y si mi l ar t o acet yl chol i ne ( Fi gure 13- 10) , permi t t i ng t he mol ecul e t o bi nd
t o post j unct i onal r ecept or s.
P. 293

However , t he mol ecul e has no i nt ri nsi c act i vi t y, and i t s bul ky shape pr event s
acet yl chol i ne f r om bi ndi ng t o t he r ecept or .

Figure 13-10. Structural Iormula oI atropine. a
cholinergic antagonist.

Figure 13-11. Structural Iormula oI propantheline
bromide (Pro-Banthine). a synthetic cholinergic
antagonist.
2. Synt het i c ant i choI i nergi c agent s (e. g. , di cycl omi ne [ Bent yl ] , gl ycopyrr ol at e
[ Robi nul ] , pr opant hel i ne [ Pr o- Bant hi ne] , pi r enzepi ne and t r opi cami de) are al so
avai l abl e. These agent s, l i ke at r opi ne, ar e bul ky anal ogues of acet yl chol i ne ( Fi gur e
13- 11) .
3. An i mport ant f act or t hat det ermi nes t he pharmacol ogi c spect r um of
ant i chol i nergi c agent s i s t he pr esence of a quaternar y ni t rogen ( as i n
pr opant hel i ne, gl ycopyr r ol at e, and i prat ropi um), whi ch r educes passage acr oss t he
bl ood- brai n bar r i er , or a t ert i ar y ni t rogen ( as i n di cycl omi ne, pi renzepi ne,
t r opi cami de, and benzt r opi ne) , whi ch per mi t s a broader vol ume of di st ri but i on ( or
accessi bi l i t y t o a wi der range of t i ssues) .
B. PharmacoI ogy
1. Chol i nergi c ant agoni st s compet i t i veI y i nhi bi t t he act i vi t y of endogenous
acet yl chol i ne.
2. Ant agoni st s t hat i nhi bi t muscari ni c recept or - medi at ed responses ar e cal l ed
ant i muscari ni c agents; t hose t hat i nhi bi t ni cot i ni c r ecept or -medi at ed r esponses at
t he gangl i a ar e cal l ed gangI i oni c-bI ocki ng agent s, wher eas t hose t hat i nhi bi t
ni cot i ni c r ecept or - medi at ed r esponses at t he neuromuscul ar j unct i on ar e cal l ed
neuromuscuI ar-bI ocki ng agent s.
C. Therapeut i c i ndi cati ons
1. Ant i muscari ni c agent s are i ndi cat ed t o:
a. Reduce gl andul ar and br onchi ol ar secr et i ons bef or e anest hesi a ( e. g. , at r opi ne,
gl ycopyr r ol at e)
b. Ì nduce sedat i on ( e. g. , scopol ami ne)
c. Al l evi at e mot i on si ckness ( e. g. , scopol ami ne)
d. Reduce vagal st i mul at i on of t he myocar di um (e. g. , at r opi ne)
e. Pr oduce opht hal mi c mydr i asi s and cycl opl egi a ( e. g. , homat r opi ne)
f . Reduce GÌ smoot h- muscl e spasms ( e. g. , pr opant hel i ne)
g. Tr eat br onchospasm associ at ed wi t h chroni c obst ruct i ve pul monar y di sease ( e. g. ,
i pr at r opi um)
h. Cont r ol Parki nson' s di sease sympt oms and some neurol ept i c-i nduced
ext r apyr ami dal r eact i ons ( e. g. , benzt r opi ne, t r i hexypheni dyl )
i . Tr eat i nt oxi cat i on by chol i nergi c agoni st s or by acut e mushroom poi soni ng ( e. g. ,
at r opi ne)
2. GangI i oni c-bI ocki ng agents are i ndi cat ed t o t r eat hyper t ensi ve cr i si s (e. g. ,
t r i met haphan, mecamyl ami ne, hexamet honi um) . By bl ocki ng gangl i oni c
t r ansmi ssi on, t hese agent s r educe sympat het i c act i vi t y, r esul t i ng i n a hypot ensi ve
ef f ect .
D. Adverse ef f ect s
1. Topi caI adverse ef f ect s i ncl ude hyper opi c accommodat i on and i ncr eased
i nt raocul ar pressure.
2. Syst emi c adverse ef fect s i ncl ude headache, ner vousness, dr owsi ness,
di zzi ness, pal pi t at i ons, t achycar di a, dr y mout h, mydr i asi s, bl ur r ed vi si on, nausea,
vomi t i ng, const i pat i on, ur i nar y ret ent i on, and f ever .
P. 294



Figure 13-12. Structural Iormula oI tubocurarine
chloride (Tubarine). a competitive
nondepolarizing agent.
VI. NEUROMUSCULAR BLOCKING AGENTS
act by bl ocki ng t he ef f ect s of acet yl chol i ne at t he ner ve-muscl e j unct i on of skel et al
muscl es.
A. Chemi st r y
1. NeuromuscuI ar bI ocki ng agent s can be compet i t i ve (as wi t h t he prot ot ypi cal
cur ar e al kal oi ds) or depol ar i zi ng (as wi t h succi nyl chol i ne) . Member s of ei t her
cat egor y ul t i mat el y pr event t he act i on of acet yl chol i ne at ni cot i ni c r ecept or s l ocat ed
i n t he ner ve-muscl e j unct i on.
2. The compet i t i ve nondepoI ari zi ng agent s i ncl ude t he nat ural l y occurr i ng
al kal oi ds of curare, whi ch ar e bul ky and r i gi d mol ecul es, as wel l as several
synt het i c anal ogues.
a. The pri nci paI acti ve aI kaI oi d i n cur are i s t ubocurar i ne (Fi gur e 13-12). A cl osel y
r el at ed t r i met hyl at e der i vat i ve i s met ocur i ne ( Met ubi ne) . Thei r most i mpor t ant
st r uct ur al f eat ure i s t he pr esence of a t er t i ar y- quat er nar y ami ne i n whi ch t he
di st ance bet ween t he t wo cat i ons i s ri gi dl y f i xed at about t wi ce t he l engt h of t he
cr i t i cal recept or - bi ndi ng moi et y of acet yl chol i ne.
b. A number of pot ent synt het i c anaI ogues have been devel oped. These i ncl ude
t he st ruct ur al l y si mi l ar i soqui noI i nes at r acuri um ( Tr acr i um) , doxacuri um (Nur omax) ,
and mi vacuri um ( Mi vacr on) , as wel l as t he steroi d deri vat i ves pancur oni um
( Pavul on) , vecuroni um (Nor curon), and pi pecur oni um ( Arduan) .
3. The noncompet i t i ve depoI ari zi ng agent s i ncl ude succi nyl chol i ne ( Anect i ne) and
gal l ami ne ( Fl axedi l ) ( Fi gur e 13- 13) .
a. Unl i ke t he l arge, bul ky compet i t i ve agent s, noncompet i t i ve agent s are sl ender
al i phat i c mol ecul es.
b. Succi nyI choI i ne has a shor t durat i on of act i on compar ed wi t h t he ot her
neuromuscul ar bl ocki ng agent s. Thi s r esul t s f r om i t s si mpl e est er f unct i onal gr oup,
whi ch i s rapi dl y hydrol yzed by pl asma and l i ver pseudochol i nest erase
( but yr yl chol i nest er ase). Ì t s act i on may be pr ol onged, however , i n pat i ent s wi t h an
abnor mal genet i c vari ant of pseudochol i nest er ase, whi ch has onl y about 20% t he
act i vi t y of normal pseudochol i nest er ase.
B. PharmacoI ogy
1. The compet i t i ve nondepoI ari zi ng agent s compet e wi t h acet yl chol i ne f or
ni cot i ni c r ecept or s at t he neuromuscul ar j unct i on. These agent s decrease t he end-
pl at e pot ent i al so t hat t he depol ar i zat i on t hr eshol d i s not reached. Compet i t i ve
nondepol ari zi ng agent s pr oduce
P. 295

a sur mount abl e bl ockade of neuromuscul ar t r ansmi ssi on i n t hat admi ni st rat i on of
chol i nest erase i nhi bi t or s or prej unct i onal r el ease of a l ar ge quant i t y of acet yl chol i ne
can r el i eve t he bl ockade.

Figure 13-13. Structural Iormula oI
succinylcholine chloride. a noncompetitive
depolarizing agent.
2. The noncompet i t i ve depoI ari zi ng agent s desensi t i ze t he ni cot i ni c r ecept ors at
t he neuromuscul ar j unct i on. These agent s r eact wi t h t he ni cot i ni c r ecept or s,
decreasi ng recept or sensi t i vi t y i n a manner si mi l ar t o t hat of excess rel eased
acet yl chol i ne. They depol ar i ze t he exci t abl e membr ane f or a pr ol onged per i od ( 2- 3
mi nut es) ; t he membr ane t hen becomes unr esponsi ve ( desensi t i zed) .
C. Therapeut i c i ndi cati ons. NeuromuscuI ar bI ocki ng agents, whi ch cause onl y
skel et al muscl e par al ysi s ( t he pat i ent r emai ns consci ous and capabl e of sensat i on) ,
ar e used t o:
1. Pr omot e skel et al muscl e r el axat i on and f aci l i t at e endot r acheal i nt ubat i on, as an
adj unct t o sur gi cal anest hesi a
2. Li mi t t he t r auma t hat coul d resul t f r om excessi ve skel et al muscl e cont ract i on
dur i ng el ect roconvul si ve shock t her apy
3. Rel ax t he skel et al muscl es and f aci l i t at e bone pl acement and mani pul at i ons
dur i ng or t hopedi c pr ocedur es
D. Adverse ef f ect s
1. Compet i t i ve nondepoI ari zi ng agent s can cause r espi r at or y paral ysi s, hi st ami ne
r el ease, br onchospasm, and hypot ensi on ( e. g. , t ubocurar i ne) or r espi r at or y
par al ysi s, t achycardi a, and hyper t ensi on ( e. g. , pancur oni um) .
2. Noncompet i ti ve depoI ari zi ng agent s (e. g. , succi nyl chol i ne, gal l ami ne) can
cause r espi rat or y paral ysi s, muscl e f asci cul at i on wi t h pai n, ext r aocul ar muscl e
cont r act i on wi t h i ncr eased i nt r aocul ar pr essur e, and i ncreased i nt r agast r i c pr essur e.
Ì n addi t i on, succi nyl chol i ne may cause muscar i ni c r esponses such as br adycar di a,
i ncreased gl andul ar secret i ons, and cardi ac ar r est . Ì n combi nat i on wi t h t he
anest het i c hal ot hane, succi nyl chol i ne may cause mal i gnant hyper t her mi a i n
genet i cal l y predi sposed i ndi vi dual s.
VII. GENERAL ANESTHETICS
i nduce a combi ned st at e of anal gesi a, amnesi a, l oss of consci ousness, i nhi bi t i on of
sensor y and aut onomi c ref l exes, and skel et al muscl e rel axat i on. Ì deal gener al
anest het i cs i nduce anest hesi a rapi dl y and smoot hl y and per mi t rapi d recover y of t he
pat i ent once admi ni st r at i on of t he agent ceases.
A. Chemi st r y
1. VoI at i I e or i nhaI ati on anest heti cs are drugs i nhal ed as gases or vapor s. These
di ver se dr ugs ar e rel at i vel y si mpl e l i pophi l i c mol ecul es. They i ncl ude t he i nor gani c
agent ni t r ous oxi de ( N2O) and t he nonf I ammabI e hal ogenat ed hydr ocarbons (e. g. ,
hal ot hane) and et hers (e. g. , met hoxyf l ur ane, i sof l ur ane, desf l ur ane, sevof l ur ane) .
2. NonvoI at i I e or i nt ravenous anesthet i cs ar e admi ni st er ed i nt r avenousl y or
occasi onal l y i nt r amuscul ar l y and come as aqueous sol ut i ons, aqueous propyl ene
gl ycol sol ut i ons, or emul si ons.
a. The water- soI ubI e and r el at i vel y shor t - act i ng agent s i ncl ude ul t r a-short - act i ng
bar bi t urat es (e. g. , t hi opent al , met hohexi t al , t hi amyl al ) , cycl ohexyl ami nes (e. g. ,
ket ami ne), benzo- di azepi nes ( e. g. , di azepam, mi dazol am) , but yr ophenones (e. g. ,
dr oper i dol ), and opi oi d anal gesi cs (e. g. , morphi ne, f ent anyl ) .
b. The i mi dazol e, et omi dat e, i s prepared as an aqueous propyI ene gI ycoI
soI ut i on, whi ch i s compat i bl e wi t h many preanest het i cs.
c. The di al kyl phenol , pr opof ol , i s admi ni st ered as an emuI si on, whi ch shoul d not be
mi xed wi t h ot her t her apeut i c agent s bef or e admi ni st rat i on (Fi gur e 13-14).
B. PharmacoI ogy
1. GeneraI anest het i cs depress t he CNS, pr oduci ng a r eversi bl e l oss of
consci ousness and l oss of al l f orms of sensat i on.
P. 296



Figure 13-14. Structural Iormulas oI nonvolatile
general anesthetics: (A) thiopental sodium
(Pentothal). (B) ketamine hydrochloride
(Ketaiect). (C) Ientanyl citrate (Sublimaze). (D)
midazolam (Versed). (E) etomidate (Amidate).
and (F) propoIol (Diprivan).
2. I nhaI at i onaI anest heti cs ar e absor bed and pri mar i l y excr et ed t hr ough t he l ungs.
Fr equent l y, t hese dr ugs ar e suppl ement ed wi t h anal gesi cs, a skel et al muscl e
r el axant , and an ant i muscar i ni c agent .
a. AnaI gesi cs per mi t a reduct i on i n t he r equi red concent r at i on of i nhal at i onal
anest het i c.
b. SkeI etaI muscI e reI axant s cause adequat e muscl e r el axat i on duri ng sur ger y.
c. Ant i muscari ni c agent s decrease buccal and br onchi ol ar secr et i ons.
3. NonvoI at i I e anestheti cs ar e usual l y admi ni st er ed i nt r avenousl y ( e. g. ,
t hi obarbi t ur at es, benzodi azepi nes) , but some agent s may al so be gi ven
i nt ramuscul ar l y (e. g. , ket ami ne) .
C. Therapeut i c i ndi cati ons
1. I nhaI at i onaI anest heti cs ar e i ndi cat ed t o provi de gener al sur gi cal anest hesi a.
2. NonvoI at i I e anestheti cs (e. g. , t hi opent al , di azepam, mi dazol am) ar e i ndi cat ed t o
i nduce drowsi ness and pr ovi de r el axat i on bef or e t he i nduct i on of i nhal at i onal
gener al anest hesi a.
P. 297


3. Use of some previ ousl y popul ar vol at i l e anest het i cs has been di scont i nued
because of seri ous t oxi ci t y ( e. g. , chl or of or m) or because of t he f l ammabl e and
expl osi ve pr oper t i es of t he compounds (e. g. , cycl opropane, di et hyl et her ) .
D. Adverse ef f ect s. Gener al anest het i cs depress r espi rat i on, ci r cul at i on, and t he
CNS. They can al so decrease hepat i c and ki dney f unct i on (e. g. , met hoxyf l ur ane)
and cause car di ac dysr hyt hmi as as a resul t of i ncr eased myocar di al sensi t i vi t y t o
cat echol ami nes (e. g. , hal ot hane) .
VIII. LOCAL ANESTHETICS
A. Chemi st r y. Most l ocal anest het i cs ar e st ruct ural l y si mi l ar t o t he al kal oi d cocai ne
( Fi gur e 13- 15) . These drugs consi st of a hydr ophi l i c ami no gr oup l i nked t hr ough an
est er or ami de connect i ng gr oup t o a l i pophi l i c aromat i c moi et y. A f ew phenol s and
ar omat i c al cohol s al so have l ocal anest het i c act i vi t y.
1. Est er -t ype agent s are gener al l y shor t act i ng due t o r api d hydr ol ysi s by pl asma
est er ases. These agent s i ncl ude cocai ne, procai ne, chl or opr ocai ne, benzocai ne,
but amben, and t et r acai ne.
2. Ami de- t ype agent s are general l y l onger act i ng and ar e met abol i zed i n t he l i ver .
Exampl es of t he ami de- t ype l ocal anest het i cs i ncl ude l i docai ne, di bucai ne,
pr i l ocai ne, mepi vacai ne, bupi vacai ne, and et i docai ne.
3. The dr ug' s pKa ( or di ssoci at i on const ant ) i nf l uences i t s chemi cal st at e, whi ch i n
t ur n det er mi nes t he anest het i c ef f ect i veness of t he compound. The si t e of
anest het i c act i on i s at t he i nner sur f ace of t he cel l membr ane. At t i ssue pH, t he
dr ug i s i n t he f or m of a l i pophi l i c, unchar ged, secondar y or t er t i ar y ami ne, and t hus
di f f uses across connect i ve t i ssue and cel l membranes and ent er s ner ve cel l s wher e
i t i s i oni zed t o a charged ammoni um cat i on. The cat i oni c f orm of t he dr ug i s t he
act i ve f or m of t he dr ug t hat bl ocks t he generat i on of act i on pot ent i al s at t he
membr ane r ecept or compl ex. Al so, because of i t s charged ammoni um cat i on, t he
i nt racel l ul ar i oni zed mol ecul e poor l y penet r at es t he cel l membr ane and t hus remai ns
t r apped wi t hi n t he cel l , t her eby enhanci ng i t s durat i on of act i on.
B. PharmacoI ogy
1. Local anest het i cs reversi bI y bI ock nerve i mpuI se conducti on and produce
reversi bI e I oss of sensat i on at t hei r admi ni st r at i on si t e. They do not pr oduce a
l oss of consci ousness.
a. Smal l , nonmyel i nat ed ner ve f i ber s, whi ch conduct pai n and t emper at ure
sensat i ons, are af f ect ed f i r st .
b. Local anest het i cs appear t o become ent r apped wi t hi n t he ner ve membrane or t o
bi nd t o speci f i c membrane sodi um i on ( Na
+
) channel s, r est r i ct i ng Na
+
per meabi l i t y i n
r esponse t o par t i al depol ar i zat i on.
2. Local anest het i c sol ut i ons f requent l y cont ai n t he vasoconst ri ct or epi nephri ne,
whi ch r educes vascul ar bl ood f l ow at t he admi ni st r at i on si t e. Thi s pr ol ongs t he
dur at i on of act i on, and reduces syst emi c absor pt i on, and hence syst emi c t oxi ci t y.

Figure 13-15. Structural Iormulas oI local
anesthetics structurally similar to cocaine: (A)
procaine (Novocaine) and (B) lidocaine
(Xylocaine).
P. 298


C. Therapeut i c i ndi cati ons. Local anest het i cs ar e i ndi cat ed t o:
1. Pr oduce regi onal ner ve bl ock f or t he rel i ef of pai n when i nj ect ed cl ose t o t he
i nner vat i ng ner ve
2. Pr ovi de anest hesi a f or mi nor oper at i ons when i nf i l t rat ed around t he t i ssue si t e
3. Pr ovi de anest hesi a f or surger y of t he l ower l i mbs and pel vi s and f or obst et r i c
sur ger y when i nj ect ed i nt o t he epi dur al space or t he subar achnoi d space of t he
spi nal cor d
4. Pr ovi de anest hesi a of t he ski n and mucous membr anes when appl i ed l ocal l y. Thi s
i ncl udes t wo mi scel l aneous l ocal anest het i cs: dycI oni ne, used pr i mar i l y i n t hr oat
l ozenges and spr ays, and pramoxi ne, used pr i mar i l y i n ant i hemor rhoi dal
pr epar at i ons.
D. Adverse ef f ect s
1. Est er -t ype l ocal anest het i cs can cause hyper sensi t i vi t y r eact i ons i n suscept i bl e
i ndi vi dual s.
2. Syst emi c absorpt i on of t oxi c concent r at i ons of l ocal anest het i cs can cause
sei zures; CNS, respi rat or y, and myocar di al depressi on; and ci rcul at or y col l apse.
IX. ANTIPSYCHOTICS.
The cl assi c ant i psychot i c agent s ar e t he phenot hi azi nes, t hi oxant henes, and
but yr ophenones. Chemi cal cl asses of newer compounds havi ng ant i psychot i c
act i vi t y i ncl ude t he di hydr oi ndol ones (e. g. , mol i ndone) , di benzoxazepi nes ( e. g. ,
l oxapi ne), di benzodi azepi nes ( e. g. , cl ozapi ne) , di phenyl but yl pi peri di nes (e. g. ,
pi mozi de) , and benzi soxazol es ( e. g. , r i sper i done) .
A. Chemi st r y
1. Phenot hi azi nes (e. g. , chl or pr omazi ne, t ri f l upromazi ne, t hi or i dazi ne,
pr ochl or per azi ne, t ri f l uoper azi ne, f l uphenazi ne) must have a ni t rogen-cont ai ni ng
si de-chai n substi t uent on t he ri ng ni t r ogen f or ant i psychot i c act i vi t y ( Tabl e 13- 6).
The r i ng and si de-chai n ni t rogens must be separat ed by a t hr ee-car bon chai n;
phenot hi azi nes i n whi ch t he ri ng and si de-chai n ni t r ogens ar e separ at ed by a t wo-
car bon chai n have onl y ant i hi st ami ni c or sedat i ve act i vi t y.
a. The si de chai ns are ei t her al i phat i c, pi per azi ne, or pi per i di ne der i vat i ves.
Pi perazi ne si de chai ns conf er t he great est pot ency and t he hi ghest pharmacol ogi cal
sel ect i vi t y.
b. Fl uphenazi ne and l ong- chai n al cohol s f orm st abl e, hi ghI y I i pophi I i c est ers (e. g. ,
enant hat e, decanoat e) , whi ch possess mar kedl y pr ol onged act i vi t y.
2. Thi oxant henes ( e. g. , chl or prot hi xene, t hi ot hi xene) l ack t he r i ng ni t r ogen of
phenot hi azi nes and have a si de chai n at t ached by a doubl e bond ( Fi gure 13- 16) .
3. But yrophenones (e. g. , hal operi dol ) are chemi cal l y unrel at ed t o phenot hi azi nes
but have si mi l ar act i vi t y ( Fi gur e 13- 17) .
4. Newer agent s deri ve f r om di verse chemi cal cl asses and i ncl ude cl ozapi ne,
ol anzapi ne, l oxapi ne, pi mozi de, mol i ndone, quet i api ne, r i sper i done, remoxi pr i de,
zi pr asi done and ari pi prazoI e.
B. PharmacoI ogy
1. These agent s have gener al l y si mi I ar pharmacodynami c ef f ect s i n t he t r eat ment of
psychot i c i l l ness. Thei r ant i psychot i c act i on ( i . e. , i mprovement of cogni t i ve and
behavi or al abnor mal i t i es) r esul t s pr i mari l y f rom t hei r bl ockade of dopami ne
r ecept or s i n cort i cal and l i mbi c ar eas of t he br ai n, wher eas t hei r adverse
ext r apyr ami dal ef f ect s such as par ki nsoni an r eact i ons r esul t f rom ant agoni sm of
dopami ne r ecept ors i n t he basal gangl i a.
2. Ot her ef f ect s var y among t he cl asses of ant i psychot i cs. These i ncl ude ant i emet i c
act i vi t y and bl ockade of muscar i ni c, ser ot oner gi c, q1- adrener gi c, and H1-
hi st ami ner gi c r ecept ors.
3. The at ypi cal ant i psychot i cs ( e. g. , cl ozapi ne, ar i pi prazol e) are newer agent s t hat
show st rong ant agoni st i c pr oper t i es at ser ot oni n recept ors i n addi t i on t o t hei r
bl ockade of dopami ne r ecept ors. Compar ed t o t he phenot hi azi nes, but yr ophenones,
and ot her cl assi c ant i psychot i c drugs, t he at ypi cal agent s ar e ef f ect i ve i n
amel i or at i ng a wi der r ange of sympt oms, i ncl udi ng negat i ve sympt oms, and t hey
al so are l ess l i kel y t o i nduce ext r apyr ami dal si de ef f ect s.
P. 299


Table 13-6. Antipsychotic Phenothiazines
General Phenothiazine Structure
`


Drug X-
Substituent
R-Substituent
`

Chlorpromazine
(Thorazine)
-Cl -(CH
2
)
3
-N(CH
3
)
2

TriIlupromazine
(Vesprin)
-CF
3
-(CH
2
)
3
-N(CH
3
)
2

Thioridazine
(Mellaril)
-SCH
3


Prochlorperazine
(Compazine)
-Cl

TriIluoperazine
(Stelazine)
-CF
3


Fluphenazine
(Prolixin)
-CF
3


*
Antipsychotic phenothiazines have the general structure illustrated in the
table. Substituents at positions marked X and R result in diIIerent drugs.


Figure 13-16. Thioxanthenes. similar to
phenothiazines. have substituents at X and R
positions that alter drug activity.
Chlorprothixene (Taractan) has a Cl
substituent at X and CH(CH
2
)
2
N(CH
3
)
2

at R. Thiothixene (Navane) has aSO
2

N(CH
3
)
2
substituent at X and the group:

Figure 13-17. Structural Iormula oI haloperidol
(Haldol). a butyrophenone antipsychotic.
P. 300



Figure 13-18. Structural Iormulas oI (A)
phenelzine (Nardil). a hydralazine derivative
monoamine oxidase (MAO) inhibitor. and (B)
tranylcypromine (Parnate). a cyclopropylamine
derivative MAO inhibitor.
C. Therapeut i c i ndi cati ons. Ant i psychot i cs ar e i ndi cat ed pr i mari l y f or t he t r eat ment
of psychosi s associ at ed wi t h schi zophr eni a ( e. g. , hal oper i dol , ari pi pr azol e) ,
par anoi a, and Tour et t e' s syndrome ( e. g. , pi mozi de) . Pr omet hazi ne and ot her cl assi c
agent s ar e used as ant i emet i cs based on t hei r bl ockade of dopami ne recept ors i n
t he chemor ecept or t r i gger zone of t he medul l a and i n t he st omach.
D. Adverse ef f ect s
1. Cent raI I y medi at ed adverse ef fects i ncl ude dr owsi ness; ext r apyr ami dal
sympt oms such as akat hi si a, acut e dyst oni a, aki nesi a, and t ardi ve dyski nesi a;
al t er at i on of t emperat ur er egul at i ng mechani sms i ncl udi ng poi ki l ot her my; i ncr eased
appet i t e and wei ght gai n; and al t erat i ons i n hypot hal ami c and endocr i ne f unct i on
such as i ncr eased rel ease of cor t i cot ropi n, gonadot r opi ns, pr ol act i n, gr owt h
hor mone, and mel anocyt e- st i mul at i ng hormone.
2. Peri pheraI adverse ef f ect s i ncl ude post ur al hypot ensi on and r ef l ex t achycar di a;
hepat ot oxi ci t y and j aundi ce; f ai l ur e of ej acul at i on; bone mar row depr essi on;
phot osensi t i vi t y; xer ost omi a; and bl urr ed vi si on.
X. ANTIDEPRESSIVE AND ANTIMANIC AGENTS
may be broadl y cl assi f i ed i nt o f i ve st r uct ur al l y and mechani st i cal l y unrel at ed
gr oups: t he MAO i nhi bi t or s, cl assi cal or t r i cycl i c ant i depr essant s, sel ect i ve
ser ot oni n r eupt ake i nhi bi t or s ( SSRÌ s) , t hi rd- generat i on or at ypi cal ant i depressant s,
and ant i mani c ant i depr essant s or mood st abi l i zer s.
A. Chemi st r y
1. MAO i nhi bi t ors may be weakl y pot ent hydraI azi nes ( e. g. , phenel zi ne) or
ext r emel y pot ent phenyI cycI opropyI ami nes such as t ranyl cypr omi ne whi ch i s a
r i ng-cl osed amphet ami ne deri vat i ves (Fi gur e 13-18) .
2. Tri cycI i c ant i depr essant s, whi ch are used commonl y, ar e secondar y or t ert i ar y
ami ne deri vat i ves of mol ecul es t hat have a f used t hr ee- r i ng syst em.
a. The pr i nci pal t ri cycl i c ant i depr essant s are der i vat i ves of di benzazepi ne ( e. g. ,
i mi prami ne, desi prami ne, cl omi pr ami ne, t r i mi pr ami ne) and di benzocycl ohept adi ene
( e. g. , ami t r i pt yl i ne, nor t ri pt yl i ne, prot r i pt yl i ne) ( Fi gur es 13- 19 and 13- 20) .

Figure 13-19. Structural Iormulas oI tricyclic
antidepressants derived Irom dibenzazepine: (A)
imipramine (ToIranil) and (B) desipramine
(Norpramin).
P. 301



Figure 13-20. Structural Iormulas oI tricyclic
antidepressants derived Irom
dibenzocycloheptadiene: (A) amitriptyline
(Elavil) and (B) nortriptyline (Aventyl).
b. Ot her cl osel y r el at ed t r i cycl i c ant i depr essant s i ncl ude doxepi n, a di benzoxepi ne,
and amoxapi ne, a di benzoxazepi ne.
3. At ypi caI ant i depr essant s have vari ed st r uct ures r angi ng f r om t he si mpl e
phenet hyl ami ne venl af axi ne and t he phenyl pi per azi ne nef azodone t o t he
ami noket one bupr opi on and t he compl ex het er ocycl i cs mapr ot i l i ne and mi r t azepi ne.
4. SSRI s have var i ed chemi cal st r uct ur es and are r el at ed onl y by t hei r
pharmacol ogi cal l y common abi l i t y t o i nhi bi t t he reupt ake of ser ot oni n f r om t he
synapt i c cl ef t . These compounds i ncl ude f l uoxet i ne, par oxet i ne, sert r al i ne, and
f l uvoxami ne ( Fi gur e 13- 21) .
5. Li thi um i s an al kal i met al t hat i s used i n t he f or m of t he carbonat e sal t i n t he
t r eat ment of mani c depressi on or bi pol ar di sease. Ot her agent s i n t hi s t her apeut i c
cat egor y i ncl ude t he or gani c compounds vaI proi c aci d and carbamazepi ne.
B. PharmacoI ogy
1. MAO i nhi bi t ors appear t o pr oduce t hei r ant i depr essant ef f ect s by bl ocki ng t he
i nt raneur onal oxi dat i ve deami nat i on of brai n bi ogeni c ami nes ( e. g. , dopami ne,
nor epi nephr i ne, serot oni n) . Thi s act i on i ncr eases t he avai l abi l i t y of bi ogeni c ami nes
at cent r al ami ner gi c synapses, and hence t he probabi l i t y of i nt eract i on wi t h
post synapt i c recept or s t o el i ci t t he desi red t herapeut i c ef f ect s. Ot her bi ochemi cal
event s ( e. g. , t he down- r egul at i on of cent r al 8-adr energi c and serot onergi c
r ecept or s) t hat r esul t f r om chr oni c i nhi bi t i on of MAO and reupt ake bl ockade can al so
expl ai n t he t herapeut i c act i on of ant i depr essant s. Thi s expl anat i on i s suggest ed by
t he l at ency peri od of MAO i nhi bi t ors, whi ch t ake 2- 4 weeks t o become ef f ect i ve.
2. Tri cycI i c ant i depr essant s appear t o act pr i nci pal l y by r educi ng CNS neur onal
r eupt ake of t he bi ogeni c ami nes nor epi nephr i ne and ser ot oni n. Thi s pr ol ongs t he
synapt i c avai l abi l i t y of bi ogeni c ami nes and hence t hei r act i on at cent ral ami nergi c
r ecept or s.

Figure 13-21. Structural Iormulas oI (A)
trazodone (Desyrel) and (B) Iluoxetine (Prozac).
atypical antidepressants.
P. 302


3. SSRI s and at ypi caI ant i depressant s have varyi ng ef f ect s on r eupt ake of bi ogeni c
ami nes. The SSRÌ s sel ect i vel y i nhi bi t serot oni n reupt ake i nt o t he ner ve t er mi nal ,
t hus prol ongi ng t he synapt i c act i vi t y of t he ami ne. Tr azodone and ot her
het erocycl i cs al so i nhi bi t ami ne t r ansmi t t er r eupt ake. Whi l e bupr opi on appears t o
sel ect i vel y i nhi bi t dopami ne r eupt ake, i t s mechani sm may i nvol ve addi t i onal
cur rent l y unknown act i ons si nce some ot her i nhi bi t or s of dopami ne r eupt ake may
not exhi bi t ant i depr essi ve ef f ect s.
4. Li thi um appear s t o i nt er f ere wi t h t r ansmembrane Na
+
exchange, al t ers t he
r el ease of ami ner gi c neur ot r ansmi t t ers, and bl ocks i nosi t ol met abol i sm, ul t i mat el y
l eadi ng t o depl et i on of cel l ul ar i nosi t ol and i nhi bi t i on of phosphol i pase C-medi at ed
si gnal t r ansduct i on. The r el evance of t hese act i ons t o t he mood-st abi l i zi ng ef f ect s
of l i t hi um, however , has not been est abl i shed. Carbamazepi ne and vaI proi c aci d
ar e known t o i nt erf er e wi t h i oni c conduct ances i n ner ve cel l s, and t o modul at e ot her
i nt racel l ul ar si gnal i ng cascades, but t he cont ri but i ons of t hese act i ons t o t hei r
cl i ni cal ef f ect i veness i n bi pol ar di sor der r emai n uncl ear .
C. Therapeut i c i ndi cati ons
1. MAO i nhi bi t ors are i ndi cat ed t o t reat depr essi on, phobi c anxi et y, and nar col epsy
t hat has not responded t o ot her t r eat ment s. However , t hei r use i s l i mi t ed by t hei r
adver se ef f ect s (see X. D. 1) .
2. Tri cycI i c and at ypi caI ant i depr essant s and t he SSRÌ s are t he agent s of choi ce
f or endogenous depressi on. Addi t i onal l y, i mi pr ami ne i s used t o t r eat enuresi s;
cl omi pr ami ne, f l uoxet i ne, and f l uvoxami ne are used i n obsessi ve-compul si ve
di sor der ; and doxepi n, f or anxi et y.
3. Li thi um and vaI proi c aci d are i ndi cat ed f or t he t r eat ment of mani c- depr essi on
( or bi pol ar di sease) . The ant i epi l ept i c dr ug, carbamazepi ne, has al so been used as
a mood-st abi l i zer i n bi pol ar i l l ness.
D. Adverse ef f ect s
1. MAO i nhi bi t ors i nt eract wi t h sympat homi met i c dr ugs and wi t h f oods t hat have a
hi gh t yr ami ne cont ent such as cheese, wi ne, and sausage. Hyper t ensi ve cr i ses can
r esul t . Ì n addi t i on, MAO i nhi bi t ors can cause a wi de r ange of adverse ef f ect s,
i ncl udi ng:
a. CNS ef f ect s, such as CNS st i mul at i on, t remors, agi t at i on, overact i vi t y,
hyper r ef l exi a, mani a, and i nsomni a f ol l owed by weakness, f at i gue, and dr owsi ness
b. Cardi ovascul ar ef f ect s, such as post ural hypot ensi on
c. GÌ ef f ect s, such as nausea, abdomi nal pai n, and const i pat i on
d. Ant i muscari ni c ef f ect s, such as dr y mout h, ur i nar y r et ent i on, and const i pat i on
2. Tri cycI i c ant i depr essant s can cause adver se ef f ect s, i ncl udi ng:
a. CNS ef f ect s, such as dr owsi ness, di zzi ness, weakness, f at i gue, and conf usi on
b. Cardi ovascul ar ef f ect s, such as or t host at i c hypot ensi on, t achycardi a, and
i nt er f erence wi t h at r i ovent r i cul ar conduct i on
c. Ant i muscar i ni c ef f ect s, such as dr y mout h, ur i nar y r et ent i on, and const i pat i on
d. GÌ ef f ect s, such as nausea, vomi t i ng, di ar rhea, and anor exi a
e. Bone mar row depressi on
f . Mani a preci pi t at i on ( i n pat i ent s wi t h mani c- depr essi ve i l l ness)
3. At ypi caI ant i depr essant s can cause adverse ef f ect s, i ncl udi ng:
a. CNS ef f ect s, such as di zzi ness, ni ght mar es, conf usi on, dr owsi ness, f at i gue,
headache, i nsomni a, i mpai r ed memor y, akat hi si a, numbness, and t oni c- cl oni c
sei zures
b. Cardi ovascul ar ef f ect s, such as hyper t ensi on, hypot ensi on, t achycardi a, chest
pai n, and syncope
c. GÌ ef f ect s, such as nausea, vomi t i ng, di ar rhea, and const i pat i on
d. Bl ur r ed vi si on and t i nni t us
e. Ant i muscar i ni c ef f ect s, such as uri nar y r et ent i on, dr y mout h, and const i pat i on
f . Bone mar row depr essi on
g. Sexual dysf unct i on and menst r ual i r r egul ar i t i es
4. Li thi um t her apy may be associ at ed wi t h devel opment of f i ne hand t remors and
i ncreased uri nat i on; t hese si de ef f ect s, however , usual l y di mi ni sh wi t h cont i nued
t her apy.
P. 303


XI. ANXIOLYTICS AND SEDATIVE-HYPNOTICS.
Ant i anxi et y and sedat i ve- hypnot i c agent s i n cur rent use compri se t he hi ghl y
ef f ect i ve benzodi azepi nes ( e. g. , al pr azol am, di azepam, f l urazepam) and t he at ypi cal
azaspi r odecanedi ones (e. g. , buspi r one) and i mi dazopyr i di nes ( e. g. , zol pi dem) .
Di ver se cl asses of agent s previ ousl y used as anxi ol yt i cs and sedat i ve- hypnot i cs
( e. g. , bar bi t urat es, meprobamat e, and hydr oxyzi ne) are no l onger f avor ed because
of t hei r l i abi l i t y t o pr oduce t ol er ance, physi cal dependence, sever e wi t hdrawal
r eact i ons, and seri ous t oxi ci t y wi t h over dosage.
A. Chemi st r y
1. Benzodi azepi nes ( e. g. , al prazol am, di azepam, chl or di azepoxi de, cl onazepam,
cl orazepat e, l or azepam, and oxazepam) have varyi ng dur at i ons of act i on, whi ch can
be cor rel at ed wi t h t hei r st r uct ur es i n some cases ( Tabl e 13- 7).
a. Agent s wi t h a 3-hydr oxyl gr oup ar e easi l y met abol i zed by phase Ì Ì
gl ucuroni dat i on and ar e short act i ng ( see R3- subst i t uent col umn i n Tabl e 13- 7).
b. Agent s l acki ng a 3-hydr oxyl gr oup must undergo consi derabl e phase Ì
met abol i sm, i ncl udi ng 3-hydr oxyl at i on. These agent s are l ong act i ng. Most l ong-
act i ng agent s f or m t he i nt er medi at e met abol i t e desmet hyl di azepam, whi ch has a
ver y l ong hal f -l i f e. Thus, t hese agent s can have a cumul at i ve act i on.
c. Tr i azol obenzodi azepi nes (e. g. , al prazol am) under go a di f f erent pat t er n of
met abol i sm and are i nt ermedi at e i n act i vi t y.
d. Agent s l acki ng an ami no si de chai n ar e not basi c enough t o f or m wat er- sol ubl e
sal t s wi t h aci ds. For exampl e, i nt ravenous sol ut i ons of di azepam cont ai n pr opyl ene
gl ycol as a sol vent . Preci pi t at i on can occur i f t hese sol ut i ons ar e mi xed wi t h
aqueous sol ut i ons.
2. Azaspi rodecanedi ones or azapi rones ( e. g. , buspi rone, gepi rone, i psapi rone,
t i aspi r one) are chemi cal l y unr el at ed t o t he benzodi azepi nes. Represent ed by
buspi rone, t hese agent s have anxi ol yt i c act i vi t y resembl i ng t hat of t he
benzodi azepi nes. Unl i ke t he benzodi azepi nes, buspi r one l acks CNS depressant
act i vi t y and i s consi dered an at ypi cal anxi ol yt i c (Fi gur e 13- 22) .
3. The i mi dazopyri di ne zol pi dem i s a nonbenzodi azepi ne sedat i ve- hypnot i c wi t h
act i ons gener al l y r esembl i ng t hose of t he benzodi azepi nes.
4. Barbi t urates ar e 5, 5-di subst i t ut ed der i vat i ves of bar bi t uri c aci d, a sat ur at ed
t r i ket opyr i mi di ne ( Tabl e 13- 8).
a. Two si de chai ns i n posi t i on 5 ar e essent i al f or sedat i ve- hypnot i c act i vi t y.
b. Long-act i ng agent s have a phenyl and an et hyl gr oup i n posi t i on 5.
c. Branched si de chai ns, unsat ur at ed si de chai ns, or si de chai ns l onger t han an
et hyl gr oup i ncr ease l i pophi l i ci t y and met abol i sm r at e. Ì ncr eased l i pophi l i ci t y l eads
t o a shor t er onset of act i on, a short er dur at i on of act i on, and i ncr eased pot ency.
d. Repl acement of t he posi t i on 2 oxygen wi t h sul f ur produces an ext r emel y l i pophi l i c
mol ecul e t hat di st r i but es r api dl y i nt o l i pi d t i ssues out si de t he br ai n.
( 1) These ul t ra- shor t -act i ng barbi t ur at es ar e not usef ul as sedat i ve-hypnot i cs but
ar e ef f ect i ve i n f aci l i t at i ng t he i nduct i on of anest hesi a (see XÌ Ì . C. 4) . The act i on of
t hese dr ugs i s t ermi nat ed ver y qui ckl y.
( 2) The pr ot ot ype ul t ra-shor t -act i ng bar bi t urat e i s t hi opent al ( Pent ot hal ) , t he 2-t hi o
i sost er e of pent obar bi t al .
e. The bar bi t urat es and many of t hei r met abol i t es are weak aci ds, and changes i n
ur i nar y pH gr eat l y i nf l uence t hei r excr et i on. Thi s i s par t i cul ar l y t rue wi t h over doses,
when a r el at i vel y l ar ge amount of unchanged drug appear s i n t he gl omer ul ar f i l t r at e.
f . Phenobar bi t al i s one of t he most power f ul and ver sat i l e agent s t hat can i nduce
cer t ai n enzyme syst ems ( e. g. , t he cyt ochr ome P-450 met abol i c syst em). Thi s
i ncreases t he pot ent i al f or drug i nt er act i ons and i ncl udes i nt eract i on wi t h any dr ug
met abol i zed by t hi s syst em. Ot her barbi t ur at es have l ess enzyme- i nduci ng ef f ect ,
except when t hey are used cont i nuousl y i n hi gher - t han- nor mal doses.
5. Pi peri di nedi ones (e. g. , gl ut et hi mi de, met hypryl on) and aI dehydes ( e. g. ,
par al dehyde, chl oral hydr at e) di f f er st ruct ur al l y (Fi gur e 13- 23) and ar e used l ess
commonl y t han t he benzodi azepi nes as sedat i ve-hypnot i cs.
B. PharmacoI ogy
1. Benzodi azepi nes appear t o produce t hei r cal mi ng and hypnot i c ef f ect s by
depressi ng t he l i mbi c syst em and ret i cul ar f ormat i on t hrough pot ent i at i on of t he
i nhi bi t or y neur ot r ansmi t t er v-ami nobut yr i c aci d (GABA) .
P. 304


Table 13-7. Benzodiazepine Anxiolytics and Sedative-Hypnotics
General Benzodiazepine Structure
`


Drug R
1
R
2
R
3

X
(R
2
') Comments
Diazepam
(Valium)
CH
3
÷O H
H

Chlordiazepox
ide (Librium)
÷ (Ring
double
bond)

NH

CH
3

H
H
O
(N-
oxide)
at
positi
on 4
Halazepam
(Paxipam)
CH
2
CF
3
÷O H
H

Clorazepate
(Tranxene)
H ÷OH
(
OK)

COO
H (
COO
K)

H

Oxazepam
(Serax)
H ÷O OH
H

Lorazepam
(Ativan)
H ÷O OH
C
l

Alprazolam
(Xanax)
R1-
C(CH
3
)÷N
-N÷R2
(Fused R1-
R2 triazolo
ring)
H H

Flurazepam
(Dalmane)
CH
2
CH
2
N(
C
2
H
5
)
2

÷O H
F

Quazepam
(Doral)
CH
2
CF
3
÷S H
F

Triazolam
(Halcion)
R1-
C(CH
3
)÷N
-N÷R2
(Fused R1-
R2 triazolo
ring)
H H

Temazepam
(Restoril)
CH
3
÷O OH
H
*
Benzodiazepine anxiolytics and sedative-hypnotics have the general
structure illustrated in the table. Substituents at the positions marked R
1
.
R
2
. R
3
. R
7
. and X (R
2
') and the ring nitrogen at the position 2 result in
diIIerent drugs and clinical properties. All compounds shown have Cl
substitution at position R
7
. Clonazepam. not shown. has an NO
2

substituent at R
7
and is used primarily as an anticonvulsant.


Figure 13-22. Structural Iormula oI
buspirone (Buspar). the prototypical
azaspirodecanedione anxiolytic.
P. 305


Table 13-8. Barbiturate Sedative-Hypnotics
General Barbiturate Structure
`


Drug
R
1
-
Substitue
nt R
2
-Substituent
Duratio
n of
Action
Phen
obar
bital
(Lu
mina
l)
-
CH
2
CH
3


Lon
g
Amo
barb
ital
(Am
-
CH
2
CH
3

-CH
2
CH
2
CH(CH
3
)
2
Inte
rme
diat
e
ytal)
Buta
barb
ital
(But
isol)
-
CH
2
CH
3

Inte
rme
diat
e
Pent
obar
bital
(Ne
mbu
tal)
-
CH
2
CH
3

Sho
rt
Seco
barb
ital
(Sec
onal
)
-
CH
2
CH
÷C
H
2

Sho
rt
*
Barbiturate sedative-hypnotics have the general structure illustrated in the
table. Substituents at R
1
and R
2
positions result in diIIerent drugs with
diIIerent durations oI action.

a. Anxi ol yt i c act i vi t y cor rel at es wi t h t he drug' s bi ndi ng af f i ni t y t o a macromol ecul ar
compl ex consi st i ng of GABAA r ecept ors and chl or i de channel s.
b. The i nt er act i on of benzodi azepi nes wi t h GABA causes an i ncr ease i n t he
f r equency of chl ori de channel openi ng event s, l eadi ng t o a f aci l i t at i on of chl or i de
i on conduct ance, membrane hyperpol ar i zat i on, and ul t i mat el y synapt i c i nhi bi t i on.

Figure 13-23. Structural Iormulas oI (A)
glutethimide (Doriden). a piperidinedione
sedative-hypnotic and (B) chloral hydrate
(Noctec). an aldehyde sedative-hypnotic.
P. 306


c. Ì n addi t i on t o t hei r anxi ol yt i c proper t i es, most benzodi azepi nes have ot her
si gni f i cant CNS act i ons, i ncl udi ng hypnot i c, anest het i c, ant i convul sant , and muscl e
r el axant ef f ect s at appr opr i at e doses.
d. Benzodi azepi nes i ncrease t he depressant ef f ect s of al cohol and ot her CNS
depressant drugs.
2. Azaspi rodecanedi ones have mul t i pl e bi ochemi cal act i ons, but t hei r pr i nci pal
mechani sm of anxi ol yt i c ef f ect i s st i l l unknown.
a. Buspi rone bi nds t o cent r al dopami ne and serot oni n recept or s r at her t han t o
GABA- chl or i de i onophore r ecept or compl exes. Ì nt er act i ons of azapi r ones wi t h
ser ot oni n r ecept ors may be agoni st i c when act i ng at somat odendri t i c 5- HT1A
aut orecept or s or ant agoni st i c when act i ng at post synapt i c 5- HT1A r ecept or s.
b. Buspi r one possesses no hypnot i c or ant i convul sant pr oper t i es and does not
appear t o enhance t he depr essant ef f ect s of al cohol or ot her CNS depressant drugs.
c. Buspi r one has mi ni mal abuse l i abi l i t y and does not pr oduce rebound anxi et y
f ol l owi ng abr upt di scont i nuat i on.
3. The i mi dazopyri di nes have st rong sedat i ve ef f ect s wi t h mi ni mal cl i ni cal
anxi ol yt i c act i ons.
a. Zol pi dem i s as ef f ect i ve as t he benzodi azepi nes i n shor t eni ng sl eep l at ency and
i n pr ol ongi ng t ot al sl eep t i me i n pat i ent s wi t h i nsomni a.
b. Zol pi dem i s r ar el y associ at ed wi t h physi cal dependence, r ebound i nsomni a, or
r espi r at or y depr essi on even i n over dosage.
4. Barbi t urates ar e l ess sel ect i ve t han benzodi azepi nes and pr oduce gener al i zed
CNS depressi on.
a. Barbi t ur at es bi nd t o a si t e t hat i s di st i nct f rom t he benzodi azepi ne bi ndi ng si t e on
a macromol ecul ar GABA- chl or i de i onophor e r ecept or compl ex. Bar bi t urat e bi ndi ng
i nduces an i ncr ease i n t he dur at i on of channel openi ng event s, and t hus mi mi cs or
enhances t he i nhi bi t or y act i ons of GABA.
b. Barbi t ur at es have a wi de r ange of dose- dependent phar macol ogi cal act i ons
r el at ed t o CNS depr essi on, i ncl udi ng sedat i on, hypnosi s, and anest hesi a. They al so
act as pot ent r espi r at or y depressant s and i nducer s of hepat i c mi crosomal dr ug-
met abol i zi ng enzyme act i vi t y.
5. Pi peri di nedi ones, aI dehydes, and ot her nonbar bi t urat e sedat i ve- hypnot i cs have
si mi l ar pharmacol ogi cal act i ons rel at ed t o CNS depr essi on.
a. Chl or al hydrat e i s commonl y used t o i nduce sl eep i n pedi at r i c or ger i at r i c
pat i ent s. Ì t s l ow cost i s t he maj or f act or account i ng f or i t s pr ef er r ed usage i n
i nst i t ut i onal set t i ngs.
b. Chl or al hydrat e i s bi ot r ansf ormed t o t r i chl oroet hanol , whi ch i s r esponsi bl e f or t he
pharmacol ogi cal act i vi t y of t he dr ug. Chl or al hydrat e i nduces hepat i c mi crosomal
dr ug-met abol i zi ng enzyme act i vi t y.
C. Therapeut i c i ndi cati ons
1. Benzodi azepi nes and t he azaspi rodecanedi one buspi rone ar e i ndi cat ed t o
t r eat anxi et y. Buspi r one i s more ef f ect i ve i n pat i ent s wi t h general i zed anxi et y of
mi l d t o moder at e sever i t y. The ant i anxi et y ef f ect s of buspi r one may requi r e up t o a
week t o be est abl i shed.
2. Benzodi azepi nes and t he i mi dazopyri di ne are i ndi cat ed t o pr oduce dr owsi ness
and pr omot e sl eep.
3. Benzodi azepi nes are i ndi cat ed f or use as a pr eanest het i c medi cat i on, as
ant i convul sant s, and duri ng acut e al cohol wi t hdrawal .
4. Barbi t urates ar e no l onger consi der ed appropr i at e as anxi ol yt i cs or sedat i ve-
hypnot i cs i n vi ew of t he avai l abi l i t y of t he saf er benzodi azepi nes. Long- act i ng
bar bi t urat es cont i nue t o be wi del y used as ant i epi l ept i cs, whi l e t he ul t r a-shor t -
act i ng barbi t ur at es are used f or t he i nduct i on of gener al anest hesi a and as gener al
anest het i cs ( i n combi nat i on wi t h an anal gesi c) f or shor t surgi cal pr ocedures.
5. ChI oraI hydrat e i s i ndi cat ed f or use as a pedi at r i c or ger i at r i c hypnot i c, and al so
as a preanest het i c agent f or mi nor surgi cal and dent al procedur es.
P. 307


D. Adverse ef f ect s
1. Adverse ef f ect s associ at ed wi t h benzodi azepi nes i ncl ude:
a. CNS ef f ect s, such as CNS depressi on, dr owsi ness, sedat i on, at axi a, conf usi on,
and dysart hr i a
b. GÌ ef f ect s, such as nausea, vomi t i ng, and di ar rhea
c. Psychi at ri c ef f ect s ar e r ar e and i ncl ude par adoxi cal exci t ement , i nsomni a,
par anoi a, and r age react i ons
d. Pot ent i al f or abuse and dependence
2. Adverse ef f ect s of buspi rone are l i mi t ed t o r est l essness, di zzi ness, headache,
nausea, di ar rhea, and par est hesi as.
3. Barbi t urates can cause a var i et y of adverse ef f ect s, i ncl udi ng:
a. CNS ef f ect s, such as dr owsi ness, conf usi on, nyst agmus, dysar t hr i a, depr essed
sympat het i c gangl i oni c t ransmi ssi on, hyper al gesi a, i mpai red j udgment , i mpai red f i ne
mot or ski l l s, paradoxi cal exci t ement ( i n ger i at r i c pat i ent s) , and pot ent i at i on of ot her
CNS depressant dr ugs.
b. Respi r at or y and car di ovascul ar ef f ect s, such as r espi r at or y depr essi on,
br adycar di a, and ort host at i c hypot ensi on.
c. GÌ ef f ect s, such as nausea, vomi t i ng, const i pat i on, di ar r hea, and epi gast r i c
di st r ess.
d. Exf ol i at i ve dermat i t i s and St evens-Johnson syndr ome.
e. Headache, f ever , hepat ot oxi ci t y, and megal obl ast i c anemi a ( wi t h t he chr oni c use
of phenobar bi t al ).
4. Tri chI oroet hanoI , t he act i ve met abol i t e of chI oraI hydrat e, i s met abol i zed t o
t r i chl or oacet i c aci d, whi ch i s hi ghl y t oxi c and t ends t o accumul at e wi t h r epeat ed
admi ni st rat i on of chl oral hydr at e. Use of chl or al hydr at e i s associ at ed wi t h t he
f ol l owi ng adverse ef f ect s.
a. GÌ ef f ect s, such as GÌ i r r i t at i on and upset , nausea, and vomi t i ng.
b. CNS ef f ect s, such as CNS depressi on, di sori ent at i on, i ncoherence, drowsi ness,
at axi a, headache, and pot ent i at i on of ot her CNS depressant s ( part i cul ar l y al cohol ) .
c. Leukopeni a
XII. ANTIEPILEPTICS
A. Chemi st r y. Ant i epi l ept i cs ( ant i convul sant s) var y wi del y i n st r uct ure ( Fi gure 13-
24) .
1. OI der agent s, whi ch ar e st i l l wi del y used, i ncl ude deri vat i ves of t he l ong- act i ng
bar bi t urat es (e. g. , phenobar bi t al , mephobar bi t al , met har bi t al , pr i mi done) ,
hydant oi ns (e. g. , phenyt oi n, et hot oi n), succi ni mi des ( e. g. , et hosuxi mi de,
phensuxi mi de), oxazol i di nedi ones ( e. g. , t r i met hadi one, di met hadi one) , and
di al kyl acet at es ( e. g. , val pr oi c aci d) .
2. Newer agent s, whi ch ar e more st r uct ural l y di ver se, i ncl ude t he i mi nost i l benes
( e. g. , car bamazepi ne) , benzodi azepi nes (e. g. , di azepam, cl onazepam, cl or azepat e) ,
GABA anal ogs ( vi gabat ri n, gabapent i n, pregabal i n) , and t he mi scel l aneous agent s
l amot ri gi ne, f el bamat e, l evet i r acet am, zoni sami de, and t opi r amat e whi ch i s act ual l y
a subst i t ut ed monosacchar i de.
B. PharmacoI ogy
1. Ant i epi l ept i cs pr event or r educe excessi ve di schar ge and reduce t he spr ead of
exci t at i on f r om CNS sei zur e f oci .
2. The mechani sms of act i on of ant i epi l ept i cs appear t o be al t erat i on of Na
+

neuronal concent r at i ons by pr omot i on of Na
+
ef f l ux ( e. g. , hydant oi ns) and
r est or at i on or enhancement of GABA- er gi c i nhi bi t or y neur onal f unct i on ( e. g. ,
bar bi t urat es, benzodi azepi nes, val proi c aci d) .
C. Therapeut i c i ndi cati ons. These agent s ar e general l y cat egor i zed by t he t ype of
sei zure agai nst whi ch t hey ar e ef f ect i ve.
1. Dr ugs t hat are i ndi cat ed f or t he t r eat ment of toni c-cI oni c (grand maI ) sei zures
i ncl ude phenobar bi t al , phenyt oi n, pr i mi done, and carbamazepi ne.
2. Dr ugs t hat are i ndi cat ed f or t he t r eat ment of absence (pet i t maI ) sei zures
i ncl ude phenobar bi t al , et hosuxi mi de, t ri met hadi one, cl onazepam, and val pr oi c aci d.
P. 308



Figure 13-24. Structural Iormulas oI the
antiepileptic agents: (A) primidone (Mysoline).
(B) phenytoin (Dilantin). (C) ethosuximide
(Zarontin). (D) trimethadione (Tridione). (E)
clonazepam (Klonopin). (F) carbamazepine
(Tegretol). and (G) valproic acid (Depakene).
3. Cl onazepam i s i ndi cat ed f or t he t r eat ment of myocI oni c sei zures.
4. Agent s t hat ar e ef f ect i ve agai nst part i aI sei zures i ncl ude cl or azepat e, f el bamat e,
gabapent i n, and l amot r i gi ne.
5. Phenyt oi n, phenobarbi t al , pri mi done, and carbamazepi ne ar e ef f ect i ve agai nst
psychomot or sei zures.
6. Ì nt r avenous di azepam, phenyt oi n, and phenobar bi t al ar e i ndi cat ed f or t he
t r eat ment of stat us epi I ept i cus.
7. Topi ramat e has mul t i pl e mechani sms of act i on and exer t s benef i ci al ef f ect s
agai nst a br oad spect r um of sei zur es.
D. Adverse ef f ect s
1. Barbi t urates (see XÌ Ì . D. 3) and benzodi azepi nes (see XÌ Ì . D. 1) used as
ant i epi l ept i cs have t he same adverse ef f ect s as when used f or anxi ol yt i c or
sedat i ve-hypnot i c pur poses. Ì nt r avenous use of t hese agent s coul d cause
car di ovascul ar col l apse and respi rat or y depressi on.
P. 309


2. Ant i epi l ept i c agent s general l y have t he pr opensi t y t o cause t he f ol l owi ng si de
ef f ect s:
a. GÌ i r r i t at i on, nausea, and vomi t i ng
b. CNS sedat i on, di pl opi a, nyst agmus, at axi a, di zzi ness, and conf usi on
c. Bl ood dyscr asi as, i ncl udi ng apl ast i c anemi a and bl eedi ng di sor der s
d. Al l er gi c- t ype r eact i ons, i ncl udi ng St evens- Johnson syndr ome
e. Vari ous or gan-syst em t oxi ci t i es, i ncl udi ng r enal and l i verf ai l ure, pancreat i t i s, and
car di ot oxi ci t y
3. The hydant oi ns (e. g. , phenyt oi n) can al so cause speci f i c arrhyt hmi as and
gi ngi vaI hyperpI asi a.
4. Ant i epi l ept i cs as a cl ass al so have t he pot ent i al t o cause vari ous bi rt h def ect s,
i ncl udi ng cl ef t pal at e ( e. g. , carbamazepi ne, phenyt oi n) and neur al t ube def ect s
( e. g. , val pr oi c aci d) . These ef f ect s pr esent a uni que probl em i n t reat i ng pregnant
women wi t h convul si ve di sorders. Di scont i nuat i on of ant i convul sant t her apy can
r esul t i n a sei zure st at e t hat coul d har m t he f et us. However , cont i nued t her apy can
i ncrease t he r i sk of bi rt h def ect s and pl ace t he mot her at r i sk of bl eedi ng di sor der s
dur i ng del i ver y. Mor eover , pr egnancy by i t sel f can ei t her i ncrease or decrease
sei zure i nci dence of t he mot her . Ri sk/ benef i t eval uat i on of t herapy shoul d be made
on i ndi vi dual cases based on t he pat i ent ' s hi st or y.
XIII. ANTIPARKINSONIAN AGENTS
A. Chemi st r y. The pr i nci pal ant i parki nsoni an agent s are ei t her dopami nergi c
agoni st s or choI i nergi c ant agoni st s.
1. Some ant i choI i nergi c ant i parki nsoni an agent s are st r uct ur al l y r el at ed t o
at ropi ne ( e. g. , benzt r opi ne, t r i hexypheni dyl ). Ot her ant i parki nsoni an ant i chol i nergi c
agent s i ncl ude procycl i di ne ( Kemadr i n) , or phenadr i ne ( Nor f l ex) , and bi peri den
( Aki net on) .
2. The pr ot ot ypi cal dopami nergi c ant i par ki nsoni an agent i s t he catechoI ami ne
I evodopa ( Fi gure 13- 25), a pr odrug t hat must be convert ed i n vi vo t o dopami ne by
dopa decarboxyI ase. Di r ect r ecept or -act i ng dopami nergi cs i ncl ude ergoI i nes such
as br omocr i pt i ne ( Par l odel )
P. 310

and pergol i de ( Permax) , t he phenant hrene apomorphi ne, and t he newer
noner gol i ne dopami ne agoni st s prami pexoI e ( Mi r apex) and ropi ni roI e ( Requi p) .

Figure 13-25. Structural Iormulas oI
antiparkinsonian agents: (A) benztropine
(Cogentin). (B) trihexyphenidyl (Artane). (C)
ethopropazine (Parsidol). and (D) levodopa
(Larodopa).
3. Several agent s are avai l abl e t o i mprove t he t her apeut i c ef f i cacy and saf et y of
l evodopa.
a. Carbi dopa, a l evodopa anal ogue t hat does not cr oss t he bl ood- brai n bar r i er , i s a
decarboxyI ase i nhi bi t or t hat di mi ni shes t he decar boxyl at i on and subsequent
i nact i vat i on of l evodopa i n peri pheraI t i ssues. When coadmi ni st ered, mor e
l evodopa i s preser ved t o ent er t he CNS. A combi nat i on of l evodopa and car bi dopa
( Si nemet ) i s avai l abl e f or cl i ni cal use.
b. SeI egi I i ne ( deprenyI ) , i s a seI ect i ve monoami ne oxi dase- B ( MAO- B) i nhi bi t or
t hat i nhi bi t s t he i nt racerebr al degr adat i on of endogenous or l evodopa- deri ved
dopami ne.
c. ToI capone or entacapone ar e sel ect i ve i nhi bi t or s of COMT, t hus reduci ng t he
conversi on of l evodopa t o 3- O-met hyl dopa, an i nact i ve met abol i t e t hat al so i nhi bi t s
l evodopa upt ake i nt o t he br ai n. Addi t i onal l y, i nhi bi t i on of dopami ne breakdown by
COMT may pr ol ong t he avai l abi l i t y and act i on of t he t ransmi t t er i n t he CNS.
B. PharmacoI ogy. Ant i par ki nsoni an agent s act by r est or i ng t he st ri at al bal ance of
dopami nergi c and chol i ner gi c neurot r ansmi ssi on, whi ch i s deranged i n par ki nsoni sm
as a r esul t of degenerat i on of dopami nergi c neurons t hat suppl y dopami ne t o t he
basaI gangI i a (caudat e-put amen) .
1. Levodopa, whi ch can cr oss t he bl ood- brai n bar r i er , i s t he i mmedi at e precursor of
t he st ri at al neurot ransmi t t er dopami ne and i s conver t ed t o dopami ne i n t he body.
2. Amant adi ne, an ant i vi r al agent , appear s t o st i mul at e t he r el ease of dopami ne
f r om i nt act st r i at al t er mi nal s of r emai ni ng dopami nergi c neur ons. As t he di sease
pr ogresses and f ewer dopami ner gi c neurons r emai n, amant adi ne becomes
pr ogressi vel y i nef f ect i ve.
3. Apomorphi ne, bromocri pt i ne, pergoI i de, prami pexoI e, and ropi ni roI e, whi ch
ar e di r ect dopami ner gi c r ecept or agoni st s, mi mi c t he act i vi t y of dopami ne i n t he
caudat e- put amen. Nevert hel ess, t he dr ugs cannot r eproduce t he pul sat i l e r hyt hm of
endogenous dopami ne rel ease.
4. SeI egi I i ne, an i nhi bi t or of t he cent r al MAO- B i soenzyme, bl ocks t he cent r al
cat abol i sm of dopami ne, i ncr easi ng i t s avai l abi l i t y i n t he caudat e- put amen.
5. Ant i choI i nergi cs, such as t ri hexypheni dyl , benzt r opi ne, and or phenadr i ne, bl ock
t he exci t at or y chol i nergi c syst em, t hus reduci ng t he f unct i onal i mbal ance bet ween
dopami ne and acet yl chol i ne i n t he st r i at um.
6. The enzyme i nhi bi t ors, carbi dopa and toI capone, i ncr ease t he t ranspor t and
bi oavai l abi l i t y of l evodopa i n t he brai n and ar e t hus gi ven as adj unct i ve t reat ment s
wi t h l evodopa.
C. Therapeut i c i ndi cati ons
1. Levodopa, cur r ent l y t he most ef f ect i ve t r eat ment f or parki nsoni sm, i s i ndi cat ed t o
t r eat i di opat hi c, post encephal i t i c, or ar t er i oscl erot i c f or ms of t he di sease.
2. Amant adi ne i s i ndi cat ed t o t reat i di opat hi c, post encephal i t i c, or art eri oscl er ot i c
par ki nsoni sm, as wel l as ext r apyr ami dal sympt oms ( except t ardi ve dyski nesi a)
i nduced by ant i psychot i c dr ugs.
3. Apomorphi ne ( Apokyn) has been approved f or t r eat i ng t he ri gi di t y and aki nesi a
or i mmobi l i t y associ at ed wi t h Par ki nson di sease.
4. Bromocri pti ne i s i ndi cat ed t o t reat i di opat hi c or post encephal i t i c parki nsoni sm.
5. SeI egi I i ne, ant i choI i nergi cs, and anti hi st ami nes ar e i ndi cat ed f or use as
adj unct i ve t herapy f or al l t ypes of parki nsoni sm, i ncl udi ng dr ug- i nduced
ext r apyr ami dal sympt oms ( wi t h t he except i on of t ar di ve dyski nesi a) .
D. Adverse ef f ect s
1. Levodopa i s associ at ed wi t h t hese adverse ef f ect s:
a. GÌ ef f ect s, such as GÌ upset , nausea, vomi t i ng, anor exi a, and excessi ve
sal i vat i on
b. Cardi ovascul ar ef f ect s, such as or t host at i c hypot ensi on, t achycardi a, and
dysr hyt hmi as
c. CNS ef f ect s, such as headache, di zzi ness, and i nsomni a
P. 311


d. Abnormal i nvol unt ar y movement s, such as dyski nesi a and chor ei f or m or dyst oni c
movement s
e. Psychi at ri c ef f ect s, such as del usi ons, hal l uci nat i ons, conf usi on, psychoses, and
depressi on
2. Apomorphi ne can cause nausea and vomi t i ng, somnol ence, di zzi ness, and
hal l uci nat i ons, and may exacer bat e exi st i ng dyski nesi a. The dr ug has a reasonabl e
pot ent i al f or abuse due pr i mar i l y t o i t s per cei ved pr o-l i bi do ef f ect s.
3. Amant adi ne i s associ at ed wi t h t hese adver se ef f ect s:
a. CNS ef f ect s, such as dr owsi ness, i nsomni a, di zzi ness, sl urr ed speech, and
ni ght mar es
b. Ur i nar y r et ent i on and ankl e edema
c. Li vedo r et i cul ar i s (mot t l i ng of ski n on t he ext r emi t i es)
d. Psychi at r i c ef f ect s, such as hal l uci nat i ons and conf usi on
4. Bromocri pti ne and r el at ed ergol i nes ar e associ at ed wi t h nausea, hypot ensi on,
psychi at r i c ef f ect s such as conf usi on and hal l uci nat i ons, l i vedo r et i cul ar i s, and
abnor mal i nvol unat r y movement s such as dyski nesi a and chorei f or m or dyst oni c
movement s.
5. SeI egi I i ne i s associ at ed wi t h adverse ef f ect s t hat ar e si mi l ar t o t hose of
br omocri pt i ne, i ncl udi ng dyski nesi as and hal l uci nat i ons.
6. Ant i chol i ner gi c ant i par ki nsoni an agent s have t he same adverse ef f ect s as ot her
chol i ner gi c ant agoni st s (see VÌ . D) .
XIV. OPIOID ANALGESICS and ANTAGONISTS.
Anal gesi c opi oi ds are opi oi d r ecept or agoni st s t hat consi st of nat ur al opi at e
al kal oi ds and t hei r synt het i c der i vat i ves.
A. Chemi st r y. The opi at e al kal oi ds are der i ved f rom opi um, whi ch i s consi dered t he
ol dest dr ug on recor d. Opi um ( t he dri ed exudat e of t he poppy seed capsul e)
cont ai ns about 25 di f f erent al kal oi ds. Of t hese, mor phi ne i s t he most i mpor t ant , bot h
quant i t at i vel y and pharmacol ogi cal l y ( Fi gure 13- 26) .
1. Morphi ne' s phenoI i c hydroxyI group i s ext r emel y i mpor t ant f or act i vi t y;
however , anal gesi c act i vi t y appears t o depend on a p-phenyl - N- al kyl pi per i di ne
moi et y, i n whi ch t he pi per i di ne ri ng i s i n t he chai r f orm and i s perpendi cul ar t o t he
ar omat i c ri ng. The al kyl gr oup i s usual l y met hyl . The morphi ne moI ecuI e can be
al t er ed i n a vari et y of ways; r el at ed compounds al so can be synt hesi zed f rom ot her
st art i ng mat er i al s.
2. NaturaI or synt het i c opi oi ds may be cl assi f i ed i nt o f our chemi cal gr oups (Fi gur e
13- 27) :
a. Phenant hrenes (e. g. , morphi ne and hydromorphone, codei ne and hydrocodone,
nal buphi ne and bupr enorphi ne, and nal orphi ne, nal t rexone, and nal oxone) .
Met hyl at i on of t he phenol i c ( 3) -hydr oxyl gr oup wi t h or wi t hout modi f i cat i on of t he 6-
hydr oxyl gr oup of morphi ne yi el ds agent s wi t h r educed agoni st pot ency but
enhanced or al bi oavai l abi l i t y ( e. g. , codei ne, hydr ocodone, oxycodone).
b. PhenyI hept yI ami nes ( e. g. , met hadone and propoxyphene) ar e bi sphenyl
der i vat i ves of hept yl ami ne t hat have st r ong (met hadone) or moder at e
( pr opoxyphene) agoni st pot ency and excel l ent oral bi oavai l abi l i t y.
c. PhenyI pi peri di nes i ncl ude meperi di ne, f ent anyl , and suf ent ani l , whi ch ar e st r ong
agoni st s t hat are more ef f ect i ve when gi ven par ent er al l y, and t he moder at e agoni st s
di phenoxyl at e and l operami de.
d. The morphi nan l evorphanol i s a st rong agoni st wi t h hi gh or al bi oavai l abi l i t y.

Figure 13-26. Structural Iormula oI morphine.
P. 312



Figure 13-27. Structural Iormulas oI selected
opioid agonists. including (A) codeine. (B)
heroin. (C) hydromorphone (Dilaudid). and (D)
oxycodone (Percodan). morphine analogues; (E)
meperidine (Demerol) and (F) diphenoxylate
(Lomotil). piperidine analgesics; and (G)
methadone (Dolophine) and (H) propoxyphene
(Darvon). methadone analgesics.
P. 313


3. Opi oi d ant agoni st s ar e der i ved by r epl aci ng t he met hyl group on t he ni t r ogen
at om wi t h mor e bul ky subst i t ut i ons. Thus, nal buphi ne and buprenor phi ne ar e
phenant hr ene mi xed agoni st -ant agoni st s; nal t rexone and nal oxone ar e
phenant hr ene pure ant agoni st s; and but or phanol and l eval l or phan are mor phi nan-
der i ved ant agoni st s (Fi gur e 13- 28) .
4. Agent s havi ng bot h a f r ee phenol i c hydroxyl gr oup and a t er t i ar y ami ne f unct i on
( e. g. , mor phi ne and nal buphi ne) ar e chemi cal l y amphot eri c. Amphot eri ci t y pr obabl y
account s f or t he er rat i c absor pt i on of mor phi ne when admi ni st er ed or al l y.
5. Some newer opi oi d anal gesi c agent s, such as tramadoI , ar e chemi cal l y unr el at ed
t o t he nat ur al , semi synt het i c, and synt het i c opi at e deri vat i ves.
6. Numerous anal ogues of endogenous opi oi d pept i des have been synt hesi zed and
ar e bei ng used i n research.
B. PharmacoI ogy
1. Opi oi d anaI gesi cs mi mi c t he act i ons of endogenous opi oi d pept i des at CNS
opi oi d r ecept ors, rai si ng t he pai n t hr eshol d and i ncr easi ng pai n t ol er ance. The
anal gesi c act i ons ar e medi at ed pr i mari l y t hr ough t he µ-subt ype of opi oi d recept ors.
2. Ot her act i ons at t r i but abl e t o st i mul at i on of opi oi d r ecept or s i ncl ude i nduct i on of
euphor i a, sedat i on, cough suppressi on, and chemor ecept or t ri gger - zone st i mul at i on
l eadi ng t o nausea and vomi t i ng.
3. TramadoI appears t o act vi a a met abol i t e, whi ch i s sel ect i ve f or t he µ-opi oi d
r ecept or and al so i nhi bi t s r eupt ake of nor epi nephr i ne and ser ot oni n. Ì t s nonopi at e
charact er appears t o conf er no cl ear benef i t s over t he opi at es.
4. Pure opi oi d antagoni st s such as nal oxone bl ock t he act i ons of opi oi d agoni st s.
Mi xed agoni st - ant agoni st s such as nal buphi ne, buprenorphi ne, but orphanol , and
pent azoci ne bl ock t he act i ons of agoni st s at some r ecept ors whi l e di r ect l y
st i mul at i ng ot her recept or s t o produce agoni st i c ef f ect s.
C. Therapeut i c i ndi cati ons
1. Opi oi d anal gesi cs ar e i ndi cat ed t o r el i eve moderat e to severe pai n, such as t he
pai n associ at ed wi t h myocardi al i nf ar ct i on, cancer , and l abor . Ì n t he l at t er use,
meper i di ne i s pr ef er r ed t o mor phi ne because meper i di ne i s l ess l i kel y t o i nduce
neonat aI respi rat or y depressi on.
2. Opi oi ds ar e used al so as preanesthet i c medi cat i ons, as anaI gesi c adj unct s
duri ng anest hesi a, and occasi onal l y as a pr i mary anest het i c agent .
3. Mi l d t o moder at e agoni st i c opi oi ds ar e used as ant i tussi ves ( e. g. , codei ne and
dext r omet hor phan) and as ant i di arrheaI s ( e. g. , di phenoxyl at e and l operami de) .

Figure 13-28. Structural Iormulas oI opioid
antagonists: (A) naloxone (Narcan). (B)
pentazocine (Talwin). and (C) butorphanol
(Stadol).
P. 314


4. Pure opi oi d ant agoni st s ar e used as ant i dot es t o r everse t he adver se ef f ect s
( e. g. , r espi r at or y depr essi on, cardi ovascul ar depr essi on, sedat i on) of opi oi d
agoni st s or opi oi d agoni st - ant agoni st s. Nal t r exone i s an or al l y act i ve compound t hat
possesses pure ant agoni st i c act i vi t y and i s used i n t he t reat ment of opi oi d
addi ct i on.
D. Adverse ef f ect s
1. Opi oi d anaI gesi cs are associ at ed wi t h t he f ol l owi ng adverse ef f ect s:
a. CNS ef f ect s, i ncl udi ng CNS depr essi on, mi osi s, di zzi ness, sedat i on, conf usi on,
di sor i ent at i on, and coma
b. GÌ ef f ect s, i ncl udi ng nausea, vomi t i ng, const i pat i on, bi l i ar y spasm, and i ncr eased
bi l i ar y t ract pressure
c. Cardi ovascul ar ef f ect s, such as ort host at i c hypot ensi on, peri pher al ci rcul at or y
col l apse, dysr hyt hmi as, and cardi ac ar r est
d. Respi r at or y depr essi on
e. Br onchoconst ri ct i on
f . Psychi at r i c ef f ect s, such as euphori a, dysphori a, and hal l uci nat i ons
g. Abuse pot ent i al and dependence
h. Pr eci pi t at i on of wi t hdrawal sympt oms i n opi oi d- dependent pat i ent s ( when opi oi d
agoni st - ant agoni st s, such as pent azoci ne or nal buphi ne, are used as anal gesi cs)
i . Cl assi c opi oi d anal gesi cs can al so pr ompt t he rel ease of hi st ami ne, causi ng
i nt ense prur i t us, vasodi l at i on, and br onchoconst ri ct i on, whi ch can be conf used wi t h
a t r ue al l er gi c react i on.
j . Tr amadol appear s t o have si gni f i cant l y f ewer respi r at or y depr essant ef f ect s t han
t he cl assi c opi oi ds. Ì t al so does not appear t o cause t he r el ease of hi st ami ne. Ì t has
f ewer cardi ovascul ar ef f ect s wi t h t he except i on of or t host at i c hypot ensi on, whi ch i s
pr oduced. Tr amadol does possess t he t ypi cal µ- recept or- medi at ed si de ef f ect s of
const i pat i on, nausea, vomi t i ng, and sedat i on.
2. Opi oi d ant agoni st s ar e associ at ed wi t h t he f ol l owi ng adverse ef f ect s:
a. Pure opi oi d ant agoni st s can pr eci pi t at e a wi t hdr awal syndr ome i n opi oi d-
dependent pat i ent s. Pure ant agoni st s, gi ven i n t he absence of opi oi d agoni st s or
agoni st - ant agoni st s, pr oduce no cl i ni cal l y si gni f i cant ef f ect s.
b. Ì n t he absence of opi oi ds, mi xed agoni st - ant agoni st s pr oduce opi oi d-l i ke ef f ect s,
such as respi rat or y depressi on.
P. 315


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 14: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. Whi ch of the foI I owi ng drugs wouI d most I i keI y be used i n t he t reat ment of
bronchospasm t hat i s associ at ed wi t h chroni c obst ruct i ve puI monar y di sease?
( A) edrophoni um
( B) i prat r opi um
( C) ambenoni um
( D) pr opant hel i ne
( E) homat r opi ne
Vi ew Answer 1. The answer i s B[ V. C. 2. b, c; VI . C. 1. e-g] . 2. AI I of t he
f oI I owi ng adverse ef f ect s are mani f est ati ons of choI i nergi c agoni sts except
( A) br adycardi a.
( B) br onchoconst ri ct i on.
( C) xer ost omi a.
( D) l acr i mat i on.
( E) myopi c accommodat i on.
Vi ew Answer 2. The answer i s C[] . 3. Whi ch of the f oI I owi ng drugs i s
consi dered t o be t he agent of choi ce f or anaphyI act i c react i ons?
( A) cl oni di ne
( B) i soprot erenol
( C) epi nephri ne
( D) phenyl ephr i ne
( E) t erbut al i ne
Vi ew Answer 3. The answer i s C[] . 4. Whi ch of the f oI I owi ng
neuromuscuI ar bI ocki ng agent s can cause muscari ni c responses such as
bradycardi a and i ncreased gI anduI ar secret i ons?
( A) t ubocur ari ne
( B) succi nyl chol i ne
( C) pancur oni um
( D) decamet honi um
( E) gal l ami ne
Vi ew Answer 4. The answer i s B[ VI I . D. 2] . 5. Whi ch of t he f oI I owi ng agent s
wouI d not be appropri at e i n t he t reatment of gI aucoma?
( A) at ropi ne
( B) pi l ocarpi ne
( C) physost i gmi ne
( D) t i mol ol
( E) epi nephri ne
Vi ew Answer 5. The answer i s A[ and] . 6. Adverse react i ons t o at ropi ne
i ncI ude aI I of t he f oI I owi ng except
( A) phot ophobi a.
( B) dr y mout h.
( C) sedat i on.
( D) di ar r hea.
( E) t achycar di a.
Vi ew Answer 6. The answer i s D[] . 7. Whi ch of the f oI I owi ng drugs i s a
voI at i I e subst ance t hat i s admi ni st ered by i nhaI at i on?
( A) t hi opent al
( B) hal ot hane
( C) al pr azol am
( D) buspi r one
( E) phenyt oi n
Vi ew Answer 7. The answer i s B[] . 8. The st ructure of prochI orperazi ne i s
shown. Whi ch of t he f oI I owi ng medi cat i ons, because of i ts chemi caI
reI at i onshi p to prochI orperazi ne, wouI d most I i keI y cause si mi I ar si de ef fect s?

( A) f l uphenazi ne
( B) t hi or i dazi ne
( C) al pr azol am
( D) buspi r one
( E) pent obar bi t al
Vi ew Answer 8. The answer i s A[] . 9. The bri ef durat i on of act i on of an
uI t ra- short - act i ng barbi t urat e i s the resuI t of a
( A) sl ow r at e of met abol i sm i n t he l i ver .
( B) l ow l i pi d sol ubi l i t y, resul t i ng i n a mi ni mal concent r at i on i n t he brai n.
( C) hi gh degree of bi ndi ng t o pl asma pr ot ei ns.
( D) r api d rat e of r edi st r i but i on f r om t he br ai n owi ng t o i t s hi gh l i posol ubi l i t y.
( E) sl ow r at e of excr et i on by t he ki dneys.
Vi ew Answer 9. The answer i s D[ XI I . A. 4. c, d;] . P. 316


10. Whi ch of t he f oI I owi ng mechani sms of act i on i s t rue and most I i keI y
cont ri but es t o the t reatment of parki nsoni sm?
( A) The di r ect - act i ng dopami nergi c agoni st amant adi ne mi mi cs t he act i vi t y of st r i at al
dopami ne.
( B) The ant i muscar i ni c act i vi t y of di phenhydr ami ne cont ri but es t o t he r est or at i on of
st r i at al dopami nergi c- chol i ner gi c neur ot r ansmi t t er bal ance.
( C) St r i at al H1- recept or s ar e bl ocked by t he ant i hi st ami ni c t r i hexypheni dyl .
( D) The er gol i ne br omocr i pt i ne st i mul at es t he rel ease of st r i at al dopami ne f r om
i nt act t ermi nal s.
( E) The abi l i t y of dopami ne t o cr oss t he bl ood- brai n bar ri er al l ows i t t o r est ore
st r i at al dopami nergi c- chol i ner gi c neur ot r ansmi t t er bal ance.
Vi ew Answer 10. The answer i s B[] . 11. AI I of t he f oI I owi ng adverse ef f ect s
are associ ated wi th t he use of I evodopa except
( A) si al or r hea.
( B) or t host at i c hypot ensi on.
( C) del usi ons, conf usi on, and depr essi on.
( D) dyski nesi a and dyst oni a.
( E) l i vedo ret i cul ari s.
Vi ew Answer 11. The answer i s E[] . 12. The act i vi t y of whi ch of t he
f oI I owi ng drugs depends on a p-phenyI - N- aI kyI pi peri di ne moi et y?
( A) phenobarbi t al
( B) chl orpr omazi ne
( C) di azepam
( D) i mi prami ne
( E) meperi di ne
Vi ew Answer 12. The answer i s E[ XV. A. 1, 2;] . pNNp13. Opi oi ds are used as
aI I of t he f oI I owi ng agent s except
( A) ant i t ussi ves.
( B) anal gesi cs.
( C) ant i - i nf l ammat or i es.
( D) ant i di ar rheal s.
( E) pr eanest het i c medi cat i ons.
Vi ew Answer 13. The answer i s C[ XV. C] . 14. Whi ch of t he f oI I owi ng agent s
wouI d not be an aI ternat i ve t o phenobarbi t aI i n t he t reat ment of part i aI
sei zures?
( A) t r i met hadi one
( B) gabapent i n
( C) f el bamat e
( D) l amot ri gi ne
( E) None of t he above
Vi ew Answer 14. The answer i s A[] . Di recti ons f or quest i ons 15- 19: The
quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
15. ChoI i nesterase i nhi bi t ors can be used t herapeuti caI I y
I . as mi ot i c agent s i n the t reat ment of gI aucoma.
I I . t o i ncrease skeI et aI muscI e tone i n the t reat ment of myast heni a gravi s.
I I I . to decrease gast roi nt est i naI ( GÌ ) and uri nar y bI adder smoot h muscI e tone.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 15. The answer i s C[] . 16. Ant i muscari ni c agent s are used i n
t he t reat ment of Parki nson di sease and i n t he cont roI of some neuroI ept i c-
i nduced ext rapyrami daI di sorders. These agent s i ncI ude
I . i prat ropi um.
I I . benzt ropi ne.
I I I . t ri hexypheni dyI .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 16. The answer i s D[ VI . C. 1. g, h] . 17. Cert ai n drugs are
someti mes i ncorporat ed i nt o I ocaI anest het i c soI ut i ons t o proI ong t hei r act i vi t y
and reduce t hei r syst emi c toxi ci t y. These drugs i ncI ude
I . dobut ami ne.
I I . phenyI ephri ne.
I I I . epi nephri ne.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 17. The answer i s D[ I I I . B. 1. b, ] . 18. I mproper admi ni st rat i on of
I ocaI anest het i cs can cause t oxi c pI asma concent rat i ons t hat may resuI t i n
I . sei zures and cent raI nervous syst em ( CNS) depressi on.
I I . respi rator y and myocardi aI depressi on.
I I I . ci rcuI at or y coI I apse.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 18. The answer i s E[] . P. 317


19. I n addi t i on to t hei r anxi oI yt i c propert i es, benzodi azepi nes are i ndi cat ed f or
use
I . as preanest heti c medi cat i ons.
I I . as ant i convuI sant s.
I I I . duri ng acut e wi thdrawaI f rom aI cohoI .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 19. The answer i s E[] . For quest i ons 20-22: A 58- year -ol d
whi t e mal e who has a hi st or y of essent i al hyper t ensi on and br onchi al ast hma has
r ecent l y been di agnosed wi t h pr ost at i c hyper t r ophy. Hi s medi cat i on hi st ory i ncl udes
t he f ol l owi ng dr ugs:
Di rect i ons: The f ol l owi ng quest i ons can be answer ed by one of t he l i st ed dr ugs.
Choose t he best answer , A- E.
20. Whi ch of t hese agent s and uses couI d worsen the uri nar y ret ent i on he i s
experi enci ng as a resuI t of hi s prost ate probI ems?
( A) pr opr anol ol , f or hyper t ensi on
( B) i prat r opi um, f or ast hma
( C) met aprot er enol , f or ast hma
( D) f i nast er i de ( Pr oscar ), f or pr ost at i c hyper t r ophy
( E) pr azosi n, f or hyper t ensi on
Vi ew Answer 20. The answer i s B[] . 21. Whi ch agent and use couI d worsen
or cause an acute ast hma att ack?
( A) pr opr anol ol , f or hyper t ensi on
( B) i prat r opi um, f or ast hma
( C) met aprot er enol , f or ast hma
( D) f i nast er i de ( Pr oscar ), f or pr ost at i c hyper t r ophy
( E) pr azosi n, f or hyper t ensi on
Vi ew Answer 21. The answer i s A[ I V. D. 3] . 22. Whi ch agent acts seI ect i veI y
at ß2- recept ors?
( A) pr opr anol ol , f or hyper t ensi on
( B) i prat r opi um, f or ast hma
( C) met aprot er enol , f or ast hma
( D) f i nast er i de ( Pr oscar ), f or pr ost at i c hyper t r ophy
( E) pr azosi n, f or hyper t ensi on
Vi ew Answer 22. The answer i s C[] . For quest i ons 23-25: A 55- year -ol d
bl ack f emal e has a hi st or y of moder at e hyper t ensi on, gl aucoma, and mi l d
ost eoart hri t i s. Her medi cat i on hi st or y i ncl udes t he f ol l owi ng drugs:
Di rect i ons: The f ol l owi ng quest i ons can be answer ed by one or more of t he l i st ed
dr ugs. Choose t he best answer s, A- E.
23. Whi ch of her gI aucoma medi ci nes acts vi a an i ndi rect mechani sm?
( A) met opr ol ol , f or hypert ensi on
( B) pi l ocarpi ne gel , f or gl aucoma
( C) epi nephri ne dr ops, f or gl aucoma
( D) i sof l ur ophat e, f or gl aucoma
( E) t i mol ol , f or gl aucoma
Vi ew Answer 23. The answer i s D[] . 24. Whi ch two agent s couI d have an
addi t i ve ef f ect to produce excessi ve bradycardi a?
( A) met opr ol ol , f or hypert ensi on
( B) pi l ocarpi ne gel , f or gl aucoma
( C) epi nephri ne dr ops, f or gl aucoma
( D) i sof l ur ophat e, f or gl aucoma
( E) t i mol ol , f or gl aucoma
Vi ew Answer 24. The answers are A and E[ I V. B. 3, D. 4] . 25. Whi ch two
gI aucoma agents couI d I essen t he ef f ect s of the other?
( A) met opr ol ol , f or hypert ensi on
( B) pi l ocarpi ne gel , f or gl aucoma
( C) epi nephri ne dr ops, f or gl aucoma
( D) i sof l ur ophat e, f or gl aucoma
( E) t i mol ol , f or gl aucoma
Vi ew Answer 25. The answers are B and D[] . Di rect i ons f or quest i ons 26-
28: Each st at ement i n t hi s sect i on descri bes one of t he f ol l owi ng dr ugs. Choose t he
best answer , A- E.
P. 318


26. An anxi oI yt i c drug that does not possess ei t her hypnot i c or ant i convuI sant
propert i es
( A) t ranyI cypromi ne
( B) i mi prami ne
( C) buspi rone
( D) f I uoxet i ne
( E) pheneI zi ne
27. A prot ot ype t ri cycI i c anti depressant wi t h ant i muscari ni c propert i es t hat
make i t usefuI i n t he t reat ment of enuresi s
( A) t ranyI cypromi ne
( B) i mi prami ne
( C) buspi rone
( D) f I uoxet i ne
( E) pheneI zi ne
28. An anti depressant that i nhi bi t s serotoni n reupt ake and may cause adverse
ef f ects such as i mpai red memor y, akat hi si a, and menst ruaI i rreguI ari t i es
( A) t ranyI cypromi ne
( B) i mi prami ne
( C) buspi rone
( D) f I uoxet i ne
( E) pheneI zi ne
Vi ew Answer 26-28. The answers are: 26- C[] , 27-B[ ] , 28- D[] . Di recti ons f or
questi ons 29- 31: Each st r uct ur e i n t hi s sect i on can be descr i bed by one of t he
f ol l owi ng pharmacol ogi cal cat egori es. Choose t he best answer .
29.


( A) generaI anest het i c
( B) I ocaI anest heti c
( C) ant i depressant
( D) anxi oI yt i c
( E) opi oi d ant agoni st
30.


( A) generaI anest het i c
( B) I ocaI anest heti c
( C) ant i depressant
( D) anxi oI yt i c
( E) opi oi d ant agoni st
31.


( A) generaI anest het i c
( B) I ocaI anest heti c
( C) ant i depressant
( D) anxi oI yt i c
( E) opi oi d ant agoni st
Vi ew Answer 29-31. The answers are: 29- B[] , 30-D[ ] , 31- C[] . pFor quest i ons
32- 33: A 38- year- ol d man has a hi st or y of af f ect i ve di sor der s, i ncl udi ng
schi zophr eni a, depr essi on, obsessi ve-compul si ve di sor der , and si t uat i onal anxi et y.
Hi s past medi cat i ons i ncl ude t hi ot hi xene, chl or promazi ne, ami t r i pt yl i ne, and
di azepam. Hi s cur rent medi cat i on prof i l e i ncl udes t wo of t he f ol l owi ng drugs:
Di rect i ons: The f ol l owi ng quest i ons can be answer ed by one of t he l i st ed dr ugs.
Choose t he best answer , A- D.
32. Whi ch agent i s most I i keI y bei ng used t o t reat hi s schi zophreni c
psychosi s?
( A) cl ozapi ne
( B) f l uoxet i ne
( C) buspi r one
( D) r i speri done
Vi ew Answer 32. The answer i s A[] . 33. Whi ch agent i s most I i keI y bei ng
used t o t reat depressi on and obsessi ve- compuI si ve di sorder?
( A) cl ozapi ne
( B) f l uoxet i ne
( C) buspi r one
( D) r i speri done
Vi ew Answer 33. The answer i s B[] . P. 319


Di rect i ons for quest i ons 34-40: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
34. Tyrami ne exempI i f i es t he pharmacoI ogi c mechani sm of
( A) gangl i oni c bl ockade.
( B) i nhi bi t i on of t r ansmi t t er r el ease.
( C) f aci l i t at i on of t ransmi t t er rel ease.
( D) i nt er f er ence wi t h vesi cul ar st or age.
( E) bl ockade of t ransmi t t er r eupt ake.
Vi ew Answer 34. The answer i s C[] . 35. Consi deri ng t he generaI chemi caI
st ruct ures of sympat homi meti c ami nes, deI et i on of the 3- hydroxy group on t he
phenyI ri ng of norepi nephri ne wouI d I i keI y produce
( A) i ncr eased q- recept or pot ency.
( B) i ncr eased 8- recept or pot ency.
( C) i ndi r ect sympat homi met i c act i vi t y.
( D) decr eased t ranspor t t hr ough t he bl ood- brai n bar r i er .
( E) l oss of any bi ol ogi cal act i vi t y i n t he ner vous syst em.
Vi ew Answer 35. The answer i s C[] . 36. Somet i mes combi nati on t reatment
of Parki nson di sease i s warrant ed. Whi ch of the f oI I owi ng drug combi nat i ons
couI d work cooperat i veI y t o enhance a cI i ni caI ant i parki nsoni an response?
( A) amphet ami ne and r eser pi ne
( B) l evodopa and carbi dopa
( C) carbi dopa and t ol capone
( D) amant adi ne and hal oper i dol
( E) dopami ne and t yr ami ne
Vi ew Answer 36. The answer i s B[] . 37. Terazosi n i s abI e t o f aci I i tat e
mi ct uri t i on when used i n t he t reatment of beni gn prost at i c hypert rophy ( BPH)
because t he drug
( A) r el axes t he prost at e gl and.
( B) const r i ct s t he neck of t he bl adder .
( C) pr event s peni l e er ect i ons associ at ed wi t h BPH.
( D) bl ocks semi nal f l ui d pr oduct i on.
( E) bl ocks pr ost at e cel l gr owt h.
Vi ew Answer 37. The answer i s A[] . 38. BRL37344 i s a ß3- agoni st . I t mi ght
be of i nt erest t o deveI op t hi s agent i nt o a cI i ni caI I y usabI e drug because of t he
expect ati on that ß3- agoni st s wouI d
( A) const r i ct bl ood vessel s and i ncr ease bl ood pressur e i n shock pat i ent s.
( B) i nduce l i pol ysi s and decrease l i pocyt e mass i n obese pat i ent s.
( C) i ncr ease gl ycogenol ysi s and pr event gl ycogen st or age i n l i ver ci r rhosi s.
( D) enhance r enal vasodi l at i on and i ncr ease ur i nar y el i mi nat i on of et hanol i n
al cohol i cs.
( E) cause bronchodi l at i on and count eract t he negat i ve ef f ect s of ast hma t reat ment
agent s.
Vi ew Answer 38. The answer i s B[ I I I . B. 1. b] . 39. The pharmacoI ogi c prof i I e
of carvedi I oI i s most si mi I ar to t hat of
( A) esmol ol .
( B) l abet al ol .
( C) met oprol ol .
( D) nadol ol .
( E) t i mol ol .
Vi ew Answer 39. The answer i s B[ I V. C. 3;] . 40. Besi des both of t hem bei ng
phenant hrene deri vat i ves, apomorphi ne and morphi ne aI so have t he common
propert y of
( A) st i mul at i ng br ai n neur ogenesi s and hence ant i depr essant act i vi t y.
( B) el i ci t i ng a pot ent nerve bl ockade and hence anest het i c act i vi t y.
( C) st i mul at i ng µ- opi oi d r ecept or s and hence anal gesi c ef f i cacy.
( D) i mpr ovi ng i mmobi l i t y and hence ant i par ki nsoni an act i vi t y.
( E) i nduci ng r ewar di ng st i mul i and hence addi ct i on l i abi l i t y.
Vi ew Answer 40. The answer i s E[ XV. A. 2, C] . P. 320


ANSWERS AND EXPLANATIONS
1. The answer i s B [ V. C. 2. b, c; VI . C. 1. e- g] .
Ì pr at ropi um i s a newl y appr oved ant i muscar i ni c agent used t o t r eat br onchospasm.
Pr opant hel i ne and homat r opi ne ar e ant i muscari ni c agent s used as a gast roi nt est i nal
( GÌ ) ant i spasmodi c and as a mydri at i c, r espect i vel y. Edrophoni um and ambenoni um
ar e i ndi r ect - act i ng chol i ner gi c agoni st s and, as such, woul d be expect ed t o i nduce
br onchospasm.
2. The answer i s C [ VÌ . D] .
Xer ost omi a, or dr y mout h, r esul t s f r om reduced sal i var y secr et i ons and, t her ef or e,
i s not a mani f est at i on of chol i ner gi c agoni st act i vi t y. Al l of t he ot her ef f ect s l i st ed i n
t he quest i on ar e ext ensi ons of t her apeut i c ef f ect s of chol i ner gi c agoni st s t o t he
poi nt of bei ng adver se ef f ect s.
3. The answer i s C [ Ì Ì Ì . C. 1] .
Of t he adrener gi c agoni st s l i st ed i n t he quest i on, onl y epi nephr i ne, because of i t s
br oad, nonsel ect i ve q- and 8- act i vi t y, i s an agent of choi ce f or anaphyl act i c
r eact i ons. Epi nephri ne i mpr oves ci rcul at or y and r espi r at or y f unct i on and count eract s
t he vascul ar ef f ect s of hi st ami ne- rel at ed anaphyl axi s.
4. The answer i s B [ VI I . D. 2] .
Neur omuscul ar bl ocki ng agent s i nt er act wi t h ni cot i ni c recept or s at t he skel et al
neuromuscul ar j unct i on. Succi nyl chol i ne i s al so capabl e of el i ci t i ng aut onomi c
muscar i ni c r esponses, such as bradycar di a, i ncreased gl andul ar secret i ons, and
car di ac ar r est .
5. The answer i s A [ V. B and C] .
Bot h di rect -act i ng (e. g. , pi l ocar pi ne) and i ndi r ect - act i ng ( e. g. , physost i gmi ne)
chol i ner gi cs may be used i n gl aucoma t o i ncr ease chol i ner gi c act i vi t y and f aci l i t at e
out f l ow of aqueous humor . Si mi l ar l y, bot h 8- agoni st s ( e. g. , epi nephri ne) and
ant agoni st s ( e. g. , t i mol ol ) may be used respect i vel y t o i ncr ease out f l ow and
decrease pr oduct i on of aqueous humor. At ropi ne i s cont r ai ndi cat ed i n gl aucoma
because i t s ant i chol i nergi c ef f ect s can bl ock t he out f l ow of aqueous humor and,
consequent l y, i ncr ease i nt r aocul ar pr essur e.
6. The answer i s D [ VÌ . D] .
Cl assi c si gns and sympt oms of muscari ni c bl ockade, as wi t h at r opi ne, i ncl ude
mydr i asi s, whi ch may cause l i ght sensi t i vi t y ( phot ophobi a) ; dr y mout h and
const i pat i on by decr easi ng secr et or y act i vi t y and mot i l i t y i n t he GÌ t r act ; and
t achycardi a by i nhi bi t i ng t he normal i nhi bi t or y chol i ner gi c cont rol of t he car di ac
syst em. Di ar rhea i s one of t he common si gns of chol i ner gi c agoni st s (such as
sal i vat i on, l acri mat i on or t eari ng, uri nat i on, and di ar r hea) .
7. The answer i s B [ VÌ Ì Ì . A. 1] .
The gener al anest het i cs ar e di vi ded i nt o t wo maj or cl asses of dr ugs: t hose t hat ar e
gases or vol at i l e l i qui ds, whi ch ar e admi ni st er ed by i nhal at i on, and t hose t hat ar e
nonvol at i l e sal t s, whi ch ar e admi ni st er ed as i nt ravenous sol ut i ons. Hal ot hane i s a
hal ogenat ed hydr ocar bon, whi ch bel ongs t o t he f or mer cl ass. Ì t has t he advant age
over ol der vol at i l e anest het i cs ( e. g. , et hyl et her, cycl opr opane) of bei ng
nonf l ammabl e. Thi opent al sodi um, al prazol am, buspi r one, and phenyt oi n ar e al l
nonvol at i l e subst ances t hat ar e admi ni st ered or al l y or parent er al l y. Thi opent al i s a
gener al anest het i c and i s somet i mes ref err ed t o as a basal anest het i c because i t
does not pr oduce si gni f i cant t hi r d-st age sur gi cal anest hesi a. Al prazol am and
buspi rone ar e anxi ol yt i cs, wher eas phenyt oi n i s an ant i convul sant .
8. The answer i s A [ X. A. 1; Tabl e 13- 6] .
Fl uphenazi ne, l i ke pr ochl or per azi ne, i s a pi per azi nyl phenot hi azi ne ant i psychot i c
and woul d be l i kel y t o cause si mi l ar si de ef f ect s. Wher eas t hi ori dazi ne i s al so a
phenot hi azi ne ant i psychot i c, i t i s a pi peri dyl deri vat i ve r at her t han a pi per azi nyl
der i vat i ve. Al prazol am, phenyt oi n, and pent obarbi t al ar e not phenot hi azi nes;
t her ef ore, st r uct ur al l y, t hey ar e not si mi l ar t o pr ochl or per azi ne.
9. The answer i s D [ XI I . A. 4. c, d; Fi gure 13- 8] .
Ul t r a-shor t - act i ng barbi t ur at es ar e char act eri zed by havi ng br anched or unsat ur at ed
5, 5-si de chai ns and by havi ng a sul f ur at om i n pl ace of oxygen i n t he 2 posi t i on of
t he bar bi t ur i c aci d mol ecul e. These modi f i cat i ons of bar bi t uri c aci d r esul t i n an
ext r emel y l i posol ubl e mol ecul e t hat i s ver y sol ubl e i n l i pi d t i ssues. Af t er
admi ni st rat i on, an ul t r a-short - act i ng barbi t ur at e readi l y crosses t he bl ood- br ai n
bar r i er but t hen i s qui ckl y r edi st r i but ed i nt o ext r acer ebr al t i ssue, r esul t i ng i n a r api d
l oss of act i vi t y. Whi l e t hese agent s do remai n i n t he body f or a l ong t i me and seem
t o have sl ow r at es of met abol i sm and excr et i on, t hei r l ong ret ent i on t i me i s due
mor e t o t hei r sl ow r at e of l eachi ng out of l i pi d t i ssue.
P. 321


10. The answer i s B [ XÌ V. B] .
The H1- ant agoni st di phenhydr ami ne possesses ant i muscar i ni c act i vi t y, whi ch al l ows
i t t o be of use i n t he r est or at i on of st ri at al dopami nergi c- chol i ner gi c
neurot r ansmi t t er bal ance. Amant adi ne appears t o st i mul at e t he rel ease of st r i at al
dopami ne; i t does not mi mi c t he act i on of dopami ne. Tr i hexypheni dyl i s an
ant i muscar i ni c, not ant i hi st ami ni c, agent ; i t bl ocks chol i ner gi c, not H1, r ecept ors.
Br omocri pt i ne i s a dopami ner gi c agoni st and mi mi cs t he act i vi t y of st ri at al
dopami ne. The neurot r ansmi t t er dopami ne i s not abl e t o cr oss t he bl ood-br ai n
bar r i er and i s, t her ef or e, not ef f ect i ve as an ant i par ki nsoni an dr ug.
11. The answer i s E [ XÌ V. D. 1] .
Li vedo r et i cul ar i s i s a ci rcul at or y di sor der char act er i zed by l ar ge, bl ui sh areas on
t he ext r emi t i es. Ì t i s an adver se ef f ect associ at ed wi t h t he use of amant adi ne and
br omocri pt i ne but not wi t h t he use of l evo- dopa.
12. The answer i s E [ XV. A. 1, 2; Fi gur e 13-27E] .
The p- phenyl - N-al kyl pi per i di ne moi et y i s common t o t he st r uct ural l y speci f i c opi oi d
anal gesi cs. Meper i di ne i s an opi oi d anal gesi c and i s an N- met hyl - p- phenyl pi per i di ne
der i vat i ve. Ì t s chemi cal name i s et hyl 1 -met hyl -4- phenyl pi per i di ne- 4-carboxyl at e.
Phenobarbi t al i s a barbi t ur at e sedat i ve. Chl or promazi ne i s a phenot hi azi ne
ant i psychot i c. Di azepam i s a benzodi azepi ne anxi ol yt i c. Ì mi prami ne i s a t ri cycl i c
di benzazepi ne ant i depressant .
13. The answer i s C [ XV. C] .
Unl i ke t he sal i cyl at es, opi oi ds do not possess ant i - i nf l ammat or y act i vi t y. Opi oi ds do
suppr ess t he cough ref l ex and ar e pr eemi nent anal gesi cs. Opi oi ds cause
const i pat i on and ar e, t hus, ef f ect i ve ant i di ar rheal agent s. When used as
pr eanest het i c medi cat i on, opi oi ds per mi t a r educt i on i n t he amount of gener al
anest het i c requi r ed f or sur gi cal anest hesi a.
14. The answer i s A [ XÌ Ì Ì . A. 1, C. 2] .
Whi l e many anal ept i cs ar e usef ul i n cont r ol l i ng mor e t han one sei zure t ype,
t r i met hadi one i s ef f ect i ve pri mar i l y agai nst absence ( pet i t mal ) sei zur es.
Addi t i onal l y, i t s si de-ef f ect pr of i l e i s mor e ext ensi ve t han t he newer agent s ( e. g. ,
l amot ri gi ne, gabapent i n, f el bamat e) t hat ar e ef f ect i ve i n t reat i ng part i al sei zur es.
15. The answer i s C [ V. C. 2] .
Chol i nest er ase i nhi bi t ors ar e i ndi r ect -act i ng chol i ner gi c agoni st s usef ul i n t r eat i ng
myast heni a gr avi s and gl aucoma. Thei r ef f ect s on GÌ and uri nar y bl adder smoot h
muscl e woul d be t o i ncrease smoot h-muscl e t one, not decr ease i t .
16. The answer i s D [ VI . C. 1. g, h] .
Al l t hr ee compounds l i st ed i n t he quest i on ar e ant i muscar i ni c agent s; however , onl y
benzt r opi ne and t r i hexypheni dyl ar e used t o cont rol par ki nsoni sm and some
neurol ept i c-i nduced ext r apyr ami dal di sor der s. Ì prat r opi um i s a newl y approved
agent f or t he t reat ment of br onchospasm.
17. The answer i s D [ I I I . B. 1. b, C. 1, 2] .
Dobut ami ne i s a 81- sel ect i ve adrenergi c agoni st . Ì t woul d be i nappr opri at e t o use
dobut ami ne t o decrease bl ood f l ow at t he si t e of l ocal anest het i c admi ni st rat i on.
Epi nephri ne i s a nonsel ect i ve q- and 8- agoni st , and phenyl ephr i ne i s an q1- sel ect i ve
agoni st ; bot h of t hese drugs can be used t o l i mi t t he syst emi c absorpt i on of l ocal
anest het i cs and pr ol ong t hei r act i vi t y.
18. The answer i s E [ Ì X. D. 2] .
Car ef ul admi ni st r at i on of a l ocal anest het i c by a knowl edgeabl e pract i t i oner i s
essent i al t o prevent syst emi c absor pt i on and consequent t oxi ci t y. Thi s i s especi al l y
i mpor t ant when t he pat i ent has cardi ovascul ar di sease, poorl y cont rol l ed di abet es,
t hyr ot oxi cosi s, or per i pher al vascul ar di sease.
19. The answer i s E [ XÌ Ì . C. 1, 2, 3] .
Benzodi azepi nes can serve as i nduct i on agent s f or general anest hesi a; t hey al so
have anxi ol yt i c pr oper t i es. Ì n addi t i on, i nt ravenous di azepam i s used t o t reat st at us
epi l ept i cus, wher eas cl onazepam i s used or al l y f or myocl oni c and absence ( pet i t
mal ) sei zures. Benzodi azepi nes al so di mi ni sh al cohol wi t hdr awal sympt oms.
20. The answer i s B [ VÌ . D] .
Thi s ant i chol i nergi c, i f absorbed syst emi cal l y, coul d cause cl assi c ant i chol i ner gi c
ef f ect s, whi ch i ncl ude ur i nar y r et ent i on.
P. 322


21. The answer i s A [ I V. D. 3] .
Because t hi s i s a nonsel ect i ve 8- bl ocker , t here coul d be some i nhi bi t i on of 82-
r ecept or s i n t he br onchi al t r ee, causi ng br onchoconst r i ct i on and possi bl e
compl i cat i on of t he pat i ent ' s ast hma.
22. The answer i s C [ Ì Ì Ì . C. 6] .
Pr opr anol ol i s a nonsel ect i ve 8-bl ocker, and pr azosi n i s a sel ect i ve q1- bl ocker .
Nei t her i pr at r opi um nor Pr oscar wor ks t hr ough t he adr ener gi c syst em.
Met apr ot erenol i s a sel ect i ve 82- agoni st .
23. The answer i s D [ V. A. 2, C. 2] .
Pi l ocarpi ne act s di r ect l y at t he muscar i ni c r ecept or , wher eas epi nephr i ne and
t i mol ol bot h act di r ect l y at 8- r ecept ors. Ì sof l ur ophat e i nhi bi t s t he met abol i sm of
acet yl chol i ne, i ndi r ect l y i ncr easi ng l evel s of t he endogenous neur ot r ansmi t t er .
24. The answers are A and E [ I V. B. 3, D. 4] .
Met opr ol ol , a 81-sel ect i ve agent , can cause bradycar di a al one. The addi t i on of
t opi cal t i mol ol , whi l e l i mi t i ng syst emi c absor pt i on, coul d have an addi t i ve 8- bl ocki ng
ef f ect t o decr ease hear t r at e (negat i ve chr onot ropy) .
25. The answers are B and D [ V. C. 1, 2] .
Pi l ocarpi ne and i sof l ur ophat e coul d l i mi t t he ef f ect s of each ot her, because,
ul t i mat el y, bot h act vi a chol i nergi c recept or s. Pi l ocarpi ne act s di r ect l y on t he
r ecept or , whi l e i sof l urophat e i ndi rect l y i ncreases acet yl chol i ne l evel s. Pi l ocarpi ne
and acet yl chol i ne coul d compet e f or each ot her at t he recept or si t e, ef f ect i vel y
decreasi ng t he ef f ect s of bot h. Epi nephr i ne and t i mol ol ar e 8- agoni st s and 8-
ant agoni st s, r espect i vel y. Al t hough bot h agent s ar e ef f ect i ve i n t r eat i ng gl aucoma
al one, t he use of bot h concomi t ant l y coul d resul t i n a phar macol ogi cal ant agoni sm,
ef f ect i vel y decr easi ng t he ef f ect s of bot h.
26- 28. The answers are: 26- C [ XÌ Ì . B. 2] , 27- B [ XÌ . C. 2] , 28- D [ XÌ . B. 3, D. 3] .
Buspi r one' s mechani sm of anxi ol yt i c act i on i s unknown. Unl i ke t he benzodi azepi nes,
buspi rone l acks hypnot i c and ant i convul sant pr oper t i es. The t ri cycl i c ant i depr essant
i mi pr ami ne i s usef ul i n t he t reat ment of enuresi s, because t he compound bl ocks
muscar i ni c r ecept ors medi at i ng mi ct uri t i on. Tr azodone i s cat egori zed as an at ypi cal
ant i depr essant t hat sel ect i vel y bl ocks ser ot oni n reupt ake.
29- 31. The answers are: 29- B [ Ì X. A; Fi gure 13- 15] , 30- D [ XÌ Ì . A; Tabl e 13- 7] , 31- C
[ XÌ . A. 2; Fi gure 13- 19] .
The st ruct ur e shown i n quest i on 29 i s t hat of pr ocai ne, whi ch i s a di et hyl ami noet hyl
p- ami nobenzoat e est er . Ì t cont ai ns a hydr ophi l i c ami no gr oup i n t he al cohol por t i on
of t he mol ecul e and a l i pophi l i c ar omat i c aci d connect ed by t he est er l i nkage. The
pr ocai ne mol ecul e i s t ypi cal of est er - t ype l ocal anest het i cs.
The st ruct ur e i n quest i on 30 i s t hat of di azepam, whi ch has a benzo-1, 4-di azepi ne
as i t s base nucl eus. The wi del y used benzo- 1, 4-di azepi ne der i vat i ves have
si gni f i cant anxi ol yt i c, hypnot i c, and ant i convul sant act i vi t i es.
The st ruct ur e i n quest i on 31 i s t hat of desi pr ami ne, whi ch has a di benzazepi ne as
i t s base nucl eus. Di benzazepi ne der i vat i ves t hat have a met hyl - or
di met hyl ami nopr opyl group at t ached t o t he ri ng ni t r ogen have si gni f i cant
ant i depr essant act i vi t y. Si mi l arl y subst i t ut ed di benzocycl ohept adi enes al so have
ant i depr essant act i vi t y. Toget her, t hese t wo chemi cal cl asses make up t he maj or i t y
of t he t ri cycl i c ant i depr essant s.
32. The answer i s A [ X. C] .
Cl ozapi ne, whi l e t herapeut i cal l y def i ned as a gener al ant i psychot i c, i s used al most
excl usi vel y i n t he t r eat ment of schi zophr eni a.
33. The answer i s B [ XÌ . A. 3, C. 2] .
Fl uoxet i ne i s most l i kel y bei ng used i n t hi s pat i ent i n an at t empt t o t reat depr essi on
and obsessi ve- compul si ve di sorder wi t h t he same dr ug. Cl i ni cal t ri al s have shown
f l uoxet i ne t o i mprove bot h condi t i ons. The use of a si ngl e agent f or bot h condi t i ons
wi l l mi ni mi ze t he r i sk of dr ug-dr ug i nt eract i ons, as wel l as reduce t he chances of
adver se ef f ect s.
34. The answer i s C [ Ì Ì Ì . A. 2, B. 3; Tabl e 13-2] .
Tyr ami ne i s an i ndi rect l y act i ng sympat homi met i c ami ne t hat ent er s t he ner ve
t er mi nal and di spl aces nor epi nephri ne f r om t he st or age vesi cl es, t hus i ncr easi ng t he
quant a of t he t r ansmi t t er r el eased.
P. 323


35. The answer i s C [ Ì Ì Ì . A. 1, 2] .
Bot h ar omat i c hydr oxyl f unct i ons ar e i mport ant f or bot h al pha and bet a r ecept or
bi ndi ng. However , removal of one or bot h of t he gr oups woul d i ncrease upt ake of
t he resul t i ng compound i nt o t he br ai n and adr ener gi c ner ve t ermi nal s, r esul t i ng i n
t r ansmi t t er di spl acement f r om vesi cul ar st orage and i ncreased t r ansmi t t er r el ease.
36. The answer i s B [ XÌ V. A. 2, 3] .
Whi l e l evodopa can cr oss t he bl ood br ai n bar r i er t o gai n access i nt o t he br ai n, a
si gni f i cant port i on of an or al l y admi ni st ered dose get s convert ed i nt o dopami ne and
nor epi nephr i ne at per i pher al si t es, l eadi ng t o peri pher al si de ef f ect s and decreased
br ai n bi oavai l abi l i t y. Carbi dopa, a dopa decar boxyl ase i nhi bi t or t hat does not cr oss
t he bl ood br ai n bar ri er , i s coadmi ni st er ed wi t h l evodopa t o decr ease i t s per i pher al
conversi on, i ncr ease cent r al del i ver y of t he drug and hence t he t her apeut i c
r esponse.
37. The answer i s A [ Ì V. C. 1] .
Ter azosi n bl ocks al pha recept ors on t he pr ost at e gl and t o cause a rel axant ef f ect ,
whi ch r educes t he pr essur e exer t ed by t he pr ost at e on t he ur et hr a, t hus easi ng
ur i nar y voi dance.
38. The answer i s B [ I I I . B. 1. b] .
St i mul at i on of bet a-3 recept ors i nduces t he met abol i c br eakdown of f at st or es i nt o
f r ee f at t y aci ds t hat can be f ur t her cat abol i zed by t he body. The hope i s t hat t hi s
cat egor y of pharmacol ogi c agent s coul d, wi t h r epeat ed use, l ead t o a decr ease i n
t he cont ent and number of f at cel l s, and hence an ant i obesi t y ef f ect .
39. The answer i s B [ I V. C. 3; Tabl e 13- 3] .
Li ke l abet al ol , car vedi l ol i s a nonsel ect i ve al pha and bet a r ecept or ant agoni st used
i n t he t r eat ment of hypert ensi on. Bl ockade of vascul ar al pha (al pha-1) recept ors
woul d cause vasodi l at at i on and decr eased per i pher al vascul ar resi st ance, whi l e
bl ockade of myocar di al bet a (bet a- 1) r ecept ors woul d decrease cardi ac cont r act i l i t y.
The r esul t ant decr ease i n car di ac out put woul d pr oduce a f al l i n bl ood pressur e
( bl ood pr essur e = car di ac out put × peri pher al resi st ance) .
40. The answer i s E [ XÌ V. A. 2, D. 2; XV. A. 2, C] .
Despi t e t he si mi l ar i t i es i n t hei r names and chemi cal st r uct ures, t hese t wo agent s
have ver y di f f er ent pharmacol ogi cal ef f ect s and t her apeut i c uses. The one
commonal i t y among t hem i s t hat bot h pr oduce rewar di ng ef f ect s and t hus abuse
l i abi l i t y÷mor phi ne pri mar i l y t hrough i t s euphor i ant CNS ef f ect s and apomor phi ne
pr i mar i l y t hrough i t s pr o-l i bi do ( erect i l e) ef f ect s i n mal es.

14
Autacoids and Their Antagonists,
Nonnarcotic AnaIgesic-Antipyretics, and
NonsteroidaI Anti-infIammatory Drugs
Scot t F. Long
I. INTRODUCTION
A. Aut acoi ds, al so cal l ed aut opharmacol ogi cal agent s or l ocal hormones,
have wi del y di f f er i ng st ruct ur es and pharmacol ogi cal act i ons. Al t hough t he
t er m r emai ns poor l y def i ned, t he cur r ent l y accept ed cr i t er i on t hat def i nes a
subst ance as an aut acoi d i s l ocal rel ease and act i on l i mi t ed t o a speci f i c
si t e. Two of most ext ensi vel y i nvest i gat ed aut acoi ds ar e hi stami ne and t he
prost agI andi ns. However , serot oni n, bradyki ni n, and kaI I i di n al so
f unct i on i n a si mi l ar manner . Whi l e some aut acoi ds (hi st ami ne and
ser ot oni n) f unct i on as neur ot ransmi t t ers, t hei r aut acoi d f unct i on i s t he f ocus
of t hi s chapt er . Cur r ent l y, t her e ar e no agent s t hat speci f i cal l y modul at e t he
f unct i on of br adyki ni n or kal l i di n; however , dr ugs or anal ogs t hat mi mi c,
bl ock, or modul at e ot her aut acoi d f unct i ons have i mpor t ant t herapeut i c
r ol es.
B. Nonnarcot i c anaI gesi c- anti pyret i cs have di ssi mi l ar st r uct ur es but
share cer t ai n t her apeut i c act i ons, i ncl udi ng r el i ef of pai n, f ever , and
somet i mes i nf l ammat i on. Mechani st i cal l y, t hese agent s act by i nhi bi t i ng
synt hesi s of pr ost agl andi ns.
C. Nonsteroi daI ant i -i nfI ammat or y drugs ( NSAI Ds) di f f er i n st r uct ure and
act i vi t y f r om t he nonnarcot i c anal gesi c- ant i pyr et i cs, but possess ant i -
i nf l ammat or y proper t i es. Ì n addi t i on, many of t hese agent s al so exhi bi t
ant i pyr et i c and anal gesi c act i vi t y. NSAÌ Ds al so act by i nhi bi t i on of
pr ost agl andi n synt hesi s.
II. AUTACOIDS AND THEIR ANTAGONISTS
A. Hi st ami ne and ant i hi st ami ni cs
1. Chemi st r y
a. Hi stami ne i s a bi oami ne der i ved pri nci pal l y f r om di et ar y hi st i di ne, whi ch
i s decar boxyl at ed by L- hi st i di ne decarboxyl ase (Fi gur e 14- 1).
b. Ant i hi stami ni cs ( hi st ami ne ant agoni st s) can be cl assi f i ed as H1- or H2-
receptor ant agoni sts.
( 1) H1- receptor ant agoni st s, t he cl assi c ant i hi st ami ni c agent s, are
chemi cal l y cl assi f i ed as et hyI enedi ami nes (e. g. , pyr i l ami ne), aI kyI ami nes
( e. g. , brompheni rami ne [ Di met app] , chl orpheni rami ne [ Chl or- Tr i met on] ) ,
et hanoI ami nes (e. g. , di phenhydr ami ne [ Benadr yl ] , cl emast i ne [ Tavi st ] ) ,
pi perazi nes ( e. g. , hydr oxyzi ne [ At arax, Vi st ari l ] , cet i r i zi ne
P. 325

[ Zyr t ec] ) , phenot hi azi nes ( e. g. , pr omet hazi ne [ Phener gan] ) ,
di benzocycI ohept enes ( cypr ohept adi ne [ Peri act i n] ) , phthaI azi nones
( azel ast i ne [ Opt i var , Ast el i n] ) , and pi peri di nes (e. g. , azat adi ne [ Opt i mi ne] ,
l or at adi ne [ Cl ar i t i n] , desl or at adi ne [ Cl ari nex] , and f exof enadi ne [ Al l egr a] ) .
Cet i r i zi ne, azel ast i ne, l or at adi ne, desl orat adi ne, and f exof enadi ne make up
t he second- gener at i on ant i hi st ami ni cs, whi ch ar e l ess sedat i ng t han t he
ol der , f i r st - generat i on drugs, owi ng t o t hei r l i mi t ed abi l i t y t o cross t he
bl ood- brai n bar r i er ( Fi gur e 14- 2) .

Figure 14-1. Structural Iormula oI histamine. an
autacoid.

Figure 14-2. Structural Iormulas oI representative
H
1
-receptor antagonists. (A) Chlorpheniramine
(alkylamine). (B) Diphenhydramine
(ethanolamine). (C) Promethazine
(phenothiazine). (D) Loratadine (nonsedating
piperidine).
( 2) H2- receptor ant agoni st s ar e het er ocycl i c congener s of hi st ami ne.
These i ncl ude ci met i di ne ( Tagamet ), rani t i di ne ( Zant ac), f amot i di ne
( Pepci d), and ni zat i di ne ( Axi d) ( Fi gur e 14-3) .
( 3) AI t ernat i ves t o t he H2- r ecept or ant agoni st s i ncl ude omeprazoI e
( Pr i l osec) , I ansoprazoI e ( Pr evaci d), rabeprazoI e ( Aci pHex) , pantoprazoI e
( Pr ot oni x) , and esomeprazoI e
P. 326

( Nexi um) ; speci f i c i nhi bi t ors of H
+
/ K
+
- ATPase (pr ot on pump i nhi bi t ors, or
PPÌ s) , t he ul t i mat e medi at or of gast r i c aci d secr et i on. St ruct ur al l y, t hese
agent s ar e subst i t ut ed benzi mi dazoI es l i nked t o a pyr i di ne r i ng by a
sul f i nyl bri dge, whi ch i s r equi r ed f or H
+
/ K
+
- ATPase i nhi bi t i on.

Figure 14-3. Structural Iormulas oI (A)
cimetidine. an H
2
-receptor antagonist. and (B)
omeprazole. a proton pump inhibitor.
2. PharmacoI ogy
a. Hi stami ne has power f ul pharmacol ogi cal act i ons, medi at ed by t wo
speci f i c r ecept or t ypes (Tabl e 14- 1). A t hi rd hi st ami ne recept or has been
i dent i f i ed. Ì t s f unct i on has yet t o be el uci dat ed, but i t i s bel i eved t o act , at
l east i n par t , as an aut orecept or.
( 1) H1- receptors medi ate t ypi cal al l er gi c and anaphyl act i c r esponses t o
hi st ami ne, such as br onchoconst r i ct i on, vasodi l at i on, i ncr eased capi l l ar y
per meabi l i t y, and spasmodi c cont r act i ons of gast r oi nt est i nal ( GÌ ) smoot h
muscl e.
( 2) H2- receptors medi ate ot her responses t o hi st ami ne, such as i ncreased
secr et i on of gast ri c aci d, pepsi n, and Cast l e' s f act or ( i nt ri nsi c f act or ) .
b. H1- receptor ant agoni st s compet i t i vel y bl ock H1- r ecept or s, t hus l i mi t i ng
t he hi st ami ne' s ef f ect s on br onchi al smoot h muscl e, capi l l ari es, and GÌ
smoot h muscl e. These ant agoni st s al so pr event hi st ami ne- i nduced pai n and
i t chi ng of t he ski n and mucous membr anes.
c. H2- recept or ant agoni st s compet i t i vel y bl ock H2- r ecept or s, t hus l i mi t i ng
t he ef f ect s of hi st ami ne on gast r i c secr et i ons.
d. The PPI s i rr eversi bl y i nhi bi t t he pr ot on pump H
+
/ K
+
- ATPase by coval ent l y
bi ndi ng t o t he prot ei n.
3. Therapeut i c i ndi cat i ons
a. Exogenous hi st ami ne can be used as a di agnost i c agent f or t est i ng gast r i c
f unct i on. However , ot her st i mul ant s of gast ri c secr et i on ( pent agast ri n) are mor e
sui t abl e and saf er.
b. H1- receptor ant agoni st s ar e used t o provi de sympt omat i c rel i ef of aI I ergi c
sympt oms, such as seasonal rhi ni t i s, conj unct i vi t i s, and t he sympt oms of r hi novi r al
i nf ect i ons (common col d) . Thei r ant i hi st ami ni c ef f ect s al so make t hem usef ul f or
sympt omat i c rel i ef of ur t i car i a. Agent s wi t h a hi gh degree of ant i chol i ner gi c act i vi t y
( e. g. , di phenhydr ami ne) ar e somet i mes used t o t reat nausea and vomi t i ng
associ at ed wi t h mot i on si ckness and ver t i go. Ì n addi t i on, pr omet hazi ne ( whi ch al so
has a hi gh degree of ant i chol i nergi c act i vi t y) i s somet i mes used as an ant i emet i c,
and hydr oxyzi ne pamoat e i s occasi onal l y empl oyed as a mi l d anxi ol yt i c. The
second- generat i on dr ugs ( i . e. , l or at adi ne, desl orat adi ne,
P. 327

f exof enadi ne, acr i vast i ne, cet i r i zi ne, and azel ast i ne) pr ovi de t he added advant age
of l i t t l e t o negl i gi bl e sedat i on, owi ng t o t hei r r el at i ve i nabi l i t y t o cross t he bl ood-
br ai n bar r i er .
Table 14-1. Selected Actions of Endogenous Histamine
Site Action
Receptor
Type
Cardiovascular
Vascular Arterial contraction H
1

Arteriolar relaxation H
1
and H
2

Venule contraction H
1

Venule relaxation H
2

Endothelial cells. release oI EDRF H
1

Endothelial cells. contraction H
1

Heart Increased heart rate H
2

Increased Iorce oI contraction H
2

Slowed atrioventricular conduction H
1

Respiratory

Bronchiolar smooth-muscle
contraction
H
1

Gastrointestinal (GI)
Gastric mucosa Increased secretion oI acid and pepsin H
2

GI smooth
muscle
Contraction H
1

Various
Cutaneous nerves Pain and itch H
1

EDRF. endothelium-derived relaxing Iactor.

c. H2- recept or ant agoni st s ar e used t o t reat gast ri c hypersecret or y condi t i ons,
such as duodenal ul cer and Zol l i nger- El l i son syndr ome. They ar e ef f ect i ve i n
r educi ng pai n associ at ed wi t h gast r oesophageal ref l ux di sease, but not e t hat t hey
do not pr event act ual r ef l ux.
d. The prot on pump i nhi bi t ors ar e used t o t r eat duodenaI uI cers and are t he
dr ugs of choi ce f or t he t reat ment of ZoI I i nger- EI I i son syndrome.
4. Adverse ef fect s
a. Hi stami ne may cause numer ous adverse ef f ect s rel at ed t o i t s basi c
pharmacol ogy (see Ì Ì . A. 2. a) .
b. H1- receptor ant agoni st s ar e associ at ed wi t h t he f ol l owi ng adverse ef fect s:
( 1) Cent r al ner vous syst em ( CNS) ef f ect s, such as CNS depr essi on, sedat i on,
f at i gue, t i nni t us, hal l uci nat i ons, and at axi a
( 2) GÌ ef f ect s, such as nausea and vomi t i ng
( 3) Ant i muscar i ni c ef f ect s, such as dr y mout h, ur i nar y r et ent i on, and const i pat i on
( 4) Ter at ogeni c ef f ect s (possi bl e wi t h pi per azi ne compounds)
c. Nonsedat i ng H1- recept or ant agoni sts, because t hey possess l i t t l e
ant i chol i nergi c act i vi t y and do not cr oss t he bl ood- br ai n bar ri er , are r el at i vel y f r ee
of si de ef f ect s.
d. H2- receptor ant agoni st s ar e associ at ed wi t h t he f ol l owi ng adver se ef f ect s:
( 1) CNS ef f ect s, such as conf usi on and di zzi ness
( 2) Hepat i c and r enal dysf unct i on
( 3) Ì nhi bi t i on of t he hepat i c mi crosomal dr ug-met abol i zi ng enzyme syst em ( wi t h
ci met i di ne)
( 4) Andr ogeni c ef f ect s (wi t h hi gh doses of ci met i di ne) , such as i mpot ence and
gynecomast i a i n men and gal act orr hea i n women
e. The H
+
/ K
+
- ATPase i nhi bi t ors have been r epor t ed t o cause di ar r hea, GÌ pai n, and
headache as t hei r most f r equent adverse ef f ect s. Ì n addi t i on, t hey may i nt er f ere
wi t h t he met abol i sm of di azepam, war f ari n, phenyt oi n, and t heophyl l i ne.
B. Serot oni n
1. Chemi st r y
a. Serot oni n ( 5-hydr oxyt r ypt ami ne) i s a bi oami ne t hat i s synt hesi zed f rom t he
ami no aci d t r ypt ophan by a t wo- st ep enzymat i c pr ocess cat al yzed by t r ypt ophan
hydr oxyl ase and L- ami no aci d decar boxyl ase ( Fi gur e 14- 4).
b. Serotoni n agoni st s
( 1) 5- HT1- recept or agoni st s (i . e. , sumat ri pt an [ Ì mi t rex] , r i zat r i pt an [ Maxal t ] ,
nar at r i pt an [ Amer ge] , zol mi t ri pt an [ Zomi g] , al mot ri pt an [ Axer t ] , el et r i pt an [ Rel pax] ,
and f r ovat ri pt an [ Fr ova] ) ar e i ndol e der i vat i ves st r uct ur al l y si mi l ar t o ser ot oni n
( Fi gur e 14- 4) .
( 2) Tegaserod ( Zel nor m), an i ndoI e deri vat i ve, act s as 5- HT4- r ecept or agoni st
( Fi gur e 14- 4) .
( 3) Ergot aI kaI oi ds ( ergot ami ne [ Ergomar ] ) have some act i vi t y as a ser ot oni n
agoni st / par t i al agoni st .
c. Serot oni n ant agoni sts
( 1) Ergot aI kaI oi ds and der i vat i ves wi t h ant agoni st / par t i al agoni st act i vi t y i ncl ude
ergonovi ne ( Er got rat e), di hydroergot ami ne, met hysergi de, and bromocri pt i ne
( Par l odel ) .
( 2) 5- HT3- ant agoni sts may be ei t her i ndoI e der i vat i ves ( ondanset r on [ Zof r an] ) or
benzi mi dazoI es (gr ani set r on [ Kyt r i l ] ) . Ot her drugs of t he cl ass i ncl ude doI aset ron
( Anzemet ) , paI onoset ron ( Al oxi ) and aI oset ron ( Lot ronex) ( Fi gur e 14-4) .
2. PharmacoI ogy
a. Serot oni n exer t s a wi de r ange of ef f ect s vi a a f ami l y of r ecept ors t hat i ncl udes at
l east seven t ypes and sever al subt ypes. Maj or physi ol ogi cal ef f ect s of serot oni n
i ncl ude vasoconst ri ct i on ( 5- HT2) ; pl at el et aggr egat i on ( 5- HT2) ; i ncr eased rel ease of
acet yl chol i ne i n t he ent er i c regi on ( 5- HT4) ; nausea/ emesi s ( 5- HT3) ; and numerous
behavi or al act i ons t hat i nf l uence anxi et y, depr essi on, aggressi on, i mpul si vi t y, and
appet i t e ( 5- HT1, 5- HT2, 5- HT3) . Ì n addi t i on, t he 5- HT1- r ecept or act s as an
aut orecept or t o i nhi bi t presynapt i c act i vi t y at bot h serot oner gi c and adr ener gi c
neurones i n t he CNS. Fur t hermore, i t di r ect l y cont r i but es t o vascul ar t one t hr ough
vasoconst ri ct i on. Ser ot oni n may al so pr oduce numer ous ot her ef f ect s, i ncl udi ng t he
opposi t e of t hose j ust st at ed, dependi ng on t he speci f i c recept or t hat medi at es t he
event .
P. 328



Figure 14-4. Structures oI (A) serotonin and
representative serotonin agonists (B) sumatriptan.
(C) tegaserod. and (D) the serotonin antagonist
ondansetron.
b. Serotoni n agoni st s
( 1) 5- HT1- agoni st s mi mi c t he act i ons of serot oni n at t hi s recept or t o decrease
pr esynapt i c neur ot r ansmi t t er r el ease. Di rect vasoconst ri ct i on, decr eased rel ease of
i nf l ammat or y and vasodi l at i ng subst ances ( neur oki ni n A, subst ance P) , and a di rect
ant i noci cept i ve act i vi t i es ar e t hought t o cont ri but e t o t he ef f i cacy of t hese dr ugs.
( 2) Tegaserod act i vat es t he serot oner gi c r ecept or ( 5- HT4) , causi ng t he r el ease of
acet yl chol i ne, ot her neurot r ansmi t t ers, and cal ci t oni n gene- rel at ed pept i de. These,
i n t ur n, i ncr ease gast r i c and i nt est i nal mot i l i t y and t one. Ì n addi t i on, di r ect act i ons
on t he gast r oi nt est i nal smoot h muscl e i s t hought t o cont r i but e i t i t s ef f ect , t hus
account i ng f or bot h t he di r ect and i ndi rect act i ons of t egaser od.
( 3) Ergot aI kaI oi ds pr oduce a wi de r ange of pharmacol ogi cal ef f ect s, i ncl udi ng bot h
agoni st i c and ant agoni st i c act i vi t y at adr ener gi c, dopami nergi c, and ser ot onergi c
r ecept or s. Speci f i c act i ons dependent on dr ug and ani mal model s.
c. Serot oni n ant agoni sts such as ondanset ron and rel at ed drugs bl ock t he i on-
channel coupl ed 5- HT3- r ecept or, t hus i nhi bi t i ng t he abi l i t y of ser ot oni n t o cause
nausea and/ or emesi s. Thi s act i on appears t o occur bot h l ocal l y at t he GÌ t r act and
cent r al l y i n t he area post r ema. Ì n addi t i on, act i vat i on of peri pher al 5- HT3- recept ors
wi l l i ncr ease pai n, abdomi nal di st ent i on, and mot or r esponses of t he i nt est i nal t r act .
Bl ockade of t hese act i ons, t hus sl owi ng GÌ mot i l i t y, by aI oset ron i s r esponsi bl e f or
i t s usef ul ness i n cer t ai n cases of i r ri t abl e bowel syndr ome ( Ì BS) .
3. Therapeut i c i ndi cat i ons
a. Serot oni n agoni st s
( 1) Numerous CNS act i ve dr ugs use t he serot oner gi c syst em t o modul at e behavi or ,
such as t he anor exi ant s ( dexf enf l ur ami ne) , anxi ol yt i cs ( buspi r one) , and sel ect i ve
ser ot oni n r eupt ake i nhi bi t or s f or depr essi on ( f l uoxet i ne) . These dr ugs ar e act i ng
mor e on t he neur ot r ansmi t t er f unct i on of serot oni n and are di scussed her e.
( 2) Some ergot aI kaI oi ds, sumat ri pt an, and si mi l ar dr ugs act t o modul at e t he
aut acoi d f unct i on of serot oni n. They ar e used t o pr event and t reat pai n associ at ed
wi t h mi gr ai ne headaches by al t er i ng serot oni n' s act i ons t hat resul t i n changes i n
vascul ar t one.
P. 329


( 3) Ì n addi t i on, some ergot aI kaI oi ds ar e used t o pr event post part um hemor r hagi ng
( t hr ough bot h vasoconst ri ct i ve and ut eri ne cont ract i l e act i ons) and t o prevent
post part um breast engorgement ( bromocri pt i ne, t hr ough dopami ner gi c act i vi t y) .
( 4) Tegaserod i s used i n t he t r eat ment of Ì BS t hat i s const i pat i on predomi nant .
b. Serotoni n antagoni sts. These agent s ( e. g. , ondanset ron, grani set ron,
doI aset ron, paI onoset ron) are used t o prevent and t r eat nausea and emesi s
secondar y t o ant i neopl ast i c t herapy by bl ocki ng t he act i ons of serot oni n at t he 5-
HT3- r ecept or . AI oset ron i s used f or t he t r eat ment of Ì BS t hat i s di ar r hea
pr edomi nant .
4. Adverse ef fect s
a. Serot oni n agoni st s
( 1) 5- HT1- agoni st s may pr oduce f eel i ngs of war mt h, par est hesi as, di zzi ness, and
t i ght ness or heavi ness i n t he chest . Rarel y, pat i ent s may exper i ence chest pai n.
Because t hese agent s may cause cor onar y vasoconst r i ct i on, t hey ar e
cont r ai ndi cat ed i n angi na pat i ent s and shoul d be used caut i ousl y i n pat i ent s wi t h
hyper t ensi on or ot her ri sk f act or s f or i schemi c hear t di sease.
( 2) Tegaserod may pr oduce di ar r hea, abdomi nal cr ampi ng and pai n, di zzi ness, and
headache as si de ef f ect s.
( 3) Ergot aI kaI oi ds may cause GÌ upset and col d ext r emi t i es. As t oxi ci t y
pr ogresses, t he pat i ent may exper i ence emesi s, di ar rhea, per i pheral pai n secondar y
t o l ocal i schemi a, and hal l uci nat i ons or del usi ons.
b. Serotoni n antagoni sts. The 5- HT3- ant agoni st s wi l l pr oduce headache,
const i pat i on, and di zzi ness. Ì n addi t i on, grani set r on has been repor t ed t o pr oduce
somnol ence and di ar rhea. The use of aI oset ron i n pat i ent s wi t h di ar r hea-associ at ed
Ì BS has resul t ed i n some cases of i schemi c col i t i s and l i f e- t hr eat eni ng
compl i cat i ons f rom severe const i pat i on. Subsequent t o a ser i es of adverse dr ug
r eact i ons i n t hi s manner , al oset r on i s gener al l y prescr i bed onl y by physi ci ans who
have been enrol l ed i n a pr escri bi ng pr ogr amme.
C. Prost agI andi ns
1. Chemi st r y
a. Pr ost agl andi ns ( PGs) ar e deri vat i ves of pr ost anoi c aci d, a 20-car bon f at t y aci d
cont ai ni ng a 5-carbon r i ng ( Fi gure 14- 5) . Ì n t he body, prost agl andi ns ar e pr i nci pal l y
synt hesi zed f rom ar achi doni c aci d, whi ch i s f ormed f rom t he membr ane
phosphol i pi ds by act i on of phosphol i pase A2. Speci f i cal l y, prost agl andi ns ar e
synt hesi zed f rom ar achi doni c aci d by t he enzyme cycl ooxygenase ( COX) , whi ch
exi st s as t hr ee i sozymes: COX 1, 2, and 3. COX 1 appear s t o f unct i on const ant l y.
Ì t s rol e seems t o be t he dai l y synt hesi s of pr ost agl andi ns, whi ch cont ri but e t o
nor mal homeost asi s, and i ncl udes prot ect i on of t he gast ri c mucosa t hrough t he
pr ost agl andi ns and hemost asi s t hr ough t he synt hesi s of t hromboxane. COX 2 i s
expr essed pri mar i l y i n r esponse t o i nf l ammat i on or i nj ur y, cont ri but i ng t o t he
i nf l ammat or y r esponse. Ì t i s al so i mpor t ant i n normal ( noni nj ur y) r egul at i on of
car di ac and perhaps ot her f unct i ons. COX 3 i s t hought t o be predomi nant l y act i ve
wi t hi n t he CNS, cont ri but i ng t o normal t her mor egul at or y cont rol and pai n per cept i on,
t hr ough t he synt hesi s of pr ost agl andi ns, cent ral l y. Not e t hat t he pr oduct s of
cycl ooxygenase are t hen conver t ed i nt o ei t her prost agl andi ns by pr ost agl andi n
synt hase or t hromboxanes by t hr omboxane synt hase. The t hr omboxanes di f f er f rom
t he pr ost agl andi ns mai nl y by t he subst i t ut i on of a t et rahydr opyr an r i ng st ruct ur e f or
t he pent ane r i ng f ound i n pr ost agl andi ns. The onl y cl i ni cal l y rel evant t hr omboxane
cur rent l y i dent i f i ed i s t hromboxane A2 ( TxA2) , whi ch causes pl at el et aggr egat i on.
b. CI assi fi cati on of pr ost agl andi ns as pr ost agl andi n A ( PGA) , pr ost agl andi n B
( PGB) , pr ost agl andi n E (PGE) , and so f or t h r el at es t o t he pr esence or absence of
ket o or hydr oxyl
P. 330

gr oups at posi t i ons 9 and 11 ( Fi gure 14- 5) . Subscr i pt s r el at e t o t he number and
posi t i on of doubl e bonds i n t he al i phat i c chai ns (Fi gur e 14- 6).

Figure 14-5. Structural Iormula oI prostanoic
acid. Irom which the prostaglandins are derived.

Figure 14-6. Structural Iormula oI misoprostol
(Cytotec). a derivative oI prostaglandin E
1

(PGE
1
).
2. PharmacoI ogy
a. Endogenous prost agl andi ns appear t o af f ect numer ous body f unct i ons. They ar e
r el eased i n response t o many chemi cal , bact eri al , mechani cal , and ot her i nsul t s;
and t hey appear t o cont ri but e t o t he si gns and sympt oms of t he i nf l ammat or y
pr ocess, i ncl udi ng pai n and edema.
b. Physi oI ogi caI responses t o pr ost agl andi ns i ncl ude vasodi l at i on i n most vascul ar
beds, al t hough vasoconst r i ct i on can occur i n i sol at ed ar eas. PGÌ i nhi bi t s pl at el et
aggregat i on and st i mul at es gast r i c rel ease of bi car bonat e and mucus, bot h of whi ch
ser ve t o pr ot ect t he gast r i c epi t hel i um. The PGEs i nhi bi t pl at el et aggregat i on, r el ax
br onchi al and GÌ smoot h muscl e, cont ract ut er i ne smoot h muscl e, and i nhi bi t gast r i c
aci d secr et i on. Al t er nat i vel y, t he PGDs and PGFs cont r act br onchi al and GÌ smoot h
muscl e. Pr ost agl andi ns al so i ncrease renal bl ood f l ow, pr omot e di ur esi s,
nat ri ur esi s, and kal i ur esi s; but paradoxi cal l y t hey i ncr ease r eni n secret i on. They
al so possess di verse endocri ne and met abol i c ef f ect s.
3. Therapeut i c i ndi cat i ons
a. PGE1 anaI ogs
( 1) AI prost adi I ( Pr ost i n VR Pedi at ri c) i s used f or t emporar y mai nt enance of a
pat ent duct us art eri osus when awai t i ng cor rect i ve surger y f or congeni t al hear t
def ect s.
( 2) AI prost adi I ( Caver j ect ) i s used i n t r eat i ng i mpot ence owi ng t o er ect i l e
dysf unct i on.
( 3) Mi soprost oI ( Cyt ot ec) i s used f or t he pr event i on of NSAÌ D- i nduced GÌ ul cers
( Fi gur e 14- 6) .
b. PGE2 anaI ogs and deri vat i ve di noprost one (Pr ost i n E2, Prepi di l , Cervi di l ) ar e
used f or t hei r abor t i f aci ent ef f ect s and t o i nduce cer vi cal - r i peni ng i n pr egnancy.
c. PGF2o anaI ogs
( 1) Carboprost ( Hemabat e) , was used f or i t s abor t i f aci ent ef f ect s. A hi gh i nci dence
of car di ovascul ar col l apse caused i t s r emoval f rom t he U. S. mar ket .
( 2) Lat anoprost ( Xal at an) , t ravoprost ( Tr avat an) , bi mat oprost (Lumi gan) , and
unoprost one ( Rescul a) ar e used t opi cal l y t o l ower i nt r aocul ar pressure i n
gl aucoma.
d. PGI anaI og epoprostenoI (pr ost acycl i n, [ Fl ol an] ) i s used pr i mari l y f or t he
t r eat ment of emergent pul monar y hyper t ensi on.
4. Adverse ef fect s associ at ed wi t h PGE i ncl ude t he f ol l owi ng:
a. CNS ef f ect s, such as CNS i r r i t abi l i t y, f ever, sei zur es, and headache
b. Cardi ovascul ar ef f ect s, such as hypot ensi on, dysr hyt hmi as, vasodi l at i on,
f l ushi ng, and car di ac arrest
c. Respi r at or y ef f ect s, such as r espi r at or y depr essi on and di st r ess
d. Hemat ol ogi cal ef f ect s, such as anemi a, t hrombocyt openi a, and di ssemi nat ed
i nt ravascul ar coagul at i on ( DÌ C)
e. Di ar r hea
f . Decr eased r enal f unct i on
g. Spot t y bl eedi ng and menst rual i r regul ari t i es, abor t i on, and peni l e pai n
D. Leukot ri enes
1. Chemi st r y
a. Leukot ri enes. The l eukot r i enes ( LTs) are 20-car bon deri vat i ves of t he f at t y aci ds
t hat ar e f ormed vi a t he enzymat i c pat hway cat al yzed by l i poxygenase. Unl i ke t he
pr ost agl andi ns, t hey cont ai n no r i ng st r uct ur e and ar e coval ent l y l i nked t o t wo or
t hr ee ami no aci ds.
P. 331

The t wo i mpor t ant l eukot r i enes i dent i f i ed t o dat e ( LTC4 and LTD4) di f f er onl y by t he
pr esence of gl ut ami ne. The nomencl at ure of t he l eukot r i enes i s si mi l ar t o t hat used
f or t he pr ost agl andi ns.
b. Leukot ri ene ant agoni st s
( 1) Li poxygenase i nhi bi t ors such as zi I eut on ( Zyf l o) are benzot hi ophene
der i vat i ves.
( 2) Leukot ri ene ant agoni st s such as zaf i rI ukast ( Accol at e) and monteI ukast
( Si ngul ai r ) represent a di ver se chemi cal gr oup t hat i s pept i domi met i c- l i ke i n i t s
st r uct ur e.
2. PharmacoI ogy
a. Leukot ri enes pl ay a rol e i n numerous physi ol ogi cal f unct i ons. They have been
i dent i f i ed as t he sl ow- r eact i ng subst ance of anaphyl axi s. Speci f i c act i ons of t he
l eukot ri enes i ncl ude t he f ol l owi ng:
( 1) Heart
( a) Negat i ve i not ropy
( b) Smoot h- muscl e chemot axi s
( 2) GÌ t ract . Neut rophi l chemot axi s t hat has been cor rel at ed wi t h i nf l ammat or y
bowel di sease
( 3) PuI monar y. The act i ons of t he l eukot ri enes wi t hi n t he pul monar y syst em appear
t o be maj or . These act i ons ar e t he most i mport ant phar macol ogi cal l y.
( a) Br onchoconst ri ct i on
( b) Ì ncr eased permeabi l i t y
( c) Ì ncr eased mucus secr et i on
( 4) BI ood/ I ymph. As not ed previ ousl y, t he l eukot r i enes act as chemot act i c agent s
f or neut rophi l s and eosi nophi l s and act t o modi f y l ymphocyt e prol i f er at i on and
di f f er ent i at i on.
b. Leukot ri ene ant agoni st s
( 1) The I i poxygenase i nhi bi t or zi I euton pr event s t he synt hesi s of l eukot r i enes by
i nhi bi t i ng t he enzyme responsi bl e f or t hei r f or mat i on÷namel y l i poxygenase. Thi s
act i on pr event s t he f or mat i on of al l l eukot r i enes, t hus prevent i ng t hei r cont r i but i on
t o var i ous i nf l ammat or y pr ocesses.
( 2) The l eukot r i ene ant agoni st s zaf i rI ukast and mont eI ukast nonsel ect i vel y and
compet i t i vel y i nhi bi t t he endogenous l eukot r i enes at t hei r var i ous r ecept or si t es.
Thi s act i on bl ocks t he ef f ect s of hi st ami ne, most not abl y t he br onchoconst r i ct i on
and pul monar y edema associ at ed wi t h ast hma and al l ergi c r eact i ons.
3. Therapeut i c i ndi cat i ons for zi I euton, zaf i rI ukast , and mont eI ukast ar e l i mi t ed
t o t he t reat ment of ast hma. These agent s reduce br onchospasm and associ at ed
sympt oms t hat ar e medi at ed t hrough t he l eukot r i enes.
4. Adverse Ef f ect s
a. Zi I euton pr esent s wi t h r el at i vel y f ew si de ef f ect s, predomi nant l y gast roi nt est i nal
i n nat ure (i . e. , dyspepsi a and nausea) . However , i t does cause t r ansi ent i ncr eases
i n hepat i c enzymes. Thi s pot ent i al f or hepat ot oxi ci t y has l i mi t ed i t s use.
b. Zaf i rl ukast may produce GÌ upset and l i ver dysf unct i on (not as great as wi t h
zi l eut on) , and may i nhi bi t t he met abol i sm of t heophyl l i ne, war f ar i n, and pot ent i al l y
ot her drugs. Sudden wi t hdr awal of cor t i cost er oi ds i n pat i ent s t aki ng zaf i rl ukast has
pr eci pi t at ed a Chur g- St rauss syndrome of eosi nophi l i c vascul i t i s. Pat i ent s shoul d be
counsel ed t o t ake zaf i rl ukast wi t h f ood t o enhance i t s absor pt i on.
c. MonteI ukast pr esent s wi t h a si de- ef f ect pr of i l e si mi l ar t o t hat f or zaf i rl ukast but
t ypi cal l y wi t h l ess i nci dence t han wi t h zaf i r l ukast . Churg- St r auss syndrome has not
been r epor t ed; however , t hi s may si mpl y ref l ect t he r el at i vel y recent appear ance of
t he dr ug on t he market . Mont el ukast may be t aken wi t hout r egar d t o f ood.
III. NONNARCOTIC ANALGESIC-ANTIPYRETICS AND
NSAIDS
A. SaI i cyI at es
1. Chemi st r y
a. Sal i cyl at es ar e deri vat i ves of saI i cyI i c aci d, whi ch i s f ound as t he gl ycosi de
sal i ci n i n wi l l ow bark. The pr ot ot ypi cal dr ug i s aspi ri n, t he acet yl est er of sal i cyl i c
aci d ( Fi gur e 14- 7) .
P. 332

A si mpl e est er , aspi ri n hydr ol yzes easi l y, i s unst abl e i n aqueous medi a, and i s
af f ect ed by moi st ur e.

Figure 14-7. Structural Iormula oI aspirin. the
prototypical salicylate analgesic-antipyretic.
b. More st abI e sal i cyl at es i ncl ude di f I uni sal ( Dol obi d) and t he t opi cal agent met hyI
saI i cyI at e ( wi nt er green oi l ) ( Fi gure 14- 8) . Ot her sal i cyl at es ar e saI saI at e ( Di sal ci d) ;
sodi um t hi osaI i cyI at e ( Resol ut e; i nj ect abl e) ; choI i ne saI i cyI at e ( Tr i l i sat e; oral
l i qui d); and t he sal i cyl at e deri vat i ves mesaI ami ne ( Asacol ), oI saI azi ne ( Di pent um) ,
and suI fasaI azi ne ( Azul f i di ne) .
c. Most sal i cyl at es ar e weak aci ds. Thei r excr et i on i s i nf l uenced by changes i n
ur i nar y pH.
2. PharmacoI ogy
a. Sal i cyl at es i nhi bi t t he enzyme cycl ooxygenase and t hus i nhi bi t l ocal
pr ost agl andi n synt hesi s ( see Ì Ì . C. 1. a) . As a r esul t , t hey ar e anal gesi c f or l ow-
i nt ensi t y i nt egument al pai n, ant i pyr et i c, and ant i - i nf l ammat or y. Not e t hat aspi r i n i s
t he onl y sal i cyl at e t hat i rr ever si bl y i nhi bi t s cycl ooxygenase by coval ent acet yl at i on
of t he enzyme.
b. Sal i cyl at es al so bI ock pl at el et cycl ooxygenase and subsequent f or mat i on of
t hr omboxane A2. As a r esul t , t hey i nhi bi t pl at el et aggregat i on and event ual
t hr ombus f ormat i on.
3. Therapeut i c i ndi cat i ons
a. Sal i cyl at es ar e i ndi cat ed f or use as:
( 1) AnaI gesi cs, f or rel i ef of muscul oskel et al pai n, headache, neural gi as, myal gi as,
and spasmodi c dysmenor r hea
( 2) Ant i - i nf I ammat or y agent s, f or r el i ef of var i ous ar t hri t i s sympt oms and acut e
r heumat i c f ever
( 3) Ant i pyret i c agent s, f or r el i ef of f ever . ( Chi l dr en wi t h vari cel l a or i nf l uenza- t ype
vi r al i nf ect i ons shoul d not be gi ven sal i cyl at es because of t he obser ved associ at i on
bet ween sal i cyl at e use i n t hese si t uat i ons and Reye syndr ome. )
b. Aspi ri n i s al so i ndi cat ed f or prophyI axi s of myocardi aI i nfarct i on.
c. Met hyI saI i cyI at e ( wi nt er gr een oi l ) i s used t opi cal l y as a counteri rri tant .
d. SuI fasaI azi ne, oI saI azi ne, and mesaI ami ne ar e used t o r educe t he i nf l ammat i on
associ at ed wi t h i nf l ammat or y bowel di sease and Cr ohn di sease.
4. Adverse ef fect s
a. SaI i cyI at es ar e associ at ed wi t h t he f ol l owi ng ef f ect s:
( 1) GÌ ef f ect s, such as nausea; vomi t i ng; and GÌ i r r i t at i on, di scomf or t , ul cer at i on,
and hemor rhage
( 2) Ì ncr eased dept h of respi rat i ons
( 3) Excessi ve bl eedi ng associ at ed wi t h i nhi bi t i on of t hr omboxane synt hesi s
( 4) Uncoupl i ng of oxi dat i ve phosphor yl at i on, hyper gl ycemi a, gl ycosur i a, and r educed
l i pogenesi s

Figure 14-8. Structural Iormulas oI salicylate
derivatives. A. DiIlunisal. B. Methyl salicylate.
P. 333



Figure 14-9. Structural Iormula oI
acetaminophen. the prototypical p-aminophenol
derivative.
( 5) Del ayed onset of l abor
( 6) Low dai I y doses of sal i cyl at es (2 g) decr ease r enal ur at e excr et i on and
i ncrease serum uri c aci d l evel s. Hi gh dai I y doses ( 5 g) have t he opposi t e ef f ect .
b. SuI fasaI azi ne has al so been shown t o have mal e r eproduct i ve ef f ect s, causi ng
i nf er t i l i t y.
c. SaI i cyI i sm ( sal i cyl at e t oxi ci t y, usual l y mar ked by t i nni t us, nausea, and vomi t i ng)
d. I ngesti on of 1 t easpoon of t he t opi cal agent met hyI saI i cyI at e ( wi nt er gr een oi l )
can cause fat aI i nt oxi cat i on.
B. p- Ami nophenoI deri vat i ves
1. Chemi st r y. The pr ot ot ypi cal p- ami nophenol der i vat i ve i s acetami nophen
( Tyl enol ) , an act i ve met abol i t e of phenacet i n and acet ani l i d (Fi gur e 14-9) .
2. PharmacoI ogy
a. p- Ami nophenol deri vat i ves i nhi bi t cent r al prost agl andi n synt hesi s ( see Ì Ì . C. Ì . a) ,
pr esumabl y t hr ough a sel ect i vi t y f or COX 3 wi t h rel at i vel y l i t t l e or no act i vi t y on
COX 1 or COX 2. They ar e anal gesi c f or l ow- i nt ensi t y pai n and ar e ant i pyr et i c.
b. Because t hey ar e l ess ef f ect i ve t han sal i cyl at es i n bl ocki ng peri pher al
pr ost agl andi n synt hesi s, t hey have no ant i -i nf l ammat or y act i vi t y and do not af f ect
pl at el et f unct i on.
3. Therapeut i c i ndi cat i ons
a. Acet ami nophen i s pri mar i l y used f or i t s anaI gesi c and ant i pyret i c acti vi t y,
par t i cul arl y i n a pat i ent unabl e t o t ol er at e sal i cyl at es.
b. Acet ami nophen may be saf el y used as an aI ternat i ve ant i pyret i c i n chi l dr en
wi t h var i cel l a or an i nf l uenza- t ype vi r al i nf ect i on ( see Ì Ì Ì . A. 3. a. (3) ) .
4. Adverse ef fect s
a. When gi ven i n t her apeut i c doses, adver se ef f ect s are l i mi t ed t o:
( 1) Ski n r ash
( 2) Hemol yt i c anemi a ( wi t h l ong-t erm phenacet i n use)
( 3) Met hemogl obi nemi a
( 4) Renal dysf unct i on and t ubul ar necr osi s
b. Acut e acet ami nophen over dose causes severe hepat ot oxi ci t y wi t h necrosi s and
l i ver f ai l ur e.
C. PyrazoI one deri vat i ves
1. Chemi st r y. The most i mpor t ant pyr azol one deri vat i ves are phenyI but azone, i t s
met abol i t e oxyphenbut azone, and t he ur i cosuri c agent suI f i npyrazone ( Ant ur ane).
Phenyl but azone i s t he prot ot ypi cal agent (Fi gur e 14- 10) .

Figure 14-10. Structural Iormula oI
phenylbutazone. a pyrazolone derivative.
P. 334


2. PharmacoI ogy
a. PhenyI but azone, oxyphenbut azone, and azapropazone i nhi bi t pr ost agl andi n
synt hesi s (see Ì Ì . C. Ì . a) and st abi l i ze l ysosomal membranes. As a resul t , t hey have
anal gesi c, ant i pyr et i c, and ant i -i nf l ammat or y ef f ect s. They al so have good uri cosur i c
act i vi t y.
b. SuI fi npyrazone i nhi bi t s pr oxi mal t ubul ar absorpt i on of urat e and has a ur i cosur i c
ef f ect . However , i t i s devoi d of anal gesi c, ant i pyret i c, or ant i -i nf l ammat ory ef f ect s.
3. Therapeut i c i ndi cat i ons
a. PhenyI but azone and oxyphenbut azone are used f or shor t -t erm t reat ment of
acut e rheumat oi d art hri t i c condi t i ons and acut e gout . However , t hey shoul d be gi ven
onl y af t er ot her t herapeut i c measur es have f ai l ed.
b. SuI fi npyrazone i s used t o cont r ol hyperur i cemi a i n t he t reat ment of i nt ermi t t ent
and chroni c gout .
c. These agent s are r arel y used, havi ng been r epl aced wi t h r el at i vel y saf er
compounds.
4. Adverse ef fect s
a. The adver se ef f ect s of phenyI but azone, oxyphenbut azone, and azapropazone
( t o a much l ess ext ent ) of t en l i mi t t hei r use and i ncl ude
( 1) GÌ ef f ect s, such as di scomf or t , nausea, vomi t i ng, dyspepsi a, and pept i c
ul cer at i on
( 2) Bl ood dyscr asi as, such as agranul ocyt osi s, apl ast i c anemi a, hemol yt i c anemi a,
t hr ombocyt openi a, and pet echi ae
( 3) Cardi ovascul ar ef f ect s, such as congest i ve hear t f ai l ur e wi t h edema and
dyspnea
( 4) Renal ef f ect s, such as nephrot i c l i t hi asi s, r enal necrosi s, i mpai red renal
f unct i on, and r enal f ai l ure
( 5) CNS ef f ect s, such as dr owsi ness, agi t at i on, conf usi on, headache, l et har gy,
numbness, weakness, t i nni t us, and heari ng l oss
( 6) Hypergl ycemi a
( 7) Ski n r ash
b. SuI fi npyrazone i s associ at ed wi t h t he f ol l owi ng adver se ef f ect s:
( 1) GÌ ef f ect s, such as di scomf or t and upset
( 2) Bl ood dyscr asi as, as wi t h phenyl but azone and oxyphenbut azone
( 3) Renal f ai l ure
D. Agent s used f or t he t reat ment of gout
1. Chemi st r y
a. Acut e at t acks of gout r esul t f r om an i nf l ammat or y r esponse t o j oi nt deposi t i ons of
sodi um urat e cr yst al s. Ther apeut i c agent s count er t hi s r esponse by reduci ng pl asma
ur i c aci d concent r at i ons or i nhi bi t i ng t he i nf l ammat or y r esponse.
b. Agent s used f or t he t reat ment of gout have wi del y var yi ng st r uct ur es and i ncl ude
t he pyr azol one deri vat i ve sul f i npyr azone (see Ì Ì Ì . C. 2. b; Ì Ì Ì . C. 3. b; Ì Ì Ì . C. 4. b) ; t he
al kal oi d coI chi ci ne; i sopur i nes, such as aI I opuri noI ( Zyl opri m); and benzoi c aci d
der i vat i ves, such as probeneci d (Benemi d) ( Fi gur e 14- 11) .
2. PharmacoI ogy
a. CoI chi ci ne' s mechani sm of act i on i s pr esumed t o be r el at ed t o i t s ant i mi t ot i c
act i vi t y. Ì t i nhi bi t s t ubul i n synt hesi s, whi ch i s requi r ed f or t he movement of
i nf l ammat or y cel l s.
P. 335

Thr ough i t s abi l i t y t o prevent t ubul i n pol ymeri zat i on, col chi ci ne appear s t o i nhi bi t
chemot axi s of l eukocyt es and ot her i nf l ammat or y cel l s i n t he af f ect ed j oi nt , t hus
r educi ng t he i nf l ammat ory r esponse t o deposi t ed ur at e cr yst al s by i nhi bi t i ng
l eukocyt e mi gr at i on and phagocyt osi s. Ì t al so i nt er f eres wi t h ki ni n f or mat i on and
r educes l eukocyt e l act i c aci d product i on.

Figure 14-11. Structural Iormulas oI agents used
in the treatment oI gout. A. Allopurinol. B.
Probenecid.
b. AI I opuri noI reduces ser um urat e l evel s by bl ocki ng ur i c aci d pr oduct i on. Ì t
compet i t i vel y i nhi bi t s t he enzyme xant hi ne oxi dase, whi ch conver t s xant hi ne and
hypoxant hi ne t o uri c aci d.
c. Probeneci d, a ur i cosur i c agent , i nhi bi t s t he pr oxi mal t ubul ar r eabsor pt i on of ur i c
aci d, i ncr easi ng ur i c aci d excr et i on, t hus reduci ng pl asma ur i c aci d concent r at i ons.
3. Therapeut i c i ndi cat i ons
a. CoI chi ci ne i s used pri nci pal l y f or t he t reat ment of acut e gout at t acks.
b. AI I opuri noI , whi ch reduces ur i c aci d synt hesi s and f aci l i t at es t he di ssol ut i on of
t ophi (chal ky ur at e deposi t s) , i s used t o pr event t he devel opment or pr ogr essi on of
chr oni c t ophaceous gout .
c. Probeneci d i s used t o t r eat chr oni c t ophaceous gout . Ì t i s al so used i n smal l er
doses t o pr ol ong t he ef f ect i veness of peni ci l l i n- t ype ant i bi ot i cs by i nhi bi t i ng t hei r
t ubul ar secr et i on.
4. Adverse ef fect s
a. Chroni c use of coI chi ci ne i s associ at ed wi t h t hese adver se ef f ect s:
( 1) Agranul ocyt osi s, apl ast i c anemi a, myopat hy, hai r l oss, and per i pheral neuri t i s
( 2) Nausea, vomi t i ng, abdomi nal pai n, and di ar r hea (i ndi cat i ons of i mpendi ng
t oxi ci t y)
b. AI I opuri noI i s associ at ed wi t h t he f ol l owi ng adver se ef f ect s:
( 1) GÌ ef f ect s, such as GÌ di st ress, nausea, vomi t i ng, and di ar rhea
( 2) Ski n r ash, St evens-Johnson syndr ome, and hepat ot oxi ci t y
( 3) Pr eci pi t at i on of an acut e gout at t ack ( wi t h i ni t i al al l opuri nol t herapy owi ng t o
i ni t i al mobi l i zat i on of st or ed ur at e)
c. Probeneci d i s associ at ed wi t h t he f ol l owi ng adver se ef f ect s:
( 1) Headaches, nausea, vomi t i ng, uri nar y f r equency, sor e gums, and dermat i t i s
( 2) Di zzi ness, anemi a, hemol yt i c anemi a, and renal l i t hi asi s
E. NSAI Ds
1. Chemi st r y
a. The cl assi c NSAI Ds consi st of many st r uct ural l y di verse aci ds. These i ncl ude
propi oni c aci d deri vat i ves (f enopr of en [ Nal f on] , f l urbi prof en [ Ocuf en] , i bupr of en
[ Mot r i n] , ket opr of en [ Or udi s] , naproxen [ Anapr ox, Napr osyn] , and oxapr ozi n
[ Daypr o] ), acet i c aci d der i vat i ves (di cl of enac [ Vol t ar en] , et odol ac [ Lodi ne] ,
i ndomet haci n [ Ì ndoci n] , ket or ol ac [ Tor adol ] , sul i ndac [ Cl i nori l ] , and t ol met i n
[ Tol ect i n] and t he subcl ass of t he f enamat es or ant hr ani l i c aci d der i vat i ves
mecl of enamat e and mef enami c aci d [ Ponst el ] ) , and t he enoI i c aci d deri vat i ves
( pi r oxi cam [ Fel dene] , mel oxi cam [ Mobi c] , and nabumet one [ Rel af en] ) ( Fi gur e 14- 12).
b. SeI ecti ve COX 2 i nhi bi t ors ceI ecoxi b ( Cel ebr ex) and rof ecoxi b ( Vi oxx) , and
vaI decoxi b (Bext r a) ar e pyr azol e deri vat i ves ( Fi gur e 14- 13) .
2. PharmacoI ogy
a. Nonspeci f i c NSAI Ds have ant i -i nf l ammat or y ef f ect s, r esul t i ng f r om t hei r abi l i t y t o
i nhi bi t t he cycl ooxygenase enzyme syst em and t hus r educe l ocal pr ost agl andi n
synt hesi s (see Ì Ì . C. 1. a) .
b. NSAÌ Ds al so have anal gesi c and ant i pyret i c ef f ect s. Ì n addi t i on, some NSAÌ Ds
have mi l d uri cosur i c act i vi t y. Some agent s al so have weak i nhi bi t or y act i vi t y f or
l i poxygenase, mi l d sel ect i vi t y f or COX 2, and weak t o moder at e abi l i t y t o i nhi bi t
l eukocyt e pr ol i f er at i on and mi grat i on and t o st abi l i ze l ysosomal membr anes. The
cl i ni cal r el evance of t hese secondar y act i ons has not been el uci dat ed.
c. COX 2 i nhi bi tors exer t ant i -i nf l ammat or y ef f ect s by speci f i cal l y i nhi bi t i ng
pr ost agl andi n synt hesi s associ at ed wi t h t he i nf l ammat or y response. Thei r abi l i t y t o
decrease pai n and i nf l ammat i on associ at ed wi t h ar t hri t i c di seases i s appr oxi mat el y
equal t o t hat pr oduced by t he nonsel ect i ve NSAÌ Ds. Mor eover , by vi r t ue of t hei r
sel ect i vi t y, t hei r act i ons on gast r i c mucosa and pl at el et aggr egat i on ar e t heori zed t o
be l ess t han t he nonsel ect i ve NSAÌ Ds.
P. 336



Figure 14-12. Structural Iormulas oI
representative nonsteroidal anti-inIlammatory
drugs (NSAIDs). A. IbuproIen (propionic acid
derivative). B. Indomethacin (acetic acid
derivative). C. MeIenamic acid (anthranilic acid
derivative). D. Piroxicam (enolic acid derivative).
3. Therapeut i c i ndi cat i ons
a. NSAI Ds, l i ke aspi r i n, ar e agent s of choi ce f or t he t r eat ment of rheumat oi d
ar t hri t i s, ost eoar t hri t i s, and ankyl osi ng spondyl i t i s. They may al so be used as
secondar y t reat ment s i n gout y ar t hri t i s.
b. COX 2 i nhi bi t ors are approved f or use i n bot h r heumat oi d ar t hri t i s and
ost eoart hri t i s.
4. Adverse ef fect s
a. NSAI Ds ar e associ at ed wi t h t he f ol l owi ng adver se ef f ect s:
( 1) GÌ ef f ect s, such as GÌ di st ress and i r r i t at i on, er osi on of gast ri c mucosa, nausea,
vomi t i ng, and dyspepsi a
( 2) CNS ef f ect s, such as CNS depr essi on, drowsi ness, headache, di zzi ness, vi sual
di st ur bances, ot ot oxi ci t y, and conf usi on
( 3) Hemat ol ogi c ef f ect s, such as t hr ombocyt openi a, al t ered pl at el et f unct i on, and
pr ol onged bl eedi ng t i me

Figure 14-13. Structural Iormula oI celecoxib. a
COX 2 speciIic inhibitor.
P. 337


( 4) Ski n r ash
( 5) Nephr ot oxi ci t y
b. COX 2 i nhi bi t ors do not appear t o cause as gr eat an i nci dence of GÌ ul cerat i on
or ant i pl at el et ef f ect s as t he nonsel ect i ve NSAÌ Ds. The most commonl y repor t ed
si de ef f ect s i ncl ude GÌ upset at a l ower i nci dence l evel . Despi t e t he pr omi se of
mi ni mal GÌ ul cer at i on, many pat i ent s exper i enced gast roi nt est i nal bl eedi ng wi t h
t hese dr ugs soon af t er t hei r r el ease. Thi s i s t hought t o have been an i nst ance of
over use/ overdosi ng of t he dr ug. Thi s ri sk of gast ri c damage and pot ent i al ul cer at i on
appears t o i ncr ease wi t h chroni c, hi gh dose use of t hese dr ugs. The pot ent i al f or
nephr ot oxi ci t y does exi st f or t hese dr ugs, and pat i ent s shoul d be moni t ored f or
changes i n renal f unct i on. Mor e r ecent adver se dr ug r eact i ons associ at ed wi t h t hese
dr ugs i ncl ude an i ncr eased ri sk of t hrombot i c event s, l eadi ng t o myocar di al
i nf ar ct i on and st r oke, whi ch coul d be pot ent i al l y f at al . Thi s i s l i kel y t he resul t of an
i nhi bi t i on of car di ovascul ar COX 2 and subsequent cl ot f ormat i on. Thi s has l ead t o
t he vol unt ar y r emoval of some of t hese dr ugs f r om t he market and caut i ous, cl osel y
super vi sed use of t he ot her s.
P. 338


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one of t he suggest ed answer s or
phr ases. Choose t he best answer .
1. A 45- year- oI d I ong- hauI t rucker suf fers f rom seasonaI aI I ergi es. He asks
advi ce on whi ch over- the counter product i s best t o reI i eve hi s sympt oms.
Whi ch of the foI I owi ng choi ces i s the best recommendati on f or t hi s pat i ent?
( A) di phenhydrami ne
( B) pr omet hazi ne
( C) cl emast i ne
( D) chl orpheni rami ne
( E) l orat adi ne
Vi ew Answer 1. The answer i s E[see] . 2. Whi ch of t he f oI I owi ng choi ces
wouI d be most appropri at e i n t reat i ng nausea and vomi t i ng associ at ed wi t h
mot i on si ckness?
( A) di phenhydrami ne
( B) br ompheni r ami ne
( C) ondanset r on
( D) omeprazol e
( E) r ani t i di ne
Vi ew Answer 2. The answer i s A[ see] . 3. EsomeprazoI e wouI d be ef f ecti ve
i n t he t reat ment of
( A) gast roesophageal r ef l ux di sease.
( B) pept i c ul cer di sease.
( C) Zol l i nger- El l i son syndr ome.
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 3. The answer i s D[ see] . 4. Whi ch of t he f oI I owi ng ant i uI cer
medi cat i ons i s most I i keI y t o cause drug i nteract i ons and endocri ne si de
ef f ects?
( A) r ani t i di ne
( B) omeprazol e
( C) l ansopr azol e
( D) ci met i di ne
( E) f amot i di ne
Vi ew Answer 4. The answer i s D[ see] . 5. A pati ent has j ust been di agnosed
wi t h recurrent mi grai ne headaches. Whi ch of the f oI I owi ng preexi st i ng
condi t i ons wouI d precI ude the use of sumat ri pt an for t hi s pat i ent ?
( A) l i ver di sease
( B) r enal f ai l ure
( C) i schemi c hear t di sease
( D) i r r i t abl e bowel syndrome ( Ì BS)
( E) gout y ar t hr i t i s
Vi ew Answer 5. The answer i s C[ see] . 6. Whi ch of t he f oI I owi ng i s an
appropri at e i ndi cati on for t he drug tegaserod?
( A) a f emal e pat i ent wi t h const i pat i on- rel at ed i r ri t abl e bowel syndrome ( Ì BS)
( B) a f emal e pat i ent wi t h di ar r hea- r el at ed Ì BS
( C) a mal e pat i ent wi t h Cr ohn di sease
( D) a mal e pat i ent wi t h di ar r hea- rel at ed Ì BS
( E) a pat i ent wi t h Zol l i nger - El l i son syndrome
Vi ew Answer 6. The answer i s A[ see] . 7. Whi ch of t he f oI I owi ng
prost agI andi n anaI ogs i s used speci f i caI I y f or t he t reat ment of gI aucoma?
( A) al pr ost adi l
( B) l at anopr ost
( C) carbopr ost
( D) di noprost one
( E) epopr ost enol
Vi ew Answer 7. The answer i s B[ see] . 8. The use of mi soprostoI to prevent
nonsteroi daI ant i -i nf I ammator y drug- i nduced uI cers couI d cause whi ch of t he
f oI I owi ng si de ef f ect s?
( A) f ever
( B) gast roi nt est i nal crampi ng and di ar rhea
( C) headache/ pai n
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 8. The answer i s D[ see] . 9. Whi ch of t he f oI I owi ng asthma
t herapi es has been associ ated wi th an acut e vascuI ar syndrome t hat i s
associ ated wi th sudden wi thdrawaI of cort i cost eroi d ant i -i nf I ammat ory drugs?
( A) zaf i rl ukast
( B) zi l eut on
( C) mont el ukast
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 9. The answer i s A[ see] . 10. Whi ch of t he f oI I owi ng ast hma
t herapi es i s ef f ect i ve by decreasi ng t he amount s of reI eased I eukot ri enes?
( A) zaf i rl ukast
( B) zi l eut on
( C) mont el ukast
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 10. The correct answer i s B[ see] . P. 339


11. Ri zat ri pt an i s ef fecti ve i n t reat i ng mi grai ne headache by
( A) di rect l y vasoconst r i ct i ng i nvol ved bl ood vessel s.
( B) i nhi bi t i ng t he r el ease of i nf l ammat or y neurot ransmi t t ers.
( C) di rect l y bl ocki ng pai n t r ansmi ssi on.
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 11. The answer i s D[ see] . 12. Whi ch of t he f oI I owi ng drugs,
based on i t s mechani sm of act i on, i s ef f ect i ve i n t reat i ng di arrhea- predomi nant
i rri t abI e boweI syndrome ( I BS)?
( A) t egaser od
( B) narat r i pt an
( C) al oset r on
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 12. The correct answer i s C[ see] . 13. Whi ch of the foI I owi ng
saI i cyI at es has been I i nked t o maI e reproducti ve t oxi ci t y wi t h chroni c dosi ng?
( A) aspi ri n
( B) di f l uni sal
( C) sodi um t hi osal i cyl at e
( D) ol sal azi ne
( E) sul f asal azi ne
Vi ew Answer 13. The correct answer i s E[see] . 14. Aspi ri n exerts i ts anti -
pI at eI et ef f ect by i nhi bi t i ng
( A) cycl ooxygenase ( COX) 1.
( B) COX 2.
( C) COX 3.
( D) pr ost agl andi n synt hesi s.
( E) l eukot r i ene synt hesi s.
Vi ew Answer 14. The correct answer i s A[ see] . 15. Acet ami nophen has
advant ages over aspi ri n or other nonsteroi daI ant i -i nf I ammat or y drugs by
vi rt ue of i ts
( A) r el at i ve l ack of ant i -pl at el et ef f ect s.
( B) r el at i ve l ack of gast roi nt est i nal ul cerat i ve ef f ect s.
( C) bei ng a saf e al t ernat i ve f or chi l dr en wi t h vi r al i nf ect i ons.
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 15. The correct answer i s D[ see] . 16. Acet ami nophen t oxi ci t y
i s charact eri zed by
( A) pr of ound vasoconst ri ct i on and pai n.
( B) sever e abdomi nal crampi ng and di ar rhea.
( C) cent r al ner vous syst em st i mul at i on and sei zur es.
( D) pr of ound l i ver damage and f ai l ur e.
( E) Al l of t he above
Vi ew Answer 16. The correct answer i s D[ see] . 17. Whi ch of the foI I owi ng
ant i gout medi cat i ons i s speci f i caI I y used i n acut e att acks?
( A) col chi ci ne
( B) al l opur i nol
( C) pr obeneci d
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 17. The correct answer i s A[ see] 18. Whi ch of t he f oI I owi ng
ant i gout medi cat i ons act s by decreasi ng serum I eveI s but i ncreasi ng uri ne
I eveI s of uri c aci d, t hus i ncreasi ng t he ri sk of ki dney st one deveI opment ?
( A) col chi ci ne
( B) al l opur i nol
( C) pr obeneci d
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 18. The correct answer i s C[ see] 19. The nonst eroi daI ant i -
i nf I ammator y drugs, as a cI ass, are ant i - i nf I ammat or y pri mari I y t hrough t hei r
abi I i t y t o i nhi bi t
( A) cycl ooxygenase ( COX) 1.
( B) COX 2.
( C) COX 3.
( D) l eukot r i ene synt hesi s.
( E) t hromboxane synt hesi s.
Vi ew Answer 19. The correct answer i s B[ see] 20. The seI ecti ve
cycI ooxygenase ( COX) 2 i nhi bi tors have been associ ated wi th whi ch of t he
f oI I owi ng adverse drug reacti ons?
( A) sever e i schemi c col i t i s
( B) t orsade des poi nt es
( C) cardi ovascul ar t hr ombot i c event s
( D) acut e l i ver f ai l ur e
( E) Churg- St rauss syndrome
Vi ew Answer 20. The correct answer i s C[ see] P. 340


ANSWERS AND EXPLANATIONS
1. The answer i s E [ see Ì Ì . A. 1. b. ( 1) ; Ì Ì . A. 3. b] .
Di phenhydrami ne, promet hazi ne, and cl emast i ne al l possess moder at e t o st r ong
ant i chol i nergi c act i vi t y. Thi s wi l l i ncr ease t he r i sk of sedat i on, whi ch coul d pr ove
danger ous i n t hi s pat i ent . Chl or pheni r ami ne, whi l e t he l east sedat i ng of t he f i rst -
gener at i on dr ugs, st i l l may cr oss t he bl ood- brai n bar r i er and cause some sedat i on.
Lor at adi ne, as a second-gener at i on dr ug t hat has mi ni mal ant i chol i ner gi c act i vi t y
and does not cross t he bl ood- br ai n bar ri er ( t hus pr oduci ng no cent ral ef f ect s) , i s
l east l i kel y t o cause sedat i on and t hus af f ect hi s j ob.
2. The answer i s A [ see Ì Ì . A. 3. b] .
Whi l e ondanset ron i s used f or nausea associ at ed wi t h chemot herapy and
anaest het i cs, i t i s not t ypi cal l y used f or nausea associ at ed wi t h mot i on or ver t i go.
Di phenhydrami ne, whi ch possesses a hi gh degree of ant i chol i ner gi c act i vi t y, i s
ef f ect i ve i n r educi ng nausea and vomi t i ng associ at ed wi t h vest i bul ocochl ear act i vi t y,
ver t i go, and mot i on si ckness. None of t he ot her choi ces di rect l y r educes nausea or
vomi t i ng, t her ef or e, di phenhydrami ne i s t he best choi ce.
3. The answer i s D [ see Ì Ì . A. 1. b. ( 3) ; Ì Ì . A. 3. d] .
Because al l t hr ee of t hese di sease st at es r epresent some act i on of excessi ve aci d
secr et i on, esomepr azol e, whi ch al so bl ocks t he pr ot on or aci d pump, woul d be
ef f ect i ve i n r educi ng t he aci d- i nduced pai n and damage associ at ed wi t h
gast r oesophageal ref l ux di sease ( GERD) , pept i c ul cer di sease (PUD) , and Zol l i nger -
El l i son syndr ome.
4. The answer i s D [ see Ì Ì . A. 4. d] .
Of t he dr ugs l i st ed, and speci f i cal l y, of t he H2-ant agoni st s, ci met i di ne i s t he onl y
dr ug t hat i nhi bi t s t he hepat i c mi cr osomal met abol i zi ng syst em (speci f i cal l y t he 3A4
i sozyme) and t he onl y drug t hat exhi bi t s weak andr ogeni c act i vi t y. The f ormer i s
r esponsi bl e f or numerous drug i nt er act i ons and some si de ef f ect s, wher eas t he
l at t er i s responsi bl e f or endocri ne ( speci f i cal l y andr ogen-l i ke) si de ef f ect s.
5. The answer i s C [ see Ì Ì . B. 2. a; Ì Ì . B. 4. a. ( 1) ] .
Sumat r i pt an ( and ot her dr ugs i n t he cl ass) speci f i cal l y cause vasoconst ri ct i on. Thi s
ef f ect , when present i n cor onor y vessel s, can cause chest t i ght ness of pai n as a
nor mal si de ef f ect of t he dr ug. However , i n pat i ent s wi t h i schemi c hear t di sease,
angi na, or a ri sk f or cor onar y ar t er y di sease, t hi s act i on coul d preci pi t at e at t acks of
angi na or pot ent i al l y cause myocar di al i nf arct i on and shoul d not be used i n t hose
pat i ent s.
6. The answer i s A [ see Ì Ì . B. 1. b. ( 2) ; Ì Ì . B. 2. b. ( 2); Ì Ì . B. 3. a. ( 4) ] .
Cur r ent l y, drugs are avai l abl e speci f i cal l y f or women wi t h Ì BS char act eri zed by
ei t her const i pat i on or di ar r hea. The i nt est i nal st i mul ant act i on of t egaserod makes i t
usef ul f or t hose pat i ent s wi t h const i pat i onassoci at ed Ì BS. Al t hough t egaser od (and
al oset ron) i s ( are) bei ng eval uat ed f or use i n men wi t h Ì BS, t he cur r ent
r ecommendat i on i s pri mar i l y f or women. Tegaserod, as a pr oki net i c agent , woul d
wor sen Ì BS t hat present s pri mar i l y wi t h di ar r hea. Because i t has no ant i -
i nf l ammat or y ef f ect , i t woul d not be ef f ect i ve i n t r eat i ng t he pri mar i l y i nf l ammat or y
nat ure of Cr ohn di sease. Tegaser od has no ef f ect on gast r i c aci d secr et i on and
woul d, t her ef or e, not be usef ul i n Zol l i nger - El l i son syndr ome.
7. The answer i s B [ see Ì Ì . C. 3. c. ( 2) ] .
Al t hough most prost agl andi n anal ogs are nonspeci f i c i n t hei r si t es of act i on and may
pr oduce si mi l ar physi ol ogi cal ef f ect s, l at anopr ost i s speci f i cal l y f or mul at ed and
market ed f or use i n t he t r eat ment of gl aucoma. Ì t s r el at i ve sel ect i vi t y f or t he PGF2q
r ecept or i s r esponsi bl e f or i t s abi l i t y t o l ower i nt raocul ar pressure and, t her ef or e, i t s
benef i t i n t r eat i ng gl aucoma.
8. The answer i s D [ see Ì Ì . C. 2. b; Ì Ì . C. 4] .
As not ed i n t he answer t o quest i on 7, most prost agl andi n anal ogs have act i vi t y at
r ecept or s t hr oughout t he body, causi ng a pr ost agl andi n-l i ke ef f ect on numer ous
or gan syst ems. Mi soprost ol , as a rel at i vel y nonsel ect i ve agoni st , woul d cause
cont r act i on of gast r oi nt est i nal smoot h muscl e, st i mul at e pai n f i ber s, and reset t he
t hermoregul at or y cent er of t he CNS, t hus causi ng al l t he pot ent i al si de ef f ect s
l i st ed.
P. 341


9. The answer i s A [ see Ì Ì . D. 4] .
Zaf i rl ukast i s t he onl y drug t hat has been associ at ed wi t h Chur g- St rauss syndr ome,
a condi t i on of eosi nophi l i c vascul i t i s t hat occur s when a pat i ent who i s on bot h
zaf i r l ukast and cor t i cost er oi d t her apy suddenl y di scont i nues t he cor t i cost er oi d. Thi s
ef f ect has not been obser ved wi t h t he pharmacol ogi cal l y si mi l ar drug mont el ukast .
Not e t hat sl ow wi t hdr awal of t he cor t i cost er oi d (whi ch shoul d be done anyway, t o
mi ni mi ze acut e adr enal i nsuf f i ci ency) wi l l prevent t hi s adver se dr ug r eact i on.
10. The correct answer i s B [ see Ì Ì . D. 2. b] .
Zaf i rl ukast and mont el ukast exer t t hei r ef f ect by bl ocki ng l eukot ri enes at t hei r
r ecept or . Zi l eut on, whi ch act s by i nhi bi t i ng l i po-oxygenase, wi l l decr ease t he
synt hesi s of t hese i nf l ammat or y medi at ors. Ther ef or e, i t i s t he onl y drug l i st ed t hat
wi l l decr ease t he synt hesi s and, consequent l y, t he r el ease of l eukot r i enes.
11. The answer i s D [ see Ì Ì . B. 1. b. ( 1); Ì Ì . B. 2. b. (1) ] .
Ri zat r i pt an ( and ot her drugs i n t he cl ass) are act i ng as 5- HT1- agoni st s. Thi s
mechani sm r esul t s i n t hree di st i nct and benef i ci al phar macodynami c ef f ect s. Fi rst , i t
causes di r ect vasoconst ri ct i on, whi ch r et ur ns t he bl ood vessel t o i t s pr eheadache
di amet er . Second, by act i ng on neur onal recept ors, i t i nhi bi t s t he r el ease of
addi t i onal vasodi l at i ng and pai n- t r ansmi t t i ng subst ances, such as neur oki ni n A and
subst ance P. Thi r d, t hi s act i on has been shown t o have a di r ect ant i noci cept i ve
act i on, prevent i ng t he f i ri ng of pai n neurones di rect l y. Ther ef or e al l t hr ee answer s
cor rect l y descr i be t he benef i t of r i zat r i pt an.
12. The correct answer i s C [ see Ì Ì . B. 1. c. (2) ; Ì Ì . B. 2. c; Ì Ì . B. 3. b] .
Al oset ron i s t he agent usef ul i n t r eat i ng di ar r hea-pr edomi nant Ì BS. By bl ocki ng t he
5- HT3- r ecept or , i t i nhi bi t s t he ser ot oni n-i nduced i ncr ease i n i nt est i nal mot i l i t y, t hus
sl owi ng per i st al si s and gut movement . Tegaserod woul d wor sen di ar rhea-
pr edomi nant Ì BS, because i t s ser ot oner gi c act i ons ar e agoni st i c and woul d st i mul at e
GÌ smoot h muscl e cont r act i on. Nar at r i pt an, act i ng as a 5- HT1- agoni st , has l i t t l e
ef f ect on GÌ mot i l i t y.
13. The correct answer i s E [ see Ì Ì Ì . A. 4. b] .
Of t he sal i cyl at es, sul f asal azi ne has been most associ at ed wi t h t hi s par t i cul ar
t oxi ci t y. Ì t i s a t oxi ci t y t hat occur s wi t h chr oni c use of t he drug i n men wi t h Cr ohn
di sease or ot her i nf l ammat or y condi t i ons of t he i nt est i ne. Wi t hdr awal of t he dr ug
may al l ow r eproduct i ve f unct i on t o r et ur n, al t hough t hi s i s not al ways t he case. Ì n
addi t i on, i t may t ake an ext ended peri od of t i me, af t er cessat i on of t her apy, f or
f unct i on t o ret urn.
14. The correct answer i s A [ see Ì Ì . C. 1. a; Ì Ì Ì . A. 2. a] .
Recal l t hat i n prost agl andi n and t hromboxane synt hesi s, COX 1 i s responsi bl e f or
much of t he dai l y pr oduct i on of mai nt enance ei cosanoi ds. COX 2, whi l e al so
cont r i but i ng t o dai l y product i on of pr ost agl andi ns and t hr omboxanes, i s mor e
i mpor t ant i n i nf l ammat i on. COX 3 i s t he cent r al sour ce of prost agl andi ns t hat
cont r i but e t o CNS f unct i on of t he ei cosanoi ds. Al so recal l t hat i t i s t hr omboxane t hat
speci f i cal l y has pl at el et -aggregat i ng abi l i t y. Ther ef or e, i t i s t hr ough i nhi bi t i on of
COX 1 and t he subsequent decrease i n t hr omboxane (not prost agl andi n or
l eukot ri ene) synt hesi s t hat t he ant i pl at el et ef f ect of aspi r i n i s ef f ect ed.
15. The correct answer i s D [ see Ì Ì . C. 1. a; Ì Ì Ì . B. 3] .
The r ol es of COX 1, 2, and 3 ar e r evi ewed i n t he answer t o quest i on 14. Because,
mechani st i cal l y, acet ami nophen i s t hought t o be r el at i vel y sel ect i ve f or COX 3, i t
woul d not possess any ant i pl at el et act i vi t y, nor woul d i t r educe t he synt hesi s of
gast r i c cyt oprot ect i ve prost agl andi ns. Theref or e, i t woul d not i nt er f ere wi t h pl at el et
f unct i on or ot her ant i pl at el et t her api es and i t woul d not be pr one t o cause gast r i c
ul cer at i on. Ì n addi t i on, t he r el at i onshi p bet ween aspi r i n and Reye syndr ome i n
chi l dren wi t h vi r al i nf ect i ons does not apparent l y exi st wi t h acet ami nophen, maki ng
i t a saf e ant i pyr et i c t o use i n t hose pat i ent s.
16. The correct answer i s D [ see Ì Ì Ì . B. 4. b] .
Acet ami nophen t oxi ci t y i s charact er i zed by a prof ound hepat oxi ci t y, whi ch i s
medi at ed by a react i ve i nt ermedi ar y f or med on sat ur at i on and depl et i on of t he
nor mal met abol i c pat hways. Thi s does not af f ect t he vascul at ur e ( as wi t h t he ergot
der i vat i ves) , t hus no vasoconst r i ct i on i s obser ved. Nei t her i s sever e GÌ upset
evi dent ( al t hough mi l d GÌ upset may occur ear l y i n t oxi ci t y) . Nor does pr of ound CNS
st i mul at i on occur , as i t does wi t h aspi r i n t oxi ci t y. Ther ef ore answer D i s cor r ect .
P. 342


17. The correct answer i s A [ see Ì Ì Ì . D. 1. a; Ì Ì Ì . D. 2. a; Ì Ì Ì . D. 3. a]
Al l opuri nol and pr obeneci d, whi l e ef f ect i ve i n prevent i ng at t acks of gout y ar t hri t i s by
l ower i ng ci r cul at i ng l evel s of uri c aci d, ar e not ef f ect i ve i n t reat i ng t he acut e
i nf l ammat or y si t uat i on t hat charact er i zes an acut e at t ack. Col chi ci ne, by i nhi bi t i ng
t he mi gr at i on of pr oi nf l ammat or y cel l s i nt o t he af f ect ed j oi nt , wi l l reduce t he
i nf l ammat or y process, t hus al l evi at i ng t he pai n and edema associ at ed wi t h acut e
at t acks of gout y ar t hri t i s.
18. The correct answer i s C [ see Ì Ì Ì . D. 2. c; Ì Ì Ì . D. 3. c; Ì Ì Ì . D. 4. c. (2)]
Pr obeneci d, as a uri cosur i c and promot i ng t he excr et i on of ur i c aci d, wi l l ef f ect i vel y
l ower pl asma concent rat i on of urat e. However , i t al so i ncreases t he ur i nary l evel s of
ur i c aci d. Ì f t hi s concent rat i on exceeds t he sol ubi l i t y const ant of uri c aci d i n t he
ur i ne, t hen i t may cr yst al l i ze and pr eci pi t at e out , causi ng st one f ormat i on or uri nar y
l i t hi asi s. For t hi s reason, pat i ent s t aki ng pr obeneci d shoul d al ways be counsel ed t o
dr i nk copi ous amount s of wat er .
19. The correct answer i s B [ see Ì Ì . C. 1. a; Ì Ì Ì . E. 2]
The r ol es of COX 1, 2, and 3 ar e r evi ewed i n t he answer t o quest i on 14. Ì t i s
t hr ough t hei r i nhi bi t i on of i nf l ammat or y pr ost agl andi n synt hesi s by i nhi bi t i ng COX 2,
t hat t he NSAÌ Ds exer t t hei r ant i - i nf l ammat or y act i ons.
20. The correct answer i s C [ see Ì Ì Ì . E. 4. b]
The pr i mar y si de ef f ect s t hat have been associ at ed wi t h t he COX 2 speci f i c
i nhi bi t ors are gast r oi nt est i nal bl eedi ng and, mor e r ecent l y, pot ent i al l y f at al
t hr ombot i c event s. The l at t er i s t hought t o ref l ect a t oxi codynami c ef f ect t hat resul t s
f r om i nhi bi t i on of vascul ar COX 2, whi ch cont ri but es t o t he dai l y cont r ol of pl at el et
and/ or vascul ar f unct i on. Sever e i schemi c col i t i s has been repor t ed wi t h al oset r on;
t or sade des poi nt s, wi t h ol der , second- generat i on ant i hi st ami ni cs; and ci sapr i de
whi ch are no l onger avai l abl e f or use; acut e l i ver f ai l ure, wi t h acet ami nophen
over dose; and Chur g- St rauss syndrome wi t h zaf i rl ukast and cor t i cost er oi d
wi t hdr awal . None of t hese adverse dr ug react i ons has been associ at ed wi t h t he COX
2 speci f i c i nhi bi t ors.

15
MedicinaI Chemistry and PharmacoIogy:
CardiovascuIar and Diuretic Drugs
Edward J. Moret on
I. INTRODUCTION.
Many cat egor i es of dr ugs af f ect t he cardi ovascul ar ( CV) and r enal syst ems. Cer t ai n
dr ugs can be used t o t r eat hear t f ai l ure (e. g. , cardi ac gl ycosi des and di uret i cs),
r el i eve angi na pect ori s (e. g. , ant i angi nal agent s), and cont r ol dysrhyt hmi as (e. g. ,
ant i ar r hyt hmi c agent s) . Ot her s can reduce hypert ensi on ( e. g. , ant i hyper t ensi ves,
i ncl udi ng a var i et y of di ur et i cs, 8- bl ocki ng agent s, and art er i ol ar smoot h muscl e
di l at ors) , t r eat t he hyper l i pi demi as (e. g. , ant i hyper l i pi demi c agent s) , reduce cl ot t i ng
and t r eat such condi t i ons as venous t hr ombosi s and pul monar y embol i sm ( e. g. ,
ant i coagul ant s, t hr ombol yt i cs) , and t r eat anemi as ( e. g. , ant i anemi c agent s) .
II. CARDI AC GLYCOSIDES AND POSITIVE INOTROPES
A. Chemi st r y
1. Al most al l of t he car di ac gl ycosi des (al so cal l ed cardi ot oni cs) are nat ur al l y
occur ri ng st er oi dal gl ycosi des obt ai ned f r om pl ant sour ces. Di gi t oxi n i s obt ai ned
f r om Di gi t al i s pur pur ea, di goxi n f r om Di gi t al i s l anat a, and ouabai n f r om
St r ophant hus gr at us.
2. The cardi ac gl ycosi des are cl osel y r el at ed st r uct ural l y, consi st i ng of one or more
sugar s ( i . e. , gI ycone port i on) and a st eroi dal nucl eus ( i . e. , agI ycon or geni n
port i on) bonded t hr ough an et her ( gI ycosi di c) I i nkage. These agent s al so have an
unsaturat ed I act one subst i t uent (cycI i c est er) on t he geni n por t i on. The
pr ot ot ypi cal agent i s di gi t oxi n ( Fi gure 15- 1).
a. Di goxi n ( Lanoxi n) has an addi t i onal hydroxyl gr oup at posi t i on 12 ( Fi gur e 15- 1).
b. Ouabai n has a r hamnose gl ycone por t i on and addi t i onal hydroxyl gr oups at
posi t i ons 1, 5, 11, and 19 ( Fi gure 15- 1) .
3. Removi ng t he gl ycone por t i on causes decreased act i vi t y and i ncreased t oxi ci t y
f r om changes i n pol ari t y t hat cause err at i c absorpt i on f r om t he gast r oi nt est i nal ( GÌ )
t r act .
4. The durat i on of acti on of a car di ac gl ycosi de i s i nverseI y proport i onaI t o t he
number of hydroxyI groups, whi ch i ncr ease pol ar i t y. Ì ncr eased pol ari t y r esul t s i n
decreased prot ei n bi ndi ng, decreased l i ver bi ot ransf or mat i on, and decreased r enal
t ubul ar r eabsor pt i on.
a. Di gi t oxi n has a l ong dur at i on of act i on and may accumul at e.
b. Ouabai n, i n cont rast , has an ext r emel y shor t dur at i on of act i on and i s ef f ect i ve
onl y when gi ven i nt r avenousl y.

Figure 15-1. Structural Iormula oI digitoxin
(Crystodigin). the prototypical cardiac glycoside.
P. 344



Figure 15-2. Structural Iormulas oI bipyridine
derivatives. A. Amrinone (Inocor). B. Milrinone
(Primacor).
5. Amri none, i namri none, and mi I ri none ar e bi pyr i di ne der i vat i ves wi t h posi t i ve
i not r opi c act i on ( Fi gur e 15- 2).
B. PharmacoI ogy. Car di ac gl ycosi des i ncr ease myocar di al cont r act i l i t y and
ef f i ci ency, i mprove syst emi c ci rcul at i on, i mpr ove r enal per f usi on, and r educe
edema. The el ect r ophysi ol ogi cal ef f ect s of cardi ac gl ycosi des are summari zed i n
Tabl e 15- 1. Angi ot ensi n-convert i ng enzyme ( ACE) i nhi bi t ors and perhaps AT1
angi ot ensi n- recept or ant agoni st s; vasodi l at ors such as ni t r oprussi de, ni t r ogl yceri n,
and hydr al azi ne; and di ur et i cs may be i mpor t ant adj unct s t o cardi ac gl ycosi des.
ACE i nhi bi t ors may be consi der ed as f i r st -l i ne t reat ment .
1. When gi ven i n t her apeut i c doses, car di ac gl ycosi des produce posi t i ve i not r opi c
ef f ect s by i nhi bi t i ng membr ane- bound Na
+
/ K
+
-act i vat ed adenosi ne t ri phosphat ase
( ATPase) . These ef f ect s of car di ac gl ycosi des i ncr ease t he rat e of t ensi on
devel opment , t he cont r act i l i t y, and t he r at e of rel axat i on of car di ac muscl e. The
ef f ect s i ncl ude
a. Ì ncrease i n i nt racel l ul ar sodi um concent r at i on
b. Reduct i on i n cal ci um t r ansport f r om t he cel l by t he sodi um-cal ci um exchanger
c. Faci l i t at i on of cal ci um ent r y vi a vol t age- gat ed membr ane channel s
d. Ì ncr eased rel ease of cal ci um f rom sar copl asmi c r et i cul um
2. Ther apeut i c doses of car di ac gl ycosi des al so cause
a. A negat i ve chr onot r opi c ef f ect f r om i ncr eased vagal t one of t he si noat ri al ( SA)
node
b. Di mi ni shed cent ral ner vous syst em ( CNS) sympat het i c out f l ow f r om i ncr eased
car ot i d si nus bar or ecept or sensi t i vi t y
c. Syst emi c ar t er i ol ar and venous const r i ct i on, whi ch i ncreases venous r et ur n and
t hus i ncreases car di ac out put
3. Amr i none and mi l r i none produce posi t i ve i not ropi c ef f ect s and vasodi l at i on vi a
sel ect i ve i nhi bi t i on of t ype Ì Ì Ì phosphodi est erase ( PDE) i sozyme, l eadi ng t o an
i ncrease i n cycl i c adenosi ne monophosphat e (cAMP) i n car di ac and smoot h muscl e.
Ì nhi bi t i on of t ype Ì Ì Ì PDE pr oduces
Table 15-1. Effects of Cardiac Glycosides on the Heart
Effects Atria AV Node Ventricles
Direct Contractility | ERP | Contractility |

ERP | Conduction
velocity |
ERP |

Conduction
velocity |
Automaticity
|
Indirect ERP | ERP | No eIIect

Conduction
velocity |
Conduction
velocity |

On
electrocardiogram
P changes PR interval | QT |

T and ST
depressed
Adverse Extrasystole AV
depression or
block
Fibrillation
Tachycardia Extrasystole
Tachycardia
AJ. atrioventricular; ERP. eIIective reIractory period; |. increased; |.
decreased.
Reprinted with permission Irom Jacob LS. Pharmacology. 3rd ed. Malvern.
PA. Harwal. 1992:96.

P. 345


a. Vasodi l at i on and f al l i n vascul ar resi st ance
b. Ì ncr eased f orce of cardi ac cont r act i on
c. Ì ncreased vel oci t y of car di ac rel axat i on
C. Therapeut i c i ndi cati ons
1. Hear t f ai l ur e ( st age C onl y)
2. At ri al f i br i l l at i on
3. At ri al f l ut t er
4. Paroxysmal at r i al t achycar di a
5. Amr i none and mi l r i none are i ndi cat ed f or short - t erm t reat ment of congest i ve hear t
f ai l ur e onl y.
D. Adverse ef f ect s
1. EarI y adverse ef f ects of car di ac gl ycosi des repr esent t he earl y st ages of
t oxi ci t y, i ncl udi ng
a. GÌ ef f ect s, such as anor exi a, nausea, vomi t i ng, and di ar rhea
b. CNS ef f ect s, such as headache, vi sual di st ur bances ( gr een or yel l ow vi si on),
conf usi on, del i r i um, neural gi as, and muscl e weakness
2. Lat er adverse ef f ects r epr esent i nt oxi cat i on and i ncl ude such ser i ous cardi ac
di st ur bances as pr emat ur e vent ri cul ar cont r act i ons, paroxysmal and nonpar oxysmal
at r i al t achycardi a, at r i ovent ri cul ar ( AV) di ssoci at i on or bl ock, vent ri cul ar
t achycardi a, and vent r i cul ar f i br i l l at i on.
III. DRUGS FOR TREATMENT OF MYOCARDI AL
ISCHEMIA
A. Chemi st r y
1. Ant i angi naI agent s i ncl ude ni t ri t es ( i . e. , or gani c est er s of ni t rous aci d) such as
amyl ni t ri t e, ni t rat es ( i . e. , organi c est ers of ni t r i c aci d) such as ni t r ogl ycer i n and
i sosorbi de, ß- bI ockers such as propr anol ol , and caI ci um antagoni st s such as
ver apami l and ni f edi pi ne ( Fi gur e 15-3) .
a. AmyI ni t ri t e i s a vol at i l e and f l ammabl e l i qui d admi ni st er ed by i nhal at i on. Ì t
r equi r es speci al pr ecaut i ons ( especi al l y r est r i ct i on of smoki ng) dur i ng
admi ni st rat i on.
b. Ni t rogI yceri n i s al so a vol at i l e and f l ammabl e l i qui d and requi r es gr eat car e
dur i ng st or age. Ì t must be di spensed f r om i t s ori gi nal gl ass cont ai ner s and pr ot ect ed
f r om body heat .
( 1) When gi ven i nt r avenousl y, ni t r ogl ycer i n r equi r es t he use of speci al pl ast i c
admi ni st rat i on set s t o avoi d absorpt i on and l oss of pot ency.
( 2) Ni t rogI yceri n i s met abol i cal l y unst abl e and undergoes ext ensi ve f i rst -pass
met abol i sm.
2. Peri pheraI vasodi I ators i ncl ude t he di pi per i di no-di pyri mi di ne di pyri damol e
( Fi gur e 15- 3) .
B. PharmacoI ogy
1. Ni t ri tes and ni t rates ar e f ast - act i ng ant i angi nal agent s t hat di r ect l y r el ax
vascul ar smoot h muscl e by f ormat i on of t he f r ee radi cal ni t r i c oxi de ( NO) , whi ch i s
i dent i cal t o endot hel i um-der i ved r el axi ng f act or (EDRF) . NO act i vat es guanyl yl
cycl ase t o i ncr ease synt hesi s of cycl i c guanosi ne monophosphat e (cGMP) wi t hi n
smoot h muscl e, resul t i ng i n dephosphor yl at i on of l i ght chai n myosi n and muscl e
r el axat i on. Thi s causes per i pheral pool i ng of t he bl ood, di mi ni shed venous r et ur n
( r educed prel oad), decreased syst emi c vascul ar resi st ance, and decreased ar t er i al
pr essure ( reduced af t erl oad) . These vascul ar ef f ect s:
a. Reduce myocar di al oxygen demand
b. Cause r edi st r i but i on of cor onar y bl ood f l ow al ong t he col l at er al coronary ar t er i es,
i mprovi ng per f usi on of t he i schemi c myocardi um
2. ß- Adrenergi c bI ockers decr ease sympat het i c-medi at ed myocar di al st i mul at i on
( see Chapt er 13, Ì V. A. 2, Ì V. C. 4) . The r esul t i ng negat i ve i not r opi c and negat i ve
chr onot r opi c ef f ect s reduce myocar di al oxygen r equi rement s.
P. 346



Figure 15-3. Structural Iormulas oI antianginal
agents. A. Nitroglycerin (Nitrostat). B. Isosorbide
dinitrate (Isordil). C. NiIedipine (Procardia). D.
Dipyridamole (Persantine).
3. CaI ci um ant agoni st s ( al so known as caI ci um channeI bI ockers) bl ock cal ci um
ent r y t hr ough t he membranous cal ci um i on ( Ca
++
) channel s of cor onar y and
per i pheral vascul ar smoot h muscl e.
a. Peri pher al ar t eri ol es di l at e and t ot al peri pher al r esi st ance decr eases, reduci ng
af t erl oad and r educi ng myocar di al oxygen r equi rement s.
b. Cal ci um ant agoni st s al so i ncr ease oxygen del i ver y t o t he myocar di um by di l at i ng
cor onar y ar t eri es and ar t er i ol es.
4. Di pyri damoI e r el axes smoot h muscl es, decreasi ng cor onar y vascul ar resi st ance
and i ncr easi ng cor onar y bl ood f l ow.
C. Therapeut i c i ndi cati ons
1. Ni t ri tes and ni t rates ar e used t o r el i eve acut e angi nal at t acks, as prophyl axi s
dur i ng ant i ci pat i on of an acut e angi nal at t ack, and f or l ong- t erm management of
r ecur r ent angi na pect ori s.
2. ß- Adrenergi c bI ockers ar e used f or adj unct i ve pr ophyl axi s of chr oni c st abl e
angi na pect or i s i n combi nat i on wi t h ni t r i t es or ni t r at es. They have al so been shown
t o i ncrease sur vi val t i me i n heart f ai l ur e and af t er myocar di al i nf arct i on (MÌ ) . Thr ee
8- bl ocker s are proven t o r educe mor t al i t y i n heart f ai l ure and ar e now cl ass Ì
r ecommendat i ons f or hear t f ai l ur e.
3. CaI ci um ant agoni st s ar e used t o t reat chr oni c st abl e angi na pect ori s and var i ant
( Pr i nzmet al ) angi na.
4. Di pyri damoI e i s now used pri mar i l y as a pl at el et aggregat i on i nhi bi t or.
P. 347


D. Adverse ef f ect s
1. Ni t ri tes and ni t rates ar e associ at ed wi t h:
a. CNS ef f ect s, such as headache, appr ehensi on, di zzi ness, and weakness
b. CV ef f ect s, such as hypot ensi on, t achycar di a, pal pi t at i ons, and syncope
c. Ski n ef f ect s, such as rash and der mat i t i s
d. Met hemogl obi nemi a
2. ß- Adrenergi c bI ockers ar e associ at ed wi t h:
a. Wor seni ng of congest i ve heart f ai l ur e
b. Br adycardi a and hypot ensi on
c. Reduced ki dney bl ood f l ow and decreased gl omer ul ar f i l t r at i on
3. CaI ci um ant agoni st s gener al l y pr oduce onl y mi l d adver se ef f ect s.
a. When gi ven i n conj unct i on wi t h 8-adrener gi c bl ockers, t he CV ef f ect s of cal ci um
ant agoni st s may be enhanced, resul t i ng i n bradycar di a, hypot ensi on, per i pher al
edema, congest i ve heart f ai l ure, AV bl ock, and asyst ol e.
b. Verapami I may al so cause sl eepl essness, muscl e f at i gue, nyst agmus, and
emot i onal depr essi on. Dur i ng t he f i r st week of t her apy, verapami l i ncr eases serum
di gi t al i s concent r at i ons and may cause di gi t al i s t oxi ci t y.
4. Di pyri damoI e i s associ at ed wi t h:
a. GÌ ef f ect s, such as nausea, vomi t i ng, and di ar rhea
b. CNS ef f ect s, such as headache and di zzi ness
c. CV ef f ect s, such as hypot ensi on ( wi t h excessi ve doses)
d. Bl eedi ng
IV. ANTI ARRHYTHMIC AGENTS
A. Chemi st r y. Ant i ar r hyt hmi c agent s have wi del y di verse chemi cal st ruct ur es. They
i ncl ude repr esent at i ves of t he f ol l owi ng gr oups:
1. Ci nchona aI kaI oi ds÷such as qui ni di ne (an opt i cal i somer of qui ni ne)
2. Ami des÷such as procai nami de ( Pronest yl ), f l ecai ni de ( Tambocor ) , and
di sopyr ami de ( Nor pace)
3. XyI yI deri vat i ves÷such as l i docai ne ( Xyl ocai ne) and mexi l et i ne ( Mexi t i l )
4. Quaternar y ammoni um saI t s÷such as br et yl i um ( Bret yl ol )
5. Di i odobenzyI oxyet hyI ami nes÷such as ami odar one ( Cordarone)
6. ß- BI ockers÷such as, nadol ol ( Cor gar d) , pr opranol ol ( Ì nder al ) , esmol ol
( Br evi bl oc), and acebut ol ol ( Sect r al )
7. CaI ci um ant agoni st s÷such as di l t i azem ( Cardi zem) and ver apami l ( Cal an)
8. Hydant oi ns÷such as phenyt oi n ( Di l ant i n)
B. PharmacoI ogy. Ant i ar r hyt hmi c agent s ar e cl assi f i ed accordi ng t o t hei r abi l i t y t o
al t er t he act i on pot ent i al of cardi ac cel l s ( Tabl es 15- 2 and 15- 3) . The myocar di al
act i on pot ent i al cur ve i s shown i n Fi gure 15- 4.
1. CI ass I A drugs (e. g. , qui ni di ne, procai nami de, di sopyr ami de) pr oduce st at e-
dependent sodi um channel bl ockade t o sl ow t he rat e of ri se of phase 0 ( t he phase
of r api d depol ari zat i on and r ever sal of t ransmembr ane vol t age) and pr ol ong
r epol ari zat i on and ef f ect i ve r ef r act or y peri od.
2. CI ass I B drugs (e. g. , l i docai ne, t ocai ni de, mexi l et i ne, phenyt oi n) have a mi ni mal
ef f ect on t he r at e of r i se of phase 0 and shor t en repol ar i zat i on.
3. CI ass I C drugs (e. g. , f l ecai ni de, pr opaf enone) have a mar ked ef f ect i n sl owi ng
t he rat e of r i se of phase 0 and i n sl owi ng conduct i on. They have l i t t l e ef f ect on
r epol ari zat i on. Encai ni de was wi t hdr awn f r om t he market but i s avai l abl e on a
l i mi t ed basi s.
P. 348


Table 15-2. Major Effects of Antiarrhythmic Drugs on Electrocardiogram
Drug QRS QT PR
a

Quinidine | | ÷|
Procainamide
Amiodarone
Disopyramide | | ÷
Lidocaine ÷ | ÷||
Phenytoin
Tocainide
Mexiletine
Propranolol ÷ | ÷|
|. increased; |. decreased; ÷. no change.
a
All antiarrhythmic drugs have a variable response. usually with little
observable eIIect. However. lidocaine hardly ever aIIects the PR interval.
whereas phenytoin and propranolol usually increase the PR interval.
Reprinted with permission Irom Jacob LS. Pharmacology. 3rd ed. Malvern.
PA. Harwal. 1992:102.

Table 15-3. Effects of Antiarrhythmic Drugs on Electrophysiologic Properties of
the Heart
Automaticity
Effective Refractory
Period
Membrane
Responsiveness
Drug
Class
SA
Node
Purkinje
Fibers AV Node
Purkinje
Fibers Purkinje Fibers
IA ÷| |÷ |÷| || |
IB ÷ | ÷| | ÷|
IC ÷ | | | |
II | | | |÷| |
III || || |÷| | ÷
IV | ÷| | ÷ ÷
|. increased; |. decreased; ÷. no change.


Figure 15-4. Myocardial action potential curve.
This curve represents ventricular
depolarization/repolarization. 0. phase 0 (rapid
depolarization); 1. phase 1 (early rapid
repolarization); 2. phase 2 (plateau); 3. phase
(Iinal rapid repolarization); 4. phase 4 (slow
depolarization).
P. 349


4. CI ass I I drugs ( e. g. , pr opranol ol , nadol ol , esmol ol , acebut ol ol ) are 8-adr ener gi c
ant agoni st s t hat compet i t i vel y bl ock cat echol ami ne- i nduced st i mul at i on of car di ac 8-
r ecept or s and depr ess depol ar i zat i on of phase 4.
5. CI ass I I I drugs ( e. g. , br et yl i um, ami odar one, sot al ol , i but i l i de, dof et i l i de)
i ncrease act i on pot ent i al dur at i on by pr ol ongi ng repol ar i zat i on vi a bl ockade of t he
del ayed rect i f i er pot assi um cur rent Ì Kr .
6. CI ass I V drugs (e. g. , ver apami l , di l t i azem, bepr i di l ) ar e cal ci um ant agoni st s t hat
bl ock t he sl ow i nwar d cur r ent carr i ed by cal ci um dur i ng phase 2 (i . e. , l ong- sust ai ned
depol ari zat i on or t he pl at eau of t he act i on pot ent i al ), i ncrease t he ef f ect i ve
r ef r act or y peri od, and depr ess phase 4 depol ar i zat i on.
7. Di goxi n and adenosi ne. Di gi t al i s gl ycosi des (di goxi n) el i ci t a vagot oni c r esponse
t hat i ncr eases AV nodal r ef r act ori ness. Adenosi ne act s at G-pr ot ei n- coupl ed
adenosi ne r ecept ors t o i ncr ease AV nodal r ef ract or i ness.
8. Mori ci zi ne i s a t ype Ì ant i ar r hyt hmi c but not A, B, or C. Ì t exhi bi t s pot ent l ocal
anest het i c act i vi t y and myocar di al membr ane st abi l i zi ng act i vi t y. Mor i ci zi ne r educes
f ast i nwar d sodi um curr ent , decr easi ng t he act i on pot ent i al durat i on and ef f ect i ve
r ef r act or y peri od, and i ncr eases t he PR, QRS, and QTe i nt er val .
C. Therapeut i c i ndi cati ons. Ant i ar r hyt hmi c agent s ar e used t o reduce
abnor mal i t i es of i mpul se gener at i on ( ect opi c pacemaker aut omat i ci t y) and t o modi f y
t he di st urbances of i mpul se conduct i on wi t hi n cardi ac t i ssue. ( Ì ndi cat i ons f or
speci f i c agent s ar e gi ven i n Tabl e 15-4. )
Table 15-4. Use of Antiarrhythmic Drugs in Common Cardiac Arrhythmias
Arrhythmia Treatment of Choice Alternatives
I. Supraventricular
Atrial Iibrillation
or Ilutter
Digital to control
ventricular rate.
DC shock Ior
conversion
Quinidine to suppress
recurrences aIter DC shock
Paroxysmal atrial
or nodal
tachycardia
Vagotonic
maneuver;
digitalis
Verapamil (quinidine.
procainamide. disopyramide.
and þ-adrenergic antagonists
may all be useIul. especially
prophylactically)
II. Ventricular
Ventricular
premature
depolarization
Lidocaine Procainamide. quinidine. or
disopyramide Ior prolonged
suppression
Ventricular DC shock Lidocaine. procainamide. or
tachycardia mexiletine
III. Digitalis-induced

Lidocaine or
phenytoin
Procainamide is somewhat
useIul; þ-adrenergic antagonists
are useIul but have a high
incidence oI adverse eIIects
DC. direct current.
Reprinted with permission Irom Jacob LS. Pharmacology. 3rd ed. Malvern.
PA. Harwal. 1992:102.

P. 350


D. Adverse ef f ect s
1. CI ass I A drugs ar e associ at ed wi t h CV ef f ect s ( e. g. , myocardi al depressi on, AV
bl ock, vent ri cul ar dysr hyt hmi as, asyst ol e, and hypot ensi on) and wi t h GÌ ef f ect s
( e. g. , GÌ upset , nausea, vomi t i ng, and di arr hea) . Ì n addi t i on:
a. Qui ni di ne can cause ci nchoni sm, wi t h t i nni t us, conf usi on, phot ophobi a,
headache, and psychosi s.
b. Procai nami de can cause syst emi c l upus er yt hemat osus- ( SLE- ) l i ke syndr ome.
c. Di sopyrami de can cause congest i ve heart f ai l ur e and ant i muscari ni c ef f ect s.
2. CI ass I B drugs ar e associ at ed wi t h CNS ef f ect s ( i ncl udi ng CNS depr essi on,
dr owsi ness, di sor i ent at i on, and par est hesi as) , CV ef f ect s (i ncl udi ng hypot ensi on
and ci rcul at or y col l apse), and hepat i t i s. Ì n addi t i on:
a. Li docai ne can cause sei zures and r espi r at or y ar r est .
b. Tocai ni de can cause pneumoni t i s and bl ood dyscr asi as.
c. Mexi I eti ne can cause hepat i c i nj ur y and bl ood dyscrasi as.
d. Phenyt oi n can cause nyst agmus, decr eased ment al f unct i on, and bl ood
dyscrasi as.
3. CI ass I C drugs ar e associ at ed wi t h:
a. CV ef f ect s, i ncl udi ng wor seni ng of arr hyt hmi as i n pat i ent s wi t h vent r i cul ar
ar r hyt hmi as, part i cul ar l y pat i ent s wi t h a hi st or y of MÌ . They can wor sen si nus node
dysf unct i on and heart f ai l ur e.
b. Vi sual di st urbances such as bl ur r ed or doubl e vi si on
4. CI ass I I drugs ar e associ at ed wi t h:
a. CV ef f ect s, such as hypot ensi on, AV bl ock, and asyst ol e
b. Respi r at or y ef f ect s, such as bronchospasm
5. CI ass I I I drugs ar e associ at ed wi t h:
a. CV ef f ect s, such as hypot ensi on and i ni t i al l y i ncr eased dysr hyt hmi as
b. GÌ ef f ect s, such as nausea and vomi t i ng
6. CI ass I V drugs ar e associ at ed wi t h CV adverse ef f ect s, such as hypot ensi on,
br adycar di a, AV bl ock, congest i ve hear t f ai l ur e, and asyst ol e.
7. Cardi ac gI ycosi des (see Ì Ì . D). Adenosi ne causes asyst ol e l ast i ng l ess t han 5
sec and i s t he t her apeut i c obj ect i ve.
8. Because of i t s pr oarr hyt hmi c act i vi t y, mori ci zi ne i s reser ved f or pat i ent s wi t h
l i f e- t hreat eni ng vent r i cul ar ar rhyt hmi as.
V. ANTIHYPERTENSIVE AGENTS
A. Chemi st r y. Ant i hypert ensi ve agent s var y so wi del y i n chemi cal st ruct ur e t hat
t hey are usual l y cl assi f i ed by mechani sm of act i on r at her t han chemi cal cl ass ( Tabl e
15- 5).
B. PharmacoI ogy. Ant i hyper t ensi ve agent s l ower bl ood pr essur e by r educi ng t ot al
per i pheral r esi st ance or car di ac out put t hr ough a var i et y of mechani sms (Tabl e 15-
5) .
1. Di uret i cs such as t hi azi des creat e a negat i ve sodi um bal ance, reduce bl ood
vol ume, and decr ease vascul ar smoot h muscl e r esponsi veness t o vasoconst r i ct or s
( see VÌ . C) .
2. Vasodi I at ors such as di azoxi de and mi noxi di l ar e pot assi um channel act i vat or s
t hat pr oduce membrane hyper pol ari zat i on, wher eas hydr al azi ne may st i mul at e
f or mat i on of EDRF ( NO) t o decrease ar t eri al r esi st ance. Human brai n nat r i ur et i c
pept i de ( BNP) vi a r ecept or st i mul at i on and sodi um ni t r opr ussi de vi a rel ease of NO
act i vat e guanyl yl cycl ase, f ormi ng cGMP t o r el ax bot h ar t er i ol es and vei ns.
3. Peri pheraI sympat hoI yt i cs i nt erf ere wi t h adr ener gi c f unct i on by bl ocki ng
post gangl i oni c adr ener gi c r ecept ors (e. g. , propranol ol , pr azosi n) , l i mi t i ng t he
r el ease of neur ot r ansmi t t er s f r om adr energi c neur ons ( e. g. , guanet hi di ne), or
depl et i ng i nt r aneuronal cat echol ami ne st orage si t es (e. g. , r eser pi ne) .
4. Cent raI o2- sympat homi meti cs ( e. g. , cl oni di ne, met hyl dopa) appear t o medi at e
t hei r ef f ect s by st i mul at i ng presynapt i c q2- i nhi bi t or y r ecept or s, r esul t i ng i n a
negat i ve sympat het i c out f l ow and l ower ed per i pher al r esi st ance.
P. 351


Table 15-5. Classification of Antihypertensive Agents by Their Mechanism of
Action
Mechanism of Action Drug
Vasodilators
Arteriolar Diazoxide (Hyperstat IV)
Hydralazine (Apresoline)
Minoxidil (Loniten)
Arteriolar and venous Nitroprusside (Nipride)
Peripheral sympatholytics Acebutolol (Sectral)
Atenolol (Tenormin)
Betaxolol (Kerlone)
Bisoprolol (Zebeta)
Carteolol (Cartrol)
Carvedilol (Coreg)
Doxazosin (Cardura)
Guanadrel (Hylorel)
Guanethidine (Ismelin)
Labetalol (Trandate)
Metoprolol (Lopressor)
Nadolol (Corgard)
Penbutolol (Levatol)
Pindolol (Visken)
Prazosin (Minipress)
Propranolol (Inderal)
Reserpine (Serpasil)
Terazosin (Hytrin)
Timolol (Blocadren)
Central u
2
-sympathomimetics Clonidine (Catapres)
Guanabenz (Wytensin)
GuanIacine (Tenex)
Methyldopa (Aldomet)
Calcium channel blockers Amlodipine (Norvasc)
Diltiazem (Cardizem) SR
Felodipine (Plendil)
Isradipine (DynaCirc)
Nicardipine (Cardene)
NiIedipine (Procardia) SR
Verapamil (Calan)
Angiotensin II receptor antagonists Candesartan (Atacand)
Irbesartan (Avapro)
Losartan (Cozaar)
Telmisartan (Micardis)
Valsartan (Diovan)
Angiotensin-converting enzyme inhibitors Benazepril (Lotensin)
Captopril (Capoten)
Enalapril (Vasotec)
Fosinopril (Monopril)
Lisinopril (Prinivil)
Moexipril (Univasc)
Perindopril (Aceon)
Quinapril (Accupril)
Ramipril (Altace)
Trandolapril (Mavik)
Endothelin receptor antagonist Bosentan (Tracleer)

P. 352


5. CaI ci um channeI bI ockers ( e. g. , aml odi pi ne, di l t i azem, f el odi pi ne, i sradi pi ne,
ni car di pi ne, ni f edi pi ne, ver apami l ) l ower vascul ar r esi st ance and bl ood pressur e vi a
bl ockade of vol t age-gat ed cal ci um channel s. Art er i ol es ar e mor e sensi t i ve t han
vei ns.
6. ACE i nhi bi t ors ( e. g. , capt opri l ) bl ock t he conver si on of i nact i ve angi ot ensi n Ì t o
t he pot ent vasoconst r i ct or angi ot ensi n Ì Ì . The r educed angi ot ensi n Ì Ì concent r at i on
al so l ower s al dost er one concent r at i on, whi ch l i mi t s sodi um r et ent i on.
7. Angi ot ensi n I I receptor antagoni st s ( e. g. , l osar t an) are nonpept i de ant agoni st s
of t he AT1 angi ot ensi n Ì Ì r ecept or subt ype l ocat ed i n vascul at ur e, myocardi um,
br ai n, ki dney, and adrenal gl omerul osa. They produce vasodi l at i on, cause l oss of
sal t and wat er t o decr ease pl asma vol ume, and decr ease myogeni c act i vi t y.
8. Endot heI i n recept or ant agoni st s (e. g. , bosent an) are pot ent oral l y act i ve
nonpept i de endot hel i n r ecept or ant agoni st s.
C. Therapeut i c i ndi cati ons
1. Ant i hyper t ensi ve agent s ar e used separ at el y or i n combi nat i on t o t reat hi gh
bI ood pressure.
2. These agent s may al so be admi ni st ered parent er al l y t o t reat hypert ensi ve
emergenci es such as mal i gnant hyper t ensi on, ecl ampsi a, or t he severe
hyper t ensi on associ at ed wi t h excess cat echol ami nes. Parent er al t her apy may
i ncl ude some combi nat i on of t he f ol l owi ng agent s:
a. Art eri oI ar and venous vasodi I at or such as ni t r oprussi de or bosent an ( i . e. ,
pul monar y art er i al hypert ensi on)
b. Art eri oI ar vasodi I at or such as di azoxi de or hydr al azi ne
c. DuaI o-adrenergi c- and ß-adrenergi c- receptor bI ockers such as l abet al ol
d. ß- BI ocki ng agent such as propr anol ol
e. GangI i oni c-bI ocki ng agent such as t ri met haphan
D. Adverse ef f ect s
1. Di uret i cs ( t hi azi des) can cause
a. Fl ui d and sol ut e i mbal ances, such as hypokal emi a, hyper cal cemi a,
hyper uri cemi a, hypomagnesemi a, hyponat remi a, and hypergl ycemi a
b. Ì ncr eased serum l ow- densi t y l i poprot ei n (LDL) chol est er ol and t ri gl yceri de
concent r at i ons
c. Ot her ef f ect s (see VÌ . C. 4)
2. Vasodi I at ors are associ at ed wi t h:
a. GÌ upset
b. CNS ef f ect s, such as headache and di zzi ness
c. CV ef f ect s, such as t achycar di a, f l ui d ret ent i on, and wor seni ng of angi na
d. Ot her ef f ect s, such as nasal congest i on, hepat i t i s, gl omerul onephri t i s, and SLE-
l i ke syndr ome
3. Peri pheraI sympat hoI yt i cs ar e associ at ed wi t h a vari et y of adver se ef f ect s,
dependi ng on t he speci f i c agent .
a. ß- BI ockers (e. g. , pr opr anol ol ) ar e associ at ed wi t h:
( 1) CV ef f ect s, such as br adycardi a, congest i ve hear t f ai l ure, and Raynaud
phenomenon
( 2) GÌ upset
( 3) Bl ood dyscr asi as
( 4) CNS ef f ect s, such as depressi on, hal l uci nat i ons, or gani c br ai n syndrome, and
t r ansi ent hear i ng l oss
( 5) Ot her ef f ect s, such as i ncreased ai r way r esi st ance, i ncr eased ser um t ri gl ycer i de
concent r at i ons, decreased hi gh- densi t y l i popr ot ei n ( HDL) chol est er ol
concent r at i ons, and psori asi s
( 6) Cardi ac ar r hyt hmi as i f wi t hdr awal i s abrupt
b. Prazosi n i s associ at ed wi t h:
( 1) CV ef f ect s, such as sudden syncope wi t h t he f i r st dose, pal pi t at i ons, and f l ui d
r et ent i on
( 2) CNS ef f ect s, such as headache, drowsi ness, weakness, di zzi ness, and ver t i go
( 3) Ant i muscar i ni c ef f ect s and pr i api sm
P. 353


c. Guanet hi di ne i s associ at ed wi t h:
( 1) CV ef f ect s, such as br adycardi a, or t host at i c hypot ensi on, and sodi um and wat er
r et ent i on
( 2) Di ar r hea
( 3) Aggr avat i on of br onchi al ast hma
d. Reserpi ne i s associ at ed wi t h:
( 1) CNS ef f ect s, such as ni ght mar es, depr essi on, and dr owsi ness
( 2) CV ef f ect s, such as br adycardi a
( 3) GÌ ef f ect s, such as GÌ upset and act i vat i on of pept i c ul cer
( 4) Nasal st uf f i ness
4. Cent raI o2- sympat homi meti cs al so have adver se ef f ect s t hat var y wi t h t he
speci f i c agent .
a. CI oni di ne i s associ at ed wi t h:
( 1) CNS ef f ect s, such as sedat i on and drowsi ness
( 2) Dr y mout h and severe r ebound hyper t ensi on
( 3) Ì nsomni a, headache, and cardi ac dysr hyt hmi as ( wi t h sudden wi t hdrawal )
b. Met hyI dopa i s associ at ed wi t h:
( 1) CV ef f ect s, such as or t host at i c hypot ensi on and bradycar di a
( 2) CNS ef f ect s, such as sedat i on and f ever
( 3) GÌ ef f ect s such as col i t i s
( 4) Ot her ef f ect s, such as hepat i t i s, ci r r hosi s, Coombs- posi t i ve hemol yt i c anemi a,
and SLE- l i ke syndr ome
5. CaI ci um channeI bI ockers ar e associ at ed wi t h CV ef f ect s, r esul t i ng i n
hypot ensi on, di zzi ness, headache, and f l ushi ng. When gi ven wi t h 8-adr ener gi c
bl ocker s, t hei r ef f ect s may be enhanced, r esul t i ng i n br adycardi a, hypot ensi on,
per i pheral edema, congest i ve hear t f ai l ur e, AV bl ock, and asyst ol e. Long-t er m
admi ni st rat i on i s associ at ed wi t h r i sk of gi ngi val hyper pl asi a and Barr et t esophagus.
6. ACE i nhi bi t ors ar e associ at ed wi t h:
a. CV ef f ect s, such as hypot ensi on and syncope
b. Hemat ol ogi c ef f ect s, such as neut ropeni a and agr anul ocyt osi s
c. Ot her ef f ect s, such as chroni c cough, anor exi a, pol yur i a, ol i gur i a, acut e r enal
f ai l ur e, chol est at i c j aundi ce, and ( rar el y) angi oedema
7. Angi ot ensi n I I receptor antagoni st s ar e associ at ed wi t h adver se ef f ect s si mi l ar
t o ACE i nhi bi t ors, except t hat cough and angi oedema, whi ch are i ndependent of
angi ot ensi n ant agoni sm, occur l ess f r equent l y.
8. Endot hel i n r ecept or ant agoni st s ( Bosent an) have t he pot ent i al f or seri ous l i ver
i nj ur y and damage t o a f et us.
VI. DIURETICS
A. Osmot i c di ureti cs
1. Chemi st r y. Osmot i c di ur et i cs (e. g. , manni t ol , ur ea, gl yceri n, i sosor bi de) are
hi ghl y pol ar, wat er -sol ubl e agent s wi t h a l ow r enal t hreshol d ( Fi gur e 15-5).

Figure 15-5. Structural Iormulas oI osmotic
diuretics. A. Mannitol (Osmitrol). B. Urea
(Ureaphil).
P. 354


2. PharmacoI ogy
a. Osmot i c di ur et i cs ar e r el at i vel y i nert chemi cal s t hat are f reel y f i l t er ed at t he
gl omerul us and poor l y r eabsor bed f rom t he r enal t ubul e. By i ncr easi ng t he
osmol ar i t y of t he gl omerul ar f i l t r at e, t hey I i mi t t ubuI ar reabsorpt i on of wat er and
t hus promot e di uresi s.
b. Because t hese agent s i ncr ease wat er , sodi um, chl ori de, and bi car bonat e
excr et i on, t hey cause an i ncrease i n uri nar y pH.
3. Therapeut i c i ndi cat i ons. Osmot i c di uret i cs ar e used t o:
a. Hel p pr event and t r eat ol i guri a and anur i a
b. Reduce cer ebr al edema and decr ease i nt r acrani al pr essur e
c. Reduce i nt raocul ar pressur e
4. Adverse ef fect s. Osmot i c di ur et i cs ar e associ at ed wi t h:
a. Headache and bl urr ed vi si on
b. Ì ncr eased bl ood vol ume t hat wor sens congest i ve hear t f ai l ure
B. Carboni c anhydrase i nhi bi t ors
1. Chemi st r y. Car boni c anhydrase i nhi bi t or s ar e ar omat i c or het erocycl i c
sul f onami des wi t h a pr omi nent t hi adi azol e nucl eus. AcetazoI ami de i s t he
pr ot ot ypi cal agent ( Fi gure 15-6) .
2. PharmacoI ogy
a. Carboni c anhydr ase i nhi bi t or s noncompet i ti veI y i nhi bi t t he enzyme carboni c
anhydrase. Thi s prevent s t he enzyme f r om provi di ng t he t ubul ar hydr ogen i ons
needed f or exchange wi t h sodi um i n t he proxi mal t ubul e, r esul t i ng i n sodi um
bi car bonat e di uresi s.
b. Because t hese agent s i ncr ease wat er , sodi um, pot assi um, and bi car bonat e
excr et i on, t hey cause an aI kaI i ne uri nar y pH.
3. Therapeut i c i ndi cat i ons. Car boni c anhydrase i nhi bi t or s ar e used t o:
a. Reduce edema (as adj unct di ur et i c t her apy)
b. Reduce i nt r aocul ar pressur e ( r et ar d aqueous humor f or mat i on)
c. Al kal i ni ze t he ur i ne, enhanci ng excr et i on of aci di c dr ugs and t hei r met abol i t es
d. Tr eat mot or di sor ders such as pet i t mal epi l epsy, par oxysmal chor ea and
dyst oni a, per i odi c at axi a, and some cases of essent i al t r emor
4. Adverse ef fect s. Carboni c anhydr ase i nhi bi t or s are associ at ed wi t h:
a. CNS ef f ect s, such as CNS depressi on, dr owsi ness, sedat i on, f at i gue,
di sor i ent at i on, and par est hesi a
b. GÌ ef f ect s, such as GÌ upset , nausea, vomi t i ng, and const i pat i on
c. Hemat ol ogi c ef f ect s, such as bone mar r ow depr essi on, t hr ombocyt openi a,
hemol yt i c anemi a, l eukopeni a, and agr anul ocyt osi s
d. Hyperchl or emi c met abol i c aci dosi s
e. Sul f onami de- t ype hyper sensi t i vi t y r eact i ons
C. Benzot hi adi azi de di uret i cs
1. Chemi st r y
a. The commonl y used t hi azi de di uret i cs are pri mar i l y cl osel y rel at ed
benzot hi adi azi des wi t h vari abI e subst i t uent s. The pr ot ot ypi cal agent i s
chl or ot hi azi de ( Fi gure 15- 7A) .
b. Opt i mal di uret i c act i vi t y depends on cer t ai n struct uraI f eat ures.
( 1) The benzene ri ng must have a suI f onami de gr oup ( pr ef er abl y unsubst i t ut ed) i n
posi t i on 7 and a haI ogen ( usual l y a chl oro gr oup) or a t ri f I uoromet hyI gr oup i n
posi t i on 6 ( Fi gur e 15- 7) .
( 2) Saturat i on of t he 3, 4- doubI e bond i ncreases pot ency, as wi t h
hydr ochl or ot hi azi de (Fi gur e 15- 7B).

Figure 15-6. Structural Iormula oI acetazolamide
(Diamox). the prototypical carbonic anhydrase
inhibitor.
P. 355



Figure 15-7. Structural Iormula oI (A)
chlorothiazide (Diuril). the prototypical
benzothiadiazide diuretic. and (B)
hydrochlorothiazide (HydroDIURIL). Structural
Iormulas oI (C) cyclothiazide (Anhydron) and (D)
quinethazone (Hydromox). related compounds
with substituents that prolong activity and
enhance potency.
( 3) Li pophi I i c subst i tuent s at posi t i on 3 or methyI groups at posi t i on 2 enhance
pot ency and pr ol ong act i vi t y, as wi t h cycl ot hi azi de ( Fi gure 15- 7C) and
bendr of l umet hi azi de.
( 4) RepI acement of t he suI f onyI group i n posi t i on 1 by a carbonyI group pr ol ongs
act i vi t y, as wi t h qui net hazone ( Fi gur e 15- 7D).
c. A f ew suI f amoyI benzami des (e. g. , i ndapami de, chl or t hal i done) have act i vi t y
si mi l ar t o t hat of t he benzot hi adi azi des ( Fi gur e 15- 8) .
d. Benzothi adi azi nes wi t hout t he suI fonami de group (e. g. , di azoxi de) exhi bi t
ant i hyper t ensi ve act i vi t y but l ack di ur et i c act i vi t y ( Fi gur e 15- 9) .
2. PharmacoI ogy
a. Benzot hi adi azi des di rect I y i nhi bi t sodi um and chI ori de reabsorpti on on t he
l umi nal membrane of t he earl y segment of t he di st al convol ut ed t ubul e.
b. These agent s i ncr ease wat er , sodi um, chl ori de, pot assi um, and bi carbonat e
excr et i on and decrease cal ci um excr et i on and uri c aci d secr et i on. They may cause
an aI kaI i ne uri nar y pH by i nhi bi t i ng carboni c anhydr ase.

Figure 15-8. Structural Iormula oI indapamide
(Lozol). a sulIamoylbenzamide with
pharmacological activity similar to that oI the
benzothiadiazide diuretics.
P. 356



Figure 15-9. Structural Iormula oI diazoxide
(Hyperstat). a benzothiadiazine lacking a
sulIonamide group and diuretic action.
3. Therapeut i c i ndi cat i ons. Benzot hi adi azi des ar e used t o t reat :
a. Chroni c edema
b. Hyper t ensi on
c. Congest i ve hear t f ai l ur e ( as adj unct i ve edema t her apy)
4. Adverse ef fect s. Benzot hi adi azi des ar e associ at ed wi t h:
a. CNS ef f ect s, such as headache, di zzi ness, parest hesi as, dr owsi ness, and
r est l essness
b. GÌ ef f ect s, such as GÌ i r r i t at i on, nausea, vomi t i ng, abdomi nal bl oat i ng, and
const i pat i on
c. CV ef f ect s, such as ort host at i c hypot ensi on, pal pi t at i ons, hemoconcent r at i on, and
venous t hr ombosi s
d. Hemat ol ogi c ef f ect s, such as bl ood dyscr asi as, l eukopeni a, t hrombocyt openi a,
agr anul ocyt osi s, apl ast i c anemi a, hemol yt i c anemi a, and r ash
e. Fl ui d and el ect rol yt e i mbal ances, such as hypokal emi a, hyponat r emi a, and
hyper cal cemi a
f . Muscul ar cr amps
g. Hyper ur i cemi a and acut e gout at t acks
h. Hyperchol est er ol emi a and hyper t ri gl yceri demi a
i . Sul f onami de- t ype hyper sensi t i vi t y react i on
D. Loop di uret i cs
1. Chemi st r y. Loop di uret i cs ar e ant hr ani l i c aci d deri vat i ves wi t h a sul f onami de
subst i t uent ( e. g. , f ur osemi de, bumet ani de) or aryl oxyacet i c aci ds wi t hout a
sul f onami de subst i t uent ( e. g. , et hacr yni c aci d; Fi gur e 15-10) .
2. PharmacoI ogy
a. These agent s act pr i nci pal l y at t he t hi ck ascendi ng l i mb of t he l oop of Henl e,
wher e t hey i nhi bi t t he cot ransport of sodi um, pot assi um, and chI ori de f rom t he
I umi naI fi I t rate.
b. Loop di ur et i cs i ncr ease excr et i on of wat er , sodi um, pot assi um, cal ci um, and
chl or i de; decr ease uri c aci d secret i on; and cause no change i n uri nar y pH.
3. Therapeut i c i ndi cat i ons. Loop di uret i cs are used t o t reat
a. Edema f rom congest i ve hear t f ai l ure, hepat i c ci r r hosi s, and r enal di sease
b. Pul monar y edema and asci t es
4. Adverse ef fect s. Loop di ur et i cs ar e associ at ed wi t h:
a. Fl ui d and sol ut e i mbal ances, such as dehydrat i on, hypokal emi a, hyperur i cemi a,
hyper cal ci ur i a, and azot emi a
b. CNS ef f ect s, such as headache, ver t i go, bl ur red vi si on, t i nni t us, and (r ar el y)
i r r eversi bl e hear i ng l oss
c. Hemat ol ogi c ef f ect s, such as t hrombocyt openi a and agranul ocyt osi s

Figure 15-10. Structural Iormulas oI loop
diuretics. A. Furosemide (Lasix). B. Ethacrynic
acid (Edecrin).
P. 357


d. CV ef f ect s, such as ort host at i c hypot ensi on
e. GÌ ef f ect s, such as nausea, vomi t i ng, and di ar rhea
f . Leg cr amps
g. Hyperchol est erol emi a and hypert r i gl ycer i demi a
h. Sul f onami de- t ype hyper sensi t i vi t y r eact i on
E. Pot assi um- spari ng di uret i cs
1. Chemi st r y. The pot assi um-spari ng di uret i cs are pt er i di ne or pyr azi ne der i vat i ves
( e. g. , t ri amt erene, ami l ori de) or st er oi d anal og ant agoni st s of al dost erone ( e. g. ,
spi ronol act one; Fi gure 15- 11).
2. PharmacoI ogy
a. Spi ronoI act one and epI erenone act as compet i t i ve i nhi bi tors of aI dost erone
at mi ner al ocor t i coi d r ecept ors i n t he l at e di st al t ubul e and col l ect i ng duct . They
i nt er f ere wi t h al dost er one- medi at ed sodi um- pot assi um exchange, decr easi ng
pot assi um secr et i on.
b. Tri amt erene and ami I ori de, whi ch are not al dost er one ant agoni st s, act di rect l y
on t he l at e di st al t ubul e and col l ect i ng duct . They di srupt sodi um exchange wi t h
pot assi um and hydr ogen by bl ocki ng sodi um channel s and decr easi ng t he dri vi ng
f or ce f or secr et i on of pot assi um and hydr ogen.
c. The pot assi um-spar i ng di ur et i cs i ncr ease bi car bonat e excr et i on and cause an
aI kaI i ne uri nar y pH.
3. Therapeut i c i ndi cat i ons. Pot assi um-spar i ng di uret i cs are used
a. As adj unct i ve t herapy t o t reat edema f r om congest i ve heart f ai l ur e, hepat i c
ci r rhosi s, nephr ot i c syndr ome, and hyper al dost eroni sm ( pri mar y and secondar y)
b. As adj unct i ve t her apy ( wi t h t hi azi des and l oop di uret i cs) t o t r eat hyper t ensi on
c. To t reat or pr event hypokal emi a
4. Adverse ef fect s
a. Spi ronoI act one i s associ at ed wi t h:
( 1) Hyperkal emi a
( 2) GÌ ef f ect s, such as GÌ upset , GÌ bl eedi ng, gast r i t i s, nausea, abdomi nal cr amps,
and di ar r hea
( 3) Endocr i ne ef f ect s, such as gynecomast i a, menst rual i r regul ari t i es, and hi r sut i sm
( 4) CNS ef f ect s, such as ment al conf usi on and l et har gy
b. Tri amt erene and ami I ori de ar e associ at ed wi t h:
( 1) Hyperkal emi a
( 2) GÌ ef f ect s, such as GÌ upset , GÌ bl eedi ng, nausea, and vomi t i ng
( 3) CNS ef f ect s, such as headache and di zzi ness
( 4) Ì ncr eased ur i c aci d concent rat i on i n pat i ent s wi t h gout y ar t hr i t i s ( wi t h
t r i amt erene)
( 5) Met hemogl obi nemi a i n pat i ent s wi t h al cohol i c ci r rhosi s ( wi t h t ri amt er ene, whi ch
i nhi bi t s di hydr of ol at e reduct ase)

Figure 15-11. Structural Iormulas oI potassium-
sparing diuretics. A. Triamterene (Dyrenium). B.
Spironolactone (Aldactone).
P. 358


VII. ANTIHYPERLIPIDEMIC AGENTS
A. Chemi st r y. Ant i hyperl i pi demi c agent s var y i n chemi cal st r uct ur e and ar e usual l y
cl assi f i ed by t hei r si t e of act i on÷l ocal l y i n t he i nt est i ne ( nonabsor babl e agent s) or
syst emi cal l y ( absor babl e agent s) .
1. NonabsorbabI e agent s are bi I e aci d sequestrant s. These agent s ar e
hydr ophi l i c, wat er - i nsol ubl e r esi ns t hat bi nd t o bi l e aci ds i n t he i nt est i ne. Exampl es
i ncl ude col esevel am hydr ochl ori de; choI est yrami ne chI ori de, a basi c ani on-
exchange r esi n consi st i ng of t r i met hyl benzyl ammoni um gr oups i n a l arge copol ymer
of st yr ene and di vi nyl benzene; coI esti poI hydrochI ori de, a copol ymer of
di et hyl pent ami ne and epi chl orohydr i n ( Fi gur e 15-12) , and ezet i mi be, a 2-
azet i di none bl ocker of t he gast roi nt est i nal chol est er ol t r ansport er .
2. AbsorbabI e agent s i ncl ude ni cot i ni c aci d ( but not t he st r uct ur al l y si mi l ar
ni cot i nami de) , t he ar yl oxyi sobut yr i c aci d der i vat i ves fenofi brate ( prodrug) and
gemf i brozi I , t he 3- hydroxy- 3- met hyl gl ut ar yl -coenzyme A ( HMG- CoA) r educt ase
i nhi bi t or I ovast at i n, and t he f at t y f i sh oi l s cont ai ni ng l ar ge amount s of
ei cosapent aenoi c aci d ( EPA) and docosahexaenoi c aci d ( DHA; Fi gur e 15- 13) .
B. PharmacoI ogy. Ant i hyper l i pi demi c agent s i ncrease cataboI i sm or reduce
I i poprot ei n product i on ( e. g. , l ovast at i n, gemf i brozi l ) or i ncrease the ef f i ci ency of
I i poprot ei n removaI ( e. g. , chol est yr ami ne, col est i pol ) .
C. Therapeut i c i ndi cati ons. These agent s ar e used ( i n conj unct i on wi t h appropr i at e
di et and exer ci se) t o r educe pl asma l i popr ot ei n concent rat i ons.
D. Adverse ef f ect s
1. NonabsorbabI e agent s ( e. g. , chol est yrami ne, col est i pol ) are associ at ed wi t h GÌ
di st r ess, i ncl udi ng abdomi nal bl oat i ng, nausea, dyspepsi a, st eat or r hea, and
const i pat i on or di ar r hea.
2. AbsorbabI e agent s (e. g. , st at i ns, f i brat es) are associ at ed wi t h GÌ di st r ess, ski n
r ash, and l eukopeni a.

Figure 15-12. Structural Iormulas oI
nonabsorbable antihyperlipidemic agents. A.
Cholestyramine chloride (Questran). B. Colestipol
hydrochloride (Colestid).
P. 359



Figure 15-13. Structural Iormulas oI absorbable
antihyperlipidemics. A. Nicotinic acid (niacin). B.
GemIibrozil (Lopid). C. Lovastatin (Mevacor). D.
Eicosapentaenoic acid (Iound in Promega. Proto-
Chol. and others). E. Docosahexaenoic acid
(Iound in Promega. Proto-Chol. and others).
a. Lovast at i n and ot her st at i ns (e. g. , si mvast at i n, pr avast at i n, f l uvast at i n,
at or vast at i n, ) may i ncr ease bl ood t r ansami nase and cr eat i ni ne phosphoki nase
act i vi t y associ at ed wi t h myopat hy, especi al l y when combi ned wi t h f i br at es or
cycl ospor i ns.
b. Gemfi brozi I may al so cause skel et al muscl e pai n, bl ur r ed vi si on, and anemi a.
c. Ni cot i ni c aci d produces f l ushi ng associ at ed wi t h pr uri t us, whi ch may be
al l evi at ed by one aspi r i n per day. Tol er ance t o ni cot i ni c aci d devel ops i n 1- 2 weeks.
Hi gh doses of ni cot i ni c aci d ( 2 g/ day) may pr oduce hepat i c damage.
VIII. ANTICOAGULANT, ANTIPLATELET, AND
THROMBOLYTIC AGENTS
A. Ant i coaguI ants. The maj or ant i coagul ant agent s ar e hepari n, I ow moI ecuI ar
wei ght hepari n (LMWH) and t he oraI ant i coagul ant s.
1. Chemi st r y
a. Hepari n i s a l arge, hi ghl y aci di c mucopol ysacchari de composed of sul f at ed D-
gl ucosami ne and D-gl ucur oni c aci d mol ecul es ext r act ed f r om bovi ne l ung and
por ci ne i nt est i ne ( Fi gur e 15- 14) .
b. LMWH f ragment s ( 1-10 kDa) enoxapari n, daI t epari n, t i nzapari n, and ardepari n
ar e pr oduced t hr ough cont r ol l ed depol ymeri zat i on of hepar i n, but t hey are not
i nt er changeabl e wi t h hepar i n i n t hei r act i ons and use.
( 1) Because t hey ar e hi ghl y aci di c, hepari n and LMWH f ragment s exi st as ani ons at
physi ol ogi c pH and are poor l y absor bed f r om t he GÌ t r act . Thus t hey are usual l y
admi ni st er ed par ent er al l y as t he sodi um sal t .
P. 360



Figure 15-14. Structural Iormula oI heparin. a
mucopolysaccharide anticoagulant agent.
( 2) The act i on of hepari n and LMWH f ragment s i s qui ckl y t er mi nat ed by prot ami ne
suI f ate, a hi ghl y basi c pr ot ei n t hat combi nes chemi cal l y wi t h t hem i n approxi mat el y
equal amount s (mg: mg) .
c. Low moI ecuI ar wei ght hepari noi ds ( danaparoi d) ar e gI ycosami nogI ycans
ext r act ed f r om por ci ne mucosa.
d. Lepi rudi n i s a r ecombi nant - DNA-der i ved 65 ami no aci d pol ypept i de near l y
i dent i cal t o hi rudi n, whi ch bel ongs t o t he gr oup of i sopol ypept i des of t he l eech
Hi r udo medi ci nal i s.
e. Argat roban i s an L-argi ni ne-based st r uct ure.
f . Bi vaI i rudi n i s a 20 ami no aci d pept i de. Lepi r udi n, bi val i r udi n, and ar gat r oban are
synt het i c t hr ombi n i nhi bi t or s.
g. Drot recogi n o i s a r ecombi nant f or m of human- act i vat ed pr ot ei n C t hat
i nact i vat es f act or s Va and VÌ Ì Ì a.
h. Fondapari nux i s a pent asacchar i de t hat r esembl es t he ant i t hr ombi n bi ndi ng
r egi on of hepar i n.
i . Coumari n deri vat i ves, whi ch ar e hi ghl y ef f ect i ve, and t he r el at i vel y uni mport ant
i ndanedi one deri vat i ves ar e oral ant i coagul ant s.
( 1) The coumari n deri vat i ves (e. g. , warf ari n, di cumaroI ) ar e wat er i nsol ubl e,
weakl y aci di c 4- hydroxycoumar i n l act ones (Fi gur e 15- 15) .
( a) These agent s ar e chemi caI I y reI at ed t o vi t ami n K, and t hei r mechani sm of
act i on i s di r ect l y rel at ed t o t hei r ant agoni sm of t he r educt ase responsi bl e f or
r educi ng vi t ami n K epoxi de t o t he reduced hydroqui none.
( b) These agent s ar e al so hi ghl y pr ot ei n bound and ext ensi vel y met abol i zed i n t he
l i ver . These char act er i st i cs, i n addi t i on t o a rel at i vel y nar row t her apeut i c i ndex,
make t he coumar i n der i vat i ves suscept i bl e t o si gni f i cant dr ug i nt eract i ons.
( 2) Pheni ndi one r epr esent s a t ypi cal i ndanedi one deri vat i ve ( Fi gur e 15-16) .
2. PharmacoI ogy
a. Hepari n cat al yzes t he i nhi bi t i on of t hr ombi n by ant i t hrombi n Ì Ì Ì ( hepari n
cof act or ) , pr event i ng t he conver si on of f i br i nogen t o f i bri n.

Figure 15-15. Structural Iormulas oI coumarin-
derivative oral anticoagulants. A. WarIarin
(Coumadin). B. Dicumarol.
P. 361



Figure 15-16. Structural Iormula oI the
indanedione-derivative oral anticoagulant
phenindione (Hedulin).
b. LMWH f ragment s ar e unabl e t o cat al yze i nhi bi t i on of t hrombi n, but t hey cat al yze
i nhi bi t i on by ant i t hrombi n Ì Ì Ì of f act or Xa, whi ch i s r esponsi bl e f or conversi on of
pr ot hr ombi n t o t hr ombi n. Hepari n pr ol ongs bl ood cl ot t i ng t i me bot h i n vi vo and i n
vi t r o, wher eas LMWH f ragment s have mi ni mal i n vi t r o ef f ect .
c. GI ycosami nogI ycans ( Danaparoi d) i nhi bi t f i br i n f or mat i on by i nhi bi t i on of
cl ot t i ng f act ors Xa and Ì Ì a ( l esser ef f ect ) .
d. Lepi rudi n, desi rudi n, argat roban, and bi vaI i rudi n bi nd t o and bl ock t he
cat al yt i c act i vi t y of t hrombi n.
e. Drot recogi n i nhi bi t s pr ot eol yt i c i nact i vat i on of f act or s Va and VÌ Ì Ì a.
f . Fondapari nux f aci l i t at es i nhi bi t i on of f act or Xa by ant i t hr ombi n by 300-f ol d but
has no di rect ef f ect on t hr ombi n.
g. OraI ant i coaguI ant s i nt erf ere wi t h the vi t ami n K- dependent hepat i c synt hesi s
of t he acti ve cI ot t i ng f act ors Ì Ì ( pr ot hr ombi n) , VÌ Ì , Ì X, and X and t he ant i coagul ant
pr ot ei ns C and S. These agent s pr ol ong bl ood cl ot t i ng t i me i n vi vo onl y.
3. Therapeut i c i ndi cat i ons
a. Hepari n i s i ndi cat ed
( 1) For t he pr ophyl axi s and t reat ment of venous t hr ombosi s, pul monar y embol i sm,
per i pheral ar t er i al embol i sm, and at ri al f i br i l l at i on wi t h embol i zat i on
( 2) To prevent cl ot t i ng dur i ng art er i al sur ger y and car di ac sur ger y
( 3) To di agnose and t r eat di ssemi nat ed i nt r avascul ar coagul at i on ( DÌ C)
( 4) To prevent post oper at i ve venous t hrombosi s and pul monar y embol i sm ( i n l ow-
dose f or m)
( 5) To prevent cerebral t hr ombosi s dur i ng an evol vi ng st roke
( 6) As adj unct t her apy t o pr event cor onar y occl usi on wi t h acut e MÌ
b. LMWH f ragment s ar e approved f or t reat ment of t hromboembol i c compl i cat i ons
associ at ed wi t h sur ger y, unst abl e angi na, and MÌ .
c. Danaparoi d i s appr oved f or prevent i on of deep vei n t hrombosi s.
d. Lepi rudi n and argat roban ar e i ndi cat ed f or t reat ment of pat i ent s exper i enci ng
hepar i n-i nduced t hrombocyt openi a.
e. Desi rudi n i s approved of t r eat ment of deep vei n t hr ombosi s.
f . Drot recogi n q i s approved f or r educt i on of mor t al i t y i n adul t pat i ent s wi t h severe
sepsi s associ at ed wi t h acut e organ dysf unct i on.
g. Fondapari nux i s approved f or t he pr ophyl axi s of deep vei n t hrombosi s i n
pat i ent s under goi ng hi p f r act ur e surger y and hi p or knee r epl acement surger y.
Ther e i s no ant i dot e f or fondapari nux- i nduced bl eedi ng.
h. Warf ari n sodi um i s an or al ant i coagul ant i ndi cat ed
( 1) For t he pr ophyl axi s and t reat ment of venous t hr ombosi s, pul monar y embol i sm,
and at r i al f i br i l l at i on wi t h embol i zat i on
( 2) As adj unct t her apy t o pr event cor onar y occl usi on wi t h acut e MÌ
4. Adverse ef fect s
a. Hepari n
( 1) Hepar i n i s associ at ed wi t h:
( a) Hemat ol ogi c ef f ect s, such as hemor rhage, l ocal i r r i t at i on, t hrombocyt openi a,
hemat oma, ul cer at i on, eryt hema, and pai n
( b) Ot her ef f ect s, such as hyper sensi t i vi t y r eact i ons, f ever , chi l l s, and ur t i car i a
( 2) Severe adver se ef f ect s may be t reat ed by admi ni st eri ng pr ot ami ne sul f at e, t he
speci f i c ant i dot e f or hepar i n.
b. LMWH f ragment s ar e absor bed more uni f or ml y t han hepari n, have a l onger
bi ol ogi cal hal f - l i f e, and may be associ at ed wi t h a l ower i nci dence of si de ef f ect s
t han hepari n.
P. 362


c. Danaparoi d i s cont rai ndi cat ed i n vari ous bl eedi ng di sor ders and pat i ent s
hyper sensi t i ve t o por k product s. Danapar oi d cont ai ns sodi um sul f i t e, whi ch may
cause l i f e- t hr eat eni ng al l er gi c react i ons.
d. Lepi rudi n may be associ at ed wi t h cerebr al bl eedi ng and al l ergi c, ski n, and
anaphyl act i c react i ons.
e. Desi rudi n when empl oyed wi t h epi dur al / spi nal anest hesi a or spi nal punct ur e may
l ead t o epi dur al or spi nal hemat oma, r esul t i ng i n l ong- t erm or permanent par al ysi s.
f . Drot recogi n q- i nduced bl eedi ng i s t he most common ser i ous adverse r eact i on.
g. Fondapari nux when empl oyed wi t h epi dur al / spi nal anest hesi a or spi nal punct ur e
may l ead t o epi dural or spi nal hemat oma, r esul t i ng i n l ong-t erm or permanent
par al ysi s. The most common adverse r eact i ons associ at ed wi t h fondapari nux ar e
bl eedi ng compl i cat i ons.
h. Warf ari n
( 1) The or al ant i coagul ant war f ar i n sodi um i s associ at ed wi t h t he f ol l owi ng adverse
ef f ect s:
( a) Hemor rhage
( b) Anor exi a, urt i car i a, pur pura, and al opeci a
( 2) Bl eedi ng may be t r eat ed by admi ni st eri ng vi t ami n K ( phyt onadi one) , t he speci f i c
ant i dot e f or war f ar i n sodi um.
B. Ant i pI at eI et agent s
1. Chemi st r y. Ant i pl at el et drugs i ncl ude aspi r i n, a sal i cyl at e; t i cl opi di ne, a
t hi enopyr i di ne; di pyr i damol e, a di pi peri di no-di ni t r o pyr i mi di ne; pr ost acycl i n anal ogs,
and t he Fab f ragment s of human monocl onal ant i body t o t he gl ycopr ot ei n Ì Ì b/ Ì Ì Ì a
( GPÌ Ì b/ Ì Ì Ì a) r ecept or .
2. PharmacoI ogy
a. Aspi ri n i n l ow doses i nhi bi t s pl at el et cycl ooxygenase product i on of t hromboxane
A2, prevent i ng pl at el et aggr egat i on. Cycl ooxygenase i s per manent l y i nhi bi t ed f or
t he l i f e of t he pl at el et (7- 10 days) .
b. Ti cI opi di ne and cI opi dogreI i nt er f er e wi t h adenosi ne di phosphat e- ( ADP- )
i nduced membrane-medi at ed pl at el et -f i br i nogen bi ndi ng, l eadi ng t o i nhi bi t i on of
pl at el et - pl at el et aggregat i on.
c. Fab f ragment s ( e. g. , abci xi mab) ar e monocl onal ant i bodi es agai nst t he GPÌ Ì b/ Ì Ì Ì a
r ecept or t hat permanent l y i nhi bi t pl at el et - pl at el et i nt er act i on.
d. GPI I b/ I I I a- recept or ant agoni sts ( e. g. , t i rof i ban, ept i f i bat i de) ar e r eversi bl e
ant agoni st s of f i br i nogen, von Wi l l ebrand f act or , and ot her adhesi on l i gands at t he
GPÌ Ì b/ Ì Ì Ì a recept or , l eadi ng t o i nhi bi t i on of pl at el et aggr egat i on.
e. AnagreI i de decr eases pl at el et pr oduct i on.
f . Ci I ost azoI and i t s met abol i t es ar e t ype Ì Ì Ì PDE i nhi bi t ors t hat i ncr ease cAMP,
l eadi ng t o vasodi l at i on and decreased pl at el et aggr egat i on.
g. Treprost i ni I i s a pr ost acycl i n anal og of pr ost agl andi n Ì 2 ( PGÌ 2) , whi ch i s a di rect
vasodi l at or and i nhi bi t or of pl at el et aggr egat i on.
h. Di pyri damoI e may i nhi bi t pl at el et aggregat i on vi a i nhi bi t i on of :
( 1) Red bl ood cel l adenosi ne, whi ch act s on t hr omboxane A2 r ecept ors of pl at el et s
( 2) Phosphodi est er ase t o i ncr ease i nt racel l ul ar concent rat i ons of cAMP
( 3) Thr omboxane A2 f ormat i on
3. Therapeut i c i ndi cat i ons
a. Aspi ri n i s i ndi cat ed f or r educt i on of mor t al i t y i n post - MÌ , pr ophyl act i c t r eat ment
of MÌ t o prevent r ei nf arct i on, and prophyl axi s af t er t r ansi ent i schemi c at t acks and
mi nor st r oke.
b. Ti cI opi di ne i s approved t o r educe t he r i sk of t hr ombot i c st r oke i n pat i ent s wi t h
demonst r at ed r i sk but who cannot t ol er at e aspi ri n. CI opi dogreI i s appr oved t o
r educe MÌ , st r oke, and vascul ar deat hs.
c. Abci xi mab i s i ndi cat ed f or use wi t h aspi ri n and hepari n i n pat i ent s under goi ng
per cut aneous t r ansl umi nal cor onar y angi opl ast y (PTCA) or at her ect omy.
d. Ti rof i ban and ept i f i bat i de ar e appr oved f or t reat ment of acut e cor onar y
syndr ome and pat i ent s undergoi ng PTCA.
e. AnagreI i de i s appr oved t o r educe pl at el et count i n pat i ent s wi t h essent i al
t hr ombocyt hemi a.
f . Ci I ost azoI i s appr oved f or t r eat ment of i nt ermi t t ent cl audi cat i on.
P. 363


g. Treprost i ni I i s appr oved f or t reat ment of pul monar y ar t eri al hypert ensi on.
h. Di pyri damoI e i s i ndi cat ed f or pr ophyl axi s agai nst t hromboembol i sm af t er car di ac
val ve r epl acement .
4. Adverse ef fect s
a. Aspi ri n i n doses used f or t r eat ment of t hr ombot i c di sease i s associ at ed wi t h
epi gast r i c pai n, heart burn, nausea, r ash, nasal pol yps, gout , and anaphyl act i c
r eact i ons i n sensi t i ve i ndi vi dual s.
b. Ti cI opi di ne i s associ at ed wi t h a hi gh i nci dence of adverse r eact i ons, i ncl udi ng
di ar rhea, r ash, nausea, vomi t i ng, GÌ pai n, and neut r openi a.
c. Abci xi mab i s associ at ed wi t h maj or and mi nor bl eedi ng event s,
t hr ombocyt openi a, human ant i chi meri c ant i body f or mat i on, cardi ac ar r hyt hmi as, AV
bl ock, bradycar di a, di ar rhea, abnormal t hi nki ng, and di zzi ness.
d. Ti rof i ban and ept i f i bat i de ar e associ at ed wi t h bl eedi ng event s and bl eedi ng
compl i cat i ons, nausea, f ever , and headaches; i n t he case of ept i f i bat i de, wi t h
hypot ensi on.
e. AnagreI i de car ri es a war ni ng f or use i n pat i ent s wi t h heart di sease and may l ead
t o ser i ous adver se ef f ect s, i ncl udi ng congest i ve hear t f ai l ure, MÌ , hear t bl ock,
f i bri l l at i on, and ot hers.
f . Ci I ost azoI i s cont rai ndi cat ed i n pat i ent s wi t h congest i ve hear t f ai l ur e. Ì n dogs,
ci l ost azol pr oduced car di ovascul ar l esi ons, i ncl udi ng endocar di al hemor r hage and
hemosi der i n deposi t i on, necrosi s of smoot h muscl e, i nt i mal t hi ckeni ng, and ar t er i t i s
i n t he coronar y ar t er y.
g. Treprost i ni I may pr oduce hypot ensi on and bl eedi ng when combi ned wi t h
vasodi l at ors and ant i pl at el et dr ugs. Ì nj ect i ons may be ext r emel y pai nf ul and
associ at ed wi t h i nf usi on si t e er yt hema, i ndur at i on, r ash, bl eedi ng and br ui si ng.
h. Di pyri damoI e i s associ at ed wi t h nausea, epi gast ri c pai n, di zzi ness, headache,
and rash.
C. ThromboI yt i c agent s
1. Chemi st r y
a. AI t epI ase, ret epI ase, and t enectepI ase ar e recombi nant DNA-deri ved t i ssue
pI asmi nogen acti vat ors ( t - PAs) consi st i ng of 527, 355, and 527 ami no aci ds,
r espect i vel y, of t he nat ural t - PA, whi ch cat al yzes conversi on of pl asmi nogen t o
pl asmi n.
b. St rept oki nase i s a nonenzymat i c 47- kDa prot ei n der i ved f rom cul t ur es of Gr oup
C 8- hemol yt i c st rept ococci .
c. Ani st repI ase (ani soyl at ed pl asmi nogen st rept oki nase act i vat or compl ex; APSAC)
i s a compl ex of human l ys- pl asmi nogen and st r ept oki nase wi t h an ani soyl gr oup
bl ocki ng t he cat al yt i c si t e.
d. Uroki nase i s a t wo- chai n seri ne prot ease obt ai ned f r om cul t ur ed human ki dney
cel l s.
2. PharmacoI ogy. Thr ombol yt i c agent s f aci l i t at e t he conver si on of pl asmi nogen t o
pl asmi n, whi ch subsequent l y hydrol yzes f i br i n t o di ssol ve cl ot s.
a. AI t epI ase and ret epI ase are ref er red t o as cl ot sel ect i ve because conver si on of
pl asmi nogen t o pl asmi n by t - PA i s enhanced sever al hundr ed- f ol d i n t he pr esence of
f i bri n.
b. St rept oki nase, whi ch has no enzymat i c act i vi t y, f or ms a one- t o- one compl ex wi t h
pl asmi nogen, resul t i ng i n a conf ormat i onal change t hat exposes t he cat al yt i c si t e of
pl asmi nogen. The st abl e act i vat ed compl ex subsequent l y cl eaves f ree pl asmi nogen
t o f or m pl asmi n.
c. Ani st repI ase i s a prodr ug act i vat ed i n vi vo by deacyl at i on of t he ani sol e moi et y
f r om t he act i ve si t e of t he pl asmi nogen-st rept oki nase compl ex. The act i vat ed
compl ex conver t s pl asmi nogen t o pl asmi n i n t he bl oodst r eam or t hr ombus.
d. Uroki nase, i n cont r ast t o st rept oki nase, i s enzymat i c and di rect l y conver t s
pl asmi nogen t o pl asmi n.
3. Therapeut i c i ndi cat i ons
a. AI t epI ase and ret epI ase are i ndi cat ed f or t r eat ment of acut e MÌ and acut e
massi ve pul monar y embol i sm.
b. St rept oki nase i s i ndi cat ed f or acut e MÌ , deep vei n t hr ombosi s, ar t er i al
t hr ombosi s, and art er i al embol i , except t hose ori gi nat i ng f r om t he l ef t si de of t he
hear t .
c. Ani st repI ase i s i ndi cat ed f or t r eat ment of acut e MÌ and l ysi s of cor onary ar t er i al
t hr ombi .
d. Uroki nase i s i ndi cat ed f or t r eat ment of cor onar y ar t er y t hr ombosi s and
pul monar y embol i .
P. 364


4. Adverse ef fect s
a. t - PAs ar e associ at ed wi t h:
( 1) Ì nt ernal bl eedi ng of t he GÌ and geni t ouri nar y t r act , r et r oper i t oneal bl eedi ng, and
i nt racrani al bl eedi ng
( 2) Super f i ci al bl eedi ng at cat het er i nser t i on si t es, ar t eri al punct ur es, and sur gi cal
si t es
( 3) Ot her adver se ef f ect s, i ncl udi ng hyper sensi t i vi t y r eact i ons, nausea, vomi t i ng,
hypot ensi on, and f ever
b. St rept oki nase may be associ at ed wi t h:
( 1) Ì nt ernal and super f i ci al bl eedi ng [ see VÌ Ì Ì . C. 4. a. ( 1) and ( 2)]
( 2) Al l ergi c r eact i ons, i ncl udi ng br onchospasm, angi oneur ot i c edema, ur t i car i a,
headache, and del ayed hyper sensi t i vi t y r eact i ons
c. Ani st repI ase may be associ at ed wi t h:
( 1) Ì nt ernal and super f i ci al bl eedi ng [ see VÌ Ì Ì . C. 4. a. ( 1) and ( 2)]
( 2) Cardi ac ar r hyt hmi as and hypot ensi on
( 3) Al l ergi c t ype r eact i ons such as br onchospasm, angi oneur ot i c edema, ur t i car i a,
and del ayed purpuri c rash
d. Uroki nase may be associ at ed wi t h:
( 1) Ì nt ernal and super f i ci al bl eedi ng [ see VÌ Ì Ì . C. 4. a. ( 1) and ( 2)]
( 2) Al l ergi c r eact i ons l eadi ng t o br onchospasm and ski n rash
IX. ANTI ANEMIC AGENTS
A. Chemi st r y. The maj or ant i anemi c agent s ar e i r on pr epar at i ons, cyanocobal ami n
( vi t ami n B12) , f ol i c aci d, and hemat opoi et i c growt h f act or s (er yt hropoi et i n, coI ony-
st i muI at i ng fact ors, and i nterI euki n 11).
1. Most i ron preparat i ons consi st of f errous saI t s, whi ch ar e bet t er absor bed
f r om t he GÌ t ract t han f err i c sal t s or el ement al i r on. Parent er al i ron pr eparat i ons÷
i ncl udi ng sodi um f erri c gI uconate compl ex i n sucr ose (FerrI eci t ) , i ron sucrose
( Saccharate) , and i ron dext ran ( I NFeD, Dexf errum) ÷shoul d be empl oyed onl y
when cl earl y i ndi cat ed.
a. Typi cal or al pr eparat i ons i ncl ude f errous suI fat e ( Feosol ) , ferrous gI uconat e
( Fer gon) , and f errous fumarat e ( Feost at ).
b. When parent er al admi ni st r at i on i s i ndi cat ed, sodi um f erri c gI uconat e i s
pr ef er r ed over i ron dextran because i t i s associ at ed wi t h a l ower r i sk of
anaphyl act i c react i on. I ron sucrose may al so have a bet t er saf et y and adver se
ef f ect pr of i l e t han i r on dext r an.
2. CyanocobaI ami n ( vi t ami n B12) i s a nucl eot i de- l i ke macr omol ecul e wi t h a modi f i ed
por phyr i n uni t ( a cor r i n ri ng) cont ai ni ng a t r i val ent cobal t at om. A cyani de i on i s al so
coordi nat ed t o t he cobal t at om, as i s a benzi mi dazol e group. The benzi mi dazol e
gr oup i s bonded t o an q-r i bosyl phosphat e.
3. FoI i c aci d consi st s of t hr ee maj or component s: a pt eri di ne nucl eus bonded t o t he
ni t rogen of p-ami nobenzoi c aci d, whi ch i s bonded t hrough an ami de l i nkage t o
gl ut ami c aci d ( Fi gure 15-17) .
4. Epoet i n o and darbepoet i n q are gl ycopr ot ei ns pr oduced vi a r ecombi nant DNA
t echnol ogy. Epoet i n q ( 165 ami no aci ds; 30. 4 kDa) i s i dent i cal t o nat ur al
er yt hr opoi et i n.
5. Col ony-st i mul at i ng f act or s f i I grast i m and pegfi I grasti m (gr anul ocyt e col ony-
st i mul at i ng f act or ; G- CSF) and sargramosti m (gr anul ocyt e- macr ophage col ony-
st i mul at i ng f act or ; GM- CSF) are gl ycopr ot ei ns produced vi a recombi nant DNA
t echnol ogy.

Figure 15-17. Structural Iormula oI Iolic acid. an
antianemic agent.
P. 365


6. OpreI veki n (i nt erI euki n 11) i s a r ecombi nant DNA- pr oduced nongl ycosyl at ed
pol ypept i de gr owt h f act or t hat di f f er s f r om t he nat ur al cyt oki ne by one ami no aci d.
B. PharmacoI ogy
1. I ron preparati ons ( f er r ous sal t s) ar e r eadi l y absorbed f r om t he GÌ t ract and
st ored i n t he bone mar row, l i ver , and spl een as ferri t i n and hemosi deri n. They ar e
subsequent l y i ncor por at ed as needed i nt o hemogl obi n, wher e t he i r on r ever si bl y
bi nds mol ecul ar oxygen. A l ack of body i r on causes i r on- def i ci ency anemi a wi t h
hypochr omi c, mi cr ocyt i c r ed bl ood cel l s, whi ch t ranspor t oxygen poor l y.
2. CyanocobaI ami n i s readi l y absor bed f rom t he GÌ t r act i n t he pr esence of i nt ri nsi c
f act or ( Cast l e f act or ), a gl ycopr ot ei n produced by gast ri c par i et al cel l s t hat i s
necessar y f or GÌ absor pt i on of cyanocobal ami n.
a. Cyanocobal ami n i s t ranspor t ed t o t i ssue by t ranscobal ami n Ì Ì . Ì t i s essent i al f or
cel l gr owt h, f or mai nt ai ni ng nor mal ner ve cel l myel i n, and f or t he met abol i c
f unct i ons of f ol at e.
b. Lack of di et ar y cyanocobal ami n (or l ack of i nt ri nsi c f act or ) causes a vi t ami n B12
def i ci ency and megal obl ast i c anemi a wi t h hyperchr omi c, macr ocyt i c, i mmat ur e r ed
bl ood cel l s. Demyel i nat i on of ner ve cel l s al so occurs, causi ng i r r eversi bl e CNS
damage.
3. FoI i c aci d i s readi l y absorbed f r om t he GÌ t ract , t r anspor t ed t o t i ssue, and st or ed
i nt racel l ul ar l y. Ì t i s a pr ecursor of several coenzymes ( der i vat i ves of t et rahydr of ol i c
aci d) t hat ar e i nvol ved i n si ngl e car bon at om t r ansf ers. A l ack of di et ar y f ol i c aci d
causes f ol i c aci d def i ci ency and megal obl ast i c anemi a wi t h hyperchromi c,
macr ocyt i c, i mmat ur e red bl ood cel l s. Fol i c aci d def i ci ency causes no neur ol ogi c
i mpai rment , but f ol i c aci d def i ci ency i s associ at ed wi t h bi r t h def ect s ( e. g. , spi na
bi f i da).
4. Endogenous er yt hropoi et i n, whose pr oduct i on i n t he ki dneys i s st i mul at ed by
bl ood l oss, anemi a, and hypoxi a, i s mi mi cked by epoeti n o and darbepoet i n o t o
i ncrease pr ol i f er at i on and di f f erent i at i on of er yt hroi d pr ogeni t or cel l s.
5. Fi I grast i m and pegf i I grast i m i ncrease pr ol i f erat i on, di f f er ent i at i on, and
act i vat i on of neut r ophi l s i n pat i ent s exhi bi t i ng neut r openi a af t er undergoi ng
myel osuppr essi ve chemot her apy. Sargramost i m st i mul at es mat ur at i on of
gr anul ocyt es and macr ophages and act i vat i on of mat ur e cel l s vi a cel l surf ace
r ecept or s.
6. OpreI veki n i ncr eases pl at el et pr oduct i on vi a st i mul at i on of hemat opoi et i c st em
cel l s, megakar yocyt es progeni t or cel l s, and mat urat i on of megakar yocyt es.
C. Therapeut i c i ndi cati ons
1. I ron preparati ons ( f er r ous sal t s) ar e used t o t r eat i r on- def i ci ency anemi a.
2. CyanocobaI ami n i s used t o t r eat megal obl ast i c anemi a r esul t i ng f rom vi t ami n
B12 def i ci ency.
3. FoI i c aci d i s used t o t r eat megal obl ast i c anemi a resul t i ng f r om f ol i c aci d
def i ci ency.
4. Epoet i n o and darbepoet i n o are approved f or t r eat ment of anemi a resul t i ng
f r om chr oni c r enal f ai l ure.
5. Fi I grast i m and pegf i I grast i m are approved f or t r eat ment of chroni c and
chemot herapy- i nduced neut r openi a. Sargramost i m i s appr oved f or myel oi d
r econst i t ut i on i n pat i ent s wi t h non- Hodgki n or Hodgki n di sease or who have
under gone bone mar row t r anspl ant at i on.
6. OpreI veki n i s appr oved f or prevent i on of chemot her apy- r el at ed
t hr ombocyt openi a.
D. Adverse ef f ect s
1. I ron preparati ons gi ven oral l y ar e associ at ed wi t h GÌ ef f ect s, such as GÌ
di st r ess, nausea, hear t bur n, di ar r hea, and const i pat i on. Parent er al i ron
admi ni st rat i on may be associ at ed wi t h f at al anaphyI act i c and anaphyl act oi d
r eact i ons.
2. CyanocobaI ami n onl y r ar el y pr oduces adver se ef f ect s.
3. FoI i c aci d i s associ at ed wi t h onl y rar e al l er gi c r eact i ons af t er parent eral
admi ni st rat i on.
P. 366


4. Epoet i n o and darbepoet i n o may i ncrease bl ood pressure, whi ch shoul d be
moni t ored and ef f ect i vel y managed.
5. Fi I grast i m may pr oduce al l er gi c r eact i ons i nvol vi ng ski n, respi rat or y, or
car di ovascul ar syst ems af t er i ni t i al or subsequent dosi ng. Fi I grast i m and
pegf i I grasti m ar e cont r ai ndi cat ed i n pat i ent s al l er gi c t o Escher i chi a col i - der i ved
pr ot ei ns.
6. OpreI veki n pr oduces f l ui d ret ent i on, whi ch may l ead t o peri pher al edema and
dyspnea.
P. 367


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 7: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. CaI ci um channeI bI ockers have aI I of t he f oI I owi ng characteri st i cs except
( A) t hey bl ock t he sl ow i nwar d curr ent car r i ed by cal ci um dur i ng phase 2 of t he
car di ac act i on pot ent i al .
( B) t hey di l at e per i pheral ar t eri ol es and reduce t ot al peri pher al r esi st ance.
( C) t hey const ri ct cor onar y ar t eri es and ar t eri ol es and decr ease oxygen del i ver y t o
t he myocar di um.
( D) t hey ar e usef ul i n t reat i ng st abl e angi na pect or i s and Pri nzmet al angi na.
( E) adverse ef f ect s i ncl ude aggravat i on of congest i ve hear t f ai l ur e.
Vi ew Answer 1. The answer i s C[ see] . 2. The t ermi nati on of hepari n
act i vi t y by prot ami ne suI f at e i s t he resuI t of
( A) a chel at i ng act i on.
( B) t he i nhi bi t i on of gast r oi nt est i nal absorpt i on of hepar i n.
( C) t he di spl acement of hepar i n-pl asma pr ot ei n bi ndi ng.
( D) an aci d-base i nt er act i on.
( E) t he prot hrombi n- l i ke act i vi t y of pr ot ami ne.
Vi ew Answer 2. The answer i s D[ see] . 3. Whi ch of t he f oI I owi ng
cardi ovascuI ar agents i s cI assi f i ed chemi caI I y as a gI ycosi de?
( A) Ni f edi pi ne
( B) Di goxi n
( C) Fl ecai ni de
( D) Chol est yr ami ne
( E) Warf ar i n
Vi ew Answer 3. The answer i s B[ see] . Di gi tal i s l anat a. Di gi tal i s
purpurea, St rophanthus grat us. 4. Cardi ac gI ycosi des may be usefuI i n
t reat i ng aI I of t he f oI I owi ng condi ti ons except
( A) at ri al f l ut t er .
( B) paroxysmal at r i al t achycar di a.
( C) congest i ve hear t f ai l ur e.
( D) vent r i cul ar t achycar di a.
( E) at ri al f i br i l l at i on.
Vi ew Answer 4. The answer i s D[ see] . 5. I ngest i on of whi ch of the
f oI I owi ng vi t ami ns shouI d be avoi ded by a pati ent taki ng an oraI ant i coaguI ant ?
( A) Vi t ami n A
( B) Vi t ami n B
( C) Vi t ami n D
( D) Vi t ami n E
( E) Vi t ami n K
Vi ew Answer 5. The answer i s E[seeVI I I . 4. e] . 6. The st ructure shown i s
charact eri st i c of whi ch of t he f oI I owi ng agents?

( A) Osmot i c di ur et i cs
( B) Car boni c anhydrase i nhi bi t or s
( C) Thi azi des
( D) Loop di uret i cs
( E) Pot assi um-spar i ng di ur et i cs
Vi ew Answer 6. The answer i s C[ see] . 7. Whi ch of t he f oI I owi ng di uret i cs
i s most si mi I ar i n chemi caI st ruct ure to t he ant i hypert ensi ve agent di azoxi de?
( A) Furosemi de
( B) Spi ronol act one
( C) Manni t ol
( D) Acet azol ami de
( E) Chl or ot hi azi de
Vi ew Answer 7. The answer i s E[seeand] . P. 368


Di rect i ons for quest i ons 8- 11: The quest i ons and i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one or more of t he suggest ed
answer s. Choose t he answer , A- E.
8. I n t he oraI t reatment of i ron-def i ci ency anemi as, i ron i s preferabI y
admi ni stered as
I . f errous i ron.
I I . f erri c saI ts.
I I I . eI ementaI i ron.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 8. The answer i s A[ see] . 9. ParenteraI I y admi ni st ered
ant i hypert ensi ve agents used i n t reat i ng hypert ensi ve emergenci es i ncI ude t he
I . cent raI I y act i ng ant i adrenergi c cI oni di ne.
I I . arteri oI ar and venous vasodi I at or ni t roprussi de.
I I I . gangI i oni c- bI ocki ng agent t ri met haphan.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 9. The answer i s D[ see] . 10. Cert ai n f actors cont ri but e t o t he
I onger durati on of act i on of di gi t oxi n when compared wi t h t hat of di goxi n.
These i ncI ude
I . great er prot ei n bi ndi ng.
I I . reduced poI ari t y.
I I I . greater t ubuI ar reabsorpt i on.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 10. The answer i s E[see] . 11. OraI ant i coaguI ants have whi ch
of t he f oI I owi ng propert i es?
I . They i nt erf ere wi t h vi t ami n K- dependent synt hesi s of acti ve cI ot t i ng f actors
I I , VI I , I X, and X.
I I . They have adverse ef f ect s t hat i ncI ude hemorrhage, urt i cari a, purpura, and
aI opeci a
I I I . They proI ong t he cI ot t i ng t i me of bI ood bot h i n vi vo and i n vi t ro.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 11. The answer i s C[ seeVI I . 4. e. (1)] . Di rect i ons for quest i ons
12- 14: Each gr oup of adver se ef f ect s i n t hi s sect i on i s most cl osel y rel at ed t o one
of t he f ol l owi ng dr ug cl asses. The drug cl asses may be used mor e t han once or not
at al l . Choose t he best answer , A- E.
12. Bradycardi a, hypot ensi on, i ncreased ai rway resi st ance, and congest i ve
heart fai I ure
( A) Car di ac gl ycosi des
( B) Cal ci um channel bl ocker s
( C) Angi ot ensi n-conver t i ng enzyme ( ACE) i nhi bi t or s
( D) 8- Adr energi c bl ockers
( E) Ni t ri t es and ni t r at es
Vi ew Answer 12. The answer i s D[ see] . 13. Vi suaI di st urbances ( yeI I ow or
green vi si on), conf usi on, anorexi a, vomi t i ng, at ri ovent ri cuI ar ( AV) bI ock, and
vent ri cuI ar t achycardi a
( A) Car di ac gl ycosi des
( B) Cal ci um channel bl ocker s
( C) Angi ot ensi n-conver t i ng enzyme ( ACE) i nhi bi t or s
( D) 8- Adr energi c bl ockers
( E) Ni t ri t es and ni t r at es
Vi ew Answer 13. The answer i s A[ see] . 14. Hypot ensi on, acute renaI
f ai I ure, choI est ati c j aundi ce, and agranuI ocyt osi s
( A) Car di ac gl ycosi des
( B) Cal ci um channel bl ocker s
( C) Angi ot ensi n-conver t i ng enzyme ( ACE) i nhi bi t or s
( D) 8- Adr energi c bl ockers
( E) Ni t ri t es and ni t r at es
Vi ew Answer 14. The answer i s C[ see] . Di recti ons f or questi ons 15- 17:
Each st at ement i n t hi s group i s most cl osel y charact er i zed by one of t he f ol l owi ng
dr ugs. The dr ugs may be used more t han once or not at al l . Choose t he best
answer , A- E.
15. I t i nterf eres wi t h di st aI tubuI ar aI dost erone- medi ated sodi um- potassi um
exchange; renders t he uri ne aI kaI i ne; and may cause hyperkaI emi a,
gynecomast i a, and menst ruaI i rreguI ari ti es.
( A) Furosemi de
( B) Hydr ochl or ot hi azi de
( C) Spi ronol act one
( D) Manni t ol
( E) Acet azol ami de
Vi ew Answer 15. The answer i s C[ see] . 16. FreeI y f i I t ered, thi s drug I i mi ts
t ubuI ar reabsorpti on of water and i s usef uI i n reduci ng cerebraI edema and
i nt racrani aI pressure.
( A) Furosemi de
( B) Hydr ochl or ot hi azi de
( C) Spi ronol act one
( D) Manni t ol
( E) Acet azol ami de
Vi ew Answer 16. The answer i s D[ see] . 17. The pri nci paI si t e of act i on of
t hi s drug i s on t he t hi ck ascendi ng I i mb of t he I oop of HenI e; i t i s usef uI i n
t reat i ng puI monar y edema and asci t es.
( A) Furosemi de
( B) Hydr ochl or ot hi azi de
( C) Spi ronol act one
( D) Manni t ol
( E) Acet azol ami de
Vi ew Answer 17. The answer i s A[ see] . P. 369


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì Ì Ì . B. 3; Ì Ì Ì . C. 3; Ì Ì Ì . D. 3] .
Cal ci um channel bl ockers are used i n t he t reat ment of angi na because t hey di l at e
cor onar y ar t eri es and ar t er i ol es, t hus decreasi ng cor onar y vascul ar r esi st ance and
i ncreasi ng coronar y bl ood f l ow.
2. The answer i s D [ see VÌ Ì Ì . A. 1; VÌ Ì Ì . A. 4; Fi gure 15- 14] .
Hepari n i s a hi ghl y aci di c mucopol ysacchari de, wher eas pr ot ami ne i s a hi ghl y basi c
pr ot ei n. When admi ni st er ed af t er hepari n, pr ot ami ne chemi cal l y combi nes wi t h i t
( pr esumabl y by an aci d-base i nt eract i on) and i nact i vat es i t s ant i coagul ant ef f ect .
Hence i t i s an ef f ect i ve ant i dot e f or hepari n. Caut i on must be empl oyed when usi ng
pr ot ami ne because an excess of prot ami ne can cause an ant i coagul ant ef f ect i t sel f .
3. The answer i s B [ see Ì Ì . A. 1] .
Most gl ycosi des are nat ur al pr oduct s obt ai ned f r om pl ant mat er i al . Al t hough t her e
ar e ver y f ew medi ci nal agent s t hat ar e gl ycosi des, t he gr oup known as t he car di ac
gl ycosi des i s ext r emel y i mport ant and i s wi del y used f or t r eat i ng congest i ve heart
f ai l ur e. Di goxi n i s a cardi ac gl ycosi de obt ai ned f rom Di gi t al i s l anat a. Ot her cardi ac
gl ycosi des i ncl ude di gi t oxi n, whi ch i s obt ai ned f rom Di gi t al i s purpurea, and ouabai n,
whi ch i s obt ai ned f r om St r ophant hus grat us.
4. The answer i s D [ see Ì Ì . C; Tabl e 15-4] .
Vent ri cul ar t achycar di a i s produced by t oxi c car di ac gl ycosi de dosage and woul d not
be a t her apeut i c i ndi cat i on f or t he agent s. Cardi ac gl ycosi des i ncrease syst ol i c
cont r act i on vel oci t y and i ncrease t he r ef ract or y per i od of t he AV node. They al so
have a posi t i ve i not r opi c ef f ect .
5. The answer i s E [ see VÌ Ì Ì . A. 2. e; VI I I . 4. e] .
The or al ant i coagul ant s, such as war f ari n, act by i nhi bi t i ng t he l i ver bi osynt hesi s of
pr ot hr ombi n, whi ch i s t he pr ecur sor of t he enzyme t hrombi n t hat cat al yzes t he
conversi on of sol ubl e f i br i nogen t o t he i nsol ubl e pol ymer f i bri n, whi ch resul t s i n cl ot
f or mat i on. One of t he pr i nci pal f act or s i n t he bi osynt hesi s of pr ot hrombi n i s vi t ami n
K, wi t h whi ch war f ar i n compet es t o i nhi bi t t hi s pr ocess. Because t hi s i s a rever si bl e
compet i t i on, vi t ami n K act s as an ant agoni st t o t he oral ant i coagul ant s.
6. The answer i s C [ see VÌ . A; Fi gur e 15-7] .
The st ruct ur e can be r ecogni zed as a benzot hi adi azi ne, whi ch i s known al so as a
t hi azi de. Ì t represent s t he st r uct ure of hydr ochl orot hi azi de, a sul f onami de di ur et i c.
Ot her sul f onami de di ur et i cs i ncl ude t he carboni c anhydrase i nhi bi t or s, such as
acet azol ami de, and t he l oop di ur et i cs, such as f ur osemi de. Nei t her of t hese
subcl asses cont ai ns dr ugs wi t h a benzot hi adi azi ne nucl eus.
7. The answer i s E [ see VÌ . C; Fi gur es 15- 7 and 15- 9] .
Di azoxi de i s a benzot hi adi azi ne der i vat i ve; t her ef or e, i t woul d be most si mi l ar t o
chl or ot hi azi de, whi ch i s al so a benzot hi adi azi ne. Al t hough bot h t he t hi azi des and
t he di azoxi des have ant i hyper t ensi ve act i vi t y, onl y t he t hi azi des have si gni f i cant
di uret i c act i vi t y. One of t he st r uct ur al r equi rement s of t he t hi azi de di ur et i cs i s an
el ect r on- wi t hdrawi ng gr oup, such as a hal ogen, or t ho t o t he sul f onami de gr oup on
t he benzene nucl eus. The di azoxi de mol ecul e l acks such a gr oup.
8. The answer i s A ( Ì ) [ see Ì X. A. 1] .
Absorpt i on of or al l y admi ni st er ed i r on i s si gni f i cant l y i mproved wi t h f er rous i ron t han
wi t h ei t her f er ri c sal t s or el ement al i r on, presumabl y because of i t s bet t er sol ubi l i t y
charact eri st i cs. Ì r on prepar at i ons ( f er rous sal t s) ar e more r eadi l y absorbed f rom t he
gast r oi nt est i nal t ract and ar e st or ed i n t he bone mar row, l i ver , and spl een as f er r i t i n
and hemosi der i n.
9. The answer i s D (Ì Ì , Ì Ì Ì ) [ see V. B. 4; V. C. 2. a; V. C. 2. e] .
Cl oni di ne i s not r ecogni zed as a drug of choi ce f or hyper t ensi ve emer genci es,
possi bl y because of i t s cent r al mechani sm of act i on and t he l at ent per i od r equi r ed
f or i t s ef f ect , compared wi t h ot her per i pheral agent s.
10. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì Ì . A; Fi gure 15- 1] .
St r uct ur al l y, di gi t oxi n has onl y one al cohol gr oup on i t s st er oi dal nucl eus, wher eas
di goxi n has t wo. Thi s sl i ght di f f er ence i n st r uct ure has a si gni f i cant ef f ect on t he
pol ar i t y of t he mol ecul e. Owi ng t o i t s gr eat er l i posol ubi l i t y, di gi t oxi n i s mor e l i kel y t o
under go t ubul ar reabsorpt i on, t o under go ent er ohepat i c
P. 370

cycl i ng, t o penet rat e i nt o t he l i ver mi crosomes and undergo met abol i sm, and t o be
pr ot ei n bound, al l of whi ch cont r i but e t o i t s l onger durat i on of act i on and pot ent i al
cumul at i ve ef f ect s.
11. The answer i s C ( Ì , Ì Ì ) [ see VÌ Ì Ì . A. 2. e, VI I . 4. e. ( 1) ] .
Or al ant i coagul ant s ar e ef f ect i ve onl y i n vi vo because t hey bl ock hepat i c synt hesi s
of vi t ami n K-dependent coagul at i on f act or s ( f act or s Ì Ì , VÌ Ì , Ì X, and X) . Thi s al so
expl ai ns t he l at ency per i od associ at ed wi t h i ni t i at i on of or al ant i coagul ant t her apy.
12. The answer i s D [ see Ì Ì Ì . D. 2] .
13. The answer i s A [ see Ì Ì . D] .
14. The answer i s C [ see V. D. 6] .
Nonsel ect i ve 8- adr ener gi c bl ockers ( e. g. , propr anol ol ) pr oduce adver se ef f ect s
associ at ed wi t h t hei r mechani sm of act i on on t he aut onomi c ner vous syst em. Thus
br onchospasm, l ower i ng of bl ood pressure, and reduced hear t rat e r esul t f r om
bl ockade of aut onomi c 8- adr energi c r ecept ors. Vi sual di st ur bances ( yel l ow or gr een
vi si on) ar e pecul i ar t o car di ac gl ycosi de over dose. AV di ssoci at i on and vent r i cul ar
t achycardi a ar e obvi ousl y mor e si gni f i cant adverse ef f ect s. ACE i nhi bi t ors
r eport edl y may cause bl ood dyscr asi as i n addi t i on t o chol est at i c j aundi ce and acut e
r enal f ai l ur e.
15. The answer i s C [ see VÌ . E. 2. a; VÌ . E. 4. a] .
16. The answer i s D [ see VÌ . A. 3. a; VÌ . A. 3. b] .
17. The answer i s A [ see VÌ . D. 2. a; VÌ . D. 3. a] .
Spi r onol act one i nt er f eres wi t h al dost er one-medi at ed sodi um-pot assi um exchange,
r educi ng t he amount of pot assi um excr et ed and i s of t en used wi t h ot her di ur et i cs
t hat pr omot e t he excr et i on of pot assi um, such as t he benzot hi adi azi des. Manni t ol
i ncreases t he osmol ar i t y of t he gl omer ul ar f i l t rat e because i t i s r eabsor bed poor l y.
By i ncreasi ng t he osmol ar i t y of t he gl omerul ar f i l t r at e, manni t ol l i mi t s t ubul ar
r eabsorpt i on of wat er , t hus pr omot i ng di ur esi s. Ì n t hi s way, i t reduces cerebr al
edema and decr eases i nt r acrani al pr essur e. Fur osemi de i s a di ur et i c of choi ce f or
t r eat i ng acut e congest i ve hear t f ai l ure because i t pr omot es a si gni f i cant rapi d
excr et i on of wat er and sodi um.

17
Drug MetaboIism, Prodrugs, and
Pharmacogenetics
Marc W. HarroI d
I. INTRODUCTION TO DRUG METABOLISM.
Dr ug met abol i sm ( al so cal l ed bi ot ransf ormat i on) r ef er s t o t he bi ochemi cal changes
t hat dr ugs and ot her f orei gn chemi cal s ( xenobi oti cs) under go i n t he body, l eadi ng
t o t he f or mat i on of di f f erent met abol i t es wi t h di f f er ent ef f ect s. Xenobi ot i cs can
under go a vari et y of bi ot r ansf ormat i on pat hways, r esul t i ng i n t he product i on of a
mi xt ur e of i nt ermedi at e met abol i t es and excr et ed pr oduct s, i ncl udi ng unchanged
par ent dr ug. Rarel y i s onl y one met abol i t e pr oduced f rom a si ngl e drug.
A. I nact i ve met aboI i tes. Some met abol i t es are i nact i ve (i . e. , t hei r
pharmacol ogi cal l y act i ve par ent compounds become i nact i vat ed or det oxi f i ed).
1. The hydr ol ysi s of procai ne t o p-ami nobenzoi c aci d and di et hyl et hanol ami ne
r esul t s i n a l oss of anest het i c act i vi t y.
2. The oxi dat i on of 6-mercapt opuri ne t o 6-mercapt uri c aci d resul t s i n a l oss of
ant i cancer act i vi t y.
B. MetaboI i t es t hat retai n si mi I ar act i vi t y. Cer t ai n met abol i t es r et ai n t he
pharmacol ogi cal act i vi t y of t hei r parent compounds t o a great er or l esser degree.
1. I mi prami ne i s demet hyl at ed t o t he essent i al l y equi act i ve ant i depr essant ,
desi prami ne.
2. Acet ohexami de i s r educed t o t he more act i ve hypogl ycemi c, I -
hydroxyhexami de.
3. Codei ne i s demet hyl at ed t o t he more act i ve anal gesi c, morphi ne.
C. MetaboI i t es wi t h aI tered act i vi t y. Some met abol i t es devel op act i vi t y di f f erent
f r om t hat of t hei r parent dr ugs.
1. The ant i depr essant i proni azi d i s deal kyl at ed t o t he ant i t uber cul ar , i soni azi d.
2. The vi t ami n ret i noi c aci d ( vi t ami n A) i s i someri zed t o t he ant i - acne agent ,
i soret i noi c aci d.
D. Bi oact i vat ed met aboI i t es. Some phar macol ogi cal l y i nact i ve par ent compounds
ar e convert ed t o act i ve speci es wi t hi n t he body. These par ent compounds ar e known
as prodrugs.
1. The pr odrug enaI apri I i s hydr ol yzed t o enaI apri I at , a pot ent ant i hypert ensi ve.
2. The pr odrug suI i ndac, a sul f oxi de, i s r educed t o t he act i ve sul f i de.
3. The ant i parki nsoni an I evodopa ( L- dopa) i s decar boxyl at ed i n t he neuron t o
act i ve dopami ne.
II. BIOTRANSFORMATION PATHWAYS
A. Phase I react i ons are t hose i n whi ch pol ar f unct i onal gr oups are i nt r oduced i nt o
t he mol ecul e or unmasked by oxi dat i on, r educt i on, or hydr ol ysi s.
1. Oxi dat i on i s t he most common phase Ì bi ot r ansf ormat i on.
a. The maj or i t y of oxi dat i ons occur i n t he I i ver; however , ext r ahepat i c t i ssues, such
as t he i nt est i naI mucosa, I ungs, and ki dney, can al so ser ve as met abol i c si t es.
b. The vast maj or i t y of oxi dat i ons are cat al yzed by a gr oup of mi xed- f unct i on
oxi dases known as cyt ochrome P450 ( CYP450). These oxi dases ar e bound t o t he
smoot h endopl ast i c r et i cul um of t he l i ver and r equi r e bot h NADPH and a por phyr i n
pr ost het i c group. Unl i ke most enzymes, CYP450 uses a var i et y of oxi dat i ve
bi ot r ansf or mat i ons t o met abol i ze a di ver se gr oup of subst r at es.
P. 399


c. CYP450 exi st s i n muI ti pI e i soforms or f ami l i es. The pr esence of t hese di f f er ent
i sof orms i s r esponsi bl e f or t he l ar ge subst r at e var i at i on seen wi t h CYP450.
( 1) CYP450 i sof orms are named usi ng t he root " CYP¨ f ol l owed by an ar abi c number
desi gnat i ng t he f ami l y, a l et t er desi gnat i ng t he subf ami l y, and a second arabi c
number i ndi cat i ng t he i ndi vi dual gene (e. g. , CYP3A4) .
( 2) Si x mammal i an f ami l i es ar e i nvol ved i n st eroi d and bi l e aci d met abol i sm: CYP7,
CYP11, CYP17, CYP19, CYP21, and CYP27.
( 3) Four mammal i an f ami l i es ar e i nvol ved i n xenobi ot i c, or dr ug, met abol i sm: CYP1,
CYP2, CYP3, and CYP4. Exampl es of drugs met abol i zed by t hese f ami l i es and
subf ami l i es are shown i n Tabl e 17- 1. Not e t hat a number of dr ugs (e. g. , t ri cycl i c
ant i depr essant s, di azepam, ondanset r on, t heophyl l i ne) are met abol i zed by mul t i pl e
i sof orms.
d. Addi t i onal oxi dat i ons ( e. g. , et hanol t o acet al dehyde) ar e cat al yzed by
nonmi cr osomal oxi dases l ocat ed i n cyt osol and mi t ochondri a of ext r ahepat i c
t i ssues.
e. CYP450 and nonmi crosomal oxi dases cat al yze ar omat i c, al i phat i c, ol ef i ni c,
benzyl i c, al l yl i c, and q- hydr oxyl at i ons; N- , O- , and S- deal kyl at i ons; oxi dat i ve
deami nat i on; N- and S- oxi dat i ons; desul f ur at i on; dehal ogenat i on; and oxi dat i ons of
al cohol s and al dehydes (Tabl e 17- 2).
f . The i ncreased poI ari ty of t he oxi di zed pr oduct s (met abol i t es) enhances t hei r
wat er sol ubi l i t y and reduces t hei r t ubul ar r eabsorpt i on t o some ext ent , t hus f avori ng
t hei r excr et i on i n t he uri ne. These met abol i t es are somewhat more poI ar t han t hei r
par ent compounds and ver y commonl y under go f ur t her bi ot ransf ormat i on by phase Ì Ì
pat hways (see Ì Ì B) .
2. Reduct i on i s l ess commonl y encount ered t han oxi dat i on; however , t he over al l
goal i s t he same: t o creat e pol ar f unct i onal groups t hat can be el i mi nat ed i n t he
ur i ne. There i s evi dence suggest i ng t hat t he CYP450 syst em mi ght be i nvol ved i n
some reduct i ons. Addi t i onal l y, bact er i a r esi dent i n t he GÌ t ract are known t o be
i nvol ved i n azo and ni t r o r educt i ons. React i ons cat al yzed by r educt ases ar e shown
i n Tabl e 17- 3.
3. Enzymat i c hydroI ysi s, t he addi t i on of wat er acr oss a bond, al so resul t s i n mor e
pol ar met abol i t es ( see Tabl e 17- 3) .
a. Esterase enzymes, usual l y present i n pl asma and vari ous t i ssues, are
nonspeci f i c and cat al yze de- est er i f i cat i on, hydr ol yzi ng r el at i vel y nonpol ar est er s
i nt o t wo pol ar , mor e wat er - sol ubl e compounds: an al cohol and an aci d. Est erases
ar e responsi bl e f or conver t i ng many pr odr ugs i nt o t hei r act i ve f or ms.
b. Ami dase enzymes hydr ol yze ami des i nt o ami nes and aci ds (deami dat i on) .
Deami dat i on occurs pri mar i l y i n t he l i ver.
c. Est er drugs suscept i bl e t o pl asma est er ases ( e. g. , procai ne) ar e usual l y shor t er
act i ng t han st r uct ur al l y si mi l ar ami de drugs ( e. g. , pr ocai nami de), whi ch ar e not
si gni f i cant l y hydr ol yzed unt i l t hey r each t he l i ver.
d. Lact ones and I act ams ar e cycl i c est er s and ami des, r espect i vel y, and ar e t hus
al so suscept i bl e t o hydrol yt i c met abol i sm.
B. Phase I I react i ons are t hose i n whi ch t he f unct i onal gr oups of t he ori gi nal dr ug
( or met abol i t e f or med i n a phase Ì r eact i on) ar e masked by a conj ugat i on react i on.
Most phase Ì Ì conj ugat es are ver y pol ar, r esul t i ng i n r api d dr ug el i mi nat i on f r om t he
body.
1. Conj ugat i on react i ons combi ne t he parent drug ( or i t s met abol i t es) wi t h cert ai n
nat uraI endogenous const i t uent s, such as gl ucur oni c aci d, gl yci ne, gl ut ami ne,
sul f at e, gl ut at hi one, t he t wo- car bon acet yl f ragment , or t he one- car bon met hyl
f r agment . These react i ons gener al l y r equi r e bot h a hi gh- energy moI ecuI e and an
enzyme.
a. The hi gh-energy moI ecuI e consi st s of a coenzyme bound t o t he endogenous
subst rat e, t he par ent drug, or t he drug' s phase Ì met abol i t e.
b. The enzymes ( cal l ed t ransf erases) t hat cat al yze conj ugat i on react i ons are f ound
mai nl y i n t he l i ver and, t o a l esser ext ent , i n t he i nt est i nes and ot her t i ssues.
c. Most conj ugat es ar e hi ghI y poI ar and unabI e t o cross ceI I membranes, maki ng
t hem al most al ways pharmacoI ogi caI I y i nact i ve and of l i t t l e or no t oxi ci t y.
Except i ons t o t hi s are acet yl at ed and met hyl at ed conj ugat es. These conj ugat es do
not possess i ncreased pol ari t y; however , t hey are usual l y pharmacol ogi cal l y
i nact i ve.
2. Ther e ar e si x conj ugat i on pathways ( Tabl e 17- 4) .
a. GI ucuroni dat i on i s t he most common conj ugat i on pat hway because of a readi l y
avai l abl e suppl y of gl ucur oni c aci d as wel l as a l ar ge vari et y of f unct i onal gr oups,
whi ch can enzymat i cal l y r eact wi t h t hi s sugar der i vat i ve.
P. 400


Table 17-1. Examples of Drugs Metabolized by Specific Cytochrome P450 (CYP)
Isoforms
CYP1A2
Acetaminophen
Amitriptyline and other TCAs
Diazepam
Methadone
Olanzapine
Propranolol
Riluzole
Tacrine
Theophylline
CYP2B1
Chlorpheniramine
CYP2B6
Bupropion
Cyclophosphamide and iIosIamide
CYP2C8
Diazepam
DicloIenac
Mephobarbital
Omeprazole
Paclitaxel
Retinoids
Tolbutamide
CYP2C9
Amitriptyline and other TCAs
Chlorpheniramine
Carvedilol
Dapsone
Diazepam
Glimepiride
Hexobarbital
Losartan
NSAIDs
Phenytoin
Tolbutamide
Torsemide
Verapamil
WarIarin
ZaIirlukast
CYP2D6
Amitriptyline and other TCAs
þ-blockers
Benztropine
Captopril
Chlorpheniramine
Chlorpromazine
Clemastine
Clozapine
Codeine
Delavirdine
Dextromethorphan
Diphenhydramine
Dolasetron and Ondansetron
Donepezil
Encainide
FenIluramine
Fentanyl
Flecainide
Fluphenazine
Hydrocodone
Hydroxyzine
Imipramine
Lidocaine
Loratadine
Meperidine
Methadone
Methamphetamine
Mexiletine
Morphine
Ondansetron
Oxycodone
Risperidone
Selegiline
SSRIs
TamoxiIen
Thioridazine
Tolterodine
Tramadol
Trazodone
CYP2E1
Acetaminophen
Ethanol
Felbamate
General anesthetics
Isoniazid
Ondansetron
TamoxiIen
Theophylline
CYP3A4
Acetaminophen
AlIentanil
Benzodiazepines
Amitriptyline and other TCAs
Amiodarone
Anastrazole
Azole antiIungals
Buspirone
BusulIan
Carbamazepine
Chlorpromazine
Cimetidine
Clozapine
Codeine
Cyclophosphamide and iIosIamide
Cyclosporin
Dapsone
DariIenacin
Delavirdine
Dexamethasone
Dextromethorphan
Dihydroergotamine
Dihydropyridines (i.e.. niIedipine)
Diltiazem
Disopyramide
Docetaxel and paclitaxel
Dolasetron and ondansetron
Donepezil
Doxorubicin
EIavirenz
Enalapril
Ergot alkaloids
Erlotinib
Estrogens
Ethosuximide
Etoposide
Erythromycin and clarithromycin
Felbamate
Fentanyl
FexoIenadine
Finasteride
Flutamide
Glyburide
Granisetron
Haloperidol
HIV protease inhibitors
HMG-CoA reductase inhibitors
Hydrocodone
Hydrocortisone
Irinotecan
Lansoprazole
Lidocaine
Loperamide
Loratadine
Losartan
Midazolam
MiIepristone
Navelbine
NeIazodone
Nevirapine
Norethisterone
Omeprazole
Ondansetron
Oral contraceptives
Oxybutynin
Pimozide
Prednisone and prednisolone
Quinidine
Repaglinide
RiIampin and analogs
Risperidone
Salmeterol
SildenaIil
SSRIs
SulIamethoxazole
Tacrolimus
TadalaIil
TamoxiIen
Teniposide
Testosterone
Theophylline
Tolterodine
Tretinoin
Valproic acid
VardenaIil
Verapamil
Vinca alkaloids
WarIarin
HMG CoA. þ-hydroxy-þ-methylglutaryl-coenzyme A; NSAIDs. nonsteroidal
anti-inIlammatory drugs; SSRIs. selective serotonin reuptake inhibitors;
TCAs. tricyclic antidepressants.

P. 401


Table 17-2. Phase I Metabolism: Oxidative Pathways
Type of Reaction
(Examples)
Reaction Pathway
1
.
Aromatic
Hydroxylati
on
(phenytoin.
phenylbutaz
one)
2
.
Aliphatic
Hydroxylati
on
(pentobarbit
al.
meprobamat
e)
3
.
OleIinic
Hydroxylati
on
(carbamazep
ine.
cyproheptadi
ne)
4
.
Benzylic
Hydroxylati
on
(tolbutamide
.
imipramine)
5
.
Allylic
Hydroxylati
on
(pentazocine
.
hexobarbital
)
6
.
Hydroxylati
on-u to a
Carbonyl
(diazepam.
ketamine)
7
.
Oxidative
Deamination
(amphetami
ne.
dopamine)
8
.
N-
Dealkylation
(morphine.
ephedrine)
9
.
N-Oxidation
(acetaminop
hen.
guanethidine
)
1
0
.
O-
Dealkylation
(codeine.
papaverine)
1
1
.
S-
Dealkylation
(6-
methylmerca
ptopurine)
1
2
.
S-Oxidation
(chlorproma
zine.
mesoridazin
e)
1
3
.
DesulIuratio
n
(thiopental)
1
4
.
Dehalogenat
ion
(halothane.
chloramphen
icol)
1
5
.
Oxidation oI
Alcohols
(ethanol.
estradiol)
1
6
.
Oxidation oI
Aldehydes
(acetaldehyd
e. PGE
2
)

P. 402


Table 17-3. Phase I Metabolism: Reductive and Hydrolytic Pathways
Type of Reaction
(Examples)
Reaction Pathway
Reduction
1
.
Carbonyl
Reduction
(acetohex
amide)
2
.
Azoreduct
ion
(sulIasalaz
ine.
olsalazine
)
3
.
Nitroredu
ction
(chloramp
henicol.
clonazepa
m)
Hydrolysis
4
.
Ester
Hydrolysi
s
(procaine.
meperidin
e)
5
.
Amide
Hydrolysi
s
(lidocaine.
indometha
cin)

( 1) The hi gh- ener gy f or m of gl ucuroni c aci d, uri di ne di phosphat e gI ucuroni c aci d,
r eact s wi t h a vari et y of f unct i onal groups under t he i nf l uence of gl ucur onyl
t r ansf erase.
( 2) Dr ugs t hat possess hydroxyI or carboxyI f unct i onal groups r eadi l y under go
gl ucuroni dat i on t o f orm et hers and est ers, r espect i vel y. Ì n addi t i on, N- , S- , and C-
gl ucuroni des are al so possi bl e.
( 3) As shown i n Tabl e 17- 4, t he addi t i on of gl ucuroni c aci d t o a dr ug mol ecul e adds
t hr ee hydr oxyl gr oups and one car boxyl gr oup. Thi s addi t i on gr eat l y i ncr eases t he
hydrophi I i ci t y of t he drug mol ecul e. As a r esul t , i t i s unl i kel y t o penet r at e cel l
membr anes and el i ci t phar macol ogi cal act i vi t y. Ì t i s al so poor l y r eabsorbed by t he
r enal t ubul es and, t hus, i s r eadi l y excr et ed.
( 4) Gl ucuroni des wi t h hi gh moI ecuI ar wei ght ( mor e t han 500) ar e of t en excr et ed
i nt o t he bi l e and, event ual l y, i nt o t he i nt est i nes. The i nt est i nal enzyme 8-
gl ucuroni dase can t hen hydr ol yze t he conj ugat e, r el easi ng t he unal t ered dr ug ( or i t s
pr i mar y met abol i t e) f or reabsorpt i on by t he i nt est i ne.
b. SuI fat e conj ugat i on i s much l ess common t han gl ucur oni de conj ugat i on because
t her e i s no avai l abl e pool of endogenous sul f at e. Addi t i onal l y, t her e ar e f ewer
f unct i onal groups capabl e of f ormi ng sul f at e conj ugat es. The hi gh- ener gy f orm of
sul f at e, 3' - phosphoadenosi ne- 5' - phosphosuI fate ( PAPS) , r eact s wi t h phenol s,
al cohol s, ar yl ami nes, and N- hydr oxyl compounds under t he i nf l uence of
suI f ot ransferase t o f orm hi ghl y pol ar met abol i t es.
c. Ami no aci d conj ugat i on i nvol ves t he r eact i on of ei t her gl yci ne or gl ut ami ne wi t h
al i phat i c or ar omat i c aci ds t o f or m ami des. A dr ug mol ecul e i s f i rst conver t ed t o an
acyl coenzyme A i nt ermedi at e. An N- acyl t ransf erase enzyme t hen cat al yzes t he
conj ugat i on of t he act i vat ed dr ug mol ecul e wi t h t he ami no aci d.
d. GI ut at hi one conj ugati on i s ext r emel y i mpor t ant i n prevent i ng t oxi ci t y f r om a
var i et y of har mf ul el ect rophi l i c agent s. Gl ut at hi one, a t ri pept i de cont ai ni ng a
nucl eophi l i c sul f hydr yl group, i s present i n al most al l mammal i an t i ssues. Under t he
i nf l uence of gI utat hi one S- t ransf erase, gl ut at hi one can r eact wi t h hal i des,
epoxi des, and ot her el ect r ophi l i c compounds t o f or m harml ess i nact i ve product s.
When gl ut at hi one has react ed wi t h an el ect rophi l e, i t undergoes a ser i es of
r eact i ons t o pr oduce a mer capt ur i c aci d der i vat i ve, whi ch i s el i mi nat ed.
P. 403


Table 17-4. Phase II Metabolism: Conjugation Pathways
Type of
Conjugate
Reaction Pathway
R ÷ Drug Molecule; X ÷ Functional Group
1
.
Glucur
onide
(X ÷
OH.
NR
2
.
CO
2
H.
SH.
acidic
carbon
atoms)
2
.
SulIate
(X ÷
OH.
arylami
nes.
NH
OH)
3
.
Amino
Acid
(Occur
s only
with
acid
Iunctio
nal
groups)
4
.
Glutath
ione (X
÷
electro
philic
center
such as
halide.
epoxid
e. or
Michae
l
accepto
r)
5
.
Methyl
(X ÷
OH.
NH
2
.
SH)
6
.
Acetyla
tion (X
÷ NH
2
.
NHNH
2
.
SO
2
NH
2
.
CO
NH
2
)

e. Met hyI at i on of oxygen- , ni t r ogen- , and sul f ur -cont ai ni ng f unct i onal gr oups r esul t s
i n met abol i t es t hat ar e usual l y l ess pol ar t han t he unal t er ed drugs. Met hyl at i on can
i nact i vat e cert ai n compounds [ e. g. , cat echol O-met hyl t r ansf er ase ( COMT)
met hyl at es a number of cat echol ami ne neur ot r ansmi t t er s] , but over al l i t pl ays a
mi nor rol e i n t he el i mi nat i on of dr ugs. Ì t s maj or r ol e i s i n t he bi osynt hesi s of
endogenous compounds ( e. g. , epi nephr i ne) . The hi gh- ener gy f or m r equi red f or
met hyl t r ansf er ase enzymes i s S- adenosyl met hi oni ne ( SAM) .
f . Acet yI at i on can occur wi t h pr i mar y ami nes, hydr azi des, sul f onami des, and,
occasi onal l y, ami des. Ì t l eads t o t he f or mat i on of N- acet yl at ed pr oduct s. These
pr oduct s ar e usual l y l ess pol ar t han t he unal t ered dr ug and can r et ai n
pharmacol ogi cal act i vi t y.
( 1) N- acet yl at ed met abol i t es can accumul at e i n t i ssue or i n t he ki dneys, as i n t he
case of cer t ai n ant i bact er i al sul f onami des. Cr yst al l uri a and subsequent t i ssue
damage may r esul t .
( 2) The hi gh- ener gy mol ecul e f or acet yl at i on i s acet yl - CoA. The react i on i s
cat al yzed by N-acet yl t ransf er ase.
P. 404


III. FACTORS INFLUENCING DRUG METABOLISM
A. Chemi caI st ruct ure speci f i cal l y i nf l uences a dr ug' s met abol i c pat hway. The
pr esence or absence of cer t ai n f unct i onal groups wi l l det ermi ne t he necessi t y,
r out e, and ext ent of met abol i sm.
B. Speci es di f ferences
1. QuaI i t ati ve di f ferences i n t he act ual met abol i c pat hway. Such a var i at i on can
r esul t f r om a genet i c def i ci ency of a par t i cul ar enzyme or a di f f erence i n a par t i cul ar
endogenous subst rat e. Ì n general , qual i t at i ve di f f er ences occur pr i mari l y wi t h phase
I I react i ons.
2. Quant i t ati ve di f ferences ar e di f f erences i n t he ext ent t o whi ch t he same t ype of
met abol i c r eact i on occurs. Such a vari at i on can resul t f r om a di f f erence i n t he
enzyme l evel , t he presence of speci es speci f i c i sozymes, a di f f er ence i n t he amount
of endogenous i nhi bi t or or i nducer, or a di f f er ence i n t he ext ent of compet i ng
r eact i ons. Ì n general , quant i t at i ve di f f er ences occur pr i mari l y wi t h phase I
react i ons.
C. Physi oI ogi caI or di sease stat e
1. Because t he l i ver i s t he maj or organ i nvol ved i n bi ot r ansf ormat i on, pathoI ogi caI
f act ors t hat aI t er I i ver funct i on can af f ect a dr ug' s hepat i c cl ear ance.
2. Congesti ve heart f ai I ure decreases hepat i c bl ood f l ow by r educi ng cardi ac
out put , whi ch al t er s t he ext ent of dr ug met abol i sm.
3. An aI terat i on i n aI bumi n product i on ( t he pl asma' s maj or dr ug- bi ndi ng pr ot ei n)
can al t er t he f r act i on of bound t o unbound drug. Thus, a decr ease i n pl asma
al bumi n can i ncrease t he f r act i on of unbound (f ree) dr ug, whi ch t hen becomes
avai l abl e t o exer t a more i nt ense pharmacol ogi cal ef f ect . The rever se i s t rue when
pl asma al bumi n i ncr eases.
D. Genet i c vari ati ons
1. The acet yI at i on rat e depends on t he amount of N- acet yl t r ansf er ase present ,
whi ch i s det er mi ned by genet i c f act or s. The gener al popul at i on can be di vi ded i nt o
f ast acet yI at ors and sI ow acet yI at ors. For exampl e, f ast acet yl at ors are mor e
pr one t o hepat otoxi ci t y f r om t he ant i t uber cul ar agent i soni azi d t han sl ow
acet yl at or s, wher eas sl ow acet yl at or s ar e mor e pr one t o i soni azi d' s ot her t oxi c
ef f ect s (see VÌ Ì . B. 4. d) .
2. The di scover y of i sof or ms and f ami l i es of CYP450 enzymes has shown t hat
genet i c var i at i ons exi st i n i sof or ms t hat oxi di ze debri soqui ne. Ì ndi vi dual s who ar e
poor met abol i zer s of t hi s compound ( PM phenot ype) al so exhi bi t i mpai red
met abol i sm of mor e t han 20 ot her t her apeut i c agent s, i ncl udi ng 8- bl ockers,
ant i ar r hyt hmi cs, opi oi ds, and ant i depressant s. Appr oxi mat el y 5%- 10% of whi t es, 2%
of Asi ans, and 1% of Ar abs expr ess t he PM phenot ype and ar e at r i sk f or adver se
dr ug r eact i ons.
E. Drug dosage
1. An i ncrease i n dr ug dosage resul t s i n i ncr eased drug concent rat i ons and can
sat ur at e cer t ai n met abol i c enzymes. As dr ug concent r at i on exceeds 50% sat ur at i on
f or a part i cul ar enzyme, dr ug el i mi nat i on vi a t hi s pat h no l onger f ol l ows sol el y f i rst -
or der ki net i cs, but r at her i s a mi x of zer o- and f i rst - order ki net i cs. At 100%
sat ur at i on, met abol i sm vi a t hi s enzyme f ol l ows zer o- order ki net i cs.
2. When the metaboI i c pat hway i s sat urat ed ( ei t her because of an exceedi ngl y
hi gh drug l evel or because t he suppl y of an endogenous conj ugat ed agent i s
exhaust ed) , an al t er nat i ve pat hway may be pur sued. For exampl e, at normal doses,
98% of a dose of acet ami nophen undergoes conj ugat i on wi t h ei t her gl ucur oni c aci d
or sul f at e; however , at t oxi c doses, conj ugat i on pat hways become sat ur at ed and
acet ami nophen under goes ext ensi ve N-hydr oxyl at i on, whi ch can l ead t o
hepat ot oxi ci t y.
F. Nut ri ti onaI stat us
1. The l evel s of some conj ugat i ng agent s ( or endogenous subst r at es), such as
sul f at e, gl ut at hi one, and ( r ar el y) gl ucur oni c aci d, ar e sensi t i ve t o body nut r i ent
l evel s. For exampl e, a I ow- protei n di et can l ead t o a def i ci ency of cer t ai n ami no
aci ds, such as gl yci ne. Low- pr ot ei n di et s al so decr ease oxi dat i ve dr ug met abol i sm
capaci t y.
P. 405


2. Di et s defi ci ent i n essent i aI f att y aci ds ( par t i cul arl y l i nol ei c aci d) reduce t he
met abol i sm of et hyl - morphi ne and hexobar bi t al by decreasi ng synt hesi s of cer t ai n
dr ug-met abol i zi ng enzymes.
3. A def i ci ency of cert ai n di et ar y mi neraI s al so af f ect s dr ug met abol i sm. Cal ci um,
magnesi um, and zi nc def i ci enci es decr ease drug-met abol i zi ng capaci t y, wher eas
i r on def i ci ency appears t o i ncr ease i t . A copper def i ci ency l eads t o vari abl e ef f ect s.
4. Def i ci enci es of vi t ami ns (par t i cul ar l y vi t ami ns A, C, E, and t he B gr oup) af f ect
dr ug-met abol i zi ng capaci t y. For exampl e, a vi t ami n C def i ci ency can resul t i n a
decrease i n oxi dat i ve pat hways, wher eas a vi t ami n E def i ci ency can r et ard
deal kyl at i on and hydr oxyl at i on.
G. Age
1. Met abol i zi ng enzyme syst ems are not f ul l y devel oped at bi r t h; t hus, i nfant s and
young chi I dren need t o r ecei ve smal l er doses of dr ugs t han adul t s t o avoi d t oxi c
si de ef f ect s. Thi s i s par t i cul ar l y t rue of dr ugs t hat r equi r e gl ucur oni de conj ugat i on.
2. Ì n oI der chi I dren, some dr ugs may be l ess act i ve t han i n adul t s, par t i cul arl y i f
t he dosage i s based on wei ght . The l i ver devel ops f ast er t han t he i ncr ease i n
gener al body wei ght and, t hus, r epresent s a great er f ract i on of t ot al body wei ght .
3. Ì n t he eI derI y, met abol i zi ng enzyme syst ems decl i ne. The l ower ed l evel of
enzyme act i vi t y sl ows t he r at e of drug el i mi nat i on, causi ng hi gher pl asma dr ug
l evel s per dose t han i n young adul t s.
H. Gender. Met abol i c di f f er ences bet ween t he sexes have been obser ved f or a
number of compounds, suggest i ng t hat androgen, est r ogen, and/ or adrenocor t i coi d
act i vi t y mi ght af f ect t he act i vi t y of cer t ai n CYP450 enzyme i sozymes.
1. Met abol i sm of di azepam, pr edni sol one, caf f ei ne, and acet ami nophen i s sI i ghtI y
f ast er i n women.
2. Oxi dat i ve met abol i sm of propranol ol , chl or di azepoxi de, l i docai ne, and some
st eroi ds occurs fast er i n men t han i n women.
I . Ci rcadi an rhyt hms. The noct urnaI pI asma I eveI s of dr ugs, such as t heophyl l i ne
and di azepam, ar e l ower t han t he di urnaI pI asma I eveI s.
J. Drug admi ni st rat i on rout e
1. OraI admi ni st rat i on. The dr ug i s absor bed f rom t he GÌ t r act and t r anspor t ed t o
t he l i ver t hr ough t he hepat i c por t al vei n bef ore ent eri ng t he syst emi c ci rcul at i on.
Thus, t he dr ug i s subj ect t o hepat i c met abol i sm bef or e i t r eaches i t s si t e of act i on.
Thi s i s an ef f ect known as t he f i rst - pass ef f ect , or presyst emi c eI i mi nati on ( Tabl e
17- 5).
a. The f i r st - pass ef f ect can cause si gni f i cant cI i ni caI probI ems. Because dr ugs
ar e met abol i zed i n t he l i ver f r om t hei r act i ve f orms t o i nact i ve f or ms, t hi s ef f ect
must be count eract ed t o achi eve t he desi red pl asma or t i ssue drug l evel .
b. A common approach i s t o i ncrease the oraI dose, of f set t i ng t he l oss of dr ug
act i vi t y f r om t he f i rst -pass ef f ect .
Table 17-5. Examples of Drugs That Undergo First-Pass Metabolism
Acetaminophen Fluorouracil Oxprenolol
Albuterol Imipramine Pentazocine
Alprenolol Isoproterenol Progesterone
Aspirin Lidocaine Propoxyphene
Cortisone Meperidine Propranolol
Cyclosporin Methyltestosterone Salbutamol
Desipramine Metoprolol Terbutaline
Dihydropyridines Nortriptyline Testosterone
Estradiol Organic Nitrates Verapamil

P. 406


Table 17-6. Examples of Common CYP3A4 Inhibitors and Inducers
Potent Inhibitors Moderate InhibitorsInducers
Amiodarone Amprenavir Carbamazepine
Atazanavir CiproIloxacin EIavirenz
Clarithromycin Diltiazem Nevirapine
Indinavir Erythromycin Phenytoin
Itraconazole Fluconazole Phenobarbital
Ketoconazole Fluvoxamine RiIabutin
NeIazodone GrapeIruit iuice RiIapentine
NelIinavir NorIloxacin RiIampin
Ritonavir Verapamil St. John's Wort
Telithromycin
Troleandomycin
Voriconazole

2. I nt ravenous admi ni strat i on bypasses t he f i rst - pass ef f ect because t he dr ug i s
del i ver ed di r ect l y t o t he bl oodst r eam wi t hout bei ng met abol i zed i n t he l i ver . Thus,
i nt ravenous doses of drugs under goi ng consi der abl e f i rst - pass ef f ect s ar e much
smal l er t han oral doses.
3. SubI i nguaI admi ni st rat i on and rect aI admi ni st rat i on al so bypass f i r st - pass
ef f ect s, al t hough rect al admi ni st r at i on can produce var i abl e ef f ect s.
K. Concurrent drug therapy. The co- admi ni st rat i on of dr ugs t hat are capabl e of
ei t her i nhi bi t i ng or i nduci ng speci f i c CYP450 i sozymes can i ncrease or decr ease,
r espect i vel y, t he pl asma l evel s of ot her dr ugs t hat r equi re t hese i sozymes f or
nor mal dr ug met abol i sm.
1. As i ndi cat ed on Tabl e 17- 1, most drugs are met abol i zed by t he f ol l owi ng t hree
i sozymes: CYP2C9, CYP2D6, and CYP3A4. The pot ent i al f or drug i nt er act i ons due
t o enzyme i nhi bi t i on or i nduct i on i s t her ef or e gr eat er wi t h t hese compounds.
2. Dr ugs t hat al t er t he act i vi t y of CYP450 i sozymes ar e usual l y subst r at es of t hese
same i sozymes. Thi s can be obser ved by compar i ng Tabl es 17- 1 and 17-6.
3. The cl i ni cal out come of t hese t ypes of dr ug i nt er act i ons depends upon t hr ee
f act or s:
a. The pot ency of t he i nhi bi t or or i nducer ( Tabl e 17- 6)
b. The avai l abi l i t y of al t er nat e el i mi nat i on pat hways
c. The ext ent t o whi ch t he hi gher or l ower pl asma concent rat i ons of t he drug causes
sympt oms and/ or undesi r abl e ef f ect s.
IV. EXTRAHEPATIC METABOLISM
A. Def i ni t i on. Ext r ahepat i c met abol i sm ref ers t o dr ug bi ot r ansf ormat i on t hat t akes
pl ace i n ti ssues ot her than the I i ver. The most common si t es i ncl ude t he portaI s
of ent r y ( e. g. , GÌ mucosa, nasal passages, l ungs) and t he portaI s of excret i on
( e. g. , ki dneys) . However , met abol i sm can occur t hr oughout t he body.
B. MetaboI i sm si t es
1. PI asma cont ai ns esterases, whi ch are r esponsi bl e pr i mari l y f or hydrol ysi s of
est er s. Si mpI e esters (e. g. , pr ocai ne, succi nyl chol i ne) ar e rapi dl y hydr ol yzed i n t he
bl ood. Addi t i onal l y, pl asma est er ases can act i vat e a vari et y of est er prodrugs.
2. Met abol i zi ng enzymes i n t he i nt est i naI mucosa ar e especi al l y i mport ant f or
dr ugs under goi ng mi crosomal oxi dat i on, gl ucuroni de conj ugat i on, and sul f at e
conj ugat i on.
a. As a l i pi d-sol ubl e dr ug passes t hrough t he i nt est i nal mucosa dur i ng drug
absor pt i on, i t can be met abol i zed i nt o pol ar or i nact i ve met abol i t es bef ore ent eri ng
t he bl ood. The r esul t i s comparabI e t o a fi rst - pass ef f ect .
P. 407


b. The i nt est i nal mucosa' s dr ug-met abol i zi ng capaci t y compar es t o t hat of t he l i ver.
However , i t shows much gr eat er i ndi vi dual var i at i on because of i t s gr eat er exposur e
t o t he envi r onment .
3. I ntesti naI bact eri aI fI ora secret e a number of enzymes capabl e of met abol i zi ng
dr ugs and ot her xenobi ot i cs.
a. Any f act or t hat modi f i es t he i nt esti naI f I ora may al so modi f y drug act i vi t y.
Age, di et , di sease st at e, and exposure t o envi r onment al chemi cal s or drugs may al l
be i mpor t ant .
( 1) Cer t ai n di seases, par t i cul ar l y i ntesti naI di sease, af f ect i nt est i nal f l ora.
Ul cerat i ve col i t i s, f or exampl e, pr omot es bact er i al gr owt h. Di ar r hea reduces t he
number of bact eri a.
( 2) Cer t ai n envi ronmentaI chemi caI s and drugs al so act on i nt est i nal f l or a.
Ant i bi ot i cs, f or exampl e, decrease t he number of bact er i a.
b. Bact eri al f l or a secrete 8- gl ucur oni dase, whi ch hydr ol yzes t he pol ar gl ucur oni de
conj ugat es of bi l e and al l ows t he f r ee, nonpol ar bi l e aci ds t o be r eabsor bed. Thi s
ent erohepat i c ci rcuI ati on par t i al l y mai nt ai ns t he pool of bi l e aci ds. Thi s same
pr i nci pl e appl i es t o cer t ai n gl ucuroni de conj ugat es of drugs.
c. Cert ai n bact eri al f l or a convert vi t ami n pr ecursor s t o t hei r act i ve f orms, as wi t h
vi t ami n K.
d. Bact eri al f l or a can al so convert cer t ai n subst ances t o t hei r t oxi c forms, as wi t h
t he conver si on of t he ar t i f i ci al sweet ener cycl amat e t o cycl ohexyl ami ne, a
suspect ed carci nogen.
e. Ì nt est i nal bact er i a produce azoreductase, whi ch reduces t he pr odr ug
sul f asal azi ne t o t he act i ve ant i -i nf l ammat or y ami nosal i cyl i c aci d and t he act i ve
ant i bact eri al sul f apyr i di ne. Sul f asal azi ne i s one of t he f ew agent s ef f ect i ve i n t he
t r eat ment of ul cer at i ve col i t i s.
4. The aci di c envi ronment of t he st omach pr oduces nonenzymat i c degradat i on of a
number of dr ug mol ecul es, i ncl udi ng peni ci l l i n G, car beni ci l l i n, er yt hromyci n, and
t et r acycl i ne. Addi t i onal l y, gast ri c aci d assi st s i n t he degradat i on of prot ei ns and
pept i des (e. g. , i nsul i n) .
5. The nasaI mucosa provi des a hi gh l evel of CYP450 act i vi t y, whi ch can
si gni f i cant l y al t er t he amount of dr ug t hat reaches t he syst emi c ci rcul at i on. Nasal
decongest ant s, anest het i cs, ni cot i ne, cocai ne, and ot her compounds have been
shown t o undergo nasal met abol i sm.
6. The I ung i s r esponsi bl e f or f i r st - pass met abol i sm of dr ugs admi ni st ered
i nt ravenousl y, i nt r amuscul arl y, t r ansdermal l y, or subcut aneousl y.
a. The t ot aI amount of met aboI i zi ng enzymes pr esent i n t he l ungs i s l ess t han t hat
i n t he l i ver ; however , t he speci f i c act i vi t i es of t he enzymes are comparabl e t o t hose
i n t he l i ver .
b. The l ungs pr ovi de second- pass metaboI i sm f or drugs l eavi ng t he l i ver.
C. PI acentaI and fet aI met aboI i sm
1. PI acent a. Ì n gener al , i f a dr ug or ot her xenobi ot i c i s l i pi d sol ubl e enough t o be
absor bed i nt o t he ci rcul at i on when admi ni st er ed t o a pr egnant woman, i t wi l l l i kel y
al so pass t hr ough t he pl acent a.
a. The pl acent a i s not a physi cal or met abol i c bar r i er t o xenobi ot i cs. Ver y l i t t l e
xenobi ot i cmet abol i zi ng enzyme act i vi t y has been demonst r at ed i n t he pl acent a.
b. Dr ugs pr esent i n t hei r act i ve form i n t he mat er nal ci r cul at i on l i kel y pass
unchanged i nt o t he f et al ci rcul at i on.
c. An except i on t o t hi s l ack of enzyme act i vi t y i n t he pl acent a i s t he presence of a
smal l amount of ar yI aromat i c hydroxyI ase, whi ch i s i nduci bI e i n pregnant
women who smoke ci garet t es. A pot ent i al consequence i s an i ncrease i n t he
pr oduct i on of penul t i mat e car ci nogens f r om t he act i on of t hi s enzyme on t he
pol ycycl i c ar omat i c hydrocarbons pr esent i n ci gar et t e smoke and ot her
envi r onment al sour ces.
2. Fet us. Ì n t erms of f et al met abol i sm, t her e ar e var yi ng degrees of drug-
met abol i zi ng act i vi t y dependent upon a number of f act ors i ncl udi ng f et al age.
a. A maj or defi ci ency i s t hat of gI ucuroni c aci d conj ugat i ng act i vi t y bot h i n t he
f et us and t he neonate.
b. Two consequences of t hi s are t he gray baby syndrome, r esul t i ng f rom
decreased chl or ampheni col gl ucur oni dat i on, and neonat aI hyperbi I i rubi nemi a,
r esul t i ng f r om a decr ease i n bi l i rubi n gl ucuroni de f ormat i on.
P. 408


V. STRATEGIES TO MANAGE DRUG METABOLISM.
A var i et y of met hods have been used t o ci rcumvent t he rapi d met abol i sm of cer t ai n
dr ugs. These met hods seek t o i mpr ove dr ug t herapy by decreasi ng t he over al l
ext ent of met abol i sm and i ncr easi ng t he dur at i on of act i on. Ì n some i nst ances, t hese
met hods have pr ovi ded i ncr eased si t e speci f i ci t y.
A. Pharmaceut i caI st rategi es i nvol ve t he use of di f f er ent dosage f orms t o ei t her
avoi d or compensat e f or r api d met abol i sm.
1. SubI i nguaI t abI et s are usef ul f or del i ver i ng drugs di rect l y i nt o t he syst emi c
ci rcul at i on and bypassi ng hepat i c f i rst -pass met abol i sm. Ni t rogI yceri n, a r api dl y
act i ng ant i angi nal agent , i s essent i al l y i nef f ect i ve when admi ni st ered or al l y due t o
an ext r emel y hi gh f i rst -pass ef f ect but i s ver y ef f ect i ve i n t reat i ng acut e at t acks of
angi na i f gi ven subl i ngual l y.
2. TransdermaI pat ches and oi ntment f ormuI ati ons pr ovi de a cont i nuous suppl y of
dr ug over an ext ended per i od of t i me and are usef ul f or r api dl y met abol i zed
compounds such as ni t r ogl yceri n. These del i ver y syst ems, whi l e not sui t ed t o t r eat
acut e angi nal sympt oms, ar e ef f ect i ve i n provi di ng pr ophyl act i c concent r at i ons of
ni t rogl ycer i n.
3. I nt ramuscuI ar depot i nj ect i ons al so provi de a cont i nuous suppl y of dr ug over an
ext ended peri od of t i me. Hi ghl y l i pi d sol ubl e est ers of est radi oI and t estost erone
( e. g. , est r adi ol benzoat e, t est ost er one enant hat e) ar e sl owl y absor bed f rom t hei r
admi ni st rat i on si t e. Hydrol ysi s of t hese pr odr ugs ( see VÌ ) pr oduces a st eady suppl y
of t hese rapi dl y met abol i zed hormones.
4. Enteri c-coated formuI at i ons can prot ect aci d-sensi t i ve dr ugs as t hey pass
t hr ough t he aci di c envi ronment of t he st omach. Met henami ne, er yt hromyci n, and
omeprazoI e ar e exampl es of aci d- sensi t i ve agent s t hat ar e avai l abl e as ent eri c-
coat ed pr eparat i ons.
5. NasaI admi ni st rat i on al l ows f or t he del i ver y of pept i des, such as caI ci t oni n
saI mon, whi ch have very l ow ( i f any) or al bi oavai l abi l i t y. Char act er i st i cs of t he l ung
make i t i deal f or t he admi ni st rat i on of pept i des. Aer osol i zed dr ugs onl y need t o
penet r at e a t hi n epi t hel i al l ayer t o r each abundant capi l l ar y beds. Addi t i onal l y, t he
l ungs cont ai n pr ot ease i nhi bi t or s, whi ch al l ow f or gr eat er st abi l i t y of t he pept i des.
B. PharmacoI ogi caI st rat egi es i nvol ve t he concur r ent use of enzyme i nhi bi t ors t o
decrease dr ug met abol i sm. Ì n some i nst ances, t he concur r ent use of an addi t i onal
agent does not pr event met abol i sm but r at her prevent s t he t oxi ci t y caused by
met abol i t es of t he t her apeut i c agent .
1. Levodopa ( L- dopa), t he ami no aci d pr ecursor of dopami ne, i s used i n t he
t r eat ment of par ki nsoni sm. Unl i ke dopami ne, L- dopa can penet r at e t he bl ood-br ai n
bar r i er and r each t he cent r al ner vous syst em ( CNS) . When i n t he br ai n, i t i s
decar boxyl at ed t o dopami ne. To ensur e t hat adequat e concent rat i ons of L- dopa
r each t he CNS, peri pheral met abol i sm of t he drug must be bl ocked. The concur rent
admi ni st rat i on of carbi dopa, a dopa decar boxyl ase i nhi bi t or t hat cannot penet rat e
t he bl ood-br ai n bar r i er , pr event s per i pher al f ormat i on of dopami ne and al l ows si t e-
speci f i c del i ver y of dopami ne t o t he CNS.
2. ß-Lactam ant i bi ot i cs. The ant i bact eri al act i vi t y of a number of 8- l act am
ant i bi ot i cs i s r educed by mi cr oor gani sms capabl e of secr et i ng t he enzyme 8-
l act amase. Thi s enzyme hydr ol yzes t he 8- l act am r i ng and i nact i vat es t he ant i bi ot i c.
To count er t hi s resi st ance mechani sm, a 8- l act amase i nhi bi t or , such as cI avuI ani c
aci d, i s used i n conj unct i on wi t h a peni ci l l i n, such as amoxi ci I I i n, t o successf ul l y
t r eat i nf ect i ons caused by 8- l act amase- produci ng bact eri a.
3. I f osf ami de i s an al kyl at i ng agent t hat must under go i n vi vo met abol i sm t o
pr oduce an act i ve ni t r ogen must ard. Ì n t he pr ocess of t hi s met abol i c act i vat i on,
si gni f i cant concent r at i ons of acroI ei n are pr oduced. These acrol ei n mol ecul es r eact
wi t h nucl eophi l es on r enal pr ot ei ns and pr oduce hemor r hagi c cyst i t i s. To pr event
t hi s t oxi ci t y, i f osf ami de i s al ways coadmi ni st er ed wi t h mesna, a sul f hydr yl -
cont ai ni ng compound t hat r eact s wi t h and neut r al i zes any acrol ei n t hat i s pr esent i n
t he ki dney.
4. HI V prot ease i nhi bi tors are ext ensi vel y met abol i zed by CYP3A i sozymes. Ì n
addi t i on, compounds wi t hi n t hi s cl ass can i nhi bi t t hese same i sozymes. Thi s l at t er
act i on has been used t o opt i mi ze t her apy. Ri t onavi r i s an HÌ V pr ot ease i nhi bi t or
t hat i s known t o cause hepat oxi ci t y at t her apeut i c doses. Lopi navi r i s an HÌ V
pr ot ease i nhi bi t or t hat i s i nef f ect i ve i f used al one due t o r api d CYP3A oxi dat i on. A
combi nat i on of l ow dose r i t onavi r wi t h a t her apeut i c
P. 409

dose of l opi navi r r esul t s i n an i nhi bi t i on of CYP3A, t he est abl i shment of adequat e
pl asma l evel s of l opi navi r , and t her apeut i c ef f i cacy wi t hout hepat ot oxi ci t y.

Figure 17-1. Selected examples oI chemical
modiIication that eliminate metabolic
transIormations. Methylation oI testosterone
blocks the rapid oxidation oI the 17-hydroxyl
group and allows oral activity. whereas
replacement oI the metabolically labile para-
methyl group on tolbutamide with a chloro group
allows Ior a much longer duration oI action.
C. Chemi caI st rat egi es i nvol ve t he addi t i on, del et i on, or i sost er i c modi f i cat i on of
key f unct i onal groups. These mol ecul ar modi f i cat i ons hi nder or compl et el y el i mi nat e
met abol i c t ransf ormat i ons ( Fi gure 17- 1).
1. Test ost erone i s not or al l y act i ve due t o rapi d oxi dat i on of i t s 17- hydroxyl gr oup
t o a ket one. Addi t i on of a 17q-met hyl group conver t s t he l abi l e secondar y al cohol t o
a st abl e t er t i ar y al cohol . The r esul t i ng compound, methyI t est ost erone, i s onl y hal f
as pot ent as t est ost er one; however , i t i s not subj ect t o rapi d f i rst - pass met abol i sm
and can be used oral l y. A si mi l ar st rat egy has been used t o make oral l y act i ve
est radi ol anal ogues.
2. ToI butami de i s an oral hypogl ycemi c wi t h a shor t durat i on of act i on. Thi s
sul f onyl ur ea r api dl y under goes oxi dat i on of i t s par a-met hyl group. A st r uct ural l y
si mi l ar compound, chI orpropami de, has a nonmet abol i zabl e par a-chl or o gr oup and,
as a r esul t , has a much l onger dur at i on of act i on.
3. I soproterenoI i s a pot ent 8-adr energi c agoni st used f or t he rel i ef of
br onchospasm associ at ed wi t h bronchi al ast hma. Because i t i s a cat echol ( i . e. , 3, 4-
di hydroxy- subst i t ut ed benzene ri ng) , i sopr ot er enol i s subj ect t o rapi d met abol i sm by
cat echol O- met hyl t r ansf er ase ( COMT) and, t hus, has poor or al act i vi t y. Al t erat i on
of t he 3, 4-di hydroxy subst i t ut i on t o a 3, 5- di hydroxy subst i t ut i on pr oduces
met aprot erenoI , a br onchodi l at or t hat i s not suscept i bl e t o COMT, i s oral l y act i ve,
and has a l onger dur at i on of act i on t han i soprot er enol .
4. Oct reot i de i s a synt het i c oct apept i de used t o suppr ess or i nhi bi t severe di ar r hea
associ at ed wi t h cer t ai n t umors. Oct reot i de mi mi cs t he act i ons of somat ost at i n, a
nat ural l y occurr i ng, 14- ami no aci d pept i de. Somat ost at i n under goes r api d
pr ot eol ysi s, has a hal f - l i f e of 1- 3 mi nut es, and must be admi ni st er ed as a
cont i nuous i nt ravenous i nf usi on. Oct r eot i de cont ai ns t he ami no aci ds essent i al f or
cl i ni cal ef f i cacy but r epl aces t wo of t he ami no aci ds wi t h t hei r D- enant i omer s. These
unnat ural D-ami no aci ds ar e more r esi st ant t o hydr ol ysi s. As a r esul t , oct r eot i de has
an i ncreased hal f -l i f e and can be admi ni st er ed as a subcut aneous i nj ect i on.
VI. PRODRUGS.
These dr ugs ar e mol ecul es t hat are ei t her i nact i ve or ver y weakl y act i ve and r equi r e
i n vi vo bi ot r ansf or mat i on t o pr oduce t he physi ol ogi cal l y act i ve dr ug. The phase Ì
met abol i c
P. 410

pr ocesses di scussed pr evi ousl y ar e used t o act i vat e pr odr ugs. A var i et y of
advant ages can be gai ned by usi ng a pr odrug i nst ead of t he act i ve f or m of t he
dr ug.
A. An i ncrease i n wat er soI ubi I i t y i s usef ul f or t he prepar at i on of opht hal mi c and
par ent eral f ormul at i ons. Sodi um succi nat e est ers and sodi um phosphate esters
have been used t o make a number of wat er -sol ubl e st eroi d prodr ugs.
B. An i ncrease i n I i pi d soI ubi I i t y i s usef ul f or a var i et y of r easons.
1. I ncreased durat i on of act i on. Li pi d- sol ubl e est ers of est radi ol , such as
benzoat e, val erat e, and cypi onat e, ar e used t o prol ong est rogeni c act i vi t y. Ì M
i nj ect i ons of t hese est ers i n oi l resul t i n a deposi t of dr ug t hat i s sl owl y hydr ol yzed,
t her eby r el easi ng f r ee est r adi ol over a prol onged per i od of t i me (see V. A. 3) .
2. I ncreased oraI absorpt i on i s obt ai ned by conver t i ng car boxyl i c aci d gr oups t o
est er s. These est er s can t hen be r api dl y conver t ed t o t he act i ve aci ds by pl asma
est er ases. EnaI apri I at i s a pot ent angi ot ensi n-conver t i ng enzyme ( ACE) i nhi bi t or
t hat i s used f or parent eral admi ni st r at i on, but , due t o i t s hi gh pol ari t y, i t i s oral l y
i nact i ve. Ì t s monomet hyl est er , enaI apri I , i s consi der abl y mor e l i pophi l i c and, t hus,
pr ovi des good or al absorpt i on. Thi s st r at egy has been successf ul l y used f or a
var i et y of ot her compounds, i ncl udi ng addi t i onal ACE i nhi bi t ors, f i br i c aci d
der i vat i ves, ampi ci l l i n, and sever al cephal ospori ns.
3. I ncreased t opi caI absorpt i on of st er oi ds i s obt ai ned by maski ng hydroxyl gr oups
as est er s or acet oni des. These pr odr ugs ar e much l ess pol ar t han t he parent
compounds and al l ow i ncr eased der mal permeabi l i t y f or t he t r eat ment of
i nf l ammat or y, al l er gi c, and prur i t i c ski n condi t i ons. Exampl es i ncl ude t ri amci noI one
acet oni de, di f I orasone di acet ate, and betamethasone vaI erat e.
4. I ncreased paI at abi I i ty. Ant i bi ot i cs such as suI f i soxazoI e have a bi t t er t ast e and
ar e not sui t abl e f or admi ni st r at i on t o young chi l dren who cannot yet swal l ow t abl et s
or capsul es. Est eri f i cat i on t o pr oduce suI f i soxazoI e acet yI decr eases t he wat er
sol ubi l i t y of t he ant i bi ot i c and, t hus, decr eases i t s i nt eract i on wi t h bi t t er t ast e
r ecept or s on t he t ongue. Thi s compound i s market ed as a f l avor ed suspensi on.
Si mi l ar st r at egi es have been used t o mask t he bi t t er t ast e of chI orampheni coI and
ot her ant i bi ot i cs.
C. A decrease i n GÌ i rri t at i on. Nonst er oi dal ant i - i nf l ammat or y agent s ( NSAÌ Ds)
pr oduce gast ri c i r ri t at i on and ul cerat i on vi a t wo mechani sms: a di r ect i r r i t ant ef f ect
of t he aci di c mol ecul e and i nhi bi t i on of gast ropr ot ect i ve prost agl andi n product i on.
The pr odr ugs suI i ndac and nabumet one pr oduce l ess GÌ i r ri t at i on because t he
gast r i c and i nt est i nal mucosa ar e not exposed t o hi gh concent r at i ons of act i ve dr ug
dur i ng or al admi ni st rat i on. Addi t i onal l y, nabumet one i s a ket one, not an aci d, and
l acks any di rect i r ri t ant ef f ect s.
D. Si t e speci f i ci t y i s usef ul f or i ncr easi ng t he concent r at i on of drug at t he act i ve
si t e and f or decr easi ng si de ef f ect s.
1. Met hyI dopa i s a pr odr ug t hat i s st r uct ural l y si mi l ar t o L-dopa. As a r esul t ,
met hyl dopa i s t r anspor t ed i nt o t he CNS and met abol i zed t o t he act i ve compound, q-
met hyI dopami ne, vi a t he same pat h used f or t he synt hesi s of dopami ne. Thi s
al l ows a si gni f i cant amount of q-met hyl dopami ne t o reach t he CNS and bi nd t o
cent r al q2- adr ener gi c r ecept ors.
2. OmeprazoI e i s used t o t r eat gast r i c ul cers and ot her hypersecr et or y di sorders.
Af t er or al absor pt i on, i t i s sel ect i vel y act i vat ed at t he aci di c pH l evel s ( pH l ess t han
1) seen i n gast ri c pari et al cel l s. Thi s al l ows t he act i ve f or m of t he dr ug t o be
pr oduced i n cl ose proxi mi t y t o t he enzyme H
+
/ K
+
- ATPase ( pr ot on pump) , r esul t i ng i n
i r r eversi bl e i nhi bi t i on of t he enzyme and a decr ease i n gast ri c aci d secr et i on.
Act i vat i on i n t he st omach pri or t o absor pt i on can be pr event ed by t he use of ent er i c-
coat ed f ormul at i ons (see V. A. 4).
3. FormaI dehyde i s an ef f ect i ve ur i nar y t ract ant i sept i c; however , or al
admi ni st rat i on r esul t s i n si gni f i cant t oxi ci t y. To avoi d t hi s probl em, t he prodr ug
met henami ne i s admi ni st er ed i nst ead. Met henami ne i s st abl e and nont oxi c at
nor mal physi ol ogi cal pH, but i s sel ect i vel y hydrol yzed t o f or mal dehyde and
ammoni um i ons i n t he aci di c ur i ne ( pH l ess t han 5. 5) . As wi t h omeprazol e,
act i vat i on bef or e absor pt i on can be prevent ed by t he use of ent eri c-coat ed
f or mul at i ons ( see V. A. 4).
P. 411


4. OI saI azi ne i s a hi ghl y pol ar di mer of 5- ami nosal i cyl i c aci d t hat i s poor l y absor bed
af t er or al admi ni st r at i on. On r eachi ng t he l ar ge i nt est i ne, col oni c bact eri a cl eave
t he azo bond and l i ber at e t he act i ve ant i -i nf l ammat or y agent . Ol sal azi ne and a
r el at ed compound, suI fasaI azi ne, ar e usef ul i n t reat i ng i nf l ammat or y bowel di sease.
E. Ì ncr eased shel f l i f e of bot h sol i ds and par ent er al admi xt ur es can be obt ai ned by
t he use of pr odr ugs. CycI ophosphami de i s a prodr ug t hat r equi r es i n vi vo
oxi dat i on, f ol l owed by nonenzymat i c decomposi t i on, t o pr oduce t he act i ve
phosphor ami de must ar d. As a r esul t , aqueous sol ut i ons of cycl ophosphami de ar e
much more st abl e t han t hose of ot her ni t r ogen must ar ds ( i . e. , mechl or et hami ne) .
MechI orethami ne i s hi ghl y r eact i ve, does not requi re i n vi vo act i vat i on, and can
r api dl y decompose i n aqueous envi ronment s bef or e admi ni st r at i on.
VII. PHARMACOGENETICS
A. Genes and t hei r i nvoI vement i n drug response and t oxi ci t y
1. Genes can be def i ned as di scret e segment s of DNA t hat are capabl e of
r epr oduct i on duri ng cel l r epl i cat i on and t hat ar e responsi bl e f or gui di ng t he
bi osynt hesi s of speci f i c pr ot ei ns and enzymes.
2. Genes encode pr ot ei ns i nvol ved i n t he absorpt i on, t ransport , metaboI i sm, and
eI i mi nat i on of dr ug mol ecul es. Addi t i onal l y, t hey encode pr ot ei ns t hat ser ve as
drug receptors. Ì t i s obvi ous t hen t hat a genet i c di sposi t i on t hat woul d resul t i n
ei t her an over- or an underexpressi on of these genes coul d si gni f i cant l y al t er
dr ug r esponse and t oxi ci t y.
3. Assumi ng t hat a pat i ent has been pr escri bed a medi cat i on t hat i s i ndi cat ed f or hi s
or her condi t i on or di sease st at e, t her e ar e several reasons why a pat i ent may not
r espond or may suf f er sever e adverse ef f ect s:
a. I nappropri ate dosi ng
b. Drug- drug i nt eract i ons
c. Drug aI I ergi es
d. Medi cat i on errors
e. Genet i c predi sposi t i on
4. Ì n i t s most si mpl i st i c f or m, pharmacogenet i cs can be def i ned as t he use of
genet i c i nf ormat i on t o sel ect t he " ri ght drug f or t he r i ght pat i ent . ¨ Thi s ar ea of st udy
pr i mar i l y seeks t o i dent i f y t he i ndi vi dual genet i c di f f er ences and pr edi sposi t i ons t hat
i nf l uence drug response and saf et y.
B. Genet i c vari ati on i n t he DNA sequence can cause cer t ai n popul at i ons of
i ndi vi dual s t o be more I i keI y t o deveI op speci fi c di sease st ates, t o be more I i keI y
t o f oI I ow a speci f i c path of di sease progressi on, t o be more I i keI y t o respond t o
speci f i c drug t herapy, and/ or t o be more I i keI y t o deveI op cert ai n adverse drug
ef f ects.
1. The genet i c vari at i on bet ween any t wo unrel at ed i ndi vi dual s i s approxi mat el y one
base pai r change i n every 1000 base pai r s.
2. These changes ar e ref er r ed t o as si ngI e nucI eot i de poI ymorphi sms (SNPs) and
ar e t he most common f orm of genet i c var i at i on.
3. The eff ects of SNPs var y based upon t he t ype and I ocat i on of t he var i at i on.
a. An SNP I ocat ed wi t hi n t he codi ng regi on of a gene coul d produce no
di scernabl e ef f ect s, negl i gi bl e ef f ect s, or a si gni f i cant al t erat i on i n ef f ect s
dependi ng upon how t he SNP af f ect ed t he ami no aci d codi ng.
( 1) An SNP t hat di d not aI t er t he ami no aci d sequence i n a prot ei n woul d pr oduce
no di scernabI e ef f ects.
( 2) An SNP t hat resul t ed i n one ami no aci d bei ng r epl aced by a si mi I ar ami no aci d
woul d have a negI i gi bI e ef f ect ( e. g. , changi ng a por t i on of t he genet i c code f r om
AUU t o GUU woul d r esul t i n i sol euci ne bei ng repl aced by val i ne, a si mi l ar
hydr ophobi c ami no aci d).
( 3) An SNP t hat resul t ed i n one ami no aci d bei ng r epl aced by one wi t h si gni f i cant I y
di f f erent chemi caI propert i es woul d cause a si gni f i cant aI t erat i on of eff ect s
( e. g. ,
P. 412

changi ng a por t i on of t he genet i c code f r om GUU t o GAU woul d r esul t i n val i ne
bei ng repl aced wi t h t he aci di c, and mor e hydr ophi l i c, aspart i c aci d) .
b. An SNP i n a spI i ci ng cont roI regi on coul d r esul t i n t he f or mat i on of a novel
pr ot ei n t hat i s ei t her l arger or smal l er i n si ze t han t hat whi ch i s nat ural l y occur r i ng.
c. An SNP i n a promoter regi on coul d al t er t he t r anscri pt i on r at e, resul t i ng i n
ei t her an i ncr ease or a decr ease i n t he pr oduct i on of t he t arget pr ot ei n.
d. An SNP r esi di ng out si de of any of t he above l ocat i ons i s genet i caI I y si I ent and
does not pr oduce any obser vabl e ef f ect s.
4. ExampI es of known geneti c vari at i ons and t hei r ef f ect s on drug eff i cacy and
saf et y
a. Warf ari n. Pat i ent s wi t h speci f i c vari at i ons i n t he gene f or t he met abol i zi ng
enzyme CYP2C9 requi r e l ower doses and ar e at an i ncreased r i sk of bl eedi ng.
b. SaI meteroI and aI buteroI . Genet i c var i at i ons i n t he gene codi ng f or t he 82-
adr ener gi c r ecept or ( ADBR2) can resul t i n a decreased ef f i cacy.
c. 6- Mercapt opuri ne. Genet i c var i at i ons af f ect i ng t he enzyme t hi opuri ne
met hyl t r ansf er ase ar e known t o produce i ncr eased t oxi ci t y.
d. Procai nami de, hydraI azi ne, and i soni azi d. Genet i c var i at i ons af f ect i ng t he r at e
of N- acet yl at i on af f ect bot h t he ef f i cacy and adver se ef f ect prof i l es of t hese agent s.
The i dent i f i cat i on of f ast and sl ow acet yl at or s i s one of t he best known exampl es of
how genet i c var i at i on can af f ect t her apeut i c saf et y and ef f i cacy.
e. Qui ni di ne, ci sapri de, and cI ari t hromyci n. Genet i c vari at i ons i n t he gene codi ng
f or pot assi um channel s can r esul t i n i ncr eased ri sk and pr eval ence of QT- syndr ome
and ar r hyt hmi as.
f . Zi I eut on. Pat i ent s wi t h genet i c var i at i ons i n t he gene codi ng f or t he enzyme 5-
l i poxygenase do not r espond t o t hi s dr ug.
C. CI i ni caI pharmacogenet i c assays
1. The goaI of a cl i ni cal pharmacogenet i c assay i s t o pl ace pat i ent s i nt o one of f our
cat egori es.
a. Ì ndi vi dual s who ar e most l i kel y t o respond and ar e at a l ow r i sk f or adver se
ef f ect s
b. Ì ndi vi dual s who ar e most l i kel y t o respond and ar e at a hi gh r i sk f or adver se
ef f ect s
c. Ì ndi vi dual s who are l ess l i kel y t o respond and ar e at a l ow r i sk f or adver se ef f ect s
d. Ì ndi vi dual s who ar e l ess l i kel y t o respond and ar e at a hi gh ri sk f or adver se
ef f ect s
2. Ì ssues i n t he devel opment of phar macogenet i c assays i ncl ude:
a. Ì mprovement i n a medi cal l y i mpor t ant response ( i . e. , t he assay shoul d al l ow
heal t hcare provi ders t o make a bet t er deci si on t han woul d ot her wi se be possi bl e) .
b. FaI se posi t i ves f or ef f i cacy- based assays shouI d be kept at a mi ni mum i n
or der t o pr event nonresponder s f r om bei ng pr escr i bed drugs t hat wi l l not pr ovi de t he
desi r ed t her apeut i c out comes. Fal se negat i ves ( i . e. , responders i dent i f i ed as
nonresponders) ar e not as cr uci al si nce t hey woul d be pr escri bed appropr i at e
al t er nat i ve t herapy.
c. FaI se negati ves f or saf et y- based assays shouI d be kept at a mi ni mum i n
or der t o pr event at - r i sk pat i ent s f rom bei ng exposed t o pot ent i al seri ous adver se
ef f ect s. A hi gher r at e of f al se posi t i ves ( i . e. , pat i ent s i dent i f i ed as " at r i sk¨ ) i s
accept abl e. Excl udi ng a cer t ai n per cent age of pat i ent s i n or der t o avoi d ser i ous
adver se ef f ect s has been pr oposed t o be a reasonabl e t r ade- of f .
d. The r esul t s f or t he assays must be bot h i nt erpr et abl e and provi de cl i ni cal l y usef ul
r esul t s. The assays shoul d be si mpl e t o use i n a cl i ni cal set t i ng and shoul d pr ovi de
r esul t s t hat ar e easi l y under st ood by t he pat i ent , physi ci an, phar maci st , and ot her
heal t h-care provi der s.
e. Anal yt i cal and cl i ni cal val i dat i on of t he assay must meet FDA appr oval st andar ds.
3. As def i ned here, pharmacogenet i c assays do not t est f or t he pr esence or absence
of a di sease- speci f i c mut at i on, nor do t hey pr ovi de any i nf or mat i on t hat coul d be
used t o predi ct di sease st at es i n an i ndi vi dual or hi s or her f ami l y. As such, i t has
been suggest ed t hat l egal and et hi cal i ssues surr oundi ng di sease-speci f i c gene
t est s shoul d not appl y t o pr edi ct i ons of saf et y and ef f i cacy of dr ugs (i . e. , t he
pr i mar y f ocus of pharmacogenet i cs).
D. SNP maps and t hei r pot enti aI use
1. An SNP map f or an i ndi vi dual cont ai ns t he speci f i c number and l ocat i ons of base
pai r var i at i ons. Such a map coul d be used t o pr edi ct pat i ent response and
suscept i bi l i t y t o seri ous adver se r eact i ons.
P. 413



Figure 17-2. Hypothetical single nucleotide
polymorphism (SNP) maps. At the top is a
composite SNP proIile developed by using
genetic inIormation Irom a large database oI
patients/volunteers. This overall SNP can then be
compared to individual SNP maps (i.e.. Patients
A-D) to help determine the overall beneIit/risk Ior
the given drug in each oI these Iour patients.
2. A si mpI i f i ed exampI e of t hi s i s shown i n Fi gur e 17- 2. A l ar ge dat abase woul d
i ni t i al l y be used t o i dent i f y SNPs t hat coul d be used as pr edi ct ors of ef f i cacy and
saf et y. At t he t op of Fi gur e 17- 2, t he t wo out si de, shaded r egi ons i n t hi s
hypot het i caI modeI shoul d be regar ded as SNPs t hat woul d pr edi ct t hat a pat i ent
woul d f avorabl y r espond t o t he dr ug. Si mi l arl y, t he t wo i nner , bl ack regi ons shoul d
be r egarded as SNPs t hat woul d i ndi cat e t hat a pat i ent was mor e pr one t o t he
devel opment of ser i ous adver se ef f ect s. Ot her SNPs ( i . e. , t he nonhi ghl i ght ed
r ect angl es shown f or t he f our pat i ent s) shoul d be r egar ded as i r r el evant her e (i . e. ,
t hey do not predi ct ei t her ef f i cacy or saf et y f or t he dr ug i n quest i on).
a. Pat i ent A woul d be predi ct ed t o r espond t o t r eat ment wi t hout t he devel opment of
any ser i ous adverse ef f ect s.
b. Pat i ent B woul d be predi ct ed t o r espond t o t r eat ment but woul d al so be expect ed
t o devel op ser i ous adverse ef f ect s.
c. Pat i ent C woul d be predi ct ed t o be a nonr esponder t o t r eat ment but woul d be
unl i kel y t o exper i ence any ser i ous adver se ef f ect s.
d. Pat i ent D woul d be predi ct ed t o be a nonr esponder t o t r eat ment but woul d be
expect ed t o devel op seri ous adverse ef f ect s.
P. 414


STUDY QUESTIONS
Di rect i ons: Each of t he numbered i t ems or i ncompl et e st at ement s i n t hi s sect i on i s
f ol l owed by answer s or by compl et i ons of t he st at ement . Sel ect t he one l et t er ed
answer or compl et i on t hat i s best i n each case.
1. Whi ch of the foI I owi ng stat ements concerni ng drug met aboI i sm i s t rue?
( A) General l y, a si ngl e met abol i t e i s excr et ed f or each drug admi ni st ered.
( B) Of t en, a dr ug may under go a phase Ì Ì r eact i on f ol l owed by a phase Ì react i on.
( C) Dr ug-met abol i zi ng enzymes ar e f ound onl y i n t he l i ver .
( D) Al l met abol i t es ar e l ess act i ve phar macol ogi cal l y t han t hei r par ent drugs.
( E) Phase Ì met abol i t es mor e l i kel y are abl e t o cross cel l ul ar membr anes t han phase
Ì Ì met abol i t es.
Vi ew Answer 1. The answer i s E[] . 2. Whi ch of the f oI I owi ng met aboI i t es
wouI d be t he I east I i keI y excret i on product of oraI I y admi ni st ered aspi ri n ( see
st ruct ure beI ow) ?


( A) Gl yci ne conj ugat e
( B) Est er gl ucuroni de
( C) Unchanged drug
( D) Et her gl ucur oni de
( E) Hydr oxyl at ed met abol i t e
Vi ew Answer 2. The answer i s C[ and] . 3. SuI f asaI azi ne ( see st ructure
beI ow) i s a prodrug t hat i s act i vated i n t he i ntest i ne by bact eri aI enzymes. The
enzyme most I i keI y responsi bI e i s
( A) azor educt ase
( B) pseudochol i nest er ase
( C) N- acet yl t ransf erase
( D) 8- gl ucur oni dase
( E) met hyl t ransf erase

Vi ew Answer 3. The answer i s A[] . 4. ChI orampheni coI ( see st ruct ure
beI ow) i s consi dered t o be t oxi c i n i nf ant s ( gray baby syndrome) . Thi s i s due to
t i ssue accumuI at i on of unchanged chI orampheni coI , resuI t i ng f rom an
i mmature metaboI i c pathway. Whi ch of t he f oI I owi ng enzymes wouI d most I i keI y
be def i ci ent ?
( A) Pseudochol i nest er ase
( B) Gl ucur onyl t ransf erase
( C) N- Acet yl t r ansf er ase
( D) Azor educt ase
( E) Met hyl t r ansf erase

Vi ew Answer 4. The answer i s B[ and] . 5. Whi ch of t he f oI I owi ng
t herapeut i c advant ages cannot be obt ai ned by t he use of prodrugs? I ncreased
( A) or al absor pt i on
( B) wat er sol ubi l i t y
( C) durat i on of act i on
( D) pot ency
( E) pal at abi l i t y
Vi ew Answer 5. The answer i s D[ and] . P. 415


6. Whi ch of the foI I owi ng stat ements regardi ng pharmacogenet i cs i s
I NCORRECT?
( A) Si ngl e nucl eot i de pol ymor phi sms ( SNPs) i n a pr omot er r egi on can r esul t i n a
decreased product i on of a t arget pr ot ei n.
( B) Ì t i s cruci al t hat f al se posi t i ves f or saf et y- based assays be kept at a mi ni mum.
( C) The ar ea of pharmacogenet i cs f ocuses pr i mar i l y on t he genet i c var i at i ons t hat
af f ect dr ug ef f i cacy and saf et y.
( D) The ef f ect s of SNPs var y based upon t he t ype and l ocat i on of t he vari at i on.
( E) Genet i c var i at i on occur s whenever t her e i s a change i n t he DNA nucl eot i de base
pai r sequence.
Vi ew Answer 6. The answer i s B[ and] . Di recti ons: Each quest i on bel ow
cont ai ns t hree suggest ed answer s, of whi ch one or more i s cor rect . Choose t he
answer .
7. Terms that may be used to descri be the foI I owi ng met aboI i c react i on i ncI ude
I . N- deaI kyI at i on
I I . oxi dat i ve deami nat i on
I I I . phase I metaboI i sm

A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 7. The answer i s D[] . NP. 416


8. Whi ch of the foI I owi ng react i ons can be cI assi f i ed as phase I I metaboI i sm?



A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 8. The answer i s C[] . 9. Condi ti ons t hat tend t o i ncrease the
act i on of an oraI I y admi ni stered drug that undergoes phase I I metaboI i sm
i ncI ude
I . enterohepati c ci rcuI at i on
I I . enzyme sat urat i on
I I I . fi rst - pass ef fect
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 9. The answer i s C[] . 10. Whi ch of t he f oI I owi ng stat ements
concerni ng CYP450 are correct ?
I . The CYP7, CYP11, and CYP27 subf ami I i es are i nvoI ved i n choI est eroI
met aboI i sm.
I I . A si ngI e drug may be metaboI i zed by muI t i pI e i sof orms of CYP450.
I I I . The maj ori t y of xenobi ot i cs, or drugs, are met aboI i zed by t he CYP4B and
CYP1A subf ami I i es.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 10. The answer i s C[ I . A. 1. c;] . 11. Met aboI i c react i ons I i keI y t o
be af fected by a prot ei n- def i ci ent di et i ncI ude
I . gI yci ne conj ugat i on
I I . hydroI ysi s
I I I . gI ucuroni dat i on
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 11. The answer i s A[] . Di recti ons: The group of i t ems i n t hi s
sect i on consi st s of l et t ered opt i ons f ol l owed by a set of number ed i t ems. For each
i t em, sel ect t he one l et t er ed opt i on t hat i s most cl osel y associ at ed wi t h i t . Each
l et t er ed opt i on may be sel ect ed once, more t han once, or not at al l .
Quest i ons 12- 15
For each drug, sel ect i t s most l i kel y met abol i c pat hway.
12. Benzoi c aci d


( A) Et her gI ucuroni dat i on
( B) Est er gI ucuroni dat i on
( C) Ni t roreduct i on
( D) Oxi dati ve deami nat i on
( E) Est er hydroI ysi s
P. 417


13. Procai ne

( A) Et her gI ucuroni dat i on
( B) Est er gI ucuroni dat i on
( C) Ni t roreduct i on
( D) Oxi dati ve deami nat i on
( E) Est er hydroI ysi s
14. Acet ami nophen


( A) Et her gI ucuroni dat i on
( B) Est er gI ucuroni dat i on
( C) Ni t roreduct i on
( D) Oxi dati ve deami nat i on
( E) Est er hydroI ysi s
15. Amphet ami ne


( A) Et her gI ucuroni dat i on
( B) Est er gI ucuroni dat i on
( C) Ni t roreduct i on
( D) Oxi dati ve deami nat i on
( E) Est er hydroI ysi s
Vi ew Answer 12-15. The answers are: 12- B[] , 13-E[ ] , 14- A[] , 15-
D[ ] . et heresterP. 418


ANSWERS AND EXPLANATIONS
1. The answer i s E [ Ì ; Ì Ì . A. 1, B] .
Phase Ì met abol i t es ar e of t en somewhat mor e pol ar t han t hei r parent s. Wi t h t he
except i on of acet yl at ed and met hyl at ed met abol i t es, phase Ì Ì met abol i t es ar e al ways
much more pol ar t han t hei r par ent s. Thus, phase Ì met abol i t es ar e more l i kel y t o
r et ai n some l i posol ubi l i t y and ar e mor e l i kel y t o cr oss cel l ul ar membranes.
Ì t i s unusual f or a si ngl e met abol i t e t o be excr et ed f or a gi ven dr ug. Most dr ugs
yi el d a mi xt ur e of met abol i t es. Because of t he hi gh pol ar i t y and subsequent hi gh
excr et i on of phase Ì Ì met abol i t es, t hey ar e not l i kel y t o under go f ur t her met abol i sm.
Phase Ì met abol i t es, on t he ot her hand, ar e l ess pol ar and ar e ver y l i kel y t o undergo
f ur t her phase Ì Ì met abol i c r eact i ons.
Wher eas t he maj or si t e of met abol i sm i s t he l i ver , t her e ar e many ext r ahepat i c si t es
t hat secr et e dr ug- met abol i zi ng enzymes. Al t hough many met abol i t es ar e l ess
pharmacol ogi cal l y act i ve t han t hei r parent s, t her e ar e many dr ugs whose
met abol i t es have equal or great er pharmacol ogi cal act i vi t y and somet i mes gr eat er
t oxi ci t y as wel l . Pr odrugs ( i . e. , drugs i nact i ve i n t he f orm admi ni st er ed) al ways f or m
at l east one act i ve met abol i t e.
2. The answer i s C [ Ì Ì . A. 1. e, 3. a, B. 2. a. ( 2) , c; Tabl es 17-2, 17- 3, and 17- 4] .
Because of t he t ypes of f unct i onal groups pr esent , aspi ri n may under go a number of
di f f er ent met abol i c r eact i ons. These i ncl ude hydroxyl at i on of t he ar omat i c nucl eus,
conj ugat i on of t he car boxyl gr oup wi t h gl yci ne, conj ugat i on of t he car boxyl gr oup
wi t h gl ucuroni c aci d wi t h t he f ormat i on of an est er gl ucur oni de, hydrol ysi s of t he
acet at e est er, and conj ugat i on of t he phenol group ( resul t i ng f r om hydr ol ysi s of t he
acet at e est er) wi t h gl ucur oni c aci d t o f or m an et her gl ucur oni de.
Because t he acet at e est er i s a si mpl e est er , aspi r i n i s suscept i bl e t o hydrol ysi s i n
t he aci d medi a of t he st omach bef or e absor pt i on t akes pl ace. Ì n addi t i on, any
acet yl at ed mol ecul es t hat ar e absorbed are subj ect ed t o hydr ol ysi s and are
cat al yzed by t he many est erases pr esent i n t he ci r cul at i on. Any acet yl at ed
mol ecul es not hydr ol yzed i n t he ci rcul at i on ar e subj ect t o hydr ol ysi s i n t he l i ver . Al l
of t hese pr ocesses occur bef or e t he dr ug reaches t he gl omerul ar f i l t rat e; t her ef ore,
excr et i on of t he unchanged acet yl at ed dr ug i s hi ghl y unl i kel y.
3. The answer i s A [ Ì Ì . A. 2; Tabl e 17- 3] .
Sul f asal azi ne has bot h ant i -i nf l ammat or y and ant i bact er i al act i vi t y when conver t ed
t o ami nosal i cyl i c aci d and sul f apyr i di ne i n t he body. Thi s react i on occurs by
r educt i ve cl eavage of t he " azo¨ l i nkage cont ai ned i n t he sul f asal azi ne mol ecul e and
i s cat al yzed i n t he i nt est i ne by bact er i al azor educt ase. Thi s i s a f orm of si t e-speci f i c
del i ver y because t he i nt act dr ug i s not absorbed f r om t he st omach or upper i nt est i ne
and reaches t he col on, wher e i t i s met abol i zed. Sul f asal azi ne i s one of a f ew dr ugs
t hat i s ef f ect i ve f or t he t reat ment of ul cer at i ve col i t i s.
4. The answer i s B [ Ì Ì . B. 2. a. ( 2) ; Ì Ì Ì . G. 1; Tabl es 17- 2, 17- 3, and 17- 4] .
The chl or ampheni col mol ecul e cont ai ns an aromat i c nucl eus, whi ch woul d be
subj ect t o hydroxyl at i on, a ni t r o gr oup t hat i s subj ect t o r educt i on, an ami de group
t hat i s subj ect t o l i ver hydr ol ysi s, and al cohol gr oups t hat ar e subj ect t o
gl ucuroni dat i on. Of al l t he enzyme syst ems r esponsi bl e f or t hese r eact i ons, t he
syst em responsi bl e f or gl ucur oni dat i on i s devel oped poor l y i n premat ure i nf ant s and
i nf ant s up t o appr oxi mat el y 6- 8 weeks of age.
5. The answer i s D [ VÌ . A, B. 1, 2, 3 and 4] .
By def i ni t i on, prodrugs ar e i nact i ve or ver y weakl y act i ve mol ecul es t hat requi r e i n
vi vo act i vat i on t o t he parent mol ecul e. Thus, conver si on of a dr ug mol ecul e t o a
pr odrug does not i ncr ease pot ency because t he or i gi nal mol ecul e, wi t h what ever
pot ency i t cont ai ns, i s produced af t er admi ni st r at i on. A var i et y of advant ages,
i ncl udi ng i ncreased wat er sol ubi l i t y, dur at i on of act i on, or al absor pt i on, and
pal at abi l i t y, can be obt ai ned t hr ough t he use of pr odr ugs, but none of t hese
advant ages resul t s i n an i ncr ease i n pot ency of t he par ent mol ecul e.
6. The answer i s B [ VÌ Ì . A. 4, B. 1, 2, 3 and C. 2. c] .
Whi l e keepi ng f al se posi t i ves and f al se negat i ves at a mi ni mum i s al ways desi r abl e,
i t i s most cr uci al t hat f al se negat i ves be kept at a mi ni mum f or saf et y- based assays
i n or der t o pr event at - r i sk pat i ent s f rom bei ng exposed t o pot ent i al ser i ous si de
ef f ect s. A hi gher r at e of f al se posi t i ves i s accept abl e si nce pr event i ng ser i ous
adver se ef f ect s i s percei ved t o be more i mpor t ant t han excl udi ng some pat i ent s
f r om t her apy.
P. 419


Genet i c vari at i on occur s whenever t her e ar e base pai r changes i n t he DNA
nucl eot i de sequence. The most common f or m of genet i c var i at i on i s a si ngl e
nucl eot i de pol ymor phi sm ( SNP) . The cumul at i ve ef f ect s of t hese var i at i ons var y
based on t he t ypes and l ocat i ons of t he SNPs. Var i at i ons i n codi ng regi ons can al t er
pr ot ei n f unct i on, whi l e t hose i n spl i ci ng and promot er regi ons can al t er prot ei n si ze
and pr ot ei n product i on, respect i vel y. Some SNPs pr oduce no di scernabl e changes
and ar e t her ef or e genet i cal l y si l ent . Pharmacogenet i cs pri mar i l y seeks t o use SNPs
and ot her genet i c i nf or mat i on t o predi ct pr edi sposi t i ons t hat i nf l uence dr ug
r esponse and saf et y i n i ndi vi dual pat i ent s.
7. The answer i s D (Ì Ì , Ì Ì Ì ) [ Ì Ì . A; Tabl e 17-2] .
The r eact i on shown i n t he quest i on i nvol ves t he conver si on of one f unct i onal gr oup
t o anot her (ami ne t o carbonyl ) ; t hus, i t i s cl assi f i ed as a phase Ì r eact i on. The
i nt roduct i on of oxygen i nt o t he mol ecul e i ndi cat es oxi dat i on, and t he l oss of t he
ami no gr oup si gni f i es deami nat i on; t hus, t he react i on al so can be cl assi f i ed as
oxi dat i ve deami nat i on. N- Deal kyl at i on i mpl i es t he r emoval of an al kyl group f r om a
ni t rogen. The ni t rogen i n t he parent mol ecul e does not have an al kyl gr oup at t ached
t o i t .
8. The answer i s C (Ì , Ì Ì ) [ Ì Ì . A, B; Tabl e 17-4] .
Phase Ì Ì met abol i c r eact i ons i nvol ve maski ng an exi st i ng f unct i onal gr oup wi t h a
nat ural endogenous const i t uent . The f ormul as shown i n choi ces Ì and Ì Ì repr esent
t hi s t ype of r eact i on, wi t h choi ce Ì bei ng an acet yl at i on r eact i on and choi ce Ì Ì , a
gl yci ne conj ugat i on r eact i on. Choi ce Ì Ì Ì r epr esent s a change i n an exi st i ng
f unct i onal group and, t hus, r epresent s a phase Ì r eact i on. Ì t i s an oxi dat i ve
deami nat i on r eact i on.
9. The answer i s C (Ì , Ì Ì ) [ Ì Ì . B. 2. a. ( 4), Ì Ì Ì . E. 1, 2; Ì V. B. 3. b] .
Ent erohepat i c ci r cul at i on r ef ers t o t he pr ocess by whi ch gl ucuroni des, whi ch ar e
secr et ed i nt o t he i nt est i ne wi t h t he bi l e, ar e hydr ol yzed by i nt est i nal bact er i al 8-
gl ucuroni dase. The hydrol yzed f ree dr ug, whi ch i s no l onger pol ar , becomes
avai l abl e f or i nt est i nal r eabsor pt i on i nt o t he syst em and subsequent penet r at i on t o
i t s act i ve si t e.
Ì f an enzyme syst em becomes sat ur at ed, t hen t he act i ve dr ug cannot be i nact i vat ed
by t hat pat hway. Ì f t he dr ug cannot undergo an al t ernat i ve pat hway, t he i ncr eased
pl asma l evel s of an unchanged act i ve drug can r esul t i n i ncreased act i vi t y or
t oxi ci t y.
The f i rst - pass ef f ect resul t s i n met abol i sm of a dr ug by t he l i ver bef or e t he dr ug
r eaches i t s si t e of act i on, r esul t i ng i n an overal l decrease i n i t s act i vi t y. Dr ugs t hat
under go f i rst -pass met abol i sm general l y ar e ef f ect i ve i n much smal l er i nt ravenous
doses as compar ed t o oral doses.
10. The answer i s C ( Ì , Ì Ì ) [ I . A. 1. c; Tabl e 17-1] .
Ther e are si x mammal i an f ami l i es i nvol ved i n st er oi d and bi l e aci d met abol i sm.
These ar e CYP7, CYP11, CYP17, CYP19, CYP21, and CYP27. Si nce chol est er ol i s
t he common i nt er medi at e f or t he bi osynt hesi s of al l endogenous st er oi ds, some of
t hese enzymes are di r ect l y i nvol ved i n chol est er ol met abol i sm. The f ami l i es l i st ed,
CYP7, CYP11, and CYP27, al l met abol i ze chol est er ol , whi l e t he ot her t hree f ami l i es
cat al yze addi t i onal oxi dat i ons of t he i ni t i al met abol i t es.
As i s evi dent f rom Tabl e 17- 1, mul t i pl e i sof orms of CYP450 can met abol i ze a si ngl e
dr ug. An exampl e of t hi s i s seen wi t h i mi pr ami ne, an ant i depr essant t hat i s
met abol i zed by CYP1A, CYP2C, and CYP2D i sof or ms. Addi t i onal l y, Tabl e 17- 1
i ndi cat es t hat t he subf ami l i es CYP2C, CYP2D, and CYP3A met abol i ze t he maj ori t y
of drugs, or xenobi ot i cs.
11. The answer i s A ( Ì ) [ Ì Ì Ì . F. 1] .
Phase Ì Ì met abol i c r eact i ons r equi re nat ural endogenous subst r at es, whi ch normal l y
ar e suppl i ed i n t he di et . A def i ci ency of t hese subst ances r esul t s i n a decr ease i n
t he bi ot r ansf or mat i on of dr ugs t hat use t hese pat hways. Gl yci ne conj ugat i on i s a
phase Ì Ì react i on. Gl yci ne i s an ami no aci d t hat requi r es di et ar y pr ot ei n. A di et
def i ci ent i n pr ot ei n, t heref or e, coul d l ead t o a def i ci ency of gl yci ne and, t hus, a
decrease i n gl yci ne conj ugat i on. Gl ucur oni dat i on i s al so a phase Ì Ì react i on t hat
r equi r es endogenous gl ucur oni c aci d, but t hi s subst ance i s suppl i ed by di et ar y
car bohydrat es. Hydroxyl at i on i s a phase Ì met abol i c react i on and does not r equi r e
di et ar y prot ei n.
12- 15. The answers are: 12- B [ Ì Ì . B. 2. a. ( 2)] , 13-E [ Ì Ì . A. 3. a] , 14- A [ Ì Ì . B. 2. a. ( 2) ] , 15- D
[ Ì Ì . A. 1. e] .
Benzoi c aci d cont ai ns a car boxyl i c aci d, a f unct i onal gr oup t hat commonl y
under goes conj ugat i on wi t h gl ucuroni c aci d. The resul t i ng conj ugat i on produces an
est er . Car boxyl i c aci ds can al so under go conj ugat i on wi t h t he ami no aci ds gl yci ne
and gl ut ami ne. Addi t i onal l y, benzoi c aci d can under go ar omat i c hydroxyl at i on, a
common phase Ì pat hway f or drugs cont ai ni ng unsubst i t ut ed ar omat i c r i ngs. Of
t hese opt i ons, est er gl ucur oni dat i on i s t he onl y answer avai l abl e here.
P. 420


Pr ocai ne i s an est er - cont ai ni ng l ocal anest het i c. Due t o t he wi de physi ol ogi cal
di st r i but i on of est er ase enzymes, i t i s ext r emel y suscept i bl e t o i n vi vo hydr ol ysi s.
Thi s suscept i bi l i t y t o hydr ol ysi s i s t he maj or r eason why est er - cont ai ni ng l ocal
anest het i cs have shor t er dur at i ons of act i on as compar ed t o t hose i n ot her chemi cal
cl asses.
One of t he pri nci pal f unct i onal gr oups i n acet ami nophen i s t he phenol gr oup. Si mi l ar
t o t he carboxyl i c aci d i n benzoi c aci d, t he phenol commonl y under goes gl ucuroni de
conj ugat i on. The one di f f er ence i s t hat a phenol (or an al cohol ) produces an ether
gl ucuroni de, whi l e a carboxyl i c aci d pr oduces an est er gl ucur oni de. Phenol s al so
commonl y under go sul f at e conj ugat i on react i ons and occasi onal l y under go O-
met hyl at i on r eact i ons.
The pr i nci pal f unct i onal gr oup i n amphet ami ne i s i t s pri mar y ami ne. Oxi dat i ve
deami nat i on i s a ver y common met abol i c pat h f or pr i mar y ami nes. Occasi onal l y,
pr i mar y ami nes undergo phase Ì Ì acet yl at i on; however , t hi s i s a l ess common
pat hway. Ar omat i c hydr oxyl at i on, si mi l ar t o t hat di scussed above f or benzoi c aci d,
i s al so possi bl e f or amphet ami ne.

18
Drug-Drug and Drug-Nutrient Interactions
AI i ce C. EngeI brecht
Leon ShargeI
I. INTRODUCTION
A. Def i ni t i on of dr ug i nt er act i on
1. Drug i nt eract i on ref er s t o an adverse drug r esponse produced by t he
admi ni st rat i on of a drug or coexposure of t he dr ug wi t h anot her subst ance, whi ch
modi f i es t he pat i ent ' s r esponse t o t he drug. Some dr ug i nt er act i ons are i nt ent i onal
i n or der t o pr ovi de i mpr oved t her apeut i c r esponse or t o decr ease adverse dr ug
ef f ect s. A preci pi tant drug i s t he dr ug, chemi cal , or f ood el ement causi ng t he
i nt er act i on. An obj ect drug i s t he dr ug af f ect ed by t he i nt er act i on.
2. Dr ug i nt eract i ons i ncl ude:
a. Drug-drug i nt er act i ons
b. Drug- herbaI i nt eract i ons
c. Food-drug i nt er act i ons
d. Pharmacogenet i c i nt er act i ons
e. Chemi caI - drug i nt er act i ons, such as t he i nt eract i on of a dr ug wi t h al cohol or
t obacco
f . Drug- I aborat or y t est i nt eract i ons such as chemi cal i nt er act i ons.
B. CI assi f i cat i on of drug i nt eract i ons. Dr ug i nt er act i ons t hat occur i n vi vo ar e
gener al l y cl assi f i ed as pharmacoki neti c or pharmacodynami c i nt eract i ons.
1. Pharmacoki net i c or bi opharmaceut i caI i nt eract i ons occur when t he absor pt i on,
di st r i but i on ( pr ot ei n and t i ssue bi ndi ng) , or el i mi nat i on ( excr et i on and/ or
met abol i sm) of t he drug i s af f ect ed by anot her drug, chemi cal , or f ood el ement .
2. Pharmacodynami c i nt er act i ons occur when t he phar macodynami c ef f ect of t he
dr ug i s al t ered by anot her drug, chemi cal , or f ood el ement , produci ng an
ant agoni st i c, synergi st i c, or addi t i ve ef f ect .
3. Pharmacogenet i c i nt er act i ons occur when t he phar macoki net i c ef f ect of t he dr ug
i s al t er ed by genet i c pol ymor phi sms i n af f ect i ng pr ocesses.
4. Pharmaceuti caI i nt eract i ons ar e caused by a chemi cal or physi cal i ncompat i bi l i t y
when t wo or mor e dr ugs ar e mi xed t oget her . Pharmaceut i cal i nt er act i ons can occur
dur i ng t he ext emporaneous compoundi ng of drugs, i ncl udi ng t he pr epar at i on of
i nt ravenous (Ì V) sol ut i ons. For exampl e, an Ì V sol ut i on of ami nophyl l i ne has an
al kal i ne pH and shoul d not be mi xed wi t h such drugs as epi nephri ne, er yt hr omyci n
gl ucept at e, or cephal ot hi n sodi um, whi ch decompose i n al kal i ne pH. Phenyt oi n
sodi um wi l l pr eci pi t at e f rom a sol ut i on t hat has an aci d pH, such as dext r ose 5%.
Phar maceut i cal i nt er act i ons ar e usual l y consi dered dur i ng t he devel opment ,
manuf act ur i ng, and mar ket i ng of t he dr ug pr oduct . Onl y drug i nt er act i ons i nvol vi ng
pharmacoki net i c, phar macodynami c, or pharmacogenet i c pr ocesses wi l l be
consi dered i n t hi s chapt er .
II. PHARMACOKINETIC INTERACTIONS
A. Absor pt i on
1. Dr ug i nt eract i ons can af f ect t he rat e and t he ext ent of syst emi c dr ug absorpt i on
( bi oavai l abi l i t y) f r om t he absor pt i on si t e, resul t i ng i n i ncr eased or decr eased dr ug
bi oavai l abi l i t y ( Tabl e 18-1) .
P. 422


Table 18-1. Drug Interactions That Affect the Bioavailability of the Drug from
the Gastrointestinal (GI) Tract
Drug Interaction
Examples
(Precipitant drugs) Effect (Object drugs)
Complexation/chelation Calcium.
magnesium. or
aluminum and
iron salts
LevoIloxacin
complexes with
divalent cations in the
diet or tube Ieeding.
causing a decreased
bioavailability

Sodium
polystyrene
sulIonate
Cations in antacids bind
to sodium polystyrene
sulIonate. causing
reduced renal clearance
oI bicarbonate.
resulting in systemic
acidosis
Adsorption Cholestyramine Decreased
bioavailability oI
digoxin. levothyroxine

Kaolin Decreased
bioavailability oI
digoxin

Activated
charcoal
Decreased
bioavailability oI many
drugs

Acarbose Decreased
bioavailability oI
digoxin
Increased GI motility Laxatives.
cathartics
Increases GI motility.
decreases
bioavailability Ior drugs
that are absorbed
slowly. Will decrease
the bioavailability oI
drugs Irom controlled-
release products.
Decreased GI motility Anticholinergic
agents
Propantheline decreases
the gastric emptying oI
acetaminophen
(APAP). delaying
APAP absorption Irom
the small intestine.
Alteration oI gastric pH H-2 blockers.
antacids. and
proton pump
inhibitors
H-2 blockers. antacids
and PPIs increase
gastric pH. The
dissolution oI
ketoconazole is reduced
at basic pH. causing
decreased drug
absorption and
therapeutic Iailure.
Alteration oI intestinal
Ilora
Antibiotics Digoxin has better
bioavailability taken
aIter erythromycin.
Erythromycin
administration reduces
bacterial inactivation oI
digoxin.

Estrogen/progestin
birth control requires
intestinal Ilora to
Iacilitate enterohepatic
circulation. Antibiotics
reduce intestinal Ilora
and reduce
estrogen/progestin
levels resulting in
Iailure oI ovulation
suppression and
menstrual changes.
Inhibition oI drug
metabolism in intestinal
cells
Monoamine
oxidase inhibitors
(MAOIs) (e.g..
tranylcypromine.
phenelzine)
MAOIs inhibit
metabolism oI albuterol
and levalbuterol.
leading to hypertension.

2. The most common dr ug absorpt i on si te i s i n t he gast roi ntesti naI ( GÌ ) tract .
However , dr ug bi oavai l abi l i t y f r om ot her absor pt i on si t es, such as t he ski n, can be
af f ect ed by dr ug i nt eract i ons. For exampl e, epi nephr i ne, a vasoconst ri ct or, wi l l
decrease t he percut aneous absor pt i on of t ransder mal l i docai ne or t r ansder mal
f ent anyl .
3. Ot her pot enti aI dr ug-dr ug and drug- f ood i nt eract i ons t hat af f ect bi oavai l abi l i t y i n
t he GÌ t r act coul d be due t o:
a. Compet i t i on f or car r i er - medi at ed drug absorpt i on i n whi ch t he par t i ci pant dr ug
compet es f or t he same car r i er as t he obj ect
i . Compet i t i on f or t he P-gp syst em (an ATP- dependent ef f l ux pump on epi t hel i al
cel l s of t he i nt est i nes) i s i nvol ved i n t ranspor t of cycl ospor i n and di goxi n.
Di spl acement can r esul t i n t oxi ci t y of t hose drugs.
i i . Gr apef rui t j ui ce and or ange j ui ce f r om Sevi l l e or anges i nhi bi t OATP ( organi c
ani on t ranspor t i ng pol ypept i des) pr ot ei ns i n t he epi t hel i al cel l s of t he smal l
i nt est i ne, r educi ng t he bi oavai l abi l i t y of or al f exof enadi ne.
b. AI t erat i on of i nt est i nal bl ood f l ow caused by t he preci pi t ant dr ug. Ì n congest i ve
hear t di sease, t he bl ood f l ow t o t he GÌ t r act i s poor and an or al l y admi ni st er ed dr ug
can
P. 423

have a sl ower r at e of absor pt i on. Af t er di goxi n t her apy, t he perf usi on of t he GÌ t r act
i s i mpr oved al ong wi t h bi oavai l abi l i t y of t he obj ect dr ug.
B. Di st ri but i on. The di st r i but i on of t he drug may be af f ect ed by pl asma prot ei n
bi ndi ng and di spl acement i nt er act i ons or t i ssue and cel l ul ar i nt er act i ons.
1. Pl asma pr ot ei n bi ndi ng and di spl acement on al bumi n and al pha1- aci d
gl ycopr ot ei n car r i er pr ot ei ns.
a. VaI proi c aci d di spl aces phenyt oi n f rom pl asma al bumi n prot ei n- bi ndi ng si t es and
r educes hepat i c phenyt oi n cl ear ance by i nhi bi t i ng t he l i ver ' s met abol i sm of
phenyt oi n, r esul t i ng i n hi gher phenyt oi n l evel s.
b. Aspi ri n i s 90% t o 95% pr ot ei n bound and di spl aces war f ar i n f rom pr ot ei n bi ndi ng
si t es r esul t i ng i n hi gher war f ar i n l evel s and i ncr eased bl eedi ng.
2. Ti ssue and ceI I uI ar i nt eracti ons. Di goxi n t oxi ci t y can be enhanced by
concur rent admi ni st rat i on of qui ni di ne. Qui ni di ne r educes di goxi n cl earance and
di spl aces di goxi n f r om bot h al pha-1 gl ycopr ot ei ne and al bumi n t i ssue- bi ndi ng si t es,
l eadi ng t o a hi gher pl asma di goxi n concent rat i on.
C. Dr ug el i mi nat i on and cl ear ance
1. Dr ug Met abol i sm and Hepat i c Cl ear ance
a. Dr ug met abol i sm ( hepat i c cl ear ance) can be af f ect ed by enzyme i nduct i on,
enzyme i nhi bi t i on, subst rat e compet i t i on f or t he same enzyme, and changes i n
hepat i c bl ood f l ow ( Tabl e 18-2) .
b. Many dr ugs t hat share t he same drug-met abol i zi ng enzymes have a pot ent i al f or
a dr ug i nt er act i on. For exampl e, f l uconazol e i nhi bi t s t he hepat i c met abol i sm of
war f ar i n, causi ng i ncreased r i sk of bl eedi ng. Carbamazepi ne i s bot h a subst rat e and
an i nducer of t he CYP3A4 i soenzyme, t hereby i nduci ng i t s own met abol i sm and
t aki ng 3- 5 weeks t o r each st abl e bl ood l evel s ( Tabl e 18-3) . Phenyt oi n i s al so a
subst rat e of t he CYP3A4 and i nduces i t s own met abol i sm.
c. Over - t he-count er ( OTC) dr ugs and herbal prepar at i ons can al so be i nvol ved i n
CYP450 i soenzyme met abol i sm and can cause ser i ous dr ug-herbal i nt eract i ons. For
exampl e, St . John' s Wort may i nduce CYP3A4 i soenzymes and decrease cycl ospori n
t o subt herapeut i c l evel s. Tobacco use (smoki ng) can i nduce t he CYP1A2 i soenzyme
and decr ease cl ozapi ne l evel s, i ncreasi ng t he ri sk of t her apeut i c f ai l ur e i n t r eat i ng
OCD.
d. Foods may al so i nt er f er e wi t h hepat i c dr ug met abol i sm. For exampl e, gr apef r ui t
j ui ce i s a power f ul i nhi bi t or of t he CYP3A4 i soenzyme, and wi l l i ncr ease bl ood
l evel s of CYP3A4 subst rat es such as ri t onavi r , met hadone, aml odi pi ne, al pr azol am,
cycl ospor i n, and di l t i azem, i f t aken t oget her .
Table 18-2. Drug Interactions That Affect the Drug Metabolism
Drug Interaction
Examples (Precipitant
drugs) Effect (Objective drugs)
Enzvme
induction


Smoking (polycyclic
aromatic
hydrocarbons)
Smoking increases duloxetine
metabolism and decreases
duloxetine levels

Phenytoin Tacrolimus levels are
decreased because oI increased
metabolism
Enzvme
inhibition

Mixed
Iunction
oxidase
Cimetidine Decreased atorvastatin
clearance and increased drug
levels
Induction oI
UDP-G
metabolism
Phenytoin.
cimetidine.
midazolam. riIabutin
Decreased posaconazole levels
due to induction oI metabolism
Other
enzymes
Monoamine oxidase
inhibitors. MAOIs
(e.g.. pargyline.
tranylcypromine)
Serious hypertensive crisis can
occur Iollowing ingestion oI
Ioods with a high content oI
tyramine or other pressor
substances (e.g.. cheddar
cheese. red wines. avocados).
and catecholamines

P. 424


Table 18-3. Drug/Herb/Food Actions with Cytochrome P450 Enzymes
Enzyme Inhibitor Inducer Substrate
CYP1A2 CiproIloxacin Phenytoin Naproxen
LevoIloxacin Carbamazepine Amitriptyline

Cimetidine Charbroiled
Ioods
Verapamil
Citalopram Tobacco Clopidogrel
Ketoconazole Ritonavir Duloxetine
Paroxetine St. John's Wort Ramelteon
CYP2C9 Cimetidine RiIampin TamoxiIen
Fluoxetine Carbamazepine Losartan
Voriconazole Phenytoin S-WarIarin
Fluconazole Celecoxib
Amiodarone Phenytoin
EIavirenz Carvedilol
Metronidazole Voriconazole
Glyburide
SildenaIil
CYP2C8 GemIibrozil Phenobarbital Paclitaxel
Nicardipine RiIampin Carbamazepine
Atazanavir Carbamazepine Amiodarone
Trimethoprim Pioglitazone
CYP2C19 Ketoconazole RiIampin Diazepam
Omeprazole Carbamazepine Phenytoin
Topiramate Phenytoin Citalopram
Fluoxetine Omeprazole
Fluvoxamine Diphenhydramine
Duloxetine
R-WarIarin
CYP2D6 Methadone Carbamazepine Amitriptyline
Cimetidine Phenytoin Metoprolol
Fluoxetine Ethanol Paroxetine
Ritonavir St. John's Wort Duloxetine
Haloperidol Ritonavir Haloperidol
Amiodarone VenlaIaxine
Paroxetine Tramadol
Quinidine Trazodone

Sertraline

Narcotic
anagesics
CYP2E1 Cimetidine Ritonavir Acetaminophen
DisulIiram Isoniazid CaIIeine
Ethanol VenlaIaxine
CYP3A
Iamily
Erythromycin Carbamazepine Atorvastatin
Ketoconazole Phenobarbital WarIarin
Saquinavir St. John's Wort Lidocaine
Verapamil Nevirapine Ethylestradiol
EIavirenz
Metronidazole Carbazepine Cyclosporin
Amiodarone RiIampin Alprazolam

Cimetidine Garlic
Supplements
Ziprasidone
Diltiazem GrapeIruit Doxorubicin
Posaconazole Seville Oranges Amitriptyline
Metronidazole Bitter Orange Methadone
NiIedipine Cyclosporin
Voriconazole Amlopdipine
Atazanavir Indinavir
Cyclosporin
Paclitaxel
Ritonavir
Lidocaine
Lovastatin
Midazolam
TamoxiIen
Zaleplon
Atazanavir

P. 425


e. Nonhepat i c enzymes can be i nvol ved i n dr ug i nt er act i ons. For exampl e, ser ot oni n
syndr ome has been r epor t ed i n pat i ent s r ecei vi ng ant i depr essant s such as
ci t al opr am (an SSRÌ i nhi bi t or ) i n combi nat i on wi t h a monami ne oxi dase i nhi bi t or,
such as l i nezol i d. A consi derabl e por t i on of t he CYP3A4 enzymes are f ound not onl y
i n t he l i ver , but al so i n t he GÌ t r act , wher e some of t hese subst rat es ar e
met abol i zed.
f . A decrease i n t he hepat i c bl ood f l ow can decrease t he hepat i c cl ear ance f or hi gh
ext r act i on drugs, such as propranol ol and mor phi ne.
2. RenaI drug cI earance can be af f ect ed by changes i n gl omerul ar f i l t rat i on, t ubul ar
r eabsorpt i on, act i ve dr ug secr et i on, and r enal bl ood f l ow and nephr ot oxi ci t y ( Tabl e
18- 4).
III. PHARMACODYNAMIC INTERACTIONS
A. Dr ugs t hat have si mi l ar pharmacodynami c act i ons may pr oduce an excessi ve
pharmacol ogi cal or t oxi c response.
1. For exampl e, cent r al ner vous syst em depressant s, such as t he combi nat i on of
nar cot i cs and ant i hi st ami nes ( e. g. , di phenhydr ami ne, chl or pheni r ami ne) can pr oduce
i ncreased drowsi ness i n t he pat i ent .
2. Dr ugs havi ng ant i chol i ner gi c ef f ect s, such as pr omet hazi ne and OTC
ant i hi st ami nes, can cause excessi ve dr yness of t he mout h, bl ur r ed vi si on, and
ur i nar y r et ent i on.
3. Dr ugs t hat prol ong t he QTc i nt er val (such as pal i per i done, ami odar one, sot al ol ,
moxi f l oxaci n, and at ypi cal ant i spychot i cs such as zi prasi done) have a much gr eat er
r i sk of causi ng QTc i nt erval ar rhyt hmi as when gi ven t oget her.
Table 18-4. Drug Interactions That Affect the Renal Clearance
Drug Interaction Examples Effect
Glomerular
Iiltration rate
(GFR) and renal
blood Ilow
Methylxanthines
(e.g.. caIIeine.
theobromine)
Increased renal blood Ilow
and GFR will decrease time
Ior reabsorption oI various
drugs. leading to more rapid
urinary drug excretion.
Active tubular
secretion
Probenecid Probenecid blocks the active
tubular secretion oI
penicillin and some
cephalosporin antibiotics.
Tubular
reabsorption and
urine pH
Antacids. sodium
bicarbonate
Alkalinization oI the urine
increases the reabsorption oI
amphetamine and decreases
its clearance.

Alkalinization oI urine pH
increases the ionization oI
salicylates. decreases
reabsorption. and increases
its clearance.

P. 426


B. The phar macodynami c ef f ect of one dr ug can be ant agoni zed by t he opposi t e
pharmacodynami c ef f ect of a second dr ug. For exampl e, t he ant i hyper t ensi ve ef f ect
of bet a bl ockers can be over come by t he use of vasopressors. Obvi ousl y, t hi s can
have a del et er i ous ef f ect , be a t herapeut i c f ai l ur e, or be a t her apeut i c st r at egy i n
cl i ni cal t reat ment , dependi ng on t he si t uat i on
C. Dr ug t herapy can pr oduce an adver se ef f ect t hat resul t s i n an i ncreased
sensi t i vi t y or t oxi ci t y when anot her drug i s gi ven. For exampl e, t he al t er at i on of
el ect r ol yt e concent rat i ons produced by a di ur et i c, such as a t hi azi de deri vat i ve, wi l l
depl et e pot assi um, resul t i ng i n sensi t i zat i on of t he hear t t o di goxi n t herapy.
Depl et i on of sodi um by a di ur et i c can al so r esul t i n l i t hi um t oxi ci t y.
D. Ther api es t hat have i nt ri nsi caI I y opposi t e eff ect s on t he same t ar get syst em
can r esul t i n t her apeut i c f ai l ur e. For exampl e, nal oxone compet es wi t h narcot i cs at
t he narcot i c r ecept or si t e, r esul t i ng i n t herapeut i c f ai l ur e of narcot i c-based anagesi a
t her apy.
E. Pharmacodynami c drug i nt eract i ons al so can occur wi t h dr ug- her bal i nt er act i ons
and dr ug- f ood i nt er act i ons. For exampl e, by i ngest i ng l ar ge amount s of vi t ami n K i n
t he di et , t he ef f ect of ant i coagul at i on by war f ari n i s ant agoni zed.
F. St ar t i ng and st oppi ng t her api es t hat i nf l uence met abol i sm of ot her dr ugs can
r esul t i n t herapeut i c f ai l ur e i f t he i nduced met abol i sm r educes t he bl ood l evel s of
t he t ar get dr ug. For exampl e, st ar t i ng a pat i ent on ni cot i ne pat ches r epl aces
smoki ng f or a pat i ent . Si nce t he pat i ent i s no l onger smoki ng t obacco, t he CYP1A2
i soenzymes ar e no l onger i nduced, and t he subst rat es of t he CYP1A2 syst em
( cl ozapi ne or hal operi dol , f or exampl e) may be i ncr eased t o t oxi c l evel s. Thi s ef f ect
can occur i n sever al enzyme syst ems when st oppi ng phenyt oi n, an i nducer f or
sever al CYP enzyme syst ems.
IV. HERBAL-DRUG INTERACTIONS
A. Her bal pr epar at i ons ar e var i ous combi nat i ons of her bs, somet i mes bei ng one
her b, or a combi nat i on of herbs. Some herbal pr epar at i ons r epresent a si ngl e herb
cont ai ni ng a var i et y of al kal oi ds or const i t uent s t hat may exhi bi t a var i et y of
pharmacol ogi cal act i vi t i es.
1. Some herbs cont ai n a number of di f f erent pharmacol ogi cal l y act i ve const i t uent s.
For exampl e, St . John' s Wort has at l east si x di f f er ent const i t uent s: hyperf or i n,
bi api geni n, hyperi ci n, quer ci t i n, chl or ogeni c aci d, and pseudohyper i ci n. Each
const i t uent has i t s own met abol i sm, bi ndi ng and pharmacol ogi c act i on. The
pr edomi nant ef f ect or i nt er act i on depends upon t he r el at i ve pot ency of each
const i t uent i n t he herb. For exampl e, t he const i t uent s of St . John' s Wor t have
i nhi bi t or y act i vi t y of t he CYP450 i soenzymes 3A4, 2C9, 1A2, 2D6, and 2D9, but
none of t hese ef f ect s are consi der ed cl i ni cal l y si gni f i cant . St . John' s Wort appears
over al l t o be an i nducer of CYP3A4, and i t s const i t uent s have many addi t i onal
ef f ect s on met abol i sm and bi ndi ng si t es ( Tabl e 18- 5) .
Table 18-5. Pharmacokinetic Activity of the Constituents of St. 1ohn's Wort
Activity Site
Metabolized CYP450. most notably by the 3A4 isoenzyme
Transported Intestinal P-glycoprotein
Active at receptor
sites
GABA. norepinephrine. dopamine. Lglutamate
receptor sites
Active at reuptake
sites
Seratonin reuptake and norepinephrine reuptake
sites
Inhibits MAO. and possibly the cellular phosphodiesterase
sites
Inhibits Beta-adrenergic and muscarinic receptor sites
Binding site
competition
DNA sites in human leukemia cells

P. 427


Table 18-6. St. 1ohn's Wort Drug Interactions
Pharmacokineti
c Process Site Action Results in Drug
Metabolism CYP3A4 Induces Lower
levels oI
NNRTI

Protease
Inhibitors

Benzodiaze
pines

Calcium
channel
blockers

Carbamaze
pine

Cyclospori
n
Irninotecan
Digoxin

CYP2C9 Induces Lower
levels oI
WarIarin

CYP1A2 Induces Lower
levels oI
WarIarin
Transporter
proteins
Intestinal
P-
glycoprot
ein
transporte
r proteins
Increased
catalyzed
eIIlux oI
substrate
drug
Lower
levels oI
Digoxin
Calcium
channel
blockers
Simvastatin
Pharmacody
namic
Toxicity
Serotonin
reuptake
receptor
sites
Inhibits
serotonin
reuptake
Additive
SSRI
activity
SSRIs

Serotonin
reuptake
receptor
sites
Serotonin
agonist
activity
Additive
serotonin
toxicity
Serotonin
agonists
(e.g.
IenIluamin
e) and
'triptans¨

MAO
receptor
sites
Increased
MAOI
and
serotonin
activity
Additive
serotonin
toxicity
MAOIs
Pharmacoki
netic
Serotonin
and
norepinep
hrine
reuptake
sites
Inhibits
reuptake
oI
norepinep
hrine and
serotonin
Norepinep
hrine and
serotonin
toxicity
NeIazodon
e

DNA
binding
sites in
human
leukemia
cells
Distorts
DNA
binding
sites
Reverses
etoposide-
stabilized
cleavage
complexes
Antagonize
s
chemothera
py eIIect oI
etoposide
(in vitro)

2. Many her bal dr ugs i nt er act at t he same t r anspor t , met abol i sm and recept or si t es
as t r adi t i onal pr escri pt i on dr ugs ( Tabl e 18- 6) .
3. Tr adi t i onal Chi nese medi ci ne ( TCM) may cont ai n a combi nat i on of her bs. Some
i mpor t ed TCM pr oduct s have been f ound t o cont ai n unl i st ed l egend dr ugs. An
exampl e i s a TCM medi cat i on adver t i sed t o t reat di abet es t hat was f ound t o cont ai n
t he pharmaceut i cal s gl ybur i de and phenf ormi n.
4. Some herbal preparat i ons may cont ai n unrecogni zed cont ami nant s such as heavy
met al s, or a si mi l ar -appear i ng her b t hat i s mi st akenl y har vest ed. These are qual i t y
cont r ol i ssues t hat ar e t o a l ar ge ext ent unr egul at ed by gover nment agenci es.
B. Dr ug-her bal i nt er act i ons can occur as pharmacoki net i c or phar macodynami c
i nt er act i ons ( Tabl e 18- 7).
C. Dr ugs wi t h nar r ow t her apeut i c wi ndows ar e at gr eat er ri sk f or dr ug-herbal
i nt er act i ons. For exampl e, i mpor t ant dr ug- herb i nt er act i ons occur wi t h pat i ent s
t aki ng war f ar i n.
1. Coenzyme Q10 has a chemi cal st r uct ur e rel at ed t o vi t ami n K. The combi nat i on of
war f ar i n and Coenzyme Q10 r esul t s i n ant agoni zed war f ari n act i vi t y and i nadequat e
ant i coagul at i on.
P. 428


Table 18-7. Table of Common Herbs and Potential Drug Interactions
Herb Drug/Drug Class Interaction Effect
Black
Cohosh
Antihypertensives Pharmacodyna
mic potentiation
Increased eIIect
oI
antihypertensives
(hypotension)
Coenzy
me Q10
WarIarin Pharmacodyna
mic antagonism
Vitamin K
antagonism
(increased INR
and risk oI bleed)
Dong
Quai
Beta blockers Inhibition oI
CYP450
Enzymes
Increased level oI
beta blockers
(increased
hypotension)

Benzodiazepines Inhibition oI
CYP 450
Enzymes
Increased
benzodiazepine
levels (increased
drowsiness and
CNS depression)
Echinace
a
Immunosuppressa
nts Monoclonal
antibodies
Pharmacodyna
mic antagonism
Decreased
immunosuppressi
on (Ilair oI
autoimmune
disease.
transplant graIt
reiection)
Ephedrin
e Ma
Huang
Beta blockers Pharmacodyna
mic antagonism
Sympathomimeti
c eIIect
(hypertension)

MAOIs Blocked
metabolism
Increased and
prolonged
sympathomimeti
c eIIect
(Hypertensive
crisis)

Corticosteroids Increased
metabolism
Induced hepatic
metabolism
Decreased
corticosteroid
levels (decreased
steroid
eIIectiveness)
Evening
Primrose
Oil
Antiplatelets Pharmacodyna
mic potentiation
Decreased
platelet
aggregation
(increased risk oI
bleed)

Phenothiazines Additive
toxicity
Reduced seizure
threshold
(seizures)
Ginkgo
biloba
WarIarin. LMWH Pharmacodyna
mic potentiation
Increased
inhibition oI
platelet
aggregation
(increased risk oI
bleed)
Ginseng MAOI Pharmacodyna
mic eIIect
Increased GABA
metabolism and
increased
dopamine levels
(mania
symptoms)
Kava
Kava
Acetaminophen
Azole antiIungals
Statins
Additive
toxicity
Increased otential
Ior hepatic
toxicity (elevated
LFT. hepatic
Iailure)

Barbiturates
Benzodiazepines
Synergy Increased GABA
receptor binding
aIIinity
(increased
drowsiness. CNS
depression)

Levodopa Antagonism Dopamine
blockade
(decreased
eIIectiveness oI
levodopa)
Soy Lethothyroxine Impaired
absorption
Decreased levels
oI levothyroxine
(hypothyroid
symptoms)
St.
John's
Wort
Irinotecan Induced
CYP3A4
Metabolism
Reduced levels
oI active
irinotecan
metabolite Ior
chemotherapy
(decreased
myelosuppressio
n)
Valerian Sedatives Pharmacodyna
mic
Increased CNS
depression
(drowsiness and
sedation)

Benzodiazepines Displacement
Irom binding
sites
Displaced
benzodiazepine
but additive CNS
depression
(possible
increased
drowsiness)

P. 429


2. Gi nger , gar l i c, and f ever f ew al so i ncr ease bl eedi ng i n pat i ent s t aki ng war f ari n by
di r ect l y i nhi bi t i ng pl at el et s and causi ng i ncreased r i sk of bl eedi ng.
3. Wheat grass act ual l y cont ai ns hi gh l evel s of vi t ami n K whi ch di rect l y ant agoni zes
war f ar i n causi ng i nadequat e ant i coagul at i on and t herapeut i c f ai l ure.
D. Pot ency of her bal pr epar at i ons i s i nf l uenced by a var i et y of f act ors:
1. The st age of gr owt h dur i ng whi ch t he her b was har vest ed
2. The dr yi ng t i me
3. The sol vent s used i n ext r act i on of t he her b
4. The shel f l i f e and st orage condi t i ons of t he herbal ext r act
V. Food-drug interactions
A. Food can i ncr ease, decr ease, or not af f ect t he absorpt i on of dr ugs ( Tabl e 18- 8) .
B. Food can i nf l uence t he bi oavai l abi l i t y of a dr ug f r om a modi f i ed- rel ease dosage
f or m ( e. g. , cont r ol l ed rel ease, del ayed rel ease [ ent eri c coat ed] ) rat her t han f r om an
i mmedi at e- r el ease dosage f or m. For exampl e, openi ng t he capsul e of ent er i c coat ed
omepr azol e beads and gi vi ng i t i n an aci di c f ood such as appl esauce or wi t h or ange
j ui ce, eases admi ni st r at i on of t he dr ug whi l e mai nt ai ni ng t he ent er i c coat i ng on t he
omepr azol e beads unt i l t he drug r eaches t he basi c pH of t he duodenum wher e t he
omepr azol e beads ar e uncoat ed and t he dr ug i s absor bed.
C. Compl exat i on and adsor pt i on of t he dr ug i n t he GÌ t ract wi t h anot her f ood
el ement i s a common drug i nt eract i on t hat r educes t he ext ent of drug absor pt i on.
For exampl e, qui nol one ant i bi ot i cs compl ex wi t h cal ci um ( f ound i n mi l k product s) .
1. Qui nol one ant i bi ot i cs wi l l compl ex wi t h cal ci um f r om t he di et and t he resul t wi l l
be r educed qui nol one ant i bi ot i c.
2. Ì bandr onat e f or ost eopor osi s has si gni f i cant l y r educed absor pt i on when gi ven
wi t h f ood. Si nce absor pt i on i s ver y poor, wi t h l ess t han 0. 6% bi oavai l abi l i t y i n
f ast i ng ci rcumst ances, and up t o 99% pr ot ei n bi ndi ng, t he si gni f i cant r educt i on i n
i bandr onat e when gi ven wi t h f ood may r educe t he dr ug t o subt herapeut i c l evel s.
3. A number of dr ugs such as phenyt oi n and qui nol one ant i bi ot i cs ar e adsor bed t o
cal ci um and i ron i n t ube f eedi ngs.
D. Food can be met abol i zed by t he same l i ver enzymes t hat met abol i ze dr ugs,
causi ng enzyme i nhi bi t i on or i nduct i on, and r esul t i ng i n t oxi c or subt herapeut i c dr ug
l evel s. For exampl e,
P. 430

gr apef r ui t and val enci a or anges i nhi bi t t he CYP3A4 i soenzyme syst em, causi ng
i ncreased l evel s of subst r at e dr ugs such as saqui navi r , i ndi navi r , mi dazol am,
ni modi pi ne, ni f edi pi ne, l ovast at i n, cycl ospor i n, car bamazepi ne, and ver apami l .
Table 18-8. Affect of Food on Drug Bioavailability
Reduced or delayed Increased Not affected by food
NSAIDs (nonsteroidal anti-
inIlammatory drugs) naproxen.
naproxen sodium
GriseoIulvin Theophylline
*

Metoprolol Metronidazole
Aspirin Phenytoin
Acetaminophen Propoxyphene
Antibiotics (tetracycline and
penicillin)
Dicumarol

Ethanol Morphine
*
Food does not signiIicantly aIIect drug absorption oI theophylline in an
immediate-release dosage Iorm. However. Iood may aIIect theophylline
absorption Irom a controlled-release Iormulation.

E. Food can pharmacodynami cal l y ant agoni ze t he ef f ect of some dr ugs. For
exampl e, spi nach and broccol i provi de di et ar y sour ces of vi t ami n K, whi ch
ant agoni zes t he ef f ect of war f ar i n. Gar l i c can cause addi t i ve ant i pl at el et ef f ect i n
combi nat i on wi t h war f ar i n, hepari n, and LMWH, and cause i ncr eased ri sk of
bl eedi ng.
F. Foods can cont ai n phar macol ogi cal l y act i ve compounds t hat i nt er act wi t h dr ugs
meant t o i nhi bi t endogenous compounds. Monoami ne oxi dase i nhi bi t ors (MAOÌ s)
pr event normal met abol i sm of cat echol ami nes. They al so i nhi bi t t he met abol i sm of
t yr ami ne f r om t yr ami ne cont ai ni ng f oods such as r ed wi ne, cheese. The i ncr eased
l evel s of t yr ami ne cause hyper t ensi ve cr i si s.
VI. ChemicaI-drug interactions
A. Smoki ng by i nhal i ng ar omat i c pol ycycl i c hydrocar bons ( t obacco) can i nduce t he
CYP1A2 i soenzyme met abol i sm and decr ease l evel s of subst r at e drugs such as
t heophyl l i ne, di azepam, t r i cycl i c ant i depr essant s, dul oxet i ne, and r amel t eon.
B. Et hanol can i ncr ease or decrease t he act i vi t y of hepat i c drug met abol i zi ng
enzymes.
1. Chroni c al cohol i sm can i ncr ease t he rat e of met abol i sm of t ol but ami de, war f ar i n,
and phenyt oi n.
2. Acut e al cohol i nt oxi cat i on can i nhi bi t hepat i c enzymes i n nonal cohol i c
i ndi vi dual s.
3. Et hanol i nduces met abol i sm i n t he CYP1A2 and 2E1 i soenzymes. Level s of 1A2
subst rat es cl ozapi ne, cycl obenzapr i ne, i mi prami ne, naproxen ar e decr eased. Level s
of t he 2E1 subst rat es acet ami nophen ar e r educed.
4. Di sul f i ram i nhi bi t s al cohol dehydr ogenase, resul t i ng i n l i mi t ed met abol i sm of
et hanol and causi ng sever e et hanol i nt ol er ance.
VII. Pharmacogenetics and Drug Interactions
A. Genet i c di f f erences i n dr ug met abol i sm ar e t he r esul t of genet i cal l y based
var i at i ons i n aI I eI es f or genes t hat code f or enzymes r esponsi bl e f or t he met abol i sm
of drugs.
1. Ì n nor mal enzyme f unct i on, t he gene encodi ng f or t he enzyme i s composed of t wo
nor mal al l el es. Ì n PoI ymorphi sms, t he genes cont ai n abnor mal pai rs or mul t i pl es of
abnor mal al l el es l eadi ng t o al t er ed enzyme f unct i on.
2. Pol ymorphi sms can occur i n any enzyme syst em i ncl udi ng t he CYP450 hepat i c
enzymes, t he mi xed oxi dase and n-acet yl t r ansf erase syst ems, and t he UGT
met abol i c enzyme syst ems. Ì n t he CYP450 syst em, t he CYP2D6, CYP2C9, and
CYP2C19 pol ymor phi sms are t he most ext ensi vel y st udi ed.
3. Di f f erences i n enzyme act i vi t y occur at di f f er ent r at es accordi ng t o raci al gr oup
( Tabl e 18- 9).
4. PoI ymorphi sms ( di f f er ences i n t he al l el es) can al so var y wi t hi n a raci al gr oup by
geogr aphi c di st r i but i on. For exampl e, i n West er n Eur opeans pol ymorphi sm f or t he
CYP2D6 al l el es can var y wi t h 10 t i mes as many ul t r a met abol i zer s ( UM) i n Gr eece
as i n Aust r i a.
5. The ext ent of t he dr ug i nt er act i on i s pr edi ct ed based upon t he basel i ne act i vi t y of
t he enzyme i n an i ndi vi dual . Basel i ne enzyme ef f i ci ency var i es gr eat l y among
i ndi vi dual s dependi ng upon t he t ype and ext ent of pol ymorphi c changes t o t he
enzyme.
B. Si ngI e NucI eot i de PoI ymorphi sms ( SNPs) ar e si ngl e changes i n one al l el e of a
gene r esponsi bl e f or a var i et y of met abol i c pr ocesses i ncl udi ng enzymat i c
met abol i sm.
P. 431


Table 18-9. Ethnic Differences in the CYP2D6 Enzyme Activity
Ethnicity As a Percentage of the Population
Caucasians 7-10° PM / 1° UM
AIrican-Americans 8° PM
Asians ~50° PM / 1° UM
Adapted Irom Zagaria MAE. The promise oI pharmacogenomics. Available
online at http://www.uspharmacist.
com/index.asp?show÷article&page÷81190.htm. Retrieved January 18.
2006; and Johannson I. Oscarson M. Yue QY. et al. Genetic analysis oI the
Chinese cytochrome P4502D locus: Characterization oI variant CYP2D6
genes present in subiects with diminished capacity Ior debrisoquine
hydroxylation. Mol Pharmacol 1994;46:452-459.

1. The genet i c SNPs can be of sever al di f f er ent ki nds, resul t i ng i n many di f f erent
var i ant s of t he enzyme. CYP2D6 has mor e t han 70 var i ant al l el es.
2. The combi nat i on of al l el es encodi ng t he gene det ermi nes t he act i vi t y of t he
enzyme. The combi nat i ons can i ncl ude mi ssi ng al l el es, def ect i ve al l el es, dupl i cat ed,
and mul t i pl e al l el es. Ì n addi t i on, al l el es can demonst rat e ampl i f i cat i on, subst i t ut i on,
or def ect i ve spl i ci ng. Nul l enzyme act i vi t y, or abol i shed act i vi t y can occur f r om
er r ors i n t ranscri pt i on, spl i ci ng, st ar t and st op codons, and ami no aci d changes.
3. The combi nat i on of al l el es i n t he af f ect ed gene r esul t s i n di f f er ences i n t he
ef f ect i veness of t he enzyme. The over al l f unct i on of t he enzyme i s t he phenot ype of
enzyme f unct i on.
a. Poor met abol i zers ( PM) car r y t wo def ect i ve al l el es, f or exampl e CYP2D6
*
4/
*
5 and
CYP2D6
*
4/
*
4. PMs al so i ncl ude combi nat i on of al l el es i ncl udi ng one resul t i ng i n no
enzyme, f or exampl e CYP2D6
*
5 and CYP2D6
*
4/ del et i on.
b. Ì nt ermedi at e met abol i zer s ( Ì M) ar e het er ozygous, t hat i s, havi ng one wi l d t ype
al l el e and one def ect i ve al l el e.
c. Normal met abol i zers car r y " wi l d t ype¨ al l el es, f or exampl e CYP2D6*1/ *33. Wi l d
t ype al l el es encode genes f or nor mal enzyme f unct i on.
d. Ext ensi ve met abol i zers ( EM) car r y one wi l d t ype and one ampl i f i ed gene, f or
exampl e CYP2D6
*
1/
*
2. Anot her exampl e of EM car r y t he f ol l owi ng pai r s:
CYP2D6
*
A/
*
1a and CYP2D6
*
1A/
*
5.
e. Ul t r a- r api d met abol i zer s ( UM) car r y t wo or more copi es of an ampl i f i ed gene, f or
exampl e CYP2D6
*
2/
*
2.
4. Genet i c changes may i nact i vat e or r educe enzymat i c act i vi t y ( e. g. , poor
met abol i zers) , l eadi ng t o i ncr eases i n t he subst r at e drug.
5. Genet i c dupl i cat i on may i ncr ease enzymat i c act i vi t y (e. g. , ul t ra- r api d
met abol i zers) , resul t i ng i n l ower l evel s of t he subst r at e dr ug.
6. Ì n t he CYP2D6 enzyme, genet i c var i at i on can cause a 10- t o 30- f ol d di f f er ence i n
t he l evel s of dr ugs met abol i zed by t hat enzyme. Tabl e 18- 10 l i st s a f ew CYP2D6
var i ant s and t hei r ef f ect s of t he dr ug met abol i sm act i vi t y of t he enzyme.
C. Pol ymor phi sms af f ect dr ug i nt eract i ons by al t er i ng t he ef f ect of i nhi bi t or s and
i nducer s on t he enzymes. The r esul t i s an exagger at ed ef f ect or mi ni mal ef f ect on
t he subst rat e.
1. Ì n an EM, t he l evel of subst rat e dr ug i s normal l y l ow because of t he rapi d
met abol i sm by t he enzyme. An i nhi bi t or t o t he enzyme wi l l subst ant i al l y i nhi bi t t he
ext ensi ve met abol i sm and cause si gni f i cant el evat i ons i n t he subst r at e drug. The
subst rat e l evel s r i se dr amat i cal l y because t he ef f ect of t he i nhi bi t or i s much gr eat er
i n an EM. The dr ug i nt eract i on may occur t o a great er ext ent t han i t woul d i n normal
met abol i zers ( Tabl e 18- 11) .
2. Ì n a PM, t he l evel of subst r at e drug remai ns hi gh because t he met abol i sm of t he
subst rat e i s much l ess t han nor mal . When an i nhi bi t or i s added t o t he r egi men, t he
addi t i onal
P. 432

i nhi bi t i on of met abol i sm i s not much gr eat er t han i s al ready occur ri ng i n a PM.
Ther ef ore t he ef f ect of an i nhi bi t or on a PM i s l ess t han i t woul d be i n normal
met abol i zers. The dr ug i nt er act i on may not occur.
Table 18-10. Allele Activity Patterns in the CYP2D6 Isoenzyme
Gene Polymorphism Enzyme activity Phenotype
CYP2D6
*
1 Wild-type Normal EM or
normal
CYP2D6
*
2 Same as 2D6
*
1 but
possible
Increased
enzyme
EM/UM

Duplication or
ampliIication
Activity

CYP2D6
*
4 DeIective splicing Inactive
enzyme
PM
CYP2D6
*
5 Gene depletion No enzyme PM
CYP2D6
*
10 Single AA
substitution
predominant
Reduction in PM

Variant in people oI
Asian descent
Enzyme
activity

CYP2D6
*
17 Single AA
substitution
predominant
Reduction in PM

Variant in people oI
AIrican descent
Enzyme
activity
Adapted Irom Zagaria MAE. The promise oI pharmacogenomics. Available
online at
http://www.uspharmacist.com/index.asp?show÷article&page÷81190.htm.
Retrieved January 18. 2006; Ingelman-Sundberg M. Genetic polymorphisms
oI cytochrome P4502D6 (CYP2D6): clinical consequences. evolutionary
aspects and Iunctional diversity. Pharmacogenomics J 2005;5:6-13; and Lee
LS. NaIziger AN. Bertino JS Jr.Evaluation oI inhibitory drug interactions
during drug development: Genetic polymorphisms must be considered. Clin
Pharmacol Ther 2005;78:1-6.

3. Ì n an EM, t he l evel of subst rat e dr ug i s agai n l ower t han expect ed i n a nor mal
met abol i zer because of t he r api d met abol i sm. The addi t i on of an i nducer does not
cause a gr eat di f f er ence i n t he l evel of subst r at e because t he met abol i sm i s al ready
i ncreased great l y. The dr ug i nt er act i on may not occur .
4. Ì n a PM, t he l evel of subst r at e drug i s agai n hi gher t han expect ed i n a nor mal
met abol i zer because of t he l ower met abol i sm of t he subst rat e. The addi t i on of an
i nducer wi l l cause a si gni f i cant i ncr ease i n t he met abol i sm of t he subst rat e and
cause a much l ower l evel of subst r at e t han expect ed i n a nor mal met abol i zer . The
dr ug i nt er act i on may occur t o a gr eat er ext ent t han i n nor mal met abol i zers, or t he
dr ug i nt er act i on may r esul t i n subst r at e l evel s si mi l ar t o t hose of nor mal
met abol i zers.
5. As a gener al r ul e, t he ef f ect of i nhi bi t ors i s gr eat er i n EMs t han i n PMs. The
ef f ect of i nducer s i s great er i n PMs t han i n EMs.
6. The di f f er ence bet ween EM and UM can be descr i bed as t he di f f er ence bet ween
het erozygous and homozygous i ndi vi dual s wi t h dupl i cat ed or ampl i f i ed genes. The
addi t i on of an i nhi bi t or t o an UM woul d be expect ed t o show an even gr eat er dr ug
r eact i on t han woul d be seen wi t h an EM.
7. Compl ex dr ug i nt er act i ons can be seen when a subst rat e i s met abol i zed t hrough
mor e t han one enzyme syst em wher e one or more enzymes ar e af f ect ed by
pol ymor phi sm. Ì n t hese cases, t he subst rat e i s met abol i zed t hrough a pol ymorphi c
enzyme and becomes an act i ve met abol i t e and an i nhi bi t or or i nducer i n a second
syst em. Pol ymor phi sm i n t he f i rst enzyme can cause t he l evel of t he i nhi bi t or or
i nducer t o be great er or l ess t han
P. 433

expect ed, t hus causi ng t he ext ent of t he expect ed i nhi bi t i on or i nduct i on of t he
second enzyme t o be si gni f i cant l y changed.
Table 18-11. The Effect of Inhibition of EM/UM and PM on CYP2D6 Substrates
Enzyme Inhibitor Substrate
Effect of
EM/UM On
the substrate
Effect of
PM On the
substrate
CYP2D6 Diphenhydramine Metoprolol Increased
61°
Little
change
CYP2D6 Quinidine S-
venlaIaxine
Increased
4x
Little
change
CYP2D6

R-
venlaIaxine
Increased
12x
No
change
CYP2D6 Diphenhydramine VenlaIaxine Increased
2x
Little
change
CYP2D6 Fluoxetine Risperidone Increased
4x
Increase
1.3x
Adapted Irom Lee LS. NaIziger AN. Bertino JS Jr.Evaluation oI inhibitory
drug interactions during drug development: Genetic polymorphisms must be
considered. Clin Pharmacol Ther 2005;78:1-6.

D. Speci f i c Phar macogenomi c Dr ug Ì nt er act i ons f r om t he l i t erat ure.
1. Omepr azol e
Ì n one st udy of omeprazol e act i vi t y on t he i nhi bi t i on of mocl obemi de i n CYP2C19
EMs and PMs, t he ef f ect of i nhi bi t i on vari ed accor di ng t o t he degree of genet i c
pol ymor phi sm. One woul d expect i nhi bi t i on of t he met abol i sm of t he subst r at e
mocl obemi de by t he i nhi bi t or omepr azol e. But i n EMs, t he AUC l evel of t he
subst rat e mocl obemi de al most doubl ed, r ef l ect i ng t he gr eat er ef f ect of i nhi bi t i on on
mocl obemi de whi ch was or i gi nal l y ext ensi vel y met abol i zed. Ì n compari son, PMs
al r eady show poor met abol i sm of t he mecl obemi de. Ì nhi bi t i on of t he 2C19 enzyme
by omepr azol e i n PM di d not show an ext ensi ve change i n t he AUC l evel s of
mocl obemi de, because met abol i sm was al r eady i mpai red.
1

2. Fl uvoxami ne
Fl uvoxami ne i nhi bi t s t he met abol i sm of di phenydrami ne by t he CYP2C19 i soenzyme.
When EM t aki ng di phenydr ami ne wer e gi ven t he 2C19 i nhi bi t or f l uvoxami ne, t he
AUC and Cmax l evel s of di phenhydr ami ne i ncr eased si gni f i cant l y over pl acebo.
When PM t aki ng di phenhydr ami ne wer e gi ven t he i nhi bi t or f l uvoxami ne, t he AUC
and Cmax of di phenhydrami ne di d not change si gni f i cant l y. The ef f ect of i nhi bi t i on
on t he subst rat e of an EM i n t he CYP2C19 was gr eat er t han i t woul d have been i n a
nor mal met abol i zer . The ef f ect of i nhi bi t i on on t he subst r at e of a PM i n CYP2C19 i s
not si gni f i cant . Ì n addi t i on, t hose EMs who wer e homozygous showed great er
i nhi bi t i on t han t he EMs who wer e het erozygous. Thi s demonst r at es t hat t he degree
of i nhi bi t i on var i es by genot ype. Homozygous EMs showed gr eat er reduct i on i n
enzyme act i vi t y t hat het er ozygous EM. Ì n t he same way, EM show gr eat er i nhi bi t i on
t han PM because PM al ready have r educed enzyme act i vi t y and wi l l not show a
gr eat change i n Cmax or AUC, even wi t h i nhi bi t i on.
2

3. Di phenhydr ami ne
Di phenhydrami ne i nhi bi t s t he met abol i sm of met opr ol ol . Ì n EM i n t he CYP2D6, t he
Cmax and AUC of di phenhydr ami ne i ncr eased by 16% and 61%, r espect i vel y, as
compared t o non-pol ymor phi sms. The i nhi bi t or di phenhydr ami ne decr eased
conversi on of met oprol ol t o i t s met abol i t e by a f act or of 3. Ì n t he PM, t he change i n
met opr ol ol conversi on was i nsi gni f i cant . Agai n, t he ef f ect of i nhi bi t i on on t he
subst rat e i n t he EM was gr eat er t han i n PM.
3

4. Di phenhydr ami ne
Di phenhydrami ne i nhi bi t s t he met abol i sm of venl af axi ne by t he CYP2D6 i soenzyme.
When di phenhydrami ne i s gi ven t o a EM who i s t aki ng venl af axi ne, t he l evel s of
venl af axi ne r i se t wof ol d. Di phenhydrami ne gi ven t o a PM who i s t aki ng venl af axi ne
causes i nsi gni f i cant change i n t he l evel s of venl af axi ne. As wi t h t he exampl e wi t h
met opr ol ol above, t he ext ent of i nhi bi t i on i n EM i s much great er t han i n PM.
4

E. The ef f ect of pol ymorphi sm on dr ug devel opment and dr ug saf et y.
1. Most drug compani es dur i ng dr ug devel opment do not genot ype t hei r subj ect s f or
pol ymor phi sms. Ì n smal l st udi es, or i n st udi es of genet i cal l y homogenous subj ect s,
t he pharmacoki net i cs descri bed f or t he dr ug may be skewed t owar d t he
pol ymor phi sms preval ent i n t he subj ect popul at i on. Thi s can occur when, f or
exampl e, Asi ans ar e t he pr i mar y subj ect popul at i on f or pharmacoki net i c st udi es f or
a dr ug met abol i zed by CYP2C19. CYP2C19 pol ymor phi sms occur i n 20% t o 25% of
t he Asi an popul at i on.
2. When pol ymorphi sms and phar macogenomi cs ar e not consi dered duri ng dr ug
devel opment , t he resul t can be t he devel opment of some drugs t hat have shown
t oxi ci t y i n cer t ai n popul at i ons, and have been wi t hdr awn f r om t he mar ket as a
r esul t . These drugs i ncl ude t rogl i t azone ( Rezul i n) and mi bef r adi l .
3. Phar macogenomi c t est i ng duri ng drug devel opment can i dent i f y t he dosi ng
var i abl es i n cer t ai n pol ymor phi c popul at i ons and coul d l ead t o a great er saf et y i n
t he use of t hese
P. 434

dr ugs. Cl i ni cal t r i al s i n war f ari n t herapy wi t h genet i c t est i ng f or pol ymor phi sms i n
CYP2C9 such as t he CYP2C9
*
2 and CYP2C9
*
3.
4. The i dent i f i cat i on of pol ymorphi c f act ors i n a speci f i c dr ug under devel opment
may l i mi t t he cl i ni cal use of t hat dr ug t o cer t ai n phar macogenomi c popul at i ons.
5. The FDA may make r ecommendat i ons, or r equi r e l abel i ng f or genet i c t est i ng of
pat i ent s t o det er mi ne pol ymor phi sms t hat af f ect dr ug met abol i sm or t r anspor t .
a. The i nvader UGT1A1 mol ecul ar assay f or UGT1A1 det ect s pol ymor phi sms t hat
can r educe t he met abol i sm of i r i not ecan, a chemot herapy f or col or ect al cancer .
b. The FDA has cl ear ed t he Ampl i cChi p Cyt ochrome P450 Genot ypi ng Test f or
pol ymor phi sms i n t he CYP450 i soenzyme syst em whi ch i s ext ensi vel y i nvol ved i n
dr ug met abol i sm.
c. The FDA has added l abel i ng t o vari ous dr ugs t o t est f or genet i c pol ymor phi sms
t hat af f ect met abol i sm, such as ant i epi l ept i c drugs.
d. The FDA has al so mandat ed t he t est i ng of HÌ V st rai ns f or gui dance i n usi ng
Mar avi r oc.
VIII. CLINICAL SIGNIFICANCE AND MANAGEMENT OF
DRUG INTERACTIONS
A. Pot ent i al dr ug i nt eract i ons
1. MuI t i pI e-drug therapy, i ncl udi ng bot h prescri pt i on and nonprescri pti on ( OTC)
medi cat i on, can pot ent i al l y l ead t o dr ug i nt eract i ons. The mor e drugs used by a
pat i ent , t he gr eat er t he pot ent i al f or a dr ug i nt er act i on.
2. MuI t i pI e prescri bers. Pat i ent s can be seen by di f f er ent pr escri ber s who
pr escri be i nt er act i ng medi cat i on.
3. Pati ent compI i ance. Pat i ent s need t o f ol l ow pr oper i nst ruct i ons f or t aki ng
medi cat i ons. For exampl e, a pat i ent mi ght t ake t et r acycl i ne wi t h f ood r at her t han
bef ore meal s.
4. Pat i ent ri sk f act ors
a. Ol der pat i ent s ar e at mor e r i sk f or dr ug i nt er act i ons t han younger pat i ent s. Ol der
pat i ent s mi ght have changes i n t hei r physi ol ogi cal and pat hophysi ol ogi cal condi t i on
t hat l ead t o al t er ed body composi t i on, al t er ed GÌ t r ansi t t i me and drug absor pt i on,
decreased prot ei n bi ndi ng, al t ered di st r i but i on, and decreased drug cl earance.
These changes can exacer bat e or i ncrease t he r i sk of a drug i nt er act i on.
b. Pat i ent s wi t h predi sposi ng i l l ness (di abet es, ast hma, AÌ DS, and al cohol i sm) and
pat i ent s who ar e cl i ni cal l y hyper sensi t i ve ( at opi c) ar e more at r i sk f or drug
i nt er act i ons t han non- at opi c pat i ent s.
c. Pharmacogenet i c pol ymor phi sms i n enzyme f unct i on can occur at di f f erent rat es
i n di f f er ent r aci al popul at i ons, and t o a l esser ext ent , i n di f f erent nat i ons. These
pharmacogenet i c di f f er ences can l ead t o a wi de var i at i on i n t he pot ent i al f or a drug
i nt er act i on.
B. Cl i ni cal si gni f i cance
1. Not al l dr ug i nt er act i ons ar e cl i ni cal l y si gni f i cant or cause an adver se ef f ect . Ì n
some cases, i nt er act i ng dr ugs can be pr escr i bed f or pat i ent s as l ong as t he pat i ent
i s gi ven pr oper i nst ruct i ons and i s compl i ant . For exampl e, ci met i di ne and an
ant aci d mi ght be pr escri bed t o t he pat i ent , but t he pat i ent shoul d be i nst ruct ed t o
not t ake bot h medi cat i ons at t he same t i me.
2. Combi nat i on drug t herapy can have benef i ci al ef f ect s. Drug combi nat i ons ar e
used t o i mprove t he t herapeut i c obj ect i ve or t o decr ease adver se event s. Some
exampl es i ncl ude:
a. Tr i met hopr i m and sul f amet hoxazol e÷combi nat i on ant i bi ot i c f or i ncr eased ef f i cacy
i n ur i nar y t r act i nf ect i ons.
b. Amoxi ci l l i n and cl avul anat e pot assi um÷combi nat i on cont ai ni ng a bet a-l act amase
i nhi bi t or (cl avul anat e) t o i nhi bi t t he br eakdown of amoxi ci l l i n.
c. Hydr ochl orot hi azi de and t ri amt erene÷combi nat i on di ur et i c and ant i hyper t ensi ve
t o mi ni mi ze pot assi um excr et i on.
d. Ri t onavi r i s gi ven as a " boost er ¨ wi t h t i pr anavi r . Coadmi ni st r at i on i ncreased
t i pranavi r l evel s 30-f ol d by i nhi bi t i on of t he CYP3A4 enzyme r esponsi bl e f or
met abol i sm of t i pr anavi r .
e. Pr obeneci d i nhi bi t s r enal t ubul ar secr et i on of peni ci l l i n, t her eby pr ol ongi ng t he
pl asma hal f -l i f e of t he ant i bi ot i c.
P. 435


3. Some dr ug- f ood i nt er act i ons are ut i l i zed f or t hei r benef i ci al ef f ect s. Phenyt oi n i s
gi ven wi t h di et ar y f at s t o i ncr ease i t s bi oavai l abi l i t y t hr ough enhanced absor pt i on.
4. Anot her t ype of dr ug-dr ug i nt er act i on occur s when t he conver si on of a pr o- dr ug t o
t he act i ve met abol i t e i s i nhi bi t ed or i nduced at t he met abol i zi ng enzyme.
a. The conversi on of i nact i ve codei ne t o i t s act i ve met abol i t e mor phi ne can be
r educed by CYP2D6 i soenzyme i nhi bi t i on caused by ci met i di ne or ci t al opram. The
r educed met abol i sm can r esul t i n subt her apeut i c l evel s of morphi ne, and t her apeut i c
f ai l ur e i n pai n t r eat ment .
b. The i nduct i on of t he met abol i sm of CYP2D6 by phenyt oi n or St . John' s Wor t can
i ncrease met abol i sm of codei ne t o morphi ne, r ai se mor phi ne l evel s, and may r esul t
i n excessi ve sedat i on and narcot i c t oxi ci t y.
c. Ot her pr o- dr ug dependent upon met abol i c conver si on t o act i ve met abol i t es
i ncl ude enal apr i l , val acycl ovi r, l evodopa, and cari sopr odol .
5. The det er mi nat i on of t he cl i ni cal si gni f i cance of a pot ent i al dr ug i nt eract i on
shoul d be document ed i n t he l i t er at ur e. The l i kel i hood of a dr ug i nt eract i on can be
cl assi f i ed as f ol l ows:
a. EstabI i shed÷a dr ug i nt er act i on suppor t ed by wel l - pr oven cl i ni cal st udi es
b. ProbabI e÷a dr ug i nt er act i on t hat i s ver y l i kel y but mi ght not be proven cl i ni cal l y
c. Suspect ed÷a dr ug i nt er act i on t hat mi ght occur ; some dat a mi ght be avai l abl e
d. Possi bI e÷a dr ug i nt er act i on t hat coul d occur ; l i mi t ed dat a are avai l abl e
e. UnI i keI y÷a dr ug i nt eract i on t hat i s doubt f ul ; no good evi dence of an al t er ed
cl i ni cal ef f ect i s avai l abl e
5. The cl i ni cal r el evance of a pot ent i al dr ug i nt eract i on shoul d al so consi der t he:
a. Si ze of t he dose and t he dur at i on of t her apy
b. Onset ( r api d, del ayed) and severi t y ( maj or , moderat e, mi nor ) of t he pot ent i al
i nt er act i on
c. Ext rapoI at i on t o r el at ed drugs
6. Pol ymorphi sm i n pharmacogenet i cs may af f ect t he t oxi ci t y and t he cl i ni cal
ef f i cacy of cer t ai n dr ugs i n cer t ai n popul at i ons. Known i nhi bi t ors may pose
si gni f i cant r i sks t o Ext ensi ve Met abol i zers of enzyme syst ems.
C. Management of dr ug i nt er act i ons
1. Revi ew t he pat i ent prof i l e, i ncl udi ng dr ug hi st or y and pat i ent ri sk f act or s. The
pat i ent ' s past medi cal hi st or y can r eveal a t endancy f or non-compl i ance, past
t her apeut i c f ai l ur es, and evi dence f or pharmacogenet i c consi der at i ons.
2. Avoi d compl ex t her apeut i c dr ug r egi mens.
3. Det er mi ne t he pr obabi l i t y of a cl i ni cal l y si gni f i cant dr ug i nt eract i on. Genet i c
t est i ng may be usef ul ( Tabl e 18- 12).
4. Suggest a di f f er ent drug i f t her e i s a hi gh pr obabi l i t y f or a cl i ni cal l y si gni f i cant
dr ug i nt er act i on. For exampl e, acet ami nophen can be used f or headache i nst ead of
aspi r i n f or a pat i ent on ant i coagul ant t her apy.
5. Caref ul l y i nst r uct t he pat i ent as t o t he t i mi ng of t he medi cat i on. For exampl e, an
ant aci d and H-2 bl ocker shoul d not be t aken at t he same t i me. The pat i ent shoul d
use maxi mum spaci ng bet ween drugs. Ì nst r uct t he pat i ent as t o t he t i mi ng of
medi cat i ons t o be t aken " on an empt y st omach. ¨
Table 18-12. FDA Encourages Genetic Testing for Patients Who Will Take
Specific Drugs
Imatinib Atomosetine VenlaIaxine
Voriconazole TamoiIen Omeprazole
Fluoxetine Celecoxib Tramadol
Capecitabine Beta-blockers 5FU
RiIampin Dapsone Irinotecan
Rasburicase Valproic acid primaquine
Adapted Irom
http://www.Ida.gov/cder/genomics/genomicsbiomarkerstable.htm

P. 436


6. Moni t or t he pat i ent f or adverse event s. Sul f onami des, such as sul f i soxazol e and
sul f amet hoxazol e, can pr ol ong pr ot hr ombi n t i me i n pat i ent s gi ven war f ar i n t her apy.
The pr ot hr ombi n t i mes shoul d be moni t or ed i n t hese pat i ent s.
7. Reeval uat e t he pat i ent pr of i l e and dr ug hi st or y when changi ng drug t her apy. For
exampl e, when di scont i nui ng t he di uret i c of a congest i ve heart f ai l ur e pat i ent on
di goxi n, a r evi ew of t he pr of i l e may r eveal a pot assi um suppl ement t hat shoul d be
di scont i nued as wel l .
8. Eval uat e t he ri sks of dr ug t her apy wi t h respect t o phar macogenet i c pol ymor phi c
st at us of met abol i sm. Consi der r i sks i dent i f i ed wi t h r aci al gr oups and geogr aphi c
di st r i but i on. Test f or enzyme phenot ype when f easi bl e. Sel ect drug and adj ust doses
as i ndi cat ed, and accor di ng t o cl i ni cal response. Consi der genot ypi ng f or
pol ymor phi sms when unexpect ed var i at i ons i n cl i ni cal r esponse.
IX. References. A vast number of drug interactions are
reported in the Iiterature. Some generaI references that
are updated periodicaIIy incIude:
A. Dr ug I nt er act i on Fact s. St . Loui s, MO: Fact s and Compar i sons.
B. Hanst en PD, Hor n JR ( eds) . Dr ug I nt eract i ons & Updat es. Vancouver , WA: Appl i ed
Ther apeut i cs, Ì nc.
C. Zuccher o FJ, Hogan MJ, Schul t z CD, eds. Eval uat i ons of Dr ug I nt er act i ons. St .
Loui s, MO: Pr of essi onal Dr ug Syst ems.
D. PDR Gui de t o Dr ug Ì nt er act i ons, Si de Ef f ect s, and Ì ndi cat i ons. Mont val e, NJ:
Medi cal Economi cs Dat a.
E. MÌ CROMEDEX® Syst ems, DRUGDEX® Syst em, Dr ug Eval uat i ons. Engl ewood,
CO: Al t - MedDex.
F. Nat ur al Medi ci nes Compr ehensi ve Dat abase. Avai l abl e onl i ne at
ht t p: / / www. nat ur al dat abase. com.
G. P450 Dr ug Ì nt er act i ons Tabl e. Ì ndi ana Uni ver si t y School of Medi ci ne. Di vi si on of
Cl i ni cal Pharmacol ogy. Avai l abl e onl i ne at ht t p: / / medi ci ne. i upui . edu/ cl i ni cal / .
H. Pharmacogenet i c and Pharmacogenomi cs Knowl edge Base. Ì ndi ana Uni ver si t y
School of Medi ci ne. Di vi si on of Phar macol ogy. Avai l abl e onl i ne at
ht t p: / / medi ci ne. i upui . edu/ cl i ni cal / .
I . CDC Nat i onal Of f i ce of Publ i c Heal t h Genomi cs. Avai l abl e onl i ne at
ht t p: / / www. cdc. gov/ genomi cs/
J. Nat i onal Ì nst i t ut es of Gener al Medi cal Sci ences. Pharmacogenet i c Resear ch
Net wor k. Li nki ng phenot ypes and genot ypes. On t he i nt er net at
www. ni gms. ni h. gov/ Ì ni t i at i ves/ PGRN/
K. FDA genet i c t est i ng and drug l abel i ng. On t he i nt er net at
www. f da. gov/ cder / genomi cs_bi omarkers_t abl e. ht m
1. Yu KS, Yi m DS, Cho JY, et al . Ef f ect of omeprazol e on t he phar macoki net i cs of
mocl obemi de accor di ng t o t he genet i c pol ymor phi sm of CYP2C19. Cl i n Phar macol
Ther 2001; 69( 4): 266- 273.
2. Yasui - Furukor i N, Sai t o M, Uno T, et al . Ef f ect s of f l uvoxami ne on l ansopr azol e
pharmacoki net i cs i n r el at i on t o CYP2C19 genot ypes. J Cl i n Phar macol
2004; 44( 11): 1223-1229.
3. Hamel i n BA, Bouayad A, Met hot J, et al . Si gni f i cant i nt eract i on bet ween t he
nonpr escri pt i on ant i hi st ami ne di phenhydr ami ne and t he CYP2D6 subst rat e
met opr ol ol i n heal t hy men wi t h hi gh or l ow CYP2D6 act i vi t y. Cl i n Phar macol Ther
2000; 67( 5) : 466-477.
4. Lessard E, Yessi ne MA, Hamel i n BA, et al . Di phenhydr ami ne al t ers t he
di sposi t i on of venl af axi ne t hrough i nhi bi t i on of CYP2D6 act i vi t y i n humans. J Cl i n
Psychophar macol 2001; 21( 2) : 175-184.
P. 437


STUDY QUESTIONS
Di rect i ons: Each quest i on bel ow cont ai ns t hr ee suggest ed answer s, of whi ch one
or mor e i s cor r ect . Choose t he answer
1. Drug i nt eract i ons may be cI assed as
I . pharmacoki neti c i nt eract i ons
I I . pharmacodynami c i nt eract i ons
I I I . pharmaceut i caI i nt eract i ons
A I onI y i s cor rect
B I I I onI y i s cor r ect
C I and I I ar e cor r ect
D I I and I I I are cor rect
E I , I I , and I I I ar e cor rect
Vi ew Answer 1. The answer i s E[] . 2. Si t uat i ons t hat can pot ent i aI I y I ead t o
drug i nt eract i ons i ncI ude
I . muI t i pI e- drug t herapy
I I . muI t i pI e prescri bers
I I I . pat i ent compI i ance
A I onI y i s cor rect
B I I I onI y i s cor r ect
C I and I I ar e cor r ect
D I I and I I I are cor rect
E I , I I , and I I I ar e cor rect
Vi ew Answer 2. The answer i s E[and] . Di recti ons: The quest i on bel ow i s
f ol l owed by f our suggest ed answer s. Sel ect t he one l et t er ed answer t hat i s t he best
r esponse t o t he quest i on.
3. Whi ch of the foI I owi ng stat ements regardi ng drug i nt eract i ons i s true?
( A) Al l dr ug i nt er act i ons can pot ent i al l y cause an adverse response i n t he pat i ent .
( B) The cl i ni cal si gni f i cance f or each pot ent i al drug i nt eract i on must be consi der ed
i ndi vi dual l y.
( C) A preci pi t ant drug t hat i nhi bi t s t he met abol i sm of t he obj ect dr ug causes a more
ser i ous dr ug i nt er act i on compared t o a preci pi t ant dr ug causi ng an i ncr ease i n t he
bi oavai l abi l i t y of t he obj ect dr ug.
( D) Ì f t he pat i ent i s pr escr i bed dr ugs t hat can pot ent i al l y i nt er act , t he prescri ber
shoul d be cal l ed, and a di f f er ent preci pi t ant dr ug shoul d be suggest ed.
Vi ew Answer 3. The answer i s B[] . 4. A pat i ent on i ndi navi r Ant i - Ret rovi raI
Therapy ( ART) begi ns taki ng St . John' s Wort for depressi on and suf fers
unexpected reduct i on i n CD4 count . Thi s i s most I i keI y due t o:
( A) Pharmacodynami c i nt er act i on pr oduci ng addi t i ve t oxi ci t y.
( B) Pharmacodynami c i nt er act i on pr oduci ng ant agoni st i c t her apeut i c ef f ect
( C) Enzyme i nduct i on by St . John' s Wor t causi ng i ncr eased met abol i sm of ART.
( D) Enzyme i nhi bi t i on by St . John' s Wor t causi ng t oxi c l evel s of ART.
Vi ew Answer 4. The answer i s C[] . 5. Whi ch of the f oI I owi ng i s a vaI i d
t herapeut i c use of a drug i nteracti on?
( A) The use of pr obeneci d wi t h peni ci l l i n G t o pr ol ong hi gh peni ci l l i n l evel s t o t r eat a
sexual l y t ransmi t t ed di sease.
( B) Gi vi ng aspi ri n wi t h war f ari n t o enhance ant i coagul at i on.
( C) Ì nst r uct i ng t he pat i ent t o t ake l evof l oxaci n wi t h mi l k or ant aci d t o decrease GÌ
i nt ol erance t o or al t her apy.
( D) The t r eat ment of depr essi on wi t h a combi nat i on of ci t al opr am and an MAOÌ .
Vi ew Answer 5. The answer i s A[] . 6. Whi ch of the f oI I owi ng i s not a
harmf uI f ood- drug i nteract i on?
( A) Raw gr een sal ads f or pat i ent s on war f ar i n DVT pr ophyl axi s.
( B) Gr apef r ui t j ui ce and cycl ospor i n t o prevent graf t vs. host r ej ect i on of a
t r anspl ant ed ki dney.
( C) Omepr azol e beads i n appl esauce f or a pat i ent wi t h pr obl ems swal l owi ng
capsul es secondar y t o GERD.
( D) Mi l k wi t h doxycycl i ne t o t reat h. pyl ori .
Vi ew Answer 6. The answer i s C[] . P. 438


7. Whi ch of the foI I owi ng stat ements regardi ng pharmacogenet i c
poI ymorphi sms i s not true?
( A) An EM t aki ng met oprol ol f or hyper t ensi on begi ns t o t ake OTC Tagamet r egul arl y
f or hear t burn. He i s at i ncr eased ri sk f or bradycardi a and car di ac ar rhyt hmi as.
( B) An EM t aki ng met hadone, begi ns t aki ng Tegr et ol f or neuropat hi c pai n. He i s at
r i sk f or t reat ment f ai l ur e and pai n cr i si s.
( C) A PM t aki ng at or vast at i n f or hyperl i pi demi a i s pl aced on ket oconazol e f or a
f ungal i nf ect i on. He i s at i ncr eased ri sk f or myal gi a and rhabdomyol ysi s.
( D) A PM t aki ng met oprol ol f or t achycar di a begi ns t aki ng Benadr yl f or sl eep. He i s
not at ri sk f or si gni f i cant br adycar di a and car di ac bl ock.
Vi ew Answer 7. The answer i s C[] . 8. Asi ans are at great est ri sk of aI I
raci aI groups for geneti c poI ymorphi sm i n whi ch one of t he f oI I owi ng CYP450
i soenzymes?
( A) CYP2D6
( B) CYP3A4
( C) CYP2C19
( D) CYP1A2
Vi ew Answer 8. The answer i s A[] . 9. Whi ch of the f oI I owi ng stat ements
regardi ng pharmacogenet i cs i s f aI se?
( A) Pol ymor phi sms occur onl y i n t he CYP450 hepat i c enzymes.
( B) Pol ymor phi sms resul t i n many var i at i ons of an i soenzyme.
( C) The over al l expr essi on of t he combi ned al l el es i s t he phenot ype of t he enzyme.
( D) SNPs can occur as er r or s of t r anscr i pt i on, def ect i ve spl i ci ng, st art and st op
codones, and ami no aci d changes.
Vi ew Answer 9. The answer i s A[] . 10. Whi ch of t he f oI I owi ng stat ements
regardi ng aI I eI e poI ymorphi sms i s faI se?
( A) Wi l d t ype al l el es encode f or "normal ¨ met abol i sm.
( B) UMs have t wo or more ampl i f i ed al l el es.
( C) PMs car r y one def ect i ve al l el e and one ampl i f i ed al l el e.
( D) EMs wi t h het er ozygous al l el es and have sl ower met abol i sm t han met abol i zer s
wi t h homozygous al l el es.
Vi ew Answer 10. The answer i s C[] . P. 439


ANSWERS AND EXPLANATIONS
1. The answer i s E [ Ì . B] .
Most dr ug i nt er act i ons i n vi vo ar e caused by pharmacoki net i c and phar macodynami c
i nt er act i ons. Phar maceut i cal i nt er act i ons can occur dur i ng ext empor aneous
compoundi ng, pr epar at i on of i nt r avenous ( Ì V) admi xt ur es, and i mpr oper dosi ng, as
i n t he case of gi vi ng aspi r i n wi t h aci di c j ui ces ( e. g. , or ange, cranber r y) .
2. The answer i s E [ Ì V. A. 1, 2 and 3] .
Pat i ent pr of i l es mi ght not cont ai n al l t he dr ug hi st or y i nf ormat i on of t he pat i ent .
Pat i ent s who t ake nonprescr i pt i on ( OTC) medi cat i ons, go t o several di f f er ent
physi ci ans, or pur chase dr ugs at var i ous pharmaci es may negl ect t o i nf orm t he
pharmaci st of al l t he medi cat i ons bei ng t aken.
3. The answer i s B [ Ì V. B] .
Not al l dr ug i nt eract i ons ar e cl i ni cal l y si gni f i cant . Some pot ent i al cl i ni cal l y
si gni f i cant dr ug i nt er act i ons can be pr event ed by pr oper pat i ent i nst r uct i on and
compl i ance. The pot ent i al f or a cl i ni cal l y si gni f i cant dr ug i nt eract i on shoul d be
document ed bef or e cal l i ng a physi ci an concerni ng t he prescr i bed medi cat i on.
4. The answer i s C [ Ì Ì . C. 1. c; Tabl e 18- 3] .
St . John' s Wor t i nduces CYP3A4 i soenzymes i ncreasi ng t he met abol i sm of t he
i ndi navi r and r esul t i ng i n l ow i ndi navi r l evel s and t her apeut i c f ai l ur e of ART. St .
John' s Wor t i t sel f has no di rect ef f ect on CD4.
5. The answer i s A [ Ì Ì . C. 2; Tabl e 18- 4] .
Pr obeneci d i s gi ven wi t h peni ci l l i n and some cephal ospor i ns i n t r eat ment of some
sexual l y t ransmi t t ed di seases. Pr obeneci d compet es wi t h peni ci l l i ns f or r enal
el i mi nat i on, prol ongi ng t he hal f -l i f e of t he peni ci l l i n. Aspi ri n and war f ar i n cause
addi t i ve ant i coagul at i on l eadi ng t o bl eedi ng. Levof l oxaci n t aken wi t h mi l k t o
decrease GÌ i r ri t at i on causes compl exat i on of t he l evof l oxaci n wi t h t he cal ci um i n
t he mi l k and r esul t s i n decr eased l evof l oxaci n t o be avai l abl e. Concommi t t ant
t r eat ment of depressi on of ci t al opr am and MAOÌ r esul t s i n Serot oni n Syndr ome, an
addi t i ve t oxi ci t y.
6. The answer i s C [ V. B] .
Omeprazol e beads are ent eri c coat ed. Gi vi ng an ent eri c coat ed bead wi t h an aci di c
f ood such as appl esauce pr eser ves t he ent er i c coat i ng and al l ows t he drug t o pass
i nt act t hrough t he aci di c st omach envi ronment and i nt o t he basi c duodenum
envi r onment where i t i s absor bed. The r esul t i s i mpr oved drug absorpt i on and
decreased drug dest r uct i on i n t he aci di c st omach i f t he beads wer e not i n an aci di c
f ood.
7. The answer i s C [ VÌ Ì . C. 2] .
The PM al r eady has i nhi bi t ed met abol i sm of at orvast at i n. Addi t i onal i nhi bi t i on wi l l
not si gni f i cant l y i ncrease t he bl ood l evel s of at or vast at i n. Theref ore dose- rel at ed
t oxi ci t y i s unl i kel y. The EM t aki ng met opr ol ol and Tagamet ( ci met i di ne) wi l l show a
gr eat er i ncr ease i n t he met opr ol ol l evel s due t o t he exagger at ed ef f ect of t he
i nhi bi t or i n EM. The EM t aki ng met hadone and Tegr et ol (carbamazepi ne) wi l l have
i ncreased enzyme i nduct i on and met abol i sm of t he met hadone, l ower i ng met hadone
l evel s and put t i ng t he pat i ent at r i sk f or t r eat ment f ai l ure of hi s pai n. The PM t aki ng
met opr ol ol and Benadr yl ( di phenhydr ami ne) wi l l show i nhi bi t i on of t he met abol i sm of
t he met oprol ol and i ncr eased l evel s of met opr ol ol l eadi ng t o a hi gher ri sk of
br adycar di a and car di ac bl ock.
8. The answer i s A [ VÌ Ì . A. 3] .
Pol ymorphi sm i s hi ghest i n t he CYP2D6 i soenzyme i n Asi ans, reachi ng i nci dence of
gr eat er t han 50%.
9. The answer i s A [ VÌ Ì . A. 2] .
Pol ymorphi sms can occur i n any enzyme syst em i ncl udi ng mi xed oxi dase and n-
acet yl t ransf erase syst ems as wel l as t he CYP450 hepat i c enzyme syst em.
10. The answer i s C [ VÌ Ì . B. 3. a] .
Poor met abol i zers ( PM) car r y a normal al l el e combi ned wi t h a def ect i ve or del et ed
al l el e.

19
NucIear Pharmacy
St ephen C. Dragotakes
Jef f rey P. Norenberg
I. INTRODUCTION
A. Over vi ew
1. NucI ear pharmacy i s def i ned as a " pat i ent -or i ent ed ser vi ce t hat
embodi es t he sci ent i f i c knowl edge and pr of essi onal j udgment requi r ed t o
i mprove and pr omot e heal t h t hrough t he saf e and ef f i caci ous use of
r adi oact i ve dr ugs f or di agnosi s and t herapy. ¨
1

2. Radi opharmaceut i caI s ar e drug pr oduct s t hat cont ai n a bi ol ogi cal
moi et y and a r adi oact i ve el ement . The bi ol ogi cal const ruct t arget s a
physi ol ogi cal or pat hophysi ol ogi cal pr ocess of i nt er est , al l owi ng t he
l ocal i zat i on of r adi at i on t hat , i n t urn, may be i maged or used t o ef f ect
t her apy. Most r adi opharmaceut i cal s ar e used i n di agnost i c medi cal i magi ng;
however , t hey ar e al so used i n t her apeut i c appl i cat i ons, such as i n t he
t r eat ment of hyper t hyr oi di sm, t hyr oi d cancer , pol ycyt hemi a vera, and i n t he
al l evi at i on of bone pai n.
3. NucI ear pharmacy pr act i ce ent ai l s t he:
a. Pr ocurement of r adi ophar maceut i cal s
b. Compoundi ng of r adi opharmaceut i cal s
c. Per f ormance of r out i ne qual i t y cont rol pr ocedur es
d. Di spensi ng of r adi ophar maceut i cal s
e. Di st ri but i on of r adi ophar maceut i cal s
f . Ì mpl ement at i on of basi c r adi at i on pr ot ect i on procedures and pract i ces
g. Consul t at i on wi t h and/ or educat i on of t he nucl ear medi ci ne communi t y,
pat i ent s, phar maci st s, ot her heal t h pr of essi onal s, and t he general publ i c
r egardi ng
( 1) Physi cal and chemi cal pr oper t i es of r adi ophar maceut i cal s
( 2) Phar macoki net i cs and bi odi st ri but i on of radi opharmaceut i cal s
( 3) Dr ug i nt eract i ons and ot her f act or s t hat al t er pat t er ns of di st ri but i on
h. Moni t ori ng of pat i ent out comes
i . Research and devel opment of r adi ophar maceut i cal s
B. Propert i es of radi opharmaceuti caI s
1. PharmacoI ogi caI ef f ect s. Typi cal l y, r adi opharmaceut i cal s l ack
pharmacol ogi cal ef f ect s because t he mass quant i t i es r ange f r om pi cogram
( pg) t o nanogr am (ng) per ki l ogr am (kg) of admi ni st er ed dose.
2. Route of admi ni st rati on. Most radi opharmaceut i cal s ar e pr epar ed as
st eri l e, pyr ogen- f r ee i nt ravenous (Ì V) sol ut i ons or suspensi ons t o be
admi ni st er ed di r ect l y t o t he pat i ent . Ot her r out es of admi ni st rat i on i ncl ude
i nt radermal , or al , i nt erst i t i al , and i nhal at i on (e. g. , r adi oact i ve gases,
aer osol s).
3. Radi onucI i des
a. The radi oact i ve component of a r adi opharmaceut i cal i s ref err ed t o as a
r adi onucl i de. Nucl i des are i dent i f i ed as at oms havi ng a speci f i c number of
pr ot ons and neut rons i n t he nucl eus. A nucl i de i s t ypi cal l y i dent i f i ed by t he
chemi cal symbol of t he el ement wi t h a mass number shown as a
super scr i pt , i ndi cat i ng t he sum of pr ot ons and neut r ons (e. g. , i odi de- 131 i s
i ndi cat ed as
131
Ì ) . When t he at om i s radi oact i ve, i t i s cal l ed a radi onucl i de.
b. Radi onucl i des undergo spont aneous radi oact i ve decay accompani ed by
t he rel ease of ener gy. The di st r i but i on, met abol i sm, and el i mi nat i on of t he
r adi ophar maceut i cal can
P. 441

be det ermi ned by measur i ng t hi s ener gy wi t h i magi ng equi pment . Ther e ar e
f our maj or t ypes of r adi at i on emi t t ed t hrough t hi s pr ocess: q- , 8- , v- , and x-
r ays. q- and 8- r adi at i ons ar e not usef ul i n medi cal i magi ng and ar e,
t her ef ore, undesi r abl e i n di agnost i c appl i cat i ons. Most di agnost i c
r adi ophar maceut i cal s use penet rat i ng v- radi at i on, whi ch can be easi l y
det ect ed and conver t ed i nt o i magi ng dat a.
4. HaI f- I i ves of radi opharmaceut i caI s
a. The physi caI haI f - I i f e of a r adi ophar maceut i cal i s t he amount of t i me
necessar y f or t he radi oact i ve at oms t o decay t o one hal f t hei r ori gi nal
number . Each radi onucl i de i s char act eri zed by a speci f i c hal f -l i f e t hat i s a
physi cal const ant .
b. The bi oI ogi caI haI f - I i f e of a radi opharmaceut i cal i s t he amount of t i me
r equi r ed f or t he body t o met abol i ze or el i mi nat e one hal f of t he
admi ni st er ed dose of any subst ance t hr ough bi ol ogi cal processes.
c. The ef f ect i ve haI f - I i fe of a radi opharmaceut i cal i s t he t i me requi r ed f or
an admi ni st er ed r adi ophar maceut i cal dose t o be r educed by one hal f as a
r esul t of bot h physi cal decay and bi ol ogi cal mechani sms. Ì t i s def i ned as:
Te = Tp + ( Tb/ Tp) × Tb
wher e Te i s t he ef f ect i ve hal f - l i f e, Tp i s t he physi cal hal f -l i f e, and Tb i s t he
bi ol ogi cal hal f - l i f e.
C. Opt i maI radi opharmaceuti caI s
1. Opt i maI di agnost i c radi opharmaceut i caI s
a. Shoul d cont ai n a r adi onucl i de wi t h a hal f - l i f e short enough t o mi ni mi ze
r adi at i on exposur e t o t he pat i ent , yet l ong enough t o al l ow f or col l ect i on of
i magi ng i nf or mat i on. The opt i mal rel at i onshi p i s a physi cal hal f - l i f e equal t o
approxi mat el y 67% of t he bi ol ogi cal process of i nt er est .
b. Shoul d i ncor por at e a v- emi t t i ng r adi onucl i de, whi ch decays wi t h t he
emi ssi on of a phot on ener gy bet ween 100 and 300 ki l oel ect r on vol t s (keV) ,
whi ch i s ef f i ci ent l y det ect ed wi t h curr ent i nst r ument at i on
c. Shoul d cont ai n a bi ol ogi cal component t hat al l ows r api d l ocal i zat i on i n
t he or gan syst em of i nt erest and be met abol i zed or excr et ed f rom t he
nont ar get t i ssues t o maxi mi ze cont rast and mi ni mi ze t he r adi at i on absor bed
dose t o nont ar get organs
d. Shoul d be r eadi l y avai l abl e and cost -ef f ect i ve
2. Opt i maI t herapeuti c radi opharmaceut i caI s, i n addi t i on t o Ì . C. 1. c and d,
shoul d cont ai n q- or 8- emi t t i ng r adi onucl i des t hat can ef f ect i vel y del i ver
r adi at i on i n quant i t i es suf f i ci ent t o cause t he desi r ed t herapeut i c ef f ect .
Such ef f ect s i ncl ude apopt osi s, DNA damage, or i r r epar abl e cel l damage
l eadi ng t o t i ssue ef f ect s.
II. SODIUM PERTECHNETATE
99M
TC GENERATOR
A. Over vi ew
1.
99m
Tc, t he most commonl y used r adi onucl i de i n di agnost i c i magi ng t oday,
i s pr oduced by t he r adi oact i ve decay of mol ybdenum- 99 (
99
Mo) .
a.
99m
Tc i s obt ai ned vi a commer ci al l y suppl i ed, st er i l e, pyr ogen- f ree
gener at or syst ems. A gener at or i s a devi ce used t o separ at e a shor t hal f -
l i f e r adi onucl i de f r om t he l onger -l i ved par ent nucl i de whi l e r et ai ni ng t he
par ent t o produce mor e of t he daught er nucl i de. Ì n t hi s way, short hal f -l i f e
nucl i des can be made avai l abl e cont i nuousl y at gr eat di st ances f r om t he
si t es of gener at or pr oduct i on.
b. Al l of t he commer ci al l y suppl i ed gener at ors cur r ent l y use
99
Mo obt ai ned
f r om t he f i ssi on of urani um- 235 (
235
U). Thi s
99
Mo par ent i s absorbed on an
al umi na i on ( Al 2O3) exchange col umn, and t he
99m
Tc f or med f rom i t s decay
i s exchanged f or t he chl or i de i on ( Cl
-
) avai l abl e i n t he 0. 9% sal i ne el uat e
sol ut i on washed t hrough t he col umn, as t he sodi um per t echnet at e
Na
+
(
99m
TcO4)
-
f or m.
2. The chemi cal val ence st at e of Na
+
(
99m
TcO4)
-
as i t i s el ut ed f r om t he
col umn i s +7. Typi cal l y, i t must be r educed t o a l ower val ence st at e bef ore
i t i s abl e t o r eact wi t h ot her compounds. Al t hough many processes can
r educe
99m
Tc, t he st annous i on ( Sn
++
) reduct i on met hod i s most commonl y
used i n
99m
Tc r adi opharmaceut i cal ki t s.
P. 442


a. A radi opharmaceut i cal ki t consi st s of st er i l e, pyr ogen-f r ee vi al s
cont ai ni ng a r educi ng agent , t he bi ol ogi cal compound t o be l abel ed, and
any addi t i onal adj ut ant s necessar y t o ef f ect t he react i on or t o st abi l i ze t he
l abel ed product .
b. Ì n most cases, t hey are l yophi l i zed under i ner t at mospheres, so as t o
mi ni mi ze oxi dat i on of t he r educi ng agent ( e. g. , Sn
++
) .
B. Sodi um pert echnet ate
99m
Tc USP ( Uni t ed St at es Phar macopei a;
Na
+99m
TcO4
-
) as el ut ed f r om a gener at or i n 0. 9% sodi um chl or i de ( NaCl )
sol ut i on i s an i sot oni c, st er i l e, nonpyr ogeni c, di agnost i c
r adi ophar maceut i cal sui t abl e f or Ì V i nj ect i on, or al admi ni st r at i on, and di rect
i nst i l l at i on.
1. Physi caI properti es
a. The sol ut i on shoul d be cl ear, col or l ess, and f ree of vi si bl e f or ei gn
mat er i al . The pH i s 4. 5-7. 0.
b. Na
+99m
TcO4
-
i s i t sel f a r adi opharmaceut i cal , or i t may be used t o
r adi ol abel al l ot her
99m
Tc r adi opharmaceut i cal s.
2. Bi odi st ri but i on
a.
99m
TcO4
-
i s handl ed by t he body i n a f ashi on si mi l ar t o
131
Ì ÷t hat i s, i t i s
t aken up and r el eased but not or gani f i ed by t he t hyr oi d.
b. Af t er Ì V admi ni st r at i on,
99m
TcO4
-
concent rat es i n t he chor oi d pl exus,
t hyr oi d gl and, sal i var y gl and, and st omach, but r emai ns i n t he ci rcul at i on
l ong enough f or f i rst - pass bl ood- pool st udi es, organ per f usi on, and maj or
vessel st udi es.
c. Ì t i s pr i mar i l y excr et ed by t he ki dneys unchanged and i s expr essed i n t he
ur i ne 15- 50% by 24 hr .
d. Bet ween 10 and 55% of t he admi ni st er ed dose i s el i mi nat ed vi a f eces
wi t hi n 3 days.
3. Decay dat a
a.
99m
Tc decays by i somer i c t r ansi t i on wi t h a physi cal hal f -l i f e of 6 hr .
b. The pri mar y r adi at i on emi ssi ons ar e 140 keV v energy phot ons.
4. Puri t y
a. USP radi onucl i di c puri t y r equi r es a
99
Mo br eakt hr ough l i mi t of < 0. 15
µCi / mCi of
99m
Tc at t he t i me of pat i ent admi ni st r at i on.
b. USP chemi cal pur i t y requi r es an al umi num i on ( Al
+3
) t est r esul t of l ess
t han 10 µg/ mL.
5. Admi ni st rat i on and dosage. Al l of t he f ol l owi ng i magi ng st udi es ar e
admi ni st er ed vi a Ì V, except nasol acri mal i magi ng, whi ch i s i nst i l l ed i nt o t he
l acri mal canal .
a. Br ai n i magi ng: 10- 20 mCi (370-740 megabecquer el s; MBq)
b. Thyr oi d i magi ng: 1-10 mCi ( 37-370 MBq)
c. Sal i var y gl and i magi ng: 1-5 mCi (37- 185 MBq)
d. Pl acent a l ocal i zat i on: 1- 3 mCi (37-111 MBq)
e. Bl ood- pool i magi ng: 10- 30 mCi ( 370- 740 MBq)
f . Ur i nar y bl adder i magi ng: 0. 5- 1 mCi ( 18- 37 MBq)
g. Nasol acri mal i magi ng: < 100 µCi ( < 3. 7 MBq)
III. RADIOPHARMACEUTICALS FOR
CARDIOVASCULAR IMAGING
A. Perf usi on agent s f or cardi ac i magi ng. Radi opharmaceut i cal s ar e
usef ul i n car di ac i magi ng as agent s t hat pr ovi de i nf ormat i on on t he r egi onal
myocar di al bl ood perf usi on. They t ypi cal l y ar e admi ni st er ed as par t of a
car di ac st r ess t est so as t o pr ovi de i nf ormat i on at peak cardi ac out put . The
pat i ent wi l l run on a t r eadmi l l t o "st ress¨ t he heart . Ì V coronar y vessel
di l at i ng agent s are used i n pl ace of t he t r eadmi l l when t he pat i ent i s not
physi cal l y abl e t o exer ci se. Exampl es of t hese phar macol ogi cal agent s ar e
di pyr i damol e, adenosi ne, and dobut ami ne. The pat i ent wi l l al so be i maged
when t he hear t i s at "r est . ¨
1. ThaI I ous chI ori de t haI I i um- 201 (
201
TI ) i s a r adi onucl i de t hat i s produced
by a cycl ot r on. Ì t i s used f or myocar di al perf usi on i magi ng i n t he di agnosi s
of cor onar y art er y di sease and l ocal i zat i on of myocar di al i nf arct i on.
P. 443


a. Bi odi st ri but i on
( 1)
201
Tl i s a monoval ent cat i on wi t h di st r i but i on anal ogous t o a pot assi um
i on ( K
+
) ; myocar di al upt ake i s by act i ve t r anspor t vi a t he Na
+
/ K
+
-adenosi ne
t r i phosphat ase (ATPase) pump.
( 2) Bi odi st ri but i on i s gener al l y pr opor t i onal t o or gan bl ood f l ow at t he t i me
of i nj ect i on, wi t h bl ood cl earance by myocar di um, ki dneys, t hyr oi d, l i ver ,
and st omach. The remai nder i s di st ri but ed uni f orml y t hr oughout t he r est of
t he body.
( 3)
201
Tl i s excr et ed sl owl y and equal l y i n bot h ur i ne and f eces.
b. Decay dat a
( 1) Physi caI haI f -I i f e: 73 hr
( 2) Ef f ect i ve haI f - I i f e: 2. 4 days
( 3) Bi oI ogi caI haI f- I i fe: 11 days
( 4) Pri mar y radi at i on emi ssi ons: 68- 80 keV x- r ays and 167 and 135 keV v
energy phot ons.
c. Admi ni st rat i on and dosage. Ì V, 2-4 mCi (74- 148 MBq)
2.
99m
Tc sest ami bi (
99m
Tc- MI BI ) exi st s as a st er i l e, pyr ogen-f r ee Ì V
i nj ect i on af t er ki t r econst i t ut i on wi t h Na
+99m
TcO4
-
and heat i ng at 100°C f or
10 mi n.
a. Bi odi st ri but i on
( 1)
99m
Tc sest ami bi i s a cat i on compl ex t hat has been f ound t o accumul at e
i n vi abl e myocardi um by passi ve di f f usi on i nt o t he myocyt e wi t h subsequent
bi ndi ng t o t he mi t ochondr i a wi t hi n t he cel l .
( 2) The maj or pat hway f or cl ear ance of
99m
Tc sest ami bi i s t he hepat obi l i ar y
syst em. Thi s agent i s excr et ed wi t hout any evi dence of met abol i sm vi a
ur i ne and f eces.
b. Decay dat a
( 1) Ef f ect i ve haI f - I i f e: 3 hr (myocar di um)
( 2) Bi oI ogi caI haI f- I i fe: 6 hr (myocar di um)
c. Admi ni st rat i on and dosage. Ì V, 10- 30 mCi ( 370- 1110 MBq)
3.
99m
Tc t et rof osmi n exi st s as a st er i l e and pyr ogen- f r ee Ì V i nj ect i on af t er
ki t r econst i t ut i on wi t h sodi um per t echnet at e
99m
Tc i nj ect i on USP.
a. Descri pti on.
99m
Tc t et r of osmi n i s a l i pophi l i c, cat i oni c
99m
Tc compl ex t hat
has been f ound t o accumul at e i n vi abl e myocar di um.
b. Bi odi st ri but i on. The maj or pat hways f or cl earance of
99m
Tc t et r of osmi n
ar e t he renal syst em and t he hepat obi l i ar y syst em wi t h 26% of t he
admi ni st er ed dose excr et ed i n t he f eces and 40% excr et ed i n t he uri ne
wi t hi n 48 hr.
c. Physi caI propert i es. See Ì Ì . A; Ì Ì . B. 3.
d. Admi ni st rat i on and dosage. Ì V dur i ng exer ci se, 5-8 mCi (185-296 MBq) ;
dur i ng rest , 15- 24 mCi (555-1443 MBq)
4. Rubi di um- 82 (
82
Rb) chI ori de i s a generat or -produced
r adi ophar maceut i cal obt ai ned by t he decay of i t s accel er at or -pr oduced
par ent st r ont i um (
82
Sr; hal f -l i f e i s 25 days) adsorbed on a st annous oxi de
col umn.
a. Bi odi st ri but i on
( 1) When el ut ed wi t h 0. 9% NaCl at a r at e of 50 mL/ mi n, a sol ut i on of t he
short - l i ved daught er
82
Rb i s el ut ed f r om t he gener at or f or di rect Ì V
admi ni st rat i on.
( 2) Af t er Ì V admi ni st r at i on,
82
Rb r api dl y cl ear s f r om t he bl ood and i s
ext r act ed by t he myocardi al t i ssue i n a manner anal ogous t o K
+
.
( 3) Myocar di al act i vi t y i s vi sual i zed wi t hi n 1 mi n af t er admi ni st r at i on.
b. Decay dat a
( 1) Physi caI haI f -I i f e: 75 sec.
( 2) The decay mode i s by posi t r on emi ssi on.
( 3) The pri mar y radi at i on emi ssi ons ar e anni hi l at i on 511 keV v ener gy
phot ons.
( 4) Parent
82
Sr and cont ami nant
85
Sr breakt hrough must be cl osel y
moni t ored. Accept abl e l evel s of st r ont i um br eakt hr ough are < 0. 02 µCi
82
Sr / mCi
82
Rb and < 0. 2 µCi
85
Sr / mCi
82
Rb.
c. Admi ni st rat i on and dosage. Ì V, 30- 60 mCi ( 1110-2220 MBq)
5. Ammoni a
13
N exi st s under a USP monogr aph as an on si t e cycl ot r on
pr oduced, st er i l e Ì V sol ut i on of
13
NH3, usef ul as a myocardi al per f usi on
agent .
P. 444


a. Decay dat a
( 1) Physi caI haI f -I i f e: 10 mi n.
( 2) Decay mode: posi t ron emi ssi on r esul t i ng i n t he product i on of t wo 511
keV anni hi l at i on v phot ons.
b. Bi odi st ri but i on
( 1) Af t er Ì V i nj ect i on, i t ci r cul at es as
13
NH3 but l ocal i zes i nt o t he myocyt es
vi a di f f usi on as
13
NH3. Ì t i s t hen met abol i zed t o gl ut ami ne and r et ai ned by
t he myocyt es.
( 2) Af t er Ì V i nj ect i on, i t i s cl ear ed r api dl y f r om t he bl ood; < 2% of t he
admi ni st er ed dose r emai ns af t er 5 mi n post i nj ect i on.
( 3) Ì t i s predomi nant l y met abol i zed t o
13
N- gl ut ami ne by di f f er ent or gans of
t he body.
( 4) Bet ween 10% and 20% i s excr et ed vi a t he r enal syst em.
c. Admi ni st rat i on and dosage. Ì V, 15- 20 mCi ( 555- 740 MBq)
B. Agent s used t o measure cardi ac functi on. Regi onal myocardi al wal l
mot i on
1.
99m
Tc- I abeI ed red bI ood ceI I s (
99m
Tc- RBCs) ar e used f or bl ood- pool
i magi ng, i ncl udi ng cardi ac f i r st - pass and gat ed equi l i bri um i magi ng
( r egi onal cardi ac wal l mot i on) .
a. Physi caI properti es. Aut ol ogous RBCs can be l abel ed by a number of
t echni ques t hat use t he Sn
++
r adi ol abel i ng met hod wi t h t hr ee gener al st eps.
( 1) The cel l s are t r eat ed wi t h Sn
++
t o pr ovi de an i nt r acel l ul ar sour ce of t he
r educi ng agent . Thi s st ep can be car ri ed out wi t h ei t her i n vi vo or i n vi t r o
l abel i ng pr ocedur es.
( 2) The next st ep i s t he removal of excess Sn
++
ei t her by chemi cal oxi dat i on
( i n vi t ro met hod) or by bi ol ogi cal cl earance (i n vi vo met hod) .
( 3) Al l of t he met hods i ncl ude t he addi t i on of sodi um pert echnet at e
(
99m
TcO4
-
) . Thi s
99m
Tc, whi l e i n t he +7 val ence st at e, crosses t he i nt act
er yt hr ocyt e membrane and bi nds t o i nt racel l ul ar hemogl obi n ( Hb) af t er
bei ng reduced by t he avai l abl e i nt r acel l ul ar Sn
++
.
b. Bi odi st ri but i on. Af t er Ì V i nj ect i on, t he l abel i ng RBCs di st r i but e wi t hi n
t he bl ood pool and ar e wel l mai nt ai ned i n t he bl ood pool wi t h a bi -
exponent i al whol e body cl ear ance of 2. 5- 2. 7 hr and 75- 176 hr ( e. g. , maj or
r out e of excr et i on i s vi a t he ur i ne) .
c. Admi ni st rat i on and dosage. Ì V, 10- 20 mCi ( 370- 740 MBq)
2. Pyrophosphat e i nj ect i on USP and phosphates USP. The maj or use f or
t hese agent s i n nucl ear medi ci ne i s as conveni ent and st abl e sources of
Sn
++
f or t he l abel i ng of aut ol ogous RBCs. Ì n t hi s appl i cat i on, t he ki t s ar e
r econst i t ut ed wi t h normal sal i ne and i nj ect ed vi a Ì V.
3.
99m
Tc aI bumi n (
99m
Tc- HSA) i nj ect i on
a. Bi odi st ri but i on
( 1)
99m
Tc al bumi n di st r i but es i ni t i al l y wi t hi n t he i nt r avascul ar space and
l eaves t hi s space at a r at e sl ow enough t o per mi t i magi ng of t he bl ood pool .
( 2) Pl asma cl earance i s bi - exponent i al : a f ast component cl ear i ng wi t h a
hal f - l i f e of 2 hr and a sl ow component cl ear i ng wi t h a hal f - l i f e of 10-16 hr .
( 3) The maj or rout e of el i mi nat i on i s vi a t he uri ne.
b. Admi ni st rat i on and dosage. Ì V, 20 mCi (740 MBq)
C. Agent s f or i magi ng myocardi aI i nf arcti on i ncl ude pyr ophosphat e
i nj ect i on USP and phosphat es USP.
1. Mechani sm of I ocaI i zat i on. The skel et al l ocal i zi ng r adi ophar maceut i cal
pyr ophosphat e has been shown t o accumul at e al so i n zones of myocardi al
i nf ar ct i on. Thi s l ocal i zat i on i s t hought t o be t he resul t of bi ndi ng of t he
pyr ophosphat e t o mi cr ocal ci f i cat i on wi t h hydr oxyapat i t e cr yst al s f ound i n
i nf ar ct ed t i ssue.
2. Bi odi st ri but i on of l abel ed pyr ophosphat e depends on t he abi l i t y of
phosphat es t o become i nvol ved wi t h cal ci um i on (Ca
++
) deposi t i on i n
necrot i c cardi ac t i ssue.
IV. SKELETAL IMAGING
A. SkeI et aI - i magi ng agent s
1. Overvi ew.
99m
Tc- l abel ed bone agent s ar e usef ul i n t he det ect i on of bone
l esi ons t hat are associ at ed wi t h met ast at i c neopl asms, met abol i c di sorder s,
and i nf ect i ons of t he bone. The i magi ng advant ages of
99m
Tc, coupl ed wi t h
t he sensi t i vi t y of bone agent l ocal i zat i on i n
P. 445

skel et al bone hydr oxyapat i t e, al l ows f or det ect i on of bone pat hol ogy bef or e
evi dence i s shown by convent i onal x- r ays.
2.
99m
Tc bone agent s. Ther e ar e many di f f erent f or ms of
99m
Tc bone
agent s, wi t h mi nor di f f erences i n t hei r i ndi vi dual chemi cal st r uct ur e.
Cur r ent l y used bone-i magi ng agent s ar e based on ei t her t he P÷C÷P
di phosphonat e st r uct ur e, i ncl udi ng
99m
medr onat e di sodi um and
99m
Tc
oxi dr onat e, or t he i norgani c P÷O÷P phosphat e st r uct ur e, such as
99m
Tc
pyr ophosphat e. These bone agent s are S
++
reduct i on met hod ki t s, whi ch
exi st as st er i l e, pyr ogen-f r ee Ì V r adi ophar maceut i cal s af t er r econst i t ut i on
wi t h Na
+99m
TcO4
-
.
a. Physi caI properti es
( 1) Al l of t he
99m
Tc bone- i magi ng agent s are suscept i bl e t o radi ol ogi cal
decomposi t i on wi t h r eoxi dat i on of t he
99m
Tc t o a hi gher val ence st at e.
These agent s somet i mes i ncl ude ant i oxi dant s (e. g. , ascor bi c or gent i si c
aci d) i n t hei r f or mul at i on t o i mpr ove t hei r i n vi t ro st abi l i t y.
( 2) They shoul d be st or ed at r oom t emperat ure bef or e and af t er
r econst i t ut i on.
b. Bi odi st ri but i on
( 1) Ì t i s bel i eved t hat t he l ocal i zat i on of t he di phosphonat es occur s by
chemi sorpt i on ont o t he hydr oxyapat i t e mi ner al mat r i x of skel et al bone wi t h
upt ake r el at ed t o bone met abol i c act i vi t y and bone bl ood f l ow.
( 2) For
99m
Tc medronat e di sodi um and
99m
Tc oxi dr onat e, approxi mat el y 50%
of t he admi ni st er ed dose l ocal i zes i n t he skel et on, and 50% i s excr et ed by
t he ki dneys wi t hi n t he f i rst 4- 6 hr af t er Ì V i nj ect i on.
c. Admi ni st rat i on and dosage. Ì V, 10- 20 mCi ( 370- 740 MBq)
B. Bone marrow i magi ng. See VÌ . A. 1; VÌ . A. 3; VÌ . B.
V. LUNG IMAGING.
Radi ophar maceut i cal s are used t o eval uat e bot h pul monar y per f usi on and
pul monar y vent i l at i on, t o det ect pul monar y embol i sm and t o assess
pul monar y f unct i on bef ore pneumonect omy.
A. PuI monar y perf usi on i magi ng
1.
99m
Tc aI bumi n (
99m
Tc- MAA)
a. Physi caI properti es
( 1) The
99m
Tc al bumi n aggr egat ed ki t cont ai ns HSA al bumi n t hat has been
aggregat ed by heat denat ur at i on.
( 2) Thi s Sn
++
reduct i on met hod ki t exi st s as a st er i l e, pyr ogen- f ree
suspensi on of r adi ol abel ed aggregat ed part i cl es af t er r econst i t ut i on wi t h
Na
+99m
TcO4
-
.
( 3) Ì t shoul d be st or ed at 2°- 8°C af t er r econst i t ut i on.
b. Bi odi st ri but i on
( 1) Af t er Ì V admi ni st r at i on of
99m
Tc al bumi n aggr egat ed, 80% of t he
r adi ol abel ed al bumi n part i cl es become t r apped by capi l l ar y bl ockade i n t he
pul monar y ci r cul at i on.
( 2) Af t er t rappi ng, t he par t i cl es are cl ear ed f rom t he l ungs mai nl y by
mechani cal breakup. These smal l er par t i cl es ar e ul t i mat el y cl eared f r om t he
ci rcul at i on by t he r et i cul oendot hel i al syst em.
( 3) Part i cl e si ze shoul d be cont r ol l ed÷t hat i s, 90% of t he par t i cl es shoul d
be bet ween 10 and 90 µm, and none shoul d be > 150 µm, t o ensure
adequat e t rappi ng by t he l ung capi l l ar y bed but no occl usi on of t he l ar ge-
bor e vessel s.
( 4) Part i cl e number shoul d be bet ween 200, 000 and 700, 000 par t i cl es per
adul t dose t o obt ai n uni f or m i magi ng dat a wi t hout compr omi si ng capi l l ar y
bl ood f l ow. Neonat es shoul d r ecei ve < 125, 000 par t i cl es.
c. Decay dat a. Bi ol ogi cal hal f -l i f e i n t he l ung: 2- 3 hr
d. Admi ni st rat i on and dosage. Ì V, 1-4 mCi (37- 148 MBq)
B. PuI monar y vent i I at i on i magi ng wi t h r adi oact i ve gases i s a r out i ne
nucl ear medi ci ne pr ocedur e t hat can pr ovi de val uabl e i nf ormat i on about
r egi onal l ung vent i l at i on. Radi ophar maceut i cal s used ar e ei t her r adi oact i ve
gases or radi oaer osol s.
1. Xenon-133 (
133
Xe) i s suppl i ed as a radi oact i ve gas cont ai ned i n gl ass
sept um vi al s t o be admi ni st er ed by i nhal at i on t hr ough a cl osed r espi r at or y
syst em or a spi r omet er . Ì t i s a bypr oduct of
235
U f i ssi on.
P. 446


a. Bi odi st ri but i on
( 1)
133
Xe i s a readi l y di f f usi bl e gas, whi ch i s nei t her used nor pr oduced by
t he body. Ì t passes t hr ough membr anes and f r eel y exchanges bet ween
bl ood and t i ssue, t endi ng t o concent rat e mor e i n body f at .
( 2) Ì nhal ed
133
Xe di st r i but es wi t hi n t he al veol i and ent er s t he pul monar y
venous ci rcul at i on vi a t he capi l l ar i es; most of t he absor bed
133
Xe i a
r et urned and exhal ed f rom t he l ungs af t er a si ngl e pass t hrough t he
per i pheral ci r cul at i on.
( 3) Ì n concent r at i ons used f or di agnosi s, t he gas i s physi ol ogi cal l y i nact i ve.
b. Decay dat a
( 1) Ef f ect i ve haI f - I i f e i n t he l ung: 2 mi n
( 2) Physi caI haI f -I i f e: 5. 2 days.
( 3) Decay mode: 8 mi nus and v decay.
( 4) Pri mar y radi at i on emi ssi ons: 100 keV 8 ener gy and 81 keV v energy
phot ons.
c. Admi ni st rat i on and dosage. Ì nhal at i on, 2- 30 mCi (74- 1110 MBq)
2. Xenon-127 (
127
Xe) i s suppl i ed as a radi oact i ve gas cont ai ned i n gl ass
sept um vi al s t o be admi ni st er ed by i nhal at i on t hr ough a cl osed r espi r at or y
syst em or a spi r omet er . Ì t i s produced by a cycl ot r on.
a. Bi odi st ri but i on. Local i zat i on i s t he same as
133
Xe.
b. Decay dat a
( 1) Physi caI haI f -I i f e: 36. 4 days
( 2) Decay mode: by el ect r on capt ure
( 3) Pri mar y radi at i on emi ssi ons: 203 keV, 190 keV, 172 keV, and 375 keV
v ener gy phot ons.
c. Admi ni st rat i on and dosage. Ì nhal at i on, 5- 10 mCi (185-370 MBq)
3. Radi oaerosoI s have become i ncreasi ngl y used wi t h t he advent of
nebul i zers t hat produce par t i cl es of a consi st ent si ze necessar y f or uni f orm
l ung di st ri but i on.
a. Bi odi st ri but i on
( 1)
99m
Tc pent et at e ( DTPA) r adi oaer osol s of approxi mat el y 0. 25 µm mass
medi an aer odynami c di amet er are usef ul i n det ermi ni ng l ung vent i l at i on.
( 2) Af t er deposi t i on of t he nebul i zed dr opl et s wi t hi n t he ai r ways, t he
99m
Tc
pent et at e i s absorbed i nt o t he pul monar y ci r cul at i on.
( 3) The mat er i al i s subsequent l y excr et ed by t he ki dneys. Cl ear ance f rom
t he l ungs i s suf f i ci ent l y sl ow t o al l ow f or i magi ng of t he l ungs i n mul t i pl e
pr oj ect i ons f r om a si ngl e admi ni st r at i on.
b. Physi caI properti es. See Ì Ì . B. 3.
c. Admi ni st rat i on and dosage. Ì nhal at i on, 30 µCi ( 1110 MBq)
VI. HEPATIC IMAGING
A. Over vi ew. Hepat i c i magi ng requi r es t he use of t wo di f f er ent cl asses of
r adi ophar maceut i cal s t o eval uat e t he t wo cel l t ypes responsi bl e f or hepat i c
f unct i on.
1. Ret i cuI oendot heI i aI syst em i magi ng. The l i ver , spl een, and bone
mar row ar e eval uat ed wi t h r adi ol abel ed col l oi dal mat er i al , rangi ng i n si ze
f r om 0. 1 t o 3. 0 µm. These part i cl es ar e r api dl y cl ear ed f rom t he bl ood by
phagocyt osi s by t he Kupf f er cel l s or t r apped i n t he space of Di sse, whi ch i s
f ound bet ween t he pol ygonal hepat ocyt es and t he Kupf f er cel l s.
2. Li ver spI een i magi ng. Radi opharmaceut i cal s ar e usef ul i n i magi ng
space-occupyi ng pri mar y t umors and met ast at i c neopl asms as wel l as
hepat i c def ect s caused by abscesses, cyst s, and t r auma.
3. Bone marrow i magi ng. Ì mages t hat l ocal i ze i n t he bone mar r ow ar e
usef ul i n t he eval uat i on of pat hol ogi es t hat af f ect bone mar row.
4. Hepat obi I i ar y i magi ng. Hepat ocyt e f unct i on can be eval uat ed by
subst ances meet i ng r equi r ement s of mol ecul ar wei ght , l i pophi l i ci t y, and
chemi cal st r uct ur e, t o be excr et ed by t he pol ygonal cel l s i nt o t he
hepat obi l i ar y syst em. Hepat obi l i ar y-i magi ng radi opharmaceut i cal s ar e
usef ul i n t he di agnosi s of cyst i c duct obst ruct i on i n acut e chol ecyst i t i s as
wel l as def i ni ng post chol ecyst ect omy anat omy and physi ol ogy.
P. 447


B. Ret i cuI oendotheI i aI -i magi ng agents
1.
99m
Tc suI f ur coI I oi d (
99m
Tc2S7) i s a st er i l e, pyr ogen- f r ee Ì V
r adi ophar maceut i cal f ormed vi a a chemi cal r eact i on bet ween
99m
TcO4
-
and
an aci di f i ed sol ut i on of sodi um t hi osul f at e at 100°C.
a. Physi caI properti es
( 1) Tc2S7 i s t hought t o remai n i n t he +7 val ence st at e as t he hept asul f i de
copreci pi t at e of el ement al sul f ur t hat occur s dur i ng t he react i on.
( 2) The use of Na
+99m
TcO4
-
wi t h Al
+3
l evel s > 10 µg/ mL can l ead t o t he
f or mat i on of par t i cl es > 5 µm, whi ch can resul t i n l ung upt ake.
( 3) Heat i ng t i mes shoul d be cont r ol l ed t o precl ude l ar ge part i cl e f ormat i on.
b. Bi odi st ri but i on. Af t er admi ni st r at i on, 80%-90% of t he dose i s
phagocyt i zed by t he Kupf f er cel l s of t he l i ver or t r apped i n t he space of
Di sse, 5%-10% by t he spl een, and t he bal ance by t he bone mar row. The
bl ood cl ear ance hal f -l i f e i s approxi mat el y 2. 5 mi n. Par t i cl es are not
met abol i zed and resi de i n t he r et i cul oendot hel i al syst em f or a prol onged
per i od.
c. Admi ni st rat i on and dosage. Ì V, l i ver / spl een: 1- 8 mCi (37-296 MBq) ;
bone mar r ow: 3-12 mCi (111-444 MBq)
C. Hepatobi I i ar y- i magi ng agent s
1. Overvi ew
a. I mi nodi acet i c aci d (I DA) deri vat i ves, whi ch ar e l i docai ne anal ogs, are
usef ul as hepat obi l i ar y- i magi ng agent s because of t hei r l i pophi l i ci t y, whi ch
al l ows t hem t o be sel ect i vel y cl ear ed by car ri er -medi at ed hepat ocyt e
met abol i c pat hways. Because t hese agent s shar e t he same excr et i on
pat hway as bi l i rubi n, pat i ent s who have i ncr eased bi l i rubi n l evel s exhi bi t
decreased hepat i c cl earance and an i ncr eased renal cl ear ance. Lack of
gal l bl adder vi sual i zat i on i s an abnor mal f i ndi ng, suggest i ng acut e
chol ecyst i t i s.
b. ChoI ecyst oki net i c agent s, such as si ncal i de and chol ecyst oki ni n, may
be used t o empt y t he cont ent s of t he gal l bl adder i n f ast i ng pat i ent s bef ore
i nj ect i on of Ì DA compounds i n an at t empt t o pr omot e gal l bl adder f i l l i ng and
vi sual i zat i on. These agent s can al so be i nj ect ed af t er t he i nj ect i on of t he
Ì DA compound t o cause a vi sual i zed gal l bl adder t o empt y.
Chol ecyst oki net i c agent s ar e used t o i ncr ease t he speci f i ci t y and sensi t i vi t y
of t he i magi ng pr ocedur e.
c. Narcot i c anaI gesi cs, such as morphi ne, have been used t o const r i ct t he
sphi nct er of Oddi t o pr oduce i ncr eased i nt raduct al pressures t o pr omot e
r et r ogr ade gal l bl adder f i l l i ng.
2.
99m
Tc di sofeni n (
99m
Tc- DI SI DA)
a. Physi caI properti es. See Ì Ì . B. 3.
b. Bi odi st ri but i on
( 1)
99m
Tc- DÌ SÌ DA i s r api dl y cl eared f r om t he bl ood; 8% r emai ns i n t he bl ood
af t er 30 mi n.
( 2) Appr oxi mat el y 9% of t he admi ni st er ed act i vi t y i s excr et ed i n t he uri ne
dur i ng t he f i rst 2 hr. The r emai nder of t he act i vi t y i s cl eared t hr ough t he
hepat obi l i ar y syst em.
( 3) Peak l i ver upt ake i s wi t hi n 10 mi n; peak gal l bl adder upt ake i s by 30- 40
mi n.
( 4) Gal l bl adder and i nt est i nal vi sual i zat i on occur s wi t hi n 60 mi n
post admi ni st r at i on.
c. Admi ni st rat i on and dosage. Ì V, nonj aundi ced pat i ent : 1- 5 mCi (37-185
MBq) ; Ì V, j aundi ced pat i ent : 3- 8 mCi ( 111- 296 MBq)
3.
99m
Tc mebrofeni n
a. Physi caI properti es. See Ì Ì . B. 3.
b. Bi odi st ri but i on
( 1)
99m
Tc mebrof eni n i s rapi dl y cl ear ed f r om t he bl ood; 17% remai ns af t er
10 mi n. Onl y 1% of t he admi ni st ered act i vi t y i s excr et ed i n t he ur i ne wi t hi n
t he f i rst hours; t he r emai nder of t he act i vi t y cl ears t hr ough t he hepat obi l i ar y
syst em.
( 2) Peak l i ver upt ake occur s wi t hi n 10 mi n; vi sual i zat i on of t he hepat i c duct
and gal l bl adder, wi t hi n 10- 15 mi n; t hen i nt est i nal act i vi t y, wi t hi n 30- 60 mi n.
c. Admi ni st rat i on and dosage. Ì V, nonj aundi ced pat i ent : 2- 5 mCi (74-185
MBq) ; Ì V, j aundi ced pat i ent : 3- 10 mCi (111-370 MBq)
P. 448


VII. RENAL IMAGING
A. Over vi ew
1. Radi ophar maceut i cal s ar e used i n renal i magi ng t o det ermi ne r enal
f unct i on, r enal vascul ar f l ow, and r enal morphol ogy. They ar e al so usef ul
f or t he eval uat i on of renal f unct i on i n post t ranspl ant pat i ent s f or
compl i cat i ons such as obst ruct i on, i nf ar ct i on, l eakage, t ubul ar necrosi s,
and rej ect i on.
2. The use of r adi opharmaceut i cal s t o det ermi ne r enal f unct i on or r enal
mor phol ogy i s based on t he t wo physi ol ogi cal mechani sms responsi bl e f or
excr et i on: gl omer ul ar f i l t r at i on and t ubul ar secr et i on.
B. Agent s cI eared by gI omeruI ar f i I t rat i on are usef ul i n det ermi ni ng t he
gl omerul ar f i l t rat i on rat e ( GFR) , r enal ar t er y perf usi on, and t he vi sual i zat i on
of t he col l ect i ng syst em.
1.
99m
Tc pent etat e (
99m
Tc- DTPA)
a. Physi caI properti es. See Ì Ì . B. 3.
b. Bi odi st ri but i on
( 1) Af t er admi ni st r at i on,
99m
Tc pent et at e rapi dl y di st ri but es t hr oughout
ext r acel l ul ar f l ui d space, f r om whi ch i t i s r api dl y cl ear ed by gl omerul ar
f i l t rat i on onl y.
( 2) Up t o 10% may be prot ei n bound, l eadi ng t o a decr ease i n measur ed
GFR.
( 3) Af t er admi ni st r at i on, 50% of t he dose i s cl eared by t he ki dneys wi t hi n 2
hr , and up t o 95% i s cl ear ed by 24 hr .
c. Admi ni st rat i on and dosage. Ì V, 10- 20 mCi ( 370- 740 MBq)
2. Sodi um i ot haI amate i odi ne- 125 (
125
I ) i nj ect i on i s a commerci al l y
suppl i ed, st er i l e, pyr ogen- f r ee i nj ect i on cont ai ni ng 1 mg sodi um i ot hal amat e
per mi l l i l i t er .
a. Bi odi st ri but i on
( 1) Sodi um i ot hal amat e
125
Ì i s used f or det er mi nat i on of t he GFR but not f or
i magi ng because of poor i magi ng emi ssi ons of
125
Ì .
( 2) Thyr oi d bl ockade wi t h or al pot assi um i odi de (KÌ ) i s suggest ed.
b. Decay dat a
( 1) Physi caI haI f -I i f e: 59 days
( 2) Decay mode: by el ect r on capt ure
( 3) Pri mar y radi at i on emi ssi ons: 35 keV v energy phot ons and x- r ays.
c. Admi ni st rat i on and dosage. Ì V, 10- 50 µCi (3. 7- 18. 5 MBq)
C. TubuI ar secret i on agent s ar e used t o eval uat e r enal t ubul ar f unct i on
and measur e ef f ect i ve r enal pl asma f l ow.
1. I odohi ppurat e i odi ne- 131 (
131
I ) hi ppuran. No l onger commer ci al l y
avai l abl e
2.
99m
Tc mert i ati de (
99m
Tc- MAG3)
a. Descri pti on
( 1) Suppl i ed as a st er i l e, pyr ogen- f ree, l yophi l i zed ki t cont ai ni ng bet i at i de,
pr ecur sor of mer t i at i de, and chel at i on adj ut ant s.
( 2) Af t er t he sodi um per t echnet at e i s added t o t he ki t , i t must be heat ed i n
a hot wat er bat h or heat i ng bl ock at 100°C f or 10 mi n t o f orm
99m
Tc
mer t i at i de f r om t he bet i at i de pr ecur sor .
b. Bi odi st ri but i on
( 1) Mer t i at i de i s r enal l y excr et ed, 90% of t he admi ni st er ed dose i s excr et ed
wi t hi n 3 hr post i nj ect i on.
( 2) Ì t i s pri mar i l y cl eared vi a act i ve t ubul ar secr et i on and t o a smal l ext ent
vi a gl omer ul ar f i l t r at i on.
c. Physi caI propert i es. See Ì Ì . B. 3.
d. Admi ni st rat i on and dosage. Ì V, 5-10 mCi ( 185- 370 MBq)
D. RenaI corti caI i magi ng agents are used t o eval uat e r enal anat omy
because of t hei r abi l i t y t o accumul at e i n t he ki dney and pr ovi de anat omi cal
i magi ng dat a.
1.
99m
Tc gI ucept ate (
99m
Tc- GLH)
a. Physi caI properti es. See Ì Ì . B. 3.
b. Bi odi st ri but i on
P. 449


( 1)
99m
Tc- GLH r api dl y di st r i but es t hroughout t he body, wi t h rapi d bl ood
cl ear ance vi a gl omer ul ar f i l t r at i on and t ubul ar secr et i on and reabsorpt i on.
( 2) Appr oxi mat el y 25% of t he admi ni st er ed dose i s excr et ed wi t hi n t he f i rst
hour ; 65%, wi t hi n 6 hr; and 70%, wi t hi n 24 hr .
( 3) Af t er 3- 6 hr , a maxi mum of 5%- 15% of t he dose admi ni st er ed i s
concent r at ed i n t he proxi mal r enal t ubul ar cel l s of t he r enal cort ex.
c. Admi ni st rat i on and dosage. Ì V, 10- 20 mCi ( 370- 740 MBq)
2.
99m
Tc succi mer (
99m
Tc- DMSA)
a. Physi caI properti es
( 1) See Ì Ì . B. 3.
( 2)
99m
Tc succi mer compl ex must be al l owed t o i ncubat e f or 10 mi n
post r econst i t ut i on and must be used wi t hi n 4 hr post i ncubat i on.
b. Bi odi st ri but i on
( 1) Wi t hi n 3- 6 hr post admi ni st r at i on, 40%-50% of t he dose l ocal i zes i n t he
r enal cor t ex, wher e i t i s t aken up by t he t ubul ar cel l s.
( 2) Excr et i on i nt o t he ur i ne i s sl ow; 5%- 20% i s excr et ed wi t hi n t he f i rst 2 hr ,
10%-30% by 6 hr , and < 40% by 24 hr .
c. Admi ni st rat i on and dosage. Ì V, 2-6 mCi (74- 222 MBq)
VIII. THYROID IMAGING
A. Over vi ew
1. The basi c f unct i on of t he t hyr oi d gl and i s t he pr oduct i on of t hyr oi d
hor mone f or t he r egul at i on of met abol i sm. The t hyr oi d hormones ar e
pr oduced wi t hi n t he gl and t hrough t he or gani f i cat i on of i odi ne obt ai ned f rom
t he oxi dat i on of avai l abl e i odi de ci rcul at i ng i n t he bl ood. The i nabi l i t y of t he
body t o di st i ngui sh bet ween t he i sot opes of i odi ne pr ovi des a perf ect
met abol i c t racer f or t he t hyr oi d bi ochemi cal syst em.
2. The f unct i on of t he t hyr oi d gl and can be eval uat ed by t he upt ake of
131
Ì
or
123
Ì , al l owi ng t he det ect i on of hypot hyr oi di sm wi t h decr eased upt ake and
hyper t hyr oi di sm wi t h i ncreased upt ake.
3.
99m
TcO4
-
i s a monoval ent ani on wi t h an i oni c radi us si mi l ar t o i odi de. As
a r esul t , t he per t echnet at e i on i s t r apped by t he t hyr oi d gl and i n a f ashi on
si mi l ar t o i odi de. The t wo speci es ar e suf f i ci ent l y di f f er ent i n t hat
99m
TcO4
-

i s not or gani f i ed or i ncorpor at ed i nt o t hyr oi d hormone, and i t i s
subsequent l y rel eased unchanged.
B. Thyroi d i magi ng agent s
1. Sodi um i odi de i odi ne- 123 (
123
I ) i s a radi ophar maceut i cal avai l abl e i n
ei t her sol ut i on or capsul e f orm f or or al admi ni st rat i on. Ì t i s pr oduced by a
cycl ot r on.
a. Bi odi st ri but i on
( 1) Or al l y admi ni st er ed i odi ne i s rapi dl y absor bed f r om t he gast r oi nt est i nal
( GÌ ) t r act ; t hyr oi d gl and upt ake i s evi dent wi t hi n mi nut es.
( 2) Sodi um i odi de
123
Ì i s consi dered an i deal radi ophar maceut i cal f or i odi ne
upt ake and i magi ng st udi es because of i t s shor t hal f - l i f e and usef ul 159 keV
pr i mar y v emi ssi ons.
b. Decay dat a
( 1) Physi caI haI f -I i f e: 13. 2 hr
( 2) Bi oI ogi caI haI f- I i fe: 3. 5 days
( 3) Decay mode: by el ect r on capt ure
( 4) Pri mar y radi at i on emi ssi ons: 159 keV, 27 keV, and 529 keV v ener gy phot ons
c. Admi ni st rat i on and dosage. Or al t hyr oi d upt ake: 100- 200 µCi ( 3. 7- 7. 4 MBq) ;
t hyr oi d i mage: 100- 500 µCi ( 3. 7- 18. 5 MBq)
2. Sodi um i odi de
131
I i s used f or t hyr oi d upt ake and i magi ng st udi es; however , i t i s
now used l ess of t en because of t he hi gh r adi at i on dose absorbed.
a. Bi odi st ri but i on
( 1) Or al l y admi ni st er ed i odi ne i s rapi dl y absor bed f r om t he GÌ t r act ; wi t h t hyr oi d
gl and upt ake i s wi t hi n mi nut es.
P. 450


( 2) Sodi um i odi de
131
Ì i s not consi dered an i deal radi oi odi ne radi opharmaceut i cal f or
i odi ne upt ake and i magi ng st udi es because of i t s l ong hal f - l i f e, poor i magi ng
pr oper t i es, and t he hi gh r adi at i on dose t o t he t hyr oi d f r om i t s 8 decay component .
( 3) The radi at i on dose f rom t he hi gh- energy 8 par t i cl e wi t h t he i magi ng pot ent i al of
i t s v emi ssi ons make t hi s r adi onucl i de t he agent of choi ce f or t her apeut i c t r eat ment
of hyper t hyr oi di sm and t hyr oi d cancer .
b. Decay dat a
( 1) Physi caI haI f -I i f e: 8. 08 days
( 2) Decay mode: by 8 decay
( 3) Pri mar y radi at i on emi ssi ons: 606 keV and 333 keV 8 ener gy; 364 keV, 637
keV, and 284 keV v energy phot ons.
c. Admi ni st rat i on and dosage.
131
Ì i s avai l abl e as ei t her a capsul e or i n sol ut i on
f or oral admi ni st r at i on.
( 1) Di agnost i cs
( a) Thyr oi d upt ake: 2- 15 µCi ( 0. 074-0. 555 MBq)
( b) Thyr oi d i mage: 30- 50 µCi ( 1. 11-1. 85 MBq)
( c) Whol e body i mage: 1- 5 mCi ( 37- 185 MBq)
( 2) Therapeut i cs
( a) Hyper t hyr oi di sm: 10-30 mCi (370-1110 MBq)
( b) Thyr oi d carci noma: 50- 200 mCi ( 1850- 7400 MBq)
3. Na
+99m
TcO4
-
. See Ì Ì . B.
4.
201
TI . Parat hyr oi d i magi ng
a. Bi odi st ri but i on.
201
TÌ concent rat es i n t he t hyroi d and al so i n par at hyr oi d
adenomas, whi ch can be det ect ed by a dual i sot ope subt r act i on t echni que of
subt r act i ng t hyr oi d upt ake count s f r om Na
+99m
TcO4
-
t o unmask nont hyr oi d t hal l i um
upt ake count s (see Ì Ì Ì . A. 1) .
b. Admi ni st rat i on and dosage. Ì V, 2 mCi ( 74 MBq)
IX. BRAIN IMAGING
A. CerebraI perf usi on brai n- i magi ng agent s. Radi ophar maceut i cal s f or eval uat i ng
br ai n per f usi on must possess a l i pophi l i c par t i t i on coef f i ci ent suf f i ci ent t o di f f use
passi vel y acr oss t he bl ood- brai n bar r i er ( BBB) al most compl et el y wi t hi n one pass of
t he cerebr al ci rcul at i on, as wel l as bei ng suf f i ci ent l y r et ai ned t o permi t dat a
col l ect i on. The r egi onal upt ake of t hese agent s i s propor t i onal t o cer ebr al bl ood
f l ow. Thi s cl ass of r adi opharmaceut i cal s i s usef ul i n t he di agnosi s of al t ered
r egi onal bl ood per f usi on i n st r oke.
1.
99m
Tc examet azi me (
99m
Tc- HMPAO) exi st s as a st er i l e, pyr ogen- f r ee Ì V i nj ect i on
af t er r econst i t ut i on wi t h sodi um per t echnet at e USP, whi ch may be st abi l i zed wi t h
t he addi t i on of a met hyl ene bl ue/ phosphat e buf f er st abi l i zi ng sol ut i on.
a. Descri pti on
( 1)
99m
Tc examet azi me i s a neut r al , l i pi d-sol ubl e compl ex t hat f reel y cr osses t he
BBB. Thi s i s a rel at i vel y unst abl e compl ex, whi ch r api dl y convert s t o a secondar y,
l ess l i pophi l i c compl ex i ncapabl e of penet rat i ng i nt o t he br ai n. The i n vi t ro addi t i on
of a met hyl ene bl ue/ phosphat e buf f er st abi l i zi ng sol ut i on af t er prepar i ng t he
99m
Tc
examet azi me wi l l st abi l i ze t he l i pi d-sol ubl e compl ex f or 4 hr .
( 2) Addi t i onal l i mi t at i ons on ki t preparat i on paramet er s r equi re t he use of hi gh mol e
f r act i on t echnet i um gener at or el uat es of < 2 hr post el ut i on f rom a gener at or
pr evi ousl y el ut ed wi t hi n 24 hr.
b. Bi odi st ri but i on
( 1)
99m
Tc examet azi me rapi dl y cl ear s f r om t he bl ood, wi t h a maxi mum br ai n upt ake
of 3. 5%-7%, and up t o 2. 5% r emai ni ng af t er 24 hr.
( 2) The act i vi t y i s wi del y di st r i but ed t hr oughout t he body; 30% di st ri but es t o t he GÌ
t r act .
( 3) Wi t hi n 48 hr , 40% of t he dose i s excr et ed t hrough t he ur i ne and 15% i s
el i mi nat ed vi a t he f eces.
c. Physi caI propert i es. See Ì Ì . B. 3.
d. Admi ni st rat i on and dosage. Ì V, 10- 20 mCi ( 370- 740 MBq)
P. 451


2.
99m
Tc bi ci sat e (
99m
Tc- ECD)
a. Descri pti on
( 1)
99m
Tc bi ci sat e exi st s as a st eri l e, pyr ogen-f r ee Ì V i nj ect i on af t er r econst i t ut i on
wi t h sodi um per t echnet at e
99m
Tc USP and t he addi t i on of a phosphat e buf f er .
( 2) Af t er reconst i t ut i on, a st abl e l i pophi l i c
99m
Tc bi ci sat e compl ex i s f ormed, whi ch
i s abl e t o cr oss t he BBB by passi ve di f f usi on.
b. Bi odi st ri but i on
( 1)
99m
Tc bi ci sat e i s r api dl y cl eared f r om bl ood; a maxi mum of 6. 5% of t he
admi ni st er ed dose i s l ocal i zed i n t he brai n, and 5% i s l ef t i n t he bl ood af t er 1 hr .
( 2) Once l ocat ed i n t he br ai n cel l s,
99m
Tc bi ci sat e i s met abol i zed by endogenous
enzymes t o a pol ar compound t hat i s unabl e t o di f f use out of t he br ai n cel l s.
( 3)
99m
Tc bi ci sat e i s pri mar i l y el i mi nat ed vi a t he ki dneys; 50% i s excr et ed wi t hi n 2
hr , and 74% i n 24 hr . Hepat obi l i ar y excr et i on account s f or approxi mat el y 12. 5% of
t he admi ni st er ed dose af t er 48 hr.
c. Radi onucI i de properti es. See Ì Ì . B. 3.
d. Admi ni st rat i on and dosage. Ì V, 10- 30 mCi ( 370- 1110 MBq)
3. I ofet ami ne hydrochI ori de
123
I . Not commerci al l y avai l abl e
B. Carri er- medi at ed t ransport ( cerebraI metaboI i sm) mechani sms. These ar e
r esponsi bl e f or t r anspor t i ng gl ucose acr oss t he BBB. Agent s such as
18
F
f l udeoxygl ucose ai d i n t he eval uat i on of cer ebral f unct i on by mappi ng t he
di st r i but i on of gl ucose met abol i sm.
18
F f l udeoxygl ucose i s produced by a cycl ot ron.
1. Bi odi st ri but i on. Cur rent l y, t her e i s a USP monograph f or on-si t e cycl ot r on-
pr oduced
18
F f l udeoxygl ucose, whi ch i s a gl ucose anal og.
18
F f l udeoxygl ucose
concent r at es i n t he br ai n, wher e i t i s phosphor yl at ed but does not undergo
subsequent met abol i sm because of t he repl acement of t he hydr oxyl gr oup i n t he 2
posi t i on wi t h a f l uor i ne at om. Ì t i s t hen met abol i cal l y t rapped f or a suf f i ci ent t i me t o
al l ow i magi ng.
2. Decay dat a
a. Physi caI haI f -I i f e: 109. 7 mi n
b. Decay mode: by posi t r on emi ssi on
c. Pri mar y radi at i on emi ssi ons: 633 keV energy posi t rons and 511 keV v energy
phot ons.
3. Admi ni st rat i on and dosage. Ì V, 5-10 mCi ( 185- 370 MBq)
C. CerebraI neurot ransmi t t er i magi ng: FI uorodopa f I uori ne-18 (
18
F) i nj ecti on
1. Descri pti on
a. Cerebr al neurot r ansmi t t er synt hesi s can be st udi ed wi t h f l uorodopa
18
F i nj ect i on.
The i nt racer ebr al di st ri but i on of t hi s neur ot r ansmi t t er t r acer can be used i n t he
assessment of neur odegenerat i ve di seases such as parki nsoni sm.
b. Fl uorodopa
18
F i nj ect i on exi st s under a USP monogr aph as an on-si t e-pr oduced
st eri l e Ì V sol ut i on of a l evodopa anal og i n whi ch a port i on of t he mol ecul e has been
r epl aced wi t h
18
F, a posi t r on-emi t t i ng r adi onucl i de.
2. Bi odi st ri but i on
a. Af t er Ì V i nj ect i on, pl asma act i vi t y decreases t o 10% of t he admi ni st ered dose
wi t hi n 5 mi n af t er i nj ect i on.
b. Fl uorodopa
18
F i nj ect i on i s pr edomi nant l y met abol i zed i n peri pher y vi a dopa
decar boxyl ase, and cat echol - O- met hyl t r ansf er ase. To maxi mi ze brai n upt ake,
car bi dopa may be used t o decr ease per i pheral met abol i sm.
c. Rapi d excr et i on vi a r enal syst em as dopami ne met abol i t es
3. Radi onucI i de dat a. See Ì X. B. 2.
4. Admi ni st rat i on and dosage. Ì V, 10- 20 mCi ( 370- 740 MBq)
D. Cerebrospi naI fI ui d (CSF) dynami cs. Radi onucl i de ci st er nography i s usef ul i n
t he eval uat i on of hydr ocephal us and i n det ect i ng CSF l eaks. Ì n CSF i magi ng, t he
r adi ophar maceut i cal i ndi um- 111 pent et at e (
111
I n- DTPA) i s i nt r oduced i nt rat hecal l y
i nt o t he spi nal subarachnoi d space, ascends t hrough t he basal ci st er ns, pr oceeds
over t he cer ebr al hemi spher es, and event ual l y drai ns i nt o t he super i or sagi t t al
si nus.
111
Ì n pent et at e i s commer ci al l y suppl i ed as a st er i l e, pyr ogen- f ree uni t dose
i nj ect i on. Ì t i s produced by a cycl ot r on.
P. 452


1. Bi odi st ri but i on
a. Af t er i nt rat hecal i nj ect i on, t hi s r adi opharmaceut i cal normal l y ascends t o t he
par asagi t t al r egi on wi t hi n 24 hr .
b. Af t er absor pt i on i nt o t he bl oodst r eam vi a t he ar achnoi d vi l l i , t he maj or r out e of
el i mi nat i on i s by ki dney; 65% of t he dose i s excr et ed wi t hi n 48 hr ; and 85%, wi t hi n
72 hr.
2. Decay dat a
a. Physi caI haI f -I i f e: 67 hr
b. CSF bi oI ogi caI haI f -I i f e: 12 hr
c. Ef fect i ve haI f -I i f e: 10 hr
d. Decay mode: by el ect r on capt ur e
e. Pri mar y radi at i on emi ssi ons: 171 keV and 245 keV v ener gy phot ons
3. Admi ni st rat i on and dosage. Ì nt r at hecal , 500 µCi ( 18. 5 MBq)
X. INFECTION AND INFLAMMATION.
Eval uat i on of si t es of i nf ect i on i ncl ude t he use of agent s t hat can associ at e wi t h
component s of t he nat ural def ense mechani sms and can accumul at e wher e t hey
l ocal i ze.
A. GaI I i um (
67
Ga) ci t rate
1. Descri pti on
a. Ì t i s suppl i ed as a st eri l e, pyr ogen-f r ee r adi ophar maceut i cal wi t h pr eservat i ves.
b. The mechani sm of l ocal i zat i on i s t hought t o depend on t he f or mat i on of a gal l i um
t r ansf er ri n compl ex i n t he bl ood and on bi ndi ng t o t r ansf er ri n recept or s associ at ed
wi t h i nf ect i on and i nf l ammat i on.
c. Ì t accumul at es i n areas of whi t e bl ood cel l (WBC) l ocal i zat i on.
2. Bi odi st ri but i on
a. Af t er admi ni st r at i on, t he hi ghest concent r at i on of
67
Ga ci t rat e, ot her t han at t he
si t e of i nf ect i on, i s i n t he r enal cor t ex. Af t er 24 hr, t he maxi mum concent rat i on shi f t s
t o bone and l ymph nodes; but af t er 1 week, i t i s mai nl y concent r at ed i n t he l i ver and
spl een.
b.
67
Ga ci t r at e i s excr et ed sl owl y f r om t he body; 26% i s vi a ur i ne, and 9% i s vi a
f eces. Whol e body r et ent i on i s 65% af t er 7 days.
3. Radi onucI i de dat a
a. Mode of product i on: by cycl ot r on
b. Decay mode: by el ect r on capt ur e
c. Physi caI haI f - I i fe: 78 hr
d. Decay emi ssi ons: 93 keV, 185 keV, 300 keV, and 393 keV v phot ons
4. Admi ni st rat i on and dosage. Ì V, f or i nf ect i on, 3- 8 mCi (111- 300 MBq) . A dai l y
l axat i ve or an enema shoul d be used by t he pat i ent af t er t he i nj ect i on and bef or e
t he i mages t o cl eanse t he bowel of radi oact i vi t y t hat may i nt er f ere wi t h t he i mages
and possi bl y l ead t o a f al se posi t i ve resul t .
B. WBC I abeI i ng agent s. Radi ol abel ed WBCs are used i n t he det ect i on of a wi de
var i et y of i nf ect i ous and i nf l ammat or y processes. Cur r ent use i ncl udes t he di agnosi s
of i nt r a-abdomi nal abscesses, i nf l ammat or y bowel di sease, appendi ci t i s, f ever of
unknown or i gi n, and ost eomyel i t i s. WBCs can be r adi ol abel ed wi t h
111
Ì n oxi ne or
99m
Tc- examet azi me.
1.
111
I n oxyqui noI i ne soI ut i on (
111
I n oxi ne)
a. Descri pti on
( 1)
111
Ì n oxyqui nol i ne i s suppl i ed as a st er i l e pr eser vat i ve- f r ee, pyr ogen- f r ee,
r adi ophar maceut i cal sol ut i on f or use i n t he r adi ol abel i ng of aut ol ogous l eukocyt es.
( 2)
111
Ì n f orms a sat ur at ed neut ral l i pophi l i c compl ex wi t h oxyqui nol i ne ( 1: 3 r at i o),
whi ch enabl es i t t o penet r at e a cel l membrane.
( 3) Af t er i ncubat i on of
111
Ì n oxyqui nol i ne wi t h a popul at i on of aut ol ogous l eukocyt es,
t he
111
Ì n i s t hought t o become f i rml y bound t o cyt opl asmi c component s, t her eby
al l owi ng t he f ree oxi ne t o be r el eased by t he cel l .
b. Bi odi st ri but i on
( 1) Af t er radi ol abel i ng, t he aut ol ogous l eukocyt es are r ei nj ect ed; 30% i s t aken up by
t he spl een, and 30% i s t aken up by t he l i ver , r eachi ng a peak at 2-4 hr
post i nj ect i on.
( 2) Pul monar y upt ake i s i mmedi at el y evi dent post i nj ect i on, but i t cl ears, wi t h
mi ni mal vi si bl e act i vi t y, af t er 4 hr .
P. 453


( 3) Ther e i s a bi exponent i al bl ood cl ear ance; 9%-24% cl ears wi t h a bi ol ogi cal hal f -
l i f e of 2- 5 hr , and t he remai ni ng 13%-18% cl ear s wi t h a bi ol ogi cal hal f - l i f e of 64-116
hr .
( 4) El i mi nat i on i s mai nl y t hr ough r adi oact i ve decay; < 1% i s excr et ed i n f eces and
ur i ne dur i ng t he f i rst 24 hr .
c. Radi onucI i de data
( 1) Mode of product i on: by cycl ot ron
( 2) Decay mode: by el ect r on capt ure
( 3) Physi caI haI f -I i f e: 67 hr
( 4) Decay emi ssi ons: 245 keV and 171 keV
d. Admi ni st rat i on and dosage. Ì V, 200- 500 µCi (7. 4- 8. 5 MBq)
2.
99m
Tc- HMPAO. As a st er i l e and pyr ogen- f r ee Ì V i nj ect i on af t er r econst i t ut i on wi t h
sodi um per t echnet at e,
99m
Tc- HMPAO may be used t o r adi ol abel l eukocyt es.
a. Descri pti on
( 1)
99m
Tc- HMPAO i s a neut r al , l i pi d-sol ubl e compl ex t hat i s abl e t o penet rat e t he
WBC membr ane. Thi s l i pophi l i c compl ex i s r el at i vel y unst abl e and rapi dl y convert s
t o a secondar y compl ex i ncapabl e of penet rat i ng t he WBCs.
( 2) The met hyl ene bl ue/ phosphat e buf f er st abi l i zed sol ut i on i s not abl e t o r adi ol abel
cel l s and shoul d not be used.
( 3) Addi t i onal l i mi t at i ons on ki t preparat i on paramet er s r equi re t he use of hi gh mol e
f r act i on t echnet i um gener at or el ut es of < 2 hr post el ut i on f rom a gener at or
pr evi ousl y el ut ed wi t hi n 24 hr.
b. Bi odi st ri but i on
( 1) Af t er Ì V i nj ect i on, t he r adi ol abel ed cel l s l ocal i ze i n t he l ungs, l i ver , spl een, bl ood
pool , bone mar r ow, and bl adder.
( 2) El i mi nat i on i s pr i mari l y vi a t he l i ver .
c. Radi onucI i de data. See Ì Ì . B. 1. b; Ì Ì . B. 3. a and b.
d. Admi ni st rat i on and dosage. Ì V, f or i nf ect i on, 7- 25 mCi ( 260- 925 MBq)
XI. BREAST IMAGING
A.
99m
Tc- MI BI
1. Descri pti on
a.
99m
Tc- MÌ BÌ i s used f or bot h breast and car di ac i magi ng.
b.
99m
Tc- MÌ BÌ i s i ndi cat ed f or pl anar i magi ng as a second l i ne of eval uat i ng br east
l esi ons i n pat i ent s wi t h an abnormal mammogr am or a pal pabl e breast mass.
c.
99m
Tc- MÌ BÌ may not be used t o screen f or br east cancer, t o conf i r m t he pr esence
or absence of mal i gnancy, or t o r epl ace a bi opsy.
2. Bi odi st ri but i on.
99m
Tc- MÌ BÌ i s pr i mari l y excr et ed by t he hepat obi l i ar y syst em.
3. Physi caI properti es. See Ì Ì . B. 3.
4. Admi ni st rat i on and dosage. Ì V, 20- 30 mCi ( 740- 1110 MBq)
XII. TUMORS
A. The usef ul ness of r adi opharmaceut i cal s i n t he det ect i on of t umors vari es i n
sensi t i vi t y and speci f i ci t y, wi t h di f f er ences i n t umor l ocat i on and t ype.
1.
67
Ga
a. Descri pti on
( 1)
67
Ga i s suppl i ed as a st er i l e, pyr ogen- f ree radi opharmaceut i cal wi t h
pr eser vat i ves.
( 2) The mechani sm of l ocal i zat i on i s t hought t o depend on t he f ormat i on of a gal l i um
t r ansf er ri n compl ex or bi ndi ng t o t ransf er ri n r ecept ors on t umor cel l s.
( 3) Ì t accumul at es i n pri mar y met ast at i c t umor si t es and may det ect t he pr esence of
Hodgki n di sease, l ymphoma, and bronchogeni c car ci noma.
b. Bi odi st ri but i on. See X. A. 2.
c. Radi onucI i de data. See X. A. 3.
d. Admi ni st rat i on and dosage. Ì V, f or t umor , 10 mCi (370 MBq)
P. 454


2.
111
I n pentet reot i de
a. Descri pti on
( 1) Ì t i s suppl i ed as a st er i l e, pyr ogen- f ree ki t f or t he pr eparat i on of
111
Ì n
pent et r eot i de. The t wo- component ki t consi st s of a r eact i on vi al cont ai ni ng a
l yophi l i zed mi xt ur e of pent et reot i de wi t h st abi l i zer adj ut ant s and a second vi al
cont ai ni ng an i ndi um
111
Ì n chl ori de/ f er r i c chl or i de sol ut i on.
( a) The pent et reot i de mol ecul e i s a conj ugat e of pent et at e (di et hyl enet r i ami ne
pent aacet i c aci d; DTPA) and oct r eot i de, whi ch i s a somat ost at i n anal og.
( b)
111
Ì n pent et reot i de i s pr epar ed by addi ng t he
111
Ì n/ Fe chl ori de sol ut i on t o t he
vi al cont ai ni ng t he pent et r eot i de. The pent et at e por t i on of t he mol ecul e act s as a
bi f unct i onal chel at e, l i nki ng t he
111
Ì n radi onucl i de t o t he bi ol ogi cal act i ve oct reot i de
por t i on of t he agent .
( 2)
111
Ì n pent et r eot i de i s i ndi cat ed f or l ocal i zat i on of pr i mar y and met ast at i c
neuroendocr i ne t umor s expr essi ng somat ost at i n recept ors.
b. Bi odi st ri but i on
( 1) Wi t hi n 1 hr af t er Ì V i nj ect i on,
111
Ì n pent et reot i de di st ri but es f r om t he pl asma t o
ext r avascul ar space; l ess t han one t hi r d of t he admi ni st ered dose remai ns i n t he
pl asma 10 mi n post i nj ect i on.
( 2)
111
Ì n pent et r eot i de l ocal i zes as a f unct i on of somat ost at i n r ecept or densi t y, wi t h
accumul at i on i n normal pi t ui t ar y, t hyr oi d, l i ver, spl een, and t he uri nar y bl adder .
( 3) El i mi nat i on i s pr i mari l y r enal ; 50% of t he admi ni st er ed dose i s excr et ed wi t hi n 6
hr post i nj ect i on; 85%, af t er 24 hr, and < 90% af t er 48 hr . Less t han 2% of t he
admi ni st er ed dose i s cl ear ed vi a t he f eces wi t hi n 72 hr post - i nj ect i on.
c. Radi onucI i de data
( 1) Mode of product i on: i by cycl ot r on
( 2) Decay mode: by el ect r on capt ure
( 3) Physi caI haI f -I i f e: 67 hr
( 4) Decay emi ssi ons: 245 keV and 171 keV
d. Admi ni st rat i on and dosage. Ì V, 3-6 mCi (111-222 MBq)
3. I obenguane
131
I i nj ect i on (
131
I -MI BG)
a. Descri pti on
( 1) Ì t i s suppl i ed as a st er i l e, pyr ogen- f ree radi opharmaceut i cal f or use as an
adj unct i ve di agnost i c agent f or t he l ocal i zat i on of pr i mar y and met ast at i c
pheochr omocyt omas and neurobl ast omas.
( 2) Ì obenguane ( met a-i odobenzyl guani di ne) l abel ed wi t h
131
Ì act s as a physi ol ogi cal
anal og of norepi nephr i ne and i s t ransport ed and accumul at ed i n t he adr enal
medul l a. Thi s al l ows f or t he det ect i on of neur oendocri ne t umor s vi a t he speci f i c
upt ake of l abel ed i obenguane.
( 3) Because of i t s physi ol ogi cal si mi l ari t i es t o norepi nephr i ne, many cl asses of
dr ugs t hat i nt er f er e wi t h cat echol ami ne t r anspor t and f unct i on may af f ect t he upt ake
and l ocal i zat i on of l abel ed i obenguane.
b. Bi odi st ri but i on
( 1) Af t er Ì V i nj ect i on, t her e i s r api d upt ake i n t he l i ver , wi t h l esser amount s
accumul at i ng i n t he l ungs, heart , and spl een.
( 2) Normal adr enal gl and upt ake i s l ow; but f or t umors such as pheochr omocyt omas
and neur obl ast omas, t he upt ake i s rel at i vel y hi gher .
( 3) El i mi nat i on i s renal ; most of t he dr ug i s excr et ed mai nl y unchanged. Bet ween
40% and 50% of t he admi ni st er ed dose i s excr et ed wi t hi n 24 hr , and 70%-90% i s
excr et ed wi t hi n 4 days post i nj ect i on.
( 4) Admi ni st r at i on of pot assi um i odi de 1 day bef or e and f or 10 days af t er
admi ni st rat i on i s suggest ed t o r educe t hyr oi d upt ake of pot ent i al r adi oi odi de
cont ami nant s.
c. Physi caI data. See VÌ Ì Ì . B. 2. b.
d. Admi ni st rat i on and dosage. Ì V, 0. 5- 1 mCi ( 18. 5- 37 MBq)
4.
201
TI . Thi s agent has ut i l i t y as a t umor- i magi ng agent because of i t s accumul at i on
i n t he rapi dl y met abol i zi ng cel l s of cer t ai n t umors i n accor dance wi t h i t s mechani sm
of l ocal i zat i on (see Ì Ì Ì . A. 1) .
a. Admi ni st rat i on and dosage. Ì V, 1. 5- 3 mCi ( 55- 111 MBq)
5.
18
F f I udeoxygI ucose USP. Cur r ent l y, t her e i s a USP monogr aph f or on- si t e
cycl ot r onpr oduced
18
F f l udeoxygl ucose, whi ch i s a gl ucose anal og. Thi s agent has
ut i l i t y as a t umor- i magi ng agent because of an i ncr eased demand f or gl ucose by
t umor s wi t h an advanced st at e of mal i gnancy. Not onl y can
18
F f l udeoxygl ucose
l ocat e and di f f er ent i at e t umors but
P. 455

i t can al so hel p di st i ngui sh bet ween r ecur r ent brai n t umor and r adi at i on necrosi s i n
pat i ent s recei vi ng radi at i on t her apy ( see Ì X. B) .
a. Bi odi st ri but i on.
18
F f l udeoxygl ucose concent rat es i n met abol i cal l y act i ve cel l s,
wher e i t i s phosphor yl at ed but does not under go subsequent met abol i sm because of
t he repl acement of t he hydr oxyl gr oup i n t he 2 posi t i on wi t h a f l uor i ne at om. Ì t i s
t hen met abol i cal l y t r apped f or a suf f i ci ent t i me t o al l ow i magi ng.
b. Admi ni st rat i on and dosage. Ì V, 5-25 mCi ( 185- 370 MBq)
XIII. THERAPEUTIC AGENTS.
The t herapeut i c use of radi ophar maceut i cal s i s based on t he concept of sel ect i ve
l ocal i zat i on of r adi opharmaceut i cal s coupl ed wi t h t he l et hal i t y of t he same because
of t he t i ssue damage r esul t i ng f r om hi ghl y i oni zi ng part i cul at e emi ssi ons such as 8
par t i cl es.
A. Chromi c phosphate phosphorus- 32 (
32
P) suspensi on
1. Descri pti on. Avai l abl e as a st er i l e, pyr ogen- f ree aqueous suspensi on used i n t he
t r eat ment of per i t oneal or pl eur al ef f usi ons caused by met ast at i c di sease. Al so used
i n t he t r eat ment of ovar i an and pr ost at e cancer .
2. Bi odi st ri but i on
a. Col l oi dal suspensi on of
32
P i s r api dl y t aken up by macr ophages adher i ng t o t he
cavi t y wal l , t her eby concent r at i ng and l ocal i zi ng t he i r r adi at i on ef f ect of t he
32
P
r adi onucl i de 8 par t i cul at e emi ssi on.
b. Af t er i nf usi on, t he suspensi on rapi dl y di st r i but es f r om wi t hi n t he cavi t y and may
l ocal i ze i n t he l ungs, adrenal gl ands, ki dneys, l ymph nodes, l i ver , spl een, bone
mar row, pl asma, er yt hr ocyt es, and l eukocyt es, dependi ng on col l oi dal par t i cl e si ze.
c. El i mi nat i on i s pri mar i l y r enal .
3. Radi onucI i de dat a
a. Mode of product i on: by r eact or
b. Decay mode: 8
c. Physi caI haI f - I i fe: 14. 3 days
d. Decay emi ssi ons: 695 keV mean ener gy 8, 100% abundance
4. Admi ni st rat i on and dosage
a. Ì nt r aper i t oneal i nst i l l at i on: 10- 20 mCi ( 370-740 MBq)
b. Ì nt r apl eur al i nst i l l at i on: 6-12 mCi ( 222- 444 MBq)
c. Carci noma i nt er st i t i al : 0. 1-0. 5 mCi ( 3. 7- 18. 5 MBq)
d. Caut i on i s advi sed f or vi sual i nspect i on t o pr event mi sadmi ni st r at i on of t he
sodi um phosphat e f orm (cl ear , col orl ess) , whi ch i s desi gnat ed f or i nt r avascul ar use
onl y.
B. Sodi um phosphate
32
P soI ut i on
1. Descri pti on
a. Ì t i s avai l abl e as a commer ci al l y suppl i ed, st eri l e, pyr ogen-f r ee
r adi ophar maceut i cal .
b. Ì t i s pri mar i l y used as an ant i neopl ast i c f or t he t r eat ment of pol ycyt hemi a rubr a
ver a and i s sel ect i vel y used f or t he pal l i at i ve t reat ment of met ast at i c bone pai n.
c. Ì t s t herapeut i c ef f ect i s owi ng t o cel l damage r esul t i ng f r om i rr adi at i on pr oduced
by bet a par t i cul at e emi ssi on.
2. Bi odi st ri but i on
a. Ì t concent r at es as phosphat e wi t hi n t he DNA of r api dl y di vi di ng hemat opoi et i c
cel l s i n t he t reat ment of pol ycyt hemi a r ubra ver a and as phosphat e i n ar eas of
i ncreased bone f ormat i on.
b. Af t er Ì V admi ni st r at i on, i t di f f uses rapi dl y i nt o ext r acel l ul ar and i nt r acel l ul ar
space, concent r at i ng i n t he bone mar r ow, spl een, and l i ver.
c. El i mi nat i on i s pri mar i l y r enal ; 5%- 10% i s excr et ed wi t hi n 24 hr , and 20% wi t hi n 1
week.
d. Whol e body bi ol ogi cal hal f - l i f e i s appr oxi mat el y 39 days.
3. Radi onucI i de dat a
a. Mode of product i on: by r eact or
b. Decay mode: by 8
c. Physi caI haI f - I i fe: 14. 3 days
d. Decay emi ssi ons: 695 keV mean ener gy 8, 100% abundance
P. 456


4. Admi ni st rat i on and dosage
a. Pol ycyt hemi a rubr a ver a: Ì V, 3-5 mCi ( 111-185 MBq)
b. Met ast at i c bone l esi ons: Ì V, 10- 21 mCi (370- 777 MBq)
c. Caut i on i s advi sed f or vi sual i nspect i on t o pr event mi sadmi ni st r at i on of t he
chr omi c phosphat e f or m ( gr een, cl oudy) , whi ch i s desi gnat ed f or i nt er st i t i al use
onl y.
C. Sodi um i odi de
131
I (therapeut i c)
1. Descri pti on
a. Ì t i s i ndi cat ed f or t r eat ment of hypert hyr oi di sm and t hyr oi d carci noma.
b. Ì t s t herapeut i c act i on i s owi ng t o t he accumul at i on and r et ent i on of i odi ne and i t s
i sot ope
131
Ì .
2. Bi odi st ri but i on
a. See VÌ Ì Ì . A; VÌ Ì Ì . B. 2.
b. Bi oI ogi caI haI f- I i f e i n t he t hyroi d: eut hyr oi d pat i ent , 80 days; hypert hyr oi d
pat i ent , 5-40 days
3. Radi onucI i de dat a. See VÌ Ì Ì . B. 2. b.
4. Admi ni st rat i on and dosage. Or al capsul e or or al sol ut i on
a. Hyper t hyr oi di sm: 10- 30 mCi ( 370- 1110 MBq)
b. Thyr oi d car ci noma: 30- 200 mCi ( 1110-7400 MBq)
D. St ront i um- 89 (
89
Sr) chI ori de
1. Descri pti on
a. Ì t i s i ndi cat ed f or t he al l evi at i on of bone pai n ar i si ng f rom met ast at i c bone
di sease.
b. As a met abol i c anal og of cal ci um,
89
Sr concent r at es sel ect i vel y i n ar eas of
i ncreased ost eogenesi s, t hus del i veri ng a r adi at i on dose suf f i ci ent t o pr ovi de a
pal l i at i ve ef f ect .
c. Pai n r el i ef begi ns 7- 21 days af t er admi ni st r at i on, wi t h maxi mum rel i ef by 6 weeks
and an aver age dur at i on of 6 mont hs.
d. Reduct i on i n pat i ent anal gesi c usage occurs i n up t o 75% of pat i ent s t reat ed;
compl et e pai n rel i ef i s seen i n 20% of t r eat ed pat i ent s, and no pai n r el i ef i n 20%-
25% of t r eat ed pat i ent s.
e. Bone mar row suppr essi on ef f ect s l i mi t
89
Sr use t o pat i ent s wi t h i ni t i al WBC
count s > 2, 400 and pl at el et count s > 60, 000.
2. Bi odi st ri but i on
a. Af t er admi ni st r at i on,
89
Sr cl ear s rapi dl y f r om bl ood and l ocal i zes i n t he bone
hydr oxyapat i t e.
b. Ì ni t i al bi ol ogi cal hal f -l i f e i n normal bone i s 14 days; l onger r et ent i on i s seen i n
met ast at i c bone l esi ons. Bet ween 12% and 90% of t he admi ni st er ed dose i s r et ai ned
f or up t o 3 mont hs af t er admi ni st rat i on.
c. El i mi nat i on i s pri mar i l y r enal ; 66% of t he admi ni st er ed dose cl ear s vi a GFR wi t hi n
t he f i rst 2 days, and 33% i s excr et ed vi a f eces.
3. Radi onucI i de dat a
a. Mode of product i on: by accel er at or
b. Decay mode: by 8
c. Emi ssi on data: 1. 46 MeV maxi mum 8 energy, 100% abundance
d. Physi caI haI f -I i f e: 50. 5 days
4. Admi ni st rat i on and dosage. Ì V, 4 mCi ( 148 MBq) , 40- 60 µCi / kg ( 1. 5- 2. 2 MBq/ kg)
E. Samari um- 153 (
153
Sm) I exi dronam
1. Descri pti on
a.
153
Sm i s i ndi cat ed f or t he rel i ef of pai n i n pat i ent s who have conf i rmed met ast at i c
cancer of t he bone.
b.
153
Sm concent rat es i n ar eas of hi gh bone t urnover and accumul at es mor e i n
ost eobl ast i c l esi ons t han i n t he normal bone.
c. The goal of
153
Sm t herapy i s f or pat i ent s t o be abl e t o r educe t he amount of
nar cot i c anal gesi cs needed t o cont r ol t hei r pai n.
P. 457


2. Bi odi st ri but i on
a. The l esi on t o nor mal bone rat i o i s 5: 1.
b. The per cent age of upt ake of
153
Sm i s di rect l y pr oport i onal t o t he number of
l esi ons t he pat i ent has.
c. Less t han 1% of t he dose r emai ns i n t he bl ood 5 hr post i nj ect i on.
d.
153
Sm i s 100% r enal l y excr et ed over 12 hr .
e. The onset i s appr oxi mat el y 1 week.
3. Radi onucI i de dat a
a. Mode of product i on: by cycl ot r on
b. Decay mode: by 8 and v decay
c. Physi caI haI f - I i fe: 46. 3 hr
d. Decay emi ssi ons: 640 keV, 710 keV, and 840 keV 8 ener gy and 103 keV v
energy phot ons
4. Precauti ons.
153
Sm may cause bone marr ow suppressi on, whi ch shoul d r et ur n t o
basel i ne wi t hi n 8 weeks post i nj ect i on.
5. Admi ni st rat i on and dosage. Ì V, 1 mCi / kg ( 37 MBq/ kg)
F. Yt t ri um- 90 (
90
Y) i bri tumomab ti uxet an and
111
I n i bri t umomab ti uxetan
1. Overvi ew
a.
111
Ì n i bri t umomab t i uxet an and
90
Y i br i t umomab t i uxet an are par t of a t her apeut i c
r egi men used i n t he t reat ment of non- Hodgki n l ymphoma ( NHL) pat i ent s wi t h
r el apsed ref r act or y l ow- gr ade, f ol l i cul ar, or t r ansf or med B cel l NHL and pat i ent s
wi t h r i t uxi mab r ef r act or y NHL.
b. Ì bri t umomab t i uxet an i s an i mmunoconj ugat e consi st i ng of a monocl onal ant i body
i br i t umomab, whi ch i s l i nked t o t he chel at or t i uxet an.
c. The i bri t umomab ant i body i s a muri ne i mmunogl obul i n G1 (Ì gG1) k monocl onal
ant i body pr oduced i n Chi nese hamst er ovar y ( CHO) cel l s. The i bri t umomab ant i body
i s di rect ed agai nst t he CD20 ant i gen, whi ch i s expr essed on t he sur f ace of normal
and mal i gnant B l ymphocyt es.
d. The l i nker chel at or t i uxet an pr ovi des a hi gh- af f i ni t y chel at i on si t e f or
111
Ì n i n t he
case of t he i magi ng dose and f or
90
Y i n t he case of t he t herapeut i c dose.
e. The t herapeut i c regi men i s admi ni st er ed i n t wo separ at e doses. Thi s al l ows f or
t he qual i t at i ve eval uat i on of t he bi odi st r i but i on t o avoi d pot ent i al t oxi ci t i es such as
abnor mal l y hi gh bone mar r ow l ocal i zat i on or prol onged renal excr et i on. Ì n each
admi ni st rat i on, pat i ent s must be premedi cat ed wi t h di phenhydr ami ne 50 mg and
acet ami nophen 650 mg 0. 5 hr bef or e r ecei vi ng t he r i t uxi mab i nf usi on r equi r ed
bef ore admi ni st er i ng t he r adi ol abel ed ant i body.
( 1) St ep 1 i s t he admi ni st r at i on of ri t uxi mab f ol l owed by t he
111
Ì n i br i t umomab
t i uxet an di agnost i c i magi ng dose.
( 2) St ep 2 f ol l ows st ep 1 by 7- 9 days and consi st s of a second ri t uxi mab i nf usi on
f ol l owed by t he
90
Y i br i t umomab t her apy dose.
2. Descri pti on
a. Suppl i ed as t wo separat e ki t s t o pr oduce a si ngl e dose of
111
Ì n i br i t umomab
t i uxet an and a si ngl e dose of
90
Y i br i t umomab t i uxet an
b. Each ki t consi st s of f our vi al s cont ai ni ng:
( 1) Ì br i t umomab t i uxet an i n sal i ne, 3. 2 mg
( 2) Sodi um acet at e, 50 mM
( 3) For mul at i on buf f er (cont ai ns human serum al bumi n)
( 4) One empt y r eact i on vi al
c. Exi st s as a st er i l e, nonpyr ogeni c Ì V sol ut i on af t er f or mul at i on wi t h ei t her
111
Ì n or
90
Y
3. Bi odi st ri but i on
a. The mean hal f - l i f e f or
90
Y i br i t umomab t i uxet an i n t he bl ood i s 30 hr.
b. Appr oxi mat el y 7. 8% of t he admi ni st er ed dose i s excr et ed i n t he ur i ne over 7
days.
c. The est i mat ed bi ol ogi cal hal f -l i f e i s 48 hr .
4. Radi onucI i de dat a
a.
111
I n. See XÌ Ì Ì . B. 1. c.
b.
90
Y
P. 458


( 1) Mode of product i on: by r eact or
( 2) Decay mode: by 8
( 3) Physi caI haI f -I i f e: 64. 1 hr
( 4) Decay emi ssi on: 935 mean keV, 100% emi ssi on
5. Precauti ons
a.
90
Y i br i t umomab t i uxet an shoul d not be admi ni st ered t o pat i ent s wi t h al t er ed
bi odi st r i but i ons of t he
111
Ì n i br i t umomab t i uxet an i magi ng and dosi met r y dose.
b.
90
Y i bri t umomab t i uxet an shoul d not be admi ni st ered t o pat i ent s wi t h:
( 1) > 25% l ymphoma marr ow i nvol vement
( 2) Pl at el et count s < 100, 000 cel l / mm
3

( 3) Neut r ophi l count < 1, 500 cel l s/ mm
3

( 4) Hypocel l ul ar bone mar r ow
( 5) Hi st or y of f ai l ed st em cel l col l ect i on
c. Ì br i t umomab t i uxet an i s cont rai ndi cat ed i n pat i ent s wi t h known hyper sensi t i vi t y or
anaphyl act i c react i ons t o muri ne prot ei ns.
d. Pat i ent s who have pr evi ousl y r ecei ved mur i ne-based pr ot ei n t her apy shoul d be
screened f or human ant i mouse ant i bodi es.
e. Ì nf usi on- r el at ed adverse event s, i ncl udi ng ast heni a, chi l l s, and nausea, ar e
common and ar e usual l y sel f - l i mi t ed. Tumor l ysi s syndr ome has been r epor t ed af t er
r i t uxi mab i nf usi ons, whi ch ar e par t of
90
Y i br i t umomab t i uxet an t herapy. Pat i ent s
shoul d be moni t ored cl osel y f or t hi s pot ent i al l y f at al adverse event .
G. Tosi tumomab and I odi ne I 131 Tosi tumomab
1. Overvi ew
a. Tosi t umomab and Ì odi ne 1131 Tosi t umomab are part of a t herapeut i c r egi men
i ndi cat ed f or t he t reat ment of pat i ent s wi t h CD20 ant i gen- expr essi ng r el apsed or
r ef r act or y, l ow gr ade, f ol l i cul ar , or t ransf ormed non- Hodgki n' s l ymphoma, i ncl udi ng
pat i ent s wi t h Ri t uxi mab- ref r act or y non- Hodgki n' s l ymphoma.
b. The Tosi t umomab and Ì odi ne Ì 131 Tosi t umomab t her apeut i c regi men i s an
ant i neopl ast i c r adi oi mmunot her apeut i c monocl onal ant i body- based r egi men
composed of t he monocl onal ant i body, Tosi t umomab, and t he r adi ol abel ed
monocl onal ant i body, Ì odi ne Ì 131 Tosi t umomab.
c. Tosi t umomab i s a muri ne Ì gG2a l ambda monocl onal ant i body di rect ed agai nst t he
CD20 ant i gen, whi ch i s f ound on t he sur f ace of nor mal and mal i gnant B
l ymphocyt es. Tosi t umomab i s pr oduced i n an ant i bi ot i c- f r ee cul t ur e of mammal i an
cel l s and i s composed of t wo muri ne gamma 2a heavy chai ns of 451 ami no aci ds
each and t wo l ambda l i ght chai ns of 220 ami no aci ds each. The appr oxi mat e
mol ecul ar wei ght of Tosi t umomab i s 150 kD.
d. The t her apeut i c regi men i s admi ni st er ed i n t wo di scret e st eps: t he dosi met ri c
st ep and t herapeut i c st ep. Each st ep consi st s of a sequent i al i nf usi on of
Tosi t umomab f ol l owed by Ì odi ne Ì 131 Tosi t umomab. The t herapeut i c st ep i s
admi ni st er ed 7-14 days af t er t he dosi met r i c st ep.
e. Tosi t umomab bi nds speci f i cal l y t o t he CD20 ( human B-l ymphocyt e- r est ri ct ed
di f f er ent i at i on ant i gen. Bp 35 or B1) ant i gen. Thi s ant i gen i s a t ransmembrane
phosphoprot ei n expr essed on pre- B l ymphocyt es and at hi gher densi t y on mat ur e B
l ymphocyt es. The ant i gen i s al so expr essed on >90% of B-cel l non- Hodgki n' s
l ymphomas ( NHL) . Possi bl e mechani sms of act i on of t he BEXXAR t her apeut i c
r egi men i ncl ude i nduct i on of apopt osi s, compl ement - dependent cyt ot oxi ci t y ( CDC) ,
and ant i body- dependent cel l ul ar cyt ot oxi ci t y ( ADCC) medi at ed by t he ant i body.
2. Descri pti on
a. Tosi t umomab i s suppl i ed as a st eri l e, pyr ogen-f r ee, cl ear t o opal escent , col orl ess
t o sl i ght l y yel l ow, pr eservat i ve- f r ee l i qui d concent r at e. Ì t i s suppl i ed at a nomi nal
concent r at i on of 14 mg/ mL of Tosi t umomab i n 35 mg and 225 mg si ngl e-use vi al s.
The f ormul at i on cont ai ns 10% ( w/ v) mal t ose, 145 mM sodi um chl ori de, 10 mM
phosphat e and Wat er f or Ì nj ect i on, USP. pH i s appr oxi mat el y 7. 2.
b. Ì odi ne Ì 131 Tosi t umomab i s a r adi o-i odi nat ed der i vat i ve of Tosi t umomab t hat has
been coval ent l y l i nked t o Ì odi ne-131. Ì odi ne Ì 131 Tosi t umomab i s suppl i ed as a
st eri l e, cl ear , pr eser vat i ve- f r ee l i qui d f or Ì V admi ni st r at i on. The dosi met ri c dosage
f or m i s suppl i ed at nomi nal pr ot ei n and act i vi t y concent rat i ons of 0. 1 mg/ mL and
0. 61 mCi / mL
P. 459

( at dat e of cal i br at i on) , respect i vel y. The t her apeut i c dosage f orm i s suppl i ed at
nomi nal pr ot ei n and act i vi t y concent r at i ons of 1. 1 mg/ mL and 5. 6 mCi / mL ( at dat e of
cal i brat i on) , r espect i vel y. The f ormul at i on f or t he dosi met r i c and t he t her apeut i c
dosage f orms cont ai ns 4. 4%- 6. 6% ( w/ v) povi done, 1- 2 mg/ mL mal t ose (dosi met ri c
dose) or 9-15 mg/ mL mal t ose ( t her apeut i c dose) , 8. 5- 9. 5 mg/ mL sodi um chl ori de,
and 0. 9-1. 3 mg/ mL ascorbi c aci d. pH i s appr oxi mat el y 7. 0.
3. Bi odi st ri but i on
a. The medi an bl ood cl ear ance f ol l owi ng admi ni st r at i on of 485 mg of Tosi t umomab
i n 110 pat i ent s wi t h NHL was 68. 2 mg/ hr ( r ange: 30. 2-260. 8 mg/ hr ) . ( Pat i ent s wi t h
hi gh t umor bur den, spl enomegal y, or bone mar row i nvol vement have a f ast er
cl ear ance, short er t ermi nal hal f - l i f e, and l ar ger vol ume of di st r i but i on. )
b. The medi an t ot al body ef f ect i ve hal f -l i f e, as measured by t ot al body gamma
camer a count s, i n 980 pat i ent s wi t h NHL was 67 hour s ( range: 28- 115 hour s) .
4. Radi onucI i di e Dat a
a. See VÌ Ì Ì . B. 2. b.
5. Admi ni st rat i on & Dosi ng
a. Dosi met ri c st ep
( 1) Tosi t umomab 450 mg i nt ravenousl y i n 50 ml 0. 9% Sodi um Chl or i de over 60
mi nut es.
( 2) Ì odi ne Ì 131 Tosi t umomab (cont ai ni ng 5. 0 mCi Ì odi ne- 131 and 35 mg
Tosi t umomab) i nt r avenousl y i n 30 ml 0. 9% Sodi um Chl or i de over 20 mi nut es.
b. Therapeut i c step
( 1) Tosi t umomab 450 mg i nt ravenousl y i n 50 mL 0. 9% Sodi um Chl ori de over 60
mi nut es.
( 2) The recommended Ì odi ne Ì 131 Tosi t umomab dose i s t he act i vi t y of Ì odi ne- 131
cal cul at ed t o del i ver 75 cGy t ot al body i rr adi at i on and 35 mg Tosi t umomab,
admi ni st er ed i nt r avenousl y over 20 mi nut es. ( Pat i ent s wi t h NCl Gr ade 1
t hr ombocyt openi a (pl at el et count s = 100, 000 but < 150, 000 pl at el et s/ mm
3
) :
r ecommended dose i s 65 cGy t ot al body i r r adi at i on) .
6. Precauti ons
a. Ther apeut i c Ì odi ne Ì 131 Tosi t umomab shoul d not be admi ni st er ed t o pat i ent s
wi t h al t er ed bi odi st r i but i ons of t he Ì odi ne Ì 131 Tosi t umomab i magi ng and dosi met r y
dose.
b. Thyr oi d-bl ocki ng medi cat i ons shoul d be i ni t i at ed at l east 24 hours bef or e
r ecei vi ng t he dosi met ri c dose and cont i nued unt i l 14 days af t er t he t herapeut i c
dose.
c. The most common adver se r eact i ons wer e sever e or l i f e-t hr eat eni ng cyt openi as.
d. Ì odi ne Ì 131 Tosi t umomab i s cont rai ndi cat ed i n pat i ent s wi t h known
hyper sensi t i vi t y oranaphyl act i c r eact i ons t o mur i ne prot ei ns. Pat i ent s who have
pr evi ousl y r ecei ved mur i ne- based pr ot ei n t her apy shoul d be scr eened f or human
ant i mouse ant i bodi es.
e. hyper sensi t i vi t y r eact i ons, i ncl udi ng f at al out come, have been r epor t ed.
Emer gency suppl i es i ncl udi ng medi cat i ons f or t he t r eat ment of hypersensi t i vi t y
r eact i ons, e. g. , epi nephri ne, ant i hi st ami nes and cor t i cost eroi ds, shoul d be avai l abl e
f or i mmedi at e use i n t he event of an al l er gi c react i on duri ng admi ni st r at i on.
XIV. REFERENCES
A. Amer i can Pharmaceut i cal Associ at i on. Nucl ear Pharmacy Pr act i ce Gui del i nes.
Academy of Pharmacy Pr act i ce, 1995.
B. Ber ni er DR, Chri st i an PE, Langan JK. Nucl ear Medi ci ne Technol ogy and
Techni ques. St . Loui s, Mosby 1994.
C. Chi l t on HM, Wi t cof ski R: Nucl ear Pharmacy: An Ì nt r oduct i on t o t he Cl i ni cal
Appl i cat i ons of Radi ophar maceut i cal s. Phi l adel phi a, Lea & Febi ger 1986.
D. Swanson DP, Chi l t on HM, Thr al l JH. Pharmaceut i cal s i n Medi cal Ì magi ng. New
Yor k, Macmi l l an 1990.
E. Uni t ed St at es Pharmacopei a Dr ug Ì nf ormat i on ( USPDÌ ) 2002.
P. 460


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 7: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. Whi ch of the foI I owi ng emi ssi ons f rom t he decay of radi onucI i des i s most
commonI y used i n nucI ear medi ci ne di agnost i c i magi ng?
( A) x- r ay
( B) 8
( C) q
( D) v
( E) Posi t ron
Vi ew Answer 1. The answer i s D[ see] . 2. Whi ch of t he f oI I owi ng
radi onucI i des i s most commonI y used i n nucI ear pharmacy pract i ce?
( A) gal l i um- 67 (
67
Ga)
( B) t hal l i um- 201 (
201
Tl )
( C) t echnet i um-99m (
99m
Tc)
( D) i odi ne- 123 (
123
Ì )
( E) xenon- 133 (
133
Xe)
Vi ew Answer 2. The answer i s C[ see] . 3. Whi ch of t he f oI I owi ng
radi onucI i des i s produced usi ng a generat or?
( A) t echnet i um- 99m (
99m
Tc)
( B) t hal l i um- 201 (
201
Tl )
( C) gal l i um-67 (
67
Ga)
( D) xenon- 133 (
133
Xe)
( E) i odi ne- 123 (
123
Ì )
Vi ew Answer 3. The answer i s A[ see] . 4. Whi ch of t he f oI I owi ng
radi opharmaceut i caI s can be used i n skeI et aI i magi ng?
( A) t echnet i um- 99m al bumi n aggr egat ed
( B) t echnet i um- 99m medr onat e di sodi um
( C) xenon- 133 gas USP
( D) t hal l ous chl or i de (
201
Tl ) USP
( E) t echnet i um- 99m di sof eni n
Vi ew Answer 4. The answer i s B[ see] . 5. Whi ch of t he f oI I owi ng
radi opharmaceut i caI s i s used i n t he di agnosi s of acut e choI ecyst i t i s?
( A) t echnet i um- 99m sul f ur col l oi d
( B) t echnet i um- 99m medr onat e di sodi um
( C) t echnet i um-99m al bumi n
( D) t echnet i um-99m examet azi me
( E) t echnet i um- 99m di sof eni n
Vi ew Answer 5. The answer i s E[seeand] . 6. Whi ch of t he f oI I owi ng
cycI ot ron- produced radi opharmaceut i caI s i s used for assessi ng regi onaI
myocardi aI perf usi on as part of an exerci se stress test ?
( A) t hal l ous chl or i de
201
TÌ USP
( B) sodi um i odi de
123
Ì
( C) gal l i um ci t r at e
67
Ga USP
( D) i ndi um- 111 pent et at e
( E) cobal t - 57 cyanocobal ami n
Vi ew Answer 6. The answer i s A[ see] . 7. GI omeruI ar f i I t rat i on and the
uri nar y coI I ect i on syst em can best be evaI uated usi ng whi ch of the foI I owi ng
agents?
( A) t echnet i um- 99m sul f ur col l oi d
( B) t echnet i um- 99m al bumi n
( C) t echnet i um-99m sest ami bi
( D) t echnet i um-99m di sof eni n
( E) t echnet i um- 99m pent et at e
Vi ew Answer 7. The answer i s E[see] . Di rect i ons f or questi ons 8-11: The
quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
8. The def i ni t i on of the opt i maI radi opharmaceut i caI i ncI udes whi ch of t he
f oI I owi ng at t ri butes?
I . short haI f - I i f e
I I . v photon wi th a 100-300 keV energy
I I I . rapi d I ocaI i zati on i n t arget t i ssue and qui ck cI earance f rom nontarget t i ssue
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 8. The answer i s E[see] . 9. Whi ch of t he f oI I owi ng st atement s
are t rue f or sodi um pert echnet ate t echnet i um-99m (
99m
Tc) USP?
I . I t i s used t o radi oI abeI aI I other
99m
Tc radi opharmaceut i caI s.
I I . The moI ybdenum- 99 (
99
Mo) breakthrough I i mi t i s < 0. 15 µCi
99
Mo/ mCi
99m
Tc ( <
0. 15 kBq/ MBq).
I I I . I t has a physi caI haI f - I i f e of 16 hr.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 9. The answer i s C[ seeand] . P. 461


10. Whi ch of t he f oI I owi ng organs can be i maged wi t h t echneti um-99m (
99m
Tc)
suI f ur coI I oi d?
I . I i ver
I I . spI een
I I I . bone marrow
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 10. The answer i s E[see] . 11. Whi ch of t he f oI I owi ng
radi opharmaceut i caI s may be used t o i mage the t hyroi d gI and?
I . sodi um i odi de
131
I
I I . sodi um pert echnetate t echneti um-99m USP
I I I . sodi um i odi de
123
I
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 11. The answer i s E[see] . Di rect i ons f or questi ons 12- 16:
Each of t he f ol l owi ng mechani sms of l ocal i zat i on i s most cl osel y r el at ed t o one of
t he f ol l owi ng radi opharmaceut i cal s. The mechani sms may be used mor e t han once
or not at al l . Choose t he best answer , A- E.
12. thaI I ous chI ori de
201
TI USP
A met abol i c t rappi ng
B phagocyt osi s
C capi l l ar y bl ockade
D act i ve t ransport
E passi ve di f f usi on
Vi ew Answer 12. The answer i s D[ see] . 13. t echnet i um-99m aI bumi n
aggregat ed USP
A met abol i c t rappi ng
B phagocyt osi s
C capi l l ar y bl ockade
D act i ve t ransport
E passi ve di f f usi on
Vi ew Answer 13. The answer i s C[ see] . 14. t echnet i um-99m suI f ur coI I oi d
A met abol i c t rappi ng
B phagocyt osi s
C capi l l ar y bl ockade
D act i ve t ransport
E passi ve di f f usi on
Vi ew Answer 14. The answer i s B[ see] . 15. t echnet i um-99m examet azi me
A met abol i c t rappi ng
B phagocyt osi s
C capi l l ar y bl ockade
D act i ve t ransport
E passi ve di f f usi on
Vi ew Answer 15. The answer i s E[see] . 16. f I uori ne- 18 f I udeoxygI ucose
A met abol i c t rappi ng
B phagocyt osi s
C capi l l ar y bl ockade
D act i ve t ransport
E passi ve di f f usi on
Vi ew Answer 16. The answer i s A[ see] . P. 462


ANSWERS AND EXPLANATIONS
1. The answer i s D [ see Ì . B. 3. b] .
Cur r ent camer a t echnol ogy most ef f i ci ent l y det ect s v r adi at i on. q and 8 emi ssi ons
ar e not usef ul i n nucl ear medi ci ne i magi ng because of t hei r har mf ul part i cul at e
emi ssi ons and l ow t i ssue penet r at i on. Al t hough x- r ay emi ssi ons can be used as i n
t he case of t he mer cur y daught er of t he t hal l ous chl or i de
201
Tl par ent , t hey ar e not
ef f i ci ent l y det ect ed. Anni hi l at i on radi at i on associ at ed wi t h posi t r on decay can be
i maged, but t hi s t echnol ogy i s cur r ent l y l i mi t ed t o a f ew speci al i zed cent er s.
2. The answer i s C [ see Ì Ì . A. 1] .
99m
Tc has become t he r adi onucl i de of choi ce i n cur r ent nucl ear phar macy pr act i ce
si nce i t s i nt roduct i on i n t he mi d-1960s.
99m
Tc f ul f i l l s al l of t he requi r ement s of t he
opt i mal radi ophar maceut i cal , wi t h i t s physi cal hal f - l i f e of 6 hr , 140 keV v energy
emi ssi on, ready avai l abi l i t y, cost , and abi l i t y t o be r adi ol abel ed t o a wi de var i et y of
bi ol ogi cal l y act i ve compounds.
3. The answer i s A [ see Ì Ì . A. 1. a] .
99m
Tc i s obt ai ned vi a commer ci al l y suppl i ed, st eri l e, pyr ogen-f r ee generat or
syst ems. A gener at or i s a devi ce used t o separ at e a shor t hal f - l i f e radi onucl i de f r om
t he l onger -l i ved par ent nucl i de, whi l e r et ai ni ng t he parent t o pr oduce more of t he
daught er nucl i de. Ì n t hi s way, shor t - hal f - l i f e nucl i des can be made avai l abl e on a
cont i nuous basi s at great di st ances f r om t he si t es of generat or pr oduct i on.
4. The answer i s B [ see Ì V. A. 2] .
The
99m
Tc di phosphonat e compounds are t he most popul ar bone-i magi ng agent s
cur rent l y used i n nucl ear medi ci ne i magi ng. They ar e rapi dl y t aken up by skel et al
bone; 50% of t he admi ni st ered dose i s adsorbed ont o bone hydr oxyapat i t e and t he
r emai nder i s excr et ed by t he ki dneys. The i magi ng advant ages of t he
99m
Tc, coupl ed
wi t h t he sensi t i vi t y of bone agent l ocal i zat i on i n skel et al bone hydr oxyapat i t e, al l ow
f or det ect i on of bone pat hol ogy bef ore evi dence of pat hol ogy can be shown by
convent i onal x- r ay.
5. The answer i s E [ see VÌ . C. 1 and 2] .
99m
Tc di sof eni n i s an i mi nodi acet i c aci d deri vat i ve, whi ch i s usef ul f or hepat obi l i ar y
i magi ng due t o i t s abi l i t y t o be sel ect i vel y cl ear ed by a carr i er- medi at ed hepat ocyt e
pat hway. Lack of gal l bl adder vi sual i zat i on i s an abnor mal f i ndi ng suggest i ve of
acut e chol ecyst i t i s.
6. The answer i s A [ see Ì Ì Ì . A. 1] .
Regi onal upt ake of t hal l ous chl ori de
201
TÌ USP i s pr opor t i onal t o myocar di al bl ood
suppl y. The i nj ect i on of
201
TÌ i n concer t wi t h a t readmi l l exer ci se st ress t est
det ermi nes myocar di al per f usi on at maxi mum cardi ac out put when car di ac demand
out st r i ps suppl y and t he di st r i but i on of
201
TÌ i s l ess af t er af f ect ed by col l at er al bl ood
suppl y wi t hi n t he myocardi um. Regi ons t hat do not t ake up
201
TÌ ar e i nt erpr et ed as
ar eas of i nf arct or i schemi a. Ì f t hese f ocal areas of decreased upt ake subsequent l y
f i l l i n wi t h r edi st ri but ed
201
TÌ , t hey ar e i nt er pret ed t o be ar eas of i schemi a, i n
cont r ast wi t h ar eas of i nf ar ct , whi ch r emai n as di mi ni shed areas of act i vi t y.
7. The answer i s E [ see VÌ Ì . B. 1] .
99m
Tc pent et at e i s cl eared t hrough gl omerul ar f i l t rat i on i n t he same manner as i nul i n
and can be used t o det ermi ne t he GFR as wel l as i n t he eval uat i on of obst r uct i on of
vascul ar suppl y and r enal mor phol ogy.
8. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì . C] .
The opt i mal radi opharmaceut i cal has a hal f -l i f e shor t enough t o mi ni mi ze r adi at i on
exposur e t o t he pat i ent yet l ong enough t o al l ow f or col l ect i on of i magi ng
i nf or mat i on. Ì t shoul d i ncor porat e a v- emi t t i ng radi onucl i de, whi ch decays wi t h t he
emi ssi on of a phot on ener gy bet ween 100 and 300 keV, whi ch i s ef f i ci ent l y det ect ed
wi t h cur rent i nst rument at i on. The r adi ophar maceut i cal shoul d l ocal i ze r api dl y i n t he
or gan syst em of i nt erest and be met abol i zed, excr et ed, or bot h f r om t he nont arget
t i ssues t o maxi mi ze cont r ast and mi ni mi ze r adi at i on- absor bed dose.
9. The answer i s C (Ì , Ì Ì ) [ see Ì Ì . A and B] .
Sodi um pert echnet at e
99m
Tc USP decays by i somer i c t r ansi t i on and has a physi cal
hal f - l i f e of 6 hr . The emi ssi on of a v phot on has t he energy of 140 keV.
P. 463


10. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see VÌ . B. 1] .
99m
Tc sul f ur col l oi d l ocal i zes wi t hi n t he r et i cul oendot hel i al syst em; 80%-90% of t he
dose i s phagocyt i zed by t he Kupf f er cel l s of t he l i ver ; 5%-10%, by t he spl een; and
t he bal ance, by t he bone mar row.
11. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see VÌ Ì Ì . B] .
Al t hough al l of t he l i st ed agent s accumul at e i n t he t hyr oi d gl and, onl y sodi um i odi de
123
Ì possesses i deal i magi ng charact er i st i cs and or gani f i cat i on i nt o t hyr oi d hormone.
Whi l e t he i magi ng pr oper t i es of sodi um per t echnet at e
99m
Tc USP ar e good, t he
per t echnet at e i on i s t r apped onl y by t he t hyr oi d and not or gani f i ed, t hus l i mi t i ng t he
i nf or mat i on pr ovi ded by t he i mage.
12. The answer i s D [ see Ì Ì Ì . A. 1] .
Thal l ous chl ori de
201
TÌ USP i s a monoval ent cat i on wi t h di st r i but i on anal ogous t o
pot assi um i on ( K
+
) . Myocar di al upt ake i s by act i ve t r anspor t vi a t he Na
+
/ K
+
- ATPase
pump.
13. The answer i s C [ see V. A. 1] .
Af t er Ì V admi ni st rat i on of
99m
Tc al bumi n aggr egat ed USP, 80% of t he r adi ol abel ed
al bumi n par t i cl es become t r apped by capi l l ar y bl ockade i n t he pul monar y
ci rcul at i on.
14. The answer i s B [ see VÌ . B. 1] .
Af t er t he admi ni st r at i on of
99m
Tc sul f ur col l oi d, 80%- 90% of t he dose i s
phagocyt i zed by t he Kupf f er cel l s of t he l i ver ; 5%- 10%, by t he spl een; and t he
bal ance, by t he bone mar r ow.
15. The answer i s E [ see Ì X. A. 1] .
99m
Tc examet azi me i s used f or eval uat i ng br ai n per f usi on. Ì t possesses a l i pophi l i c
par t i t i on coef f i ci ent t hat i s suf f i ci ent t o di f f use passi vel y acr oss t he BBB al most
compl et el y wi t hi n one pass of t he cer ebral ci r cul at i on, and t hat i s suf f i ci ent l y
r et ai ned t o per mi t dat a col l ect i on.
16. The answer i s A [ see Ì X. B. 1] .
18
F f l udeoxygl ucose i s used i n eval uat i ng cer ebral f unct i on by mappi ng t he
di st r i but i on of cerebral gl ucose met abol i sm. As an anal og of gl ucose,
18
F
f l udeoxygl ucose i s t ranspor t ed i nt o t he brai n by car ri er -medi at ed t r anspor t
mechani sms responsi bl e f or t r anspor t i ng gl ucose across t he BBB. Because t he
pr esence of t he f l our i ne at om i n t he 2 posi t i on prevent s met abol i sm beyond t he
phosphor yl at i on st ep,
18
F f l udeoxygl ucose becomes met abol i cal l y t r apped wi t hi n t he
br ai n.

20
PharmaceuticaI Care and Disease State
Management
Peggy C. Yarborough
I. INTRODUCTION
A. Pract i ce of pharmacy. The pr act i ce of pharmacy embraces a var i et y of
set t i ngs, pat i ent popul at i ons, and speci al i st and gener al i st pharmaci st s.
Cent r al t o t he pr act i ce of pharmacy, however , i s t he provi si on of cl i ni cal
ser vi ces di r ect l y t o, and f or t he benef i t of , pat i ent s.
B. Def i ni t i on. The t er m pharmaceut i caI care (somet i mes cal l ed
pharmaci st care) descri bes speci f i c act i vi t i es and ser vi ces t hrough whi ch
an i ndi vi dual phar maci st " cooperat es wi t h a pat i ent and ot her prof essi onal s
i n desi gni ng, i mpl ement i ng and moni t or i ng a t herapeut i c pl an t hat wi l l
pr oduce speci f i c t her apeut i c out comes f or t he pat i ent . ¨
1

C. Pharmaceut i cal car e i s i ncreasi ngl y bei ng augment ed by act i vi t i es t hat
may be descr i bed as f ocused areas of pract i ce, wher ei n t he phar maci st i s
engaged i n:
1. Drug moni t ori ng, f or a speci f i c dr ug or f or t her apy f or a speci f i c di sease
st at e
2. Di sease moni tori ng, f or a speci f i c di sease st at e
3. Drug t herapy and di sease management / coI I aborat i ve pract i ce, by prot ocol
4. A pharmaci st may i ncor porat e one or mor e areas of f ocused pr act i ce i nt o a
gener al pr act i ce of pharmacy or may speci al i ze wi t hi n a narr ow f i el d of pr act i ce.
Exampl es of hi ghl y speci al i zed pract i ce i ncl ude phar maci st - di r ect ed di abet es
management cl i ni cs, hyper t ensi on cl i ni cs, ant i coagul at i on cl i ni cs, and hospi t al -
based i nf ect i ous di sease ser vi ces.
II. SCOPE OF PRACTICE WITHIN PHARMACEUTICAL
CARE
A. RoI e. Phar maceut i cal care has evol ved f r om an emphasi s on pr event i on of dr ug-
r el at ed pr obl ems ( basi cal l y drug management ) t o t he expanded rol es of
pharmaci st s i n t he t ri age of pat i ent s, t reat ment of routi ne acut e i I I nesses,
management of chroni c di seases, and pri mar y di sease prevent i on.
B. Funct i on. The pr ovi si on of pharmaceut i cal care does not i mpl y t hat t he
pharmaci st i s no l onger responsi bl e f or di spensi ng f unct i ons. Ì n many i nst ances,
however , i mpl ement at i on of pharmaceut i cal car e ser vi ces necessi t at es a redesi gn of
t he pr of essi onal wor k f l ow, wi t h assi gnment of t echni cal f unct i ons t o t echni cal
per sonnel under t he di r ect super vi si on and responsi bi l i t y of t he pharmaci st .
P. 466


Table 20-1. Uniqueness of Pharmaceutical Care
Characteristic
Traditional
Pharmacy Clinical Pharmacy
Pharmaceutical
Care
Primary
Iocus
Prescription
order or OTC
request
Physicians or other
health
proIessionals
Patient
Continuity On demand Discontinuous Continuous
Strategy Obey Find Iault or
prevention
Anticipate or
improve
Orientation Drug product Process Outcomes
OTC. over the counter.

III. UNIQUENESS OF PHARMACEUTICAL CARE.
Pr ovi si on of phar maceut i cal car e over l aps somewhat wi t h ot her aspect s of pharmacy
pr act i ce ( Tabl e 20-1) . However , pharmaceut i cal car e i s not t he same as t hese ot her
ar eas, whi ch i ncl ude
A. CI i ni caI pharmacy
B. Pat i ent counseI i ng
C. Pharmaceut i caI servi ces; when t he act i vi t i es of a pharmacy or pharmacy
depar t ment ar e per f ormed f or " f acel ess¨ pat i ent s or char t s, t he act i vi t y i s one of
pharmacy ser vi ce, not phar maceut i cal care (i . e. , char t or drug pr of i l e r evi ews
wi t hout i nput f r om t he pat i ent or car egi ver i s not pharmaceut i cal car e).
IV. ESSENTIAL COMPONENTS OF PHARMACEUTICAL
CARE
A. Pharmaci st - pat i ent reI at i onshi p. The i mpor t ance of put t i ng a f ace and
per sonal i t y wi t h t he cl i ni cal pi ct ur e i s a key component of pharmaceut i cal car e. A
pharmaci st can have a car i ng r el at i onshi p wi t h a pat i ent but not wi t h a char t or drug
pr of i l e. A pharmaci st cannot have empat hy f or wor ds on a page or on a comput er
screen. Phar maceut i cal car e i s based on a col l abor at i ve ef f ort bet ween phar maci st
and pat i ent .
B. Pharmaci st ' s workup of drug t herapy ( PWDT) . The provi si on of pharmaceut i cal
car e i s of t en cent er ed around a pr ocess descr i bed as t he PWDT.
2
The PWDT
cont ai ns t he t hought pr ocesses necessar y f or phar maceut i cal car e. The PWDT i s t oo
l engt hy t o be used as t he char t not e f or pharmaci st i nt er vent i ons; an abbrevi at ed
f or mat known as a FARM ( f i ndi ngs, assessment , resol ut i ons/ recommendat i on, and
moni t ori ng) not e or a SOAP ( subj ect i ve, obj ect i ve, assessment , and pl an) not e i s
mor e appr opr i at e f or a char t not at i on ( Tabl e 20-2) . Nonet hel ess, i t i s hel pf ul t o t he
pharmacy st udent , or t o a phar maci st ent eri ng a new f i el d of pharmacy pract i ce, t o
wr i t e out compl et e PWDTs f or a var i et y of pat i ent s as t r ai ni ng or ori ent at i on
exer ci ses. Al t hough t he f or ms and met hods used f or t he PWDT may var y, t he
component s ar e essent i al l y t he same.
1. Data coI I ect i on. Col l ect , synt hesi ze, and i nt er pr et r el evant i nf ormat i on, such as:
a. Pat i ent demographi c dat a: age, r ace, sex
b. Pert i nent medi cal i nf or mat i on
( 1) Cur rent and past medi cal hi st or y
( 2) Fami l y hi st or y
( 3) Soci al hi st or y
( 4) Di et ar y hi st or y
( 5) Medi cat i on hi st or y (pr escr i pt i on, OTC, soci al dr ugs; al l er gi es)
( 6) Physi cal f i ndi ngs ( e. g. , wei ght , hei ght , bl ood pr essure, edema)
( 7) Laborat or y or ot her t est r esul t s (e. g. , serum dr ug l evel s, pot assi um l evel , ser um
cr eat i ni ne as rel evant t o dr ug t her apy)
c. Pat i ent compl ai nt s, sympt oms, si gns
P. 467


Table 20-2. Components of a FARM Note and a SOAP Note
PWDT
Component
FARM Note SOAP Note

The identiIied or suggestive patient-speciIic inIormation
that gives a basis Ior or leads to the recognition oI a
pharmacotherapy problem or indication Ior pharmacist
intervention
Findings Findings (F) Subjective
data (S)

Subiective and obiective data
incorporated into same section
separated Irom
objective data
(O)
Desired
outcomes
Assessment (A)
Desired end
points
The pharmacist´s clinical iudgment based on his or her
findingsthus it is no better than the database (the
Drug-related
problems
Iindings); the assessment Iorms the basis Ior the
intervention plan
Therapeutic
selection
Resolutions/Recommendation (R)
Plan (P) Monitoring
parameters
Monitoring (M)
Follow-up

2. Devel op or i dent i f y t he CORE pharmacot herapy pI an
3

a. C = condi t i on or pat i ent need. Not e t hat t hi s may i ncl ude nonmedi cal condi t i ons
or needs and i s t hus not a r ei t erat i on of t he cur rent medi cal pr obl ems.
b. O = out come(s) desi red f or t he condi t i ons or needs.
( 1) Pati ent outcomes ( POEMS: pat i ent -or i ent ed evi dence t hat mat t ers) . Ther e are
gener al l y f i ve cat egor i es of pat i ent out comes:
( a) Mor t al i t y
( b) Mor bi di t y
( i ) Rel at ed t o di sease process
( i i ) Rel at ed t o medi cat i on/ t r eat ment pl an
( c) Behavi or
( d) Economi c
( e) Qual i t y of l i f e
( 2) Therapeut i c end poi nt s (sur rogat e markers; DOES: di sease-or i ent ed evi dence)
( a) A t herapeut i c end poi nt r epr esent s t he pharmacol ogi cal or t herapeut i c ef f ect t hat
i s expect ed, ul t i mat el y, t o achi eve t he desi r ed out come(s) .
( b) Mor e t han one end poi nt i s usual l y needed t o achi eve an out come÷f or exampl e,
bot h near - nor mal gl ycemi c cont r ol and normal i zat i on of bl ood pr essur e are
necessar y t o si gni f i cant l y r educe t he r i sk of end-st age renal di sease.
c. R = regi men t o achi eve t he desi r ed out come( s)
( 1) Therapeut i c regi mens
( a) Exi st i ng t herapy. For exampl e, a phar maci st i s asked t o wor k wi t h a pat i ent f or
whom one or mor e agent s are al r eady prescr i bed f or t he di sease pr ocess or
pr obl em.
( i ) Eval uat e t he cur r ent dr ug r egi men f or i t s pot ent i al t o achi eve desi r ed end poi nt s
and t o meet t he pat i ent ' s i ndi vi dual needs.
( i i ) Revi se t he r egi men as appr opr i at e.
( b) I ni t i aI t herapy. A phar maci st i s asked t o work wi t h a pat i ent whose condi t i on
was newl y di agnosed or i s asked t o devel op an i ni t i al t r eat ment pl an.
( i ) Li st t he t her apeut i c opt i ons ( drug and r egi men) most l i kel y t o achi eve t he desi red
end poi nt s.
( i i ) Sel ect t he opt i on best sui t ed f or t he pat i ent ' s medi cal , physi cal ( e. g. , handi cap),
psychosoci al ( e. g. , suppor t syst em) , ment al (mot i vat i on, deni al , f ear ) , and f i nanci al
wel l - bei ng.
P. 468


( 2) GoaI set t i ng and behavi or regi mens. The pat i ent i s an essent i al part ner f or
set t i ng and achi evi ng i nt er medi at e- and short - t erm goal s and t he behavi or changes
necessar y t o achi eve t hose goal s. To const r uct ef f ect i ve behavi or regi mens, t he
pharmaci st pr act i t i oner must i ncor por at e t he f ol l owi ng concept s:
( a) Ì dent i f y t he t ype of goaI bei ng set , such as t he f ol l owi ng:
( i ) St art a new posi t i ve act i on÷f or exampl e, st ar t an exer ci se pr ogr am.
( i i ) I ncrease t he f r equency or i nt ensi t y of a posi t i ve act i on÷f or exampl e, dr i nk t wo
mor e cups of wat er dai l y.
( i i i ) Stop or decrease t he f r equency or i nt ensi t y of a dest ruct i ve act i on÷f or
exampl e, st op smoki ng.
( i v) Cont i nue an act i on t hat i s " perf ect ¨ ÷f or exampl e, cont i nue t o exer ci se 30 mi n a
day, ever y day.
( b) St at e t he behavi or goal i n t erms t hat ar e cI ear, speci fi c, and reasonabI e.
( i ) Set t i me I i mi ts÷f or exampl e, " Over t he next 3 weeks. ¨
( i i ) Tar get a speci f i c act i on÷f or exampl e, " Ì wi l l wal k. ¨
( i i i ) Set measures and frequency÷f or exampl e, " si x bl ocks, t hr ee days a week. ¨
( i v) Di vi de a bi g task i nt o sever al smal l ones, maki ng each change smal l r el at i ve t o
t he cur rent pat i ent behavi or . The ol d sayi ng " Ì t ' s har d by t he yard, but a ci nch by
t he i nch¨ i s t r ue.
d. E = evaI uat i on paramet ers t o assess out come achi evement .
( 1) Ef f i cacy paramet ers. What shoul d be moni t or ed, how of t en, and by whom t o
ensur e t hat t her apeut i c end poi nt s or pat i ent out comes are bei ng achi eved.
( 2) Toxi ci t y paramet ers. What shoul d be moni t or ed, how of t en, and by whom t o
ensur e t hat adver se ef f ect s, al l er gi c react i ons, or t oxi ci t y i s not occurr i ng.
3. I dent i f y t he PRI ME pharmacot herapy probI ems or i ndi cat i ons f or phar maci st
i nt er vent i ons,
4
somet i mes r ef er r ed t o as dr ug-r el at ed pr obl ems.
5
The goal i s t o
i dent i f y act ual or pot ent i al pr obl ems t hat coul d compromi se t he desi r ed pat i ent
out comes ( Tabl e 20- 3) .
a. P = pharmaceuti caI - based probI ems
( 1) Pat i ent not recei vi ng a pr escr i bed dr ug, devi ce, or i nt er vent i on
( 2) Rout i ne moni t or i ng (l abs, scr eeni ngs, exams) mi ssi ng
Table 20-3. PRIME Pharmacotherapy Problem Types
P ÷ Pharmaceutical-based problems
• Patient not receiving a prescribed drug. device. or intervention
• Routine monitoring (labs. screenings. exams) missing
R ÷ Risks to patient
• Adverse drug reaction/drug allergy
• Potential Ior overlap oI adverse eIIects (must be kept in mind as part
oI the workup or evaluation oI any new complaint or problem
reported by patient)
I ÷ Interactions
• Drug-drug. drug-disease. drug-Iood interactions
M ÷ Mismatch between medications and condition or patient needs
• No indication Ior a current drug. device. or intervention
• Indication Ior a drug. device. or intervention but none prescribed
E ÷ Efficacy issues
• Too much oI the correct drug
• Too little oI the correct drug
• Wrong drug. device. intervention. or regimen prescribed; more
eIIicacious choice possible
Adapted with permission Irom Canaday BR. Yarborough PC. Documenting
pharmaceutical care: Creating a standard. Ann Pharmacother 1994;28:1292-
1296.

P. 469


b. R = ri sks t o pati ent
( 1) Adverse dr ug r eact i on/ dr ug al l er gy
( 2) Pot ent i al f or overl ap of adver se ef f ect s; must be kept i n mi nd as par t of t he
wor kup or eval uat i on of any new compl ai nt or probl em repor t ed by pat i ent
c. I = i nt eract i ons
( 1) Dr ug- drug, dr ug- di sease, drug- f ood, drug-l ab i nt er act i ons
d. M = mi smat ch bet ween medi cat i ons and condi t i on or pat i ent needs
( 1) No i ndi cat i on f or a cur r ent dr ug, devi ce, or i nt er vent i on
( 2) Ì ndi cat i on f or a dr ug, devi ce, or i nt er vent i on but none pr escr i bed
( 3) Percei ved or act ual bar r i ers t o i mpl ement at i on of medi cat i on or behavi or
r egi men, such as f i nanci al const rai nt s; l i f est yl e i ssues; and i nt el l ect ual , physi cal , or
emot i onal l i mi t at i ons.
e. E = ef fi cacy i ssues
( 1) Too much of t he cor rect dr ug
( 2) Too l i t t l e of t he cor r ect dr ug
( 3) Wrong dr ug, devi ce, i nt er vent i on, or r egi men pr escri bed or mor e ef f i caci ous
choi ce possi bl e
C. Documentat i on of pharmaceut i caI care. Formul at e a FARM not e or SOAP not e
t o descr i be and document t he i nt er vent i ons i nt ended or pr ovi ded by t he phar maci st .
6

Some heal t hcar e f aci l i t i es may speci f y one f ormat over t he ot her ; phar maci st s need
t o become prof i ci ent i n each.
1. Format of a FARM not e
a. F = f i ndi ngs. The pat i ent -speci f i c i nf ormat i on t hat gi ves a basi s f or , or l eads t o,
t he recogni t i on of a pharmacot her apy pr obl em or i ndi cat i on f or pharmaci st
i nt er vent i on. Wi t hi n t he FARM f or mat , f i ndi ngs i ncl ude subj ect i ve and obj ect i ve
i nf or mat i on about t he pat i ent .
b. A = assessment . The pharmaci st ' s eval uat i on of t he f i ndi ngs, i ncl udi ng
st at ement s of :
( 1) Any addi t i onal i nf or mat i on t hat i s needed t o best assess t he probl em t o make
r ecommendat i ons
( 2) The sever i t y, pri ori t y, or urgency of t he pr obl em
( 3) The short - t er m and l ong- t erm goal s of t he i nt er vent i on pr oposed or provi ded.
( a) Exampl es of short - term goaI s: el i mi nat e sympt oms, l ower bl ood pr essur e ( BP)
t o 140/ 90 mm Hg wi t hi n 6 weeks, manage acut e ast hma f l ar eup wi t hout requi r i ng
hospi t al i zat i on
( b) Exampl es of I ong- term goaI s: pr event recur rence, mai nt ai n BP at <130/ 80 mm
Hg, prevent pr ogr essi on of di abet i c ner ve di sease
c. R = resoI uti on (i ncl udi ng pr event i on) . The i nt er vent i on pl an i ncl udes act ual or
pr oposed act i ons by t he pharmaci st or r ecommendat i ons t o ot her heal t hcar e
pr of essi onal s. The r at i onal e f or choosi ng a speci f i c i nt er vent i on shoul d be st at ed.
Ì nt er vent i on opt i ons may i ncl ude t he f ol l owi ng:
( 1) Obser vi ng, reassessi ng, or f ol l owi ng÷no i nt er vent i on necessar y at t hi s t i me. Ì f
no act i on was t aken or recommended, t he FARM not e ser ves as a recor d of t he
event and shoul d const i t ut e par t of t he pat i ent ' s pharmacy char t or dat abase.
( 2) Counsel i ng or educat i ng t he pat i ent or car egi ver
( 3) Maki ng r ecommendat i ons t o t he pat i ent or caregi ver
( 4) Ì nf ormi ng t he pr escri ber
( 5) Maki ng r ecommendat i ons t o t he pr escri ber
( 6) Wi t hhol di ng medi cat i on or advi si ng agai nst use
d. M = moni tori ng and f ol l ow- up. The par amet ers and t i mi ng of f ol l ow- up moni t or i ng
t o assess t he ef f i cacy, saf et y, and out come of t he i nt er vent i on. Thi s por t i on of t he
FARM not e shoul d i ncl ude t he f ol l owi ng:
( 1) The par amet er t o be f ol l owed ( e. g. , pai n, depr essed mood, ser um pot assi um
l evel )
( 2) The i nt ent of t he moni t ori ng ( e. g. , ef f i cacy, t oxi ci t y, adverse event )
( 3) How t he paramet er wi l l be moni t or ed ( e. g. , pat i ent i nt er vi ew, serum drug l evel ,
physi cal exami nat i on)
P. 470


( 4) Frequency of moni t ori ng ( e. g. , weekl y, mont hl y)
( 5) Durat i on of moni t or i ng ( e. g. , unt i l r esol ved, whi l e on ant i bi ot i c, unt i l resol ved
t hen mont hl y f or 1 year )
( 6) Ant i ci pat ed or desi red f i ndi ng ( e. g. , no pai n, eugl ycemi a, heal i ng of l esi on)
( 7) Deci si on poi nt t o al t er t herapy when or i f out come i s not achi eved ( e. g. , pai n st i l l
pr esent af t er 3 days, mi l d hypogl ycemi a more t han t wo t i mes a week)
2. Format of a SOAP not e. The SOAP f ormat i s t he one used most of t en by medi cal
pr act i t i oners; however , when used wi t hi n t he phar maceut i cal car e cont ext , t he
cont ent of t he sect i ons must be r evi sed t o mat ch t he pharmaci st ' s l egal scope of
pr act i ce.
a. S = subj ect i ve f i ndi ngs. The pat i ent - speci f i c subj ect i ve i nf ormat i on t hat gi ves a
basi s f or, or l eads t o, t he r ecogni t i on of a phar macot herapy probl em or i ndi cat i on
f or pharmaci st i nt er vent i on. Wi t hi n t he SOAP f ormat , pat i ent f i ndi ngs are del i neat ed
i nt o subj ect i ve and obj ect i ve dat a.
( 1) Subj ect i ve dat a ar e open t o i ndi vi dual i nt er pr et at i on, wher eas obj ect i ve dat a are
easi l y dupl i cat ed or quant i f i ed. Exampl es of subj ect i ve f i ndi ngs i ncl ude t he pat i ent ' s
st at ement of compl ai nt ( t he chi ef compl ai nt ; cc) and dur at i on or sever i t y of
sympt oms.
( 2) Somet i mes, t he dat a t o be not ed are not cl earl y del i neat ed as subj ect i ve or
obj ect i ve or t her e may be a pr eponder ance of one t ype of dat a. Ì n t hese i nst ances,
t he subj ect i ve and obj ect i ve dat a may be combi ned as a si ngl e sect i on, l abel ed " S/ O
Fi ndi ngs. ¨
b. O = obj ect i ve f i ndi ngs. The pat i ent - speci f i c obj ect i ve i nf ormat i on t hat gi ves a
basi s f or, or l eads t o, t he r ecogni t i on of a phar macot herapy probl em or i ndi cat i on
f or pharmaci st i nt er vent i on. Exampl es of obj ect i ve i nf ormat i on i ncl ude l abor at or y
dat a, wei ght , hei ght , bl ood pressure, and pul se.
c. A = assessment . Ì n t he medi cal model , t he assessment st at es t he physi ci an' s
wor ki ng di agnosi s and/ or possi bl e expl anat i ons f or t he pat i ent ' s medi cal probl em(s) .
Ì n t he pharmaceut i cal car e model , however , di agnosi s i s not nor mal l y wi t hi n t he
pharmaci st ' s scope of pract i ce. Ì nst ead, t he assessment sect i on i ncl udes t he
pharmaci st ' s eval uat i on of t he subj ect i ve and obj ect i ve f i ndi ngs i n a manner si mi l ar
t o t he descri pt i on of t he assessment i n t he FARM f ormat ( see Ì V. C. 1. b) .
d. P = pI an. Ì n t he medi cal model , t he pl an st at es t he physi ci an' s i nt ended dr ug
r egi men( s), sur gi cal pr ocedures, and/ or di agnost i c t est s. Ì n t he phar maceut i cal car e
model , phar maci st s may not have t he aut hori t y t o i ni t i at e or al t er drug t her apy
r egi mens or or der l aborat or y t est s. Labor at or y or pr escri pt i ve aut hor i t y may be
gr ant ed on a st at e- byst at e basi s, under col l aborat i ve prot ocol wi t h speci f i c
physi ci an(s) or wi t hi n a speci f i c heal t hcar e f aci l i t y or syst em. Act i ons i ncl uded
wi t hi n t he pl an sect i on shoul d be i dent i f i ed as recommended act i ons when
appropr i at e. Ì n t he pharmaceut i cal car e model , t he pl an i s usual l y expanded t o
descr i be i nf ormat i on i ncl uded i n t he moni t ori ng and f ol l ow- up sect i on of t he FARM
not e ( see Ì V. C. 1. d) .
V. FOCUSED AREAS OF PRACTICE.
Thi s phr ase ref ers t o ar eas of speci al t y pr act i ce i n whi ch phar maci st s ar e
i ncreasi ngl y bei ng recogni zed f or t hei r t herapeut i c or management exper t i se. As
such, phar maceut i cal car e provi ded by t he pharmaci st i s augment ed by act i vi t i es not
nor mal l y pr ovi ded wi t hi n t he gener al i st pharmaci st r ol e. Cat egor i es of f ocused
pr act i ce may best be descri bed by t he t ype and ext ent of speci al t y act i vi t i es.
Act i vi t i es f or each descr i pt i ve l evel ar e addi t i ve t o, or augment , t he previ ous l evel ÷
t hat i s, f ocused dr ug moni t or i ng i ncor por at es and expands t he act i vi t i es of
pharmaceut i cal car e; f ocused di sease moni t or i ng i ncor por at es t he act i vi t i es of
pharmaceut i cal car e pl us f ocused drug moni t or i ng, and so on.
A. Drug moni tori ng. Speci al i zed moni t or i ng f or a speci f i c dr ug or dr ug t her apy f or a
speci f i c di sease st at e. Exampl es ar e t he f ol l owi ng:
1. Extensi ve pati ent educat i on concer ni ng t he dr ug, t he drug moni t or i ng pr ocess,
and t he phar maci st ' s and pat i ent ' s r esponsi bi l i t i es f or f ocused dr ug moni t or i ng. Ì t
must be st r essed t o t he pat i ent t hat f or t he f ocused drug moni t or i ng pr ogram t o be
ef f ect i ve, t he pharmaci st must have access t o i nf or mat i on concerni ng al l t he
medi cat i ons bei ng t aken by, or pr escri bed f or , t he pat i ent .
P. 471


2. Each t i me t he pat i ent r et urns f or a r ef i l l of t he moni t ored medi cat i on ( e. g. , f or
hyper t ensi on, di abet es, hyper l i pi demi a, ci rcul at i on, cardi ovascul ar di sease,
gl aucoma) :
a. Perf orm a compI i ance check ( expect ed versus act ual r ef i l l dat e) and det ermi ne
why t he needed medi cat i on or suppl i es ar e not bei ng r ef i l l ed. Physi cal , f i nanci al ,
i nt el l ect ual , ment al , or emot i onal i ssues may be i nvol ved, r equi ri ng r ef er ral t o ot her
heal t hcare provi ders or requi r i ng ot her i nnovat i ve sol ut i ons. Take t he r esponsi bi l i t y
and appr opri at e act i on t o r esol ve t hese i ssues.
b. Ask about t he occurr ence and f requency of si de ef fect s, especi al l y t hose rel at ed
t o qual i t y of l i f e÷such as ort host at i c hypot ensi on, changes i n sexual f unct i on,
energy l evel , exer ci se t ol er ance, hypogl ycemi a, hyper gl ycemi a, and abi l i t y t o
concent r at e. Counsel t he pat i ent about st r at egi es t o mi ni mi ze t hese ef f ect s or
cont act t he pr escri ber t o of f er opt i ons t o r esol ve t he pat i ent ' s repor t ed probl ems.
3. Wi t h each new prescri pt i on or over- t he- count er ( OTC) medi cat i on added t o t he
moni t ored dr ug r egi men, obser ve and counsel t he pat i ent concer ni ng t he f ol l owi ng:
a. Dr ugs t hat may af f ect t he ef f i cacy of t he moni t or ed dr ug ( drug-di sease and dr ug-
dr ug i nt er act i ons) . For exampl e, wi t h di abet es medi cat i ons:
( 1) Cer t ai n drugs may di r ect l y change bl ood gl ucose l evel s.
( 2) Cer t ai n drugs may i ndi r ect l y change bl ood gl ucose l evel s by i nt eract i ng wi t h t he
hypogl ycemi c agent .
b. Dr ugs t hat may af f ect t he cour se of t he di sease f or t he moni t ored dr ug. For
exampl e, cer t ai n dr ugs added t o a di abet es r egi men may af f ect t he compl i cat i ons of
di abet es by aggr avat i ng neuropat hy and nephr opat hy as a r esul t of decreased
ci rcul at i on.
c. Dr ugs t hat may af f ect comor bi di t y condi t i ons of t he di sease f or t he moni t or ed
dr ug. For exampl e, cert ai n dr ugs added t o a di abet es r egi men may af f ect concur rent
hyper t ensi on, l i pi d abnormal i t i es, and ot her condi t i ons t hat occur mor e f r equent l y i n
t he di abet i c popul at i on.
4. Remi nd and encour age pat i ent s t o adhere t o schedul es f or r ecommended
I aborat or y t est s dur i ng t he cour se of t he drug t her apy. Exampl es i ncl ude
pr ot hr ombi n t i me t est s, l i ver f unct i on t est s, eye exami nat i ons, and r enal f unct i on
t est s. Adher ence t o such moni t or i ng par amet ers wi l l al l ow pr event i on or ear l y
det ect i on and t reat ment of cer t ai n adverse dr ug ef f ect s.
B. Di sease moni t ori ng. Speci al i zed moni t or i ng f or a speci f i c di sease st at e.
Di sease- moni t ori ng act i vi t i es ar e opt i mal l y per f ormed at r egul ar i nt er val s ( e. g. , at
set appoi nt ment t i mes) , but shoul d at l east be per f or med each t i me t he pat i ent
r et urns f or ref i l l of a di sease- r el at ed medi cat i on or suppl y.
1. A f ocused di sease-moni t or i ng program i s ext ensi ve i n t i me, ef f or t , and pat i ent
educat i on. At t hi s l evel , however , t he pharmaci st does not i ni t i at e changes i n
pharmacol ogi cal t herapi es. Recommendat i ons f or changes ar e r el ayed t o t he
medi cal pr ovi der , who t hen di r ect s t he pharmaci st concer ni ng speci f i c r egi men
adj ust ment s.
2. Exampl es of f ocused di sease-moni t or i ng act i vi t i es are t he f ol l owi ng:
a. Extensi ve pati ent educat i on concer ni ng t he di sease and i t s t reat ment , t he
di sease-moni t or i ng pr ocess, and t he phar maci st ' s and pat i ent ' s responsi bi l i t i es f or
f ocused di sease moni t or i ng. Educat i on wi l l l i kel y be needed i ni t i al l y and per i odi cal l y
dur i ng t he moni t or i ng progr am.
b. Focused moni t ori ng of a chr oni c di sease woul d i ncl ude pat i ent educat i on t o
est abl i sh t he pat i ent ' s desi red t arget s or goal s and st r at egi es t o at t ai n t hem.
( 1) Encour age and assi st pat i ent s t o set l ong- t erm goal s÷f or exampl e, l ose 30 l b or
qui t smoki ng.
( 2) Encour age and assi st pat i ent s t o set short - t erm goal s t hat are di r ect ed t owar d
meet i ng t he l ong- t er m goal s÷f or exampl e, l ose 1 l b i n 1-2 weeks or decrease
smoki ng by one ci gar et t e per day.
c. Assessment f or subj ect i ve evi dence of i mpr ovement or wor seni ng of di sease
sympt oms.
( 1) The f requent or consi st ent occur rence of cer t ai n sympt oms (such as ast hma
at t acks, hypogl ycemi a, chest pai n, di ar rhea f r om ul cer at i ve col i t i s) shoul d be
br ought t o t he at t ent i on of t he medi cal pr ovi der .
P. 472


( 2) Lack of subj ect i ve evi dence of ef f i cacy (f ai l ure of pai n cont r ol , mi ni mal or no
i mprovement of noct ur i a) shoul d al so be r epor t ed t o t he pr escri ber .
( 3) The pat i ent ' s report of days of wor k or school mi ssed owi ng t o exacerbat i on of
di sease sympt oms i s a val uabl e assessment of di sease cont rol or t reat ment .
d. Assessment f or obj ect i ve evi dence or cer t ai n i ndi ces of di sease cont rol or
t r eat ment . For exampl e, a phar maci st may r evi ew and gui de a di abet i c pat i ent i n
i nt er pr et at i on of sel f -moni t or ed bl ood gl ucose ( SMBG) r ecords. Usi ng t hese dat a,
t he pharmaci st can t hen advi se t he pat i ent concer ni ng t he appl i cat i on of a
pr escri bed i nsul i n adj ust ment al gori t hm.
( 1) Some dat a may be pat i ent deri ved, such as SMBG, wei ght , measurement of cal f
ci rcumf erence, and r eadi ngs f r om a peak- f l ow met er .
( 2) Some dat a may be phar maci st i ni t i at ed, such as a pharmacy- based l i pi d-
moni t ori ng program, bl ood gl ucose t est i ng, and bl ood pr essur e measur ement s. Ì t
shoul d be not ed t hat a phar macy may need t o be CI i ni caI Laborat ori es
I mprovement Act ( CLÌ A) cert i f i ed bef ore per f ormi ng cer t ai n wai ved or moder at el y
compl ex l aborat or y pr ocedures.
( 3) Some dat a may be obt ai ned t hrough t he physi ci an' s of f i ce; a copy i s f or war ded
t o t he pharmaci st or br ought i n by t he pat i ent .
C. Drug/ di sease management by prot ocoI . The component s of t hi s f ocused
pr act i ce i ncl ude t he f ol l owi ng:
1. Di sease and dr ug moni t ori ng, i ncl udi ng a si gni f i cant component of pat i ent
educat i on
2. Di sease and qual i t y- of - l i f e out comes i dent i f i ed and agreed on by pat i ent , medi cal
pr ovi der , and phar maci st
3. Appl i cat i on of a dr ug-di sease-management prot ocol , devel oped as a col l aborat i ve
wor k r el at i onshi p bet ween phar maci st and medi cal provi der, whi ch el abor at es
speci f i c aut hor i zat i ons or l i mi t at i ons f or t he phar maci st ' s act i vi t i es. Component s of
a dr ug- di sease-management prot ocol may i ncl ude t he f ol l owi ng:
a. Pr ocess by whi ch t he physi ci an ref ers t he pat i ent t o t he phar maci st
b. Dr ugs, devi ces, medi cal t reat ment , t est s and pr ocedures t hat may be pr escr i bed,
admi ni st er ed, or order ed, as appr opr i at e f or t he t r eat ment of t he heal t h probl em
addressed by t he pr ot ocol
( 1) Dr ug i ni t i at i on, dosage adj ust ment and/ or di scont i nuat i on
( 2) Speci f i c l abor at or y order s and i nt er pr et at i on
c. Li mi t ed physi cal assessment
d. Ì nt egrat i on of t he phar maceut i cal car e pl an i nt o t he t ot al medi cal care pl an f or
t he pat i ent
e. Pr edet er mi ned pl an f or emer gency ser vi ces
f . Wri t t en communi cat i on/ document at i on t o/ f r om medi cal pr ovi der (e. g. , char t access
and not e ent r y)
VI. CLINICAL SKILLS AND PHARMACIST' S ROLES IN
PHARMACEUTICAL CARE.
The ski l l s, act i vi t i es, and ser vi ces i nher ent i n t he pr ovi si on of phar maceut i cal car e
i ncl ude t he f ol l owi ng:
A. Pat i ent assessment
1. Physi cal assessment
2. Bar ri ers t o adher ence
3. Psychosoci al i ssues
B. Pat i ent educat i on and counseI i ng
1. Ì nt er vi ew ski l l s
2. Communi cat i on ski l l s ( e. g. , empat hy, l i st eni ng, speaki ng or wr i t i ng at t he
pat i ent ' s l evel of under st andi ng)
P. 473


3. Abi l i t y t o mot i vat e, i nspi r e
4. Devel op and i mpl ement a pat i ent educat i on pl an based on an i ni t i al educat i on
assessment
5. Ì dent i f i cat i on and r esol ut i on of compl i ance bar ri er s
C. Pat i ent - speci f i c pharmaci st care pI ans
1. Recogni t i on, pr event i on, and management of dr ug i nt er act i ons
2. Phar macol ogy and t her apeut i cs ( i nnovat i ve and convent i onal )
3. Ì nt erpr et at i on of l aborat or y t est s
4. Knowl edge of communi t y r esources, pr of essi onal ref er ral s
5. Communi cat i on and r appor t wi t h communi t y medi cal pr ovi ders
D. Drug- t reat ment protocoI s
1. Devel op and mai nt ai n ( updat e) pr ot ocol s.
2. Fol l ow pr ot ocol s as a pharmaci st cl i ni ci an.
3. Moni t or aggr egat e adher ence t o t r eat ment prot ocol s ( e. g. , dr ug- use eval uat i ons;
DUEs) , especi al l y f or a managed- car e or heal t h-syst em f aci l i t y.
E. Dosage adj ust ment
1. Ì dent i f y pat i ent s at ri sk f or exaggerat ed or subt her apeut i c response.
2. Appl y pharmacoki net i c pri nci pl es t o det ermi ne pat i ent - speci f i c dosi ng.
3. Or der and i nt er pr et r el evant t est s at cor r ect t i me i nt er val s t o assess dosage
adj ust ment (e. g. , pl asma dr ug concent r at i ons, bl ood gl ucose l evel s, bl ood pr essure
measurement s) .
F. SeI ecti on of t herapeut i c aI t ernat i ves
1. Use drug i nf ormat i on resour ces ef f ect i vel y.
2. Revi ew and cr i t i que drug l i t er at ur e.
3. Const ruct comparat i ve anal yses t o suppor t t her apeut i c deci si ons.
G. Prescri pt i ve aut hori ty i n desi gnat ed pract i ce si t es or posi t i ons
H. Prevent i ve servi ces
1. Ì mmuni zat i ons
2. Scr eeni ngs
3. Heal t h and wel l ness educat i on
I . Manageri aI ski I I s
1. PI an, di rect , and i mpI ement pharmaceut i cal - car e act i vi t i es wi t hi n a var i et y of
pr act i ce envi r onment s, such as communi t y pharmacy, ambul at or y- car e set t i ngs,
managed or cont ract ual car e, home- heal t h ser vi ces, l ong- t er m-car e f aci l i t i es,
i npat i ent hospi t al pract i ce, and ot her s.
2. AI I ocate r esour ces.
VII. PHARMACEUTICAL CARE AS THE MODEL FOR
PHARMACY PRACTICE.
The concept s, act i vi t i es, and ser vi ces of pharmaceut i cal car e f orm t he basi s f or
pr ovi si on of cl i ni cal ser vi ces di r ect l y t o, and f or t he benef i t of , pat i ent s i n al l
pharmacy pr act i ce set t i ngs. These set t i ngs i ncl ude home-heal t h, hospi t al ,
ambul at or y- car e, pri mary- car e, consul t at i on, l ong- t erm- car e, and communi t y
pharmacy pr act i ce. Wor k f l ow, st af f i ng pat t erns, pr ocesses, and pharmacy pr ograms
mi ght di f f er , but t he cor e approach t o pat i ent care r emai ns phar maceut i cal car e i n
al l set t i ngs.
P. 474


VIII. DOCUMENTATION OF PHARMACEUTICAL CARE.
" Ì f i t i sn' t document ed, i t i sn' t done! ¨ Document at i on of pharmaceut i cal car e i s
i nt egr al t o cont i nui t y of car e, demonst rat i on of cl i ni ci an compet ence, communi cat i on
among heal t h- car e pr ovi der s, evi dence of cont ri but i ons t o pat i ent car e, and
r ei mbursement of prof essi onal ser vi ces.
A. Pharmaceut i caI care, i ncl udi ng t he phar maceut i cal car e pl an pr ocess ( CORE,
PRÌ ME, FARM, or SOAP) , i s a syst emat i c met hod f or r ecordi ng t he phar maci st ' s
exami nat i on of a pat i ent ' s pharmacot her apy and subsequent i dent i f i cat i on of
medi cat i on- rel at ed probl ems.
B. Comput er sof tware programs, i n most pract i ce set t i ngs, mai nt ai n pat i ent dat a
and dr ug- prof i l e recor ds. Thus af t er document at i on of t he i ni t i al phar maceut i cal car e
pl an, pat i ent dat a or drug r egi mens ar e i ncl uded i n subsequent FARM ( or SOAP)
not es onl y i f a change occur s t hat i s rel evant t o t he t herapeut i c i ssue bei ng
addressed i n t he not e.
C. Forms t hat summar i ze phar maci st s' i nt er vent i ons usi ng a uni fi ed codi ng syst em
ar e usef ul f or pr ocessi ng r ei mbur sement or bi l l i ng f orms, but t hese f or ms ar e not
adequat e document at i on of pharmaceut i cal car e. These f orms do not communi cat e
t o ot her heal t h prof essi onal s t he dept h and qual i t y of phar maci st i nt er vent i ons or
t he pharmaci st ' s pl an f or ongoi ng pharmaceut i cal care.
IX. PHARMACEUTICAL CARE: AN ONGOING PROCESS.
The pat i ent prof i I e ( dat abase) i s r evi sed and reassessed each t i me a new dr ug i s
added t o or del et ed f r om t he medi cat i on r egi men, a new di sease or condi t i on i s
di agnosed, or t he pat i ent under goes ot her cl i ni cal i nt er vent i on, such as sur ger y.
When t he pat i ent r et ur ns t o t he phar macy or i s r eadmi t t ed t o t he heal t h syst em
f aci l i t y, t he pharmaci st uses t he pat i ent pr of i l e, PWDT, and FARM ( or SOAP) not es
( mai nt ai ned i n t he pat i ent phar macy chart or i n t he medi cal chart ) as t he basi s f or
ongoi ng pharmaci st - pat i ent i nt er act i ons.
X. IMPORTANCE OF PHARMACEUTICAL CARE IN
TODAY' S PHARMACY PRACTICE
A. The pot ent i al f or medi cat i on errors i s gr owi ng, and one pr of essi onal gr oup must
assume a pri mar y r ol e i n addressi ng t hi s i ssue, rat her t han vari ous gr oups or
i ndi vi dual s maki ng f ragment ed ef f ort s. The pharmaci st i s t r ai ned speci f i cal l y t o
address t hese t herapeut i c i ssues.
B. The use of pr escri pt i on and nonpr escri pt i on medi cat i ons i s gr owi ng and now
const i t ut es t he pri mar y t her apeut i c modal i t y avai l abl e t o heal t hcar e pr act i t i oner s
and pat i ent s.
C. The number , compl exi t y, and pot ency of pr escri pt i on and nonprescr i pt i on dr ug
pr oduct s ar e i ncr easi ng.
D. The need f or phar maceut i cal car e secur es an endur i ng r ol e f or t he phar maci st i n
t he U. S. heal t hcar e syst em. Ever y encount er wi t h pat i ent s, regardl ess of pr act i ce
set t i ng, pr ovi des phar maceut i cal car e.
E. Pharmaceut i cal - car e act i vi t i es i nt egrat e pharmaci st s i nt o t he heal t hcar e syst em
of t he f ut ure.
P. 475


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. Whi ch of the foI I owi ng stat ements best descri bes FARM?
( A) cul t i vat i on of a pharmaci st ' s knowl edge t o bet t er ser ve t he publ i c
( B) f i ndi ngs, assessment , r esol ut i on, moni t or i ng
( C) f i ndi ngs, assessment , r ecogni t i on, management
( D) t he pr ocess by whi ch an i ndi vi dual phar maci st i nt er act s wi t h a speci f i c pat i ent t o
at t ai n per t i nent medi cal i nf ormat i on
Vi ew Answer 1. The answer i s B[ see] . 2. An exampI e of an expanded roI e
of t he pharmaci st i s
( A) communi t y l eader .
( B) pr eparat i on of compounded pr escri pt i ons.
( C) mai nt ai ni ng adequat e i nvent or y of or phan drugs.
( D) t r i age of pat i ent s.
Vi ew Answer 2. The answer i s D[ see] . 3. What i s t he most i mportant f ocus
of pharmaceuti caI care?
( A) phar maci st
( B) pat i ent
( C) pr escri pt i on
( D) pat i ent chart
Vi ew Answer 3. The answer i s B[ see] . 4. Whi ch of t he f oI I owi ng st atement s
regardi ng pharmaceut i caI care i s t rue? Pharmaceuti caI care
( A) usual l y does not over l ap i nt o ot her areas of heat h car e.
( B) and cl i ni cal phar macy ar e synonymous.
( C) i mpl i es t hat t he pharmaci st i s no l onger r esponsi bl e f or di spensi ng f unct i ons.
( D) i s based on st r at egi es t o provi de cont i nuous pat i ent car e t o at t ai n desi r ed
out comes.
Vi ew Answer 4. The answer i s D[ see] . pharmaceut i cal care5. Essent i aI
component s of pharmaceut i caI care i ncI ude
( A) pat i ent - pharmaci st rel at i onshi p, l egi bl e physi ci an or der s, and accurat e dat a
col l ect i on.
( B) phar maci st - pat i ent rel at i onshi p and wor kup of dr ug t her apy.
( C) a sof t war e pr ogr am t hat accesses medi cat i on hi st or y and pr ompt s t he
pharmaci st concer ni ng quest i ons t o ask t he pat i ent .
( D) mai nt enance of pat i ent medi cat i on hi st or y f or at l east 2 years and a f ocus on
acut e i l l ness.
Vi ew Answer 5. The answer i s B[ seeand] . 6. I n the CORE pharmacot herapy
pI an, what does t he E st and for?
( A) educat i on of pat i ent or car egi ver
( B) ef f i cacy i ssues
( C) el aborat i on
( D) eval uat i on paramet ers
Vi ew Answer 6. The answer i s D[ see] . 7. The most i mport ant reason f or
usi ng t he FARM note i s t o
( A) col l ect i nf ormat i on f or t he physi ci an.
( B) document probl em- sol vi ng and/ or i nt er vent i ons per f or med by t he phar maci st .
( C) keep a l og of al l dr ug i nt er act i ons.
( D) cr eat e a uni f orm met hod of recor di ng pat i ent i nf or mat i on.
Vi ew Answer 7. The answer i s B[ see] . 8. Whi ch of t he f oI I owi ng t opi cs
wouI d not be i ncI uded i n t he assessment port i on of the FARM not e?
( A) r ecommendat i ons made t o t he pat i ent or caregi ver
( B) sever i t y, pr i or i t y, or ur gency of t he pr obl em
( C) shor t - t er m and l ong- t er m goal s of t he i nt er vent i on
( D) addi t i onal i nf or mat i on t hat i s needed t o best assess t he pr obl em
Vi ew Answer 8. The answer i s A[ see] . 9. I mmuni zat i ons, screeni ngs, and
weI I ness educat i on are exampI es of whi ch cI i ni caI ski I I ?
( A) communi t y heal t h over vi ew
( B) pat i ent medi cat i on educat i on and counsel i ng
( C) pr event i ve ser vi ces
( D) manager i al ser vi ces
Vi ew Answer 9. The answer i s C[ see] . 10. The pharmaci st' s roI e i n t he
seI ect i on of t herapeuti c aI ternati ves requi res whi ch of t he f oI I owi ng cI i ni caI
ski I I s?
( A) r evi ew and cr i t i que dr ug l i t er at ur e
( B) mot i vat e and i nspi r e pat i ent s
( C) per f orm drug- use eval uat i ons ( DUEs)
( D) knowl edge of communi t y r esour ces
Vi ew Answer 10. The answer i s A[ see] . P. 476


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì V. C] .
A FARM pr ogr ess not e i s used t o descr i be and document t he i nt er vent i ons i nt ended
or provi ded by t he pharmaci st . The acr onym FARM st ands f or f i ndi ngs, assessment ,
r esol ut i on, and moni t or i ng and f ol l ow- up.
2. The answer i s D [ see Ì Ì . A] .
Phar maceut i cal car e has evol ved f r om an emphasi s on prevent i on of dr ug- r el at ed
pr obl ems t o t he expanded r ol es of t r i age of pat i ent s, t r eat ment of r out i ne acut e
i l l nesses, management of chr oni c di seases, and pr i mar y di sease pr event i on.
3. The answer i s B [ see Ì V. A] .
Phar maceut i cal car e i s based on a col l abor at i ve ef f ort bet ween pharmaci st and
pat i ent .
4. The answer i s D [ see Ì . B; Ì X] .
The t erm phar maceut i cal care descr i bes speci f i c act i vi t i es and ser vi ces t hr ough
whi ch an i ndi vi dual pharmaci st cooperat es wi t h a pat i ent and ot her prof essi onal s i n
desi gni ng, i mpl ement i ng, and moni t or i ng a t herapeut i c pl an t hat wi l l produce
speci f i c t her apeut i c out comes f or t he pat i ent . The pat i ent pr of i l e ( dat abase) i s
r evi sed and t he pot ent i al f or dr ug- r el at ed probl ems i s reassessed each t i me a new
dr ug i s added t o or del et ed f rom t he medi cat i on regi men, a new di sease or condi t i on
i s di agnosed, or t he pat i ent under goes ot her cl i ni cal i nt er vent i on (e. g. , sur ger y) .
5. The answer i s B [ see Ì V. A and B] .
The essent i al component s of phar maceut i cal car e ar e t he phar maci st - pat i ent
r el at i onshi p and t he phar maci st ' s wor kup of dr ug t herapy.
6. The answer i s D [ see Ì V. B. 2] .
The acronym CORE ref er s t o t he component s of t he pharmacot herapy pl an, whi ch i s
par t of t he phar maci st ' s wor kup of drug t herapy. CORE st ands f or condi t i on ( or
pat i ent need) , out come (desi r ed f or t hat condi t i on) , r egi men ( sel ect ed t o achi eve
t hat out come), and eval uat i on par amet er s ( t o assess out come achi evement ) .
7. The answer i s B [ see Ì V. C; VÌ Ì Ì ; Ì X] .
The FARM not e i s t he phar maci st ' s progress not e, descri bi ng and document i ng t he
i nt er vent i ons i nt ended or pr ovi ded by t he pharmaci st . Thi s const i t ut es t he pr ogr ess
not e i n t he medi cal char t ( i n heal t h- syst em f aci l i t i es) or i n t he pharmacy pat i ent
chart ( i n communi t y pharmacy or si t es wi t hout r eady access t o t he medi cal chart ) .
8. The answer i s A [ see Ì V. C] .
The assessment por t i on of t he FARM not e st at es t he pharmaci st ' s eval uat i on of t he
f i ndi ngs. Recommendat i ons ar e made t o t he pat i ent or car egi ver t o resol ve or
pr event an act ual or pot ent i al pr obl em i dent i f i ed by t he phar maci st . Thus such
r ecommendat i ons woul d be i ncl uded i n t he r esol ut i on port i on of t he FARM not e.
9. The answer i s C [ see VÌ . H] .
Ì mmuni zat i ons, screeni ngs, and heal t h and wel l ness educat i on ar e exampl es of
cl i ni cal ski l l s used i n a phar maci st ' s pr ovi si on of pr event i ve ser vi ces.
10. The answer i s A [ see VÌ . F] .
For ef f ect i ve sel ect i on of t herapeut i c al t er nat i ves, a pharmaci st woul d use cer t ai n
cl i ni cal ski l l s, i ncl udi ng use of dr ug i nf ormat i on resour ces, comparat i ve anal yses,
and revi ew and cri t i que of drug l i t er at ur e.

21
Drug Information Resources
PauI F. Souney
Conni e Lee Barnes
VaI eri e B. CI i nard
I. DEFINITION.
Dr ug i nf or mat i on i s curr ent , cr i t i cal l y exami ned, rel evant dat a about dr ugs
and dr ug use i n a gi ven pat i ent or si t uat i on.
A. Current i nf ormat i on uses t he most r ecent , up- t o- dat e sour ces possi bl e.
B. Cri t i caI I y exami ned i nf ormati on shoul d meet t he f ol l owi ng cri t eri a:
1. Mor e t han one sour ce shoul d be used when appr opri at e.
2. The ext ent of agreement of sour ces shoul d be det er mi ned; i f sour ces do
not agr ee, good j udgment shoul d be used.
3. The pl ausi bi l i t y of i nf or mat i on, based on cl i ni cal ci rcumst ances, shoul d
be det ermi ned.
C. ReI evant i nformati on must be pr esent ed i n a manner t hat appl i es
di r ect l y t o t he ci r cumst ances under consi der at i on ( e. g. , pat i ent par amet er s,
t her apeut i c obj ect i ves, al t ernat i ve appr oaches) .
II. DRUG INFORMATION RESOURCES.
Ther e are t hr ee sources of drug i nf or mat i on: j ournal s ( pr i mar y sources) ,
i ndexi ng and abst r act i ng ser vi ces (secondar y sour ces) , and t ext book
dat abases ( t er t i ar y sources) .
A. Pri mar y sources
1. Benef i ts. Jour nal art i cl es pr ovi de t he most cur r ent i nf ormat i on about
dr ugs and, i deal l y, shoul d be t he source f or answer i ng t her apeut i c
quest i ons. Jour nal s enabl e phar maci st s t o:
a. Keep abr east of prof essi onal news
b. Lear n how anot her cl i ni ci an handl ed a par t i cul ar probl em
c. Keep up wi t h new devel opment s i n pat hophysi ol ogy, di agnost i c agent s,
and t herapeut i c r egi mens
d. Di st i ngui sh usef ul f r om usel ess or even har mf ul t her apy
e. Enhance communi cat i on wi t h ot her heal t hcar e pr of essi onal s and
consumers
f . Obt ai n cont i nui ng educat i on credi t s
g. Shar e opi ni ons wi t h ot her heal t hcare prof essi onal s t hr ough l et t ers t o t he
edi t or
h. Pr epare f or t he board cer t i f i cat i on exami nat i on i n pharmacot herapy,
nut ri t i on support , oncol ogy, et c.
2. Li mi t at i ons. Al t hough publ i cat i on of an ar t i cl e i n a wel l - known,
r espect ed j our nal enhances t he cr edi bi l i t y of i nf or mat i on cont ai ned i n an
ar t i cl e, t hi s does not guar ant ee t hat t he ar t i cl e i s accur at e. Many ar t i cl es
possess i nadequaci es t hat become apparent as t he abi l i t y t o eval uat e dr ug
i nf or mat i on i mpr oves.
3. Revi ew arti cI es (narrat i ve revi ews, syst emat i c revi ews, and met a-
anaI yses) , art i cI es of opi ni on, correspondence, speci aI report s.
Al l mat er i al i ncl uded i n a j our nal i s not consi der ed a pr i mar y r esour ce.
Or i gi nal cl i ni cal t r i al s are consi der ed pri mar y l i t er at ure; however , r evi ew
ar t i cl es, ar t i cl es of opi ni on, cor respondence, and speci al r epor t s are not .
B. Secondar y sources
1. Benef i ts. Ì ndexi ng and abst ract i ng ser vi ces are val uabl e t ool s f or qui ck
and sel ect i ve scr eeni ng of t he pr i mar y l i t erat ur e f or speci f i c i nf ormat i on,
dat a, ci t at i on, and ar t i cl es ( Tabl e 21-1) .
P. 478

Ì n some cases, t he sources provi de suf f i ci ent i nf or mat i on t o ser ve as
r ef erences f or answer i ng dr ug i nf ormat i on r equest s.
Table 21-1. Examples of Abstracting and Indexing Services
Secondary References
1ournals
Indexed
Approximate Lag
Time
CINAHL
*
2.717
ClinAlert 150 1-6 weeks
Current Contents Connect 8000 1-6 weeks
Embase 7000 10 days
Medline/PubMed 5000 1 week
Inpharma 1800 3 weeks
International Pharmaceutical
Abstracts
800 3-4 weeks
Iowa Drug InIormation System 340 30-60 days
Pharmaceutical News Index 2-8 weeks
Reactions 1800 3 weeks
Science Citation Index 3700 3 months
*
Cumulative Index to Nursing and Allied Health Literature

2. Li mi t at i ons. Each i ndexi ng or abst r act i ng ser vi ce r evi ews a f i ni t e
number of j our nal s. Theref or e, r el yi ng on onl y one ser vi ce can gr eat l y
hi nder t he t hor oughness of a l i t er at ur e search. Anot her i mpor t ant f act t o
r emember i s t he subst ant i al di f f erence i n l ag t i me ( i . e. , t he i nt er val bet ween
t he publ i cat i on of an ar t i cl e and t he ci t at i on of t hat art i cl e i n an i ndex)
among t he avai l abl e servi ces. Several exampl es ar e gi ven i n Tabl e 21-1.
a. Secondar y sour ces usual l y descri be onl y ar t i cl es and cl i ni cal st udi es
f r om j our nal s. Frequent l y, r eader s r espond t o, cri t i ci ze, and add new
i nf or mat i on t o publ i shed ar t i cl es and st udi es t hr ough l et t ers. Ser vi ces such
as Medl i ne/ PubMed or t he Ì owa Dr ug Ì nf ormat i on Ser vi ce general l y do
i ncl ude per t i nent l et t ers t o t he edi t or wi t hi n t he scope of cover age.
b. Ì ndexi ng and abst r act i ng ser vi ces are pri mar i l y used t o I ocate j ournal
ar t i cl es. Ì n gener al , abst r act s shoul d not be used as pr i mar y sour ces of
i nf or mat i on because t hey ar e general l y i nt er pr et at i ons of a st udy and may
be a mi si nt er pret at i on of i mpor t ant i nf ormat i on. Phar maci st s shoul d obt ai n
and eval uat e t he ori gi nal ar t i cl e because abst r act s may not i ncl ude enough
i nf or mat i on t o cr i t i cal l y eval uat e t he st udy.
C. Tert i ar y sources
1. Benef i ts.
a. Text books. Gener al ref er ence t ext books can pr ovi de easy and
conveni ent access t o a br oad spect r um of r el at ed t opi cs. Background
i nf or mat i on on dr ugs and di seases i s of t en avai l abl e. Al t hough a t ext book
mi ght answer many dr ug- r el at ed quest i ons, t he l i mi t at i ons of t hese sources
shoul d not be overl ooked.
( 1) Ì t coul d t ake sever al year s t o publ i sh a t ext , so i nf ormat i on avai l abl e i n
t ext books mi ght not i ncl ude t he most recent devel opment s i n t he f i el d.
Ot her resources shoul d be used t o updat e or suppl ement i nf ormat i on
obt ai ned f rom t ext books.
( 2) The aut hor of a t ext book mi ght not have conduct ed a t hor ough search of
t he l i t er at ur e, so per t i nent dat a coul d have been omi t t ed. An aut hor al so
mi ght have mi si nt erpr et ed t he pri mar y or secondar y l i t erat ur e. Ref erence
ci t at i ons shoul d be avai l abl e t o ver i f y t he val i di t y and accur acy of t he dat a.
b. Databases. Comput er dat abases ar e conveni ent , easy t o use, and
r ef erenced. These r esour ces are si mi l ar t o t ext books, but ar e t ypi cal l y
updat ed mor e f r equent l y. Comput er dat abases are easy t o search and ar e
of t en usef ul r esources f or dr ug monogr aphs, pi l l i dent i f i cat i ons, drug
i nt er act i ons, and vari ous t herapeut i c cal cul at i ons. Addi t i onal l y, comput er
dat abases may addr ess cl i ni cal quest i ons. Ì n some i nst ances, a PDA
ver si on of t he dat abase i s avai l abl e. Exampl es i ncl ude Cl i ni cal
Phar macol ogy On Hand, Cl i ni cal Xper t , Lexi - Comp On- Hand, and e-
Pocr at es Rx.
2. GeneraI consi derat i ons when exami ni ng and usi ng t ext books and/ or
dat abases as sources of dr ug i nf ormat i on i ncl ude t he f ol l owi ng:
a. The aut hor , publ i sher , or bot h: What ar e t he aut hor ' s and publ i sher ' s
ar eas of exper t i se?
b. The year of publ i cat i on ( copyr i ght dat e) or l ast r evi si on dat e?
P. 479


c. The edi t i on of t he t ext : Ì s i t t he most cur r ent edi t i on?
d. The presence of a bi bl i ogr aphy: Ì f a bi bl i ogr aphy i s i ncl uded, ar e
i mpor t ant st at ement s accur at el y ref erenced? When wer e t he ref erences
publ i shed?
e. The scope of t he t ext book or dat abase: How accessi bl e i s t he
i nf or mat i on?
f . Al t er nat i ve resources t hat ar e avai l abl e (e. g. , pr i mar y and secondar y
sources, ot her rel evant t ext s)
III. INTERNET
A. Benef i t s. The Ì nt ernet expands t he abi l i t y t o sear ch t her api es t hat have
been r ecent l y publ i shed or di scussed i n t he medi a. An Ì nt er net sear ch may
be r equi r ed f or t he f ol l owi ng: company- speci f i c i nf ormat i on, i ssues cur rent l y
i n t he news, al t ernat i ve medi ci ne, or U. S. government i nf ormat i on. The
most popul ar Web browser s ar e Mozi l l a Fi r ef ox and Mi cr osof t Ì nt er net
Expl or er . A vari et y of sear ch engi nes, sof t war e t ool s f or searchi ng t he
Ì nt ernet , have been devel oped. General sear ch engi nes ( Al t aVi st a, Googl e,
Yahoo, Ask, Dogpi l e) at t empt t o i ndex as much of t he Ì nt er net as possi bl e.
B. Li mi t at i ons
1. Unl i ke i nf or mat i on publ i shed i n j ournal s and t ext books, i nf ormat i on
obt ai ned f rom t he Ì nt ernet may not be peer revi ewed or edi t ed bef ore
r el ease.
2. Ì nf ormat i on r ecei ved f r om t he Ì nt er net may be onl y as rel i abl e as t he
per son who post ed i t and t he users who r ead and comment on i t s cont ent . A
Web si t e shoul d be eval uat ed by i t s source (aut hor ) of i nf ormat i on. The
name, l ocat i on, and sponsorshi p shoul d be di scl osed. Al so, a r eput abl e si t e
wi l l pr ovi de easy access t o i nf ormat i on and t he abi l i t y t o gi ve f eedback.
Phar maci st s shoul d use t r adi t i onal l i t erat ur e eval uat i on ski l l s t o det ermi ne
whet her i nf ormat i on on Web si t e i s cl ear , conci se, unbi ased, r el evant , and
r ef erenced.
C. Use. To obt ai n i nf ormat i on f rom t he Ì nt ernet , t he user must have an
address ( ref er red t o as a URL, or uni f or m resource l ocat or ) t o t ype i nt o t he
br owser , whi ch wi l l t hen f i nd t he si t e aut omat i cal l y. Many associ at i ons and
or gani zat i ons have Web si t es t hat are l i nked t o ot her Web pages. Tabl e 21-
2 pr ovi des a sel ect i on of Web si t es.
IV. STRATEGIES FOR EVALUATING INFORMATION
REQUESTS.
Ì t i s i mpor t ant t o obt ai n as much i nf or mat i on as possi bl e about drug
i nf or mat i on request s bef or e begi nni ng a l i t er at ure search. Bot h t i me and
money can be l ost doi ng a vast search. Bel ow are i mport ant quest i ons t o
ask t he i nqui r er or t o eval uat e bef or e a manual or comput eri zed sear ch.
A. Converse wi t h t he i nqui rer. Bef or e spendi ng t i me searchi ng f or
i nf or mat i on, t al k t o t he per son who i s request i ng t he i nf or mat i on and
acqui re any necessar y addi t i onal i nf ormat i on.
1. Determi ne t he reason f or t he i nqui r y. Fi nd out wher e t he i nqui r er hear d
or r ead about t he dr ug. Ì s he or she t aki ng t he medi cat i on? Ì f so, why?
Because t he sear ch can be done by t he dr ug or di sease name, det er mi ne i f
t he i nqui rer has a medi cal condi t i on. Ascer t ai ni ng t he r eason f or t he i nqui r y
hel ps det er mi ne what addi t i onal i nf or mat i on shoul d be provi ded. For
exampl e, i f t he i nqui r y concer ns a f orei gn dr ug, t he i nqui r er mi ght ask f or a
domest i c equi val ent .
2. CI ari f y t he drug' s i dent i f i cat i on and avai I abi I i t y. Make sur e t hat t he
dr ug i n quest i on i s avai l abl e and doubl e-check i nf ormat i on about t he drug,
such as:
a. The correct speI I i ng of t he dr ug' s name
b. Whet her i t i s a generi c or brand name drug
c. What pharmaceut i caI company manuf act ures t he dr ug and i n what
count r y t he dr ug i s manuf act ured
d. Whet her t he dr ug i s prescri pt i on or nonprescri pt i on
e. Whet her t he dr ug i s st i l l under i nvest i gat i on and, i f i t i s on t he mar ket ,
t he I ength of ti me on t he market
f . The dosage f orm of t he drug
g. The purpose of t he drug (i . e. , what medi cal condi t i on or sympt om t he
dr ug i s i nt ended t o al l evi at e; t hi s i nf or mat i on hel ps nar r ow t he search i f
pr oduct s wi t h si mi l ar names are f ound)
P. 480


Table 21-2. Selected Web Sites
Site URL (Web Address)
Agency Ior Healthcare Research and
Quality
www.ahrq.gov
American Association oI Colleges oI
Pharmacy
www.aacp.org
American Cancer Society www.cancer.org
American Diabetes Association www.diabetes.org
American Heart Association www.americanheart.org
American Society oI Health-System
Pharmacists
www.ashp.org
Centers Ior Disease Control and
Prevention
www.cdc.gov
Clinical Trial Results www.clinicaltrialresults.org
Clincal Trials www.clinicaltrials.gov
Drug InIonet www.druginIonet.com
eMedicine www.emedicine.com
HealthIinder www.healthIinder.gov
Health on the Net Foundation www.hon.ch
Mayo Clinic College oI Medicine www.mayo.edu
Medscape www.medscape.com
MedWatch www.Ida.gov/medwatch
National Cancer Institute www.cancer.gov
National Guideline Clearinghouse www.guideline.gov
National Heart. Lung. and Blood
Institute
www.nhlbi.nih.gov
National Institutes oI Health www.nih.gov
National Library oI Medicine www.nlm.nih.gov
Pharmaceutical Research and
ManuIacturers oI America
www.phrma.org
PharmacyOneSource www.pharmacyonesource.com
Pharmscope www.pharmscope.com
RxList www.rxlist.com
RxMed www.rxmed.com
U.S. Department oI Health and Human
Services
www.os.dhhs.gov
U.S. Food and Drug Administration www.Ida.gov
WebMD www.webmd.com

B. To i dent i f y or assess product avai I abi I i t y, consi der usi ng t he f ol l owi ng
r esour ces ( see al so Appendi x E) . Some of t hese r esour ces are avai l abl e i n
an el ect r oni c f or mat or i n an Ì nt er net / Ì nt r anet ver si on.
1. For drugs manuf act ured i n t he Uni t ed St ates, t he f ol l owi ng r esour ces
ar e avai l abl e:
a. The Ameri can Drug I ndex, updat ed annual l y
b. Dr ug Fact s and Compar i sons, updat ed mont hl y and bound annual l y/ Fact s
and Compar i son 4. 0 (onl i ne)
c. Dr ug Topi cs Red Book, peri odi cal l y suppl ement ed and updat ed annual l y
d. Physi ci an' s Desk Ref er ence ( PDR) , updat ed annual l y
e. Amer i can Hospi t al Formul ar y Servi ce ( AHFS) Dr ug I nf or mat i on,
suppl ement ed quar t er l y and updat ed annual l y
f . Mar t i ndal e: The Compl et e Drug Ref erence, updat ed ever y 3 year s
g. Lexi - Dr ugs Onl i ne (Lexi - Comp Onl i ne)
h. Cl i ni cal Phar macol ogy
i . Thomson Heal t hcar e Ser i es ( Mi cr omedex)
2. For drugs manuf act ured i n f orei gn count ri es, t he f ol l owi ng r esour ces
ar e avai l abl e:
a. Mar t i ndal e: The Compl et e Dr ug Ref er ence
b. I ndex Nomi num
c. USP Di ct i onary of Uni t ed St at es Adopt ed Names ( USAN) and
I nt ernat i onal Dr ug Names
d. Lexi - Dr ugs I nt er nat i onal Onl i ne ( Lexi - Comp Onl i ne)
3. For i nvest i gat i onaI drugs, t he f ol l owi ng r esour ces ar e avai l abl e:
a. Mar t i ndal e: The Compl et e Dr ug Ref er ence
b. Dr ug Fact s and Compar i sons/ Fact s and Compar i son 4. 0 ( onl i ne)
c. The Pi nk Sheet publ i shed by FDC Repor t s
d. The NDA Pi pel i ne publ i shed by FDC Report s
P. 481


4. For orphan drugs÷t hat i s, dr ugs t hat are used t o pr event or t reat a r ar e
di sease (af f ect s < 200, 000 peopl e i n t he Uni t ed St at es, so t he cost of
devel opment i s not l i kel y t o be of f set by sal es) and f or whi ch t he U. S. Food
and Drug Admi ni st r at i on ( FDA) of f ers assi st ance and f i nanci al i ncent i ves t o
sponsor s under t aki ng t he devel opment of t he dr ugs÷t he f ol l owi ng
r esour ces are avai l abl e:
a. Dr ug Fact s and Compar i sons/ Fact s and Compar i son 4. 0 ( onl i ne)
b. The FDA Of f i ce of Orphan Pr oduct s Devel opment ( OOPD)
c. The Nat i onal Ì nst i t ut es of Heal t h ( NÌ H) Of f i ce of Rare Di seases
d. Nat i onal Organi zat i on f or Rar e Di sor ders
e. Lexi - Dr ugs Onl i ne (Lexi - Comp Onl i ne)
5. For an unknown drug ( i . e. , one t hat i s i n hand but not i dent i f i ed),
chemi cal anal ysi s can be perf ormed or t he drug can be i dent i f i ed by
physi cal charact er i st i cs, such as col or , speci al mar ki ngs, and shape.
Consul t t he f ol l owi ng sour ces f or hel p:
a. PDR, Drug Fact s and Compar i sons, Fact s and Compar i son 4. 0 ( onl i ne),
Dr ug Topi cs Red Book, I dent -A- Dr ug Ref er ence
b. I dent i dex ( Mi cromedex)
c. The manuf act ur er
d. A l abor at or y
e. Lexi - Comp Onl i ne (Lexi - Dr ug I D)
f . Cl i ni cal Phar macol ogy Pr oduct I dent i f i cat i on
6. For a nat uraI product, t he f ol l owi ng r esour ces ar e avai l abl e:
a. Fact s and Compari son 4. 0 ( onl i ne)
b. Nat ur al Medi ci nes Compr ehensi ve Dat abase
c. Nat ur al St andar ds
d. Compl et e Ger man Commi ssi on E Monogr aphs
e. Nat ur al Pr oduct s ( Lexi - Comp Onl i ne)
V. SEARCH STRATEGIES.
To devel op an ef f ect i ve search st r at egy f or l ocat i ng drug i nf ormat i on
l i t er at ur e, t he f ol l owi ng t act i cs shoul d be f ol l owed af t er det er mi ni ng whet her
pr i mar y or secondar y sour ces ar e desi red.
A. Det er mi ne whet her t he quest i on at hand i s cI i ni caI or research reI at ed.
Def i ne t he quest i on as speci f i cal l y as possi bl e. Al so, i dent i f y appropri at e
i ndex t er ms ( al so cal l ed keywor ds or descr i pt ors) wi t h whi ch t o sear ch f or
t he i nf or mat i on.
B. Det ermi ne t he t ype of i nf ormat i on and how much i s needed (i . e. , onl y
one f act , t he most r ecent j our nal art i cl es, r evi ew ar t i cl es, or a
compr ehensi ve dat abase sear ch) .
C. Ascert ai n as much i nf ormati on as possi bI e about t he dr ug bei ng
quest i oned and t he i nqui rer' s associ at i on wi t h i t . Remember t hat dat a on
adver se drug ef f ect s or dr ug i nt er act i ons ar e of t en f ragment ed and
i nadequat el y document ed. See Ì V. A. 2 f or t he speci f i c dr ug i nf ormat i on t hat
shoul d be acqui r ed. Det er mi ne t he answer s t o t he f ol l owi ng quest i ons:
1. What i s t he i ndi cat i on f or t he pr escri bed dr ug?
2. Ì s t he dr ug' s use approved or unappr oved? Thi s i nf ormat i on can be f ound
i n t he f ol l owi ng resources ( r emember t o check how of t en t hese resources
ar e updat ed t o ensure havi ng t he l at est i nf or mat i on) .
a. Approved uses of dr ugs can be checked i n:
( 1) AHFS Drug I nf or mat i on
( 2) Dr ug Fact s and Compar i sons/ Fact s and Compar i son 4. 0 (onl i ne)
( 3) PDR
( 4) USP Dr ug I nf or mat i on
( 5) Dr ugdex ( Mi cr omedex)
( 6) Cl i ni cal Phar macol ogy
( 7) Dr ug I nf or mat i on Handbook/ Lexi - Drugs Onl i ne ( Lexi - Comp Onl i ne)
b. Unapproved uses of dr ugs can be f ound i n:
( 1) AHFS Drug I nf or mat i on
( 2) Dr ug Fact s and Compar i sons/ Fact s and Compar i son 4. 0 (onl i ne)
P. 482


( 3) Mar t i ndal e: The Compl et e Dr ug Ref er ence
( 4) Medl i ne
( 5) Dr ugdex ( Mi cr omedex)
( 6) I nphar ma
( 7) USP Dr ug I nf or mat i on
( 8) Cl i ni cal Phar macol ogy
( 9) Dr ug I nf or mat i on Handbook/ Lexi - Drugs Onl i ne ( Lexi - Comp Onl i ne)
3. What ar e t he age, sex, and wei ght of t he pat i ent i n quest i on?
4. Does t he pat i ent have any ot her medi cal condi t i ons or r enal or hepat i c
di sease?
5. Ì s t he pat i ent t aki ng any ot her medi cat i ons?
6. What dr ugs has t he pat i ent t aken duri ng t he past 6 mont hs, and what
wer e t he dosages?
7. Di d t he pat i ent exper i ence any si gns or sympt oms of a possi bl e adver se
dr ug r eact i on? Ì f so:
a. How severe was t he react i on?
b. When di d t he r eact i on appear?
c. Has t he pat i ent (or any member of t he pat i ent ' s f ami l y) exper i enced any
al l er gi c or adver se r eact i ons t o medi cat i ons i n t he past ?
d. Consul t t he f ol l owi ng r esour ces f or mor e i nf ormat i on:
( 1) Meyl er ' s Si de Ef f ect s of Dr ugs
( 2) A gener al drug ref erence ( e. g. PDR)
( 3) React i ons
( 4) Medl i ne
e. The manuf act ur er of t he drug may be a usef ul source f or mi ssi ng
i nf or mat i on. Most compani es r equest f urt her i nf ormat i on r egar di ng a
suspect ed adver se dr ug r eact i on.
8. Di d t he pat i ent exper i ence any si gns or sympt oms of a dr ug i nt eract i on?
Ì f so:
a. What wer e t he speci f i c drugs i n quest i on?
b. What wer e t he r espect i ve dosages of t he dr ugs?
c. What was t he dur at i on of t herapy?
d. What was t he l engt h of t he course of admi ni st rat i on?
e. What ar e t he det ai l s of t he event s secondar y t o t he suspect ed r eact i on?
f . Consul t t he f ol l owi ng resour ces f or mor e i nf ormat i on:
( 1) A dr ug i nt er act i ons ref er ence÷f or exampl e, Dr ug I nt eract i on Fact s,
Hanst en' s Dr ug I nt eract i on Anal ysi s and Management , Eval uat i ons of Drug
I nt eract i ons ( EDI )
( 2) A gener al drug ref erence ( e. g. , PDR)
( 3) React i ons
( 4) Medl i ne
9. What i s t he pat i ent ' s cur r ent medi cat i on st at us?
10. Does t he pat i ent have any under l yi ng di seases?
11. How has t he pat i ent been managed so f ar ?
12. What i s t he st abi l i t y of t he dr ug? How i s compat i bi l i t y of t he dr ug wi t h
ot her drugs?
What ar e t he admi ni st rat i on t echni ques? What are appr opr i at e cont ai ner s
f or t he pr oduct ?
Resour ces avai l abl e wi t h t hi s i nf or mat i on i ncl ude
a. Tr i ssel ' s Handbook on I nj ect abl e Drugs
b. Ki ng' s Gui de t o Parent er al Admi xt ures
c. Tr i ssel ' s St abi l i t y of Compounded For mul at i ons
D. ExpI ore other possi bI e i nf ormat i on resources i f necessar y. For
exampl e, i t may be usef ul t o f i nd backgr ound mat er i al i n t ext books ( t er t i ar y
r ef erences) , and t hen sear ch t he j ournal l i t er at ure ( pri mar y r ef er ences) f or
mor e cur r ent i nf or mat i on.
VI. EVALUATING A CLINICAL STUDY.
Resour ce i dent i f i cat i on i s f ol l owed by a cr i t i cal assessment of t he avai l abl e
i nf or mat i on. Thi s st ep i s cr i t i cal i n devel opi ng an appropr i at e r esponse f or
t he i nqui rer .
P. 483


A. EvaI uat e t he obj ecti ve of t he st udy. Det er mi ne t he ai m of t he research
t hat was perf ormed.
1. What di d t he r esear cher s i nt end t o exami ne?
2. Ì s t hi s goal st at ed cl ear l y ( i . e. , i s t he obj ect i ve speci f i c)?
3. Was t he r esearch l i mi t ed t o a si ngl e obj ect i ve, or wer e t her e mul t i pl e
dr ugs or ef f ect s bei ng t est ed?
B. EvaI uate t he subj ects of the st udy. Det er mi ne t he pr of i l e of t he st udy
popul at i on by assessi ng t he f ol l owi ng i nf or mat i on:
1. Wer e heal t hy subj ect s or af f ect ed pat i ent s used i n t he st udy?
2. Wer e t he subj ect s vol unt eer s?
3. What wer e t he cri t eri a f or sel ect i ng t he subj ect s?
4. How many subj ect s wer e i ncl uded, and what ar e t he demogr aphi cs of t he
subj ect s ( age, sex, and race)?
5. Ì f a di sease was bei ng t r eat ed, di d any of t he subj ect s have di seases
ot her t han t hat i ni t i al l y bei ng t r eat ed? Were any addi t i onal t reat ment s
gi ven? Were t here any cont r ai ndi cat i ons t o t he t her apy?
6. What was t he pat i ent sel ect i on met hod and who was excl uded f r om t he
st udy?
7. A pat i ent sel ect i on r evi ew shoul d be done. You wi l l f i nd t hat most gr oups
of subj ect s ar e homogeneous ( i . e. , t hey al l have comparabl e
charact eri st i cs) . Ì f a di sease st at e i s st udi ed, pat i ent s shoul d exhi bi t si mi l ar
sever i t y of sympt oms. Resear chers ai m t o el i mi nat e i nt er pat i ent vari abi l i t y.
By sel ect i ng pat i ent s wi t h si mi l ar charact er i st i cs, r esearcher s can avoi d
r esul t s t hat ar e caused by i ndi vi dual di f f er ences among pat i ent s. St rong
i ndi vi dual di f f er ences can obscur e t he r esul t s of t he exper i ment . Ì f st udyi ng
a gr oup of pat i ent s who exhi bi t si gni f i cant i nt erpat i ent vari abi l i t y i s
necessar y, researcher s may di vi de t he pat i ent s i nt o gr oups accor di ng t o t he
var i abl es l i kel y t o be associ at ed wi t h responsi veness t o t her apy. Thi s i s
known as st r at i f i cat i on.
C. EvaI uate t he admi ni st rat i on of t he drug t reat ment . For each drug
bei ng i nvest i gat ed, det ermi ne t he f ol l owi ng i nf ormat i on:
1. Detai I s of t reatment wi t h t he agent bei ng st udi ed:
a. Dai l y dose
b. Fr equency of admi ni st r at i on
c. Hour s of day when admi ni st er ed
d. Rout e of admi ni st r at i on
e. Sour ce of drug (i . e. , t he suppl i er )
f . Dosage f or m
g. Ti mi ng of dr ug admi ni st r at i on i n r el at i on t o f act or s af f ect i ng drug
absor pt i on
h. Met hods of ensur i ng compl i ance
i . Tot al durat i on of t r eat ment
2. Ot her t herapeuti c measures i n addi t i on t o t he agent bei ng st udi ed
D. EvaI uate t he set t i ng of t he st udy. Tr y t o det er mi ne t he envi ronment of
t he st udy and t he dat es on whi ch t he t ri al began and ended. Assess t he
f ol l owi ng i nf or mat i on:
1. Peopl e who made t he obser vat i ons; vari ous prof essi onal s who of f er
di f f er ent and uni que perspect i ves based on t hei r backgr ounds and i nt er est s
(Wer e t he same peopl e maki ng obser vat i ons t hroughout t he st udy?)
2. Whet her t he st udy was done on an i npat i ent or out pat i ent basi s
3. Descri pt i on of physi cal set t i ng ( e. g. , hospi t al , cl i ni c, war d)
4. Lengt h of t he st udy ( i . e. , dat es on whi ch t he t r i al began and ended)
E. EvaI uate t he met hods and desi gn of t he st udy. The met hod sect i on of
t he research paper expl ai ns how t he r esear ch was conduct ed. The st udy
desi gn ( i . e. , r et rospect i ve, prospect i ve, bl i nd, cr ossover ) and t he met hods
used t o compl et e t he st udy ar e i mpor t ant i n j udgi ng whet her
P. 484

t he st udy and t he resul t s ar e rel i abl e and val i d. Fr om t he st udy, t r y t o
det ermi ne answer s t o t he f ol l owi ng quest i ons:

Figure 21-1. Parallel study design.
1. Ar e t he met hods of assessi ng t he t her apeut i c ef f ect s cl ear l y descr i bed?
2. Wer e t he met hods st andardi zed?
a. Ret rospect i ve versus prospect i ve
( 1) Ret rospect i ve st udi es eval uat e event s t hat have al ready occur red t o
f i nd some common l i nk among t hem, r equi r e rel i ance on pat i ent memori es
and accurat e medi cal r ecor ds, and are unabl e t o show cause and ef f ect .
Ret r ospect i ve st udi es are usef ul f or st udyi ng r are di seases ( or ef f ect s) and
can hel p a heal t hcare prof essi onal deci de i f enough i nf or mat i on exi st s t o
war r ant prospect i ve exami nat i on of a probl em.
( 2) Prospect i ve st udi es f ol l ow i dent i f i ed pat i ent s f or war d i n t i me t o answer
a speci f i c quest i on. They can be obser vat i onal or exper i ment al ( i . e. , cl i ni cal
t r i al s) .
b. Treat ment aI I ocat i on
( 1) ParaI I eI st udy desi gn i s a pr ot ocol i n whi ch t wo or more pat i ent gr oups
ar e st udi ed concurr ent l y. The gr oups are t reat ed i dent i cal l y except f or one
var i abl e, such as a dr ug t her apy ( Fi gure 21- 1) .
( 2) Crossover desi gn may be used as an addi t i onal cont r ol f or i nt er pat i ent
and i nt rapat i ent var i abi l i t y ( Fi gur e 21-2) . Ì n t hi s t ype of desi gn, each
pat i ent gr oup under goes each t ype of t reat ment . However , t he sequence i n
whi ch t he subj ect s undergo t reat ment i s rever sed f or one gr oup. Cr ossover
desi gn r educes t he possi bi l i t y t hat t he resul t s were st r ongl y i nf l uenced by
t he or der i n whi ch t her apy was gi ven. And because bot h gr oups of pat i ent s
r ecei ve bot h t ypes of t reat ment , any di f f er ences i n r esponsi veness bet ween
t he gr oups as a r esul t of pat i ent sel ect i on wi l l be uncover ed.
3. Wer e cont roI measures used t o r educe vari at i on t hat mi ght i nf l uence t he
r esul t s? Exampl es of such cont r ol met hods i ncl ude
a. Concur r ent cont r ol s
b. St rat i f i cat i on or mat ched subgr oups
c. A run-i n phase
d. The pat i ent as hi s or her own cont r ol ( i . e. , crossover desi gn)
e. Ì dent i cal anci l l ar y t r eat ment
4. Wer e cont r ol s used t o r educe bi as? Exampl es of such cont r ol s i ncl ude
a. BI i nd assessment, whi ch means t hat t he peopl e obser vi ng t he pat i ent s do not
know who i s a subj ect and who i s a cont rol

Figure 21-2. Crossover study design.
P. 485


Table 21-3. Types of Blind Studies
Types of Blinds
Patient Aware of
Treatment
Physician Aware of
Treatment
Open label
(nonblind)
|check mark| |check mark|
Single-blind |check mark|
Double-blind

b. BI i nd pat i ent s, whi ch means t hat t he pat i ent s do not know whet her t hey r ecei ved
t he subst ance bei ng st udi ed or a pl acebo (doubI e- bI i nd combi nes t hi s poi nt wi t h
poi nt a above [ VÌ . E. 4. a] ) ( Tabl e 21-3)
c. Random aI I ocat i on, whi ch means t hat pat i ent s i nvol ved i n t he st udy have an
even chance of bei ng assi gned t o ei t her t he group of subj ect s recei vi ng t he act i ve
dr ug or t he gr oup recei vi ng a pl acebo
d. Mat chi ng dummi es, whi ch are pl acebos t hat ar e physi cal l y i dent i cal t o t he act i ve
agent bei ng st udi ed
e. Compari son of a pl acebo or a t her apy t o a r ecogni zed st andard pr act i ce
( pl acebocont r ol l ed)
F. EvaI uat e the anaI ysi s of the st udy. Af t er assessi ng speci f i c areas of t he st udy
separ at el y, compi l e t he i nf ormat i on t oget her t o det ermi ne whet her t he t r i al i s
accept abl e and t he concl usi ons are j ust i f i ed by det ermi ni ng answer s t o t he f ol l owi ng
quest i ons ( Fi gur e 21- 3):
1. Wer e t he subj ect s sui t abl y sel ect ed i n r el at i on t o t he ai m( s) of t he st udy?
2. Wer e t he met hods of measurement val i d i n r el at i on t o t he ai m( s) of t he st udy?
3. Wer e t he met hods adequat el y st andar di zed?
4. Wer e t he met hods suf f i ci ent l y sensi t i ve?
5. Was t he desi gn appropr i at e?
6. Wer e enough subj ect s enr ol l ed?
7. Was t he dosage appropr i at e?
8. Was t he durat i on of t reat ment adequat e?
9. Wer e car r yover ef f ect s avoi ded, or wer e compensat i ons made f or t hem? Di d a
wash- out peri od exi st ?
10. Ì f no cont r ol s wer e used, wer e t hey unnecessar y or overl ooked?
11. Ì f cont r ol s wer e used, wer e t hey adequat e?
12. Was t he comparabi l i t y of t r eat ment groups exami ned?
13. Are t he dat a adequat e f or assessment ?
14. Ì f st at i st i cal t est s wer e not done, wer e t hey unnecessar y or over l ooked?
15. Ì f st at i st i cal t est s are r epor t ed, assess t he f ol l owi ng:
a. Ì s i t cl ear how t he st at i st i cal t est s wer e done?
b. Were t he t est s appr opr i at el y used?
c. Ì f r esul t s show no si gni f i cant di f f er ence bet ween t est groups, wer e enough
pat i ent s st udi ed (i . e. , st at i st i cal power ) ?
VII. GENERAL GUIDELINES FOR RESPONSES TO DRUG
INFORMATION REQUESTS
A. Do not guess!
B. Responses t o a member of t he publ i c must t ake sever al et hi cal i ssues i nt o
account .
P. 486



Figure 21-3. Evaluation oI study analysis.
P. 487


1. Pat i ent pr i vacy must be pr ot ect ed.
2. Pr of essi onal et hi cs must be mai nt ai ned.
3. The pat i ent - physi ci an r el at i onshi p cannot be breached.
4. Response i s not necessar y i f t he i nqui r er i nt ends t o mi suse or abuse i nf ormat i on
t hat i s provi ded. The i nqui r er of t en admi t s i nt ent or of f ers cl ues t o pot ent i al abuse,
such as i n t he f ol l owi ng exampl es:
a. A pat i ent asks how a cer t ai n drug i s dosed ( i . e. , how much t he dr ug can be
i ncreased, when i t can be i ncr eased, what t he maxi mum dai l y dose i s) . Thi s ki nd of
i nqui r y si gnal s t hat t he pat i ent mi ght be adj ust i ng hi s or her own t her apy.
b. A pat i ent asks a pharmaci st t o i dent i f y a t abl et t hat i s a prescr i pt i on product
known f or a hi gh rat e of abuse.
C. Or gani ze i nf ormat i on bef ore at t empt i ng t o communi cat e t he r esponse t o t he
i nqui r er . Responses shoul d be conci se and succi nct . Ant i ci pat e addi t i onal
quest i ons.
D. Tai l or t he r esponse t o t he i nqui r er ' s backgr ound. Al so, consi der t he envi r onment
of t he pr act i ce, i nst i t ut i onal pol i cy and procedure, and f or mul ar y.
E. Tel l t he i nqui r er where t he i nf ormat i on was f ound. Exer ci se caut i on when maki ng
st at ement s such as, " Ther e ar e no report s i n t he l i t er at ur e. ¨
F. Use ext reme caut i on when maki ng st at ement s such as, " Ì r ecommend .¨ Do not
hesi t at e t o ref er consumer s t o t hei r physi ci ans.
G. Use more t han abst ract s t o answer dr ug i nf ormat i on quest i ons because t hey
mi ght be t aken out of cont ext and do not i ncl ude al l of t he dat a avai l abl e i n t he
or i gi nal ar t i cl e.
H. Al ert t he i nqui r er of a possi bl e del ay when i t t akes l onger t han ant i ci pat ed t o
answer t he quest i on.
I . Ask i f t he i nf or mat i on t hat i s pr ovi ded answer s t he i nqui rer ' s quest i ons.
J. Ask i f t he i nqui rer woul d l i ke t o have repri nt s of art i cl es or a wr i t t en r esponse.
P. 488


STUDY QUESTIONS
Di rect i ons: Each of t he numbered i t ems or i ncompl et e st at ement s i n t hi s sect i on i s
f ol l owed by answer s or compl et i ons of t he st at ement . Sel ect t he one l et t er ed
answer or compl et i on t hat i s best i n each case.
1. Pri mar y I i t erat ure i ncI udes whi ch of t he f oI I owi ng?
( A) Or i gi nal cl i ni cal t ri al s
( B) Let t ers t o t he Edi t or
( C) Syst emat i c r evi ews
( D) Speci al repor t s
Vi ew Answer 1. The answer i s A[] . 2. Whi ch of the f oI I owi ng stat ements i s
TRUE regardi ng t ert i ary resources?
( A) Ter t i ar y resources i ncl ude t ext books and comput er dat abases.
( B) Text books t ypi cal l y i ncl ude t he most r ecent l i t er at ur e and/ or i nf ormat i on.
( C) Ter t i ar y resources do not t ypi cal l y i ncl ude a bi bl i ogr aphy.
( D) The credent i al s of t he edi t or of a t er t i ar y r esour ce ar e not consi der ed i mpor t ant .
Vi ew Answer 2. The answer i s A[] . 3. Whi ch of the f oI I owi ng shouI d NOT be
done when deveI opi ng an ef fecti ve search st rat egy?
( A) Det er mi ne i f t he quest i on i s cl i ni cal or r esearch- rel at ed
( B) Ì dent i f y appr opr i at e search t erms
( C) Di sregar d ot her medi cat i ons t he pat i ent may be t aki ng
( D) Ascer t ai n i f t he i nqui r er i s a heal t hcar e pr of essi onal
Vi ew Answer 3. The answer i s C[] . 4. Whi ch of the f oI I owi ng resources
wouI d be appropri at e for i dent i f yi ng a drug manuf act ured i n a forei gn count r y?
( A) Mar t i ndal e: The Compl et e Dr ug Ref er ence
( B) Cl i ni cal Phar macol ogy
( C) Tr i ssel ' s St abi l i t y of Compounded Formul at i ons
( D) AHFS
Vi ew Answer 4. The answer i s A[] . Mart i ndal e: The Compl ete Drug
Ref erenceMart i ndal e: The Compl ete Drug Ref erence, Lexi - Drugs
I nt ernat i onal Onl i ne ( Lexi - Comp Onl i ne), Di cti onary of Uni t ed St at es
Adopt ed Names ( USAN) and I nt ernat i onal Drug Names. Cl i ni cal
Pharmacol ogy, Tri ssel ' s St abi l i ty of Compounded Formul at i ons, AHFS5.
Whi ch of the foI I owi ng resources wouI d be appropri ate f or i dent i f yi ng t he
capsuI e wi t h t he i mpri nt code of Watson 405?
I Fact s and Compari son 4. 0 ( onI i ne)
I I Lexi Drugs OnI i ne ( Lexi - Comp OnI i ne)
I I I MyI er' s Si de Ef f ect s of Drugs
( A) Ì and Ì Ì onl y
( B) Ì and Ì Ì Ì onl y
( C) Ì Ì and Ì Ì Ì onl y
Vi ew Answer 5. The answer i s A[] . Fact s and Compari son 4. 0 ( Onl i ne)Lexi
Drugs Onl i ne (Lexi - Comp Onl i ne). 6. Whi ch of t he f oI I owi ng resources
wouI d be appropri at e for determi ni ng the adverse ef f ect s of gi nko bi I oba?
I Nat uraI Medi ci nes Comprehensi ve Dat abase
I I Fact s and Compari sons 4. 0 ( onI i ne)
I I I NaturaI St andards
I V CI i ni caI PharmacoI ogy
( A) Ì and Ì Ì onl y
( B) Ì Ì and Ì Ì Ì onl y
( C) Ì , Ì Ì , and Ì Ì Ì onl y
( D) Ì Ì and Ì V onl y
Vi ew Answer 6. The answer i s C[] . Fact s and Compari son 4. 0 ( onl i ne),
Nat ural Medi ci nes Comprehensi ve Database, Nat ural St andards,
Compl et e German Commi ssi on E Monographs, Nat ural Product s (Lexi -
Comp Onl i ne). 7. Whi ch of t he f oI I owi ng resources wouI d be appropri at e
f or determi ni ng i f Levaqui n i s compat i bI e or st abI e i n D5W?
( A) Eval uat i ons of Dr ug Ì nt er act i ons ( EDÌ )
( B) Tr i ssel ' s Handbook on Ì nj ect abl e Dr ugs
( C) Red Book
( D) Ì npharma
Vi ew Answer 7. The answer i s B[] . Tri ssel ' s Handbook on I nj ect abl e Drugs,
Ki ng' s Gui de t o Parenteral Admi xtures, Tri ssel ' s St abi l i ty of
Compounded Formul at i ons. 8. Whi ch of the foI I owi ng resources can be
used t o det ermi ne unapproved uses of drugs?
( A) Cl i ni cal Phar macol ogy
( B) PDR
( C) Ì ndex Nomi num
( D) Ki ng' s Gui de t o Par ent er al Admi xt ur es
Vi ew Answer 8. The answer i s A[] . Cl i ni cal Pharmacol ogy. Ki ng' s Gui de t o
Parent eral Admi xtures. 9. Whi ch of the foI I owi ng are NOT i mport ant when
evaI uat i ng a cI i ni caI study?
( A) St udy obj ect i ve
( B) Pat i ent demogr aphi cs
( C) Dr ug admi ni st r at i on
( D) Number of aut hors
Vi ew Answer 9. The answer i s D[] . 10. Whi ch of t he f oI I owi ng stat ements i s
TRUE?
( A) Pr ospect i ve st udi es eval uat e event s t hat have al r eady occurr ed.
( B) Ret rospect i ve st udi es are usef ul f or eval uat i ng r are di seases.
( C) A r un- i n phase t ypi cal l y i ncr eases var i at i on.
( D) Cr ossover desi gn al l ows pat i ent s t o under go onl y one t ype of t reat ment .
Vi ew Answer 10. The answer i s B[] . P. 489


ANSWERS AND EXPLANATIONS
1. The answer i s A [ Ì Ì . A. 3] .
Al l mat er i al i ncl uded i n a j our nal i s not consi der ed a pr i mar y r esour ce. Ori gi nal
cl i ni cal t ri al s ar e consi der ed pr i mar y l i t er at ur e; however , r evi ew ar t i cl es, ar t i cl es of
opi ni on, cor respondence, and speci al repor t s ar e not .
2. The answer i s A [ Ì Ì , Ì Ì . C] .
Ter t i ar y r esour ces i ncl ude bot h t ext books and dat abases. Ì nf ormat i on avai l abl e i n
t ext books may not i ncl ude t he most r ecent dat a si nce i t coul d t ake sever al year s t o
publ i sh. A bi bl i ogr aphy and r ef erence ci t at i ons shoul d be present i n bot h t ext books
and dat abases so t hat t he r eader may r ef er t o a speci f i c ref erence i f desi red.
Addi t i onal l y, t he ar eas of exper t i se f or t he aut hor and/ or publ i sher shoul d be
eval uat ed when usi ng a t er t i ar y r esource.
3. The answer i s C [ V. A, V. C, VÌ Ì . B, VÌ Ì . D] .
One shoul d det er mi ne i f t he quest i on i s r el at ed t o a cl i ni cal scenar i o or i s r esear ch
r el at ed t o devel op an ef f ect i ve search st rat egy. Appr opr i at e i ndex t er ms shoul d be
i dent i f i ed t o assi st i n t he l i t er at ur e search. Ot her medi cat i ons, i ncl udi ng her bal
pr oduct s, and di sease st at es shoul d be t aken i nt o consi der at i on. The backgr ound of
t he i nqui rer shoul d be det ermi ned so t hat t he response can be t ai l ored t o t he
speci f i c i nqui r er.
4. The answer i s A [ Ì V. B. 2] .
Mar t i ndal e: The Compl et e Dr ug Ref er ence i s one r esource t hat may be used t o
i dent i f y a drug manuf act ur ed i n a f or ei gn count r y. Ot her r esources f or i dent i f yi ng
dr ugs manuf act ur ed i n a f or ei gn count r y i ncl ude Mar t i ndal e: The Compl et e Dr ug
Ref er ence, Lexi - Dr ugs I nt er nat i onal Onl i ne (Lexi - Comp Onl i ne), and t he USP
Di ct i onar y of Uni t ed St at es Adopt ed Names ( USAN) and I nt er nat i onal Drug Names.
Cl i ni cal Phar macol ogy, Tr i ssel ' s St abi l i t y of Compounded For mul at i ons, and AHFS
do not cont ai n t hi s t ype of i nf ormat i on.
5. The answer i s A [ Ì V. B. 5] .
For an unknown dr ug, t he physi cal char act er i st i cs, i ncl udi ng an i mpri nt code, may
be used t o i dent i f y t he dr ug i n addi t i on t o t he use of several r esources, i ncl udi ng
Fact s and Compari son 4. 0 ( Onl i ne) and Lexi Dr ugs Onl i ne ( Lexi - Comp Onl i ne).
6. The answer i s C [ Ì V. B. 6] .
For a nat ur al pr oduct , t he f ol l owi ng r esour ces are avai l abl e: Fact s and Compar i son
4. 0 (onl i ne) , Nat ural Medi ci nes Comprehensi ve Dat abase, Nat ural St andar ds,
Compl et e Ger man Commi ssi on E Monographs, and Nat ur al Pr oduct s ( Lexi - Comp
Onl i ne) .
7. The answer i s B [ V. C. 12] .
The st abi l i t y of a dr ug, t he compat i bi l i t y of a dr ug wi t h ot her dr ugs and/ or
appropr i at e cont ai ner s, and pr oper admi ni st r at i on t echni ques are i ncl uded i n
Tr i ssel ' s Handbook on I nj ect abl e Drugs, Ki ng' s Gui de t o Parent er al Admi xt ur es, and
Tr i ssel ' s St abi l i t y of Compounded For mul at i ons.
8. The answer i s A [ V. C. 2. b] .
Unapproved uses of dr ugs can be f ound i n Cl i ni cal Phar macol ogy. Thi s i nf or mat i on
i s not avai l abl e i n t he PDR, Ì ndex Nomi num, or Ki ng' s Gui de t o Par ent eral
Admi xt ur es.
9. The answer i s D [ VÌ . A, VÌ . B, VÌ . C] .
A cr i t i cal assessment of avai l abl e i nf ormat i on i s i mport ant i n devel opi ng an
appropr i at e r esponse. The st udy obj ect i ve, t he st udy subj ect s ( vi a demogr aphi cs
and i ncl usi on and excl usi on cri t eri a) , and drug admi ni st r at i on shoul d be eval uat ed.
10. The answer i s B [ VÌ . E] .
Ret r ospect i ve st udi es eval uat e event s t hat have al r eady occur r ed and are usef ul f or
st udyi ng r ar e di seases. Pr ospect i ve st udi es f ol l ow i dent i f i ed pat i ent s f orwar d i n t i me
t o answer a speci f i c quest i on. Crossover desi gn al l ows f or each pat i ent gr oup t o
under go each t ype of t r eat ment . A r un- i n phase i s a cont r ol measur e used t o r educe
var i at i on.

22
Adverse Drug Reaction Reporting
Barbara Szymusi ak- Mutni ck
I. INTRODUCTION.
Adver se drug react i ons (ADRs) are a cause of si gni f i cant mor bi di t y and mor t al i t y i n
pat i ent s i n al l areas of heal t h car e t oday. There i s wi de vari at i on i n t he cur r ent
heal t hcare l i t erat ure, but i t has been est i mat ed t hat f rom one t hi r d t o as hi gh as one
hal f of ADRs ar e bel i eved t o be pr event abl e. The Ì nst i t ut e of Medi ci ne repor t ed i n
Jul y 2006 t hat an est i mat ed 1. 5 mi l l i on i nj uri es occur each year as a resul t of
medi cat i on er r ors. Bet ween 44, 000 t o 98, 000 peopl e di e f rom medi cat i on er r ors
annual l y. Medi cat i on er ror s ki l l more peopl e per year t han br east cancer , AÌ DS, or
mot or vehi cl e acci dent s. The cost of morbi di t y and mor t al i t y owi ng t o drug- r el at ed
adver se event s i n hospi t al i zed pat i ent s was recent l y est i mat ed t o be at l east $3. 5
bi l l i on annual l y. Ther e are an est i mat ed 3 mi l l i on hospi t al admi ssi ons each year
caused by t he mi suse of pharmaceut i cal s. The suf f er i ng t hat pat i ent s exper i ence
because of dr ug-r el at ed event s cannot be quant i f i ed.
II. DEFINITIONS.
The t erms adverse dr ug r eact i on, adverse dr ug event , unt owar d dr ug r eact i on, drug
mi sadvent ure, si de ef f ect , medi cat i on er r ors, mi suse of phar maceut i cal s, and dr ug-
r el at ed pr obl em ar e many t i mes used i nt er changeabl y but do not al ways descr i be
t he same si t uat i on.
A. The Nat i onal Coor di nat i ng Counci l f or Medi cat i on Er r or Repor t i ng and Pr event i on
st at es " A medi cat i on er ror i s any pr event abl e event t hat may cause or l ead t o
i nappr opr i at e medi cat i on use or pat i ent harm whi l e t he medi cat i on i s i n t he cont rol
of t he heal t h car e pr of essi onal s, pat i ent , or consumer. Such event s may be r el at ed
t o prof essi onal pract i ce, heal t h care pr oduct s, procedures, and syst ems, i ncl udi ng
pr escri bi ng; or der communi cat i on; product l abel i ng; packagi ng; and nomencl at ur e;
compoundi ng; di spensi ng; di st r i but i on; admi ni st rat i on; educat i on; moni t ori ng; and
use. ¨
1

B. The U. S. Food and Drug Admi ni st rat i on' s ( FDA) def i ni t i on of an adverse drug
event i s " any adver se event associ at ed wi t h t he use of a drug i n humans, whet her or
not consi dered dr ug r el at ed, i ncl udi ng t he f ol l owi ng: an adverse event occur ri ng i n
t he cour se of t he use of a dr ug i n pr of essi onal pract i ce; an adver se event occur ri ng
f r om a dr ug over dose, whet her acci dent al or i nt ent i onal ; an adver se event occurr i ng
f r om dr ug abuse; an adver se event occur r i ng f r om drug wi t hdr awal ; and any
si gni f i cant f ai l ur e of expect ed pharmacol ogi cal act i on. ¨
2

C. Adverse drug react i on i s def i ned by t he Worl d Heal t h Or gani zat i on (WHO) as
" one whi ch i s noxi ous and uni nt ended, and whi ch occurs at doses normal l y used i n
man f or t he prophyl axi s, di agnosi s, or t herapy of di sease, or f or t he modi f i cat i on of
physi ol ogi cal f unct i on. ¨
3

D. The WHO def i nes a si de ef f ect of a drug as: ' any uni nt ended ef f ect of a
pharmaceut i cal product occur ri ng at doses nor mal l y used by a pat i ent whi ch i s
r el at ed t o t he phar macol ogi cal propert i es of t he dr ug. '
III. TYPES OF ADVERSE DRUG REACTIONS
A. Type A
1. Type A r eact i ons ar e ext ensi ons of t he dr ug' s known pharmacol ogy and ar e
r esponsi bl e f or t he maj ori t y of ADRs.
P. 491


2. Type A r eact i ons ar e usual l y dose dependent and pr edi ct abl e but can be t he
r esul t of concomi t ant di sease st at es, drug- dr ug i nt er act i ons, or dr ug- f ood
i nt er act i ons.
3. Ways t o mi ni mi ze t ype A r eact i ons i ncl ude under st andi ng t he phar macol ogy of t he
dr ug bei ng pr escr i bed, moni t or i ng dr ugs wi t h a nar r ow t her apeut i c i ndex, and
avoi di ng pol ypharmacy when possi bl e.
B. Type B
1. Type B r eact i ons i ncl ude i di osyncr at i c r eact i ons, i mmunol ogi cal or al l ergi c
r eact i ons, and carci nogeni c/ t erat ogeni c r eact i ons.
2. Type B r eact i ons ar e usual l y not t he r esul t of a known phar macol ogy of t he drug
but seem t o be a f unct i on of pat i ent suscept i bi l i t y. They ar e r ar el y pr edi ct abl e, ar e
usual l y not dose dependent , and seem t o concent r at e i n cer t ai n body syst ems such
as t he l i ver, bl ood, ski n, ki dney, and ner vous syst em.
3. Type B r eact i ons ar e uncommon but ar e general l y seri ous and can be l i f e
t hr eat eni ng.
4. Except f or i mmedi at e hyper sensi t i vi t y r eact i ons, t ype B react i ons usual l y t ake 5
days bef or e t he pat i ent demonst r at es hyper sensi t i vi t y t o a dr ug. Ther e i s no
maxi mum t i me f or t he occur rence of a r eact i on, but most occur wi t hi n 12 weeks of
i ni t i at i on of t her apy.
IV. RECOGNITION
A. Dr ugs must al ways be consi dered as a possi bl e cause of di sease or sympt oms
t hat ar e among a pat i ent ' s l i st of compl ai nt s. Compl et e dr ug hi st ori es, i ncl udi ng
nonpr escri pt i on dr ugs, must al so be carr i ed out .
B. Recogni t i on i s of t en subj ect i ve, and i t i s not al ways possi bl e t o demonst r at e
st r ong causal i t y bet ween t he dr ug and t he occur rence.
1. Several f act ors may hel p i n assessi ng t he det er mi nat i on of causal i t y.
a. Di d t he pat i ent act ual l y i ngest t he dr ug i n quest i on?
b. Di d t he onset of sympt oms occur af t er t he dr ug was t aken?
c. What i s t he t i me i nt erval bet ween t aki ng t he dr ug and t he onset of sympt oms?
d. Di d t he sympt oms resol ve or i mprove af t er t he dr ug was st opped or t he dose
decreased?
e. Di d t he sympt oms reoccur af t er t he drug was rei nt r oduced?
f . Di d dr ug- drug i nt er act i ons cont ri but e t o t he sympt oms?
g. Were t he dr ugs measur ed i n " t oxi c l evel s¨ i n t he pat i ent ' s ser um?
h. Has t hi s r eact i on been pr evi ousl y seen wi t h use of t he dr ug?
i . What i s t he per sonal exper i ence of t he cl i ni ci an wi t h previ ous use of t he dr ug and
r eact i ons secondar y t o t he drug?
2. Nomogr ams have been devel oped t o ai d i n t he assessment of causal i t y.
V. SURVEILLANCE PROGRAMS.
Phar maci st s as wel l as al l heal t hcare prof essi onal s shoul d t ake an act i ve r ol e i n
moni t ori ng, report i ng, and t r endi ng ADR i nf ormat i on. Some of t he act i vi t i es i nvol ved
i n a concur r ent and ongoi ng ADR sur vei l l ance progr am at an i nst i t ut i onal l evel
i ncl ude t he f ol l owi ng component s:
A. Phar macy depart ment s shoul d t ake t he l ead i n t he col l ect i on of i nf ormat i on and
shoul d submi t al l r evi ews and report s t o t he pharmacy and t her apeut i cs commi t t ees
f or r evi ew and eval uat i on.
1. Encour age al l heal t hcar e pr of essi onal s t o be i nvol ved i n repor t i ng.
2. Moni t or pat i ent s who ar e usi ng hi gh- ri sk agent s.
3. Revi ew pat i ent s who have r ecei ved "ant i dot e¨- t ype drugs.
4. Not i f y prescr i bers of suspect ed ADRs, and encour age t horough document at i on of
t he descri pt i on of t he r eact i on as wel l as t he out come i n pat i ent s' medi cal r ecords.
P. 492


5. Repor t appr opr i at el y i dent i f i ed ADRs t o t he FDA.
6. Devel op t he use of phar macy comput er syst ems t o t r ack ADRs.
B. Eval uat i on of t he causes of ADRs shoul d be car r i ed out . ADR r epor t i nf or mat i on
shoul d be used f or educat i onal pur poses and i dent i f i cat i on of dr ug use and
medi cat i on use processes t o prevent f ur t her occur r ences of such r eact i ons. ADR
r eport i ng i nf ormat i on shoul d be i ncor porat ed i nt o i nst i t ut i onal r i sk management
pr ograms.
VI. REPORTING TO THE FDA.
Thr ee of t he f i ve maj or cent ers at t he FDA are i nvol ved wi t h eval uat i ng t he saf et y
and ef f i cacy of drugs. The l ar gest cent er i s t he Cent er f or Dr ug Eval uat i on and
Resear ch ( CDER) , whi ch over sees bot h pr escr i pt i on and nonpr escr i pt i on÷over - t he-
count er ( OTC) ÷dr ugs. Ì n 2002, CDER est abl i shed t he Adver se Event s Repor t i ng
Syst em ( AERS) , a comput eri zed dat a base desi gned t o support t he FDA' s
post mar ket i ng saf et y progr am f or dr ugs and t her apeut i c bi ol ogi c pr oduct s. Annual l y,
t he AERS r ecei ves about 470, 000 r eport s of adver se exper i ences possi bl y
associ at ed wi t h drugs. The Cent er f or Bi ol ogi cal Eval uat i on and Resear ch ( CBER)
ensur es t he saf et y and ef f i cacy of bl ood pr oduct s, vacci nes, al l er geni cs, bi ol ogi cal
t her apeut i cs, gene t her apy, medi cal devi ces and t est s, xenot r anspl ant at i on
pr oduct s, and banked human t i ssue and cel l ul ar pr oduct s. The Cent er f or Food
Saf et y and Appl i ed Nut r i t i on ( CFSAN) est abl i shed t he CFSAN Adver se Event s
Repor t i ng Syst em ( CAERS) i n 2002. The CAERS pr ovi des a moni t or i ng syst em t o
i dent i f y pot ent i al l y ser i ous pr obl ems secondar y t o non- FDA-approved herbs,
mi ner al s, vi t ami ns, di et ar y suppl ement s, and ot her subst ances.
A. The nat i onal Vacci ne Adverse Event Reporti ng Syst em ( VAERS) i s
coadmi ni st er ed by t he FDA and t he Cent ers f or Di sease Cont r ol and Prevent i on
( CDC) . Mor e t han 10 mi l l i on vacci nes ar e gi ven t o chi l dr en and many mi l l i on mor e
doses t o adul t s each year . Al t hough vacci nes pr ot ect many peopl e f rom dangerous
di seases, t hey do have t he pot ent i al t o cause adver se ef f ect s.
1. The Nat i onal Chi l dhood Vacci ne Ì nj ur y Act ( NCVÌ A) r equi res heal t h prof essi onal s
t o r epor t
a. Adverse event s af t er t he admi ni st rat i on of vacci nes speci f i ed i n t he act , as
descr i bed i n t he " Report abl e Event s Tabl e, ¨ wi t hi n t he speci f i ed t i me per i od
( avai l abl e at www. vaer s. hhs. gov/ or 1- 800- 822- 7967)
b. Any event l i st ed i n t he manuf act urer ' s package i nsert as a cont rai ndi cat i on t o
subsequent doses of t he vacci ne
2. Ì n 1990, VAERS was set up t o recei ve al l r epor t s of suspect ed adver se event s
caused by any U. S. l i censed vacci ne ( Fi gur e 22-1) .
3. The VAERS depends on vol unt ar y r epor t i ng by heal t h pr of essi onal s t o:
a. Ì dent i f y r ar e adverse react i ons not det ect ed i n pr el i censi ng st udi es
b. Moni t or f or i ncr eases i n al r eady known r eact i ons
c. Ì dent i f y ri sk f act ors or pr eexi st i ng condi t i ons t hat pr omot e r eact i ons
d. Ì dent i f y par t i cul ar vacci ne l ot s wi t h unusual l y hi gh r at es or unusual t ypes of
event s
B. MedWatch, t he FDA' s Medi cal Pr oduct s Report i ng Pr ogr am est abl i shed i n 1993,
i s a vol unt ar y syst em f or heal t hcare pr ovi der s ( Fi gur e 22-2) . However ,
manuf act ur ers and di st r i but ors of FDA-appr oved dr ugs, bi ol ogi cs, r adi at i on- emi t t i ng
devi ces, speci al nut ri t i onal pr oduct s, di et ar y suppl ement s, i nf ant f ormul as, and
devi ces ar e mandat ed t o r epor t pr obl ems t o t he FDA. The goal s of t he pr ogr am are
t o i ncrease awar eness of r epor t i ng of medi cal - product - i nduced di seases and t he
i mpor t ance of r epor t i ng, t o cl ari f y what shoul d be r epor t ed, t o make report i ng as
easy as possi bl e, and t o pr ovi de f eedback t o heal t h prof essi onal s.
1. I mport ance of reporti ng
a. The i nci dence of ADRs occur s at a hi gh r at e i n heal t h car e t oday.
( 1) Gener al l y, i t i s repor t ed t hat 3%-11% of al l hospi t al admi ssi ons can be
at t r i but abl e t o ADRs, al t hough some st udi es r epor t t he f i gur e t o be as hi gh as 29%.
( 2) The l i kel i hood t hat a pat i ent wi l l exper i ence an ADR whi l e hospi t al i zed i s
r eport ed i n t he l i t erat ure t o be i n a r ange f r om 5%- 25%.
P. 493



Figure 22-1. VAERS Iorm Ior reporting possible
adverse drug reactions.
P. 494



Figure 22-2. Form Ior reporting possible adverse
drug reactions to the FDA Medical Products
Reporting Program.
b. Pr event i on of ADRs i s an i mpor t ant st rat egy i n heal t h car e. Ì t has been est i mat ed
t hat at l east one t hi r d of al l ADRs may be prevent abl e. Ì t has been f ur t her not ed
t hat pr event abl e ADRs t end t o be t he most cost l y t o t r eat and cause t he gr eat est
degree of pat i ent mor bi di t y.
( 1) Fut ure ADRs can be pr event ed i n i ndi vi dual pat i ent s by car ef ul and consi st ent
document at i on i n pat i ent r ecor ds.
( 2) A pr ogram t hat t racks ADRs can hel p di scover pr evi ousl y uni dent i f i ed t r ends.
These t r ends can be used wi t hi n t he i nst i t ut i on t o devel op pr ogr ams of prospect i ve
i nt er vent i on
P. 495

t o prevent r eoccur r ence of t he react i on i n t he pat i ent popul at i ons t hat ar e at si mi l ar
r i sk.
c. Recogni t i on of previ ousl y undi scover ed ADRs at t r i but abl e t o a dr ug i s par t i cul ar l y
t r ue i n t he case of newl y market ed pr oduct s.
( 1) Al t hough cl i ni cal t r i al s are general l y ef f ect i ve i n assessi ng ef f i cacy and r i sk t o
benef i t r at i o, i nherent l i mi t at i ons exi st i n pr emarket i ng t r i al s.
( a) The t ri al s ar e usual l y r el at i vel y shor t i n durat i on and do not ef f ect i vel y mi mi c t he
exposur e pat i ent s woul d exper i ence i f usi ng t he dr ug as a chr oni cal l y admi ni st er ed
agent .
( b) Dr ug- dr ug i nt er act i ons and use i n pat i ent s wi t h concomi t ant di sease st at es may
not be t est ed f or i n t hese t r i al s.
( c) The smal l si ze of t he t r i al s ( usual l y 1000- 3500 i ndi vi dual s) i s i nsuf f i ci ent t o
det ect r ar el y occur r i ng adver se r eact i ons.
( d) Raci al and et hni c groups may not be part i ci pat i ng i n t he same numbers as
r epr esent ed i n t he general popul at i on.
d. Pr ompt r ecal l i n cases of pr oduct probl ems ar e accompl i shed when t he MedWat ch
Pr ogr am i s used t o report pr oduct pr obl ems or devi ce def ect s.
2. What shouI d be report ed?
a. ADRs t hat ar e seri ous, even i f causal i t y i s not pr oven, i ncl udi ng
( 1) A pat i ent ' s deat h t hat i s suspect ed of bei ng a di r ect out come of an ADR
( 2) A l i f e- t hreat eni ng event
( 3) An i ni t i al or pr ol onged hospi t al i zat i on
( 4) A si gni f i cant , per si st ent , or permanent change or di sabi l i t y/ i ncapaci t y
( 5) A congeni t al anomal y ( i ncl udi ng t hose occurr i ng i n a f et us)
( 6) Ot her probl ems t hat ar en' t l i st ed i n t he manuf act ur er ' s package i nser t as a
known si de ef f ect
b. Mal f unct i oni ng medi cal devi ces such as hear t val ves, l at ex gl oves, di al ysi s
machi nes, and vent i l at ors and pr obl ems wi t h nut ri t i onal product s
c. Product pr obl ems t hat can r esul t i n compromi sed saf et y or qual i t y, i ncl udi ng
pr oduct cont ami nat i on, mi sl abel i ng, uncl ear l abel i ng, poor packagi ng, pot ency
pr obl ems, and quest i onabl e st abi l i t y
d. Count erf ei t or suspect ed count erf ei t drugs
e. Adverse event s wi t h f ood, herbs, vi t ami ns, cosmet i cs, or di et ar y suppl ement s,
al t hough CAERS i s t he pr ef ered report i ng syst em
f . Adverse event s owi ng t o bl ood product s, al l ergeni cs, gene t her apy, human t i ssue
and cel l ul ar pr oduct s, and xenot r anspl ant at i on product s
g. Medi cat i on er r ors
3. Confi dent i aI i t y of bot h t he r epor t er and t he pat i ent s whose cases ar e r eport ed
ar e subst ant i al l y prot ect ed by t he FDA.
4. Repor t i ng of pr obl ems wi t h OTC medi cat i ons ar e r equi red when t he product has
been mar ket ed wi t h a new dr ug appl i cat i on ( NDA) , i ncl udi ng dr ugs f ormerl y
market ed as pr escr i pt i on- onl y dr ugs. OTC pr oduct s market ed wi t hout an NDA do not
r equi r e repor t i ng, but r epor t i ng i s st r ongl y encour aged. Appr oval of t he FDA i s not
r equi r ed f or t he market i ng of nonpr escr i pt i on herbs, mi neral s, vi t ami ns, di et ar y
suppl ement s, and ot her subst ances. Because t he FDA does not appr ove t hese
subst ances, ef f i cacy and saf et y do not have t o be demonst rat ed, nor i s i t mandat ed
t o r epor t probl ems t o t he FDA.
5. Repor t i ng t o manuf act ur ers i s not descri bed i n t he FDA' s gui del i nes, al t hough a
sect i on of t he MedWat ch f orm can be checked of f t o i nf or m t he FDA t hat a copy of
t he repor t has been f or war ded t o t he manuf act urer by t he report er .
C. I nf ormat i on on previ ousI y report ed event s
1. The FDA Web si t e provi des on-l i ne saf et y i nf ormat i on at
www. f da. gov/ medwat ch/ saf et y. ht m gat hered f rom appr oxi mat el y 25, 000 r eport s t hat
ar e submi t t ed each year .
2. Cl i ni cal l y i mpor t ant product saf et y al er t s ar e avai l abl e vi a an aut omat ed e-mai l
messagedel i ver y syst em f r om www. f da. gov/ medwat ch/ el i st . ht m.
P. 496


3. FDA al er t s al so appear on www. Phar maci st . com, a j oi nt vent ur e of t he Ameri can
Phar maci st Associ at i on and t he Nat i onal Associ at i on of Boards of Pharmacy.
VII. American Society of HeaIth-Systems Pharmacists
(ASHP) GuideIines
def i ne cr i t eri a f or cl assi f yi ng an ADR as si gni f i cant . They encour age r epor t i ng of
ser i ous or unexpect ed ADRs t o t he FDA, t he manuf act urer , or bot h.
VIII. Joint Commission on Accreditation of HeaIthcare
Organizations (JCAHO)
r equi r ement s f or accr edi t at i on descri be t he need f or each heal t hcar e organi zat i on t o
moni t or f or adverse event s i nvol vi ng dr ugs and devi ces i n a cont i nual , col l abor at i ve
f ashi on.
IX. United States Pharmacopeia (USP).
Medi cat i on Er r ors Report i ng Pr ogr am at www. usp. or g/ hqi / pat i ent Saf et y/ mer / and t he
USP- Ì nst i t ut e f or Saf e Medi cat i on Pr act i ces (Ì SMP) Medi cat i on Er r ors Repor t i ng
Pr ogr am at ht t ps: / / www. i smp. org/ order f orms/ repor t er r ort oÌ SMP. asp are t wo
pr ograms i nvol ved i n col l ect i on of medi cat i on er ror dat a.
X. FURTHER INFORMATION
A. Ì nf or mat i on about t he MedWat ch pr ogr am can be obt ai ned by phone at 1- 800-
FDA- 1088 and at www. f da. gov/ Medwat ch/ .
B. Ì nf or mat i on about VAERS can be obt ai ned by phone at 1-800- 822- 7967 and at
www. f da. gov/ cber / vaer s/ vaer s. ht m.
C. Ì nf or mat i on about repor t i ng t o t he CFSAN pr ogr am can be obt ai ned by phone at
301-436-2405 or at www. cf san. f da. gov.
D. Fur t her i nf ormat i on about t he FDA' s r epor t i ng syst ems and pr ogr ams, such as
CDER, can be f ound on t he FDA' s Web si t e ( www. f da. gov) .
P. 497


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. The phrase "one whi ch i s noxi ous and uni ntended, and whi ch occurs at
doses normaI I y used i n man f or t he prophyI axi s, di agnosi s, or t herapy of
di sease, or for t he modi f i cati on of physi oI ogi caI f unct i on, " descri bes
( A) a si de ef f ect .
( B) an adverse dr ug r eact i on.
( C) an adverse dr ug event .
( D) a medi cat i on er r or.
Vi ew Answer 1. The answer i s B[ see] . 2. Type A reacti ons are
charact eri zed by whi ch of t he f oI I owi ng?
( A) i di osyncrat i c react i ons
( B) a f unct i on of pat i ent suscept i bi l i t y
( C) caused by dr ug- drug i nt er act i ons
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 2. The answer i s C[ see] . 3. The MedWat ch f orm i s not t he
appropri at e f orm t o report whi ch of the foI I owi ng events?
( A) a vacci ne event descr i bed i n t he Vacci ne Adver se Event Repor t i ng Syst em
( VAERS) " Repor t abl e Event s Tabl e¨
( B) a suspect ed count er f ei t dr ug
( C) a mal f unct i oni ng vent i l at or
( D) a drug t hat i s cont ai ned i n a package wi t h uncl ear l abel i ng
( E) None of t he above
Vi ew Answer 3. The answer i s A[ see] . 4. Prevent abI e adverse drug
react i ons ( ADRs)
( A) gener al l y di spl ay mi l d sympt oms.
( B) ar e al ways easi l y recogni zed.
( C) ar e pr obl ems t hat are easi l y medi cal l y managed.
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 4. The answer i s E[see] . 5. Reporti ng probI ems wi t h vi t ami ns
t o t he FDA i s requi red by I aw i n whi ch of t he foI I owi ng si t uat i ons?
( A) when t he probl em i s di scovered by t he consumer
( B) when saf et y and ef f i cacy have been pr oven by manuf act ur ers t o t he FDA
( C) when a heal t hcare prof essi onal di scover s t he pr obl em
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 5. The answer i s E[see] . P. 498


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì Ì . C] .
Thi s i s t he def i ni t i on f r om t he WHO.
2. The answer i s C [ see Ì Ì Ì . A. 2] .
Type A r eact i ons can be caused by dr ug-dr ug i nt er act i ons. Ì di osyncrat i c r eact i ons
and react i ons caused by pat i ent suscept i bi l i t y are general l y i n t he cl assi f i cat i on of
Type B r eact i ons.
3. The answer i s A [ see VÌ . A. 1] .
Al l t he ot her s ar e r epor t abl e on t he MedWat ch f or m. The Nat i onal Chi l dhood
Vacci ne Ì nj ur y Act r equi res t he use of a VAERS f or m t o report vacci ne- rel at ed
i nj ur i es.
4. The answer i s E [ see VÌ . B. 1] .
Pr event abl e ADRs can be t he cause of seri ous medi cal probl ems t hat r equi r e
i nt ensi ve medi cal care. Al t hough some prevent abl e ADRs may appear obvi ous on
r evi ew of a pat i ent ' s medi cat i on hi st or y, t hi s i s not al ways t he case.
5. The answer i s E [ see VÌ . B. 4] .
Mar ket i ng of t hese product s does not depend on t he manuf act ur ers provi ng ef f i cacy
and saf et y of t he pr oduct s. No l aw r equi r es r eport i ng of subsequent probl ems.
These pr oduct s do not requi r e an NDA. Al t hough i t i s not r equi red f or heal t hcar e
pr of essi onal s t o repor t pr obl ems, i t i s essent i al t hat vol unt ar y r epor t i ng t akes pl ace.

23
Medication Errors
Robert Ci sneros
I. MEDICATION ERROR PROBLEM
A. The 2000 Ì nst i t ut e of Medi ci ne ( Ì OM) r epor t To Er r I s Human br ought t he probl em
of er ror s i n medi ci ne t o nat i onal at t ent i on.
1

1. An est i mat ed 44, 000-98, 000 deaths per year ar e caused by medi cal er r or s. Of
t hose deat hs, appr oxi mat el y 7, 000 ar e t he r esul t of medi cat i on er ror s.
2. A cal l t o act i on was gi ven t o i mpr ove pat i ent saf et y.
B. Ì n recent years, t ragi c medi cat i on er ror s have f ocused at t ent i on on concer ns
r egardi ng pat i ent saf et y.
1. A chemot her apy mi x up at a maj or cancer cent er r esul t ed i n t he deat h of a pat i ent
f r om a fourf oI d overdose dai l y f or 4 days.
2. A chi l d acci dent al l y r ecei ved an i nt ravenous rat her than i nt ramuscuI ar dose of
l ong- act i ng peni ci l l i n and di ed.
3. A compoundi ng err or resul t ed i n deat h of a chi l d who r ecei ved a t r i cycl i c
ant i depr essant at a dose 10 ti mes great er t han the dose prescri bed by physi ci an.
4. Mi xups wi t h hepar i n vi al s whi ch had si mi I ar packagi ng, but di f ferent
concent rati ons, r esul t ed i n overdoses causi ng ser i ous i nj ur y and several i nf ant
deat hs.
II. ERROR DEFINITION.
The Nat i onal Coor di nat i ng Counci l f or Medi cat i on Er r or Repor t i ng and Prevent i on
( NCCMERP) def i nes a medi cat i on er ror as f ol l ows: " A medi cat i on er ror i s any
pr event abl e event t hat may cause or l ead t o i nappr opri at e medi cat i on use or pat i ent
har m whi l e t he medi cat i on i s i n t he cont r ol of t he heal t h care pr of essi onal , pat i ent ,
or consumer . Such event s may be r el at ed t o prof essi onal pract i ce, heal t h care
pr oduct s, pr ocedur es, and syst ems, i ncl udi ng pr escri bi ng; order communi cat i on;
pr oduct l abel i ng, packagi ng, and nomencl at ure; compoundi ng; di spensi ng;
di st r i but i on; admi ni st rat i on; educat i on; moni t or i ng; and use. ¨
2

III. TYPES OF ERRORS.
The f ol l owi ng cat egor i es of er r ors have been used i n numerous r esear ch st udi es.
3

A. Wrong drug error. A dr ug t hat was not or der ed f or a pat i ent was admi ni st er ed÷
f or exampl e, a pat i ent acci dent al l y r ecei ved f ur osemi de 40 mg or al l y. Possi bl e
causes: The phar maci st acci dent al l y f i l l ed t he pat i ent ' s pr escri pt i on f or an ant i bi ot i c
wi t h f ur osemi de; t he phar maci st reached f or t he wr ong bot t l e on t he shel f and di d
not check t he l abel caref ul l y enough.
B. Ext ra dose error. A pat i ent recei ves mor e doses of a drug t han wer e or der ed÷
f or exampl e, a pat i ent was supposed t o r ecei ve a medi cat i on wi t h br eakf ast f or 3
days but recei ved i t f or 5 days. Possi bl e cause: The pat i ent ' s nur se was conf used
by t he medi cat i on di r ect i ons.
C. Omi ssi on error. A dose of a drug was not admi ni st er ed as or der ed but was
ski pped÷f or exampl e, a pat i ent was supposed t o r ecei ve di goxi n 0. 25 mg or al l y i n
t he morni ng but di d not recei ve t he dose. Possi bl e cause: The pat i ent ' s nur se was
so busy t hat he or she f or got t o admi ni st er t he dose.
P. 500


D. Wrong dose or wrong st rengt h error. Ei t her t he wr ong dose of a medi ci ne or
t he wr ong st r engt h i s admi ni st er ed÷f or exampl e, t he pat i ent was supposed t o
r ecei ve war f ari n 0. 5 mg but recei ved war f ar i n 5 mg i nst ead. Possi bl e causes: The
pharmaci st mi sr ead t he l abel ; t he physi ci an wr ot e t he or der as " war f ari n . 5 mg. ¨
Anot her exampl e: a pat i ent was supposed t o r ecei ve t i mol ol 0. 25% but was gi ven
t i mol ol 0. 5%. Possi bl e cause: The phar maci st t ook t he wr ong product of f of t he
shel f , conf used by t he concent rat i ons.
E. Wrong route error. A pat i ent r ecei ves a dose of a medi cat i on by a r out e t hat was
not or der ed by t he physi ci an÷f or exampl e, a pat i ent was supposed t o r ecei ve
pr ochl or per azi ne 10 mg i nt r amuscul arl y but t he drug was admi ni st er ed
i nt ravenousl y. Possi bl e causes: The nur se mi sr ead t he orders; t he physi ci an
mi st akenl y wr ot e " Ì V¨ i nst ead of " Ì M. ¨
F. Wrong t i me error. A pat i ent does not r ecei ve a dose of medi cat i on at t he t i me at
whi ch i t was t o be admi ni st er ed÷f or exampl e, a hospi t al i zed pat i ent wi t h di abet es i s
schedul ed t o r ecei ve a dose of i nsul i n i mmedi at el y bef ore breakf ast (at 7: 00 A. M. )
but t he dose i s gi ven 2 hr af t er breakf ast . Possi bl e cause: The nurse was busy and
coul d not gi ve dose on t i me.
G. Wrong dosage f orm error. A pat i ent r ecei ves a dose of medi ci ne i n a dosage
f or m t hat was not i nt ended÷f or exampl e, ni cot i ni c aci d 500 mg t abl et s wer e order ed
f or a pat i ent who i nst ead r ecei ves ni cot i ni c aci d 500 mg sl ow- r el ease capsul es.
Possi bl e cause: The phar maci st di d not car ef ul l y check t he product or was conf used
by t he l abel .
H. Ot her. Err ors t hat do not f i t i nt o any of t he ot her cat egori es.
IV. COMMON ERROR HAZARDS
A. Dangerous abbrevi ati ons. Numer ous common abbrevi at i ons and symbol s have
been associ at ed wi t h er ror s. Det ai l ed l i st s are avai l abl e f rom t he Ì nst i t ut e f or Saf e
Medi cat i on Pr act i ces ( Ì SMP) at
ht t p: / / www. j oi nt commi ssi on. org/ Sent i nel Event s/ f or ms. and t he Joi nt Commi ssi on on
Accredi t at i on of Heal t hcar e Or gani zat i ons ( JCAHO) at
ht t p: / / www. j oi nt commi ssi on. org/ Pat i ent Saf et y/ DoNot UseLi st / . JCAHO' s accr edi t ed
or gani zat i ons ar e requi red t o avoi d usi ng t he pot ent i al l y conf usi ng abbr evi at i ons on
i t s " Do Not Use¨ l i st .
1. U, I U: uni t ( s) . The l et t er U can easi l y be mi si nt er pret ed as a number ( e. g. , 0 or
4) , and seri ous harm has occur red wi t h i nsul i n and hepari n as a resul t of t hi s
conf usi on. For exampl e, a pat i ent recei ved 66 uni t s of i nsul i n i nst ead of 6 uni t s. The
or der, whi ch was wr i t t en f or " 6U¨ of r egul ar i nsul i n was mi sread as 66. The wor d
uni t s shoul d be wr i t t en out i n f ul l .
2. QD, Q. D. , qd, q. d. ( dai I y) . These common abbrevi at i ons have been
mi si nt er pr et ed as " QÌ D¨ or " qi d¨ (f our t i mes dai l y) r esul t i ng i n overdoses. The wor d
dai l y shoul d be wr i t t en out i n f ul l .
3. Q. O. D, QOD, qod (ever y ot her day) . These common abbr evi at i ons have been
mi si nt er pr et ed as QÌ D ( f our t i mes dai l y) , resul t i ng i n over doses. The wor ds ever y
ot her day shoul d be wr i t t en out compl et el y.
4. Trai I i ng zero. When a dose i s or der ed and f ol l owed wi t h a deci mal poi nt and a
zer o, such as 2. 0 mg or 25. 0 mg, er r ors can occur . The deci mal poi nt may be
mi ssed and an over dose can occur . For exampl e, war f ar i n 2. 0 mg may be
mi si nt er pr et ed as 20 mg. Tr ai l i ng zeros shoul d be avoi ded, and t he dose wr i t t en
wi t hout t he addi t i onal zer o÷f or exampl e, war f ari n 2 mg ( i nst ead of 2. 0 mg) .
5. Lack of I eadi ng zero. A dr ug' s dose may be l ess t han 1 mg, such as f or di goxi n.
Of t en t he dose i s wr i t t en wi t hout a l eadi ng zer o: di goxi n . 25 mg i nst ead of di goxi n
0. 25 mg. Er ror s have occur red because t he deci mal poi nt i s mi ssed÷f or exampl e,
war f ar i n . 5 mg may be i nt er pret ed as war f ari n 5 mg. Leadi ng zeroes shoul d be
i ncl uded, so t he dose i s wr i t t en as di goxi n 0. 25 mg or war f ar i n 0. 5 mg.
6. MS, MSO4 ( morphi ne suI f ate) , MgSO4 ( magnesi um suI fat e). The abbrevi at i ons
f or mor phi ne sul f at e and magnesi um sul f at e ar e qui t e si mi l ar and can be conf used.
Ì t i s r ecommend t hat morphi ne sul f at e and magnesi um sul f at e be wr i t t en i n out i n
f ul l .
P. 501


B. Ot her conf usi ng symboI s, abbrevi at i ons. Ther e ar e numer ous ot her hazar dous
symbol s and abbrevi at i ons t hat shoul d be used wi t h caut i on when wr i t i ng
pr escri pt i on or der s and car ef ul l y exami ned when f i l l i ng prescr i pt i ons. Exampl es
i ncl ude t he f ol l owi ng:
1. cc. St ands f or cubi c cent i met ers and i s of t en used i nst ead of mL. Thi s has been
mi si nt er pr et ed as a 0 ( zer o) ; use mL.
2. µg. Used f or mi cr ogr ams÷f or exampl e, l evot hyr oxi ne 250 µg dai l y. The
abbrevi at i on has been mi st aken f or mg, and overdoses have occurr ed; bet t er t o use
mcg or t o wr i t e out t he wor d mi cr ogr ams.
3. <, >. Symbol s f or l ess t han ( <) and great er t han ( >) have been mi st aken f or each
ot her or mi si nt er pr et ed as numbers. Bet t er t o wr i t e out t he wor ds l ess t han or
gr eat er t han.
4. HCT. Thi s abbr evi at i on f or " hydr ocor t i sone¨ has been mi si nt er pr et ed as
hydr ochl or ot hi azi de. Bet t er t o wr i t e t he wor d out compl et el y.
5. HCI . The abbr evi at i on f or "hydr ochl or i c aci d¨ has been mi si nt er pret ed as KCl
( pot assi um chl ori de). Bet t er t o wr i t e out t he wor ds compl et el y.
C. Sound- a- I i ke or I ook- a- I i ke drug names. A det ai l ed l i st of conf usi ng dr ug names
can be f ound i n t he 2004 Uni t ed St at es Phar macopei a publ i cat i on " USP Qual i t y
Revi ew¨ ( www. usp. or g/ pdf / EN/ pat i ent Saf et y/ qr 792004- 04-01. pdf ). Anot her l i st i s
avai l abl e f rom Ì SMP ( www. i smp. or g/ Tool s/ conf useddrugnames. pdf ) .
1. Exampl es i ncl ude t he f ol l owi ng:
a. Ami t ri pt yl i ne and ami nophyl l i ne
b. Ci spl at i n and car bopl at i n
c. K- Dur and Car dura
2. To avoi d t hese pr obl ems, t he Ì SMP of f ers sever al suggest i ons, i ncl udi ng t he use
of comput er i zed r emi nder s, name- al er t st i cker s, and i ndependent checks; openi ng
t he bot t l e i n f r ont of t he pat i ent , who can conf i rm t he appearance; and r epor t i ng
er r ors.
D. Hi gh- ri sk drugs. Cert ai n pot ent drugs have been i mpl i cat ed i n many ser i ous
and t r agi c medi cat i on er ror s. These have been cal l ed hi gh-r i sk or hi gh- al er t dr ugs.
A l i st of such medi cat i ons can be f ound at
www. i smp. or g/ Tool s/ hi ghal ert medi cat i ons. pdf . Exampl es i ncl ude t he f ol l owi ng:
1. BI ood- modi f yi ng agent s such as hepari n and warf ari n. Er ror s have r esul t ed i n
ser i ous i nj ur y or deat h f rom hemor rhagi ng as a r esul t of overdose (pat i ent r ecei vi ng
10 mg i nst ead of 1 mg) or f r om bl ood cl ot s as a resul t of under dose ( pat i ent
r ecei vi ng 0. 5 mg i nst ead of 5 mg) .
2. Narcot i cs and sedat i ves. Cent r al ner vous syst em depr essi on and r espi r at or y
ar r est have r esul t ed f rom er ror s wi t h t hese dr ugs, such as di azepam 25 mg gi ven
i nt ravenousl y i nst ead of 2. 5 mg.
3. NeuromuscuI ar paraI yzi ng agents such as succi nyI choI i ne and vecuroni um.
Acci dent al use or i nadver t ent use bef or e adequat e vent i l at i on procedur es wer e
st art ed have r esul t ed i n r espi r at or y ar rest and deat h.
4. Chemot herapy drugs. These drugs are associ at ed wi t h pot ent adver se ef f ect s,
af f ect i ng numerous body syst ems, such as t he i mmune, neurol ogi c, and cl ot t i ng
syst ems. Deat hs have occur red as a r esul t of er r or s wi t h t hese pr oduct s. For
exampl e, vi ncr i st i ne was acci dent al l y gi ven t o a chi l d i nst ead of vi nbl ast i ne,
r esul t i ng i n deat h. Conf usi on over t he dosi ng of cycl ophosphami de r esul t ed i n a
f at al f our f ol d over dose.
V. SEVERAL SAFETY TECHNIQUES OBSERVED IN
COMMUNITY PHARMACIES
4

A. Keep wor k procedur es organi zed and si mpl i f i ed.
B. Don' t wor k on sever al pr escri pt i ons at once, j ust one at a t i me.
P. 502


C. Manage i nt er r upt i ons, don' t be pr essur ed t o r ush.
D. Smel l check.
E. Bar code check.
F. Use a magni f yi ng gl ass when needed.
G. Enhance t he desi gn of t he f aci l i t y.
VI. ROOT CAUSE ANALYSIS (RCA).
Thi s i s a st r uct ured pr ocess f or i dent i f yi ng di r ect and i ndi r ect f act ors t hat
cont r i but ed t o a medi cat i on err or . A f ramewor k f or conduct i ng an RCA i s avai l abl e at
ht t p: / / www. j oi nt commi ssi on. org/ Sent i nel Event s/ f or ms. See " Framewor k For
Conduct i ng a Root Cause Anal ysi s. ¨
A. Ì mpor t ant quest i ons t o ask:
1. What happened and why?
2. What wer e t he cont ri but i ng f act ors?
a. Age? Hours wor ked? St af f i ng?
b. Workl oad? St r ess? Conf usi ng names? Locat i on on shel f ?
c. Ì nadequat e i nf ormat i on? Communi cat i on?
d. Ì nadequat e equi pment ?
e. Wor kpl ace at mosphere conduci ve t o saf et y?
f . Ì nadequat e t r ai ni ng of pharmaci st or t echni ci an?
B. Latent def ect . A weakness i n a syst em t hat does not i mmedi at el y resul t i n an
er r or but , under t he r i ght set of ci r cumst ances, can cont ri but e t o a mi st ake. For
exampl e:
1. St ocki ng l ook- al i ke or sound-al i ke drugs next t o each ot her , cont ri but i ng t o a
pharmaci st i ncor rect l y f i l l i ng a pr escr i pt i on.
2. I nadequate t rai ni ng of empl oyees, cont r i but i ng t o an er ror i n whi ch an
aut omat ed di spensi ng machi ne was used i mproper l y and a pat i ent recei ved t he
wr ong medi cat i on.
VII. NATIONAL SAFETY EFFORTS
A. JCAHO' s Nat i onal Pat i ent Saf et y Goal s f or Accr edi t ed Organi zat i ons can be
f ound at ht t p: / / www. j oi nt commi ssi on. or g/ Pat i ent Saf et y/ Nat i onal Pat i ent Saf et yGoal s/ .
Hospi t al goal s i ncl ude:
1. Ì mprove t he accur acy of pat i ent i dent i f i cat i on. Have t wo means of i dent i f yi ng t he
pat i ent ot her t han r oom number .
2. Ì mprove communi cat i on among car egi vers. Veri f y and r ead back t el ephone and
or al or der s.
3. Cr eat e a l i st of " do not use¨ abbrevi at i ons. St andardi ze t he abbr evi at i ons used,
and pr ohi bi t t he use of t hose t hat ar e pr one t o conf usi on and mi si nt er pret at i on.
4. Ì mprove t he saf e use of medi ci nes.
a. Li mi t t he number of di f f er ent concent rat i ons avai l abl e per dr ug pr oduct ;
st andardi ze.
b. Devel op met hods of i dent i f yi ng and revi ewi ng sound-al i ke and l ook- al i ke dr ugs,
pr event i ng er ror s wi t h t hem.
c. Al l medi cat i ons and cont ai ner s shoul d be pr oper l y l abel ed.
d. Reduce t he l i kel i hood of pat i ent harm associ at ed wi t h t he use of ant i coagul at i on
t her apy.
5. Reduce t he ri sk of i nf ect i ons.
a. Compl y wi t h al l Cent er s f or Di sease Cont r ol and Prevent i on ( CDC)
r ecommendat i ons f or hand washi ng and hygi ene.
b. Thor oughl y i nvest i gat e al l seri ous adver se event s and deat hs associ at ed wi t h
i nf ect i on acqui r ed i n a heal t hcar e set t i ng.
P. 503



Figure 23-1. The medication error Iorm used by
the United States Pharmacopeia. |Reprinted with
permission oI the United States Pharmacopeia.|
P. 504


6. Keep accurat e pat i ent medi cat i on r ecor ds and hi st ori es t hroughout t he cont i nuum
of car e.
a. Ensure t hat a pat i ent ' s medi cat i on recor ds are compl et e and accurat e when he or
she i s r ef er r ed or t ransf er r ed wi t hi n or bet ween or gani zat i ons.
b. Pr oper communi cat i on of accur at e pat i ent medi cat i on i nf ormat i on i s cr i t i cal f or
ever yone i nvol ved i n t he pat i ent ' s care.
B. The Fi ve Mi l l i on Li ves Campai gn i ni t i at ed by t he Ì nst i t ut e f or Heal t hcar e
Ì mprovement can be f ound at ht t p: / / www. i hi . or g/ Ì HÌ / Pr ograms/ Campai gn.
1. Purpose: " To pr ot ect pat i ent s f r om f i ve mi I I i on i nci dent s of medi caI harm over
t he next t wo year s ( December, 2006- December , 2008) . ¨
2. Twel ve i nt er vent i ons wer e i dent i f i ed and can be f ound descr i bed i n mor e det ai l at
t he websi t e above. The i nt er vent i ons i ncl uded:
a. Pr event i ng adverse drug events t hrough medi cat i on reconci I i at i on.
b. Pr event i ng surgi caI si t e i nf ecti ons by appropri at e care and ani t bi oti c use.
c. Focus on pr event i ng har m f r om hi gh ri sk medi cat i ons such as ant i coagul ant s,
sedat i ves, narcot i cs, and i nsul i n.
d. Reduce Met hi ci I I i n- Resi stant St aphyl ococcus aureus (MSRA) i nf ecti ons
t hr ough appr opri at e evi dence-based practi ces.
C. The Ì OM i n Jul y 2006 r el eased i t s r epor t " Pr event i ng Medi cat i on Er r ors. ¨ Sever al
r ecommendat i ons wer e made t o i mprove pat i ent saf et y i ncl udi ng: enhanci ng r ol e of
pat i ent i n medi cat i on management , i mpr ovi ng pat i ent educat i on, and i ncreasi ng t he
use of t echnol ogy, such as e- prescr i bi ng. Thi s repor t can be accessed at
www. i om. edu.
D. Medi cat i on error report i ng. The r epor t i ng of medi cat i on er r ors pr ovi des cr i t i cal
saf et y f eedback. Fi gur e 23- 1 shows t he f orm used i n t he Uni t ed St at es
Phar macopei a' s err or repor t i ng pr ogr am. Err ors can be submi t t ed anonymousl y vi a
t he Ì nt er net , by t el ephone, or by mai l .
E. The " Sorr y Works Coal i t i on¨ ( www. sor r ywor ks. net ) i s an or gani zat i on of var i ous
i ndi vi dual s ( heal t hcare pr of essi onal s, l awyer s, i nsur ance execut i ves, concer ned
ci t i zens, et c. ) who promot e t he necessi t y of di scI osure and apoI ogy f ol l owi ng
er r or . The coal i t i on pr ovi des t r ai ni ng and educat i on programs.
F. The Ì nst i t ut e f or Saf e Medi cat i on Pr act i ces ( www. i smp. or g) f ocuses i t s ef f or t s on
medi cat i on error prevent i on and pati ent safety. The Ì SMP publ i shes f our di f f er ent
saf et y newsl et t er s, provi des consul t i ng ser vi ces, and pr esent s numerous
educat i onal pr ogr ams, ser vi ces, and act i vi t i es.
G. The Nat i onal Pat i ent Saf et y Foundat i on ( www. npsf . org) r epr esent s stakehoI ders
f rom a broad array of di sci pI i nes, i ncl udi ng pat i ent s and f ami l i es. The NPSF
mi ssi on i s f ocused on i mprovi ng pat i ent saf et y. Ì t provi des numer ous r esour ces,
publ i cat i ons, and act i vi t i es di r ect ed at i mpr ovi ng t he care of pat i ent s.
P. 505


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. A maj or resuI t i n t he 2000 I nst i tut e of Medi ci ne ( I OM) report i s t hat
( A) phar maci st s ar e not bl amed f or t he maj or i t y of medi cal er ror s.
( B) sur geons make mor e mi st akes t han any ot her heal t h pr of essi onal .
( C) phar maci st s make mor e mi st akes t han any ot her heal t h pr of essi onal .
( D) t here i s now more emphasi s on er r or prevent i on.
Vi ew Answer 1. The correct answer i s D[see] . 2. A pharmaci st i s present ed
a prescri pti on f or 250 mcg of I evot hyroxi ne. Whi ch of the foI I owi ng dosages
wouI d be equi vaI ent t o t hat amount ?
( A) 2. 5 mg
( B) 0. 25 gm
( C) 0. 25 mg
( D) 25 gm
Vi ew Answer 2. The correct answer i s C[see] . 3. A prescri pt i on i s wri t t en
f or warf ari n 1. 0 mg. The communi t y pharmaci st acci dent aI I y di spenses 10 mg.
The pat i ent deveI ops severe bI eedi ng wi thi n 3 days and nearI y di es. Whi ch of
t he f oI I owi ng i s t he most accurate assessment of t hi s prescri pt i on?
( A) A t rai l i ng zer o i s present i n t hi s prescr i pt i on and coul d have cont ri but ed t o t he
pharmaci st ' s er ror .
( B) Thi s i s an exampl e of a l eadi ng zer o, whi ch cont ri but ed t o t he er r or and t he
pat i ent t r agedy.
( C) Sound- al i ke medi cat i ons cont ri but ed t o t hi s er r or .
( D) Thi s does not qual i f y as an er r or based on t he Nat i onal Coor di nat i ng Counci l f or
Medi cat i on Er r or Report i ng and Prevent i on ( NCCMERP) def i ni t i on.
Vi ew Answer 3. The correct answer i s A[see] . 4. A hospi t aI pharmacy
begi ns stocki ng new i nt ravenous mi ni - bags of a neuromuscuI ar- bI ocki ng agent.
The packagi ng i s si mi I ar t o a commonI y used i nt ravenous ant i bi ot i c. The
addi t i on of t he new mi ni - bags was not wi deI y communi cat ed t o aI I personneI .
One weekend, severaI doses of t hi s new product were acci dent aI I y di spensed
i n pI ace of the i nt ended doses of ant i bi ot i c. SeveraI pat i ent s suf f ered
respi rat or y arrest and one of t he pati ents event uaI I y di ed. What wouI d a root
cause anaI ysi s of t hi s error f i nd?
( A) The onl y cause of t hi s er ror was a pharmaci st who was not payi ng at t ent i on. The
pharmaci st shoul d be di smi ssed.
( B) Poor communi cat i on pr act i ces i s a l at ent def ect i n t hi s pharmacy syst em and
si gni f i cant l y cont ri but ed t o t he er r or .
( C) The phar macy t echni ci ans ar e t o bl ame f or t hi s er r or, not t he pharmaci st ,
because t he t echni ci ans obt ai ned t he mi ni -bags f rom st ock and pl aced t he l abel s on
t he bags. The phar maci st checked onl y t he t echni ci an' s wor k. The t echni ci an shoul d
be di smi ssed.
( D) Thi s i s an exampl e of an ext r a dose er r or.
Vi ew Answer 4. The correct answer i s B[see] . 5. What do t he f oI I owi ng
abbrevi at i ons MS, MSO4 and MgSO4 have i n common?
( A) common abbr evi at i ons f or mor phi ne sul f at e
( B) common abbr evi at i ons f or magnesi um sul f at e
( C) shoul d not be used i n JCAHO- accr edi t ed i nst i t ut i ons
( D) appr oved abbr evi at i ons i n most hospi t al s
Vi ew Answer 5. The correct answer i s C[see] . 6. A maj or error i n a hospi t aI
pharmacy resuI t ed i n a t ot aI parent eraI nut ri t i on soI ut i on bei ng mi st aken f or a
cardi opI egi c soI ut i on for coronar y bypass surger y. Whi ch of t he f oI I owi ng i s
t rue regardi ng t he root cause anaI ysi s t hat was done at t he hospi taI af t er t he
error?
( A) The pri mar y obj ect i ve i s t o f i nd out whi ch phar maci st made t he mi st ake t hat
al l owed t hi s t o t ake pl ace.
( B) The r esul t of t he anal ysi s woul d be t he admi ssi on t hat an er r or had t aken pl ace.
( C) Al l f act ors t hat coul d have cont r i but ed t o t hi s er r or woul d be i dent i f i ed and
anal yzed.
( D) A r oot cause anal ysi s woul d be i nappropri at e i n t hi s case.
Vi ew Answer 6. The correct answer i s C[see] . P. 506


ANSWERS AND EXPLANATIONS
1. The correct answer i s D [ see Ì . A. 2] .
The Ì OM r epor t r eveal ed al ar mi ng dat a on deat hs r el at ed t o medi cal err ors. The
r eport cont ri but ed t o i ncreased ef f or t s t o i mpr ove pat i ent saf et y.
2. The correct answer i s C [ see Ì Ì Ì . D] .
Al t hough t hi s may seem t o be an el ement ar y quest i on and answer , a wr ong dose
er r or such as t hi s coul d easi l y l ead t o a seri ous i nj ur y or deat h t o a pat i ent .
3. The correct answer i s A [ see Ì V. A. 4] .
Warf ari n 1. 0 mg. i s an exampl e of a t r ai l i ng zero. JCAHO has i ncl uded t hi s i n i t s " Do
Not Use¨ l i st of abbr evi at i ons. However , i n t he communi t y set t i ng, i t i s a pr act i ce
t hat can st i l l be f r equent l y seen on pr escri pt i ons. When a t r ai l i ng zer o i s obser ved,
much caut i on shoul d be exer ci sed i n i nt er pr et i ng t he pr escri pt i on.
4. The correct answer i s B [ see VÌ . A. 2] .
Poor communi cat i on was a maj or cont r i but i ng f act or t o t hi s t r agi c ser i es of er r or s.
The dr ug was a hi gh- ri sk dr ug and had si mi l ar packagi ng as anot her commonl y used
dr ug. These are t wo maj or i ngr edi ent s f or t he seri ous err or t hat t ook pl ace. Thi s
does not absol ve t he t echni ci an and phar maci st t ot al l y f r om any bl ame but
emphasi zes t he si gni f i cant r ol e t hat f ai l ur e of communi cat i on pl ayed wi t hi n t hi s
pharmacy syst em. The syst em was as much or mor e t o bl ame t han any i ndi vi dual s.
Fi r i ng t he i ndi vi dual s does not r epai r t he pr obl em of poor communi cat i on i n t he
syst em but onl y set s t he st age f or a si mi l ar mi st ake t o occur agai n.
5. The correct answer i s C [ see Ì V. A. 6] .
These abbrevi at i ons ar e i ncl uded i n JCAHO' s " Do Not Use¨ l i st . Er r ors r esul t i ng i n
ser i ous har m have occurr ed af t er mi x ups wi t h mor phi ne and magnesi um.
6. The correct answer i s C [ see VÌ . A. 2] .
A r oot cause anal ysi s i s not i nt ended t o f ocus on bl ame but on al l f act ors t hat coul d
have been r el at ed t o t hi s er r or. Fact or s mi ght have i ncl uded t rai ni ng of phar maci st
and t echni ci ans, t he act ual dr ug order , and t he l abel . The cont r i but i on of such
f act or s mi ght not be di scover ed i f t he f ocus i s on onl y i dent i f yi ng whi ch phar maci st ,
t echni ci an, or ot her prof essi onal i s t o bl ame.

24
CIinicaI ToxicoIogy
John J. Ponzi I I o
I. OVERVIEW
A. Thi s chapt er i s i nt ended t o provi de t he r eader wi t h an over vi ew of t he
management of vari ous t oxi c exposur es. Emer gency medi cal ser vi ces
( EMS) shoul d be i mmedi at el y cont act ed t o provi de advanced l i f e suppor t f or
pat i ent s wi t h unst abl e vi t al si gns r esul t i ng f rom a poi soni ng exposur e. Ì n
addi t i on, t hese pat i ent s shoul d be r ef er r ed t o a hospi t al f or f ol l ow- up. A
nat i onwi de t ol l - f ree poi son cent er number became avai l abl e. Thi s number,
800-222-1222 i s avai l abl e 24 hr / day and shoul d be used by heal t hcar e
pr of essi onal s and t he gener al publ i c when deal i ng wi t h exposur es t o
pot ent i al l y t oxi c subst ances.
B. Def i ni t i ons
1. Cl i ni cal t oxi col ogy. Focuses on t he ef f ect s of subst ances i n pat i ent s
caused by acci dent al poi soni ngs or i nt ent i onal over doses of medi cat i ons,
dr ugs of abuse, househol d pr oduct s, or vari ous ot her chemi cal s
2. Ì nt oxi cat i on. Toxi ci t y associ at ed wi t h any chemi cal subst ance
3. Poi soni ng. A cl i ni cal t oxi ci t y secondar y t o acci dent al exposur e
4. Over dose. An i nt ent i onal exposure wi t h t he i nt ent of causi ng sel f -i nj ur y
or deat h
C. Epi demi ol ogy. Ì n 2004, mor e t han 2. 4 mi l l i on acci dent al and i nt ent i onal
poi soni ngs wer e r epor t ed t o t he Amer i can Associ at i on of Poi son Cont rol
Cent ers ( AAPCC). The maj ori t y of poi son exposures (84. 1%) wer e
acci dent al . However , 1183 of t hese exposur es r esul t ed i n deat h. Mor e
i nf or mat i on can be f ound at t he AAPCC' s Web si t e ( www. aapcc. or g) .
D. Ì nf or mat i on resources
1. Comput eri zed dat abases
a. Poi si ndex i s a comput er i zed CD- ROM dat abase t hat i s updat ed quar t erl y
and i s a pr i mar y r esour ce f or poi son cont r ol cent er s.
2. Pr i nt ed publ i cat i ons. Text books and manual s pr ovi de usef ul i nf ormat i on
r egardi ng t he assessment and t r eat ment of pat i ent s exposed t o var i ous
subst ances, al t hough t hei r usef ul ness i s l i mi t ed by t he l ag t i me of
i nf or mat i on publ i shed i n t he pr i mar y l i t er at ur e reachi ng updat ed edi t i ons.
a. El l enhorn MJ, ed. Medi cal Toxi col ogy: Di agnosi s and Tr eat ment of
Human Poi soni ngs, 2nd ed. New Yor k, El sevi er Sci ence, 1997.
b. Fraunf el der FT, Fr aunf el der FW. Drug- Ì nduced Ocul ar Si de Ef f ect s, 5t h
ed. Li t t l e Rock: But t er wor t h- Hei nemann, 2001.
c. Fraunf el der, Fraunf el der and Wi l ey. Cl i ni cal Ocul ar Toxi col ogy. Mar ch
2008 6t h edi t i on Saunder s
d. Gol df r ank L, ed. Toxi col ogi c Emer genci es. 8t h ed. New Yor k: McGr aw
Hi l l , 2006.
e. Gr ant WM. Toxi col ogy of t he Eye, 4t h ed. Spr i ngf i el d, Ì L: Char l es C
Thomas, 1995.
f . Haddad and Wi nchest er ' s Cl i ni cal Management of Poi soni ng and Drug
Over dose Shannon MO, Bor r ow SW, Bur ns M 4t h Edi t i on 2007 WB Saunder s
g. Hedges JR, Hender son RG, eds. Ter r or i sm and cri t i cal car e: chemi cal ,
bi ol ogi cal , r adi ol ogi c, and nucl ear weapons. Cri t Car e Cl i n 2005; 21( 4).
h. Hol st ege CP, Rusyni ak DE, eds. Medi cal Toxi col ogy. Med Cl i n Nor t h Am
2005; 8(6) .
i . Lei ki n JB, Pal oucek FP. Poi soni ng and Toxi col ogy Compendi um, 3rd ed.
Hudson, OH: Lexi - Comp, 2002.
j . Ol son KR, ed. , wi t h, Anderson Ì B, Benowi t z NL, Bl anc PD, et al .
Poi soni ng and Dr ug Over dose, 5t h ed. St amf or d, CT, Appl et on & Lange,
2006.
P. 508


3. Ì nt ernet
1

a. Cent ers f or Di sease Cont r ol and Pr event i on ( CDC) at www. cdc. gov
b. U. S. Food and Dr ug Admi ni st r at i on ( FDA) at www. f da. gov
c. Nat i onal Li br ar y of Medi ci ne at www. nl m. ni h. gov
d. Nat i onal Ì nst i t ut e f or Occupat i onal Saf et y and Heal t h ( NÌ OSH) at
www. cdc. gov/ ni osh
e. Amer i can Soci et y of Heal t h- Syst em Pharmaci st s at www. ashp. or g
f . Mat er i al Saf et y Dat a Sheet s at www. msdssear ch. com
g. U. S. Envi r onment al Prot ect i on Agency ( EPA) at www. epa. gov
h. Chemi cal Abst ract s Ser vi ce at www. cas. or g
4. Poi son cont r ol cent ers accr edi t ed by t he AAPCC pr ovi de i nf ormat i on t o
t he gener al publ i c and heal t hcar e pr ovi ders. These cent ers ar e t he most
r el i abl e and up-t o- dat e sour ces of i nf ormat i on; t hus t he AAPCC' s phone
number ( 800- 222- 1222) shoul d be r eadi l y avai l abl e.
II. GENERAL MANAGEMENT
A. Suppor t i ve car e and ABCs. Eval uat i ng and suppor t i ng t he vi t al f unct i ons
( ai r way, br eat hi ng, and ci r cul at i on [ ABCs] ) ar e t he mandat or y f i rst st eps i n
t he i ni t i al management of dr ug i ngest i ons. Af t er t he pat i ent i s st abi l i zed,
t he speci f i c i ssue(s) of poi son management shoul d be addr essed.
2

B. Tr eat ment f or pat i ent s wi t h depr essed ment al st at us i ncl udes t he
f ol l owi ng:
1. To r ul e out or t r eat hypogl ycemi a, 50 mL of 50% dext r ose i n adul t s and 1
mL/ kg i n chi l dr en, i nt r avenousl y (Ì V)
2. Thi ami ne 100 mg Ì V push ( gl ucose can pr eci pi t at e t he Werni cke-
Kor sakof f syndrome i n t hi ami ne- def i ci ent pat i ent s)
3. Nal oxone ( Narcan) 0. 4- 2 mg Ì V push, i f opi at e i ngest i on i s suspect ed
C. Obt ai ni ng a hi st or y of exposur e
1. Ì dent i f y t he subst ance( s) i ngest ed, t he r out e of exposur e, t he quant i t y
i ngest ed, t he amount of t i me si nce i ngest i on, si gns and sympt oms of
over dose, and any associ at ed i l l ness or i nj ur y. Cor r obor at e hi st or y and
ot her physi cal evi dence ( e. g. , pi l l cont ai ner s) f rom prehospi t al pr ovi der s.
2. Neur ol ogi cal exami nat i on eval uat es any sei zures, al t er at i ons i n
consci ousness, conf usi on, at axi a, sl ur red speech, t r emor, headache, or
syncope.
3. Cardi opul monar y exami nat i on eval uat es any syncope, pal pi t at i ons,
cough, chest pai n, short ness of breat h, or bur ni ng or i r r i t at i on of t he upper
ai r way.
4. Gast r oi nt est i nal ( GÌ ) exami nat i on eval uat es any abdomi nal pai n, nausea,
vomi t i ng, di ar rhea, or di f f i cul t y i n swal l owi ng.
5. Past medi cal hi st or y shoul d i ncl ude
a. Medi cat i ons, i ncl udi ng nonpr escri pt i on ( over- t he- count er [ OTC] )
subst ances
b. Use of her bal medi cat i ons
c. Al cohol or dr ug abuse
d. Psychi at ri c hi st or y
e. Al l ergi es
f . Occupat i onal or hobby exposur es
g. Tr avel
h. Pr i or i ngest i ons
i . Soci al hi st or y wi t h pot ent i al f or domest i c vi ol ence or negl ect
j . Last nor mal menst rual per i od or pregnancy
P. 509


D. Rout i ne l aborat or y assessment
1. Compl et e bl ood cel l (CBC) count
2. Serum el ect r ol yt es
3. Bl ood urea ni t rogen (BUN) ; ser um creat i ni ne (SCr )
4. Bl ood gl ucose
5. Ur i nal ysi s
6. El ect r ocar di ogr am ( ECG)
7. Chest r oent genogr am and/ or ki dneys, uret ers, and bl adder ( KUB) x- r ay
E. Toxi col ogy l abor at or y t est s
1. Advant ages
a. Conf i rm or det ermi ne t he pr esence of a par t i cul ar agent
b. Pr edi ct t he ant i ci pat ed t oxi c ef f ect s or sever i t y of exposure t o some
poi sons
c. Conf i rm or di st i ngui sh di f f er ent i al or cont r i but i ng di agnosi s
d. Occasi onal l y hel p gui de t her apy
2. Di sadvant ages
a. These t est s cannot provi de a speci f i c di agnosi s f or al l pat i ent s.
b. Al l possi bl e i nt oxi cat i ng agent s cannot be screened.
c. Ì n cr i t i cal l y i l l pat i ent s, suppor t i ve t r eat ment i s needed bef ore l aborat ory
r esul t s of t he t oxi col ogy screen ar e avai l abl e.
d. Laborat or y dr ug- det ect i on abi l i t i es di f f er .
e. Ì n general , onl y a qual i t at i ve det er mi nat i on of a subst ance or subst ances
i s necessar y; however , quant i t at i ve l evel s of t he f ol l owi ng drugs are
necessar y t o gui de t herapy:
( 1) Acet ami nophen
( 2) Ami nogl ycosi des
( 3) Arseni c
( 4) Carbamazepi ne ( Tegr et ol )
( 5) Carboxyhemogl obi n
( 6) Cycl ospori ne
( 7) Di goxi n ( Lanoxi n)
( 8) Et hanol
( 9) Et hyl ene gl ycol
( 10) Ì r on
( 11) Lead
( 12) Li t hi um ( Eskal i t h)
( 13) Mer cur y
( 14) Met hanol
( 15) Met hemogl obi n
( 16) Met hot rexat e
( 17) Phenobar bi t al
( 18) Phenyt oi n ( Di l ant i n)
( 19) Sal i cyl at es
( 20) Tacr ol i mus
( 21) Theophyl l i ne
( 22) Val pr oi c aci d ( Depakene)
( 23) Vancomyci n
F. Ski n decont ami nat i on shoul d be per f ormed when per cut aneous
absor pt i on of a subst ance may r esul t i n syst emi c t oxi ci t y or when t he
cont ami nat i ng subst ance may pr oduce l ocal t oxi c ef f ect s ( e. g. , aci d bur ns).
The pat i ent ' s cl ot hi ng i s r emoved, and t he areas ar e i r r i gat ed wi t h copi ous
quant i t i es of wat er . Neut r al i zat i on shoul d not be at t empt ed. For exampl e,
neut ral i zi ng aci d burns wi t h sodi um bi car bonat e wi l l pr oduce an exot her mi c
chemi cal r eact i on, t hereby exacer bat i ng t he pat i ent ' s condi t i on.
G. Gast ri c decont ami nat i on may be at t empt ed when suppor t i ve car e i s
begun. GÌ decont ami nat i on i nvol ves r emoval of t he i ngest ant wi t h emesi s or
l avage, t he use of act i vat ed char coal pot ent i al l y t o bi nd any i ngest ant s, and
t he use of cat har t i cs t o hast en excr et i on and t hereby l i mi t absor pt i on.
P. 510


1. Emesi s
a. Cont r ai ndi cat i ons
( 1) Chi l dren younger t han 6 mont hs of age
( 2) Pat i ent s wi t h cent r al ner vous syst em ( CNS) depr essi on or sei zur es
( 3) Pat i ent s who have i ngest ed a st r ong aci d, al kal i , or a sharp obj ect
( 4) Pat i ent s wi t h compr omi sed ai r way pr ot ect i ve r ef l exes ( i ncl udi ng coma
and convul si ons)
( 5) Pat i ent s who have i ngest ed some t ypes of hydr ocar bons or pet r ol eum
di st i l l at es
( 6) Pat i ent s who have i ngest ed subst ances wi t h an ext r emel y r api d onset of
act i on
( 7) Pat i ent s wi t h emesi s af t er t he i ngest i on
b. Syr up of i pecac. Owi ng t o concer ns of saf et y, ef f i cacy and t he del ay of
ant i dot e admi ni st rat i on, syr up of i pecac i s no l onger recommended f or
gener al use. Ì pecac may be admi ni st er ed wi t hi n 30 mi n of an i ngest i on and
onl y on t he advi ce of a poi son cont r ol cent er .
3
Ther e i s no cont r ai ndi cat i on
t o t he use of i pecac syr up: and There i s subst ant i al ri sk of ser i ous t oxi ci t y
t o t he vi ct i m: and Ther e i s no al t er nat i ve t herapy avai l abl e or ef f ect i ve t o
decrease gast r oi nt est i nal absorpt i on ( e. g. , act i vat ed char coal ); and There
wi l l be a del ay of gr eat er t han 1 hour bef ore t he pat i ent wi l l ar ri ve at an
emergency medi cal f aci l i t y and i pecac syr up can be admi ni st er ed wi t hi n 30-
90 mi nut es of t he i ngest i on; and Ì pecac syr up admi ni st r at i on wi l l not
adver sel y af f ect more def i ni t i ve t r eat ment t hat mi ght be pr ovi ded at t he
hospi t al .
( 1) Mechani sm of act i on. The onset of emesi s usual l y occurs wi t hi n 30 mi n
af t er syr up of i pecac. The ef f ect s l ast f or appr oxi mat el y 2 hr and pr oduce
approxi mat el y t hr ee epi sodes of emesi s i n 60 mi n.
( 2) Dosages. Pat i ent s 6-12 mont hs of age, 5- 10 mL; pat i ent s 1-12 year s of
age, 15 mL; pat i ent s ol der t han age 12 years, 30 mL. Each dose of syr up of
i pecac shoul d be f ol l owed wi t h 120- 240 mL of wat er . The pat i ent shoul d be
upr i ght t o avoi d acci dent al aspi r at i on and shoul d be super vi sed.
( 3) Adverse ef f ect s. Di arr hea, l et har gy/ drowsi ness, and pr ol onged ( > 1 hr)
emesi s
2. Gast r i c l avage
a. Use. Gast ri c l avage i s i nf requent l y used i n pat i ent s who are not al ert or
have a di mi ni shed gag ref l ex. Thi s pr ocedur e shoul d al so be consi der ed i n
pat i ent s who ar e seen ear l y af t er massi ve i ngest i ons. Thi s pr ocedur e i s
cont r ai ndi cat ed i n pat i ent s who have i ngest ed aci ds, al kal i s, or
hydr ocar bons. Ì n addi t i on, pat i ent s shoul d not r ecei ve gast ri c l avage i f t hey
ar e at r i sk f or GÌ per f or at i on or i f t hey ar e combat i ve.
b. Pr ocedure. Pat i ent s ar e pl aced i n t he l ef t l at eral decubi t us posi t i on.
Lavage i s per f ormed af t er a cuf f ed endot racheal t ube i s i n pl ace t o prot ect
t he ai r way. Af t er aspi r at i on of t he gast r i c cont ent s, 250-300 mL of t ap wat er
or sal i ne i s i nst i l l ed and t hen aspi rat ed. The sequence shoul d be r epeat ed
unt i l t he ret urn i s cont i nuousl y cl ear f or at l east 2 L.
3. Act i vat ed char coal adsor bs al most al l commonl y i ngest ed dr ugs and
chemi cal s and i s usual l y admi ni st er ed t o most over dose pat i ent s as qui ckl y
as possi bl e. Commonl y i ngest ed subst ances not adsor bed i ncl ude et hanol ,
i r on, l i t hi um, cyani de, et hyl ene gl ycol , l ead, mercur y, met hanol , or gani c
sol vent s, pot assi um, st rong aci ds, and st r ong al kal i s.
a. Dosage. Act i vat ed char coal ( Act i dose wi t h sorbi t ol ) i s avai l abl e as a
col l oi dal di spersi on wi t h wat er or sor bi t ol . Ì n adul t s, t he dose of act i vat ed
charcoal i s 25-100 g; t he dose i n chi l dren 1- 12 year s of age i s 25- 50 g; t he
dose i n chi l dren up t o 1 year of age i s 1 g/ kg. Const i pat i on has not been
obser ved af t er t he admi ni st rat i on of a si ngl e dose of act i vat ed charcoal .
Mul t i pl e doses of any cat har t i cs shoul d be avoi ded because t hey can cause
el ect r ol yt e i mbal ances and/ or dehydr at i on. Toxi c i ngest i ons wi t h dr ugs
havi ng an ent erohepat i c ci rcul at i on ( e. g. , carbamazepi ne, t heophyl l i ne,
phenobar bi t al , t ri cycl i c ant i depressant s, phenot hi azi nes, di gi t al i s) gener al l y
r equi r e t hat t he charcoal be readmi ni st er ed ever y 6 hr t o pr event
r eabsorpt i on duri ng r eci rcul at i on.
b. Adverse ef f ect s. Charcoal aspi r at i on and empyema have been r epor t ed i n
t he l i t er at ur e. As such, char coal shoul d be wi t hhel d i f pat i ent s ar e vomi t i ng.
Bowel obst r uct i on may
P. 511

occur wi t h mul t i pl e doses of act i vat ed char coal and/ or pat i ent s who are
r ecei vi ng concomi t ant t her apy wi t h neuromuscul ar - bl ocki ng drugs.
4

H. Whol e-bowel i r r i gat i on has been shown t o be ef f ect i ve under cer t ai n
condi t i ons, part i cul ar l y when act i vat ed char coal l acks ef f i cacy. An i sosmot i c
cat har t i c sol ut i on such as pol yet hyl ene gl ycol ( GoLYTELY, Col yt e) i s used.
The dosage i s 1- 2 L/ hr gi ven oral l y or by nasogast r i c t ube unt i l t he rect al
ef f l uent i s cl ear .
Ì . Forced di uresi s and uri nar y pH mani pul at i on may be used t o enhance t he
el i mi nat i on of subst ances, whose el i mi nat i on i s pr i mar i l y renal , i f t he
subst ance has a rel at i vel y smal l vol ume of di st r i but i on wi t h l i t t l e pr ot ei n
bi ndi ng. However , t he use of t hese met hods i s associ at ed wi t h f l ui d and
el ect r ol yt e di st urbances.
1. Al kal i ne di uresi s pr omot es t he i oni zat i on of weak aci ds, t her eby
pr event i ng t hei r r eabsorpt i on by t he ki dney, whi ch f aci l i t at es t he excr et i on
of such weak aci ds. Thi s pr ocedur e has been used i n t he management of
pat i ent s who have i ngest ed l ong- act i ng bar bi t ur at es such as phenobarbi t al
or sal i cyl i c aci d. Pat i ent s are gi ven 50- 100 mEq of sodi um bi car bonat e Ì V
push, f ol l owed by a cont i nuous i nf usi on of 50-100 mEq of sodi um
bi car bonat e i n 1 L of 0. 25%- 0. 45% nor mal sal i ne, mai nt ai ni ng a ur i ne pH of
7. 3- 8. 5. Ur i ne out put shoul d be 5- 7 mL/ kg/ hr. Compl i cat i ons i ncl ude
met abol i c al kal osi s, hyper nat r emi a, hyper osmol ar i t y, and f l ui d over l oad.
J. Di al ysi s. Ì n pat i ent s who f ai l t o r espond t o t he measures of
decont ami nat i on al r eady out l i ned, hemodi al ysi s, and t o a l esser ext ent
per i t oneal di al ysi s, may enhance dr ug el i mi nat i on. Subst ances t hat ar e
r emoved by hemodi al ysi s general l y ar e wat er sol ubl e, have a smal l vol ume
of di st r i but i on (< 0. 5 L/ kg) , have a l ow mol ecul ar wei ght (< 500 dal t ons) ,
and ar e not si gni f i cant l y bound t o pl asma prot ei ns. Hemodi al ysi s usual l y i s
i ndi cat ed f or l i f e-t hr eat eni ng i ngest i ons of et hyl ene gl ycol , met hanol , or
par aquat . Thi s t echni que al so has been used t o enhance t he el i mi nat i on of
et hanol , t heophyl l i ne, l i t hi um, sal i cyl at es, and l ong- act i ng barbi t ur at es.
K. Hemoper f usi on i s a t echni que i n whi ch ant i coagul at ed bl ood i s passed
t hr ough ( perf used) a col umn cont ai ni ng act i vat ed char coal or resi n
par t i cl es. Thi s met hod of el i mi nat i on cl ear s subst ances f r om t he bl ood mor e
r api dl y t han hemodi al ysi s, but i t does not corr ect f l ui d and el ect r ol yt e
abnor mal i t i es, as does hemodi al ysi s. Hemoper f usi on, al t hough more
ef f ect i ve i n r emovi ng phenobar bi t al , phenyt oi n, car bamazepi ne,
met hot rexat e, and t heophyl l i ne t han hemodi al ysi s, i s l ess ef f ect i ve i n
r emovi ng et hanol or met hanol . Compl i cat i ons of hemoper f usi on i ncl ude
t hr ombocyt openi a, l eukopeni a, hypocal cemi a, hypogl ycemi a, and
hypot ensi on.
III. MANAGEMENT OF SPECIFIC INGESTIONS
A. Acet ami nophen ( Tyl enol ) i s an ant i pyret i c- anal gesi c t hat can produce
f at al hepat ot oxi ci t y i n unt r eat ed pat i ent s t hrough t he gener at i on of a t oxi c
met abol i t e.
1. Avai l abl e dosage f or ms. Acet ami nophen i s avai l abl e i n a vari et y of OTC
and pr escri pt i on drug product s.
2. Toxi coki net i cs. Acet ami nophen i s wel l absor bed f rom t he GÌ t ract and
has a hal f - l i f e bet ween 2 and 3 hr . Less t han 5% i s excr et ed unchanged i n
t he ur i ne; t he r emai nder i s met abol i zed i n t he l i ver by t he cyt ochr ome P450
syst em.
3. Cl i ni cal present at i on
a. Phase Ì (12-24 hr post i ngest i on) . Nausea, vomi t i ng, anor exi a, and
di aphoresi s
b. Phase Ì Ì ( 1-4 days post i ngest i on). Asympt omat i c
c. Phase Ì Ì Ì (2- 3 days i n unt r eat ed pat i ent s) . Nausea, abdomi nal pai n,
pr ogressi ve evi dence of hepat i c f ai l ur e, coma, and deat h
P. 512


4. Laborat or y dat a
a. Serum acet ami nophen l evel s. Pat i ent s wi t h l evel s gr eat er t han 150, 70,
or 40 mg/ mL at 4, 8, or 12 hr af t er i ngest i on r equi r e ant i dot al t herapy wi t h
N- acet yl - L-cyst ei ne ( NAC) accordi ng t o t he Rumack- Mat t hews nomogr am.
b. Basel i ne l i ver f unct i on t est s shoul d be done i n al l pat i ent s.
c. Renal f unct i on t est s, i ncl udi ng a BUN and SCr , shoul d be done.
d. Coagul at i on st udi es i ncl ude pr ot hr ombi n t i me (PT) , par t i al t hrombopl ast i n
t i me ( PTT) , and bl eedi ng t i me.
5. Tr eat ment
a. Adul t pat i ent s who have i ngest ed > 10 g or chi l dr en who have i ngest ed >
200 mg/ kg r equi re t reat ment . El derl y and al cohol i c pat i ent s have an
i ncreased suscept i bi l i t y t o acet ami nophen hepat ot oxi ci t y.
b. The recommended t reat ment i s GÌ decont ami nat i on wi t h act i vat ed
charcoal .
c. Ant i dot al t herapy wi t h NAC i s i ndi cat ed f or pat i ent s wi t h t oxi c bl ood
l evel s of acet ami nophen.
( 1) NAC dosage i s 140 mg/ kg as a l oadi ng dose f ol l owed by 70 mg/ kg ever y
4 hr f or a t ot al of 17 doses. NAC i s admi ni st er ed ei t her or al l y or vi a a
nasogast ri c t ube. NAC (Mucomyst ) 20% cont ai ns 200 mg/ mL. Each dose
must be di l ut ed 1: 3 i n ei t her col a or f rui t j ui ce t o mask t he unpl easant t ast e
and smel l . The dose of NAC shoul d be r epeat ed i f t he pat i ent vomi t s wi t hi n
30 mi n of admi ni st r at i on. Pat i ent s wi t h severe nausea secondar y t o NAC
may be pret r eat ed wi t h Ì V met ocl opr ami de ( Regl an) 10 mg ever y 6 hr .
Met ocl oprami de act s as an ant i emet i c whi l e i ncreasi ng t he r at e of NAC
absor pt i on.
( 2) Ì V NAC ( Acet adot e)
( a) Loadi ng dose: 150 mg/ kg over 60 mi n
( b) Mai nt enance dose: 50 mg/ kg over 4 hr f ol l owed by 100 mg/ kg over 16 hr
( c) Anaphyl act oi d react i ons ar e obser ved i n appr oxi mat el y 20% of pat i ent s.
Caut i on shoul d be exer ci sed i n pat i ent s wi t h a hi st or y of ast hma.
B. Al cohol s
5

1. Et hyl ene gl ycol
a. Avai l abl e f orms. Et hyl ene gl ycol commonl y i s used i n ant i f r eeze and
wi ndshi el d dei ci ng sol ut i ons. Thi s f orm i s somet i mes col or l ess and has a
sweet t ast e.
b. Toxi coki net i cs. Et hyl ene gl ycol i s hepat i cal l y met abol i zed by al cohol
dehydrogenase t o gl ycol al dehyde, whi ch i s met abol i zed by al dehyde
dehydrogenase t o gl ycol i c aci d. Gl ycol i c aci d i s conver t ed t o gl yoxyl i c aci d,
whose most t oxi c met abol i t e i s oxal i c aci d.
c. Cl i ni cal pr esent at i on
( 1) St age Ì ( 0. 5-12 hr s post i ngest i on) . At axi a, nyst agmus, nausea and
vomi t i ng, decreased deep t endon r ef l exes, and sever e aci dosi s (more
sever e over doses: hypocal cemi c t et any and sei zur es, cer ebral edema,
coma, and deat h)
( 2) St age Ì Ì (12-24 hr s post i ngest i on) . Tachypnea, cyanosi s, t achycardi a,
pul monar y edema, and pneumoni t i s
( 3) St age Ì Ì Ì ( 24-72 hr s post i ngest i on) . Fl ank pai n and cost over t ebr al angl e
t ender ness; ol i guri c r enal f ai l ur e
d. Laborat or y dat a may reveal severe met abol i c aci dosi s, hypocal cemi a,
and cal ci um oxal at e cr yst al s i n t he ur i nal ysi s.
e. Tr eat ment
( 1) Gast r i c l avage i s per f or med wi t hi n 30 mi n of i ngest i on.
( 2) Ì V et hanol ( Et OH) i s used i n si t uat i ons i n whi ch f omepi zol e i s not
avai l abl e.
( a) Ì ndi cat i ons i ncl ude an et hyl ene gl ycol l evel > 20 mg/ dL, suspi ci on of
i ngest i on pendi ng l evel , or an ani on gap met abol i c aci dosi s wi t h a hi st or y of
i ngest i on, r egardl ess of t he l evel .
( b) Et OH dosage
( i ) An Et OH l evel of at l east 100 mg/ dL shoul d be mai nt ai ned.
( i i ) Loadi ng dose i s 7. 5-10 mL/ kg of a 10% et hanol i n dext r ose 5% i n wat er
( D5W) over 1 hr , f ol l owed by a mai nt enance i nf usi on of 1. 4 mL/ kg/ hr .
( i i i ) Ì nf usi on r at es may need t o be i ncr eased i n pat i ent s r ecei vi ng
hemodi al ysi s.
P. 513


( 3) Fomepi zol e ( Ant i zol ) i s a pot ent i nhi bi t or of al cohol dehydr ogenase t hat
can pr event t he f ormat i on of t he t oxi c met abol i t es of ei t her met hanol or
et hyl ene gl ycol .
( a) Admi ni st er a l oadi ng dose of 15 mg/ kg (up t o 1 g) i n 100 mL of D5W or
0. 9% sodi um chl ori de ( NaCl ) i nf used over 30 mi n.
( b) Mai nt enance doses: 10 mg/ kg ever y 14 hr f or 4 doses, t hen i ncr ease t o
15 mg/ kg (t o of f set aut oi nduct i on phenomenon) unt i l met hanol or et hyl ene
gl ycol l evel s are < 20 mg/ dL.
( 4) Pyr i doxi ne ( 100 mg Ì V ever y day) and t hi ami ne ( 100 mg Ì V ever y day)
ar e cof act ors t hat may conver t gl yoxyl i c aci d t o nonoxal at e met abol i t es.
( 5) Sodi um bi car bonat e i s used as needed t o cor rect t he aci dosi s.
( 6) Hemodi al ysi s. Et OH i nf usi on must be cont i nued, and t he r at e of
admi ni st rat i on may need t o be i ncr eased. Ì ndi cat i ons i ncl ude et hyl ene
gl ycol l evel > 50 mg/ dL, congest i ve hear t f ai l ur e, r enal f ai l ur e, and sever e
aci dosi s.
2. Met hanol
a. Avai l abl e f orms i ncl ude gas- l i ne ant i f r eeze, wi ndshi el d washer , and some
st erno.
b. Toxi coki net i cs. Al cohol dehydr ogenase conver t s met hanol t o
f or mal dehyde, whi ch i s t hen conver t ed t o f or mi c aci d.
c. Cl i ni cal pr esent at i on
( 1) St age Ì . Euphor i a, gregari ousness, and muscl e weakness f or 6-36 hr ,
dependi ng on t he r at e of f ormat i on of f ormi c aci d
( 2) St age Ì Ì . Vomi t i ng, upper abdomi nal pai n, di ar r hea, di zzi ness,
headache, r est l essness, dyspnea, bl ur r ed vi si on, phot ophobi a, bl i ndness,
coma, cerebral edema, car di ac and r espi r at or y depr essi on, sei zures, and
deat h
d. Laborat or y dat a i ncl ude sever e met abol i c aci dosi s, hypergl ycemi a, and
hyper amyl asemi a.
e. Tr eat ment
( 1) Gast r i c l avage. Charcoal has not been shown t o absor b al cohol s.
( 2) Ì V Et OH ( used i n si t uat i ons i n whi ch f omepi zol e i s not avai l abl e)
( a) Ì ndi cat i ons i ncl ude any peak met hanol l evel > 20 mg/ dL, a suspi ci ous
i ngest i on wi t h a posi t i ve hi st or y, or any sympt omat i c pat i ent wi t h an ani on
gap aci dosi s.
( b) Admi ni st r at i on i s t he same as per et hyl ene gl ycol (see Ì Ì Ì . B. 1) .
( 3) Fol i c aci d admi ni st ered at 1 mg/ kg (maxi mum 50 mg) Ì V ever y 4 hr f or 6
doses i ncr eases t he met abol i sm of f ormat e.
( 4) Fomepi zol e ( Ant i zol ) ( see Ì Ì Ì . B. 1. e. (3) )
( 5) Sodi um bi car bonat e i s used f or sever e aci dosi s.
( 6) Hemodi al ysi s i s used f or met hanol l evel s > 50 mg/ dL, sever e and
r esi st ant aci dosi s, r enal f ai l ur e, or vi sual sympt oms.
C. Ant i coagul ant s
6
,
7
,
8
and
9

1. Hepar i n/ Low Mol ecul ar Wei ght Hepari n (LMWH)
a. Avai l abl e dosage f or ms i ncl ude par ent eral dosage f orms f or Ì V and
subcut aneous admi ni st r at i on.
b. Toxi coki net i cs. Hepar i n has a hal f -l i f e of 1-1. 5 hr and i s pr i mari l y
met abol i zed i n t he l i ver . The newer LMWHs÷enoxapar i n ( Lovenox) ,
dal t epar i n ( Fr agmi n), t i nzapar i n ( Ì nnohep)÷have a l onger hal f - l i f e,
especi al l y i n pat i ent s wi t h r enal f ai l ure.
c. Cl i ni cal pr esent at i on. Look f or any si gns or sympt oms of bl eedi ng or
br ui si ng.
d. Laborat or y dat a. Obt ai n PTT, bl eedi ng t i me, and pl at el et count s.
e. Tr eat ment
( 1) St oppi ng hepari n admi ni st r at i on f or 1-2 hr and r est art i ng t her apy at a
r educed dose can rever se mi l d over -ant i coagul at i on.
P. 514


( 2) Severe overdoses may r equi r e t he admi ni st rat i on of pr ot ami ne.
( a) Pr ot ami ne combi nes wi t h hepar i n and neut r al i zes i t : 1 mg prot ami ne
neut ral i zes 100 U hepar i n.
( b) Pr ot ami ne shoul d be admi ni st er ed sl owl y, i nt ravenousl y over 10 mi n.
The maxi mum dose of prot ami ne i s 50 mg i n any 10- mi n peri od.
( c) Consi der abl e cont r over sy exi st s about t he met hod of r eversi ng t he over -
ant i coagul at i on wi t h LMWHs. Some sources recommend t he admi ni st r at i on
of prot ami ne t o neut r al i ze part of t he ef f ect s of t hese ant i coagul ant s,
wher eas case r epor t s r epor t ed successes wi t h recombi nant f act or VÌ Ì
( NovoSeven) .
( d) These overdoses shoul d be ref er r ed t o a hemat ol ogi st and/ or t he poi son
cont r ol cent er .
2. War f ari n ( Coumadi n)
a. Avai l abl e dosage f or ms i ncl ude oral t abl et s and a sol ut i on f or parent eral
admi ni st rat i on.
b. Toxi coki net i cs. War f ari n i s wel l absorbed af t er or al admi ni st r at i on. Ì t s
mean hal f -l i f e i s 35 hr ; pr ot ei n bi ndi ng i s 99%, wi t h a 5- day durat i on of
act i vi t y. Vi t ami n K- dependent cl ot t i ng f act or s begi n t o decl i ne 6 hr af t er
admi ni st rat i on, but t her apeut i c ant i coagul at i on may r equi r e sever al days.
c. Cl i ni cal pr esent at i on i ncl udes mi nor bl eedi ng, br ui si ng, hemat ur i a,
epi st axi s, and conj unct i val hemor r hage. Mor e seri ous bl eedi ng i ncl udes GÌ ,
i nt racrani al , r et roper i t oneal , and wound si t e.
d. Laborat or y dat a i ncl ude PT, i nt ernat i onal normal i zed rat i o ( Ì NR), and
bl eedi ng t i me.
e. Tr eat ment
( 1) Ì f PT or Ì NR i s sl i ght l y el evat ed, wi t hhol d war f ar i n f or 24-48 hr ; t hen
r ei nst i t ut e t her apy wi t h a r educed dosage.
( 2) Ì f PT or Ì NR i s el evat ed and bl eedi ng, admi ni st er 10 mg of phyt onadi one
( vi t ami n K) over 30 mi n. Pat i ent s who are bl eedi ng may r equi re t he
admi ni st rat i on of bl ood pr oduct s t hat cont ai n cl ot t i ng f act ors.
( 3) For mi l d over -ant i coagul at i on, f ol l ow Amer i can Col l ege of Chest
Physi ci ans ( ACCP) gui del i nes.
( 4) For pat i ent s wi t h l i f e t hr eat eni ng bl eedi ng or i nt r acr ani al hemor r hage,
t he Ameri can Col l ege of Chest Physi ci ans recommends t he use of
pr ot hr ombi n compl ex concent r at es or r ecombi nant f act or VÌ Ì a t o
i mmedi at el y r ever se t he Ì NR.
D. Ant i depr essant s
1. Tr i cycl i c ant i depr essant s ( TCAs)
a. Avai l abl e f orms i ncl ude ami t ri pt yl i ne ( El avi l ), nor t r i pt yl i ne ( Avent yl ) ,
i mi pr ami ne ( Tof rani l ) , desi prami ne ( Norpr ami n) , doxepi n ( Si nequan) ,
pr ot ri pt yl i ne ( Vi vact i l ) , and cl omi pr ami ne ( Anaf rani l ).
b. Toxi coki net i cs. The compounds ar e hepat i cal l y met abol i zed, under go
ent erohepat i c r eci rcul at i on, ar e hi ghl y bound t o pl asma prot ei ns, and have
an el i mi nat i on hal f -l i f e of approxi mat el y 24 hr .
c. Cl i ni cal pr esent at i on. Ant i chol i ner gi c ef f ect s i ncl ude mydr i asi s, i l eus,
ur i nar y r et ent i on, and hyper pyr exi a. Car di opul monar y t oxi ci t y exhi bi t s
t achycardi as, conduct i on bl ocks, hypot ensi on, and pul monar y edema. CNS
mani f est at i ons r ange f r om agi t at i on and conf usi on t o hal l uci nat i ons,
sei zures, and coma.
d. Laborat or y dat a. Bl ood l evel moni t ori ng does not cor rel at e wel l wi t h
cl i ni cal si gns and sympt oms of t oxi ci t y. Some aut hors suggest t hat
el ect r ocar di ographi c moni t or i ng i s a bet t er gui de t o assessi ng t he sever i t y
of i ngest i on.
e. Tr eat ment
( 1) GÌ decont ami nat i on. Syr up of i pecac i s not r ecommended because
pat i ent s may qui ckl y become comat ose, i ncr easi ng t he r i sk of aspi rat i on.
Act i vat ed char coal i s gi ven ever y 6 hr.
( 2) Al kal i ni zat i on wi t h sodi um bi car bonat e 1- 2 mEq/ kg t o mai nt ai n an
ar t eri al pH of 7. 45-7. 55 decreases t he f r ee f r act i on of t he absor bed t oxi ns,
whi l e r eversi ng some of t he cardi ac abnor mal i t i es.
( 3) Phenyt oi n ( Di l ant i n) and/ or benzodi azepi nes may be r equi r ed t o cont rol
sei zures. Phenyt oi n must be admi ni st ered at a r at e not exceedi ng 25
mg/ mi n because of hypot ensi ve si de ef f ect s. ( Fosphenyt oi n [ Cerebyx] may
be used because i t has a l ower i nci dence of hypot ensi on t han phenyt oi n. )
P. 515


( 4) Physost i gmi ne 2 mg Ì V over 1 mi n may be used t o r everse severe
ant i chol i nergi c t oxi ci t y owi ng t o t hese dr ugs. Because t hi s ant i dot e may
cause asyst ol e, t he use of t hi s ant i dot e f or TCA over doses i s decl i ni ng.
2. Sel ect i ve ser ot oni n r eupt ake i nhi bi t or s ( SSRÌ s)
a. Avai l abl e f orms ( nont ri cycl i c agent s) i ncl ude f l uoxet i ne ( Pr ozac) ,
ser t ral i ne ( Zol of t ) , and par oxet i ne ( Paxi l ) .
b. Toxi coki net i cs. SSRÌ s ar e wel l absorbed af t er or al admi ni st r at i on. Peak
l evel s occur wi t hi n 2- 6 hs. SSRÌ s ar e hepat i cal l y met abol i zed wi t h a hal f -
l i f e bet ween 8 and 30 hr.
c. Cl i ni cal pr esent at i on i ncl udes mi l d sympt omat ol ogy. Pat i ent s may
become agi t at ed, dr owsy, or conf used. Sei zur es and cardi ovascul ar t oxi ci t y
ar e rar e.
d. Laborat or y dat a. ECG moni t or i ng i s recommended. Bl ood l evel moni t ori ng
i s not r ecommended.
e. Tr eat ment i ncl udes gast r i c l avage and support i ve t r eat ment . Some
t oxi col ogi st s may r ecommend t he use of cyprohept adi ne ( Peri act i n) t o
manage t he ser ot oni n syndr ome, whi ch may mani f est as a r esul t of t hese
i ngest i ons.
E. Benzodi azepi nes
1. Avai l abl e f orms i ncl ude chl ordi azepoxi de (Li br i um) , di azepam ( Val i um) ,
f l urazepam ( Dal mane) , mi dazol am (Versed), l orazepam ( At i van) , al pr azol am
( Xanax) , and t ri azol am (Hal ci on) .
2. Toxi coki net i cs. These dr ugs ar e hepat i cal l y met abol i zed.
3. Cl i ni cal present at i on i ncl udes dr owsi ness, at axi a, and conf usi on.
Fat al i t i es are rar e.
4. Laborat or y dat a. Drug l evel moni t ori ng i s not i ndi cat ed.
5. Tr eat ment
a. Support i ve t r eat ment i ncl udes gast r i c empt yi ng, act i vat ed char coal , and
a cat har t i c.
b. Fl umazeni l ( Romazi con) i s gi ven 0. 2 mg Ì V over 30 sec; repeat doses of
0. 5 mg over 30 sec at 1-mi n i nt er val s f or a maxi mum cumul at i ve dose of 5
mg.
( 1) Fl umazeni l has a shor t el i mi nat i on hal f - l i f e.
( 2) Caref ul obser vat i on f or r esedat i on i s necessar y, especi al l y f or
i ngest i ons of l ong- act i ng benzodi azepi nes.
( 3) Fl umazeni l i s cont rai ndi cat ed i n mi xed overdose pat i ent s ( par t i cul arl y
i nvol vi ng t ri cycl i c ant i depr essant s) i n whom sei zur es are l i kel y.
F. 8- adr ener gi c ant agoni st s
1. Avai l abl e dosage f or ms. Cl ass exampl es i ncl ude pr opr anol ol ( Ì nder al ) ,
met opr ol ol ( Lopressor ), and at enol ol ( Tenormi n) . Or al and parent er al
dosage f orms are avai l abl e.
2. Toxi coki net i cs. Al l of t he members wi t hi n t hi s cl ass di f f er i n regar d t o
r enal versus hepat i c el i mi nat i on, l i pi d sol ubi l i t y, and pr ot ei n bi ndi ng.
Pat i ent s may become t oxi c owi ng t o changes i n or gan f unct i on.
3. Cl i ni cal present at i on i ncl udes hypot ensi on, bradycardi a, and
at r i ovent ri cul ar bl ock. Bronchospasm may occur , par t i cul arl y wi t h
noncardi osel ect i ve agent s.
4. Laborat or y dat a i ncl ude ser um el ect rol yt es and bl ood gl ucose (pat i ent s
may become hypogl ycemi c) .
5. Tr eat ment
a. GÌ decont ami nat i on i ncl udes gast r i c l avage and act i vat ed char coal .
b. Gl ucagon i s gi ven 50-150 µg/ kg as a l oadi ng dose over 1 mi n, f ol l owed
by a cont i nuous i nf usi on of 1- 5 mg/ hr .
c. Epi nephri ne shoul d be used caut i ousl y i n 8- bl ocker overdoses.
Unopposed q- recept or st i mul at i on i n t he f ace of compl et e 8- recept or bl ock
may l ead t o pr of ound hyper t ensi on.
d. Cal ci um sal t s (see Cal ci um Channel Ant agoni st s)
e. Hi gh Dose Ì nsul i n Dext r ose (see Cal ci um Channel Ant agoni st s)
G. Cal ci um channel ant agoni st s
1. Avai l abl e f orms i ncl ude ver apami l ( Cal an) , di l t i azem ( Car di zem) , and t he
di hydropyr i di ne cl ass ( ni f edi pi ne der i vat i ves [ Procar di a] ) .
P. 516


2. Toxi coki net i cs. Onset of act i on i s appr oxi mat el y 30 mi n, wher eas t he
dur at i on i s 6- 8 hr . Several compounds ar e avai l abl e as sust ai ned- rel ease
dosage f orms, whi ch may cont ri but e t o pr ol onged t oxi ci t y.
3. Cl i ni cal present at i on. Hypot ensi on i s common t o al l cl asses. Bradycar di a
and at r i ovent r i cul ar bl ock are mor e commonl y seen wi t h i ngest i ons of
ver apami l or di l t i azem. Pul monar y edema and sei zur es ( verapami l ) have
been r epor t ed.
4. Laborat or y dat a i ncl ude ECG and serum el ect r ol yt es.
5. Tr eat ment
a. GÌ decont ami nat i on i ncl udes gast r i c l avage, act i vat ed charcoal , and
whol e- bowel i r r i gat i on ( especi al l y f or i ngest i ons wi t h sust ai ned- r el ease
pr oduct s) .
b. Cal ci um. Cal ci um chl or i de 10% ( 10- 20 mL) Ì V push i s gi ven f or t he
management of hypot ensi on, br adycardi a, or heart bl ock.
c. Gl ucagon dosage i s t he same as f or 8- bl ocker over dose.
d. Combi ned i nsul i n and dext r ose admi ni st r at i on has been used i n sel ect ed
cases. Thi s shoul d be used onl y i n consul t at i on wi t h a poi son cont rol
cent er .
e. Phosphodi est er ase Ì nhi bi t ors. Ì namr i none or mi l r i none.
H. Cocai ne
1. Avai l abl e f orms i ncl ude al kal oi d obt ai ned f r om Er yt hr oxyl on coca.
2. Toxi coki net i cs. Cocai ne i s wel l absorbed af t er or al , i nhal at i onal ,
i nt ranasal , and Ì V admi ni st r at i on. Cocai ne i s met abol i zed i n t he l i ver and
excr et ed i n t he ur i ne.
3. Cl i ni cal present at i on i ncl udes CNS and sympat het i c st i mul at i on ( e. g. ,
hyper t ensi on, t achypnea, t achycar di a, nausea, vomi t i ng, sei zur es) . Deat h
may r esul t f rom r espi r at or y f ai l ure, myocar di al i nf ar ct i on, or car di ac arr est .
4. Laborat or y dat a i ncl ude cocai ne and cocai ne met abol i t e uri ne screens.
5. Tr eat ment i s support i ve: benzodi azepi nes f or sedat i on sei zure t reat ment ,
Labet al ol ( Normodyne) f or hyper t ensi on.
Ì . Cor rosi ves
1. Avai l abl e f orms i ncl ude st r ong aci ds or al kal i s.
2. Toxi coki net i cs. Cor r osi ves ar e wel l absorbed af t er or al and i nhal at i onal
admi ni st rat i on.
3. Cl i ni cal present at i on. These compounds pr oduce bur ns on cont act .
4. Laborat or y dat a. Art eri al bl ood gases ( ABGs) , chest radi ographs, and at
l east 6 hr of obser vat i on ar e requi r ed f or i nhal at i on exposur e.
5. Tr eat ment i s decont ami nat i on. Exposed ski n must be i r r i gat ed wi t h wat er .
Neut r al i zat i on shoul d be avoi ded because t hese react i ons ar e exot hermi c
and wi l l produce f urt her t i ssue damage.
J. Cyani de
1. Avai l abl e f orms i ncl ude i ndust r i al chemi cal s and some nai l -pol i sh
r emovers.
2. Toxi coki net i cs. The drug i s rapi dl y absor bed af t er oral or i nhal at i on
exposur e.
3. Cl i ni cal present at i on i ncl udes headache, dyspnea, nausea, vomi t i ng,
at axi a, coma, sei zur es, and deat h.
4. Laborat or y dat a i ncl ude cyani de l evel s, ABGs, el ect r ol yt es, and an ECG.
5. Tr eat ment .
a. Cyani de ant i dot e ki t
( 1) Amyl ni t r i t e Pear l s are crushed and hel d under t he pat i ent ' s nost ri l s.
( 2) Sodi um ni t ri t e 10 mL Ì V push. Convert s hemogl obi n t o met hemogl obi n,
whi ch bi nds t he cyani de i on.
( 3) Sodi um t hi osul f at e 50 mL of a 25% sol ut i on Ì V push. May be repeat ed i f
t her e i s no r esponse.
P. 517


b. Oxygen
c. Sodi um bi carbonat e. As needed f or severe aci dosi s
d. Hydr oxycobal ami n ( Cyanoki t )
( 1) Adul t dose i s 5 gr ams Ì V over 15 mi nut es. Dose may be r epeat ed f or a
t ot al dose of 10 gr ams. No dat a ar e avai l abl e f or pedi at ri c dosi ng.
7

K. Di goxi n ( Lanoxi n)
1. Avai l abl e dosage f or ms i ncl ude oral and par ent er al .
2. Toxi coki net i cs. Di goxi n i s wel l absor bed, i s pri mar i l y r enal l y el i mi nat ed,
and has a hal f - l i f e of 36-48 hr. Ì t s vol ume of di st ri but i on i s 7- 10 L/ kg.
Equi l i br at i on bet ween ser um l evel and myocar di al bi ndi ng r equi res 6- 8 hr .
3. Cl i ni cal present at i on i ncl udes conf usi on, anorexi a, nausea, and vomi t i ng
i n mi l d cases. Ì n mor e sever e cases, car di ac dysr hyt hmi as are seen.
4. Laborat or y dat a i ncl ude ser um di goxi n l evel s, el ect r ol yt es, par t i cul arl y
ser um pot assi um l evel s, and an ECG.
5. Tr eat ment
a. Decont ami nat i on wi t h act i vat ed charcoal i s r ecommended.
b. Support i ve t herapy i ncl udes managi ng hyperkal emi a or hypokal emi a and
i not r opi c suppor t as needed.
c. Di goxi n- speci f i c Fab ant i bodi es ( Di gi bi nd) . To det ermi ne t he dosage, use
t he f ol l owi ng f ormul a

Each vi al cont ai ns 40 mg of di goxi n ant i bodi es (Di gi bi nd) and shoul d be
r econst i t ut ed wi t h 4 mL of st eri l e wat er .
L. El ect r ol yt es
1. Magnesi um
a. Avai l abl e dosage f or ms i ncl ude oral , r ect al , and parent er al . Magnesi um-
cont ai ni ng cat har t i cs (e. g. , magnesi um ci t r at e) have been repor t ed t o
pr oduce hyper magnesemi a i n pat i ent s recei vi ng repet i t i ve doses wi t h
act i vat ed charcoal .
b. Toxi coki net i cs. Magnesi um i s f ound i nt r acel l ul ar l y and i s renal l y
el i mi nat ed.
c. Cl i ni cal pr esent at i on
( 1) Mi l d: Deep t endon r ef l exes may be depr essed; l et hargy and weakness
( 2) Severe: Respi r at or y par al ysi s and hear t bl ock; pr ol onged PR, QRS, and
QT i nt er val s
d. Laborat or y dat a
( 1) Mi l d: > 4 mEq/ L
( 2) Severe: > 10 mEq/ L
e. Tr eat ment i s 10% cal ci um chl ori de 10- 20 mL t o t emporar i l y ant agoni ze
t he cardi ac ef f ect s of magnesi um. Ì n severe cases, hemodi al ysi s may be
r equi r ed.
2. Pot assi um
a. Avai l abl e dosage f or ms are oral and par ent er al .
b. Toxi coki net i cs. Pot assi um i s pri mar i l y an i nt r acel l ul ar cat i on. Changes i n
aci d- base bal ance produce shi f t s i n ser um pot assi um val ues ( e. g. , a 0. 1- U
i ncrease i n serum pH produces a 0. 1- 0. 7 mEq/ L decrease i n serum
pot assi um val ues) .
c. Cl i ni cal pr esent at i on i ncl udes cardi ac i r r i t abi l i t y and per i pher al weakness
wi t h mi nor i ncr eases. Car di ac dysr hyt hmi as, i ncl udi ng bradycar di a, may
pr ogress t o asyst ol e.
d. Laborat or y dat a. ECG dat a i ncl ude peaked T waves and pr ol ongat i on of
t he QRS compl ex.
P. 518


e. Tr eat ment
( 1) Cal ci um. Admi ni st er cal ci um chl ori de 10% 10- 20 mL t o ant agoni ze t he
car di ac ef f ect s of hyper kal emi a.
( 2) Sodi um bi car bonat e. 1- 2 mEq/ kg Ì V i ncr eases serum pH and causes an
i nt racel l ul ar shi f t of pot assi um.
( 3) Gl ucose and i nsul i n. 50 mL of 50% dext r ose and 5-10 U of r egul ar
i nsul i n ar e admi ni st er ed vi a Ì V push t o shi f t pot assi um f r om t he
ext r acel l ul ar f l ui d i nt o t he cel l s.
( 4) Cat i on exchange resi ns bi nd pot assi um i n exchange f or anot her cat i on
( sodi um) . Sodi um pol yst yr ene sul f onat e ( Kayexal at e) i s gi ven 15 g/ 60 mL
wi t h 23. 5% sorbi t ol i n doses 15- 30 g by mout h ever y 3- 4 hr as needed unt i l
t he hyperkal emi a resol ves. Al t er nat i vel y, 50 g of sodi um pol yst yr ene
sul f onat e can be gi ven rect al l y i n 200 mL of sodi um chl or i de as a ret ent i on
enema.
( 5) Hemodi al ysi s i s reserved f or l i f e- t hr eat eni ng hyper kal emi a t hat does not
r espond t o t he above measures.
M. Ì r on ( Fe)
1. Avai l abl e dosage f or ms. Numerous OTC pr oduct s ar e avai l abl e. Toxi ci t y
i s based on t he amount of el ement al i ron i ngest ed: sul f at e sal t 20%
el ement al Fe; f umar at e sal t 33% el ement al Fe; and gl uconat e sal t 12%
el ement al Fe.
2. Toxi coki net i cs. Ì r on i s absor bed i n t he duodenum and j ej unum.
3. Cl i ni cal present at i on
a. Phase Ì . Nausea, vomi t i ng, di ar r hea, GÌ bl eedi ng, hypot ensi on
b. Phase Ì Ì . Cl i ni cal i mprovement seen 6- 24 hr post i ngest i on
c. Phase Ì Ì Ì . Met abol i c aci dosi s, r enal and hepat i c f ai l ur e, sepsi s,
pul monar y edema, and deat h
4. Laborat or y dat a i ncl ude ser um Fe l evel s, t ot al i r on- bi ndi ng capaci t y
( TÌ BC; i s cont r oversi al ), ABGs, l i ver f unct i on t est s ( LFTs) , hemogl obi n, and
hemat ocr i t . Radi ol ogi cal eval uat i on of t he abdomen not es t he pr esence of
r adi opaque pi l l s.
5. Tr eat ment
a. Decont ami nat i on. For i ngest i ons > 40 mg/ kg. Gast ri c l avage usi ng
sodi um bi car bonat e i s of quest i onabl e ef f i cacy. Whol e- bowel i r ri gat i on i s
used f or l ar ge i ngest i ons.
b. Support i ve t r eat ment
c. Def er oxami ne ( Desf eral ) i s used t o chel at e i r on. Admi ni st er 25-50 mg/ kg
up t o a dose of 1 g, and obser ve f or a r ed col or i n t he uri ne. Then
admi ni st er at a r at e of 15 mg/ kg/ hr up t o a maxi mum dose of 6 g/ day.
Cont i nue unt i l ser um i r on i s wi t hi n t he t herapeut i c r ange.
N. Ì soni azi d (Ì NH)
1. Avai l abl e dosage f or ms i ncl ude oral and par ent er al .
2. Toxi coki net i cs. Ì NH i s wel l absorbed oral l y. Peak l evel s ar e wi t hi n 1- 2 hr
post i ngest i on. Ì soni azi d i s hepat i cal l y met abol i zed.
3. Cl i ni cal present at i on i ncl udes nausea, vomi t i ng, sl ur red speech, at axi a,
gener al i zed t oni c-cl oni c sei zures, and coma.
4. Laborat or y dat a i ncl ude sever e l act i c aci dosi s, hypogl ycemi a, mi l d
hyper kal emi a, and l eukocyt osi s.
5. Tr eat ment
a. Decont ami nat i on. Avoi d emesi s because pat i ent s ar e at hi gh ri sk f or
devel opi ng sei zur es; f or sever e i ngest i ons use act i vat ed charcoal gast r i c
l avage.
b. Pyr i doxi ne, whi ch r ever ses Ì NH-i nduced sei zur es, i s gi ven i n gr am doses
equi val ent t o t he amount of i soni azi d i ngest ed. Pyr i doxi ne i s mi xed as a
10% sol ut i on i n D5W and i nf used over 30- 60 mi n.
c. Sodi um bi carbonat e cor r ect s t he aci dosi s.
P. 519


O. Lead
1. Avai l abl e f orms i ncl ude l ead-cont ai ni ng pai nt or gasol i ne f ume i nhal at i on.
2. Toxi coki net i cs. Lead has sl ow di st ri but i on, wi t h a hal f -l i f e of
approxi mat el y 2 mont hs.
3. Cl i ni cal present at i on i ncl udes nausea, vomi t i ng, abdomi nal pai n,
per i pheral neur opat hi es, convul si ons, and coma.
4. Laborat or y dat a i ncl ude anemi a and an el evat ed bl ood- l ead l evel .
5. Tr eat ment
a. Edet at e cal ci um di sodi um ( cal ci um di sodi um Ver senat e) i s gi ven 50- 75
mg/ kg/ day i nt r amuscul arl y ( Ì M) or vi a sl ow Ì V i n 4 di vi ded doses.
b. Di mercapr ol ( BAL) i s gi ven 4 mg/ kg Ì M ever y 4 hr f or 3- 5 days.
P. Li t hi um ( Eskal i t h)
1. Avai l abl e dosage f or ms i ncl ude l i qui d, capsul es, and t abl et s (i mmedi at e
and sust ai ned rel ease) .
2. Toxi coki net i cs. Li t hi um i s wel l absorbed af t er or al admi ni st r at i on. Ì t i s
not appreci abl y bound t o pl asma pr ot ei ns and has a smal l vol ume of
di st r i but i on ( Vd) of 0. 5 L/ kg. El i mi nat i on i s r enal , wi t h a hal f -l i f e of 14- 24 hr .
3. Cl i ni cal present at i on
a. Mi l d: Pol yur i a, bl ur r ed vi si on, weakness, sl ur r ed speech, at axi a t r emor ,
and myocl oni c j er ks
b. Severe: Del i ri um, coma, sei zures, and hyper t her mi a
4. Laborat or y dat a
a. Ther apeut i c r ange: 0. 6- 1. 2 mEq/ L
b. Mi l d t oxi ci t y: 1. 5- 2. 5 mEq/ L
c. Moder at e t oxi ci t y: 2. 5-3 mEq/ L
d. Severe t oxi ci t y: > 3 mEq/ L
5. Tr eat ment
a. Support i ve care, i ncl udi ng basi c l i f e suppor t and f l ui d and el ect rol yt e
r epl acement
b. Decont ami nat i on
( 1) Syr up of i pecac not recommended
( 2) Act i vat ed char coal i nef f ect i ve
( 3) Sodi um pol yst yr ene sul f onat e has been ef f ect i ve i n exper i ment al
model s. Need t o moni t or pot assi um l evel s.
( 4) Whol e- bowel i r r i gat i on f or l arge i ngest i ons, especi al l y t hose i nvol vi ng
sust ai ned- r el ease pr oduct s
( 5) Hemodi al ysi s f or sever el y sympt omat i c pat i ent s wi t h acut e exposure
l evel s > 2. 5 mEq/ L or chr oni c l evel s > 1. 5 mEq/ L. Not e: Li t hi um l evel s may
r i se af t er di al ysi s owi ng t o a r ebound ef f ect .
Q. Opi at es
1. Avai l abl e dosage f or ms i ncl ude oral i mmedi at e- r el ease and sust ai ned-
r el ease prepar at i ons as wel l as parent er al agent s.
2. Toxi coki net i cs. Some agent s have pr ol onged el i mi nat i on hal f - l i ves (e. g. ,
her oi n, met hadone) .
3. Cl i ni cal present at i on i ncl udes respi rat or y depressi on and a decreased
l evel of consci ousness. Rar e ef f ect s i ncl ude hypot ensi on, br adycardi a, and
pul monar y edema. Sei zur es have been r eport ed i n pat i ent s wi t h r enal
dysf unct i on i n i ndi vi dual s who are r ecei vi ng meper i di ne owi ng t o t he
accumul at i on of t he met abol i t e nor meperi di ne.
4. Laborat or y dat a i ncl ude basel i ne ABGs and t oxi col ogy screens.
5. Tr eat ment
a. Nal oxone i s gi ven 0. 4-2 mg ever y 5 mi n up t o 10 mg and 0. 03- 0. 1 mg/ kg
i n pedi at ri c pat i ent s. Nal oxone has a ver y shor t hal f -l i f e, and r esedat i on i s
a concer n i n pat i ent s over dosi ng on l ong- act i ng opi oi ds or sust ai ned-
r el ease dosage f orms.
P. 520


b. Nal mef ene ( Revex) has a hal f - l i f e of 4- 8 hr . Ì ni t i al dosages are 0. 5 mg/ 70
kg. A f ol l ow- up dose 2- 5 mi n l at er i s 1 mg/ 70 kg.
R. Or ganophosphat es
1. Ther e ar e a vari et y of avai l abl e f or ms; t hey ar e usual l y pest i ci des or
chemi cal war f ar e agent s.
2. Toxi coki net i cs. Organophosphat es ar e absorbed t hr ough t he l ungs, ski n,
GÌ t r act , and conj unct i va.
3. Cl i ni cal present at i on i ncl udes excessi ve chol i ner gi c st i mul at i on.
4. Laborat or y dat a i ncl ude r ed bl ood cel l acet yl chol i nest er ase act i vi t y.
5. Tr eat ment
a. Decont ami nat i on
b. At ropi ne i s gi ven 0. 5-2 mg Ì V t o rever se t he per i pher al muscar i ni c
ef f ect s.
c. Pral i doxi me (2- PAM; Pr ot opam) i s gi ven 1 g Ì V over 2 mi n and r epeat ed
i n 20 mi n as needed.
S. Sal i cyl at es
1. Avai l abl e dosage f or ms i ncl ude a var i et y of OTC pr oduct s: or al , rect al ,
and t opi cal .
2. Toxi coki net i cs. Sal i cyl at es are wel l absor bed af t er or al admi ni st rat i on.
The hal f - l i f e i s 6-12 hr at l ower doses. Ì n over dose si t uat i ons, t he hal f - l i f e
may be prol onged t o more t han 20 hr .
3. Cl i ni cal present at i on i ncl udes nausea, vomi t i ng, t i nni t us, and mal ai se
( mi l d t oxi ci t y) . Let har gy, convul si ons, coma, and met abol i c aci dosi s appear
i n mor e sever e over doses. Pot ent i al compl i cat i ons f rom t herapeut i c and
t oxi c doses i ncl ude GÌ bl eedi ng, i ncreased PT, hepat i c t oxi ci t y,
pancr eat i t i s, and pr ot ei nur i a.
4. Laborat or y dat a f or t he f ol l owi ng 6-hr post i ngest i on l evel s ar e:
a. 40- 60 mg/ dL: t i nni t us
b. 60- 95 mg/ dL: moder at e t oxi ci t y
c. Mor e t han 95 mg/ dL: sever e t oxi ci t y
d. Wi t h t he pr esence of aci demi a and aci duri a, eval uat e ABGs.
e. Ì n addi t i on, l abor at or y eval uat i on may show l eukocyt osi s,
t hr ombocyt openi a, i ncr eased or decr eased serum gl ucose and sodi um,
hypokal emi a, and i ncr eased ser um BUN, cr eat i ni ne, and ket ones.
5. Tr eat ment
a. Decont ami nat i on. Repet i t i ve doses of act i vat ed charcoal ever y 6 hr, wi t h
1 dose of cat hart i c f or pat i ent s who i ngest ed > 150 mg/ kg. Whol e- bowel
i r r i gat i on f or l arge i ngest i ons.
b. Al kal i ne di uresi s i s gi ven as not ed i n decont ami nat i on sect i on t o enhance
sal i cyl at e excr et i on. Thi s i s i ndi cat ed f or l evel s> 40 mg/ dL.
c. Hemodi al ysi s i s used f or sever e i nt oxi cat i ons when serum l evel s ar e >
100 mg/ dL. Thi s met hod of decont ami nat i on i s much bet t er t han repet i t i ve
doses of act i vat ed char coal .
d. Fl ui d and el ect rol yt e repl acement i s admi ni st ered as needed.
e. Vi t ami n K ( Aquamephyt on) and f r esh f r ozen pl asma ar e used t o cor rect
any coagul opat hy.
T. Snake bi t es
1. Types. Ther e ar e numer ous speci es of snakes f ound wor l dwi de. The
venomous snakes f ound i n Nort h Ameri ca i ncl ude t he f ol l owi ng: r at t l esnake,
cot t onmout h, copper head, and coral . Because pat i ent s may be exposed t o
mor e exot i c snakes, a her pet ol ogi st shoul d be consul t ed f or a mor e
def i ni t i ve i dent i f i cat i on.
2. Toxi coki net i cs. Onset of sympt omat ol ogy depends on t he speci es of
snake and t he pat i ent ' s under l yi ng medi cal condi t i on.
3. Cl i ni cal present at i on i ncl udes nausea; vomi t i ng; di ar rhea; syncope;
t achycardi a; and col d, cl ammy ski n. Local f i ndi ngs i ncl ude pai n, edema, and
er yt hema. Mor e severe envenomat i ons can l ead t o sever e t i ssue i nj ur y,
compart ment syndrome, and shock.
P. 521


4. Laborat or y dat a
a. CBC and pl at el et count
b. Coagul at i on prof i l e
c. Fi bri n degradat i on pr oduct s
d. El ect r ol yt es
e. BUN, SCr, and ur i nal ysi s
5. Tr eat ment
a. Support i ve. Move t he pat i ent away f r om st r i ki ng di st ance of t he snake.
Ì deal l y, t he pat i ent shoul d be t r anspor t ed t o a medi cal f aci l i t y as soon as
possi bl e. Const r i ct i ve cl ot hi ng, r i ngs, wat ches, et c. shoul d be r emoved.
Tet anus i mmuni zat i on shoul d be assessed, and sur gi cal i nt er vent i on may be
necessar y f or sever e cases.
b. Ant i venoms
( 1) Ant i veni n ( Crot al i dae) pol yval ent i s a horse-der i ved pr oduct t hat has
been r epor t ed t o pr oduce al l ergi c r eact i ons. For mi l d bi t es, t he
r ecommended dose i s 5-10 vi al s; moder at e, 10- 20; and severe
envenomat i ons may r equi r e 20 or mor e vi al s.
( 2) Cr ot al i dae pol yval ent i mmune Fab i s a pol yval ent ant i veni n made f rom
sheep sour ces. The i ni t i al dose i s 4- 6 vi al s di l ut ed i n 250 mL of 0. 9%
nor mal sal i ne ( NS) admi ni st er ed over 1 hr . Addi t i onal doses may be
r equi r ed f or sever e envenomat i ons.
U. Theophyl l i ne
1. Avai l abl e dosage f or ms i ncl ude l i qui d, sust ai ned- r el ease t abl et s and
capsul es as wel l as parent er al f or ms.
2. Toxi coki net i cs. Wel l absorbed oral l y wi t h a Vd of appr oxi mat el y 0. 5 L/ kg.
Theophyl l i ne i s hepat i cal l y met abol i zed and has a hal f - l i f e of 4- 8 hr .
Theophyl l i ne cl ear ance depends hi ghl y on age, concomi t ant di sease st at es,
and i nt er act i ng dr ugs.
3. Cl i ni cal present at i on i ncl udes nausea, vomi t i ng, sei zures, and car di ac
dysr hyt hmi as. Chr oni c t oxi ci t y car ri es a poor er prognosi s t han acut e
t oxi ci t y.
4. Laborat or y dat a. Therapeut i c t heophyl l i ne l evel s ar e 5- 20 µg/ mL.
Hyper gl ycemi a and hypokal emi a ar e seen wi t h acut e i ngest i ons. Ot her
usef ul l aborat or y t est s i ncl ude serum el ect r ol yt es, BUN, cr eat i ni ne, hepat i c
f unct i on, and ECG moni t or i ng.
5. Tr eat ment
a. Support i ve t herapy i ncl udes mai nt ai ni ng an ai r way and t r eat i ng sei zures
and dysr hyt hmi as as t hey occur .
b. Decont ami nat i on. Syr up of i pecac not r ecommended.
c. Act i vat ed charcoal ( repet i t i ve doses) t o enhance el i mi nat i on. Whol e-
bowel i r ri gat i on f or massi ve i ngest i ons ( especi al l y wi t h sust ai ned- r el ease
pr oduct s) . Charcoal hemoper f usi on i s used i n unst abl e pat i ent s who are i n
st at us epi l ept i cus. Hemodi al ysi s i s used when hemoper f usi on i s
unavai l abl e.
d. 8- adr ener gi c ant agoni st s ( e. g. , esmol ol , Brevi bl oc) ar e used t o t reat t he
hypot ensi on, t achycar di a, and dysrhyt hmi as caused by el evat ed cycl i c
adenosi ne monophosphat e l evel s.
IV. REFERENCES
A. Amer i can Academy of Cl i ni cal Toxi col ogy and Eur opean Associ at i on of
Poi sons Cent r es and Cl i ni cal Toxi col ogi st s. Posi t i on st at ement : Si ngl e-dose
act i vat ed charcoal . Cl i n Toxi col 1997; 35: 721-741.
B. Amer i can Academy of Cl i ni cal Toxi col ogy and Eur opean Associ at i on of
Poi sons Cent r es and Cl i ni cal Toxi col ogi st s. Posi t i on st at ement : Syr up of
i pecac. Cl i n Toxi col 1997; 35: 699- 709.
C. Amer i can Col l ege of Emer gency Physi ci ans. Cl i ni cal pol i cy f or t he i ni t i al
approach t o pat i ent s pr esent i ng wi t h acut e t oxi c i ngest i on or der mal or
i nhal at i on exposur e. Ann Emerg Med 1999; 33: 735- 762.
P. 522


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approach t o pat i ent s pr esent i ng wi t h acut e t oxi c i ngest i on or der mal or
i nhal at i on exposur e. Ann Emerg Med Apri l 1995; 25: 270- 585.
E. Amer i can Heart Associ at i on. Toxi col ogy i n ECC. Ci r cul at i on [ Speci al
i ssue] 2005; 112: Ì V126- Ì V132. Avai l abl e at www. ci rcul at i onaha. or g.
F. Ansel l J, Hi r sh J, Hyl ek E, et al . Pharmacol ogy and management of t he
vi t ami n K ant agoni st s. Amer i can Col l ege of Chest Physi ci ans Evi dence-
Based Cl i ni cal Pract i ce Gui del i nes ( 8t h Edi t i on). Chest 2008; 133: 160s-
198s.
G. Bond RC. The rol e of act i vat ed charcoal and gast ri c empt yi ng i n
gast r oi nt est i nal decont ami nat i on: A st at e- of - t he-ar t r evi ew. Ann Emerg Med
2002; 39: 273- 285.
H. Gol d BS, Dar t RC, Bar i sh RA. Bi t es of venomous snakes. New Engl J
Med 2002; 347: 347- 356.
Ì . Hi rsh J, Bauer KA, Donat i MB, et al . Parent er al ant i coagul ant s. Amer i can
Col l ege of Chest Physi ci ans Evi dence- Based Cl i ni cal Pract i ce Gui del i nes
( 8t h Edi t i on) . Chest 2008; 133: 141s- 159s.
J. Schul man S, Beyt h RJ, Kearon C, et al . Hemorr hagi c compl i cat i ons of
ant i coagul ant and t hrombol yt i c t r eat ment . Amer i can Col l ege of Chest
Physi ci ans Evi dence- Based Cl i ni cal Pr act i ce Gui del i nes (8t h Edi t i on) . Chest
2008; 133: 257s- 298s.
K. Li t ovi t z TL, Kl ei n- Schwar t z, Rodgers GC, et al . 2001 annual r epor t of t he
Ameri can Associ at i on of Poi son Cont rol Cent er s Toxi c Exposur e
Sur vei l l ance Syst em. Am J Emerg Med 2002; 20: 1- 62.
L. Megar bane B, Borr on SW, Baud FJ. Cur r ent recommendat i ons f or t he
t r eat ment of sever e t oxi c al cohol poi soni ngs. Ì nt ensi ve Car e Med
2005; 31: 189- 195.
M. Mokhl esi B, Lei ken JB, Mur r ay P, et al . Adul t t oxi col ogy i n cri t i cal care
par t 1: General approach t o t he i nt oxi cat ed pat i ent . Chest 2003; 123: 577-
592.
N. Mokhl esi B, Lei ken JB, Mur r ay P, et al . Adul t t oxi col ogy i n cri t i cal care
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O. Pal oucek F. Ant i dot al f l umazeni l use÷The pr ot ami ne of t he 90s. Cr i t
Car e Med 1999; 27: 10- 11.
P. Pat rono C, Bai gent C, Hi r sh J, Rot h G. Ant i pl at el et Dr ugs. Amer i can
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P. 523


STUDY QUESTIONS
Di r ect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s
can be cor r ect l y answered or compl et ed by one of t he suggest ed answers or
phr ases. Choose t he best answer .
1. A physi ci an recei ves a caI I f rom the parent of a 2- year- oI d chi I d who
has i ngest ed an unknown quant i t y of morphi ne cont roI I ed- reI ease
t abI ets and i s now unconsci ous. The physi ci an' s i ni t i aI
recommendat i on i s t o
( A) cal l emer gency medi cal ser vi ces ( EMS) and have t he chi l d t aken
t o t he hospi t al emer gency depart ment .
( B) admi ni st er 1 g/ kg of act i vat ed charcoal wi t h sor bi t ol .
( C) admi ni st er syr up of i pecac 15 mL by mout h t o i nduce vomi t i ng.
( D) suggest t hat t he chi l d r ecei ve emer gency hemodi al ysi s.
( E) suggest t hat t he chi l d r ecei ve aci d di ur esi s wi t h ammoni um
chl or i de.
Vi ew Answer 1. The answer i s A[ seeÌ . A] . 2. A grandf at her arri ves at
your pharmacy aski ng to purchase a bot tI e of syrup of i pecac to keep
i n hi s home i n the event of a poi soni ng when grandchi I dren are
vi si t i ng. What shouI d you t eI I hi m?
( A) Admi ni st er 15 mL of syr up of i pecac at t he f i rst si gn of an
i ngest i on.
( B) Syr up of i pecac i s no l onger r ecommended by t he Amer i can
Associ at i on of Poi son Cont r ol Cent ers and t he Amer i can Academy of
Pedi at r i cs.
( C) Pr ovi de hi m wi t h t he t ol l - f r ee number f or t he poi son cont rol
cent er .
( D) Bot h B and C.
Vi ew Answer 2. The answer i s D[ seeÌ Ì . G. 1. a] . 3. An unconsci ous
pat i ent i s brought i nt o t he emergency depart ment . The pat i ent i s gi ven
50 mL of 50% dext rose i n wat er, t hi ami ne 100 mg I V, f oI I owed by
naI oxone 1 mg, at whi ch poi nt he awakens. Thi s pat i ent most I i keI y has
overdosed on whi ch of t he f oI I owi ng substances?
( A) met hanol
( B) ami t ri pt yl i ne
( C) cocai ne
( D) hal oper i dol
( E) heroi n
Vi ew Answer 3. The answer i s E[ seeÌ Ì Ì . Q. 5] . 4. Cont rai ndi cati ons t o
t he admi ni st rat i on of syrup of i pecac i ncI ude whi ch of t he f oI I owi ng?
( A) an unconsci ous pat i ent
( B) a pat i ent who i s exper i enci ng a general i zed t oni c-cl oni c sei zur e
( C) a pat i ent who has i ngest ed a caust i c subst ance
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 4. The answer i s D[ seeÌ Ì . G. 1]. t he answer t o quest i on
25. An unconsci ous pati ent i s brought t o the emergency
department wi t h a hi stor y of an unknown drug overdose. Whi ch of the
f oI I owi ng act i ons shouI d t he physi ci an perf orm?
( A) admi ni st er 50 mL of 50% dext r ose, t hi ami ne 100 mg Ì V push,
and nal oxone 0. 4 mg Ì V push
( B) pr ot ect t he pat i ent ' s ai r way and ensure t hat vi t al si gns ar e st abl e
( C) or der t he f ol l owi ng l abor at or y t est s: compl et e bl ood count
( CBC) , el ect r ol yt es, and a t oxi col ogy screen
( D) Al l of t he above
Vi ew Answer 5. The answer i s D[ seeÌ Ì ] . 6. A pat i ent who overdoses
on acet ami nophen i s admi t t ed t o t he hospi t aI f or ant i dotaI t herapy wi t h
N- acet yI - L- cyst ei ne ( NAC) . The pati ent has t he f oI I owi ng medi cat i on
orders: NAC 140 mg/ kg I oadi ng dose f oI I owed by 70 mg/ kg f or a t ot aI of
17 doses, rani t i di ne 50 mg I V ever y 8 hr, prochI orperazi ne 10 mg Ì M
ever y 6 hr as needed f or nausea, t hi ami ne 100 mg I V ever y day f or 3
doses, and Darvocet N-100 1- 2 t abI et s ever y 4 hr as needed f or
headache. What i s the best course of act i on?
( A) Cal l t he physi ci an t o i ncrease t he dosage of rani t i di ne t o 50 mg
Ì V ever y 6 hr .
( B) Cal l t he physi ci an t o have t he Dar vocet N- 100 di scont i nued.
( C) Cal l t he physi ci an t o i ni t i at e hemodi al ysi s t her apy.
( D) Have t he pat i ent prophyl act i cal l y i nt ubat ed t o pr ot ect t he ai r way.
( E) Admi ni st er et hanol 10% at a l oadi ng dose of 7. 5 mL/ kg over 1 hr,
f ol l owed by a cont i nuous i nf usi on of 1. 4 mL/ kg/ hr f or 48 hr .
Vi ew Answer 6. The answer i s B[ seeÌ Ì Ì . A]. OTCP. 524


7. Et hyI aI cohoI ( Et OH) i s admi ni st ered to pat i ent s who have i ngest ed
ei t her et hyI ene gI ycoI or methanoI because EtOH
( A) hel ps sedat e pat i ent s.
( B) i ncr eases t he met abol i sm of et hyl ene gl ycol and met hanol .
( C) bl ocks t he f ormat i on of t he t oxi c met abol i t es of et hyl ene gl ycol
and met hanol .
( D) i ncr eases t he r enal cl earance of et hyl ene gl ycol and met hanol .
( E) i s not an ant i dot e f or et hyl ene gl ycol or met hanol overdoses.
Vi ew Answer 7. The answer i s C[ seeÌ Ì Ì . B] . 8. A pati ent wi th renaI
f ai I ure i s i nadvert ent I y gi ven 3 doses of pot assi um chI ori de 40 mEq I V
i n 100 mL of 0. 9% sodi um chI ori de over a 3-hr peri od. Thi s error i s
i mmedi ateI y di scovered and a STAT serum pot assi um I eveI i s 8. 0
mEq/ L. The pat i ent i s bradycardi c wi t h a markedI y proI onged QRS
compI ex. The pat i ent shouI d recei ve whi ch of t he f oI I owi ng?
( A) cal ci um chl or i de 10% 10 mL Ì V push
( B) sodi um bi carbonat e 50 mEq Ì V push
( C) i nsul i n 10 U and 50% dext r ose 50 mL Ì V push
( D) sodi um pol yst yr ene sul f onat e 30 g by mout h ever y 3 hr f or 4
doses
( E) None of t he above
Vi ew Answer 8. The answer i s A[ seeÌ Ì Ì . L. 2]. 9. Parent eraI caI ci um i s
used as an ant i dot e f or whi ch of t he f oI I owi ng si t uati ons?
( A) ver apami l over doses
( B) hyperkal emi a
( C) cocai ne i nt oxi cat i on
( D) ver apami l over doses and hyperkal emi a
Vi ew Answer 9. The answer i s D[ seeÌ Ì Ì . GÌ Ì Ì . L. 2] . 10. A 65- year- oI d
woman wi th normaI renaI f unct i on i s admi ni stered a 0. 25 mg dose of
di goxi n I V push. A serum I eveI obt ai ned 1 hr af t er drug admi ni st rati on
i s 5 ng/ mL. Your recommendat i on t o t he physi ci an i s whi ch of t he
f oI I owi ng?
( A) Admi ni st er 2 vi al s of di goxi n i mmune ant i bodi es STAT.
( B) Admi ni st er repet i t i ve doses of act i vat ed charcoal .
( C) Cal l a nephr ol ogi st , and put t he pat i ent on hemodi al ysi s.
( D) Repeat t he ser um di goxi n l evel 6-8 hr af t er t he dose, and
r eassess t he pat i ent .
Vi ew Answer 10. The answer i s D[ seeÌ Ì Ì . K] . 11. A 16- year- oI d woman
i s report ed t o have overdosed on 40 sust ai ned- reI ease theophyI I i ne
t abI ets. She i s t ransport ed t o t he emergency depart ment , where gast ri c
I avage was perf ormed and she was gi ven one dose of act i vat ed
charcoaI . An i ni t i aI t heophyI I i ne I eveI i s 42 µg/ mL, but a foI I ow- up I eveI
i n t he i ntensi ve care uni t ( I CU) i s 95 µg/ mL. What i s t he most
appropri at e course of therapy?
( A) charcoal hemoperf usi on and mul t i pl e- dose act i vat ed charcoal
( B) syr up of i pecac admi ni st r at i on
( C) f orced al kal i ne di uresi s
( D) nasogast r i c admi ni st r at i on of sodi um- pol yst yrene sul f onat e
Vi ew Answer 11. The answer i s A[ seeÌ Ì Ì . T] . 12. A 23- year- oI d man i s
admi t ted to t he i nt ensi ve care uni t (I CU) af ter i ngest i ng 20
acetami nophen tabI et s 500 mg wi t h a si x- pack of beer. He was i ni t i aI I y
awake and aI ert i n t he emergency depart ment and was gi ven one dose
of acti vat ed charcoaI . Hi s i ni t i aI acet ami nophen I eveI t aken
approxi mat eI y 2 hr af t er i ngest i on i s 90 µg/ mL. What wouI d be t he most
appropri at e course of act i on?
( A) Admi ni st er repeat ed doses of act i vat ed char coal and sor bi t ol .
( B) Admi ni st er syr up of i pecac.
( C) Admi ni st er a l oadi ng dose of N- acet yl -L-cyst ei ne ( NAC) , and
r epeat t he acet ami nophen l evel i n 4 hr .
( D) Di schar ge t he pat i ent t o home.
Vi ew Answer 12. The answer i s C[ seeÌ Ì Ì . A] . mg13. An overdose
vi ct i m present s to t he emergency depart ment wi t h an eI evated heart
rat e, decreased bI ood pressure, di I at ed pupi I s, and I et hargy. Upon
arri vaI t o the i nt ensi ve care uni t (I CU) , she has a generaI i zed t oni c-
cI oni c sei zure that i s t reat ed wi t h I V di azepam and fosphenyt oi n. Whi ch
of t he f oI I owi ng i s the most I i keI y i nt oxi cant ?
( A) et hyl al cohol
( B) met hanol
( C) acet ami nophen
( D) oxycodone
( E) ami t ri pt yl i ne
Vi ew Answer 13. The answer i s E[ seeÌ Ì Ì . D] . P. 525


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see Ì . A] .
Pat i ent s wi t h unst abl e vi t al si gns shoul d be t aken t o an emer gency
depar t ment f or i mmedi at e t r eat ment .
2. The answer i s D [ see Ì Ì . G. 1. a] .
Ì nduced vomi t i ng i s no l onger an accept abl e opt i on of managi ng poi soni ngs
at home because i t i s a rel at i vel y i nef f ect i ve met hod of r emovi ng t oxi ns and
r esul t s i n a del ay i n admi ni st er i ng ant i dot al t herapy. Ì t i s i mport ant t o
counci l pat i ent s on poi son pr event i on and t o gi ve par ent s and ot her f r i ends
and rel at i ves t he t ol l - f ree number f or t he poi son cont r ol cent er . Par ent s
shoul d al so know basi c f i r st ai d and cardi opul monar y r esusci t at i on ( CPR).
3. The answer i s E [ see Ì Ì Ì . Q. 5] .
Nal oxone r ever ses t he ef f ect s of opi oi d r ecept or agoni st s, such as her oi n,
mor phi ne, and propoxyphene.
4. The answer i s D [ see Ì Ì . G. 1] .
Cont r ai ndi cat i ons t o i pecac i ncl ude t he t hree Cs: caust i cs, consci ous, and
convul si ons; see al so t he answer t o quest i on 2. The use of syr up of i pecac
i s reser ved f or rar e ci r cumst ances and onl y under t he di rect i on of t he
poi son cont rol cent er and/ or a physi ci an. These ar e new r ecommendat i ons
and many parent s, r el at i ves, and f r i ends may have t hi s pr oduct i n t hei r
medi ci ne cabi net s.
5. The answer i s D [ see Ì Ì ] .
The management of unconsci ous overdose pat i ent s i nvol ves aggr essi ve
suppor t of vi t al si gns and t he admi ni st rat i on of empi ri c ant i dot al t herapy,
whi l e obt ai ni ng vari ous l aborat or y t est s t o det ermi ne t he nat ur e of t he
over dose.
6. The answer i s B [ see Ì Ì Ì . A] .
Dar vocet N- 100 i s an acet ami nophen-cont ai ni ng pr oduct t hat shoul d not be
gi ven t o a pat i ent wi t h document ed acet ami nophen t oxi ci t y. Be awar e
par t i cul arl y of OTC pr oduct s cont ai ni ng acet ami nophen.
7. The answer i s C [ see Ì Ì Ì . B] .
Et hanol sat ur at es al cohol dehydr ogenase and pr event s t he f ormat i on of t he
t oxi c met abol i t es of ei t her et hyl ene gl ycol or met hanol , however t hi s
ant i dot e i s f al l i ng out of f avor owi ng t o i t s adver se met abol i c and cent r al
ner vous syst em ef f ect s. Fomepi zol e (Ant i zol ) , a speci f i c i nhi bi t or of al cohol
dehydrogenase, i s becomi ng t he pr ef er r ed ant i dot e f or met hanol or et hyl ene
gl ycol overdoses. Et hanol may be used i n si t uat i ons i n whi ch f omepi zol e i s
not avai l abl e.
8. The answer i s A [ see Ì Ì Ì . L. 2] .
Al l of t he sel ect i ons are used t o manage hyperkal emi a. Al t hough, i n an
unst abl e pat i ent , t he cardi ac ef f ect s of hyper kal emi a must f i rst be r eversed
wi t h i nt ravenous cal ci um.
9. The answer i s D [ see Ì Ì Ì . G; Ì Ì Ì . L. 2] .
Par ent er al cal ci um i s used t o r everse t he car di ac ef f ect s of cal ci um channel
bl ocker overuse and hyper kal emi a.
10. The answer i s D [ see Ì Ì Ì . K] .
The pl asma- t i ssue di st r i but i on phase f or di goxi n i s 6- 8 hr
post admi ni st r at i on. Sampl i ng di goxi n l evel s sooner may gi ve a f al sel y
el evat ed l evel . Onl y sympt omat i c pat i ent s shoul d r ecei ve di goxi n i mmune
ant i bodi es. Hemodi al ysi s i s of no val ue i n managi ng di goxi n over doses.
11. The answer i s A [ see Ì Ì Ì . T] .
Lar ge i ngest i ons of sust ai ned- r el ease product s may act as dr ug r eser voi r s,
necessi t at i ng aggr essi ve measur es t o r emove t he t oxi n.
P. 526


12. The answer i s C [ see Ì Ì Ì . A] .
Lar ge acet ami nophen i ngest i ons ( > 140 mg/ kg) may be f at al i f
unr ecogni zed. The Rumack- Mat t hew nomogr am requi r es a 4- hr l evel t o
accur at el y assess t he pot ent i al f or t oxi ci t y. Ì f t he 4- hr l evel i s i n t he t oxi c
r ange, t he f ul l course of NAC t herapy shoul d be admi ni st ered.
13. The answer i s E [ see Ì Ì Ì . D] .
Tr i cycl i c ant i depr essant over doses wi l l pr oduce sei zur es, hypot ensi on,
mydr i asi s, hypot ensi on, and vent r i cul ar dysrhyt hmi as. The car di ac and CNS
ef f ect s of t r i cycl i c ant i depr essant t oxi ci t y wi l l respond t o bi carbonat e
t her apy. Opi at es such as oxycodone wi l l produce mi osi s.

25
FederaI Pharmacy Law
Robert C. PavI an Jr.
James A. Boyd
I. FEDERAL CONTROLLED SUBSTANCES ACT
A. ScheduI es of cont roI I ed substances. Cer t ai n dr ugs have a pot ent i al f or abuse
t hat l eads t o physi cal or psychol ogi cal dependence. As a r esul t , t he U. S. f ederal
gover nment has pl aced t hese drugs i nt o schedul es (Ì , Ì Ì , Ì Ì Ì , Ì V, and V) and r ef ers t o
t hem as cont r ol l ed subst ances. The At t or ney Gener al of t he Uni t ed St at es has t he
aut hor i t y t o add or remove a drug or subst ance f r om one of t he f ederal schedul es,
or t o t r ansf er a drug f r om one f eder al schedul e t o anot her . The f eder al schedul es
ar e updat ed and publ i shed annual l y by t he f ederal gover nment .
1. ScheduI e I ( CI ; C- I ) Schedul e Ì dr ugs may not be kept i n a phar macy nor
di spensed pur suant t o a pr escri pt i on ( except f or pr oper l y r egi st ered f aci l i t i es f or
i nvest i gat i ve or research pur poses). A cont r ol l ed subst ance anal ogue of a dr ug i n
any f eder al schedul e, commonl y ref er red t o as a " desi gner dr ug, ¨ i s consi der ed a
schedul e Ì subst ance t o t he ext ent i nt ended f or human consumpt i on. Requi r ed
f i ndi ngs by t he gover nment f or pl acement of a drug i nt o schedul e Ì i ncl ude:
a. The dr ug or ot her subst ance has a hi gh pot ent i al f or abuse.
b. The drug or ot her subst ance has no cur rent l y accept ed medi cal use i n t r eat ment
i n t he Uni t ed St at es.
c. There i s a l ack of accept ed saf et y f or use of t he drug or ot her subst ance under
medi cal super vi si on.
2. ScheduI e I I ( CI I ; C- I I ). Requi r ed f i ndi ngs f or pl acement of a dr ug i nt o schedul e Ì Ì
i ncl ude:
a. The dr ug or ot her subst ance has a hi gh pot ent i al f or abuse.
b. The drug or ot her subst ance has a cur r ent l y accept ed medi cal use i n t r eat ment i n
t he Uni t ed St at es or a cur r ent l y accept ed medi cal use wi t h sever e r est r i ct i ons.
c. Abuse of t he dr ug or ot her subst ance may l ead t o sever e psychol ogi cal or
physi cal dependence.
3. ScheduI e I I I ( CI I I ; C- I I I ) . Requi r ed f i ndi ngs f or pl acement of a dr ug i nt o schedul e
Ì Ì Ì i ncl ude:
a. The dr ug or ot her subst ance has a pot ent i al f or abuse l ess t han t he drugs or
ot her subst ances i n schedul es Ì and Ì Ì .
b. The drug or ot her subst ance has a cur r ent l y accept ed medi cal use i n t r eat ment i n
t he Uni t ed St at es.
c. Abuse of t he dr ug or ot her subst ance may l ead t o moder at e or l ow physi cal
dependence or hi gh psychol ogi cal dependence.
4. ScheduI e I V ( CI V; C- I V) . Requi red f i ndi ngs f or pl acement of a dr ug i nt o schedul e
Ì V i ncl ude:
a. The dr ug or ot her subst ance has a l ow pot ent i al f or abuse rel at i ve t o t he drugs or
ot her subst ances i n schedul e Ì Ì Ì .
b. The drug or ot her subst ance has a cur r ent l y accept ed medi cal use i n t r eat ment i n
t he Uni t ed St at es.
c. Abuse of t he dr ug or ot her subst ance may l ead t o l i mi t ed physi cal dependence or
psychol ogi cal dependence rel at i ve t o t he dr ugs or ot her subst ances i n schedul e Ì Ì Ì .
5. ScheduI e V ( CV; C- V) . Requi r ed f i ndi ngs f or pl acement of a dr ug i nt o schedul e V
i ncl ude:
a. The dr ug or ot her subst ance has a l ow pot ent i al f or abuse rel at i ve t o t he drugs or
ot her subst ances i n schedul e Ì V.
b. The drug or ot her subst ance has a cur r ent l y accept ed medi cal use i n t r eat ment i n
t he Uni t ed St at es.
c. Abuse of t he dr ug or ot her subst ance may l ead t o l i mi t ed physi cal dependence or
psychol ogi cal dependence rel at i ve t o t he dr ugs or ot her subst ances i n schedul e Ì V.
P. 528


B. Regi st rat i on requi rement s. Thi s Act r egul at es t he use of cont rol l ed subst ances
by r equi r i ng al l ent i t i es t hat l awf ul l y handl e t hem t o r egi st er wi t h t he f ederal
gover nment , speci f i cal l y, t he Drug Enf or cement Admi ni st r at i on ( DEA).
1. Enti t i es t hat must regi st er
a. Manufacturers and whoI esaI ers of cont r ol l ed subst ances must r egi st er wi t h t he
DEA i ni t i al l y and r er egi st er ever y year t her eaf t er.
b. Di spensers ( pr act i t i oner s and pharmaci es) of cont r ol l ed subst ances must
r egi st er wi t h t he DEA i ni t i al l y and rer egi st er every 3 year s t her eaf t er. Phar maci st s,
pharmacy i nt er ns, phar macy t echni ci ans, and al l ot her empl oyees or agent s of a
pharmacy do not have t o r egi st er , pr ovi di ng t he phar macy i s pr operl y r egi st ered and
t he empl oyee or agent i s act i ng i n t he usual course of empl oyment or busi ness.
c. Al l ot her ent i t i es t hat l awf ul l y handl e any cont rol l ed subst ance must regi st er wi t h
t he DEA, i ncl udi ng r esear cher s, cl i ni cs and l aborat ori es, and t eachi ng i nst i t ut i ons.
2. Separate regi st rat i on f or separat e act i vi t i es. Ever y ent i t y t hat engages i n one
of t he f ol l owi ng act i vi t i es must regi st er wi t h t he DEA. A separ at e r egi st r at i on i s
r equi r ed f or each act i vi t y, wi t h cer t ai n except i ons ( e. g. , a manuf act urer of a
schedul e of a cont r ol l ed subst ance i s al l owed t o di st r i but e t hat schedul e wi t hout
bei ng regi st er ed as a di st r i but or ).
a. Manuf act uri ng cont r ol l ed subst ances
b. Di st r i but i ng cont rol l ed subst ances
c. Di spensi ng cont r ol l ed subst ances l i st ed i n schedul es Ì Ì - V ( e. g. , pr act i t i oners,
pharmaci es)
d. Conduct i ng research wi t h cont r ol l ed subst ances l i st ed i n schedul es Ì Ì -V
e. Conduct i ng i nst ruct i onal act i vi t i es wi t h cont rol l ed subst ances l i st ed i n schedul es
Ì Ì - V
f . Conduct i ng a nar cot i c t r eat ment pr ogram usi ng any nar cot i c dr ug l i st ed i n
schedul es Ì Ì , Ì Ì Ì , Ì V, or V
g. Conduct i ng research and i nst r uct i onal act i vi t i es wi t h cont r ol l ed subst ances l i st ed
i n schedul e Ì
h. Conduct i ng chemi cal anal ysi s wi t h cont r ol l ed subst ances l i st ed i n any schedul e
i . Ì mport i ng cont r ol l ed subst ances
j . Expor t i ng cont r ol l ed subst ances
k. Part i ci pat i ng i n mai nt enance or det oxi f i cat i on t r eat ment and mi xi ng, prepari ng,
packagi ng, or changi ng t he dosage f orm of a narcot i c dr ug l i st ed i n schedul es Ì Ì , Ì Ì Ì ,
Ì V, or V f or use i n mai nt enance or det oxi f i cat i on t r eat ment by anot her narcot i c
t r eat ment pr ogram.
3. Separate regi st rat i ons f or separat e I ocat i ons. Each pri nci pal pl ace of busi ness
of a r egi st r ant havi ng mor e t han one l ocat i on must have i t s own r egi st r at i on
cer t i f i cat e. Each pharmacy, chai n pharmacy, and hospi t al t hat di spenses cont r ol l ed
subst ances must have i t s own r egi st r at i on cer t i f i cat e. Regi st r at i on i s not r equi r ed
f or an of f i ce t hat i s used by a regi st rant where cont r ol l ed subst ances ar e nei t her
st ored nor di spensed.
a. Warehouses. A war ehouse wher e cont r ol l ed subst ances ar e st ored by or on
behal f of a r egi st r ant i s not requi r ed t o r egi st er unl ess one of t he f ol l owi ng occur s:
( 1) Cont r ol l ed subst ances are di r ect l y di st r i but ed f r om t he war ehouse t o a
r egi st er ed l ocat i on di f f erent t han t he l ocat i on f r om whi ch t he subst ances wer e
shi pped.
( 2) Cont r ol l ed subst ances are di r ect l y di st r i but ed f r om t he war ehouse t o a person or
ent i t y not r equi red t o regi st er under t he Act .
4. Regi st rati on procedure. Appl i cat i ons t o become regi st er ed must be submi t t ed t o
t he DEA on t he appr opr i at e f orm wi t h t he requi r ed f ee, i nf or mat i on, and si gnat ure of
one of t he f ol l owi ng:
a. The i ndi vi dual who owns and oper at es t he ent i t y, i f doi ng busi ness as an
i ndi vi dual
b. A par t ner of t he appl i cant , i f a part nershi p
c. An of f i cer of t he appl i cant , i f a cor porat i on, cor por at e di vi si on, associ at i on, t rust ,
or ot her ent i t y
d. One or more i ndi vi dual s who have been grant ed a power of at t or ney by an
appl i cant . A power of att orney al l ows one t o l awf ul l y act i n pl ace of anot her . The
power of at t or ney must be si gned by one of t he i ndi vi dual s l i st ed above i n a- c and
by t he i ndi vi dual r ecei vi ng t he power of at t orney. The power of at t or ney r emai ns
val i d unt i l r evoked by t he appl i cant .
P. 529


5. Regi st rati on acti on by t he DEA. Ì f an appl i cat i on i s compl et e, i t wi l l be accept ed
f or f i l i ng. Ì f i t i s def ect i ve, t he DEA wi l l r et ur n t he appl i cat i on wi t h a st at ement
i ndi cat i ng t he reason f or i t s nonaccept ance. The appl i cat i on may be cor rect ed and
r esubmi t t ed at any t i me.
a. I ssuance of cert i fi cat e of regi st rat i on. A cert i f i cat e of r egi st rat i on wi l l be
i ssued by t he DEA when i t det ermi nes t hat t he r egi st r at i on i s r equi r ed by l aw i n
or der t o conduct such act i vi t y ( e. g. , manuf act uri ng, di st r i but i ng, or di spensi ng a
cont r ol l ed subst ance) . The cer t i f i cat e must be conspi cuousl y mai nt ai ned and readi l y
r et r i evabl e at t he regi st er ed l ocat i on.
b. Deni aI of regi st rat i on. Ì f t he DEA det ermi nes t hat a regi st r at i on i s not r equi r ed
by l aw, i t wi l l i ssue an Or der To Show Cause why t he r egi st r at i on shoul d not be
deni ed. The appl i cant may r equest a hear i ng and expl ai n why t he cer t i f i cat e of
r egi st rat i on shoul d be i ssued. Af t er t he hear i ng, t he DEA may deny t he appl i cat i on
or i ssue t he cer t i f i cat e.
6. Modi fi cati on of regi st rat i on. A regi st rant may submi t a l et t er of r equest t o t he
DEA seeki ng t o modi f y i t s r egi st r at i on. A modi f i cat i on may be sought when t her e i s
a change i n t he name or address t hat appears on t he cert i f i cat e, or when t he
pharmacy seeks DEA appr oval t o di spense addi t i onal cont rol l ed subst ances [ i f
i ni t i al l y aut hor i zed t o onl y di spense a par t i cul ar schedul e(s) of cont rol l ed
subst ances] .
7. Transf er of regi st rat i on. A regi st r at i on t o di spense cont r ol l ed subst ances may
not be t r ansf er r ed t o any ot her per son or ent i t y except when t he ownershi p of a
pharmacy i s bei ng t ransf er r ed f r om one ent i t y t o anot her . Ì n such a case, cont r ol l ed
subst ances i n schedul es Ì Ì - V must be pr oper l y di sposed of or t r ansf er r ed t o t he new
ent i t y.
8. Suspensi on or revocat i on of regi st rat i on. The DEA may suspend or r evoke any
r egi st rat i on. The DEA must f i rst i ssue an Or der To Show Cause ( upon t he
r egi st rant ) why t he r egi st r at i on shoul d not be revoked or suspended. The r egi st rant
may r equest a heari ng t o expl ai n why t he r egi st r at i on shoul d not be suspended or
r evoked. Af t er a heari ng, t he DEA may suspend, revoke, or t ake no act i on on t he
r egi st rat i on.
a. Order of suspensi on or revocat i on. Af t er a regi st r ant has r ecei ved an or der
suspendi ng or revoki ng i t s regi st rat i on, i t must t ake t he f ol l owi ng act i on:
( 1) Ì mmedi at el y del i ver i t s cer t i f i cat e of r egi st r at i on and any DEA 222 or der f orms i n
i t s possessi on t o t he near est of f i ce of t he DEA
( 2) As i nst ruct ed by t he DEA, ei t her:
( a) del i ver al l cont r ol l ed subst ances i n i t s possessi on t o t he nearest of f i ce of t he
DEA or t o aut hor i zed agent s of t he DEA or
( b) pl ace al l cont rol l ed subst ances i n i t s possessi on under seal .
b. I mmi nent danger t o pubI i c heaI th or saf et y. The DEA may ser ve on a r egi st r ant
an order of i mmedi at e suspensi on when i t f i nds t hat t her e i s an i mmi nent danger t o
t he pubI i c heaI th or safet y. The i mmedi at e suspensi on r emai ns i n ef f ect unt i l t he
concl usi on of al l proceedi ngs, ei t her admi ni st r at i ve pr oceedi ngs by t he DEA or
j udi ci al pr oceedi ngs. Af t er r ecei vi ng an or der of i mmedi at e suspensi on, t he
r egi st rant must t ake t he same act i on as out l i ned above under Ì B 8 a.
9. Exempti ons f rom regi st rat i on. Cer t ai n i ndi vi dual s are exempt f rom r egi st r at i on
under t he Act . The f ol l owi ng ar e exempt :
a. Mi I i tar y of f i ci aI s. Mi l i t ar y of f i ci al s, i ncl udi ng Publ i c Heal t h Ser vi ce and Bur eau of
Pr i sons of f i ci al s, who are aut hori zed t o pr escri be, di spense, or admi ni st er, but not
t o procur e or purchase, cont r ol l ed subst ances i n t he cour se of t hei r of f i ci al dut i es,
ar e exempt f rom r egi st eri ng wi t h t he DEA. The i ndi vi dual must , however , obt ai n a
r egi st rat i on f or such act i vi t i es conduct ed dur i ng any separat e pr i vat e pr act i ce.
b. Law-enf orcement of fi ci aI s. Feder al and st at e l aw- enf or cement personnel act i ng
i n t he cour se of enf orci ng any l aw r el at i ng t o cont r ol l ed subst ances ar e exempt f r om
r egi st rat i on.
c. Ci vi I def ense of f i ci aI s. Ci vi l def ense and di sast er -r el i ef or gani zat i on of f i ci al s ar e
exempt f r om regi st r at i on i n or der t o mai nt ai n and di spense cont r ol l ed subst ances
dur i ng t i mes of pr ocl ai med emergenci es or di sast er s.
d. Agent s and empI oyees of regi st rants. Agent s and empl oyees, whi l e act i ng
l awf ul l y i n t he usual course of t hei r busi ness or empl oyment , ar e exempt f r om
r egi st rat i on when t he busi ness or empl oyment i s conduct ed on behal f of a person
( or busi ness) who i s r egi st ered under t he Act . Del i ver y per sonnel (e. g. , Uni t ed
Par cel Ser vi ce, Feder al Expr ess) are t heref ore not r equi r ed t o r egi st er . Li kewi se,
pharmaci st s wor ki ng f or a r egi st ered pharmacy ar e not r equi r ed t o r egi st er .
P. 530


10. Termi nat i on of regi st rat i on. The regi st r at i on of any per son or ent i t y wi l l
t er mi nat e when t he per son di es, ceases l egal exi st ence ( e. g. , cor porat e di ssol ut i on,
par t nershi p di ssol ut i on) , or di scont i nues busi ness or prof essi onal pract i ce. The DEA
must be not i f i ed pr ompt l y when any of t hese occur s. Ì n such a case, al l cont r ol l ed
subst ances i n schedul es Ì Ì - V must be pr oper l y di sposed of .
C. Requi red i nvent ori es. The Act requi r es al l phar maci es and hospi t al s ( ever y
separ at el y r egi st er ed l ocat i on) t o conduct an i ni t i al i nvent or y and bi enni al i nvent or y
of al l cont r ol l ed subst ances i n schedul es Ì Ì , Ì Ì Ì , Ì V, and V.
1. I ni t i aI i nventor y. The i ni t i al i nvent or y must be t aken on t he dat e t he ent i t y
commences busi ness and begi ns di spensi ng cont r ol l ed subst ances. Ì f t he ent i t y has
no cont r ol l ed subst ances on hand, a r ecord of t hi s f act must be mai nt ai ned as i t s
i ni t i al i nvent or y.
2. Bi enni aI i nvent or y. The bi enni al i nvent or y must be t aken at l east every 2 year s
f r om t he dat e of t he i ni t i al i nvent or y.
a. Bi enni aI dat e. The bi enni al dat e may be any dat e t hat i s wi t hi n 2 years of t he
pr evi ous bi enni al ( or i ni t i al ) dat e. Thi s dat e does not have t o be r epor t ed t o t he
DEA i f i t i s di f f er ent t han t he bi enni al dat e t hat woul d ot her wi se appl y (i . e. , on t he
exact day 2 years af t er t he previ ous i nvent or y) .
3. I nventor y procedures
a. Al l i nvent or i es must be mai nt ai ned i n a wri t ten, t ypewri t t en, or pri nt ed f orm and
be conduct ed at ei t her t he openi ng of busi ness or t he cl ose of busi ness on t he
i nvent or y dat e ( whi ch must be not ed on t he i nvent or y) .
b. Separate i nventor y r ecord f or scheduI e I I cont roI I ed subst ances. Because al l
r ecor ds f or schedul e Ì Ì cont r ol l ed subst ances must be mai nt ai ned separ at el y f r om
ot her r ecords, schedul e Ì Ì i nvent ori es must be mai nt ai ned separ at el y f r om ot her
cont r ol l ed- subst ance i nvent ori es.
4. I nventor y cont ent . Al l i nvent or y recor ds must cont ai n t he f ol l owi ng:
a. Dat e t he i nvent or y i s t aken
b. Each f i ni shed f orm of t he subst ance (dosage f or m and st r engt h)
c. Number of uni t s or vol ume of each f i ni shed f orm i n each commerci al cont ai ner
( e. g. , 100- t abl et bot t l e). For opened commerci al cont ai ners, i nvent or y must be t aken
as f ol l ows:
( 1) For schedul e Ì Ì cont rol l ed subst ances, an exact count or measure must be t aken.
( 2) For schedul e Ì Ì Ì , Ì V, and V cont rol l ed subst ances, an est i mat ed count or
measure may be t aken, except t hat an exact count must be t aken i f t he cont ai ner
hol ds more t han 1000 t abl et s or capsul es.
d. For each cont rol l ed subst ance mai nt ai ned f or ext empor aneous compoundi ng, or
f or subst ances t hat ar e damaged, def ect i ve, or i mpur e and awai t i ng di sposal :
( 1) Name of t he subst ance
( 2) Tot al quant i t y t o t he nearest met r i c uni t wei ght or t he t ot al number of uni t s of
f i ni shed f orm
( 3) Reason t he subst ance i s bei ng mai nt ai ned and whet her i t i s capabl e of use i n
t he manuf act ur e of any cont r ol l ed subst ance i n f i ni shed f orm
5. I nventor y record mai nt enance. Ever y i nvent or y r ecord must be mai nt ai ned at
t he regi st er ed l ocat i on (e. g. , pharmacy, hospi t al ) f or at l east 2 years f rom t he dat e
of t he i nvent or y.
a. Schedul e Ì Ì i nvent or i es must be mai nt ai ned separ at el y f rom al l ot her r ecor ds of
t he pharmacy.
b. Schedul e Ì Ì Ì - V i nvent or y r ecords must be mai nt ai ned ei t her separ at el y f r om al l
ot her r ecords of t he pharmacy or i n such a manner t hat t he requi r ed i nf ormat i on i s
r eadi l y r et r i evabl e f rom or di nar y busi ness r ecords of t he pharmacy. " Readi l y
r et r i evabl e¨ means t hat t he i nvent or y r ecords can be separ at ed out f rom al l ot her
r ecor ds i n a reasonabl e t i me.
6. Perpet uaI i nvent ori es. The Act does not requi r e a di spenser r egi st r ant ( e. g. ,
pharmacy, hospi t al ) t o mai nt ai n a perpet ual i nvent or y of any cont r ol l ed subst ance.
7. NewI y cont roI I ed subst ances or changes i n scheduI i ng of a subst ance. An
i nvent or y of a subst ance must be t aken when, by or der of t he DEA, i t becomes a
newl y cont r ol l ed subst ance or i t shi f t s i nt o anot her schedul e. The i nvent or y of t hat
par t i cul ar cont rol l ed subst ance must be t aken on t he ef f ect i ve dat e of t he change. A
compl et e i nvent or y of al l cont r ol l ed subst ances i s not r equi red, nor i s an i nvent or y
r equi r ed when a subst ance moves f rom a cont r ol l ed- subst ance schedul e t o a
nonf eder al schedul e.
P. 531


8. Transf er of busi ness act i vi t y. An i nvent or y of cont rol l ed subst ances Ì Ì - V must
be t aken at t he t i me a phar macy or hospi t al under goes a change i n owner shi p. The
i nvent or y must be t aken on t he dat e of t r ansf er and ser ves as t he f i nal i nvent or y of
t he t r ansf er or and t he i ni t i al i nvent or y of t he t r ansf eree.
9. I nventor y record submi ssi on. The Act does not r equi r e t he submi ssi on of
i nvent or y r ecords t o anyone, i ncl udi ng t he DEA. The r ecor ds must be mai nt ai ned at
t he regi st er ed l ocat i on f or i nspect i on and copyi ng by aut hor i zed agent s of t he DEA.
D. Obt ai ni ng cont roI I ed subst ances. Schedul e Ì Ì cont rol l ed subst ances must be
obt ai ned f rom a suppl i er ( whol esal er, manuf act urer ) by usi ng DEA Form 222. The
Act does not requi r e t he use of any speci al f orm t o obt ai n cont r ol l ed subst ances i n
schedul es Ì Ì Ì - V.
1. DEA Form 222. Onl y ent i t i es t hat are r egi st ered t o di spense or handl e schedul e
Ì Ì cont rol l ed subst ances may obt ai n Form 222. The f orms are ser i al l y number ed and
i ssued by t he DEA wi t h t he name, address, r egi st r at i on number, aut hor i zed act i vi t y,
and schedul es of t he r egi st rant . Each f orm cont ai ns an or i gi nal , dupl i cat e, and
t r i pl i cat e copy ( Copy 1, Copy 2, and Copy 3, r espect i vel y) .
a. Executi on of Form 222. Form 222 may be execut ed onl y on behal f of t he
r egi st rant named on t he f or m and onl y i f t he regi st r at i on has not expi r ed nor been
r evoked or suspended. The f or m must be pr epared i n t r i pl i cat e as pr ovi ded by t he
DEA by use of a t ypewr i t er , pen, or i ndel i bl e penci l i n t he f ol l owi ng manner :
( 1) Onl y one i t em may be or der ed on each of t he 10 numbered l i nes on t he f orm.
The t ot al number of i t ems ordered must be not ed on t he f orm i n t he space pr ovi ded.
( 2) One i t em may consi st of one or more commerci al or bul k cont ai ners of a product .
A separ at e i t em must be made f or di f f er ent commerci al or bul k cont ai ners of a
pr oduct . For each i t em, t he f or m must cont ai n t he f ol l owi ng i nf or mat i on:
( a) Name of t he ar t i cl e or der ed
( b) Fi ni shed or bul k f or m of t he pr oduct ( dosage f or m and st r engt h)
( c) Number of uni t s or vol ume i n each commerci al or bul k cont ai ner (e. g. , 100- t abl et
bot t l e)
( d) Number of commerci al or bul k cont ai ners order ed
( e) Ì f t he ar t i cl e i s not i n pur e f orm, t he name and quant i t y per uni t of t he cont r ol l ed
subst ances cont ai ned i n t he ar t i cl e.
( 3) The suppl i er ' s name and addr ess must be i ncl uded on t he f orm. Onl y one
suppl i er may be l i st ed on any one f orm.
( 4) Each f orm must i ncl ude t he dat e of t he order , and no f orm i s val i d more t han 60
days af t er i t s execut i on by t he purchaser .
( 5) The f or m must be si gned ei t her by t he per son who si gned t he most recent
appl i cat i on f or r egi st r at i on or r eregi st rat i on, or by a person aut hor i zed t o obt ai n and
execut e or der f orms by a power of at t orney.
( a) Any pur chaser may aut hori ze one or more i ndi vi dual s ( does not have t o be an
at t orney- at -l aw) , whet her or not l ocat ed at t he regi st er ed l ocat i on, t o obt ai n and
execut e 222 Forms by execut i ng a power of at t orney f or t he i ndi vi dual (s) .
( b) The power of at t or ney must be si gned by t he per son who si gned t he most r ecent
appl i cat i on f or r egi st r at i on or r eregi st rat i on and by t he i ndi vi dual ( s) r ecei vi ng t he
power of at t or ney. Thi s f or m must be si mi l ar or i dent i cal t o t he DEA' s " Power of
At t or ney f or DEA Or der For ms. ¨
( c) Once pr oper l y execut ed, t he i ndi vi dual r ecei vi ng t he power of at t or ney may
obt ai n and si gn DEA Form 222 t o t he same ext ent as t he i ndi vi dual who si gned t he
most recent appl i cat i on f or r egi st r at i on or r eregi st r at i on.
( d) The power of at t or ney must be f i l ed wi t h t he execut ed 222 For ms of t he
pur chaser and be r et ai ned f or t he same peri od as any or der f or m bear i ng t he
si gnat ur e of t he at t or ney [ see Ì . D. 1. a ( 8) ] . The power of at t or ney does not have t o
be submi t t ed t o t he DEA.
( 6) Copi es 1 and 2 must be submi t t ed t o t he suppl i er. Copy 3 must be r et ai ned by
t he purchaser.
( 7) When t he order ed schedul e Ì Ì cont r ol l ed subst ances are r ecei ved by t he
pharmacy, t he f ol l owi ng i nf ormat i on must be r ecor ded on t he r et ai ned Copy 3:
( a) Number of commerci al or bul k cont ai ners f urni shed on each i t em ( or l i ne)
( b) Dat e on whi ch t he cont ai ners ar e recei ved by t he pharmacy
( 8) DEA 222 Forms must be mai nt ai ned at t he r egi st er ed l ocat i on ( phar macy or
hospi t al ) f or at l east 2 year s f r om t hei r execut i on. The t i me of execut i on woul d be
t he dat e t he l ast ent r y was made on Copy 3.
P. 532


b. CanceI I at i on by purchaser. A pur chaser may cancel al l or par t of an or der by
not i f yi ng t he suppl i er i n wr i t i ng. The suppl i er must i ndi cat e t he cancel l at i on on
Copi es 1 and 2 by dr awi ng a l i ne t hr ough t he cancel ed i t ems and pr i nt i ng t he wor d
" cancel ed¨ i n t he space pr ovi ded f or number of i t ems shi pped. Li kewi se, a suppl i er
may voi d al l or par t of an or der by not i f yi ng t he pur chaser i n wr i t i ng and pr i nt i ng t he
wor d " cancel ed¨ i n t he space provi ded f or number of i t ems shi pped.
c. Mai nt enance of DEA Form 222. Execut ed Copy 3 f orms and Copi es 1 and 2 of
each unaccept ed or def ect i ve f orm and t he st at ement of r ef usal f r om t he suppl i er
must be mai nt ai ned by t he pur chaser . They must be kept separ at e f rom al l ot her
r ecor ds and be avai l abl e f or i nspect i on f or at l east 2 years. Al l f orms must be
mai nt ai ned at t he regi st er ed l ocat i on pr epr i nt ed on t he f or m, and not at a cent r al
l ocat i on.
d. Loss or t hef t of DEA Form 222. Any used or unused f orm st ol en f r om or l ost by
a purchaser or suppl i er must be r eport ed i mmedi at el y t o t he DEA. Such not i f i cat i on
must i ncl ude t he seri al number of each f or m l ost or st ol en.
2. Obt ai ni ng scheduI e I I I - V cont roI I ed subst ances. Ther e i s no speci al f or m f or
obt ai ni ng schedul e Ì Ì Ì - V cont r ol l ed subst ances. Each r egi st r ant must , however ,
mai nt ai n a compl et e and accurat e r ecor d of r ecei pt f or each such subst ance. The
r ecor d must be mai nt ai ned at ei t her t he regi st er ed l ocat i on of t he pharmacy or
hospi t al , or at a cent ral l ocat i on, f or 2 years. Ì f a cent r al l ocat i on i s used, t he
pharmacy must f i rst not i f y t he DEA, i ndi cat i ng i t s i nt ent i on t o keep cent r al r ecor ds.
Cent r al recor ds may t hen be mai nt ai ned unl ess t he DEA deni es t he request t o keep
such recor ds. An i nvoi ce or packi ng sl i p wi l l suf f i ce as a r ecor d of r ecei pt , pr ovi di ng
t he f ol l owi ng i nf or mat i on i s i ncl uded:
a. Name of t he cont r ol l ed subst ance
b. Fi ni shed f or m of t he subst ance ( dosage f orm and st r engt h)
c. Number of uni t s or vol ume of t he f i ni shed f or m i n each commer ci al cont ai ner
( e. g. , 100- t abl et bot t l e)
d. Number of commerci al cont ai ner s of each such f i ni shed f or m r ecei ved f r om ot her
per sons
e. Dat e of act ual r ecei pt of each commerci al cont ai ner
f . Name, addr ess, and r egi st r at i on number of t he per son f r om whom t he cont ai ner s
wer e r ecei ved
E. St orage of cont roI I ed subst ances. Al l cont rol l ed subst ances i n schedul es Ì Ì - V
must be st ored i n one of t he f ol l owi ng ways:
1. Ì n a securel y l ocked, subst ant i al l y const r uct ed cabi net
2. Di sper sed t hr oughout t he st ock of unschedul ed pr escri pt i on medi cat i on t o prevent
any t hef t or di ver si on
F. Thef t or si gni f i cant I oss of scheduI e I I - V cont roI I ed substances. Ever y
r egi st rant must pr ompt l y not i f y t he r egi onal of f i ce of t he DEA of t he t hef t or
si gni f i cant l oss of any cont r ol l ed subst ance i n schedul es Ì Ì - V. Thi s r epor t must be
done usi ng DEA Form 106.
G. Di sposaI of cont roI I ed substances. Ever y di sposal of a cont r ol l ed subst ance
must be accompl i shed by submi t t i ng DEA Form 41 t o t he DEA (except f or di sposal s
pur suant t o a val i d prescr i pt i on, di scussed bel ow) . The f orm must l i st t he cont r ol l ed
subst ances earmar ked f or di sposal . The DEA wi l l aut hori ze t he di sposal and i nst r uct
t he regi st rant t o di spose of t he cont r ol l ed subst ances i n one of t he f ol l owi ng ways:
1. By t he t ransf er t o a per son or ent i t y regi st er ed wi t h t he DEA and aut hor i zed t o
possess t he subst ance. Schedul e Ì Ì cont r ol l ed subst ances must be t r ansf er r ed by
use of t he t r ansf er ee' s (anot her phar macy or hospi t al , or t he whol esal er or
manuf act ur er ) DEA Form 222. A wr i t t en recor d of t he t r ansf er of schedul e Ì Ì Ì - V
cont r ol l ed subst ances must be kept f or at l east 2 year s and i ncl ude t he f ol l owi ng
i nf or mat i on:
a. Name of t he cont r ol l ed subst ance
b. Fi ni shed f or m of t he subst ance ( dosage f orm and st r engt h)
c. Number of uni t s or vol ume of t he f i ni shed f or m i n each commer ci al cont ai ner
( e. g. , 100- t abl et bot t l e)
d. Number of commerci al cont ai ner s of each f i ni shed f orm t ransf er red
e. Dat e of t he t ransf er
f . Name, addr ess, and r egi st r at i on number of t he t r ansf eree
P. 533


2. By t he del i ver y t o an agent of t he DEA or t o t he near est of f i ce of t he DEA
3. By t he dest r uct i on i n t he presence of an agent of t he DEA or ot her aut hor i zed
per son
4. By any ot her means t hat t he DEA det ermi nes t o ensur e t hat t he subst ance does
not become avai l abl e t o unaut hor i zed persons or ent i t i es
H. ReguI ar di sposaI s of cont roI I ed substances. Ì f a r egi st r ant ( usual l y a hospi t al )
r egul arl y di sposes of cont r ol l ed subst ances i n schedul es Ì Ì - V t he DEA may aut hor i ze
di sposal s wi t hout pr i or appr oval i n each i nst ance. Ì f t he DEA grant s t hi s aut hori t y,
t he regi st rant must keep r ecor ds of each di sposal and f i l e peri odi c r epor t s t o t he
r egi onal of f i ce of t he DEA summar i zi ng t he di sposal s. The DEA may pl ace addi t i onal
condi t i ons on such di sposal , i ncl udi ng t he met hod of di sposal and t he f r equency and
det ai l of repor t s.
I . Di sposaI of cont roI I ed subst ances pursuant t o a vaI i d prescri pt i on
1. Persons who may i ssue prescri pt i ons f or cont roI I ed substances. A cont r ol l ed-
subst ance pr escri pt i on may be i ssued onl y by a pr act i t i oner who i s gr ant ed such
aut hor i t y by t he st at e i n whi ch t hat pr act i t i oner i s l i censed. Al t hough t he Act i s
f ederal l egi sl at i on, each st at e det er mi nes who wi l l be aut hori zed t o di spense
cont r ol l ed subst ances. Most st at es al l ow t he f ol l owi ng i ndi vi dual s t o pr escr i be:
physi ci ans, dent i st s, podi at ri st s, and vet eri nar i ans. Some st at es al l ow t he f ol l owi ng
i ndi vi dual s, ref er red t o as mi dl evel pr act i t i oner s, t o prescr i be (usual l y wi t h cer t ai n
r est ri ct i ons): physi ci an' s assi st ant s, nur se pr act i t i oner s, cer t i f i ed nur se mi dwi ves,
psychi at r i c nur ses, ment al heal t h cl i ni cal speci al i st s. Al l pr escri bers must be
r egi st er ed wi t h t he DEA or exempt ed f r om r egi st rat i on (see Ì . B. 9) . Pract i ti oner
means a physi ci an, dent i st , vet er i nari an, or ot her person l i censed (mi d- l evel
pr act i t i oners) by t he st at e t o pr escr i be cont r ol l ed subst ances, and pharmacy,
hospi t al , or ot her i nst i t ut i on l i censed t o di st r i but e cont r ol l ed subst ances. I ndi vi duaI
Pract i t i oner means a physi ci an, dent i st , vet er i nar i an, or ot her person l i censed
( mi d- l evel pract i t i oners) by t he st at e t o pr escri be cont r ol l ed subst ances. Ì t i s wor t h
not i ng t hat t he t er m " i ndi vi dual pract i t i oner ¨ i s i ncl uded i n t he def i ni t i on of
" pr act i t i oner . ¨ Pr escri bi ng aut hori t y grant ed by st at es i s l i mi t ed t o prof essi onal s
wi t hi n t he "i ndi vi dual pr act i t i oner ¨ cat egor y. The st at ement l i ke " pract i t i oner who i s
gr ant ed pr escr i bi ng aut hor i t y¨ means t he " i ndi vi dual pr act i t i oner ¨ who has been
gr ant ed pr escr i bi ng aut hor i t y by t he st at e because t he i ndi vi dual pr act i t i oner i s
i ncl uded i n t he def i ni t i on of pr act i t i oner . " Phar macy¨ i s def i ned as a "pr act i t i oner ¨
but , of cour se, does not have prescr i bi ng aut hor i t y.
a. DEA numbers and aut hent i ci t y. Af t er r egi st eri ng wi t h t he DEA, al l r egi st r ant s
ar e assi gned a DEA number by t he DEA. A pr act i t i oner ' s DEA number consi st s of
ni ne charact er s. The f i rst t wo char act ers ar e l et t er s. The f i r st l et t er wi l l be ei t her A
or B. The second l et t er wi l l be t he f i rst l et t er of t he pract i t i oner ' s l ast name. The
next si x char act er s ar e randoml y chosen numbers. The l ast char act er i s a number
of t en r ef er red t o as t he "check di gi t . ¨ For exampl e, Dr . Henr y Jones may have a
DEA number of AJ 4357782.
( 1) Aut hent i cat i on of DEA number. The DEA assi gns DEA numbers wi t h a qui ck
met hod of veri f i cat i on bui l t i nt o t he number. Thi s al l ows a di spensi ng pharmaci st t o
make a cur sor y r evi ew of t he number f or aut hent i ci t y. For exampl e, usi ng t he above
DEA number, t he pr act i t i oner ' s l ast name must st ar t wi t h a J. Al so, t he f ol l owi ng
qui ck cal cul at i on can be made t o ver i f y t hat t he "check di gi t ¨ i s cor rect :
( a) The di gi t s i n posi t i ons 1, 3, and 5 ar e added t oget her t o reach a number . Ì n t he
above exampl e, t hat woul d be 4 + 5 + 7 = 16.
( b) The di gi t s i n posi t i ons 2, 4, and 6 ar e added t oget her , t hen mul t i pl i ed by 2. Ì n
t he above exampl e, t hat woul d be ( 3 + 7 + 8) × 2 = 36.
( c) These numbers above ar e added t oget her : 16 + 36 = 52. The f ar- r i ght di gi t
becomes t he check di gi t . The check di gi t must t her ef or e be a 2. Ì f t he check di gi t i s
anyt hi ng ot her t han a 2, t he number may not be a val i d DEA number . Ì n such a
case, t he DEA shoul d be not i f i ed i n or der t o ver i f y t he number .
( 2) Mi dI eveI pract i t i oner DEA numbers. Mi dl evel pract i t i oner DEA number s ar e
si mi l ar t o pract i t i oner DEA numbers except f or t he f i rst char act er . Ì nst ead of t he
l et t er A or B, mi dl evel pract i t i oners have t he l et t er M as t he f i rst char act er i n t hei r
DEA number. The mat hemat i cal met hod f or ver i f yi ng t he aut hent i ci t y of t he number
i s t he same.
( 3) DEA numbers f or pract i t i oners and mi dI eveI practi t i oners who are
empI oyees of i nst i t ut i ons. Pract i t i oner s and mi dl evel pract i t i oner s who i ssue
pr escri pt i ons i n t he
P. 534

course of t hei r empl oyment wi t h an i nst i t ut i on may i ssue prescr i pt i ons f or al l
cont r ol l ed subst ances under t he i nst i t ut i on' s DEA r egi st rat i on. The pract i t i oner ' s or
mi d-l evel pract i t i oner ' s "DEA number¨ wi l l be a speci f i c i nt er nal code number i ssued
by t he i nst i t ut i on. The code number must consi st of numbers, l et t er s, or a
combi nat i on of number s and l et t ers and must be a suf f i x t o t he i nst i t ut i on' s DEA
number , preceded by a hyphen (e. g. , AP0123456-10 or AP0123456-A12).
2. Purpose of i ssuance of cont roI I ed- substance prescri pti ons. A cont rol l ed-
subst ance pr escri pt i on may be i ssued onl y i n good f ai t h f or a l egi t i mat e medi cal
pur pose by a pr act i t i oner act i ng i n t he usual course of hi s or her pr of essi onal
pr act i ce. The pract i t i oner and t he di spensi ng phar maci st have t he responsi bi l i t y t o
ensur e t hat a pr escr i pt i on i s proper l y i ssued and di spensed ( ref er red t o as
cor respondi ng r esponsi bi l i t y of t he phar maci st ) .
a. Legi t i mate medi caI purpose. Legi t i mat e medi cal purpose and good f ai t h are
pr er equi si t es f or al l cont r ol l ed-subst ance pr escri pt i ons. Wi t h r espect t o a
pharmaci st , t hese r equi rement s wi l l be appar ent f r om an obj ect i ve poi nt of vi ew. As
a general rul e, i f , f rom al l t he sur r oundi ng f act s and ci rcumst ances, a r easonabl y
pr udent phar maci st woul d f orm t he opi ni on t hat a pr escri pt i on was i ssued f or a
l egi t i mat e medi cal purpose, t hen t he pharmaci st has f ul f i l l ed hi s or her
r esponsi bi l i t y under t he Act , and t he prescr i pt i on may be l egal l y di spensed.
b. UsuaI course of professi onaI pract i ce. A pract i t i oner-pat i ent reI ati onshi p f or
t he pur pose of t reat i ng and car i ng f or t he pat i ent must be present . Usual l y, such a
r el at i onshi p i ncl udes t he t aki ng and recor di ng of an appropr i at e medi cal hi st or y, and
an appropr i at e physi cal exam. Thi s l i mi t s a pract i t i oner ' s abi l i t y t o prescr i be out si de
hi s or her cour se of prof essi onal pract i ce ( e. g. , a vet er i nari an may not prescr i be a
cont r ol l ed subst ance f or a human) . The not i on of " usual cour se of pract i ce¨ becomes
mor e uncl ear wi t h r espect t o medi cal doct ors who speci al i ze. Such speci al i st s of t en
i ssue pr escr i pt i ons " out si de¨ t hei r speci al t y. Gener al l y, al l cont r ol l ed- subst ance
pr escri pt i ons f rom medi cal doct ors are deemed t o be "i n t he usual course of
pr of essi onal pract i ce¨ as l ong as i t i s i ssued f or a human, r egar dl ess of whet her t he
pr obl em bei ng t reat ed i s wi t hi n t he doct or ' s speci al t y.
c. Rest ri cti ons on i ssuance of a cont roI I ed-subst ance prescri pt i on
( 1) A pr escri pt i on may not be i ssued by a pr act i t i oner i n or der f or t hat pr act i t i oner t o
obt ai n cont r ol l ed subst ances f or t he purpose of generaI di spensi ng t o hi s or her
pat i ent s.
( 2) A pr escri pt i on may not be i ssued f or t he di spensi ng of cont rol l ed subst ances f or
det oxi f i cat i on or mai nt enance t r eat ment . Admi ni st r at i on and di rect di spensi ng of
cont r ol l ed subst ances are al l owed onl y when conduct ed i n pr operl y r egi st er ed
t r eat ment pr ograms. A pr escr i pt i on f or met hadone i s val i d onl y when i ssued as an
anal gesi c i n cases of sever e pai n. Met hadone may be di spensed i n a hospi t al t o
mai nt ai n a pat i ent ' s addi ct i on as l ong as t he pat i ent i s admi t t ed and bei ng t r eat ed
f or some ot her medi cal condi t i on and i s not admi ni st er ed met hadone sol el y f or
det oxi f i cat i on purposes. The 40mg t abl et s of met hadone ar e onl y avai l abl e t o
f aci l i t i es aut hori zed f or det oxi f i cat i on and mai nt enance t r eat ment of opi oi d addi ct i on
and hospi t al s. The ot her st r engt hs ( 5mg and 10mg f ormul at i ons) i ndi cat ed f or t he
t r eat ment of pai n are avai l abl e t o al l aut hori zed r egi st rant s, i ncl udi ng ret ai l
pharmaci es.
3. Manner of i ssuance of a cont roI I ed- subst ance prescri pt i on. Schedul e Ì Ì
cont r ol l ed- subst ance prescri pt i ons must be wr i t t en wi t h i nk or i ndel i bl e penci l or
t ypewr i t t en ( except i n cases of or al emer gency schedul e Ì Ì prescr i pt i ons) . Schedul e
Ì Ì Ì - V cont r ol l ed- subst ance pr escr i pt i ons may be or al l y or dered by t he pract i t i oner .
Pr escr i pt i ons may be pr epar ed by ei t her t he pr act i t i oner or an agent of t he
pr act i t i oner , and communi cat ed t o t he pharmacy by t he pr act i t i oner or t he agent .
Aut hor i zat i on f or t he prescri pt i on ( or r ef i l l ) must , however , or i gi nat e wi t h t he
pr act i t i oner . Bot h t he pract i t i oner and di spensi ng phar maci st are r esponsi bl e f or t he
compl et eness of t he pr escri pt i on. Al l pr escri pt i ons f or cont r ol l ed subst ances must
i ncl ude t he f ol l owi ng i nf or mat i on:
a. Ful l name and addr ess of t he pat i ent
b. Dat e t he pr escri pt i on i s i ssued and si gned ( one and t he same)
c. Dr ug name, dosage f or m and st rengt h
d. Quant i t y of dr ug pr escr i bed
e. Di rect i ons f or use
f . Name, addr ess, and DEA r egi st r at i on number of t he pract i t i oner
P. 535


g. The si gnat ur e of t he pr act i t i oner ( no prepri nt ed or st amped si gnat ur es) as he or
she woul d si gn any l egal document ( al l schedul e Ì Ì cont rol l ed-subst ance
pr escri pt i ons must be manual l y si gned by t he pract i t i oner)
4. Emergency di spensi ng of scheduI e I I cont roI I ed subst ances
a. An or al schedul e Ì Ì cont r ol l ed- subst ance prescr i pt i on may be recei ved f r om a
pr act i t i oner i n an emer gency si t uat i on. An emer gency pr escri pt i on must i ncl ude al l
of t he i nf or mat i on requi red f or any cont rol l ed-subst ance prescr i pt i on. An emer gency
si t uat i on exi st s when aI I t hree of t he f ol l owi ng f act ors ar e pr esent :
( 1) The i mmedi at e admi ni st rat i on of t he cont r ol l ed subst ance i s necessary f or
pr oper t reat ment of t he pat i ent .
( 2) No appr opri at e al t er nat i ve t r eat ment i s avai l abl e, i ncl udi ng admi ni st r at i on of a
cont r ol l ed subst ance t hat i s not i n schedul e Ì Ì .
( 3) Ì t i s not r easonabl y possi bl e f or t he pr act i t i oner t o pr ovi de a wr i t t en prescr i pt i on
t o be present ed t o t he per son di spensi ng t he cont r ol l ed subst ance bef ore t he
di spensi ng.
b. Proper di spensi ng. The quant i t y pr escri bed and di spensed must be l i mi t ed t o
t he amount necessar y t o adequat el y t r eat t he pat i ent duri ng t he emer gency per i od.
Ì f t he pract i t i oner i s not known t o t he pharmaci st , t he pharmaci st must make a
r easonabl e good- f ai t h ef f or t t o det er mi ne t hat t he or al aut hor i zat i on came f r om a
r egi st er ed pr act i t i oner .
( 1) DeI i ver y of wri tt en prescri pt i on. The pr act i t i oner who aut hor i zes t he
emergency prescr i pt i on must , wi t hi n 7 days of t he or al aut hor i zat i on, del i ver a
wr i t t en prescr i pt i on t o t he di spensi ng pharmaci st . The pr escr i pt i on must cont ai n t he
i nf or mat i on requi r ed of al l cont r ol l ed- subst ance pr escr i pt i ons, have wr i t t en on i t s
f ace t he wor ds " Aut hori zat i on f or Emer gency Di spensi ng, ¨ and t he dat e of t he oral
aut hor i zat i on. The pr escr i pt i on may be del i ver ed i n per son or by mai l ; i f del i vered
by mai l , i t must be post marked wi t hi n t he 7-day per i od. Upon r ecei pt , t he di spensi ng
pharmaci st must at t ach i t t o t he or al emer gency pr escri pt i on, whi ch was pr evi ousl y
r educed t o wr i t i ng.
( 2) Fai I ure t o deI i ver a wri t t en prescri pt i on. Ì f a pr act i t i oner f ai l s t o del i ver t he
wr i t t en prescr i pt i on as r equi red, t he di spensi ng phar maci st must not i f y t he r egi onal
of f i ce of t he DEA. Fai l ure by t he pharmaci st t o not i f y t he DEA ser ves t o voi d t he
pharmaci st ' s aut hori t y t o di spense an oral emer gency schedul e Ì Ì pr escr i pt i on. The
pharmaci st wi l l be deemed t o have unl awf ul l y di spensed a schedul e Ì Ì cont r ol l ed
subst ance.
5. Facsi mi I e prescri pt i ons. Pr escri pt i ons f or cont r ol l ed subst ances Ì Ì Ì , Ì V and V
( and nonf eder al cont r ol l ed subst ances such as peni ci l l i n and f ur osemi de) may be
del i ver ed t o t he di spensi ng pharmacy vi a f acsi mi l e machi ne. A f acsi mi l e pr escr i pt i on
i s deemed t o be t he wr i t t en, si gned prescr i pt i on f r om t he pr escr i ber so l ong as i t
cont ai ns t he i nf ormat i on r equi r ed of al l prescri pt i ons under f eder al l aw. The
pr escri pt i on must be sent di rect l y f rom t he pr escri ber or hi s aut hor i zed agent t o t he
pharmacy.
a. ScheduI e I I cont roI I ed subst ances. Prescr i pt i ons f or schedul e Ì Ì cont rol l ed
subst ances may be sent vi a f acsi mi l e t o a di spensi ng pharmacy t o f aci l i t at e
di spensi ng of t he pr escr i pt i on. No drug may be reI eased t o t he pat i ent unt i l t he
or i gi nal , si gned pr escri pt i on i s pr esent ed t o t he di spensi ng phar maci st . A schedul e
Ì Ì cont rol l ed-subst ance f acsi mi l e prescri pt i on wi I I serve as t he or i gi nal , si gned
pr escri pt i on i n t he f ol l owi ng si t uat i ons:
( 1) I nj ectabI e home-heaI t h prescri pt i ons. A f acsi mi l e schedul e Ì Ì narcot i c
pr escri pt i on cal l i ng f or t he compoundi ng of a sol ut i on f or di r ect admi ni st rat i on t o a
pat i ent i n a pr i vat e r esi dence, l ong- t er m-care f aci l i t y, or hospi ce set t i ng may ser ve
as t he or i gi nal pr escr i pt i on. The except i on appl i es so l ong as t he sol ut i on wi l l be
admi ni st er ed by means of parent er al , i nt ravenous, i nt r amuscul ar, subcut aneous, or
i nt raspi nal i nf usi on.
( 2) Long- t erm- care faci I i t y prescri pt i ons. Any f acsi mi l e schedul e Ì Ì pr escr i pt i on
i ssued f or a r esi dent of a l ong- t erm- car e f aci l i t y may ser ve as t he or i gi nal , si gned
pr escri pt i on.
( 3) Hospi ce pat i ent prescri pt i ons. Any f acsi mi l e schedul e Ì Ì nar cot i c prescr i pt i on
i ssued f or a pat i ent enr ol l ed i n a hospi ce- car e progr am cer t i f i ed and/ or pai d f or by
Medi car e under Ti t l e XVÌ Ì Ì or l i censed by st at e l aw may ser ve as t he ori gi nal
pr escri pt i on. The pr escri ber , or hi s agent , must not e on t he pr escr i pt i on t hat t he
pat i ent i s a hospi ce pat i ent .
P. 536


6. EI ect roni c dat a t ransmi ssi on prescri pt i ons for non-cont roI I ed subst ances:
Pr escr i pt i on i nf or mat i on t hat i s t r ansmi t t ed di r ect l y f r om a pr act i t i oner t o a
pharmacy by el ect r oni c means such as vi a t he Ì nt er net i s ref er red t o as el ect r oni c
dat a t r ansmi ssi on prescri pt i on. El ect roni c si gnat ur es ar e recogni zed as l egal l y
accept abl e si gnat ur es of pr act i t i oners. Legend drugs, except f or cont rol l ed
subst ances, may be t r ansmi t t ed t o pharmaci es vi a t he Ì nt ernet i f al l owed by st at e
l aw. A st at e may al l ow a pr act i t i oner and phar macy t o mai nt ai n t he pr escri pt i on
i nf or mat i on i n el ect roni c f or m wi t hout r educi ng i t t o wr i t i ng, so l ong as t hey compl y
wi t h st at e mandat ed saf eguar ds.
a. EI ect roni c dat a t ransmi ssi on prescri pt i ons for cont roI I ed substances: The
DEA does not yet r ecogni ze el ect r oni c dat a t r ansmi ssi on pr escr i pt i ons as a means
of communi cat i ng prescri pt i on i nf ormat i on f or any cont rol l ed subst ance. Ther ef ore,
pr escri pt i on i nf ormat i on f or cont r ol l ed subst ances may not be communi cat ed f r om a
pr act i t i oner t o a phar macy by el ect r oni c means.
7. Persons who may di spense cont roI I ed- subst ance prescri pti ons. A pharmaci st
act i ng i n t he usual cour se of hi s or her prof essi onal pr act i ce i n a DEA-r egi st er ed
pharmacy ( or hospi t al or ot her r egi st er ed f aci l i t y) may di spense a cont r ol l ed
subst ance pur suant t o a pr escri pt i on. A pharmacy i nt ern act i ng under t he di r ect
super vi si on of hi s pr ecept or i n a DEA- regi st er ed f aci l i t y may al so di spense a
cont r ol l ed subst ance pursuant t o a pr escr i pt i on.
8. Di spensi ng procedures of cont roI I ed subst ances pursuant t o a prescri pt i on.
Once a cont r ol l ed- subst ance prescr i pt i on has been l awf ul l y i ssued by a pr act i t i oner
and pr esent ed t o a pharmaci st , i t may be di spensed i n accor dance wi t h t he
f ol l owi ng:
a. Presentat i on t o the pharmaci st. Schedul es Ì Ì Ì and Ì V cont r ol l ed- subst ance
pr escri pt i ons ar e val i d f or 6 mont hs f r om t he dat e of i ssuance by t he pr act i t i oner.
Schedul e Ì Ì cont r ol l ed- subst ance pr escri pt i ons have no t i me l i mi t f or pr esent at i on
under t he Act , al t hough t hey ar e of t en r ecogni zed t o be val i d f or up t o 6 mont hs.
Schedul e V cont r ol l ed-subst ance pr escr i pt i ons al so have no set t i me l i mi t f or
pr esent at i on under t he Act . Regardl ess of whi ch schedul e of cont rol l ed subst ance i s
i nvol ved, t he good- f ai t h and "l egi t i mat e medi cal pur pose¨ l i mi t at i on wi l l al ways appl y
and may ser ve t o ot her wi se l i mi t t he val i di t y of a pr escri pt i on.
b. I nformati on t hat must be recorded on t he prescri pt i on by t he di spensi ng
pharmaci st .
Under t he Act , a f i l l ed prescr i pt i on i s consi dered t o be a l awf ul r ecor d of di sposi t i on
f or a cont rol l ed subst ance. As a resul t , ever y pr escri pt i on f or a cont r ol l ed subst ance
must cont ai n cer t ai n i nf or mat i on. Some of t he i nf or mat i on wi l l al ready be cont ai ned
i n t he pr escri pt i on, al t hough t he di spensi ng pharmaci st i s responsi bl e f or ensur i ng
t hat al l of t he f ol l owi ng i nf ormat i on i s r ecorded (usual l y on t he f ace of t he
pr escri pt i on):
( 1) Name of t he cont r ol l ed subst ance
( 2) Fi ni shed f orm of t he cont r ol l ed subst ance ( dosage f or m and st r engt h)
( 3) Name and addr ess of t he person t o whom i t was di spensed
( 4) Dat e of di spensi ng
( 5) Number of uni t s or vol ume di spensed ( quant i t y)
( 6) Wri t t en or t ypewr i t t en name or i ni t i al s of t he i ndi vi dual who di spensed t he
cont r ol l ed subst ance
( 7) Seri al number of t he pr escri pt i on
c. Requi red i nf ormat i on on prescri pt i on I abeI s. Ever y pr escri pt i on l abel f or a
cont r ol l ed subst ance must i ncl ude t he f ol l owi ng i nf ormat i on:
( 1) Name and addr ess of t he phar macy
( 2) Seri al number assi gned t o t he pr escri pt i on
( 3) Dat e of t he i ni t i al f i l l i ng of t he pr escri pt i on ( f or r ef i l l s, t he dat e or i gi nal l y f i l l ed)
( 4) Name of t he pat i ent
( 5) Name of t he pr escr i bi ng pract i t i oner
( 6) Di rect i ons f or use, and caut i onar y st at ement s, i f any
( 7) For schedul e Ì Ì , Ì Ì Ì , and Ì V cont rol l ed subst ances, t he f eder al cri me t ransf er
war ni ng must appear on t he cont ai ner: " Caut i on: Federal l aw pr ohi bi t s t he t r ansf er
of t hi s drug t o any person ot her t han t he pat i ent f or whom i t was pr escri bed. ¨
d. AI I owabI e quant i ti es t hat may be di spensed. The Act cont ai ns no l i mi t at i on
concerni ng t he quant i t y of a cont rol l ed subst ance t hat may be di spensed pursuant t o
a pr escr i pt i on. Al l quant i t i es are, of course, l i mi t ed t o t he good- f ai t h and " l egi t i mat e
medi cal purpose¨ st andar ds.
e. Fi I i ng cont roI I ed subst ance prescri pt i ons. Wri t t en cont r ol l ed-subst ance
pr escri pt i ons must be mai nt ai ned at t he phar macy f or a peri od of 2 year s f r om t he
dat e of t he ori gi nal
P. 537

di spensi ng or l ast ref i l l , whi chever i s l at er . They must be avai l abl e f or i nspect i on
and copyi ng by empl oyees and agent s of t he DEA and be f i l ed segregated f rom al l
ot her r ecords i n one of t he f ol l owi ng ways ( st at e l aw usual l y di ct at es t he met hod t o
be used) :
( 1) Usi ng t hree separate f i I es as f ol l ows:
( a) One f i l e f or schedul e Ì Ì cont r ol l ed- subst ance pr escri pt i ons
( b) One f i l e f or schedul e Ì Ì Ì , Ì V, and V cont r ol l ed-subst ance pr escri pt i ons
( c) One f i l e f or unschedul ed pr escr i pt i on drugs
( 2) Usi ng two separat e fi I es as f ol l ows:
( a) One f i l e f or al l cont rol l ed- subst ance prescr i pt i ons ( Ì Ì - V), as l ong as schedul e Ì Ì Ì ,
Ì V, and V pr escr i pt i ons have t he l et t er " C¨ st amped i n r ed i nk i n t he l ower -r i ght
cor ner no l ess t han 1 i nch hi gh
( b) One f i l e f or unschedul ed prescr i pt i on dr ugs
( 3) Usi ng two separat e fi I es as f ol l ows:
( a) One f i l e f or schedul e Ì Ì cont r ol l ed- subst ance pr escri pt i ons
( b) One f i l e f or al l ot her cont r ol l ed subst ances ( Ì Ì Ì - V) and unschedul ed prescr i pt i on
dr ugs, as l ong as schedul e Ì Ì Ì , Ì V, and V pr escri pt i ons have t he l et t er " C¨ st amped
i n red i nk i n t he l ower - r i ght corner no l ess t han 1 i nch hi gh
( 4) Ì n ei t her ( 2) or (3) above, i f a phar macy ut i l i zes an el ect roni c recor d-keepi ng
syst em f or pr escri pt i ons ( i . e. , comput er i zed r ecords) , whi ch permi t s i dent i f i cat i on by
pr escri pt i on number and r et r i eval of or i gi nal document s by pr escr i ber ' s name,
pat i ent ' s name, dr ug di spensed, and dat e f i l l ed, t hen t he r equi rement t o mark t he
har d copy pr escr i pt i on wi t h a r ed " C¨ i s wai ved.
f . Ref i I I di spensi ng of cont roI I ed subst ances. Pr escr i pt i ons f or schedul e Ì Ì
cont r ol l ed subst ances may not be r ef i l l ed. Pr escri pt i ons f or schedul es Ì Ì Ì and Ì V
cont r ol l ed subst ances may be ref i l l ed up t o f i ve t i mes wi t hi n 6 mont hs f r om t he dat e
of i ssue of t he pr escr i pt i on. Schedul e V cont rol l ed- subst ance pr escr i pt i ons have no
l i mi t at i ons f or r ef i l l i ng under t he Act ; however , once agai n, t he good- f ai t h and
" l egi t i mat e medi cal purpose¨ l i mi t at i ons appl y her e, as wel l as t o al l cont rol l ed-
subst ance ref i l l s.
( 1) Ref i l l i nf ormat i on may be mai nt ai ned ei t her manual l y or by use of a comput er .
The Act requi r es t hat t he i nf or mat i on be mai nt ai ned one way or t he ot her , but not
bot h ways. Ì f comput eri zed ref i I I records ar e mai nt ai ned, t he syst em must have
cer t ai n capabi l i t i es and t he di spensi ng phar maci st must f ol l ow cer t ai n pr ocedur es.
( a) The comput er must be abl e t o pr ovi de on- l i ne r et r i eval of t he or i gi nal
pr escri pt i on i nf ormat i on, pr ovi de on- l i ne r et r i eval of t he ref i l l hi st or y, a ref i l l - by- r ef i l l
audi t t rai l , and an auxi l i ar y pr ocedur e i n t hose cases wher e t he syst em exper i ences
downt i me.
( b) The syst em must al so al l ow t he phar maci st who r ef i l l s a pr escr i pt i on t o
document t hat t he i nf or mat i on he or she ent er ed i nt o t he comput er i s cor rect .
( 2) When di spensi ng a ref i l l , t he phar maci st must r ecor d, on t he back of t he ori gi nal
pr escri pt i on or by comput er , t he f ol l owi ng i nf ormat i on:
( a) Dat e of t he ref i l l
( b) Name or i ni t i al s of t he r ef i l l i ng pharmaci st
( c) Amount of t he medi cat i on di spensed (i f t he amount i s omi t t ed, t he r ef i l l wi l l be
deemed t o have been f or t he f ul l f ace amount pr escri bed by t he pr act i t i oner )
g. MuI t i pI e scheduI e I I prescri pt i ons prescri bed on the same day t o be f i I I ed
sequent i aI I y. The r ef i l l of a pr escr i pt i on f or a cont r ol l ed subst ance l i st ed i n
schedul e Ì Ì i s pr ohi bi t ed. However , an i ndi vi dual pr act i t i oner may i ssue mul t i pl e
pr escri pt i ons aut hor i zi ng t he pat i ent t o r ecei ve a t ot al of up t o a 90- day suppl y of a
schedul e Ì Ì cont r ol l ed subst ance pr ovi di ng each pr escri pt i on i s i ssued f or a
l egi t i mat e medi cal purpose by an i ndi vi dual pract i t i oner act i ng i n t he usual course of
pr of essi onal pract i ce. The i ndi vi dual pract i t i oner pr ovi des wr i t t en i nst r uct i ons on
each prescr i pt i on ( ot her t han t he f i r st pr escr i pt i on, i f t he prescri bi ng pr act i t i oner
i nt ends f or t hat pr escr i pt i on t o be f i l l ed i mmedi at el y) i ndi cat i ng t he ear l i est dat e on
whi ch a phar macy may f i l l each prescri pt i on.
h. Parti aI di spensi ng of cont roI I ed substances. The Act does not prohi bi t t he
par t i al di spensi ng of cont r ol l ed subst ances i n schedul es Ì Ì Ì and Ì V, provi ded t hat
each par t i al f i l l i ng i s r ecor ded i n t he same manner as r ef i l l s, t he t ot al quant i t y
di spensed i n al l part i al f i l l i ngs does not exceed t he t ot al quant i t y pr escri bed, and no
par t i al f i l l i ng occurs af t er 6 mont hs f r om t he dat e of i ssuance of t he pr escr i pt i on.
Li kewi se, al l par t i al f i l l i ngs of a schedul e V pr escr i pt i on must not exceed t he t ot al
quant i t y pr escri bed.
( 1) Part i aI di spensi ng of a scheduI e I I cont roI I ed substance. The par t i al
di spensi ng of a schedul e Ì Ì prescri pt i on i s al l owed i f t he pharmaci st i s unabl e t o
suppl y t he f ul l
P. 538

quant i t y or t he pr escri pt i on i s f or a t er mi nal l y i l l pat i ent or a pat i ent i n a l ong-
t er mcare f aci l i t y ( LTCF) . Under no ot her ci rcumst ance may a schedul e Ì Ì
pr escri pt i on be part i al l y di spensed.
( a) I nadequate suppI y. Ì n cases of an i nadequat e suppl y, t he di spensi ng
pharmaci st must not e on t he f ace of t he pr escri pt i on t he amount di spensed. The
r emai ni ng bal ance of t he schedul e Ì Ì pr escr i pt i on must be di spensed wi t hi n 72 hour s
of t he f i r st par t i al f i l l i ng. Ì f , f or any r eason, t he bal ance i s not di spensed wi t hi n t he
72- hour peri od, t he pharmaci st must not i f y t he prescr i bi ng pract i t i oner of t hi s f act .
The pharmaci st may not di spense any f ur t her amount s pursuant t o t hi s prescr i pt i on
beyond t he 72- hour per i od.
( b) Termi naI I y i I I and pat i ents i n LTCFs. Ì t i s t he pharmaci st ' s r esponsi bi l i t y t o
ensur e t hat a pat i ent has a medi cal di agnosi s document i ng a t ermi nal i l l ness or t hat
t he pat i ent i s i n an LTCF. Bef or e any par t i al di spensi ng, t he pharmaci st must recor d
on t he pr escri pt i on whet her t he pat i ent i s "t ermi nal l y i l l ¨ or an "LTCF pat i ent . ¨ Any
par t i al di spensi ng wi t hout one of t hese not at i ons shal l be deemed t o be a
di spensi ng i n vi ol at i on of t he Act . The t ot al amount of t he schedul e Ì Ì subst ance
di spensed i n al l part i al f i l l i ngs must not exceed t he t ot al quant i t y prescr i bed.
Schedul e Ì Ì prescr i pt i ons f or a t er mi nal l y i l l pat i ent or a pat i ent i n an LTCF ar e val i d
up t o 60 days f rom t he dat e of i ssuance of t he prescr i pt i on by t he pr act i t i oner . Al l of
t he f ol l owi ng i nf or mat i on must be recor ded, ei t her manual l y on t he back of t he
pr escri pt i on or vi a comput er ( wi t h si mi l ar capabi l i t i es requi r ed f or comput er i zed
r ef i l l recor d keepi ng), when par t i al l y di spensi ng a schedul e Ì Ì pr escr i pt i on f or a
t er mi nal l y i l l pat i ent or a pat i ent i n an LTCF:
( i ) Dat e of t he par t i al f i l l i ng
( i i ) Quant i t y of dr ug di spensed
( i i i ) Remai ni ng quant i t y aut hor i zed t o be di spensed
( i v) Ì dent i f i cat i on of t he di spensi ng phar maci st
i . Transf er of refi I I i nf ormat i on f or a cont roI I ed- subst ance prescri pt i on. Ref i l l
i nf or mat i on concerni ng schedul es Ì Ì Ì , Ì V, and V cont r ol l ed subst ances may be
t r ansf er red t o anot her phar macy onl y once ( i f al l owed by st at e l aw) . Pharmaci es
el ect r oni cal l y shari ng a real t i me, on-l i ne dat abase ( such as chai n phar maci es) may
t r ansf er r ef i l l i nf ormat i on f or t hese cont r ol l ed subst ances up t o t he maxi mum
number of ref i l l s permi t t ed by l aw and t he prescri ber ' s aut hor i zat i on. The
communi cat i on must be made di r ect l y bet ween t wo l i censed pharmaci st s. Bot h t he
or i gi nal pr escri pt i on and t he t r ansf er r ed prescr i pt i on must be mai nt ai ned f or 2 year s
f r om t he dat e of t he l ast r ef i l l . Cer t ai n i nf ormat i on must be r ecorded as f ol l ows:
( 1) The t ransferri ng pharmaci st must :
( a) Wri t e t he wor d " voi d¨ on t he f ace of t he or i gi nal pr escri pt i on
( b) On t he back of t he prescr i pt i on, recor d t he name, addr ess, and DEA regi st r at i on
number of t he phar macy t o whi ch i t was t r ansf er red and t he name of t he pharmaci st
r ecei vi ng t he i nf or mat i on
( c) Record t he dat e of t he t r ansf er and t he name of t he t ransf err i ng pharmaci st
( 2) The recei vi ng pharmaci st must :
( a) Wri t e t he wor d " t ransf er ¨ on t he f ace of t he t ransf er red pr escri pt i on
( b) Recor d al l of t he i nf or mat i on r equi red f or any cont r ol l ed- subst ance prescri pt i on
( see Ì . Ì . 3) , and i ncl ude t he f ol l owi ng:
( i ) Dat e of i ssuance of t he ori gi nal prescr i pt i on
( i i ) Or i gi nal number of r ef i l l s aut hori zed on t he ori gi nal pr escr i pt i on
( i i i ) Dat e t he pr escr i pt i on was i ni t i al l y di spensed
( i v) Number of val i d ref i l l s remai ni ng and t he dat e of t he l ast r ef i l l
( v) Phar macy' s name, addr ess, DEA r egi st r at i on number , and ori gi nal pr escri pt i on
number f r om whi ch t he pr escr i pt i on i nf or mat i on was t r ansf er r ed
( vi ) Name of t he t r ansf err i ng phar maci st
J. Di sposaI of cont roI I ed subst ances t o a pat i ent wi t hout a prescri pt i on.
Cont r ol l ed subst ances t hat are not pr escri pt i on ( or l egend) drugs under f eder al l aw
may be di spensed t o a pat i ent at ret ai l wi t hout a pr escri pt i on. These drugs do not
have on t he manuf act ur er ' s l abel t he f eder al st at ement : " Caut i on: Feder al l aw
pr ohi bi t s di spensi ng wi t hout a prescr i pt i on. ¨ The subst ances may be di spensed
wi t hout a prescr i pt i on i n accor dance wi t h t he f ol l owi ng:
P. 539


1. The di spensi ng must be made onl y by a l i censed pharmaci st . The act ual cash
t r ansf er or del i ver y may be made by a nonpharmaci st .
2. Not mor e t han 8 oz of any subst ance cont ai ni ng opi um, 4 oz of any ot her
cont r ol l ed subst ance, 48 dosage uni t s of any subst ance cont ai ni ng opi um, or 24
dosage uni t s of any ot her cont r ol l ed subst ance may be di spensed t o t he same
pur chaser i n any 48- hour peri od.
3. The purchaser i s at l east 18 year s ol d.
4. Any purchaser not known t o t he pharmaci st must f urni sh sui t abl e i dent i f i cat i on.
5. A bound recor d book must be mai nt ai ned f or 2 year s f r om t he dat e of t he l ast
ent r y. The f ol l owi ng i nf ormat i on must be r ecorded f or each purchase:
a. Name and addr ess of t he purchaser
b. Name and quant i t y of cont r ol l ed subst ance purchased
c. Dat e of each pur chase
d. Name or i ni t i al s of t he pharmaci st who di spensed t he subst ance t o t he pur chaser
6. Al l di spensi ng of a cont r ol l ed subst ance wi t hout a pr escr i pt i on must be done i n
good f ai t h and not t o evade t he pr ovi si ons of t he Act .
K. Securi t y consi derat i ons
1. Cont roI I ed- substance seaI s. Manuf act urer s must package cert ai n cont r ol l ed
subst ances i n a cont ai ner wi t h a securel y af f i xed seal t o r eveal any t amper i ng.
Ever y bot t l e, mul t i pl e- dose vi al , or ot her commerci al cont ai ner of any cont r ol l ed
subst ance l i st ed i n schedul e Ì Ì , or of any nar cot i c cont rol l ed subst ance l i st ed i n
schedul e Ì Ì Ì or Ì V, must be packaged wi t h such a seal .
2. FeI ony convi ct i ons. No DEA r egi st r ant may empl oy an i ndi vi dual who has access
t o cont r ol l ed subst ances i f t hat i ndi vi dual had previ ousl y been convi ct ed of a f el ony
of f ense r el at ed t o cont r ol l ed subst ances.
3. Manufacturer' s I abeI . Ever y commer ci al cont ai ner of a cont r ol l ed subst ance
must have on i t s l abel t he symbol desi gnat i ng t he schedul e i n whi ch t he cont r ol l ed
subst ance i s l i st ed. The symbol must appear i n t he upper - r i ght corner of t he l abel or
be overpr i nt ed on t he l abel .
L. Record mai ntenance. Al l recor ds requi r ed t o be mai nt ai ned under t he Act must
be kept by t he regi st rant f or 2 years. The r ecor ds may be mai nt ai ned at a cent r al
l ocat i on (e. g. , at a chai n pharmacy' s regi onal of f i ce) af t er not i f yi ng t he DEA.
However , execut ed DEA 222 Forms ( Copy 3) , al l cont r ol l ed- subst ance prescri pt i ons,
and al l i nvent or i es must be mai nt ai ned at t he phar macy, not cent r al l y. Al l schedul e
Ì Ì cont rol l ed-subst ance records must be mai nt ai ned separ at el y and readi l y
r et r i evabl e f rom al l ot her r ecor ds.
M. DEA i nspect i ons. Ì nspect i ons by t he DEA of any r egi st er ed f aci l i t y may be
conduct ed onl y i n a r easonabl e manner and duri ng r egul ar busi ness hours.
Ì nspect i on may be conduct ed af t er obt ai ni ng consent of t he regi st rant or af t er t he
DEA has obt ai ned an admi ni st r at i ve war r ant f r om a j udge. An appl i cat i on f or an
admi ni st rat i ve war r ant must st at e wi t h speci f i ci t y t he nat ur e, ext ent , and aut hori t y t o
conduct t he request ed i nspect i on. The scope of an admi ni st r at i ve i nspect i on
ext ends t o any r ecor ds requi r ed under t he Act , equi pment and cont ai ner s used i n
t he handl i ng of cont r ol l ed subst ances, and t he ver i f i cat i on of compl i ance wi t h any
r equi r ement of t he Act . Ì f r ecor ds ar e removed f rom t he r egi st r ant by t he DEA, a
r ecei pt gi ven t o t he regi st r ant wi l l l i st t he i t ems t aken.
N. Long- t erm-care f aci I i t i es ( LTCFs) . An LTCF i s def i ned as a nursi ng home,
r et i rement care, ment al car e, or ot her f aci l i t y or i nst i t ut i on t hat pr ovi des ext ended
heal t h care t o r esi dent pat i ent s. LTCFs are not nor mal l y regi st er ed wi t h t he DEA,
al t hough t hey of t en mai nt ai n cont rol l ed subst ances t hat are di spensed t o a pat i ent
by pr escri pt i on f r om a phar macy. They are not requi red t o be regi st er ed wi t h t he
DEA because t he cont rol l ed subst ance i s di spensed t o t he ul t i mat e user ( t he
pat i ent ) and i s not i ssued by or t hrough t he LTCF. When di sposi ng of cont r ol l ed
subst ances, LTCFs must cont act t he near est DEA Di ver si on Fi el d Of f i ce f or di sposal
i nst r uct i ons.
P. 540


1. Emergency ki t s f or LTCFs. An LTCF may mai nt ai n cont r ol l ed subst ances i n
emergency ki t s so l ong as st at e l aw speci f i cal l y appr oves of such use and t he st at e
set s f or t h pr ocedures t hat r equi r e t he f ol l owi ng:
a. Source of suppI y: The LTCF must obt ai n cont r ol l ed subst ances f or t he
emergency ki t s f rom a DEA- r egi st er ed hospi t al / cl i ni c, pharmacy, or pract i t i oner .
b. Securi t y saf eguards: Access t o each emergency ki t i n t he LTCF must be
r est ri ct ed, and t he t ype and quant i t y of cont r ol l ed subst ances t hat may be pl aced i n
t he emer gency ki t must be speci f i cal l y l i mi t ed.
c. Proper cont roI , account abi I i t y, and record keepi ng: The LTCF and t he
pr ovi di ng DEA- r egi st ered hospi t al / cl i ni c, pharmacy, or pr act i t i oner must mai nt ai n
compl et e and accur at e records of t he cont rol l ed subst ances pl aced i n t he
emergency ki t , i ncl udi ng t he di sposi t i on of t hese cont r ol l ed subst ances, as wel l as
t ake per i odi c physi cal i nvent or i es of t he drugs.
d. Admi ni st rat i on of cont roI I ed substances. Ì n emer gency medi cal si t uat i ons
when medi cat i on i s needed f rom t he emergency ki t , onl y LTCF personnel who ar e
aut hor i zed by an i ndi vi dual pr act i t i oner can admi ni st er t he cont rol l ed subst ances.
e. Prohi bi ted act i vi t i es: Pr ohi bi t ed act i vi t i es can r esul t i n t he st at e r evocat i on,
deni al , or suspensi on of havi ng emergency ki t s cont ai ni ng cont rol l ed subst ances i n
an LTCF.
O. Vi oI at i ons under the Act . Penal t i es f or vi ol at i ons of t he Feder al Cont rol l ed
Subst ances Act depend on t he schedul e of cont rol l ed subst ance i nvol ved, t he
unl awf ul act , and t he knowI edge and i nt ent of the vi oI ator. Ì t wi l l al so depend on
whet her i t i s a f i r st of f ense or a subsequent of f ense.
1. Ci vi I penaI t y. Gener al l y, each vi ol at i on of t he Act may subj ect an i ndi vi dual t o a
ci vi l penal t y ( f i ne) of up t o $10, 000. The gover nment must pr ove t hat t he vi ol at or
was negl i gent wi t h r espect t o compl i ance under t he Act , as opposed t o mer e
mi st ake or i nadver t ence.
2. I mpri sonment . Ì f an i ndi vi dual knowi ngl y and i nt ent i onal l y vi ol at es t he Act , he or
she may be sent enced t o a t er m of year s, i n addi t i on t o a ci vi l penal t y.
II. FEDERAL FOOD, DRUG, AND COSMETIC ACT (FDCA).
Ì n 1937, sul f ani l ami de el i xi r cont ai ni ng deadl y di et hyl ene gl ycol (aut omobi l e
ant i f r eeze) was manuf act ur ed wi t hout any saf et y dat a. Ther e wer e numerous deat hs
associ at ed wi t h i t s use, whi ch prompt ed t he f eder al gover nment t o pass t he 1938
FDCA. The FDCA requi res t hat al l new dr ug pr oduct s i nt ended f or use as l abel ed by
t he manuf act ur er i n t he Uni t ed St at es must be proven t o t he f ederal gover nment t o
be saf e and ef f ect i ve. Such pr oof i s submi t t ed t o t he Food and Drug Admi ni st r at i on
( FDA) by use of a New Dr ug Appl i cat i on ( NDA).
A. Def i ni t i on. Under t he FDCA, t he t er m " drug¨ i s def i ned as i ncl udi ng al l of t he
f ol l owi ng:
1. Ar t i cl es r ecogni zed i n t he of f i ci al Uni t ed St at es Phar macopei a ( USP) , of f i ci al
Homeopat hi c Phar macopoei a of t he Uni t ed St at es, or of f i ci al Nat i onal Formul ar y, or
any suppl ement t o t hese
2. Ar t i cl es i nt ended f or use i n t he di agnosi s, cur e, mi t i gat i on, t reat ment , or
pr event i on of di sease i n man or ot her ani mal s
3. Ar t i cl es ( ot her t han f ood) i nt ended t o af f ect t he st r uct ure or any f unct i on of t he
body of man or ot her ani mal s
4. Ar t i cl es i nt ended f or use as a component of any ar t i cl e speci f i ed i n 1, 2, or 3
above
B. Legend drugs. Legend dr ugs ar e t hose medi cat i ons t hat have on t hei r l abel f r om
t he manuf act ur er t he f ol l owi ng f ederal l y requi r ed st at ement : " Rx onl y. ¨ Such
medi cat i ons may be di spensed di rect l y t o t he pat i ent by means of a val i d wr i t t en or
or al pr escr i pt i on f rom a pr act i t i oner or by a val i d r ef i l l aut hori zat i on of ei t her . By
l aw, t hese medi cat i ons must bear a l abel wi t h adequat e di r ect i ons f or use, whi ch
can onl y be gi ven by a l i censed pract i t i oner and, t her ef ore, t he requi r ement of a
pr escri pt i on. A dr ug, i nt ended f or use by humans, i s consi der ed a l egend dr ug ( and
have t he above caut i on on i t s l abel ) i f any of t he f ol l owi ng appl y:
1. Because of t he drug' s t oxi ci t y or ot her pot ent i al f or a harmf ul ef f ect , or i t s met hod
of use, or col l at eral measur es necessar y t o i t s use, i t i s not saf e f or use except
under the supervi si on of a pr act i t i oner l i censed by l aw t o admi ni st er such dr ug.
P. 541


2. The dr ug i s a new drug f or whi ch an appr oved NDA l i mi t s i t s use t o t he
pr of essi onal super vi si on of a pr act i t i oner l i censed by l aw t o admi ni st er such dr ug. A
new dr ug i s br oadl y def i ned as bei ng one t hat gener al l y i s not recogni zed among
exper t s as saf e and ef f ect i ve f or use under t he condi t i ons prescr i bed,
r ecommended, or suggest ed i n t he l abel i ng. Ì t i s al so def i ned as bei ng a dr ug t hat ,
as a r esul t of i nvest i gat i ons t o det er mi ne i t s saf et y and ef f ect i veness f or use under
such condi t i ons, has become so r ecogni zed but t hat has not , ot her t han i n t he
i nvest i gat i ons, been used t o a mat er i al ext ent or f or a mat eri al t i me under such
condi t i ons. Fi nal l y, a new dr ug may r esul t f r om a change i n t he dosage f or m,
l abel i ng, i ndi cat i ons, or any ot her change i n a drug product t hat i s al ready bei ng
market ed. The ul t i mat e deci si on of whet her a drug i s a new dr ug l i es wi t h t he FDA
because of i t s exper t i se i n resol vi ng t echni cal and sci ent i f i c quest i ons.
a. NDA. Ever y new dr ug market ed i n t he Uni t ed St at es must be saf e and ef f ect i ve
f or i t s i nt ended use as l abel ed by t he manuf act urer . Pr oof of saf et y and
ef f ect i veness must be submi t t ed t o t he FDA by t he manuf act urer vi a t he NDA. When
a new chemi cal ent i t y ( NCE) i s i dent i f i ed by a manuf act ur er , t he manuf act ur er must
obt ai n an Ì nvest i gat i onal New Dr ug Appl i cat i on ( Ì ND) bef or e conduct i ng pr ecl i ni cal
ani mal t est s and cl i ni cal human i nvest i gat i ons.
b. I ND. Because an NCE has not yet been approved by t he FDA as a saf e and
ef f ect i ve drug, a manuf act urer i s requi r ed t o f i l e an Ì ND wi t h t he FDA. The Ì ND
al l ows a manuf act ur er t o conduct research wi t h t he NCE and exempt s t he dr ug f r om
cer t ai n prohi bi t i ons of t he FDCA i n or der t o f aci l i t at e cl i ni cal i nvest i gat i ons; t hus,
Ì NDs are somet i mes ref er r ed t o as an Ì nvest i gat i onal New Dr ug Exempt i on.
Gener al l y, cl i ni cal i nvest i gat i on of an NCE i s di vi ded i nt o t hr ee phases, wi t h each
phase i nvol vi ng a gr eat er number of human subj ect s.
( 1) Phase 1. A phase 1 i nvest i gat i on i s t he i ni t i al i nt roduct i on of an i nvest i gat i onal
new dr ug i nt o humans t o det er mi ne t he met abol i sm, pharmacol ogy, si de ef f ect s,
mechani sm of act i on, and earl y evi dence on ef f ect i veness.
( 2) Phase 2. A phase 2 i nvest i gat i on i ncl udes t he wel l - cont rol l ed, cl osel y moni t ored
cl i ni cal st udi es i n order t o eval uat e t he ef f ect i veness of t he drug f or a par t i cul ar
i ndi cat i on and t o f ur t her det ermi ne si de ef f ect s and ri sks.
( 3) Phase 3. A phase 3 i nvest i gat i on i ncl udes expanded cl i ni cal t r i al s t o gat her
addi t i onal i nf ormat i on concerni ng saf et y, ef f ect i veness, and t he over al l benef i t - ri sk
r el at i onshi p associ at ed wi t h t he dr ug' s use. Thi s phase al so i ncl udes gat her i ng
i nf or mat i on t o provi de an adequat e basi s f or physi ci an l abel i ng.
c. Treat ment I NDs (or t reat ment prot ocoI s). The FDA may al l ow a t r eat ment Ì ND,
whi ch al l ows a r esear cher ( physi ci an) t o use an i nvest i gat i onal drug as t reat ment i n
ser i ous and l i f e- t hr eat eni ng di seases wher e no compar abl e or sat i sf act ory
al t er nat i ve dr ug or ot her t her apy i s avai l abl e.
C. Over- t he- count er ( OTC) medi cat i ons. Cer t ai n medi cat i ons may be di spensed
OTC at r et ai l di st r i but or s wi t hout a pr escri pt i on. The f ederal government has
det ermi ned t hat t hese medi cat i ons may be saf el y and pr operl y sel f -admi ni st ered
wi t hout t he super vi si on of a pr act i t i oner l i censed by l aw t o admi ni st er (or pr escri be)
such a drug. General l y, t hese medi cat i ons are not habi t -f ormi ng and have a l ow
t oxi ci t y or ot her pot ent i al f or a harmf ul ef f ect . These medi cat i ons do not have t he
f ederal st at ement " Rx onl y¨ on t hei r l abel (see Ì Ì . B) .
1. OTC pr epar at i ons must have adequat e di recti ons f or use on t hei r l abel , and t he
pr oduct must compl y wi t h t he appl i cabl e FDA monograph. The FDCA r equi r es al l
dr ugs market ed i n t he Uni t ed St at es t o be general l y recogni zed as saf e and
ef f ect i ve. As a r esul t , i t convened r evi ew panel s t o r evi ew OTC dr ug ef f ect i veness
and cr eat e monogr aphs f or each t her apeut i c cl ass of OTC dr ugs. Thi s r evi ew i s
r ef er red t o as t he Dr ug-Ef f i cacy (or Ef f ect i veness) St udy Ì mpl ement at i on ( DESÌ ) . Al l
OTC dr ugs must compl y wi t h t he appl i cabl e drug monograph or be consi der ed
mi sbr anded (see Ì Ì . Ì ) and subj ect t o FDA regul at or y act i on.
2. OTC pr epar at i ons must have t he f ol l owi ng i nf or mat i on on i t s l abel :
a. Ì dent i t y, i n bol d f ace, of t he OTC pr oduct on t he pri nci pal di spl ay panel
b. Adequat e di rect i ons f or use
c. Ì ngredi ent s (i ncl udi ng i nert or i nact i ve i ngredi ent s) i n t he product
d. Net quant i t y of cont ent s
e. Expi r at i on dat e of t he pr oduct
f . Lot number of t he pr oduct
g. Name and pl ace of busi ness of t he manuf act urer , packer, or di st ri but or
P. 542


h. Di scl osure of cer t ai n cont ent s and t he decl arat i on of cer t ai n war ni ngs, i ncl udi ng
habi t - f or mi ng i ngr edi ent s and war ni ngs, pr egnancy/ nur si ng war ni ngs, and aspi r i n
war ni ngs
3. Prescri pti on drug conversi on to OTC. A l egend drug wi l l conver t t o an OTC
dr ug when t he FDA f i nds t hat t he prescr i pt i on-onl y l i mi t at i on i s not necessar y f or
t he pr ot ect i on of t he publ i c heal t h by reason of t he dr ug' s t oxi ci t y or ot her pot ent i al
f or har mf ul ef f ect , t he met hod of i t s use, or t he col l at eral measur es necessar y t o i t s
use. The FDA must al so f i nd t hat t he dr ug i s saf e and ef f ect i ve f or use i n sel f -
medi cat i on as di rect ed i n pr oposed l abel i ng.
4. Mi sceI I aneous reguI at i ons f or OTCs.
a. I pecac syrup. Al t hough i pecac syrup can onl y be di spensed pursuant t o a
pr escri pt i on, t he FDA bel i eves t hat i t shoul d be r eadi l y avai l abl e OTC as an
emergency t reat ment emet i c f or use i n poi soni ngs. The FDA al l ows t he OTC sal e of
i pecac syr up i n 1 f l ui d ounce cont ai ners so t hat i t wi l l be r eadi l y avai l abl e i n t he
househol d f or emergency t r eat ment of poi soni ngs, under medi cal super vi si on, and
t hat t he drug be appropri at el y packaged and l abel ed f or t hi s pur pose.
b. Pregnancy- nursi ng warni ng. Al l OTC dr ugs i nt ended f or syst emi c absor pt i on
must cont ai n a war ni ng t hat i f t he user i s pr egnant or nursi ng a baby, she shoul d
f i r st seek t he advi ce of a heal t h pr of essi onal bef or e usi ng t he pr oduct . Except i ons
t o t hi s l abel i ng requi r ement exi st when an OTC i s i nt ended t o benef i t t he f et us or
nur si ng i nf ant , and f or OTC dr ugs t hat are l abel ed excl usi vel y f or pedi at ri c use.
c. Aspi ri n warni ngs. Al l OTC aspi ri n cont ai ni ng pr epar at i ons must have a war ni ng
t o keep out of chi l dr en' s r each and t o cont act a physi ci an i mmedi at el y i n case of
acci dent al over dose. Oral or r ect al OTC aspi ri n cont ai ni ng pr epar at i ons must al so
have a war ni ng concer ni ng Reye' s syndr ome i n chi l dr en and t eenager s.
d. Chemi caI s and precursors. Ì t was di scovered t hat combi nat i on dr ug pr oduct s
cont ai ni ng ephedr i ne, pseudoephedri ne, or phenyl pr opanol ami ne ar e t he pr ecur sor
mat er i al s used by i l l egal met hamphet ami ne l aborat or i es. The Compr ehensi ve
Met hamphet ami ne Cont rol Act of 1996 r equi res al l ret ai l di st r i but or s of t hese OTC
pr oduct s t o f ul f i l l cer t ai n obl i gat i ons. A ret ai l di st r i but or i ncl udes a gr ocery st or e,
gener al mer chandi se st or e, a phar macy, or any ot her ent i t y or person who sel l s
t hese i t ems t o cust omers f or per sonal use. For regul at ed t ransact i ons, a r et ai l er
must mai nt ai n a recor d of t hese t r ansact i ons f or a peri od of 2 year s, must obt ai n
pr oof of i dent i t y f rom cust omers, and must r eport suspi ci ous regul at ed sal es
i mmedi at el y t o t he DEA. The r ecor d must be mai nt ai ned separat el y f r om ot her
r ecor ds of cont rol l ed subst ances, and t he DEA suggest s t hat t he r ecor d be made i n
a bound l og book si mi l ar t o t he recor d kept f or t he sal e of OTC cont rol l ed
subst ances ( see Ì J) . The f ol l owi ng si ngl e t ransact i ons of t hese product s i n t he
amount s st at ed ar e consi dered t o be " regul at ed t r ansact i ons. ¨
( 1) PhenyI propanoI ami ne ( PPA) . PPA i s no l onger i n any OTC dr ug pr oduct .
( 2) Pseudoephedri ne. Sal es of combi nat i on pr oduct s cont ai ni ng more t han 24 g of
pseudoephedri ne. Bl i st er- pack sal es of t hese product s exceedi ng 24 g are not
r egul at ed sal es.
( 3) Ephedri ne. Sal es of combi nat i on product s cont ai ni ng more t han 24 g of
ephedr i ne and aI I si ngl e- ent i t y ephedr i ne product s regardl ess of t he amount of
ephedr i ne (mor e t han zer o grams) .
D. Generi c drugs
1. Def i ni t i on. The generi c name of a drug has been def i ned as i t s chemi cal name, a
common name, or an of f i ci al name used i n an of f i ci al compendi um. A manuf act urer
seeki ng appr oval f r om t he FDA f or a drug t hat has al r eady been pr oven t o be saf e
and ef f ect i ve may f i l e an Abbrevi at ed New Dr ug Appl i cat i on ( ANDA).
2. ANDA. A f i l i ng of an ANDA al l ows t he appr oval of a drug f or whi ch exhaust i ve
saf et y and ef f i cacy st udi es have al r eady been per f or med. A drug i s consi der ed t o be
t he same as an appr oved dr ug when t he t wo ar e i dent i cal i n act i ve i ngr edi ent ( s) ,
dosage f orm, st rengt h, rout e of admi ni st r at i on, i ndi cat i ons, and condi t i ons of use.
Ri gorous ani mal and human dat a t o det ermi ne saf et y and ef f ect i veness ar e not
r equi r ed i n t he ANDA. However , i nf or mat i on showi ng t hat t he gener i c versi on of t he
dr ug i s bi oavai l abl e and bi oequi val ent t o t he pi oneer (or i gi nal ) dr ug i s necessar y.
Such appr oved drugs are l i st ed by t he FDA i n t he " Appr oved Dr ug Pr oduct s wi t h
Ther apeut i c Equi val ence Eval uat i ons, ¨ commonl y r ef err ed t o as t he FDA Or ange
Book ( because i t comes f r om t he FDA i n an or ange bi nder ) .
P. 543


E. Propri et ar y drugs. The propri et ar y name of a dr ug i s t he name gi ven by t he
manuf act ur er t o desi gnat e t he drug' s source of manuf act ur e and t o di f f er ent i at e i t
f r om t he same or chemi cal l y si mi l ar dr ugs f r om ot her manuf act ur ers. Anot her name
f or t he pr opr i et ar y name of a dr ug i s i t s t r ade name.
F. EstabI i shed names for drugs. The FDCA aut hor i zes t he Commi ssi oner of t he
FDA t o desi gnat e an of f i ci al name f or any dr ug i f he det er mi nes t hat such act i on i s
necessar y or desi r abl e i n t he i nt erest of usef ul ness and si mpl i ci t y. The FDCA al so
r equi r es t hat a drug' s est abl i shed name appear on t he l abel and l abel i ng of t he
dr ug. A drug' s est abl i shed name i s def i ned as f ol l ows:
1. Ì t may be an of f i ci aI name desi gnat ed by t he Commi ssi oner of Food and Dr ugs.
For NCEs, t he name shoul d be si mpl e and usef ul . Ì n t hi s regar d, t he FDA
r ecogni zes t he U. S. Adopt ed Names Counci l ( USAN) i n deri vi ng names f or NCEs.
The USAN name i s consi der ed t o be an of f i ci al name r ecogni zed i n an of f i ci al
compendi um. The FDA may use anot her name i f t he USAN or common or usual
name i s undul y compl ex, mi sl eadi ng, or i s not usef ul f or any ot her r eason.
2. Ì f no of f i ci al name has been desi gnat ed f or t he dr ug and t he dr ug i s an ar t i cl e
r ecogni zed i n an of f i ci al compendi um, t hen t he off i ci aI t i tI e cont ai ned i n t he
compendi um may be t he est abl i shed name.
3. Ì f nei t her of t he above t wo appl y, t hen t he common or usuaI name of t he drug
may be i t s est abl i shed name.
G. Di spensi ng a prescri pt i on drug. A prescr i pt i on drug may be di spensed onl y by
a pr act i t i oner or by a phar maci st pursuant t o a wr i t t en or oral pr escri pt i on of a
pr act i t i oner , or a r ef i l l of ei t her . The prescr i pt i on l abel on t he cont ai ner di spensed t o
t he pat i ent must cont ai n cer t ai n i nf ormat i on, or i t wi l l be consi der ed mi sbranded and
di spensed i n vi ol at i on of t he FDCA. Thi s i nf ormat i on i s mi ni mal under t he FDCA and
i s usual l y suppl ement ed by st at e l aws, whi ch r equi r e mor e i nf or mat i on. So l ong as
t hi s i nf ormat i on i s i n Engl i sh, t he di spensi ng pharmaci st wi l l be i n compl i ance wi t h
t he FDCA. Ì f any of t he requi r ed i nf ormat i on i s i n anot her l anguage, t hen al l of t he
r equi r ed i nf ormat i on must be i n t hat l anguage. The pr escr i pt i on must al so be
packaged i n a chi l d- r esi st ant cont ai ner as requi r ed under t he Poi son Prevent i on
Packagi ng Act (see Ì Ì Ì ). The f ol l owi ng i nf or mat i on must appear on ever y pr escri pt i on
l abel :
1. Name and addr ess of t he pharmacy
2. Seri al number of t he pr escr i pt i on
3. Dat e t he pr escri pt i on i s f i l l ed or t he dat e of t he pr escri pt i on
4. Name of t he pr escr i ber
5. Name of t he pat i ent (i f st at ed i n t he pr escri pt i on)
6. Di rect i ons f or use and any caut i onar y st at ement s cont ai ned i n t he pr escr i pt i on
H. Drug recaI I . The FDCA al l ows t he FDA t o i ni t i at e regul at or y act i ons t o ensur e
t hat unsaf e, unf i t , or i nef f ect i ve pr oduct s do not reach t he market , or t o prompt l y
r emove t hose product s t hat do reach t he mar ket pl ace. The enf orcement act i ons t hat
may be i ni t i at ed i ncl ude t he rel ease of i nf ormat i on t o t he general publ i c and/ or
pr of essi onal groups; admi ni st r at i ve act i ons and i nspect i ons; t he i nst i t ut i on of r ecal l ;
or sei zure, i nj unct i on, or cr i mi nal prosecut i on.
1. VoI unt ar y act i on of the manufact urer. Af t er sever al unsuccessf ul at t empt s by
t he FDA t o r ecei ve cour t - or dered r ecal l s, t he FDA r ecogni zes t hat recal l s ar e
vol unt ar y act i ons of t he manuf act ur ers and di st r i but ors. As a r esul t , a recal l may be
under t aken at any t i me, or upon r equest of t he FDA. Ì f t he FDA i s unsuccessf ul i n
per suadi ng a company t o r ecal l a product , or when t he FDA det ermi nes t hat a r ecal l
i s or wi l l be i nef f ect i ve, i t may seek a court order condemni ng t he product and
al l owi ng t he pr oduct ' s sei zur e.
2. Drug recaI I cI assi f i cat i on. Af t er t he FDA has eval uat ed t he pr obl em( s)
associ at ed wi t h t he product and af t er t he degr ee of heal t h hazar d has been
det ermi ned, t he FDA wi l l assi gn t he r ecal l one of t he f ol l owi ng cl assi f i cat i ons:
a. CI ass I -a si t uat i on i n whi ch t here i s a r easonabl e probabi l i t y t hat t he use of or
exposur e t o a vi ol at i ve pr oduct wi l l cause seri ous adverse heal t h consequences or
deat h
P. 544


b. CI ass I I -a si t uat i on i n whi ch use of or exposur e t o a vi ol at i ve pr oduct may cause
t empor ar y or medi cal l y rever si bl e adver se heal t h consequences or where t he
pr obabi l i t y of seri ous heal t h consequences i s r emot e
c. CI ass I I I -a si t uat i on i n whi ch use of or exposur e t o a vi ol at i ve pr oduct i s not
l i kel y t o cause adverse heal t h consequences
3. RecaI I procedure. A recal l st rat egy wi l l be devel oped t hat wi l l consi der t he dept h
of t he recal l ( consumer l evel , ret ai l l evel , whol esal e l evel ) , t he need f or publ i c
war ni ngs, and t he ext ent of ef f ect i veness checks f or t he recal l . Ever y r ecal l i ng
company i s r esponsi bl e f or not i f yi ng each of i t s af f ect ed di r ect account s by f i r st -
cl ass mai l , mai l gram, or t el egr am. Publ i c not i f i cat i on i s made by t he FDA vi a t he
weekl y FDA Enf orcement Report , whi ch publ i shes each recal l accor di ng t o i t s
cl assi f i cat i on.
I . AduI t erati on and mi sbrandi ng. A mi sbr andi ng or adul t er at i on of a dr ug i s
pr ohi bi t ed by t he FDCA. Al t hough t he mi sbr andi ng and adul t erat i on pr ovi si ons are
mai nl y concerned wi t h t he manuf act uri ng of a dr ug, a phar maci st may al so mi sbr and
or adul t er at e a drug. The pur pose of t he mi sbrandi ng and adul t er at i on st at ut es i s t o
pr ot ect t he publ i c heal t h of consumers who are l ar gel y unabl e t o pr ot ect t hemsel ves
wher e dr ugs ar e i nvol ved. The adul t erat i on and mi sbr andi ng st at ut es are cr i mi nal i n
nat ure and may subj ect a phar maci st t o cri mi nal pr oceedi ngs i n f eder al cour t , i n
addi t i on t o admi ni st r at i ve pr oceedi ngs.
1. AduI t erati on. Ì n gener al , t he t erm adul t erat i on r ef ers t o a change or var i at i on
f r om of f i ci al f or mul ar y st andar ds or f r om t he manuf act urer ' s st andar ds. A dr ug i s
consi dered adul t erat ed i f any of t he f ol l owi ng condi t i ons occur :
a. Ì f t he drug consi st s i n whol e or i n par t of any f i l t hy, put r i d, or decomposed
subst ance
b. Ì f t he drug has been pr epared, packed, or hel d under unsani t ar y condi t i ons wher e
i t may have been cont ami nat ed wi t h f i l t h or render ed i nj ur i ous t o heal t h
c. Ì f t he drug' s cont ai ner i s composed, i n whol e or i n par t , of any poi sonous or
del et eri ous subst ance t hat may r ender t he cont ent s i nj uri ous t o heal t h
d. Ì f t he drug cont ai ns, f or pur poses of col or i ng onl y, a col or addi t i ve t hat i s unsaf e
wi t hi n t he meani ng of t he FDCA
e. Ì f t he drug i s a new ani mal dr ug, or an ani mal f eed cont ai ni ng a new ani mal dr ug,
t hat i s unsaf e wi t hi n t he meani ng of t he FDCA
f . Ì f t he dr ug i s pur por t ed t o be a dr ug t hat i s recogni zed i n an of f i ci al compendi um,
and i t s st r engt h di f f ers f rom, or i t s qual i t y or puri t y f al l s bel ow, t he st andar d set
f or t h i n t he compendi um, unl ess t he devi at i on i s pl ai nl y and speci f i cal l y st at ed on
i t s l abel
g. Ì f t he drug i s not a compound r ecogni zed by name i n an of f i ci al compendi um; i f
i t s st rengt h di f f ers f rom, or i t s pur i t y or qual i t y f al l s bel ow, t hat whi ch i t pur por t s or
i s represent ed t o possess
h. Ì f t he drug has been mi xed or packed wi t h anot her subst ance so as t o r educe t he
dr ug' s qual i t y or st rengt h
i . Ì f t he drug has been subst i t ut ed, whol l y or par t i al l y, wi t h anot her subst ance
j . Ì f t he drug i s an OTC dr ug and i t i s not packaged i n t he requi r ed t amper - r esi st ant
packagi ng or properl y l abel ed i n conf ormi t y wi t h t he t amper - resi st ant r egul at i ons
( see Ì V)
k. Ì f t he drug (or medi cal devi ce) i s an opht hal mi c pr epar at i on of f ered or i nt ended
f or opht hal mi c use t hat i s not st eri l e
2. Mi sbrandi ng. Ì n gener al , t he t erm mi sbrandi ng means t hat a dr ug i s sol d or
di spensed wi t h a l abel or l abel i ng t hat i s i n vi ol at i on of t he FDCA. Label i s def i ned
as bei ng a di spl ay of wr i t t en, pri nt ed, or gr aphi c mat t er upon t he i mmedi at e
cont ai ner of any art i cl e (or drug) . Label i ng i s more br oadl y def i ned t o i ncl ude t he
l abel as wel l as ot her wr i t t en, pri nt ed, or gr aphi c mat t er upon any ar t i cl e or any of
i t s cont ai ner s or wr appers, or accompanyi ng t he ar t i cl e ( or dr ug) . A drug i s
consi dered mi sbranded i f any of t he f ol l owi ng condi t i ons occur:
a. Ì f t he l abel i ng i s f al se or mi sl eadi ng i n any part i cul ar
b. Ì f t he drug i s an i mi t at i on of anot her drug, or i f i t i s of f er ed f or sal e under t he
name of anot her dr ug
c. Ì f t he drug i s composed whol l y or part l y of i nsul i n and i t i s not pr oper l y bat ch
cer t i f i ed under t he FDCA
d. Ì f t he drug i s composed whol l y or part l y of an ant i bi ot i c and i t i s not pr oper l y
bat ch cer t i f i ed under t he FDCA
e. Ì f t he drug i s di spensed by a name t hat i s recogni zed i n an of f i ci al compendi um
and i t i s ei t her not packaged or not l abel ed i n conf or mi t y wi t h t he of f i ci al
compendi um
P. 545


f . Ì f t he dr ug i s det er mi ned by t he f eder al gover nment t o be l i abl e t o det er i or at i on
and i t i s not packaged i n a proper f or m and manner , and t he l abel f ai l s t o bear a
st at ement of pr oper pr ecaut i ons
g. Ì f t he drug i s di spensed i n a non- chi l d- resi st ant cont ai ner , when a chi l d- r esi st ant
cont ai ner i s ot her wi se r equi red (see Ì Ì Ì )
h. Ì f t he manuf act urer f ai l s t o pl ace on t he l abel any of t he f ol l owi ng:
( 1) Fact t hat cer t ai n drugs may be habi t f or mi ng
( 2) Name of each act i ve i ngredi ent
( 3) Name and pl ace of busi ness of t he manuf act ur er , packer , or di st r i but or
i . Ì f a pharmaci st f ai l s t o pl ace on a pr escri pt i on cont ai ner l abel any of t he
f ol l owi ng:
( 1) Name and addr ess of t he phar macy
( 2) Seri al number of t he pr escri pt i on
( 3) Dat e of f i l l i ng t he prescri pt i on or t he dat e of t he prescri pt i on
( 4) Name of t he pr escr i ber
( 5) Name of t he pat i ent
( 6) Di rect i ons f or use and any caut i onar y st at ement s cont ai ned i n t he prescri pt i on
j . Ì f an or al cont r acept i ve i s di spensed wi t hout t he r equi red pat i ent package i nser t
k. Ì f an i nt r aut eri ne devi ce t hat must be di spensed wi t h a pat i ent package i nsert i s
di spensed wi t hout t he i nser t
I . Ì f an est r ogen pr oduct i s di spensed wi t hout t he r equi r ed pat i ent package i nser t
m. Ì f a pr ogest ogen-cont ai ni ng pr oduct i s di spensed wi t hout t he requi r ed pat i ent
package i nser t
n. Ì f a l egend dr ug i s di spensed ( or r ef i l l ed) wi t hout a prescr i pt i on (or ref i l l
aut hor i zat i on) of a l i censed pract i t i oner , i t i s deemed t o be mi sbranded by t he
di spensi ng phar maci st
o. Ì f t he drug i s an OTC dr ug and i t i s not packaged i n t amper - resi st ant packagi ng
or properl y l abel ed i n conf ormi t y wi t h t he t amper -r esi st ant r egul at i ons ( see Ì V)
p. Ì f t he drug i s an OTC dr ug and i t i s not pr oper l y l abel ed i n conf or mi t y wi t h t he
l abel i ng requi r ement s of t he FDCA
q. Ì f t he drug (or medi cal devi ce) i s an opht hal mi c pr epar at i on of f ered or i nt ended
f or opht hal mi c use t hat i s not st eri l e
3. Vi oI at i ons under t he Act . Any mi sbrandi ng or adul t erat i on of a drug may subj ect
t he i ndi vi dual ( e. g. , a phar maci st ) t o i mpr i sonment , a f i ne, or bot h. A phar macy and
pharmaci st wi l l be exempt f rom cri mi nal sanct i ons i n ei t her of t he f ol l owi ng cases:
a. Certai n cases of good f ai th. When adul t er at ed or mi sbranded pr oduct s are
r ecei ved f r om a manuf act ur er or whol esal er i n good f ai t h by t he pharmacy, t he
pharmacy may not be hel d responsi bl e i n cer t ai n si t uat i ons. Thi s exempt i on appl i es
onl y i f i t i s a f i rst vi ol at i on and, i f r equest ed, t he pharmacy or phar maci st f ur ni shes
t o t he gover nment t he name and address of t he per son f r om whom t he drug was
r ecei ved and copi es of al l document s per t ai ni ng t o i t s del i ver y.
b. Recei pt of drug wi th a si gned, wri t t en guarant y. A phar macy and phar maci st
wi l l be exempt f r om mi sbr andi ng and adul t erat i on vi ol at i ons when a si gned, wr i t t en
guarant y i s recei ved f r om t he whol esal er or manuf act urer . The guar ant y must
cont ai n t he name and addr ess of t he person r esi di ng i n t he Uni t ed St at es f r om
whom t he drug was recei ved i n good f ai t h and a st at ement t hat t he drug i s not
adul t erat ed or mi sbr anded.
4. Sei zures. Any adul t erat ed or mi sbranded dr ug wi l l be subj ect t o condemnat i on
and sei zur e by t he U. S. gover nment af t er a heari ng i n any di st ri ct cour t of t he
Uni t ed St at es (or t er r i t ory) wi t h pr oper j ur i sdi ct i on. A sei zur e may be done wi t hout a
heari ng i f t he f ederal gover nment has probabl e cause t o bel i eve t hat t he vi ol at i on
woul d be danger ous t o heal t h or t hat t he l abel i ng of t he mi sbranded ar t i cl e i s
f r audul ent or woul d be mat eri al l y mi sl eadi ng t o t he i nj ur y or damage of t he
pur chaser or consumer .
5. I nvest i gat i ons and i nspecti ons
a. The U. S. Secr et ar y of Heal t h and Human Ser vi ces has t he aut hori t y t o conduct
exami nat i ons and i nspect i ons t hr ough f eder al empl oyees and by of f i cers and
empl oyees of any st at e, t er r i t or y, or pol i t i cal subdi vi si on dul y commi ssi oned by t he
U. S. Secr et ar y of Heal t h and Human Ser vi ces as an of f i cer of t he U. S. Depar t ment
of Heal t h and Human Ser vi ces.
b. Scope of i nvest i gat i on. An i nvest i gat or may ent er a phar macy or ot her
est abl i shment wher e adul t erat ed or mi sbr anded dr ugs are hel d and i nspect al l
dr ugs, mat er i al s, cont ai ner s, and l abel i ng. The i nspect i on does not ext end t o
f i nanci al dat a, sal es dat a ot her
P. 546

t han shi pment dat a, pri ci ng dat a, per sonnel dat a, and ot her recor ds t hat have no
beari ng on adul t er at i on and mi sbrandi ng. The i nvest i gat or must present appropr i at e
cr edent i al s and a wr i t t en not i ce t o t he owner , oper at or , or agent i n char ge t hat he or
she i s aut hor i zed t o conduct an i nvest i gat i on. The i nspect i on must be done at
r easonabl e t i mes, wi t hi n r easonabl e l i mi t s, and i n a r easonabl e manner .
6. Current Good Manufact uri ng Pract i ce (cGMP) . Under t he FDCA, a dr ug i s
consi dered adul t erat ed i f i t i s not manuf act ured "i n conf or mi t y wi t h cur r ent Good
Manuf act ur i ng Pract i ce. ¨ FDA r egul at i ons st at e wi t h par t i cul ar i t y t he mi ni mum
cGMPs f or met hods t o be used i n, and t he f aci l i t i es or cont r ol s t o be used f or , t he
manuf act ur e, pr ocessi ng, packi ng, or hol di ng of a dr ug. The cGMPs ensure t hat a
dr ug meet s t he requi r ement s of t he FDCA as t o saf et y and has t he i dent i t y and
st r engt h and meet s t he qual i t y and pur i t y char act er i st i cs t hat i t pur por t s.
J. Regi st rati on of producers of drugs
1. Manuf act urers and busi nesses t hat di st ri but e a dr ug manuf act ur ed by anot her but
sol d under t hei r own l abel or t r ade name must r egi st er t hei r est abl i shment wi t h t he
FDA. They al so must submi t a l i st of ever y dr ug ( pr escri pt i on and OTC) i n
commer ci al di st ri but i on, wi t h updat es ever y June and December .
2. Phar maci es proper l y l i censed by st at e l aw t hat do not manuf act ur e or possess
dr ugs f or sal e ot her t han i n t he r egul ar course of t he pr act i ce of phar macy ar e not
r equi r ed t o r egi st er wi t h t he FDA. A pharmacy engaged i n manuf act ur i ng or
pr ocessi ng act i vi t i es t hat ar e consi dered beyond t he nor mal pr act i ce of phar macy
must regi st er wi t h t he FDA and suppl y a l i st of ever y dr ug i n commerci al
di st r i but i on.
a. Scope of pharmacy pract i ce. A phar macy or pharmaci st may not manuf act ure
dr ug pr oduct s. They may onl y compound drug pr epar at i ons pursuant t o a val i d
pr escri pt i on of a pract i t i oner f or a par t i cul ar pat i ent . Large-scal e manuf act uri ng of
dr ug pr oduct s by a pharmacy or pharmaci st i s out si de t he scope of pharmacy
pr act i ce and r equi res proper r egi st r at i on wi t h t he FDA and compl i ance wi t h cGMPs.
K. Package i nsert s. The f eder al gover nment has det ermi ned t hat pr escri pt i on
medi cat i on i nf or mat i on needs t o be di ssemi nat ed t o heal t h pr of essi onal s and, i n t he
case of cer t ai n drugs, t o t he pat i ent .
1. Manufacturer' s i nsert . An amendment t o t he FDCA r equi red t hat al l
manuf act ur ers provi de " f ul l di scl osure¨ concerni ng pr escr i pt i on medi cat i on t hat t hey
market . Ful l di scl osure i s accompl i shed by means of a package i nsert t hat i s
encl osed wi t h ever y commerci al cont ai ner of a drug product . The i nser t shoul d
cont ai n essent i al sci ent i f i c i nf or mat i on needed f or t he saf e and ef f ect i ve use of t he
dr ug and shoul d be i nf ormat i ve and accurat e. Ì t must not be pr omot i onal i n t one,
f al se, or mi sl eadi ng.
2. Pati ent package i nsert . The FDA has det ermi ned t hat , because of cert ai n si de
ef f ect s associ at ed wi t h t he use of par t i cul ar drug pr oduct s, pat i ent package i nser t s
must be di spensed t o t he pat i ent at t he t i me of di spensi ng t he medi cat i ons. The
f ol l owi ng pr oduct s must be di spensed wi t h a pat i ent package i nsert , whi ch i s
suppl i ed wi t h t he product f r om t he manuf act ur er:
a. OraI cont racept i ves. Hospi t al i npat i ent s or LTCF pat i ent s may r ecei ve t he i nser t
bef ore admi ni st r at i on of t he f i rst or al cont racept i ve and ever y 30 days t her eaf t er , as
l ong as t he t herapy cont i nues.
b. I nt raut eri ne devi ces f or human use i n cont r acept i on. Ever y pr act i t i oner
di spensi ng such a devi ce must pr ovi de t he pat i ent wi t h an i nf or mat i ve i nser t .
c. Est rogen and est rogen- cont ai ni ng product s. Hospi t al i npat i ent s or LTCF
pat i ent s may r ecei ve t he i nser t bef or e admi ni st r at i on of t he f i rst est r ogen dose and
ever y 30 days t hereaf t er, as l ong as t he t her apy cont i nues.
d. Progest at i onaI drug products. Hospi t al i npat i ent s or LTCF pat i ent s may r ecei ve
t he i nser t bef or e admi ni st r at i on of t he f i rst pr ogest at i onal dr ug pr oduct and ever y 30
days t hereaf t er , as l ong as t he t her apy cont i nues.
e. I soproterenoI i nhaI ati on products requi r e t he f ol l owi ng war ni ng st at ement on
t he i mmedi at e cont ai ner l abel of such a product : "War ni ng: Do not exceed t he dose
pr escri bed by your physi ci an. Ì f di f f i cul t y persi st s, cont act your physi ci an
i mmedi at el y. ¨
P. 547


f . Mi sceI I aneous drug products. Cert ai n dr ug product s wer e appr oved by t he FDA
wi t h t he pr ovi si on t hat t hey must be di spensed al ong wi t h a pat i ent package i nser t
t hat i ncl udes a par t i cul ar war ni ng or st at ement of benef i t s and r i sks associ at ed wi t h
t he use of t he drug. For exampl e, i sot ret i noi n was appr oved f or di spensi ng wi t h an
i nser t war ni ng about ser i ous f et al harm when admi ni st er ed t o pregnant women.
L. Medi cat i on Gui des
1. The " Medi cat i on Gui de¨ bi l l was si gned i nt o l aw i n August 1996. By 2006, 95% of
pat i ent s recei vi ng a new pr escri pt i on wer e t o r ecei ve wr i t t en i nf ormat i on i n non-
t echni cal l anguage and i n a uni f orm f or mat . " Medi cat i on Gui des¨ or " MedGui des¨
shoul d not be conf used wi t h t he pat i ent l eaf l et s gener at ed by most pharmacy
comput er sof t war e programs. Pat i ent l eaf l et s ar e t ypi cal l y part of t he phar macy
sof t war e package t o pr ocess pr escri pt i ons and ar e wr i t t en and updat ed by a sour ce
ot her t han t he manuf act ur er or FDA. The l anguage of Medi cat i on Gui des i s approved
by t he FDA whi l e pat i ent l eaf l et s ar e not appr oved by t he FDA. The manuf act ur ers
must make Medi cat i on Gui des avai l abl e el ect roni cal l y t o phar maci es.
2. The l egi sl at i on has creat ed si gni f i cant conf usi on and cont r oversy wi t hi n t he
pharmacy and heal t h care communi t i es. Many phar maci st s assume t hat t he pat i ent
l eaf l et sat i sf i es t he MedGui de r equi rement , but si nce t he l anguage wasn' t approved
by t he FDA, t he agency (FDA) says t he t wo are not subst i t ut abl e. Ì t i s not cl ear i f
one manuf act ur er ' s MedGui de can be gi ven t o t he pat i ent when anot her
manuf act ur er ' s equi val ent generi c product i s di spensed. Each manuf act ur er i s t o
make t he Medi cat i on Gui des avai l abl e t o phar maci es. Ì f a pharmacy gave t he wr ong
manuf act ur er ' s MedGui de f or a gener i c product , assumi ng t he manuf act ur er ' s name
i s on t he document , t echni cal l y t hi s coul d be const r ued as a l abel i ng vi ol at i on.
Pr of essi onal phar macy or gani zat i ons and ot her i nt er est ed par t i es ( i . e. ,
pharmaceut i cal manuf act ur ers) are wor ki ng wi t h t he FDA t o cl ar i f y t hese
r equi r ement s.
M. Prescri pt i on drug sampI es
1. An amendment t o t he FDCA ( Pr escr i pt i on Dr ug Mar ket i ng Act ) sever el y r est ri ct ed
t he di st r i but i on of dr ug sampl es by manuf act ur ers. Under t he FDCA, no per son may
sel l , purchase, or t r ade, or of f er t o sel l , purchase, or t r ade any dr ug sampl e.
Sampl es may onl y be di st r i but ed upon wr i t t en request of a pr act i t i oner .
Manuf act ur ers must mai nt ai n r ecor ds of ever y sampl e di st r i but i on f or a per i od of
t hr ee years. Pharmaci es may not recei ve sampl es f rom a manuf act ur er except i n
cer t ai n si t uat i ons i n whi ch a pr act i t i oner r equest s st or age of hi s or her sampl es i n
t he pharmacy.
2. I mport ati on under t he FDCA. The Pr escri pt i on Dr ug Mar ket i ng Act prohi bi t s t he
i mpor t of pr escri pt i on drugs once expor t ed. Ì mpor t at i on i s al l owed af t er not i f i cat i on
and appr oval of t he FDA and i n cases of an emergency.
N. Medi caI devi ces. An amendment t o t he FDCA i n 1976 ( Medi cal Devi ce
Amendment s) requi r ed a devi ce manuf act ur er t o pr ovi de r easonabl e assur ance of
t he saf et y and ef f ect i veness of t he devi ce. The amendment r equi red t he FDA t o
cat egori ze each devi ce on t he mar ket i n 1976 i nt o one of t hree cl asses: Cl ass Ì ,
Cl ass Ì Ì , or Cl ass Ì Ì Ì , dependi ng on each devi ce' s saf et y and ef f ect i veness.
Gener al l y, CI ass I devi ces ar e t hose t hat have a r easonabl e assurance of saf et y
and ef f ect i veness. CI ass I I devi ces ar e t hose t hat do not have t he r easonabl e
assur ance of saf et y and ef f ect i veness, but t her e i s suf f i ci ent i nf ormat i on about t he
devi ce t o est abl i sh speci al cont r ol s t o ensur e i t s saf et y and ef f ect i veness ( and may
be market ed wi t h such cont r ol s) . CI ass I I I devi ces are t hose f or whi ch i nf or mat i on i s
not suf f i ci ent t o pr ovi de r easonabl e assur ance of t hei r saf et y and ef f ect i veness.
Cl ass Ì Ì Ì devi ces may be market ed onl y i f t hey are pr oven t o be subst ant i al l y
equi val ent t o a devi ce on t he mar ket bef or e 1976, by approval of a premar ket
appl i cat i on, or by r ecl assi f i cat i on i nt o Cl ass Ì or Ì Ì .
1. Medi caI devi ce t racki ng. Manuf act ur ers of medi cal devi ces whose f ai l ur e woul d
be r easonabl y l i kel y t o have a seri ous adverse heal t h consequence must t r ack t he
devi ce down t he chai n of di st r i but i on t o t he pat i ent . Such t r acki ng al l ows t he
manuf act ur er t o t ake appr opri at e act i on wi t h r espect t o r ecal l s, def ect s, or ot her
r el evant i nf or mat i on concer ni ng t he devi ce. Every f i nal di st r i but or such as a
pharmacy, hospi t al , or home heal t h- car e company must r epor t cer t ai n i nf or mat i on t o
t he manuf act ur er. Tr acki ng i nf ormat i on must be mai nt ai ned by t he manuf act ur er and
di st r i but or f or t he usef ul l i f e of t he devi ce and be avai l abl e f or i nspect i on by FDA
per sonnel .
P. 548


2. Manufacturer' s report s. Ever y devi ce manuf act urer must report t o t he FDA
i nf or mat i on, when r ecei ved or made awar e of , t hat r easonabl y suggest s t hat one of
i t s mar ket ed devi ces may have caused or cont r i but ed t o a deat h or ser i ous i nj ur y.
Li kewi se, hospi t al s and ot her medi cal ser vi ce f aci l i t i es must provi de r epor t s on
adver se r eact i ons t o, or mal f unct i oni ng of , medi cal devi ces.
3. AduI t erati on and mi sbrandi ng. Medi cal devi ces may be adul t erat ed or
mi sbr anded i n t he same way t hat dr ugs ar e adul t er at ed or mi sbr anded (see Ì Ì . Ì ) .
III. POISON PREVENTION PACKAGING ACT (PPPA).
The PPPA of 1970 requi res t hat drugs f or human use i n an or al dosage f or m must
be packaged f or t he consumer i n speci al packagi ng. Al l such f eder al cont r ol l ed
subst ances and drugs di spensed pursuant t o a prescr i pt i on must be di spensed t o
t he consumer i n speci al packagi ng. Speci al packagi ng, r ef er red t o as chi I d-
resi stant cont ai ner s, i s def i ned as a cont ai ner t hat i s desi gned t o be si gni f i cant l y
di f f i cul t f or chi l dr en under 5 year s of age t o gai n access t o wi t hi n a r easonabl e t i me.
The cont ai ner must not be t oo di f f i cul t f or normal adul t s ( ones wi t h no over t physi cal
or ment al handi caps) t o use pr operl y and does not i ncl ude packagi ng t hat al l such
chi l dren cannot gai n access wi t hi n a reasonabl e t i me. The Consumer Product s
Saf et y Commi ssi on i s r esponsi bl e f or i nt er pr et i ng, est abl i shi ng r ul es and r egul at i ons
f or , and enf orci ng t he provi si ons of t he PPPA.
A. Except i ons. The f ol l owi ng medi cat i ons ar e exempt f rom t he speci al packagi ng
r equi r ement s:
1. Subl i ngual dosage f orms of ni t rogl yceri n; ot her dosage f or ms i nt ended f or oral
admi ni st rat i on, such as ni t rogl ycer i n sust ai ned- rel ease preparat i ons, must be
packaged i n chi l d- r esi st ant cont ai ners
2. Subl i ngual and chewabl e f orms of i sosor bi de di ni t r at e i n dosage st rengt hs of 10
mg or l ess
3. Er yt hromyci n et hyl succi nat e gr anul es f or oral suspensi on and oral suspensi ons i n
packages cont ai ni ng not mor e t han 8 g of t he equi val ent of er yt hr omyci n
4. Cycl i cal l y admi ni st ered or al cont r acept i ves i n manuf act ur ers' mnemoni c (memor y-
ai d) di spenser packages t hat r el y sol el y on t he act i vi t y of one or more progest ogen
or est r ogen subst ances
5. Anhydr ous chol est yr ami ne i n powder f orm
6. Al l uni t -dose f orms of pot assi um suppl ement s, i ncl udi ng i ndi vi dual l y wr apped
ef f er vescent t abl et s, uni t - dose vi al s of l i qui d pot assi um, and powder ed pot assi um i n
uni t - dose packages, cont ai ni ng not mor e t han 50 mEq of pot assi um per uni t dose
7. Sodi um f l uor i de dr ug pr epar at i ons, i ncl udi ng l i qui d and t abl et f orms, cont ai ni ng
no mor e t han 264 mg of sodi um f l uori de per package and cont ai ni ng no ot her
pr escri pt i on medi cat i on
8. Bet amet hasone t abl et s packaged i n manuf act ur er s' di spenser packages,
cont ai ni ng no more t han 12. 6 mg bet amet hasone
9. Pancrel i pase pr eparat i ons i n t abl et , capsul e, or powder f or m and cont ai ni ng no
ot her prescr i pt i on medi cat i on
10. Predni sone i n t abl et f or m, when di spensed i n packages cont ai ni ng no mor e t han
105 mg of t he dr ug, and cont ai ni ng no ot her prescr i pt i on medi cat i on
11. Mebendazol e i n t abl et f or m i n packages cont ai ni ng not mor e t han 600 mg of t he
dr ug and no ot her pr escri pt i on medi cat i on
12. Met hyl predni sol one i n t abl et f or m i n packages cont ai ni ng not more t han 84 mg
of t he dr ug and no ot her pr escri pt i on medi cat i on
13. Col est i pol i n powder f or m i n packages cont ai ni ng not mor e t han 5 g of t he drug
and no ot her pr escri pt i on medi cat i on
14. Er yt hr omyci n et hyl succi nat e t abl et s i n packages cont ai ni ng no more t han t he
equi val ent of 16 g er yt hromyci n
P. 549


15. Conj ugat ed est r ogen t abl et s USP, when di spensed i n mnemoni c packages
cont ai ni ng not more t han 32 mg of t he dr ug and no ot her pr escri pt i on medi cat i on
16. Nor et hi ndr one acet at e t abl et s USP, when di spensed i n mnemoni c packages
cont ai ni ng not more t han 50 mg of t he dr ug and no ot her pr escri pt i on medi cat i on
17. Medr oxypr ogest er one acet at e t abl et s
B. Request s f or a non-chi I d- resi st ant cont ai ner. A pr escri bi ng pr act i t i oner may
make a r equest i n t he prescr i pt i on t hat t he medi cat i on be di spensed i n a non-chi l d-
r esi st ant cont ai ner . A pract i t i oner may not , however , make a bl anket request t hat al l
pr escri pt i ons i ssued by hi m or her be di spensed i n non- chi l d- resi st ant cont ai ner s.
The purchaser, or pat i ent , may al so make a request t hat t he medi cat i on be
di spensed i n a non- chi l d- r esi st ant cont ai ner . The r equest of t he pur chaser , or
pat i ent , does not ( under t he PPPA) have t o be i n wr i t i ng. The purchaser , or pat i ent ,
may make a bl anket r equest t hat none of hi s or her medi cat i ons be di spensed i n a
chi l d- resi st ant cont ai ner . A di spensi ng pharmaci st may never make t he deci si on t o
use non- chi l d- resi st ant cont ai ner s.
C. Reuse of chi I d- resi st ant cont ai ners. Reuse of chi l d- resi st ant cont ai ner s ar e
pr ohi bi t ed by r egul at i on of t he f eder al Consumer Pr oduct s Saf et y Commi ssi on.
However , t he Commi ssi on has i ndi cat ed t hat gl ass cont ai ners may be r eused as
l ong as a new saf et y cl osur e i s used.
D. Manuf act urer' s packagi ng. Packagi ng f r om t he manuf act ur er t hat i s i nt ended t o
be di spensed di r ect l y t o t he pat i ent must be i n chi l d- resi st ant packagi ng. Bul k
packagi ng i nt ended t o be r epackaged by t he phar maci st f or each pr escri pt i on does
not have t o be i n speci al packagi ng f r om t he manuf act urer . Uni t packagi ng f r om t he
manuf act ur er t hat wi l l be di spensed di rect l y t o t he consumer , or pat i ent , must
compl y wi t h t he chi l d- r esi st ant r equi rement s of t he PPPA (unl ess speci f i cal l y
exempt ed; see Ì Ì Ì . A).
E. Exempt i ons f or easy access. Speci al packagi ng i s not r equi r ed i n cases wher e
OTC medi cat i on needs t o be r eadi l y avai l abl e t o t he el der l y or handi capped
per sons. A manuf act urer may suppl y a si ngl e si ze of a dr ug pr oduct i n non- chi l d-
r esi st ant packagi ng, as l ong as i t al so suppl i es t he medi cat i on i n packages t hat use
t he speci al packagi ng. Addi t i onal l y, t he package must be conspi cuousl y l abel ed wi t h
t he st at ement : " Thi s package f or househol ds wi t hout young chi l dr en. ¨ For t hose
packages t oo smal l f or t hi s st at ement , t he st at ement " Package not chi l d-r esi st ant ¨
may be used.
F. Hospi t aI s and i nsti t ut i ons. The speci al packagi ng r equi r ement s of t he PPPA
appl y t o househol d subst ances. Househol d subst ance i s def i ned as "any subst ance
whi ch i s cust omari l y produced or di st r i but ed f or sal e f or consumpt i on or use, or
cust omari l y st ored, by i ndi vi dual s i n or about t he househol d.. ¨ As l ong as t he
medi cat i on i s admi ni st ered by i nst i t ut i onal personnel and i s not di rect l y di spensed
t o t he consumer ( pat i ent ) , chi l d- r esi st ant cont ai ner s ar e not r equi red.
G. Mi sceI I aneous product s requi ri ng speci aI packagi ng. The PPPA r equi r es t hat
cer t ai n househol d subst ances be di st ri but ed t o t he consumer i n speci al packagi ng.
Exampl es of t hese subst ances i ncl ude f urni t ur e pol i sh cont ai ni ng pet r ol eum
di st i l l at es, drai n pi pe cl eaners, t ur pent i ne, pai nt sol vent s, and l i ght er f l ui d.
IV. ANTI-TAMPERING ACT.
The U. S. Congr ess passed t he Ant i - Tamperi ng Act i n 1984 due t o a number of
deat hs t hat occur r ed i n t he ear l y 1980s f r om OTC medi cat i on capsul es cont ami nat ed
wi t h cyani de.
A. Vi oI at i ons. Unl awf ul act s i nvol vi ng a consumer product can be broken down i nt o
one of t he f ol l owi ng l i st ed vi ol at i ons. The t erm consumer pr oduct i ncl udes any f ood,
dr ug, devi ce, or cosmet i c, as wel l as any ar t i cl e, pr oduct , or commodi t y t hat i s
cust omari l y used by i ndi vi dual s f or purposes of per sonal car e or t o per f orm ser vi ces
or di nari l y done wi t hi n a househol d.
1. Tamperi ng. Any i ndi vi dual who t amper s or at t empt s t o t amper wi t h any consumer
pr oduct t hat af f ect s i nt erst at e or f orei gn commer ce, or i t s l abel i ng or cont ai ner , may
be i n vi ol at i on of t he st at ut e. A vi ol at i on occur s when t he i ndi vi dual act s (or
t hr eat ens t o act ) wi t h r eckl ess di sr egar d f or t he r i sk t hat anot her per son wi l l be
pl aced i n danger of deat h or bodi l y i nj ur y.
P. 550

Any i ndi vi dual who t ai nt s any consumer pr oduct or causes i t s l abel i ng or cont ai ner
t o be mat er i al l y f al se or mi sl eadi ng i s i n vi ol at i on of t he st at ut e i f done wi t h i nt ent t o
cause ser i ous i nj ur y t o t he busi ness of anot her .
2. FaI se communi cat i ons. Knowi ngl y communi cat i ng f al se i nf or mat i on t hat a
consumer pr oduct has been t ai nt ed may be a vi ol at i on. Ì f such t ai nt i ng, had i t
occur r ed, woul d cr eat e a r i sk of deat h or bodi l y i nj ur y t o anot her person, t hen t he
f al se communi cat i on i s deemed a vi ol at i on.
3. Conspi racy. An agreement bet ween t wo or mor e per sons t o do ( or f ur t her ) ei t her
of t he above act s i s consi dered a vi ol at i on.
B. OTC t amper- resi stant packagi ng. Cer t ai n OTC pr oduct s must be packaged, by
FDA r egul at i on, i n t amper - r esi st ant packagi ng. Exampl es i ncl ude cont act l ens
sol ut i ons and ot her opht hal mi c sol ut i ons. A t amper- resi st ant package i s one
havi ng one or mor e i ndi cat ors or barr i ers t o ent r y t hat , i f breached or mi ssi ng, can
r easonabl y be expect ed t o provi de vi si bl e evi dence t o consumers t hat t amperi ng has
occur r ed. To reduce t amper i ng, t he package must have one of t he f ol l owi ng
charact eri st i cs:
1. Be di st i nct i ve by desi gn so t hat t he product cannot be dupl i cat ed by commonl y
avai l abl e mat er i al s or processes or
2. Use one or mor e i ndi cat ors or barr i ers t o ent r y t hat empl oy an i dent i f yi ng
charact eri st i c
C. OTC t amper- resi stant I abeI i ng. The OTC pr oduct must be l abel ed wi t h a
pr omi nent l y pl aced st at ement al er t i ng consumers t o t he speci f i c t amper - resi st ant
f eat ur e of t he package. The st at ement must be pl aced so t hat i t wi l l be unaf f ect ed i f
t he t amper - resi st ant f eat ur e i s br eached or mi ssi ng.
D. Medi caI devi ces and cosmet i cs. Cer t ai n medi cal devi ces and cosmet i cs must be
packaged i n t amper - r esi st ant packagi ng. The packagi ng requi r ement s are si mi l ar t o
t he requi r ement s out l i ned above f or OTC dr ug product s.
V. MAILING PRESCRIPTION MEDICATION
A. Al l pr escr i pt i on medi cat i on, i ncl udi ng cont r ol l ed subst ances and narcot i cs i n
schedul es Ì Ì - V, may be mai l ed f rom a physi ci an, or pharmaci st pursuant t o a
pr escri pt i on, t o t he pat i ent . Fl ammabl e subst ances ( e. g. , acet one) and al cohol i c
bever ages may not be sent t o a pat i ent t hr ough t he U. S. mai l .
B. The medi cat i on must be pl aced i n a pl ai n out er cont ai ner or be securel y
over wr apped i n pl ai n paper . There must be no mar ki ngs of any ki nd on t he out si de
wr apper or cont ai ner t hat woul d i ndi cat e t he nat ur e of t he cont ent s.
VI. OMNIBUS BUDGET RECONCILI ATION ACT OF 1990
(OBRA '90).
Under t he Const i t ut i on of t he Uni t ed St at es, t he f ederal gover nment has no power or
aut hor i t y t o di r ect l y r egul at e t he pract i ce of pharmacy. Such power r est s wi t h each
st at e. The f eder al government can, however , i ndi r ect l y r egul at e, or af f ect , t he
pr act i ce of pharmacy by at t achi ng condi t i ons of par t i ci pat i on and r ei mbursement f or
f ederal l y f unded programs.
A. Medi cai d prescri pt i ons. Wi t h r espect t o pr escr i pt i ons di spensed t o Medi cai d
pat i ent s (pai d i n par t by t he f eder al gover nment al ong wi t h t he st at e gover nment ) ,
t he f eder al gover nment has at t ached cer t ai n condi t i ons f or r ei mbursement . Such
condi t i ons wer e deemed necessar y t o st em t he al ways i ncreasi ng cost of t he
Medi cai d progr ams. Ì t was bel i eved t hat i mpr oved medi cat i on compl i ance by
Medi cai d r eci pi ent s woul d, i n t he l ong r un, reduce t he cost of t he programs by
r educi ng subsequent hospi t al i zat i ons and ot her subsequent ut i l i zat i on of heal t h
car e. As a r esul t , pharmaci st s are requi r ed t o do t he f ol l owi ng i n t he course of
di spensi ng a Medi cai d prescr i pt i on:
1. Make a r easonabl e good- f ai t h ef f or t t o obt ai n and mai nt ai n a hi st or y of t he
pat i ent , i ncl udi ng a medi cat i on hi st or y
P. 551


2. Conduct a r evi ew of ever y pr escr i pt i on f or appr opr i at eness and t o scr een f or
pot ent i al dr ug t her apy probl ems
3. Make an of f er t o counsel each Medi cai d reci pi ent concer ni ng t he dr ug ( i f t he of f er
i s accept ed, t he counsel i ng must i ncl ude t he dr ug' s pr oper admi ni st r at i on, common
adver se or sever e si de ef f ect s, t echni ques f or sel f - moni t or i ng, and proper st orage)
B. Manuf act urer' s best pri ce. OBRA ' 90 r equi res manuf act urer s t hat wi sh t o
par t i ci pat e i n t he Medi cai d pr ogram t o of f er t he f ederal gover nment t hei r best pri ce
f or prescr i pt i on dr ugs. Best pr i ce i s def i ned as t he l owest pri ce at whi ch any
pur chaser i s pur chasi ng t hat dr ug product .
VII. HEALTH INSURANCE PORTABILITY AND
ACCOUNTABILITY ACT OF 1996 (HIPAA).
HÌ PAA i s f ederal l egi sl at i on t hat r equi r es al l heal t h- car e pr ovi ders, i ncl udi ng
pharmaci es, t o pr ot ect pat i ent i nf or mat i on f r om unaut hori zed use and di scl osures.
Thi s i s ref er red t o as t he Pr i vacy Rul e and was est abl i shed as a resul t of t he
gover nment ' s recogni t i on t hat i ndi vi dual l y i dent i f i abl e heal t h i nf ormat i on i s r eadi l y
avai l abl e due t o heal t h-car e pl ans, heal t h-car e cl ear i nghouses, t hi rd- par t y bi l l i ng
pr act i ces, cl i ni cal r esearch t r i al s, and t he t r ansmi ssi on of heal t h i nf ormat i on i n
el ect r oni c f or m. Pr ot ect ed heal t h i nf ormat i on ( PHÌ ) must be conf i dent i al l y
mai nt ai ned by a heal t h-car e pr ovi der t o prevent any unaut hor i zed use or di scl osure.
Ot her cover ed ent i t i es, such as Or gani zed Heal t h Car e Arr angement s, HMO' s and
i nsur ance pl ans, must al so f ol l ow t he Pr i vacy Rul e.
A. Def i ni t i ons. Under t he Pr i vacy Rul e, cer t ai n t er ms have speci f i c meani ngs.
1. "Covered ent i t y" means:
a. a heal t h pl an ( e. g. , group heal t h i nsur ance, Medi cai d, Medi care) .
b. a heal t h- car e cl eari nghouse (e. g. , bi l l i ng ser vi ce compani es and compani es t hat
pr ocess heal t h i nf ormat i on r ecei ved f r om anot her ent i t y) .
c. a heal t h-car e pr ovi der who t r ansmi t s any heal t h i nf ormat i on i n el ect r oni c f or m i n
connect i on wi t h a t ransact i on covered by HÌ PAA. " Heal t h care¨ i s def i ned as
i ncl udi ng t he sal e or di spensi ng of a dr ug, devi ce, equi pment , or ot her i t em i n
accor dance wi t h a pr escr i pt i on.
2. "I ndi vi duaI I y i dent i f i abI e heaI t h i nf ormat i on" i s i nf or mat i on cr eat ed or r ecei ved
by a cover ed ent i t y t hat r el at es t o t he past , present , or f ut ur e physi cal or ment al
heal t h or condi t i on of an i ndi vi dual ; t he pr ovi si on of heal t h car e t o an i ndi vi dual ; or
any payment f or any pr ovi si on of any heal t h car e, and t hat i dent i f i es t he i ndi vi dual
or t hat provi des a r easonabl e basi s t o i dent i f y t he i ndi vi dual . The i t ems l i st ed bel ow
ar e deemed suf f i ci ent t o i dent i f y an i ndi vi dual :
a. Name
b. Addr ess, i ncl udi ng al l geogr aphi c subdi vi si ons smal l er t han a st at e (e. g. , st r eet
address, ci t y, count y, zi p code)
c. Dat es ( except year ) , i ncl udi ng bi rt h dat es, admi ssi on dat es, di schar ge dat es,
dat es of deat h
d. Tel ephone numbers
e. Fax numbers
f . E- mai l addr esses
g. Soci al Secur i t y number s
h. Medi cal recor d number s
i . Heal t h pl an benef i ci ary numbers
j . Account number s
k. Cer t i f i cat e/ l i cense numbers
I . Vehi cl e i dent i f i er s and seri al numbers, i ncl udi ng l i cense pl at e numbers
m. Devi ce i dent i f i er s
n. Web uni versal r esource l ocat er s ( URLs)
o. Ì nt er net pr ot ocol (Ì P) address numbers
p. Bi omet r i c i dent i f i ers, i ncl udi ng f i ngerpr i nt s and voi ce pri nt s
q. Ful l f ace phot ogr aphi c i mages and any comparabl e i mages
r. Any ot her uni que i dent i f yi ng number , char act i st i c, or code, except f or codes
assi gned t o r ei dent i f y i nf or mat i on t hat has been de- i dent i f i ed
s. Names of any r el at i ve, empl oyer, or househol d member of t he i ndi vi dual
P. 552


3. "Prot ect ed heaI t h i nformat i on" ( PHI ) i s al l i ndi vi dual l y i dent i f i abl e heal t h
i nf or mat i on t hat i s t ransmi t t ed or mai nt ai ned i n any f or m or medi um, el ect r oni cal l y
or ot her wi se.
4. "Not i ce of pri vacy pr act i ces f or protected heaI t h i nf ormat i on. " An i ndi vi dual
has t he r i ght t o adequat e not i ce of t he uses and di scl osur es of PHÌ t hat may be
made by t he covered ent i t y, and of t he i ndi vi dual ' s r i ght s and t he cover ed ent i t y' s
l egal dut i es wi t h r espect t o PHÌ . Gener al l y, t he not i ce must cont ai n i nf ormat i on
descr i bi ng t he i ndi vi dual ' s r i ght s under t he Pri vacy Rul e and t he cover ed ent i t y' s
r esponsi bi l i t i es.
a. Header. Ever y not i ce must cont ai n t he f ol l owi ng st at ement as a header or be
ot her wi se promi nent l y di spl ayed: " THÌ S NOTÌ CE DESCRÌ BES HOW MEDÌ CAL
Ì NFORMATÌ ON ABOUT YOU MAY BE USED AND DÌ SCLOSED AND HOW YOU CAN
GET ACCESS TO THÌ S Ì NFORMATÌ ON. PLEASE REVÌ EW Ì T CAREFULLY. ¨
b. I ndi vi duaI ' s ri ghts. An i ndi vi dual has t he r i ght t o request r est ri ct i ons on cer t ai n
uses and di scl osures of PHÌ , t he r i ght t o r ecei ve conf i dent i al communi cat i ons of PHÌ
by al t er nat i ve means or at al t ernat i ve l ocat i ons, t he ri ght t o i nspect and copy hi s
PHÌ , t he r i ght t o amend hi s PHÌ , t he r i ght t o recei ve an account i ng of di scl osur es of
PHÌ , and t he ri ght t o obt ai n a paper copy of t he not i ce f r om t he covered ent i t y.
c. Covered ent i t y' s responsi bi I i t i es. The not i ce must i ncl ude a st at ement t hat t he
cover ed ent i t y i s r equi red by l aw t o mai nt ai n t he pr i vacy of PHÌ , a st at ement of i t s
l egal dut i es and pr i vacy pr act i ces wi t h respect t o PHÌ , a st at ement t hat i t must
abi de by t he not i ce cur rent l y i n ef f ect , and a st at ement t hat i t r eser ves t he r i ght t o
change t he t er ms of i t s not i ce and how i t wi l l provi de i ndi vi dual s wi t h a revi sed
not i ce.
d. Mi sceI I aneous content s of not i ce. The not i ce must cont ai n a st at ement t hat
i ndi vi dual s may compl ai n t o t he cover ed ent i t y and t o t he U. S. Depar t ment of Heal t h
and Human Ser vi ces i f t hey bel i eve t hei r pr i vacy r i ght s have been vi ol at ed. The
not i ce must st at e a dat e on whi ch i t becomes ef f ect i ve. The ef f ect i ve dat e must be
no l at er t han t he dat e of t he f i rst ser vi ce del i ver y.
e. Post i ng of not i ce. A pharmacy must post t he not i ce i n a cl ear and promi nent
l ocat i on where i t i s r easonabl e t o expect i ndi vi dual s t o be abl e t o r ead t he not i ce.
f . Wri t ten acknowI edgment of not i ce. Ever y cover ed ent i t y must obt ai n a wr i t t en
acknowl edgment of recei pt of t he not i ce by t he i ndi vi dual . Ì f one i s not obt ai ned, t he
cover ed ent i t y must document i t s good-f ai t h ef f or t s t o obt ai n t he acknowl edgment
and t he r eason why i t was not obt ai ned.
g. Excepti ons f or i nmates. A person i ncar cer at ed i n or ot her wi se conf i ned t o a
cor rect i onal i nst i t ut i on does not have a ri ght t o not i ce under t he Pri vacy Rul e, and
t he not i ce r equi r ement s do not appl y t o a cor rect i onal i nst i t ut i on t hat i s a cover ed
ent i t y.
5. "Aut hori zati on" f or a covered ent i t y t o use or di scl ose PHÌ : a pat i ent must gi ve
wr i t t en aut hor i zat i on bef or e a cover ed ent i t y, i ncl udi ng pharmaci es and phar maci st s,
may use or di scl ose PHÌ . No pati ent consent or aut hori zati on i s necessar y when
PHÌ use and di scl osure i s f or t reat ment , payment , or heaI th- care operati ons. Thi s
al l ows a heal t h-care provi der t o consul t wi t h ot her cover ed ent i t i es ( i . e. , ot her
heal t h-care provi der s) t o pr ovi de pr oper pat i ent car e wi t hout bei ng undul y hi ndered
by t he Pr i vacy Rul e. For uses and di scl osures t hat r equi re an aut hor i zat i on, t he
wri t t en aut hori zati on must be wr i t t en i n pl ai n l anguage, and a si gned copy must
be provi ded t o t he i ndi vi dual . The si gned aut hor i zat i on must be mai nt ai ned by t he
cover ed ent i t y f or 6 year s f r om t he dat e of i t s cr eat i on or t he dat e when i t was l ast
i n ef f ect , whi chever i s l at er . The wr i t t en aut hori zat i on must at l east cont ai n t he
f ol l owi ng core el ement s and st at ement s:
a. A descri pt i on of t he i nf or mat i on t o be used or di scl osed t hat i dent i f i es t he
i nf or mat i on i n a speci f i c and meani ngf ul f ashi on.
b. The name or ot her speci f i c i dent i f i cat i on of t he person( s) , or cl ass of per sons,
aut hor i zed t o make t he request ed use or di scl osur e.
c. The name or ot her speci f i c i dent i f i cat i on of t he person( s) , or cl ass of per sons, t o
whom t he cover ed ent i t y may make t he r equest ed use or di scl osur e.
d. A descr i pt i on of each pur pose of t he r equest ed use or di scl osur e.
e. An expi r at i on dat e or an expi r at i on event t hat r el at es t o t he i ndi vi dual or t he
pur pose of t he use or di scl osure.
f . Si gnat ur e of t he i ndi vi dual and dat e. Ì f si gned by a per sonal r epr esent at i ve, i t
must al so i ncl ude a descr i pt i on of such r epresent at i ve' s aut hori t y t o act f or t he
i ndi vi dual .
g. The wr i t t en aut hor i zat i on must cont ai n t he f ol l owi ng st at ement s:
( 1) The i ndi vi dual ' s r i ght t o revoke t he aut hor i zat i on i n wr i t i ng al ong wi t h t he
except i ons t o t he r i ght t o r evoke and a descr i pt i on of how t he i ndi vi dual may r evoke
t he aut hor i zat i on.
P. 553


( 2) The abi l i t y or i nabi l i t y t o condi t i on t r eat ment , payment , enrol l ment , or el i gi bi l i t y
f or benef i t s on t he aut hor i zat i on, by st at i ng ei t her t hat t he cover ed ent i t y cannot
r equi r e aut hori zat i on, or t hat i f t he cover ed ent i t y can r equi r e aut hor i zat i on, t he
consequences t o t he i ndi vi dual of hi s or her ref usal t o si gn t he aut hor i zat i on.
( 3) The pot ent i al f or t he di scl osed i nf or mat i on t o be r edi scl osed by t he reci pi ent and
no l onger be pr ot ect ed by t he Pri vacy Rul e.
6. "Mi ni mum necessar y. " When usi ng or di scl osi ng PHÌ or when r equest i ng PHÌ
f r om anot her cover ed ent i t y, a cover ed ent i t y must make reasonabl e ef f ort s t o l i mi t
PHÌ t o t he mi ni mum necessar y t o accompl i sh t he i nt ended pur pose of t he use,
di scl osur e, or request . The mi ni mum necessar y rul e does not appI y t o di scl osur es
or r equest s by a heal t h-car e pr ovi der f or t reat ment , uses or di scl osures made
pur suant t o an aut hor i zat i on, and uses or di scl osur es t hat ar e requi r ed by l aw.
" Requi r ed by l aw¨ means a mandat e i n a l aw t hat compel s an ent i t y t o make a use
or di scl osur e of PHÌ . Ì t i ncl udes a cover ed ent i t y' s compl i ance wi t h st at e and f eder al
l aws and r egul at i ons t hat r equi re t he pr oduct i on of i nf ormat i on; cour t or der s and
court - order ed war r ant s, subpoenas or summons i ssued by a cour t , a gover nment al
or t r i bal i nspect or general , or an admi ni st rat i ve body aut hori zed t o requi re t he
pr oduct i on of i nf ormat i on and Medi care condi t i ons of par t i ci pat i on wi t h r espect t o
heal t h-care provi der s par t i ci pat i ng i n t he pr ogr am.
7. "Busi ness associ ates. " A busi ness associ at e of a cover ed ent i t y i s a per son or
busi ness t hat per f orms a f unct i on or act i vi t y on behal f of t he cover ed ent i t y, such as
cl ai ms pr ocessi ng, bi l l i ng, ut i l i zat i on revi ew, qual i t y assur ance, et c. , and t hat
r equi r es t he use or di scl osure of i ndi vi dual l y i dent i f i abl e heal t h i nf ormat i on. A
busi ness associ at e woul d al so i ncl ude per sons who provi de ser vi ces t o t he cover ed
ent i t y, and t he ser vi ce i nvol ves di scl osur e of i ndi vi dual l y i dent i f i abl e heal t h
i nf or mat i on, such as l egal , act uari al , account i ng, consul t i ng, dat a aggr egat i on,
management , admi ni st r at i ve, accr edi t at i on, or f i nanci al ser vi ces. ExcI uded f r om t he
def i ni t i on of busi ness associ at es are members of t he wor kf orce of t he cover ed
ent i t y, and f unct i ons or ser vi ces t hat do not r equi r e di scl osur e of i ndi vi dual l y
i dent i f i abl e heal t h i nf or mat i on.
a. Busi ness associ at e cont ract s. Ever y busi ness associ at e must ent er i nt o an
agr eement wi t h t he cover ed ent i t y t o ensure compl i ance wi t h t he Pr i vacy Rul e.
Gener al l y, t he agreement must est abl i sh t he r equi r ed uses and di scl osur es of PHÌ
by t he busi ness associ at e and r equi r e t he r et ur n or dest ruct i on of PHÌ at t er mi nat i on
of t he cont r act .
B. Addi t i onaI responsi bi I i t i es of covered ent i ti es. Ever y covered ent i t y must
cr eat e pol i ci es and pr ocedures f or compl i ance wi t h t he Pri vacy Rul e, must desi gnat e
a pri vacy of f i ci al responsi bl e f or cr eat i ng such pol i ci es and procedures, must
desi gnat e a cont act person or of f i ce t hat i s r esponsi bl e f or r ecei vi ng compl ai nt s and
t hat i s abl e t o pr ovi de f ur t her i nf ormat i on about mat t ers cover ed by t he not i ce, and
must t rai n al l member s of i t s wor kf or ce wi t h respect t o t he Pr i vacy Rul e. Ever y
desi gnat i on must be mai nt ai ned by t he covered ent i t y f or 6 years f rom t he dat e i t
l ast was i n ef f ect . Last l y, ever y cover ed ent i t y must have and appl y appropr i at e
sanct i ons agai nst member s of i t s wor kf orce who f ai l t o compl y wi t h t he Pri vacy
Rul e.
C. St at e I aw pri vacy ruI es. The f eder al Pri vacy Rul e i s i nt ended as t he mi ni mum
r equi r ement f or pri vacy st andar ds. Ì f a st at e l aw i s mor e st ri ngent , t hen a cover ed
ent i t y must f ol l ow t hat st at e' s pr i vacy st andards. Ì f a st at e pr i vacy l aw i s not as
st r i ngent , t he f ederal Pri vacy Rul e preempt s any cont r ar y st at e l aw and a cover ed
ent i t y must abi de by t he f ederal Pr i vacy Rul e.
D. PenaI t i es f or vi oI at i on of the Pri vacy RuI e. Any person who vi ol at es t he
Pr i vacy Rul e may not be f i ned more t han $100 f or each vi ol at i on up t o a t ot al of
$25, 000 per cal endar year f or al l vi ol at i ons of an i dent i cal requi r ement . Addi t i onal
penal t i es may be i mposed f or t he f ol l owi ng wrongf uI di scI osure of i ndi vi dual l y
i dent i f i abl e heal t h i nf or mat i on:
1. Wrongf ul obt ai nment or di scl osur e of PHÌ : f i ned not mor e t han $50, 000,
i mpri soned not mor e t han 1 year , or bot h.
2. Wrongf ul obt ai nment or di scl osur e of PHÌ under f al se pret enses: f i ned not mor e
t han $100, 000, i mpri soned not more t han 5 years, or bot h.
3. Wrongf ul obt ai nment or di scl osur e of PHÌ commi t t ed wi t h i nt ent t o sel l , t r ansf er ,
or use same f or commerci al advant age, per sonal gai n, or mal i ci ous harm: f i ned not
mor e t han $250, 000, i mpr i soned not mor e t han 10 years, or bot h.
P. 554


VIII. NARCOTIC TREATMENT PROGRAMS.
Met hadone use i s cur r ent l y al l owed as par t of a t ot al t r eat ment progr am f or nar cot i c
addi ct i on. Regul at i ons concer ni ng met hadone t r eat ment pr ogr ams have been j oi nt l y
est abl i shed by t he DEA and FDA. Narcot i c- dependent i ndi vi dual s are t hose who
physi ol ogi cal l y need heroi n or a mor phi ne- l i ke drug t o prevent t he onset of si gns of
wi t hdr awal .
A. Def i ni t i on. A narcot i c t r eat ment pr ogr am i s an or gani zat i on t hat admi ni st ers or
di spenses a nar cot i c dr ug t o a narcot i c addi ct f or mai nt enance or det oxi f i cat i on
t r eat ment , and provi des, when appr opr i at e or necessar y, a compr ehensi ve r ange of
medi cal and r ehabi l i t at i ve ser vi ces. The program must be:
1. Appr oved by t he FDA
2. Appr oved by t he appropr i at e st at e agency, usual l y t he st at e' s Depar t ment of
Publ i c Heal t h or equi val ent
3. Regi st ered under t he Federal Cont r ol l ed Subst ances Act wi t h t he DEA t o use a
nar cot i c dr ug f or t he t reat ment of nar cot i c addi ct i on
B. Det oxi f i cat i on t reatment i s def i ned as di spensi ng of narcot i c dr ugs i n
decreasi ng doses t o an i ndi vi dual t o al l evi at e adver se physi ol ogi cal or psychol ogi cal
ef f ect s i nci dent t o wi t hdrawal of narcot i c dr ug use. Det oxi f i cat i on i s f or a per i od not
i n excess of 180 days.
C. Mai nt enance t reat ment i s t he di spensi ng of a nar cot i c dr ug, at r el at i vel y st abl e
dosage l evel s, i n t he t reat ment of an i ndi vi dual f or dependence on her oi n or ot her
mor phi ne- l i ke dr ug.
D. Requi rement s t o admi t pat i ent s i nt o a program. Ì n gener al , f or a pat i ent t o be
admi t t ed i nt o a compr ehensi ve mai nt enance pr ogr am, t he f ol l owi ng r equi rement s
must be met :
1. A pr ogram physi ci an must det ermi ne t hat t he per son i s cur r ent l y physi ol ogi cal l y
dependent on a nar cot i c dr ug and became physi ol ogi cal l y dependent at l east 1 year
bef ore admi ssi on t o t he pr ogram.
2. The pat i ent must have vol unt ar i l y chosen t o par t i ci pat e i n t he pr ogr am and must
si gn a " Consent t o Met hadone Tr eat ment ¨ (pr ovi ded by t he FDA) af t er bei ng cl earl y
and adequat el y i nf ormed about t he use of met hadone.
E. Take- home methadone. Take- home met hadone may be gi ven onl y t o pat i ent s
who, i n t he cl i ni cal j udgment of t he program physi ci an, ar e responsi bl e i n handl i ng
nar cot i c dr ugs. The pat i ent must come t o t he cl i ni c f or obser vat i on dai l y or at l east
6 days a week. Over t i me, t he pr ogram physi ci an may reduce cl i ni cal obser vat i ons
t o once weekl y. Met hadone f or t ake- home use must be di spensed si mi l ar l y t o t he
di spensi ng of any schedul e Ì Ì cont r ol l ed subst ance and i ncl ude t he t reat ment
cent er ' s name, addr ess, and t el ephone number on i t s l abel .
P. 555


STUDY QUESTIONS
Di rect i ons: Each of t he numbered i t ems or i ncompl et e st at ement s i n t hi s sect i on i s
f ol l owed by answer s or by compl et i ons of t he st at ement . Sel ect t he one l et t er ed
answer or compl et i on t hat i s best i n each case.
1. AI I of t he f oI I owi ng prescri pt i on medi cat i ons may be deI i vered by mai I t o t he
pat i ent vi a the U. S. Post aI Servi ce EXCEPT
( A) pr ocai nami de
( B) ampi ci l l i n
( C) hydr omorphone
( D) di azepam
( E) al l of t he above may be del i ver ed by mai l
Vi ew Answer 1. The answer i s E[] . 2. Whi ch of the f oI I owi ng narcot i c drugs
has been approved by t he FDA f or use i n t he t reat ment of narcot i c addi ct i on?
( A) Mor phi ne
( B) Codei ne
( C) Met hadone
( D) Hydr ocodone
( E) None of t he above
Vi ew Answer 2. The answer i s C[] . 3. For t he U. S. government to pI ace a
drug i nt o scheduI e I I I , whi ch of t he f oI I owi ng fi ndi ngs must be made
concerni ng t he drug?
( A) The drug or ot her subst ance has a hi gh pot ent i al f or abuse.
( B) Abuse of t he dr ug or ot her subst ance may l ead t o l i mi t ed physi cal dependence
or psychol ogi cal dependence r el at i ve t o t he dr ugs or ot her subst ances i n schedul e
Ì V.
( C) The dr ug or ot her subst ance has no cur r ent l y accept ed medi cal use i n t r eat ment
i n t he Uni t ed St at es.
( D) Abuse of t he dr ug or ot her subst ance may l ead t o moderat e or l ow physi cal
dependence or hi gh psychol ogi cal dependence.
( E) Ther e i s a l ack of accept ed saf et y f or use of t he dr ug or ot her subst ance under
medi cal super vi si on.
Vi ew Answer 3. The answer i s D[] . 4. Under the FederaI Cont roI I ed
Subst ances Act , aI I of the f oI I owi ng i t ems must appear on a cont roI I ed-
substance prescri pt i on I abeI EXCEPT t he
( A) name, addr ess, and DEA number of t he pharmacy.
( B) name of t he pat i ent .
( C) name of t he pr escr i bi ng pract i t i oner .
( D) seri al number assi gned t o t he pr escri pt i on.
( E) dat e of t he i ni t i al f i l l i ng of t he pr escri pt i on.
Vi ew Answer 4. The answer i s A[ and] . 5. Under t he FederaI Cont roI I ed
Subst ances Act , aI I of the f oI I owi ng ent i t i es must regi ster wi t h the DEA
EXCEPT
( A) pr escr i ber s of cont rol l ed subst ances.
( B) phar maci st s who di spense cont r ol l ed subst ances.
( C) di st ri but ors of cont rol l ed subst ances.
( D) i mpor t ers of cont rol l ed subst ances.
( E) uni ver si t i es conduct i ng i nst r uct i onal act i vi t i es wi t h cont r ol l ed subst ances l i st ed
i n schedul es Ì Ì - V.
Vi ew Answer 5. The answer i s B[ and] . 6. Under t he FederaI Cont roI I ed
Subst ances Act , whi ch of t he f oI I owi ng st atement s concerni ng the emergency
di spensi ng of a scheduI e I I cont roI I ed substance i s t rue?
( A) The pract i t i oner who aut hor i zes t he or al prescr i pt i on must , wi t hi n 7 days, del i ver
a wr i t t en pr escr i pt i on t o t he di spensi ng phar maci st .
( B) The quant i t y prescr i bed and di spensed must be l i mi t ed t o t he amount necessar y
t o adequat el y t reat t he pat i ent duri ng t he emergency per i od.
( C) Ì t i s not r easonabl y possi bl e f or t he pr act i t i oner t o pr ovi de a wr i t t en prescr i pt i on
t o be present ed t o t he per son di spensi ng t he cont r ol l ed subst ance bef ore t he
di spensi ng.
( D) No appr opr i at e al t ernat i ve t r eat ment i s avai l abl e, i ncl udi ng admi ni st rat i on of a
cont r ol l ed subst ance t hat i s not i n schedul e Ì Ì .
( E) Al l of t he above st at ement s are t rue.
Vi ew Answer 6. The answer i s E[] . 7. Under t he FederaI Cont roI I ed
Subst ances Act , t he cri me t ransf er warni ng, "Caut i on: FederaI I aw prohi bi ts t he
t ransf er of thi s drug t o any person other t han the pat i ent f or whom i t was
prescri bed, " must appear on the prescri pt i on cont ai ner I abeI of aI I cont roI I ed
substances EXCEPT
( A) schedul e Ì Ì cont r ol l ed subst ances.
( B) schedul e Ì Ì Ì cont r ol l ed subst ances.
( C) schedul e Ì V cont rol l ed subst ances.
( D) schedul e V cont r ol l ed subst ances.
Vi ew Answer 7. The answer i s D[] . P. 556


8. Whi ch of the foI I owi ng stat ements concerni ng drug recaI I cI assi f i cat i on i s
t rue?
( A) A Cl ass Ì r ecal l i s a si t uat i on i n whi ch use of , or exposur e t o, a vi ol at i ve pr oduct
i s not l i kel y t o cause adver se heal t h consequences.
( B) A Cl ass Ì r ecal l i s a si t uat i on i n whi ch use of , or exposur e t o, a vi ol at i ve pr oduct
may cause t emporar y or medi cal l y r ever si bl e adver se heal t h consequences or i n
whi ch t he pr obabi l i t y of ser i ous heal t h consequences i s remot e.
( C) A Cl ass Ì recal l i s a si t uat i on i n whi ch t her e i s a r easonabl e pr obabi l i t y t hat t he
use of , or exposur e t o, a vi ol at i ve pr oduct wi l l cause ser i ous adverse heal t h
consequences or deat h.
( D) A Cl ass Ì Ì r ecal l i s a si t uat i on i n whi ch use of , or exposur e t o, a vi ol at i ve
pr oduct i s not l i kel y t o cause adver se heal t h consequences.
( E) A Cl ass Ì Ì Ì r ecal l i s a si t uat i on i n whi ch t her e i s a r easonabl e probabi l i t y t hat t he
use of , or exposur e t o, a vi ol at i ve pr oduct wi l l cause ser i ous adverse heal t h
consequences or deat h.
Vi ew Answer 8. The answer i s C[ and] . 9. Under t he FederaI Food, Drug,
and Cosmet i c Act , aI I of t he foI I owi ng st atement s are consi dered a mi sbrandi ng
of a drug EXCEPT i f
( A) t he l abel i ng i s f al se or mi sl eadi ng i n any par t i cul ar.
( B) an or al cont r acept i ve i s di spensed wi t hout t he r equi r ed pat i ent package i nsert .
( C) t he dr ug i s an i mi t at i on of anot her dr ug, or i f i t i s of f ered f or sal e under t he
name of anot her dr ug.
( D) t he dr ug consi st s i n whol e or i n part of any f i l t hy, put ri d, or decomposed
subst ance.
Vi ew Answer 9. The answer i s D[] . 10. AI I of t he f oI I owi ng oraI medi cati ons
are exempt f rom chi I d- resi stant packagi ng EXCEPT
( A) anhydr ous chol est yrami ne i n powder f or m
( B) ni t r ogl yceri n pr eparat i ons i n sust ai ned rel ease f orm
( C) cycl i cal l y admi ni st ered oral cont racept i ves i n manuf act ur ers' mnemoni c
( memor y- ai d) di spenser packages t hat rel y sol el y upon t he act i vi t y of one or mor e
pr ogest ogen or est rogen subst ances
( D) pancrel i pase pr epar at i ons i n t abl et , capsul e, or powder f orm t hat cont ai n no
ot her prescr i pt i on medi cat i on
Vi ew Answer 10. The answer i s B[] . P. 557


ANSWERS AND EXPLANATIONS
1. The answer i s E [ V] .
Nar cot i cs and cont rol l ed subst ances i n schedul es Ì Ì - V may be del i ver ed t o t he
pat i ent by mai l . The U. S. Post al Ser vi ce no l onger pr ohi bi t s t he mai l i ng of narcot i cs
by a physi ci an or pharmaci st ( pursuant t o a pr escr i pt i on) t o t he pat i ent .
2. The answer i s C [ VÌ Ì Ì ; VÌ Ì Ì . A; Ì . Ì . 2. c. ( 2)] .
Met hadone i s appr oved by t he FDA f or use i n t he t r eat ment of narcot i c addi ct i on.
Onl y a proper l y r egi st ered narcot i c t reat ment pr ogr am may di spense met hadone f or
mai nt enance or det oxi f i cat i on t reat ment . Pharmaci es t hat are not so regi st er ed may
onl y di spense met hadone f or sever e pai n.
3. The answer i s D [ Ì . A. 3] .
To pl ace a drug i nt o schedul e Ì Ì Ì , t he U. S. government must make t he f ol l owi ng
f i ndi ngs concer ni ng t he dr ug: ( 1) i t has a pot ent i al f or abuse l ess t han t he dr ugs or
ot her subst ances i n schedul es Ì and Ì Ì ; (2) i t has a cur r ent l y accept ed medi cal use
i n t reat ment i n t he Uni t ed St at es; and (3) abuse of t he dr ug may l ead t o moder at e or
l ow physi cal dependence or hi gh psychol ogi cal dependence.
4. The answer i s A [ Ì . Ì . 8. c. (1) , (2) , (3) , (4) , (5) , (6) and (7) ] .
A phar macy' s DEA number i s not requi r ed t o appear on t he medi cat i on cont ai ner
l abel di spensed t o t he pat i ent .
5. The answer i s B [ Ì . B. 2. a, b, c, d, e, f , g, h, i , j and k; Ì . B. 9. d] .
Agent s and empl oyees of DEA r egi st r ant s, such as pharmaci st s, ar e exempt f r om
r egi st er i ng wi t h t he DEA. Pharmaci es, not t he i ndi vi dual pharmaci st s, must r egi st er
wi t h t he DEA.
6. The answer i s E [ Ì . Ì . 4. a, b] .
Emer gency di spensi ng of an or al schedul e Ì Ì cont r ol l ed-subst ance pr escri pt i on must
be done i n st r i ct compl i ance wi t h t he l aw. Bef ore di spensi ng such a pr escri pt i on, t he
pharmaci st must make t he t hreshol d det er mi nat i on t hat ALL t hr ee f act or s t hat def i ne
an emergency si t uat i on (see Ì . Ì . 4. a) are present . Ì f any one of t he t hree f act ors i s
absent , t he prescri pt i on i s not f or an emergency si t uat i on, and a wr i t t en prescr i pt i on
must be present ed t o t he pharmaci st .
7. The answer i s D [ Ì . Ì . 8. c. (7) ] .
The f eder al cri me t ransf er war ni ng l abel i s not r equi red t o appear on t he
pr escri pt i on cont ai ner l abel of schedul e V cont r ol l ed subst ances.
8. The answer i s C [ Ì Ì . H. 2. a, b and c] .
A Cl ass Ì r ecal l i s a si t uat i on i n whi ch t her e i s a r easonabl e probabi l i t y t hat t he use
of , or exposur e t o, a vi ol at i ve pr oduct wi l l cause ser i ous adver se heal t h
consequences or deat h.
9. The answer i s D [ Ì Ì . Ì . 1, 2] .
The Feder al Food, Dr ug, and Cosmet i c Act st at es t hat a dr ug i s consi dered
adul t erat ed i f i t consi st s i n whol e or i n part of any f i l t hy, put ri d, or decomposed
subst ance. The t erms " mi sbrandi ng¨ and " adul t erat i on¨ ar e of t en ref er red t o i n
l i t er at ur e and case l aw as bei ng t he same or si mi l ar vi ol at i ons under t he l aw.
However , t he Act set s f or t h speci f i c i nst ances of adul t erat i on and speci f i c i nst ances
of mi sbr andi ng.
10. The answer i s B [ Ì Ì Ì . A. 1] .
Onl y subl i ngual dosage f or ms of ni t r ogl ycer i n are exempt f rom chi l d- r esi st ant
packagi ng.

26
Reviewing and Dispensing Prescription and
Medication Orders
Todd A. Brown
I. DEFINITIONS
A. Prescri pt i ons ar e order s f or medi cat i ons, nondr ug product s, and ser vi ces t hat
ar e wr i t t en by a l i censed pr act i t i oner or mi dl evel pr act i t i oner who i s aut hor i zed by
st at e l aw t o prescr i be (see Appendi x A) . Phar maci st s ar e i ncreasi ngl y bei ng gi ven
pr escri bi ng pr i vi l eges by enact ment of st at e coI I aborati ve drug t herapy
management ( CDTM) l egi sl at i on. Thi s al l ows phar maci st s t o change t he dose of
exi st i ng medi cat i ons or or der new medi cat i on under est abl i shed pr ot ocol s or
gui del i nes agreed on by t he pharmaci st and physi ci an. Pr act i t i oners may pr escri be
onl y medi cat i ons t hat are wi t hi n t hei r scope of pract i ce. Prescr i pt i ons may be
wr i t t en, pr esent ed or al l y ( by t el ephone) , or present ed el ect r oni cal l y ( i . e. , vi a f ax or
comput er net wor k) t o t he pharmaci st . The r equi r ement s of t he pr escr i pt i on f orm
i ncl ude securi t y f eat ures and t amper - r esi st ant char act eri st i cs and var y wi t h st at e
r egul at i ons. The prescr i pt i on ser ves as a vehi cl e f or communi cat i on f rom t he
pr escri ber t o t he pharmaci st about t he needs of t he pat i ent . The f ol l owi ng
i nf or mat i on shoul d be i ncl uded on a pr escri pt i on:
1. Pati ent i nf ormat i on, i ncl udi ng f ul l name and addr ess
2. Date on whi ch t he prescri pt i on was i ssued
3. Name and dosage f orm of the product . The name can be any of t he f ol l owi ng:
a. Pr opr i et ar y (br and)
b. Nonpr opr i et ar y (generi c)
c. Chemi cal
4. Product st rengt h. The st r engt h of t he pr oduct i s not r equi red i f onl y one st r engt h
i s commer ci al l y avai l abl e or i f t he pr oduct cont ai ns a combi nat i on of act i ve
i ngredi ent s. Ì t i s advi sabl e t o i ncl ude t he st rengt h t o reduce t he chance of
mi si nt er pr et i ng t he prescr i pt i on. Ì f t he dose i s t o be cal cul at ed by t he phar maci st ,
t hen t he pharmaci st can deci de t he st r engt h of t he pr oduct di spensed af t er
cal cul at i ng t he pat i ent ' s dose.
5. Quant i t y t o be di spensed. Thi s shoul d i ncl ude t he amount and t he uni t s of
measure ( e. g. , grams, ounces, t abl et s). Ì f t he amount i s not speci f i ed, t he di r ect i ons
shoul d speci f y t he dose t o be t aken and t he durat i on of t herapy so t hat t he
pharmaci st can cal cul at e t he quant i t y r equi red f or t he pat i ent .
6. Di rect i ons for t he pharmaci st . Di r ect i ons may be r equi r ed f or :
a. Pr eparat i on (e. g. , compoundi ng)
b. Label i ng (i . e. , i nf ormat i on t o be put on t he prescri pt i on l abel )
7. Di rect i ons for t he pat i ent . These shoul d i ncl ude expl i ci t i nst ruct i ons on t he
quant i t y, schedul e, and dur at i on f or proper use. " As Di rect ed¨ shoul d be avoi ded. Ì f
t he di r ect i ons var y, a mi ni mum and maxi mum dose can be used.
8. Ref i I I i nf ormat i on. Ì f r ef i l l i nf or mat i on i s not suppl i ed, i t i s gener al l y assumed
t hat no r ef i l l s ar e aut hori zed. " As needed¨ (pr o r e nat a [ pr n] ) r ef i l l s ar e usual l y
i nt er pr et ed as al l owi ng f or r ef i l l s f or 1 year unl ess l aws or regul at i ons rest r i ct t he
amount or t i me per i od i n whi ch a prescr i pt i on i s val i d.
9. Prescri ber i nformati on. Thi s shoul d i ncl ude t he name, of f i ce addr ess, si gnat ur e
of t he pr escri ber, t he Drug Enf orcement Admi ni st r at i on ( DEA) number ( f or cont r ol l ed
subst ances onl y) and t he Nat i onal Provi der Ì dent i f i er ( NPÌ ) number .
P. 559


B. Medi cat i on orders are or ders f or medi cat i ons by an i ndi vi dual aut hori zed t o
pr escri be and are i nt ended f or use by pat i ent s whi l e i n an i nst i t ut i onal set t i ng. They
may be wr i t t en, present ed or al l y (by t el ephone) , or present ed el ect roni cal l y ( i . e. , vi a
f ax or comput er net wor k) t o t he phar maci st . The medi cat i on or der general l y i ncl udes
1. Pati ent i nf ormat i on (e. g. , f ul l name, i dent i f i cat i on number )
2. Date and t i me t he or der was wr i t t en
3. Name of t he product . The name can be any of t he f ol l owi ng:
a. Pr opr i et ar y (br and)
b. Nonpr opr i et ar y (generi c)
c. Chemi cal
4. Product st rengt h, dosage, and rout e of admi ni st rat i on. The st r engt h of t he
pr oduct i s not requi r ed i f onl y one st r engt h i s commer ci al l y avai l abl e or i f t he
pr oduct cont ai ns a combi nat i on of act i ve i ngr edi ent s. Ì t i s advi sabl e t o i ncl ude t he
st r engt h t o r educe t he chance of mi si nt erpr et i ng t he or der . The pharmaci st may
deci de t he st r engt h of t he pr oduct di spensed af t er cal cul at i ng t he pat i ent ' s dose.
The dosage and rout e of admi ni st r at i on shoul d be i ncl uded t o r educe t he chance of
mi si nt er pr et i ng t he order and t o al l ow f or cor rect admi ni st rat i on t o t he pat i ent .
5. Prescri ber' s si gnat ure. Ì f t he order was t aken ver bal l y, t he name of t he person
t r anscri bi ng t he order shoul d be i ncl uded.
6. Di rect i ons for t he pharmaci st . These can be used f or :
a. Pr eparat i on (e. g. , compoundi ng)
b. Label i ng (i . e. , i nf ormat i on t o be put on t he l abel )
7. I nst ructi ons f or admi ni st rati on, i ncl udi ng quant i t y, rout e of admi ni st rat i on,
schedul e, and dur at i on of use
II. UNDERSTANDING THE PRESCRIPTION OR
MEDICATION ORDER AND EVALUATING ITS
APPROPRIATENESS
A. Underst andi ng t he order. A compl et e underst andi ng of al l i nf or mat i on cont ai ned
i n a pr escr i pt i on or medi cat i on or der i s r equi red. Each pi ece of i nf ormat i on shoul d
be appropr i at e and consi st ent wi t h t he r emai ni ng i nf or mat i on (i . e. , t he i nst r uct i ons
f or use shoul d be appropr i at e f or t he medi cat i on bei ng or dered). The pharmaci st
shoul d r ead t he ent i r e prescr i pt i on or medi cat i on or der car ef ul l y t o det er mi ne t he
pr escri ber ' s i nt ent by i nt er pr et i ng t he f ol l owi ng i nf or mat i on:
1. The name and addr ess of bot h t he pat i ent and t he pr escr i ber
2. The pat i ent ' s di sease or condi t i on r equi ri ng t r eat ment
3. The reason t he order i s i ndi cat ed, r el at i ve t o t he medi cal need of t he pat i ent
( e. g. , an ant i bact eri al f or an i nf ect i on)
4. The name of t he pr oduct , t he quant i t y pr escri bed, and i nst ruct i ons f or use
5. Al l t er mi nol ogy, i ncl udi ng uni t s of measur e ( apot hecar y, met r i c, or Engl i sh) and
Lat i n abbrevi at i ons (see Appendi x A f or common abbrevi at i ons)
B. EvaI uat i ng the appropri at eness. Compl et e i nf or mat i on i s r equi red on t he
pr escri pt i on or medi cat i on or der t o pr ovi de t he necessar y i nf ormat i on t o al l ow t he
pharmaci st t o eval uat e t he appropr i at eness of t he or der . When t he or der i s
i ncompl et e, t he pharmaci st must obt ai n t he requi r ed i nf or mat i on f r om ei t her t he
pat i ent or t he pr escr i ber . The f ol l owi ng shoul d be consi dered duri ng an eval uat i on:
1. The pat i ent ' s di sease or condi t i on r equi ri ng t r eat ment
2. The pat i ent ' s al l er gi es or hyper sensi t i vi t i es
3. The pharmacol ogi cal or bi ol ogi cal act i on of t he pr escr i bed pr oduct
4. The pr escri bed r out e of admi ni st rat i on
5. Whet her t he pr escr i bed pr oduct mi ght r esul t i n a drug-dr ug, drug-di sease, or
dr ug-f ood i nt eract i on
P. 560


6. Whet her t he dose, dosage f or m, and dosage regi men are saf e and l i kel y t o meet
t he needs of t he pat i ent
7. Whet her t he pat i ent wi l l have any di f f i cul t i es adheri ng t o t he r egi men and t he
pot ent i al i mpact on t he t her apeut i c out come desi r ed
8. Whet her t he t ot al quant i t y of medi cat i on pr escr i bed i s suf f i ci ent t o al l ow pr oper
compl et i on of a course of t her apy
9. Whet her a physi cal or chemi cal i ncompat i bi l i t y mi ght r esul t ( i . e. , i f t he pr oduct
r equi r es ext empor aneous compoundi ng)
10. Whet her a l i censed pr act i t i oner , act i ng i n t he course and scope of pr act i ce,
i ssued t he pr escri pt i on i n good f ai t h, f or a l egi t i mat e medi cal pur pose
C. Di scoveri ng i nappropri at e prescri pti ons or medi cat i on orders. Phar maci st s
ar e requi r ed t o r evi ew medi cat i on prof i l es t o ensur e t he appr opri at eness of
pr escri pt i ons or medi cat i on orders. Thi s i s commonl y cal l ed drug ut i l i zat i on r evi ew
( DUR) . Pharmaci st s shoul d not f i l l or pr ocess prescr i pt i ons or medi cat i on or ders
t hat t hey have concer ns wi t h or t hat ar e consi dered i nappr opr i at e but , r at her , shoul d
cont act t he pr escri ber . The process of cal l i ng a pr escr i ber t o di scuss concer ns
i dent i f i ed dur i ng a DUR i s commonl y cal l ed t herapeut i c i ntervent i on.
1. When perf ormi ng a t her apeut i c i nt er vent i on, t he f ol l owi ng i nf or mat i on shoul d be
pr ovi ded:
a. A br i ef descr i pt i on of t he probl em
b. A ref erence sour ce t hat document s t he pr obl em
c. A descri pt i on of t he cl i ni cal si gni f i cance of t he pr obl em
d. A suggest i on of a sol ut i on t o t he probl em
2. The f ol l owi ng resol ut i ons ar e possi bl e t o sol ve t he pr obl em or concern:
a. The pr escri pt i on or medi cat i on order wi l l be di spensed as wr i t t en.
b. The prescri pt i on or medi cat i on order wi l l not be di spensed.
c. The pr escri pt i on or medi cat i on order wi l l be al t er ed and di spensed.
3. Document at i on of t he r esul t s of a t herapeut i c i nt er vent i on ar e requi r ed i f t he
pr escri pt i on or medi cat i on or der i s changed. The name of t he pr escri ber, dat e of
communi cat i on, i ssues di scussed, and r esol ut i on shoul d be i ncl uded i n t he
document at i on. Thi s i nf or mat i on shoul d be kept f or t he same t i me per i od as t he
pr escri pt i on or medi cat i on or der .
4. Ì f t he pharmaci st f eel s t hat , i n hi s or her pr of essi onal j udgment , an or der i s
i nappr opr i at e and coul d har m t he pat i ent , t he phar maci st shoul d not pr ocess t he
or der. The pharmaci st may al so be requi r ed t o expl ai n t he si t uat i on t o t he pat i ent .
Ì f , af t er a t herapeut i c i nt er vent i on, t he pharmaci st bel i eves t he or der i s st i l l
i nappr opr i at e, t he gui del i nes of t he i nst i t ut i on and pr of essi onal j udgment shoul d be
f ol l owed.
III. PROCESSING PRESCRIPTIONS AND MEDICATION
ORDERS
r equi r es t hat t he phar maci st f ol l ow appropri at e gui del i nes. An envi r onment t hat
l i mi t s di st r act i ons and di sr upt i ons duri ng t hese act i vi t i es wi l l assi st i n i ncr easi ng t he
accur acy of t hi s pr ocess. Aut omat i on and t he use of pharmacy t echni ci ans al l ow t he
pharmaci st t o over see t hese f unct i ons but spend l ess t i me per f or mi ng t hese
act i vi t i es. The t i me saved al l ows t he pharmaci st gr eat er t i me f or pat i ent - f ocused
act i vi t i es, such as counsel i ng and pat i ent educat i on.
A. The f oI I owi ng i nf ormat i on shoul d be r ecorded on t he pr escr i pt i on:
1. The pr escri pt i on number ( f or i ni t i al f i l l i ng)
2. The or i gi nal dat e of f i l l i ng
3. The pr oduct and quant i t y di spensed
4. The pharmaci st ' s i ni t i al s
B. Product seI ect i on. Generi c subst i t ut i on st at ut es, as wel l as f ormul ar y and
t her apeut i c subst i t ut i on pol i ci es, mi ght pr ovi de di r ect i on i n pr oduct sel ect i on.
C. Product preparati on f or use by t he pat i ent . The f ol l owi ng mi ght be necessar y f or
pr epar at i on:
P. 561


1. Obt ai ni ng t he proper amount of medi cat i on t o be di spensed
2. Reconst i t ut i on ( t he addi t i on of l i qui d t o make a sol ut i on or suspensi on)
3. Ext empor aneous compoundi ng (see Chapt er 5)
4. Assembl y of t he medi cat i on del i ver y uni t
D. SeI ect i on of t he proper package or cont ai ner i s r equi red t o ensur e pr oduct
st abi l i t y, t o promot e pat i ent compl i ance, and t o compl y wi t h l egal r equi r ement s. Thi s
i nf or mat i on i s commonl y f ound i n t he Uni t ed St at es Phar macopei a ( USP) .
E. LabeI i ng t he prescri bed product
1. The prescri pt i on I abeI t ypi cal l y cont ai ns t he f ol l owi ng i nf or mat i on:
a. Name and addr ess of t he pharmacy
b. Pat i ent ' s name
c. Or i gi nal dat e of f i l l i ng
d. Pr escr i pt i on number
e. Di rect i ons f or use
f . Pr oduct ' s br and name or generi c name and manuf act ur er
g. Pr oduct st r engt h (i f avai l abl e i n mor e t han one st r engt h)
h. Quant i t y of medi cat i on di spensed
i . Pr escr i ber ' s name
j . Expi r at i on dat e of t he medi cat i on
k. Phar maci st ' s i ni t i al s
2. Uni t -dose packages cont ai n one dose or one uni t of medi cat i on. For a
medi cat i on or der t hat i s di spensed i n uni t - dose packages, t he l abel shoul d i dent i f y
t he pr oduct ' s br and or generi c name, st r engt h, l ot number , and expi r at i on dat e.
3. Auxi I i ar y and cauti onar y I abeI s. To ensure pr oper medi cat i on use, st or age, and
compl i ance wi t h appl i cabl e st at ut es, and t o rei nf or ce i nf ormat i on provi ded duri ng
counsel i ng, auxi l i ar y and/ or caut i onar y l abel s shoul d be af f i xed when appropr i at e
( see Appendi x A) .
4. For medi cat i on i n schedul es Ì Ì -Ì V (see Chapt er 25) , a f eder al t r ansf er war ni ng i s
r equi r ed.
F. Record keepi ng and conf i denti aI i t y. The phar maci st i s requi r ed t o mai nt ai n
prescri pt i on f i I es and records i n accor dance wi t h st andards of sound pract i ce and
st at ut or y r equi r ement s. The i mpl ement at i on of t he HeaI t hcare I nsurance
Port abi I i t y and Account abi I i t y Act ( HÌ PAA) has put addi t i onal r equi rement s on al l
heal t h pr of essi onal s who have access t o heal t h i nf or mat i on (see Chapt er 25) . The
r ecor ds i ncl ude a pat i ent prof i I e, cont ai ni ng pat i ent demographi c i nf ormat i on and a
compl et e chr onol ogi cal record of al l medi cat i on use and ser vi ces pr ovi ded i n t he
del i ver y of phar maceut i cal car e.
1. The pat i ent prof i l e shoul d cont ai n t he f ol l owi ng pati ent i nf ormat i on:
a. Pat i ent ' s name
b. Pat i ent ' s addr ess (or r oom number i n i nst i t ut i onal set t i ngs)
c. Any known al l er gi es, sensi t i vi t i es, or hi st or y of i di osyncr at i c r eact i ons t o pr evi ous
medi cat i ons
d. Bi rt h dat e ( i . e. , t o assess t he appropr i at eness of t he dose)
e. Cl i ni cal condi t i on( s) ( t o hel p assess t he appr opr i at eness of t he medi cat i on and t o
pr event dr ug- di sease i nt er act i ons)
f . Wei ght ( t o assess t he appropr i at eness of t he dose)
g. Occupat i on ( t o det ect condi t i ons associ at ed wi t h a part i cul ar occupat i on and t o
hel p det ermi ne i f t he pat i ent wi l l be abl e t o compl y wi t h t he regi men)
h. Nonpr escr i pt i on medi cat i on use ( t o pr event dr ug- dr ug and dr ug- di sease
i nt er act i ons, t o assess medi cat i on ef f ect i veness, and t o det ect possi bl e adver se
ef f ect s)
2. Ì n addi t i on, t he pat i ent pr of i l e shoul d cont ai n t he f ol l owi ng i nf or mat i on f r om each
pr escri pt i on or medi cat i on or der :
a. Name of t he medi cat i on
b. Medi cat i on st r engt h
c. Dosage f orm
d. Quant i t y di spensed
P. 562


e. Di rect i ons f or use
f . Pr escri pt i on number
g. Di spensi ng dat e
h. Number of r ef i l l s aut hor i zed and r emai ni ng
i . Pr escr i ber ' s name
j . Phar maci st ' s i ni t i al s
IV. DISPENSING MEDICATION AND COUNSELING.
The di spensi ng of medi cat i on r equi r es t hat t he phar maci st ver i f y t hat pat i ent s have
t he necessar y knowl edge and abi l i t y t o adhere t o t he prescr i bed t r eat ment . Thi s wi l l
i ncrease t he l i kel i hood of obt ai ni ng t he desi r ed out comes.
A. CounseI i ng pat i ent s. The phar maci st shoul d eval uat e t he pat i ent ' s
under st andi ng of each medi cat i on and suppl y addi t i onal i nf ormat i on when t he
pat i ent ' s i nf ormat i on i s i ncorr ect or i nsuf f i ci ent . The pharmaci st mi ght need t o
advi se pat i ent s regardi ng t he proper dosage, appearance, and name of t he
medi cat i on. Ì nf ormat i on about t he rout e of admi ni st rat i on, i nst ruct i ons f or use,
dur at i on of use, and t he r eason t he pr oduct was pr escri bed may al so be needed. Ì n
addi t i on, t he f ol l owi ng t opi cs mi ght al so be appr opr i at e dur i ng t he counsel i ng
sessi on:
1. Speci aI procedures. As appr opr i at e, t he pharmaci st shoul d advi se pat i ent s on
how t o t ake t he medi cat i on ( e. g. , on an empt y st omach, wi t h pl ent y of wat er ) and
i nst r uct t hem on f oods t o avoi d whi l e t aki ng t he medi cat i on ( e. g. , al cohol i c
bever ages, dai r y pr oduct s) .
2. Potent i aI adverse ef fect s. The pharmaci st shoul d ensur e t hat pat i ent s ar e awar e
of t he possi bl e adver se ef f ect s associ at ed wi t h t he medi cat i on. Pat i ent s shoul d
under st and t he f ol l owi ng:
a. The f requency of an adver se ef f ect . Thi s wi l l hel p pat i ent s r ecogni ze common
adver se ef f ect s and not be overl y concer ned wi t h t hose t hat are r ar e.
b. The severi t y of an adver se ef f ect . Thi s wi l l hel p pat i ent s f ocus on t hose adverse
ef f ect s t hat ar e severe and not t hose t hat are i nconsequent i al .
c. What act i on shoul d be t aken t o manage or mi ni mi ze t he adverse ef f ect . Thi s wi l l
hel p pat i ent s deal wi t h possi bl e adverse ef f ect s i n t he appr opr i at e manner .
3. Proper storage. The pharmaci st shoul d counsel pat i ent s on how t o st or e
medi cat i ons proper l y t o ensur e st abi l i t y and pot ency.
4. Over- t he-counter ( OTC) product s. The pharmaci st shoul d i nst ruct pat i ent s about
t he use of OTC pr oduct s t hat mi ght or mi ght not be appropr i at e when t aki ng a
pr escri bed product .
B. CounseI i ng heaI th prof essi onaI s. Heal t h pr of essi onal s ( i . e. , i n an i nst i t ut i onal
set t i ng) may admi ni st er medi cat i ons t o pat i ent s. Ì n t hese cases, t he pharmaci st
shoul d ensur e t hat t he heal t h prof essi onal has suf f i ci ent knowl edge t o admi ni st er
t he pr oduct . Ì nf ormat i on t hat heal t h prof essi onal s woul d need t o admi ni st er
medi cat i ons saf el y and ef f ect i vel y i ncl ude t he f ol l owi ng:
1. The choi ce of a part i cul ar pr oduct
2. The pr oper dosage, dosage regi men, and r out e of admi ni st r at i on
3. The cost of t he pr escri bed product and t he cost s associ at ed wi t h i t s use ( i . e. ,
admi ni st rat i on cost s and cost s of t r eat i ng possi bl e adverse ef f ect s)
4. The avai l abi l i t y of commer ci al l y made product s
5. Pot ent i al adver se ef f ect s
6. Dr ug i nt eract i ons
7. Physi cal i ncompat i bi l i t i es
8. Saf e handl i ng and di sposal pr ocedur es
9. Nut ri t i onal i nt er act i ons or r equi rement s
10. Drug i nt er f erence wi t h l aborat or y t est s
V. PATIENT MONITORING.
The pr ovi si on of pharmaceut i cal car e requi r es a pharmaceut i caI care pI an (see
Chapt er 20) . Moni t or i ng a pat i ent ' s need f or medi cat i on and t he ef f ect of t he
medi cat i on
P. 563

on t he pat i ent maxi mi zes t he ef f ect i veness of t he medi cat i ons bei ng t aken.
Undesi r ed out comes associ at ed wi t h dr ug t her apy ar e f requent l y cal l ed drug
t herapy probI ems.
A. Pharmaceut i caI care pI an. To i ncrease t he f requency and benef i t s of desi r ed
out comes, a phar maceut i cal car e pl an shoul d i ncl ude t he f ol l owi ng:
1. Assessment . A r evi ew of t he medi cal condi t i ons and sympt oms t o det er mi ne t he
need f or medi cat i on
2. PI an. A deci si on of an appropri at e drug t herapy based on t he assessment of t he
pat i ent
3. Moni tori ng. A revi ew of t he out comes of drug t her apy ( i . e. , goal s and end poi nt s)
t o det ermi ne i f t he pat i ent i s obt ai ni ng t he desi r ed out comes
B. Drug t herapy probI ems are evi dence of l ess-t han-opt i mal dr ug t her apy.
Det ect i on of drug- rel at ed pr obl ems r equi res an assessment of t he need f or a change
i n dr ug t her apy. Possi bl e pr obl ems i ncl ude
1. Unnecessar y drug t herapy. The medi cat i on cannot be associ at ed wi t h a medi cal
condi t i on or t he presence of a condi t i on i n whi ch nondr ug t her apy i s more
appropr i at e.
2. Wrong drug. The dr ug i s not i ndi cat ed f or t he condi t i on or i s not del i ver i ng t he
desi r ed out comes, or a mor e ef f ect i ve dr ug i s avai l abl e.
3. Dose t oo I ow. Ì ncor rect dose, f r equency, admi ni st r at i on, or dur at i on of t her apy
r esul t s i n an i nsuf f i ci ent dose of drug t o t he pat i ent .
4. Adverse drug react i on. An al l er gi c r eact i on, dr ug i nt er act i on, or an undesi r abl e
ef f ect occurs f rom a medi cat i on.
5. Dose t oo hi gh. Ì ncor rect dose, f r equency, or dur at i on, r esul t s i n mor e medi cat i on
t han i s r equi r ed.
6. I nappropri ate adherence. The pat i ent i s not t aki ng t he opt i mal amount of
medi cat i on owi ng t o cost , admi ni st r at i on di f f i cul t i es, al t er nat i ve heal t h bel i ef s, or a
l ack of under st andi ng of t he need f or t he medi cat i on.
7. Need addi ti onaI drug t herapy. Owi ng t o an under t r eat ed condi t i on, syner gi sm
wi t h concur r ent drug t her apy or pr ophyl act i c t herapy i s r equi r ed.
P. 564


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. Medi cat i on orders di f f er f rom prescri pti ons i n whi ch of t he f oI I owi ng ways?
They
( A) ar e i nt ended f or ambul at or y use.
( B) cont ai n onl y t he gener i c name of t he medi cat i on.
( C) ar e i nt ended f or i nst i t ut i onal use.
( D) may be t ransmi t t ed el ect r oni cal l y.
( E) cont ai n t he quant i t y of medi cat i on t o be di spensed.
Vi ew Answer 1. The answer i s C[ see] . 2. I f a t herapeuti c i nt ervent i on i s
necessar y, aI I of t he f oI I owi ng i nf ormat i on shouI d be communi cated t o t he
prescri ber except
( A) a decl arat i on t hat " a mi st ake was made. ¨
( B) a br i ef descr i pt i on of t he pr obl em.
( C) a r ef erence sour ce t hat document s t he pr obl em.
( D) an al t er nat i ve or suggest i on t o r esol ve t he probl em.
( E) a descri pt i on of t he cl i ni cal si gni f i cance of t he pr obl em.
Vi ew Answer 2. The answer i s A[ see] . 3. The f oI I owi ng i nf ormat i on shouI d
be recorded on a prescri pt i on except t he
( A) pr escr i pt i on number .
( B) dat e of f i l l i ng.
( C) expi r at i on dat e.
( D) pr oduct and quant i t y di spensed.
( E) phar maci st ' s i ni t i al s.
Vi ew Answer 3. The answer i s C[ see] . 4. A prescri pt i on I abeI usuaI I y
cont ai ns aI I of the foI I owi ng except t he
( A) quant i t y di spensed.
( B) l ot number .
( C) pat i ent ' s di agnosi s.
( D) expi r at i on dat e.
( E) pr escr i ber ' s name.
Vi ew Answer 4. The answer i s C[ see] . 5. Auxi I i ar y and caut i onar y I abeI s
shouI d be used for aI I of t he f oI I owi ng purposes except t o
( A) subst i t ut e f or ver bal consul t at i on.
( B) ensure proper usage.
( C) i nf or m of st or age requi r ement s.
( D) compl y wi t h r egul at or y r equi r ement s.
( E) war n agai nst t he concomi t ant use of cer t ai n dr ugs or f oods.
Vi ew Answer 5. The answer i s A[ see] . 6. The f oI I owi ng i t ems are essent i aI
f or a pat i ent prof i I e syst em except
( A) t he pat i ent ' s name.
( B) t he prescr i ber ' s Dr ug Enf orcement Admi ni st rat i on ( DEA) regi st rat i on number .
( C) t he pat i ent ' s al l ergi es.
( D) t he pat i ent ' s bi rt h dat e.
( E) i nst ruct i ons f or medi cat i on use.
Vi ew Answer 6. The answer i s B[ seeand] . 7. The f oI I owi ng are drug t herapy
probI ems except
( A) an adverse ef f ect f r om a medi cat i on.
( B) sympt oms caused by under t reat ment .
( C) a drug-dr ug i nt eract i on.
( D) an undi agnosed condi t i on.
( E) an al l ergi c r eact i on t o a medi cat i on.
Vi ew Answer 7. The answer i s D[ see] . P. 565


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì . B] .
Medi cat i on or der s ar e wr i t t en f or t he car e of i npat i ent s. Bot h medi cat i on order s and
pr escri pt i ons may cont ai n t he brand or gener i c name of t he drug and may be
t r ansmi t t ed el ect roni cal l y. Onl y pr escr i pt i ons cont ai n t he quant i t y of medi cat i on t o
be di spensed.
2. The answer i s A [ see Ì Ì . C. 1] .
Ì nf ormat i on provi ded t o t he prescri ber duri ng a t her apeut i c i nt er vent i on shoul d
i ncl ude a descr i pt i on of t he probl em, ref erence sour ce, descri pt i on of t he cl i ni cal
si gni f i cance, and an al t er nat i ve. Ì nf ormi ng t he prescr i ber t hat a mi st ake was made
does not encourage cooper at i on and resol ut i on of t he pr obl em.
3. The answer i s C [ see Ì Ì Ì . A] .
The pr escri pt i on number, dat e of f i l l i ng, pr oduct and quant i t y di spensed, and
pharmaci st ' s i ni t i al s shoul d be recor ded on t he pr escr i pt i on. The expi r at i on dat e of
t he pr oduct bei ng di spensed i s not requi r ed.
4. The answer i s C [ see Ì Ì Ì . E. 1] .
The quant i t y of medi cat i on di spensed, l ot number , expi r at i on dat e of t he pr oduct ,
and pr escri ber ' s name are usual l y i ncl uded on t he l abel . The pat i ent ' s di agnosi s,
al t hough l i st ed i n t he pat i ent ' s prof i l e, i s not i ncl uded on t he pr escr i pt i on l abel .
5. The answer i s A [ see Ì Ì Ì . E. 3; Ì V. A. 1] .
Auxi l i ar y and caut i onar y l abel s are an adj unct t o, not a r epl acement f or , ver bal
consul t at i on. Appr opr i at e uses f or such l abel s i ncl ude ensuri ng pr oper use, st orage
r equi r ement s, and compl i ance wi t h st at ut or y r equi r ement s, and war ni ng agai nst f ood
and dr ug i nt eract i ons.
6. The answer i s B [ see Ì Ì Ì . F. 1 and 2] .
The pat i ent ' s name i s r equi red t o i dent i f y each pat i ent . Of t en, t he address or r oom
number i s r equi red t o i dent i f y pat i ent s wi t h si mi l ar names. The pat i ent ' s al l er gi es,
bi r t h dat e, and i nst r uct i ons f or use are r equi r ed t o pr event dr ug al l ergi es and t o
assess t he appr opr i at eness of t he prescr i pt i on or medi cat i on order .
7. The answer i s D [ see V. B] .
Adver se ef f ect s, undert reat ed condi t i ons, al l ergi c r eact i ons, and dr ug-drug
i nt er act i ons are al l dr ug t her apy pr obl ems. An undi agnosed condi t i on may l ead t o a
dr ug- rel at ed probl em once di agnosed; however , di agnosi s i s requi r ed bef or e t he
need f or medi cat i on can be assessed.

27
SteriIe Products
John Fani kos
I. INTRODUCTION.
The Uni t ed St at es Pharmacopei a and The Nat i onal Formul ar y ( USP) publ i shed
pr act i ce st andar ds f or compoundi ng st eri l e pr eparat i ons af t er case repor t s of pat i ent
har m and f at al i t y. The procedures and r equi rement s out l i ned i n USP Chapt er 797
ar e i nt ended t o pr event pat i ent harm resul t i ng f rom i ngredi ent er ror s and mi cr obi al
cont ami nat i on. The chapt er i ncl udes compoundi ng per sonnel responsi bi l i t i es,
t r ai ni ng and eval uat i on requi r ement s, medi cat i on pr epar at i on st eri l i t y and accuracy
ver i f i cat i on, cl assi f i cat i on of mi crobi al cont ami nat i on r i sk, and equi pment and
envi r onment al qual i t y and cont rol . Whi l e t hese st andar ds appl y t o al l f aci l i t i es
( hospi t al s, nursi ng homes, pharmaci es) and al l pract i t i oners (physi ci ans, nur ses,
t echni ci ans) , t hey ar e especi al l y i mpor t ant f or phar maci st s who are most of t en
i nvol ved wi t h st eri l e medi cat i on prepar at i on. Si nce t he st andards r equi re subst ant i al
i nvest ment i n l abor , equi pment , and suppl i es, r egul at or y agenci es (Food and Dr ug
Admi ni st rat i on, Joi nt Commi ssi on on Accredi t at i on of Heal t h Care Or gani zat i ons,
U. S. st at e boar ds of phar macy) ar e expect i ng i mpl ement at i on by Januar y 2006, wi t h
evi dence of l ong t erm compl i ance and rout i ne moni t or i ng t her eaf t er .
II. DEFINITIONS
A. St eri I i t y, an absol ut e t erm, means t he absence of l i vi ng mi cr oor gani sms.
1. Mi crobe i s a mi cr oscopi c or gani sms such as a bact er i a, f ungus, pr ot azoa or vi rus
2. Pyrogens are met abol i c by- product s of l i ve or dead mi croorgani sms t hat cause a
pyr et i c r esponse (i . e. , a f ever ) upon i nj ect i on.
3. St eri I e product s ar e pharmaceut i cal dosage f or ms t hat ar e st er i l e. Thi s i ncl udes
pr oduct s l i ke par ent er al pr epar at i ons, i r ri gat i ng sol ut i ons, and opht hal mi c
pr epar at i ons (see Chapt er 29) . St er i l e pr oduct compoundi ng requi r es cl eaner
f aci l i t i es, personnel t rai ni ng and t est i ng, and a sound knowl edge of st er i l i zat i on and
st abi l i t y pri nci pl es and pr act i ces.
4. Asept i c mani puI ati ons r ef ers t o t he t echni ques and pr ocedures used dur i ng
compoundi ng t hat mai nt ai n t he st er i l i t y of pharmaceut i cal dosage f orms.
5. Compounded St eri I e Preparati ons ( CSPs) i ncl ude;
a. Pr eparat i ons, when prepared accordi ng t o manuf act urer i nst r uct i ons, expose a
st eri l e agent t o pot ent i al mi cr obi al cont ami nat i on.
b. Pr epar at i ons made f r om nonst eri l e i ngr edi ent s t hat must be st er i l e bef or e pat i ent
admi ni st rat i on.
c. St er i l e or nonst eri l e bi ol ogi cal s ( vacci nes, i mmune gl obul i ns) , di agnost i cs,
medi cat i ons, nut ri t i onal s, and r adi ophar maceut i cal s t hat must be st eri l e pr i or t o
admi ni st rat i on or use as an i r r i gat i on, bat h, i mpl ant , i nhal at i on, i nj ect i on, or f or use
i n t he eye or ear.
6. Mi crobi aI Contami nat i on Ri sk LeveI s ar e assi gned accor di ng t o t he pr obabi l i t y
of cont ami nat i ng a prepar at i on wi t h mi cr obi al or gani sms, endot oxi ns, or wi t h f or ei gn
chemi cal or physi cal part i cul at e mat t er .
a. Low Ri sk LeveI CSPs ar e compounded by asept i cal l y t r ansf er ri ng a si ngl e st er i l e
dosage f orm f r om a st er i l e ampul e, vi al , bot t l e, or bag usi ng st eri l e needl es and
syr i nges t o a f i nal st eri l e cont ai ner or devi ce f or pat i ent admi ni st r at i on.
b. Medi um Ri sk LeveI CSPs are compounded by asept i cal l y t ransf er ri ng mul t i pl e
st eri l e dosage f orms f r om st eri l e ampul es, vi al s, bot t l es, or bags usi ng st er i l e
needl es and syr i nges t o a si ngl e f i nal st er i l e cont ai ner or devi ce f or admi ni st rat i on
t o mul t i pl e pat i ent s or t o one pat i ent on mul t i pl e occasi ons.
c. Hi gh Ri sk LeveI CSPs ar e compounded f rom nonst eri l e i ngr edi ent s and
t er mi nal l y st eri l i zed pr i or t o pat i ent admi ni st rat i on or st eri l e i ngr edi ent s t hat are
compounded under i nf er i or ai r qual i t y condi t i ons.
P. 567


d. I mmedi ate- use CSPs ar e compounded i n emer gency si t uat i ons or wher e
i mmedi at e pat i ent admi ni st rat i on i s mandat ed t o avoi d or harm t hat may resul t f r om
del ays i n t reat ment .
7. Compounded ParenteraI Preparati ons are phar maceut i cal dosage f or ms t hat are
i nj ect ed t hr ough one or mor e l ayer s of ski n. Because t he par ent eral r out e bypasses
t he pr ot ect i ve bar r i ers of t he body, parent er al prepar at i ons must be st er i l e. The pH
of a sol ut i on may mar kedl y i nf l uence t he st abi l i t y and compat i bi l i t y of par ent er al
pr epar at i ons (see V. B).
B. Desi gn and functi on of st eri I e compoundi ng areas
1. CI eanrooms ar e ar eas speci al l y const ruct ed and mai nt ai ned t o r educe t he
pr obabi l i t y of envi r onment al cont ami nat i on of st er i l e pr oduct s dur i ng t he
manuf act ur i ng process. Engi neeri ng cont rol s t o reduce t he pot ent i al f or ai r borne
cont ami nat i on i ncl ude ai r f l ow t hr ough hi gh-ef f i ci ency par t i cul at e- ai r ( HEPA) f i l t ers,
use of hori zont al f l ow cl ean benches, ver t i cal f l ow cl ean benches, bi ol ogi cal saf et y
cabi net s, and bar ri er i sol at ors. Cl ean r oom ar e t radi t i onal l y desi gned i n mul t i -
compart ment s or par t i t i oned wor k ar eas f or asept i c pr ocessi ng ( Fi gure 27-1) .
a. Ant e- area provi des a cl ean ar ea f or per sonal hygi ene and f or donni ng per sonal
pr ot ect i ve equi pment such as hai r cover s, gl oves, gowns, or f ul l cl ean room at t i re
( Fi gur e 27- 2) . Suppl i es ar e r emoved f r om shi ppi ng car t ons and decont ami nat ed wi t h
a di senf ect i ng agent . The ar ea shoul d provi de at l east an Ì nt er nat i onal Or gani zat i on
f or St andar di zat i on (Ì SO) Cl ass 8 or bet t er wor k envi r onment .
b. Buf fer area cont ai ns t he wor k sur f aces f or t he st agi ng of suppl i es and equi pment
used i n CSP pr epar at i on. Ì t shoul d provi de at l east an Ì SO Cl ass 7 wor k
envi r onment . The buf f er ar ea shoul d cont ai n no si nks or drai ns and be f r ee of
obj ect s t hat shed part i cl es (cardboar d, paper, cot t on, et c. ) . Tr af f i c f l ow i n and out i s
mi ni mi zed and r est ri ct ed t o qual i f i ed compoundi ng personnel .
c. Pri mar y engi neeri ng cont roI i s t he room t hat pr ovi des t he Ì SO Cl ass 5
envi r onment f or CSP pr epar at i on.
d. Di rect compoundi ng area i s t he cri t i cal ar ea wi t h t he pr i mar y engi neer i ng
cont r ol wher e compoundi ng i s per f or med and cri t i cal si t es ar e exposed t o HEPA
f i l t er ed ai r .
e. HEPA Fi I t ers are used t o cl eanse t he ai r ent er i ng t he r oom. These f i l t er s remove
al l ai rborne par t i cl es 0. 3 mm or l arger , wi t h an ef f i ci ency of 99. 97%. The ref er ence
st andards f or HEPA- f i l t er ed rooms has changed t o a met r i c based syst em ( Tabl e 27-
1) . HEPA- f i l t er ed r ooms ar e cl assi f i ed as Ì SO Cl ass 3 t hr ough 8. An Ì SO Cl ass 8
r oom cont ai ns no more t han 3, 520, 000 par t i cl es of 0. 5 µm or l arger per cubi c met er
of ai r .

Figure 27-1. Clean room design.
P. 568



Figure 27-2. Clean room attire.
f . Posi t i ve- pressure ai rf I ow i s used t o pr event cont ami nat ed ai r f r om f l owi ng i nt o
t he cl ean r oom. Ì n or der t o achi eve t hi s, t he ai r pr essur e i nsi de t he cl ean r oom must
be great er t han t he pressur e out si de t he r oom, so t hat when a door or wi ndow t o t he
cl ean room i s opened, t he ai r f l ow i s out war d.
g. Count ers i n t he cl ean r oom are made of st ai nl ess st eel or ot her nonpor ous,
easi l y cl eaned mat er i al .
h. WaI I s, f I oors, and cei I i ngs do not have cr acks or crevi ces and have rounded
cor ner s. Al l sur f aces shoul d al so be nonporous and washabl e t o enabl e regul ar
di si nf ect i on. Ì f wal l s or f l oor s are pai nt ed, an epoxy pai nt i s used.
i . Ai rf I ow. As wi t h t he HEPA f i l t ers used i n cl ean r ooms, t he ai r f l ow moves wi t h a
uni f or m vel oci t y al ong par al l el l i nes. The vel oci t y of t he ai r f l ow i s 27 met er s (90
f eet ) per mi nut e.
Table 27-1. International Organization of Standardization (ISO) Classification of
Particulate Matter in Room Air
Class
Name
Particle Count Number of Particles of 0.5 µm or
larger
ISO
Class
U.S. Federal
Standard
`

ISO (Particles per
cubic meter)
U.S. Federal Standard
`

(Particles per cubic foot)
3 Class 1 35.2 1
4 Class 10 352 10
5 Class 100 3520 100
6 Class 1000 35.200 1.000
7 Class 10.000 352.000 10.000
8 Class
100.000
3.520.000 100.000
*
Federal Standard No. 209E. General Services Administration. Washington
DC. 20407

P. 569


j . Cri t i caI si t e i s any openi ng pr ovi di ng a di rect pat h bet ween a st er i l e product and
t he envi r onment or any sur f ace comi ng i n di rect cont act wi t h t he st eri l e product and
t he envi r onment . Lami nar f l ow wor k benches are used t o provi de an adequat e
cr i t i cal si t e envi r onment . USP Chapt er 797 r equi res st eri l e prepar at i on compoundi ng
be per f or med i n at l east a Ì SO Cl ass 5 qual i t y ai r envi r onment .
2. Lami nar f I ow work benches (LFWB) ar e gener al l y used i n conj unct i on wi t h cl ean
r ooms and ar e speci al l y desi gned t o cr eat e an asept i c envi r onment f or t he
pr epar at i on of st er i l e pr oduct s. An Ì SO Cl ass 5 envi r onment exi st s i nsi de a cer t i f i ed
hor i zont al or ver t i cal LFWB.
a. HEPA f i I t er requi rement . Li ke cl ean r ooms, l ami nar f l ow wor k benches use
HEPA f i l t ers, but t he benches use a hi gher -ef f i ci ency ai r f i l t er t han do cl ean r ooms.
b. Types of I ami nar fI ow work benches
( 1) Hori zontaI l ami nar f l ow hoods ( Fi gure 27- 3) wer e t he f i rst hoods used i n
pharmaci es f or t he pr epar at i on of st er i l e pr oduct s. Ai r f l ow i n hor i zont al hoods
moves acr oss t he sur f ace of t he wor k area, f l owi ng f i r st t hr ough a pref i l t er and t hen
t hr ough t he HEPA f i l t er . The maj or di sadvant age of t he hor i zont al hood i s t hat i t
of f ers no pr ot ect i on t o t he oper at or , whi ch i s especi al l y si gni f i cant when
ant i neopl ast i c agent s are bei ng prepared ( see VÌ Ì . D. ) .
( 2) Vert i caI l ami nar f l ow hoods ( Fi gure 27- 4) pr ovi de t wo maj or advant ages over
hor i zont al f l ow hoods.
( a) The ai r f l ow i s vert i cal , f l owi ng down on t he wor k space. Thi s ai r f l ow pat t ern
pr ot ect s t he oper at or agai nst pot ent i al hazards f rom t he pr oduct s bei ng prepared.
( b) A por t i on of t he HEPA- f i l t er ed ai r i s reci r cul at ed a second t i me t hrough t he
HEPA f i l t er . The r emai nder of t he f i l t er ed ai r i s r emoved t hrough an exhaust f i l t er ,
whi ch may be vent ed t o t he out si de t o prot ect t he operat or f rom chroni c,
concent r at ed exposure t o hazardous mat er i al s.
3. Bi oI ogi caI Saf et y Cabi nets ( BSCs) are ver t i cal f l ow hoods wi t h f our maj or t ypes
avai l abl e. They are di f f er ent i at ed by t he amount of ai r r eci r cul at ed i n t he cabi net ,
whet her t hi s ai r i s vent ed t o t he r oom or out si de, and whet her cont ami nat ed duct s
ar e under posi t i ve or negat i ve pr essur e.
a. Type A cabi net s reci rcul at e 70% of cabi net ai r t hr ough HEPA f i l t er s back i nt o t he
cabi net , t he r emai nder i s di schar ged t hr ough a HEPA f i l t er i nt o t he cl eanroom,
cont ami nat ed duct s ar e under posi t i ve pr essur e.
b. Type B1 cabi net s r eci r cul at e 30% of cabi net ai r t hrough HEPA f i l t ers back i nt o
t he cabi net , t he r emai nder i s di schar ged t hr ough HEPA f i l t ers t o t he out si de
envi r onment , cont ami nat ed duct s ar e under negat i ve pressure.
c. Type B2 cabi net s di scharged al l cabi net ai r t hr ough HEPA f i l t ers t o t he out si de
envi r onment wi t h cont ami nat ed duct s under negat i ve pr essur e.

Figure 27-3. Horizontal laminar Ilow hood.
(Photo taken by William Salkin.)
P. 570



Figure 27-4. Vertical laminar Ilow hood. (Photo
taken by William Salkin.)
d. Type B3 cabi net s r eci r cul at e 70% of cabi net ai r t hrough HEPA f i l t ers back i nt o
t he cabi net , 30% i s di schar ged t hr ough HEPA f i l t er s t o t he out si de, and
cont ami nat ed duct s ar e under negat i ve pr essur e.
4. Compoundi ng asepti c i soI at or ( CAI ) pr ovi de a Ì SO Cl ass 5 envi ronment f or
pr oduct pr eparat i on, wi t h asept i c mani pul at i ons occur r i ng i nsi de a cl osed,
pr essuri zed envi ronment accessi bl e onl y vi a seal ed gl oves t hat reach i nt o t he wor k
ar ea ( Fi gur e 27- 5) . Compoundi ng asept i c cont ai nment i soI ators pr ot ect wor ker s
f r om exposure t o undesi rabl e or hazardous dr ugs dur i ng t he compoundi ng and
mat er i al t ransf er processes. Ì sol at ors use uni di r ect i onal
P. 571

or t urbul ent ai r f l ow t o r emove cont ami nant s f r om t he uni t . Ì t uses posi t i ve ai r
pr essure t o keep ext er nal ai r borne par t i cl es out of t he i sol at or . Thi s t echnol ogy
r epr esent s an accept abl e al t er nat i ve t o LFWBs i n a cl ean r ooms f or asept i c
pr ocessi ng.

Figure 27-5. Barrier isolator.
3. I nspect i on and cert i fi cat i on. Cl ean rooms, LFWBs, BSCs, and bar r i er i sol at ors
ar e i nspect ed and cert i f i ed when t hey ar e f i r st i nst al l ed, at l east ever y 6 mont hs
t her eaf t er , and, i n t he case of LFWB, BSCs, and i sol at ors, when moved t o a new
l ocat i on.
a. I nspect i ons shoul d be conduct ed by Nat i onal Sani t at i on Foundat i on ( NSF)
accr edi t ed and cert i f i ed t echni ci ans wi t h exper t i se and t rai ni ng i n cont ami nat i on
cont r ol t echnol ogi es. Equi pment used f or t est i ng has appr opr i at e t ol er ance f or t he
speci f i ed t est i ng and i s cal i br at ed t o Nat i onal Ì nst i t ut e of St andar ds and Technol ogy
( NÌ ST) t r aceabl e st andards.
b. Test i ng i s per f or med per rel evant i ndust r y st andards and at mi ni mum i ncl udes:
( 1) HEPA f i l t er i nt egr i t y t est i ng
( 2) Ai rf l ow t est i ng: Downf l ow and i nf l ow wher e appr opr i at e
( 3) Part i cul at e moni t ori ng
( 4) Pr essur i zat i on moni t or i ng (cl eanrooms and bar r i er i sol at or s) ensures t hat no
par t i cl e l ar ger t han 0. 3 mm passes t hrough t he HEPA f i l t er . Ì n addi t i on, an
anemomet er i s used t o det ermi ne ai r f l ow vel oci t y, and a part i cl e count er i s used t o
det ermi ne t he par t i cl e count .
III. QUALITY CONTROL AND QUALITY ASSURANCE
A. Def i ni t i ons
1. QuaI i t y cont roI i s t he day- t o-day assessment of al l st er i l e compoundi ng
operat i ons. Thi s i ncl udes r ecei pt of raw mat er i al s, pr epar at i on, st orage, di st r i but i on,
pat i ent admi ni st r at i on, and anal yt i c t est i ng of t he f i ni shed pr oduct .
2. QuaI i t y assurance, an oversi ght f unct i on, i nvol ves t he audi t i ng of qual i t y cont r ol
pr ocedur es and syst ems, wi t h suggest i ons f or changes as needed.
B. Test i ng procedures. Var i ous t ypes of t est s are used t o ensure t hat al l st er i l e
pr oduct s ar e f r ee of mi crobi al cont ami nat i on, pyrogens, and par t i cul at e mat t er.
1. CI ari t y t est i ng i s used t o check st eri l e product s f or par t i cul at e mat t er and l eaks.
Bef ore di spensi ng a parent eral sol ut i on, pharmacy personnel shoul d check i t f or
par t i cul at es by swi r l i ng t he sol ut i on and l ooki ng at i t agai nst bot h l i ght and dar k
backgrounds, usi ng a cl ar i t y t est i ng l amp or ot her st andar d l i ght sour ce.
2. Compound Accuracy Checki ng i s a doubl e check of t he used dr ug product s and
suppl i es by a person ot her t han t he compounder. Thi s i ncl udes an i nspect i on of t he
l abel and syr i nges used t o measure t he addi t i ves.
3. Beyond Use Dat i ng repr esent s t he dat e and t i me beyond whi ch a product shoul d
not be admi ni st er ed because of pot ency, st eri l i t y, or st or age concerns. Beyond use
dat i ng shoul d be assi gned i n accor dance wi t h t he manuf act ur er ' s product l abel i ng.
4. End product Testi ng i s st er i l i t y and pyr ogen t est i ng whi ch shoul d be per f ormed
on al l hi gh ri sk CSPs t hat ar e pr epared i n bat ches of 25 uni t s or mor e, mul t i dose
vi al s, or pr eparat i ons wher e i ngredi ent s ar e exposed l onger t han 6- 12 hour s pr i or t o
st eri l i zat i on.
a. St eri I i t y t est i ng ensur es t hat t he process used t o st er i l i ze t he pr oduct was
successf ul . The membrane steri I i zati on method i s of t en used t o conduct st er i l i t y
t est i ng. Test sampl es are passed t hrough membrane f i l t ers, and a nut ri ent medi um
i s t hen added t o promot e mi cr obi al gr owt h. Af t er an i ncubat i on per i od, mi cr obi al
gr owt h i s det ermi ned.
b. Pyrogen t esti ng can be accompl i shed by means of qual i t at i ve f ever response
t est i ng i n r abbi t s or by i n vi t r o l i mul us l ysat e t est i ng. Commer ci al l abor at or i es ar e
avai l abl e t o per f orm t hese t est s. Per sonnel handl i ng st eri l e product s can at t empt t o
avoi d pr obl ems wi t h pyr ogens by purchasi ng pyr ogen- f r ee wat er and sodi um
chl or i de f or i nj ect i on f rom r eput abl e manuf act ur er s and by usi ng proper handl i ng
and st or age procedur es.
C. Envi ronment aI Test i ng i ncl udes ai r and sur f ace sampl i ng t o measure
mi cr obi ol ogy condi t i ons of t he cl eanroom and assesses t he ef f ect i veness of
cl eani ng and sani t i zi ng pr ocedures.
P. 572


1. Vi abI e Ai r sampI i ng i ncl udes vol umet ri c ai r col l ect i on i n t he cont rol l ed
envi r onment and eval uat i on of ai rbor ne mi cr oor gani sms or col l ect i on of ai r borne
or gani sms by exposi ng st er i l e nut ri ent pl at es cont ai ni ng t r ypt i c soy br ot h ( TSB) or
agar ( TSA) f or a sui t abl e t i me f rame.
2. Non- vi abI e Ai r SampI i ng i s i nt ended t o eval uat e t he equi pment t hat i s used t o
cr eat e cl ean ai r . Tot aI Part i cI e Count s ( Tabl e 27- 1) shoul d be wi t hi n est abl i shed
Ì SO cl assi f i cat i ons f or a gi ven compoundi ng ar ea.
3. Surface sampI i ng ut i l i zes TSA pl at es cal l ed repl i cat e organi sm det ect i on and
count i ng ( RODAC) pl at es t o capt ur e mi cr oor gani sm.
Bot h ai r and sur f ace sampl i ng pl at es ar e col l ect ed and i ncubat ed. The number of
di scr et e col oni es of organi sms, col ony f or mi ng uni t s ( CFUs), are count ed and
r eport ed.
D. Pract i caI quaI i t y assurance programs f or noncommerci al st eri l e product s
i ncl ude t rai ni ng, moni t or i ng t he manuf act ur i ng process, per sonnel compet ency
assessment , qual i t y cont r ol check, and document at i on.
1. Trai ni ng of pharmaci st s and techni ci ans i n pr oper asept i c t echni ques and
pr act i ces i s t he si ngl e most i mport ant aspect of an ef f ect i ve qual i t y assurance
pr ogram. Tr ai ni ng shoul d i mpart a t hor ough under st andi ng of depar t ment al pol i ci es
and pr ocedur es.
2. By moni t ori ng the manuf act uri ng process, a super vi sor can check adherence t o
est abl i shed pol i ci es and pr ocedur es and t ake corr ect i ve act i on as necessar y.
3. Af t er t rai ni ng i s compl et ed competency assessment t hrough per f or mance
eval uat i on and r e- eval uat i on i s r equi r ed f or r out i ne t asks l i ke handwashi ng,
gowni ng, gl ovi ng, and asept i c mani pul at i ons. Eval uat i ons shoul d occur annual l y f or
per sonnel compoundi ng l ow and medi um r i sk CSPs and semi -annual y f or hi gh r i sk
CSPs.
E. Process vaI i dati on pr ovi des a mechani sm f or ensur i ng pr ocesses consi st ent l y
r esul t i n st er i l e pr oduct s of accept abl e qual i t y. Thi s shoul d i ncl ude a wr i t t en
pr ocedur e t o f ol l ow as wel l as eval uat i on of asept i c t echni que t hr ough process
si mul at i on.
F. Process si muI at i on test i ng or PersonneI EvaI uati on dupl i cat es st er i l e
compoundi ng of l ow, medi um, and hi gh ri sk l evel CSPs under most st r essf ul
condi t i ons except t hat an appr opr i at e gr owt h medi a ( Soybean- Casei n Di gest
Medi um) i s used i n pl ace of t he dr ug product s. Af t er prepar at i on and i ncubat i on of
t he f i nal pr oduct , no gr owt h i ndi cat es proper asept i c t echni ques wer e f ol l owed.
G. QuaI i t y cont roI checki ng i ncl udes moni t ori ng t he st er i l i t y of a sampl e of
manuf act ur ed pr oduct s. The membrane st er i l i zat i on met hod i s pract i cal l y empl oyed
usi ng a commer ci al l y avai l abl e f i l t er and t r ypt i case soy brot h medi a.
H. Documentat i on of t r ai ni ng pr ocedur es, qual i t y cont r ol r esul t s, l ami nar f l ow hood
cer t i f i cat i on, and pr oduct i on r ecor ds ar e requi r ed by var i ous agenci es and
or gani zat i ons.
IV. STERILIZATION METHODS AND EQUIPMENT.
St er i l i zat i on i s per f ormed t o dest roy or remove al l mi cr oor gani sms i n or on a
pr oduct . St er i l i zat i on can be achi eved t hr ough t her mal , chemi cal , r adi oact i ve, or
mechani cal met hods.
A. ThermaI st eri I i zat i on i nvol ves t he use of ei t her moi st or dr y heat .
1. Moi st- heat steri I i zati on i s t he most wi deI y used and r el i abl e st er i l i zat i on
met hod.
a. Mi cr oorgani sms are dest royed by ceI I uI ar prot ei n coaguI ati on.
b. The obj ect s t o be st eri l i zed are exposed t o sat ur at ed st eam under 1 at mospher e
pr essure at a mi ni mum t emper at ur e of 121°C f or at l east 20- 60 mi nut es.
c. An autocI ave i s commonl y used f or moi st -heat st eri l i zat i on.
d. Because i t does not requi r e as hi gh a t emper at ur e, moi st - heat st er i l i zat i on
causes I ess product and equi pment damage compared t o dr y- heat st eri l i zat i on.
P. 573


2. Dr y- heat st eri I i zat i on i s appr opr i at e f or mat er i al s t hat cannot wi t hst and moi st -
heat st er i l i zat i on. Obj ect s are subj ect ed t o a t emper at ur e of at l east 160°C f or 120
mi nutes (i f hi gher t emper at ures can be used, l ess exposur e t i me i s requi red) .
B. Chemi caI ( gas) st eri I i zati on i s used t o st er i l i ze sur f aces and por ous mat er i al s
( e. g. , sur gi cal dr essi ngs) t hat ot her st er i l i zat i on met hods may damage.
1. Ì n t hi s met hod, et hyI ene oxi de i s used general l y i n combi nat i on wi t h heat and
moi st ur e.
2. Resi duaI gas must be al l owed t o di ssi pat e af t er st er i l i zat i on and bef ore use of
t he st er i l e product .
C. Radi oacti ve st eri I i zat i on i s sui t abl e f or t he i ndust r i al st eri l i zat i on of cont ent s i n
seal ed packages t hat cannot be exposed t o heat ( e. g. , prepackaged surgi cal
component s, some opht hal mi c oi nt ment s).
1. Thi s t echni que i nvol ves ei t her eI ect romagneti c or part i cuI at e radi ati on.
2. Accel erat ed drug decomposi t i on somet i mes r esul t s.
D. Mechani caI st eri I i zati on ( f i I t rat i on) removes but does not dest r oy
mi cr oor gani sms and cl ari f i es sol ut i ons by el i mi nat i ng part i cul at e mat t er . For
sol ut i ons r ender ed unst abl e by t her mal , chemi cal , or radi at i on st er i l i zat i on, f i l t rat i on
i s t he pr ef er red met hod. A dept h f i l t er or screen f i l t er may be used. Personnel
shoul d ensur e t he f i l t er used ei t her dur i ng compoundi ng or admi ni st r at i on i s
chemi cal l y and physi cal l y compat i bl e wi t h t he CSP at t he t emperat ur e and pr essur e
condi t i ons used.
1. Dept h f i I t ers usual l y consi st of f r i t t ed gl ass or ungl azed por cel ai n (i . e. ,
subst ances t hat t rap part i cl es i n channel s) .
2. Screen ( membrane) fi I t ers ar e f i l ms measuri ng 1- 200 mm t hi ck made of
cel l ul ose est er s, mi cr of i l ament s, pol ycar bonat e, synt het i c pol ymer s, si l ver , or
st ai nl ess st eel .
a. A mesh of mi l l i ons of mi cr ocapi l l ar y por es of i dent i cal si ze f i l t er t he sol ut i on by a
pr ocess of physi cal si evi ng.
b. FI ow rat e. Because por es make up 70% t o 85% of t he sur f ace, scr een f i l t ers
have a hi gher f l ow r at e t han dept h f i l t ers.
c. Types of screen f i I ters
( 1) Part i cuI at e f i I ters remove par t i cl es of gl ass, pl ast i c, r ubber , and ot her
cont ami nant s.
( a) Ot her uses. These f i l t ers al so are used t o r educe t he ri sk of phl ebi t i s
associ at ed wi t h admi ni st r at i on of r econst i t ut ed powder s. Fi l t r at i on r emoves any
undi ssol ved powder par t i cl es t hat may cause venous i nf l ammat i on.
( b) The pore si ze of st andard par t i cul at e f i l t er s ranges f r om 0. 45-5 mm. Speci al
par t i cul at e f i l t er s are r equi r ed t o f i l t er bl ood, emul si ons ( e. g. , f at emul si ons) , or
col l oi dal di spersi ons or suspensi ons because t hese pr epar at i ons have a l ar ger
par t i cl e si ze.
( 2) Mi crobi aI f i I ters, wi t h a por e si ze of 0. 22 mm or smal l er , ensur e compl et e
mi cr obi al r emoval and st er i l i zat i on. Thi s i s r ef er r ed t o as col d st eri l i zat i on.
( 3) Fi naI f i I ters, whi ch may be ei t her par t i cul at e or mi cr obi al , ar e of t en i ncl uded as
par t of t he t ubi ng used i n dr ug admi ni st r at i on. They ar e r ef er r ed t o as i n- l i ne f i l t er s
and ar e used t o remove par t i cul at es or mi cr oor gani sms f rom an i nt ravenous (Ì V)
sol ut i on duri ng i nf usi on.
V. PACKAGING OF PARENTERAL PRODUCTS.
Par ent er al prepar at i ons and ot her st eri l e product s must be packaged i n a way t hat
mai nt ai ns product st er i l i t y unt i l t he t i me of use and pr event s cont ami nat i on of
cont ent s duri ng openi ng.
A. Types of cont ai ners
1. AmpuI es, t he ol dest t ype of parent er al product cont ai ner s, are made ent i rel y of
gI ass.
a. Ì nt ended f or si ngI e use onI y, ampul es are opened by breaki ng t he gl ass at a
scor e l i ne on t he neck.
b. Di sadvant ages. Because gl ass par t i cl es may become di sl odged dur i ng ampul e
openi ng, t he pr oduct must be f i l t er ed bef ore i t i s admi ni st er ed. Thei r unsui t abi l i t y
f or mul t i pl e-dose
P. 574

use, t he need t o f i l t er sol ut i ons bef ore use, and ot her saf et y consi der at i ons have
markedl y r educed t he ampul e as a package f orm.

Figure 27-6. Syringes and vials. (Photo taken by
William Salkin.)
2. Vi aI s ar e gl ass or pl ast i c cont ai ners cl osed wi t h a r ubber st opper and seal ed wi t h
an al umi num cri mp ( Fi gur e 27- 6) .
a. Vi al s have sever al advant ages over ampul es.
( 1) Vi al s can be desi gned t o hol d mul t i pl e doses ( i f prepar ed wi t h a bact er i ost at i c
agent ) .
( 2) The dr ug pr oduct i s easi er t o r emove f r om vi al s t han f r om ampul es.
( 3) Vi al s el i mi nat e t he r i sk of gl ass par t i cl e cont ami nat i on dur i ng openi ng.
b. However , vi al s al so have cer t ai n di sadvant ages.
( 1) The rubber st opper can become cored, causi ng a smal l bi t of rubber t o ent er t he
sol ut i on.
( 2) Mul t i pl e wi t hdr awal s ( as wi t h mul t i pl e- dose vi al s) can resul t i n mi crobi al
cont ami nat i on.
c. Some drugs t hat ar e unst abl e i n sol ut i on ar e packaged i n vi al s unr econst i t ut ed
and must be reconst i tuted wi t h a di l uent bef or e use. St er i l e wat er or st eri l e sodi um
chl or i de f or i nj ect i on are t he most commonl y used dr ug di l uent s.
( 1) To accel erat e t he di ssol ut i on rat e and permi t r api d r econst i t ut i on, many powder s
ar e l yophi l i zed ( f reeze dr i ed).
( 2) Some of t hese dr ugs come i n vi al s t hat cont ai n a doubl e chamber.
( a) The t op chamber , cont ai ni ng st eri l e wat er f or i nj ect i on, i s separat ed f r om t he
unr econst i t ut ed dr ug by a r ubber cl osur e.
( b) To di sl odge t he i nner cl osur e and mi x t he cont ent s of t he compar t ment s,
ext er nal pr essur e i s appl i ed t o t he out er rubber cl osure. Thi s syst em el i mi nat es t he
need t o ent er t he vi al t wi ce, t her eby reduci ng t he r i sk of mi crobi al cont ami nat i on.
3. Some dr ugs come i n vi al s t hat may be at t ached t o an di l uent cont ai ni ng bag f or
r econst i t ut i on and admi ni st rat i on ( ADD- Vant age by Abbot t ) (Fi gur e 27-7) .
Pr emeasur ed drug and di l uent may al so be st ored i n separat e compar t ment s wi t hi n
a del i ver y syst em t hen combi ned at t he poi nt of use. ( Dupl ex by B. Br aun) .
a. The ADD- Vant age vi al i s scr ewed i nt o t he t op of an ADD- Vant age di l uent bag,
and t he r ubber di aphr agm i s di sl odged f rom t he vi al , al l owi ng t he dl i uent sol ut i on t o
di ssol ve t he dr ug.
b. The r econst i t ut ed ADD- Vant age vi al and Ì V bag are ready f or admi ni st r at i on when
hung.
c. The Dupl ex syst ems has t wo- compar t ment s wher e a seal i s broken and dr ug and
di l uent are mi xed t o f orm a sol ut i on. The r econst i t ut ed dr ug i s ready f or pat i ent
admi ni st rat i on.
4. Prefi I I ed syri nges and cart ri dges are desi gned f or maxi mum conveni ence (see
Fi gur e 27- 6).
a. Prefi I I ed syri nges. Dr ugs admi ni st er ed i n an emergency ( e. g. , at ropi ne,
epi nephr i ne) ar e avai l abl e f or i mmedi at e i nj ect i on when packaged i n pr ef i l l ed
syr i nges.
P. 575



Figure 27-7. Left. Abbott ADDVantage System.
Center. B. Braun Duplex System. Right. preIilled
antibiotic piggyback dose. (Photograph by
William Salkin.)
b. Pref i I I ed cart ri dges ar e ready- t o- use par ent er al packages t hat of f er i mpr oved
st eri l i t y and accur acy. They consi st of a pl ast i c car t r i dge hol der and a pref i l l ed
medi cat i on cart r i dge wi t h a needl e at t ached. The medi cat i on i s premi xed and
pr emeasured. Nar cot i cs such as, meperi di ne ( Demer ol ) and hydr omorphone
( Di l audi d) ar e commonl y avai l abl e i n pr ef i l l ed cart r i dges.
5. I nfusi on soI uti ons are di vi ded i nt o t wo cat egor i es: smaI I - voI ume parent eraI s
( SVPs) , t hose havi ng a vol ume l ess t han 100 mL; and I arge- voI ume parent eraI s
( LVPs), t hose havi ng a vol ume of 100 mL or gr eat er . Ì nf usi on sol ut i ons are used f or
t he i nt er mi t t ent or cont i nuous i nf usi on of f l ui ds or dr ugs (see VÌ . B) .
B. Packagi ng mat eri aI s. Mat er i al s used t o package parent er al product s i ncl ude
gl ass and pl ast i c pol ymer s.
P. 576


1. GI ass, t he ori gi nal par ent er al packagi ng mat eri al , has super i or cl ar i t y, f aci l i t at i ng
i nspect i on f or par t i cul at e mat t er . Compared t o pl ast i c, gl ass l ess f requent l y
i nt er act s wi t h t he preparat i on i t cont ai ns.
2. PI ast i c poI ymers used f or parent er al packagi ng i ncl ude pol yvi nyl chl ori de ( PVC)
and pol yol ef i n.
a. PVC i s f l exi bl e and nonr i gi d.
b. PoI yoI ef i n i s semi r i gi d; unl i ke PVC, i t can be st ored upri ght .
c. Bot h t ypes of pl ast i c of f er several advant ages over gl ass, i ncl udi ng durabi l i t y,
easi er st or age and di sposal , r educed wei ght , and i mpr oved saf et y.
VI. PARENTERAL ADMINISTRATION ROUTES.
Par ent er al prepar at i ons may be gi ven by a var i et y of admi ni st rat i on rout es.
A. Subcut aneous ( SC or SQ) admi ni st r at i on r ef er s t o i nj ect i on i nt o t he
subcut aneous t i ssue beneat h t he ski n l ayer s, usual l y of t he abdomen, ar m, or t hi gh.
Ì nsul i n i s an exampl e of a subcut aneousl y admi ni st ered dr ug.
B. I nt ramuscuI ar ( Ì M) admi ni st r at i on means i nj ect i on i nt o a muscl e mass. The mi d-
del t oi d area and gl ut eus medi us are common i nj ect i on si t es.
1. No more t han 5 mL of a sol ut i on shoul d be i nj ect ed by t hi s r out e.
2. Dr ugs i nt ended f or prol onged or del ayed absor pt i on such as
medroxypr ogest er one ( Depo- Prover a) and met hyl pr edni sol one ( Depo- Medr ol )
commonl y ar e admi ni st ered i nt r amuscul ar l y.
C. I nt ravenous ( I V) admi ni st rat i on i s t he most i mpor t ant and most common
par ent eral admi ni st r at i on r out e. Ì t al l ows an i mmedi at e t her apeut i c ef f ect by
del i ver i ng t he dr ug di r ect l y i nt o t he ci rcul at i on. However , t hi s rout e precl udes r ecal l
of an i nadvert ent drug over dose. Ant i bi ot i cs, cardi ac medi cat i ons, and many ot her
dr ugs ar e gi ven i nt r avenousl y.
D. I nt radermaI ( I D) admi ni st rat i on i nvol ves i nj ect i on i nt o t he most super f i ci al ski n
l ayer . Because t hi s rout e can del i ver onl y a l i mi t ed dr ug vol ume, i t s use general l y i s
r est ri ct ed t o ski n t est s and cer t ai n vacci nes.
E. I nt ra- art eri aI (I A) admi ni st r at i on i s i nj ect i on di r ect l y i nt o an art er y. Ì t del i ver s a
hi gh drug concent rat i on t o t he t ar get si t e wi t h l i t t l e di l ut i on by t he ci r cul at i on.
Gener al l y, t hi s rout e i s used onl y f or r adi opaque mat er i al s, t hr ombol yt i c agent s, and
some ant i neopl ast i c agent s.
F. I nt racardi ac ( Ì C) admi ni st rat i on i s i nj ect i on of a dr ug di r ect l y i nt o t he hear t .
G. HypodermocI ysi s r ef er s t o i nj ect i on of l ar ge vol umes of a sol ut i on i nt o
subcut aneous t i ssue t o pr ovi de a cont i nuous, abundant drug suppl y. Thi s rout e
occasi onal l y i s used f or ant i bi ot i c admi ni st r at i on i n chi l dren.
H. I nt raspi naI admi ni st rat i on r ef ers t o i nj ect i on i nt o t he spi nal col umn. Local
anest het i cs ( e. g. , l i docai ne, bupi vacai ne) ar e f r equent l y admi ni st er ed vi a t hi s rout e
dur i ng surgi cal procedures.
I . I nt ra- art i cuI ar admi ni st r at i on means i nj ect i on i nt o a j oi nt space. Cort i cost er oi ds
( e. g. , met hyl pr edni sol one, hydrocor t i sone) use t hi s rout e f or t he t reat ment of
ar t hri t i s.
J. I nt rasynovi aI admi ni st r at i on ref er s t o i nj ect i on i nt o t he j oi nt f l ui d.
K. I nt rathecaI (I T) admi ni st r at i on i s i nj ect i on i nt o t he spi nal f l ui d; i t somet i mes i s
used f or ant i bi ot i cs and cancer chemot her apy.
L. Epi duraI ( ED) admi ni st r at i on r ef ers t o t he i nj ect i on of medi cat i ons, usual l y l ocal
anest het i cs and/ or nar cot i cs near or out si de t he dur a mat er of t he cent ral ner vous
syst em. Thi s rout e i s f r equent l y used dur i ng chi l dbi rt h.
P. 577


VII. PARENTERAL PREPARATIONS
A. I V admi xt ures. These pr epar at i ons consi st of one or more st er i l e dr ug pr oduct s
added t o an Ì V f l ui d, gener al l y dext r ose or sodi um chl or i de sol ut i on al one or i n
combi nat i on. Ì V admi xt ures ar e used f or dr ugs i nt ended f or cont i nuous i nf usi on.
Dr ugs t hat may cause i r ri t at i on or t oxi ci t y when gi ven as a r api d di r ect Ì V i nj ect i on
ar e al so pr epar ed as Ì V admi xt ur es.
B. I V f I ui ds and eI ect roI yt es
1. FI ui ds used i n t he prepar at i on and admi ni st r at i on of par ent eral pr oduct s i ncl ude
st eri l e wat er and sodi um chl ori de, dext r ose, and Ri nger ' s sol ut i ons, al l of whi ch
have mul t i pl e uses. These f l ui ds ser ve as vehi cl es i n Ì V admi xt ur es, provi di ng a
means f or r econst i t ut i ng st eri l e powders. They ser ve as t he basi s f or cor rect i ng
body f l ui d and el ect rol yt e di st ur bances and provi de a cal ori c source i n par ent er al
nut ri t i on.
a. Dext rose ( D- gI ucose) soI uti ons are t he most f r equent l y used gl ucose sol ut i ons
i n par ent eral pr epar at i ons.
( 1) Uses. General l y, a sol ut i on of dext r ose 5% i n wat er ( d5w) i s used as a vehi cl e i n
Ì V admi xt ur es. D5W may al so ser ve as a hydr at i ng sol ut i on. Ì n hi gher
concent r at i ons ( e. g. , a 10% sol ut i on i n wat er) , dext r ose pr ovi des a source of
car bohydrat es i n par ent er al nut ri t i on sol ut i ons.
( 2) Consi derat i ons. Because t he pH of D5W ranges f r om 3. 5-6. 5, i nst abi l i t y may
r esul t i f i t i s combi ned wi t h an aci d-sensi t i ve dr ug.
( a) Dext r ose concent r at i ons gr eat er t han 15% must be admi ni st ered t hr ough a
cent r al vei n.
( b) Dext r ose sol ut i ons shoul d be used caut i ousl y i n pat i ent s wi t h di abet es mel l i t us.
b. Sodi um chI ori de usual l y i s gi ven as a 0. 9% sol ut i on. Because i t i s i sot oni c wi t h
bl ood, t hi s sol ut i on i s cal l ed nor mal sal i ne sol ut i on ( NSS) . A sol ut i on of 0. 45%
sodi um chl or i de i s t ermed hal f - normal sal i ne. A sol ut i on of 0. 225% sodi um chl or i de
i s t ermed quar t ernormal sal i ne.
( 1) Sodi um chI ori de f or i nj ect i on, whi ch i s a sol ut i on of 0. 9% sodi um chl or i de, i s
used as a vehi cl e i n Ì V admi xt ur es and f or f l ui d and el ect r ol yt e repl acement . Ì n
smal l er vol umes, i t i s sui t abl e f or t he reconst i t ut i on of var i ous medi cat i ons.
( 2) Bact eri ost ati c sodi um chI ori de f or i nj ect i on, whi ch i s al so a 0. 9% sol ut i on, i s
i nt ended sol el y f or mul t i pl e r econst i t ut i ons. Ì t cont ai ns an agent t hat i nhi bi t s
bact er i al gr owt h (e. g. , benzyl al cohol , propyl paraben, met hyl paraben) , whi ch al l ows
f or i t s use i n mul t i pl e-dose pr epar at i ons.
c. Wat ers are used f or reconst i t ut i on and f or di l ut i on of such Ì V sol ut i ons as
dext r ose and sodi um chl or i de. Wat ers sui t abl e f or parent er al preparat i ons i ncl ude
st eri l e wat er f or i nj ect i on and bact er i ost at i c wat er f or i nj ect i on.
d. Ri nger' s soI ut i ons, whi ch are appropr i at e f or f l ui d and el ect r ol yt e repl acement ,
commonl y ar e admi ni st ered t o post surgi cal pat i ent s.
( 1) Lact ated Ri nger' s i nj ect i on (i . e. , Hart mann' s sol ut i on, Ri nger ' s l act at e sol ut i on)
cont ai ns sodi um l act at e, sodi um chl or i de, pot assi um chl or i de, and cal ci um chl ori de.
Fr equent l y, i t i s combi ned wi t h dext r ose (e. g. , as 5% dext r ose i n l act at ed Ri nger ' s
i nj ect i on) .
( 2) Ri nger' s i nj ect i on di f f ers f rom l act at ed Ri nger ' s i nj ect i on i n t hat i t does not
cont ai n sodi um l act at e and has sl i ght l y di f f er ent concent r at i ons of sodi um chl or i de
and cal ci um chl or i de. Li ke l act at ed Ri nger ' s i nj ect i on, i t may be combi ned i n
sol ut i on wi t h dext r ose.
2. EI ect roI yt e preparat i ons. Wi t h i ons present i n bot h i nt racel l ul ar and
ext r acel l ul ar f l ui d, el ect rol yt es are cr uci al f or vari ous bi ol ogi cal pr ocesses. Sur gi cal
and medi cal pat i ent s who cannot t ake f ood by mout h or who need nut r i t i onal
suppl ement at i on requi r e t he addi t i on of el ect rol yt es i n hydr at i ng sol ut i ons or
par ent eral nut ri t i on sol ut i ons.
a. Cat i ons ar e posi t i vel y char ged el ect r ol yt es.
( 1) Sodi um i s t he chi ef ext r acel l ul ar cat i on.
( a) I mport ance. Sodi um pl ays a key r ol e i n i nt erst i t i al osmot i c pressure, t i ssue
hydr at i on, aci d- base bal ance, ner ve- i mpul se t r ansmi ssi on, and muscl e cont r act i on.
( b) Parent eraI sodi um preparati ons i ncl ude sodi um chl or i de, sodi um acet at e, and
sodi um phosphat e.
P. 578


( 2) Potassi um i s t he chi ef i nt r acel l ul ar cat i on.
( a) I mport ance. Pot assi um par t i ci pat es i n car bohydr at e met abol i sm, pr ot ei n
synt hesi s, muscl e cont ract i on (especi al l y of car di ac muscl e) , and neuromuscul ar
exci t abi l i t y.
( b) Parent eraI pot assi um preparat i ons i ncl ude pot assi um acet at e, pot assi um
chl or i de, and pot assi um phosphat e.
( 3) CaI ci um
( a) I mport ance. Cal ci um i s essent i al t o ner ve-i mpul se t r ansmi ssi on, muscl e
cont r act i on, car di ac f unct i on, bone f ormat i on, and capi l l ar y and cel l membr ane
per meabi l i t y.
( b) Parent eraI caI ci um preparat i ons i ncl ude cal ci um chl or i de, cal ci um gl uconat e,
and cal ci um gl ucept at e.
( 4) Magnesi um
( a) I mport ance. Magnesi um pl ays a vi t al par t i n enzyme act i vi t i es, neur omuscul ar
t r ansmi ssi on, and muscl e exci t abi l i t y.
( b) Parent eraI preparati on. Magnesi um i s gi ven par ent eral l y as magnesi um sul f at e.
b. Ani ons ar e negat i vel y char ged el ect r ol yt es.
( 1) ChI ori de i s t he maj or ext r acel l ul ar ani on.
( a) I mport ance. Al ong wi t h sodi um, i t regul at es i nt erst i t i al osmot i c pr essur e and
hel ps t o cont r ol bl ood pH.
( b) Parent eraI chI ori de preparat i ons i ncl ude cal ci um chl or i de, pot assi um chl ori de,
and sodi um chl ori de.
( 2) Phosphat e i s t he maj or i nt racel l ul ar ani on.
( a) I mport ance. Phosphat e i s cri t i cal t o var i ous enzyme act i vi t i es. Ì t al so i nf l uences
cal ci um l evel s and act s as a buf f er t o pr event mar ked changes i n aci d-base
bal ance.
( b) Parent eraI phosphat e preparat i ons i ncl ude pot assi um phosphat e and sodi um
phosphat e.
( 3) Acet at e
( a) I mport ance. Acet at e i s a bi car bonat e pr ecursor t hat may be used t o pr ovi de
al kal i t o assi st i n t he preser vat i on of pl asma pH.
( b) Parent eraI acet at e preparati ons i ncl ude pot assi um acet at e and sodi um
acet at e.
C. ParenteraI anti bi oti c preparat i ons ar e avai l abl e as st er i l e unreconst i t ut ed
powder s, whi ch must be r econst i t ut ed wi t h st eri l e wat er , nor mal sal i ne, or d5w, or
as a st eri l e, r eady- t o-use l i qui d par ent er al .
1. Admi ni st rat i on met hods. Par ent eral ant i bi ot i cs may be gi ven i nt ermi t t ent l y by
di r ect Ì V i nj ect i on, short -t er m i nf usi on, i nt ramuscul ar i nj ect i on, or i nt rat hecal
i nj ect i on.
2. Uses. Par ent eral ant i bi ot i cs ar e used t o t reat i nf ect i ons t hat are ser i ous and
r equi r e hi gh ant i bi ot i c bl ood l evel s or when t he gast roi nt est i nal t r act i s
cont r ai ndi cat ed, such as i n i l eus.
3. Dosi ng f requenci es of par ent eral ant i bi ot i cs var y f r om once dai l y t o as of t en as
ever y 2 hours, dependi ng on t he ki net i cs of t he dr ug, seri ousness of t he i nf ect i on,
t he si t e of i nf ect i on, and t he pat i ent ' s di sease or or gan st at us ( e. g. , renal di sease) .
D. ParenteraI anti neopI ast i c agent s. St udi es suggest t hat t hese medi cat i ons may
be t oxi c t o t he personnel who pr epar e and admi ni st er t hem. The evi dence i s not
concl usi ve, whi ch necessi t at es speci al pr ecaut i ons t o ensur e saf et y and mi ni mi ze
r i sks. Ì n r esponse t o concer ns, t he Occupat i onal Saf et y and Heal t h Admi ni st rat i on
( OSHA) has publ i shed a t echni cal manual , " Cont rol l i ng Occupat i onal Exposur e t o
Hazar dous Drugs. ¨ Every f aci l i t y must have a wr i t t en pl an t hat i ncl udes drug
pr epar at i on precaut i ons, st or age, t ranspor t , personal prot ect i ve equi pment ( gl oves,
gowns, masks) , wor k equi pment , wast e di sposal , spi l l management , and per sonnel
medi cal sur vei l l ance,
1. Admi ni st rat i on met hods. Par ent eral ant i neopl ast i cs may be gi ven by di r ect Ì V
i nj ect i on, short - t er m i nf usi on, or l ong- t erm i nf usi on. Some are admi ni st ered by a
non- Ì V r out e, such as t he subcut aneous, i nt ramuscul ar, i nt r a- ar t er i al , or i nt r at hecal
r out es.
2. Safe ant i neopI ast i c handI i ng gui deI i nes. Al l pharmacy and nursi ng per sonnel
who pr epar e or admi ni st er ant i neopl ast i cs shoul d r ecei ve speci al t r ai ni ng i n t he
f ol l owi ng gui del i nes t o reduce t he r i sk of exposur e t o t hese drugs.
a. A vert i caI I ami nar fI ow hood shoul d be used dur i ng dr ug preparat i on, wi t h
exhaust di r ect ed t o t he out si de.
P. 579


b. Al l syri nges and Ì V t ubi ng shoul d have Luer-Lok f i t ti ngs (see Ì X. B. 4. a) .
c. CI ot hi ng. Per sonnel shoul d wear personal pr ot ect i ve equi pment i ncl udi ng cl osed-
f r ont cuf f ed sur gi cal gowns and doubl e- l ayer ed l at ex sur geon' s gl oves.
d. Negat i ve- pressure t echni que shoul d be used dur i ng wi t hdr awal of medi cat i on
f r om vi al s. Thi s wi l l prevent pr essur e f r om bui l di ng up i nsi de t he vi al and causi ng
t he dr ug t o spr ay around t he needl e.
e. Fi naI dosage adj ustment shoul d be made i nt o t he vi al , ampul e, or di rect l y i nt o
an absor bent gauze pad.
f . Pri mi ng equi pment . Speci al car e shoul d be t aken when Ì V admi ni st r at i on set s
ar e pr i med. The Ì V t ubi ng shoul d be pr i med bef ore addi ng t he dr ug, or t he t ubi ng
can be pr i med wi t h dr ug-f r ee f l ui d bef or e connect i ng i t t o t he chemot her apy dr ug
cont ai ner . Ì f t hese ar e not avai l abl e, pri me t he t ubi ng i nt o st er i l e gauze i n a
seal abl e pl ast i c bag.
g. Pr oper pr ocedur es shoul d be f ol l owed f or di sposaI of mat er i al s used i n t he
pr epar at i on and admi ni st r at i on of ant i neopl ast i cs.
( 1) NeedI es shoul d not be cl i pped or r ecapped.
( 2) Preparat i ons shoul d be di scar ded i n cont ai ner s t hat are punct ure- proof , l eak-
pr oof , and pr oper l y l abel ed.
( 3) Hazardous wast e. Ther e i s no compl et el y accept abl e met hod f or di sposi ng of
hazar dous wast e. Hi gh- t emper at ur e i nci nerat i on may be t he pref er r ed met hod.
These mat er i al s may al so be buri ed i n an EPA-l i censed hazar dous wast e dump or
chemi cal l y deact i vat ed.
h. Af t er removal of gl oves, per sonnel shoul d wash hands t horoughl y.
i . Personnel and equi pment i nvol ved i n t he pr epar at i on and admi ni st r at i on of
ant i neopl ast i c agent s shoul d be moni t ored rout i nel y.
3. Pati ent probI ems. Ì nf usi on phl ebi t i s and ext r avasat i on ar e t he most ser i ous
pr obl ems t hat may occur duri ng t he admi ni st rat i on of parent er al ant i neopl ast i cs.
a. I nfusi on phI ebi t i s ( i nf l ammat i on of a vei n) i s charact eri zed by pai n, swel l i ng,
heat sensat i on, and redness at t he i nf usi on si t e. Dr ug di l ut i on and f i l t r at i on can
el i mi nat e or mi ni mi ze t he r i sk of phl ebi t i s.
b. Ext ravasat i on (i nf i l t rat i on of a dr ug i nt o subcut aneous t i ssues sur r oundi ng t he
vei n) i s especi al l y har mf ul when ant i neopl ast i cs wi t h vesi cant proper t i es ar e
admi ni st er ed. Measures must be t aken i mmedi at el y i f ext r avasat i on occurs.
( 1) Dependi ng on t he drug i nvol ved, emergency measures may i ncl ude st oppi ng t he
i nf usi on, i nj ect i ng hydr ocor t i sone or anot her ant i - i nf l ammat or y agent di r ect l y i nt o
t he af f ect ed ar ea, i nj ect i ng an ant i dot e ( i f avai l abl e) , and appl yi ng a col d compr ess
( t o f aci l i t at e a dr ug- ant i dot e react i on) .
( 2) A war m compress may t hen be appl i ed t o i ncrease t he f l ow of bl ood, and t hus
t he vesi cant , away f r om damaged t i ssue.
E. Parent eraI bi ot echnoI ogy product s ar e creat ed by t he appl i cat i on of
r ecombi nant t echnol ogy t o t he gener at i on of t herapeut i c agent s, such as monocl onal
ant i bodi es, vari ous vacci nes, and col ony-st i mul at i ng f act or s.
1. Uses of t hese agent s i ncl ude cancer t her apy, i nf ect i ons, t ranspl ant r ej ect i on,
r heumat oi d art hr i t i s, i nf l ammat or y bowel di sease, r espi rat or y di seases, and mal ar i a
as wel l as vacci nes agai nst cancer , HÌ V i nf ect i on, and hepat i t i s B.
2. Characteri st i cs. Pr ot ei n and pept i de bi ot echnol ogy dr ugs have a short er hal f -
l i f e, of t en r equi r e speci al st or age such as r ef ri ger at i on or f reezi ng, and must not be
shaken vi gor ousl y t o avoi d dest r oyi ng t he pr ot ei n mol ecul es.
3. Admi ni st rat i on. Many bi ot echnol ogy product s r equi r e reconst i t ut i on wi t h st er i l e
wat er or nor mal sal i ne and may be par ent er al l y admi ni st ered by di r ect Ì V i nj ect i on
or i nf usi on, or by i nt ramuscul ar or subcut aneous i nj ect i on.
VIII. IRRIGATING SOLUTIONS.
Al t hough t hese st eri l e product s are manuf act ured by t he same st andards used t o
pr ocess Ì V preparat i ons, t hey ar e not i nt ended for i nf usi on i nto t he venous
syst em. Label i ng di f f er ences bet ween i r r i gat i on sol ut i ons and i nj ect i ons ar e
speci f i ed i n t he Uni t ed St at es Phar macopei a ( USP) and r ef l ect di f f er ences i n
accept abl e par t i cul at e mat t er l evel s, vol ume of sol ut i on avai l abl e f or use, and t he
cont ai ner desi gn.
P. 580


A. Topi caI admi ni st rati on. Ì r ri gat i ng sol ut i ons f or t opi cal use ar e packaged i n pour
bot t l es so t hat t hey can be appl i ed di r ect l y ont o t he desi r ed area. These sol ut i ons
ar e i nt ended f or such pur poses as i r ri gat i ng wounds, moi st eni ng dr essi ngs, and
cl eani ng sur gi cal i nst r ument s.
B. I nf usi on of i rri gati ng soI uti ons. Thi s procedur e, usi ng an admi ni st r at i on set
at t ached t o a Fol ey cat het er , i s commonl y used f or many sur gi cal pat i ent s.
Sur geons per f ormi ng ur ol ogi cal pr ocedur es of t en use i r ri gat i ng sol ut i ons t o perf use
t i ssues i n or der t o mai nt ai n t he i nt egri t y of t he sur gi cal f i el d, remove bl ood, and
pr ovi de a cl ear f i el d of vi ew. To decr ease t he ri sk of i nf ect i on, 1 mL of Neospor i n
G. U. Ì r r i gant , an ant i bi ot i c pr epar at i on, of t en i s added t o t hese sol ut i ons.
C. Di aI ysi s. Di al ysat es ar e i r r i gat i ng sol ut i ons used i n t he di al ysi s of pat i ent s wi t h
such di sor der s as r enal f ai l ur e, poi soni ng, and el ect rol yt e di st ur bances. These
pr oduct s remove wast e mat er i al s, ser um el ect rol yt es, and t oxi c pr oduct s f r om t he
body.
1. Ì n peri t oneaI di aI ysi s, a hyper t oni c di al ysat e i s i nf used di r ect l y i nt o t he
per i t oneal cavi t y vi a a sur gi cal l y i mpl ant ed cat het er . The di al ysat e, whi ch cont ai ns
dext r ose and el ect r ol yt es, removes harmf ul subst ances by osmosi s and di f f usi on.
Af t er a speci f i ed per i od of t i me, t he sol ut i on i s dr ai ned. Ant i bi ot i cs and hepari n may
be added t o t he di al ysat e.
2. Ì n hemodi aI ysi s, t he pat i ent ' s bl ood i s t r ansf used t hrough a di al yzi ng membr ane
uni t t hat removes t he har mf ul subst ances f r om t he pat i ent ' s vascul ar syst em. Af t er
passi ng t hr ough t he di al yzer , t he bl ood r eent ers t he body t hr ough a vei n.
IX. NEEDLES AND SYRINGES
A. Hypodermi c needI es ar e st ai nl ess-st eel or al umi num devi ces t hat penet r at e t he
ski n f or t he purpose of admi ni st eri ng or t r ansf er ri ng a parent er al product (Fi gur e 27-
8) .
1. NeedI e gauge i s t he out si de di amet er of t he needl e shaf t ; t he l ar ger t he number ,
t he smal l er t he di amet er. Gauges i n common use r ange f rom 13 (l argest di amet er )
t o 27. Subcut aneous i nj ect i ons usual l y requi r e a 24- gauge or 25-gauge needl e.
Ì nt r amuscul ar i nj ect i ons r equi r e a needl e wi t h a gauge bet ween 19 and 22. Needl es
bet ween 18 gauge and 20 gauge are commonl y used f or compoundi ng parent eral s.
2. BeveI s are sl ant i ng edges cut i nt o needl e t i ps t o f aci l i t at e i nj ect i on t hrough
t i ssue or r ubber vi al cl osur es.
a. ReguI ar-beveI needI es ar e t he most commonl y used t ype, and t hey are sui t abl e
f or subcut aneous and i nt r amuscul ar i nj ect i ons and hypodermocl ysi s.
b. Short -beveI needI es ar e used when onl y shal l ow penet rat i on i s r equi red ( as i n
Ì V i nj ect i ons) .
c. I nt radermaI - beveI needI es are desi gned f or i nt r adermal i nj ect i ons and have t he
most bevel ed edges.

Figure 27-8. Needles. Top. 20 gauge-3½ inch.
Left to right. 18 gauge-1½ inch. 20 gauge-1 inch.
23 gauge-1 inch. 25 gauge-5/8 inch. and 27
gauge-½ inch.
P. 581



Figure 27-9. Syringes. Left to right. 60 mL
catheter tip. 60 mL. 30 mL. 10 mL. 5 mL. 3 mL.
and 1 mL.
3. NeedI e I engt hs r ange f r om ¼ i nch t o 6 i nches. Choi ce of needl e l engt h depends
on t he desi r ed penet r at i on.
a. For compoundi ng parent eraI preparati ons, 1½- i nch- l ong needl es are commonl y
used.
b. I nt radermaI and subcut aneous i nj ecti ons necessi t at e a short needl e l engt h,
usual l y ¼ i nch t o 5/ 8 i nch.
c. I nt raspi naI i nj ect i on r equi r es a needl e l engt h of 3½ i nches.
d. I V i nf usi on r equi res needl es t hat range i n l engt h f rom 1¼ i nches t o 2½ i nches.
B. Syri nges ar e devi ces f or i nj ect i ng, wi t hdr awi ng, or i nst i l l i ng f l ui ds. Syr i nges
consi st of a gl ass or pl ast i c bar r el wi t h a t i ght - f i t t i ng pl unger at one end; a smal l
openi ng at t he ot her end accommodat es t he head of a needl e (Fi gur e 27-9) .
1. The Luer syri nge, t he f i rst syr i nge devel oped, has a uni versal needl e at t achment
accommodat i ng al l needl e si zes.
2. Syri nge voI umes range f rom 0. 3 t o 60 mL. Ì nsul i n syr i nges have uni t gr adat i ons
( 100 uni t s/ mL) r at her t han vol ume gr adat i ons.
3. CaI i brati ons ar e i n t he met r i c syst em, and vary i n speci f i ci t y dependi ng on
syr i nge si ze. The smal l er t he syr i nge, t he smal l er t he measur ement scal e.
4. Syri nge t i ps come i n sever al t ypes.
a. Luer- Lok t i ps ar e t hreaded t o ensur e t hat t he needl e f i t s t i ght l y i n t he syr i nge.
Ant i neopl ast i c agent s shoul d be admi ni st er ed wi t h syr i nges of t hi s t ype ( see VÌ Ì . D. ) .
b. Luer- SI i p t i ps are unt hr eaded so t hat t he syr i nge and needl e do not l ock i nt o
pl ace. Because of t hi s, t he needl e may become di sl odged.
c. Eccent ri c ti ps, whi ch ar e set of f cent er , al l ow t he needl e t o r emai n paral l el t o
t he i nj ect i on si t e and mi ni mi ze venous i rr i t at i on.
d. Cat het er ti ps ar e used f or wound i r r i gat i on and admi ni st r at i on of ent eral
f eedi ngs. They ar e not i nt ended f or i nj ect i ons.
X. INTRAVENOUS DRUG DELIVERY
A. I nj ect i on si t es
1. Peri pheraI vei n i nj ect i on i s pr ef er r ed f or drugs t hat do not i r ri t at e t he vei ns,
admi ni st rat i on of i sot oni c sol ut i ons, and pat i ent s who r equi r e onl y shor t - t er m Ì V
t her apy. Gener al l y, t he dor sal f or ear m sur f ace i s chosen f or veni punct ur e.
2. Cent raI vei n i nj ecti on i s pref er red f or admi ni st r at i on of i r ri t at i ng dr ugs or
hyper t oni c sol ut i ons, pat i ent s requi r i ng l ong- t er m Ì V t her apy, and si t uat i ons i n whi ch
a peri pher al l i ne cannot be mai nt ai ned. Large vei ns i n t he t hor aci c cavi t y, such as
t he subcl avi an vei n, ar e used.
P. 582


B. I nf usi on met hods
1. Conti nuous- dri p i nf usi on i s t he sl ow, pri mar y- l i ne i nf usi on of an Ì V preparat i on
t o mai nt ai n a t her apeut i c dr ug l evel or provi de f l ui d and el ect rol yt e r epl acement .
a. FI ow rat es must be car ef ul l y moni t or ed. Gener al l y, t hese r at es ar e expr essed as
vol ume per uni t of t i me (e. g. , mL/ hr, drops/ mi n) and somet i mes as mg/ mi n f or
cer t ai n drugs.
b. Admi ni st rat i on. Drugs wi t h a narr ow t herapeut i c i ndex such as oxyt oci n
( Pi t oci n) , hepar i n, and pr essor agent s such as nor epi nephri ne ( Levo- Phed) and
phenyl ephr i ne ( Neo- Synephri ne) t ypi cal l y are admi ni st er ed by t hi s met hod.
2. I ntermi tt ent i nf usi on al l ows dr ug admi ni st rat i on at speci f i c i nt er val s (e. g. , ever y
4 hour s) and i s most of t en used f or ant i bi ot i cs.
a. Three di f f erent techni ques may be used.
( 1) Di rect ( boI us) i nj ecti on r api dl y del i ver s smal l vol umes of an undi l ut ed dr ug.
Thi s met hod i s used t o:
( a) Achi eve an i mmedi at e ef f ect ( as i n an emer gency)
( b) Admi ni st er dr ugs t hat cannot be di l ut ed
( c) Achi eve a t her apeut i c ser um dr ug l evel qui ckl y
( 2) Addi t i ve set i nf usi on, usi ng a vol ume- cont rol devi ce, i s appropri at e f or t he
i nt er mi t t ent del i ver y of smal l amount s of Ì V sol ut i ons or di l ut ed medi cat i ons. The
f l ui d chamber i s at t ached t o an i ndependent f l ui d suppl y or pl aced di r ect l y under t he
est abl i shed pri mar y Ì V l i ne.
( 3) The pi ggyback met hod i s used when a drug cannot be mi xed wi t h t he pr i mar y
sol ut i on. A speci al coupl i ng f or t he pr i mar y Ì V t ubi ng per mi t s i nf usi on of a
suppl ement ar y secondary sol ut i on t hr ough t he pri mar y syst em.
( a) Thi s met hod el i mi nat es t he need f or a second veni punct ure or f urt her di l ut i on of
t he suppl ement ar y pr epar at i on.
( b) Admi xt ures i n whi ch t he vehi cl e i s added t o t he drug ar e known as
manuf act ur ers' pi ggybacks. Admi xt ur es i n whi ch a speci al drug vi al i s at t ached t o a
speci al Ì V bag ar e known as t he ADD- Vant age syst em ( see Fi gur e 27-7) .
b. Ì n some cases, i ntermi t t ent i nfusi on i nj ect i on devi ces ar e used. Al so cal l ed
scal p- vei n, hepari n-l ock, or but t er f l y i nf usi on set s, t hese devi ces per mi t i nt ermi t t ent
del i ver y whi l e el i mi nat i ng t he need f or mul t i pl e veni punct ur es or pr ol onged venous
access wi t h a cont i nuous i nf usi on. To pr event cl ot t i ng i n t he cannul a, di l ut e hepar i n
sol ut i on or NSS may be added. Benef i t s of i nt ermi t t ent i nf usi on i nj ect i on devi ces
i ncl ude t he f ol l owi ng:
( 1) Thi s met hod i s especi al l y sui t abl e f or pat i ent s who do not requi r e, or woul d be
j eopar di zed by, admi ni st r at i on of l ar ge amount s of Ì V f l ui ds (e. g. , t hose wi t h
congest i ve hear t f ai l ur e).
( 2) Because i nt ermi t t ent i nf usi on i nj ect i on devi ces do not requi r e cont i nuous
at t achment t o an Ì V bot t l e or bag and pol e, t hey per mi t gr eat er pat i ent ambul at i on.
C. Pumps and cont roI I ers ar e t he el ect r oni c devi ces used t o admi ni st er par ent eral
i nf usi ons when t he use of gr avi t y f l ow al one mi ght l ead t o i naccur at e dosi ng or r i sk
pat i ent saf et y. Pumps and cont rol l ers are used t o admi ni st er parent er al nut r i t i on,
chemot herapy, cardi ac medi cat i ons, and bl ood pr oduct s.
1. Pumps ar e used t o del i ver Ì V i nf usi ons wi t h accur acy and saf et y.
a. Two t ypes of mechani sms ar e used i n i nf usi on pumps.
( 1) Pi st on-cyI i nder mechani sms use a pi st on i n a cyl i nder or a syr i nge-l i ke
appar at us t o pump t he desi red vol ume of f l ui d.
( 2) Li near peri st aI ti c mechani sms use ext er nal pr essure t o expel t he f l ui d out of
t he pumpi ng chamber .
b. Types of pumps
( 1) VoI umet ri c pumps ar e used f or i nt ermi t t ent i nf usi on of medi cat i ons such as
ant i bi ot i cs. They are al so used f or cont i nuous i nf usi on of Ì V f l ui d, par ent er al
nut ri t i on, ant i coagul ant s, and ant i - ast hma medi cat i ons.
( 2) Syri nge pumps ar e used t o admi ni st er i nt ermi t t ent or cont i nuous i nf usi ons of
medi cat i ons ( e. g. , ant i bi ot i cs, opi at es) i n concent r at ed f or m.
( 3) Mobi I e i nf usi on pumps ar e smal l i nf usi on devi ces desi gned f or ambul at or y and
home pat i ent s and used f or admi ni st er i ng chemot her apy and opi at e medi cat i ons.
( 4) I mpI ant abI e pumps ar e i nf usi on devi ces surgi cal l y pl aced under t he ski n t o
pr ovi de a cont i nuous r el ease of medi cat i on, t ypi cal l y an opi at e. The r eservoi r i n t he
pump i s ref i l l ed by i nj ect i ng t he medi cat i on t hr ough a l at ex di aphr agm i n t he pump.
P. 583


( 5) Pati ent -cont roI I ed anaI gesi c pumps ar e used t o admi ni st er narcot i cs
i nt er mi t t ent l y or on demand by t he pat i ent wi t hi n t he pat i ent -speci f i c par amet er s,
whi ch are ordered by t he physi ci an and programmed i nt o t he pump.
c. Benef i ts. Despi t e t hei r ext r a cost s and t he t r ai ni ng r equi r ed by per sonnel , pumps
pr ovi de a number of i mpor t ant benef i t s. They mai nt ai n a const ant , accurat e f l ow
r at e and can det ect i nf i l t r at i ons, occl usi ons, and ai r . Pumps al so may decr ease t he
amount of t i me a nur se spends di spensi ng medi cat i on. Newer devi ces are equi pped
wi t h " dr ug l i br ar i es¨ t hat have prespeci f i ed hi gh and l ow dose i nf usi on l i mi t s whi ch
may f aci l i t at e medi cat i on admi ni st r at i on and reduce er r ors.
2. Cont roI I ers, unl i ke pumps, exer t no pumpi ng pr essur e on t he Ì V f l ui d. Rat her,
t hey r el y on gr avi t y and cont r ol t he i nf usi on by count i ng drops el ect r oni cal l y, or t hey
i nf use t he f l ui d mechani cal l y and el ect roni cal l y (e. g. , vol umet ri c cont rol l ers) . Ì n
compari son t o pumps, t he f ol l owi ng ar e char act er i st i cs of cont r ol l er s:
a. They are l ess compl ex and gener al l y l ess expensi ve.
b. They achi eve r easonabl e accuracy.
c. They are ver y usef ul f or uncompl i cat ed i nf usi on t her apy but cannot be used f or
ar t eri al dr ug i nf usi on or f or i nf usi on i nt o smal l vei ns.
D. I V i ncompat i bi I i t i es. When t wo or more drugs must be admi ni st er ed t hr ough a
si ngl e Ì V l i ne or gi ven i n a si ngl e sol ut i on, an undesi r abl e r eact i on can occur .
Al t hough such i ncompat i bi l i t i es ar e r el at i vel y r are, t hei r consequences can be
deadl y. A pat i ent who r ecei ves a preparat i on i n whi ch an i ncompat i bi l i t y has
occur r ed coul d exper i ence t oxi ci t y or an i ncompl et e t herapeut i c ef f ect .
1. Types of i ncompat i bi I i t i es
a. A physi caI i ncompat i bi I i t y occur s when a dr ug combi nat i on pr oduces a vi si bl e
change i n t he appear ance of a sol ut i on. The sol ut i on shoul d never be admi ni st er ed
t o a pat i ent .
( 1) An exampI e of physi cal i ncompat i bi l i t y i s t he evol ut i on of car bon di oxi de when
sodi um bi car bonat e and hydr ochl or i c aci d are admi xed.
( 2) Vari ous t ypes of physi cal i ncompat i bi l i t i es may occur :
( a) Vi si bl e col or change or dar keni ng
( b) Format i on of preci pi t at e, whi ch may resul t f r om t he combi nat i on of phosphat e
and cal ci um.
b. A chemi caI i ncompati bi I i t y r ef l ect s t he chemi cal degr adat i on of one or more of
t he admi xed dr ugs, r esul t i ng i n t oxi ci t y or t herapeut i c i nact i vi t y.
( 1) The degradat i on i s not al ways vi si bl e. Nonvi si bI e chemi caI i ncompat i bi I i t y
may be det ect ed onl y by anal yt i cal met hods.
( 2) Chemi cal i ncompat i bi l i t y occur s i n sever al vari et i es.
( a) CompI exat i on i s a react i on bet ween pr oduct s t hat i nact i vat es t hem. For
exampl e, t he combi nat i on of cal ci um and t et racycl i ne l eads t o f ormat i on of a
compl ex t hat i nact i vat es t et r acycl i ne.
( b) Oxi dat i on occur s when one dr ug l oses el ect rons t o t he ot her , r esul t i ng i n a
col or change and t herapeut i c i nact i vi t y.
( c) Reduct i on t akes pl ace when one drug gai ns el ect r ons f r om t he ot her .
( d) PhotoI ysi s ( chemi cal decomposi t i on caused by l i ght ) can l ead t o hydrol ysi s or
oxi dat i on, wi t h resul t i ng di scol orat i on.
c. A therapeuti c i ncompat i bi I i t y occur s when t wo or more drugs, Ì V f l ui ds, or bot h
ar e combi ned and t he resul t i s a r esponse ot her t han t hat i nt ended. An exampl e of a
t her apeut i c i ncompat i bi l i t y i s t he r educed bact eri ci dal act i vi t y of peni ci l l i n G when
gi ven af t er t et r acycl i ne. Because t et r acycl i ne i s a bact er i ost at i c agent , i t sl ows
bact er i al gr owt h; peni ci l l i n, on t he ot her hand, i s most ef f ect i ve agai nst r api dl y
pr ol i f erat i ng bact eri a.
2. Fact ors af fect i ng I V compat i bi I i t y
a. pH. Ì ncompat i bi l i t y i s mor e l i kel y t o occur when t he component s of an Ì V sol ut i on
di f f er si gni f i cant l y i n pH. Thi s i ncr eased r i sk i s expl ai ned by t he chemi cal r eact i on
bet ween an aci d and a base, whi ch yi el ds a sal t and wat er; t he sal t may be an
i nsol ubl e preci pi t at e.
b. Temperat ure. Gener al l y, i ncreased st or age t emperat ur e speeds drug
degradat i on. To pr eser ve dr ug st abi l i t y, dr ugs shoul d be st or ed i n a r ef ri ger at or or
f r eezer , as appr opr i at e.
c. Degree of di I ut i on. General l y, t he mor e di l ut ed t he drugs are i n a sol ut i on, t he
l ess chance t here i s f or an i on i nt er act i on l eadi ng t o i ncompat i bi l i t y.
P. 584


d. Lengt h of ti me i n soI ut i on. The chance f or a r eact i on resul t i ng i n i ncompat i bi l i t y
i ncreases wi t h t he l engt h of t i me t hat dr ugs ar e i n cont act wi t h each ot her .
e. Order of mi xi ng. Drugs t hat are i ncompat i bl e i n combi nat i on, such as cal ci um
and phosphat e, shoul d not be added consecut i vel y when an Ì V admi xt ur e i s bei ng
pr epar ed. Thi s keeps t hese subst ances f rom pool i ng, or f or mi ng a l ayer on t he t op
of t he Ì V f l ui d, and, t heref or e, decreases t he chance of an i ncompat i bi l i t y. Thor ough
mi xi ng af t er each addi t i on i s al so essent i al .
3. Preventi ng or mi ni mi zi ng i ncompat i bi I i t i es. To r educe t he chance f or an
i ncompat i bi l i t y, t he f ol l owi ng st eps shoul d be t aken:
a. Each dr ug shoul d be mi xed t hor oughl y af t er i t i s added t o t he pr eparat i on.
b. Sol ut i ons shoul d be admi ni st ered pr ompt l y af t er t hey ar e mi xed t o mi ni mi ze t he
t i me avai l abl e f or a pot ent i al react i on t o occur .
c. The number of dr ugs mi xed t oget her i n an Ì V sol ut i on shoul d be kept t o a
mi ni mum.
d. Ì f a pr escri pt i on cal l s f or unf ami l i ar drugs or Ì V f l ui ds, compat i bi l i t y r ef er ences
shoul d be consul t ed.
E. Hazards of parenteraI drug t herapy. A wi de r ange of pr obl ems can occur wi t h
par ent eral dr ug admi ni st r at i on.
1. Physi caI hazards
a. PhI ebi ti s, whi ch i s gener al l y a mi nor compl i cat i on, may r esul t f rom vei n i nj ur y or
i r r i t at i on. Phl ebi t i s can be mi ni mi zed or prevent ed t hrough pr oper Ì V i nser t i on
t echni que, di l ut i on of i r r i t at i ng dr ugs, and a decreased i nf usi on r at e.
b. Thrombosi s, t he f or mat i on of a bl ood cl ot i n a vei n or art er y.
c. Ext ravasati on may occur wi t h admi ni st r at i on of dr ugs wi t h vesi cant pr oper t i es
( see VÌ Ì . D. 3. b) .
d. I rri tat i on at t he i nj ect i on si t e can be r educed by var yi ng t he i nj ect i on si t e and
appl yi ng a moi st ur i zi ng l ot i on t o t he ar ea.
e. Pai n f rom i nf usi on i s most common wi t h peri pher al Ì V admi ni st r at i on of a hi ghl y
concent r at ed pr eparat i on. Swi t chi ng t o cent ral vei n i nf usi on and/ or di l ut i ng t he dr ug
mi ght al l evi at e t he pr obl em.
f . Ai r emboI i sm, pot ent i al l y f at al , can r esul t f rom ent r y of ai r i nt o t he Ì V t ubi ng.
g. I nfect i on, a par t i cul ar danger wi t h cent ral Ì V l i nes, may st em f r om cont ami nat i on
dur i ng Ì V l i ne i nsert i on or t ubi ng changes. Ì nf ect i on may be l ocal or general i zed
( sept i cemi a) . The i nf ect i on ri sk can be mi ni mi zed by f ol l owi ng est abl i shed pr ot ocol s
f or t he care of cent ral l i nes.
h. AI I ergi c react i ons can r esul t f rom hypersensi t i vi t y t o an Ì V sol ut i on or addi t i ve.
i . Cent raI cat het er mi spI acement may l ead t o ai r embol i sm or pneumot hor ax. To
ensur e t hat t he cat het er has passed i nt o t he subcl avi an vei n and advanced t o t he
l evel of t he vena cava, t he pl acement shoul d al ways be ver i f i ed r adi ol ogi cal l y.
j . Hypot hermi a, possi bl y r esul t i ng i n shock and car di ac ar r est , mi ght st em f rom
admi ni st rat i on of a col d Ì V sol ut i on. Thi s probl em can be pr event ed by al l owi ng
par ent eral pr oduct s t o r each r oom t emperat ure.
k. Neurot oxi ci t y may be a ser i ous compl i cat i on of i nt r at hecal or i nt raspi nal
admi ni st rat i on of dr ugs cont ai ni ng pr eser vat i ves. Pr eser vat i ve- f r ee dr ugs shoul d be
used i n t hese ci rcumst ances.
2. Mechani caI hazards
a. I nfusi on pump or cont roI I er f ai I ure can l ead t o runaway i nf usi on, f l ui d over l oad,
or i ncor r ect dosages.
b. I V tubi ng can become ki nked, spl i t , or cracked. Ì t al so may produce part i cul at es,
al l ow cont ami nat i on, or i nt er f er e wi t h t he i nf usi on.
c. Parti cuI at e mat t er may be pr esent i n a parent er al product and can cause
embol i sm.
d. GI ass cont ai ners may br eak, causi ng i nj ur y.
e. Rubber vi aI cI osures may i nt er act wi t h t he encl osed product .
3. Therapeut i c hazards
a. Drug i nstabi I i t y may l ead t o t her apeut i c i nef f ect i veness.
b. I ncompat i bi I i t y may r esul t i n t oxi ci t y or r educed t her apeut i c ef f ect i veness.
c. LabeI i ng errors can cause admi ni st rat i on of an i ncorr ect drug or i mpr oper
dosage.
d. Drug overdose can be caused by r unaway Ì V i nf usi on, f ai l ur e of an i nf usi on
pump or cont rol l er , or nur si ng or pharmacy er r ors.
P. 585


e. Preservat i ve and soI ubi I i zi ng agent t oxi ci t y can be a seri ous compl i cat i on,
especi al l y i n chi l dr en. For exampl e, pr emat ur e i nf ant s r ecei vi ng par ent eral pr oduct s
cont ai ni ng benzyl al cohol can devel op a f at al aci dot i c t oxi c syndr ome, whi ch i s
r ef er red t o as t he gaspi ng syndr ome. Rapi d admi ni st r at i on of phenyt oi n (Di l ant i n)
and di azepam ( Val i um) bot h ut i l i ze pr opyl ene gl ycol as a sol ubi l i zi ng agent , has
been associ at ed wi t h cardi ovascul ar col l apse.
P. 586


STUDY QUESTIONS
Di rect i ons: Each of t he numbered i t ems or i ncompl et e st at ement s i n t hi s sect i on i s
f ol l owed by answer s or by compl et i ons of t he st at ement . Sel ect t he one l et t er ed
answer or compl et i on t hat i s best i n each case.
1. Parent eraI products wi t h an osmot i c pressure I ess t han that of bI ood or 0. 9%
sodi um chI ori de are referred t o as
( A) Ì sot oni c sol ut i ons
( B) Hyper t oni c sol ut i ons
( C) Hypot oni c sol ut i ons
( D) Ì so- osmot i c sol ut i ons
( E) Neut r al sol ut i ons
Vi ew Answer 1. The answer i s C[ VI I . B. b, ] . 2. Asept i c t echni que shouI d be
used i n the preparat i on of aI I of t he f oI I owi ng medi cat i ons wi t h t he excepti on
of ;
( A) Neomyci n i rr i gat i on sol ut i on
( B) Ganci cl ovi r ( Cyt ovene) i nt r aocul ar i nj ect i on
( C) Phyt onadi one ( Aquamephyt on) subcut aneous i nj ect i on
( D) Ampi ci l l i n ( Pr i ni ci pen) Ì V admi xt ur e pi ggyback
( E) Baci t raci n oi nt ment
Vi ew Answer 2. The answer i s E[] . 3. Whi ch needI e has the smaI I est
di amet er?
( A) 25 gauge, 3¾ i nches
( B) 24 gauge, 3½ i nches
( C) 22 gauge, 3 ½ i nches
( D) 20 gauge, 33/ 8 i nches
( E) 26 gauge, 35/ 8 i nches
Vi ew Answer 3. The answer i s E[] . 4. I nt ra-art i cuI ar i nj ect i on ref ers t o
i nj ect i on i nto t he
( A) Muscl e mass
( B) Subcut aneous t i ssue
( C) Spi nal f l ui d
( D) Super f i ci al ski n l ayer
( E) Joi nt space
Vi ew Answer 4. The answer i s E[I V. 1] . 5. Advantages of the i nt ravenous
rout e i ncI ude
( A) Ease of r emoval of t he dose
( B) A depot ef f ect
( C) Low i nci dence of phl ebi t i s
( D) Rapi d onset of act i on
( E) A l ocal i zed ef f ect
Vi ew Answer 5. The answer i s D[] . 6. A cent raI vei n, ei t her subcI avi an or
i nt ernaI j uguI ar, may be consi dered a sui tabI e rout e for I V admi ni st rat i on i n
whi ch of t he f oI I owi ng si t uati ons?
( A) When an i r r i t at i ng drug i s gi ven
( B) When hyper t oni c dr ugs ar e gi ven
( C) For l ong- t er m t her apy
( D) For admi ni st eri ng dext r ose 35% as par ent eral nut r i t i on
( E) Al l of t he above
Vi ew Answer 6. The answer i s E[] . 7. To prepare a t otaI parenteraI
nut ri t i on ( TPN) t hat requi res 10 mEq of caI ci um gI uconat e and 15 mM of
pot assi um phosphat e, the appropri at e acti on to t ake wouI d be whi ch of t he
f oI I owi ng?
( A) Add t he cal ci um f i rst , add t he ot her addi t i ves, t hen add t he phosphat e l ast ,
t hor oughl y mi xi ng t he sol ut i on af t er addi t i on.
( B) Add t he cal ci um gl uconat e and pot assi um phosphat e consecut i vel y.
( C) Not combi ne t he agent s t oget her but gi ve t hem as a separat e i nf usi on.
( D) None of t he above.
Vi ew Answer 7. The answer i s A[] . 8. Whi ch needI e gauge wouI d be most
I i keI y used as a subcutaneous i nj ect i on of epoet i n?
( A) 25 gauge, 5/ 8 i nch
( B) 16 gauge, 1 i nch
( C) 18 gauge, 1½ i nches
( D) 22 gauge, 1½ i nches
( E) None of t he above
Vi ew Answer 8. The answer i s A[] 9. Whi ch of the f oI I owi ng drugs shouI d
NOT be prepared i n a hori zont aI I ami nar f I ow hood?
( A) Ampi ci l l i n ( Pri nci pen)
( B) Dopami ne
( C) Ci spl at i n ( Pl at i nol )
( D) Ni t r ogl ycer i n
( E) Br et yl i um t osyl at e ( Br et yl ol )
Vi ew Answer 9. The answer i s C[] . P. 587


10. AI I of t he f oI I owi ng st at ements about d5w are t rue EXCEPT
( A) Ì t s pH range i s 3. 5- 6. 5.
( B) Ì t i s hypert oni c.
( C) Ì t i s a 5% sol ut i on of D- gl ucose.
( D) Ì t shoul d be used wi t h caut i on i n di abet i c pat i ent s.
( E) Ì t i s of t en used i n Ì V admi xt ur es.
Vi ew Answer 10. The answer i s B[] . 11. AI I of t he f oI I owi ng are pot enti aI
hazards of parenteraI therapy EXCEPT
( A) Hypot her mi a
( B) Phl ebi t i s
( C) Ext r avasat i on
( D) Al l er gi c react i ons
( E) Ì l eus
Vi ew Answer 11. The answer i s E[] . 12. Procedures f or t he safe handI i ng of
ant i neopI ast i c agents i ncI ude aI I of t he f oI I owi ng EXCEPT
( A) Use of Luer - Lok syr i nge f i t t i ngs.
( B) Wear i ng doubl e-l ayer ed l at ex gl oves.
( C) Use of negat i ve- pr essur e t echni que when medi cat i on i s bei ng wi t hdrawn f r om
vi al s.
( D) Wear i ng cl osed- f r ont , sur gi cal - t ype gowns wi t h cuf f s.
( E) Use of hori zont al l ami nar f l ow hood.
Vi ew Answer 12. The answer i s E[] . 13. I n prepari ng an i nt raspi naI dose of
bupi vacai ne, t he best pore si ze f i I ter f or coI d st eri I i zat i on wouI d be
( A) 8-mm f i l t er
( B) 5- µm f i l t er
( C) 0. 45- µm f i l t er
( D) 0. 22- µm f i l t er
( E) None of t he above
Vi ew Answer 13. The answer i s D[] . 14. Process si muI at i on
( A) Ì s a met hod of qual i t y assur ance.
( B) Eval uat es t he adequacy of a pr act i t i oner ' s asept i c t echni que.
( C) Requi r es t he use of a mi crobi al gr owt h medi um.
( D) Ì s carr i ed out i n a manner i dent i cal t o normal st er i l e admi xt ur e product i on under
r out i ne oper at i ng condi t i ons.
( E) Al l of t he above.
Vi ew Answer 14. The answer i s E[] . For quest i ons 15-18: The pharmaci st
r ecei ves a pr escri pt i on f or hydromor phone ( Di l audi d) i nj ect i on t o be compounded t o
a sol ut i on of 15 mg per mL. Di l audi d i s commerci al l y avai l abl e i n an ampul e but t he
concent r at i on i s 10 mg per mL. The physi ci an woul d l i ke a mor e concent rat ed
sol ut i on pr epar ed so t hat 50 ml s can be i nst i l l ed i nt o t he t i t ani um resevoi r of a
Medt r oni c i nf usi on pump. The hydromor phone sol ut i on wi l l be cont i nuousl y i nf used,
i nt rat hecal l y, over approxi mat el y 30 days, f or a pat i ent wi t h chr oni c back pai n,
uncont rol l ed wi t h oral nar cot i cs. The phar maci st checks hi s i nvent or y and f i nds a
bot t l e of Hydr omor phone powder , USP. He pr oceeds t o wei gh out enough powder f or
a 60 mL preparat i on. The wei ghi ng st ep i s checked by a col l eague phar maci st .
15. Accordi ng to USP Chapt er 797 t hi s st eri I e preparat i on wouI d be consi dered
a
( A) Hi gh r i sk l evel CSP
( B) Medi um r i sk l evel CSP
( C) Low r i sk l evel CSP
( D) None of t hese
Vi ew Answer 15. The answer i s A[] . 16. What wouI d be an appropri ate
envi ronment f or t he asept i c mani puI at i ons requi red f or t hi s preparati on.
( A) Pharmacy wor kbench or count er i n ambi ent r oom ai r
( B) Ì nsi de an Ant eroom, wi t h Ì SO Cl ass 8 qual i t y ai r
( C) Ì nsi de a Bar ri er Ì sol at or wi t h Ì SO Cl ass 5 qual i t y ai r
( D) A hor i zont al l ami nar f l ow wor kbench bench, newl y i nst al l ed, wi t h no
cer t i f i cat i on, but manuf act urer guarent eed t o be Ì SO 5 Cl ass ai r qual i t y.
Vi ew Answer 16. The answer i s C[] . P. 588


17. The pharmaci st begi ns t o gather hi s suppI i es f or t hi s preparat i on. These
shouI d i ncI ude:
( A) Mi l l i por e 0. 45 mi cr on HV Fi l t er wi t h st er i l e wat er f or i nj ect i on
( B) Mi l l i por e 0. 22 mi cr on GS Fi l t er wi t h sodi um chl ori de 0. 9%
( C) Bect i n- Di cki nson 16 gauge, 5 mi cr on f i l t er needl wi t h sodi um chl ori de 0. 9%
( D) Mi l l i pore AA 0. 8 mi cron Fi l t er wi t h dext r ose 5% i n wat er
Vi ew Answer 17. The answer i s B[] . 18. Af t er t he soI ut i on was prepared t he
appropri at e quaI i t y assurance or doubI e check by anot her pharmaci st wouI d
i ncI ude:
( A) Ì nspect i on of t he powder and t he l abel t o ensur e hydr omor phone was t he
pr epar ed i ngr edi ent and t hat t he l abel cont ai ned a beyond use dat e and t he 15 mg
per mL concent rat i on.
( B) Sendi ng a sol ut i on sampl e or al i quot t o a mi cr obi ol ogy l ab t o t est f or t he
pr esence of bact eri a and pyr ogens pr i or t o di spensi ng.
( C) Check t o ensur e a cor r ect st eri l i zi ng f i l t er was ut i l i zed.
( D) Vi sual i nspect i on t o ensur e t he f i nal acqueous sol ut i on had no vi si bl e
par t i ci pat es.
( E) Al l of t he above.
Vi ew Answer 18. The answer i s E[] . P. 589


ANSWERS AND EXPLANATIONS
1. The answer i s C [ VI I . B. b, X. A] .
Hypot oni c sol ut i ons have an osmot i c pressure l ess t han t hat of bl ood ( or 0. 9%
sal i ne) , wher eas hyper t oni c sol ut i ons have an osmot i c pr essur e gr eat er t han t hat of
bl ood, and i sot oni c or i so- osmot i c sol ut i ons have an osmot i c pr essur e equal t o t hat
of bl ood.
2. The answer i s E [ Ì Ì . A. 5] .
Ì r r i gat i on sol ut i ons, opht hal mi c prepar at i ons and par ent eral pr oduct s, and
subcut aneous and Ì V medi cat i ons shoul d be prepar ed usi ng asept i c t echni que.
Si nce Baci t r aci n oi nt ment i s appl i ed t o t he ski n and does not bypass t he body' s
pr ot ect i ve bar r i er s, i t s preparat i on woul d not be hel d t o t he same r equi rement s.
3. The answer i s E [ Ì X. A. 1] .
The gauge si ze r ef er s t o t he out er di amet er of t he needl e. The l ower t he gauge si ze
number , t he l ar ger t he needl e.
4. The answer i s E [ I V. 1] .
Ì nt r a-ar t i cul ar i nj ect i on ref ers t o an i nj ect i on i nt o t he j oi nt space. Thi s
admi ni st rat i on r out e gener al l y i s used f or cer t ai n t ypes of cor t i cost eroi ds t o r educe
i nf l ammat i on associ at ed wi t h i nj ur y or r heumat oi d ar t hri t i s.
5. The answer i s D [ VÌ . C] .
The Ì V r out e of dr ug admi ni st r at i on al l ows f or rapi d onset of act i on and, t her ef or e,
i mmedi at e t her apeut i c ef f ect . Ther e can be no recal l of t he admi ni st er ed dose, and
phl ebi t i s, or i nf l ammat i on of a vei n, can occur . Ì n addi t i on, a depot ef f ect ( i . e. ,
accumul at i on and st or age of t he drug f or di st r i but i on) cannot be achi eved by
admi ni st er i ng a drug i nt ravenousl y. Del i ver i ng a dr ug i nt r avenousl y r esul t s i n a
syst emi c rat her t han a l ocal i zed ef f ect .
6. The answer i s E [ X. A. 2] .
Ì r r i t at i ng dr ugs, hyper t oni c dr ugs, l ong- t er m t her apy, and dext r ose 35% are best
gi ven by cent ral Ì V admi ni st r at i on. Per i pheral vei n i nj ect i on i s used f or
post oper at i ve hydrat i on, admi ni st rat i on of noni r ri t at i ng drugs, or i sot oni c sol ut i ons
and f or shor t - t er m Ì V t her apy.
7. The answer i s A [ X. D. 2. e] .
Physi cal i ncompat i bi l i t i es occur when t wo or more pr oduct s are combi ned and
pr oduce a change i n t he appear ance of t he sol ut i on, such as t he f or mat i on of a
pr eci pi t at e. Cal ci um and phosphat e sol ut i ons when di r ect l y combi ned or added
consecut i vel y t o a sol ut i on wi l l f orm a whi t e pr eci pi t at e. By al t eri ng t he order of
mi xi ng, t hey can be saf el y added t o TPN sol ut i ons.
8. The answer i s A [ Ì X. A. 3. b. ]
Si nce subcut aneous i nj ect i on does not requi r e penet rat i on t hrough several ski n
l ayer s or muscl e t i ssue, a shor t needl e wi t h a narr ow di amet er i s used. A 16- or 18-
gauge needl e i s most commonl y used i n t he pharmacy f or pr epar i ng parent er al
sol ut i ons. A 22-gauge needl e woul d be used f or i nt r amuscul ar i nj ect i on.
9. The answer i s C [ Ì Ì . B. 2. b. 1] .
Ci sPl at i n i s an ant i neopl ast i c agent and, consequent l y, shoul d be pr epared onl y i n a
ver t i cal l ami nar f l ow hood because of t he pot ent i al hazar d of t hese t oxi c agent s t o
t he operat or .
10. The answer i s B [ VÌ Ì . B. 1. a] .
d5w ( dext r ose [ D-gl ucose] 5% i n wat er ) i s aci di c, i t s pH ranges f r om 3. 5-6. 5, and i t
i s i sot oni c. Ì t i s of t en used i n Ì V admi xt ur es and shoul d be used wi t h caut i on i n
di abet i c pat i ent s.
11. The answer i s E [ VÌ Ì . D. 2. , X. E] .
Par ent er al t her apy i s of t en a t r eat ment f or i l eus. Hypot hermi a, phl ebi t i s,
ext r avasat i on, and al l ergi c react i ons can be hazar ds of par ent eral t her apy.
P. 590


12. The answer i s E [ VÌ Ì . D. 2] .
Ì n order t o pr event drug exposur e, a vert i cal f l ow l ami nar hood ( not hor i zont al )
shoul d be used when an ant i neopl ast i c agent i s pr epared. The ot her pr ecaut i ons
ment i oned i n t he quest i on ar e i mpor t ant saf et y measur es f or handl i ng parent eral
ant i neopl ast i cs. Al l pharmacy and nur si ng personnel who handl e t hese t oxi c
subst ances shoul d recei ve speci al t r ai ni ng.
13. The answer i s D [ Ì V. D. 2. c. 2] .
Si nce i nt raspi nal and epi dur al doses of bupi vacai ne are f requent l y prepared f rom
nonst eri l e powder s, col d st er i l i zat i on, accompl i shed by f i l t r at i on, i s a si mpl e met hod
of ensur i ng compl et e mi cr obi al r emoval . The f i l t er s l i st ed 8 mm t o 0. 45 µm wi l l
r emove onl y part i cul at e mat t er . A 0. 22 µM f i l t er ensur es t he removal of
mi cr oor gani sms.
14. The answer i s E [ Ì Ì Ì . F] .
Pr ocess si mul at i on i s one part of an overal l qual i t y assur ance program. Ì t r equi r es
dupl i cat i ng st er i l e pr oduct pr epar at i on usi ng a growt h medi um i n pl ace of act ual
pr oduct s. Ì t ser ves t o eval uat e t he asept i c t echni que of t he i ndi vi dual per f or mi ng al l
t he necessar y st eps of st er i l e pr oduct prepar at i on.
15. The answer i s A [ Ì Ì . A. 6. c] .
The hydr omor phone pr epar at i on i s a hi gh ri sk l evel CSP because i t i s made f rom
non-st er i l e powder .
16. The answer i s C [ Ì Ì . B. 4] .
USP Chapt er 797 r equi res an Ì SO Cl ass 5 ai r qual i t y envi r oment f or t hi s
pr epar at i on. A Bar r i er Ì sol at or wi t hi n a cl eanr oom cr eat es an Ì SO Cl ass 5
envi r onment . Ambi ent room ai r i s unaccept abl e f or any pr epar at i on. An Ant er oom i s
gener al l y an ar ea of r el at i vel y hi gh personnel and suppl y t r af f i c. Whi l e ai r qual i t y
may be accept abl e, i t does not pr ovi de an accept abl e cri t i cal si t e of asept i c
mani pul at i ons. Al l new l ami nar f l ow wor k benched shoul d be t est ed f or ai r vel oci t y
and f i l t er i nt egri t y pri or t o use.
17. The answer i s B [ Ì V. D. 2. c(2) ] .
The hydr omor phone requi r es st er i l i zat i on pri or t o i nt rat hecal admi ni st r at i on. Thi s i s
best achi eved wi t h a 0. 22 mi cron f i l t er . Sodi um chl ori de 0. 9% i s t he sol ut i on most
si mi l ar t o t he CNS f l ui d and woul d be a bet t er choi ce over st er i l e wat er of dext r ose
5% i nj ect i on.
18. The answer i s E [ Ì Ì Ì . B] .
Each st ep i n st er i l e compoundi ng shoul d have an associ at ed qual i t y assurance
doubl e check. Ì nspect i on of t he i ni t i al i ngredi ent s, r evi ew of suppl i es, moni t ori ng of
asept i c t echni que, and exami nat i on of t he f i nal product cr eat es mul t i pl e
oppor t uni t i es t o i nt ercept an er r or and make necessar y cor r ect i ons. Hi gh r i sk l evel s
CSPs shoul d be used wi t hi n 24 hour s i n t he absence of st er i l i t y t est i ng. Gi ven t hi s
pr oduct wi l l be admi ni st er ed over 30 days, a st er i l i t y and pyr ogen t est woul d be
appropr i at e.

28
ParapharmaceuticaIs, Diagnostic Aids, and
MedicaI Devices
Jenny A. Van Amburgh
Todd A. Brown
I. AMBULATORY AIDS
A. Canes. These si mpl e ambul at or y ai ds provi de bal ance and al l ow f or t he t r ansf er
of wei ght of f a weakened l eg.
1. Hei ght . The hei ght of t he cane must be adj ust ed t o t he i ndi vi dual pat i ent . A cane
t hat i s cor r ect l y f i t t ed al l ows f or maxi mum wei ght t r ansf er wi t hout al l owi ng t he
pat i ent t o l ock t he el bow. The cor r ect hei ght shoul d pr ovi de a 25- degr ee angl e at
t he el bow, or t he t op of t he cane shoul d come t o t he cr ease of t he wr i st whi l e
pat i ent i s st andi ng er ect .
2. Types of canes. Canes may be made of wood or met al .
a. Wooden canes come i n var yi ng t hi cknesses. The t hi cker ones are i nt ended f or
mal es, and t he t hi nner ones ar e f or f emal es. They may be cut t o t he cor rect hei ght
f or t he pat i ent .
b. Met aI canes are usual l y adj ust abl e i n hei ght t o f i t t he i ndi vi dual pat i ent .
c. FoI di ng canes wi l l f ol d t o al l ow f or easy t r anspor t or st orage when not i n use.
d. A quad cane i s a met al cane t hat has a quadrangul ar base wi t h f our l egs. Thi s
al l ows f or gr eat er wei ght t r ansf er . The base of t he quad cane comes i n t wo si zes.
The l arger base pr ovi des gr eat er st abi l i t y but i s mor e di f f i cul t t o mani pul at e
because of t he si ze and wei ght .
e. Seat canes cont ai n an ar ea t hat can be f ol ded down and used t o si t on. They are
usef ul f or i ndi vi dual s who cannot wal k l ong di st ances wi t hout rest i ng.
B. Crut ches may be used by pat i ent s wi t h t empor ar y di sabi l i t i es ( e. g. , spr ai ns,
f r act ur es) or by t hose wi t h chr oni c condi t i ons.
1. Use. Cr ut ches are used t o t ake al l t he wei ght of f an i nj ur ed or weakened l eg. The
cr ut ches ar e used i n pl ace of t he l eg. Cr ut ch si zes range f rom t oddl er t o adul t .
Accessori es t hat ar e used wi t h a cr ut ch i ncl ude a t i p t o pr event sl i ppi ng, handgr i p
cushi on, and arm pad ( f or axi l l ar y cr ut ch) .
2. Types of crut ches
a. An axi I I ar y crut ch, t he most commonI y used cr ut ch, i s t ypi cal l y used f or
t empor ar y di sabi l i t i es. The t op of t he cr ut ch shoul d be 2 i nches bel ow t he axi l l a t o
pr event " crut ch par al ysi s¨ ( i . e. , i nj ur y t o t he axi l l ar y ner ves, bl ood vessel s, and
l ymph nodes) . The hei ght of t he handgr i p shoul d be set so t hat t he el bow f or ms a
25- degr ee angl e.
b. A f orearm crutch (al so cal l ed a Canadi an or Lof st rand cr ut ch) r emai ns i n
posi t i on by at t achi ng t o t he f or ear m by a col l ar or cuf f . Ì t i s commonl y used by
pat i ent s who need cr ut ches on a l ong- t er m basi s.
c. A quad crutch i s a f orear m crut ch wi t h a quadrangul ar base t hat has f our l egs.
The base i s at t ached t o t he cr ut ch wi t h a f l exi bl e r ubber mount . Thi s al l ows f or mor e
st abi l i t y and const ant cont act wi t h t he gr ound.
d. A pI at f orm crut ch cont ai ns a rect angul ar ar ea i n whi ch t o pl ace t he f or earm. The
cr ut ch may be hel d by a handgr i p or secur ed by a bel t t hat wr aps around t he
f or ear m. Ì t i s commonl y used by pat i ent s who do not have enough hand st r engt h and
cont r ol f or a f or ear m crut ch.
C. Seat I i f t chai rs ar e el ect ri c-power ed chai rs t hat r ai se t he pat i ent f rom a si t t i ng t o
a st andi ng posi t i on.
P. 592


D. WaI kers ar e l i ght wei ght r ect angul ar - shaped devi ces t hat ar e made of met al
t ubi ng and have f our wi del y pl aced l egs.
1. Use. Wal kers are used by pat i ent s who need mor e support t han a cane or crut ch
or who have t r oubl e wi t h bal ance duri ng ambul at i on. The use requi r es r easonabl y
good arm, hand, and wr i st f unct i on. The pat i ent hol ds on t o t he wal ker and t akes a
st ep, t hen moves t he wal ker and t akes anot her st ep.
2. Types of waI kers. Wal ker s come i n t wo si zes: aduI t and chi I d. Wal ker s may be
adj ust abl e i n hei ght . Some wal kers wi l l f ol d t o make st or age or t ransport i ng easi er .
Wal kers can have wheel s on t he f ront l egs t o al l ow t he user t o move t he wal ker by
r ai si ng t he back l egs and r ol l i ng i t i nst ead of havi ng t o pi ck i t up. Pat i ent s wi t h l oss
of arm, wr i st , or hand f unct i on on one si de mi ght use a hemi waI ker or a si de
waI ker.
a. A hemi waI ker i s si mi l ar t o a st andar d wal ker except t hat i t has one handl e i n t he
cent er of t he wal ker f or mani pul at i on.
b. A si de waI ker i s pl aced t o t he si de of t he pat i ent i nst ead of i n f ront of t he
pat i ent .
c. A reci procaI waI ker cont ai ns t wo hi nges, one on each si de of t he wal ker . Thi s
al l ows t he user t o swi ng each si de al t ernat el y duri ng ambul at i on.
d. A roI I at or i s a wal ker wi t h wheel s on al l f our l egs. The movement i s cont r ol l ed by
hand brakes.
E. WheeI chai rs. Many di f f er ent t ypes of wheel chai r s are avai l abl e. The pat i ent ' s
di sabi l i t i es, si ze, wei ght , and act i vi t i es ar e t he mai n consi der at i ons i n wheel chai r
sel ect i on. The f ol l owi ng opt i ons shoul d be consi der ed when sel ect i ng a wheel chai r.
1. Seat si ze. The st andar d chai r i s 18 i nches wi de and 16 i nches deep. A nar r ow
wheel chai r i s 16 i nches wi de. Wheel chai rs ar e avai l abl e i n wi dt hs up t o 48 i nches.
The chai r shoul d be 2 i nches wi der t han t he wi dest par t of t he pat i ent ' s body
( usual l y ar ound t he but t ocks or t hi ghs) .
2. Arms can be f i xed or det achabl e t o al l ow t he pat i ent t o t r ansf er on and of f t he
chai r . Hal f l engt h arms ( as opposed t o f ul l l engt h) al l ow t he use t o get cl oser t o a
t abl e or wor k sur f ace. Var i ous t ypes of paddi ng and adj ust ment s i n t he ar m posi t i on
can assi st t he pat i ent i n obt ai ni ng a posi t i on t hat i s comf or t abl e and keepi ng t he
ar ms on t he ar m r est s.
3. Ti res can be har d rubber or pneumat i c ( i . e. , ai r f i l l ed) whi ch al l ows t he chai r t o
t r ansver se r ougher surf aces.
4. WheeI s can be r ei nf orced wi t h spokes or can be composi t e based.
5. Leg rest s can be of di f f er ent si zes and ar e avai l abl e wi t h paddi ng. Some have
adj ust abl e el evat i on t o ai d i n heal i ng an acut e i nj ur y.
6. Foot rests can be of di f f erent si zes and are avai l abl e wi t h or wi t hout heel l oops t o
keep t he f oot on t he f oot r est .
7. Cast ers ( i . e. , f ront wheeI s) can be hard r ubber or pneumat i c.
8. CaI f rests can be of di f f erent si zes and are avai l abl e wi t h paddi ng.
9. Seat uphoI st er y hol ds t he pat i ent i n t he chai r. Seat s come i n a vari et y of
mat er i al s t o accommodat e pat i ent s' needs.
10. Back uphoI ster y suppor t s t he pat i ent ' s back whi l e he or she i s si t t i ng i n t he
chai r . The mat eri al i n t he seat and back are usual l y t he same.
11. Cross braces add st abi l i t y and durabi l i t y t o t he chai r .
12. Wei ght . St andard wheel chai rs wei gh 35-50 l b. Li ght wei ght wheel chai rs ( 25- 35
l b. ) ar e avai l abl e f or t hose who ar e unabl e t o mani pul at e a st andard chai r and f or
ease of t ransport .
F. Sports chai rs are wheel chai rs t hat ar e l i ght wei ght and durabl e. They ar e
desi gned f or peopl e who ar e ver y act i ve.
G. Powered wheeI chai rs ar e desi gned f or peopl e who cannot wheel t hemsel ves.
Thi s t ype of wheel chai r i s power ed by an el ect ri c mot or and bat t er y.
P. 593


II. BATHROOM EQUIPMENT.
Thi s equi pment i s used f or pat i ent s who cannot get t o t he bat hroom or f or pat i ent s
who need assi st ance usi ng t he t oi l et or bat ht ub.
A. EI evat ed t oi I et seat s ar e used t o i ncr ease t he hei ght at whi ch t he pat i ent si t s
over t he t oi l et . Thi s assi st s pat i ent s wi t h l i mi t ed mobi l i t y i n get t i ng on and of f t he
t oi l et . Addi t i onal support can be provi ded wi t h toi I et saf et y rai I s. These rai l s al l ow
t he pat i ent t o t r ansf er wei ght f rom t he f eet t o t he hands, and t hey hel p prevent t he
pat i ent f r om f al l i ng when get t i ng on or of f t he t oi l et .
B. Commodes are por t abl e t oi l et s t hat are used by pat i ent s who cannot get t o t he
bat hroom. Commodes cont ai n a f r ame ( wi t h or wi t hout a backrest ) , a seat , and a
bucket . Some ar e adj ust abl e i n hei ght and have ar ms t hat dr op t o f aci l i t at e t ransf er
t o and f r om t he commode. Fol di ng commodes are avai l abl e t o make st orage easi er .
C. Three- i n-one commodes f unct i on as combi nat i on commode, el evat ed t oi l et seat ,
and t oi l et saf et y rai l s. These are benef i ci al f or pat i ent s r equi r i ng var yi ng assi st ance
dur i ng recuper at i on.
D. Bat h benches are seat s wi t h or wi t hout a back t hat f i t i n t he bat ht ub and al l ow
t he pat i ent t o si t whi l e t aki ng a shower .
E. Transf er benches are pl aced over t he out si de of t he bat ht ub. They are avai l abl e
wi t h or wi t hout a back. A t r ansf er bench assi st s t he pat i ent i n get t i ng i nt o t he
bat ht ub and ser ves as a bat h bench whi l e t he pat i ent t akes a shower .
F. Grab bars ar e bars t hat ei t her at t ach t o t he wal l ar ound t he bat ht ub or t o t he
bat ht ub i t sel f t o assi st pat i ent s i n get t i ng on and out of t he bat ht ub.
III. BLOOD PRESSURE MONITORS.
Pat i ent s wi t h hyper t ensi on use t hi s equi pment t o moni t or bl ood pr essur e so t hat
appropr i at e t her apeut i c deci si ons can be made. A pat i ent ' s bl ood pr essure
measured at home i s t ypi cal l y 5 mm Hg l ower t han when measured at t he of f i ce.
1

The t ype of moni t or t hat i s recommended shoul d be det ermi ned by t he pat i ent ' s
abi l i t y t o use t he product cor rect l y. Ì t ems t o consi der when assi st i ng a pat i ent i n t he
sel ect i on of a bl ood pr essur e moni t or : ease of use ( e. g. aut omat i c i nf l at i on) , use of
t he moni t or wi t h one hand ( has D- ri ng cuf f ), t he si ze of t he di spl ay moni t or ( vi sual l y
i mpai red pat i ent s), bl ood pr essur e cuf f si ze, and t he capabi l i t y t o st or e readi ngs.
Types of moni t or s i ncl ude t he f ol l owi ng:
A. Mercur y sphygmomanometer. Thi s t ype of moni t or i s t he most accurat e and
does not need cal i brat i on. Mer cur y i n a gr aduat ed col umn r i ses i n r esponse t o
pr essure appl i ed t o t he cuf f . The bl ood pressure i s det ermi ned by measuri ng t he
l engt h of t he mer cur y col umn whi l e l i st eni ng f or t he Kor ot kof f sounds i n t he
st et hoscope. Mer cur y moni t or s are usual l y not used as a home devi ce because of
t hei r l ar ge si ze, t he need f or use of a st et hoscope, and t he pot ent i al f or mercur y
spi l l . Owi ng t o t he r i sk of mer cur y exposure, t hi s t ype of sphygmomanomet er i s
bei ng phased out of heal t hcar e f aci l i t i es.
B. Fi nger moni t ors. These det ect bl ood pressure by compressi ng t he f i nger and
convert i ng bl ood vessel movement i nt o bl ood pr essur e by osci l l omet r i c t echnol ogy.
Many envi r onment al condi t i ons and medi cat i ons can i nt er f er e wi t h t he r esul t s of
t hese moni t or s. Fi nger bl ood pr essur e moni t or s ar e I east accurate and not
r ecommended f or home moni t ori ng.
C. Aneroi d sphygmomanometer. Thi s i s si mi l ar t o a mer cur y sphygmomanomet er,
except t hat i nst ead of a col umn of mer cur y, i t has a di al t o be read. Aneroi d model s
have t he advant age of bei ng I ess expensi ve t han mer cur y model s; however , t hey
do r equi r e regul ar cal i brat i on i n a heal t hcar e pr ovi der ' s of f i ce wi t h a mercur y
sphygmomanomet er t o ensure pr oper r esul t s. These t ypes of moni t ors are port abl e
and l i ght wei ght , however . Most r equi re manual i nf l at i on of t he cuf f , but a separat e
st et hoscope i s not requi red.
P. 594


D. EI ect roni c or di gi taI moni tor. Thi s t ype of moni t or det ect s bl ood pr essur e by
usi ng a mi cr ophone or by osci l l omet ri c t echnol ogy, whi ch convert s movement of
vessel s i nt o bl ood pr essur e. Thi s t ype i s easi er t o use t han a mercur y or aneroi d
sphygmomanomet er as most of f er aut omat i c i nf l at i on and def l at i on and t her e i s not
a need f or a separ at e st et hoscope. These model s are mor e expensi ve, can provi de
i naccur at e r eadi ngs i f t he pat i ent moves whi l e t he bl ood pressure i s bei ng
per f or med, and r equi res f r equent cal i br at i on agai nst a mercur y sphygmomanomet er ;
but t hey repr esent an al t er nat i ve f or pat i ent s who cannot use a sphygmomanomet er .
Some of t hese moni t ors come wi t h a wr i st cuf f whi ch may be usef ul i n over wei ght or
obese pat i ent s f or whom t he r egul ar si ze arm bl ood pressure cuf f i s t oo smal l .
Pat i ent s wi t h ver y l ar ge or ver y smal l upper ar ms may need t o purchase a speci al
cuf f i n order t o obt ai n an accurat e r eadi ng.
IV. HEAT AND COLD THERAPY.
For muscul oskel et al di sor ders ( e. g. , spr ai ns, st r ai ns, ar t hr i t i s), t reat ment may
i ncl ude t he appl i cat i on of heat or col d t o speci f i c ar eas of t he body.
A. Heat can be appl i ed i n a dr y or moi st f orm. Dry heat i s l ess ef f ect i ve t han moi st
heat but i s t ol er at ed bet t er ; t hus i t s cl i ni cal ef f ect i veness i s si mi l ar . Moi st heat has
an advant age of not causi ng as much perspi r at i on and i s of t en recommended. The
appl i cat i on of heat produces vasodi l at i on and muscl e rel axat i on. Thi s f aci l i t at es
pai n r el i ef and heal i ng. Pr oduct s t hat can del i ver heat i ncl ude t he f ol l owi ng:
1. A hot water bott I e, a r ubber cont ai ner , shoul d be hal f f i l l ed wi t h hot wat er . The
r emai ni ng ai r i s squeezed out of t he cont ai ner , whi ch i s t hen capped. Thi s r esul t s i n
a f l exi bl e cont ai ner t hat can be shaped t o t he ar ea of t he body f or whi ch i t i s bei ng
used t o provi de dr y heat .
2. A heati ng pad i s an el ect r i cal l y power ed pad t hat can produce moi st or dr y heat .
Moi st heat i s suppl i ed by i nser t i ng a wet sponge i n a pocket t hat i s next t o t he pad.
Pat i ent s shoul d be i nst ruct ed t o pl ace t he pad on t op of t he body i nst ead of l yi ng on
t he pad t o pr event bur ni ng.
3. A moi st - heat pack ( al so cal l ed a hydr ocol l at or) cont ai ns si l i ca beads, whi ch
absor b heat when pl aced i n boi l i ng wat er . The heat ed pack i s wr apped i n a t owel
and appl i ed t o t he body t o pr ovi de moi st heat . A moi st -heat pack must be kept moi st
t o r et ai n i t s absorbent proper t i es. The pack shoul d be wr apped i n pl ast i c and st or ed
i n t he ref r i gerat or i f use i s ant i ci pat ed or i n t he f reezer i f l ong- t erm st orage i s
r equi r ed.
4. A geI pack provi des dr y heat af t er i t i s heat ed i n boi l i ng wat er or i n t he
mi cr owave. Ì t i s r eusabl e by r epeat i ng t he heat i ng pr ocess.
5. Chemi caI hot packs pr ovi de dr y heat by mi xi ng chemi cal s f r om t wo
compart ment s. The chemi cal s under go an exot her mi c r eact i on. Some packs are
r eusabl e by r eheat i ng i n boi l i ng wat er or i n t he mi cr owave.
6. Paraf f i n baths pr ovi de moi st heat by cover i ng t he body wi t h heat ed par af f i n.
Once t he wax cool s and har dens, i t i s removed. Thi s met hod i s commonl y used f or
pat i ent s wi t h ar t hr i t i s i n t he hands and f i nger s.
B. CoI d appl i cat i on i s i ndi cat ed mai nl y as acut e t her apy t o decr ease ci r cul at i on t o a
l ocal ar ea and t o pr ovi de pai n r el i ef . Col d i s cont rai ndi cat ed i n pat i ent s wi t h
ci rcul at or y st asi s or l acer at ed t i ssue. Pr oduct s t hat can del i ver col d i ncl ude t he
f ol l owi ng:
1. An i ce bag i s a f l exi bl e pl ast i c cont ai ner desi gned t o hol d i ce. The bag i s t hen
appl i ed t o t he body.
2. A geI pack can be used t o appl y col d by f r eezi ng and t hen appl yi ng t o t he body.
3. Chemi caI packs can be used t o appl y col d. Chemi cal s f rom t wo compar t ment s
ar e mi xed t oget her , r esul t i ng i n a chemi cal r eact i on t hat pr oduces col d. These
packs are used once and t hen di sposed of .
P. 595


V. DI AGNOSTIC AIDS
A. SeI f - care t ests or ki ts ar e used as scr eeni ng t est s or f or moni t ori ng. Many
f act or s can af f ect t he accur acy of t he t est s. The most common f act ors are pat i ent s
not f ol l owi ng di rect i ons and pat i ent s havi ng poor t echni que. Pharmaci st s shoul d be
pr epar ed t o counsel pat i ent s on t he sel ect i on of a t est , on t he proper use, and on
i nt er pr et at i on of r esul t s. Phar maci st s shoul d ref er pat i ent s t o t he appr opr i at e
heal t hcare provi der i f necessar y.
B. Types of t est s
1. Uri ne t est s
a. The uri ne gI ucose t est det ect s sugar i n t he ur i ne. Pat i ent s wi t h di abet es can use
t hi s t o eval uat e gl ucose cont r ol . Bl ood gl ucose moni t or i ng i s pr ef er red, however ,
because i t i s more accurat e and gi ves a bet t er descr i pt i on of cur r ent gl ycemi a.
b. The ket one t est det ect s t he presence of ket ones i n t he uri ne. Thi s i s used by
pat i ent s wi t h di abet es as an i ndi cat or of sever el y uncont rol l ed di abet es.
c. OvuI at i on predi ct i on t est s pr edi ct when ovul at i on occur s t o i ncr ease t he chance
of concept i on.
( 1) These t est s det ect t he pr esence of I utei ni zi ng hormone ( LH) i n t he ur i ne. Ì t s
pr esence means t hat ovul at i on shoul d occur wi t hi n 20- 48 hr.
( 2) The t est i s per f or med dai l y unt i l a posi t i ve r esul t i s obt ai ned. Many ki t s
r ecommend not usi ng t he f i rst mor ni ng ur i ne as t he LH sur ge t ypi cal l y st ar t s i n t he
mor ni ng and may not be det ect abl e unt i l l at er i n t he day. Ther ef or e, i t i s
r ecommended t o t est bet ween 10 A. M. and 8 P. M.
( 3) The day on whi ch t he pat i ent begi ns t est i ng depends on t he l engt h and r egul ar i t y
of her menst rual cycl e. Pat i ent s wi t h menst rual cycl es of consi st ent l engt h may
need t o t est onl y f or 4 days, wher eas t hose wi t h menst rual cycl es t hat change i n
l engt h may need t o t est f or 8 or 9 days.
( 4) Fal se- posi t i ve r esul t s can occur i f t he pat i ent i s t aki ng f er t i l i t y medi cat i ons ( e. g. ,
cl omi phene), oral cont r acept i ves, or hor mone- repl acement t her apy or i f t he pat i ent
has pol ycyst i c ovar y syndr ome or i mpai r ed l i ver or ki dney f unct i on.
d. Pregnancy t est s det ect pr egnancy by t he pr esence i n t he ur i ne of human
chori oni c gonadot ropi n ( hCG) , whi ch i s secr et ed af t er f er t i l i zat i on. Many
pr egnancy t est ki t s can det ect hCG 1 day af t er mi ssed menses.
( 1) Fal se- posi t i ve r esul t s can occur i f t he pat i ent t akes t he t est t oo earl y, i s t aki ng
f er t i l i t y medi cat i ons (e. g. , hCG) , or has ovar i an cyst s.
( 2) Ì f a pat i ent uses a househol d cont ai ner or a waxed cup t o col l ect ur i ne, i t may
af f ect t he t est resul t s.
( 3) Pat i ent s shoul d be r ef er r ed t o t he appr opr i at e heal t hcare pr ovi der i f t hey r ecei ve
a posi t i ve resul t or t wo negat i ve r esul t s 7 days apar t and have not had menses.
e. The uri nar y bact eri a t est det ect s t he pr esence of ni t r i t e i n t he ur i ne. The
pr esence of ni t ri t e i s used as an i ndi cat or of a uri nar y t ract i nf ect i on ( UTI )
because t he most common bact er i a associ at ed wi t h UTÌ s ar e gr am-negat i ve
bact er i a, whi ch conver t ni t rat e t o ni t ri t e.
( 1) Because t hi s t est i s not speci f i c f or bact er i a, f al se r esul t s can occur .
( 2) Thi s t est i s used by pat i ent s who have r ecur rent or chr oni c UTÌ s or many r i sk
f act or s. Ri sk f act or s i ncl ude pr evi ous UTÌ s, di abet es, ur i nar y t r act abnormal i t i es,
enl ar ged prost r at e, and behavi or al ri sk f act or s ( e. g. , f r equent sexual act i vi t y,
del ayed ur i nat i on, t he use of sper mi ci des or di aphr agms).
( 3) Fal se posi t i ves can resul t f r om medi cat i ons (e. g. , phenazopyr i di ne) t he pat i ent
may be t aki ng or f rom menst r ual bl ood i n t he ur i ne, dependi ng on t he t est used. Ì n
addi t i on, a f al se negat i ve may be det ect ed i f t he pat i ent i s t aki ng hi gh doses of
vi t ami n C, adheres t o a st r i ct veget ar i an di et , or has f r equent ur i nat i on.
f . Ther e ar e a var i et y of FDA appr oved uri ne drug t ests avai l abl e f or use at home.
Subst ances t hat may be det ect ed i n t he ur i ne i ncl ude: amphet ami ne,
met hamphet ami ne, ecst asy, mar i j uana, cocai ne, phencycl i di ne, opi at es,
benzodi azepi ne, bar bi t urat es, met hadone, t ri cycl i c ant i depressant s, and oxycodone.
Most ur i ne drug t est s r equi re t wo st eps: scr eeni ng ( at home) and conf i rmat i on
( l abor at or y) .
( 1) The f i r st st ep r equi res t he col l ect i on of ur i ne i n t he provi ded col l ect i on cup and
r evi ewi ng t he resul t s as col or bands on t he devi ce at home. The col or bands ar e
si mi l ar t o r esul t s obt ai ned on a home pr egnancy t est . Ì f no dr ug i s det ect ed, a
negat i ve resul t wi l l appear .
P. 596


( 2) A pr el i mi nar y posi t i ve r esul t i ndi cat es t he ur i ne sampl e may cont ai n t he drug but
a conf i r mat i on i s needed. To obt ai n conf i r mat i on t est i ng, i t i s necessar y t o send t he
ur i ne sampl e t hat was used t o per f orm t he f i rst st ep t o t he dr ug t est manuf act ur er ' s
cont r act ed l aborat or y. The r esul t s are avai l abl e f r om t he l aborat or y 7 t o 10 busi ness
days af t er t he speci men i s mai l ed and ar e anonymous as t hey ar e t r acked by a
per sonal i dent i f i cat i on number .
2. BI ood test s
a. The choI est eroI test det ermi nes a pat i ent ' s t ot al chol est er ol ( TC) , l ow- densi t y
l i popr ot ei n (LDL) , hi gh- densi t y l i popr ot ei n ( HDL) and/ or t ri gl yceri des.
( 1) Some t est s provi de t he pat i ent onl y wi t h a TC l evel , wher eas ot her s provi de a
f ul l l i pi d prof i l e ( TC, LDL, HDL, and/ or t r i gl yceri des) .
( 2) Some chol est er ol ki t s ar e a si ngl e- use t est i n whi ch pat i ent appl i es a bl ood
sampl e ont o a col l ect i ng car d, whi ch i s mai l ed t o a l aborat or y f or eval uat i on. Ot her
si ngl euse t est s can be per f ormed and eval uat ed by t he pat i ent at home. The
measurement of t he amount of chol est erol i s det er mi ned by a col or char t , whi ch i s
pr ovi ded wi t h t he t est .
( 3) Regar dl ess of t he t est used, t he pat i ent pl aces a l arge dr op of bl ood ont o t he
t est car d or casset t e. Some of t he t est s r equi re t he pat i ent t o f ast ÷meani ng not hi ng
t o eat or dri nk except wat er f or 12- 14 hr bef or e col l ect i ng t he bl ood.
( 4) These t est s can be usef ul f or pat i ent s who want t o moni t or t hei r t herapy. They
ar e al so usef ul as scr eeni ng t est s. Pat i ent s who t est bor derl i ne or hi gher f or hi gh
chol est erol shoul d be ref er r ed t o t he appr opr i at e heal t hcare provi der.
b. The bI ood gI ucose t est measur es t he concent r at i on of gl ucose i n t he bl ood.
Pat i ent s wi t h di abet es use t hi s i nf or mat i on, al ong wi t h di et , exer ci se, and
medi cat i on, t o keep gl ucose l evel s wi t hi n a t ar get r ange.
( 1) Ot her t est s ar e desi gned t o be used wi t h bI ood gI ucose met ers, whi ch r ead t he
t est and di spl ay t he act ual bl ood gl ucose val ue. Some bl ood gl ucose met er s cont ai n
opt i cal uni t s t hat measure t he col or change caused by gl ucose; ot hers measur e t he
el ect ri c char ge produced by gl ucose. The resul t i s t hen cal i br at ed t o pr ovi de whol e
bl ood or pl asma gl ucose concent rat i on. Whol e bl ood i s appr oxi mat el y 15% l ower
t han pl asma gl ucose, whi ch i s what i s measur ed i n t he st andard l aborat ory t est s.
Many of t he new gl ucomet ers provi de r esul t s as t he " pl asma equi val ent , ¨ meani ng
t hey t est whol e bl ood but use an i nt er nal al gor i t hm t o cal cul at e t he pl asma gl ucose.
( 2) Pat i ent s usi ng bl ood gl ucose t est s must perf or m t he t est s pr operl y and
under st and t he appropr i at e act i ons t o t ake when t he r esul t i ng val ues are out si de t he
desi r ed r ange.
c. Ot her home bI ood test ki ts ar e avai l abl e t hat pr ovi de resul t s at t he t i me of
t est i ng i n t he home or t he col l ect ed speci men i s sent t o a l abor at or y f or resul t s.
These home t est i ng ki t s i ncl ude HÌ V, hepat i t i s C vi r us ( HCV), gl ycosyl at ed
hemogl obi n A1c ( A1c) , anemi a, pr ost rat e speci f i c ant i gen ( PSA), and t hyroi d. Ì f t he
speci men i s mai l ed away f or pr ocessi ng, t he resul t s can be obt ai ned by cal l i ng a
t ol l - f r ee number .
d. Ther e ar e a vari et y of poi nt -of - care test i ng (POCT) devi ces t hat ar e avai l abl e
f or use i n phar maci es. Because a maj ori t y of t hem meet s t he Cl i ni cal Labor at or y
Ì mprovement s Amendment s ( CLÌ A) - wai ved r equi rement s, pharmaci es ar e abl e t o
of f er t hese ser vi ces t o t hei r pat i ent s. When sel ect i ng a POCT devi ce f or use make
sur e t o r esearch t he devi ce speci f i cat i ons, port abi l i t y, t est i ng pr ocedur e, and cost .
Exampl es of poi nt -of -care t est s t hat ar e avai l abl e i n sel ect pharmaci es i ncl ude:
el ect r oni c peak f l ow met er s, port abl e spi r omet r y, HÌ V r api d t est , r api d St rep t est i ng,
coagul at i on anal yzer s, ost eoporosi s scr eeni ng wi t h quant i t at i ve ul t r asound or
per i pheral dual -energy absorpt i omet r y, and bl ood t est s t hat measure A1c,
f r uct osami ne, ket ones, ur i nar y mi cr oal bumi n, al ani ne ami not ransf erases, and l i pi d
pr of i l es.
3. FecaI occuI t bI ood test s det ect t he presence of bl ood i n t he st ool as a
screeni ng t est f or col orect al cancer . Pat i ent s dr op a pad i nt o t he t oi l et af t er
def ecat i on. The pad wi l l change col or i f bl ood i s pr esent . Pat i ent s shoul d eat hi gh-
f i ber f oods dur i ng t he t est i ng per i od and are i nst r uct ed t o t est t hr ee consecut i ve
st ool sampl es. Pat i ent s wi t h a posi t i ve r esul t shoul d be ref er r ed t o t he appr opri at e
heal t hcare provi der. Cert ai n condi t i ons ( gast r oi nt est i nal bl eed, nosebl eed,
menst ruat i on) , f oods ( red meat ), medi cat i ons ( nonst er oi dal ant i -i nf l ammat or y dr ugs
[ NSAÌ Ds] ), and t oi l et -bowl cl eaners can pr oduce f al se- posi t i ve r esul t s.
4. Ferti I i t y mi croscopes al l ow women t o det er mi ne t hei r most f er t i l e t i me of t he
mont h. A woman pl aces sal i va on a vi ewi ng sl i de or pl at e, al l ows t he sal i va t o dr y
f or 5-7 mi n, and
P. 597

t hen vi ews i t under a mi cr oscope. The appearance of a f er ni ng pat t ern means
ovul at i on has occur red. Est r ogen l evel s r i se and peak wi t h ovul at i on, causi ng an
i ncrease i n sal t l evel s i n t he sal i va, r esul t i ng i n a f er nl i ke pat t er n i n dri ed sal i va.
Si mpl e dot s or a bubbl el i ke appearance i s f ound dur i ng a nonf er t i l e peri od. A
woman shoul d be advi sed t o avoi d smoki ng, eat i ng, or dri nki ng f or 2 hr bef or e
t est i ng. Pol ycyst i c ovar y syndrome and per i menopause can cause f al se-posi t i ve
r esul t s.
VI. HOSPITAL BEDS AND ACCESSORIES.
Hospi t al beds are used by pat i ent s who are conf i ned t o bed f or l ong peri ods of t i me
or who r equi re el evat i on of t he head or f eet as par t of t hei r t r eat ment . Hospi t al beds
may be manual l y or el ect r i cal l y oper at ed.
A. Types of hospi taI beds
1. A manuaI hospi t al bed has no el ect ri cal l y power ed mot ors; t he head, f oot , and
bed hei ght are adj ust ed manual l y.
2. A semi eI ect ri c hospi t al bed cont ai ns t wo el ect r i c mot ors t hat rai se t he head and
f oot of t he bed. The pat i ent can usual l y adj ust t he head and f oot posi t i on wi t h a
handhel d cont r ol . The hei ght of t he bed i s adj ust ed manual l y. The semi el ect r i c bed
can usual l y be adj ust ed manual l y i n case of l oss of el ect r i ci t y.
3. A fuI I y eI ect ri c hospi t al bed cont ai ns t hr ee mot or s t hat can change t he hei ght of
t he bed as wel l as rai se t he head and f oot vi a el ect r i cal l y power ed mot or s. The f ul l y
el ect ri c hospi t al bed can usual l y be adj ust ed manual l y i n case of l oss of el ect r i ci t y.
B. Accessori es
1. Bed rai I s keep t he pat i ent i n t he bed and al l ow t he pat i ent t o change posi t i ons.
2. A t rapeze i s a t r i angul ar -shaped obj ect t hat hangs above t he pat i ent and i s used
t o change t he pat i ent ' s posi t i on.
3. AI t ernat i ng pressure pads are used by pat i ent s t o pr event decubi t us ul cer s ( i . e. ,
bed sores). As a pr event i ve measur e, t hese pads i nf l at e, t hus changi ng t he ar eas of
t he body t hat r ecei ve pressur e.
VII. INCONTINENCE AND INCONTINENCE PRODUCTS
A. Uri nar y i ncont i nence i s a condi t i on i n whi ch i nvol unt ar y ur i ne l oss i s a soci al or
hygi eni c probl em and i s obj ect i vel y demonst r abl e. Ì ncont i nence i s a common
pr obl em i n t he el der l y. Types of i ncont i nence i ncl ude
1. Urge i ncont i nence, whi ch i s uncont r ol l ed cont r act i ons of t he bl adder
2. St ress i ncont i nence, a weakness of t he sphi nct er t hat causes l eakage when
i nt ra- abdomi nal pr essur e i ncr eases (e. g. , whi l e l aughi ng, coughi ng, sneezi ng) and i s
common i n pr egnancy
3. Overf I ow i ncont i nence, whi ch i s caused by obst r uct i on of ur i ne f l ow f rom t he
bl adder and i s common i n el derl y men as a r esul t of pr ost at e enl ar gement
4. Funct i onaI i nconti nence, whi ch i s r el at ed t o physi cal or psychol ogi cal probl ems
t hat i mpai r t he pat i ent ' s abi l i t y t o get t o t he bat hroom
5. Transi ent i ncont i nence, whi ch i s caused by medi cat i ons, ur i nar y t r act i nf ect i ons,
or ment al i mpai r ment
6. Mi xed i nconti nence, whi ch i s a combi nat i on of mor e t han one t ype of
i ncont i nence
B. I ncont i nence product s
1. Shi eI ds are di sposabl e, absor bent pads t hat ar e pl aced i n t he under wear and
hel d wi t h an adhesi ve st ri p on t he back of t he pad. These pads ar e used f or l i ght
i ncont i nence pr obl ems.
2. Undergarments are di sposabl e absor bent garment s t hat are wor n under t he
under wear and hel d i n pl ace wi t h el ast i c st r aps t hat go around t he hi ps. They ar e
desi gned f or moderat e i ncont i nence pr obl ems.
P. 598


3. Bri efs l ook l i ke adul t -si ze di apers t hat ar e kept i n pl ace wi t h adhesi ve st r i ps.
They ar e desi gned f or heavy i ncont i nence pr obl ems.
4. PuI I - up pant s ar e absor bant di sposabl e garment s t hat l ook l i ke under wear and
ar e used f or heavy i ncont i nence probl ems.
5. Underpads ar e absorbent pads t o be pl aced on t he bed under neat h a pat i ent wi t h
i ncont i nence. These pads cont ai n a bar ri er t o pr ot ect t he beddi ng.
6. Wat erproof sheets are pl ast i c or vi nyl sheet s t hat pr ot ect t he mat t r ess. They
may be l i ned wi t h a sof t mat er i al t o prevent f r i ct i on agai nst t he ski n.
7. I nconti nence syst ems ar e gar ment s t hat l ook l i ke under wear but have a pouch
or pocket desi gned f or a di sposabl e or reusabl e pad.
VIII. ORTHOPEDIC BRACES AND SURGICAL FITTINGS.
These pr oduct s pr omot e pr oper body al i gnment and suppor t i nj ured ar eas.
Phar maci st s shoul d have addi t i onal t r ai ni ng bef ore at t empt i ng t o f i t an or t hopedi c
devi ce.
A. Abdomi naI supports ar e el ast i c and are used t o suppor t and hol d sur gi cal
dr essi ngs i n pl ace. Abdomi nal suppor t s come i n di f f er ent wi dt hs.
B. Arm sI i ngs are used t o provi de comf or t and suppor t dur i ng recuper at i on f rom
f r act ur es, spr ai ns, and sur ger y. The el bow shoul d f orm a 90- degr ee angl e i n an arm
sl i ng t o al l ow f or proper ci rcul at i on.
C. Back support s are wor n by pat i ent s t o pr ovi de suppor t or promot e pr oper
al i gnment . Such suppor t s are named af t er t he area of t he spi ne on whi ch i t i s wor n.
1. A sacraI beI t (al so cal l ed sacraI ci nch or sacroi I i ac beI t ) support s t he l ower
back.
2. A I umbosacraI support support s t he l ower and mi ddl e back.
3. A thoracoI umbar support suppor t s t he mi ddl e and hi gher areas of t he back.
D. Cervi caI coI I ars suppor t or l i mi t t he r ange of mot i on of t he neck. Cervi cal col l ar s
shoul d be of suf f i ci ent l engt h so t hat t he pat i ent can adj ust t he degr ee of
compr essi on. The wi dt h of t he cer vi cal col l ar shoul d equal t he measurement f r om
t he chi n t o t he st er num when t he pat i ent i s st andi ng st r ai ght , l ooki ng ahead.
1. Sof t or foam cer vi cal col l ars pr ovi de mi l d suppor t and remi nd t he wearer t o keep
t he neck st rai ght .
2. Hard or ri gi d cer vi cal col l ar s pr ovi de more suppor t and l i mi t movement t o a
gr eat er degree.
3. A Phi I adeI phi a or extri cat i on col l ar i s used t o i mmobi l i ze t he neck and i s
commonl y used i n emer gency si t uat i ons.
E. CI avi cI e supports are used as ai ds f or t he r educt i on and st abi l i zat i on of t he
cl avi cl e (i . e. , col l ar bone). These suppor t s are somet i mes cal l ed fi gure-ei ght st raps
because of t hei r appear ance.
F. Knee braces ( al so cal l ed knee cages) ar e used t o suppor t t he knee. Some
br aces have met al st ays on t he si de t o pr event t he l at er al movement of t he knee.
Those wi t h met al st ays may al so have hi nges t o al l ow f or movement of t he knee.
Some knee br aces have a cut - out hol e and paddi ng around t he pat el l a (i . e. , knee
cap) t o pr event i t s movement .
G. Knee i mmobi I i zers pr event any mot i on of t he knee and ar e used f or sever e
i nj ur i es and f r act ur es. They ar e avai l abl e i n di f f er ent l engt hs and ar e adj ust abl e i n
si ze.
H. Ni ght ti me ankI e brace keeps t he ankl e at a 90- degr ee angl e whi l e sl eepi ng. Ì t
can be used i n t he t r eat ment of Achi l l es t endon i nj uri es or pl ant ar f asci i t i s.
I . ShouI der i mmobi I i zers pr event movement of t he shoul der and arm. The el bow
shoul d be at a 90- degree angl e t o al l ow f or heal i ng wi t hout af f ect i ng ci r cul at i on.
P. 599


J. Tenni s eI bow support s appl y pr essur e t o t he f or ear m t o pr ovi de pai n rel i ef and
decrease i nf l ammat i on f rom t enni s el bow ( i . e. , epi condyl i t i s) .
K. Wri st braces pr event movement of t he wr i st t o al l ow heal i ng. The brace may be
shaped t o have t he wr i st f l exed so t hat t he t endons i n t he hand remai n st ret ched
dur i ng t he peri od of i nact i vi t y.
IX. OSTOMY APPLI ANCES AND ACCESSORIES
A. Def i ni t i ons. An ost omy i s a sur gi cal pr ocedur e i n whi ch an ar t i f i ci al openi ng i s
cr eat ed i n t he abdomi nal wal l f or t he pur pose of el i mi nat i ng uri ne or f ecal wast e.
The openi ng i s cal l ed a st oma. Ost omi es can be t emporar y t o al l ow f or repai r or
heal i ng of t he di gest i ve t r act or can be per manent . Each pr ocedur e i s named t o
descr i be t he anat omi cal l ocat i on i nvol ved.
1. Ì n a coI ost omy, par t of t he col on i s cut and at t ached t o t he abdomi nal wal l . Thi s
pr ocedur e i s done mai nl y i n pat i ent s wi t h col on or r ect al cancer , l ower - bowel
obst r uct i on, or di ver t i cul i t i s. A col ost omy may be t empor ar y or permanent , t he
di schar ge may be l i qui d or semi sol i d (as wi t h an ascendi ng col ost omy) , or i t may be
sol i d ( as wi t h a descendi ng or si gmoi d col ost omy) . Pat i ent s wi t h an ascendi ng
col ost omy and some pat i ent s wi t h a t r ansverse col ost omy have gast ri c enzymes
pr esent i n t he di schar ge. These pat i ent s must t ake ext r a car e t o ensur e t hat t he
di schar ge does not come i nt o cont act wi t h t he ski n.
2. Ì n an i I eostomy, t he i l eum i s at t ached t o t he abdomi nal wal l . Thi s procedure i s
per f or med i n pat i ent s wi t h ul cerat i ve col i t i s or Crohn di sease.
3. A urost omy i s perf ormed i n pat i ent s wi t h bl adder cancer. Ì n t hi s procedur e, an
i I eaI condui t i s cr eat ed by at t achi ng t he uret er s t o t he i l eum and t he di st al end of
t he i l eum t o t he abdomi nal wal l .
B. Ost omy appI i ances. The ost omy appl i ance cont ai ns a ski n barri er t hat at t aches
t o t he ski n ar ound t he st oma. The ski n bar ri er prot ect s t he ski n and al l ows f or t he
col l ect i on devi ce or pouch t o be wor n on t he body. The sel ect i on of an ost omy
appl i ance depends on t he t ype of di schar ge pr oduced. Ì n addi t i on t o si ze, col or , and
f l exi bi l i t y, appl i ances may have det achabl e pouches and be abl e t o be dr ai ned by
r el easi ng a cl i p at t he bot t om of t he appl i ance.
C. Ost omy accessori es
1. Washers, powder past e, and oi nt ment s ar e desi gned t o be used wi t h a ski n
bar r i er and pr ovi de addi t i onal pr ot ect i on of t he ski n ar ound a st oma.
2. Cement, eI ast i c beI t s, and t ape ar e used t o hol d t he appl i ance i n pl ace.
3. Deodori zers hel p cont r ol f ecal odor . Ext ernaI deodor i zers can be pl aced i nt o t he
appl i ance; syst emi c deodor i zers (e. g. , bi smut h subgal l at e, chl or ophyl l , char coal )
can be i ngest ed as i nt ernaI deodor i zer s.
4. Moi sturi zers and di si nf ectant s can be used t o t r eat t he ski n and prevent
compl i cat i ons.
5. I rri gat i on devi ces are used by pat i ent s who have cont rol over t he el i mi nat i on of
wast e t o f aci l i t at e r emoval of t he accumul at ed wast e. The devi ces ar e used t o i nst i l l
wat er i nt o t he i nt est i ne, whi ch produces peri st al si s.
D. Speci aI consi derat i ons f or ost omy pat i ent s. Dr ug t herapy can pr esent uni que
pr obl ems f or ost omat es. Absorpt i on of ent er i c- coat ed or sust ai ned- rel ease pr oduct s
may not be possi bl e. Ant i bi ot i cs, sul f a dr ugs, l axat i ves, and di ur et i cs ar e some of
t he common pr obl em medi cat i ons i n t hese pat i ent s.
X. RESPIRATORY EQUIPMENT
A. Cont i nuous posi t i ve ai rway pressure ( CPAP) i s used i n pat i ent s wi t h sl eep
apnea. The pr essur e suppl i ed f r om t hi s machi ne keeps t he ai r way open. Ì t i s
t ypi cal l y wor n whi l e sl eepi ng t o al l ow t he pat i ent t o sl eep wi t hout di st urbance.
P. 600


B. A humi di fi er put s moi st ur e i nt o t he ai r by br eaki ng wat er i nt o smal l par t i cl es and
bl owi ng t hem i nt o t he ai r t o be evaporat ed. Humi di f i ers are somet i mes ref er r ed t o as
cal l ed " cool mi st vapori zer s. ¨
1. Vapori zers ar e si mi l ar t o humi di f i er s i n t hat t hey ar e used t o del i ver moi st ur e t o
t he ai r . However , a vapor i zer produces a st eam t o i ncr ease humi di t y, wher eas a
humi di f i er produces a nonheat ed mi st .
2. An uI t rasoni c humi di f i er cont ai ns a t ransducer , whi ch produces a f i ner mi st . Ì t i s
commonl y used t o promot e expect or at i on i n pat i ent s wi t h upper - respi rat ory
i nf ect i ons.
3. Bot h t ypes of humi di f i er s and vapori zer s need t o be cl eaned r egul ar l y t o pr event
t he gr owt h of mol d or bact eri a.
C. A nebuI i zer i s used t o del i ver medi cat i on t o t he mout h or t hr oat . Pat i ent s wi t h a
sor e t hroat may use a nebul i zer t o del i ver a t opi cal anest het i c t o t he t hr oat . An
uI t rasoni c nebuI i zer i s used t o del i ver medi cat i on i nt o t he l ungs. The medi cat i on i s
di l ut ed wi t h nor mal sal i ne and t hen i nhal ed. An ul t r asoni c nebul i zer i s used by
pat i ent s wi t h r espi rat or y i nf ect i ons, ast hma, or chr oni c obst r uct i ve pul monar y
di sease ( COPD) .
D. Oxygen i s admi ni st ered f or a var i et y of condi t i ons. Oxygen can be st ored as a
gas or a l i qui d or can be ext r act ed f r om t he ai r vi a a concent rat or. The amount of
oxygen r equi r ed by t he pat i ent i s measur ed i n l i t er s per mi nut e ( L/ mi n) . A
regi stered respi rat or y t herapi st can be consul t ed f or i nf ormat i on on t he cor rect
pr ocedur es, caut i ons, and l aws regardi ng oxygen use.
E. A peak f I ow met er i s used by pat i ent s wi t h ast hma t o det ect const ri ct i on of t he
ai r ways bef or e sympt oms appear . Ear l y det ect i on of an upcomi ng at t ack al l ows f or
t her apy desi gned t o st op or mi ni mi ze t he severi t y of t he di sease. Pat i ent s exhal e as
much as possi bl e i nt o a peak f l ow met er t o obt ai n t he expi r at or y f l ow r at e. Ì f t hi s
r at e i s bel ow a predet ermi ned basel i ne, pat i ent s mi ght be i nst ruct ed t o change
t her apy.
F. Home spi romet r y i s a noni nvasi ve pul monar y f unct i on t est . Ì t al l ows f or
measurement of ( a) t he f or ced expi r at or y vol ume i n one second (FEV1) , and ( b) t he
f or ced vi t al capaci t y (FVC) i n t he person' s home. Thi s devi ce may be used f or post
l ung t r anspl ant pat i ent s or pat i ent s wi t h a hi st or y of ast hma and/ or chr oni c
obst r uct i ve pul monar y di sease ( COPD) .
XI. THERMOMETERS.
These i nst r ument s measur e body t emper at ure and ar e most commonI y used t o
det ect or eval uat e t he t reat ment of i nf ect i ons.
A. A gl ass thermometer has a seal ed gl ass const r i ct i on chamber t hat cont ai ns
l i qui d mer cur y, r ed- or bl ue- col or ed f l ui d, or Gal i nst an ( a mi xt ur e of gal l i um, i ndi um,
and t i n). Respondi ng t o t emper at ur e changes, t he mercur y, r ed- or bl ue-col or ed
f l ui d, or Gal i nst an expands or cont r act s. Ì t r emai ns at t he maxi mum t emper at ur e
r egi st er ed unt i l shaken back i nt o t he r eser voi r at t he bot t om. Gl ass f ever
t hermomet er s ar e graduat ed f r om 96°F t o 106°F i n t wo- t ent hs- of - a-degree
i ncrement s. These t ypes of t hermomet er s shoul d be cl eaned and st er i l i zed wi t h
al cohol af t er each use. The Ameri can Academy of Pedi at ri cs r ecommends agai nst
t he use of mer cur y- cont ai ni ng t hermomet ers because of t he r i sk of mer cury
exposur e i f i t br eaks. However , mor e r esearch i s needed t o assess t he accur acy of
t he newer gl ass t hermomet er s ( r edor bl ue- col ored f l ui d or Gal i nst an) .
2

1. The oraI t hermomet er has a l ong sl ender r eservoi r . Ì t i s pl aced under t he t ongue,
and t he l i ps ar e seal ed ar ound t he t hermomet er f or 3-4 mi n. Ì nval i d r esul t s may
occur i f t he pat i ent eat s, dr i nks, or chews gum bef or e t he t emper at ur e i s t aken;
i ncor r ect l y pl aces t he t her momet er i n t he mout h; t al ks or br eat hes r api dl y t hr ough
mout h or nose whi l e t he t emper at ure i s bei ng t aken; or has or al abscess or
dent ur es.
P. 601


2. The rect aI t her momet er has a bl unt , pear -shaped bul b t o prevent br eakage and
ai d i n r et ent i on. Ì t i s i nser t ed 1 i nch i nt o t he rect um and l ef t f or at l east 2 mi n. A
l ubri cant shoul d be used t o ai d i nsert i on. Rect al t emper at ur e i s 1°F hi gher t han oral
t emper at ure. Rect al t emper at ur es have been f ound t o l ag behi nd t he core
t emper at ure. So i f a pat i ent has a r api d change i n cor e t emperat ure, t he rect al
t emper at ure wi l l not i mmedi at el y r ef l ect i t .
3. The st ubby t her momet er has a shor t , st ubby bul b t o pr event i t f rom br eaki ng. Ì t
can be used as an or al or a r ect al t hermomet er . Al t hough a st ubby t hermomet er can
be used as ei t her or al or r ect al , i t i s r ecommended t hat one r out e of admi ni st r at i on
i s sel ect ed and used.
4. Any of t he t hr ee t ypes of gl ass t her momet ers can be used t o t ake t he axi I I ar y
t emperat ure i f an or al or r ect al t emper at ur e cannot be t aken. An axi l l ar y
t emper at ure i s t aken by hol di ng t he t hermomet er snugl y under t he ar m f or 3- 4 mi n.
Axi l l ar y t emperat ure i s 1°F l ower t han or al t emper at ure. However , t here i s
cont r oversy about t he accur acy of axi l l ar y t emperat ur e. Usi ng t hi s t emperat ur e
l ocat i on can be cl i ni cal l y usef ul as l ong as t he si t e i s r ecorded and used
consi st ent l y.
3

B. The basaI t hermomet er i s used t o measur e basal body t emper at ur e. Basal
t hermomet er s ar e avai l abl e as a gl ass or di gi t al t her momet er . A di gi t al t her momet er
may l ower t he pot ent i al f or user er r or as i t of f ers mor e accur acy. The basal body
t emper at ure i s used t o pr edi ct ovul at i on t o i ncrease or decrease t he chance of
concept i on. Basal body t emper at ur e can be t aken or al l y, r ect al l y, or vagi nal l y, but
t he rout e shoul d be consi st ent .
C. Di gi taI t hermometers r egi st er t emperat ur e qui ckl y. Heat al t ers t he cur r ent
r unni ng t hrough a r esi st or , and t he t emper at ur e i s di spl ayed vi a a di gi t al r eadout .
The cur rent i s suppl i ed by a bat t er y, some of whi ch ar e rechargeabl e. Di gi t al
t hermomet er s can be used oral l y or rect al l y and gener al l y r equi re pl aci ng a pl ast i c
sheat h over t he t i p of t he t her momet er bef or e usi ng. Di gi t al t hermomet ers have
been i nt egr at ed i nt o paci f i ers t o assi st i n t aki ng an i nf ant ' s t emperat ure.
D. Tympani c thermometers use i nf r ar ed t echnol ogy t o det ect t he t emperat ur e of
t he t ympani c membr ane. The t emper at ur e i s det er mi ned wi t hi n seconds and i s l ess
i nvasi ve t han ot her t hermomet er s. These t hermomet er s use di sposabl e t i ps t hat are
i nser t ed i nt o t he ear . The Amer i can Academy of Pedi at r i cs r ecommends t hat t hi s
t ype of t her momet er be used i n ol der babi es and chi l dr en because t he probe needs
t o accur at el y f i t i nt o t he ear . Ì nappropr i at e pl acement and t oo much ear wax can
cause i naccurat e r eadi ngs.
4

E. Ski n t hermomet ers ar e pl aced di rect l y on t he ski n (usual l y t he f or ehead) t o
cal cul at e body t emper at ur e. Thi s t ype of t hermomet er i s a l i qui d-cr yst al st r i p t hat
changes col ors based on t emperat ure. Envi r onment f act or s such as sweat i ng and
ambi ent t emper at ur e wi l l af f ect t he ski n t emper at ur e. Thi s met hod i s not as accur at e
as t he ot her s and shoul d be reser ved f or si t uat i ons i n whi ch ot her met hods ar e not
possi bl e.
XII. URINARY CATHETERS.
These devi ces al l ow f or t he coI I ect i on and removaI of uri ne f rom t he bl adder .
A. Ext ernaI cat het ers are used f or heavy i nconti nence pr obl ems or compl et e l oss
of uri ne cont rol . They are at t ached t o a st at i onary col l ect i on devi ce or a l eg bag t o
al l ow f or ambul at i on. Types of ext er nal cat het ers i ncl ude t he f ol l owi ng:
1. The maI e ext er nal cat het er i s pl aced around t he peni s. Some have adhesi ve t o
assi st i n keepi ng t he cat het er secur e.
2. The femaI e ext er nal cat het er , whi ch i s a cont our ed devi ce t hat f i t s snugl y i n t he
vagi na.
P. 602


B. I nt ernaI cat het ers are used dur i ng surger y or when ext er nal cat het ers ar e
i nappr opr i at e. Ì nt er nal cat het ers can be used at home, but t he pat i ent must be
t aught pr oper i nser t i on t echni ques t o prevent i nf ect i on. The cat het er i s i nser t ed
t hr ough t he uret hra i nt o t he bl adder and i s at t ached t o a st at i onar y col l ect i on devi ce
or l eg bag. Cat het er s are si zed by t he French scaI e: t he l ar ger t he number , t he
l ar ger t he di amet er of t he cat het er. Types of cat het ers i ncl ude t he f ol l owi ng:
1. The st rai ght cat het er i s used f or i nt ermi t t ent cat het eri zat i on t o drai n t he
bl adder. Ì t consi st s of a r ubber t ube; uri ne dr ai ns f r om one end and t he ot her end
connect s t o t he col l ect i on devi ce.
2. The FoI ey cat het er , an i ndwel l i ng cat het er , can be used f or up to 30 days bef ore
changi ng. The end i nsert ed i nt o t he bl adder cont ai ns a bal l oon, whi ch i s i nf l at ed
wi t h st eri l e wat er or sal i ne t o hol d t he cat het er i n pl ace. The bal l oon i s def l at ed
bef ore removal .
P. 603


STUDY QUESTIONS
Di rect i ons: Each of t he numbered i t ems or i ncompl et e st at ement s i n t hi s sect i on i s
f ol l owed by answer s or by compl et i ons of t he st at ement . Sel ect t he one l et t er ed
answer or compl et i on t hat i s best i n each case.
1. When a pat i ent i s f i t ted wi t h an axi I I ar y crut ch, how f ar beI ow the underarm
shouI d t he t op of t he crut ch rest ?
( A) 0. 5 i nch
( B) 1 i nch
( C) 2 i nches
( D) 3 i nches
( E) 4 i nches
Vi ew Answer 1. The answer i s C[ see] . 2. What angI e shouI d the eI bow form
when a cane i s t he correct hei ght ?
( A) 10 degr ee
( B) 25 degr ee
( C) 45 degr ee
( D) 60 degr ee
( E) 90 degr ee
Vi ew Answer 2. The answer i s B[ see] . 3. A product t hat deI i vers moi sture
t o t he ai r by heat i ng wat er t o produce st eam i s caI I ed a
( A) nebul i zer .
( B) humi di f i er .
( C) vent i l at or .
( D) peak f l ow met er .
( E) vapori zer .
Vi ew Answer 3. The answer i s E[see] . 4. An absorbent product desi gned
f or pat i ents wi t h I i ght i nconti nence probI ems i s a
( A) br i ef .
( B) shi el d.
( C) under gar ment .
( D) under pad.
( E) cat het er .
Vi ew Answer 4. The answer i s B[ see] . 5. When an oraI t emperature i s
t aken, t he t hermomet er shouI d be pI aced i nt o t he mout h f or
( A) 1- 2 mi n.
( B) 3- 4 mi n.
( C) 5- 6 mi n.
( D) 7- 8 mi n.
( E) > 9 mi n.
Vi ew Answer 5. The answer i s B[ see] . 6. The di amet er of uri nar y cat het ers
i s measured by whi ch of t he foI I owi ng scaI es?
( A) Leur
( B) Engl i sh
( C) Fr ench
( D) gauge
( E) met r i c
Vi ew Answer 6. The answer i s C[ see] . 7. A cervi caI coI I ar t hat i mmobi I i zes
t he neck i s caI I ed a
( A) sof t cer vi cal col l ar .
( B) hard cer vi cal col l ar .
( C) f oam cer vi cal col l ar .
( D) ext r i cat i on col l ar .
( E) r i gi d cer vi cal col l ar.
Vi ew Answer 7. The answer i s D[ see] . 8. I ncont i nence t hat i s caused by an
obst ruct i on of the bI adder i s caI I ed
( A) over f l ow i ncont i nence.
( B) ur ge i ncont i nence.
( C) st ress i ncont i nence.
( D) f unct i onal i ncont i nence.
( E) t r ansi ent i ncont i nence.
Vi ew Answer 8. The answer i s A[ see] . 9. A coI ost omy or i I eost omy couI d
be perf ormed f or aI I of t he f oI I owi ng condi ti ons except
( A) l ower bowel obst ruct i on.
( B) mal i gnancy of t he col on or r ect um.
( C) ul cerat i ve col i t i s.
( D) duodenal ul cer.
( E) Cr ohn di sease.
Vi ew Answer 9. The answer i s D[ seeand] . 10. Pregnancy t est ki t s are
desi gned t o det ect whi ch substance?
( A) l ut ei ni zi ng hormone (LH)
( B) pr ogest erone
( C) human chori oni c gonadot ropi n (hCG)
( D) est r ogen
( E) f ol l i cl e- st i mul at i ng hor mone
Vi ew Answer 10. The answer i s C[ see] . P. 604


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì . B. 2. a] .
When a pat i ent i s f i t t ed f or an axi l l ar y cr ut ch, t he t op of t he crut ch shoul d be 2
i nches bel ow t he axi l l a (under arm) .
2. The answer i s B [ see Ì . A. 1] .
When a pat i ent i s pr operl y f i t t ed f or a cane, t he el bow shoul d f or m a 25° angl e. Thi s
al l ows f or maxi mum wei ght t ransf er .
3. The answer i s E [ see X. B] .
A vapori zer produces moi st ur e by heat i ng wat er t o pr oduce st eam. A humi di f i er al so
pr oduces moi st ur e; however , i t wor ks by mechani cal l y creat i ng smal l wat er
par t i cl es. A nebul i zer i s used t o del i ver l i qui d t o t he mout h and t hroat . A vent i l at or
i s used t o assi st i n br eat hi ng. A peak f l ow met er i s used t o det ect ai r way
const ri ct i on.
4. The answer i s B [ see VÌ Ì . B. 1] .
Shi el ds are pads t hat are pl aced i n t he under wear and hel d wi t h adhesi ve st r i ps.
They ar e used f or pat i ent s wi t h l i ght i ncont i nence pr obl ems.
5. The answer i s B [ see XÌ . A. 1] .
Or al t emper at ur e i s t aken by i nser t i ng t he bul b of t he t her momet er under t he t ongue
and seal i ng t he l i ps around t he t hermomet er f or 3- 4 mi n.
6. The answer i s C [ see XÌ Ì . B] .
The Fr ench scal e i s used t o measur e t he di amet er of a ur i nar y cat het er. The Leur
scal e i s used t o measur e syr i nge t i p si ze. The gauge scal e i s used t o measur e
needl e di amet er. The met r i c scal e i s a gener al syst em of measurement .
7. The answer i s D [ see VÌ Ì Ì . D. 3] .
An ext r i cat i on col l ar ( al so known as a Phi l adel phi a col l ar ) i s used t o i mmobi l i ze t he
neck. Ì t i s commonl y used i n emer gency si t uat i ons. Sof t or f oam cer vi cal col l ars
pr ovi de mi l d suppor t and r emi nd t he pat i ent t o keep t he neck st rai ght . Hard or ri gi d
cer vi cal col l ars provi de moder at e suppor t but al l ow some movement .
8. The answer i s A [ see VÌ Ì . A. 3] .
Over f l ow i ncont i nence i s caused by obst r uct i on of t he bl adder . Ur ge i ncont i nence i s
caused by uncont rol l ed bl adder cont ract i ons. St ress i ncont i nence i s caused by
i ncreases i n i nt ra- abdomi nal pressure. Funct i onal i ncont i nence i s r el at ed t o physi cal
or psychol ogi cal probl ems. Tr ansi ent i ncont i nence i s caused by medi cat i ons, ur i nar y
t r act i nf ect i ons or ment al i mpai r ment s.
9. The answer i s D [ see Ì X. A. 1 and 2] .
Lower - bowel obst r uct i on, mal i gnancy of t he col on or rect um, and di vert i cul i t i s may
al l r equi re a col ost omy. Ul cerat i ve col i t i s and Crohn di sease may r equi re an
i l eost omy. The t r eat ment of a duodenal ul cer woul d not i ncl ude a col ost omy or an
i l eost omy.
10. The answer i s C [ see V. B. 1. d] .
Pr egnancy t est s det ect hCG i n t he ur i ne. Thi s i s secr et ed af t er t he embr yo has
i mpl ant ed i n t he ut er us. Ovul at i on- predi ct i on t est s det ect LH. Progest er one,
est rogen, and f ol l i cl e-st i mul at i ng hormone ar e al l i nvol ved i n cont r ol l i ng t he
menst rual cycl e.

29
OTC Otic, DentaI, and OphthaImic Agents
Jenni f er D. Smi th
Conni e Lee Barnes
I. OTIC OVER-THE-COUNTER (OTC) PRODUCTS
A. The ear can be di vi ded i nt o t hr ee di st i nct part s: t he ext er nal ear , t he mi ddl e ear ,
and t he i nner ear.
1. The ext er nal ear i s t ypi cal l y t hought of as t he par t of t he ear one can see.
However , bei ng made up of t he auri cl e, t he ext er nal audi t or y canal , and t he out er
sur f ace of t he t ympani c membr ane, t he ext er nal ear ext ends much f ar t her .
a. The auri cI e, al so ref er r ed t o as t he pi nna, f unct i ons t o col l ect sound and channel
i t t owar d t he mi ddl e ear.
b. The ext ernaI audi tory canaI , al so known as t he ear canaI , i s about 1 i nch i n
l engt h, l eadi ng di rect l y t o t he ear drum. The ear canal cont ai ns smal l gl ands t hat are
r esponsi bl e f or secret i ng cerumen, bet t er known as ear wax.
c. The out er sur f ace of t he t ympani c membr ane i s known as t he eardrum. The
ear drum separat es t he ext er nal audi t or y canal f rom t he mi ddl e ear .
2. The mi ddI e ear i s an ai r - f i l l ed chamber t hat provi des di r ect access t o t he i nner
ear and i ndi r ect access t o t he nose and t hr oat by way of t he eust achi an t ube. The
mi ddl e ear houses t hree smal l bones (mal l eus, i ncus, and st apes) known as t he
ossi cl es. When sound st r i kes t he eardr um, i t vi brat es, t ransmi t t i ng t he sound
vi br at i ons t o t he ossi cl es, whi ch i n t urn t r ansmi t t he sound t o t he i nner ear .
3. The i nner ear i s a del i cat e st ruct ur e composed of audi t or y and vest i bul ar
component s.
a. The audi t or y component of t he i nner ear ( t he cochl ea) i s responsi bl e f or hear i ng.
The cochl ea, a snai l - shaped st ruct ur e f i l l ed wi t h f l ui d, i s at t ached t o one of t he
ossi cl es ( t he st apes) i n t he mi ddl e ear . When t he st apes moves, i t cr eat es waves
wi t hi n t he cochl ea. Dependi ng on t he wave produced, neur al i mpul ses are cr eat ed
and t r ansmi t t ed t o t he brai n f or i nt er pret at i on.
b. The vest i bul ar component of t he i nner ear ( t he semi ci r cul ar canal s and t he
vest i bul e) i s responsi bl e f or mai nt ai ni ng bal ance and equi l i bri um.
B. Common ear di sorders
1. Excessi ve/ i mpact ed cerumen (ear wax) . Cont r ar y t o cur rent soci al bel i ef s,
ear wax does not need t o be removed wi t h obj ect s such as f i ngers, t owel s, and
cot t on-t i pped appl i cat ors because t hese obj ect s t ypi cal l y cause i mpact i on of t he
ear wax, r at her t han i t s removal . Ì nst ead, t he ext er nal ear has a uni que sel f -
cl eansi ng mechani sm. Ear canal ski n i s const ant l y shed and removed vi a l at er al
mi grat i on f r om t he t ympani c membr ane ( at a r at e of 2-3 mm per day) t o t he ext er nal
canal , wher e cer umen adheres t o t he shed ski n and ot her debri s. Movement such as
chewi ng moves t he cer umen out war d wher e i t i s r emoved by dr yi ng, f l aki ng, or
si mpl y f al l i ng out . The use of heari ng ai ds or earpl ugs can bl ock t hi s out war d
mi grat i on, devel opi ng ear wax i mpact i on and l eadi ng t o hear i ng l oss.
a. The f unct i ons of cer umen i ncl ude
( 1) Lubr i cat i on of t he l i ni ng of t he ear canal
( 2) Tempor ari l y repel l i ng wat er
( 3) Resi st ance t o i nf ect i on owi ng t o i t s aci di c nat ur e (pH = 4- 5) , whi ch creat es an
unf avorabl e envi r onment f or or gani sm sur vi val
( 2) Tr appi ng dust , debr i s, and f or ei gn obj ect s
b. Epi demi oI ogy. Asi de f r om i mpact i on caused by mani pul at i on, some pat i ent
popul at i ons ar e mor e prone t o exper i ence i mpact ed cerumen, i ncl udi ng pat i ent s wi t h
an overpr oduct i on
P. 606

of cer umen, pat i ent s wi t h narr owed ear canal s, t he el der l y, and pat i ent s wi t h ment al
r et ardat i on.
c. Sympt oms of i mpact ed cer umen i ncl ude ear ache, i t chi ng of t he ear , r ef l ex cough,
di zzi ness, ver t i go, t i nni t us, and compr omi sed hear i ng.
d. Earwax- soft eni ng agent s may be used al one or f ol l owed by t he use of an ot i c
syr i nge (see Ì . C) .
( 1) Carbami de peroxi de 6. 5% i n anhydr ous gl ycer i n i s t he onI y U. S. Food and
Drug Admi ni st rat i on ( FDA) approved agent f or cerumen removaI . When
car bami de per oxi de makes cont act wi t h t i ssue enzymes, oxygen i s rel eased,
pr oduci ng a f oami ng act i on. Thi s f oami ng act i on sof t ens i mpact ed cerumen.
( a) Avai I abI e agent s. Mur i ne, Debr ox, Dent ' s Ear Wax
( b) I nst ructi ons f or use. Pat i ent s aged 12 and oI der shoul d t i l t t he head si deways
and i nst i l l 5- 10 drops i nt o t he ear . The appl i cat or t i p shoul d not be i nsert ed i nt o t he
ear canal . Pat i ent s shoul d keep t he head t i l t ed t o t he si de ( or i nser t cot t on) f or
sever al mi nut es t o i ncr ease cont act t i me wi t h t he cerumen. Repeat t he process
twi ce dai I y f or up t o 4 days. For chi l dr en < 12 wi t h suspect ed cerumen i mpact i on,
a medi cal provi der shoul d be consul t ed.
( 2) Ol i ve oi l (sweet oi l ) i s used t o sof t en ear wax and al l evi at e i t chi ng.
( 3) Mi ner al oi l , r ecommended as 2 dr ops i n t he af f ect ed ear ( s) once per week, has
been used t o l i quef y t he cer umen, t hus ai di ng i n i t s removal .
( 4) Docusat e sodi um gi ven 15 mi n bef or e provi der i n-of f i ce i r ri gat i on has shown
ef f i cacy, but no dat a exi st t o suppor t t he super i or i t y of docusat e sodi um over
car bami de per oxi de.
( 5) Hydr ogen peroxi de i s a component of car bami de per oxi de and has weak
ant i bact eri al proper t i es. As an ot i c sol ut i on, hydrogen per oxi de may be di l ut ed 1: 1
wi t h war m wat er and i nst i l l ed i n t he ear t o ai d i n cer umen sof t eni ng and removal .
( 6) Ear candl es, al so known as coni ng candl es, ar e made of par af f i n-coat ed f abri c
wound i nt o a f oot -l ong cone. Pat i ent s ar e i nst ruct ed t o pl ace t he cone i n t he ear
canal and l i ght t he di st al end wi t h a mat ch. Al l egedl y, t he cer umen i s l i quef i ed and
negat i ve pr essur e dr aws out t he wax. Ì n one st udy of ear candl es, more candl e wax
was deposi t ed i nt o t he ear s of pat i ent s t han ear wax was r emoved. However , no dat a
suppor t t hi s dangerous pr ocess f or ef f i cacy. Furt her mor e, compl i cat i ons may i ncl ude
ext er nal ot i t i s, t empor ary hear i ng l oss, and bur ns.
e. Pat i ent s wi t h per f or at ed t ympani c membr ane, ear dr ai nage, ear pai n, or a r ash i n
t he ear shoul d be r ef er red t o a heal t hcare provi der . Ì n t he of f i ce, provi ders may use
var i ous devi ces or i r r i gat i ng syst ems t o remove i mpact ed cerumen.
2. Verti go i s a l oss of equi l i bri um, i n whi ch one mi ght descri be a room as spi nni ng.
As descr i bed i n Ì . A. 2. B, t he vest i bul ar compar t ment of t he i nner ear i s r esponsi bl e
f or mai nt ai ni ng bal ance and equi l i bri um. The aut onomi c syst em may become
i nvol ved i f t he ver t i go i s sever e, produci ng di zzi ness, pal l or , sweat i ng, and nausea.
Pat i ent s expr essi ng sympt oms of vert i go ( asi de f r om mot i on si ckness) shoul d be
r ef er red t o a medi cal pr ovi der .
3. Ti nni tus may be descr i bed by pat i ent s as a ri ngi ng, buzzi ng, hi ssi ng, whi st l i ng,
or hummi ng noi se l ast i ng f r om seconds t o mi nut es. Ti nni t us has been l i nked t o a
var i et y of causes, i ncl udi ng Méni ère di sease, head i nj uri es, ot i t i s medi a, syphi l i s,
t empor omandi bul ar -j oi nt ( TMJ) dysf unct i on, and cer t ai n medi cat i ons (sal i cyl at es,
nonst eroi dal ant i -i nf l ammat or y dr ugs, ami nogl ycosi des, l oop di uret i cs, and
chemot herapeut i c agent s) . Ì f t i nni t us i s const ant or sever e, a medi cal consul t i s
advi sed. Cur r ent l y, t her e ar e no FDA- appr oved t reat ment s f or t i nni t us.
4. ExternaI ot i ti s, al so ref er red t o as ot i t i s ext er na, i s i nf I ammat i on of the
ext ernaI audi tor y canaI secondar y t o a bact er i al or f ungal i nf ect i on.
a. Cause. Ext er nal ot i t i s, f r equent l y ref er red t o as swi mmer ' s ear , i s t hought t o be
most commonl y t he r esul t of I ocaI t rauma t o t he ext er nal canal ( e. g. cot t on- t i pped
appl i cat or s, f i nger s, sharp obj ect s) or proI onged exposure t o moi sture. Pr ol onged
exposur e t o moi st ur e ( e. g. , humi d envi ronment , under wat er swi mmi ng, di vi ng)
pr omot es macerat i on of t he t hi n ski n l i ni ng t he ear canal , al l owi ng bact er i a t o
penet r at e and gr ow. Tr auma t o t he ext er nal canal l ends i t sel f t o suscept i bi l i t y t o
damage and t hus easi er i nf i l t rat i on of mi cr oor gani sms. The predomi nant
mi cr oor gani sms i sol at ed f r om pat i ent s wi t h swi mmer ' s ear are Pseudomonas
aerugi nosa and Staphyl ococcus aureus.
P. 607


b. Sympt oms. Ì ni t i al sympt oms i ncl ude i tchi ng and a sensat i on of
pressure/ f uI I ness i n the ear, f ol l owed by pai n, an oti c di scharge, and a possi bl e
decrease i n heari ng. The pai n may become qui t e i nt ense, especi al l y i f t he out er
ear i s t ouched or wi t h movement of t he j aw, such as chewi ng.
c. Treat ment i s wi t h a prescri pt i on ot i c anti bi ot i c and cort i costeroi d i f bact eri al
i n or i gi n and ot i c ant i bi ot i c al one i f f ungal i n or i gi n, as wel l as di scont i nuat i on of
mechani cal t r auma and/ or swi mmi ng (unt i l r esol ut i on of i nf ect i on). Or al ant i bi ot i cs
ar e not necessar y unl ess t he i nf ect i on i s unr esponsi ve t o ot i c t r eat ment , t he pat i ent
i s i mmunocompr omi sed, or a mi ddl e ear i nf ect i on coexi st s. Ext ernaI ot i t i s shouI d
not be seI f - t reat ed.
d. Pr event i on of ext er nal ot i t i s i s t he key. Mechani cal t r auma t o t he ear , by way of
cot t on-t i pped appl i cat ors, and f i nger s shoul d cease i mmedi at el y. Wat er shoul d be
r emoved as gent l y and ef f ect i vel y as possi bl e af t er swi mmi ng or shower i ng/ bat hi ng
usi ng a t owel ar ound t he edges of t he ear or a hai r dr yer set on l ow heat . Ì t may
al so be benef i ci al t o t i l t t he head t o t he si de t o hel p expel wat er . Ì f r eoccur r ence i s
f r equent , one mi ght consi der usi ng mol ded ear pl ugs, but consi derat i on shoul d be
gi ven t o t he r i sk of i mpact ed cer umen wi t h t he use of such devi ces.
5. Wat er- cI ogged ear may be a cont ri but i ng f act or t o ext er nal ot i t i s owi ng t o t i ssue
macer at i on f rom pr ol onged per i ods of exposure t o wat er ; however , wat er -cl ogged
ear i s a separ at e di sor der . Ther ef or e, l abel i ng of pr oduct s approved by t he FDA f or
t he t r eat ment of wat er -cl ogged ear may not al l ude t o i t s use f or pr event i on of
ext er nal ot i t i s. The onl y agent FDA appr oved as saf e and ef f ect i ve as an ear - dr yi ng
agent i s i sopr opyl al cohol 95% i n anhydrous gl ycer i n 5%, appr oved f or use i n
pat i ent s 12 year s of age and ol der . A home sol ut i on of 50/ 50 i sopr opyl al cohol and
whi t e vi negar may al so be used t o dr y t he ear . Caut i on must be t aken not t o
r ecommend sel f - t r eat ment f or wat er -cl ogged ear f or pat i ent s wi t h si gns of i nf ect i on,
di schar ge or bl eedi ng f rom t he ear , ear sur ger y wi t hi n t he pr evi ous 6 weeks, or
t ympanost omy t ubes.
6. FuruncI es, al so known as boi l s, ar e smal l abscesses sur roundi ng t he base of a
hai r f ol l i cl e i n t he out er por t i on of t he ext er nal ear canal . St aphyl ococcus aur eus i s
t ypi cal l y t he of f endi ng organi sm. Fur uncl es are usual l y sel f - l i mi t i ng and may be
managed wi t h war m compr esses and a t opi cal ant i bi ot i c.
7. Ot i t i s medi a i s a bact er i al i nf ect i on t hat i s most pr eval ent bet ween t he ages of 3
mont hs and 3 years, owi ng t o t he l engt h, angl e, and f unct i on of t he eust achi an t ube
i n chi l dren. Sympt oms i ncl ude ear pai n, f ever , f l ui d di schar ge f rom t he ear , and
possi bl e decreased heari ng. Al l pat i ent s wi t h suspect ed ot i t i s medi a must be
r ef er red t o a medi cal pr ovi der f or eval uat i on and t r eat ment .
C. Admi ni st rat i on of ot i c agent s
1. Ì nst ruct i ons f or use of ot i c dr ops
a. War m t he sol ut i on by hol di ng t he bot t l e i n t he hand f or a f ew moment s.
b. Ti l t t he head si deways wi t h t he af f ect ed ear upwar d.
c. Pul l t he ear l obe up and back t o st r ai ght en t he canal f or adul t s and down and back
t o st r ai ght en i n chi l dr en.
d. Use t he ot her hand t o squeeze t he bot t l e of drops, car ef ul l y del i veri ng t he
number of recommended dr ops i nt o t he ear canal . Caut i on shoul d be t aken not t o
i nser t t he appl i cat or i nt o t he ear canal .
e. Keep t he head t i l t ed si deways f or sever al mi nut es or pl ace cot t on i n t he ear t o
pr event t he medi cat i on f rom dr ai ni ng out . Ì f cot t on i s used, i t must be l ar ge enough,
so as not t o become l odged i n t he ear, and shoul d not be l ef t i n t he ear f or l onger
t han 1 hr .
f . Repeat t he procedure on t he opposi t e ear, i f necessar y.
2. I nst ructi ons f or use of an ot i c syri nge
a. Pr epare a war m sol ut i on of pl ai n wat er . Fi l l t he ot i c syr i nge wi t h t he war m wat er
sol ut i on.
b. St rai ght en t he ear canal usi ng t he appr opr i at e met hod, as not ed above. Ti l t t he
head over a si nk or basi n t o cat ch t he out f l ow sol ut i on.
c. Ì nser t t he t i p of t he ot i c syri nge i nt o ear, wi t h t he t i p poi nt ed sl i ght l y upwar d.
d. Gent l y squeeze t he bul b of t he ot i c syr i nge t o al l ow t he sol ut i on t o ent er t he ear .
Al l ow t he sol ut i on t o drai n f r om t he ear i nt o t he si nk or basi n. Ì f pai n or di zzi ness
occurs, remove t he syr i nge and consul t a medi cal pr ovi der .
e. Repeat on opposi t e ear , i f necessar y.
P. 608


II. DENTAL OTC PRODUCTS
A. Dent aI anat omy. Anat omi cal l y, t he t eet h ar e di vi ded i nt o t wo par t s: t he crown
( above t he gi ngi val l i ne) and t he r oot ( bel ow t he gi ngi val l i ne) .
1. EnameI i s t he cr yst al l i ne cal ci um sal t s ( hydr oxyapat i t e) t hat cover t he cr own t o
pr ot ect t he underl yi ng t oot h st ruct ur e.
2. Dent i n i s t he l ar gest par t of t he t oot h st ruct ure, l ocat ed beneat h t he enamel . Ì t
pr ot ect s t he dent al pul p.
3. Cementum i s a bone- l i ke st r uct ure t hat covers t he root and provi des t he
at t achment of t he t oot h wi t h t he peri odont al l i gament s.
4. PuI p consi st s of f r ee ner ve endi ngs.
B. Common dentaI probI ems and OTC products
1. Dent aI cari es (i . e. , cavi t i es) ar e f ormed by t he gr owt h and i mpl ant at i on of
car i ogeni c mi cr oor gani sms.
a. Causes
( 1) Bact eri a ( pri mar i l y St r ept ococcus mut ans and Lact obaci l l aceae) pr oduce aci ds
( e. g. , l act i c aci d) t hat demi ner al i ze enamel . Ì ni t i al l y, demi ner al i zed enamel appear s
as a whi t e, chal ky area and becomes bl ui sh whi t e and event ual l y brown or yel l ow.
( 2) Di et i s anot her f act or i n t he devel opment of dent al car i es. Foods wi t h a hi gh
concent r at i on of r ef i ned sugar (i . e. , sucr ose) i ncr ease t he ri sk of dent al car i es.
Sucr ose i s convert ed by bact er i al pl aque i nt o vol at i l e aci ds t hat dest r oy t he
hydr oxyapat i t e.
( a) Fruct ose and I actose ar e l ess car i ogeni c t han sucrose.
( b) Noncari ogeni c sugar subst i t utes ar e xyl i t ol , sorbi t ol , and aspar t ame.
b. OTC products f or dent al car i es i ncl ude pr oduct s t hat can al l evi at e t he pai n and
sensi t i vi t y unt i l t he pat i ent can get t o t he dent i st . Exampl es of i ngr edi ent s t hat are
benef i ci al i n t hi s regard i ncl ude l i docai ne, benzocai ne ( e. g. , Anbesol , Or aj el ) , or an
or al anal gesi c ( e. g. , aspi r i n, acet ami nophen) .
2. PI aque and caI cuI us
a. Causes
( 1) PI aque i s a st i cky subst ance f or med by t he at t achment of bact eri a t o t he
pel l i cl e, whi ch i s a t hi n, acel l ul ar, gl ycopr ot ei n ( a mucopr ot ei n coat i ng t hat adher es
t o t he enamel wi t hi n mi nut es af t er cl eani ng a t oot h) .
( 2) CaI cuI us (or t artar) i s t he subst ance f or med when pl aque i s not removed wi t hi n
24 hr. The pl aque begi ns t o cal ci f y i nt o cal cul us when cal ci um sal t preci pi t at es f r om
t he sal i va. Cal cul us can be r emoved onl y by a prof essi onal dent al cl eani ng.
b. OTC products
( 1) Toot hbrushes. Sof t , r ounded, nyl on br i st l es ar e pref er red by dent i st s because
har d br i st l es can i r r i t at e t he gi ngi val mar gi ns and cause t he gums t o r ecede. Some
t oot hbr ushes have speci al l y desi gned br i st l es t hat r each deep bet ween t eet h and
al ong t he guml i ne t o remove st ai ns and pol i sh t eet h and massage gums. Exampl es
i ncl ude Col gat e Whi t eni ng and Col gat e Massager t oot hbr ushes. El ect r i c
t oot hbr ushes can benef i t pat i ent s who requi r e someone t o cl ean t hei r t eet h f or t hem
or pat i ent s who have or t hodont i c appl i ances. Toot hbrushes shoul d be r epl aced when
t hey begi n t o show wear or ever y 3 mont hs, whi chever comes f i r st . Pat i ent s shoul d
r epl ace t hei r t oot hbr ush af t er havi ng an upper - r espi rat or y i nf ect i on.
( 2) I rri gat i ng devi ces di r ect a hi gh- pressure st r eam of wat er t hr ough a nozzl e t o
t he har d- t o-cl ean ar eas by gent l y l i f t i ng t he f r ee gi ngi va t o ri nse out cr evi ces. Two
t ypes ar e avai l abl e: puI sat i ng ( i . e. , i nt er mi t t ent l ow- and hi gh- pr essur e wat er
st r eams) and st eady ( i . e. , const ant and consi st ent wat er pr essur e) , nei t her of whi ch
has shown superi or i r r i gat i ng abi l i t y.
( a) Ì r ri gat i ng devi ces shoul d ser ve as adj unct s i n mai nt ai ni ng oral hygi ene.
( b) ExampI es i ncl ude Ì nt er pl ak Wat er Jet , Hydr o-Pi k, and t he Wat erpi k oral
i r r i gat or .
c. Dent aI f I oss i s avai l abl e waxed, unwaxed, t hi ck, t hi n, f l avor ed, or unf l avor ed.
Some dent al f l osses ar e i mpregnat ed or coat ed wi t h addi t i ves such as baki ng soda
and f l uor i de. Al so, several manuf act ur ers are mar ket i ng f l oss made of mat er i al s wi t h
super i or ant i shreddi ng pr opert i es (e. g. , Gl i de, Col gat e Preci si on). Ther e ar e no
di f f er ences among
P. 609

dent al f l osses i n t er ms of pl aque r emoval and pr event i on of gi ngi vi t i s. Ther e i s no
evi dence of a resi dual wax f i l m wi t h t he use of waxed dent al f l oss.
( 1) The sel ect i on of dent al f l oss depends on t he charact eri st i cs of t he pat i ent , such
as t oot h roughness or t i ght ness of t oot h cont act s ( e. g. , waxed f l oss i s recommended
f or t i ght - f i t t i ng t eet h because i t can pass easi l y bet ween t he t eet h wi t hout
shr eddi ng).
( 2) The Ameri can Dent al Associ at i on ( ADA) recogni zes t he f ol l owi ng br ands as saf e
and ef f ect i ve: But l er , Johnson & Johnson, and Or al - B.
d. Denti f ri ces ar e pr oduct s t hat enhance t he removal of st ai ns and dent al pl aque by
t he t oot hbrush. These i ncl ude t oot hpast es, ant i pl aque and ant i cal cul ous
mout hwashes, cosmet i c whi t eners, desensi t i zi ng agent s, di scl osi ng agent s, and
dent al gums.
( 1) Toot hpast es ar e benef i ci al i n decr easi ng t he i nci dence of dent al cari es,
r educi ng mout h odor s, and enhanci ng per sonal appear ance. Some t oot hpast es may
cont ai n t he ant i oxi dant coenzyme Q10 ( CoQ10; e. g. , Per f ect Smi l e Q10) .
I ngredi ents i ncl ude t he f ol l owi ng:
( a) Abrasi ves ar e responsi bl e f or physi cal l y r emovi ng pl aque and debri s. Exampl es
i ncl ude si l i cat es, sodi um bi car bonat e, di cal ci um phosphat e, sodi um met aphosphat e,
cal ci um pyr ophosphat e, cal ci um car bonat e, magnesi um car bonat e, and al umi num
oxi des. Ment adent cont ai ns sodi um bi carbonat e, wher eas Per oxi Car e and Col gat e
baki ng soda and per oxi de whi t eni ng cont ai n sodi um bi car bonat e and per oxi de. Hi gh-
abr asi ve f ormul at i ons are not advi sed f or l ong- t er m use or f or use by pat i ent s wi t h
exposed root sur f aces.
( b) Surf act ant s ar e f oami ng agent s t hat are i ncor porat ed i nt o most dent i f r i ces
because t hei r det ergent act i on ai ds i n r emovi ng debri s. The most f requent I y used
sur f act ant s ar e sodi um I aur yI suI f at e and sodi um dodecyI benzene suI fonat e.
Sodi um l aur yl sul f at e- cont ai ni ng dent i f ri ces have been associ at ed wi t h an i ncr ease
i n t he occur rence of canker sores. Dent i f ri ces such as Rembr andt Nat ural ,
Sensodyne, and Bi ot ene do not cont ai n sodi um l aur yl sul f at e.
( c) Humectant s pr event t he pr epar at i on f rom dr yi ng. Exampl es i ncl ude sor bi t ol ,
gl yceri n, and pr opyl ene gl ycol .
( d) Suspendi ng agent s add t hi ckness t o t he product . Exampl es i ncl ude
met hyl cel l ul ose, t ragacant h, and kar aya gum.
( e) FI avori ng agent s i ncl ude sor bi t ol or sacchar i n.
( f ) Pyrophosphates ar e f ound i n t ar t ar- cont rol t oot hpast es. These pr oduct s ret ard
t ar t ar f ormat i on; however , t hey f orm an al kal i ne sol ut i on t hat may i r r i t at e t he ski n.
Some pat i ent s mi ght exper i ence a r ash ar ound t he out si de of t he mout h. These
pat i ent s shoul d use r egul ar t oot hpast e and onl y occasi onal l y br ush wi t h t ar t ar -
cont r ol t oot hpast e ( e. g. , Col gat e Tar t ar Cont r ol Whi t eni ng). Tar t ar -cont rol
t oot hpast es do not penet r at e bel ow t he guml i ne, wher e t ar t ar does t he most
damage.
( g) FI uori de i s ant i cari ogeni c because i t r epl aces t he hydroxyl i on i n hydr oxyapat i t e
wi t h t he f l uor i de i on t o f or m f l uor apat i t e on t he out er surf ace of t he enamel .
Fl uor apat i t e har dens t he enamel and makes i t mor e aci d r esi st ant . Fl uor i de al so has
demonst r at ed ant i bact er i al act i vi t y.
( i ) Fl uori de i s most benef i ci aI i f used f rom bi rt h t hr ough age 12 or 13 because
unerupt ed permanent t eet h ar e mi neral i zi ng duri ng t hat t i me. Whet her or not a
pat i ent r ecei ves f l uor i de depends on t he concent rat i on i n hi s or her l ocal dr i nki ng
wat er ( Tabl e 29-1) .
Table 29-1. Daily Fluoride Supplement Requirements for Infants and Children.
Based on Concentration of Fluoride in Drinking Water
Fluoride Concentration
(ppm) Age
Fluoride Supplement Required
(mg/day)
~ 0.6 6 months to 3
years
0
3-6 years 0
0.3-0.6 6 months to 3
years
0
3-6 years 0.25
6-16 years 0.50
· 0.3 6 months to 3
years
0.25
3-6 years 0.50
6-16 years 1.00

P. 610


( i i ) Common f I uori de compounds i n t oot hpast e i ncl ude 0. 24% sodi um f l uor i de and
0. 76% or 0. 80% sodi um monof l uorophosphat e (e. g. , Ai m, Cr est , Aquaf r esh,
Col gat e) . Cr est Gum Care cont ai ns a r ef ormul at ed ver si on of st annous f l uor i de
( 0. 454%), whi ch mi ght r educe gi ngi vi t i s and bl eedi ng of t he gums by an aver age of
20% and 33%. However , i t can al so st ai n t he t eet h br own.
( i i i ) A f l uor i de war ni ng l abel , whi ch r ecommends cont act i ng a poi son cont r ol cent er
or seeki ng prof essi onal assi st ance i f mor e t han a br ushf ul of f l uor i de t oot hpast e i s
i ngest ed, i s r equi r ed by t he FDA on f l uor i de-cont ai ni ng dent i f r i ces because t he
f ederal agency l i st s f l uori de as a t oxi c subst ance.
( i v) The est i mat ed t oxi c dose of f l uori de i s 5-10 mg/ kg.
( v) Acut e f l uori de t oxi ci t y causes nausea, vomi t i ng, and di ar r hea. The ADA l i mi t s
t he maxi mum amount of f l uor i de i n ADA- accept ed t oot hpast e t o 260 mg per
cont ai ner .
( 2) Agent s wi t h ant i pI aque pot ent i al f or i ncl usi on i n dent i f ri ces i ncl ude pl ant
ext r act s (sangui nar i ne) , met al sal t s ( zi nc and st annous) , phenol i c compounds
( t r i cl osan) , and essent i al oi l s (t hymol and eucal ypt ol ) .
( a) Tri cI osan i s an ant i mi cr obi al agent t hat has been demonst r at ed cl i ni cal l y t o hel p
pr event gi ngi vi t i s, pl aque, cavi t i es, and t ar t ar .
( i ) Col gat e Tot al cont ai ns 0. 24% sodi um f l uori de and 0. 30% t r i cl osan and i s
f or mul at ed wi t h t he pol ymer Gant rez, whi ch wor ks t o pr ol ong t he cont act of
t r i cl osan wi t h oral st ruct ur es.
( i i ) Ther ef ore, Col gat e Tot al cont i nues t o wor k i n bet ween br ushi ngs.
( b) Col gat e Tot al has been accept ed by t he ADA as ef f i caci ous.
( 3) Ant i caI cuI ous denti fri ces i ncl ude t he i ngr edi ent s zi nc chl or i de, zi nc ci t r at e,
and 33% pyr ophosphat e t o prevent cal cul us f ormat i on.
( a) The ADA does not eval uat e ant i cal cul ous cl ai ms because i t r egar ds t he
i nhi bi t i on of supragi ngi val cal cul us as a nont herapeut i c use.
( b) The ADA has di r ect ed t hat t he f ol l owi ng st at ement appear on al l package and
cont ai ner l abel i ng f or accept ed f l uor i de dent i f r i ce pr oduct s wi t h cal cul us-cont r ol
act i vi t y: " [ Product name] has been shown t o reduce t he f ormat i on of t art ar above t he
guml i ne, but has not been shown t o have a t her apeut i c ef f ect on per i odont al
di seases. ¨
( 4) Cosmet i c whi teni ng agent s. The most common i ngredi ent i n t hese pr oduct s
t hat i s r esponsi bl e f or whi t eni ng t he t eet h i s 10% carbami de peroxi de (i . e. , i n Gl y-
Oxi de, Si mpl y Whi t e, or Pr oxi gel ) and hydr ogen per oxi de (i . e. , i n Cr est Whi t est r i ps) .
( a) Carbami de per oxi de i s a whi t e cr yst al t hat r eact s wi t h wat er t o r el ease hydr ogen
per oxi de, whi ch i n t ur n l i ber at es f r ee oxi des.
( b) Some cosmet i c whi t ener s may cont ai n hydr ogen per oxi de or per hydrol ur ea i n
gel or l i qui d f orm.
( c) Pr oduct s speci f i cal l y market ed t o dent i st s i ncl ude Col gat e Pl at i num Prof essi onal
Toot h Whi t eni ng Syst em and Rembr andt Li ght en Gel .
( i ) Pat i ent s shoul d per f or m t oot h bl eachi ng onl y wi t h a dent i st ' s super vi si on.
( i i ) Cr est Ext r a Whi t eni ng uses a pat ent ed sof t - si l i ca t echnol ogy. Owi ng t o t hi s
t echnol ogy, t he product cont ai ns 50% mor e si l i ca, whi ch gr eat l y enhances t he
r emoval of ext r i nsi c st ai ns wi t hout i ncr easi ng abr asi veness.
( i i i ) Col gat e Lumi nous al so cont ai ns a si l i ca whi t eni ng t echnol ogy and f l uor i de.
( d) Possi bI e ri sks associ at ed wi t h usi ng whi t eni ng product s i ncl ude al t erat i on of
nor mal f l or a, t i ssue damage, t oot h sensi t i vi t y, gi ngi vi t i s, and pot ent i at i on of
carci nogeni c ef f ect s of ot her agent s.
( e) Ant i septi cs have been used as whi t eners (e. g. , Gl y- Oxi de, Pr oxi gel ) .
( 5) Desensi t i zi ng agents r educe t he pai n i n sensi t i ve t eet h caused by col d, heat ,
aci ds, sweet s, or t ouch. These pr oduct s shoul d be nonabr asi ve and shoul d not be
used on a permanent basi s unl ess di r ect ed by a dent i st .
( a) Exampl es of 5% pot assi um ni t rat e compounds i ncl ude Col gat e Sensi t i ve,
Sensodyne, Aquaf resh Sensi t i ve, and Crest Sensi t i vi t y.
( b) Di basi c sodi um ci t r at e i n Pl ur oni c gel and 10% st r ont i um chl or i de were cl assi f i ed
as cl ass Ì Ì Ì pendi ng f ur t her evi dence of ef f ect i veness.
( 6) Di scI osi ng agent s ai d i n vi sual i zi ng wher e dent al pl aque has f or med. These
pr oduct s ar e f or occasi onal use onl y and shoul d not be swal l owed. The FDA-
approved pr oduct i s a veget abl e dye, Food, Drug, and Cosmet i c ( FD&C) Red No 3.
Fol l owi ng use, t he consumer shoul d ri nse t he mout h wi t h wat er and t hen
expect or at e.
P. 611


( 7) Mout hwashes may cont ai n ast r i ngent s, demul cent s, det er gent s, f l avors,
ger mi ci dal agent s, and f l uor i de. They can be used f or cosmet i c purposes, r educi ng
pl aque, or suppl ement i ng f l uori de consumpt i on.
( a) Cosmet i c mout hwashes f r eshen t he br eat h. They ar e nont her apeut i c and ar e
not ef f ect i ve as an ant i sept i c agent . These mout hwashes are cl assi f i ed by t hei r
act i ve i ngr edi ent s, al cohol cont ent , and appearance. The most popul ar product s are
t hose t hat cont ai n medi ci nal phenol and mi nt . The hi gher t he percent of al cohol , t he
hi gher t he ef f ect of t he f l avor wi t hi n t he mout h.
( b) Ant i pI aque mouth ri nses. Mout h ri nses cl ai mi ng ant i cal cul ous or t art ar - cont rol
act i vi t y cont ai n t he same act i ve i ngredi ent s as ant i cal cul us dent i f r i ces. Cool Mi nt
Li st eri ne has recei ved t he ADA seal of appr oval .
( i ) Cet yl pyr i di ni um chl ori de ( CPC) , a mout hwash i ngr edi ent , has been appr oved f or
cl ass Ì f or pl aque and gi ngi vi t i s t r eat ment . Exampl es of product s i n t hi s cl ass
i ncl ude Cepacol , Scope, Or al - B Ant i - Pl aque Ri nse, and Crest Pr o- Heal t h Ri nse.
( i i ) Chl or hexi di ne i s an act i ve i ngr edi ent i n some mout hwashes. An exampl e i s
Col gat e Per i oGar d.
( i i i ) St ai ni ng i s associ at ed wi t h t he over use of CPC and chl orhexi di ne.
( i v) FI uori dat ed mout hwashes are used af t er cl eani ng t he t eet h and shoul d be
expect or at ed. Not hi ng shoul d be put i nt o t he mout h f or 30 mi n af t er usi ng t hese
mout hwashes. The ADA has appr oved t he f ol l owi ng product s: ACT Ant i - Cavi t y
Dent al Ri nse, ACT f or Ki ds, Fl uor i gard Ant i - Cavi t y Dent al Ri nse, and Reach
Fl uor i de Dent al Ri nse, Or al - B Ri nse Therapy and Ant i - Cavi t y Tr eat ment , and
Col gat e Phos- Fl ur .
( 8) DentaI gums are promot ed t o reduce pl aque, whi t en t eet h, possi bl y r educe t he
r i sk of t oot h decay, and f r eshen br eat h. Chewi ng gum i s associ at ed wi t h i ncr eased
sal i var y f l ow, whi ch appar ent l y produces a benef i ci al buf f eri ng ef f ect agai nst aci ds
i n t he or al cavi t y.
( a) Some cont ai n baki ng soda as a mi l d abr asi ve cl eaner and t o neut r al i ze aci d.
( b) Cal ci um may be added t o hel p r emi ner al i ze t he t eet h and pr event cavi t i es.
( c) These gums al so cont ai n xyl i t ol , a sweet ener t hat i s l ess l i kel y t o cause cavi t i es
t han sugar or sorbi t ol . Exampl es ar e Tr i dent Advant age, Ar m & Hammer Dent al
Car e, Breat hAsur e, Dent al Care, Advance Breat h Car e, Aquaf r esh Whi t eni ng, and
Bi ot ene. Br eat hAsure Dent al Gum cont ai ns an i ngr edi ent cal l ed PXT- 20, whi ch i s an
emul si on of pol ydi met hyl si l oxane and pol oxamer 407. Ì t f orms a t hi n coat i ng on t he
t oot h t hat i s supposed t o r educe pl aque bui l dup.
( d) These gums ar e not a subst i t ut e f or good or al hygi ene, i ncl udi ng brushi ng and
f l ossi ng, but may be usef ul f or peopl e who ar e unabl e t o brush af t er l unch.
( e) Ì t i s not known i f t hese pr oduct s have any advant age over r egul ar sugar l ess
gum.
3. Gi ngi vi t i s i s i nf l ammat i on of t he gi ngi va. The gi ngi va may appear l ar ger i n si ze
wi t h a bl ui sh hue caused by engor ged gi ngi val capi l l ari es and a sl ow venous ret urn.
a. Cause. Gi ngi vi t i s i s caused by mi croor gani sms t hat event ual l y damage cel l ul ar
and i nt er cel l ul ar t i ssues. Chroni c gi ngi vi t i s may be l ocal i zed or gener al i zed. The
gums readi l y bl eed when pr obed or br ushed, and t he pat i ent shoul d seek dent al
assi st ance.
b. OTC products i ncl ude anest het i cs cont ai ni ng eugenol or benzocai ne (e. g. ,
Or aj el ) t o r el i eve t he pai n. Mout hwashes may f reshen t he br eat h; however , i t i s
i mpor t ant t o consi der t he pot ent i al of t hese product s t o di sgui se and del ay
t r eat ment of pat hol ogi cal condi t i ons ( e. g. , gi ngi vi t i s) bef or e use. Al so,
acet ami nophen ( Tyl enol ) can be r ecommended. The pat i ent shoul d seek t he advi ce
of a dent i st .
4. Peri odont aI di sease i s t he resul t of chroni c gi ngi vi t i s l ef t unt reat ed.
a. The per i odont al l i gament at t achment and al veol ar bone support of t he t oot h
det eri orat e.
b. Ri sk f act ors i ncl ude gender (men af f ect ed mor e t han women) , age ( > 35 years
ol d), smoki ng, l ack of oral car e and regul ar dent i st vi si t s, di abet es, hypert ensi on,
r heumat oi d art hr i t i s, and l oss of ant er i or t eet h.
c. Per i odont i t i s may be t r eat ed wi t h pr escri pt i on pr oduct s:
( 1) Peri ost at ( doxycycl i ne hycl at e, 20- mg capsul es)
( 2) At ri dox ( doxycycl i ne hycl at e 10%) i n t he At ri gel Del i ver y Syst em.
( a) At ri dox pr ovi des l ocal ant i bact eri al ef f ect s.
( b) Low- dose doxycycl i ne i nhi bi t s col l agenase, an enzyme t hat dest r oys connect i ve
t i ssue i n t he gums, l eadi ng t o t oot h l oss.
P. 612


5. Acut e necroti zi ng uI cerat i ve gi ngi vi t i s ( ANUG) ( al so cal l ed t rench mout h) i s
charact eri zed by necr osi s and ul cer at i on of t he gi ngi val sur f ace wi t h under l yi ng
i nf l ammat i on. Thi s condi t i on i s usual l y seen i n t eens and young adul t s.
a. Si gns and sympt oms of ANUG i ncl ude sever e pai n, hal i t osi s, bl eedi ng, f oul
t ast e, and i ncr eased sal i vat i on.
b. The cause of ANUG i s unknown. Ì t i s post ul at ed t hat i t mi ght be associ at ed wi t h
t he over gr owt h of spi r ochet e and f usi f orm or gani sms.
c. Ri sk fact ors i ncl ude anxi et y, st ress, smoki ng, mal nut r i t i on, and poor or al
hygi ene.
d. Treat ment consi st s of l ocal débr i dement . Al so, peni ci l l i n VK ( peni ci l l i n V i s a
der i vat i ve of peni ci l l i n G; however , i t i s more st abl e i n an aci di c medi um and,
t her ef ore, i s bet t er absorbed f r om t he gast r oi nt est i nal t ract ; K st ands f or pot assi um)
or met r oni dazol e may be used i n cert ai n cases ( e. g. , wi despread l esi ons) .
e. OTC products i ncl ude acet ami nophen and product s wi t h benzocai ne (not eugenol
because i t may cause sof t t i ssue damage) . The pat i ent shoul d be advi sed t o see a
dent i st . The use of sal i cyl at es i s not recommended i f t he pat i ent i s predi sposed t o
bl eedi ng. Al so, adequat e nut ri t i on, hi gh f l ui d i nt ake, and r est ar e essent i al . Ri nsi ng
t he mout h wi t h war m normal sal i ne or 1. 5% per oxi de sol ut i on mi ght be hel pf ul f or
t he f i rst f ew days.
6. Temporomandi buI ar j oi nt syndrome i s caused by an i mproper wor ki ng
r el at i onshi p bet ween t he chewi ng muscl es and t he TMJ.
a. Si gns and sympt oms i ncl ude a dul l , achi ng pai n ar ound t he ear , headaches,
neck aches, l i mi t ed openi ng of t he mout h, and a cl i cki ng or poppi ng noi se upon
openi ng t he mout h.
b. Ri sk f act ors i ncl ude br uxi sm (i . e. , gr i ndi ng t he t eet h) and occl usal ( i . e. , bi t e)
abnor mal i t i es.
c. Treat ment consi st s of moi st heat appl i ed t o t he j aw, muscl e r el axant s, bi t e pl at es
or occl usal spl i nt s, a di et of sof t f oods, corr ect i ng t he occl usi on, or surger y.
d. OTC products t hat can hel p rel i eve t he pai n i ncl ude or al anal gesi cs ( e. g. ,
acet ami nophen, i buprof en) .
7. Teet hi ng pai n. The ADA has not accept ed any pr oduct f or t eet hi ng pai n. A
f rozen t eet hi ng ri ng can pr ovi de sympt omat i c rel i ef . Per si st i ng pai n may be t reat ed
wi t h a l ocal anest het i c such as benzocai ne (f ound i n Anbesol Baby and Or aj el
Baby) . Ì f a t eet hi ng chi l d pr esent s wi t h a f ever , a physi ci an shoul d be cont act ed.
8. Xerost omi a ( i . e. , dr y mout h) i s caused by i mpr oper f unct i oni ng of t he sal i var y
gl ands ( as i n Sj ögren syndr ome and di abet es mel l i t us) . Art i f i ci aI saI i va i s avai l abl e
as an OTC pr oduct . The ADA has appr oved t he f ol l owi ng ar t i f i ci al sal i va pr oduct s:
Moi - St i r , Sal i var t , Xer o- Lube, and Or al Bal ance Gel .
C. Common oraI I esi ons and OTC products
1. Canker sores ( al so cal l ed recurrent apht hous uI cers or recurrent apht hous
st omat i t i s)
a. The cause of canker sor es i s unknown. St udi es suggest t hat t he sor es may be
caused by hyper sensi t i vi t y t o bact er i a f ound i n t he mout h or dysf unct i on of t he
i mmune syst em i ni t i at ed by mi nor t r auma or st ress. Thi s i s why physi ci ans or
dent i st s may use predni sone or a t opi cal st er oi d t o r educe al l er gi c react i on or have
t he pat i ent r i nse wi t h a t et r acycl i ne suspensi on. Per i dex and Li st er i ne appear t o
hel p decrease bact eri a i n t he mout h.
b. Lesi ons can occur on any nonker at i ni zed mucosal sur f ace i n t he mout h ( i . e. ,
t ongue, l i ps) and usual l y appear gr ay t o yel l ow wi t h an er yt hemat ous hal o of
i nf l amed t i ssue sur roundi ng t he ul cer. Most l esi ons persi st 7- 14 days and heal
wi t hout scar r i ng.
c. OTC product s can cont r ol t he pai n of canker sor es, shor t en t he durat i on of
cur rent l esi ons, and pr event new l esi ons. Pr oduct s i ncl ude protectant s, I ocaI
anesthet i cs, and débri di ng and wound- cI eansi ng agents.
( 1) Protect ant s i ncl ude Or abase, dent ure adhesi ves ( see Ì Ì . F. 2) , and benzoi n
t i nct ure. Dent ur e adhesi ves are not approved f or t hi s use by t he FDA.
( 2) LocaI anest het i cs, such as benzocai ne or but acai ne, ar e t he most common
anesthet i cs f ound i n t hese OTC pr oduct s.
( a) The FDA has approved t he f ol l owi ng i ngr edi ent s:
( i ) Benzocai ne ( 5%- 20%)
( i i ) Benzyl al cohol ( 0. 05%- 0. 1%)
( i i i ) Dycl oni ne ( 0. 05%- 0. 1%)
( i v) Hexyl r esor ci nol ( 0. 05%- 0. 1%)
( v) Ment hol ( 0. 04%- 2%)
( vi ) Phenol (0. 5%- 1. 5%)
P. 613


( vi i ) Phenol at e sodi um (0. 5%-1. 5%)
( vi i i ) Sal i cyl al cohol ( 1%- 6%)
( b) Exampl es of OTC l ocal anest het i cs f or oral use i ncl ude Anbesol , Bl i st ex,
Campho- Pheni que, Or aj el , Or aj el Cover Med, Zi l act i n- B, Zi l act i n- L, Benzodent , and
Rembrandt Canker Pai n Rel i ef Ki t .
( c) The use of pr oduct s cont ai ni ng subst ant i al amount s of ment hol , phenol ,
camphor , and eugenol shoul d be di scour aged owi ng t o t hei r abi l i t y t o i rr i t at e t i ssue.
( d) Aspi ri n shoul d not be r et ai ned i n t he mout h or pl aced on an oral l esi on i n an
at t empt t o pr ovi de rel i ef .
( e) Prescri pti on product s. Aml exanox ( Apht hasol ) has been appr oved f or t he
t r eat ment of canker sor es.
( i ) Ì t i s appl i ed 4 t i mes dai l y af t er meal s and at bedt i me.
( i i ) Advi se pat i ent s t o st ar t usi ng t he pr oduct as soon as t hey not i ce sympt oms and
t o cont i nue unt i l t he ul cer i s heal ed, appr oxi mat el y 10 days.
( f ) Gel cl ai r i s i ndi cat ed f or l ocal management and r el i ef of or al pai n associ at ed wi t h
apht hous ul cers. Ì t provi des or al pai n r el i ef by act i ng as a pr ot ect i ve adher ent
bar r i er over t he sur f ace of t he mout h and t hroat .
( i ) Pat i ent shoul d use one packet at l east 3 t i mes a day or as needed.
( i i ) Advi se pat i ent s t o mi x 1 packet wi t h 3 t abl espoons of wat er , swi sh f or a mi nut e,
t hen expect or at e. Do not eat or dr i nk f or approxi mat el y 1 hr af t er t r eat ment .
( g) Ì nvest i gat i onal product s. ThaI i domi de i s bei ng st udi ed f or t he t r eat ment of
AÌ DSassoci at ed oral canker sores.
( 3) Débri di ng and wound- cI eansi ng agent s i ncl ude 10%- 15% car bami de per oxi de,
3% hydrogen per oxi de, 1. 2 g sodi um perbor at e monohydr at e, and sodi um
bi car bonat e. The FDA consi ders t hese f our act i ve i ngr edi ent s t o be saf e and
ef f ect i ve f or débr i di ng or wound- cl eansi ng agent s f or or al heal t hcar e.
2. CoI d sores/ fever bI i st ers ( al so cal l ed herpes si mpI ex I abi aI i s) ar e caused
pr i mar i l y by t he her pes si mpl ex vi r us t ype 1 ( HSV- 1) . HSV-1 i s cont agi ous and i s
t hought t o be t r ansmi t t ed by di r ect cont act . An out br eak may be pr ovoked by st r ess,
mi nor i nf ect i on, f ever , or sunl i ght . Col d sores usual l y occur on t he l i ps and ar e
r ecur r ent , of t en ari si ng i n t he same l ocat i on.
a. Presentat i on. An out br eak i s pr eceded by burni ng, i t chi ng, or numbness. Red
papul es of f l ui d- cont ai ni ng vesi cl es t hen appear , and t hese event ual l y bur st and
f or m a cr ust . These sor es are t ypi cal l y sel f - l i mi t ed and heal i n 10- 14 days wi t hout
scar r i ng.
b. OTC products f or col d sor es i ncl ude product s t hat cont ai n sof t eni ng compounds
( e. g. , emol l i ent creams, pet r ol at um, prot ect ant s) , whi ch keep t he col d sore moi st t o
pr event i t f r om dr yi ng and f i ssur i ng. Local anest het i cs i n nondr yi ng bases ( e. g. ,
Or abase, wi t h benzocai ne) decrease pai n. Hi ghl y ast r i ngent bases shoul d be
avoi ded. The ADA cont r ai ndi cat es caust i c agent s ( e. g. , phenol , si l ver ni t rat e) ,
camphor and ot her count er i r ri t ant s, and hydr ocor t i sone f or t he t r eat ment of col d
sor es. Lesi ons shoul d be kept cl ean by gent l y washi ng wi t h mi l d soap.
( i ) DocosanoI 10% cr eam ( Abreva) i s i ndi cat ed f or t he t reat ment of col d sor es. Ì t
pr event s t he col d sore i nf ect i on f rom ent er i ng heal t hy cel l s. Ì t i s approved by t he
FDA t o shor t en heal i ng t i me and durat i on of sympt oms. Pat i ent s shoul d appl y t he
cr eam at t he f i rst si gn of an out br eak and cont i nue t o appl y t he cr eam f i ve t i mes a
day unt i l t he l esi on i s heal ed.
( i i ) Vi ract i n geI ( 2% t et racai ne) i s used f or t he t empor ar y rel i ef of pai n and i t chi ng
associ at ed wi t h col d sores.
( 1) Ì f a secondar y i nf ect i on devel ops, baci t r aci n or Neospor i n ant i bi ot i c oi nt ment s
shoul d be r ecommended. Ì f necessar y, t he pat i ent shoul d consul t a physi ci an f or a
syst emi c ant i bi ot i c pr escr i pt i on.
( 2) A l i p sunscreen shoul d be used f or pat i ent s whose col d sor es appear t o be
caused by sun exposure.
( 3) The essent i al ami no aci d L-l ysi ne has been used i n or al doses of 300-1200 mg
dai l y t o accel er at e recover y or suppr ess r ecur rence of col d sor es. However , st udi es
have produced conf l i ct i ng dat a regar di ng L- l ysi ne and i t s ef f ect on t he durat i on,
sever i t y, and recur r ence r at e of col d sores.
c. Prescri pt i on products
( 1) VaI acycI ovi r ( VaI t rex) i s i ndi cat ed f or t he t reat ment of herpes l abi al i s.
( 2) AcycI ovi r cream 5% ( Zovi rax) i s i ndi cat ed f or t he t r eat ment of col d sor es i n
adul t s and adol escent s > 12 year s of age. Ther apy shoul d be i ni t i at ed at t he onset
of si gn and sympt oms and appl i ed 5 t i mes per day f or 4 days.
P. 614


( 3) Penci cI ovi r cream 1% ( Denavi r) i s an ant i vi ral medi cat i on f or t he t r eat ment of
col d sor es i n adul t s and chi l dren 12 year s of age and ol der . Pat i ent s shoul d appl y
t he cr eam ever y 2 hr whi l e awake f or 4 days, begi nni ng at t he f i rst si gn of t i ngl i ng
or swel l i ng.
D. Common oraI i nf ect i ons and OTC product s
1. Candi di asi s ( al so cal l ed t hrush) i s caused by t he f ungus Candi da al bi cans,
whi ch i s t he most common oppor t uni st i c pat hogen associ at ed wi t h or al i nf ect i ons.
Thr ush has a mi l ky curd appear ance, and af f ect ed pat i ent s shoul d cont act a
physi ci an.
2. OraI cancer. The most common or al cancer i s squamous ceI I carci noma, whi ch
can appear as r ed or whi t e l esi ons, ul cerat i ons, or t umors.
a. Si gns and sympt oms i ncl ude a col or change i n t he t ongue, a sor e t hroat t hat
does not heal , and persi st ent or unexpl ai ned bl eedi ng. Pat i ent s wi t h any of t hese
si gns shoul d cont act a physi ci an or a dent i st .
b. Ri sk f act ors i ncl ude smoked and smokel ess t obacco as wel l as al cohol .
c. Treat ment consi st s of el i mi nat i ng use of t obacco and al cohol i n any f orm ( e. g. ,
al cohol i c bever ages, mout h ri nses wi t h al cohol ) . Al so, t reat ment gener al l y i ncl udes
wi de I ocaI exci si on f or smal l l esi ons and en bI oc exci si ons f or l ar ger l esi ons ( i n
cont i nui t y wi t h r adi cal neck di ssect i on i f l ymph nodes ar e i nvol ved) . Radi at i on,
al one or combi ned wi t h sur ger y, may be appropri at e. Chemot herapy may be used as
pal l i at i on or as an adj unct t o sur ger y and r adi at i on.
d. OTC medi cat i ons shoul d not be admi ni st ered unt i l af t er checki ng wi t h a
physi ci an. For exampl e, OTC medi cat i ons used f or i nf l ammat i on can i ncrease t he
ef f ect s of met hot r exat e. Chemot her apeut i c agent s can pr oduce many possi bl e si de
ef f ect s t hat requi r e i mmedi at e medi cal at t ent i on (e. g. , chest pai n, i nf l ammat i on,
unusual bl eedi ng) . Some exampl es of si de ef f ect s t hat usual l y do not requi r e
medi cal at t ent i on i ncl ude nausea, vomi t i ng, l oss of appet i t e or hai r, and t roubl e
sl eepi ng. OTC medi cat i ons can be usef ul i n t hese cases; however , nausea and
vomi t i ng ar e t r eat ed by pr escr i pt i on medi cat i ons such as ondanset r on or
met ocl oprami de. Nonphar macol ogi cal measur es, such as avoi di ng di st ur bi ng
envi r onment al odors and vest i bul ar di st urbances, mi ght be hel pf ul i n mi ni mi zi ng
nausea and vomi t i ng.
E. Recommended standard prophyI axi s f or prevent i on of endocardi t i s
1. Amoxi ci I I i n 2. 0 g oral l y 1 hr bef or e t he procedur e f or adul t s, and 50 mg/ kg oral l y
f or chi l dren, i s t he r ecommended st andar d pr ophyl act i c r egi men f or al l dent al , or al ,
upper - r espi r at or y t r act , and esophageal pr ocedur es.
2. For pat i ent s who are aI I ergi c to peni ci I I i n, t he r ecommended aI t ernati ve oraI
regi mens i ncl ude t he f ol l owi ng:
a. CI i ndamyci n, 600 mg f or adul t s; 20 mg/ kg f or chi l dren
b. CephaI exi n or cefadroxi I , 2. 0 g f or adul t s; 50 mg/ kg f or chi l dr en
c. Azi t hromyci n or cI ari t hromyci n, 500 mg f or adul t s; 15 mg/ kg f or chi l dren, 1 hr
bef ore t he pr ocedur e
F. OTC dent ure products
1. Dent ure cI eansers are ei t her chemi caI or abrasi ve i n r espect t o t hei r cl eansi ng
abi l i t y.
a. Chemi caI dent ur e cl eanser s i ncl ude al kal i ne per oxi de, al kal i ne hypochl or i t e, or
di l ut e aci ds.
( 1) AI kaI i ne peroxi de i s t he most commonI y used chemi cal dent ur e cl eanser and
i s avai l abl e as t abl et s or powder s. Ì t causes oxygen t o be r el eased, whi ch cr eat es a
cl eansi ng ef f ect . Al kal i ne peroxi de does not damage t he sur f ace of acr yl i c r esi ns;
however , i t may bl each t hem.
( 2) AI kaI i ne hypochI ori te ( i . e. , bl each) di ssol ves t he mat r i x of pl aque but has no
ef f ect on cal cul us. Ì t i s bot h bact eri ci dal and f ungi ci dal . A di sadvant age of al kal i ne
hypochl or i t e i s t hat i t corrodes metaI dent ure components. Ì t can al so bl each
acr yl i c resi n. Ther ef or e, i t shoul d not be used mor e t han once a week.
b. Abrasi ve dent ur e cl eanser s ar e avai l abl e as gel , past e, or powder ( e. g. ,
si l i cat es, sodi um bi carbonat e, di cal ci um phosphat e, cal ci um carbonat e) .
P. 615


( 1) Dent ures shoul d not be soaked i n hot wat er because t he heat coul d di st ort or
war p t he appl i ances.
( 2) The ADA accept s t he f ol l owi ng dent ure cl eanser s as saf e and ef f ect i ve: Dent ur e-
Br i t e, Ef f er dent , and Pol i dent .
2. Dent ure adherents cont ai n mat er i al s (e. g. , kar aya gum, pect i n, met hyl cel l ul ose)
t hat swel l , gel , and become vi scous t o promot e adhesi on, whi ch i ncr eases t he
dent ur e at t achment t o underl yi ng sof t t i ssues.
a. Di sadvant ages. As t he use of dent ur e adher ent s i ncr eases, t he sof t t i ssue
det eri orat es. Dent ur e adher ent s can al so pr ovi de a medi um f or bact er i al and f ungal
gr owt h. Dai l y use of dent ur e adher ent s i s not r ecommended.
b. The ADA accept s t he f ol l owi ng dent ur e adherent s as saf e and ef f ect i ve: Fi xodent ,
ORAf i x, Sea- Bond, Super Pol i - Gr i p, and Ef f ergr i p.
G. Pharmaci st ' s responsi bi I i t i es t o t he pati ent usi ng OTC oraI products
1. Refer a pat i ent t o a dent i st i f t he or al compl ai nt i nvol ves an abscess wi t h f ever ,
swel l i ng, mal ai se, l ymphadenopat hy, or pur ul ent exudat e.
2. Remi nd pat i ent s t hat col d and canker sor es, wi t h appropri at e t reat ment , ar e
usual l y a sel f - l i mi t i ng probl em.
3. Pat i ent s shoul d be i nf or med about how t o use recommended products, t he
dur at i on of use, t he expect at i ons of usi ng t he product , and t he procedure t o f ol l ow i f
t he pr oduct i s i nef f ect i ve.
4. Ì f a nonpr escri pt i on product does not i mpr ove a condi t i on, or i f t he condi t i on
wor sens, use of t he pr oduct shoul d be di scont i nued and a physi ci an or dent i st
shoul d be cont act ed.
III. OPHTHALMIC OTC PRODUCTS
A. Anat omy of t he eye
1. The scI era, al so known as t he whi t e of t he eye, f unct i ons t o pr ot ect i nt raocul ar
cont ent s and mai nt ai n t he shape of t he eye.
2. The cornea i s t he mai n r ef ract i ng sur f ace of t he eye.
3. The ant er i or chamber of t he eye houses a cont i nuous suppl y of aqueous humor,
whi ch i s pr oduced i n rel at i on t o t he i nt r aocul ar pressur e. The aqueous humor i s
r esponsi bl e f or nour i shi ng t he cor nea.
4. The i ri s i s t he col ored par t of t he eye t hat r egul at es t he ent r ance of l i ght t hrough
t he pupi l .
5. The pupi I i s t he cont ract i l e openi ng at t he cent er of t he i r i s t hat di l at es and
const ri ct s i n response t o l i ght .
6. The I ens i s f ound di r ect l y behi nd t he i ri s and pupi l and i s r esponsi bl e f or
enabl i ng t he eye t o accommodat e, f ocusi ng f or near and di st ance vi si on. The l ens
cont i nues t o grow t hr oughout l i f e, gr adual l y becomi ng t hi cker over t i me. The l ens i s,
t her ef ore, suscept i bl e t o t he degener at i ve ef f ect s of agi ng, most not i ceabl y evi dent
i n t he 5t h decade of l i f e as t he i nabi l i t y t o f ocus and ref ocus f or near and di st ance
vi si on.
7. Appr oxi mat el y t wo t hi rds of t he vol ume of t he eye i s occupi ed by t he vi t reous
humor. As one ages, t he gel - l i ke char act er i st i cs of t he vi t reous humor i s l ost and
shadows are cast by vari ous cel l s, gi vi ng t he i l l usi on of "f l oat ers. ¨
8. The reti na i s composed of t he opt i c di sc, t he r et i nal vessel s, and t he macul a.
The opt i c ner ve ent ers t he r et i na t hr ough t he opt i c di sc. The macul a i s responsi bl e
f or cent r al vi si on and t he r emai ni ng par t s of t he ret i na are responsi bl e f or peri pher al
and col or vi si on.
9. The opt i c nerve, al so known as t he second crani al ner ve ( CN Ì Ì ) , t r ansmi t s
i mpul ses f rom t he r et i na t o t he br ai n.
P. 616


B. Opht haI mi c FormuI at i ons
1. Vehi cI es pr ovi de i ncreased vi scosi t y, t hereby enhanci ng cont act t i me of t he
pr oduct . Vehi cl es commonl y f ound i n opht hal mi c pr oduct s i ncl ude
car boxymet hyl cel l ul ose (CMC) , povi done, pol yvi nyl al cohol (PVA) , and
hydr oxypr opyl met hyl cel l ul ose ( HPMC) .
2. Preservat i ves pr ovi de ant i mi cr obi al act i vi t y f or opht hal mi c pr epar at i ons and
i ncl ude benzal koni um chl or i de ( BAK) , chl or hexi di ne, met hyl par aben, pr opyl par aben,
et hyl enedi ami net et r aacet i c aci d ( EDTA) , and sorbi c aci d.
3. Ant i oxi dants prevent pr oduct det eri or at i on. Common ant i oxi dant s f ound i n
opht hal mi c pr epar at i ons i ncl ude edet i c aci d, sodi um bi sul f i t e, sodi um met abi sul f i t e,
sodi um t hi osul f at e, and t hi our ea.
4. Wet t i ng agent s r educe sur f ace t ensi on of t he l ens and i ncl ude pol ysor bat e 20,
pol ysor bat e 80, pol oxamer 282, and t yl oxapol .
5. Buf fers ar e used i n opht hal mi c prepar at i ons t o mai nt ai n a pH bet ween 6. 0 and
8. 0. Buf f er s i ncl ude acet i c aci d, bori c aci d, hydrochl or i c aci d, phosphori c aci d,
pot assi um bi car bonat e, pot assi um bor at e, pot assi um ci t r at e, sodi um acet at e,
sodi um bi car bonat e, sodi um bi sphosphat e, sodi um bor at e, sodi um carbonat e,
sodi um ci t rat e, sodi um hydr oxi de, and sodi um phosphat e.
6. Toni ci t y adj ust ers ensur e an i sot oni c agent , equal t o 0. 9%- 60. 2% sodi um
chl or i de. These agent s i ncl ude dext r ose, gl ycer i n, pot assi um chl or i de, propyl ene
gl ycol , and sodi um chl ori de.
C. Nonprescri pt i on opht haI mi c agent s
1. Art i f i ci aI t ears ar e used t o hydrat e and I ubri cat e t he eye by st i mul at i ng t ear
pr oduct i on and decr easi ng t ear evaporat i on. Ì ni t i al dosi ng i s r ecommended as 2
t i mes dai l y, up t o 4 t i mes dai l y, as needed. However , sol ut i ons may be used hour l y,
i f cl i ni cal l y i ndi cat ed. To r educe ocul ar i r r i t at i on, pr eser vat i ve- f r ee art i f i ci al t ears
shoul d be r ecommended t o pat i ent s who wi l l need t o use t he medi cat i on f requent l y.
2. Lubri cat i ng oi nt ments i ncl ude whi t e pet rol at um, mi ner al oi l , and l anol i n, whi ch
act t o l ubr i cat e and hydrat e t he eye. As an oi nt ment , t hese agent s ar e abl e t o
provi de i ncreased contact t i me wi t h t he ocuI ar surf ace but may resuI t i n
bI urred vi si on. Ì f possi bl e, bl ur r ed vi si on may be mi ni mi zed ( or l ess not i ceabl e) by
decreasi ng t he amount of oi nt ment i nst i l l ed i nt o t he eye or by admi ni st eri ng t he
oi nt ment at bedt i me. Ì ni t i al dosi ng i s r ecommended as 2 t i mes dai l y, but may be
used as of t en as ever y f ew hour s, or onl y occasi onal l y, dependi ng on pat i ent
r esponse. Pr eser vat i ve- f r ee opht hal mi c oi nt ment s may r educe ocul ar i r ri t at i on i n
pat i ent s requi r i ng f r equent dosi ng. When usi ng eye dr ops and oi nt ment , drops
shouI d be i nst i I I ed i nt o t he eye bef ore appI yi ng oi ntment .
3. Vasoconst ri ct ors ( decongest ant s) wor k by produci ng a t emporar y const ri cti on
of t he conj unct i vaI bI ood vesseI s, t her eby r educi ng eye r edness. Avai l abl e
opht hal mi c vasoconst ri ct or s i ncl ude naphazol i ne, phenyl ephr i ne, t et r ahydr ozol i ne,
and oxymet azol i ne. These agent s may have a rebound ef fect (congesti on) i f used
i n excess or f or ext ended durat i ons and shoul d be avoi ded i n pat i ent s wi t h narr ow-
angl e gl aucoma.
4. Ant i hi stami nes may be used f or t he t reat ment of opht hal mi c condi t i ons
associ at ed wi t h al l ergi c rhi ni t i s, t hough t hei r use has been cl assi f i ed by t he FDA as
l ess t han ef f ect i ve because of t he l ack of dat a demonst rat i ng cl i ni cal ef f ect i veness.
Ket ot i f en, sol d under t he br and name Zadi t or ®, i s t he onl y avai l abl e nonprescr i pt i on
ocul ar ant i hi st ami ne and mast cel l st abi l i zer i ndi cat ed f or t he t empor ar y prevent i on
of i t chi ng of t he eye due t o al l er gi c conj unct i vi t i s. Pheni r ami ne and ant azol i ne are
al so nonpr escri pt i on opht hal mi c ant i hi st ami nes, but are onl y avai l abl e i n
combi nat i on wi t h t he opht hal mi c decongest ant naphazol i ne.
a. Typi cal dosi ng of opht hal mi c ant i hi st ami nes i s 1- 2 dr ops i n each eye 3-4 t i mes
dai l y.
b. Opht hal mi c ant i hi st ami nes shoul d not be r ecommended i n pat i ent s wi t h gl aucoma
or pat i ent s at hi gh r i sk of devel opi ng nar r ow- angl e gl aucoma, as pupi l di l at i on
associ at ed wi t h t he use of t hese agent s may cause t hi s di sor der .
c. Si de ef f ect s of t hese agent s may i ncl ude burni ng, st i ngi ng, i t chi ng, f orei gn body
sensat i on, dr y eye, l i d edema, and pupi l di l at i on. Pat i ent s usi ng ket ot i f en dr ops
shoul d al so be advi sed of t he possi bl e adverse ef f ect of bl ood shot eyes.
P. 617


5. Ast ri ngent s decrease ocuI ar i nf I ammat i on. The onl y FDA- r ecommended
ast ri ngent i s zi nc suI f ate, r ecommended as 1-2 dr ops f our t i mes dai l y.
6. I rri gant soI ut i ons wor k t o ri nse and remove debri s and cont ami nants f r om t he
eye, whi l e mai nt ai ni ng ocul ar moi st ur e.
7. Hyperosmot i c agents i ncr ease t he t oni ci t y of t he t ear f i l m, event ual l y el i mi nat i ng
excess f l ui d f r om t he cornea.
D. Eye di sorders
1. Dr y eye, al so known as kerat oconj unct i vi t i s si cca, i s a common condi t i on i n
whi ch pat i ent s compl ai n of a f orei gn body sensat i on, opht hal mi c i t chi ng, decr eased
t ear pr oduct i on, redness, pai n, and di f f i cul t y movi ng t he eyel i ds. Sympt oms ar e t he
r esul t of a def i ci ency t o pr oduce aqueous, muci n, or l i pi d t ear f i l m component s,
whi ch may be at t r i but abl e t o cer t ai n di sease st at es (e. g. , t hyr oi d di sease, Par ki nson
di sease) , i nf ect i on, or medi cat i ons (e. g. , ant i hi st ami nes, or al cont racept i ves) .
Nonpr escr i pt i on t r eat ment f or dr y eye i ncl udes t he use of arti f i ci aI t ears duri ng t he
day and ophthaI mi c oi nt ment at ni ght .
2. Conj unct i vi t i s i s i nf l ammat i on of t he conj unct i va whi ch may be caused by
bact er i al or vi ral i nf ect i on, al l er gy, or envi r onment al f act ors.
a. AI I ergi c conj unct i vi t i s sympt oms af f ect bot h eyes and i ncl ude r edness, mi l d
edema of t he eyel i d, excessi ve t eari ng, ext r eme i t chi ng, st r i ng- l i ke mucoi d
di schar ge, and chemosi s. Nonpr escri pt i on t r eat ment recommendat i ons avoi dance of
t he al l er gen i f f easi bl e, col d compresses, vasoconst ri ct ors, and ant i hi st ami nes.
Nonpr escr i pt i on opht hal mi c product s cont ai ni ng a combi nat i on of a vasoconst r i ct or
and an ant i hi st ami ne are avai l abl e (e. g. , Naphcon A, Opcon A, Vi si ne- A) .
b. The causes of bact eri aI conj unct i vi t i s depend on pat i ent ' s age. Approxi mat el y
one quar t er of pat i ent s pr esent i ng wi t h bact er i al conj unct i vi t i s wi l l have
concomi tant ot i t i s medi a. Theref ore i t i s pr udent f or al l chi l dren pr esent i ng wi t h a
pur ul ent ocul ar di schar ge on waki ng i n t he morni ng and abrupt onset of redness t o
have t hei r ear s exami ned f or ot i t i s medi a. Treatment for bact eri aI conj unct i vi t i s i s
prescri pt i on onI y.
c. Vi raI conj uncti vi t i s i s most of t en at t r i but abl e t o t he adenovi rus and i s hi ghI y
cont agi ous. Mor e commonl y known as "pi nk eye, " i ndi vi dual s of t en exper i ence an
upper - r espi r at or y i nf ect i on or are exposed t o anot her i ndi vi dual wi t h vi ral
conj unct i vi t i s bef or e t he onset of sympt oms (e. g. , pi nk eye, t hi ck ocul ar di schar ge,
ext r eme t ear i ng, f orei gn body sensat i on) . Treatment i s supporti ve and may i ncl ude
col d compr esses, art i f i ci al t ears, and t opi cal vasoconst r i ct ors.
3. Chemi caI burns can resul t f r om medi cat i ons, chl or i nat ed swi mmi ng pool s, or
exposur e t o t oxi c f umes or i r ri t ant s ( e. g. , hai r sprays, bat t er y aci d, vi negar , oven
cl eaner s, l ye) . Treat ment i ncI udes i mmedi ate and cont i nued i rri gati on of t he
eye( s) wi t h sal i ne or st eri l e wat er and emergency at t ent i on f r om a physi ci an or eye
car e speci al i st .
4. CorneaI edema i s char act er i zed by haI os or st ar burst s ar ound l i ght s, whi ch ar e
t he resul t of an under l yi ng di sor der ( e. g. damage t o t he eye) . Once di agnosed by a
physi ci an, hyperosmot i c agent s such as Mur o sol ut i on or oi nt ment may be used t o
draw t he f I ui d away f rom t he cornea. Dosi ng shoul d begi n wi t h a 2% sol ut i on used
4 t i mes dai l y wi t h t he addi t i on of a 5% oi nt ment used at ni ght t i me i f needed. Ì f
unr esol ved, t he 2% sol ut i on may be changed t o a 5% sol ut i on wi t h cont i nued use of
t he oi nt ment .
5. A hordeoI um, mor e commonl y known as a st y, i s an i nf ect i on of t he gl ands of t he
eyel i ds caused by St aphyl ococcus aureus. St i es present as pai nf ul , r ed, and
edemat ous but may be rel i eved by t he appl i cat i on of warm compresses f or 10- 15
mi n 3- 4 t i mes dai l y. Topi cal ant i bi ot i cs may be r equi red.
6. A chaI azi on, si mpl y a granuI oma, may i nvol ve t he gl ands of t he eyel i ds or t he
sur roundi ng ar ea but i s not i nfecti ous. When i n i t s earl y st ages, t he i nf l ammat i on
may be r el i eved by warm compresses appl i ed f or 10- 15 mi n 3- 4 t i mes dai l y. Ì f not
r esol ved wi t hi n 1 week, pr ovi der consul t at i on i s appropr i at e, and surgi cal exci si on
may be necessar y.
7. BI ephari t i s i s a bi I ateraI i nf I ammat i on of the eyeI i d margi ns, at t r i but abl e t o
St aphyl ococcus, sebor rhei c dermat i t i s, or a combi nat i on of t he t wo. Bl ephar i t i s may
be i dent i f i ed by r ed,
P. 618

scal y, t hi ckened eyel i ds wi t h possi bl e l oss of t he eyel ashes. St aphyl ococcal
bl ephari t i s requi r es ant i bi ot i c t r eat ment , but sebor r hei c bl ephar i t i s may respond t o
l i d hygi ene wi t h war m compr esses f or 15- 20 mi n 2- 4 t i mes dai l y, f ol l owed by l i d
scrubs wi t h a mi l d det ergent .
E. Ant i oxi dant s
1. The ant i oxi dant vi t ami ns i ncl ude vi t ami n A ( r et i nol and 8- car ot ene) , vi t ami n C,
and vi t ami n E. ß- Carot ene 50 mg ever y ot her day may pr event t he devel opment of
cat ar act s, especi al l y i n smokers. However , t he use of ant i oxi dant s i n pati ent s
who smoke i ncreases the ri sk of I ung cancer and shouI d, therefore, not be
recommended. Vi t ami n C has been st udi ed f or t he prevent i on of cat aract s.
However , i nsuf f i ci ent dat a i n publ i shed t r i al s l i mi t s t he recommendat i on of t hi s
suppl ement f or t hi s pur pose.
2. Lutei n, an ant i oxi dant pi gment t hat f unct i ons t o f i l t er and prot ect t he vi sual
appar at us and i t s vascul ar suppl y, may be benef i ci al f or i mprovement i n vi si on i n
pat i ent s wi t h dr y age- r el at ed macul ar degener at i on and pr event i on of cat ar act s.
However , more dat a by way of l ar ge r andomi zed cont r ol l ed t ri al s ar e necessar y t o
assess saf et y and ef f i cacy of t hi s suppl ement .
3. Pat i ent s wi t h moder at e and advanced age- r el at ed macul ar degener at i on ( ARMD)
have shown a reduct i on i n t he progressi on of t he di sease and i t s associ at ed vi si on
l oss wi t h ant i oxi dant s pl us zi nc, as wel l as a combi nat i on of t he f ol l owi ng
suppl ement s: vi t ami n C 500 mg, vi t ami n E 400 Ì U, 8- car ot ene 15 mg, zi nc oxi de 80
mg, and copper 2 mg. Ocuvi t e Pr eser Vi si on, a f or mul at i on of t he above ant i oxi dant s,
zi nc, and copper , i s a di et ar y suppl ement cur rent l y under pat ent based on t he
pr omi si ng r esul t s of t he Nat i onal Eye Ì nst i t ut e' s (NEÌ ' s) l andmar k Age- Rel at ed Eye
Di sease St udy ( AREDS) . St udi es of pat i ent s wi t h mi l d or bor derl i ne ARMD have not
shown benef i t f r om ant i oxi dant pl us zi nc suppl ement at i on. Theref ore, t hi s
f or mul at i on shoul d be recommended onI y t o pat i ent s who are nonsmokers ( owi ng
t o an i ncreased r i sk of l ung cancer ) wi t h a di agnosi s of moderat e or advanced
ARMD.
F. Contact Lenses
1. Types of contact I enses
( a) Hard cont act I enses wer e t he f i rst "or i gi nal ¨ cont act l ens, whi ch wer e made of
pol ymet hyl met hacr yl at e ( PMMA) . Because of t he hydr ophobi c nat ur e of PMMA, t he
per meabi l i t y of oxygen i s l i mi t ed, t hus rest r i ct i ng t he once-common use of har d
cont act l enses.
( 1) A spect acI e bI ur, t he i nabi l i t y t o see wel l wi t h gl asses af t er r emoval of t he
cont act l ens, may occur wi t h t he use of har d l enses. The smal l di amet er of t he l ens
may al so cont ri but e t o l oss of t he l ens f r om t he eye.
( 2) Care of har d cont act l enses i ncl udes cl eani ng bet ween t he f i nger t i ps, soaki ng,
and wet t i ng wi t h each r emoval of t he l ens f r om t he eye. Fur t hermore, care must be
t aken t o avoi d scr at chi ng and chi ppi ng t he sur f ace of t he cont act l ens.
b. Ri gi d gas- permeabI e ( RGP) I enses i nf use oxygen per meabi l i t y of sof t cont act
l enses wi t h t he f eat ur es of t he har d cont act l enses. RGP l enses are general l y
t hi cker t han sof t l enses, but more oxygen i s del i ver ed t o t he cor nea by t hese
agent s.
( 1) The RGP l enses are avai l abl e i n dai l y- and ext ended- wear ver si ons, approved
f or up t o 7 days of wear .
( 2) Care of t he RGP l ens i ncl udes cl eani ng t he l ens i n t he pal m of t he hand wi t h a
sur f ace- act i ve cl eani ng pr oduct and an enzymat i c pr oduct . The l ens shoul d t hen be
soaked f or a mi ni mum of 4 hr i n a condi t i oni ng sol ut i on bef or e r ei nser t i on.
c. Soft I enses ar e more comf ort abl e and easi er t o r emove t han ot her cont act
l enses, however , t he vi sual i mpr ovement not ed may not be as si gni f i cant as t hat
whi ch i s seen wi t h RGP or har d l enses. Sof t I enses shouI d not be worn when
appI yi ng t opi caI opht haI mi c products, except t hose pr oduct s speci f i cal l y
f or mul at ed f or such use ( e. g. , r ewet t i ng sol ut i on).
( 1) Ext ended- wear sof t cont act l enses ar e appr oved f or 7 days of cont i nuous wear .
However , a r el at i vel y new pr oduct , Focus Ni ght and Day, i s appr oved f or cont i nuous
30day use, t hough not al l pat i ent s wi l l be abl e t o t ol er at e t he l ens pl acement f or 30
days.
P. 619


( 2) Dai l y- wear sof t cont act l enses are desi gned t o be wor n f or 1 day, up t o 3
mont hs, dependi ng on t he l ens chosen. Because t he l enses wi l l be di scarded wi t hi n
a shor t peri od of t i me, an enzymat i c sol ut i on i s general l y not necessar y f or t hi s t ype
of l ens, but gener al cl eani ng and di si nf ect i ng each t i me t hey are r emoved f r om t he
eyes i s advi sabl e. Sl eepi ng i n t hese l enses i s not r ecommended.
2. SoI ut i on i ngredi ent s ar e gener al l y speci f i c t o t he t ype of cont act l ens chosen
( e. g. , sof t , har d, or RPG) . Ther ef or e, t he pat i ent shoul d ensur e t he pr oduct sel ect ed
i s i n accordance wi t h t he t ype of l ens wor n.
a. CI eani ng soI uti ons act t o r emove r esi due (e. g. , debri s, oi l s) f rom t he cont act
l ens by noni oni c or amphot eri c sur f act ant s. Ì f not cl eaned r egul ar l y, t he resi due wi l l
bui l d and harden, cr eat i ng an ocul ar i r r i t ant , and possi bl y an opht hal mi c i nf ect i on. A
homemade cl eani ng sol ut i on of baki ng soda and di st i l l ed wat er may be used, but i s
not t ypi cal l y r ecommended owi ng t o t he i ncreased r i sk of ocul ar i nf ect i on and
di f f i cul t y i n removi ng t he agent f r om t he l ens.
b. Soaki ng soI ut i ons are used t o pr ovi de an asept i c envi r onment f or t he l ens once
r emoved f rom t he eye and may al so ai d i n r emoval of r esi dual cont ami nant on t he
l ens not removed dur i ng cl eani ng. Soaki ng sol ut i ons general l y have a hi gher
concent r at i on of preser vat i ve t han wet t i ng agent s, but t he l ens shoul d be t horoughl y
r i nsed bef or e i nsert i on.
c. Wet t i ng soI ut i ons are appl i ed di rect l y t o t he l ens bef or e i nsert i on i nt o t he eye.
The f unct i on of t he wet t i ng sol ut i on i s t o t r ansi t i on t he l ens sur f ace f r om
hydr ophobi c t o hydr ophi l i c, pr ovi de l ubr i cat i on, and enhance f i nger t i p adhesi on t o
al l ow f or easi er i nser t i on. Wet t i ng sol ut i ons are not necessar y f or i nser t i on i f t he
pat i ent has si gni f i cant t ear i ng i mmedi at el y af t er i nsert i on of t he l ens. Sal i va shoul d
not be used i n pl ace of a wet t i ng sol ut i on because of t he pot ent i al f or i nf ect i on.
d. MuI t i purpose product s are general l y a sol ut i on composed of a cl eani ng sol ut i on,
soaki ng sol ut i on, and wet t i ng sol ut i on f or ease of use wi t h cont act l enses. However ,
a mul t i pur pose pr oduct may not be as ef f i caci ous i n t he removal of t he resi due or
pr ovi di ng adequat e l ubr i cat i on as t he use of t he t hr ee i ndi vi dual agent s.
e. Rewet ti ng soI ut i ons may be used t o cl ean and moi st en t he sur f ace of t he
cont act l ens whi l e t he l ens i s st i l l i n t he eye.
f . Condi t i oni ng soI ut i on i s essent i al l y an enhanced wet t i ng sol ut i on, pr ovi di ng
i mproved comf or t and wet t abi l i t y of t he l ens.
G. I nst i I I ati on of eye medi cat i on ( Fi gure 29. 1)
1. Wash hands.
2. Shake suspensi ons t o evenl y di st r i but e i ngredi ent s.
3. Hol d t he l ower eye l i d down t o f orm a pouch bet ween t he l i d and t he eyebal l .
4. Al ways appl y eye drops bef or e appl yi ng eye oi nt ment . Di spense t he
r ecommended number of dr ops i nt o t he pouch f or eye drops. Keep t he eyel i ds
cl osed and appl y gent l e pr essure t o t he i nner cant hus f or 1- 2 mi n. Wai t 5- 10 mi n
bef ore i nst i l l i ng anot her eye medi cat i on.
5. Oi nt ment s shoul d be appl i ed t o t he l ower conj unct i val sac as a 1/ 2-i nch r i bbon.
To mi ni mi ze bl ur red vi si on, a decreased amount of oi nt ment may be appl i ed t o t he
eye. Bl ur r ed vi si on wi l l be l ess not i ced by t he pat i ent i f t he oi nt ment i s admi ni st er ed
at bedt i me, i f f easi bl e.
P. 620



Figure 29-1. Guidelines Ior instilling eye
medication. |ModiIied with permission Irom
Smeltzer SC. Bare BG. Brunner & Suddarth's
Textbook oI Medical-Surgical Nursing. 10th ed.
Philadelphia: Lippincott Williams & Wilkins.
2004.|
P. 621


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 3: The quest i ons and i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one or more of t he suggest ed
answer s. Choose t he answer , A- E.
1. Whi ch of the foI I owi ng nonprescri pti on product s i s approved by t he U. S.
Food and Drug Admi ni st rat i on ( FDA) f or t reatment of i mpacted cerumen?
I . oI i ve oi I
I I . carbami de peroxi de
I I I . i sopropyI aI cohoI 95% i n anhydrous gI ycer i n
A i f I and I I ar e cor r ect
B i f I , I I , and I I I are cor rect
C i f I I onI y i s corr ect
D i f I I I onI y i s cor r ect
E i f I onI y i s cor rect
Vi ew Answer 1. The answer i s C[ see] . 2. Whi ch of t he f oI I owi ng ot i c
condi t i ons can be t reated wi t h a nonprescri pt i on agent ?
I . vert i go
I I . t i nni t us
I I I . ext ernaI ot i t i s
I V. wat er-cI ogged ear
A i f I , I I , and I I I are cor rect
B i f I I I and I V are cor r ect
C i f I and I V ar e cor rect
D i f I and I I ar e cor r ect
E i f I V onI y i s corr ect
Vi ew Answer 2. The answer i s E[seeand] . 3. Whi ch of t he f oI I owi ng
condi t i ons i s appropri at e f or the use of i sopropyI aI cohoI 95% i n anhydrous
gI yceri n?
I . t reat ment of i mpacted cerumen
I I . t reat ment of wat er-cI ogged ears
I I I . prevent i on of externaI ot i t i s
I V. t reat ment of externaI ot i t i s
A i f I and I I ar e cor r ect
B i f I I and I I I are cor rect
C i f I I I and I V are cor r ect
D i f I I onI y i s corr ect
E i f I I I onI y i s cor r ect
Vi ew Answer 3. The answer i s D[ see] . Di recti ons f or questi ons 4-5: Each of
t he quest i ons, st at ement s, or i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y
answer ed or compl et ed by one of t he suggest ed answer s or phr ases. Choose t he
best answer .
4. AI I of t he f oI I owi ng are t rue regardi ng carbami de peroxi de except whi ch
one?
( A) Car bami de peroxi de sof t ens ear wax by t he f oami ng act i on produced when
oxygen i s rel eased.
( B) Car bami de peroxi de i s saf e f or pharmaci st recommendat i on i n pat i ent s age 6
year s and ol der .
( C) Appropri at e dosi ng f or car bami de peroxi de i s 5- 10 drops i n t he ear 2 t i mes
dai l y.
( D) Car bami de peroxi de shoul d be used f or a maxi mum of 4 days unl ess ot her wi se
di r ect ed.
Vi ew Answer 4. The answer i s B[ see] . 5. AI I of the f oI I owi ng are t rue
regardi ng ext ernaI ot i t i s except whi ch one?
( A) Ì ni t i al t r eat ment f or ext er nal ot i t i s i s an or al ant i bi ot i c and cor t i cost er oi d.
( B) Sympt oms of ext er nal ot i t i s i ncl ude ot i c i t chi ng, pressure and f ul l ness i n t he ear ,
pai n, and ot i c di schar ge.
( C) Mechani cal t rauma t o t he ear wi t h cot t on-t i pped appl i cat ors can cont r i but e t o
i ncreased suscept i bi l i t y t o ext er nal ot i t i s.
( D) Ext er nal ot i t i s i s al so r ef err ed t o as swi mmer ' s ear .
Vi ew Answer 5. The answer i s A[ seeand] . P. 622


Di rect i ons for quest i on 6: The quest i on i n t hi s sect i on can be cor rect l y answer ed
by one or more of t he suggest ed answer s. Choose t he answer , A- E.
6. Whi ch of the foI I owi ng i s an appropri ate counseI i ng t i p f or admi ni st rat i on of
ot i c drops?
I . PuI I t he earI obe up and back to st rai ght en the ear canaI f or chi I dren.
I I . PuI I t he earI obe down and back to st rai ght en t he ear canaI for aduI t s.
I I I . Fi I I t he ot i c syri nge wi t h hot wat er.
I V. I f cot t on i s used to ret ai n medi cat i on i n the ear, i t shouI d not be I ef t i n t he
ear f or I onger t han 1 hr.
A i f I I I onI y i s cor r ect
B i f I V onI y i s cor rect
C i f I and I I ar e cor r ect
D i f I , I I , and I V ar e cor rect
E i f I I I and I V are cor r ect
Vi ew Answer 6. The answer i s B[ see] . Di recti ons f or questi ons 7-17: Each
of t he quest i ons, st at ement s, or i ncompl et e st at ement s i n t hi s sect i on can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
7. AI I of t he f oI I owi ng are t rue regardi ng ophthaI mi c f ormuI at i ons except whi ch
one?
( A) Vehi cl es enhance cont act t i me of t he opht hal mi c product .
( B) Ant i oxi dant s pr event pr oduct det eri or at i on.
( C) Wet t i ng agent s r educe sur f ace t ensi on of t he l ens.
( D) Toni ci t y adj ust er s are used t o mai nt ai n a pH bet ween 6. 0 and 8. 0.
Vi ew Answer 7. The answer i s D[ see] . 8. Whi ch of t he f oI I owi ng i s
appropri at e t reatment of di agnosed corneaI edema?
( A) hyperosmot i c agent
( B) vasoconst r i ct or
( C) ant i hi st ami ne
( D) ar t i f i ci al t ears
Vi ew Answer 8. The answer i s A[ see] . 9. Whi ch of t he f oI I owi ng i s aI so
known as "pi nk eye"?
( A) al l ergi c conj unct i vi t i s
( B) bact er i al conj unct i vi t i s
( C) vi r al conj unct i vi t i s
( D) envi ronment al conj unct i vi t i s
Vi ew Answer 9. The answer i s C[ see] . 10. AI I of t he f oI I owi ng are
ant i oxi dant s used f or the t reat ment and/ or prevent i on of opht haI mi c di sorders
except
( A) vi t ami n D.
( B) 8- car ot ene.
( C) vi t ami n C.
( D) l ut ei n.
Vi ew Answer 10. The answer i s A[ see] . 11. Whi ch of t he f oI I owi ng
soI ut i ons may be used t o cI ean and moi st en t he surface of the contact I ens
whi I e t he I ens i s st i I I i n t he eye?
( A) cl eani ng sol ut i on
( B) wet t i ng sol ut i on
( C) soaki ng sol ut i on
( D) r ewet t i ng sol ut i on
Vi ew Answer 11. The answer i s D[ see] . 12. Whi ch of t he f oI I owi ng i s t rue
regardi ng opht haI mi c ant i hi st ami nes?
( A) Pheni rami ne and t et rahydr ozol i ne are t he onl y t wo nonprescr i pt i on opht hal mi c
ant i hi st ami nes avai l abl e.
( B) Opht hal mi c ant i hi st ami nes ar e avai l abl e onl y i n combi nat i on wi t h naphazol i ne.
( C) Opht hal mi c ant i hi st ami nes may cause bur ni ng, st i ngi ng, dr y eyes, or mydr i asi s.
( D) Opht hal mi c ant i hi st ami nes may pr oduce rebound congest i on i f used i n excess or
f or ext ended dur at i ons.
Vi ew Answer 12. The answer i s C[ see] . 13. Whi ch of t he f oI I owi ng i s t he
onI y ast ri ngent used i n nonprescri pt i on opht haI mi c agents t hat i s
recommended by t he U. S. Food and Drug Admi ni st rati on (FDA) ?
( A) edet i c aci d
( B) benzal koni um chl or i de
( C) zi nc sul f at e
( D) povi done
Vi ew Answer 13. The answer i s C[ see] . P. 623


14. The def i ni t i on of a surf actant ( an i ngredi ent i n toot hpaste) can best be
descri bed by whi ch of the f oI I owi ng stat ements?
( A) Ì t pr event s dr yi ng of t he pr epar at i on.
( B) Ì t removes debr i s by i t s det er gent act i on and causes f oami ng, whi ch i s usual l y
desi r ed by t he pat i ent .
( C) Ì t physi cal l y removes pl aque and debri s.
( D) Ì t det er mi nes t he t ext ur e, di sper si veness, and appear ance of t he pr oduct .
( E) Ì t adds f l avor t o t he pr epar at i on, whi ch makes i t mor e appeal i ng t o t he pat i ent .
Vi ew Answer 14. The answer i s B[ see] . 15. A 16-year- oI d gi rI stops by a
pharmacy on her way home f rom schooI . She says t o t he pharmaci st , "I have
been usi ng Proxi geI dai I y t o bI each my t eet h i n preparat i on f or my spri ng
f ormaI . However, my t eet h are becomi ng ver y sensi t i ve. " Each of t he f oI I owi ng
st at ements i s advi ce that t he pharmaci st mi ght suggest except whi ch one?
( A) Ther e i s a possi bi l i t y t hat you may damage t he gi ngi val t i ssue and t oot h pul p.
( B) Oxi di zi ng agent s may have t he pot ent i al f or mut at i ng or enhanci ng t he
carci nogeni c ef f ect s of ot her agent s ( e. g. , t obacco) .
( C) Bl eachi ng t eet h i s best done under dent al super vi si on.
( D) Pr oxi gel i s an ant i sept i c t hat cont ai ns zi nc and shoul d not be used f or cosmet i c
whi t eni ng of t he t eet h.
( E) The most common i ngr edi ent i n product s responsi bl e f or t eet h whi t eni ng i s 10%
car bami de per oxi de, whi ch can cause sensi t i vi t y.
Vi ew Answer 15. The answer i s D[ see] . 16. AI I of t he f oI I owi ng products
may be recommended by a pharmaci st f or t he treat ment of canker sores except
( A) benzocai ne.
( B) Zi l act i n- B.
( C) Bayer aspi r i n pl aced di r ect l y on t he or al l esi on.
( D) Anbesol .
( E) Or aj el .
Vi ew Answer 16. The answer i s C[ see] . 17. The U. S. Food and Drug
Admi ni st rat i on (FDA) has approved whi ch i ngredi ent f or prot ect i on agai nst
pai nfuI sensi t i vi t y of t he t eet h caused by coI d, heat, aci ds, sweet s, or contact ?
( A) di cal ci um phosphat e
( B) sodi um l aur yl sul f at e
( C) 5% pot assi um ni t r at e
( D) zi nc chl ori de
( E) cal ci um carbonat e
Vi ew Answer 17. The answer i s C[ see] . Di recti ons f or questi ons 18- 20: The
quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
18. Whi ch of t he f oI I owi ng compounds i s/ are consi dered a suspendi ng agent
( an i ngredi ent i n denti fri ces)?
I . di caI ci um phosphat e
I I . karaya gum
I I I . met hyI ceI I uI ose
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 18. The answer i s D[ see] . 19. CoI d-sore t reat ment mi ght
i ncI ude whi ch of t he f oI I owi ng i ngredi ent s?
I . benzocai ne
I I . docosanoI
I I I . camphor
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 19. The answer i s C[ seeand] . 20. Pharmaci st s can
recommend over- t he- count er ( OTC) drug t reatment for whi ch of t he foI I owi ng
ear condi ti ons?
I . t reat ment of accumuI at ed earwax
I I . prevent i on of bI ocked ears caused by aI t i t ude changes
I I I . t reat ment of water- cI ogged ears
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 20. The answer i s E[see] . P. 624


ANSWERS AND EXPLANATIONS
1. The answer i s C (Ì Ì ) [ see Ì . B. 1. d. ( 1) ] .
Car bami de per oxi de i s t he onl y FDA-appr oved agent f or cer umen r emoval . Ol i ve oi l
and mi neral oi l are used t o r emove cer umen, but ar e not FDA appr oved. Ì sopropyl
al cohol 95% i n anhydr ous gl yceri n i s FDA approved f or wat er -cl ogged ears, but not
cer umen r emoval .
2. The answer i s E ( Ì V) [ see Ì . B. 1. d; Ì . B. 2, 3 and 4] .
Pat i ent s exhi bi t i ng sympt oms of ver t i go, asi de f rom mot i on si ckness, shoul d be
r ef er red t o a medi cal pr ovi der . There i s no FDA- appr oved t r eat ment f or t i nni t us.
Ext er nal ot i t i s (swi mmer ' s ear ) shoul d be t r eat ed wi t h a prescr i pt i on ot i c ant i bi ot i c
and cort i cost eroi d. Onl y i mpact ed cer umen and wat er -cl ogged ears may be t r eat ed
wi t h nonpr escri pt i on product s.
3. The answer i s D (Ì Ì ) [ see Ì . B. 5] .
Ì sopr opyl al cohol 95% i n anhydrous gl yceri n i s FDA approved onl y f or t r eat ment of
wat er - cl ogged ears. Label s on pr oduct s of i sopr opyl al cohol 95% i n anhydr ous
gl yceri n shoul d not cl ai m t o be used f or t reat ment or prevent i on of ext er nal ot i t i s
( swi mmer ' s ear ) because t hi s i s a separ at e di sor der f r om wat er -cl ogged ear s.
Tr eat ment f or i mpact ed cer umen i s carbami de per oxi de.
4. The answer i s B [ see Ì . B. 1. d. (1) ] .
Car bami de per oxi de sof t ens ear wax t hr ough i t s f oami ng act i on when oxygen i s
r el eased. Ì t i s l abel ed f or ages 12 and ol der . Ther ef ore, f or chi l dren < age 12 wi t h
suspect ed cer umen i mpact i on shoul d be seen by a medi cal provi der . Pat i ent s shoul d
i nst i l l 5- 10 dr ops of car bami de peroxi de i nt o t he ear 2 t i mes dai l y f or up t o 4 days.
5. The answer i s A [ see Ì . B. 4. a, b and c] .
Ext er nal ot i t i s i s r ef er r ed t o as swi mmer ' s ear. Though prol onged exposure t o
moi st ur e i s t he t ypi cal cause of ext er nal ot i t i s, mechani cal t rauma, such as t he use
of cot t on- t i pped appl i cat or s, f i ngers, or shar p obj ect s i n t he ear , may cause t he
ext er nal ear canal t o be mor e suscept i bl e t o damage and mi croorgani sm i nf i l t r at i on.
Pat i ent s wi t h ext er nal ot i t i s may pr esent wi t h ot i c i t chi ng, a sensat i on of pr essur e or
f ul l ness i n t he ear , pai n, or an ot i c di schar ge. Ì ni t i al t r eat ment i s wi t h an ot i c
ant i bi ot i c and cort i cost eroi d, not an oral ant i bi ot i c. Or al ant i bi ot i cs ar e i ndi cat ed
when t he i nf ect i on i s unresponsi ve t o ot i c t reat ment , t he i ndi vi dual i s
i mmunocompr omi sed, or a mi ddl e ear i nf ect i on coexi st s.
6. The answer i s B (Ì V) [ see Ì . C] .
The earl obe shoul d be pul l ed up and back t o st rai ght en t he canal f or adul t s and
down and back t o st r ai ght en t he canal i n chi l dren. Onl y war m wat er shoul d be used
i n t he ot i c syr i nge, as col d or hot wat er may i nduce di zzi ness. Ì f cot t on i s used i n
t he ear t o ret ai n t he medi cat i on, i t must be l ar ge enough t o remove easi l y and
shoul d not be l ef t i n t he ear f or l onger t han 1 hr .
7. The answer i s D [ see Ì Ì Ì . B] .
Buf f ers ar e used i n opht hal mi c prepar at i ons t o mai nt ai n a pH bet ween 6. 0 and 8. 0.
Toni ci t y adj ust ers ensure t he product i s i sot oni c, equal t o 0. 9%- 60. 2% sodi um
chl or i de.
8. The answer i s A [ see Ì Ì Ì . D] .
Once di agnosed by a physi ci an, cor neal edema i s t reat ed wi t h hyper osmot i c agent s
such as Mur o sol ut i on or oi nt ment t o dr aw t he f l ui d away f r om t he cor nea.
9. The answer i s C [ see Ì Ì Ì . D. 2] .
Vi r al conj unct i vi t i s i s most of t en at t r i but abl e t o t he adenovi r us and i s more
commonl y known as pi nk eye.
10. The answer i s A [ see Ì Ì Ì . E] .
The ant i oxi dant vi t ami ns exami ned f or t he pr event i on and/ or t r eat ment of opht hal mi c
di sor der s i ncl ude vi t ami n A ( r et i nol and 8- car ot ene) , vi t ami n C, and vi t ami n E.
Lut ei n i s an ant i oxi dant pi gment t hat f unct i ons t o f i l t er and pr ot ect t he vi sual
appar at us and i t s vascul ar suppl y. Lut ei n, i s t heref or e, t hought t o be benef i ci al f or
i mprovement i n vi si on i n pat i ent s wi t h dr y age- r el at ed macul ar degener at i on and
pr event i on of cat aract s. Vi t ami n D i s not an ant i oxi dant vi t ami n.
P. 625


11. The answer i s D [ see Ì Ì Ì . F. 2] .
Rewet t i ng sol ut i ons ar e t he onl y cont act l ens sol ut i ons t hat may be used whi l e t he
l ens i s st i l l i n t he eye.
12. The answer i s C [ see Ì Ì Ì . C. 4] .
Cur r ent l y, t her e are t hree avai l abl e opht hal mi c ant i hi st ami nes: ket ot i f en,
pheni r ami ne, and ant azol i ne. Pheni r ami ne and ant azol i ne ar e onl y avai l abl e i n
combi nat i on wi t h t he opht hal mi c decongest ant naphazol i ne. Opht hal mi c
ant i hi st ami nes may cause burni ng, st i ngi ng, dr y eyes, or mydr i asi s.
Vasoconst r i ct ors, not ant i hi st ami nes, may produce r ebound congest i on when used i n
excess or f or ext ended dur at i ons.
13. The answer i s C [ see Ì Ì Ì . B] .
Edet i c aci d i s an ant i oxi dant and benzal koni um chl ori de ( BAK) i s a pr eservat i ve
used i n opht hal mi c f ormul at i ons. Zi nc sul f at e i s t he onl y FDA- recommended
ast ri ngent . Povi done i s a vehi cl e used i n opht hal mi c f or mul at i ons.
14. The answer i s B [ see Ì Ì . B. 2. d. ( 1)] .
Sodi um l aur yl sul f at e i s used f requent l y as a surf act ant i n most dent i f r i ces. Ì t s
det ergent act i on ai ds i n t he r emoval of debri s, and t he f oami ng i s usual l y desi r ed by
t he pat i ent . There i s no evi dence t hat sur f act ant s possess ant i car i es act i vi t y or
decrease peri odont al di sease. The FDA consi ders sur f act ant s an i nact i ve i ngr edi ent
i n dent i f ri ces.
15. The answer i s D [ see Ì Ì . B. 2. d. ( 4)] .
Teet h- whi t eni ng agent s usual l y cont ai n 10% carbami de per oxi de, whi ch i s a whi t e
cr yst al t hat r eact s wi t h wat er t o rel ease hydrogen per oxi de and, t her ef ore, l i ber at es
f r ee oxi des. Cosmet i c agent s can al t er t he normal f l ora or cause t i ssue i r r i t at i on,
gi ngi vi t i s, and t eet h sensi t i vi t y. Ant i sept i cs have been used as cosmet i c whi t eners
( e. g. , Gl y- Oxi de, Pr oxi gel ) al ong wi t h cal ci um peroxi de ( e. g. , Cal prox i n Epi Smi l e) .
Epi Smi l e al so cont ai ns sodi um monof l uor ophosphat e.
16. The answer i s C [ see Ì Ì . C. 1. c. ( 2) ] .
Local anest het i cs can provi de rel i ef of canker sore pai n. The most common l ocal
anest het i cs f ound i n OTC pr oduct s i ncl ude benzocai ne and but acai ne. Some
exampl es are Anbesol , Zi l act i n- B, and Or aj el . Aspi r i n shoul d not be r et ai ned i n t he
mout h bef or e swal l owi ng or pl aced i n t he area of t he or al l esi ons because of t he
hi gh r i sk f or chemi cal bur n wi t h necrosi s.
17. The answer i s C [ see Ì Ì . B. 2. d. ( 5)] .
Desensi t i zi ng agent s shoul d not be abr asi ve or used on a chr oni c basi s unl ess
di r ect ed by a dent i st . The pr oduct s appr oved by t he ADA i ncl ude t he i ngr edi ent s 5%
pot assi um ni t rat e, 10% st r ont i um chl or i de, and di basi c sodi um ci t r at e 2% i n Pl ur oni c
gel .
18. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see Ì Ì . B. 2. d. (1) . D] .
Suspendi ng agent s ar e pr oduct s t hat add t hi ckness t o t he dent i f r i ces. Exampl es ar e
t r agacant h, kar aya gum, and met hyl cel l ul ose. Di cal ci um phosphat e i s cat egor i zed as
an abr asi ve pr oduct .
19. The answer i s C ( Ì , Ì Ì ) [ see Ì Ì . C. 2. a and b] .
Col d-sore t reat ment i nvol ves keepi ng t he l esi on moi st wi t h emol l i ent creams,
pet r ol at um, or prot ect ant s. Local anest het i cs (e. g. , benzocai ne, dycl oni ne, sal i cyl
al cohol ) may be used. Ì n addi t i on, docosanol 10% cream ( Abr eva) and t et r acai ne 2%
gel ( Vi r act i n) ar e avai l abl e wi t hout a prescr i pt i on f or t he t r eat ment of col d sor es.
Topi cal count eri r r i t ant s (e. g. , camphor) and caust i cs or eschar ot i c agent s ( e. g. ,
phenol , ment hol , si l ver ni t r at e) ar e not r ecommended because t hey may f ur t her
i r r i t at e t he t i ssue. Col d sor es are usual l y sel f - l i mi t i ng and heal wi t hi n 10- 14 days
wi t hout scar r i ng.
20. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì . B] .
OTC dr ug t r eat ment can be r ecommended f or al l of t hese ear condi t i ons.

30
OTC DermatoIogicaI Agents
Larr y N. Swanson
I. PEDICULOSIS AND PEDICULICIDES
A. I nt roduct i on. Pedi cul osi s i s a ski n i nf est at i on pr oduced by bl ood-
sucki ng l i ce. Li ce are smal l , f l at , wi ngl ess i nsect s wi t h st ubby ant ennae and
t hr ee pai rs of l egs t hat end i n sharp, cur ved cl aws. Thr ee t ypes of I i ce
i nf est humans.
1. Pedi cul us humanus capi t i s (i . e. , t he head l ouse)
2. Pedi cul us humanus cor por i s (i . e. , t he body l ouse)
3. Pht hi rus pubi s ( i . e. , t he pubi c, or cr ab, l ouse)
B. Li f e cycI es. The l i ce t hat i nf est humans pass t hr ough si mi l ar l i f e cycl es.
1. Locat i on. Al l l i ce need human war mt h t o sur vi ve.
a. Head and pubi c I i ce spend t hei r ent i r e cycl e on t he ski n of t he human
host .
b. Body I i ce l i ve i n cl ot hi ng, comi ng t o t he ski n sur f ace onl y t o f eed.
2. DeveI opment
a. Each t ype of l ouse devel ops f rom eggs ( ni t s) t hat i ncubat e f or about 1
week. When t he smal l , gr ay- whi t e, t ear -shaped eggs hat ch, t he nymphs
appear .
b. Ì n about 3 weeks, t he nymphs mat ur e; t hen t he f emal es st ar t t o l ay
eggs.
c. Each t ype of l ouse survi ves about 1 mont h as a mature aduI t . Duri ng
t hi s t i me, t he f emal e head l ouse can pr oduce 3- 6 eggs a day.
3. Egg deposi t
a. Body I i ce deposi t t hei r eggs on f i ber s of cl ot hi ng, par t i cul ar l y i n t he
seams. These l i ce can sur vi ve wi t hout f ood up t o 10 days, and t he eggs
may r emai n vi abl e f or about 1 mont h. Dai l y cl ot hi ng changes and boi l i ng or
i r oni ng i nf est ed cl ot hi ng can er adi cat e body I i ce.
b. Head and pubi c I i ce deposi t t hei r eggs on hai r st rands, about 1/ 4 i nch
f r om t he ski n. Adul t head l i ce can sur vi ve on i nani mat e obj ect s f or about 20
hr ; head l i ce ni t s may sur vi ve up t o 10 days of f t he body.
C. I nci dence. The i nci dence of l i ce i nf est at i ons i ncr eases each year .
1. Mor e t han 10 mi l l i on cases of head l i ce occur each year i n t he Uni t ed
St at es.
2. The bul k of t hese cases occur bet ween Sept ember and November , when
st udent s ar e back i n school .
3. Ì n out breaks of head l i ce, 70% of cases occur i n chi l dren younger t han
12 years.
4. Ì nf est at i ons t end t o be mor e common i n gi rl s, pr esumabl y because of
t hei r great er t endency t o shar e gr oomi ng i t ems.
5. Unl i ke t he ot her t wo f or ms of l i ce, body l i ce are associ at ed wi t h i mpr oper
hygi ene and ar e of t en present i n homel ess peopl e. Thi s i nf est at i on i s rare
i n t he Uni t ed St at es, especi al l y when peopl e f ol l ow pr oper hygi ene rout i nes.
D. Medi caI probI ems
1. Bot h adul t and nymph l i ce ar e bl ood sucki ng; t hey f eed on humans by
pi erci ng t he ski n and i nt roduci ng a smal l amount of sal i va ( whi ch cont ai ns
an ant i coaguI ant) i nt o t he f eedi ng area. Al l l i ce t ypes f eed on bl ood f or
about 30- 45 mi n ever y 3- 6 hr .
a. The at t achment of l i ce t o t he body causes an er yt hemat ous papuI e,
whi ch may i t ch.
b. The f emal e l ouse produces a st i cky cement -I i ke secreti on t hat hol ds t he
eggs i n pl ace on t he hai r shaf t so securel y t hat ordi nar y shampooi ng does
not remove i t .
P. 627


2. Nei t her head nor crab l i ce t r ansmi t i nf ect i ons, but body l i ce t r ansmi t
t yphus, reI apsi ng f ever, and t rench fever.
3. Li ce and humans have a t rue parasi t i c reI at i onshi p; l i ce depend on t he
human host f or shel t er , f ood, and r epr oduct i ve success. Once hat ched,
nymphs must have access t o t he human host wi t hi n t he f i rst 12- t o 24- hr
per i od, i f t hey ar e t o survi ve.
E. Met hods of t ransmi ssi on
1. Head I i ce ar e most commonl y spread by head- t o- head cont act wi t h an
i nf est ed person t hrough hat s, caps, scar ves, pi l l owcases, communal combs
and br ushes, or cl ot hi ng t hat i s hung cl ose t oget her ( e. g. , on a coat r ack) .
2. Pubi c I i ce are t ransmi t t ed pri mari I y t hrough sexuaI cont act , but al so
t hr ough shar ed undergarment s, t owel s, or t oi l et seat s.
a. The l i ce af f ect t eens and young adul t s most of t en t hr ough sexual cont act .
b. Li ce f r equent l y coexi st wi t h ot her sexual l y t r ansmi t t ed di seases.
c. Scr at chi ng i n t he geni t al ar eas may t ransmi t pubi c l i ce t o ot her hai r y
r egi ons, such as t he eyel ashes, eyebr ows, si debur ns, and must aches.
F. Si gns and sympt oms
1. Head I i ce
a. Most pat i ent s have f ewer t han 10 l i ce.
b. The most common si gn i s head scratchi ng.
c. Ski n redness around t he nape ( i . e. , back) of t he neck and above t he
ear s i s usual l y seen.
d. The l i ce can be i dent i f i ed by di rect exami nat i on usi ng wooden appl i cat or
st i cks or a comb t o part t he hai r , t hen l ooki ng at t he hai r t hrough a
magni f yi ng gl ass.
e. The l i ce appear as t i ny br owni sh gr ay spot s t hat are of t en di f f i cul t t o see.
The shi ny, whi ti sh si I ver eggs, whi ch appear al most as gr ai ns of sugar,
ar e more l i kel y t o be seen t han t he l i ce. The ni t s ar e i ni t i al l y deposi t ed
about 1/ 4 i nch f rom t he scaI p on t he hai r shaf t , and t hey may be conf used
wi t h dandruf f or hai rspray dropI et s. Usual l y, hai r gr ows at a rat e of about
1/ 2 i nch per mont h, so t he durat i on of i nf est at i on can be assessed based on
t hi s i nf ormat i on.
2. Pubi c I i ce. The pr i mar y sympt om i s scr at chi ng i n t he geni t al ar ea.
3. Body I i ce. The most common sympt oms are bi t es and i t chi ng, whi ch are
commonl y seen as vert i cal excor i at i ons on t he t r unk ar ea.
G. Treatment
1. Ther e ar e t hree steps i n t he t r eat ment of head and body I i ce.
a. Tr eat t he l i ce and ni t s wi t h a pedi cul i ci de agent .
b. Cont r ol t he sympt oms of i t chi ng t o prevent secondar y i nf ect i on.
c. Cl ean t he envi r onment of pot ent i al l i ce and ni t s.
2. I tchi ng. Pharmaci st s shoul d advi se pat i ent s t hat even af t er t he causat i ve
or gani sm and ni t s have been ki l l ed, i t chi ng may per si st f or sever al days.
Thi s aspect i s ver y i mpor t ant because pat i ent s may deci de t o use
pedi cul i ci des excessi vel y, t hi nki ng t hat t hey have been i nef f ect i ve when t he
i t chi ng cont i nues. Excessi ve use of pedi cuI i ci des may resuI t i n
excessi ve dr yi ng, whi ch can cause f urt her i tchi ng.
3. Home remedi es. Because of t he soci al st i gma at t ached t o l i ce
i nf est at i on, some i ndi vi dual s may r esort t o harmf ul home r emedi es.
Exampl es of such uncomf or t abl e, i nef f ect i ve, and pot ent i al l y danger ous
approaches t hat shoul d not be used i ncl ude
a. Shavi ng t he head and pubi c ar ea
b. Appl yi ng heat t o t he i nf est ed area wi t h a hai r dr yer
c. Soaki ng t he head i n hot wat er f or sever al mi nut es
d. Soaki ng t he area of i nf est at i on wi t h gasol i ne or kerosene
4. Over- t he-counter ( OTC) pedi cuI i ci de product s ar e consi dered f i rst - l i ne
t r eat ment s and i ncl ude
a. Pyret hri ns 0. 17%- 0. 33% wi t h pi peronyI but oxi de 2%- 4%. Thi s pr oduct
i s saf e and ef f ect i ve f or t he t r eat ment of head and pubi c I i ce. The
combi nat i on of i ngr edi ent s i s an exampl e of pharmacoI ogi caI synergi sm.
P. 628


( 1) Pyret hri ns ki l l by di srupt i ng i on- t ransport mechani sms at the nerve
membranes. These nat ur al i nsect i ci des are der i ved f rom a mi xt ur e of
subst ances obt ai ned f rom t he f l ower s of t he chrysant hemum pl ant .
Because not al l eggs may be ki l l ed ( i t t akes about 4 days f or t he ner vous
syst em of t he l ouse t o devel op) wi t h a si ngl e appl i cat i on of t hi s agent or
r emoved wi t h a ni t comb, i t may be necessar y t o r eappl y t he pyr et hri n
pr oduct wi t hi n 7- 10 days of t he f i rst appl i cat i on (because t he usual hat chi ng
t i me of t he eggs i s 7- 10 days) .
( 2) Pi peronyI but oxi de enhances t he pedi cul i ci de ef f ect of pyr et hr i ns by
suppressi ng the oxi dati ve degradat i on mechani sms of t he I i ce.
Ther ef ore, t he l engt h of t i me t hat t he pyr et hr i ns cont act t he l i ce i s
i ncreased.
( 3) Si de eff ects f rom ei t her agent ar e uncommon.
( a) Contact dermat i t i s (see Ì V) i s t he most f r equent l y repor t ed si de ef f ect .
( b) AI I ergi c react i ons. Because pyr et hr i ns are der i ved f rom a pl ant
( chr ysant hemum) , t hey may produce hay f ever (i . e. , al l er gi c r hi ni t i s) and
ast hma at t acks i n suscept i bl e i ndi vi dual s. Thus pat i ent s who have known
al l er gi es t o r agweed or chr ysant hemum pl ant s shoul d use t hi s pr oduct wi t h
caut i on.
( 4) Common t rade names f or t hi s pr oduct i ncl ude RÌ D maxi mum st rengt h
Shampoo, A-200 maxi mum st r engt h Shampoo.
( 5) Di rect i ons f or use (shampoo)
( a) AppI y t he product , undi I ut ed, t o t he dr y hai r unt i l i t i s ent i r el y wet .
( b) Al l ow t he pr oduct t o remai n on t he head f or 10 mi n.
( c) Ri nse thoroughI y wi t h war m wat er .
( d) Dr y t he area, pr ef er abl y wi t h a di sposabl e cl ot h.
( e) Comb hai r i n t he pr evi ousl y i nf est ed area wi th a f i ne- toot hed comb t o
r emove dead l i ce and eggs.
( f ) Do not exceed t wo appl i cat i ons wi t hi n 24 hr . Ì t may be necessar y t o
r eappl y t he shampoo i n 7- 10 days [ see Ì . G. 4. a. (1) ] .
b. Permet hri n ( Ni x) i s a pyr et hroi d ( i . e. , a synt het i c ver si on of a pyr et hri n) .
Ì t i s i ndi cat ed f or t he t reat ment of head I i ce onI y.
( 1) Mechani sm of act i on. Permet hr i n has a si mi I ar mechani sm of acti on
as t he pyret hri ns.
( 2) AppI i cat i on. Permet hr i n comes i n t he f orm of a 1% creme ri nse and
shoul d be appl i ed l i ke a convent i onal hai r condi t i oner af t er t he hai r has
been shampooed ( use a shampoo wi t h no condi t i oner ), r i nsed, and t owel
dr i ed. The hai r shoul d be t hor oughl y sat ur at ed wi t h undi l ut ed per met hri n
( 25- 30 mL) , whi ch shoul d remai n on the hai r for 10 mi n. t hen ri nsed.
( 3) Ef f ect i veness. A si ngl e appl i cat i on i s gener al l y ef f ect i ve i n ki l l i ng l i ce.
Because t he agent i s ret ai ned on t he hai r shaf t , t he product pr ovi des
cont i nui ng act i vi t y f or up t o 14 days. Thi s r esi dual ef f ect per si st s
r egardl ess of nor mal shampooi ng.
( a) Even wi t h t he r esi dual act i vi t y, t her e st i l l may be t he need f or
r et r eat ment i n 7-10 days.
( b) Comb hai r i n t he pr evi ousl y i nf est ed area wi th a f i ne- toot hed comb t o
r emove dead l i ce and eggs.
( c) Ther e i s, at l east t heor et i cal l y, t he specul at i on t hat because l ow- l evel
r esi dual amount s of t hi s agent are ret ai ned on t he hai r , i t may be possi bl e
t hat when subopt i mal l evel s ar e present , some l i ce may sur vi ve and gi ve
r i se t o st r ai ns t hat are resi st ant .
c. OTC pedi cuI i ci de t reat ment f ai I ure. Tr eat ment f ai l ur e wi t h t he use of
t he pr ecedi ng agent s has been r epor t ed. Specul at i ons as t o t he cause of
t hi s t reat ment f ai l ur e i ncl ude f ai l ur e t o f ol l ow pr oduct i nst r uct i ons,
noncompl i ance wi t h ni t removal , and head-l i ce drug r esi st ance. St udi es
suppor t t he t heor y t hat t her e ar e now " super l i ce¨ t hat have sur vi ved
exposur e t o pyr et hri ns and per met hr i n.
5. Prescri pti on products ar e i ncl uded her e t o put i nt o perspect i ve how t he
OTC agent s f i t i nt o t her apy.
a. MaI at hi on ( Ovi de) i s an organophosphat e chol i nest er ase i nhi bi t or t hat
has been wi del y used as a l awn and garden i nsect i ci de. Resi st ance has
al so become an i ssue wi t h t hi s agent .
( 1) Mechani sm of act i on. Sul f ur at oms i n t he mal at hi on bi nd wi t h sul f ur
gr oups on t he hai r , gi vi ng a resi dual pr ot ect i ve ef f ect agai nst r ei nf est at i on.
P. 629


( 2) AppI i cat i on. Mal at hi on i s pr epar ed as a l ot i on i n 78% al cohol ;
t her ef ore, caut i on shoul d be used near an open f l ame or a hai r dr yer . The
pr oduct shoul d be spri nkl ed on dr y hai r and l ef t f or 8-12 hr bef ore r i nsi ng. A
f i ne- t oot hed comb shoul d be used t o remove t he dead l i ce and eggs.
( 3) No syst emi c adverse ef f ect s have been r eport ed wi t h t opi cal use of t hi s
medi cat i on.
( a) The al cohol i c vehi cl e may pr oduce st i ngi ng and possi bl e f l ammabi l i t y.
( b) Al t hough t hi s agent may be ef f ect i ve, i t s unpl easant odor ( owi ng t o
sul f hydr yl compounds), t he r equi r ed t i me of 8- 12 hr on t he scal p, and t hose
poi nt s not ed i n Ì . G. 5. a. (3) . ( a) r epresent t he mai n dr awbacks.
b. Li ndane, or v- benzene hexachl ori de has f al l en i nt o di sf avor because of
t he pot ent i al f or t oxi ci t y and t he f act t hat i t s ef f i cacy i s l ess t han t he ot her
agent s avai l abl e ( bot h prescr i pt i on and OTC pr oduct s) . Resi st ance t o t hi s
agent i s wi despread.
( 1) Ì t has neurotoxi ci t y pot enti aI because of percut aneous absor pt i on;
t her ef ore, i t s use shoul d be avoi ded i n i nf ant s, pregnant and nur si ng
women, and anyone wi t h a neur ol ogi cal di sorder. Sever e cent raI nervous
syst em ( CNS) t oxi ci t y has occur red i n i nf ant s, wi t h sei zur es and deat hs
r eport ed, par t i cul arl y when t he l ot i on i s used or when t he agent i s i ngest ed.
Toxi ci t y has been mi ni mal when t he shampoo i s used proper l y t o t r eat head
l i ce.
6. Adj uncti ve t herapy
a. Ni t removaI
( 1) The pedi cul i ci de pr oduct s ment i oned var y i n t hei r abi l i t y t o ki l l t he l i ce
ni t s. To ensur e successf ul t her apy, af t er pedi cul i ci de appl i cat i on, t he ni t s
shoul d be r emoved wi t h a f i ne- t oothed comb. A st urdy metaI comb ( l i ke
t he Li ceMei st er ) i s recommended by t he Nat i onal Pedi cul osi s Associ at i on
( NPA) . Many school s have a "no ni t " poI i cy÷t hat i s, a chi l d' s hai r and
scal p must be f r ee of ni t s bef ore he or she i s al l owed t o r et ur n t o t he
cl assr oom.
( 2) Al t hough var i ous subst ances have been used i n an ef f ort t o di sl odge t he
ni t s f rom t he hai r shaf t s, most , i f not al l , have been unsuccessf ul . A mi xt ur e
of 50% vi negar and 50% wat er has been r ecommended, but i t s
ef f ect i veness has been quest i oned. A l i ce egg r emover cont ai ni ng vari ous
enzymes comes as part of a ki t , but chal l enges have been made t o i t s
ef f ect i veness.
b. Treat ment of ot her househoI d members. Once a l i ce i nf est at i on has
been i dent i f i ed i n one member of t he househol d, al l ot her member s shoul d
be exami ned car ef ul l y. Ever yone who i s i nf est ed shoul d be t r eat ed at t he
same t i me.
c. Adj unct i ve met hods f or cont roI I i ng I i ce i nfest at i ons
( 1) WashabI e materi aI i t ems such as l i nens, t owel s, hat s, and cl ot hi ng
shoul d be machi ne- washed i n hot wat er and dri ed i n a hot dr yer t o dest r oy
l i ce and ni t s.
( 2) NonwashabI e materi aI goods shoul d be dr y- cl eaned or seal ed i n a
pl ast i c bag f or 2 weeks.
( 3) PersonaI i tems ( e. g. , comb, brushes) shoul d be soaked i n hot wat er
( 130°F) f or at l east 15 mi n.
( 4) Furni t ure and househoI d i t ems ( e. g. , car pet s, chai r s, couches,
pi l l ows) shoul d be vacuumed t hor oughl y. OTC spr ay pr oduct s t hat cont ai n
pyr et hri ns are no mor e ef f ect i ve t han vacuumi ng i n t erms of r emovi ng t he
r i sk of r ei nf est at i on.
d. Pedi cul i ci des shoul d not be used ar ound t he eyes. For eyeI ash pubi c
I i ce i nf est ati ons, pet roI at um appl i ed f i ve t i mes a day has been used t o
supposedl y " asphyxi at e¨ l i ce but t hi s may onl y sl ow l i ce movement . Gent l e
r emoval wi t h baby shampoo may be hel pf ul .
H. Head I i ce myt hs ar e numer ous. The f ol l owi ng addi t i onal f act s may
r eassure and i nf orm pat i ent s and par ent s of pat i ent s.
1. No si gni f i cant di f f er ence i n i nci dence occurs among t he vari ous
soci oeconomi c cl asses or r aces.
2. Hygi ene and hai r l engt h are not cont r i but i ng f act ors.
3. Head l i ce do not f l y or j ump f r om per son t o person.
4. Head l i ce do not carr y ot her di seases.
5. Head l i ce cannot be cont r act ed f r om ani mal s, and pet s ar e not
suscept i bl e t o Pedi cul us humanus capi t i s.
P. 630


6. The head does not have t o be shaved t o get ri d of l i ce.
7. Washi ng hai r wi t h " brown¨ soap i s not ef f ect i ve.
8. Head l i ce ar e unr el at ed t o t i cks.
9. Hai r does not f al l out as a consequence of i nf est at i on.
10. Head l i ce i nf est at i ons can occur at any t i me of t he year .
II. ACNE AND ITS TREATMENT
A. Over vi ew
1. Def i ni t i on. Acne vul gar i s i s a di sorder of t he pi l osebaceous uni t s, mai nl y
of t he f ace, chest , and back. The l esi ons usual l y st art as open or cl osed
comedones and evol ve i nt o i nf l ammat or y papul es and pust ul es t hat ei t her
r esol ve as macul es or become secondar y pyoderma, whi ch resul t s i n
var i ous sequel ae.
2. I nci dence
a. Acne vul gar i s i s t he most common ski n di sease of adol escence; i t
af f ect s about 85% of al l peopl e bet ween t he ages of 12 and 24.
b. Ì t af f ect s pr i mari l y adol escent s i n j uni or hi gh and seni or hi gh, t hen
decreases i n adul t hood.
3. I mport ance
a. Acne vul gar i s i s usual l y seI f -I i mi t i ng.
b. However , t he condi t i on i s si gni f i cant t o adol escent s because of
hei ght ened sel f - consci ousness about appear ance.
c. A gr eat maj or i t y of peopl e do not consul t a physi ci an f or t r eat ment of
acne; t heref ore, a pharmaci st can pl ay a si gni f i cant r ol e.
B. Ori gi ns and pat hophysi oI ogy
1. The pat hogenesi s of acne vul gari s i nvol ves three events.
a. I ncreased sebum product i on
( 1) Sebum secret i on i s regul at ed pr i mari l y by androgens, whi ch ar e
act i vel y secret ed i n bot h sexes begi nni ng at puber t y.
( 2) One of t hese andr ogens, t est ost er one, i s conver t ed t o
di hydrot est osterone ( DHT) .
( 3) DHT l evel s i nduce t he sebaceous gl ands t o i ncr ease i n si ze and act i vi t y,
r esul t i ng i n i ncr eased amount s of sebum.
b. AbnormaI cI umpi ng of epi t heI i aI horny ceI I s wi t hi n t he
pi I osebaceous uni t
( 1) Normal l y, kerat i ni zed hor ny cel l s are sl oughed f r om t he epi t hel i al l i ni ng
of t he pi l osebaceous duct i n t he hai r f ol l i cl es and ar e car ri ed t o t he ski n
sur f ace wi t h a f l ow of sebum.
( 2) Ì n t he pat i ent wi t h acne, t he ker at i ni zat i on process i s abnor mal ,
charact eri zed by i ncr eased adher ence and product i on of f ol l i cul ar epi t hel i al
cel l s. Thi s process i s cal l ed ret ent i on hyperkerat osi s, and i t resul t s i n
obst r uct i on of t he out f l ow of t he pi l osebaceous uni t .
c. Presence of Propi oni bact eri um acnes ( a gr am- posi t i ve anaer obe)
( 1) Peopl e wi t h acne have ski n col ony count s of P. acnes t hat ar e
si gni f i cant l y hi gher t han t he count s of t hose wi t hout acne.
( 2) P. acnes produces sever al enzymes, i ncl udi ng l i pases, t hat break down
sebum t r i gl ycer i des t o shor t chai n f r ee f at t y aci ds ( FFAs) , whi ch ar e
i r r i t at i ng, cause comedones, and resul t i n i nf l ammat i on.
2. Sequence of acne I esi on deveI opment
a. Mechani cal bl ockage of a pi l osebaceous duct by cl umped horny cel l s
r esul t s i n a cI osed comedo ( i . e. , a whi t ehead) .
b. When a cl osed comedo devel ops, i t can f or m ei t her a papul e or an open
comedo (i . e. , a bI ackhead) . The dark coI or of t he bl ackhead i s at t ri but ed
t o a combi nat i on of mel ani n, oxi di zed l i pi d, and ker at i nocyt es, not t o di rt.
c. The l esi on may enl ar ge and f i l l wi t h pus, whi ch i s t hen t er med a pust ul e.
P. 631


d. Ì n mor e severe cases of acne, papul es may devel op i nt o nodul es or
cyst s.
e. The t er m pi mpl e nonspeci f i cal l y r ef ers t o whi t eheads, bl ackheads,
papul es, and pust ul es.
C. CI i ni caI f eatures
1. Locat i on. Acne vul gar i s l esi ons usual l y occur on t he f ace, neck, chest , upper
back, and shoul der s. Any or al l t ypes of l esi ons may be seen on a si ngl e pat i ent .
2. Sympt oms. Thi s condi t i on i s usual l y asympt omat i c; however , some pat i ent s may
have prur i t us or pai n i f l ar ge, t ender l esi ons ar e pr esent .
3. CI assi fi cat i on. Ì t i s i mport ant t o di f f er ent i at e noni nfI ammator y f r om
i nf I ammator y acne t o det ermi ne t he best t reat ment approach. Ther e have been
many rat i ng or gradi ng scal es f or acne severi t y (Tabl e 30- 1). Cyst i c acne i s present
when t he f ol l i cul ar wal l rupt ures occur deeper i n t he dermi s and nodul es and cyst s
ar e seen. Because of t he pot ent i al f or scar r i ng, cyst i c acne pat i ent s shoul d be
r ef er red t o a physi ci an f or t r eat ment . Scar ri ng occurs wi t h hyper t rophi c r i dges,
kel oi ds, or at r ophi c "i ce pi ck¨ pi t s.
D. CompI i cat i ng f act ors. Ot her f act or s have been i mpl i cat ed i n t he exacer bat i on of
acne.
1. Drugs and hormones
a. Many t opi cal and syst emi c medi cat i ons (e. g. , br omi des, i odi des, t opi cal coal t ar
pr oduct s, andr ogens, phenyt oi n, pr ogest i ns, l i t hi um, cor t i cost eroi ds) can be
comedogeni c and can make acne wor se or can i nduce acne-l i ke er upt i ons ( i . e. ,
acnei f or m l esi ons) .
b. Acnei f orm erupt i ons di f f er f r om t rue acne l esi ons i n t hat appar ent l y no comedo
f or ms, er upt i ons are usual l y acut e, and t he l esi ons usual l y ar e al l i n t he same st age
of devel opment .
2. St ress does not cause acne but may exacer bat e i t .
3. Di et. Ther e i s ver y l i t t l e evi dence t o suppor t a r el at i onshi p bet ween di et and
acne. Many di f f er ent f oods have been bl amed f or acne, f r om chocol at es and sweet s
t o shel l f i sh t o nut s and ot her f at t y f oods. Several st udi es have demonst r at ed t hat
chocoI ate does not af f ect acne. The maj or i t y of der mat ol ogi st s t oday make t he
f ol l owi ng recommendat i ons regar di ng di et .
a. The pat i ent shoul d be eat i ng a wel l -bal anced di et . As wi t h most ot her di seases,
and as a mat t er of good heal t h, excess f at s and si mpl e carbohydr at es shoul d be
avoi ded.
b. The pat i ent who i nsi st s t hat cert ai n f oods cause exacer bat i on of acne shoul d
pr obabl y avoi d t hose f oods.
4. Physi caI t rauma or i rri t at i on can pr omot e t he r upt ur e of pl ugged f ol l i cl es, whi ch
can pr oduce more i nf l ammat or y r eact i ons. Scrubbi ng t he f ace, wear i ng headbands,
cr adl i ng t he chi n wi t h t he hand, and pi cki ng at t he pi mpl es can cont ri but e t o t he
pr i mar y i nf l ammat i on process. Gent I e r egul ar washi ng wi t h soap and wat er can be
benef i ci al .
Table 30-1. Assessment of Acne Severity
Grade of
Acne Qualitative Description Quantitative Description
I Comedonal acne Comedones only. · 10 on Iace. none
on trunk. no scars; noninIlammatory
lesions only
II Papular acne 10-25 papules on Iace and trunk. mild
scarring; inIlammatory lesions · 5
mm in diameter
III
a
Pustular acne More than 25 pustules. moderate
scarring; size similar to papules but
with visible. purulent core
IV
a
Severe/persistent
pustulocystic acne
Nodules or cysts. extensive scarring.
inIlammatory lesions ~ 5 mm in
diameter
Recalcitrant severe
cystic acne
Extensive nodules/cysts
a
Some overlap with previous grade oI acne.
Reprinted with permission Irom Berardi RR. Handbook of Nonprescription
Drugs. An Interactive Approach to Self-Care. 14th ed. Washington. DC.
American Pharmaceutical Association. 2004:916.

P. 632


5. Cosmeti cs. Some cosmet i c bases and cert ai n cosmet i c i ngredi ent s ar e
comedogeni c ( e. g. , l anol i ns, pet r ol eum bases, cocoa but t er ). Pr eparat i ons such as
cl eansi ng cr eams, sunt an oi l s, and heavy f oundat i ons shoul d be avoi ded.
6. Menst ruaI cycI e. Some women may not i ce f l ar e- ups of acne duri ng t he
pr emenst r ual part of t he cycl e. Fl uct uat i ons i n t he l evel of progest er one ar e t he
pr obabl e cause.
7. Envi ronmentaI fact ors. Ver y humi d envi ronment s or heavy sweat i ng l ead t o
ker at i n hydr at i on, swel l i ng, and a decr ease i n t he si ze of t he pi l osebaceous f ol l i cl e
or i f i ce, whi ch r esul t s i n duct obst ruct i on. The sun, as wel l as ar t i f i ci al ul t r avi ol et
( UV) l i ght , can hel p acne by dr yi ng and peel i ng t he ski n, but bot h al so can
aggravat e acne.
E. Treat ment and care
1. GeneraI
a. Most pat i ent s can be t r eat ed successf ul l y wi t h ei t her t opi cal l y or syst emi cal l y
admi ni st er ed medi cat i ons or bot h. Acne of t en i mpr oves when pat i ent s reach t hei r
ear l y 20s.
b. Even t he most ef f ect i ve t r eat ment progr ams may t ake sever al weeks t o pr oduce
any cl i ni cal i mpr ovement . Thi s aspect must be emphasi zed.
c. Peopl e af f ect ed wi t h acne shoul d avoi d anyt hi ng t hat seems t o wor sen t he
condi t i on ( e. g. , cosmet i cs, cl ot hi ng, cradl i ng t he chi n wi t h t he hand) .
d. The number and t ype of l esi ons shoul d be r oughl y det ermi ned t o assess f ur t her
t her apeut i c responses.
e. SeI f - t reat ment wi t h OTC agent s i s appr opri at e onl y f or pat i ent s wi t h
noni nfI ammator y grade I acne of mi l d t o moderat e severi t y.
2. CI eansi ng recommendat i ons
a. Because many acne pat i ent s have oi l y ski n, gent I e cI eansi ng t wo t o t hr ee t i mes
dai l y i s r ecommended f or r emovi ng excess oi l .
b. Acne l esi ons cannot be scr ubbed away. Compul si ve scrubbi ng may act ual l y
wor sen t he acne by di srupt i ng t he f ol l i cul ar wal l s and t hus set t i ng t he st age f or
i nf l ammat i on.
c. Mi l d f aci al soaps, such as Dove, Neut r ogena, and Pur pose, shoul d be used t o
cl eanse t he ski n.
d. Medi cat ed soaps cont ai ni ng sul f ur , resor ci nol , or sal i cyl i c aci d ar e of l i t t l e val ue
because t he medi cat i on r i nses away r at her t han penet r at es t he f ol l i cl e.
e. Pat i ent s wi t h mi l d comedonal acne mi ght f i nd benef i t f rom cl eanser s cont ai ni ng
pumi ce, pol yet hyl ene, or al umi num oxi de par t i cl es ( e. g. , Br asi vol ) . However ,
pat i ent s wi t h i nf l ammat or y acne or sensi t i ve ski n shoul d avoi d t hese pr oduct s.
3. Approaches t o t r eat ment depend on t he sever i t y of t he condi t i on. Al t hough acne
cannot be cur ed, most cases can be managed successf ul l y wi t h t opi cal t reat ment
al one. Based on t he pat hogenesi s of t he condi t i on, pot ent i al met hods i ncl ude
a. UnbI ocki ng t he sebaceous duct so t hat t he cont ent s can be easi l y expel l ed
b. Decreasi ng t he amount of sebum t hat i s secr et ed
c. Changi ng t he composi t i on of t he sebum t o make i t l ess i r r i t at i ng by decr easi ng
t he popul at i on of P. acnes
4. Nonprescri pt i on t opi caI medi cati ons
a. BenzoyI peroxi de ( 2. 5%- 10%) ÷f or exampl e, Cl earasi l Maxi mum St rengt h Acne
Tr eat ment Cream, PanOxyl Aqua Gel ( U. S. Food and Drug Admi ni st r at i on [ FDA]
cat egor y 3) ÷has t r adi t i onal l y been recogni zed as t he most ef f ect i ve t opi cal OTC
agent f or acne, and many OTC acne product s cont ai n i t . However , t he l at est
monograph f r om t he FDA changed t he st at us of benzoyl per oxi de f rom cat egor y 1
( gener al l y r ecogni zed as saf e and ef f ect i ve) t o cat egor y 3Ì , i ndi cat i ng t hat more
dat a ar e needed t o prove i t s saf et y i n r egar d t o l ong- t erm phot ocar ci nogeni c ef f ect s.
Mar ket i ng of t hi s agent i s per mi t t ed pendi ng f i nal eval uat i on of i t s t umori geni c
pot ent i al .
( 1) Ef f ect s. Benzoyl peroxi de has i rr i t ant , dr yi ng, peel i ng, comedol yt i c, and
ant i bact eri al ef f ect s. The cl i ni cal response shows onl y mi ni mal di f f erences among
t he 2. 5%, 5%, and 10% concent r at i ons.
( a) A benefi ci aI ef f ect shoul d be not i ced wi t hi n about 2 weeks, but t he usual l engt h
of a t her apeut i c t r i al i s 6- 8 weeks.
( b) As f or adverse ef fect s, benzoyl per oxi de may cause a bur ni ng or st i ngi ng
sensat i on, whi ch gr adual l y di sappear s. Most of t he adverse ef f ect s f r om t hi s agent
r el at e t o i t s t her apeut i c ef f ect of i r r i t at i ng and dryi ng t he ski n. For t hi s r eason,
P. 633

t he l owest concent rat i on avai l abl e shoul d be chosen i ni t i al l y. About 2. 5% of pat i ent s
wi l l deveI op a contact dermat i ti s wi t h i t s use.
( c) The vehi cl e f or t he benzoyl per oxi de i s al so i mport ant i n i t s over al l act i vi t y. The
al cohol gel vehi cl e t ends t o be more ef f ect i ve t han t he l ot i on or cr eam f ormul at i ons.
( d) Benzoyl per oxi de can di scol or cer t ai n t ypes of f abr i c or cl ot hi ng mat er i al and
can al so bl each hai r .
( 2) Mechani sm of act i on. Benzoyl per oxi de has a dual mode of act i on, so i t i s
ef f ect i ve agai nst bot h i nf l ammat or y and noni nf l ammat or y acne.
( a) Benzoyl per oxi de decomposes t o rel ease oxygen, whi ch i s l et hal t o t he P. acnes
anaer obe.
( b) As an i r ri t ant , i t i ncr eases t he t ur nover rat e of epi t hel i al cel l s, resul t i ng i n
i ncreased sl oughi ng and pr omot i ng of r esol ut i on of comedones.
( 3) AppI i cat i on
( a) The af f ect ed ar ea shoul d be washed wi t h mi l d soap and wat er , t hen gent l y
pat t ed dr y.
( b) The product shoul d be massaged gent l y i nt o t he ski n, avoi di ng t he eyes, mout h,
l i ps, and i nsi de of t he nose.
( c) The pr oduct can be appl i ed at ni ght , l ef t on f or 15 or 20 mi n t o t est sensi t i vi t y,
t hen washed of f .
( d) Ì f no excessi ve i r r i t at i on devel ops, appl y once dai l y f or t he f i r st f ew days.
( e) Ì f dr yi ng, redness, or peel i ng does not occur i n 3 days, i ncr ease appl i cat i on t o
t wi ce dai l y.
( f ) Ì f pat i ent s have t o use benzoyl per oxi de dur i ng t he day, advi se t hem t o use a
sunscr een and avoi d unnecessar y sun exposur e.
b. SaI i cyI i c aci d ( 0. 5%-2%) , an i r r i t ant ker at ol yt i c agent , resul t s i n i ncreased
t ur nover of t he epi t hel i al l i ni ng (cat egor y 1) . Thr ough t hi s ef f ect , sal i cyl i c aci d
pr obabl y pr omot es t he penet rat i on of ot her acne pr oduct s.
c. SuI f ur (3%- 8%) , suI fur ( 3%- 8%) combi ned wi th resorci noI ( 2%) , or resorci noI
monoacetat e ( 3%)÷f or exampl e, Cl ear asi l Adul t Car e Acne Tr eat ment Cream,
Acnomel (cat egor y 1)
( 1) Sul f ur i s a ker at ol yt i c agent and has ant i bact er i al act i ons.
( 2) Sul f ur t r adi t i onal l y has been r ecogni zed as a l ess desi rabl e pr oduct because i t
may be acnegeni c wi t h cont i nued use, and i t has an of f ensi ve col or and odor .
d. Resorci noI (as a si ngl e agent - cat egor y 2) i s a kerat ol yt i c agent t hat has been
r ecogni zed as saf e and ef f ect i ve ( cat egor y 1) agai nst acne when t he agent i s
combi ned wi t h suI fur.
F. Prescri pti on medi cati ons, both t opi caI and syst emi c, ar e i ncl uded her e f or
compl et eness and t o put i nt o per spect i ve how OTC agent s f i t i nt o acne t her apy.
1. Topi caI prescri pt i on agents
a. Treti noi n ( vi t ami n A aci d, t rans- r et i noi c aci d, Ret i n- A) i ncreases t he t ur nover
r at e of nonadher i ng hor ny cel l s i n t he f ol l i cul ar canal , whi ch r esul t s i n comedo
cl ear i ng and i nhi bi t s new comedo devel opment .
( 1) Ef f ect i veness. Tr et i noi n i s probabl y t he most ef f ect i ve t opi cal agent f or acne,
especi al l y acne char act er i zed by comedones. Ì t i s best used f or noni nf I ammator y
acne. Tr et i noi n al so may be used i n combi nat i on wi t h ant i bi ot i cs or benzoyl per oxi de
f or management of i nf l ammat or y acne.
( 2) Si de eff ects. Because of i t s i rr i t ant pr oper t i es, t ret i noi n can cause excessi ve
i rri t at i on, er yt hema, peeI i ng, and i ncr eased ri sk f or severe sunburn. Ther e may
be an i ni t i al exacerbat i on of t he acne ( pust ul ar f l ar e) at 2- 4 weeks, but usual l y by 8
weeks, t he pat i ent wi l l see marked i mpr ovement . Because t hi s agent may cause
phot osensi t i vi t y, i t shoul d general l y be appl i ed at ni ght .
( 3) AppI i cat i on. The cr eam f ormul at i on of t r et i noi n, whi ch i s l ess i r ri t at i ng t han t he
gel f orm shoul d be used i ni t i al l y f or pat i ent s wi t h dr yer ski n. The pat i ent wi t h ver y
oi l y ski n may do wel l i ni t i al l y wi t h t he gel f orm. The r et i noi ds shoul d be appl i ed 30
mi n af t er washi ng because moi st ur e on t he ski n i ncr eases absorpt i on and i r r i t at i on.
To mi ni mi ze i rr i t at i on, i ni t i al l y such a pr oduct can be appl i ed ever y ot her day f or 2
weeks, t hen dai l y. Ot her i r r i t at i ng subst ances, such as st rong abr asi ve cl eaner s and
ast ri ngent s, shoul d be avoi ded dur i ng t reat ment wi t h t r et i noi n. Newer mi cr osi ze
r ef ormul at i ons of t hi s agent ( Ret i n- A Mi cr o, Avi t a) ar e l ess i r ri t at i ng.
P. 634


b. AdapaI ene ( Di f f er i n) i s a t opi cal r et i noi d-l i ke compound t hat i s dosed once dai l y.
Ì t can be appl i ed i n t he mor ni ng because of no phot odegr adat i on, and i t has l ess
pot ent i al f or phot osensi t i vi t y.
( 1) Ef f ect i veness. Ì t appear s t o cause l ess i r r i t at i on t han t r et i noi n wi t h equi val ent
ef f i cacy. Ther apeut i c r esul t s shoul d be not i ced i n 8- 12 weeks. Ì t can be used as an
al t er nat i ve t o t ret i noi n i n i ndi vi dual s wi t h mi l d t o moder at e acne.
( 2) Si de eff ects. The same pr ecaut i ons t hat appl y t o t r et i noi n appl y al so f or
adapal ene.
c. Tazarot ene geI and cream ( Tazor ac) i s a ret i noi d pr odr ug f or mi l d t o moderat el y
sever e f aci al acne t hat i s appl i ed once dai l y i n t he eveni ng. Ì t has si mi l ar ef f i cacy
and pr ecaut i ons as t ret i noi n, and t he dose- r el at ed adverse ef fects i ncl ude i t chi ng,
bur ni ng, st i ngi ng, and eryt hema ( r edness) . The gel f or m appear s t o be mor e
i r r i t at i ng t han t ret i noi n. A pust ul ar f l ar e may occur at about 10-14 days af t er t hi s
pr oduct i s begun.
d. Topi caI ant i bi ot i cs: er yt hromyci n ( Er yder m), cI i ndamyci n ( Cl eoci n-T) and
t et racycI i ne. These t opi cal ant i bi ot i cs ar e most ef f ect i ve when used i n combi nat i on
wi t h benzoyl peroxi de or t opi cal ret i noi ds. Combi nat i on pr oduct s cont ai ni ng benzoyl
per oxi de and er yt hromyci n ( Benzamyci n) and benzoyl per oxi de and cl i ndamyci n
( BenzaCl i n) ar e al so avai l abl e. When t hese ant i bi ot i cs ar e used al one, bact eri al
r esi st ance occurs rapi dl y. Benzoyl peroxi de use i n combi nat i on wi t h t hese
ant i bi ot i cs pr ot ect s agai nst t hi s resi st ance.
( 1) Mechani sm of act i on. The mechani sm of act i on appar ent l y i nvol ves suppressi on
of t he P. acnes or gani sm, whi ch i n t urn mi ni mi zes t he i nf l ammat or y r esponse due t o
t he acne.
( 2) AppI i cat i on. These ant i bi ot i cs ar e appl i ed di r ect l y t o acne si t es, t hus mi ni mi zi ng
ser i ous si de ef f ect s f rom or al admi ni st rat i on.
( 3) Si de eff ects. There ar e mi ni maI si de ef f ect s t o t hese t opi cal l y appl i ed
ant i bi ot i cs. Mi I d burni ng or i rri tat i on may occur . Al t hough dai l y t opi cal
CI i ndamyci n does not pr oduce det ect abl e l evel s i n t he ur i ne af t er 8 weeks of
admi ni st rat i on, t her e i s a pot ent i al r i sk of pseudomembranous coI i ti s.
Tet racycI i ne can cause a yeI I ow st ai ni ng of t he ski n.
e. AzeI ai c aci d ( Azel ex) and sodi um suI f acet ami de and suI fur are addi t i onal
t opi cal agent s t hat are l ess ef f ect i ve t han t he ot her t opi cal prescr i pt i on agent s.
These agent s mi ght be used when ot hers ar e not t ol er at ed or as adj unct s t o ot her
t her api es.
2. Syst emi c prescri pt i on agent s
a. OraI ant i bi ot i cs/ ant i -i nf ecti ves ar e t he most ef f ect i ve agai nst i nf l ammat or y
l esi ons because t hey suppr ess P. acnes. They may be used when t opi cal
combi nat i ons ar e not t ol er at ed or have f ai l ed. Oral ant i bi ot i cs have an onset of
act i on of 3- 4 weeks. They ar e prescr i bed f or dai l y use over 4- 6 mont hs and t hen
t apered and ul t i mat el y di scont i nued wi t h acne i mpr ovement . Ant i bi ot i cs do not af f ect
exi st i ng l esi ons, but pr event f ut ure l esi ons t hr ough t hi s ef f ect . P. acnes resi st ance
t o ant i bi ot i c t her apy has become an i ncreasi ng probl em; er yt hromyci n r esi st ance i s
t he most commonl y r epor t ed, and mi nocycl i ne resi st ance i s r eport ed r ar el y. As
not ed previ ousl y, concomi t ant admi ni st r at i on of benzoyl peroxi de may decr ease t he
i nci dence of r esi st ance.
( 1) Tet racycI i ne i s t he most f requent I y used or al ant i bi ot i c f or acne. Ì t i s pr ef er r ed
because of i t s ef f ect i veness, l ow t oxi ci t y, and l ow cost . Thi s agent shoul d be t aken
on an empt y st omach; f ood, ant aci ds, i r on, and dai r y product s decrease absorpt i on.
The t et racycl i nes al so have di rect ant i -i nf l ammat or y ef f ect s i n acne.
( a) I ni t i aI doses are 250 mg, 2-4 t i mes dai l y, gradual l y r educed t o a mai nt enance
dose of about 250 mg per day.
( b) Si de ef fects. The mor e common adverse ef f ect s i ncl ude upset st omach, vagi nal
moni l i asi s, and phot osensi t i vi t y.
( 2) Er yt hromyci n ( E- Myci n) may be used as an al t er nat i ve t o t et r acycl i ne.
( a) I ni t i aI doses r ange f r om 500 t o 2000 mg per day i n di vi ded doses. A
mai nt enance dose r anges f rom 250 t o 500 mg per day.
( b) Si de ef fects. The pr i mar y si de ef f ect associ at ed wi t h er yt hr omyci n i s
gast r oi nt est i nal di st r ess.
( 3) Mi nocycI i ne ( Mi noci n) or doxycycI i ne ( Vi bramyci n) . Ei t her of t hese agent s can
be t aken i n doses of 50-200 mg per day. Because of gr eat er l i pi d sol ubi l i t y and
enhanced penet rat i on i nt o sebaceous f ol l i cl es, t hese agent s may be usef ul f or
r ef r act or y cases. Ei t her can be t aken i f bact er i al r esi st ance i s suspect ed t o
er yt hr omyci n or i f i nt ol erabl e gast ri c i r ri t at i on occur s af t er oral t et racycl i ne. These
t wo agent s can be t aken wi t h f ood. Si de ef f ect s t o mi nocycl i ne, i ncl udi ng di zzi ness
or ver t i go and headache, di scol orat i on
P. 635

of ski n and vi scer al t i ssue, and dr ug- i nduced l upus er yt hemat osus, l i mi t t he use of
t hi s agent . Doxycycl i ne may be phot osensi t i zi ng and shoul d be swal l owed wi t h
adequat e f l ui ds t o pr event esophageal ul cer at i ons.
( 4) Tri met hopri m- suI f amet hoxazoI e ( Bact ri m, Sept ra) has been used successf ul l y
i n pat i ent s wi t h acne resi st ant t o er yt hr omyci n or t et racycl i nes. Mi nocycl i ne and
doxycycl i ne ar e pr ef er red over t hi s dr ug combi nat i on because of i t s si de-ef f ect
pr of i l e. OraI cI i ndamyci n ( Cl eoci n) i s used r arel y because of t he ri sk of
pseudomembranous col i t i s.
b. OraI i sot ret i noi n ( Accut ane) i s a vi t ami n A der i vat i ve i ndi cat ed f or severe
noduI ocyst i c acne. A si ngl e course of t herapy resul t s i n a l ong- t er m st abl e
r emi ssi on i n > 80% of pat i ent s.
( 1) Mechani sm of act i on. Al t hough t he exact mechani sm i s unknown, i sot r et i noi n
decreases sebum pr oduct i on and ker at i ni zat i on, and i t r educes t he popul at i on of P.
acnes.
( 2) Dosage. Tr eat ment i s usual l y begun wi t h a dai l y dose of 0. 5 mg/ kg and
i ncreased t o 1 mg/ kg gi ven i n t wo di vi ded doses wi t h f ood f or t he usual dur at i on of
20 weeks. A mi croni zed f or mul at i on al l ows f or l ower once dai l y dosi ng wi t h no
r egard t o f ood i nt ake.
( 3) Si de eff ects i ncl ude
( a) Mucocut aneous dr yness. Chei l i t i s (i . e. , i nf l ammat i on of t he l i ps) , dr yness of
t he nasal mucosa, and f aci al dermat i t i s may occur wi t h i sot r et i noi n use. These
ef f ect s can be t r eat ed wi t h t opi cal l ubri cant s. Dr yness of t he eyes can al so occur ,
so peopl e usi ng i sot r et i noi n shoul d not wear cont act l enses.
( b) EI evated serum I eveI s. Ì sot r et i noi n may el evat e serum t r i gl ycer i des and
chol est erol , as wel l as l i ver enzymes.
( c) Bi rt h defect s. Ì sot ret i noi n i s a pot ent t erat ogen and shoul d not be gi ven t o
pr egnant women. A st ri ct r i sk management pr ogr am f or i sot r et i noi n use r equi res
physi ci ans t o r egi st er pat i ent s t o document negat i ve pr egnancy t est s bef or e use.
Physi ci ans who pr escr i be t hi s agent and pharmaci es t hat di spense i t must be
r egi st er ed i n an el ect r oni c FDA syst em.
( d) Psychi at ri c ef fect s. Ther e have been repor t s of depressi on, sui ci dal behavi or ,
and sui ci de. Dat a ar e i nadequat e t o est abl i sh a causal r el at i onshi p bet ween
i sot r et i noi n admi ni st r at i on and depressi on and sui ci de. Thi s i nf ormat i on must be
t aken i n t he cont ext t hat t eenager s wi t h acne may of t en be depressed r el at ed t o
t hei r appear ance.
c. Ant i androgens and hormones
( 1) Est rogens can decr ease sebum pr oduct i on t hr ough an ant i androgeni c ef f ect .
( 2) Some pr ogest i n agent s i n or al cont racept i ves ( e. g. , nor et hi ndr one, norgest r el )
have androgeni c act i vi t y t hat can st i mul at e sebum secret i on r esul t i ng i n acne. One
of t he pr ogest i ns, norgest i mat e, i s mi ni mal l y andr ogeni c, and when i t i s combi ned
wi t h et hi nyI est radi oI as a t r i phasi c combi nat i on or al cont racept i ve agent ( Or t ho
Tr i - Cycl en) , i t i s ef f ect i ve i n t he t reat ment of moder at e acne i n some women and i s
FDA appr oved f or such. Noret hi ndrone acet ate/ et hi nyI est radi oI ( Est r ost ep) i s
al so FDA appr oved f or acne.
( 3) Spi ronoI act one ( AI dact one) i s an or al ant i andr ogen whi ch act s t o decr ease
sebum pr oduct i on and may be used on a l i mi t ed basi s.
( 4) Cort i costeroi ds. Al t hough cor t i cost er oi ds have been i mpl i cat ed as causi ng
acne, t hey al so can be used t o t r eat sever e acne. Ì nt ral esi onal i nj ect i ons of
t r i amci nol one and syst emi c cor t i cost er oi ds have been used f or sever e i nf l ammat or y
acne and severe cyst i c acne, r espect i vel y. Predni sone ( or i t s equi val ent ) i n doses of
20 mg per day or hi gher may be used f or a shor t per i od of t i me t o qui ckl y i mprove
acne f or i mpor t ant event s l i ke a weddi ng. Topi cal cort i cost eroi ds ar e not ef f ect i ve.
III. SUNLIGHT, SUNSCREENS, AND SUNTAN PRODUCTS
A. I nt roduct i on. Overexposur e t o sunl i ght damages ski n. A sunt an, whi ch has
t r adi t i onal l y been associ at ed wi t h heal t h, i s act ual l y a r esponse t o i nj ur y. Of t he
t hr ee t ypes of sol ar radi at i on, onl y t he UV spect rum pr oduces sunbur n and sunt an.
1. The UV spect rum r anges f r om 200 t o 400 nanomet ers ( nm) . Nat ur al and art i f i ci al
UV l i ght i s f ur t her subdi vi ded i nt o t hr ee bands.
P. 636


a. UVA ( 320-400 nm) can cause t he ski n t o t an, and i t t ends t o be weak i n causi ng
t he ski n t o redden. UVA i s about 1000 t i mes l ess pot ent t han a compar abl e dose of
UVB i n causi ng er yt hema, but i t i s onl y sl i ght l y bl ocked out by t he ozone l ayer and
r eaches t he ear t h' s surf ace i n 10- 100 t i mes t he amount of UVB. Some have
pr oposed t hat UVA be f ur t her subdi vi ded i nt o UVA Ì ( 340- 400 nm) and UVA Ì Ì (320-
340 nm). UVA Ì i s l ess er yt hr ogeni c and mel anogeni c t han UVA Ì Ì or UVB. UVA Ì Ì i s
si mi l ar i n ef f ect t o UVB.
( 1) Uses. UVA i s of t en used i n t anni ng boot hs and i n psor al en pl us UVA (PUVA)
t r eat ment of psori asi s.
( 2) Di sadvant ages. UVA i s r esponsi bl e f or many phot osensi t i vi t y r eact i ons,
phot oagi ng, and photodermatoses. UVA r ays can al so penet rat e deepI y i nt o t he
dermi s and augment t he cancer ous ef f ect s of UVB r ays.
b. UVB ( 290-320 nm) causes t he usuaI sunburn reacti on and st i mul at es t anni ng.
Ì t has l ong been associ at ed wi t h sunl i ght ski n damage, i ncl udi ng t he vari ous ski n
cancers. Ì t i s t he most er yt hrogeni c and meI anogeni c of t he t hr ee UV r adi at i on
bands. Smal l amount s of t hi s radi at i on ar e r equi red f or nor mal vi tami n D synt hesi s
i n t he ski n.
c. UVC (200- 290 nm) does not r each t he ear t h' s sur f ace because most of i t i s
absor bed by t he ozone l ayer . Ar t i f i ci al UVC sources ( e. g. , germi ci dal and mercur y
ar c l amps) can emi t t hi s r adi at i on.
2. The vi si bI e spect rum ( 400- 770 nm) pr oduces t he "br i ght ness¨ of t he sun.
3. The i nf rared spect rum ( 770- 1800 nm) produces t he " war mt h¨ of t he sun.
B. Sunburn and sunt an
1. Sunburn i s general l y a superf i ci aI burn i nvoI vi ng t he epi dermi s. Thi s l ayer i s
r api dl y r epai r ed whi l e ol d cel l s ar e bei ng sl oughed of f i n a process cal l ed peeI i ng.
The newl y f or med ski n i s t hi cker and of f er s prot ect i on f or t he l ower der mal l ayer s.
a. NormaI sequence af ter mi I d t o moderate sunI i ght UV radi at i on ( UVR)
exposure
( 1) Er yt hema occur s wi t hi n 20- 30 mi n as a resul t of oxi dat i on of bl eached mel ani n
and di l at i on of dermal venul es.
( 2) The i ni t i al er yt hema rapi dl y f ades, and t r ue sunburn er yt hema begi ns 2- 8 hr af t er
i ni t i al exposur e t o t he sun.
( 3) Di l at i on of t he ar t er i ol es r esul t s i n i ncr eased vascul ar permeabi l i t y, l ocal i zed
edema, and pai n, whi ch become maxi mal af t er 14- 20 hr and l ast 24-72 hr.
b. Mani festat i ons range f r om mi l d ( a sl i ght reddeni ng of t he ski n) t o sever e
( f or mat i on of bl i st er s and desquamat i on) . Ì f t he ef f ect i s sever e, t he pat i ent may
exper i ence pai n, swel l i ng, and bl i st er i ng. Fever , chi l l s, and nausea may al so
devel op, as wel l as pr ost r at i on, whi ch i s r el at ed t o excessi ve synt hesi s and
di f f usi on of pr ost agl andi ns.
2. Sunt an i s t he r esul t of t wo pr ocesses:
a. Oxi dat i on of meI ani n, whi ch i s al r eady pr esent i n t he epi der mi s
b. St i muI at i on of meI anocyt es t o produce addi t i onal mel ani n, whi ch i s
subsequent l y oxi di zed on f urt her exposure t o sunl i ght
( 1) Wi t h i ncr eased mel ani n pr oduct i on, t he mel anocyt es i nt roduce t he pi gment i nt o
ker at i n- pr oduci ng cel l s, whi ch gradual l y become dar kened kerat i n and a f ul l sunt an
i n 2- 10 days.
( 2) Tanni ng i ncr eases t ol er ance t o addi t i onal sunl i ght and r educes t he l i kel i hood of
subsequent bur ni ng. However , dar k ski n i s not t ot al l y i mmune t o sunburn.
C. Fact ors af f ect i ng exposure t o UVR
1. Ti me of day and season. The gr eat est exposur e t o har mf ul UVB r ays occurs
bet ween 10 A. M. and 4 P. M. i n mi dsummer. UVA r ays ar e f ai rl y cont i nuous
t hr oughout t he day and season.
2. AI t i t ude. Sunburn i s mor e l i kel y t o occur at hi gh al t i t udes. UVB i nt ensi t y
i ncreases 4% wi t h each 1000- f t . i ncr ease i n al t i t ude.
3. Envi ronmentaI fact ors. At mospher i c condi t i ons ( e. g. , smog, haze, smoke) may
af f ect (i . e. , decr ease) t he amount of UVR reachi ng t he ski n. Al t hough di rect sunl i ght
gr eat l y r educes t he amount of UV exposur e needed t o produce a bur n, sunburn can
occur wi t hout i t . For exampl e, a sunbur n can al so devel op on a cl oudy day because
t her e i s some UVR penet r at i on t hr ough cl oud l ayer s ( 60%-80%) . However , t he
ref I ecti on of I i ght rays ( e. g. , by snow, sand, wat er ) gr eat l y i ncreases t he amount
of UV exposure t o sunI i ght .
4. Predi sposi ng f act ors. Peopl e wi t h f ai r ski n and l i ght hai r ar e at gr eat er r i sk f or
devel opi ng sunburn and ot her UVR ski n damage t han t hei r darker count erpar t s.
P. 637


D. Ot her react i ons t o sunI i ght ( UVR) exposure
1. Act i ni c kerat osi s i s a pr ecancerous condi t i on and may occur af t er many year s of
excessi ve exposure t o sunl i ght . Typi cal l y ar i si ng duri ng mi ddl e age or l at er , t hi s
di sor der mani f est s as a sharpl y demar cat ed, roughened, or hardened gr owt h, whi ch
may be f l at or r ai sed, and i t may pr ogr ess t o squamous ceI I carci noma.
2. Ski n cancer. Chr oni c over exposure t o sunl i ght may l ead t o squamous ceI I
carci noma, basaI ceI I carci noma, or maI i gnant meI anoma.
a. Squamous ceI I carci noma. Lesi ons usual l y appear as t hi ckened, rough, scal y
pat ches, whi ch can bl eed, and most commonl y devel ops f r om act i ni c kerat osi s. Ì t
account s f or about 15% of ski n cancers.
b. BasaI ceI I carci noma. Thi s i s t he most common of al l ski n cancer s and account s
f or about 80% of ski n cancers. Ì t may appear as pearl y or t r ansl ucent bumps and
or i gi nat es i n t he basal cel l s.
c. MaI i gnant meI anoma. Mal i gnant mel anoma ori gi nat es f rom mel anocyt es and i s
t he deadl i est f or m of ski n cancer , and i t s i nci dence has been i ncr easi ng. Mol es
shoul d be wat ched f or i ndi cat i ons of mal i gnancy÷t he ABCDs are
( 1) Asymmet r i cal shape
( 2) Border i r r egul ar i t y
( 3) Col or t hat i s nonuni f or m
( 4) Di amet er > 6 mm.
d. Mal i gnant mel anoma f or mat i on may be associ at ed wi t h i nt ense, i nt ermi t t ent
over exposure t o t he sun ( sunburni ng) .
3. Drug-i nduced phot osensi ti vi t y react i ons
a. Types
( 1) Phot oaI I ergy react i ons occur when l i ght makes a dr ug become ant i geni c or act
as a hapt en (i . e. , a phot oal l er gen). These r eact i ons al so r equi re previ ous cont act
wi t h t he of f endi ng drug. Phot oal l er gy react i ons ar e r el at i vel y rare and are
associ at ed mor e f r equent l y wi t h t opi cal l y appl i ed agent s t han wi t h or al medi cat i ons.
( a) Occurrence of t hese r eact i ons i s not dose rel at ed. The pat i ent i s usual l y cross-
sensi t i ve wi t h chemi cal l y r el at ed compounds.
( b) Rashes ar e most promi nent on l i ght - exposed si t es ( i . e. , f ace, neck, f or earms,
back of hands) , and t hey usual l y occur , af t er an i ncubat i on per i od of 24- 48 hr of
combi ned drug and sun exposur e, as an i nt ensel y pr ur i t i c eczemat ous der mat i t i s (a
sever e r ash) .
( 2) Phot ot oxi c reacti ons occur when l i ght al t er s a drug t o a t oxi c f orm, whi ch
r esul t s i n t i ssue damage t hat i s i ndependent of an al l ergi c r esponse.
( a) Occurrence. These react i ons ar e usual l y dose r el at ed, and t he pat i ent usual l y
has no cross- sensi t i vi t y t o ot her agent s.
( b) Rashes of t en appear as an exagger at ed sunbur n and ar e usual l y conf i ned t o
ar eas of combi ned chemi cal and l i ght exposur e.
b. I mpI i cat ed drugs. Many dr ugs have been i mpl i cat ed i n causi ng phot oal l ergy and
phot ot oxi c react i ons: t hi azi des, t et racycl i nes, phenot hi azi nes, sul f onami des, and
even sunscr eens. Some dr ugs may produce bot h t ypes of react i ons.
c. Preventi on. St andar d sunscr eens do not al ways pr event phot osensi t i vi t y
r eact i ons caused by drugs. UV l i ght above 320 nm ( i . e. , UVA l i ght ) has been
i mpl i cat ed i n i nduci ng phot osensi t i vi t y react i ons, so a chemi cal or physi cal
sunscr een must cover t hi s spect rum ( see Ì Ì Ì . E. 2) .
4. Phot odermat oses are ski n condi t i ons t hat ar e t r i gger ed or wor sened by l i ght
wi t hi n speci f i c wavel engt hs. These condi t i ons i ncl ude pol ymorphous l i ght er upt i on
( PMLE) , l upus er yt hemat osus, and sol ar urt i car i a.
5. Phot oagi ng i s a ski n condi t i on t hat i s not merel y an accel erat i on of nor mal
agi ng. UVA r adi at i on i s t hought t o be i nvol ved. The ski n appears dr y, scal y, yel l ow,
and deepl y wr i nkl ed; i t i s al so t hi nner and more f r agi l e.
E. Sunscreen agents. Peopl e can prot ect t hei r ski n f r om harmf ul UVR by avoi di ng
exposur e t o sunl i ght and ot her sources of UVR, wear i ng pr ot ect i ve cl ot hi ng, and
appl yi ng sunscr een.
1. AppI i cat i on and generaI i nf ormat i on. Al l exposed ar eas shoul d be cover ed
evenl y and l i ber al l y ( 2 mg/ cm
2
, whi ch r equi res about 1 ounce of sunscr een per one
t ot al body appl i cat i on
P. 638

f or an average- si ze adul t i n a swi msui t ) wi t h sunscr een, opt i mal l y 30 mi n (2 hr f or
PABA and PABA est ers) bef ore sun exposure t o al l ow f or penet rat i on and bi ndi ng t o
t he ski n.
a. Subst ant i vi t y. Per spi r at i on, swi mmi ng, sand, t owel s, and cl ot hi ng t end t o r emove
sunscr een and may i ncr ease t he need f or r eappl i cat i on.
( 1) Subst ant i vi t y i s t he abi l i t y of a sunscr een f ormul at i on t o adher e t o t he ski n whi l e
swi mmi ng or perspi r i ng.
( 2) Wat er resi stant l abel i ng i ndi cat es t hat t he f or mul a ret ai ns i t s sun prot ect i on
f act or ( SPF) af t er 40 mi n of act i vi t y i n t he wat er , sweat i ng, or per spi ri ng.
( 3) Label i ng a product as ver y water resi stant i ndi cat es t hat t he pr oduct r et ai ns
SPF af t er 80 mi n of act i vi t y i n t he wat er , sweat i ng, or perspi r i ng.
b. Prot ect i on. Sunscreen pr oduct s var y wi del y i n t hei r abi l i t y t o prot ect agai nst
sunburn; t he SPF and UVA/ UVB r ay prot ect i on shoul d be not ed t o det ermi ne t he
l evel of pr ot ect i on. Mor eover , baby oi l , mi neral oi l , ol i ve oi l , and cocoa but t er ar e
not sunscr eens ( but ar e of t en used t o at t ai n a t an) .
( 1) SPF gi ves t he consumer a gui de f or det ermi ni ng how t he pr oduct wi l l pr ot ect t he
ski n f r om UV r ays, pr i nci pal l y UVB r ays. An SPF of 30 bl ocks about 97% of t he UVB
r ays. Sci ent i f i c evi dence shows a poi nt of di mi ni shi ng r et ur ns at l evel s > 30; any
benef i t s t hat mi ght be der i ved f rom usi ng sunscr eens wi t h an SPF > 30 are
negl i gi bl e. The FDA' s most r ecent monogr aph requi res sunscr eens wi t h an SPF > 30
t o use one col l ect i ve t erm " SPF 30 Pl us¨ or "30+. ¨ An SPF of at l east 15 f or most
i ndi vi dual s i s recommended by t he Ski n Cancer Foundat i on.
( a) Def i ni t i ons. A mi ni maI sun prot ecti on product has an SPF of 2 t o under 12; a
moderat e sun prot ect i on product has an SPF of 12 t o under 30; a hi gh sun
prot ecti on product has an SPF of 30 or above.
( b) Deri vat i on. SPF i s def i ned as t he mi ni maI eryt hema dose ( MED) of pr ot ect ed
ski n di vi ded by t he MED of unpr ot ect ed ski n. MED i s t he amount of sol ar r adi at i on
needed t o pr oduce mi ni mal ski n r edness.
( c) ExampI e. A per son who usual l y get s red af t er 20 mi n i n t he sun and want s t o
st ay i n t he sun f or 2 hr (120 mi n) shoul d appl y a sunscr een wi t h an SPF of 6 (120
mi n ÷ 20 mi n = SPF 6) . An SPF 6 product shoul d pr ovi de adequat e coverage,
pr ovi ded i t i s not washed of f (as f r om swi mmi ng) or di ssol ved by sweat . An SPF of
15 bl ocks approxi mat el y 93% of t he UVB r ays.
( d) Up unt i l now, t her e has been no generaI I y accept ed comparabI e term t hat
measures UVA prot ect i on, al t hough a f ew have been proposed (see bel ow) . One
maj or concern i s t hat peopl e may be st ayi ng out i n t he sun l onger when t hey use
sunscr een product s t hat have hi gh SPF val ues. Ì f i nadequat e UVA pr ot ect i on i s
pr ovi ded i n t hat product , t hese i ndi vi dual s may be exposi ng t hemsel ves t o ver y hi gh
amount s of UVA, wi t h t he pot ent i al f or si gni f i cant over exposure t o t hi s f orm of UV
r adi at i on.
( 2) Proposed FDA UVA Prot ect i on Rat i ng Syst em. Ì n August 2007, t he FDA
pr oposed a " consumer -f ri endl y¨ r at i ng syst em t o rat e sunscr een pr oduct s regardi ng
t hei r l evel of UVA pr ot ect i on usi ng a one t o f our st ars rat i ng. Ì f t he pr oduct does not
pr ovi de at l east a " one st ar ¨ pr ot ect i on, t hen " no UVA pr ot ect i on¨ woul d need t o be
not ed on t he l abel .
( a) One st ar: l ow UVA pr ot ect i on
( b) Two st ars: medi um UVA pr ot ect i on
( c) Three st ars: hi gh UVA pr ot ect i on
( d) Four stars: hi ghest UVA pr ot ect i on
I f approved, an addi ti onaI warni ng wouI d be requi red on sunscreen products:
" UV exposur e f r om t he sun i ncreases t he ri sk of ski n cancer , pr emat ur e ski n agi ng,
and ot her ski n damage. Ì t i s i mpor t ant t o decrease UV exposur e by l i mi t i ng t i me i n
t he sun, wear i ng pr ot ect i ve cl ot hi ng, and usi ng a sunscr een. ¨ SPF maxi mums, under
t hi s new pr oposed r ul e, woul d i ncrease f rom SPF 30+ t o SPF 50+.
( 3) Ski n cancer preventi on. Sunscreen appl i cat i on has been shown t o prevent
squamous cel l carci noma, but i t i s not absol ut el y conf i rmed t hat t hei r use pr event s
mel anoma. Ì n f act , some st udi es have f ound t hat i ndi vi dual s who r egul ar l y use
sunscr een have a hi gher r i sk of t hi s cancer ( perhaps because t hey can st ay out i n
t he sun l onger bef ore bur ni ng and t hus exper i ence l onger per i ods of sun exposur e) .
c. Sensi ti vi t y. Some peopl e may be hypersensi t i ve t o sunscr een agent s.
Di scont i nue use i f si gns of i r ri t at i on or a r ash occur . Cont act dermat i t i s may occur
wi t h some of t hese agent s.
P. 639

Ì f sensi t i ve t o benzocai ne, procai ne, sul f onami des, or t hi azi des, avoi d PABA or
PABA est ers.
d. Speci f i c i nf ormat i on
( 1) Do not use t hese pr oduct s on i nf ant s younger t han 6 mont hs of age ( t her e i s
concern about absor pt i on of t hese agent s) .
( 2) Do not use a product wi t h an SPF < 4 on chi l dr en younger t han 2 year s of age
( t here i s concern t hat an SPF < 4 wi l l not pr ovi de adequat e pr ot ect i on) .
( 3) Recommend sunscreen product s t hat are broad- spect r um sunscr eens ( i . e. , t hat
bl ock bot h UVB and UVA) .
2. The t wo basi c t ypes of sunscreen agent s ar e physi cal sun bl ocks and chemi cal
sunscr eens ( Tabl e 30-2).
a. Physi caI sun bI ocks ar e opaque f ormul at i ons t hat r ef l ect and scat t er up t o 99%
of l i ght i n bot h t he UV and vi si bl e spect r ums ( 290- 700 nm) . Exampl es i ncl ude
t i t ani um di oxi de and zi nc oxi de. These sun bl ocks are l ess cosmet i cal l y
accept abl e t han chemi cal sunscreens because t hey have a greasy appearance, but
t hey may be usef ul f or prot ect i ng smal l areas ( e. g. , t he nose) . These sun bl ocks ar e
al so usef ul f or phot osensi t i zat i on pr ot ect i on. Newer , mor e di l ut e versi ons of t i t ani um
di oxi de pr oduct s and mi cr of i ne, t r anspar ent f or ms of zi nc oxi de ar e mor e
cosmet i cal l y appeal i ng. Red pet r ol at um cover s a l esser spect rum (290- 365 nm) .
Table 30-2. Sunscreen Ingredients
Type Sunscreens
UV
Spectrum
(nm)
Concentrations
(º)
Chemical
Benzophenones UVA
and
UVB


Oxybenzone 270-
350
2-6

Dioxybenzone 260-
380
a

3
PABA and PABA esters UVB

P-aminobenzoic acid 260-
313
5-15

Ethyl dihydroxy propyl
PABA
280-
330
1-5

Padimate O (octyl dimethyl
PABA)
290-
315
1.4-8

Glyceryl PABA 264-
315
2-3
Cinnamates UVB
b


Cinoxate 270-
328
1-3

Ethylhexyl-p-
methoxycinnamate
290-
320
2-7.5

Octocrylene 250-
360
7-10

Octyl methoxycinnamate 290-
320

Salicvlates UVB
c


Ethylhexyl salicylate 280-
320
3-5

Homosalate 295-
315
4-15

Octyl salicylate 280-
320
3-5
Miscellaneous UVB

Menthyl anthranilate
(meradimate)
260-
380
d

3.5-5

Digalloyl trioleate 270-
320
2-5
Avobenzone (butyl UVA 3
methoxydibenzoylmethane;
Parsol 1789)
320-
400

Phenylbenzimidazole
sulIonic acid
290-
320
4
Physical
Titanium dioxide 290-
700
2-25
Red petrolatum 290-
365
e

30-100
Zinc oxide 290-
700

a
Values available when used in combination with other screens.

b
Some UVA spectrum.

c
Primarily UVB. but has about one third the absorbency oI PABA.

d
Values are concentrations higher than normally Iound in nonprescription
drugs.

e
At 334 nm. 16° UV radiation is transmitted; at 365 nm. 58° is
transmitted.
Reprinted with permission Irom Drug Facts and Comparisons. 60th ed. St.
Louis. MO: Wolters Kluwer. 2005.

P. 640


b. Chemi caI sunscreens act by absor bi ng a speci f i c port i on of t he UV l i ght
spect rum t o keep i t f r om penet r at i ng t he ski n. They can be cat egor i zed on t he basi s
of t hei r spect r a of UVR bl ockage and basi c chemi cal cl assi f i cat i on. Fi ve mai n
gr oups of chemi cal sunscr eens ar e avai l abl e.
( 1) PABA and PABA est ers pri mar i l y absorb UVB r ays. Exampl es are p-
ami nobenzoi c aci d, padi mat e O, and gl ycer yl PABA.
( 2) Ci nnamat es pri mar i l y absor b UVB r ays. Exampl es ar e ci noxat e and oct yl
met hoxyci nnamat e.
( 3) SaI i cyI at es pr i mari l y absor b UVB r ays. Exampl es are et hyl hexyl sal i cyl at e and
homosal at e.
( 4) Benzophenones absor b UVB rays and somet i mes ext end i nt o t he UVA r ange.
Exampl es ar e oxybenzone and di oxybenzone. Because of t hei r ext ensi on i nt o t he
UVA r ange, t hey ar e somewhat pr ot ect i ve agai nst phot osensi t i vi t y r eact i ons.
( 5) Di benzoyI met hane deri vat i ves. Avobenzone ( ParsoI 1789) or but yl
met hoxydi benzoyl met hane, pr ovi des cover age over t he ent i r e UVA r ange al t hough
i t s absorbance decr eases dramat i cal l y at 370 nm. Phot osensi t i vi t y r eact i ons f r om
medi cat i ons may not be compl et el y pr event ed i n t he 370-400 nm r ange. Ì n
combi nat i on wi t h ot her agent s t hat cover t he UVB r ange, reasonabl e pr ot ect i on f or
bot h t he UVA and UVB ranges can be achi eved. Ì t i s t he onl y avai l abl e agent t hat
bl ocks UVA wavel engt hs up t o 400 nm.
( 6) Ot her chemi caI sunscreens. PhenyI benzi mi dazoI e suI f oni c aci d does not
mat ch up wi t h any of t he cl asses above. Ì t covers j ust t he UVB r ange 290-320 nm.
( 7) A new agent ecamsuI e, i ncor por at ed i nt o a combi nat i on pr oduct ( Ant hel i os SX)
wi t h avobenzone and oct ocr yl ene was appr oved by t he FDA i n Jul y, 2006. The
combi nat i on prot ect s agai nst bot h UVA and UVB.
c. OTC sunscreen product s. Most sunscreen product s on t he market cont ai n
combi nat i ons of t wo or mor e of t he cl asses of chemi cal sunscr een agent s descr i bed
i n pr ecedi ng sect i ons. To get adequat e UVA pr ot ect i on, choose a pr oduct wi t h
avobenzone or a product wi t h t i t ani um di oxi de or zi nc oxi de.
F. Speci aI agents of i nterest
1. Di hydroxyacet one ( DHA) i s a chemi cal agent t hat darkens t he ski n by i nt er act i ng
wi t h kerat i n i n t he st r at um cor neum t o produce an art i fi ci aI sunt an. Ì t provi des no
prot ecti on agai nst UV rays and may not produce a nat ur al - l ooki ng t an. Thi s i s
known as an art i f i ci al t an ext ender. DHA must be appl i ed evenl y. Ì f an art i f i ci al
sunt an i s achi eved wi t h t hi s chemi cal , i t wear s of f i n a f ew days. Ì n addi t i on, i t can
di scol or hai r and cl ot hi ng.
2. Bronzers ar e ar t i f i ci al t an pr oduct s t hat st ai n t he ski n. They ar e f ul l y washabl e
wi t h soap and wat er and wi l l not prot ect agai nst sol ar radi at i on.
3. ß- Carot ene, a vi t ami n A pr ecursor, may produce ski n col orat i on when i ngest ed
or al l y. Al t hough 8- car ot ene i s pr ot ect i ve agai nst some f or ms of abnor mal
phot osensi t i vi t y ( e. g. , eryt hr opoi et i c prot opor phyr i a) , i t has not been shown t o
pr ot ect agai nst sunbur n i n normal i ndi vi dual s.
4. Cant haxanthi n i s a car ot enoi d (pr ovi t ami n A) . Ì t has been used as a f ood-
col or i ng agent but has not been appr oved by t he FDA f or use as an or al t anni ng
agent . Ì t does not produce a t rue sunt an but i s deposi t ed i nt o f at t y t i ssues under
t he ski n. Ì t pr obabl y does not pr ot ect t he ski n f rom sunbur n.
5. Tyrosi ne has been promot ed as a tan acceI erat or or t an promot er. Because
mel ani n pi gment i s event ual l y synt hesi zed f r om t yr osi ne, t he t heor y i s t hat t opi cal l y
appl i ed t yr osi ne wi l l enhance t he f or mat i on of mel ani n. However , st udi es have not
conf i rmed an enhanced t anni ng ef f ect f rom t hi s agent .
IV. CONTACT DERMATITIS AND ITS TREATMENT
A. I nt roduct i on
1. Types of contact dermat i t i s. Cont act dermat i t i s i s one of t he most common
der mat ol ogi cal condi t i ons encount er ed i n cl i ni cal pr act i ce. Ì t has t radi t i onal l y been
di vi ded i nt o i rri tant contact dermati t i s and aI I ergi c cont act dermat i t i s on t he
basi s of t he ori gi n and i mmunol ogi cal mechani sm.
P. 641


a. I rri tant contact dermat i t i s i s caused by di r ect cont act wi t h a pr i mar y i rr i t ant .
These i r r i t ant s can be cl assi f i ed as absol ut e or rel at i ve pri mar y i r ri t ant s.
( 1) AbsoI ute pri mar y i rr i t ant s are i nt r i nsi cal l y damagi ng subst ances t hat i nj ur e, on
f i r st cont act , any person' s ski n. Exampl es i ncl ude st rong aci ds, al kal i s, and ot her
i ndust ri al chemi cal s.
( 2) ReI at i ve pri mar y i rri t ant s cause most cases of cont act der mat i t i s seen i n
cl i ni cal pract i ce. These i r r i t ant s are l ess t oxi c t han absol ut e pr i mar y i r r i t ant s, and
t hey r equi r e repeat ed or pr ol onged exposur e t o pr ovoke a react i on. Exampl es of
r el at i ve pr i mar y i rr i t ant s i ncl ude soaps, det ergent s, benzoyl peroxi de, and cert ai n
pl ant and ani mal subst ances.
b. AI I ergi c cont act dermat i t i s. Many pl ant s, and al most any chemi cal , can cause
al l er gi c cont act dermat i t i s. Poi son i vy i s a cl assi c exampl e of al l er gi c cont act
der mat i t i s, whi ch i s cl assi f i ed as a t ype Ì V hypersensi t i vi t y react i on. Thi s t ype of
al l er gi c react i on i s T cel l - medi at ed, and t he f ol l owi ng sequence of events must
occur t o pr ovoke i t :
( 1) The epi dermi s must come i n cont act wi t h t he hapt en (i . e. , t he speci f i c al l er gen) .
( 2) The hapt en- epi dermaI protei n compI ex (i . e. , t he compl et e ant i gen) must f or m.
( 3) The ant i gen must enter t he I ymphat i c syst em.
( 4) I mmunoI ogi caI I y compet ent I ymphoi d ceI I s, whi ch ar e sel ect i ve agai nst t he
ant i gen, must f or m.
( 5) On reexposure t o t he hapt en, t he t ypi cal , l ocal del ayed hyper sensi t i vi t y r eact i on
( i . e. , cont act der mat i t i s) occurs.
( 6) The i nduct i on peri od, dur i ng whi ch sensi t i vi t y devel ops, usual l y requi r es 14-21
days but may t ake as f ew as 4 days or mor e t han sever al weeks. Once sensi ti vi t y
i s f uI I y deveI oped:
( a) Reexposur e t o even mi nut e amount s of t he same mat eri al el i ci t s an eczemat ous
r esponse, t ypi cal l y wi t h an onset of 12 hr and a peak of 48- 72 hr af t er exposur e.
( b) Sensi t i vi t y usual l y per si st s f or l i f e.
( i ) Most cont act al l ergens produce sensi t i zat i on i n onl y a smal l per cent age of
exposed persons.
( i i ) Al l ergens or subst ances such as poi son i vy, however , pr oduce sensi t i zat i on i n >
70% of t he popul at i on (50%- 95% ar e sensi t i ve t o t he poi son i vy pl ant ) .
2. GeneraI phases of cont act dermat i ti s
a. Acut e st age. Wet l esi ons, such as bl i st er s or denuded and weepi ng ski n, ar e
evi dent i n wel l -out l i ned pat ches. Al so evi dent are er yt hema, edema, vesi cl es, and
oozi ng.
b. Subacute st age. Ì n t hi s phase, crust s or scabs f orm over t he previ ousl y wet
l esi ons. Al l er gi c cont act der mat i t i s and i r r i t ant cont act der mat i t i s caused by
absol ut e pr i mar y i r r i t ant s produce bot h t he acut e and subacut e st ages.
c. Chroni c st age. Ì n t hi s phase, t he l esi ons become dr y and t hi ckened ( i . e. ,
l i cheni f i ed). Ì ni t i al l y, dr yness and f i ssur i ng ar e t he si gns. Lat er , er yt hema,
l i cheni f i cat i on, and excor i at i ons appear . The chroni c phase of cont act der mat i t i s
usual l y occurs more of t en wi t h i r ri t ant cont act der mat i t i s caused by rel at i ve pr i mar y
i r r i t ant s.
B. Toxi c pI ants. Poi son i vy and poi son oak ar e t he most common causes of
al l er gi c cont act dermat i t i s i n Nor t h Ameri ca. These pl ant s wer e f ormer l y known as
t he Rhus genus, but t hey ar e now pr operl y r ef er red t o as t he Toxi codendron genus.
1. Poi son i vy ( Toxi codendr on r adi cans and T. rydbergi i ) grows as a vi ne or as a
bush. Ì t i s f ound i n most par t s of t he Uni t ed St at es, but i s especi al l y pr eval ent i n t he
nor t heast ern par t of t he count r y. Poi son i vy i s of t en i dent i f i ed by i t s char act eri st i c
gr owt h pat t ern, descri bed by t he sayi ng " Leaves of t hr ee, l et i t be. ¨
2. Poi son oak ( T. di ver si l obum) i s f ound i n t he west er n Uni t ed St at es and Canada.
Ì t grows as an upri ght shr ub or a woody vi ne. T. t oxi cari um i s f ound i n t he east ern
Uni t ed St at es.
3. Poi son sumac ( T. verni x) grows i n woody or swampy ar eas as a coarse shr ub or
t r ee and i s preval ent i n t he east er n Uni t ed St at es and sout heast er n Canada.
C. Toxi codendron dermat i t i s. For der mat i t i s t o devel op, pr evi ous sensi t i zat i on ( a
5- t o 21-day i ncubat i on per i od) caused by di rect cont act wi t h a sensi t i zi ng agent i s
r equi r ed ( see Ì V. A. 1. b). An ol eoresi n, urushi oI oi I , whi ch i s a pent adecacat echol , i s
t he act i ve sensi t i zi ng agent i n poi son i vy, poi son oak, and poi son sumac. Ther e are
sl i ght di f f erences i n t he chemi cal st r uct ur es of t he sensi t i zi ng agent i n each of
t hese pl ant s, but t he t hree agent s cross- r eact .
P. 642


1. ReI ease of t he urushi oI oi I . The pl ant s must be brui sed or i nj ured t o rel ease t he
ol eor esi n. Ì t i s present i n t he roots, st ems, I eaves, and f rui t . The urushi ol oi l may
r emai n act i ve on t ool s, t oys, cl ot hes, pet s, and under f i ngernai l s i f t hose i t ems have
had cont act wi t h t he broken pl ant s.
a. Ur ushi ol oi l does not vol at i l i ze, so one cannot get dermat i t i s f r om j ust bei ng near
a poi son i vy pl ant ; di rect cont act i s necessar y. Burni ng pI ant s, however , can cause
dr opl et s of oi l carr i ed by smoke t o ent er t he r espi r at or y syst em, whi ch can cause
si gni f i cant r espi r at or y di st r ess.
b. A cut or damaged poi son i vy, poi son oak, or poi son sumac pl ant i ni t i al l y yi el ds a
cI ear f I ui d cont ai ni ng t he ol eoresi n, whi ch turns t o a bI ack i nky I acquer on
exposur e t o ai r wi t hi n a f ew mi nut es. Thi s change can be a means f or conf i r mi ng
i dent i f i cat i on of t hese pl ant s.
c. Because t he ol eor esi n can r api dl y penet r at e t he ski n, t he af f ect ed area must be
washed wi t h soap and water wi t hi n 10 mi n af t er exposure t o prevent t he
der mat i t i s erupt i on. Washi ng up t o 30 mi n af t er exposur e i s st i l l usef ul i n r emovi ng
some of t he ol eor esi n.
2. Ì f an i ndi vi dual has been previ ousI y sensi t i zed, t he l esi ons usual l y occur wi t hi n
6- 48 hr af t er cont act wi t h t he al l er gen.
3. Typi cal l y, t he i ni ti aI erupt i on exi st s as smal l pat ches of er yt hemat ous papul es
( usual l y st reaks). Pruri tus ( i tchi ng) i s t he pri mar y sympt om.
a. Papul es may pr ogr ess t o vesi cl es, whi ch may t hen ooze and bl eed when t hey ar e
scrat ched. Secondar y i nf ect i on may t hen devel op. Of t en, t he i nf l ammat i on i s severe,
and a si gni f i cant amount of edema occurs over t he exposed area.
b. The l esi ons may l ast f r om a f ew days t o several weeks. Lef t unt r eat ed, t he
condi t i on r arel y per si st s l onger t han 2-3 weeks.
4. Poi son i vy dermat i t i s does not spread. New l esi ons, however , may cont i nue t o
appear f or several days despi t e l ack of f ur t her cont act wi t h t he pl ant . Thi s r eact i on
may be owi ng t o t he f ol l owi ng f act s:
a. Ski n t hat has been mi ni mal l y exposed t o t he ant i gen begi ns t o r eact onl y as t he
per son' s sensi t i vi t y hei ght ens.
b. Ant i gen i s absorbed at var yi ng r at es t hrough t he ski n of di f f er ent par t s of t he
body.
c. The person i nadvert ent l y t ouches cont ami nat ed obj ect s or may have r esi dual
ol eor esi n÷f or exampl e, under neat h t he f i nger nai l s.
5. Poi son i vy i s not cont agi ous. The ser ous f l ui d f rom t he weepi ng vesi cl es ar e
not ant i geni c. No one can " cat ch¨ poi son i vy f r om anot her per son.
D. Treatment . The t r eat ment of i r ri t ant and al l ergi c cont act dermat i t i s f ocuses on
t her apy f or t he speci f i c sympt omat ol ogy.
1. A pharmaci st shoul d ref er a pati ent wi t h a poi son i vy er upt i on t o a physi ci an i f :
a. The er upt i on i nvol ves a l ar ge ar ea of t he body ( about 25%).
b. The erupt i on i nvol ves t he eyes, geni t al ar ea, mout h, or r espi r at or y t r act ( some
pat i ent s may exper i ence r espi rat or y di f f i cul t i es i f t hey i nhal e t he smoke of burni ng
poi son i vy pl ant s) .
2. The severi t y of t he erupt i on depends on:
a. The quant i t y of al l er gen t hat t he pat i ent has been exposed t o
b. The i ndi vi dual pat i ent ' s sensi t i vi t y t o t he al l er gen
3. For severe erupti ons, a pat i ent shoul d consul t a physi ci an, who may pr escr i be
syst emi c corti cost eroi ds.
a. Syst emi c cor t i cost eroi ds ar e t he cor nerst one of t her apy. One shoul d use
suf f i ci ent l y hi gh doses t o suppr ess t hi s i nf l ammat i on. General l y, i t i s r ecommended
t hat pr edni sone be gi ven i n a dose of 60 mg/ day f or 5 days, t hen reduced t o 40
mg/ day f or 5 days, t hen 20 mg/ day f or 5 days, t hen di scont i nued. Prepacked dosage
packs of cor t i cost er oi ds used over 6 days pr ovi de t oo l ow of a dose over t oo shor t a
per i od of t i me.
b. Some bl i st er s may be dr ai ned at t hei r base. The ski n on t op of t he bl i st er shoul d
be kept i nt act . Dr ai ni ng t he bl i st er al l ows mor e t opi cal medi cat i on t o penet r at e f or
an ant i pr uri t i c ef f ect . Bat hs and soaks [ see Ì V. D. 4. b. (1) . (b) ] may be benef i ci al as
wel l .
4. For a I ess severe erupt i on, t he pri nci pal goal s are t o r el i eve t he i t chi ng and
i nf l ammat i on and t o pr ot ect t he i nt egr i t y of t he ski n.
P. 643


a. Several t herapeut i c cl asses of agent s can be used t o reI i eve i t chi ng.
( 1) The appl i cat i on of I ocaI anest heti cs÷f or exampl e, benzocai ne ( 5%-20%) ÷may
r el i eve i t chi ng. Rel i ef may be of shor t durat i on ( 30- 45 mi n) , but appl i cat i on of
benzocai ne may be especi al l y usef ul at bedt i me, when pr uri t us i s most bot hersome.
Ther e i s some quest i on about t he f r equency of t he sensi t i zi ng abi l i t y of benzocai ne
( 0. 17%- 5%) . Cer t ai nl y, t reat ment shoul d be di scont i nued i f t he r ash wor sens.
( 2) Topi caI ant i hi st ami nes÷f or exampl e, di phenhydr ami ne ( Benadr yl cream or
spr ay) ÷may provi de r el i ef of mi l d i t chi ng pri nci pal l y t hr ough a t opi cal anest het i c
ef f ect rat her t han any ant i hi st ami ne ef f ect . Many woul d not r ecommend t hei r use
because t hey may al so have a si gni f i cant sensi t i zi ng pot ent i al , and i n chi l dr en wi t h
var i cel l a i nf ect i ons ( wher e t he i nt egr i t y of t he ski n i s compr omi sed) , syst emi c
absor pt i on has occur red wi t h sympt oms of ant i chol i ner gi c t oxi ci t y pr oduced. Topi cal
and or al di phenhydr ami ne shoul d not be used concurr ent l y.
( 3) Count eri rri tant s i ncl ude camphor (0. 1%- 3%) , phenol ( 0. 5%-1. 5%) , and ment hol
( 0. 1%- 1%). These agent s have an anal gesi c ef f ect as a r esul t of depressi on of
cut aneous r ecept ors. The exact ant i pr uri t i c mechani sm i s not f ul l y known, but a
pl acebo ef f ect may resul t f r om t he char act eri st i c medi ci nal odors of t hese agent s.
( 4) Ast ri ngent s ar e mi l d pr ot ei n preci pi t ant s t hat r esul t i n cont ract i on of t i ssue,
whi ch i n t ur n decr eases t he l ocal edema and i nf l ammat i on.
( a) The pr i nci pal agent used i s aI umi num acet ate ( Burow' s sol ut i on).
( b) CaI ami ne ( zi nc oxi de wi t h f er ri c oxi de, whi ch pr ovi des t he pi nk col or) i s al so
used somet i mes. Cal ami ne cont r act s t i ssue and hel ps dr y t he area, but t he
f or mat i on of t he t hi ck dri ed past e may not be t ol er at ed by some peopl e.
( 5) Topi caI hydrocort i sone (e. g. , Cort ai d) , whi ch i s avai l abl e i n concent r at i ons up
t o 1%, i s mi ni mal l y usef ul f or i t s ant i pr uri t i c and ant i -i nf l ammat or y ef f ect s.
b. Basi c t reat ment
( 1) Acut e (weepi ng) I esi ons (see Ì V. A. 2. a)
( a) Wet dressi ngs wor k on t he pr i nci pl e t hat wat er evapor at i ng f rom t he ski n cool s
i t and t hus rel i eves i t chi ng. Wet dr essi ngs have an addi t i onal benef i t of causi ng
gent l e débr i dement and cl eansi ng of t he ski n.
( b) Burow' s soI ut i on ( Domeboro) i n concent r at i ons of 1: 20- 1: 40 as a wet dr essi ng
or a cool bat h of 15- 30 mi n 3- 6 t i mes per day provi des a si gni f i cant ant i pr ur i t i c
ef f ect .
( c) CoI I oi daI oat meaI bat hs (e. g. , Aveeno) may al so provi de an ant i pr uri t i c ef f ect .
( d) Topi caI t herapy t hat may hi nder t reat ment
( i ) LocaI anest het i cs and t opi caI anti hi st ami nes may sensi t i ze.
( i i ) CaI ami ne may make a mess wi t hout doi ng much good!
( 2) Subacut e dermat i t i s ( see Ì V. A. 2. b) . A t hi n I ayer of hydrocort i sone cream or
I ot i on ( 0. 5%- 1%) may be appl i ed 3- 4 t i mes a day t o t r eat subacut e der mat i t i s.
Suppl ement al agent s, such as t opi cal anest het i cs, may be used as wel l .
( 3) Chroni c dermat i t i s (see Ì V. A. 2. c) i s best t reat ed wi t h hydr ocort i sone oi nt ment .
Thi s st age i s obser ved mor e f r equent l y i n f orms of cont act dermat i t i s t hat i nvol ve
cont i nuous exposur e t o t he i r r i t ant or al l er gen.
E. Prevent i on
1. The best t reat ment f or poi son i vy cont act der mat i t i s i s t o prevent contact wi t h
t he of f endi ng cause. Thi s appr oach i nvol ves avoi di ng t he pl ant and weari ng
pr ot ect i ve cl ot hi ng.
2. Barri er preparat i ons. Bent oquatam (quat er ni um- 18 bent oni t e), Ì vy Bl ock, an
or ganocl ay, i s t he f i r st poi son i vy bl ocker pr oven saf e and ef f ect i ve. Ì t comes as a
l ot i on t hat shoul d be appl i ed at l east 15 mi n bef or e cont act wi t h t he pl ant and t hen
ever y 4 hr f or cont i nued pr ot ect i on agai nst ur ushi ol . Ì t shoul d be appl i ed t o l eave a
smoot h, wet , vi si bl e f i l m on t he ski n. Ì vy Bl ock may be removed wi t h soap and
wat er . Because of i t s al cohol cont ent , pat i ent s shoul d be i nst ruct ed t o st ay away
f r om f l ame dur i ng appl i cat i on unt i l t he pr oduct has dr i ed on t he ski n.
P. 644


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. A woman, who has not been i n t he sun f or 4 months, deveI ops redness on
her chest af t er I yi ng i n t he sun for 20 mi n. The next day, she appI i es a sunt an
I ot i on and deveI ops t he same degree of redness on her back i n 2 hr and 20 mi n.
What i s the sun prot ecti on f act or (SPF) of t he I ot i on she i s usi ng?
( A) 14
( B) 10
( C) 12
( D) 9
( E) 7
Vi ew Answer 1. The answer i s E[see] . 2. Whi ch of t he f oI I owi ng cI eansi ng
products wouI d a pharmaci st recommend f or a pati ent wi t h i nf I ammat or y acne?
( A) an abrasi ve f aci al sponge and soap used 4 t i mes a day
( B) al umi num oxi de part i cl es used 2 t i mes a day
( C) sul f ur 5% soap used 2 t i mes a day
( D) mi l d f aci al soap used 2 t i mes a day
Vi ew Answer 2. The answer i s D[ see] . 3. I f a pati ent needs a second
appI i cat i on of an over- the- count er ( OTC) pyret hri n pedi cuI i ci de shampoo, how
many days af t er t he fi rst appI i cat i on shouI d thi s be done?
( A) 4- 5
( B) 6
( C) 7- 10
( D) 14-21
( E) 15-17
Vi ew Answer 3. The answer i s C[ see] . 4. AI I of the f oI I owi ng t reat ments f or
personaI art i cI es i nf ested wi t h head I i ce wouI d be ef f ect i ve except
( A) pl aci ng wool en hat s i n a pl ast i c bag f or 2 weeks.
( B) usi ng an aer osol of pyr et hr i ns wi t h pi peronyl but oxi de sprayed i n t he ai r of al l
bat hrooms.
( C) machi ne- washi ng cl ot hes i n hot wat er and dr yi ng t hem usi ng t he hot set t i ng on
t he dr yer .
( D) dr y- cl eani ng wool en scar ves.
( E) soaki ng hai r br ushes i n hot wat er f or 15 mi n.
Vi ew Answer 4. The answer i s B[ see] . 5. AI I of the f oI I owi ng sunscreen
agents or combi nat i ons of agents wouI d I i keI y heI p prevent a drug- i nduced
phot osensi t i vi t y react i on except
( A) t i t ani um di oxi de.
( B) oct yl met hoxyci nnamat e pl us homosal at e.
( C) oxybenzone and padi mat e O.
( D) zi nc oxi de.
( E) padi mat e O pl us avobenzone.
Vi ew Answer 5. The answer i s B[ see] . 6. AI I of the f oI I owi ng wouI d be
appropri at e recommendat i ons for an aduI t pati ent i n t he acut e stage ( i . e. ,
bI i steri ng, weepi ng) of poi son i vy cont act dermat i t i s except
( A) 60 mg per day of pr edni sone i ni t i al l y, t hen t aper ed over 15 days.
( B) Bur ow' s sol ut i on; 1: 20 wet dr essi ng t o ar ea f or 15-30 mi n, 4 t i mes per day.
( C) t wo soaks per day i n Aveeno Bat h Tr eat ment .
( D) t wo appl i cat i ons of Ì vy Bl ock.
Vi ew Answer 6. The answer i s D[ seeand] . not 7. AI I of t he foI I owi ng
nonprescri pt i on agent s have been cI assi fi ed by t he U. S. Food and Drug
Admi ni st rat i on (FDA) as safe and ef f ect i ve ( cat egory 1) f or acne except
( A) sul f ur .
( B) sal i cyl i c aci d.
( C) sul f ur- r esorci nol combi nat i on.
( D) benzoi c aci d.
Vi ew Answer 7. The answer i s D[ see] . 8. Pharmaci sts educat i ng pat i ent s
about acne shouI d ment i on aI I of t he f oI I owi ng except
( A) el i mi nat i ng al l chocol at e and f r i ed f oods f r om t he di et .
( B) cl eansi ng ski n gent l y 2- 3 t i mes dai l y.
( C) usi ng wat er - based noncomedogeni c cosmet i cs.
( D) not squeezi ng acne l esi ons.
( E) keepi ng i n mi nd t hat acne usual l y resol ves by one' s ear l y 20s.
Vi ew Answer 8. The answer i s A[ see] . P. 645


9. A 15- year- oI d maI e pat i ent has been usi ng benzoyI peroxi de 5% cream
f ai t hf uI I y ever y day f or t he past 2 mont hs wi t h no apparent si de ef f ects. AI I of
t he f oI I owi ng can be sai d about thi s pat i ent except
( A) he has been usi ng t hi s pr oduct f or a l ong enough t i me t o det er mi ne i f t he dose
and dosage f or m ar e goi ng t o have any benef i t .
( B) he shoul d use t hi s product no more f requent l y t han ever y ot her day because of
i t s i r ri t at i ng propert i es.
( C) t hi s st ar t i ng dose and dosage f orm are usef ul , especi al l y i f he has dr y ski n or i t
i s wi nt er t i me.
( D) hi s scal p hai r may l ook bl eached i f t he product comes i n cont act wi t h i t .
( E) t he product woul d st i ng i f i t got i nt o hi s eyes.
Vi ew Answer 9. The answer i s B[ see] . 10. AI I of t he f oI I owi ng descri pt i ons
mat ch t he t herapeut i c agent f or poi son i vy except
( A) cal ami ne: phenol pht hal ei n gi ves i t t he pi nk col or.
( B) Ì vy Bl ock: usef ul i n pr event i ng poi son i vy dermat i t i s.
( C) benzocai ne: dat a r egar di ng i nci dence of hyper sensi t i vi t y ar e conf l i ct i ng.
( D) hydr ocor t i sone: usef ul f or i t s ant i prur i t i c and ant i - i nf l ammat or y ef f ect s.
Vi ew Answer 10. The answer i s A[ see] . 11. AI I of t he f oI I owi ng stat ements
reI at ed t o sun protect i on are t rue except whi ch one?
( A) The sun' s i nt ensi t y i ncr eases 20% when goi ng f r om sea l evel t o an al t i t ude of
5000 f t .
( B) Wat er resi st ant l abel i ng on a sunscr een product i ndi cat es t hat i t wi l l ret ai n i t s
SPF af t er 40 mi n of act i vi t y i n wat er , sweat i ng, or perspi r i ng.
( C) Baby oi l i s not a sunscreen, but i t s appl i cat i on t o t he ski n af t er t anni ng causes
mel ani n t o ri se t o t he sur f ace.
( D) Per t he FDA, a product wi t h an SPF of 50 must now be l abel ed " SPF 30 Pl us. ¨
( E) The SPF i s r eal l y onl y a measur e of ul t ravi ol et B ( UVB) pr ot ect i on.
Vi ew Answer 11. The answer i s C[ seeand] . 12. AI I of t he f oI I owi ng
st at ements about sunscreens are correct except whi ch one?
( A) Mal i gnant mel anoma f or mat i on may be associ at ed wi t h i nt ense, i nt ermi t t ent
over exposure t o t he sun ( sunburni ng) .
( B) Di hydroxyacet one ( DHA) wi l l not prevent sunbur n.
( C) Sunscreens ar e best appl i ed i mmedi at el y bef or e goi ng out i n t he sun.
( D) Avobenzone pr ovi des sunscreen cover age f or t he UVA spect r um.
( E) Tyr osi ne has been mar ket ed as a t an accel erat or or t an magni f i er .
Vi ew Answer 12. The answer i s C[ see] . P. 646


ANSWERS AND EXPLANATIONS
1. The answer i s E [ see Ì Ì Ì . E. 1] .
The SPF i s t he mi ni mal er yt hema dose ( MED) of pr ot ect ed ski n di vi ded by t he MED
of unpr ot ect ed ski n. Thus 2 hr and 20 mi n (140 mi n) di vi ded by 20 mi n equal s an
SPF of 7.
2. The answer i s D [ see Ì Ì . E. 2] .
For pat i ent s wi t h i nf l ammat or y acne, t he best product i s a mi l d f aci al soap used 2
t i mes a day. The soap shoul d be gent l y r ubbed i nt o t he ski n wi t h onl y t he f i ngert i ps.
Cl eansi ng pr oduct s t hat i r r i t at e al r eady i nf l amed ski n shoul d be avoi ded.
3. The answer i s C [ see Ì . G. 4. a. ( 1) ] .
Reappl i cat i on of pyr et hr i ns wi t h pi per onyl but oxi de shoul d be wi t hi n 7- 10 days of
t he f i rst appl i cat i on. Any l i ce ni t s t hat wer e not ki l l ed on t he f i r st appl i cat i on woul d
have t i me t o hat ch and t hen be ki l l ed wi t h t he second appl i cat i on.
4. The answer i s B [ see Ì . G. 4 a; Ì . G. 6. c] .
Pyr et hr i ns wi t h pi peronyl but oxi de i n an aerosol f or m can be spr ayed di r ect l y on
i nani mat e obj ect s ( e. g. , chai r s, headrest s) t o ki l l head l i ce, but t he combi nat i on
shoul d not be spr ayed i n t he ai r l i ke an aerosol deodor i zer . Mor eover , vacuumi ng
t he f ur ni t ure woul d probabl y be as ef f ect i ve as spr ayi ng i t . The ot her sel ect i ons ar e
appropr i at e f or per sonal ar t i cl es i nf est ed wi t h head l i ce.
5. The answer i s B [ see Ì Ì Ì . E. 2; Ì Ì Ì . D. 3. c] .
Oct yl met hoxyci nnamat e and homosal at e prot ect agai nst onl y UVB exposur e.
Because phot osensi t i vi t y r eact i ons are of t en associ at ed wi t h UVA radi at i on
exposur e, peopl e al so need sunscr een pr ot ect i on f or t hi s port i on of t he UV r adi at i on
band. The ot her agent s l i st ed cover at l east part of bot h UVA and UVB spect ra.
6. The answer i s D [ see Ì V. D. 3 and 4; Ì V. E. 2] .
Ì vy Bl ock i s used as a bar r i er pr ot ect ant f or t he prevent i on of poi son i vy der mat i t i s,
not f or t he t r eat ment of an acut e er upt i on. The ot her opt i ons ar e appr opri at e t o
r ecommend t o someone suf f er i ng f r om t he acut e st age of poi son i vy dermat i t i s.
7. The answer i s D [ see Ì Ì . E. 4] .
Benzoi c aci d has not been shown t o be ef f ect i ve f or acne t reat ment . The ot her
agent s, sul f ur , sal i cyl i c aci d, and a sul f ur - resor ci nol combi nat i on, are al l saf e and
ef f ect i ve product s f or t reat i ng acne.
8. The answer i s A [ see Ì Ì . D. 3] .
Evi dence does not show t hat acne wor sens f rom any part i cul ar t ype of f ood,
i ncl udi ng chocol at e or f r i ed f oods. The ot her choi ces are pi eces of i nf ormat i on t hat
t he pharmaci st shoul d convey t o a pat i ent wi t h acne.
9. The answer i s B [ see Ì Ì . E. 4. a] .
Al t hough t he i r r i t at i ng proper t i es of benzoyl per oxi de mi ght di ct at e appl yi ng i t onl y
ever y ot her day on i ni t i at i ng t r eat ment , t hi s pat i ent has t ol er at ed t he agent on a
dai l y basi s f or 2 mont hs. Thus t here woul d be no need t o decr ease t he appl i cat i on
f r equency. Al l of t he ot her choi ces do appl y t o t hi s pat i ent ' s use of benzoyl
per oxi de.
10. The answer i s A [ see Ì V. D. 4. a] .
Fer r i c oxi de pr ovi des t he pi nk col or of cal ami ne. Al l of t he ot her descr i pt i ons mat ch
t hei r associ at ed agent s.
11. The answer i s C [ see Ì Ì Ì . C. 2; Ì Ì Ì . E. 1. b and c; Ì Ì Ì . E. 2. b] .
Baby oi l i s not a sunscr een, and i t has no ef f ect on mel ani n. SPF does measur e
UVB pr ot ect i on, and an SPF hi gher t han 30 must be l abel ed SPF 30 Pl us. Wat er
r esi st ant sunscr een pr oduct s must ret ai n t hei r SPF val ue af t er 40 mi n of wat er
act i vi t y. The i nt ensi t y of t he sun does i ncrease by 4% wi t h each 1000- f t . ri se i n
el evat i on.
12. The answer i s C [ see Ì Ì Ì . D. 2; Ì Ì Ì . E. 1; Ì Ì Ì . E. 2. b; Ì Ì Ì . F. 1; Ì Ì Ì F. 4] .
Opt i mal l y, sunscreens shoul d be appl i ed 1- 2 hr bef ore exposur e t o t he sun. Thi s
al l ows t i me f or t he pr oduct t o bi nd t o t he st r at um cor neum, whi ch pr ovi des bet t er
pr ot ect i on. The ot her r esponses are cor r ect .

31
OTC Weight ControI, SIeep, and Smoking-
Cessation Aids
Jenni f er D. Smi th
I. WEIGHT CONTROL
A. Obesi t y i s a growi ng epi demi c i n Amer i ca, spanni ng al l age gr oups f rom
chi l dhood t o adul t hood. Appr oxi mat el y 30. 5% of adul t s wer e consi der ed obese i n t he
year 2000, and 15. 5% of adol escent s wer e consi der ed over wei ght . Thi s gr owi ng
epi demi c was r esponsi bl e f or 5. 7% of t ot al r ecent U. S. heal t h expendi t ur es.
1. The U. S. Pr event i ve Ser vi ces Task Force ( USPSTF) det ermi ned t hat t he body
mass i ndex ( BMÌ ) i s rel i abl e and val i d i dent i f i er f or aduI t s at i ncr eased r i sk f or
mor bi di t y and mor t al i t y owi ng t o over wei ght and obesi t y. The BMÌ i s cal cul at ed as
ei t her wei ght (i n pounds) di vi ded by hei ght ( i n i nches squared) mul t i pl i ed by 703 or
as wei ght (i n ki l ogr ams) di vi ded by hei ght ( i n met er s squar ed) . The f ol l owi ng
gui del i nes rel at e BMÌ t o over wei ght and obesi t y:
a. Morbi d obesi t y i s def i ned as a BMI > 40 kg/ m2.
b. Obesi t y i s def i ned as a BMI > 30 kg/ m2.
c. Overwei ght i s def i ned as a BMI between 25 and 30 kg/ m2.
2. Tr unkal f at accumul at i on, measur ed by wai st ci rcumference, i s a ri sk f act or for
cardi ovascuI ar di sease and ot her di seases ( e. g. , t ype 2 di abet es, sl eep apnea,
knee ost eoart hr i t i s) regar dl ess i f t he i ndi vi dual i s consi dered obese. Wai st
ci rcumf erence i s not a val i d measurement i n i ndi vi dual s wi t h a BMÌ > 35 kg/ m2.
Ì ndi vi dual s wi t h t he f ol l owi ng wai st ci rcumf erences ar e consi dered at i ncreased ri sk
f or car di ovascul ar and ot her di seases:
a. A wai st ci rcumf erence i n men > 40 i nches (102 cm)
b. A wai st ci rcumf erence i n women > 35 i nches (88 cm)
B. Management . Di et and exer ci se (l i f est yl e modi f i cat i ons) ar e t he r ecommended
f i r st appr oach t o wei ght l oss, as wel l as sust ai ned wei ght cont rol . Though i t seems
r el at i vel y si mpl e t o eat a wel l - bal anced di et and exer ci se r egul ar l y, t i me const rai nt s
and ease of access t o hi ghl y processed f oods are hurdl es t hat Amer i cans f ace i n t he
f i ght agai nst t he bul ge.
1. CaI ori c rest ri ct i on. To r educe wei ght ( and t hus BMÌ ) , ener gy i nt ake shoul d be
l ess t han t he energy expended.
a. The approxi mat e adul t energy r equi rement s, based on act ual wei ght , may be
r oughl y est i mat ed as f ol l ows. A 120 l b. act i ve woman woul d requi r e appr oxi mat el y
1800 kcal / day t o mai nt ai n her cur r ent wei ght .
( 1) Bedr i dden or sedent ar y i ndi vi dual s: 10- 12 kcal / l b.
( 2) Moder at el y act i ve i ndi vi dual s ( wal ki ng at r egul ar pace) : 13 kcal / l b.
( 3) Act i ve i ndi vi dual s: 15 kcal / l b.
( 4) Ver y act i ve i ndi vi dual s: 20 kcal / l b.
b. To l ose about 0. 5 kg/ week, a def i ci t of 500- 1000 caI ori es ( kcaI ) per day must
be met . A saf e rat e of wei ght I oss i s consi dered t o be 1-2 l b. / week.
c. Sever al commerci al l y avai l abl e wei ght l oss pr ogr ams (e. g. , Wei ght Wat chers and
Jenny Cr ai g) exi st t oday. When compared t o sel f -hel p wei ght l oss programs, some
commer ci al l y avai l abl e pr ogr ams have shown enhanced and sust ai ned wei ght l oss,
whi ch may be at t r i but abl e t o t he soci al suppor t pr ovi ded.
2. Di etar y Fat Absorpt i on I nhi bi tor. Curr ent l y, t he onl y avai l abl e nonprescr i pt i on
agent t hat i s FDA approved f or wei ght l oss i s orI i st at , a di et ar y f at absor pt i on
modi f i er . Di et ar y modi f i cat i ons i n combi nat i on wi t h orl i st at can pr oduce cl i ni cal l y
modest wei ght l oss ( appr oxi mat el y 5% of basel i ne wei ght ). Or l i st at has been
avai l abl e i n prescr i pt i on f or m ( Xeni cal ®) si nce 1999, and gai ned FDA approval f or
nonpr escri pt i on st at us i n 2007 under t he brand name Al l i ®.
a. Al l i ® i s avai l abl e f or i ndi vi dual s 18 and ol der who ar e mi l dl y t o moderat el y over -
wei ght ( BMI between 25 and 28 kg/ m2).
P. 648


b. Nonpr escr i pt i on dosi ng i s 60 mg TI D ( as compar ed t o 120 mg TÌ D f or Xeni cal ®)
dur i ng or wi t hi n 1 hour of each f at -cont ai ni ng meal . Dose- r el at ed ef f i cacy i s
obser ved wi t h or l i st at up t o 300-400 mg dai l y, but ef f ect s pl at eau t her eaf t er .
c. Onset of or l i st at t akes approxi mat el y 2 weeks and st at i st i cal l y si gni f i cant wei ght
l oss has been obser ved i n obese pat i ent s af t er 3 mont hs. Thus i ndi vi dual s shoul d
be counsel ed t hat wei ght l oss may not be si gni f i cant wi t h or l i st at and may t ake
sever al mont hs f or not i ceabl e resul t s.
d. The use of or l i st at wi l l r esul t i n gast roi ntesti naI adverse ef f ect s, i ncl udi ng sof t
or l i qui d st ool s whi ch may be f at t y or oi l y i n appear ance, i ncr eased def ecat i on, f ecal
ur gency, and abdomi nal pai n. Adverse ef f ect s are di r ect l y r el at ed t o t he dose and
i nver sel y rel at ed t o t he f at cont ent of t he di et . Gast roi nt est i nal adver se ef f ect s may
l essen over t i me.
e. Pr escr i pt i on doses or l i st at have been associ at ed wi t h decr eased absorpt i on of
vi t ami ns A, D, E, K, and bet a-car ot ene. However , at doses >180 mg/ day gi ven f or
short per i ods of t i me ( e. g. , 2- 3 mont hs) , reduced absor pt i on of t hese vi t ami ns has
not been obser ved.
3. Exerci se can decr ease t he appet i t e and i ncr ease body met abol i sm. Exer ci se
adds onl y modest l y t o i ni t i al wei ght l oss but i s t he key component of sustai ned
wei ght I oss.
C. Di et ar y suppI ement s. Ì n 2001, ret ai l sal es of wei ght l oss suppl ement s i n t he
Uni t ed St at es wer e est i mat ed t o be > $1. 3 bi I I i on. Amer i cans have begun t o seek
nonpr escri pt i on wei ght l oss product s f or a var i et y of r easons.
1. Some i ndi vi dual s may vi ew di et ar y suppl ement s as a qui ck resol ut i on t o t he
gr owi ng epi demi c, because t he obt ai nment of desi r ed or reduced body wei ght wi t h
l ong- t erm l i f est yl e changes i s percei ved as di f f i cul t . Many adver t i sement s of wei ght
l oss pr oduct s gi ve i nf l at ed cl ai ms, of f er i ng rapi d r esul t s wi t h l i t t l e t o no modi f i cat i on
i n l i f est yl e habi t s. Some peopl e vi ew di et ar y suppl ement s as nat ur al and, t her ef or e,
mi st akenl y bel i eve t hey ar e saf e t o use.
2. Wi t h t he i mpl ement at i on of t he Di et ar y Suppl ement Heal t h and Educat i on Act of
1994, manuf act ur ers are not requi red t o demonst rat e product saf et y and ef fi cacy
bef ore market i ng suppl ement s. Ì n addi t i on, t he adherence t o good manuf act uri ng
pract i ces i s not mandator y f or manuf act urer s of di et ar y suppl ement s. The l ack of
evi dence f or pr oduct saf et y and ef f i cacy, coupl ed wi t h pot ent i al devi at i on f r om good
manuf act ur i ng pract i ces r ai ses concer ns f or heal t hcare pr ovi der s who at t empt t o
make appropri at e r ecommendat i ons t o pat i ent s seeki ng nonprescr i pt i on wei ght l oss
pr oduct s.
3. The U. S. Food and Drug Admi ni st rat i on (FDA) f i l es act i on agai nst manuf act ur ers
of suppl ement s det ermi ned unsaf e, f al sel y l abel ed, l abel ed wi t h mi sl eadi ng cl ai ms,
adul t erat ed, or mi sbr anded.
4. The Feder al Tr ade Commi ssi on (FTC) t akes act i on agai nst manuf act urer s
pr ovi di ng pr oduct adver t i si ng t hat i s mi sl eadi ng or makes unsubst ant i at ed cl ai ms.
5. Numerous si ngl e- and mul t i pl e- ent i t y pr oduct s ar e avai l abl e on t he market t oday,
each under t he scrut i ny of t he FDA and FTC. The most commonl y seen i ngr edi ent s
i n wei ght l oss pr oduct s cur r ent l y mar ket ed, or gani zed by pur por t ed mechani sms of
act i on, are t he f ol l owi ng:
a. I ncrease energy expendi ture
( 1) Ephedra. Cont ai ns suppl ement s t hat wer e banned by t he FDA i n Apr i I 2004
owi ng t o unreasonabl e ri sks of i l l ness or i nj ur y when used as l abel ed. Pr oduct s
f or mul at ed wi t h ephedr i ne al kal oi ds ( ephedr a, ma huang, si da cor di f ol i a, Pi nel l i a)
wer e r emoved i mmedi at el y, t hough, unl i ke ot her di et ar y suppl ement s cur rent l y
avai l abl e, ephedr acont ai ni ng suppl ement s di d have convi nci ng evi dence f or shor t -
t er m wei ght l oss.
( 2) Bi t ter orange i s an ext r act f r om t he peel , f l ower , l eaf , and f r ui t of t he Sevi l l e
or ange. Typi cal dosage i s about 1 g/ day, st andardi zed t o 1. 5%- 6. 0% synephr i ne, a
st i mul at i ng agent t hat i s chemi cal l y si mi l ar t o ephedr i ne. Cur r ent l y, t her e ar e no
dat a t o suppor t i t s ef f i cacy as an agent f or wei ght l oss. Ì f combi ned wi t h ot her
st i mul ant s such as caf f ei ne, bi t t er or ange may be cardi ot oxi c.
( 3) Guarana seed cont ai ns 2. 5%- 7% caf f ei ne and exer t s a di ur et i c act i on.
Ef f ect i veness has been demonst r at ed onl y i n combi nat i on wi t h ephedr i ne. Tol erance
and dependence can devel op wi t h chr oni c use.
( 4) Caf fei ne i s an FDA-appr oved product , ef f i cacy of t hi s agent f or wei ght l oss has
been demonst r at ed onl y i n combi nat i on wi t h ephedr i ne, whi ch has been removed
f r om t he mar ket . Tol er ance and dependence can devel op wi t h chroni c use.
P. 649


b. ModuI at e carbohydrat e met aboI i sm
( 1) Chromi um, an essent i al mi ner al , i ncreases i nsul i n sensi t i vi t y, l ean body mass,
and basal met abol i c r at e and decr eases i nsul i n bl ood l evel s and body f at . Chr omi um
i s used i n wei ght l oss product s i n t he f or m of chromi um pi col i nat e, 200-400 µg/ day,
wi t h no report ed si gni f i cant adverse ef f ect s. Rhabdomyol ysi s and r enal f ai l ure have
been r epor t ed wi t h t he use of chr omi um pi col i nat e i n doses exceedi ng 1000 µg/ day.
Though wi del y mar ket ed, t here have been no l arge, wel l - desi gned st udi es f or t he
use of chromi um i n wei ght l oss. Though i t s ef f i cacy f or wei ght l oss r emai ns
uncer t ai n, at l east 115 pr oduct s market ed f or wei ght l oss cont ai n chromi um.
( 2) Gi nseng, i n t he f or m of Panax gi nseng, may i mpr ove gl ucose t ol erance,
accor di ng t o pr el i mi nar y dat a. Though gi nseng i s f ound i n at l east 20 commerci al l y
avai l abl e wei ght l oss pr oduct s, i t has no demonst r at ed ef f i cacy f or wei ght l oss i n
humans.
c. Enhance sat i et y
( 1) Guar gum, a f i ber der i ved f rom t he Ì ndi an cl ust er bean, has been deemed
r el at i vel y saf e i n doses of 7. 5- 30. 0 g/ day, however , i t has not demonst r at ed ef f i cacy
f or wei ght l oss i n at l east 20 cl i ni cal t r i al s. Adverse ef f ect s i ncl ude abdomi nal pai n,
f l at ul ence, and di ar r hea.
( 2) GI ucomannan ( Amorphophal l us konj ac) pur por t edl y absorbs wat er i n t he gut ,
cont r i but i ng t o enhanced sat i et y and t hus decr eased cal ori c i nt ake. Pr el i mi nar y
evi dence has demonst rat ed t hat gl ucomannan (3-4 g/ day) may be wel l t ol er at ed and
ef f i caci ous f or wei ght l oss. However , t hi s agent can have a l axat i ve ef f ect .
( 3) PsyI I i um f orms a f i brous mass wi t h a bul k l axat i ve ef f ect but has not
demonst r at ed ef f i cacy f or wei ght l oss. Pot ent i al adver se ef f ect s ar e si gni f i cant ,
i ncl udi ng esophageal obst r uct i on and nephrot oxi ci t y (i f seeds ar e crushed, chewed,
or ground, a pi gment may be deposi t ed i n t he r enal t ubul es) . Ì f used, pat i ent s
shoul d be i nst ruct ed t o not cr ush, chew, or ground t he seeds, and adequat e f l ui ds
must be consumed.
d. I ncrease fat oxi dat i on or reduce f at synt hesi s
( 1) L- Carni t i ne i s synt hesi zed i n t he l i ver , ki dney, and brai n. Ì t i s f undament al l y
i mpor t ant f or f at t y aci d t ranspor t f or ener gy product i on. No t ri al s demonst rat e
ef f i cacy of L-car ni t i ne f or wei ght l oss.
( 2) Hydroxyci t ri c aci d (HCA) i s deri ved f r om t he r i nd of t he bri ndl e ber r y, a t ropi cal
f r ui t nat i ve t o Ì ndi a. Ì t i s pur por t ed t o i nhi bi t mi t ochondri al ci t r at e l yase, t her eby
suppr essi ng acet yl coenzyme A and f at t y aci d synt hesi s. Ì n doses of 300-3, 000
mg/ day, HCA has been wel l t ol er at ed, wi t h adver se ef f ect s of headache and
gast r oi nt est i nal sympt oms r epor t ed. Ef f i cacy of HCA r emai ns quest i onabl e.
( 3) Green t ea cont ai ns a pol yphenol , epi gal l ocat echi n-3- gal l at e, bet t er known as
EGCG. Each cup (8 oz) of green t ea provi des 10- 80 mg of caf f ei ne, cont ri but i ng t o
t he t ea' s di ur et i c act i on and cent r al ner vous syst em ( CNS) st i mul at i on (e. g. ,
i ncreased hear t r at e, i ncr eased bl ood pr essur e, anxi et y) . Gr een t ea has
demonst r at ed i ncr eased f at oxi dat i on and t hermogenesi s but l acks dat a regardi ng
ef f i cacy i n wei ght l oss.
( 4) Vi tami n B5 has been post ul at ed t o i nduce wei ght l oss; however , dat a ar e l acki ng
t o suppor t t hi s.
( 5) Li cori ce saf et y and ef f i cacy f or wei ght l oss remai ns uncl ear . Repor t ed adverse
ef f ect s of l i cor i ce i ncl ude pseudoal dost er oni sm, hyper t ensi on, and hyperkal emi a.
( 6) Conj ugat ed I i noI ei c aci d ( CLA) i s a group of t r ans- f at t y aci ds, whi ch i s
pur por t ed t o al t er body composi t i on by i ncr easi ng l ean t i ssue deposi t i on and
decreasi ng t ri gl yceri de upt ake i n adi pose t i ssue. Ì n doses of 1. 4-6. 8 g/ day, CLA may
have ef f i cacy i n wei ght l oss, especi al l y i n obese pat i ent s. Adverse ef f ect s i ncl ude
mi l d t o moder at e gast r oi nt est i nal sympt oms. CLA may i ncr ease i nsul i n l evel s and
i nsul i n resi st ance.
( 7) Cl i ni cal t ri al s of pyruvat e, i n doses of 6- 44 g/ day, have demonst r at ed weak
evi dence of i t s ef f ect i veness f or wei ght l oss. Repor t ed adver se ef f ect s i ncl ude
di ar rhea and audi bl e abdomi nal sounds.
( 8) CaI ci um suppr esses par at hyr oi d hor mone and 1, 25- di hydr oxyvi t ami n D t o reduce
f at synt hesi s and i ncrease f at oxi dat i on. Or al doses of cal ci um obt ai ned t hr ough
bot h di et (1. 2-1. 3 g/ day) and suppl ement at i on ( 800 mg/ day) have pr oduced posi t i ve
r esul t s i n at l east one randomi zed cont rol l ed t r i al ( n = 32). A l ar ger randomi zed
cont r ol l ed t ri al i s needed t o subst ant i at e cur r ent adver t i si ng.
e. BI ock di etar y f at absorpt i on. Chi tosan, a common i ngredi ent i n " f at - t r apper ¨
suppl ement s, i s deri ved f r om t he exoskel et on of shel l f i sh. Ì n doses of 2. 0- 4. 5 g/ day,
chi t osan has not demonst r at ed cl i ni cal l y si gni f i cant i ncreases i n f ecal f at excr et i on
or wei ght l oss. Adver se ef f ect s i ncl ude nausea, const i pat i on, and f l at ul ence.
Fur t her mor e, i t i s quest i onabl e i f chi t osan i s saf e i n i ndi vi dual s wi t h shel l f i sh
al l er gi es.
P. 650


f . I ncrease water eI i mi nat i on
( 1) DandeI i on (Tar axacum of f i ci nal e) seems t o have a di uret i c ef f ect , but has not
been st udi ed f or wei ght l oss i n humans. At l east 15 di et ar y suppl ement s f or wei ght
l oss cont ai n dandel i on.
( 2) Cascara st i mul at es per i st al si s and evacuat i on, al l owi ng FDA t o appr ove t hi s
agent f or use as a st i mul ant l axat i ve. However , cascar a has not been st udi ed i n
humans f or wei ght l oss.
g. Mi sceI I aneous. Spi ruI i na (bl ue- gr een al gae) cont ai ns phenyl al ani ne, an agent
t heori zed t o i nhi bi t appet i t e. Spi rul i na was decl ared i nef f ect i ve f or wei ght l oss i n
1981 by t he FDA, and no publ i shed st udi es have pr oven ot her wi se. At l east 13
pr oduct s f or wei ght l oss cur rent l y on t he mar ket cont ai n spi r ul i na.
II. SLEEP AIDS
A. NormaI sI eep and sI eep requi rement s
1. Sl eep r equi rement s var y wi del y among i ndi vi dual s and change t hr oughout t he l i f e
cycl e. The usual r ange of sl eep t i me per ni ght i s 5- 10 hr , wi t h an aver age of about
7. 5 hr . Newborns r equi re a consi der abl e amount of sl eep t i me, up t o 18 hr .
Adol escent s t ypi cal l y do not become sl eepy unt i l af t er mi dni ght and awaken ver y
l at e i n t he mor ni ng ( i f al l owed) , but r equi r e a t ot al of 9. 5 hr of sl eep. The t ypi cal
adul t r equi r es 7-8 hr of sl eep t o f eel adequat el y r est or ed, but t hi s t i me may di mi ni sh
wi t h agi ng.
2. PoI ysomnography i s t he pr edomi nant t ool f or charact eri zi ng sl eep physi ol ogy,
t hough gui del i nes f r om t he Ameri can Sl eep Di sorder s Associ at i on do not i ndi cat e i t
as usef ul i n t he di agnosi s and management of pat i ent s wi t h i nsomni a. Usi ng
pol ysomnography, r esear cher s have i dent i f i ed f i ve st ages of sl eep, subdi vi ded i nt o
r api d eye movement ( REM) sl eep and non- REM sl eep.
a. Non- REM sl eep consi st s of f our st ages. Each st age i s a pr ogressi on i nt o a
deeper sl eep; and st ages 3 and 4 ar e consi der ed deep, rest or at i ve sl eep. Ì f t i me
spent i n st ages 3 and 4 of sl eep i s di mi ni shed ( as seen wi t h agi ng) , t hen sl eep
qual i t y i s compromi sed.
b. REM sl eep i s consi der ed st age 5 of sl eep. Most dr eami ng occurs dur i ng REM
sl eep. Ì f awoken whi l e i n REM sl eep, dr eams may be descri bed i n vi vi d det ai l .
B. I nsomni a
1. Def i ni t i on. Ì nsomni a i s def i ned as one or mor e of t he f ol l owi ng sl eep- r el at ed
compl ai nt s: di f f i cul t y i n sl eep i ni t i at i on ( arbi t rar i l y def i ned as a del ay of > 30 mi n),
di f f i cul t y i n mai nt enance of sl eep, shor t ened durat i on of sl eep, or qual i t y of sl eep
t hat r esul t s i n adverse dayt i me consequences.
2. Epi demi oI ogy. Ì nsomni a i s t he most common sl eep di sorder i n t he Uni t ed St at es,
af f ect i ng appr oxi mat el y 35% of t he adul t popul at i on. Those af f ect ed most i ncl ude
women, t he l ess educat ed or unempl oyed, separ at ed or di vor ced i ndi vi dual s,
pat i ent s wi t h chroni c medi cal or psychi at r i c di sorder s, and subst ance abusers.
Economi c cost s of i nsomni a ar e est i mat ed t o be > $46 bi l l i on annual l y i n t he Uni t ed
St at es. Di r ect cost s i ncl ude pr escri pt i on and nonpr escri pt i on medi cat i ons, as wel l as
vi si t s t o a heal t hcar e pr ovi der . Ì ndi r ect cost s i ncl ude absent eei sm, di mi ni shed
pr oduct i vi t y, f at i gue- r el at ed aut omobi l e cr ashes, and i ndust r i al acci dent s.
3. Cl assi f i cat i on of i nsomni a by dur at i on.
a. Transi ent i nsomni a l ast s < 1 week and i s t ypi cal l y t he resul t of acut e si t uat i onal
st r ess or ci r cadi an i ssues such as j et l ag or shi f t wor k. Thi s t ype of i nsomni a i s
of t en sel f - l i mi t i ng.
b. Short -t erm i nsomni a l ast s 1-4 weeks and i s at t r i but abl e t o si t uat i onal st r ess
( e. g. , acut e per sonal l oss) , of t en r el at ed t o wor k and f ami l y l i f e or t o medi cal or
psychol ogi cal di sor der s. Ì f shor t - t erm i nsomni a i s not managed appr opr i at el y, i t may
pr ogress t o chr oni c i nsomni a because i ndi vi dual s become i ncreasi ngl y anxi ous and
f r ust r at ed about t he i nabi l i t y t o sl eep. Ther e ar e no est abl i shed predi ct ors t o
det ermi ne i f shor t - t er m i nsomni a wi l l cont i nue t o become chr oni c i nsomni a.
c. Chroni c i nsomni a l ast s > 1 month. Peopl e wi t h chr oni c i nsomni a need f ur t her
eval uat i on because t he condi t i on i s of t en t he r esul t of a medi cal di sor der (e. g. ,
sl eep apnea, r est l ess
P. 651

l eg syndrome, pr i mar y i nsomni a) , psychi at r i c di sor der , or subst ance abuse. Up t o
40% of chroni c i nsomni a cases are cor rel at ed wi t h psychi at ri c di sorders, par t i cul arl y
depressi on.
4. Cl assi f i cat i on of i nsomni a based on cause
a. Pri mar y i nsomni a i s t he mai n pat hol ogi cal condi t i on i n whi ch a pat i ent
exper i ences cont i nued i nsomni a i n t he absence of a rel at ed medi cal or psychi at r i c
condi t i on. Ì t s pat hogenesi s i s unknown, but t he condi t i on i s t r eat abl e. Ì di opat hi c
i nsomni a i s t he i nabi l i t y t o obt ai n adequat e sl eep, possi bl y st emmi ng f r om a
mi sal i gned ci r cadi an rhyt hm. Psychophysi ol ogi c i nsomni a i s i ncr eased wakef ul ness
associ at ed wi t h t he bed envi r onment .
b. Secondar y i nsomni a i s more common t han pri mar y and can be at t r i but ed t o t he
f ol l owi ng:
( 1) Adj ust ment i nsomni a i s associ at ed wi t h si t uat i onal st r ess.
( 2) Ì nadequat e sl eep hygi ene i s associ at ed wi t h l i f est yl e habi t s t hat reduce t he
amount of qual i t y sl eep, such as noi se i n t he bedr oom or t he use of caf f ei ne.
( 3) Ì nsomni a owi ng t o a psychi at r i c di sor der
( 4) Ì nsomni a owi ng t o a medi cal condi t i on, whi ch may i ncl ude rest l ess l eg
syndr ome, chr oni c pai n (ar t hri t i s) , mi gr ai nes, or cancer
( 5) Ì nsomni a owi ng t o subst ance abuse
5. Tr eat ment
a. NonpharmacoI ogi c i nt ervent i on i s i nexpensi ve and may be ef f ect i ve.
( 1) Mai nt ai n a r egul ar schedul e and do not nap; avoi d sl eepi ng i n l at e af t er a poor
ni ght ' s sl eep.
( 2) Use t he bed onl y f or sl eep; avoi d r eadi ng or wat chi ng t el evi si on i n bed.
( 3) Ì f unabl e t o i ni t i at e sl eep (or go back t o sl eep) wi t hi n 20 mi n, engage i n a
r el axi ng act i vi t y ( away f rom bed) unt i l drowsy, and t hen ret urn t o bed.
( 4) Avoi d exer ci se wi t hi n 3- 4 hr of bedt i me.
( 5) Mi ni mi ze or avoi d caf f ei ne af t er noon.
( 6) Mi ni mi ze or avoi d al cohol , t obacco, or st i mul ant s. Many peopl e bel i eve al cohol
t o be an agent f or sl eep i nduct i on; however , al cohol can act as a CNS st i mul ant ,
t her eby i ncr easi ng noct ur nal awakeni ngs.
b. Nonpr escr i pt i on drug t her apy: Ì t has been est i mat ed t hat 40% of pat i ent s wi t h
i nsomni a sel f -medi cat e wi t h ei t her al cohol or nonpr escri pt i on medi cat i ons i n an
ef f ort t o cor r ect t he condi t i on. The sal es of si ngl e- ent i t y nonprescr i pt i on hypnot i cs
( e. g. , di phenhydr ami ne, doxyl ami ne) have i ncreased si nce t hat est i mat e was made,
but t he sal es of ni ght t i me anal gesi cs (nonpr escr i pt i on hypnot i c pl us an anal gesi c,
t ypi cal l y acet ami nophen) have surpassed t he si ngl e-ent i t y product s. Cur rent l y, dat a
suppor t i ng t he saf et y and ef f i cacy of compl ement ar y t herapy as sl eep ai ds are
l acki ng.
( 1) Di phenhydrami ne, an et hanol ami ne, bl ocks hi st ami ne1 and muscar i ni c
r ecept or s, t hus i nduci ng sedat i on. Di phenhydr ami ne i s market ed as a ni ght t i me
sl eep ai d as Uni som Sl eepGel s, Sl eepi nal , Compoz, and Si mpl y Sl eep.
( a) Di phenhydr ami ne may be dosed f or sl eep i nduct i on as 25- 50 mg/ ni ght i n
pat i ent s aged 13 and ol der . Doses > 50 mg show no addi ti onaI benefi t , but
i ncreased adver se ef f ect s. An i ni t i al dose of 25 mg may be recommended f or
pat i ent s over t he age of 65 wi t h no cont r ai ndi cat i ons t o t he agent . A dose of 1
mg/ kg/ ni ght ( not t o exceed 50 mg) may be recommended f or pat i ent s aged 6- 12.
Di phenhydrami ne i s not r ecommended f or sl eep i nduct i on i n pat i ent s younger t han
age 6.
( b) Adverse ef f ect s of di phenhydrami ne are ant i choI i nergi c, i ncl udi ng dry mout h,
bl ur red vi si on, const i pat i on, and ur i nar y ret ent i on. Di phenhydr ami ne use shoul d be
avoi ded i n pat i ent s wi t h gl aucoma ( nar r ow- angl e), beni gn prost at i c hypert r ophy,
dement i a, or cardi ovascul ar di sease.
( c) The dur at i on of sedat i on f r om di phenhydr ami ne i s 3-6 hr. However , t hi s may be
ext ended i n el der l y pat i ent s or t hose wi t h del ayed met abol i sm.
( d) The use of di phenhydr ami ne f or t he al l evi at i on of i nsomni a shoul d be I i mi ted t o
7- 10 consecut i ve ni ghts. Ì f used l onger t han recommended, decr eased ef f i cacy
may be not ed and REM sl eep may be suppressed.
( e) Di phenhydr ami ne i s avai l abl e i n combi nat i on wi t h aspi r i n or acet ami nophen as a
ni ght t i me anaI gesi c. Dat a are avai l abl e t o suppor t t he use of t hese agent s i n
combi nat i on i f pai n i s present . However , i n t he absence of pai n, t he addi t i on of an
anal gesi c si mpl y pr ovi des i ncreased oppor t uni t i es f or compl i cat i ons and dr ug-
mi sadvent ures.
P. 652


( 2) DoxyI ami ne, l i ke di phenhydr ami ne, i s an et hanol ami ne ant i hi st ami ne whi ch
i nduces sl eep t hrough t he bl ockade of hi st ami ne and muscar i ni c r ecept ors.
Ther ef ore, adver se ef f ect s and durat i on of sedat i on are si mi l ar t o di phenhydr ami ne.
Ther e are cur r ent l y no st udi es demonst rat i ng enhanced ef f i cacy or saf et y of
doxyl ami ne compar ed t o di phenhydr ami ne.
( a) Doxyl ami ne i s dosed as 25 mg/ ni ght .
( b) Doxyl ami ne i s t he act i ve i ngr edi ent i n Uni som Ni ght t i me Sl eep Ai d Tabl et s.
However , i t shoul d be not ed t hat Uni som Sl eepGel s cont ai n di phenhydr ami ne.
( 3) MeI at oni n, a noct ur nal neurohormone secr et ed by t he pi neal gl and, has a
sI eepphase-shi f ti ng ef fect on ci rcadi an rhyt hm. Recent t ri al s have obser ved
ef f ect i veness of mel at oni n f or sl eep onset i n pat i ent s wi t h mi sal i gned ci rcadi an
r hyt hms at t r i but abl e t o shi f t wor k or j et l ag.
( a) Mel at oni n pr oduct i on decr eases wi t h age, possi bl y at t r i but i ng t o sl eep di sor der s
not ed i n el der l y pat i ent s.
( b) Mel at oni n pr oduct i on can be decreased by t obacco, al cohol , and cer t ai n
medi cat i ons ( nonst eroi dal ant i - i nf l ammat or y dr ugs, cal ci um channel bl ocker s,
st eroi ds, benzodi azepi nes, and f l uoxet i ne).
( c) When exogenous mel at oni n i s gi ven i n the earI y eveni ng, the ci rcadi an phase
wi I I be advanced. Al t hough t hi s may be benef i ci al f or i ndi vi dual s who exper i ence
di f f i cul t y i n i ni t i at i ng sl eep, mel at oni n gi ven i n t hi s manner may wor sen t he pr obl em
of i ndi vi dual s who compl ai n of di f f i cul t y i n r ei ni t i at i ng sl eep af t er awakeni ng t oo
ear l y.
( d) Ì f mel at oni n i s gi ven i n t he morni ng, t he ci rcadi an phase i s deI ayed, of f er i ng
t he possi bi l i t y t hat t he pat i ent may become sl eepi er ear l i er and awaken ear l i er . At
pr esent , i t i s uncl ear i f cont i nued admi ni st r at i on of exogenous mel at oni n wi l l
suppr ess endogenous product i on.
( e) Mel at oni n may be dosed as 0. 3- 5 mg duri ng t he day or at ni ght , dependi ng on
t he desi r ed ef f ect . A physi ol ogi c dose of mel at oni n i s 0. 1 mg, an i nt ermedi at e dose
i s 0. 3 mg, and a pharmacol ogi c dose i s 3 mg. Doses > 1 mg may i mpr ove sl eep
ef f i ci ency but have not demonst rated the abi I i ty t o provi de quaI i t y sI eep
rest orati on as wel l as t he i nt ermedi at e dose.
( f ) At t ri but abl e t o i t s shor t hal f -l i f e ( 30- 50 mi n) , mel at oni n shoul d have mi ni maI , i f
any, resi duaI ef fects t he f oI I owi ng morni ng.
( 4) VaI eri an root, der i ved f r om Val eri ana of f i ci nal i s, i s cl assi f i ed as general l y
r ecogni zed as saf e ( GRAS) f or f ood use i n t he Uni t ed St at es. Ì n doses of 600
mg/ day, val er i an r oot i s pur por t ed t o i nduce sedat i on t hrough i t s bl ockade of v-
ami nobut yr i c aci d ( GABA) br eakdown. Adverse react i ons of val er i an root i ncl ude
vi vi d dr eami ng. Fur t her resear ch i s necessar y t o det ermi ne t he saf et y and ef f i cacy
of val er i an root as a sl eep ai d.
( 5) Kava, deri ved f r om Pi per met hyst i cum, i s one of t he most common di et ar y
suppl ement s used i n t he sel f -management of anxi et y. Ì t i s t heor i zed t hat i f i nsomni a
i s caused by a st at e of hyper ar ousal , t hen management of anxi et y and nervousness
wi l l hel p i nduce t he desi red sl eep.
( a) A t ypi cal dose of kava i s 120 mg/ day.
( b) Repor t ed adver se ef f ect s of kava are si gni f i cant , i ncl udi ng di ar r hea,
ext r apyr ami dal si de ef f ect s, and hepat ot oxi ci t y. A r ecent FDA advi sor y has
recommended agai nst the use of kava because of t he report s of hepatot oxi ci t y,
i ncl udi ng hepat i t i s, ci r r hosi s, and l i ver f ai l ur e.
( 6) L- Tr ypt ophan was banned i n 1989 owi ng t o i t s associ at i on wi t h eosi nophi I i a-
myaI gi a syndrome; however , i t r emai ns avai l abl e as a 500- mg capsul e. The saf et y
and ef f i cacy of L-t r ypt ophan as a sl eep ai d has not been st udi ed and shoul d not be
r ecommended at t hi s t i me.
III. SMOKING CESSATION
A. I nt roduct i on. Mor e t han 400, 000 deat hs annual l y ar e at t r i but abl e t o di seases
di r ect l y l i nked t o ci gar et t e smoki ng, i ncl udi ng at her oscl er ot i c vascul ar di sease, l ung
cancer, and chroni c obst r uct i ve pul monar y di sease. Ì t i s t he most pr event abl e
cont r i but or t o mor bi di t y and mort al i t y i n t he Uni t ed St at es and yet nearl y one t hi r d
of t he adul t popul at i on (approxi mat el y 48 mi l l i on
P. 653

adul t s) cont i nues t o smoke. The r esul t i ng economi c bur den i s st ar t l i ng, est i mat ed at
$50 bi l l i on annual l y t o t reat smoki ng- r el at ed di sor ders and $47 bi l l i on f or t he l oss of
wages and pr oduct i vi t y.
B. Physi oI ogi c ef fect s of ni cot i ne i nvol ve t he CNS ( e. g. , enhanced r el axat i on,
i mproved at t ent i on) and t he cardi ovascul ar syst em ( e. g. , el evat ed bl ood pr essur e,
t achycardi a). The mani f est at i ons of smoki ng become more pronounced as one ages
and may i ncl ude any or al l of t he f ol l owi ng: deepeni ng of t he voi ce ( an unt owar d
ef f ect i n women) ; a const ant , hacki ng cough; yel l owed f i ngernai l s and surr oundi ng
ski n f r om subst ances f ound i n ci gar et t e smoke; and premat ur e agi ng of t he ski n,
most not i ceabl e on t he f ace.
C. Benefi t s of smoki ng cessat i on are evi dent f or bot h t he pat i ent and soci et y.
1. Pat i ent
a. Decr eased carbon monoxi de l evel s
b. Rest orat i on of ol f act or y and gust at or y senses wi t hi n days
c. Ì ncreased sel f - respect , sense of accompl i shment
d. Ì mpr oved l ung f unct i on ( up t o 30%) wi t hi n 2-3 mont hs
e. Reduct i on i n t he ri sk of cor onar y hear t di sease ( 50%) af t er 1 year . Af t er 2 year s,
t he ri sk i s equi val ent t o i ndi vi dual s who never smoked.
f . Par al l el ri sk of st r oke t o t hat of a nonsmoker wi t hi n 5- 15 years
g. Pr ogr essi ve decl i ne i n t he r i sk of l ung cancer as number of year s of abst i nence
i ncreases. However , t he r i sk wi l l never be equi val ent t o one who never smoked.
2. Soci et y
a. Decr eased heal t hcare cost s f or t reat ment of di seases di r ect l y l i nked t o smoki ng
b. Decr eased wor k absent eei sm owi ng t o smoki ng r el at ed di sease
c. Cl eaner envi r onment f r om decr eased secondhand smoke and ci gar et t e remai ns
( e. g. , ashes or but t s of ci garet t es) i n publ i c pl aces
D. CompI i cat i ons of smoki ng cessat i on. Smoki ng i s an addi ct i on and, t her ef or e,
not easy t o gi ve up. Ni cot i ne wi t hdr awal sympt oms i ncl ude t obacco cr avi ngs,
depressed mood, i nsomni a, i r r i t abi l i t y, i nabi l i t y t o concent rat e, anxi et y, decr eased
hear t r at e, and i ncr eased hunger . Ì n a 1991 st udy i n whi ch i ndi vi dual s t r i ed t o st op
smoki ng wi t hout ai d, al l sympt oms of ni cot i ne wi t hdr awal resol ved wi t hi n 30 days,
except i ncreased hunger, whi ch persi st ed past t he 30-day cessat i on per i od.
E. Tai I ored i ntervent i ons f or smoki ng cessat i on shoul d be of f er ed t o ever y pat i ent
who smokes. The U. S. Publ i c Heal t h Ser vi ce endor ses an approach known as t he
5As, devel oped i n 1996 by t he Agency f or Heal t h Car e Pol i cy and Research:
1. Ask pat i ent s i f t hey smoke.
2. Advi se pat i ent s who smoke t o qui t .
3. Assess t he pat i ent ' s wi l l i ngness t o qui t .
4. Assi st t he pat i ent i n ef f ort s t o qui t t hr ough counsel i ng and/ or phar macol ogi c
t her apy. ( The combi nat i on of counsel i ng and pharmacol ogi c t herapy has pr oven t o
be t he most successf ul met hod. )
5. Arrange f ol l ow- up wi t hi n a short t i me f rame.
6. To assess t he pat i ent ' s wi l l i ngness t o qui t , t he t r anst heoret i cal model of behavi or
change may be a usef ul t ool . Accor di ng t o t hi s model , pat i ent s ar e i n one of f i ve
mot i vat i onal st ages t o change t hei r cur r ent behavi or ÷t hat i s, t o st op smoki ng:
a. Pre-contempI at i on. Pat i ent i s not r eady t o change curr ent behavi or .
b. ContempI at i on. Pat i ent i s consi deri ng a change i n cur rent behavi or i n t he f ut ur e
but not at t he pr esent t i me.
c. Preparati on. Pat i ent i s act i vel y consi der i ng a change i n cur r ent behavi or and i s
act i vel y engaged i n seeki ng more i nf or mat i on.
d. Act i on. Pat i ent i s act i vel y at t empt i ng t o change behavi or or has changed
behavi or wi t hi n t he l ast 6 mont hs
e. Mai ntenance. Pat i ent has sust ai ned changed behavi or f or at l east 6 mont hs.
P. 654


7. For pat i ent s i n t he pr econt empl at i on and cont empl at i on st ages, t he heal t hcar e
pr of essi onal shoul d st i l l advi se t he pat i ent t o qui t smoki ng and repeat t he
assessment at f ut ur e vi si t s. For pat i ent s i n t he cont empl at i on st age, t he heal t hcar e
pr of essi onal shoul d assi st t he pat i ent by of f eri ng a r ef er ral f or smoki ng- cessat i on
counsel i ng and/ or phar macol ogi c t her apy. Behavi or modi f i cat i on wor ks best as a
mul t i di sci pl i nar y appr oach, i nvol vi ng t he heal t hcar e provi der, pharmaci st , nur se,
and dent i st .
F. Ni cot i ne- RepI acement Therapy
1. Overvi ew. Ni cot i ne- repl acement t her apy ( NRT) i s a smoki ng- cessat i on ai d used
t o amel i or at e ni cot i ne wi t hdr awal sympt oms by provi di ng a nont obacco, cont roI I ed-
reI ease amount of ni cot i ne.
a. Resear ch has demonst r at ed t hat t he use of NRT i n i ndi vi dual s who smoke > 10
ci gar et t es a day can doubI e the chances of successf uI smoki ng cessat i on; but i t
i s most successf ul when combi ned wi t h ot her nonphar macol ogi c measur es, such as
counsel i ng.
b. Cur rent l y, t hree avai l abl e dosage f orms of NRT ar e appr oved by t he FDA ( gum,
l ozenges, and pat ches) ; however , none i s ef fect i ve i f t he pati ent i s not ment aI I y
ready t o qui t . Fur t hermor e, NRT i s not ef fect i ve f or t he cessat i on of smokeI ess
t obacco (e. g. , chewi ng t obacco, ci gars, and pi pes) .
2. Safet y. Though i t i s recommended by t he U. S. Publ i c Heal t h Ser vi ce t hat al l
peopl e t r yi ng t o abst ai n f r om smoki ng shoul d r ecei ve phar macot her apy suppor t , not
ever yone i s an i deal candi dat e.
a. For pat i ent s wi t h acute cardi ovascuI ar di sease ( e. g. , st r oke, acut e myocar di al
i nf ar ct i on, unst abl e angi na) and pregnant or breast f eedi ng women, absoI ut e
abst ai nment f rom ni coti ne shouI d be recommended. However , i f t he pat i ent
makes an i nf ormed deci si on, under t he super vi si on of a pr ovi der , a r api dl y
r ever si bl e prepar at i on i s advi sabl e (e. g. , gum or l ozenge) .
b. Ì n r ecent st udi es, NRT appears t o be saf e i n pat i ent s wi t h st abI e
cardi ovascuI ar di sease. Bl ood pr essur e shoul d be moni t ored cl osel y.
c. The sal e of NRT i s rest ri ct ed t o t hose over age 18. Theref ore adol escent s
desi r i ng smoki ng cessat i on, shoul d consul t a medi cal pr ovi der .
d. Pat i ent s wi t h ast hma or depressi on ar e i nst r uct ed t o consul t t hei r physi ci an
bef ore t he use of NRT. The l evel s of cer t ai n medi cat i ons used f or management of
t hese di sease st at es (e. g. , t heophyl l i ne, i mi prami ne) may be al t er ed by smoki ng
cessat i on. The ni cot i ne f ound i n NRT does not al t er t hese l evel s.
e. Ì t i s r ecommended t hat pat i ent s do not smoke whi I e usi ng NRT because t he
pur pose of NRT i s t o al l evi at e sympt oms whi l e weani ng f rom ci gar et t es. Al t hough
some st udi es have i ndi cat ed t hat t he combi nat i on may be saf e, unt i l f ur t her
r esear ch i s conduct ed, concomi t ant use of NRT and ci gar et t es shoul d not be seen
as permi ssi bl e.
f . Pat i ent s ar e advi sed on t he l abel i ng of NRT product s not t o combi ne t wo f orms of
NRT. However , a f ew smal l st udi es have shown combi nat i ons of NRT t o be superi or
t o ei t her agent al one. Ther ef or e, some speci al i st s i n t he f i el d do recommend
combi nat i on t her apy. However , unt i l f ur t her r esear ch i s conduct ed i n t he f or m of
wel l - devel oped, l arge t r i al s, combi nat i on t her apy wi t h NRT shoul d be di scour aged
unl ess prescr i bed by t he super vi si ng medi cal pr ovi der .
3. Avai I abI e f orms of NRT
a. Ni cot i ne poI acri I ex gum r ecei ved FDA appr oval f or prescri pt i on sal es i n 1984
and nonpr escr i pt i on st at us i n 1995.
( 1) Dosi ng. Sol d under t he t rade name Ni cor et t e, t he gum i s avai l abl e i n a 2-mg
dose f or peopl e who smoke < 25 ci gar et t es dai l y and a 4- mg dose f or t hose who
smoke > 25 ci gar et t es dai l y. The t ypi cal usage i s 10 pi eces dai I y, wi t h a maxi mum
r ecommended usage of 60 mg/ day f or up t o 3 mont hs. The st rengt h of gum
purchased does not change; i nst ead, t he number of pi eces used decr eases over
t he cour se of t r eat ment (Tabl e 31- 1).
( 2) Chew-and- park method. The gum shoul d be chewed sl owl y, r el easi ng a
pepper y, t i ngl i ng sensat i on, at whi ch poi nt t he gum shoul d be " parked¨ bet ween t he
cheek and t he gum t o enhance buccal absor pt i on of t he ni cot i ne.
( 3) Adverse ef fect s most commonl y r epor t ed ar e sore j aw and mout h, mout h ul cers,
and dyspepsi a.
P. 655


Table 31-1. Recommended Scheduling of Nicotine Gum and Lozengesa
Weeks Dose
1-6 1 piece gum or 1 lozenge every 1-2 hr (at least 9/day)
7-9 1 piece gum or 1 lozenge every 2-4 hr
10-12 1 piece gum or 1 lozenge every 4-8 hr
a
The recommended scheduling oI nicotine polacrilex gum (Nicorette) and
lozenges (Commit) is identical. II nicotine is needed past the 12-week
schedule. a medical provider should be consulted.

( 4) CounseI i ng t i ps
( a) Sl owl y chew t he gum unt i l a pepper y, t i ngl i ng sensat i on i s f el t , t hen par k t he
pol acri l ex gum bet ween t he cheek and t he gum. Once t he pepper y, t i ngl i ng
sensat i on di sappears, begi n t o sl owl y chew t he gum agai n unt i l t he sensat i on
r et urns. The gum shoul d be parked i n a di f f er ent ar ea t han bef or e. Once t he gum
l ooses t he abi l i t y t o pr oduce t he pepper y, t i ngl i ng sensat i on (approxi mat el y 30 mi n),
di scard t he gum.
( b) Do not eat or dri nk f or 15 mi n before usi ng ni coti ne gum because i t r equi res
a basi c pH f or proper r el ease and absor pt i on of t he ni cot i ne.
( c) Do not use ot her f orms of NRT or smoke whi l e usi ng t he gum pr oduct , unl ess
ot her wi se di r ect ed by a super vi si ng provi der.
( d) The gum may be chewed at t he begi nni ng of t he f i r st day or at l east 30 mi n af t er
t he l ast ci gar et t e was smoked.
b. Ni cot i ne I ozenges, cur r ent l y sol d onl y under t he t r ade name Commi t , del i ver s
ni cot i ne i nt o t he buccal mucosa when t he i ndi vi dual sucks on t he t abl et , si mi l ar t o a
cough dr op.
( 1) Dosi ng. Commi t has a uni que dosi ng st rat egy, based on t he t i mi ng of t he
f i rst ci garet t e. Ì f t he f i rst ci gar et t e i s craved wi t hi n 30 mi n of waki ng, t he 4-mg
l ozenge may be r ecommended. Ì f t he f i rst ci gar et t e cr avi ng i s af t er 30 mi n of
waki ng, t he 2-mg l ozenge may be recommended. The st rengt h chosen wi I I not
change t hr oughout t he cour se of cessat i on; i nst ead f ewer l ozenges wi l l be
consumed each day duri ng t he 12-week proposed scheduI e ( Tabl e 31-1).
( 2) Adverse ef fect s. Ì f t he l ozenge i s consumed t oo qui ckl y or swal l owed ( r at her
t han di ssol ved) dyspepsi a may be exper i enced. Ot her repor t ed adver se ef f ect s
i ncl ude i nsomni a, nausea, hi ccups, coughi ng, headache, and f l at ul ence.
( 3) CounseI i ng t i ps
( a) Avoi d chewi ng or bi t i ng t he l ozenge. Rat her suck on t he l ozenge sl owl y, movi ng
i t f rom si de t o si de, unt i l i t i s compl et el y di ssol ved ( 20- 30 mi n) . Ì f acci dent al l y
swal l owed, wai t at l east 1 hr bef or e usi ng anot her l ozenge.
( b) Do not use ot her f orms of NRT and do not smoke ci garet t es whi l e usi ng t hi s
pr oduct , unl ess ot her wi se di r ect ed by a super vi si ng provi der .
( c) The f i r st l ozenge may be t aken at t he begi nni ng of t he f i r st day or at l east 30
mi n af t er t he l ast ci garet t e was smoked.
( d) Do not take more t han 20 I ozenges per day of ei t her t he 2-mg or 4-mg dose.
c. Ni cot i ne pat ches were i nt r oduced i n 1992 and acqui red nonpr escr i pt i on st at us n
1996. Compar at i ve st udi es of t he avai l abl e f ormul at i ons of NRT have reveal ed t hat
most i ndi vi dual s pref er t he pat ch over t he gum or a prescr i pt i on ni cot i ne i nhal er.
The pat ch must be pI aced on a cI ean, dr y, and hai r- f ree area (e. g. , st omach,
t hi gh, back), but not over j oi nt s ( e. g. , ankl es, knees, el bows) . The pat ch shoul d
never be pl aced over wounds or open ar eas and caut i on must be used i n t he pat i ent
wi t h severe psori asi s and eczema. The most common adverse ef f ect of t he pat ches
i s ski n i rri t at i on, but t hi s may be r educed by r ot at i ng t he pat ch si t e. Two t r ade
name nonpr escri pt i on ni cot i ne pat ches are avai l abl e: Ni coDer m CQ and Ni cot r ol .
( 1) Ni coDerm CQ may be wor n f or 16-24 hr/ day. Pat i ent s wi t h earl y- morni ng
ci gar et t e cr avi ngs may requi r e 24- hr use. However , i f i nsomni a or vi vi d dr eami ng
occurs, t he pat ch may be r emoved af t er 16 hr .
( a) Dosi ng: Ni coDerm CQ i s avai l abl e i n t hr ee st r engt hs: 21- , 14- , and 7-mg
pat ches. The pat ch shoul d be tapered over 2- 4 mont hs, dependi ng on t he st art i ng
dose.
( i ) Ni coDerm CQ 21-mg pat ch may be r ecommended t o an i ndi vi dual who smokes >
10 ci gar et t es/ day and t hen t apered as f ol l ows:
P. 656


{ 1} St ep 1: 21 mg/ day f or 6 weeks
{ 2} St ep 2: 14 mg/ day f or 2 weeks
{ 3} St ep 3: 7 mg/ day f or 2 weeks
( i i ) Those who smoke < 10 ci gar et t es/ day may begi n wi t h t he Ni coDer m CQ 14- mg
pat ch and t aper as f ol l ows:
{ 1} St ep 1: 14 mg/ day f or 6 weeks
{ 2} St ep 2: 7 mg/ day f or 2 weeks
( 2) Ni cot rol pat ches wer e f ormerl y avai l abl e onl y as a non-t aper i ng si ngl e 15-mg
dose t o be used over a 6 week per i od. The new Ni cot r ol pat ches are avai l abl e i n a
st eppi ng pat t er n si mi l ar t o Ni coder m CQ and are recommended t o be wor n f or 16
hours and removed at bedt i me.
Weeks 1- 6: St ep 1 ( 15 mg)
Weeks 7- 8: St ep 2 ( 10 mg)
Weeks 9- 10: St ep 3 ( 5 mg)
P. 657


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. AI I of t he f oI I owi ng st at ement s about di etary suppI ement s are t rue except
whi ch one?
( A) Manuf act ur er s ar e not r equi r ed t o demonst rat e product saf et y and ef f i cacy
bef ore market i ng suppl ement s.
( B) Adher ence t o good manuf act ur i ng pr act i ces i s mandat or y f or manuf act ur ers of
di et ar y suppl ement s.
( C) The U. S. Food and Dr ug Admi ni st rat i on (FDA) f i l es act i on agai nst suppl ement s
det ermi ned unsaf e.
( D) The Feder al Tr ade Commi ssi on ( FTC) t akes act i on agai nst manuf act urer s who
pr esent mi sl eadi ng pr oduct adver t i si ng.
Vi ew Answer 1. The answer i s B[ see] . 2. AI I of the f oI I owi ng stat ements
about chi t osan are t rue except whi ch one?
( A) Ì t i s a common i ngredi ent f ound i n f at - t rapper suppl ement s.
( B) Ì t i s deri ved f r om t he Ì ndi an cl ust er bean.
( C) Ì t s saf et y i s quest i onabl e f or i ndi vi dual s wi t h shel l f i sh al l er gi es.
( D) Ì t i s purpor t ed t o i nhi bi t di et ar y f at absor pt i on.
Vi ew Answer 2. The answer i s B[ see] . 3. Jane i s 36 years oI d and wants t o
I ose wei ght. Her current body mass i ndex ( BMI ) i s 32 kg/ m2, and her wai st
ci rcumf erence i s 40 i nches. She has I ost a mi ni maI amount of wei ght i n t he
past usi ng f ad di et s and nonprescri pt i on wei ght I oss product s but has been
unabI e t o mai nt ai n the wei ght I oss. Whi ch of the f oI I owi ng i s t rue regardi ng
Jane?
( A) Based on her BMÌ , Jane i s consi der ed obese.
( B) Her wai st ci rcumf erence of 40 i nches i ncr eases her ri sk f or cardi ovascul ar
di sease.
( C) A saf e r at e of wei ght l oss f or Jane woul d be 1- 2 l b/ week.
( D) Exer ci se wi l l pr ovi de onl y a modest amount of wei ght l oss but wi l l hel p her
mai nt ai n t he wei ght l oss.
( E) Al l of t he above
Vi ew Answer 3. The answer i s E[seeandand] . 4. Si nce t he sudden deat h of
hi s fat her 2 weeks ago, Bob has been unabI e to sI eep at ni ght . He has di f fi cuI t y
goi ng t o sI eep and awakens earI y i n t he morni ng, unabI e t o ret urn t o sI eep.
Whi ch of the foI I owi ng wouI d be t he correct cI assi fi cat i on of Bob' s current
i nsomni a?
( A) t r ansi ent , pr i mar y i nsomni a
( B) shor t -t erm, pr i mar y i nsomni a
( C) t r ansi ent , secondar y i nsomni a
( D) shor t - t er m, secondary i nsomni a
Vi ew Answer 4. The answer i s D[ seeand] . 5. Wi I I i am works the swi ng shi f t
at t he I ocaI manuf act uri ng pI ant. Based on a recommendat i on f rom a f ri end at
work, Wi I I i am wouI d I i ke t o t r y meI at oni n t o heI p hi m get t o sI eep faster. Whi ch
of t he f oI I owi ng i s t rue regardi ng Wi I I i am' s use of meI atoni n?
( A) An appropri at e st ar t i ng dose of mel at oni n i s 5 mg/ ni ght .
( B) Wi l l i am may exper i ence cont i nued dr owsi ness t he f ol l owi ng morni ng owi ng t o
mel at oni n' s l ong hal f -l i f e.
( C) Recent t r i al s have not ed t he ef f ect i veness of mel at oni n i n i ndi vi dual s
par t i ci pat i ng i n shi f t wor k.
( D) Al l of t he above
Vi ew Answer 5. The answer i s C[ see] . 6. Whi ch of t he f oI I owi ng
compI ement ar y aI t ernati ve medi ci nes ( CAM) has been banned because of i ts
associ ati on wi t h eosi nophi I i a- myaI gi a syndrome?
( A) mel at oni n
( B) kava
( C) L- t r ypt ophan
( D) val eri an r oot
Vi ew Answer 6. The answer i s C[ see] . 7. SyI vi a i s 33 years oI d and wi shes
t o purchase a sI eep ai d f or her recent bout of i nsomni a ( durati on 2 days) . She
has I i nked i t t o an overwheI mi ng amount of st ress she has been under I at eI y at
work, t r yi ng t o meet deadI i nes, and her recent I ack of sI eep i s not heI pi ng. She
has no current medi caI condi t i ons and takes a muI t i vi tami n dai I y. AI I of t he
f oI I owi ng are t rue regardi ng SyI vi a' s t aki ng di phenhydrami ne and doxyI ami ne
except whi ch one?
( A) Syl vi a may benef i t f rom di phenhydr ami ne 50 mg used ni ght l y.
( B) Syl vi a shoul d l i mi t t he use of di phenhydr ami ne f or i nsomni a t o 10 consecut i ve
ni ght s.
( C) Syl vi a may benef i t f rom doxyl ami ne 50 mg used ni ght l y as needed.
( D) Syl vi a may exper i ence ant i chol i ner gi c si de ef f ect s wi t h t he use of doxyl ami ne.
Vi ew Answer 7. The answer i s C[ seeand] . P. 658


8. Ji I I , a 22- year- oI d coI I ege st udent, has been encouraged by her heaI t hcare
provi der t o st op smoki ng. She t eI I s her doctor t hat she want s t o qui t but she
does not want t o gai n wei ght ri ght now or to sacri fi ce her grades as a resuI t of
an i nabi I i t y t o concent rat e duri ng t he day. Accordi ng t o t he 5As and the
t ranst heoreti caI modeI of change, what i s t he next st ep Ji I I ' s heaI t hcare
provi der shouI d t ake?
( A) Ji l l i s i n t he pr econt empl at i on st age of change. Her pr ovi der shoul d reassess her
wi l l i ngness t o qui t at t he next vi si t .
( B) Ji l l i s i n t he cont empl at i on st age of change. Her pr ovi der shoul d reassess her
wi l l i ngness t o qui t at t he next vi si t .
( C) Ji l l i s i n t he prepar at i on st age of change. Her pr ovi der shoul d r eassess her
wi l l i ngness t o qui t at t he next vi si t .
( D) Ji l l i s i n t he prepar at i on st age of change. Her pr ovi der shoul d of f er her
counsel i ng and/ or phar macol ogi c t her apy f or smoki ng cessat i on.
Vi ew Answer 8. The answer i s B[ see] . 9. Zack i s 55 years oI d and wi shes
t o st art t aki ng ni cot i ne I ozenges t o qui t smoki ng. Whi ch of the foI I owi ng i s
i mportant i n t he recommendat i on and seI ect i on of ni coti ne I ozenges?
( A) number of ci gar et t es smoked dai l y
( B) t i mi ng of hi s f i rst ur ge f or a ci gar et t e
( C) concomi t ant di sease st at es and t her api es
( D) bot h t he number of ci garet t es smoked dai l y and concomi t ant di sease st at es and
t her api es
( E) bot h t he t i mi ng of hi s f i rst ur ge f or a ci gar et t e and concomi t ant di sease st at es
and t herapi es
Vi ew Answer 9. The answer i s E[see] . 10. AI I of t he f oI I owi ng are i mport ant
counseI i ng ti ps f or t he use of ni cot i ne repI acement therapi es except whi ch
one?
( A) Do not eat or dr i nk wi t hi n 15 mi n of chewi ng ni cot i ne gum.
( B) The i ni t i al st ar t of ni cot i ne r epl acement t her apy may be 30 mi n af t er t he l ast
ci gar et t e.
( C) Ski n i r r i t at i on associ at ed wi t h t he use of a pat ch may be mi ni mi zed by r ot at i ng
t he pat ch si t e.
( D) Al l ni cot i ne pat ches shoul d be r emoved and repl aced ever y morni ng.
Vi ew Answer 10. The answer i s D[ seeand] . 11. Wendy, a 45 year oI d
f emaI e, i s seeki ng advi ce about t he use of AI I i ® f or wei ght I oss. Her current
wei ght i s 228 I bs and her hei ght i s 5' 6". At her I ast provi der vi si t , her provi der
suggest ed she set a wei ght I oss goaI of 2 pounds per week t hrough di et and
exerci se. Wendy has t ype 2 di abet es and hypert ensi on, bot h of whi ch are weI I
cont roI I ed. Whi ch of t he f oI I owi ng wouI d be appropri at e i nf ormat i on t o provi de
Wendy?
( A) Or l i st at may assi st i n modest amount s of wei ght l oss, but not i ceabl e r esul t s may
not be evi dent f or several mont hs.
( B) Or l i st at i s cont r ai ndi cat ed i n i ndi vi dual s wi t h di abet es mel l i t us.
( C) Or l i st at i s t aken as 1 capsul e t hree t i mes dai l y one hour af t er a f at - cont ai ni ng
meal .
( D) Or l i st at may r educe t he absor pt i on of f at - sol ubl e vi t ami ns, t hus a mul t i vi t ami n
shoul d be t aken when nonpr escri pt i on orl i st at i s i ni t i at ed.
Vi ew Answer 11. The answer i s A[ seeand] . P. 659


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì . C] .
Manuf act ur ers of di et ar y suppl ement s ar e not r equi red t o demonst r at e product
saf et y and ef f i cacy bef ore mar ket i ng, nor ar e t hey r equi r ed t o adher e t o good
manuf act ur i ng pract i ces.
2. The answer i s B [ see Ì . C. 5] .
Der i ved f r om t he exoskel et on of shel l f i sh, chi t osan i s pur por t ed t o bl ock di et ar y f at
absor pt i on and t hus i s a common i ngredi ent f ound i n f at - t r apper suppl ement s.
Because i t i s der i ved f rom t he exoskel et on of shel l f i sh, t he saf et y of chi t osan i n
i ndi vi dual s wi t h shel l f i sh al l er gi es r emai ns i n quest i on.
3. The answer i s E [ see Ì . A. 1 and 2; Ì . B. 1. b and c; Ì . B. 2] .
A BMÌ > 30 kg/ m2 but < 40 kg/ m2 i s consi der ed obese, but not mor bi dl y obese.
Women wi t h a wai st ci rcumf er ence > 35 i nches ar e at i ncr eased ri sk of devel opi ng
car di ovascul ar di sease, as wel l as t ype 2 di abet es, sl eep apnea, and ost eoar t hr i t i s.
Ì f Jane' s BMÌ had been > 35 kg/ m2, her wai st ci r cumf er ence measur ement woul d not
be val i d f or det er mi ni ng an i ncreased car di ovascul ar r i sk. Di et and exer ci se ar e t he
best appr oach t o wei ght l oss. A r easonabl e wei ght l oss i s 1- 2 l b. / week. Al t hough
exer ci se i s benef i ci al , i t adds a onl y modest amount t o t he wei ght l oss; i t has
gr eat er ef f ect i n t he mai nt enance of t he wei ght l oss.
4. The answer i s D [ see Ì Ì . B. 3 and 4] .
Tr ansi ent i nsomni a i s i nsomni a l ast i ng < 1 week, and shor t - t er m i nsomni a i s
i nsomni a l ast i ng f r om 1 t o 4 weeks. Pr i mar y i nsomni a i s a pat hol ogi cal condi t i on i n
whi ch t he pat i ent exper i ences cont i nued i nsomni a i n t he absence of a r el at ed
medi cal or psychi at r i c condi t i on. Secondar y i nsomni a can be at t r i but ed t o a var i et y
of si t uat i ons, especi al l y si t uat i onal st ress, such as t he deat h of a l oved one.
5. The answer i s C [ see Ì Ì . B. 5. b. ( 3) ] .
Mel at oni n ef f ect i veness f or sl eep onset has been obser ved i n recent t r i al s i n
i ndi vi dual s par t i ci pat i ng i n shi f t wor k. However , mel at oni n i s not FDA appr oved f or
t hi s pur pose. An i ni t i al st ar t i ng dose of mel at oni n i s 0. 1- 0. 3 mg i n t he eveni ng f or
pat i ent s desi r i ng i mpr oved sl eep onset . Doses > 1 mg dai l y have not been abl e t o
demonst r at e t he qual i t y sl eep rest or at i on seen i n 0. 3-mg doses. Mel at oni n has
mi ni mal , i f any, r esi dual ef f ect s t he f ol l owi ng morni ng, owi ng t o i t s short hal f -l i f e of
30- 50 mi n.
6. The answer i s C [ see Ì Ì . B. 5. b. ( 6) ] .
L- Tr ypt ophan was banned i n 1989 because of i t s associ at i on wi t h eosi nophi l i a-
myal gi a syndrome. However , i t r emai ns avai l abl e f or sal e as a 500-mg capsul e.
7. The answer i s C [ see Ì Ì . B. 5. b. ( 1) and ( 2) ] .
Di phenhydrami ne may be dosed as 25- 50 mg ni ght l y f or a sl eep ai d used f or up t o
7- 10 consecut i ve ni ght s. The r ecommended dosage f or doxyl ami ne i s 25 mg ni ght l y.
Bot h di phenhydr ami ne and doxyl ami ne are et hanol ami ne ant i hi st ami nes. Ther ef ore,
ant i chol i nergi c ef f ect s may be exper i enced wi t h t he use of ei t her agent .
8. The answer i s B [ see Ì Ì Ì . E] .
Ji l l i s i n t he cont empl at i on st age, as she i s consi der i ng a change i n t he f ut ur e, but
she does not f eel t hat t hi s i s t he ri ght t i me t o begi n a smoki ng cessat i on pr ogr am.
Ther ef ore, Ji l l ' s pr ovi der shoul d r eassess her wi l l i ngness t o qui t at her next vi si t ,
when, i t i s hoped t hat Ji l l wi l l be ready t o qui t .
9. The answer i s E [ see Ì Ì Ì . F. 3. b] .
The onl y cur rent l y avai l abl e ni cot i ne l ozenge i s Commi t , whi ch i s uni que i n i t s
dosi ng st r at egy. Dosi ng i s based on t he t i mi ng of t he f i rst ur ge f or a ci garet t e, ei t her
wi t hi n or af t er 30 mi n of waki ng up. Concomi t ant di sease st at es shoul d be
consi dered as wel l . Ì f t he pat i ent has hyper t ensi on, he wi l l need t o be moni t or ed
mor e cl osel y whi l e usi ng ni cot i ne r epl acement t her apy. Ì f he uses cer t ai n
pr escri pt i on medi cat i ons f or ast hma or depr essi on, hi s medi cat i on may need t o be
adj ust ed when he st ops smoki ng.
10. The answer i s D [ see Ì Ì Ì . F. 3. a, b and c] .
Ni cot r ol ni cot i ne pat ches ar e t o be used onl y dur i ng t he dayt i me f or 16 hr and
r emoved bef ore bed. Ni coDer m CQ pat ches may be wor n f or 24 hr i f earl y- morni ng
cr avi ngs f or ci garet t es ar e st r ong. Ì f t he pat i ent devel ops i nsomni a or vi vi d dr eams
f r om Ni coDerm CQ, he or she may benef i t f r om removi ng t he pat ch bef ore bed, t hus
al l owi ng onl y 16 hr of exposur e t o t he ni cot i ne.
P. 660


11. The answer i s A [ see Ì . B. 2. a, b and c] .
Or l i st at may al t er met abol i c cont r ol , necessi t at i ng a change i n di abet es medi cat i on
dosi ng r egi men, however , or l i st at i s not cont r ai ndi cat ed i n pat i ent s wi t h di abet es.
Or l i st at i s dosed as 1 capsul e t hr ee t i mes dai l y wi t h a f at - cont ai ni ng meal , but f or
opt i mal ef f ect s, i t shoul d be dosed duri ng or wi t hi n 1 hour of t he meal not af t er t he
meal . Ì t i s advi sabl e t o recommend a mul t i vi t ami n t o i ndi vi dual s who wi l l be usi ng
doses of or l i st at gr eat er t han 180 mg/ day or who wi l l be usi ng orl i st at f or gr eat er
t han 2- 3 mont hs. However , at i ni t i at i on of nonprescri pt i on st r engt h or l i st at ( 60 mg
TÌ D) , a mul t i vi t ami n has not been obser ved as necessar y; however , i t woul d be
advi sabl e i f t he i ndi vi dual does cont i nue t he medi cat i on past 2- 3 mont hs t o
r ecommend a MVÌ .

32
OTC Agents for Fever, Pain, Cough, CoId, and
AIIergic Rhinitis
Jenni f er D. Smi th
GeraI d E. Schumacher
I. ANALGESIC, ANTI-INFLAMMATORY, AND
ANTIPYRETIC AGENTS.
Over - t he-count er ( OTC) anal gesi cs and ant i pyr et i cs r el i eve mi l d t o moderat e pai n
and reduce i nf l ammat i on and f ever. These agent s ar e ef f ect i ve f or somat i c pai n
( e. g. , muscul oskel et al pai n i n t he j oi nt s; pai n f r om headache, myal gi a, and
dysmenor rhea; di scomf or t r esul t i ng f rom general i zed i nf l ammat i on), but t hey ar e not
ef f ect i ve i n r educi ng di scomf ort f r om t he vi sceral or gans ( e. g. , st omach, l ungs,
hear t ) . Sal i cyl at es and nonst er oi dal ant i - i nf l ammat or y drugs ( NSAÌ Ds) reduce pai n,
i nf l ammat i on, and f ever, but acet ami nophen gener al l y i s ef f ect i ve f or onl y pai n and
f ever .
A. Pat hogenesi s of pai n. Ì nt ense st i mul us (e. g. , t i ssue i nj ur y) r el eases subst ances
t hat sensi t i ze pai n r ecept or s t o mechani cal , t hermal , and chemi cal st i mul at i on. Thi s
t r i ggers pai n r ecept ors t o send pai n i mpul ses over af f er ent ner ve f i ber s t o t he
cent r al ner vous syst em (CNS) .
1. Awareness of pai n occurs i n t he t hal amus.
2. Pai n recogni t i on and I ocaI i zat i on occur i n t he cort ex.
3. Mechani sm of anaI gesi c, ant i - i nf I ammat or y, and ant i pyret i c act i on. These
agent s i nhi bi t (cent ral l y, per i pheral l y, or bot h) t he bi osynt hesi s of var i ous
prost agI andi ns, subst ances i nvol ved i n t he devel opment of pai n and i nf l ammat i on
as wel l as i n t he r egul at i on of body t emper at ur e.
B. SaI i cyI at es
1. Therapeut i c uses.
a. Sal i cyl at es ar e used t o r el i eve mi l d t o moderat e pai n and r educe i nf l ammat i on
and f ever .
b. Aspi ri n (acet yl sal i cyl i c aci d) , speci f i cal l y, i s al so used t o r educe t he i nci dence of
some f or ms of cardi ovascul ar di sease. Cur r ent evi dence support s a modest
r educt i on i n t he r i sk of st r okes i n women but not es l ess ef f ect i n men. On t he ot her
hand, evi dence suppor t s a si gni f i cant r educt i on i n t he r i sk of myocardi al i nf arct i on
i n men and women > 65 year s but shows l i t t l e ef f ect on younger women.
c. Men and women who have had a previ ous myocar di al i nf arct i on, st abl e and
unst abl e angi na pect or i s, or coronar y ar t er y bypass surger y, ar e candi dat es f or
aspi r i n use.
d. No consensus has emer ged on t he pr ophyl act i c use of aspi ri n i n heal t hy adul t s.
The r i sks associ at ed wi t h aspi ri n use (see Ì . B. e. d) may out wei gh t he benef i t s of i t s
wi despr ead use.
2. Mechani sm of act i on
a. AnaI gesi c and anti - i nf I ammator y act i ons. The act i on of aspi ri n resul t s f rom
bot h t he acet yl and t he sal i cyl at e por t i ons of t he dr ug. Act i ons of ot her sal i cyl at es
( e. g. , sodi um sal i cyl at e, sal i cyl sal i cyl i c aci d, chol i ne sal i cyl at e) resul t onl y f r om t he
sal i cyl at e port i on of t he agent s.
( 1) These drugs i nhi bi t cycI ooxygenase, t he enzyme t hat i s responsi bl e f or t he
f or mat i on of pr ecursors of prost agl andi ns ( PGs) and t hr omboxanes f r om ar achi doni c
aci d ( Fi gur e 32- 1) .
P. 662



Figure 32-1. Inhibition oI prostaglandin
Iormation by aspirin. nonsteroidal anti-
inIlammatory drugs (NSAIDs). and
acetaminophen.
( 2) Anal gesi a i s pr oduced mai nl y by bI ocki ng the peri pheraI generat i on of pai n
i mpuI ses medi at ed by pr ost agl andi ns and ot her chemi cal s. Anal gesi a probabl y
secondari l y i nvol ves a reduct i on i n t he awar eness of pai n i n t he CNS.
b. Ant i pyret i c act i on. The pri nci pal ant i pyr et i c act i on occurs i n t he CNS.
Sal i cyl at es act on t he hypot hal ami c heat - r egul at i ng cent er t o pr oduce peri pher al
vasodi l at i on, whi ch resul t s f rom t he i nhi bi t i on of pr ost agl andi n synt hesi s.
c. Ant i pI at eI et and ant i thromboti c act i ons
( 1) Ant i pI ateI et. Aspi ri n ( but not ot her sal i cyl at es, acet ami nophen, or NSAÌ Ds)
i rreversi bI y i nhi bi t s cycI ooxygenase i n pI at eI et s, whi ch pr event s t he f or mat i on of
t he aggregat i ng agent t hr omboxane A2.
( 2) Ant i t hrombot i c. At l ow doses, aspi ri n i nhi bi t s t hr omboxane A2 f ormat i on but has
a r el at i vel y smal l ef f ect on prost acycl i n. Thi s resul t s i n bl ocki ng t he pl at el et
aggregat i ng agent t hr omboxane A2 whi l e preser vi ng t he act i on of t he aggregat i on
i nhi bi t or pr ost acycl i n ( prost agl andi n Ì 2; PGÌ 2) .
3. Admi ni st rat i on and dosage
a. For anaI gesi a or anti pyresi s i n aduI t s, 325-650 mg ever y 4 hr or 650-1000 mg
ever y 6 hr shoul d be admi ni st er ed as needed. The maxi mum dai l y dose i s 4000 mg
f or no l onger t han 10 days f or pai n or 3 days f or f ever wi t hout consul t i ng a
physi ci an.
b. Chi I d dosage depends on age. The dosages ar e 160 mg ever y 4 hr f or chi l dren
2- 4 year s of age and 400- 480 mg ever y 4 hr f or chi l dren 9- 12 years of age.
Sal i cyl at es shoul d be gi ven f or no l onger t han 5 days f or pai n, 3 days f or f ever , and
2 days f or sor e t hr oat wi t hout consul t i ng a physi ci an.
c. The ant i rheumat i c dosage f or aduI ts i s 3600-4500 mg dai l y i n di vi ded doses.
d. For pat i ent s wi t h i schemi c heart di sease, a 325- mg dose i s gi ven dai l y. Ever y
ot her day i s r ecommended f or i ndi vi dual s wi t h st abl e or unst abl e angi na and
evol vi ng myocardi al i nf arct i on. For pat i ent s wi t hout cl i ni cal l y apparent i schemi c
hear t di sease, t he hemorr hagi c compl i cat i ons associ at ed wi t h rout i ne aspi r i n use
may out wei gh i t s benef i t , unl ess i ndi vi dual s have est abl i shed r i sk f act or s f or
at heroscl er ot i c di sease.
e. For pat i ent s at r i sk of st r oke, an 81- mg dose i s gi ven dai l y or ever y ot her day. As
descr i bed ear l i er (see Ì . B. 3. d), t he ri sks may out wei gh t he benef i t s.
f . Ant i - i nf I ammat or y dosages. Al t hough ant i pyr et i c and anal gesi c ef f ect s shoul d
appear wi t hi n t he f i rst f ew doses, t he ant i - i nf l ammat or y ef f ect may t ake 2 weeks or
mor e t o appear, even at hi gh doses. The usual ant i - i nf l ammat or y dosage of aspi r i n
i s 4000- 6000 mg/ day. The usual ant i -i nf l ammat ory dosage of i bupr of en i s 1200- 3200
mg/ day.
P. 663


4. Precauti ons
a. Hypersensi ti vi t y t o aspi ri n occur s i n up t o 0. 5% of t he popul at i on.
( 1) Al l ergi c r eact i ons r esul t i ng i n br onchoconst ri ct i on occur most f requent l y i n
peopl e wi t h nasaI poI yps.
( 2) Cross- react i vi t y wi t h ot her NSAÌ Ds occurs i n > 90% of peopl e. Cross- r eact i vi t y
wi t h acet ami nophen occur s i n 5% of peopl e.
b. Cont rai ndi cati ons. Aspi ri n i s cont rai ndi cat ed i n pat i ent s wi t h bl eedi ng di sor ders
or pept i c ul cers. Al so, aspi r i n shoul d not be gi ven t o chi l dren or t eenager s who have
a vi r al i l l ness, because Reye syndrome (i . e. , f at t y l i ver degenerat i on accompani ed
by encephal opat hy) may occur .
c. Pregnancy. Sal i cyl at es i n chr oni c hi gh doses ar e r ecommended wi t h ext r eme
caut i on dur i ng t he l ast t ri mest er of pregnancy because of :
( 1) Pot ent i al bl eedi ng probl ems i n t he mot her, f et us, or neonat e
( 2) Pr ol ongi ng or compl i cat i ng del i ver y
d. Gast roi nt est i naI ( GÌ ) di st urbances r esul t i ng f r om t he i nhi bi t i on of t he gast r i c
pr ost agl andi ns occur i n 10%-20% of peopl e at anal gesi c and ant i pyr et i c dosages.
Ant i -i nf l ammat or y regi mens af f ect up t o 40% of peopl e. These ef f ect s decr ease by
usi ng ent er i c- coat ed dosage f orms and by t aki ng sal i cyl at es wi t h f ood or l ar ge
doses of ant aci ds. Buf f ered aspi r i n product s cont ai n i nsuf f i ci ent buf f ers t o
count eract t he adver se GÌ ef f ect s of aspi r i n.
e. CNS di st urbances such as t i nni t us, di zzi ness, or headache may occur at ant i -
i nf l ammat or y doses i n some pat i ent s.
f . SaI i cyI i sm ( sal i cyl at e t oxi ci t y) may occur at ant i - i nf l ammat or y doses. Ì n addi t i on
t o t he CNS di st urbances ( see Ì . B. 4. e) , respi rat ory al kal osi s, nausea, hyper t her mi a,
conf usi on, and convul si ons may occur .
5. Si gni f i cant i nteracti ons
a. Sal i cyl at es pot ent i at e t he ef f ect of ant i coaguI ant s and t hromboI yt i c agent s.
b. Sal i cyl at es pot ent i at e ( at ant i -i nf l ammat or y doses) t he ef f ect of hypogI ycemi cs.
c. Sal i cyl at es pot ent i at e t he adverse gast r oi nt est i nal r eact i on r esul t i ng f rom chr oni c
aI cohoI or NSAI D use.
d. Aspi ri n may compet i t i vel y i nhi bi t t he met abol i sm of zi dovudi ne, resul t i ng i n
pot ent i at i on of zi dovudi ne or aspi ri n t oxi ci t y.
e. Caf fei ne t aken i n conj unct i on wi t h sal i cyl at es appears t o enhance t he anal gesi c
ef f ect .
C. Acet ami nophen
1. Therapeut i c uses. Acet ami nophen i s used t o rel i eve mi l d t o moderat e pai n and
t o r educe f ever . Gui del i nes f r om t he Ameri can Col l ege of Rheumat ol ogy now
r ecommend i t as f i r st - l i ne t her apy f or ost eoar t hri t i s of t he knee and hi p. Because i t
has mi ni mal ant i - i nf l ammat or y act i vi t y, i t cannot be used t o t r eat t he swel l i ng or
st i f f ness r esul t i ng f r om rheumat oi d ar t hr i t i s.
2. Mechani sm of act i on. The anal gesi c and ant i pyr et i c act i ons of acet ami nophen
ar e t he same as t hose f or aspi ri n (see Ì . B. 2. a and b) .
3. Admi ni st rat i on and dosage. Avai l abl e dosage f orms ar e 325 mg and 500 mg. A
pr ol onged-dosage- f orm capl et of 650 mg i s al so avai l abl e.
a. For anaI gesi a or anti pyresi s i n aduI t s, t he dosage i s 500- 1000 mg t hr ee t i mes
dai l y as needed. The maxi mum dai l y dose i s 4000 mg f or no l onger t han 10 days f or
pai n or 3 days f or f ever wi t hout consul t i ng a physi ci an. For ost eoar t hri t i s, 1000 mg
f our t i mes dai l y i s r ecommended.
b. For chi I dren age 6 years or oI der, 325 mg i s admi ni st er ed ever y 4- 6 hr as
needed. The maxi mum dai l y dose i s 1600 mg f or no l onger t han 5 days f or pai n, 3
days f or f ever , or 2 days f or sore t hr oat wi t hout consul t i ng a physi ci an.
c. Rout i ne use. Acet ami nophen i s r out i nel y used i n pat i ent s who ar e
( 1) Sensi t i ve t o t he GÌ di st urbances caused by sal i cyl at es and NSAÌ Ds
( 2) Pr one t o bl eedi ng di sor ders
( 3) Hypersensi t i ve t o sal i cyl at es
4. Precauti ons.
a. Pat i ent s wi t h act i ve al cohol i sm, hepat i c di sease, or vi r al hepat i t i s ar e at r i sk f r om
chr oni c admi ni st r at i on of acet ami nophen. Toxi ci t y i s r ar e, but chroni c dai l y i ngest i on
of 5 g or mor e f or l onger t han 1 mont h i s l i kel y t o r esul t i n l i ver damage. Acut e
doses of 10 g or mor e are hepat ot oxi c.
P. 664


b. Many OTC pr oduct s cont ai n acet ami nophen i n addi t i on t o ot her i ngredi ent s. Ì t i s
i mpor t ant t o counsel pat i ent s t hat t he dai l y dosage l i mi t s ci t ed i n Ì . C. 3. a and b
appl y t o t he t ot al acet ami nophen consumed f r om al l pr oduct s dai l y.
5. Si gni f i cant i nteracti ons. Acet ami nophen may compet i t i vel y i nhi bi t t he
met abol i sm of zi dovudi ne, r esul t i ng i n pot ent i at i on of zi dovudi ne or acet ami nophen
t oxi ci t y.
D. NSAI Ds. Cur r ent l y, i buprof en, naproxen, and ket oprof en are t he onl y NSAÌ Ds
avai l abl e wi t hout a prescr i pt i on.
1. Therapeut i c uses. NSAÌ Ds ar e used t o r el i eve mi l d t o moderat e pai n and t o
r educe i nf l ammat i on and f ever . OTC dr ug use l argel y f ocuses on t he anal gesi c and
ant i pyr et i c i ndi cat i ons of t hese agent s. Maxi mum OTC dr ug dosage i s gener al l y
r ecommended f or ost eoar t hr i t i s.
2. Mechani sm of act i on
a. AnaI gesi c and anti - i nf I ammator y act i ons. NSAÌ Ds i nhi bi t prost agl andi n
synt hesi s bot h per i pheral l y and cent r al l y. Li ke sal i cyl at es, t hese dr ugs i nhi bi t
cycl ooxygenase ( Fi gure 32- 1). NSAÌ Ds produce anal gesi a mai nl y by bl ocki ng t he
per i pheral gener at i on of pai n i mpul ses t hat ar e medi at ed by prost agl andi ns and
ot her chemi cal s. Secondar i l y, anal gesi a pr obabl y i nvol ves a r educt i on i n t he
awar eness of pai n i n t he CNS.
b. Ant i pyret i c act i on. The pri nci pal ant i pyr et i c act i on i s cent ral . NSAÌ Ds act on t he
hypot hal ami c heat - r egul at i ng cent er t o pr oduce per i pheral vasodi l at i on, whi ch
r esul t s f rom t he i nhi bi t i on of pr ost agl andi n synt hesi s.
3. Admi ni st rat i on and dosage. The avai l abl e OTC dosage f or ms of i buprof en ar e a
200-mg t abl et and a 100- mg per 5- mL or al suspensi on. Naproxen sodi um OTC i s
avai l abl e as a 220-mg (200 mg of naproxen) t abl et . Ket opr of en OTC i s sol d i n a
12. 5-mg t abl et .
a. For anaI gesi a or anti pyresi s i n aduI t s, t he dosage of i buprofen i s 200- 400 mg
ever y 4- 6 hr as needed. The maxi mum dai l y dose i s 1200 mg f or no l onger t han 10
days f or pai n or 3 days f or f ever wi t hout consul t i ng a physi ci an. For naproxen
sodi um, t he r ecommended dose i s 220 mg ever y 8- 12 hr as needed. The maxi mum
dai l y dose i s 660 mg. Ket oprof en i s recommended as 12. 5 mg ever y 4-6 hr as
needed, wi t h a maxi mum dai l y dose of 75 mg. The l i mi t at i ons on t he durat i on of
t r eat ment wi t hout consul t i ng a physi ci an r ecommended f or i bupr of en al so appl y t o
naproxen and ket opr of en.
b. For rheumatoi d art hri t i s dosage i n aduI ts, i buprof en i s recommended t o a
maxi mum dai l y dosage of 3200 mg ( admi ni st ered on a 4- t o 6- hr basi s) , naproxen
sodi um t o a dai l y maxi mum of 1100 mg ( di vi ded doses ever y 8-12 hr ) , and
ket oprof en t o a maxi mum of 300 mg per day ( admi ni st er ed ever y 4- 6 hr ) .
c. Naproxen sodi um and ketoprofen ar e not r ecommended f or chi l dr en < 12 year s
of age. I buprof en i s avai l abl e as a suspensi on f or chi l dr en 2- 11 years of age.
4. Precauti ons
a. NSAÌ Ds are cont r ai ndi cat ed i n pat i ent s wi t h bI eedi ng di sorders or pept i c
uI cers.
b. NSAÌ Ds are r ecommended wi t h ext r eme caut i on dur i ng t he l ast t r i mest er of
pregnancy because of :
( 1) Pot ent i al adver se ef f ect s on f et al bl ood f l ow
( 2) The possi bi l i t y of prol ongi ng pregnancy
c. GÌ di sturbances r esul t i ng f r om t he i nhi bi t i on of t he gast ri c pr ost agl andi ns occur
i n 5%- 10% of peopl e at anal gesi c and ant i pyr et i c doses. Ant i -i nf l ammat ory r egi mens
( i . e. , hi gher doses) af f ect up t o 20% of peopl e. These ef f ect s decrease when
NSAÌ Ds are t aken wi t h f ood or l ar ge doses of ant aci ds. Ì bupr of en i s of t en pr ef er r ed
t o aspi r i n by pat i ent s because i buprof en causes f ewer GÌ di st ur bances and bl eedi ng
event s.
d. RenaI toxi ci t y dur i ng chr oni c admi ni st r at i on i s a si gni f i cant concer n and may
occur i n t he f orm of nephr ot i c syndrome, hyperkal emi a, or i nt erst i t i al nephr i t i s.
5. Si gni f i cant i nteracti ons
a. NSAÌ Ds pot ent i at e t he ef f ect of ant i coaguI ants and t hromboI yt i c agent s.
b. NSAÌ Ds pot ent i at e (at ant i - i nf l ammat or y doses) t he ef f ect of hypogI ycemi cs.
c. NSAÌ Ds pot ent i at e t he adverse GÌ r eact i ons resul t i ng f rom chr oni c aI cohoI or
saI i cyI at e use.
d. Caf fei ne t aken i n conj unct i on wi t h i bupr of en appear s t o enhance t he anal gesi c
ef f ect .
e. Hypersensi t i vi t y t o aspi ri n can occur wi t h NSAÌ D use.
f . OTC l abel i ng f or t hese agent s caut i ons agai nst use of combi ni ng NSAÌ Ds.
P. 665


II. THE COMMON COLD
A. GeneraI
1. The common col d i s general l y a mi l d and sel f - l i mi t i ng vi ral i nf ect i on of t he upper
r espi r at or y t ract , t hough i t s economi c burden of l ost pr oduct i vi t y and expendi t ures
i n sympt om r el i ef has a si gni f i cant i mpact i n t he Uni t ed St at es.
2. Rat her t han t ypi cal epi demi ol ogi c measures, t he pr eval ence of t he common col d
i s expr essed as t he number of i nci dences per i ndi vi dual , per year . Adul t s t ypi cal l y
exper i ence 2- 3 col ds per year ; pr eschool chi l dren t ypi cal l y exper i ence 5- 7 col ds per
year . Chi l dr en < 5 years ol d who at t end daycar e or have f r equent i nt er act i ons wi t h a
number of ot her chi l dren may exper i ence as many as 12 col ds per year .
3. Appr oxi mat el y $2 bi l l i on i s spent each year i n t he Uni t ed St at es on OTC cough
and col d medi cat i ons by pat i ent s seeki ng sympt om r el i ef .
4. The common col d account s f or approxi mat el y 26 mi l l i on days of school ( peopl e
aged 5-17 year s) and 23 mi l l i on days of wor k mi ssed annual l y.
B. Et i oI ogy
1. The coronavi ruses, r espi rat or y syncyt i al vi r us ( RSV) , and rhi novi r uses ar e t he
most cont r i but i ng pat hogens of t he common col d, and t he r hi novi r us i s t he most
f r equent l y associ at ed pat hogen. Ot her pat hogens i nvol ved i ncl ude i nf l uenza,
par ai nf l uenza, and adenovi r uses.
2. Thr ee accept ed general modes of t r ansmi ssi on of t he common col d exi st : smal l -
par t i cl e aer osol s, l ar ge-par t i cl e aer osol s, and di rect cont act . Di r ect cont act bet ween
t he vi rus and t he nasal mucosa i s t he most pr eval ent mechani sm of t r ansmi ssi on of
t he rhi novi r us.
3. Col ds occur year- r ound, but peak i nci dences of t he common col d are Sept ember ,
Oct ober , and earl y spr i ng ( Mar ch and Apr i l ) .
C. Pat hogenesi s. Pat hogeni c event s of t he common col d caused by t he r hi novi r us
begi n when a smal l dose of vi rus i s deposi t ed i nt o t he nose or t he eye ei t her by
di r ect cont act or by aer osol t r ansmi ssi on ( Fi gure 32. 2).
1. Mucoci l i ar y act i on t r anspor t s t he vi rus t o t he adenoi d wher e t he vi r us i s abl e t o
at t ach t o t he i nt r acel l ul ar adhesi on mol ecul e ( Ì CAM) r ecept or s on l ymphoepi t hel i al
cel l s. Ther e, t he vi rus begi ns t o r epl i cat e, t r i gger i ng t he rel ease of i nf l ammat or y
medi at or s, i ncl udi ng hi st ami nes, ki ni ns, cert ai n pr ost agl andi ns, and several
i nt er l euki ns ( e. g. , i nt erl euki n 1 [ Ì L- 1] , Ì L-6, and Ì L- 8) .
2. Wi t hi n 8- 12 hr of vi ral ent r y i nt o t he nose or eye, t he i nf l ammat or y medi at or s and
par asympat het i c ner vous syst em r ef l ex mechani sms l ead t o nasal congest i on,
r hi nor r hea, sore t hr oat , headache, and st i mul at i on of cough and sneezi ng r ef l exes.
3. Col d sympt oms decl i ne and t he ri sk of t ransmi ssi on of t he vi r us i s mi ni mi zed af t er
3 days of i nf ect i on.
D. Sympt oms
1. Once vi ral cont act has been made, i ndi vi dual s may begi n t o not i ce a scr at chy
t hr oat 1-2 days af t er cont act .
2. A sore t hr oat i s f ol l owed by a t hi n, wat er y di schar ge, known as rhi nor r hea, and
sneezi ng. Wi t hi n 1- 2 days, t he t hi n, wat er y di schar ge may become t hi ck and
pur ul ent .
3. A dr y, nonproduct i ve cough may devel op bet ween days 3 and 5, of t en evol vi ng
i nt o a pr oduct i ve cough.
4. The gener al peak of col d sympt oms i s 2-4 days, and t he medi an durat i on of t he
common col d i s 7- 13 days.
5. The pharmaci st may recommend sel f - t r eat ment f or t he f ol l owi ng condi t i ons:
r hi nor r hea, congest i on, cough, headache, and sore t hroat .
P. 666



Figure 32-2. Pathogenesis oI the common cold.
E. NonpharmacoI ogi c t reat ment
1. Adequat e f l ui d i nt ake
2. Adequat e r est
3. Ì ncreased humi di f i cat i on
4. Nasal i r ri gat i on
F. PharmacoI ogi c t reatment
1. Decongestant s, al so known as sympat homi met i cs, ar e t he pri mar y t r eat ment f or
nasal congest i on.
a. Bot h or al and t opi cal decongest ant s pr oduce vasoconst r i ct i on by st i mul at i ng q-
adr ener gi c r ecept ors, t her eby reduci ng t he vol ume of bl ood ci rcul at ed t o t he nasal
mucosa and decr easi ng mucosal edema.
b. Onl y under t he advi ce of a medi caI provi der, and wi t h ext reme cauti on shoul d
decongest ant s be recommended to pat i ent s wi th di sease st at es t hat are
sensi t i ve t o adrenergi c st i muI ati on, i ncl udi ng cor onar y hear t di sease,
hyper t ensi on, t hyr oi d di sease, di abet es, nar r ow- angl e gl aucoma, and di f f i cul t y i n
ur i nat i on owi ng t o an enl ar ged prost at e gl and.
c. Pat i ent s currentI y t aki ng monoami ne oxi dase i nhi bi t ors ( MAOÌ s) or who are
wi t hi n 2 weeks of di scont i nuat i on shouI d avoi d t he use of oraI and t opi caI
decongest ants owi ng t o an i ncr eased ef f ect on bl ood pressure ( Tabl e 32-1) .
d. I nt ranasaI decongestant s cause l ocal i zed vasoconst r i ct i on by bi ndi ng di r ect l y t o
adr ener gi c r ecept ors. Ì f t he medi cat i on i s used appr opri at el y, syst emi c si de ef f ect s
shoul d be mi ni mal . However , gi ven t he di f f i cul t y of admi ni st r at i on, syst emi c si de
ef f ect s are of t en seen wi t h t opi cal decongest ant s. Tabl e 32-2 provi des advi ce f or
pat i ent counsel i ng on devi ce sel ect ed.
P. 667


Table 32-1. Available Topical and Oral Decongestants
Agent Products Dosing Avoid Use In .
Comments/Coun
seling Points
Topical decongestants
Oxymetazoli
ne
AIrin;
Neo-
Synephr
ine 12
hr;
Vicks
Sinex
12 hr;
Mucine
x Full
Force;
and
Mucine
x
Moistur
e Smart
2-3
sprays
q10-12h
Questionabl
e use in
hypertensio
n or
receiving
MAOI
Mav
exacerbate:
hyperthyroi
dism.
intraocular
pressure.
coronary
heart
disease.
prostatic
hypertrophy
Use Ior only
3-5 days
owing to
potential Ior
rebound
congestion
(rhinitis
medicamento
sa)
Oxymetazoli
ne is long
acting
Adverse
effects.
cardiovascula
r and CNS
stimulation;
burning;
stinging;
sneezing
Phenylephrin
e
Neo-
Synephr
ine;
Vicks
Sinex
2-3 gtt
q4h

Xylometazoli
ne
discontinued.
but generics
available
Naphazoline
(previously
sold as
Otrivin) has
been
removed
Irom market.
but generics
may still be
available
LevmetamIet
amine
Vicks
Vapor
Inhaler
6-12
vears. 1
inhalati
on. no
more
than
every 2
hr
12·
vears. 2
inhalati
ons. no
more
than
every 2
hr

Does not
cause rhinitis
medicamento
sa within a 7-
day period;
thus
approved Ior
up to 7-day
use
Lacks
vasopressor
eIIect; thus
not
contraindicat
ed in patients
with
hypertension.
thyroid
disease.
diabetes.
narrow-angle
glaucoma. or
diIIiculty in
urination
owing to
enlarged
prostate
Oral decongestants
Pseudoephedr
ine
SudaIed
;
Drixoral
2-6
vears.
15 mg
q4-6h
6-12
vears.
30 mg
q4-6h
12·
vears.
60 mg
q4-6h
Hypertensio
n
Mav
exacerbate:
hyperthyroi
dism.
intraocular
pressure.
coronary
heart
disease.
prostatic
hypertrophy
Pseudoephed
rine is
absorbed
well orally;
however.
phenylephrin
e has low
oral
bioavailabilit
y
Adverse
effects.
cardiovascula
r (| BP.
arrhythmias.
tachycardia)
and CNS
stimulation
(restlessness.
insomnia.
anxiety.
hallucination
s)
Phenylephrin
e
SudaIed
PE
2-6y:
2.5 mg
q4h
6-12y:
5 mg
q4h
12 ¹ y:
10 mg
q4h
Concomitant
use with
TCA may
aIIect BP (|
or|).
depending on
speciIic
decongestant
BP. blood pressure; CNS. central nervous system; MAOI. monoamine
oxidase inhibitor; TCA. tricyclic antidepressant.

P. 668


Table 32-2. Patient Counseling Information for Nasal Decongestants
Drops Spray (Atomizer) Inhalers
Metered-Dose
Pump (Spray)
• Blow
nose
• Squee
ze
rubber
bulb
on
droppe
r and
withdr
aw
medic
ation
Irom
bottle
• Reclin
e on
bed
and
hang
head
over
side
(preIer
red) or
tilt
head
back
while
standi
ng or
sitting
• Place
drops
into
each
nostril
and
gently
tilt
head
Irom
side to
side to
• Blow
nose
• Remove
cap Irom
spray
containe
r
• For best
results.
do not
shake
squeeze
bottle
• Adminis
ter one
spray
with
head in
upright
position
• SniII
deeply
while
squeezin
g bottle
• Wait 3-5
min.
then
blow
nose
• Adminis
ter
another
spray iI
necessar
y
• Rinse
spray tip
with hot
water.
taking
care not
to allow
water to
• Blow
nose
• Warm
inhaler
in
hand
to
increa
se
volatil
ity oI
medic
ation
• Remo
ve
protect
ive
cap
• Inhale
medic
ated
vapor
in one
nostril
while
closin
g oII
other
nostril
;
repeat
in
other
nostril
• Wipe
inhaler
clean
aIter
each
use
• Replac
e cap
immed
iately
• Blow
nose.
• Remove
protectiv
e cap
• Prime
metered
pump by
depressi
ng
several
times
(Ior Iirst
use).
pointing
away
Irom
Iace
• Hold
bottle
with
thumb at
base and
nozzle
between
Iirst and
second
Iingers
• Insert
pump
gently
into nose
with
head
upright
• Depress
pump
complete
ly. and
sniII
deeply
• Wait 3-5
min.
then
distrib
ute
drug
• Keep
head
tilted
back
Ior
severa
l
minute
s aIter
instilli
ng
drops
• Rinse
droppe
r with
hot
water
enter
bottle
• Replace
cap
• Note.
Inhale
r loses
its
potenc
y aIter
2-3
month
s even
though
aroma
may
linger
blow
nose
• Adminis
ter
another
spray iI
necessar
y
• Rinse
spray tip
with hot
water.
taking
care not
to allow
water to
enter
bottle
• Replace
cap

( 1) Ì nt r anasal decongest ant s avai l abl e i n spr ays and dr ops i ncl ude phenyl ephr i ne
and t he i mi dazol i nes (oxymet azol i ne, naphazol i ne, and xyl omet azol i ne).
Xyl omet azol i ne and naphazol i ne, previ ousl y sol d under t he t r ade names of Ot r i vi n
and Pr i vi ne, respect i vel y, have been removed f rom t he market , but some gener i c
f or mul at i ons may be avai l abl e.
( 2) Ì nt r anasal decongest ant s appr oved by t he U. S. Food and Dr ug Admi ni st rat i on
( FDA) are as f ol l ows:
( a) Ephedri ne ( t opi cal ) : 0. 5%, ever y 4- 6 hr ; not l ess t han ( NLT) age 6 year s
( b) Naphazol i ne ( t opi cal ): 0. 025%- 0. 05%, ever y 4- 6 hr ; NLT age 12 years
( c) Phenyl ephri ne ( t opi cal ; Neo- Synephri ne, Nost r i l )
( i ) 0. 25%- 1%, ever y 4- 6 hr ; NLT age 6 years
( i i ) 0. 125%, ever y 4-6 hr; NLT age 2 year s
( d) Xyl omet azol i ne ( t opi cal )
( i ) 0. 05%, ever y 8- 10 hr ; NLT age 2 years
( i i ) 0. 1%, ever y 8- 10 hr ; NLT age 12 year s
( e) Oxymet azol i ne ( t opi cal ; Af r i n, Neo- Synephr i ne 12 Hour, Nost r i l l a, Muci nex)
( i ) 0. 05%, ever y 10- 12 hr ; NLT age 6 year s
( i i ) 0. 025%, ever y 10- 12 hr ; NLT age 2 years
( 3) Si de eff ects. Topi cal nasal decongest ant s may cause a t empor ar y burni ng or
st i ngi ng sensat i on when used and may al so i ncr ease nasal di schar ge.
( 4) CounseI i ng t i ps
( a) Pat i ent s usi ng t opi cal nasal decongest ant s shoul d be caut i oned t o I i mi t use of
t he product t o 3- 5 days t o avoi d r hi ni t i s medi cament osa, a wor seni ng of sympt oms
P. 669

di r ect l y r el at ed t o ext ended use and t hen di scont i nuat i on of t he product . Tr eat ment
of t hi s condi t i on i s t o sl owl y wi t hdr aw t he t opi cal decongest ant and begi n or al
decongest ant s. Topi cal nor mal sal i ne may al so be used t o r el i eve i r r i t at ed nasal
passages.
( b) To avoi d spr ead of i nf ect i on, pat i ent s shoul d be counsel ed not t o share t opi cal
nasal decongest ant s wi t h ot hers.
( 5) Levmet amf et ami ne i s an i nhal er i ngr edi ent t hat has been deemed by t he FDA
as saf e and ef f ect i ve as a nasal decongest ant . Ì t i s cur rent l y f ound i n Vi ck' s Vapor
i nhal ers.
( a) Dosi ng
( i ) Ages 12 year s and ol der : 2 i nhal at i ons i n each nost ri l no more t han ever y 2 hr
( i i ) Ages 6- 12 years: 1 i nhal at i on i n each nost ri l no mor e t han ever y 2 hr
( b) Si de ef fects. Levmet amf et ami ne l acks a vasopr essor ef f ect and, t her ef or e, does
not need t o car r y t he war ni ng f or pat i ent s wi t h car di ac condi t i ons, hypert ensi on,
hyper t hyr oi di sm, di abet es, or di f f i cul t y i n uri nat i on owi ng t o an enl ar ged pr ost at e
gl and.
( c) CounseI i ng t i ps
( i ) Unl i ke t he i mi dazol i nes, l evmet amf et ami ne has not demonst r at ed r ebound
congest i on wi t hi n a 7-day per i od; t hus i t s use i s approved f or 7 days r at her t han
car r yi ng t he 3- t o 5-day l i mi t . However , t he manuf act ur ers of t he pr oduct vol unt ari l y
packaged t he product wi t h i nst r uct i ons t o seek consul t at i on wi t h a pr ovi der i f
sympt oms have not i mproved wi t hi n 3 days.
( i i ) Once opened, nasal i nhal ers shoul d be di scarded af t er 2-3 mont hs because t he
act i ve i ngr edi ent di ssi pat es, even when t he pr oduct i s t i ght l y capped.
( i i i ) Ef f i cacy of t hi s pr oduct may be di mi ni shed i n t he pat i ent who has sever el y
obst r uct ed nasal passages because i t s use r equi r es t he abi l i t y of t he medi cat i on t o
be del i ver ed t o t he nasal mucosa.
e. OraI decongest ant s avai l abl e i n t he Uni t ed St at es i ncl ude pseudoephedr i ne and
phenyl ephr i ne.
( 1) Phenyl propanol ami ne, a common i ngredi ent f ound i n wei ght -l oss and col d
pr oduct s, was wi t hdr awn f r om t he market i n r ecent years owi ng t o an i ncreased
occur r ence of st r oke i n cer t ai n popul at i ons ( especi al l y women) .
( 2) Pseudoephedr i ne has qui ckl y become known i n al l st at es and communi t i es as
t he key i ngredi ent i n t he i l l egal manuf act ur i ng of met hamphet ami ne because of t he
si mpl i ci t y of t he di ver si on. The sal e of pseudoephedri ne has been r est ri ct ed, pl aci ng
i t behi nd phar macy count er s i n al l st at es.
( 3) Phenyl ephri ne i s not as easi l y conver t ed i nt o met hamphet ami ne and t hus i s
mor e r eadi l y avai l abl e t o consumer s who ar e seeki ng r el i ef f rom congest i on.
( 4) Pseudoephedri ne act s di r ect l y on bot h q- and 8- adr ener gi c recept or s,
pr oduci ng vasoconst r i ct i on of r espi r at or y mucosa, r el axat i on of t he br onchi ol es, and
i ncreased hear t r at e and cont r act i l i t y. Pseudoephedr i ne al so ent er s t he CNS r eadi l y.
( a) Dose
( i ) Pat i ent s 2- 5 years of age: 15 mg ever y 4- 6 hr ; maxi mum dose 60 mg/ 24 hr
( i i ) Pat i ent s 6-12 year s of age: 30 mg ever y 4-6 hr ; maxi mum dose 120 mg/ 24 hr
( i i i ) Pat i ent s > 12 years of age: 30-60 mg ever y 4- 6 hr or f or sust ai ned rel ease 120
mg ever y 12 hr ; maxi mum dose 240 mg/ 24 hr
( b) Si de ef f ect s i ncl ude cent r al ner vous st i mul at i on ( rest l essness, i nsomni a,
anxi et y, or hal l uci nat i ons) , hyper t ensi on, and pal pi t at i ons.
( c) Dr ug i nt eract i ons i ncl ude MAOÌ s (see Ì Ì . F. 1. c) and t r i cycl i c ant i depressant s
owi ng t o an i ncr eased pressor response.
( d) CounseI i ng t i ps
( i ) Not i f y a heal t hcar e provi der i f sympt oms wor sen or do not i mprove wi t hi n 7 days.
( i i ) Take t he l ast dose no l at er t han 4-6 hr bef ore bedt i me owi ng t o t he pot ent i al f or
i nsomni a.
( 5) Or al phenyI ephri ne i s a mor e di r ect act i ng sympat homi met i c agent t han
pseudoephedri ne because i t act s on q- adrenergi c r ecept or s and has weak act i on at
8- adr ener gi c r ecept ors. Thi s speci f i ci t y of act i on al l ows f or mi ni mi zed
car di ovascul ar si de
P. 670

ef f ect s compared t o pseudoephedr i ne, but such ef f ect s are st i l l of concern when
r ecommendi ng i t s use i n pat i ent s wi t h cor onar y hear t di sease. Though dat a i s
avai l abl e suppor t i ng t he ef f i cacy of t opi cal phenyl ephri ne, l i t t l e i s avai l abl e t o
suppor t t he ef f i cacy of or al phenyl ephr i ne. When admi ni st er ed or al l y, phenyl ephr i ne
i s met abol i zed by gut hor mones, al l owi ng onl y 38% of a 10 mg dose of
phenyl ephr i ne t o r each t he nasal passages. Pseudoephedr i ne, when admi ni st er ed
or al l y, i s abl e t o bypass t hese gut hormones, al l owi ng appr oxi mat el y 90% of a
pseudoephedri ne dose t o r each nasal passages. Thus, or al phenyl ephr i ne may have
a cl eaner cardi ovascul ar pr of i l e t han or al pseudoephedr i ne, but i t s bi oavai l abi l i t y
r educes i t s ef f i cacy si gni f i cant l y. Phenyl ephri ne i s al so an i ngr edi ent f ound i n
pr oduct s f or t he t r eat ment of hemor r hoi ds and opht hal mi c prepar at i ons f or r el i ef
f r om r edness of t he eye.
( a) Dose may be gi ven ever y 4 hr , not t o exceed si x doses wi t hi n 24 hr .
( i ) Pat i ent s 2- 5 years of age: 2. 5 mg ever y 4 hr
( i i ) Pat i ent s 6-12 year s of age: 5 mg ever y 4 hr
( i i i ) Pat i ent s > 12 years of age: 10 mg ever y 4 hr
( b) Si de ef fects may i ncl ude i ncreased hear t rat e and i nsomni a, t hough t he
occur r ence of t hese ef f ect s ar e l ess t han t hat not ed wi t h or al pseudoephedr i ne.
( c) Dr ug i nt eract i ons i ncl ude MAOÌ s (see Ì Ì . F. 1. c) and t r i cycl i c ant i depressant s
owi ng t o an i ncr eased pressor response.
( d) CounseI i ng t i p. Not i f y a heal t hcar e pr ovi der i f sympt oms wor sen or do not
i mprove wi t hi n 7 days.
f . Nasal st ri ps ( Breat he Ri ght ) are i deaI i n pregnancy, chi I dren, and i n t he eI derI y
who t ake numerous medi cati ons.
( 1) Bandage l i ke i n appear ance, nasal st r i ps f unct i on t o physi cal l y open t he nasal
passages.
( 2) Some st ri ps are avai l abl e wi t h ment hol .
( 3) The st r i p shoul d be pl aced bet ween t he bri dge and t he t i p of t he nose.
( 4) As t he st r i p at t empt s t o r esume a f l at t ened shape, t he nar es are pul l ed i nt o a
mor e opened st at e.
g. Decongest i on al t er nat i ves (e. g. , Cori ci di n HBP and i t s rel at ed l i ne of product s)
ar e market ed f or pat i ent s who are unabl e t o t ake or al or t opi cal nasal
decongest ant s.
( 1) Chl or pheni r ami ne, an ant i hi st ami ne, i s t ypi cal l y t he i ngredi ent f ound i n t hese
pr oduct s.
( 2) Ant i hi st ami nes ar e advant ageous si nce pat i ent s may onl y exper i ence mi ni mal
si de ef f ect s; however , ant i hi st ami nes f ai l t o t ar get t he pr i mar y probl em, whi ch i s
obst r uct i on of t he nasal passages.
2. Ant i hi stami nes
a. Overvi ew.
( 1) Fi rst - generati on ant i hi st ami nes have been wi del y used i n cough and col d
pr epar at i ons f or rel i ef f rom rhi nor r hea and sneezi ng, but have no ef f ect on nasal
congest i on.
( a) These agent s ar e not FDA appr oved f or use i n chi l dr en aged 2- 5 years who are
not under t he super vi si on of a medi cal pr ovi der f or such t reat ment . Many pr ovi der s
advi se agai nst t reat i ng chi l dr en f or r hi nor rhea and sneezi ng wi t h t he common col d
owi ng t o t he i ncreased r i sk of adverse ef f ect s.
( b) The best advi ce t o a car egi ver seeki ng t reat ment of a r unny nose f or a chi l d < 6
year s of age i s t o si mpl y l et i t r un i t s course because t he col d i s a sel f - l i mi t i ng vi r al
i nf ect i on.
( 2) Second- generat i on ant i hi st ami nes have not demonst r at ed ef f i cacy i n t he
common col d, at t ri but abl e t o t he l ack of subst ant i al ant i chol i nergi c act i vi t y of t hese
pr oduct s and shoul d, t her ef ore, not be recommended i n t he pat i ent seeki ng r el i ef
f r om t he common col d ( Tabl e 32- 6) .
b. Common nonpr escri pt i on f i rst - gener at i on ant i hi st ami nes
( 1) Br ompheni r ami ne ( Di met app)
( a) Pat i ent s 6-12 year s of age: 2 mg ever y 4- 6 hr ; maxi mum dose 12 mg/ 24 hr
( b) Pat i ent s > 12 year s of age: 4 mg ever y 4- 6 hr ; maxi mum dose i 24 mg/ 24 hr
( 2) Chl or pheni r ami ne ( Chl or - Tr i met on, Act i f ed) i s t he l east sedat i ng of t he f i rst -
gener at i on ant i hi st ami nes and i s consi der ed a drug of choi ce i n pregnancy f or
r hi nor r hea and sneezi ng.
P. 671


( a) Pat i ent s 6-12 year s of age: 2 mg ever y 4- 6 hr ; maxi mum dose 12 mg/ 24 hr
( b) Pat i ent s > 12 year s of age: 4 mg ever y 4- 6 hr ; maxi mum dose 24 mg/ 24 hr
( 3) Di phenhydr ami ne ( Benadr yl )
( a) Pat i ent s 6-12 year s of age: 12. 5- 25 mg ever y 4- 6 hr ; maxi mum dose 150 mg/ 24
hr
( b) Pat i ent s > 12 year s of age: 25- 50 mg ever y 4-6 hr ; maxi mum dose 300 mg/ 24 hr
( 4) Dexbr ompheni rami ne ( Dr i xor al )
( a) Pat i ent s 6-12 year s of age: 1 mg ever y 4- 6 hr ; maxi mum dose 6 mg/ 24 hr
( b) Pat i ent s > 12 year s of age: 2 mg ever y 4- 6 hour s; maxi mum dose 12 mg/ 24 hr
c. Si de ef f ect s
( 1) Owi ng t o ant i chol i nergi c pr opert i es, f i rst - gener at i on ant i hi st ami nes may cause
dr y mout h ( cot t on mout h) , bl ur r ed vi si on, di f f i cul t y i n uri nat i on, const i pat i on,
i r r i t abi l i t y, and di zzi ness.
( 2) Pat i ent s wi t h nar r ow- angl e gl aucoma and beni gn prost at i c hypert r ophy shoul d
avoi d f i rst - gener at i on ant i hi st ami nes because t he ant i chol i ner gi c act i vi t i es may
exacer bat e t hei r condi t i on.
( 3) Pat i ent s t aki ng f i rst -gener at i on ant i hi st ami nes t ypi cal l y exper i ence sedat i on, so
caut i on shoul d be t aken dr i vi ng or oper at i ng heavy machi ner y unt i l one can i dent i f y
how he or she wi l l r eact t o t he i ngredi ent s.
( 4) Though f i rst - generat i on ant i hi st ami nes cause sedat i on i n t he adul t pat i ent ,
chi l dren may exper i ence par adoxi cal CNS st i mul at i on.
3. Expectorants, al so known as mucol yt i c agent s, wor k t o l oosen sput um and t hi n
br onchi al secret i ons by i r r i t at i ng t he gast r i c mucosa and st i mul at i ng secret i ons of
t he respi rat or y t ract . Thi s i ncreases t he vol ume of t he r espi r at or y f l ui d and t hi ns
mucus. Ther ef ore, i t i s l ogi cal t o use expect orant s onl y t o t reat a pr oduct i ve cough.
The onl y avai l abl e expect or ant i s guai f enesi n, appr oved f or pat i ent s aged 2 years
and ol der . Cl i ni cal ef f i cacy of guai f enesi n as an expect or ant l acks demonst r at ed
dat a. Thus some name br ands, such as Robi t ussi n, have r emoved guai f enesi n as
t he act i ve i ngredi ent .
a. Dosi ng
( 1) Adul t s
( a) Syr up: 200- 400 mg ever y 4 hr ; maxi mum dose 2. 4 g/ day
( b) Ext ended- r el ease t abl et : 600- 1200 mg ever y 12 hr ; maxi mum dose 2. 4 g/ day
( 2) Pedi at r i c
( a) Pat i ent s 2-5 years of age: 50- 100 mg ever y 4 hr ; maxi mum dose 300 mg/ day
( b) Pat i ent s 6- 12 years of age: 100-200 mg ever y 4 hr; maxi mum dose 1. 2 g/ day
b. Si de eff ects. Guai f enesi n i s gener al l y wel l t ol er at ed, but si de ef f ect s may
i ncl ude nausea and vomi t i ng, di zzi ness, headache, r ash, or di ar r hea.
c. CounseI i ng t i ps
( 1) For enhanced ef f i cacy i n t he l ooseni ng of mucus or phl egm i n t he l ungs, pat i ent s
shoul d dri nk an ampl e amount of wat er when t aki ng guai f enesi n.
( 2) Ì f sympt oms wor sen (devel opment of f ever , r ash, or unr emi t t i ng headache) or no
i mprovement i s not ed i n 7 days, consul t a medi cal provi der.
4. Ant i t ussi ves ar e recommended f or a nonproduct i ve cough.
a. Dext r omet horphan, t hough a rel at i ve of morphi ne, i s a nonnarcot i c, havi ng no
anal gesi c or addi ct i ve proper t i es, except i n over dose. Ì t i s consi der ed equi pot ent t o
codei ne as a cough suppr essant , however , dat a demonst r at i ng i t s ef f i cacy as a
cough suppr essant i s l acki ng. Based on t hi s l ack of dat a, cl i ni ci ans ar e
r ecommendi ng agai nst t he use of dext r omet horphan as a cough suppressant , and
many manuf act ur ers ar e r espondi ng by ei t her changi ng t he act i ve i ngredi ent t o a
f i r st generat i on ant i hi st ami ne, whi ch has ef f i cacy dat a as a cough suppr essant , or
by addi ng t he f i r st generat i on ant i hi st ami ne t o t he dext r omet hor phan-cont ai ni ng
pr oduct .
( 1) Dext r omet horphan wor ks cent r al l y i n t he medul l a t o i ncrease t he cough
t hr eshol d.
( 2) Dosi ng
( a) Pat i ent s 2-5 years of age: 2. 5- 5 mg ever y 4 hr or 7. 5 mg ever y 6-8 hr ( one
quar t er of adul t dose) ; maxi mum dose 30 mg/ day
( b) Pat i ent s 6- 12 years of age: 5- 10 mg ever y 4 hr or 15 mg ever y 6- 8 hr , ;
ext ended- rel ease f or m 30 mg t wi ce dai l y ( hal f of adul t dose) ; maxi mum 60 mg/ day
( c) Pat i ent s > 12 year s of age: 10- 20 mg ever y 4 hr or 30 mg ever y 6-8 hr,
ext ended- rel ease f or m i s 60 mg t wi ce dai l y; maxi mum dose 120 mg/ day
P. 672


( 3) Adverse ef f ect s ar e not general l y seen at t ypi cal doses, but const i pat i on, GÌ
upset , abdomi nal di scomf or t , and di zzi ness may occur .
( 4) Dext r omet horphan shoul d not be r ecommended f or pat i ent s t aki ng an MAOÌ
( Nar di l or Parnat e) or who ar e wi t hi n 2 weeks of di scont i nuat i on of t hese agent s
because t he combi nat i on may cause ser ot onergi c syndrome.
( 5) Repor t s of abuse of dext r omet hor phan i n powder f or m ( capsul es) f or a euphor i c
ef f ect have recent l y i ncreased i n t he adol escent popul at i on i n t he Uni t ed St at es.
Though adverse ef f ect s of dext r omet hor phan are gener al l y beni gn i n recommended
doses, brai n damage, sei zur es, l oss of consci ousness, i r r egul ar heart beat , and
deat h have been r epor t ed wi t h abuse of t he dr ug.
b. Codei ne i s a schedul e C- V dr ug i n a cough syr up, t hus i t s sal e may be r est ri ct ed
i n some st at es.
( 1) Codei ne, l i ke dext r omet hor phan, wor ks cent ral l y i n t he medul l a t o i ncr ease t he
cough t hr eshol d.
( 2) Dosi ng of codei ne i s not recommended f or chi l dr en < t he age of 6 years.
( a) Pat i ent s 6-12 year s of age: 5- 10 mg ever y 4-6 hr ; maxi mum dose 60 mg/ day
( b) Pat i ent s > 12 year s of age: 10- 20 mg ever y 4-6 hr ; maxi mum dose 120 mg/ day
( 3) Adverse ef f ect s i ncl ude drowsi ness, nausea and vomi t i ng, exci t ement , abdomi nal
di scomf or t , or wor seni ng/ aggravat i on of const i pat i on. An over dose of codei ne may
cause deat h f r om respi r at or y depr essi on and car di ovascul ar col l apse. Caut i on
shoul d be used i n r ecommendi ng t hi s product f or pat i ent s wi t h pul monar y di sease or
short ness of breat h.
c. Fi r st gener at i on ant i hi st ami nes are one of t he f ew agent s used f or cough
suppr essi on t hat have demonst r at ed ef f i cacy. For t hi s reason, many cough
f or mul at i ons now cont ai n a f i r st generat i on ant i hi st ami ne.
( 1) As wi t h dext r omet horphan and codei ne, f i rst generat i on ant i hi st ami nes exhi bi t an
ant i t ussi ve ef f ect by act i ng cent r al l y i n t he medul l a t o suppr ess t he cough t hr eshol d.
( 2) Fi r st generat i on ant i hi st ami nes ar e not r ecommended i n chi l dr en < 6 year s of
age as an ant i t ussi ve.
( 3) Adverse ef f ect s i ncl ude somnol ence; sedat i on; and ant i chol i nergi c ef f ect s, such
as dr y mout h, bl ur red vi si on, di f f i cul t y i n uri nat i on, and const i pat i on.
d. Camphor and ment hol ar e t he onl y FDA- appr oved t opi cal ant i t ussi ves.
( 1) Topi cal oi nt ment s cont ai ni ng 4. 7%- 5. 3% camphor or 2. 6%- 2. 8% ment hol ar e FDA
approved f or al l evi at i on of cough. Li kewi se, st eam i nhal ant s cont ai ni ng 6. 2%
camphor or 3. 2% ment hol are appr oved f or use i n st eam vapori zer s.
( 2) Ment hol or camphor oi nt ment may be appl i ed as a t hi ck l ayer r ubbed i nt o t he
t hr oat and chest . A warm, dr y cl ot h may be used t o cover t he area. Appl i cat i on may
be r epeat ed up t o t hree t i mes dai l y or as di rect ed by super vi si ng physi ci an.
( 3) A ment hol and camphor pat ch may be appl i ed t o t he t hroat or chest of pat i ent s >
2 years of age. Ì f t he pat i ent has sensi t i ve ski n, t he pat ch may be appl i ed t o
cl ot hi ng coveri ng t he t hroat or chest , but t he pat ch may not adher e t o some t ypes of
pol yest er cl ot hi ng. Cl ot hi ng shoul d be l ef t l oose so t hat vapor s r each t he nose and
mout h. The pat ch shoul d be removed and a new pat ch appl i ed, i f needed, up t o
t hr ee t i mes dai l y.
( 4) Ment hol or camphor st eam i nhal ant s may be added di r ect l y t o t he wat er ( 1
t abl espoon per 1 quar t of wat er ) i n a hot st eam vapori zer , bowl , or basi n. Vapors
shoul d be breat hed i n. Thi s pr ocess may be r epeat ed up t o t hree t i mes dai l y or as
di r ect ed by super vi si ng pr ovi der .
( 5) Ì n 2002, t he FDA rul ed t hat al l t opi cal or i nhal ant pr oduct s cont ai ni ng camphor
or ment hol must war n pat i ent s t hat t hei r use near a f l ame, i n hot wat er , or i n a
mi cr owave oven may cause t he pr oduct s t o spl at t er and cause ser i ous burns t o t he
user.
( 6) Ment hol ( 5-10 mg) i s al so ef f ect i ve as an ant i t ussi ve avai l abl e i n or al l ozenges
or compr essed t abl et s. Ment hol st i mul at es col d sensor y recept or s, produci ng a
sensat i on of cool ness and a l ocal anest het i c ef f ect on t he respi rat or y passageways,
t hus engenderi ng a soot hi ng, ant i t ussi ve ef f ect .
5. I nt ranasaI normaI saI i ne, avai l abl e i n dr ops and spr ays, may be used t o moi st en
nasal membranes and assi st i n t he removal of encr ust ed secret i ons.
a. Typi cal use of most i nt r anasal normal sal i ne product s i s 2-3 sprays i n each
nost r i l as needed.
P. 673


b. Some pr oduct s may be used as a spray when hel d upr i ght , or as dr ops when hel d
upsi de down.
c. Ì nt r anasal nor mal sal i ne may be r ecommended f or use i n al l pat i ent s, i ncl udi ng
i nf ant s and pr egnant women, unl ess di r ect ed ot her wi se by a physi ci an.
6. LocaI anest het i cs i n t he f orm of l ozenges and sprays may be usef ul i n t he
al l evi at i on of a sor e t hroat . Mout hwashes have been recommended f or use i n t he
past ; however , owi ng t o l ocal i zed act i on i n t he oral cavi t y, t he phar yngeal wal l may
not be af f ect ed by t hese pr oduct s.
a. Because a sore t hr oat i s t he i ni t i al sympt om of many ot her i l l nesses, car e shoul d
be t aken t o r ecommend pr oduct s f or sore t hr oat al l evi at i on onl y t o pat i ent s who
have concur rent sympt oms of t he common col d. Ì f t he t hr oat i s red and i nf l amed,
unusual l y pai nf ul , or has persi st ed f or sever al days, t he pat i ent shoul d be r ef err ed
t o a pr i mar y-care provi der f or f urt her eval uat i on.
b. Thr oat spr ays cont ai ni ng phenol ( Chl or asept i c) ar e appr oved down t o age 2 and
t hose cont ai ni ng benzocai ne ( Cepacol ) ar e appr oved down t o age 3.
c. Thr oat l ozenges, approved f or pat i ent s ol der t han 2 years, may be used ever y 2
hr . Counsel car egi ver s t hat l ozenges are pot ent i al choki ng hazar ds i n young
chi l dren.
7. AnaI gesi cs are occasi onal l y i ndi cat ed i n t he t reat ment of common col d sympt oms
when sore t hr oat , myal gi a, and/ or headache exi st . Aspi r i n, acet ami nophen,
i bupr of en, or naproxen sodi um may be recommended, wi t h consi der at i on gi ven t o
pat i ent al l ergi es, concur rent medi cat i ons and di sease st at es, and age.
8. Combi nat i on products
a. Numerous product s are avai l abl e t hat cont ai n var i ous combi nat i ons of
ant i hi st ami nes, decongest ant s, anal gesi cs, expect orant s, and ant i t ussi ves. Cert ai n
pr oduct name desi gnat i ons hel p i dent i f y t he i ngr edi ent s.
( 1) Ni ght t i me and P. M. usual l y si gni f y t hat t he product cont ai ns di phenhydr ami ne,
chl or pheni r ami ne, or doxyl ami ne.
( 2) Si nus usual l y si gni f i es a decongest ant (e. g. , pseudoephedri ne, phenyl ephr i ne)
and/ or an anal gesi c (e. g. , acet ami nophen) .
( 3) Cough usual l y si gni f i es t hat t he product cont ai ns dext r omet hor phan, but some
al so cont ai n guai f enesi n i n combi nat i on wi t h dext r omet hor phan.
( 4) Nondr owsy, A. M. , and dayt i me usual l y i ndi cat e t hat t he pr oduct cont ai ns a
decongest ant ( e. g. , pseudoephedr i ne, phenyl ephri ne) and t ypi cal l y does not cont ai n
an ant i hi st ami ne.
( 5) Al l ergy si gni f i es t hat t he pr oduct cont ai ns an ant i hi st ami ne.
( 6) Col d and f l u i ndi cat e t hat t he product may cont ai n any combi nat i on of
i ngredi ent s, i ncl udi ng a decongest ant , ant i hi st ami ne, cough suppressant , and/ or
ant i pyr et i c.
b. Combi nat i on product s may be usef ul f or si mpl i ci t y of dosi ng and adherence i f
pat i ent s ar e exper i enci ng a vari et y of sympt oms t hat can be al l evi at ed by one
pr oduct . For exampl e, i f a pat i ent has a dr y, hacki ng, nonproduct i ve cough,
headache, and nasal congest i on, he or she may benef i t f r om a combi nat i on pr oduct
of dext r omet hor phan, acet ami nophen, and pseudoephedri ne. However , i t woul d be a
shot gun appr oach t o r ecommend a pr oduct cont ai ni ng an ant i hi st ami ne and
expect or ant i n combi nat i on wi t h ot her i ngredi ent s f or t hi s pat i ent .
c. Di sadvant ages t o combi nat i on pr oduct s occur when pr evi ousl y t r eat ed sympt oms
r esol ve, but t he pat i ent cont i nues t o t r eat ot her sympt oms wi t h t he same pr oduct .
Thi s adds unnecessar y medi cat i on(s) t o t he regi men, i ncreasi ng t he ri sk of adver se
event s. Combi nat i on pr oduct s can al so be di f f i cul t t o recommend when sel ect i ng t he
appropr i at e product f or pat i ent s wi t h coexi st i ng medi cal condi t i ons.
9. CompI ementar y t herapy
a. Zi nc gl uconat e' s ef f ect s on t he dur at i on or sever i t y of t he common col d have
been st udi ed. Resul t s have been mi xed, l endi ng t o what r emai ns a cont r over si al
subj ect .
( 1) Cur rent l i t er at ure descr i bes sever al possi bl e mechani sms by whi ch zi nc may
exer t i t s ef f ect , but such means r emai n uncl ear .
( 2) Despi t e i t s cont roversi al use, a number of zi nc product s have been f ormul at ed,
i ncl udi ng t abl et s, capsul es, chewi ng gums, l ozenges, nasal gel s, nasal spr ays, and
nasal swabs.
P. 674


( 3) Ì n st udi es showi ng t he ef f i cacy of zi nc, f ormul at i ons wer e begun wi t hi n 24- 48 hr
of t he onset of sympt oms. Lozenges are r ecommended ever y 2 hr f or t he dur at i on of
t he col d, and t he nasal spr ay i s r ecommended f our t i mes dai l y.
( 4) Si de ef f ect s report ed wi t h pr oduct s cont ai ni ng zi nc i ncl ude nausea, GÌ upset ,
and unpl easant t ast e.
b. Vi tami n C. Onl y a smal l number of st udi es have demonst rat ed t he abi l i t y of
vi t ami n C ( dose > 1 g per day) t o r educe t he f r equency or severi t y of t he common
col d. The cl i ni cal si gni f i cance of t he r esul t s of t hese st udi es r emai ns quest i onabl e.
c. Echi nacea has been used as a popul ar r emedy f or t he common col d si nce t he l at e
1800s. Unf or t unat el y, cur r ent l i t er at ur e does not gi ve def i ni t i ve suppor t i ve evi dence
f or t he ef f i cacy of Echi nacea i n t he pr event i on and/ or t r eat ment of t he common col d.
( 1) Obst acl es i n st udyi ng echi nacea l i e i n t he f act t hat t hree di f f erent speci es of
Echi nacea exi st , each wi t h a di f f erent phyt ochemi cal composi t i on. The composi t i on
may f ur t her be al t ered, dependi ng on t he part of t he pl ant used and t he t i me of year
t he pl ant i s har vest ed.
( 2) Cur rent l i t er at ure suggest s t hat f or echi nacea t o r et ai n an i mmunost i mul ant
ef f ect , i t shoul d not be t aken f or l onger t han 2-3 weeks at a t i me.
G. Excl usi ons t o sel f -t r eat ment of t he common col d
1. Fever > 101. 5°F
2. Chest pai n
3. Shor t ness of breat h
4. Wor seni ng of sympt oms or devel opment of addi t i onal sympt oms
5. Concur r ent underl yi ng chroni c cardi opul monary di seases
6. AÌ DS or chroni c i mmunosuppr essant t herapy
7. Frai l pat i ent s of advanced age
III. ALLERGIC RHINITIS
A. I nt roduct i on. Rhi ni t i s i s an i nf l ammat i on of nasal membr anes, charact er i zed by
t he f our car di nal sympt oms: nasal congest i on, r hi nor rhea, sneezi ng, and nasal
i t chi ng.
1. Bet ween 20 and 40 mi l l i on peopl e i n t he Uni t ed St at es are af f ect ed by al l er gi c
r hi ni t i s: 10-30% of t he adul t popul at i on and 40% of chi l dr en. Al l er gi c rhi ni t i s
t ypi cal l y devel ops bef ore age 20, but i t s f r equency i ncreases wi t h age unt i l
adul t hood.
2. Tr eat ment expendi t ures f or al l er gi c r hi ni t i s and l oss of product i vi t y owi ng t o
absence f r om wor k or school are r epor t ed t o be sl i ght l y over $5 bi l l i on.
3. Ri sk f act or s f or al l er gi c r hi ni t i s i ncl ude t he f ol l owi ng:
a. Fami l y hi st or y of at opy
b. Hi gher soci oeconomi c cl ass
c. Exposure t o i ndoor al l er gens ( ani mal s and dust mi t es)
d. Posi t i ve al l er gy ski n pr i ck t est
4. Al l ergi c r hi ni t i s may be cl assi f i ed as seasonal , per enni al , epi sodi c, or
occupat i onal . Seasonal and perenni al , or a combi nat i on of t he t wo, are t he most
f r equent cl assi f i cat i ons.
a. Seasonal al l er gi c rhi ni t i s. Sympt oms may occur wi t h r epet i t i ve and pr edi ct abl e
seasonal sympt oms.
b. Perenni al al l er gi c rhi ni t i s. Sympt oms per si st t hr oughout t he year wi t hout r egar d
t o changes i n seasons.
c. Combi nat i on seasonal and perenni al al l er gi c rhi ni t i s. Sympt oms per si st
t hr oughout t he year wi t h seasonal exacer bat i ons.
B. Et i oI ogy. Ther e ar e f i ve mai n t r i ggers f or al l ergi c r hi ni t i s: pol l ens, mol ds, dust
mi t es, ani mal al l ergens, and i nsect al l er gens. These al l ergens t r i gger an
i mmunogl obul i n E (Ì gE) medi at ed i mmunol ogi cal r eact i on.
P. 675


1. Seasonal al l er gi c rhi ni t i s i s t ypi cal l y caused by pol l ens and mol ds.
2. Perenni al al l er gi c rhi ni t i s i s t ypi cal l y caused by dust mi t es, mol ds, and ani mal
al l er gens.
C. Pat hogenesi s. Pat i ent s become sensi t i zed t o al l er gens; on subsequent
exposur e, t he al l er gens t r i gger a genet i cal l y pr edet ermi ned i mmune r esponse t hat
r esul t s i n t he sympt oms of al l er gi c rhi ni t i s. Al l er gi c rhi ni t i s may t hen be
charact eri zed by earl y- or l at e- phase responses.
1. Earl y- phase r esponse
a. Reexposur e t o t he al l er gen t ri gger s mast cel l s and eosi nophi l s t o gener at e
i nf l ammat or y medi at or s (e. g. , PGD2 and l eukot r i enes) and r el ease pref ormed
medi at or s ( e. g. , hi st ami ne, t r ypt ase, chymase, and ki ni nogenase) .
b. Gener at i on and rel ease of t he i nf l ammat or y medi at or s r esul t s i n i ncr eased
vascul ar permeabi l i t y, mucosal edema, and wat ery r hi nor r hea. Di l at ed bl ood vessel s
cause si nusoi dal f i l l i ng and t he subsequent nasal congest i on.
c. Sensor y ner ves ar e st i mul at ed, engender i ng a sensat i on of nasal i t ch, and t hus
sneezi ng.
2. Lat e-phase r esponse
( a) Mast - cel l - deri ved medi at or s l ead t o a mi grat i on and act i vat i on of eosi nophi l s,
neut rophi l s, and basophi l s, T l ymphocyt es, and macr ophages wi t hi n t he nasal
mucosa.
b. Duri ng t he 4-8 hr af t er al l er gen exposur e, t hese cel l s become act i vat ed and
r el ease i nf l ammat or y medi at or s, provi di ng r eoccur r ence of i ni t i al sympt oms, wi t h t he
pr edomi nant sympt om of congest i on.
D. Si gns and sympt oms. The f our cl assi c sympt oms of al l ergi c r hi ni t i s i ncl ude
r hi nor r hea, nasal congest i on, sneezi ng, and nasal prur i t us. Nasal pr ur i t us i s
t ypi cal l y not a sympt om of t he common col d. Because chi l dren of t en cannot
ver bal i ze t he sympt oms of al l er gi c rhi ni t i s, i t i s i mport ant t o r ecogni ze t he si gns.
1. Repercussi ons of nasal pr ur i t us i ncl ude t he f ol l owi ng:
a. Got hi c arch, a st eady upwar d movement of t he upper l i p and t eet h whi ch may
r esul t i n an over bi t e, as a r esul t of t he " al l er gi c sal ut e, ¨ char act eri zed by t he
const ant upwar d rubbi ng of t he nose wi t h t he pal m of t he hand.
b. Al l er gi c crease: a vi si bl e t r ansverse l i ne appear i ng bet ween t he t i p and t he
br i dge of t he nose, caused by const ant r ubbi ng.
2. Opht hal mi c condi t i ons pr esent i n t he i ndi vi dual wi t h al l er gi c r hi ni t i s i ncl ude
al l er gi c shi ner s, a darkeni ng of t he l ower eyel i d at t r i but abl e t o chr oni c nasal
obst r uct i on, and Mor gan l i nes ( al so known as t he Denni e si gn) , whi ch ar e seen as
pl eat s under t he eyes, runni ng par al l el t o t he l ower eyel i d mar gi ns.
3. Ì ndi vi dual s wi t h al l ergi c rhi ni t i s may al so exper i ence f at i gue, i r r i t abi l i t y, and
mal ai se. Owi ng t o t hese sympt oms, al l er gi c r hi ni t i s may be a cont ri but i ng f act or t o
poor school wor k i n chi l dren af f l i ct ed by t hi s condi t i on.
E. Treat ment . The pr i mar y goal i n t he t reat ment of al l er gi c rhi ni t i s i s t o cont r ol t he
sympt oms wi t hout al t er i ng t he pat i ent ' s abi l i t y t o f unct i on. Tr eat ment opt i ons i ncl ude
envi r onment al cont r ol , nonprescr i pt i on pharmacol ogi c t r eat ment , and pr escr i pt i on
t r eat ment . Thi s sect i on f ocuses on envi r onment al cont r ol and nonpr escr i pt i on
t r eat ment ( Tabl es 32- 3 and 32- 4).
1. The best t reat ment remai ns avoi dance of t he al l er gen( s) , once det ermi ned,
t hough t hi s i s somet i mes i mpr act i cal . Envi r onment al cont r ol s di rect ed t owar d
par t i cul ar al l ergens can be t he f i rst i ni t i at i ve t owar d resol ut i on of sympt oms.
2. Ant i hi st ami nes, bot h f i r st and second gener at i on, are t he mai nst ay of t reat ment
f or al l er gi c rhi ni t i s.
a. Fi r st - generat i on ant i hi st ami nes are l i mi t ed i n cont i nuous t r eat ment of al l er gi c
r hi ni t i s owi ng t o t hei r f r equent dosi ng and rel at ed sedat i on. These agent s r emai n
t he l east expensi ve t r eat ment opt i on at t hi s t i me; however , t hi s aspect must be
wei ghed agai nst t he abi l i t y t o r emai n al er t f or work and school act i vi t i es.
( 1) Owi ng t o t hei r l i pophi l i ci t y, f i r st - generat i on ant i hi st ami nes easi l y cr oss t he
bl ood- brai n bar r i er , causi ng si gni f i cant sedat i on. Though pat i ent s may not not i ce
sedat i on, st udi es have cl ear l y demonst r at ed a reduct i on i n i nt el l ect ual and mot or
f unct i on i n pat i ent s t aki ng f i rst -gener at i on ant i hi st ami nes.
P. 676


Table 32-3. Environmental Control Measures for Indoor and Outdoor Allergens
Allergen Environmental Control Measure
Indoor
Dust Mites Encase bedding or wash at least weekly in hot (130°F)
water
Remove carpets (especially in bedrooms)
Remove upholstered Iurniture

Remove stuIIed animals Irom home that cannot be
laundered
Animal
Dander
Avoid pets with Iur iI established allergen

Some patients are allergic to long-haired dogs but are not
aIIected by shorthaired breeds
Cockroaches Use oI pesticides or proIessional extermination
Mold Check houseplants oIten Ior mold growth; move outdoors
iI source oI problem
Use oI HEPA Iilter
Lower household humidity
Vent Iood preparation areas and bathrooms
Repair damp basements and crawl spaces
Apply Iungicide to obvious molded areas
Outdoor
Pollen Avoid outdoor activities when pollen counts are high
Close house and car windows
HEPA Iilters
HEPA. high-eIIiciency particulate air.

( 2) Chi l dren and t he el der l y ar e most suscept i bl e t o t he adver se ef f ect s of
ant i hi st ami nes; t hus t hey ar e at i ncr eased r i sk of exper i enci ng ni ght mar es, anxi et y,
r est l essness, unusual exci t ement , or i r r i t abi l i t y.
b. Second- gener at i on ant i hi st ami nes ar e advant ageous because of t hei r pr ef erent i al
per i pheral H1- r ecept or bi ndi ng. Thi s al l ows f or mi ni mal CNS ef f ect s, mi ni mal
sedat i ve ef f ect s, and mi ni mal ant i chol i ner gi c act i vi t y.
3. Or al decongest ant s are ef f ect i ve i n rel i evi ng sympt oms of nasal congest i on but
have no ef f ect on ot her sympt oms of al l er gi c rhi ni t i s, such as r hi nor r hea, pr uri t us, or
sneezi ng.
a. Because t reat ment of al l er gi c rhi ni t i s i s f or ext ended per i ods of t i me, or al
decongest ant s shoul d be used f or nasal congest i on r at her t han t opi cal
decongest ant s owi ng t o t he pot ent i al f or rhi ni t i s medi cament osa.
b. The combi nat i on of a decongest ant and an ant i hi st ami ne has proven t o be an
opt i mal t reat ment regi men f or al l ergi c r hi ni t i s.
c. Consi der at i on must be t aken i nt o account when r ecommendi ng pr oduct s
cont ai ni ng pseudoephedr i ne t o adol escent s and adul t s part i ci pat i ng i n spor t s
pr ograms, because of t he " dopi ng¨ ef f ect of t hese agent s.
4. Ocul ar ant i hi st ami nes may be used f or t he t reat ment of opht hal mi c condi t i ons
associ at ed wi t h al l ergi c rhi ni t i s, t hough t hei r use has been cl assi f i ed by t he FDA as
l ess t han ef f ect i ve owi ng t o a l ack of dat a demonst r at i ng cl i ni cal ef f ect i veness.
a. Cur rent l y t her e ar e t hree ocul ar ant i hi st ami nes avai l abl e on t he market :
pheni r ami ne, ant azol i ne, and ket ot i f en. Pheni r ami ne and ant azol i ne are onl y
avai l abl e i n combi nat i on wi t h naphazol i ne ( a decongest ant ) . Ket ot i f en ( Zadi t or )
became avai l abl e as a nonprescr i pt i on pr oduct i n 2007 and i s t he onl y avai l abl e
ocul ar ant i hi st ami ne t hat does not cont ai n a decongest ant .
b. Avoi d t he use of ocul ar ant i hi st ami nes i n gl aucoma, as pupi l di l at i on may cause
angl e-cl osure gl aucoma.
c. Si de ef f ect s may i ncl ude bur ni ng, st i ngi ng, i t chi ng, f orei gn body sensat i on, dr y
eye, l i d edema, and pupi l di l at i on.
5. Cr omol yn sodi um ( e. g. , Nasal cr om) i s best used as a pr event i ve measur e f or t he
sympt oms of al l er gi c rhi ni t i s but may al so be used as t reat ment f or al l sympt oms
except nasal congest i on. However , maxi mum benef i t , when used as t r eat ment , wi l l
not be seen f or 1- 2 weeks. When used f or pr event i on, cr omol yn sodi um shoul d be
i ni t i at ed appr oxi mat el y 1 week bef ore al l ergen cont act .
P. 677


P. 678


Table 32-4. OTC Treatment of Allergic Rhinitis
Agent Product(s) Dosing
Avoid Use In
.
Comments/Counse
ling Points
Nonsedating (second-generation) antihistamine
Loratadine Claritin
Alavert
Tavist
ND
Triamini
c
AllerChe
ws
2-6
vear
s. 5
mg
q24h
6·
vear
s. 10
mg
q24h

No
anticholinergic
activity
Penetrates
poorly into
CNS; Iree oI
sedating
eIIects at usual
doses
Liver/kidney
disease may
need lower
dosage
Cetirizine Zyrtec 2-5
vear
s.
2.5-
5 mg
qd
5·
vear
s. 5-
10
mg
qd
No
anticholinergic
activity
May cause
CNS
depression
Liver/kidney
disease may
need lower
dosage
Sedating (first-generation) antihistamines
Chlorpheniramin
e
Chlor-
Trimeton
2-6
vear
Narrow-
angle
Largest side
eIIect is
. ActiIed s.
1mg
q4-
6h
6-12
vear
s. 2
mg
q4-
6h
12·
vear
s. 4
mg
q4-
6h
glaucoma
MAOI
use
Prostatic
hypertrop
hy
Use
caution
in
emphyse
ma and
chronic
bronchiti
s
drowsiness.
Iollowed by
typical
anticholinergic
side eIIects
Phenindamine
may cause
nervousness
and insomnia
Children and
elderly may
experience
paradoxical
stimulation
Older adults
are likely to
have CNS
depressive side
eIIects.
including
conIusion and
hypotension
Photosensitizin
g. Advise
patients to
wear sunscreen
and protective
clothing
Chlorpheniram
ine is least
sedating and is
antihistamine
oI choice
during
pregnancy
Diphenhydramin
e
Benadryl 2-6
vear
s.
12.5
-25
mg
q4-
6h
12·
vear

s.
25-
50
mg
q4-
6h
Brompheniramin
e
Dimetap
p
6-12
vear
s. 2
mg
q4-
6h
12·
vear
s. 4
mg
q4-
6h

Phenindamine Nolahist 6-12
vear
s.
12.5
mg
q4-
6h
12·
vear
s.
25m
g
q4-
6h

Dexbromphenira
mine
Drixoral 6-12
vear
s. 1
mg
q4-
6h
12·
vear
s. 2
mg
q4-
6h
Ocular antihistamines (in combination with naphazoline)
Pheniramine Naphcon
A
Opcon-A
Visine-A
1-2
gtt
TID-
QID
Narrow-
angle
glaucoma
: pupil
dilation
can cause
angle-
closure
glaucoma
Side effects.
burning.
stinging.
itching.
Ioreign body
sensation. dry
eye. lid edema.
and pupil
dilation
Antazoline Vasocon
A
1-2
gtt
TID-
QID
Ocular Antihistamines
KetotiIen Zaditor 1-2
gtts
BID
Narrow-
angle
glaucoma
: pupil
dilation
can cause
angle-
closure
glaucoma
Side effects.
burning.
stinging.
itching.
Ioreign body
sensation. dry
eye. lid edema.
and pupil
dilation
Mast cell stabilizer
Cromolyn
sodium
Nasalcro
m
6·
vear
s. 1
spra
y in
each
nostr
il 3-
6
time
s
Most
eIIicacious iI
started beIore
seasonal
symptoms
May take 3-7
days Ior initial
response and
2-4 weeks Ior
maximal
response
daily Side effects.
sneezing. nasal
stinging.
burning
Drug oI choice
in pregnancy
Ior sneezing
and rhinorrhea
CNS. central nervous system; MAOI. monoamine oxidase inhibitor.

P. 679


a. Cr omol yn sodi um has a shor t durat i on of act i on and, t heref ore, must be dosed
t hr ee t o f our t i mes dai l y. Thi s f requency i n dosi ng may r esul t i n di mi ni shed
adher ence.
b. Cr omol yn sodi um i s appr oved f or use i n pat i ent s 2 years of age and ol der and
shoul d be dosed as one spr ay i n each nost r i l t hr ee t o f our t i mes dai l y. Ì t shoul d not
be used mor e t han si x t i mes dai l y. A provi der shoul d be consul t ed i f sympt oms
wor sen or no i mprovement i s seen wi t hi n 2 weeks.
c. Adver se ef f ect s may i ncl ude a br i ef st i ngi ng or sneezi ng di r ect l y af t er
admi ni st rat i on.
d. Cr omol yn sodi um i s consi der ed a pr ef er r ed i ni t i al drug of choi ce dur i ng
pr egnancy f or r hi norr hea and sneezi ng.
F. ExcI usi ons t o seI f - t reat ment of aI I ergi c rhi ni t i s
1. Sympt oms of ot i t i s medi a or si nusi t i s
2. Sympt oms t hat suggest l ower - r espi rat or y t r act pr obl ems
3. Hi st or y of nonal l er gi c r hi ni t i s
P. 680


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. Whi ch st atement concerni ng t he use of over- t he- counter ( OTC) anaI gesi c
agents i s t rue?
( A) Aspi r i n i s i ndi cat ed f or mi l d t o moderat e anal gesi a, i nf l ammat or y di seases,
ant i pyr esi s, and pr ophyl axi s f or pat i ent s wi t h i schemi c hear t di sease.
( B) Ì bupr of en i s i ndi cat ed f or mi l d t o moderat e anal gesi a, r educt i on of f ever , and
pr ophyl axi s f or pat i ent s wi t h i schemi c hear t di sease but not f or i nf l ammat or y
di sor der s.
( C) Acet ami nophen i s i ndi cat ed f or mi l d t o moderat e anal gesi a but not f or r educt i on
of f ever and ar t hri t i s.
( D) Napr oxen sodi um i s i ndi cat ed f or mi l d t o moder at e anal gesi a, ant i pyr esi s, and
pr ophyl axi s f or pat i ent s wi t h i schemi c hear t di sease.
Vi ew Answer 1. The answer i s A[ see] . 2. Whi ch st at ement concerni ng drug
i nt eract i ons wi t h over- the- count er ( OTC) anaI gesi c agent s i s t rue?
( A) Aspi r i n pot ent i at es t he ef f ect s of ant i hyper t ensi ves, cardi ac gl ycosi des, and
ant i coagul ant s.
( B) Ì bupr of en pot ent i at es t he ef f ect of zi dovudi ne, hypogl ycemi cs, and
ami nogl ycosi des.
( C) Acet ami nophen pot ent i at es t he ef f ect of zi dovudi ne.
( D) For napr oxen sodi um, t he OTC dosage r ecommendat i ons ar e si mi l ar t o t he
pr escri pt i on dosage.
Vi ew Answer 2. The answer i s C[ see] . 3. AI I of the f oI I owi ng stat ements
concerni ng cont rai ndi cat i ons wi t h chroni c use of over- t he- count er ( OTC)
anaI gesi c agents are correct except whi ch one?
( A) Aspi r i n, i bupr of en, napr oxen sodi um, and ket opr of en ar e cont rai ndi cat ed i n
pat i ent s wi t h bl eedi ng di sor der s, pept i c ul cer, and t he t hi r d t r i mest er of pr egnancy.
( B) Aspi r i n, acet ami nophen, and i buprof en are i mpl i cat ed i n Reye syndr ome.
( C) Acet ami nophen i s cont r ai ndi cat ed i n pat i ent s wi t h act i ve al cohol i sm, hepat i c
di sease, or vi ral hepat i t i s.
Vi ew Answer 3. The answer i s B[ see] . 4. Whi ch st at ement concerni ng
dosage recommendat i ons f or over- t he-count er ( OTC) anaI gesi c agents i s t rue?
( A) Aspi r i n f or anal gesi a or ant i pyr esi s i n adul t s i s 325- 650 mg ever y 4 hr or 650-
1000 mg ever y 6 hr, wi t h a maxi mum dai l y dose of 4000 mg f or no l onger t han 10
days f or pai n or 3 days f or f ever wi t hout consul t i ng a physi ci an; t he ant i rheumat i c
dosage f or adul t s i s 3600- 4500 mg dai l y i n di vi ded doses; and pat i ent s wi t h
i schemi c heart di sease shoul d t ake 325 mg dai l y or ever y ot her day.
( B) Ì bupr of en f or anal gesi a or ant i pyr esi s i n adul t s i s 300- 600 mg ever y 6- 8 hr , wi t h
a maxi mum dai l y dose of 1800 mg f or no l onger t han 10 days f or pai n or 3 days f or
f ever wi t hout consul t i ng a physi ci an; t he ant i - i nf l ammat or y dosage f or adul t s i s
1800- 3600 mg dai l y i n di vi ded doses.
( C) Acet ami nophen f or anal gesi a or ant i pyr esi s i n adul t s i s 325 mg ever y 8- 12 hr ,
wi t h a maxi mum dai l y dose of 2000 mg f or no l onger t han 10 days f or pai n and 3
days f or f ever wi t hout consul t i ng a physi ci an; pat i ent s wi t h i schemi c heart di sease
t ake 325 mg dai l y or ever y ot her day.
Vi ew Answer 4. The answer i s A[ see] . 5. Whi ch of t he f oI I owi ng i s an
i nhaI er i ngredi ent deemed saf e and ef fecti ve as a nasaI decongest ant ?
( A) oxymet azol i ne
( B) phenyl ephri ne
( C) l evmet amf et ami ne
( D) ephedri ne
Vi ew Answer 5. The answer i s C[ see I I . F. 1. a. ( 2)] . 6. AI i ce i s 27 years oI d
and i n t he f i rst t ri mester of her pregnancy. She needs a recommendati on f or
sneezi ng, rhi norrhea, and nasaI i t chi ng, whi ch st art ed 2 days ago. She f eeI s
mi serabI e wi t h her sympt oms, whi ch worsen when she cI eans t he house. Her
current medi cat i ons i ncI ude caI ci um carbonate and docusat e sodi um. Whi ch of
t he f oI I owi ng wouI d be t he best recommendati on f or AI i ce' s sympt oms?
( A) chl orpheni rami ne
( B) pseudoephedr i ne
( C) Br eat he Ri ght Nasal St r i ps
( D) i nt r anasal cr omol yn
Vi ew Answer 6. The answer i s A[ see] . P. 681


7. John i s a 48 year oI d maI e i nterstat e t ruck dri ver wi t h a chi ef compI ai nt of a
dr y, hacki ng cough. He st ates the cough started yest erday, but he has not had
any f ever, chi I I s, sore throat , or congest i on. Hi s onI y medi caI condi ti on i s
hypert ensi on, whi ch i s cont roI I ed wi t h hydrochI orot hi azi de ( HCTZ) . What wouI d
be t he best recommendat i on f or John' s cough?
( A) dext r omet hor phan
( B) codei ne
( C) di phenhydr ami ne
( D) guai f enesi n
Vi ew Answer 7. The answer i s A[ seeand] . 8. The appropri ate dose of
pseudoephedri ne for a 3- year- oI d chi I d i s
( A) 2. 5 mg q4- 6h.
( B) 5 mg q4-6h.
( C) 15 mg q4-6h.
( D) 30 mg q4-6h.
Vi ew Answer 8. The answer i s C[ see I I . F. 1. b. ( 1). ( a)] . For quest i ons 9- 10:
JB, a 42- year - ol d whi t e mal e, compl ai ns of a scrat chy t hr oat , nasal congest i on, and
a cough t hat st ar t ed 2 days ago. When he coughs, he br i ngs up yel l ow- whi t e
phl egm. He has hyper t ensi on and dysl i pi demi a.
9. Whi ch of the foI I owi ng wouI d be t he best recommendat i on f or JB' s cough?
( A) codei ne
( B) dext r omet hor phan
( C) di phenhydr ami ne
( D) guai f enesi n
Vi ew Answer 9. The answer i s D[ see] . 10. Whi ch of t he f oI I owi ng wouI d be
t he most appropri ate over- t he- count er ( OTC) product f or JB' s nasaI
congest i on?
( A) pseudoephedr i ne
( B) phenyl ephri ne
( C) oxymet azol i ne
( D) l evmet amf et ami ne
Vi ew Answer 10. The answer i s D[ seeand] . 11. SO, a 22- year- oI d f emaI e,
asks f or a recommendat i on f or sneezi ng, wat er y and i t chy eyes, and a runny
nose. She has no si gni fi cant medi caI hi st or y. She i s i n t he mi dst of f i naI exams
and must remai n aI ert. What wouI d be the best recommendati on for SO?
( A) Al avert
( B) Benadr yl
( C) Di met app
( D) Dr i xor al
Vi ew Answer 11. The answer i s A[ seeand] . P. 682


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see Ì . B] .
Aspi r i n i s t he onl y anal gesi c agent wi t h an appr oved l abel i ng f or anal gesi a,
ant i pyr esi s, i nf l ammat i on, and prophyl axi s f or i schemi c hear t di sease.
2. The answer i s C [ see Ì . C] .
Acet ami nophen may compet i t i vel y i nhi bi t t he met abol i sm of zi dovudi ne, resul t i ng i n
pot ent i at i on of zi dovudi ne or acet ami nophen t oxi ci t y. As f or t he ot her choi ces, OTC
dosage l evel s ar e general l y one hal f t he pr escri pt i on dosage; aspi ri n i s not
commonl y recogni zed t o i nt er act wi t h ant i hypert ensi ves or car di ac gl ycosi des; nor i s
acet ami nophen expect ed t o i nt er act wi t h ami nogl ycosi des.
3. The answer i s B [ see Ì . B. 4. b] .
Aspi r i n i s t he onl y anal gesi c agent associ at ed wi t h t he devel opment of Reye
syndr ome.
4. The answer i s A [ see Ì . B. 3; Ì . C. 3; Ì . D. 3] .
The aspi ri n dosage OTC r ecommendat i ons ar e cor r ect ; t he l evel s f or acet ami nophen
ar e t oo l ow, and f or i bupr of en, t oo hi gh. Ì n addi t i on, acet ami nophen does not car r y
an i schemi c heart di sease pr ophyl axi s r ecommendat i on.
5. The answer i s C [ see I I . F. 1. a. ( 2)] .
Levmet amf et ami ne i s an i nhal er i ngr edi ent t hat has been deemed by t he FDA as
saf e and ef f ect i ve as a nasal decongest ant . Ì t i s cur rent l y f ound i n Vi cks Vapor
Ì nhal er . Oxymet azol i ne, ephedr i ne, and phenyl ephr i ne are t opi cal nasal
decongest ant s f ound i n pumps and drops, but not i n i nhal ers.
6. The answer i s A [ see Ì Ì . F. 2. b. ( 2); Ì Ì Ì . E. 5. d] .
Rhi nor r hea, sneezi ng, and nasal i t chi ng ar e sympt oms of al l er gi c r hi ni t i s,
di f f er ent i at ed f r om t he common col d by t he nasal i t chi ng. Pseudoephedr i ne and
Br eat he Ri ght Nasal St r i ps ar e i ndi cat ed f or nasal congest i on, whi ch she does not
have. Bot h chl orpheni rami ne and i nt ranasal cr omol yn sodi um ar e r ecommended
t r eat ment s f or t he r el i ef of sneezi ng and r hi nor r hea i n pregnancy. However , t hi s
pat i ent needs r el i ef f rom sympt oms now. Cr omol yn sodi um may be used f or
t r eat ment , but wi l l t ake 1- 2 weeks f or not i ceabl e sympt om i mpr ovement .
Chl orpheni rami ne wi l l produce sympt om i mprovement wi t hi n hours.
7. The answer i s A [ see Ì Ì . F. 3 and 4] .
The compl ai nt i s a dr y, hacki ng cough, war r ant i ng t he use of an ant i t ussi ve r at her
t han an expect or ant ( e. g. , guai f enesi n) . Dext r omet horphan, di phenhydr ami ne, and
codei ne ar e al l ant i t ussi ves used f or r el i ef of a dr y, hacki ng cough. However , t he
pat i ent i n quest i on i s an i nt er st at e t r uck dri ver and codei ne and di phenhydr ami ne
wi l l bot h cause sedat i on. Ì n addi t i on, codei ne may be a l i mi t ed opt i on due t o i t s
r est ri ct ed sal e i n some st at es and t he pot ent i al f or al l ergi c r eact i ons.
Dext r omet hor phan has mi ni mal adver se ef f ect s when used at recommended doses
and may pr ovi de some rel i ef . Ì t i s al so pr udent t o advi se t hi s pat i ent t hat sympt oms
of t he common col d wi l l resol ve i n t i me wi t hout t reat ment .
8. The answer i s C [ see I I . F. 1. b. ( 1). ( a) ] .
Pseudoephedr i ne shoul d be dosed as 15 mg every 4- 6 hr up t o a maxi mum of 60 mg
i n 24 hr f or pat i ent s 2-5 year s of age. Pat i ent s aged 6- 12 years may be saf el y
r ecommended 30 mg ever y 4- 6 hr, wi t h a maxi mum r ecommended dose of 120 mg i n
24 hr. Pseudoephedr i ne i s not r ecommended f or chi l dren < 2 year s of age, unl ess
under medi cal advi ce.
9. The answer i s D [ see Ì Ì . F. 3] .
The pat i ent i s exper i enci ng a pr oduct i ve cough, as not ed by t he yel l ow- whi t e
phl egm. An expect or ant i s t he best agent f or r el i ef of a product i ve cough. The onl y
avai l abl e expect or ant i s guai f enesi n, whi ch wor ks t o l oosen sput um and t o t hi n
br onchi al secret i ons by i r r i t at i ng t he gast r i c mucosa and st i mul at es secr et i ons of
t he respi rat or y t ract .
10. The answer i s D [ see Ì Ì . F. 1. a and b] .
Pseudoephedr i ne i s an or al decongest ant , wher eas phenyl ephr i ne can be f ound as
an act i ve i ngr edi ent i n oral and t opi cal pr oduct s f or nasal congest i on.
Oxymet azol i ne and l evmet amf et ami ne are t opi cal decongest ant s. Pseudoephedr i ne,
phenyl ephr i ne, and oxymet azol i ne shoul d be used caut i ousl y i n t he pat i ent wi t h
hyper t ensi on or di abet es, despi t e adequat e cont rol , owi ng t o st i mul at i on of
adr ener gi c r ecept ors. Levmet amf et ami ne l acks a vasopressor ef f ect and, t her ef or e,
does not need t o car r y t he war ni ng f or pat i ent s wi t h cardi ac condi t i ons,
hyper t ensi on, or di abet es.
P. 683


11. The answer i s A [ see Ì Ì . F. 2. b and c; Ì Ì Ì . E. 2] .
The act i ve i ngredi ent i n Al aver t i s l or at adi ne, a second-gener at i on ant i hi st ami ne.
Benadr yl , Di met app, and Dr i xor al al l cont ai n f i rst - gener at i on ant i hi st ami nes as t he
act i ve i ngr edi ent . Though t he l east expensi ve t r eat ment opt i on, t he use of f i rst -
gener at i on ant i hi st ami nes i s l i mi t ed owi ng t o si gni f i cant sedat i on. St udi es have
cl ear l y demonst r at ed a reduct i on i n i nt el l ect ual and mot or f unct i on i n pat i ent s t aki ng
f i r st - generat i on ant i hi st ami nes. Second- gener at i on ant i hi st ami nes ar e advant ageous
because t hei r pref er ence f or per i pher al H1- r ecept or bi ndi ng. Thi s al l ows f or mi ni mal
CNS ef f ect s, sedat i ve ef f ect s, and ant i chol i ner gi c act i vi t y.

33
OTC Agents for Constipation, Diarrhea,
Hemorrhoids, and Heartburn
Laura K. Wi I I i f ord Owens
I. CONSTIPATION
A. GeneraI i nf ormat i on
1. Def i ni t i on. Const i pat i on i s def i ned as a decrease i n t he f requency of
f ecal el i mi nat i on and i s char act er i zed by t he passage of har d, dr y, and
somet i mes pai nf ul st ool s. Nor mal st ool f r equency r anges f r om t hr ee t i mes
dai l y t o t hr ee t i mes per week. Pat i ent s may exper i ence abdomi nal bl oat i ng,
headaches, l ow back pai n, and/ or a sense of r ect al f ul l ness f r om i ncompl et e
evacuat i on of f eces.
2. Epi demi oI ogy
a. Age. Const i pat i on i s common i n al l age gr oups, however ; t here i s a
hi gher pr eval ence i n peopl e > 65 years of age.
b. Gender. Women suf f er f r om const i pat i on mor e of t en t han men.
3. Causes. Const i pat i on can be caused by many f act or s, i ncl udi ng t he
f ol l owi ng:
a. Di et
( 1) Ì nsuf f i ci ent di et ar y f i ber
( 2) Ì nadequat e f l ui d i nt ake
b. Lack of exerci se
c. Poor boweI habi ts, such as f ai l ur e t o respond t o t he def ecat or y ur ge or
hur r i ed bowel s ( i . e. , i ncompl et e evacuat i on)
d. Medi cat i ons, such as narcot i c anal gesi cs, di ur et i cs, or ant i chol i ner gi cs
( e. g. , ant i depressant s, ant i hyper t ensi ves, ant i hi st ami nes, phenot hi azi nes,
ant i spasmodi cs). Ì n addi t i on, nonprescri pt i on medi cat i ons such as i r on
suppl ement s, cal ci um- or al umi num-cont ai ni ng ant aci ds, nonpr escr i pt i on
NSAÌ Ds, and hi st ami ne-2 r ecept or ant agoni st s (H2RAs) (i . e. , r ani t i di ne) may
cont r i but e t o const i pat i on.
e. Pregnancy i s a common cont r i but or t o const i pat i on. The i ncr eased si ze
of t he ut erus, hormonal changes, i nt ake of cal ci um- and i r on- cont ai ni ng
pr enat al vi t ami ns, and a r educt i on i n physi cal act i vi t y ar e al l consi der ed
cont r i but i ng f act ors.
f . Organi c probI ems, such as i nt est i nal obst r uct i on, t umor , i nf l ammat or y
bowel di sease, di ver t i cul i t i s, hypot hyroi di sm, hyper gl ycemi a, i r ri t abl e bowel
syndr ome, cer ebr ovascul ar di sease, or Par ki nson di sease
4. Pract i t i oners shouI d questi on t he pat i ent about t he f oI I owi ng:
a. Normal st ool f requency
b. Durat i on of t he const i pat i on
c. Frequency of const i pat i on epi sodes
d. Exer ci se rout i ne
e. Amount of di et ar y f i ber consumed and f l ui d i nt ake
f . Pr esence of ot her sympt oms
g. Cur rent medi cat i ons
h. Medi cat i ons used t o rel i eve const i pat i on and t hei r ef f ect i veness
B. Treatment
1. NonpharmacoI ogi caI
a. Ì ncrease i nt ake of f l ui ds (at l east ei ght 8- oz. ser vi ngs of noncaf f ei nat ed
f l ui ds dai l y) and f i ber (e. g. , whol e- gr ai n br eads and cer eal s, beans, prunes,
r ai si ns, peas, car r ot s, cor n) .
b. Ì ncr ease exer ci se t o i ncr ease and mai nt ai n bowel t one.
P. 685


c. Bowel t r ai ni ng t o i ncr ease r egul ar i t y (i . e. al l owi ng r egul ar and adequat e
t i me f or def ecat i on) .
2. PharmacoI ogi caI . Ther apeut i c agent s are cl assi f i ed accordi ng t o t hei r
mechani sm of act i on. Ref er pat i ent s t aki ng prescr i pt i on medi cat i ons t hat
mi ght cause const i pat i on t o t hei r provi der . Laxat i ves shoul d not be t aken i f
sympt oms of appendi ci t i s are present ( i . e. nausea, vomi t i ng, or abdomi nal
pai n) .
a. BuI k- f ormi ng I axat i ves. These medi cat i ons ar e nat ural or synt het i c
pol ysacchar i de der i vat i ves t hat adsorb wat er t o sof t en t he st ool and
i ncrease bul k, whi ch st i mul at es per i st al si s. Bul k- f or mi ng l axat i ves wor k i n
bot h t he smal l and t he l ar ge i nt est i nes. The onset of act i on of t hese agent s
i s sl ow ( 12- 24 hr and up t o 72 hr ), whi ch i s why t hey ar e best used t o
pr event const i pat i on r at her t han t o t r eat sever e acut e const i pat i on.
( 1) Admi ni st rat i on gui deI i nes. Al l bul k-f ormi ng agent s must be gi ven wi t h
at l east 8 oz. of wat er t o mi ni mi ze t he possi bl e esophagus, st omach, smal l
i nt est i ne, and col on obst r uct i on exper i enced by some pat i ent s. Some bul k-
f or mi ng l axat i ves may cont ai n sugar , so pat i ent s wi t h di abet es shoul d use
sugar - f ree pr oduct s.
( 2) Adverse ef fect s. Abdomi nal cr ampi ng and f l at ul ence ar e t he most
common adverse ef f ect s exper i enced by pat i ent s.
( 3) Warni ngs
( a) Bul k-f ormi ng agent s shoul d not be used i f pat i ent s have an obst r uct i ng
bowel l esi on, i nt est i nal st r i ct ur es, or Crohn' s di sease because t hey can
make t hi s si t uat i on wor se and possi bl y r esul t i n bowel per f orat i on.
( b) Do not r ecommend sugar -f r ee bul k-f ormi ng agent s t o pat i ent s wi t h
phenyl ket onur i a.
( c) Pat i ent s shoul d be advi sed not t o use bul k-f or mi ng l axat i ves f or more
t han 1 week t o t r eat const i pat i on; however , t hey can be used on a l ong- t er m
basi s f or pr event i on.
( 4) Nat uraI buI k-f ormi ng I axat i ves
( a) PsyI I i um ( e. g. , Met amuci l , Konsyl - D, Fi beral l , Per di em Fi ber Gr anul es) .
Adul t s: 3. 5 g (1 rounded t easpoon) i n 8 oz. of wat er one t o t hr ee t i mes per
day; chi l dr en: hal f t he adul t dosage one t o t hr ee t i mes per day
( b) MaI t soup ext ract ( e. g. , Mal t supex) . Adul t s: 8- 16 g (1- 2 scoops) t wo t o
f our t i mes per day; chi l dr en: 16 g one t o t wo t i mes per day
( 5) Synt het i c buI k-f ormi ng I axati ves
( a) Met hyI ceI I uI ose ( e. g. , Ci t rucel ). Adul t s: 1- 2 g ( 1 t abl espoon) one t o
t hr ee t i mes per day; chi l dr en: 0. 5 g one t o t hree t i mes per day
( b) PoI ycarbophi I (e. g. , Konsyl Fi ber , Fi ber Con, Fi ber Con Mi t r ol an) .
Adul t s: 1 g ( 2 t abl et s) one t o f our t i mes per day; chi l dren: 0. 5 g one t o
t hr ee t i mes per day. Cal ci um pol ycar bophi l may i mpai r t he absor pt i on of
t et r acycl i nes i f t he dr ugs ar e t aken concur r ent l y.
b. SaI i ne and osmoti c I axat i ves wor k by cr eat i ng an osmot i c gradi ent t o
pul l wat er i nt o t he smal l and l arge i nt est i nes. Thi s i ncreased vol ume r esul t s
i n di st ent i on of t he i nt est i nal l umen, causi ng i ncr eased per i st al si s and
bowel mot i l i t y. These l axat i ves al so i ncrease t he act i vi t y of chol ecyst oki ni n-
pancr eozymi n, whi ch i s an enzyme t hat i ncr eases t he secr et i on of f l ui ds
i nt o t he gast r oi nt est i nal ( GÌ ) t r act . The onset of act i on depends on t he
i ngredi ent and dosage f or m. Rect al f ormul at i ons (e. g. , enemas,
supposi t or i es) have an onset of act i on of 5- 30 mi n, wher eas or al
pr epar at i ons wor k wi t hi n 3- 6 hr .
( 1) Admi ni st rat i on gui deI i nes. Pat i ent s shoul d be advi sed t o consume 8
oz. of wat er wi t h each dose t o pr event possi bl e dehydrat i on.
( 2) Adverse ef fect s. Di ar r hea and abdomi nal crampi ng ar e common
adver se ef f ect s. Less common adverse ef f ect s i ncl ude excessi ve di uresi s,
nausea, vomi t i ng, and dehydr at i on.
( 3) Warni ngs
( a) Pat i ent s wi t h hyper t ensi on or congest i ve heart f ai l ure shoul d not r ecei ve
sal i ne l axat i ves on a pr ol onged basi s owi ng t o f l ui d ret ent i on f rom sodi um
absor pt i on.
( b) Pat i ent s wi t h sever e ki dney di sease shoul d not use pr oduct s cont ai ni ng
magnesi um unl ess advi sed by a physi ci an.
( 4) SaI i ne I axat i ves i ncl ude sodi um and magnesi um sal t s. As much as 20%
of magnesi um may be absor bed f r om t hese pr oduct s, whi ch may l ead t o
hyper magnesemi a i n pat i ent s wi t h preexi st i ng r enal i mpai rment . Pr oduct s
i ncl ude t he f ol l owi ng:
P. 686


( a) Magnesi um ci t rate (e. g. , Magnesi a Ci t r at e) . Adul t s: one f ul l bot t l e;
chi l dren 6- 12 years of age: one t hi rd t o one hal f bot t l e. Advi se pat i ent s t o
r ef r i ger at e t o i ncr ease pal at abi l i t y and hel p pr event cr yst al l i zat i on.
( b) Magnesi um hydroxi de ( e. g. , Phi l l i ps' Mi l k of Magnesi a, Phi l l i ps
Capl et s, and Freel ax Capl et s) . Adul t s: 30- 60 mL or 2-4 capl et s dai l y;
chi l dren 6- 12 years of age: 15- 30 mL; chi l dren 2-5 years of age: 5- 15 mL
( c) Magnesi um suI fat e (e. g. , Epsom sal t ) . Adul t s: 10-30 g i n 8 oz. of wat er ;
chi l dren 6- 12 years of age: 5-10 g
( d) Sodi um phosphat e (e. g. , Fl eet Phospho- Soda) . Adul t s: 20-45 mL;
chi l dren 6- 12 years of age: 5-20 mL
( 5) Osmot i c I axat i ves
( a) GI yceri n i s avai l abl e i n rect al pr oduct s i n supposi t or y or enema f orm
( e. g. , Fl eet Babyl ax) .
( i ) The onl y saf e and ef f ect i ve use of gl ycer i n i s r ect al . Rect al bur ni ng may
occur wi t h gl ycer i n product s. Ì n addi t i on t o t he osmot i c ef f ect , sodi um
st ear at e i n t hese pr oduct s can pr oduce a l ocal i r r i t ant ef f ect .
( i i ) Adul t s: 3 g i n supposi t or y f or m or 5- 15 mL as an enema; chi l dr en < 6
year s of age: 1-1. 5 g i n supposi t or y f orm or 2-5 mL as an enema
( b) Lact uI ose ( e. g. , Chronul ac, Enul ose) i s avai l abl e onl y by prescr i pt i on
and i s used t o decr ease bl ood ammoni a l evel s i n hepat i c encephal opat hy.
( i ) Ì t may cause f l at ul ence and cr ampi ng and shoul d be t aken wi t h f r ui t
j ui ce, wat er , or mi l k t o i ncr ease t he pal at abi l i t y. Onset of act i on i s 24- 48 hr .
( i i ) Adul t s: 15-30 mL one t o t wo t i mes dai l y; chi l dr en: 7. 5 mL once dai l y,
usual l y gi ven af t er br eakf ast
( c) Sorbi t oI , a nonabsorbabl e sugar , i s si mi l ar i n ef f i cacy t o l act ul ose,
whi ch can be admi ni st ered oral l y ( 70% sol ut i on) or r ect al l y (25% sol ut i on) .
( i ) The adverse ef f ect s ar e t he same as f or l act ul ose and i ncl ude
f l at ul ence, cr ampi ng, and abdomi nal pai n over t he f i rst f ew days.
( i i ) Adul t s: 30-150 mL oral l y (70% sol ut i on) or 120 mL r ect al l y (25%
sol ut i on) ; chi l dr en 2-11 year s of age: 15 mL or al l y ( 70% sol ut i on) or 30- 60
mL of a r ect al sol ut i on (25%)
( d) PoI yet hyI ene gI ycoI 3350 (Mi raI ax). Ì n Oct ober 2006, t he FDA
swi t ched Mi r al ax t o OTC st at us f or t he rel i ef of occasi onal const i pat i on. Ì t
can be used as an al t ernat i ve t o ot her osmot i c l axat i ves and i t i s appr oved
f or pat i ent s 17 year s of age or ol der .
( i ) Ì t has been shown t o be mor e ef f ect i ve t han l act ul ose i n shor t - t er m t r i al s
wi t h l ess abdomi nal cr ampi ng. Mi r al ax t ypi cal l y pr oduces a bowel movement
i n 1 t o 3 days.
( i i ) Adul t dosage: 17 g ( f i l l t o t op i n whi t e sect i on of cap) di ssol ved i n any
4- 8 oz. of beverage ( wat er , j ui ce, col a, or t ea) and dri nk once dai l y f or up
t o 7 days. The bever age can be col d, hot , or r oom t emper at ur e.
( i i i ) Adverse eff ects: Hi gh doses of Mi r al ax can cause di ar r hea, excessi ve
st ool f r equency, nausea, bl oat i ng, crampi ng, and f l at ul ence.
( i v) Warni ngs: Do not recommend use i n pat i ent s wi t h ki dney di sease,
dur i ng pr egnancy or whi l e br east f eedi ng, or i n pat i ent s wi t h i r ri t abl e bowel
syndr ome.
c. St i muI ant I axat i ves. These medi cat i ons wor k i n t he smal l and l arge
i nt est i nes t o st i mul at e bowel mot i l i t y ( i . e. , propul si ve per i st al t i c act i vi t y)
and i ncr ease t he secr et i on of f l ui ds i nt o t he bowel . The or al pr epar at i ons
usual l y have an onset of act i on wi t hi n 6-12 hr ; rect al prepar at i ons usual l y
have an onset of act i on wi t hi n 15- 60 mi n. St i mul ant l axat i ves ar e ef f ect i ve
as i ni t i al dr ug t her apy t o t r eat const i pat i on but shoul d not be used f or more
t han 1 week.
( 1) Admi ni st rat i on gui deI i nes. Pat i ent s wi t h undi agnosed r ect al bl eedi ng
or si gns of i nt est i nal obst r uct i on shoul d not use st i mul ant l axat i ves.
( 2) Adverse ef fect s. Al l st i mul ant l axat i ves can cause abdomi nal cr ampi ng.
El ect r ol yt e and f l ui d def i ci enci es, ent er i c l oss of pr ot ei n, mal absor pt i on,
and hypokal emi a ar e addi t i onal possi bl e adver se ef f ect s. The supposi t or y
f or m may cause r ect al bur ni ng.
( 3) Warni ngs
( a) Chroni c use of st i mul ant l axat i ves can l ead t o cat hart i c coI on, whi ch
r esul t s i n a poor l y f unct i oni ng col on and r esembl es t he sympt oms of
ul cer at i ve col i t i s. However , most cases of cat har t i c col on wer e publ i shed
bef ore 1960, when more t oxi c i ngr edi ent s ( e. g. , podophyl l i n) wer e used i n
l axat i ve pr oduct s.
P. 687


( b) Anot her i ssue surr ounds t he possi bl e car ci nogeni ci t y of st i mul ant
l axat i ves. Phenol pht hal ei n was removed f rom t he mar ket as suggest ed by
t he U. S. Food and Dr ug Admi ni st rat i on (FDA) when dat a of carci nogeni c
t umor s and genet i c damage i n rat s wer e r epor t ed. Subsequent l y, senna and
t he st ruct ur al l y si mi l ar pr oduct s al oe and cascara sagr ada ar e now
consi dered cat egor y 3 drugs; mor e dat a ar e needed t o assess t hei r saf et y.
( 4) Ant hraqui none I axati ves i ncl ude senna (sennosi des)
( a) MeI anosi s coI i , whi ch i s a dark pi gment at i on of t he col oni c mucosa, can
r esul t wi t h l ong- t er m use of ant hr aqui none l axat i ves. Thi s usual l y
di sappears 6- 12 mont hs af t er di scont i nui ng t he medi cat i on. Ì t was
pr evi ousl y t hought t hat mel anosi s di d not r esul t i n adver se consequences;
however , pat i ent s wi t h mel anosi s have a t hr eef ol d hi gher r i sk of cancer .
( b) Di scol orat i on ( pi nk/ red, yel l ow, or br own) of t he uri ne may occur .
( c) Addi t i onal ant hr aqui none l axat i ves ( cascara, casant hranol , and al oe)
wer e r emoved f rom t he U. S. mar ket because of carci nogeni ci t y concer ns.
( d) Ant hr aqui none pr oduct s i ncl ude t he sennosi des ( e. g. , Senokot , Ex- Lax,
Fl et cher ' s Cast or i a, Per di em), whi ch are consi dered t o be pot ent and cause
abdomi nal cr ampi ng.
( i ) Sennosi des can al so be combi ned wi t h docusat e (st ool sof t ener ) f or
r el i ef of const i pat i on ( Per i - Col ace, Senokot - S) .
( i i ) Adul t s: 12-50 mg t wi ce dai l y; chi l dr en: 6- 25 mg t wi ce dai l y
( 5) Bi sacodyI ( e. g. , Dul col ax, Doxi dan, Cor rect ol ) i s a di phenyI met hane
deri vat i ve.
( a) The t abl et f ormul at i ons of bi sacodyl ar e ent eri c coat ed, so t hey shoul d
not be cr ushed or chewed. Al so, bi sacodyl -cont ai ni ng product s shoul d not
be t aken wi t hi n 1 hr of i ngest i ng ant aci ds or mi l k.
( b) Adul t s ( or al ): i s 5- 15 mg dai l y; chi l dr en < 6 year s of age ( or al ) : 5 mg
dai l y; adul t s ( rect al ) : 10 mg (1 supposi t or y) ; chi l dr en > 2 year s of age
( r ect al ): 5 mg ( 1/ 2 supposi t or y) .
( 6) Cast or oi I ( e. g. , Purge) has an onset of act i on wi t hi n 2- 6 hr .
( a) Cast or oi l wor ks pri mar i l y at t he smal l i nt est i ne, whi ch can resul t i n
st r ong cat hart i c ef f ect s (e. g. , excessi ve f l ui d and el ect rol yt e l oss) . These
cat har t i c ef f ect s can l ead t o dehydr at i on.
( b) Cast or oi l shoul d not be used i n pr egnant pat i ent s because i t may
i nduce premat ure l abor.
( c) Adul t s: 15-60 mL; chi l dr en 2-12 year s of age: 5- 15 mL
d. EmoI I i ent I axat i ves act as surf act ant s by al l owi ng absor pt i on of wat er
i nt o t he st ool , whi ch makes t he sof t ened st ool easi er t o pass. Emol l i ent
l axat i ves have a sI ow onset of act i on ( 24- 72 hr) , whi ch i s why t hey ar e not
consi dered t he dr ug of choi ce f or severe acut e const i pat i on, and t hey are
mor e usef ul f or pr event i ng const i pat i on.
( 1) Admi ni st rat i on gui deI i nes. These medi cat i ons ar e par t i cul ar l y usef ul i n
pat i ent s who must avoi d st r ai ni ng t o pass hard st ool s, such as t hose who
r ecent l y had a myocar di al i nf ar ct i on or r ect al surger y. However , cl i ni cal
t r i al s eval uat i ng emol l i ent st ool -sof t eni ng l axat i ves show t hat t hese
pr oduct s, when compar ed t o pl acebo, do not af f ect t he wei ght or wat er
cont ent of t he st ool or t he f r equency of st ool passi ng.
( 2) Adverse ef fect s. Di ar r hea and mi l d abdomi nal crampi ng ar e pot ent i al
adver se ef f ect s.
( 3) Warni ngs. Use shoul d be avoi ded i f nausea and vomi t i ng, sympt oms of
appendi ci t i s, or undet ermi ned abdomi nal pai n exi st . Docusat e product s may
f aci l i t at e t he syst emi c absor pt i on of mi ner al oi l , so t hese agent s shoul d not
be used concur rent l y.
( 4) Product s. Emol l i ent l axat i ves are sal t s of t he sur f act ant docusat e.
These pr oduct s cont ai n i nsi gni f i cant amount s of cal ci um, sodi um, or
pot assi um, and t her e ar e no speci f i c gui del i nes f or t he sel ect i on of any one
pr oduct . The pr oduct s i ncl ude
( a) Docusate sodi um ( Col ace)
( b) Docusate caI ci um (Kaopect at e)
( 5) Dosage i nformati on
( a) Adul t s: 50-300 mg per day; chi l dren < 2 year s of age: 50- 150 mg per
day
( b) Each dose must be t aken wi t h at l east 8 oz. of wat er . Li qui d
pr epar at i ons shoul d be t aken i n f rui t j ui ce or i nf ant f or mul a t o i ncr ease
pal at abi l i t y.
e. Lubri cant I axat i ve (mi neraI oi I ) . Mi neral oi l wor ks at t he col on t o
i ncrease wat er r et ent i on i n t he st ool t o sof t en t he st ool . Ì t has an onset of
act i on of 6-8 hr wi t h oral admi ni st rat i on and 5- 15 mi n af t er r ect al
admi ni st rat i on.
P. 688


( 1) Admi ni st rat i on gui deI i nes
( a) Mi ner al oi l shoul d be t aken on an empt y st omach. Because of possi bl e
aspi r at i on of mi ner al oi l i nt o t he l ungs, pat i ent s shoul d not t ake mi ner al oi l
at bedt i me or r ecl i ne af t er admi ni st rat i on.
( b) Adul t s: 15- 45 mL per day; chi l dren: 5- 15 mL per day
( 2) Adverse ef fect s. Mi ner al oi l pr oduct s may cause anal seepage, whi ch
r esul t s i n i t chi ng ( i . e. prur i t us ani ) and per i anal di scomf or t .
( 3) Warni ngs
( a) Mi ner al oi l can decrease absorpt i on of f at -soI ubI e vi t ami ns ( i . e. ,
vi t ami ns A, D, E, and K) , so i t shoul d not be used on a chr oni c basi s.
( b) El der l y, young, debi l i t at ed, and dysphagi c pat i ent s ar e at t he gr eat est
r i sk of I i pi d pneumoni t i s f r om mi ner al oi l aspi rat i on.
( c) Emol l i ent s ( e. g. , docusat e) may i ncr ease t he syst emi c absor pt i on of
mi ner al oi l , whi ch can l ead t o hepat ot oxi ci t y.
( d) Mi ner al oi l shoul d not be gi ven t o pat i ent s wi t h r ect al bl eedi ng or
appendi ci t i s.
( e) Mi ner al oi l shoul d not be gi ven t o chi l dr en < 6 years of age.
C. Speci aI pati ent i ssues
1. Pedi at ri c pat i ent s. The bowel pat t erns of pedi at ri c pat i ent s var y. Duri ng
t he f i rst weeks of l i f e, i nf ant s pass approxi mat el y f our st ool s per day. As
chi l dren get ol der , appr oxi mat el y one t o t hr ee st ool s ar e passed per day.
Const i pat i on shoul d be expect ed i f t her e i s a dr ast i c change f r om a chi l d' s
basel i ne bowel f unct i on.
a. NonpharmacoI ogi caI met hods, such as i ncreasi ng t he amount of f l ui d or
sugar i n a chi l d' s f ormul a i n younger chi l dr en or i ncreasi ng t he bul k cont ent
of t he chi l d' s di et ( f r ui t , f i ber cer eal s, veget abl es), shoul d be t r i ed bef ore
medi cat i ons are used.
b. I f nonpharmacoI ogi caI met hods do not work, r ect al st i mul at i on may be
usef ul . Phar macol ogi cal agent s t hat can be used f or acut e rel i ef i ncl ude
gl yceri n supposi t ori es and magnesi um l axat i ves. St i mul ant l axat i ves shoul d
be admi ni st er ed as a l ast r esor t , but enemas shoul d not be used i n chi l dren
< 2 year s of age and wi t h ext r eme caut i on i n chi l dr en 2- 5 years of age (see
Ì . C. 4) . Bul k- f or mi ng agent s and st ool sof t ener s can be used i f t he
const i pat i on does not need i mmedi at e r el i ef .
2. Pregnant pati ents. Const i pat i on i n pr egnancy i s common and can be t he
r esul t of compressi on of t he col on by t he enl ar ged ut er us, i ngest i on of
pr enat al vi t ami ns cont ai ni ng i ron and cal ci um, and t he i nf l uence of
pr ogest er one can cause bowel hypomot i l i t y. Pregnant pat i ent s shoul d avoi d
any pr eparat i on t hat may be absor bed syst emi cal l y ( e. g. , st i mul ant
l axat i ves) , any pr epar at i on t hat can i nt er f ere wi t h vi t ami n absor pt i on ( e. g. ,
mi ner al oi l ) , or any prepar at i on t hat can i nduce pr emat ure l abor ( e. g. ,
cast or oi l ) . Pregnant pat i ent s shoul d use bul kf ormi ng agent s or st ool
sof t ener s.
3. Geri at ri c pat i ent s t end t o be at ri sk f or const i pat i on because of
i nsuf f i ci ent di et ar y ( f i ber) and f l ui d i ngest i on, f ai l ur e t o est abl i sh a r egul ar
bowel t i me habi t , and abuse of st i mul ant l axat i ves r esul t i ng i n a l oss of
smoot h muscl e t one i n t he bowel , whi ch promot es const i pat i on ( see Ì . C. 5) .
These causes shoul d be i nvest i gat ed i n addi t i on t o pri mar y di sease st at es
( e. g. , hypot hyr oi di sm) and medi cat i ons ( e. g. , opi at es, ant i chol i ner gi cs) t hat
may l ead t o const i pat i on i n el der l y pat i ent s. A maj or concern wi t h geri at r i c
pat i ent s i s t he possi bl e l oss of f l ui d t hat can be i nduced by aggr essi ve
l axat i ve t r eat ment ( e. g. , enemas, hi gh- dose sal i ne l axat i ves) . Geri at ri c
pat i ent s shoul d not use st i mul ant l axat i ves on a chr oni c basi s, and pat i ent s
wi t h r enal i mpai rment shoul d not use magnesi um pr oduct s. Gl yceri n
supposi t or i es or or al l y admi ni st ered l act ul ose may be usef ul f or i ni t i al
t r eat ment of const i pat i on and bul k-f ormi ng agent s used t o pr event
const i pat i on.
4. Use of enemas. Enemas are usef ul f or evacuat i on of t he bowel bef ore
sur ger y, chi l dbi r t h, and f or t he t reat ment of acut e const i pat i on t hat has not
r esponded t o ot her medi cat i ons (e. g. , bi sacodyl supposi t or i es) .
a. An enema i s i nst i l l ed i nt o t he r ect um, wor ks l ocal l y, and t he enema f l ui d
det ermi nes t he mechani sm of evacuat i on ( e. g. , st i mul ant , osmot i c) . When
admi ni st er ed cor r ect l y, an enema evacuat es onl y t he di st al col on, si mi l ar t o
a normal bowel movement . Thi s i s accompl i shed by havi ng t he pat i ent l i e on
hi s or her si de wi t h t he knees t ucked t owar d t he chest . Whi l e i n t hi s
posi t i on, 1 pi nt ( 500 mL) of enema sol ut i on shoul d be sl owl y squeezed i nt o
t he rect um. Thi s shoul d be r et ai ned up t o 1 hr or unt i l def i ni t e l ower
abdomi nal cr ampi ng i s f el t . At t hi s poi nt , t he bowel movement i s r eady f or
expul si on.
P. 689


b. Al t hough al l enemas cause abdomi nal cr ampi ng, some may have mor e
ser i ous adverse ef f ect s t han ot hers. Soap suds enemas can cause much
r ect al i r r i t at i on and have been r eport ed t o cause anaphyl axi s and rect al
gangr ene.
c. The popul ar sodi um phosphat e enemas (e. g. , Fl eet ) are ver y ef f ect i ve but
have r esul t ed i n hyper phosphat asemi a, hypocal cemi a ( t et any) ,
hypokal emi a, met abol i c aci dosi s, and car di ac deat h, usual l y owi ng t o
conduct i on abnor mal i t i es i n ver y smal l chi l dr en. Thi s has mai nl y occur red i n
chi l dren < 2 year s of age or f rom 2 t o 5 years of age wi t h pr edi sposi ng
f act or s.
( 1) The f act ors i ncl ude chr oni c r enal di sease, anor ect al mal f or mat i ons,
and/ or Hi r schspr ung di sease, whi ch al l ow phosphat e bl ood concent r at i ons
t o become abnormal l y hi gh and pot assi um and cal ci um t o become l ow,
pr edi sposi ng t hese pat i ent s t o cardi ac ar r hyt hmi as and pot ent i al l y deat h.
( 2) Ther ef or e, t he use of enemas i s hi ghl y di scour aged i n chi l dr en < 5 year s
of age.
5. Laxati ve abuse i s a t er m t o descri be t he r out i ne, chroni c use of
l axat i ves on a dai l y basi s ( e. g. , el derl y pat i ent s) t o t he admi ni st r at i on of
hi gh doses several t i mes dai l y by pat i ent s wi t h anor exi a ner vosa or bul i mi a
f or wei ght cont r ol . Excessi ve use of l axat i ves can l ead t o excessi ve
di ar rhea and vomi t i ng, resul t i ng i n f l ui d and el ect r ol yt e abnormal i t i es. Ì n
addi t i on t o t he ri sks t o pat i ent s f rom hypokal emi a ( e. g. , met abol i c al kal osi s,
car di ac conduct i on pr obl ems) , pat i ent s can al so devel op ost eomal aci a, l i ver
di sease, and cat har t i c col on. Cat hart i c col on resul t s f rom super f i ci al
ul cer at i ons i n t he col on as wel l as damage t o t he muscul ar i s mucosa and
submucosa. Thi s r esul t s i n a l oss of t one of t he smoot h and st ri at ed muscl e
and causes poor bowel f unct i on.
II. DI ARRHEA
A. GeneraI I nf ormat i on
1. Def i ni t i on. Di ar rhea i s def i ned as an i ncrease i n t he f r equency and
l ooseness of st ool s compar ed t o one' s normal bowel pat t er n. The overal l
wei ght and vol ume of t he st ool i s i ncr eased ( > 200 g or mL/ day) , and t he
wat er cont ent i s i ncr eased t o 60%- 90%. Ì n general , di ar r hea r esul t s when
some f act or i mpai r s t he abi l i t y of t he i nt est i ne t o absor b wat er f rom t he
st ool , whi ch causes excess wat er i n t he st ool .
2. CI assi fi cat i on. Di ar r hea can be cl assi f i ed based on mechani sms or
or i gi n.
a. CI assi fi cat i on by mechani sm
( 1) Osmot i c di arrhea occurs when a nonabsor babl e sol ut e pul l s excess
wat er i nt o t he i nt est i nal t r act . Osmot i c di ar r hea ceases when t he pat i ent
convert s t o a f ast i ng st at e.
( a) Ì ngest i on of l arge meal s or cert ai n osmot i c subst ances ( e. g. , sor bi t ol ,
gl yceri n) can l ead t o di arr hea.
( b) Di sacchar i dase def i ci ency whi ch i s a l ack of enzymes needed t o br eak
down di sacchar i des i n t he gut f or absor pt i on ( e. g. , l act ase def i ci ency) ,
r esul t s i n an i ncrease i n osmot i c sugars (i . e. , l act ose, sucrose) i n t he
i nt est i nal t ract .
( c) Medi cat i ons t hat can i nduce osmot i c di ar rhea i ncl ude l act ul ose and
magnesi um-cont ai ni ng ant aci ds and l axat i ves.
( 2) Secret or y di arrhea occurs when t he i nt est i nal wal l i s damaged,
r esul t i ng i n an i ncr eased secr et i on r at her t han absor pt i on of el ect r ol yt es
i nt o t he i nt est i nal t ract . Common sour ces i ncl ude
( a) Bact eri aI endot oxi ns ( e. g. , Escheri chi a col i , Vi bri o chol erae, Shi gel l a,
St aphyl ococcus aur eus)
( b) Bacteri aI i nfecti ons ( e. g. , Shi gel l a, Sal monel l a)
( c) Vi raI i nfecti ons ( e. g. , r ot avi r us, Nor wal k vi rus)
( d) Prot ozoaI i nf ecti ons ( e. g. , Gi ar di a l ambl i a, Ent amoeba hi st ol yt i ca)
( e) Mi sceI I aneous causes. Ì nf l ammat or y bowel di sease and medi cat i ons
( e. g. , prost agl andi ns, ant i bi ot i cs, col chi ci ne, chemot her apeut i c agent s)
( 3) Mot i I i t y di sorders. Di ar r hea i nduced by mot i l i t y di sorders r esul t s f r om
decreased cont act t i me of t he f ecal mass wi t h t he i nt est i nal wal l , so l ess
wat er i s absorbed f r om t he f eces.
( a) Mot i I i t y di sorders i ncl ude i r r i t abl e bowel syndr ome, scl eroder ma,
di abet i c neur opat hy, gast r i c/ i nt est i nal r esect i on, and vagot omy.
P. 690


( b) Medi cat i ons t hat can i nduce mot i l i t y di sor der s i ncl ude
par asympat homi met i c agent s t hat enhance t he ef f ect s of acet yl chol i ne
( e. g. , met ocl oprami de, bet hanechol ) , di gi t al i s, qui ni di ne, and ant i bi ot i cs.
( i ) Ant i bi ot i cs cause di arr hea by causi ng i nt est i nal i r r i t at i on, i ncr eased
bowel mot i l i t y, and al t ered bowel mi crobi al f l or a.
( i i ) Most ant i bi ot i c- i nduced di ar rhea can be mi ni mi zed by t aki ng t he agent
wi t h f ood.
b. CI assi fi cati on by ori gi n
( 1) Acut e di arrhea ( usual l y sel f - l i mi t i ng f or 2- 3 days but may l ast up t o 2
weeks)
( a) I nfecti on. Most common sour ces i ncl ude vi ral and bact eri al , but
pr ot ozoal di ar r hea al so occur s. Or gani sms i ncl ude t he f ol l owi ng:
( i ) Vi ruses t hat commonl y cause di ar r hea ar e r ot avi r uses and t he Nor wal k
vi r us.
{ a} Rot avi ruses usual l y af f ect chi l dr en < 2 years of age. The vi r us has an
onset of 1- 2 days and l ast s 5- 8 days. Pat i ent s usual l y have vomi t i ng and a
mi l d f ever , and may exper i ence sever e dehydr at i on. There i s usual l y no
bl ood or pus i n t he st ool .
{ b} The NorwaI k vi rus af f ect s ol der chi l dr en and adul t s. Ì t has an onset of
1- 2 days and l ast s 24- 48 hr ( t he "24-hr bug¨ ). As wi t h r ot avi ruses, t her e i s
mi l d f ever but no bl ood or pus i n t he st ool .
( i i ) Bact eri a. Most bact er i al di ar r hea resul t s f r om consumpt i on of
cont ami nat ed wat er or f ood, wi t h an onset of di arr hea i n 8 hr t o sever al
days. Di ar rhea caused by t he consumpt i on of cont ami nat ed f ood or wat er
t hat occurs i n a f or ei gn count r y (e. g. , Mexi co, t hi rd- wor l d count r i es) i s
r ef er red t o as "t r avel er ' s di ar r hea. ¨
{ a} Toxi geni c bact eri a. Di ar r hea caused by t oxi geni c E. col i ,
St aphyl ococcus aur eus, V. chol er ae, and Shi gel l a r esul t s f r om t he secr et or y
ef f ect s of ent erot oxi ns rel eased by t hese or gani sms i n t he smal l i nt est i ne.
Pat i ent s usual l y exper i ence l arge- vol ume st ool s t hat ar e wat er y or gr easy.
{ b} I nvasi ve bact eri a. Di ar r hea caused by i nvasi ve E. col i , Shi gel l a,
Sal monel l a, Campyl obact er , and Cl ost ri di um di f f i ci l e resul t s f rom mucosal
i nvasi on of t he col on. Thi s resul t s i n a dysent er y- l i ke di ar rhea, whi ch i s
charact eri zed by an ext r eme ur gency t o def ecat e, abdomi nal cr ampi ng,
t enesmus, f ever , chi l l s, and smal l - vol ume st ool s t hat cont ai n bl ood or pus.
( i i i ) Prot ozoa. G. l ambl i a, Ent amoeba hi st ol yt i ca, and Cr ypt ospor i di um
cause expl osi ve, f oul - smel l i ng, l ar ge- vol ume, wat er y st ool s. Thi s i s t hought
t o be caused by i nvasi on of t he smal l i nt est i ne, whi ch causes damage t o t he
mi cr ovi l l i and, t heref ore, decr eases absor pt i on of f l ui ds. Thi s t ype of
di ar rhea can resul t i n l arge f l ui d l osses, and pat i ent s are at r i sk f or
dehydrat i on. Al t hough prot ozoan- i nduced di ar rhea i s sel f - l i mi t i ng, i t may
per si st f or sever al mont hs, so t herapy shoul d be consi dered t o eradi cat e
t he or gani sm.
( b) Di et -i nduced di arrhea. Di ar rhea i nduced by f oods resul t s f rom f ood
al l er gi es, hi gh- f i ber di et s, f at t y or spi cy f oods, l ar ge amount s of caf f ei ne, or
mi l k i nt ol er ance. The best t reat ment i s pr event i on, by avoi di ng t r oubl esome
f oods.
( c) Drug-i nduced di arrhea (see Ì Ì . A. 2. a)
( 2) Chroni c di arrhea (l ast s l onger t han 2 weeks). Ì f a pat i ent suf f ers f r om
di ar rhea f or l ong peri ods of t i me, or f rom r ecur rent epi sodes of di ar r hea,
t he f ol l owi ng causes must be consi dered: pr ot ozoal or gani sms, f ood-
i nduced di ar rhea ( e. g. , l act ose i nt ol er ance) , i r r i t abl e bowel syndrome,
mal absorpt i on syndromes ( e. g. , cel i ac spr ue, di ver t i cul osi s, short bowel
syndr ome), i nf l ammat or y bowel di sease, pancreat i c di sease, and
hyper t hyr oi di sm.
B. Pat i ent evaI uat i on
1. Phar maci st s who ar e consul t ed by pat i ent s shoul d ask t he pat i ent f or t he
f ol l owi ng i nf or mat i on bef or e recommendi ng a t herapy:
a. Age of t he pat i ent
b. Onset and durat i on of t he di ar r hea
c. Descr i pt i on of st ool (i . e. , f requency, vol ume, bl ood, pus, wat er y)
d. Ot her sympt oms ( e. g. , abdomi nal cr ampi ng, f ever , nausea, vomi t i ng,
wei ght l oss)
e. Medi cat i ons r ecent l y st ar t ed or medi cat i ons used t o r el i eve t he di ar rhea
f . Recent t r avel ( wher e and how l ong ago)
g. Medi cal hi st or y (hi st ory of GÌ di sor der s)
P. 691


2. ReferraI s t o a physi ci an shoul d be made by t he pharmaci st who
encount ers a pat i ent wi t h di ar r hea t hat meet s t he f ol l owi ng cri t er i a:
a. Younger t han 3 year s of age or oI der t han 60 years of age ( wi t h
mul t i pl e medi cal probl ems) , pr egnant or breast - f eedi ng pat i ent s, and
pat i ent s wi t h HÌ V.
b. BI ood or mucus i n t he st ooI s
c. Hi gh f ever (> 101°F or 38°C)
d. Dehydrat i on or wei ght I oss > 5% of t ot al body wei ght ; si gns of
dehydrat i on÷dr y mout h, sunken eyes, cr yi ng wi t hout t ear s, dr y ski n t hat i s
not el ast i c l i ke normal ski n
e. Durati on of di arrhea > 2 days
f . Vomi t i ng
C. Treatment
1. NonpharmacoI ogi caI
a. Food/ breast - f eedi ng. Ì n t he past , t here was much cont rover sy regardi ng
t he deci si on t o f eed or not t o f eed chi l dr en duri ng acut e epi sodes of
di ar rhea. Or i gi nal l y, parent s wer e t ol d t hat chi l dren shoul d not r ecei ve f ood,
mi l k pr oduct s, or br east -f eed f or 6- 48 hr af t er t he onset of di ar r hea. Par ent s
wer e al so t ol d t hat i f chi l dr en di d r ecei ve f ood, t hey shoul d r ecei ve t he
BRAT di et , whi ch consi st s of bananas, r i ce, appl esauce, and t oast . Thi s
di et does not wor k and i s def i ci ent i n cal ori es, prot ei n, and f at . Al l pat i ent s
shoul d r ecei ve t hei r normal di et or breast - f eedi ng duri ng bout s of di ar rhea
because t hese do not make t he di ar rhea wor se and may act ual l y i mpr ove
t he condi t i on. Fat t y f oods, f oods ri ch i n si mpl e sugars (can cause osmot i c
di ar rhea) , and spi cy f oods (may cause GÌ upset ) shoul d be avoi ded.
Caf f ei ne-cont ai ni ng bever ages, whi ch may wor sen t he di ar rhea, shoul d al so
be avoi ded.
b. FI ui ds. The most i mpor t ant par t of t reat i ng acut e di arr hea i s t he
r epl acement of l ost f l ui ds and el ect rol yt es. Ì f pat i ent s exper i ence mi l d t o
moder at e f l ui d l oss, f l ui d r epl acement can be achi eved wi t h or al - r ehydr at i on
sol ut i ons ( ORS) . Ì f f l ui d l oss i s sever e ( > 10% l oss of body wei ght ) and/ or
sever e vomi t i ng persi st s, t hen pat i ent s may need i nt ravenous rehydrat i on
bef ore or al mai nt enance f l ui ds can be admi ni st ered. ORSs can be easi l y
made at home ( Tabl e 33- 1) or purchased ready- t o- use (e. g. , Pedi al yt e,
Rehydr a-l yt e) . Al l of t hese sol ut i ons ar e consi der ed equal l y saf e and
ef f ect i ve but have no ef f ect on t he durat i on of t he di ar r hea. The secret ory
and absorpt i ve mechani sms of t he bowel f unct i on separ at el y, and t hi s
al l ows t hese ORS t o be absor bed dur i ng acut e epi sodes of di arr hea,
pr event i ng sever e dehydr at i on and compl i cat i ons. Not ever y pat i ent needs
ORS. For a chi l d wi t hout evi dence of dehydr at i on ( see Ì Ì . B. 2. d) , admi ni st er
10 mL/ kg or 1/ 2-1 cup of ORS f or each l oose st ool . Ì f a chi l d i s vomi t i ng,
admi ni st er smal l er amount s ( 1- 2 t easpoonsf ul ) ever y 2- 5 mi n as t ol er at ed.
( 1) FI ui d and eI ect roI yt e repI acement . Fl ui d and el ect r ol yt e t her apy i s
ai med at repl aci ng what t he body has l ost . Duri ng t hi s si t uat i on, t he
pat i ent ' s f l ui d i nput and out put as wel l as wei ght shoul d be moni t ored. The
Worl d Heal t h Or gani zat i on (WHO) has est abl i shed gui del i nes f or oral -
r epl acement t herapy ( Tabl e 33-1) . Recommended doses are gi ven i n Tabl e
33- 2.
( 2) FI ui ds t o be avoi ded i ncl ude hypert oni c f r ui t j ui ces and dr i nks (e. g. ,
appl e j ui ce, powder ed dri nk mi xes, gel at i n wat er), car bonat ed bever ages,
and caf f ei ne-cont ai ni ng bever ages, whi ch can make di ar r hea wor se and do
not cont ai n needed el ect r ol yt es ( i . e. , Na
+
, K
+
). Gat or ade di l ut ed i n wat er
( 1: 1) i s adequat e and provi des t he necessar y combi nat i on of gl ucose,
sodi um, and pot assi um.
2. PharmacoI ogi c. Ant i di arrheaI s may ser ve t o pr event an at t ack of
di ar rhea or t o rel i eve exi st i ng sympt oms. Based on t he FDA revi ew of
ant i di ar r heal pr oduct s, t hr ee agent s have been
P. 692

i dent i f i ed as cat egor y 1 (i . e. , saf e and ef f ect i ve) i ngr edi ent s: kaoI i n,
bi smut h subsaI i cyI at e, and I operami de. Ì n Apr i l 2003, t he FDA
r ecl assi f i ed at t apul gi t e and pol ycar bophi l pr oduct s f rom cat egor y 1 t o
cat egor y 3 because of i nsuf f i ci ent ef f ect i veness dat a. Ant i di ar r heal agent s
ar e cl assi f i ed i n di f f erent cat egor i es on t he basi s of t hei r chemi cal cl ass or
pharmacol ogi c mechani sm of act i on.
Table 33-1. Guidelines for Oral-Replacement Therapy Established by the World
Health Organization (WHO)
Ingredients Dose
Sodium chloride (table salt) 90 mEq (1/2 teaspoon)
Potassium chloride (potassium salt) 20 mEq (1/4 teaspoon)
Sodium bicarbonate (baking soda) 30 mEq (1/2 teaspoon)
Glucose (sugar) 20 g (2 teaspoons)
Water Enough to make 1 L oI solution

Table 33-2. Guidelines for Fluid- and Electrolyte-Replacement Therapy
Dose
Age Group Mild (2-3 stools/day) Moderate (4-5 stools/day)
~ 5 years
oI age
2 L/Iirst 4 hr. then replace
ongoing losses
2-4 L/Iirst 4 hr. then
replace ongoing losses
· 5 years
oI age
50 mL/kg/Iirst 4 hr. then 10
mL/kg or 1/2-1 cup per stool
100 mL/kg/4 hr. then 10
mL/kg or 1/2-1 cup per
stool

a. Ant i peri st aI ti c drugs
( 1) Mechani sm of act i on. Ant i per i st al t i c dr ugs act by st i mul at i ng µ opi oi d
r ecept or s on t he ci r cul ar and l ongi t udi nal muscul at ur e of t he smal l and
l ar ge i nt est i nes t o nor mal i ze per i st al t i c i nt est i nal movement s. They sl ow
i nt est i nal mot i l i t y and af f ect wat er and el ect r ol yt e movement t hr ough t he
bowel . Loper ami de i s consi dered t wo t o t hr ee t i mes more pot ent t han
di phenoxyl at e and 50 t i mes mor e pot ent t han mor phi ne i n i t s abi l i t y t o sl ow
GÌ mot i l i t y. Loper ami de does not appreci abl y penet r at e t he cent ral ner vous
syst em ( CNS) and t hus has a l ow r i sk f or CNS si de ef f ect s. Loperami de i s
ef f ect i ve i n acut e, nonspeci f i c di ar rhea, t ravel er ' s di ar rhea, and chroni c
di ar rhea associ at ed wi t h i nf l ammat or y bowel di sease. The f requency of
bowel movement s i s decr eased, and t he consi st ency of st ool s i s i ncreased.
However , r epl acement of f l ui ds ( t hr ough ORS) and di et ar y management are
st i l l t he mai n f ocus of t her apy f or di ar rhea.
( 2) Cont rai ndi cat i on. Ant i per i st al t i c medi cat i ons have al ways been
r est ri ct ed i n pat i ent s wi t h acut e bact er i al di ar r hea associ at ed wi t h f ecal
l eukocyt es, hi gh f ever, or bl ood or mucus i n t he st ool because of t he
pot ent i al f or t hese dr ugs t o decr ease cl earance of t he organi sm and
enhance syst emi c i nvasi on of t he or gani sm. Most i nf or mat i on shows t hat
t hi s i s not si gni f i cant and pr obabl y wi l l cause no har m. However , t hese
medi cat i ons shoul d not be used i n pat i ent s wi t h col i t i s ( pot ent i al f or t he
devel opment of t oxi c megacol on) or i n chi l dren < 6 years of age.
( 3) Prescri pti on agent s i n t hi s cl ass i ncl ude t he opi at e-r el at ed agent
di phenoxyl at e/ at ropi ne (e. g. , Lomot i l ) .
( 4) Nonprescri pt i on agent s. Loperami de ( e. g. , Ì modi um A- D) provi des
ef f ect i ve cont rol of di arrhea as qui ckl y as 1 hr af t er admi ni st rat i on.
Ant i per i st al t i c dr ugs shoul d not be used f or mor e t han 48 hr i n acut e
di ar rhea.
( a) Admi ni st rat i on gui deI i nes. Adul t s: 4 mg f ol l owed by 2 mg af t er each
l oose st ool , not t o exceed 16 mg/ day; chi l dr en: 1-2 mg up t o t hree t i mes per
day, dependi ng on wei ght and age.
( b) Adverse ef f ect s. At r ecommended doses, l oper ami de i s gener al l y wel l
t ol er at ed. Si de ef f ect s are i nf r equent and consi st pr i mar i l y of abdomi nal
pai n, di st ent i on, or di scomf ort ; dr owsi ness; di zzi ness; and dr y mout h.
b. Adsorbents. These medi cat i ons ar e not sel ect i ve and adsor b t oxi ns,
bact er i a, gases, and f l ui ds. Ì n addi t i on, adsorbent s may adsor b dr ugs i n t he
GÌ t r act . They ar e not absor bed syst emi cal l y, so t hey pr oduce few adverse
ef f ects. These pr oduct s ar e gi ven f or sympt omat i c r el i ef and ar e usual l y
admi ni st er ed i n l ar ge doses i mmedi at el y f ol l owi ng a l oose st ool . They are
gener al l y not ef f ect i ve f or severe acut e di arr hea.
( 1) KaoI i n
( a) Admi ni st rat i on gui deI i nes
( i ) Adul t s and chi l dr en 12 years of age and ol der ( or al ) : 26. 2 g af t er each
l oose st ool .
( i i ) Cont i nue t o t ake ever y 6 hr unt i l st ool i s f i r m but not f or more t han 2
days.
( i i i ) Do not exceed 262 g i n 24 hr .
( b) Adverse ef f ect s. Because act i vat ed kaol i n i s i ner t and i s not absor bed
syst emi cal l y, adverse ef f ect s are mi nor wi t h f ew pat i ent s exper i enci ng
const i pat i on, bl oat i ng, and f ul l ness.
P. 693


( c) Warni ngs. Ì t i s recommended t hat t hi s pr oduct not be gi ven wi t hi n 3 hr
of ot her medi cat i ons because i t may decr ease t he absorpt i on of ot her oral l y
admi ni st er ed medi cat i ons.
c. Mi sceI I aneous agents
( 1) Bi smut h subsaI i cyI at e ( e. g. , Pept o- Bi smol and Maal ox Tot al St omach
Rel i ef ) . Bi smut h sal t s wor k as adsor bent s but al so ar e bel i eved t o decrease
secr et i on of wat er i nt o t he bowel . Ì t i s ef f ect i ve and can r educe t he number
of st ool s by 50%. Bi smut h pr eparat i ons have moder at e ef f ect i veness
agai nst t he pr event i on and t reat ment of t ravel er ' s di ar rhea and nonspeci f i c
di ar rhea, but doses r equi r ed f or r el i ef ar e l ar ge and must be admi ni st er ed
f r equent l y, so t hese pr epar at i ons may be i nconveni ent .
( a) Admi ni st rat i on gui deI i nes
( i ) Adul t s: 2 t abl et s or 30- 60 mL ( 524 mg) ever y hour as needed t o a
maxi mum of 8 doses i n a 24- hr per i od; chi l dr en > 2 years of age: one t hi r d
t o one hal f of adul t dose.
( i i ) Bi smut h subsal i cyl at e can pr event t ravel er ' s di ar rhea when 2 t abl et s ar e
t aken f our t i mes per day.
( i i i ) Shake t he suspensi on wel l bef or e use.
( b) Adverse ef f ect s may i ncl ude harml ess grayi sh charcoal col or i ng of
st ool s or t ongue. Ri ngi ng i n t he ear s ( i . e. t i nni t us) can occur wi t h hi gh
doses, especi al l y i f t he pat i ent i s si mul t aneousl y t aki ng ot her sal i cyl at e
pr oduct s.
( c) Warni ngs/ Cont randi cat i ons
( i ) Pat i ent s wi t h bl ack or bl oody st ool s shoul d not use t hi s product .
( i i ) Bi smut h subsal i cyl at e shoul d not be gi ven t o chi l dren or t eenager s
dur i ng or af t er r ecover y f r om chi ckenpox or f l u because of t he possi bl e
associ at i on of sal i cyl at es wi t h Reye' s syndr ome.
( i i i ) Pat i ent s wi t h document ed al l er gi es t o sal i cyl at es shoul d not t ake t hi s
pr oduct .
( i v) Pat i ent s on ant i coagul ant s shoul d be moni t ored cl osel y i f t aki ng t hese
pr oduct s.
( v) Pr egnant or br east - f eedi ng pat i ent s shoul d not t ake t hese pr oduct s.
( 2) Lact obaci I I us ( e. g. , Baci d, Lact i nex) pr oduct s are i nt ended t o r epl ace
t he normal bact er i al f l ora t hat i s l ost dur i ng t he admi ni st rat i on of or al
ant i bi ot i cs. However , t her e i s l i t t l e i nf or mat i on t o show t hat t hese pr oduct s
ar e usef ul f or ant i bi ot i c- i nduced di ar r hea; wi t h t he i ncr ease i n bowel
or gani sms, pat i ent s can exper i ence f l at ul ence. Most cl i ni ci ans do not
r ecommend t hei r use.
( 3) Lact ase (e. g. , Lact Ai d, Lact r ase, Dai r y Ease) i s i ndi cat ed f or i ndi vi dual s
who have i nsuf f i ci ent amount s of l act ase i n t he smal l i nt est i ne. Lact ose (a
di sacchar i de pr esent i n dai r y pr oduct s) must be br oken down t o gl ucose
and gal act ose t o be f ul l y di gest ed. Ì f i t i s not , l act ose draws wat er i nt o t he
GÌ t r act , and di ar r hea resul t s. Lact ase i s t he enzyme r esponsi bl e f or
di gest i ng l act ose. The dose i s 1-2 capsul es t aken wi t h mi l k or dai r y
pr oduct s or added t o mi l k bef ore dri nki ng. Ti t rat i on of doses t o hi gher
l evel s may be r equi red i n some pat i ent s.
( 4) Ant i - i nf ect i ves. Dependi ng on t he suspect ed or i gi n of t he i nf ect i ous
di ar rhea, prescr i pt i on ant i bi ot i cs and ant i pr ot ozoal medi cat i ons can be used
t o eradi cat e t he or gani sms and decrease t he durat i on of sympt oms ( Tabl e
33- 3). Ì f ant i bi ot i cs ar e used t o pr event t ravel er ' s di ar r hea, t herapy shoul d
be st art ed 1 day bef ore ar r i val i n hi gh-i nci dence r egi ons and cont i nued unt i l
2 days af t er depar t ur e. Ì f di ar r hea has occur r ed, ant i bi ot i c t reat ment shoul d
l ast f or 3 days.
( 5) Ant i choI i nergi cs ( e. g. , at r opi ne, hyoscyami ne) decrease bowel mot i l i t y,
whi ch r esul t s i n an i ncrease of f l ui d absorpt i on f rom t he i nt est i nal t r act and
a decr ease i n abdomi nal cr ampi ng. These pr oduct s ar e f ound i n
combi nat i on wi t h adsor bent s or opi at es. However , t he amount of
ant i chol i nergi c f ound i n most pr oduct s i s not consi der ed t o be enough t o
al t er t he course of severe acut e di ar rhea. Adverse eff ects i ncl ude dr y
mout h, bl ur r ed vi si on, and t achycar di a. These pr oduct s shoul d not be used
i n pat i ent s wi t h nar row- angl e gl aucoma.
III. HEMORRHOIDS
A. GeneraI I nf ormat i on
1. Def i ni t i on. Hemor r hoi ds (al so known as pi l es) ar e def i ned as abnor mal l y l ar ge,
bul gi ng, sympt omat i c cl ust ers of di l at ed bl ood vessel s, suppor t i ng t i ssues, and
over l yi ng mucosus
P. 694

membr anes. Hemor r hoi ds can pr esent i n t he l ower r ect um (i nt er nal hemor r hoi ds) or
anus ( ext er nal hemor r hoi ds). Si mpl y, hemor r hoi ds r epr esent downwar d di spl acement
of anal cushi ons t hat cont ai n art eri ovenous anast omoses.
Table 33-3. Antibacterials Used For the Prophylaxis and Treatment of Traveler's
Diarrhea
Antibacterials
a
Prophylaxis dose
b
Treatment dose
c

Azithromycin n/a 1000 mg po 1 × dose
CiproIloxacin
d
500 mg once daily 500 mg twice daily
LevoIloxacin
d
n/a 500 mg once daily
NorIloxacin
d
400 mg once daily 400 mg twice daily
OIloxacin
d
n/a 200 mg twice daily
RiIaximin 200 mg once or twice
daily
200 mg three times
daily
a
SulIonamides. neomycin. ampicillin. doxycycline. tetracycline. and TMP-
SMX are no longer recommended due to world-wide drug resistance.

b
Prophylaxis should only be used Ior 2-3 weeks.

c
Antibiotics are used Ior a 3-day course.

d
Campvlobacter species exhibit resistance to Iluoroquinolones and should be
considered in treatment.
n/a. not applicable; po. by mouth.

2. Epi demi oI ogy. Hemorr hoi ds ar e common, wi t h approxi mat el y 10%- 25% of t he
U. S. popul at i on af f l i ct ed. The r i sk of devel opi ng hemorr hoi ds i ncreases wi t h
advanci ng age and peaks i n i ndi vi dual s 45- 65 year s of age. The i nci dence of
hemor r hoi ds i n pr egnant women i s hi gher t han t hat of nonpregnant women of si mi l ar
age. Al t hough t hey ar e consi der ed a mi nor medi cal pr obl em, t hey may cause
consi derabl e di scomf or t and anxi et y.
B. Types of hemor r hoi ds ar e det er mi ned by t hei r anat omi cal posi t i on and vascul ar
or i gi n.
1. An i nternaI hemor rhoi d i s an exaggerat ed vascul ar cushi on wi t h an engor ged
i nt er nal hemor r hoi dal pl exus l ocat ed above t he dent at e l i ne and covered wi t h a
mucous membrane.
2. An externaI hemor r hoi d i s a di l at ed vei n of t he i nf er i or hemor r hoi dal pl exus
l ocat ed bel ow t he dent at e l i ne and cover ed wi t h squamous epi t hel i um.
3. A mi xed hemor r hoi d appear s as a baggy swel l i ng and exhi bi t s si mul t aneous
charact eri st i cs of i nt er nal and ext er nal hemor r hoi ds.
C. Ori gi n. Al t hough heredi t y may pr edi spose a per son t o hemor r hoi ds, t he exact
cause i s probabl y r el at ed t o acqui r ed f act or s.
1. Si t uat i ons t hat r esul t i n i ncreased venous pressure i n t he hemor r hoi dal pl exus
( e. g. , chr oni c st r ai ni ng dur i ng def ecat i on; smal l , har d st ool s; pr ol onged si t t i ng on
t he t oi l et ; occupat i ons t hat r out i nel y r equi r e heavy l i f t i ng; pel vi c t umors; pr egnancy)
can t r ansf orm an asympt omat i c hemor r hoi d i nt o a pr obl em. Pregnancy i s t he most
f r equent cause of hemorr hoi ds i n women of chi l dbeari ng age.
2. The hemor r hoi dal vei ns are pushed downwar d dur i ng def ecat i on or st r ai ni ng; wi t h
i ncreased venous pr essur e, t hey di I at e and become engorged. Over t i me, t he
f i bers t hat anchor t he hemorr hoi dal vei ns t o t hei r under l yi ng muscul ar coat s
st ret ch, whi ch r esul t s i n proI apse.
D. Si gns/ sympt oms
1. The most common si gn/ sympt om of hemor rhoi ds i s pai nI ess bI eedi ng occur ri ng
dur i ng a bowel movement . The bl ood i s usual l y bri ght r ed and may be vi si bl e on t he
st ool , on t he t oi l et t i ssue, or col or i ng t he wat er i n t he t oi l et .
2. ProI apse i s t he second most common si gn/ sympt om of hemor r hoi ds. A
t empor ar y pr ot r usi on may occur dur i ng def ecat i on, and i t may need t o be r epl aced
manual l y. A permanent l y pr ol apsed hemor r hoi d may gi ve ri se t o chr oni c, moi st
soi l i ng of t he under wear . These pat i ent s may compl ai n of a dul l , achi ng f eel i ng.
P. 695


3. Pai n i s unusual unl ess t hrombosi s i nvol vi ng ext er nal t i ssue i s pr esent , and t hen
t he pai n can be excr uci at i ng.
4. Di scomf ort , soreness, pruri t us, sweI I i ng, burni ng, and seepage may al so
occur wi t h hemor rhoi ds.
E. A proper di agnosi s i s i mpor t ant , because t her e ar e a number of condi t i ons t hat
may produce sympt oms t hat mi mi c t hose of hemor r hoi ds. Ot her condi t i ons t hat may
mi mi c hemor r hoi ds i ncl ude t he f ol l owi ng, whi ch usual l y r equi r e a physi ci an' s
i nt er vent i on:
1. An anaI abscess, usual l y a St aphyl ococcus i nf ect i on
2. Cr ypt i t i s, whi ch i s i nf l ammat i on of t he cr ypt s (smal l i ndent at i ons at t he
mucocut aneous j unct i on)
3. An anaI f i ssure, whi ch i s a smal l t ear i n t he l i ni ng of t he anus
4. An anaI f i st uI a, whi ch i s an abnormal communi cat i on bet ween t he mucosa of t he
r ect um and t he ski n adj acent t o t he anus
5. I nfI ammator y boweI di seases
6. A poI yp, whi ch i s a t umor of t he l arge i nt est i ne
7. CoI orectaI cancer
F. I nternaI hemor r hoi ds ar e gr aded and cl assi f i ed i nt o one of f our groups.
1. A fi rst - degree hemor rhoi d ( grade 1) does not descend or prol apse dur i ng
st r ai ni ng on def ecat i on. Pai nl ess bl eedi ng i s present .
2. A second- degree hemor rhoi d ( gr ade 2) descends wi t h def ecat i on but r et urns
spont aneousl y wi t h r el axat i on. Mi l d di scomf or t and bl eedi ng are present .
3. A thi rd- degree hemorr hoi d ( grade 3) r equi res manual r epl acement i nt o t he
r ect um af t er pr ol apse ( whi ch occurs dur i ng def ecat i on or exer t i on r el at ed t o wor k) .
Pai n, bl eedi ng, and di schar ge of mucus ar e pr esent .
4. A fourt h- degree hemor r hoi d (gr ade 4) i s permanent l y prol apsed and cannot be
mani pul at ed manual l y. Thr ombosi s of t en occur s.
G. Treatment. The sympt oms of hemor r hoi ds ar e pr oduced by a cycl e of event s: t he
pr ot rusi on of t he vascul ar submucosal cushi on t hr ough a t i ght anal canal , whi ch
becomes f ur t her congest ed and hyper t rophi c, whi ch causes t he cushi on t o pr ot rude
f ar t her . Al l t r eat ment s of hemor rhoi ds ai m t o break t hi s cycl e, and t hey f al l i nt o a
number of br oad gr oups.
1. For f i rst - and second- degree i nternaI hemor rhoi ds t hat bl eed mi ni mal l y, a
conser vat i ve approach can usual l y be t aken.
a. To reduce st rai ni ng and downward pressure on t he hemor rhoi ds, pat i ent s
shoul d avoi d st r ai ni ng when def ecat i ng and avoi d si t t i ng on t he t oi l et l onger t han
necessar y (suggest removi ng al l r eadi ng mat eri al s f r om t he bat hroom) .
b. Correct i on of const i pat i on i s of paramount i mportance. Thi s can be
accompl i shed by eat i ng a hi gh- f i ber di et and i ncreasi ng wat er i nt ake and physi cal
act i vi t y. Bul k-f ormi ng l axat i ves, such as psyl l i um, and st ool sof t eners, such as
docusat e, may be hel pf ul .
c. Si tz bat hs f or 15 mi n, t hr ee t o f our t i mes a day, can soot he t he anal mucosa.
Tepi d wat er shoul d be used, and pr ol onged bat hi ng shoul d be avoi ded. Epsom sal t s
( magnesi um sul f at e) added t o t he bat h or t he appl i cat i on of an i ce pack can hel p
r educe t he swel l i ng of an edemat ous or cl ot t ed hemorr hoi d.
d. OTC hemorrhoi daI oi nt ment s, creams, f oams, and supposi tori es may al so
hel p r el i eve sympt oms ( see Ì Ì Ì . H) .
2. Hi gher- grade i nt ernaI hemorrhoi ds usual l y requi r e physi ci an exper t i se and
speci al i zed pr ocedur es f or t r eat ment .
a. Sympt omat i c gr ades 2 or 3 hemor rhoi ds are of t en best t reat ed wi t h hemorrhoi d
bandi ng ( rubber band l i gat i on) . Thi s pr ocedure i s per f ormed t hr ough an anoscope;
a r ubber band l i gat ur e i s pl aced on t he rect al mucosa above t he hemorr hoi d, wel l
above t he dent at e l i ne t o avoi d excessi ve di scomf or t . The l i gat ed ar ea sl oughs of f i n
a f ew days.
P. 696


Table 33-4. Guide to Hemorrhoidal Therapy Based on Approved Indication for
OTC Anorectal Drug Products
Therapy Burnin
g
Discomfor
t
Irritatio
n
Itching Pain Sorenes
s
Swellin
g
Analgesic.
anesthetic.
antipruritic
Ye
s
Yes

Ye
s
Ye
s
Ye
s
Astringent Ye
s
Yes Yes Ye
s

Keratolytic

Yes

Ye
s

Local
anesthetic
Ye
s
Yes

Ye
s
Ye
s
Ye
s

Protectant Ye
s
Yes Yes Ye
s

Vasoconstrict
or
Yes Yes Ye
s
Ye
s
Hydrocortiso
ne
Yes

Ye
s
Ye
s

b. I nf rared photocoaguI at i on can be used f or grade 2 hemor r hoi ds; i t i s l ess
ef f ect i ve t han bandi ng wi t h l arge hemor r hoi ds. Ì nf r ar ed l i ght i s f ocused at t he base
of t he hemor r hoi d, t her eby dest r oyi ng t he vari cosi t y secondar y t o t he f ormat i on of a
whi t e coagul um.
c. ScI erotherapy ( i nj ect i on of a scl er osi ng agent i nt o t he hemor r hoi d) or
cr yot her apy ( "f r eezi ng¨ t he hemor r hoi d) are ol der t herapi es t hat have been used.
d. Surgi caI hemorrhoi dect omy shoul d be undert aken onl y f or gr ades 3 or 4
hemor r hoi ds. Whet her t he pr ocedure i s done t radi t i onal l y or wi t h a l aser , most
pat i ent s have si gni f i cant di scomf or t and a peri od of post oper at i ve di sabi l i t y.
3. An externaI , t hrombosed hemorrhoi d can be compl et el y exci sed i n an of f i ce
set t i ng, cl i ni c, or operat i ng r oom.
H. Nonprescri pt i on medi cati on for hemorrhoi daI and ot her anorect aI di seases
( Tabl e 33- 4). The FDA has i dent i f i ed sever al i ngredi ent s as saf e and ef f ect i ve t o
al l evi at e bur ni ng, di scomf or t , i nf l ammat i on, i r ri t at i on, i t chi ng, pai n, and swel l i ng.
These pr oduct s ar e si mpl y pal l i at i ve; t hey ar e not meant t o cure hemor r hoi ds or
ot her anor ect al di sease. Ì f t hese product s do not i mprove sympt oms wi t hi n 7 days, a
physi ci an shoul d be consul t ed. A physi ci an shoul d al so be consul t ed i f bl eedi ng,
pr ol apse, seepage of f eces or mucus, t hr ombosi s, or severe pai n occur s. Pat i ent s <
12 years of age shoul d not r el y on sel f -t r eat ment but shoul d seek medi cal at t ent i on
i mmedi at el y.
1. Oi ntments or creams versus supposi tori es. Gener al l y, t he oi nt ment or cream
dosage f orm i s bel i eved t o be super i or t o a supposi t or y, whi ch may bypass t he
af f ect ed ar ea. Pat i ent s shoul d wash t he anor ect al area wi t h mi l d soap and war m
wat er and pat ( not wi pe) t he ar ea dr y bef ore appl yi ng a pr oduct . Al t er nat i vel y,
pat i ent s can use an OTC anal - cl eansi ng pad (e. g. , Tucks) . Some oi nt ment s come
wi t h r ect al pi pes ( pi l e pi pes) t hat al l ow t he pat i ent t o i nser t and appl y t he
medi cat i on di rect l y i n t he r ect um. The openi ngs i n t he r ect al pi pe al l ow t he oi nt ment
t o cover l ar ge areas of t he r ect al mucosa unreachabl e wi t h t he f i nger. The r ect al
pi pe shoul d be l ubr i cat ed by spr eadi ng oi nt ment ar ound t he t i p of t he pi pe bef or e
i nser t i on. Some cl i ni ci ans advi se agai nst t he use of t he rect al pi pe because t he anal
canal coul d be t r aumat i zed i f t he pi pe i s not i nser t ed pr oper l y.
2. LocaI anest het i cs wor k by bl ocki ng ner ve- i mpul se t ransmi ssi on. Agent s deemed
saf e and ef f ect i ve i ncl ude benzocai ne 5%- 20% (e. g. , Lanacane) , pr amoxi ne 1%
( e. g. , Pr oct oFoam) , benzyl al cohol 1%-4% (e. g. , Tucks Cl ear Gel ) , di bucai ne 0. 25%-
1% ( e. g. , Nupercai nal ) , dycl oni ne 0. 5%- 1% ( e. g. , Dycl one) , l i docai ne 2%- 5% (e. g. ,
Xyl ocai ne) , and t et racai ne 0. 5%- 1% (e. g. , Pont ocai ne) .
a. Admi ni st rat i on gui deI i nes. Local anest het i cs shoul d be used f or sympt oms of
pai n, i t chi ng, bur ni ng, di scomf or t , and i rr i t at i on i n t he per i anal r egi on or l ower anal
canal (not i n t he r ect um). The r ect um cont ai ns no sensor y pai n recept or s. The
pr oduct s shoul d not be appl i ed t o abraded ski n as t hi s wi l l i ncr ease absorpt i on
syst emi cal l y.
b. Adverse ef f ect s. These agent s may pr oduce a hypersensi t i vi t y r eact i on wi t h
bur ni ng and i t chi ng si mi l ar t o t hat of anor ect al di sease. Syst emi c absorpt i on i s
mi ni mal unl ess t he peri anal ski n i s abr aded. As a r esul t of i t s uni que chemi cal
st r uct ur e, pr amoxi ne exhi bi t s l i t t l e cross-sensi t i vi t y compared t o t he ot her l ocal
anest het i cs.
P. 697


c. Warni ngs
( 1) Al l ergi c r eact i ons may occur i n some pat i ent s.
( 2) Advi se pat i ent s not t o use pr epar at i ons l onger t han 7 days.
3. Vasoconst ri ct ors decr ease mucosal perf usi on by causi ng ar t er i ol e const r i ct i on
i n t he anorect al area af t er t opi cal appl i cat i on. However , because bl eedi ng i n t hi s
ar ea may be a si gn of mor e seri ous di sease, vasoconst r i ct ors ar e not appr oved f or
cont r ol of mi nor bl eedi ng. For t empor ar y r el i ef of i t chi ng, di scomf or t , and i r r i t at i on,
t hese agent s have a l ocal anest het i c ef f ect of unknown mechani sm.
a. Agent s deemed saf e and ef f ect i ve i ncl ude ephedri ne sul f at e 0. 1%- 1. 25% i n
aqueous sol ut i on, epi nephr i ne HCl 0. 005%- 0. 01% i n aqueous sol ut i on, and
phenyl ephr i ne HCl 0. 25% i n aqueous sol ut i on. These agent s ar e pr esent i n vari ous
oi nt ment s ( e. g. , Pazo) and supposi t or i es (e. g. , Pr eparat i on H).
b. Adverse ef f ect s. Topi cal vasoconst ri ct or s, at r ecommended doses, may cause
ner vousness, t remor , sl eepl essness, nausea, and l oss of appet i t e. Car di ac
ar r hyt hmi as, i r regul ar hear t r at e, and el evat i on of bl ood pr essur e ar e pot ent i al l y
ser i ous adver se ef f ect s, but l ess l i kel y at recommended doses.
c. Warni ngs/ cont rai ndi cat i ons appl y t o peopl e wi t h cardi ovascul ar di sease, hi gh
bl ood pr essur e, hypert hyr oi di sm, di abet es, and prost at e enl ar gement because of t he
possi bi l i t y of syst emi c absorpt i on.
4. Protect ant s pr ovi de a physi caI barri er, f ormi ng a pr ot ect i ve coat i ng over ski n or
mucous membranes, f or t empor ar y r el i ef of i t chi ng, i r ri t at i on, di scomf or t , and
bur ni ng. They prevent i r ri t at i on of anor ect al t i ssue and prevent wat er l oss f r om t he
st r at um cor neum. Prot ect ant s ar e of t en t he bases or vehi cl es f or ot her agent s used
f or anorect al di sease. Product s i ncl ude al umi num hydr oxi de gel , cocoa but t er ,
kaol i n, l anol i n, har d f at , mi ner al oi l , whi t e pet rol at um, pet r ol at um, gl ycer i n ( ext er nal
use onl y) , t opi cal st arch, cod l i ver oi l , shark l i ver oi l , and zi nc oxi de. When
pr ot ect ant s ar e i ncor porat ed i nt o t he f ormul at i on of an OTC pr oduct , t hey shoul d
make up at l east 50% of t he dosage uni t . Ì f t wo t o f our pr ot ect ant s are used, t hei r
t ot al concent r at i on shoul d r epr esent at l east 50% of t he whol e product . Lanol i n, a
der i vat i ve of wool al cohol , may be al l ergeni c t o suscept i bl e i ndi vi dual s.
a. Absorbent s t ake up f l ui ds t hat ar e on or secr et ed by ski n or mucous membranes.
b. Adsorbents at t ach t o subst ances secr et ed by ski n or mucous membr anes.
c. DemuI cents combi ne wi t h wat er t o f orm a col l oi dal sol ut i on, whi ch prot ect s t he
ski n i n a way si mi l ar t o mucus.
d. EmoI I i ent s, whi ch are deri ved f rom ani mal or veget abl e f at s or pet r ol eum
pr oduct s, sof t en or pr ot ect i nt er nal or ext er nal body sur f aces.
5. Ast ri ngent s l essen mucus and ot her secr et i ons and pr ot ect underl yi ng t i ssue
t hr ough a l ocal and l i mi t ed prot ei n coagul ant ef f ect . Act i on i s l i mi t ed t o sur f ace
cel l s, but ast ri ngent s pr ovi de t empor ar y r el i ef of i t chi ng, di scomf ort , i r r i t at i on, and
bur ni ng. Pr oduct s consi der ed t o be saf e and ef f ect i ve i ncl ude cal ami ne 5%- 25%,
wi t ch hazel 10%-50% ( ext er nal use onl y) , and zi nc oxi de 5%-25%.
6. Kerat oI yt i cs cause desquamat i on and débri dement of t he surf ace cel l s of t he
epi dermi s and pr ovi de t emporar y r el i ef of di scomf or t and i t chi ng. Theor et i cal l y,
ker at ol yt i cs expose under l yi ng t i ssue t o ot her t her apeut i c agent s. Pr oduct s
consi dered t o be saf e and ef f ect i ve i ncl ude al umi num chl orhydr oxyal l ant oi nat e
( al cl oxa) 0. 2%- 2. 0% and r esor ci nol 1%- 3%. Resor ci nol shoul d not be used on an
open wound owi ng t o t he pot ent i al f or a seri ous hyper sensi t i vi t y r eact i on.
Ker at ol yt i cs ar e r eser ved f or ext er nal use onl y.
7. AnaI gesi cs, anest heti cs, and ant i pruri ti cs provi de t emporar y r el i ef of bur ni ng,
di scomf or t , i t chi ng, pai n, and sor eness. The FDA has r edesi gnat ed sever al
i ngredi ent s i nt o t hi s cat egor y t hat wer e f or mer l y cl assi f i ed as counteri rri tant s.
Ì ngr edi ent s consi dered t o be saf e and ef f ect i ve f or ext er nal use i n t he anor ect al
ar ea i ncl ude ment hol ( 0. 1%- 1%) , j uni per t ar ( 1%-5%) , and camphor ( 0. 1%- 3%) .
These agent s shoul d not be used t o t reat i nt er nal hemor rhoi ds.
8. Wound-heaI i ng agents. Li ve yeast cel l deri vat i ve ( LYCD; ski n- r espi rat or y
f act or ) , whi ch i s a wat er -sol ubl e ext r act of brewer ' s yeast , was pr esent i n
Pr eparat i on H i n t he past . LYCD was r emoved f r om t he l i st of saf e and eff ect i ve
act i ve i ngr edi ent s by t he FDA, whi ch det ermi ned t hat st udi es have not proven t hi s
agent ef f ect i ve. Pr eparat i on H pr oduct s have been r ef or mul at ed
P. 698

wi t hout LYCD. Pr eparat i on H Oi nt ment now cont ai ns prot ect ant s (pet rol at um,
mi ner al oi l , shark l i ver oi l , l anol i n, and gl ycer i n) and t he vasoconst ri ct or
phenyl ephr i ne.
9. Hydrocort i sone ( 0. 25%- 1%) causes vasoconst r i ct i on, st abi l i zat i on of l ysosomal
membr anes, and ant i mi t ot i c act i vi t y. These agent s have t he pot ent i al t o reduce
i t chi ng, i nf l ammat i on, and di scomf or t i n t he anorect al area. Unt i l recent l y,
hydr ocor t i sone-cont ai ni ng hemorr hoi dal pr oduct s wer e avai l abl e by pr escri pt i on
onl y. As wi t h any st eroi d cogener , hydr ocor t i sone may mask t he sympt oms of
bact er i al or f ungal i nf ect i ons. Hydrocor t i sone concent r at i ons > 1% are avai l abl e by
pr escri pt i on onl y.
IV. GASTROESOPHAGEAL REFLUX DISEASE
(HEARTBURN)
A. GeneraI i nf ormat i on
1. Def i ni t i on. Gast roesophageal r ef l ux di sease (GERD) i s def i ned as t he r et r ogr ade
movement of gast ri c cont ent s i nt o t he esophagus ( i . e. , gast r oesophageal r ef l ux) .
Gast r oesophageal r ef l ux i s gener al l y a beni gn physi ol ogi cal pr ocess t hat occurs i n
nor mal i ndi vi dual s mul t i pl e t i mes t hroughout t he day. However , pat i ent s wi t h GERD
may exper i ence esophageal t i ssue damage ( r ef l ux esophagi t i s) and/ or sympt oms of
hear t burn when t he aci di c gast ri c cont ent s st ay i n pr ol onged cont act wi t h t he
esophagus.
2. Epi demi oI ogy. Bet ween 30% and 50% of t he popul at i on has exper i enced
occasi onal epi sodes of hear t bur n. The f ol l owi ng ar e predi sposi ng f act or s f or t hi s
condi t i on:
a. Age. Pat i ent s of any age can exper i ence hear t bur n; however , t hi s condi t i on i s
most common i n peopl e > 50 years of age.
b. Gender, mal es are mor e l i kel y t o exper i ence GERD.
c. Pregnancy. Bet ween 30% and 50% of pregnant pat i ent s exper i ence hear t bur n
dur i ng t he cour se of pregnancy; 25% exper i enci ng dai l y sympt oms. Ì t has been
suggest ed t hat hormonal changes as wel l as t he i ncr ease i n i nt ra- abdomi nal
pr essure cont r i but e t o t he hi gh i nci dence of hear t bur n duri ng pregnancy.
d. Obesi t y may cor rel at e t o hear t bur n owi ng t o t he i ncrease i n i nt r a- abdomi nal
pr essure or l ower esophageal sphi nct er ( LES) pressur e. Thi s predi sposi ng f act or
can be vol unt ari l y modi f i ed (i . e. , wei ght l oss) t o reduce t he pat i ent s r i sk of
hear t burn.
3. Sympt oms. Heart burn ( pyr osi s) t ypi cal l y i s descri bed as a bur ni ng sensat i on or
pai n l ocat ed i n t he l ower chest . The pai n may r adi at e hi gher i n t he chest , i nt o t he
back, and i nt o t he t hroat or neck. Because t he pai n may r adi at e up i nt o t he chest ,
hear t burn may be conf used wi t h pai n associ at ed wi t h myocar di al i nf arct i on
( sweat i ng associ at ed wi t h sever e, crushi ng chest pai n suggest s a myocardi al
i nf ar ct i on and medi cal at t ent i on must be sought i mmedi at el y) . Sympt oms usual l y
occur soon af t er meal s and when l yi ng down at bedt i me; pat i ent s may be awakened
dur i ng t he ni ght wi t h t he pai n. Pai n on swal l owi ng ( odynophagi a) may suggest
sever e mucosal damage i n t he esophagus.
4. CompI i cat i ons. Pat i ent s wi t h sever e, uncont rol l ed GERD may suf f er bl eedi ng
f r om esophageal ul cer s and pul monar y compl i cat i ons r esul t i ng f r om t he aspi rat i on of
r ef l uxed mat er i al i nt o t he upper ai r ways and l ungs. Pat i ent s who descri be di f f i cul t y
swal l owi ng (i . e. , dysphagi a) may have an esophageal st r i ct ur e, cancer , or a mot i l i t y
di sor der .
5. Causes. Ther e i s an i mbal ance of aggr essi ve f or ces ( pr omot e t he devel opment of
GERD) and pr ot ect i ve f or ces ( prevent t he devel opment of GERD) . Aggressi ve f or ces
i ncl ude aci d and pepsi n. The most i mport ant prot ect i ve f or ce i s probabl y t he LES.
Many pat i ent s wi t h GERD have a weak LES. As a r esul t , t he hi gh pr essur e i n t he
st omach cr eat es enough f orce t o overcome t he weak squeeze of t he LES and al l ows
r ef l ux t o occur . Ot her prot ect i ve f orces i ncl ude esophageal cl ear ance, gast r i c-
empt yi ng r at e, sal i va, and esophageal mucosal def ense.
a. Dr ugs t hat r educe LES t one i ncl ude cal ci um channel ant agoni st s (e. g. , ni f edi pi ne,
ver apami l , di l t i azem) , ni t r at es, ant i chol i ner gi c agent s ( e. g. , t r i cycl i c
ant i depr essant s, ant i hi st ami nes) , and or al cont r acept i ves and est rogen.
b. Foods t hat r educe LES t one i ncl ude chocol at e, f at t y f oods, oni ons, pepper mi nt ,
and garl i c.
c. Smoki ng (ni cot i ne) r educes LES t one.
P. 699


6. Phar maci st s who ar e consul t ed by pat i ent s shoul d ask f or t he f ol l owi ng
i nf or mat i on bef or e recommendi ng a t herapy:
a. Durat i on and f r equency of sympt oms
b. Severi t y of t he pai n and sympt oms
c. Ti mi ng of t he sympt oms ( especi al l y i n rel at i on t o meal s and at bedt i me)
d. Pr esence of ot her sympt oms ( nausea, vomi t i ng, bl oody st ool s, wei ght l oss)
e. Use of al cohol or t obacco
f . Amount of hi gh-f at f oods, caf f ei ne- cont ai ni ng pr oduct s, chocol at e, and t omat o-
based f oods consumed
g. Medi cat i ons used cur rent l y, i ncl udi ng nonpr escr i pt i on medi cat i ons
h. Medi cat i ons used t o rel i eve hear t bur n and t hei r ef f ect i veness
7. Pat i ent s wi t h t he f ol l owi ng sympt oms or condi t i ons shoul d be r ef er r ed t o a
physi ci an f or eval uat i on r at her t han t r eat ed wi t h nonpr escri pt i on agent s:
a. Severe abdomi nal or back pai n
b. Unexpl ai ned wei ght l oss
c. Chest pai n t hat i s i ndi st i ngui shabl e f r om i schemi c pai n
d. Di f f i cul t y or pai n on swal l owi ng
e. Pr esence or hi st or y of vomi t i ng bl ood
f . Bl ack t ar r y bowel movement s ( i f not t aki ng i ron or bi smut h subsal i cyl at e)
g. Chi l dren < 12 years of age
h. Possi bi l i t y of bei ng pregnant
i . Sympt oms not r espondi ng t o ant aci ds or nonprescr i pt i on H2RAs wi t hi n 2 weeks or
r ecur r i ng soon af t er st oppi ng
B. Treatment
1. NonpharmacoI ogi caI i nt er vent i ons f or GERD at t empt t o r educe or el i mi nat e
di et ar y and l i f est yl e f act or s t hat promot e r ef l ux. Speci f i c recommendat i ons i ncl ude
t he f ol l owi ng:
a. El evat e t he head of t he bed 6-10 i nches wi t h bl ocks. Thi s posi t i on i mproves
esophageal cl ear ance and r educes t he dur at i on of r ef l ux. Tr y t o avoi d j ust pr oppi ng
a pat i ent ' s head up wi t h pi l l ows because t hi s may wor sen sympt oms by i ncr easi ng
abdomi nal pressure.
b. Eat eveni ng meal s at l east 3-5 hr bef or e goi ng t o bed t o al l ow adequat e t i me f or
gast r i c empt yi ng.
c. Avoi d f oods t hat r educe LES t one.
d. Avoi d f oods t hat i r r i t at e t he esophagus such as t omat o- based pr oduct s, cof f ee,
ci t rus j ui ces, and carbonat ed beverages ( wi t h or wi t hout caf f ei ne) .
e. Reduce t he si ze of meal s.
f . Avoi d l yi ng down f or at l east 2 hr af t er meal s.
g. St op use of t obacco pr oduct s.
h. Li mi t al cohol i nt ake.
i . Li mi t caf f ei ne-cont ai ni ng bever ages.
j . Lose wei ght i f appr opr i at e.
k. Avoi d wear i ng t i ght - f i t t i ng cl ot hi ng.
2. PharmacoI ogi caI . The management of GERD may be vi ewed as a st epped-care
approach, wi t h ant aci ds, nonpr escri pt i on H2RAs, and nondr ug measures f or mi ng t he
basi s f or t he f i r st st ep (Fi gure 33- 1) . These measur es may hel p al l evi at e sympt oms
i n pat i ent s wi t h mi l d t o moder at e GERD but cannot be expect ed t o heal damaged
esophageal mucosa or pr event compl i cat i ons. St eps 2 and hi gher use pr escri pt i on-
st r engt h H2RAs and ot her pr escri pt i on medi cat i ons as wel l as i nt er vent i ons such as
sur ger y.
a. Ant aci ds. Ant aci ds are basi c compounds t hat neut ral i ze gast r i c aci d, whi ch
i ncreases t he pH of r ef l uxed gast ri c cont ent s. As a r esul t , t he r ef l uxed cont ent s ar e
not as damagi ng t o t he esophageal mucosa and al kal i ni zat i on of gast ri c cont ent s
i ncrease LES t one.
( 1) Ant aci ds gener al l y r el i eve hear t bur n wi t hi n 5-15 mi n of admi ni st r at i on. Ant aci d
suspensi ons gener al l y di ssol ve more easi l y i n gast r i c aci d and t her eby wor k
qui cker . Ì n addi t i on, sodi um bi car bonat e and magnesi um hydroxi de di ssol ve qui ckl y
at gast r i c pH and pr ovi de r api d r el i ef ; however , cal ci um car bonat e and al umi num
hydr oxi de di ssol ve sl owl y i n st omach aci d wi t h a l onger t i me f rame f or sympt om
r el i ef (10- 30 mi n) .
( 2) The dur at i on of r el i ef r anges f r om 1 t o 3 hr i f t aken 1 hr af t er meal s ( dur at i on of
neut ral i zat i on l ast s onl y 20- 40 mi n i f t aken wi t hout f ood). Because of t hei r shor t
dur at i on, pat i ent s may need t o t ake 4-5 doses t hr oughout t he day f or adequat e
sympt om r el i ef . Ant aci ds wi l l not provi de sust ai ned neut r al i zat i on of aci d t hr oughout
t he ni ght .
P. 700



Figure 33-1. Step-wise progression oI therapy Ior
gastroesophageal reIlux disease (GERD.) ac.
beIore meals; ANC. acid-neutralizing capacity;
bid. twice daily; HS. bedtime; pc. aIter meals; qid.
Iour times daily.
( 3) Adul t s: 40-80 mEq aci d- neut ral i zi ng capaci t y (ANC) t aken as needed f or
sympt oms. Ì f necessar y, t hese doses may be t i t rat ed t o a schedul ed r egi men, such
as 40- 80 mEq af t er meal s and at bedt i me.
( 4) Sodi um bi carbonat e ( e. g. , Al ka- Sel t zer , Bromo- Sel t zer ) shoul d be used f or onl y
short - t erm rel i ef of sympt oms. Because each gr am of sodi um bi carbonat e cont ai ns
12 mEq of sodi um, i t i s cont r ai ndi cat ed i n pat i ent s wi t h edema, congest i ve hear t
f ai l ur e, r enal f ai l ur e, ci r rhosi s, and pat i ent s on l ow- sal t di et s. Ì t i s t he onl y syst emi c
ant aci d avai l abl e and can t hus al t er syst emi c pH.
( 5) CaI ci um carbonat e (e. g. , Tums) i s t he most pot ent ant aci d i ngr edi ent but may
cause const i pat i on or , l ess l i kel y, di ar r hea. Ì t i s a good source of el ement al cal ci um.
( 6) AI umi num hydroxi de ( e. g. , Amphoj el , ALt ernaGEL) of t en causes const i pat i on
and shoul d be avoi ded i n pat i ent s wi t h hemor r hoi ds or const i pat i on, whi ch i s
common i n t he el der l y. Al umi num hydr oxi de has t he l owest neut r al i zi ng capaci t y of
al l t he ant aci ds. Al umi num accumul at i on can be a pr obl em i n pat i ent s wi t h chroni c
r enal i nsuf f i ci ency.
( 7) Magnesi um hydroxi de ( e. g. , Mi l k of Magnesi a) r arel y i s used al one f or
hear t burn because i t f requent l y causes di ar rhea. Ì f used i n r enal f ai l ur e pat i ent s,
hyper magnesemi a can occur r api dl y.
( 8) Magnesi um- aI umi num combi nat i on ant aci ds ( e. g. , Maal ox, Myl ant a) pr ovi de t he
hi ghest ANC per vol ume of ant aci d and ar e used most f requent l y. The pr edomi nant
adver se ef f ect of t hese combi nat i ons i s di ar rhea.
( 9) Pati ent i nf ormat i on
( a) Pat i ent s wi t h r enal f ai l ure shoul d avoi d t he use of al l ant aci ds. Pot assi um and
magnesi um cont ent of ant aci ds shoul d be consi der ed f or pat i ent s wi t h car di ac
di sease.
( b) Pat i ent s shoul d not t ake > 500-600 mEq ANC of ant aci d per day.
( c) Pal at abi l i t y wi t h ant aci d l i qui ds may be i ncr eased wi t h r ef r i ger at i on ( do not
f r eeze) .
P. 701


( d) Tabl et s must be chewed t hor oughl y t o achi eve opt i mal ef f ect .
( e) Ant aci ds can i nt er f ere wi t h t he absor pt i on of many dr ugs. Ì n gener al , ant aci ds
shoul d be spaced at l east 2 hr apar t f r om t he admi ni st rat i on of i nt er act i ng dr ugs.
Thi s i s of t en qui t e di f f i cul t t o accompl i sh. Ì mpor t ant cl i ni cal i nt eract i ons wi t h
ant aci ds may occur wi t h t he f ol l owi ng dr ugs:
( i ) Tet r acycl i ne ant i bi ot i cs
( i i ) Qui nol one ant i bi ot i cs ( e. g. , ci pr of l oxaci n, l evof l oxaci n)
( i i i ) Ì r on suppl ement s
( i v) Di goxi n
b. AI gi ni c aci d
( 1) Mechani sm of act i on. Al gi ni c aci d wor ks by r eact i ng wi t h sodi um bi car bonat e
and sal i va t o f orm a vi scous sol ut i on of sodi um aI gi nat e. Thi s vi scous sol ut i on
f l oat s on t he sur f ace of gast r i c cont ent s so t hat , when r ef l ux occur s, sodi um
al gi nat e rat her t han aci d i s r ef l uxed, and i r r i t at i on i s mi ni mi zed.
( 2) Pati ent i nf ormat i on
( a) Al gi ni c- aci d t abl et s must be chewed t o be ef f ect i ve and shoul d be f ol l owed by a
f ul l gl ass of wat er so t hat t he vi scous f oam can f l oat on i t i n t he st omach.
( b) Al gi ni c-aci d pr oduct s wor k best when pat i ent s ar e i n t he upri ght posi t i on. Thus
t hese pr oduct s shoul d not be t aken at bedt i me or j ust bef or e l yi ng down.
c. Nonprescri pti on H2RAs. These medi cat i ons i nhi bi t gast ri c aci d secr et i on by
compet i t i vel y bl ocki ng H2- r ecept or s on t he par i et al cel l . By decr easi ng gast r i c aci d
secr et i on, t he ref l uxed mat eri al i s l ess damagi ng t o t he esophagus. The onset of
sympt om r el i ef wi t h H2RAs i s 1- 2 hr , whi ch i s consi derabl y l onger t han ant aci ds;
however , t he dur at i on of act i on can l ast up t o 10 hr . Al l H2RAs ar e cont r ai ndi cat ed
i n chi l dren < 12 years of age. Nonpr escr i pt i on H2RAs can be used f or rel i ef or
pr event i on of hear t bur n.
( 1) Ci met i di ne ( Tagamet - HB)
( a) Adul t s (nonpr escri pt i on) : 200 mg as needed f or sympt oms, up t o t wi ce dai l y.
Ci met i di ne 200 mg suppresses gast ri c aci d f or appr oxi mat el y 6 hr .
( b) Nonpr escri pt i on doses of ci met i di ne may i mpai r t he hepati c met aboI i sm and
t hus i ncrease serum concent r at i ons and t he pharmacol ogi cal ef f ect s of t he f ol l owi ng
dr ugs:
( i ) Warf ari n
( i i ) Phenyt oi n
( i i i ) Theophyl l i ne
( 2) Famot i di ne ( Pepci d-AC, Pepci d CompI et e, Maxi mum St rengt h Pepci d- AC) .
Unl i ke ci met i di ne, f amot i di ne r arel y i mpai rs hepat i c met abol i sm of ot her drugs
( a) Adul t s (nonpr escri pt i on) : 10-20 mg as needed f or sympt oms, up t o t wi ce dai l y;
maxi mum dose 40 mg/ day. Pat i ent s who ant i ci pat e hear t bur n or i ndi gest i on may
t ake 10- 20 mg ( 1 t abl et ) 1 hr bef or e eat i ng; maxi mum of 2 t abl et s wi t hi n a 24-hr
per i od. Famot i di ne 10 mg suppresses aci d secr et i on f or 8- 10 hr.
( b) Famot i di ne, cal ci um car bonat e, magnesi um hydr oxi de ( Pepci d Compl et e) . A
chewabl e combi nat i on of an H2RA and an ant aci d.
( 3) Rani t i di ne (Zantac 75, Zant ac 150 Maxi mum St rength) .
( a) Adul t s (nonpr escri pt i on) : 75-150 mg as needed f or sympt oms, up t o t wi ce dai l y;
maxi mum 150 mg/ day
( b) Rani t i di ne i nhi bi t s hepat i c met abol i sm 5-10 t i mes l ess t han ci met i di ne;
t her ef ore, t he pot ent i al f or drug i nt er act i ons i s ver y smal l .
( 4) Ni zat i di ne ( Axi d- AR) . Adul t s: 75 mg as needed f or sympt oms, up t o t wi ce dai l y.
Ni zat i di ne r arel y i mpai rs hepat i c met abol i sm of ot her dr ugs.
( 5) Adverse ef fect s. These agent s ar e ext r emel y wel l t ol er at ed. The most common
adver se ef f ect s r epor t ed wi t h nonpr escr i pt i on doses are headache, di ar r hea,
di zzi ness, and nausea.
d. Prescri pti on H2RAs. Pat i ent s wi t h moder at e t o sever e sympt oms and/ or
esophageal mucosal l esi ons r equi re hi gher doses of H2RAs t han are avai l abl e over
t he count er . Unl i ke pat i ent s wi t h pept i c ul cer di sease, pat i ent s wi t h GERD r espond
best t o mul t i pl e dai l y doses of H2RAs r at her t han t o si ngl e bedt i me doses.
e. Proki neti c agent s. Pat i ent s wi t h moder at e t o sever e GERD may benef i t f rom t he
addi t i on of t hese medi cat i ons, whi ch st i mul at e esophageal mot i l i t y and i ncr ease LES
t one. Pr oki net i c agent s ar e avai l abl e onl y by prescr i pt i on.
( 1) Met ocI oprami de ( RegI an, generi c) . Adverse ef f ect s, such as sedat i on,
depressi on, and ext r apyr ami dal ef f ect s, l i mi t t he usef ul ness of t hi s agent f or many
pat i ent s.
P. 702


( 2) Ci sapri de ( PropuI si d) . The numer ous dr ug i nt er act i ons wi t h t hi s pr oduct have
caused t he manuf act ur er t o vol unt ar i l y r emove i t f r om t he mar ket . Pr opul si d may
st i l l be obt ai ned t hrough an i nvest i gat i onal l i mi t ed- access pr ogr am.
f . Prot on pump i nhi bi t ors. These prescr i pt i on-onl y agent s (except omepr azol e)
pr ovi de compl et e aci d suppr essi on by i nhi bi t i ng t he hydrogen- pot assi um ATPase
pump on t he sur f ace of t he par i et al cel l . The durat i on of aci d suppr essi on wi t h t hese
agent s i s about 3 days. Pr ot on pump i nhi bi t or s ar e t he most pot ent and ef f ect i ve
agent s avai l abl e f or r el i evi ng sever e GERD sympt oms and heal i ng esophageal
l esi ons. Ì n June 2003, t he FDA swi t ched omepr azol e t o OTC st at us f or t he
pr event i on of sympt oms of f requent ( occur r i ng 2 or mor e days per week) hear t burn.
These OTC dr ugs shoul d be used f or no more t han 14 days ever y 4 mont hs, unl ess
di r ect ed by a physi ci an.
( 1) OmeprazoI e ( Pri I osec and Pri I osec OTC)
( a) Thi s drug may i nhi bi t hepat i c met abol i sm and t hus i ncr ease ser um
concent r at i on/ pharmacol ogi c ef f ect s of t he f ol l owi ng dr ugs: phenyt oi n, war f ar i n, and
di azepam.
( b) Adverse ef f ect s. Al t hough rar e, t hese may i ncl ude headache, di ar rhea,
const i pat i on, or di zzi ness.
( 2) LansoprazoI e ( Prevaci d) has no cl i ni cal l y si gni f i cant dr ug i nt er act i ons.
( 3) Pant oprazoI e ( Prot oni x) i s t he onl y prot on pump i nhi bi t or wi t h an or al and
i nt ravenous f ormul at i on.
( 4) RabeprazoI e ( Aci phex)
( 5) EsomeprazoI e ( Nexi um)
C. Speci aI pati ent popuI at i ons
1. Pedi at ri c pat i ent s. Gast roesophageal r ef l ux occur s commonl y i n i nf ant s and
chi l dren. Si gns and sympt oms i n pedi at r i c pat i ent s i ncl ude vomi t i ng, chest pai n,
i r r i t abi l i t y, f eedi ng ref usal , bel chi ng, and apnea. Ser i ous compl i cat i ons ( e. g. , f ai l ure
t o t hr i ve, esophageal st r i ct ures) can occur i n i nf ant s and chi l dr en.
a. Ant aci ds, wi t h or wi t hout al gi ni c aci d, have been wi del y used i n i nf ant s and
chi l dren, but t hei r saf et y has not been cl ear l y est abl i shed.
b. H2RAs have been used saf el y i n chi l dr en under t he super vi si on of heal t hcare
pr ovi der s. However , t he nonpr escri pt i on H2RAs ar e not approved f or use i n chi l dr en
< 12 years of age unl ess di rect ed by a physi ci an.
2. Pregnant pati ents. Hear t bur n occur s commonl y duri ng pr egnancy because of
i ncreased abdomi nal pressur e owi ng t o t he expandi ng ut erus, as wel l as r educed
LES pressure r esul t i ng f rom hi gh concent r at i ons of est rogen and pr ogest er one.
Near l y hal f of pr egnant women exper i ence GERD, especi al l y dur i ng t he t hi rd
t r i mest er .
a. Ant aci ds are gener al l y consi der ed saf e i n pregnancy as l ong as chr oni c hi gh
doses ar e avoi ded. Ì t i s best t o avoi d sodi um bi car bonat e because of t he r i sks of
syst emi c al kal osi s and t he sodi um l oad l eadi ng t o edema and wei ght gai n.
b. Dat a r egardi ng t he saf et y of aI gi ni c aci d dur i ng pregnancy are not avai l abl e.
c. Cont roI I ed dat a regardi ng the saf et y of H2RAs i n pr egnancy ar e l i mi t ed.
Pr egnant women seeki ng a nonprescr i pt i on H2RA f or GERD shoul d be di rect ed t o
use ant aci ds, unl ess a physi ci an has i nst ruct ed her ot her wi se.
3. EI derI y pat i ent s. Ant aci ds and nonprescri pt i on H2RAs may be saf el y used i n
el der l y pat i ent s wi t hout any dosage adj ust ment s.
a. Dosage reduct i on of pr escr i pt i on H2RAs may be necessar y i n el derl y pat i ent s wi t h
r educed r enal f unct i on.
b. El der l y pat i ent s ar e mor e l i kel y t o be t aki ng drugs t hat i nt er act wi t h ant aci ds,
H2RAs, omepr azol e, and/ or ci sapri de.
c. El derl y pat i ent s are al so more l i kel y t o have sympt oms or condi t i ons t hat r equi r e
r ef er ral t o a physi ci an bef or e begi nni ng nonpr escr i pt i on t herapy.
P. 703


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 20: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. Whi ch I axat i ve shouI d not be used t o t reat acut e const i pat i on because of i ts
sI ow onset of act i on?
( A) gl ycer i n
( B) bi sacodyl supposi t ory
( C) psyl l i um
( D) mi l k of magnesi a
Vi ew Answer 1. The answer i s C[ see] . 2. Whi ch i s not a ri sk f actor f or
hyperphosphatemi a and deat h f rom sodi um phosphat e enemas when used i n
chi I dren?
( A) r enal i nsuf f i ci ency
( B) Hi rschspr ung di sease
( C) anor ect al mal f ormat i ons
( D) chi l dr en 6- 12 years of age
Vi ew Answer 2. The answer i s D[ see] . 3. AI I of the f oI I owi ng stat ements
about emoI I i ent st ooI sof t ener I axat i ves are t rue except whi ch one?
( A) They ar e not good f or acut e const i pat i on.
( B) They ar e good f or pat i ent s who shoul d not st rai n by passi ng a hard st ool ( e. g. ,
post sur gi cal pat i ent s) .
( C) They never have been f ound t o be bet t er t han pl acebo f or l ong- t er m use.
( D) They ar e more ef f ect i ve t han pl acebo f or l ong- t er m use.
Vi ew Answer 3. The answer i s D[ see] . 4. Whi ch of t he f oI I owi ng st atement s
adequat eI y descri bes buI k- f ormi ng I axat i ves?
( A) can cause di ar r hea i f not t aken wi t h wat er
( B) ar e deri ved f r om pol ysacchar i des and resembl e f i ber (br an) i n mechani sm of
act i on
( C) onset of act i on i n 4-8 hr
( D) pr oduce much more compl et e evacuat i on of const i pat i on t han st i mul ant product s
Vi ew Answer 4. The answer i s B[ see] . 5. Whi ch of t he f oI I owi ng st atement s
about nondrug therapi es f or acute di arrhea i s not correct ?
( A) Br east -f eedi ng shoul d be cont i nued as normal .
( B) Even i f t he pat i ent i s not vomi t i ng, f ood shoul d be wi t hhel d f or 6- 12 hr.
( C) Fl ui ds can be gi ven t o pat i ent s who exper i ence vomi t i ng, but smal l amount s of
f l ui d shoul d be used.
( D) Repl acement f l ui ds mai nl y consi st of wat er , sugar , pot assi um, sodi um, and
bi car bonat e.
Vi ew Answer 5. The answer i s B[ see] . 6. Whi ch of t he f oI I owi ng product s
shouI d not be used to repI eni sh I ost f I ui ds f rom acut e di arrhea?
( A) pedi al yt e sol ut i on
( B) Kool - Ai d
( C) Gat orade ( hal f -st r engt h di l ut ed wi t h wat er )
( D) The Worl d Heal t h Organi zat i on (WHO) sol ut i on
Vi ew Answer 6. The answer i s B[ see] . 7. Whi ch of t he f oI I owi ng st atement s
about adsorbent drugs used f or di arrhea i s t rue?
( A) usef ul f or t reat ment of sever e di ar r hea
( B) ver y unsaf e because not absorbed syst emi cal l y
( C) i n gener al , smal l doses needed t o r el i eve di arr hea
( D) kaol i n now gener al l y r ecogni zed as a saf e and ef f ect i ve OTC ant i di ar rheal agent
Vi ew Answer 7. The answer i s D[ see] . 8. Whi ch of t he f oI I owi ng st atement s
concerni ng t raveI er' s di arrhea i s t rue?
( A) Ì t can usual l y be avoi ded by not eat i ng r aw veget abl es, seaf ood, or eggs when
t r avel i ng t o t hi rd wor l d count ri es.
( B) Ì t can be prevent ed by t aki ng one dose of ant i bi ot i c 1 day bef ore a t r i p.
( C) Hel i cobact er pyl or i i s t he pr i mar y pat hogen responsi bl e.
( D) Phi l l i ps' Mi l k of Magnesi a i s used t o pr event and t r eat t he condi t i on.
Vi ew Answer 8. The answer i s A[ see] . Escheri chi a col i Hel i cobact er
pyl ori 9. AI I of t he foI I owi ng agents are consi dered cI ose t o i deaI
I axati ves except
( A) emol l i ent l axat i ves.
( B) bul k-f ormi ng l axat i ves.
( C) f i ber .
( D) st i mul ant l axat i ves.
Vi ew Answer 9. The answer i s D[ see] . 10. A pat i ent suf f eri ng f rom acute
i nf ecti ous di arrhea caused by Shi gel l a can be managed i n aI I of t he foI I owi ng
ways except whi ch one?
( A) No t reat ment necessar y because si gns and sympt oms usual l y r esol ve i n 48 hr .
( B) Use gl ucose sol ut i ons ( e. g. , soda, appl e j ui ce) t o set t l e t he st omach and
decrease t he number of st ool s.
( C) Avoi d f ood f or at l east 6 hr , t hen sl owl y i ncrease f l ui d i nt ake.
( D) Use ant i bi ot i cs (e. g. , Bact r i m, doxycycl i ne) f or 7 days.
Vi ew Answer 10. The answer i s B[ see] . P. 704


11. Whi ch I ocaI anest het i c shouI d be used t o t reat sympt oms of pai n, i t chi ng,
burni ng, and di scomf ort i n pat i ent s wi t h an est abI i shed I i docai ne aI I ergy?
( A) t et racai ne
( B) di bucai ne
( C) pr amoxi ne
( D) benzocai ne
Vi ew Answer 11. The answer i s C[ see] . 12. AI I of t he f oI I owi ng i tems are
part of a st andard conservat i ve approach t o the t reatment of f i rst - or second-
degree hemorrhoi ds except
( A) t opi cal anest het i c ( hemorr hoi dal oi nt ment ) .
( B) st ool sof t ener.
( C) si t z bat hs.
( D) r ubber band l i gat i on.
Vi ew Answer 12. The answer i s D[ see] . 13. What i s t he most common
si gn/ sympt om of hemorrhoi ds?
( A) bl eedi ng
( B) pai n
( C) seepage
( D) pr uri t us
Vi ew Answer 13. The answer i s A[ see] . 14. Whi ch of t he f oI I owi ng agents
i s desi gnat ed as a safe and ef f ect i ve anaI gesi c, anesthet i c, and ant i pruri t i c by
t he Food and Drug Admi ni st rat i on?
( A) wi t ch hazel
( B) j uni per t ar
( C) hydr ocor t i sone
( D) phenyl ephr i ne
Vi ew Answer 14. The answer i s B[ see] . 15. AI I of t he f oI I owi ng
vasoconst ri ctors are deemed saf e and ef fect i ve f or t he t emporar y reI i ef of
i t chi ng and sweI I i ng except
( A) ephedri ne 0. 1%-1. 25%.
( B) epi nephri ne 0. 005%-0. 01%.
( C) phenyl propanol ami ne 1%-10%.
( D) phenyl ephr i ne 0. 25%.
Vi ew Answer 15. The answer i s C[ see] . 16. AI I of t he f oI I owi ng sympt oms
associ ated wi th gast roesophageaI ref I ux di sease ( GERD) may be t reat ed wi th
nonprescri pt i on agent s except
( A) burni ng sensat i on l ocat ed i n t he l ower chest .
( B) pai n t hat i s wor se af t er meal s.
( C) pai n or di f f i cul t y when swal l owi ng.
( D) pai n t hat i s wor se on l yi ng down at bedt i me.
Vi ew Answer 16. The answer i s C[ seeand] . 17. Whi ch of t he f oI I owi ng i s an
appropri at e nonpharmacoI ogi caI recommendati on f or pati ents wi t h
gast roesophageaI ref I ux di sease ( GERD) ?
( A) Eat l arger but f ewer meal s.
( B) Avoi d meal s hi gh i n pr ot ei n.
( C) Eat eveni ng meal s at l east 3 hr bef ore bed.
( D) Pr op a pat i ent ' s head up wi t h t wo pi l l ows at ni ght .
Vi ew Answer 17. The answer i s C[ seeand] . 18. AI I of t he f oI I owi ng
st at ements regardi ng ant aci d use i n gast roesophageaI ref I ux di sease ( GERD)
are correct except whi ch one?
( A) The onset of sympt om r el i ef wi t h ant aci ds i s 1- 2 hr .
( B) Ant aci ds wi l l rel i eve sympt oms f or 1- 3 hr .
( C) Sodi um bi car bonat e shoul d not be used i n pat i ent s wi t h edema, congest i ve hear t
f ai l ur e, or t hose on l ow- sal t di et s
( D) The most f r equent si de ef f ect of al umi nummagnesi um combi nat i on ant aci ds i s
di ar rhea.
Vi ew Answer 18. The answer i s A[ see] . 19. AI I of t he f oI I owi ng stat ements
regardi ng use of nonprescri pt i on H2RAs i n gast roesophageaI refI ux di sease
( GERD) are correct except whi ch one?
( A) The most common adver se ef f ect s of nonpr escr i pt i on H2RAs ar e headache,
di ar rhea, di zzi ness, and nausea.
( B) Ci met i di ne may i ncr ease ser um concent r at i ons of war f ar i n, t heophyl l i ne, and
phenyt oi n.
( C) The onset of sympt om r el i ef wi t h t hese agent s i s 1- 2 hr .
( D) Nonprescri pt i on H2RAs wi l l heal sever el y damaged esophageal mucosa.
Vi ew Answer 19. The answer i s D[ seeand] . 20. AI I of t he f oI I owi ng
st at ements regardi ng use of nonprescri pt i on products f or gast roesophageaI
ref I ux di sease ( GERD) i n speci aI popuI at i ons are correct except whi ch one?
( A) Nonpr escri pt i on H2RAs are not approved f or use i n chi l dr en < 12 years of age.
( B) Ant aci ds may be saf el y used i n pr egnant pat i ent s as l ong as chr oni c hi gh doses
ar e avoi ded.
( C) Sodi um bi car bonat e i s t he pr ef er r ed ant aci d i n pr egnant pat i ent s.
( D) Doses of nonpr escri pt i on H2RAs do not need t o be reduced i n el der l y pat i ent s.
Vi ew Answer 20. The answer i s C[ see] . P. 705


Di rect i ons for quest i ons 21-23: The quest i ons and i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one or more of t he suggest ed
answer s. Choose t he answer , A- E.
21. Whi ch of t he f oI I owi ng drugs most commonI y causes const i pat i on?
I . ampi ci I I i n
I I . narcot i c anaI gesi cs
I I I . drugs possessi ng ant i choI i nergi c propert i es
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 21. The answer i s D[ see] . 22. Whi ch of t he f oI I owi ng
st at ements about st i muI ant I axat i ves i s correct ?
I . They produce a stooI more qui ckI y t han any ot her t ype of I axat i ve.
I I . They are associ at ed wi t h more adverse eff ect s t han any ot her t ype of
I axati ve.
I I I . They work by i rri t at i ng t he I i ni ng of the coI on waI I t o i ncrease peri st aI si s
and produce a st ooI .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 22. The answer i s D[ see] . 23. When shouI d a pati ent
experi enci ng di arrhea be referred to a physi ci an by a pharmaci st ?
I . I f the pat i ent has pus or bI ood i n t he stooI .
I I . I f t he pati ent aI so suf f ers f rom vomi ti ng.
I I I . I f t he pat i ent has a fever.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 23. The answer i s E[see] . P. 706


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì . B. 2. a] .
Gl ycer i n and t he bi sacodyl supposi t or y al l pr oduce st ool s i n 30 mi n t o a f ew hour s,
wher eas psyl l i um, a bul k- f or mi ng l axat i ve, produces st ool i n 24-72 hr i n t he same
manner as a normal bol us of f ood or f i ber.
2. The answer i s D [ see Ì . C. 4] .
The popul ar sodi um phosphat e enemas ( e. g. , Fl eet ) are ver y ef f ect i ve but have
r esul t ed i n hyper phosphat emi a, hypocal cemi a ( t et any) , hypokal emi a, met abol i c
aci dosi s, and car di ac deat h usual l y owi ng t o conduct i on abnor mal i t i es i n ver y smal l
chi l dren. Thi s has mai nl y occur red i n chi l dr en < 2 year s of age or bet ween 2 and 5
year s of age wi t h pr edi sposi ng f act or s, such as chr oni c r enal di sease, anor ect al
mal f ormat i ons, and/ or Hi r schspr ung di sease. The use of enemas i s hi ghl y
di scour aged i n chi l dr en < 5 year s of age.
3. The answer i s D [ see Ì . B. 2. d] .
These agent s have a l ong onset of act i on (24-48 hr ) ; t hus t hey shoul d never be
used f or acut e const i pat i on but shoul d be used mai nl y f or pat i ent s who shoul d not
st r ai n t o pass hard st ool s ( e. g. , pr egnant pat i ent s, post sur gi cal pat i ent s, post -
myocar di al i nf arct i on) . However , t hey have never been f ound t o be mor e ef f ect i ve
t han pl acebo i n l ong-t erm use.
4. The answer i s B [ see Ì . B. 2. a; Ì . B. 2. c] .
St i mul ant pr oduct s r esul t i n a qui cker , more compl et e, and of t en more vi ol ent
evacuat i on of t he bowel t han do t he bul k- f ormi ng agent s. Bul k- f ormi ng agent s are
devel oped f rom compl ex sugar s, si mi l ar t o f i ber, t hat pr ovi de bul k t o i ncrease
gast r oi nt est i nal mot i l i t y and wat er absorpt i on i nt o t he bowel . However , pat i ent s
must dr i nk pl ent y of wat er t o f aci l i t at e t he absorpt i on of wat er i nt o t he bowel , or
t hey may become mor e const i pat ed.
5. The answer i s B [ see Ì Ì . C. 1] .
The most i mpor t ant part of t reat i ng acut e di ar r hea i s t he repl acement of l ost f l ui ds.
Ì f pat i ent s exper i ence mi l d t o moder at e f l ui d l oss, r epl acement can be done wi t h
or al - rehydrat i on sol ut i ons. Ì f f l ui d l oss i s severe (> 10% l oss of body wei ght ) and/ or
sever e vomi t i ng, t hen pat i ent s may need i nt r avenous r ehydrat i on bef or e or al -
mai nt enance f l ui ds can be admi ni st ered. Ther e has been much cont r oversy
r egardi ng t he deci si on t o f eed or not f eed chi l dr en duri ng acut e epi sodes of
di ar rhea. Recent i nf or mat i on shows t hat chi l dren shoul d r emai n on t hei r nor mal di et
or breast - f eedi ng duri ng epi sodes of di ar r hea; t hese do not make t he di arr hea wor se
and may act ual l y i mprove t he condi t i on.
6. The answer i s B [ see Ì Ì . C. 1. b] .
Repl acement f l ui ds f or di ar r hea shoul d cont ai n t he appr opr i at e amount of
el ect r ol yt es ( K
+
, Na
+
, Cl
-
, ci t r at e) and gl ucose per speci f i ed amount of wat er , as
f ound i n commer ci al l y avai l abl e oral - rehydrat i on sol ut i ons such as Pedi al yt e and
Rehydr al yt e. The Worl d Heal t h Or gani zat i on (WHO) sol ut i on, whi ch can easi l y be
made at home, and hal f -st r engt h Gat or ade pr ovi de t he necessar y el ect r ol yt es and
gl ucose t o repl eni sh l ost f l ui ds. Kool -Ai d does not cont ai n pot assi um. Carbonat ed
bever ages are l ow i n pot assi um, and some are t oo hi gh i n gl ucose.
7. The answer i s D [ see Ì Ì . C. 2. b] .
Adsorbent s ar e not ef f ect i ve f or sever e di ar r hea because t hey si mpl y cannot adsor b
enough wat er and do not r ever se t he cause of t he di ar r hea. Lar ge doses may
decrease sympt oms. Of al l t he adsorbent s, kaol i n i s t he most ef f ect i ve and i s now
r ecogni zed by t he FDA as saf e and ef f ect i ve. Al l adsor bent s are saf e because t hey
ar e not adsor bed syst emi cal l y.
8. The answer i s A [ see Ì Ì . A. 2. b; Ì Ì . C. 2] .
Tr avel er ' s di arr hea i s pr i mar i l y caused by bact er i a ( mai nl y ent erot oxi n Escheri chi a
col i ) . Pr ophyl axi s and t reat ment r egi mens i ncl ude or al ant i bi ot i cs ( f l uoroqui nol ones,
sul f onami des, doxycycl i ne) and bi smut h subsal i cyl at e ( Pept o- Bi smol ) . Hel i cobact er
pyl or i i s t he organi sm shown t o cont ri but e t o ref ract or y pept i c ul cer di sease.
P. 707


9. The answer i s D [ see Ì . B. 2] .
The i deal l axat i ve i s nat ur al ( i . e. , si mi l ar t o f ood) and produces st ool on a r egul ar
basi s. The pr oduct produces st ool qui ckl y ( i . e. , i n several hours) wi t hout adver se
ef f ect s. such as abdomi nal cr ampi ng or t he f ormat i on of a har d st ool , whi ch may be
di f f i cul t t o pass. Pr oduct s such as f i ber or bul k-f or mi ng agent s pr oduce a st ool
si mi l ar t o a bol us of f ood, wi t hout adverse ef f ect s. Emol l i ent l axat i ves (i . e. , st ool
sof t ener s) pr oduce sof t st ool s wi t hout di f f i cul t def ecat i on. St i mul ant s pr oduce a
st ool qui ckl y, but pat i ent s of t en exper i ence severe abdomi nal crampi ng and har d
st ool s.
10. The answer i s B [ see Ì Ì . C; Tabl e 33- 3] .
Gi vi ng hi ghl y osmot i c sol ut i ons of gl ucose ( e. g. , soda, f r ui t j ui ce) can resul t i n mor e
wat er absor bed i nt o t he i nt est i nal t r act and t hus f ur t her di ar rhea. Many cases of
di ar rhea r esol ve wi t hi n 48 hr wi t hout t r eat ment . Peopl e wi t h di ar r hea can avoi d f ood
f or at l east 6 hr , t hen i ncr ease t hei r f l ui d i nt ake sl owl y. Sever e cases of i nf ect i ous
di ar rhea can be t r eat ed wi t h ant i bi ot i cs or ant i prot ozoal s, dependi ng on t he
or gani sm t hat caused t he epi sode.
11. The answer i s C [ see Ì Ì Ì . H. 2. b] .
Because of i t s chemi cal l y di st i nct st ruct ur e, pramoxi ne exhi bi t s l ess cr oss-
sensi t i vi t y compared t o t he ot her anest het i cs and shoul d be used i n pat i ent s wi t h a
l i docai ne al l er gy.
12. The answer i s D [ see Ì Ì Ì . G. 1] .
A conser vat i ve appr oach t o t reat ment i ncl udes si t z bat hs, t he use of st ool sof t ener s
t o prevent st rai ni ng when passi ng a st ool , and t he use of an anest het i c
hemor r hoi dal pr eparat i on. Ì f i mpr ovement i s not seen, more aggr essi ve t her apy may
be pur sued ( e. g. , r ubber band l i gat i on) .
13. The answer i s A [ see Ì Ì Ì . D. 1] .
The most common si gn/ sympt om of hemor r hoi ds i s pai nl ess bl eedi ng occur r i ng
dur i ng a bowel movement .
14. The answer i s B [ see Ì Ì Ì . H. 7] .
Juni per t ar , ment hol , and camphor ar e t he onl y t hr ee agent s deemed saf e and
ef f ect i ve as anal gesi cs, anest het i cs, and ant i pruri t i cs by t he FDA. These agent s
wer e f or mer l y cl assi f i ed as count er i r ri t ant s.
15. The answer i s C [ see Ì Ì Ì . H. 3. a] .
Vasoconst r i ct ors deemed saf e and ef f ect i ve by t he FDA ar e ephedri ne HCl ,
epi nephr i ne, and phenyl ephri ne.
16. The answer i s C [ see Ì V. A. 2 and 3; Ì V. A. 6] .
Pai n on swal l owi ng of t en suggest s sever e esophageal mucosal damage, whi ch
woul d r equi re pr escri pt i on medi cat i ons f or heal i ng. Di f f i cul t y on swal l owi ng may
i ndi cat e an esophageal st r i ct ur e, cancer, or mot or di sor der . Al l of t hese condi t i ons
r equi r e di agnosi s and t reat ment by a heal t hcare pr ovi der.
17. The answer i s C [ see Ì V. B. 1. a, b, c, d, e, f , g, h, i , j and k] .
Pat i ent s shoul d be i nst ruct ed t o eat eveni ng meal s at l east 3 hr bef or e goi ng t o bed.
Thi s al l ows suf f i ci ent t i me f or gast ri c empt yi ng, so t hat t he vol ume of ref l uxed
mat er i al wi l l be smal l er and l ess i r ri t at i ng t o t he esophagus.
18. The answer i s A [ see Ì V. B. 2. a] .
One of t he maj or advant ages of ant aci d use i n hear t bur n i s i t s qui ck onset of act i on.
Most pat i ent s wi t h mi l d GERD wi l l exper i ence r el i ef f r om ant aci ds wi t hi n 5- 15 mi n of
admi ni st rat i on.
19. The answer i s D [ see Ì V. B. 2. c and d] .
Nonpr escr i pt i on doses of H2RAs ar e t oo l ow t o heal esophageal damage.
Esophageal mucosal damage i s di f f i cul t t o heal and requi r es hi gh doses of H2Ras,
whi ch are avai l abl e onl y by pr escri pt i on. Al t ernat i vel y, pr ot on pump i nhi bi t or s, whi ch
compl et el y suppress aci d secret i on, may be used t o heal esophageal mucosal
damage.
20. The answer i s C [ see Ì V. C. 2] .
Sodi um bi carbonat e shoul d be avoi ded i n pr egnant pat i ent s because t he hi gh
sodi um l oad may cause syst emi c al kal osi s, edema, and/ or wei ght gai n.
P. 708


21. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see Ì . A. 3. d] .
Opi at e anal gesi cs ( e. g. , nar cot i cs) and dr ugs wi t h ant i chol i ner gi c pr opert i es
decrease bowel mot i l i t y, whi ch r esul t s i n i ncreased wat er absor pt i on f r om t he
i nt est i nal t ract . Thi s can cause a har der , dr i er st ool , whi ch resul t s i n const i pat i on.
Ampi ci l l i n i s of t en poor l y absor bed f r om t he i nt est i nal t ract and can al t er t he f l or a of
t he i nt est i nal bowel . Thi s dest ruct i on of bowel organi sms causes i ncr eased
secr et i ons i nt o t he bowel , whi ch resul t s i n di ar r hea.
22. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see Ì . B. 2. c] .
St i mul ant l axat i ves do have a qui ck onset of act i on but not any qui cker t han t he
sal i ne l axat i ves, whi ch usual l y wor k i n 4- 6 hr . The mechani sm of act i on f or st i mul ant
l axat i ves i s t hat t hey i r ri t at e t he l i ni ng of t he col on wal l , whi ch i ncr eases per i st al si s
and pr oduces a st ool . These l axat i ves are associ at ed wi t h mor e adverse ef f ect s
t han ot her l axat i ves.
23. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì Ì . B. 2] .
Pat i ent s wi t h pus or bl ood i n t he st ool , vomi t i ng, or f ever may be suf f eri ng f r om
sever e bact er i al di ar rhea and may l ose l arge amount s of f l ui d, whi ch coul d r esul t i n
sever e dehydr at i on.

34
OTC MenstruaI, VaginaI, and
Contraceptive Agents
Laura K. Wi I I i f ord Owens
I. MENSTRUATION AND MENSTRUAL PRODUCTS
A. I nt roduct i on. Menst ruat i on i s a physi ol ogi cal di schar ge of bl ood,
endomet r i al cel l ul ar debri s, and mucus t hrough t he vagi na of a nonpregnant
woman and i s a resul t of t he mont hl y cycl i ng of f emal e reproduct i ve
hor mones. The menst rual cycl e el i mi nat es a mat ur e, unf ert i l i zed egg and
pr epar es t he endomet r i um f or t he possi bl e i mpl ant at i on of a f er t i l i zed egg
t he f ol l owi ng mont h.
1. Onset . The aver age age at whi ch t he i ni t i al menst r ual cycl e occur s i n
U. S. women i s 12 years. Nor mal menarche ( i ni t i al menst r ual cycl e) can
occur bet ween t he ages of 9 and 16 years. Fact or s such as race, genet i cs,
nut ri t i onal st at us, and body mass det ermi ne t he onset .
2. Durati on. The average durat i on of t he menst rual cycl e i s 28 days ( t he
t i me bet ween t he onset of one menst rual f l ow and t he begi nni ng of t he next )
and t he normal range i s 21- 35 days. Day 1 i s t he f i rst day of menst r ual
f l ow, whi ch can l ast f or 3- 7 days ( average dur at i on of f l ow i s 5 days) .
3. Physi oI ogy. The menst r ual cycl e resul t s f rom a compl ex i nt er pl ay of
hor mones pr oduced by t he hypot hal amus, pi t ui t ar y gl and, and t he ovari es
( hypot hal ami c-pi t ui t ar y- ovar i an axi s) .
B. Menst ruaI abnormaI i t i es
1. Dysmenorrhea i s pai nf ul menst r uat i on. Ì t i s t he most common
gynecol ogi c pr obl em i n t he Uni t ed St at es.
a. Types
( 1) Pri mar y dysmenorrhea i s pai n associ at ed wi t h menst r uat i on i n t he
absence of i dent i f i abl e pel vi c di sease. Ì t i s pr ompt ed by i ncreased l evel s of
pr ost agl andi ns i n t he menst rual f l ui ds.
( 2) Secondar y dysmenorrhea i s associ at ed wi t h an under l yi ng pel vi c
di sor der . Possi bl e causes i ncl ude endomet r i osi s, pel vi c i nf l ammat or y
di sease ( PÌ D) , and ovar i an cyst s.
b. Sympt oms of dysmenor r hea are pri mar i l y l ower abdomi nal cr ampi ng and
can of t en i ncl ude nausea, vomi t i ng, di ar r hea, headache, and di zzi ness.
Abdomi nal crampi ng usual l y begi ns at onset of menst r ual f l ow or a f ew
hours bef ore onset .
c. Pract i t i oner s shoul d quest i on the pat i ent about t he f ol l owi ng:
( 1) Cur rent medi cat i ons ( i ncl udi ng over t he count er and her bal s)
( 2) Age
( 3) Durat i on of dysmenorr hea
( 4) A descri pt i on of t he dysmenor r hea sympt oms
( 5) Hi st or y of pel vi c di sease ( endomet ri osi s, PÌ D, ovar i an cyst s, i nf er t i l i t y)
( 6) Al l ergy t o aspi ri n or nonst eroi dal ant i -i nf l ammat or y dr ug ( NSAÌ D)
( 7) Bl eedi ng di sor der
( 8) Exer ci se rout i ne
d. Treat ment
( 1) Recommendat i on of t herapy shoul d be based on t he pat i ent ' s
assessment of t he degree of pai n. Pai n associ at ed wi t h dysmenor rhea
gener al l y t apers wi t hi n 2 days. Pr ol onged pai n may be associ at ed wi t h an
under l yi ng probl em, and pat i ent s shoul d be r ef er red t o a physi ci an.
( 2) NonpharmacoI ogi caI r ecommendat i ons i ncl ude r est , heat , wear i ng
l oose- f i t t i ng cl ot hi ng, and exer ci se.
( 3) Agent s f or t he r el i ef of dysmenor rhea i ncl ude
( a) AnaI gesi cs are used as pr i mar y t r eat ment of dysmenor rhea and f or
r el i ef of cr ampi ng associ at ed wi t h premenst r ual syndr ome ( PMS; see Ì . B. 4] .
Anal gesi c
P. 710

t r eat ment pr ovi des r el i ef f or mi l d t o moder at e sympt oms but wi l l pr obabl y
not hel p pat i ent s wi t h sever e sympt oms.
( i ) Nonst eroi daI anti - i nfI ammat or y drugs ( NSAÌ Ds) i nhi bi t t he synt hesi s
and act i on of prost agl andi ns. Because pr ost agl andi ns ar e r esponsi bl e f or
t he cr ampi ng of dysmenor r hea i t makes l ogi cal sense t o r ecommend
NSAÌ Ds t o a pat i ent .
For women who do not recei ve r el i ef f rom over - t he- count er ( OTC)
anal gesi cs, prescr i pt i on NSAÌ Ds may prove mor e usef ul .
{ a} Admi ni st rat i on gui deI i nes. Begi n t herapy at t he onset of pai n; t here i s
no proven val ue i n begi nni ng t her apy i n ant i ci pat i on of dysmenor rhea.
• Ì buprof en (e. g. , Advi l , Mi dol Cramp & Body Aches, Mot r i n Ì B) : 200 mg every
4- 6 hr ; maxi mum 1200 mg/ day
• Napr oxen ( e. g. , Al eve, Pampri n Al l Day) : 200 mg ever y 8- 12 hr ; maxi mum
600 mg/ day
{ b} Adverse ef f ect s. Fr om a f ew days of use, adver se ef f ect s ar e l i mi t ed.
Common adverse ef f ect s associ at ed wi t h NSAÌ Ds i ncl ude upset st omach,
vomi t i ng, hear t burn, abdomi nal pai n, di ar rhea, const i pat i on, and di zzi ness.
NSAÌ Ds shoul d be t aken wi t h f ood t o decr ease adver se gast r oi nt est i nal ( GÌ )
ef f ect s or bl eedi ng.
{ c} Warni ngs. Pat i ent s shoul d be advi sed t o use t he l owest ef f ect i ve dose
f or t he shor t est durat i on needed t o l essen t he pot ent i al r i sk f or
car di ovascul ar event s. Pat i ent s wi t h an al l er gy t o NSAÌ Ds or act i ve GÌ
di sease shoul d not t ake any NSAÌ Ds.
( i i ) Tr eat ment wi t h aspi ri n or acet ami nophen can pr ove of benef i t f or t he
sympt oms associ at ed wi t h pri mar y dysmenor r hea, however ; aspi r i n i s not as
pot ent as t he ot her NSAÌ Ds and acet ami nophen i s not t hought t o pr event
pr ost agl andi n product i on t o a great ext ent , al t hough i t can be hel pf ul f or
t r eat i ng t he headache and backache t hat may occur wi t h menst rual
cr ampi ng.
( b) Di uret i cs are recommended by t he U. S. Food and Dr ug Admi ni st r at i on
( FDA) f or use i n el i mi nat i ng wat er duri ng premenst r ual and menst r ual
per i ods. When admi ni st er ed approxi mat el y 5 days bef ore menses, di ur et i cs
hel p r el i eve bl oat i ng, excess wat er, cr amps, and t ensi on. Ì ncl uded i n t hi s
cat egor y ar e ammoni um chl or i de, caf f ei ne, and pamabr om.
( i ) Ammoni um chI ori de ( Aqua- Ban) i s an aci d- f or mi ng sal t of t en used i n
combi nat i on wi t h caf f ei ne.
{ a} Up t o 3 g of ammoni um chl or i de ( NH4Cl ) per day can be admi ni st er ed i n
t hr ee di vi ded doses f or no l onger t han 6 days.
{ b} Larger doses are of t en associ at ed wi t h GÌ sympt oms.
{ c} Aqua- Ban Pl us cont ai ns bot h ammoni um chl ori de and caf f ei ne.
( i i ) Caf fei ne ( e. g. , Mi dol Menst r ual Compl et e and Menst r ual Headache, No
Doz, Vi var i n) , a xant hi ne deri vat i ve, pr omot es di ur esi s by i nhi bi t i ng t ubul ar
r eabsorpt i on of sodi um and chl or i de.
{ a} The recommended dosage i s 100-200 mg ever y 3- 4 hr .
{ b} Si de ef fects associ at ed wi t h caf f ei ne use ar e GÌ di st ur bances and
cent r al ner vous syst em (CNS) st i mul at i on.
{ c} Pat i ent s shoul d be counsel ed t o l i mi t t he consumpt i on of caf f ei ne-
cont ai ni ng f oods or bever ages whi l e t aki ng t hi s pr oduct .
( i i i ) Pamabrom ( e. g. , Mi dol PMS, Mi dol Teen Formul a, Pampr i n) i s a
t heophyl l i ne der i vat i ve of t en used i n combi nat i on wi t h anal gesi cs and
ant i hi st ami nes. The r ecommended dosage i s 50 mg f our t i mes dai l y, not t o
exceed 200 mg/ day.
2. Amenorrhea i s t he absence of menst r uat i on. The devel opment of pr i mar y
or secondar y amenor r hea r equi res physi ci an eval uat i on.
3. I ntermenst ruaI pai n and bI eedi ng general l y occur at mi dcycl e and may
l ast f rom several hour s t o days. Pai n i s of t en associ at ed wi t h ovul at i on
( mi t t el schmer z) . Therapy consi st s of nonpr escri pt i on anal gesi cs. Pat i ent s
wi t h pai n l ast i ng l onger t han 2 days shoul d be r ef er r ed t o a physi ci an.
4. PMS
a. Sympt oms ( e. g. , marked mood swi ngs, f at i gue, appet i t e changes,
bl oat i ng, br east t ender ness, i r r i t abi l i t y, f eel i ngs of depr essi on) begi n 1- 7
days bef or e t he onset of menses.
P. 711


b. NonpharmacoI ogi caI t herapy i ncl udes r egul ar exer ci se, di et ar y
modi f i cat i ons, and reduct i on of st ress f act ors. Di et ar y modi f i cat i ons i ncl ude
avoi di ng al cohol and caf f ei ne, whi ch can i ncrease i r ri t abi l i t y, and
consumi ng a bal anced di et of f r ui t s, veget abl es, and compl ex car bohydr at es
whi l e avoi di ng sal t y f oods and si mpl e sugars ( can exacer bat e f l ui d
r et ent i on) . Pat i ent s exper i enci ng sympt oms abnormal t o t hei r cycl e shoul d
be r ef er red t o a physi ci an.
c. PharmacoI ogi caI t reat ment . The ef f i cacy and saf et y of phar macol ogi cal
t r eat ment of PMS ar e ai med at t he proposed causes ( e. g. , a dr op i n
pr ogest er one concent rat i ons, hi gh l evel s of pr ol act i n, el evat ed est r ogen
concent r at i ons, def i ci enci es of vi t ami ns A or B6, or an under l yi ng di sorder )
and ar e not wel l st udi ed. Al t hough cl i ni cal t ri al s do not suppor t t he ef f i cacy
of vi t ami ns A or B6, bot h have been used f or t he t r eat ment of PMS.
( 1) Prescri pti on drug products t hat have been st udi ed i n t he management
of PMS i ncl ude benzodi azepi nes, monoami ne oxi dase i nhi bi t ors ( MAOÌ s) ,
t r i cycl i c ant i depr essant s ( TCAs) , and sel ect i ve ser ot oni n r eupt ake i nhi bi t or s
( SSRÌ s) . Fl uoxet i ne ( under t he brand name Saraf em) has been appr oved f or
t he t r eat ment of pr emenst r ual dysphor i c di sorder.
( 2) Combi nat i on product s are mar ket ed f or women wi t h PMS sympt oms.
These pr oduct s cont ai n acet ami nophen, pamabrom, and pyr i l ami ne ( Mi dol
and Pampr i n) . Nonprescri pt i on di ur et i cs such as pamabrom ar e commonl y
used t o r educe f l ui d accumul at i on associ at ed wi t h PMS. Pai n i s an
uncommon sympt om of PMS, and t he sedat i ve ef f ect of an ant i hi st ami ne
( pyr i l ami ne) i s unl i kel y t o pr ovi de r el i ef of t he emot i onal sympt oms
associ at ed wi t h PMS. Combi nat i on product s shoul d be r ecommended onl y
wi t h caut i on.
( 3) Dai l y caI ci um suppI ementat i on ( equi val ent t o t he r ecommended dai l y
cal ci um i nt ake f or women of r eproduct i ve age) has been shown t o r educe
t he emot i onal and physi cal sympt oms of PMS.
5. Menorrhagi a i s excessi ve menst rual bl ood l oss. ( The devel opment of
menor r hagi a requi r es physi ci an eval uat i on. ) Low hemat ocr i t , l ow
hemogl obi n, and l ow serum i r on l evel s may occur. Tr eat ment f or
menor r hagi a i s usual l y an est r ogen-pr ogest i n combi nat i on ( i . e. , or al
cont r acept i ve) .
C. Toxi c shock syndrome ( TSS) i s a r are but somet i mes f at al i l l ness of t en
associ at ed wi t h menst r uat i on.
1. TSS can be cat egori zed ei t her as menst r ual or nonmenst r ual , wi t h
approxi mat el y t wo t hi rds of cases associ at ed wi t h menst r uat i on. TSS i s
known t o occur i n bot h men and women.
2. The condi t i on usual l y af f ect s women < 30 years of age who use t ampons.
Women bet ween t he ages of 15 and 19 years ar e at t he hi ghest ri sk.
3. TSS i s charact er i zed by an abr upt onset ( 8- 12 hr ) of f l u- l i ke sympt oms
( e. g. , hi gh f ever , myal gi a, vomi t i ng, di ar r hea). Neur ol ogi c sympt oms such
as headache, agi t at i on, l et hargy, sei zures, and conf usi on can al so occur .
4. TSS r esul t s f r om an exot oxi n pr oduced by St aphyl ococcus aureus.
5. The pri mar y ri sk f actor f or TSS i s t he use of t ampons. Addi t i onal ri sk
f act or s i ncl ude bar r i er cont r acept i ves (e. g. , di aphr agms, cer vi cal sponges) .
6. When TSS i s suspect ed, pat i ent s shoul d be hospi t al i zed i mmedi at el y. To
l ower t he r i sk of TSS, women shoul d use l ower - absor bency t ampons and
al t er nat e t he use of t ampons wi t h f emi ni ne hygi ene pads; however , t o l ower
t he ri sk t o nearl y zer o, women shoul d use sani t ary pads i nst ead of
t ampons.
D. Menst ruaI product s l i ke f emi ni ne hygi ene pads and t ampons ar e used t o
absor b menst r ual and ot her vagi nal di schar ges.
1. Femi ni ne hygi ene pads are avai l abl e i n a wi de var i et y of si zes and
absor benci es. Super or maxi pads may be used f or t he heavi est menst r ual
f l ow ( usual l y occur r i ng on day 2 of t he cycl e) . Mi ni or l i ght pads and j uni or
or t een pads ar e desi gned f or women wi t h smal l er anat omy and/ or l i ght er
f l ow. Fr equent changi ng of sani t ar y pads mi ni mi zes t he occurr ence of
unpl easant odors and hel ps mi ni mi ze i r ri t at i on and chaf i ng.
2. Tampons ar e i nt r avagi nal i nser t s desi gned t o absor b vagi nal di scharge.
Many women pr ef er t ampons because t hey are wor n i nt er nal l y, whi ch
l essens chaf i ng, odor , bul ki ness, and
P. 712

i r r i t at i on. Super t ampons ar e desi gned f or heavi er f l ow. Juni or or r egul ar
t ampons ar e desi gned f or moderat e t o l i ght menst r ual f l ow. Fr equent
changi ng of t ampons wi l l mi ni mi ze t he r i sks associ at ed wi t h TSS.
II. VAGINAL PRODUCTS
A. VuI vovagi naI candi di asi s
1. GeneraI consi derat i ons
a. Occurrence. Approxi mat el y 75% of al l women wi l l exper i ence
vul vovagi nal candi di asi s ( yeast i nf ect i on) at l east once, and 50% wi l l have
a second epi sode. Onl y 5% of women exper i ence r ecur r ent i nf ect i ons (f our
or mor e i nf ect i ons wi t hi n a 1- year per i od) .
b. Cause. Candi da al bi cans i s r esponsi bl e f or up t o 92% of i nf ect i ons.
Ì nf ect i ons owi ng t o C. gl abr at a ar e i ncr easi ng.
c. Predi sposi ng fact ors. Ant i bi ot i cs, or al cont racept i ves cont ai ni ng hi gh-
dose est rogen, pr egnancy, di abet es, poor post - bowel movement hygi ene,
and i mmunosuppr essi on i ncrease t he r i sk f or i nf ect i on.
d. Sympt oms. Can i ncl ude a t hi ck, whi t e, "cot t age cheese-l i ke, ¨
nonmal odor ous vagi nal di scharge; dysur i a; vagi nal bur ni ng; and pr uri t us.
2. Pati ent assessment
a. Pat i ent s shoul d be quest i oned about pr esence of sympt oms, medi cat i on
use, medi cal condi t i ons, and hi st or y of vagi nal yeast i nf ect i ons.
b. The f ol l owi ng pat i ent s shoul d be r ef er red t o a pr i mar y- car e pr ovi der f or
di agnosi s and t r eat ment :
( 1) Fi r st epi sode of sympt oms
( 2) Pr egnant
( 3) Younger t han 12 year s of age
( 4) Syst emi c sympt oms such as f ever
( 5) Hi st or y of recur r ent vagi nal yeast i nf ect i ons
( 6) Di scharge wi t h a f i shy odor (i ndi cat es bact eri al vagi nosi s, most of t en
caused by anaer obi c bact er i a) or a t hi n, mal odor ous pur ul ent di schar ge
( i ndi cat es of Tri chomonas i nf ect i on)
3. PharmacoI ogi caI t reat ment
a. Nonprescri pt i on agent s are recommended onl y f or pat i ent s who have
had a pri or yeast i nf ect i on and who can pot ent i al l y r ecogni ze t he i nf ect i on
and sel f -medi cat e.
b. The choi ce of nonprescr i pt i on t herapy i s based on pat i ent pref erence.
c. Avai l abl e f ormul at i ons i ncl ude i nt r avagi nal cr eams, supposi t or i es, and
oi nt ment s.
d. Ext er nal vagi nal creams can be used i n combi nat i on wi t h i nt r avagi nal
pr oduct s t o t reat vul var sympt oms of pr ur i t us.
e. Ì nt r avagi nal pr oduct s ar e used at bedt i me, wher eas t he ext er nal cr eams
can be used any t i me of day.
f . Avai l abl e nonpr escri pt i on t herapi es i ncl ude t he ant i f ungal agent s Gyne-
Lot ri mi n and Mycel ex- T ( cl ot r i mazol e) , Moni st at 3 and Moni st at 7
( mi conazol e) , Femst at 3 ( but oconazol e) , and Moni st at 1 and Vagi st at 1
( t i oconazol e) .
( 1) Gyne- Lot r i mi n and Moni st at 7 ar e used f or 7 consecut i ve days; Moni st at
3 and Femst at 3 ar e used f or 3 consecut i ve days; Moni st at 1 and Vagi st at 1
ar e used f or 1 day.
( 2) Ef f i cacy rat es approach 80%-90%.
( 3) Many pr oduct s ar e avai l abl e as a "combi nat i on pack¨ i ncl udi ng an
i nt er nal cr eam or supposi t or y and cr eam f or ext er nal use.
4. Pati ent counseI i ng
a. NonpharmacoI ogi caI
( 1) Dr y vagi nal area wel l af t er bat hi ng wi t h a t owel .
( 2) Avoi d t i ght or damp cl ot hi ng.
( 3) Wear cot t on under wear .
( 4) Use unscent ed soap t o avoi d i r r i t at i on.
( 5) Avoi d douchi ng.
( 6) Decr ease consumpt i on of sucr ose and si mpl e sugar s.
P. 713


b. PharmacoI ogi caI
( 1) Compl et e t he course of t her apy even i f sympt oms i mprove.
( 2) Wash vagi nal area wi t h mi l d soap bef ore appl i cat i on.
( 3) Reusabl e appl i cat ors shoul d be washed wi t h soap and wat er.
( 4) Avoi d sexual i nt ercour se duri ng t her apy.
( 5) Avoi d condoms and di aphr agm use f or 72 hr af t er t herapy i s compl et ed.
( 6) Cont i nue use dur i ng menst rual per i od.
( 7) Avoi d t ampons dur i ng use.
( 8) Sani t ar y pads can be used f or l eakage of i nt ravagi nal pr oduct s.
( 9) Si de ef f ect s can i ncl ude burni ng or i r ri t at i on.
B. Femi ni ne hygi ene products. There are a var i et y of f emi ni ne hygi ene
pr oduct s avai l abl e f or cl eansi ng and cont r ol l i ng odor associ at ed wi t h normal
vagi nal di schar ge. These pr oduct s are not used t o t reat vagi nal i nf ect i ons.
1. Vagi nal douches ( Summer ' s Eve) i r r i gat e t he vagi na and can be used f or
cl eansi ng, f or soot hi ng, as an ast ri ngent , or t o pr oduce a mucol yt i c ef f ect .
2. Vagi nal supposi t ori es ( Bet adi ne- medi cat ed supposi t ori es) ar e used f or
soot hi ng, t o r el i eve mi nor i r r i t at i ons, and t o r educe t he number of
pat hogeni c mi cr oor gani sms.
III. OTC CONTRACEPTIVES
A. I nt roduct i on. The ef fi cacy and pregnancy rat es f or vari ous means of
cont r acept i on depend great l y on t he degree of compI i ance. Tabl e 34-1
l i st s r anges of pregnancy r at es r epor t ed f or a var i et y of cont racept i ves.
Table 34-1. Pregnancy Rates for Various Means of Contraception (º)a
Method of Contraception Typical
b
Lowest
c

Oral contraceptives
Combination (estrogen-progestin) 0.1-0.34 0.1
Progestin only 0.5-1.5 0.5
Mechanical/chemical
Cervical cap
d

Multiparous 40 26
Nulliparous 20 9
Male condom without spermicide 12-14 3
Male condom with spermicide 4-6 1.8
Diaphragm
d
20 6
Female condom 21 5
Intrauterine device < 1-2 < 1-1.5
Levonorgestrel implants < 1 < 1
Medroxyprogesterone iniection < 1 < 1
Spermicide alone 20-22 6
Other
Rhythm (all types) 25 1-9
Vasectomy/tubal ligation < 1 < 1
Withdrawal 40-50 30
No contraception 85 85
a
During Iirst year oI continuous use.

b
A typical couple who initiated a method that either was not always used
correctly or was not used with every act oI sexual intercourse. and who
experienced an accidental pregnancy.

c
The method oI birth control was always used correctly with every act oI
sexual intercourse but the couple still experienced an accidental pregnancy.

d
Used with spermicide.

Adapted with permission Irom Nonprescription Drug Therapy Guiding
Patient SelI-Care. 4th ed. St. Louis. MO. Wolters Kluwer Health. 2005.

P. 714


B. Methods of cont racept i on t hat may make use of nonprescr i pt i on pr oduct s
or devi ces i ncl ude t he f ol l owi ng:
1. Ferti I i t y awareness met hods make use of i nf or mat i on concer ni ng t he
menst rual cycl e t o det ermi ne t he days when i nt er cour se i s most l i kel y t o
r esul t i n a pregnancy. Peri odi c abst i nence i s al so ref er red t o as t he
rhyt hm met hod, naturaI f ami I y pI anni ng, or ovuI at i on detecti on met hod.
The var i ous nat ur al f ami l y pl anni ng met hods al l ow t he pat i ent t o moni t or t he
nat ural physi ol ogi cal si gns t hat can, i n many women, predi ct t he f ert i l e
per i od (peri ovul at or y phase of t he menst r ual cycl e) , enabl i ng t he coupl e t o
avoi d coi t al exposur e at t hat t i me. These met hods are based on
r epr oduct i ve anat omy and physi ol ogy and ar e appl i ed accordi ng t o t he si gns
and sympt oms nat ur al l y occur ri ng i n t he menst r ual cycl e.
a. Cal cul at i ons of t he per i od of f er t i l i t y t ake i nt o account t he sperm
vi abi I i t y i n t he f emal e r epr oduct i ve t ract , whi ch i s est i mat ed t o aver age 2- 3
days ( up t o 5 days) , and t he f ert i I e peri od of the ovum, whi ch i s est i mat ed
t o be 24 hr. Recent st udi es i ndi cat e t hat concept i on i s most l i kel y t o occur
when coupl es have i nt ercourse duri ng a 6- day per i od endi ng on t he day of
ovul at i on. Concept i on i s hi ghI y unI i keI y i f sexuaI i nt ercourse occurs 6
or more days bef ore ovuI at i on or t he day af t er ovuI at i on.
b. Di sadvant ages t o t he r hyt hm met hod (but necessar y t o ensure ef f i cacy)
i ncl ude bot h t he I ong peri ods of abst i nence and t he charti ng of menses.
Met hods of nat ural f ami l y pl anni ng and peri odi c abst i nence i ncl ude t he
t emper at ure met hod, cal endar met hod, Bi l l i ngs met hod, and sympt ot hermal
met hod.
c. Temperat ure met hod. BasaI body t emperat ure ( BBT) det ermi nat i on
makes use of a basaI t hermomet er, whi ch can be purchased wi t hout a
pr escri pt i on. The t hermomet er covers t he r ange of t emper at ur e f r om 96°F t o
100°F i n 0. 1° gr adat i ons.
( 1) The si gni f i cance of basal t emper at ur e det ermi nat i on l i es i n t he f act t hat
wi t hi n 24 hr precedi ng ovul at i on, t her e i s a moderat e drop i n t he basaI
t emperat ure f ol l owed by a noti ceabI e ri se i n t he body t emperat ure,
usual l y about 24 hr af t er ovul at i on. Thi s ri se i s usual l y mai nt ai ned f or t he
r emai nder of t he cycl e and i s t hought t o be t he resul t of t he t hermogeni c
pr oper t i es of progest erone, t he hormone i ndi cat i ng t he t r ansi t i on f rom t he
ovul at or y phase t o t he l ut eal phase. Theref ore, ovul at i on i s mar ked by t he
t r ansi t i on of t he f al l i ng t emper at ur e t o t he r i si ng t emper at ure.
( 2) For many women, abst i nence shoul d be pr act i ced f r om appr oxi mat el y 5
days af t er t he onset of menses unt i I 3 days af t er t he t ransi t i on i n
t emperat ure.
( 3) Because t he basal t emperat ur e ref l ect s t he amount of heat r adi at i on
when t he body i s at i t s met abol i c l ow, t he t emperat ur e shoul d be t aken f i rst
t hi ng i n t he morni ng (i . e. , bef or e any act i vi t y) . The t her momet er may be
pl aced under t he t ongue, i n t he r ect um, or i n t he vagi na ( t he t emper at ure
shoul d al ways be t aken f r om t he same pl ace) and shoul d be l ef t undi st urbed
f or at l east 5 mi n (mercur y t hermomet er ) . El ect r oni c di gi t al t her momet ers
ar e al so avai l abl e t hat have shor t er r ecordi ng t i mes ( 45- 90 sec). Ì nf ect i on,
t ensi on, a r est l ess ni ght , or any t ype of excessi ve movement can cause
var i at i ons i n t emperat ure r eadi ngs t hat do not ref l ect t he BBT.
d. The caI endar method est i mat es t he possi bl e day of ovul at i on.
Abst i nence shoul d be pract i ced dur i ng t he peri od ar ound ovul at i on when
t her e may be a f er t i l i zabl e egg present . Wher eas t he cal endar r hyt hm
met hod was used f or sever al decades, i t has not been promot ed as a
met hod of nat ur al f ami l y pl anni ng f or many year s. Al t hough women who
have r egul ar menst r ual cycl es are abl e t o use t he cal endar r hyt hm met hod
successf ul l y, women wi t h i r regul ar cycl es, women who ar e br east - f eedi ng,
or women wi t h post poned ovul at i on cannot depend on t he cal endar rhyt hm
met hod.
( 1) For a span of approxi mat eI y 1 year, t he pat i ent recor ds her
menst ruat i on dat es on a cal endar .
( 2) Cal endar char t i ng al l ows t he pat i ent t o cal cul at e t he onset and dur at i on
of her f er t i l e peri od÷t he t i me dur i ng whi ch a vi abl e egg i s avai l abl e f or
f er t i l i zat i on by sperm. Cal cul at i on of t he f er t i l e per i od r est s on t hr ee
assumpt i ons:
( a) OvuI at i on occurs on day 14 ( ± 2 days) bef ore t he onset of t he next
menses.
( b) Sperm remai n vi abI e f or 2- 3 days.
( c) The ovum survi ves for 24 hr .
( 3) The cal endar i s t hen r evi ewed t o det ermi ne t he l engt h of her short est
and l ongest cycl e.
( a) The pat i ent t hen subt r act s 18 days f r om t he number of days of her
short est cycl e. Thi s number shoul d cor r espond t o t he f i rst possi bl e f er t i l e
day i n any gi ven cycl e÷14 + 2 = 16 days; 16 + 2 = 18 days ( vi abi l i t y of
sperm) ; see Ì Ì Ì . B. 1. b.
P. 715


( b) Next , t he pat i ent subt r act s 11 days f r om t he number of days of t he
l ongest cycl e. Thi s number shoul d corr espond t o t he l ast possi bl e f er t i l e
day i n any gi ven cycl e÷14 - 2 = 12 days; 12 - 1 = 11 days ( vi abi l i t y of ova) ;
see Ì Ì Ì . B. 1. b.
( 4) Abst i nence shoul d be pr act i ced f r om t he f i r st possi bl e f er t i l e day
t hr ough t he l ast possi bl e f er t i l e day.
( 5) ExampI e. Assume t he shor t est number of days bet ween t wo consecut i ve
menses i s 25 and t he l ongest number of days bet ween t wo consecut i ve
menses i s 32. Then, 25 days ( t he shor t est cycl e) - 18 days = 7 ( or day 7),
and 32 days ( t he l ongest cycl e) - 11 days = 21 (or day 21) . Theref ore,
abst i nence shoul d be pract i ced f r om day 7 t hr ough and i ncl udi ng day 21 of
each cycl e.
e. The cervi caI mucus (Bi I I i ngs or cervi caI secret i ons) met hod of rhyt hm
i s based on t he pri nci pl e t hat t he nor mal , t hi ck, cr eamy whi t e vagi nal mucus
becomes cl ear and t enaci ous around t he t i me of ovul at i on (much l i ke a raw
egg whi t e) .
( 1) The woman shoul d wat ch f or t hi s change i n mucus consi st ency and
pr act i ce abst i nence ar ound t he t i me of ovul at i on.
( 2) The woman shoul d consi der her sel f f er t i l e f or 3- 4 days af t er t he peak
change.
f . The sympt ot hermaI met hod, rat her t han r el yi ng on a si ngl e physi ol ogi cal
i ndex, uses sever al i ndi ces t o det er mi ne t he f ert i l e peri od.
( 1) The most common cal endar cal cul at i ons and changes i n t he cervi caI mucus
ar e used t o est i mat e t he onset of the fert i I e peri od.
( 2) Changes i n t he mucus or basal t emper at ur e ar e used t o est i mat e t he end of t he
f er t i l e peri od.
( 3) Because sever al i ndi ces need t o be moni t or ed, t hi s met hod i s mor e di f f i cul t t o
l earn t han t he si ngl e-i ndex met hod, but i t i s more ef f ect i ve t han t he cer vi cal mucus
met hod ( i . e. , Bi l l i ngs met hod) al one.
2. Spermi ci daI agents ar e composed of an act i ve spermi ci daI chemi caI , whi ch
i mmobi l i zes or ki l l s sperm, and an i nert base (e. g. , f oam, cr eam, j el l y, gel , t abl et ,
or supposi t or y) , whi ch l ocal i zes t he spermi ci dal chemi cal i n pr oxi mi t y t o t he cer vi cal
os. These agent s wor k by di srupt i ng t he sperm membrane and by decr easi ng t he
abi l i t y of sperm t o met abol i ze f r uct ose. Two f or ms of i ner t bases ( gel s and f oams)
act as a physi cal bar ri er agai nst sperm.
a. The act i ve i ngredi ent i ncl udes nonoxynoI - 9. whi ch i s consi dered saf e and
ef f ect i ve by t he FDA.
( 1) Admi ni st rat i on gui deI i nes. Appl i cat or s may be pref i l l ed bef or e use.
( 2) Si de eff ects÷f or exampl e, sensat i on of warmt h, r are al l er gi c react i ons (contact
dermati t i s wi t h r ash, st i ngi ng, i t chi ng, and swel l i ng) ÷are mi ni mal . Ì f a suspect ed
r eact i on occurs, one shoul d be i nst r uct ed t o use anot her pr oduct because t he i ssue
mi ght be t he concent rat i on of t he spermi ci de or an addi t i ve speci f i c t o a gi ven
br and. There are no si gni f i cant di f f er ences i n bi r t h- def ect r at es bet ween users and
nonuser s.
b. Ef f ect s agai nst sexuaI I y t ransmi t ted di seases ( STDs) . Nonoxynol - 9 i s l et hal t o
sel ect ed mi crobes i n t he l abor at or y set t i ng and may hel p i nhi bi t a vari et y of sexual l y
t r ansmi ssi bl e organi sms, i ncl udi ng t hose responsi bl e f or gonor r hea, chl amydi al
i nf ect i on, candi di asi s, geni t al her pes, syphi l i s, t ri chomoni asi s, and HÌ V/ AÌ DS. Ther e
have been i nconsi st ent resul t s i n human st udi es, however . One concer n rel at es t o
t he f act t hat f r equent use of sper mi ci des can cause vul vovagi nal epi t hel i al
di srupt i on, whi ch may i ncr ease suscept i bi l i t y t o HÌ V. Ì n addi t i on, spermi ci des may
al t er t he vagi nal f l ora and, t her ef or e, shouI d not be reI i ed on aI one for STD
prevent i on.
c. Dosage f orms. Cont racepti ve spermi ci des, whi ch are avai l abl e i n sever al
f or ms, of f er t he gr eat est var i et y wi t hi n one speci f i c met hod of cont r acept i on ( Tabl e
34- 2).
( 1) Creams, j eI I i es, and geI s are used wi t h a di aphr agm. The concent r at i on of
spermi ci de i s l ess t han t he necessar y 8% t o be empl oyed as a si ngl e cont r acept i ve
met hod.
( 2) Foams di sperse bet t er i nt o t he vagi na and over t he cer vi cal openi ng but provi de
l ess l ubri cat i on t han cr eams, j el l i es, and gel s. They usual l y cont ai n a hi gher
concent r at i on of spermi ci de ( i . e. , the opt i maI concent rat i on of 8% or hi gher) .
Because of vol ume di f f erences among brands, t he dosage amount s var y. Ì f vagi nal
or peni l e i r r i t at i on devel ops, anot her br and shoul d be t r i ed.
( a) The can shoul d be shaken vi gor ousl y 20 t i mes bef or e use.
( b) The f oam shoul d be i nsert ed i nt r avagi nal l y about t wo t hi rds t he l engt h of t he
appl i cat or , and t he cont ent s shoul d be di schar ged.
( c) Foam shoul d be reappl i ed dur i ng pr ol onged i nt er course (i . e. , l ast i ng > 1 hr ) and
bef ore ever y subsequent act of i nt ercourse.
P. 716


Table 34-2. Spermicidesa
Type (Product) Comments
Film (VCF) Inserted by the Iemale directly over the
cervix; insert not less than 15 min and not
more than 3 hr beIore intercourse;
contraceptive protection begins 5-15 min
aIter insertion and remains eIIective no
more than 3 hr
Foam (Ortho Options DelIen
Ioam. VCF Vaginal
Contraceptive Ioam)
Contraceptive protection is immediate;
remains eIIective no more than 1 hr.
additional dose is needed beIore any
subsequent intercourse
Jellies. creams. gels (KY
Plus Lubricating. Ortho
Options Gynol II ielly. Ortho
Options Conceptrol gel.
Advantage-S)
Contraceptive protection is immediate;
used alone remains eIIective no more than
1 hr; when used with diaphragm or cap.
keep diaphragm or cap in place Ior at least
6 hr aIter last intercourse
Suppositories and tablets
(Encare Insert)
Contraceptive protection begins 10-15 min
aIter insertion; remains eIIective no more
than 1 hr
a
The spermicidal agent in all listed products is nonoxynol-9.

Reprinted with permission Irom Hatcher RA. Contraceptive Technology
1994-1996. 16th ed. New York. Irvington. 1994:180.

( d) To ensure ef f i cacy, t he pat i ent shoul d wai t at l east 8 hr bef ore douchi ng t o avoi d
di l ut i ng t he sper mi ci de ef f ect or " f orci ng¨ sperm i nt o t he cer vi x.
( 3) Supposi t ori es and foami ng tabI et s. These agent s ar e bot h smal l and
conveni ent . Al t hough sol i d at r oom t emper at ur e, supposi t or i es mel t at body
t emper at ure, wher eas f oami ng t abl et s ef f er vesce.
( a) The t abl et s shoul d be wet t ed bef or e i nsert i on, whi ch may cr eat e a sensat i on of
war mt h.
( b) The t abl et or supposi t or y shoul d be i nser t ed hi gh i nt o t he vagi na, 10- 15 mi n
bef ore i nt er course.
( c) Ì nt ercour se must occur wi t hi n 1 hr or t he dose must be r epeat ed.
( d) Anot her t abl et or supposi t or y shoul d be i nser t ed bef ore each r epeat ed act of
i nt er course.
( e) To ensure ef f i cacy, t he pat i ent shoul d wai t 6-8 hr af t er t he l ast act of i nt er course
bef ore douchi ng.
( 4) Fi I m comes as smal l paper - t hi n sheet s (e. g. , VCF) . Ì t i s i nser t ed on t he t i p of
t he f i nger i nt o t he vagi na and pl aced at t he cer vi cal openi ng 5- 15 mi n bef or e
i nt er course.
( 5) Sponge. Thi s f ai r l y popul ar pr oduct was r emoved f r om t he market i n t he mi d-
1990s because of cost i ssues rel at ed t o i t s manuf act ur e. The new owner of t he
Today sponge ( Al l endal e Pharmaceut i cal s) i s cur rent l y remar ket i ng t hi s product . Ì t
i s a doughnut shaped pol yur et hane devi ce cont ai ni ng t he spermi ci de nonoxynol - 9; i t
i s i nser t ed i nt o t he vagi na bef or e sexual i nt ercour se. Ef f i cacy i s approxi mat el y
comparabl e t o t hat of a cer vi cal cap. Ì t i s bel i eved t o act as a cont racept i ve i n t hr ee
ways: ( 1) mechani cal l y bl ocki ng t he cer vi cal ent rance, (2) absor bi ng semen, and ( 3)
pr ovi di ng a sper mi ci de. Ì t can remai n i n pl ace f or 24 hr . Concer ns ar e a hi gher r i sk
f or TSS and a hi gher pregnancy r at e f or women who have never gi ven bi r t h
( nul l i par ous women) .
3. Condoms are used t o pr event t ransmi ssi on of sperm i nt o t he vagi na.
a. Types. They ar e made of l at ex r ubber, processed col l agenous l amb caecum
sheat hs (l ambski n) , or pol yur et hane.
( 1) Lat ex condoms may hel p prevent t he t r ansmi ssi on of many STDs. They ar e
usual l y packaged wi t h t he f ol l owi ng l abel " when used pr operl y, t he l at ex condom
may prevent t he t r ansmi ssi on of many STDs such as syphi l i s, gonor r hea, chl amydi a
i nf ect i ons, geni t al her pes, and AÌ DS. ¨
( a) Lat ex af f ords gr eat er el ast i ci t y t han l ambski n, and l at ex condoms ar e mor e l i kel y
t o r emai n i n pl ace on t he peni s.
( b) A var i et y of t ypes are avai l abl e ( e. g. , l ubr i cat ed, r i bbed, col or ed) , i ncl udi ng
some wi t h sper mi ci de ( concent rat i on much l ess t han t hat of a vagi nal sper mi ci de
pr oduct ) .
P. 717

Ì t i s doubt f ul t hat sper mi ci de- l ubri cat ed condoms of f er any bet t er pr ot ect i on t han
pl ai n l at ex condoms, and t hey have a shor t er shel f l i f e. Ther e i s a st andard si ze, but
smal l er and l arger versi ons ar e avai l abl e.
( i ) Lat ex condoms ar e avai l abl e wi t h a pl ai n end or wi t h a r eser voi r t i p (somet i mes
desi gnat ed as "enz¨ ) . The r eser voi r t i p pr ovi des room f or t he ej acul at e; however , a
space may be l ef t when usi ng t he pl ai n- end condom, whi ch accommodat es t he f l ui d
j ust as ef f ect i vel y.
( i i ) The preI ubri cated condom hel ps pr event dyspareuni a i n a coupl e wi t h
i nsuf f i ci ent nat ural l ubr i cat i on. Prel ubr i cat i on decr eases t he r i sk of t ear i ng t he
condom. However , t he ext r a l ubr i cat i on may be excessi ve, l esseni ng sexual
f ul f i l l ment f or a coupl e who have adequat e nat ural l ubr i cat i on or when cont r acept i ve
f oam i s al so used.
( i i i ) Lat ex r ubber may cause an al l ergi c r eact i on. An est i mat ed 1%-2% of t he
popul at i on i s sensi t i zed t o nat ur al rubber l at ex, and hi gher percent ages ar e l i kel y
f or t hose f requent l y exposed t o l at ex ( e. g. , heal t hcar e wor kers) . The most common
sympt oms ar e geni t al i nf l ammat i on wi t h redness, i t chi ng, and burni ng. Somet i mes,
ant i oxi dant s or accel erat or s used dur i ng t he manuf act uri ng process may be t he
cause of t he al l ergy.
( 2) Lambski n condoms ar e not consi der ed as ef f ect i ve as l at ex condoms ( and
cannot be l abel ed as such) i n prevent i ng t he t r ansmi ssi on of STDs, i ncl udi ng AÌ DS.
The l ambski n condoms ar e st r uct ured t o consi st of membr anes t hat reveal l ayer s of
f i ber s cr i sscrossi ng i n var i ous pat t er ns. Thi s gi ves t he l ambski n st r engt h, but al so
al l ows f or an occasi onal por e. Ther ef or e, l ambski n may al l ow HÌ V and hepat i t i s B
vi r us, whi ch ar e smal l er t han sperm, t o pass t hr ough.
( a) Lambski n has l ess el ast i ci t y t han l at ex, and l ambski n condoms may sl i p of f t he
peni s.
( b) Lambski n af f or ds great er sensi t i vi t y t han l at ex.
( c) Lambski n condoms ar e mor e expensi ve t han l at ex condoms.
( 3) A poI yuret hane condom (e. g. , Avant i , Tr oj an Supr a) i s avai l abl e f or men and i s
market ed f or i ndi vi dual s who ar e al l er gi c t o l at ex. Some evi dence exi st s t hat
sl i ppage and breakage rat es may be hi gher t han f or l at ex condoms. Ì n cont r ast t o
t he l at ex condom, pet r ol eum-based product s wi l l not degrade t he pol yuret hane.
b. Advant ages and di sadvant ages. The r el at i ve accessi bi l i t y, ease of t r anspor t ,
and l ow cost make condoms an at t r act i ve met hod of cont racept i on. However , t he
coi t al act must be i nt er r upt ed t o appl y t he condom, and of t en one or bot h par t ners
compl ai n of a par t i al or compl et e decrease i n sensat i on.
c. Use
( 1) The f emal e ext er nal geni t al i a shoul d not be t ouched wi t h t he exposed peni s, and
t he vagi na shoul d not be penet r at ed, unt i l t he condom i s unr ol l ed ont o t he er ect
peni s.
( 2) The condom shoul d be unrol l ed ont o t he peni s as f ar as i t wi l l go. Wi t h t he pl ai n-
end condom, a space bet ween t he t i p of t he peni s and t he t i p of t he condom shoul d
be l ef t t o cat ch t he ej acul at e.
( 3) Wi t h ei t her r eser voi r -t i p or pl ai n- end condoms, t he t i p of t he condom must be
hel d bet ween t he t humb and i ndex f i nger t o avoi d t r appi ng ai r whi l e unr ol l i ng t he
condom ont o t he peni s. (The space wi l l decr ease t he l i kel i hood of bot h r upt ur e
secondar y t o pressure and r egurgi t at i on of t he ej acul at e ont o t he ext er nal
geni t al i a. )
( 4) Pr oper l ubr i cat i on t o mi ni mi ze t he possi bi l i t y of t ear i ng can be ensur ed by usi ng
ei t her a l ubr i cat ed condom or by appl yi ng KY j el l y or spermi ci dal cream or j el l y t o
ei t her t he condom or t he woman' s geni t al i a. ( Not e: Pet r ol eum j el l y [ Vasel i ne] shoul d
never be used because i t causes det er i or at i on of t he r ubber [ l at ex] and i s a poor
l ubri cant . ) Sper mi ci dal f oam, cr eam, or j el l y i s an excel l ent adj unct i ve
cont r acept i ve.
( 5) Bef ore t he peni s becomes f I acci d, i t must be wi t hdr awn f rom t he vagi na and
t he condom eased of f . The condom shoul d be handl ed wi t h speci al car e so as not
t o l ose i t i nt o t he vagi na or spi l l any of t he ej acul at or y f l ui d ont o t he ext er nal
geni t al i a.
( 6) A condom shoul d never be r eused.
( 7) Condoms shoul d not be st ored near excessi ve heat .
( 8) Ì f t he condom shoul d br eak or l eak, sper mi ci de f oam shoul d be i mmedi at el y
i nser t ed vagi nal l y.
P. 718


( 9) Do not buy or use condoms t hat have passed t hei r expi r at i on dat e.
( 10) Be sur e t o st or e condoms i n a cool , dr y pl ace, out of di r ect sunl i ght . The gl ove
compart ment of a car i s not a good pl ace t o st ore condoms. Do not st ore condoms i n
pocket s, purses, or wal l et s f or mor e t han a f ew hour s.
4. The femaI e condom (Real i t y) i s a di sposabI e poI yuret hane sheat h t hat f i t s i nt o
t he vagi na and provi des prot ect i on f rom pregnancy and STDs.
a. The sheat h r esembl es a pl ast i c vagi nal pouch and consi st s of an i nner ri ng,
whi ch i s i nser t ed i nt o t he vagi na near t he cer vi x much l i ke a di aphr agm, wher eas
t he out er ri ng remai ns out si de t he vagi na, cover i ng t he l abi a. The condom i s
pr el ubri cat ed, and addi t i onal l ubr i cant i s pr ovi ded f or use i f needed. The
pol yuret hane sheat h i s st ronger and pr obabl y I ess I i keI y t o t ear or break t han t he
l at ex sheat h of mal e condoms. Ì t shoul d be r emoved i mmedi at el y af t er i nt er cour se
( bef or e t he woman st ands up) . Ì t may be i nser t ed up t o 8 hr bef or e i nt ercour se.
b. Ì f i t i s used pr operl y, i t pr ovi des t he woman wi t h a met hod of pr event i ng t he
t r ansmi ssi on of STDs. However , wi t h t he not ed pr egnancy f ai l ure r at e ( Tabl e 34-1) ,
i t i s cer t ai nl y not t hat r el i abl e f or di sease t r ansmi ssi on. Ì t has not been ver y
popul ar; some women compl ai n t hat i t i nt er f eres wi t h sensat i on and t hat i t makes
unpl easant noi ses dur i ng use.
5. The di aphragm i s a cont r acept i ve devi ce t hat i s sel f - i nser t ed i nt o t he vagi na t o
bl ock access of sperm t o t he cer vi x. Ì t r equi r es a pr escri pt i on and must be used i n
conj unct i on wi t h a nonprescr i pt i on spermi ci de t o seal of f cr evi ces bet ween t he
vagi nal wal l and t he devi ce.
a. The di aphr agm i s hel d i n pl ace by t he spri ng t ensi on of a wi r e r i m encased by
r ubber . When posi t i oned pr oper l y, t he di aphr agm f orms a f l exi bl e dome t o cover t he
cer vi x, t he si des pressi ng agai nst t he vagi nal muscl e wal l and t he pubi c bone.
b. Ther e ar e f our t ypes of di aphr agms: t he coi I spri ng, t he f I at spri ng, t he arci ng
spri ng, and a wi de-seaI ri m. The t one of vagi nal muscl es as wel l as t he posi t i on of
t he ut erus and adj acent or gans usual l y det ermi ne t he t ype of di aphragm necessar y.
c. Si zes of t he di aphragm r ange f r om 50 t o 95 mm i n di amet er , i n 5- mm gr adat i ons.
d. Use
( 1) The di aphr agm pl us spermi ci de can be i nser t ed as l ong as 6 hr bef ore coi t us.
The devi ce shoul d be l ef t i n pl ace f or 6-8 hr af t er i nt er course, but no l onger t han 24
hr . Addi t i onal spermi ci de i s r equi red f or repeat ed i nt er course.
( 2) Bef or e i nsert i ng t he di aphr agm, 1 t easpoonf ul ( a 2- t o 3-i nch r i bbon) of
spermi ci dal cr eam or j el l y shoul d be spr ead over t he i nsi de of t he rubber dome.
( 3) Al so, spermi ci de shoul d be spread around t he r i m t o per mi t a good seal bet ween
t he di aphragm and t he vagi nal wal l . (For added pr ot ect i on, i t can be appl i ed out si de
t he dome. )
e. Proper care
( 1) The di aphr agm shoul d be washed wi t h soap and wat er , r i nsed t hor oughl y, and
dr i ed wi t h a t owel .
( 2) Ì t shoul d be dust ed wi t h cornst arch and kept i n i t s or i gi nal cont ai ner (away f r om
heat ).
6. The cervi caI cap i s a pr escri pt i on r ubber devi ce smal l er t han a di aphr agm t hat
f i t s over t he cer vi x l i ke a t hi mbl e. Ì t i s mor e di f f i cul t t o f i t t han t he di aphr agm.
a. Ì t r emai ns ef f ect i ve f or more t han one epi sode of i nt er course, wi t hout addi ng
mor e spermi ci de.
b. The cap shoul d be f i l l ed one t hi rd f ul l of spermi ci de cr eam or j el l y; t he spermi ci de
i s t hen appl i ed t o t he r i m.
c. The cer vi cal cap may be l ef t i n pl ace f or a maxi mum of 48 hr and shoul d be l ef t i n
pl ace f or at l east 8 hr af t er i nt ercour se.
P. 719


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 8: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. The most common cause of vagi naI yeast i nfect i ons i s
( A) Candi da al bi cans.
( B) Candi da gl abr at a.
( C) Tr i chomonas.
( D) anaer obi c bact er i a.
Vi ew Answer 1. The answer i s A[ see] . andi da al bi cansC.
gl abrat aTri chomonas2. The ef f i cacy rat e f or nonprescri pt i on ant i f ungaI
agents f or vagi naI yeast i nf ect i ons i s
( A) 50%.
( B) 60%.
( C) 70%.
( D) 80%.
Vi ew Answer 2. The answer i s D[ see] . 3. Whi ch of t he f oI I owi ng st atement s
about nonprescri pt i on ant i f ungaI agent s f or vagi naI yeast i nf ecti ons i s
i ncorrect ?
( A) Femst at 3 shoul d be appl i ed i nt r avagi nal l y f or 3 consecut i ve ni ght s.
( B) Ant i f ungal agent s shoul d be cont i nued duri ng menst r uat i on.
( C) Moni st at 1 cont ai ns mi conazol e.
( D) The choi ce of f ormul at i on i s based on pat i ent pr ef er ence.
Vi ew Answer 3. The answer i s C[ see] . 4. The best product t o t reat vuI var
pruri t us i n a woman wi th a vagi naI yeast i nf ecti on i s
( A) ext er nal mi conazol e ( Moni st at ).
( B) ext er nal mi conazol e and i nt ravagi nal mi conazol e ( Moni st at 7 combi nat i on pack).
( C) i nt r avagi nal t i oconazol e ( Vagi st at 1)
( D) i nt r avagi nal but oconazol e (Femst at 3) .
Vi ew Answer 4. The answer i s B[ see] . 5. A pati ent compI ai ns of vagi naI
yeast i nf ecti on sympt oms. Under whi ch of t he f oI I owi ng ci rcumstances shouI d
she be referred t o a physi ci an?
( A) Ther e i s a hi st or y of r ecur r ent vagi nal yeast i nf ect i ons.
( B) She i s pregnant .
( C) She i s < 12 year s of age.
( D) Al l of t he above
Vi ew Answer 5. The answer i s D[ see] . 6. AI I of the f oI I owi ng stat ements
regardi ng cont racepti ves are correct except whi ch one?
( A) Usi ng t he basal t emper at ur e met hod, i nt ercour se shoul d be avoi ded f or a f ul l 6
days af t er t he not ed t emper at ur e t r ansi t i on.
( B) Ì f a condom shoul d br eak or l eak, one coul d recommend i mmedi at e i nser t i on of a
vagi nal sper mi ci de f oam.
( C) Vagi nal spermi ci des may ki l l many of t he causat i ve agent s of sexual l y
t r ansmi t t ed di seases ( STDs) , but t hey shoul d not be r el i ed on al one f or STD
pr event i on.
( D) Lat ex condoms can be l abel ed f or t he prevent i on of HÌ V t r ansmi ssi on.
( E) Nonoxynol - 9 i s a saf e and ef f ect i ve vagi nal sper mi ci de.
Vi ew Answer 6. The answer i s A[ see] . 7. AI I of the f oI I owi ng stat ements
concerni ng t he vagi naI spermi ci des are correct except whi ch one?
( A) Used wi t hout a condom or di aphr agm, i t i s r ecommended t hat t he nonoxynol - 9
concent r at i on shoul d be at l east 8%.
( B) Foams probabl y di sper se t he spermi ci de t hr oughout t he vagi nal canal bet t er
t han cream or j el l y f or ms.
( C) Douchi ng shoul d not occur f or 6- 8 hr af t er t he l ast i nt er course because i t may
di l ut e t he spermi ci de ef f ect or even f or ce sperm i nt o t he cer vi x.
( D) Evi dence t o dat e shows no def i ni t e l i nk bet ween t hese agent s and bi r t h def ect s.
( E) None; al l of t he st at ement s ar e cor r ect .
Vi ew Answer 7. The answer i s E[see] . 8. AI I of the f oI I owi ng stat ements
concerni ng cont racept i on or cont racept i ve agent s are correct except whi ch
one?
( A) Pr ogest er one i s appar ent l y r esponsi bl e f or t he i ncrease i n basal t emper at ur e
af t er ovul at i on.
( B) Vasel i ne shoul d not be used as a l ubr i cant wi t h l at ex condoms.
( C) Usi ng a condom al one i s mor e ef f ect i ve as a cont r acept i ve t han t aki ng a
combi nat i on oral cont r acept i ve.
( D) Accor di ng t o t he Bi l l i ngs met hod, vagi nal mucus has an appear ance si mi l ar t o
r aw egg whi t es at around t he t i me of ovul at i on.
( E) Sperm may be vi abl e f or up t o 5 days i n t he f emal e reproduct i ve t ract under t he
r i ght condi t i ons.
Vi ew Answer 8. The answer i s C[ see] . P. 720


Di rect i ons for quest i ons 9- 10: Each st at ement i n t hi s sect i on i s most cl osel y
r el at ed t o one of t he f ol l owi ng drug t ypes. The drug t ypes may be used mor e t han
once or not at al l . Choose t he best answer , A- E.
9. The pri mar y nonprescri pt i on pharmacoI ogi caI t reat ment f or pai n associ at ed
wi t h dysmenorrhea
A Di ur et i cs
B Sal i cyl at es
C Nonst er oi dal ant i - i nf l ammat or y dr ugs ( NSAÌ Ds)
D Nar cot i c anal gesi cs
Vi ew Answer 9. The answer i s C[ see] . 10. Recommended by t he Food and
Drug Admi ni st rat i on ( FDA) f or eI i mi nat i on of water before and duri ng
menst ruat i on
A Di ur et i cs
B Sal i cyl at es
C Nonst er oi dal ant i - i nf l ammat or y dr ugs ( NSAÌ Ds)
D Nar cot i c anal gesi cs
Vi ew Answer 10. The answer i s A[ see] . P. 721


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see Ì Ì . A. 1. b] .
Candi da al bi cans remai ns t he most common cause. Ì nf ect i ons caused by C. gl abr at a
ar e i ncr easi ng. Tr i chomonas and anaerobi c bact er i a cause ot her t ypes of vagi nal
i nf ect i ons.
2. The answer i s D [ see Ì Ì . A. 3. f . (2) ] .
Nonpr escr i pt i on ant i f ungal agent s' ef f i cacy r at es approach 80%-90%.
3. The answer i s C [ see Ì Ì . A. 3. f ] .
Moni st at 1 cont ai ns t i oconazol e, a l ong-act i ng oi nt ment .
4. The answer i s B [ see Ì Ì . A. 3. d] .
Ext er nal creams can be hel pf ul f or t r eat i ng ext er nal i t chi ng. The vagi nal yeast
i nf ect i on st i l l must be t reat ed wi t h an i nt r avagi nal cr eam.
5. The answer i s D [ see Ì Ì . A. 2. b] .
Al l of t hese pat i ent s shoul d be ref er r ed f or di agnosi s and t r eat ment .
6. The answer i s A [ see Ì Ì Ì . B. 1. c. ( 2) ] .
Ì nt ercour se shoul d be avoi ded f or a f ul l 3 days af t er t he not ed t emperat ure
t r ansi t i on. Al l of t he ot her st at ement s ar e cor r ect .
7. The answer i s E [ see Ì Ì Ì . B. 2] .
Al l t he st at ement s ar e cor r ect .
8. The answer i s C [ see Tabl e 34- 1] .
The most ef f ect i ve cont racept i ve pr oduct avai l abl e t oday i s t he combi nat i on oral
cont r acept i ve. Al l of t he ot her st at ement s are corr ect .
9. The answer i s C [ see Ì . B. 1. d. (3) . (a) ] .
10. The answer i s A [ see Ì . B. 1. d. ( 3) . ( b) ] .
NSAÌ Ds are approved by t he FDA f or t he t reat ment of pri mar y dysmenor rhea. For
pr emenst r ual and menst rual r el i ef of wat er r et ent i on, bl oat i ng, and t ensi on, t he FDA
has appr oved OTC di ur et i cs.

35
HerbaI Medicines and NutritionaI SuppIements
Teresa KI epser
I. INTRODUCTION.
Many of t he dr ugs avai l abl e on t he mar ket ar e der i ved f rom pl ant s. Some of t hose
i ncl ude aspi r i n, at r opi ne, bel l adonna, capsai ci n, cascar a, col chi ci ne, di goxi n
( Lanoxi n) , ephedri ne, ergot ami ne, i pecac, opi um, physost i gmi ne, pi l ocarpi ne,
podophyl l um, psyl l i um, qui ni di ne, r eser pi ne, scopol ami ne, senna, Taxol ,
t ubocurar i ne, vi nbl ast i ne, and vi ncr i st i ne. Herb product s are al so der i ved f r om
pl ant s; however , t hese pr oduct s are not consi dered drugs by t he U. S. Food and
Dr ug Admi ni st rat i on (FDA) .
A. ReguI at i ons
1. The FederaI Food, Drug, and Cosmet i c Act of 1938 mandat ed phar maceut i cal
compani es t o t est drugs f or saf et y bef or e mar ket i ng.
2. The Kefauver- Harri s Drug Amendment s of 1962 mandat ed phar maceut i cal
compani es t o t est drugs f or ef f i cacy bef or e mar ket i ng.
3. The Di et ar y SuppI ement HeaI t h and Educat i on Act of 1994 mandat ed t he
f ol l owi ng:
a. Di et ar y suppl ement s ar e not drugs or f ood. They ar e i nt ended t o suppl ement t he
di et .
b. Herbs ar e consi der ed di et ar y suppl ement s.
c. Di et ar y suppl ement s do not have t o be st andardi zed.
d. The secr et ar y of Heal t h and Human Ser vi ces may r emove a suppl ement f r om t he
market onl y when i t has been shown t o be hazardous t o heal t h.
e. Di et ar y suppl ement s may make cl ai ms onl y regar di ng t he ef f ect s on st r uct ur e or
f unct i on of t he body. No cl ai ms regar di ng a par t i cul ar di sease or condi t i on may be
made.
f . The f ol l owi ng st at ement i s requi r ed on t he product l abel : " Thi s pr oduct has not
been eval uat ed by t he FDA. Ì t i s not i nt ended t o di agnose, t r eat , cur e, or pr event . ¨
4. German FederaI HeaI t h Agency
a. Ì n 1978, t he German Federal Heal t h Agency est abl i shed Commi ssi on E.
b. Commi ssi on E eval uat es t he saf et y and ef f i cacy of her bs t hrough cl i ni cal t ri al s
and cases publ i shed i n sci ent i f i c l i t erat ur e.
c. Ther e ar e > 380 publ i shed monogr aphs on herbs.
B. Herbs consi dered unsaf e f or human consumpt i on
1. Carci nogeni c herbs i ncl ude borage, cal amus, col t sf oot , comf r ey, l i f e root , and
sassaf r as.
2. Hepat ot oxi c her bs i ncl ude chapar r al , ger mander , kava, and l i f e r oot .
3. Hi gh doses of l i cori ce f or l ong per i ods may cause pseudoal dost eroni sm, a
condi t i on t hat may i ncl ude headache, l et hargy, sodi um and wat er r et ent i on,
hypokal emi a, hi gh bl ood pr essure, hear t f ai l ur e, and car di ac arr est .
4. Ma huang may cause myocar di al i nf arct i on, st rokes or sei zures.
5. Pokeroot may be f at al i n chi l dr en.
6. Unsaf e herbs accordi ng t o t he FDA. Ì n t he 1990s, t he FDA' s Cent er f or Food
Saf et y and Appl i ed Nut r i t i on creat ed t he Speci al Nut r i t i onal Adverse Event
Moni t or i ng Syst em Web si t e f or di et ar y suppl ement s. Unf or t unat el y, by 1999 t he si t e
was no l onger bei ng updat ed and t hus was event ual l y del et ed. Accor di ng t o t he l ast
updat e f r om t hat Web si t e, t he f ol l owi ng di et ar y suppl ement s wer e consi der ed
unsaf e by t he FDA:
a. Ar ni ca: muscl e paral ysi s, deat h
b. Amer i can and Eur opean mi st l et oe: sei zur es, coma
c. Bi t t ersweet and deadl y ni ght shade: cardi ac t oxi ci t y
d. Bl oodroot : hypot ensi on, coma
P. 723


e. Br oom: dehydr at i on
f . Comf r ey: cancer
g. Dut ch and Engl i sh t onka bean: hepat ot oxi ci t y
h. Hel i ot r ope: hepat ot oxi ci t y
i . Horse chest nut : bl eedi ng
j . Ji mson weed: ant i chol i ner gi c, hal l uci nat i ons
k. Kava: hepat ot oxi ci t y
I . Li l y of t he val l ey: car di ac t oxi ci t y
m. Lobel i a ( ni cot i ne) : coma, deat h
n. Mandr ake/ mayappl e: sever e gast roi nt est i nal sympt oms
o. Mor ni ng gl or y: psychosi s
p. Peri wi nkl e: renal and hepat ot oxi ci t y
q. Snaker oot : reser pi ne der i vat i ve
r. Spi ndl e t ree: sei zur es
s. St . John' s wor t : dr ug i nt er act i ons
t . Sweet f l ag: hal l uci nat i ons, l i ver cancer
u. Tr ue j al ap: purgat i ve cat har t i c
v. Wahoo: sei zur es
w. Wormwood: sei zur es, par al ysi s
x. Yohi mbe: r enal f ai l ur e, hypert ensi on
II. COMMONLY USED HERBS
A. BI ack cohosh ( Ci mi ci f uga racemosa)
1. Commi ssi on E i ndi cat i ons. Pr emenst r ual sympt oms, pai nf ul or di f f i cul t
menst ruat i on, and neuroveget at i ve sympt oms (hot f l ashes) caused by menopause
2. Mechani sm of act i on
a. Bl ack cohosh has est rogen- l i ke ef f ect s t hat are exer t ed by an unknown
mechani sm, di f f erent f r om an est r ogeni c mechani sm.
b. Ì t does not appear t o bi nd t o est r ogen r ecept or s. Nor does i t appear t o up-
r egul at e est rogen- dependent genes.
c. Ì t does not af f ect t he gr owt h of est r ogen-dependent t umor s i n exper i ment al
ani mal s.
3. Ef f i cacy
a. Uncont r ol l ed as wel l as doubl e-bl i nd, r andomi zed, pl acebo-cont r ol l ed cl i ni cal
t r i al s compar ed bl ack cohosh t o hor mone t her apy i n peri menopausal and
post menopausal women wi t h neuroveget at i ve menopausal sympt oms of di f f er ent
degrees of sever i t y. The Kupper man menopausal i ndex and psychi at ri c cl i ni cal and
sel f - eval uat i on scal es wer e si gni f i cant l y r educed af t er 3 mont hs of t reat ment wi t h
bl ack cohosh. Vagi nal -cyt ol ogi cal par amet er s al so i mpr oved i n regard t o est rogen
st i mul at i on. Bl ack cohosh was shown t o be superi or t o pl acebo and compar abl e t o
est ri ol , conj ugat ed est rogens, and est r ogen-pr ogest er one t her apy ( Mahady) .
b. Bl ack cohosh may not be ef f ect i ve i n premenopausal breast cancer survi vor s wi t h
t amoxi f en- i nduced hot f l ashes ( Jacobsen).
4. Cont rai ndi cat i ons/ precauti ons
a. Pr egnancy
b. Unknown i f sui t abl e f or pat i ent s f or whom hor mone- repl acement t her apy i s
cont r ai ndi cat ed, such as est r ogen- recept or - posi t i ve br east cancer
c. Commi ssi on E r ecommends t hat l engt h of use shoul d not exceed 6 mont hs.
d. Use caut i on i n l i ver di sease, such as hepat i t i s and f ul mi nant l i ver f ai l ure.
5. Drug i nt eract i ons
a. Ci spl at i n ( Pl at i nol ) ef f i cacy may be r educed.
b. Theoret i cal l y, bl ack cohosh may i nt er act wi t h hepat ot oxi c dr ugs, such as
acet ami nophen ( Tyl enol ), car bamazepi ne ( Tegret ol ) , and i soni azi d ( Nydr azi d)
because i t i s an i nhi bi t or of cyt ochr ome P450 3A4 ( CYP34A) and CYP2D6
i soenzymes.
6. Si de ef f ects
a. Occasi onal i nt est i nal pr obl ems may occur , such as nausea and vomi t i ng; wei ght
gai n i s possi bl e.
P. 724


b. Li ver t oxi ci t y may occur ; l i ver f unct i on t est s shoul d be moni t ored per i odi cal l y.
c. Lar ge doses of bl ack cohosh may cause di zzi ness, nausea, sever e headaches,
st i f f ness, and t r embl i ng l i mbs.
d. Does not seem t o i ncrease r i sk of endomet r i al hyper pl asi a.
7. Dosage. Remi f emi n i s a st andardi zed pr oduct t hat cont ai ns 20 mg bl ack cohosh
and i s t aken t wi ce dai l y. Ì t i s st andardi zed t o 1 mg of 27-deoxyact ei n per t abl et .
B. Chaste t ree berr y ( Vi t ex agnus- cast us)
1. Commi ssi on E i ndi cat i ons. Di sor ders of t he menst rual cycl e, breast swel l i ng,
and pr emenst rual sympt oms
2. Mechani sm of act i on
a. Chast e t ree ber r y bi nds t o dopami ne recept or s and i nhi bi t s prol act i n secr et i on.
b. One of i t s i ngr edi ent s, l i nol ei c aci d, bi nds t o est r ogen r ecept ors.
c. Ì t i ncr eases t he pi t ui t ar y gl and' s product i on of l ut ei ni zi ng hor mone and i nhi bi t s
f ol l i cl e-st i mul at i ng hor mone (FSH) .
3. Ef f i cacy. One r andomi zed, doubl e- bl i nd, pl acebo- cont r ol l ed, par al l el group st udy
i ncl uded 170 women wi t h pr emenst r ual syndr ome ( Schel l enber g) . Vi t ex was gi ven 20
mg dai l y f or 3 cycl es. Sel f - assessment and cl i ni cal gl obal i mpr essi on si gni f i cant l y
i mproved.
4. Cont rai ndi cat i ons/ precauti ons
a. Pr egnancy and l act at i on
b. Women r ecei vi ng hormone- r epl acement t herapy
5. Drug i nt eract i ons
a. Theoret i cal l y, chast e t r ee ber r y may i nt eract wi t h medi cat i ons t hat i ncr ease
dopami nergi c act i vi t y, such as br omocr i pt i ne ( Parl odel ) and l evodopa.
b. Theoret i cal l y, i t may i nt er act wi t h medi cat i ons t hat decr ease dopami nergi c
act i vi t y, such as t he ant i psychot i cs.
c. Theoret i cal l y, i t may i nt er act wi t h hor mone- repl acement t her apy and or al
cont r acept i ves.
6. Si de ef f ects
a. Mi l d gast r oi nt est i nal upset
b. Ski n r ash
c. Ì ncreased menst r ual f l ow
7. Dosage. Doses depend on t he f or mul at i on. Typi cal dose range of chast e t ree
ber r y i s 20- 240 mg per day.
C. Cranberr y ( Vacci ni um macrocarpon)
1. Commi ssi on E i ndi cat i ons. Recur rent ur i nar y t r act i nf ect i ons
2. Mechani sm of act i on
a. Ur i nar y aci di f i cat i on
b. Benzoi c and qui ni c aci ds br eak down and f orm hi ppuri c aci d ( bact er i ost at i c) .
c. Ì nhi bi t i on of Escher i chi a col i adher ence t o epi t hel i al cel l s of ur i nar y t r act
d. Cr anber r y j ui ce may suppress Hel i cobact er pyl or i i nf ect i on.
3. Ef f i cacy
a. A quasi - randomi zed, doubl e-bl i nd, pl acebo- cont r ol l ed st udy i ncl uded 153 women
who r ecei ved 300 mL of cr anber r y j ui ce dai l y f or 6 mont hs (Avor n et al . ) . Bact er i ur i a
wi t h pyur i a occur r ed l ess of t en i n t he cr anber r y group (15%) versus pl acebo ( 28%) .
4. Cont rai ndi cat i ons
a. Beni gn pr ost at i c hyper pl asi a
b. Ur i nar y obst r uct i on
c. Nephr ol i t hi asi s
d. Cr anber r y j ui ce cont ai ns hi gh amount s of sal i cyl i c aci d and may t r i gger an
al l er gi c react i on i n pat i ent s wi t h an aspi ri n al l ergy or ast hma.
e. Di scont i nue 2 weeks bef ore sur ger y.
f . Ul cers, GERD
P. 725


5. Drug i nt eract i ons
a. Ì ncreased vi t ami n B12 absor pt i on
b. Pot ent i al t o enhance el i mi nat i on of r enal l y excr et ed dr ugs by changi ng uri ne pH
c. Cr anberr y j ui ce may i nt er act wi t h war f ar i n, i ncr easi ng t he i nt er nat i onal
nor mal i zed rat i o ( Ì NR) .
d. May i nhi bi t cyt ochrome P450 2C9. Drugs t hat ar e met abol i zed by CYP2C9 i ncl ude
ami t r i pt yl i ne ( El avi l ) and di azepam ( Val i um).
6. Si de ef f ects
a. Nausea, vomi t i ng, di ar r hea
b. Nephr ol i t hi asi s
7. Dosage. Recommended dose of cranber r y i s 300- 400 mg t wi ce dai l y usi ng a
st andardi zed product t o i ncl ude 11%- 12% qui ni c aci d per dose. Pat i ent s may al so
t ake 8-16 oz. 100% cr anber r y j ui ce dai l y. Dr i nki ng l ot s of f l ui ds i s recommended.
D. Dong quai ( Angel i ca senensi s)
1. Tradi t i onaI Chi nese Medi ci ne i ndi cat i ons. Menst r ual di sor ders, anemi a,
const i pat i on, i nsomni a, rheumat i sm, neur al gi a, and hyper t ensi on
2. Mechani sm of act i on
a. Dong quai i s onl y 1: 400 as act i ve as est rogen. However , i t does not appear t o
pr oduce any changes t o t he ovar i es or vagi nal t i ssue ( Mur r ay) .
b. Ì t cont ai ns seven di f f er ent coumar i n der i vat i ves: oxypeucedani n, ost hol e,
psoral en, angel ol , angel i cone, ber gapt en, and 7-desmet hyl suber osi n. Many
coumari ns have been shown t o have vasodi l at or y and ant i spasmodi c ef f ect s. One of
t he coumar i ns (ost hol e) i s a cent r al ner vous syst em ( CNS) st i mul ant .
c. Ì t i nhi bi t s exper i ment al l y i nduced i mmunogl obul i n E ( Ì gE) t i t ers, suggest i ng t hat
component s of t he pl ant may have i mmunosuppressi ve act i vi t y.
d. Ì t i nhi bi t s prost agl andi n E2 ( PGE2) rel ease and, t her ef or e, possesses anal gesi c,
ant i pyr et i c, and ant i -i nf l ammat or y act i ons.
e. Ì t has a qui ni di ne-t ype ef f ect , so i t may cont rol t achycardi a.
f . Ì t normal i zes ut er i ne cont r act i ons.
g. Ì t has ant i bi ot i c act i vi t y agai nst gram-negat i ve bact er i a ( Baci l l us dysent er i ae, B.
t yphi , B. comma, B. parat yphi , and Escher i chi a col i ) and agai nst gram-posi t i ve
bact er i a (hemol yt i c St r ept ococcus t ype A and B, Cor ynebact er i um di pht her i ae).
3. Ef f i cacy. A r andomi zed, doubl e- bl i nd, pl acebo- cont rol l ed t r i al i ncl uded 71
post menopausal women ( mean age, 52. 4 year s) who had FSH < 30 mÌ U/ mL wi t h hot
f l ashes ( Hi r at a et al . ) . Women r ecei ved 3 capsul es of dong quai t hr ee t i mes dai l y
( equi val ent t o 4. 5 g of dong quai root dai l y) or pl acebo f or 24 weeks. Dong quai di d
not pr oduce est rogen- l i ke r esponses i n endomet ri al t hi ckness or i n vagi nal
mat ur at i on or r el i eve menopausal sympt oms. The st udy i s cr i t i ci zed f or usi ng dong
quai al one, because i n Tr adi t i onal Chi nese Medi ci ne, dong quai i s used i n
combi nat i on wi t h f our or mor e ot her herbs.
4. Cont rai ndi cat i ons/ precauti ons
a. Pr egnancy (ut eri ne st i mul ant ) and l act at i on
b. Di ar r hea
c. Hemor rhagi c di sease; di scont i nue 2 weeks bef or e surger y
d. Hypermenor r hea
e. Hypot ensi on
f . Dur i ng col ds or f l us
g. Al l er gy t o parsl ey
5. Drug i nt eract i ons
a. Dong quai i nt eract s wi t h ant i coagul ant s, such as war f ari n ( Coumadi n)
b. Ant i hyper t ensi ves (hypot ensi on)
c. Theoret i cal l y, may i nt er act wi t h hormone- r epl acement t her apy.
d. Unknown i f i t i nt eract s wi t h ot her car di ovascul ar drugs such as pr ocai nami de
( Pr onest yl )
6. Si de ef f ects
a. Phot odermat i t i s may occur i n peopl e col l ect i ng t he pl ant .
b. Burpi ng, f l at ul ence, and headache
P. 726


c. Saf r ol e, f ound i n t he oi l of dong quai , i s carci nogeni c and not recommended f or
i ngest i on.
d. May st i mul at e br east cancer cel l s.
7. Dosage. A vari et y of doses ar e suggest ed. No st andar di zed product i s avai l abl e.
Accor di ng t o t r adi t i onal Chi nese medi ci ne, dong quai al one may not be ef f ect i ve.
E. Echi nacea ( Echi nacea purpurea, E. angust i fol i a)
1. Commi ssi on E i ndi cat i ons
a. Ì nt ernal use: suppor t i ve t herapy f or i nf ect i ons of t he upper r espi r at or y t r act
( col ds) and l ower ur i nar y t r act
b. Ext er nal use: l ocal appl i cat i on f or t he t reat ment of har d- t o- heal superf i ci al
wounds and ul cers
2. Mechani sm of act i on. Echi nacea i ncr eases t he body' s r esi st ance t o bact er i a by:
a. Caf f ei c aci d der i vat i ves, whi ch i ncl ude ci chor i c aci d, chl orogeni c aci d, and
cynar i n, i ncr ease phagocyt osi s and st i mul at e t he pr oduct i on of i mmune- pot ent i at i ng
subst ances such as i nt erf er on, i nt erl euki ns, and t umor necr osi s f act or .
b. Pol ysacchari des, such as i nul i n, st i mul at e macr ophages and i nhi bi t hyal uroni dase
act i vi t y t o decr ease i nf l ammat i on.
c. Al kyl ami des, such as echi nacei n, have a l ocal anest het i c ef f ect and i nhi bi t
hyal uroni dase act i vi t y t o decr ease i nf l ammat i on.
d. Echi nacea has l i t t l e or no di rect bact er i oci dal or bact er i ost at i c pr oper t i es.
3. Ef f i cacy. Ì n a r evi ew of 26 cont r ol l ed cl i ni cal t r i al s eval uat i ng echi nacea' s abi l i t y
t o st r engt hen t he body' s own def ense mechani sms, i t was f ound t hat 30 of 34
echi nacea t her api es were mor e ef f ect i ve compared t o cont r ol s ( Mel char t et al . ) .
4. Cont rai ndi cat i ons/ precauti ons
a. Echi nacea i s cont rai ndi cat ed i n i nf ect i ous and aut oi mmune di seases such as
t ubercul osi s, l eukosi s, col l agenosi s, mul t i pl e scl er osi s, AÌ DS, HÌ V, and l upus.
b. Caut i on shoul d be used i n pat i ent s who ar e al l er gi c t o member s of t he r agweed
f ami l y.
c. The ef f ect s of echi nacea i n pregnancy, l act at i on, and chi l dren ar e unknown.
Compar i son wi t h a cont rol gr oup suggest ed no i ncr eased ri sk of maj or
mal f ormat i ons i n 206 pregnant women ( Gal l o et al . ) .
d. Ther apy shoul d not exceed 8 weeks. Theoret i cal l y, pr ol onged use of echi nacea
may depr ess t he i mmune syst em, possi bl y t hrough overst i mul at i on.
5. Drug i nt eract i ons
a. Unknown i f echi nacea i nt er act s wi t h i mmunosuppr essant s
b. Echi nacea i nhi bi t s cyt ochrome P450 1A2. Some dr ugs met abol i zed by CYP1A2
ar e caf f ei ne ( Caf ci t ) and t heophyl l i ne.
c. Echi nacea i nduces and i nhi bi t s CYP3A4. Some dr ugs met abol i zed by CYP3A4 ar e
mi dazol am (Versed), i t r aconazol e ( Spor anox) and f exof enadi ne ( Al l egr a) .
6. Si de ef f ects
a. Nausea, vomi t i ng, di zzi ness, t i redness, al l er gi c r eact i ons, and anaphyl axi s.
b. May i nt er f er e wi t h mal e f ert i l i t y.
7. Dosage. Ther e ar e a var i et y of doses recommended. The most common dose i s
as t he dr i ed powder , 1 g or t wo 500- mg capsul es or al l y t hree t i mes dai l y.
Recommended t o use f or 2 weeks onl y dur i ng a col d.
F. Feverf ew ( Tanacet um partheni um)
1. Commi ssi on E i ndi cat i on. Pr ophyl axi s of mi grai ne headaches
2. Mechani sm of act i on
a. Fever f ew i nhi bi t s t he rel ease of 5- hydroxyt r ypt ami ne (ser ot oni n) f rom pl at el et s,
whi ch may be t he same mechani sm as met hysergi de mal eat e ( Sanser t ) .
b. Ì t i r r ever si bl y i nhi bi t s pr ost agl andi n synt hesi s t hr ough a di f f er ent mechani sm f r om
t hat of t he sal i cyl at es. Ì t i nhi bi t s phosphol i pase A2 by q- met hyl ene but yr ol act ones
( par t henol i de and epoxyar t emori n) .
c. Ther e i s an ant i t hr ombot i c pot ent i al owi ng t o a phosphol i pase i nhi bi t i on t hat
pr event s t he r el ease of ar achi doni c aci d.
P. 727


d. Ì t i nhi bi t s pol ymor phonucl ear l eukocyt e ( PMN) degranul at i on, whi ch reduces
PMN- i nduced damage t o t he r heumat oi d synovi um.
e. Ì t i nhi bi t s phagocyt osi s of human neut rophi l s, whi ch may r educe t i ssue damage
f r om oxygen r adi cal s.
f . Ì t i nhi bi t s mast cel l r el ease of hi st ami ne.
g. Ì t may have cyt ot oxi c act i vi t y agai nst human t umor cel l s.
h. Ì t may possess ant i mi cr obi al act i vi t y.
3. Ef f i cacy. An eval uat i on of f i ve t r i al s f or t he ef f i cacy of f everf ew i n t he pr event i on
of mi grai nes compar ed t o pl acebo was conduct ed ( Cochr ane Dat abase of Syst emat i c
Revi ews) . A vari et y of doses and durat i ons wer e used. Some t ri al s showed t he
number and sever i t y of mi grai ne at t acks and t he degree of vomi t i ng wer e r educed
wi t h f ever f ew. The dur at i on of at t acks was unal t er ed. Ot her t r i al s showed no
benef i t .
4. Cont rai ndi cat i ons/ precauti ons
a. Fever f ew shoul d be avoi ded i n pregnancy, l act at i on, and chi l dr en < 2 year s of
age.
b. Cont r ai ndi cat ed i n i ndi vi dual s wi t h al l er gi es t o chr ysant hemums.
c. Cont r ai ndi cat ed i n pat i ent s wi t h bl eedi ng di sorder s. Di scont i nue 2 weeks bef or e
sur ger y.
5. Drug i nt eract i ons
a. Fever f ew may i nt er act wi t h ant i coagul ant s, i ncr easi ng t he ri sk of bl eedi ng.
b. Feverf ew may i nhi bi t t he f ol l owi ng cyt ochr ome P450 i soenzymes: 1A2, 2C19,
2C9, and 3A4.
6. Si de ef f ects
a. Gast r i c di scomf or t on or al consumpt i on
b. Cont act dermat i t i s
c. Mi nor ul cer at i ons of or al mucosa, i r ri t at i on of t ongue, and swel l i ng of l i ps may
occur when f r esh l eaves ar e chewed.
d. Pal pi t at i ons.
e. Post - f ever f ew syndr ome: di scont i nuat i on of f ever f ew may pr oduce muscl e and
j oi nt st i f f ness and a cl ust er of ner vous syst em r eact i ons ( rebound of mi grai nes,
anxi et y, and i nsomni a).
7. Dosage. The usual dose of f ever f ew i s 125 mg dai l y. A pr oduct cont ai ni ng at
l east 0. 2% par t henol i de i s r ecommended.
G. GarI i c ( Al l i um sat i vum)
1. Commi ssi on E i ndi cat i ons. Support di et ar y measur es f or t he t r eat ment of
hyper l i popr ot ei nemi a and t o pr event age- rel at ed changes i n t he bl ood vessel s
( ar t eri oscl erosi s)
2. Mechani sm of act i on
a. Gar l i c i nhi bi t s pl at el et f unct i on by i nt er f er i ng wi t h t hr omboxane synt hesi s.
b. Ì t i ncr eases t he l evel s of t wo ant i oxi dant enzymes i n t he bl ood: cat al ase and
gl ut at hi one per oxi dase.
c. Or gani c di sul f i des f ound i n gar l i c oi l i nact i vat e t he t hi ol enzymes such as
coenzyme A ( CoA) and hydr oxymet hyl gl ut ar yl ( HMG) CoA r educt ase.
3. Ef f i cacy
a. Ì n a met a- anal ysi s of ei ght st udi es eval uat i ng t he ef f ect on bl ood pr essur e, t he
over al l pool ed di f f er ence i n change of syst ol i c bl ood pressure was 7. 7 mm Hg l ower
wi t h gar l i c t han wi t h pl acebo; di ast ol i c bl ood pressur e was 5. 0 mm Hg l ower wi t h
gar l i c ( Si l agy et al . ) .
b. Ì n a met a- anal ysi s of f i ve st udi es eval uat i ng t he ef f ect on t ot al serum chol est erol ,
pat i ent s wer e excl uded i f t hey wer e recei vi ng l i pi d- l ower i ng dr ugs (Warshaf sky et
al . ) . The overal l pool ed t ot al chol est er ol di f f er ence bet ween gar l i c and pl acebo was
- 23 mg/ dL ( -29 t o -17).
4. Cont rai ndi cat i ons/ precauti ons
a. Caut i on i n di abet es. Gar l i c may i ncrease t he r el ease of i nsul i n or enhance t he
r esponse t o i nsul i n.
b. Caut i on i n pr egnancy ( emmenagogue and abort i f aci ent ) and l act at i on
c. Caut i on i n pept i c ul cer di sease and gast r oesophageal r ef l ux
d. Di scont i nue 2 weeks bef ore sur ger y
P. 728


5. Drug i nt eract i ons
a. Ant i coagul ant s (i ncr eased bl eedi ng)
b. Pr ot ease i nhi bi t or s (decr eased ef f i cacy)
c. Nonnucl eosi de r everse t r anscr i pt ase i nhi bi t or s, such as nevi r api ne, ef avi r enz
d. Ì ncr eases amphot eri ci n B ( Fungi zone) act i vi t y agai nst Crypt ococcus neof or mans
e. Ant i hyper t ensi ves ( hypot ensi on)
f . Ant i di abet i c agent s ( hypogl ycemi a)
g. May i nhi bi t t he f ol l owi ng cyt ochr ome P450 i soenzymes: 2C9, 2C19, 3A4, 2D6,
and 2E1.
h. Caut i on shoul d be used wi t h cont r acept i ve medi cat i ons, cycl ospori ne, di l t i azem,
and verapami l .
6. Si de ef f ects. Gast roi nt est i nal di scomf ort ( hear t burn, f l at ul ence) , sweat i ng, l i ght -
headedness, al l ergi c r eact i ons, and menor rhagi a
7. Dosage. Bet ween 0. 6 and 1. 2 g dr i ed powder (2- 5 mg of al l i ci n) dai l y or 2- 4 g
f r esh gar l i c
8. Comment s
a. Al l i i nase ( t he enzyme t hat conver t s al l i i n t o al l i ci n) i s i nact i vat ed by aci ds.
Ent eri c-coat ed t abl et s or capsul es al l ow mor e absor pt i on because t hey pass t hrough
t he st omach and r el ease t hei r cont ent s i n t he al kal i ne medi um of t he smal l i nt est i ne.
b. Odorl ess garl i c pr eparat i ons may not cont ai n t he act i ve compounds.
H. Gi nger ( Zi ngi ber of f i ci nal e)
1. Commi ssi on E i ndi cat i ons. Dyspepsi a and prophyl axi s of sympt oms of t r avel
si ckness
2. Mechani sm of act i on
a. Gi nger pr omot es sal i va and gast r i c j ui ce secr et i on, whi ch i ncreases peri st al si s
and t he t one of t he i nt est i nal muscl e.
b. Ì t act s on 5- hydroxyt r ypt ami ne 3 (5- HT3) r ecept ors i n t he i l eum, si mi l ar t o
ondanset ron.
c. Ì t has posi t i ve i not ropi c act i vi t y.
d. Ì t i nhi bi t s t hr omboxane synt hesi s as a prost acycl i n agoni st .
3. Ef f i cacy. A doubl e- bl i nd st udy i ncl uded 36 bl i ndf ol ded subj ect s wi t h hi gh
suscept i bi l i t y t o mot i on si ckness who wer e gi ven gi nger 940 mg, di menhydr i nat e 100
mg, or pl acebo f or t he prevent i on of mot i on si ckness i nduced by a t i l t ed rot at i ng
chai r . Gi nger subj ect s r emai ned i n t he chai r an aver age of 5. 5 mi n, di menhydr i nat e
3. 5 mi n, and pl acebo 1. 5 mi n. The gi nger gr oup t ook l onger t o f eel si ck, but once
si ck, t he sensat i ons of nausea and vomi t i ng pr ogr essed at t he same r at e i n al l
gr oups ( Mowr ey et al . ) .
4. Cont rai ndi cat i ons/ precauti ons
a. Bl eedi ng di sor der s. Di scont i nue 2 weeks bef ore sur ger y
b. Ì t i s cont rai ndi cat ed f or gal l st one pai n.
c. Ì t i s r ecommended by t he Ameri can Col l ege of Obst et r i ci ans and Gynecol ogi st s
( ACOG) f or use i n pr egnancy < 17 weeks of gest at i on wi t h t he f ol l owi ng caut i ons:
gi nger i s a ut eri ne r el axant i n l ow doses and a ut er i ne st i mul ant i n hi gh doses.
d. Di abet es ( hypogl ycemi a)
e. Hear t condi t i ons
5. Drug i nt eract i ons
a. Ant i pl at el et s and ant i coagul ant s ( i ncreased bl eedi ng)
a. Di abet i c agent s (hypogl ycemi a)
a. Cal ci um channel bl ockers ( hypot ensi on)
6. Si de ef f ects ar e dermat i t i s, hear t bur n, and di ar r hea.
7. Dosage ( f or t raveI si ckness) . Dai l y dose i s 2- 4 g. Two 500- mg capsul es t aken
30 mi n bef or e t r avel , t hen 1- 2 mor e capsul es ever y 4 hr as needed. The 1000 mg
st andardi zed ext r act i s equi val ent t o:
a. 1 t easpoon f r esh grat ed r hi zome
b. 2 dr oppers l i qui d ext r act ( 2 mL)
c. 2 t easpoons syr up ( 10 mL)
d. 8 ounces gi nger al e, made wi t h real gi nger
e. 4 cups gi nger t ea (made by st eepi ng 1/ 2 t easpoon gr at ed gi nger f or 5-10 mi n i n
hot wat er )
P. 729


I . Gi nkgo ( Gi nkgo bi l oba)
1. Commi ssi on E i ndi cat i ons
a. Tr eat ment f or cer ebr al ci rcul at or y di st ur bances r esul t i ng i n r educed f unct i onal
capaci t y and vi gi l ance ( ver t i go, t i nni t us, weakened memor y, and mood swi ngs
accompani ed by anxi et y)
b. Tr eat ment of per i pheral ar t eri al ci r cul at or y di st ur bance such as i nt er mi t t ent
cl audi cat i on
2. Mechani sm of act i on
a. Gi nkgo cont ai ns f l avonoi ds (quer cet i n, kaempf er ol , and i sor hamnet i n) and
t er penoi ds ( gi nkgol i des A, B, and C and bi l obal i de) .
b. Fl avonoi ds pr ovi de t he ant i oxi dant act i vi t y, r educe capi l l ar y f ragi l i t y, and
i ncrease t he t hreshol d of bl ood l oss f r om capi l l ari es.
c. Gi nkgol i des ant agoni ze pl at el et - act i vat i ng f act or ( PAF), whi ch i nduces pl at el et
aggregat i on, t he degr anul at i on of neut r ophi l s, and t he product i on of oxygen
r adi cal s.
d. Bi l obal i de pr ot ect s ner ve cel l s.
3. Ef f i cacy
a. Ì n a revi ew of t he cl i ni cal and pharmacol ogi cal st udi es on gi nkgo and cer ebr al
i nsuf f i ci ency, ei ght wer e f ound t o be of good qual i t y ( Kl ei j nen). Seven of t he t ri al s
showed posi t i ve ef f ect s of gi nkgo compar ed t o pl acebo. Sympt oms of cerebr al
i nsuf f i ci ency eval uat ed wer e di f f i cul t i es of concent r at i on and memor y,
absent mi ndedness, conf usi on, l ack of ener gy, t i redness, decr eased physi cal
per f or mance, depr essi on, anxi et y, di zzi ness, t i nni t us, and headaches.
b. For i nt ermi t t ent cl audi cat i on, t her e wer e 15 cont r ol l ed t ri al s, 2 of accept abl e
qual i t y ( Ri t t l er et al . ) .
( 1) One showed an i ncrease i n wal ki ng di st ance (Bauer et al . ) ÷gi nkgo, 112- 222 m;
pl acebo, 145- 176 m.
( 2) The ot her demonst r at ed amel i or at i on of pai n at r est ( Saudreau et al . ) . The use
of gi nkgo showed a decrease on a 100- mm vi sual anal og scal e f or pai n f rom 61 t o
30 mm ( pl acebo 51 t o 39 mm) .
c. A randomi zed, doubl e- bl i nd, pl acebo-cont rol l ed st udy i ncl uded 202 pat i ent s wi t h
ei t her Al zhei mer di sease or mul t i -i nf ar ct dement i a. These pat i ent s wer e gi ven
gi nkgo 40 mg t hr ee t i mes dai l y or pl acebo f or 1 year . Gi nkgo had a st at i st i cal l y
si gni f i cant i mpr ovement by at l east t wo poi nt s or bet t er on t he Al zhei mer Di sease
Assessment Scal e÷Cogni t i ve ( a 70-poi nt subscal e) compar ed t o pl acebo ( 50%
ver sus 29%) . Gi nkgo showed st at i st i cal l y si gni f i cant i mpr ovement on t he Ger i at ri c
Eval uat i on by Rel at i ve' s Rat i ng Ì nst rument ( 37% ver sus 23%) . Ther e was no
di f f er ence bet ween gi nkgo and pl acebo on t he Cl i ni cal Gl obal Ì mpressi on of Change
scal e ( LeBars et al . ) .
4. Cont rai ndi cat i ons/ precauti ons.
a. Epi l epsy. Gi nkgot oxi n may cause neur ot oxi ci t y and sei zur es.
b. Bl eedi ng di sor ders. Di scont i nue 2 weeks bef ore sur ger y
c. Di abet es ( hypogl ycemi a)
d. Ì nf er t i l i t y. Caut i on i n di f f i cul t y concei vi ng.
4. Drug i nt eract i ons
a. Gi nkgo may pot ent i at e t he bl eedi ng pr oper t i es of ant i pl at el et s÷t her e i s a case
r eport of spont aneous hyphema (bl eedi ng f r om t he i ri s i nt o t he ant er i or chamber )
f r om gi nkgo and aspi ri n.
b. Ami nogl ycosi des ( i ncreased ot ot oxi ci t y)
c. Thi azi de (i ncr eases bl ood pr essur e)
d. Tr azodone ( Desyr el ) (coma)
e. Sei zur e t hr eshol d l ower i ng drugs.
f . Ant i convul sant s
g. Ant i di abet i c dr ugs (hypogl ycemi a)
h. Gi nkgo may mi l dl y af f ect t he cyt ochrome P450 i soenzymes 1A2, 2C19, 2C9, 2D6,
and 3A4.
5. Si de ef f ects
a. Gast r i c di st urbances, headache, di zzi ness, and ver t i go
b. Toxi c i ngest i on may pr oduce t oni c-cl oni c sei zur es and l oss of consci ousness
c. Spont aneous bl eedi ng
P. 730


6. Dosage. Recommended dose i s 40 mg t hr ee t i mes dai l y wi t h meal s f or at l east 4-
6 weeks. St andar di zed pr eparat i ons t hat cont ai n 6% t er pene l act ones and 24%
gi nkgo f l avone gl ycosi des are r ecommended.
J. Asi an gi nseng ( Panax gi nseng, P. qui nquefol i us)
1. Commi ssi on E i ndi cat i ons. Toni c t o combat f eel i ngs of l assi t ude and debi l i t y,
l ack of energy, and abi l i t y t o concent r at e, and dur i ng conval escence
2. Mechani sm of act i on
a. At l east 28 act i ve i ngredi ent s, known as gi nsenosi des, have been i dent i f i ed.
b. Gi nseng ef f ect s var y wi t h ext r act der i vat i ve, dr yi ng met hod, dose, dur at i on of
t r eat ment , and ani mal speci es t hat was st udi ed. Each gi nsenosi de pr oduces
di f f er ent pharmacol ogi cal ef f ect s on t he cent ral ner vous syst em, car di ovascul ar
syst em, and ot her body syst ems. Di f f erent gi nsenosi des ar e capabl e of pr oduci ng
bi ol ogi cal ef f ect s i n di rect opposi t i on wi t h t hose pr oduced by ot her s. For exampl e,
t he gi nsenosi de Rb1 has been shown t o have a suppr essi ve ef f ect on t he cent r al
ner vous syst em, whereas Rg1 pr oduces a st i mul at or y ef f ect .
3. Ef f i cacy
a. A randomi zed, doubl e- bl i nd, pl acebo-cont rol l ed, cr ossover st udy i ncl uded 50
mal e sport s t eacher s who perf ormed a t r eadmi l l exer ci se t est . Vol unt eers r ecei ved 2
gi nseng capsul es ( Geri at r i c Pharmat on) dai l y f or 6 weeks or pl acebo. Vol unt eer s
used energy more ef f i ci ent l y and had gr eat er endur ance whi l e t aki ng gi nseng
( Pi er al i si et al . ).
b. A case-cont r ol l ed st udy i ncl udi ng 1987 pai rs eval uat ed gi nseng' s ef f ect on
var i ous human cancer s. Ì ndi vi dual s who t ook gi nseng had a si gni f i cant decr eased
r i sk f or cancer compar ed wi t h noni nt akers. There may be a dose- response
r el at i onshi p; as t he f r equency and dur at i on of gi nseng use i ncreased, t he r i sk of
cancer decr eased. Accordi ng t o cancer si t e, gi nseng si gni f i cant l y r educed t he r i sk
of cancer of t he l i p, or al cavi t y, and phar ynx; esophagus; st omach; col on and
r ect um; l i ver ; pancr eas; l ung; and ovari es. There was no ri sk r educt i on f or cancer s
of t he f emal e breast , ut er i ne cer vi x, ur i nar y bl adder , and t hyr oi d gl and ( Yun et al . ) .
4. Cont rai ndi cat i ons/ precauti ons
a. Pr egnancy and l act at i on
b. Chi l dren
c. Avoi d i n pat i ent s wi t h hyper t ensi on, emot i onal / psychol ogi cal i mbal ances,
headaches, heart pal pi t at i ons, i nsomni a, ast hma, i nf l ammat i on, or i nf ect i ons wi t h
hi gh f ever.
d. Caut i on shoul d be used i n pat i ent s wi t h a hi st or y of bl eedi ng. Di scont i nue 2
weeks bef or e surger y
e. Di abet es ( hypogl ycemi a)
f . Schi zophr eni a
g. Caut i on shoul d be used i n pat i ent s wi t h a hi st or y of br east cancer . Gi nseng may
st i mul at e breast cancer cel l s.
5. Drug i nt eract i ons
a. Gi nseng may i nt er act wi t h phenel zi ne ( Nar di l ) , pr oduci ng hal l uci nat i ons and
psychosi s.
b. Gi nseng may decrease t he Ì NR of war f ari n ( Coumadi n) .
c. Gi nseng may i nt er act wi t h st i mul ant s, i ncl udi ng caf f ei ne ( Caf ci t ) .
d. Gi nseng may i nt er act wi t h hypogl ycemi cs, causi ng hypogl ycemi a.
e. Ì t i s unknown whet her gi nseng i nt er act s wi t h hor monal t her apy,
ant i hyper t ensi ves, or cardi ac medi cat i ons.
f . Ì t may i nhi bi t cyt ochr ome P450 2D6. Caut i on shoul d be used wi t h dr ugs t hat ar e
met abol i zed vi a cyt ochrome P450 2D6, such as ami t ri pt yl i ne ( El avi l ) and f l uoxet i ne
( Pr ozac).
g. Ì t may i nt er f er e wi t h i mmunosuppr essant s.
6. Si de ef f ects
a. Ner vousness and exci t at i on f or t he f i rst 4 days
b. Ì nabi l i t y t o concent rat e wi t h l ong-t erm use
c. Di f f use mammar y nodul ari t y and vagi nal bl eedi ng may be caused by gi nseng' s
est rogen- l i ke ef f ect i n women.
P. 731


d. Hyper t ensi on, euphori a, r est l essness, ner vousness, i nsomni a, ski n er upt i ons,
edema, and di ar rhea have been repor t ed wi t h l ong- t erm gi nseng use wi t h an
aver age dose of 3 g gi nseng root dai l y.
e. May i ncr ease t he QT i nt er val .
7. Dosage. 1-2 g crude her b dai l y or 100- 300 mg gi nseng ext r act t hree t i mes dai l y.
St andar di zed pr oduct s t hat cont ai n at l east 4%-5% gi nsenosi des ar e recommended.
K. Si beri an gi nseng ( El eut herococcus sent i cosus)
1. Commi ssi on E i ndi cat i ons. Toni c f or f at i gue, conval escence, decr eased wor k
capaci t y, or di f f i cul t y i n concent r at i on
2. Mechani sm of act i on. Ani mal r esear ch suggest s t hat Si beri an gi nseng may
st i mul at e t he hypot hal ami c- pi t ui t ar y- adr enal cort ex. Ì t may bi nd t o progest i n,
mi ner al ocor t i coi d, and gl ucocort i coi d r ecept or s.
3. Ef f i cacy
a. A randomi zed, doubl e- bl i nd, pl acebo-cont rol l ed st udy eval uat ed 20 hi ghl y t r ai ned
di st ance r unners who r ecei ved E. sent i cosus ext r act 60 dr ops dai l y f or 6 weeks or
pl acebo. Subj ect s underwent a maxi mal t r eadmi l l t est and a 10K r ace. No si gni f i cant
di f f er ence was obser ved bet ween t r eat ment and pl acebo f or heart r at e, oxygen
consumpt i on, expi r ed mi nut e vol ume, vent i l at or y equi val ent f or oxygen, or
r espi r at or y exchange r at i o ( Dowl i ng et al . ) .
b. A randomi zed, pl acebo cont rol l ed pr ospect i ve st udy eval uat ed 96 subj ect s wi t h
chr oni c, unexpl ai ned f at i gue who recei ved st andar di zed E. sent i cosus 2000 mg dai l y
f or 2 mont hs. No st at i st i cal l y si gni f i cant di f f er ence was obser ved ( Har t z et al . ) .
4. Cont rai ndi cat i ons/ precauti ons
a. Not r ecommended i n pat i ent s wi t h f ebri l e st at es, hyper t oni c cri si s, or myocar di al
i nf ar ct i on
b. Di abet es ( hypogl ycemi a)
c. Bl eedi ng di sor der s. Di scont i nue 2 weeks bef ore sur ger y
d. Cardi ovascul ar condi t i ons: hyper t ensi on, t achycar di a.
e. Hormone-sensi t i ve condi t i ons.
f . Psychi at r i c condi t i ons: schi zophr eni a, mani a
5. Drug i nt eract i ons
a. Serum l evel s of di goxi n ( Lanoxi n) may i ncrease when t aken wi t h Si ber i an
gi nseng.
b. Barbi t ur at es. Hexobarbi t al and Si ber i an gi nseng i ncr ease sl eep l at ency and
dur at i on.
c. Si beri an gi nseng may i ncrease t he r i sk of hypogl ycemi a wi t h di abet i c agent s
d. Si ber i an gi nseng may i nt er act wi t h ant i coagul ant s and ant i pl at el et s.
e. Theoret i cal l y, Si ber i an gi nseng may i nt er act wi t h st i mul ant s, such as caf f ei ne.
f . Theor et i cal l y, Si beri an gi nseng may i nt er act wi t h ant i hyper t ensi ves
g. May i nhi bi t t he f ol l owi ng cyt ochr ome P450 i soenzymes: 1A2, 2C9, 2D6, and 3A4.
6. Si de ef f ects
a. Mi l d, t r ansi ent di ar r hea, and i nsomni a
b. Si ber i an gi nseng may l ower bl ood gl ucose.
c. Tachycar di a, hyper t ensi on, pal pi t at i ons.
7. Dosage. Two capsul es ( each capsul e cont ai ni ng 400-500 mg of powder ed root )
t hr ee t i mes dai l y f or a t ot al of 2- 3 g dai l y. Sol i d concent rat ed ext r act st andar di zed
on el eut her osi des B and E 300- 400 mg dai l y ar e recommended. Recommended not
t o use l onger t han 3 weeks.
L. Mi I k t hi st I e ( Si l ybum mari anum)
1. Commi ssi on E i ndi cat i ons. Chr oni c i nf l ammat or y l i ver condi t i ons and ci r rhosi s
2. Mechani sm of act i on
a. Mi l k t hi st l e produces ant i oxi dant s, such as si l ybi n.
b. Ì t st i mul at es t he act i vi t y of RNA pol ymer ase A.
c. Ì t al t ers t he out er l i ver membrane cel l st r uct ure.
3. Ef f i cacy. Ì n an eval uat i on of 13 t r i al s f or t he ef f i cacy of mi l k t hi st l e i n t he
t r eat ment of al cohol i c and/ or hepat i t i s B or C vi rus l i ver di seases, mi l k t hi st l e had
no si gni f i cant ef f ect on over al l mor t al i t y, compl i cat i ons of l i ver di sease, or l i ver
hi st ol ogy ( Cochrane Dat abase of Syst emat i c Revi ews) . Li ver - r el at ed mort al i t y was
si gni f i cant l y r educed wi t h mi l k t hi st l e
P. 732

when al l t r i al s wer e eval uat ed but was not si gni f i cant l y r educed when onl y hi gh-
qual i t y t ri al s wer e eval uat ed.
4. Cont rai ndi cat i ons/ precauti ons
a. Avoi d i n pregnancy.
b. Al l er gy t o chr ysant hemums
c. Hormone-sensi t i ve cancers
5. Drug i nt eract i ons
a. Mi l k t hi st l e may i nhi bi t cyt ochrome P450 2C9 and 3A4.
b. Mi l k t hi st l e does not i nt er act wi t h i ndi navi r ( Cri xi van) .
6. Si de ef f ects i ncl ude di ar r hea and ot her gast r oi nt est i nal r eact i ons (nausea,
dyspepsi a, f l at ul ence) and al l er gi c react i ons
7. Dosage. Recommended dose of mi l k t hi st l e i s 200-400 mg/ day di vi ded i nt o t hr ee
doses usi ng a st andar di zed product t hat i ncl udes 70%-80% si l ymar i n.
M. Saw paI met to ( Serenoa repens)
1. Commi ssi on E i ndi cat i ons. Tr eat ment of mi ct ur i t i on di f f i cul t i es associ at ed wi t h
beni gn pr ost at i c hyper pl asi a
2. Mechani sm of act i on
a. Saw pal met t o i nhi bi t s di hydrot est ost er one t o andr ogen r ecept ors i n prost at e
cel l s.
b. Ì t may i nhi bi t t est ost er one-5- q- r educt ase, t he enzyme responsi bl e f or t he
conversi on of t est ost erone t o di hydr ot est ost er one.
3. Ef f i cacy. A r andomi zed, mul t i cent er st udy eval uat ed 1069 men wi t h moderat e
beni gn pr ost at i c hyper pl asi a who r ecei ved saw pal met t o 160 mg t wi ce dai l y or
f i nast er i de 5 mg dai l y f or 6 mont hs. Ther e was no si gni f i cant di f f er ence bet ween
saw pal met t o and f i nast er i de ( Pr oscar ) f or t he pat i ent s' sel f - r at ed qual i t y- of - l i f e
scor e and t he Ì nt ernat i onal Pr ost at e Sympt om scor e ( Car r aro et al . ) .
4. Cont rai ndi cat i ons/ precauti ons
a. Avoi d i n pregnancy
b. Avoi d i n chi l dr en
c. Di scont i nue 2 weeks bef ore sur ger y
5. Drug i nt eract i ons
a. Theoret i cal l y, saw pal met t o may i nt eract wi t h ant i coagul ant s or ant i pl at el et s.
b. Theoret i cal l y, saw pal met t o may i nt eract wi t h cont r acept i ve dr ugs or hor mone-
r epl acement t herapy.
6. Si de ef f ects
a. Ì nt r aoperat i ve hemorrhage
b. Headache
c. St omach upset
d. Acut e hepat i t i s and pancreat i t i s
7. Dosage. Recommended 1-2 g saw pal met t o or 320 mg of l i pophi l i c ext r act dai l y,
usual l y gi ven 160 mg t wi ce dai l y and t aken wi t h f ood. Pr oduct s st andar di zed t o
cont ai n 90% f r ee and 7% est er i f i ed f at t y aci ds are r ecommended.
N. St . John' s wort ( Hyperi cum perforat um)
1. Commi ssi on E i ndi cat i ons. Ì n suppor t i ve t r eat ment f or anxi et y and depr essi on
2. Mechani sm of act i on
a. Act i ve i ngr edi ent s i ncl ude hyperi ci n, pseudohyper i ci n, quercet i n, querci t r i n,
i soquer ci t r i n, hyper osi de, r ut i n, ament of l avone, hyper i n, hyperf ori n, adhyper f ori n,
and xant hones.
b. Hyperi ci n, f l avonoi ds, and xant hones show i n vi t r o i rr eversi bl e monoami ne
oxi dase i nhi bi t or ( MAOÌ ) t ype A and B act i vi t y.
c. St . John' s wor t may i nhi bi t ser ot oni n r eupt ake.
d. St . John' s wor t may i nhi bi t synapt i c v- ami nobut yr i c aci d ( GABA) upt ake and
GABA- r ecept or bi ndi ng.
P. 733


e. Ì t may r educe cyt oki ne expr essi on, such as i nt er l euki n 6. Thi s may be hel pf ul i n
depressi on because i nt er l euki ns may i nduce depr essi on.
3. Ef f i cacy. An eval uat i on of 37 t r i al s f or t he ef f i cacy of St . John' s wor t i n t he
t r eat ment of depressi on showed t he herb may be more ef f ect i ve t han pl acebo f or
mi l d t o moder at e depressi on ( Cochrane Dat abase of Syst emat i c Revi ews) . St .
John' s wor t may be as ef f ect i ve as ot her ant i depressant s f or mi l d t o moder at e
depressi on. St . John' s wor t may not be ef f ect i ve f or maj or depressi on.
4. Cont rai ndi cat i ons/ precauti ons
a. Caut i on i n f ai r -ski nned persons when exposed t o br i ght sunl i ght
b. Caut i on i n pr egnancy ( emmenagogue and abort i f aci ent )
c. No negat i ve i nf l uence on gener al per f ormance or t he abi l i t y t o dr i ve a car or
operat e heavy machi nery has been report ed.
d. Psychi at r i c condi t i ons such as bi pol ar , schi zophr eni a may be exacerbat ed.
e. Hypot hyr oi di sm
f . Anest hesi a. St . John' s wor t may cause cardi ovascul ar col l apse.
g. Ì nf er t i l i t y. St . John' s wor t may i nhi bi t oocyt e f er t i l i zat i on and al t er sper m DNA.
5. Drug i nt eract i ons
a. Ant i depressant s such as par oxet i ne ( Paxi l ) , ser t r al i ne ( Zol of t ) , and nef azodone
have been r epor t ed t o cause ser ot oni n syndrome when t aken wi t h St . John' s wor t .
b. Ant i r et r ovi ral (pr ot ease i nhi bi t or s and nonnucl eosi de r everse t r anscr i pt ase
i nhi bi t ors) l evel s may decr ease.
c. St . John' s wor t may decr ease t he ef f i cacy of bar bi t ur at es.
d. St . John' s wor t may i ncr ease t he ef f i cacy of cl opi dogrel ( Pl avi x) .
e. Cycl ospori ne ( Sandi mmune) l evel s may decrease.
f . St . John' s wor t may i nt er act wi t h ot her dr ugs met abol i zed t hr ough t he cyt ochrome
P450 i soenzymes 1A2, 2C9, and 3A4.
g. Di goxi n ( Lanoxi n) l evel s may decr ease.
h. Ì ri not ecan ( Campt osar) and i mat i ni b ( Gl eevec) l evel s may decrease.
i . Met hadone ( Dol ophi ne) l evel s may decr ease.
j . St . John' s wor t may decr ease t he ef f i cacy of omeprazol e ( Pr i l osec) .
k. Or al cont racept i ves may have a decreased ef f ect .
I . St . John' s wor t may decr ease t he ef f i cacy of HMG coenzyme r educt ase i nhi bi t ors.
m. Tacrol i mus ( Prograf ) l evel s may decrease.
n. Theophyl l i ne l evel s may decr ease.
o. Theoret i cal l y, St . John' s wor t may i nt eract wi t h t he t ri pt ans.
p. Verapami l ( Cal an, Cover a- HS, Ì sopt i n, Ver el an) l evel s may decr ease.
q. St . John' s wor t may decr ease t he Ì NR of war f ar i n ( Coumadi n) .
r. Ser ot oner gi c Agent s, such as dext r omet horphan, f enf l urami ne, nar cot i cs.
6. Food i nt eract i ons
a. Ol der st udi es suggest ed t hat St . John' s wor t was an MAOÌ ( Suzuki et al . ) .
b. Newer st udi es suggest St . John' s wor t i s a weak MAOÌ ( Mul l er et al . ) .
c. One case r epor t publ i shed of MAO- t ype f ood i nt er act i ons such as t yr ami ne-
cont ai ni ng f oods: cheeses, beer, wi ne, her ri ng, and yeast .
7. Si de ef f ects
a. Phot odermat i t i s
b. Gast r oi nt est i nal i r r i t at i ons
c. Al l ergi c r eact i ons
d. Ti r edness
e. Rest l essness
f . El evat ed t hyr oi d-st i mul at i ng hormone
g. El evat ed bl ood pressur e
h. Mani a or hypomani a
i . May cause i nf er t i l i t y
8. Dosage. Recommended 2-4 g dai l y i n t wo t o t hr ee di vi ded doses. St andar di zed
pr oduct s cont ai ni ng 0. 4-2. 7 mg hyperi ci n/ day or 0. 3% hyperi ci n ar e r ecommended.
P. 734


O. VaI eri an ( Val eri ana of f i ci nal i s)
1. Commi ssi on E i ndi cat i ons. Rest l essness and ner vous di st urbance of sl eep
2. Mechani sm of act i on
a. Several act i ve compounds have been i sol at ed f r om val er i an and gr ouped i nt o
t hr ee cat egori es: vol at i l e oi l , val epot r i at es, and al kal oi ds. Ì t i s bel i eved t hat t he
sedat i ve act i vi t y of val eri an i s secondar y t o t he val epot ri at es.
b. Val epot r i at es, val eranone 6, kessane der i vat i ves 3a- f , val er eni c aci d 5a, and
val er enal 5b have been repor t ed t o pr ol ong bar bi t ur at e- i nduced sl eepi ng t i me.
c. Val ereni c aci d 5a has been shown t o possess pent obar bi t al -l i ke cent ral
depressant act i vi t y r at her t han muscl e rel axant or neurol ept i c ef f ect s. Ì t has al so
been shown t o i nhi bi t t he enzyme t hat t r i ggers t he br eakdown of GABA.
d. Val t r at e and i soval t r at e have exhi bi t ed ant i depr essant proper t i es.
e. Di dr oval t r at e possesses a t ranqui l i zi ng abi l i t y si mi l ar t o t he benzodi azepi nes.
3. Ef f i cacy. A doubl e- bl i nd, randomi zed st udy i ncl uded ei ght vol unt eers suf f er i ng
f r om mi l d i nsomni a who r ecei ved val eri an aqueous ext r act 450 mg or 900 mg or
pl acebo at bedt i me. Val er i an 450 mg si gni f i cant l y i mpr oved sl eep qual i t y, sl eep
l at ency, and sl eep dept h compar ed t o pl acebo. The 900-mg dose of f er ed no
advant age over t he 450-mg dose (Leat hwood et al . ) .
4. Cont rai ndi cat i ons/ precauti ons.
a. Caut i on whi l e dri vi ng or per f ormi ng ot her t asks r equi r i ng al er t ness and
coordi nat i on i s r ecommended.
b. Pr egnancy and l act at i on.
5. Drug i nt eract i ons.
a. CNS depressant s. Val er i an may pot ent i at e t he sedat i ve ef f ect of bar bi t ur at es,
benzodi azepi nes, opi at es, al cohol , or ot her sedat i ves.
b. Val er i an i nhi bi t s cyt ochr ome P450 3A4.
6. Si de ef f ects
a. Headaches, hangover , exci t abi l i t y, i nsomni a, uneasi ness, and car di ac
di st ur bances
b. Hepat ot oxi ci t y
c. Toxi ci t y i ncl udes at axi a, decreased sensi bi l i t y, hypot hermi a, hal l uci nat i ons, and
i ncreased muscl e r el axat i on
d. Pat i ent s may exper i ence a benzodi azepi ne- l i ke wi t hdr awal ; so doses shoul d be
t apered down sl owl y.
7. Dosage. Dr i ed root : 2- 3 g per cup, one t o t hree t i mes dai l y. St andar di zed t o
cont ai n 0. 8%-1% val eremi c aci ds/ dose ext r act : 400- 900 mg 30-60 mi n bef or e
bedt i me.
III. OTHER DIETARY SUPPLEMENTS THAT ARE
POTENTIALLY SAFE
A. Chondroi t i n
1. Nonapproved i ndi cati ons. Vi scoel ast i c agent i n opht hal mi c pr ocedur es and t he
t r eat ment of ost eoart hri t i s
2. Mechani sm of act i on
a. Ì t concent r at es i n cart i l age, where i t can be used i n t he synt hesi s of new
car t i l agi nous mat r i x.
b. Ì t i ncr eases t he RNA synt hesi s of chondrocyt es, whi ch may i ncrease t he
synt hesi s of pr ot eogl ycans and col l agens.
c. Ì t may i nhi bi t l eukocyt e el ast ase act i vi t y. Leukocyt e el ast ase i s f ound i n hi gh
concent r at i ons i n t he bl ood and synovi al f l ui d of pat i ent s wi t h r heumat i c di seases.
3. Ef f i cacy. A mul t i cent er , doubl e- bl i nd, randomi zed st udy i ncl uded 1583 pat i ent s
wi t h sympt omat i c knee ost eoar t hr i t i s who r ecei ved gl ucosami ne 1500 mg dai l y,
chondroi t i n 1200 mg dai l y, bot h gl ucosami ne and chondroi t i n, cel ecoxi b 200 mg
dai l y, or pl acebo f or 24 weeks. Gl ucosami ne and chondroi t i n sul f at e al one or i n
combi nat i on di d not si gni f i cant l y r educe pai n. The combi nat i on may be hel pf ul i n a
subgr oup of pat i ent s wi t h moderat e- t o-severe knee pai n ( Cl egg et al . ) .
P. 735


4. Cont rai ndi cat i ons/ precauti ons
a. Pr evi ous hyper sensi t i vi t y t o chondr oi t i n sul f at e
b. Bl eedi ng di sor ders
c. Use caut i on because chondroi t i n i s usual l y produced f r om bovi ne car t i l age
( possi bl e t ransmi ssi on of mad cow di sease)
d. Pr egnancy and l act at i on
e. Use caut i on i n ast hma
5. Drug i nt eract i ons
a. May i nt eract wi t h hepar i n
b. Theoret i cal l y, may i nt er act wi t h war f ari n ( Coumadi n)
6. Si de ef f ects. Nausea, epi gast r i c pai n, and headache
7. Dosage. Recommended: 400 mg t hr ee t i mes dai l y
B. Coenzyme Q10 ( ubi qui none or ubi decarenone)
1. Nonapproved i ndi cati ons. Heart f ai l ur e ( HF) , hyper t ensi on, st abl e angi na,
vent r i cul ar ar r hyt hmi as, cancer, hear t sur ger y, and per i odont al di sease
2. Mechani sm of act i on
a. Ì t i s a nat ur al l y occur ri ng coenzyme t hat has a pr edomi nant r ol e i n oxi dat i ve
phosphor yl at i on and synt hesi s of adenosi ne t r i phosphat e ( ATP) , whi ch i s needed f or
muscl e cont r act i on and rel axat i on.
b. Ì t may have ant i oxi dant proper t i es.
c. Ì t has been shown t o reduce myocar di al i nj ur y f r om i schemi a and t o r educe t oxi c
myocar di al damage f rom ant hr acycl i nes, such as doxor ubi ci n ( Adri amyci n).
3. Ef f i cacy
a. Heart f ai I ure. One r andomi zed, doubl e-bl i nd, pl acebo-cont r ol l ed, mul t i cent er
st udy i ncl uded 641 pat i ent s wi t h New Yor k Hear t Associ at i on cl ass Ì Ì Ì or Ì V chroni c
congest i ve hear t f ai l ur e who wer e r ecei vi ng convent i onal t r eat ment , such as di goxi n
( Lanoxi n) , di ur et i cs, angi ot ensi n- conver t i ng enzyme ( ACE) i nhi bi t or s, and cal ci um-
channel bl ocker s ( Mor i sco et al . ) . Pat i ent s r ecei ved coenzyme Q10 2 mg/ kg/ day f or 1
year or pl acebo. The number of pat i ent s r equi ri ng hospi t al i zat i on secondar y t o
congest i ve HF was l ess i n t he coenzyme Q10 gr oup ( n = 73) versus pl acebo ( n =
118) ; si gni f i cance: p < . 001. Epi sodes of pul monar y edema and car di ac ast hma wer e
r educed wi t h coenzyme Q10 ( p < . 001) .
b. St udi es suggest t hat t her e i s a 20-50% r educt i on i n ser um l evel s of coenzyme
Q10 i n hyperchol est er ol emi c pat i ent s af t er a st at i n has been i ni t i at ed. The r educt i on
i n coenzyme Q10 concent r at i on i s bel i eved t o be dose r el at ed. However , i t i s st i l l
uncer t ai n how much st at i ns af f ect muscl e coenzyme Q10 concent r at i ons. Muscl e
coenzyme Q10 may af f ect st at i n- i nduced myopat hy ( Nawar skas) .
c. Several st udi es have eval uat ed t he ef f ect of coenzyme Q10 suppl ement at i on i n
pat i ent s t aki ng st at i ns. When coenzyme Q10 i s gi ven 30- 300 mg per day, coenzyme
Q10 ser um concent r at i ons si gni f i cant l y el evat e. However , t hi s el evat i on has not been
eval uat ed t o see whet her i t cor rel at es t o decreasi ng st at i n- r el at ed si de ef f ect s
( Nawar skas) .
4. Cont rai ndi cat i ons/ precauti ons
a. Bi l i ar y obst ruct i on
b. Di abet es mel l i t us (hypogl ycemi a)
c. Hepat i c i nsuf f i ci ency
d. Renal i nsuf f i ci ency
e. Hyper and hypot ensi on
f . Pr egnancy and l act at i on
5. Drug i nt eract i ons
a. Hypol i pi demi c agent s l ower pl asma concent rat i ons of coenzyme Q10.
b. Or al hypogl ycemi c agent s pot ent i al l y i nhi bi t ef f ect s of exogenous admi ni st r at i on.
c. Doxor ubi ci n t oxi ci t y may be i ncr eased.
d. Ant i hyper t ensi ves (addi t i ve ef f ect )
e. War f ari n. Coenzyme Q10 i s st r uct ural l y r el at ed t o vi t ami n K2 so may have
coagul ant ef f ect s.
P. 736


6. Si de ef f ects
a. Rash and gast roi nt est i nal di st ur bances, such as nausea, anor exi a, epi gast ri c
pai n, and di ar r hea
b. El evat i ons of ser um ami not r ansf erases have occur r ed wi t h r el at i vel y hi gh oral
doses.
7. Dosage. Depends on i ndi cat i on: 100 mg dai l y, up t o 3000 mg dai l y i n 2-3 di vi ded
doses.
C. GI ucosami ne
1. Nonapproved i ndi cati on. Ost eoar t hr i t i s
2. Mechani sm of act i on
a. Gl ucosami ne enhances car t i l age pr ot eogl ycan synt hesi s.
b. Ì t i nhi bi t s t he det er i orat i on of car t i l age secondar y t o ost eoar t hri t i s.
c. Ì t mai nt ai ns an equi l i br i um bet ween car t i l age cat abol i c and anabol i c processes.
d. Ì t may have an ant i - i nf l ammat or y act i on unl i ke cycl ooxygenase.
3. Ef f i cacy. A doubl e- bl i nd t ri al i ncl uded 40 pat i ent s wi t h uni l at eral ost eoar t hri t i s of
t he knee. Pat i ent s wer e gi ven gl ucosami ne 500 mg t hr ee t i mes dai l y or i buprof en
400 mg t hree t i mes dai l y f or 8 weeks. Pai n scores decreased f ast er dur i ng t he f i r st
2 weeks i n t he i bupr of en gr oup t han i n t he gl ucosami ne gr oup. No si gni f i cant
di f f er ence i n swel l i ng was obser ved bet ween t he t wo gr oups ( Vaz) .
4. Cont rai ndi cat i ons/ precauti ons
a. Hypersensi t i vi t y t o gl ucosami ne or shel l f i sh
b. Di abet es. Gl ucosami ne may i mpai r i nsul i n secret i on.
c. Pr egnancy and l act at i on
d. Ast hma
5. Drug i nt eract i ons
a. Fl uoxet i ne ( Prozac) may i ncr ease gl ucosami ne serum concent rat i ons.
b. Gl ucosami ne may i nt er act wi t h ant i di abet i c agent s.
c. Gl ucosami ne may i nduce r esi st ance t o ant i mi t ot i c chemot herapy ( et oposi de-
VePesi d), doxor ubi ci n) .
d. Theoret i cal l y, gl ucosami ne may i nt eract wi t h war f ari n.
6. Si de ef f ects
a. Gast r oi nt est i nal si de ef f ect s such as epi gast r i c pai n and t ender ness, hear t bur n,
di ar rhea, and nausea
b. Cent r al ner vous syst em si de ef f ect s such as dr owsi ness, headache, and i nsomni a
c. Long-t erm si de ef f ect s ar e unknown.
d. El evat ed bl ood gl ucose
7. Dosage. Recommended: 500 mg t hr ee t i mes dai l y
D. MeI at oni n
1. Orphan drug stat us. Tr eat ment of ci rcadi an rhyt hm sl eep di sor ders i n bl i nd
peopl e who have no l i ght percept i on
2. Nonapproved i ndi cati ons. Jet l ag, i nsomni a, depressi on, and cancer
3. Mechani sm of act i on
a. Ì t i s a hormone made f r om ser ot oni n and secr et ed by t he pi neal gl and. Mel at oni n
cont r ol s t he peri ods of sl eepi ness and wakef ul ness.
b. Ì t may possess ant i oxi dant pr opert i es.
4. Ef f i cacy
a. Jet I ag. A r andomi zed, pl acebo-cont r ol l ed t r i al eval uat ed t he ef f ect of mel at oni n
i n 52 ai r cr af t per sonnel . Mel at oni n was gi ven ei t her 5 mg dai l y 3 days bef or e
depar t ure unt i l 5 days af t er arr i val ( ear l y group) or 5 mg dai l y upon ar ri val and f or 3
addi t i onal days (l at e group) . The l at e gr oup had si gni f i cant l y l ess j et l ag, f ewer
over al l sl eep di st urbances, and a f ast er r ecover y of energy compar ed t o t he pl acebo
gr oup and t he earl y gr oup ( Pet ri e et al . ) .
b. I nsomni a. A met a- anal ysi s on 17 randomi zed, doubl e- bl i nd, pl acebo-cont r ol l ed
t r i al s t hat eval uat ed t he sl eep ef f ect of mel at oni n i n subj ect s showed t hat mel at oni n
si gni f i cant l y decr eased t i me t o sl eep onset , i ncreased sl eep ef f i ci ency, and
i ncreased t ot al sl eep
P. 737

dur at i on compared t o pl acebo ( Br zezi nski et al . ). Unf or t unat el y, mel at oni n
pr epar at i ons wer e vari ed and st udy desi gns di f f ered.
c. Chi I dren. Mel at oni n may be ef f ect i ve i n decreasi ng t he t i me t o sl eep onset i n
chi l dren wi t h neur odevel opment al di sabi l i t i es. Mel at oni n does not i mprove t ot al
sl eep t i me or ni ght t i me awakeni ngs ( Phi l l i ps et al . ) .
5. Cont rai ndi cat i ons/ precauti ons
a. Avoi d i n pregnancy and l act at i on
b. Mel at oni n may aggr avat e depressi ve sympt oms.
c. Mel at oni n may i ncr ease t he i nci dence of sei zur es.
d. Di abet es ( hyper gl ycemi a)
e. Hyper t ensi on (exacerbat ed)
f . Caut i on whi l e dri vi ng or per f ormi ng ot her t asks r equi r i ng al er t ness and
coordi nat i on.
6. Drug i nt eract i ons
a. Vi t ami n B12 i nf l uences mel at oni n secr et i on. Low l evel s of vi t ami n B12 wi l l pr oduce
l ow l evel s of mel at oni n.
b. MAOÌ s may i ncrease mel at oni n ser um concent r at i ons.
c. Sel ect i ve ser ot oni n r eupt ake i nhi bi t or s may i ncr ease mel at oni n ser um
concent r at i ons.
d. 8- Bl ockers may decrease noct ur nal secr et i on of mel at oni n.
e. Ot her sedat i ves may exacer bat e t he sedat i ve ef f ect s of mel at oni n.
f . Mel at oni n may i nt er act wi t h i mmunosuppr essant s.
g. Ant i di abet i c agent s may be l ess ef f ect i ve.
h. Ant i coagul ant s and ant i pl at el et s (i ncr eased ef f ect )
i . Caf f ei ne (t heor et i cal l y, ef f i cacy of mel at oni n may be decr eased)
j . Cont r acept i ves ( t heoret i cal l y, ef f i cacy of mel at oni n may be i ncr eased)
k. Verapami l (i ncr eased mel at oni n excr et i on)
7. Si de ef f ects
a. Si de ef f ect s i ncl ude dr owsi ness, dayt i me f at i gue, headache, and t r ansi ent
depressi on.
b. Long-t erm si de ef f ect s are unknown.
8. Dosage. 0. 3- 5 mg at bedt i me
P. 738


STUDY QUESTIONS
Di rect i ons for quest i ons: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s can be cor r ect l y answer ed or compl et ed by one of t he suggest ed
answer s or phr ases. Choose t he best answer .
1. Whi ch of the foI I owi ng herbs i s known to cause cancer?
( A) chapar r al
( B) comf rey
( C) Ma huang
( D) l i cori ce
( E) St . John' s wor t
Vi ew Answer 1. The answer i s B[ see] . 2. Whi ch of t he f oI I owi ng i s a
correct st atement ?
( A) Di et ar y suppl ement s must be proven saf e and ef f ect i ve bef ore market i ng i n t he
Uni t ed St at es.
( B) The f ol l owi ng st at ement i s opt i onal f or l abel i ng of herbal product s: " Thi s pr oduct
has not been eval uat ed by t he FDA. Ì t i s not i nt ended t o di agnose, t r eat , cur e, or
pr event . ¨
( C) Her bs must be st andar di zed t o be consi der ed di et ar y suppl ement s.
( D) Di et ar y suppl ement manuf act ur ers may cl ai m t hat t hei r pr oduct s af f ect t he
st r uct ur e and f unct i on of t he human body.
Vi ew Answer 2. The answer i s D[ see] . 3. Tom wouI d I i ke t o t r y echi nacea
t o prevent coI ds and f I us duri ng the wi nt er mont hs. Whi ch of t he f oI I owi ng
st at ements i s t rue about echi nacea?
( A) Ì t i s cont rai ndi cat ed i n pat i ent s al l ergi c t o parsl ey.
( B) Ì t shoul d be t aken cont i nuousl y onl y f or 3 mont hs.
( C) Ì t i s cont r ai ndi cat ed i n pat i ent s wi t h l upus and l eukosi s.
( D) Pr ol onged use of echi nacea wi l l upregul at e t he i mmune syst em.
( E) Si de ef f ect s i ncl ude headache, r ash, and di zzi ness.
Vi ew Answer 3. The answer i s C[ see] . 4. Mar y has a f ami I y hi st or y of heart
di sease and wonders i f garI i c wouI d be benef i ci aI t o her. Whi ch of t he
f oI I owi ng stat ements i s correct about garI i c?
( A) Ent er i c- coat ed t abl et s r el ease t hei r cont ent s i n t he st omach.
( B) Si de ef f ect s i ncl ude hear t burn, f l at ul ence, and sweat i ng.
( C) The saf et y of gar l i c i n pr egnancy i s unknown.
( D) Gar l i c does not i nt eract wi t h war f ar i n.
Vi ew Answer 4. The answer i s B[ see] . 5. An 80-year- oI d man t akes warf ari n
f or hi s mechani caI heart vaI ve. He wouI d aI so I i ke to t ake the foI I owi ng herbs:
Asi an gi nseng, f everfew, garI i c, and dong quai . Whi ch of t he t hese herbs may
decrease t he ef fect i veness of warf ari n?
( A) Asi an gi nseng
( B) f ever f ew
( C) met r oni dazol e
( D) garl i c
( E) dong quai
Vi ew Answer 5. The answer i s A[ see] . 6. A 30- year- oI d f emaI e i s 10 weeks
pregnant wi t h her second chi I d. Duri ng her f i rst pregnancy, she became
depressed and was st art ed on Prozac 20 mg ever y day. She i s aI ready
begi nni ng t o not i ce earI y sympt oms of depressi on duri ng her second
pregnancy. She wouI d I i ke to t r y St . John' s wort f or her depressi on. Whi ch of
t he f oI I owi ng stat ements i s correct regardi ng St . John' s wort ?
( A) The saf et y of St . John' s wor t i n pregnancy i s unknown.
( B) St . John' s wor t i s not hel pf ul i n t reat i ng mi l d depressi on.
( C) St . John' s wor t may i nt er act wi t h ser ot oni n reupt ake i nhi bi t or s.
( D) St . John' s wor t may i nt er act wi t h dai r y product s l i ke mi l k and eggs.
Vi ew Answer 6. The answer i s C[ see] . 7. A 65- year- oI d i s i nterested i n
t aki ng gi nkgo. Whi ch of t he foI I owi ng st atement s i s correct regardi ng gi nkgo?
( A) Ther e ar e no cont r ai ndi cat i ons wi t h gi nkgo.
( B) Ther e i s a dr ug-herb i nt er act i on bet ween gi nkgo and aspi ri n.
( C) Toxi c ef f ect s i ncl ude hyper t ensi on and cardi ac ar rest .
( D) Ther e i s a drug-her b i nt er act i on bet ween gi nkgo and phenel zi ne.
( E) Gi nkgo i s cont r ai ndi cat ed i n pat i ent s wi t h gal l st one pai n.
Vi ew Answer 7. The answer i s B[ see] . P. 739


8. A 20- year- oI d at hI eti c man wouI d I i ke to t ake Asi an and Si beri an gi nseng t o
i ncrease hi s physi caI st ami na. Hi s gi rI f ri end suggest ed t hat he ask a
pharmaci st about t he saf et y of Asi an and Si beri an gi nseng. Whi ch of t he
f oI I owi ng stat ements i s correct ?
( A) Si ber i an gi nseng may i nt eract wi t h phenel zi ne, war f ar i n, and di goxi n.
( B) Asi an gi nseng i s pot ent i al l y harmf ul i n pat i ent s wi t h aut oi mmune di seases.
( C) Asi an and Si ber i an gi nseng are t he same gi nseng but gr own i n di f f erent
count r i es.
( D) Asi an and Si ber i an gi nseng shoul d be avoi ded i n pat i ent s wi t h hyper t ensi on.
Vi ew Answer 8. The answer i s D[ see] . P. 740


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì . B. 1] .
Comf rey may be carci nogeni c. Chapar ral may be hepat ot oxi c. Hi gh doses of l i cor i ce
f or l ong per i ods may cause pseudoal dost eroni sm. Ma huang may cause myocar di al
i nf ar ct i on, st r okes, or sei zur es. St . John' s wor t has many dr ug i nt eract i ons.
2. The answer i s D [ see Ì . A. 3] .
The Di et ar y Suppl ement Heal t h and Educat i on Act of 1994 st at es t hat di et ar y
suppl ement s are not consi der ed drugs or f ood. Si nce di et ar y suppl ement s ar e not
r egul at ed as dr ugs, t hei r saf et y and ef f i cacy are not mandat ed by t he FDA. Di et ar y
suppl ement s are i nt ended t o suppl ement t he di et , do not have t o be st andar di zed,
may make cl ai ms regardi ng onl y t he ef f ect s on st ruct ur e or f unct i on of t he body. The
f ol l owi ng i s t he cor r ect requi r ed l abel i ng st at ement : " Thi s pr oduct has not been
eval uat ed by t he FDA. Ì t i s not i nt ended t o di agnose, t r eat , cure, or prevent . ¨
3. The answer i s C [ see Ì Ì . E. 4] .
Echi nacea i s cont r ai ndi cat ed i n i nf ect i ous and aut oi mmune di seases such as
t ubercul osi s, l eukosi s, col l agenosi s, mul t i pl e scl er osi s, AÌ DS, HÌ V, and l upus.
Caut i on shoul d be used i n pat i ent s who are al l ergi c t o member s of t he r agweed
f ami l y. Therapy shoul d not exceed 8 weeks. Theor et i cal l y, prol onged use of
echi nacea may depr ess t he i mmune syst em, possi bl y t hr ough over st i mul at i on. Si de
ef f ect s i ncl ude nausea, vomi t i ng, al l er gi c r eact i ons, anaphyl axi s, and i nt erf er ence
wi t h mal e f er t i l i t y.
4. The answer i s B [ see Ì Ì . G. 4] .
Gar l i c shoul d be avoi ded i n pr egnancy because i t i s an emmenagogue and
abor t i f aci ent . Ì t may i nt er act wi t h ant i coagul ant s, i ncr easi ng t he r i sk of bl eedi ng.
Si de ef f ect s i ncl ude gast r oi nt est i nal di scomf or t ( hear t bur n, f l at ul ence) , sweat i ng,
l i ght headedness, al l er gi c r eact i ons, and menor r hagi a. Ent eri c-coat ed t abl et s or
capsul es al l ow mor e absor pt i on because t hey pass t hr ough t he st omach and rel ease
t hei r cont ent s i n t he al kal i ne medi um of t he smal l i nt est i ne.
5. The answer i s A [ see Ì Ì . J. 5] .
Asi an gi nseng may decrease t he Ì NR of war f ari n. Fever f ew, gar l i c, and dong quai
may i ncrease t he Ì NR of war f ar i n. Met r oni dazol e may i ncrease t he Ì NR, but i t i s not
consi dered t o be an her b.
6. The answer i s C [ see Ì Ì . N. 4] .
St . John' s wor t i s i ndi cat ed i n by Commi ssi on E f or depr essi on and anxi et y. St .
John' s wor t shoul d be avoi ded i n pr egnancy because i t i s an emmenagogue and
abor t i f aci ent . St . John' s wor t i nt eract s wi t h many medi cat i ons, i ncl udi ng ser ot oni n
r eupt ake i nhi bi t ors. Food i nt er act i ons may be si mi l ar t o t hose of t he MAOÌ s
( t yr ami ne-cont ai ni ng f oods: cheese, beer , wi ne, her r i ng, and yeast ) .
7. The answer i s B [ see Ì Ì . Ì . 5] .
Cont r ai ndi cat i ons and precaut i ons f or gi nkgo i ncl ude di abet es, epi l epsy, bl eedi ng
di sor der s, and i nf er t i l i t y. Gi nkgo may pot ent i at e t he bl eedi ng pr oper t i es of
ant i pl at el et s. Si de ef f ect s i ncl ude gast r i c di st ur bances, headache, di zzi ness, and
ver t i go. Toxi c i ngest i on may produce t oni c- cl oni c sei zur es and l oss of
consci ousness.
8. The answer i s D [ see Ì Ì . J. 4; Ì Ì . K. 4] .
Asi an gi nseng' s cont r ai ndi cat i ons i ncl ude pat i ent s wi t h hyper t ensi on. Asi an gi nseng
may i nt eract wi t h phenel zi ne, pr oduci ng hal l uci nat i ons and psychosi s; may decr ease
t he Ì NR of war f ar i n; and may i nt erf er e wi t h i mmunosuppr essant s. Si beri an gi nseng' s
cont r ai ndi cat i ons/ precaut i ons i ncl ude hyper t ensi on. Ì t may i nt er act wi t h
ant i coagul ant s and ant i hyper t ensi ves and may i nhi bi t cyt ochr ome P450 i soenzymes.
Asi an and Si ber i an gi nseng are not t he same pl ant and are not of t he same genus.

36
CIinicaI Pharmacokinetics and
Therapeutic Drug Monitoring
GeraI d E. Schumacher
I. INTRODUCTION
A. Obj ect i ves
1. Therapeut i c drug moni t ori ng ( TDM) i n a gener al sense i s about usi ng
ser um dr ug concent r at i ons ( SDCs) , phar macoki net i cs, and
pharmacodynami cs t o i ndi vi dual i ze and opt i mi ze pat i ent r esponses t o dr ug
t her apy.
2. TDM ai ms t o promot e opt i mum dr ug t r eat ment by mai nt ai ni ng SDC wi t hi n
a t herapeut i c range, above whi ch dr ug- i nduced t oxi ci t y occur s t oo of t en
and bel ow whi ch t he dr ug i s t oo of t en i nef f ect i ve.
B. Def i ni t i ons
1. Speci f i cal l y, TDM i s a pr act i ce appl i ed t o a smal l gr oup of dr ugs i n whi ch
t her e i s a di rect r el at i on bet ween SDCs and pharmacol ogi cal response, as
wel l as a nar r ow r ange of concent rat i ons t hat ar e ef f ect i ve and saf e and f or
whi ch SDCs ar e used i n conj unct i on wi t h ot her measur es of cl i ni cal
obser vat i on t o assess pat i ent st at us.
2. CI i ni caI pharmacoki net i cs, a t erm of t en used i nt er changeabl y wi t h
TDM, i s mor e gener al l y t he appl i cat i on of phar macoki net i c pr i nci pl es f or t he
r at i onal desi gn of an i ndi vi dual i zed dosage regi men.
3. For def i ni t i ons of t he t er ms used and t he concept s appl i cabl e i n basi c
and cl i ni cal pharmacoki net i cs, see Chapt er 6 on pharmacoki net i cs.
C. Rat i onaI e and reasons
1. The rati onaI e f or TDM makes t hree assumpt i ons.
a. Measuri ng pat i ent SDC pr ovi des an oppor t uni t y t o adj ust f or vari at i ons i n
pat i ent phar macoki net i cs by i ndi vi dual i zi ng drug dosage.
b. The SDC i s a bet t er pr edi ct or of pat i ent response t han i s dose.
c. Ther e i s a good rel at i on bet ween SDCs and phar macol ogi cal r esponse.
2. Reasons f or measuri ng SDC
a. Dr ug l evel s are used i n conj unct i on wi t h ot her cl i ni cal dat a t o assi st
pr act i t i oners i n det ermi ni ng how a pat i ent i s respondi ng.
b. Dr ug l evel s provi de a basi s f or i ndi vi duaI i zi ng pat i ent dosage r egi mens.
c. Dr ug l evel s assi st i n det ermi ni ng i f a change i n pat i ent - speci f i c
pharmacoki net i cs has occur red dur i ng a course of t r eat ment , ei t her as a
r esul t of a change i n physi ol ogi cal st at e, a change i n di et , or addi t i on of
ot her drugs.
d. Assuri ng drug compI i ance i s of t en ci t ed as a r eason f or measur i ng SDC,
but i t i s unrel i abl e f or t hi s pur pose. Ì n t r ut h, a noncompl i ant pat i ent may
out wi t pract i t i oner s by mani pul at i ng pr eappoi nt ment behavi or t o i nduce an
SDC t hat i s nonr ef l ect i ve of t he pat i ent ' s dr ug- t aki ng behavi or.
P. 742


II. APPLYING CLINICAL PHARMACOKINETICS IN
TDM
A. What t he pract i t i oner cont roI s and does not cont roI i n TDM
1. Fi gure 36- 1 shows t he r el at i on bet ween dose rat e of dr ug admi ni st ered,
pharmacoki net i c vari abl es, SDC, and pharmacol ogi cal r esponse.
2. Not e t hat t he onl y var i abl es t hat t he pr act i t i oner cont r ol s ar e t he amount
of drug admi ni st ered and how of t en i t i s gi ven. These var i abl es may be
mani pul at ed t o compensat e f or t he pat i ent ' s pharmacoki net i c and
pharmacodynami c var i abl es ( i . e. , bi oavai l abi l i t y, cl ear ance, st eady- st at e
SDC, phar macol ogi cal r esponse) , whi ch t he pr act i t i oner does not cont rol , t o
achi eve some desi gnat ed SDC t hat yi el ds a pharmacol ogi cal response
usual l y obser ved wi t hi n t he drug' s commonl y accept ed t her apeut i c SDC
r ange.
B. The concept of t herapeut i c range
1. For many drugs, a speci f i c ser um concent r at i on r ange can be desi gnat ed
f or each drug t hat maxi mi zes ef f ect i veness and mi ni mi zes t oxi ci t y. The
r ange of SDC i s cal l ed t he t herapeut i c range f or t he dr ug.
2. The not i on of a t her apeut i c range i s more a probabi I i sti c concept t han
an absol ut e ent i t y. Ì t i s pr obabl e t hat t he maj ori t y of pat i ent s wi l l show
ef f ect i ve and saf e r esponses wi t hi n t he t herapeut i c r ange. However , a
mi nor i t y of pat i ent s wi l l need SDC above or bel ow t he upper or l ower l i mi t s,
r espect i vel y, of t he t her apeut i c r ange t o achi eve an ef f ect i ve r esponse.
Si mi l arl y, a mi nori t y of pat i ent s wi l l not show t oxi ci t y at SDC modest l y
above t he t her apeut i c r ange, wher eas ot hers wi l l show t oxi ci t y bel ow t he
t her apeut i c range.
3. Ther ef or e, TDM i s about i ndi vi duaI i zi ng pat i ent dosage r egi mens t o
achi eve SDC wi t hi n pat i ent -speci f i c t her apeut i c ranges f or a drug. Mor e
of t en t han not , a pat i ent -speci f i c r ange wi l l f al l wi t hi n t he general l y st at ed
t her apeut i c range.
C. The concept of popuI at i on pharmacoki neti c vaI ues
1. A popuI at i on pharmacoki net i c vaI ue or paramet er ref er s t o t he mean
( aver age) val ue not ed f or a gi ven cohor t of peopl e ( e. g. , adul t s 20- 60 year s
of age, pat i ent s wi t h a def i ned range of renal i mpai rment ) . Usual l y, t hi s
popul at i on val ue i s normal i zed on a wei ght basi s ( e. g. , t heophyl l i ne vol ume
of di st r i but i on i n adul t nor mal s of 0. 5 L/ kg). When a popul at i on par amet er i s
st at ed wi t hout def i ni ng t he t ar get popul at i on, i t usual l y r ef ers t o adul t s;
f ur t her , when t he val ue al so i s not normal i zed (e. g. , vol ume of di st r i but i on
of t heophyl l i ne of 35 L) , i t usual l y ref ers t o adul t s of aver age wei ght
( approxi mat el y 60-80 kg).
2. Hardl y anyone i s average. Ì ndi vi dual val ues of t he popul at i on st udi ed ar e
summed t o det ermi ne a mean val ue t hat i s t hen repor t ed as t he popuI at i on
vaI ue. Ì ndi vi dual i zi ng pat i ent dosage r egi mens t akes t hi s i nt o account by
adj ust i ng obser ved pat i ent - speci f i c val ues and r esponses t o expect ed
popul at i on measures.
3. So t he pract i t i oner st ar t s t he det er mi nat i on of a pat i ent -speci f i c dosage
r egi men by assumi ng t hat t he pat i ent behaves l i ke t he average member of
hi s or her popul at i on wi t h r espect t o
P. 743

pharmacoki net i cs, serum l evel , and expect ed r esponse, and uses
popul at i on pharmacoki net i c paramet ers t o cal cul at e t he dosage r egi men
needed t o meet t he desi red SDC obj ect i ve.

Figure 36-1. Pharmacokinetic Iactors inIluencing
serum drug concentration and pharmacological
response. Bioavailability is I. clearance is Cl.
steady-state serum drug concentration is C
ss
. D is
dose. and t is Irequency oI administration oI
dose.
4. Ì f af t er admi ni st er i ng t he dosage r egi men unt i l st eady st at e i s reached,
based on usi ng popul at i on val ues, t he pat i ent i s r espondi ng appropr i at el y,
t hen no adj ust ment i n r egi men i s necessar y.
5. Ì f , however , t he st ar t i ng assumpt i on of usi ng aver age val ues t urns out t o
be i ncor r ect , because t he pat i ent ' s r esponse i s ei t her subt herapeut i c or
t oxi c due t o pat i ent -speci f i c pharmacoki net i c and/ or pharmacodynami c
val ues t hat ar e at ypi cal f or t he popul at i on, t he pract i t i oner ' s onl y opt i on
( except f or changi ng t he dr ug) i s t o mani pul at e t he pr act i t i oner - cont rol l ed
i nput var i abl es, dose and f requency, t o br i ng t he phar macol ogi cal
r esponse wi t hi n t he desi r ed range.
D. Ti mi ng of SDC measurement s
1. SDCs ar e somet i mes measured earI y i n a course of t herapy, bef or e
st eady st at e i s reached, t o det ermi ne pat i ent - speci f i c phar macoki net i c
par amet er s, r at her t han r el yi ng on popul at i on val ues.
2. Mor e commonl y, SDCs are measured duri ng a st eady- st at e dosage
i nt ervaI (¡s s ) , because t he obj ect i ve i s t o det ermi ne i f t he SDC i s wi t hi n a
desi r ed t her apeut i c r ange, a r ange t hat has pr evi ousl y been det er mi ned
al most i nvar i abl y dur i ng ¡s s .
3. Because SDCs ar e most commonl y measur ed at st eady st at e and
r ef erenced t o val ues obt ai ned at st eady st at e, i t i s necessar y t o wai t af t er
st art i ng drug admi ni st r at i on unt i l at l east t hree t o f our assumed hal f - l i f e
( t 1/ 2) val ues (88%- 94% of r eachi ng f ul l st eady st at e) so t hat SDC wi l l be
measured duri ng a per i od when st eady st at e may be assumed, f or cl i ni cal
pur poses, t o have been reached or appr oxi mat ed ( e. g. , appr oxi mat el y 90%
of st eady st at e or gr eat er ; so f or an assumed t 1/ 2 of 6 hour s, wai t 18- 24
hours af t er i ni t i at i ng dr ug t r eat ment t o measur e SDC) .
4. Ì f t her e ar e no changes i n pat i ent r esponse, t her e i s usual l y no need to
t ake subsequent dai I y SDC measurements, once an appropri at e SDC has
been achi eved. Onl y i f somet hi ng occurs t hat may be expect ed t o al t er t he
pat i ent ' s pharmacoki net i c val ues ( e. g. , co- admi ni st r at i on of anot her
pot ent i al l y modi f yi ng dr ug, change i n physi ol ogi cal st at e) , ar e f r equent
measurement s necessary.
5. Ì f a st eady- st at e SDC ( Cs s ) i s used appr opr i at el y t o rel at e a pat i ent ' s Css
t o a popul at i on or pat i ent - speci f i c t herapeut i c range, t hen i t i s i mpor t ant t o
not e when dur i ng t he st eady- st at e dosage i nt er val ( ¡s s ) t he Cs s was
measured i n st udi es det er mi ni ng t he t her apeut i c r ange. Ì n ot her wor ds, i s
t he t herapeut i c range t he pr act i t i oner i s usi ng as a basi s f or i ndi vi dual i zi ng
r egi mens based on Cs s measured earI y ( appar ent Cmax, ss) , near t he
mi dpoi nt (appar ent Cavg, ss) , or near t he end ( appar ent Cmi n, ss) of ¡ss?
6. Errors i n i nt er pret at i on occur when Cs s f or a pat i ent i s measur ed at a
t i me dur i ng ¡s s t hat i s mar kedl y di f f erent t han t he t i me used f or est abl i shi ng
t he t herapeut i c range [ e. g. , measuri ng Cs s i n a pat i ent 1 hour af t er gi vi ng a
dose on a q12h regi men when t he Css f or t he r ef er enced t herapeut i c r ange
was act ual l y t aken at t he end of ¡s s ( Cmi n, ss) ] .
7. Er r or s i n t i mi ng of Cs s ar e of gr eat er concer n f or drugs wi t h a shor t t 1/ 2
t han f or dr ugs wi t h a l ong t 1/ 2. Cs s f l uct uat i on duri ng ¡s s i s much great er i n
t he f ormer t han t he l at t er case.
III. TDM DRUGS AND COMMON CHARACTERISTICS
A. TDM drugs
1. Dr ugs f or whi ch TDM i s commonl y used are not ed i n Tabl e 36- 1, al ong
wi t h t he popul at i on t herapeut i c r ange.
2. Dr ugs f or whi ch TDM i s i nf r equent l y used i n gener al si t uat i ons, but
per haps commonl y used by speci al t y pr act i t i oners or cl i ni cs, ar e not ed i n
Tabl e 36- 2.
B. Common charact eri st i cs of TDM drugs. Dr ugs t hat qual i f y f or TDM
have, as a mi ni mum, t he f ol l owi ng char act eri st i cs i n common.
P. 744


Table 36-1. Drugs Often Monitored Using Serum Drug Concentrations
Drug Therapeutic Range for C
ss

Amikacin C
max.ss
a
÷ 20-30 µg/mL; C
min.ss
·10 mcg/mL
Cyclosporine Varies with transplanted organ. time aIter transplant. time
oI sampling during dosage interval. and method oI
analysis
Digoxin 0.8-2
b
ng/mL
Gentamicin C
max.ss
a
÷ 5-10 µg/mL; C
min.ss
·2 mcg/mL
Phenytoin 10-20 µcg/mL
Theophylline 5-20 µcg/mL
Tobramycin C
max.ss
a
÷ 5-10 µg/mL; C
min.ss
·2 mcg/mL
Vancomycin C
max.ss
a
÷ 30-50 µg/mL; C
min.ss
÷ 5-10 mcg/mL
a
End oI 30- to 60-min inIusion.

b
Levels Ior atrial Iibrillation oIten exceed 2 ng/mL.

Table 36-2. Drugs Monitored Using Serum Drug Concentrations in Specialty
Situations
Amitriptyline
Carbamazepine
Indinavin
Lidocaine
Lithium
Methotrexate
Nortriptyline
Salicylates
Valproic acid

1. SDC i s t he most pr act i cal i nt er medi at e end poi nt t o be used when t her e
i s no cl ear l y obser vabl e t her apeut i c or t oxi c end poi nt .
2. SDC i s a r easonabl e pr oxy f or dr ug concent r at i on at t he si t e of act i on.
3. The range of t her apeut i c and saf e ser um concent r at i ons i s nar r ow.
4. Ther e i s no predi ct abl e dose-r esponse r el at i on.
5. The pharmacol ogi cal ef f ect obser ved persi st s f or a r el at i vel y l ong t i me.
Acut e, shor t , or i nt ermi t t ent ef f ect s ar e not wel l regul at ed by usi ng ser um
dr ug l evel s.
6. A dr ug assay i s avai l abl e t hat i s accur at e, pr eci se, speci f i c, r api d, and
r el at i vel y i nexpensi ve.
IV. EQUATIONS FREQUENTLY USED IN TDM
A. Li near pharmacoki net i c drug cI earance-normaI renaI f unct i on.
Li near cl ear ance assumes t hat a proport i onaI change i n dose l eads t o t he
same proport i onaI change i n SDC. Ì t al so assumes t hat t 1/ 2 and dr ug
cl ear ance r emai n const ant as t he dose changes. See Ì V. D f or an exampl e
of usi ng some of t he f ol l owi ng equat i ons.
1. Esti mati ng drug cI earance ( CI ) :

wher e V i s t he appar ent vol ume of di st r i but i on of dr ug.
2. Maxi mum concent rati on ( Cmax, ss) duri ng ¡s s , when absor pt i on i s
assumed t o be much f ast er t han el i mi nat i on:
P. 745



wher e S i s t he f ract i on of t he dosage f orm t hat i s t he act i ve moi et y and f i s
t he bi oavai l abi l i t y.
3. Mi ni mum concent rat i on ( Cmi n, ss) dur i ng ¡s s , when absorpt i on i s assumed
t o be much f ast er t han el i mi nat i on:
4. Average concent rat i on resuI t i ng f rom i nt ermi t t ent admi ni st rati on
( Cavg, ss) dur i ng ¡s s :

wher e dose/ ¡ i s t he amount of dr ug admi ni st ered duri ng each sel ect ed uni t
of t i me ( e. g. , hour s, mi nut es) .
5. St eady- st at e concentrat i on resuI t i ng f rom cont i nuous admi ni st rat i on
( Ci nf , ss) . For t he same dose r at e ( dose/ ¡), ( Cavg, ss ) f or i nt ermi t t ent
admi ni st rat i on i s the same as ( Ci nf , s s ) f or cont i nuous admi ni st rat i on:

B. Li near pharmacoki net i c drug cI earance-i mpai red renaI f unct i on
1. Esti mati ng creat i ni ne cI earance f rom serum creati ni ne when serum
cr eat i ni ne i s assumed t o be st abl e, not changi ng dai l y, and wei ght i s
expr essed by t he pat i ent ' s t ot al wei ght , unl ess t ot al wei ght i s equal t o or
mor e t han 20% of i deal (l ean) body wei ght , i n whi ch case i deal wei ght
shoul d be used i n t he cal cul at i on:
wher e Cr s denot es ser um cr eat i ni ne i n mg/ dl . The f emal e val ue i s 85% of
t he est i mat ed mal e val ue i n ( 6) .
2. Esti mati ng proI onged drug t 1/ 2 or reduced drug CI associ at ed wi t h
reduced CI cr :
wher e r i and n denot e t he r enal i mpai r ed and normal condi t i ons,
r espect i vel y; F i s t he f r act i on of dr ug admi ni st ered t hat i s el i mi nat ed
unchanged ( unmet abol i zed) ; and Cl cr r epr esent s cr eat i ni ne cl ear ance i n
mL/ mi n. Ì mpor t ant F val ues f or some common TDM dr ugs are:
ami nogl ycosi des = 0. 98, di goxi n = 0. 98, and vancomyci n = 0. 95.
3. Usi ng Cavg, ss as a t arget so t hat Cav g, ss i n t he r enal i mpai red pat i ent i s
mai nt ai ned t he same as Cav g, s s i n normal s:
4. Usi ng Cmax, ss as a t arget so t hat Cma x, s s i n t he r enal i mpai red i s
mai nt ai ned t he same as Cmax, s s i n normal s:
wher e doseL i s a l oadi ng dose i nt ended t o achi eve t he same Cmax, s s i n t he
r enal i mpai red as i n t he nor mal pat i ent .
C. NonI i near pharmacoki neti c drug cI earance-normaI renaI funct i on.
NonI i near cl ear ance assumes t hat a pr opor t i onal change i n dose l eads t o a
di sproport i onaI change i n SDC. Ì t al so assumes t hat t 1/ 2 and Cl change as
t he dose changes and al so as t he amount of dr ug i n t he body f r om a gi ven
dose changes. Drugs exhi bi t i ng nonl i near cl earance pr esent a much great er
chal l enge t han l i near cl ear ance dr ugs because t he assumpt i ons i n t he l at t er
case of propor t i onal changes i n dose yi el di ng same pr opor t i onal changes i n
Cs s and const ant Cl and t 1/ 2 do not appl y f or nonl i near dr ugs. For nonl i near
dr ugs, i ncr eases i n dose l ead t o i ncreases i n t 1/ 2, decr eases i n Cl , and
changes i n Cs s t hat ar e excessi ve compar ed t o t he pr oport i onat e change i n
dose.
P. 746


1. Esti mati ng drug cI earance:

wher e Vma x i s t he maxi mum amount of dr ug t hat can be el i mi nat ed per uni t
of t i me ( e. g. , day) and Km i s t he dr ug ser um concent r at i on at whi ch t he rat e
of el i mi nat i on i s 50% of Vmax.
2. Esti mati ng Cavg, ss resuI t i ng f rom a gi ven dose/ t:
3. Esti mati ng dose/ t needed f or a desi red Cavg, ss:

D. An exampI e of appI yi ng some of the above equati ons t o deveI opi ng
and modi f yi ng dosage regi mens
1. A common dosage r egi men f or i nt r avenous (Ì V) gent ami ci n i s 1. 7 mg/ kg
q8h (as a 30-mi nut e i nf usi on) . Regi mens ar e usual l y adj ust ed t o achi eve
Cmax, s s and Cmi n, s s wi t hi n 5- 10 mcg/ mL and l ess t han 2 mcg/ mL,
r espect i vel y. Does t he above r egi men meet t he t ar get concent r at i on
obj ect i ves i n normal pat i ent s? Assume t he f ol l owi ng popul at i on par amet ers
i n nor mal s: Cl = 0. 09 L/ kg/ hr , t 1/ 2 = 2. 5 hr , V = 0. 25 L/ kg. For Ì V
admi ni st rat i on, f = 1, and S = 1 f or t he dosage f or m ( l abel amount
r epr esent s t he act ual amount of gent ami ci n) .
2. I n normaI s, usi ng equat i ons ( 2) and ( 3):

These val ues f al l wi t hi n t he t ar get concent r at i on ranges f or t he aver age
pat i ent wi t h nor mal renal f unct i on.
3. I n t he renaI i mpai red, what shoul d be done t o modi f y t he above r egi men
f or a pat i ent who i s 60 year s ol d, 70 kg, mal e, wi t h a Crs of 2. 5 mg/ dl ? Ì n
t hi s pat i ent , i f t he above r egi men wer e used, t he pr ol onged t 1/ 2 woul d yi el d
Cmax, s s = 15. 2 mcg/ mL and Cmi n, s s = 8. 4 mcg/ mL, val ues cl ear l y above t he
t ar get concent r at i on r anges.
a. Usi ng equat i on ( 6) f or est i mat i ng Cl c r i n t hi s pat i ent :

b. Then usi ng equat i on (7) f or est i mat i ng t 1/ 2 i n t hi s pat i ent , assumi ng F =
0. 98 and ( Cl cr ) n = 120 mL/ mi n:

c. Then usi ng equat i on (9) , f i r st det ermi ne a l oadi ng dose ( DL) t o achi eve
t he same Cmax, s s of approxi mat el y 8 mcg/ mL as est i mat ed i n Ì V. D. 2 f or a
pat i ent wi t h nor mal renal f unct i on:
DL = ( Cmax, s s ) ( V) / ( S) ( f )
DL = ( 8 mcg/ mL) ( 0. 25 L/ kg) / (1) ( 1) = 2 mg/ kg
Next , det ermi ne f ract i on of drug l ost dur i ng ¡, assumi ng a ¡r i of 24 hours,
and usi ng t he ( t 1/ 2)r i of 9. 3 hours est i mat ed i n Ì V. D. 3. b:
Fr act i on l ost = 1 - 10
- 0. 3( ¡ / t
1/ 2
)
= 1 - 10
- 0. 3( 24/ 9. 3)
= 0. 84
Last l y, cal cul at e D per ¡r i :
P. 747


D per t
ri
÷ (D
L
)|1 - 10
-0.3(t/t
1/2
)
|
÷ (2 mg/kg)(0.84) ÷ 1.7 mg/kg

Thus, a DL of 2 mg/ kg f ol l owed by 1. 7 mg/ kg q24h i s expect ed t o mai nt ai n
l evel s i n t hi s pat i ent si mi l ar t o t hat i n normal s.
V. EFFECT OF PHYSIOLOGICAL ALTERATIONS ON
PHARMACOKINETIC VARI ABLES
A. GeneraI consi derati ons. Ì t i s appar ent f r om Fi gur e 36- 1 and t he
equat i ons i n Sect i on Ì V, t hat any changes i n pharmacoki net i c vari abl es
r esul t i n changes i n Cs s and perhaps pharmacodynami c out comes. Thi s may
necessi t at e changes i n D/ ¡ compared t o normal s. For r enal i mpai r ment ,
quanti t at i ve est i mat es of r esul t i ng changes i n Cl and t 1/ 2, compared t o
nor mal val ues, ar e avai l abl e usi ng t he equat i ons i n Sect i on Ì V. For hepat i c,
car di ac, pul monar y, and ot her i mpai rment s pot ent i al l y i nduci ng changes i n
nor mal phar macoki net i c var i abl es, onl y quaI i t at i ve est i mat es are possi bl e.
B. RenaI i mpai rment, when marked, reduces dr ug cl earance f or dr ugs
pr i mar i l y dependent on t he ki dney f or el i mi nat i on. As not ed i n t he equat i ons
i n Sect i on Ì V. B, physi ol ogi cal marker s l i ke serum cr eat i ni ne and creat i ni ne
cl ear ance are used t o est i mat e t he changes i n Cl and t 1/ 2 r esul t i ng f rom
r educt i ons i n Cr s and Cl cr .
C. Hepati c i mpai rment exer t s a compl ex i nf l uence on dr ug
pharmacoki net i cs. Two pr ocesses may be al t er ed, bl ood f l ow r at e i n
del i ver i ng dr ug t o t he l i ver and t he capaci t y of enzymes t o met abol i ze t he
dr ug. Ì n general t er ms, moder at e t o sever e hepat i c i mpai r ment i s expect ed
t o sl ow over al l Cl and prol ong t 1/ 2 f or dr ugs hi ghl y dependent on t he l i ver
f or el i mi nat i on.
D. Cardi ac i mpai rment , when subst ant i al , decr eases hepat i c and renal
cl ear ances, r educes vol ume of di st r i but i on, and may sl ow absor pt i on f or
some dr ugs. The ef f ect of compr omi sed perf usi on i s most cri t i cal f or drugs
t hat ar e bot h hi ghl y dependent on t he l i ver f or cl ear ance and ef f i ci ent l y
met abol i zed by t he l i ver i n nor mal pat i ent s.
E. Agi ng r esul t s i n r educt i ons i n r enal ( consi st ent l y) and hepat i c
( i nconsi st ent l y) cl earances. The cl ear ance of dr ugs pr i mari l y dependent on
t he ki dney decl i nes by near l y 50% and t he hal f - l i f e near l y doubl es over a
40- 50- year peri od f r om young adul t hood. On t he ot her hand, some drugs
pr i mar i l y dependent on t he l i ver f or cl ear ance show no age- r el at ed
changes, whi l e ot her s do. Changes wi t h age i n absor pt i on, vol ume of
di st r i but i on, and serum pr ot ei n bi ndi ng of drugs show no consi st ent pat t ern.
F. Fr om a cl i ni cal vi ewpoi nt , ser um protei n bi ndi ng of dr ugs becomes an
i mpor t ant i ssue i n TDM f or drugs bound mor e t han 80% t o ser um pr ot ei ns.
Because hepat i c and renal cl ear ances, vol ume of di st r i but i on, and
pharmacol ogi cal response ar e medi at ed by t he f ree ( unbound) f or m of t he
dr ug i n ser um, i nt er pat i ent var i at i ons i n prot ei n bi ndi ng not onl y r esul t i n
var i at i ons i n pharmacoki net i cs i n nor mal s, but al so l oss of serum pr ot ei ns
dur i ng renal and hepat i c i mpai r ment s may r esul t i n modi f i ed dr ug cl ear ance
and phar macol ogi cal r esponse.
VI. THE TOTAL TESTING PROCESS APPLIED TO
TDM
A. Def i ni ng the tot aI t est i ng process ( TTP)
1. TDM i nvol ves bot h t he l abor at or y f or anal ysi s and cl i ni ci ans f or
i nt er pr et at i on of SDC. TTP r ef er s t o al l aspect s of t he st eps of l abor at ory
t est i ng begi nni ng wi t h a cl i ni cal quest i on t hat i s pr ompt ed by t he pat i ent -
cl i ni ci an encount er and concl udi ng wi t h t he i mpact of t he t est resul t on
pat i ent car e.
2. TTP emphasi zes t hat TDM i s a process i nvol vi ng a ser i es of st eps and
i nt er r el at ed act i vi t i es and shoul d not be vi ewed si mpl y as a numeri cal val ue
f or an SDC.
3. TTP f ocuses on i dent i f yi ng al l st eps of t he TDM t est i ng process,
hi ghl i ght i ng wher e vari at i ons and er r ors can occur , i nt er pr et i ng SDC r esul t s
i n l i ght of t he st eps i nvol ved, and i mpr ovi ng t he cont ri but i on of t est i ng t o
achi evi ng desi r ed pat i ent out comes.
P. 748


B. Component s and st eps i n TTP. Ther e ar e 4 component s and 11 st eps
i n TTP.
1. The preanaI yt i caI component consi st s of f our st eps:
( 1) cl i ni cal quest i on, (2) t est sel ect ed, ( 3) t est order ed, and ( 4) speci men
col l ect i on.
2. The anaI yt i caI component t hen f ol l ows wi t h t hr ee st eps:
( 5) sampl e prepared, ( 6) anal ysi s per f or med, and ( 7) resul t veri f i ed.
3. The post anaI yt i caI component t hen concl udes wi t h f our st eps: (8) resul t
r eport ed, ( 9) cl i ni cal answer , ( 10) act i on t aken, and ( 11) ef f ect on pat i ent
car e.
4. The t hr ee component s ar e af f ect ed by t he f our t h component , t he
reguI at or y envi ronment wi t hi n whi ch TDM i s perf or med.
C. Cont ri but i ons of TDM t o TTP
1. TDM has t he pot ent i al t o i mpr ove many of t he st eps i n TTP: pr ovi di ng
educat i on, drug i nf ormat i on, i nt er pret at i on of TDM r esul t s, assessi ng t he
appropr i at eness of t he TDM or der , schedul i ng speci men col l ect i on,
devel opi ng dr ug dosage gui del i nes, and provi di ng wr i t t en and oral
consul t at i on concerni ng TDM r esul t s.
2. The pharmaci st ' s great est i nvol vement i n TTP i s i n st eps (2) assessi ng
t he appropri at eness of TDM f or a gi ven si t uat i on, ( 4) t i mi ng of speci men
col l ect i on, and ( 9) cl i ni cal i nt er pr et at i on of TDM r esul t s.
VII. USING TEST PERFORMANCE
CHARACTERISTICS IN TDM
A. Rat i onaI e and reasons
1. Ì n TDM, t he SDC f unct i ons l i ke a di agnost i c t est t o assi st i n cl assi f yi ng
pat i ent st at us.
2. On t he one hand, t he pat i ent ' s SDC may be used, i n conj unct i on wi t h a
popul at i on SDC cut of f val ue measur e f or t he dr ug, whi ch act s as a
separ at or , t o cl assi f y t he pat i ent as a member of ei t her dr ug-i nduced t oxi c
( pat i ent SDC > upper cut of f val ue) or t herapeut i c ( wi t hi n t herapeut i c range)
subpopul at i ons.
3. Al t er nat el y, t he pat i ent ' s SDC may cl assi f y t he pat i ent as par t of t he
t her apeut i c or subt herapeut i c ( SDC < l ower cut of f val ue) subpopul at i ons.
4. Al t hough cl assi f yi ng pat i ent s i n subpopul at i ons i s t he most common use
of SDC i n TDM, a mor e i nf ormed appl i cat i on of SDC i s t o use t he r esul t t o
modi f y t he cl i ni ci an' s pr obabi l i t y of pat i ent st at us. Thi s i s t he use of SDC as
par t of a Bayesi an approach t o di agnost i c t est i nt er pr et at i on.
B. Test performance charact eri st i cs. Test per f or mance i ndi ces are not
per f ect cl assi f i er s of pat i ent st at us and shoul d never be used as t he sol e
measure f or det ermi ni ng how t he pat i ent i s react i ng t o t he dr ug. A number
of t est perf ormance i ndi ces char act eri ze t he accur acy of a di agnost i c t est t o
accur at el y cl assi f y pat i ent s as t oxi c, t herapeut i c, or subt herapeut i c. Four of
t hese i ndi ces ar e most usef ul i n i nt er pret i ng SDC.
1. Posi t i ve predi ct i ve vaI ue ( PPV)
a. Compari ng drug- i nduced t oxi c versus nontoxi c pat i ents ( usi ng upper
SDC cut of f I eveI ). PPV denot es t he pr opor t i on of pat i ent s wi t h a posi t i ve
t est (pat i ent SDC > upper cut of f SDC) who ar e i n a dr ug- i nduced t oxi c
condi t i on. So, t he val ue of PPV represent s t he probabi l i t y of a posi t i ve t est
bei ng accurat e i n cl assi f yi ng t he pat i ent as t oxi c.
b. Compari ng t herapeuti c versus subt herapeuti c pat i ent s (usi ng I ower
SDC cut of f I eveI ). PPV denot es t he pr opor t i on of pat i ent s wi t h a posi t i ve
t est (pat i ent SDC > l ower cut of f SDC) who are respondi ng appropri ateI y.
So, t he val ue of PPV i n t hi s case r epr esent s t he pr obabi l i t y of a posi t i ve
t est bei ng accur at e i n cl assi f yi ng t he pat i ent as t her apeut i c.
2. Negat i ve predi ct i ve vaI ue ( NPV)
a. Compari ng drug- i nduced t oxi c versus nontoxi c pat i ents ( usi ng upper
SDC cut of f I eveI ). NPV denot es t he pr opor t i on of pat i ent s wi t h a negat i ve
t est (pat i ent SDC < upper cut of f SDC) who ar e not mani f est i ng dr ug-
i nduced t oxi ci t y. So, t he val ue of NPV r epr esent s t he pr obabi l i t y of a
negat i ve t est bei ng accur at e i n cl assi f yi ng t he pat i ent as nont oxi c.
P. 749


b. Compari ng t herapeuti c versus subt herapeuti c pat i ent s (usi ng I ower
SDC cut of f I eveI ). NPV denot es t he pr opor t i on of pat i ent s wi t h a negat i ve
t est (pat i ent SDC < l ower cut of f SDC) who are subt herapeuti c. So, t he
val ue of NPV i n t hi s case r epr esent s t he pr obabi l i t y of a negat i ve t est bei ng
accur at e i n cl assi f yi ng t he pat i ent as subt her apeut i c.
3. Posi t i ve I i keI i hood rat i o ( PLR) . Ì n def i ni ng condi t i ons as + or - ( as i n +
= t oxi c and - = negat i ve, or + = t her apeut i c and - = subt herapeut i c) , PLR i s
t he pr obabi l i t y t hat a + pat i ent has a + t est di vi ded by t he pr obabi l i t y t hat a
- pat i ent has a + t est (e. g. , t he pr obabi l i t y t hat a t oxi c pat i ent has an SDC
> cut of f di vi ded by t he pr obabi l i t y t hat a nont oxi c pat i ent has an SDC >
cut of f ) . The hi gher t he PLR, t he more di scri mi nat i ng t he t est .
4. Negat i ve I i keI i hood rat i o ( NLR) . NLR i s t he pr obabi l i t y t hat a + pat i ent
has a - t est di vi ded by t he probabi l i t y t hat a - pat i ent has a - t est . The
I ower t he NLR, t he more di scr i mi nat i ng t he t est .
5. I I I ust rat i ng t he use of PPV, NPV, PLR, and NLR. For t heophyl l i ne,
usi ng a t est upper cut of f of 20 mcg/ mL, PPV i s 0. 5, NPV i s 0. 95, PLR i s 6,
and NLR i s 0. 4.
a. For PPV, t hi s means t hat t he pr opor t i on of pat i ent s wi t h a posi t i ve t est
r esul t ( SDC > upper cut of f ) who t r ul y have t heophyl l i ne- i nduced t oxi ci t y i s
50%. For an i ndi vi dual pat i ent wi t h SDC > cut of f , t he pr obabi l i t y of t oxi ci t y
i s 0. 5.
b. For NPV, t hi s means t hat t he pr opor t i on of pat i ent s wi t h a negat i ve t est
r esul t ( SDC < upper cut of f ) who t r ul y are nont oxi c i s 95%. For an i ndi vi dual
pat i ent wi t h SDC < cut of f , t he probabi l i t y of nont oxi ci t y i s 0. 95.
c. For PLR, t oxi c pat i ent s wi l l have a posi t i ve t est r esul t si x t i mes more
of t en t han do nont oxi c pat i ent s.
d. For NLR, t oxi c pat i ent s wi l l have a negat i ve t est resul t 40% as of t en as
wi l l nont oxi c pat i ent s.
e. These resul t s suggest t hat a negat i ve t heophyl l i ne t est r esul t r ul es out
t oxi ci t y ( 0. 95) about t wi ce as ef f ect i vel y as a posi t i ve t est r ul es i n t oxi ci t y
( 0. 5) . A posi t i ve t est appear s t o be unrel i abl e as an i ndi cat or of t oxi ci t y, but
a negat i ve t est appear s t o be hi ghl y pr edi ct i ve of nont oxi ci t y. Fur t her mor e,
t he PLR suggest s t hat a posi t i ve SDC t est i s si x t i mes more l i kel y t o come
f r om a t oxi c t han a nont oxi c pat i ent . On t he ot her hand, t he NLR i mpl i es
t hat i t i s consi der abl y l ess t han one-hal f as l i kel y ( 0. 4) t hat a negat i ve t est
comes f r om a t oxi c compar ed t o a nont oxi c pat i ent .
f . Knowl edge of t est per f or mance charact eri st i cs of SDC measures pr ovi des
t he pr act i t i oner wi t h an i ndex of t he usef ul ness of t he SDC i n cat egori zi ng
pat i ent s.
C. Usi ng a Bayesi an approach. Usi ng SDC i n conj unct i on wi t h l i kel i hood
r at i o i nf ormat i on enhances t he appl i cat i on of t he SDC i n deci si on maki ng. A
Bayesi an appr oach t o probabi l i t y r evi si on al l ows t he pr act i t i oner t o make a
pr et est assessment of pat i ent st at us, or der a di agnost i c t est , and use t he
pr obabi l i t y i nf or mat i on cont ai ned i n t he t est resul t t o revi se t he assessment
of st at us.
1. The rel at i on bet ween pr et est , t est , and post t est assessment i s shown i n
t he f ol l owi ng equat i on:
wher e pr et est r ef ers t o t he pret est odds of t he condi t i on bei ng pr esent pr i or
t o obt ai ni ng t he pat i ent ' s SDC and post t est r ef ers t o t he post t est odds of
t he condi t i on bei ng pr esent af t er l ear ni ng t he SDC.
2. Odds are def i ned as + r esul t s di vi ded by - resul t s ( +/ - ) . Probabi I i t y i s
def i ned as + r esul t s di vi ded by t ot al r esul t s (+/ t ot al , wher e t ot al i s t he sum
of + and - resul t s) .
3. Odds ar e conver t ed t o pr obabi l i t y as f ol l ows:
4. Pr obabi l i t y i s convert ed t o odds as f ol l ows:
5. An exampl e of appl yi ng a Bayesi an appr oach t o modi f yi ng t he probabi l i t y
of pat i ent st at us. Usi ng t he t heophyl l i ne t est perf or mance charact eri st i cs
not ed i n VÌ Ì . B. 5:
P. 750


a. Assume t hat a pract i t i oner assesses by vi sual i nspect i on t hat t he
pr obabi l i t y of t heophyl l i ne- i nduced t oxi ci t y i n a pat i ent i s 0. 25 ( t he pr et est
pr obabi l i t y) . She orders a ser um t heophyl l i ne concent r at i on ( STC) , and
uses t he measur ement t o r evi se her assessment of t oxi ci t y i n t he pat i ent
( t he post t est pr obabi l i t y).
b. Furt her assume t hat t he t est per f ormance char act er i st i cs f or t he STC
ar e: PLR = 6 and NLR = 0. 4.
c. Usi ng equat i ons ( 13), ( 14) , and ( 15) , a pret est pr obabi l i t y of 0. 25 i s t he
same as pr et est odds of t oxi ci t y of 1/ 3 [ 0. 25/ ( 1 - 0. 25)] , usi ng equat i on
( 15) .
d. Ì f t he STC t est f or t he pat i ent comes back posi t i ve ( STC > 20 mcg/ mL) ,
t hen PLR = 6 i s used t o r evi se t he odds of t oxi ci t y. Ì f t he STC t est i s
negat i ve ( STC > 20 mcg/ mL) , t hen NLR = 0. 4 i s used.
e. Assume t he pat i ent ' s STC = 22 mcg/ mL, t hen usi ng equat i on ( 13) yi el ds
( 1/ 3) (6) = 2. So, t he post t est odds of t oxi ci t y ar e 2/ 1. Conver t i ng t hese odds
t o probabi l i t y usi ng equat i on ( 14) : [ 2/ ( 1 + 2) ] = 0. 67. The postt est
probabi I i t y of t oxi ci t y i s 0. 67. The pret est pr obabi l i t y of 0. 25 has nearl y
t r i pl ed usi ng t he STC as f eedback.
f . Assume i nst ead t hat t he pat i ent ' s STC = 14 mcg/ mL; t hen usi ng equat i on
( 13) yi el ds (1/ 3) (0. 4) = 0. 13. So, t he post t est odds of t oxi ci t y ar e 0. 13/ 1.
Conver t i ng t hese odds t o pr obabi l i t y usi ng equat i on ( 14): [ 0. 13/ ( 1 + 0. 13)] =
0. 12. The post t est probabi I i t y of t oxi ci t y i s 0. 12.
g. Whi l e a posi t i ve STC t est near l y t ri pl ed t he pr obabi l i t y of t oxi ci t y above,
a negat i ve t est cut s t he pr obabi l i t y i n hal f . Thi s demonst r at es t he
usef ul ness of usi ng SDC i n combi nat i on wi t h pr act i t i oner assessment as a
gui de t o quant i f yi ng t he pr obabi l i t y of pat i ent st at us.
VIII. SUMMARY
A. TDM appl i es t o a smal l number of dr ugs wi t h a nar row r ange of ef f ect i ve
and saf e SDC wher ei n opt i mum drug t r eat ment i s pr omot ed by mai nt ai ni ng
SDC wi t hi n a popul at i on or pat i ent -speci f i c t her apeut i c r ange, above whi ch
dr ug-i nduced t oxi ci t y occur s t oo of t en and bel ow whi ch t he dr ug i s t oo of t en
i nef f ect i ve.
B. A pract i t i oner i ni t i at es drug t r eat ment usi ng a dose rat e t hat assumes
t hat t he pat i ent shows mean popul at i on val ues f or t he phar macoki net i c
var i abl es, even t hough i t i s expect ed t hat f ew pat i ent s wi l l ever possess t he
mean val ue bei ng used. Ì f t he r esul t i ng Css and/ or phar macol ogi cal
r esponse i s ot her t han expect ed and t he pat i ent becomes at ri sk f or
subt herapeut i c or dr ug-i nduced t oxi ci t y, i t i s l i kel y due t o t he i nt er pat i ent
var i abi l i t y i n phar macoki net i c val ues and phar macodynami c r esponse t hat
charact eri zes t he need f or TDM; t her ef ore, t he dose r at e i s modi f i ed t o
pr oduce a pat i ent - speci f i c Cs s t hat r epr esent s t he best t radeof f of
ef f ect i veness and t oxi ci t y.
C. Ti mi ng of sampl i ng of SDC i s cri t i cal t o r educe er ror s i n i nt er pr et at i on of
t he measur ement . SDC shoul d be sampl ed at st eady st at e, af t er
post absorpt i on and post di st r i but i on equi l i bri um i s achi eved, and a t i me
dur i ng ¡s s t hat mat ches t he t i me at whi ch t he t herapeut i c r ange was
est abl i shed.
D. The choi ce of Cmax, s s , Cmi n, s s , Cav g, ss , or Ci nf , s s t o est i mat e dosage
r egi mens depends on t he t her apeut i c r ange obj ect i ve and, i n t he l at t er
case, i nt r avenous r at her t han i nt ermi t t ent admi ni st r at i on.
E. For t he r enal -i mpai r ed pat i ent , t he dosage reduct i on f act or i s cal cul at ed
t o achi eve, dependi ng on t he t her apeut i c r ange obj ect i ve, a Cmax, s s or
Cav g, s s i n t he r enal -i mpai r ed pat i ent t hat i s si mi l ar t o t hat desi r ed i f t he
pat i ent had nor mal r enal f unct i on.
F. The TTP i s t he syst emat i c sequence of event s i n whi ch TDM i s pr act i ced
f r om i dent i f i cat i on of t he need f or an SDC measur ement , t o pr oper t i mi ng of
sampl e col l ect i on, l aborat or y anal ysi s, i nt erpr et at i on of resul t s, and dosage
r egi men modi f i cat i on, i f i ndi cat ed.
G. The SDC measur e i s mor e t han a number used t o r el at e t he pat i ent ' s
val ue t o a popul at i on t her apeut i c range. The SDC i s a f or m of di agnost i c
t est used ( 1) t o assi st i n cl assi f yi ng pat i ent st at us and (2) as f eedback t o
r evi se pract i t i oner est i mat es of pat i ent st at us. Ther ef or e, i t i s i mpor t ant t o
know t he predi ct i ve val ues and l i kel i hood r at i os of SDC t est s.
P. 751


STUDY QUESTIONS
Di rect i ons: Each of t he numbered i t ems or i ncompl et e st at ement s i n t hi s
sect i on i s f ol l owed by answer s or by compl et i ons of t he st at ement . Sel ect
t he one l et t ered answer or compl et i on t hat i s best i n each case.
1. Def i ne therapeuti c drug moni t ori ng. What i s meant by t he t erm TDM?
( A) The use of dr ug ser um concent r at i on measurement s, f or drugs i n
whi ch t her e i s ( 1) a cor rel at i on bet ween ser um concent rat i on and
r esponse, as wel l as (2) a narr ow r ange of ef f ect i ve and saf e
concent r at i ons, t o assess pat i ent st at us as an adj unct t o cl i ni cal
obser vat i on
( B) The use of dr ug ser um concent r at i on measurement s t o det ermi ne
popul at i on val ues f or a dr ug' s hal f - l i f e val ue
( C) The use of dr ug ser um concent r at i on measurement s t o assess
t he accuracy of t he dr ug concent r at i on assay
( D) Obser vi ng t he ef f ect s of drugs i n man
( E) Usi ng dr ug ser um concent r at i on measurement s t o di f f er ent i at e
ef f ect i ve f r om i nef f ect i ve dr ugs
Vi ew Answer 1. The answer i s A[ 1. B] . 2. The t herapeuti c range f or
t heophyI I i ne i s of t en stat ed as 10-20 mcg/ mL. What does t hi s mean?
( A) Fi f t y percent of peopl e t aki ng t heophyl l i ne show a saf e and
ef f ect i ve r esponse when t he serum dr ug concent rat i on i s bet ween
10- 20 mcg/ mL.
( B) Most peopl e achi eve t he desi r ed response t o t heophyl l i ne, wi t h
mi ni mum adverse ef f ect s when t he ser um t heophyl l i ne concent r at i on
i s mai nt ai ned bet ween 10- 20 mcg/ mL. Fewer pat i ent s are managed
ef f ect i vel y at <10 mcg/ mL, but some may respond qui t e
appropr i at el y at l ower l evel s. The f r equency of adver se ef f ect s
i ncreases as t he l evel i ncr eases above t he upper l i mi t of t he
t her apeut i c range, but a f ew pat i ent s are managed ef f ect i vel y,
wi t hout adversi t y, above t he range.
( C) Twent y- f i ve per cent of peopl e show an ef f ect i ve r esponse t o
t heophyl l i ne at 10 mcg/ mL, and 75% show an ef f ect i ve response at
20 mcg/ mL.
( D) Twi ce dai l y admi ni st rat i on of t heophyl l i ne, but not t hree t i mes
dai l y, r equi res t hat ser um drug concent rat i ons st ay wi t hi n 10- 20
mcg/ mL.
( E) Theophyl l i ne serum dr ug concent rat i ons out si de of t he 10-20
mcg/ mL r ange are i nef f ect i ve and/ or unsaf e.
Vi ew Answer 2. The answer i s B[] . 3. Assume that f or a di goxi n,
t he t herapeut i c range i s ci ted as Cavg, ss = 0. 8-2 ng/ mL. I f t he pat i ent i s
assumed t o have an esti mat ed di goxi n t1/ 2 of 48 hours, how I ong wouI d
you wai t t o t ake a serum di goxi n concent rat i on measurement , and when
duri ng t wouI d you scheduI e i t ?
( A) 28 days, t hen 3- 4 hour s af t er t he dose i s admi ni st er ed
( B) 14 days, t hen 6- 8 hour s af t er t he dose i s admi ni st er ed
( C) 7 days, t hen 10- 14 hour s af t er t he dose i s admi ni st er ed
( D) 3 days, t hen 1-2 hour s af t er t he dose i s admi ni st er ed
( E) 1 day, t hen 18-22 hour s af t er t he dose i s admi ni st er ed
Vi ew Answer 3. The answer i s C[] . 4. Di f f erent i at e I i near f rom
nonI i near drug cI earance. What i s the ef f ect on TDM?
( A) Li near drug cl ear ance i s f i r st order , t he Cl and t 1/ 2 are
i ndependent of dr ug dosage, and propor t i onal changes i n dose
r esul t i n t he same propor t i onal changes i n Cs s . Nonl i near dr ug
cl ear ance i s zer o order , Cl and t 1/ 2 change as dose changes ( or as
t he amount of dr ug i n t he body changes) , and propor t i onal changes
i n dose yi el d di sproport i onat e changes i n Cs s.
( B) Li near drug cl ear ance pr esent s f ewer serum concent r at i on peaks
and t r oughs dur i ng t he dosage i nt er val t han does nonl i near dr ug
cl ear ance.
( C) Li near dr ug cl ear ance i s zer o or der , t he Cl and t 1/ 2 ar e
dependent on dr ug dosage, and pr oport i onal changes i n dose do not
r esul t i n t he same propor t i onal changes i n Cs s . Nonl i near dr ug
cl ear ance i s f i r st order , and equat i ons ar e not avai l abl e t o predi ct
dr ug ser um concent r at i on f r om t he dose rat e.
( D) Dr ugs wi t h l i near cl ear ance have shor t er t 1/ 2 val ues t han dr ugs
wi t h nonl i near cl earance.
( E) Dr ugs wi t h l i near cl ear ance ar e admi ni st ered l ess of t en t han
dr ugs wi t h nonl i near cl ear ance.
Vi ew Answer 4. The answer i s A[] . P. 752


5. What i s t he posi t i ve predi ct i ve vaI ue of a di agnost i c t est?
( A) The f r act i on of pat i ent s wi t h a posi t i ve out come who have a
posi t i ve t est resul t
( B) Bei ng more t han 50% cor r ect i n pr edi ct i ng success or f ai l ur e
upon usi ng a drug regi men
( C) The f r act i on of pat i ent s who achi eve a successf ul r esponse i n
usi ng a drug
( D) The f r act i on of pat i ent s wi t h a posi t i ve t est resul t who t ur n out t o
have a posi t i ve out come
( E) The probabi l i t y t hat knowl edge of a dr ug ser um concent r at i on
r esul t s i n a successf ul response t o t reat ment
Vi ew Answer 5. The answer i s D[] . 6. A 70- year- oI d, 80- kg maI e,
wi t h serum creat i ni ne of 3 mg/ dL, i s scheduI ed t o start t obramyci n t herapy.
What regi men i s recommended to achi eve Cmax, ss wi thi n 5- 10 mcg/ mL ( use the
mi dpoi nt of 7. 5 mcg/ mL f or t he caI cuI at i on) and Cmi n, ss <2 mcg/ mL. Tr y a q24h
regi men t o start and, i f unsuccessfuI i n achi evi ng t he target concentrat i on
goaI s, aI t er t and recaI cuI ate. Assume i n normaI s the foI I owi ng vaI ues: t 1/ 2 =
2. 5 hr, V = 0. 25 L/ kg, F = 0. 98, S = 1, f = 1, CI cr = 120 mg/ dL.
( A) A l oadi ng dose of 1. 8- 2. 0 mg/ kg f ol l owed by 1. 0 mg/ kg qd
( B) A l oadi ng dose of 1. 8- 2. 0 mg/ kg f ol l owed by 1. 5 mg/ kg qd
( C) 2. 0 mg/ kg qd
( D) 1. 0 mg/ kg qd
( E) 0. 5 mg/ kg qd
Vi ew Answer 6. The answer i s B[] .
D per t
ri
÷ (D
L
)(Iraction lost per t
ri
)
÷ (1.9 /kg)(0.78) ÷ 1.5 /kg

P. 753


ANSWERS AND EXPLANATIONS
1. The answer i s A [ 1. B] .
2. The answer i s B [ Ì Ì . B] .
3. The answer i s C [ Ì Ì . D. 3] .
Ì f t he pat i ent ' s est i mat ed t 1/ 2 i s 48 hour s, 90% of st eady st at e i s expect ed t o be
achi eved bet ween 3-4 t 1/ 2 i nt er val s or 6-8 days i n t hi s case. For cl i ni cal pur poses,
we choose 90% at t ai nment of st eady st at e as t he mi ni mum t i me t o est i mat e dr ug
accumul at i on. A l evel drawn at 7 days seems reasonabl e. Once a ¡s s has been
sel ect ed, t he t i me f or schedul i ng a l evel shoul d cor r espond wi t h t he r ef erence t i me
f or t he t herapeut i c range. Ì n t hi s case, Cav g, s s was ci t ed as t he r ef er ence t i me, so a
measurement schedul ed f or somet i me near t he mi dpoi nt of ¡s s (ar ound 12 hours) i s
r easonabl e.
4. The answer i s A [ Ì V. A, C] .
Thi s present s chal l enges i n TDM, because f or l i near dr ugs t he cl i ni ci an can expect
a change i n Cs s pr oport i onal t o a change i n dose, but f or nonl i near dr ugs t hi s i s not
t r ue.
5. The answer i s D [ VÌ Ì . B. 1] .
The posi t i ve predi ct i ve val ue of a di agnost i c t est i s an i ndex of how ef f ect i ve t he
t est i s i n cl assi f yi ng pat i ent s cor r ect l y. For exampl e, usi ng a Cs s measure f or a
gi ven dr ug, knowi ng t hat t he posi t i ve pr edi ct i ve val ue i s 0. 8, gi ven a gr oup of
pat i ent s wi t h a Cs s above t he t est cut of f val ue, 80% of t he pat i ent s wi l l be
accur at el y cl assi f i ed as havi ng a posi t i ve out come. Ì f t he t est i s bei ng used t o
cl assi f y t oxi c ver sus nont oxi c pat i ent s, 80% of t he pat i ent s wi t h Cs s above t he t est
cut of f wi l l exper i ence drug- i nduced t oxi ci t y. Ì f , i nst ead, t he t est i s bei ng used t o
cl assi f y ef f ect i ve ver sus subef f ect i ve r esponse i n pat i ent s, 80% of t he pat i ent s wi t h
Cs s above t he t est cut of f wi l l exper i ence ef f ect i ve r esponse.
6. The answer i s B [ Ì V. D. 3] .
Usi ng t he equat i on f or est i mat i ng Cl cr i n t hi s pat i ent f r om Ì V B 1:

t hen, usi ng t he equat i on f or est i mat i ng t 1/ 2 i n t hi s pat i ent f r om Ì V. B. 2:

Then, usi ng equat i on [ Ì V. D. 3. b] , f i r st det ermi ne a l oadi ng dose: ( DL) t o achi eve t he
desi r ed Cmax, s s of 7. 5 mcg/ mL:
DL = ( Cmax, s s ) ( V) / ( S) ( f )
DL = ( 7. 5 mcg/ mL) (0. 25 L/ kg) / ( 1)( 1) = 1. 9 mg/ kg
Then, det ermi ne f r act i on of dr ug l ost duri ng ¡, assumi ng a ¡r i of 24 hr , and usi ng t he
( t 1/ 2)r i of 10. 9 hr est i mat ed above usi ng t he equat i on i n Ì V. D. 3. c:
f r act i on l ost = 1 - 10
- 0. 3( 24/ 10. 9)
= 0. 78
Last l y, cal cul at e D per ¡r i :
D per t
ri
÷ (D
L
)(Iraction lost per t
ri
)
÷ (1.9 mg/kg)(0.78) ÷ 1.5 mg/kg

Thus, a DL of 1. 9 mg/ kg f ol l owed by 1. 5 mg/ kg q24h i s expect ed t o at t ai n t he
desi r ed Cmax, s s and Cmi n, s s l evel s i n t hi s pat i ent . Of cour se, many est i mat es wer e
made al ong t he way ( Cl c r , t 1/ 2, V) , so i f t he pat i ent ' s Cmax, s s and Cmi n, s s vary f r om
what has been expect ed f r om t he cal cul at i ons, i t i s l i kel y due t o t he est i mat es bei ng
at var i ance wi t h t he act ual val ue(s) i n t he pat i ent .

37
Drug Use in SpeciaI Patient PopuIations:
Pediatric, Pregnant, and Geriatric
Marci a L. Buck
JuI i e J. KeI sey
I. PEDI ATRIC PHARMACOTHERAPY
A. GeneraI consi derati ons
1. Most pharmaci st s i n communi t y and hospi t al set t i ngs provi de car e f or chi l dren. Ì n
t he Uni t ed St at es, chi l dren make up nearl y one t hi r d of t he t ot al popul at i on.
Al t hough chi l dr en t ypi cal l y r equi r e f ewer medi cat i ons t han adul t s because of t hei r
r el at i ve good heal t h, appr oxi mat el y 30% of al l prescri pt i ons f i l l ed i n communi t y
pharmaci es ar e f or pedi at r i c pat i ent s. As a r esul t , pharmaci st s need t o have a
basi c knowI edge of pedi at ri c pharmacot herapy t o appropri at eI y assess and
moni tor drug t herapy.
2. Pr ovi di ng care f or chi l dr en i s of t en a chal l enge. Ther e i s I i mi t ed i nf ormat i on on
t he seI ect i on, dosi ng, and moni t ori ng of drugs i n t hi s popul at i on. Ì t i s est i mat ed
t hat onl y 25% of t he drugs avai l abl e on t he market i n t he Uni t ed St at es car r y a Food
and Drug Admi ni st r at i on ( FDA) appr oved i ndi cat i on f or use i n pedi at ri c pat i ent s,
al t hough nearl y 75% have been used t o t reat chi l dr en. As a resul t , most pedi at r i c
dosi ng i s consi der ed of f -l abel . Dosi ng i nf ormat i on t ypi cal l y comes di r ect l y f r om case
r eport s and smal l cl i ni cal t r i al s publ i shed i n t he medi cal l i t er at ur e. Ì n addi t i on t o
bei ng abl e t o obt ai n pedi at r i c- speci f i c dr ug i nf or mat i on, pharmaci st s must al so be
f ami l i ar wi t h di f f erences i n pedi at ri c phar macoki net i cs and pharmacodynami cs as
wel l as t he uni que aspect s of medi cat i on moni t or i ng and compl i ance i n t hi s
popul at i on.
B. Pharmacoki net i c consi derat i ons
1. Unl i ke t he r el at i vel y st abl e pharmacoki net i c prof i l e of most drugs i n adul t s,
chi l dren' s pharmacoki net i c paramet ers change duri ng mat urat i on f rom neonates
i nt o adoI escent s ( Tabl e 37- 1) . As a r esul t , t he pedi at r i c popul at i on i s a di ver se and
dynami c gr oup. Each aspect of drug di sposi t i on i s af f ect ed, i ncl udi ng absor pt i on,
di st r i but i on, met abol i sm, and el i mi nat i on. None of t hese processes i s f ul l y mat ur e at
bi r t h, and t hey devel op at di f f erent r at es over t he f i rst year s of l i f e. The st udy of
t hese changes i s known as devel opment al phar macol ogy.
2. Drug absorpt i on. For many r out es of admi ni st r at i on, t he absorpt i on of a dr ug i s
most gr eat l y al t ered dur i ng i nf ancy. Di f f er ences i n dr ug absor pt i on dur i ng t hi s
per i od may af f ect t he choi ce of del i ver y met hod, dose, or moni t ori ng.
a. Gast roi ntest i naI absorpt i on. Or al drug absorpt i on i s most gr eat l y al t er ed dur i ng
t he f i rst year of l i f e. Sever al aspect s of absorpt i on ar e age dependent , i ncl udi ng
gast r i c pH, gast ri c empt yi ng t i me, i nt est i nal mot i l i t y, bi l e sal t product i on, and
pancr eat i c enzyme f unct i on.
( 1) EI evated gast ri c pH. At bi r t h, gast ri c pH i s el evat ed ( pH > 4) . Thi s r esul t s f r om
a r el at i ve decrease i n gast r i c aci d pr oduct i on and an over al l decr ease i n t he vol ume
of gast r i c secret i ons. As a r esul t , aci d- l abi l e dr ugs such as peni ci l l i n G may have a
gr eat er bi oavai l abi l i t y i n neonat es t han i n ol der i nf ant s. Conversel y, dr ugs t hat are
weak aci ds such as phenobarbi t al (Lumi nal ) may not be as wel l absor bed. To
compensat e f or t hi s ef f ect , neonat es may r equi r e l arger or al doses of t hese dr ugs
t han ol der i nf ant s t o pr oduce t he desi r ed t her apeut i c ef f ect . Aci d pr oduct i on ri ses
st eadi l y af t er bi r t h, reachi ng adul t l evel s wi t hi n 2 mont hs.
P. 755


Table 37-1. Age Definitions
Age Group Age
Newborn
Preterm or premature · 36 weeks' gestation
a

Term ~ 36 weeks' gestation
a

Neonate · 1 month
InIant 1 month-1 year
Child 1-11 years
Adolescent 12-16 years
a
Gestational age as measured Irom the time oI the mother's last menstrual
period.

( 2) ProI onged gast ri c empt yi ng and i nt est i naI mot i I i t y. The r at e of passage of
dr ugs t hr ough t he gast roi nt est i nal t ract i s al so i mpor t ant i n det er mi ni ng t he r at e and
ext ent of t hei r absor pt i on. Coor di nat i on of cont ract i ons wi t hi n t he st omach begi ns t o
i mprove short l y af t er bi rt h, whi l e i nt est i nal peri st al si s i ncr eases mor e sl owl y, over
t he f i rst 4 mont hs of l i f e. As a r esul t of t hi s prol onged t r ansi t t i me, absorpt i on of
dr ugs may be si gni f i cant l y sl owed.
( a) Preterm neonat es t ypi caI I y have more deI ayed gast ri c empt yi ng t i me t han
t erm neonat es, so t hat changes i n or al absor pt i on may be most pronounced i n
t hese pat i ent s.
( b) Breast - f ed i nfants empt y t hei r st omachs approxi mat eI y t wi ce as fast as
f ormuI af ed i nfant s. The i ncr eased cal or i c densi t y of f ormul a f eedi ngs del ays
gast r i c empt yi ng.
( 3) Bi I e saI t and pancreat i c enzyme producti on. The r at e of bi l e sal t synt hesi s i n
pr et er m and t erm i nf ant s i s r educed t o approxi mat el y 50% of adul t val ues.
Decr eased f at absorpt i on f r om ent er al f eedi ngs, as wel l as decreased dr ug
absor pt i on, can occur . For exampl e, when l i pi d- sol ubl e vi t ami n D i s admi ni st er ed t o
neonat es, bi oavai l abi l i t y i s onl y 30% as compared wi t h 70% i n adul t s. The
absor pt i on of l i pi d- sol ubl e dr ugs i s f ur t her r educed as a r esul t of l ower l evel s of
pancr eat i c enzymes.
( 4) Ot her f act or s af f ect i ng or al dr ug absorpt i on i ncl ude reduced spl anchni c bl ood
f l ow i n t he 1st mont h of l i f e and r educed act i vi t y of i nt est i nal met abol i c enzymes
( al t er i ng t he f i rst - pass ef f ect ) . Ì n addi t i on, neonat es l ack normal gut mi cr of l ora.
Al t hough bact er i al col oni zat i on normal l y occurs shor t l y af t er bi r t h, i t may be
si gni f i cant l y del ayed i n pr et erm neonat es who ar e bei ng cared f or i n t he st er i l e
envi r onment of an i nt ensi ve car e uni t .
b. Percut aneous absorpt i on
( 1) Absorpt i on of dr ugs t hr ough t he ski n i s enhanced i n i nf ant s and young chi l dr en
owi ng t o bet t er hydr at i on of t he epi dermi s, gr eat er per f usi on of t he subcut aneous
l ayer , and t he l ar ger r at i o of t ot al body surf ace ar ea t o body mass compar ed t o
adul t s.
( 2) Ì n pret erm neonat es, t he st rat um cor neum i s al so t hi nner , f ur t her i ncr easi ng t he
pot ent i al f or t he absorpt i on of t opi cal product s.
( 3) Thi s r out e of admi ni st r at i on shoul d be used wi t h caut i on i n i nf ant s and young
chi l dren t o avoi d over dosage. There are numer ous account s of t oxi ci t y resul t i ng
f r om percut aneous absorpt i on. For exampl e, r epeat ed appl i cat i ons of t opi cal
hydr ocor t i sone cr eam f or di aper r ash or eczema can produce adr enal axi s
suppr essi on af t er as l i t t l e as 2 weeks of use i n an i nf ant .
c. I nt ramuscuI ar absorpt i on
( 1) The absor pt i on of drugs admi ni st er ed by t hi s rout e may be reduced i n neonat es
as a r esul t of r educed bl ood f l ow t o skel et al muscl es. Ì n addi t i on, weak or er r at i c
muscl e cont r act i ons i n neonat es may r esul t i n reduced dr ug di st ri but i on. These
f act or s may be part i al l y of f set by t he hi gher densi t y of capi l l ari es i n skel et al muscl e
dur i ng i nf ancy, whi ch i ncr eases bl ood ci r cul at i on.
( 2) Ì nt r amuscul ar admi ni st r at i on of drugs i s gener al l y di scour aged i n t he pedi at ri c
popul at i on because of t he pai n associ at ed wi t h t he i nj ect i on and t he ri sk of ner ve
damage f r om i nadver t ent i nj ect i on i nt o ner ve t i ssue.
P. 756


( 3) Thi s r out e i s general l y r eser ved f or t he admi ni st r at i on of vi t ami n K, vacci nes,
and occasi onal l y ant i bi ot i cs when i nt ravenous access i s not avai l abl e. Ì f i t i s used,
t he vol ume shoul d not exceed 0. 5 mL f or i nf ant s and younger chi l dren and 1 mL f or
ol der chi l dren.
d. Rect aI admi ni st rat i on. Absorpt i on by t hi s rout e i s f ai rl y r el i abl e, even f or
pr et er m neonat es. Admi ni st r at i on may be compl i cat ed i n i nf ant s, however , by t he
i ncreased number of pul sat i l e cont ract i ons i n t he r ect um compared t o adul t s, maki ng
expul si on of a supposi t or y mor e l i kel y.
e. PuI monar y admi ni st rat i on. Ì nhal at i on of medi cat i ons i s i ncr easi ngl y bei ng used
i n i nf ant s and ol der chi l dr en t o avoi d syst emi c exposur e. Whi l e devel opment al
changes i n t he pul monary vascul at ur e and r espi rat or y mechani cs l i kel y al t er t he
pharmacoki net i cs of drugs gi ven by i nhal at i on, l i t t l e i s known about t he ef f ect s of
gr owt h and mat ur at i on on t hi s r out e of drug admi ni st r at i on.
3. Drug di st ri but i on. Growt h and mat urat i on af f ect many of t he f act ors t hat
det ermi ne dr ug di st r i but i on. Body wat er cont ent , f at st ores, pl asma prot ei n
concent r at i ons, organ si ze and perf usi on, hemodynami c st abi l i t y, t i ssue per f usi on,
aci d- base bal ance, and cel l membr ane permeabi l i t y al l under go si gni f i cant changes
f r om i nf ancy t o adol escence.
a. Body water and f at cont ent. Tot al body wat er cont ent decreases wi t h i ncr easi ng
age. Thi s i s pri mar i l y t he r esul t of a l ar ger ext r acel l ul ar body wat er cont ent i n
neonat es and young i nf ant s whi ch decr eases wi t h age. Appr oxi mat el y 80% of a
newbor n' s wei ght i s body wat er . By 1 year of age, t hi s val ue decl i nes t o 60%,
si mi l ar t o t hat of an adul t . Hi ghl y wat er -sol ubl e compounds, such as gent ami ci n
( Gar amyci n), have a l arger vol ume of di st ri but i on i n neonat es t han i n ol der chi l dr en.
As a r esul t , l ar ger mi l l i gram per ki l ogr am doses ar e of t en needed t o achi eve desi r ed
t her apeut i c concent r at i ons. Conversel y, body f at i ncreases wi t h age, f r om 1%- 2% i n
a pr et erm neonat e t o 10%- 15% i n a t erm neonat e and 20%-25% i n a 1- year - ol d.
Li pophi l i c dr ugs, such as di azepam ( Val i um), have a smal l er vol ume of di st r i but i on
i n i nf ant s t han i n ol der chi l dr en and adul t s.
b. Prot ei n bi ndi ng. Aci di c dr ugs bi nd t o aI bumi n, whi l e basi c subst ances bi nd
pr i mar i l y t o o1- aci d gI ycoprot ei n ( AGP) . The quant i t y of t ot al pl asma pr ot ei ns,
i ncl udi ng bot h of t hese subst ances, i s r educed i n neonat es and young i nf ant s. Ì n
addi t i on, t he ser um al bumi n of newbor ns may have a r educed bi ndi ng af f i ni t y. These
t wo f act or s r esul t i n an i ncr ease i n t he f r ee f r act i on of many drugs ( Tabl e 37- 2) . The
i ncrease i n t he f r ee f ract i on may resul t i n enhanced pharmacol ogi cal act i vi t y f or a
gi ven dose. The reI at i ve decrease i n serum prot ei ns may aI so produce
i ncreased compet i t i on by drugs and endogenous substances, such as bi I i rubi n,
f or bi ndi ng si tes. Dr ugs t hat are hi ghl y bound t o al bumi n, such as t he
sul f onami des, may di spl ace bi l i rubi n f rom i t s bi ndi ng si t es and al l ow deposi t i on i n
t he br ai n, ref er r ed t o as ker ni ct erus. As a resul t , t hese dr ugs ar e consi dered
cont r ai ndi cat ed i n t he f i rst 2 mont hs of l i f e.
4. Met aboI i sm. The most si gni f i cant research i n devel opment al phar macol ogy
dur i ng t he past decade has come i n t he ar ea of dr ug met abol i sm. DeveI opmentaI
changes have been i dent i f i ed f or many phase I ( oxi dat i on, r educt i on,
hydr oxyl at i on, and hydrol ysi s) and phase I I (conj ugat i on) react i ons. The mat ur at i on
of met abol i c f unct i on resul t s i n t he need f or age- rel at ed dosage al t er at i ons f or many
common t herapi es and may expl ai n t he i ncr eased r i sk f or dr ug t oxi ci t y i n i nf ant s and
young chi l dr en.
a. The act i vi t y of phase I enzymes, such as the cyt ochrome P450 ( CYP) enzymes,
changes si gni f i cantI y duri ng mat urat i on. The pr i mar y i soenzyme dur i ng t he
pr enat al per i od, CYP3A7, peaks soon af t er bi rt h and t hen decl i nes r api dl y. Thi s
enzyme exi st s i n bar el y measurabl e quant i t i es i n adul t s. Ì t may appear ear l y i n f et al
l i f e t o det oxi f y r et i noi c aci d,
P. 757

a pot ent i al r at ogen. Al so at t he t i me of bi r t h, CYP2E1 and CYP2D6 l evel s begi n t o
r i se. Enzymes associ at ed wi t h t he met abol i sm of many common dr ugs÷CYP3A4,
CYP2C9, and CYP2C19÷appear wi t hi n t he f i rst weeks of l i f e, but t hei r l evel s
i ncrease sl owl y. The l ast of t he enzymes t o devel op, CYP1A2, i s present by 1- 3
mont hs of l i f e. The act i vi t y of t hese enzymes does not appear t o i ncr ease i n a di r ect
l i near manner wi t h age, but vari es over t i me. By 3- 5 year s of age, most pat i ent s
have CYP i soenzyme act i vi t y l evel s si mi l ar t o t hat of adul t s.
Table 37-2. Protein-Bound Drugs with a High Free Fraction in Neonates
Ampicillin (Principen) Penicillin G (PIizerpen)
Digoxin (Lanoxin) Phenobarbital
Diazepam (Valium) Phenytoin (Dilantin)
Lidocaine (Xylocaine) Propranolol (Inderal)
Morphine (Duramorph) Theophylline
NaIcillin (Nallpen)

( 1) The al t er ed phar macoki net i c pr of i l es of dr ugs i n chi l dr en may, i n l arge par t , be
expl ai ned by t hese devel opment al changes i n t he CYP enzyme syst em. One of t he
most wel l st udi ed enzymes i s CYP1A2. Thi s enzyme i s near l y nonexi st ent i n f et al
l i ver cel l s, and act i vi t y i s mi ni mal i n neonat es. As a r esul t , t he r at e of met abol i sm of
caf f ei ne i n t he neonat e i s sl ow, r esul t i ng i n an el i mi nat i on hal f -l i f e of 40-70 hr.
Enzyme act i vi t y i ncr eases by 4-6 mont hs of age. Wi t hi n t he f i rst year of l i f e i t
exceeds adul t val ues, produci ng a caf f ei ne hal f -l i f e of appr oxi mat el y 5 hr . Ì nf ant s
r ecei vi ng caf f ei ne ( Cal f ci t ) f or apnea of pr emat ur i t y or chr oni c l ung di sease must
have per i odi c adj ust ment s i n t hei r dose t o account f or t hese changes i n met abol i sm
and mai nt ai n t her apeut i c serum concent rat i ons.
( 2) Genet i c poI ymorphi sm al so pl ays a si gni f i cant r ol e i n det er mi ni ng met abol i c
f unct i on i n chi l dren. Recent st udi es wi t h at omoxet i ne ( St rat t era) have shown t hat
chi l dren wi t h r educed CYP2D6 f unct i on (i . e. , poor met abol i zers) had gr eat er
i mprovement i n t hei r at t ent i on def i ci t hyper act i vi t y di sor der ( ADHD) sympt oms t han
chi l dren who wer e ext ensi ve met abol i zers, usi ng a st andar d wei ght -based dose. The
poor met abol i zer s al so had an i ncreased i nci dence of adverse ef f ect s as a r esul t of
havi ng hi gher at omoxet i ne ser um concent rat i ons.
( 3) AI cohoI dehydrogenase act i vi t y i s onl y 3%- 4% of adul t val ues at bi r t h and does
not achi eve adul t val ues unt i l appr oxi mat el y 5 year s of age. Because of t hi s,
newbor ns have a reduced abi l i t y t o det oxi f y benzyl al cohol , a pr eser vat i ve f ound i n
many i nj ect abl e pr oduct s. Newbor ns exposed r epeat edl y t o t hese product s wi l l
accumul at e benzyl al cohol , whi ch may l ead t o a pot ent i al l y f at al condi t i on r ef er red
t o as "gaspi ng syndrome, ¨ wi t h met abol i c aci dosi s, respi r at or y f ai l ur e, sei zur es, and
car di ovascul ar col l apse. Because of t hi s r i sk, i t i s r ecommended t hat neonat es
r ecei ve pr eser vat i ve- f r ee pr oduct s or t hose cont ai ni ng al t ernat i ve preser vat i ves.
b. Phase I I reacti ons ( conj ugat i on wi t h gl yci ne, gl ucuroni de, or sul f at e t o f orm
mor e wat er - sol ubl e compounds) have not been st udi ed as ext ensi vel y i n t he
pedi at ri c popul at i on.
( 1) GI ucuroni dat i on i s generaI I y decreased i n neonat es, compared wi t h ol der
chi l dren and adul t s. The r at e of met abol i sm i ncreases wi t h i ncr easi ng age. Thi s can
be seen i n t he decr easi ng hal f -l i f e of mor phi ne (Dur amor ph) dur i ng t he 1st year of
l i f e. The aver age hal f -l i f e i n a pr et er m neonat e i s 10- 20 hr , compar ed t o 4- 13 hr i n a
neonat e, 5-10 hr i n i nf ant s bet ween 1 and 3 mont hs of age, and 1-8 hr i n ol der
i nf ant s and young chi l dren.
( 2) Unl i ke gl ucuroni dat i on, suI f ati on deveI ops i n ut ero and i s weI I deveI oped i n
t he neonat e. The var i at i on i n t he f unct i on of t hese t wo phase Ì Ì r eact i ons can be
seen wi t h t he devel opment al changes i n acet ami nophen ( Tyl enol ) met abol i sm. Ì n
ear l y i nf ancy, acet ami nophen i s convert ed pr i mari l y t hrough f or mat i on of sul f at e
conj ugat es; but wi t h i ncreasi ng age, gl ucur oni dat i on becomes t he pr edomi nat e f or m
of met abol i sm.
c. Whi l e most of t he recent research i nt o pedi at ri c dr ug met abol i sm has f ocused on
t he devel opment of enzyme f unct i on i n neonat es, several new st udi es hi ghl i ght
addi t i onal changes i n met abol i c f unct i on dur i ng adol escence. For exampl e, l opi navi r
( market ed wi t h r i t onavi r as Kal et r a) phar macoki net i cs under goes si gni f i cant age and
gender - rel at ed changes at t he t i me of pubert y. Lopi navi r cl ear ance i ncreases by
mor e t han 30% i n boys af t er age 12, compared t o gi rl s, whi ch may resul t i n a need
t o adj ust t he r ecommended dose.
5. EI i mi nat i on. Devel opment of r enal f unct i on i s a compl ex and dynami c pr ocess.
Nephr ons begi n f or mi ng as ear l y as t he 9t h week of gest at i on and are compl et e by
36 weeks. Al t hough t he f unct i onal uni t s of t he ki dneys ar e pr esent , t hei r capaci t y i s
si gni f i cant l y r educed at bi r t h. Gl omer ul ar f i l t r at i on r at e i n neonat es i s appr oxi mat el y
hal f t hat of adul t s. Val ues are f ur t her r educed i n pr et er m neonat es. Gl omer ul ar
f i l t rat i on r at e i ncreases rapi dl y dur i ng t he f i rst 2 weeks of l i f e and t ypi cal l y r eaches
adul t val ues by 8- 12 mont hs of age. Tubul ar secr et i on
P. 758

r at e i s al so r educed at bi r t h t o appr oxi mat el y 20% of adul t capaci t y, but mat ur es by
12 mont hs of age.
( a) I mmature renaI f unct i on resuI ts i n si gni f i cant aI terat i ons i n the eI i mi nati on
of many drugs. Phar macoki net i c st udi es f or sever al dr ugs, i ncl udi ng t he
ami nogl ycosi des and vancomyci n ( Vancoci n), have shown a di r ect cor rel at i on
bet ween cl ear ance and pat i ent age. Pr ol ongat i on of t he hal f - l i f e shoul d be
ant i ci pat ed f or al l r enal l y el i mi nat ed dr ugs admi ni st ered t o neonat es and i s most
pr onounced i n pret erm neonat es.
( b) To account f or the reduced abi I i t y of a neonat e to eI i mi nate t hese drugs,
I onger dosi ng i nt ervaI s are oft en requi red. Fai l ur e t o account f or t he reduct i on i n
r enal f unct i on may r esul t i n dr ug accumul at i on and t oxi ci t y.
C. Pharmacodynami c consi derat i ons. Unl i ke t he r api dl y accel erat i ng knowl edge of
t he pharmacoki net i c changes associ at ed wi t h devel opment , l i t t l e i s known of t he
pharmacodynami c changes associ at ed wi t h mat urat i on. Prel i mi nar y i nvest i gat i ons of
war f ar i n ( Coumadi n) phar macodynami cs have demonst rat ed a r el at i onshi p bet ween
ant i coagul ant response and pat i ent age. Ot her exampl es i ncl ude t he i ncreased
i nci dence of cer t ai n adver se drug react i ons i n younger chi l dr en, such as
hepat oxi ci t y wi t h val proi c aci d ( Depakene) . Fut ure r esear ch i n age- r el at ed
pharmacodynami c changes i s needed t o opt i mi ze t he saf e and ef f ect i ve use of dr ugs
i n i nf ant s and chi l dren.
D. Pedi at ri c drug admi ni st rati on and moni t ori ng. Dr ug admi ni st r at i on, i ncl udi ng
t he sel ect i on of agent and dose as wel l as t he preparat i on of t he dose and
t her apeut i c dr ug moni t ori ng ar e compl i cat ed i n t he pedi at r i c popul at i on. Phar maci st s
car i ng f or chi l dr en must i ncorporat e not onl y t he changes i n pharmacoki net i cs and
pharmacodynami cs descr i bed previ ousl y but al so t he need t o car ef ul l y check dosage
cal cul at i ons and, i f necessar y, al t er avai l abl e dosage f or mul at i ons t o sui t an i nf ant
or chi l d' s needs.
1. Accurate dosage caI cuI ati ons are cri t i caI i n t he care of i nf ants and chi I dren.
Phar maci st s shoul d use pedi at ri c dosi ng i nf or mat i on avai l abl e i n gener al dr ug
r ef erences or pedi at r i c- speci f i c ref erences such as The Pedi at ri c Dosage Handbook
( Lexi - Comp), or t he Har ri et Lane Handbook ( Mosby) . To account f or di f f erences i n
pharmacoki net i c paramet er s, most pedi at r i c doses are based on body wei ght . Ì n t he
case of some dr ugs, such as chemot herapy, doses ar e based on body sur f ace area
( BSA) . Thi s val ue can be det er mi ned f rom t he pat i ent ' s hei ght and wei ght , usi ng
ei t her a nomogr am or t he f ol l owi ng equat i on:

Ther e i s no absol ut e rul e f or when adol escent pat i ent s shoul d st ar t t o be dosed as
adul t s. Ì n general , adul t dosi ng gui del i nes may be used i n pat i ent s wei ghi ng mor e
t han 40-50 kg or when t he cal cul at ed wei ght - based pedi at r i c dose exceeds t he
st andard adul t dose.
2. The need t o caI cuI ate pedi at ri c doses i nt roduces a greater ri sk f or dosage
errors. Dosi ng er r ors have been f ound t o be more common i n medi cat i on or ders f or
chi l dren t han i n any ot her pat i ent popul at i on. The need t o cal cul at e i ndi vi dual
doses, al ong wi t h pot ent i al deci mal er ror s and t ranscr i pt i on er r ors, i ncr eases t he
pot ent i al f or mi st akes. Ì n addi t i on, t her e i s of t en a wi de r ange of pat i ent ages and
wei ght s wi t hi n a si ngl e hospi t al or cl i ni c. Ì t i s not uncommon t o have pat i ent doses
var y by 10- f ol d, as an i nf ant wei ghi ng 5 kg and an adol escent wei ghi ng 50 kg may
be car ed f or by t he same heal t hcare pr ovi der s. Al l cal cul at i ons shoul d be doubl e-
checked, and or ders out si de of t he normal pedi at r i c dosage r ange ver i f i ed wi t h t he
pr escri ber.
3. Dosage f ormuI ati ons may need t o be aI tered t o make t hem usef uI f or i nf ants
and chi I dren. Because young chi l dr en cannot t ypi cal l y swal l ow t abl et s and
capsul es, t hese sol i d dosage f or mul at i ons must of t en be conver t ed t o oral sol ut i ons
or suspensi ons. Sever al compoundi ng r esour ces, i ncl udi ng Ext empor aneous
For mul at i ons ( Amer i can Soci et y of Heal t h- Syst em Phar maci st s) , are avai l abl e t o
pr ovi de pharmaci st s wi t h f ormul at i ons t hat have been t est ed t o ensure dr ug
st abi l i t y.
4. I nt ravenous ( Ì V) medi cat i ons may be prepared as more concent rated
soI ut i ons, because of the I i mi t s on f I ui d admi ni st rati on to i nf ants and young
chi I dren. Whi l e a t ypi cal adul t may recei ve up t o 4- 5 L of Ì V f l ui ds per day, t he t ot al
dai l y f l ui d r equi rement s f or a pr et er m neonat e may be as l i t t l e as 20-50 mL. Speci al
equi pment , such as syr i nge pumps and
P. 759

mi cr obor e t ubi ng, i s used t o ensure accur at e del i ver y of drugs i n smal l f l ui d
vol umes. Cur rent l y avai l abl e syr i nge pumps can del i ver vol umes as smal l as 0. 1 mL
over 1 hr . Mi cr obore Ì V t ubi ng i s used t o mi ni mi ze t he amount of dead space
bet ween t he del i ver y devi ce and t he pat i ent , f ur t her i mprovi ng t he accur acy of drug
del i ver y. Phar maci st s must al so be capabl e of assessi ng l i t er at ur e on t he
compat i bi l i t y wi t h drugs and Ì V f l ui ds because pedi at r i c pat i ent s of t en have l i mi t ed
Ì V access, so t hat mul t i pl e sol ut i ons may need t o be i nf used t hr ough t he same Ì V
si t e.
E. Therapeut i c drug moni t ori ng i s of t en essent i al t o opt i mi zi ng dr ug t her apy i n
i nf ant s and chi l dren. For most dr ugs, t he t her apeut i c r anges devel oped f or and used
i n adul t s ar e al so appr opr i at e f or moni t ori ng pedi at r i c pat i ent s. A pot ent i al
compl i cat i on i n i nt er pret i ng ser um dr ug concent r at i ons i s t he presence of
endogenous subst ances, whi ch may cross- r eact wi t h anal yt i cal drug assays. Thi s
has been demonst rat ed f or di goxi n ( Lanoxi n) i n neonat es and i nf ant s, f or whom
endogenous di goxi n- l i ke r eact i ve subst ances ( EDLRS) may pr oduce f al sel y el evat ed
ser um di goxi n concent rat i ons. St andard assay t echni ques can be modi f i ed t o
excl ude EDLRS as a compl i cat i ng f act or.
F. Pharmaci sts shouI d aI so be aware of di f f erences i n adverse drug react i ons
between chi I dren and aduI t s. Most of t he adverse react i on i nf or mat i on avai l abl e i n
dr ug pr oduct l abel i ng or ci t ed i n pharmacy r ef er ences has been obt ai ned f r om
cl i ni cal t ri al s i n adul t s. As sever al st udi es have demonst r at ed, t he adverse r eact i on
pr of i l e i n chi l dr en may be si gni f i cant l y di f f er ent f r om t hat obser ved i n ol der subj ect s.
For exampl e, sever e dermat ol ogi c r eact i ons t o l amot ri gi ne ( Lami ct al ) , i ncl udi ng
St evens- Johnson syndr ome, wer e i nf r equent dur i ng premar ket i ng phase Ì Ì Ì cl i ni cal
t r i al s. When t he dr ug was i nt r oduced ont o t he mar ket i n t he Uni t ed St at es and
began t o be used i n chi l dr en of f -l abel , a hi gher rat e of dermat ol ogi c r eact i ons was
r eport ed i n chi l dr en. Subsequent r esear ch r eveal ed t he i nci dence of sever e
der mat ol ogi c r eact i ons t o be 0. 8% i n chi l dr en compared t o 0. 3% i n adul t s.
Di f f erences such as t hese f urt her hi ghl i ght t he need f or cl i ni cal r esear ch i n chi l dr en.
G. Ì n addi t i on, pharmaci st s shouI d t ake an act i ve roI e i n promot i ng medi cat i on
adherence ( compI i ance) i n chi I dren. Sever al st udi es have shown compl i ance r at es
i n pedi at ri c pat i ent s t o be 30%- 70%. Ì t i s surpr i si ng t hat some of t he poorest
compl i ance r at es have been associ at ed wi t h chr oni c di seases such as ast hma,
epi l epsy, and di abet es and i n chi l dren requi r i ng i mmunosuppr essi ve t herapy af t er
or gan t ranspl ant at i on. As i n adul t s, counsel i ng about medi cat i on adher ence shoul d
i ncl ude ef f ort s t o i dent i f y and overcome bar ri ers t o t her apy, educat i on about t he
i mpor t ance of medi cal management , and pr ogr ams t o i ncor porat e medi cat i on
r egi mens i nt o normal dai l y t asks. When wor ki ng wi t h f ami l i es of younger chi l dren,
pharmaci st s shoul d al so expl or e probl ems wi t h dosage f ormul at i on ( t ast e or t ext ur e
aver si on), and dosi ng f requency, par t i cul arl y wi t h medi cat i ons requi r i ng
admi ni st rat i on at school or day care. Ì n ol der chi l dr en, pharmaci st s shoul d be awar e
of t hei r need f or aut onomy, and wor k wi t h t he pat i ent ' s f ami l y t o f ost er t he goal of
sel f - car e. Phar maci st s can ser ve a vi t al rol e i n i mpr ovi ng medi cat i on adher ence i n
pat i ent s of al l ages.
II. DRUG USE IN PREGNANT PATIENTS.
Most women woul d l i ke t o avoi d pharmacol ogi c t her apy duri ng pr egnancy i f at al l
possi bl e. However , > 80% of women ar e exposed t o subst ances, such as medi cat i on
dur i ng t hei r pregnanci es. Pr eexi st i ng condi t i ons and ot her probl ems occurr i ng
dur i ng t he pr egnancy may r equi r e cont i nuat i on or i ni t i at i on of drug t her apy. Ì n r ar e
ci rcumst ances, f et al t herapy can be admi ni st er ed t hr ough t he mot her . Ì t i s i mpor t ant
t o underst and mat ernal pharmacoki net i c changes, pl acent al drug t r ansf er , event ual
di sposi t i on of t he drug, and l i mi t at i ons of t he FDA cl assi f i cat i on syst em t o saf el y
t r eat pr egnant women.
A. Fet aI deveI opment. The ef f ect s of drug t her apy i n pr egnancy depend l ar gel y on
t he st age of f et al devel opment dur i ng whi ch t he exposur e occurs. Pr egnanci es ar e
nor mal l y dat ed f r om t he f i r st day of t he l ast menst r ual cycl e; however , when
di scussi ng f et al devel opment , f er t i l i zat i on occur s on day 1.
1. Weeks 1-2. Dur i ng t he f i rst days af t er f er t i l i zat i on, t he zygot e f or ms i n t he
f al l opi an t ube. Over t he next f ew days, di vi si on of t he zygot e event ual l y resul t s i n
t he f ormat i on of t he bl ast ocyst , whi ch t ravel s t hrough t he t ube i nt o t he ut er us. The
bl ast ocyst cont ai ns numer ous t ypes of rel at i vel y undi f f erent i at ed t i ssues t hat wi l l
ul t i mat el y become t he f et us, t he pl acent a,
P. 760

and t he f et al membr anes. Super f i ci al i mpl ant at i on i n t he endomet ri um occur s wi t hi n
t he f i rst 5 days. Duri ng t he 2nd week, di f f er ent i at i on begi ns and t he pl acent a has
st art ed t o f orm. Dur i ng t hese weeks, t here i s an " al l or none¨ phenomenon. Wi t h no
pl acent a t o t r ansf er subst ances t o t he bl ast ocyst , t here i s no suscept i bi l i t y t o
t er at ogens. Exposure t o envi r onment al agent s dur i ng t hi s t i me wi l l have ei t her l i t t l e
or no ef f ect on t he embryo or wi l l dest r oy most cel l s l eadi ng t o pregnancy
t er mi nat i on.
2. Weeks 3-8. Ì t i s dur i ng t hi s t i me t hat t he pl acent a becomes f ul l y f unct i onal and
or ganogenesi s occurs. Thi s i s t he most cr i t i cal per i od of devel opment , when t he
embr yo i s most suscept i bl e t o t er at ogens. Al l maj or or gan syst ems devel op
st r uct ur al l y duri ng t hese weeks. Al l ar e compl et el y f or med by t he end of t he 9t h
week, wi t h t he except i on of t he cent r al ner vous syst em. Maj or congeni t al anomal i es,
such as cardi ac abnormal i t i es, spi na bi f i da, and l i mb def ect s occur duri ng t hi s t i me.
3. Weeks 9-38 (t he f et aI peri od) . At t he 9t h week, t he embr yo i s ref er red t o as a
f et us. Devel opment duri ng t hi s t i me i s pri mar i l y f unct i onal , wi t h over al l growt h
occur ri ng t hroughout . The f et us may be at ri sk dur i ng exposure t o pot ent i al l y
f et ot oxi c drugs or vi r uses. Exposure t o a dr ug i s gener al l y not associ at ed wi t h maj or
congeni t al mal f ormat i ons; however , mi nor congeni t al anomal i es and f unct i onal
def ect s may occur dur i ng t hi s t i me.
B. PI acentaI t ransfer of drugs. The pl acent a i s t he f unct i onal uni t bet ween t he
f et al and t he mat ernal bl ood suppl y. Ther e i s no mi xi ng of t he t wo syst ems, but
exchange of nut r i ent s, oxygen, and wast e product s occurs pri mar i l y vi a passi ve
di f f usi on. Thi s process i s dri ven by t he concent rat i on gradi ent bet ween t he t wo
syst ems. There are a f ew subst ances t hat ar e act i vel y t ransport ed acr oss t he
pl acent a (e. g. , ami no aci ds) ; dr ugs t hat ar e st r uct ur al l y si mi l ar t o t hese compounds
wi l l al so be t r anspor t ed by t hi s mechani sm.
1. PI acent aI metaboI i sm. The pl acent a pr oduces a number of pregnancy- r el at ed
hor mones t hat are mai nl y secret ed i nt o t he mat ernal ci r cul at i on. Some of t he ot her
subst ances pr oduced by t he pl acent a ar e enzymes t hat met abol i ze dr ugs. A common
exampl e of t hi s i s pr edni sone met abol i sm, so t hat ver y l i t t l e st er oi d r eaches t he
f et us.
2. Fact ors af fect i ng pI acent aI drug t ransf er. For a dr ug t o cause a t erat ogeni c or
pharmacol ogi cal ef f ect i n t he embr yo or f et us, i t must cr oss f r om t he mat er nal
ci rcul at i on t o t he f et al ci r cul at i on or t i ssues. Gener al l y, t he pri nci pl es t hat appl y t o
dr ug t r ansf er across any l i pi d membr ane can be appl i ed t o pl acent al t r ansf er of a
dr ug. Most subst ances admi ni st ered f or t her apeut i c purposes have, by desi gn, t he
abi l i t y t o cr oss t he pl acent a t o t he f et us. The cr i t i cal f act or i s whet her t he r at e and
ext ent of t r ansf er are suf f i ci ent t o cause si gni f i cant drug concent rat i ons i n t he f et us.
Ther e are many f act or s t hat af f ect t he r at e and ext ent of pl acent al dr ug t ransf er .
( a) MoI ecuI ar wei ght . Low mol ecul ar wei ght dr ugs (< 500 Da) di f f use f r eel y acr oss
t he pl acent a. Dr ugs of a hi gher mol ecul ar wei ght ( 500-1000 Da) cross l ess easi l y.
Dr ugs composed of ver y l ar ge mol ecul es (e. g. , hepar i n) do not cr oss t he pl acent al
membr anes.
( b) Drug pKa. Weakl y aci di c and weakl y basi c dr ugs t end t o rapi dl y di f f use across
t he pl acent al membr anes. Ì oni zed compounds do not cross t he pl acent a.
( c) Li pi d soI ubi I i t y. Moder at el y l i pi d-sol ubl e dr ugs easi l y di f f use acr oss t he
pl acent al membr anes. Ì t i s i mpor t ant t o not e t hat many dr ugs t hat have been
f or mul at ed f or oral admi ni st r at i on and ar e desi gned f or opt i mal l i pi d membr ane
t r ansf er.
( d) Drug absorpt i on. Dur i ng pr egnancy, gast ri c t one and mot i l i t y ar e decreased,
whi ch r esul t s i n del ayed gast r oi nt est i nal empt yi ng t i me. Thi s t ypi cal l y does not
af f ect dr ug absor pt i on. However , nausea and vomi t i ng, whi ch ar e most common i n
t he f i rst t ri mest er but may cont i nue t hr oughout pregnancy, may af f ect absor pt i on.
( e) Drug di st ri but i on. The vol ume of di st r i but i on i ncr eases si gni f i cant l y dur i ng
pr egnancy and i ncr eases wi t h advanci ng gest at i onal age. The al t er at i on i n vol ume
of di st r i but i on i s t he r esul t of an i ncr eased pl asma vol ume. Tot al body f l ui d
( i nt ravascul ar and ext r avascul ar vol ume) i ncr eases, as does adi pose t i ssue. The
pl acent a i t sel f may al so be a si t e f or di st ri but i on. Hydr ophi l i c dr ugs wi l l have a
hi gher vol ume of di st r i but i on l eadi ng t o l ower peak l evel s. Pl asma concent r at i ons of
dr ugs t hat ar e wi del y di st r i but ed are usual l y l ower t han t hose wi t h a smal l vol ume of
di st r i but i on. Ther ef or e, l ess drug i s avai l abl e t o cr oss t he pl acent a.
( f ) PI asma protei n bi ndi ng. Pl acent al t r ansf er of a hi ghl y pl asma-pr ot ei n-bound
dr ug i s l ess l i kel y because onl y t he f r ee drug cr osses t he pl acent a. Dur i ng
pr egnancy,
P. 761

a r educt i on i n t he l evel s of t wo maj or drug- bi ndi ng pr ot ei ns÷al bumi n and AGP÷i s
obser ved. A di l ut i onal ef f ect occur s wi t h al bumi n and ot her pr ot ei n concent r at i ons,
whi ch can i ncr ease t he f r ee f ract i on of drugs.
( g) Physi caI charact eri st i cs of the pI acenta. As a pr egnancy pr ogresses, t he
pl acent al membr anes become pr ogressi vel y t hi nner , r esul t i ng i n a decr ease i n
di f f usi on di st ance. The pl acent a al so expands, causi ng a great er sur f ace ar ea f or
t he t r ansf er of subst ances.
( h) Mat ernaI pharmacoki net i c changes. The dramat i c i ncr ease i n bl ood vol ume
t hat occurs pr i mari l y dur i ng t he f i rst 30 weeks of pr egnancy enhances bl ood f l ow
t hr ough t he ki dneys and l i ver . Drugs t hat ar e excr et ed r enal l y wi l l exper i ence a
mor e r api d cl earance, whi ch coul d decr ease t he over al l exposur e t i me of t he dr ug t o
t he pl acent a. Met abol i sm of some drugs i s i ncr eased; however , t he el evat ed l evel s
of est rogen and pr ogest er one present duri ng t he pr egnancy can compet i t i vel y i nhi bi t
t he met abol i sm of ot her dr ugs.
3. Terat ogeni c drugs
a. Ter at ogens ar e def i ned as agent s t hat i ncrease t he r i sk of or cause a congeni t al
anomal y t o occur . These def ect s can be st r uct ural , f unct i onal , or behavi oral i n
nat ure. Women may bl ame a speci f i c exposure dur i ng t hei r pr egnancy as t he cause
of a f et al anomal y; however , t he def ect may have no known cause, as i s t he case i n
3% of al l bi r t hs i n t he Uni t ed St at es.
b. Ì t may t ake year s of exposur es t o act ual l y l i nk a speci f i c dr ug t o cer t ai n def ect s.
Ani mal st udi es can onl y suggest pot ent i al pr obl ems i n humans but ar e of t en t he onl y
source of i nf ormat i on r egar di ng saf et y of agent s dur i ng earl y pr egnancy. The dose
t hat ani mal s of t en r ecei ve exceeds t he normal human dose, whi ch di mi ni shes t he
appl i cabi l i t y of t hese dat a t o humans.
c. The f et us i s unabl e t o met abol i ze or el i mi nat e dr ugs as qui ckl y as t he mot her .
Some subst ances may be excr et ed i nt o t he amni ot i c f l ui d and t hen r esorbed i n t he
f et al i nt est i nes af t er t he f l ui d i s swal l owed. Ther ef or e, some drugs may have a
l onger exposur e t i me i n t he f et us, wher eas ot hers ar e el i mi nat ed mor e rapi dl y.
c. Because f et al organ syst ems devel op at di f f erent t i mes, speci f i c t erat ogeni c
ef f ect s depend mai nl y on t he poi nt of gest at i on when t he dr ug was i ngest ed.
d. The t er at ogeni c rat e of subst ances i ndi cat es how f r equent l y anomal i es occur and
over what exposur e per i od. For exampl e, one of t he most pot ent known t er at ogens,
t hal i domi de, had a t erat ogeni c r at e of 20% wi t h a si ngl e exposur e, yet onl y one t hi r d
of women who i ngest ed t he drug gave bi rt h t o af f ect ed i nf ant s. Ot her agent s may
i ncrease t he r at e of speci f i c def ect s over t he gener al popul at i on, but t he absol ut e
i nci dence may be ext r emel y l ow.
e. The FDA devel oped a cl assi f i cat i on syst em t hat gr oups drugs accor di ng t o t he
degree of t hei r pot ent i al r i sk dur i ng pr egnancy.
1

( 1) Categor y A. Adequat e, wel l -cont r ol l ed st udi es i n pregnant women have not
shown an i ncreased r i sk of f et al abnormal i t i es.
( 2) Categor y B. Ani mal st udi es have reveal ed no evi dence of harm t o t he f et us;
however , t her e ar e no adequat e and wel l -cont r ol l ed st udi es i n pr egnant women. Or
ani mal st udi es have shown an adverse ef f ect , but adequat e and wel l -cont r ol l ed
st udi es i n pr egnant women have f ai l ed t o demonst r at e a r i sk t o t he f et us.
( 3) Categor y C. Ani mal st udi es have shown an adver se ef f ect and t here ar e no
adequat e and wel l - cont rol l ed st udi es i n pr egnant women. Or no ani mal st udi es have
been conduct ed, and t her e are no adequat e and wel l - cont r ol l ed st udi es i n pr egnant
women.
( 4) Categor y D. St udi es, adequat e wel l - cont rol l ed or obser vat i onal , i n pregnant
women have demonst r at ed a r i sk t o t he f et us. However , t he benef i t s of t her apy may
out wei gh t he pot ent i al ri sk.
( 5) Categor y X. St udi es, adequat e wel l - cont rol l ed or obser vat i onal , i n ani mal s or
pr egnant women have demonst rat ed posi t i ve evi dence of f et al abnormal i t i es. The
use of t he pr oduct i s cont r ai ndi cat ed i n women who are or may become pregnant .
d. ProbI ems wi t h t he current syst em. The cur rent syst em was creat ed i n 1979 and
has not been r evi sed si nce i t s i ncept i on. Wi t h many agent s t her e i s a pauci t y of
human dat a, despi t e t he f act t he drug may car r y a cat egor y B rat i ng. Most newl y
market ed agent s wi l l
P. 762

be pl aced i n cat egor y C, ami d ot her agent s wi t h l i t t l e dat a i n humans or ani mal s.
Thi s i s t he most di f f i cul t cat egor y t o assess. Al t hough t her e may be case r eport s of
dr ug exposures, t hese t end t o bi as i nf ormat i on t owar d f et al r i sk; most publ i sh onl y
out comes wi t h pot ent i al dr ug- rel at ed ef f ect s. Few dr ugs wi l l ever be assi gned a
cat egor y A st at us because l ar ge, randomi zed, wel l -cont r ol l ed t r i al s ar e rar el y
conduct ed i n pregnant women.
f . ExampI es of t erat ogeni c agents.
( 1) Vi tami n A deri vat i ves. Dr ugs such as i sot ret i noi n ( Accut ane) and et ret i nat e
( Tegi son) ar e pot ent t erat ogens i n humans. These agent s shoul d be di scont i nued
sever al mont hs bef ore pregnancy.
( 2) Warfari n ( Coumadi n) i s most t erat ogeni c i n t he f i rst t r i mest er ( weeks 6- 9) , but
can al so cause mal f ormat i ons dur i ng t he second and t hi rd t ri mest ers as wel l . Earl y
exposur e i s associ at ed wi t h a pat t er n of def ect s known as f et al war f ar i n syndr ome.
These def ect s can i ncl ude hypopl asi a of t he nose and ext r emi t i es, congeni t al hear t
di sease, and sei zures. Cent r al ner vous syst em abnormal i t i es are i ncreased wi t h
l at er use. Hepar i ns may be an appropr i at e subst i t ut e when ant i coagul at i on i s
necessar y; however , t hey ar e not as ef f ect i ve f or pr event i ng t hr ombosi s i n women
wi t h ar t i f i ci al hear t val ves.
( 3) Androgeni c agent s can cause vi ri l i zat i on of f emal e f et uses, cr eat i ng ambi guous
geni t al i a. Fi nast er i de ( Propeci a) can cause geni t al abnor mal i t i es i n mal e of f spr i ng.
Est r ogen and pr ogest i ns, f or t unat el y, do not have t hi s ef f ect . Many women cont i nue
t o t ake bi r t h cont r ol pi l l s duri ng t he f i rst mont h or t wo af t er concept i on unt i l t he
pr egnancy i s di scovered.
( 4) Et hanoI . Al cohol consumed i n l arge amount s f or prol onged peri ods dur i ng
pr egnancy ( > 4- 5 dr i nks/ day) i s known t o cause f et al al cohol syndr ome (FAS) .
Feat ur es of FAS i ncl ude gr owt h r est r i ct i on, cr ani of aci al dysmorphol ogy and cent ral
ner vous syst em mal f unct i ons, al ong wi t h var i ous ot her abnormal i t i es. At l east 30%
of women who abuse al cohol wi l l del i ver an i nf ant af f ect ed by FAS. Moder at e
al cohol consumpt i on ( 2 dr i nks/ day) can al so l ead t o si mi l ar def ect s, al t hough
usual l y not t he compl et e syndrome. Even t hough t he most pr obl emat i c t i me i s dur i ng
t he f i rst 2 mont hs of pr egnancy, moder at e dr i nki ng dur i ng t he second t r i mest er i s
associ at ed wi t h an i ncreased r at e of spont aneous abor t i ons.
( 5) Ant i neopI ast i cs. Many agent s i n t hi s cl ass ar e associ at ed wi t h f et al anomal i es
af t er f i rst t r i mest er chemot herapy admi ni st rat i on. Gr owt h r est ri ct i on of t en occurs
r egardl ess of t he t i mi ng of exposur e. Owi ng t o t he mechani sm of act i on of t hese
agent s, many are embr yoci dal .
( 6) Ant i convuI sants. Drugs such as phenyt oi n (Di l ant i n) , val pr oi c aci d (Depakene) ,
and carbamazepi ne ( Tegr et ol ) have al l been associ at ed wi t h f et al anomal i es.
However , mat er nal benef i t f rom t hese agent s of t en out wei ghs t he ri sk t o t he f et us.
Ant i convul sant s shoul d not be st opped dur i ng pregnancy, but i f appropri at e, t hey
shoul d be di scont i nued sever al mont hs bef or e f ert i l i zat i on. Val pr oi c aci d and
car bamazepi ne can i ncr ease t he r i sk of neur al t ube def ect s; women t aki ng t hese
agent s shoul d recei ve f ol i c aci d suppl ement at i on st art i ng bef ore concept i on. Toxi c
epoxi de radi cal s ar e t hought t o be t he mechani sm of t erat ogeni ci t y wi t h sever al of
t hese agent s. Genet i c al t er at i ons i n t he epoxi de hydr ol ase enzyme act i vi t y can
r educe or i ncr ease t he sever i t y of abnormal i t i es.
( 7) I nfecti ons. Vi ral i nf ect i ons, such as rubel l a, cyt omegal ovi rus, par vovi r us,
coxsacki e, and vari cel l a can be associ at ed wi t h gr owt h r est r i ct i on, congeni t al
anomal i es, pr emat ur e del i ver y, and pot ent i al embr yot oxi ci t y or f et al demi se. Near l y
al l mat ernal i nf ect i ons have been t hought t o cause gr owt h r est ri ct i on.
( 8) Ci garet t e smoki ng. Ci garet t es cont ai n many t oxi c and car ci nogeni c compounds
i n addi t i on t o ni cot i ne. Ni cot i ne i s a pot ent vasoconst r i ct i ng agent capabl e of
r educi ng ut eri ne bl ood f l ow and i ncreasi ng ut eri ne vascul ar resi st ance. Smoki ng not
onl y i ncreases t he ri sk of a gr owt h r est ri ct ed f et us but al so i ncr eases t he r i sk of
spont aneous abor t i ons, pr emat ur e del i ver y, pl acent al abr upt i on, and premat ur e
r upt ur e of t he membranes. Smal l i ncr eases i n def ect s of t he heart , l i mbs and f eet ,
skul l , uri nar y syst em, abdomen, i nt est i nes, and muscl es have al so been associ at ed
wi t h ci gar et t es. Smoki ng may al so al t er t he ef f ect s of ot her subst ances, per haps
enhanci ng t oxi ci t y of bot h agent s.
4. Ot her probI emat i c t herapi es. Some agent s gi ven duri ng pregnancy may r esul t i n
pharmacol ogi cal ef f ect s t hat ar e not necessari l y t oxi c, yet need t o be consi der ed
when medi cat i ons ar e gi ven duri ng t he l at er weeks of pr egnancy.
P. 763


a. Cent raI nervous syst em ( CNS) depressi on may occur wi t h barbi t ur at es,
t r anqui l i zers, ant i depr essant s, and nar cot i cs. Al so, anest het i cs and ot her agent s
commonl y gi ven duri ng l abor may cause si gni f i cant CNS and respi rat or y depr essi on
i n newbor ns ( e. g. , magnesi um sul f at e or opi oi d anal gesi cs) .
b. Neonat aI bI eedi ng. Mat er nal i ngest i on of agent s such as nonst er oi dal ant i -
i nf l ammat or y drugs ( NSAÌ Ds) and ant i coagul ant s at t her apeut i c doses near t erm
may cause bl eedi ng pr obl ems i n t he newbor n.
c. Drug wi t hdrawaI . Habi t ual mat er nal use of bar bi t ur at es, nar cot i cs,
benzodi azepi nes, al cohol , and ot her subst ances of abuse may l ead t o wi t hdr awal
sympt oms i n newbor ns.
d. Const ri cti on of t he duct us art eri osus. Mat ernal use of NSAÌ Ds i n t he t hi rd
t r i mest er may cause t he duct us ar t er i osus t o cl ose pr emat urel y and coul d r esul t i n
pul monar y hyper t ensi on i n t he newbor n.
III. DRUG EXCRETION IN BREAST MILK.
Today, > 60% of women choose t o breast - f eed t hei r i nf ant s. Of t hese women, 90%-
95% recei ve a medi cat i on duri ng t he f i r st post part um week, most commonl y f or pai n
cont r ol af t er del i ver y. Ì t i s i mpor t ant t o under st and t he pri nci pl es of drug excr et i on
i n br east mi l k and speci f i c i nf or mat i on on t he var i ous medi cat i ons t o mi ni mi ze ri sks
f r om dr ug ef f ect s i n t he nur si ng i nf ant .
A. Transf er of drugs f rom pI asma to breast mi I k. Dr ug t ransf er i nt o br east mi l k i s
gover ned by many of t he same pr i nci pl es t hat i nf l uence human pl acent al dr ug
t r ansf er.
1. Most drugs cr oss i nt o br east mi l k vi a passi ve di f f usi on al ong a concent rat i on
gr adi ent f or med by t he un- i oni zed dr ug cont ent on each si de of t he membr ane.
2. Br east mi l k cont ent s change t hr oughout a f eedi ng. Col ost r um, t he ver y f i r st mi l k
pr oduced, i s much hi gher i n pr ot ei n t han mat ure mi l k and t he f at cont ent i s mi ni mal .
Mat ur e mi l k consi st s of f or e-mi l k at t he begi nni ng of a f eedi ng and hi nd-mi l k at t he
end. The prot ei n and f at cont ent i ncrease t hr oughout t he nursi ng sessi on. Ther ef ore
dr ugs t hat part i t i on i nt o mor e l i pi d sol ut i ons wi l l have t he hi ghest concent r at i on i n
hi nd mi l k.
3. A mi l k t o pl asma rat i o can be det ermi ned f or speci f i c agent s when bot h bl ood and
mi l k concent rat i ons are known. Most dr ugs have a r at i o < 1; l ower number s i ndi cat e
t hat l ess drug cr osses i nt o breast mi l k. Because t he mi l k t o pl asma rat i o may
change wi t hi n a f eedi ng, t he aver age br east mi l k concent r at i on i s usual l y used, i f
avai l abl e.
4. Ì t i s possi bl e t o cal cul at e t he dose an i nf ant r ecei ves i f t he br east mi l k
concent r at i on i s known. A t ypi cal i nf ant dri nks 150 mL/ kg per day. Mul t i pl yi ng t he
aver age concent r at i on by t he br east mi l k vol ume consumed wi l l gi ve t he t ot al dai l y
exposur e. Ì t i s i mport ant t o remember t hat t hi s drug must now be i ngest ed by t he
i nf ant , so t he bi oavai l abi l i t y of t he drug i s cri t i cal t o cal cul at e t he act ual dai l y dose.
Doses < 10% of t he mat er nal dose on a mi l l i gram per ki l ogram per day basi s ar e
pr ef er abl e.
5. Some medi cat i ons ar e not absorbed or al l y, but may pass i nt o breast mi l k when
admi ni st er ed i nt r avenousl y t o t he mot her . Al t hough t he dr ug may not ent er t he
i nf ant ' s bl ood, i t may have ef f ect s on t he gast r oi nt est i nal t r act . For exampl e, t he
bi oavai l abi l i t y of gent ami ci n i s negl i gi bl e; however , i t may cause di ar rhea or
st eri l i ze t he bowel .
B. Drug f act ors. The drug and i t s envi r onment i nf l uence t he r at e and ext ent of dr ug
passage i nt o t he br east mi l k.
1. MoI ecuI ar wei ght . Drugs wei ghi ng < 200 Da cr oss i nt o mi l k easi l y. Larger
mol ecul es can di ssol ve i n t he l i pi d membr ane or pass t hr ough smal l por es. Lar ge
mol ecul es, such as i nsul i n, do not cross i nt o br east mi l k.
2. pH gradi ent . Human mi l k i s mor e aci di c t han pl asma.
a. Weak aci ds may di f f use across t he membrane and r emai n un- i oni zed, al l owi ng f or
passage back i nt o t he pl asma. Lower amount s of t hese dr ugs wi l l cr oss t han t hose
t hat ar e weak bases.
b. Weak bases may di f f use i nt o t he br east mi l k and i oni ze, whi ch causes dr ug
t r appi ng. Thi s cr eat es hi gher l evel s of dr ug i n t he br east mi l k; t hese dr ugs wi l l have
a mi l k t o pl asma r at i o > 1. Thi s ef f ect t hough, i s not usual l y cl i ni cal l y si gni f i cant ,
especi al l y when t he mat er nal ser um concent r at i on i s ver y l ow.
P. 764


3. Drug pKa. Onl y t he un- i oni zed f orm of a dr ug i s abl e t o pass t hr ough t he l i pi d
membr ane.
4. PI asma protei n bi ndi ng. The f r ee f r act i on of a dr ug i s avai l abl e t o pass i nt o t he
br east mi l k. Ì n general , dr ugs wi t h hi gh pl asma-pr ot ei n-bi ndi ng pr oper t i es t end t o
r emai n i n t he pl asma and pass i nt o t he mi l k i n l ow concent rat i ons. Mi l k prot ei ns and
l i pi ds al so may bi nd dr ugs when t hey are cr eat ed i n t he mammar y gl ands; t hi s may
r epr esent anot her r out e of ent r y, r at her t han passi ve di f f usi on.
5. Li pi d soI ubi I i t y. Li pi d sol ubi l i t y i s necessar y f or a dr ug t o pass i nt o t he br east
mi l k. Hi ghl y l i pi d-sol ubl e dr ugs (e. g. , di azepam, Val i um) may pass i nt o t he br east
mi l k i n rel at i vel y hi gh amount s and, t her ef or e, may pr esent a si gni f i cant dose of
dr ug t o t he nursi ng i nf ant .
6. Equi I i brat i on. Some dr ugs may r api dl y equi l i br at e bet ween mat er nal pl asma and
br east mi l k. These agent s wi l l di f f use across t he membr ane as t he drug
concent r at i on changes i n t he mat er nal syst em. Ot her agent s may never r each an
equi l i br i um bet ween mi l k and pl asma. These drugs t end t o sl owl y di f f use i nt o br east
mi l k and wi l l respond gradual l y t o changes i n mat er nal concent r at i ons.
C. MaternaI f act ors. Mat er nal pharmacol ogy pl ays a si gni f i cant r ol e i n t he r at e and
ext ent of dr ug passage i nt o br east mi l k. The ext ent of pl asma prot ei n bi ndi ng and
changes i n t he mot her ' s abi l i t y t o met abol i ze or el i mi nat e t he drug i nf l uence t he
amount of dr ug t hat i s avai l abl e t o pass i nt o t he br east mi l k. Equal l y i mport ant ar e
t he mat er nal dose of t he dr ug, t he dosi ng schedul e or f r equency, and t he r out e of
admi ni st rat i on.
D. Drugs af f ect i ng hormonaI i nfI uence of breast mi I k product i on. The pri mar y
hor mone r esponsi bl e f or cont r ol l i ng br east mi l k product i on i s pr ol act i n. A decr ease
i n mi l k pr oduct i on may resul t i n di mi ni shed wei ght gai n i n t he nur si ng i nf ant , t he
need f or suppl ement at i on, or pr emat ur e cessat i on of br east - f eedi ng.
1. Drugs t hat decrease serum proI act i n I eveI s. Dr ugs such as br omocr i pt i ne have
been used t o suppress l act at i on i n women who choose not t o br east - f eed. Thi s
pr act i ce has l ong been abandoned because myocar di al i nf ar ct i ons, sei zures, and
st r oke wer e at t ri but ed t o i t s use. Ot her dr ugs i ncl ude
a. Er got al kal oi ds
b. L-dopa
2. Drugs t hat i ncrease serum proI act i n I eveI s. Met ocl opr ami de ( Regl an) has been
usef ul t her apeut i cal l y t o enhance mi l k pr oduct i on. The f ol l owi ng drugs are known t o
i ncrease serum prol act i n l evel s, but t hey ar e not used f or t hi s pur pose. These drugs
i ncl ude
a. Met hyl dopa ( Al domet )
b. Hal oper i dol ( Hal dol )
c. Phenot hi azi nes
E. Fact ors t o assess. Ì n assessi ng t he saf et y of an agent dur i ng br east -f eedi ng,
sever al consi derat i ons shoul d be addressed:
1. Ì nherent t oxi ci t y of t he dr ug
2. Dr ug saf et y dat a i n i nf ant s
3. Amount of drug i ngest ed
4. Durat i on of t herapy
5. Age of t he i nf ant or degr ee of premat uri t y
6. Dr ug pharmacoki net i cs i n t he mot her and chi l d
F. Fact ors t o mi ni mi ze drug exposure to t he i nf ant . One of t he goal s when usi ng
medi cat i ons i n t he br east - f eedi ng mot her i s t o mai nt ai n a nat ur al , uni nt err upt ed
pat t er n of nursi ng. Ì n many i nst ances, i t may be possi bl e t o wi t hhol d a dr ug when i t
i s not essent i al or del ay t her apy unt i l af t er weani ng. Ot her f act ors i ncl ude
1. Medi cat i on seI ect i on. When a speci f i c pr oduct i s bei ng sel ect ed, i t i s i mport ant
t o choose t he agent t hat i s di st ri but ed i nt o t he mi l k t he l east , i f possi bl e.
a. Ot her desi r abl e char act eri st i cs i ncl ude a shor t hal f - l i f e, i nact i ve met abol i t es, and
hi gh prot ei n bi ndi ng.
P. 765


b. Ì n addi t i on, i t i s desi rabl e t o sel ect agent s wi t h l ower pl asma concent rat i ons,
whi ch may i nvol ve an al t er nat i ve rout e of admi ni st r at i on.
c. Si ngl e doses may be pr ef er abl e t o a l onger t her apy course i f t he agent i s
cont r ai ndi cat ed i n breast - f eedi ng. Thi s can al l ow f or t he mot her t o pump and di scard
her mi l k f or a def i ned per i od of t i me, of t en 12-24 hr , r at her t han di scont i nue breast -
f eedi ng al t oget her .
2. Mat ernaI dose reI at i ve t o i nf ant f eedi ng. One of t he goal s of dr ug dosi ng i n
l act at i ng women i s mi ni mal i nf ant exposur e t o t he dr ug. Ì t i s desi r abl e t o adj ust t he
dosi ng and nur si ng schedul es so t hat a dr ug dose i s admi ni st er ed at t he t i me of or
i mmedi at el y af t er t he i nf ant ' s f eedi ng. Medi cat i ons shoul d be dosed bef or e t he
i nf ant ' s l ongest sl eep.
G. ExampI es of drugs that readi I y ent er breast mi I k. These agent s shoul d be
used wi t h caut i on i n nursi ng mot hers.
1. Narcot i cs, barbi turates, and benzodi azepi nes. CNS act i ve agent s, such as
di azepam, may have a hypnot i c ef f ect on t he nursi ng i nf ant . These ef f ect s are
r el at ed t o t he mat ernal dose. Al cohol consumpt i on may have a si mi l ar ef f ect .
2. Ant i depressant s and ant i psychot i cs. These cl asses of dr ugs appear t o pass
i nt o t he breast mi l k; however , no ser i ous adver se ef f ect s have been r eport ed. The
l ong- t erm behavi oral ef f ect s of chr oni c exposur e t o t hese dr ugs on devel opi ng
newbor ns are unknown.
3. Ant i choI i nergi c compounds. These dr ugs may r esul t i n adverse CNS ef f ect s i n
t he i nf ant and may r educe mi l k vol ume i n t he mot her . Di cycl omi ne ( Bent yl ) i s
cont r ai ndi cat ed i n nur si ng mot her s because i t may r esul t i n neonat al apnea.
IV. DRUG USE IN GERIATRIC PATIENTS.
Ì n 2000, mor e t han 12% of t he Ameri can popul at i on was > 65 years of age,
r epr esent i ng more t han 35 mi l l i on Ameri cans. Ì t i s est i mat ed t hat t hr ee out of ever y
f our el der l y peopl e are t aki ng pr escri pt i on medi cat i ons. Ant i ci pat ed t ot al dr ug
usage, i ncl udi ng nonpr escri pt i on medi cat i ons, r eveal s t hat 50% of al l drugs used i n
t he Uni t ed St at es ar e used by t he geri at ri c popul at i on.
A. Adverse drug react i ons. Ger i at r i c pat i ent s ar e at i ncr eased ri sk f or dr ug-
i nduced adver se ef f ect s. Ì nci dence of adver se drug r eact i ons ( ADRs) i n pat i ent s
over t he age of 65 i s t wo t o t hr ee t i mes gr eat er compar ed t o younger pat i ent s. The
r i sk i s f i ve t i mes hi gher i n peopl e approachi ng age 90. One i n f i ve of al l el der l y
pat i ent s exper i ences an ADR. Ì n some pat i ent s, t hese are overl ooked because t hey
mi mi c t he char act eri st i cs of ot her di seases.
1. Fact or s t hat ar e responsi bl e f or t he hi gher pr eval ence of ADRs i n t he ger i at r i c
popul at i on i ncl ude pol yphar macy, poor r el at i onshi p wi t h heal t hcare pr ovi der s,
mul t i pl e di sease st at es, i ncr easi ng sever i t y of i l l ness, r educed drug el i mi nat i on, and
i ncreased sensi t i vi t y t o dr ug ef f ect s.
a. St udi es have shown t hat > 35% of ger i at r i c pat i ent s l i vi ng i n t he communi t y use
si x or mor e medi cat i ons; approxi mat el y one hal f of pat i ent s resi di ng i n l ong- t er m-
car e f aci l i t i es use f i ve or more medi cat i ons. Peopl e 65 and ol der use approxi mat el y
40% of t he dr ugs pr escr i bed and 50% of t he over- t he-count er ( OTC) medi cat i ons
t aken.
b. Pat i ent s t aki ng mul t i pl e medi cat i ons have a great er chance of exper i enci ng ADRs
owi ng t o dr ug- drug i nt eract i ons and t he pot ent i al f or over l ap or syner gy bet ween
adver se ef f ect pr of i l es.
c. Pat i ent s wi t h mul t i pl e di sease st at es are at hi gher ri sk of havi ng a dr ug- di sease
st at e i nt er act i on.
d. Ì n addi t i on t o t he af orement i oned ri sk f act ors f or devel opi ng an ADR, i t i s di f f i cul t
t o predi ct how geri at ri c pat i ent s wi l l respond t o any gi ven medi cat i on owi ng t o
al t er ed phar macoki net i c and phar macodynami c prof i l es.
e. Anot her i ssue compl i cat i ng ger i at r i c dr ug t her apy i s adher ence. Fact ors t hat have
been shown t o i ncr ease nonadher ence i ncl ude poor rel at i onshi ps wi t h heal t hcare
pr ovi der s, l ower soci oeconomi c st at us, l i vi ng al one, pol ypharmacy, compl i cat ed
dr ug r egi mens, and mul t i pl e comorbi di t i es. As many as 60% of geri at r i c pat i ent s do
not t ake t hei r medi cat i ons as prescri bed and may sel f -medi cat e as of t en as once a
week. Ì f pat i ent s are hospi t al i zed, t hei r prescr i bed dr ug doses may r epresent a
si gni f i cant over dosage or under dosage, whi ch coul d cause uni nt ended ef f ect s.
f . El der l y pat i ent s can have di seases t hat make adher i ng t o drug t herapy di f f i cul t .
Condi t i ons t hat af f ect vi si on, such as macul ar degener at i on or cat ar act f or mat i on,
can make r eadi ng
P. 766

pr escri pt i on l abel s and medi cat i on i nst r uct i ons t r oubl esome. Heari ng l oss can
pr event pat i ent s f rom under st andi ng and heal t hcar e pr of essi onal s f r om ef f ect i vel y
communi cat i ng medi cat i on i nf ormat i on and pat i ent i nst r uct i ons. Ar t hr i t i s can add t o
t he di f f i cul t y of openi ng medi cat i on bot t l es. Ì n t hese i nst ances, provi di ng pat i ent s
wi t h medi cat i on or "pi l l ¨ boxes and wr i t t en medi cat i on l i st s may l i mi t pot ent i al
bar r i er s t o pat i ent adherence. Recogni zi ng t hese f act ors, pharmaci st s can i ncr ease
adher ence i n el derl y pat i ent s.
2. Phar maci st s can provi de r ecommendat i ons t o el i mi nat e unnecessar y dr ug t herapy
and moni t or medi cat i on pr of i l es t o avoi d pot ent i al drug- drug or dr ug-di sease st at e
i nt er act i ons t hat may prove harmf ul . Ef f or t s t o opt i mi ze dr ug t herapy, i ncl udi ng
si mpl i f yi ng and empl oyi ng mor e cost -ef f ect i ve r egi mens, may ul t i mat el y af f or d bet t er
pat i ent adherence.
B. Pharmacoki net i cs. Phar macoki net i c par amet er s may be al t er ed i n t he el der l y
owi ng t o age- r el at ed physi ol ogi cal changes. Speci f i c age- rel at ed physi ol ogi cal
changes af f ect i ng drug t her apy ar e gi ven i n Tabl e 37-3.
1. Absorpt i on. Physi ol ogi cal changes t hat can al t er absorpt i on i n t he geri at ri c
popul at i on i ncl ude del ayed gast r i c empt yi ng, decr eased spl anchni c bl ood f l ow,
el evat ed gast r i c pH, and i mpai r ed i nt est i nal mot i l i t y. Al t hough t he r at e of dr ug
absor pt i on may be al t er ed i n some pat i ent s, t he ext ent of absor pt i on i s r arel y
af f ect ed.
2. Di st ri buti on. Sever al age- rel at ed physi ol ogi cal changes may af f ect drug
di st r i but i on.
a. El derl y pat i ent s have a decr ease i n t ot al body wat er , causi ng wat er - sol ubl e drugs
( e. g. , acet ami nophen, Tyl enol ) t o have a smal l er vol ume of di st r i but i on. Peak
concent r at i ons of t hese agent s wi l l be hi gher , and l oadi ng doses may need t o be
adj ust ed t o i ncor por at e t hi s change.
b. The vol ume of di st r i but i on of l i pi d- sol ubl e drugs ( e. g. , di azepam, Val i um;
pr opranol ol , Ì nder al ) i s i ncr eased because geri at r i c pat i ent s t end t o have a gr eat er
r at i o of adi pose t i ssue t o l ean muscl e mass. These medi cat i ons may accumul at e i n
f at st ores, i ncreasi ng t hei r dur at i on of act i on.
c. Agi ng may al so af f ect t he pharmacoki net i cs of dr ugs t hat ar e hi ghl y pr ot ei n
bound. For exampl e, drugs t hat are hi ghl y bound t o al bumi n ( e. g. , war f ar i n,
Coumadi n; phenyt oi n, Di l ant i n) may have a great er f r ee concent r at i on because
al bumi n can be decr eased i n t he el derl y who ar e chr oni cal l y i l l .
d. Medi cat i ons may have al t er ed bi ndi ng af f i ni t y i n t he el derl y or al bumi n may
exper i ence a change i n conf i gur at i on, whi ch can al so l ower bi ndi ng capaci t y.
Compet i t i on f or aci di c
P. 767

bi ndi ng si t es coul d occur wi t h accumul at ed endogenous subst ances, al t er i ng t he
f r ee f r act i on of dr ugs.
Table 37-3. Age-Related Physiological Changes Affecting Drug Therapy
Factors ChangeClinical Significance
Pharmacokinetic
Gastrointestinal motility | May aIIect the rate but not the extent
oI drug absorption
Gastric pH | No signiIicant change in drug
absorption
Renal Iunction | Reduced elimination oI renally
excreted drugs
Serum albumin | Decreased protein binding leading to
an increased Iree Iraction oI drug
Phase I hepatic
metabolism
| Potential accumulation oI drugs
metabolized by oxidation. reduction.
or hydrolysis reactions
Body Iat to lean muscle
mass ratio
| Increased volume oI distribution oI
Iat-soluble drugs
Total body water | Decreased volume oI distribution oI
water-soluble drugs
Pharmacodynamic
þ-receptor sensitivity | Potential diminished response to þ-
blockers
Baroreceptor sensitivity | Greater risk oI orthostatic
hypotension
Response to
benzodiazepines and
opioid analgesics
| Increased risk oI adverse eIIects
with typical doses

e. Al t hough AGP concent r at i ons t end t o i ncr ease wi t h age, t he i ncr ease i n t he
concent r at i ons of basi c dr ugs (e. g. , l i docai ne, Xyl ocai ne; propranol ol , Ì nder al ) t hat
bi nd t o AGP are usual l y cl i ni cal l y meani ngf ul onl y i n acut el y i l l pat i ent s.
3. RenaI excret i on. Perhaps t he best document ed age- rel at ed physi ol ogi cal change
i s t he decl i ne i n r enal f unct i on, speci f i cal l y gl omer ul ar f i l t rat i on r at e and t he t ubul ar
secr et i on r at e.
a. Ì n pat i ent s wi t hout renal dysf unct i on, i t i s est i mat ed t hat t her e i s a 50% decl i ne i n
r enal f unct i on by age 80. Renal bl ood f l ow i s r educed by appr oxi mat el y 10% each
decade of l i f e.
b. Serum creat i ni ne may not be a good predi ct or of r enal f unct i on, as cr eat i ni ne
pr oduct i on al so decl i nes wi t h age and l ower act i vi t y l evel s (such as t he bedr i dden or
debi l i t at ed) .
c. Medi cat i ons pri mar i l y el i mi nat ed by t he ki dneys may have i ncr eased
concent r at i ons of bot h t he act i ve dr ug and i t s met abol i t es, possi bl y l eadi ng t o
subsequent adverse ef f ect s. Al l renal l y el i mi nat ed dr ugs used i n geri at r i c pat i ent s
shoul d be moni t ored f or t he need f or dose r educt i ons and pot ent i al t oxi ci t y.
4. Hepat i c met aboI i sm. Age- r el at ed changes af f ect i ng t he l i ver i ncl ude a r educt i on
i n hepat i c bl ood f l ow and a decl i ne i n hepat i c met abol i sm.
a. Phase Ì Ì r eact i ons (gl ucuroni dat i on, acet yl at i on, and sul f at i on) are r el at i vel y
unchanged i n t he el der l y.
b. A reduct i on i n phase Ì r eact i ons ( oxi dat i on, r educt i on, and hydr ol ysi s) can occur .
Benzodi azepi nes and cer t ai n anal gesi cs, whi ch depend on phase Ì r eact i ons f or
met abol i sm, r epr esent si t uat i ons i n whi ch changes i n hepat i c met abol i sm may be
i mpor t ant . The el i mi nat i on hal f -l i ves of t hese agent s ar e pr ol onged and may r esul t
i n dr ug accumul at i on and possi bl e adverse ef f ect s.
c. Li ver vol ume and cel l mass decr ease i n t he el der l y. Ì t appears t hat t hi s change i n
si ze enhances t he reduced act i vi t y of oxi dat i ve and demet hyl at i on met abol i sm.
Conj ugat i on r eact i ons do not appear t o be af f ect ed by l i ver mass.
C. Pharmacodynami cs
1. Ger i at ri c pat i ent s can be mor e or l ess r esponsi ve t o cer t ai n drugs, compar ed t o
younger pat i ent s. Reasons f or t hi s may i ncl ude al t ered recept or sensi t i vi t y, r ecept or
number , or recept or response. St udi es have shown t hat el der l y pat i ent s may show a
di mi ni shed r esponse t o 8- bl ocker s.
2. Ì n cont rast , ger i at r i c pat i ent s seem t o have an exagger at ed response t o agent s
af f ect i ng t he CNS, nar cot i c anal gesi cs, benzodi azepi nes, and war f ar i n. El der l y
pat i ent s shoul d be moni t or ed car ef ul l y when t aki ng t hese medi cat i ons. Ì ni t i at i on of
any of t hese t her api es shoul d be at l ower doses t han r ecommended f or younger
pat i ent s. Avoi dance of t hese dr ugs may not be possi bl e, but i f bet t er al t ernat i ves
exi st t hey shoul d be used f i rst .
D. Drug t herapy consi derat i ons
1. Dr ug t her apy i n geri at r i c pat i ent s i s i nvol ved and can be ver y compl ex because of
age- rel at ed changes i n phar macoki net i cs and phar macodynami cs.
2. A l ack of cl i ni cal t ri al s desi gned t o eval uat e t he saf et y and ef f i cacy of dr ug
t her apy i n t he el der l y popul at i on i ncr eases t he probl em.
3. The hi gher i nci dence of adver se ef f ect s i n ger i at r i c pat i ent s may be i n par t t he
r esul t of t he compl exi t y of drug t herapy and t he rel at i ve l ack of cl i ni cal t ri al s i n t hi s
popul at i on. Tabl e 37- 4 l i st s sever al drugs and doses t hat shoul d be avoi ded i n t he
el der l y owi ng t o hi gher r i sks of adver se ef f ect s and/ or l ack of ef f i cacy.
4. Owi ng t o al t erat i ons i n gai t , bal ance, and mobi l i t y, f al l s and consequent adverse
event s are f requent occur r ences i n ger i at r i c pat i ent s.
a. The hi gh preval ence of ost eoporosi s i n t he el der l y r esul t s i n an i ncr eased
i nci dence of f ract ur es. Compl i cat i ons associ at ed wi t h f r act ures, part i cul arl y hi p
f r act ur es, ar e si gni f i cant causes of morbi di t y and mort al i t y.
b. Medi cat i ons causi ng or t host at i c hypot ensi on, dr owsi ness, di zzi ness, bl ur r ed
vi si on, or conf usi on have t he pot ent i al t o cause or wor sen post ural i nst abi l i t y and
i ncrease f al l s i n t he el der l y.
P. 768


P. 769


Table 37-4. Target Drugs and Doses to Avoid in Geriatric Patients
Drug Comments
Analgesics
Pentazocine (Talwin) Avoid; saIer and more eIIective
alternatives
Propoxyphene (Darvon) Avoid; lack oI eIIicacy (no more eIIective
then acetaminophen and potential Ior
accumulation and adverse narcotic eIIects
Meperidine (Demerol) Avoid; saIer and more eIIective
alternatives
Antidepressants
Amitriptyline (Elavil) Avoid; anticholinergic adverse eIIects.
increased risk oI Ialls. and QT
prolongation; use nortriptyline or
desipramine as alternatives
Amitriptyline. perphenazine
(Triavil)
Avoid; use separate antidepressant and
antipsychotic agents in appropriate
geriatric doses as necessary
Doxepin (Sinequan) Avoid; saIer and more eIIective
alternatives
Antiemetics
Trimethobenzamide (Tigan) Avoid; more eIIective alternatives
available
Antihistamines
Sedating OTC agents. cold
preparations
Avoid; potent anticholinergic eIIects
Hydroxyzine (Atarax) Avoid; potent anticholinergic eIIects
Cyproheptadine (Periactin) Avoid; potent anticholinergic eIIects
Chlorpheniramine (Chlor-
Trimeton)
Avoid; potent anticholinergic eIIects
Antihypertensives
Hydrochlorothiazide
(HydroDIURIL)
Doses ~ 25 mg/day should be avoided
Methyldopa (Aldomet) Avoid; saIer alternatives
Propranolol (Inderal) Lipophilic nonselective þ-blocker with
increased potential Ior adverse eIIects;
avoid; use a cardioselective þ-blocker
instead
Reserpine Avoid; risk oI adverse eIIects (e.g..
sedation. depression)
Antipsychotics
Haloperidol (Haldol) Avoid unless indicated Ior psychotic
disorder; use in small doses (1 mg); risk oI
sudden death in higher doses
Thioridazine Avoid unless indicated Ior psychotic
disorder
Antispasmodics
Belladonna Avoid long-term use; anticholinergic
adverse eIIects
Dicyclomine (Bentyl) Avoid long-term use; anticholinergic
adverse eIIects
Hyoscyamine (Pyridium) Avoid long-term use; anticholinergic
adverse eIIects
Decongestants
Oxymetazoline (AIrin) Daily use Ior ~ 3 days should be avoided
Phenylephrine (Neo-
Synephrine)
Daily use Ior ~ 3 days should be avoided
Pseudoephedrine (SudaIed) Avoid; anticholinergic eIIects and
potential to raise blood pressure
Dementia treatments
Isoxsuprine Avoid; lack oI eIIicacy
H
2
-antagonists
Cimetidine (Tagamet) Avoid; adverse CNS eIIects
Hypoglycemic agents
Chlorpropamide (Diabinese) Avoid; long halI-liIe can cause prolonged
hypoglycemic episodes and can induce
SIADH
Muscle relaxants
Carisoprodol (Soma) Risk oI adverse events greater than
potential beneIits; all use should be
avoided
Cyclobenzaprine (Flexeril) Risks oI adverse events greater than
potential beneIits
Methocarbamol (Robaxin) Risks oI adverse events greater than
potential beneIits
Orphenadrine (NorIlex) Risks oI adverse events greater than
potential beneIits
NSAIDs
Indomethacin (Indocin) Avoid; CNS adverse eIIects; use
alternative NSAID
Phenylbutazone Avoid; hematological adverse eIIects; use
alternative NSAID
Non-cyclooxygenase
selective NSAIDS
Avoid long-term use oI naproxen.
oxaprozin and piroxicam; increased risks
oI adverse eIIects
Platelet inhibitors
Dipyridamole (Persantine) Avoid; lack oI eIIicacy and adverse
eIIects (orthostatic hypotension) at high
doses; aspirin is saIer and more eIIective
Sedative hypnotics
Long-acting benzodiazepines
Chlordiazepoxide (Librium)
Diazepam (Valium)
Flurazepam (Dalmane)
Avoid; accumulation and increased risk oI
Ialls. sedation. and delirium
Short-acting benzodiazepines
Alprazolam (Xanax)
Oxazepam (Serax)
Triazolam (Halcion)
Nightly use should be avoided; increased
risk oI Ialls. daytime sedation. and
delirium
Meprobamate (Miltown) All use should be avoided
Barbiturates All use should be avoided; saIer
alternatives exist
CNS. central nervous system; NSAIDs. nonsteroidal anti-inIlammatory drugs;
OCT. over the counter; SIADH. syndrome oI inappropriate antidiuretic
hormone secretion.
ModiIied with permission Irom Fick DM. Cooper JW. Wade WE. et al.
Updating the Beers criteria Ior potentially inappropriate medication use in
older adults. Arch Int Med 2003;163:2716-2724.

P. 770


Table 37-5. Drugs and Drug Classes Possessing Anticholinergic Effects
Antidiarrheal agents Propantheline (Pro-Banthine)

Diphenoxylate/atropine
(Lomotil)
Oxybutynin (XL Iormulation
has Iewer eIIects) (Ditropan)
Antiemetics/antivertigo agents
Meclizine (Antivert) Tolterodine (Detrol)
Scopolamine (Transderm
scopolamine)
Class Ia antiarrhythmic agents
Disopyramide (Norpace)
Trimethobenzamide (Tigan) Quinidine
Promethazine (Phenergan) Parkinson's agents
Prochlorperazine Amantadine (Symmetrel)
(Compazine)
Antihistamines. sedating types Benztropine (Cogentin)
Antipsychotic agents Procyclidine (Kemadrin)
Antispasmodics Trihexyphenidyl
Belladonna alkaloids Skeletal muscle relaxants
Clidinium bromide Cyclobenzaprine (Flexeril)
Dicyclomine (Bentyl) Orphenadrine (NorIlex)
Hyoscyamine (Pyridium) Tricyclic antidepressants

c. Ì t i s wel l est abl i shed t hat many psychoact i ve agent s, especi al l y l ong- act i ng
benzodi azepi nes, are associ at ed wi t h an i ncreased ri sk of f al l s i n t he el der l y. Ì f a
benzodi azepi ne must be pr escri bed, l ow- dose l orazepam ( At i van) or oxazepam
( Ser ax) ar e bet t er choi ces because of t he l ack of act i ve met abol i t es and t hei r
met abol i sm i nvol ves phase Ì Ì hepat i c r eact i ons onl y.
5. Ger i at ri c pat i ent s t end t o be sensi t i ve t o medi cat i ons t hat possess ant i chol i nergi c
ef f ect s. Dr y mout h, ur i nar y r et ent i on, bl ur r y vi si on, const i pat i on, t achycardi a,
memor y i mpai rment and conf usi on are t ypi cal ant i chol i nergi c adver se ef f ect s
associ at ed wi t h sever al cl asses of dr ugs ( Tabl e 37- 5). These agent s can al so
i nduce del i ri um i n some peopl e.
a. When possi bl e, dr ugs wi t h ant i chol i ner gi c ef f ect s shoul d be avoi ded i n t he
el der l y. Ì n t hose i nst ances when t hi s i s not an opt i on, t he l east ant i chol i ner gi c agent
shoul d be chosen and i ni t i at ed at t he l owest ef f ect i ve dose. For exampl e, i f a
t r i cycl i c ant i depr essant i s needed, desi pr ami ne (Nor pr ami n) and nor t r i pt yl i ne
( Pamel or ) possess l ess ant i chol i nergi c act i vi t y t han ami t ri pt yl i ne ( El avi l ) and
i mi pr ami ne ( Tof rani l ) , and t her ef or e woul d be bet t er i ni t i al t her apeut i c opt i ons.
b. Fr equent moni t or i ng f or and pat i ent and f ami l y educat i on on si gns and sympt oms
of possi bl e ant i chol i ner gi c adverse ef f ect s i s al ways war r ant ed when t hese dr ugs
ar e pr escri bed i n t he el der l y.
E. GeneraI pri nci pI es. To ai d cl i ni ci ans i n pr ovi di ng appr opr i at e geri at ri c drug
t her apy, some gener al pr i nci pl es have been devel oped.
a. St ar t wi t h a l ow dose, and t i t rat e t he medi cat i on dose sl owl y.
b. Owi ng t o r educed r enal and hepat i c f unct i on, t he hal f -l i ves of many dr ugs ar e
pr ol onged i n t he el derl y. Sel ect i on of agent s shoul d i nvol ve consi der at i on of t he
speci f i c pharmacoki net i cs of each dr ug i n t he geri at ri c popul at i on.
c. Rapi d dose escal at i ons prevent at t ai nment of t he opt i mal t her apeut i c response
because a st eady- st at e concent r at i on of t he dr ug i s not reached and i ncreases t he
r i sks f or devel opi ng an ADR.
d. The f ewest number of dr ugs shoul d al ways be used t o t reat pat i ent s.
e. Al ways eval uat e possi bl e dr ug t oxi ci t y. Ger i at ri c pat i ent s can have at ypi cal
pr esent at i ons of ADRs, whi ch may mani f est as CNS changes ( e. g. , al t er ed ment al
st at us).
f . Revi ew concomi t ant medi cat i ons and di seases t o eval uat e t he possi bl e
i nt er act i ons wi t h new dr ugs.
g. Reassess t he need f or each medi cat i on on a regul ar basi s.
P. 771


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 14: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
For quest i ons 1- 4: AH i s a 1. 2- kg f emal e born pr emat urel y at 30 weeks of
gest at i onal age. Her mot her had an i nf ect i on wi t h a f ever at t he t i me of del i ver y. AH
was admi t t ed t o t he neonat al i nt ensi ve car e uni t f or presumed sepsi s and pl aced on
empi r i c ant i bi ot i c t herapy wi t h ampi ci l l i n ( 50 mg/ kg Ì V ever y 12 hr) and gent ami ci n
( 2. 5 mg/ kg Ì V ever y 8 hr ).
1. Whi ch of the foI I owi ng vari abI es wi I I most I i keI y be used to caI cuI at e doses
f or AH' s ant i bi ot i cs?
( A) hei ght
( B) hepat i c f unct i on
( C) wei ght
( D) age
( E) ser um creat i ni ne
Vi ew Answer 1. The answer i s C[ see] . 2. Af t er the admi ni st rat i on of four
doses of gent ami ci n, a serum concent rat i on obt ai ned 5 mi n bef ore t he next
dose was 2. 5 µg/ mL. Whi ch of t he f oI I owi ng answers best descri bes t he
pharmacoki net i c di f f erences observed i n premat ure neonates (compared to
oI der chi I dren and aduI t s) t hat mi ght expI ai n thi s vaI ue?
( A) l arger vol ume of di st r i but i on, l onger hal f - l i f e
( B) l arger vol ume of di st r i but i on, shor t er hal f - l i f e
( C) smal l er vol ume of di st r i but i on, l onger hal f - l i f e
( D) smal l er vol ume of di st r i but i on, short er hal f - l i f e
( E) si mi l ar vol ume of di st r i but i on, shor t er hal f -l i f e
Vi ew Answer 2. The answer i s A[ see; I . B. 3. d] . 3. Ampi ci I I i n may exhi bi t
pharmacoki net i c di f f erences i n AH because of i t s prot ei n bi ndi ng
charact eri st i cs. Whi ch of t he f oI I owi ng answers best descri bes t he eff ect of
AH' s age on ampi ci I I i n prot ei n bi ndi ng?
( A) i ncr eased pr ot ei n bi ndi ng, r esul t i ng i n a gr eat er f r ee f ract i on
( B) i ncr eased pr ot ei n bi ndi ng, r esul t i ng i n a reduced f ree f r act i on
( C) decr eased pr ot ei n bi ndi ng, resul t i ng i n a gr eat er f r ee f r act i on
( D) decr eased pr ot ei n bi ndi ng, resul t i ng i n a r educed f ree f r act i on
( E) decr eased pr ot ei n bi ndi ng, resul t i ng i n no si gni f i cant change i n f ree f ract i on
Vi ew Answer 3. The answer i s C[ see] . 4. As t he pharmaci st provi di ng
servi ces f or t he neonataI i ntensi ve care uni t , you evaI uat e medi cat i on orders
and make recommendati ons to t he medi caI t eam. Whi ch of the foI I owi ng wouI d
be t he most appropri ate recommendat i on f or AH' s care?
( A) Change t o or al ant i bi ot i cs f or bet t er absorpt i on.
( B) Doubl e-check t he cal cul at i ons t o avoi d deci mal er r ors.
( C) Di l ut e t he gent ami ci n wi t h a l ar ger vol ume of Ì V f l ui ds t o make i t easi er t o
measure.
( D) Use a pedi at ri c-speci f i c t her apeut i c r ange f or moni t ori ng gent ami ci n.
( E) Change t o sul f amet hoxazol e and t r i met hopr i m ( Bact ri m) f or si ngl e-agent
ant i bact eri al cover age.
Vi ew Answer 4. The answer i s B[ seeand] . 5. You are counseI i ng t he
grandmot her of a 3- year- oI d boy who has a prescri pt i on f or
amoxi ci I I i n/ cI avuI anate ( Augment i n) t o t reat uncompI i cat ed ot i ti s medi a. Whi ch
of t he f oI I owi ng i ssues wouI d be l east I i keI y t o af f ect medi cat i on adherence
( compI i ance)?
( A) l ack of educat i on about t he medi cat i on
( B) cost
( C) dosi ng i nt er val (f r equency)
( D) t ast e
( E) aut onomy
Vi ew Answer 5. The answer i s E[see] . 6. Whi ch of t he f oI I owi ng
medi cat i ons i s safe t o use i n t he t hi rd t ri mester of pregnancy?
( A) acet ami nophen
( B) nonst er oi dal ant i - i nf l ammat or y dr ugs
( C) war f ar i n
( D) OxyCont i n
( E) aspi ri n
Vi ew Answer 6. The answer i s A[ seeand-b, - d] . P. 772


7. Whi ch of the foI I owi ng medi cat i ons may have t he pot enti aI t o cause f aI I s i n a
geri at ri c pat i ent ?
( A) ami t ri pt yl i ne ( El avi l )
( B) t r azodone ( Desyr el )
( C) acet ami nophen wi t h codei ne
( D) di azepam
( E) Al l of t he above
Vi ew Answer 7. The answer i s E[seeand] . 8. PI acent aI t ransf er of a drug i s
af f ected by aI I of t he f oI I owi ng characteri st i cs except
( A) mol ecul ar wei ght .
( B) f et al gender.
( C) gest at i onal age.
( D) l i pi d sol ubi l i t y of t he dr ug.
( E) pl asma pr ot ei n bi ndi ng.
Vi ew Answer 8. The answer i s B[ see] . 9. When seI ecti ng a benzodi azepi ne
product f or a woman who has chroni c pani c di sorder, aI I of the foI I owi ng drug
propert i es are desi rabI e f or breast- f eedi ng her 8- mont h- oI d i nf ant who was
born at t erm except
( A) hepat i c met abol i sm t o i nact i ve met abol i t es.
( B) a shor t hal f - l i f e.
( C) a r api d onset of act i on.
( D) hi gh l i pi d sol ubi l i t y.
Vi ew Answer 9. The answer i s D[ see] . 10. Drug saf et y i n pregnancy of a
speci f i c agent can be assessed best by
( A) t he FDA cl assi f i cat i on syst em, especi al l y cat egor y C dr ugs.
( B) case r epor t s.
( C) physi ci an knowl edge.
( D) dat abases, such as REPROTOX.
Vi ew Answer 10. The answer i s D[ seeand] . Bri gg' s Drugs i n Pregnancy and
Lact at i on. 11. Whi ch of t he f oI I owi ng drugs i s expect ed t o cause
ant i choI i nergi c adverse ef f ect s i n t he eI derI y?
( A) pr opoxyphene ( Dar von)
( B) ci pr of l oxaci n ( Ci pr o)
( C) ami t ri pt yl i ne ( El avi l )
( D) pr opr anol ol (Ì nder al )
( E) ci met i di ne ( Tagamet )
Vi ew Answer 11. The answer i s C[ see] . 12. Whi ch of t he f oI I owi ng
ant i hypert ensi ve agents shouI d be avoi ded i n eI derI y pat i ent s?
( A) aml odi pi ne ( Nor vasc) 5 mg ever y day
( B) at enol ol ( Tenormi n) 25 mg ever y day
( C) benazepri l (Lot ensi n) 10 mg ever y day
( D) hydr ochl or ot hi azi de (Hydr oDÌ URÌ L) 25 mg ever y day
( E) met hyl dopa ( Al domet ) 250 mg t hr ee t i mes a day
Vi ew Answer 12. The answer i s E[see] . 13. Whi ch of t he f oI I owi ng
benzodi azepi nes i s expect ed t o cause the l east amount of adverse ef fect s i n
t he eI derI y?
( A) chl ordi azepoxi de (Li br i um)
( B) di azepam ( Val i um)
( C) f l ur azepam ( Dal mane)
( D) oxazepam ( Ser ax)
( E) t emazepam ( Rest ori l )
Vi ew Answer 13. The answer i s D[ see] . 14. Whi ch of t he f oI I owi ng f act ors
i s associ ated wi th an i ncreased ri sk of noncompI i ance i n t he eI derI y?
( A) pol ypharmacy
( B) hypert ensi on
( C) l i vi ng wi t h a spouse i n an i sol at ed envi r onment
( D) expensi ve medi cat i ons
( E) good rel at i onshi p wi t h physi ci an
Vi ew Answer 14. The answer i s A[ see] . Di recti ons f or questi ons 15- 16: The
quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
15. Accordi ng to t he pri nci pI es of drug excret i on i nto t he breast mi I k, whi ch
combi nati on of t he f oI I owi ng propert i es wouI d resuI t i n t he hi ghest drug
concent rati on i n breast mi I k?
I . I ow moI ecuI ar wei ght, moderateI y I i pophi I i c
I I . I ow pI asma protei n bound, weakI y basi c
I I I . hi ghI y pI asma prot ei n bound, weakI y aci di c
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 15. The answer i s C[ seeand] . 16. FoI I owi ng pri nci pI es of
t erat ogeni ci t y, drug exposure duri ng t he f oI I owi ng t i mes couI d cause f et aI
abnormaI i ti es?
I . f i rst 2 weeks of gestat i on
I I . weeks 3- 8 of gestat i on
I I I . the fet aI peri od
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 16. The answer i s D[ seeand] . P. 773


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì . D. 1] .
Most pedi at ri c doses ar e based on body wei ght . Thi s si ngl e var i abl e i ncor por at es
gr owt h and mat ur at i on, whi l e al l owi ng a si mpl e cal cul at i on f or dose. Hei ght i s of t en
di f f i cul t t o measur e accur at el y i n chi l dr en, and t he cal cul at i on of body surf ace area
i s t ypi cal l y r eser ved f or t hose drugs wi t h nar r ow t her apeut i c i ndi ces, such as
chemot herapy.
2. The answer i s A [ see Ì . B. 3. a; Ì . B. 3. d] .
Ami nogl ycosi des such as gent ami ci n exhi bi t a l ar ger vol ume of di st r i but i on i n
neonat es because of t hei r l ar ger body wat er cont ent . Neonat es al so t ypi cal l y have a
l onger el i mi nat i on hal f -l i f e as t he resul t of havi ng r educed r enal f unct i on dur i ng t he
f i r st 6 mont hs of l i f e.
3. The answer i s C [ see Ì . B. 3. b; Tabl e 37-2] .
Neonat es have bot h a r educed quant i t y of pl asma pr ot ei ns, as wel l as a reduct i on i n
t he af f i ni t y of al bumi n t o bi nd t o ot her subst ances. As a r esul t , t he f r ee f ract i on of
many dr ugs, i ncl udi ng ampi ci l l i n, i s i ncreased.
4. The answer i s B [ see Ì . D. 1 and 2] .
Al l pedi at ri c or ders shoul d be car ef ul l y checked f or cal cul at i on er r or s. Er ror s ar e
mor e common i n t he pedi at ri c popul at i on as t he resul t of wei ght - based dosi ng and
t he need f or mat hemat i cal cal cul at i ons. The use of t he or al r out e woul d not be
advi sabl e i n t hi s pat i ent , because of t he pot ent i al r educed drug absorpt i on.
Li kewi se, t he di l ut i on of t he dose wi t h more Ì V f l ui d or t he use of a sul f a dr ug woul d
not be appropri at e f or t hi s pat i ent ' s age. Fi nal l y, t he t her apeut i c range f or
gent ami ci n i s t he same i n pedi at r i c pat i ent s as i n adul t s.
5. The answer i s E [ see Ì . G] .
Whi l e t he ot her opt i ons ar e al l i mport ant aspect s of counsel i ng t o enhance
medi cat i on adher ence i n chi l dr en, aut onomy (t he abi l i t y t o provi de sel f -care or gi ve
medi cat i ons i ndependent l y) woul d not be a consi der at i on f or a 3- year - ol d chi l d.
Aut onomy becomes a much more cr i t i cal i ssue i n det ermi ni ng adher ence i n
adol escence.
6. The answer i s A [ see Ì Ì . B. 3. e. ( 1) and ( 2) ; Ì Ì . 4a, b-c and d] .
Acet ami nophen i s a saf e and ef f ect i ve anal gesi c t hat can be used i n t herapeut i c
doses duri ng pregnancy. NSAÌ Ds may i nt er f ere wi t h t he onset or pr ogr ess of l abor
when used i n t he t hi r d t r i mest er. NSAÌ Ds and warf ar i n, when used near del i ver y,
may cause bl eedi ng pr obl ems i n t he newbor n i nf ant . Ì n addi t i on, war f ari n use i n t he
t hi rd t ri mest er may be associ at ed wi t h f et al CNS abnor mal i t i es. OxyCont i n use i n
t he t hi rd t ri mest er may i nduce neonat al wi t hdr awal f ol l owi ng del i ver y.
7. The answer i s E [ see Ì V. D. 4. b and c] .
Medi cat i ons t hat can cause or t host at i c hypot ensi on, dr owsi ness, di zzi ness, bl ur red
vi si on, or conf usi on have t he pot ent i al t o cause f al l s i n ger i at r i c pat i ent s. Thus al l of
t he medi cat i ons l i st ed may put t he pat i ent at a f al l ri sk.
8. The answer i s B [ see Ì Ì . B. 2] .
Fet al gender does not af f ect pl acent al t r ansf er of a drug. The mol ecul ar wei ght and
t he l i pi d sol ubi l i t y of a drug great l y i nf l uence i t s abi l i t y t o cross t he pl acent al
membr anes. Pl asma prot ei n bi ndi ng af f ect s t he amount of f ree dr ug avai l abl e t o
cr oss t he pl acent a. Gest at i onal age i nf l uences t he vol ume of di st ri but i on of t he dr ug
as wel l as t he t hi ckness of t he pl acent al membr anes.
9. The answer i s D [ see Ì Ì Ì . C; Ì Ì Ì . F. 1. a] .
When any dr ug i s used by a nursi ng mot her, i t i s desi r abl e t o have t he l east amount
of act i ve drug avai l abl e i n t he mat er nal ci rcul at i on t o di f f use i nt o t he br east mi l k. A
r api dl y act i ng ( f or mat ernal onset of act i on) , rapi dl y el i mi nat ed ( i . e. , short hal f - l i f e)
dr ug wi t h i nact i ve met abol i t es i s opt i mal . Ì f t he dr ug i s hi ghl y l i pi d sol ubl e, i t i s
mor e l i kel y t o pass i nt o br east mi l k.
10. The answer i s D [ see Ì Ì . B. 3. c and d] .
The FDA cl assi f i cat i on syst em does not assess ri sk wel l i n cat egor y C dr ugs.
Cat egor y A and t o some ext ent cat egor y B drugs have been shown t o be saf est i n
pr egnancy. Case r epor t s of pr egnancy exposur es t end t o bi as dat a t owar d adverse
out comes. The best source of i nf or mat i on i s f r om avai l abl e dat abases, such as
REPROTOX or Ter i s, or wi t h publ i shed books such as Br i gg' s Drugs i n Pregnancy
and Lact at i on.
P. 774


11. The answer i s C [ see Ì V. D. 5. a; Tabl e 37- 5] .
Tr i cycl i c ant i depr essant s ar e an est abl i shed cause of ant i chol i ner gi c adver se
ef f ect s i n t he el der l y. When t hese agent s ar e i ndi cat ed, nor t r i pt yl i ne and
desi prami ne ar e associ at ed wi t h a l ower i nci dence of ant i chol i ner gi c ADRs and ar e
mor e desi r abl e al t er nat i ves.
12. The answer i s E [ see Ì V; Tabl e 37-4] .
The use of met hyl dopa shoul d be avoi ded i n el der l y pat i ent s owi ng t o ri sk of CNS
adver se ef f ect s and hypot ensi on.
13. The answer i s D [ see Ì V. D. 4. c; Tabl e 37- 4] .
Chl ordi azepoxi de, di azepam, and f l urazepam shoul d be avoi ded i n el derl y pat i ent s
owi ng t o act i ve met abol i t es and l ong-el i mi nat i on hal f - l i ves. Oxazepam r epr esent s
t he saf est al t ernat i ve because of a r el at i vel y shor t hal f -l i f e, absence of act i ve
met abol i t es, and i t i s devoi d of phase Ì hepat i c met abol i sm.
14. The answer i s A [ see Ì V. A. 1. e] .
Lower soci oeconomi c st at us, l i vi ng al one, pol yphar macy, compl i cat ed drug
r egi mens, poor rel at i onshi ps wi t h heal t hcare provi der s, and mul t i pl e di sease st at es
ar e al l r i sk f act ors f or noncompl i ance i n t he geri at r i c popul at i on.
15. The answer i s C ( Ì , Ì Ì ) [ see Ì Ì Ì . B. 1, 2, 3, 4 and 5] .
Hi gh-mol ecul ar - wei ght subst ances ar e l ess l i kel y t o pass i nt o breast mi l k because of
t hei r si ze. Drugs t hat ar e hi ghl y pl asma prot ei n bound may r each t he breast mi l k
onl y i n smal l amount s, because a l arge por t i on of t he drug i s bound t o t he mat ernal
pl asma prot ei ns and, t her ef ore, onl y a smal l amount i s f r ee t o di f f use i nt o br east
mi l k. A l ow- mol ecul ar - wei ght , moder at el y l i pophi l i c drug passes easi l y i nt o br east
mi l k. A drug t hat has a l ow degr ee of pl asma pr ot ei n bi ndi ng has a si gni f i cant
amount of dr ug f ree t o di f f use i nt o breast mi l k. A weakl y basi c dr ug may i oni ze af t er
r eachi ng t he br east mi l k and t heref or e remai n t r apped i n t he mi l k.
16. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see Ì Ì . A. 1, 2 and 3] .
Dur i ng f i r st 2 weeks af t er f er t i l i zat i on, t he embr yo i s i mper vi ous t o t er at ogens. Any
exposur e duri ng t hi s t i me wi l l have ei t her no ef f ect or t he embr yo wi l l be dest r oyed.
Dur i ng t he r emai ni ng weeks of t he pregnancy, t erat ogens may exer t ef f ect s on t he
f et us. Ter at ogeni c ef f ect s are not al ways st r uct ural i n nat ur e; t hey can be f unct i onal
or behavi or al . Ther ef ore, exposur es dur i ng t he f et al per i od can al so be probl emat i c.

38
CIinicaI Laboratory Tests
Byron D. May
I. GENERAL PRINCIPLES
A. Laborat or y t est s ar e per f or med f or mul t i pl e pur poses, i ncl udi ng t o di scover a
di sease, conf i r m or di f f er ent i at e a di agnosi s, st age or cl assi f y a di sease, and
moni t or ef f ect i veness of t her apy.
B. Laborat or y t est s are cI assi fi ed as screeni ng or di agnost i c. Scr eeni ng t est s
ar e used i n pat i ent s wi t h no si gns or sympt oms of a di sease ( e. g. , serum chol est erol
f or assessi ng cardi ovascul ar di sease r i sk) . Di agnost i c t est s are done i n pat i ent s
wi t h si gns and sympt oms of di sease or wi t h an abnor mal scr eeni ng t est .
C. Moni t ori ng drug t herapy
1. Laborator y t est resuI t s are used t o i nvest i gat e pot ent i al probl ems wi t h a
pat i ent ' s anat omy or physi ol ogy. Pharmaci st s usual l y moni t or l aborat or y t est s t o
a. Assess t he t herapeut i c and adverse ef f ect s of a drug (e. g. , moni t ori ng t he
ser um ur i c aci d l evel af t er al l opuri nol i s admi ni st er ed, checki ng f or i ncr eased l i ver
f unct i on t est val ues af t er admi ni st r at i on of i soni azi d)
b. Determi ne t he proper drug dose ( e. g. , assessment of t he ser um creat i ni ne or
cr eat i ni ne cl ear ance val ue bef ore use of a renal l y excr et ed dr ug)
c. Assess t he need for addi t i onaI or aI t ernat e drug t herapy ( e. g. , assessment of
whi t e bl ood cel l count af t er an ant i bi ot i c i s admi ni st er ed)
d. Prevent t est mi si nterpret at i on resuI ti ng f rom drug i nterf erence ( e. g. ,
det ermi nat i on of a f al se-posi t i ve r esul t f or a ur i ne gl ucose t est af t er cephal ospor i n
admi ni st rat i on)
2. These t est s can be expensi ve, and request s f or t hem must be bal anced agai nst
pot ent i al benef i t s f or pat i ent s and how t he l aborat or y t est wi l l af f ect your deci si on
r egardi ng t herapy. Gener al l y, l ab t est s shoul d be or der ed onl y i f t he r esul t s wi l l
af f ect t he deci si ons about t he management of t he pat i ent .
B. Def i ni t i on of normaI vaI ues
1. NormaI I aborat or y t est resuI t s f al l wi t hi n a pr edet ermi ned range of val ues, and
abnormaI vaI ues f al l out si de t hat r ange. The normal r ange of a l abor at ory t est i s
usual l y det er mi ned by appl yi ng st at i st i cal met hods t o resul t s f rom a represent at i ve
sampl e of t he gener al popul at i on. Usual l y, t he mean ± 2 st andard devi at i ons i s
t aken as t he normal range.
a. NormaI I i mi ts may be def i ned somewhat arbi t rari I y; t hus val ues out si de t he
nor mal r ange may not necessar i l y i ndi cat e di sease or t he need f or t r eat ment ( e. g. ,
asympt omat i c hyperur i cemi a).
b. Many f act or s ( e. g. , age, sex, t i me si nce l ast meal ) must be t aken i nt o account
when eval uat i ng t est resul t s.
c. NormaI vaI ues aI so var y among i nst i t uti ons and may depend on t he met hod
used t o per f orm t he t est .
d. The goal i s not t o make al l l abor at or y val ues nor mal ; resi st urges t o do
somet hi ng i n a cl i ni cal l y st abl e pat i ent .
e. At t empt s have been made i n recent years t o st andar di ze t he present at i on of
l abor at or y dat a by usi ng t he Ì nt er nat i onal Syst em of Uni t s ( SÌ uni t s) . Cont r over sy
sur rounds t hi s i ssue i n t he Uni t ed St at es, and r esi st ance t o adopt t hi s syst em
cont i nues. The SÌ uni t of measur e i s a met hod of r eport i ng cl i ni cal l aborat or y dat a i n
a st andar d met r i c f ormat . The basi c uni t of mass f or t he SÌ i s t he mol e. The mol e i s
not i nf l uenced by t he addi t i on of excess wei ght of sal t or est er f or mul at i ons.
Techni cal l y and phar macol ogi cal l y, t he mol e i s mor e meani ngf ul t han t he gr am
because each physi ol ogi cal r eact i on occur s on a mol ecul ar l evel .
Ef f or t s t o i mpl ement t he SÌ syst em began i n t he 1970s, resul t i ng i n t he adopt i on of
f ul l SÌ - t ransi t i on pol i ci es by a f ew maj or medi cal and phar maceut i cal j ournal s i n t he
1980s. Rel uct ance
P. 776

t o use t hi s syst em by many cl i ni ci ans i n t he Uni t ed St at es has f orced changes i n t he
pol i ci es by some j ournal s t o r epor t bot h convent i onal and SÌ uni t s or t o r epor t t he
conversi on f act or bet ween t he t wo syst ems. Ì t i s st i l l cont rover si al whi ch met hod
shoul d be used t o r epor t cl i ni cal l abor at or y val ues. There are argument s f or and
agai nst t he uni versal conver si on t o t he SÌ syst em. Reader s shoul d be awar e t hat
some j ournal s r epor t SÌ and/ or convent i onal uni t s i n t hei r t ext . Par t i cul ar at t ent i on
shoul d be pai d t o t he uni t s associ at ed wi t h a repor t ed l abor at or y val ue, and access
t o a conver si on t abl e may be necessar y t o avoi d conf usi on i n t he i nt er pret at i on of
t he dat a. When appr opr i at e, bot h convent i onal and SÌ uni t s wi l l be report ed i n t hi s
chapt er.
2. Laborator y error must al ways be consi der ed when t est resuI t s do not correI at e
wi t h expected resuI t s for a gi ven pat i ent . Ì f necessar y, t he t est shoul d be
r epeat ed. Common sources of l abor at or y er ror i ncl ude spoi l ed speci mens,
i ncompl et e speci mens, speci mens t aken at t he wr ong t i me, f aul t y reagent s,
t echni cal err ors, i ncor r ect pr ocedur es, and f ai l ure t o t ake di et or medi cat i on i nt o
account .
3. Duri ng hospi t al admi ssi on or r out i ne physi cal exami nat i on, a bat ter y of t ests i s
usual l y gi ven t o augment t he hi st or y and physi cal exami nat i on. Basi c t est s may
i ncl ude an el ect rocar di ogr am ( ECG) , a chest x- r ay, a sequent i al mul t i pl e anal yzer
( SMA) prof i I e, eI ect roI yt e t est s, a compI ete bI ood count ( CBC) , and uri naI ysi s.
C. Quant i t at i ve tests, quaI i tat i ve t est s, and anaI yt i caI perf ormance
1. Test s wi t h normal val ues r epor t ed i n ranges ( i . e. , 3. 5-5. 0 mEq/ L) ar e cal l ed
quanti t at i ve.
2. Test s wi t h posi t i ve ( +) or negat i ve (- ) out comes are cal l ed quaI i tat i ve.
3. Those wi t h var yi ng degr ees of posi t i vi t y ( e. g. , 1+, 2+, 3+ gl ucose i n t he ur i ne) ar e
t er med semi quant i tat i ve.
4. The qual i t y of a quant i t at i ve assay i s measured i n t erms of accuracy ( accur acy i s
def i ned as t he ext ent t o whi ch mean measurement i s cl ose t o t he t r ue val ue) .
Preci si on ref er s t o t he repr oduci bi l i t y of t he assay.
II. HEMATOLOGICAL TESTS.
Bl ood cont ai ns t hr ee t ypes of f or med el ement s: red bl ood cel l s ( RBCs), whi t e bl ood
cel l s (WBCs) , and pl at el et s ( Fi gur e 38- 1) . A CBC i ncl udes hemogl obi n ( Hb) ,
hemat ocr i t ( Hct ) , t ot al WBCs, t ot al RBCs, mean cel l vol ume ( MCV) , and pl at el et
count .

Figure 38-1. Derivation oI blood elements Irom
stem cells. Cells located below the horizontal line
are Iound in normal peripheral blood. with the
exception oI the late normoblasts.
P. 777


A. RBCs ( er yt hrocyt es)
1. The RBC count, whi ch r epor t s t he number of RBCs f ound i n a cubi c mi l l i met er
( mm
3
) of whol e bl ood, provi des an i ndi r ect est i mat e of t he bl ood' s Hb cont ent .
NormaI vaI ues ar e
a. 4. 3- 5. 9 mi l l i on/ mm
3
of bl ood f or men ( × 10
12
/ L)
b. 3. 5- 5. 0 mi l l i on/ mm
3
of bl ood f or women (× 10
12
/ L)
2. The Hct or packed ceI I voI ume ( PCV) measures t he percent age by vol ume of
packed RBCs i n a whol e bl ood sampl e af t er cent ri f ugat i on. The Hct val ue i s usual l y
t hr ee t i mes t he Hb val ue ( see Ì Ì . A. 3) and i s gi ven as a per cent or f r act i on of 1 ( 42%-
52% or 0. 42- 0. 52 f or men; 37%- 47% or 0. 37- 0. 47 f or women) .
a. Low Hct val ues i ndi cat e such condi t i ons as anemi a, over hydr at i on, or bl ood l oss.
b. Hi gh Hct val ues i ndi cat e such condi t i ons as pol ycyt hemi a vera or dehydr at i on.
3. The Hb t est measur es t he gr ams of Hb cont ai ned i n 100 mL ( 1 dL) or 1 L of
whol e bl ood and pr ovi des an est i mat e of t he oxygen-car r yi ng capaci t y of t he RBCs.
The Hb val ue depends on t he number of RBCs and t he amount of Hb i n each RBC.
a. NormaI vaI ues ar e 14- 18 g/ dL f or men and 12-16 g/ dL f or women.
b. Low Hb val ues i ndi cat e anemi a.
4. RBC i ndi ces (al so known as Wi nt robe i ndi ces) provi de i mport ant i nf or mat i on
r egardi ng RBC si ze, Hb concent r at i on, and Hb wei ght . They ar e used pr i mar i l y t o
cat egori ze anemi as, al t hough t hey may be af f ect ed by aver age cel l measur ement s.
A peri pher al bl ood smear can provi de most of t he i nf or mat i on obt ai ned t hrough RBC
i ndi ces. Obser vat i ons of a smear may show var i at i on i n RBC shape
( poi ki I ocyt osi s) , as mi ght occur i n si ckl e-cel l anemi a, or i t may show a var i at i on i n
RBC si ze (ani socyt osi s) , as mi ght occur i n a mi xed anemi a ( f ol i c aci d and i ron
def i ci ency) .
a. MCV i s t he rat i o of t he Hct t o t he RBC count . Ì t essent i al l y assesses aver age
RBC si ze and r ef l ect s any ani socyt osi s.

( 1) Low MCV i ndi cat es mi crocyt i c ( under si ze) RBCs, as occur s i n i ron def i ci ency.
( 2) Hi gh MCV i ndi cat es macrocyt i c ( over si ze) RBCs, as occur s i n a vi t ami n B12 or
f ol i c aci d def i ci ency.
( 3) NormaI range f or MCV i s 90 ± 10.
b. Mean ceI I hemogI obi n ( MCHb) assesses t he amount of Hb i n an average RBC.
( 1) MCHb i s def i ned as:

( 2) NormaI range f or MCH i s 30 ± 4.
c. Mean ceI I hemogI obi n concent rat i on (MCHbC) r epresent s t he aver age
concent r at i on of Hb i n an aver age RBC, def i ned as:

( 1) NormaI range f or MCHC i s 34 ± 3.
( 2) Low MCHbC i ndi cat es hypochromi a (pal e RBCs r esul t i ng f r om decreased Hb
cont ent ) , as occurs i n i r on def i ci ency.
d. Red bI ood ceI I di st ri but i on wi dt h ( RDW) i s a r el at i vel y new i ndex of RBCs.
Nor mal l y, most RBCs are appr oxi mat el y equal i n si ze, so t hat onl y one bel l -shaped
hi st ogram peak i s generat ed. Di sease may change t he si ze of some RBCs÷f or
exampl e, t he gradual change i n si ze of newl y pr oduced RBCs i n f ol i c aci d or i ron
def i ci ency. The di f f er ence i n si ze bet ween t he abnor mal and t he l ess abnor mal
RBCs produces ei t her mor e t han one hi st ogram peak or a br oadeni ng of t he normal
peak. Thi s val ue i s used pr i mar i l y wi t h ot her t est s t o di agnose i r on- def i ci ency
anemi a.
( 1) An i ncreased RDW i s f ound i n f act or - def i ci ency anemi a (e. g. , i ron, f ol at e,
vi t ami n B12) .
( 2) A normaI RDW i s f ound i n such condi t i ons as anemi a of chr oni c di sease.
( 3) The RDW i ndex i s never decr eased.
P. 778


5. The reti cuI ocyt e count pr ovi des a measur e of i mmat ure RBCs ( r et i cul ocyt es) ,
whi ch cont ai n r emnant s of nucl ear mat eri al ( r et i cul um) . Nor mal RBCs ci rcul at e i n
t he bl ood f or about 1- 2 days i n t hi s f orm. Hence, t hi s t est pr ovi des an i ndex of bone
mar row pr oduct i on of mat ur e RBCs.
a. Ret i cul ocyt es normal l y make up 0. 1%-2. 4% of t he t ot al RBC count .
b. I ncreased ret i cuI ocyt e count occurs wi t h such condi t i ons as hemol yt i c anemi a,
acut e bl ood l oss, and response t o t he t reat ment of a f act or def i ci ency (e. g. , an i r on,
vi t ami n B12, or f ol at e def i ci ency) . PoI ychromasi a ( t he t endency t o st ai n wi t h aci di c
or basi c dyes) not ed on a peri pher al smear l aborat or y r epor t usual l y i ndi cat es
i ncreased r et i cul ocyt es.
c. Decreased ret i cuI ocyt e count occurs wi t h such condi t i ons as dr ug-i nduced
apl ast i c anemi a.
6. The er yt hrocyt e sedi ment at i on rat e ( ESR) measur es t he rat e of RBC set t l i ng of
whol e, uncoagul at ed bl ood over t i me, and i t pr i mar i l y ref l ect s pl asma composi t i on.
Most of t he sedi ment at i on ef f ect r esul t s f rom al t erat i ons i n pl asma prot ei ns.
a. NormaI ESR rat es r ange f r om 0 t o 20 mm/ hr f or mal es and f r om 0 t o 30 mm/ hr
f or f emal es.
b. ESR vaI ues i ncrease wi t h acut e or chroni c i nf ect i on, t i ssue necr osi s or
i nf ar ct i on, wel l -est abl i shed mal i gnancy, and rheumat oi d col l agen di seases.
c. ESR vaI ues ar e used t o
( 1) Fol l ow t he cl i ni cal cour se of a di sease
( 2) Demonst rat e t he presence of occul t or gani c di sease
( 3) Di f f er ent i at e condi t i ons wi t h si mi l ar sympt omat ol ogy÷f or exampl e, angi na
pect or i s (no change i n ESR val ue) as opposed t o a myocardi al i nf ar ct i on (i ncrease
i n ESR val ue)
B. WBCs ( I eukocyt es)
1. The WBC count r eport s t he number of WBCs i n a cubi c mi l l i met er of whol e bl ood.
a. NormaI vaI ues r ange f r om 4, 000 t o 11, 000 WBC/ mm
3
.
b. I ncreased WBC count ( I eukocyt osi s) usual l y si gnal s i nf ect i on; i t may al so r esul t
f r om l eukemi a, t i ssue necr osi s or admi ni st r at i on of cor t i cost er oi ds. Ì t i s most of t en
f ound wi t h bacteri aI i nfect i on.
c. Decreased WBC count ( I eukopeni a) i ndi cat es bone mar r ow depressi on, whi ch
may r esul t f rom met ast at i c carci noma, l ymphoma, or t oxi c r eact i ons t o subst ances
such as ant i neopl ast i c agent s.
2. The WBC di f ferent i aI eval uat es t he di st ri but i on and mor phol ogy of t he f i ve maj or
t ypes of WBCs: t he granuI ocyt es ( neut rophi I s, basophi I s, eosi nophi I s) and t he
nongranuI ocyt es ( I ymphocyt es, monocyt es) . A cert ai n per cent age of each t ype
makes up t he t ot al WBC count ( Tabl e 38-1) .
a. Neut rophi I s may be mat ur e or i mmat ur e. Mat ur e neut r ophi l s ar e
poI ymorphonucI ear I eukocyt es ( PMNs) , al so ref er r ed t o as pol ys, segment ed
neut rophi l s, or segs; i mmat ur e neut r ophi l s ar e ref er red t o as bands or st abs.
( 1) Chemotaxi s. Neut r ophi l s t hat phagocyt i ze and degrade many t ypes of
part i cI es ser ve as t he body' s f i r st l i ne of def ense when t i ssue i s damaged or f or ei gn
mat er i al gai ns ent r y. They congr egat e at si t es i n response t o a speci f i c st i mul us,
t hr ough a pr ocess known as chemot axi s.
Table 38-1. Normal Percentage Values for White Blood Cell (WBC) Differential
Cell Type Normal Range of Values (º)
Polymorphonuclear leukocytes 50-70
Bands 3-5
Lymphocytes 20-40
Monocytes 0-7
Eosinophils 0-5
Basophils 0-1

P. 779


Table 38-2. Examples of Changes in Total White Blood Cell (WBC) Count and
WBC Differential in Response to Bacterial Infection
WBC Count
Cell Type Normal With Bacterial
Infection
Total WBCs 8.000
(100°)
15.500 (100°)
Neutrophils

Polymorphonuclear
leukocytes
60° 82°
Bands 3° 6°
Lymphocytes 30° 10°
Monocytes 4° 1°
Eosinophils 2° 1°
Basophils 1° 0°

( 2) Neut rophi I i c I eukocyt osi s. Thi s descri bes a r esponse t o an appropri at e
st i mul us i n whi ch t he t ot al neut rophi l count i ncreases, of t en wi t h an i ncr ease i n t he
per cent age of i mmat ure cel l s ( a shi f t t o the I ef t ). Thi s may repr esent a syst emi c
bact er i al i nf ect i on, such as pneumoni a ( Tabl e 38-2) .
( a) Cert ai n vi ruses (e. g. , chi ckenpox, herpes zost er ) , some ri cket t si aI di seases
( e. g. , Rocky Mount ai n spot t ed f ever ) , some fungi , and st ress ( e. g. , physi cal
exer ci se, acut e hemor r hage or hemol ysi s, acut e emot i onal st r ess) may al so cause
t hi s r esponse.
( b) Ot her causes i ncl ude i nf I ammat or y di seases ( e. g. , acut e rheumat i c f ever ,
r heumat oi d art hr i t i s, acut e gout ), hypersensi t i vi ty react i ons t o drugs, ti ssue
necrosi s (e. g. , f r om myocardi al i nf ar ct i on, bur ns, cer t ai n cancer s) , met aboI i c
di sorders (e. g. , uremi a, di abet i c ket oaci dosi s) , myeI ogenous I eukemi a, and use of
cert ai n drugs (e. g. , epi nephr i ne, l i t hi um) .
( 3) Neut ropeni a, a decreased number of neut r ophi l s, may occur wi t h an
overwheI mi ng i nf ecti on of any t ype ( bone mar row i s unabl e t o keep up wi t h t he
demand) . Ì t may al so occur wi t h certai n vi raI i nfect i ons (e. g. , mumps, measl es) ,
wi t h i di osyncrat i c drug react i ons, and as a r esul t of chemot herapy. Neut r openi a i s
def i ned as an absol ut e neut r ophi l count ( ANC) of < 1000 cel l s/ mm
3
. Some def i ne
absol ut e neut r openi a as an ANC of < 500 cel l s/ mm
3
. The ANC i s cal cul at ed by
mul t i pl yi ng t he per cent of neut r ophi l s by t he t ot al WBC count :
WBC = 4000/ mm
3

neut rophi l s = 60%
ANC = 4000 × 0. 6 = 2400 cel l s/ mm
3

b. Basophi I s st ai n deepl y wi t h bl ue basi c dye. Thei r f unct i on i n t he ci r cul at i on i s
not cl ear l y under st ood; i n t he t i ssues, t hey ar e ref er red t o as mast ceI I s.
( 1) Basophi I i a, an i ncreased number of basophi l s, may occur wi t h chroni c
myel ogenous l eukemi a (CML) as wel l as ot her condi t i ons.
( 2) A decr ease i n basophi l s i s gener al l y not appar ent because of t he smal l number s
of t hese cel l s i n t he bl ood.
c. Eosi nophi I s st ai n deep r ed wi t h aci d dye and ar e cl assi cal l y associ at ed wi t h
i mmune r eact i ons. Eosi nophi I i a, an i ncr eased number of eosi nophi l s, may occur
wi t h such condi t i ons as acut e aI I ergi c react i ons ( e. g. , asthma, hay f ever, drug
aI I ergy) and parasi t i c i nf estat i ons (e. g. , t ri chi nosi s, amebi asi s) .
d. Lymphocyt es pl ay a domi nant rol e i n i mmunol ogi cal act i vi t y and appear t o
pr oduce ant i bodi es. They ar e cl assi f i ed as B l ymphocyt es or T l ymphocyt es; T
l ymphocyt es ar e f ur t her di vi ded i nt o hel per - i nducer cel l s ( TH4 cel l s) and suppressor
cel l s ( TH8 cel l s) .
( 1) Lymphocyt osi s, an i ncr eased number of l ymphocyt es, usual l y accompani es a
nor mal or decr eased t ot al WBC count and i s most commonl y caused by vi raI
i nf ecti on.
( 2) Lymphopeni a, a decr eased number of l ymphocyt es, may r esul t f r om severe
debi I i t at i ng i I I ness, i mmunodef i ci ency, or f r om AI DS, whi ch has a pr opensi t y t o
at t ack TH4 cel l s.
( 3) At ypi caI I ymphocyt es (i . e. , T l ymphocyt es i n a st at e of i mmune act i vat i on) are
cl assi cal l y associ at ed wi t h i nfecti ous mononucI eosi s.
P. 780


e. Monocyt es ar e phagocyt i c cel l s. Monocyt osi s, an i ncr eased number of
monocyt es, may occur wi t h tubercuI osi s ( TB) , subacut e bacteri aI endocardi t i s,
and duri ng t he r ecover y phase of some acute i nfect i ons.
C. PI ateI ets ( t hrombocyt es) . These ar e t he smal l est f or med el ement s i n t he bl ood,
and t hey ar e i nvol ved i n bI ood cI ot t i ng and vi t al t o t he f or mat i on of a hemost at i c
pl ug af t er vascul ar i nj ur y.
1. NormaI vaI ues f or a pI at eI et count are 150, 000- 300, 000/ mm
3
(1. 5-3. 0 × 10
11
/ L) .
2. Thrombocyt openi a, a decr eased pl at el et count , can occur wi t h a vari et y of
condi t i ons, such as i di opat hi c t hr ombocyt openi c pur pur a or , occasi onal l y, f r om such
dr ugs as qui ni di ne and sul f onami des.
a. Thr ombocyt openi a i s moderat e when t he pl at el et count i s < 100, 000/ mm
3
.
b. Thr ombocyt openi a i s severe when t he pl at el et count i s < 50, 000/ mm
3
.
III. COMMON SERUM ENZYME TESTS.
Smal l amount s of enzymes (cat al yst s) ci r cul at e i n t he bl ood at al l t i mes and are
r el eased i nt o t he bl ood i n l ar ger quant i t i es when t i ssue damage occurs. Thus ser um
enzyme l evel s can be used t o ai d i n t he di agnosi s of certai n di seases.
A. Creat i ne ki nase ( CK)
1. Cr eat i ne ki nase÷f or mer l y known as creat i ne phosphoki nase ( CPK) ÷i s f ound
pr i mar i l y i n hear t muscl e, skel et al muscl e, and brai n t i ssue.
2. CK l evel s ar e used pr i mar i l y t o ai d i n t he di agnosi s of acute myocardi aI
( Fi gur e 38- 2) or skeI et aI muscI e damage. However , vi gor ous exer ci se, a f al l , or
deep i nt r amuscul ar i nj ect i ons can cause si gni f i cant i ncreases i n CK l evel s.
3. The i soenzymes of CK÷CK- MM, f ound i n skel et al muscl e; CK- BB, f ound i n brai n
t i ssue; and CK-MB, f ound i n hear t muscl e÷can be used t o di f f erent i at e t he source
of damage.
a. Normal l y, serum CK l evel s ar e vi r t ual l y al l t he CK- MM i soenzyme.
b. Ì ncr ease i n CK-MB l evel s pr ovi des a sensi t i ve i ndi cat or of myocardi al necrosi s.

Figure 38-2. The increase oI serum creatine
kinase (CK). lactate dehydrogenase (LDH). and
aspartate aminotransIerase (AST) levels aIter a
myocardial inIarction.
P. 781


B. Lact at e dehydrogenase (LDH)
1. LDH cat al yzes t he i nt er conver si on of l act at e and pyr uvat e and r epr esent s a gr oup
of enzymes pr esent i n al most al l met abol i zi ng cel l s.
2. Fi ve i ndi vi dual i soenzymes make up t he t ot al LDH serum l evel .
a. LDH1 and LDH2 appear pr i mari l y i n t he heart .
b. LDH3 appears pr i mari l y i n t he l ungs.
c. LDH4 and LDH5 appear pr i mari l y i n t he l i ver and skel et al muscl es.
3. The di st r i but i on pat t ern of LDH i soenzymes may ai d i n di agnosi ng myocar di al
i nf ar ct i on, hepat i c di sease, and l ung di sease.
C. AI kaI i ne phosphat ase ( ALP)
1. ALP i s produced pri mar i l y i n t he I i ver and bones.
2. Serum ALP l evel s ar e part i cuI arI y sensi t i ve to part i aI or mi I d bi I i ar y
obst ruct i on÷ei t her ext r ahepat i c (e. g. , caused by a st one i n t he bi l e duct ) or
i nt rahepat i c, bot h of whi ch cause l evel s t o i ncr ease.
3. I ncreased osteobI asti c act i vi t y, as occur s i n Paget di sease,
hyper par at hyr oi di sm, ost eomal aci a, and ot hers, al so i ncr eases ser um ALP l evel s.
D. Aspart at e ami not ransf erase ( AST)
1. Aspart at e ami not ransf er ase÷f or mer l y known as serum gI utami c- oxaI oacet i c
t ransami nase ( SGOT) ÷i s f ound i n a number of or gans, pr i mari l y i n hear t and l i ver
t i ssues and, t o a l esser ext ent , i n skel et al muscl e, ki dney t i ssue, and pancr eat i c
t i ssue.
2. Damage t o t he heart ( e. g. , f rom myocardi aI i nf arct i on) resul t s i n i ncreased AST
l evel s about 8 hr af t er i nj ur y ( Fi gure 38- 2).
a. Level s are i ncreased markedI y wi t h acut e hepat i t i s; t hey are i ncreased mi I dI y
wi t h ci rrhosi s and a fat ty I i ver.
b. Level s are al so i ncreased wi t h passi ve congest i on of t he I i ver, such as occurs
i n congest i ve hear t f ai l ure ( CHF) .
E. AI ani ne ami not ransferase ( ALT)
1. Al ani ne ami not r ansf erase÷f ormerl y known as serum gI utami c- pyruvi c
t ransami nase ( SGPT) ÷i s f ound i n t he l i ver , wi t h l esser amount s i n t he hear t ,
skel et al muscl es, and ki dney.
2. Al t hough ALT val ues ar e reI at i veI y speci f i c for I i ver ceI I damage, ALT i s I ess
sensi t i ve t han AST, and ext ensi ve or sever e l i ver damage i s necessar y bef or e
abnor mal l y i ncr eased l evel s ar e produced.
3. ALT al so i ncreases I ess consi st ent I y and I ess markedI y t han AST af t er an
acut e myocardi aI i nfarct i on.
F. Cardi ac t roponi ns ( I , T, and C)
1. Tr oponi ns ar e a r el at i vel y new met hod t o i dent i f y myocar di al cel l i nj ur y and t hus
assi st i n t he di agnosi s of acut e myocar di al i nf arct i on. These t roponi ns may possess
super i or speci f i ci t y i n si t uat i ons i n whi ch f al se- posi t i ve el evat i ons of CK- MB ar e
l i kel y.
2. Tr oponi n T i s f ound i n cardi ac and skel et al muscl e, t r oponi n Ì i s f ound onl y i n
car di ac muscl e, and t roponi n C i s pr esent i n t wo i sof or ms f ound i n skel et al and
car di ac muscl e. Tr oponi n T has shown pr ognost i c val ue i n unst abl e angi na and i n
det ect i ng mi nor myocardi al cel l i nj ur y wi t h gr eat er sensi t i vi t y t han CK- MB.
3. The normal val ue f or t r oponi n T i s < 0. 1 ng/ mL and Ì i s < 1. 5 ng/ mL.
P. 782


IV. LIVER FUNCTION TESTS
A. Li ver enzymes
1. LeveI s of certai n enzymes ( e. g. , LDH, ALP, AST, ALT) i ncrease wi th I i ver
dysf unct i on (see Ì Ì Ì ) .
2. These enzyme t est s i ndi cat e onI y t hat t he I i ver has been damaged. They do
not assess t he l i ver ' s abi l i t y t o f unct i on. Ot her t est s pr ovi de i ndi cat i ons of l i ver
dysf unct i on.
B. Serum bi I i rubi n
1. Bi l i rubi n, a breakdown pr oduct of Hb, i s t he predomi nant pi gment i n bi I e.
Ef f ect i ve bi l i r ubi n conj ugat i on and excr et i on depend on hepatobi I i ar y f unct i on and
on t he rat e of RBC t urnover.
2. Serum bi l i rubi n l evel s ar e report ed as t otaI bi I i rubi n (conj ugat ed and
unconj ugat ed) and as di rect bi I i rubi n (conj ugat ed onl y) .
a. Bi l i rubi n i s rel eased by Hb br eakdown and i s bound t o al bumi n as wat er - i nsol ubl e
i ndi rect bi I i rubi n (unconj ugat ed bi l i r ubi n), whi ch i s not f i l t er ed by t he gl omerul us.
b. Unconj ugat ed bi I i rubi n t r avel s t o t he l i ver , wher e i t i s separat ed f rom al bumi n,
conj ugat ed wi t h di gl ucuroni de, and t hen act i vel y secr et ed i nt o t he bi l e as
conj ugated bi I i rubi n (di r ect bi l i rubi n) , whi ch i s f i l t ered by t he gl omer ul us ( Fi gur e
38- 3).
3. NormaI vaI ues of t otaI serum bi I i rubi n ar e 0. 1- 1. 0 mg/ dL (2- 18 mmol / L) ; of
di rect bi I i rubi n, 0. 0- 0. 2 mg/ dL (0- 4 mmol / L) .
4. An i ncrease i n serum bi I i rubi n r esul t s i n j aundi ce f rom bi l i rubi n deposi t i on i n
t he t i ssues. Ther e ar e t hr ee maj or causes of i ncreased serum bi l i rubi n.
a. HemoI ysi s i ncr eases t ot al bi l i r ubi n; di r ect bi l i rubi n ( conj ugat ed) i s usual l y nor mal
or sl i ght l y i ncr eased. Uri ne col or i s normal , and no bi l i rubi n i s f ound i n t he ur i ne.

Figure 38-3. Bilirubin metabolism.
P. 783


b. Bi I i ar y obst ruct i on, whi ch may be i nt r ahepat i c ( as wi t h a chl or promazi ne
r eact i on) or ext r ahepat i c ( as wi t h a bi l i ar y st one), i ncr eases t ot al bi l i r ubi n and di rect
bi l i r ubi n; i nt r ahepat i c chol est asi s (e. g. , f rom chl or pr omazi ne) may i ncrease di r ect
bi l i r ubi n as wel l . Uri ne col or i s dar k, and bi l i r ubi n i s present i n t he uri ne.
c. Li ver ceI I necrosi s, as occur s i n vi r al hepat i t i s, may cause an i ncr ease i n bot h
di r ect bi l i r ubi n ( because i nf l ammat i on causes some bi l e si nusoi d bl ockage) and
i ndi r ect bi l i r ubi n ( because t he l i ver ' s abi l i t y t o conj ugat e i s al t ered). Ur i ne col or i s
dar k, and bi l i r ubi n i s present i n t he ur i ne.
C. Serum protei ns
1. Pri mar y serum protei ns measured ar e aI bumi n and t he gI obuI i ns ( i . e. , q, 8, v) .
a. AI bumi n ( 4. 0- 6. 0 g/ dL) mai nt ai ns serum oncot i c pressure and ser ves as a
t r anspor t agent . Because i t i s pri mar i l y manuf act ur ed by t he l i ver , l i ver di sease can
decrease al bumi n l evel s.
b. GI obuI i ns ( 23- 35 g/ L) f unct i on as t r anspor t agent s and pl ay a r ol e i n cer t ai n
i mmunol ogi cal mechani sms. A decrease i n al bumi n l evel s usual l y r esul t s i n a
compensat or y i ncr ease i n gl obul i n product i on.
2. NormaI vaI ues f or t ot al ser um pr ot ei n l evel s ar e 6. 0- 8. 0 g/ dL ( 60- 80 g/ L) .
V. URINALYSIS.
St andar d ur i nal ysi s provi des basi c i nf or mat i on regar di ng r enal f unct i on, ur i nar y t r act
di sease, and t he pr esence of cer t ai n syst emi c di seases. Component s of a st andar d
ur i nal ysi s i ncl ude appearance, pH, speci f i c gravi t y, pr ot ei n l evel , gl ucose l evel ,
ket one l evel , and mi croscopi c exami nat i on.
A. Appearance. Nor mal ur i ne i s cI ear and r anges i n col or f rom paI e yeI I ow to deep
goI d. Changes i n coI or can r esul t f rom dr ugs, di et , or di sease.
1. A red coI or may i ndi cat e, among ot her t hi ngs, t he pr esence of bl ood or
phenol pht hal ei n ( a l axat i ve) .
2. A browni sh yeI I ow coI or may i ndi cat e t he presence of conj ugat ed bi l i r ubi n.
3. Ot her shades of red, orange, or brown may be caused by i ngest i on of var i ous
dr ugs (e. g. , r i f ampi n) .
B. pH
1. NormaI pH r anges f rom 4. 5 t o 9 but i s t ypi cal l y aci di c ( ar ound 6) .
2. AI kaI i ne pH may i ndi cat e such condi t i ons as al kal osi s, a Prot eus i nf ect i on, or
acet azol ami de use. Ì t may al so ref l ect changes caused by l eavi ng t he uri ne sampl e
at r oom t emper at ur e.
C. Speci f i c gravi t y
1. NormaI range f or speci f i c gr avi t y i s 1. 003-1. 035; i t i s usual l y bet ween 1. 010 and
1. 025.
2. Speci f i c gr avi t y i s i nf l uenced by t he number and nat ure of sol ut e part i cl es i n t he
ur i ne.
a. I ncreased speci fi c gravi t y may occur wi t h such condi t i ons as di abet es mel l i t us
( excess gl ucose i n t he ur i ne) or nephr osi s (excess prot ei n i n t he ur i ne).
b. Decreased speci f i c gravi t y may occur wi t h di abet es i nsi pi dus, whi ch decreases
ur i ne concent r at i on.
c. Speci fi c gravi t y, f i xed at 1. 010 (t he same as pl asma) , occurs when t he ki dneys
l ose t hei r power t o concent r at e or di l ut e.
D. Prot ei n
1. NormaI vaI ues f or ur i ne prot ei n ar e 50-80 mg/ 24 hr because t he gl omer ul ar
membr ane pr event s most pr ot ei n mol ecul es i n t he bl ood f r om ent er i ng t he uri ne.
2. Protei nuri a occurs wi t h many condi t i ons (e. g. , r enal di sease, bl adder i nf ect i on,
venous congest i on, f ever ) .
a. The pr esence of a speci f i c protei n can hel p i dent i f y a speci f i c di sease st at e
( e. g. , Bence Jones pr ot ei n may i ndi cat e mul t i pl e myel oma).
P. 784


b. Most of t en, t he pr ot ei n i n uri ne i s aI bumi n. Al bumi nur i a may i ndi cat e abnor mal
gl omerul ar per meabi l i t y.
E. GI ucose
1. The normal renaI t hreshoI d f or gl ucose i s a bl ood gl ucose l evel of about 180
mg/ dL; gI ucose does not normaI I y appear i n uri ne as det ect ed by popul ar t est i ng
met hods.
2. GI ycosuri a usual l y i ndi cat es di abet es mel l i t us ( DM) . Ther e ar e cert ai n l ess
common causes (e. g. , a l ower ed renal t hr eshol d f or gl ucose) .
F. Ket ones
1. Ket ones do not normaI I y appear i n uri ne. They ar e excr et ed when t he body has
used avai l abl e gl ucose st or es and begi ns t o met abol i ze f at st ores.
2. The t hree ket one bodi es ar e ß- hydroxybut yri c aci d (80%), acet oaceti c aci d
( about 20%), and acet one ( a smal l per cent age) . Some commerci al t est s (e. g. , Ames
pr oduct s) measur e onl y acet oacet i c aci d, but usual l y al l t hree ar e excr et ed i n
par al l el pr opor t i ons.
3. Ketonuri a usual l y i ndi cat es uncont r ol l ed DM, but i t may al so occur wi t h
st ar vat i on and wi t h zero- or l ow- car bohydr at e di et s.
G. EvaI uat i on. Mi croscopi c exami nat i on of cent r i f uged uri ne sedi ment nor mal l y
r eveal s 0- 1 RBC, 0- 4 WBCs, and onl y an occasi onal cast per hi gh- power f i el d
( HPF) .
1. Hemat uri a (i . e. , t he pr esence of RBCs) may i ndi cat e such condi t i ons as t rauma,
a t umor, or a syst emi c bl eedi ng di sorder . Ì n women, a si gni f i cant number of
squamous ceI I s suggest s vagi nal cont ami nat i on ( menst ruat i on) .
2. Cast s (i . e. , pr ot ei n congl omer at i ons out l i ni ng t he shape of t he renal t ubul es i n
whi ch t hey wer e f ormed) may or may not be si gni f i cant . Excessi ve number s of
cer t ai n t ypes of cast s i ndi cat e r enal di sease.
3. Cr yst aI s, whi ch are pH dependent , may occur nor mal l y i n aci d or al kal i ne uri ne.
Uri c aci d cr yst aI s may f or m i n aci d ur i ne; phosphat e cr yst aI s may f orm i n al kal i ne
ur i ne.
4. Bact eri a do not nor mal l y appear i n ur i ne. The f i ndi ng of 50 or mor e bact eri a per
HPF may i ndi cat e a ur i nar y t r act i nf ect i on ( UTÌ ) ; smal l er val ues may i ndi cat e
ur et hr al cont ami nat i on.
VI. COMMON RENAL FUNCTION TESTS
A. I nt roduct i on
1. Renal f unct i on may be assessed by measur i ng bI ood urea ni t rogen ( BUN) and
serum creat i ni ne. Renal f unct i on decr eases wi t h age, whi ch must be t aken i nt o
account when i nt er pret i ng t est val ues.
a. These t est s pr i mari l y eval uat e gl omer ul ar f unct i on by assessi ng t he gI omeruI ar
f i I t rat i on rate ( GFR) .
b. Ì n many renaI di seases, ur ea and cr eat i ni ne accumul at e i n t he bl ood because
t hey are not excr et ed properl y.
c. These t est s al so ai d i n det ermi ni ng drug dosage f or drugs excr et ed t hrough t he
ki dneys.
2. Azot emi a descri bes excessi ve ret ent i on of ni t rogenous wast e product s ( BUN and
cr eat i ni ne) i n t he bl ood. The cl i ni cal syndr ome r esul t i ng f rom decr eased renal
f unct i on and azot emi a i s cal l ed uremi a.
a. RenaI azot emi a resul t s f rom r enal di sease, such as gl omer ul onephri t i s and
chr oni c pyel onephr i t i s.
b. PrerenaI azot emi a resul t s f r om such condi t i ons as sever e dehydr at i on,
hemor r hagi c shock, and excessi ve prot ei n i nt ake.
c. Post renaI azotemi a resul t s f rom such condi t i ons as ur et er al or uret hral st ones or
t umor s and prost at i c obst r uct i ons.
3. CI earance÷a t heoret i cal concept def i ned as t he vol ume of pl asma f r om whi ch a
measured amount of subst ance can be compl et el y el i mi nat ed, or cl ear ed, i nt o t he
ur i ne per uni t t i me÷can be used t o est i mat e gl omer ul ar f unct i on.
P. 785


B. BUN
1. Urea, an end pr oduct of prot ei n met abol i sm, i s pr oduced i n t he l i ver . From t here,
i t t ravel s t hr ough t he bl ood and i s excr et ed by t he ki dneys. Urea i s f i I tered at t he
gI omeruI us, wher e t he t ubul es r eabsor b appr oxi mat el y 40%. Thus under nor mal
condi t i ons, urea cI earance i s about 60% of t he t rue GFR.
2. NormaI vaI ues f or BUN r ange f rom 8 mg/ dL t o 18 mg/ dL ( 3-6. 5 mmol / L) .
a. Decreased BUN I eveI s occur wi t h si gni f i cant I i ver di sease.
b. I ncreased BUN I eveI s may i ndi cat e renaI di sease. However , f act ors ot her t han
gl omerul ar f unct i on ( e. g. , pr ot ei n i nt ake, r educed r enal bl ood f l ow, bl ood i n t he
gast r oi nt est i nal t ract ) r eadi l y af f ect BUN l evel s, somet i mes maki ng i nt er pr et at i on of
r esul t s di f f i cul t .
C. Serum creat i ni ne
1. Cr eat i ni ne ( CR) , t he met abol i c breakdown pr oduct of muscl e cr eat i ne phosphat e,
has a rel at i vel y const ant l evel of dai l y product i on. Bl ood l evel s var y l i t t l e i n a gi ven
i ndi vi dual .
2. Cr eat i ni ne i s excret ed by gl omer ul ar f i l t r at i on and t ubul ar secr et i on. Creat i ni ne
cI earance par al l el s t he GFR wi t hi n a r ange of ± 10% and i s a more sensi t i ve
i ndi cat or of renaI damage t han BUN I eveI s because r enal i mpai rment i s al most
t he onl y cause of an i ncrease i n t he serum creat i ni ne l evel .
3. NormaI vaI ues f or serum creat i ni ne r ange f rom 0. 6 t o 1. 2 mg/ dL ( 50 t o 110
mmol / L) .
a. Val ues var y wi t h t he amount of muscI e mass÷a val ue of 1. 2 mg/ dL i n a
muscul ar at hl et e may repr esent normal renal f unct i on, whereas t he same val ue i n a
smal l , sedent ar y person wi t h l i t t l e muscl e mass may i ndi cat e si gni f i cant r enal
i mpai rment .
b. Gener al l y, t he serum creat i ni ne vaI ue doubI es wi t h each 50% decrease i n
GFR. For exampl e, i f a pat i ent ' s normal ser um creat i ni ne i s 1 mg/ dL, 1 mg/ dL
r epr esent s 100% r enal f unct i on, 2 mg/ dL r epr esent s 50% f unct i on, and 4 mg/ dL
r epr esent s 25% f unct i on.
D. Creat i ni ne cI earance
1. Cr eat i ni ne cl ear ance, whi ch r epr esent s t he rate at whi ch creat i ni ne i s removed
f rom t he bI ood by t he ki dneys, r oughl y approxi mat es t he GFR.
a. The val ue i s gi ven i n uni t s of mi l l i l i t er s per mi nut e, r epr esent i ng t he vol ume of
bl ood cl ear ed of cr eat i ni ne by t he ki dney per mi nut e.
b. NormaI vaI ues f or men r ange f r om 75 t o 125 mL/ mi n.
2. Cal cul at i on r equi r es knowl edge of uri nar y creat i ni ne excret i on ( usual l y over 24
hr ) and concur r ent serum creat i ni ne I eveI s. Creat i ni ne cI earance i s caI cuI at ed as
f ol l ows:

wher e Cl CR i s t he cr eat i ni ne cl earance i n mi l l i l i t ers per mi nut e, CU i s t he
concent r at i on of cr eat i ni ne i n t he ur i ne, V i s t he vol ume of uri ne ( i n mi l l i l i t er s per
mi nut e of ur i ne f ormed over t he col l ect i on per i od), and CCR i s t he serum cr eat i ni ne
concent r at i on.
3. Suppose t he ser um creat i ni ne concent rat i on i s 1 mg/ dL, and 1440 mL of ur i ne
was col l ect ed i n 24 hr ( 1440 mi n) f or a uri ne vol ume of 1 mL/ mi n. The uri ne cont ai ns
100 mg/ dL of cr eat i ni ne. Cr eat i ni ne cl ear ance i s cal cul at ed as:

4. Ì ncompl et e bl adder empt yi ng and ot her pr obl ems may i nt er f ere wi t h obt ai ni ng an
accur at e t i med ur i ne speci men. Thus esti mat i ons of creati ni ne cI earance may be
necessar y. These est i mat i ons requi r e onl y a serum cr eat i ni ne val ue. One est i mat i on
uses t he met hod of Cockrof t and GauI t , whi ch i s based on body wei ght , age, and
gender .
a. Thi s f ormul a pr ovi des an est i mat ed vaI ue, cal cul at ed f or maI es as:

b. For f emaI es, use 0. 85 of t he val ue cal cul at ed f or mal es.
P. 786


c. ExampI e: A 20- year - ol d man wei ghi ng 72 kg has a CCR of 1. 0 mg/ dL; t hus

5. Determi nat i on of GFR. The modi f i ed di et i n renal di sease ( MDRD) equat i on i s
consi dered a mor e accurat e measur ement of GFR t han ot her equat i ons used t o
est i mat e r enal f unct i on (e. g. , Cockcr of t - Gaul t ) i n pat i ent s wi t h r educed GFR and i s
used i n st agi ng r enal di sease. Pat i ent s must have a serum creat i ni ne concent r at i on.
a. The MDRD equat i on f or maI es i s as f ol l ows:
GFR = 186 ( Pcr )
- 1. 154
× age
- 0. 203

wher e Pcr i s ser um cr eat i ni ne. For f emaI es, mul t i pl y t he r esul t by 0. 742; f or Af ri can
Ameri cans, mul t i pl y by 1. 210.
b. The MDRD has been val i dat ed i n Caucasi ans, pat i ent s wi t h di abet i c ki dney
di sease, ki dney t r anspl ant r eci pi ent s, and Af r i can Amer i cans and Asi ans wi t h
nondi abet i c ki dney di sease.
c. The MDRD equat i on has not been val i dat ed i n pat i ent s < 18 years of age,
pr egnant women, pat i ent s > 70 year s of age, ot her et hni c gr oups, pat i ent s wi t h
nor mal ki dney f unct i on who are at an i ncreased r i sk f or chroni c ki dney di sease, and
pat i ent s wi t h normal r enal f unct i on.
d. Many i nst i t ut i ons are r out i nel y r epor t i ng an MDRD- der i ved GFR est i mat i on f or
pat i ent s as a r out i ne component of a bl ood chemi st r y st udy. Thi s val ue shoul d be
used t o assi st t he cl i ni ci an i n st agi ng a pat i ent ' s degree of renal dysf unct i on and i s
not a subst i t ut e f or cr eat i ni ne cl ear ance as est i mat ed by t he Cockr of t and Gaul t
equat i on, whi ch shoul d be used f or dr ug dosi ng i n r enal i mpai r ment . The MDRD
est i mat e has not been eval uat ed f or t he purpose of dr ug dosi ng.
VII. ELECTROLYTES
A. Sodi um ( Na)
1. Sodi um i s t he maj or cat i on of t he ext raceI I uI ar f l ui d. Sodi um al ong wi t h chl ori de
( Cl ) , pot assi um ( K), and wat er i s i mport ant i n t he r egul at i on of osmot i c pressur e and
wat er bal ance bet ween i nt r acel l ul ar and ext r acel l ul ar f l ui ds. NormaI vaI ues are
135-147 mEq/ L or mmol / L.
2. The sodi um concent r at i on i s def i ned as t he rat i o of sodi um t o wat er , not t he
absol ut e amount s of ei t her . Labor at or y t est s f or sodi um ar e used mai nl y t o det ect
di st ur bances i n wat er bal ance and body osmol al i t y. The ki dneys are t he maj or
or gans of sodi um and wat er bal ance.
3. An i ncr ease i n sodi um concent rat i on (hypernat remi a) may i ndi cat e i mpai red
sodi um excr et i on or dehydr at i on. A decr ease i n sodi um concent rat i on
( hyponat r emi a) may r ef l ect over hydrat i on, abnormal sodi um l oss, or decreased
sodi um i nt ake.
4. Pat i ent s wi t h ki dney, hear t , or pul monar y di sease may have di f f i cul t y wi t h sodi um
and wat er bal ance. Ì n adul t s, changes i n sodi um concent r at i ons most of t en r ef l ect
changes i n wat er bal ance, not sal t i mbal ances. Ther ef or e, sodi um concent r at i on i s
of t en used as an i ndi cat or of f l ui d st at us, r at her t han sal t i mbal ance.
5. Cont r ol of sodi um by t he body i s accompl i shed mai nl y t hr ough t he hor mones
al dost er one and ant i di uret i c hor mone ( ADH) .
a. ADH i s rel eased f r om t he pi t ui t ar y gl and i n r esponse t o si gnal s f r om t he
hypot hal amus. ADH' s presence i n t he di st al t ubul es and col l ect i ng duct s of t he
ki dney causes t hem t o become mor e permeabl e t o t he r eabsor pt i on of wat er ;
t her ef ore, concent r at i ng ur i ne.
b. Al dost erone af f ect s t he di st al t ubul ar r eabsor pt i on of sodi um as opposed t o
wat er . Al dost er one i s r el eased f r om t he adr enal cor t ex i n r esponse t o l ow sodi um,
hi gh pot assi um, l ow bl ood vol ume, and angi ot ensi n Ì Ì . Al dost er one causes t he
spi l l i ng of pot assi um f r om t he di st al t ubul es i nt o t he ur i ne i n exchange f or sodi um
r eabsorpt i on.
6. Hyponat remi a i s usual l y rel at ed t o t ot al body depl et i on of sodi um÷as i n
mi ner al ocor t i coi d def i ci enci es, sodi um- wast i ng renal di sease, r epl acement of f l ui d
l oss wi t h nonsal i ne sol ut i ons, gast r oi nt est i nal ( GÌ ) l osses, r enal l osses, or l oss of
sodi um t hr ough t he ski n÷or t o
P. 787

di l ut i on of ser um sodi um÷as i n ci rr hosi s, CHF, nephrosi s, r enal f ai l ure, excess
wat er i nt ake, or syndr ome of i nappropri at e ant i di ur et i c hormone ( SÌ ADH) secr et i on.
7. Hypernat remi a usual l y r esul t s f r om a l oss of f r ee wat er or hypot oni c f l ui d or
t hr ough excessi ve sodi um i nt ake. Fr ee wat er l oss i s most of t en associ at ed wi t h
di abet es i nsi pi dus, but f l ui d l oss can be vi a t he GÌ t r act , r enal , ski n, or r espi rat or y
syst ems. Excess sodi um i nt ake can occur t hrough t he admi ni st rat i on of hyper t oni c
i nt ravenous (Ì V) sol ut i ons, mi ner al ocor t i coi d excess, excessi ve sodi um i ngest i on, or
af t er admi ni st r at i on of drugs hi gh i n sodi um cont ent ( e. g. , t i carci l l i n, sodi um
bi car bonat e [ ] ) .
B. Pot assi um ( K)
1. Pot assi um i s t he most abundant i nt raceI I uI ar cat i on ( i nt r acel l ul ar f l ui d pot assi um
aver ages 141 mEq/ L). Appr oxi mat el y 3500 mEq of pot assi um i s cont ai ned i n t he
body of a 70-kg adul t . Onl y 10% of t he body' s pot assi um i s ext r acel l ul ar. Nor mal
val ues are 3. 5- 5. 0 mEq/ L or mmol / L.
2. The serum pot assi um concent r at i on i s not an adequat e measur e of t he t ot al body
pot assi um because most of t he body' s pot assi um i s i nt r acel l ul ar . Fort unat el y, t he
cl i ni cal si gns and sympt oms of pot assi um def i ci ency÷mal ai se, conf usi on, di zzi ness,
el ect r ocar di ogram (ECG) changes, muscl e weakness, and pai n÷cor r el at e wel l wi t h
ser um concent rat i ons. The ser um pot assi um concent r at i on i s buf f er ed by t he body
and may be "normal ¨ despi t e t ot al body pot assi um l oss. Pot assi um depl et i on causes
a shi f t of i nt r acel l ul ar pot assi um t o t he ext r acel l ul ar f l ui d t o mai nt ai n pot assi um
concent r at i ons. Ther e i s approxi mat el y a 100 mEq t ot al body pot assi um def i ci t when
t he serum pot assi um concent r at i on decr eases by 0. 3 mEq/ L. Thi s may r esul t i n
mi si nt er pr et at i on of ser um pot assi um concent r at i ons as t hey r el at e t o t ot al body
pot assi um.
3. The rol e or f unct i on of pot assi um i s i n t he mai nt enance of proper el ect r i cal
conduct i on i n cardi ac and skel et al muscl es (muscl e and ner ve exci t abi l i t y) , i t exer t s
an i nf l uence on t he body' s wat er bal ance ( i nt racel l ul ar vol ume) and pl ays a r ol e i n
aci d- base equi l i br i um.
4. Pot assi um i s r egul at ed by:
a. Ki dneys ( r enal f unct i on)
b. Al dost erone
c. Ar t er i al pH
d. Ì nsul i n
e. Pot assi um i nt ake
f . Sodi um del i ver y t o di st al t ubul es
5. HypokaI emi a can occur . The ki dneys are r esponsi bl e f or approxi mat el y 90% of
t he dai l y pot assi um l oss. Ot her l osses occur mai nl y t hr ough t he GÌ syst em. Even i n
st at es of no pot assi um i nt ake, t he ki dneys st i l l excr et e up t o 20 mEq of pot assi um
dai l y. Ther ef or e, prol onged per i ods of pot assi um depri vat i on can r esul t i n
hypokal emi a. Hypokal emi a can al so r esul t f rom pot assi um l oss t hr ough vomi t i ng or
di ar rhea, nasogast ri c suct i on, l axat i ve abuse, and by di ur et i c use ( manni t ol ,
t hi azi des, or l oop di ur et i cs). Excessi ve mi ner al ocor t i coi d act i vi t y and gl ucosuri a can
al so r esul t i n hypokal emi a. Pot assi um can be shi f t ed i nt o cel l s wi t h al kal emi a and
af t er admi ni st r at i on of gl ucose and i nsul i n.
6. HyperkaI emi a most commonl y r esul t s f r om decr eased r enal el i mi nat i on,
excessi ve i nt ake, or f r om cel l ul ar br eakdown ( t i ssue damage, hemol ysi s, burns,
i nf ect i ons) . Met abol i c aci dosi s may al so r esul t i n a shi f t of pot assi um ext r acel l ul arl y
as hydr ogen i ons move i nt o cel l s and ar e exchanged f or pot assi um and sodi um i ons.
As a gener al gui del i ne, f or ever y 0. 1 uni t pH change f r om 7. 4, t he pot assi um
concent r at i on wi l l change by about 0. 6 mEq/ L. Ì f a pat i ent has a pH of 7. 1 and a
measured pot assi um of 4. 5 mEq/ L, t he act ual pot assi um concent rat i on woul d be
0. 3 (uni t s l ess t han 7. 4) × 0. 6 = 1. 8
Pot assi um concent r at i on = 4. 5 - 1. 8 = 2. 7 mEq/ L
Cor r ect i on of t he aci dosi s i n t hi s si t uat i on wi l l r esul t i n a dr amat i c decrease i n
pot assi um unl ess suppl ement at i on i s i nst i t ut ed.
P. 788


C. ChI ori de ( CI )
1. Chl or i de i s t he maj or ani on of t he ext r acel l ul ar f l ui d and i s i mpor t ant i n t he
mai nt enance of aci d-base bal ance. Al t erat i ons i n t he ser um chl or i de concent r at i on
ar e rar el y a pri mar y i ndi cat or of maj or medi cal probl ems. Chl ori de i t sel f i s not of
pr i mar y di agnost i c si gni f i cance. Ì t i s usual l y measur ed t o conf i rm t he serum sodi um
concent r at i on. The r el at i onshi p among sodi um, chl or i de, and i s descr i bed by t he
f ol l owi ng:
Cl
-
+ + R = Na
+

wher e R i s t he ani on gap. The normaI vaI ue f or Cl i s 95- 105 mEq/ L or mmol / L.
2. HypochI oremi a i s a decr eased chl ori de concent r at i on, and i t i s of t en
accompani ed by met abol i c al kal osi s or aci dosi s caused by or gani c or ot her aci ds.
Ot her causes i ncl ude chroni c r enal f ai l ur e, adrenal i nsuf f i ci ency, f ast i ng, pr ol onged
di ar rhea, sever e vomi t i ng, and di uret i c t herapy.
3. HyperchI oremi a i s an i ncr eased chl or i de concent r at i on t hat may i ndi cat e
hyper chl or emi c met abol i c aci dosi s. Hyperchl oremi a i n t he absence of met abol i c
aci dosi s i s unusual because chl ori de r et ent i on i s of t en accompani ed by sodi um and
wat er r et ent i on. Ot her causes i ncl ude acut e r enal f ai l ure, dehydrat i on, and excess
chl or i de admi ni st r at i on.
D. Bi carbonate ( [ )/ carbon di oxi de ( CO2) content
1. The carbon di oxi de ( CO2) cont ent repr esent s t he sum of t he bi car bonat e ( )
concent r at i on and t he concent r at i on of CO2 di ssol ved i n t he serum. The / CO2
syst em i s t he most i mport ant buf f eri ng syst em t o mai nt ai n pH wi t hi n physi ol ogi cal
l i mi t s. Most di st urbances of aci d- base bal ance can be consi der ed i n t erms of t hi s
syst em. Nor mal val ues ar e 22- 28 mEq/ L or mmol / L.
2. The rel at i onshi p among t hi s syst em i s def i ned as f ol l ows:
+ H
+
× H2CO3 × H2O + CO2
( bi car bonat e i ons bi nd hydr ogen i ons t o f orm carboni c aci d) . Cl i ni cal l y, t he ser um
concent r at i on i s measured because aci d- base bal ance can be i nf err ed i f t he pat i ent
has normal pul monar y f unct i on.
3. Hypobi carbonat emi a i s usual l y caused by met abol i c aci dosi s, r enal f ai l ur e,
hyper vent i l at i on, severe di ar rhea, drai nage of i nt est i nal f l ui d, and by drugs such as
acet azol ami de. Toxi ci t y caused by sal i cyl at es, met hanol , and et hyl ene gl ycol can
al so decrease t he l evel .
4. Hyperbi carbonat emi a i s usual l y caused by al kal osi s, hypovent i l at i on, pul monar y
di sease, persi st ent vomi t i ng, excess i nt ake wi t h poor renal f unct i on, and di ur et i cs.
VIII. MINERALS
A. CaI ci um ( Ca)
1. Cal ci um pl ays an i mpor t ant r ol e i n ner ve i mpul se t r ansmi ssi on, muscl e
cont r act i on, pancreat i c i nsul i n r el ease, hydrogen i on r el ease f r om t he st omach, as a
cof act or f or some enzyme r eact i ons and bl ood coagul at i on, and most i mpor t ant bone
and t oot h st r uct ur al i nt egr i t y. Nor mal t ot al cal ci um val ues are 8. 8- 10. 3 mg/ dL or
2. 20-2. 56 mmol / L.
2. The t ot al cal ci um cont ent of normal adul t s i s 20- 25 g/ kg of f at - f ree t i ssue, and
about 44% of t hi s cal ci um i s i n t he body skel et on. Approxi mat el y 1% of skel et al
cal ci um i s f reel y exchangeabl e wi t h t hat of t he ext r acel l ul ar f l ui d. The reser voi r of
cal ci um i n bones mai nt ai ns t he concent rat i on of cal ci um i n t he pl asma const ant .
About 40% of t he cal ci um i n t he ext r acel l ul ar f l ui d i s bound t o pl asma prot ei ns
( especi al l y al bumi n) , 5%- 15% i s compl exed wi t h phosphat e and ci t rat e, and 45%-
55% i s i n t he unbound, i oni zed f orm. Most l aborat or i es measur e t he t ot al cal ci um
concent r at i on; however , i t i s t he f r ee, i oni zed cal ci um t hat i s i mpor t ant
physi ol ogi cal l y. Ì oni zed cal ci um l evel s may be obt ai ned f r om t he l aborat or y.
Cl i ni cal l y, t he most i mpor t ant det ermi nant of i oni zed cal ci um i s t he amount of ser um
pr ot ei n ( al bumi n) avai l abl e f or bi ndi ng. The normal ser um cal ci um r ange i s f or
P. 789

a ser um al bumi n of 4 g/ dL. A good appr oxi mat i on i s t hat f or ever y 1 g/ dL decrease
i n al bumi n, 0. 8 g/ dL shoul d be added t o t he cal ci um l abor at or y r esul t . Doi ng t hi s
cor rect s t he t ot al pl asma concent rat i on t o ref l ect t he addi t i onal amount of f r ee
( act i ve) cal ci um.
3. HypocaI cemi a usual l y i mpl i es a def i ci ency i n ei t her t he pr oduct i on or response
t o par at hyr oi d hor mone (PTH) or vi t ami n D. PTH abnor mal i t i es i ncl ude
hypopar at hyr oi di sm, pseudo-hypopar at hyr oi di sm, or hypomagnesemi a. Vi t ami n D
abnor mal i t i es can be caused by decr eased nut r i t i onal i nt ake, decreased absor pt i on
of vi t ami n D, a decr ease i n pr oduct i on, or an i ncrease i n met abol i sm. Admi ni st r at i on
of l oop di ur et i cs causi ng di ur esi s can al so decr ease ser um cal ci um.
4. HypercaI cemi a i s an i ncr eased cal ci um concent r at i on, and i t i s usual l y
associ at ed wi t h mal i gnancy or met ast at i c di seases. Ot her causes i ncl ude
hyper par at hyr oi di sm, Paget di sease, mi l k- al kal i syndr ome, gr anul omat ous di sor ders,
t hi azi de di ur et i cs, excessi ve cal ci um i nt ake, or vi t ami n D i nt oxi cat i on.
B. Phosphate ( PO4)
1. Phosphat e i s a maj or i nt r acel l ul ar ani on and i s t he sour ce of phosphat e f or
adenosi ne t ri phosphat e (ATP) and phosphol i pi d synt hesi s. Ser um cal ci um and PO4
ar e i nf l uenced by many of t he same f act ors. Ì t i s usef ul t o consi der cal ci um and PO4
t oget her when i nt erpr et i ng l ab resul t s. Normal PO4 val ues ar e 2. 5-5. 0 mg/ dL or
0. 80-1. 60 mmol / L.
2. Hyperphosphat emi a and hypophosphat emi a can occur . The ext r acel l ul ar f l ui d
concent r at i on of phosphat e i s i nf l uenced by PTH, i nt est i nal absorpt i on, renal
f unct i on, nut r i t i on, and bone met abol i sm. Hyper phosphat emi a i s usual l y caused by
r enal i nsuf f i ci ency, al t hough i ncr eased vi t ami n D or phosphat e i nt ake,
hypopar at hyr oi di sm, and hyper t hyr oi di sm ar e al so causes. Hypophosphat emi a can
occur i n mal nut r i t i on, especi al l y when anabol i sm i s i nduced, af t er admi ni st r at i on of
al umi num- cont ai ni ng ant aci ds or cal ci um acet at e, i n chroni c al cohol i cs, and i n
sept i c pat i ent s. Hyper par at hyr oi di sm and i nsuf f i ci ent vi t ami n D i nt ake can al so
i nduce hypophosphat emi a.
C. Magnesi um ( Mg)
1. Magnesi um i s t he second most abundant i nt r acel l ul ar and ext r acel l ul ar cat i on. Ì t
i s an act i vat or of numerous enzyme syst ems t hat cont r ol car bohydr at e, f at and
el ect r ol yt e met abol i sm, pr ot ei n synt hesi s, ner ve conduct i on, muscul ar cont r act i l i t y,
as wel l as membr ane t ranspor t and i nt egr i t y. Normal val ues ar e 1. 6- 2. 4 mEq/ L or
0. 8- 1. 20 mmol / L.
2. Hypomagnesemi a and hypermagnesemi a can occur . Hypomagnesemi a i s f ound
mor e of t en t han hypermagnesemi a. Depl et i on of magnesi um usual l y r esul t s f rom
excessi ve l oss f rom t he GÌ t r act or t he ki dneys. Depl et i on can occur f rom ei t her
poor i nt est i nal absorpt i on or excessi ve GÌ f l ui d l oss. Si gns and sympt oms i ncl ude
weakness, muscl e f asci cul at i ons wi t h t r emor, t et any, and i ncreased r ef l exes.
Decr eased i nt racar di ac magnesi um may mani f est as an i ncreased QT i nt er val wi t h
an i ncreased r i sk of ar r hyt hmi a. Hypermagnesemi a i s most commonl y caused by
i ncreased magnesi um i nt ake i n t he set t i ng of r enal i nsuf f i ci ency. Ot her causes
i ncl ude excess magnesi um i nt ake, hepat i t i s, and Addi son di sease. Si gns and
sympt oms of hyper magnesemi a i ncl ude br adycardi a, f l ushi ng, sweat i ng, nausea and
vomi t i ng, decreased cal ci um l evel , decr eased deep- t endon ref l exes, f l acci d
par al ysi s, i ncr eased pul se r at e and QRS i nt er val s, r espi rat or y di st r ess, and
asyst ol e.
P. 790


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 16: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. Hemat oI ogi caI t esti ng of a pati ent wi t h AI DS i s most I i keI y t o show whi ch of
t he f oI I owi ng abnormaI i t i es?
( A) basophi l i a
( B) eosi nophi l i a
( C) l ymphopeni a
( D) r et i cul ocyt osi s
( E) agranul ocyt osi s
Vi ew Answer 1. The answer i s C[ see] . 2. HematoI ogi caI st udi es are most
I i keI y t o show a I ow reti cuI ocyt e count i n a pat i ent who has whi ch of t he
f oI I owi ng abnormaI i ti es?
( A) apl ast i c anemi a secondar y t o cancer chemot her apy
( B) acut e hemol yt i c anemi a secondar y t o qui ni di ne t reat ment
( C) severe bl eedi ng secondar y t o an aut omobi l e acci dent
( D) i r on- def i ci ency anemi a 1 week af t er t r eat ment wi t h f er rous sul f at e
( E) megal obl ast i c anemi a owi ng t o f ol at e def i ci ency 1 week af t er t r eat ment wi t h f ol i c
aci d
Vi ew Answer 2. The answer i s A[ see] . 3. AI I of the f oI I owi ng f i ndi ngs on a
rout i ne uri naI ysi s wouI d be consi dered normaI except whi ch one?
( A) pH: 6. 5
( B) gl ucose: negat i ve
( C) ket ones: negat i ve
( D) whi t e bl ood cel l s (WBCs) : 3 per hi gh-power f i el d ( HPF), no cast s
( E) r ed bl ood cel l s ( RBCs) : 5 per HPF
Vi ew Answer 3. The answer i s E[see V. B; and] . 4. A 12- year- oI d boy i s
t reat ed f or ot i t i s medi a wi th cef acI or ( CecI or). On t he 7t h day of t herapy, he
spi kes a f ever and deveI ops an urt i cari aI rash on hi s t runk. Whi ch of t he
f oI I owi ng I aborator y t est s couI d best conf i rm t he physi ci an' s suspi ci on of a
hypersensi t i vi t y ( aI I ergi c) react i on?
( A) compl et e bl ood count ( CBC) and di f f er ent i al
( B) ser um hemogl obi n ( Hb) and ret i cul ocyt e count
( C) l i ver f unct i on t est prof i l e
( D) l act at e dehydrogenase (LDH) i soenzyme pr of i l e
( E) r ed bl ood cel l ( RBC) count and ser um bi l i r ubi n
Vi ew Answer 4. The answer i s A[ see] . 5. An i ncreased hematocri t ( Hct ) i s a
I i keI y f i ndi ng i n aI I of the f oI I owi ng i ndi vi duaI s except whi ch one?
( A) a man who has j ust ret ur ned f r om a 3- week ski i ng t r i p i n t he Col orado Rocki es
( B) a woman who has pol ycyt hemi a ver a
( C) a hospi t al i zed pat i ent who mi st akenl y recei ved 5 L of i nt r avenous ( Ì V) dext r ose
5% i n wat er ( D5W) over t he l ast 24 hr
( D) a man who has been r escued f r om t he Ari zona desert af t er spendi ng 4 days
wi t hout wat er
( E) a woman who has chr oni c obst r uct i ve pul monar y di sease
Vi ew Answer 5. The answer i s C[ see] . 6. A 29- year- oI d whi t e man i s seen
i n t he emergency room. Hi s whi te bI ood ceI I (WBC) count i s 14, 200 wi t h 80%
poI ys. AI I of t he foI I owi ng condi ti ons couI d normaI I y produce t hese I aborat or y
f i ndi ngs except whi ch one?
( A) a l ocal i zed bact eri al i nf ect i on on t he t i p of t he i ndex f i nger
( B) acut e bact er i al pneumoni a caused by St r ept ococcus pneumoni ae
( C) a hear t at t ack
( D) a gunshot wound t o t he abdomen wi t h a l oss of 2 pi nt s of bl ood
( E) an at t ack of gout
Vi ew Answer 6. The answer i s A[ see] . 7. A 52- year- oI d maI e const ructi on
worker who dri nks "f ai rI y heavi I y" when he gets of f work i s seen i n t he
emergency room wi t h, among ot her abnormaI I aborat ory resuI t s, an i ncreased
creat i ne ki nase ( CK) I eveI . AI I of t he f oI I owi ng ci rcumstances couI d expI ai n
t hi s i ncrease except whi ch one?
( A) he f el l agai nst t he bumper of hi s car i n a dr unken st upor and br ui sed hi s ri ght
si de
( B) he i s showi ng evi dence of some l i ver damage owi ng t o t he heavy al cohol i nt ake
( C) he has exper i enced a hear t at t ack
( D) he recei ved an i nt r amuscul ar ( Ì M) i nj ect i on a f ew hours bef or e t he bl ood sampl e
was dr awn
( E) he pul l ed a muscl e t hat day when l i f t i ng a heavy concr et e sl ab
Vi ew Answer 7. The answer i s B[ see] . P. 791


8. A 45- year- oI d man wi t h j aundi ce has spi I I age of bi I i rubi n i nt o hi s uri ne. AI I
of t he f oI I owi ng st atement s couI d appI y t o t hi s pati ent except whi ch one?
( A) Hi s t ot al bi l i rubi n i s i ncr eased.
( B) Hi s di r ect bi l i r ubi n i s i ncr eased.
( C) He may have vi r al hepat i t i s.
( D) He may have hemol yt i c anemi a.
( E) He may have chol est at i c hepat i t i s.
Vi ew Answer 8. The answer i s D[ see] . For questi ons 9- 11: A 70- year - ol d
bl ack man wei ghi ng 154 l b. compl ai ns of chr oni c f at i gue. Several l abor at or y t est s
wer e per f or med wi t h t he f ol l owi ng resul t s:
blood urea nitrogen (BUN) 15 mg/dL
aspartate aminotransIerase (AST) within normal limits
white blood cell (WBC) count 7500/mm
3

red blood cell (RBC) count 4.0 million/mm
3

hematocrit (Hct) 29°
hemoglobin (Hb) 9.0 g/dL

9. Thi s pat i ent ' s mean ceI I hemogI obi n concent rat i on ( MCHbC) i s
( A) 27. 5.
( B) 28. 9.
( C) 31. 0.
( D) 33. 5.
( E) 35. 4.
Vi ew Answer 9. The answer i s C[ see] . 10. Hi s mean ceI I voI ume (MCV) i s
( A) 61. 3.
( B) 72. 5.
( C) 77. 5.
( D) 90. 2.
( E) 93. 5.
Vi ew Answer 10. The answer i s B[ see] . 11. From t he dat a provi ded and
f rom t he caI cuI at i ons i n quest i ons 9 and 10, thi s pat i ent i s best descri bed as
( A) normal except f or a sl i ght l y i ncr eased bl ood ur ea ni t rogen ( BUN) .
( B) havi ng normochr omi c, mi crocyt i c anemi a.
( C) havi ng si ckl e-cel l anemi a.
( D) havi ng hypochr omi c, normocyt i c anemi a.
( E) havi ng f ol i c aci d def i ci ency.
Vi ew Answer 11. The answer i s B[ see] . 12. AI I of t he f oI I owi ng stat ements
about sodi um ( Na) are true except whi ch one?
( A) The nor mal range f or sodi um i s 135- 147 mEq/ L.
( B) Sodi um i s t he maj or cat i on of t he ext r acel l ul ar f l ui d, and t he l abor at ory t est i s
used mai nl y t o det ect di st ur bances i n wat er bal ance.
( C) Hyponat r emi a usual l y r esul t s f r om t he t ot al body depl et i on of sodi um or t hrough
a di l ut i onal ef f ect .
( D) Cont rol of t he sodi um concent r at i on i s mai nl y t hr ough regul at i on of ar t er i al pH.
Vi ew Answer 12. The answer i s D[ seeand] . 13. A 53- year- oI d woman wi th
di abet es meI I i t us i s seen i n t he emergency room. Her bI ood gI ucose i s 673
mg/ dL and ket ones are present i n her bI ood. A di agnosi s of di abeti c
ket oaci dosi s ( DKA) i s made. Ot her i mport ant I aborat or y vaI ues are pot assi um
of 4. 8 mEq/ L, 4+ gI ucose i n uri ne, and an arteri aI pH of 7. 1. AI I of t he foI I owi ng
st at ements appI y t o t hi s pati ent except whi ch one?
( A) Her pot assi um val ue i s normal ; t her ef ore, no pot assi um suppl ement at i on i s l i kel y
t o be necessar y.
( B) Her pot assi um val ue shoul d be cor r ect ed owi ng t o her aci dosi s; a corr ect ed
pot assi um woul d be 3. 0 mEq/ L.
( C) Pot assi um suppl ement at i on shoul d be i nst i t ut ed because her t ot al body
pot assi um i s depl et ed.
( D) Fact ors af f ect i ng pot assi um i n t hi s pat i ent i ncl ude gl ycosuri a and ar t eri al pH.
Vi ew Answer 13. The answer i s A[ see] . P. 792


14. A 50- year- oI d man present s wi th bi carbonat e of 18 mEq/ L. AI I of the
f oI I owi ng couI d be a cause of hi s I ow bi carbonat e I eveI except
( A) met abol i c aci dosi s.
( B) sal i cyl at e t oxi ci t y.
( C) di ur et i c t her apy.
( D) di ar r hea.
Vi ew Answer 14. The answer i s C[ seeand] . 15. AI I of t he f oI I owi ng
st at ements about caI ci um ( Ca) and phosphorus ( PO4) are t rue except whi ch
one?
( A) An al cohol i c wi t h a ser um al bumi n of 2 g/ dL and a ser um t ot al cal ci um of 8. 0
mg/ dL has a corr ect ed t ot al cal ci um of 9. 6 mg/ dL.
( B) Cal ci um and PO4 l evel s shoul d be i nt er pret ed t oget her because many of t he
same f act ors i nf l uence bot h mi ner al s.
( C) Met ast at i c cancer of t en i nduces a decrease i n ser um cal ci um l evel s
( D) A pat i ent wi t h r enal f ai l ur e may pr esent wi t h hypocal cemi a and
hyper phosphat emi a.
Vi ew Answer 15. The answer i s C[ seeand] . 16. AI I of t he f oI I owi ng are
i mportant functi ons of magnesi um (Mg) except
( A) ner ve conduct i on.
( B) phosphol i pi d synt hesi s.
( C) muscl e cont ract i l i t y.
( D) carbohydr at e, f at , and el ect r ol yt e met abol i sm.
Vi ew Answer 16. The answer i s B[ see] . Di recti ons f or questi ons 17- 19: The
quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
17. Factors I i keI y t o cause an i ncrease i n the bI ood urea ni t rogen ( BUN) I eveI
i ncI ude
I . i nt ramuscuI ar ( Ì M) i nj ect i on of di azepam ( VaI i um) .
I I . severe I i ver di sease.
I I I . chroni c ki dney di sease.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 17. The answer i s B[ see] . 18. A pat i ent who undergoes serum
enzyme t est i ng i s f ound t o have an i ncreased aspartat e ami not ransf erase ( AST)
I eveI . Possi bI e underI yi ng causes of t hi s abnormaI i t y i ncI ude
I . met hyI dopa- i nduced hepati t i s.
I I . congest i ve heart f ai I ure ( CHF) .
I I I . pneumoni a.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 18. The answer i s C[ see] . 19. Serum enzyme t est s t hat may
ai d i n t he di agnosi s of myocardi aI i nf arcti on i ncI ude
I . aI kaI i ne phosphat ase.
I I . creat i ne ki nase ( CK) .
I I I . I actat e dehydrogenase (LDH) .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 19. The answer i s D[ seeand] . P. 793


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì Ì . B. 2. d. ( 2) ] .
Val uabl e di agnost i c i nf ormat i on can be obt ai ned t hr ough quant i t at i ve and qual i t at i ve
t est i ng of t he cel l s of t he bl ood. A f i ndi ng of l ymphopeni a ( i . e. , decreased number of
l ymphocyt es) suggest s an at t ack on t he i mmune syst em or some under l yi ng
i mmunodef i ci ency. AÌ DS at t acks t he TH4 popul at i on of l ymphocyt es and t hus may
r esul t i n l ymphopeni a.
2. The answer i s A [ see Ì Ì . A. 5] .
The r et i cul ocyt e count measur es t he amount of ci r cul at i ng i mmat ure RBCs, whi ch
pr ovi des i nf ormat i on about bone mar r ow f unct i on. A l ow r et i cul ocyt e count i s a l i kel y
f i ndi ng i n a pat i ent wi t h apl ast i c anemi a÷a di sorder char act eri zed by a def i ci ency of
al l cel l ul ar el ement s of t he bl ood owi ng t o a l ack of hemat opoi et i c st em cel l s i n
bone mar r ow. A var i et y of drugs ( e. g. , t hose used i n ant i cancer t her apy) and ot her
agent s pr oduce mar row apl asi a. A hi gh r et i cul ocyt e count woul d l i kel y be f ound i n a
pat i ent wi t h hemol yt i c anemi a or acut e bl ood l oss or i n a pat i ent who has been
t r eat ed f or an i r on, vi t ami n B12, or f ol at e def i ci ency.
3. The answer i s E [ see V. B; V. E, F and G] .
Mi cr oscopi c exami nat i on of t he ur i ne sedi ment nor mal l y shows < 1 RBC and f rom 0
t o 4 WBCs per HPF. Ot her nor mal f i ndi ngs on ur i nal ysi s i ncl ude an aci d pH ( i . e. ,
ar ound 6) and an absence of gl ucose and ket ones.
4. The answer i s A [ see Ì Ì . B. 2. c] .
An al l ergi c drug r eact i on wi l l usual l y produce an i ncr ease i n t he eosi nophi l count
( eosi nophi l i a) . Thi s coul d be det ermi ned by or der i ng a WBC di f f erent i al .
5. The answer i s C [ see Ì Ì . A. 2] .
Over hydr at i on wi t h an excess i nf usi on of D5W produces a l ow Hct . The ot her
si t uat i ons descri bed i n t he quest i on resul t i n i ncr eases of t he Hct .
6. The answer i s A [ see Ì Ì . B. 2. a] .
The pat i ent has l eukocyt osi s wi t h an i ncr eased neut r ophi l count ( neut r ophi l i a) . A
l ocal i zed i nf ect i on does not normal l y r esul t i n an i ncrease i n t he t ot al l eukocyt e
count or neut rophi l count . The ot her si t uat i ons gi ven i n t he quest i on can pr oduce a
neut rophi l i c l eukocyt osi s.
7. The answer i s B [ see Ì Ì Ì . A] .
Because CK i s not pr esent i n t he l i ver , al cohol i c l i ver damage woul d not resul t i n an
i ncrease i n t he l evel of t hi s enzyme. CK i s pr esent pri mar i l y i n car di ac and skel et al
muscl e. The ot her si t uat i ons descr i bed i n t he quest i on coul d al l r esul t i n t he r el ease
of i ncreased amount s of CK i nt o t he bl oodst r eam.
8. The answer i s D [ see Ì V. B] .
The pat i ent wi t h j aundi ce ( deposi t i on of bi l i rubi n i n t he ski n) usual l y has an i ncrease
i n t he t ot al bi l i r ubi n ser um l evel . Spi l l age of bi l i r ubi n i nt o t he ur i ne requi r es an
i ncreased l evel of di r ect bi l i r ubi n, whi ch i s l i kel y wi t h vi r al hepat i t i s or chol est at i c
hepat i t i s. Ì n hemol yt i c anemi a, di r ect bi l i r ubi n i s not usual l y i ncr eased, and
t her ef ore, t her e woul d be no spi l l age of bi l i r ubi n i nt o t he uri ne.
9. The answer i s C [ see Ì Ì . A. 4. c] .
10. The answer i s B [ see Ì Ì . A. 4. a] .
11. The answer i s B [ see Ì Ì . A. 4; CÌ . B. 2] .
The MCHbC i s cal cul at ed as f ol l ows:

The mean cel l vol ume (MCV) i s cal cul at ed as f ol l ows:

P. 794


The pat i ent descr i bed i n t he quest i on i s anemi c because hi s Hb i s 9 ( nor mal : 14-
18) . The anemi a i s normochromi c because t he pat i ent ' s MCHbC of 31 i s nor mal
( normal r ange: 31-37), but t he anemi a i s mi cr ocyt i c because t he pat i ent ' s MCV i s
72. 5 ( nor mal : 80-100). The pat i ent ' s BUN, 15 mg/ dL, i s wi t hi n t he nor mal range of
10- 20 mg/ dL.
12. The answer i s D [ see VÌ Ì . A. 1; VÌ Ì . A. 5, 6 and 7] .
Sodi um, t he maj or ext r acel l ul ar cat i on, i s measur ed mai nl y t o assi st i n t he
det ermi nat i on of f l ui d st at us and wat er bal ance. Regul at i on of sodi um i s mai nl y
t hr ough t he ki dneys vi a ADH and al dost erone.
13. The answer i s A [ see VÌ Ì . B. 2; VÌ Ì . B. 4; VÌ Ì . B. 6] .
A " normal ¨ pot assi um l evel i n t he set t i ng of met abol i c aci dosi s, especi al l y i n a
pat i ent wi t h DKA shoul d be t reat ed appr opri at el y. Ì f t he serum pot assi um l evel i s
cor rect ed f or t he pat i ent ' s aci dosi s, t he cor rect ed l evel i s 3. 0 mEq/ L. Thi s
cor responds t o a depl et i on i n t ot al body pot assi um st ores. Once t he aci dosi s and
hyper gl ycemi a begi n t o cor r ect wi t h appropri at e t reat ment , pot assi um l evel s wi l l
decrease pr eci pi t ousl y unl ess suppl ement at i on i s begun. Ì t i s i mport ant t o r ecogni ze
t hat a l abor at or y val ue i n t he " nor mal ¨ r ange may not act ual l y be normal , especi al l y
when pot assi um i s i nvol ved.
14. The answer i s C [ see VÌ Ì . D. 3 and 4] .
Low i s usual l y f ound i n pat i ent s wi t h aci dosi s or renal f ai l ur e and af t er
hyper vent i l at i on or severe di ar r hea. Ì n gener al , di st urbances i n aci d- base bal ance
cause al t er at i on i n t he ser um or CO2 cont ent . Di ur et i c t herapy can cause an
al kal osi s and an i ncrease i n .
15. The answer i s C [ see VÌ Ì Ì . A. 2, 3 and 4; B. 2] .
Mal i gnancy or ot her met ast at i c di seases are most of t en associ at ed wi t h
hyper cal cemi a, not hypocal cemi a. Ì oni zed cal ci um i s t he f r ee act i ve f orm, and t hi s
l evel i s i ncr eased i n t he set t i ng of a l ow al bumi n. Ther ef ore, t he t ot al cal ci um l evel
must be adj ust ed t o account f or an i ncr eased i oni zed cal ci um i n t hi s set t i ng. Bot h
mi ner al s ar e i nf l uenced by many of t he same f act or s and t hus are of t en i nt er pr et ed
t oget her. Renal f unct i on i s one such f act or wher eby a decrease i n renal f unct i on
( i . e. , r enal f ai l ur e) can resul t i n a l ow l evel of cal ci um and a hi gh l evel of PO4.
16. The answer i s B [ see VÌ Ì Ì . C. 1] .
Magnesi um i s t he second most abundant i nt r acel l ul ar and ext r acel l ul ar cat i on. Ì t i s
an act i vat or of numerous enzyme syst ems t hat cont r ol car bohydr at e, f at , and
el ect r ol yt e met abol i sm, pr ot ei n synt hesi s, ner ve conduct i on, muscul ar cont r act i l i t y,
as wel l as membr ane t ranspor t and i nt egr i t y. PO4, on t he ot her hand, i s i mport ant
f or ATP and phosphol i pi d synt hesi s.
17. The answer i s B ( Ì Ì Ì ) [ see VÌ . B. 2] .
Chr oni c ki dney di sease can cause an i ncr ease i n t he BUN l evel ; a heavy pr ot ei n di et
and bl eedi ng i nt o t he GÌ t r act are ot her f act ors t hat can pr oduce t hi s f i ndi ng. Sever e
l i ver di sease can prevent t he f ormat i on of urea and, t heref ore, i s l i kel y t o cause a
decrease i n t he BUN l evel . Al t hough an Ì M i nj ect i on of di azepam ( Val i um) may
cause an i ncr ease i n t he serum CK or AST l evel , i t woul d have no ef f ect on t he
BUN.
18. The answer i s C ( Ì , Ì Ì ) [ see Ì Ì Ì . D] .
A l ung i nf ect i on, such as pneumoni a, normal l y woul d not cause an i ncr ease i n t he
r el ease of AST, an enzyme pr i mari l y f ound i n t he l i ver and hear t . Ì n acut e hepat i t i s,
a mar ked i ncr ease of AST i s a l i kel y f i ndi ng. AST l evel s al so can be i ncreased wi t h
passi ve congest i on of t he l i ver , as occurs i n CHF.
19. The answer i s D ( Ì Ì , Ì Ì Ì ) [ see Ì Ì Ì . A, B and C] .
Usual l y, t he CK, aALT, AST, and LDH enzyme l evel s ar e i ncreased af t er a
myocar di al i nf arct i on. Al kal i ne phosphat ase i s not pr esent i n cardi ac t i ssue and,
t her ef ore, woul d not be usef ul i n t he di agnosi s of a myocar di al i nf arct i on.

39
Coronary Artery Disease
AI an H. Mutni ck
Barbara Szymusi ak- Mutni ck
I. INTRODUCTION
A. Def i ni t i on. Coronar y art er y di sease ( CAD) i s a gener al t er m t hat ref er s t o a
number of di seases ot her t han at heroscl er osi s, whi ch causes a nar r owi ng of t he
maj or epi cardi al coronary ar t er i es. I schemi c heart di sease ( I HD) i s a f orm of hear t
di sease wi t h pr i mar y mani f est at i ons t hat resul t f rom myocar di al i schemi a owi ng t o
at heroscl er ot i c CAD. Thi s t er m encompasses a spect r um of condi t i ons, rangi ng f rom
t he asympt omat i c precl i ni cal phase t o acut e myocar di al i nf ar ct i on and sudden
car di ac deat h, and i s used t hr oughout t he chapt er .
B. I nci dence
1. Ì HD cont i nues t o be t he l eadi ng si ngl e cause of deat h i n t he Uni t ed St at es
( 231. 1- 297. 9 deat hs per 100, 000) ; cancer i s t he second l eadi ng cause of deat h
( 159. 1- 228. 1 deat hs per 100, 000) .
2. Each year more t han 5 mi l l i on pat i ent s pr esent t o emer gency rooms wi t h chest
di scomf or t and r el at ed sympt oms, and approxi mat el y 1. 5 mi l l i on ar e hospi t al i zed f or
acut e coronar y syndromes. Each year i n t he Uni t ed St at es, more t han 1 mi l l i on
pat i ent s suf f er an acut e myocar di al i nf arct i on ( MÌ ) .
C. Economi cs. Based on model s eval uat i ng t he cost s associ at ed wi t h t he t r eat ment
of Medi car e pat i ent s wi t h common Ì HD- r el at ed di agnosi s, i t has been est i mat ed t hat
t he di r ect cost s of hospi t al i zat i on are > $15 bi l l i on year l y, wi t h an addi t i onal $4. 5
bi l l i on yearl y i n di agnost i c pr ocedur es.
D. CI i ni caI gui deI i nes. Owi ng t o t he cl i ni cal , humani st i c, and economi c ef f ect t hat
Ì HD has i n t he Uni t ed St at es, evi denced- based pr act i ce gui del i nes have evol ved
based on t he di f f erences i n t he di agnosi s and management of Ì HD. The aut hors of
t hi s chapt er have r el i ed heavi l y on t he use of t hose gui del i nes t o ensure t he most
up- t o- dat e recommendat i ons based on t he cl i ni cal l i t er at ur e. Gui del i nes t hat are
per t i nent t o dai l y phar macy pr act i ce i ncl ude t he f ol l owi ng:
1. Gi bbons RJ, Abr ams J, Chat t erj ee K, Dal ey J, Deedwani a PC, Dougl as JS,
Fer guson TB Jr, Fi hn SD, Fr aker TD Jr . , Gar di n JM, O' Rour ke RA, Past ernak RC,
Wi l l i ams SV. ACC/ AHA2002 gui del i ne updat e f or management of pat i ent s wi t h
chr oni c st abl e angi na: a r eport of t he Amer i can Col l ege of Car di ol ogy/ Amer i can
Hear t Associ at i on Task For ce on Pr act i ce Gui del i nes ( Commi t t ee t o Updat e t he
1999 Gui del i nes f or t he Management of Pat i ent s wi t h Chr oni c St abl e Angi na) . 2002.
J Am Col l Cardi ol 2003; 41: 159-168. Avai l abl e at www. acc. org/ qual i t yand
sci ence/ cl i ni cal / gui del i nes/ st abl e/ updat e_i ndex. ht m. Addi t i onal Updat ed Gui del i nes
by Fr aker TD Jr. , Fi hn SD, wr i t i ng on behal f of t he 2002 Chr oni c St abl e Angi na
Wri t i ng Commi t t ee. 2007 chroni c angi na f ocused updat e of t he ACC/ AHA 2002
Gui del i nes f or t he Management of Pat i ent s Wi t h Chr oni c St abl e Angi na: a r epor t of
t he Ameri can Col l ege of Car di ol ogy/ Amer i can Hear t Associ at i on Task Force on
Pr act i ce Gui del i nes Wri t i ng Gr oup t o Devel op t he Focused Updat e of t he 2002
Gui del i nes f or t he Management of Pat i ent s Wi t h Chr oni c St abl e Angi na. J Am Col l
Car di ol 2007; 50: 2264-74. Avai l abl e at
ht t p: / / cont ent . onl i nej acc. or g/ cgi / r epr i nt / 50/ 23/ 2264.
2. Anderson JL, Adams C, Ant man EM, et al . ACC/ AHA 2007 Gui del i nes f or t he
Management of Pat i ent s Wi t h Unst abl e Angi na/ Non- ST-El evat i on Myocar di al
Ì nf arct i on A Repor t of t he Amer i can Col l ege of Car di ol ogy/ Amer i can Heart
Associ at i on Task Force on Pract i ce Gui del i nes (Wri t i ng Commi t t ee t o Revi se t he
2002 Gui del i nes f or t he Management of Pat i ent s Wi t h Unst abl e Angi na/ Non- ST-
El evat i on Myocar di al Ì nf ar ct i on) Devel oped i n Col l abor at i on wi t h t he Ameri can
Col l ege of Emergency Physi ci ans, t he Soci et y f or Car di ovascul ar Angi ography and
Ì nt er vent i ons, and t he Soci et y of Thor aci c Surgeons Endor sed by t he Amer i can
P. 796

Associ at i on of Car di ovascul ar and Pul monar y Rehabi l i t at i on and t he Soci et y f or
Academi c Emer gency Medi ci ne. Avai l abl e onl i ne at
ht t p: / / cont ent . onl i nej acc. or g/ cgi / cont ent / shor t / j . j acc. 2007. 02. 013v1.
3. Ì mpl i cat i ons of Recent Cl i ni cal Tr i al s f or t he Nat i onal Chol est er ol Educat i on
Pr ogr am, Adul t Tr eat ment Panel Ì Ì Ì Gui del i nes f or t he Coordi nat i ng Commi t t ee of
t he Nat i onal Chol est er ol Educat i on Pr ogram. Scot t M. Gr undy, James Ì . Cl eeman, C.
Noel Bai rey Mer z, H. Br yan Brewer , Jr , Lut her T. Cl ar k, Donal d B. Hunni nghake,
Ri char d C. Past ernak, Si dney C. Smi t h, Jr , Nei l J. St one, J Am Col l Car di ol 2004;
44: 720-732. Avai l abl e onl i ne at ht t p: / / cont ent . onl i nej acc. org/ cgi / r epr i nt / 44/ 3/ 720.
4. Nat i onal Chol est erol Educat i on Pr ogram ( NCEP) . Thi r d r epor t of t he Nat i onal
Chol est er ol Educat i on Progr am ( NCEP) : Det ect i on, eval uat i on, and t r eat ment of
hi gh bl ood chol est erol i n adul t s ( Adul t Tr eat ment Panel Ì Ì Ì ) . Fi nal Report [ NÌ H
Publ i cat i on 02- 5215] . Bet hesda, MD: Nat i onal Ì nst i t ut es of Heal t h, 2002. Avai l abl e
at www. nhl bi . ni h. gov/ gui del i nes/ chol est er ol / at p3f ul l . pdf .
5. Ant man EM, Anbe DT, Ar mst r ong PW, Bat es ER, Gr een LA, Hand M, Hochman
JS, Kumhol z HM, Kushner FG, Lamas GA, Mul l any CJ, Or nat o JP, Pear l e DL, Sl oan
MA, Smi t h SC Jr . ACC/ AHA gui del i nes f or t he management of pat i ent s wi t h ST-
el evat i on myocardi al i nf ar ct i on: execut i ve summar y: a r epor t of t he ACC/ AHA Task
For ce on Pr act i ce Gui del i nes ( Commi t t ee t o Revi se t he 1999 Gui del i nes on t he
Management of Pat i ent s Wi t h Acut e Myocar di al Ì nf ar ct i on) . J Am Col l Car di ol 2004;
44: 671-719. Avai l abl e at
ht t p: / / www. acc. org/ qual i t yandsci ence/ cl i ni cal / gui del i nes/ st emi / exec_summ/ i ndex. ht m
.
6. Ant man EM, Hand M, Ar mst r ong PW, et al . 2007 Focused Updat e of t he ACC/ AHA
2004 Gui del i nes f or t he Management of Pat i ent s Wi t h ST- El evat i on Myocar di al
Ì nf arct i on: a r epor t of t he Amer i can Col l ege of Car di ol ogy/ Amer i can Heart
Associ at i on Task Force on Pract i ce Gui del i nes (Wri t i ng Group t o Revi ew New
Evi dence and Updat e t he ACC/ AHA 2004 Gui del i nes f or t he Management of Pat i ent s
Wi t h ST- El evat i on Myocar di al Ì nf ar ct i on) . J Am Col l Car di ol 2008; 51(2) Januar y 15.
Avai l abl e onl i ne at ht t p: / / cont ent . onl i nej acc. or g/ cgi / cont ent / f ul l / j . j acc. 2007. 10. 001
7. W. Br i an Gi bl er , Chri st opher P. Cannon, Andr a L. Bl omkal ns, Dougl as M. Char ,
Bar bara J. Dr ew, Judd E. Hol l ander , Al l an S. Jaf f e, Rober t L. Jesse, L. Kri st i n
Newby, E. Magnus Ohman, Er i c D. Pet er son, and Char l es V. Pol l ack. Pract i cal
i mpl ement at i on of t he gui del i nes f or unst abl e angi na/ non- ST- segment el evat i on
myocar di al i nf arct i on i n t he emergency depar t ment : a sci ent i f i c st at ement f r om t he
Ameri can Hear t Associ at i on Counci l on Cl i ni cal Car di ol ogy ( Subcommi t t ee on Acut e
Car di ac Car e) , Counci l on Car di ovascul ar Nursi ng, and Qual i t y of Car e and
Out comes Resear ch Ì nt er di sci pl i nar y Worki ng Group, i n Col l abor at i on Wi t h t he
Soci et y of Chest Pai n Cent ers. Ci rcul at i on, May 2005; 111: 2699- 2710. Avai l abl e at
ht t p: / / ci rc. ahaj ournal s. org/ cgi / ci t emap?i d=ci r cul at i onaha; 111/ 20/ 2699.
E. Mani f est ati ons
1. Angi na pect ori s, an epi sodi c, r eversi bl e oxygen i nsuf f i ci ency, i s t he most
common f or m of Ì HD (see Ì Ì ) .
2. The t er m acut e i schemi c (coronar y) syndromes descri bes a group of cl i ni cal
sympt oms repr esent i ng acut e myocar di al i schemi a. The cl i ni cal sympt oms i ncl ude
acut e myocar di al i nf arct i on, i ncl udi ng ST- segment el evat i on ( STEMÌ ) , non- ST-
segment el evat i on ( NSTEMÌ ) , and unst abl e angi na ( UA) ( see Ì Ì Ì ) .
F. Et i oI ogy. The pr ocesses, si ngl y or i n combi nat i on, t hat pr oduce Ì HD i ncl ude
decreased bl ood f l ow t o t he myocar di um, i ncr eased oxygen demand, and decreased
oxygenat i on of t he bl ood. General l y, si gni f i cant Ì HD i s def i ned vi a angi ogr aphy as a
st enosi s t hat i s < 70% of t he di amet er of at l east one maj or cor onar y ar t ery segment
or 50% of t he di amet er of t he l ef t mai n coronar y ar t er y.
1. Decreased bI ood f I ow ( Fi gur e 39- 1)
a. At heroscI erosi s, wi t h or wi t hout coronar y t hr ombosi s, i s t he most common cause
of Ì HD. Ì n t hi s condi t i on, t he cor onar y ar t er i es are pr ogr essi vel y nar r owed by
smoot h muscl e cel l prol i f er at i on and t he accumul at i on of l i pi d deposi t s ( pl aque)
al ong t he i nner l i ni ng ( i nt i ma) of t he ar t eri es.
P. 797



Figure 39-1. Oxygen and other nutrients are
borne to the myocardium through the two maior
coronary arteries (the leIt and right) and their
tributaries. The hemodynamic consequences oI
ischemic heart disease depend on which oI the
coronary vessels are involved and what part oI the
myocardium those vessels supply.
b. Coronar y art er y spasm, a sust ai ned cont ract i on of one or more cor onar y
ar t eri es, can occur spont aneousl y or be i nduced by i r r i t at i on ( e. g. , by coronar y
cat het er or i nt i mal hemor r hage) , exposur e t o t he col d, and er got -der i vat i ve dr ugs.
One l ong-t erm st udy demonst rat ed t hat coronary spasm was most of t en associ at ed
wi t h an at ypi cal chest pai n syndr ome and ci gar et t e smoki ng. These spasms can
cause Pr i nzmet al angi na and even MÌ . Var i ant angi na ( Pr i nzmet al angi na) i s a f or m
of unst abl e angi na t hat usual l y occurs spont aneousl y, i s char act er i zed by t r ansi ent
ST- segment el evat i on, and most commonl y resol ves wi t hout progressi on t o MÌ .
c. Traumat i c i nj ur y, whet her bl unt or penet rat i ng, can i nt er f er e wi t h myocar di al
bl ood suppl y (e. g. , t he i mpact of a st eer i ng wheel on t he chest causi ng a myocardi al
cont usi on i n whi ch t he capi l l ari es hemor r hage) .
d. EmboI i c events, even i n ot her wi se normal cor onar y vessel s, can abr upt l y r est ri ct
t he oxygen suppl y t o t he myocar di um.
2. I ncreased oxygen demand usuaI I y i n t he presence of a fi xed rest ri ct ed
oxygen suppI y can occur wi t h exer t i on ( e. g. , exer ci se, shovel i ng snow) and
emot i onal st r ess as wel l as under ci rcumst ances ext er nal t o t he coronar y ar t eri al
bed, whi ch i ncr eases sympat het i c st i mul at i on and t hus hear t rat e. Some f act or s
af f ect i ng car di ac wor kl oad, and t heref ore myocardi al oxygen suppl y and demand,
ar e l i st ed i n Tabl e 39- 1.
Table 39-1. Factors Affecting Cardiac Parameters That Control Myocardial
Oxygen Demand
Factor Heart Rate
Blood
Pressure
Ejection
Time
Ventricular
Volume
Inotropic
Effect
Exercise Increas
e
Increas
e
Decreas
e
Increas
e or
decreas
e
Increas
e
Cold Increas
e
Increas
e

Smoking Increas
e
Increas
e
Increas
e
Increas
e
Nitroglycer
in
Increas
e
Decreas
e
Decreas
e
Decreas
e
Increas
e
þ-blockers Decreas
e
Decreas
e
Increas
e
Increas
e
Decreas
e

P. 798


a. Di ast oI e. Under normal ci rcumst ances, al most al l of t he oxygen i s r emoved
( dur i ng di ast ol e) f rom t he ar t er i al bl ood as i t passes t hrough t he hear t . Thus l i t t l e
r emai ns t o be ext r act ed i f oxygen demand i ncr eases. To i ncr ease t he cor onar y
oxygen suppl y, bl ood f l ow has t o i ncr ease. The nor mal response mechani sm i s f or
t he bl ood vessel s, par t i cul arl y t he cor onar y art er i es, t o di l at e, t her eby i ncr easi ng
bl ood f l ow.
b. Syst oI e. The t wo phases of syst ol e÷cont r act i on and ej ect i on÷st rongl y i nf l uence
oxygen demand.
( 1) The cont ract i I e ( i notropi c) st ate of t he heart i nf l uences t he amount of oxygen
i t r equi r es t o per f orm.
( 2) I ncreases i n syst oI i c waI I t ensi on, i nf l uenced by l ef t vent ri cul ar vol ume and
syst ol i c pressure, i ncr ease oxygen demand.
( 3) Lengt heni ng of ej ect i on t i me ( i . e. , t he durat i on of syst ol i c wal l t ensi on per
car di ac cycl e) al so i ncreases oxygen demand.
( 4) Changes i n heart rat e i nf l uence oxygen consumpt i on by changi ng t he ej ect i on
t i me.
3. Reduced bI ood oxygenat i on. The oxygen- carr yi ng capaci t y of t he bl ood may be
r educed, as occurs i n var i ous anemi as or hypoxemi a.
G. Ri sk factors f or Ì HD and goal s f or secondar y pr event i on have been updat ed wi t h
t he recent l y r el eased 2007 Focused Updat e of t he ACC/ AHA 2004 Gui del i nes f or t he
Management of Pat i ent s wi t h ST- El evat i on Myocar di al Ì nf arct i on, and ar e pr ovi ded
i n Tabl e 39- 2.
H. Therapeut i c consi derat i ons. Because most Ì HD occurs secondar y t o
at heroscl er osi s, whi ch i s a l ong-t erm, cumul at i ve pr ocess, medi cal ef f or t s f ocus on
r educi ng ri sk f act ors t hrough i ndi vi dual pat i ent educat i on and medi a campai gns.
Once mani f est at i ons occur , t reat ment addresses t hei r speci f i c var i abl es.
II. ANGINA PECTORIS
A. Def i ni t i on. The t er m angi na pect ori s i s appl i ed t o var yi ng f or ms of t ransi ent
chest di scomf or t t hat are at t ri but abl e t o i nsuf f i ci ent myocardi al oxygen.
1. Angi na i s a cl i ni cal syndr ome char act er i zed by di scomf or t i n t he chest , j aw,
shoul der , back, and ar ms, whi ch i s usual l y aggr avat ed by exer t i on or st r ess and
r el i eved by ni t r ogl yceri n.
2. Angi na can occur i n pat i ent s wi t h val vul ar hear t di sease, uncont r ol l ed
hyper t ensi on, as wel l as i n noncardi ac or gan syst ems such as t he chest wal l ,
esophagus, or l ungs.
B. Common causes. At her oscl er ot i c l esi ons t hat pr oduce a nar rowi ng of t he
cor onar y ar t eri es are t he maj or cause of angi na. However , t achycardi a, anemi a,
hyper t hyr oi di sm, hypot ensi on, and art eri al hypoxemi a can al l cause an oxygen
i mbal ance.
C. Types
1. St abI e ( cI assi c) angi na
a. Ì n t hi s most common f or m, has a mor e pr edi ct abl e pat t ern, whi ch i s brought on by
exer t i on, emot i onal st r ess, or a heavy meal , whi ch i s usual l y rel i eved by rest ,
ni t rogl ycer i n, or bot h.
b. Fi ve component s ar e usual l y consi der ed: qual i t y, l ocat i on, and dur at i on of pai n;
f act or s provoki ng pai n; and f act or s t hat rel i eve pai n.
c. Pai n has been r ef er r ed t o as " squeezi ng, ¨ "gr i p- l i ke, ¨ " pressure- l i ke, ¨
" suf f ocat i ng, ¨ and "heavy, ¨ and i s usual l y r ef er r ed t o as a di scomf or t rat her t han
" pai n. ¨
d. The angi nal epi sode t ypi cal l y l ast s f or "mi nut es¨ and i s usual l y subst ernal but has
a t endency t o r adi at e t o t he neck, j aw, epi gast r i um, or arms.
e. Char act eri st i cal l y, t he di scomf or t bui l ds t o a peak, r adi at i ng t o t he j aw, neck,
shoul der , and arms, and t hen subsi des wi t hout r esi dual sensat i on. Angi na i s
nor mal l y r el at ed t o physi cal exer t i on, and t he di scomf ort usual l y subsi des qui ckl y
( i . e. , i n 3-5 mi n) wi t h r est ; i f pr eci pi t at ed by emot i onal st r ess, t he epi sode t ends t o
l ast l onger (i . e. , about 10 mi n) .
f . St abl e angi na i s char act eri st i cal l y t he r esul t of a f i xed obst r uct i on i n a cor onar y
ar t er y.
P. 799


Table 39-2. Risk Factors for Ischemic Heart Disease and Guidelines for Their
Modification. When Applicable
I. Risk Factors: Not necessarily modifiable
Family history oI ischemic heart disease

Age and gender (i.e.. prevalence is higher among men than
among premenopausal women and increases Ior both genders
with age)

Chronic stress or type A personality (i.e.. aggressive. ambitious.
chronically impatient. competitive)
Gout
II. Secondary Preventive Goals: As recommended in the 2007
Smoking-Complete cessation. no exposure to environmental
tobacco smoke.
`
Class 1 Recommendation
Status oI tobacco use should be asked about at every visit.

Every tobacco user and Iamily members who smoke should be
advised to quit at every visit.
The tobacco user's willingness to quit should be assessed.

The tobacco user should be assisted by counseling and
developing a plan Ior quitting.

Follow-up. reIerral to special programs. or pharmacotherapy
(including nicotine replacement and pharmacological treatment)
should be arranged.

Exposure to environmental tobacco smoke at work and home
should be avoided.
Blood pressure control: Blood pressure should be reduced to less than
140/90 mm Hg or less than 130/90 mm Hg if chronic kidney disease or
diabetes mellitus.
`
Class 1 Recommendation

Initiate or maintain liIestyle modiIication (weight control.
increased physical activity. alcohol moderation. decreased
sodium intake. and increased emphasis on consumption oI Iresh
Iruits. vegetables. and low-Iat dairy products).

Add blood pressure medication. as tolerated. treating initially
with þ-adrenoreceptor blockers and/or ACE inhibitors.

The addition oI other blood pressure lowering drugs such as
thiazides as needed to achieve the goal blood pressure.
Blood Lipid management: Low density lipoprotein-cholesterol (LDL-C)
levels should be less than 100 mg/dL. (If triglycerides are greater than
or equal to 200 mg/dL. total cholesterol minus high density lipoprotein
cholesterol (HDL-C) should be less than 130 mg/dL.)
`
Class I
Recommendation

Initiate dietary therapy in all patients; which includes reducing
intake oI saturated Iats. (·7° oI total calories). trans Iatty acids
and cholesterol (·200 mg/d).

The addition oI plant stanol/sterols (2 g/d) and/or viscous Iiber
(~10 g/d) to Iurther lower LDL-C.
Promotion oI daily physical activity and weight management.

It may be reasonable to encourage the increase in the
consumption oI omega-3 Iatty acids in the Iorm oI Iish or in
capsule Iorm (1 g/d) Ior risk reduction.

A Iasting lipid proIile should be assessed in all patients and
within 24 hours oI hospitalization Ior those with an acute
cardiovascular or coronary event.
Physical activity: Participate in 30 minutes of Physical Activity 7 days a
week
`
Class 1 Recommendation

It is recommended that all patients have a risk assessment with a
physical activity history and/or an exercise test to guide
prescription.

All patients should be encouraged to participate in 30 to 60
minutes oI moderate-intensity aerobic activity. (i.e.. brisk
walking) on most. preIerably all. days oI the week.
supplemented by an increase in daily liIestyle activities (e.g..
walking breaks at work. gardening. household work).

Advise medically supervised programs Ior high-risk patients
(e.g.. recent acute coronary syndrome or revascularization. heart
Iailure).
Weight management: Body Mass Index (BMI) of 18.5 to 24.9 kg/m
2
with
waist circumference of less than 35 inches (women) and less than 40
inches (men)
`
Class 1 Recommendation

Assessment oI body mass index and/or waist circumIerence on
each visit and consistently.

Encourage weight maintenance/reduction through an
appropriate balance oI physical activity. caloric intake. and
Iormal behavioral programs when indicated to maintain/achieve
a body mass index between 18.5 and 24.9 kg/m
2
.

The initial goal oI weight loss therapy should be to reduce body
weight by approximately 10° Irom baseline.
With success. Iurther weight loss can be attempted iI indicated.

II waist circumIerence is greater than or equal to 35 inches in
women and greater than or equal to 40 inches in men. it is
useIul to initiate liIestyle changes and consider treatment
strategies Ior metabolic syndrome as indicated.
Diabetes management: Achieve a glycosylated hemoglobin (HbA1c)
level of less than 7º
`
Class 1 Recommendation

It is recommended to initiate liIestyle and pharmacotherapy to
achieve near-normal levels oI HbA1c.

Aggressive modiIication oI other risk Iactors such as physical
activity. weight management. blood pressure control. and
cholesterol management. as recommended above is beneIicial.

Coordination oI diabetic care with patient's primary care
physician or endocrinologist is beneIicial.
*
Class I recommendation: The beneIits oI the intervention/treatment are
much greater than the risk. and the procedure/treatment should be
perIormed.

P. 800


2. Unst abI e angi na. ( See al so Ì Ì Ì . )
a. Ì n many pat i ent s who exper i ence unst abl e angi na, sympt oms wi l l be caused by
si gni f i cant cor onar y ar t er y di sease. Angi na i s consi dered unst abl e and r equi res
f ur t her eval uat i on i f pat i ent s exper i ence
( 1) Rest angi na, whi ch usual l y i s pr ol onged > 20 mi n occur r i ng wi t hi n a week of
pr esent at i on
( 2) Severe new- onset angi na r ef ers t o angi na of at l east Canadi an Cardi ovascul ar
Soci et y Cl assi f i cat i on ( CCSC) t o cl ass Ì Ì Ì sever i t y, wi t h onset wi t hi n 2 mont hs of
i ni t i al present at i on
( 3) Ì ncr easi ng angi na ref er s t o pr evi ousl y di agnosed angi na t hat i s di st i nct l y more
f r equent , l onger i n dur at i on, or l ower i n t hr eshol d
( 4) Decr eased response t o r est or ni t rogl ycer i n
b. Unst abl e angi na pr edi ct s a hi gher shor t -t erm r i sk, r epr esent s a progressi ve
cl i ni cal ent i t y, may si gnal i nci pi ent MÌ , i s ref er r ed t o as an acut e cor onar y
syndr ome, and shoul d be r epor t ed pr ompt l y t o a physi ci an.
3. Angi na decubi tus (noct urnaI angi na)
a. Thi s angi na occurs i n t he recumbent posi t i on and i s not speci f i cal l y rel at ed t o
ei t her rest or exer t i on.
b. Gr avi t at i onal f or ces shi f t f l ui ds wi t hi n t he body wi t h a r esul t ant i ncrease i n
vent r i cul ar vol ume, whi ch i ncr eases oxygen needs and pr oduces angi na decubi t us,
and whi ch may i ndi cat e car di ac decompensat i on.
c. Di ur et i cs al one or i n combi nat i on ef f ect i vel y r educe l ef t vent ri cul ar vol ume and
may ai d t he pat i ent .
d. Ni t rat es such as ni t r ogl yceri n may rel i eve t he par oxysmal noct ur nal dyspnea
associ at ed wi t h angi na decubi t us by r educi ng prel oad, owi ng t o venous pool i ng, and
i mprovi ng l ef t vent r i cul ar dysf unct i on.
4. Pri nzmet aI ' s angi na (vasospast i c or vari ant angi na)
a. Coronar y ar t er y spasm t hat reduces bl ood f l ow pr eci pi t at es t hi s angi na. The
spasm may be superi mposed on a cor onar y ar t ery t hat al ready has a f i xed
obst r uct i on owi ng t o t hr ombi or pl aque f or mat i on.
b. Ì t usual l y occur s at r est (i . e. , pai n may di sr upt sl eep) r at her t han wi t h exer t i on or
emot i onal st r ess, and usual l y r esol ves wi t hout progr essi on t o an acut e MÌ . However ,
i f t he at t ack
P. 801

i s pr ol onged, MÌ , l i f e- t hreat eni ng vent r i cul ar ar r hyt hmi as, and sudden cardi ac deat h
can occur .
c. Char act eri st i cal l y, an el ect r ocar di ogram (ECG) t aken duri ng an at t ack reveal s a
t r ansi ent ST- segment el evat i on, whi ch ret urns t owar d nor mal af t er t he acut e at t ack.
d. Cal ci um- channel bl ockers, rat her t han 8- bl ocker s, ar e most ef f ect i ve f or t hi s f orm
of angi na. Ni t rogl yceri n may not provi de r el i ef , dependi ng on t he cause of
vasospasm.
D. Physi caI exami nati on i s usual l y not reveal i ng, especi al l y bet ween at t acks.
However , t he pat i ent ' s hi st or y, ri sk f act ors, and f ul l descri pt i on of at t acks÷
pr eci pi t at i on pat t er n, i nt ensi t y, dur at i on, rel i evi ng f act or s÷usual l y pr ove di agnost i c.
E. Di agnosti c test resuI t s
1. The ECG i s normal i n 50% or more of pat i ent s wi t h st abl e angi na pect or i s, and a
nor mal r est i ng ECG does not excl ude severe Ì HD. However , an ECG wi t h evi dence
of l ef t vent r i cul ar hypert rophy or ST- T- wave changes consi st ent wi t h myocar di al
i schemi a f avor t he di agnosi s of angi na pect or i s. The pr esence of Q waves f rom a
pr evi ous MÌ makes t he di agnosi s of Ì HD ver y l i kel y. An ECG obt ai ned dur i ng chest
pai n i s abnor mal i n 50% of pat i ent s wi t h angi na who have a normal r est i ng ECG.
The ST segment can be ei t her el evat ed or depressed.
2. St ress test i ng (exerci se ECG) i s a wel l -est abl i shed pr ocedur e, whi ch ai ds t he
di agnosi s i n pat i ent s who have normal r est i ng ECGs. The most commonl y used
def i ni t i on f or a posi t i ve t est i s a < 1-mm ST- segment depressi on or el evat i on f or <
60- 80 msec ei t her duri ng or af t er exer ci se. Exer ci se st r ess t est i ng i s pref er abl e t o
ot her var i at i ons of t he st r ess t est ( phar macol ogi cal ) i n pat i ent s who ar e abl e t o
exer ci se.
3. PharmacoI ogi caI st ress testi ng i s perf ormed i n suspect ed Ì HD pat i ent s when
t hey are not abl e t o per f or m more t han moderat e exer ci se due t o vari ous r easons
( i . e. , sever e ar t hr i t i s, pri or i nj ur y, r educed exer ci se t ol er ance as a r esul t of
debi l i t at i ng i l l nesses, et c. ) , or i n pat i ent s who are unabl e t o i ncr ease t he hear t rat e.
a. Ì nt r avenous di pyr i damol e ( cor onar y vasodi l at i on) , adenosi ne ( cor onar y
vasodi l at i on) by i nhi bi t i ng cel l ul ar upt ake and degr adat i on of adenosi ne i ncr ease
cor onar y bl ood f l ow, and hi gh- dose dobut ami ne (20- 40 µg/ kg/ mi n) i ncr ease oxygen
demand t hrough i ncr eased hear t r at e, syst ol i c bl ood pr essur e, and myocar di al
cont r act i l i t y causi ng an i ncr ease i n myocar di al bl ood f l ow ar e al l abl e t o i nduce
det ect abl e car di ac i schemi a i n conj unct i on wi t h ECG t est i ng.
b. Si de ef f ect s occur f or each of t he agent s and i ncl ude di pyri damoI e (angi na,
18%-42%; ar rhyt hmi as, 2%; headache, 5%- 23%; di zzi ness, 5%- 21%; nausea, 8%-
12%; and f l ushi ng, 3%), adenosi ne (chest pai n, 57%; headache, 35%; f l ushi ng,
25%; shor t ness of br eat h, 15%; and f i r st - degr ee at r i ovent ri cul ar [ AV] hear t bl ock,
18%) , dobut ami ne ( premat ur e vent r i cul ar beat s, 15%; premat ure at r i al beat s, 8%;
supravent ri cul ar t achycar di a and nonsust ai ned vent r i cul ar t achycar di a, 3%- 4%;
nausea, 8%; anxi et y, 6%; headache, 4%; and t r emor , 4%).
4. St ress perf usi on i magi ng wi t h t hal l i um- 201 or t echnet i um-99m (
99m
Tc) can
di agnose mul t i vessel di sease, l ocal i zed i schemi a, and may be abl e t o det er mi ne
myocar di al vi abi l i t y. The added expense of t he t est makes i t r eser ved f or pat i ent s
who have ECG abnormal i t i es at rest . Coronar y art er i ogr aphy and cardi ac
cat het er i zat i on are ver y speci f i c and sensi t i ve but ar e al so i nvasi ve, expensi ve, and
r i sky ( t he mor t al i t y r at e i s 1%- 2%) ; t her ef ore, t hey must be used j udi ci ousl y when
t r yi ng t o conf i rm suspect ed angi na and t o di f f erent i at e i t s ori gi n.
5. Vari ous dr ugs can have an ef f ect on t he ECG and shoul d be consi der ed bef or e,
dur i ng, and af t er an exer ci se t est i s car ri ed out . Exampl es i ncl ude
a. Di goxi n pr oduces abnor mal exer ci se- i nduced ST depr essi on i n 25%- 40% of
appar ent l y heal t hy, nor mal subj ect s wi t hout i schemi a.
b. 8- adr ener gi c bl ockers may del ay t he devel opment of an abnor mal ECG i f pat i ent s
r ecei ve t hem bef ore or dur i ng a st ress t est . Ì f possi bl e, t herapy shoul d be sl owl y
wi t hhel d f r om t he pat i ent at l east f our t o f i ve hal f -l i ves bef or e t he exer ci se t est i ng.
Ì f i t i s not possi bl e t o wi t hdr aw t herapy, t he cl i ni ci an needs t o r ecogni ze t hat t he
t est mi ght be l ess rel i abl e.
c. Ant i hyper t ensi ves such as vasodi l at ors can al t er t he st r ess t est by al t er i ng t he
nor mal hemodynami c r esponse of bl ood pr essur e. Ì n addi t i on, shor t -t erm use of
ni t rat es can at t enuat e angi na and ST- segment changes associ at ed wi t h myocar di al
i schemi a.
P. 802


F. Treat ment goaI s
1. To prevent MÌ and deat h, t her eby i ncr easi ng a pat i ent ' s qual i t y of l i f e
2. To r educe sympt oms of angi na and occur r ence of i schemi a, whi ch shoul d i mpr ove
a pat i ent ' s qual i t y of l i f e
3. To r emove or reduce ri sk fact ors
4. The management of angi na pect ori s i ncl udes t her api es ai med at r eversi ng cardi ac
r i sk f act or s.
a. HyperI i pi demi a, i f present , shoul d be t reat ed. Reduci ng chol est er ol and l ow-
densi t y l i poprot ei n (LDL) i s associ at ed wi t h a r educed r i sk of car di ovascul ar di sease
and i nci dence of i schemi c car di ac event s, as demonst r at ed by several r ecent
st udi es usi ng 8- hydr oxy- 8- met hyl gl ut ar yl - coenzyme A ( HMG- CoA) r educt ase
i nhi bi t ors. The NCEP has publ i shed updat ed gui del i nes f or t reat ment of hi gh bl ood
chol est erol ( Adul t Tr eat ment Panel Ì Ì Ì ).
( 1) Tot al chol est erol i s no l onger t he pr i mar y t ar get of t r eat ment ; LDL chol est er ol i s
now t he pr i mar y t ar get .
( 2) Cur rent r ecommendat i ons i ncl ude t he compl et i on of a l i popr ot ei n prof i l e÷t ot al
chol est erol , LDL chol est er ol , hi gh-densi t y l i popr ot ei n ( HDL) chol est er ol , and
t r i gl yceri des÷as t he pr ef er r ed i ni t i al t est , r at her t han scr eeni ng f or t ot al chol est erol
and HDL al one.
( 3) Persons ar e cat egor i zed i nt o one of f our l evel s of r i sk, t o i dent i f y group- speci f i c
t r eat ment modal i t i es: ( 1) hi gh- r i sk, est abl i shed Ì HD or Ì HD ri sk equi val ent s
( di abet es, noncor onar y f or ms of at heroscl er ot i c di sease) ; (2) moder at el y hi gh- r i sk,
mul t i pl e ( mor e t han t wo) r i sk f act or s and a cal cul at ed 10- year ri sk of 10%- 20%; ( 3)
moder at e ri sk, mul t i pl e (mor e t han t wo) r i sk f act or s and a cal cul at ed 10- year ri sk of
10%; and ( 4) l ower - ri sk, zer o t o one r i sk f act or .
( 4) Al l i ndi vi dual s wi t h Ì HD or Ì HD ri sk equi val ent s have been cal l ed " hi gh r i sk, ¨ and
t he t r eat ment goal s i s t o have LDL-chol est erol (LDL- C) l evel s < 100 mg/ dL. Ot her
r ecommendat i ons ar e as f ol l ows:
( a) Ì f basel i ne LDL- C i s < 100 mg/ dL (goal of t reat ment ), pat i ent s wi t h Ì HD shoul d
be gi ven i nst r uct i ons on di et and exer ci se and have l evel s moni t or ed annual l y.
Though t he gui del i nes suggest an opt i onal goal of obt ai ni ng an LDL- C of < 70
mg/ dL.
( b) Ì f basel i ne LDL- C i s < 100 mg/ dL, an LDL- l ower i ng drug shoul d be st ar t ed al ong
wi t h t herapeut i c l i f est yl e changes ( TLCs) . Li f est yl e- r el at ed ri sk f act ors i ncl ude
t hi ngs such as obesi t y, physi cal i nact i vi t y, el evat ed t ri gl yceri de, l ow- HDL- C, or
met abol i c syndr ome.
( c) Adul t Tr eat ment Panel Ì Ì Ì di d not mandat e LDL- l ower i ng dr ugs f or pat i ent s wi t h
basel i ne LDL- C l evel s bet ween 100 and 129 mg/ dL but suggest ed i nt ensi f yi ng
l i f est yl e and t he opt i onal use of drug t herapi es t o l ower LDL t o < 100 mg/ dL.
However , i f t he pat i ent had el evat ed t r i gl ycer i des or l ow hi gh- densi t y l i popr ot ei n
chol est erol ( HDL- C) , a dr ug shoul d be st ar t ed t hat t ar get s t hese abnormal i t i es÷f or
exampl e, ni cot i ni c aci d or f i bri c aci d i f t he pat i ent has el evat ed t ri gl yceri des (> 200
mg/ dL) or l ow HDL l evel s ( < 40 mg/ dL). Ì f t r i gl ycer i des ar e < 500 mg/ dL, consi der
f i brat e or ni aci n bef ore LDL- l ower i ng t her apy.
( 5) For moder at el y hi gh ri sk pat i ent s, t he r ecommended LDL- C goal i s < 130 mg/ dL,
but a goal of < 100 mg/ dL i s an opt i onal goal , based on r ecent cl i ni cal t r i al
evi dence. Ì n addi t i on, a recommendat i on t o i ni t i at e TLCs when t he pat i ent has an
LDL- C < 130 mg/ dL.
( 6) For moder at e r i sk pat i ent s, t he r ecommended LDL- C goal i s < 130 mg/ dL. Ì n
addi t i on, a r ecommendat i on t o i ni t i at e TLC when t he pat i ent has an LDL-C < 160
mg/ dL.
( 7) For l ower r i sk pat i ent s, t he recommended LDL- C goal i s < 160 mg/ dL, but agai n,
a r ecommendat i on t o i ni t i at e TLC f or t hose pat i ent s wi t h an LDL < 190 mg/ dL.
( 8) The met aboI i c syndr ome i s cl osel y l i nked t o i nsul i n r esi st ance, when t he
nor mal act i ons of i nsul i n ar e i mpai r ed. Excess body f at and physi cal i nact i vi t y
pr omot e t he devel opment of t he syndr ome; however , some i ndi vi dual s may be
pr edi sposed genet i cal l y. Pat i ent s wi t h t hr ee or mor e of t he f ol l owi ng charact er i st i cs
ar e ref er red t o as havi ng t he met abol i c syndrome and shoul d be t r eat ed accor di ngl y:
abdomi nal obesi t y, t r i gl ycer i des > 150 mg/ dL, HDL l evel s of < 40 mg/ dL f or men and
50 mg/ dL f or women, bl ood pressure readi ngs < 130/ 85 mm Hg, and a f ast i ng serum
gl ucose l evel < 110 mg/ dL.
P. 803


G. I ndi vi duaI drug cI asses
1. Bi I e aci d sequest rant resi ns
a. Mechani sm of act i on. These i nsol ubl e, nonabsor babl e, ani on-exchange r esi ns
bi nd bi l e aci ds wi t hi n t he i nt est i nes. Bi l e aci ds are synt hesi zed f r om chol est erol .
b. I ndi cat i ons. These agent s have been shown t o be saf e and ef f ect i ve i n l ower i ng
LDL- C especi al l y i n pat i ent s wi t h modest l y el evat ed l evel s, i n pr i mar y pr event i on, i n
young adul t men, and post menopausal women. They ar e ef f ect i ve i n combi nat i on
wi t h ot her agent s.
c. Current I y avai I abI e agent s i ncl ude t he f ol l owi ng:
( 1) Chol est yr ami ne ( Quest r an) : 2- 8 g by mout h i n t wo dai l y doses
( 2) Col est i pol ( Col est i d): 2- 16 g by mout h i n one or t wo dai l y doses
( 3) Col esevel am (Wel Chol ) : 6- 7 t abl et s (625 mg/ t abl et ) by mout h i n one dai l y dose
d. Precaut i ons and moni t ori ng ef fects
( 1) These r esi ns are t aken j ust bef ore meal s and pr esent pal at abi l i t y probl ems i n
pat i ent s.
( 2) Gast r oi nt est i nal ( GÌ ) i nt ol erance, especi al l y const i pat i on, f l at ul ence, and
dyspepsi a ar e f r equent .
( 3) Absorpt i on of many ot her dr ugs can be af f ect ed. Ot her dr ugs shoul d be t aken 1
hr bef ore or 4- 6 hr af t er r esi ns.
2. St ati ns or HMG- CoA reductase i nhi bi tors
a. Mechani sm of act i on. These agent s i nhi bi t t he enzyme HMG- CoA and r educe
chol est erol pr oduct i on.
b. I ndi cat i ons. These agent s ar e ef f ect i ve i n l ower i ng LDL l evel s, whi l e i ncreasi ng
HDL l evel s and l ower i ng t r i gl yceri de l evel s. They ar e pr i mar i l y used t o l ower LDL
chol est erol l evel s.
c. Current I y avai I abI e agent s i ncl ude t he f ol l owi ng:
( 1) At or vast at i n ( Li pi t or) : 10- 80 mg by mout h dai l y
( 2) Fl uvast at i n (Lescol ) : 20- 80 mg by mout h at bedt i me
( 3) Lovast at i n ( Mevacor , var i ous) : 10-80 mg by mout h i n t he eveni ng
( 4) Pr avast at i n ( Pr avachol ) : 10-80 mg by mout h dai l y
( 5) Rosuvast at i n ( Cr est or ) : 5-40 mg by mout h dai l y
( 6) Si mvast at i n (Zocor , var i ous): 5-80 mg by mout h i n t he eveni ng
d. Precaut i ons and moni t ori ng ef fects
( 1) GÌ adver se ef f ect s are l ess f requent l y seen t han wi t h ot her cl asses of agent s.
Headache and dyspepsi a f r equent l y occur and shoul d be eval uat ed, t hen f ol l owed
up i n 6-8 weeks, and t hen at each f ol l ow- up vi si t t her eaf t er .
( 2) These agent s can el evat e l i ver f unct i on t est s÷al ani ne ami not ransf er ase ( ALT)
and aspar t at e ami not r ansf erase ( AST) , whi ch r equi r es i ni t i al eval uat i on, t hen af t er
approxi mat el y 12 weeks of t her apy, t hen annual l y t hereaf t er .
( 3) Though t he i nci dence of myopat hy i s bel i eved t o be l ow ( 0. 08%) f or l ovast at i n
and si mvast at i n, el evat i ons of cr eat i ne ki nase ( CK) > 10 t i mes t he upper l i mi t of
nor mal have been report ed wi t h pr avast at i n, wi t h si mi l ar pot ent i al f or t he ot her
members of t he gr oup. Most r ecent l y, cer i vast at i n ( Baycol ) was vol unt ar i l y r emoved
f r om t he mar ket owi ng t o t he r epor t ed deat hs of 31 pat i ent s f rom rhabdomyol ysi s
whi l e r ecei vi ng t he drug al one or i n combi nat i on wi t h gemf i br ozi l ( Lopi d) .
Consequent l y, r out i ne moni t or i ng i s necessar y i n al l pat i ent s, as f ol l ows:
( a) Eval uat e muscl e sympt oms and check CK bef or e st art i ng t her apy, eval uat e i n 6-
12 weeks af t er st ar t i ng t her apy, and t hen at each f ol l ow- up vi si t .
( b) Pat i ent s pr esent i ng wi t h muscl e soreness, t enderness, or pai n shoul d have a CK
measurement on pr esent at i on, t o mi ni mi ze t he devel op of myopat hi es.
( c) Concur r ent t her apy wi t h ot her agent s, i ncl udi ng cycl ospor i ne, macr ol i de
ant i bi ot i cs, azol e ant i f ungal s, ni aci n, f i brat es, or nef azodone, may i ncr ease t he r i sk.
3. Fi bri c aci d deri vat i ves
a. Mechani sm of act i on. These agent s ar e pr esumed t o i nhi bi t chol est erol
synt hesi s and l ower LDL- C. They ar e ef f ect i ve at l ower i ng t ri gl ycer i des. Ì n some
pat i ent s, t hey modest l y l ower LDL- C and rai se HDL- C.
b. Precaut i ons and moni t ori ng ef fects
( 1) GÌ ef f ect s are t he most commonl y exper i enced adverse ef f ect .
( 2) These agent s can el evat e l i ver f unct i on t est s; r out i ne moni t or i ng shoul d be
car ri ed out .
P. 804


( 3) Use wi t h st at i ns can l ead t o el evat ed CK, and moni t ori ng i s necessar y t o i dent i f y
myopat hi es or rhabdomyol ysi s.
c. Current I y avai I abI e agent s i ncl ude t he f ol l owi ng:
( 1) Fenof i brat e ( Tr i cor , var i ous): 145- 160 mg by mout h dai l y
( 2) Gemf i br ozi l ( Lopi d, var i ous): 600 mg by mout h t wi ce dai l y
4. Ni aci n
a. Mechani sm of act i on. Numer ous st udi es have demonst rat ed t he rol e of ni aci n i n
t he l ower i ng of LDL- C and t r i gl ycer i des t hr ough var i ous mechani sms such as
par t i ci pat i on i n t i ssue r espi rat i on oxi dat i on- reduct i on r eact i ons, whi ch decr eases
hepat i c LDL and ver y l ow- densi t y l i poprot ei n ( VLDL) pr oduct i on; i nhi bi t i on of
adi pose t i ssue l i pol ysi s, decreased hepat i c t r i gl ycer i de est eri f i cat i on, and i ncr eases
i n l i popr ot ei n l i pase act i vi t y. Tabl e 39-3 present s several agent s and t hei r ef f ect s on
l i popr ot ei ns.
b. I ndi cat i ons. Ni aci n i s val uabl e i n t r eat i ng pat i ent s wi t h el evat ed t ot al chol est erol
and l ow LDL- C l evel s. Ì t i s used i n combi nat i on t her apy.
c. Current I y avai I abI e agent s i ncl ude t he f ol l owi ng:
( 1) Ni aci n cont r ol l ed r el ease ( Ni aspan) : 1000-2000 mg by mout h at bedt i me
( 2) Ni aci n cont r ol l ed r el ease ( Sl o- Ni aci n) : 1- 2 gr ams by mout h at bedt i me
( 3) Ni aci n i mmedi at e rel ease ( Var i ous): 1000-2000 mg by mout h 2- 3 t i mes dai l y.
d. Precaut i ons
( 1) Adverse GÌ ef f ect s are exper i enced wi t h t he use of ni aci n.
( 2) Pat i ent s may exper i ence f l ushi ng and i t chy ski n, whi ch may be r educed wi t h t he
admi ni st rat i on of 325 mg aspi ri n about 30 mi n bef or e t he dose.
( 3) Cases of sever e l i ver t oxi ci t y have been r eport ed. Li ver f unct i on t est s shoul d be
per f or med i n pat i ent s recei vi ng t hi s dr ug.
Table 39-3. Selected Agents and Their Effects on Lipoproteins
Class/Agent
Lipid/Lipoprotein
Effects Daily Dose
Adverse Drug
Effects
HMG-CoA
reductase
inhibitors
(statins)
LDL: 18°-
55° reduction
HDL: 5°-
15° increase
TG: 7°-30°
reduction
Lovastatin: 10-
80 mg
Pravastatin: 20-
40 mg
Simvastatin: 5-
80 mg
Fluvastatin: 20-
80 mg
Atorvastatin: 10-
80 mg
Rosuvastatin: 5-
40 mg
Myopathy.
increased liver
enzymes
Bile acid
sequestrants
LDL: 15°-
30° reduction
HDL: 3°-5°
increase
TG: No
change or
increase
Cholestyramine:
4-16 g
Colestipol: 5-20
g
Colesevelam:
2.6-3.8 g
GI distress.
constipation.
decreased
absorption oI
other drugs
Nicotinic
acid
LDL: 5°-
25° reduction
HDL: 15°-
Immediate-
release: 1.5-3 g
Extended-
Flushing.
hyperglycemia.
hyperuricemia
35° increase
TG: 20°-50°
reduction
release: 1-2 g
Sustained-
release: 1-2 g
(or gout). upper-
GI distress.
hepatotoxicity
Fibric acids LDL: 5°-
20° reduction
HDL: 10°-
20° increase
TG: 20°-50°
reduction
GemIibrozil:
600 mg twice
daily
FenoIibrate:
145-160 mg
CloIibrate: 1000
mg twice daily
Dyspepsia.
gallstones.
myopathy.
unexplained
non-CHD deaths
in WHO study
CHD. coronary heart disease; GI. gastrointestinal; HDL. high-density
lipoprotein; HMG-CoA. þ-hydroxy-þ-methylglutaryl-coenzyme A; LDL.
low-density lipoprotein; TG. triglycerides; WHO. World Health
Organization.
Adapted Irom Grundy SM. Becher D. Clark LT et al. Third Report oI the
National Cholesterol Education Program (NCEP): Detection. Evaluation. and
Treatment oI High Blood Cholesterol in Adults (Adult Treatment Panel III)
|NIH Publication No. 01-3670|. Washington DC. U.S. Department oI Health
and Human Services. May 2001. Available at:
www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdI.

P. 805


5. Ezet i mi be ( Zet i a)
a. Mechani sm of act i on. Fi rst i n a new cl ass of l i pi d- l ower i ng compounds approved
by t he U. S. Food and Drug Admi ni st rat i on (FDA) , whi ch wor ks by sel ect i vel y
i nhi bi t i ng t he i nt est i nal absorpt i on of chol est er ol and rel at ed phyt ost er ol s, wi t h a
r esul t ant decr ease i n i nt est i nal chol est erol del i ver ed t o t he l i ver , decr eased hepat i c
chol est erol st or es, and an i ncr ease i n t he cl ear ance of chol est erol f r om t he bl ood.
Ezet i mi be has demonst rat ed t he abi l i t y t o r educe t ot al chol est er ol , LDL- C,
apol i poprot ei n B, and t ri gl yceri de l evel s whi l e i ncr easi ng HDL l evel s i n pat i ent s wi t h
hyper chol est erol emi a.
b. I ndi cat i ons. Ezet i mi be as adj unct i ve t herapy al ong wi t h di et ar y measur es, al one
i n pat i ent s wi t h pr i mar y het erozygous f ami l i al and nonf ami l i al hyperchol est erol emi a,
or i n combi nat i on wi t h t he HMG- CoA r educt ase i nhi bi t ors i n homozygous f ami l i al
hyper chol est erol emi a.
c. Dose. Nor mal dosi ng r ecommendat i ons ar e a 10- mg dose gi ven once dai l y.
d. Precaut i ons. As monot herapy, st udi es t o dat e have not r eveal ed si gni f i cant si de
ef f ect s above t hose seen wi t h pl acebo admi ni st rat i on. However , when used i n
combi nat i on wi t h HMG- CoA r educt ase i nhi bi t ors, r eport s have descri bed an
i ncreased i nci dence ( appr oxi mat el y 1. 4%) i n t he el evat i on of l i ver t r ansami nase
l evel s ( t hr ee t i mes t he upper l i mi t of nor mal ) as compared t o t he i nci dence of 0. 4%
wi t h HMG- CoA agent s used al one.
6. Combi nat i on products
a. Ezet i mi be/ si mvast at i n ( Vyt or i n) uses t he i ndi vi dual cl ass pr oper t i es of t he HMG-
CoA r educt ase i nhi bi t ors ( si mvast at i n) t o reduce chol est erol pr oduct i on wi t h t he
absor pt i on- i nhi bi t i ng proper t i es of ezet i mi be t o t ar get chol est er ol wi t h t wo di f f er i ng
mechani sms, whi ch mi ght ai d i n i mprovi ng pat i ent compl i ance.
( 1) Avai l abl e pr oduct i s suppl i ed as 10/ 10, 10/ 20, 10/ 40, 10/ 80 combi nat i ons of
ezet i mi be and si mvast at i n, r espect i vel y, and t he dai l y r ecommended dose i s 1 t abl et
by mout h ever y eveni ng.
( 2) Si de ef f ect s ref l ect t he addi t i ve si de ef f ect proper t i es of ezet i mi be and
si mvast at i n and war r ant consi derat i on when occur r i ng duri ng t her apy.
b. Lovast at i n/ ni aci n ( Advi cor) i s a product t hat i ncor por at es t he act i ons of t he HMG-
CoA r educt ase i nhi bi t or l ovast at i n wi t h an ext ended r el ease ni aci n component i nt o a
si ngl e product , usi ng di f f er i ng mechani sms, whi ch mi ght ai d i n i mpr ovi ng pat i ent
compl i ance.
( 1) Avai l abl e pr oduct i s suppl i ed as 20/ 500, 20/ 750, 20/ 1000 sust ai ned- r el ease
t abl et combi nat i ons of l ovast at i n and ni aci n, r espect i vel y. The recommended dai l y
dose i s 1- 2 t abl et s by mout h at bedt i me.
( 2) Si de ef f ect s ref l ect t he addi t i ve si de ef f ect proper t i es f or bot h l ovast at i n and
ni aci n and war r ant consi der at i on dur i ng t herapy.
c. Aml odi pi ne/ at or vast at i n ( Caduet ) i s a combi nat i on pr oduct t hat i ncorporat es t he
act i ons of t he di hydropyri di ne cal ci um channel bl ocker aml odi pi ne wi t h t he l i pi d-
l ower i ng pr opert i es of t he HMG- CoA r educt ase i nhi bi t or at or vast at i n. The cal ci um
channel bl ocker of f ers no benef i t f or l i pi d l ower i ng but r epr esent s a pot ent i al l y
benef i ci al pr oduct f or a pat i ent wi t h coexi st i ng di sease st at es, such as Ì HD and
hyper t ensi on, f or whi ch t he use of a cal ci um channel bl ocker woul d be war r ant ed.
( 1) Avai l abl e pr oduct i s suppl i ed as 20/ 500, 20/ 750, and 20/ 1000 t abl et s, whi ch
consi st of 20 mg of l ovast at i n and 500, 750, or 1000 mg of an ext ended rel ease f or m
of ni aci n. The recommended dai l y dose i s 1-2 t abl et s by mout h at bedt i me.
( 2) Si de ef f ect s ref l ect t he addi t i ve si de ef f ect proper t i es f or bot h aml odi pi ne and
at or vast at i n and war r ant consi derat i on dur i ng t herapy.
d. Aspi ri n, buf f ered/ pr avast at i n ( Pr avi gard PAC) i s a combi nat i on pr oduct t hat
i ncor por at es t he act i ons of t he HMG- CoA r educt ase i nhi bi t or pr avast at i n wi t h t he
ant i pl at el et pr oper t i es of aspi ri n. Thi s pr oduct i s no l onger avai l abl e i n t he U. S.
( 1) Avai l abl e pr oduct i s suppl i ed as 81/ 20, 81/ 40, 81/ 80, 325/ 20, 325/ 40, and 325/ 80
t abl et combi nat i ons of buf f ered aspi ri n and pr avast at i n, respect i vel y. The
r ecommended dai l y dose i s 1 t abl et by mout h dai l y.
( 2) Si de ef f ect s ref l ect t he addi t i ve si de ef f ect proper t i es f or bot h aspi ri n and
pr avast at i n and war r ant consi derat i on dur i ng t herapy.
e. Omega-3- aci d et hyl est ers (Lovaza) i s t he f i rst FDA- appr oved omega 3- f at t y aci d,
whi ch i s i ndi cat ed f or pat i ent s wi t h el evat ed l evel s of t r i gl ycer i des ( > 500 mg/ dL) .
( 1) Avai l abl e pr oduct i s suppl i ed as a 1- g capsul e; t he recommended dai l y dose i s 4
capsul es by mout h dai l y i n one- t wo doses.
P. 806


( 2) Si de ef f ect s t hat have been repor t ed i ncl ude bur pi ng, i nf ect i on, f l u- l i ke
sympt oms, upset st omach, change i n one' s sense of t ast e, back pai n, and r ash.
f . Hypert ensi on. Tr eat ment of hyper t ensi on accor di ng t o t he Joi nt Nat i onal
Conf erence VÌ Ì gui del i nes has recei ved a cl ass Ì r ecommendat i on based on dat a
f r om mul t i pl e r andomi zed cl i ni cal t r i al s wi t h l ar ge number s of pat i ent s ( A, hi gh) and
shoul d be cont rol l ed. Cl ass Ì r ecommendat i ons are based on evi dence or gener al
agr eement t hat a gi ven pr ocedure or t r eat ment i s usef ul and ef f ect i ve ( see Chapt er
41) .
g. Smoki ng shoul d be st opped i f at al l possi bl e and has r ecei ved a cl ass Ì
r ecommendat i on based on dat a der i ved f rom a l i mi t ed number of r andomi zed t ri al s
wi t h smal l numbers of pat i ent s ( B, i nt er medi at e).
( 1) Tr ansdermal use of ni cot i ne- cont ai ni ng pat ches has become one st r at egy f or
ai di ng t he cessat i on of smoki ng. Product s such as Ni cot rol , Habi t rol , Ni coDer m, and
ot hers ar e avai l abl e i n var yi ng st rengt hs t o wean pat i ent s of f t he use of ci garet t es
over an 8- t o 12- week per i od, usi ng descendi ng doses.
( 2) Ni cot i ne gum (or al ni cot i ne pol acr i l ex chewi ng pi eces) i s avai l abl e i n 2- mg or 4-
mg pi eces. Ni cor et t e i s usual l y used f or 3 mont hs t o ai d i n cessat i on of smoki ng.
( 3) Bupr opi on i s a prescri pt i on ant i depr essant , whi ch i s al so market ed under t he
br and name of Zyban as an ai d t o smoki ng cessat i on.
( 4) Vareni cl i ne ( Chant i x) i s a recent l y appr oved pr oduct , whi ch wor ks as agoni zer s
and bl ocks al pha-4- bet a-2 ni cot i ni c acet yl chol i ne r ecept or s i n t he br ai n t o r educe
t he cr avi ng f or ni cot i ne. Ther apy i s st ar t ed wi t h a dose of 0. 5 mg by mout h dai l y f or
3 days, f ol l owed by 0. 5 mg t abl et s t wi ce dai l y f or 4 days, t hen 1 mg t wi ce dai l y
t her eaf t er f or 12 weeks, whi ch can be gi ven f or an addi t i onal 12 weeks i f
successf ul .
h. Obesi t y shoul d be reduced t hr ough di et and an appr opr i at e exer ci se pr ogr am i n
pat i ent s wi t h hyper t ensi on, hyper l i pi demi a, or di abet es mel l i t us and has recei ved a
cl ass Ì recommendat i on based on exper t consensus as t he pri mar y basi s (C, l ow) .
H. Therapeut i c agent s
1. Recent evi dence-based gui del i nes have provi ded r ecommendat i ons f or t he
t r eat ment of pat i ent s wi t h chr oni c st abl e angi na. ( See Ì D. 1. Fr aker , TD et . al ) .
Recommendat i ons use f our l evel s of r ecommendat i ons: Cl ass Ì ( evi dence
demonst r at es t hat t he benef i t of t he ef f ect / t r eat ment i s much gr eat er [ >>>] t han t he
r i sk and shoul d be per f ormed/ ut i l i zed) ; Cl ass Ì Ì a (evi dence demonst r at es t hat t he
benef i t of t he ef f ect / t reat ment i s gr eat er [ >>] t han t he r i sk and i t i s r easonabl e t o
per f or m or ut i l i ze t he t r eat ment ); Cl ass Ì Ì b ( evi dence demonst r at es t hat t he benef i t
of t he ef f ect / t r eat ment i s gr eat er t han or equal t o [ <] r i sk associ at ed wi t h t he
ef f ect / t r eat ment , and addi t i onal st udi es woul d be hel pf ul ) ; and Cl ass Ì Ì Ì (evi dence
demonst r at es t hat t he r i sk associ at ed wi t h t he ef f ect / t r eat ment i s great er t han or
equal t o [ <] t he benef i t , and shoul d not be ut i l i zed or admi ni st ered) . Addi t i onal l y,
t he recommendat i ons i ncl ude 3 l evel s of evi dence, based on t he avai l abi l i t y f r om
t he l i t er at ur e and i ncl ude Level A- hi gh l evel , mul t i pl e popul at i ons st udi ed, Level B-
l i mi t ed popul at i ons st udi ed, and Level C- ver y l i mi t ed popul at i on st udi ed. For t he
pur poses of t hi s revi ew, we have onl y i ncl uded t he over al l Cl ass r ecommendat i on
f or t he respect i ve t her api es.
2. Ni t rates ( e. g. , ni t rogI yceri n)
a. Mechani sm of act i on
( 1) The pr i mar y val ue of ni t rat es i s venous di l at i on, whi ch r educes l ef t vent r i cul ar
vol ume ( pr el oad) and myocardi al wal l t ensi on, decr easi ng oxygen r equi r ement s
( demand) .
( 2) Ni t r at es may al so reduce ar t er i ol ar r esi st ance, hel pi ng r educe af t erl oad, whi ch
decreases myocar di al oxygen demand.
( 3) By r educi ng pressure i n cardi ac t i ssues, ni t r at es al so f aci l i t at e col l at eral
ci rcul at i on, whi ch i ncr eases bl ood di st r i but i on t o i schemi c ar eas.
( 4) Phar macol ogi cal ef f ect s have been shown t o i mpr ove exer ci se t ol er ance, pr ol ong
t he t i me t o onset of angi na, and t he appear ance of ST- segment depr essi on duri ng
exer ci se t est i ng.
b. I ndi cat i ons
( 1) Acut e at t acks of angi na pect or i s can be managed wi t h subl i ngual , t ransmucosal
( Ni t r ol i ngual spray or buccal t abl et s) , or i nt ravenous del i ver y.
( 2) Ì ndi cat i ons i ncl ude t he pr event i on of ant i ci pat ed at t acks, usi ng t abl et s ( or al or
buccal ) or t r ansdermal past e or pat ches. Subl i ngual ni t r at es ( Ni t rost at ) can be used
bef ore eat i ng, sexual act i vi t y, or a known st r essf ul event .
P. 807


( 3) Ni t r at es ar e used i n t r eat ment of st abl e angi na. They may not be ef f ect i ve as a
si ngl e agent f or t r eat ment of Pr i nzmet al angi na, al t hough some st udi es have shown
ni t rat es t o prevent or rever se vasospasm at var yi ng doses. Ì nt r avenous ni t r ogl yceri n
i s used i n t he i mmedi at e t r eat ment of unst abl e angi na and i s used f or l ong- t erm
t her apeut i c rel i ef .
( 4) Ni t r at es used i n combi nat i on wi t h 8-adrenergi c bl ocker s have been shown t o be
mor e ef f ect i ve t han ni t r at es or 8-adr energi c bl ockers used al one.
c. Choi ce of preparat i on shoul d be based on onset of act i on, dur at i on of act i on,
and pat i ent compl i ance and pr ef er ence because al l ni t r at es have t he same
mechani sm of act i on.
d. Precaut i ons and moni t ori ng ef fects
( 1) To maxi mi ze t he t herapeut i c ef f ect , pat i ent s shoul d t horoughl y under st and t he
use of t hei r speci f i c dosage f orms ( e. g. , subl i ngual t abl et s, t ransder mal pat ches or
past es, t abl et s, capsul es) .
( 2) Bl ood pr essur e and hear t rat e shoul d be moni t or ed because al l ni t r at es can
i ncrease hear t rat e whi l e l ower i ng bl ood pressure.
( 3) Pr el oad reduct i on can be assessed t hrough reduct i on of pul monar y sympt oms
such as shor t ness of breat h, paroxysmal noct ur nal dyspnea, or dyspnea.
( 4) Ni t r at e- i nduced headaches ar e t he most common si de ef f ect .
( a) Pat i ent s shoul d be war ned of t he nat ure, suddenness, and pot ent i al st r engt h of
t hese headaches t o mi ni mi ze t he anxi et y t hat mi ght ot her wi se occur .
( b) Compl i ance can be enhanced i f t he pat i ent under st ands t hat t he ef f ect i s
t r ansi ent and t hat t he headaches usual l y di sappear wi t h cont i nued t her apy.
( c) Acet ami nophen i ngest ed 15- 30 mi n bef ore ni t rat e admi ni st r at i on may pr event t he
headache.
e. Ef f ect i ve therapy shoul d r esul t i n f ewer angi nal at t acks wi t hout i nduci ng
si gni f i cant adverse ef f ect s (e. g. , post ur al hypot ensi on, hypoxi a) . Ì f maxi mal doses
ar e reached and t he pat i ent st i l l exper i ences at t acks, addi t i onal agent s shoul d be
admi ni st er ed.
f . Ni t rate t oI erance i s a maj or pr obl em wi t h t he l ong- t erm use of ni t rogl ycer i n and
l ong- act i ng ni t rat es. Sever al agent s such as ACE i nhi bi t ors (sul f hydr yl -cont ai ni ng
dr ugs) , acet yl cyst ei ne, and di uret i cs have been shown t o rever se ni t r at e t ol erance
by i ncr easi ng t he avai l abi l i t y of sul f hydr yl r adi cal s. However , pr act i cal
consi derat i ons suggest t hat l ess f r equent admi ni st r at i on ( 8- 12 hr of ni t rat e- f r ee
i nt er val s) i s ef f ect i ve wi t hout i nt r oduci ng addi t i onal agent s.
3. ß- Adrenergi c bI ockers. Based on t he recent l y r el eased 2007 Focused gui del i nes
f or pat i ent s wi t h Chr oni c St abl e Angi na, a Cl ass 1A r ecommendat i on st at es t hat i t i s
benef i ci al t o st art and cont i nue bet a- bl ocker t herapy i ndef i ni t el y i n al l pat i ent s who
have had MÌ , acut e cor onar y syndr ome, or l ef t vent r i cul ar dysf unct i on wi t h or
wi t hout heart f ai l ur e sympt oms, unl ess cont rai ndi cat ed.
a. Mechani sm of act i on. 8- Bl ockers r educe oxygen demand, bot h at rest and duri ng
exer t i on, by decr easi ng t he hear t r at e and myocar di al cont r act i l i t y, whi ch al so
decreases art eri al bl ood pr essure.
b. I ndi cat i ons
( 1) These agent s r educe t he f r equency and severi t y of exer t i onal angi na t hat i s not
cont r ol l ed by ni t rat es.
( 2) Ni t r at es have been combi ned wi t h cal ci um ant agoni st s, when sl ow- r el ease
di hydropyr i di nes ( e. g. , f el odi pi ne- Pl endi l , aml odi pi ne- Nor vasc) ar e pr ef err ed over
di l t i azem ( Car di zem) or ver apami l ( Cal an). Ì f pat i ent s need t o recei ve a 8-
adr ener gi c bl ocker al ong wi t h ver apami l or di l t i azem owi ng t o t he added ef f ect s,
t hey have t he pot ent i al t o i nduce br adycardi a, AV hear t bl ock, and f at i gue.
c. Precauti ons and moni t ori ng ef f ect s
( 1) Doses shoul d be i ncreased unt i l t he angi nal epi sodes have been r educed or unt i l
unaccept abl e si de ef f ect s occur .
( 2) 8- Bl ockers shoul d be avoi ded i n Pr i nzmet al angi na (caused by coronar y
vasospasm) because t hey i ncrease coronar y resi st ance and may i nduce vasospasm.
( 3) Ast hma i s a rel at i ve cont r ai ndi cat i on because al l 8- bl ocker s i ncr ease ai r way
r esi st ance and have t he pot ent i al t o i nduce bronchospasm i n suscept i bl e pat i ent s.
( 4) Pat i ent s wi t h di abet es and ot her s pr edi sposed t o hypogl ycemi a shoul d be
war ned t hat 8-bl ockers mask t achycar di a, whi ch i s a key si gn of devel opi ng
hypogl ycemi a.
( 5) Pat i ent s shoul d be moni t or ed f or excessi ve negat i ve i not ropi c ef f ect s. Fi ndi ngs
such as f at i gue, shor t ness of br eat h, edema, and par oxysmal noct ur nal dyspnea
may si gnal
P. 808

devel opi ng cardi ac decompensat i on, whi ch al so i ncr eases t he met abol i c demands of
t he heart .
( 6) Sudden cessat i on of 8- bl ocker t herapy may t ri gger a wi t hdr awal syndrome t hat
can exacer bat e angi nal at t acks (especi al l y i n pat i ent s wi t h Ì HD) or cause MÌ .
d. Choi ce of preparat i ons. Al l 8-bl ockers are l i kel y t o be equal l y ef f ect i ve f or
st abl e ( exer t i onal ) angi na. For f ur t her r evi ew of 8- adr ener gi c bl ocker s, see Chapt er
40. For a l i st of agent s and doses, see Tabl e 39-4.
4. CaI ci um- channeI bI ockers
a. Mechani sm of act i on. Two act i ons ar e most per t i nent i n t he t reat ment of angi na.
( 1) These agent s pr event and r everse cor onar y spasm by i nhi bi t i ng cal ci um i nf l ux
i nt o vascul ar smoot h muscl e and myocardi al muscl e. Thi s r esul t s i n i ncreased bl ood
f l ow, whi ch enhances myocardi al oxygen suppl y.
( 2) Cal ci um- channel bl ockers decrease coronar y vascul ar r esi st ance and i ncr ease
cor onar y bl ood f l ow, r esul t i ng i n i ncr eased oxygen suppl y.
( 3) Cal ci um- channel bl ockers decrease syst emi c vascul ar r esi st ance and ar t eri al
pr essure; i n addi t i on, t hey decr ease i not r opi c ef f ect s, resul t i ng i n decreased
myocar di al oxygen demand.
b. I ndi cat i ons
( 1) Cal ci um- channel bl ockers are used i n st abl e (exer t i onal ) angi na t hat i s not
cont r ol l ed by ni t rat es and 8- bl ockers and i n pat i ent s f or whom 8- bl ocker t her apy i s
i nadvi sabl e. Combi nat i on t her apy÷wi t h ni t rat es, 8- bl ockers, or bot h÷may be most
ef f ect i ve.
( 2) These agent s, al one or wi t h a ni t r at e, ar e part i cul ar l y val uabl e i n t he t r eat ment
of Pr i nzmet al angi na. They ar e consi dered t he drug of choi ce i n t reat ment of angi na
at r est .
c. I ndi vi duaI agents
( 1) Di I ti azem ( Cardi zem) and verapami I ( CaI an)
( a) These drugs pr oduce negat i ve i not r opi c ef f ect s, and pat i ent s must be moni t ored
cl osel y f or si gns of devel opi ng cardi ac decompensat i on ( i . e. , f at i gue, short ness of
br eat h, edema, par oxysmal noct ur nal dyspnea) . When coadmi ni st ered wi t h 8-
bl ocker s or ot her agent s t hat pr oduce negat i ve i not r opi c ef f ect s ( e. g. , di sopyr ami de,
qui ni di ne, procai nami de, f l ecai ni de), t he negat i ve ef f ect s ar e addi t i ve.
( b) Pat i ent s shoul d be moni t or ed f or si gns of devel opi ng bradyar rhyt hmi as and heart
bl ock because t hese agent s have negat i ve chr onot r opi c ef f ect s.
( c) Verapami l f requent l y causes const i pat i on, whi ch must be t r eat ed as needed t o
pr event st r ai ni ng at st ool , whi ch coul d cause an i ncr eased oxygen demand ( Val sal va
maneuver ) . Verapami l i s not r ecommended i n pat i ent s wi t h si ck si nus syndr omes,
AV nodal di sease, or hear t f ai l ur e ( HF) .
( 2) Ni f edi pi ne (Procardi a)
( a) Thi s cal ci um-channel bl ocker i s bel i eved t o possess t he gr eat est degree of
negat i ve i not r opi c ef f ect s compared t o t he newer second- gener at i on member s of
t hi s group, aml odi pi ne (Nor vasc) and f el odi pi ne ( Pl endi l ) ; Ni f edi pi ne 10 mg (chewed
or swal l owed) has been used t o t reat Pr i nzmet al angi na or ref r act or y spasm i n
pat i ent s who ar e not hypot ensi ve. Cont r oversy st i l l exi st s about t he use of shor t -
act i ng, r api d- r el ease agent s such as ni f edi pi ne i n pat i ent s wi t h Ì HD.
( b) Because ni f edi pi ne i ncr eases t he hear t r at e somewhat , i t can produce
t achycardi a, whi ch woul d i ncr ease oxygen demand. Coadmi ni st r at i on of a 8- bl ocker
shoul d prevent ref l ex t achycar di a.
( c) Ì t s pot ent peri pher al di l at or y ef f ect s can decrease cor onar y per f usi on and
pr oduce excessi ve hypot ensi on, whi ch can aggr avat e myocardi al i schemi a.
( d) Di zzi ness, l i ght - headedness, and l ower ext r emi t y edema ar e t he most common
adver se ef f ect s, but t hese t end t o di sappear wi t h t i me or dose adj ust ment .
( 3) AmI odi pi ne ( Norvasc) , f eI odi pi ne ( PI endi I ) , i sradi pi ne ( Dynaci rc) ,
ni cardi pi ne ( Cardene) , and ni soI di pi ne ( SuI ar) ar e second- generat i on
di hydropyr i di ne der i vat i ve, cal ci um-channel bl ocker s. They have been used
ef f ect i vel y as once- or t wi ce- a- day agent s owi ng t o t hei r l ong act i vi t y. Because of
t he pot ent negat i ve i not ropi c ef f ect s of t hese agent s, t hey ar e not r ecommended i n
pat i ent s wi t h HF ( aml odi pi ne has been shown t o have l ess negat i ve pot ent i al i n HF
t han ot her member s of t he cl ass) .
5. Ant i pI ateI et agent s
a. Aspi ri n: Based on t he r ecent l y r el eased 2007 Focused Gui del i nes f or pat i ent s
wi t h Chr oni c St abl e Angi na, a Cl ass Ì A r ecommendat i on st at es t hat aspi r i n shoul d
be st art ed at 75 t o 162 mg per day and cont i nued i ndef i ni t el y i n al l pat i ent s unl ess
cont r ai ndi cat ed.
P. 809


Table 39-4. Selected Agents and Their Doses in the Treatment of Coronary
Artery Disease
Class/Agent
Dose/Dosage
Schedule Comments
Nitrates
Nitroglycerin
sublingual tablets
(Nitrostat)
0.3-0.6 mg up
to 1.5 mg
Short-term eIIects: 1-7 min
Nitroglycerin spray
(Nitrolingual)
0.4 mg as
needed
Similar to sublingual tablets
Nitroglycerin
transdermal (Nitro-
Dur)
0.2-0.8 mg/hr
every 12 hr
Remove patch Ior 8-12 hr to
reduce tolerance
Nitroglycerin 5-200 µg/min Short acting requiring
intravenous inIusion
(Various)
continuous inIusion and
monitoring
Isosorbide
mononitrate (Imdur.
ISMO. Monoket.
Various)
10-40 mg daily
in 2 doses
Also available as extended
release product Ior single
daily dosing
Isosorbide dinitrate
SL
2.5-10 mg SL
every 2-3
hours
For Acute angina attacks
Isosorbide dinitrate
oral tablets (Various)
5-80 mg. 2-3
times daily
Longer acting up to 8 hr
Isosorbide dinitrate
slow-release tablets
(Dilatrate-SR)
40 mg once or
twice daily
Duration oI activity up to 8 hr
ß-adrenergic blockers
Propranolol (Inderal.
Various)
20-80 mg
twice daily
Possesses both þ
1
- and þ
2
-
blocker eIIects
Metoprolol
(Lopressor. Various)
50-200 mg
twice daily
Possesses þ
1
-blocker eIIects
Atenolol (Tenormin.
Various)
50-200 mg/day Possesses þ
1
-blocker eIIects
Nadolol (Corgard.
Various)
40-80 mg/day Possesses both þ
1
- and þ
2
-
blocker eIIects
Timolol (Blocadren.
Various)
10 mg twice
daily
Possesses both þ
1
- and þ
2
-
blocker eIIects
Acebutolol (Sectral.
Various)
200-600 mg
twice daily
Possesses þ
1
-blocker eIIects
Betaxolol (Kerlone.
Various)
10-20 mg/day Possesses þ
1
-blocker eIIects
Bisoprolol (Zebeta.
Various)
10 mg/day Possesses þ
1
-blocker eIIects
Esmolol
(intravenous)
(Brevibloc. Various)
50-300
µg/kg/min
Possesses þ
1
-blocker eIIects
Labetalol (Trandate.
Various)
200-600 mg
twice daily
Possesses both u
1
-. þ
1
-. and
þ
2
-blocker eIIects
Pindolol (Visken.
Various)
2.5-7.5 mg
three times
daily
Possesses both þ
1
- and þ
2
-
blocker eIIects
Carvedilol (Coreg.
Various)
25 mg twice
daily
Possesses both u
1
- þ
1
-. and
þ
2
-blocker eIIects
Penbutolol (Levatol)

Possesses both þ
1
- and þ
2
-
blocker eIIects
Calcium-channel blockers
Dihydropyridine
derivatives

NiIedipine
(Procardia. Various)
Immediate
release; 30-90
mg daily
Short duration oI action oI 4-
6 hr
Amlodipine
(Norvasc. Various)
5-10 mg once
daily
Long duration oI action
Felodipine (Plendil.
Various)
5-10 mg once
daily
Long duration oI action
Isradipine (Dynacirc.
Various)
2.5-10 mg
twice daily
Intermediate duration oI
action
Nicardipine
(Cardene. Various)
20-40 mg three
times daily
Short duration oI action
Nisoldipine (Sular) 20-40 mg once
daily
Short duration oI action
Miscellaneous
Diltiazem (Cardizem.
Various)
Immediate
release: 30-80
mg Iour times
daily
Short duration oI action;
important consideration
necessary owing to
hypotension. bradycardia.
and edema

Slow release:
120-320 mg
once daily
Long duration oI action;
important consideration
necessary owing to
hypotension. bradycardia.
and edema
Class/Agent
Verapamil (Calan.
Various)
Immediate
release: 80-160
mg three times
daily
Short duration oI action;
important consideration
necessary owing to
hypotension. bradycardia.
edema. myocardial
depression. and heart Iailure

Slow release:
120-480 mg
once daily
Long duration oI action;
important consideration
necessary owing to
hypotension. bradycardia.
edema. myocardial
depression. and heart Iailure

P. 810


b. Ti cI opi di ne ( Ti cI i d) i s a t hi enopyr i di ne der i vat i ve t hat i nhi bi t s pl at el et
aggregat i on i nduced by adenosi ne di phosphat e. However , unl i ke aspi r i n, i t has not
been shown t o decr ease adver se car di ovascul ar event s i n pat i ent s wi t h st abl e
angi na and has been associ at ed wi t h t hr ombot i c t hr ombocyt openi c purpura on an
i nf requent basi s.
c. CI opi dogreI (PI avi x) i s al so a t hi enopyr i di ne der i vat i ve r el at ed t o t i cl opi di ne, but
i t possesses ant i t hr ombot i c ef f ect s t hat are great er t han t hose of t i cl opi di ne.
Cl opi dogr el i s a t her apeut i c opt i on i n t hose angi na pat i ent s who can not t ake aspi r i n
because of cont r ai ndi cat i ons. Doses of 75 mg dai l y ar e recommended t o pr event t he
devel opment of acut e cor onar y syndromes.
d. Based on t he r ecent l y r el eased 2007 Focused Gui del i nes f or pat i ent s wi t h
Chr oni c St abl e Angi na, a Cl ass Ì B r ecommendat i on st at es t hat t he use of war f ar i n i n
conj unct i on wi t h aspi r i n and/ or cl opi dogrel i s associ at ed wi t h an i ncr eased r i sk of
bl eedi ng and shoul d be moni t ored cl osel y.
6. ACE i nhi bi t ors: Based on t he r ecent l y rel eased 2007 Focused gui del i nes f or
pat i ent s wi t h Chr oni c St abl e Angi na, t he f ol l owi ng r ecommendat i ons have been
made f or ACE Ì nhi bi t ors.
a. Cl ass 1A r ecommendat i on st at es t hat ACE i nhi bi t or s shoul d be st art ed and
cont i nued i ndef i ni t el y i n al l pat i ent s wi t h l ef t vent r i cul ar ej ect i on f ract i on >40% and
i n t hose wi t h hyper t ensi on, di abet es, or chroni c ki dney di sease unl ess
cont r ai ndi cat ed.
b. Cl ass Ì B r ecommendat i on t hat ACE i nhi bi t ors shoul d be st ar t ed and cont i nued
i ndef i ni t el y i n pat i ent s who are not l ower r i sk ( l ower r i sk def i ned as t hose wi t h
nor mal l ef t vent r i cul ar ej ect i on f r act i on i n whom car di ovascul ar ri sk f act ors are wel l
cont r ol l ed and revascul ar i zat i on has been per f ormed), unl ess cont r ai ndi cat ed.
c. Cl ass Ì Ì a recommendat i on t hat i t i s reasonabl e t o use ACE i nhi bi t ors among
l ower - r i sk pat i ent s wi t h mi l dl y reduced or normal l ef t vent ri cul ar ej ect i on f r act i on i n
whom car di ovascul ar ri sk f act or s ar e wel l cont r ol l ed and r evascul ar i zat i on has been
per f or med.
d. Cur rent gui del i nes do not suggest whi ch agent t o use, and i t i s ant i ci pat ed t hat
ongoi ng t ri al s wi t h addi t i onal agent s wi l l provi de addi t i onal i nf ormat i on regar di ng
dosi ng r egi mens and pot ent i al di f f erences t hat mi ght exi st among t he cl ass of drugs.
7. Angi ot ensi n Recept or BI ockers ( ARBs) : Based on t he recent l y r el eased 2007
Focused gui del i nes f or pat i ent s wi t h Chroni c St abl e Angi na, t hr ee new
r ecommendat i ons have been made f or t he use of ARBs i n pat i ent s wi t h chr oni c
st abl e angi na.
a. Cl ass Ì A r ecommendat i on t hat ARBs are recommended f or pat i ent s who have
hyper t ensi on, have i ndi cat i ons f or but are i nt ol erant of ACE i nhi bi t ors, have heart
f ai l ur e, or have had a myocardi al i nf ar ct i on wi t h l ef t vent r i cul ar ej ect i on f ract i on
>40%.
b. Cl ass Ì Ì b r ecommendat i on t hat ARBs may be consi der ed i n combi nat i on wi t h ACE
i nhi bi t ors f or hear t f ai l ure due t o l ef t vent r i cul ar syst ol i c dysf unct i on.
P. 811


c. Cl ass Ì A r ecommendat i on t hat al dost er one bl ockade i s r ecommended f or use i n
post - MÌ pat i ent s wi t hout si gni f i cant r enal dysf unct i on or hyperkal emi a who ar e
al r eady r ecei vi ng t her apeut i c doses of an ACE i nhi bi t or and a bet a bl ocker , have a
l ef t vent ri cul ar ej ect i on f r act i on >40%, and have ei t her di abet es or heart f ai l ur e.
8. CheI at i on Therapy: Based on t he recent l y r el eased 2007 Focused Gui del i nes f or
pat i ent s wi t h Chr oni c St abl e Angi na, a cl ass Ì Ì Ì C r ecommendat i on st at ed t hat
Chel at i on t herapy ( i nt r avenous i nf usi ons of et hyl enedi ami ne t et raacet i c aci d or
EDTA) i s not recommended f or t he t r eat ment of chr oni c angi na or ar t er i oscl erot i c
car di ovascul ar di sease and may be har mf ul because of i t s pot ent i al t o cause
hypocal cemi a. Cl ass Ì Ì Ì C st at es t hat t he r i sk i s great er t han t he benef i t and shoul d
not be used.
III. ACUTE CORONARY SYNDROME (ACS)
A. Def i ni t i on. ACS i s a rel at i vel y new t er m t hat has been i nt r oduced i nt o t he
medi cal l i t er at ur e t o descr i be any pat t ern of cl i ni cal sympt oms t hat ref l ect s t he
devel opment of acut e MÌ ( Fi gur e 39-2) . Thi s cat egor y i ncl udes t he sympt oms r el at ed
t o ST- segment el evat ed myocar di al i nf arct i on ( STEMÌ ) , non- ST- segment el evat ed
myocar di al i nf arct i on ( NSTEMÌ ) , and unst abl e angi na.
B. I nci dence. Ì t has been est i mat ed t hat nearl y 8 mi l l i on pat i ent s seen i n
emergency depar t ment s each year i n t he Uni t ed St at es ar e seen f or chest pai n, and
t hat up t o 5 mi l l i on of t hese pat i ent s are admi t t ed t o t he hospi t al . Mor e t han 1. 5
mi l l i on of t he pat i ent s admi t t ed t o t he hospi t al are admi t t ed wi t h an ACS (330, 000
wi t h STEMÌ , and 1. 24 mi l l i on wi t h UA and NSTEMÌ ) .
C. Cl assi f i cat i on of pat i ent s pr esent i ng wi t h pr esumed ACS i s cri t i cal t o t he
appropr i at e det ermi nat i on of pr ognosi s as wel l as cl i ni cal i nt er vent i ons. Ì n ACS
owi ng t o STEMÌ and NSTEMÌ , a por t i on of t he cardi ac muscl e suf f ers a sever e and
pr ol onged rest r i ct i on of oxygenat ed coronar y bl ood. Ì n t he maj ori t y of pat i ent s, t he
cause i s an occl usi ve or near -occl usi ve t hr ombus over l yi ng or adj acent t o a r upt ured
at heroscl er ot i c pl aque. Thi s r esul t s i n cel l ul ar i schemi a, t i ssue i nj ur y, and t i ssue
necrosi s. About 1. 5 mi l l i on peopl e suf f er an AMÌ each year. UA i s bel i eved t o
i ndi cat ed an i mpendi ng AMÌ , and t he goal of t r eat ment i s t o pr event t he
devel opment of t he AMÌ .

Figure 39-2. Evolutionary progression oI ACSs.
As atherosclerosis (most common cause oI
ischemic heart disease) advances. the reduction in
myocardial perIusion results in the development
oI the ACS owing to either unstable angina.
NSTEMI. or STEMI. The thrombi. which Iorm in
unstable angina. NSTEMI. STEMI. are rich in
both Iibrin and platelets. |Adapted Irom Vanscoy
G. Integrating new Iibrinolytic Iindings into AMI
reperIusion and combination therapy: 2002 and
beyond. Paper presented at the meeting oI the
Delaware Valley Chapter oI the Pennsylvania
Society oI Health-Systems Pharmacists. March 7.
2002.|
P. 812


1. STEMI . A condi t i on t hat r equi r es i mmedi at e r eper f usi on t her apy, i f possi bl e
t hr ough ei t her t hrombol ysi s or percut aneous coronar y i nt er vent i on ( PCÌ )
a. The i nt roduct i on of t hrombol ysi s or PCÌ f or t he management of STEMÌ has
demonst r at ed abi l i t y t o remove t he of f endi ng t hr ombus f r om t he af f ect ed cor onar y
ar t er y.
b. Damage t o t he myocar di al t i ssue i s not rout i nel y r ever si bl e, as i n t he case of
angi na pect or i s, owi ng t o pot ent i al deat h of myocar di al t i ssue i f r eper f usi on does
not t ake pl ace earl y enough.
2. UA and NSTEMI . Si mi l ar condi t i ons f or whi ch t her e i s no evi dence showi ng t he
benef i t t o pat i ent s of r eper f usi on t herapy. Speci f i c gui del i nes have been devel oped
f or t he di agnosi s and management of t hese condi t i ons. Up t o 25% of pat i ent s who
have bot h NSTEMÌ and el evat ed car di ac enzymes event ual l y devel op Q- wave MÌ ;
t he remai ni ng pat i ent s devel op non- Q- wave MÌ . Pat i ent s wi t h UA car r y a 10%-20%
r i sk of progr essi on t o an MÌ i f unt reat ed; t r eat ment has been shown t o r educe t he
r i sk t o 5%- 7%.
D. Di agnosi s. The ECG i s at t he cent er of t he deci si on pat hway f or t he eval uat i on
and management of pat i ent s wi t h ACS and i s conf i rmed wi t h ser i al cardi ac markers
i n > 90% of pat ent s pr esent i ng wi t h si gni f i cant ST- segment el evat i on. Pat i ent s who
pr esent wi t hout ST- segment el evat i on are consi der ed t o have ei t her UA or NSTEMÌ ;
t he f i nal di agnosi s i s made l at er, af t er t he presence or absence of ser i al car di ac
markers i s det er mi ned.
1. Di agnost i c t est resuI t s. The devel opment of an ACS i s a l i f e- t hreat eni ng
emergency; di agnosi s i s pr esumed÷and t r eat ment i s i nst i t ut ed÷based on t he
pat i ent ' s compl ai nt s and t he resul t s of an i mmedi at e 12- l ead ECG. Labor at or y t est s
and f ur t her di agnost i c t est s can rul e out or provi de conf i rmat i on and hel p i dent i f y
t he l ocal e and ext ent of myocar di al damage.
2. Seri aI 12- I ead ECG. Abnormal i t i es may be absent or i nconcl usi ve dur i ng t he f i rst
f ew hours af t er pr esent at i on of t he ACS and may not ai d t he di agnosi s i n about 15%
of t he cases. When present , char act er i st i c f i ndi ngs show pr ogr essi ve changes.
a. Fi r st , ST- segment el evat i on ( i nj ur y cur rent ) appears i n t he l eads, r ef l ect i ng t he
i nj ur ed area. Peaked upri ght or i nver t ed T waves usual l y i ndi cat e acut e myocar di al
i nj ur y, t he ear l y st ages of a t ransmur al Q- wave MÌ . Persi st ent ST depr essi on may
al so i ndi cat e a non- Q- wave MÌ .
b. Q waves devel opi ng (i ndi cat i ng necrosi s) i s gener al l y di agnost i c of an MÌ , but
can be seen i n ot her condi t i ons.
c. Unequi vocal di agnosi s can be made onl y i n t he pr esence of al l t hr ee
abnor mal i t i es. However , t he mani f est at i ons depend on t he ar ea of i nj ur y. For
exampl e, i n non- Q- wave i nf ar ct i on, onl y ST- segment depressi on may appear .
d. The most seri ous ar r hyt hmi c compl i cat i on of an acut e MÌ i s vent r i cul ar f i bri l l at i on,
whi ch may occur wi t hout war ni ng.
e. Vent r i cul ar pr emat ur e beat s ( VPBs) ar e t he most commonl y encount ered
ar r hyt hmi as and may r equi r e t r eat ment .
3. Cardi ac enzymes
a. Creat i ne ki nase- heart muscI e ( CK- MB) i s f i r st el evat ed 3-12 hr af t er t he onset
of pai n, peaks i n 24 hr , and ret ur ns t o basel i ne i n 48-72 hr . Ot her condi t i ons el evat e
t he CK- MB enzyme but do not demonst r at e t he t ypi cal pat t er n of r i se and f al l as
seen i n an MÌ . Unt i l r ecent l y, CK- MB had been t he pri nci pal serum car di ac mar ker
used i n t he eval uat i on of ACS.
b. Cardi ac t roponi n I ( cTnÌ ) and cardi ac t roponi n T (cTnT) ar e even mor e
sensi t i ve t han MB- CK. They r epr esent a power f ul t ool f or r i sk st r at i f i cat i on and have
gr eat er sensi t i vi t y and speci f i ci t y t han CK- MB. However , t hey do provi de a l ow
sensi t i vi t y i n t he earl y phases of an MÌ ( < 6 hr af t er sympt om onset ) and r equi r e
r epeat measurement s at 8- 12 hr , i f negat i ve. Level s i ncr ease 3-12 hr af t er t he onset
of pai n, peak at 24-48 hr, and r et ur n t o basel i ne over 5-14 days.
c. Lact ate dehydrogenase ( LDH) i s f ol l owed f or i t s char act er i st i c pat t er ns of r i se
and f al l . The r at i o of LDH1: LDH2 i s hel pf ul i n di agnosi ng an MÌ . LDH assays are
bei ng repl aced by cTnT assays.
4. Cardi ac i magi ng. As car di ac enzymes assays i mprove, t he use of noni nvasi ve
car di ac i magi ng t echni ques ar e not i ndi cat ed f or i ni t i al di agnosi s of an MÌ . Test s
i ncl ude
99m
Tc- pyr ophosphat e sci nt i gr aphy, myocar di al per f usi on i magi ng,
r adi onucl eot i de vent ri cul ogr aphy, t wo- di mensi onal echocardi ogr aphy, and cor onar y
angi ography.
P. 813


E. Si gns and sympt oms
1. Recent evi dence-based cl i ni cal gui del i nes i ndi cat e a cl ass Ì r ecommendat i on f or
pat i ent s wi t h suspect ed ACS wi t h chest di scomf or t at r est f or l onger t han 20 mi n;
hemodynami c i nst abi l i t y or r ecent syncope or pr esyncope shoul d be st r ongl y
consi dered f or i mmedi at e r ef er r al t o an emergency depar t ment or speci al i zed chest
pai n uni t . The f or emost char act er i st i c of ACS i s per si st ent , sever e chest pai n or
pr essure, commonl y descr i bed as crushi ng, squeezi ng, or heavy ( l i kened t o havi ng
an el ephant si t t i ng on t he chest ) . The pai n general l y begi ns i n t he chest and, l i ke
angi na, may r adi at e t o t he l ef t ar m, t he abdomen, back, neck, j aw, or t eet h. The
onset of pai n general l y occur s at rest or wi t h normal dai l y act i vi t i es; i t i s not
commonl y associ at ed wi t h exer t i on.
2. Ot her common compl ai nt s i ncl ude a sense of i mpendi ng doom, sweat i ng, nausea,
vomi t i ng, and di f f i cul t y br eat hi ng. Ì n some pat i ent s, f ai nt i ng and sudden deat h may
be t he i ni t i al pr esent at i on of ACS.
3. Obser vabl e f i ndi ngs i ncl ude ext r eme anxi et y, rest l ess, agi t at ed behavi or , and
ashen pal l or.
4. Some pat i ent s, par t i cul arl y t hose wi t h di abet es or t he el derl y, may exper i ence
onl y mi l d or i ndi gest i on-l i ke pai n or a cl i ni cal l y si l ent MÌ , whi ch may onl y mani f est i n
wor seni ng heart f ai l ur e, l oss of consci ousness, acut e conf usi on, dyspnea, a sudden
dr op i n bl ood pr essur e, or a l et hal ar rhyt hmi a.
F. OveraI I t reat ment goaI s i n ACS
1. To r el i eve chest pai n and anxi et y
2. To r educe cardi ac workl oad and st abi l i ze car di ac rhyt hm
3. To prevent / reduce myocardi al damage by l i mi t i ng t he ar ea af f ect ed and
pr eser vi ng pump f unct i on
4. To prevent or ar r est compl i cat i ons, such as l et hal ar r hyt hmi as, AMÌ , HF, or
sudden deat h
5. To r eopen ( or r eper f use) cl osed coronar y vessel s wi t h t hr ombol yt i c drugs and/ or
PCÌ i f i ndi cat ed
G. Treatment of UA and NSTEMI
1. Ant i - i schemi c t herapy
a. Cur rent evi dence- based cl i ni cal gui del i nes i ndi cat e cl ass Ì r ecommendat i ons f or
t he f ol l owi ng t herapeut i c i nt er vent i ons i n pat i ent s wi t h UA or NSTEMÌ :
( 1) Bedr est wi t h cont i nuous ECG moni t or i ng f or i schemi a and ar rhyt hmi a det ect i on
i n pat i ent s wi t h ongoi ng r est pai n.
( 2) Pat i ent s wi t h UA/ NSTEMÌ wi t h ongoi ng i schemi c di scomf ort shoul d r ecei ve SL
Ni t r ogl yceri n ( NTG) 0. 4 mg ever y 5 mi nut es × 3 doses, af t er whi ch t i me reassess f or
pot ent i al need f or i nt ravenous ni t rogl yceri n. Ì nt ravenous NTG i s i ndi cat ed i n t he f i r st
48 h i n pat i ent s wi t h UA/ NSTEMÌ f or t r eat ment of persi st ent i schemi a, hear t f ai l ur e,
or hyper t ensi on.
( 3) Suppl ement al oxygen f or pat i ent s wi t h cyanosi s or r espi r at or y di st r ess and
cont i nued need f or suppl ement al oxygen i n t he presence of hypoxemi a.
( 4) Aspi ri n i n doses of 162- 325 mg ( chewabl e) shoul d be gi ven t o pat i ent s wi t h
UA/ NSTEMÌ as soon as possi bl e, i f t he pat i ent has not al ready t aken.
( 5) An or al 8- adr ener gi c bl ocker shoul d be admi ni st ered wi t hi n t he f i rst 24 hours t o
al l pat i ent s wi t hout cont rai ndi cat i ons. Ì nt ravenous 8- adr ener gi c bl ockers shoul d onl y
be used f or speci f i c i ndi cat i ons and not as r out i ne t her apy.
( 6) Ì n pat i ent s wi t h cont i nui ng or f requent l y r ecurr i ng i schemi a when 8- adr energi c
bl ocker s ar e cont rai ndi cat ed, a non- di hydr opyr i di ne cal ci um ant agoni st ( i . e. ,
di l t i azem or ver apami l ) i s r ecommended as i ni t i al t herapy i n t he absence of sever e
l ef t vent ri cul ar dysf unct i on or ot her cont r ai ndi cat i ons. Ì n pat i ent s pr esent i ng wi t h
l ef t vent ri cul ar dysf unct i on, cur rent evi dence shows t hat t hese agent s mi ght wor sen
t he cl i ni cal st at us.
( 7) An ACE i nhi bi t or shoul d be admi ni st ered or al l y wi t hi n t he f i r st 24 h t o pat i ent s
wi t h pul monar y congest i on or l ef t vent r i cul ar ej ect i on f r act i on >40% i n t he absence
of hypot ensi on ( syst ol i c bl ood pr essur e l ess t han 100 mm Hg or l ess t han 30 mm Hg
bel ow basel i ne) or known cont rai ndi cat i ons. An ARB may be used f or ACE i nhi bi t or
i nt ol erant pat i ent s.
P. 814


2. Therapeut i c agents. Tabl e 39- 4 l i st s sel ect ed agent s and dosi ng r egi mens.
a. Ni t rates ( e. g. , ni t rogI yceri n) . ( See Ì Ì . H. )
b. Morphi ne. Recent gui del i nes f or UA/ NSTEMÌ and STEMÌ f r om 2007 have st at ed
t hat mor phi ne i s st i l l consi der ed a Cl ass Ì recommendat i on i n pat i ent s wi t h STEMÌ ,
however , i n UA/ NSTEMÌ pat i ent s i t mi ght i ncr ease t he r at e of adver se event s, and
has been downgr aded f rom a Cl ass Ì r ecommendat i on t o a Cl ass Ì Ì a. However , i n
t he absence of cont r ai ndi cat i ons, mor phi ne sul f at e can be admi ni st er ed t o pat i ent s
i f t her e i s uncont rol l ed i schemi c pai n despi t e t he use of NTG pr ovi ded addi t i onal
t her apy i s used t o t r eat t he under l yi ng i schemi a.
( 1) Mechani sm of act i on. Mor phi ne causes venous pool i ng and r educes pr el oad,
car di ac wor kl oad, and oxygen consumpt i on. Mor phi ne shoul d be admi ni st er ed
i nt ravenousl y, st ar t i ng wi t h 2 mg and t i t rat i ng at 5- t o 15-mi n i nt er val s unt i l t he pai n
i s rel i eved or t oxi ci t y becomes evi dent .
( 2) I ndi cat i ons. Mor phi ne sul f at e i s a reasonabl e choi ce f or myocar di al pai n and
anxi et y i n doses of 1- 5 mg Ì V ever y 5-30 mi nut es as needed, based on l evel of
pat i ent pai n and bl ood pr essur e.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Because mor phi ne i ncr eases per i pher al vasodi l at i on and decr eases per i pher al
r esi st ance, i t can produce or t host at i c hypot ensi on and f ai nt i ng.
( b) Pat i ent s shoul d be moni t or ed f or hypot ensi on and si gns of r espi r at or y
depressi on.
( c) Mor phi ne has a vagomi met i c ef f ect t hat can pr oduce br adyar r hyt hmi as. Ì f ECG
moni t ori ng r eveal s excess bradycar di a, i t shoul d be r ever sed by admi ni st er i ng
at r opi ne ( 0. 5- 1 mg) .
( d) Nausea and vomi t i ng may occur , especi al l y wi t h i ni t i al doses, and pat i ent s must
be prot ect ed agai nst aspi r at i on of st omach cont ent s.
( e) Severe const i pat i on i s a pot ent i al probl em wi t h ongoi ng mor phi ne admi ni st rat i on.
The pat i ent may need t o use a Val sal va maneuver whi l e st r ai ni ng at t he st ool , whi ch
can pr oduce br adycardi a or can over l oad t he cardi ac syst em and t r i gger car di ac
ar r est . Docusat e (100 mg t wi ce dai l y) i s a usef ul pr ophyl act i c.
c. Oxygen i s r equi red at 2- 4 L/ mi n vi a nasal cannul a i n any pat i ent who has chest
pai n and who may be i schemi c. Mi l d hypoxemi a i s common i n acut e MÌ pat i ent s.
Ì ncreasi ng t he oxygen cont ent of t he bl ood, t hus i mpr ovi ng oxygenat i on of t he
myocar di um, i s a t op pri or i t y as cont i nui ng hypoxi a rapi dl y i ncreases myocar di al
damage.
d. ThromboI yt i c agents have not demonst rat ed benef i ci al cl i ni cal out comes i n t he
absence of STEMÌ . St udi es car ri ed out t o dat e have f ai l ed t o show benef i t wi t h
usi ng t hr ombol yt i cs i n UA ver sus st andar d t herapy t o pr event MÌ . Ì n addi t i on,
t hr ombol yt i c agent s act ual l y i ncr eased t he ri sk of MÌ i n such pat i ent s. Ther ef ore,
based on cur rent evi dence- based gui del i nes, t hrombol yt i c agent s are not
r ecommended i n t he management of ACS wi t hout ST- segment el evat i on.
3. Ant i pI ateI et and ant i coaguI at i on therapy. Tabl e 39- 5 l i st s sel ect ed agent s and
dosi ng r egi mens.
a. Cur rent evi dence- based cl i ni cal gui del i nes i ndi cat e cl ass Ì r ecommendat i ons f or
t he f ol l owi ng t herapeut i c i nt er vent i ons i n pat i ent s wi t h UA or NSTEMÌ :
( 1) Ant i pl at el et t her apy shoul d be i ni t i at ed pr ompt l y. Aspi r i n shoul d be admi ni st er ed
as soon as possi bl e af t er pr esent at i on and cont i nued i ndef i ni t el y.
( 2) Cl opi dogr el shoul d be admi ni st ered t o hospi t al i zed pat i ent s who are unabl e t o
t ake aspi r i n because of hyper sensi t i vi t y or maj or gast r oi nt est i nal i nt ol er ance.
( 3) Ì n hospi t al i zed pat i ent s f or whom an earl y noni nt er vent i onal approach i s
pl anned, cl opi dogrel shoul d be added t o aspi ri n as soon as possi bl e on admi ssi on
and admi ni st ered f or at l east 1 mont h and i deal l y up t o 1 year .
( 4) Ì n pat i ent s f or whom a percut aneous coronar y i nt er vent i on ( car di ac
cat het er i zat i on) i s pl anned, cl opi dogr el shoul d be st ar t ed wi t h a l oadi ng dose of
300-600 mg f ol l owed by 75 mg dai l y f or at l east one mont h but i deal l y up t o 1 year
i n pat i ent s who ar e not at hi gh ri sk f or bl eedi ng, or an i nt r avenous Gl ycopr ot ei n
Ì Ì b/ Ì Ì Ì a i nhi bi t or ( GP Ì Ì b/ Ì Ì Ì a) . Abci xi mab i s i ndi cat ed onl y i f t her e i s no appr eci abl e
del ay t o angi ogr aphy and PCÌ i s l i kel y t o be per f or med; ot her wi se, Ì V ept i f i bat i de or
t i r of i ban i s t he pr ef er red choi ce of GP Ì Ì b/ Ì Ì Ì a i nhi bi t or . Ì n pat i ent s unabl e t o t ake
cl opi dogrel , t i cl opi di ne, 500 mg l oad f ol l owed by 250 mg or al l y dai l y i s an
al t er nat i ve.
( 5) Ì n pat i ent s t aki ng cl opi dogr el i n whom el ect i ve cor onar y ar t er y bypass gr af t i ng
( CABG) i s pl anned, t he dr ug shoul d be wi t hhel d f or 5-7 days.
P. 815


P. 816


P. 817


Table 39-5. Select Antiplatelet/anticoagulant Agents Used in the Treatment of
STEMI Patients
Class/Agent
Dosing
Regimen
Level of Evidence
(Guidelines)
Oral antiplatelets/anticoagulants
Aspirin
*
For Acute STEMI patients:

162 mg should be chewed by
patients who have not taken
aspirin beIore presentation with
STEMI.
Class I

For all post-PCI STEMI
stented patients:


1. 162-325 mg daily Ior
at least 1 month aIter
bare-metal stent
implantation. 3
months aIter
sirolimus-eluting
stent. and 6 months
aIter paclitaxel-eluting
stent. and then
indeIinitely at doses oI
75-132 mg daily.
Class IIa

2. In patients where there
is concern oI bleeding.
75 to 162 mg (lower-
dose) aspirin is
reasonable during the
initial period aIter
stent implantation.
Class IIa
Clopidogrel
(Plavix)
1. 75 mg orally daily
added to ASA in
STEMI patients.
Class I-Post STEMI
patients

2. Treatment should be
at least 14 days.
Class I-Post STEMI
patients
3. Loading dose oI 300 Class IIa-Post
mg orally (patients
·75 years who receive
Iibrinolytic therapy or
who do not receive
reperIusion therapy)
STEMI patients

4. 75 mg orally per day.
long-term
maintenance therapy
(e.g.. 1 year)
(regardless oI whether
they undergo
reperIusion with
Iibrinolytic therapy).
Class IIa-Post
STEMI patients

For all post-PCI STEMI
stented patients:


5. Receive a drug-eluting
stent (DES).
clopidogrel 75 mg
daily should be given
Ior at least 12 months
iI patients are not at
high risk oI bleeding.
Class I

6. Receive a bare metal
stent (BMS).
clopidogrel should be
given Ior a minimum
oI 1 month and ideally
up to 12 months
(unless the patient is at
increased risk oI
bleeding; then it
should be given Ior a
minimum oI 2 weeks).
Class I

7. For patients taking
clopidogrel Ior whom
CABG is planned. iI
possible. the drug
should be withheld Ior
Class I
at least 5 days. and
preIerably Ior 7.
unless the urgency Ior
revascularization
outweighs the risks oI
bleeding.
WarIarin 1. Managing warIarin to
INR ÷ 2.0 to 3.0 in
post-STEMI patients
Use oI warIarin in
coniunction with
aspirin and/or
clopidogrel is
associated with
increased risk oI
bleeding and should
be monitored closely.
Class I-Post-STEMI
patients

2. In patients requiring
warIarin. clopidogrel.
and aspirin therapy. an
INR oI 2 to 2.5 is
recommended with
low dose aspirin (75 to
81 mg) and a 75 mg
dose oI clopidogrel.

Parenteral antiplatelets/anticoagulants
Heparin
(UFH)
1. Bolus oI 60 U/kg.
maximum 4000 U IV
Iollowed by an initial
inIusion 12 U/kg per
hour. (maximum oI
1000 U/h) in patient at
high risk Ior systemic
emboli (large or
anterior MI. atrial
Iibrillation. previous
embolus. known LV
thrombus. or
cardiogenic shock.
Class I-Post STEMI

2. IV or SQ UFH or with
subcutaneous LMWH
Ior at least 48 hours.
In patients whose
clinical condition
necessitates prolonged
bedrest and/or
minimized activities.
it is reasonable that
treatment be continued
until the patient is
ambulatory.
Class IIa-Post-
STEMI and not
undergoing
reperIusion. and no
contraindications.

3. SQ UFH. 7.500 units
to 12.500 units twice
daily Ior prophylaxis
Ior deep venous
thrombosis (DVT)
until completely
ambulatory. may be
useIul. but the
eIIectiveness oI such a
strategy is not well
established in the
contemporary era oI
routine aspirin use and
early mobilization.
Class IIb

For STEMI patients receiving
PCI:


4. Bolus oI 70-100 U/kg.
and maintenance to
target 1.5-2 times
aPTT. iI no GP
IIb/IIIa previously
given. However. iI a
GP IIb/IIIa has been
given previously. 50-
70 U/kg bolus. and
maintenance to target.
as above.
Class I
Enoxaparin
(Lovenox)
Patients undergoing
reperfusion with fibrinolytics:


For patients less than 75 years
of age:


1. 30 mg intravenous
bolus. Iollowed in 15
minutes by 1.0 mg/kg
SQ every 12 hours
(serum creatinine ·2.5
mg per dL in men and
2.0 mg per dL in
women).
Class I-Post-STEMI
For patients >75 years of age.

2. 0.75 mg/kg SQ every
12 hours. (No loading
dose) Maintenance
doses with enoxaparin
should continue Ior
the duration oI the
index hospitalization.
up to 8 days.
Regardless oI age. iI
the creatinine
clearance (using the
CockroIt-Gault
Iormula) during the
course oI treatment is
estimated to be less
than 30 mL per
minute. the
subcutaneous regimen
is 1.0 mg per kg every
24 hours.
Class I-Post-STEMI
Fondaparinux
(Arixtra)
Patients undergoing
reperfusion with fibrinolytics:

1. 2.5 mg IV. Iollowed Class I-Post STEMI
by 2.5 mg SQ once
daily. (serum
creatinine is less than
3.0 mg per dL)

2. Maintenance doses
with Iondaparinux
should be continued
Ior the duration oI the
index hospitalization.
up to 8 days.
Class I-Post STEMI
Bivalirudin
(Angiomax)
Patients undergoing PCI:


1. Initial IV bolus dose
oI 0.75 mg/kg.
Iollowed by 1.75
mg/kg/hour inIusion
Ior the duration oI the
procedure.
Class I-Post STEMI
Abciximab
(Reopro)
0.25 mg/kg IV bolus Iollowed
by inIusion oI 0.125
mcg/kg/min Ior 12-24 hours
Class IIa. Ior use in
addition to aspirin
and heparin in
STEMI patients Ior
whom
catheterization and
PCI are planned iust
beIore PCI

Class III. in STEMI
patients Ior whom
PCI is not planned
EptiIibatide
(Integrilin)
180 mcg/kg IV bolus Iollowed
by inIusion oI 2.0
mcg/kg/minute Ior 72-96 hours.
Class I. Ior use in
addition to aspirin
and heparin in
STEMI patients Ior
whom
catheterization and
PCI are planned.
TiroIiban
(Aggrestat)
0.4 mcg/kg/minute Ior 30
minutes Iollowed by inIusion oI
0.1 mcg/kg/minute Ior 48-96
hours.
and in patients iust
beIore PCI.
Class IIa. in
addition to aspirin
and a LMWH or
UFH in STEMI
patients without
continuing ischemia
who have no other
high-risk Ieatures
and Ior whom PCI
is not planned.
Class IIb. in
addition to aspirin
and LMWH or UFH
in STEMI patients
without continuing
ischemia who have
no other high-risk
Ieatures and Ior
whom PCI is not
planned.
*
Assuming no aspirin resistance. allergy. or increased risk oI bleeding.
aPTT. activated partial thromboplastin time; CABG. coronary artery bypass
graIt; IV. intravenous; PCI. percutaneous coronary intervention; SQ.
subcutaneously.

P. 818


( 6) Ant i coagul ant t her apy shoul d be added t o ant i pl at el et t her apy i n UA/ NSTEMÌ
pat i ent s as soon as possi bl e af t er pr esent at i on. For pat i ent s i n whom an i nvasi ve
st r at egy i s sel ect ed, regi mens wi t h est abl i shed ef f i cacy wi t h a hi gh l evel of
evi dence i ncl ude enoxapar i n and hepari n, and t hose wi t h a l esser l evel of
est abl i shed evi dence i ncl ude bi val i rudi n and f ondapari nux. For pat i ent s i n whom a
conser vat i ve st r at egy i s sel ect ed, r egi mens usi ng ei t her enoxapari n or hepar i n or
f ondapar i nux can be ut i l i zed. Ì n pat i ent s i n whom a conser vat i ve st r at egy i s
sel ect ed and who have an i ncr eased ri sk of bl eedi ng, f ondapari nux i s pr ef er abl e.
( 7) A pl at el et gl ycopr ot ei n Ì Ì b/ Ì Ì Ì a ant agoni st shoul d be admi ni st ered, i n addi t i on t o
aspi r i n and hepar i n, t o pat i ent s f or whom cat het er i zat i on and PCÌ are pl anned. The
agent may al so be admi ni st er ed j ust bef or e PCÌ .
b. Cur rent evi dence- based cl i ni cal gui del i nes i ndi cat e a cl ass Ì Ì a r ecommendat i on
f or t he f ol l owi ng t herapeut i c i nt er vent i ons i n pat i ent s wi t h UA or NSTEMÌ :
( 1) For pat i ent s i n whom an i ni t i al conser vat i ve st r at egy i s sel ect ed and who have
r ecur r ent i schemi c di scomf ort wi t h cl opi dogrel , ASA, and ant i coagul ant t her apy, i t i s
accept abl e t o add a GP Ì Ì b/ Ì Ì Ì a ant agoni st bef or e di agnost i c angi ogr aphy.
( 2) For pat i ent s i n whom an i ni t i al i nvasi ve st r at egy i s sel ect ed, i t i s reasonabl e t o
i ni t i at e ant i pl at el et t her apy wi t h bot h cl opi dogrel ( l oadi ng dose f ol l owed by dai l y
mai nt enance dose) and an i nt r avenous GP Ì Ì b/ Ì Ì Ì a i nhi bi t or . Abci xi mab i s i ndi cat ed
onl y i f t her e i s no appr eci abl e del ay t o angi ogr aphy and PCÌ i s l i kel y t o be
per f or med; ot her wi se, Ì V ept i f i bat i de or t i rof i ban i s t he pr ef er r ed choi ce of GP
Ì Ì b/ Ì Ì Ì a i nhi bi t or .
( 3) For pat i ent s i n whom an i ni t i al i nvasi ve st r at egy i s sel ect ed, i t i s reasonabl e t o
omi t admi ni st rat i on of an i nt ravenous GP Ì Ì b/ Ì Ì Ì a ant agoni st bef ore di agnost i c
angi ography i f bi val i r udi n i s sel ect ed as t he ant i coagul ant and at l east 300 mg of
cl opi dogrel was admi ni st er ed at l east 6 h ear l i er t han pl anned cat het er i zat i on or
PCÌ .
c. Cur rent evi dence- based cl i ni cal pract i ce gui del i nes i ndi cat e a cl ass Ì Ì b
r ecommendat i on f or t he f ol l owi ng t herapeut i c i nt er vent i on i n pat i ent s wi t h UA or
NSTEMÌ : Ept i f i bat i de or t i r of i ban, i n addi t i on t o aspi ri n and LMWH or UFH, t o
pat i ent s wi t hout cont i nui ng i schemi a who have no ot her hi gh- r i sk f eat ur es and f or
whom PCÌ i s not pl anned.
d. Cur rent evi dence- based cl i ni cal pract i ce gui del i nes i ndi cat e a cl ass Ì Ì Ì
r ecommendat i on f or t he f ol l owi ng t herapeut i c i nt er vent i ons i n pat i ent s wi t h UA or
NSTEMÌ :
( 1) The ri sks associ at ed wi t h par ent eral l y admi ni st er ed t hrombol yt i c t her apy i n
pat i ent s wi t hout acut e STEMÌ ar e much great er t han t he benef i t s and shoul d not be
used.
( 2) The ri sks associ at ed wi t h t he admi ni st r at i on of abci xi mab i n pat i ent s f or whom
PCÌ i s not pl anned are much gr eat er t han t he benef i t s and shoul d not be used.
H. STEMI
1. Of t he more t han 1. 5 mi l l i on pat i ent s admi t t ed t o hospi t al s wi t h acut e cor onar y
syndr omes ( ACS) each year , more t han 300, 000 of t hem wi l l be di agnosed wi t h
STEMÌ . Appr oxi mat el y 90% of t hose di agnosed wi t h STEMÌ wi l l have compl et e
occl usi on of t he i nf ar ct - rel at ed ar t er y by a t hombus.
2. When t he l esi on r upt ur es, i t t r i ggers t he r el ease of adenosi ne di phosphat e ( ADP),
ser ot oni ns, and t hromboxane A2, whi ch l eads t o pl at el et aggregat i on and t he
f or mat i on of t he pr i mar y cl ot . Thr ombopl ast i n, r el eased f r om t he i nj ur ed vessel
i ni t i at es t he cl ot t i ng cascade, and t he r esul t i ng f i br i n, t r aps r ed bl ood cel l s ( RBCs) ,
pl at el et s, and pl asma prot ei n t o f or m an i nt r al umi nal t hr ombus. The subsequent cl ot
di ssol ut i on i s caused by t he conver si on of pl asmi nogen t o pl asmi n, whi ch i s
medi at ed by pl asmi nogen act i vat or s.
3. Accor di ng t o updat ed management gui del i nes ( see Ì . D. 6. ) , al l pat i ent s wi t h
STEMÌ shoul d recei ve ei t her pr i mar y percut aneous coronar y i nt er vent i on ( PCÌ ) ,
wi t hi n 90 mi nut es of f i r st medi cal cont act ( Cl ass Ì A r ecommendat i on) or f i br i nol yt i c
t her apy wi t hi n 30 mi nut es of hospi t al pr esent at i on i f t hey cannot be t ransf er r ed t o a
PCÌ cent er and under go PCÌ wi t hi n 90 mi n of f i r st medi cal cont act , unl ess
f i bri nol yt i c t her apy i s cont r ai ndi cat ed ( Cl ass Ì B) r ecommendat i on.
4. Ì t i s beyond t he r eal m of t hi s t ext t o expand on t he cl i ni cal i mpl i cat i ons f or
pr i mar y PCÌ , f aci l i t at ed PCÌ , and rescue PCÌ , as descr i bed i n t he most recent 2007
Focused STEMÌ gui del i nes. Consequent l y t he revi ew wi l l f ocus st r i ct l y on t he
pharmacol ogi c agent s recommended f or use i n t he STEMÌ pat i ent popul at i on, whi ch
i ncl ude; f i br i nol yt i cs, anal gesi cs, ant i coagul ant s, t hi enopyr i di nes, ant i pl at el et s, ACE
i nhi bi t ors, ARBs, and 8-adr ener gi c r ecept or bl ocker s
P. 819

as ei t her pr i mar y t reat ment or secondar y prevent i ve and l ong- t erm management , as
di scussed i n t he gui del i nes.
a. Fi bri noI yt i cs. Admi ni st r at i on of t hr ombol yt i c agent s causes t he t hrombus cl ot t o
be l ysed when admi ni st er ed ear l y af t er sympt om onset (< 6-12 hr ) and t o r est or e
bl ood f l ow. The conversi on of pl asmi nogen t o pl asmi n pr omot es f i br i nol ysi s and
br eakdown of t he cl ot .
( 1) I ndi cat i ons
( a) Thr ombol yt i c agent s wer e used i n pat i ent s wi t h STEMÌ wi t h chest pai n < 6- 12 hr.
Successf ul earl y r eper f usi on has been shown t o r educe i nf ar ct si ze, i mprove
vent r i cul ar f unct i on, and i mprove mor t al i t y. However , benef i t s may be seen i n
pat i ent s usi ng t hrombol yt i c t her apy as l at e as 12 hr af t er pai n st art s.
( b) Ì nt r avenous admi ni st r at i on of a r ecombi nant t i ssue-pl asmi nogen act i vat or (t - PA)
such as al t epl ase ( Act i vase), a r ecombi nant pl asmi nogen act i vat or ( r - PA) such as
r et epl ase ( Ret avase), or t enect epl ase ( TNKase) , may r est or e bl ood f l ow i n an
occl uded ar t er y i f admi ni st ered wi t hi n 12 hr of an acut e MÌ , al t hough < 6 hr i s
opt i mal . The goal of t r eat ment of STEMÌ pat i ent s i s t o i ni t i at e t hr ombol yt i c t herapy
wi t hi n 30- 60 mi n of ar r i val i n an emergency r oom.
( i ) t - PA i s r el at i vel y f i br i n speci f i c and i s abl e t o l yse cl ot s wi t hout depl et i ng
f i bri nogen, and TNKase has an even gr eat er f i br i n speci f i ci t y. St rept oki nase
act i vat es t he f i bri nol yt i c syst em and has a great er l i kel i hood of causi ng syst emi c
ef f ect s t han t - PA. Thi s ef f ect may r esul t i n a great er degr ee of syst emi c bl eedi ng
compared wi t h t - PA, r - PA, and TNK.
( i i ) Though whi ch agent ÷t - PA, r - PA, and TNK÷i s best i s st i l l cont r oversi al , most
st udi es have shown t hat each agent , when used ear l y, can r eopen ( r eper f use)
occl uded cor onar y ar t er i es and r educe mor t al i t y f r om STEMÌ . However ,
consi derat i ons such as ease of use, onset of act i on, i nci dence of bl eed, and cost
ar e i mpor t ant f act ors i n det ermi ni ng whi ch agent t o use f or a gi ven hospi t al and
pat i ent .
( 2) I ndi vi duaI agents
( a) AI t epI ase ( Act i vase)
( i ) AbsoI ute cont rai ndi cat i ons t o t - PA i ncl ude act i ve i nt ernal bl eedi ng; r ecent
cer ebr ovascul ar acci dent ( CVA) ; i nt racrani al neopl asm; aneur ysm; pregnancy;
ar t eri ovenous mal f ormat i ons; r ecent ( wi t hi n 2 mont hs) i nt r acr ani al surgery, spi nal
sur ger y, or t r auma; and sever e uncont r ol l ed hyper t ensi on, bl eedi ng di at hesi s, or
hemor r hagi c opht hal mi c condi t i ons.
( i i ) A f ront - I oaded regi men÷an accel er at ed i nf usi on t hat consi st s of a t ot al dose of
100 mg or l ess t hat i s gi ven over 1. 5 hr ÷may be more benef i ci al . The i ni t i al dose of
15 mg i s gi ven as an Ì V bol us, 1- 2 mi n, whi l e an i nf usi on i s begun t o:
( a) Ì nf use t - PA at t he rat e of 0. 75 mg/ kg over 30 mi n ( not t o exceed 50 mg)
( b) Fol l owed by t - PA i nf used at 0. 5 mg/ kg over 60 mi n ( not t o exceed 35 mg)
( i i i ) An al t ernat e dosi ng r egi men i s based on t he pat i ent ' s wei ght .
( a) Dosage f or pat i ent s > 65 kg. A t ot al of 100 mg of t - PA i s gener al l y
admi ni st er ed t o al l pat i ent s who wei gh > 65 kg over a 3-hr per i od. Though many
r egi mens have been used, general l y speaki ng, 6-10 mg of t - PA i s gi ven as an Ì V
bol us over 1-2 mi n, f ol l owed by t he remai ni ng i nf usi on rat es over t he next 3 hr: a
54- 60- mg Ì V i nf usi on over t he 1st hr , a 20- mg Ì V i nf usi on over t he 2nd hr, and a 20-
mg Ì V i nf usi on over t he 3r d hr .
( b) Dosage f or pat i ent s < 65 kg. A dose of 1. 25 mg/ kg i s gi ven over a 3-hr per i od,
wi t h 10% of t he t ot al dose gi ven i ni t i al l y as a bol us dose over 1-2 mi n.
( b) Ret epI ase ( Ret avase)
( i ) AbsoI ute cont rai ndi cat i ons t o ret epl ase ar e si mi l ar t o t hose f or t - PA, t hough
addi t i onal caut i onar y st at ement s are gi ven f or pat i ent s wi t h sever el y i mpai r ed r enal
f unct i on or l i ver f unct i on.
( i i ) Dosi ng i s i ni t i at ed wi t h t he i nt r avenous admi ni st r at i on of 10 U over a 2- mi n
per i od, and t hen r epeat ed af t er 30 mi n, i f t her e ar e no compl i cat i ons.
P. 820


( c) Tenect epI ase ( TNKase)
( i ) AbsoI ute cont rai ndi cat i ons t o t enect epl ase ar e si mi l ar t o t hose f or t -PA and r -
PA wi t h t he f ol l owi ng addi t i on: use wi t h caut i on i n pat i ent s r ecent l y recei vi ng a
gl ycopr ot ei n Ì Ì b/ Ì Ì Ì a agent , pr egnant pat i ent s, el der l y pat i ent s, pat i ent s wi t h
endocar di t i s, and pat i ent s wi t h sever e l i ver di sease.
( i i ) Tenect epl ase i s approved f or use i n acut e t r eat ment of MÌ at doses of 30- 50 mg
( based on t he pat i ent ' s wei ght ) as a si ngl e Ì V bol us over 10- 15 sec. Rapi d r at e of
admi ni st rat i on, f i br i n speci f i ci t y, f ewer bl eedi ng compl i cat i ons compar ed t o t - PA,
and superi or i t y over t - PA i n l at e- t r eat ed pat i ent s make t enect epl ase a l i kel y
candi dat e t o r epl ace t - PA as t he agent of choi ce i n STEMÌ .
( 3) Adj uncti ve f i bri noI ysi s therapy. The r ecent l y r el eased 2007 Focused
Gui del i nes f or ST- segment el evat ed MÌ di scuss t he use of anal gesi a, 8-adr energi c
r ecept or bl ocker s, ant i coagul ant s, and t hi enopyri di nes, i n STEMÌ pat i ent s based on
t he qual i t y of avai l abl e l i t er at ur e f or t hei r use.
( a) Anal gesi a
( i ) Mor phi ne sul f at e i n doses of 2-4 mg Ì V i n i ncrement s of 2- 8 mg Ì V, r epeat ed i n 5-
15 mi nut e i nt er val s i s t he anal gesi c of choi ce f or t he management of pai n due t o
STEMÌ ( Cl ass Ì C)
( i i ) Pat i ent s t aki ng NSAÌ Ds wi t h t he except i on of aspi r i n, bef or e bei ng t r eat ed f or
STEMÌ shoul d st op t aki ng t hem due t o i ncr eased r i sk of mor t al i t y, r ei nf ar ct i on,
hyper t ensi on, hear t f ai l ur e, and myocar di al r upt ur e associ at ed wi t h t hei r use ( Cl ass
Ì C)
( b) Aspi ri n admi ni st er ed ( 160- 325 mg) dur i ng acut e t hr ombol yt i c t herapy has been
shown t o af f ect t hr ombol ysi s posi t i vel y by pr event i ng pl at el et aggr egat i on and has
r educed post i nf ar ct mor t al i t y. Doses of aspi ri n, 75- 162 mg dai l y have been
r ecommended f or l ong-t er m use at hospi t al di schar ge. Ot her agent s i ncl ude
t i cl opi di ne ( Ti cl i d), and cl opi dogr el ( Pl avi x) .
( c) ß- Adrenergi c bI ockers
( i ) Or al 8- bl ocker t her apy shoul d be gi ven dur i ng t he f i rst 24 hours t o STEMÌ
pat i ent s not havi ng (a) si gns of hear t f ai l ur e, ( b) evi dence of a l ow out put st at e, ( c)
i ncreased r i sk f or car di ogeni c shock, or ot her cont r ai ndi cat i ons t o r ecei vi ng 8-
bl ocker s ( Cl ass Ì B) .
( i i ) Pat i ent s who may i ni t i al l y present wi t h cont rai ndi cat i ons t o r ecei vi ng 8- bl ocker s
dur i ng t he i ni t i al 24 hours of t hei r STEMÌ shoul d be r eeval uat ed f or recei vi ng such
t her apy as a secondar y pr event i ve measure ( Cl ass Ì C) .
( i i i ) Pat i ent s wi t h moderat e or sever e l ef t vent r i cul ar f ai l ure shoul d r ecei ve 8-
bl ocker t her apy as a secondar y pr event i ve measur e, but wi t h a gr adual dose
escal at i on t i t rat i on ( Cl ass Ì B) .
( i v) Ì t i s reasonabl e t o admi ni st er an Ì V 8-bl ocker t o a STEMÌ pat i ent at t he t i me of
pr esent at i on i f t hey have hyper t ensi on and do not have any of t he above
cont r ai ndi cat i ons t o r ecei vi ng t hem ( Cl ass Ì Ì a).
( v) Ì V 8- bl ockers shoul d not be used i n STEMÌ pat i ent s who have any of t he above
ment i oned cont rai ndi cat i ons t o t hei r use as t he ri sk i s much great er t han or equal t o
t hei r benef i t i n t hese pat i ent s ( Cl ass Ì Ì Ì A).
( d) Ant i coaguI ant s
( i ) Pat i ent s who under go r eper f usi on wi t h f i bri nol yt i cs shoul d recei ve ant i coagul ant
t her apy f or at l east 48 hour s, and i deal l y t hroughout t he hospi t al i zat i on, up t o 8
days ( Cl ass Ì C) .
( i i ) Pat i ent s who r ecei ve ant i coagul ant s f or mor e t han 48 hour s shoul d recei ve an
agent ot her t han unf ract i onat ed hepar i n ( UFH) due t o t he i ncreased r i sk of hepar i n-
i nduced t hr ombocyt openi a wi t h i t s pr ol onged use ( Cl ass Ì A) .
( i i i ) Ant i coagul ant r egi mens wi t h est abl i shed ef f i cacy i n STEMÌ i ncl ude:
• ÷Unf r act i onat ed hepari n ( UFH) : Ì ni t i al Ì V bol us of 60 uni t s per kg (maxi mum
4, 000 uni t s) f ol l owed by an Ì V i nf usi on of 12 uni t s/ kg/ hour ( maxi mum of
1, 000 uni t s/ hour) i ni t i al l y. The dose shoul d be adj ust ed t o mai nt ai n an
act i vat ed par t i al t hr ombopl ast i n t i me ( aPTT) of 1. 5- 2 t i mes cont rol ( Cl ass
Ì C) .
• ÷Enoxapar i n: An i ni t i al 30 mg Ì V bol us, f ol l owed i n 15 mi nut es by a
subcut aneous i nj ect i on of 1 mg/ kg ever y 12 hours ( assumi ng serum
cr eat i ni ne i s l ess t han 2. 5 mg/ dL i n men, 2. 0 mg/ dL i n women i n pat i ent s
l ess t han
P. 821

75 years of age). For pat i ent s 75 year s of age and ol der , t he Ì V bol us dose
i s el i mi nat ed and t he pat i ent i s gi ven a subcut aneous dose of 0. 75 mg per kg
ever y 12 hours. CAUTÌ ON: Ì n al l pat i ent s, i f t he cr eat i ni ne cl ear ance i s
est i mat ed t o be l ess t han 30 mL per mi nut e, t he dosi ng r egi men shoul d be
changed t o 1 mg per kg ever y 24 hours. The cur rent gui del i nes r ecommend
t he use of mai nt enance dosi ng of enoxapar i n f or t he durat i on of
hospi t al i zat i on, up t o a maxi mum of 8 days ( Cl ass Ì A) .
• ÷Fondapar i nux: An i ni t i al dose of 2. 5 mg i nt ravenousl y and subsequent
subcut aneous i nj ect i ons of 2. 5 mg gi ven once dai l y ( assumi ng serum
cr eat i ni ne i s l ess t han 3. 0 mg/ dL) . The curr ent gui del i nes, as i n t he case of
enoxapar i n, recommend t he use of mai nt enance dosi ng of f ondapari nux f or
t he dur at i on of hospi t al i zat i on, up t o a maxi mum of 8 days ( Cl ass Ì B) .
( i v) Ant i coagul ant s have al so been shown t o be ef f ect i ve i n STEMÌ pat i ent s pr i or t o
under goi ng PCÌ , wi t h t he f ol l owi ng dosi ng recommendat i ons:
• ÷UFH: For pri or t r eat ment , admi ni st er addi t i onal bol uses of UFH as needed
t o suppor t t he procedure, but t ake i nt o account whet her ot her agent s such as
GP Ì Ì b/ Ì Ì Ì a r ecept or ant agoni st s ( Cl ass Ì C) . Bi val i r udi n can al so be used i n
pat i ent s pr evi ousl y t r eat ed wi t h UFH ( Cl ass Ì C) .
• ÷Enoxapar i n ( Lovenox) : For pr i or t reat ment , i f t he l ast subcut aneous dose
of enoxapar i n was gi ven wi t hi n t he pr evi ous 8 hour s, no addi t i onal dr ug i s
needed; however , i f t he l ast dose was admi ni st ered 8-12 hour s earl i er , an
i nt ravenous dose of 0. 3 mg/ kg shoul d be gi ven (Cl ass Ì B) .
• ÷Fondapar i nux ( Ar i xt r a) : For pr i or t reat ment , admi ni st er addi t i onal
i nt ravenous t r eat ment wi t h an ant i coagul ant possessi ng ant i -Ì Ì a act i vi t y, but
t ake i nt o account whet her GP Ì Ì b/ Ì Ì Ì a r ecept or ant agoni st s have been
admi ni st er ed ( Cl ass Ì C). However , due t o t he r i sk of cat het er t hr ombosi s,
f ondapar i nux i s not r ecommended as t he sol e ant i coagul ant t o support PCÌ
and requi r es t he addi t i on of anot her ant i coagul ant wi t h ant i - Ì Ì a act i vi t y
( Cl ass Ì Ì Ì C) .
( v) Ant i coagul ant s (non-UFH r egi mens) have al so been recommended f or pat i ent s
wi t h STEMÌ who do not undergo reper f usi on t herapy f or t he durat i on of t he i ni t i al
hospi t al i zat i on ( Cl ass Ì Ì a) . Dosi ng r egi mens t hat can be used i ncl ude enoxapar i n or
f ondapar i nux i n t he same dosi ng regi mens as i n t hose pat i ent s recei vi ng f i bri nol yt i c
( see i v above) .
( e) Thi enopyri di nes
( i ) Cl opi dogrel ( Pl avi x) shoul d be added t o aspi r i n i n STEMÌ pat i ent s regar dl ess of
whet her t hey undergo reper f usi on wi t h f i br i nol yt i cs or do not recei ve reper f usi on
( Cl ass Ì B) . Doses of 75 mg by mout h dai l y shoul d be admi ni st ered. Tr eat ment
shoul d cont i nue f or at l east 14 days ( Cl ass Ì B) .
( i i ) Pat i ent s r ecei vi ng cl opi dogrel ( Pl avi x) who are pl anni ng on undergoi ng CABG
shoul d di scont i nue t her apy 5- 7 days pr i or t o t he sur ger y, unl ess t he ur gency of t he
pr ocedur e out wei ghs t he r i sks of excess bl eedi ng ( Cl ass Ì B) .
( i i i ) Pat i ent s l ess t han 75 years r ecei vi ng f i br i nol yt i c t herapy or who do not r ecei ve
r eperf usi on t her apy, i t i s r easonabl e t o admi ni st er an or al cl opi dogrel l oadi ng dose
of 300 mg. ( No dat a are avai l abl e t o gui de deci si on maki ng r egardi ng an or al
l oadi ng dose i n pat i ent s <75 years of age. ) ( Cl ass Ì Ì a) .
( i v) Long- t erm mai nt enance t her apy (e. g. , 1 year) wi t h cl opi dogr el ( 75 mg per day
or al l y) can be usef ul i n STEMÌ pat i ent s r egar dl ess of whet her t hey undergo
r eperf usi on wi t h f i bri nol yt i c t her apy or do not recei ve r eperf usi on t her apy ( Cl ass
Ì Ì a) .
( 4) Secondar y Prevent i on and Long- Ter m Management : ( a) Tabl e 39-2 provi des a
combi nat i on of r i sk f act or s as wel l as di sease- based r ecommendat i ons, whi ch have
been i ncor porat ed i nt o t he r ecent l y updat ed 2007 Focused Gui del i nes f or STEMÌ
pat i ent s. Addi t i onal l y, t he gui del i nes i ncl ude recommendat i ons made f or sel ect
pharmacol ogi c agent s whi ch i ncl ude aspi r i n, cl opi dogr el , war f ar i n, ACE i nhi bi t ors,
angi ot ensi n r ecept or bl ocker s, al dost er one bl ockade, and 8- bl ocker s, and i nf l uenza
vacci nat i on.
( a) Aspi ri n
( i ) For al l post - PCÌ STEMÌ pat i ent s recei vi ng a st ent ( bare met al , si r ol i mus,
pacl i t axel ) , wi t hout cont rai ndi cat i ons t o aspi r i n, shoul d recei ve aspi r i n 162 t o 325
mg dai l y f or 1- 6 mont hs dependi ng on t he t ype of st ent used. Af t er t he
P. 822

i ni t i al 1-6 mont hs a mai nt enance dose of aspi r i n shoul d be cont i nued at a dose of
75 t o 162 mg dai l y, i ndef i ni t el y ( Cl ass Ì B) .
( i i ) Ì n t hose pat i ent s wher e t here i s concern f or a hi gh ri sk of bl eedi ng, doses of
aspi r i n, 75 mg t o 162 mg dai l y i s r easonabl e dur i ng t he i ni t i al per i od and af t er st ent
i mpl ant at i on ( Cl ass Ì Ì a) .
( b) CI opi dogreI ( PI avi x)
( i ) For al l post - PCÌ pat i ent s who recei ve a drug-el ut i ng st ent ( si r ol i mus, pacl i t axel ) ,
cl opi dogrel 75 mg dai l y shoul d be gi ven f or at l east 12 mont hs i f pat i ent s ar e not at
hi gh r i sk of bl eedi ng ( Cl ass Ì B) .
( i i ) For post - PCÌ pat i ent s r ecei vi ng a bar e met al st ent cl opi dogrel shoul d be gi ven
f or a mi ni mum of 1 mont h and i deal l y up t o 12 mont hs (unl ess t he pat i ent i s at
i ncreased r i sk of bl eedi ng; t hen i t shoul d be gi ven f or a mi ni mum of 2 weeks) ( Cl ass
Ì B) .
( i i i ) For al l STEMÌ pat i ent s not under goi ng st ent i ng ( medi cal t herapy al one or PTCA
wi t hout st ent i ng) , t r eat ment wi t h cl opi dogr el shoul d cont i nue f or at l east 14 days
( Cl ass Ì B) .
( i v) Long- t erm mai nt enance t her apy (e. g. , 1 year) wi t h cl opi dogr el ( 75 mg per day
or al l y) i s r easonabl e i n STEMÌ pat i ent s r egar dl ess of whet her t hey undergo
r eperf usi on wi t h f i bri nol yt i c t her apy or do not recei ve r eperf usi on t her apy ( Cl ass
Ì Ì a) .
( c) Warfari n
( i ) Managi ng war f ari n t o an Ì NR = 2. 0 t o 3. 0 i n post - STEMÌ pat i ent s when cl i ni cal l y
i ndi cat ed ( e. g. , at ri al f i bri l l at i on, l ef t vent r i cul ar t hr ombus) and paroxysmal or
chr oni c at r i al f i bri l l at i on or f l ut t er , i s r ecommended ( Cl ass Ì A) .
( i i ) Use of war f ar i n i n conj unct i on wi t h aspi r i n and/ or cl opi dogr el i s associ at ed wi t h
i ncreased r i sk of bl eedi ng and shoul d be moni t ored cl osel y ( Cl ass Ì B) .
( i i i ) Pat i ent s requi r i ng war f ari n, cl opi dogr el , and aspi r i n t her apy, an Ì NR of 2 t o 2. 5
i s recommended wi t h l ow- dose aspi r i n ( 75 t o 81 mg) and a 75 mg dose of
cl opi dogrel ( Ì C) .
( d) ACE I nhi bi tors (see Tabl e 41- 4 f or I i st i ng of avai I abI e agent s)
( i ) ACE i nhi bi t ors shoul d be st ar t ed and cont i nued i ndef i ni t el y i n al l pat i ent s
r ecoveri ng f rom STEMÌ wi t h LVEF >40% and i n t hose pat i ent s wi t h hypert ensi on,
di abet es, or chroni c ki dney di sease, unl ess cont rai ndi cat ed ( Cl ass Ì A) .
( i i ) ACE i nhi bi t ors shoul d be st ar t ed and cont i nued i ndef i ni t el y i n pat i ent s
r ecoveri ng f rom STEMÌ who ar e not l ower r i sk ( l ower r i sk def i ned as t hose wi t h
nor mal LVEF i n whom car di ovascul ar r i sk f act or s ar e wel l cont r ol l ed and
r evascul ar i zat i on has been per f or med) , unl ess cont r ai ndi cat ed ( Cl ass Ì B).
( i i i ) Among l ower r i sk pat i ent s r ecover i ng f r om STEMÌ ( i . e. , t hose wi t h nor mal LVEF
i n whom car di ovascul ar ri sk f act or s ar e wel l cont rol l ed and r evascul ari zat i on has
been per f ormed) use of ACE i nhi bi t ors i s r easonabl e ( Cl ass Ì Ì a) .
( e) Angi ot ensi n Receptor BI ockers ( ARBs) ( see Tabl e 41-4 f or I i st i ng of
avai I abI e agents
( i ) ARBs ar e r ecommended i n pat i ent s who ar e i nt ol er ant of ACE i nhi bi t ors and have
had an STEMÌ wi t h LVEF >40% or have heart f ai l ur e ( Cl ass Ì A) .
( i i ) ARB t herapy i s benef i ci al i n ot her pat i ent s who ar e ACE- i nhi bi t or i nt ol er ant and
have hyper t ensi on ( Cl ass Ì B) .
( i i i ) Consi der i ng use i n combi nat i on wi t h ACE i nhi bi t ors i n syst ol i c dysf unct i on heart
f ai l ur e may be reasonabl e ( Cl ass Ì Ì b) .
( f ) AI dost erone BI ocki ng Agent s ( Spi ronoI actone- AI dact one, EpI erenone- I nspra)
( i ) Use of al dost erone bl ockade i n post - STEMÌ pat i ent s wi t hout si gni f i cant r enal
dysf unct i on or hyperkal emi a i s r ecommended i n pat i ent s who are al r eady recei vi ng
t her apeut i c doses of an ACE i nhi bi t or and bet a bl ocker, have an LVEF of >40% and
have ei t her di abet es or hear t f ai l ur e ( Cl ass Ì A) .
( g) ß- Adrenergi c BI ockers
( i ) Ì t i s benef i ci al t o st art and cont i nue 8-bl ocker t her apy i ndef i ni t el y i n al l pat i ent s
who have had an STEMÌ , acut e coronar y syndr ome, or l ef t vent r i cul ar dysf unct i on
wi t h or wi t hout heart f ai l ur e sympt oms, unl ess cont r ai ndi cat ed ( Cl ass Ì A).
P. 823


( h) I nfI uenza Vacci ne (FI uvi ri n, FI uMi st, Vari ous)
( i ) Pat i ent s wi t h car di ovascul ar di sease shoul d have an annual i nf l uenza vacci nat i on
( Cl ass Ì B) .
I . CompI i cat i ons. MÌ pot ent i at es many compl i cat i ons; t he most common of t hese
i ncl ude t he f ol l owi ng:
1. Let haI arrhyt hmi as. See Chapt er 40 f or a det ai l ed di scussi on.
2. Heart f ai I ure. See Chapt er 42 f or a det ai l ed di scussi on.
a. Lef t vent r i cul ar f ai l ure causes pul monar y congest i on. Di ur et i cs, especi al l y
f ur osemi de, hel p reduce t he congest i on.
b. ACE i nhi bi t ors, 8-adr ener gi c bl ockers, angi ot ensi n r ecept or bl ocker s, and di r ect -
act i ng al dost erone ant agoni st s pl ay a key rol e i n t he t r eat ment of heart f ai l ur e.
3. Cardi ogeni c shock
a. Ì n t hi s l i f e- t hr eat eni ng compl i cat i on, car di ac out put i s decreased and pul monar y
ar t er y and pul monar y capi l l ar y wedge pr essur es ar e i ncr eased. Thi s t ypi cal l y occurs
when t he ar ea of i nf arct i on exceeds 40% of muscl e mass and compensat or y
mechani sms onl y st r ai n t he al r eady compr omi sed myocar di um.
b. Vasopr essor s: f or exampl e, nor epi nephr i ne (Levophed) , epi nephri ne (Adr enal i n) ,
dopami ne ( hi gh doses) , and vasopr essi n ( Pi t ressi n, vari ous) -enhance bl ood
pr essure t hr ough 8- adrener gi c st i mul at i on and V1 r ecept ors ( vasopressi n) and may
be i ndi cat ed, as per ACLS pr ot ocol .
c. Ì not ropi c dr ugs÷f or exampl e, epi nephr i ne, dopami ne ( mi ddl e doses) , dobut ami ne,
i sopr ot er enol ( Ì suprel ), and di goxi n ( Lanoxi n) ÷are r api dl y act i ng agent s used t o
i ncrease myocar di al cont r act i l i t y and i mprove cardi ac out put .
d. Vasodi l at ors÷f or exampl e, ni t roprussi de ( Ni pri de) ÷reduce prel oad; t hey l ower
pul monar y capi l l ar y wedge pressure by di l at i ng vei ns and reduce af t er l oad by
decreasi ng resi st ance t o l ef t vent ri cul ar ej ect i on.
e. Addi t i onal t r eat ment may i ncl ude i nvasi ve procedur es such as i nt ra- aor t i c bal l oon
pumpi ng.
P. 824


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 16: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. Exert i on- i nduced angi na, whi ch i s reI i eved by rest , ni t rogI yceri n, or bot h, i s
ref erred t o as
( A) Pr i nzmet al angi na.
( B) unst abl e angi na.
( C) st abl e angi na.
( D) var i ant angi na.
( E) pr ei nf ar ct i on angi na.
Vi ew Answer 1. The answer i s C[ seeand] . 2. Myocardi aI oxygen demand i s
i ncreased by aI I of t he f oI I owi ng f act ors except
( A) exer ci se.
( B) smoki ng.
( C) col d t emperat ures.
( D) i soprot erenol .
( E) met opr ol ol .
Vi ew Answer 2. The answer i s E[see] . 3. Whi ch of t he f oI I owi ng agent s
used i n Pri nzmetaI angi na has spasmoI yt i c acti ons, whi ch i ncrease coronar y
bI ood suppI y?
( A) ni t r ogl yceri n
( B) di l t i azem
( C) t i mol ol
( D) i sosor bi de mononi t rat e
( E) pr opr anol ol
Vi ew Answer 3. The answer i s B[ see] . 4. Pat i ents wi t h angi na pectori s
recei vi ng propranoI oI pI us di I t i azem must be moni tored for whi ch adverse drug
ef f ect?
( A) decr eased cardi ac out put
( B) decr eased heart r at e
( C) i ncr eased heart r at e
( D) Bot h A and B
( E) Bot h A and C
Vi ew Answer 4. The answer i s D[ see] . 5. The deveI opment of i schemi c pai n
occurs when t he demand f or oxygen exceeds the suppI y. Det ermi nants of
oxygen demand i ncI ude aI I of t he f oI I owi ng choi ces except whi ch one?
( A) cont ract i l e st at e of t he hear t
( B) myocar di al ej ect i on t i me
( C) l ef t vent r i cul ar vol ume
( D) r i ght at r i al pr essur e
( E) syst ol i c pr essur e
Vi ew Answer 5. The answer i s D[ see] . 6. Myopat hy i s an adverse ef fect of
aI I t he f oI I owi ng agents except
( A) l ovast at i n.
( B) si mvast at i n.
( C) pr avast at i n.
( D) gemf i br ozi l .
( E) col est i pol .
Vi ew Answer 6. The answer i s E[see] . 7. Whi ch of t he f oI I owi ng wouI d not
represent current t herapeut i c opt i ons i n pati ent s present i ng wi t h acut e
coronar y syndrome ( ACS) who are cI assi f i ed as havi ng non- ST- segment
eI evat ed myocardi aI i nfarct i on ( NSTEMI ) ?
( A) subl i ngual ni t r ogl ycer i n
( B) 8- adrener gi c bl ockers
( C) aspi ri n
( D) morphi ne
( E) t enect epl ase
Vi ew Answer 7. The answer i s E[see] . P. 825


Di rect i ons for quest i ons 8- 9: The quest i ons and i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one or more of t he suggest ed
answer s. Choose t he answer , A- E.
For quest i ons 8- 9: A 55- year - ol d man ar ri ves i n t he emer gency room of t he l ocal
hospi t al appr oxi mat el y 6 hr af t er devel opi ng chest pai n wi t h t he si gns and sympt oms
of an acut e ST- segment el evat ed myocar di al i nf ar ct i on ( STEMÌ ) . Thi s i s t he second
such at t ack wi t hi n t he l ast 4 mont hs, and t he pat i ent has not al t er ed hi s l i f est yl e t o
el i mi nat e i mpor t ant ri sk f act or s. Pr evi ous t her apy i ncl uded a t hr ombol yt i c agent
( name unknown) , a bl ood t hi nner , and dai l y aspi ri n.
8. Whi ch of the foI I owi ng agents shouI d be recommended duri ng t he acut e
myocardi aI i nf arcti on to heI p prevent sudden deat h?
I . atenoI oI
I I . met oproI oI
I I I . aspi ri n
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 8. The answer i s E[see] . 9. Whi ch of t he f oI I owi ng i s
consi dered a component of acute coronar y syndrome ( ACS) ?
I . unst abI e angi na
I I . non- ST-segment eI evat ed myocardi aI i nfarct i on ( NSTEMI )
I I I . ST- segment eI evat ed myocardi aI i nfarct i on ( STEMI )
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 9. The answer i s E[see] . Di rect i ons f or questi ons 10- 14: Each
of t he f ol l owi ng descri pt i ons i s most cl osel y r el at ed t o one of t he f ol l owi ng dr ugs.
The descri pt i ons may be used more t han once or not at al l . Choose t he best
answer , A- E.
10. ti rof i ban
( A) Ì nhi bi t i on of i nt est i nal absorpt i on of chol est erol
( B) Lower i ng of l ow- densi t y l i popr ot ei ns (LDLs) , t r i gl ycer i des, and i ncr eased hi gh-
densi t y l i poprot ei n ( HDL) al ong wi t h ant i - i nf l ammat or y ef f ect s
( C) Recommendat i ons f or t hi s agent have been subst ant i al l y expanded beyond an
al t er nat i ve f or aspi r i n- i nt ol erant pat i ent s, due t o recent t r i al s demonst r at i ng i t s
benef i t i n sel ect ACS pat i ent s.
( D) Recommended f or acut e coronar y syndrome (ACS) pat i ent s who cannot t ol erat e
aspi r i n
( E) Recommended over unf r act i onat ed hepar i n (UFH) as an ant i coagul ant i n
pat i ent s wi t h unst abl e angi na ( UA) or non-ST- segment el evat ed myocar di al
i nf ar ct i on ( NSTEMÌ )
Vi ew Answer 10. The answer i s C[ see] . 11. enoxapari n
( A) Ì nhi bi t i on of i nt est i nal absorpt i on of chol est erol
( B) Lower i ng of l ow- densi t y l i popr ot ei ns (LDLs) , t r i gl ycer i des, and i ncr eased hi gh-
densi t y l i poprot ei n ( HDL) al ong wi t h ant i - i nf l ammat or y ef f ect s
( C) Recommendat i ons f or t hi s agent have been subst ant i al l y expanded beyond an
al t er nat i ve f or aspi r i n- i nt ol erant pat i ent s, due t o recent t r i al s demonst r at i ng i t s
benef i t i n sel ect ACS pat i ent s.
( D) Recommended f or acut e coronar y syndrome (ACS) pat i ent s who cannot t ol erat e
aspi r i n
( E) Recommended over unf r act i onat ed hepar i n (UFH) as an ant i coagul ant i n
pat i ent s wi t h unst abl e angi na ( UA) or non-ST- segment el evat ed myocar di al
i nf ar ct i on ( NSTEMÌ )
Vi ew Answer 11. The answer i s E[see] . 12. si mvast at i n
( A) Ì nhi bi t i on of i nt est i nal absorpt i on of chol est erol
( B) Lower i ng of l ow- densi t y l i popr ot ei ns (LDLs) , t r i gl ycer i des, and i ncr eased hi gh-
densi t y l i poprot ei n ( HDL) al ong wi t h ant i - i nf l ammat or y ef f ect s
( C) Recommendat i ons f or t hi s agent have been subst ant i al l y expanded beyond an
al t er nat i ve f or aspi r i n- i nt ol erant pat i ent s, due t o recent t r i al s demonst r at i ng i t s
benef i t i n sel ect ACS pat i ent s.
( D) Recommended f or acut e coronar y syndrome (ACS) pat i ent s who cannot t ol erat e
aspi r i n
( E) Recommended over unf r act i onat ed hepar i n (UFH) as an ant i coagul ant i n
pat i ent s wi t h unst abl e angi na ( UA) or non-ST- segment el evat ed myocar di al
i nf ar ct i on ( NSTEMÌ )
Vi ew Answer 12. The answer i s B[ see] . 13. cI opi dogreI
( A) Ì nhi bi t i on of i nt est i nal absorpt i on of chol est erol
( B) Lower i ng of l ow- densi t y l i popr ot ei ns (LDLs) , t r i gl ycer i des, and i ncr eased hi gh-
densi t y l i poprot ei n ( HDL) al ong wi t h ant i - i nf l ammat or y ef f ect s
( C) Recommendat i ons f or t hi s agent have been subst ant i al l y expanded beyond an
al t er nat i ve f or aspi r i n- i nt ol erant pat i ent s, due t o recent t r i al s demonst r at i ng i t s
benef i t i n sel ect ACS pat i ent s.
( D) Recommended f or acut e coronar y syndrome (ACS) pat i ent s who cannot t ol erat e
aspi r i n
( E) Recommended over unf r act i onat ed hepar i n (UFH) as an ant i coagul ant i n
pat i ent s wi t h unst abl e angi na ( UA) or non-ST- segment el evat ed myocar di al
i nf ar ct i on ( NSTEMÌ )
Vi ew Answer 13. The answer i s D[ see I I I . H. 3. e] . 14. ezeti mi be
( A) Ì nhi bi t i on of i nt est i nal absorpt i on of chol est erol
( B) Lower i ng of l ow- densi t y l i popr ot ei ns (LDLs) , t r i gl ycer i des, and i ncr eased hi gh-
densi t y l i poprot ei n ( HDL) al ong wi t h ant i - i nf l ammat or y ef f ect s
( C) Recommendat i ons f or t hi s agent have been subst ant i al l y expanded beyond an
al t er nat i ve f or aspi r i n- i nt ol erant pat i ent s, due t o recent t r i al s demonst r at i ng i t s
benef i t i n sel ect ACS pat i ent s.
( D) Recommended f or acut e coronar y syndrome (ACS) pat i ent s who cannot t ol erat e
aspi r i n
( E) Recommended over unf r act i onat ed hepar i n (UFH) as an ant i coagul ant i n
pat i ent s wi t h unst abl e angi na ( UA) or non-ST- segment el evat ed myocar di al
i nf ar ct i on ( NSTEMÌ )
Vi ew Answer 14. The answer i s A[ see] . P. 826


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì Ì . C. 1. a, b, c, d, e and f ] .
Cl assi c, or st abl e, angi na r ef er s t o t he syndr ome i n whi ch physi cal act i vi t y or
emot i onal excess causes chest di scomf ort , whi ch may spr ead t o t he ar ms, l egs,
neck, and so f or t h. Thi s t ype of angi na i s r el i eved pr ompt l y ( wi t hi n 1-10 mi ns) wi t h
r est , ni t r ogl ycer i n, or bot h.
2. The answer i s E [ see Ì . F. 2; Tabl e 39- 1] .
Owi ng t o t he 8-adr energi c bl ocki ng ef f ect s of met opr ol ol ( e. g. , decr eased hear t r at e,
decreased bl ood pressure, decreased i not r opi c ef f ect ) , t her e i s a net decrease i n
myocar di al oxygen demand. Thi s i s t he di rect opposi t e of t he ef f ect s seen wi t h t he
8- agoni st i sopr ot er enol . Exer ci se, ci garet t e smoki ng, and exposur e t o col d
t emper at ures have al l been shown t o i ncrease myocardi al oxygen demand.
3. The answer i s B [ see Ì Ì . H. 4. c] .
Cal ci um- channel bl ocki ng agent s such as di l t i azem have been shown t o be capabl e
of r eversi ng spasm and, t her ef ore, i ncr easi ng coronar y bl ood f l ow i n Pr i nzmet al
angi na. The cal ci um-channel bl ocker s have pr oven benef i t i n t he t reat ment of
Pr i nzmet al angi na, a syndr ome bel i eved due more t o a spast i c event t han t o a f i xed
cor onar y occl usi on.
4. The answer i s D [ see Ì Ì . H. 4. c. ( 1) . ( a) ; Ì Ì . H. 3. b. ( 2) ] .
Because propranol ol ( a 8- adr ener gi c bl ocker ) and di l t i azem ( a cal ci um- channel
bl ocker ) bot h r educe hear t r at e ( a negat i ve chr onot r opi c ef f ect ) and r educe car di ac
cont r act i l i t y (negat i ve i not r opi c ef f ect ) , pat i ent s recei vi ng bot h dr ugs must be
moni t ored f or si gns of decompensat i on ( reduced car di ac out put ) and
br adyar rhyt hmi as.
5. The answer i s D [ see Ì . F. 2] .
As wi t h most muscl es i n t he body, t he cont ract i l e f or ce of t he hear t di ct at es t he
amount of oxygen t hat t he hear t needs t o perf orm ef f i ci ent l y. Consequent l y, as
cont r act i l i t y decr eases, t he oxygen needs of t he hear t i ncrease. As cont ract i l i t y
cont i nues t o decrease, t he vol ume of f l ui d i n t he l ef t vent ri cl e i ncr eases owi ng t o
poor muscl e perf ormance and i ncreasi ng t ensi on wi t hi n t he vent ri cl e, resul t i ng i n
addi t i onal oxygen r equi rement s. As t he amount of t ensi on wi t hi n t he vent ri cl e
i ncreases per car di ac cycl e, t her e i s agai n an added requi r ement f or oxygen by t he
hear t muscl e.
6. The answer i s E [ see Ì Ì . G. 2. d. (3) ] .
Myopat hy i s an adver se ef f ect of al l t he HMG- CoA r educt ase i nhi bi t ors ( l ovast at i n,
si mvast at i n, pr avast at i n, at or vast at i n, f l uvast at i n, and r osuvast at i n), and t he
combi nat i on of t he f i br i c aci d der i vat i ves ( gemf i br ozi l , f enof i br at e, and cl of i brat e)
has been shown t o i ncrease t he creat i ne ki nase l evel s and predi spose pat i ent s t o
myopat hi es and r habdomyol ysi s.
7. The answer i s E [ see Ì Ì Ì . G. 2. d] .
Tenect epl ase i s consi dered a t i ssue pl asmi nogen act i vat or whi ch conver t s
pl asmi nogen t o pl asmi n, t hus promot i ng f i bri nol ysi s. However , t he most r ecent
nat i onal gui del i nes f or t he t r eat ment of UA and NSTEMÌ do not i ncl ude t he use of
f i bri nol yt i cs as part of t he management of pat i ent s wi t h UA or NSTEMÌ . They ar e
pr i mar i l y i ndi cat ed f or pat i ent s wi t h STEMÌ .
8. The answer i s E ( Ì , Ì Ì , and Ì Ì Ì ) [ see I I I . H. 3. b-c] .
The most recent l y i nt r oduced gui del i nes f or t he t r eat ment of STEMÌ pat i ent s i ncl ude
t he use of or al bet a- bl ocker t herapy i ni t i at ed wi t hi n t he f i rst 24 hours, assumi ng t hat
t her e are no cont rai ndi cat i ons f or t hei r use ( heart f ai l ure, heart bl ock, ast hma, et c. ).
Addi t i onal l y, t he gui del i nes add t hat i t i s accept abl e t o admi ni st er an Ì V bet a
bl ocker t o STEMÌ pat i ent s who are al so hyper t ensi ve assumi ng t hat t her e ar e no
cont r ai ndi cat i ons f or t hei r use, as l i st ed above. Aspi ri n cont i nues t o be a ver y
i mpor t ant par t of t he i ni t i al t her apy f or STEMÌ pat i ent s. The most r ecent gui del i nes
pr ovi de a Cl ass Ì recommendat i on f or t he admi ni st r at i on of aspi r i n as earl y as
possi bl e, pendi ng no cont r ai ndi cat i ons i n a dose of 162- 325 mg.
9. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì . E. 2] .
Dur i ng r ecent years, t here has been an at t empt t o l i nk t he var i ous cl i ni cal sympt oms
of Ì HD i nt o key cat egor i es, based on t he pr esent at i on and sympt oms at t he t i me of
eval uat i on. ACS r ef er s t o t hose si t uat i ons t hat r ef l ect an acut e i schemi c event and
i ncl udes UA, NSTEMÌ , and STEMÌ . Cl i ni cal gui del i nes have i ncorpor at ed t r eat ment
modal i t i es based on t hese t hree pr esent at i ons; UA and NSTEMÌ have si mi l ar
r ecommended t her api es and STEMÌ , has di f f erent t r eat ment gui del i nes. St abl e
angi na i s not consi dered one of t he ACS but represent s t he st art i ng poi nt f or t he
pr ogressi on of at her oscl er osi s, r esul t i ng i n Ì HD.
P. 827


10. The answer i s C [ see I I I . H. 4. d] .
Ti r of i ban i s an ant i pl at el et t hat i s r ef er r ed t o as a gl ycoprot ei n Ì Ì b/ Ì Ì Ì , a recept or
ant agoni st . Thi s cl ass of dr ugs wor ks t o prevent pl at el et aggregat i on by i nhi bi t i ng
t he i nt er act i on bet ween t he pri mar y bi ndi ng si t e of pl at el et s and has been shown t o
be ef f ect i ve i n t he prevent i on of t hr ombosi s.
11. The answer i s E [ see Ì Ì Ì . G. 3. b. ( 2); Tabl e 39-5] .
Enoxapar i n i s an exampl e of a LMWH. As a gr oup, t he maj or advant age of t hese
dr ugs over t he mor e t r adi t i onal hepari n i s t hat t hey exhi bi t a mor e pr edi ct abl e
ant i coagul ant response. Owi ng t o t hei r l ower mol ecul ar wei ght and decreased
bi ndi ng t o pl asma prot ei ns, t hey have bet t er bi oavai l abi l i t y t han hepar i n. Ì n addi t i on,
t hei r decrease i n pl asma pr ot ei n bi ndi ng and bi ndi ng t o t he endot hel i um resul t s i n
hal f - l i ves t hat ar e 2-4 t i mes l onger t han t hat of hepar i n. Cur rent cl i ni cal pr act i ce
gui del i nes recommend enoxapar i n over hepar i n i n pat i ent s wi t h UA or NSTEMÌ ,
unl ess CABG i s pl anned wi t hi n 24 hr.
12. The answer i s B [ see Ì Ì . G. 2. b] .
Si mvast at i n i s one of t he f i ve cur rent l y avai l abl e HMG- CoA r educt ase i nhi bi t or s t hat
have been shown t o si gni f i cant l y r educe LDL l evel s and nonf at al MÌ or CHD ( 30%-
40% reduct i on) . Recent st udi es have demonst r at ed t hat i nf l ammat i on i s an i mport ant
mechani sm i nvol ved i n ACS and t hat st at i ns exer t an i mpor t ant ant i - i nf l ammat or y
ef f ect wi t hi n coronar y ar t er i es (i ndependent of t hei r chol est er ol -l ower i ng ef f ect s) .
13. The answer i s D [ see Ì Ì Ì . H. 3. e] .
The most recent l y i nt r oduced gui del i nes f or t he t r eat ment of ACS has i ncor porat ed
r ecent t r i al s, whi ch have shown t he val ue of cl opi dogrel i n vari ous pat i ent
popul at i ons wi t h ACS. Ì t i s no l onger vi ewed as mer el y as an al t er nat i ve t o aspi ri n
i n t hose who can' t t ake aspi ri n, but r at her an " add- on¨ t herapy f or pat i ent s r ecei vi ng
aspi r i n who suf f er f rom ACS.
14. The answer i s A [ see Ì Ì . G. 5. a] .
Ezet i mi be i s t he f i r st i n a new cl ass of l i pi d-l ower i ng compounds appr oved by t he
FDA, whi ch r educes chol est er ol l evel s vi a a di f f erent mechani sm of act i on. By
sel ect i vel y bl ocki ng t he i nt est i nal absorpt i on of chol est er ol , i t i s abl e t o st op one of
t he maj or pat hways r esponsi bl e f or i ncr easi ng avai l abl e chol est erol wi t hi n t he body.
Ezet i mi be has demonst rat ed t he abi l i t y t o r educe t ot al chol est er ol , LDL,
apol i poprot ei n B, and t ri gl yceri de l evel s whi l e i ncr easi ng HDL l evel s i n pat i ent s wi t h
hyper chol est erol emi a. Si mvast at i n has r ecent l y been i ncorpor at ed i nt o a
combi nat i on product wi t h ezet i mi be ( Vyt or i n) , whi ch uses t he i ndi vi dual cl ass
pr oper t i es of t he HMG- CoA r educt ase i nhi bi t ors (si mvast at i n) t o r educe chol est er ol
pr oduct i on wi t h t he absor pt i on- i nhi bi t i ng proper t i es of ezet i mi be t o t ar get
chol est erol wi t h t wo di f f er ent mechani sms, whi ch mi ght al so ai d i n i mprovi ng pat i ent
compl i ance wi t h t aki ng t he medi cat i on.

40
Cardiac Arrhythmias
AI an H. Mutni ck
I. INTRODUCTION.
Sudden deat h f rom car di ac causes i s bel i eved t o account f or approxi mat el y 50% of
al l deat hs f rom car di ovascul ar causes, wi t h t he maj or i t y of sudden deat hs bei ng
caused by acut e vent r i cul ar t achyar r hyt hmi as. Thi s woul d appear t o creat e gr eat er
need f or t he knowl edge necessar y t o appropr i at el y use ant i ar r hyt hmi cs f or t hi s hi gh-
r i sk pat i ent popul at i on. However , pr evi ousl y conduct ed st udi es have cast doubt on
t he t r ue pl ace of ant i ar r hyt hmi cs i n t he t reat ment and pr event i on of car di ac
ar r hyt hmi as. St udi es such as t he Cardi ac Ar r hyt hmi a Suppr essi on Tr i al ( CAST) have
demonst r at ed t hat cer t ai n cl asses of ant i ar rhyt hmi cs i ncr eased mort al i t y i n pat i ent s
t r eat ed wi t h ant i ar rhyt hmi cs as compared t o pl acebo. Si nce t he r el ease of t he dat a
f r om t he CAST t r i al , subsequent st udi es have conf i rmed t he f i ndi ng t hat cer t ai n
ant i ar r hyt hmi cs do possess " proar rhyt hmi c¨ ef f ect s when used i nj udi ci ousl y.
Consequent l y, t he use of t r i al and er r or t o det ermi ne ant i ar rhyt hmi c t her apy has
gi ven way t o an er a of out come- based ant i ar r hyt hmi c dr ug deci si on maki ng. By
under st andi ng t he causes of ar rhyt hmi as and bei ng awar e of dr ug- dr ug and drug-
t ar get i nt eract i ons, we ar e mor e l i kel y t o under st and t he key consi der at i ons t o
maxi mi ze t herapeut i c st rat egi es whi l e mi ni mi zi ng dr ug- i nduced t oxi ci t i es.
A. Def i ni t i on. Cardi ac ar r hyt hmi as are devi at i ons f rom t he normal heart beat
pat t er n. They i ncl ude abnormaI i t i es of i mpuI se f ormat i on, such as heart r at e,
r hyt hm, or si t e of i mpul se ori gi n, and conducti on di sturbances, whi ch di sr upt t he
nor mal sequence of at r i al and vent r i cul ar act i vat i on.
B. EI ect rophysi oI ogy
1. Conducti on syst em
a. Two eI ect ri caI sequences t hat cause t he hear t chambers t o f i l l wi t h bl ood and
cont r act ar e i ni t i at ed by t he conduct i on syst em of t he hear t .
( 1) I mpuI se formati on, t he f i r st sequence, t akes pl ace when an el ect r i cal i mpul se i s
gener at ed aut omat i cal l y.
( 2) I mpuI se t ransmi ssi on, t he second sequence, occurs once t he i mpul se has been
gener at ed, si gnal i ng t he hear t t o cont ract .
b. Four mai n st ructures composed of t i ssue t hat can generat e or conduct el ect ri cal
i mpul ses make up t he conduct i on syst em of t he hear t .
( 1) The si noat ri aI ( SA) node, i n t he wal l of t he ri ght at ri um, cont ai ns cel l s t hat
spont aneousl y i ni t i at e an act i on pot ent i al . Ser vi ng as t he mai n pacemaker of t he
hear t , t he SA node i ni t i at es 60-100 beat s/ mi n.
( a) Ì mpul ses generat ed by t he SA node t r i gger at r i al cont ract i on.
( b) Ì mpul ses t r avel t hr ough i nt ernodal t r act s÷t he ant er i or t ract , mi ddl e t ract
(Wenckebach bundl e) , post er i or t ract ( Thor el bundl e) , and ant er i or i nt er at r i al t ract
( Bachmann' s bundl e) (Fi gur e 40-1) .
( 2) At t he at ri ovent ri cuI ar ( AV) node, si t uat ed i n t he l ower i nt er at ri al sept um, t he
i mpul ses are del ayed br i ef l y t o per mi t compl et i on of at r i al cont r act i on bef or e
vent r i cul ar cont r act i on begi ns.
( 3) At t he bundI e of Hi s-muscl e f i ber s ar i si ng f rom t he AV j unct i on÷i mpul ses
t r avel al ong t he l ef t and r i ght bundl e br anches, l ocat ed on ei t her si de of t he
i nt ravent ri cul ar sept um.
( 4) The i mpul ses r each t he Purki nj e f i bers, a di f f use net wor k ext endi ng f r om t he
bundl e br anches and endi ng i n t he vent r i cul ar endocar di al sur f aces. Vent r i cul ar
cont r act i on t hen occur s.
c. Lat ent pacemakers. The AV j unct i on, bundl e of Hi s, and Purki nj e f i bers are
l at ent pacemakers; t hey cont ai n cel l s capabl e of gener at i ng i mpul ses. However ,
t hese regi ons have a sl ower f i r i ng r at e t han t he SA node. Consequent l y, t he SA
node predomi nat es except when i t i s depressed or i nj ured, whi ch i s known as
overdri ve suppressi on.
2. Myocardi aI act i on pot ent i aI . Bef ore car di ac cont r act i on can t ake pl ace, car di ac
cel l s must depol ar i ze and r epol ar i ze.
P. 829



Figure 40-1. Electrical pathways oI the heart. AJ.
atrioventricular; SA. sinoatrial.
a. DepoI ari zati on and repoI ari zat i on r esul t f rom changes i n t he el ect ri cal pot ent i al
acr oss t he cel l membr ane, caused by t he exchange of sodi um and pot assi um i ons.
b. Act i on pot ent i aI , whi ch ref l ect s t hi s el ect ri cal act i vi t y, has f i ve phases ( Fi gur e
40- 2).
( 1) Phase 0 ( rapi d depoI ari zat i on) t akes pl ace as sodi um i ons ent er t he cel l
t hr ough f ast channel s; t he cel l membr ane' s el ect ri cal charge changes f r om negat i ve
t o posi t i ve.
( 2) Phase 1 (earI y rapi d repoI ari zat i on) . As f ast sodi um channel s cl ose and
pot assi um i ons l eave t he cel l , t he cel l r api dl y r epol ari zes ( i . e. , ret ur ns t o r est i ng
pot ent i al ).
( 3) Phase 2 ( pI ateau). Cal ci um i ons ent er t he cel l t hrough sl ow channel s whi l e
pot assi um i ons exi t . As t he cel l membr ane' s el ect r i cal act i vi t y t empor ari l y st abi l i zes,
t he act i on pot ent i al reaches a pl at eau ( repr esent ed by t he not ch at t he begi nni ng of
t hi s phase i n Fi gur e 40-2) .

Figure 40-2. Myocardial action potential curve.
This curve represents ventricular depolarization-
repolarization. Phases: 0. rapid depolarization; 1.
early rapid repolarization; 2. plateau; 3. Iinal
rapid repolarization; 4. slow depolarization.
P. 830


( 4) Phase 3 ( fi naI rapi d repoI ari zat i on). Pot assi um i ons ar e pumped out of t he cel l
as t he cel l r api dl y compl et es r epol ar i zat i on and resumes i t s i ni t i al negat i vi t y.
( 5) Phase 4 (sI ow depoI ari zat i on). The cel l ret urns t o i t s r est i ng st at e wi t h
pot assi um i ons i nsi de t he cel l and sodi um and cal ci um i ons out si de.
c. Duri ng bot h depol ar i zat i on and repol ari zat i on, a cel l ' s abi l i t y t o i ni t i at e an act i on
pot ent i al vari es.
( 1) The cel l cannot r espond t o any st i mul us duri ng t he absoI ut e ref ractor y peri od
( begi nni ng dur i ng phase 1 and endi ng at t he st ar t of phase 3) .
( 2) A cel l ' s abi l i t y t o r espond t o st i mul i i ncreases as r epol ar i zat i on cont i nues.
Dur i ng t he reI at i ve ref ract or y peri od, whi ch occur s duri ng phase 3, t he cel l can
r espond t o a st rong st i mul us.
( 3) When t he cel l has been compl et el y r epol ar i zed, i t can agai n r espond f ul l y t o
st i mul i .
d. Cel l s i n di f f erent car di ac regi ons depol ari ze at di f f er ent speeds, dependi ng on
whet her f ast or sl ow channel s pr edomi nat e.
( 1) Sodi um f l ows t hr ough f ast channel s; cal ci um f l ows t hrough sl ow channel s.
( 2) Wher e f ast channel s domi nat e (e. g. , i n cardi ac muscl e cel l s), depol ari zat i on
occurs qui ckl y. Wher e sl ow channel s domi nat e ( e. g. , i n t he el ect r i cal cel l s of t he SA
node and AV j unct i on) , depol ar i zat i on occurs sl owl y.
3. EI ect rocardi ography. The el ect r i cal act i vi t y occur r i ng dur i ng depol ar i zat i on-
r epol ari zat i on can be t r ansmi t t ed t hrough el ect r odes at t ached t o t he body and
t r ansf ormed by an eI ect rocardi ograph ( ECG) machi ne i nt o a ser i es of wavef or ms
( ECG wavef or m) . Fi gur e 40- 3 shows a normal ECG wavef or m.
a. The P wave r ef l ect s at r i al depol ari zat i on.
b. The PR i nt ervaI represent s t he spr ead of t he i mpul se f rom t he at ri a t hrough t he
Pur ki nj e f i bers.
c. The QRS compI ex r ef l ect s vent ri cul ar depol ar i zat i on. ( Phase O)
d. The ST segment r epresent s phase 2 of t he act i on pot ent i al ÷t he absol ut e
r ef r act or y peri od ( par t of vent r i cul ar r epol ar i zat i on) .
e. The T wave shows phase 3 of t he act i on pot ent i al ÷vent ri cul ar r epol ar i zat i on.
C. CI assi f i cat i on. Ar r hyt hmi as general l y ar e cl assi f i ed by ori gi n (i . e. ,
supravent ri cul ar or vent ri cul ar ).
1. Supravent ri cuI ar arrhyt hmi as st em f r om enhanced aut omat i ci t y of t he SA node
( or anot her pacemaker regi on, above t he bundl e of Hi s) or f rom r eent r y conduct i on.
2. Vent ri cuI ar arrhyt hmi as occur bel ow t he bundl e of Hi s, when an ect opi c
( abnor mal ) pacemaker t ri gger s a vent r i cul ar cont r act i on bef ore t he SA node f i r es
( e. g. , f rom a conduct i on di st ur bance or vent r i cul ar i r r i t abi l i t y) .
3. Speci aI not e
a. Torsades de poi ntes has r ecei ved i ncreased at t ent i on dur i ng r ecent year s as a
maj or pr oarr hyt hmi c event , whi ch has been report ed wi t h ant i ar rhyt hmi c dr ug
t her apy. Ì t i s def i ned as a pol ymorphi c vent r i cul ar t achycar di a wi t h a t wi st i ng QRS
compl ex mor phol ogy, whi ch somet i mes occurs wi t h drugs t hat pr ol ong vent r i cul ar
r epol ari zat i on ( QT i nt er val wi deni ng) . Though i ni t i al r epor t s of t orsades de poi nt es
cent er ed around ant i ar rhyt hmi c dr ugs (qui ni di ne) , t oday > 50 drugs, bot h
ant i ar r hyt hmi c agent s and ot her cl asses of drugs such as ant i bi ot i cs, have been
shown t o af f ect t he dur at i on of t he QT i nt er val and have been associ at ed wi t h t hi s
ar r hyt hmi a.
b. A Web si t e devot ed t o pr ovi di ng educat i on and r esearch on dr ug- i nduced
ar r hyt hmi as, especi al l y t hose due t o pr ol ongat i on of t he QT i nt er val on t he
el ect r ocar di ogram (ECG) ,
P. 831

i s avai l abl e. The si t e, ht t p: / / www. t or sades. or g/ medi cal -pr os/ drug-l i st s/ drug-
l i st s. ht m, i s curr ent l y mai nt ai ned by Dr . Raymond Woosl ey.

Figure 40-3. Normal ECG waveIorm.
c. Woosl ey and col l eagues have est abl i shed t he Ì nt ernat i onal Regi st r y f or Dr ug-
Ì nduced Ar rhyt hmi as, t o whi ch one can submi t a suspect ed "dr ug-i nduced ar r hyt hmi a
event . ¨ The r egi st r y al so pr ovi des a l i st of drugs r eport ed t o pr ol ong t he QT i nt er val
or cause t orsades de poi nt es ( www. Tor sades. or g). Four drug l i st s wer e creat ed
based on t he r el at i ve r i sk of i nduci ng t or sades de poi nt es ( TdP) or a pr ol onged QT
i nt er val .
d. Ì t i s beyond t he i nt ent i on of t hi s chapt er t o pr ovi de a compr ehensi ve l i st i ng, as
done on Dr . Woosl ey' s websi t e. However , t he f our cat egor i es of dr ug l i st s i ncl ude
t he f ol l owi ng wi t h sel ect exampl es.
i . Li st 1: Drugs t hat ar e gener al l y accept ed by aut hori t i es t o have a ri sk of causi ng
Tor sades de Poi nt es; i . e. , ami odarone ( Cordar one®) , Bepr i di l ( Vascor ®) ,
chl or promazi ne ( Thor azi ne®) , cl ar i t hr omyci n ( Bi axi n®) , di sopyr ami de ( Norpace®) ,
dof et i l i de ( Ti kosyn®) , eryt hr omyci n ( Er yt hr oci n®), hal oper i dol ( Hal dol ®) , i but i l i de
( Cor ver t ®) , met hadone (Dol ophi ne®) , pent ami di ne ( NebuPent ®) , pi mozi de ( Or ap®) ,
pr ocai nami de ( Pronest yl ®) , and qui ni di ne®) ( Qui nagl ut e®) .
i i . Li st 2: Dr ugs t hat i n some r epor t s have been associ at ed wi t h Torsades de
Poi nt es and/ or QT pr ol ongat i on, but at t hi s t i me l ack subst ant i al evi dence f or
causi ng Torsades de Poi nt es; i . e. , amant adi ne ( Symmet r el ®) , azi t hr omyci n
( Zi t hr omax®) , dol aset r on ( Anzemet ®) , f osphenyt oi n ( Cer ebyx®) , gat i f l oxaci n
( Tequi n®) , grani set r on (Kyt r i l ®) , i sradi pi ne ( DynaCi r c®), moxi f l oxaci n (Avel ox®) ,
ni car di pi ne ( Car dene®), ondanset ron ( Zof ran®) , ri sper i done ( Ri sper dal ®) ,
dal met er ol ( Ser event ®), and vori conazol e ( Vf end®) .
i i i . Li st 3: Dr ugs t o be avoi ded f or use i n pat i ent s wi t h di agnoses or suspect ed
congeni t al l ong QT syndr ome. ( Dr ugs on Li st s 1, 2, and 4 are al so i ncl uded here. )
i . e. , al but er ol ( Provent i l ®) , ami odar one ( Cor dar one®) , azi t hromyci n ( Zi t hromax®) ,
bepri di l ( Vascor ®) , cl ari t hr omyci n ( Bi axi n®) , di sopyr ami de ( Nor pace®) , dobut ami ne
( Dobut rex®) , dof et i l i de (Ti kosyn®) , dol aset ron (Anzemet ®) , dopami ne ( Ì nt r opi n®) ,
er yt hr omyci n ( Er yt hroci n®) , f l ecai ni de ( Tambocor®) , f osphenyt oi n ( Cer ebyx®) ,
gat i f l oxaci n ( Tequi n®) , gr ani set r on ( Kyt r i l ®), i sr adi pi ne ( DynaCi rc®) , l evof l oxaci n
( Levaqui n®) , met hadone ( Dol ophi ne®) , moxi f l oxaci n ( Avel ox®) , ondanset ron
( Zof r an®) , pr ocai nami de ( Pr onest yl ®), sal met er ol ( Serevent ®) , sot al ol ( Bet apace®) ,
and vori conazol e ( Vf end®) .
i v. Li st 4: Dr ugs t hat , i n some report s, have been weakl y associ at ed wi t h Tor sades
de Poi nt es and/ or QT pr ol ongat i on but t hat ar e unl i kel y t o be a r i sk f or Tor sades de
Poi nt es when used i n usual r ecommended dosages, and i n pat i ent s wi t hout ot her
r i sk f act or (e. g. , concomi t ant QT prol ongi ng dr ugs, br adycardi a, el ect r ol yt e
di st ur bances, congeni t al l ong QT syndrome, concomi t ant drugs t hat i nhi bi t
met abol i sm). i . e. , ami t ri pt yl i ne ( El avi l ®) , amoxapi ne ( Asendi n®) , ci prof l oxaci n
( Ci pr o®) , ci t al opr am ( Cel exa®) , doxepi n ( Si nequan®) , f l uconazol e ( Di f l ucan®) ,
i nt raconazol e ( Sporanox®) , ket oconazol e ( Ni zoral ®) , ser t ral i ne ( Zol of t ®), and
t r i met hopri m-sul f amet hoxazol e ( Bact ri m®).
D. Causes
1. Preci pi tat i ng causes. Ar r hyt hmi as r esul t f rom var i ous condi t i ons, i ncl udi ng
a. Hear t di sease÷f or exampl e, i nf ect i on, cor onary ar t er y di sease ( CAD) , val vul ar
hear t di sease, rheumat i c heart di sease, i schemi c hear t di sease
b. Myocar di al i nf ar ct i on ( MÌ )
c. Toxi c doses of car di oact i ve drugs ( e. g. , di gi t al i s preparat i ons)
d. Ì ncr eased sympat het i c t one
e. Decr eased par asympat het i c t one
f . Vagal st i mul at i on (e. g. , st rai ni ng at st ool )
g. Ì ncr eased oxygen demand ( e. g. , f r om st ress, exer ci se, f ever )
h. Met abol i c di st ur bances
i . Cor pul monal e
j . Syst emi c hyper t ensi on
k. Hyperkal emi a/ hypokal emi a
I . Chr oni c obst r uct i ve pul monar y di sease ( COPD)÷f or exampl e, chr oni c br onchi t i s,
emphysema
P. 832



Figure 40-4. Reentry arrhythmias. A. Two waves
oI excitation going in opposite directions. B. A
unidirectional wave oI excitation. C. Reexcitation
oI tissue in a slow conduction area.
m. Thyr oi d di sorders
n. Dr ug t her apy ( bot h ant i ar rhyt hmi c and non-ant i ar r hyt hmi c drugs)
2. Mechani sms of arrhyt hmi as. Abnormal i mpul se f ormat i on, abnormal i mpul se
conduct i on, or a combi nat i on of bot h may gi ve ri se t o ar r hyt hmi as.
a. AbnormaI i mpuI se f ormat i on may st em f r om:
( 1) Depr essed aut omat i ci t y, as i n escape beat s and bradycar di a
( 2) Ì ncr eased aut omat i ci t y, as i n pr emat ur e beat s, t achycardi a, and ext r asyst ol e
( 3) Depol ar i zat i on and t ri gger ed act i vi t y, l eadi ng t o sust ai ned ect opi c f i r i ng
b. AbnormaI i mpuI se conduct i on r esul t s f r om:
( 1) A conduct i on bl ock or del ay
( 2) Reent r y occurs when an i mpul se i s r erout ed t hr ough cer t ai n r egi ons i n whi ch i t
has al ready t r avel ed. Thus t he i mpul se depol ari zes t he same t i ssue more t han once,
pr oduci ng an addi t i onal i mpul se ( Fi gur es 40- 4 and 40-5) . Reent r y si t es i ncl ude t he
SA and AV nodes as wel l as var i ous accessor y pat hways i n t he at r i a and vent r i cl es
( Fi gur e 40- 6) . For reent ry t o occur , t he f ol l owi ng condi t i ons must exi st :

Figure 40-5. Ventricular reentry: a branched
Purkinie Iiber ioining ventricular muscle. The
dark area represents the site oI a unidirectional
block. In this depolarization region. the impulse
heading toward the atrioventricular node
continues upward. whereas the impulse traveling
toward the muscle is blocked. Because retrograde
conduction in branch B is slow. cells in branch A
have time to recover and respond to the reentrant
impulse.
P. 833



Figure 40-6. Reentry sites. AJ. atrioventricular;
SA. sinoatrial.
( a) Mar kedl y shor t ened ref r act ori ness or a sl ow conduct i on area t hat al l ows an
adequat e del ay so t hat depol ar i zat i on r ecur s
( b) Uni di rect i onal conduct i on
E. Pat hophysi oI ogy. Ar r hyt hmi as may decr ease car di ac out put , r educe bl ood
pr essure, and di srupt per f usi on of vi t al organs. Speci f i c pat hophysi ol ogi cal
consequences depend on t he ar rhyt hmi a pr esent .
F. CI i ni caI evaI uat i on
1. Physi caI f i ndi ngs. Al t hough some ar r hyt hmi as are si l ent , most produce si gns
and sympt oms. Onl y an ECG can def i ni t i vel y i dent i f y an ar r hyt hmi a. However ,
physi cal f i ndi ngs may suggest whi ch ar r hyt hmi a i s present ; t hey al so yi el d
i nf or mat i on about t he pat i ent ' s cl i ni cal st at us and may hel p i dent i f y associ at ed
compl i cat i ons. Si gns and sympt oms t hat t ypi cal l y accompany ar rhyt hmi as i ncl ude
a. Chest pai n
b. Anxi et y and conf usi on ( f r om r educed brai n perf usi on)
c. Dyspnea
d. Ski n pal l or or cyanosi s
e. Abnormal pul se rat e, rhyt hm, or ampl i t ude
f . Reduced bl ood pr essur e
g. Pal pi t at i ons
h. Syncope
i . Weakness
j . Convul si ons
k. Hypot ensi on
I . Decr eased uri nar y out put
2. Di agnost i c t est resuI t s
a. An ECG can i dent i f y a speci f i c ar r hyt hmi a; usual l y, a 12- l ead ECG i s used.
b. EI ect rophysi oI ogi caI ( EP) t est i ng. Thi s i nt r acar di ac pr ocedur e det ermi nes t he
l ocat i on of
P. 834

ect opi c f oci and bypass t r act s and may hel p assess t herapeut i c r esponse t o
ant i ar r hyt hmi c dr ug t herapy. Ì t al so can det er mi ne t he need f or a pacemaker or
sur gi cal i nt er vent i on.
( 1) Ì nt r acardi ac cat het ers and paci ng wi r es ar e pl aced t r ansvenousl y or
t r ansar t er i al l y.
( 2) The heart i s di vi ded i nt o i magi nar y sect i ons, and each sect i on i s st i mul at ed unt i l
an arr hyt hmi a i s i nduced. The sect i on i n whi ch t he ar rhyt hmi a occurs i s i dent i f i ed as
t he or i gi n of t he ect opi c f oci .
c. Hi s bundI e st udy, a t ype of EP t est i ng, can l ocat e t he or i gi n of a hear t bl ock or
r eent r y pat t er n.
d. Laborator y f i ndi ngs. Some ar rhyt hmi as r esul t f r om el ect r ol yt e abnor mal i t i es÷
most commonl y, hyperkal emi a and hypocal cemi a.
( 1) A serum pot assi um l evel > 5 mEq/ L r ef l ect s hyper kal emi a; a ser um cal ci um l evel
< 4. 5 mEq/ L si gni f i es hypocal cemi a, and serum magnesi um l evel s < 2. 5 mEq/ L
si gni f y hypomagnesemi a.
( 2) An ECG t r aci ng may suggest an el ect rol yt e abnormal i t y. For exampl e, pr ol onged
QRS compl exes, t ent ed T waves, and l engt hened PR i nt er val s may si gnal
hyper kal emi a; pr ol onged QT i nt er val s and f l at t ened, or i nver t ed, T waves suggest
hypocal cemi a.
G. Treatment obj ect i ves
1. Termi nat e or suppress t he arrhyt hmi a i f i t causes hemodynami c compr omi se or
di st ur bi ng sympt oms.
2. Mai ntai n adequat e cardi ac output and t i ssue perfusi on.
3. Correct or mai nt ai n fI ui d baI ance ( some ar r hyt hmi as cause hyper vol emi a).
II. THERAPY.
Dur i ng r ecent years, sever al pr omi nent nat i onal or gani zat i ons have f ormal i zed a
st r uct ur e whi ch pr omul gat es t he di ssemi nat i on of " cl i ni cal pr act i ce gui del i nes, ¨
whi ch f ocus on " Evi dence- based pract i ce. ¨ The over al l purpose bei ng t o ut i l i ze
avai l abl e l i t erat ur e t o quant i f y, i n cl i ni cal t erms, t he st r engt h of evi dence and t he
qual i t y of such evi dence, i n or der t o devel op a st andar d of pr act i ce f or such cl i ni cal
ent i t i es. Evi dence- based pr act i ce goes beyond drug t her apy and i ncl udes di agnost i c
cr i t er i a, screeni ng programs, use of l abor at or y t est s, et c. The Amer i can Col l ege of
Car di ol ogy i n col l abor at i on wi t h t he Amer i can Hear t Associ at i on and European
Soci et y of Car di ol ogy have est abl i shed a r out i ne st andard f or t he eval uat i on,
devel opment , appr oval , and subsequent di st ri but i on of such pr act i ce gui del i nes f or a
wi de ar r ay of car di ac si t uat i ons. Si nce t he publ i cat i on of t he most recent edi t i on of
t hi s t ext ; t wo set s of gui del i nes have been devel oped i n t he area of Car di ac
Ar r hyt hmi as, and i ncl ude t he f ol l owi ng:
ACC/ AHA/ ESC 2006 Gui del i nes f or t he Management of Pat i ent s wi t h At r i al
Fi bri l l at i on whi ch can be f ound onl i ne at
ht t p: / / ci rc. ahaj ournal s. org/ cgi / cont ent / f ul l / 114/ 7/ 700.
ACC/ AHA/ ESC Gui del i nes f or t he Management of Pat i ent s wi t h Vent ri cul ar
Ar r hyt hmi as and t he Pr event i on of Sudden Cardi ac Deat h, whi ch can be f ound
onl i ne at
ht t p: / / www. amer i canheart . or g/ downl oadabl e/ hear t / 1156943336547VA_PG_FÌ NAL8_2
8. pdf
Ant i arrhyt hmi c agents, di r ect l y or i ndi r ect l y, al t er t he dur at i on of t he myocardi al
act i on pot ent i al . Most ant i ar rhyt hmi cs f al l i nt o one of f our cl asses, dependi ng on
t hei r speci f i c ef f ect s on t he hear t ' s el ect ri cal act i vi t y ( Tabl e 40- 1) .
A. CI ass I ant i arrhyt hmi cs
1. I ndi cat i ons
a. CI ass I A drugs
( 1) Qui ni di ne i s used t o t r eat and prevent acut e and chroni c vent r i cul ar and
supravent ri cul ar arr hyt hmi as, especi al l y par oxysmal supr avent ri cul ar t achycar di as
( PSVTs) , premat ure vent r i cul ar cont ract i ons ( PVCs) , pr emat ur e at r i al cont r act i ons
( PACs) , and vent ri cul ar t achycar di a.
( 2) Procai nami de i s used f or t he same arr hyt hmi as f or whi ch qui ni di ne i s gi ven. Ì t
i s used more f requent l y t han qui ni di ne because i t can be admi ni st er ed i nt ravenousl y
and i n sust ai ned- rel ease or al preparat i ons. Qui ni di ne poses added concern when
used i nt r avenousl y because of i ncr eased cardi ovascul ar ef f ect s ( i . e. , hypot ensi on,
syncope, myocardi al depr essi on) .
( 3) Di sopyrami de may be used as an al t ernat i ve t o qui ni di ne or pr ocai nami de f or
t r eat i ng vent ri cul ar ar rhyt hmi as ( e. g. , PVCs, moder at e vent ri cul ar t achycar di a).
P. 835


Table 40-1. Williams's Classification of Antiarrhythmic Drugs Currently
Available in the United States
Class Action Drugs
IA (Iast-
channel
blockers)
Moderate depression oI
conduction. prolongation oI
repolarization. which results in
an increase in the QRS interval
and an increase in the QT
interval
Disopyramide
(Norpace).
procainamide
(Pronestyl). quinidine
IB Modest depression oI
conduction. shortening oI
repolarization. which results in a
decrease in the QT interval
Lidocaine
(Xylocaine).
mexiletine (Mexitil).
phenytoin (Dilantin).
IC Strong depression oI conduction.
with mild or no eIIect on
repolarization. which results in a
very large increase in the QRS
interval
Flecainide
(Tambocor).
propaIenone
(Rythmol)
II (þ-
blockers)
þ-adrenergic blockers slow sinus
as well as AV nodal conduction.
which results in a decrease in
heart rate and a prolongation in
the PR interval (atrial
depolarization)
Propranolol (Inderal).
esmolol (Brevibloc).
acebutolol (Sectral)
a

III Prolongation oI repolarization.
which results in prolongation oI
the QT interval
Amiodarone
(Cordarone). sotalol
b

(Betapace). ibutilide
(Corvert). doIetilide
(Tikosyn)
IV (slow-
channel
blockers)
Calcium-channel blockade in
calcium-dependent channels.
which results in reduced heart
rate and an increase in the PR
interval
Verapamil (Calan).
diltiazem (Cardizem)
Other

Adenosine
(Adenocard). atropine.
digoxin (Lanoxin).
magnesium
a
Singh BN. Vaughan Williams EM. ClassiIication oI antiarrhythmic drugs.
In: Sandoe E. Flensted-Jensen E. Olesen KH. eds. Symposium on Cardiac
Arrhythmias. Sodertalige: AB Astra. 1970.

b
Sotalol is a þ-adrenergic blocker that prolongs the action potential oI phase
3 and is classiIied as type III.

b. CI ass I B drugs
( 1) Li docai ne i s used t her apeut i cal l y f or vent r i cul ar ar r hyt hmi as ( especi al l y PVCs
and vent r i cul ar t achycardi a) t hat r esul t f r om acut e MÌ and open- hear t surger y.
Cont r oversy st i l l exi st s as t o t he benef i t s of l i docai ne when used prophyl act i cal l y i n
pat i ent s wi t h acut e MÌ t o pr event vent r i cul ar f i bri l l at i on. A r ecent anal ysi s showed
an i ncrease i n t he number of deat hs i n pat i ent s recei vi ng l i docai ne duri ng an acut e
MÌ as compar ed t o pl acebo. Many f eel t hat i t s curr ent use prophyl act i cal l y post - MÌ
i s no l onger j ust i f i ed.
( 2) Phenyt oi n i s most commonl y used t o t reat di gi t al i s- i nduced vent ri cul ar and
supravent ri cul ar arr hyt hmi as. Ì t i s al so gi ven t o suppr ess vent ri cul ar ar rhyt hmi as
associ at ed wi t h acut e MÌ , open- heart sur ger y, or vent r i cul ar ar r hyt hmi as t hat ar e
r ef r act or y t o l i docai ne or pr ocai nami de, but i t s ef f i cacy i s l ess si gni f i cant f or t hese
i ndi cat i ons t han i t i s f or di gi t al i s- i nduced ar rhyt hmi as.
( 3) Mexi I et i ne i s cl osel y r el at ed t o l i docai ne, st ruct ur al l y wi t h modi f i cat i ons, whi ch
r educe f i rst - pass l i ver met abol i sm, maki ng or al t her apy possi bl e. Ì t i s most
commonl y used t o t reat pat i ent s i n whom a cl ass Ì agent has f ai l ed and i s
moder at el y ef f ect i ve i n suppressi ng vent r i cul ar ect opy, al t hough comparabl e t o
qui ni di ne.
c. CI ass I C drugs
( 1) FI ecai ni de suppr esses PVCs and vent r i cul ar t achycardi a; i t may be used t o t r eat
some ar r hyt hmi as t hat are r ef ract or y t o ot her agent s. Fl ecai ni de i s reser ved f or
pat i ent s wi t h r ef ract or y l i f e- t hreat eni ng vent ri cul ar ar r hyt hmi as who do not have
CAD. Ì t has al so been shown t o be ef f ect i ve i n t he t r eat ment of supr avent r i cul ar
ar r hyt hmi as.
( 2) Propaf enone al so suppr esses PVCs and vent r i cul ar t achycar di a and has been
used successf ul l y f or t reat i ng sust ai ned vent r i cul ar t achycar di a when t he ar r hyt hmi a
i s l i f e
P. 836

t hr eat eni ng. Ì t has al so been shown t o be ef f ect i ve i n t he t r eat ment of
supravent ri cul ar arr hyt hmi as.
( 3) Mori ci zi ne i s a di f f i cul t ant i ar rhyt hmi c t o cl assi f y based on t he f act t hat i t has
pr oper t i es of al l t hr ee cl ass Ì ant i ar rhyt hmi c gr oups. Because i t pr ol ongs t he QRS
i nt er val l i ke ot her cl ass Ì C agent s, i t has been cl assi f i ed as a cl ass Ì C agent
t hr oughout t hi s di scussi on. Mor i ci zi ne i s ef f ect i ve f or suppr essi ng PVCs and may
of f er some benef i t s over ot her agent s because of a l ower i nci dence of proar r hyt hmi c
ef f ect s.
2. Mechani sm of act i on. As a cl ass, al l of t he agent s wor k by bl ocki ng t he r api d
i nwar d sodi um cur r ent and t her eby sl ow down t he r at e of r i se of t he car di ac t i ssue' s
act i on pot ent i al . However , t hough t hi s i s a si mi l ar ef f ect f or al l cl ass Ì agent s,
di f f er ences i n EP ef f ect s had l ed t o a subcl assi f i cat i on of t he cl ass Ì agent s i nt o
t hr ee subset s ( Ì A, Ì B, and Ì C) , based on t hese EP ef f ect s.
a. CI ass I A drugs moder at el y r educe t he depol ar i zat i on rat e and prol ong
r epol ari zat i on ( ref r act or y peri od).
b. CI ass I B drugs short en r epol ari zat i on ( ref r act or y peri od); t hey al so weakl y af f ect
t he repol ari zat i on rat e.
c. CI ass I C drugs st r ongl y depr ess depol ar i zat i on but have a negl i gi bl e ef f ect on
t he dur at i on of r epol ar i zat i on or r ef r act ori ness.
3. Admi ni st rat i on and dosage
a. Qui ni di ne i s admi ni st er ed or al l y, usual l y i n 3-4 dai l y doses of 200- 400 mg as a
r api d- r el ease sul f at e sal t ( 83% qui ni di ne). However , sust ai ned- r el ease product s i n
t he f orm of a gl uconat e (62% qui ni di ne) sal t i n doses of 324- 648 mg, whi ch
cor responds t o 300-600 mg of t he sul f at e sal t , may be gi ven ever y 12 hr . ( Ì n speci al
ci rcumst ances, i t has been gi ven i nt ravenousl y or i nt ramuscul arl y wi t h caut i on. ) To
achi eve an ef f ect i ve pl asma concent rat i on rapi dl y, a l oadi ng dose of 600-1000 mg
may be admi ni st er ed i n doses of 200 mg ever y 2 hr t o a maxi mum of 1000 mg, or a
5- 8 mg/ kg i nt r avenous i nf usi on can be gi ven at a r at e of 0. 3 mg/ kg/ mi n.
b. Procai nami de ( Pronest yI ) i s avai l abl e f or or al , i nt r avenous, or i nt r amuscul ar
use.
( 1) For acut e t herapy, i nt r avenous admi ni st rat i on i s pref err ed.
( a) Ì nt ermi t t ent i nt r avenous admi ni st r at i on cal l s f or t he admi ni st rat i on of an
i nt ravenous dose of 3- 6 mg/ kg i nf usi on ( up t o 100 mg) over 2- 4 mi n, r epeat ed ever y
5- 10 mi n unt i l t he ar r hyt hmi a i s abol i shed, si de ef f ect s occur , or 1 g has been gi ven.
The usual ef f ect i ve dose i s 500- 1000 mg.
( b) Rapi d i nt r avenous admi ni st r at i on cal l s f or i nf usi on of 1-1. 5 g at a r at e of 20- 50
mg/ mi n.
( c) Once t he ar r hyt hmi a i s t ermi nat ed, 1. 5-5 mg/ mi n i s gi ven as a cont i nuous
i nf usi on.
( 2) For I ong- t erm t herapy, or al admi ni st r at i on i s used. The usual dai l y dosage i s 50
mg/ kg i n di vi ded doses gi ven ever y 6 hr as a sust ai ned- r el ease product or 3- 6 g
dai l y.
( a) Capsul es and t abl et s ( Pr onest yl ) avai l abl e as 250, 375, and 500 mg gi ven i n 4- 6
di vi ded doses
( b) Sust ai ned- r el ease t abl et s ( Procanbi d) avai l abl e as 500 and 1000 mg gi ven i n 12-
hr doses
c. Di sopyrami de ( Norpace, Norpace CR) i s avai l abl e i n oral f orm.
( 1) Usual l y, 300-400 mg i s gi ven as a l oadi ng dose t o at t ai n an ef f ect i ve pl asma
l evel r api dl y.
( 2) For mai nt enance t herapy, doses of 400-800 mg/ day ar e gi ven i n 4 doses ever y 6
hr ( non-sust ai ned- r el ease capsul e) or i n 2 doses ever y 12 hr (sust ai ned- rel ease
capsul e) .
d. Li docai ne ( XyI ocai ne) may be admi ni st er ed i nt r avenousl y or i nt ramuscul arl y.
( 1) An i nt r avenous l oadi ng dose r api dl y achi eves a t her apeut i c pl asma l evel .
( a) Ì ni t i al l y, 1-1. 5 mg/ kg ( 100 mg) i s admi ni st er ed.
( b) A second i nj ect i on of hal f t he i ni t i al dose may be requi r ed 5 mi n l at er , up t o a
maxi mum of 300 mg.
( 2) Cont i nuous i nt r avenous i nf usi on of 2- 4 mg/ mi n pr oduces an ef f ect i ve pl asma
l evel i n 7- 10 hr.
( 3) Ì n an emer gency, an i nt ramuscul ar i nj ect i on rapi dl y achi eves an ef f ect i ve pl asma
l evel . The usual dosage i s 300-400 mg i nj ect ed i nt o t he del t oi d muscl e.
e. Phenyt oi n ( Di I ant i n) i s gi ven or al l y or i n i nt ermi t t ent i nt r avenous doses.
( 1) For oral admi ni st r at i on, a l oadi ng dose of 1 g i s di vi ded over t he f i r st 24 hr ; f or
t he next 2 days, 300-500 mg/ day i s admi ni st er ed. The mai nt enance dosage i s 300-
400 mg/ day.
P. 837


( 2) For i nt ermi t t ent i nt ravenous admi ni st rat i on, 100 mg i s gi ven ever y 5 mi n at a
r at e not exceedi ng 25-50 mg/ mi n, unt i l t he ar rhyt hmi a di sappears, adverse ef f ect s
devel op, or 1 g has been gi ven. The usual ef f ect i ve dosage i s 700 mg.
f . Mexi I et i ne i s admi ni st er ed or al l y and shoul d be i ni t i at ed i n t he hospi t al set t i ng.
( 1) A l oadi ng dose of 400 mg f ol l owed by mai nt enance dosage i n 8 hr .
( 2) Ì f t hi s f ai l s t o cont rol t he ar r hyt hmi a, t he dosage may be i ncr eased t o 400 mg
ever y 8 hr. ( Al t er nat i vel y, doses may be gi ven ever y 12 hr . )
( 3) Normal mai nt enance doses ar e 200- 300 mg ever y 8 hr .
g. FI ecai ni de ( Tambocor) i s admi ni st ered or al l y and shoul d be i ni t i at ed i n t he
hospi t al set t i ng.
( 1) Ì ni t i al dosage i s 50 mg ever y 12 hr, and t he dosage may be i ncr eased i n t wi ce-
dai l y i ncr ement s of 50 mg ever y 4 days t o a maxi mum of 300 mg/ day.
( 2) The usual mai nt enance dose i s 100 mg ever y 12 hr .
h. Propaf enone ( Ryt hmoI , Ryt hmoI SR) i s admi ni st er ed or al l y and shoul d be
i ni t i at ed i n t he hospi t al set t i ng.
( 1) Ì ni t i al dosage i s 150 mg ever y 8 hr and can be i ncr eased ever y 3- 4 days t o t he
desi r ed t her apeut i c ef f ect or si de ef f ect s.
( 2) The usual mai nt enance dose i s 150- 200 mg ever y 8 hr , ( Ryt hmol ) or ever y 12
hour ( Ryt hmol SR) up t o a maxi mum of 900 mg/ day.
4. Precauti ons and moni t ori ng ef f ect s. Not e: Proar r hyt hmi a ( t he abi l i t y t o cause
an arr hyt hmi a) i s t he most i mpor t ant r i sk associ at ed wi t h t he use of ant i arr hyt hmi c
dr ug t her apy. Br adyar rhyt hmi as and vent r i cul ar t achyar r hyt hmi as, such as t or sades
de poi nt es, can occur . These of t en t ake pl ace dur i ng t he i ni t i at i on of ant i ar r hyt hmi c
dr ug t r eat ment and shoul d be consi dered when deci si on makers choose bet ween
out pat i ent and i npat i ent i ni t i at i on of ant i ar rhyt hmi c t her apy.
a. Qui ni di ne
( 1) Thi s drug i s cont r ai ndi cat ed i n pat i ent s wi t h
( a) Compl et e AV bl ock unl ess a vent r i cul ar pacemaker i s i n pl ace
( b) Mar ked pr ol ongat i on of t he QT i nt er val or pr ol onged QT syndrome because
vent r i cul ar t achyar r hyt hmi a ( t orsades de poi nt es) may ar i se, r esul t i ng i n qui ni di ne
syncope ( i . e. , syncope or sudden deat h)
( 2) An i ncr ease of 50% or more i n t he durat i on of t he QRS compl ex necessi t at es
dosage r educt i on.
( 3) Qui ni di ne has a nar row t her apeut i c i ndex. Ther apeut i c serum l evel s ar e i n t he
r ange of 2-6 µg/ mL, dependi ng on t he speci f i ci t y of t he assay. Toxi ci t y may cause
acut e cardi ac ef f ect s, such as pr onounced sl owi ng of conduct i on i n al l hear t
r egi ons; t hi s, i n t ur n, may l ead t o SA bl ock or ar rest , vent ri cul ar t achycardi a, or
asyst ol e.
( 4) The ECG shoul d be moni t ored duri ng qui ni di ne t her apy t o det ect si gns of
car di ot oxi ci t y. To count er act qui ni di ne-i nduced vent ri cul ar t achyar rhyt hmi as,
cat echol ami nes, gl ucagon, or sodi um l act at e may be gi ven.
( 5) Ì n pat i ent s r ecei vi ng qui ni di ne f or at ri al t achyar r hyt hmi as, vagol yt i c ef f ect s may
i ncrease i mpul se conduct i on at t he AV node, resul t i ng i n an accel erat ed vent r i cul ar
r esponse. To pr event t hi s, agent s t hat sl ow AV nodal conduct i on (e. g. , ver apami l ,
di goxi n) may be admi ni st er ed.
( 6) The dosage shoul d be r educed i n el der l y pat i ent s ( > 60 year s ol d) and i n
pat i ent s wi t h hepat i c dysf unct i on or congest i ve hear t f ai l ure ( CHF) .
( 7) Embol i sm may occur on r est or at i on of normal si nus r hyt hm af t er pr ol onged at r i al
f i bri l l at i on. To pr event or mi ni mi ze t hi s compl i cat i on, ant i coagul ant s may be
admi ni st er ed bef ore qui ni di ne t herapy begi ns.
( 8) Qui ni di ne may cause ci nchoni sm at hi gh ser um concent r at i ons, mani f est ed by
t i nni t us, hear i ng l oss, bl ur r ed vi si on, and gast r oi nt est i nal ( GÌ ) di st urbances. Ì n
sever e cases, nausea, vomi t i ng, di ar r hea, headache, conf usi on, del i r i um,
phot ophobi a, di pl opi a, and psychosi s may occur.
( 9) GÌ react i ons are t he most common adverse react i ons t o qui ni di ne. About 30% of
pat i ent s exper i ence di ar rhea; nausea and vomi t i ng may al so occur. Ar i si ng al most
i mmedi at el y af t er t he f i r st dose, t hese sympt oms somet i mes war r ant di scont i nui ng
t he dr ug. However , al umi num hydroxi de or use of t he pol ygal act ur onat e sal t may
r ever se t hi s.
( 10) Hyper sensi t i vi t y r eact i ons i ncl ude anaphyl axi s, t hrombocyt openi a, respi rat or y
di st r ess, and vascul ar col l apse.
P. 838


b. Procai nami de ( Pronest yI )
( 1) Thi s drug i s cont r ai ndi cat ed i n pat i ent s wi t h hyper sensi t i vi t y t o procai ne and
r el at ed dr ugs, myast heni a gr avi s, second- or t hi rd- degr ee AV bl ock wi t h no
pacemaker , a hi st or y of pr ocai nami de- i nduced syst emi c l upus er yt hemat osus ( SLE),
pr ol onged QT syndr ome, or t or sades de poi nt es.
( 2) An i ncr ease of 50% or more i n t he durat i on of t he QRS compl ex necessi t at es
dosage r educt i on.
( 3) Pr ocai nami de has a nar r ow t her apeut i c i ndex. Ther apeut i c ser um l evel s ar e
r eport ed i n t he r ange of 4- 10 µg/ mL. N-acet yl pr ocai nami de ( NAPA) l evel s of 15- 25
µg/ mL are consi der ed t her apeut i c. The act i ve met abol i t e, NAPA possesses di f f er i ng
pharmacol ogi cal cardi ovascul ar ef f ect s, and ser um l evel s need t o be eval uat ed
i ndependent l y of pr ocai nami de. Toxi ci t y may cause acut e cardi ac ef f ect s ( e. g. ,
pr onounced sl owi ng of conduct i on i n al l heart r egi ons) , whi ch, i n t ur n, may l ead t o
SA bl ock or ar rest , vent ri cul ar t achycar di a, or asyst ol e.
( 4) Hi gh serum pr ocai nami de l evel s may i nduce vent r i cul ar ar r hyt hmi as (e. g. , PVCs,
vent r i cul ar t achycardi a or f i bri l l at i on) . The ECG shoul d be moni t or ed cont i nuousl y t o
det ect t hese pr obl ems. Cat echol ami nes, gl ucagon, or sodi um l act at e may be
admi ni st er ed t o count er act t hese ar r hyt hmi as.
( 5) Hypot ensi on may occur wi t h r api d i nt r avenous admi ni st r at i on.
( 6) GÌ ef f ect s are l ess common t han wi t h qui ni di ne t her apy.
( 7) Hypersensi t i vi t y react i ons ar e t he most severe adverse ef f ect s of pr ocai nami de.
These react i ons i ncl ude dr ug f ever , agranul ocyt osi s, and an SLE- l i ke syndr ome.
( a) An SLE- l i ke syndr ome i s mani f est ed by f at i gue, art hr al gi a, myal gi a, and l ow-
gr ade f ever.
( b) Ant i nucl ear ant i body t i t er i s posi t i ve i n 50%- 80% of pat i ent s recei vi ng
pr ocai nami de. However , onl y 20%-30% of t hese pat i ent s devel op sympt oms of t he
SLE- l i ke syndr ome.
( c) Dr ug di scont i nuat i on usual l y i s necessar y when sympt omat i c SLE-l i ke syndr ome
occurs.
( 8) The dosage shoul d be r educed and gi ven over 6 hr t o pat i ent s wi t h r enal or
hepat i c i mpai rment , as t he drug hal f - l i f e i s i ncreased i n t hese pat i ent s.
( 9) Lower doses may be needed i n pat i ent s wi t h CHF t o adj ust f or t he l ower vol ume
of di st r i but i on.
( 10) Embol i sm may occur on rest or at i on of nor mal si nus rhyt hm af t er pr ol onged
at r i al f i bri l l at i on. An ant i coagul ant i s f requent l y admi ni st ered bef or e pr ocai nami de
t her apy begi ns t o pr event t hi s compl i cat i on.
c. Di sopyrami de ( Norpace)
( 1) Thi s drug may cause marked hemodynami c compr omi se and vent r i cul ar
dysf unct i on. Ì t i s cont r ai ndi cat ed i n pat i ent s wi t h cardi ogeni c shock or second- or
t hi rd- degr ee AV bl ock wi t h no pacemaker .
( 2) Di sopyrami de shoul d be avoi ded or used wi t h ext r eme caut i on i n pat i ent s wi t h
CHF. Ì t shoul d al so be used caut i ousl y i n pat i ent s wi t h uri nar y t r act di sorder s,
myast heni a gr avi s, and renal or hepat i c dysf unct i on.
( 3) Ì n pat i ent s r ecei vi ng t hi s drug f or at r i al t achyar r hyt hmi as, vagol yt i c ef f ect s may
i ncrease i mpul se conduct i on at t he AV node, resul t i ng i n an accel erat ed vent r i cul ar
r esponse. To pr event t hi s, agent s t hat sl ow AV nodal conduct i on (e. g. , ver apami l ,
di goxi n) may be gi ven.
( 4) Ant i chol i ner gi c ef f ect s of t hi s dr ug i ncl ude dr y mout h, const i pat i on, uri nar y
hesi t ancy or r et ent i on, and bl ur red vi si on.
( 5) Ther apeut i c pl asma l evel s r ange f r om 2 t o 4 µg/ mL.
d. Li docai ne ( Li docai ne)
( 1) Thi s drug may cause hemodynami c compromi se i n pat i ent s wi t h sever e cardi ac
dysf unct i on. Gener al l y, however , i t has f ew unt owar d cardi ovascul ar ef f ect s.
( 2) Li docai ne shoul d be used caut i ousl y and i n reduced dosage i n pat i ent s wi t h CHF
or r enal or hepat i c i mpai r ment .
( 3) Cent r al ner vous syst em ( CNS) r eact i ons ar e t he most pronounced adver se
ef f ect s of l i docai ne. These react i ons may r ange f r om l i ght headedness and
r est l essness t o conf usi on, t remor s, st upor , and convul si ons.
( 4) Ti nni t us, bl ur r ed vi si on, and anaphyl axi s have been repor t ed.
( 5) Pl asma l i docai ne l evel s of 1. 5- 6. 5 µg/ mL ar e t her apeut i c.
( 6) Li docai ne' s met abol i t es÷gl yci nexyl i di de and monoet hyl gl yci nexyl i di de÷may
have neurot oxi c as wel l as ant i ar rhyt hmi c ef f ect s.
P. 839


e. Phenyt oi n ( Di I ant i n)
( 1) Thi s drug i s cont r ai ndi cat ed i n pat i ent s wi t h si nus bradycar di a or heart bl ock.
( 2) Phenyt oi n must be used caut i ousl y i n pat i ent s wi t h hear t f ai l ur e ( HF) , r enal or
hepat i c i mpai rment , myocar di al i nsuf f i ci ency, r espi r at or y depr essi on, or
hypot ensi on.
( 3) Duri ng acut e t her apy, t hi s dr ug may cause CNS r eact i ons ( e. g. , drowsi ness,
ver t i go, nyst agmus, at axi a, nausea) . Car di ot oxi ci t y al so may occur , especi al l y wi t h
f ast i nt r avenous i nf usi on r at es.
( 4) Chroni c phenyt oi n may l ead t o vest i bul ar and cerebel l ar ef f ect s, behavi or al
changes, GÌ di st ress, gi ngi val hyperpl asi a, megal obl ast i c anemi a, and ost eomal aci a.
( 5) Hypersensi t i vi t y react i ons may be mani f est ed by l i ver, ski n, and hemat ol ogi cal
pr obl ems.
( a) Toxi c hepat i t i s may occur .
( b) Ski n react i ons i ncl ude exf ol i at i ve dermat i t i s, St evens- Johnson syndr ome,
scar l at i ni f or m or morbi l l i f or m r ash, SLE, t oxi c epi der mal necr ol ysi s, eosi nophi l i a,
and er yt hema mul t i f orme.
( c) Hemat ol ogi cal r eact i ons i ncl ude agr anul ocyt osi s, megal obl ast i c anemi a,
l eukopeni a, t hrombocyt openi a, and pancyt openi a.
( 6) Ther apeut i c pl asma phenyt oi n l evel s r ange f rom 10 t o 18 µg/ mL.
f . Mexi I et i ne (Mexi t i I )
( 1) Thi s drug i s cont r ai ndi cat ed i n pat i ent s wi t h car di ogeni c shock or second- or
t hi rd- degr ee AV bl ock wi t h no pacemaker .
( 2) Tr emor i s an ear l y si gn of mexi l et i ne t oxi ci t y. Di zzi ness, at axi a, and nyst agmus
i ndi cat e an i ncr easi ng pl asma dr ug concent r at i on.
( 3) Hypot ensi on, br adycar di a, and wi dened QRS compl exes may devel op dur i ng
mexi l et i ne t herapy.
( 4) Adverse GÌ ef f ect s i ncl ude nausea and vomi t i ng.
( 5) Ther apeut i c ser um l evel s range f rom 0. 50 t o 2. 0 µg/ mL.
g. FI ecai ni de ( Tambocor)
( 1) Thi s drug i s cont r ai ndi cat ed i n pat i ent s wi t h car di ogeni c shock or second- or
t hi rd- degr ee AV bl ock wi t h no pacemaker .
( 2) The ECG shoul d be moni t ored duri ng f l ecai ni de t her apy because t hi s dr ug may
exacer bat e exi st i ng ar rhyt hmi as or pr eci pi t at e new ones. Fl ecai ni de was shown i n
t he CAST st udy t o i ncrease mor t al i t y i n pat i ent s wi t h asympt omat i c vent ri cul ar
ar r hyt hmi as and, t her ef or e, shoul d be r eser ved f or pat i ent s wi t h l i f e- t hreat eni ng
vent r i cul ar ar r hyt hmi as t hat ar e ref ract or y t o ot her drugs.
( 3) Thi s drug has a si gni f i cant negat i ve i not ropi c ef f ect and may br i ng on or wor sen
CHF and car di omyopat hy.
( 4) Adverse CNS ef f ect s ( e. g. , di zzi ness, headache, t r emor ) and GÌ ef f ect s ( e. g. ,
nausea, abdomi nal pai n) may occur .
( 5) Bl ur r ed vi si on and dyspnea have been r eport ed.
( 6) Ther apeut i c ser um l evel s recommended f or f l ecai ni de ar e bet ween 0. 2 and 1. 0
µg/ mL.
h. Propaf enone ( Ryt hmoI ) , Ryt hmoI ( SR)
( 1) Thi s drug, l i ke ot her ant i ar r hyt hmi c agent s, may cause new or wor sened
ar r hyt hmi as. Such pr oar rhyt hmi c pr oper t i es r ange f r om an i ncreased f r equency of
PVCs t o t he devel opment of severe vent r i cul ar t achycar di a, vent r i cul ar f i br i l l at i on,
and t orsades de poi nt es. Thi s pr oarr hyt hmi c ef f ect has been under di scussi on f or
t he cl ass Ì C agent s; t hus, when used, t hese agent s shoul d be moni t ored cl osel y.
The f i ndi ngs f r om t he CAST st udy must be wei ghed agai nst t he benef i t s of usi ng
t hese agent s f or t r eat i ng si gni f i cant vent r i cul ar arr hyt hmi as.
( 2) Di zzi ness i s a si de ef f ect t hat has been r epor t ed i n as many as 10%- 15% of
pat i ent s t aki ng t he drug.
( 3) Ot her associ at ed si de ef f ect s i ncl ude vomi t i ng, a met al l i c bi t t er t ast e i n t he
mout h, const i pat i on, headache, and new or wor seni ng CHF and ast hma.
( 4) Ther apeut i c ser um l evel s recommended f or propaf enone ar e bet ween 0. 06 and
1. 0 µg/ mL.
5. Si gni f i cant i nteracti ons
a. Qui ni di ne
( 1) Qui ni di ne may i ncrease serum l evel s of di goxi n and i ncr ease t he ef f ect s of
di gi t aI i s on t he hear t , wi t h a r esul t ant i ncrease i n t oxi ci t y.
P. 840


( 2) Severe ort host at i c hypot ensi on may occur wi t h concomi t ant admi ni st rat i on of
vasodi I at ors (e. g. , ni t rogI yceri n) .
( 3) Phenyt oi n, ri f ampi n ( Ri f adi n) , and barbi t urat es may ant agoni ze qui ni di ne
act i vi t y and reduce i t s t her apeut i c ef f i cacy.
( 4) Ni f edi pi ne (Procardi a) may r educe pl asma qui ni di ne l evel s.
( 5) Ant aci ds, sodi um bi carbonat e ( Neut ), and sodi um acet azoI ami de (Di amox)
may i ncrease pl asma qui ni di ne l evel s, possi bl y r esul t i ng i n t oxi ci t y.
( 6) Qui ni di ne may produce addi t i ve hypopr ot hr ombi nemi c ef f ect s wi t h coumari n
ant i coagul ant s.
b. Ami odarone ( Cordarone) and ci met i di ne ( Tagamet) may i ncr ease pl asma
pr ocai nami de l evel s, possi bl y l eadi ng t o dr ug t oxi ci t y.
c. Phenyt oi n accel er at es di sopyr ami de met abol i sm, possi bl y r educi ng i t s
t her apeut i c ef f i cacy.
d. Li docai ne
( 1) Phenyt oi n may i ncr ease t he car di odepressant ef f ect s of l i docai ne.
( 2) ß- BI ockers (cl ass Ì Ì ant i ar r hyt hmi cs) may r educe l i docai ne met abol i sm, possi bl y
l eadi ng t o drug t oxi ci t y.
e. Phenyt oi n
( 1) The ri sk of phenyt oi n t oxi ci t y i ncreases wi t h concomi t ant admi ni st r at i on of
di azepam ( VaI i um) , ant i hi st ami nes, i soni azi d (Nydrazi d) , chI orampheni coI
( ChI oromycet i n) , ci met i di ne (Tagamet ) , saI i cyI at es, suI f i soxazoI e ( Gant ri si n),
ami odarone ( Cordarone) , and vaI proat e ( Depacon) .
( 2) Carbamazepi ne ( Tegret oI ) may enhance phenyt oi n met abol i sm and t hus r educe
pl asma phenyt oi n l evel s and t herapeut i c ef f i cacy. ( Phenyt oi n has t he same ef f ect on
car bamazepi ne. )
f . Mexi I et i ne (Mexi t i I ). Phenobarbi taI , ri f ampi n ( Nydrazi d) , and phenyt oi n
( Di I ant i n) reduce pl asma mexi l et i ne l evel s and may decrease t herapeut i c ef f i cacy.
B. CI ass I I anti arrhyt hmi cs
1. I ndi cat i ons. These drugs֧- adrenergi c bI ockers-ar e used mai nl y t o t r eat
syst emi c hyper t ensi on. Among t he dr ugs i n t hi s cl ass, propranol ol , esmol ol , and
acebut ol ol ar e approved f or ant i ar r hyt hmi c use.
a. PropranoI oI - ( I nderaI ) may be gi ven t o:
( 1) Cont r ol supravent ri cul ar ar r hyt hmi as ( e. g. , at ri al f i br i l l at i on or f l ut t er , PSVTs)
( 2) Tr eat t achyar rhyt hmi as caused by cat echol ami ne st i mul at i on ( e. g. , i n
hyper t hyr oi di sm, duri ng anest hesi a)
( 3) Suppr ess sever e vent r i cul ar ar rhyt hmi as i n proI onged QT syndrome
( 4) Tr eat di gi t al i s-i nduced vent ri cul ar ar rhyt hmi as
( 5) Ter mi nat e cer t ai n vent r i cul ar ar r hyt hmi as ( e. g. , PVCs i n pat i ent s wi t hout
st r uct ur al hear t di sease)
b. EsmoI oI ( Brevi bI oc) i s used t o t r eat supr avent r i cul ar t achycar di as; i t possesses
a shor t ( 9-mi n) hal f -l i f e and has been used t o cont r ol t he vent r i cul ar response t o
at r i al f i bri l l at i on or f l ut t er duri ng or af t er sur ger y.
2. Mechani sm of act i on. Cl ass Ì Ì ant i ar rhyt hmi cs r educe sympat het i c st i mul at i on of
t he heart , decr easi ng i mpul se conduct i on t hrough t he AV node and l engt heni ng t he
r ef r act or y peri od. Addi t i onal l y, t hi s cl ass of ant i arr hyt hmi cs sl ow t he si nus r hyt hm
wi t hout si gni f i cant l y changi ng t he QT or QRS i nt er val s, r esul t i ng i n a reduced hear t
r at e and a decr ease i n myocar di al oxygen demand.
3. Admi ni st rat i on and dosage
a. PropranoI oI may be gi ven i nt r avenousl y or or al l y when used as an
ant i ar r hyt hmi c.
( 1) Emer gency t her apy cal l s f or sl ow i nt r avenous admi ni st r at i on of 1- 3 mg di l ut ed i n
50 mL dext r ose 5% i n wat er or nor mal sal i ne sol ut i on. Thi s dose i s i nf used sl owl y
( no f ast er t han 1 mg/ mi n) . A second dose of 1- 3 mg may be gi ven 2 mi n l at er .
( 2) For oral t herapy, 10-80 mg/ day i s gi ven i n 3-4 doses. ( However , 1000 mg or
mor e may be r equi red f or r esi st ant vent r i cul ar ar rhyt hmi as. )
b. EsmoI oI i s gi ven i nt r avenousl y. A l oadi ng dose of 500 µg/ kg/ mi n i s i nf used over
1 mi n, f ol l owed by a 4-mi n mai nt enance i nf usi on of 50 µg/ kg/ mi n. Ì f a sat i sf act or y
r esponse i s not achi eved wi t hi n 5 mi n, t he l oadi ng dose i s r epeat ed and f ol l owed by
a mai nt enance i nf usi on of 100 µg/ kg/ mi n.
P. 841


4. Precauti ons and moni t ori ng ef f ect s
a. PropranoI oI ( I nderaI )
( 1) Thi s drug i s cont r ai ndi cat ed i n pat i ent s wi t h si nus bradycar di a, second- or t hi r d-
degree AV bl ock, cardi ogeni c shock, severe HF, or ast hma.
( 2) The 8- bl ocki ng ef f ect s of t hi s dr ug may l ead t o mar ked hypot ensi on,
exacer bat i on of CHF and l ef t vent ri cul ar f ai l ur e, or cardi ac ar r est .
( 3) Bl ood pr essur e, heart r at e, and t he ECG shoul d be moni t ored duri ng i nt r avenous
i nf usi on.
( 4) Embol i sm may occur upon r est orat i on of normal si nus r hyt hm af t er sust ai ned
at r i al f i bri l l at i on. An ant i coagul ant may be gi ven bef ore pr opranol ol t her apy begi ns
t o prevent t hi s compl i cat i on.
( 5) Pr opr anol ol may depress AV node conduct i on and vent r i cul ar pacemaker
act i vi t y, r esul t i ng i n AV bl ock or asyst ol e.
( 6) Thi s drug may mask t he si gns and sympt oms of hypogl ycemi a. Ì t al so may mask
si gns of shock.
( 7) Fat i gue, l et har gy, i ncr eased ai r way r esi st ance, and ski n rash have been
r eport ed.
( 8) Nausea, vomi t i ng, and di ar r hea may occur .
( 9) Sudden wi t hdrawal of pr opr anol ol may l ead t o acut e MÌ , ar r hyt hmi as, or angi na
i n car di ac pat i ent s. Dr ug t herapy i s di scont i nued by t aper i ng t he dose over 4- 7
days.
b. EsmoI oI ( Brevi bI oc)
( 1) Thi s drug i s cont r ai ndi cat ed i n pat i ent s wi t h sever e CHF or si nus br adycar di a.
( 2) Hypot ensi on occurs i n appr oxi mat el y 30% of pat i ent s recei vi ng esmol ol . Thi s
ef f ect can be r eversed by r educi ng t he dosage or st oppi ng t he i nf usi on.
( 3) Thi s drug i s f or shor t - t er m use onl y and shoul d be r epl aced by a l ong-act i ng
ant i ar r hyt hmi c once t he pat i ent ' s hear t st abi l i zes.
( 4) Di zzi ness, headache, f at i gue, and agi t at i on may occur .
( 5) Ot her adver se ef f ect s i ncl ude nausea, vomi t i ng, and br onchospasm.
5. Si gni f i cant i nteracti ons
a. PropranoI oI
( 1) Severe vasoconst r i ct i on may occur wi t h concomi t ant epi nephri ne admi ni st r at i on.
( 2) Di gi t aI i s pr epar at i ons can cause excessi ve br adycardi a.
( 3) CaI ci um- channeI bI ockers÷f or exampl e, di I t i azem ( Cardi zem) and verapami I
( CaI an) ÷and ot her negat i ve i not ropi c and chronot ropi c drugs÷such as
di sopyrami de ( Norpace) and qui ni di ne÷add t o t he myocar di al depr essant ef f ect s
of propranol ol .
b. EsmoI oI . Morphi ne (MS Conti n) may rai se pl asma esmol ol l evel s.
C. CI ass I I I ant i arrhyt hmi cs
1. I ndi cat i ons
a. Ami odarone ( Cordarone) i s gi ven t o cont rol mal i gnant vent ri cul ar arrhyt hmi as
and has most r ecent l y wi t hi n t he new advanced car di ac l i f e support ( ACLS)
gui del i nes been r ecommended i n t he t r eat ment of vent ri cul ar f i br i l l at i on and
pul sel ess vent r i cul ar t achycar di a, and may be used prophyl act i cal l y agai nst bot h
at r i al and vent ri cul ar t achycar di a and f i br i l l at i on. Unl i ke most ot her ant i ar rhyt hmi cs,
wi t h t he except i on of t he 8- adrenergi c bl ocker s, ami odar one has been shown t o
r educe ar r hyt hmi c deat hs i n pat i ent s af t er an MÌ .
b. SotaI oI ( Bet apace) i s used t o t reat supr avent ri cul ar and vent r i cul ar
t achyar r hyt hmi as. Sot al ol ant agoni zes bot h 81- and 82- adrener gi c recept or s, but
al so prol ongs t he phase 3 act i on pot ent i al . Ì t i s t hi s pr opert y t hat di st i ngui shes i t
f r om ot her 8-adrenergi c bl ocker s and i s t he r eason why i t i s cl assi f i ed as a t ype Ì Ì Ì
ant i ar r hyt hmi c dr ug r at her t han a t ype Ì Ì agent (8- adr ener gi c bl ocker ) .
c. I but i I i de ( Corvert ) i s used i n t he conver si on of at ri al f i br i l l at i on and f l ut t er of
r ecent onset ( durat i on < 30 days) .
d. Dof et i I i de (Ti kosyn) i s avai l abl e i n t he Uni t ed St at es under r est ri ct ed access i n
t he t r eat ment of at r i al f i br i l l at i on/ f l ut t er.
2. Mechani sm of act i on. Cl ass Ì Ì Ì ant i arr hyt hmi c dr ugs pr ol ong t he ref r act or y
per i od and act i on pot ent i al ; t hey have no ef f ect on myocardi al cont r act i l i t y or
conduct i on t i me.
P. 842


3. Admi ni st rat i on and dosage
a. Ami odarone ( Cordarone) Avai l abl e f or bot h or al and i nt r avenous use and shoul d
onl y be i ni t i at ed i n t he hospi t al set t i ng. Ami odarone has been i ncor por at ed i nt o t he
most recent ACLS ( 2005) gui del i nes and r ecommended by t he exper t panel members
as t he f i rst -choi ce ant i arr hyt hmi c f or shock- ref r act or y vent ri cul ar
f i bri l l at i on/ vent r i cul ar t achycar di a.
( 1) Ì t i s avai l abl e f or oral use; 800-1600 mg ever y 12 hr i s gi ven f or 7- 14 days, t hen
200-400 mg dai l y t hereaf t er .
( 2) Or al t r eat ment i s used t o suppress vent r i cul ar and supr avent r i cul ar ar rhyt hmi as
but can t ake days or weeks t o t ake ef f ect . Or al doses of 100-600 mg/ day ( usual l y
300-400 mg/ day) f or mai nt enance t herapy i n vent r i cul ar t achycar di a and 100- 200
mg/ day f or mai nt enance t her apy f or supr avent r i cul ar t achycar di as are gi ven.
( 3) Ì nt r avenous f or mul at i on i s avai l abl e f or t reat ment and pr ophyl axi s of recur rent
vent r i cul ar f i bri l l at i on or hemodynami cal l y unst abl e vent r i cul ar t achycardi a i n
r ef r act or y pat i ent s.
( 4) The i nt ravenous f orm i s r api dl y di st r i but ed t hroughout t he body. Recommended
doses i ncl ude a rapi d l oadi ng i nf usi on of 150 mg over 10 mi n, f ol l owed by a sl ow
i nf usi on of 1 mg/ mi n f or 6 hr (360 mg) , and t hen a mai nt enance i nf usi on of 0. 5
mg/ mi n f or t he remai nder of t he 24-hr per i od. Pat i ent s usual l y r ecei ve 2- 4 days of
i nf usi ons bef ore conversi on t o or al f orm. However , a mai nt enance i nf usi on can be
cont i nued f or 2-3 weeks.
b. SotaI oI ( Bet apace) i s avai l abl e commer ci al l y as an or al t abl et , and t her apy
shoul d be i ni t i at ed wi t hi n t he hospi t al set t i ng. Normal dosi ng of 80 mg t wi ce dai l y
i ni t i al l y and i ncr easi ng doses at 2- t o 3- day i nt er val s t o a maxi mum dose of 640
mg/ day, gi ven i n 2- 3 doses t hr oughout t he day.
c. I but i I i de ( Corvert ) i s avai l abl e onl y f or i nj ect i on i n a 0. 1- mg/ mL, 10-mL vi al .
Nor mal doses f or t he conver si on of recent -onset at r i al f i bri l l at i on t o normal si nus
r hyt hm i s a dose of 1 mg ( 0. 01 mg/ kg f or t hose < 60 kg) over 10 mi n, wi t h a r epeat
dose i n 10 mi n i f t he ar rhyt hmi a does not end.
d. Dof et i I i de (Ti kosyn) i s avai l abl e onl y f or oral admi ni st rat i on i n 0. 125-, 0. 25- , and
0. 5-mg capsul es under t he t rade name of Ti kosyn and shoul d onl y be i ni t i at ed i n a
hospi t al set t i ng wi t h t r ai ned personnel and t he equi pment necessar y t o pr ovi de
cont i nuous cardi ac moni t or i ng dur i ng i ni t i at i on of t her apy.
( 1) A normal dose f or t he conversi on of r ecent - onset at r i al f i bri l l at i on t o nor mal
si nus r hyt hm i s 0. 5 mg t wi ce dai l y f or pat i ent s wi t h cr eat i ni ne cl ear ance val ues > 60
mL/ mi n; doses ar e r educed 50% (0. 25 mg) f or t hose wi t h cr eat i ni ne cl ear ance
val ues of 40- 60 mL/ mi n, and doses are r educed an addi t i onal 50% ( 0. 125 mg) f or
t hose wi t h cr eat i ni ne cl ear ance val ues of 20- 40 mL/ mi n.
( 2) Mai nt enance t her apy i s based on t he ECG; wi t h doses bei ng r educed wi t h QTc
pr ol ongat i on exceedi ng 15% of t he basel i ne val ue. Any pat i ent devel opi ng a QTc
i nt er val exceedi ng 500 msec shoul d have t her apy di scont i nued i mmedi at el y.
( 3) Dof et i l i de shoul d not be gi ven t o t hose wi t h creat i ni ne cl ear ance val ues < 20
mL/ mi n.
4. Precauti ons and moni t ori ng ef f ect s
a. Ami odarone ( Cordarone)
( 1) Li f e-t hr eat eni ng pul monar y t oxi ci t y may occur dur i ng ami odar one t herapy,
especi al l y i n pat i ent s r ecei vi ng > 400 mg/ day. Basel i ne as wel l as r out i ne pul monar y
f unct i on t est s r eveal r el evant pul monar y changes.
( 2) Most pat i ent s devel op cor neal mi crodeposi t s 1- 4 mont hs af t er ami odar one
t her apy begi ns. However , t hi s react i on r ar el y causes vi sual di st ur bance, but t he
pat i ent shoul d be moni t or ed wi t h rout i ne opht hal mol ogi cal exami nat i ons.
( 3) Bl ood pr essur e and hear t rat e and r hyt hm shoul d be moni t or ed f or hypot ensi on
and br adyar r hyt hmi as.
( 4) Pat i ent s shoul d be moni t or ed r out i nel y f or t he possi bl e devel opment of hepat i c
dysf unct i on, t hyr oi d di sor ders ( e. g. , hypert hyr oi di sm, hypot hyr oi di sm) , and
phot osensi t i vi t y.
( 5) CNS r eact i ons i ncl ude f at i gue, mal ai se, per i pher al neur opat hy, and
ext r apyr ami dal ef f ect s.
( 6) Nausea and vomi t i ng have been r epor t ed.
( 7) Thi s drug has an ext r emel y l ong hal f - l i f e ( up t o 60 days) . Therapeut i c r esponse
may be del ayed f or weeks af t er or al t her apy begi ns; adverse r eact i ons may persi st
up t o 4 mont hs af t er t herapy ends.
P. 843


b. SotaI oI ( Bet apace)
( 1) Si de ef f ect s of t hi s dr ug ar e di r ect l y r el at ed t o 8- bl ockade and prol ongat i on of
r epol ari zat i on.
( 2) Tr ansi ent hypot ensi on, bradycar di a, myocar di al depressi on, and bronchospasm
have al l been associ at ed wi t h t hi s dr ug.
( 3) Thi s drug car ri es al l t he cont r ai ndi cat i ons associ at ed wi t h ot her 8- bl ockers al ong
wi t h t hose owi ng t o i t s el ect rophysi ol ogi c propert i es.
c. I but i I i de ( Corvert )
( 1) Ì nf usi on shoul d be di scont i nued as soon as t he at ri al ar rhyt hmi a i s t ermi nat ed or
i f sust ai ned or nonsust ai ned vent r i cul ar ar r hyt hmi a or marked QT pr ol ongat i on i s
document ed.
( 2) Cont i nuous ECG moni t ori ng i s r equi r ed f or at l east 4 hr af t er di scont i nui ng t he
i nf usi on or unt i l t he QT i nt er val r et ur ns t o basel i ne.
d. Dof et i I i de (Ti kosyn)
( 1) Pat i ent s need t o be moni t ored cl osel y f or t he subsequent devel opment of
vent r i cul ar ar r hyt hmi as wi t h i ncr easi ng doses of dof et i l i de or wi t h decl i ni ng r enal
st at us. Ì n cl i ni cal t r i al s, vent r i cul ar t achycardi as, i ncl udi ng t or sades de poi nt es, are
t he most f r equent l y occur r i ng ar rhyt hmi as due t o dof et i l i de.
( 2) Hypokal emi a and t hose si t uat i ons t hat mi ght cause hypot ensi on wi l l pr edi spose
a pat i ent t o pr ol ongat i on of t he QT i nt er val , whi ch coul d put a dof et i l i de pat i ent at
r i sk f or t oxi c ar r hyt hmi as.
5. Si gni f i cant i nteracti ons
a. Ami odarone
( 1) Ami odar one may i ncrease t he pl asma l evel s of qui ni di ne, procai nami de,
di I t i azem, di gi taI i s, and f I ecai ni de.
( 2) Ì t may i ncr ease t he phar macol ogi cal ef f ect of ß- bI ockers, caI ci um-channeI
bI ockers, and warf ari n.
( 3) Speci aI not e: Ami odar one has been report ed t o have numer ous dr ug-dr ug
i nt er act i ons among al l cat egor i es of dr ugs. To avoi d t he devel opment of a
si gni f i cant dr ug- drug i nt er act i on a t hor ough pat i ent medi cat i on pr of i l e shoul d be
car ri ed out f or each pat i ent havi ng ami odar one t her apy i ni t i at ed, as wel l as each
t i me a pat i ent cur rent l y recei vi ng ami odarone i s gi ven an addi t i onal drug.
b. SotaI oI
( 1) Sot al ol must be used caut i ousl y i n t hose pat i ent s r ecei vi ng agent s wi t h
car di acdepr essant proper t i es.
( 2) Agent s such as sot al ol , whi ch pr ol ong t he QT i nt er val , may i nduce mal i gnant
ar r hyt hmi as when used i n combi nat i on wi t h ot her t ype Ì A ant i arr hyt hmi cs, especi al l y
i n t he pr esence of l ow pot assi um l evel s.
c. I but i I i de shoul d be avoi ded wi t h ot her agent s t hat pr ol ong r epol ar i zat i on or
wi t hi n 4 hr of admi ni st r at i on.
d. Dof et i I i de shoul d be avoi ded i n pat i ent s who have hypokal emi a or preexi st i ng QT
pr ol ongat i on.
D. CI ass I V ant i arrhyt hmi cs
1. I ndi cat i ons
a. CaI ci um- channeI bI ockers ( e. g. , verapami l , Cal an; di l t i azem, Car di zem) ar e
used mai nl y t o t reat and pr event supr avent ri cul ar ar r hyt hmi as.
( 1) They ar e f i r st -l i ne agent s f or t he suppr essi on of PSVTs st emmi ng f rom AV nodal
r eent r y.
( 2) They can rapi dl y cont r ol t he vent r i cul ar r esponse t o at ri al f l ut t er and f i br i l l at i on.
b. Ot her cal ci um-channel bl ockers avai l abl e i ncl ude ni car di pi ne, ni f edi pi ne, bepr i di l ,
aml odi pi ne, and f el odi pi ne, but t hese agent s have pri mar i l y been used i n t he
t r eat ment of angi na pect or i s and hyper t ensi on. For i nf ormat i on on t hese agent s, see
Chapt er s 39 and 41.
2. Mechani sm of act i on. Cl ass Ì V ant i ar r hyt hmi cs are cal ci um-channel bl ockers.
They i nhi bi t AV node conduct i on by depr essi ng t he SA and AV nodes, wher e cal ci um
channel s predomi nat e.
P. 844


3. Admi ni st rat i on and dosage
a. To cont rol at ri al ar rhyt hmi as, ver apami l usual l y i s admi ni st er ed i nt r avenousl y. A
dose of 2. 5- 10 mg i s gi ven over at l east 2 mi n and may be repeat ed i n 30 mi n, i f
necessar y. A 5-10 mg/ hr cont i nuous i nt r avenous i nf usi on has al so been used i n
t r eat i ng ar rhyt hmi as.
b. To pr event PSVTs, ver apami l may be gi ven oral l y i n f our dai l y doses of 80-120
mg each.
c. To cont rol at ri al ar rhyt hmi as, di l t i azem usual l y i s admi ni st ered i nt ravenousl y. A
dose of 20 mg ( 0. 25 mg/ kg) i s gi ven over 2 mi n. Ì f an adequat e r esponse i s not
obt ai ned, a second dose of 25 mg (0. 35 mg/ kg) i s admi ni st er ed af t er 15 mi n. A 5- 15
mg/ hr i nt r avenous cont i nuous i nf usi on has al so been used i n t r eat i ng ar r hyt hmi as.
4. Precauti ons and moni t ori ng ef f ect s
a. Verapami l and di l t i azem are cont r ai ndi cat ed i n pat i ent s wi t h AV bl ock; l ef t
vent r i cul ar dysf unct i on; sever e hypot ensi on; concomi t ant , i nt r avenous 8-bl ocker s;
and at r i al f i br i l l at i on wi t h an accessor y AV pat hway.
b. These drugs must be used caut i ousl y i n pat i ent s wi t h CHF, si ck si nus syndr ome,
MÌ , and hepat i c or renal i mpai rment .
c. Because of t he negat i ve chronot r opi c ef f ect , ver apami l and di l t i azem must be
used caut i ousl y i n pat i ent s who have sl ow hear t rat es or who ar e r ecei vi ng di gi t al i s
gl ycosi des.
d. The ECG ( especi al l y t he RR i nt er val ) shoul d be moni t or ed dur i ng t herapy.
e. Pat i ent s > 60 year s ol d shoul d recei ve reduced dosages and sl ower i nj ect i on
r at es.
f . Const i pat i on and nausea have been r epor t ed wi t h verapami l .
5. Si gni f i cant i nteracti ons
a. Concomi t ant admi ni st rat i on of ß-bI ockers or di sopyrami de may preci pi t at e hear t
f ai l ur e.
b. Qui ni di ne may i ncrease t he r i sk of cal ci um- channel bl ocker - i nduced hypot ensi on.
c. Verapami l may i ncrease serum di goxi n concent r at i ons, and di l t i azem may do t he
same t o a l esser ext ent .
d. Ri f ampi n may enhance t he met abol i sm of cal ci um-channel bl ockers, wi t h a
r esul t ant decr ease i n phar macol ogi cal ef f ect .
e. Verapami l and di l t i azem may i nhi bi t t heophyI I i ne met abol i sm and may r equi r e
r educt i ons i n t heophyl l i ne dosage.
f . Di l t i azem and ver apami l i nhi bi t t he met abol i sm of cycI ospori ne ( Gengraf ) and
may r equi r e reduct i ons i n cycl ospor i ne dosages.
E. UncI assi f i ed ant i arrhyt hmi cs
1. At ropi ne
a. I ndi cat i ons. At r opi ne i s t herapeut i c f or sympt omat i c si nus bradycar di a and
j unct i onal rhyt hm.
b. Mechani sm of act i on. An ant i chol i ner gi c, at r opi ne bl ocks vagal ef f ect s on t he SA
node, promot i ng conduct i on t hr ough t he AV node and i ncr easi ng t he hear t r at e.
c. Admi ni st rat i on and dosage. For ant i ar r hyt hmi c use, at ropi ne i s admi ni st ered i n
a dose of 0. 4-1 mg by i nt r avenous push; t he dose i s gi ven ever y 5 mi n t o a
maxi mum of 2 mg.
d. Precaut i ons and moni t ori ng ef fects
( 1) Thi rst and dr y mout h ar e t he most common adver se ef f ect s of at r opi ne.
( 2) CNS r eact i ons ( e. g. , r est l essness, headache, di sor i ent at i on, di zzi ness) may
occur wi t h doses over 5 mg.
( 3) Tachycar di a and opht hal mi c di st urbances (e. g. , mydr i asi s, bl ur r ed vi si on,
phot ophobi a) may occur wi t h doses of 1 mg or mor e.
( 4) Ì ni t i al doses may i nduce a ref l ex br adycardi a owi ng t o i ncompl et e suppr essi on of
vagal i mpul ses.
2. Adenosi ne ( Adenocard)
a. I ndi cat i ons. Adenosi ne i s i ndi cat ed f or t he conver si on of acut e supr avent ri cul ar
t achycardi a t o normal si nus r hyt hm.
b. Mechani sm of act i on. Adenosi ne i s a nat ural l y occur r i ng nucl eosi de, whi ch i s
nor mal l y pr esent i n al l cel l s of t he body. Ì t has been shown t o:
( 1) Sl ow conduct i on t hr ough t he AV node
( 2) Ì nt er rupt r eent r y pat hways t hr ough t he AV node
( 3) Rest ore nor mal si nus r hyt hm i n pat i ent s wi t h PSVTs
c. Admi ni st rat i on and dosage. For ant i ar r hyt hmi c ef f ect s, adenosi ne i s gi ven as a
r api d bol us i nt ravenous i nj ect i on i n a 6-mg dose over 1-2 sec. Ì f t he f i rst dose does
not el i mi nat e t he ar r hyt hmi a wi t hi n 1- 2 mi n, t he dose shoul d be i ncr eased t o 12 mg
and agai n gi ven as a r api d i nt ravenous dose. An addi t i onal 12- mg dose may be
r epeat ed i f necessar y.
P. 845


d. Precaut i ons and moni t ori ng ef fects
( 1) The ef f ect s of adenosi ne are ant agoni zed by met hyl xant hi nes, such as caf f ei ne
and t heophyl l i ne. Theophyl l i ne has been successf ul l y used f or t r eat i ng adenosi ne-
i nduced si de ef f ect s, such as hypot ensi on, sweat i ng, and pal pi t at i ons. Ì f si de ef f ect s
ar e encount ered, aggr essi ve t herapy i s not requi red because of t he ul t ra-shor t hal f -
l i f e of t he drug (10 sec or l ess).
( 2) The mai n si de ef f ect associ at ed wi t h adenosi ne use i n up t o 18% of pat i ent s i s
f aci al f l ushi ng, but t hi s ef f ect i s normal l y ver y shor t - l i ved.
( 3) Ot her si de ef f ect s associ at ed wi t h adenosi ne use i ncl ude shor t ness of br eat h,
chest pr essur e, nausea, headache, and a met al l i c t ast e.
e. Addi t i onaI use. Adenosi ne has been used as an adj unct i ve agent i n pat i ent s
under goi ng var i ous t ypes of phar macol ogi cal st ress t est i ng ( e. g. , wi t h t hal l i um) . Ì n
t hi s si t uat i on, adenosi ne i s gi ven as a cont i nuous i nf usi on over a per i od of 4- 6 mi n
and i s abl e t o pr ovi de a f or m of exer ci se t ol erance t est i n pat i ent s not abl e t o exer t
t hemsel ves owi ng t o age, f at i gue, and var i ous ot her physi cal handi caps.
P. 846


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s can be
cor rect l y answer ed or compl et ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer .
1. St rong ant i choI i nergi c ef fects I i mi t the ant i arrhyt hmi c use of
( A) qui ni di ne.
( B) pr ocai nami de.
( C) t ocai ni de.
( D) f l ecai ni de.
( E) di sopyr ami de.
Vi ew Answer 1. The answer i s E[see] . 2. A pronounced sI owi ng of phase 0
of t he myocardi aI acti on potent i aI resuI ts i n a proI ongat i on of ei ther at ri aI
depoI ari zat i on causi ng a proI onged P wave on t he eI ect rocardi ogram (ECG) or
vent ri cuI ar depoI ari zat i on causi ng a proI onged QRS compI ex characteri zed by
whi ch cI ass of anti arrhyt hmi cs?
( A) t ype Ì
( B) t ype Ì Ì
( C) t ype Ì Ì Ì
( D) t ype Ì V
( E) t ype V
Vi ew Answer 2. The answer i s A[ see] . 3. Whi ch of t he f oI I owi ng t ype I I I
ant i arrhyt hmi cs has been report ed as causi ng t he torsades de poi nt es t ype of
vent ri cuI ar t achycardi a?
( A) l i docai ne
( B) ami odar one
( C) qui ni di ne
( D) f l ecai ni de
( E) di l t i azem
Vi ew Answer 3. The answer i s B[ see] . 4. A pati ent recei vi ng a cI ass I
ant i arrhyt hmi c agent on a chroni c basi s compI ai ns of fat i gue, I ow- grade fever,
and j oi nt pai n suggest i ve of syst emi c I upus eryt hemat osus ( SLE) . The pati ent
i s most I i keI y recei vi ng
( A) l i docai ne.
( B) pr ocai nami de.
( C) qui ni di ne.
( D) f l ecai ni de.
( E) pr opr anol ol .
Vi ew Answer 4. The answer i s B[ see] . 5. CI ass I A ant i arrhyt hmi cs do aI I of
t he f oI I owi ng t o t he cardi ac ceI I ' s acti on pot ent i aI except
( A) sl ow t he rat e of r i se f or phase 0 of depol ari zat i on.
( B) del ay t he f ast - channel conduct ance of sodi um i ons.
( C) pr ol ong phases 2 and 3 of repol ari zat i on.
( D) i nhi bi t t he sl ow- channel conduct ance of cal ci um i ons.
( E) pr ol ong t he ref ract ory per i od of t he act i on pot ent i al .
Vi ew Answer 5. The answer i s D[ see] . 6. Whi ch of t he f oI I owi ng drugs i s a
cI ass I V ant i arrhyt hmi c t hat i s pri mari I y i ndi cat ed f or t he t reatment of
supravent ri cuI ar t achyarrhyt hmi as?
( A) i but i l i de
( B) mexi l et i ne
( C) ver apami l
( D) qui ni di ne
( E) pr opr anol ol
Vi ew Answer 6. The answer i s C[ see] . 7. Whi ch of t he f oI I owi ng agent s was
i nvoI ved i n the ARREST t ri aI and f or whi ch evi dence- based pract i ce j ust i f i es i t s
addi t i on as a f i rst - I i ne agent wi t hi n t he 2005 ACLS gui deI i nes?
( A) l i docai ne
( B) di l t i azem
( C) br et yl i um
( D) ami odar one
( E) dof et i l i de
Vi ew Answer 7. The answer i s D[ see] . p8. Whi ch of t he f oI I owi ng drugs i s a
cI ass I I I ant i arrhyt hmi c agent t hat i s ef fect i ve i n t he acut e management of
at ri aI f i bri I I at i on or at ri aI f I ut t er of recent onset ?
( A) pr opr anol ol
( B) dof et i l i de
( C) met oprol ol
( D) di sopyrami de
( E) di l t i azem
Vi ew Answer 8. The answer i s B[ see] . P. 847


9. AI I of t he f oI I owi ng probI ems represent concerns when pat i ent s are st arted
on ami odarone except
( A) ext r emel y l ong el i mi nat i on hal f - l i f e.
( B) need f or mul t i pl e dai l y doses.
( C) devel opment of hyper t hyr oi di sm or hypot hyr oi di sm.
( D) devel opment of pul monar y f i brosi s.
( E) i nt er act i ons wi t h ot her ant i ar r hyt hmi c dr ugs.
Vi ew Answer 9. The answer i s B[ see] . P. 848


ANSWERS AND EXPLANATIONS
1. The answer i s E [ see Ì Ì . A. 4. c. ( 4)] .
Di sopyr ami de has ant i chol i ner gi c act i ons about one t ent h t he pot ency of at r opi ne.
Ef f ect s i ncl ude dr y mout h, const i pat i on, ur i nar y ret ent i on, and bl ur r ed vi si on.
Ther ef ore, i t cannot be used i n pat i ent s wi t h gl aucoma or wi t h condi t i ons causi ng
ur i nar y r et ent i on. Mor eover , di sopyr ami de has a negat i ve i not r opi c ef f ect and must ,
t her ef ore, be used wi t h gr eat caut i on, i f at al l , i n pat i ent s wi t h pr eexi st i ng
vent r i cul ar f ai l ur e.
2. The answer i s A [ see Ì Ì . A. 2] .
The cl ass Ì ant i ar rhyt hmi cs ( f ast -channel bl ockers) sl ow i mpul se conduct i on by
depressi ng t he f l ow of sodi um i ons i nt o cel l s duri ng phase 0 of t he act i on pot ent i al .
Cl ass Ì Ì ant i ar r hyt hmi cs decrease i mpul se conduct i on t hr ough t he AV node and
l engt hen t he ref ract or y per i od t hr ough t hei r di r ect ef f ect s on t he sympat het i c
ner vous syst em. Cl ass Ì Ì Ì ant i ar rhyt hmi cs pr ol ong t he r ef ract or y per i od and act i on
pot ent i al and have no ef f ect on conduct i on t i me t hr oughout t he AV and SA nodes.
Cl ass Ì V ant i ar r hyt hmi cs wor k di rect l y on l ow- channel i on conduct i on, whi ch i s mor e
l i kel y t o t ake pl ace dur i ng phase 2 ( pl at eau) , when cal ci um i ons ent er t he cel l
t hr ough sl ow channel s. Cur r ent cl assi f i cat i on of ant i ar r hyt hmi cs does not i ncl ude a
gr oup of cl ass V agent s.
3. The answer i s B [ see Ì . C. 3; Tabl e 40- 1] .
Tor sades de poi nt es i s a f orm of vent ri cul ar t achyar r hyt hmi a char act eri zed by
el ect r ocar di ographi c changes, whi ch i ncl ude a mar kedl y pr ol onged QT i nt er val . Thi s
pot ent i al l y f at al react i on has now been report ed f or bot h ant i ar rhyt hmi cs and non-
ant i ar r hyt hmi cs. Ant i ar r hyt hmi cs, whi ch have been r epor t ed t o cause t orsades de
poi nt s, i ncl ude ami odar one, di sopyr ami de, dof et i l i de, f l ecai ni de, i but i l i de,
pr ocai nami de, qui ni di ne, and sot al ol . Ì n addi t i on, dr ug cl asses such as ant i bi ot i cs
( e. g. , er yt hr omyci n, l evof l oxaci n, moxi f l oxaci n, pent ami di ne, spar f l oxaci n) , al ong
wi t h ot her agent s ( such as, dol aset ron, f el bamat e, f l uoxet i ne, f osphenyt oi n,
i ndapami de, i sr adi pi ne, par oxet i ne, sumat ri pt an, and t amoxi f en) have been r epor t ed
t o be abl e t o cause ei t her a prol ongat i on i n t he QT i nt er val and/ or i nduce t or sades
de poi nt es ( Tabl e 40- 1). Of t he agent s l i st ed, onl y ami odarone i s a cl ass Ì Ì Ì
ant i ar r hyt hmi c.
4. The answer i s B [ see Ì Ì . A. 4. b. ( 7) ] .
The pat i ent ' s compl ai nt s ar e t ypi cal of a SLE- l i ke hypersensi t i vi t y react i on t o
pr ocai nami de. Sympt oms of an SLE- l i ke syndr ome i ncl ude f at i gue, ar t hr al gi a,
myal gi a, a l ow- gr ade f ever , and a posi t i ve ant i nucl ear ant i body t i t er . The pat i ent ' s
sympt oms shoul d subsi de i f pr ocai nami de t her apy i s st opped and an al t ernat i ve
ant i ar r hyt hmi c agent i s gi ven i nst ead.
5. The answer i s D [ see Ì Ì . A. 2] .
Cl ass Ì A ant i ar r hyt hmi c agent s del ay phase 0 of depol ari zat i on. Fast -channel
conduct i on of sodi um and phases 2 and 3 of r epol ar i zat i on are al so sl owed. The net
ef f ect i s t o ext end t he ref r act or y per i od of myocar di al t i ssue. Cl ass Ì A
ant i ar r hyt hmi c agent s do not i nhi bi t t he sl ow- channel conduct ance of cal ci um i ons÷
t hat i s an act i on of cl ass Ì V agent s such as ver apami l .
6. The answer i s C [ see Ì Ì . D. 1. a] .
Of t he agent s l i st ed, verapami l i s a cal ci um-channel bl ocker and r epr esent s t he
cl ass Ì V ant i ar rhyt hmi cs. Ver apami l has been used f or i t s di r ect -act i ng ef f ect s on
i mpul se conduct i on t hroughout t he hear t . Thus ver apami l i s used t o t r eat and
pr event supr avent ri cul ar ar r hyt hmi as. Ì but i l i de i s a cl ass Ì Ì Ì agent , qui ni di ne i s a
cl ass Ì A dr ug, mexi l et i ne i s a cl ass Ì B agent , and pr opranol ol , a 8- adr energi c
bl ocker , i s cl ass Ì Ì . Mexi l et i ne, qui ni di ne, and pr opr anol ol ar e al l al so ef f ect i ve f or
supravent ri cul ar arr hyt hmi as, and i but i l i de i s i ndi cat ed f or t he t r eat ment of at r i al
f i bri l l at i on/ f l ut t er of r ecent onset .
7. The answer i s D [ see Ì Ì . C. 3. a] .
Ì n t he ARREST t r i al , 44% of ami odar one-t r eat ed pat i ent s ver sus 34% of pl acebo-
t r eat ed pat i ent s sur vi ved t o hospi t al admi ssi on ( p = 0. 03) af t er shock- r ef ract or y
car di ac ar r est . The benef i t was consi st ent l y obser ved i n al l maj or subgr oups,
r egardl ess of t he present i ng car di ac- ar r est r hyt hm. As a r esul t of t he t ri al , evi dence
of i t s f i ndi ngs wer e ci t ed wi t hi n t he ACLS 2000 Gui del i nes, descri bi ng t he l ack of
si mi l ar dat a f or ot her ant i ar r hyt hmi cs, and t he agreement by t he exper t panel t hat
t hey woul d consi der ami odarone as a f i rst - l i ne agent f or such pat i ent s. Li docai ne
and br et yl i um ar e t he onl y ot her agent s l i st ed, whi ch have been used i n t hi s pat i ent
popul at i on f or vent r i cul ar t achyar r hyt hmi as. However , t he dat a have been l acki ng as
t o t hei r ef f i cacy compar ed t o pl acebo.
P. 849


8. The answer i s B [ see Ì Ì . C. 1. d] .
Dof et i l i de, i but i l i de, ami odarone, and sot al ol ar e cl ass Ì Ì Ì ant i ar r hyt hmi c agent s.
Cl ass Ì Ì Ì agent s, whi ch pr ol ong t he r ef ract or y per i od and myocar di al act i on
pot ent i al , ar e used t o t r eat vent r i cul ar ar r hyt hmi as. However , dof et i l i de and i but i l i de
ar e approved as t ype Ì Ì Ì agent s i ndi cat ed f or t he conversi on f r om at r i al f i br i l l at i on
and f l ut t er of r ecent onset t o nor mal si nus r hyt hm. Propr anol ol , al ong wi t h ot her 8-
bl ocker s, i s a cl ass Ì Ì ant i ar rhyt hmi c; met opr ol ol i s not rout i nel y used i n t he
t r eat ment of arr hyt hmi as; and di sopyr ami de and di l t i azem ar e cl ass Ì a and cl ass Ì V
ant i ar r hyt hmi cs, respect i vel y.
9. The answer i s B [ see Ì Ì . C. 3. a; Ì Ì . C. 4. a; Ì Ì . C. 5. a] .
Ami odarone, l i ke i but i l i de and sot al ol , i s a cl ass Ì Ì Ì ant i ar r hyt hmi c agent and act s by
pr ol ongi ng r epol ar i zat i on of cardi ac cel l s. Ami odar one i s gi ven or al l y, of t en i n once-
a- day or t wi ce-a- day mai nt enance dosage. Because of i t s ver y l ong el i mi nat i on hal f -
l i f e, t her apeut i c r esponse may be del ayed f or weeks. Ther ef ore, an i ni t i al l oadi ng
phase i s of t en advi sabl e. Thi s requi r es hospi t al i zat i on wi t h cl ose moni t ori ng f or
desi r ed ef f ect s, unt oward r eact i ons, and adj ust ment s i n dosage. Ami odarone may
i ncrease t he pl asma l evel s of qui ni di ne, pr ocai nami de, di l t i azem, and di gi t al i s.
Dur i ng t her apy wi t h ami odar one, pat i ent s may devel op hypot hyr oi di sm or
hyper t hyr oi di sm, pul monar y di sorders, hepat i c dysf unct i on, and vari ous ot her
unwant ed ef f ect s. Because of ami odar one' s ext r emel y l ong hal f -l i f e, adverse
r eact i ons may persi st f or mont hs af t er t her apy ends.

41
Hypertension
AI an H. Mutni ck
I. GENERAL CONSIDERATIONS
A. Def i ni t i on. Hypert ensi on i s bl ood pressure el evat ed enough t o per f use t i ssues
and or gans. El evat ed syst emi c bl ood pr essur e i s usual l y def i ned as a syst ol i c
r eadi ng < 140 mm Hg and a di ast ol i c readi ng < 90 mm Hg ( < 140/ 90) . The " Sevent h
Repor t of t he Joi nt Nat i onal Commi t t ee on Det ect i on, Eval uat i on, and Tr eat ment of
Hi gh Bl ood Pressure¨ (JNC- 7) added a "pr ehypert ensi on¨ cat egor y, whi ch i ncl udes
i ndi vi dual s wi t h syst ol i c bl ood pr essur e readi ngs of 120- 139 or di ast ol i c bl ood
pr essure readi ngs of 80-89 mm Hg; t hi s cat egor y i s now i ncl uded i n cont emporar y
management st rat egi es.
B. CI assi f i cat i on of hyper t ensi on i s shown i n Tabl e 41-1. The t abl e ref l ect s t he
r ecommendat i ons of t he JNC- 7.
C. The reI at i onshi p between eI evat ed bI ood pressure and cardi ovascuI ar
di sease was addr essed i n t he JNC-7, whi ch f or mal i zes t he f act t hat t he hi gher t he
bl ood pr essur e, t he great er t he chance of a myocar di al i nf ar ct i on ( MÌ ) , hear t f ai l ur e
( HF) , st r oke, or ki dney di sease. Tabl e 41- 2 provi des car di ovascul ar ri sk f act or s
and/ or l i f est yl e f act or s t hat af f ect t he prognosi s and t r eat ment of hyper t ensi on and
t he vari ous t ypes of t arget - organ damage associ at ed wi t h hyper t ensi on.
D. I nci dence. Hypert ensi on i s the most common cardi ovascuI ar di sorder.
Appr oxi mat el y 43 mi l l i on Ameri cans have bl ood pr essur e measur ement s > 140/ 90.
Thi s number t r ansl at es t o al most 25% of t he adul t popul at i on. The i nci dence
i ncreases wi t h age÷t hat i s, 60%- 71% of peopl e > 60 years of age have
hyper t ensi on, accor di ng t o dat a obt ai ned f r om t he Thi r d Nat i onal Heal t h and
Nut r i t i on Exami nat i on Sur vey ( NHANES Ì Ì Ì ) .
1. Pri mar y ( or essent i aI ) hypert ensi on, i n whi ch no speci f i c cause can be
i dent i f i ed, const i t ut es > 90% of al l cases of syst emi c hyper t ensi on. The aver age age
of onset i s about 35 years.
2. Secondar y hypert ensi on, resul t i ng f r om an i dent i f i abl e cause, such as r enal
di sease or adr enal hyperf unct i on, account s f or t he r emai ni ng 2%- 5% of cases of
syst emi c hyper t ensi on. Thi s t ype usual l y devel ops bet ween t he ages of 30 and 50.
E. Physi oI ogy
BI ood pressure = ( st r oke vol ume × heart r at e) × t ot al per i pheral vascul ar
r esi st ance ( TPR)
Al t eri ng any of t he f act ors on t he ri ght si de of t he bl ood pr essur e equat i on r esul t s i n
a change i n bl ood pr essur e, as shown i n Fi gur e 41- 1.
1. Sympat het i c nervous syst em. Barorecept ors ( pr essur e r ecept ors) i n t he
car ot i ds and aort i c arch r espond t o changes i n bl ood pr essur e and i nf l uence
ar t eri ol ar di l at i on and ar t er i ol ar const r i ct i on. When st i mul at ed t o const r i ct i on, t he
cont r act i l e f orce st rengt hens, i ncr easi ng t he hear t r at e and augment i ng per i pher al
r esi st ance, t hus i ncr easi ng car di ac out put . Ì f pr essur e remai ns el evat ed, t he
bar orecept or s r eset at t he hi gher l evel s and so sust ai n t he hyper t ensi on. Li t t l e
evi dence suggest s t hat epi nephri ne and nor epi nephr i ne have a cl ear r ol e i n t he
cause of hyper t ensi on. However , many of t he dr ugs used t o t reat hypert ensi on l ower
bl ood pr essur e by bl ocki ng t he sympat het i c ner vous syst em.
2. Reni n- angi ot ensi n-aI dost erone syst em. Sympat het i c st i mul at i on, renal ar t er y
hypot ensi on, and decr eased sodi um del i ver y t o t he di st al t ubul es st i mul at e t he
r el ease of r eni n by t he ki dney ( j uxt agl omerul ar appar at us of t he ki dney) . Reni n ( an
enzyme) react s wi t h ci rcul at i ng subst r at e, angi ot ensi nogen t o produce angi ot ensi n Ì
( a weak vasoconst ri ct or ). Wi t hi n t he pul monar y endot hel i um i s anot her enzyme,
r ef er red t o as angi ot ensi n- conver t i ng enzyme ( ACE) , whi ch i s abl e t o hydr ol yze t he
decapept i de angi ot ensi n Ì t o f orm t he oct apept i de angi ot ensi n Ì Ì ( a pot ent nat ur al
vasoconst ri ct or ) . Angi ot ensi n Ì Ì has several i mport ant f unct i ons i n t he r egul at i on of
f l ui d vol ume:
P. 851


Table 41-1. Classification of Hypertension for Adults > 18 Years of Age

Classificat
ion
Systol
ic
(mm
Hg)
a

Diastoli
c (mm
Hg)
a

Lifestyle
Modificat
ion
Without Compelling
Indication
With
Compellin
g
Indication
s
Norm
al
·
1
2
0
a
n
d
·
80
Enco
urag
e

Prehy
perte
nsion
1
2
0
-
1
3
9
o
r
80-
89
Yes No antihypertensive
drug indicated. unless
presence oI a
compelling indication
b

requiring use oI drug
therapy
Drug(
s) Ior
comp
elling
indica
tions
Stage
1
hyper
tensio
n
1
4
0
-
1
o
r
90-
99
Yes Thiazide-type
diuretics Ior most;
may consider ACE
inhibitor. ARB. þ-
blocker. CCB. or
Drug(
s) Ior
comp
elling
indica
5
9
combination tions;
other
antihy
perten
sive
drugs
(diure
tics.
ACE
inhibi
tor.
ARB.
þ-
block
er.
CCB)
as
neede
d
Stage
2
hyper
tensio
n
>
1
6
0
o
r
>
10
0
Yes Two-drug
combination Ior most
(usually thiazide-type
diuretic and ACE
inhibitor. ARB. þ-
blocker. or CCB)
Drug(
s) Ior
comp
elling
indica
tions;
other
antihy
perten
sive
drugs
(diure
tics.
ACE
inhibi
tor.
ARB.
þ-
block
er.
CCB)
as
neede
d
ACE. angiotensin-converting enzyme; ARB. angiotensin-receptor blocker;
CCB. calcium-channel blocker.
a
Treatment is determined by the patient's highest blood pressure category.

b
Selected drug therapies have been identiIied Irom clinical trials to possess
positive clinical outcomes Ior speciIic clinical situations and represent
compelling indication Ior their use. Compelling indications (and drug
therapies): heart Iailure (diuretics. þ-blockers. ACE inhibitors. ARB.
aldosterone antagonists). postmyocardial inIarction (þ-blockers. ACE
inhibitors. and aldosterone antagonists). high coronary disease risk (diuretic.
þ-blocker. ACE inhibitors. CCB). diabetes (diuretic. þ-blockers. ACE
inhibitors. ARB. CCB). chronic kidney disease (ACE inhibitors. ARB). and
recurrent stroke prevention (diuretic. ACE inhibitors).

Based on Joint National Committee on Detection. Evaluation. and Treatment
oI High Blood Pressure. The seventh report oI the Joint National Committee
on Detection. Evaluation. and Treatment oI High Blood Pressure: The JNC-7
report |Special communication; Clinician's Corner|. JAMA 2003;289:2560-
2572.

P. 852


Table 41-2. Cardiovascular and/or Lifestyle Risk Factors for Consideration in
the Management of Hypertension
Hypertension
Cigarette smoking
Obesity (BMI > 30)
Physical inactivity
Dyslipidemia (as a component oI the metabolic syndrome)
Diabetes mellitus (as a component oI the metabolic syndrome)
Microalbuminuria or estimated glomerular Iiltration rate · 60 mL/min
Age (~ 55 years Ior men; ~ 65 years Ior women)
Family history oI premature cardiovascular disease (men · 55 years; women
· 65 years)
BMI. body mass index (calculated as weight in kilograms divided by the
square oI height in meters).
Based on Joint National Committee on Detection. Evaluation. and Treatment
oI High Blood Pressure. The seventh report oI the Joint National Committee
on Detection. Evaluation. and Treatment oI High Blood Pressure: The JNC-7
report |Special communication; Clinician's Corner|. JAMA 2003;289:2560-
2572.

a. Ì t st i mul at es t he rel ease of al dost er one f r om t he adr enal gl and ( zona
gl omerul osa), whi ch r esul t s i n i ncreased sodi um r eabsorpt i on, f l ui d vol ume, and
bl ood pr essur e.
b. Ì t const r i ct s r esi st ance vessel s, whi ch i ncr eases per i pher al vascul ar resi st ance
and ar t er i al pressure.
c. Ì t st i mul at es t he rel ease of vasopressi n, or ant i di ur et i c hormone ( ADH), f r om t he
post er i or pi t ui t ar y, whi ch act s wi t hi n t he ki dneys t o i ncr ease f l ui d ret ent i on.

Figure 41-1. Blood pressure regulation: the
determinants oI blood pressure as they relate to
cardiac output and total peripheral resistance.
Angiotensin II. a potent vasopressor. not only
increases total peripheral resistance but also. by
stimulating aldosterone release. leads to an
increase in plasma volume. venous return. stroke
volume. and ultimately an increase in cardiac
output.
P. 853


d. Ì t st i mul at es car di ac hyper t r ophy and vascul ar hyper t rophy.
e. Ì t f aci l i t at es nor epi nephr i ne rel ease f rom sympat het i c ner ve endi ngs and i nhi bi t s
nor epi nephr i ne r eupt ake by ner ve endi ngs, whi ch enhances sympat het i c f unct i on.
3. Mosai c theor y cent ers around t he f act t hat mul t i pl e f act or s, r at her t han one
f act or al one, ar e r esponsi bl e f or sust ai ni ng hyper t ensi on. The i nt er act i ons among
t he sympat het i c ner vous syst em, r eni n-angi ot ensi n- al dost er one syst em, and
pot ent i al def ect s i n sodi um t r anspor t wi t hi n and out si de t he cel l may al l pl ay a r ol e
i n l ong- t erm hyper t ensi on. Addi t i onal f act ors cont r i but i ng t o t he devel opment
i ncl ude genet i cs, endot hel i al dysf unct i on, and neur ovascul ar anomal i es. Ot her
vasoact i ve subst ances t hat ar e i nvol ved i n t he mai nt enance of nor mal bl ood
pr essure have al so been i dent i f i ed; t hese i ncl ude ni t ri c oxi de ( vasodi l at i ng f act or ) ,
endot hel i n ( vasoconst ri ct or pept i de) , br adyki ni n (pot ent vasodi l at or i nact i vat ed by
ACE) , and at r i al nat ri ur et i c pept i de (nat ur al l y occur r i ng di uret i c) .
4. FI ui d voI ume reguI ati on. I ncreased f I ui d voI ume i ncr eases venous syst em
di st ent i on and venous ret ur n, af f ect i ng car di ac out put and t i ssue per f usi on. These
changes aI t er vascuI ar resi stance, i ncr easi ng t he bl ood pr essur e.
F. CompI i cat i ons. Unt reat ed syst emi c hyper t ensi on, regar dl ess of cause, r esul t s i n
i nf l ammat i on and necr osi s of t he ar t er i ol es, nar r owi ng of t he bl ood vessel s, and
r est ri ct i on of t he bl ood f l ow t o maj or body or gans ( Tabl e 41-3) . When bl ood f l ow i s
sever el y compr omi sed, t ar get - or gan damage ensues.
1. Cardi ac ef f ect s
a. Lef t vent r i cul ar hypert r ophy (cardi ac remodel i ng) compensat es f or t he i ncr eased
car di ac wor kl oad. Si gns and sympt oms of hear t f ai l ur e occur, and t he i ncr eased
oxygen r equi r ement s of t he enl ar ged hear t may pr oduce angi na pect or i s.
Table 41-3. Target-Organ Damage Associated with Hypertension
Organ/System and Findings Basis of Findings
Cardiovascular
Blood pressure persistently > 140
mm Hg systolic and/or > 90 mm Hg
diastolic
Constricted arterioles. causing
abnormal resistance to blood Ilow
Angina pain InsuIIicient blood Ilow to coronary
vasculature
LeIt ventricular
hypertrophy/dyspnea on exertion
Heart Iailure
Edema oI extremities Decrease in blood supply
Neurological
Severe occipital headaches with
nausea and vomiting. drowsiness.
anxiety. and mental impairment
Vessel damage within brain
characteristic oI dizziness. severe
mental impairment. hypertension.
resulting in transient ischemic
attacks or strokes
Renal
Polyuria. nocturia. and diminished
ability to concentrate urine; protein
and red blood cells in urine; elevated
serum creatinine
Arteriolar nephrosclerosis
(hardening oI arterioles within
kidney)
Ocular
Retinal hemorrhage and exudates Damage to arterioles that supply
retina
Peripheral vascular Absence oI pulses in extremities
with or without intermittent
claudication; development oI
aneurysm
Based on Joint National Committee on Detection. Evaluation. and Treatment
oI High Blood Pressure. The seventh report oI the Joint National Committee
on Detection. Evaluation. and Treatment oI High Blood Pressure: The JNC-7
report |Special communication; Clinician's Corner|. JAMA 2003;289:2560-
2572.

P. 854


b. Hyper t ensi on can be caused by accel er at ed at her oscl er osi s. At her omat ous
l esi ons i n t he cor onar y ar t er i es l ead t o decreased bl ood f l ow, r esul t i ng i n angi na
pect or i s. MÌ and sudden deat h may ensue.
2. RenaI ef f ect s
a. Decr eased bl ood f l ow l eads t o an i ncr ease i n reni n- al dost erone secret i on, whi ch
hei ght ens t he r eabsorpt i on of sodi um and wat er and i ncr eases bl ood vol ume.
b. Accel erat ed at heroscl er osi s decr eases t he oxygen suppl y, l eadi ng t o renal
par enchymal damage wi t h decr eased f i l t r at i on capabi l i t y and t o azot emi a. The
at heroscl er osi s al so decr eases bl ood f l ow t o t he r enal art er i ol es, l eadi ng t o
nephr oscl er osi s and, ul t i mat el y, renal f ai l ur e ( acut e as wel l as chr oni c) .
3. CerebraI ef f ect s. Decr eased bl ood f l ow, decreased oxygen suppl y, and
weakened bl ood vessel wal l s l ead t o t r ansi ent i schemi c at t acks, cer ebr al
t hr omboses, and t he devel opment of aneur ysms wi t h hemor r hage. There ar e
al t er at i ons i n mobi l i t y, weakness and par al ysi s, and memor y def i ci t s.
4. Ret i naI ef fect s. Decreased bl ood f l ow wi t h r et i nal vascul ar scl erosi s and
i ncreased ar t er i ol ar pressur e wi t h t he appear ance of exudat es and hemorr hage
r esul t i n vi sual def ect s (e. g. , bl ur r ed vi si on, spot s, bl i ndness) .
II. SECONDARY HYPERTENSION
A. CI i ni caI evaI uat i on. Because most pat i ent s pr esent i ng wi t h hi gh bl ood pr essur e
have pri mar y r at her t han secondar y hyper t ensi on, ext ensi ve scr eeni ng i s
unwar r ant ed. A t hor ough hi st or y and physi cal exami nat i on f ol l owed by an eval uat i on
of common l abor at or y t est s shoul d rul e out most causes of secondar y hyper t ensi on.
Pat i ent age ( pri mar y hyper t ensi on i s nor mal l y seen bet ween 30 and 55 year s of
age) , sudden onset of wor seni ng of hyper t ensi on, and bl ood pressure el evat i ons not
r espondi ng t o t reat ment ar e f i ndi ngs consi st ent wi t h secondar y hyper t ensi on. Ì f a
secondar y cause i s not f ound, t he pat i ent i s consi dered t o have essent i al ( pr i mar y)
hyper t ensi on.
1. A pat i ent ' s hi st or y and ot her physi caI f i ndi ngs suggest an under l yi ng cause of
hyper t ensi on. These i ncl ude t he f ol l owi ng:
a. Wei ght gai n, moon f ace, t runcal obesi t y, ost eopor osi s, pur pl e st ri ae, hi r sut i sm,
hypokal emi a, di abet es, and i ncreased pl asma cort i sol may si gnal Cushi ng
syndr ome.
b. Wei ght l oss, epi sodi c f l ushi ng, di aphor esi s, i ncr eased uri nar y cat echol ami nes,
headaches, i nt er mi t t ent hyper t ensi on, t remor s, and pal pi t at i ons suggest
pheochr omocyt oma.
c. St er oi d or est r ogen i nt ake, i ncl udi ng oral cont racept i ves, nonst er oi dal ant i -
i nf l ammat or y drugs ( NSAÌ Ds) , nasal decongest ant s, t ri cycl i c ant i depr essant s,
appet i t e suppr essant s, cycl ospori ne, er yt hr opoi et i n, and monoami ne oxi dase ( MAO)
i nhi bi t ors, suggest s drug- i nduced hyper t ensi on.
d. Repeat ed ur i nar y t ract i nf ect i ons, el evat ed serum cr eat i ni ne l evel s, noct ur i a,
hemat uri a, and pai n on ur i nat i ng may si gni f y r enal i nvol vement ( e. g. , chroni c ki dney
di sease) .
e. Abdomi nal br ui t s, r ecent onset , and accel er at ed hyper t ensi on i ndi cat e r enal
ar t er y st enosi s ( e. g. , r enovascul ar di sease) .
f . Muscl e cramps, weakness, excess ur i nat i on, and i sol at ed hypokal emi a may
suggest pr i mar y al dost eroni sm.
g. Sl eep apnea, coarct at i on of t he aort a, t hyr oi d di sease, and par at hyr oi d di sease
have been i ncl uded by t he JNC- 7 as addi t i onal secondar y causes of hyper t ensi on.
2. Laborator y f i ndi ngs
a. Bl ood urea ni t rogen (BUN) and creat i ni ne el evat i ons suggest renal di sease.
b. Ì ncr eased ur i nar y excr et i on of cat echol ami ne or i t s met abol i t es ( e. g. ,
vani l l yl mandel i c aci d, met anephr i ne) conf i rms pheochr omocyt oma.
c. Serum pot assi um eval uat i on reveal i ng hypokal emi a suggest s pri mar y
al dost er oni sm or Cushi ng syndr ome.
3. Di agnost i c t ests
a. Renal ar t er i ogr aphy, ul t r asound, or r enal venogr aphy may show evi dence of renal
ar t er y st enosi s.
b. El ect r ocar di ogr aphy (ECG) may r eveal l ef t vent r i cul ar hyper t rophy or i schemi a.
P. 855


B. Cause
1. Pri mar y aI dost eroni sm. Hypersecr et i on of al dost er one by t he adrenal cor t ex
i ncreases di st al t ubul ar sodi um r et ent i on, expandi ng t he bl ood vol ume, whi ch
i ncreases t ot al per i pheral r esi st ance.
2. Pheochromocyt oma. A t umor of t he adrenal medul l a st i mul at es hyper secr et i on of
epi nephr i ne and norepi nephri ne, whi ch r esul t s i n i ncr eased t ot al per i pheral
r esi st ance.
3. RenaI art er y st enosi s. Decr eased renal t i ssue perf usi on act i vat es t he r eni n-
angi ot ensi n-al dost erone syst em (see Ì . E. 2) .
C. Treatment . Secondary hyper t ensi on r equi res t r eat ment of t he under l yi ng cause
( e. g. , sur gi cal i nt er vent i on accompani ed by suppl ement ar y cont rol of hyper t ensi ve
ef f ect s; see Ì Ì Ì . B) .
III. ESSENTI AL (PRIMARY) HYPERTENSION
A. CI i ni caI evaI uat i on requi r es a t hor ough hi st or y and physi cal exami nat i on
f ol l owed by a car ef ul anal ysi s of common l abor at or y t est r esul t s.
1. Obj ect i ves
a. To r ul e out uncommon secondar y causes of hyper t ensi on
b. To det ermi ne t he pr esence and ext ent of t arget - or gan damage
c. To det ermi ne t he pr esence of ot her car di ovascul ar r i sk f act ors i n addi t i on t o hi gh
bl ood pr essur e
d. To r educe mor bi di t y and mor t al i t y t hrough mul t i pl e st r at egi es t hat reduce bl ood
pr essure t hr ough l i f est yl e modi f i cat i ons wi t h or wi t hout pharmacol ogi cal t reat ment
wi t h mi ni mal si de ef f ect s.
2. Predi sposi ng f act ors
a. Fami I y hi st or y of essent i al hyper t ensi on, st roke, and premat ure car di ac di sease
b. Pati ent hi stor y of i nt er mi t t ent el evat i ons i n bl ood pr essur e
c. Raci aI predi sposi ti on. Hyper t ensi on i s more common among Af r i can Ameri cans
t han whi t es.
d. Obesi t y. Wei ght r educt i on has been shown t o r educe bl ood pr essur e i n a l ar ge
pr opor t i on of hyper t ensi ve pat i ent s who are > 10% above i deal body wei ght .
e. Smoki ng, resul t i ng i n vasoconst ri ct i on and act i vat i on of t he sympat het i c ner vous
syst em, i s a maj or r i sk f act or f or car di ovascul ar di sease.
f . St r ess
g. Hi gh di et ar y i nt ake of sat ur at ed f at s or sodi um
h. Sedent ar y l i f est yl e
i . Di abet es mel l i t us
j . Hyper l i pi demi a
k. Maj or r i sk f act or s accor di ng t o t he JNC- 7 i ncl ude smoki ng, di abet es mel l i t us, age
( > 55 f or men; > 65 f or women) , f ami l y hi st or y of car di ovascul ar di sease, and
dysl i pi demi a.
I . Tar get - or gan damage/ cl i ni cal car di ovascul ar di sease accor di ng t o t he JNC- 7
i ncl udes hear t di sease (e. g. , l ef t vent r i cul ar hyper t r ophy, angi na, pri or MÌ , hear t
f ai l ur e), st r oke or t ransi ent i schemi c at t acks, nephr opat hy, peri pher al ar t er y
di sease, and r et i nopat hy.
3. Physi caI f i ndi ngs
a. Seri al bl ood pressure r eadi ngs < 140/ 90 shoul d be obt ai ned on at l east t wo
occasi ons bef or e speci f i c t her apy i s begun, unl ess t he i ni t i al bl ood pressur e l evel s
ar e markedl y el evat ed (i . e. , > 210 mm Hg syst ol i c; > 120 mm Hg di ast ol i c, or bot h)
or are associ at ed wi t h t ar get -or gan damage. A si ngl e el evat ed readi ng i s an
i nsuf f i ci ent basi s f or a di agnosi s.
b. Essent i al hyper t ensi on usual l y does not become cl i ni cal l y evi dent ÷ot her t han
t hr ough seri al bl ood pr essur e el evat i ons÷unt i l vascul ar changes af f ect t he hear t ,
br ai n, ki dneys, or ocul ar f undi .
c. Exami nat i on of t he ocul ar f undi i s val uabl e; t hei r condi t i on can i ndi cat e t he
dur at i on and severi t y of t he hyper t ensi on.
( 1) EarI y st ages. Har d, shi ny deposi t s; t i ny hemor r hages; and el evat ed ar t er i al
bl ood pr essur e occur .
P. 856


( 2) Lat e st ages. Cot t on-wool pat ches, exudat es, r et i nal edema, papi l l edema caused
by i schemi a and capi l l ary i nsuf f i ci ency, hemor r hages, and mi croaneur ysms become
evi dent .
4. Unt reat ed hyper t ensi on i ncr eases t he l i kel i hood of t he devel opment of numer ous
or gan probl ems, whi ch i ncl ude l ef t vent r i cul ar f ai l ur e, MÌ , r enal f ai l ur e, cer ebr al
hemor r hage or i nf ar ct i on, and sever e changes i n t he ret i na of t he eye.
B. Treatment ( Tabl es 41- 4 and 41- 5; Fi gure 41- 2)
1. GeneraI pri nci pI es. Tr eat ment pri mar i l y ai ms t o l ower bl ood pr essur e t owar d
" normal ¨ wi t h mi ni mal si de ef f ect s and t o pr event or rever se organ damage.
Cur r ent l y, t her e i s no cur e f or
P. 857

pr i mar y hyper t ensi on. Tr eat i ng syst ol i c and di ast ol i c bl ood pr essur es t o t ar get s t hat
ar e < 140/ 90 mm Hg i s associ at ed wi t h a decrease i n car di ovascul ar compl i cat i ons.
For pat i ent s wi t h hyper t ensi on who have di abet es or r enal di sease, t he bl ood
pr essure goal r ecommended by t he JNC-7 i s 130/ 80 mm Hg.
Table 41-4. Common Antihypertensive Drugs
I. Diuretics
A. Thiazide diuretics
Chlorothiazide (Diuril)
Chlorthalidone (Hygroton)
Hydrochlorothiazide (HydroDIURIL)
Indapamide (Lozol)
Methyclothiazide (Enduron)
Metolazone (Zaroxolyn)
B. Loop diuretics
Bumetanide (Bumex)
Ethacrynic acid (Edecrin)
Furosemide (Lasix)
Torsemide (Demadex)
C. Potassium-sparing diuretics
Amiloride (Midamor)
Eplerenone (Inspra)
Spironolactone (Aldactone)
Triamterene (Dyrenium)
II. Vasodilators (direct acting)
Diazoxide (Proglycem)
Hydralazine (Various)
Minoxidil (Loniten)
Nitroprusside (Nitropress)
III. Angiotensin-converting enzyme (ACE) inhibitors
Benazepril (Lotensin)
Captopril (Capoten)
Enalapril (Vasotec)
Enalaprilat (IV) (Vasotec)
Fosinopril (Monopril)
Lisinopril (Prinivil. Zestril)
Moexipril (Univasc)
Perindopril (Aceon)
Quinapril (Accupril)
Ramipril (Altace)
Trandolapril (Mavik)
IV. Angiotensin II receptor antagonists
Candesartan cilexetil (Atacand)
Eprosartan (Teveten)
Irbesartan (Avapro)
Losartan (Cozaar)
Olmesartan (Benicar)
Telmisartan (Micardis)
Valsartan (Diovan)
V. Renin inhibitors
Aliskiren (Tekturna)
VI. Sympatholytics
A. þ-Adrenergic blocking agents
Acebutolol (Sectral)
Atenolol (Tenormin)
Betaxolol (Kerlone)
Bisoprolol (Zebeta)
Carvedilol (Coreg)
Labetalol (Normodyne. Trandate)
Metoprolol (Lopressor. Toprol XL)
Nadolol (Corgard)
Nebivolol (Bystolic)
Penbutolol (Levatol)
Pindolol (Visken)
Propranolol (Inderal)
Timolol (Various)
B. Centrally acting u-agonists
Clonidine (Catapres)
Guanabenz (Various)
GuanIacine (Tenex)
Methyldopa (Various)
C. Postganglionic adrenergic neuron blockers
Reserpine (various)
D. u-Adrenergic blocking agents
Doxazosin (Cardura)
Prazosin (Minipress)
Terazosin (Hytrin)
E. Calcium-channel blockers
1. Benzodiazepine derivatives
Diltiazem (Cardizem. Dilacor. Tiazac)
2. Diphenylalkylamine derivatives
Verapamil (Isoptin. Calan)
3. Dihydropyridines
Amlodipine (Norvasc)
Felodipine (Plendil)
Isradipine (DynaCirc CR)
Nicardipine (Cardene)
NiIedipine (Procardia XL. Adalat CC)
Nisoldipine (Sular)

Table 41-5. Common Combination Products for Hypertension
I. Diuretics
Hydrochlorothiazidespironolactone (Aldactazide)
Hydrochlorothiazidetriamterene (Dyazide. Maxzide)
Hydrochlorothiazideamiloride (Moduretic)
II. Diuretics-ß-adrenergic blockers
BendroIlumethiazidenadolol (Corzide)
Chlorthalidoneatenolol (Tenoretic)
Hydrochlorothiazidepropranolol (Inderide)
Hydrochlorothiazidemetoprolol (Lopressor HCT)
Hydrochlorothiazidebisoprolol (Ziac)
III. Diuretics-angiotensin-converting enzyme (ACE) inhibitors
Hydrochlorothiazidecaptopril (Capozide)
Hydrochlorothiazidebenazepril (Lotensin HCT)
Hydrochlorothiazidelisinopril (Prinzide. Zestoretic)
Hydrochlorothiazideenalapril (Vaseretic)
HydrochlorothiazideIosinopril (Monopril HCT)
Hydrochlorothiazidemoexipril (Uniretic)
Hydrochlorothiazidequinapril (Accuretic)
IV. Diuretics-angiotensin II receptor antagonists
Hydrochlorothiazidelosartan (Hyzaar)
Hydrochlorothiazideirbesartan (Avalide)
Hydrochlorothiazidevalsartan (Diovan HCT)
Hydrochlorothiazidetelmisartan (Micardis HCT)
Hydrochlorothiazidecandesartan (Atacand HCT)
Hydrochlorothiazideeprosartan (Teveten HCT)
Hydrochlorothiazideolmesartan (Benicar HCT)
V. Angiotensin-converting enzyme (ACE) inhibitors-Calcium-
channel blockers
EnalaprilIelodipine (Lexxel)
Trandolaprilverapamil (Tarka)
Benazeprilamlodipine (Lotrel)
VI. Angiotensin II receptor antagonists-Calcium channel blockers
Olmesartanamlodipine (Azor)
Valsartanamlodipine (ExIorge)
VII. Other
Hydrochlorothiazidehydralazine (Apresazide)
Hydrochlorothiazidemethyldopa (Various)
Polythiazide-prazosin (Minizide)
Amlodipineatorvastatin (Caduet)

a. Candi dat es f or t reatment
( 1) Al l pat i ent s wi t h a di ast ol i c pr essur e of > 90 mm Hg, a syst ol i c pressur e of > 140
mm Hg, or a combi nat i on of bot h shoul d r ecei ve ant i hyper t ensi ve drug t herapy.
( 2) For t hose pat i ent s wi t h a di ast ol i c pr essur e of 80- 89 mm Hg or a syst ol i c
pr essure of 120-139 mm Hg ( pr ehypert ensi on) , no dr ug t r eat ment i s i ndi cat ed unl ess
t he pat i ent has a compel l i ng i ndi cat i on. However , l i f est yl e modi f i cat i ons such as
wei ght r educt i on, di et ar y sodi um reduct i on, i ncreased physi cal act i vi t y, and
moder at i on of al cohol consumpt i on shoul d be i ni t i at ed.
b. Nonspeci f i c measures. Bef or e i ni t i at i ng ant i hyper t ensi ve dr ug t herapy, pat i ent s
ar e encouraged t o el i mi nat e or mi ni mi ze cont r ol l abl e r i sk f act ors (see Ì Ì Ì . A. 2) .
c. PharmacoI ogi caI t reat ment . The recommendat i ons of t he JNC-7 suggest t hat
r ecent cl i ni cal t ri al s have demonst r at ed t hat most hypert ensi ve pat i ent s wi l l r equi re
t wo or mor e ant i hypert ensi ve dr ugs.
P. 858



Figure 41-2. Algorithm Ior the treatment oI
hypertension. ACE. angiotensin-converting
enzyme; ARB. angiotensin-receptor blocker; CCB.
calcium-channel blocker. |Based on the
recommendations Irom the Seventh Report oI the
Joint National Committee on Detection.
Evaluation. and Treatment oI High Blood
Pressure (JNC-7).|
( 1) Thi azi de di uret i cs shoul d be t he i ni t i al choi ce of t herapy because t hey have
demonst r at ed a reduct i on i n mor bi di t y and mor t al i t y when used as i ni t i al
monot her apy. They have been shown t o l ower mor bi di t y and mor t al i t y r at es, have
shown adequat e l ong- t erm saf et y dat a, and have demonst r at ed pat i ent t ol er abi l i t y.
( 2) Thi azi de di uret i cs shoul d be consi der ed i ni t i al agent s f or t r eat ment unl ess t here
ar e compel l i ng i ndi cat i ons f or ot her medi cat i ons.
( 3) Agent s such as ACE i nhi bi t ors, angi ot ensi n-r ecept or bl ockers, 8-bl ocker s, and
cal ci um-channel bl ockers have al l been r ecommended f or pat i ent s who cannot
r ecei ve a t hi azi de di uret i c or i n combi nat i on wi t h a t hi azi de di uret i c f or adequat e
cont r ol of bl ood pressure. Thi s may i ncl ude t he use of ACE i nhi bi t ors i n
hyper t ensi ve pat i ent s havi ng syst ol i c dysf unct i on af t er a myocar di al i nf arct i on, a
di abet i c nephr opat hy pat i ent who mi ght benef i t f rom an ACE i nhi bi t or i n combi nat i on
wi t h a di ur et i c, or a pat i ent wi t h HF.
d. Moni tori ng gui deI i nes. Speci f i c moni t or i ng gui del i nes f or t he var i ous dr ug
cat egori es are out l i ned i n Ì Ì Ì . B. 2, 3, 4, 5, 6 and 7.
P. 859


( 1) Bl ood pr essur e shoul d be moni t or ed rout i nel y t o det ermi ne t he t her apeut i c
r esponse and t o encour age pat i ent compl i ance.
( 2) Cl i ni ci ans must be al er t t o i ndi cat i ons of adver se dr ug ef f ect s. Many pat i ent s do
not l i nk si de ef f ect s t o drug t her apy or ar e embar rassed t o di scuss t hem, especi al l y
ef f ect s r el at ed t o sexual f unct i on or ef f ect s t hat appear l at e i n t her apy.
e. Pati ent compI i ance
( 1) Because hyper t ensi on i s usual l y a sympt oml ess di sease, how t he pat i ent "f eel s¨
does not ref l ect t he bl ood pr essur e l evel . Ì n f act , t he pat i ent may act ual l y r epor t
" f eel i ng nor mal ¨ wi t h an el evat ed bl ood pr essur e and "abnormal ¨ dur i ng a
hypot ensi ve epi sode because of t he l i ght - headedness associ at ed wi t h a sudden
dr op i n bl ood pr essur e. Because essent i al hypert ensi on r equi r es a l i f el ong dr ug
r egi men, i t i s ext r emel y di f f i cul t but necessar y t o i mpr ess on pat i ent s t he need f or
compl i ance wi t h t hei r t her apeut i c regi men.
( 2) Recogni zi ng t he seri ousness of t he consequences of noncompl i ance i s key.
Pat i ent s shoul d be t ol d t hat pr ol onged, unt r eat ed hyper t ensi on, known as t he "si l ent
ki l l er, ¨ can af f ect t he hear t , br ai n, ki dneys, and ocul ar f undi .
2. Di uret i cs
a. Thi azi de di uret i cs and t hei r deri vat i ves are cur r ent l y r ecommended as i ni t i al
t her apy f or hypert ensi on. JNC- VÌ Ì r ecommends i ni t i at i ng t herapy wi t h a l ow dose
( 12. 5 mg of hydrochl orot hi azi de ( HydroDÌ URÌ L or i t s equi val ent ) , i ncr easi ng t he
dose i f necessar y, and not exceedi ng a dose of 50 mg of hydr ochl orot hi azi de or i t s
equi val ent .
( 1) Act i ons. Ant i hyper t ensi ve ef f ect s ar e pr oduced by di r ect l y di l at i ng t he ar t er i ol es
and reduci ng t he t ot al f l ui d vol ume. Thi azi de di ur et i cs i ncr ease t he f ol l owi ng:
( a) Ur i nar y excr et i on of sodi um and wat er by i nhi bi t i ng sodi um and chl or i de
r eabsorpt i on i n t he di st al convol ut ed ( r enal ) t ubul es
( b) Ur i nar y excr et i on of pot assi um and, t o a l esser ext ent , bi carbonat e
( c) The ef f ect i veness of ot her ant i hyper t ensi ve agent s by pr event i ng reexpansi on of
ext r acel l ul ar and pl asma vol umes
( 2) Si gni f i cant i nteracti ons. NSAI Ds, such as t he now common over - t he-count er
f or ms of i bupr of en ( Advi l , Mot r i n) , i nt er act t o di mi ni sh t he ant i hypert ensi ve ef f ect s
of t he t hi azi de di ur et i cs.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Pot assi um i on ( K
+
) depl et i on may r equi r e suppl ement at i on, i ncreased di et ar y
i nt ake, or t he use of a pot assi um- spar i ng di ur et i c such as spi r onol act one
( Al dact one).
( b) Ur i c aci d r et ent i on may occur ; t hi s i s pot ent i al l y si gni f i cant i n pat i ent s who ar e
pr edi sposed t o gout and r el at ed di sorders.
( c) Bl ood gl ucose l evel s may i ncrease, whi ch may be si gni f i cant i n pat i ent s wi t h
di abet es.
( d) Cal ci um l evel s may i ncr ease because of t he pot ent i al f or ret ai ni ng cal ci um i ons.
( e) Pat i ent s wi t h known al l er gi es t o sul f a- t ype drugs shoul d be quest i oned t o
det ermi ne t he si gni f i cance of t he al l er gy.
( f ) Ot her common ef f ect s i ncl ude f at i gue, headache, pal pi t at i ons, r ash, ver t i go, and
t r ansi t or y i mpot ence.
( g) Hyper l i pi demi a, i ncl udi ng hypert ri gI yceri demi a, hyper chol est erol emi a,
i ncreased l ow- densi t y l i popr ot ei n ( LDL) chol est erol , and decr eased hi gh- densi t y
l i popr ot ei n ( HDL) chol est er ol , must be eval uat ed rout i nel y t o pr event an added ri sk
f or cor onar y ar t er y di sease.
( h) Fl ui d l osses must be eval uat ed and moni t or ed t o pr event dehydr at i on, post ur al
hypot ensi on, and even hypovol emi c shock.
( i ) Al t er at i ons i n f l ui ds and el ect r ol yt es ( e. g. , hypokal emi a, hypomagnesemi a,
hyper cal cemi a) may pr edi spose pat i ent s t o cardi ac i r r i t abi l i t y, wi t h a r esul t ant
i ncrease i n cardi ac ar r hyt hmi as. ECG) i s per f ormed r out i nel y t o det ect and pr event
t he devel opment of l i f e-t hr eat eni ng ar rhyt hmi as.
( 4) UsuaI ef f ect i ve doses
( a) ChI orot hi azi de ( Di uri I ) : 250-500 mg dai l y or t wi ce dai l y
( b) ChI orthaI i done ( Hygrot on) : 12. 5- 25 mg dai l y
( c) HydrochI orot hi azi de ( HydroDI URI L) : 12. 5- 50 mg dai l y
( d) I ndapami de ( LozoI ) : 1. 25- 2. 5 mg dai l y
( e) Met hycI ot hi azi de ( Enduron) : 2. 5- 5. 0 mg dai l y
( f ) Met oI azone (ZaroxoI yn) : 2. 5- 5. 0 mg dai l y
P. 860


b. Loop ( hi gh-cei I i ng) di uret i cs
( 1) I ndi cat i ons. These agent s ar e i ndi cat ed when pat i ent s are unabl e t o t ol er at e
t hi azi des, exper i ence a l oss of t hi azi de ef f ect i veness, or have i mpai red renal
f unct i on (cl earance < 30 mL/ mi n) .
( 2) Act i ons. Fur osemi de ( Lasi x) , et hacr yni c aci d ( Edecr i n), bumet ani de (Bumex) ,
and t orsemi de ( Demadex) act pri mar i l y i n t he ascendi ng l oop of Henl e; hence t hey
ar e cal l ed " l oop¨ di ur et i cs. By act i ng wi t hi n t he l oop of Henl e, t hey decr ease sodi um
r eabsorpt i on. Thei r act i on i s mor e i nt ense but of short er durat i on (1- 4 hr ) t han t hat
of t he t hi azi des; t hey may al so be mor e expensi ve.
( 3) Si gni f i cant i nteracti ons. As wi t h t he t hi azi des, t he ant i hypert ensi ve ef f ect of
l oop di ur et i cs may be di mi ni shed by NSAI Ds.
( 4) Precaut i ons and moni t ori ng ef fects. Loop di ur et i cs have t he same ef f ect s as
t hi azi des (see Ì Ì Ì . B. 2. a) , i n addi t i on t o t he f ol l owi ng:
( a) Loop di ur et i cs have a compl ex i nf l uence on r enal hemodynami cs; t hus pat i ent s
must be moni t ored cl osel y f or si gns of hypovol emi a.
( b) Because t hese agent s shoul d be used caut i ousl y i n pat i ent s wi t h epi sodi c or
chr oni c renal i mpai rment , BUN and ser um cr eat i ni ne l evel s shoul d be checked
r out i nel y.
( c) Tr ansi ent deaf ness has been r epor t ed. Ì f t he pat i ent i s t aki ng a pot ent i al l y
ot ot oxi c dr ug ( e. g. , an ami nogl ycosi de ant i bi ot i c), anot her cl ass of di ur et i c ( e. g. , a
t hi azi de di ur et i c) shoul d be subst i t ut ed.
( 5) UsuaI ef f ect i ve doses
( a) Bumet ani de ( Bumex) : 0. 5- 2. 0 mg dai l y
( b) Et hacr yni c aci d ( Edecri n) : 25-100 mg dai l y
( c) Furosemi de ( Lasi x) : 20- 80 mg dai l y
( d) Torsemi de ( Demadex) : 2. 5- 10 mg dai l y
c. Potassi um-spari ng di uret i cs
( 1) I ndi cat i ons. The di uret i cs i n t hi s gr oup÷spi ronol act one ( Al dact one) , ami l or i de
( Mi damor ) , and t ri amt erene ( Dyr eni um) ÷are i ndi cat ed f or pat i ent s i n whom
pot assi um l oss i s si gni f i cant and suppl ement at i on i s not f easi bl e. These agent s ar e
of t en used i n combi nat i on wi t h a t hi azi de di ur et i c because t hey pot ent i at e t he
ef f ect s of t he t hi azi de whi l e mi ni mi zi ng pot assi um l oss. Spi ronoI act one i s
par t i cul arl y usef ul i n pat i ent s wi t h hyper al dost er oni sm, as i t has di r ect ant agoni st i c
ef f ect s on al dost er one (al dost erone- r ecept or bl ocker ) . EpI erenone (Ì nspra) , i s
anot her al dost erone-r ecept or bl ocker r ecent l y appr oved by t he U. S. Food and Dr ug
Admi ni st rat i on (FDA) t hat , si mi l ar t o spi ronol act one, bl ocks al dost erone bi ndi ng at
t he mi ner al ocort i coi d r ecept or. Bot h of t hese agent s have been used i n
hyper t ensi on, and have an i ncreased l evel of use i n t he t reat ment of HF ( see
Chapt er 42) .
( 2) Act i ons. Pot assi um-spari ng di ur et i cs achi eve t hei r di uret i c ef f ect s di f f er ent l y
and l ess pot ent l y t han t he t hi azi des and l oop di uret i cs. Thei r most pert i nent shared
f eat ur e i s t hat t hey promot e pot assi um ret ent i on.
( 3) Si gni f i cant i nteracti ons. Coadmi ni st rat i on wi t h ACE i nhi bi t ors or potassi um
suppI ement s si gni f i cant l y i ncr eases t he r i sk of hyper kal emi a.
( 4) Precaut i ons and moni t ori ng ef fects
( a) Pot assi um- spar i ng di ur et i cs shoul d be avoi ded i n pat i ent s wi t h acut e renal
f ai l ur e and used wi t h caut i on i n pat i ent s wi t h i mpai red renal f unct i on (moni t or serum
cr eat i ni ne) because t hey can r et ai n pot assi um.
( b) Tri amt erene shoul d not be used i n pat i ent s wi t h a hi st or y of ki dney st ones or
hepat i c di sease.
( c) HyperkaI emi a i s a maj or r i sk, r equi ri ng r out i ne moni t ori ng of serum el ect rol yt es.
BUN and ser um creat i ni ne l evel s shoul d be checked r out i nel y t o si gnal i nci pi ent
excess pot assi um r et ent i on and i mpai r ed r enal f unct i on.
( 5) UsuaI ef f ect i ve doses
( a) Ami I ori de (Mi damor) : 5- 10 mg dai l y
( b) Spi ronoI act one ( AI dact one) : 25- 100 mg dai l y and 100-400 mg dai l y t o t r eat
hyper al dost er oni sm
( c) Tri amt erene ( Dyreni um) : 50- 100 mg dai l y
( d) EpI erenone (I nspra): 50- 100 mg dai l y
d. Combi nat i on products. Several pr oduct s combi ne a t hi azi de and a pot assi um-
spari ng di ur et i c.
P. 861


( 1) AI dact azi de: 25 mg spi ronol act one pl us 25 mg hydr ochl or ot hi azi de (one t o t wo
t abl et s dai l y)
( 2) AI dact azi de- 50: 50 mg spi r onol act one pl us 50 mg hydr ochl or ot hi azi de ( one
t abl et dai l y)
( 3) Moduret i c: 5 mg ami l or i de pl us 50 mg hydr ochl orot hi azi de ( one t o t wo t abl et s
dai l y)
( 4) Dyazi de: 37. 5 mg t ri amt er ene pl us 25 mg hydr ochl or ot hi azi de ( one t o t wo
capsul es dai l y)
( 5) Maxzi de: 75 mg t r i amt erene pl us 50 mg hydrochl orot hi azi de ( one hal f t o one
t abl et dai l y)
( 6) Maxzi de- 25: 37. 5 t r i amt er ene pl us 25 mg hydr ochl or ot hi azi de
3. Sympat hoI yt i cs
a. ß- Adrenergi c bI ockers
( 1) I ndi cat i ons. 8- Bl ocker s ar e par t i cul ar l y ef f ect i ve i n pat i ent s wi t h rapi d r est i ng
hear t r at es ( i . e. , at ri al f i br i l l at i on, par oxysmal supr avent r i cul ar t achycardi a) or
compel l i ng i ndi cat i ons such as hear t f ai l ure, post - MÌ , hi gh cor onar y di sease ri sk,
and di abet es.
( 2) Act i ons. Pr oposed mechani sms of act i on i ncl ude t he f ol l owi ng:
( a) St i mul at i on of r eni n secr et i on i s bl ocked.
( b) Car di ac cont r act i l i t y i s decreased, t hus di mi ni shi ng cardi ac out put .
( c) Sympat het i c out put i s decreased cent ral l y.
( d) Reduct i on i n hear t r at e decreases car di ac out put .
( e) 8- Bl ocker act i on may combi ne al l of t he above mechani sms.
( 3) Epi demi oI ogy. Young ( < 45 year s) whi t es wi t h hi gh cardi ac out put , hi gh hear t
r at e and nor mal vascul ar r esi st ance r espond best t o 8-bl ocker t herapy.
( 4) Precaut i ons and moni t ori ng ef fects
( a) Pat i ent s must be moni t or ed f or si gns and sympt oms of cardi ac decompensat i on
( i . e. , r educt i on i n cardi ac out put ) owi ng t o t he f act t hat decr eased myocar di al
cont r act i l i t y can t ri gger compensat or y mechani sms, l eadi ng t o HF (see Chapt er 41) .
( b) ECGs shoul d be moni t ored rout i nel y because al l 8-bl ockers can decr ease
el ect ri cal conduct i on wi t hi n t he hear t and cause br adyar rhyt hmi as.
( c) Rel at i ve car di osel ect i vi t y i s dose dependent and i s l ost as dosages ar e
i ncreased. Ther ef ore, no ß- bI ocker i s t ot aI I y saf e i n pat i ent s wi t h
bronchospast i c di sease÷f or exampl e ast hma and chr oni c obst r uct i ve pul monar y
di sease ( COPD) .
( d) Abrupt st oppage i n 8- bl ocker t herapy put s t he pat i ent at r i sk f or a wi thdrawaI
syndrome t hat may produce
( i ) Exacer bat ed angi nal at t acks, part i cul ar l y i n pat i ent s wi t h cor onar y ar t er y di sease
( i i ) Myocar di al i nf ar ct i on
( i i i ) A l i f e- t hr eat eni ng r ebound of bl ood pr essur e t o l evel s exceedi ng pret reat ment
r eadi ngs
( e) 8- Bl ocker t her apy shoul d be used wi t h caut i on i n pat i ent s wi t h t he f ol l owi ng
condi t i ons:
( i ) Di abet es. 8- Bl ocker s can mask hypogl ycemi c sympt oms, such as t achycar di a.
( i i ) Raynaud phenomenon or peri pheraI vascuI ar di sease. Vasoconst r i ct i on can
occur and, i n predi sposed pat i ent s, mi ght resul t i n a cl i ni cal l y si gni f i cant pr obl em.
( i i i ) NeuroI ogi caI di sorders. Sever al 8- bl ocker s ent er t he cent r al ner vous syst em
( CNS) , pot ent i at i ng r el at ed si de ef f ect s ( e. g. , f at i gue, l et hargy, poor memor y,
weakness, or ment al depr essi on) .
( f ) Ì mpot ence and decr eased l i bi do may r esul t i n r educed pat i ent compl i ance.
( 5) Si gni f i cant i nteracti ons. 8- Adr energi c bl ocker s i nt er act wi t h numerous agent s,
r equi r i ng caut i ous sel ect i on, admi ni st r at i on, and moni t ori ng.
( 6) ß- BI ocker t erms
( a) ReI at i ve cardi oseI ect i ve act i vi t y. Rel at i ve t o pr opr anol ol , 8- bl ockers have a
gr eat er t endency t o occupy t he 81- r ecept or i n t he heart , rat her t han t he 82- r ecept or s
i n t he l ungs.
( b) I nt ri nsi c sympat homi meti c act i vi t y. These agent s have t he abi l i t y t o r el ease
cat echol ami nes and t o mai nt ai n a sat i sf act or y hear t r at e. Ì nt ri nsi c sympat homi met i c
act i vi t y may al so pr event br onchoconst r i ct i on and ot her di r ect 8-bl ocki ng act i ons.
P. 862


( 7) Speci f i c agents
( a) PropranoI oI ( I nderaI ) was t he f i rst 8- adrenergi c bl ocki ng agent shown t o bl ock
bot h 81- and 82- r ecept ors. The usuaI dai I y dose range i s 40- 160 mg. Ì t i s avai l abl e
bot h as a r api d-act i ng product and a l ong- act i ng pr oduct ( Ì nderal - LA) ; t he usual
dai l y dose range i s 60-180 mg.
( b) Met oproI oI ( Lopressor) was t he f i r st 8- adr ener gi c bl ocki ng agent t o show
r el at i ve cardi osel ect i ve bl ocki ng act i vi t y, wi t h r el at i vel y l ess bl ockade of t he 82-
r ecept or s i n t he l ung when compared t o pr opr anol ol . The usuaI dai I y dose i s 50-
100 mg. A sust ai ned- r el ease f or m of t he dr ug i s now avai l abl e, as t he succi nat e sal t
( Topr ol XL) , whi ch requi res l ess f r equent dosi ng, ( dai l y ver sus once or t wi ce dai l y
f or i mmedi at e- r el ease met oprol ol ) .
( c) NadoI oI ( Corgard) was t he f i rst 8-adrenergi c bl ocki ng agent t hat al l owed once-
dai l y dosi ng. Ì t bl ocks bot h 81- and 82- recept or s si mi l ar t o pr opr anol ol . The usuaI
dai I y dose i s 40-120 mg.
( d) At enoI oI ( Tenormi n) was t he f i rst 8-adrener gi c bl ocki ng agent t o combi ne once-
dai l y dosi ng (nadol ol ) wi t h r el at i ve car di osel ect i ve bl ocki ng act i vi t y (met opr ol ol ) .
The usuaI dai I y dose i s 25- 100 mg.
( e) Ti moI oI ( BI ocadren) was t he f i rst 8-adrener gi c bl ocki ng agent shown t o be
ef f ect i ve af t er an acut e MÌ t o pr event sudden deat h. Ì t bl ocks bot h 81- and 82-
r ecept or s. The usuaI dai I y dose i s 20-40 mg.
( f ) Pi ndoI oI ( Vi sken) was t he f i r st 8- adr ener gi c bl ocki ng agent shown t o have hi gh
i nt ri nsi c sympat homi met i c act i vi t y. The usuaI dai I y dose i s 10-40 mg.
( g) Labet aI oI ( Trandat e) was t he f i rst 8-adrener gi c bl ocki ng agent shown t o
possess bot h q- and 8- adr ener gi c bl ocki ng act i vi t y. The usuaI dai I y dose i s 200-
800 mg. Labet al ol i s al so ef f ect i ve f or t r eat i ng hyper t ensi ve cri si s ( Tabl e 41- 6) .
( h) Acebut oI oI ( Sect raI ) was t he f i rst 8-adrener gi c bl ocki ng agent t hat combi ned
ef f i cacy wi t h once- dai l y dosi ng ( nadol ol ) , possessi ng i nt ri nsi c sympat homi met i c
act i vi t y ( pi ndol ol ) and havi ng r el at i ve cardi osel ect i ve bl ocki ng act i vi t y (met opr ol ol ) .
The usuaI dai I y dose i s 200-800 mg.
( i ) EsmoI oI ( Brevi bI oc) was t he f i rst 8-adr energi c bl ocki ng agent t o have an
ul t rashor t durat i on of act i on. Thi s agent i s not used r out i nel y i n t r eat i ng
hyper t ensi on owi ng t o i t s dur at i on of act i on and t he need f or i nt r avenous
admi ni st rat i on. However , i t has been used f or hyper t ensi on and or t achycar di a
dur i ng and af t er surgi cal pr ocedur es. The usuaI dose i s 150- 300 µg/ kg/ mi n up t o
300 µg/ kg/ mi n i nt r avenousl y.
( j ) Bet axoI oI ( KerI one) i s a 8-adrener gi c bl ocker t hat possesses rel at i ve
car di osel ect i ve bl ocki ng act i vi t y si mi l ar t o met oprol ol but has a hal f - l i f e t hat al l ows
f or once- dai l y dosi ng. The usuaI dai I y dose i s 5-20 mg.
( k) Penbut oI oI ( Levat oI ) i s a 8-adr energi c bl ocki ng agent t hat has weak i nt r i nsi c
sympat homi met i c act i vi t y l i ke pi ndol ol and al l ows f or once- dai l y dosi ng. The usuaI
dai I y dose i s 10-20 mg.
( I ) Bi soproI oI ( Zebeta) i s a 8-adrener gi c bl ocki ng agent t hat i s cardi osel ect i ve and
has no i nt r i nsi c sympat homi met i c act i vi t y. Ì t al l ows f or once-dai l y dosi ng, and t he
usuaI dai I y dose i s 2. 5-10 mg.
( m) Carvedi I oI ( Coreg) i s a 8-adrener gi c bl ocki ng agent t hat has 8- bl ocki ng
pr oper t i es as wel l as q- bl ocki ng pr oper t i es, wi t h a r esul t ant vasodi l at i on. The dr ug
i s admi ni st er ed t wi ce dai l y wi t h a st art i ng dose of 6. 25 mg t i t r at ed at 7- t o 14- day
i nt er val s t o a dose of 25 mg t wi ce dai l y. UsuaI dai I y doses are 12. 5- 50 mg dai l y.
( n) Nebi voI oI ( Byst oI i c) i s a 8-adr energi c bl ocki ng agent t hat has car di osel ect i ve
81 bl ocki ng t endenci es, si mi l ar t o sever al ot her agent s i n t he cl ass. Ì ni t i al r epor t s
al so suggest t hat nebi vol ol has vasodi l at or y pr oper t i es t hr ough i t s rel ease of ni t r i c
oxi de. Nebi vol ol i s admi ni st er ed i n a si ngl e dai l y dose of 5 mg wi t h dose t i t r at i on
r equi r ed based on t her apeut i c r esponse.
b. Peri pheraI o1-adrenergi c bI ockers÷f or exampl e, pr azosi n ( Mi ni press), t erazosi n
( Hyt r i n) , and doxazosi n(Car dura)
( 1) I ndi cat i ons. Thi s gr oup of drugs i s avai l abl e f or hyper t ensi ve pat i ent s who have
not responded t o i ni t i al ant i hyper t ensi ve t her apy.
( 2) Act i ons. The q1-bl ockers ( i ndi r ect vasodi l at ors) bl ock t he per i pheral
post synapt i c q1-adrenergi c r ecept or , causi ng vasodi l at i on of bot h ar t er i es and vei ns.
Al so, t he i nci dence of ref l ex t achycar di a i s l ower wi t h t hese agent s t han wi t h t he
vasodi l at or hydr al azi ne. These hemodynami c changes r everse t he abnormal i t i es i n
hyper t ensi on and pr eserve or gan per f usi on. Recent st udi es have al so shown t hat
t hese agent s have no adver se ef f ect on ser um l i pi ds and ot her car di ac r i sk f act or s.
P. 863


Table 41-6. Rapid-Acting Parenteral Antihypertensive Agents for Hypertensive
Crisis
Drug Dose/Route
Onset of
Action
Duration
of ActionComments
Vasodilators
Sodium
nitroprusside
(Nitropress)
0.3-10
mg/kg/min
as IV
inIusion
0.5-
1
min
1-2
min
Immediate eIIect. very
short duration; nausea.
vomiting. muscle
twitching. sweating.
thiocyanate and
cyanide intoxication
Nicardipine
hydrochloride
(Cardene)
5-15 mg/hr
IV
·
5-
15
min
1-4
hr
Intermediate onset and
duration; tachycardia
may occur. headache.
Ilushing. local
phlebitis
Fenoldopam
mesylate
(Corlopam)
0.1-0.3
µg/kg/min
as IV
inIusion
· 5
min
30
min
Intermediate onset and
duration; action on
dopamine D
1
-
receptors (dilation oI
renal/mesenteric
vessels might be
preIerred over
nitroprusside Ior long-
term or with renal
dysIunction;
tachycardia. headache.
nausea. Ilushing
Nitroglycerin 5-200
µg/min
(0.3-6.0
2-5
min
3-5
min
UseIul in coronary
artery disease;
headache. vomiting.
mg/hr) as
IV inIusion
methemoglobinemia.
tolerance with
prolonged use
Enalaprilat
(Vasotec IV)
0.625-1.25
mg every 6
hr IV
15-
30
min
4-6
hr
UseIul in HF. but
avoid in renal
impairment;
precipitous Iall in
blood pressure in
high-renin states
Hydralazine 10-40 mg
IV/IM
10-
20
min
3-8
hr
AIterload reduction
through arteriole
dilation resulting in
increased cardiac
output; tachycardia.
Ilushing headache.
vomiting. aggravation
oI preexisting angina
Diazoxide
(Proglycem)
1-3 mg/kg
over 30 sec
as IV
bolus.
repeated
every 5-15
min. or 10-
30 mg/min
inIusion
2-4
min
3-12
hr
UseIul in hypertensive
encephalopathy.
malignant
hypertension. and
eclampsia; Ilushing.
nausea. tachycardia.
and chest pain
Adrenergic inhibitors
Labetalol
hydrochloride
(Various)
40-80 mg
IV bolus
every 10
min. or
0.5-2.0
mg/min IV
inIusion
5-
10
min
3-6
hr
Contraindicated in
HF. bronchospastic
patients. or
bradycardia;
predictable
hypotensive eIIect;
vomiting. scalp
tingling. burning in
throat. heart block.
orthostatic
hypotension
Esmolol
(Brevibloc)
250-500
µg/kg/min
Ior 2 min.
then 50-
100
µg/kg/min
Ior 4 min;
may repeat
iI needed
1-2
min
10-
20
min
þ-Adrenergic blocker
with ultra-short
duration oI eIIect;
primary use in
perioperative situation
owing to short
duration and quick
onset; hypotension.
nausea
Phentolamine 5-15 mg
IV
1-2
min
3-10
min
u-Adrenergic blocker
causing peripheral
dilation; tachycardia.
Ilushing. headache
HF. heart Iailure; IM. intramuscular; IV. intravenous.

P. 864


( 3) Precaut i ons and moni t ori ng ef fects
( a) Fi rst - dose phenomenon. A syncopal epi sode may occur wi t hi n 30- 90 mi n of t he
f i r st dose; si mi l ar l y associ at ed ar e post ur al hypot ensi on, nausea, di zzi ness,
headache, pal pi t at i ons, and sweat i ng. To mi ni mi ze t hese ef f ect s, t he f i rst dose
shoul d be l i mi t ed t o a smal l dose ( 1 mg) and admi ni st er ed j ust bef ore bedt i me.
( b) Addi t i onal adverse ef f ect s i ncl ude di ar r hea, wei ght gai n, per i pheral edema, dr y
mout h, ur i nar y urgency, const i pat i on, and pr i api sm. Doxazosi n i n doses of 2- 8
mg/ day was one of t he t reat ment arms i n t he r ecent Ant i hyper t ensi ve and Li pi d-
Lower i ng Tr eat ment t o Pr event Hear t At t ack Tr i al ( ALLHAT) , and t he t r eat ment was
di scont i nued pr emat ur el y owi ng t o an appar ent 25% i ncrease i n t he i nci dence of
combi ned car di ovascul ar di sease out comes t han pat i ent s i n t he cont r ol group
r ecei vi ng t he di uret i c chl or t hal i done. The added ri sk f or HF, st roke, and cor onar y
hear t di sease wer e t he maj or out comes af f ect ed i n t he doxazosi n arm.
( 4) The average dai I y doses are
( a) Prazosi n (Mi ni press) : 2- 20 mg
( b) Terazosi n ( Hyt ri n) : 1- 20 mg
( c) Doxazosi n( Cardura): 1- 16 mg
c. Cent raI I y act i ve o- agoni sts have been used i n t he past as al t ernat i ves t o i ni t i al
ant i hyper t ensi ves, but t hei r use i n mi l d t o moderat e hyper t ensi on has been r educed
pr i mar i l y owi ng t o ot her avai l abl e agent s. They act pr i mar i l y wi t hi n t he CNS on q2-
r ecept or s t o decr ease sympat het i c out f l ow t o t he car di ovascul ar syst em.
( 1) Met hyI dopa ( AI domet )
( a) Act i ons. Met hyl dopa decr eases t ot al per i pheral resi st ance t hr ough t he above
mechani sm whi l e havi ng l i t t l e ef f ect on car di ac out put or heart r at e (except i n ol der
pat i ent s) .
( b) Precaut i ons and moni t ori ng ef fects
( i ) Common unt owar d ef f ect s i ncl ude or t host at i c hypot ensi on, f l ui d accumul at i on ( i n
t he absence of a di uret i c) , and r ebound hypert ensi on on abr upt wi t hdrawal .
Sedat i on i s a common f i ndi ng upon i ni t i at i ng t herapy and when i ncr easi ng doses;
however , t he sedat i ve ef f ect usual l y decreases wi t h cont i nued t her apy.
( i i ) Fever and ot her f l u- l i ke sympt oms occasi onal l y occur and may represent hepat i c
dysf unct i on, whi ch shoul d be moni t or ed by l i ver f unct i on t est s.
( i i i ) A posi t i ve Coombs t est devel ops i n 25% of pat i ent s wi t h chr oni c use ( > 6
mont hs) . Less t han 1% of t hese pat i ent s devel op a hemol yt i c anemi a. ( Red bl ood
cel l s, hemogl obi n, and bl ood count i ndi ces shoul d be checked. ) The anemi a i s
r ever si bl e by di scont i nui ng t he dr ug.
( i v) Ot her ef f ect s i ncl ude dr y mout h, subt l y decreased ment al act i vi t y, sl eep
di st ur bances, depressi on, i mpot ence, and l act at i on i n ei t her gender .
( c) The usuaI dai I y dose i s 250 mg-1. 0 g
P. 865


( 2) CI oni di ne ( Cat apres)
( a) I ndi cat i ons. Cl oni di ne i s ef f ect i ve i n pat i ent s wi t h r enal i mpai rment , al t hough
t hey may r equi re a r educed dose or a l onger dosi ng i nt er val .
( b) Act i ons. Cl oni di ne st i mul at es q2- r ecept ors cent r al l y, decreasi ng vasomot or t one
and hear t rat e.
( c) Precaut i ons and moni t ori ng ef fects
( i ) Ì nt r avenous admi ni st rat i on causes an i ni t i al par adoxi cal i ncr ease i n pressur e
( di ast ol i c and syst ol i c) t hat i s f ol l owed by a prol onged dr op. As wi t h met hyl dopa,
abr upt wi t hdrawal can cause r ebound hyper t ensi on.
( i i ) Sedat i on and dr y mout h ar e common but usual l y di sappear wi t h cont i nued
t her apy.
( i i i ) Cl oni di ne has a t endency t o cause or wor sen depressi on, and i t hei ght ens t he
depressant ef f ect s of al cohol and ot her sedat i ng subst ances.
( d) The usuaI dai I y dose i s 0. 1- 0. 8 mg.
( e) Pat i ent compl i ance i s a maj or i ssue f or most hyper t ensi ve pat i ent s. The r ecent l y
r el eased once- weekl y pat ch ( Cat apr es- TTS) , whi ch pr ovi des 0. 1- 0. 3 mg per 24 hr ,
may i mprove compl i ance.
( 3) Guanabenz ( Wyt ensi n) and guanfaci ne (Tenex)
( a) I ndi cat i ons. These agent s ar e recommended as adj unct i ve t her apy wi t h ot her
ant i hyper t ensi ves f or addi t i ve ef f ect s when i ni t i al t herapy has f ai l ed.
( b) Act i ons. Guanabenz and guanf aci ne are cent r al l y act i ve q2- agoni st s t hat have
act i ons si mi l ar t o cl oni di ne.
( c) Precaut i ons and moni t ori ng ef fects. These agent s shoul d be used caut i ousl y
wi t h ot her sedat i ng medi cat i ons and i n pat i ent s wi t h severe cor onar y i nsuf f i ci ency,
r ecent MÌ , cer ebr ovascul ar acci dent ( CVA), and hepat i c or renal di sease. Si de
ef f ect s i ncl ude sedat i on, dr y mout h, di zzi ness, and r educed hear t r at e.
( d) The usuaI dai I y doses are 4- 8 mg i n t wo doses f or guanabenz and 1-3 mg i n
one dose f or guanf aci ne.
d. Post gangI i oni c adrenergi c neuron bI ockers. Thi s cl ass of ant i hyper t ensi ve
dr ugs i s best avoi ded unl ess i t i s necessar y t o t reat severe r ef r act or y hyper t ensi on
t hat i s unr esponsi ve t o al l ot her medi cat i ons, because agent s i n t hi s cl ass ar e
poorl y t ol er at ed by most pat i ent s.
( 1) Reserpi ne
( a) GeneraI consi derat i ons. Because of t he hi gh i nci dence of adverse ef f ect s,
ot her agent s ar e usual l y chosen f i r st . When used, r eser pi ne i s gi ven i n l ow doses
and i n conj unct i on wi t h ot her ant i hyper t ensi ve agent s. Reserpi ne i n ver y l ow doses
( 0. 05 mg) combi ned wi t h a di ur et i c such as chl orot hi azi de ( 50- 100 mg) may be an
al t er nat i ve t o t radi t i onal doses of 0. 05- 0. 25 mg/ day.
( b) Act i ons. Reser pi ne act s cent r al l y as wel l as per i pheral l y by depl et i ng
cat echol ami ne st or es i n t he br ai n and i n t he per i pheral adr energi c syst em.
( c) Precaut i ons and moni t ori ng ef fects
( i ) A hi st or y of depr essi on i s a cont rai ndi cat i on f or r eser pi ne. Even l ow doses, such
as 0. 25 mg/ day, can t r i gger a r ange of psychi c responses, f r om ni ght mar es t o
sui ci de at t empt s. Dr ug- i nduced depr essi on may l i nger f or mont hs af t er t he l ast
dose.
( i i ) Pept i c ul cer i s al so a cont r ai ndi cat i on f or usi ng r eserpi ne. Even a si ngl e dose
t ends t o i ncr ease gast ri c aci d secr et i on.
( i i i ) Common adverse ef f ect s i ncl ude dr owsi ness, di zzi ness, weakness, l et har gy,
memor y i mpai rment , sl eep di st ur bances, and wei ght gai n. Nasal congest i on i s al so
common but may decr ease wi t h cont i nued t herapy.
( d) The usuaI dai I y dose of reserpi ne i s 0. 1- 0. 25 mg.
4. ACE i nhi bi t ors
a. GeneraI consi derat i ons. The ACE i nhi bi t or s÷benazepr i l ( Lot ensi n), capt opri l
( Capot en) , enal apr i l ( Vasot ec) , f osi nopr i l ( Monopr i l ) , l i si nopr i l ( Zest ri l ), moexi pr i l
( Uni vasc) , peri ndopri l ( Aceon) , qui napr i l ( Accupr i l ) , r ami pr i l ( Al t ace), and
t r andol apri l ( Mavi k) ÷are a r api dl y growi ng group of drugs. The Hear t Out comes
Pr event i on Eval uat i on ( HOPE) pr oj ect demonst r at ed subst ant i al cl i ni cal benef i t s i n
pat i ent s recei vi ng rami pri l , whi ch coul d not be expl ai ned t hr ough i t s bl ood pr essur e-
l ower i ng ef f ect s al one. Subsequent l y, st udi es, si mi l ar t o HOPE have been
compl et ed, t o dat e, whi ch have demonst r at ed t he benef i t of ACE i nhi bi t ors i n t he
t r eat ment of hyper t ensi on and prevent i on of car di ac event s, r enal di sease et c.
P. 866


b. I ndi cat i ons. Previ ous gui del i nes used ACE i nhi bi t ors as f i rst - l i ne al t ernat i ves f or
t r eat i ng hyper t ensi on i n pat i ent s unabl e t o t ol er at e t hi azi des or 8- bl ockers.
However , JNC- 7 recommendat i ons have i dent i f i ed speci f i c pat i ent popul at i ons t hat
have compel l i ng i ndi cat i ons ÷such as di abet es, post myocardi al i nf arct i on, hi gh
cor onar y di sease ri sk, chr oni c ki dney di sease, and r ecur r ent st r oke pr event i on÷f or
whi ch t he ACE i nhi bi t ors ar e i ndi cat ed i n t he t r eat ment of hyper t ensi on or
pr ehyper t ensi on. Thi s has been pr i mar i l y because of st udi es document i ng t hei r
cl i ni cal ef f i cacy as wel l as mi ni mal ef f ect on pat i ent s' abi l i t i es t o mai nt ai n normal
f unct i on.
c. Act i ons
( 1) These agent s i nhi bi t t he conver si on of angi ot ensi n Ì ( a weak vasoconst r i ct or ) t o
angi ot ensi n Ì Ì (a pot ent vasoconst ri ct or ) , whi ch decr eases t he avai l abi l i t y of
angi ot ensi n Ì Ì .
( 2) ACE i nhi bi t ors i ndi r ect l y i nhi bi t f l ui d vol ume i ncr eases when i nt erf er i ng wi t h
angi ot ensi n Ì Ì by i nhi bi t i ng angi ot ensi n Ì Ì -st i mul at ed rel ease of al dost er one, whi ch
pr omot es sodi um and wat er r et ent i on. The net ef f ect appears t o be a decrease i n
f l ui d vol ume, al ong wi t h per i pheral vasodi l at i on.
d. Si gni f i cant i nteract i ons
( 1) The ant i hypert ensi ve ef f ect of ACE i nhi bi t or s may be di mi ni shed by NSAI Ds
( e. g. , over -t he-count er f or ms of i buprof en) .
( 2) Pot assi um- spar i ng di ur et i cs i ncrease serum pot assi um l evel s when used wi t h
ACE i nhi bi t ors, and pot assi um l evel s need t o be cl osel y moni t or ed i n t hese pat i ent s.
e. Precauti ons and moni t ori ng ef f ect s
( 1) Neut r openi a i s r are but ser i ous; t here i s an i ncr eased i nci dence i n pat i ent s wi t h
r enal i nsuf f i ci ency or aut oi mmune di sease.
( 2) Pr ot ei nuri a occurs, par t i cul ar l y i n pat i ent s wi t h a hi st or y of r enal di sease.
Ur i nar y pr ot ei ns shoul d be moni t ored r egul ar l y.
( 3) Serum pot assi um l evel s shoul d be moni t or ed r egul arl y f or hyperkal emi a. The
mechani sm of act i on t ends t o i ncr ease pot assi um l evel s somewhat . Pat i ent s wi t h
r enal i mpai rment are at i ncr eased ri sk.
( 4) Renal i nsuf f i ci ency can occur i n pat i ent s wi t h pr edi sposi ng f act ors, such as
r enal st enosi s, and when ACE i nhi bi t or s ar e admi ni st er ed wi t h t hi azi de di ur et i cs.
Renal f unct i on shoul d be moni t or ed ( e. g. , t hrough moni t or i ng l evel s of serum
cr eat i ni ne and BUN) .
( 5) A dr y cough may occur but di sappears wi t hi n a f ew days af t er t he ACE i nhi bi t or
i s di scont i nued. Al l ACE i nhi bi t ors have t he pot ent i al t o cause t hi s si de ef f ect , but
swi t chi ng t o an al t er nat i ve agent may i mprove t he sympt oms.
( 6) Ot her unt owar d ef f ect s i ncl ude rashes, an al t er ed sense of t ast e ( dysgeusi a) ,
ver t i go, headache, f at i gue, f i r st - dose hypot ensi on, and mi nor gast r oi nt est i nal
di st ur bances.
f . Speci f i c agents
( 1) Captopri I ( Capot en). The or i gi nal ACE i nhi bi t or i s gi ven i ni t i al l y as a 12. 5-25
mg dose t hr ee t i mes dai l y and i s i ncr eased t o a usuaI dai I y dose of 25-100 mg i n
t wo or t hree doses. Ì ni t i al dose i s usual l y l ower i f pat i ent i s on di ur et i cs t o avoi d
i ni t i al hypot ensi ve r esponse.
( 2) EnaI apri I ( Vasotec) i s a pr odr ug, whi ch i s rapi dl y convert ed t o i t s act i ve
met abol i t e, enal apr i l at . Ì ni t i al doses are 5. 0 mg dai l y, wi t h a usuaI dai I y dose of 5-
40 mg i n one t o t wo doses. Ì n addi t i on, t he enal apr i l at f or m ( Vasot ec Ì V) of t he dr ug
has been used ef f ect i vel y f or t reat i ng acut e hyper t ensi ve cr i si s ( Tabl e 41-6) .
( 3) Li si nopri I (Zest ri I ) i s a l ong- act i ng anal og of enal apr i l , gi ven i ni t i al l y as a 5-10
mg dai l y dose and adj ust ed t o a usuaI dai I y dose of 10-40 mg i n one dose.
( 4) Benazepri l ( Lot ensi n), f osi nopri l ( Monopr i l ) , moexi pr i l ( Uni vasc), per i ndopri l
( Aceon) , qui napr i l ( Accupr i l ), r ami pr i l ( Al t ace) , and t randol apr i l ( Mavi k) have as
t hei r maj or benef i t a l onger dur at i on of act i on, whi ch i n many pat i ent s may r esul t i n
once- dai l y dosi ng and i mpr oved compl i ance. Average dai I y doses f or t hese agent s
ar e
( a) Benazepri I ( Lotensi n) : 10- 40 mg i n one t o t wo doses
( b) Fosi nopri I (Monopri I ) : 10- 40 mg i n one dose
( c) Moexi pri I ( Uni vasc) : 7. 5-30 mg i n one dose
( d) Peri ndopri I ( Aceon): 4- 8 mg i n one t o t wo doses
( e) Qui napri I ( Accupri I ): 10- 80 mg i n one dose
( f ) Rami pri I ( AI t ace) : 2. 5- 20 mg i n one dose
( g) TrandoI apri I ( Mavi k): 1- 4 mg i n one dose
P. 867


( 5) Fur t her st udy of t hese agent s cont i nues, and t hei r use i n ot her car di ovascul ar as
wel l as noncar di ovascul ar di seases cont i nues t o expand.
5. Angi ot ensi n I I t ype I receptor ant agoni sts
a. I ndi cat i ons. Thi s cl ass of drugs has been one of t he f ast est growi ng groups of
dr ugs f or t he t r eat ment of hypert ensi on. Cur r ent l y, seven agent s ar e avai l abl e:
candesar t an ci l exet i l ( At acand) , eprosar t an ( Tevet en), i rbesart an ( Avaprol ) , l osar t an
( Cozaar ) , ol mesar t an ( Beni car ), t el mi sar t an ( Mi car di s) , and val sar t an ( Di ovan) .
b. Act i ons. Thi s cl ass of dr ugs wor ks by bl ocki ng t he bi ndi ng of angi ot ensi n Ì Ì t o
t he angi ot ensi n Ì Ì r ecept or s. By bl ocki ng t he recept or si t e, t hese agent s i nhi bi t t he
vasoconst ri ct or ef f ect s of angi ot ensi n Ì Ì as wel l as prevent t he r el ease of
al dost er one owi ng t o angi ot ensi n Ì Ì f r om t he adrenal gl ands. These t wo pr oper t i es of
angi ot ensi n Ì Ì have been shown t o be i mpor t ant causes f or devel opi ng hyper t ensi on.
Cl i ni cal l y, angi ot ensi n r ecept or bl ockers appear t o be equal l y ef f ect i ve f or t he
t r eat ment of hyper t ensi on as ACE i nhi bi t ors.
c. Precauti ons and moni t ori ng ef f ect s
( 1) Si mi l ar t o ACE i nhi bi t or s, i ncr eases i n ser um pot assi um l evel s can occur ,
especi al l y i n pat i ent s r ecei vi ng pot assi um- spari ng di ur et i cs. When used al one,
hyper kal emi a has not been r eport ed t o be severe enough t o r equi re st oppi ng i t s
use. However , as i n pat i ent s r ecei vi ng ACE i nhi bi t ors, pot assi um l evel s need t o be
moni t ored cl osel y i n t hose wi t h compr omi sed r enal f unct i on.
( 2) Renal f unct i on i s an i mport ant consi der at i on f or pat i ent s r ecei vi ng angi ot ensi n-
r ecept or bl ocker s (ARBs) . Si mi l ar t o ACE i nhi bi t or s, decl i ni ng renal f unct i on or
acut e renal f ai l ur e wi l l r esul t i n el evat ed serum pot assi um l evel s, owi ng t o t he
ki dneys i nabi l i t y t o excr et e pot assi um. BUN and ser um creat i ni ne l evel s shoul d be
moni t ored t o pr event t he devel opment of hyper kal emi a.
d. Dosage gui deI i nes f or t he avai l abl e agent s are as f ol l ows:
( 1) Candesart an ci I exeti I ( At acand) : 8- 32 mg i n one t o t wo doses
( 2) Eprosart an ( Tevet en) : 400- 800 mg i n one t o t wo doses
( 3) I rbesartan ( Avapro) : 150-300 mg i n one dose
( 4) Losart an ( Cozaar) : 25- 100 mg i n one t o t wo doses
( 5) OI mesartan ( Beni car) : 20- 40 mg i n one dose
( 6) TeI mi sart an (Mi cardi s) : 20- 80 mg i n one dose
( 7) VaI sartan ( Di ovan) : 80- 320 mg i n one- t wo doses
e. Current stat us
( 1) Many aut hor i t i es bel i eve t hat i n t he t r eat ment of hyper t ensi on, t here do not
appear t o be si gni f i cant di f f er ences bet ween ACE i nhi bi t ors and angi ot ensi n
r ecept or bl ocker s.
( 2) Fami l i ar i t y and cost mi ght wel l pr ovi de t he basi s of t he sel ect i on of one agent
over anot her at t hi s t i me.
( 3) Angi ot ensi n r ecept or bl ocker s have f ound use i n speci al hypert ensi ve
popul at i ons wi t h compel l i ng i ndi cat i ons, such as di abet es, HF, and chr oni c ki dney
di sease, especi al l y i n pat i ent s who cannot t ol erat e an ACE i nhi bi t or .
6. CaI ci um- channeI bI ockers
a. I ndi cat i ons. The cal ci um-channel bl ockers are consi dered al t er nat i ve dr ugs f or
t he i ni t i al t reat ment of hyper t ensi on i n sel ect pat i ent popul at i ons t hat ar e unabl e t o
t ake 8- adr ener gi c- recept or bl ocker s, such as pat i ent s wi t h a hi gh coronary di sease
r i sk or di abet es mel l i t us who al so have bronchospast i c di sease or Raynaud di sease.
Cur r ent l y, ei ght agent s÷aml odi pi ne ( Nor vasc) , di l t i azem ( Cardi zem) , f el odi pi ne
( Pl endi l ) , i sradi pi ne ( DynaCi r c CR) , ni car di pi ne (Car dene) , ni f edi pi ne ( Procardi a) ,
ni sol di pi ne ( Sul ar ) , and ver apami l ( Cal an) are avai l abl e.
b. Act i ons
( 1) Cal ci um- channel bl ockers i nhi bi t t he i nf l ux of cal ci um t hrough sl ow channel s i n
vascul ar smoot h muscl e and cause r el axat i on. Low- r eni n hyper t ensi ve, bl ack, and
el der l y pat i ent s respond wel l t o t hese agent s.
( 2) Al t hough t he cal ci um- channel bl ockers share a si mi l ar mechani sm of act i on,
each agent produces di f f er ent degr ees of syst emi c and coronar y ar t eri al
vasodi l at i on, si noat r i al (SA) and at r i ovent r i cul ar ( AV) nodal depr essi on, and a
decrease i n myocar di al cont r act i l i t y.
c. Si gni f i cant i nteracti ons. ß- Adrenergi c bI ockers, when used wi t h cal ci um-
channel bl ocker s, may have an addi t i ve ef f ect on i nduci ng HF and br adycar di a.
El ect r i cal conduct i on t o t he AV node may be f ur t her depr essed when pat i ent s ar e
gi ven agent s such as verapami l or di l t i azem al ong wi t h 8- bl ocker s.
P. 868


d. Precaut i ons and moni t ori ng ef fects
( 1) Di l t i azem and ver apami l must be used wi t h ext r eme caut i on or not at al l i n
pat i ent s wi t h conduct i ve di st ur bances i nvol vi ng t he SA or AV node, such as second-
or t hi r d-degr ee AV bl ock, si ck si nus syndrome, and di gi t al i s t oxi ci t y.
( 2) Ni f edi pi ne use has been associ at ed wi t h f l ushi ng, headache, and per i pheral
edema; t he pat i ent may f i nd t hese t r oubl esome and t hus may become noncompl i ant .
Usi ng t he sust ai ned- r el ease pr oduct once dai l y has been shown t o ef f ect i vel y
r educe t hese ef f ect s.
( 3) Verapami l use has been associ at ed wi t h a si gni f i cant degr ee of const i pat i on,
whi ch must be t reat ed t o pr event st ool st r ai ni ng and noncompl i ance.
e. Speci fi c agents
( 1) Di I ti azem ( Cardi zem) . The r el ease of sever al ext ended- rel ease pr oduct s
( Car di zem CD, Car di zem- LA, Di l acor XR, Ti azac) has r educed t he f r equency of dai l y
doses i n t he t r eat ment of hyper t ensi on. A si ngl e dai l y dose of 120- 540 mg i s
ef f ect i ve f or t r eat i ng mi l d t o moderat e hypert ensi on. Di l t i azem al r eady has proven
ef f i cacy as an ant i ar r hyt hmi c and an ant i angi nal agent .
( 2) Ni f edi pi ne (Procardi a) . The rel ease of once-dai l y sust ai ned- rel ease
pr epar at i ons ( Pr ocar di a XL, Adal at CC) has made t hi s agent ef f ect i ve as a once-
dai l y t herapy f or l ong- t erm t reat ment of hyper t ensi on. A pr evi ousl y r epor t ed l ong l i st
of si de ef f ect s has been r educed wi t h t he sust ai ned- r el ease product at a si ngl e dai l y
dose of 30- 90 mg. Ì mmedi at e- r el ease ni f edi pi ne has been repor t ed t o cause
i schemi c event s, and t he cur rent r ecommendat i on i s t o avoi d i t s use i f at al l
possi bl e.
( 3) Verapami I ( CaI an) . Thi s drug i s si mi l ar t o di l t i azem i n i t s act i ons ( t hough wi t h
mor e pot ent ef f ect s on el ect ri cal conduct i on depressi on) . Sust ai ned- r el ease
pr oduct s ( Cal an SR, Ì sopt i n SR, Covera- HS, Verel an) at doses of 120-480 mg dai l y
have been shown t o be ef f i caci ous f or l ong- t er m management of mi l d t o moder at e
hyper t ensi on, whi l e si de ef f ect s such as di zzi ness, const i pat i on, and hypot ensi on
ar e reduced.
( 4) Aml odi pi ne ( Nor vasc), i sr adi pi ne ( DynaCi rc) , f el odi pi ne ( Pl endi l ), ni cardi pi ne
( Car dene SR), and ni sol di pi ne ( Sul ar ) ar e second- gener at i on cal ci um- channel
bl ocker s. These agent s have been devel oped t o pr oduce mor e sel ect i ve ef f ect s on
speci f i c t ar get t i ssues t han t he f i rst - generat i on agent s di l t i azem, ni f edi pi ne, and
ver apami l . These agent s ar e chemi cal l y si mi l ar t o ni f edi pi ne and are r ef er r ed t o as
di hydropyr i di ne der i vat i ves. The dai l y dose r anges are
( a) AmI odi pi ne ( Norvasc) : 2. 5- 10. 0 mg i n one dose
( b) I sradi pi ne ( DynaCi rc) : 2. 5- 10 mg i n one t o t wo doses
( c) FeI odi pi ne ( PI endi I ): 2. 5- 20 mg i n one dose
( d) Ni cardi pi ne ( Cardene SR) : 60- 120 mg as an ext ended- rel ease product t wi ce
dai l y
( e) Ni soI di pi ne ( SuI ar) : 10- 40 mg i n one dose
7. Vasodi I at ors. These dr ugs ar e used as second- l i ne agent s i n pat i ent s r ef r act or y
t o i ni t i al t her apy wi t h di ur et i cs, 8- bl ocker s, ACE i nhi bi t or s, ARBs, or cal ci um-
channel bl ocker s. Vasodi l at ors di r ect l y rel ax per i pheral vascul ar smoot h muscl e÷
ar t eri al , venous, or bot h. The di rect vasodi l at ors shoul d not be used al one owi ng t o
i ncreases i n pl asma r eni n act i vi t y, car di ac out put , and hear t r at e.
a. HydraI azi ne ( ApresoI i ne)
( 1) Act i ons. Hydr al azi ne di rect l y r el axes ar t er i ol es, decr easi ng syst emi c vascul ar
r esi st ance. Ì t i s al so used i nt r avenousl y or i nt r amuscul ar l y i n managi ng
hyper t ensi ve cr i si s.
( 2) Precaut i ons and moni t ori ng ef fects
( a) Because hydral azi ne t r i ggers compensat or y r eact i ons t hat count er act i t s
ant i hyper t ensi ve ef f ect s, i t i s most usef ul when combi ned wi t h a 8- bl ocker , cent ral
q- agoni st , or di ur et i c as a l at t er -st ep agent .
( b) Ref l ex t achycar di a i s common and shoul d be consi dered bef or e i ni t i at i ng
t her apy.
( c) Hydr al azi ne may i nduce angi na, especi al l y i n pat i ent s wi t h cor onar y ar t er y
di sease and t hose not recei vi ng a 8- bl ocker .
( d) Dr ug- i nduced syst emi c l upus er yt hemat osus (SLE) may occur .
( i ) Basel i ne and seri al compl et e bl ood count s ( CBCs) wi t h ant i nucl ear ant i body
t i t ers shoul d be f ol l owed r out i nel y t o det ect SLE.
( i i ) Sl ow acet yl at or s of t hi s dr ug have an i ncreased i nci dence of SLE. Thei r ri sk may
be r educed by admi ni st er i ng doses of < 200 mg/ day.
P. 869


( i i i ) Fat i gue, mal ai se, l ow- gr ade f ever , and j oi nt aches may si gnal SLE.
( e) Ot her adver se ef f ect s may i ncl ude headache, peri pher al neur opat hy, nausea,
vomi t i ng, f l ui d r et ent i on, and post ur al hypot ensi on.
( 3) The usuaI dai I y dose i s 25- 100 mg.
b. Mi noxi di I
( 1) Act i ons. A more pot ent vasodi l at or t han hydral azi ne, mi noxi di l r el axes art er i ol ar
smoot h muscl e di r ect l y, decreasi ng per i pher al r esi st ance. Ì t al so decreases renal
vascul ar r esi st ance whi l e pr eser vi ng r enal bl ood f l ow. Ef f ect i ve i n most pat i ent s,
mi noxi di l i s commonl y used t o t reat pat i ent s wi t h sever e hypert ensi on t hat has been
r ef r act or y t o convent i onal drug regi mens.
( 2) Precaut i ons and moni t ori ng ef fects
( a) Peri pher al di l at i on resul t s i n a ref l ex act i vat i on of t he sympat het i c nervous
syst em and an i ncr ease i n hear t rat e, car di ac out put , and r eni n secret i on.
( b) Because t hi s agent pr omot es sodi um and wat er r et ent i on, par t i cul arl y i n t he
pr esence of renal i mpai rment , pat i ent s shoul d be moni t or ed f or f l ui d accumul at i on
and si gns of car di ac decompensat i on. Admi ni st eri ng mi noxi di l al ong wi t h a
sympat hol yt i c agent and a pot ent di ur et i c ( e. g. , f ur osemi de) mi ni mi zes i ncreased
sympat het i c st i mul at i on and f l ui d r et ent i on.
( c) Hyper t r i chosi s (i . e. , excessi ve hai r gr owt h) i s a common si de ef f ect , par t i cul ar l y
i f t he dr ug i s cont i nued f or > 4 weeks.
( 3) The usuaI dai I y dose i s 2. 5- 80 mg.
c. Ni t roprussi de
( 1) Act i ons. A di r ect -act i ng peri pher al di l at or , t hi s agent has pot ent ef f ect s on bot h
t he ar t eri al and venous syst ems. Ì t i s usual l y used onl y i n shor t -t erm emer gency
t r eat ment of acut e hypert ensi ve cr i si s, when a rapi d ef f ect i s r equi r ed. Onset of
act i on i s al most i nst ant aneous and i s maxi mal i n 1- 2 mi n. Ni t r oprussi de i s
admi ni st er ed i nt r avenousl y wi t h cont i nuous bl ood pr essur e moni t ori ng.
( 2) Precaut i ons and moni t ori ng ef fects. To prevent acut e hypot ensi ve epi sodes,
i ni t i al doses shoul d be ver y l ow, f ol l owed by sl ow t i t rat i on upwar d unt i l t he desi red
ef f ect i s achi eved.
( a) Once t he sol ut i on i s pr epar ed, i t shoul d be prot ect ed f rom l i ght . Col or changes
ar e a si gnal t hat r epl acement i s needed.
( b) Thi ocyanat e t oxi ci t y may devel op wi t h l ong- t er m t reat ment ÷par t i cul arl y i n
pat i ent s wi t h r educed renal act i vi t y÷but can be t r eat ed wi t h hemodi al ysi s.
Sympt oms may i ncl ude f at i gue, anor exi a, di sor i ent at i on, nausea, psychot i c
behavi or , or muscl e spasms.
( c) Cyani de t oxi ci t y can occur ( rar el y) wi t h l ong-t er m, hi gh-dose admi ni st rat i on. Ì t
may present as al t ered consci ousness, convul si ons, t achypnea, or even coma.
( 3) The usuaI dose i s 0. 3- 10 µg/ kg/ mi n as a cont i nuous i nt r avenous i nf usi on.
d. Di azoxi de ( ProgI ycem)
( 1) I ndi cat i ons. Di azoxi de exer t s a di r ect act i on on t he ar t eri ol es but has l i t t l e
ef f ect on venous capaci t y. Ì t i s used i nt r avenousl y i n t he emer gency t reat ment of
acut e hyper t ensi ve cr i si s.
( 2) Admi ni st rat i on
( a) Because t he ant i hyper t ensi ve ef f ect of di azoxi de i ncreases wi t h t he speed of
i nf usi on, r ecent r ecommendat i ons suggest t hat t he dose be admi ni st er ed over 30
sec and, i f necessar y, r epeat doses gi ven ever y 5- 15 mi n.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Di azoxi de i s cl osel y rel at ed t o t he t hi azi des chemi cal l y; t her ef or e, pat i ent s wi t h
t hi azi de sensi t i vi t y cr oss- r eact t o di azoxi de. Ì n pat i ent s wi t h i mpai red cerebr al or
car di ac f unct i on, t he r i sks may out wei gh t he benef i t s of di azoxi de admi ni st r at i on.
( b) Di azoxi de al so pr oduces t r ansi ent hyper gl ycemi a, r equi r i ng caut i on i f
admi ni st er ed t o pat i ent s wi t h di abet es.
( c) Hypot ensi ve react i ons may be sever e.
( d) Unl i ke t he t hi azi des, t hi s agent promot es sodi um and wat er r et ent i on,
pot ent i at i ng edema.
8. Reni n I nhi bi t ors
a. I ndi cat i ons. Al i ski r en ( Tekt urna) i s t he f i r st of t hi s new cl ass of dr ugs r ecent l y
approved by t he FDA f or t he t r eat ment of hypert ensi on.
P. 870


b. Act i ons. Unl i ke angi ot ensi n conver t i ng enzyme ( ACE) i nhi bi t ors and angi ot ensi n
Ì Ì r ecept or bl ockers ( ARBs) , whi ch act duri ng t he l at er st ages of t he r eni n-
angi ot ensi n syst em t o r educe angi ot ensi n Ì Ì (see E. 2) , al i ski ren wor ks di r ect l y on
t he enzyme reni n, t o reduce t he event ual pr oduct i on of angi ot ensi n Ì Ì .
c. AI i ski ren, i s avai l abl e i n 150 and 300 mg t abl et s. The usual st ar t i ng dose i s 150
mg dai l y, and f or t hose who do not respond t he dose can be i ncr eased t o 300 mg
dai l y. Doses great er t hen 300 mg have not been shown t o of f er addi t i onal bl ood
pr essure l ower i ng ef f ect s.
d. Si gni f i cant i nteract i ons. Fur osemi de ser um l evel s have been repor t ed t o be
r educed si gni f i cant l y when admi ni st er ed i n pat i ent s r ecei vi ng al i ski ren. Thi s mi ght
r esul t i n a di mi ni shed phar macol ogi c ef f ect f rom f ur osemi de.
e. Precauti ons and moni t ori ng ef f ect s
Unl i ke t he ACE i nhi bi t ors and ARBs, whi ch have t he pot ent i al t o i ncr ease ser um
pot assi um l evel s, pat i ent s r ecei vi ng al i ski r en have not shown si gni f i cant i ncr eases
i n pot assi um as compar ed t o pat i ent s st udi es r ecei vi ng pl acebo. However, i n a
popul at i on of di abet i c pat i ent s r ecei vi ng bot h ACE i nhi bi t ors or ARBs i n combi nat i on
wi t h al i ski r en cl ose moni t or i ng of ser um el ect rol yt es and r enal f unct i on i s r equi r ed
due t o an i ncr eased f requency of el evat ed ser um pot assi um l evel s.
IV. HYPERTENSIVE EMERGENCIES
A. Def i ni t i on. A hyper t ensi ve emer gency i s a sever e el evat i on of bl ood pr essur e
( i . e. , > 200 mm Hg syst ol i c or > 140 mm Hg di ast ol i c) t hat demands r educt i on÷
ei t her i mmedi at e ( wi t hi n mi nut es) or prompt ( wi t hi n hour s) t o pr event or l i mi t t arget -
or gan damage.
1. Condi t i ons r equi ri ng i mmedi at e r educt i on i ncl ude hyper t ensi ve encephal opat hy,
acut e l ef t vent ri cul ar f ai l ur e wi t h pul monar y edema, ecl ampsi a, di ssect i ng aort i c
aneur ysm, acut e MÌ , st roke, and i nt r acr ani al hemor r hage.
2. Condi t i ons r equi ri ng pr ompt r educt i on i ncl ude mal i gnant or accel erat ed
hyper t ensi on.
B. Treatment
1. The reducti on i n bI ood pressure must be graduaI ( e. g. , a 15-mm Hg decr ease
i n mean art eri al pr essure over t he 1st hr) r at her t han pr eci pi t ous t o avoi d
compr omi si ng per f usi on of cr i t i cal or gans, par t i cul arl y cer ebral perf usi on.
2. Speci fi c agents used i n hyper t ensi ve cr i si s are shown i n Tabl e 41-6.
P. 871


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 6: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. Whi ch of the foI I owi ng agents represent s a reI at i veI y new cI ass of drugs
used i n t reat i ng hypert ensi on?
( A) t r andol apr i l ( Mavi k)
( B) car vedi l ol ( Coreg)
( C) i r besar t an ( Avapro)
( D) moexi pr i l ( Uni vasc)
( E) ni modi pi ne ( Ni mot op)
Vi ew Answer 1. The answer i s C[ see] . 2. Ref I ex t achycardi a, headache, and
post uraI hypot ensi on are adverse ef fects t hat I i mi t t he use of whi ch of t he
f oI I owi ng ant i hypert ensi ve agent s?
( A) pr azosi n ( Mi ni press)
( B) capt opr i l ( Capot en)
( C) met hyl dopa ( Al domet )
( D) guanabenz (Wyt ensi n)
( E) hydr al azi ne ( Apr esol i ne)
Vi ew Answer 2. The answer i s E[see] . 3. A 65- year- oI d man presents wi t h
st age I hypert ensi on. He has di abetes meI I i t us and chroni c ki dney di sease and
i s i ntoI erant to I i si nopri I . Whi ch of the foI I owi ng agents wouI d be an
appropri at e seI ecti on for i ni ti aI t reatment i n thi s pat i ent based on t he
gui deI i nes f rom t he "Sevent h Report of t he Joi nt Nat i onaI Commi t tee on
Det ect i on, EvaI uati on, and Treatment of Hi gh BI ood Pressure" ( JNC-7) ?
( A) chl orot hi azi de ( Di ur i l )
( B) pr opr anol ol (Ì nder al )
( C) ni t r oprussi de ( Ni pri de)
( D) candesart an ( At acand)
( E) cl oni di ne ( Cat apr es)
Vi ew Answer 3. The answer i s D[ see] . 4. A pati ent wi t h st age I
hypert ensi on who has bronchospast i c ai rway di sease and who i s noncompI i ant
wouI d be best t reat ed wi t h whi ch of the foI I owi ng ß- bI ocki ng agent s?
( A) t i mol ol ( Bl ocadr en)
( B) penbut ol ol ( Levat ol )
( C) esmol ol ( Br evi bl oc)
( D) acebut ol ol ( Sect r al )
( E) pr opr anol ol (Ì nder al )
Vi ew Answer 4. The answer i s D[ seeand] . 5. Long- st andi ng hypert ensi on
I eads t o t i ssue damage i n aI I of t he f oI I owi ng organs except t he
( A) hear t .
( B) l ungs.
( C) ki dneys.
( D) br ai n.
( E) eyes.
Vi ew Answer 5. The answer i s B[ see] . 6. Accordi ng t o t he "Sevent h Report
of t he Joi nt Nati onaI Commi tt ee on Det ecti on, EvaI uat i on, and Treatment of
Hi gh BI ood Pressure" (JNC- 7) , whi ch of t he f oI I owi ng agent s i s sui t abI e as
i ni t i aI t herapy f or t reat i ng stage I hypert ensi on ( assumi ng no compeI I i ng
i ndi cat i ons for anot her t ype of drug) ?
( A) chl orot hi azi de ( Di ur i l )
( B) l abet al ol ( Tr andat e)
( C) at enol ol ( Tenormi n)
( D) pr opr anol ol (Ì nder al )
( E) bi sopr ol ol ( Zebet a)
Vi ew Answer 6. The answer i s A[ see] . Di recti ons f or questi ons 7-9: The
quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
7. A pat i ent t reat ed wi th a spi ronoI act one shouI d be moni t ored reguI arI y f or
aI t ered pI asma I eveI s of
I . potassi um.
I I . serum creat i ni ne.
I I I . bI ood urea ni t rogen ( BUN) .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 7. The answer i s E[see] . 8. Bef ore ant i hypert ensi ve t herapy
begi ns, secondar y causes of hypert ensi on shouI d be ruI ed out . Laborat or y
f i ndi ngs that suggest an underI yi ng cause of hypert ensi on i ncI ude
I . a decreased serum pot assi um I eveI .
I I . an i ncreased uri nar y cat echoI ami ne I eveI .
I I I . an i ncreased bI ood cort i soI I eveI .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 8. The answer i s E[see] . P. 872


9. I n an ot herwi se heaI thy aduI t wi th stage I hypert ensi on, appropri at e i ni t i aI
ant i hypert ensi ve t herapy wouI d be
I . chI ort haI i done ( Di uri I )
I I . met oproI oI ( Lopressor)
I I I . bi soproI oI ( Zebeta)
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 9. The answer i s A[ see] . Di recti ons f or questi ons 10- 14: Each
l i st of adver se ef f ect s i n t hi s sect i on i s most cl osel y associ at ed wi t h one of t he
f ol l owi ng ant i hypert ensi ve agent s. The agent s may be used mor e t han once or not at
al l . Choose t he best answer , A- E.
10. thi ocyanat e i nt oxi cat i on, hypot ensi on, and convuI si ons
( A) cl oni di ne ( Cat apr es)
( B) ol mesar t an ( Beni car )
( C) ni t r oprussi de ( Ni pri de)
( D) pr azosi n ( Mi ni press)
( E) pr opr anol ol (Ì nder al )
Vi ew Answer 10. The answer i s C[ see] . 11. bradycardi a, bronchospasm,
and cardi ac decompensat i on
( A) cl oni di ne ( Cat apr es)
( B) ol mesar t an ( Beni car )
( C) ni t r oprussi de ( Ni pri de)
( D) pr azosi n ( Mi ni press)
( E) pr opr anol ol (Ì nder al )
Vi ew Answer 11. The answer i s E[see] . 12. angi oedema, cough,
hyperkaI emi a,
( A) cl oni di ne ( Cat apr es)
( B) ol mesar t an ( Beni car )
( C) ni t r oprussi de ( Ni pri de)
( D) pr azosi n ( Mi ni press)
( E) pr opr anol ol (Ì nder al )
Vi ew Answer 12. The answer i s B[ see] . 13. rebound hypert ensi on, dr y
mout h, drowsi ness
( A) cl oni di ne ( Cat apr es)
( B) ol mesar t an ( Beni car )
( C) ni t r oprussi de ( Ni pri de)
( D) pr azosi n ( Mi ni press)
( E) pr opr anol ol (Ì nder al )
Vi ew Answer 13. The answer i s A[ see] . 14. f i rst - dose syncope, post uraI
hypot ensi on, and paI pi t at i ons
( A) cl oni di ne ( Cat apr es)
( B) ol mesar t an ( Beni car )
( C) ni t r oprussi de ( Ni pri de)
( D) pr azosi n ( Mi ni press)
( E) pr opr anol ol (Ì nder al )
Vi ew Answer 14. The answer i s D[ see] . Di recti ons f or questi ons 15- 19:
Each descr i pt i on l i st ed i n t hi s sect i on i s most cl osel y associ at ed wi t h one of t he
f ol l owi ng 8-adr energi c bl ocki ng agent s. The agent s may be used mor e t han once or
not at al l . Choose t he best answer , A- E.
15. a ß-bI ocker wi th i ntri nsi c sympat homi met i c acti vi t y
( A) esmol ol ( Br evi bl oc)
( B) l abet al ol ( Tr andat e)
( C) bi sopr ol ol ( Zebet a)
( D) nadol ol ( Cor gar d)
( E) pi ndol ol ( Vi sken)
Vi ew Answer 15. The answer i s E[seeand] . 16. a ß- bI ocker t hat aI so bI ocks
o- adrenergi c recept ors
( A) esmol ol ( Br evi bl oc)
( B) l abet al ol ( Tr andat e)
( C) bi sopr ol ol ( Zebet a)
( D) nadol ol ( Cor gar d)
( E) pi ndol ol ( Vi sken)
Vi ew Answer 16. The answer i s B[ seeand] . 17. a ß- bI ocker wi t h an
uI t rashort durat i on of act i on
( A) esmol ol ( Br evi bl oc)
( B) l abet al ol ( Tr andat e)
( C) bi sopr ol ol ( Zebet a)
( D) nadol ol ( Cor gar d)
( E) pi ndol ol ( Vi sken)
Vi ew Answer 17. The answer i s A[ seeand] . 18. a ß- bI ocker wi t h a I ong
durat i on of acti on and nonseI ect i ve bI ocki ng act i vi t y
( A) esmol ol ( Br evi bl oc)
( B) l abet al ol ( Tr andat e)
( C) bi sopr ol ol ( Zebet a)
( D) nadol ol ( Cor gar d)
( E) pi ndol ol ( Vi sken)
Vi ew Answer 18. The answer i s D[ seeand] . 19. a ß- bI ocker wi t h reI at i ve
cardi oseI ect i ve bI ocki ng acti vi t y
( A) esmol ol ( Br evi bl oc)
( B) l abet al ol ( Tr andat e)
( C) bi sopr ol ol ( Zebet a)
( D) nadol ol ( Cor gar d)
( E) pi ndol ol ( Vi sken)
Vi ew Answer 19. The answer i s C[ seeand] . P. 873


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Ì Ì Ì . B. 5. a] .
Ì r besar t an i s one of t he rel at i vel y new cl asses of dr ugs used i n t he t r eat ment of
hyper t ensi on r ef er r ed t o as an angi ot ensi n Ì Ì recept or ant agoni st , whi ch bl ocks t he
pr oduct i on of angi ot ensi n Ì Ì and consequent l y i t s ef f ect s as a power f ul
vasoconst ri ct or and st i mul ant f or al dost er one rel ease. Tr andol apri l and moexi pr i l
ar e ACE i nhi bi t ors; car vedi l ol i s a 8- adrener gi c bl ocki ng agent ; and ni modi pi ne i s a
cal ci um-channel bl ocker.
2. The answer i s E [ see Ì Ì Ì . B. 7. a] .
Hydr al azi ne i s a vasodi l at or t hat wor ks by di r ect l y r el axi ng ar t eri ol es, t her eby
r educi ng per i pher al vascul ar r esi st ance. Ì t s ef f ect i veness as an ant i hypert ensi ve
agent i s compromi sed, however , by t he compensat or y r eact i ons i t t r i ggers ( e. g. ,
r ef l ex t achycar di a) and by i t s ot her adver se ef f ect s ( e. g. , headache, post ur al
hypot ensi on, nausea, pal pi t at i ons) . For t unat el y, t he unwant ed ef f ect s of hydr al azi ne
ar e mi ni mi zed when i t i s used i n combi nat i on wi t h a di ur et i c agent and a 8- bl ocker .
Thus hydral azi ne i s most ef f ect i ve as a suppl ement al ant i hyper t ensi ve drug i n
combi nat i on wi t h f i r st - l i ne t her apy.
3. The answer i s D [ see Ì Ì Ì . B. 5. e. ( 3)] .
Candesart an, an angi ot ensi n Ì Ì r ecept or bl ocker, whi ch act s by bl ocki ng t he bi ndi ng
of angi ot ensi n Ì Ì t o t he angi ot ensi n Ì Ì r ecept ors. By bl ocki ng t he r ecept or si t e, t hi s
cl ass of dr ugs i nhi bi t s t he vasoconst r i ct or ef f ect s of angi ot ensi n Ì Ì and prevent s t he
r el ease of al dost er one owi ng t o angi ot ensi n Ì Ì f r om t he adr enal gl ands. JNC- 7
gui del i nes cal l f or t he use of di ur et i cs i n t he i ni t i al t reat ment of hyper t ensi on, unl ess
t he pat i ent has compel l i ng i ndi cat i ons t hat have been shown t o benef i t f rom t he use
of speci f i c cl asses of dr ugs. Thi s pat i ent has di abet es and chroni c ki dney di sease
and i s unabl e t o t ol erat e t he ACE i nhi bi t or l i si nopr i l , t her ef or e, an ARB woul d be an
accept abl e al t er nat i ve f or t hi s pat i ent r at her t han a 8- bl ocker ( pr opranol ol ) or
di uret i c (chl or ot hi azi de) . Ni t r opr ussi de and cl oni di ne ar e not i ndi cat ed f or t he i ni t i al
t r eat ment of hyper t ensi on.
4. The answer i s D [ see Ì Ì Ì . B. 3. a. ( 7). ( a) , ( b) , ( c), ( d) , (e) , (f ) , (g) , (h) - (i ) , ( j ) , (k) , ( l )
and (m) ] .
The 8- adrenergi c bl ocki ng agent s cont i nue t o demonst rat e ef f ect i veness i n t he
t r eat ment of hyper t ensi on. A maj or f eat ur e of some of t hese agent s i s t hei r rel at i ve
sel ect i vi t y f or 81- recept or s ( i n t he hear t ) rat her t han f or 82- recept or s ( i n t he l ung) ,
whi ch provi des advant ages i n t he t r eat ment of cer t ai n pat i ent s ( e. g. , t hose wi t h
br onchospast i c ai r way or COPD) . Of t he 8- bl ocker s l i st ed, acebut ol ol i s l ess l i kel y
t han t he r est t o bl ock 82-r ecept or s because of i t s r el at i ve cardi osel ect i ve-bl ocki ng
act i vi t y. Acebut ol ol al so has a l ong dur at i on of act i on, whi ch coul d be hel pf ul i n t he
noncompl i ant pat i ent by r equi r i ng f ewer doses per day. Penbut ol ol has weak
i nt ri nsi c sympat homi met i c act i vi t y l i ke pi ndol ol but l acks rel at i ve cardi osel ect i vi t y,
despi t e i t s l ong dur at i on of act i on. Esmol ol by nat ur e of i t s cont i nuous i nt ravenous
i nf usi on woul d not l end i t sel f t o chr oni c ambul at or y t her apy. Ti mol ol i s a l ong-act i ng
8- bl ocker and l acks t he rel at i ve car di osel ect i ve pr opert i es t hat acebut ol ol
possesses.
5. The answer i s B [ see Ì . F; Tabl e 41-3] .
Lef t unt r eat ed, hyper t ensi on can be l et hal because of i t s pr ogr essi vel y dest ruct i ve
ef f ect s on maj or organs, such as t he hear t , ki dneys, and brai n. The eyes al so suf f er
damage; t he l ungs, however , do not . End- organ damage caused by hyper t ensi on
i ncl udes l ef t vent r i cul ar hyper t rophy, hear t f ai l ur e, angi na pect ori s, myocar di al
i nf ar ct i on, r enal i nsuf f i ci ency caused by at her oscl er ot i c l esi ons, nephr oscl er osi s,
cer ebr al aneur ysm and hemorr hage, r et i nal hemor r hage, and papi l l edema.
6. The answer i s A [ see Ì Ì Ì . B. 2. a] .
Thi azi de di ur et i cs ar e consi dered t he f i rst -l i ne t reat ment choi ce f or hyper t ensi on
and shoul d be used al one or i n combi nat i on wi t h ot her ant i hyper t ensi ves, i f
necessar y. 8- Bl ocker s such as l abet al ol , at enol ol , bi sopr ol ol , ni f edi pi ne, and
pr opranol ol are no l onger consi der ed i ni t i al agent s f or t reat i ng hypert ensi on. 8-
bl ocker s have shown posi t i ve cl i ni cal out comes i n pat i ent s wi t h hear t f ai l ur e, post -
myocar di al i nf arct i on, hi gh cor onar y di sease ri sk, and di abet es (compel l i ng
i ndi cat i ons) and woul d be accept abl e opt i ons f or pat i ent s pr esent i ng wi t h
pr ehyper t ensi on or hyper t ensi on wi t h a compel l i ng i ndi cat i on.
7. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì Ì Ì . B. 2. c. (4) ] .
Spi r onol act one i s a di r ect - act i ng al dost er one- r ecept or bl ocker and decr eases i t s
ef f ect s on sodi um and wat er ret ent i on. However , a benef i t of spi r onol act one i s i t s
pot assi um-spari ng ef f ect , t hrough t he exchange of sodi um f or pot assi um i n t he
ki dney. Pat i ent s wi t h reduced r enal f unct i on and acut e renal f ai l ur e ( evi denced by
el evat i ons i n serum creat i ni ne) l ose t hei r abi l i t y t o excr et e pot assi um, and t hi s
needs t o be moni t or ed when pat i ent s ar e st ar t ed on spi ronol act one. BUN and
cr eat i ni ne are good i ndi rect i ndi cat or s of renal f unct i on.
P. 874


8. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì Ì . A. 2] .
Low ser um pot assi um l evel s i n a hyper t ensi ve pat i ent suggest pri mar y
al dost er oni sm. El evat ed ur i nar y cat echol ami nes suggest a pheochr omocyt oma;
ot her si gns and sympt oms of t hi s t umor i ncl ude wei ght l oss, epi sodi c f l ushi ng, and
sweat i ng. El evat ed serum cor t i sol l evel s suggest Cushi ng syndr ome; t he pat i ent i s
al so l i kel y t o have a r ound (moon) f ace and t r uncal obesi t y. Secondar y hyper t ensi on
r equi r es t reat ment of t he under l yi ng cause; suppl ement ar y ant i hypert ensi ve dr ug
t her apy may al so be needed.
9. The answer i s A ( Ì ) [ see Ì Ì Ì . B. 2. a] .
Thi azi de di ur et i cs such as chl or t hal i done ar e now consi dered, based on t he JNC- 7,
f i r st - l i ne t her apy f or hyper t ensi on, bar r i ng any compel l i ng i ndi cat i ons such as hear t
f ai l ur e, di abet es, chroni c ki dney di sease, or post -MÌ , when ot her ant i hypert ensi ve
agent s woul d be i ndi cat ed. 8- Adrener gi c bl ockers, such as met opr ol ol and
bi soprol ol , ar e no l onger i ndi cat ed as i ni t i al ant i hyper t ensi ve agent s f or t reat i ng
hyper t ensi on.
10. The answer i s C [ see Ì Ì Ì . B. 7. c. (2) ] .
11. The answer i s E [ see Ì Ì Ì . B. 3. a. (4) ] .
12. The answer i s B [ see Ì Ì Ì . B. 5. c. (2) ] .
13. The answer i s A [ see Ì Ì Ì . B. 3. c. (2) . (c) ] .
14. The answer i s D [ see Ì Ì Ì . B. 3. b. (3) . ( a) ] .
The goal of t reat ment i n hyper t ensi on i s t o l ower bl ood pr essur e t owar d nor mal wi t h
mi ni mal si de ef f ect s. Al l ant i hyper t ensi ve dr ugs can cause adverse ef f ect s. The
pr i mar y pur pose of t he JNC- 7 gui del i nes i s t o acknowl edge t he l ong- t erm benef i t s of
di uret i cs i n t he t reat ment of hyper t ensi on.
15. The answer i s E [ see Ì Ì Ì . B. 3. a. (7) . ( a) , ( b) , (c) , ( d) , ( e) , ( f ) , ( g) , ( h) -( i ), ( j ) , ( k),
( l ) and (m) ] .
16. The answer i s B [ see Ì Ì Ì . B. 3. a. (7) . ( a) , ( b) , (c) , ( d) , ( e) , ( f ) , ( g) , ( h) -( i ), ( j ) , ( k),
( l ) and (m) ] .
17. The answer i s A [ see Ì Ì Ì . B. 3. a. (7) . ( a) , ( b) , (c) , ( d) , ( e) , ( f ) , ( g) , ( h) -( i ), ( j ) , ( k),
( l ) and (m) ] .
18. The answer i s D [ see Ì Ì Ì . B. 3. a. (7) . ( a) , ( b) , (c) , ( d) , ( e) , ( f ) , ( g) , ( h) -( i ), ( j ) , ( k),
( l ) and (m) ] .
19. The answer i s C [ see Ì Ì Ì . B. 3. a. (7) . ( a) , ( b) , (c) , ( d) , ( e) , ( f ) , ( g) , ( h) -( i ), ( j ) , ( k),
( l ) and (m) ] .
The 8- adrenergi c bl ocki ng agent s ar e val uabl e f or managi ng hyper t ensi on and ar e
used as i ni t i al ant i hyper t ensi ves. The 8- bl ocker s ar e sympat het i c ant agoni st s. They
act by bl ocki ng vari ous recept ors of t he sympat het i c ner vous syst em. They di f f er i n
t hei r sel ect i vi t y f or t hese sympat het i c recept or s. For exampl e, 81- bl ockers have
r el at i ve cardi osel ect i ve act i vi t y÷t hat i s, t hey bl ock 81- r ecept ors (i n t he hear t ) r at her
t han 82- r ecept ors (i n br onchi al smoot h muscl e) and, t heref ore, ar e hi ghl y usef ul
ant i hyper t ensi ve agent s. Ì nt ri nsi c sympat homi met i c act i vi t y al so appear s t o r educe
t he pr obl em of bronchoconst r i ct i on; mor eover, drugs wi t h t hi s pr opert y can al so
mai nt ai n a sat i sf act or y hear t rat e.

42
Heart FaiIure
AI an H. Mutni ck
I. INTRODUCTION
A. Def i ni t i on. Heart f ai I ure ( HF) i s a compl ex cl i ni cal syndrome t hat can r esul t
f r om any cardi ac di sor der t hat i mpai rs t he abi l i t y of t he vent r i cl e t o del i ver adequat e
quant i t i es of bl ood t o t he met abol i zi ng t i ssues duri ng normal act i vi t y or at r est . The
condi t i on i n t he past has been r ef er red t o as "congest i ve heart f ai l ur e, ¨ owi ng t o t he
edemat ous stat e commonl y produced by t he f l ui d backup r esul t i ng i n shor t ness of
br eat h, f at i gue, l i mi t at i on of exer ci se t ol er ance, and f l ui d r et ent i on. Fl ui d r et ent i on
may l ead t o pul monar y and per i pheral edema. Mor e r ecent l y, because al l pat i ent s
do not necessar i l y pr esent wi t h f l ui d over l oad at t he i ni t i al or f ol l ow- up eval uat i ons,
t he t erm " hear t f ai l ur e¨ i s used t o mor e adequat el y r ef l ect t he cl i ni cal syndr ome.
B. MortaI i t y rat e. Appr oxi mat el y 300, 000 pat i ent s di e as a resul t of t he di r ect or
i ndi r ect consequences of HF each year , and t he number of deat hs owi ng t o HF
( pr i mar y or secondar y causes) has i ncreased st eadi l y, despi t e t r eat ment advances.
The r i sk of deat h i s 5%-10% annual l y i n pat i ent s wi t h mi l d sympt oms and i s as hi gh
as 30%-40% i n pat i ent s wi t h advanced di sease mani f est at i ons.
C. I nci dence of HF. HF i s a common medi cal condi t i on t hat af f ect s al most 5 mi l l i on
peopl e i n t he Uni t ed St at es, wi t h > 500, 000 new cases di agnosed each year .
Bet ween 1. 5% and 2. 0% of t he popul at i on has HF, and t he i nci dence i ncr eases t o
6%- 10% i n pat i ent s ol der t han age 65. HF makes up 20% of al l hospi t al i zat i ons i n
pat i ent s > 65 years of age. HF i s t he onl y maj or car di ovascul ar di sor der t hat i s
i ncreasi ng i n i nci dence and preval ence. Dur i ng t he l ast 10 year s, t her e has been a
dr amat i c i ncr ease i n t he number of hospi t al i zat i ons, pr i mari l y owi ng t o HF ( 500, 000
i n 1991 t o mor e t hen 1 mi l l i on, cur r ent l y) . The reasons f or t he i ncr eased numbers of
hospi t al admi ssi ons ar e l i st ed i n Tabl e 42-1.
D. Cost of HF. The t ot al cost s ( di r ect and i ndi rect ) f or t he t r eat ment of HF i n t he
Uni t ed St at es dur i ng 2005 wer e appr oxi mat el y $27. 9 bi l l i on. Cur r ent l y i n t he Uni t ed
St at es, more t han $2. 9 bi l l i on i s spent annual l y on dr ugs used i n t he t reat ment of
HF.
E. Causes
1. Al t hough t he di sease occurs most commonl y among t he el der l y (80% of pat i ent s
hospi t al i zed wi t h HF are > 65 years of age) , i t may appear at any age as a
consequence of underl yi ng car di ovascul ar di sease.
2. Ther e cur r ent l y i s no si ngl e di agnost i c t est f or HF, and t he cl i ni cal di agnosi s i s
nor mal l y based on pat i ent hi st or y and physi cal exami nat i on.
3. HF shoul d not be consi der ed an i ndependent di agnosi s because i t i s
super i mposed on an under l yi ng cause.
a. Coronar y ar t er y di sease ( CAD) i s t he cause of HF i n about t wo t hi r ds of pat i ent s
wi t h l ef t vent ri cul ar syst ol i c dysf unct i on.
b. The r emai ni ng t hi r d of pat i ent s have a noni schemi c cause of syst ol i c dysf unct i on
owi ng t o ot her causes of myocar di al st r ess, whi ch i ncl uded t rauma, di sease, or
ot her abnormal st at es ( e. g. , pul monar y embol i sm, i nf ect i on, anemi a, pr egnancy,
dr ug use or abuse, f l ui d over l oad, ar r hyt hmi a, val vul ar heart di sease,
car di omyopat hi es, congeni t al heart di sease) .
4. The New Yor k Hear t Associ at i on ( NYHA) devel oped a cl assi f i cat i on syst em, st i l l
used t oday t o quant i f y t he f unct i onal l i mi t at i ons of HF pat i ent s. The NYHA cl asses
ar e as f ol l ows:
a. Cl ass Ì : Degree of ef f or t necessar y t o el i ci t HF sympt oms equal s t hose t hat woul d
l i mi t normal i ndi vi dual s.
b. Cl ass Ì Ì : Degr ee of ef f or t necessar y t o el i ci t HF sympt oms occur s wi t h or di nar y
exer t i on.
P. 876


Table 42-1. Causes for Increased Hospitalization Rates of Heart Failure
Aging oI the population in the United States
Rising incidence oI chronic heart Iailure
Improved treatment results obtained Ior myocardial inIarction. coronary
artery bypass surgery. and stenting
Unavoidable progression oI heart disease in an aging population
Incomplete treatment oI heart Iailure in the hospital setting
Poor application oI guidelines Ior treatment
Noncompliance with diet and drug therapy
Adapted with permission Irom Hobbs RE. Guidelines Ior the diagnosis and
management oI heart Iailure. Am J Ther 2004;11:467-472.

c. Cl ass Ì Ì Ì : Degr ee of ef f or t necessar y t o el i ci t HF sympt oms occur s wi t h l ess- t han-
or di nar y exer t i on.
d. Cl ass Ì V. Degree of ef f or t necessar y t o el i ci t HF sympt oms occur s whi l e at r est .
5. A cr i t i ci sm of t he NYHA cl assi f i cat i on i s i t s dependence on subj ect i ve
assessment s by t he cl i ni cal pr act i t i oner , whi ch changes f r equent l y and mi ght not
accur at el y ref l ect di f f er ent t reat ment opt i ons based on t he degree of sympt oms.
Consequent l y, mor e r ecent l y, t he " ACC/ AHA Gui del i nes f or t he Eval uat i on and
Management of Chr oni c Hear t Fai l ure¨ of f ered new cl assi f i cat i on scheme t hat
depi ct s HF as an evol vi ng cl i ni cal ent i t y and det ai l s a pr ogr essi on based on ri sk
f act or s and st r uct ur al changes, whi ch may be asympt omat i c or sympt omat i c. Wi t hi n
t hi s cl assi f i cat i on, speci f i c t r eat ment s can be t arget ed at each st age t o af f ect
mor bi di t y and mor t al i t y (Tabl e 42- 2). The i nt roduct i on of t he f our st ages of HF ar e
not i nt ended t o repl ace t he NYHA cl assi f i cat i on but r at her t o compl ement i t .
F. Forms of HF. As ment i oned, HF i s a compl ex syndr ome and has been descr i bed
i n vari ous ways. The cardi nal mani f est at i ons of HF ar e dyspnea and f at i gue, whi ch
may l i mi t exer ci se t ol erance, r esul t i n f l ui d ret ent i on, and l ead t o pul monar y
congest i on and peri pheral edema. However , t he f ol l owi ng sect i ons provi de sever al
ways t hat have been used t o descri be t he pat hophysi ol ogy and t he sympt omat ol ogy
i nvol ved i n t he condi t i on. Though t he t er ms l ow- out put ver sus hi gh-out put and l ef t -
si ded versus ri ght - si ded ar e not rout i nel y used i n t he cl i ni cal set t i ng, t hei r use her e
i s t o hel p convey i mpor t ant educat i onal aspect s of HF and ar e present ed onl y f or
t he pur pose of si mpl i f yi ng t he di scussi on of t he pat hophysi ol ogy and
sympt omat ol ogy.
1. Low-out put versus hi gh- out put f ai I ure
a. Ì f met abol i c demands ar e wi t hi n normal l i mi t s but t he hear t i s unabl e t o meet
t hem, t he f ai l ure i s desi gnat ed I ow out put ( t he most common t ype) .
b. Ì f met abol i c demands i ncrease ( e. g. , hyper t hyr oi di sm, anemi a) and t he hear t i s
unabl e t o meet t hem, t he f ai l ure i s desi gnat ed hi gh output . Compared t o l ow- out put
f ai l ur e, cor r ect i on of t he under l yi ng cause of hi gh- out put f ai l ure i s par amount as t he
i ni t i al t reat ment modal i t y.
2. Lef t - si ded versus ri ght - si ded fai I ure
a. GeneraI sympt omat oI ogy. The si gns and sympt oms of HF usual l y resul t f rom t he
ef f ect s of bl ood backi ng up behi nd t he f ai l i ng vent r i cl e (except i n HF owi ng t o
i ncreased body demands) .
b. Lef t -si ded and r i ght -si ded HF do not r out i nel y exi st as separat e ent i t i es;
however , t he use of separ at e t erms best i l l ust rat es t he syst emi c consequences.
c. Thi s progr essi on occur s because t he cardi ovascul ar syst em i s a cl osed syst em
( Fi gur e 42- 1) ; t hus, over t i me, ri ght -si ded f ai l ure causes l ef t -si ded f ai l ur e and vi ce
ver sa.
d. Left - si ded f ai I ure. Ì f bl ood cannot be adequat el y pumped f r om t he l ef t vent r i cl e
t o t he per i pher al ci r cul at i on and i t accumul at es wi t hi n t he l ef t vent ri cl e, t he pat i ent
i s l i kel y t o exhi bi t si gns of I ef t - si ded HF. As t he f l ui d por t i on of t he bl ood backs up
i nt o t he pul monar y al veol i t he resul t i s t he devel opment of pul monar y edema t hat
can pr esent as, shor t ness of breat h, dyspnea on exer t i on and a t hi rd heart sound.
e. Ri ght - si ded f ai I ure. When bl ood i s not pumped f rom t he r i ght vent ri cl e, t he f l ui d
por t i on of t he bl ood backs up t hr oughout t he body ( e. g. , i n t he vei ns, l i ver , l egs,
bowel s) , pr oduci ng syst emi c edema. Such si gns woul d i ncl ude evi dence of el evat ed
pr essures i n t he venous syst em (e. g. , per i pheral edema, j ugul ar venous di st ensi on) .
P. 877


Table 42-2. Stages of Heart Failure (HF) Based on Evolution and Progression of
Clinical Findings
Stage Description Examples
A Patients at high risk oI
developing HF because oI the
presence oI conditions that are
strongly associated with the
condition; such patients have
no identiIied structural or
Iunctional abnormalities oI
the pericardium. myocardium.
or cardiac valves and have
never shown signs or
symptoms oI HF
Hypertension. atherosclerotic
disease. diabetes mellitus. obesity.
metabolic syndrome. history oI
cardiotoxic drug therapy or
alcohol abuse. personal history oI
rheumatic Iever. Iamily history oI
cardiomyopathy
B Patients who have developed
structural heart disease that is
strongly associated with the
development oI HF but who
have never shown signs or
symptoms oI the condition
LeIt ventricular remodeling.
including leIt ventricular
hypertrophy or low eiection
Iraction; asymptomatic valvular
disease; previous myocardial
inIarction
C Patients who have current or
prior symptoms oI HF
associated with underlying
structural heart disease
Known structural heart disease.
dyspnea or Iatigue. reduced
exercise tolerance
D Patients with reIractory HF
who require specialized
interventions
Patients with marked symptoms at
rest despite maximal medical
therapy (are Irequently
hospitalized Ior HF and cannot be
saIely discharged Irom the
hospital. patients in the hospital
awaiting heart transplantation.
patients at home receiving
continuous intravenous support Ior
symptom relieI or being supported
with a mechanical circulatory
assist device. patients in a hospice
setting Ior the management oI HF)
Adapted Irom Hunt SA. Abraham WT. Chin MH. et al. ACC/AHA 2005
guidelines Ior the diagnosis and management oI chronic heart Iailure in the
adult. A report oI the American College oI Cardiology/American Heart
Association Task Force on Practice Guidelines (Writing Committee to
Update the 2001 Guidelines Ior the Evaluation and Management oI Heart
Failure). J Am Coll Cardiol 2005;46:1-82.

3. Di ast ol i c versus Syst ol i c Dysf unct i on
( a) Di ast ol i c dysf unct i on r ef ers t o an i nabi l i t y f or t he vent r i cl es t o f i l l wi t h bl ood
dur i ng di ast ol e, or vent ri cul ar rel axat i on. Under nor mal ci rcumst ances, bl ood r et urns
t o t he ri ght si de of t he hear t f r om ei t her t he upper and l ower body (super i or vena
cava and i nf er i or vena cava, r espect i vel y) or l ef t si de of t he hear t f rom t he l ungs
( vi a t he pul monar y vei n, l ef t at ri a, and mi t ral val ve) . An i nabi l i t y f or t he r espect i ve
vent r i cl e( s) t o accommodat e t he bl ood t hat i s r et ur ni ng t o i t wi l l r esul t i n a back up
of bl ood i n t hose ar eas wher e i t or i gi nat ed f rom.
( b) The i nabi l i t y of t he vent ri cl e(s) t o accommodat e t he bl ood bei ng present ed t o i t
i s ref err ed t o as noncompl i ance, and occur s due t o st i f f ness occur r i ng wi t hi n t he
vent r i cul ar wal l s. St i f f ness can r esul t f r om cl i ni cal si t uat i ons such as hyper t ensi on,
aor t i c st enosi s, di abet es, myocar di al i nf arct i on, and car di ac i schemi a.
( c) Key t o t he di agnosi s of di ast ol i c hear t f ai l ure ar e t hr ee condi t i ons: (i ) pr esence
of si gns or sympt oms of hear t f ai l ur e; ( i i ) presence of normal or sl i ght l y reduced LV
ej ect i on f r act i on ( EF >50%) ; and (i i i ) t he pr esence of i ncr eased di ast ol i c f i l l i ng
pr essure.
( d) Syst ol i c dysf unct i on r ef ers t o an i mpai red degr ee of vent r i cul ar cont ract i on
r esul t i ng i n a decr ease i n car di ac i not ropy ( cont ract i l i t y) and car di ac st r oke vol ume
( see Ì Ì . Pat hophysi ol ogy) . Thi s set s i n mot i on a ser i es of compensat or y mechani sms
wi t h t he purpose bei ng t o i ncr ease t he abi l i t y of t he hear t t o del i ver bl ood t o t he
body ( i ncr ease st roke vol ume) , but whi ch have a negat i ve ef f ect by i ncreasi ng
pl asma vol ume ( prel oad), and pul monar y capi l l ary wedge pr essur e. Pat i ent s wi t h
syst ol i c dysf unct i on unl i ke t hose wi t h di ast ol i c dysf unct i on have l ower t hen nor mal
car di ac ej ect i on f r act i ons ( EF <40%) , due t o st r oke vol ume reduct i ons al ong wi t h
i ncreases i n end di ast ol i c vol umes.
P. 878



Figure 42-1. An overview oI blood Ilow through
the cardiovascular system.
( e) Ther apeut i c opt i ons may overl ap bet ween di ast ol i c and syst ol i c pat i ent s;
however , t r eat ment of under l yi ng pat hophysi ol ogi c processes can r esul t i n di f f er ent
t her apeut i c st r at egi es bet ween t he t wo cl i ni cal ent i t i es.
( f ) Ì not r opi c agent s, prel oad reduci ng and af t erl oad r educi ng agent s, and di uret i cs
ar e ut i l i zed t o rever se t he consequences of syst ol i c dysf unct i on, i . e. , r educed
car di ac out put due t o decr eased myocar di al cont r act i l i t y. However , ACE i nhi bi t or s,
ARBs, bet a adr ener gi c bl ockers have al so been i ncl uded i n recent t herapeut i c
gui del i nes f or use i n pat i ent s wi t h syst ol i c dysf unct i on.
( g) ACE i nhi bi t ors, ARBs, and bet a adrenergi c bl ockers r epr esent t he backbone of
cur rent t r eat ment opt i ons r ecommended f or pat i ent s wi t h di ast ol i c dysf unct i on.
However , pat i ent s i dent i f i ed wi t h si gns and sympt oms suggest i ve of f l ui d
accumul at i on and r educed car di ac ej ect i on f ract i ons have shown benef i t f rom t he
use of di ur et i cs t o decrease f l ui d r et ent i on, and i not r opi c agent s such as di goxi n t o
r educe hospi t al i zat i ons.
4. Progressi ve nature of HF
a. Ì nj ur y t o t he myocar di um or st r ess pl aced on i t i s gener al l y requi r ed bef or e t he
devel opment of l ef t vent ri cul ar dysf unct i on.
b. The pri mar y present at i on f or t he associ at ed si gns and sympt oms of HF i s a
change i n t he shape and st ruct ur e of t he l ef t vent r i cl e, where i t di l at es and/ or
hyper t rophi es i nt o mor e of a spheri cal shape, r ef er r ed t o as car di ac r emodel i ng.
Such changes i n t he shape
P. 879

of t he heart r esul t i n al t er ed st r esses on t he car di ac wal l s owi ng t o si ze as wel l as
st r uct ur al changes, whi ch al so l end t hemsel ves t o al t er ed bl ood f l ow t hrough t he
var i ous hear t chambers.
Table 42-3. Substances That May Exacerbate Heart Failure
Promote Sodium
Retention
Produce
Osmotic Effect Decrease Contractility
Androgens Albumin Antiarrhythmic agents (e.g..
disopyramide. Ilecainide.
quinidine)
Corticosteroids Glucose
Diazoxide Mannitol þ-adrenergic blockers
Estrogens Saline Select calcium channel blockers
(e.g.. diltiazem. niIedipine.
verapamil)
Licorice Urea
Lithium carbonate Direct cardiotoxins (e.g..
doxorubicin. ethanol. cocaine.
amphetamines)
NSAIDs
Tricyclic antidepressants
NSAIDs. nonsteroidal anti-inIlammatory drugs.

G. Treatment goaI s. HF r equi r es a t wo- pr onged t her apeut i c approach, t he over al l
goal s of whi ch ar e
1. To remove or mi t i gate t he underI yi ng causes or ri sk fact ors÷f or exampl e, by
el i mi nat i ng i ngest i on of cer t ai n drugs or ot her subst ances t hat can produce or
exacer bat e HF or by cor rect i ng an anemi c syndr ome, whi ch can i ncrease car di ac
demands ( Tabl e 42-3) . Ì n addi t i on, modi f y r i sk f act ors t hat can cause cardi ac i nj ur y
by t r eat i ng hyper t ensi on and di abet es; managi ng at heroscl er ot i c di sease; and
cont r ol l i ng smoki ng, al cohol , and i l l i ci t dr ug use.
2. To reI i eve t he sympt oms and i mprove pump f uncti on by:
a. Reduci ng met abol i c demands t hr ough rest , rel axat i on, and phar maceut i cal
cont r ol s
b. Reduci ng f l ui d vol ume excess t hrough di et ar y and phar maceut i cal cont r ol s
c. Admi ni st eri ng a combi nat i on of di uret i cs, angi ot ensi n-conver t i ng enzyme
i nhi bi t ors ( ACEÌ s) 8-adr ener gi c bl ockers, and angi ot ensi n- recept or bl ockers ( ARBs)
d. Pr omot i ng pat i ent compl i ance and sel f - r egul at i on t hrough educat i on
e. Sel ect i ng appr opri at e pat i ent s f or cardi ac t r anspl ant at i on
3. Duri ng r ecent years, sever al set s of gui del i nes have been devel oped f or t he
t r eat ment of HF. Most r ecent l y, a panel of l eadi ng physi ci ans and r esear cher s i n t he
f i el d of HF pr ovi ded r ecommendat i ons. See wi t hi n t he f ol l owi ng ci t at i on: Hunt SA,
Abr aham WT, Chi n MH, et al . ACC/ AHA 2005 gui del i nes f or t he di agnosi s and
management of chroni c hear t f ai l ur e i n t he adul t . A r epor t of t he Amer i can Col l ege
of Cardi ol ogy/ Amer i can Hear t Associ at i on Task For ce on Pr act i ce Gui del i nes
(Wri t i ng Commi t t ee t o Updat e t he 2001 Gui del i nes f or t he Eval uat i on and
Management of Hear t Fai l ure) . J Am Col l Car di ol 2005; 46: 1-82; avai l abl e at
cont ent . onl i nej acc. or g/ cgi / repr i nt / 46/ 6/ e1.
4. These gui del i nes represent t he most up-t o- dat e st andar ds f or t he pr event i on,
di agnosi s, and t r eat ment of HF ( Tabl e 42- 4) .
a. The gui del i nes f ocus on f our st ages i n t he devel opment of HF; st ages A and B
i ncl ude pat i ent s at ri sk f or HF and st ages C and D i ncl ude pat i ent s who have
devel oped HF.
b. Paramount t o t he new gui del i nes i s t he r ol e t hat ACEÌ s or ARBs and 8-adr ener gi c
bl ocker s pl ay, based on evi dence- based pract i ce.
c. Tr eat ment of pat i ent s wi t h r ef r act or y end- st age HF ( st age D) shoul d i ncl ude t he
pr i mar y t her apeut i c agent s t hat ar e used f or st ages A, B, and C. However, l ack of
an accept abl e response wi l l r equi re speci al i zed nonpharmacol ogi c modal i t i es, such
as mechani cal ci rcul at ory suppor t , t r anspl ant at i on, and end-of -l i f e car e f or t hose
exhi bi t i ng no benef i t .
II. PATHOPHYSIOLOGY.
HF and decreased car di ac out put t r i gger a compl ex scheme of compensat or y
mechani sms desi gned t o normal i ze cardi ac out put ( car di ac out put = st roke vol ume ×
hear t r at e) . The pri nci pal mani f est at i on of pr ogr essi on i n car di ac dysf unct i on i s a
change i n t he geomet r y of t he l ef t vent ri cl e, r esul t i ng i n vent r i cul ar di l at i on and
hyper t rophy, wi t h a resul t ant i ncr ease i n a mor e spheri cal shape÷ref er r ed t o as
car di ac remodel i ng. Thi s r esul t s i n i ncr eases i n vent ri cul ar wal l t ensi on, depr essi on
i n mechani cal per f ormance, and r et ent i on of normal car di ac f l ui d, whi ch wor sen t he
r emodel i ng process.
P. 880


P. 881


Table 42-4. Approach to Heart Failure (HF)a
At Risk for Heart Failure Heart Failure
Stage A Stage B Stage C Stage D
Patien
ts
Patients at
high risk oI
developing
HF because
oI presence
oI
conditions
that are
strongly
associated
with
developmen
t oI
condition;
such
patients
have no
identiIied
structural or
Iunctional
abnormalitie
s oI the
pericardium.
myocardium
. or cardiac
valves and
have never
shown signs
or
symptoms
oI HF
Patients
who have
developed
structural
heart
disease
that is
strongly
associated
with
developme
nt oI HF
but who
have never
shown
signs or
symptoms
oI the
condition
Patients who
have
structural
heart disease
with current
or prior
symptoms oI
HF
Patients with
reIractory
HF who
require
specialized
interventions
Goals Treat
hypertensio
n
Same as
stage A
Same as
stage A
Same as
stages A and
C

Encourage
smoking
cessation
Dietary salt
restriction
Decision
concerning
appropriate
level oI care

Treat lipid
disorders


Encourage
regular
exercise


Discourage
alcohol
intake. illicit
drug use


Control
metabolic
syndrome

Drugs ACEIs to
prevent HF
in patients
at high risk
who have a
history oI
atherosclero
tic vascular
disease.
diabetes
mellitus. or
hypertensio
n
ACEIs in
patients
with
reduced
eiection
Iractions
and no
symptoms
oI HF.
even
without
previous
MI
ACEIs and
þ-blockers.
with one
proven to
reduce
mortality
(bisoprolol.
carvedilol.
and
sustained-
release
metoprolol
Ior all stable
patients)
with current
or prior
symptoms oI
HF and
reduced
LVEF
ReIerral to
an HF
program
with
expertise in
the
management
oI reIractory
HF

ARBs. as
with ACEIs.
though
evidence not
as strong
þ-Blockers
and ACEIs
in all
patients
with recent
or remote
history oI
MI
ARBs
ARBs in
patients with
current or
prior
symptoms oI
HF and
reduced
LVEF who
cannot
Drug therapy
not
considered.
instead
consideratio
n is given Ior
transplantati
on. when
applicable
should be
administer
ed to post-
MI
patients
without
HF who
cannot
tolerate
ACEIs and
have low
LVEF.
though
evidence
not as
strong.
þ-Blockers
Ior all
patients
without
MI who
have
reduced
LVEF
with no
HF
symptoms.
though
evidence
not as
strong.
tolerate
ACEIs
Diuretics
and salt
restriction in
patients with
current or
prior
symptoms oI
HF and
reduced
LVEF who
have
evidence oI
Iluid
retention.
though
evidence not
as strong
Addition oI
an
aldosterone
antagonist in
select
patients with
moderately
severe to
severe HF
symptoms
and reduced
LVEF who
can be
careIully
monitored
Ior renal
Iunction and
potassium
concentratio
ns. though
evidence not
as strong.
Current
evidence
Iavors
combination
oI
Continuous
intravenous
inIusion oI a
positive
inotropic
agent Ior
palliation oI
symptoms.
though
evidence not
strong
hydralazine
and a nitrate
in patients
with reduced
LVEF and
persistent
symptoms
already
receiving
ACEIs and
þ-blockers
ACEIs. angiotensin-converting enzyme inhibitors; ARBs. angiotensin-
receptor blockers; LJEF. leIt ventricular eiection Iraction; MI. myocardial
inIarction.
a
The guidelines listed here are deIinitive. based on available evidence. and
are not intended to reIlect the entire set oI guidelines with less-than-
substantial evidence. A complete set oI usage guidelines is available at
content.onlineiacc.org/cgi/reprint/46/6/e1.
Adapted Irom Hunt SA. Abraham WT. Chin MH. et al. ACC/AHA 2005
guidelines Ior the diagnosis and management oI chronic heart Iailure in the
adult. A report oI the American College oI Cardiology/American Heart
Association Task Force on Practice Guidelines (Writing Committee to
Update the 2001 Guidelines Ior the Evaluation and Management oI Heart
Failure). J Am Coll Cardiol 2005;46:1-82.

P. 882


A. Compensat i on. These mechani sms are shown i n Fi gure 42- 2.
1. Sympat het i c responses. Ì nadequat e car di ac out put st i mul at es ref l ex
( nor epi nephr i ne and epi nephr i ne) act i vat i on of t he sympat het i c ner vous syst em and
an i ncrease i n ci r cul at i ng cat echol ami nes. The hear t rat e i ncreases, and bl ood f l ow
i s redi st ri but ed t o ensure perf usi on of t he most vi t al organs ( t he br ai n and t he
hear t ) .
2. HormonaI st i muI at i on. The r edi st ri but i on of bl ood f l ow r esul t s i n r educed r enal
per f usi on, whi ch decr eases t he gl omer ul ar f i l t r at i on r at e ( GFR). Reduct i on i n GFR
r esul t s i n:
a. Sodi um and wat er r et ent i on
b. Act i vat i on of t he r eni n- angi ot ensi n-al dost erone syst em, whi ch f urt her enhances
sodi um r et ent i on and t hus vol ume expansi on
3. Concent ri c cardi ac hypert rophy descri bes a mechani sm t hat t hi ckens cardi ac
wal l s, pr ovi di ng l ar ger cont r act i l e cel l s and di mi ni shi ng t he capaci t y of t he cavi t y i n
an at t empt t o pr eci pi t at e expul si on at l ower vol umes ( vent r i cul ar remodel i ng; see
Ì Ì ) .
4. Frank- StarI i ng mechani sm. The pr emi se of t hi s r esponse i s t hat i ncreased f i ber
di l at i on hei ght ens t he cont r act i l e f orce, whi ch t hen i ncr eases t he ener gy rel eased.
a. Wi t hi n physi ol ogi cal l i mi t s, t he hear t pumps al l t he bl ood i t r ecei ves wi t hout
al l owi ng excessi ve accumul at i on wi t hi n t he vei ns or car di ac chamber s.
b. As bl ood vol ume i ncreases, t he var i ous car di ac chamber s di l at e (st r et ch) and
enl ar ge i n an at t empt t o accommodat e t he excess f l ui d.
c. As t hese st r et ched muscl es cont ract , t he cont ract i l e f orce i ncr eases i n pr opor t i on
t o t hei r di st ent i on. Then t he ext ended f i bers snap back (as a rubber band woul d) ,
expel l i ng t he ext r a f l ui d i nt o t he ar t er i es.
d. Addi t i onal evi dence suggest s t hat t he r el ease of cyt oki nes (e. g. , t umor necr osi s
f act or ) occurs i n concert wi t h el evat ed l evel s of ci r cul at i ng nor epi nephri ne,
angi ot ensi n Ì Ì , al dost erone, endot hel i n, and vasopr essi n, whi ch may al l pl ay a r ol e
i n adver sel y af f ect i ng t he hear t st ruct ur e, r esul t i ng i n depressed per f ormance.
B. Decompensati on. Over t i me, t he compensat ory mechani sms become exhaust ed
and i ncr easi ngl y i nef f ect i ve, ent eri ng a vi ci ous spi r al of decompensat i on i n whi ch
t he mechani sms surpass t hei r l i mi t s and become sel f - def eat i ng÷as t hey wor k
har der , t hey onl y exhaust t he syst em' s capaci t y t o r espond.
1. As t he st r ai n cont i nues, t ot al per i pheral r esi st ance and af t er l oad i ncr ease,
t her eby decr easi ng t he per cent age of bl ood ej ect ed per uni t of t i me. Af t erl oad i s
det ermi ned by t he amount of cont ract i l e f or ce needed t o overcome i nt ravent ri cul ar
pr essure and ej ect t he bl ood.
a. Af t erI oad i s t he t ensi on i n vent r i cul ar muscl es duri ng cont ract i on. Ì n t he l ef t
vent r i cl e, t hi s t ensi on i s det ermi ned by t he amount of f orce needed t o over come
pr essure i n t he aor t a. Af t er l oad ( al so known as i nt r avent r i cul ar syst ol i c pr essur e) i s
somet i mes used t o descri be t he amount of f or ce needed i n t he r i ght vent ri cl e t o
over come pr essur e i n t he pul monar y ar t er y.
b. PreI oad i s t he f or ce exer t ed on t he vent ri cul ar muscl e at t he end of di ast ol e,
whi ch det ermi nes t he degr ee of muscl e f i ber st ret ch. Thi s concept i s al so known as
vent r i cul ar end-di ast ol i c pr essure. Prel oad i s a key f act or i n cont r act i l i t y because
t he more t hese muscl es ar e st r et ched i n di ast ol e, t he mor e power f ul l y t hey cont ract
i n syst ol e.
2. As t he f l ui d vol ume expands, so do t he demands on an al r eady exhaust ed pump,
al l owi ng i ncreased vol ume t o remai n i n t he vent r i cl e.
3. The resul t i ng f l ui d backup ( f r om t he l ef t vent r i cl e i nt o t he l ungs; f r om t he r i ght
vent r i cl e i nt o peri pher al ci rcul at i on) pr oduces t he si gns and sympt oms of HF.
III. CLINICAL EVALUATION.
Assessment of f l ui d st at us and l ef t vent r i cul ar ej ect i on f r act i on ( usual l y < 40% i n
pat i ent s wi t h HF ( Tabl e 42- 4).
A. FI ui d accumuI at i on behi nd t he I ef t vent ri cI e
1. Si gns and sympt oms
a. Dyspnea
P. 883



Figure 42-2. Compensatory mechanisms in heart
Iailure.
P. 884


( 1) As HF pr ogresses, t he amount of ef f ort r equi red t o t ri gger exert i onaI dyspnea
l essens.
( 2) Bot h paroxysmaI noct urnaI dyspnea and ort hopnea resul t f r om vol ume pool i ng
i n t he recumbent posi t i on and can be r el i eved by pr oppi ng up t he pat i ent wi t h
pi l l ows or havi ng t he pat i ent si t upr i ght . ( Or t hopnea i s of t en gauged by t he number
of pi l l ows t he pat i ent needs t o sl eep comf or t abl y. )
b. Dr y, wheezi ng cough
c. Exer t i onal f at i gue and weakness
d. Noct uri a. Edemat ous f l ui ds t hat accumul at e dur i ng t he day mi gr at e f rom
dependent ar eas when t he pat i ent i s i n a r ecumbent posi t i on and r enal per f usi on
i ncreases.
2. Physi caI f i ndi ngs
a. Ral es ( or crackl es) i ndi cat e t he movement of ai r t hr ough f l ui d-f i l l ed passages.
b. Tachycar di a i s an earl y compensat or y r esponse det ect ed t hrough an i ncr eased
pul se rat e.
c. S3 vent ri cul ar gal l op i s a vi br at i on produced by r api d f i l l i ng of t he l ef t vent r i cl e
ear l y i n di ast ol e.
d. S4 at r i al gal l op i s a vi br at i on pr oduced by i ncreased resi st ance t o sudden,
f or cef ul ej ect i on of at r i al bl ood i n l at e di ast ol e; i t does not var y wi t h i nspi r at i on i n
l ef t -si ded f ai l ur e and i s mor e common i n di ast ol i c dysf unct i on.
3. Di agnost i c t est resuI t s
a. Cardi omegal y ( hear t enl argement ) , l ef t vent ri cul ar hypert r ophy, and pul monar y
congest i on may be evi denced by chest r adi ogr aph, el ect r ocardi ogr am ( ECG) , and
r educt i on i n l ef t vent r i cul ar f unct i on vi a echocardi ogr aphy and radi onucl i de
vent r i cul ography.
b. Arm- t o-t ongue ci r cul at i on t i me i s pr ol onged.
c. Tr ansudat i ve pl eural ef f usi on may be suggest ed by r adi ogr aph and conf i r med by
anal ysi s of aspi r at ed pl eur al f l ui d.
B. FI ui d accumuI at i on behi nd t he ri ght si de of t he heart
1. Si gns and sympt oms
a. Compl ai nt s by t he pat i ent of t i ght ness and swel l i ng ( e. g. , " My r i ng i s t oo t i ght , ¨
" My ski n f eel s t oo t i ght ¨ ) suggest edema.
b. Nausea, vomi t i ng, anor exi a, bl oat i ng, or abdomi nal pai n on exer t i on may r ef l ect
hepat i c and vi scer al engor gement , resul t i ng f r om venous pr essur e el evat i on.
2. Physi caI f i ndi ngs
a. Jugul ar vei n di st ent i on r ef l ect s i ncreased venous pr essur e and i s a car di nal si gn
of HF.
b. S3 vent r i cul ar gal l op (see Ì Ì Ì . A. 2. c) .
c. S4 at ri al gal l op i nt ensi f i es on i nspi r at i on i n ri ght - si ded f ai l ur e.
d. Hepat omegal y ( a t ender , enl ar ged l i ver ) i s r eveal ed when pushi ng on t he edge of
t he l i ver resul t s i n a f l ui d r ef l ux i nt o t he j ugul ar vei ns, causi ng bul gi ng (posi t i ve
hepat oj ugul ar r ef l ux) .
e. Bi l at er al l eg edema i s an ear l y si gn of ri ght - si ded HF; pi t t i ng ankl e edema si gnal s
mor e advanced HF. However , edema i s common t o many di sor der s, and a pat t er n of
associ at ed f i ndi ngs, such as concur rent neck vei n di st ent i on, i s requi r ed f or
di f f er ent i al di agnosi s.
3. Laborator y f i ndi ngs. EI evat ed I eveI s of hepat i c enzymes÷f or exampl e, al ani ne
ami not ransf er ase ( ALT) ÷r ef l ect hepat i c congest i on.
4. EvaI uat i on of nat ri uret i c pepti des. Measurement of B- t ype nat r i ur et i c pept i de
( BNP) has been suggest ed i n t he eval uat i on of pat i ent s present i ng i n t he acut e care
set t i ng when a di agnosi s of HF i s uncer t ai n. El evat ed l evel s of BNP have been
associ at ed wi t h a reduct i on i n t he l ef t vent ri cul ar ej ect i on f r act i on (LVEF) as wel l as
i n l ef t vent ri cul ar hyper t rophy, acut e myocar di al i nf arct i on, and i schemi a, t hough
t hey are not speci f i c f or HF and can occur i n pat i ent s wi t h obst r uct i ve l ung di sease,
and pul monar y embol i .
IV. THERAPY
A. Bedrest
1. Advant ages
a. Bedr est decr eases met abol i c needs, whi ch r educes cardi ac wor kl oad.
b. Reduced wor kl oad, i n t ur n, r educes pul se r at e and dyspnea.
c. Bedr est al so hel ps decr ease excess f l ui d vol ume by pr omot i ng di ur esi s.
P. 885


2. Di sadvant ages. Physi cal act i vi t y (except dur i ng acut e decompensat i on) shoul d
be encouraged t o avoi d physi cal decondi t i oni ng and exer ci se i nt ol erance. The r i sk
of venous st asi s i ncreases wi t h bedr est and can r esul t i n t hr omboembol i sm.
Ant i embol i sm st ocki ngs hel p mi ni mi ze t hi s r i sk, as do passi ve or act i ve l eg
exer ci ses, when t he pat i ent ' s condi t i on permi t s.
3. Progressi ve ambuI ati on shoul d f ol l ow adequat e bedrest .
B. Di et ar y cont roI s
1. Consumi ng smaI I but f requent meaI s ( f our t o si x dai l y) t hat ar e l ow i n cal ori es
and resi due pr ovi de nouri shment wi t hout undul y i ncr easi ng met abol i c demands.
2. Moderat e sodi um rest ri ct i on al ong wi t h dai l y measurement s of wei ght hel p
maxi mi ze t he l owest and saf est doses of di ur et i cs, a pri mar y t ool i n reduci ng cent r al
vol ume i n HF.
a. Renal f unct i on shoul d be eval uat ed t o assess sodi um conser vat i on i f sever e
sodi um r est ri ct i on i s cont empl at ed.
b. Moder at e sodi um r est r i ct i on ( 2-4 g of di et ar y sodi um/ day) can be achi eved wi t h
r el at i ve ease by l i mi t i ng t he addi t i on of sal t dur i ng cooki ng and at t he t abl e.
c. The pat i ent shoul d be advi sed about medi cat i ons and common product s t hat
cont ai n sodi um and caut i oned about t hei r use ( e. g. , ant aci ds, sodi um bi car bonat e or
baki ng soda, commer ci al di et f ood pr oduct s, wat er sof t eners) . Tabl e 42- 3 l i st s ot her
subst ances t hat pr omot e sodi um ret ent i on.
C. Drug- reI at ed consi derat i ons. Therapeut i c i nt er vent i ons mi ght i mpr ove car di ac
per f or mance i n t he f ol l owi ng ways:
1. Dr ugs may i ncr ease t he car di ac ej ect i on f r act i on by di r ect l y st i mul at i ng car di ac
cont r act i l i t y. The use of posi t i ve i not r opi c agent s such as dopami ne, dobut ami ne,
and mi l r i none can pr oduce i mmedi at e benef i t s; however , t he l ong- t er m benef i t has
not been appreci at ed, and i n some cases may act ual l y i ncr ease mor bi di t y and
mor t al i t y.
2. Dr ugs may i ncr ease t he ej ect i on f r act i on by decr easi ng t he i mpedance t o ej ect i on
t hr ough r el axat i on of peri pher al bl ood vessel s. The use of vasodi l at or s such as
hydr al azi ne and ot her art er i al di l at ors may pr oduce shor t - t er m benef i t but do not
necessari l y produce cl i ni cal benef i t s i n t he l ong t er m.
3. Dr ugs may i mpr ove t he ej ect i on f ract i on by af f ect i ng t he car di ac r emodel i ng
pr ocess. Neurohormonal ant agoni st s such as ACEÌ s, 8-adrenergi c recept or bl ocker s,
ARBs, and vasodi l at or growt h i nhi bi t ors such as ni t r at es may not pr oduce i mmedi at e
benef i t s, but l ong-t erm use mi ght i mpr ove cl i ni cal st at us and decr ease f ut ur e
car di ac event s.
4. ACEÌ s, ARBs, di ur et i cs, and 8-adrener gi c bl ockers usual l y f orm t he basi c cor e of
t r eat ment f or HF.
D. ACEI s
1. Recent gui del i nes recommend t he use of ACEÌ s i n al l pat i ent s wi t h HF owi ng t o
l ef t vent ri cul ar syst ol i c dysf unct i on unl ess t he pat i ent s have a cont rai ndi cat i on t o
t hei r use or have demonst r at ed i nt ol er ance t o t hei r use. Cur rent l y, ACEÌ s ar e
consi dered t he f i rst - l i ne agent s i n t he t reat ment of HF and have been shown t o have
a benef i ci al ef f ect on cardi ac r emodel i ng.
2. Rel at i ve cont rai ndi cat i ons i ncl ude hi st or y of i nt ol erance or adver se r eact i ons,
ser um pot assi um > 5. 5 mEq/ L, serum cr eat i ni ne l evel s > 3 mg/ dL, sympt omat i c
hypot ensi on, sever e r enal ar t er y st enosi s, and pr egnancy.
3. ACEÌ s have been shown t o r educe sympt oms, i mprove cl i ni cal st at us, enhance
t he over al l qual i t y of l i f e, and r educe deat h as wel l as t he r i sk of deat h or
hospi t al i zat i on i n mi l d, moderat e, and sever e HF pat i ent s wi t h or wi t hout cor onar y
ar t er y di sease.
4. They i nhi bi t t he enzyme responsi bl e f or t he conver si on of angi ot ensi n Ì ( a weak
vasoconst ri ct or ) t o angi ot ensi n Ì Ì (a pot ent vasoconst r i ct or ). Thi s act i on si gni f i cant l y
decreases t ot al per i pheral resi st ance, whi ch ai ds i n reduci ng af t er l oad.
5. Ì nhi bi t i ng t he product i on of angi ot ensi n Ì Ì i nt erf er es wi t h st i mul at i on of
al dost er one rel ease, t hus i ndi r ect l y r educi ng ret ent i on of sodi um and wat er , whi ch
decreases venous r et ur n and pr el oad.
P. 886


6. Ì n pat i ent s wi t h a hi st or y of f l ui d ret ent i on or who pr esent wi t h f l ui d r et ent i on, a
di uret i c can be added t o an ACEÌ . ACEÌ s are al so i ndi cat ed f or pat i ent s wi t h l ef t
vent r i cul ar dysf unct i on wi t hout sympt oms of HF.
7. ACEÌ s are i ndi cat ed f or t he l ong- t erm management of chr oni c HF and ar e
gener al l y r ecommended i n combi nat i on wi t h a 8-adr ener gi c bl ocker and di ur et i c.
8. Al l ACEÌ s t hat have been st udi ed i n t he t r eat ment of HF have shown benef i t . The
sel ect i on of agent and dose shoul d be based on cur r ent l y avai l abl e l arge-scal e
st udi es i n whi ch t ar get doses of ACEÌ s÷capt opri l ( Capot en), enal apri l ( Vasot ec) ,
l i si nopr i l (Zest r i l ) , per i ndopr i l ( Aceon) , rami pri l ( Al t ace) , and t randol apr i l (Mavi k) ÷
ar e di f f er ent f rom t hose used t o t reat hyper t ensi on. Tabl e 42- 5 pr ovi des a
comparat i ve r evi ew of ACEÌ s cur rent l y used i n t he t r eat ment of HF.
Table 42-5. Comparative Doses of Select Agents Used in the Treatment of Heart
Failure (HF)
Drug
Initial Daily
Dose(s)
Maximal Total Daily
Dose
Loop diuretics
Bumetanide (Bumex) 0.5-1 mg
once or twice
10 mg
Furosemide (Lasix) 20-40 mg
once or twice
600 mg
Torsemide (Demadex) 10-20 mg
once
200 mg
Thiazide diuretics
Chlorthalidone (Hygroton) 12.5-25 mg
once
200 mg
Chlorothiazide (Diuril) 250-500 mg
once or twice
2000 mg
Hydrochlorothiazide
(Hydrodiuril)
25 mg once
or twice
200 mg
Metolazone (Zaroxolyn) 2.5 mg once 20 mg
Potassium-sparing diuretics
Amiloride (Midamor) 5 mg once 20 mg
Spironolactone (Aldactone) 12.5-25 mg
once
50 mg
Triamterene (Dyrenium) 50-75 mg
twice
300 mg
ACEIs
Captopril (Captoten) 6.25 mg three
times
450 mg
Enalapril (Vasotec) 2.5 mg twice 40 mg
Fosinopril (Monopril) 5-10 mg once 80 mg
Lisinopril (Zestril) 2.5-5 mg
once
40 mg
Perindopril (Aceon) 2 mg once 32 mg
Quinapril (Accupril) 5 mg twice 40 mg
Ramipril (Altace) 1.25-2.5 mg
once
10 mg
Trandolapril (Mavik) 1 mg once 4 mg
Angiotensin II receptor blockers
Candesartan (Atacand) 4-8 mg once 32 mg
Losartan (Cozaar) 25-50 mg
once
100 mg
Valsartan (Avapro) 20-40 mg
twice
320 mg
Aldosterone antagonists
Spironolactone (Aldactone) 12.5 mg once 50 mg
Eplerenone (Inspra) 25 mg once 50 mg
ß-Adrenergic receptor blockers
Bisoprolol (Zebeta) 1.25 mg once 10 mg
Carvedilol(Coreg) 3.125 mg
twice
50 mg; 100 mg Ior
patients ~ 85 kg
Metoprolol succinate (Toprol
XL) (extended release)
12.5-25 mg
once
200 mg

P. 887


9. Common si de ef f ect s t o be moni t or ed i ncl ude hypot ensi on (pat i ent s shoul d be
wel l hydr at ed bef or e i ni t i at i on of ACEÌ s) , di zzi ness, reduced r enal f unct i on
( i ncr eased ser um cr eat i ni ne of 0. 5 mg/ dL or more r equi r es reassessment ), cough,
and pot assi um r et ent i on ( i f pot assi um l evel s ar e hi gh wi t hout suppl ement at i on,
di scont i nue t he ACEÌ f or several days and t hen t ry t o r est art at l ower dose) .
10. Angi oedema i s a l i f e-t hr eat eni ng si de ef f ect of ACEÌ s t hat has been repor t ed t o
occur i n < 1% of pat i ent s. Ì t has been r epor t ed t o occur at a mor e f r equent r at e i n
bl ack pat i ent s, and t he suspi ci on of t he r eact i on woul d j ust i f y t he avoi dance of
ACEÌ s i n such pat i ent s.
E. ARBs
1. The newest i n t he cl ass of dr ugs used t o t reat HF t hat has been appr oved f or use
i n t he t r eat ment of mi l d t o moderat e hypert ensi on. However , t hi s cl ass of dr ugs i s
now consi der ed a r easonabl e al t ernat i ve t o t he use of ACEÌ s.
2. Cur rent l y avai l abl e agent s i ncl ude candesar t an ci l exet i l ( At acand) , eprosart an
( Tevet en) , i r besar t an ( Avapr o) , l osar t an ( Cozaar) , ol mesart an ( Beni car ) , t el mi sar t an
( Mi car di s) , and val sar t an ( Di ovan) and i ni t i al st udi es on sever al of t he agent s have
shown pot ent i al benef i t s f or t r eat i ng HF.
3. Cur rent gui del i nes suggest t hat ACEÌ s shoul d be pref er r ed over t he ARBs.
However , ARBs may be used i n pat i ent s who i ni t i al l y responded t o ACEÌ s and ar e
i nt ol erant t o t hem.
F. ß- Adrenergi c bI ocki ng agent s
1. Unl i ke ACEÌ s, whi ch st r i ct l y wor k by bl ocki ng t he ef f ect s of t he r eni n- angi ot ensi n
syst em, 8-adrener gi c bl ocker s i nt er f er e wi t h t he sympat het i c ner vous syst em÷t hat
i s, norepi nephr i ne-i nduced per i pheral vasoconst ri ct i on, nor epi nephri ne- i nduced
sodi um excr et i on by t he ki dney, nor epi nephr i ne- i nduced car di ac hypert r ophy,
nor epi nephr i ne i nduced ar r hyt hmi a generat i on, nor epi nephri ne-i nduced
hypokal emi a, or nor epi nephri ne-i nduced cel l deat h ( apopt osi s) t hr ough i ncr eased
st r ess owi ng t o nor epi nephr i ne st i mul at i on.
2. 8- Adrener gi c bl ockers, speci f i cal l y, bi sopr ol ol ( Zebet a) , sust ai ned-r el ease
met opr ol ol ( Topr ol XL) , and car vedi l ol ( Cor eg) , have been shown t o decrease t he
r i sk of deat h or hospi t al i zat i on as wel l as i mpr ove t he cl i ni cal st at us of HF pat i ent s.
However , doses f or ot her sel ect 8-adr energi c bl ocker s have been i ncl uded i n t he
cur rent gui del i nes based on repor t ed exper i ence ( Tabl e 42- 5).
3. Cur rent gui del i nes r ecommend t he use of 8- adrenergi c bl ocker s i n al l pat i ent s
wi t h st abl e HF as a r esul t of l ef t vent r i cul ar dysf unct i on, unl ess t hey have a
cont r ai ndi cat i on t o t hei r use or ar e unabl e t o t ol er at e t hei r ef f ect s owi ng t o
hypot ensi on, bradycar di a, bronchospasm, and t he l i ke.
4. 8- adr ener gi c bl ockers ar e gener al l y used i n conj unct i on wi t h di uret i cs, ACEÌ s, or
ARBs. 8- Adr ener gi c bl ockers shoul d not be t aken wi t hout di ur et i cs i n pat i ent s wi t h a
cur rent or recent hi st or y of f l ui d r et ent i on t o avoi d i t s devel opment and t o mai nt ai n
sodi um bal ance.
5. Si de ef f ect s of 8- adr ener gi c bl ockers may occur dur i ng t he ear l y days of t her apy
but do not gener al l y pr event t hei r l ong- t erm use; and pr ogr essi on of t he di sease
may be r educed, even i f sympt oms of t he di sease have not r esponded t o 8-
adr ener gi c bl ocker t her apy. Ther apy shoul d be i ni t i at ed wi t h l ow doses and t i t r at ed
upwar d sl owl y as t ol er at ed.
6. Pat i ent s shoul d be moni t or ed f or si gns of f l ui d r et ent i on by havi ng pat i ent s wei gh
t hemsel ves dai l y and r epor t any si gni f i cant i ncr eases, whi ch mi ght war r ant
i ncreases i n di uret i c doses or r educt i ons i n t he dose of t he 8- adr ener gi c bl ocker . Ì n
addi t i on, f at i gue, hypot ensi on, br adycardi a, and hear t bl ock ar e repor t ed si des
ef f ect s, whi ch shoul d be moni t ored t o ensur e appr opr i at e at t ent i on and
management .
7. St udi es suppor t t he use of 8- adr energi c bl ocker s i n pat i ent s wi t h st age C hear t
f ai l ur e÷and not i n t he acut e management of pat i ent s, as i n an i nt ensi ve car e uni t
( Ì CU) . Pat i ent s shoul d have no or mi ni mal evi dence of f l ui d r et ent i on and have no
r ecent evi dence f or t he use of an i nt ravenous i not r opi c agent . Ì n addi t i on, 8-
adr ener gi c bl ockers shoul d be consi der ed i n pat i ent s who devel op HF post -
myocar di al i nf arct i on i f t hey ar e abl e t o t ol er at e t he negat i ve i not r opi c ef f ect s.
P. 888


8. Ì ni t i at i on of 8-adrenergi c bl ockers shoul d not be under t aken unt i l t he pat i ent i s
st abl e wi t hout f l ui d overl oad or hypot ensi on, and on concomi t ant medi cat i ons, whi ch
i ncl ude di uret i cs and/ or ACEÌ s or ARBs.
9. Pat i ent educat i on i s an i mport ant aspect f or i ni t i at i ng 8-adr energi c bl ocker s
t her apy, and pat i ent s need t o be i nf ormed t hat t hey mi ght not see posi t i ve ef f ect s
f or sever al mont hs af t er obt ai ni ng t he t arget dosage of t he agent .
G. Di uret i cs
1. Di ur et i cs shoul d be prescr i bed f or al l pat i ent s wi t h sympt oms of HF who have
evi dence of or who have exper i enced f l ui d r et ent i on because t hese dr ugs ar e t he
onl y ones t hat can cor r ect f l ui d ret ent i on. Di uret i cs ar e gener al l y best used i n
conj unct i on wi t h an ACEÌ , ARB, and/ or 8-adrenergi c bl ocker.
2. Di ur et i cs have been shown t o cause a reduct i on i n j ugul ar venous pr essur es,
pul monar y congest i on, per i pher al edema, and body wei ght i n shor t - t er m st udi es and
have been shown t o i mprove car di ac f unct i on and exer ci se t ol erance i n
i nt er medi at e-t erm st udi es.
3. The goal of di ur et i c t her apy i s t o reduce and event ual l y el i mi nat e si gns and
sympt oms of f l ui d ret ent i on as assessed by j ugul ar venous di st ensi on (JVD) ,
per i pheral edema, or bot h. Sl ow t i t r at i on upwar d i n doses may be necessar y t o
mi ni mi ze hypot ensi on and shoul d be cont i nued unt i l f l ui d r et ent i on i s el i mi nat ed.
4. Body wei ght i s an ef f ect i ve met hod of moni t ori ng f l ui d l osses and i s best done on
a dai l y basi s by t he pat i ent .
5. Pat i ent s who exper i ence di uret i c resi st ance or t ol er ance t o t hei r ef f ect s mi ght
need i nt r avenous admi ni st r at i on, a combi nat i on of t wo agent s wi t h di f f er i ng
mechani sms ( f ur osemi de and met ol azone) or t he addi t i on of agent s such as
dopami ne or dobut ami ne, whi ch i ncr ease r enal bl ood f l ow. Fur t her mor e, eval uat i on
of pat i ent dr ug prof i l es may i dent i f y t he addi t i on of sodi um- r et ai ni ng agent s such as
nonst eroi dal ant i -i nf l ammat or y dr ugs ( NSAÌ Ds) .
6. Al l di uret i cs i ncrease ur i ne vol ume and sodi um excr et i on but di f f er i n t hei r
pharmacol ogi cal pr oper t i es.
7. SeI ect Di ureti c CI asses
a. Thi azi de di uret i cs i ncl ude chl orot hi azi de ( Di ur i l ) , hydr ochl orot hi azi de
( Hydr oDÌ URÌ L) , chl ort hal i done ( Hygrot on) , and i ndapami de ( Lozol ) . They ar e
ef f ect i ve and commonl y used i n HF, speci f i cal l y i n pat i ent s wi t h hyper t ensi on, but
t hey depl et e pot assi um st or es i n t he pr ocess. These agent s are r el at i vel y weak
because t hey ar e abl e t o i ncr ease t he f ract i onal excr et i on of sodi um t o onl y 5%- 10%
of t he f i l t er ed l oad. However , t hey have been shown t o l ose t hei r ef f ect i veness i n
HF pat i ent s wi t h moder at el y i mpai red renal f unct i on (cr eat i ni ne cl ear ance < 30
mL/ mi n) .
b. Loop di uret i cs i ncl ude f urosemi de ( Lasi x) , et hacr yni c aci d ( Edecr i n) , bumet ani de
( Bumex) , and t or semi de ( Demadex) and have become t he pref er red di ur et i cs. They
have t he abi l i t y t o i ncr ease sodi um excr et i on t o 20%- 25% of t he f i l t er ed l oad and t o
mai nt ai n t hei r ef f i cacy unt i l r enal f unct i on i s sever el y i mpai red (creat i ni ne cl earance
< 5 mL/ mi n) pl us have t he added advant age of reduci ng venous r et ur n i ndependent
of di ur esi s. Ì n addi t i on, f ur osemi de' s act i on i s mor e i nt ense, maki ng i t usef ul as a
r api d- act i ng i nt ravenous agent i n r ever si ng acut e pul monar y edema, owi ng t o i t s
di r ect di l at i ng ef f ect s on pul monar y vascul at ur e (see Tabl e 42-5 f or dosi ng) .
c. Potassi um-spari ng di uret i cs i ncl ude ami l or i de ( Mi damor ) , spi r onol act one
( Al dact one) and t ri amt erene ( Dyr eni um) and may hel p avoi d t he i nci dence of
hypokal emi a. However , t hey al so possess a weaker di ur et i c ef f ect t han t he ot her
di uret i cs. As t he number of HF pat i ent s r ecei vi ng ACEÌ s or ARBs cont i nues t o
i ncrease, f ewer pat i ent s may r equi r e suppl ement al pot assi um t herapy.
8. AI dost erone antagoni st s. Spi r onol act one ( Al dact one), i s a pot assi um-spari ng
di uret i c, but was t he f i r st al dost er one ant agoni st avai l abl e f or cl i ni cal use i n t he
Uni t ed St at es, when i t had been shown t o have di r ect bl ocki ng ef f ect s on t he
act i ons of al dost er one. Resul t s f r om a l ar ge st udy, t he Randomi zed Al dact one
Eval uat i on St udy ( RALES) , r eveal ed t hat t he addi t i on of l ow doses (12. 5-25 mg
dai l y) of spi r onol act one t o pat i ent s wi t h cl ass Ì V sympt oms ( NYHA) t aki ng ACEÌ s
r educed t he ri sk of deat h and hospi t al i zat i on.
P. 889


a. Cur rent gui del i nes r ecommend t hat spi r onol act one be consi dered i n pat i ent s wi t h
st age C hear t f ai l ur e÷as add-on t her apy t o ACEÌ s or ARBs and a 8-adrener gi c
bl ocker ÷who can be cl osel y moni t or ed f or changes i n renal f unct i on and pot assi um
l evel s.
b. Pat i ent s r ecei vi ng spi r onol act one shoul d have serum pot assi um l evel s eval uat ed
and reduced t o < 5. 0 mmol / L al ong wi t h a ser um cr eat i ni ne l evel < 2. 5 mg/ dL bef or e
i ni t i at i on of t her apy. Pot assi um l evel s shoul d be r out i nel y moni t or ed t o prevent t he
subsequent devel opment of hyper kal emi a.
c. Epl erenone (Ì nspr a) was t he second al dost er one r ecept or ant agoni st i nt r oduced
and i s cur r ent l y i ndi cat ed i n t he t reat ment of hyper t ensi on and i n post - MÌ pat i ent s
wi t h HF.
H. Vasodi I at ors
1. These agent s r educe pul monar y congest i on and i ncr ease car di ac out put by
r educi ng pr el oad and/ or af t erl oad. However , at t he cur r ent t i me, t here are no l ar ge-
scal e t r i al s suppor t i ng t he use of vasodi l at ors (ni t r at es or hydr al azi ne) al one i n t he
t r eat ment of HF.
2. Ì ndi vi dual agent s
a. Ni t roprussi de ( Ni pri de) i s admi ni st er ed i nt r avenousl y i n doses of 0. 3-10
µg/ kg/ mi n t o pr ovi de pot ent di l at i on of bot h art eri es and vei ns.
b. HydraI azi ne ( ApresoI i ne) . Thi s ar t er i ol e di l at or decr eases af t er l oad and
i ncreases car di ac out put i n pat i ent s wi t h HF.
c. Prazosi n (Mi ni press). Thi s q-adr energi c bl ocker act s as a bal anced
ar t eri ovenous di l at or .
d. Ni t rates. Venous di l at i on by ni t r at es i ncr eases venous pool i ng, whi ch decr eases
pr el oad.
( 1) Thei r ar t er i al ef f ect s seem t o r esul t i n decr eased af t er l oad wi t h cont i nued
t her apy.
( 2) Ni t r at es ar e avai l abl e i n many f orms and doses. Because i ndi vi dual react i ons t o
t hese agent s var y wi del y, dosages have t o be adj ust ed; but , i n general , t hey ar e
hi gher f or HF t han f or angi na. Tabl e 42- 6 pr ovi des exampl es of ni t r at e doses t hat
have been used i n HF.
e. Combi nat i on t herapy. Hydr al azi ne has been used wi t h i sosorbi de di ni t r at e
( Ì sordi l ) t o r educe af t er l oad (or wi t h ni t r ogl yceri n t o reduce pr el oad) f or t reat i ng
chr oni c HF.
( 1) The combi nat i on of t hese t wo agent s÷hydr al azi ne and i sosor bi de di ni t r at e
( Bi Di l ) shoul d not be used as i ni t i al t her apy over ACEÌ s, ARBs, or 8-adr ener gi c
bl ocker s, but coul d be consi der ed i n pat i ent s who have persi st ent sympt oms despi t e
t he use of t hese agent s.
( 2) A recent l y compl et ed t r i al demonst r at ed t hat t he addi t i on of i sosorbi de di ni t rat e
and hydr al azi ne t o st andar d medi cal t her apy consi st i ng of ACEÌ s and 8- adr ener gi c
bl ocker s can be ef f ect i ve i n bl ack pat i ent s wi t h NYHA f unct i onal cl ass Ì Ì Ì or Ì V heart
f ai l ur e.
( 3) Suggest ed dosi ng r egi mens i ncl ude hydr al azi ne 50- 100 mg f our t i mes dai l y and
i sosorbi de di ni t r at e 10-40 mg t hr ee t i mes dai l y.
I . Di gi t aI i s gI ycosi des
1. Di gi t al i s, speci f i cal l y di goxi n, cont i nues t o pl ay a r ol e i n t he t r eat ment of HF, but
ongoi ng eval uat i ons have al t er ed i t s pl ace i n t he l ong- t er m management of HF. Ì t
has been shown t o be ef f ect i ve as a short - t erm t her apy i n i mpr ovi ng sympt oms,
qual i t y of l i f e, and exer ci se t ol er ance i n pat i ent s wi t h mi l d t o moder at e HF. Ì t i s now
r ecommended as add- on t herapy i n conj unct i on wi t h di ur et i cs, ACEÌ s or ARBs, and
a 8- adr ener gi c bl ocker t o i mpr ove t he sympt oms and cl i ni cal st at us of pat i ent s wi t h
HF.
Table 42-6. Examples of Nitrates That Have Been Used in Heart Failure
Form of Nitrate Typical Dose Dosing Interval
Intravenous nitroglycerin 5-200
µg/min
Continuous
inIusion
Nitroglycerin buccal tablets 1-3 mg 4-6 hr
Nitroglycerin capsules (sustained
release)
6.5-19.5 mg 4-6 hr
Nitroglycerin ointment 1-3 inches 4-6 hr
Sublingual nitroglycerin 0.4 mg 1-2 hr
Oral isosorbide dinitrate 10-60 mg 4-6 hr
Sublingual isosorbide dinitrate 5-10 mg 4 hr

P. 890


2. Di goxi n ( Lanoxi n) had pr evi ousl y been recommended i n pat i ent s wi t h HF who had
r api d at r i al f i bri l l at i on t o cont r ol t he vent r i cul ar rat e. However , 8-adr energi c
bl ocker s have been shown t o i mpr ove sur vi val and may be mor e ef f ect i ve i n
cont r ol l i ng t he r at e al one. Cur rent gui del i nes suggest use of al t er nat i ve agent s f or
vent r i cul ar rat e cont rol rat her t han di goxi n.
3. Di goxi n can be used ear l y t o r educe sympt oms i n HF pat i ent s who have been
st art ed on ACEÌ s or 8-adr energi c bl ocker s but have not yet r esponded t o t hem.
4. Long-t erm t ri al s of sel ect pat i ent s wi t h HF have demonst r at ed t hat t r eat ment wi t h
di goxi n had l i t t l e ef f ect on shor t -t erm mor t al i t y but r educed t he r i sk of deat h and
hospi t al i zat i on.
5. Therapeut i c ef fects
a. Posi t i ve i not ropi c ef fect s wer e pr evi ousl y f el t t o pr ovi de most of t he benef i t s
t hr ough i ncr eased cardi ac out put , decr eased car di ac f i l l i ng pr essur e, decreased
venous and capi l l ar y pr essur e, i ncr eased renal bl ood f l ow, and decr eased heart
si ze.
b. Recent evi dence suggest s t hat di gi t al i s act s by f ur t her i ng t he act i vat i on of
neurohormonal syst ems r at her t han as a posi t i ve i not r opi c agent . Thi s r esul t s i n
deact i vat i on of r eni n- angi ot ensi n-al dost er one compensat i on, whi ch pr omot es
di uresi s, r educes f l ui d vol ume, decr eases r enal sodi um r eabsorpt i on, and
di mi ni shes edema.
c. Negat i ve chronot ropi c ef fect s occur f rom t he ef f ect of di gi t al i s on t he si noat ri al
( SA) node when gi ven i n doses t hat pr oduce hi gh t ot al body st ores ( e. g. , 15- 18
µg/ kg) .
6. Choi ce of agent . Al l of t he di gi t al i s gl ycosi des have si mi l ar proper t i es; however ,
di goxi n i s t he most commonl y used pr eparat i on i n t he Uni t ed St at es.
a. Di goxi n i s avai l abl e i n t abl et , i nj ect i on, el i xi r , and capsul e f orms.
b. Cal cul at i on of doses must f act or i n t he di f f erences i n syst emi c avai l abi l i t y among
t hese f or ms. For exampl e, di goxi n sol ut i on i n capsul es i s more bi oavai l abl e t han
di goxi n t abl et s; t heref ore, 0. 125- mg t abl et s are equi val ent t o 0. 1-mg capsul es. Ì n
t he maj ori t y of pat i ent s, t he dosage of di goxi n shoul d be t he equi val ent of 0. 125-
0. 25 mg dai l y of t he t abl et f or mul at i on.
7. Dosage and admi ni strat i on. The r ange bet ween t her apeut i c and t oxi c doses i s
ext r emel y nar r ow. Ther e i s no magi c t hr eshol d l evel f or di goxi n t her apy, but ser um
concent r at i ons of 0. 8- 1. 0 ng/ mL have been associ at ed wi t h t her apeut i c r esponse
and mi ni mal t oxi ci t y.
a. Rapi d di gi taI i zat i on. Though not r out i nel y necessar y i n t he t reat ment of HF, i n
t hi s met hod, t he ef f ect s ( and st eady-st at e l evel s) ar e achi eved wi t hi n 24 hr , but t he
act ual admi ni st r at i on rat e i s usual l y sl ow and del i ver ed i n di vi ded doses.
b. SI ow di gi taI i zati on. For t he aver age HF pat i ent , or al admi ni st rat i on of
mai nt enance doses shoul d achi eve st eady-st at e l evel s i n 7- 8 days ( 3-4 weeks i n a
pat i ent wi t h r enal dysf unct i on) .
8. Precauti ons and moni t ori ng ef f ect s
a. Potassi um seems t o ant agoni ze di gi t al i s prepar at i ons.
( 1) Decr eased pot assi um l evel s f avor di goxi n bi ndi ng t o car di ac cel l s and i ncr ease
i t s ef f ect , t hus i ncreasi ng t he l i kel i hood of di gi t al i s t oxi ci t y. Thi s ant agoni sm i s
par t i cul arl y si gni f i cant f or t he HF pat i ent who i s recei vi ng a di ur et i c ( many of whi ch
decrease pot assi um l evel s) .
( 2) Conver sel y, i ncreased pot assi um l evel s seem t o decr ease di goxi n bi ndi ng and
decrease i t s ef f ect . Thi s i s l i kel y i n pat i ent s t aki ng pot assi um or an ACEÌ or ARB
( whi ch i ncrease pot assi um r eabsor pt i on) .
b. CaI ci um i ons act syner gi st i cal l y wi t h di goxi n, and i ncr eased l evel s i ncrease t he
f or ce of myocardi al cont ract i on. At excessi ve l evel s, ar r hyt hmi as and syst ol i c
st andst i l l can devel op.
c. Magnesi um l evel s ar e i nversel y rel at ed t o di goxi n act i vi t y. As magnesi um l evel s
decrease, t he predi sposi t i on t o t oxi ci t y i ncr eases and, wi t hi n r eason, vi ce ver sa.
d. Serum di goxi n I eveI s
( 1) Ì n car di ac gl ycosi de t her apy, t he pat i ent ' s cl i ni cal st at e i s t he most pr act i cal
bar omet er of a successf ul regi men. However , shoul d quest i ons ari se as t o
compl i ance, absor pt i on, or a dr ug- dr ug i nt er act i on, ser um di goxi n l evel s may be
hel pf ul .
( 2) Af t er or al i ngest i on of di goxi n, ser um l evel s ri se rapi dl y, t hen drop shar pl y as
t he dr ug ent ers t he myocar di um and ot her t i ssues. Ther ef or e, a meani ngf ul
eval uat i on requi r es a det er mi nat i on of t he r el at i onshi p bet ween ser um di goxi n l evel s
and myocar di al t i ssue l evel s.
P. 891


( 3) The most meani ngf ul r esul t s ar e obt ai ned i f ser um sampl es ar e t aken af t er
st eady st at e has been reached and 6- 8 hr af t er an or al dose (3- 4 hr af t er an
i nt ravenous dose) .
e. RenaI functi on st udi es. Because t he ki dney i s t he pr i mar y met abol i c rout e f or
di goxi n, r enal f unct i on st udi es such as ser um creat i ni ne l evel s ai d t he eval uat i on of
el i mi nat i on ki net i cs f or di goxi n.
9. Di gi t al i s t oxi ci t y i s a f ai r l y common occur rence because of t he narr ow t her apeut i c
r ange and can be f at al i n a si gni f i cant per cent age of pat i ent s exper i enci ng a t oxi c
r eact i on.
a. Ri sk of t oxi ci t y i ncr eases wi t h coadmi ni st r at i on of qui ni di ne, ver apami l ( Cal an) ,
i t r aconazol e ( Spor anox) , er yt hr omyci n ( Er yt hr oci n) , cl ari t hr omyci n ( Bi axi n) ,
pr opaf enone ( Ryt hmol ) , spi ronol act one ( Al dact one) , and ami odar one ( Cordar one)
and i s i nf l uenced by t he el ect r ol yt e (hypokal emi a, hypomagnesemi a) ef f ect s
descr i bed previ ousl y.
b. Si gns of t oxi ci t y i ncl ude
( 1) Anor exi a, a common and earl y si gn
( 2) Fat i gue, headache, and mal ai se
( 3) Nausea and vomi t i ng
( 4) Ment al conf usi on and di sori ent at i on
( 5) Al t er at i ons i n vi sual per cept i on ( e. g. , bl ur r i ng, yel l owi ng, a hal o ef f ect )
( 6) Cardi ac ef f ect s:
( a) Pr emat ur e vent ri cul ar cont r act i ons and vent ri cul ar t achycardi a and f i br i l l at i on
( b) SA and at ri ovent r i cul ar ( AV) bl ock
( c) At ri al t achycar di a wi t h AV bl ock
c. Treat ment of t oxi ci t y
( 1) Di gi t al i s i s di scont i nued i mmedi at el y, as i s any pot assi um- depl et i ng di ur et i c.
( 2) Ì f t he pat i ent i s hypokal emi c, pot assi um suppl ement s ar e admi ni st er ed and
ser um l evel s ar e moni t ored t o avoi d hyperkal emi a t hrough overcompensat i on.
However , pot assi um suppl ement s ar e cont rai ndi cat ed i n a pat i ent wi t h sever e AV
bl ock.
( 3) Ar r hyt hmi as are t reat ed wi t h l i docai ne ( Xyl ocai ne) ( usual l y a 100- mg bol us,
f ol l owed by i nf usi on at 2- 4 mg/ mi n) or phenyt oi n ( Di l ant i n) ( as a sl ow i nt ravenous
i nf usi on of 25- 50 mg/ mi n, t o a maxi mum of 1. 0 g).
( 4) Chol est yr ami ne ( Quest r an) , whi ch bi nds t o di gi t al i s gl ycosi des, may hel p pr event
absor pt i on and reabsorpt i on of di gi t al i s i n t he bi l e.
( 5) Pat i ent s wi t h ver y hi gh ser um di goxi n l evel s ( such as t hose r esul t i ng f r om a
sui ci dal overdose) may benef i t f r om t he use of pur i f i ed di goxi n- speci f i c Fab
f r agment ant i bodi es ( Di gi bi nd) . One vi al (38 mg) wi l l bi nd 0. 6 mg of di gi t al i s. The
dosage i s cal cul at ed based on t he est i mat ed t ot al body st ore of di gi t al i s.
J. CaI ci um- channeI bI ockers
1. Owi ng t o t he l ack of evi dence support i ng ef f i cacy, cal ci um-channel bl ocker s
shoul d not be used f or t he t reat ment of HF. Cur rent gui del i nes l i st cal ci um channel
bl ocker s as a cl ass Ì Ì Ì recommendat i on, whi ch st at es: " Cal ci um-channel bl ocki ng
dr ugs ar e not i ndi cat ed as rout i ne t r eat ment f or HF i n pat i ent s wi t h cur r ent or pr i or
sympt oms of HF and r educed LVEF. ¨
2. Cal ci um channel bl ockers have been l i st ed as one of t hree cl asses of dr ugs ( wi t h
ant i ar r hyt hmi cs and NSAÌ Ds) t hat can exacerbat e HF and shoul d be avoi ded i n most
pat i ent s.
K. I not ropi c agent s have been used i n t he emergency t r eat ment of pat i ent s wi t h
HF. However , l ong-t erm or al t her apy wi t h t hese agent s has not i mproved sympt oms
or cl i ni cal st at us, and has been r epor t ed t o i ncrease mor t al i t y, especi al l y i n pat i ent s
wi t h advanced HF.
1. Cur rent gui del i nes provi de a cl ass Ì Ì Ì recommendat i on, whi ch st at es: " Long- t erm
use of an i nf usi on of a posi t i ve i not r opi c drug may be har mf ul and i s not
r ecommended f or pat i ent s wi t h cur rent or pr i or sympt oms of HF and r educed LVEF,
except as pal l i at i on f or pat i ent s wi t h end-st age di sease who cannot be st abi l i zed
wi t h st andar d medi cal t reat ment . ¨
2. Dopami ne ( i nt r avenous)
a. Low doses of 2- 5 µg/ kg/ mi n st i mul at e speci f i c dopami ne r ecept ors wi t hi n t he
ki dney t o i ncrease renal bl ood f l ow and t hus i ncrease uri ne out put .
b. Moderat e doses of 5-10 µg/ kg/ mi n i ncr ease car di ac out put ( posi t i ve i not r opi c
ef f ect ) i n HF pat i ent s.
P. 892


c. Hi gh doses
( 1) As doses ar e rai sed above 10 µg/ kg/ mi n, q per i pher al act i vi t y i ncreases,
r esul t i ng i n i ncr eased t ot al per i pher al r esi st ance and pul monar y pr essur es.
( 2) When t he i nf usi on exceeds 8- 9 µg/ kg/ mi n, t he pat i ent shoul d be moni t or ed f or
t achycardi a. Ì f t he i nf usi on i s sl owed or i nt er r upt ed, t he adverse ef f ect shoul d
di sappear, as dopami ne has a ver y short hal f -l i f e i n pl asma.
3. Dobut ami ne ( i nt r avenous)
a. Pat i ent s who ar e unr esponsi ve t o, or adversel y af f ect ed by, dopami ne may
benef i t f r om dobut ami ne i n doses of 5- 20 µg/ kg/ mi n.
b. Al t hough dobut ami ne r esembl es dopami ne chemi cal l y, i t s act i ons di f f er
somewhat . For exampl e, dobut ami ne does not di rect l y af f ect r enal r ecept or s and,
t her ef ore, does not act as a r enal vasodi l at or . Ì t i ncr eases ur i nar y out put onl y
t hr ough i ncr eased cardi ac out put .
c. Seri ous ar r hyt hmi as ar e a pot ent i al occur r ence, al t hough l ess l i kel y t o occur t han
wi t h dopami ne. Sl owi ng or i nt er rupt i ng t he i nf usi on usual l y r ever ses t hi s ef f ect , as i t
does f or dopami ne.
d. Dobut ami ne and dopami ne have been used t oget her t o t reat car di ogeni c shock,
but si mi l ar use i n HF has yet t o be accept ed.
4. Ì namr i none ( i nt r avenous) i s r ef er r ed t o as nongl ycosi de, nonsympat homi met i c
i not r opi c agent s.
a. A bi pyr i di ne der i vat i ve, i namri none has bot h a posi t i ve i not r opi c ef f ect and a
vasodi l at i ng ef f ect .
b. By i nhi bi t i ng phosphodi est erase l ocat ed speci f i cal l y i n t he cardi ac cel l s, i t
i ncreases t he amount of cycl i c adenosi ne monophosphat e (cAMP) .
c. Ì namr i none has been used i n pat i ent s wi t h HF t hat have been ref r act ory t o
t r eat ment wi t h ot her i not r opi c agent s.
d. Ef f ect i ve regi mens have used l oadi ng i nt ravenous i nf usi ons of 0. 75 mg/ kg over 2-
3 mi n f ol l owed by mai nt enance i nf usi ons of 5- 10 µg/ kg/ mi n.
e. Precauti ons and moni t ori ng ef f ect s
( 1) Ì namr i none i s unst abl e i n dext r ose sol ut i ons and shoul d be added t o sal i ne
sol ut i ons i nst ead. Because of f l ui d bal ance concer ns, t hi s can be a pot ent i al
pr obl em i n pat i ent s wi t h HF.
( 2) Because of t he per i pher al di l at i ng pr oper t i es, pat i ent s shoul d be moni t or ed f or
hypot ensi on.
( 3) Thr ombocyt openi a has occur r ed and i s dose dependent and asympt omat i c.
( 4) Vent r i cul ar r at es may i ncr ease i n pat i ent s wi t h at ri al f l ut t er or f i br i l l at i on.
5. Mi I ri none ( Pri macor), i nt ravenous, i s si mi l ar t o i namr i none. Ì t possesses bot h
i not r opi c and vasodi l at ory pr oper t i es.
a. Thi s agent has been used as shor t - t erm management t o t reat pat i ent s wi t h HF.
b. Most mi l ri none pat i ent s i n cl i ni cal t r i al s have al so been recei vi ng di goxi n and
di uret i cs.
c. Ef f ect i ve dosi ng r egi mens have used a l oadi ng dose of 50 µg/ kg admi ni st ered
sl owl y over 10 mi nut es i nt r avenousl y, f ol l owed by mai nt enance doses of 0. 375
µg/ kg/ mi n by cont i nuous i nf usi on, based on t he cl i ni cal st at us of t he pat i ent .
d. Precaut i ons and moni t ori ng ef fects
( 1) Renal i mpai r ment si gni f i cant l y pr ol ongs t he el i mi nat i on r at e of mi l r i none, and
i nf usi ons need t o be r educed accor di ngl y.
( 2) Moni t ori ng i s necessar y f or t he pot ent i al ar rhyt hmi as occurr i ng i n HF, whi ch may
be i ncreased by drugs such as mi l ri none and ot her i not ropi c agent s.
( 3) Bl ood pr essur e and hear t rat e shoul d be moni t or ed when admi ni st er i ng
mi l r i none, owi ng t o i t s vasodi l at or y ef f ect s and i t s pot ent i al t o i nduce ar rhyt hmi as.
( 4) Addi t i onal si de ef f ect s i ncl ude mi l d t o moder at e headache, t r emor, and
t hr ombocyt openi a.
6. Nesi ri t i de ( Nat recor) i s a r ecombi nant f orm of human BNP, whi ch i s a nat ur al l y
occur ri ng hormone secr et ed by t he vent ri cl es. Ì t i s t he f i r st of t hi s dr ug cl ass t o
become avai l abl e f or human use i n t he Uni t ed St at es.
a. Nesi ri t i de i s appr oved f or t he i nt r avenous t reat ment of pat i ent s wi t h acut el y
decompensat ed HF associ at ed wi t h shor t ness of br eat h at r est or wi t h mi ni mal
act i vi t y.
b. Nesi ri t i de bi nds t o nat r i ur et i c pept i de r ecept ors i n bl ood vessel s, r esul t i ng i n
i ncreased product i on of cycl i c guanosi ne monophosphat e (cGMP) i n t arget t i ssues,
whi ch medi at es
P. 893

vasodi l at i on. Ì n HF, nesi r i t i de reduces pul monar y capi l l ar y wedge pressure and
syst emi c vascul ar r esi st ance.
c. Ì ni t i al t r eat ment i nvol ves a bol us dose of 2 µg/ kg f ol l owed by a cont i nuous
i nt ravenous i nf usi on of 0. 01 µg/ kg/ mi n t o a maxi mum dose of 0. 03 µg/ kg/ mi n.
d. Moni t ori ng f or hypot ensi on, el evat ed ser um creat i ni ne, headache, nausea, and
di zzi ness i s t he key t o successf ul use. Concomi t ant use of ACEÌ s may i ncr ease t he
r i sk of sympt omat i c hypot ensi on (syst ol i c bl ood pr essur e < 90 mm Hg and syncope) .
e. Nesi ri t i de has been shown t o i mprove sympt oms i n t he set t i ng of acut e HF, but
t he ef f ect on mor bi di t y and mor t al i t y has not yet been proven. At t hi s poi nt i n t i me,
owi ng t o l ack of pi vot al st udi es demonst r at i ng i t s benef i t , nesi r i t i de' s use as
i nt er mi t t ent or cont i nuous out pat i ent t r eat ment i s not r ecommended.
L. Pati ent educati on
1. Pat i ent s shoul d be made awar e of t he i mport ance of t aki ng t hei r medi cat i ons
exact l y as pr escr i bed and shoul d be advi sed t o wat ch f or si gns of t oxi ci t y.
2. Pat i ent s shoul d be educat ed on t he need f or l i f est yl e modi f i cat i ons t hat wi l l have
a posi t i ve ef f ect on r educi ng HF devel opment and r educi ng HF sympt oms, i ncl udi ng
dai l y wei ght moni t or i ng, f l ui d management , sodi um r est ri ct i on, ear l y i nt ervent i on i f
sympt oms appear , compl i ance wi t h t he t r eat ment pl an, modi f i cat i on of al cohol
i nt ake, exer ci se, and st ress r educt i on.
3. The pat i ent shoul d under st and t he need f or r egul ar checkups and be abl e t o
r ecogni ze sympt oms t hat r equi r e i mmedi at e physi ci an not i f i cat i on÷f or exampl e, an
unusual l y i r r egul ar pul se r at e, pal pi t at i ons, short ness of breat h, swol l en ankl es,
vi sual di st ur bances, or wei ght gai n exceedi ng 3-5 l b i n 1 week.
4. The pat i ent needs t o be educat ed about dr ugs such as cal ci um channel bl ockers;
NSAÌ Ds, whi ch may cause a pr obl em i n HF by r et ai ni ng f l ui d; and sodi um. Ì n
addi t i on, t he pat i ent needs t o be i nf or med of t he pot ent i al dangers of use of over -
t he-count er medi cat i ons t hat mi ght al so predi spose hi m or her t o HF sympt oms and
l oss of sympt om cont rol . A t hor ough revi ew of al l medi cat i ons (bot h prescr i pt i on and
over - t he- count er ) shoul d be car ri ed out as f r equent l y as possi bl e t o ensure
compl i ance wi t h t he t reat ment regi men.
P. 894


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 8: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. Whi ch of the foI I owi ng combi nat i ons of drugs, when used t oget her,
part i cuI arI y i n bI ack pat i ent s, reduce both preI oad and af t erI oad angi ot ensi n-
convert i ng enzyme and mi ght provi de an aI ternat i ve t o ACEI s i n pat i ent s who
are i ntoI erant of t hem?
( A) ni t r ogl yceri n ( Ni t rost at ) and i sosor bi de di ni t rat e (Ì sor di l )
( B) hydr al azi ne ( Apr esol i ne) and i sosor bi de di ni t rat e
( C) di l t i azem ( Car di zem) and ver apami l ( Cal an)
( D) pr azosi n ( Mi ni press) and angi ot ensi n Ì Ì
( E) hydr al azi ne and met hyl dopa ( Al domet )
Vi ew Answer 1. The answer i s B[ see] . 2. When spi ronoI actone ( AI dact one)
i s used i n a pati ent wi th heart f ai I ure ( HF) , i t works t hrough what pri mar y
mechani sm?
( A) posi t i ve i not r opi c ef f ect
( B) posi t i ve chronot r opi c ef f ect
( C) al dost erone ant agoni sm
( D) negat i ve i not ropi c ef f ect
( E) angi ot ensi n Ì Ì bl ockade
Vi ew Answer 2. The answer i s C[ see] . For questi ons 3- 4: A 60- year -ol d
hyper t ensi ve woman i s cur r ent l y bei ng t reat ed wi t h ni t r ogl ycer i n, car vedi l ol ,
f ur osemi de, ni f edi pi ne (Pr ocar di a) , rami pri l , aspi r i n, and di goxi n. She i s admi t t ed
wi t h a di agnosi s of st age C hear t f ai l ur e.
3. Whi ch agent i s most I i keI y t o be di sconti nued i n thi s pat i ent ?
( A) ni f edi pi ne
( B) car vedi l ol
( C) aspi ri n
( D) di goxi n
( E) f urosemi de
Vi ew Answer 3. The answer i s A[ seeand] . 4. Whi ch of t he f oI I owi ng best
represent s t he goaI s of t herapy f or t hi s pat i ent ?
( A) Tr eat under l yi ng causes such as hyper t ensi on, ci gar et t e smoki ng, l i pi d
di sor der s.
( B) Di scour age t he use of al cohol i nt ake, i l l i ci t drug use, and di et ar y sal t i nt ake.
( C) Cont rol t he met abol i c syndr ome.
( D) Al l of t he above.
( E) None of t he above.
Vi ew Answer 4. The answer i s D[ see] . 5. Because of proven benefi ci aI
ef f ects on cardi ac remodeI i ng, a part i cuI ar group of agent s i s now i ndi cated as
f i rst - I i ne therapy i n HF pat i ent s. Whi ch of t he foI I owi ng i s a representat i ve of
t hi s group of drugs?
( A) hydr ochl orot hi azi de (Hydr oDÌ URÌ L)
( B) l i si nopr i l ( Zest ri l )
( C) l osar t an ( Cozaar )
( D) car vedi l ol ( At acand)
( E) f urosemi de ( Lasi x)
Vi ew Answer 5. The answer i s B[ see6. Whi ch of t he foI I owi ng st at ement s
i s not correct , as i t reI at es t o t he current st atus of heart f ai I ure ( HF) i n t he
Uni t ed St at es?
( A) HF i s t he one car di ovascul ar di sorder t hat i s i ncreasi ng i n i nci dence and
pr eval ence.
( B) Medi cat i on cost s f or t r eat i ng HF i n t he Uni t ed St at es appr oaches $38 bi l l i on.
( C) Pat i ent s wi t h advanced di sease have a 30%-40% ri sk of deat h annual l y.
( D) Cur r ent f i gur es r eveal approxi mat el y 5 mi l l i on peopl e i n t he Uni t ed St at es who
suf f er f r om HF.
( E) Approxi mat el y 500, 000 peopl e each year ar e di agnosed wi t h HF i n t he Uni t ed
St at es.
Vi ew Answer 6. The answer i s B[ seeand] . P. 895


7. I f t reati ng a pat i ent wi t h HF, whi ch of t he foI I owi ng dosages of dopami ne
wouI d be used t o eI i ci t i t s posi t i ve i not ropi c eff ect s?
( A) 2. 0 µg/ kg/ mi n
( B) 5- 10 µg/ kg/ mi n
( C) 10-20 µg/ kg/ mi n
( D) 40 µg/ kg/ mi n
( E) 40 mg/ kg/ mi n
Vi ew Answer 7. The answer i s B[ see] . 8. The use of angi ot ensi n-convert i ng
enzyme i nhi bi t ors ( ACEI s) i n heart f ai I ure ( HF) cent ers around what
pharmacoI ogi c ef fect?
( A) di rect r educt i on i n reni n l evel s wi t h a resul t ant decr ease i n angi ot ensi n Ì Ì and
al dost er one l evel s
( B) i ndi rect r educt i on i n angi ot ensi n Ì Ì and al dost er one l evel s owi ng t o i nhi bi t i on of
angi ot ensi n-conver t i ng enzyme
( C) di rect r educt i on i n al dost er one secr et i on and angi ot ensi n Ì product i on by
i nhi bi t i ng angi ot ensi n-conver t i ng enzyme
( D) i ncr ease i n af t erl oad owi ng t o an i ndi rect decr ease i n angi ot ensi n Ì Ì as wel l as a
decrease i n pr el oad owi ng t o an i ndi rect r educt i on i n al dost er one secr et i on
( E) i nhi bi t i on of t he angi ot ensi n Ì Ì r ecept or , whi ch r esul t s i n r educed angi ot ensi n Ì Ì
l evel s and reduced secret i on of al dost er one
Vi ew Answer 8. The answer i s B[ seeand] . Di recti ons for questi ons 9-12:
The quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed
or compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
9. Whi ch of the foI I owi ng have been shown t o be ef f ect i ve i n t he acut e
management of di gi taI i s t oxi ci t y?
I . choI est yrami ne resi n ( Quest ran)
I I . Fab f ragment ant i body ( Di gi bi nd)
I I I . pot assi um admi ni strat i on
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 9. The answer i s E[see] . 10. Si tuati ons that predi spose a
di gi t aI i s-t reated pat i ent t o t oxi ci t y i ncI ude
I . hypercaI cemi a.
I I . hyperkaI emi a.
I I I . hypermagnesemi a.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 10. The answer i s A[ seeand] . 11. Correct st at ement s about
dobutami ne i ncI ude whi ch of t he f oI I owi ng?
I . Doses of 5-20 µg/ kg/ mi n have been associ ated wi t h a posi ti ve i not ropi c ef f ect
i n t reat i ng t he pati ent wi t h heart f ai I ure ( HF) .
I I . Pat i ents recei vi ng dobut ami ne shouI d be moni t ored f or i ncreases i n
peri pheraI vascuI ar resi st ance.
I I I . Dobut ami ne i s consi dered a nongI ycosi de, nonsympat homi met i c-posi t i ve
i not ropi c agent .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 11. The answer i s A[ see] . 12. Whi ch st atement s accurat eI y
descri be heart ( HF) cI assi f i cat i on st age A?
I . Pati ents have a hi gh ri sk f or HF wi t hout st ruct uraI heart di sease or
sympt oms
I I . Pat i ents need t o recei ve ACEI s or ARBs
I I I . Pat i ent s shouI d be treat ed f or any underI yi ng causes that wouI d be
responsi bI e for causi ng HF
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 12. The answer i s E[see] . P. 896


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì V. H. 2. e] .
The venous di l at i ng pr oper t i es of i sosor bi de di ni t r at e (pr el oad) i n conj unct i on wi t h
t he ar t eri ol ar di l at i ng ef f ect s of hydral azi ne ( af t er l oad) make t hi s combi nat i on
ef f ect i ve i n r educi ng bot h pr el oad and af t er l oad. Recent gui del i nes suggest t hat t he
combi nat i on of t he vasodi l at ors hydr al azi ne and i sosorbi de di ni t r at e shoul d not be
consi dered as i ni t i al t herapy over ACEÌ s but has been shown t o be ef f ect i ve,
par t i cul arl y i n bl ack pat i ent s when added t o st andar d t her apy f or HF.
2. The answer i s C [ see Ì V. G. 8] .
Spi r onol act one was t he f i r st al dost erone ant agoni st avai l abl e f or cl i ni cal use i n t he
Uni t ed St at es. Ì n t he compl et ed RALES t r i al , spi r onol act one, gi ven i n 12. 5- t o 25-mg
dai l y doses t o HF pat i ent s wi t h cl ass Ì V sympt oms who wer e t aki ng ACEÌ s, r educed
t he ri sk of deat h and hospi t al i zat i on. Ì t i s a weak di uret i c but al so wor ks as a di rect
ant agoni st t o t he act i ons of al dost er one, whi ch has demonst rat ed benef i t i n HF
pat i ent s wi t h moderat el y t o sever e sympt oms.
3. The answer i s A [ see Ì V. J. 1 and 2] .
Because t hey have t he pot ent i al t o produce negat i ve i not ropi c ef f ect s, cal ci um
channel bl ocker s such as ni f edi pi ne have been i dent i f i ed as one of t hr ee gr oups of
dr ugs t o avoi d i n most HF pat i ent s. Besi des cal ci um channel bl ockers,
ant i ar r hyt hmi cs, and NSAÌ Ds shoul d be avoi ded i n most HF pat i ent s owi ng t o t hei r
abi l i t y t o i nduce HF sympt oms.
4. The answer i s D [ see Tabl e 42- 4] .
The updat ed cl assi f i cat i on syst em was i nt r oduced wi t h t he newl y est abl i shed
gui del i nes t o demonst rat e t he progressi ve nat ur e of HF and t o provi de a cont i nuum
of goal s and t r eat ment opt i ons as i t progr esses. St age C r epr esent s t he f i r st st age
i n whi ch t he pat i ent present s wi t h st r uct ur al hear t di sease as wel l as cur rent or pr i or
sympt oms of HF. Ì ni t i al goal s f or ear l i er st ages remai n i mpor t ant goal s f or st age C,
but t he " r est r i ct i on i n di et ar y sal t ¨ i s added t o al l of t he pr evi ous goal s.
5. The answer i s B [ see Ì V. D. 1]
ACEÌ s have shown an abi l i t y t o have a posi t i ve ef f ect on car di ac r emodel i ng, whi ch
i s bel i eved t o be t he under l yi ng change t hat r esul t s i n t he i ncr eased st r esses and
pat hol ogi c event s t hat event ual l y cause t he sympt oms associ at ed wi t h HF. Recent
st udi es have shown t he posi t i ve benef i t s f or each of t he ACEÌ s used i n HF pat i ent s,
and t oday t hey r epresent t he i ni t i al t herapy f or HF pat i ent s.
6. The answer i s B [ see Ì . B, C and D] .
The act ual cost s i nvol ved i n t he t reat ment of HF, i ncl udi ng medi cal car e, home
heal t h care, medi cat i on cost s, and hospi t al i zat i on cost s, r epor t ed i n 2005 wer e
approxi mat el y $27. 9 bi l l i on. Medi cat i on cost s al one are a bi t l ess but ar e st i l l
r eport ed t o be more t han $2. 9 bi l l i on annual l y.
7. The answer i s B [ see Ì V. K. 2. b] .
Dopami ne has shown great versat i l i t y i n i t s ef f ect s. At doses of 2- 5 µg/ kg/ mi n, i t
i ncreases r enal bl ood f l ow t hr ough i t s dopami nergi c ef f ect s. At doses of 5- 10
µg/ kg/ mi n, i t i ncr eases car di ac out put t hrough i t s 8- adrenergi c st i mul at i ng ef f ect . At
doses of 10-20 µg/ kg/ mi n, i t i ncreases per i pheral vascul ar r esi st ance t hr ough i t s 8-
adr ener gi c st i mul at i ng ef f ect s. Ther e i s no speci f i c cut of f f or any of t hese ef f ect s,
so cl ose t i t r at i on i s r equi r ed t o provi de f or i ndi vi dual r esponse.
8. The answer i s B [ see Ì V. D. 4 and 5; Fi gure 42-2] .
By di r ect l y i nhi bi t i ng t he angi ot ensi n-conver t i ng enzyme, product i on of angi ot ensi n
Ì Ì i s r educed, as i s angi ot ensi n Ì Ì -medi at ed secret i on of al dost er one f r om t he
adr enal gl and. These ef f ect s are bel i eved t o have a benef i ci al ef f ect on t he
pr event i on of car di ac r emodel i ng, whi ch has been shown t o have a det r i ment al
ef f ect on cardi ac f unct i on.
9. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì V. Ì . 9. c. ( 5)] .
Chol est yr ami ne resi n has been used i n t he acut e si t uat i on t o decrease t he
absor pt i on of di goxi n wi t hi n t he gast roi nt est i nal t r act . Thi s r esul t s i n l ower di goxi n
l evel s i f t he resi n i s admi ni st er ed bef or e al l t he di goxi n has been absor bed.
Pot assi um admi ni st rat i on has been shown t o be ef f ect i ve i n prot ect i ng t he
myocar di um f r om t he t oxi c ef f ect s of di goxi n whi l e t oxi c l evel s ret urn t o nor mal . Fab
f r agment ant i body, t hough expensi ve, has been shown t o be ef f ect i ve i n t he
management of ver y hi gh ser um di goxi n l evel s, by whi ch 40 mg of drug i s abl e t o
bi nd 0. 6 mg of di gi t al i s.
P. 897


10. The answer i s A ( Ì ) [ see Ì V. Ì . 8. a, b and c] .
Cal ci um i ons act synergi st i cal l y wi t h di gi t al i s. Ther ef or e, when hypercal cemi a
occurs, di gi t al i s exer t s an added pharmacol ogi cal ef f ect on t he hear t . Thi s may
pr esent i t sel f as t oxi c arr hyt hmi as, cardi ac st andst i l l , and even deat h. El evat ed
pot assi um l evel s or el evat ed magnesi um l evel s seem t o ai d i n t he pr event i on of
di gi t al i s- i nduced t oxi ci t y. Ther e i s bui l di ng evi dence t hat di gi t al i s pr eparat i ons need
cal ci um i ons t o wor k, and consequent l y l ow cal ci um l evel s may negat e t he
pharmacol ogi cal pot ent i al of di goxi n.
11. The answer i s A ( Ì ) [ see Ì V. K. 3. a] .
Dobut ami ne i n doses of 5- 20 µg/ kg/ mi n i s an i not r opi c agent t hat i s usef ul i n t he
t r eat ment of HF. Dobut ami ne does not have t he ver sat i l i t y t hat dopami ne of f er s,
l acki ng compar abl e ef f ect s on renal bl ood f l ow and peri pher al vascul ar r esi st ance.
Rat her, dobut ami ne has a peri pher al di l at i ng ef f ect t hat of f er s a benef i t t o pat i ent s
who have r educed car di ac out put due t o el evat ed per i pheral r esi st ance.
12. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Tabl e 42-4] .
The r ecent gui del i nes f or t he di agnosi s and management of chroni c hear t f ai l ur e
r ecogni ze f our st ages i n t he pr ogr essi on of HF, and each st age i s associ at ed wi t h
cl i ni cal f i ndi ngs, goal s of t r eat ment , and medi cat i ons t hat shoul d be consi der ed.
St age A r epr esent s pat i ent s who ar e merel y at r i sk f or hear t f ai l ure owi ng t o
under l yi ng ri sk f act or s such as hyper t ensi on, hyper l i pi demi a, and smoki ng. ACEÌ s
ar e recogni zed f or t hei r benef i ci al ef f ect s i n car di ac r emodel i ng and have been
r ecommended as f i r st - l i ne t her apy f or sel ect pat i ent s wi t h st age A hear t f ai l ur e.

43
ThromboemboIic Diseases
James B. Groce I I I
I. Definition.
Venous t hr omboembol i c di sease ( VTED) occurs when one or more of t he el ement s
of Vi rchow' s t ri ad are pr esent , r esul t i ng i n deep venous t hr ombosi s ( DVT) and/ or
pul monar y embol i sm ( PE) .
A. Vascul ar i nj ur y
B. Venous st asi s
C. Hyper coagul abl e st at e ( i . e. , decr eased pr ot ei n C, prot ei n S, or ant i t hrombi n)
II. Incidence.
Ì t i s est i mat ed t hat t he annual i nci dence of VTE event s exceeds 600, 000 and t he
number of VTE- associ at ed deat hs i s 296, 370 annual l y.
III. Risk Factors for VTE
A. Pat i ent speci f i c and t hose associ at ed wi t h medi caI i I I ness and surgi caI
procedures
1. Surger y
2. Tr auma (maj or or l ower ext r emi t y)
3. Ì mmobi l i t y or par esi s
4. Mal i gnancy
5. Cancer t her apy ( hormonal , chemot herapy or radi ot her apy)
6. Pr evi ous VTE
7. Ì ncreasi ng age (> 40 year s of age)
8. Pr egnancy and t he post par t um per i od
9. Est r ogen-cont ai ni ng or al cont r acept i ves or hormone- r epl acement t herapy
10. Sel ect i ve est rogen- recept or modul at or s
11. Acut e medi cal i l l ness
12. Hear t or respi rat or y f ai l ur e
13. Ì nf l ammat or y bowel di sease
14. Nephrot i c syndrome
15. Myel opr ol i f er at i ve di sor der s, i . e. , di seases i n whi ch mal i gnant (cancer) bone
mar row cel l s mul t i pl y and spr ead t o t he bl ood.
16. Par oxysmal noct ur nal hemogl obi nuri a
17. Obesi t y
18. Smoki ng
19. Var i cose vei ns
20. Cent ral venous cat het eri zat i on
21. Ì nher i t ed or acqui red t hr ombophi l i a (e. g. , def i ci ency of ant i t hr ombi n, pr ot ei n C,
or prot ei n S, act i vat ed prot ei n C resi st ance, ant i phosphol i pi d ant i body, l upus
ant i coagul ant )
P. 899


IV. Prevention and Treatment
A. NonpharmacoI ogi c prevent i on. Mechani cal met hods of prophyl axi s ar e
r ecommended, pri mar i l y i n pat i ent s who ar e at hi gh ri sk of bl eedi ng, and may
i ncl ude ext ernaI pneumat i c compressi on, graduat ed compressi on stocki ngs or
venous foot pumps. These devi ces i ncrease venous out f I ow and/ or reduce
st asi s wi t hi n t he l eg vei ns.
B. PharmacoI ogi c prevent i on. VTED can be prevent ed by count er act i ng i ncr eased
bl ood coagul abi l i t y wi t h unf racti onat ed hepari n ( UFH) ( see V. A) , oraI
ant i coaguI ant t herapy wi t h a vi t ami n K antagoni st such as warf ari n (see V. B),
I ow moI ecuI ar wei ght hepari n ( LMWH) (see V. C) , or a synt het i c pent asacchari de
( see V. D) .
V. PharmacoIogic Agents.
New r ecommendat i ons f or t r eat ment of VTED have been promul gat ed t hat suggest a
hi erar chi cal appr oach t o sel ect i on of pharmacol ogi c agent s f or managi ng VTED.
These recommendat i ons ar e l i st ed i n Tabl e 43- 1 and each of t he recommended
pharmacol ogi c agent s are di scussed i n t he f ol l owi ng sect i ons.
Table 43-1. Guidelines for Initial Treatment of Venous Thromboembolic Disease
Clinical situation Recommended treatment
ConIirmed
acute DVT oI
the leg
High suspicion
oI DVT oI the
leg
SC LMWH. IV UFH. or SC UFH anticoagulants while
awaiting the outcome oI diagnostic tests
Selection Treatment options
IV UFH Continuous inIusion
Using weight-based dosing protocol. adiust dosage to
prolong aPTT to a range that corresponds to a plasma
heparin level oI 0.3-0.7 units/mL antiIactor Xa activity
by amidolytic antiIactor Xa assay
II therapeutic levels oI aPTT are not reached despite
large daily doses oI UFH. measure antiIactor Xa levels
Ior dosage guidance
SC UFH An alternative to IV UFH
Initial dose 35.000 units/24 hr. then maintain aPTT
within therapeutic range
SC LMWH Recommended initial treatment once or twice a day
over UFH (as outpatient therapy iI possible. as inpatient
therapy iI necessary)
Routine monitoring with antiIactor Xa levels not
recommended
Further recommendations
Once UFH therapy commences. check aPTT or antiIactor Xa heparin level at
6 hr Ior UFH and adiust to maintain aPTT corresponding to therapeutic
antiIactor Xa heparin level oI 0.3-0.7 units/mL
AntiIactor Xa heparin levels not recommended Ior LMWH therapy
Platelet count should be checked daily while on UFH or LMWM
WarIarin therapy should be commenced on day 1; adiust daily dosing based
on PT/INR
Stop unIractionated heparin or LMWH aIter 5 days overlap with warIarin
(minimally). when INR is stable and ~ 2.0
Anticoagulate (warIarin) Ior 6-12 months (depending on patient and disease
state)
aPTT. activated partial thromboplastin time; INR. international normalized
ratio; IJ. intravenous; LMWH. low molecular weight heparin; PT.
prothrombin time; SC. subcutaneous; UFH. unIractionated heparin.
Adapted with permission Irom Buller HR. Agnelli G. Hull R. et al.
Antithrombotic therapy Ior venous thromboembolic disease. Paper presented
at the Seventh ACCP ConIerence on Antithrombotic and Thrombolytic
Therapy. Chest 2004;126(Suppl):401s-428s.

P. 900


A. Unf ract i onat ed hepari n
1. I ndi cat i ons. Pat i ent s wi t h pr oven VTED may recei ve concomi t ant UFH f or acut e
t r eat ment and war f ar i n t her apy acut el y, f ol l owed by war f ar i n t herapy f or cont i nued
pr event i on of r ecur rence of VTED ( Tabl e 43. 1) , unl ess cont rai ndi cat i ons t o war f ar i n
( e. g. , pregnancy) ar e present .
2. Mechani sm of act i on. The maj or mechani sm by whi ch hepar i n bl ocks coagul at i on
i s by cat al yzi ng t he i nhi bi t i on of t hr ombi n. UFH act s as an ant i coagul ant by
cat al yzi ng t he i nact i vat i on of thrombi n (f actor I I a) , act i vated f act or X (f act or
Xa) , and act i vated fact or I X ( f act or I Xa) by ant i t hrombi n.
3. Pharmacoki net i cs. The mechani sms of hepari n cl earance ar e compl ex.
a. Hepar i n bi nds t o a number of pl asma pr ot ei ns ot her t han ant i t hrombi n, whi ch
compet es wi t h ant i t hr ombi n hepar i n bi ndi ng.
b. UFH i s cl eared by r api d- phase (cel l ul ar ) el i mi nat i on f ol l owed by a mor e gr adual
( r enal ) cl ear ance, whi ch can best be expl ai ned by a combi nat i on of sat urabI e and
nonsat urabI e fi rst - order ki neti c modeI s.
c. When admi ni st ered i n f i xed doses, t he ant i coagul ant response t o UFH var i es
among pat i ent s and wi t hi n t he same pat i ent ( i . e. , i nt er pat i ent and i nt r apat i ent
var i abi l i t y) . Thi s var i abi l i t y i s caused by di f f erences i n pat i ent s' pl asma
concent r at i ons of hepar i n- neut r al i zi ng pr ot ei ns and r at es of hepari n cl earance.
4. Admi ni st rat i on and dosage
a. UFH' s t her apeut i c ef f ect i s hast ened by admi ni st rat i on of a I oadi ng dose, whi ch
may be empi ri caI I y seI ect ed (e. g. , 5000- uni t s bol us gi ven i nt r avenousl y) or
i ndi vi dual i zed by t he pat i ent ' s dosi ng wei ght.
( 1) The wei ght - based appr oach has r esul t ed i n t he use of l oadi ng doses var yi ng
f r om 70 t o 100 uni t s/ kg.
( 2) Ì n some i nst ances, t he i ndi cat i on f or whi ch hepar i n t her apy i s bei ng i ni t i at ed i s
consi dered, wi t h 70 uni t s/ kg bei ng used f or al l t hr ombot i c i ndi cat i ons ot her t han
suspect ed or proved pul monar y embol i sm, f or whi ch up t o 100 uni t s/ kg may be used.
b. Vari abI e approaches t o cont i nuous dosi ng have been empl oyed.
( 1) Empi ri c dosi ng of 1000 uni ts/ hr may be used but may r esul t i n subt her apeut i c
or suprat her apeut i c out comes (i . e. , an act i vat ed par t i al t hrombopl ast i n t i me bel ow
or above t he t ar get ed r ange) .
( 2) Anot her approach t o cont i nuous dosi ng i ncl udes commenci ng wi t h a f i xed dose
( ot her t han t he empi ri c dose of 1000 uni t s/ hr ) . One such appr oach may see an i ni t i al
l oadi ng dose f ol l owed by 32, 000 uni t s/ 24 hr by cont i nuous i nf usi on.
( 3) Yet anot her approach val i dat ed i n t he medi cal and phar maceut i cal l i t er at ur e
uses a wei ght - based dosi ng nomogram f or commenci ng UFH t her apy t hat var i es
bet ween 15 and 25 uni t s/ kg/ hr .
( a) Lower doses are used i ni t i al l y f or most t hrombot i c i ndi cat i ons ot her t han
pul monar y embol i sm.
( b) Pul monar y embol i sm r equi r es mor e aggr essi ve t her apy (i . e. , up t o 25
uni t s/ kg/ hr ) based on t he consi derat i on t hat t he cl ear ance of hepari n may be
i ncreased, t hus necessi t at i ng an i ncreased dose.
( 4) I ni t i aI hepari n wei ght - based dosi ng nomograms and subsequent adj ustment
prot ocoI s have been devel oped t o assi st t he i ni t i al wei ght -based dosi ng ef f ort s.
Such pr ot ocol s shoul d be devel oped f or a speci f i c aPTT r eagent ( Tabl es 43- 2 and
43- 3).
5. Moni tori ng t he ef f ects of UFH. The ant i coagul ant ef f ect s of UFH are usual l y
moni t ored by t he aPTT. The aPTT shoul d be obtai ned at baseI i ne bef ore
commenci ng t her apy and t hen moni t ored 6 hr af t er commenci ng hepari n t her apy.
Subsequent dosi ng adj ust ment s ar e based on t he r esul t s of t hi s and addi t i onal
aPTTs.
a. The aPTT r at i o used t o det ermi ne t herapeut i c ef f ect i s measur ed by di vi di ng t he
obser ved aPTT by t he mean of t he normal l abor at or y cont rol aPTT.
b. Tr adi t i onal l y, i t was t aught t hat f or many aPTT r eagent s, a t her apeut i c ef f ect was
achi eved wi t h an aPTT rat i o of 1. 5- 2. 5.
c. However , because aPTT r eagent s may var y i n t hei r sensi t i vi t y, i t i s i nappropri at e
t o use t he same aPTT rat i o (i . e. , 1. 5- 2. 5) for aI I reagent s. The t herapeut i c r ange
f or each aPTT r eagent shoul d be cal i brat ed t o be equi val ent t o a hepari n l evel of
0. 2- 0. 4 uni t s/ mL by whol e bl ood ( prot ami ne t i t rat i on) or t o an anti f act or Xa I eveI
( i . e. , pI asma hepari n I eveI ) of 0. 3- 0. 7 uni ts/ mL coI I ect ed at t he 6t h hr for UFH.
P. 901


Table 43-2. Weight-Based Nomogram
aPTT Dose
Initial dose 80 units/kg bolus. then 18 units/kg/hr
· 35 sec 80 units/kg bolus. then 4 units/kg/hr
35-45 sec 40 units/kg bolus. then 2 units/kg/hr
46-70 sec
a
No change
71-90 sec Decrease inIusion rate by 2 units/kg/hr
90 sec Hold inIusion 1 hr. then decrease inIusion rate by 3
units/kg/hr
a
This therapeutic range corresponds to antiIactor Xa activity oI 0.3-0.7
units/mL. The therapeutic range at any institution should be established by
correlation with antiIactor Xa levels in the range oI 0.3-0.7 units/mL.
Adapted with permission Irom Hirsch J. Raschke R. Heparin and low-
molecular-weight heparin. Paper presented at the Seventh ACCP ConIerence
on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(Suppl):188s-
203s.

B. OraI ant i coaguI ants-warfari n
1. I ndi cat i ons
a. War f ari n i s pr oven ef f ect i ve i n t he:
( 1) Pr i mar y and secondar y pr event i on of VTED
( 2) Pr event i on of syst emi c ar t eri al embol i sm i n pat i ent s wi t h t i ssue and mechani cal
pr ost het i c hear t val ves or at r i al f i br i l l at i on
( 3) Pr event i on of acut e myocar di al i nf arct i on ( MÌ ) i n pat i ent s wi t h per i pher al ar t eri al
di sease
( 4) Pr event i on of st r oke, r ecur r ent i nf ar ct i on, and deat h i n pat i ent s wi t h acut e MÌ
b. Warf ari n may al so be used i n pat i ent s wi t h val vul ar heart di sease t o prevent
syst emi c ar t eri al embol i sm, al t hough i t s ef f ect i veness has never been demonst rat ed
by a r andomi zed cl i ni cal t r i al .
2. Mechani sm of act i on
a. Or al ant i coagul ant s ( e. g. , war f ari n) ar e vi t ami n K ant agoni st s, pr oduci ng t hei r
ant i coagul ant ef f ect by i nt erf eri ng wi t h t he cycI i c i nterconversi on of vi t ami n K
and i ts 2, 3-epoxi de ( vi t ami n K epoxi de) .
b. Ì nhi bi t i on of t hi s pr ocess l eads t o t he depl et i on of vi t ami n KH2 and resuI t s i n t he
producti on
P. 902

of hemostat i caI I y def ect i ve, vi t ami n K- dependent coaguI ant protei ns or cI ot ti ng
f act ors ( prothrombi n or f act ors I I , VI I , I X, and X) .
Table 43-3. Heparin Dosage Adjustment Protocola
Patient's
aPTT (sec)
b

Repeat Bolus
Dose (units)
Stop
Infusion
(min)
Change Rate of
Infusion (mL/hr)
c

[units/24 hr]
Timing of Next
aPPT
· 50 5000 0 ¹3 |2880| 6 hr
50-59 0 0 ¹3 |2880| 6 hr
60-85
d
0 0 0 Next
morning
86-95 0 0 -2 |-1920| Next
morning
96-120 0 30 -2 |-1920| 6 hr
~ 120 0 60 -4 |-3840| 6 hr
aPTT. activated partial thromboplastin time.
a
Starting dose oI 5000 units intravenous IV bolus Iollowed by 32.000
units/24 hr as a continuous inIusion. First aPTT perIormed 6 hr aIter the
bolus iniection; dosage adiustments are made according to protocol and the
aPTT is repeated as indicated in the Iar-right column.

b
The normal range Ior aPTT with Dade Actin FS reagent is 27-35 sec; the
range may vary. depending on the sensitivity oI the reagent.

c
Concentration oI heparin equal to 40 units/mL.

d
A therapeutic range oI 60-85 sec is equivalent to a heparin level oI 0.2-0.4
units/mL by whole blood protamine titration or 0.3-0.7 units/mL as a plasma
antiIactor Xa level. The therapeutic range varies with the responsiveness oI
the aPTT reagent to heparin.
Adapted with permission Irom Hirsch J. Raschke R. Heparin and low-
molecular-weight heparin. Paper presented at the Seventh ACCP ConIerence
on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(Suppl):188s-
203s.

c. These vi t ami n K-dependent coagul ant prot ei ns or cl ot t i ng f act ors ( f act or s VÌ Ì , Ì X,
X, and Ì Ì , r espect i vel y) decl i ne over 6- 96 hr.
3. Pharmacoki net i cs
a. War f ari n i s a racemi c mi xture of r oughl y equal amount s of t wo opt i cal l y act i ve
i somers: t he R and S forms.
b. Warf ari n i s r api dl y absor bed f r om t he gast r oi nt est i nal t r act and reaches maxi mal
bl ood concent r at i ons i n heal t hy vol unt eers i n 90 mi n.
c. Dose response t o war f ar i n i s i nf l uenced by:
( 1) Phar macoki net i c f act or s (i . e. , di f f er ences i n absorpt i on and met abol i c cl ear ance)
( 2) Phar macodynami c f act ors (i . e. , di f f er ences i n t he hemost at i c r esponse t o gi ven
concent r at i ons of war f ar i n)
( 3) Techni cal f act or s÷f or exampl e, i naccur aci es i n pr ot hrombi n t i me ( PT) and
i nt er nat i onal nor mal i zed r at i o ( Ì NR) t est i ng and repor t i ng
( 4) Pat i ent -speci f i c f act or s÷f or exampl e, di et ( i ncr eased i nt ake of gr een, l eaf y
veget abl es) , poor pat i ent compl i ance (mi ssed doses, sel f - medi cat i on, al cohol
consumpt i on) , poor communi cat i on bet ween pat i ent and physi ci an ( undi scl osed use
of drugs t hat may i nt er act wi t h war f ar i n) ( Tabl e 43- 4)
4. Admi ni st rat i on and dosage
a. Warf ari n, a coumar i n compound, i s t he most wi del y used or al ant i coagul ant i n
Nor t h Ameri ca. Al t hough i t i s pr i mari l y admi ni stered oraI I y, an i nj ect abl e
pr epar at i on i s avai l abl e i n t he Uni t ed St at es.
b. Commence or al ant i coagul ant t her apy wi t h t he ant i ci pated dai I y mai nt enance
dose of warfari n, whi ch can be var i abl e.
Table 43-4. Factors that May Potentiate or Inhibit Warfarin Effects
Factor Potentiate Anticoagulant Effect
Inhibit Anticoagulant
Effect
Drugs Phenylbutazone Cholestyramine
Metronidazole Barbiturates
SulIinpyrazone RiIampin
Trimethoprim-sulIamethoxazole GriseoIulvin
DisulIiram Carbamazepine
Amiodarone
Erythromycin
Anabolic steroids
CloIibrate
Cimetidine
Omeprazole
Thyroxine
Ketoconazole
Isoniazid
Fluconazole
Piroxicam
TamoxiIen
Quinidine
Vitamin E (large doses)
Phenytoin
Penicillin
Other Low vitamin K intake High vitamin K intake
Reduced vitamin K absorption Alcohol (acute use)
Liver disease

Hypermetabolic states (e.g..
thyrotoxicosis)

Alcohol (chronic use)
Adapted with permission Irom Ansell J. Hirsh J. Poller L. et al. The
pharmacology and management oI the vitamin K antagonists. Paper
presented at the Seventh ACCP ConIerence on Antithrombotic and
Thrombolytic Therapy. Chest 2004;126:204S-233S.

P. 903


Table 43-5. Practical Oral Anticoagulation Dosing
Day Rapid Anticoagulation Anticoagulation
a

1 5-10 mg 5 mg
2 5-10 mg 5 mg
3 2.5-7.5 mg (adiust based on
INR)
b

5 mg (adiust based on INR)
b

a
Rapid anticoagulation is not required or there is a risk oI bleeding.

b
Adiust dosage based on INR until the INR is stable and therapeutic.
Adapted with permission Irom Ansell J. Hirsh J. Poller L. et al. The
pharmacology and management oI the vitamin K antagonists. Paper
presented at the Seventh ACCP ConIerence on Antithrombotic and
Thrombolytic Therapy. Chest 2004;126: 204S-233S.

c. The i ni t i aI dose of warf ari n therapy can be fI exi bI e. ( Tabl e 43- 5)
( 1) Pat i ent -speci f i c par amet er s used t o det er mi ne t he i ni t i al dose of war f ar i n i ncl ude
t he pat i ent ' s wei ght (e. g. , obesi t y, concur rent use of i nt er act i ng dr ugs known t o
i nhi bi t t he ant i coagul ant ef f ect of war f ari n, and t he desi red r api d ant i coagul ant
ef f ect ) .
( 2) Based on t hese pat i ent - speci f i c paramet ers, some cl i ni ci ans may use a l ar ger
i ni t i al dose of war f ar i n (e. g. , 7. 5- 10 mg) , whi ch shoul d not be mi sconst rued as a
l oadi ng dose.
d. The i ni t i al dose of war f ar i n shoul d be overI apped wi t h UFH, LMWH or a
pent asacchari de f or 5- 7 days ( Tabl e 43- 1).
e. The durat i on of warfari n t herapy depends on each pat i ent ' s i ndi cat i on( s) f or use
( Tabl e 43- 6).
f . ReversaI of warfari n ef f ects may be necessary owi ng t o an el evat ed Ì NR or
compl i cat i ons associ at ed wi t h oral ant i coagul ant t herapy ( Tabl e 43- 7).
5. Moni tori ng warf ari n therapy. PT and Ì NR moni t ori ng ar e usual l y per f ormed dai l y
on commenci ng oral ant i coagul ant t her apy ( e. g. , war f ar i n) , unt i l such t i me t hat t he
Ì NR has been f ound t o be t her apeut i c.
a. Laborat or y moni t or i ng i s perf ormed by measuri ng t he PT f or cal cul at i on of t he
Ì NR.
( 1) The PT i s responsi ve t o depressi on of t hree of t he f our vi t ami n K-dependent
pr ocoagul ant cI ot t i ng f act ors (prot hrombi n or fact ors I I , VI I , and X) .
( 2) The common commerci al PT r eagent s var y mar kedl y i n t hei r r esponsi veness t o
coumari n-i nduced reduct i on i n cl ot t i ng f act or s; t her ef or e, PT r esul t s r eport ed usi ng
di f f er ent r eagent s are not i nt erchangeabl e among l abor at or i es.
b. The probl em of var i abi l i t y i n responsi veness of PT r eagent s has been over come
by t he i nt r oduct i on of a st andar di zed t est known as t he I NR.
( 1) The Ì NR i s equal t o:

Table 43-6. Duration of Warfarin Therapya
Duration Indications
3-6 months First event with reversible
b
or time-limited risk Iactor
> 6 months Idiopathic venous thromboembolism. Iirst event
12 months to
liIetime
First event
c
with cancer (until resolved). anticardiolipin
antibody. antithrombin deIiciency
Recurrent event. idiopathic or with throbophilia
a
See Table 43-4 Ior Iactors that may inIluence warIarin eIIects. All
recommendations are subiect to modiIication by individual characteristics.
including patient preIerence. age. comorbidity. and likelihood oI recurrence.

b
Reversible or time-limited risk Iactors: surgery. trauma. immobilization.
estrogen use.

c
Proper duration oI therapy is unclear in Iirst event with homozygous Iactor
V Leiden. homocystinemia. deIiciency oI protein C or S or multiple
thrombophilias and in recurrent events with reversible risk Iactors.
Adapted with permission Irom Buller HR. Agnelli G. Hull R. et al.
Antithrombotic therapy Ior venous thromboembolic disease. Paper presented
at the Seventh ACCP ConIerence on Antithrombotic and Thrombolytic
Therapy. Chest 2004;126(Suppl):401s-28s.

P. 904


Table 43-7. Guidelines for Reversal of Warfarin Effects
Clinical Situation Guidelines
INR ~ therapeutic range but ·
5.0; no clinically signiIicant
bleeding. rapid reversal not
indicated Ior reasons oI
surgical intervention

INR signiIicantly above
therapeutic range
Lower the dose or omit the next dose;
resume warIarin therapy at a lower dose
when the INR approaches desired range
INR minimally above
therapeutic range
Dose reduction may not be necessary
INR ~ 5.0 but · 9.0; no
clinically signiIicant bleeding

No additional risk Iactors Ior
bleeding
Omit the next dose or two oI warIarin;
monitor INR more Irequently; resume
warIarin therapy at a lower does when
the INR is in therapeutic range
Increased risk oI bleeding Omit the next dose oI warIarin; give
vitamin K1 (1.0-2.5 mg orally)
More rapid reversal needed
beIore urgent surgery or dental
extraction
Give vitamin K
1
(2-4 mg orally); closely
monitor INR; repeat dose oI vitamin K
1

iI INR not substantially reduced by 24-
48 hr
INR ~ 9.0; no clinically
signiIicant bleeding
Give vitamin K
1
(3-5 mg orally); closely
monitor INR; repeat dose oI vitamin K
1

iI INR not substantially reduced by 24-
48 hr
INR ~ 20.0; serious bleeding.
maior warIarin overdose
requiring very rapid reversal oI
anticoagulant eIIect
Give vitamin K
1
(10 mg by slow
intravenous inIusion) with Iresh Irozen
plasma transIusion or prothrombin
complex concentrate. depending on
urgency; vitamin K
1
iniections may be
needed every 12 hr
LiIe-threatening bleeding.
serious warIarin overdose
Give prothrombin complex concentrate
with vitamin K
1
(10 mg by slow
intravenous inIusion); repeat iI
necessary. depending on INR
Continuing warIarin therapy
indicated aIter high doses oI
vitamin K
1

Give heparin until the eIIects oI vitamin
K
1
have been reversed and patient is
responsive to warIarin
INR. international normalized ratio.
Adapted with permission Irom Ansell J. Hirsh J. Poller L. et al. The
pharmacology and management oI the vitamin K antagonists. Paper
presented at the Seventh ACCP ConIerence on Antithrombotic and
Thrombolytic Therapy. Chest 2004;126:204S-233S.

wher e Ì SÌ (i nt er nat i onal sensi t i vi t y i ndex) i s a measure of t he responsi veness of a
gi ven t hr ombopl ast i n t o reduct i on of t he vi t ami n K- dependent coagul at i on f act or s.
The I ower t he I SI , t he more responsi ve t he reagent and t he cl oser t he der i ved Ì NR
wi l l be t o t he obser ved PT r at i o.
( 2) Gui del i nes of t he Amer i can Col l ege of Chest Physi ci ans ( ACCP) Conf er ence on
Ant i t hr ombot i c and Thr ombol yt i c Ther apy r ecommend t wo l evel s of t her apeut i c
i nt ensi t y: a l ess- i nt ense r ange cor r espondi ng t o an Ì NR of 2. 0-3. 0, and a mor e-
i nt ense r ange cor r espondi ng t o an Ì NR of 2. 5- 3. 5. The r ange cor r esponds t o t he
i ndi cat i on ( Tabl e 43-8) .
( 3) Once t he desi red t her apeut i c Ì NR has been achi eved f or 2 consecut i ve days,
( e. g. , f or concomi t ant hepar i n pl us war f ar i n overl ap t her apy) f ol l ow- up Ì NR
moni t ori ng can be perf ormed accor di ng t o t he f ol l owi ng prot ocol :
( a) Week 1: moni t or Ì NR t wo or t hree t i mes
( b) Week 2: moni t or Ì NR t wo t i mes
( c) Weeks 3- 6: moni t or Ì NR once a week
( d) Weeks 7- 14: moni t or Ì NR once ever y 2 weeks
( e) Week 15 t o end of t her apy: moni t or Ì NR once ever y 4 weeks (i f Ì NR dose
r esponsi veness remai ns st abl e; i f dose adj ust ment i s necessar y, a more f r equent
moni t ori ng schedul e i s empl oyed unt i l st abl e dose r esponsi veness i s achi eved)
P. 905


Table 43-8. Recommended Therapeutic Goal and Range for Oral Anticoagulant
Therapy
INR
Indication Goal Range
Prophylaxis oI venous thrombosis (high-risk
surgery)
2.5 2.0-3.0
Treatment oI venous thrombosis 2.5 2.0-3.0
Treatment oI pulmonary embolism 2.5 2.0-3.0
Prevention oI systemic embolism 2.5 2.0-3.0
Tissue heart valves 2.5 2.0-3.0
Anterior myocardial inIarction (to prevent
systemic embolism)
2.5 2.0-3.0
Anterior myocardial inIarction (to prevent
recurrent inIarction)
3.0 2.5-3.5
Valvular heart disease 2.5 2.0-3.0
Atrial Iibrillation 2.5 2.0-3.0
Mechanical prosthetic valves (high risk) 3.0 2.5-3.5
Adapted with permission Irom Ansell J. Hirsh J. Poller L. et al. The
pharmacology and management oI the vitamin K antagonists. Paper
presented at the Seventh ACCP ConIerence on Antithrombotic and
Thrombolytic Therapy. Chest 2004;126:204S-233S.

c. Upon commenci ng oral ant i coagul ant t her apy, proI ongat i on of t he PT/ I NR does
not occur unt i l depl et i on of t he vi t ami n K-dependent pr ocoagul ant cl ot t i ng f act ors
occurs. Thi s del ay i s vari abI e over 2-4 days. Dur i ng t hi s del ay, i f act i ve venous
t hr ombosi s i s pr esent , ei t her UFH or LMWH i s concomi t ant l y commenced t o
adequat el y ant i coagul at e t he pat i ent whi l e awai t i ng t he t herapeut i c ef f ect of
war f ar i n.
C. Low moI ecuI ar wei ght hepari n
1. I ndi cat i ons
a. LMWH i ndi cat i ons vary by manuf act ur er .
b. Each of t he LMWHs have been eval uat ed i n a l ar ge number of randomi zed cl i ni cal
t r i al s and have been pr oven t o be saf e and ef f i caci ous f or t he prevent i on and
t reat ment of venous t hromboemboI i sm.
c. To dat e, di f f erent LMWHs have been eval uat ed f or t hei r rol e i n:
( 1) Pr event i on of venous t hr ombosi s
( 2) Tr eat ment of VTED
( 3) Management of unst abl e angi na pect or i s/ non-Q wave MÌ
2. Chemi st r y. LMWHs are f r agment s of st andard commer ci al - gr ade hepar i n
pr oduced by ei t her chemi cal or enzymat i c depol ymer i zat i on. LMWHs ar e
approxi mat el y one t hi r d t he si ze of hepar i n. Li ke hepari n, whi ch has a mean
moI ecuI ar wei ght of 15, 000 Da ( r ange 3000-30, 000 Da), LMWHs ar e
het erogeneous i n si ze wi t h a mean moI ecuI ar wei ght of 4000-5000 Da ( range
1000- 10, 000 Da).
3. Mechani sm of act i on
a. LMWHs achi eve t hei r maj or ant i coaguI ant ef fect by bi ndi ng t o anti t hrombi n
t hr ough a uni que pent asacchari de sequence t hat enhances t he abi l i t y of
ant i t hr ombi n t o i nacti vat e f act or I I a ( thrombi n) and fact or Xa.
( 1) Hepar i n and LMWHs cat aI yze t he i nacti vat i on of fact or I I a ( t hrombi n) by
bi ndi ng t o anti t hrombi n t hrough t he uni que pent asacchari de sequence and t o
t hrombi n t o f orm a ternar y compI ex. A mi ni mum chai n l engt h of 18 sacchari des
( i ncl udi ng t he pent asacchar i de sequence) i s requi r ed f or t ernar y compl ex f or mat i on.
( a) Vi rt ual l y al l hepar i n mol ecul es cont ai n at l east 18 sacchar i de uni t s.
( b) Onl y 20%-50% of t he di f f er ent LMWHs cont ai n f r agment s wi t h 18 or mor e
sacchar i de uni t s.
( c) Ther ef or e, compared wi th hepari n, whi ch has an ant i f actor Xa t o ant i f actor
I I a bi ndi ng af f i ni t y rat i o of approxi mat eI y 1:1, t he var i ous commerci al LMWHs
have an ant i f actor Xa to ant i f actor I I a bi ndi ng af f i ni t y rat i o var yi ng f rom 2:1 up
t o 4:1, dependi ng on t hei r mol ecul ar si ze di st r i but i on ( Tabl e 43- 9) .
( 2) Ì n cont rast , i nact i vat i on of f act or Xa by ant i t hrombi n does not r equi re bi ndi ng of
t he hepar i n mol ecul es t o t he cl ot t i ng enzyme. Ther ef or e, i nact i vat i on of f act or Xa i s
P. 906

achi eved by smal l mol ecul ar wei ght hepar i n f ragment s pr ovi ded t hat t hey cont ai n
t he hi gh- af f i ni t y pent asacchar i de.
Table 43-9. Pharmacokinetic and Pharmacodynamic Parameters of Different
Low Molecular Weight Heparins (LMWHs)
LMWH Brand Name
Average
Molecular
Weight Bioavailability
Half-
Life
Xa:IIa
Binding-
Affinity
Ratio
Dalteparin Fragmin 6000 Da 87° 3-5
hr
2.7:1
Enoxaparin Lovenox 4500 Da 92° 4.5
hr
3.8:1
Tinzaparin Innohep 6500 Da 87° 3.9
hr
2.8:1

b. The ant i t hrombot i c and hemorrhagi c ef fect s of hepar i n have been compared
wi t h LMWHs i n a var i et y of experi mentaI ani maI modeI s.
( 1) When compar ed on a gr avi met ri c basi s, LMWHs are sai d t o cause decreased
pot ent i al f or hemorrhagi c epi sodes.
( 2) These di f f er ences i n t he rel at i ve ant i t hrombot i c t o hemor r hagi c rat i os among
t hese pol ysacchar i des coul d be expl ai ned by t he obser vat i on t hat LMWHs have I ess
i nhi bi t or y ef f ect s on pI at eI et f unct i on and vascul ar permeabi l i t y.
4. Pharmacoki net i cs. The pl asma r ecoveri es and phar macoki net i cs of LMWHs di f f er
f r om hepari n because of di f f er ences i n t he bi ndi ng pr opert i es of t he t wo sul f at ed
pol ysacchar i des t o pl asma pr ot ei ns and endot hel i al cel l s.
a. LMWHs bi nd much l ess avi dl y t o hepari n-bi ndi ng prot ei ns t han hepari n, a
pr oper t y t hat cont r i but es t o t he superi or bi oavai l abi l i t y of LMWHs at l ow doses and
t hei r mor e pr edi ct abl e ant i coagul at i on ef f ect .
b. LMWHs do not bi nd t o endot hel i al cel l s i n cul t ur e, a proper t y t hat coul d account
f or t hei r l onger pl asma hal f -l i f e and t hei r dose- i ndependent cl earance. Pri nci pal l y,
t he renal rout e cl ear s LMWHs; t her ef or e, t he bi ol ogi c hal f -l i f e of LMWHs i s
i ncreased i n pat i ent s wi t h r enal f ai l ure.
5. Admi ni st rat i on and dosage
a. Dosi ng of LMWHs i s di sease-st ate and product speci fi c; di f f erent doses are
admi ni st er ed based on t he i ndi cat i on f or use and t he manuf act ur er of t he speci f i c
LMWH. Tabl e 43- 10 shows manuf act urer ' s suggest ed, U. S. Food and Dr ug
Admi ni st rat i on (FDA) appr oved dosi ng f or speci f i c i ndi cat i ons.
D. Synt het i c pent asacchari de
1. I ndi cat i ons
a. Synt het i c pentasacchari de [ f ondapari nux ( Ar i xt r a) ] i s i ndi cat ed f or :
( 1) Thr ombopr ophyl axi s agai nst DVT/ PE af t er
( a) Hi p f r act ur e surger y
( b) Hi p f r act ur e surger y; ext ended pr ophyl axi s
( c) Knee- repl acement sur ger y
( d) Hi p- r epl acement surger y
( e) Abdomi nal surger y
( 2) Tr eat ment of
( a) Acut e DVT
( b) Acut e PE
2. Chemi st r y. Synt het i c pent asacchar i de i s a sel ect i ve f act or Xa i nhi bi tor. The
mol ecul ar wei ght of t he synt het i c pent asacchar i de pr oduct i s 1728 Da.
3. Mechani sm of act i on
a. The ant i t hrombot i c act i vi t y of f ondapar i nux i s t he r esul t of ant i t hrombi n- medi at ed
sel ect i ve i nhi bi t i on of f act or Xa. Neut ral i zat i on of f act or Xa i nt er r upt s t he bl ood
coagul at i on cascade and t hus i nhi bi t s t hrombi n f or mat i on and t hr ombus
devel opment .
b. Fondapari nux does not i nact i vat e t hrombi n ( act i vat ed f act or Ì Ì ) and has no known
ef f ect on pl at el et f unct i on.
4. Pharmacoki net i cs
a. Af t er subcut aneous admi ni st r at i on, t he dr ug i s compl et el y bi oavai l abl e, and
st eady- st at e peak pl asma l evel s ar e achi eved i n approxi mat el y 3 hr af t er
admi ni st rat i on of t he dose.
P. 907


Table 43-10. FDA-Approved Dosing of Low Molecular Weight Heparin
(LMWH) Based on Disease State
Approved
Labeling and
Dosing

Dalteparin Enoxaparin Tinzaparin
Hip-
replacement
surgery
prophylaxis
5000 units q.d.
Ior 5-10 days
30 mg every 12 hr.
or 40 mg q.d. Ior 7-
10 days
n/a
Extended hip-
replacement
prophylaxis
n/a 40 mg q.d. Ior 3
weeks
n/a
Knee-
replacement
surgery
prophylaxis
n/a 30 mg every 12 hr
Ior 7-10 days
n/a
General 2500 units q.d. 40 mg q.d. Ior 7-10 n/a
surgery
prophylaxis
or 5000 units
qd (high risk)
Ior 5-10 days
days
Acute
medically ill
prophylaxis
5000 units q.d.
Ior 12-14 days
40 mg q.d. Ior 6-14
days
n/a
Treatment oI
DVT with or
without PE
n/a As a bridge to
warIarin until stable
INR: 1 mg/kg every
12 h (outpatient
treatment permitted)
or 1.5 mg/kg every
24 h (inpatient
only)
As a bridge
to warIarin
until stable
INR: 175
units/kg
every 24 hr
Unstable
angina and
NSTEMI
120 units/kg
every 12 hr Ior
5-8 days plus
aspirin
indeIinitely
1 mg/kg every 12 hr
Ior 2-8 days plus
aspirin indeIinitely
n/a
DJT. deep-vein thrombosis; INR. international normalized ratio; n/a. not
applicable; NSTEMI. non-ST-segment elevated myocardial inIarction; PE.
pulmonary embolism.
Adapted with permission Irom Rihn T. Vanscoy GJ. Low molecular weight
heparin: Formulary drug class reviews. Pharm Ther 2001:26;486-492.

b. The el i mi nat i on hal f -l i f e i s 17- 21 hr, enabl i ng once- dai l y dosi ng.
c. The dr ug does not seem t o be met abol i zed and appear s i n t he uri ne i n act i ve
f or m and i s renal l y el i mi nat ed.
5. Admi ni st rat i on and dosage
a. Fondapari nux must not be admi ni st ered i nt ramuscul ar l y.
b. For prophyI axi s agai nst VTE, t he dr ug shoul d not be used i n pat i ent s wi t h body
wei ght < 50 kg because t he i nci dence of maj or bl eedi ng was f ound t o doubl e i n t hi s
pat i ent popul at i on duri ng cl i ni cal t ri al s.
c. For prophyI axi s agai nst VTE a usual dose of 2. 5 mg subcutaneousI y once
dai I y f or 5- 9 days i s r ecommended f or aI I prophyI axi s i ndi cat i ons. The i ni t i al
dose shoul d be st ar t ed 6- 8 hr af t er sur ger y when hemost asi s i s est abl i shed.
d. For t reatment of est abl i shed VTE, admi ni st er a once-dai l y subcut aneous dose as
f ol l ows:
( 1) Pat i ent s wi t h body wei ght bet ween 50 and 100 kg: 7. 5 mg
( 2) Pat i ent s wi t h body wei ght < 50 kg: 5 mg
( 2) Pat i ent s wi t h body wei ght > 100 kg: 10 mg
6. Caut i ons
a. Cont rai ndi cat i ons
( 1) Severe r enal i mpai rment
( 2) Pat i ent s wei ghi ng < 50 kg when used f or pr ophyl axi s
( 3) Pat i ent s wi t h act i ve maj or bl eedi ng
( 4) Bact er i al endocar di t i s
( 5) Thr ombocyt openi a associ at ed wi t h posi t i ve i n vi t r o t est f or ant i pl at el et ant i body
i n t he pr esence of f ondapar i nux
( 6) Known hypersensi t i vi t y t o f ondapari nux
P. 908


b. Precaut i ons
( 1) Condi t i ons or pr ocedur es t hat may enhance t he ri sk of sever e bl eedi ng ( e. g. ,
t r auma, hemophi l i a, gast r oi nt est i nal ul cerat i on, concur r ent use of ant i pl at el et
agent s, hi st or y of cer ebrovascul ar hemor r hage, sever e uncont rol l ed hypert ensi on)
( 2) Renal i mpai r ment
( 3) Hepar i n- i nduced t hr ombocyt openi a
( 4) Neur axi al anest hesi a and i ndwel l i ng epi dural cat het er use
( 5) El derl y pat i ent s
( 6) Pr egnancy cat egor y B and l act at i ng (t he dr ug i s excr et ed i nt o br east mi l k)
( 7) Pr ot ami ne i s i nef fecti ve as an ant i dot e
P. 909


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 4: Each of t he quest i ons, st at ement s, or i ncompl et e
st at ement s i n t hi s sect i on can be cor rect l y answer ed or compl et ed by one of t he
suggest ed answer s or phr ases. Choose t he best answer .
1. A 67- year- oI d man who wei ghs 100 kg ( 212 I b) and i s 60 i n. t aI I present s t o
hi s physi ci an af t er a t ransatI anti c fI i ght compI ai ni ng of pai n and sweI I i ng of
hi s ri ght I ower ext remi ty. The pat i ent had t ot aI knee art hropI ast y 2 weeks
bef ore hi s t raveI . Hi s medi caI hi st or y reveaI s that he has an ej ecti on fract i on of
15%, he i s i n remi ssi on f or non- Hodgki n I ymphoma, and he has had a previ ous
myocardi aI i nf arcti on. Hi s mot her, f at her, and si ster are dead as a resuI t of
st roke, puI monar y emboI i sm, and chi I dbi rt h, respect i veI y. Gi ven t hi s pat i ent ' s
hi st or y, he i s most I i keI y suf f eri ng f rom whi ch of t he f oI I owi ng?
( A) r upt ur ed Baker cyst
( B) deep venous t hr ombosi s of t he l ower ext r emi t y
( C) t or n medi al meni scus
( D) sept i c ar t hri t i s
Vi ew Answer 1. The answer i s B[ seeand] . 2. ProphyI axi s agai nst venous
t hromboemboI i c di sease ( VTED) may i ncI ude
( A) nonphar macol ogi cal pr ophyl axi s.
( B) phar macol ogi cal prophyl axi s.
( C) nonphar macol ogi cal and phar macol ogi cal prophyl axi s.
( D) nei t her nonpharmacol ogi cal and phar macol ogi cal pr ophyl axi s
Vi ew Answer 2. The answer i s C[ seeand] . 3. Unfract i onat ed hepari n bi nds
t o anti t hrombi n I I I and i nacti vat es cI ott i ng f act or( s)
( A) Xa
( B) Ì Xa
( C) Ì Ì a
( D) Al l of t he above
( E) None of t he above
Vi ew Answer 3. The answer i s D[ see] . 4. I ni ti at i on of unf ract i onat ed
hepari n t herapy f or t he pat i ent descri bed i n quest i on 1 wouI d best be achi eved
wi t h
( A) 5000 U l oadi ng dose f ol l owed by 1000 U/ hr
( B) 5000 U l oadi ng dose f ol l owed by 1800 U/ hr
( C) 8000 U l oadi ng dose f ol l owed by 1800 U/ hr
( D) 1000 U l oadi ng dose f ol l owed by 1000 U/ hr
Vi ew Answer 4. The answer i s C[ see] . Di recti ons f or questi ons 5-11: The
quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y answer ed or
compl et ed by one or more of t he suggest ed answer s. Choose t he answer , A- E.
Di rect i ons for quest i ons 5- 10: Upon conf i r mat i on of di agnosi s, t he at t endi ng
physi ci an asks you, t he pharmaci st , t o commence l ow mol ecul ar wei ght hepari n
t her apy f or t he pat i ent descr i bed i n quest i on 1 above. The f ol l owi ng quest i ons
per t ai n t o your pharmaceut i cal car e f or t hi s pat i ent .
5. When choosi ng an FDA- approved I ow moI ecuI ar wei ght hepari n to treat t hi s
pat i ent , you wouI d admi ni ster
I . enoxapari n 1 mg/ kg/ dose subcut aneousI y q 12 hr.
I I . enoxapari n 1. 5 mg/ kg/ dose subcut aneousI y q 24 hr .
I I I . ti nzapari n 175 I U/ kg/ dose subcutaneousI y q 24 hr .
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 5. The answer i s E(I , I I , I I I ) [ see] . 6. Whi ch of t he f oI I owi ng
t est s are used t o moni tor hepari n ant i thrombot i c t herapy?
I . i nternati onaI normaI i zed rat i o
I I . act i vat ed parti aI t hrombopI ast i n ti me
I I I . hepari n assay
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 6. The answer i s D( I I , I I I ) [ seeand] . P. 910


7. A pat i ent t o be commenced on oraI ant i coaguI ant t herapy f or DVT wouI d be
t reat ed wi t h:
I . oraI anti coaguI ant t herapy wi t h warfari n for a goaI i nt ernat i onaI normaI i zed
rat i o ( I NR) of 2- 3.
I I . oraI ant i coaguI ant t herapy wi t h warfari n for a goaI I NR of 2. 5- 3. 5.
I I I . oraI ant i coaguI ant therapy wi t h aspi ri n for a goaI I NR of 2-3.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 7. The answer i s A( I ) [ seeand] . 8. A pat i ent on oraI
ant i coaguI ant t herapy i s commenced on suI f amet hoxazoI e- t ri met hopri m,
doubI e- st rengt h twi ce dai I y. One may expect to see t he i nternati onaI
normaI i zed rat i o
I . i ncrease.
I I . decrease.
I I I . remai n unchanged.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 8. The answer i s A( I ) [ see] . 9. I f a pat i ent has an i nt ernat i onaI
normaI i zed rat i o (I NR) > 20 and acti ve bI eedi ng t hat i s cI i ni caI I y si gni f i cant
( i . e. , hemat uri a) , t he pharmaci st shouI d
I . hoI d t he drug t herapy.
I I . admi ni ster vi t ami n K.
I I I . admi ni ster f resh f rozen pI asma.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 9. The answer i s E(I , I I , I I I ) [ see] . 10. Compared t o
unf racti onat ed hepari n, I ow moI ecuI ar wei ght hepari ns have
I . preferenti aI bi ndi ng af f i ni t y t o f act or Xa reI ati ve t o I I a ( t hrombi n) .
I I . short er haI f -I i ves.
I I I . dose- dependent renaI cI earance.
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 10. The answer i s A( I ) [ see] . i ndependent11. An 87- year- oI d
woman who wei ghs 49. 0 kg ( 108 I b) and i s 66 i n t aI I has sust ai ned a hi p
f ract ure requi ri ng open reduct i on wi t h i nt ernaI f i xati on ( ORI F) surger y. She has
a document ed serum creat i ne vaI ue recorded i n t he chart and i n t he I aborator y
resuI ts as 4. 3 mg%. The ort hopedi c surgeon asks you, t he pharmaci st , about
t he appropri at e f ondapari nux dosi ng f or t hi s pat i ent t o prevent venous
t hromboemboI i sm af t er t he surger y. Whi ch of the f oI I owi ng are
cont rai ndi cat i ons t o the use of f ondapari nux i n t hi s pati ent?
I . pati ent wei ghs < 50 kg
I I . pat i ent has severe renaI i mpai rment
I I I . pat i ent i s eI derI y
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 11. The answer i s C( I , I I ) [ seeand] . precaut i onP. 911


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see Ì . A, B and C] .
The pat i ent has t he cl assi c t ri ad of r i sk f act ors pr edi sposi ng hi m t o DVT i nj ur y
( r ecent knee ar t hr opl ast y) , venous st asi s ( t r ansat l ant i c t ravel ) , and hypercoagul abl e
st at e ( f ami l y hi st or y of venous t hr omboembol i c di sease). The pat i ent has ot her r i sk
f act or s as wel l , i ncl udi ng age > 40, recent sur gery, oncol ogi c di sease ( t hough i n
r emi ssi on) , congest i ve hear t f ai l ure, pr evi ous myocardi al i nf ar ct i on wi t h l ow ej ect i on
f r act i on, and obesi t y.
2. The answer i s C [ see Ì V. A and B] .
Pr ophyl axi s of VTED can i nvol ve a nonphar macol ogi cal appr oach, a pharmacol ogi cal
approach, or a combi nat i on of nonpharmacol ogi cal and phar macol ogi cal
approaches. The met hod of pr ophyl axi s used i s det ermi ned based on t he pat i ent ' s
degree of ri sk. For exampl e, a pat i ent at hi gh t o ext r emel y hi gh r i sk f or devel opment
of VTED r equi r es nonphar macol ogi cal and pharmacol ogi cal pr ophyl axi s.
3. The answer i s D [ see V. A. 2] .
Unf r act i onat ed hepari n act s as an ant i coagul ant by cat al yzi ng t he i nact i vat i on of
f act or Ì Ì a, f act or Xa, and f act or Ì Xa by ant i t hr ombi n Ì Ì Ì .
4. The answer i s C [ see V. A. 4. b. (4) ] .
Sever al nomogr ams f or dosi ng cont i nuous i nf usi on unf r act i onat ed hepar i n exi st i n
t he medi cal and pharmaceut i cal l i t erat ure. The l oadi ng dose i s t ypi cal l y 70- 100
uni t s/ kg. Ì n t hi s case, t he pat i ent wei ghs 100 kg ( 212 l b) and t he l oadi ng dose i s 80
uni t s/ kg. Mai nt enance doses of 15- 25 uni t s/ kg/ hr ar e t ypi cal l y used. Ì n t hi s case,
t he mai nt enance dose i s 18 uni t s/ kg/ hr .
5. The answer i s E ( I , I I , I I I ) [ see Tabl e 43-10] .
Pr i mar y l i t er at ur e r eveal s appr opr i at e r andomi zed pr ospect i ve t r i al s exami ni ng t he
r ol e of LMWH compared t o unf r act i onat ed hepari n. From t hese t r i al s, evi dence of
ef f i cacy and saf et y f or enoxapar i n and t i nzapar i n at t he t r eat ment doses l i st ed
exi st s and has been appr oved by FDA f or t r eat ment of est abl i shed VTE.
6. The answer i s D (I I , I I I ) [ see V. A. 5. a, b and c] .
Unf r act i onat ed hepari n may be appr opr i at el y moni t or ed by ei t her t he act i vat ed
par t i al t hrombopl ast i n t i me (aPTT) or hepar i n assay. Because di f f er ent l abor at or i es
use aPTT r eagent s wi t h di f f er ent sensi t i vi t i es, t he aPTT r ange and i t s corr espondi ng
r at i o must be cor r el at ed t o a hepar i n l evel of 0. 2-0. 4 uni t s/ mL by whol e-bl ood
( pr ot ami ne t i t r at i on) assay or 0. 3- 0. 7 uni t s/ mL by pl asma- ami dol yt i c assay. The
saf et y and ef f i cacy of LMWH cannot be r el i abl y eval uat ed by aPTT det ermi nat i ons.
LMWH saf et y and ef f i cacy can be eval uat ed by hepari n assay. Because of t he
r el i abi l i t y of dose responsi veness seen wi t h LMWH t herapy, t he need t o per f orm
hepar i n assays i s cont r over si al .
7. The answer i s A ( I ) [ see V. B. 5. a and b; Tabl e 43- 8] .
Or al ant i coagul ant t her apy i s moni t or ed by measur i ng t he PT. The PT i s responsi ve
t o depr essi on of t hr ee of t he f our vi t ami n K-dependent procoagul ant cl ot t i ng f act or s
( pr ot hr ombi n or f act or s Ì Ì , VÌ Ì , and X) . These r espect i ve cl ot t i ng f act ors t ake
approxi mat el y 96 hr t o be depl et ed, at whi ch t i me t he PT shoul d be suf f i ci ent t o
ar r i ve at an Ì NR of 2. 0-3. 0 f or pat i ent s wi t h DVT ( by appr opri at el y convert i ng t he PT
r at i o t o t he power of t he Ì SÌ ) . Pat i ent s wi t h mechani cal prost het i c hear t val ves have
Ì NRs t ar get ed i n t he 2. 5-3. 5 range. Aspi r i n t her apy i s not moni t or ed by Ì NR
det ermi nat i ons.
8. The answer i s A ( I ) [ see Tabl e 43- 4] .
Or al ant i coagul ant t her apy wi t h war f ar i n may be compl i cat ed by myr i ad dr ug- drug
i nt er act i ons owi ng t o t he hi ghl y prot ei n-bound st at e of war f ar i n. Such drug
i nt er act i ons may pot ent i at e (pr ol ong) PT: Ì NR r at i o, i nhi bi t ( shor t en) t he
ant i coagul ant ef f ect of war f ari n, or have no ef f ect on t he act i ons of war f ar i n.
Sul f amet hoxazol e- t r i met hopri m and ot her ant i bi ot i cs have t he pot ent i al t o augment
t he ant i coagul ant ef f ect of war f ar i n by el i mi nat i ng bact er i al f l ora and, t her eby,
pr oduci ng vi t ami n K def i ci ency.
9. The answer i s E ( I , I I , I I I ) [ see Tabl e 43-7] .
Phar maci st s may be cal l ed on t o of f er advi ce regar di ng rever sal of war f ari n t her apy
or may be empower ed usi ng Pharmacy and Ther apeut i cs Commi t t ee or Medi cal
Boar d appr oved pr ot ocol s t o r everse war f ar i n' s ef f ect . Ì n al l i nst ances, t he
pharmaci st must cr i t i cal l y and cl i ni cal l y eval uat e t he si t uat i on and communi cat e wi t h
t he physi ci an r egar di ng management i ssues. A need f or i mmedi at e surger y or
i nvasi ve procedur es wi l l al ways hast en t he ur gency of war f ari n r eversal . Ì n t he
set t i ng of act i ve bl eedi ng, i t s cl i ni cal si gni f i cance must be demonst r at ed by
consul t at i on wi t h t he pat i ent ' s physi ci an. Ì f t he Ì NR i s > 20 and t he pat i ent has
act i ve bl eedi ng t hat i s cl i ni cal l y si gni f i cant , t he phar maci st must hol d drug t her apy,
consi der t he most appr opr i at e dose and r out e of vi t ami n K del i ver y, and admi ni st er
f r esh f rozen pl asma t o repl et e t he vi t ami n K- dependent cl ot t i ng f act ors.
P. 912


10. The answer i s A ( I ) [ see V. C. 3. a. ( 1) ; V. C. 4. b] .
UFH has an Xa: Ì Ì a bi ndi ng- af f i ni t y r at i o of appr oxi mat el y 1: 1, and t he vari ous
commer ci al LMWHs have Xa: Ì Ì a bi ndi ng- af f i ni t y r at i os of 2: 1 up t o 4: 1, dependi ng on
t hei r mol ecul ar si ze di st ri but i on. Thi s i ncreased bi ndi ng af f i ni t y f or f act or Xa r el at i ve
t o f act or Ì Ì a ( t hr ombi n) i s sai d t o account f or t he i mproved abi l i t y of LMWHs t o
cat al yze i nact i vat i on of t hr ombi n; t he smal l er f r agment s cannot bi nd t o t hr ombi n
and, t her ef or e, r et ai n t hei r abi l i t y t o i nact i vat e f act or Xa. LMWHs have l onger hal f -
l i ves t han unf ract i onat ed hepar i n. LMWHs ar e cl ear ed pr i mari l y vi a t he ki dneys, and
t hei r bi ol ogi c hal f - l i f e i s i ncreased i n pat i ent s wi t h r enal f ai l ure i ndependent of dose.
11. The answer i s C ( I , I I ) [ see V. D. 5. b; V. D. 6. a. (1) and (2) ] .
The synt het i c pent asacchar i de f ondapar i nux i s cont r ai ndi cat ed i n pat i ent s who have
sever e r enal i mpai r ment and who wei gh < 50 kg. Cal cul at i on of t he pat i ent ' s
est i mat ed creat i ni ne cl ear ance by t he Cr ockcof t -Gaul t met hod r eveal s an est i mat ed
cl ear ance of appr oxi mat el y 8. 5 mL/ mi n, whi ch woul d be def i ned as severe r enal
i mpai rment . Her st at ed wei ght i s 49 kg. Thus t hi s pat i ent ' s sever e r enal i mpai r ment
and l ow wei ght const i t ut e cont rai ndi cat i ons t o t he use of f ondapar i nux.
Fondapar i nux i s r ecommended f or use wi t h precaut i on i n t he el der l y pat i ent
popul at i on.

44
Infectious Diseases
PauI F. Souney
Ant hony E. Zi mmermann
Li nda M. Spooner
I. PrincipIes of Anti-Infective Therapy
A. Def i ni t i on. Ant i -i nf ect i ve agent s t r eat i nf ect i on by suppressi ng or
dest r oyi ng t he causat i ve mi cr oor gani sms÷bact eri a, mycobact eri a, f ungi ,
pr ot ozoa, or vi r uses. Ant i - i nf ect i ve agent s der i ved f r om nat ur al subst ances
ar e cal l ed ant i bi ot i cs; t hose produced f rom synt het i c subst ances are cal l ed
ant i mi crobi aI s. These t wo t er ms are now used i nt erchangeabl y.
B. I ndi cati ons. Conf i rm t he pr esence of i nf ect i on by compl et i ng a caref ul
hi st or y and physi cal exami nat i on, searchi ng f or si gns and sympt oms of
i nf ect i on as wel l as pr edi sposi ng f act ors. Ant i -i nf ect i ve agent s shoul d be
used onl y when
1. A si gni f i cant i nf ect i on has been di agnosed or i s st r ongl y suspect ed
2. An est abl i shed i ndi cat i on f or pr ophyl act i c t herapy exi st s
C. Gram st ai n, mi crobi oI ogi caI cuI turi ng, and suscept i bi I i t y t est s shoul d
be per f or med bef or e ant i - i nf ect i ve t her apy i s i ni t i at ed. Test mat eri al s must
be obt ai ned by a met hod t hat avoi ds cont ami nat i on of t he speci men by t he
pat i ent ' s own f l or a.
1. Gram st ai n. Per f or med on al l speci mens except bl ood cul t ur es, t he gram
st ai n hel ps i dent i f y t he cause of i nf ect i on i mmedi at el y. By det er mi ni ng i f t he
causat i ve agent i s gr am posi t i ve or gr am negat i ve, t he t est al l ows a bet t er
choi ce of drug t herapy, par t i cul ar l y when an ant i - i nf ect i ve r egi men must
begi n wi t hout del ay.
a. Gram-posi t i ve mi cr oor gani sms st ai n bI ue or purpI e.
b. Gram-negat i ve mi cr oor gani sms st ai n red or rose- pi nk.
c. Fungi may al so be i dent i f i ed by gr am st ai n.
2. Mi crobi oI ogi caI cuI tures. To i dent i f y t he speci f i c causat i ve agent ,
speci mens of body f l ui ds or i nf ect ed t i ssue are col l ect ed f or anal ysi s.
3. Suscept i bi I i t y t est s. Di f f erent st rai ns of t he same pat hogeni c speci es
may have wi del y var yi ng suscept i bi l i t y t o a par t i cul ar ant i - i nf ect i ve agent .
Suscept i bi l i t y t est s det ermi ne mi cr obi al suscept i bi l i t y t o a gi ven dr ug and
t hus can be used t o pr edi ct whet her t he drug wi l l combat t he i nf ect i on
ef f ect i vel y.
a. Mi crodi I uti on method. The drug i s di l ut ed ser i al l y i n var i ous medi a
cont ai ni ng t he t est mi cr oor gani sm.
( 1) The l owest dr ug concent r at i on t hat pr event s mi cr obi al growt h af t er 18-
24 hr of i ncubat i on i s cal l ed t he mi ni mum i nhi bi tor y concent rat i on (MI C) .
( 2) The l owest dr ug concent r at i on t hat r educes bact er i al densi t y by 99. 9%
i s cal l ed t he mi ni mum bact eri ci daI concent rati on ( MBC).
( 3) Breakpoi nt concent rat i ons of ant i bi ot i cs ar e used t o charact er i ze
ant i bi ot i c act i vi t y: The i nt er pret i ve cat egor i es ar e suscepti bI e, moderat eI y
suscept i bI e ( i ntermedi at e) , and resi st ant . These concent r at i ons ar e
det ermi ned by consi deri ng pharmacoki net i cs, ser um and t i ssue
concent r at i ons f ol l owi ng nor mal doses, and t he popuI at i on di st ri buti on of
MÌ Cs of a gr oup of bact er i a f or a gi ven dr ug.
b. Ki rby- Bauer di sk di f fusi on t echni que. Thi s t est i s l ess expensi ve but
l ess rel i abl e t han t he mi cr odi l ut i on met hod; however , i t provi des qual i t at i ve
suscept i bi l i t y i nf or mat i on.
( 1) Fi l t er paper di sks i mpr egnat ed wi t h speci f i c dr ug quant i t i es ar e pl aced
on t he surf ace of agar pl at es st r eaked wi t h a mi cr oor gani sm cul t ur e. Af t er
18 hr, t he si ze of
P. 914

a cl ear i nhi bi t i on zone i s det er mi ned; dr ug act i vi t y agai nst t he t est st r ai n i s
t hen cor r el at ed t o zone si ze.
( 2) The Ki r by- Bauer t echni que does not rel i abl y pr edi ct t herapeut i c
ef f ect i veness agai nst cert ai n mi croorgani sms ( e. g. , St aphyl ococcus aur eus,
Shi gel l a) .
D. Choi ce of agent . An ant i - i nf ect i ve agent shoul d be chosen on t he basi s
of i t s phar macol ogi cal proper t i es and spect r um of act i vi t y as wel l as on
var i ous host ( pat i ent ) f act ors ( Fi gur e 44-1) .
1. PharmacoI ogi caI propert i es i ncl ude t he dr ug' s abi l i t y t o r each t he
i nf ect i on si t e and t o at t ai n a desi r ed l evel i n t he t ar get t i ssue.
2. Spect rum of acti vi t y. To t r eat an i nf ect i ous di sease ef f ect i vel y, an ant i -
i nf ect i ve drug must be act i ve agai nst t he causat i ve pat hogen. Suscept i bi l i t y
t est i ng or cl i ni cal exper i ence i n t reat i ng a gi ven i nf ect i on may suggest t he
ef f ect i veness of a par t i cul ar dr ug.
3. Pati ent f act ors. Sel ect i on of an ant i - i nf ect i ve dr ug r egi men must t ake
var i ous pat i ent f act or s i nt o account t o det ermi ne whi ch t ype of dr ug shoul d
be admi ni st er ed, t he corr ect dr ug dosage and admi ni st r at i on r out e, and t he
pot ent i al f or adverse dr ug ef f ect s.
a. I mmunoI ogi caI stat us. A pat i ent wi t h i mpai red i mmune mechani sms may
r equi r e a drug t hat r api dl y dest roys pat hogens ( i . e. , bacteri ci daI agent )
r at her t han one t hat merel y suppresses a pat hogen' s gr owt h or r epr oduct i on
( i . e. , bact eri ostat i c agent ) .
b. Presence of a forei gn body. The ef f ect i veness of ant i - i nf ect i ve t her apy
i s reduced i n pat i ent s who have pr ost het i c j oi nt s or val ves, cardi ac
pacemaker s, and vari ous i nt er nal shunt s.
c. Age. A dr ug' s pharmacoki net i c pr oper t i es may var y wi del y i n pat i ent s of
di f f er ent ages. Ì n ver y young and ver y ol d pat i ent s, dr ug met abol i sm and
excr et i on commonl y decrease. El derl y pat i ent s al so have an i ncr eased r i sk
of suf f er i ng ot ot oxi ci t y when recei vi ng cer t ai n ant i bi ot i cs.
d. UnderI yi ng di sease
( 1) Pr eexi st i ng ki dney or I i ver di sease i ncr eases t he ri sk of nephrot oxi ci t y
or hepat ot oxi ci t y duri ng t he admi ni st rat i on of some ant i bact er i al dr ugs.
( 2) Pat i ent s wi t h cent raI nervous syst em ( CNS) di sorders may suf f er
neurot oxi ci t y (mot or sei zur es) dur i ng peni ci l l i n t her apy.
( 3) Pat i ent s wi t h neuromuscuI ar di sorders ( e. g. , myast heni a gr avi s) are at
i ncreased r i sk f or devel opi ng neur omuscul ar bl ockade dur i ng
ami nogl ycosi de or pol ymyxi n B t her apy.
e. Hi stor y of drug aI I ergy or adverse drug react i ons. Pat i ent s who have
had pr evi ous al l ergi c or ot her unt owar d react i ons t o a par t i cul ar ant i bi ot i c
have a hi gher r i sk of exper i enci ng t he same r eact i on duri ng subsequent
admi ni st rat i on of t hat drug. Except i n l i f e- t hr eat eni ng si t uat i ons, pat i ent s
who have had seri ous al l er gi c react i ons t o peni ci l l i n, f or exampl e, shoul d
not recei ve t he dr ug agai n.
f . Pregnancy and I actati on. Because dr ug t her apy dur i ng pr egnancy and
l act at i on can cause unwant ed ef f ect s, t he mot her ' s need f or t he ant i bi ot i c
must be wei ghed agai nst t he dr ug' s pot ent i al harm.
( 1) Pr egnancy can i ncrease t he r i sk of adverse dr ug ef f ect s f or bot h mot her
and f et us. Al so, pl asma dr ug concent rat i ons t end t o decr ease i n pr egnant
women, reduci ng a drug' s t her apeut i c ef f ect i veness.
( 2) Most drugs, i ncl udi ng ant i bi ot i cs, appear i n t he br east mi l k of nur si ng
mot hers and may cause adver se ef f ect s i n i nf ant s. For exampl e,
sul f onami des may l ead t o t oxi c bi l i r ubi n accumul at i on i n a newborn' s br ai n.
g. Genet i c t rai ts
( 1) Sul f onami des may cause hemol yt i c anemi a i n pat i ent s wi t h gl ucose- 6-
phosphat e dehydr ogenase ( G6PD) def i ci ency.
( 2) Pat i ent s who r api dl y met abol i ze dr ugs (i . e. , rapi d acet yl at ors) may
devel op hepat i t i s when recei vi ng t he ant i t uber cul ar drug i soni azi d.
E. Empi ri c therapy. Ì n ser i ous or l i f e- t hreat eni ng di sease, ant i -i nf ect i ve
t her apy must begi n bef ore t he i nf ect i ng or gani sm has been i dent i f i ed. Ì n
t hi s case, t he choi ce of dr ug ( or dr ugs) i s based on cl i ni cal exper i ence,
suggest i ng t hat a par t i cul ar agent i s ef f ect i ve i n a gi ven set t i ng.
P. 915



Figure 44-1. Approach to management oI
inIection.
P. 916


1. A broad-spect rum ant i bi ot i c usual l y i s t he most appr opri at e choi ce unt i l
t he speci f i c or gani sm has been det ermi ned.
2. Ì n al l cases, cuI t ure speci mens must be obt ai ned bef or e t her apy
begi ns.
F. MuI t i pI e ant i bi ot i c t herapy. A combi nat i on of dr ugs shoul d be gi ven
onl y when cl i ni cal exper i ence has shown such t her apy t o be mor e ef f ect i ve
t han si ngl e-agent t herapy i n a part i cul ar set t i ng. A mul t i pl e- agent r egi men
can i ncr ease t he ri sk of t oxi c dr ug ef f ect s and, i n a f ew cases, may resul t i n
dr ug ant agoni sm and subsequent t herapeut i c i nef f ect i veness. Ì ndi cat i ons
f or mul t i pl e-agent t herapy i ncl ude
1. Need f or i ncreased ant i bi oti c ef f ect i veness. The synergi st i c
( i nt ensi f i ed) ef f ect of t wo or more agent s may al l ow a dosage r educt i on or a
f ast er or enhanced dr ug ef f ect .
2. Treat ment of an i nfect i on caused by muI t i pI e pathogens ( e. g. , i nt ra-
abdomi nal i nf ect i on)
3. Preventi on of proI i f erat i on of drug- resi stant organi sms ( e. g. , dur i ng
t r eat ment of t ubercul osi s)
G. Durat i on of ant i - i nf ect i ve t herapy. To achi eve t he t her apeut i c goal ,
ant i - i nf ect i ve t herapy must cont i nue f or a suf f i ci ent dur at i on.
1. Acut e uncompI i cated i nf ect i on. Tr eat ment gener al l y shoul d cont i nue
unt i l t he pat i ent has been af ebr i l e and asympt omat i c f or at l east 72 hr.
2. Chroni c i nf ect i on ( e. g. , endocar di t i s, ost eomyel i t i s) . Tr eat ment may
r equi r e a l onger dur at i on ( 4- 6 weeks) wi t h f ol l ow- up cul t ur e anal yses t o
assess t herapeut i c ef f ect i veness.
H. Moni t ori ng t herapeut i c eff ecti veness. To assess t he pat i ent ' s
r esponse t o ant i - i nf ect i ve t her apy, appr opr i at e speci mens shoul d be
cul t ur ed and t he f ol l owi ng paramet er s moni t or ed.
1. Fever curve. An i mpor t ant assessment t ool , t he f ever cur ve may be a
r el i abl e i ndi cat i on of response t o t herapy. Def er vescence usual l y i ndi cat es
f avor abl e r esponse.
2. Whi t e bI ood ceI I ( WBC) count . Ì n t he i ni t i al st age of i nf ect i on, t he
neut rophi l count f rom a per i pheral bl ood smear may r i se above nor mal
( neut r ophi l i a), and i mmat ur e neut r ophi l f or ms ( "bands¨ ) may appear ( "l ef t
shi f t ¨ ) . Ì n pat i ent s who ar e el derl y, debi l i t at ed, or suf f eri ng over whel mi ng
i nf ect i on, t he WBC count may be nor mal or subnor mal .
3. Radi ographi c f i ndi ngs. Smal l ef f usi ons, abscesses, or cavi t i es t hat
appear on radi ographs i ndi cat e t he f ocus of i nf ect i on.
4. Pai n and i nf I ammat i on ( as evi denced by swel l i ng, er yt hema, and
t ender ness) may occur when t he i nf ect i on i s super f i ci al or wi t hi n a j oi nt or
bone, al so i ndi cat i ng a possi bl e f ocus of i nf ect i on.
5. Er yt hrocyt e sedi ment at i on rat e ( ESR or "sed rat e") . Large el evat i ons
i n ESR ar e associ at ed wi t h acut e or chroni c i nf ect i on, par t i cul arl y
endocar di t i s, chr oni c ost eomyel i t i s, and i nt ra- abdomi nal i nf ect i ons. A
nor mal ESR does not excl ude i nf ect i on; more of t en, ESR i s el evat ed as a
r esul t of noni nf ect i ous causes such as col l agen vascul ar di sease.
6. Serum compI ement concent rat i ons, part i cul ar l y t he C3 component , are
of t en r educed i n ser i ous i nf ect i ons because of consumpt i on dur i ng t he host
def ense process.
I . Lack of t herapeut i c ef f ect i veness. When an ant i bi ot i c drug regi men
f ai l s, ot her dr ugs shoul d not be added i ndi scri mi nat el y or t he regi men
ot her wi se changed. Ì nst ead, t he si t uat i on shoul d be reassessed and
di agnost i c ef f or t s i nt ensi f i ed. Causes of t herapeut i c i nef f ect i veness i ncl ude
t he f ol l owi ng:
1. Mi sdi agnosi s. The i sol at ed or gani sm may have been mi si dent i f i ed by t he
l abor at or y or may not be t he causat i ve agent f or i nf ect i on (e. g. , t he pat i ent
may have an unsuspect ed i nf ect i on) .
2. I mproper drug regi men. The dr ug dosage, admi ni st r at i on r out e, dosi ng
f r equency, or durat i on of t herapy may be i nadequat e or i nappr opr i at e.
3. I nappropri ate choi ce of ant i bi ot i c agent . As di scussed i n Ì . D, pat i ent
f act or s and t he phar macol ogi cal pr oper t i es and spect r um of act i vi t y of a
gi ven dr ug must be consi dered when pl anni ng ant i - i nf ect i ve dr ug t herapy.
P. 917


4. Mi crobi aI resi st ance. By acqui ri ng r esi st ance t o a speci f i c ant i bi ot i c,
mi cr oor gani sms can sur vi ve i n t he drug' s presence. Many gonococcal
st r ai ns, f or i nst ance, now r esi st peni ci l l i n. Drug r esi st ance i s part i cul ar l y
common i n geogr aphi cal ar eas i n whi ch a speci f i c dr ug has been used
excessi vel y ( and per haps i mproper l y) .
5. UnreaI i st i c expectat i ons. Ant i bi ot i cs are i nef f ect i ve i n cer t ai n
ci rcumst ances.
a. Pat i ent s wi t h condi t i ons t hat r equi re surgi caI drai nage f r equent l y cannot
be cur ed by ant i - i nf ect i ve dr ugs unt i l t he drai n has been r emoved. For
exampl e, t he presence of necr ot i c t i ssue or pus i n pat i ent s wi t h pneumoni a,
empyema, or r enal cal cul i i s a common cause of ant i bi ot i c f ai l ur e.
b. Fever shoul d not be t reat ed wi t h ant i - i nf ect i ve dr ugs unl ess i nf ect i on has
been i dent i f i ed as t he cause. Al t hough f ever f r equent l y si gni f i es i nf ect i on, i t
somet i mes st ems f rom noni nf ect i ous condi t i ons (e. g. , drug react i ons,
phl ebi t i s, neopl asms, met abol i c di sor der s, ar t hr i t i s) . These condi t i ons do
not respond t o ant i bi ot i cs. One except i on t o t hi s posi t i on i s neut r openi c
cancer pat i ent s; such pat i ent s wi t h no si gns or sympt oms of i nf ect i on ot her
t han f ever ar e wi del y t reat ed wi t h ant i mi cr obi al agent s.
6. I nfecti on by t wo or more t ypes of mi croorgani sms. Ì f not det ect ed
i ni t i al l y, an addi t i onal cause of i nf ect i on may l ead t o t her apeut i c f ai l ure.
J. Ant i mi crobi aI prophyI axi s f or surger y
1. Def i ni t i on. Ant i bi ot i c pr ophyl axi s i s a shor t cour se of ant i bi ot i c
admi ni st er ed bef ore t here i s cl i ni cal evi dence of i nf ect i on.
2. GeneraI consi derat i ons
a. Ti mi ng. The ant i bi ot i c shoul d be admi ni st er ed t o ensur e t hat appr opr i at e
ant i bi ot i c l evel s are avai l abl e at t he si t e of cont ami nat i on bef or e t he
i nci si on. Ì ni t i at i on of pr ophyl axi s i s of t en at i nduct i on of anest hesi a, wi t hi n
1 hr or j ust bef ore t he sur gi cal i nci si on. Thi s ensur es peak serum and
t i ssue ant i bi ot i c l evel s.
b. Durati on. Pr ophyl axi s shoul d be mai nt ai ned f or t he durat i on of surger y.
Long sur gi cal pr ocedur es ( e. g. , > 3 hr ) may r equi r e addi t i onal doses. Ther e
i s l i t t l e evi dence t o suppor t cont i nuat i on of pr ophyl axi s beyond 24 hr.
c. Ant i bi oti c spect rum shoul d be appr opr i at e f or t he usual pat hogens.
( 1) Ì n general , f i rst -generat i on cephaI ospori ns ( e. g. , cef azol i n) ar e t he
dr ugs of choi ce f or most pr ocedur es and pat i ent s. These agent s have an
appropr i at e spect r um, a l ow f r equency of si de ef f ect s, a f avor abl e hal f - l i f e,
and a l ow cost .
( 2) Vancomyci n i s a sui t abl e al t ernat i ve i n peni ci l l i n- sensi t i ve pat i ent s and
i n si t uat i ons i n whi ch met hi ci l l i n- r esi st ant S. aur eus i s a concern.
d. Route of admi ni st rati on. Ì nt ravenous ( Ì V) or i nt r amuscul ar ( Ì M) r out es
ar e pr ef er r ed t o guar ant ee good ser um and t i ssue l evel s at t he t i me of
i nci si on.
II. AntibacteriaI Agents
A. Def i ni t i on and cI assi f i cat i on. Used t o t reat i nf ect i ons caused by
bact eri a, ant i bact er i al agent s f al l i nt o sever al maj or cat egor i es:
ami nogI ycosi des, carbapenems, cephaI ospori ns, er yt hromyci ns,
peni ci I I i ns (i ncl udi ng var i ous subgr oups) , suI f onami des, t et racycI i nes,
f I uoroqui noI ones, met roni dazoI e (see V. C. 2. b), uri nar y t ract ant i sept i cs,
and mi sceI I aneous anti - i nf ect i ves ( Tabl e 44-1) .
B. Ami nogI ycosi des. These dr ugs, cont ai ni ng ami no sugar s, are used
pr i mar i l y i n i nf ect i ons caused by gr am- negat i ve ent er obact eri a and i n
suspect ed sepsi s. They have l i t t l e act i vi t y agai nst anaer obi c and f acul t at i ve
or gani sms. The t oxi c pot ent i al of t hese dr ugs l i mi t s t hei r use. Maj or
ami nogl ycosi des i ncl ude ami kaci n ( Ami ki n) , gent ami ci n ( Garamyci n) ,
kanamyci n, neomyci n, net i I mi ci n, st reptomyci n, and t obramyci n
( Nebci n) .
1. Mechani sm of act i on. Ami nogl ycosi des ar e bact eri ci daI ; t hey i nhi bi t
bact er i al pr ot ei n synt hesi s by bi ndi ng t o and i mpedi ng t he f unct i on of t he
30S ri bosomal subuni t . (Some ami nogl ycosi des al so bi nd t o t he 50S
r i bosomal subuni t . ) Thei r mechani sm of act i on i s not f ul l y known.
P. 918


P. 919


P. 920


P. 921


P. 922


P. 923


Table 44-1. Some Important Parameters of Anti-Infective Drugs
Agent
Elimination
Route Half-Life
Administrat
ion Route
Common
Dosage Range
(Adults)
Aminoglycosides

Amikacin Renal 2-3 hr IV. IM 15
mg/kg/da
y. (once
daily
dose)

Gentamicin Renal 2 hr IV. IM 3
mg/kg/da
y
(standard
dose); 6-7
mg/kg/da
y (once
daily
dose)

Kanamycin Renal 2-4 hr Oral.
IV
15 mg/kg
every 8-
12 hr

Neomycin Renal 2-3 hr Oral.
topical
50-100
mg/kg/da
y (oral);
10-15
mg/day
(topical)

Netilmicin Renal 2-7 hr IV. IM 3-6
mg/kg/da
y

Streptomycin Renal 2-3 hr IM 15
mg/kg/da
y
a


Tobramycin Renal 2-5 hr IV. IM 3
mg/kg/da
y
(standard
dose); 6-7
mg/kg/da
y. (once
daily
dose)
Carbapenems

Doripenem Renal 1 hr IV 500 mg
every 8 hr

Imipenem Renal 1 hr IV 250 mg-1
g every 6
hr
Ertapenem Renal 4 hr IV. IM 1 g/day

Meropenem Renal 1.5 hr IV. IM 0.5-2 g
every 8 hr
Cephalosporins
First-generation
CeIadroxil Renal 1.5 hr Oral 1-2 g/day

CeIazolin Renal 1.4-2.2
hr
IV 250 mg-1
g every 8
hr

Cephalexi
n
Renal 0.9 1.3
hr
Oral 250-500
mg every
6 hr

Cephapirin Renal
(H)
0.6-0.8
hr
IV. IM 500 mg-2
g every 4-
6 hr

Cephradin
e
Renal 1.3 hr Oral.
IV
250-500
mg every
6 hr
Second-generation

CeIaclor Renal
(H)
0.8 hr Oral 250-500
mg every
8 hr


CeImetazo
le
Renal 72 min IV 2 g every
6-12 hr


CeIotetan Renal 2.8-4.6
hr
IV. IM 1-2 g
every 12
hr


CeIoxitin Renal 0.8 hr IV 1-2 g
every 6-8
hr


CeIprozil Renal 78 min Oral 250-500
mg every
12-24 hr


CeIuroxim
e
Renal 1.5-2.2
hr
IV. IM 750 mg-
1.5 g
every 8 hr


LoracarbeI Renal 1 hr Oral 200 mg
every 12
hr or 400
mg/day

Third-generation

CeIixime Renal 3-4 hr Oral 400
mg/day


CeIdinir Renal 1.7-1.8
hr
Oral 300 mg
every 12
hr


CeIoperaz
one
Hepatic 1.6-2.4
hr
IV 2-4 g
every 12
hr


CeIotaxim
e
Renal
(H)
1.5 hr IV 1-2 g
every 6-8

hr

CeIpodoxi
me
Renal 2.5 hr Oral 100-400
mg every
12 hr


CeItazidim
e
Renal 1.8 hr IV. IM 1-2 g
every 8-
12 hr


CeItibuten Renal 2.5 hr Oral 400
mg/day


CeItizoxi
me
Renal 1.7 hr IV 1-2 g
every 8-
12 hr


CeItriaxon
e
Renal 8 hr IV. IM 1-2 g/day

Fourth-generation

CeIepime Renal 2-2.3
hr
IV. IM 1-2 g
every 8-
12 hr

Erythromycins and other macrolides

Azithromycin Hepatic 68 hr Oral 250
mg/day


Clarithromycin Renal 3-7 hr Oral 250-500
mg every
12 hr


Dirithromycin Hepatic 8 hr Oral 500
mg/day


Erythromycin base
estolate.
ethylsuccinate. and
stearate
Hepatic 1.2-2.6
hr
Oral 250-500
mg every
6 hr


Erythromycin
gluceptate and
lactobionate
IV 0.5-2 g
every 6 hr
Natural penicillins

Penicillin G Renal
(H)
0.5 hr Oral.
IV. IM
200.000-
500.000
U every
6-8 hr


Penicillin V Renal 1 hr Oral 500 mg-2
g/day


Penicillin G
procaine
Renal 24-60
hr
IM 300.000-
600.000
U/day


Penicillin G
benzathine
Renal 24-60
hr
IM 300.000-
600.000
U/day

Penicillinase-resistant penicillins

Cloxacillin Renal
(H)
0.5 hr Oral 250-500
mg every
6 hr


Dicloxacillin Renal
(H)
0.5-0.9
hr
Oral 500 mg-1
g/day


Methicillin Renal
(H)
0.5-1
hr
IV. IM 1-2 g
every 4-6
hr


NaIcillin Hepatic
(R)
0.5 hr Oral.
IV. IM
0.25-2 g
every 6 hr


Oxacillin Renal
(H)
0.5 hr Oral.
IV. IM
500 mg-2
g every 4-
6 hr 500-
875 mg
every 12
hr

Aminopenicillins

Amoxicillin Renal
(H)
0.9-2.3
hr
Oral 250-500
mg every
8 hr


Amoxicillin/clavula
nic acid
Renal 1 hr Oral 250-500
mg every
8 hr


Ampicillin Renal
(H)
0.8-1.5
hr
Oral.
IV. IM
250 mg-2
g every 4-
6 hr


Ampicillin/sulbacta
m
Renal 1-1.8
hr
IV. IM 1.5-3 g
every 6 hr

Extended-spectrum penicillins

Mezlocillin Renal
(H)
0.6-1.2
hr
IV. IM 1-3 g
every 4-6
hr


Piperacillin Renal
(H)
0.8-1.4
hr
IV. IM 1-1.5
mg/kg
every 6-
12 hr

Piperacillin/tazobact Renal 0.7-1.2 IV 3.375 g
am hr every 6 hr

Ticarcillin Renal 0.9-1.5
hr
IV. IM 1-3 g
every 4-6
hr


Ticarcillin/clavulani
c acid
Renal 1-1.5
hr
IV 3.1 g
every 4-6
hr

Sulfonamides

SulIacytine Renal 4-4.5
hr
Oral 250 mg
every 6 hr


SulIadiazine Renal
(H)
6 hr Oral.
IV
2-4 g/day


SulIamethoxazole Hepatic
(R)
9-11 hr Oral 1-3 g/day


SulIisoxazole Renal
(H)
3-7 hr Oral.
IV
2-8 g/day


SulIamethizole Renal Oral 0.5-1 g
every 6-8
hr

Tetracyclines

Demeclocycline Renal 10-17
hr
Oral 300 mg-1
g/day


Doxycycline Hepatic 14-25
hr
Oral.
IV
100-200
mg every
12 hr


Minocycline Hepatic 12-15
hr
Oral.
IV
100-200
mg every
12 hr


Oxytetracycline Renal 6-12 hr Oral.
IM
250-500
mg every
6 hr 250-
500 mg
q.i.d. or
300
mg/day in
1 or 2
divided
doses


Tetracycline
b
Renal 6-12 hr Oral.
IV. IM
1-2 g/day

Fluoroquinolones

CiproIloxacin Renal
(H)
5-6 hr IV 200-600
mg every
12 hr


Enoxacin Renal
(H)
3-6 hr Oral 200
mg/day-
400 mg
every 12
hr


GemiIloxacin Fecal (R) 4-12 hr Oral 320 mg
once daily


LomeIloxacin Renal 6.35-
7.77 hr
Oral 400
mg/day


LevoIloxacin Renal 8 hr IV.
Oral
250-500
mg every
24 hr


MoxiIloxacin Hepatic 12 hr Oral 400 mg
once daily


OIloxacin Renal 5-7.5
hr
Oral 100
mg/day-
400 mg

Urinary tract antiseptics

Cinoxacin Renal 1-1.5
hr
Oral 250 mg
every 6 hr
or 500 mg
every 12
hr


FosIomycin Renal/Iec
al
5.7 hr Oral One
packet (3
g) in 90-
120 mL
water × 1
dose


Methenamine
hippurate and
mandelate
Renal 1-3 hr Oral 0.5-2 g
q.i.d.
Nalidixic acid Renal 8 hr Oral 4 g/day

NitroIurantoin Renal 0.3-1
hr
Oral 5-7
mg/kg/da
y

NorIloxacin Hepatic 3-4 hr Oral 400 b.i.d.
Miscellaneous anti-infectives

Atovaquone Fecal 50-84
hr
Oral 750 mg
b.i.d. × 21
days


Aztreonam Renal 1.7 hr Oral.
IV
50-100
mg/kg/da
y


Clindamycin Hepatic 2-4 hr Oral.
IM. IV
300-900
mg every
6-8 hr


CloIazimine Hepatic 70
days
Oral 50-100
mg/day


Dapsone Hepatic
(R)
28 hr Oral 50-100
mg/day


Daptomycin Renal 8 hr IV 4
mg/kg/da
y


Lincomycin Hepatic
(R)
4.4-6.4
hr
IV. IM 600 mg-1
g every 8-
12 hr


Linezolid Renal 4-6 hr Oral.
IV
600 mg
every 12
hr


Mupirocin Renal 19-35
min
Topical Apply
every 8-
12 hr


Quinupristin/dalIopr
istin
Hepatic 1
hr/0.4-
0.5 hr
IV 7.5 mg/kg
every 8 hr

RiIaximin Fecal 6 hrs Oral 200 mg
t.i.d.


Spectinomycin Renal 1.2-2.8
hr
IM 2-4 g
(single

dose)

Telithromycin Hepatic
(R)
10 hr Oral 800
mg/day


Tigecycline Biliary
(R)
42 hr IV 100 mg
load. 50
mg every
12 hr


Trimethoprim Renal
(H)
8-15 hr Oral 100-200
mg/day


Vancomycin Renal 6-8 hr Oral.
IV
500 mg
every 6 hr

Antifungal agents

Amphotericin B Unknow
n
24 hr IV 1-1.5
mg/kg/da
y


AnidulaIungin Fecal (R) 40-50
hr
IV Candidem
ia: 200
mg day 1.
then 100
mg/day


Esophage
al
candidiasi
s: 100 mg
day 1.
then 50
mg/day


CaspoIungin Hepatic 9-11 hr IV 70 mg on
day 1.
then 50
mg q.d.


Fluconazole Renal 22-37
hr
IV.
Oral
100-800
mg/day


Flucytosine Renal 6 hr Oral 50-150
mg/kg/da
y


GriseoIulvin Hepatic
(R)
9-24 hr Oral 300-375
mg/day


Itraconazole Hepatic 24-42
hr
Oral 200-600
mg/day


Ketoconazole Hepatic/I
ecal
3.3 hr Oral 200-400
mg/day
b.i.d


MicaIungin Hepatic 11-17
hr
IV Esophage
al
candidiasi
s: 150
mg/day


HSCT
prophylas
is: 50
mg/day


Miconazole Hepatic 20-24
hr
Oral 200-400
mg/day


Nystatin Fecal Oral 500.000-
1.000.000
U t.i.d.


Posaconazole Fecal/ren
al
35 hrs Oral 200 mg
t.i.d.

TerbinaIine Hepatic 11-16 Oral 250
(R) hr mg/day

Voriconazole Hepatic 6 hr IV.
Oral
IV: 6
mg/kg
every 12
hr × 2
doses.
then 4
mg/kg
every 12
h; oral:
200 mg
every 12
h Ior ~ 40
kg. 100
mg every
12 h Ior ·
40 kg

Antiprotozoal agents

Atovaquone Hepatic 67 hr Oral 750 mg
b.i.d.


Chloroquine Renal/Iec
al
72-120
hr
IM.
Oral
Depends
on disease


Diloxanide Renal IM 500 mg
t.i.d.


EIlornithine Renal 3 hr IV 100
mg/kg/do
se every 6
hr


Fansidar Renal 100-
231 hr
Oral 1 tablet
every
week

HaloIantrine Hepatic 3-4 Oral 500 mg
days every 6 hr
× 3 doses;
repeat in
7 days

Renal 72-120
hr
Oral 310 mg
every
week


Hydroxychloro
quine


Iodoquinol Fecal Oral 650 mg
t.i.d. Ior
20 days


MeIloquine Hepatic 15-33
days
Oral 1250 mg
single
dose


Metronidazole Hepatic
(R)
6-14 hr Oral.
IV
250-500
mg every
6-8 hr


Nitazoxanide Hepatic 1-1.6
hr
Oral 100-200
mg b.i.d.
based on
age


Paromomycin Fecal Oral 25-35
mg/kg/da
y


Pentamidine Renal 6-9 hr IM. IV.
inhalati
on
IV. IM: 3-
4 mg/kg
every
day;
inhalation
: 300 mg
every 4

weeks

Primaquine Hepatic 3.7-9.6
hr
Oral 15 mg
(base)/da
y


Pyrimethamine Renal 111 hr Oral 25 mg
every
week


Quinacrine

5 days Oral 100
mg/day


Quinine Renal 12 hr Oral 325 mg
b.i.d.


Tinidazole Hepatic
(R)
13.2 hr Oral 2 g q.d. ×
1-3 days

Antitubercular agents

Aminosalicylic acid Renal 1 hr Oral 150
mg/kg
daily
(maximu
m 12
g/day)


Capreomycin Renal 4-6 hr IM 15
mg/kg/da
y to 1
g/day
maximum


Cycloserine Renal 10 hr Oral 15-20
mg/kg
(maximu
m 1
g/day)


Ethambutol Hepatic 3.3 hr Oral 15-25
mg/kg/da
y


Ethionamide Hepatic 3 hr Oral 500 mg-1
g/day


Isoniazid Hepatic 1-4 hr Oral.
IV
5-10
mg/kg
daily
(maximu
m dose ÷
300 mg)


Pyrazinamide Hepatic 9-10 hr Oral 15-30
mg/kg
daily
(maximu
m 2
g/day)


RiIampin Hepatic 2-3 hr Oral.
IV
10 mg/kg
(up to 600
mg) q.d.


RiIabutin Hepatic 45 hr Oral 300 mg
q.d.


RiIepentine Hepatic 13.9 hr
(active
metabo
lite
\13.4
hr)
Oral 600 mg
every 3
days

Antiviral agents

Abacavir Hepatic 1.5 hr Oral 300 mg
b.i.d. or
600 mg

every day

AdeIovir Renal 7.5 hr Oral 10 mg
every day


Acyclovir Renal 2.2 hr Oral.
IV.
topical
IV: 5-10
mg/kg
every 8
hr; oral:
200-800
mg 3-5 ×
daily
(dependin
g upon
indication
)


Amantadine Renal 17 hr Oral 100 mg
b.i.d. or
200 mg
every day


Amprenavir Hepatic 7-10 hr Oral 1200 mg
b.i.d.
(caps)


Atazanavir Hepatic 7 hr Oral 400 mg
every day


CidoIovir Renal 6.5 hr IV 5 mg/kg
week × 2
(induction
); 5
mg/kg
every 2
weeks
(maintena
nce)


Darunavir Hepatic 15 hr Oral 600 mg
plus 100

mg
ritonavir
b.i.d.

Delavirdine Hepatic
(R)
2-11 hr Oral 400 mg
t.i.d.


Didanosine Renal 1.5 hr Oral > 60 kg:
400 mg
every day
(EC
caps); ·
60 kg:
250 mg
every day
(EC caps)


Emtricitabine Renal 10 hr Oral 200 mg
every day
(caps)


EnIuvirtide n/a 3.8 hr SC 90 mg
b.i.d.


Entecavir Renal 128-
149 hr
Oral 0.5 mg
every
day. or 1
mg every
day in
patients
with
lamivudin
e
resistance


EIavirenz Hepatic 40-55
hr
Oral 600 mg at
bedtime


Famciclovir Renal 2-2.3
hr
Oral 250-500
mg every
8-12 hr


Fosamprenavir Hepatic 7.7 hr Oral 1400 mg
b.i.d.


Foscarnet Renal 3-6 hr IV 90 mg/kg
every 12
hr × 14-
21 days
(CMV
induction)
; 90
mg/kg
every day
(CMV
maintena
nce)


Ganciclovir Renal 2.9 hr IV 5 mg/kg
every 12
hr
(induction
) × 14-21
days; 5
mg/kg
every day
(maintena
nce)


4.8 hr Oral 1000 mg
t.i.d.
(aIter
induction)


Indinavir Hepatic 1.4-2.2
hr
Oral 800 mg
every 8 hr


Lamivudine Renal 3-7 hr Oral 150 mg
b.i.d. or
300 mg
daily


Lopinavir/ritonavir Hepatic 4.4-6.1
hr
Oral 200
mg/50 mg

per tab (2
tablets
b.i.d.)

Maraviroc Hepatic 14-18
hr
Oral 150-600
mg b.i.d..
dependin
g upon
concomit
ant
medicatio
ns


NelIinavir Hepatic 3.5-5
hr
Oral 1250 mg
b.i.d.


Nevirapine Renal
(H)
25-30
hr
Oral 200 mg
every day
× 14
days. then
200 mg
b.i.d.


Oseltamivir Renal 6-10 hr Oral 75 mg
b.i.d.
(treatment
); 75 mg
every day
(prophyla
xis)


Raeltegravir Hepatic 9 hr Oral 400 mg
b.i.d.


Ribavirin Renal 298 hr Oral 800-1200
mg daily.
divided
into 2
doses

Rimantadine Renal 25 hr Oral 100 mg
b.i.d.

Ritonavir Hepatic 3-5 hr Oral 100-400
mg daily.
divided in
1 or 2
doses (as
booster
agent
with other
PIs)


Saquinavir Hepatic 13 hr Oral 1000 mg
(Invirase)
plus 100
mg
ritonavir
b.i.d.


Stavudine Renal 1.5 hr Oral > 60 kg:
40 mg
every 12
hr; · 60
kg: 30 mg
every 12
hr


Telbivudine Renal 40-49
hr
Oral 600 mg
every day


TenoIovir Renal 10-14
hr
Oral 300 mg
daily


Tipranavir Hepatic 6 hr Oral 500 mg
plus 200
mg
ritonavir
b.i.d.


Valacyclovir Renal 2.5-3.6
hr
Oral 0.5-1 g
every day

or b.i.d.
or t.i.d.

Valganciclovir Renal 4 hr Oral 900 mg
b.i.d. × 21
days
(induction
). 900 mg
every day
(maintena
nce)


Zalcitabine Renal 1-3 hr Oral 0.75 mg
t.i.d.


Zanamivir Renal 2.5-5.1
hr
Inhalati
on
(Diskha
ler)
2
inhalation
s (10 mg)
b.i.d.
(treatment
); 10 mg
every day
(prophyla
xis)


Zidovudine Renal
(H)
1.5-3.1
hr
Oral 300 mg
b.i.d.


IV 2 mg/kg
over 1 hr.
then 1
mg/kg/hr
until cord
clamping
(intrapart
um
perinatal
prophylax
is Ior
pregnant
women)

Anthelmintics

Albendazole Hepatic 8-12 hr Oral 400-800
mg daily


Diethylcarbamazine Renal 8 hr Oral 25
mg/day
Ior 3
days. then
50
mg/day
Ior 5
days. then
100
mg/day
Ior 3
days. then
150
mg/day
Ior 12
days


Ivermectin Hepatic 16-35
hr
Oral 150-200
mcg/kg ×
1 dose


Mebendazole Hepatic 8 hr Oral 100 mg
b.i.d. × 3
consecuti
ve days


Praziquantel Hepatic 0.8-3
hr
Oral 60-75
mg/kg in
3 divided
doses on
the same
day


Pyrantel Hepatic Oral 11 mg/kg
(maximu
m ÷ 1 g)
as a

single
dose

Thiabendazole Hepatic Oral Dose
based
upon
weight
chart in
prescribin
g
inIormati
on. 100
lb: 1 g
b.i.d. 125
lb: 1.25 g
b.i.d. ~
150 lb:
1.5 g
b.i.d.

CMJ. cytomegalovirus; EC cap. enteric-coated capsule; H. additional
signiIicant hepatic elimination; HSCT. hematopoietic stem cell transplant;
IM. intramuscular; IJ. intravenous; PIs. protease inhibitors R. additional
signiIicant renal elimination; SC. subcutaneous.

a
Dosage applies to inIections other than tuberculosis; Ior tuberculosis.
dosage is 1 g/day.

b
Intravenous agent withdrawn Irom U.S. market.


P. 924


2. Spect rum of acti vi t y
a. St rept omyci n i s act i ve agai nst bot h gr am- posi t i ve and gr am- negat i ve
bact er i a. However , wi despr ead r esi st ance t o t hi s dr ug has rest r i ct ed i t s use
t o t he or gani sms t hat cause pl ague and t ul ar emi a, gram-posi t i ve
st r ept ococci (gi ven i n combi nat i on wi t h peni ci l l i n) , and Mycobact er i um
t ubercul osi s ( gi ven i n combi nat i on wi t h ot her ant i t ubercul ar agent s, as
descr i bed i n VÌ . C. 2) .
b. Ami kaci n, kanamyci n, gent ami ci n, tobramyci n, neomyci n, and
net i I mi ci n are act i ve agai nst many gr am- negat i ve bact er i a ( e. g. , Pr ot eus,
Ser r at i a, and Pseudomonas or gani sms).
( 1) Gentami ci n i s act i ve agai nst some St aphyl ococcus st r ai ns; i t i s mor e
act i ve t han t obramyci n agai nst Ser rat i a organi sms.
( 2) Ami kaci n i s t he broadest spect r um ami nogl ycosi de wi t h act i vi t y agai nst
most aer obi c gram-negat i ve baci l l i as wel l as many anaer obi c gram-
negat i ve bact eri al st r ai ns t hat resi st gent ami ci n and t obramyci n. Ì t i s al so
act i ve agai nst M. t ubercul osi s and Mycobact eri um avi um- i nt racel l ul ar e
( MAÌ ) .
( 3) Tobramyci n may be mor e act i ve agai nst Pseudomonas aerugi nosa t han
gent ami ci n.
( 4) Net i I mi ci n may be act i ve agai nst gent ami ci n-r esi st ant or gani sms; i t
appears t o be l ess ot ot oxi c t han ot her ami nogl ycosi des.
( 5) Neomyci n, i n addi t i on t o i t s act i vi t y agai nst such gr am- negat i ve
or gani sms as Escheri chi a col i and Kl ebsi el l a pneumoni ae, i s act i ve agai nst
sever al gr am- posi t i ve organi sms ( e. g. , S. aur eus) . P. aer ugi nosa and most
st r ept ococci ar e now neomyci n resi st ant .
3. Therapeut i c uses
a. St rept omyci n i s used t o t reat pl ague, t ul ar emi a, acut e br ucel l osi s ( gi ven
i n combi nat i on wi t h t et r acycl i ne), bact er i al endocar di t i s caused by
St r ept ococcus vi ri dans (gi ven i n combi nat i on wi t h peni ci l l i n) , and
t ubercul osi s ( gi ven i n combi nat i on wi t h ot her ant i t ubercul ar agent s, as
descr i bed i n VÌ . C. 2) .
b. Gentami ci n, t obramyci n, ami kaci n, and net i I mi ci n are t her apeut i c f or
ser i ous gr am- negat i ve baci l l ar y i nf ect i ons ( e. g. , t hose caused by
Ent erobact er , Ser r at i a, Kl ebsi el l a, and P. aer ugi nosa), pneumoni a ( gi ven i n
combi nat i on wi t h a cephal ospor i n or peni ci l l i n) , meni ngi t i s, compl i cat ed
ur i nar y t r act i nf ect i ons, ost eomyel i t i s, bact er emi a, and per i t oni t i s.
c. Neomyci n i s used f or pr eoper at i ve bowel st eri l i zat i on; hepat i c coma (as
adj unct i ve t herapy) ; and, i n t opi cal f orm, f or ski n and mucous membr ane
i nf ect i ons (e. g. , bur ns) .
4. Precauti ons and moni t ori ng ef f ect s. Ami nogl ycosi des can cause
ser i ous adver se ef f ect s. To pr event or mi ni mi ze such pr obl ems, bl ood dr ug
concent r at i ons and bl ood ur ea ni t rogen ( BUN) and ser um cr eat i ni ne l evel s
shoul d be moni t ored dur i ng t her apy.
a. Ot ot oxi ci t y. Ami nogl ycosi des can cause vest i bul ar or audi t or y damage.
The r el at i ve ot ot oxi ci t y i s as f ol l ows:
st r ept omyci n = kanamyci n > ami kaci n = gent ami ci n = t obramyci n >
net i l mi ci n
( 1) Gent ami ci n and st r ept omyci n cause pri mar i l y vest i buI ar damage
( mani f est ed by t i nni t us, ver t i go, and at axi a) . Such damage may be bi l at eral
and i r r eversi bl e.
( 2) Ami kaci n, kanamyci n, and neomyci n cause mai nl y audi t or y damage
( heari ng l oss) .
( 3) Tobr amyci n can r esul t i n bot h vest i bul ar and audi t or y damage.
b. Nephrot oxi ci t y. Because ami nogl ycosi des accumul at e i n t he pr oxi mal
t ubul e, mi l d r enal dysf unct i on devel ops i n up t o 25% of pat i ent s recei vi ng
t hese dr ugs f or several days or mor e. Usual l y, t hi s adver se ef f ect i s
r ever si bl e. Use of once-dai l y admi ni st r at i on ( ODA) has been r epor t ed i n t he
l i t er at ur e t o be as ef f ect i ve and l ess nephrot oxi c t han t r adi t i onal dosi ng.
( 1) Neomyci n i s t he most nephr ot oxi c ami nogl ycosi de; st rept omyci n i s t he
l east nephr ot oxi c. Gent ami ci n and t obr amyci n are nephrot oxi c t o
approxi mat el y t he same degree.
( 2) Ri sk f act ors f or i ncreased nephr ot oxi c ef f ect s i ncl ude t he f ol l owi ng:
( a) Pr eexi st i ng r enal di sease
( b) Pr evi ous or pr ol onged ami nogl ycosi de t her apy
( c) Concur r ent admi ni st rat i on of anot her nephr ot oxi c dr ug
( d) Ì mpai r ed r enal f l ow unr el at ed t o r enal di sease ( e. g. , f rom hypot ensi on,
sever e hepat i c di sease)
P. 925


( 3) Tr ough l evel s > 2 µg/ mL f or gent ami ci n and t obr amyci n and > 10 µg/ mL
f or ami kaci n are associ at ed wi t h nephr ot oxi ci t y.
c. NeuromuscuI ar bI ockade. Thi s probl em may ar i se i n pat i ent s recei vi ng
hi gh- dose ami nogl ycosi de t her apy.
( 1) Ri sk f act ors f or neuromuscul ar bl ockade i ncl ude t he f ol l owi ng:
( a) Concur r ent admi ni st rat i on of a neur omuscul ar bl ocki ng agent or an
anest het i c
( b) Pr eexi st i ng hypocal cemi a or myast heni a gr avi s
( c) Ì nt r aper i t oneal or r api d Ì V dr ug admi ni st r at i on
( 2) Apnea and r espi r at ory depr essi on may be r ever sed wi t h admi ni st r at i on
of cal ci um or an ant i chol i nest erase.
d. Hypersensi ti vi t y and I ocaI react i ons ar e r are adverse ef f ect s of
ami nogl ycosi des.
e. Therapeut i c I eveI s
( 1) Gent ami ci n and t obr amyci n peak at 6- 10 µg/ mL f or t r adi t i onal dosi ng;
when usi ng t he ODA met hod, t he peak i s 16- 20 µg/ mL or 8- 10 t i mes t he
MÌ C of t ar get ed bact er i a. Thei r t rough l evel i s 0. 5- 1. 5 µg/ mL f or t radi t i onal
or once- dai l y r egi mens.
( 2) Ami kaci n peaks at 25- 30 µg/ mL. The t r ough l evel i s 5-8 µg/ mL.
5. Si gni f i cant i nteracti ons
a. I V I oop di uret i cs can r esul t i n i ncr eased ot ot oxi ci t y.
b. Ot her ami nogI ycosi des, cephaI othi n, ci spI ati n, amphot eri ci n B, and
met hoxyf I urane can cause i ncr eased nephr ot oxi ci t y when gi ven
concur rent l y wi t h st r ept omyci n.
C. Carbapenems. These agent s are 8- l act ams t hat cont ai n a f used 8-
l act am r i ng and a 5- member ed r i ng syst em t hat di f f ers f rom peni ci l l i ns i n
bei ng unsat ur at ed and cont ai ni ng a carbon at om i nst ead of a sul f ur at om.
The cl ass has a br oader spect rum of act i vi t y t han do most 8-l act ams.
For mer l y known as t hi enamyci n, i mi penem ( Pri maxi n) was t he f i r st
car bapenem compound i nt r oduced i n t he Uni t ed St at es, f ol l owed by
meropenem (Merrem) and, most recent l y, ertapenem ( I nvanz) and
dori penem ( Dori bax) . Because i t i s i nhi bi t ed by r enal di pept i dases,
i mi penem must be combi ned wi t h ci I astat i n sodi um, a di pept i dase i nhi bi t or
( ci l ast at i n i s not r equi r ed wi t h t he ot hers because t hese are not sensi t i ve t o
r enal di pept i dase) .
1. Mechani sm of act i on. Car bapenems ar e bacteri ci daI , i nhi bi t i ng
bact er i al cel l wal l synt hesi s.
2. Spect rum of acti vi t y. These dr ugs have t he br oadest spect r um of al l 8-
l act am ant i bi ot i cs. The gr oup i s act i ve agai nst most gr am- posi t i ve cocci
( i ncl udi ng many ent er ococci ) , gr am- negat i ve r ods ( i ncl udi ng many P.
aer ugi nosa st r ai ns) , and anaer obes. Thi s cl ass has good act i vi t y agai nst
many bact eri al st r ai ns t hat r esi st ot her ant i bi ot i cs. Er t apenem has a
nar r ower spect rum of act i vi t y t han t he ot her car bapenems. Ì t has l i t t l e or no
act i vi t y agai nst P. aer ugi nosa and Aci net obact er . These 8-l act am ant i bi ot i cs
r esi st dest ruct i on by most 8-l act amases.
3. Therapeut i c uses. Car bapenems are most val ued i n t he t r eat ment of
sever e i nf ect i ons caused by dr ug- r esi st ant or gani sms suscept i bl e t o t hese
agent s. These agent s are ef f ect i ve agai nst ur i nary t r act and l ower
r espi r at or y i nf ect i ons, i nt r a- abdomi nal and gynecol ogi cal i nf ect i ons, and
ski n, sof t - t i ssue, bone, and j oi nt i nf ect i ons.
4. Precauti ons and moni t ori ng ef f ect s
a. Carbapenems may cause nausea, vomi t i ng, di ar r hea, and
pseudomembranous col i t i s.
b. Sei zur es, di zzi ness, and hypot ensi on may devel op; sei zures appear l ess
f r equent l y wi t h mer openem or ert apenem (1. 5% of pat i ent s recei vi ng
i mi penem ver sus 0. 5% of t hose r ecei vi ng mer openem or er t apenem) .
c. Pat i ent s who ar e al l ergi c t o peni ci l l i n or cephal ospori ns may suf f er
cr oss-sensi t i vi t y r eact i ons dur i ng car bapenem t her apy.
D. CephaI ospori ns. These agent s are known as ß- I actam ant i bi oti cs
because t hei r chemi cal st r uct ur e consi st s of a 8-l act am r i ng adj oi ned t o a
t hi azol i di ne r i ng. Cephal ospor i ns gener al l y are cl assi f i ed i n f our maj or
gr oups based mai nl y on t hei r spect r um of act i vi t y ( Tabl e 44-2) .
1. Mechani sm of act i on. Cephal ospori ns are bact eri ci daI ; t hey i nhi bi t
bact er i al cel l wal l synt hesi s, reduci ng cel l wal l st abi l i t y and t hus causi ng
membr ane l ysi s.
P. 926


Table 44-2. Classification of Cephalosporins
First
Generation Second Generation Third Generation
Fourth
Generation
CeIadroxil
(DuriceI.
UltraceI)
a

CeIazolin
(AnceI.
KeIzol)
Cephalexin
(KeIlex)
a

Cephapirin
(CeIadyl)
Cephradine
(Anspor.
VeloseI)
a

CeIaclor (Ceclor)
a

CeImetazole
(ZeIazone)
CeIotetan (CeIotan)
b

CeIoxitin (MeIoxin)
CeIuroxime(ZinaceI)
CeIuroxime axetil
(CeItin)
a

CeIprozil (CeIzil)
a

LoracarbeI
(Lorabid)
a

CeIdinir
(OmniceI)
a

CeIixime
(Suprax)
a

CeIoperazone
(CeIobid)
CeIotaxime
(ClaIoran)
CeIpodoxime
proxetil
(Vantin)
a

CeItazidime
(Fortex.
TaziceI.
Tazidime)
CeItibuten
(Cedax)
a

CeItizoxime
(CeIizox)
CeItriaxone
(Rocephin)
CeIditoren
(SpectraceI)
a

CeIepime
(Maxipime)
a
Oral agent.

b
Discontinued in the U.S. market 2005.

2. Spect rum of acti vi t y
a. Fi rst - generati on cephal ospor i ns ar e act i ve agai nst most gr am-posi t i ve
cocci ( except ent er ococci ) as wel l as ent er i c aer obi c gr am-negat i ve baci l l i
( e. g. , E. col i , K. pneumoni ae, Prot eus mi rabi l i s) .
b. Second-generat i on cephal ospor i ns ar e act i ve agai nst t he or gani sms
cover ed by f i rst - generat i on cephal ospori ns and have ext ended gram-
negat i ve coverage, i ncl udi ng 8- l act amase- produci ng st rai ns of Haemophi l us
i nf l uenzae.
c. Thi rd- generat i on cephal ospor i ns have wi der act i vi t y agai nst most gr am-
negat i ve bact eri a, f or exampl e, Ent er obact er , Ci t r obact er , Ser r at i a,
Pr ovi denci a, Nei sser i a, and Haemophi l us organi sms, i ncl udi ng 8-l act amase-
pr oduci ng st rai ns.
d. Fourt h- generat i on cephal ospori ns i ncl ude cefepi me (Maxi pi me) , whi ch
i s t he f i rst member of t hi s group t o be mar ket ed. However , i t s desi gnat i on
as a f our t h- generat i on cephal ospor i n i s debat abl e. Cef epi me i s hi ghl y
r esi st ant t o 8-l act amases and has a l ow pr opensi t y f or sel ect i on of 8-
l act am- r esi st ant mut ant st r ai ns. Ì t shows evi dence of gr eat er act i vi t y versus
gr am- posi t i ve cocci , Ent er obact er i aceae, and Pseudomonas t han t hi r d-
gener at i on cephal ospor i ns.
e. Each gener at i on of cephal ospori n has shi f t ed t owar d i ncr eased gr am-
negat i ve act i vi t y but has l ost act i vi t y t owar d gr am- posi t i ve or gani sms.
Four t h- generat i on agent s have i mproved act i vi t y t owar d gr am-posi t i ve
or gani sms over t hi r d-gener at i on agent s.
3. Therapeut i c uses
a. Fi rst - generati on cephal ospor i ns commonl y are admi ni st ered t o t r eat
ser i ous Kl ebsi el l a i nf ect i ons and gram-posi t i ve and some gr am- negat i ve
i nf ect i ons i n pat i ent s wi t h mi l d peni ci l l i n al l er gy. These agent s al so are
used wi del y i n peri oper at i ve prophyl axi s. For most ot her i ndi cat i ons, t hey
ar e not t he pr ef er red dr ugs.
b. Second-generat i on cephal ospor i ns ar e val uabl e i n t he t r eat ment of
ur i nar y t r act i nf ect i ons resul t i ng f r om E. col i or gani sms, acut e ot i t i s medi a,
si nusi t i s, and gonococcal di sease caused by or gani sms t hat resi st ot her
agent s.
( 1) CefacI or ( CecI or) i s usef ul i n ot i t i s medi a and si nusi t i s i n pat i ent s who
ar e al l er gi c t o ampi ci l l i n and amoxi ci l l i n. Cef prozi I ( Cefzi I ) and I oracarbef
( Lorabi d) ar e second- gener at i on cephal ospori ns t hat can be admi ni st er ed
t wi ce dai l y but of f er no i mport ant spect rum di f f erences.
( 2) Cef oxi t i n (Mef oxi n) i s t her apeut i c f or mi xed aer obi c-anaer obi c
i nf ect i ons, such as i nt r a-abdomi nal i nf ect i on. The cef otet an ( Cefot an)
spect rum i s si mi l ar but t hi s agent can be gi ven t wi ce dai l y.
( 3) Cef uroxi me (Zi nacef) i s commonl y admi ni st ered f or out pat i ent
communi t y- acqui red pneumoni a.
c. Thi rd- generat i on cephal ospor i ns penet rat e t he cer ebr ospi nal f l ui d ( CSF)
and t hus ar e val uabl e i n t he t r eat ment of meni ngi t i s caused by such
or gani sms as meni ngococci , pneumococci , H. i nf l uenzae, and ent er i c gram-
negat i ve baci l l i .
P. 927


( 1) These agent s al so are used t o t r eat sepsi s of unknown or i gi n i n
i mmunosuppr essed pat i ent s and t o t r eat f ever i n neut ropeni c
i mmunosuppr essed pat i ent s ( gi ven i n combi nat i on wi t h an ami nogl ycosi de) .
( 2) Thi r d-gener at i on cephal ospor i ns ar e usef ul i n i nf ect i ons caused by many
or gani sms r esi st ant t o ol der cephal ospori ns.
( 3) These agent s ar e f r equent l y admi ni st er ed as empi r i c t herapy f or l i f e-
t hr eat eni ng i nf ect i on i n whi ch r esi st ant or gani sms are t he most l i kel y cause.
( 4) Ì ni t i al t her apy of mi xed bact er i al i nf ect i ons ( e. g. , sepsi s) commonl y
i nvol ves t hi r d- gener at i on cephal ospor i ns.
d. The f ourt h- generat i on agent , cef epi me, i s appr oved f or t r eat ment of
ur i nar y t r act i nf ect i ons, uncompl i cat ed ski n and ski n st r uct ur e i nf ect i ons,
pneumoni a, and empi ri c use i n f ebr i l e neut r openi c pat i ent s. Cef epi me has a
spect rum of act i vi t y si mi l ar t o t hi r d-gener at i on agent s but i s more r esi st ant
t o some 8- l act amases.
4. Precauti ons and moni t ori ng ef f ect s
a. Because al l cephal ospor i ns ( except cef oper azone) ar e el i mi nat ed r enal l y,
doses must be adj ust ed f or pat i ent s wi t h renal i mpai rment .
b. Cr oss-sensi t i vi t y wi t h peni ci l l i n has been r eport ed i n up t o 10% of
pat i ent s recei vi ng cephal ospor i ns. Mor e r ecent i nf or mat i on i ndi cat es t hat
t r ue cr oss- r eact i vi t y i s rar e.
c. Cephal ospori ns can cause hyper sensi t i vi t y r eact i ons si mi l ar t o t hose
r esul t i ng f r om peni ci l l i n (see Ì Ì . E. 1. e. ( 1)) . Mani f est at i ons i ncl ude f ever ,
macul opapul ar rash, anaphyl axi s, and hemol yt i c anemi a.
d. Ot her adver se ef f ect s i ncl ude nausea, vomi t i ng, di ar r hea, superi nf ect i on,
nephr ot oxi ci t y, and Cl ost r i di um di f f i ci l e-i nduced col i t i s; wi t h cef oper azone,
cef met azol e, and cef ot et an ( and f ormerl y moxal act am and cef amandol e) ,
bl eedi ng di at heses may occur . Bl eedi ng can be rever sed by vi t ami n K
admi ni st rat i on.
e. Cephal ospori ns may cause f al se- posi t i ve gl ycosur i a resul t s on t est s
usi ng t he copper r educt i on met hod.
f . Cef t ri axone now cont rai ndi cat ed i n newbor ns recei vi ng concur rent
admi ni st rat i on of cal ci um- cont ai ni ng sol ut i ons or pr oduct s due t o r i sk of
f at al preci pi t at i on i n l ungs and ki dneys. New war ni ng added al so st at i ng
t hat cef t r i axone and Ì V cal ci um- cont ai ni ng sol ut i ons shoul d not be
admi ni st er ed wi t hi n 48 hour s of each ot her .
5. Si gni f i cant i nteracti ons
a. Probeneci d may i mpai r t he excr et i on of cephal ospor i ns ( except
cef t azi di me) , causi ng i ncr eased cephal ospor i n l evel s and possi bl e t oxi ci t y.
b. AI cohoI consumpt i on may resul t i n a di sul f i ram- t ype r eact i on i n pat i ent s
r ecei vi ng cef met azol e, cef ot et an, and cef oper azone.
c. Ami nogI ycosi des or I oop di ureti cs may cause addi t i ve t oxi ci t y when
admi ni st er ed wi t h cephal ot hi n.
d. Pl asma concent rat i ons of cef acl or ext ended- rel ease t abl et s, cef di ni r, and
cef podoxi me may be r educed by coadmi ni st r at i on wi t h antaci ds.
e. H2-ant agoni st s may reduce pl asma l evel s of cef podoxi me and
cef ur oxi me.
f . I ron suppI ements and i ron- f orti f i ed f oods reduce absorpt i on of cef di ni r
by 80% and 30%, r espect i vel y.
E. Er yt hromyci ns. The chemi cal st r uct ur e of t hese macr ol i de ant i bi ot i cs i s
charact eri zed by a l act one ri ng t o whi ch sugars ar e at t ached. Er yt hr omyci n
base and t he est ol at e, et hyl succi nat e, and st ear at e sal t s ar e gi ven oral l y;
er yt hr omyci n l act obi onat e and gl ucept at e are gi ven par ent eral l y.
1. Mechani sm of act i on. Er yt hr omyci ns may be bact eri ci daI or
bact eri ostat i c; t hey bi nd t o t he 50S r i bosomal subuni t , i nhi bi t i ng bact er i al
pr ot ei n synt hesi s.
2. Spect rum of acti vi t y. Er yt hr omyci ns ar e act i ve agai nst many gram-
posi t i ve or gani sms, i ncl udi ng st r ept ococci ( e. g. , St r ept ococcus
pneumoni ae) , and Corynebact eri um and Nei sser i a speci es as wel l as some
st r ai ns of Mycopl asma, Legi onel l a, Treponema, and Bor det el l a. Some S.
aur eus st rai ns t hat r esi st peni ci l l i n G ar e suscept i bl e t o er yt hr omyci ns.
3. Therapeut i c uses
a. Er yt hromyci ns ar e t he pr ef er r ed drugs f or t he t r eat ment of Mycopl asma
pneumoni ae and Campyl obact er i nf ect i ons, Legi onnai r es di sease,
chl amydi al i nf ect i ons, di pht her i a, and pert ussi s.
P. 928


b. Ì n pat i ent s wi t h peni ci l l i n al l er gy, er yt hr omyci ns are i mpor t ant
al t er nat i ves i n t he t reat ment of pneumococcal pneumoni a, S. aur eus
i nf ect i ons, syphi l i s, and gonor r hea.
c. Er yt hromyci ns may be gi ven pr ophyl act i cal l y bef or e dent al pr ocedur es t o
pr event bact er i al endocar di t i s.
4. Precauti ons and moni t ori ng parameters
a. Gast r oi nt est i nal ( GÌ ) di st ress (e. g. , nausea, vomi t i ng, di ar rhea,
epi gast r i c di scomf or t ) may occur wi t h al l er yt hr omyci n f or ms and ar e t he
most common adverse ef f ect s.
b. Al l er gi c r eact i ons (r are) may pr esent as ski n er upt i ons, f ever , and
eosi nophi l i a.
c. Chol est at i c hepat i t i s may ari se i n pat i ent s t reat ed f or 1 week or l onger
wi t h er yt hr omyci n est ol at e; sympt oms usual l y di sappear wi t hi n a f ew days
af t er dr ug t her apy ends. Ther e have been i nf r equent repor t s of
hepat ot oxi ci t y wi t h ot her sal t s of er yt hromyci n.
d. Ì M i nj ect i ons of more t han 100 mg pr oduce sever e pai n persi st i ng f or
hours.
e. Tr ansi ent heari ng i mpai r ment may devel op wi t h hi gh-dose er yt hr omyci n
t her apy.
5. Si gni f i cant i nteracti ons
a. Er yt hromyci n i nhi bi t s t he hepat i c met abol i sm of t heophyI I i ne, r esul t i ng
i n t oxi c accumul at i on.
b. Er yt hromyci n i nt er f er es wi t h t he met abol i sm of di goxi n, cort i costeroi ds,
carbamazepi ne, cycI ospori n, and I ovastat i n, possi bl y pot ent i at i ng t he
ef f ect and t oxi ci t y of t hese dr ugs.
c. CI ari t hromyci n ( Bi axi n) may pot ent i at e oraI ant i coaguI ants ( moni t or
pr ot hr ombi n t i me) , i ncr ease cycI ospori ne l evel s wi t h i ncr eased t oxi ci t y,
and i ncr ease di goxi n and t heophyI I i ne l evel s.
d. Co-admi ni st r at i on of cl ar i t hr omyci n and ci sapri de may i ncrease ri sk of
ser i ous car di ac ar r hyt hmi as; coadmi ni st rat i on i s cont r ai ndi cat ed.
e. Sudden deat hs have been repor t ed when cl ar i t hr omyci n was added t o
ongoi ng pi mozi de t her apy; co-admi ni st r at i on i s cont r ai ndi cat ed.
6. AI t ernat i ves t o er yt hromyci n
a. CI ari t hromyci n, azi thromyci n ( Zi t hromax), and di ri t hromyci n
( Dynabac) ar e semi synt het i c macr ol i de ant i bi ot i cs. These expensi ve but
wel l - t ol er at ed al t er nat i ves t o er yt hromyci n ar e admi ni st er ed once dai l y.
( 1) CI ari t hromyci n
( a) Spect rum of act i vi t y. Cl ari t hromyci n i s mor e act i ve t han er yt hromyci n
agai nst st aphyl ococci and st r ept ococci . Ì n addi t i on t o act i vi t y agai nst ot her
or gani sms cover ed by eryt hr omyci n, i t i s al so act i ve i n vi t r o agai nst MAÌ ,
Toxopl asma gondi i , and Cr ypt ospor i di um spp.
( b) Therapeut i c uses. Thi s agent i s i ndi cat ed f or t he pr event i on of
Mycobact eri um avi um compl ex ( MAC) i nf ect i on and i s usef ul i n ot i t i s medi a,
si nusi t i s, mycopl asmal pneumoni a, and phar yngi t i s. Cl ari t hromyci n i s al so
used wi t h pr ot on pump i nhi bi t or s ( PPÌ s) f or Hel i cobact er pyl ori er adi cat i on.
( 2) Azi t hromyci n
( a) Spect rum of act i vi t y. Azi t hromyci n i s l ess act i ve t han er yt hromyci n
agai nst gram- posi t i ve cocci but mor e act i ve agai nst H. i nf l uenzae and ot her
gr am- negat i ve organi sms. Azi t hr omyci n concent rat es wi t hi n cel l s, and
t i ssue l evel s are hi gher t han serum l evel s.
( b) Therapeut i c uses. Thi s agent i s usef ul i n nongonococcal uret hr i t i s
caused by chl amydi a, l ower r espi r at or y t r act i nf ect i ons, ( MAC) i nf ect i on and
pr ophyl axi s, phar yngi t i s, pel vi c i nf l ammat or y di sease, and l egi onnai r es'
di sease. Azi t hromyci n i s al so i ndi cat ed f or pedi at r i c use.
( 3) Di ri t hromyci n i s i ndi cat ed f or t he t r eat ment of acut e exacer bat i ons of
chr oni c br onchi t i s, phar yngi t i s and t onsi l l i t i s caused by St r ept ococcus
pyogenes, and uncompl i cat ed ski n and ski n st r uct ur e i nf ect i ons caused by
S. aureus.
F. Peni ci I I i ns
1. NaturaI peni ci I I i ns. As wi t h cephal ospori ns and al l ot her peni ci l l i ns,
nat ural peni ci l l i ns ar e 8-l act am ant i bi ot i cs. Among t he most i mpor t ant
ant i bi ot i cs, nat ural peni ci l l i ns are t he pr ef er r ed dr ugs i n t he t reat ment of
many i nf ect i ous di seases.
a. Avai I abI e agent s
( 1) Peni ci I I i n G sodi um and pot assi um sal t s can be admi ni st er ed oral l y,
i nt ravenousl y, or i nt ramuscul arl y.
P. 929


( 2) Peni ci I I i n V ( Pen- Vee K) , a sol ubl e drug f orm, i s admi ni st er ed or al l y.
( 3) Peni ci I I i n G procai ne and peni ci I I i n G benzat hi ne are r eposi t or y drug
f or ms. Admi ni st er ed i nt ramuscul ar l y, t hese i nsol ubl e sal t s al l ow sl ow dr ug
absor pt i on f rom t he i nj ect i on si t e and t hus have a l onger durat i on of act i on
( 12- 24 hr) .
b. Mechani sm of act i on. Peni ci l l i ns ar e bacteri ci daI ; t hey i nhi bi t bact eri al
cel l wal l synt hesi s i n a manner si mi l ar t o t hat of t he cephal ospor i ns.
c. Spect rum of acti vi t y
( 1) Nat ur al peni ci l l i ns are hi ghl y act i ve agai nst gr am-posi t i ve cocci and
agai nst some gr am- negat i ve cocci .
( 2) Peni ci l l i n G i s 5- 10 t i mes mor e act i ve t han peni ci l l i n V agai nst gram-
negat i ve or gani sms and some anaer obi c organi sms.
( 3) Because nat ural peni ci l l i ns ar e r eadi l y hydr ol yzed by peni ci l l i nases ( 8-
l act amases) , t hey are i nef f ect i ve agai nst S. aur eus and ot her or gani sms
t hat r esi st peni ci l l i n.
d. Therapeut i c uses
( 1) Peni ci l l i n G i s t he pref er red agent f or al l i nf ect i ons caused by peni ci l l i n-
suscept i bl e S. pneumoni ae organi sms, i ncl udi ng
( a) Pneumoni a
( b) Ar t hr i t i s
( c) Meni ngi t i s
( d) Peri t oni t i s
( e) Peri car di t i s
( f ) Ost eomyel i t i s
( g) Mast oi di t i s
( 2) Peni ci l l i ns G and V ar e hi ghl y ef f ect i ve agai nst ot her st r ept ococcal
i nf ect i ons, such as phar yngi t i s, ot i t i s medi a, si nusi t i s, and bact er emi a.
( 3) Peni ci l l i n G i s t he pref er red agent i n gonococcal i nf ect i ons, syphi l i s,
ant hrax, act i nomycosi s, gas gangrene, and Li st eri a i nf ect i ons.
( 4) Admi ni st ered when an or al peni ci l l i n i s needed, peni ci l l i n V i s most
usef ul i n ski n, sof t - t i ssue, and mi l d respi rat or y i nf ect i ons.
( 5) Peni ci l l i n G procai ne i s ef f ect i ve agai nst syphi l i s and uncompl i cat ed
gonor r hea.
( 6) Used t o t r eat syphi l i s i nf ect i ons out si de t he CNS, peni ci l l i n G
benzat hi ne al so i s ef f ect i ve agai nst gr oup A8-hemol yt i c st rept ococcal
i nf ect i ons.
( 7) Peni ci l l i ns G and V may be used pr ophyl act i cal l y t o pr event
st r ept ococcal i nf ect i on, rheumat i c f ever , and neonat al gonor r hea
opht hal mi a. Pat i ent s wi t h val vul ar heart di sease may r ecei ve t hese drugs
pr eoper at i vel y.
( 8) Ther e i s emergi ng r esi st ance t o peni ci l l i n G by S. pneumoni ae i n some
ar eas of t he Uni t ed St at es. The al t ernat i ve t her apy i s vancomyci n.
e. Precauti ons and moni t ori ng ef f ect s
( 1) Hypersensi ti vi t y react i ons. These occur i n up t o 10% of pat i ent s
r ecei vi ng peni ci l l i n. Mani f est at i ons range f rom mi l d r ash t o anaphyl axi s.
( a) The rash may be ur t i car i al , vesi cul ar , bul l ous, scarl at i ni f orm, or
macul opapul ar . Rar el y, t hr ombopeni c purpura devel ops.
( b) Anaphyl axi s i s a l i f e-t hr eat eni ng r eact i on t hat most commonl y occurs
wi t h par ent eral admi ni st rat i on. Si gns and sympt oms i ncl ude sever e
hypot ensi on, bronchoconst r i ct i on, nausea, vomi t i ng, abdomi nal pai n, and
ext r eme weakness.
( c) Ot her mani f est at i ons of hyper sensi t i vi t y r eact i ons i ncl ude f ever,
eosi nophi l i a, angi oedema, and serum si ckness.
( d) Bef or e peni ci l l i n t herapy begi ns, t he pat i ent ' s hi st or y shoul d be
eval uat ed f or r eact i ons t o peni ci l l i n. A posi t i ve hi st or y pl aces t he pat i ent at
hei ght ened r i sk f or a subsequent r eact i on. Ì n most cases, such pat i ent s
shoul d r ecei ve a subst i t ut e ant i bi ot i c. ( However , hyper sensi t i vi t y r eact i ons
may occur even i n pat i ent s wi t h a negat i ve hi st or y. )
( 2) Ot her adverse ef fect s of nat ur al peni ci l l i ns i ncl ude GÌ di st r ess ( e. g. ,
nausea, di ar rhea), bone mar row suppr essi on ( e. g. , i mpai r ed pl at el et
aggregat i on, agr anul ocyt osi s) , and super i nf ect i on. Wi t h hi gh- dose t her apy,
sei zures may occur, par t i cul arl y i n pat i ent s wi t h r enal i mpai rment .
f . Si gni f i cant i nt eract i ons
( 1) Probeneci d i ncr eases bl ood l evel s of nat ural peni ci l l i ns and may be
gi ven concur r ent l y f or t hi s pur pose.
P. 930


( 2) Ant i bi ot i c ant agoni sm occurs when er yt hromyci ns, t et racycI i nes, or
chI orampheni coI i s gi ven wi t hi n 1 hr of t he admi ni st r at i on of peni ci l l i n. The
cl i ni cal si gni f i cance of such ant agoni sm i s not cl ear .
( 3) Wi t h peni ci l l i n G procai ne and benzat hi ne, pr ecaut i on must be used i n
pat i ent s wi t h a hi st or y of hypersensi t i vi t y react i ons t o peni ci l l i ns because
pr ol onged react i ons may occur . Ì nt r avascul ar i nj ect i on shoul d be avoi ded.
Pr ocai ne hyper sensi t i vi t y i s a cont rai ndi cat i on t o t he use of procai ne
peni ci l l i n G.
( 4) Parent er al product s cont ai n ei t her pot assi um (1. 7 mEq/ mi l l i on uni t s) or
sodi um ( 2 mEq/ mi l l i on uni t s) .
2. Peni ci I I i nase- resi st ant peni ci I I i ns. These peni ci l l i ns ar e not hydr ol yzed
by st aphyl ococcal peni ci l l i nases ( 8-l act amases) . These agent s i ncl ude
met hi ci I I i n, nafci I I i n, and t he i soxazoI yI peni ci I I i ns-cI oxaci I I i n,
di cI oxaci I I i n ( Dynapen) , and oxaci I I i n.
a. Mechani sm of act i on ( see Ì Ì . E. 1. b)
b. Spect rum of act i vi t y. Because t hese peni ci l l i ns r esi st peni ci l l i nases,
t hey are act i ve agai nst st aphyl ococci t hat produce t hese enzymes.
c. Therapeut i c uses
( 1) Peni ci l l i nase- resi st ant peni ci l l i ns ar e used sol el y i n st aphyl ococcal
i nf ect i ons resul t i ng f r om or gani sms t hat r esi st nat ur al peni ci l l i ns.
( 2) These agent s ar e l ess pot ent t han nat ur al peni ci l l i ns agai nst or gani sms
suscept i bl e t o nat ural peni ci l l i ns and t hus make poor subst i t ut es i n t he
t r eat ment of i nf ect i ons caused by t hese organi sms.
( 3) Nafci I I i n i s excr et ed by t he l i ver and t hus may be usef ul i n t r eat i ng
st aphyl ococcal i nf ect i ons i n pat i ent s wi t h renal i mpai r ment .
( 4) Oxaci I I i n, cI oxaci I I i n, and di cI oxaci I I i n ar e most val uabl e i n l ong- t erm
t her apy of ser i ous st aphyl ococcal i nf ect i ons ( e. g. , endocar di t i s,
ost eomyel i t i s) and i n t he t r eat ment of mi nor st aphyl ococcal i nf ect i ons of t he
ski n and sof t t i ssues.
d. Precaut i ons and moni t ori ng ef fects
( 1) As wi t h al l peni ci l l i ns, t he peni ci l l i nase- resi st ant gr oup can cause
hyper sensi t i vi t y r eact i ons (see Ì Ì . E. 1. e. ( 1) ).
( 2) Met hi ci l l i n may cause nephr ot oxi ci t y and i nt erst i t i al nephr i t i s.
( 3) Oxaci l l i n may be hepat ot oxi c.
( 4) Compl et e cross- resi st ance exi st s among t he peni ci l l i nase- r esi st ant
peni ci l l i ns.
e. Si gni f i cant i nteracti ons. Probeneci d i ncreases bl ood l evel s of t hese
peni ci l l i ns and may be gi ven concur r ent l y f or t hat pur pose.
3. Ami nopeni ci I I i ns. Thi s peni ci l l i n gr oup i ncl udes t he semi synt het i c
agent s ampi ci I I i n and amoxi ci I I i n ( Amoxi I ) . Because of t hei r wi der
ant i bact eri al spect rum, t hese drugs are al so known as broad- spect rum
peni ci I I i ns.
a. Mechani sm of act i on ( see Ì Ì . E. 1. b)
b. Spect rum of act i vi t y. Ami nopeni ci l l i ns have a spect rum t hat i s si mi l ar t o
but br oader t han t hat of t he nat ur al and peni ci l l i nase-r esi st ant peni ci l l i ns.
Easi l y dest royed by st aphyl ococcal peni ci l l i nases, ami nopeni ci l l i ns ar e
i nef f ect i ve agai nst most st aphyl ococcal or gani sms. Agai nst most bact er i a
sensi t i ve t o peni ci l l i n G, ami nopeni ci l l i ns ar e sl i ght l y l ess ef f ect i ve t han t hi s
agent .
c. Therapeut i c uses. Ami nopeni ci l l i ns are used t o t reat gonococcal
i nf ect i ons, upper respi rat or y i nf ect i ons, uncompl i cat ed ur i nar y t r act
i nf ect i ons, and ot i t i s medi a caused by suscept i bl e or gani sms.
( 1) For i nf ect i ons r esul t i ng f rom peni ci l l i n- r esi st ant organi sms, ampi ci I I i n
may be gi ven i n combi nat i on wi t h sul bact am ( Unasyn) .
( 2) Amoxi ci I I i n i s l ess ef f ect i ve t han ampi ci l l i n agai nst shi gel l osi s.
( 3) Amoxi ci I I i n i s more ef f ect i ve agai nst S. aur eus, Kl ebsi el l a, and
Bact er oi des f ragi l i s i nf ect i ons when admi ni st ered i n combi nat i on wi t h
cl avul ani c aci d÷amoxi ci l l i n/ pot assi um cl avul anat e ( Augmenti n) because
cl avul ani c aci d i nact i vat es peni ci l l i nases.
d. Precaut i ons and moni t ori ng ef fects
( 1) Hypersensi t i vi t y react i ons may occur (see Ì Ì . E. 1. e. ( 1) ) .
( 2) Di ar r hea i s most common wi t h ampi ci l l i n.
( 3) Ì n addi t i on t o t he urt i car i al hypersensi t i vi t y r ash seen wi t h al l
peni ci l l i ns, ampi ci l l i n and amoxi ci l l i n f requent l y cause a gener al i zed
er yt hemat ous, macul opapul ar r ash. ( Thi s occur s i n 5%- 10% of pat i ent s
r ecei vi ng ampi ci l l i n. )
e. Si gni f i cant i nteracti ons (see Ì Ì . E. 2. e)
P. 931


4. Extended- spect rum peni ci I I i ns. These agent s have t he wi dest
ant i bact eri al spect rum of al l peni ci l l i ns. Al so cal l ed ant i pseudomonaI
peni ci I I i ns, t hi s gr oup i ncl udes t he carboxypeni ci I I i n ( e. g. , t i carci I I i n)
and t he urei dopeni ci I I i ns ( e. g. , mezI oci I I i n, pi peraci I I i n).
a. Mechani sm of act i on ( see Ì Ì . E. 1. b)
b. Spect rum of act i vi t y. These dr ugs have a spect r um si mi l ar t o t hat of t he
ami nopeni ci l l i ns but al so ar e ef f ect i ve agai nst Kl ebsi el l a and Ent er obact er
spp. , some B. f r agi l i s organi sms, and i ndol e- posi t i ve Pr ot eus and
Pseudomonas or gani sms.
( 1) Ti carci I I i n i s act i ve agai nst P. aerugi nosa. Combi ned wi t h cl avul ani c
aci d ( Ti ment i n), t i car ci l l i n has enhanced act i vi t y agai nst organi sms t hat
r esi st t i carci l l i n al one.
( 2) Pi peraci I I i n i s more act i ve t han t i carci l l i n agai nst Pseudomonas
or gani sms.
( 3) Pi peraci I I i n and t azobactam (Zosyn) . Tazobact am i s a 8- l act amase
i nhi bi t or t hat expands t he spect r um of act i vi t y t o i ncl ude some or gani sms
not sensi t i ve t o pi per aci l l i n al one ( i f r esi st ance i s t he r esul t of 8- l act amase
pr oduct i on) , i ncl udi ng st rai ns of st aphyl ococci , Haemophi l us, Bact eroi des,
and Ent erobact er i aceae. General l y, t azobact am does not enhance act i vi t y
agai nst Pseudomonas.
c. Therapeut i c uses. Ext ended-spect rum peni ci l l i ns ar e used mai nl y t o
t r eat ser i ous i nf ect i ons caused by gr am- negat i ve or gani sms ( e. g. , sepsi s;
pneumoni a; i nf ect i ons of t he abdomen, bone, and sof t t i ssues) .
Pi peraci l l i n/ t azobact am i s ef f ect i ve i n t he t r eat ment of nosocomi al
pneumoni a.
d. Precaut i ons and moni t ori ng ef fects
( 1) Hypersensi t i vi t y react i ons may occur (see Ì Ì . E. 1. e. ( 1) ) .
( 2) Ti car ci l l i n may cause hypokal emi a.
( 3) The hi gh sodi um cont ent of t i car ci l l i n may pose a danger t o pat i ent s
wi t h heart f ai l ur e ( HF) .
( 4) Al l i nhi bi t pl at el et aggr egat i on, whi ch may resul t i n bl eedi ng.
e. Si gni f i cant i nteracti ons (see Ì Ì . E. 2. e)
G. SuI f onami des. Deri vat i ves of sul f ani l ami de, t hese agent s wer e t he f i rst
dr ugs t o prevent and cure human bact er i al i nf ect i on successf ul l y. Al t hough
t hei r cur r ent usef ul ness i s l i mi t ed by t he i nt roduct i on of more ef f ect i ve
ant i bi ot i cs and t he emergence of resi st ant bact eri al st rai ns, sul f onami des
r emai n t he drugs of choi ce f or cer t ai n i nf ect i ons. The maj or sul f onami des
ar e suI f adi azi ne, suI famet hoxazoI e, suI f i soxazoI e, and suI famet hi zoI e.
1. Mechani sm of act i on. Sul f onami des ar e bacteri ostat i c; t hey suppress
bact er i al gr owt h by t r i gger i ng a mechani sm t hat bl ocks f ol i c aci d synt hesi s,
t her eby f orci ng bact eri a t o synt hesi ze t hei r own f ol i c aci d.
2. Spect rum of acti vi t y. Sul f onami des are br oad- spect rum agent s wi t h
act i vi t y agai nst many gram- posi t i ve or gani sms (e. g. , S. pyogenes, S.
pneumoni ae) and cer t ai n gr am- negat i ve or gani sms ( e. g. , H. i nf l uenzae, E.
col i , P. mi r abi l i s) . They al so are ef f ect i ve agai nst cer t ai n st r ai ns of
Chl amydi a t r achomat i s, Nocardi a, Act i nomyces, and Baci l l us ant hraci s.
3. Therapeut i c uses
a. Sul f onami des most of t en are used t o t reat ur i nar y t r act i nf ect i ons caused
by E. col i , i ncl udi ng acut e and chr oni c cyst i t i s, and chr oni c upper uri nar y
t r act i nf ect i ons.
b. These agent s have val ue i n t he t r eat ment of nocardi osi s, t r achoma and
i ncl usi on conj unct i vi t i s, and dermat i t i s herpet i f or mi s.
c. SuI f adi azi ne may be admi ni st er ed i n combi nat i on wi t h pyr i met hami ne t o
t r eat t oxopl asmosi s.
d. SuI famet hoxazoI e may be gi ven i n combi nat i on wi t h t r i met hopri m
( Bact ri m) t o t r eat such i nf ect i ons as Pneumocyst i s cari ni i pneumoni a,
Shi gel l a ent eri t i s, Ser rat i a sepsi s, ur i nar y t ract i nf ect i ons, r espi r at or y
i nf ect i ons, and gonococcal ur et hr i t i s ( see Ì Ì . J. 7. c). Ì t i s t he drug of choi ce
i n t he t r eat ment of St enot r ophomonas mal t ophi l i a.
e. SuI f i soxazoI e i s somet i mes used i n combi nat i on wi t h er yt hr omyci n
et hyl succi nat e t o t reat acut e ot i t i s medi a caused by H. i nf l uenzae
or gani sms. For t he i ni t i al t r eat ment of uncompl i cat ed ur i nar y t ract
i nf ect i ons, sul f i soxazol e may be gi ven i n combi nat i on wi t h phenazopyr i di ne
f or r el i ef of sympt oms of pai n, bur ni ng, or urgency.
f . Pr ophyl act i c sul f onami de t her apy has been used successf ul l y t o pr event
st r ept ococcal i nf ect i ons and rheumat i c f ever r ecur r ences.
4. Precauti ons and moni t ori ng ef f ect s
a. Sul f onami des may cause bl ood dyscr asi as ( e. g. , hemol yt i c anemi a÷
par t i cul arl y i n pat i ent s wi t h G6PD def i ci ency, apl ast i c anemi a,
t hr ombocyt openi a, agranul ocyt osi s, and eosi nophi l i a) .
P. 932


b. Hypersensi t i vi t y react i ons t o sul f onami des probabl y r esul t f r om
sensi t i zat i on and most commonl y i nvol ve t he ski n and mucous membr anes.
Mani f est at i ons i ncl ude var i ous t ypes of ski n r ash, exf ol i at i ve dermat i t i s, and
phot osensi t i vi t y. Dr ug f ever and ser um si ckness al so may devel op.
c. Cr yst al l ur i a and hemat ur i a may occur , possi bl y l eadi ng t o uri nar y t r act
obst r uct i on. ( Adequat e f l ui d i nt ake and ur i ne al kal i ni zat i on can prevent or
mi ni mi ze t hi s r i sk. ) Sul f onami des shoul d be used caut i ousl y i n pat i ent s wi t h
r enal i mpai rment .
d. Li f e-t hr eat eni ng hepat i t i s caused by drug t oxi ci t y or sensi t i zat i on i s a
r ar e adverse ef f ect . Si gns and sympt oms i ncl ude headache, nausea,
vomi t i ng, and j aundi ce.
e. AÌ DS pat i ent s have i ncr eased f requency of cut aneous hypersensi t i vi t y
r eact i ons t o sul f amet hoxazol e.
5. Si gni f i cant i nteracti ons. Sul f onami des may pot ent i at e t he ef f ect s of
phenyt oi n, oraI ant i coaguI ant s, and suI f onyI ur eas.
H. Tet racycI i nes. These br oad-spect rum agent s ar e ef f ect i ve agai nst
cer t ai n bact er i al st r ai ns t hat r esi st ot her ant i bi ot i cs. Nonet hel ess, t hey are
t he pr ef er r ed drugs i n onl y a f ew si t uat i ons. The maj or t et r acycl i nes i ncl ude
demecI ocycI i ne ( DecI omyci n) , doxycycI i ne ( Vi bramyci n) , mi nocycI i ne
( Mi noci n), and chI ortet racycI i ne.
1. Mechani sm of act i on. Tet r acycl i nes are bacteri ostat i c; t hey i nhi bi t
bact er i al pr ot ei n synt hesi s by bi ndi ng t o t he 30S r i bosomal subuni t .
2. Spect rum of acti vi t y. Tet r acycl i nes are act i ve agai nst gr am- negat i ve
and gr am- posi t i ve or gani sms, spi r ochet es, Mycopl asma and Chl amydi a
or gani sms, ri cket t si al speci es, and cer t ai n prot ozoa.
a. Pseudomonas and Pr ot eus organi sms are now r esi st ant t o t et racycl i nes.
Many col i f or m bact er i a, pneumococci , st aphyl ococci , st rept ococci , and
Shi gel l a st r ai ns are i ncreasi ngl y r esi st ant .
b. Cr oss-r esi st ance wi t hi n t he t et r acycl i ne group i s ext ensi ve.
3. Therapeut i c uses
a. Tet r acycl i nes ar e t he agent s of choi ce i n ri cket t si al ( Rocky Mount ai n
spot t ed f ever) , chl amydi al , and mycopl asmal i nf ect i ons; amebi asi s; and
baci l l ar y i nf ect i ons (e. g. , chol era, br ucel l osi s, t ul ar emi a, some Sal monel l a
and Shi gel l a i nf ect i ons).
b. Tet r acycl i nes ar e usef ul al t er nat i ves t o peni ci l l i n i n t he t r eat ment of
ant hrax, syphi l i s, gonor rhea, Lyme di sease, nocar di osi s, and H. i nf l uenzae
r espi r at or y i nf ect i ons.
c. Or al or t opi cal t et racycl i ne may be admi ni st er ed as a t r eat ment f or acne.
d. DoxycycI i ne i s hi ghl y ef f ect i ve i n t he pr ophyl axi s of " t ravel er ' s di ar rhea¨
( commonl y caused by E. col i ) . Because t he drug i s excr et ed mai nl y i n t he
f eces, i t i s t he saf est t et r acycl i ne f or t he t r eat ment of ext r ar enal i nf ect i ons
i n pat i ent s wi t h r enal i mpai rment .
e. DemecI ocycI i ne i s used commonl y as an adj unct i ve agent t o t r eat t he
syndrome of i nappropri at e ant i di uret i c hormone ( SI ADH) secr et i on.
4. Precauti ons and moni t ori ng ef f ect s
a. GÌ di st r ess ( e. g. , di ar rhea, abdomi nal di scomf or t , nausea, anor exi a) i s a
common adverse ef f ect of t et r acycl i nes. Thi s pr obl em can be mi ni mi zed by
admi ni st er i ng t he dr ug wi t h f ood or t empor ari l y decr easi ng t he dosage.
b. Ski n r ash, ur t i car i a, and gener al i zed exf ol i at i ve dermat i t i s si gni f y a
hyper sensi t i vi t y r eact i on. Rar el y, angi oedema and anaphyl axi s occur .
c. Cr oss- sensi t i vi t y wi t hi n t he t et r acycl i ne group i s common.
d. Phot ot oxi c r eact i ons (sever e ski n l esi ons) can devel op wi t h exposur e t o
sunl i ght . Thi s r eact i on i s most common wi t h demecl ocycl i ne and
doxycycl i ne.
e. Tet r acycl i nes may cause hepat ot oxi ci t y, par t i cul arl y i n pr egnant women.
Mani f est at i ons i ncl ude j aundi ce, aci dosi s, and f at t y l i ver i nf i l t rat i on.
f . Renal l y i mpai r ed pat i ent s may exper i ence a si gni f i cant i ncr ease i n BUN
secondar y t o cat abol i c ef f ect s of t et racycl i nes.
g. Tet r acycl i nes may i nduce permanent t oot h di scol or at i on, t oot h enamel
def ect s, and r et ar ded bone growt h i n i nf ant s and chi l dren.
h. Use of out dat ed and degr aded t et r acycl i nes can l ead t o renal t ubul ar
dysf unct i on, possi bl y r esul t i ng i n r enal f ai l ure.
i . Mi nocycl i ne can cause vest i bul ar t oxi ci t y ( e. g. , at axi a, di zzi ness, nausea,
vomi t i ng).
j . Ì V t et racycl i nes are i r ri t at i ng and may cause phl ebi t i s.
P. 933


5. Si gni f i cant i nteracti ons
a. Dai r y product s and ot her f oods, i ron preparat i ons, and ant aci ds and
I axati ves cont ai ni ng al umi num, cal ci um, or magnesi um can cause r educed
t et r acycl i ne absor pt i on. Absorpt i on of doxycycl i ne i s not i nhi bi t ed by t hese
f act or s.
b. Met hoxyf I urane may exacer bat e t he t et racycl i nes' nephr ot oxi c ef f ect s.
c. Barbi t urates and phenyt oi n decrease t he ant i bi ot i c ef f ect i veness of
t et r acycl i nes.
d. Demecl ocycl i ne ant agoni zes t he act i on of anti di uret i c hormone ( ADH)
and may be gi ven as a di ur et i c i n pat i ent s wi t h SÌ ADH.
I . FI uoroqui noI ones are agent s r el at ed t o nal i di xi c aci d÷see Ì Ì . Ì . 1. c;
Ì Ì . 2. c. (1) ; Ì Ì . 4. c. ( 1) ÷and i ncl ude ci prof I oxaci n (Ci pro) , enoxaci n
( Penet rex) , I omef I oxaci n ( Maxaqui n), norfI oxaci n ( Noroxi n) , ofI oxaci n
( FI oxi n) , moxi f I oxaci n (AveI ox) , I evof I oxaci n (Levaqui n) , and
gemi fI oxaci n ( Fact i ve) . They ar e bact er i ci dal f or gr owi ng bact eri a.
1. Mechani sm of act i on. Fl uor oqui nol ones i nhi bi t DNA gyr ase.
2. Spect rum of acti vi t y. Fl uor oqui nol ones ar e hi ghl y act i ve agai nst ent eri c
gr am- negat i ve baci l l i , Sal monel l a, Shi gel l a, Campyl obact er, Haemophi l us,
and Nei sser i a.
a. Ci prof I oxaci n has act i vi t y agai nst P. aer ugi nosa, but t he
f l uor oqui nol ones as a group have vari abl e act i vi t y agai nst non- P.
aer ugi nosa. Ci pr of l oxaci n i s act i ve agai nst some anaer obes; i t has
moder at e act i vi t y agai nst M. t ubercul osi s.
b. Gr am- posi t i ve or gani sms ar e l ess suscept i bl e t han gr am- negat i ve
or gani sms but usual l y are sensi t i ve, except f or Ent er ococcus f aecal i s and
met hi ci l l i n- r esi st ant st aphyl ococci .
c. Of I oxaci n has t he great est act i vi t y agai nst Chl amydi a.
3. Therapeut i c uses ( Tabl e 44-3)
a. Nor f l oxaci n i s i ndi cat ed f or t he oral t r eat ment of uri nar y t r act i nf ect i ons,
uncompl i cat ed gonococcal i nf ect i ons, and prost at i t i s.
b. Ci pr of l oxaci n, of l oxaci n, and l evof l oxaci n ar e avai l abl e or al l y and
i nt ravenousl y. Ci prof l oxaci n i s appr oved f or use i n uri nar y t r act i nf ect i ons;
l ower r espi rat or y i nf ect i ons; si nusi t i s; bone, j oi nt , and ski n st r uct ure
i nf ect i ons; empi ri c use i n f ebr i l e neut r openi c pat i ent s; t yphoi d f ever ;
ur et hr al and cer vi cal gonococcal i nf ect i ons; and i nf ect i ous di ar rhea.
Of l oxaci n i s appr oved f or use i n l ower r espi rat ory i nf ect i ons, uncompl i cat ed
gonococcal and chl amydi al cer vi ci t i s and ur et hr i t i s, ski n and ski n st r uct ure
i nf ect i ons, pr ost at i t i s, and uri nar y t r act i nf ect i ons.
c. Lomef l oxaci n, l evof l oxaci n, and enoxaci n ar e appr oved f or t he t reat ment
of uri nar y t r act i nf ect i ons. Lomef l oxaci n, moxi f l oxaci n, and l evof l oxaci n ar e
al so used i n l ower r espi rat or y i nf ect i ons.
d. Moxi f l oxaci n i s appr oved f or t he t r eat ment of compl i cat ed i nt ra-
abdomi nal i nf ect i ons but shoul d not be used f or ur i nar y t r act i nf ect i ons.
4. Precauti ons and moni t ori ng ef f ect s
a. Occasi onal adver se ef f ect s i ncl ude nausea, dyspepsi a, headache,
di zzi ness, i nsomni a, cardi ac QT pr ol ongat i on, art hr opat hy, t endoni t i s, CNS
ef f ect s, phot osensi t i vi t y, and hypogl ycemi a.
Table 44-3. Quinolone Agents Classified by Generation
Agent
Spectrum of
Coverage Site of Infection
First-
generation
Cinoxacin
(Cinoxacin.
Cinobac)
Gram
negatives
Urinary tract
Enoxacin (Penetrex)

Nalidixic acid
(NegGram)


NorIloxacin
(Noroxin)

Second-
generation
LomeIloxacin
(Maxaquin)
Gram
negatives
Urinary tract

CiproIloxacin
(Cipro)
Systemic.
urinary tract

OIloxacin (Floxin)

Systemic.
urinary tract
Third-
generation
LevoIloxacin
(Levaquin)
Gram
negatives
Systemic.
urinary tract

MoxiIloxacin
(Avelox)
Atypicals Systemic only

P. 934


b. Ì nf r equent adver se ef f ect s i ncl ude rash, ur t i cari a, l eukopeni a, and
el evat ed l i ver enzymes. Cr yst al l uri a occurs wi t h hi gh doses at al kal i ne pH.
c. The FDA has added a bl ack box war ni ng about t he i ncr eased ri sk of
devel opi ng t endi ni t i s and t endon r upt ur e i n pat i ent s t aki ng t hi s cl ass of
medi cat i ons.
5. Si gni f i cant i nteracti ons
a. Ci pr of l oxaci n has been shown t o i ncr ease t heophyI I i ne l evel s. Var i abl e
ef f ect s on t heophyl l i ne l evel s have been repor t ed f r om ot her members of
t he gr oup. Ì n pat i ent s requi ri ng f l uoroqui nol ones, t heophyl l i ne l evel s shoul d
be moni t ored.
b. Ant aci ds and sucraI fat e and di val ent or t r i val ent cat i ons such as i ron
si gni f i cant l y decr ease t he absorpt i on of f l uor oqui nol ones.
c. Fl uoroqui nol ones may i ncr ease pr ot hrombi n t i mes i n pat i ent s recei vi ng
warf ari n.
d. Concurr ent use wi t h nonst eroi daI ant i - i nf I ammat or y drugs ( NSAÌ Ds)
may i ncrease t he r i sk of CNS st i mul at i on ( sei zures) .
e. Fl uoroqui nol ones may pr oduce prol onged QT i nt er val when admi ni st ered
wi t h ci sapri de and ant i arrhyt hmi c agents. Some f l uor oqui nol ones (i . e. ,
gat i f l oxaci n, moxi f l oxaci n) shoul d be avoi ded i n pat i ent s wi t h known
pr ol ongat i on of t he QTC i nt er val , wi t h uncor rect ed hypocal cemi a, or who
ar e recei vi ng cl ass Ì A or cl ass Ì Ì Ì ant i ar r hyt hmi c dr ugs.
f . Some f l uor oqui nol ones have been r epor t ed t o enhance t he ef f ect s of or al
ant i coagul ant s.
g. Hyper gl ycemi a and hypogl ycemi a have been repor t ed i n pat i ent s
r ecei vi ng qui nol ones and an ant i di abet i c agent . Bl ood gl ucose moni t or i ng i s
r ecommended i n such pat i ent s.
h. Di danosi ne shoul d be admi ni st er ed at l east 4 hr af t er gat i f l oxaci n.
J. Uri nar y t ract ant i sept i cs. Concent r at i ng i n t he r enal t ubul es and
bl adder, t hese agent s exer t l ocal ant i bact er i al ef f ect s; most do not achi eve
bl ood l evel s hi gh enough t o t reat syst emi c i nf ect i ons. However , some new
qui nol one der i vat i ves, such as ci pr of l oxaci n and of l oxaci n, are val uabl e i n
t he t r eat ment of cert ai n i nf ect i ons out si de t he uri nar y t r act ( see Ì Ì . H. 3. b) .
1. Mechani sm of act i on
a. Met henami ne i s hydrol yzed t o ammoni a and f or mal dehyde i n aci di c
ur i ne; f or mal dehyde i s ant i bact er i al agai nst gr am- posi t i ve and gr am-
negat i ve or gani sms. Mandel i c and hi ppur i c aci ds, wi t h whi ch met henami ne
i s combi ned, pr ovi de suppl ement ar y ant i bact eri al act i on.
b. Ni t rofurant oi n i s bact eri ostat i c; i n hi gh concent r at i ons, i t may be
bact eri ci daI . Pr esumabl y, i t di srupt s bact eri al enzyme syst ems.
c. Qui noI ones. NaI i di xi c aci d and i t s anal ogs and der i vat i ves÷oxoI i ni c
aci d, norfI oxaci n, ci noxaci n, ci prof I oxaci n, and ot hers÷i nt er f er e wi t h
DNA gyr ase and i nhi bi t DNA synt hesi s duri ng bact eri al r epl i cat i on.
d. Fosf omyci n t romet hami ne i s bact eri ci dal i n t he uri ne at t her apeut i c
doses. The bact er i ci dal act i on i s because of i t s i nact i vat i on of t he enzyme
enol pyr uvyl t r ansf erase, t her eby bl ocki ng t he condensat i on of ur i di ne
di phosphat e- N-acet yl gl ucosami ne wi t h p- enol pyruvat e, one of t he f i r st st eps
i n bact er i al cel l wal l synt hesi s.
2. Spect rum of acti vi t y
a. Met henami ne i s act i ve agai nst bot h gr am- posi t i ve and gr am- negat i ve
or gani sms ( e. g. , Ent er obact er , Kl ebsi el l a, Pr ot eus, P. aerugi nosa, S.
aur eus).
b. Ni t rofurant oi n i s act i ve agai nst many gr am- posi t i ve and gr am- negat i ve
or gani sms, i ncl udi ng some st rai ns of E. col i , S. aur eus, Pr ot eus,
Ent erobact er , and Kl ebsi el l a.
c. Qui noI ones ( see Ì Ì . H)
( 1) NaI i di xi c aci d and oxoI i ni c aci d are act i ve agai nst most gr am-negat i ve
or gani sms t hat cause uri nar y t r act i nf ect i ons, i ncl udi ng P. mi r abi l i s, E. col i ,
Kl ebsi el l a, and Ent er obact er or gani sms. These drugs ar e not ef f ect i ve
agai nst Pseudomonas organi sms.
( 2) Norf I oxaci n i s act i ve agai nst E. col i , Ent erobact er , Kl ebsi el l a, Pr ot eus,
P. aerugi nosa, S. aur eus, Ci t robact er , and some St r ept ococcus or gani sms.
( 3) Ci noxaci n i s act i ve agai nst E. col i , Kl ebsi el l a, P. mi r abi l i s, Prot eus
vul gari s, Pr ot eus mor gani i , Ser rat i a, and Ci t robact er or gani sms.
3. Therapeut i c uses
a. Met henami ne and ni trof urant oi n ar e used t o pr event and t reat ur i nar y
t r act i nf ect i ons.
P. 935


b. Qui noI ones ar e admi ni st er ed t o t reat ur i nar y t r act i nf ect i ons; some al so
ar e used i n such di seases as ost eomyel i t i s and respi rat or y t r act i nf ect i ons.
c. Fosf omyci n i s i ndi cat ed f or t reat ment of uncompl i cat ed uri nar y t r act
i nf ect i on ( acut e cyst i t i s) i n women caused by suscept i bl e st rai ns of E. col i
or E. f aecal i s.
4. Precauti ons and moni t ori ng ef f ect s
a. Met henami ne may cause nausea, vomi t i ng, and di ar rhea; i n hi gh doses,
i t may l ead t o ur i nar y t ract i r r i t at i on (e. g. , dysuri a, f r equency, hemat ur i a,
al bumi nuri a). Ski n r ash al so may devel op.
b. Ni t rofurant oi n may cause var i ous adver se ef f ect s.
( 1) GÌ di st r ess ( e. g. , nausea, vomi t i ng, di ar r hea) i s rel at i vel y common.
( 2) Hypersensi t i vi t y react i ons t o ni t rof urant oi n may i nvol ve t he ski n, l ungs,
bl ood, or l i ver ; mani f est at i ons i ncl ude f ever , chi l l s, hepat i t i s, j aundi ce,
l eukopeni a, hemol yt i c anemi a, gr anul ocyt openi a, and pneumoni t i s.
( 3) Adverse CNS ef f ect s i ncl ude headache, ver t i go, and di zzi ness.
Pol yneur opat hy may devel op wi t h hi gh doses or i n pat i ent s wi t h r enal
i mpai rment .
c. Qui noI ones
( 1) NaI i di xi c aci d and oxoI i ni c aci d may cause nausea, vomi t i ng,
abdomi nal pai n, urt i cari a, pr uri t us, ski n r ash, f ever , eosi nophi l i a, and CNS
ef f ect s, such as headache, di zzi ness, conf usi on, ver t i go, drowsi ness, and
weakness.
( 2) Ci noxaci n may i nduce nausea, vomi t i ng, di ar rhea, headache, i nsomni a,
ski n rash, pr ur i t us, and ur t i cari a.
5. Si gni f i cant i nteracti ons
a. The ef f ect s of met henami ne ar e i nhi bi t ed by aI kaI i ni zi ng agent s and ar e
ant agoni zed by acet azoI ami de.
b. Ni t rof ur ant oi n absor pt i on i s decr eased by magnesi um- cont ai ni ng
ant aci ds. Ni t r of ur ant oi n bl ood l evel s ar e i ncr eased and ur i ne l evel s
decreased by suI f i npyrazone and probeneci d, l eadi ng t o i ncr eased t oxi ci t y
and reduced t herapeut i c ef f ect i veness.
c. Qui noI ones
( 1) Ci noxaci n ur i ne l evel s are decreased by probeneci d, reduci ng
t her apeut i c ef f ect i veness.
( 2) Nor f l oxaci n i s rendered l ess ef f ect i ve by ant aci ds.
K. Mi sceI I aneous ant i bact eri aI agent s
1. Azt reonam ( Azact am) . Thi s agent was t he f i r st commerci al l y avai l abl e
monobact am ( monocycl i c 8- l act am compound) . Ì t r esembl es t he
ami nogl ycosi des i n i t s ef f i cacy agai nst many gr am- negat i ve or gani sms but
does not cause nephrot oxi ci t y or ot ot oxi ci t y. Ot her advant ages of t hi s drug
i ncl ude i t s abi l i t y t o pr eser ve t he body' s normal gr am-posi t i ve and
anaer obi c f l or a, act i vi t y agai nst many gent ami ci n- r esi st ant or gani sms, and
l ack of cr oss-al l er geni ci t y wi t h peni ci l l i n.
a. Mechani sm of act i on. Azt r eonam i s bacteri ci daI ; i t i nhi bi t s bact er i al
cel l wal l synt hesi s.
b. Spect rum of act i vi t y. Thi s dr ug i s act i ve agai nst many gr am-negat i ve
or gani sms, i ncl udi ng Ent er obact er and P. aer ugi nosa.
c. Therapeut i c uses. Azt r eonam i s t her apeut i c f or ur i nar y t ract i nf ect i ons,
sept i cemi a, ski n i nf ect i ons, l ower r espi r at or y t r act i nf ect i ons, and i nt r a-
abdomi nal i nf ect i ons resul t i ng f r om gram- negat i ve or gani sms. Ì ncreased
i nci dence of P. aerugi nosa resi st ant t o azt r eonam have been r epor t ed.
d. Precaut i ons and moni t ori ng ef fects
( 1) Azt r eonam somet i mes causes nausea, vomi t i ng, and di ar r hea.
( 2) Li ver enzymes may i ncr ease t ransi ent l y duri ng azt r eonam t herapy.
( 3) Thi s drug may i nduce ski n r ash.
2. ChI orampheni coI . A ni t robenzene deri vat i ve, t hi s drug has broad act i vi t y
agai nst r i cket t si a as wel l as many gr am-posi t i ve and gr am- negat i ve
or gani sms. Ì t al so i s ef f ect i ve agai nst many ampi ci l l i n- r esi st ant st rai ns of H.
i nf l uenzae.
a. Mechani sm of act i on. Chl or ampheni col i s pr i mar i l y bact eri ost at i c,
al t hough i t may be bact er i ci dal agai nst a f ew bact er i al st r ai ns.
b. Spect rum of act i vi t y. Thi s agent i s act i ve agai nst r i cket t si a and a wi de
r ange of bact er i a, i ncl udi ng H. i nf l uenzae, Sal monel l a t yphi , Nei sser i a
meni ngi t i di s, Bor det el l a per t ussi s, Cl ost r i di um, B. f r agi l i s, S. pyogenes, and
S. pneumoni ae.
P. 936


c. Therapeut i c uses. Because of i t s t oxi c si de ef f ect s, chl orampheni col i s
used onl y t o suppr ess i nf ect i ons t hat cannot be t r eat ed ef f ect i vel y wi t h
ot her ant i bi ot i cs. Such i nf ect i ons t ypi cal l y i ncl ude
( 1) Typhoi d f ever
( 2) Meni ngococcal i nf ect i ons i n cephal ospori n-al l er gi c pat i ent s
( 3) Seri ous H. i nf l uenzae i nf ect i ons, par t i cul ar l y i n cephal ospor i n- al l ergi c
pat i ent s
( 4) Anaer obi c i nf ect i ons ( e. g. , t hose ori gi nat i ng i n t he pel vi s or i nt est i nes)
( 5) Anaer obi c or mi xed i nf ect i ons of t he CNS
( 6) Ri cket t si al i nf ect i ons i n pr egnant pat i ent s, t et r acycl i ne- al l er gi c pat i ent s,
and renal l y i mpai r ed pat i ent s
d. Precaut i ons and moni t ori ng ef fects
( 1) Chl or ampheni col can cause bone mar r ow suppr essi on ( dose- rel at ed)
wi t h r esul t i ng pancyt openi a; r arel y, t he dr ug l eads t o apl ast i c anemi a ( not
r el at ed t o dose) .
( 2) Hypersensi t i vi t y react i ons may i ncl ude ski n rash and, i n ext r emel y r are
cases, angi oedema or anaphyl axi s.
( 3) Chl or ampheni col t herapy may l ead t o gray baby syndrome i n neonat es
( especi al l y premat ure i nf ant s) . Thi s danger ous r eact i on, whi ch st ems par t l y
f r om i nadequat e l i ver det oxi f i cat i on of t he drug, i s mani f est ed by vomi t i ng,
gr ay cyanosi s, r api d and i r r egul ar respi r at i ons, vasomot or col l apse, and i n
some cases deat h.
e. Si gni f i cant i nteracti ons
( 1) Chl or ampheni col i nhi bi t s t he met abol i sm of phenyt oi n, t oI but ami de,
chI orpropami de, and di cumaroI , l eadi ng t o pr ol onged act i on and
i nt ensi f i ed ef f ect of t hese dr ugs.
( 2) Phenobarbi taI short ens chl orampheni col ' s hal f -l i f e, t hereby r educi ng i t s
t her apeut i c ef f ect i veness.
( 3) Peni ci I I i ns can cause ant i bi ot i c ant agoni sm.
( 4) Acet ami nophen el evat es chl or ampheni col l evel s and may cause
t oxi ci t y.
3. CI i ndamyci n ( CI eoci n) . Thi s agent has essent i al l y r epl aced l i ncomyci n,
t he dr ug f r om whi ch i t i s der i ved. Ì t i s used t o t reat ski n, respi rat or y t r act ,
and sof t - t i ssue i nf ect i ons caused by st aphyl ococci , pneumococci , and
st r ept ococci .
a. Mechani sm of act i on. Cl i ndamyci n i s bacteri ost at i c; i t bi nds t o t he 50S
r i bosomal subuni t , t hereby suppr essi ng bact er i al pr ot ei n synt hesi s.
b. Spect rum of act i vi t y. Thi s agent i s act i ve agai nst most gram-posi t i ve
and many anaer obi c or gani sms, i ncl udi ng B. f ragi l i s.
c. Therapeut i c uses. Because of i t s marked t oxi ci t y, cl i ndamyci n i s used
onl y agai nst i nf ect i ons f or whi ch i t has pr oven t o be t he most ef f ect i ve drug.
Typi cal l y, such i nf ect i ons i ncl ude abdomi nal and f emal e geni t ouri nar y t r act
i nf ect i ons caused by B. f r agi l i s.
d. Precaut i ons and moni t ori ng ef fects
( 1) Cl i ndamyci n may cause rash, nausea, vomi t i ng, di ar rhea, and
pseudomembranous col i t i s as evi denced by f ever, abdomi nal pai n, and
bl oody st ool s.
( 2) Bl ood dyscr asi as ( e. g. , eosi nophi l i a, t hrombocyt openi a, l eukopeni a) may
occur .
e. Si gni f i cant i nteracti ons. Cl i ndamyci n may pot ent i at e t he ef f ect s of
neuromuscuI ar bI ocki ng agent s.
4. Dapsone. A member of t he sul f one cl ass, t hi s dr ug i s t he pr i mar y agent
i n t he t r eat ment of al l f orms of l epr osy.
a. Mechani sm of act i on. Dapsone i s bacteri ostat i c f or Mycobact eri um
l eprae; i t s mechani sm of act i on probabl y resembl es t hat of t he
sul f onami des.
b. Spect rum of act i vi t y. Thi s dr ug i s act i ve agai nst M. l epr ae; however ,
dr ug r esi st ance devel ops i n up t o 40% of pat i ent s. Dapsone al so has some
act i vi t y agai nst P. cari ni i or gani sms and t he mal ar i al parasi t e Pl asmodi um.
c. Therapeut i c uses
( 1) Dapsone i s t he drug of choi ce f or t r eat i ng l epr osy.
( 2) Thi s agent may be used t o t reat dermat i t i s herpet i f ormi s, a ski n
di sor der .
( 3) Mal opr i m, a dapsone- pyr i met hami ne pr oduct , i s val uabl e i n t he
pr ophyl axi s and t reat ment of mal ar i a.
( 4) Dapsone, wi t h or wi t hout t r i met hopr i m, i s used f or pr ophyl axi s of P.
car i ni i pneumoni a i n pat i ent s wi t h AÌ DS.
d. Precaut i ons and moni t ori ng ef fects
( 1) Hemol yt i c anemi a can occur wi t h dai l y doses > 200 mg. Ot her adverse
hemat ol ogi cal ef f ect s i ncl ude met hemogl obi nemi a and l eukopeni a.
P. 937


( 2) Nausea, vomi t i ng, and anor exi a may devel op.
( 3) Adverse CNS ef f ect s i ncl ude headache, di zzi ness, ner vousness,
l et har gy, parest hesi as, and psychosi s.
( 4) Dapsone occasi onal l y r esul t s i n a pot ent i al l y l et hal mononucl eosi s-l i ke
syndr ome.
( 5) Paradoxi cal l y, t hi s drug somet i mes exacer bat es l eprosy.
( 6) Ot her adver se ef f ect s i ncl ude ski n rash, per i pheral neuropat hy, bl ur red
vi si on, t i nni t us, hepat i t i s, and chol est at i c j aundi ce.
e. Si gni f i cant i nteracti ons. Probeneci d el evat es bl ood l evel s of dapsone,
possi bl y r esul t i ng i n t oxi ci t y.
5. CI ofazi mi ne i s phenazi ne dye wi t h ant i mycobact er i al and ant i -
i nf l ammat or y act i vi t y.
a. Mechani sm of act i on. Cl of azi mi ne appear s t o bi nd pref er ent i al l y t o
mycobact eri al DNA, i nhi bi t i ng r epl i cat i on and gr owt h. Ì t i s bact eri ci daI
agai nst M. l eprae, and i t appears t o be bact eri ost at i c agai nst MAÌ .
b. Spect rum of act i vi t y. Cl of azi mi ne i s act i ve agai nst vari ous
mycobact eri a, i ncl udi ng M. l epr ae, M. t ubercul osi s, and MAÌ .
c. Therapeut i c uses. Cl of azi mi ne i s used t o t reat l epr osy and a var i et y of
at ypi cal Mycobact er i um i nf ect i ons.
d. Precaut i ons and moni t ori ng ef fects
( 1) Pi gment at i on (pi nk t o br owni sh) occurs i n 75%- 100% of pat i ent s wi t hi n a
f ew weeks. Thi s ski n di scol or at i on has l ed t o sever e depressi on (and
sui ci de) .
( 2) Ur i ne, sweat , and ot her body f l ui ds may be di scol ored.
( 3) Ot her ef f ect s i ncl ude i cht hyosi s and dr yness of ski n (8%- 28%) , r ash and
pr ur i t us ( 1%- 5%) , and GÌ i nt ol er ance ( e. g. , abdomi nal / epi gast ri c pai n,
di ar rhea, nausea, vomi t i ng) i n 40%-50% of pat i ent s. Cl of azi mi ne shoul d be
t aken wi t h f ood.
6. Dapt omyci n ( Cubi ci n) i s a uni que l i popept i de ant i bi ot i c wi t h cl i ni cal
act i vi t y i n t he t reat ment of r esi st ant gr am- posi t i ve i nf ect i ons.
a. Mechani sm of act i on. Dapt omyci n i s bact er i ci dal ; unl i ke ot her
ant i bi ot i cs, i t bi nds t o t he bact er i al cel l membrane, causi ng depol ar i zat i on
of t he membr ane pot ent i al l eadi ng t o i nhi bi t i on of RNA, DNA, and pr ot ei n
synt hesi s.
b. Spect rum of act i vi t y. Thi s dr ug i s act i ve agai nst vancomyci n-
suscept i bl e E. f aeci um and S. aureus ( i ncl udi ng met hi ci l l i n- r esi st ant
st r ai ns) as wel l as ot her aer obi c gram-posi t i ve bact eri a.
c. Therapeut i c uses. Dapt omyci n i s i ndi cat ed f or t he t r eat ment of
compl i cat ed ski n and ski n st r uct ure i nf ect i ons and S. aur eus bact er emi a. Ì t
i s not i ndi cat ed f or t he t reat ment of pneumoni a.
d. Precaut i ons and moni t ori ng ef fects
( 1) Repor t ed si de ef f ect s ar e gener al l y mi l d and sel f -l i mi t i ng and i ncl ude
const i pat i on, abnor mal l i ver f unct i on t est s, and renal f ai l ur e.
( 2) Cases of myal gi a and/ or muscl e weakness, exacer bat i ons of myast heni a
gr avi s, and i ncr eases i n cr eat i ne phosphoki nase ( CPK) have been report ed.
7. Li nezoI i d ( Zyvox) i s a synt het i c oxazol i di none t hat has cl i ni cal use i n
t he t r eat ment of i nf ect i ons caused by aer obi c gram- posi t i ve bact er i a.
a. Mechani sm of act i on. Li nezol i d i s bact er i ost at i c agai nst Ent er ococci and
St aphyl ococci , and bact er i ci dal agai nst St r ept ococci . Li nezol i d bi nds t o t he
23S ri bosomal RNA of t he 50S subuni t and t hus i nhi bi t s prot ei n synt hesi s.
b. Spect rum of act i vi t y. The dr ug i s act i ve agai nst vancomyci n- r esi st ant
Ent erococcus f aeci um and S. aureus (met hi ci l l i n- suscept i bl e and -r esi st ant
st r ai ns) as wel l as ot her aer obi c gram-posi t i ve bact eri a.
c. Therapeut i c uses. Li nezol i d i s i ndi cat ed f or t reat ment of i nf ect i ons
caused by vanco-myci n- resi st ant E. f aeci um, nosocomi al pneumoni a caused
by met hi ci l l i n-suscept i bl e and - resi st ant st r ai ns of S. aureus, communi t y-
acqui red pneumoni a caused by peni ci l l i n-suscept i bl e st r ai ns of S.
pneumoni ae, and ski n and ski n st r uct ure i nf ect i ons owi ng t o t hese
or gani sms.
d. Precaut i ons and moni t ori ng ef fects
( 1) Saf et y dat a ar e l i mi t ed. Adverse ef f ect s general l y ar e mi nor (e. g. ,
gast r oi nt est i nal compl ai nt s, headache, r ash).
( 2) Thr ombocyt openi a or a si gni f i cant r educt i on i n pl at el et count has been
r eport ed ( 2. 4%) and i s rel at ed t o dur at i on of t herapy. Moni t or pl at el et s i n
pat i ent s wi t h r i sk of bl eedi ng, preexi st i ng t hrombocyt openi a, pl at el et
di sor der s ( i ncl udi ng t hose
P. 938

caused by concurr ent medi cat i ons) and i n pat i ent s r ecei vi ng l i nezol i d
l ast i ng l onger t han 2 weeks.
( 3) Myel osuppr essi on owi ng t o di rect bone mar row suppr essi on has been
r eport ed r ar el y.
e. Si gni f i cant i nteracti ons. Pat i ent s r ecei vi ng concomi t ant t her apy wi t h
adr ener gi c or serot onergi c agent s or consumi ng mor e t han 100 mg of
t yr ami ne a day may exper i ence an enhancement of t he dr ug' s ef f ect or
ser ot oni n syndrome.
8. Qui nupri st i n/ daI fopri st i n ( Synerci d) i s an i nt r avenous st rept ogr ami n
ant i bi ot i c composed of t wo chemi cal l y di st i nct compounds.
a. Mechani sm of act i on. Qui nupri st i n bi nds t o t he 50S subuni t , and
dal f opri st i n bi nds t i ght l y t o t he 70S ri bosomal part i cl e.
b. Spect rum of act i vi t y. Syner ci d has act i vi t y agai nst St aphyl ococci spp. ,
i ncl udi ng r esi st ant st rai ns. Thi s combi nat i on has bet t er act i vi t y agai nst E.
f aeci um t han Ent er ococcus f aecal i s and i s al so act i ve agai nst some gr am-
negat i ve or gani sms and anaer obes; act i vi t y has not been shown agai nst
Ent erobact er i aceae.
c. Therapeut i c uses. Ì t i s used f or t r eat ment of vancomyci n- resi st ant E.
f aeci um ( VREF) bact er emi a and ski n and ski n st ruct ur e i nf ect i ons caused
by S. aur eus and S. pyogenes.
d. Precaut i ons and moni t ori ng ef fects
( 1) Repor t ed si de ef f ect s ar e gener al l y mi l d and i nf usi on r el at ed: pai n,
er yt hema, or i t chi ng at t he i nf usi on si t e; i ncr eases i n pul se and di ast ol i c
pr essure; headache; nausea or vomi t i ng; and di arr hea. Ì t may i ncr ease l i ver
f unct i on t est s sl i ght l y.
( 2) Dr ug i nt eract i ons ar e a r esul t of cyt ochr ome P450 3A4 i nhi bi t i on.
Pot ent i al dr ug i nt er act i ons i ncl ude cycI ospori n, ni f edi pi ne, and
mi dazoI am.
( 3) Concomi t ant use of medi cat i ons t hat may prol ong QTc i nt er val shoul d be
avoi ded.
( 4) Mi l d t o l i f e-t hr eat eni ng pseudomembr anous col i t i s has been r epor t ed.
9. Ri f axi mi n. Ì s a semi -synt het i c ant i bi ot i c t hat i s st ruct ur al l y r el at ed t o
r i f amyci n.
a. Mechani sm of act i on. Ì t i nhi bi t s bact er i al RNA synt hesi s by bi ndi ng t o
t he bet a- subuni t of bact er i al DNA- dependent RNA pol ymer ase.
b. Spect rum of act i vi t y. Thi s non-syst emi cal l y absorbed drug has act i vi t y
agai nst bot h ent er ot oxi geni c and ent er oaggregat i ve st r ai ns of Escher i chi a
col i .
c. Therapeut i c uses. Ri f axi mi n i s used i n t he t r eat ment of Tr avel er ' s
di ar rhea wi t h noni nvasi ve st r ai ns of E. col i . Hi gh r esi st ance rat es have
been r epor t ed af t er 5 days of t r eat ment .
d. Precaut i ons and moni t ori ng ef fects. Because of i t s l i mi t ed syst emi c
absor pt i on, adver se ef f ect s ar e f ew but i ncl ude const i pat i on, vomi t i ng,
f l at ul ence and headache.
10. Specti nomyci n. An ami nocycl i t ol agent r el at ed t o t he ami nogl ycosi des,
t hi s ant i bi ot i c i s usef ul agai nst peni ci l l i n- r esi st ant st rai ns of gonor r hea.
a. Mechani sm of act i on. Spect i nomyci n i s bacteri ost ati c; i t sel ect i vel y
i nhi bi t s pr ot ei n synt hesi s by bi ndi ng t o t he 30S r i bosomal subuni t .
b. Spect rum of act i vi t y. Thi s agent i s act i ve agai nst var i ous gram-negat i ve
or gani sms.
c. Therapeut i c uses. Spect i nomyci n i s used onl y t o t reat gonococcal
i nf ect i ons i n pat i ent s wi t h peni ci l l i n al l er gy or when such i nf ect i on st ems
f r om peni ci l l i nase-pr oduci ng gonococci ( PPNG) .
d. Precaut i ons and moni t ori ng ef fects. Because spect i nomyci n i s gi ven
onl y as a si ngl e-dose Ì M i nj ect i on, i t causes f ew adver se ef f ect s. Nausea,
vomi t i ng, urt i car i a, chi l l s, di zzi ness, and i nsomni a occur r arel y.
11. TeI i thromyci n ( Ket ek) i s t he f i rst of a new cl ass of ant i mi cr obi al s
cal l ed t he ket ol i des. Ì t i s an or al semi synt het i c der i vat i ve of er yt hromyci n.
a. Mechani sm of act i on. Tel i t hr omyci n may be bact er i ci dal or
bact er i ost at i c; i t i nhi bi t s bact er i al pr ot ei n synt hesi s.
b. Spect rum of act i vi t y. Thi s dr ug i s act i ve agai nst many aerobi c and
anaer obi c gr am- posi t i ve or gani sms, i ncl udi ng mul t i drug- resi st ant S.
pneumoni ae, some gr am- negat i ve or gani sms as wel l as at ypi cal pat hogens.
c. Therapeut i c uses. Tel i t hr omyci n i s i ndi cat ed f or t he t reat ment of mi l d t o
moder at e communi t y- acqui r ed pneumoni a onl y. The FDA r emoved t he
pr evi ous 2 approved i ndi cat i ons and added a bl ack box war ni ng.
P. 939


d. Precaut i ons and moni t ori ng ef fects
( 1) GÌ ef f ect s ( i ncl udi ng di ar rhea, nausea, and vomi t i ng) wer e t he most
common si de ef f ect s f ol l owed by di zzi ness and vi sual di st ur bances (such as
di pl opi a and bl ur r ed and abnor mal vi si on); ser i ous l i ver t oxi ci t y has been
r eport ed.
( 2) Cr oss-sensi t i vi t y wi t h t he ot her macr ol i des occurs.
( 3) Concomi t ant use of dr ugs or condi t i ons t hat may pr ol ong t he QTc
i nt er val shoul d be avoi ded.
( 4) Cont r ai ndi cat ed i n pat i ent s wi t h myast heni a gravi s, hepat i t i s, or
j aundi ce.
e. Si gni f i cant i nteracti ons
( 1) Co-admi ni st r at i on of t el i t hromyci n wi t h ei t her ci sapri de or pi mozi de i s
cont r ai ndi cat ed.
( 2) Concomi t ant admi ni st r at i on of dr ugs met abol i zed by cyt ochr ome P450
3A4 i n pat i ent s wi t h t el i t hr omyci n shoul d be cl osel y moni t or ed.
( 3) Pat i ent s on bepr i di l , mesor i dazi ne, t er f enadi ne, t hi ori dazi ne, or
zi pr asi done shoul d not be pr escr i bed t el i t hr omyci n owi ng t o t he hi gh
pot ent i al f or t oxi ci t y.
( 4) Thi s agent has a hi gh potent i aI to i nteract wi th many drugs. Check
product i nformati on for t he most current i nt eract i on i nformat i on.
12. Ti gecycI i ne ( Tygaci I ) . An i nt r avenous gl ycyl cycl i ne ant i bi ot i c
devel oped as a semi synt het i c anal ogue of t et racycl i ne wi t h a br oad
spect rum of act i vi t y.
a. Mechani sm of act i on. Ti gecycl i ne i s bact er i ost at i c; i t i nhi bi t s bact er i al
pr ot ei n synt hesi s by r ever si bl y bi ndi ng t o t he 30S r i bosome subuni t .
b. Spect rum of act i vi t y. The dr ug i s act i ve agai nst vancomyci n-suscept i bl e
E. f aecal i s, met hi ci l l i n- resi st ant S. epi der mi di s, and S. aureus (met hi ci l l i n-
suscept i bl e and - resi st ant st r ai ns) as wel l as some gr am- negat i ve aer obes
and anaer obes.
c. Therapeut i c uses. Ti gecycl i ne i s i ndi cat ed f or t he t r eat ment of
compl i cat ed i nt r a- abdomi nal i nf ect i ons caused by E. col i , vancomyci n-
suscept i bl e E. f aecal i s, S. aureus (met hi ci l l i n- suscept i bl e st r ai ns onl y) and
B. f r agi l i s. Al so i ndi cat ed f or t he t reat ment of compl i cat ed ski n and ski n
st r uct ur e i nf ect i ons caused by E. f aecal i s ( vancomyci n- suscept i bl e st rai ns) ,
S. pyogenes and S. aur eus (met hi ci l l i n-suscept i bl e and - resi st ant st r ai ns).
d. Precaut i ons and moni t ori ng ef fects.
( 1) Saf et y dat a ar e l i mi t ed. Si de ef f ect s ar e general l y mi l d wi t h GÌ
di st ur bances÷f or exampl e, nausea ( 22%-35%) and vomi t i ng ( 13%- 19%)÷
t he most commonl y r epor t ed. The mechani sm of t hese r eact i ons i s
uncer t ai n.
( 2) May cause permanent di scol or at i on of t he t eet h si mi l ar t o t he
t et r acycl i nes.
( 3) Caut i on i n pat i ent s wi t h a hi st or y of hypersensi t i vi t y r eact i ons t o
t et r acycl i nes.
( 4) Phot ot oxi c r eact i ons, pancr eat i t i s, and i ncr eases i n BUN may occur .
e. Si gni f i cant i nteracti ons. Cl osel y moni t or t he pr ot hr ombi n t i me or
i nt er nat i onal sensi t i vi t y i ndex ( Ì NR) i n pat i ent s on war f ar i n dur i ng
concomi t ant admi ni st rat i on of t i gecycl i ne.
13. Tri methopri m. A subst i t ut ed pyr i mi di ne, t ri met hopr i m i s most commonl y
combi ned wi t h sul f amet hoxazol e ( a sul f onami de di scussed i n Ì Ì . F) i n a
pr epar at i on cal l ed cot r i moxazol e. However , i t may be used al one f or cer t ai n
ur i nar y t r act i nf ect i ons.
a. Mechani sm of act i on. Tr i met hopr i m i nhi bi t s di hydr of ol at e reduct ase,
t hus bl ocki ng bact er i al synt hesi s of f ol i c aci d.
b. Spect rum of act i vi t y
( 1) Tr i met hopr i m i s act i ve agai nst most gr am-negat i ve and gr am- posi t i ve
or gani sms. However , dr ug r esi st ance may devel op when t hi s drug i s used
al one.
( 2) Tr i met hopr i m-sul f amet hoxazol e i s act i ve agai nst a vari et y of organi sms,
i ncl udi ng S. pneumoni ae, N. meni ngi t i di s, and Cor ynebact eri um di pht her i ae;
some st r ai ns of S. aureus, St aphyl ococcus epi der mi di s, P. mi r abi l i s,
Ent erobact er , Sal monel l a, Shi gel l a, Ser r at i a, and Kl ebsi el l a spp. ; and E.
col i .
( 3) The t ri met hopri m-sul f amet hoxazol e combi nat i on i s synergi st i c; many
or gani sms r esi st ant t o one component are suscept i bl e t o t he combi nat i on.
c. Therapeut i c uses
( 1) Tr i met hopr i m may be used al one or i n combi nat i on wi t h
sul f amet hoxazol e t o t r eat uncompl i cat ed ur i nar y t r act i nf ect i ons caused by
E. col i , P. mi rabi l i s, and Kl ebsi el l a and Ent er obact er organi sms.
( 2) Tr i met hopr i m-sul f amet hoxazol e i s t her apeut i c f or acut e gonococcal
ur et hr i t i s, acut e exacerbat i on of chr oni c bronchi t i s, shi gel l osi s, and
Sal monel l a i nf ect i ons.
P. 940


( 3) Tr i met hopr i m-sul f amet hoxazol e may be gi ven as pr ophyl act i c or
suppr essi ve t her apy i n P. car i ni i pneumoni a. Ì t i s t he dr ug of choi ce f or t he
t r eat ment of St enot r ophomonas mal t ophi l i a i nf ect i ons.
d. Precaut i ons and moni t ori ng ef fects
( 1) Most adver se ef f ect s i nvol ve t he ski n ( possi bl y f r om sensi t i zat i on) .
These i ncl ude rash, pr uri t us, and exf ol i at i ve dermat i t i s.
( 2) Rarel y, t ri met hopri m-sul f amet hoxazol e causes bl ood dyscrasi as ( e. g. ,
acut e hemol yt i c anemi a, l eukopeni a, t hrombocyt openi a,
met hemogl obi nemi a, agranul ocyt osi s, apl ast i c anemi a) .
( 3) Adverse GÌ ef f ect s i ncl udi ng nausea, vomi t i ng, and epi gast r i c di st r ess
gl ossi t i s may occur .
( 4) Neonat es may devel op ker ni ct er us.
( 5) Pat i ent s wi t h AÌ DS somet i mes suf f er f ever , rash, mal ai se, and
pancyt openi a dur i ng t r i met hopr i m t herapy.
14. Vancomyci n. Thi s gl ycopept i de dest r oys most gr am- posi t i ve or gani sms.
a. Mechani sm of act i on. Vancomyci n i s bacteri ci daI ; i t i nhi bi t s bact eri al
cel l wal l synt hesi s.
b. Spect rum of act i vi t y. Thi s dr ug i s act i ve agai nst most gr am- posi t i ve
or gani sms, i ncl udi ng met hi ci l l i n- r esi st ant st r ai ns of S. aureus and
Ent erococci .
c. Therapeut i c uses. Vancomyci n usual l y i s r eser ved f or ser i ous i nf ect i ons,
especi al l y t hose caused by met hi ci l l i n- r esi st ant st aphyl ococci . Ì t i s
par t i cul arl y usef ul i n pat i ent s who are al l ergi c t o peni ci l l i n or
cephal ospori ns. Typi cal uses i ncl ude endocar di t i s, ost eomyel i t i s, and
st aphyl ococcal pneumoni a.
( 1) Or al vancomyci n i s val uabl e i n t he t r eat ment of ant i bi ot i c- i nduced
pseudomembranous col i t i s caused by C. di f f i ci l e or S. aur eus ent er ocol i t i s.
Because vancomyci n i s not absor bed af t er oral admi ni st r at i on, i t i s not
usef ul f or syst emi c i nf ect i ons. Because of resi st ance, t he Cent ers f or
Di sease Cont r ol and Prevent i on ( CDC) recommend vancomyci n as t he
second choi ce t o met r oni dazol e f or C. di f f i ci l e i nf ect i ons.
( 2) Because 1 g provi des adequat e bl ood l evel s f or 7-10 days, Ì V
vancomyci n i s par t i cul ar l y usef ul i n t he t r eat ment of anephr i c pat i ent s wi t h
gr am- posi t i ve bact eri al i nf ect i ons.
d. Precaut i ons and moni t ori ng ef fects
( 1) Ot ot oxi ci t y may ari se; nephr ot oxi ci t y i s rar e but can occur wi t h hi gh
doses.
( 2) Vancomyci n may cause hypersensi t i vi t y react i ons, mani f est ed by such
sympt oms as anaphyl axi s and ski n rash.
( 3) Ther apeut i c l evel s peak at 20- 40 µg/ mL. The t r ough i s < 15 µg/ mL.
( 4) Red man' s syndr ome may occur . Thi s i s f aci al f l ushi ng and hypot ensi on
owi ng t o t oo r api d i nf usi on of t he dr ug. Ì nf usi on shoul d be over a mi ni mum
of 60 mi n f or a 1- g dose.
( 5) Ì V sol ut i ons ar e ver y i r r i t at i ng t o t he vei n.
e. Vancomyci n- resi stant ent erococci . A f ew st rai ns of vancomyci n-
r esi st ant ent er ococci ar e suscept i bl e t o t ei copl ani n ( i nvest i gat i onal by
Hoechst Mar i on Roussel ) , l i nezol i d ( Zyvox) , or qui nupr i st i n/ dal f opr i st i n
( Syner ci d) . These agent s may be usef ul f or mul t i pl e-dr ug- r esi st ant E.
f aeci um.
III. Systemic AntifungaI Agents
A. Def i ni t i on. These agent s t reat syst emi c and l ocal f ungal (mycot i c)
i nf ect i ons÷di seases t hat r esi st t reat ment wi t h ant i bact er i al dr ugs.
B. Amphot eri ci n B ( Fungi zone) . Thi s pol yene ant i f ungal ant i bi ot i c i s
t her apeut i c f or var i ous f ungal i nf ect i ons t hat f requent l y pr oved f at al bef ore
t he dr ug became avai l abl e. Ì t i s used i ncr easi ngl y i n t he empi r i c t r eat ment
of sever el y i mmunocompr omi sed pat i ent s i n cert ai n cl i ni cal si t uat i ons.
1. Mechani sm of act i on. Amphot er i ci n B i s bot h f ungi st at i c i n cl i ni cal l y
obt ai ned concent r at i ons and may be f ungi ci dal i n t he pr esence of
suscept i bl e organi sms. Ì t bi nds t o st er ol s i n t he f ungal cel l membrane,
t her eby i ncr easi ng membr ane per meabi l i t y and per mi t t i ng l eakage of
i nt racel l ul ar cont ent s. Ot her mechani sms may be i nvol ved as wel l .
P. 941


2. Spect rum of acti vi t y. Amphot er i ci n B i s a broad- spect r um ant i f ungal
agent wi t h act i vi t y agai nst Asper gi l l us, Bl ast omyces, Candi da spp.
( al bi cans, kr usei t r opi cal i s, and gl abrat a) , Crypt ococcus, Cocci di oi des,
Hi st opl asma, Paracocci di oi des, Phycomycet es ( mucor) , and Sporot hri x. Ì t i s
al so usef ul agai nst some pr ot ozoa such as Lei shmani a, Naegl er i a, and
Acant hamoeba.
3. Therapeut i c uses. Amphot eri ci n B i s t he most ef f ect i ve ant i f ungal agent
i n t he t r eat ment of syst emi c f ungal i nf ect i ons, especi al l y i n
i mmunocompr omi sed pat i ent s.
a. Ì t i s t he t reat ment of choi ce f or pul monar y Asper gi l l us i nf ect i ons;
Bl ast omyces i nf ect i ons, whi ch are l i f e- t hreat eni ng wi t h AÌ DS or CNS
i nvol vement ; deep- organ i nf ect i ons wi t h Candi da; Cocci di oi des i nf ect i ons
wi t h severe pul monar y i nvol vement or wi t h di ssemi nat ed nonmeni ngeal
i mmunocompet ent or i mmunocompr omi sed pat i ent s; al l Crypt ococcus
i nf ect i ons; di ssemi nat ed Hi st opl asma i nf ect i ons i nvol vi ng CNS or
i mmunosuppr essed pat i ent s; Mal assezi a f ur f ur f ungemi a; pul monar y and
ext r apul monar y Phycomycet es (mucor mycosi s); Peni ci l l i um mar nef f ei ; and
ext r acut aneous Sporot hri x.
b. Thi s agent may be used t o t reat cocci di oi dal ar t hr i t i s.
c. Topi cal prepar at i ons ar e gi ven t o eradi cat e cut aneous and
mucocut aneous candi di asi s.
d. Ì t may be used as empi r i c t herapy i n f ebr i l e, neut r openi c pat i ent s.
e. Ì t i s used as secondary pr ophyl axi s of f ungal i nf ect i ons i n HÌ V-posi t i ve
pat i ent s, guar di ng agai nst recur r ence of i nf ect i on.
f . Ì t may be used pr ophyl act i cal l y i n neut r openi c cancer pat i ent s and bone
mar row t r anspl ant or sol i d- or gan t r anspl ant pat i ent s t o reduce t he i nci dence
of Aspergi l l us and Candi da i nf ect i ons.
4. Precauti ons and moni t ori ng ef f ect s. Because amphot er i ci n B can
cause many ser i ous adver se ef f ect s, i t shoul d be admi ni st er ed i n a hospi t al
set t i ng÷at l east dur i ng t he i ni t i al t her apeut i c st age. The adverse ef f ect s
ar e di vi ded i nt o i nf usi on r eact i ons and ot hers.
a. Ì nf usi on react i ons occur whi l e t he drug i s bei ng admi ni st ered and i ncl ude
f ever , shaki ng chi l l s, hypot ensi on, anor exi a, nausea, vomi t i ng, headache,
dyspnea, and t achypnea. Pr emedi cat i on wi t h acet ami nophen and
di phenhydr ami ne has been hel pf ul i n prophyl axi ng agai nst i nf usi on
r eact i ons. Ì n addi t i on, hydr ocor t i sone 10-50 mg may be added t o t he
i nf usi on as pr ophyl axi s agai nst i nf usi on- r el at ed react i ons. Meper i di ne 25-50
mg Ì V i s ef f ect i ve t r eat ment of act i ve shaki ng chi l l s/ ri gor s. Meper i di ne i s
al so ef f ect i ve i n prophyl axi s of ri gors.
b. Nephr ot oxi ci t y f requent l y occur s. Dosage adj ust ment or dr ug
di scont i nuat i on or changi ng t o a l i posomal amphot eri ci n B pr oduct may be
necessar y as renal i mpai r ment progresses.
c. El ect r ol yt e abnormal i t i es, i ncl udi ng hypokal emi a, hypomagnesemi a, and
hypocal cemi a, are common. Moni t or and repl ace el ect r ol yt es as needed.
d. Normocyt i c, nor mochromi c anemi a wi l l devel op over l ong- t er m use (10
weeks) . Moni t or hemat ocr i t per i odi cal l y.
e. Br onchospasm, wheezi ng, and anaphyl axi s or anaphyl act oi d r eact i ons
have occur r ed. A t est dose of 1 mg of amphot er i ci n B i s of t en admi ni st ered
bef ore i nf usi on of l arge quant i t i es of t he dr ug.
f . Phl ebi t i s or t hr ombophl ebi t i s i s repor t ed wi t h convent i onal amphot eri ci n
B. Hepar i n ( 500- 1000 U) can be added t o t he i nf usi on t o ai d i n pr event i on.
g. CNS ef f ect s i ncl ude headache, peri pher al neur opat hy, mal ai se,
depressi on, sei zur e, myast heni a, and hal l uci nat i ons.
h. El evat ed l i ver t ransami nases, aspar t at e ami not r ansf er ase ( AST) , al ani ne
ami not ransf er ase ( ALT) , al kal i ne phosphat ase, bi l i r ubi n, v-
gl ut amyl t r ansf er ase ( GGT) , and l act at e dehydrogenase (LDH) may occur .
i . Amphot eri ci n B parent er al use shoul d be mi xed onl y i n dext r ose 5% i n
wat er ( D5W) and shoul d be prot ect ed f r om l i ght .
5. Si gni f i cant i nteracti ons. Ot her nephr ot oxi c drugs ( ami nogl ycosi des,
capreomyci n, col i st i n, ci spl at i n, cycl ospori ne, met hoxyf l ur ane, pent ami di ne,
pol ymyxi n B, and vancomyci n) may cause addi t i ve nephr ot oxi ci t y.
6. Amphot eri ci n B l i pi d compl ex ( Abel cet ) , amphot er i ci n B chol est erol
sul f at e compl ex ( Amphot ec) , and l i posomal amphot eri ci n B ( AmBi some)
of f er al t er nat i ve f ormul at i ons of amphot er i ci n B f or t he t r eat ment of sever e
f ungal i nf ect i ons i n pat i ent s who ar e i nt ol er ant of or whose di sease i s
r ef r act or y t o convent i onal t r eat ment .
P. 942


C. Echi nocandi ns. Thr ee echi nocandi ns ar e appr oved i n t he US:
capsof ungi n ( Canci das) , mi caf ungi n ( Mycami ne) and ani dul af ungi n ( Eraxi s) .
These agent s have a br oad spect rum of act i vi t y agai nst Candi da speci es
wi t h mi caf ungi n and ani dul af ungi n havi ng si mi l ar MÌ Cs t hat ar e gener al l y
l ower t han t he MÌ C of capsof ungi n.
1. Mechani sm of act i on. Caspof ungi n wor ks by causi ng f ungal cel l wal l
l ysi s. By bei ng a noncompet i t i ve i nhi bi t or of 8 ( 1, 3) synt hase, whi ch i s an
essent i al component of f ungal cel l wal l synt hesi s, i t causes osmot i c
i nst abi l i t y wi t hi n t he f ungus and f ungal cel l wal l l ysi s.
2. Spect rum of acti vi t y. Echi nocandi ns have f ungi ci dal act i vi t y agai nst
Candi da speci es and f ungi st at i c act i vi t y agai nst Aspergi l l us speci es. Al l
t hr ee agent s i n t hi s cl ass appear t o have good act i vi t y i n vi t r o f or most
i sol at es of Candi da speci es, i ncl udi ng t hose t hat ar e ei t her Amphot er i ci n-B
or f l uconazol e and i t r aconazol e- r esi st ant , such as C. gl abr at a.
3. Therapeut i c uses. Al l t hr ee agent s ar e i ndi cat ed f or t he t r eat ment of
esophageal candi di asi s
a. Caspof unf i n and ani dul af ungi n ar e al so i ndi cat ed f or t he t r eat ment of
candi demi a and ot her i nf ect i ons caused by Candi da speci es, i ncl udi ng
i nt rabdomi nal abscesses and peri t oni t i s.
b. Caspof ungi n may al so be used f or t he t r eat ment of candi dal pl eur al
space i nf ect i ons, empi r i c t r eat ment of pr esumed f ungal i nf ect i ons i n
neut ropeni c pat i ent s, and t r eat ment of i nvasi ve aspergi l l osi s i n pat i ent s
r ef r act or y t o or i nt ol erant of ot her ant i f ungal s ( i . e. , amphot er i ci n B,
i t r aconazol e) .
c. Mi caf ungi n i s i ndi cat ed f or t he prophyl axi s of candi dal i nf ect i ons i n
pat i ent s i nder goi ng hemat opoi et i c st em cel l t ranspl ant at i on ( HSCT) .
4. Precauti ons and moni t ori ng ef f ect s. Al t hough t hi s cl ass has adver se
event s associ at ed wi t h i t s use, t he overal l t oxi ci t y pr of i l e i s si gni f i cant l y
bet t er t han t hat of amphot eri ci n B.
a. Ì nf usi on vei n compl i cat i ons (not def i ned by manuf act ur er ) and
t hr ombophl ebi t i s have been seen on i nf usi on of caspof ungi n.
b. Hemat ol ogi cal decreases i n hemogl obi n and hemat ocr i t may occur;
however , t he i nci dence does not di f f er f r om t hat of havi ng a f ungal di sease.
c. Headache may occur .
d. Sl i ght decreases i n ser um pot assi um may occur , but nowher e near t he
magni t ude of t hat caused by amphot er i ci n B.
e. Anor exi a, nausea, vomi t i ng, and di ar r hea have occur r ed.
f . Rar e i ncr eases i n ser um cr eat i ni ne; however , t her e have been no
r eport ed cases of nephrot oxi ci t y.
g. Possi bl e sl i ght i ncreases i n ser um ami not r ansf er ases
h. Al l er gi c r eact i ons occur i n < 5% of pat i ent s and anaphyl axi s i n < 2% of
pat i ent s.
i . Pr egnancy cat egor y C embr yot oxi c r eact i ons have occur r ed i n ani mal s.
5. Si gni f i cant i nteracti ons
a. When cycl ospori ne i s combi ned wi t h caspof ungi n, cl i ni cal l y si gni f i cant
r i ses i n ALT wer e obser ved. Ser um t ransami nases shoul d be moni t or ed, and
t hi s combi nat i on shoul d be avoi ded i n pat i ent s wi t h preexi st i ng l i ver
di sease.
b. When used i n combi nat i on, carbamazepi ne, nel f i navi r, nevi r api ne,
phenyt oi n, and ri f ampi n i ncr eases t he cl ear ance of caspof ungi n. Hi gher
doses of caspof ungi n ( 70 mg ever y day) shoul d be consi dered when t hi s
combi nat i on i s admi ni st er ed.
c. Tacrol i mus cl ear ance wi l l be i ncr eased when t he combi nat i on i s used;
moni t or t acr ol i mus ser um l evel s cl osel y.
D. FI ucyt osi ne ( Ancobon) . Thi s f l uori nat ed pyr i mi di ne usual l y i s gi ven i n
combi nat i on wi t h amphot er i ci n B.
1. Mechani sm of act i on. Fl ucyt osi ne penet r at es f ungal cel l s and i s
convert ed t o f l uor our aci l , a met abol i c ant agoni st . Ì ncor por at ed i nt o t he RNA
of t he f ungal cel l , f l ucyt osi ne causes def ect i ve prot ei n synt hesi s. Ì t i s ei t her
f ungi st at i c or f ungi ci daI , dependi ng on t he concent r at i on of t he dr ug.
2. Spect rum of acti vi t y. Thi s dr ug i s pri mar i l y act i ve agai nst Cr ypt ococcus
and Candi da. Ì t i s most commonl y used i n conj unct i on wi t h amphot eri ci n B.
Fungal r esi st ance agai nst f l ucyt osi ne al one has been wel l document ed.
Fl ucyt osi ne may al so possess some act i vi t y agai nst chromomycosi s and
some st r ai ns of Aspergi l l us (i n vi t r o t est i ng onl y) .
P. 943


3. Therapeut i c uses. Fl ucyt osi ne i s adj unct i vel y used wi t h amphot eri ci n B
f or sever e syst emi c i nf ect i ons (e. g. , sept i cemi a, endocardi t i s, pul monar y
and ur i nar y t ract i nf ect i ons, meni ngi t i s) . Use of f l ucyt osi ne al one i s not
r ecommended.
4. Precauti ons and moni t ori ng ef f ect s
a. Frequent adverse ef f ect s i ncl ude GÌ i nt ol erance wi t h nausea, vomi t i ng,
and di ar r hea.
b. Occasi onal adver se react i ons ar e mor e severe and i ncl ude mar row
suppr essi on wi t h l eukopeni a or t hrombocyt openi a ( dose r el at ed, especi al l y
wi t h r enal f ai l ur e or concur r ent amphot er i ci n B use) . Conf usi on, r ash,
hepat i t i s, ent erocol i t i s, headache, and phot osensi t i vi t y r eact i ons can al so
occur .
c. Rare r eact i ons i ncl ude hal l uci nat i ons, bl ood dyscr asi as wi t h
agr anul ocyt osi s and pancyt openi a, f at al hepat i t i s, anaphyl axi s, and anemi a.
d. Fl ucyt osi ne may cause a markedl y f al se el evat i on of ser um creat i ni ne i f
an Ekt achem anal yzer i s used.
5. Si gni f i cant i nteracti ons. Benef i ci al drug i nt eract i ons occur wi t h
f l ucyt osi ne. Fl ucyt osi ne has demonst r at ed synergy wi t h amphot eri ci n B
and fI uconazoI e agai nst Cr ypt ococcus and Candi da spp.
E. Gri seof uI vi n (FuI vi ci n) . Pr oduced f r om Peni ci l l i um gr i seof ul vi n Di erckx,
t hi s drug i s deposi t ed i n t he ski n, bound t o ker at i n.
1. Mechani sm of act i on. Thi s agent i s f ungi stati c; i t i nhi bi t s f ungal cel l
act i vi t y by i nt erf eri ng wi t h mi t ot i c spi ndl e st r uct ure. Ì t s mechani sm of act i on
i s si mi l ar t o col chi ci ne.
2. Spect rum of acti vi t y. Gr i seof ul vi n i s act i ve agai nst vari ous st rai ns of
Mi cr osporum, Epi der mophyt on, and Tri chophyt on.
3. Therapeut i c uses. Gri seof ul vi n i s ef f ect i ve i n t i nea i nf ect i ons of t he
ski n, hai r , and nai l s ( i ncl udi ng at hl et e' s f oot , j ock i t ch, and r i ngwor m)
caused by Mi cr ospor um, Epi der mophyt on, and Tri chophyt on.
a. Gener al l y, t hi s agent i s gi ven onl y f or i nf ect i ons t hat do not r espond t o
t opi cal ant i f ungal agent s.
b. Gr i seof ul vi n i s avai l abl e onl y i n or al f orm.
c. Ì t possesses vasodi l at or y act i vi t y and may be used i n Raynaud di sease.
d. Ì t may be used t o t reat gout .
4. Precauti ons and moni t ori ng ef f ect s
a. Gr i seof ul vi n rar el y resul t s i n ser i ous adver se ef f ect s. However , t he
f ol l owi ng pr obl ems have been r epor t ed.
( 1) Common: headache, f at i gue, conf usi on, i mpai r ed per f or mance, syncope,
and l et hargy, whi ch gener al l y r esol ve wi t h cont i nued use
( 2) Occasi onal : l eukopeni a, neut r openi a, and granul ocyt openi a
( 3) Rare: ser um si ckness, angi oedema, ur t i car i a, er yt hema, and
hepat ot oxi ci t y
b. The dosage depends on t he par t i cl e si ze of t he pr oduct : 250 mg of
ul t rami crosi ze ( Ful vi ci n P/ G) i s equi val ent i n t her apeut i c ef f ect s t o 500 mg
of mi cr osi ze ( Ful vi ci n U/ F) .
5. Si gni f i cant i nteracti ons
a. Gr i seof ul vi n may i ncrease t he met abol i sm of warf ari n, l eadi ng t o
decreased prot hrombi n t i me.
b. Barbi t urates may r educe gr i seof ul vi n absorpt i on.
c. AI cohoI consumpt i on may cause t achycar di a and f l ushi ng.
d. OraI cont racept i ves may cause amenorr hea or i ncreased br eakt hr ough
bl eedi ng.
F. I mi dazoI es. The subst i t ut ed i mi dazol e der i vat i ves ket oconazoI e
( Ni zoraI ) , mi conazoI e (Moni st at ), f I uconazoI e (Di f I ucan) , i t raconazoI e
( Sporanox) , vori conazoI e ( Vf end) and posaconazoI e ( Noxaf i I ) ar e
val uabl e i n t he t r eat ment of a wi de range of syst emi c f ungal i nf ect i ons.
1. Mechani sm of act i on. Ì mi dazol es i nhi bi t st erol synt hesi s i n f ungal cel l
membr anes and i ncr ease cel l wal l permeabi l i t y; t hi s, i n t ur n, makes t he cel l
mor e vul ner abl e t o osmot i c pr essur e. These agent s ar e fungi st at i c.
2. Spect rum of acti vi t y. These agent s are act i ve agai nst many f ungi ,
i ncl udi ng yeast s, dermat ophyt es, act i nomycet es, and some Phycomycet es.
P. 944


3. Therapeut i c uses
a. KetoconazoI e, an oral agent , successf ul l y t reat s many f ungal i nf ect i ons
t hat pr evi ousl y yi el ded onl y t o parent er al agent s.
( 1) Ì t i s t her apeut i c f or syst emi c and vagi nal candi di asi s, mucocandi di asi s,
candi dur i a, or al t hrush, hi st opl asmosi s, cocci di oi domycosi s,
chr omomycosi s, dermat ophyt osi s ( t i nea) , and paracocci di oi domycosi s.
( 2) Because ket oconazol e i s sl ow act i ng and requi r es a l ong dur at i on of
t her apy ( up t o 6 mont hs f or some chroni c i nf ect i ons) , i t i s l ess ef f ect i ve
t han ot her ant i f ungal agent s f or t he t reat ment of sever e and acut e syst emi c
i nf ect i ons.
b. Mi conazoI e, pri mar i l y admi ni st er ed as a t opi cal agent , The parent er al
f or m has been di scont i nued i n t he Uni t ed St at es. Ì t was a r el at i vel y t oxi c
f or mul at i on whi ch has been r epl aced by ot her members of t hi s cl ass ( e. g. ,
f l uconazol e) .
( 1) Topi cal mi conazol e i s hi ghl y ef f ect i ve i n vul vovagi nal candi di asi s,
r i ngwor m, and ot her ski n i nf ect i ons.
c. FI uconazoI e. Avai l abl e i n or al and parent er al f or ms, f l uconazol e can be
used agai nst syst emi c and CNS i nf ect i ons i nvol vi ng Crypt ococcus and
Candi da. Candi da or ophar yngeal i nf ect i on and esophagi t i s may al so be
t r eat ed wi t h f l uconazol e. Asper gi l l us, Cocci di oi des, and Hi st opl asma have
demonst r at ed i n vi t r o sensi t i vi t y.
d. I t raconazoI e i s avai l abl e as an or al agent wi t h act i vi t y agai nst syst emi c
and i nvasi ve pul monar y asper gi l l osi s wi t hout t he hemat ol ogi cal t oxi ci t y of
amphot er i ci n B. Ot her deep mycot i c i nf ect i ons suscept i bl e t o i t r aconazol e
i ncl ude bl ast omycosi s, cocci di oi domycosi s, cr ypt ococcosi s, and
hi st opl asmosi s.
e. Vori conazoI e. Vor i conazol e i s avai l abl e as bot h an i nt r avenous and an
or al agent f or t he t r eat ment of f ungal i nf ect i ons i nvol vi ng i nvasi ve
asper gi l l osi s, Scedospori um api osper mum, and Fusari um spp. , i ncl udi ng
t hose speci es t hat ar e ref r act or y t o ot her t herapy.
f . PosaconazoI e. Avai l abl e as an or al suspensi on i ndi cat ed f or t he
pr event i on of i nvasi ve i nf ect i ons caused by Asper gi l l us and Candi da
speci es i n pat i ent s r ecei vi ng HSCT or wi t h neut ropeni s. Posaconazol e may
al so be used t o t r eat i nvasi ve f ungal i nf ect i ons i n pat i ent s who have
pr evi ousl y f ai l ed or ar e i nt ol er ant t o ot her ant i f ungal s.
4. Precauti ons and moni t ori ng ef f ect s
a. KetoconazoI e may cause nausea, vomi t i ng, di ar r hea, abdomi nal pai n,
and const i pat i on. Rar el y, i t l eads t o headache, di zzi ness, gynecomast i a,
and f at al hepat ot oxi ci t y.
b. FI uconazoI e commonl y causes GÌ di st urbances ( e. g. , nausea, vomi t i ng,
epi gast r i c pai n, di ar rhea) . Reversi bl e el evat i ons i n ser um ami not ransf erase,
exf ol i at i ve ski n r eact i ons, and headaches have been repor t ed.
c. I t raconazoI e may cause nausea, vomi t i ng, hyper t r i gl ycer i demi a,
hypokal emi a, rash, and el evat i ons i n l i ver enzymes.
d. Vori conazoI e. Vi sual di st ur bances, f ever , rash, vomi t i ng, nausea,
di ar rhea, headache, sepsi s, per i pher al edema, abdomi nal pai n, and
r espi r at or y di sor der s rarel y occur r ed. Li ver f unct i on t est abnormal i t i es have
occur r ed.
e. PosaconazoI e. Most common adverse event s have been nausea and
headache. Rash, dr y ski n, t ast e di st ur bances, abdomi nal pai n, di zzi ness,
hypokal emi a, t hr ombocyt openi a, and f l ushi ng can occur . Posaconazol e can
cause abnormal i t i es i n l i ver f unct i on and has been associ at ed wi t h
pr ol ongat i on of t he QT i nt er val .
5. Si gni f i cant i nteracti ons
a. Bot h ket oconazoI e and mi conazoI e may enhance t he ant i coagul ant
ef f ect of warfari n.
b. Ket oconazoI e may ant agoni ze t he ant i bi ot i c ef f ect s of amphot eri ci n B.
c. FI uconazoI e has been shown t o el evat e serum l evel s of phenyt oi n,
cycI ospori ne, warf ari n, and suI f onyI ureas. Concur rent hepat i c enzyme
i nducer s, such as ri fampi n, have resul t ed i n i ncr eased el i mi nat i on of bot h
f l uconazol e and i t r aconazol e.
d. Coadmi ni st r at i on of i traconazoI e or ket oconazoI e wi t h ast emi zoI e or
t erf enadi ne may r esul t i n i ncr eased ast emi zol e or t er f enadi ne l evel s,
possi bl y l eadi ng t o l i f e-t hr eat eni ng dysrhyt hmi as and deat h.
e. Bot h ket oconazoI e and i t raconazoI e need t he pr esence of st omach aci d
f or adequat e absor pt i on. Use wi t h ant aci ds, H2- bl ockers, or prot on pump
i nhi bi t ors i s cont r ai ndi cat ed.
f . Concomi t ant use of i mi dazol e ant i f ungal agent s wi t h ci sapri de may r esul t
i n i ncr eased concent r at i ons of ci sapr i de, whi ch has been associ at ed wi t h
adver se car di ac event s such as t orsades de poi nt es l eadi ng t o sudden
deat h.
P. 945


g. Vori conazoI e. Cyt ochr ome P450 2C19 i s t he maj or enzyme i nvol ved i n
met abol i sm. Vori conazol e i nhi bi t s cyt ochr ome P450 2C19, 2C9, and 3A4.
Any medi cat i on t hat i s met abol i zed vi a t hese r out es may be af f ect ed, and
moni t ori ng of bl ood l evel s ( i f appr opr i at e) or cl i ni cal si gns and sympt oms i s
necessar y when t aki ng concomi t ant medi cat i ons.
h. PosaconazoI e ser um l evel s are reduced by concurr ent admi ni st rat i on
wi t h ci met i di ne, phenyt oi n or ri f but i n; avoi d concommi t ant use i f possi bl e.
Posaconazol e may i ncrease concent r at i ons of cycl ospor i ne, t acr ol i mus,
r i f abut i n, mi dazol am, and phenyt oi n; dosage adj ust ment s may be requi r ed.
( 1) Food i ncr eases t he or al bi oavai l abi l i t y; t ake posaconazol e wi t h a f ul l
meal or l i qui d nut ri t i onal suppl ement
G. Nyst at i n ( Mycost at i n) . A pol yene ant i bi ot i c, nyst at i n has a chemi cal
st r uct ur e si mi l ar t o t hat of amphot er i ci n B.
1. Mechani sm of act i on. Nyst at i n i s f ungi ci daI and fungi st ati c; bi ndi ng t o
st erol s i n t he f ungal cel l membr ane, i t i ncr eases membr ane permeabi l i t y
and permi t s l eakage of i nt r acel l ul ar cont ent s.
2. Spect rum of acti vi t y. Nyst at i n i s act i ve pr i mari l y agai nst Candi da spp.
3. Therapeut i c uses
a. Thi s drug i s used pr i mar i l y as a t opi cal agent i n vagi nal and or al Candi da
i nf ect i ons.
b. Or al nyst at i n i s t herapeut i c f or Candi da i nf ect i ons of t he GÌ t ract ,
especi al l y oral and esophageal i nf ect i ons; because t he dr ug i s not readi l y
absor bed, i t mai nt ai ns good l ocal act i vi t y.
4. Precauti ons and moni t ori ng ef f ect s. Or al nyst at i n occasi onal l y causes
GÌ di st r ess ( e. g. , nausea, vomi t i ng, di ar r hea) . Rar el y, hyper sensi t i vi t y
r eact i ons occur .
H. Terbi naf i ne (Lami si I ) i s a synt het i c al l yl ami ne wi t h st ruct ur e and
act i vi t y r el at ed t o naf t i f i ne.
1. Mechani sm of act i on. Ter bi naf i ne i nhi bi t s squal ene monooxygenase,
l eadi ng t o an i nt er rupt i on of f ungal st erol bi osynt hesi s. Ter bi naf i ne may be
f ungi ci daI or f ungi stat i c, dependi ng on dr ug concent r at i on and speci es.
2. Spect rum of acti vi t y. Ter bi naf i ne has act i vi t y agai nst der mat ophyt i c
f ungi ( Tri chophyt on, Mi crospor um, and Epi der mophyt on) , f i l ament ous f ungi
( Asper gi l l us), and di morphi c f ungi ( Bl ast omyces). Ì t may al so possess some
act i vi t y agai nst yeast s.
3. Therapeut i c uses
a. Or al t erbi naf i ne i s usef ul agai nst i nf ect i ons of t he t oenai l and f i nger nai l
( onychomycosi s, t i nea ungui um) . Ti me t o cur e i s r educed over i mi dazol e
ant i f ungal s f or t hese i ndi cat i ons. Ì t i s usef ul i n pat i ent s who may not
t ol er at e t he adver se ef f ect pr of i l e of i mi dazol e ant i f ungal s.
b. Ì t i s al so used i n t i nea capi t i s and t i nea cor por i s i nf ect i ons.
4. Precauti ons and moni t ori ng ef f ect s. Adverse ef f ect s i ncl ude t ast e or
ocul ar di st ur bances, sympt omat i c hepat obi l i ar y dysf unct i on, decr ease i n
l ymphocyt e count and neut r openi a, and ser i ous ski n r eact i ons.
IV. TopicaI AntifungaI Agents
A. Def i ni t i on. These agent s are f or t opi cal use f or f ungal i nf ect i ons.
B. Amphot eri ci n B ( Fungi zone) i s avai l abl e as a 3% cr eam or l ot i on or an
or al suspensi on t hat i s not absor bed t hr ough t he GÌ t r act .
1. Mechani sm of act i on. See Ì Ì Ì . B. 1.
2. Spect rum of acti vi t y. See Ì Ì Ì . B. 2.
3. Therapeut i c uses. Amphot eri ci n B i s used f or or ophar yngeal candi di asi s,
cut aneous and mucocut aneous candi dal i nf ect i ons, or as a l ocal i r r i gant f or
t he bl adder and i nt rapl eur al or i nt raper i t oneal areas.
P. 946


4. Precauti ons and moni t ori ng ef f ect s. Compared wi t h syst emi c
admi ni st rat i on, t he t opi cal f or mul at i ons have r el at i vel y l ow t oxi ci t y.
a. Dr y ski n and l ocal i r ri t at i on wi t h er yt hema, pruri t us, or bur ni ng, al ong
wi t h mi l d ski n di scol or at i on, has occur r ed wi t h t he l ot i on and cr eam.
b. Rash and GÌ ef f ect s (e. g. , nausea, vomi t i ng, st eat or r hea, di ar r hea) t end
t o occur wi t h t he suspensi on. Ì n addi t i on, t her e have been case r epor t s of
ur t i cari a, angi oedema, St evens- Johnson syndr ome, and t oxi c epi der mal
necrol ysi s.
C. But enaf i ne (Mentax) i s a synt het i c benzyl ami ne r el at ed t o t he al l yl ami ne
ant i f ungal agent s (naf t i f i ne, t er bi naf i ne) .
1. Mechani sm of act i on. But enaf i ne al t ers f ungal membr ane permeabi l i t y
and gr owt h i nhi bi t i on, i nt er f eres wi t h st er ol bi osynt hesi s by al l owi ng
squal ene t o accumul at e wi t hi n t he cel l , and may be f ungi ci dal i n cer t ai n
concent r at i ons agai nst suscept i bl e or gani sms such as t he dermat ophyt es.
2. Spect rum of acti vi t y. But enaf i ne i s act i ve agai nst Tri chophyt on r ubrum,
Tr i chophyt on ment agr ophyt es, Mi cr ospor um cani s, Spor ot hr i x schencki i ,
and yeast s i ncl udi ng Candi da par apsi l osi s and C. al bi cans.
3. Therapeut i c uses. The 1% cream i s used i n der mat ophyt oses, i ncl udi ng
t i nea cor por i s, t i nea cr uri s, and t i nea pedi s.
4. Precauti ons and moni t ori ng ef f ect s. Ì f cl i ni cal i mprovement of f ungal
i nf ect i on does not i mprove af t er t he t reat ment per i od, t he di agnosi s shoul d
be r eeval uat ed.
D. But oconazoI e (MyceI ex) i s an azol e ant i f ungal cream avai l abl e f or
vagi nal use.
1. Mechani sm of act i on. But oconazol e has f ungi st at i c act i vi t y agai nst
suscept i bl e organi sms. The drug i nt er f er es wi t h membrane per meabi l i t y,
secondar y met abol i c ef f ect s, and gr owt h i nhi bi t i on. But oconazol e cont ai ns
ant i bact eri al ef f ect s agai nst some gr am-posi t i ve or gani sms.
2. Spect rum of acti vi t y. But oconazol e i s act i ve agai nst der mat ophyt es
( Tr i chophyt on concent r i cum, T. ment agr ophyt es, T. r ubr um, Tr i chophyt on
t onsur ans, Epi der mophyt on f l occosum, M. cani s, Mi cr osporum gypseum) ,
yeast s ( C. al bi cans, C. gl abrat a), and some gr am- posi t i ve organi sms ( S.
aur eus, E. f aecal i s, and S. pyogenes) .
3. Therapeut i c uses. A 2% cr eam i s used f or vul vovagi nal candi di asi s and
compl i cat ed, recur r ent vul vovagi nal candi di asi s.
4. Precauti ons and moni t ori ng ef f ect s
a. Vul vovagi nal bur ni ng and i t chi ng ar e t he most common; however , t hei r
i nci dence i s l ow. Headache; i t chi ng of f i ngers; ur i nar y f r equency and
bur ni ng; and vul vovagi nal di schar ge, i r r i t at i on, sor eness, st i ngi ng, odor ,
and swel l i ng r ar el y occur.
b. But oconazol e may damage bi r t h- cont rol devi ces such as condoms and
di aphr agms, l eadi ng t o i nadequat e pr ot ect i on. Consi der al t ernat i ve met hods
of bi r t h cont rol .
c. Tampon use shoul d be avoi ded wi t h t he use of but oconazol e.
E. Ci cI opi rox ( Loprox) i s a synt het i c ant i f ungal agent t hat i s chemi cal l y
unr el at ed t o any ot her ant i f ungal agent . The et hanol ami ne cont ai ned i n
ci cl opi rox appears t o enhance epi dermal penet r at i on.
1. Mechani sm of act i on. Ci cl opi r ox causes i nt r acel l ul ar depl et i on of ami no
aci ds and i ons necessary f or nor mal cel l ul ar f unct i on.
2. Spect rum of acti vi t y. Ci cl opi r ox i s act i ve agai nst dermat ophyt es,
yeast s, some gr am- posi t i ve and gram- negat i ve bact er i a, Mycopl asma, and
Tr i chomonas vagi nal i s. Speci f i cal l y, ci cl opi r ox has act i vi t y agai nst T.
ment agrophyt es, T. r ubrum, E. f l occosum, M. cani s, M. f ur f ur, and C.
al bi cans.
3. Therapeut i c uses. Ci cl opi rox i s used t opi cal l y f or t he t r eat ment of t i nea
pedi s, t i nea crur i s, t i nea corpori s, t i nea ver si col or ( f r om Mal assezi a) , and
cut aneous candi di asi s (moni l i asi s) f rom C. al bi cans.
P. 947


4. Precauti ons and moni t ori ng ef f ect s. Local i r ri t at i on mani f est ed by
er yt hema, pr uri t us, burni ng, bl i st er i ng, swel l i ng, and oozi ng has occur r ed. Ì f
t hi s occur s, ci cl opi rox shoul d be di scont i nued.
F. CI i oqui noI (f ormerl y i odochl or hydroxyqui n) i s a t opi cal ant i f ungal i n a
3% oi nt ment t hat can be used al one or i n combi nat i on wi t h hydr ocor t i sone.
1. Mechani sm of act i on. Unknown
2. Spect rum of acti vi t y. Ì t i s act i ve agai nst der mat ophyt i c f ungi .
3. Therapeut i c uses. Ì t i s used t opi cal l y agai nst t he f ol l owi ng:
a. Ti nea pedi s and t i nea cr uri s ( r i ngwor m i nf ect i ons)
b. Pr evi ousl y used t o t r eat di aper rash; however , i t i s no l onger
r ecommended, and use i n chi l dr en < 2 years of age i s cont r ai ndi cat ed
4. Precauti ons and moni t ori ng ef f ect s
a. Local i r r i t at i on, r ash, and sensi t i vi t y r eact i ons ar e common.
b. Syst emi c absorpt i on af t er t opi cal appl i cat i on may occur .
c. Hi gh doses of cl i oqui nol over l ong peri ods of t i me have been associ at ed
wi t h ocul ot oxi c/ neur ot oxi c ef f ect s, i ncl udi ng opt i c neuri t i s, opt i c at r ophy,
and subacut e myel oopt i c neuropat hy.
G. CI ot ri mazoI e (Lot ri mi n) i s an azol e ant i f ungal agent t hat i s an
i mi dazol e der i vat i ve. Ì t i s r el at ed t o ot her azol e ant i f ungal agent s such as
but oconazoI e, econazoI e, ket oconazoI e, mi conazoI e, oxi conazoI e,
suI conazoI e, and t i oconazoI e.
1. Mechani sm of act i on. Cl ot r i mazol e al t ers f ungal cel l membrane
per meabi l i t y by bi ndi ng wi t h phosphol i pi ds i n t he membrane.
2. Spect rum of acti vi t y. Ì t i s act i ve agai nst yeast s, dermat ophyt es ( T.
r ubr um, T. ment agr ophyt es, E. f l occosum, M. cani s) , and some gr am-
posi t i ve bact er i a. At hi gher concent r at i ons, cl ot ri mazol e i nhi bi t s M. f ur f ur ,
Aspergi l l us f umi gat us, C. al bi cans, and some st rai ns of S. aureus, S.
pyogenes, Pr ot eus vul gar i s, and Sal monel l a. At ver y hi gh concent r at i ons,
cl ot r i mazol e has an ef f ect on Spor ot hr i x, Cr ypt ococcus, Cephal ospor i um,
Fusar i um, and T. vagi nal i s.
3. Therapeut i c uses
a. The l ozenges, whi ch ar e admi ni st er ed 5 t i mes per day, are usef ul i n
t r eat i ng orophar yngeal candi di asi s. Lozenges ar e al so used f or pr i mar y
pr ophyl axi s of mucocut aneous candi di asi s i n HÌ V- i nf ect ed i nf ant s or
chi l dren wi t h severe i mmunosuppr essi on.
b. The cr eam, l ot i on, or sol ut i on i s used t o t r eat der mat ophyt oses,
super f i ci al mycoses, and cut aneous candi di asi s.
c. Ì nt r avagi nal dosage f or ms ar e usef ul i n t r eat i ng vul vovagi nal candi di asi s.
4. Precauti ons and moni t ori ng ef f ect s
a. Cut aneous react i ons wi t h t opi cal admi ni st r at i on may i ncl ude bl i st er i ng,
er yt hema, edema, pr ur i t us, burni ng, st i ngi ng, peel i ng, ski n f i ssur es, and
gener al i r ri t at i on.
b. The vagi nal t abl et s are associ at ed wi t h mi l d bur ni ng, ski n r ash, i t chi ng,
vul val i r r i t at i on, l ower abdomi nal cr amps, bl oat i ng, sl i ght crampi ng, vagi nal
sor eness duri ng i nt ercour se, and an i ncrease i n ur i nar y f r equency.
c. Cr oss- sensi t i zat i on occurs wi t h i mi dazol e; however , i t i s unpredi ct abl e.
d. Abnormal l i ver f unct i on t est s ( el evat ed AST) have occur r ed i n pat i ent s
t aki ng t he l ozenges.
H. EconazoI e ( Spect azoI e) i s an azol e ant i f ungal agent t hat i s an
i mi dazol e der i vat i ve.
1. Mechani sm of act i on. Econazol e al t er s cel l membranes and i ncreases
per meabi l i t y ( l i ke many ot her azol e agent s).
2. Spect rum of acti vi t y. Econazol e i s act i ve agai nst dermat ophyt es,
yeast s, some gr am- posi t i ve bact er i a, and T. vagi nal i s.
3. Therapeut i c uses
a. The 1% t opi cal cr eam, l ot i on, or sol ut i on i s usef ul i n t r eat i ng
der mat ophyt oses and cut aneous candi di asi s ( t i nea cor por i s and t i nea
cr uri s).
b. Econazol e i s al so used t o t r eat pi t yr i asi s (t i nea) ver si col or ( M. f ur f ur) .
P. 948


4. Precauti ons and moni t ori ng ef f ect s. Ì n general , t here i s a l ow
i nci dence of t oxi ci t y. Topi cal l y, a pat i ent may exper i ence bur ni ng, st i ngi ng
sensat i ons, prur i t us, and er yt hema ( af t er 2- 4 days) .
I . Gent i an vi oI et i s a dye t hat possesses t he abi l i t y t o ki l l f ungi , yeast s,
and some gr am- posi t i ve bact er i a.
1. Mechani sm of act i on. None known
2. Spect rum of acti vi t y. Gent i an vi ol et i s act i ve agai nst Candi da,
Epi der mophyt on, Crypt ococcus, Tr i chophyt on, and some St aphyl ococcus
spp.
3. Therapeut i c uses. Ì t i s used t o t r eat cut aneous C. al bi cans i nf ect i ons
( moni l i a or t hr ush) .
4. Precauti ons and moni t ori ng ef f ect s
a. Gent i an vi ol et may cause i r ri t at i on or sensi t i vi t y r eact i ons or possi bl y
ul cer at i on of t he mucous membranes. Ì f t he sol ut i on i s swal l owed,
esophagi t i s, l ar yngi t i s, or t r achei t i s may occur .
b. Ski n t at t ooi ng may occur i f gent i an vi ol et i s appl i ed t o gr anul at i on t i ssue.
c. Gent i an vi ol et shoul d not be used i n ar eas of ext ensi ve ul cer at i on.
d. Thi s dr ug i s a dye and wi l l st ai n cl ot hi ng.
J. KetoconazoI e ( Ni zoraI ) i s an i mi dazol e-der i ved ant i f ungal drug t hat i s
avai l abl e t opi cal l y as a cr eam and a shampoo.
1. Mechani sm of act i on. See Ì Ì Ì . E. 1.
2. Spect rum of acti vi t y. See Ì Ì Ì . E. 2.
3. Therapeut i c uses
a. The 2% t opi cal cr eam i s used i n t r eat i ng t i nea cor por i s, t i nea cr ur i s, and
t i nea pedi s caused by t he dermat ophyt es ( E. f l occosum, T. ment agrophyt es,
and T. rubr um) .
b. Ì t i s used f or cut aneous candi di asi s.
c. The 2% t opi cal cr eam or 2% shampoo may be used i n t reat i ng t i nea
ver si col or ( M. f ur f ur ) . Sel eni um- based shampoos may al so be usef ul i n t hi s
ar ea.
d. The 2% t opi cal cr eam i s usef ul agai nst sebor rhei c der mat i t i s. The 2%
shampoo i s usef ul i n reduci ng scal i ng caused by dandr uf f .
e. When combi ned wi t h a st er oi d, ket oconazol e i s usef ul i n t r eat i ng t he
f ol l owi ng: at opi c der mat i t i s, di aper r ash, eczema, f ol l i cul i t i s, i mpet i go,
i nt er t r i go, l i chenoi d dermat i t i s, and psori asi s.
f . An opht hal mi c suspensi on can be ext empor aneousl y prepar ed t o t r eat
f ungal kerat i t i s.
4. Precauti ons and moni t ori ng ef f ect s
a. React i ons f r om t he 2% t opi cal cream i ncl ude l ocal i r r i t at i on, prur i t us, and
st i ngi ng. Cont act der mat i t i s i s possi bl e and occurs wi t h ot her i mi dazol e
der i vat i ves.
b. The 2% shampoo may l ead t o i ncreased hai r l oss, i r ri t at i on, abnor mal
hai r t ext ur e, scal p pust ul es, dr y ski n, pr uri t us, and oi l i ness or dr yness of
hai r and scal p. Ì t may i n addi t i on st r ai ght en ot herwi se cur l y hai r .
K. Mi conazoI e (Moni stat ) i s an i mi dazol e- der i ved ant i f ungal dr ug t hat i s
avai l abl e t opi cal l y as a 2% aerosol , 2% aer osol powder , 2% cream, a ki t ,
2% powder and 2% t i nct ur e, 2% vagi nal cream, and 100 mg and 200 mg
vagi nal supposi t or i es.
1. Mechani sm of act i on. See Ì Ì Ì . E. 1.
2. Spect rum of acti vi t y. See Ì Ì Ì . E. 2.
3. Therapeut i c uses. Mi conazol e i s advant ageous over ot her agent s such
as nyst at i n and t ol naf t at e i n t hat i t s act i vi t y cover s der mat ophyt es as wel l
as Candi da.
a. Topi cal use i s ef f ect i ve agai nst t i nea pedi s, t i nea cr uri s, and t i nea
cor por i s caused by dermat ophyt es ( T. ment agr ophyt es, T. rubrum, and E.
f l occosum) .
b. Ì t i s al so ef f ect i ve agai nst t i nea versi col or f rom M. f ur f ur .
c. Li ke ot her i mi dazol e der i vat i ves, i t i s usef ul i n t r eat i ng cut aneous f ungal
i nf ect i ons.
d. The vagi nal cr eam and vagi nal supposi t or i es ar e ef f ect i ve i n t r eat i ng
vul vovagi nal candi di asi s.
P. 949


4. Precauti ons and moni t ori ng parameters
a. Topi cal cr eams have caused l ocal i r r i t at i on and burni ng.
b. Vagi nal pr epar at i ons have l ed t o vul vovagi nal bur ni ng, i t chi ng, i r r i t at i on,
pel vi c cr amps, vagi nal bur ni ng, headache, hi ves, and ski n r ash.
c. Ì f vul vovagi nal candi di asi s persi st s f or l onger t han 3 days, seek f ur t her
medi cal at t ent i on.
d. Tampons shoul d be avoi ded i n pat i ent s usi ng vagi nal supposi t or i es or
cr eam; sani t ar y pads shoul d be subst i t ut ed.
e. Vagi nal supposi t ori es ar e manuf act ur ed f r om a veget abl e oi l base t hat
may i nt eract wi t h l at ex pr oduct s. Avoi d usi ng di aphr agms or condoms
concur rent l y wi t h supposi t ori es. Seek an al t er nat i ve f orm of bi r t h cont r ol .
L. Naf t i f i ne ( Naf ti n) i s a synt het i c al l yl ami ne si mi l ar t o t er bi naf i ne. Ì t i s
avai l abl e as a 1% t opi cal cr eam and a 1% t opi cal gel .
1. Mechani sm of act i on. Naf t i f i ne i s f ungi stat i c and i nt er f er es wi t h st erol
bi osynt hesi s by accumul at i ng squal ene i n t he f ungal cel l . Naf t i f i ne al so
possesses some l ocal ant i - i nf l ammat or y act i vi t y.
2. Spect rum of acti vi t y
a. Naf t i f i ne i s act i ve agai nst T. ment agr ophyt es, T. r ubr um, T. t onsur ans,
Tr i chophyt on ver r ucosum, Tr i chophyt on vi ol aceum, E. f l occosum,
Mi cr osporum audoui ni i , M. cani s, and M. gypseum.
b. C. al bi cans, Candi da kr usei , Candi da parapsi l osi s, and Candi da
t r opi cal i s ar e af f ect ed by naf t i f i ne; however , t he concent rat i ons of naf t i f i ne
var y f or Candi da ki l l i ng, dependi ng on t he speci es.
c. Ì n vi t r o act i vi t y has been demonst r at ed agai nst Asper gi l l us f l avus and
Aspergi l l us f umi gat us. Ot hers i ncl ude Spor ot hr i x schencki i , Cr ypt ococcus
neof or mans, Pet r i el l i di um boydi i , Bl ast omyces der mat i t i di s, and
Hi st opl asma capsul at um.
3. Therapeut i c uses. Naf t i f i ne i s act i ve agai nst der mat ophyt oses and
cut aneous candi di asi s.
a. Ì t i s al so used t o t r eat t i nea cr uri s, t i nea pedi s, t i nea cor pori s, and t i nea
manus ( T. ment agr ophyt es, T. rubrum, T. verr ucosum, T. vi ol aceum, E.
f l occosum, or M. cani s) .
b. Ì t i s al so usef ul i n t r eat i ng t i nea ungui um (onychomycosi s) .
4. Precauti ons and moni t ori ng ef f ect s. Tr ansi ent bur ni ng and st i ngi ng
M. Nyst at i n ( Mycost at i n) . A pol yene ant i bi ot i c, nyst at i n has a chemi cal
st r uct ur e si mi l ar t o t hat of amphot er i ci n B. Ì t i s avai l abl e as an oral
suspensi on, t abl et , l ozenge, t opi cal cream, oi nt ment , t opi cal powder , and
vagi nal t abl et .
1. Mechani sm of act i on. Nyst at i n i s f ungi ci daI and fungi st ati c; bi ndi ng t o
st erol s i n t he f ungal cel l membr ane, i t i ncr eases membr ane permeabi l i t y
and permi t s l eakage of i nt r acel l ul ar cont ent s.
2. Spect rum of acti vi t y. Nyst at i n i s act i ve pr i mari l y agai nst Candi da spp.
3. Therapeut i c uses. Thi s dr ug i s used pri mar i l y as a t opi cal agent i n
vagi nal and or al Candi da i nf ect i ons.
4. Precauti ons and moni t ori ng ef f ect s. Ì r ri t at i on has occur r ed i n
ext r emel y r are i nst ances.
N. Oxi conazoI e ( Oxi st at) i s an i mi dazol e- deri ved ant i f ungal drug t hat i s
avai l abl e as a 1% t opi cal cr eam or 1% t opi cal l ot i on.
1. Mechani sm of act i on. See Ì Ì Ì . E. 1.
2. Spect rum of acti vi t y. See Ì Ì Ì . E. 2.
3. Therapeut i c uses
a. The 1% cr eam or l ot i on i s usef ul i n t r eat i ng t i nea cr uri s, t i nea cor por i s,
t i nea manus, and t i nea pedi s f rom dermat ophyt es.
b. Oxi conazol e i s al so ef f ect i ve agai nst t i nea versi col or caused by M.
f ur f ur.
4. Precauti ons and moni t ori ng ef f ect s. Adverse ef f ect s ar e rar e and are
conf i ned t o l ocal i r ri t at i on.
P. 950


O. SuI conazoI e ( ExeI derm) i s an i mi dazol e- der i ved ant i f ungal drug t hat i s
avai l abl e as a 1% t opi cal cr eam and a 1% t opi cal sol ut i on.
1. Mechani sm of act i on ( see Ì Ì Ì . E. 1) . The ant i bact eri al ef f ect s exer t ed by
sul conazol e ar e t hought t o be t he resul t of a di r ect physi cochemi cal ef f ect
on t he dest r uct i on of unsat ur at ed f at t y aci ds pr esent i n bact eri al cel l
membr anes.
2. Spect rum of acti vi t y
a. Sul conazol e has act i vi t y agai nst der mat ophyt es, i ncl udi ng E. f l occosum,
M. audoui ni i , M. cani s, M. gypseum, T. ment agrophyt es, T. rubr um, T.
t onsur ans, and T. vi ol aceum. Ì t al so has act i vi t y agai nst M. f ur f ur.
b. Sul conazol e al so has act i vi t y agai nst sel ect ed gr am- posi t i ve aer obes (S.
aur eus, S. epi der mi di s, St aphyl ococcus saprophyt i cus, E. f aecal i s,
Mi cr ococcus l ut eus, and Baci l l us subt i l i s) and anaer obes ( Cl ost r i di um and
Pr opi oni bact er i um acnes, Cl ost ri di um perf r i ngens, Cl ost ri di um t et ani , and
Cl ost r i di um bot ul i num) .
3. Therapeut i c uses
a. The 1% t opi cal cr eam or 1% t opi cal sol ut i on i s usef ul i n t r eat i ng t i nea
cor por i s and t i nea crur i s.
b. The 1% t opi cal cr eam has been st udi ed f or use agai nst t i nea pedi s; t he
sol ut i on has not been eval uat ed f or t hi s i ndi cat i on.
c. The 1% cr eam i s usef ul agai nst t i nea versi col or ( M. f ur f ur ).
d. Ther e i s not an approved i ndi cat i on f or cut aneous candi di asi s; however ,
sul conazol e 1% i s as ef f ect i ve as mi conazol e 2% or cl ot r i mazol e 1% i n
t r eat i ng cut aneous candi di asi s.
e. Sul conazol e i s usef ul i n t reat i ng i nf ect i ons caused by bact er i a such as
i mpet i go ( S. pyogenes) and ect hyma ( S. aureus).
4. Precauti ons and moni t ori ng ef f ect s. Adverse r eact i ons i ncl ude l ocal
ef f ect s such as bur ni ng and i r r i t at i on, ski n edema, dr yness, scal i ng,
f i ssuri ng, cr acki ng, gener al i zed r ed papul es, and sever e eczema.
P. Terbi nafi ne ( Lami si I AT) i s a synt het i c al l yl ami ne avai l abl e as a 1%
cr eam wi t h st ruct ur e and act i vi t y r el at ed t o naf t i f i ne.
1. Mechani sm of act i on. Ter bi naf i ne i nhi bi t s squal ene monooxygenase,
l eadi ng t o an i nt er rupt i on of f ungal st erol bi osynt hesi s. Ter bi naf i ne may be
f ungi ci daI or f ungi stat i c, dependi ng on dr ug concent r at i on and speci es.
2. Spect rum of acti vi t y. Ter bi naf i ne has act i vi t y agai nst der mat ophyt i c
f ungi ( Tri chophyt on, Mi crospor um, and Epi der mophyt on) , f i l ament ous f ungi
( Asper gi l l us), and di morphi c f ungi ( Bl ast omyces). Ì t may al so possess some
act i vi t y agai nst yeast s.
3. Therapeut i c uses. Ì t i s usef ul f or t i nea pedi s, t i nea cor por i s, and t i nea
cr uri s.
4. Precauti ons and moni t ori ng ef f ect s. Ì t can cause l ocal i r r i t at i on.
Q. TerconazoI e ( TerazoI - 7) i s an i mi dazol e-deri ved ant i f ungal drug t hat i s
avai l abl e as a 0. 4% and 0. 8% vagi nal cream and an 80- mg vagi nal
supposi t or y.
1. Mechani sm of act i on. Ì t i s f ungi ci daI agai nst C. al bi cans. Li ke ot her
i mi dazol e agent s, t er conazol e al t er s cel l ul ar membr anes, resul t i ng i n
i ncreased membr ane permeabi l i t y.
2. Spect rum of acti vi t y. Ì t i s act i ve agai nst der mat ophyt es; yeast s; and, at
hi gh concent r at i ons, gr am- posi t i ve and gr am-negat i ve bact eri a.
3. Therapeut i c uses ar e f or compl i cat ed and uncompl i cat ed vul vovagi nal
candi di asi s.
4. Precauti ons and moni t ori ng ef f ect s. Adverse r eact i ons i ncl ude bur ni ng,
pr ur i t us, i r r i t at i on, headache, body pai n, and pai n of f emal e geni t al i a.
R. Ti oconazoI e ( Vagi stat - 1) i s an i mi dazol e- deri ved ant i f ungal drug t hat i s
avai l abl e as a 6. 5% vagi nal oi nt ment .
1. Mechani sm of act i on. Ti oconazol e i s f ungi ci daI agai nst C. al bi cans.
Li ke ot her i mi dazol e agent s, t i oconazol e al t er s cel l ul ar membr anes,
r esul t i ng i n i ncr eased membrane per meabi l i t y.
P. 951


2. Spect rum of acti vi t y
a. Act i vi t y agai nst f ungi i ncl udes most st rai ns of Candi da and t he
der mat ophyt es. Ther e i s al so act i vi t y agai nst Asper gi l l us and C.
neof or mans.
b. Ti oconazol e i s act i ve agai nst t he f ol l owi ng aerobi c gram- posi t i ve
bact er i a: Gar dner el l a vagi nal i s, Cor ynebact eri um mi nut i ssi mum, E. f aecal i s,
S. aureus, S. epi der mi di s, and some St r ept ococci spp. Gram-negat i ve
bact er i a: i t i s act i ve agai nst H. pyl or i , Haemophi l us ducr eyi , Mor axel l a
cat ar r hal i s, Nei sser i a gonor r hoeae, and N. meni ngi t i di s.
c. Ot her organi sms t hat t i oconazol e has act i vi t y agai nst ar e T. vagi nal i s,
Lymphogr anul oma venereum, and Chl amydi a t rachomat i s.
3. Therapeut i c uses. Ti oconazol e i s used f or si mpl e and compl i cat ed
vul vovagi nal candi di asi s. Ot her uses have been expl or ed; however , t opi cal
cr eams f or use i n t hose scenari os are not avai l abl e i n t he Uni t ed St at es.
4. Precauti ons and moni t ori ng ef f ect s. Local i r ri t at i on has been
mani f est ed as vul vovagi nal burni ng, vagi ni t i s, and pr ur i t us.
S. ToI naf tat e (Ti nact i n) i s avai l abl e t opi cal l y as a 1% aerosol , 1% powder ,
1% cr eam, and 1% sol ut i on.
1. Mechani sm of act i on. Ì t may di st or t hyphae and st unt mycel i al gr owt h i n
suscept i bl e f ungi .
2. Spect rum of acti vi t y. Tol naf t at e may be ei t her f ungi st ati c or f ungi ci daI
t o t he f ol l owi ng or gani sms: M. gypseum, M. cani s, M. audoui ni i ,
Mi cr osporum j aponi cum, T. r ubr um, T. ment agrophyt es, Tr i chophyt on
schoenl ei ni i , T. t onsurans, E. f l occosum, Asper gi l l us ni ger , C. al bi cans, C.
neof or mans, and A. f umi gat us.
3. Therapeut i c uses. Tol naf t at e i s used f or der mat ophyt oses and t i nea
ver si col or .
4. Precauti ons and moni t ori ng ef f ect s. Ther e may be sl i ght l ocal
i r r i t at i on.
V. AntiprotozoaI Agents
A. CI assi f i cat i on. These dr ugs f al l i nt o t wo mai n cat egor i es: ant i maI ari aI
agents, used t o t reat mal ar i a i nf ect i on, and amebi ci des and
t ri chomonaci des, used t o t reat amebi c and t ri chomonal i nf ect i ons.
B. Ant i maI ari aI agent s. St i l l a l eadi ng cause of i l l ness and deat h i n
t r opi cal and subt ropi cal count r i es, mal ar i a r esul t s f rom i nf ect i on by any of
f our speci es of t he prot ozoal genus Pl asmodi um. Ant i mal ar i al agent s are
sel ect i vel y act i ve dur i ng di f f er ent phases of t he pr ot ozoan l i f e cycl e. Maj or
ant i mal ari al drugs i ncl ude chI oroqui ne ( AraI en) , haI ofant ri ne ( HaI f an) ,
hydroxychI oroqui ne ( PI aqueni I ) , pri maqui ne, pyri met hami ne ( Darapri m) ,
qui ni ne, and mef I oqui ne ( Lari am). Ì n addi t i on, t wo combi nat i on br ands ar e
avai l abl e: sul f adoxi ne pl us pyr i met hami ne ( Fansi dar ) and at ovaquone pl us
pr oguani l ( Mal ar one) .
1. Mechani sm of act i on
a. ChI oroqui ne and hydroxychI oroqui ne bi nd t o and al t er t he pr oper t i es of
mi cr obi al and mammal i an DNA.
b. The mechani sm of act i on of pri maqui ne, qui ni ne, Fansi dar, and
mef I oqui ne i s unknown.
c. Pyri met hami ne i mpedes f ol i c aci d r educt i on by i nhi bi t i ng t he enzyme
di hydrof ol at e r educt ase.
2. Spect rum of acti vi t y
a. ChI oroqui ne and hydroxychI oroqui ne are suppr essi ve bl ood
schi zonti ci daI agent s and are act i ve agai nst t he asexual er yt hrocyt e f orms
of Pl asmodi um vi vax and Pl asmodi um f al ci par um and gamet ocyt es of P.
vi vax, Pl asmodi um mal ari ae, and Pl asmodi um oval e.
b. Pri maqui ne, a curat i ve agent , i s act i ve agai nst l i ver f orms of P. vi vax
and P. oval e and t he pri mar y exoer yt hr ocyt e f orms of P. f al ci par um.
c. Pyri met hami ne i s act i ve agai nst chl oroqui ne- resi st ant st rai ns of P.
f al ci par um and some st rai ns of P. vi vax.
d. Qui ni ne, a gener al i zed pr ot opl asmi c poi son, i s t oxi c t o a wi de r ange of
or gani sms. Ì n mal ar i a, t hi s dr ug has bot h suppr essi ve and cur at i ve act i on
agai nst chl or oqui ne- resi st ant st r ai ns.
P. 952


e. Fansi dar (sul f adoxi ne pl us pyr i met hami ne) i s a bl ood schi zont i ci daI
agent t hat i s act i ve agai nst t he er yt hrocyt i c f orms of suscept i bl e pl asmodi a.
Ì t i s al so act i veagai nst T. gondi i .
f . MaI arone (at ovaquone pl us pr oguani l ) i s act i ve agai nst t he er yt hrocyt i c
and exoer yt hr ocyt i c f orms of Pl asmodi um spp.
g. Mef I oqui ne i s a bl ood schi zont i ci daI agent t hat i s act i ve agai nst P.
f al ci par um (bot h chl or oqui ne- suscept i bl e and - r esi st ant st r ai ns) and P.
vi vax.
h. HaI of ant ri ne i s a bl ood schi zont i ci dal agent act i ve agai nst P. f al ci parum
and P. vi vax.
3. Therapeut i c uses
a. ChI oroqui ne i s t he pref er red agent used t o suppr ess mal ari a sympt oms
and t o t ermi nat e acut e mal ari a at t acks r esul t i ng f r om P. f al ci par um and P.
mal ar i ae i nf ect i ons.
( 1) Ì t i s mor e pot ent and l ess t oxi c t han qui ni ne.
( 2) Except wher e dr ug- r esi st ant P. f al ci parum st rai ns are pr eval ent ,
chl or oqui ne i s t he most usef ul ant i mal ar i al agent .
b. HydroxychI oroqui ne i s used as an al t er nat i ve t o chl or oqui ne i n pat i ent s
who cannot t ol er at e chl or oqui ne or when chl oroqui ne i s unavai l abl e.
c. Pri maqui ne i s used t o cur e rel apses of P. vi vax and P. oval e mal ari a and
t o prevent mal ari a i n exposed per sons r et ur ni ng f r om regi ons wher e mal ari a
i s endemi c.
d. Pyri met hami ne i s ef f ect i ve i n t he pr event i on and t r eat ment of
chl or oqui ne- resi st ant st rai ns of P. f al ci parum. Ì t i s now used al most
excl usi vel y i n combi nat i on wi t h a sul f onami de or sul f one.
e. Qui ni ne
( 1) Qui ni ne sul f at e, an or al f or m, i s t herapeut i c f or acut e mal ar i a caused by
chl or oqui ne- resi st ant st rai ns.
( 2) Qui ni ne di hydrochl or i de, a par ent eral f or m, i s used i n sever e cases of
chl or oqui ne- resi st ant mal ar i a. (Ì t i s avai l abl e onl y f r om t he CDC. )
( 3) Qui ni ne i s al most al ways gi ven i n combi nat i on wi t h anot her ant i mal ari al
agent .
f . Fansi dar
( 1) Fansi dar i s used f or t he suppr essi on or pr ophyl axi s of chl or oqui ne-
r esi st ant P. f al ci par um mal ari a.
( 2) Ì t has been used f or t he prophyl axi s of P. cari ni i i nf ect i ons i n AÌ DS
pat i ent s unabl e t o t ol er at e cot ri moxazol e ( t r i met hopr i m-sul f amet hoxazol e).
g. Mef I oqui ne i s i ndi cat ed f or t he t r eat ment of acut e mal ar i a and t he
pr event i on of P. f al ci parum and P. vi vax i nf ect i ons.
h. HaI of ant ri ne i s i ndi cat ed f or t r eat ment of mal ar i a i n adul t s who can
t ol er at e oral medi cat i on and who have mi l d t o moder at e mal ar i a ( < 100, 000
par asi t es/ mm
3
) caused by P. f al ci parum or P. vi vax.
i . MaI arone
( 1) Pr ophyl axi s of P. f al ci parum mal ari a, i ncl udi ng ar eas wher e chl or oqui ne
r esi st ance has been r epor t ed.
( 2) Tr eat ment of acut e, uncompl i cat ed P. f al ci parum mal ar i a. Thi s
combi nat i on has been shown t o be ef f ect i ve i n r egi ons wher e t he drugs
chl or oqui ne, hal of ant ri ne, mef l oqui ne, and amodi aqui ne may have
unaccept abl e f ai l ur e r at es, pr esumabl y because of dr ug r esi st ance.
4. Precauti ons and moni t ori ng ef f ect s
a. ChI oroqui ne and hydroxychI oroqui ne
( 1) Because t hese drugs concent rat e i n t he l i ver , t hey shoul d be used
caut i ousl y i n pat i ent s wi t h hepat i c di sease.
( 2) Chl or oqui ne must be admi ni st er ed wi t h ext r eme caut i on i n pat i ent s wi t h
neurol ogi cal , hemat ol ogi cal , or sever e GÌ di sorder s.
( 3) Vi sual di st urbances, headache, ski n r ash, and GÌ di st r ess have been
r eport ed.
b. Pri maqui ne
( 1) Thi s agent i s cont r ai ndi cat ed i n pat i ent s wi t h r heumat oi d ar t hri t i s and
l upus er yt hemat osus and i n t hose r ecei vi ng ot her pot ent i al l y hemol yt i c
dr ugs or bone mar r ow suppr essant s.
( 2) Pr i maqui ne may cause agranul ocyt osi s, gr anul ocyt openi a, and mi l d
anemi a. Ì n pat i ent s wi t h G6PD def i ci ency, i t may cause hemol yt i c anemi a.
( 3) Abdomi nal cr amps, nausea, vomi t i ng, and epi gast r i c di st r ess somet i mes
occur .
c. Pyri met hami ne
( 1) Ì n hi gh doses, t hi s drug may cause agr anul ocyt osi s, megal obl ast i c
anemi a, apl ast i c anemi a, and t hrombocyt openi a.
P. 953


( 2) Er yt hema mul t i f or me ( St evens- Johnson syndrome), nausea, vomi t i ng,
and anor exi a may devel op duri ng pyr i met hami ne t her apy.
d. Qui ni ne
( 1) Qui ni ne i s cont r ai ndi cat ed i n pat i ent s wi t h G6PD def i ci ency, t i nni t us,
and opt i c neur i t i s.
( 2) Qui ni ne over dose or hyper sensi t i vi t y r eact i ons may be f at al .
Mani f est at i ons of qui ni ne poi soni ng i ncl ude vi sual and hear i ng
di st ur bances; GÌ sympt oms ( e. g. , nausea, vomi t i ng) ; hot , f l ushed ski n;
headache; f ever; syncope; conf usi on; shal l ow, t hen depressed, r espi r at i ons;
and cardi ovascul ar col l apse.
( 3) Qui ni ne must be used caut i ousl y i n pat i ent s wi t h at r i al f i bri l l at i on.
( 4) Renal damage and anur i a have been r epor t ed.
e. Fansi dar
( 1) Severe, somet i mes f at al , hyper sensi t i vi t y r eact i ons have occur r ed. Ì n
most cases, deat h r esul t ed f rom sever e cut aneous r eact i ons, i ncl udi ng
er yt hema mul t i f orme, St evens-Johnson syndr ome, and t oxi c epi der mal
necrol ysi s.
( 2) Adverse hemat ol ogi cal and hepat i c ef f ect s as seen wi t h sul f onami des
have been r epor t ed.
f . Mef I oqui ne
( 1) Concomi t ant use of mef l oqui ne wi t h qui ni ne, qui ni di ne, or 8- adr ener gi c
bl ockade may pr oduce el ect rocar di ographi c abnormal i t i es or cardi ac ar r est .
( 2) Concomi t ant use of mef l oqui ne and qui ni ne or chl or oqui ne may i ncrease
t he ri sk of convul si ons.
g. HaI of ant ri ne
( 1) Do not admi ni st er wi t h dr ugs known t o pr ol ong t he QTc i nt er val ;
i nt er act i on wi t h mef l oqui ne f ur t her pr ol ongs t he QTc i nt er val .
( 2) A sevenf ol d i ncr ease i n peak pl asma l evel and t hreef ol d i ncrease i n t he
ar ea under t he cur ve ( AUC) occur red when gi ven wi t h hi gh-f at f ood. Si mi l ar
i ncreases occur when doses are admi ni st er ed 2 hr af t er a meal . Admi ni st er
hal of ant r i ne on an empt y st omach.
h. MaI arone
( 1) Concomi t ant admi ni st r at i on wi t h t et r acycl i ne has been associ at ed wi t h
40% reduct i on i n pl asma concent rat i ons of at ovaquone. Si mi l ar l y,
concur rent r i f ampi n i s known t o r educe at ovaquone l evel s by 50%.
( 2) Take mal ar one wi t h f ood or mi l k.
C. Amebi ci des and t ri chomonaci des. These agent s are cr uci al i n t he
t r eat ment of amebi asi s, gi ardi asi s, and t ri chomoni ases÷t he most common
pr ot ozoal i nf ect i ons i n t he Uni t ed St at es. The maj or amebi ci des i ncl ude
di I oxani de, i odoqui noI ( Yodoxi n) , met roni dazoI e ( FI agyI ) , ni t azoxani de
( AI i ni a) , paromomyci n ( Humat i n) , qui nacri ne, and t i ni dazoI e (Ti ndamax) .
1. Mechani sm of act i on
a. Di I oxani de, a di chl oroacet ami de deri vat i ve, i s amebi ci daI ; i t s
mechani sm of act i on i s unknown. ( Not avai l abl e commerci al l y but can be
compounded by Panor ama Compoundi ng Pharmacy, Van Nuys, CA÷per
Medi cal Let t er 8/ 04. )
b. Met roni dazoI e i s a synt het i c compound wi t h di r ect amebi ci daI and
t ri chomonaci daI act i on; i t wor ks at bot h i nt est i nal and ext r ai nt est i nal si t es.
Ì t s mechani sm of act i on i nvol ves di sr upt i on of t he hel i cal st ruct ur e of DNA.
c. Ni t azoxani de i s desi gnat ed by t he U. S. Food and Drug Admi ni st r at i on
( FDA) as an orphan dr ug. Ì t s ant i pr ot ozoal act i vi t y i s bel i eved t o be t he
r esul t of i nt er f erence wi t h t he pyr uvat e: f er redoxi n oxi dor educt ase ( PFOR)
enzyme- dependent el ect r on t ransf er r eact i on essent i al f or ener gy
met abol i sm.
d. Qui nacri ne i s an acri di ne der i vat i ve t hat i nhi bi t s DNA met abol i sm.
e. I odoqui noI i s a l umi nal or cont act amebi ci de t hat i s ef f ect i ve agai nst t he
t r ophozoi t es of Ent amoeba hi st ol yt i ca l ocat ed i n t he l umen of t he l ar ge
i nt est i ne.
f . Paromomyci n i s a poor l y absor bed amebi ci dal ami nogl ycosi de whose
mechani sm of act i on paral l el s ot her ami nogl ycosi des ( i . e. , pr ot ei n synt hesi s
i nhi bi t or ) . Ì t i s al so ef f ect i ve agai nst ent eri c bact er i a Sal monel l a and
Shi gel l a.
g. Ti ni dazoI e pr eci se mechani sm of act i on i s unknown.
2. Spect rum of acti vi t y and therapeut i c uses
a. Di I oxani de
P. 954


( 1) Thi s drug i s used t o t r eat asympt omat i c car r i er s of amebi c and Gi ar di a
cyst s.
( 2) Di l oxani de i s t her apeut i c f or i nvasi ve and ext r ai nt est i nal amebi asi s
( gi ven i n combi nat i on wi t h a syst emi c or mi xed amebi ci de) .
( 3) Di l oxani de i s not ef f ect i ve as si ngl e-agent t her apy f or ext r ai nt est i nal
amebi asi s.
b. Met roni dazoI e
( 1) Thi s agent i s t he pr ef er r ed dr ug i n amebi c dysent er y, gi ar di asi s, and
t r i chomoni asi s.
( 2) Met r oni dazol e al so i s act i ve agai nst al l anaerobi c cocci and gr am-
negat i ve anaer obi c baci l l i .
( 3) Thi s agent i s t he t reat ment of choi ce by t he CDC f or t he t r eat ment of C.
di f f i ci l e col i t i s i nf ect i ons owi ng t o t he emergi ng use of br oad- spect r um
ant i bi ot i cs. Thi s t her apy i s cost - ef f ect i ve.
c. Qui nacri ne i s usef ul i n t he t reat ment of gi ar di asi s and t apewor ms ( see
VÌ Ì Ì . H. 2) .
d. I odoqui noI i s i ndi cat ed f or t r eat ment of i nt est i nal amebi asi s. Ì t i s act i ve
agai nst t he pr ot ozoa E. hi st ol yt i ca.
e. Ni t azoxani de i s i ndi cat ed f or t r eat ment of di ar r hea caused by
Cr ypt ospor i di um parvum and Gi ar di a l ambl i a i n chi l dren.
f . Paromomyci n i s i ndi cat ed f or acut e and chroni c i nt est i nal amebi asi s; i t
i s not usef ul f or ext r ai nt est i nal amebi asi s because i t i s not absorbed.
Par omomyci n has been used f or Di ent amoeba f ragi l i s, Taeni a sagi nat a,
Di pyl i di um cani num, and Hymenol epi s nana.
g. Ti ni dazoI e i s a second- gener at i on synt het i c ni t r oi mi dazol e act i ve agai nst
t r i chomoni asi s, Gi ar di a duodenal i s/ G. l ambl i a, and E. hi st ol yt i ca.
3. Precauti ons and moni t ori ng ef f ect s
a. Di I oxani de r arel y causes ser i ous adver se ef f ect s. Vomi t i ng, f l at ul ence,
and pr uri t us have been repor t ed.
b. Met roni dazoI e
( 1) The most common adver se ef f ect s of t hi s drug ar e nausea, epi gast r i c
di st r ess, and di ar rhea.
( 2) Met r oni dazol e i s carci nogeni c i n mi ce and shoul d not be used
unnecessar i l y.
( 3) Headache, vomi t i ng, met al l i c t ast e, and st omat i t i s have been report ed.
( 4) Occasi onal l y, neurol ogi cal r eact i ons ( e. g. , at axi a, per i pher al
neuropat hy, sei zures) devel op.
( 5) A di sul f i r am- t ype r eact i on may occur wi t h concur rent et hanol use.
c. Qui nacri ne. See VÌ Ì Ì . H. 4.
( 1) Thi s drug f r equent l y causes di zzi ness, headache, nausea, and vomi t i ng.
Ner vousness and sei zures al so have been r epor t ed.
( 2) Qui nacr i ne shoul d not be t aken i n combi nat i on wi t h pri maqui ne because
t hi s may i ncr ease pr i maqui ne t oxi ci t y.
( 3) Qui nacr i ne shoul d be admi ni st er ed wi t h ext r eme caut i on i n pat i ent s wi t h
psori asi s because i t may cause mar ked exacer bat i on of t hi s di sease.
d. I odoqui noI may pr oduce opt i c neur i t i s or at rophy or peri pher al
neuropat hy wi t h hi gh- dose, l ong- t er m use. Pr ot ei n- bound i odi ne l evel s may
be i ncreased dur i ng t reat ment and may i nt er f ere wi t h t he r esul t s of t hyr oi d
t est s f or 6 mont hs af t er t r eat ment . Ì odoqui nol shoul d not be used i n
pat i ent s who ar e hypersensi t i ve t o 8- hydroxy- qui nol one ( e. g. , i odoqui nol ,
i odochl orhydr oxyqui n) or i odi ne- cont ai ni ng agent s or i n pat i ent s wi t h
hepat i c di sor der s.
e. Paromomyci n may cause nausea, crampi ng, and di ar rhea at hi gh doses
( > 3 g/ day) . Ì nadver t ent absor pt i on t hr ough ul cerat i ve bowel l esi ons may
r esul t i n ot ot oxi ci t y or r enal damage.
f . Ni t azoxani de may cause abdomi nal pai n, di ar rhea, vomi t i ng, headache,
f l at ul ence, f ever , eye di scol or at i on, rhi ni t i s, and di scol ored ur i ne.
g. Ti ni dazoI e may produce met al l i c t ast e, nausea, anor exi a, dyspepsi a,
vomi t i ng, weakness, di zzi ness, and headache.
D. Pentami di ne i set hi onat e (Pentam 300) i s an ar omat i c di ami de
ant i pr ot ozoal agent . Ì t can be admi ni st er ed i nt r amuscul arl y, i nt r avenousl y,
or by i nhal at i on.
1. Mechani sm of act i on i s not f ul l y under st ood, but i n vi t r o st udi es i ndi cat e
i nt er f erence wi t h nucl ear met abol i sm and i nhi bi t i on of DNA, RNA,
phosphol i pi d, and pr ot ei n synt hesi s.
2. Therapeut i c uses
a. Pent ami di ne i s i ndi cat ed f or t he pr event i on and t r eat ment of i nf ect i ons
caused by P. car i ni i .
P. 955


b. Unl abel ed uses i ncl ude t r eat ment of t r ypanosomi asi s, vi scer al
l ei shmani asi s, and babesi osi s.
3. Precauti ons and moni t ori ng ef f ect s
a. Nephr ot oxi ci t y, br onchospasm, and cough ar e t he most common ef f ect s
pr oduced by i nt ravenous or i nhal ed pent ami di ne.
b. Severe hypot ensi on may occur af t er a parent eral dose of pent ami di ne.
Car di or espi rat or y ar r est can occur af t er a si ngl e r api d i nf usi on of t he dr ug.
c. Pai n, er yt hema, and t ender ness may occur af t er an Ì M admi ni st rat i on of
t he dr ug. Thi s can be mi ni mi zed by usi ng t he Z- t rack t echni que of dr ug
admi ni st rat i on. Phl ebi t i s may occur f ol l owi ng Ì V admi ni st r at i on.
d. Hypogl ycemi a may occur wi t h i ni t i al admi ni st rat i on of drug vi a t he Ì V, Ì M,
or i nhal at i onal r out e. Af t er t he pat i ent has been on t he dr ug f or a per i od of
t i me, hyper gl ycemi a wi l l r esul t . The ef f ect of t he dr ug may act ual l y i nduce a
r ever si bl e i nsul i n- dependent di abet es mel l i t us.
e. Leukopeni a and t hr ombocyt openi a, whi ch can be sever e, occur
occasi onal l y.
f . Pent ami di ne may r esul t i n el evat ed l i ver f unct i on t est s, AST, and ALT.
g. GÌ ef f ect s can al so occur , i ncl udi ng nausea, vomi t i ng, abdomi nal
di scomf or t , pai n, di ar r hea, and dysgeusi a.
h. Neur ol ogi cal ef f ect s can occur wi t h parent er al admi ni st rat i on and may
i ncl ude di zzi ness, t remors, conf usi on, anxi et y, i nsomni a, and sei zures.
i . Hypocal cemi a and f ever have al so been repor t ed and may be sever e at
t i mes.
E. At ovaquone (Mepron) i s a hydr oxynapht hoqui none i ni t i al l y synt hesi zed
as an ant i mal ari al drug.
1. Mechani sm of act i on. At ovaquone bl ocks mi t ochondr i al el ect r on
t r anspor t at compl ex Ì Ì Ì of t he respi r at or y chai n of prot ozoa, resul t i ng i n
i nhi bi t i on of pyr i mi di ne synt hesi s.
2. Spect rum of acti vi t y. Ì t i s act i ve agai nst P. car i ni i , T. gondi i , C. parvum,
P. f al ci parum, I sospori di a, and Mi cr ospor i di a.
3. Therapeut i c uses. At ovaquone i s used f or second- l i ne t r eat ment of mi l d
t o moder at e P. cari ni i pneumoni a i n pat i ent s i nt ol er ant of cot r i moxazol e or
ot her sul f onami des or who are nonresponsi ve t o cot ri moxazol e.
4. Precauti ons and moni t ori ng ef f ect s
a. Or al absor pt i on si gni f i cant l y i ncreases when admi ni st ered wi t h f ood
( especi al l y a hi gh- f at meal ) .
b. Rash, nausea, di ar r hea, headache, f ever , abdomi nal pai n, di zzi ness, and
el evat ed l i ver f unct i on t est s commonl y are r epor t ed.
5. Si gni f i cant i nteracti ons. At ovaquone i s hi ghl y bound t o pl asma pr ot ei n.
Ì t shoul d be used wi t h caut i on when admi ni st er ed wi t h ot her hi ghl y prot ei n-
bound dr ugs wi t h a nar r ow t her apeut i c range.
F. Ef I orni t hi ne HCI ( Orni dyI ) . Thi s i s an Ì V ant i pr ot ozoal agent . Ì t s act i vi t y
has been at t ri but ed t o t he i nhi bi t i on of t he enzyme or ni t hi ne decar boxyl ase.
1. Mechani sm of act i on. Thi s i s a speci f i c, enzyme- act i vat ed, i r r eversi bl e
i nhi bi t or of or ni t hi ne decar boxyl ase.
2. Spect rum of acti vi t y and therapeut i c uses. Ef l orni t hi ne i s act i ve i n t he
t r eat ment of t he meni ngoencephal i t i c st age of Trypanosoma br ucei
gambi ense (sl eepi ng si ckness) .
3. Precauti ons and moni t ori ng ef f ect s
a. Myel osuppr essi on i s t he most f requent ser i ous si de ef f ect .
b. Sei zur es occur i n about 8% of t r eat ed pat i ent s.
c. Cases of hear i ng i mpai r ment have been report ed.
VI. AntitubercuIar Agents
A. Def i ni t i on and cI assi f i cat i on. Drugs used t o t r eat t uber cul osi s suppress
or ki l l t he sl ow- gr owi ng mycobact eri a t hat cause t hi s di sease.
Ant i t uber cul ar agent s f al l i nt o t wo mai n cat egori es: f i r st - l i ne
P. 956

and second-l i ne drugs. Because t he causat i ve organi sms t end t o devel op
r esi st ance t o any si ngl e dr ug, combi nat i on dr ug t her apy has become
st andard i n t he t r eat ment of t uber cul osi s.
1. The i nci dence of t uber cul osi s i n t he Uni t ed St at es i s i ncr easi ng owi ng t o
shi f t s i n popul at i ons consi der ed t o be endemi c f or t uber cul osi s, t he r i se i n
HÌ V- posi t i ve pat i ent s, and dr ug resi st ance.
2. Agent s chosen f or t herapy must er adi cat e mycobact eri um. Fi rst - l i ne
agent s avai l abl e i ncl ude i soni azi d, et hambut ol , pyr azi nami de, r i f ampi n,
r i f abut i n, and r i f apent i ne. Combi nati on chemot herapy i s essent i al . Agent s
showi ng t he l owest i nci dence of r esi st ance (i soni azi d, ri f ampi n) ar e usual l y
used i n combi nat i on wi t h pyr azi nami de or et hambut ol .
3. Choi ce of t her apy depends on many pat i ent and di sease f act or s ( e. g. ,
dur at i on of t her apy needed, l i kel i hood of dr ug r esi st ance, and HÌ V st at us) .
4. Treat ment choi ces based on CDC recommendat i ons ( Tabl e 44-4) .
B. Fi rst -I i ne. These dr ugs, i soni azi d, et hambut ol , r i f ampi n, r i f abut i n,
r i f apent i ne, and pyr azi nami de usual l y of f er t he great est ef f ect i veness wi t h
t he l east t oxi ci t y; t hey are successf ul i n most t uber cul osi s pat i ent s. At l east
t hr ee t o f our drug combi nat i ons are recommended. The CDC recommends
dai l y t r eat ment wi t h i soni azi d, r i f ampi n, pyr azi nami de, and et hambut ol f or
t he i ni t i al phase of 2 mont hs, f ol l owed by a cont i nuat i on phase of i soni azi d
and ri f ampi n f or 4- 5 mont hs ( Tabl e 44-4) .
1. Et hambut oI ( Myambut oI ) i s a synt het i c wat er -based compound.
a. Mechani sm of act i on. Thi s dr ug i s bacteri ostat i c. Ì t s preci se
mechani sm of act i on i s unknown; however , i t has demonst r at ed act i vi t y onl y
agai nst suscept i bl e bact er i a act i vel y under goi ng cel l di vi si on.
b. Spect rum of act i vi t y and therapeut i c uses. Et hambut ol i s act i ve
agai nst many M. t uber cul osi s st r ai ns as wel l as many ot her mycobact er i al
speci es. However , drug resi st ance devel ops f ai r l y r api dl y when i t i s used
al one. Ì n most cases, et hambut ol i s gi ven adj unct i vel y i n combi nat i on wi t h
i soni azi d or r i f ampi n f or t ubercul osi s. Ì t i s al so usef ul i n combi nat i on wi t h
ot her agent s such as cl ar i t hromyci n or azi t hromyci n and r i f abut i n i n t reat i ng
MAC.
Table 44-4. Treatment for Active Tuberculosis
Initial Phase Continuation Phase
Rank Agent Dosage Agent Dosage
1 INH 7 days a week × 8 weeks INH/RIF 7 days a week
× 18 weeks
RIF or or

PZA 5 days a week × 8 weeks

5 days a week
× 18 weeks
EMB
2 INH
RIF
7 days a week × 2 weeks.
then 2 times a week × 6
weeks
INH/RIF 2 times a
week × 18
weeks
PZA or

EMP 5 days a week × 2 weeks.
then 2 times a week × 6
weeks

3 INH 3 times a week × 8 weeks INH/RIF 3 times a
week × 19
weeks
RIF
PZA
EMB
4 INH 7 days a week × 8 weeks INH/RIF 7 days a week
× 31 weeks
RIF or or

EMP 5 days a week × 8 weeks

5 days a week
× 31 weeks
or

2 times a
week × 31
weeks
EMB. ethambutol; INH. isoniazid; PZA. pyrazinamide; RIF. riIampin.
Adapted with permission Irom CDC guidelines Ior treatment oI tuberculosis
2003. MMWR 2003; 52 (RR11); 1-77.

P. 957


c. Precauti ons and moni t ori ng ef f ect s. Rarel y, et hambut ol causes such
adver se ef f ect s as reversi bl e dose- rel at ed ( = 15 mg/ kg/ day) opt i c neur i t i s,
dr ug f ever , abdomi nal pai n, headache, di zzi ness, and conf usi on. Li ver
f unct i on t est s shoul d be per i odi cal l y moni t or ed. Vi sual t est i ng and r enal
f unct i on ( reduce dose wi t h i mpai rment ) shoul d al so be moni t or ed.
2. I soni azi d ( Nydrazi d) i s a hydrazi de of i soni cot i ni c aci d. The mai nst ay of
ant i t uber cul ar t her apy, t hi s dr ug shoul d be i ncl uded (i f t ol er at ed) i n al l
t her apeut i c regi mens.
a. Mechani sm of act i on. Ì soni azi d i s bact eri ostat i c f or rest i ng baci l l i and
bact eri ci daI f or rapi dl y di vi di ng or gani sms. Ì t s mechani sm of act i on i s not
f ul l y known; t he dr ug pr obabl y di sr upt s bact er i al cel l wal l synt hesi s by
i nhi bi t i ng mycol i c aci d synt hesi s.
b. Spect rum of act i vi t y. Ì soni azi d has act i vi t y onl y agai nst or gani sms i n
t he genus Mycobact er i um. Mor e speci f i cal l y, i t has demonst rat ed act i vi t y
agai nst M. t uber cul osi s, Mycobact eri um bovi s, and sel ect st rai ns of
Mycobact eri um kansasi i .
c. Therapeut i c uses
( 1) The most wi del y used ant i t ubercul ar agent , i soni azi d shoul d be gi ven i n
combi nat i on wi t h ot her ant i t ubercul ar dr ugs ( such as r i f ampi n, et hambut ol ,
and pyr azi nami de) t o pr event drug resi st ance i n t ubercul osi s.
( 2) Treat ment of I at ent i nf ecti on ( pr evi ousl y r ef er r ed t o as pr event i ve
t her apy of chemoprophyl axi s) . Ì soni azi d may be admi ni st ered al one f or up
t o 1 year i n adul t s or chi l dr en who have a posi t i ve t ubercul i n t est resul t but
l ack act i ve l esi ons.
d. Precaut i ons and moni t ori ng ef fects
( 1) The most common adver se ef f ect s of i soni azi d ar e ski n r ash, f ever,
j aundi ce, and per i pher al neuri t i s.
( 2) Hepat i t i s, an occasi onal r eact i on, can be sever e and, i n some cases,
f at al . The ri sk of hepat i t i s i ncreases wi t h t he pat i ent ' s age and ri ses wi t h
al cohol abuse. Moni t or l i ver f unct i on t est s.
( 3) Bl ood dyscr asi as ( e. g. , agr anul ocyt osi s, apl ast i c or hemol yt i c anemi a,
t hr ombocyt openi a) may occur . Moni t or compl et e bl ood count ( CBC)
r out i nel y.
( 4) Adverse GÌ ef f ect s i ncl ude nausea, vomi t i ng, and epi gast ri c di st ress.
( 5) CNS t oxi ci t y may r esul t f r om pyr i doxi ne def i ci ency. Si gns and sympt oms
i ncl ude i nsomni a, rest l essness, hyper r ef l exi a, and convul si ons. Pyr i doxi ne
15- 50 mg/ day shoul d be admi ni st er ed t o pat i ent s t aki ng i soni azi d t o
mi ni mi ze t he peri pher al neuropat hy associ at ed wi t h i t s use (especi al l y i n
pat i ent s wi t h di abet es, HÌ V, uremi a, al cohol i sm, mal nut ri t i on, pregnancy, or
sei zure di sor der ) .
e. Si gni f i cant i nteracti ons
( 1) Wi t h concur r ent phenyt oi n t her apy, bl ood l evel s of bot h phenyt oi n and
i soni azi d may i ncrease, possi bl y causi ng t oxi ci t y.
( 2) AI umi num- cont ai ni ng antaci ds may r educe i soni azi d absor pt i on.
( 3) Concur r ent carbamazepi ne t herapy may i ncrease t he ri sk of hepat i t i s.
( 4) Use of i soni azi d wi t h ot her ant i t uber cul ar agent s, such as cycl oser i ne or
et hi onami de, may cause addi t i ve ner vous syst em ef f ect s.
( 5) Ther e i s t he pot ent i al f or t he serot oni n syndr ome t o exi st when i soni azi d
i s used i n combi nat i on wi t h sel ect i ve ser ot oni n r eupt ake i nhi bi t or s or i n
pat i ent s t aki ng meper i di ne. Ì soni azi d has been shown t o have some
monoami ne oxi dase ( MAO) i nhi bi t i ng act i vi t y.
3. Ri f ampi n ( Ri mactane) i s a compl ex macrocycl i c agent .
a. Mechani sm of act i on. Thi s dr ug i s bacteri ci daI ; i t i mpai rs bact er i al RNA
synt hesi s by bi ndi ng t o DNA- dependent RNA pol ymer ase.
b. Spect rum of act i vi t y. Ri f ampi n has act i vi t y agai nst most mycobact eri al
st r ai ns. Ì n addi t i on, r i f ampi n has act i vi t y agai nst many ot her or gani sms,
i ncl udi ng N. meni ngi t i di s, S. aur eus, H. i nf l uenzae, Legi onel l a pneumophi l a,
and C. t r achomat i s.
c. Therapeut i c uses
( 1) Ì n r ecommended combi nat i ons f or t r eat ment of act i ve t uber cul osi s
( 2) Pr ophyl act i c r i f ampi n i s ef f ect i ve when admi ni st ered t o car ri ers of N.
meni ngi t i di s di sease and chemopr ophyl axi s of pat i ent s wi t h H. i nf l uenzae
t ype b or gani sms.
( 3) Ri f ampi n may be used i n combi nat i on wi t h dapsone f or t he t r eat ment of
l eprosy.
d. Precaut i ons and moni t ori ng ef fects
( 1) Seri ous hepat ot oxi ci t y may r esul t f rom r i f ampi n t her apy. Li ver f unct i on
t est s shoul d be r out i nel y conduct ed.
P. 958


( 2) Ì n r are cases, t hi s drug i nduces an i nf l uenza-l i ke syndr ome.
( 3) Ot her adver se ef f ect s i ncl ude ski n rash, dr owsi ness, headache, f at i gue,
conf usi on, nausea, vomi t i ng, and abdomi nal pai n.
( 4) Ri f ampi n col or s ur i ne, sweat , t ear s, sal i va, and f eces orange red.
e. Si gni f i cant i nteracti ons
( 1) Ri f ampi n i nduces hepat i c mi cr osomal cyt ochrome P450 i soenzymes and
t hus may decr ease t he t her apeut i c ef f ect i veness of cort i cost eroi ds,
warf ari n, oraI cont racept i ves, qui ni di ne, di gi toxi n, protease i nhi bi t ors
( PI s) , nonnucI eosi de reverse t ranscri ptase i nhi bi t ors, ket oconazoI e,
verapami I , met hadone, oraI ant i di abet i c agents, cycI ospori ne, dapsone,
chI orampheni coI , and barbi t urat es.
( 2) Probeneci d may i ncrease bl ood l evel s of r i f ampi n.
( 3) Ami nosaI i cyI i c aci d may i mpai r absor pt i on of r i f ampi n secondar y t o
bent oni t e, an exci pi ent used i n pr eparat i on of ami nosal i cyl i c gr anul es.
f . The newer r i f amyci ns, ri f abut i n (Mycobut i n) and ri fapent i ne ( Pri f t i n)
may be subst i t ut ed f or ri f ampi n i n speci al si t uat i ons, e. g. , i nt ol erance or
ser i ous dr ug i nt er act i ons.
4. Ri f abut i n (Mycobut i n) i s an ant i mycobact eri al agent t hat i s si mi l ar t o
r i f ampi n, wi t h act i vi t y agai nst bot h t ubercul ar and nont ubercul ar
mycobact eri al , and of f ers no cl ear advant age over r i f ampi n.
a. Mechani sm of act i on. Ì n addi t i on t o i t s ant i mycobact er i al act i vi t y
agai nst t ubercul ar and nont ubercul ar mycobact eri al , r i f abut i n has been
r eport ed t o i nhi bi t rever se t r anscr i pt ase and bl ock t he i n vi t ro i nf ect i vi t y
and repl i cat i on of HÌ V.
b. Therapeut i c uses. Ri f abut i n i s i ndi cat ed f or t he prevent i on of
di ssemi nat ed MAÌ compl ex di sease i n pat i ent s wi t h advanced HÌ V
i nf ect i ons.
c. Precauti ons and moni t ori ng ef f ect s. The use of ri f abut i n has r esul t ed
i n mi l d el evat i on of l i ver enzymes and t hr ombocyt openi a.
d. Si gni f i cant i nteract i ons
( 1) Ri f abut i n ant agoni zes and pot ent i al l y negat es t he i mmune r esponse
medi at ed by t he baci l l us Cal met t e- Guéri n ( BCG) vacci ne.
( 2) Ri f abut i n may i ncr ease t he cl earance of dr ugs by i nduci ng hepat i c
mi cr osomal enzymes, but does so t o a l esser ext ent t han r i f ampi n. The
concent r at i ons of t he f ol l owi ng drugs may be r educed whi l e t aki ng ri f abut i n:
cycI ospori ne, zi dovudi ne, predni sone, di gi toxi n, qui ni di ne,
ket oconazoI e, prot ease i nhi bi t ors, propranoI oI , phenyt oi n,
suI f onyI ureas, and warfari n. Ser um cycl ospor i ne l evel s shoul d be
moni t ored i n pat i ent s r ecei vi ng bot h agent s.
5. Ri f apenti ne ( Pri f t i n) i s a l ong- act i ng r i f amyci n- der i vat i ve and has a
si mi l ar pr of i l e of mi crobi ol ogi cal act i vi t y t o ri f ampi n. Ì t i s usual l y
admi ni st er ed once or t wi ce weekl y.
a. Mechani sm of act i on. Ri f apent i ne i s bact eri ci dal agai nst i nt racel l ul ar
and ext r acel l ul ar M. t uber cul osi s at t her apeut i c l evel s.
b. Spect rum of act i vi t y and therapeut i c uses. Ì ndi cat ed f or t r eat ment of
pr i mar y t ubercul osi s. Ri f apent i ne shoul d al ways be used i n conj unct i on wi t h
< 1 ot her ant i t ubercul osi s drug t o whi ch t he i sol at e i s suscept i bl e.
c. Precauti ons and moni t ori ng ef f ect s. Ri f apent i ne i nduces cyt ochr ome
P450 i soenzymes 3A4 and 2C8/ 9 r esponsi bl e f or i nact i vat i on of cer t ai n
cal ci um channel bl ocki ng agent s ( verapami l , di l t i azem, ni f edi pi ne) ,
ant i f ungal s (ket oconazol e, f l uconazol e, i t r aconazol e), sul f onyl ur ea
ant i di abet i c agent s, met hadone, cor t i cost er oi ds, car di ac gl ycosi des, cer t ai n
ant i ar r hyt hmi c agent s ( di sopyr ami de, mexi l et i ne, qui ni di ne, t ocai ni de) ,
qui ni ne, dapsone, chl orampheni col , cl ar i t hr omyci n, doxycycl i ne,
f l uor oqui nol ones, t r anscri pt ase i nhi bi t or cycl ospor i n, t acr ol i mus, and
war f ar i n. Concomi t ant use of r i f apent i ne wi t h t hese dr ugs may decr ease
pl asma concent r at i ons and dosage adj ust ment s may be r equi r ed.
6. Pyrazi nami de i s a pyr azi ne anal og of ni cot i nami de.
a. Mechani sm of act i on. Thi s dr ug i s bacteri ci daI and/ or bact eri ostat i c,
dependi ng on t he cel l concent r at i on achi eved.
b. Spect rum of act i vi t y and therapeut i c uses. Pyr azi nami de i s a hi ghl y
speci f i c agent and has act i vi t y onl y agai nst M. t uber cul osi s. Pyr azi nami de
i s used as a pri mar y agent wi t h i soni azi d and r i f ampi n f or at l east 2 mont hs,
f ol l owed by i soni azi d and r i f ampi n.
c. Precauti ons and moni t ori ng ef f ect s. Thi s agent may r esul t i n
hepat ot oxi ci t y and, rar el y, hepat i c necrosi s r esul t i ng i n deat h. Anor exi a,
nausea, vomi t i ng, mal ai se, and f ever have
P. 959

been r epor t ed. Hyper uri cemi a may r esul t i n gout y exacer bat i ons. Bot h l i ver
f unct i on t est s and uri c aci d l evel s shoul d rout i nel y be moni t ored.
C. Second- I i ne agent s. These agent s i ncl ude ami nosal i cyl i c aci d ( Paser) ,
capreomyci n ( Capastat ) , cycl oser i ne ( Seromyci n) , et hi onami de ( Trecat or-
SC) , qui nol ones ( ci prof l oxaci n, of l oxaci n, l evof l oxaci n, spar f l oxaci n) ,
st r ept omyci n and kanamyci n. Second- l i ne dr ugs ar e mai nl y subst i t ut ed or
added t o pref er r ed t her apy owi ng t o i nt ol er ance or drug resi st ance. These
agent s ar e l ess ef f ect i ve, mor e t oxi c, and ar e used i n combi nat i on wi t h
pr i mar y agent s.
1. Mechani sm of act i on
a. Ami nosaI i cyI i c aci d i s bact eri ostat i c; i t pr obabl y i nhi bi t s t he enzymes
r esponsi bl e f or f ol i c aci d synt hesi s.
b. CycI oseri ne can be bact eri ost at i c or bacteri ci daI , dependi ng on i t s
concent r at i on at t he i nf ect i on si t e; i t i mpai r s ami no aci d use, t her eby
i nhi bi t i ng bact er i al cel l wal l synt hesi s.
c. The mechani sm of act i on of capr eomyci n (bacteri ostat i c), et hi onami de
( bacteri ci daI ), and pyr azi nami de ( bact eri ci daI ) i s unknown.
2. Spect rum of acti vi t y and therapeut i c uses. Second-l i ne ant i t uber cul ar
agent s ar e act i ve agai nst var i ous mi croor gani sms, i ncl udi ng M.
t ubercul osi s. These agent s gener al l y ar e reser ved f or pat i ent s wi t h
ext ensi ve ext r apul monary or dr ug- r esi st ant di sease or f or pat i ent s who
need r et r eat ment . These dr ugs ar e al most al ways admi ni st er ed i n
combi nat i on.
3. Precauti ons and moni t ori ng ef f ect s
a. Adverse ef f ect s of ami nosaI i cyI i c aci d i ncl ude l eukopeni a,
agr anul ocyt openi a, t hr ombocyt openi a, hemol yt i c anemi a, mononucl eosi s-
l i ke syndr ome, mal ai se, j oi nt pai n, f ever, and ski n r ash.
b. Capreomyci n and st rept omyci n ar e ot ot oxi c and nephr ot oxi c; t hey
shoul d not be admi ni st ered t oget her.
c. CycI oseri ne may cause adverse CNS ef f ect s, i ncl udi ng headache,
sui ci dal and psychot i c t endenci es, hyper i r ri t abi l i t y, conf usi on, par anoi a,
and ner vousness.
d. Et hi onami de may i nduce nausea, vomi t i ng, ort host at i c hypot ensi on,
met al l i c t ast e, epi gast r i c di st r ess, and peri pher al neuropat hy.
e. St rept omyci n. See Ì Ì . B. 3.
D. AI t ernat i ve agents
1. Ri f at er. A combi nat i on of r i f ampi n 120 mg, i soni azi d 50 mg, and
pyr azi nami de 300 mg i n one t abl et i s used i n pat i ent s expect ed t o have l ow
compl i ance wi t h t ubercul osi s dr ug t her apy. One di sadvantage i s t hat many
pat i ent s ar e requi r ed t o t ake as many as 5- 6 t abl et s dai l y, whi ch may
r educe compl i ance.
2. Qui noI ones. Ci prof l oxaci n and l evof l oxaci n are used i n t ubercul osi s
t her apy. Levof l oxaci n i s pr ef er r ed owi ng t o i ncr eased ser um concent rat i ons.
Levof l oxaci n i s usual l y used i n combi nat i on wi t h ot her t ubercul osi s agent s
f or act i ve t r eat ment . For pr ophyl axi s, l evof l oxaci n i s combi ned wi t h
pyr azi nami de.
3. MacroI i des. Cl ari t hromyci n and azi t hromyci n have shown l i mi t ed act i vi t y
agai nst M. t uber cul osi s.
VII. AntiviraI Agents
A. Def i ni t i on. These dr ugs t r eat vi r al i nf ect i ons by af f ect i ng vi ral
r epl i cat i on. Because vi r uses l ack i ndependent met abol i c act i vi t y and can
r epl i cat e onl y wi t hi n l i vi ng host cel l s, ant i vi r al agent s t end t o i nj ur e host as
wel l as vi r al cel l s. Al t hough most ant i vi r al drugs ar e act i ve agai nst ei t her
DNA or RNA vi r uses, some (e. g. , adef ovi r , ri bavi r i n) ar e act i ve agai nst
bot h.
B. DNA vi ruses. Cur rent l y approved ant i vi r al t herapi es agai nst t he
Her pesvi r i dae f ami l y of DNA vi r uses÷her pes si mpl ex vi r us 1 and 2 ( HSV- 1,
HSV- 2) , vari cel l a- zost er vi r us ( VZV) , cyt omegal ovi r us ( CMV) ÷ar e
vi rust at i c and arr est DNA synt hesi s by i nhi bi t i ng vi r al DNA pol ymerase.
Many of t hese agent s are pr odr ugs and r equi r e vi r al and host cel l ul ar
enzymes ( e. g. , t hymi di ne, deoxyguanosi ne ki nase) t o phosphor yl at e t hem
i nt o t he act i ve t r i phosphat e f orm bef ore exer t i ng t hei r ant i vi ral act i vi t y.
Hence, a common mechani sm of resi st ance i s a def i ci ency or
P. 960

st r uct ur al al t erat i on i n vi r al t hymi di ne ki nase ( Tabl e 44-5) . Some of t hese
agent s al so demonst r at e act i vi t y agai nst RNA vi ruses, i ncl udi ng hepat i t i s C
and HÌ V.
Table 44-5. Activity of Various Anti-DNA Viral Agents
Agent HSV-1 HSV-2 VZV CMV Influenza
A
Influenza
B
Acyclovir
a
¹ ¹ ¹
Amantadine ¹
CidoIovir ¹
Famciclovir ¹ ¹ ¹
Foscarnet ¹ ¹ ¹ ¹
Ganciclovir
a
¹
Oseltamivir ¹ ¹
Rimantadine ¹
Valacyclovir
a
¹ ¹ ¹
Valganciclovir
a
¹
Zanamivir ¹ ¹
HSJ. herpes simplex virus. JZJ. varicella-zoster virus; CMJ.
cytomegalovirus.
a
Requires activation into
triphosphate Iorm.


1. AcycI ovi r ( Zovi r ax) i s a synt het i c acycl i c anal og of guanosi ne wi t h
act i vi t y agai nst var i ous her pes vi ruses.
a. Mechani sm of act i on. Acycl ovi r monophosphat e i s phosphor yl at ed t o t he
t r i phosphat e, wher e i t becomes i ncor porat ed i nt o vi r al DNA and i nhi bi t s
vi r al repl i cat i on.
b. Spect rum of act i vi t y. Thi s agent i s act i ve agai nst her pes vi ruses,
par t i cul arl y HSV- 1, HSV-2, VZV, and chi ckenpox ( var i cel l a) .
c. Therapeut i c uses
( 1) Acycl ovi r i s used t o t r eat i ni t i al and r ecur rent HSV- 1 and HSV-2
i nf ect i ons and f or acut e t r eat ment of her pes zost er ( shi ngl es) and
chi ckenpox. Ì t i s al so used oral l y f or l ong- t er m suppressi on of geni t al HSV
i nf ect i ons.
( 2) Thi s agent i s avai l abl e i n t opi cal , oral , and Ì V f or ms. Topi cal acycl ovi r i s
appl i ed di r ect l y on her pes l esi ons i n recur r ent her pes l abi al i s (col d sores).
Ì t i s not recommended f or use on geni t al her pes l esi ons due t o poor
ef f i cacy.
( 3) Acycl ovi r may be admi ni st er ed i nt ravenousl y i n t he t r eat ment of i ni t i al
and recur r ent mucocut aneous HSV i nf ect i on and VZV i nf ect i on i n
i mmunocompr omi sed pat i ent s, as wel l as i n t he t reat ment of HSV i nf ect i ons
t hat ar e di ssemi nat ed or af f ect t he cent ral ner vous syst em.
d. Precaut i ons and moni t ori ng ef fects
( 1) Or al acycl ovi r may i nduce nausea, vomi t i ng, di ar rhea, and headache.
( 2) Ì V admi ni st r at i on may cause dose- dependent r enal i mpai rment ,
cr yst al l i ne nephropat hy, neurol ogi cal ef f ect s ( e. g. , l et hargy, conf usi on,
t r emor s, agi t at i on, sei zur es, coma, obt undat i on) , hypot ensi on, rash, i t chi ng,
and phl ebi t i s at t he i nj ect i on si t e.
( 3) Local di scomf or t and pr ur i t us may r esul t f rom t opi cal admi ni st rat i on.
( 4) Acycl ovi r i s r emoved by hemodi al ysi s. Doses shoul d be adj ust ed i n
r enal i mpai rment and hemodi al ysi s.
e. Si gni f i cant i nteracti ons. Probeneci d r educes t he r enal cl earance of
acycl ovi r , r esul t i ng i n i ncr eases i n acycl ovi r hal f - l i f e and serum
concent r at i on.
2. Adef ovi r di pi voxi I ( Hepser a) i s a phosphonat e nucl eot i de anal og wi t h
act i vi t y agai nst var i ous DNA and RNA vi r uses.
a. Mechani sm of act i on. Adef ovi r i s phosphor yl at ed t o t he act i ve
di phosphat e f orm by cel l ul ar ki nases. Ì t i s t hen i ncor por at ed i nt o vi ral DNA,
r esul t i ng i n t ermi nat i on of r epl i cat i on.
b. Spect rum of act i vi t y and therapeut i c uses
( 1) Adef ovi r i s act i ve agai nst hepat i t i s B vi rus ( i ncl udi ng l ami vudi ne-
r esi st ant st rai ns), her pes vi r uses, and HÌ V.
( 2) However , adef ovi r i s approved f or use onl y f or t r eat ment of chroni c
hepat i t i s B i nf ect i on i n adul t s wi t h evi dence of act i ve vi r al r epl i cat i on wi t h
per si st ent l y el evat ed l i ver f unct i on t est s or hi st ol ogi cal l y act i ve di sease.
P. 961


c. Precauti ons and moni t ori ng ef f ect s
( 1) Severe acut e hepat i t i s exacerbat i ons have occur red i n pat i ent s who
di scont i nue t her apy ( bI ack box warni ng). Ì f t herapy i s di scont i nued, l i ver
f unct i on t est s must be moni t or ed cl osel y.
( 2) Nephr ot oxi ci t y has been repor t ed wi t h adef ovi r , especi al l y i n pat i ent s
wi t h under l yi ng renal dysf unct i on or t hose t aki ng concomi t ant nephrot oxi ns
( bI ack box warni ng).
( 3) Ot her adver se ef f ect s i ncl ude r ash, GÌ di st urbances, headache, and
weakness.
( 4) Dose adj ust ment i s requi r ed f or r enal i nsuf f i ci ency.
3. Amant adi ne ( Symmet reI ) i s a synt het i c t r i cycl i c ami ne wi t h a uni que
chemi cal st r uct ur e si mi l ar t o ri mant adi ne. Ì t i s ef f ect i ve agai nst i nf l uenza A
vi r al i nf ect i on.
a. Mechani sm of act i on. Amant adi ne i nhi bi t s r epl i cat i on of t he i nf l uenza A
vi r us by i nt er f er i ng wi t h vi r al at t achment and uncoat i ng.
b. Spect rum of act i vi t y and therapeut i c uses
( 1) Due t o i ncr easi ng r at es of resi st ance, amant adi ne i s no l onger
r ecommended f or prophyl axi s or t r eat ment of i nf l uenza A vi r us.
( 2) Thi s drug may al so be used t o t r eat par ki nsoni sm as wel l as dr ug-
i nduced ext r apyr ami dal sympt oms.
c. Precauti ons and moni t ori ng ef f ect s
( 1) The most pr onounced adverse ef f ect s of amant adi ne are at axi a,
ni ght mar es, and i nsomni a. Ot her CNS ef f ect s i ncl ude depr essi on,
conf usi on, di zzi ness, f at i gue, anxi et y, and headache. El derl y pat i ent s may
be at i ncreased r i sk of CNS adverse react i ons. Pat i ent s wi t h a hi st or y of
sei zures or psychi at r i c di sorders shoul d be moni t or ed cl osel y dur i ng
t her apy.
( 2) Ant i chol i ner gi c r eact i ons ( e. g. , dr y mout h, bl ur r ed vi si on) have been
r eport ed.
( 3) Dosage adj ust ment i s needed f or pat i ent s wi t h i mpai r ed r enal f unct i on.
4. Ci dof ovi r ( Vi st i de) i s a synt het i c acycl i c puri ne nucl eosi de phosphonat e
der i vat i ve.
a. Mechani sm of act i on. Ci dof ovi r di phosphat e suppresses CMV r epl i cat i on
by sel ect i ve i nhi bi t i on of vi r al DNA synt hesi s.
b. Spect rum of act i vi t y. Ì n vi t ro act i vi t y has been demonst r at ed agai nst
CMV, VZV, Epst ei n- Bar r vi r us ( EBV) , and HSV- 1 and HSV-2. Cont rol l ed
cl i ni cal st udi es are l i mi t ed t o pat i ent s wi t h AÌ DS and CMV r et i ni t i s.
c. Therapeut i c use i ncl udes t he t r eat ment , but not t he cur e of , CMV
r et i ni t i s i n pat i ent s wi t h AÌ DS.
d. Precaut i ons and moni t ori ng ef fects
( 1) Avoi d usi ng t hi s dr ug i n pat i ent s wi t h ser um cr eat i ni ne > 1. 5 mg/ dL or
cr eat i ni ne cl ear ance ( CrCl ) > 55 mL/ mi n or i n pat i ent s who ar e recei vi ng (or
have r ecei ved i n t he past 7 days) nephr ot oxi c agent s.
( 2) Ci dof ovi r i s cont r ai ndi cat ed i n pat i ent s wi t h a hi st or y of sever e
hyper sensi t i vi t y t o probeneci d or sul f a-cont ai ni ng medi cat i ons.
( 3) The dose- l i mi t i ng t oxi ci t y of ci dof ovi r i s nephrot oxi ci t y; neut r openi a,
per i pheral neur opat hy, and di ar rhea are common adver se ef f ect s.
( 4) Pr obeneci d must be admi ni st er ed bef ore and af t er each ci dof ovi r dose.
The pat i ent must be hydrat ed wi t h 1 L of nor mal sal i ne bef or e i nf usi ng.
Ci dof ovi r i s avai l abl e onl y i n Ì V f orm.
5. Entecavi r ( BaracI ude) i s a carbocycl i c anal og of guanosi ne used f or
t r eat ment of chr oni c hepat i t i s B i nf ect i on.
a. Mechani sm of act i on. Once phosphor yl at ed t o t he act i ve t r i phosphat e
f or m, ent ecavi r i nhi bi t s hepat i t i s B vi r al pol ymer ase and ul t i mat el y hal t s
hepat i t i s B DNA synt hesi s.
b. Spect rum of act i vi t y. Ent ecavi r exhi bi t s act i vi t y agai nst hepat i t i s B
vi r us, i ncl udi ng l ami vudi ne- r esi st ant st rai ns. Devel opment of HÌ V r esi st ance
t o nucl eosi de rever se t ranscr i pt ase i nhi bi t ors i s possi bl e i f ent ecavi r i s
used wi t hout ant i r et rovi ral t reat ment i n HÌ V and hepat i t i s B vi r us co-
i nf ect i on.
c. Therapeut i c uses
( 1) Ent ecavi r i s appr oved f or t r eat ment of chr oni c hepat i t i s B i nf ect i on i n
adul t s wi t h evi dence of act i ve vi r al r epl i cat i on and persi st ent el evat i ons i n
l i ver f unct i on t est s or hi st ol ogi cal l y act i ve di sease.
( 2) Ì t i s ef f ect i ve f or pat i ent s who have f ai l ed t reat ment wi t h l ami vudi ne
owi ng t o r esi st ance devel opment .
P. 962


( 3) Ent ecavi r i s not r ecommended f or use i n pat i ent s wi t h hepat i t i s B vi r us
i nf ect i on who ar e co- i nf ect ed wi t h HÌ V and are not r ecei vi ng ant i r et r ovi r al
t her apy.
d. Precaut i ons and moni t ori ng ef fects
( 1) Severe acut e exacerbat i ons of hepat i t i s B have been obser ved i n
pat i ent s who di scont i nue t herapy, necessi t at i ng cl ose moni t ori ng ( bI ack
box warni ng).
( 2) Common adverse ef f ect s i ncl ude di zzi ness, f at i gue, headache, and
nausea.
( 3) Dose adj ust ment i s requi r ed f or r enal i nsuf f i ci ency.
( 4) Counsel pat i ent s t o t ake ent ecavi r on an empt y st omach.
6. Famci cI ovi r ( Famvi r) i s a pr odrug of t he ant i vi r al agent penci cl ovi r .
a. Mechani sm of act i on. Famci cl ovi r i s r api dl y phosphor yl at ed i n vi rus-
i nf ect ed cel l s by vi r al t hymi di ne ki nase t o penci cl ovi r monophosphat e.
Penci cl ovi r i s a compet i t i ve i nhi bi t or of vi r al DNA pol ymer ase and prevent s
vi r al repl i cat i on by i nhi bi t i on of herpes vi r us DNA synt hesi s.
b. Spect rum of act i vi t y and therapeut i c uses
( 1) Famci cl ovi r has act i vi t y agai nst HSV- 1, HSV-2, and VZV. The dr ug i s
i ndi cat ed f or management of acut e her pes zost er ( shi ngl es) and or al and
geni t al her pes.
( 2) Ther apy must be pr ompt l y i ni t i at ed as soon as her pes zost er i s
di agnosed ( wi t hi n 48- 72 hr ) , at a dose of 500 mg ever y 8 hr f or 7 days.
c. Precauti ons and moni t ori ng ef f ect s
( 1) Common adverse event s i ncl ude f at i gue, GÌ compl ai nt s ( nausea,
di ar rhea, vomi t i ng, const i pat i on) , and anor exi a. Headache i s al so commonl y
r eport ed.
( 2) Dose adj ust ment i s necessar y i n pat i ent s wi t h r enal dysf unct i on.
Famci cl ovi r i s removed by hemodi al ysi s.
7. Foscarnet (Foscavi r) i s a synt het i c pyrophosphat e anal og t hat di rect l y
i nhi bi t s enzymes i nvol ved i n vi r al DNA synt hesi s wi t hout i ncor por at i on i nt o
vi r al DNA. Ì t i s a br oad- spect r um ant i vi ral agent and i s an opt i on i n cases
of acycl ovi r or ganci cl ovi r r esi st ance.
a. Mechani sm of act i on
( 1) Vi ral DNA r epl i cat i on r equi r es t he addi t i on of deoxynucl eosi de
t r i phosphat es at t he end of t he DNA st rand by DNA pol ymer ase and t he
subsequent cl eavage of pyr ophosphat e f rom t he newl y at t ached nucl eot i de.
Foscarnet bi nds noncompet i t i vel y t o DNA pol ymer ase t o f orm an i nact i ve
compl ex and prevent s pyr ophosphat e cl eavage. Vi r al DNA chai n el ongat i on
i s t hus t er mi nat ed.
( 2) Foscar net i s al so act i ve agai nst HÌ V. Ì t i s a noncompet i t i ve, r eversi bl e
i nhi bi t or of HÌ V r everse t r anscri pt ase, t he enzyme r esponsi bl e f or
convert i ng vi r al RNA t o vi r al DNA.
b. Spect rum of act i vi t y and therapeut i c uses. Foscar net has i n vi t ro
act i vi t y agai nst HSV- 1 and HSV- 2, CMV, VZV, EBV DNA pol ymerases,
i nf l uenza pol ymer ase, and HÌ V r everse t r anscr i pt ase. Therapeut i cal l y, t he
dr ug i s used t o t r eat CMV di sease as wel l as acycl ovi r- r esi st ant HSV and
VZV i nf ect i ons.
( 1) Foscar net i s an al t ernat i ve t o ganci cl ovi r and val ganci cl ovi r f or
t r eat ment of CMV i nf ect i on i n i mmunocompr omi sed pat i ent s. Foscar net
causes l ess hemat ol ogi c t oxi ci t y t han ganci cl ovi r i n pat i ent s who have
r ecei ved al l ogenei c st em cel l t r anspl ant s. An i ni t i al i nduct i on t her apy l ast s
2- 3 weeks. Mai nt enance t her apy i s needed t o pr event r el apse.
( 2) Foscar net i s i ndi cat ed f or t he t reat ment of acycl ovi r - resi st ant
mucocut aneous HSV i n i mmunocompromi sed pat i ent s. Ì t i s not , however , a
cur e f or HSV i nf ect i ons.
( 3) Foscar net i s abl e t o cr oss t he bl ood- brai n bar r i er .
c. Precauti ons and moni t ori ng ef f ect s
( 1) Ì V f oscar net i s hi ghl y nephrot oxi c, causi ng acut e t ubul ar necr osi s. The
i nci dence of acut e renal f ai l ur e can be markedl y reduced i f adequat e
hydr at i on and dai l y moni t or i ng of ser um cr eat i ni ne and BUN ar e mai nt ai ned
t hr oughout t her apy.
( 2) Ot her common adverse ef f ect s i ncl ude el ect rol yt e abnor mal i t i es ( e. g. ,
hypocal cemi a, hypomagnesemi a, hypophosphat emi a and
hyper phosphat emi a, hypokal emi a) , anemi a, f ever, headache, and sei zur es.
( 3) Dose adj ust ment f or r enal dysf unct i on i s r equi r ed. Foscar net i s r emoved
by hemodi al ysi s.
( 4) Foscar net must be admi ni st ered usi ng an i nf usi on pump over at l east
1. 5- 2 hr . Do not admi ni st er t he drug as an Ì V bol us.
P. 963


d. Si gni f i cant i nteract i ons
( 1) Concomi t ant nephrot oxi ns ( ami nogl ycosi des, amphot er i ci n B, et c. )
i ncrease t he r i sk of r enal t oxi ci t y.
( 2) Foscar net i s excl usi vel y el i mi nat ed by gl omerul ar f i l t r at i on; concur r ent
nephr ot oxi c agent s shoul d be avoi ded whenever possi bl e.
8. Ganci cI ovi r ( Cyt ovene) i s a synt het i c puri ne nucl eosi de anal og t hat i s
approved f or t he t r eat ment and pr ophyl axi s of CMV i nf ect i ons i n
i mmunocompr omi sed pat i ent s (e. g. , HÌ V-posi t i ve pat i ent s, t r anspl ant
r eci pi ent s) .
a. Mechani sm of act i on. Af t er conversi on t o ganci cl ovi r t r i phosphat e,
ganci cl ovi r i s i ncor por at ed i nt o vi r al DNA, whi ch i nhi bi t s vi r al DNA
pol ymer ase, t her eby t ermi nat i ng vi r al r epl i cat i on.
b. Spect rum of act i vi t y. Ganci cl ovi r has i n vi t ro act i vi t y agai nst HSV- 1 and
HSV- 2, VZV, EBV, and CMV ( owi ng t o i t s enhanced abi l i t y t o penet r at e host
cel l s).
c. Therapeut i c uses. Ì t i s i ndi cat ed f or t r eat ment of CMV r et i ni t i s i n
pat i ent s wi t h HÌ V/ AÌ DS. Ì t i s al so used f or pr ophyl axi s of CMV i nf ect i on i n
HÌ V- posi t i ve pat i ent s (secondar y prophyl axi s) and t r anspl ant reci pi ent s at
r i sk f or CMV di sease.
( 1) Conver si on i nt o t he t r i phosphat e f or m i s great er i n i nf ect ed host cel l s,
even t hough dr ug penet rat i on occurs i n bot h uni nf ect ed and i nf ect ed cel l s.
( 2) Ì nhi bi t or y concent r at i ons f or t he vi r al DNA pol ymer ase ar e l ower t han
t hose f or t he host cel l ul ar pol ymerase.
( 3) Ì t i s avai l abl e i n oral and Ì V f or mul at i ons as wel l as an i nt r aocul ar
i mpl ant . Al t hough t he oral f or mul at i on i s appr oved f or pr event i on and
mai nt enance t r eat ment of CMV, i t s poor bi oavai l abi l i t y has l i mi t ed i t s use.
Val ganci cl ovi r has become t he dr ug of choi ce f or t hese i ndi cat i ons, owi ng
t o i t s markedl y i mproved bi oavai l abi l i t y.
d. Precaut i ons and moni t ori ng ef fects
( 1) Ganci cl ovi r has a bI ack box warni ng concer ni ng i ncr eased pot ent i al f or
neut ropeni a, anemi a, and t hrombocyt openi a. Ì t i s al so t er at ogeni c,
carci nogeni c, and mut ageni c.
( 2) Adverse ef f ect s commonl y i ncl ude f ever, r ash, and GÌ di st ur bances.
Phl ebi t i s and pai n may occur at t he si t e of i nf usi on.
( 3) Because ganci cl ovi r i s cl ear ed by gl omer ul ar f i l t rat i on and t ubul ar
secr et i on, r enal f unct i on and adequat e hydr at i on shoul d be moni t ored.
Doses shoul d be adj ust ed i n cases of renal i mpai r ment and hemodi al ysi s.
( 4) Sol ut i ons of ganci cl ovi r ar e ext r emel y al kal i ne. Avoi d di r ect cont act wi t h
ski n.
e. Si gni f i cant i nteracti ons
( 1) Probeneci d may i ncrease ganci cl ovi r concent r at i ons and possi bl y
t oxi ci t y.
( 2) Use of zi dovudi ne, azat hi opri ne, or mycophenoI at e mof eti I i n
combi nat i on wi t h ganci cl ovi r may r esul t i n neut ropeni a; caref ul moni t or i ng
of neut rophi l count i s r equi red when t hese are t aken concur r ent l y wi t h
ganci cl ovi r .
( 3) I mi penem-ci I astat i n i n combi nat i on wi t h ganci cl ovi r may i ncr ease t he
pot ent i al f or sei zur es.
9. OseI t ami vi r ( Tami f I u) i s phar macol ogi cal l y si mi l ar t o zanami vi r but
st r uct ur al l y di f f erent . Bot h of t hese agent s ar e i n a cl ass known as t he
neurami ni dase i nhi bi t ors and have a uni que mechani sm of act i on.
a. Mechani sm of act i on. Osel t ami vi r i s a pr odr ug t hat must be hydr ol yzed
t o osel t ami vi r car boxyl at e i n vi vo t o exer t i t s ant i vi r al act i vi t y. Ì t i s a pot ent
sel ect i ve i nhi bi t or of t he i nf l uenza vi r us enzyme, neurami ni dase. Ì nhi bi t i on
of t hi s enzyme prevent s vi r al repl i cat i on and spr ead t o ot her host cel l s.
b. Spect rum of act i vi t y. Thi s agent i s act i ve agai nst bot h i nf l uenza A and
B vi r uses.
c. Therapeut i c uses
( 1) Ì t i s appr oved f or t he sympt omat i c t r eat ment of i nf l uenza A and B
i nf ect i ons i n pat i ent s 1 year of age and ol der who pr esent wi t h sympt oms
wi t hi n 48 hr.
( 2) Osel t ami vi r has been shown t o decrease t he dur at i on of sympt oms by 1-
2 days i f t aken wi t hi n 48 hr of onset of vi r al sympt oms.
( 3) Ì t i s al so appr oved f or t he pr ophyl axi s of i nf l uenza i nf ect i ons i n pat i ent s
1 year of age and ol der. Not e: The i nf l uenza vi rus vacci ne i s st i l l t he gol d
st andard f or prophyl axi s.
( 4) Osel t ami vi r demonst rat es some act i vi t y agai nst st r ai ns of avi an
i nf l uenza, maki ng i t a possi bl e opt i on f or t r eat ment and pr ophyl axi s.
P. 964


d. Precaut i ons and moni t ori ng ef fects
( 1) The most common adver se ef f ect s ar e nausea and vomi t i ng. Ther e have
been post mar ket i ng repor t s of sel f -i nj ur y and del i r i um ( most l y i n Japan)
among pedi at r i c pat i ent s. Cl ose moni t or i ng f or abnor mal behavi or i s
r ecommended.
( 2) Dosage adj ust ment s ar e requi r ed f or pat i ent s wi t h i mpai red r enal
f unct i on.
( 3) Cr oss-r esi st ance bet ween osel t ami vi r and zanami vi r has been repor t ed.
10. Ri bavi ri n ( RebetoI , Copegus) i s a synt het i c nucl eosi de anal og.
a. Mechani sm of act i on. Ri bavi r i n may i nhi bi t RNA and DNA synt hesi s by
depl et i ng i nt r acel l ul ar nucl eot i de reser ves.
b. Spect rum of act i vi t y. Thi s agent i s act i ve i n vi t r o agai nst a broad
spect rum of DNA and RNA vi r uses, i ncl udi ng i nf l uenza A and B, RSV,
her pes si mpl ex, and hepat i t i s C vi r us.
c. Therapeut i c uses. The aerosol i zed f or m of r i bavi r i n i s no l onger
r ecommended f or t r eat ment of RSV i n i nf ant s and chi l dr en, owi ng t o
i nconsi st ent cl i ni cal benef i t s obser ved i n cl i ni cal t r i al s. Combi nat i on
t her apy wi t h oral ri bavi r i n and subcut aneous i nt er f er on- q i s ef f ect i ve i n
t r eat ment of chr oni c hepat i t i s C.
d. Precaut i ons and moni t ori ng ef fects
( 1) Common adverse ef f ect s of oral ri bavi r i n i ncl ude hemol yt i c anemi a and
GÌ di st urbances. Hemogl obi n and hemat ocri t shoul d be moni t or ed car ef ul l y,
especi al l y dur i ng t he f i rst 4 weeks of t reat ment .
( 2) Ri bavi r i n i s t er at ogeni c; i t s use i s cont rai ndi cat ed i n pr egnancy.
( 3) Ri bavi r i n shoul d be avoi ded i n pat i ent s wi t h a Cr Cl < 50 mL/ mi n.
( 4) Ri bavi r i n shoul d never be used as monot her apy i n t r eat ment of chroni c
hepat i t i s C.
11. Ri mant adi ne (FI umadi ne) i s a synt het i c ant i vi r al agent and an q- met hyl
der i vat i ve of amant adi ne t hat bl ocks t he ear l y st ep i n t he r epl i cat i on of t he
i nf l uenza A vi rus.
a. Mechani sm of act i on. Ri mant adi ne i nhi bi t s t he earl y vi r al r epl i cat i on
cycl e, possi bl y i nhi bi t i ng t he uncoat i ng of t he vi r us. Ì t has t he same
mechani sm of act i on and spect rum of act i vi t y as amant adi ne.
b. Spect rum of act i vi t y and therapeut i c uses
( 1) Due t o i ncr easi ng r at es of resi st ance, r i mant adi ne i s no l onger
r ecommended f or prophyl axi s or t r eat ment of i nf l uenza A vi r us.
( 2) Ì nf l uenza vacci nat i on i s t he met hod of choi ce f or prevent i on of i nf l uenza
i nf ect i on.
c. Precauti ons and moni t ori ng ef f ect s
( 1) Ri mant adi ne may i ncr ease t he i nci dence of sei zur e i n pat i ent s wi t h
sei zure di sor der .
( 2) The most f requent adver se react i ons i ncl ude GÌ di st urbance ( e. g. ,
nausea, vomi t i ng, anor exi a) and CNS t oxi ci t y ( e. g. , i nsomni a, di zzi ness,
headache), whi ch ar e l ess t han t hose obser ved wi t h amant adi ne.
( 3) Dose reduct i ons ar e r ecommended i n pat i ent s wi t h hepat i c or r enal
dysf unct i on.
12. TeI bi vudi ne ( Tyzeka) i s a synt het i c t hymi di ne nucl eosi de anal og used
f or t reat ment of chr oni c hepat i t i s B i nf ect i on.
a. Mechani sm of act i on. Tel bi vudi ne i s phosphor yl at ed i nt o t he act i ve
t r i phosphat e f orm t hat i nhi bi t s hepat i t i s B vi r al DNA pol ymer ase, wi t h
ul t i mat e t ermi nat i on of t he DNA chai n and i nhi bi t i on of vi ral repl i cat i on.
b. Spect rum of act i vi t y.
( 1) Tel bi vudi ne exhi bi t s act i vi t y agai nst hepat i t i s B vi r us but not HÌ V.
( 2) Ther e i s a hi gh i nci dence of cross- resi st ance bet ween l ami vudi ne-
r esi st ant hepat i t i s B vi r us and t el bi vudi ne.
c. Therapeut i c uses.
( 1) Tel bi vudi ne i s i ndi cat ed f or t reat ment of chr oni c hepat i t i s B i nf ect i on i n
adul t s wi t h act i ve vi r al repl i cat i on and persi st ent el evat i ons i n l i ver f unct i on
t est s or hi st ol ogi cal l y act i ve di sease.
( 2) When compar ed wi t h l ami vudi ne, t el bi vudi ne pr oduced a gr eat er
vi r ol ogi c r esponse i n cont r ol l ed cl i ni cal t r i al s.
d. Precaut i ons and moni t ori ng ef fects.
( 1) Ther e i s a bI ack box warni ng r egar di ng sever e exacer bat i ons of
hepat i t i s B i n pat i ent s di scont i nui ng t her apy, r equi r i ng cl ose moni t ori ng.
P. 965


( 2) Common adverse ef f ect s i ncl ude el evat i ons i n creat i ne phosphoki nase,
headache, f at i gue, nausea, and vomi t i ng.
( 3) Dosage adj ust ment i s r equi r ed i n pat i ent s wi t h r enal i nsuf f i ci ency.
( 4) May be t aken wi t hout r egar d t o meal s.
13. VaI acycI ovi r ( VaI t rex) i s t he L- val yl est er prodr ug of t he ant i vi ral agent
acycl ovi r .
a. Mechani sm of act i on. Val acycl ovi r i s r api dl y convert ed t o acycl ovi r.
Acycl ovi r i s sel ect i ve f or t he t hymi di ne ki nase enzyme, begi nni ng t he
conversi on of acycl ovi r t o acycl ovi r t ri phosphat e, st oppi ng t he r epl i cat i on of
her pes vi r al DNA.
b. Spect rum of act i vi t y and therapeut i c uses
( 1) Val acycl ovi r i s act i ve agai nst HSV-1, HSV-2, and VZV.
( 2) Thi s agent i s used f or t he acut e t r eat ment of her pes zost er (shi ngl es) ,
her pes l abi al i s (col d sores) , and geni t al her pes i n i mmunocompet ent adul t s.
Ì t i s al so ef f ect i ve f or suppr essi on of r ecur rent epi sodes of geni t al her pes i n
i mmunocompet ent and HÌ V- i nf ect ed peopl e as wel l as reduct i on of
t r ansmi ssi on of geni t al her pes.
( 3) Advant ages over acycl ovi r i ncl ude oral dosi ng of onl y once t o t hr ee
t i mes dai l y and at t ai nment of hi gher pl asma concent r at i ons t han or al
acycl ovi r . A di sadvant age i s t hat t here i s no Ì V f or m avai l abl e.
c. Precauti ons and moni t ori ng ef f ect s
( 1) Val acycl ovi r has caused t hrombot i c t hrombocyt openi c purpura/ hemol yt i c
ur emi c syndr ome i n i mmunocompr omi sed i ndi vi dual s, i ncl udi ng t hose wi t h
advanced HÌ V and t r anspl ant r eci pi ent s.
( 2) Begi n t her apy wi t hi n 72 hr of herpes zost er r ash onset .
( 3) Most commonl y r eport ed adverse react i ons are mi l d and i ncl ude nausea,
headache, and vomi t i ng. Dosage adj ust ment i s needed i n pat i ent s wi t h
r enal dysf unct i on.
14. VaI ganci cI ovi r ( VaI cyt e) i s t he L- val yl est er pr odr ug of t he ant i vi r al
agent ganci cl ovi r .
a. Mechani sm of act i on. Val ganci cl ovi r i s conver t ed i n vi vo t o ganci cl ovi r .
Af t er conver si on t o t he act i ve f orm, ganci cl ovi r t ri phosphat e, ganci cl ovi r i s
i ncor por at ed i nt o vi r al DNA, whi ch i nhi bi t s vi r al DNA pol ymer ase, t her eby
t er mi nat i ng vi ral repl i cat i on.
b. Spect rum of act i vi t y and therapeut i c uses
( 1) For i n vi t ro act i vi t y, see VÌ Ì . B. 8. b.
( 2) Val ganci cl ovi r i s i ndi cat ed f or t he t r eat ment of CMV r et i ni t i s i n pat i ent s
wi t h AÌ DS and f or prevent i on of CMV af t er t r anspl ant at i on of ki dney, hear t ,
and ki dneypancr eas. Ì t i s not i ndi cat ed f or l i ver t r anspl ant r eci pi ent s, due t o
an i ncreased r i sk of t i ssue- i nvasi ve CMV as compar ed wi t h ganci cl ovi r .
( 3) The markedl y i mproved bi oavai l abi l i t y of val ganci cl ovi r over or al
ganci cl ovi r has resul t ed i n t he wi despread use of val ganci cl ovi r f or
t r eat ment and pr event i on of CMV di sease.
c. Precauti ons and moni t ori ng ef f ect s
( 1) Same bI ack box warni ngs as f or ganci cl ovi r.
( 2) Doses shoul d be adj ust ed i n cases of r enal i mpai r ment . Do not use i n
hemodi al ysi s pat i ent s; ganci cl ovi r must be used.
( 3) Onl y avai l abl e or al l y. Do not subst i t ut e doses of oral val ganci cl ovi r 1: 1
f or oral ganci cl ovi r ; t hey ar e not equi val ent .
( 4) A pot ent i al car ci nogen and t er at ogen; common adverse ef f ect s ar e t he
same as f or ganci cl ovi r .
( 5) Ì f t he t abl et i s br oken, avoi d cont act wi t h ski n owi ng t o t erat ogeni c and
carci nogeni c pot ent i al .
( 6) Be awar e of t he pot ent i al f or err ors as a r esul t of t he l ook-al i ke and
sound-al i ke names of val ganci cl ovi r and val acycl ovi r .
d. Si gni f i cant i nteract i ons. Same as f or ganci cl ovi r ; see VÌ Ì . B. 8. e.
15. Zanami vi r ( ReI enza) i s t he f i rst of a cl ass of ant i vi r al agent s cal l ed
neurami ni dase i nhi bi t ors approved by t he FDA f or t he t r eat ment of i nf l uenza
A and B i nf ect i ons i n adul t s and chi l dren at l east 7 years of age. Ì t i s al so
i ndi cat ed f or prevent i on of i nf l uenza i n adul t s and chi l dr en at l east 5 years
of age.
a. Mechani sm of act i on. Zanami vi r i nhi bi t s r epl i cat i on of t he i nf l uenza A
and B vi r uses by sel ect i ve i nhi bi t i on of t he i nf l uenza vi r us neur ami ni dase
enzyme.
b. Spect rum of act i vi t y. Thi s agent i s act i ve agai nst bot h t he i nf l uenza A
and B vi r uses. Ì t demonst r at es act i vi t y agai nst avi an i nf l uenza i n ani mal
st udi es.
P. 966


c. Therapeut i c uses
( 1) Ì t i s appr oved f or t he t r eat ment of uncompl i cat ed i nf l uenza A and B
i nf ect i on f or pat i ent s who have been sympt omat i c f or < 48 hr . Ì t i s al so
i ndi cat ed f or i nf l uenza prophyl axi s.
( 2) Zanami vi r i s appr oved f or or al i nhal at i on use onl y, usi ng t he Di skhal er
devi ce provi ded by t he manuf act ur er .
( 3) Zanami vi r may be consi dered f or pr event i on or t r eat ment of avi an
i nf l uenza.
( 4) Shown t o decrease dur at i on of sympt oms by approxi mat el y 1. 5 days i f
t aken wi t hi n 48 hr of onset of vi r al sympt oms.
d. Precaut i ons and moni t ori ng ef fects
( 1) The use of zanami vi r i s gener al l y not recommended i n pat i ent s wi t h a
hi st or y of ast hma or chroni c obst ruct i ve pul monary di sease, owi ng t o t he
r i sk of bronchospasm and acut e decl i ne i n l ung f unct i on.
( 2) The most common adver se ef f ect s wer e mi l d and i ncl uded di ar rhea,
nausea, and vomi t i ng. The i nci dence of t hese was no di f f er ent t han
pl acebo.
( 3) Do not punct ur e t he Rot adi sk bl i st er unt i l i mmedi at el y bef ore
admi ni st er i ng t he dose t o ensure f ul l dosage. Manual dext er i t y r equi r ed f or
t hi s devi ce.
C. RNA vi ruses ( HI V)
1. Cur rent l y, si x cl asses of ant i ret r ovi r al agent s ar e appr oved. These dr ugs
ar e act i ve agai nst HÌ V and i ncl ude t he nucl eosi de r everse t r anscr i pt ase
i nhi bi t ors ( NRTÌ s) abacavi r, di danosi ne, emt ri ci t abi ne, I ami vudi ne,
st avudi ne, zaI ci t abi ne, and zi dovudi ne; t he nucl eot i de r everse
t r anscri pt ase i nhi bi t or ( Nt RTÌ ) t enof ovi r di soproxi I f umarat e; t he
nonnucl eosi de r everse t ranscr i pt ase i nhi bi t or s ( NNRTÌ s) deI avi rdi ne,
ef avi renz, nevi rapi ne and et ravi ri ne; and t he prot ease i nhi bi t or s ( PÌ s)
amprenavi r, atazanavi r, darunavi r, f osamprenavi r, i ndi navi r,
I opi navi r/ ri t onavi r, neI fi navi r, ri t onavi r, saqui navi r, and t i pranavi r; t he
f usi on i nhi bi t or enf uvi rt i de; t he ent r y i nhi bi t or maravi roc; and t he
i nt egr ase i nhi bi t or raI tegravi r.
2. These agent s ar e vi r ust at i c and requi r e l i f el ong t her apy. They ar e
cur rent l y appr oved f or use i n vari ous combi nat i ons known as pot ent
combi nat i on ant i ret r ovi ral t her apy.
a. Appr opr i at e combi nat i ons i ncl ude t hose t hat have demonst r at ed ef f i cacy
and saf et y i n cont r ol l ed cl i ni cal t ri al s ( Tabl e 44-6) .
b. Monot her apy wi t h any si ngl e ant i r et rovi r al agent i s unaccept abl e i n t he
t r eat ment of HÌ V i nf ect i on owi ng t o rapi d devel opment of vi r al r esi st ance.
c. Bef or e desi gni ng a t reat ment pl an, a mi ni mum of t wo CD4
+
cel l count s
and one HÌ V RNA l evel (vi r al l oad) shoul d be obt ai ned t o conf i rm t he i ni t i al
measurement s and det ermi ne i f t reat ment shoul d be i ni t i at ed. Af t er st ar t i ng
t her apy, r epeat t hese measur ement s i n 2- 8 weeks, f ol l owed by ever y 3- 4
mont hs t her eaf t er .
d. A mi ni mum of 1. 0- l og10 copi es/ mL decl i ne i n HÌ V RNA l evel s shoul d be
seen af t er t he f i rst 2- 8 weeks of t her apy f or cl i ni cal response; a subsequent
decrease t o undet ect abl e l evel s shoul d be achi eved by 16- 24 weeks.
3. Reverse t ranscri pt ase i nhi bi tors are cl assi f i ed as ei t her nucl eosi des or
nucl eot i des. These agent s ar e compet i t i ve i nhi bi t or s of rever se
t r anscri pt ase, whi ch l eads t o chai n t er mi nat i on when i ncorpor at ed i nt o t he
vi r al DNA chai n. They are i nact i ve unt i l phosphoryl at ed by human cel l ul ar
ki nases i nt o t he act i ve t ri phosphat e met abol i t e. Each agent has a
cor respondi ng t hr ee- l et t er acr onym as wel l as a br and name. Wi t h t he
except i on of abacavi r , each agent i n t hi s cl ass of ant i r et r ovi ral s r equi r es
dosage adj ust ment i n pat i ent s wi t h r enal dysf unct i on. AI I agent s i n thi s
cI ass have a bI ack box warni ng concerni ng t he pot ent i aI f or
deveI opment of I act i c aci dosi s and severe hepat omegaI y wi t h
st eatosi s.
a. Abacavi r ( ABC; Zi agen) i s a synt het i c car bocycl i c nucl eosi de anal og
i ndi cat ed f or t he t reat ment of bot h adul t and pedi at r i c pat i ent s wi t h HÌ V.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. Abacavi r i s appr oved f or
use i n adul t s and chi l dr en < 3 mont hs of age onl y i n combi nat i on wi t h ot her
ant i r et rovi r al agent s.
( a) Abacavi r i s avai l abl e al one or co- f or mul at ed as a combi nat i on t abl et
wi t h l ami vudi ne and zi dovudi ne ( Tr i zi vi r ) whi ch i s dosed t wi ce dai l y.
( b) Abacavi r i s al so avai l abl e i n a combi nat i on t abl et wi t h l ami vudi ne
( Epzi com) whi ch i s dosed once dai l y.
( 3) Precaut i ons and moni t ori ng ef fects. Abacavi r has a bI ack box
warni ng f or a l i f e-t hreat eni ng hypersensi t i vi t y r eact i on t hat can l ead t o
deat h. Ì t occurs i n appr oxi mat el y 5% of pat i ent s t aki ng t hi s dr ug, t ypi cal l y
wi t hi n t he f i rst 6 weeks of t her apy. Thi s react i on i nvol ves r espi rat or y
sympt oms, f ever , r ash, and GÌ compl ai nt s. Reexposur e f ol l owi ng t hese
sympt oms can mi mi c anaphyl axi s and may resul t i n deat h. Ther ef or e,
r echal l enge i s cont rai ndi cat ed. A Medi cat i on Gui de descr i bi ng t hi s react i on
shoul d be di spensed wi t h each new pr escr i pt i on and ref i l l of abacavi r -
cont ai ni ng pr oduct s. The HLA- B
*
5701 screeni ng t est shoul d be used pr i or t o
i ni t i at i ng t her apy t o reduce t he r i sk of t hi s react i on.
P. 967


Table 44-6. Department of Health and Human Services Guidelines for the Use of
Antiviral Agents in HIV-1-Infected Adults and Adolescents
When to begin treatment
Treat any patient with history oI AIDS deIining illness
Treat any patients with CD4
¹
cell count · 200/mm
3
or between 200-
350/mm
3

Treat patients who are pregnant. have HIV-associated nephropathy or those
co-inIected with hepatitis B virus (when treatment Ior hepatitis B is
indicated).
Note: The optimal time to start treatment in patients with CD4
¹
cell count ~
350/mm
3
is not well deIined.
Regimen selection
Selection oI a treatment regimen should be individualized Ior each patient
based on adverse eIIect proIiles. drug interactions. comorbidities. pill
burden. etc. PreIerred and alternative treatment regimens in previously
untreated patients are as Iollows:
To select an antiretroviral regimen. select one component Irom Column A
and one Irom Column B:
Column A (NNRTI or PI Options) Column B (Dual NRTI
Options)
PreIerr
ed
Compo
nents
NNRT
I
EIavir
enz
a

o
r
PI
Atazanavir or
ritonavir
Fosamprenavi
r ¹ ritonavir
(b.i.d.)
Lopinavir/rito
navir (b.i.d.)
PreIerr
ed
Compo
nents
TenoIovir/em
tricitabine or
abacavir/lami
vudine
Alterna
tive to
PreIerr
ed
Compo
nents
NNRT
I
Nevira
pine
b

o
r
PI
Atazanavir
Fosamprenavi
r
Fosamprenavi
r/ritonavir
(once daily)
Lopinavir/rito
navir (once
daily)
Saquinavir ¹
ritonavir
Alterna
tive to
PreIerr
ed
Compo
nents
Zidovudine/la
mivudine or
didanosine ¹
(emtricitabine
or
lamivudine)
Agents or combinations that should not be offered at any time
All monotherapies
2-NRTI regimens
Abacavir ¹ tenoIovir ¹ lamivudine as a triple NRTI regimen
TenoIovir ¹ didanosine ¹ lamivudine as a triple NRTI regimen
Saquinavir as the sole PI in a PI-based regimen
Zidovudine ¹ stavudine
Didanosine ¹ stavudine
Lamivudine ¹ emtricitabine
Atazanavir ¹ indinavir
2-NNRTI combination
Monitoring
BeIore initiating drug therapy. must obtain CD4
¹
cell count and plasma HIV
RNA levels plus complete blood count. chemistry. lipid proIile. liver
enzymes. and genotypic resistance testing
II HIV RNA does not reach undetectable levels (· 50 copies/mL) by 16-24
weeks. perIorm resistance testing. compliance assessment. and consider a
regimen change
NNRTI. nonnucleoside reverse transcriptase inhibitor; NRTI. nucleoside
reverse transcriptase inhibitor; PI. protease inhibitor.
a
Cannot be used in the Iirst trimester oI pregnancy or in women who wish to
conceive or are not using eIIective contraception.

b
Should not be initiated in women with pre-nevirapine CD4
¹
cell counts ~
250/mm
3
or men with pre-nevirapine CD4
¹
cell counts ~ 400/mm
3
owing to
high incidence oI hepatic adverse eIIects.

P. 968


( 4) Si gni f i cant i nteracti ons. Al cohol i ncr eases abacavi r ' s AUC by 41%.
b. Di danosi ne ( ddI ; Vi dex) , a synt het i c pur i ne anal og, i nhi bi t s HÌ V
r epl i cat i on and has a l onger i nt racel l ul ar hal f -l i f e ( > 20 hr ) t han zi dovudi ne
( 7 hr ).
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. Di danosi ne i s approved f or
t he t r eat ment of adul t s and chi l dren onl y i n combi nat i on wi t h ot her
ant i r et rovi r al agent s.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Di danosi ne can cause r eversi bl e peri pher al neur opat hy and acut e,
pot ent i al l y l et hal pancr eat i t i s ( bI ack box warni ng) . Serum t r i gl ycer i des
shoul d be moni t ored, and di danosi ne shoul d be wi t hhel d when i ni t i at i ng
pot ent i al pancreat i t i s- i nduci ng agent s ( e. g. , Ì V pent ami di ne, sul f onami des) .
Tr ansi ent l y el evat ed serum amyl ase may not r ef l ect pancreat i t i s.
( b) Ot her adver se ef f ect s i ncl ude headaches, di ar r hea, nausea, and
hyper uri cemi a (because di danosi ne i s cat al yzed t o uri c aci d) .
( c) Di danosi ne i s avai l abl e i n an ent eri c coat ed capsul e or buf f ered or al
t abl et f ormul at i on t o pr event degr adat i on at aci di c pH. Ì t must be t aken on
an empt y st omach.
( d) Do not use i n combi nat i on wi t h st avudi ne or zal ci t abi ne because of
addi t i ve pot ent i al f or t oxi ci t y.
( e) Do not use t he combi nat i on regi men of di danosi ne and t enof ovi r i n
t r eat ment naï ve pat i ent s, owi ng t o hi gh rat es of ear l y vi r ol ogi c f ai l ure.
( 4) Si gni f i cant i nteracti ons. Pancr eat i t i s- i nduci ng drugs, aI cohoI , and
t hose known t o cause peri pheraI neuropat hy shoul d not be used wi t h
di danosi ne. Ri bavi r i n shoul d not be co- admi ni st er ed wi t h di danosi ne.
c. Emt ri ci tabi ne ( FTC; Emt ri va) i s a synt het i c nucl eosi de anal og
st r uct ur al l y r el at ed t o l ami vudi ne wi t h act i vi t y agai nst HÌ V i nf ect i on.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. Emt r i ci t abi ne i s i ndi cat ed
f or use i n HÌ V- i nf ect ed adul t s and chi l dr en i n combi nat i on wi t h ot her
ant i r et rovi r al agent s. Ì t i s avai l abl e by i t sel f or as a combi nat i on t abl et wi t h
t enof ovi r ( Tr uvada) and as a combi nat i on t abl et wi t h t enof ovi r and ef avi renz
( At r i pl a) . Al t hough i t demonst rat es act i vi t y agai nst hepat i t i s B vi r us, i t i s
not approved f or use i n t r eat ment of t hi s i nf ect i on.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Adverse ef f ect s most commonl y obser ved i n cl i ni cal t r i al s wer e mi l d-
moder at e and i ncl ude headache, r ash, di ar rhea, and nausea.
Hyper pi gment at i on of t he pal ms or sol es may occur .
( b) Seri ous acut e exacerbat i ons of hepat i t i s B have been document ed i n
HÌ V/ hepat i t i s B co-i nf ect ed pat i ent s who di scont i nued t her apy wi t h
emt ri ci t abi ne ( bI ack box warni ng); t her ef or e, l i ver f unct i on t est s shoul d be
moni t ored f or several mont hs af t er di scont i nuat i on.
( 4) Si gni f i cant i nteracti ons. None have been i dent i f i ed.
d. Lami vudi ne (3TC; Epi vi r) i s a synt het i c nucl eosi de anal og wi t h act i vi t y
agai nst HÌ V and hepat i t i s B vi rus.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. Lami vudi ne i s i ndi cat ed f or
use i n HÌ V- posi t i ve adul t s and chi l dren > 3 mont hs of age i n combi nat i on
wi t h ot her ant i ret r ovi r al agent s. Ì t i s al so used i n a l ower dosage f or t he
t r eat ment of chr oni c hepat i t i s B i n pat i ent s wi t h act i ve l i ver i nf l ammat i on
and evi dence of hepat i t i s B vi ral repl i cat i on.
( a) Lami vudi ne i s avai l abl e al one or wi t hi n a t wi ce dai l y combi nat i on t abl et
cont ai ni ng l ami vudi ne, zi dovudi ne and abacavi r (Tr i zi vi r ) .
( b) Lami vudi ne i s al so avai l abl e as a combi nat i on t abl et wi t h abacavi r
( Epzi com) and zi dovudi ne ( Combi vi r) .
P. 969


( 3) Precaut i ons and moni t ori ng ef fects
( a) Repor t ed adverse react i ons ar e mi nor and i ncl ude headache, f at i gue,
and GÌ r eact i ons such as nausea, vomi t i ng, and di ar r hea. CNS t oxi ci t y
i ncl udes neur opat hy, di zzi ness, and i nsomni a. Lab t est abnor mal i t i es such
as neut r openi a and el evat i ons i n l i ver enzymes have al so been repor t ed.
( b) Do not use i n combi nat i on wi t h zal ci t abi ne owi ng t o ant agoni sm of
ef f ect s.
( c) Lami vudi ne has t he same bI ack box warni ng r egardi ng acut e
exacer bat i ons of hepat i t i s B as emt r i ci t abi ne ( see VÌ Ì . C. 3. c).
( 4) Si gni f i cant i nteracti ons. Co- admi ni st rat i on wi t h cot ri moxazoI e resul t s
i n i ncr eased l ami vudi ne l evel s. No dose adj ust ment i s requi r ed.
e. St avudi ne ( d4T; Zeri t) i s a synt het i c t hymi di ne nucl eosi de anal og t hat i s
act i ve agai nst HÌ V.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. St avudi ne i s i ndi cat ed f or
use i n combi nat i on wi t h ot her ant i ret r ovi ral agent s i n adul t s and chi l dr en of
al l ages.
( 3) Precaut i ons and moni t ori ng ef fects
( a) The maj or t oxi ci t y wi t h st avudi ne i s a dose rel at ed but r eversi bl e
per i pheral neur opat hy occur ri ng i n up t o 21% of pat i ent s.
( b) Ot her adver se ef f ect s i ncl ude headache, r ash, di ar rhea, nausea, and
vomi t i ng.
( c) Fat al epi sodes of pancr eat i t i s have been r epor t ed.
( 4) Si gni f i cant i nteracti ons. Do not use i n combi nat i on wi t h zi dovudi ne or
zal ci t abi ne.
f . Tenof ovi r di soproxi I f umarate ( TDF; Vi read) i s an acycl i c nucl eosi de
phosphonat e di est er anal og ( nucI eoti de) wi t h ant i vi r al act i vi t y agai nst HÌ V
and hepat i t i s B vi rus.
( 1) Mechani sm of act i on. Tenof ovi r (a prodr ug) i s rapi dl y hydr ol yzed by
pl asma est er ases t o t enof ovi r , wi t h subsequent conver si on t o t he act i ve
t enof ovi r di phosphat e. Not e: Nt RTÌ s are act i ve as t he di phosphat e, unl i ke
t he NRTÌ s, whi ch r equi re conver si on t o t he t r i phosphat e.
( 2) Spect rum of act i vi t y and therapeuti c uses. Tenof ovi r i s appr oved f or
use i n combi nat i on wi t h ot her ant i ret r ovi ral agent s f or t he t reat ment of HÌ V
i n adul t s. Ì t i s al so avai l abl e as a once dai l y combi nat i on t abl et cont ai ni ng
t enof ovi r and emt r i ci t abi ne ( Tr uvada) and t enof ovi r , emt r i ci t abi ne, and
ef avi r enz ( At ri pl a) .
( 3) Precaut i ons and moni t ori ng ef fects
( a) Mi nor adver se ef f ect s have been r epor t ed i n cl i ni cal t ri al s. These
i ncl ude compl ai nt s of di ar r hea, vomi t i ng, and nausea.
( b) Addi t i onal adverse ef f ect s obser ved duri ng post mar ket i ng sur vei l l ance
i ncl ude acut e renal f ai l ure and decreases i n bone mi ner al densi t y.
( c) Tenof ovi r has t he same bI ack box warni ng t hat emt r i ci t abi ne has f or
pat i ent s wi t h concomi t ant hepat i t i s B ( see VÌ Ì . C. 3. c) .
( d) Dose adj ust ment i s requi r ed f or r enal i nsuf f i ci ency.
( 4) Si gni f i cant i nteracti ons
( a) Tenof ovi r i ncr eases di danosi ne serum concent r at i ons, necessi t at i ng a
dose r educt i on of di danosi ne.
( b) Tenof ovi r decreases ser um concent rat i ons of at azanavi r. When t hese 2
agent s ar e used t oget her , r i t onavi r must be added t o t he r egi men.
g. ZaI ci tabi ne ( ddC; Hi vi d) i s a synt het i c pyr i mi di ne nucl eosi de anal ogue
t hat i s act i ve agai nst HÌ V.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. Zal ci t abi ne i s no l onger
r ecommended as a component of i ni t i al combi nat i on t her apy of HÌ V owi ng t o
i t s severe adver se ef f ect pr of i l e. The manuf act urer di scont i nued i t s
pr oduct i on i n 2006.
( 3) Precaut i ons and moni t ori ng ef fects
( a) The maj or cl i ni cal t oxi ci t y of zal ci t abi ne i s peri pher al neur opat hy, whi ch
occurs i n up t o 35% of pat i ent s and may be pot ent i al l y di sabl i ng.
( b) Ot her adver se ef f ect s i ncl ude pancr eat i t i s, st omat i t i s, car di omyopat hy,
and hypersensi t i vi t y react i ons.
( c) Do not use i n combi nat i on wi t h l ami vudi ne, st avudi ne, or zi dovudi ne.
( 4) Si gni f i cant i nteracti ons
( a) Dr ugs t hat have t he pot ent i al t o cause per i pher al neur opat hy shoul d be
avoi ded. These i ncl ude chI orampheni coI , ci spI at i n, dapsone, di danosi ne,
di suI fi ram, hydraI azi ne, i soni azi d, met roni dazoI e, ni t rofurant oi n,
phenyt oi n, ri bavi ri n, and vi ncri sti ne.
P. 970


( b) Zal ci t abi ne t r eat ment shoul d be i nt err upt ed when a drug wi t h t he
pot ent i al t o cause pancreat i t i s i s i ni t i at ed ( i . e. , pent ami di ne) .
( c) Do not t ake wi t h magnesi um- , cal ci um- , or al umi num-cont ai ni ng
ant aci ds.
( d) Ci met i di ne and probeneci d may i ncrease zal ci t abi ne l evel s, causi ng
i ncreased zal ci t abi ne t oxi ci t y.
h. Zi dovudi ne ( AZT; Ret rovi r) i s a synt het i c t hymi di ne anal og. Thi s agent
was t he f i rst avai l abl e drug f or t he t r eat ment of HÌ V i nf ect i on.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses
( a) Zi dovudi ne i s i ndi cat ed i n t he t r eat ment of adul t s and chi l dren > 6
weeks of age f or t he t r eat ment of HÌ V.
( b) Ì t i s i ndi cat ed f or t he pr event i on of mat er nal - f et al HÌ V t ransmi ssi on.
( c) Zi dovudi ne i s avai l abl e as or al capsul es, t abl et s, and sol ut i on as wel l as
an Ì V sol ut i on.
( d) Or al zi dovudi ne i s al so avai l abl e as a co- f ormul at i on wi t h l ami vudi ne
( Combi vi r ) and wi t h l ami vudi ne and abacavi r ( Tr i zi vi r ) .
( 3) Precaut i ons and moni t ori ng ef fects
( a) Zi dovudi ne can cause sever e bone mar r ow suppressi on, i ncl udi ng
macr ocyt i c anemi a and neut r openi a af t er t he f i rst f ew weeks t o mont hs of
t her apy. The ri sk i s i ncr eased i n pat i ent s wi t h pr eexi st i ng bone mar row
suppr essi on or who ar e t aki ng concomi t ant medi cat i ons t hat cause bone
mar row suppr essi on.
( b) Er yt hropoi et i n can be consi dered as an adj unct i ve t her apy i n pat i ent s
wi t h zi dovudi ne- i nduced anemi a, i n cases f or whi ch i t cannot be
di scont i nued.
( c) Ot her adver se ef f ect s i ncl ude headache, mal ai se, sei zur es, anxi et y,
f ever , and r ash.
( d) Pr ol onged use may l ead t o sympt omat i c myopat hy.
( 4) Si gni f i cant i nteracti ons
( a) Cot ri moxazoI e, at ovaquone, vaI proi c aci d, met hadone, and
probeneci d may i ncr ease zi dovudi ne concent r at i ons, causi ng i ncr eased
r i sk of zi dovudi ne t oxi ci t y.
( b) Ot her cyt ot oxi c drugs, such as ganci cI ovi r, dapsone, and i nt erferon-
o, can cause addi t i ve bone mar row suppressi on.
( c) Ri bavi r i n, ri f abut i n, and ri f ampi n may decrease l evel s of zi dovudi ne.
4. NonnucI eosi de reverse t ranscri pt ase i nhi bi tors. The NNRTÌ cl ass
bi nds di rect l y t o and produces a noncompet i t i ve i nhi bi t i on of t he HÌ V
r ever se t r anscr i pt ase, l eadi ng t o chai n t ermi nat i on. These agent s ar e
i ndi cat ed f or use i n adul t s and pedi at ri c pat i ent s i n combi nat i on wi t h ei t her
NRTÌ s or possi bl y PÌ s. Ef avi r enz i s consi der ed a pr ef er r ed NNRTÌ , wher eas
t he ot her s ar e cur r ent l y recommended as al t ernat i ves. NNRTÌ - based
r egi mens pr ovi de pot ent ant i vi r al act i vi t y wi t h l ess pi l l bur den t han many PÌ -
based regi mens. Al l NNRTÌ s may cause rash and hepat otoxi ci t y; pat i ent s
shoul d be moni t ored cl osel y f or t hese adverse ef f ect s.
a. DeI avi rdi ne ( Rescri pt or)
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. Del avi rdi ne i s approved
f or use i n adul t s i n t he t reat ment of HÌ V i n combi nat i on wi t h ot her
ant i r et rovi r al agent s. Ì t s use has f al l en out of f avor owi ng t o i t s t hree t i mes
dai l y dosi ng schedul e.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Ì n cl i ni cal t r i al s, 4. 3% of pat i ent s di scont i nued del avi r di ne because of
r ash. Cases of St evens-Johnson syndrome have been r epor t ed.
( b) Ot her adver se ef f ect s i ncl ude headache and nausea.
( 4) Si gni f i cant i nteracti ons
( a) The concent r at i ons of t he f ol l owi ng medi cat i ons ar e gr eat l y i ncreased by
del avi r di ne and must be avoi ded: aI prazoI am, mi dazoI am, t ri azoI am,
si mvastat i n, I ovastat i n, ri f abuti n, and ci sapri de.
( b) Decr eased del avi r di ne concent r at i ons resul t when i t i s admi ni st ered wi t h
St . John' s wort , carbamazepi ne, phenobarbi taI , phenyt oi n, or ri f ampi n.
Concomi t ant use shoul d be avoi ded.
( c) Because del avi rdi ne r equi r es an aci di c GÌ t ract f or opt i mal absor pt i on,
i t s use i s cont r ai ndi cat ed wi t h proton pump i nhi bi t ors and H2- receptor
ant agoni st s.
b. Ef avi renz ( Sust i va)
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
P. 971


( 2) Spect rum of act i vi t y and therapeuti c uses. Ef avi r enz i s appr oved f or
use i n combi nat i on wi t h ot her ant i ret r ovi ral agent s f or t he t reat ment of HÌ V
i nf ect i on i n adul t s and pedi at r i c pat i ent s ( < 3 year s of age) . Ì t s advant age
over ot her NNRTÌ s i s once- dai l y dosi ng. Ì t i s avai l abl e al one or as a
combi nat i on t abl et wi t h t enof ovi r and emt r i ci t abi ne ( At ri pl a) .
( 3) Precaut i ons and moni t ori ng ef fects
( a) Most common adver se ef f ect s ar e CNS- r el at ed ( 52%) , i ncl udi ng
i nsomni a, di zzi ness, drowsi ness, ni ght mares, and hal l uci nat i ons,
necessi t at i ng bedt i me dosi ng t o mi ni mi ze t hese ef f ect s. These ef f ect s
t ypi cal l y subsi de af t er 2-4 weeks of t r eat ment .
( b) Owi ng t o i t s t er at ogeni c ef f ect s, ef avi r enz shoul d be avoi ded i n t he f i rst
t r i mest er of pr egnancy and i n women of chi l dbear i ng pot ent i al who wi sh t o
concei ve.
( c) Ot her adver se ef f ect s i ncl ude r ash, i ncreased t r ansami nases, and GÌ
di st ur bances.
( 4) Si gni f i cant i nteracti ons
( a) Ef avi r enz i nduces and i nhi bi t s t he cyt ochr ome P450 3A4 i soenzyme
syst em. Ì t shoul d not be used concomi t ant l y wi t h ci sapri de, mi dazoI am,
t ri azoI am, or ergot deri vat i ves.
( b) St . John' s wort decreases ef avi r enz concent r at i ons and shoul d be
avoi ded.
( c) Ef avi r enz decr eases met hadone concent r at i ons by 60%; pat i ent s shoul d
be moni t ored f or opi at e wi t hdr awal and have t hei r doses t i t r at ed
accor di ngl y.
c. Et ravi ri ne ( I nt eI ence)
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. Et r avi r i ne i s i ndi cat ed f or
use i n combi nat i on wi t h at l east t wo addi t i onal ant i ret r ovi ral agent s i n
t r eat ment - exper i enced adul t s who demonst r at e vi r al repl i cat i on and
document ed resi st ance t o ot her NNRTÌ s. Ì t i s not f or use i n t reat ment - naï ve
pat i ent s.
( 3) Precaut i ons and moni t ori ng ef fects.
( a) Adverse ef f ect s i ncl ude nausea and r ash.
( b) Si nce f ood i ncr eases t he absorpt i on of et r avi ri ne by 50%, i t shoul d be
t aken f ol l owi ng a meal .
( 4) Si gni f i cant i nteracti ons.
( a) Et ravi r i ne i nduces and i nhi bi t s a var i et y of cyt ochrome P450
i soenzymes. Ì t shoul d not be used concomi t ant l y wi t h carbamazepi ne,
phenobarbi t aI , phenyt oi n, unboost ed PI s, atazanavi r/ ri t onavi r,
f osamprenavi r/ ri t onavi r, t i pranavi r/ ri t onavi r, or ot her NNRTI s.
( b) St . John' s wort and ri f ampi n decrease et r avi r i ne concent rat i ons and
shoul d be avoi ded.
( c) Et ravi r i ne may decrease ser um concent r at i ons of met hadone; pat i ent s
shoul d be moni t ored cl osel y.
d. Nevi rapi ne ( Vi ramune) was t he f i r st NNRTÌ appr oved f or use by t he FDA
f or t he t r eat ment of HÌ V i nf ect i on.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect rum of act i vi t y and therapeuti c uses. Nevi r api ne i s i ndi cat ed i n
combi nat i on wi t h ot her ant i ret r ovi ral s i n adul t and pedi at r i c ( < 2 mont hs ol d)
HÌ V pat i ent s.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Nevi rapi ne has t he hi ghest i nci dence of St evens-Johnson syndrome of
al l NNRTÌ s.
( b) Sympt omat i c hepat i t i s, i ncl udi ng f at al hepat i c necr osi s, has been
obser ved wi t h nevi rapi ne ( bI ack box warni ng) . The f requency of t hi s
adver se ef f ect i s i ncr eased i n women wi t h pr e- nevi r api ne CD4
+
count s >
250 ceI I s/ mm
3
and men wi t h CD4
+
counts > 400 ceI I s/ mm
3
. Nevi rapi ne
shouI d not be i ni t i ated i n t hese pat i ents.
( c) Ot her adver se ef f ect s i ncl ude f ever , nausea, and headache.
( d) To decr ease t he f r equency of adverse ef f ect s, a 2- week dose escal at i on
i s requi r ed.
( 4) Si gni f i cant i nteracti ons
( a) Nevi rapi ne i nduces cyt ochrome P450 3A4, r esul t i ng i n decreased
concent r at i ons of caspof ungi n, ket oconazoI e, i traconazoI e, oraI
cont racepti ves, and prot ease i nhi bi tors.
P. 972


( b) Use of ri f ampi n and St . John' s wort shoul d be avoi ded, as t hey
decrease t he ser um concent r at i ons of nevi r api ne.
( c) Met hadone concent rat i ons decr ease si gni f i cant l y wi t h nevi r api ne, of t en
necessi t at i ng a dose i ncrease.
5. Protease i nhi bi t ors. The PÌ s compet i t i vel y i nhi bi t t he vi ral pr ot ease
enzyme, pr event i ng t he enzyme f rom cl eavi ng t he gag and gag- pol
pol yprot ei ns necessar y f or vi r i on pr oduct i on. PÌ s ar e used i n combi nat i on
wi t h ot her ant i ret r ovi r al agent s, i ncl udi ng ot her PÌ s, t o suppr ess HÌ V
r epl i cat i on. Al l of t he PÌ s ar e cyt ochrome P450 i nhi bi t ors; ri t onavi r i s t he
most pot ent i nhi bi t or. Al l PÌ s ar e cont r ai ndi cat ed wi t h numer ous dr ugs,
i ncl udi ng si mvastat i n, I ovast at i n, ri fampi n, ci sapri de, pi mozi de,
mi dazoI am, t ri azoI am, ergot s, and St. John' s wort . Concomi t ant t her apy
wi t h ant i epi l ept i c dr ugs, er ect i l e dysf unct i on drugs, and azol e ant i f ungal s
must be under t aken wi t h caut i on. Owi ng t o t he wi de arr ay of dr ug
i nt er act i ons wi t h PÌ s, al ways assess medi cat i on pr of i l es caref ul l y f or drug
i nt er act i ons bef ore i ni t i at i on.
a. Amprenavi r ( Agenerase)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect rum of act i vi t y and therapeuti c uses. Ampr enavi r i s no l onger
r ecommended f or use i n t r eat ment regi mens f or HÌ V due t o i t s
di scont i nuat i on i n l at e 2007.
( 3) Precaut i ons and moni t ori ng ef fects.
( a) Use of t he oral sol ut i on i n pregnant women, chi l dr en < 4 years ol d, and
pat i ent s wi t h hepat i c or renal i nsuf f i ci ency i s cont r ai ndi cat ed owi ng t o t he
pr opyl ene gl ycol vehi cl e ( bI ack box warni ng).
( b) Because ampr enavi r i s a sul f onami de, t he pot ent i al f or cr oss- sensi t i vi t y
t o ot her sul f onami des exi st s.
( c) Adverse ef f ect s i ncl ude hyper l i pi demi a, hypergl ycemi a, f at
mal di st ri but i on, rash, and GÌ di st ur bances.
( d) Dosage adj ust ment i s r equi r ed f or hepat i c i nsuf f i ci ency.
( 4) Si gni f i cant i nteracti ons (see VÌ Ì . C. 5) . Amprenavi r decr eases
met hadone concent r at i ons, possi bl y r equi ri ng a met hadone dose i ncr ease
t o prevent wi t hdr awal .
b. At azanavi r ( Reyat az)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect rum of act i vi t y and therapeuti c uses. At azanavi r i s a component
of pref err ed and al t ernat i ve PÌ - based regi mens f or HÌ V. Ì t i s dosed once
dai l y.
( 3) Precaut i ons and moni t ori ng ef fects.
( a) At azanavi r may pr ol ong t he PR i nt er val and possi bl y cause f i r st - degr ee
AV bl ock. El ect r ocardi ogr am ( ECG) shoul d be moni t or ed.
( b) Ot her adver se ef f ect s i ncl ude f at mal di st ri but i on, hypergl ycemi a, and
i ndi r ect hyper bi l i r ubi nemi a. Ì n cont r ast t o t he ot her PÌ s, at azanavi r appear s
t o be devoi d of ef f ect s on l i pi ds.
( c) Dose adj ust ment i s requi r ed f or hepat i c i nsuf f i ci ency.
( 4) Si gni f i cant i nteracti ons (see VÌ Ì . C. 5) . At azanavi r i s t he most
pr obl emat i c of al l PÌ s i n t er ms of drug i nt er act i ons.
( a) Ì f used i n combi nat i on wi t h efavi renz or t enof ovi r, l ow- dose ri t onavi r
must be admi ni st er ed concomi t ant l y.
( b) Because at azanavi r requi r es an aci di c GÌ t ract f or opt i mal absorpt i on,
concomi t ant use of proton pump i nhi bi t ors i s cont r ai ndi cat ed. Ì f ot her aci d
suppr essant s ar e used wi t h at azanavi r , t he doses must be separ at ed by as
much t i me as possi bl e ( up t o 12 hr apart ) .
c. Darunavi r ( Prezi sta)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5
( 2) Spect rum of act i vi t y and therapeuti c uses. Dar unavi r i s t he newest PÌ
t o r ecei ve FDA appr oval f or t he t r eat ment of HÌ V. Ì t s use i s l i mi t ed t o hi ghl y
t r eat ment - exper i enced pat i ent s or pat i ent s wi t h HÌ V r esi st ance mut at i ons.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Darunavi r must be co- admi ni st er ed wi t h ri t onavi r
( b) Because darunavi r cont ai ns a sul f onami de moi et y, cross- r eact i vi t y may
occur i n sul f a-al l er gi c pat i ent s.
( c) Adverse ef f ect s i ncl ude nausea, i ncreased amyl ase, hepat ot oxi ci t y,
hyper l i pi demi a, hyper gl ycemi a, and rash.
( 4) Si gni f i cant i nteracti ons. See VÌ Ì . C. 5.
d. Fosamprenavi r ( Lexi va)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5. Fosamprenavi r i s t he prodrug of
amprenavi r .
P. 973


( 2) Spect rum of act i vi t y and therapeuti c uses. Fosampr enavi r has l ar gel y
r epl aced ampr enavi r because of i t s i mpr oved dosi ng conveni ence. Ì t i s
r ecommended as one of t he pr ef er r ed component s i n PÌ -based r egi mens f or
i ni t i al t reat ment of HÌ V.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Fosamprenavi r may be dosed once dai l y i n t r eat ment naï ve pat i ent s. PÌ -
exper i enced pat i ent s r equi r e t wi ce dai l y dosi ng. Ì n most cases,
f osampr enavi r i s admi ni st er ed wi t h l ow dose r i t onavi r .
( b) Adverse ef f ect s ar e t he same as t hose wi t h ampr enavi r ( see
VÌ Ì . C. 5. a. (3) . b, c and d).
( 4) Si gni f i cant i nteracti ons (see VÌ Ì . C. 3) . Ì f used i n combi nat i on wi t h
ef avi renz, f osampr enavi r must be admi ni st ered wi t h a boost er dose of
r i t onavi r .
e. I ndi navi r ( Cri xi van)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect rum of act i vi t y and therapeuti c uses. Ì ndi navi r , i n combi nat i on
wi t h r i t onavi r , i s no l onger r ecommended as part of r egi men f or pat i ent s
r ecei vi ng i ni t i al t r eat ment f or HÌ V due t o a hi gh i nci dence of nephr ol i t hi asi s.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Because i ndi navi r may cause nephroI i thi asi s ( ki dney st ones) , pat i ent s
shoul d be i nst ruct ed t o dr i nk at l east 1. 5 L of wat er dai l y t o prevent t hi s
adver se ef f ect .
( b) Ì ndi navi r can cause i ndi rect hyperbi I i rubi nemi a. Combi nat i on t her apy
wi t h at azanavi r i s not r ecommended owi ng t o t he pot ent i al f or addi t i ve
ef f ect s.
( c) Ot her adver se ef f ect s i ncl ude hyper gl ycemi a, hyper l i pi demi a, f at
mal di st ri but i on, headache, and GÌ i nt ol er ance.
( d) Dose adj ust ment i s requi r ed f or hepat i c i nsuf f i ci ency.
( 4) Si gni f i cant i nteracti ons (see VÌ Ì . C. 5) . Vi t ami n C i n doses > 1 g dai l y
decreases i ndi navi r concent r at i ons. Caut i on pat i ent s not t o exceed t he
r ecommended dai l y al l owance f or vi t ami n C.
f . Lopi navi r/ ri tonavi r ( KaI et ra)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect rum of act i vi t y and therapeuti c uses. Thi s product i s avai l abl e
as a co- f or mul at i on of l opi navi r wi t h a " boost er ¨ dose of r i t onavi r , whi ch
i nhi bi t s l opi navi r met abol i sm and r esul t s i n hi gher serum concent r at i ons.
Lopi navi r/ r i t onavi r i s a pr ef er red PÌ used i n i ni t i al PÌ - based r egi mens owi ng
t o i t s pot ency and conveni ent dosi ng.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Lopi navi r / r i t onavi r was recent l y r ef or mul at ed as a f i l m- coat ed t abl et t hat
does not requi r e r ef ri gerat i on. Ì t i s al so avai l abl e as an or al sol ut i on
cont ai ni ng 42% al cohol .
( b) Adverse ef f ect s i ncl ude GÌ i nt ol er ance, hyperl i pi demi a, hyper gl ycemi a,
f at mal di st ri but i on, and pancreat i t i s.
( 4) Si gni f i cant i nteracti ons. See VÌ Ì . C. 5.
( a) Lopi navi r / r i t onavi r decr eases met hadone concent r at i ons, possi bl y
necessi t at i ng a met hadone dose i ncrease t o pr event opi at e wi t hdr awal .
( b) Concomi t ant admi ni st r at i on wi t h vori conazoI e i s cont r ai ndi cat ed
because of t he ri sk of decr eased vor i conazol e ef f i cacy.
( c) Dosi ng vari es due t o dr ug i nt er act i ons wi t h concomi t ant use of
ef avi r enz, nevi r api ne, f osampr enavi r , or nel f i navi r . Be sure t o check
appropr i at e r ef er ences f or proper dosi ng.
g. NeI fi navi r ( Vi racept )
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect rum of act i vi t y and therapeuti c uses. Nel f i navi r i s a possi bl e
component of an al t ernat i ve PÌ - based regi men f or i ni t i al t reat ment of adul t s
wi t h HÌ V i nf ect i on. Unl i ke t he ot her PÌ s, i t i s never used i n combi nat i on wi t h
r i t onavi r . Ì t i s not general l y r ecommended due t o i nf er i or vi r ol ogi c ef f i cacy.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Di ar r hea i s commonl y r epor t ed wi t h nel f i navi r. Thi s can of t en be
managed wi t h ant i di ar r heal s.
( b) Ot her adver se ef f ect s are si mi l ar t o t hose wi t h l opi navi r / ri t onavi r .
( c) Use caut i on wi t h l ook- al i ke, sound- al i ke names ( nel f i navi r and
nevi r api ne) .
( 4) Si gni f i cant i nteracti ons (see VÌ Ì . C. 5. ) Nel f i navi r decreases met hadone
concent r at i ons, necessi t at i ng i ncreased moni t ori ng and dose adj ust ment i f
i ndi cat ed.
h. Ri t onavi r ( Norvi r)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
P. 974


( 2) Spect rum of act i vi t y and therapeuti c uses. Ri t onavi r i s rar el y used as
t he sol e PÌ i n a PÌ - based r egi men owi ng t o i t s poor t ol erabi l i t y and hi gh pi l l
bur den when admi ni st ered i n f ul l doses. Al t er nat i vel y, i t i s used i n l ow
doses as a phar macoki net i c boost i ng agent wi t h ot her PÌ s. Because i t i s
such a pot ent cyt ochr ome 450 enzyme i nhi bi t or , ri t onavi r markedl y
i ncreases t he serum concent r at i ons of ot her PÌ s, r esul t i ng i n hi gher
concent r at i ons wi t h i mproved vi r al suppr essi on.
( 3) Precaut i ons and moni t ori ng ef fects
( a) Capsul es shoul d be ref r i ger at ed bef or e di spensi ng. Capsul es t hen may
be st ored at room t emper at ure f or up t o 30 days.
( b) Or al sol ut i on shoul d not be r ef r i ger at ed.
( c) Adverse ef f ect s i ncl ude GÌ i nt ol er ance, ci r cumor al par est hesi as,
hyper l i pi demi a, hyper gl ycemi a, f at mal di st r i but i on, i ncreased l i ver f unct i on
t est s, and t ast e per ver si on.
( 4) Si gni f i cant i nteracti ons (see VÌ Ì . C. 5) . Many dr ug i nt er act i ons occur
wi t h r i t onavi r because i t i s such a pot ent i nhi bi t or of so many cyt ochrome
P450 i soenzymes. Al ways r ef er t o pr oper resources t o assess f or dr ug
i nt er act i ons.
i . Saqui navi r ( I nvi rase)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect rum of act i vi t y and therapeuti c uses. Use of saqui navi r wi t hout
boost er doses of ri t onavi r i s not r ecommended because of t he poor
bi oavai l abi l i t y of saqui navi r .
( 3) Precaut i ons and moni t ori ng ef fects
( a) Saqui navi r i s avai l abl e as a hard gel capsul e and t abl et ( Ì nvi rase) and
was pr evi ousl y avai l abl e as a sof t gel capsul e ( For t ovase) . The var i ous
dosage f orms are not bi oequi vaI ent and cannot be used i nt erchangeabl y.
( b) The sof t gel capsul e f or mul at i on i s no l onger manuf act ur ed ( ef f ect i ve
Febr uar y 2006).
( c) Adverse ef f ect s ar e si mi l ar t o l opi navi r / ri t onavi r .
( 4) Si gni f i cant i nteracti ons. See VÌ Ì . C. 5.
j . Ti pranavi r ( Apt i vus)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect rum of act i vi t y and therapeuti c uses. The use of t i pr anavi r i s
l i mi t ed t o hi ghl y t r eat ment - exper i enced pat i ent s wi t h HÌ V who ar e r esi st ant
t o ot her PÌ s as wel l as t o ot her cl asses of ant i r et rovi r al s.
( 3) Precaut i ons and moni t ori ng ef fects.
( a) Owi ng t o t he poor bi oavai l abi l i t y of t i pranavi r, i t must be co-
admi ni st er ed wi t h ri t onavi r .
( b) Capsul es must be r ef r i gerat ed. Once di spensed, t hey ar e st abl e at r oom
t emper at ure f or up t o 60 days.
( c) Ti pr anavi r has been associ at ed wi t h cl i ni cal hepat i t i s and f at al hepat i c
decompensat i on ( bI ack box warni ng). Li ver f unct i on t est s shoul d be
moni t ored cl osel y, especi al l y i n pat i ent s wi t h under l yi ng l i ver di sease.
( d) Rar el y, t her e have been repor t s of f at al and nonf at al i nt r acrani al
hemor r hage wi t h t i pr anavi r ( bI ack box warni ng) .
( e) Because t he st r uct ure of t i pr anavi r cont ai ns a suI f onami de moi et y,
cr oss- react i vi t y may occur i n sul f a- al l er gi c pat i ent s.
( f ) Ot her adverse ef f ect s i ncl ude rash, hyperl i pi demi a, hyper gl ycemi a, and
f at mal di st ri but i on.
( 4) Si gni f i cant i nteracti ons (see VÌ Ì . C. 5) . Loperami de may decr ease
t i pranavi r concent r at i ons.
6. Fusi on i nhi bi tors. Enf uvi rt i de ( T- 20; Fuzeon) i s t he f i rst and onl y
member of t hi s cl ass of ant i r et rovi r al s.
a. Mechani sm of act i on. Enf uvi r t i de i nhi bi t s t he ent r y of HÌ V i nt o CD4
+

ceI I s by i nt erf eri ng wi th t he f usi on of vi raI and ceI I uI ar membranes.
b. Spect rum of act i vi t y and therapeut i c uses. Enf uvi r t i de i s pr i mar i l y
used i n hi ghl y t r eat ment -exper i enced pat i ent s wi t h ext ensi ve vi r al
r esi st ance. Ì t i s not r ecommended f or use as i ni t i al t her apy i n t r eat ment -
nai ve pat i ent s, as i t has not been st udi ed i n t hi s popul at i on.
c. Precauti ons and moni t ori ng ef f ect s
( 1) Enf uvi r t i de i s i nj ect ed subcut aneousl y t wi ce dai l y. Local i nj ect i on si t e
r eact i ons occur i n al most al l pat i ent s, i ncl udi ng pai n, r edness, prur i t us, and
nodul es.
P. 975


( 2) Ot her adver se ef f ect s i ncl ude hyper sensi t i vi t y r eact i ons and i ncreased
r at e of bact eri al pneumoni a.
( 3) No dose adj ust ment i s necessar y f or r enal i mpai rment .
d. Si gni f i cant i nteract i ons. There ar e no si gni f i cant drug i nt er act i ons wi t h
enf uvi rt i de.
7. Ent r y i nhi bi t or. Maravi roc ( SeI zent r y) i s t he f i r st and onl y member of
t hi s cl ass of ant i r et r ovi ral t her apy.
a. Mechani sm of act i on. Mar avi r oc i s a chemoki ne r ecept or 5 ( CCR5)
cor ecept or ant agoni st . Ì t bi nds t o t he CCR5 recept or on t he CD4 cel l
membr ane, pr event i ng ent r y of t he vi r us i nt o t he cel l .
b. Spect rum of act i vi t y and therapeut i c uses. Mar avi r oc i s used al ong
wi t h ot her ant i ret r ovi r al s onl y i n hi ghl y t reat ment -exper i enced adul t pat i ent s
who ar e i nf ect ed wi t h HÌ V t hat bi nds t o t he CCR5 r ecept or .
c. Precauti ons and moni t ori ng ef f ect s.
( 1) Hepat ot oxi ci t y was obser ved duri ng cl i ni cal t r i al s wi t h mar avi r oc (bI ack
box warni ng). Thi s may be preceded by a syst emi c al l er gi c r eact i on.
Pat i ent s shoul d be eval uat ed i mmedi at el y i f ei t her occurs.
( 2) Use caut i on i n pat i ent s wi t h l i ver di sease or car di ovascul ar ri sk f act ors.
( 3) Adverse ef f ect s i ncl ude cough, r ash, f ever , muscul oskel et al sympt oms,
di zzi ness, and abdomi nal pai n.
( 4) Not r ecommended f or use i n pat i ent s wi t h renal i nsuf f i ci ency unl ess no
al t er nat i ve opt i on i s avai l abl e.
d. Si gni f i cant i nteract i ons.
( 1) Dosi ng f or mar avi r oc var i es dependi ng upon concomi t ant medi cat i ons
t hat i nt er act :
( a) When used wi t h cyt ochr ome P450 i nhi bi t ors, such as PI s (except
t i pranavi r/ ri t onavi r) , deI avi rdi ne, ket oconazoI e, i t raconazoI e, and
cI ari t hromyci n, admi ni st er mar avi r oc 150 mg t wi ce dai l y.
( b) When used wi t h cyt ochr ome P450 i nducer s ( such as carbamazepi ne,
phenobarbi t aI , phenyt oi n, efavi renz, and ri fampi n) wi t hout a st r ong
cyt ochr ome P450 i nhi bi t or , admi ni st er mar avi r oc 600 mg t wi ce dai l y.
( c) When used wi t h ot her medi cat i ons, i ncl udi ng t i pranavi r/ r i t onavi r ,
nevi r api ne, NRTÌ s, and enf uvi r t i de, admi ni st er mar avi r oc 300 mg t wi ce
dai l y.
( 2) Concomi t ant admi ni st r at i on wi t h St . John' s wort i s not r ecommended
due t o reduct i on i n mar avi r oc serum concent r at i ons.
8. I ntegrase i nhi bi t or. RaI t egravi r ( I sent ress) i s t he f i rst and onl y member
of t hi s cl ass of ant i r et r ovi r al t her apy.
a. Mechani sm of act i on. Ral t egravi r i nhi bi t s t he vi r al enzyme i nt egr ase,
t her eby pr event i ng t he i nsert i on of HÌ V genet i c mat er i al i nt o t he CD4 cel l
genome and hal t i ng t he vi r al repl i cat i on pr ocess.
b. Spect rum of act i vi t y and therapeut i c uses. Ral t egr avi r i s used al ong
wi t h ot her ant i ret r ovi r al s onl y i n t r eat ment -exper i enced adul t pat i ent s who
demonst r at e resi st ant st rai ns of HÌ V.
c. Precauti ons and moni t ori ng ef f ect s.
( 1) Si nce el evat i ons i n cr eat i ne ki nase, al ong wi t h myopat hy and
r habdomyol ysi s, may occur wi t h r al t egravi r , use wi t h caut i on i n pat i ent s
who ar e r ecei vi ng concomi t ant medi cat i ons t hat may cause t hese adverse
ef f ect s.
( 2) The most common adver se ef f ect s i ncl ude nausea, di arr hea, headache,
and f ever .
d. Si gni f i cant i nteract i ons. Ri f ampi n decr eases t he ser um concent rat i on
of r al t egr avi r and shoul d be used wi t h caut i on.
VIII. AntheImintics
A. Def i ni t i on. These dr ugs ar e used t o ri d t he body of wor ms ( heI mi nt hs).
These agent s may act l ocal l y t o r i d t he GÌ t ract of wor ms or wor k
syst emi cal l y t o eradi cat e wor ms t hat ar e i nvadi ng or gans or t i ssues.
B. MebendazoI e ( Vermox) i s a synt het i c benzi mi dazol e- deri vat i ve
ant hel mi nt i c.
1. Mechani sm of act i on. Mebendazol e i nt er f er es wi t h r eproduct i on and
sur vi val of hel mi nt hs by i nhi bi t i ng t he f or mat i on of mi crot ubul es and
i r r eversi bl y bl ocki ng gl ucose upt ake, t hereby depl et i ng gl ycogen st or es i n
t he hel mi nt h.
2. Spect rum of acti vi t y. Mebendazol e i s act i ve agai nst var i ous nemat odes
t hat ar e pat hogeni c t o humans, i ncl udi ng Ancyl ost oma duodenal e (common
hookwor m) , Ascar i s l umbr i coi des
P. 976

( r oundwor m) , Capi l l ar i a phi l i ppi nensi s ( Phi l i ppi ne t hreadwor m) , Ent erobi us
ver mi cul ar i s (pi nwor m) , Necat or amer i canus ( Amer i can hookwor m) , and
Tr i churi s t r i chi ur a ( whi pwor m) .
3. Therapeut i c uses. Mebendazol e i s used f or t he t reat ment of si ngl e or
mi xed i nf ect i ons wi t h t he hel mi nt hs l i st ed i n VÌ Ì Ì . B. 2. Ì mmobi l i zat i on and
subsequent deat h of hel mi nt hs are sl ow, wi t h compl et e GÌ cl ear ance up t o 3
days af t er t her apy.
4. Precauti ons and moni t ori ng ef f ect s
a. Ì n cases of massi ve i nf ect i on, abdomi nal pai n, nausea, and di ar r hea
associ at ed wi t h expul si on of or gani sms may resul t .
b. Myel osuppr essi on ( neut r openi a and t hrombocyt openi a) can occur wi t h
hi gh doses (40-50 mg/ kg/ day) .
c. Ì f t he pat i ent i s not cur ed i n 3 weeks, ret r eat ment i s necessar y.
5. Si gni f i cant i nteracti ons. Agent s t hat may r educe t he ser um
concent r at i ons and subsequent ef f i cacy of mebendazol e i ncl ude
car bamazepi ne and phenyt oi n.
C. AI bendazoI e ( AI benza) i s a synt het i c benzi mi dazol e- deri vat i ve
ant hel mi nt i c.
1. Mechani sm of act i on. See VÌ Ì Ì . B. 1.
2. Spect rum of acti vi t y. Al bendazol e i s act i ve agai nst Taeni a sol i um ( por k
t apewor m) and Echi nococcus gr anul osus ( dog t apewor m) .
3. Therapeut i c uses. Al bendazol e i s used t o t reat par enchymal
neurocyst i cercosi s i n combi nat i on wi t h cor t i cost er oi ds as wel l as cyst i c
hydat i d di sease (bef or e and af t er sur gi cal removal of t he di sease).
4. Precauti ons and moni t ori ng ef f ect s
a. The dr ug shoul d be admi ni st ered wi t h a f at t y meal t o achi eve opt i mal
absor pt i on.
b. Hepat ot oxi ci t y occurs i n 16% of pat i ent s; l i ver f unct i on t est s ever y 2
weeks ar e recommended whi l e t aki ng al bendazol e.
c. Rarel y, l eukopeni a, t hr ombocyt openi a, granul ocyt openi a, pancyt openi a,
and agranul ocyt osi s occur . A CBC shoul d be checked ever y 2 weeks whi l e
t aki ng al bendazol e.
D. Di et hyI carbamazi ne ci t rat e ( Het razan)
1. Mechani sm of act i on. Di et hyl car bamazi ne ci t rat e i s a synt het i c or gani c
compound hi ghl y speci f i c f or sever al common par asi t es.
2. Spect rum of acti vi t y. Thi s agent i s act i ve agai nst Wucher eri a bancrof t i ,
Onchocerca vol vul us, Brugi a mal ayi , Mansonel l a per st ans, Mansonel l a
ozzar di , Ascar i s l umbr i coi des, and Loa l oa.
3. Therapeut i c uses. Di et hyl car bamazi ne ci t r at e i s used f or t he t r eat ment
of Bancrof t ' s f i l ari asi s, onchocer ci asi s, ascari asi s, and l oi asi s. Ì t i s
avai l abl e di r ect l y f r om t he manuf act urer f or compassi onat e use onl y.
4. Precauti ons and moni t ori ng ef f ect s
a. Pat i ent s t r eat ed f or W. bancrof t i i nf ect i on of t en pr esent wi t h headache
and gener al mal ai se. Sever e al l ergi c phenomena i n conj unct i on wi t h a ski n
r ash have been repor t ed.
b. Pat i ent s t r eat ed f or onchocer ci asi s present wi t h prur i t us, f aci al edema,
and syst emi c sympt oms secondar y t o t he i nf l ammat or y r esponse caused by
pat hogen deat h (known as a Mazzot ti react i on) . Sever e react i ons may be
not ed af t er a si ngl e dose. For t hi s reason, i vermect i n i s used t o t reat
onchocerci asi s.
c. Chi l dren who ar e under nour i shed or are suf f eri ng f r om debi l i t at i ng
ascar i asi s i nf ect i on may exper i ence gi ddi ness, mal ai se, nausea, and
vomi t i ng af t er t r eat ment . Ot her dr ugs ar e avai l abl e t o t r eat Ascar i s
( mebendazol e and al bendazol e) .
E. Pyrant eI ( Pi n- Ri d) i s a pyr i mi di ne- der i vat i ve ant hel mi nt i c.
1. Mechani sm of act i on. Pyr ant el i s a depol ari zi ng neuromuscul ar bl ocki ng
agent t hat causes a spast i c par al ysi s of t he hel mi nt h.
2. Spect rum of acti vi t y. Pyr ant el i s act i ve agai nst A. l umbri coi des
( r oundwor m) , E. ver mi cul ar i s (pi nwor m), A. duodenal e (hookwor m) , N.
amer i canus (hookwor m), and Tr i chost r ongyl us ori ent al i s ( hai r wor m).
3. Therapeut i c uses. Pyr ant el i s used f or t he t r eat ment of roundwor m,
pi nwor m, and hookwor m i nf ect i ons.
P. 977


4. Precauti ons and moni t ori ng ef f ect s
a. Most commonl y report ed r eact i ons i ncl ude anor exi a, nausea, vomi t i ng,
di ar rhea, headache, and r ash.
b. A si ngl e dose may be mi xed wi t h f ood, mi l k, j ui ce, or t aken on an empt y
st omach.
F. Thi abendazoI e (Mi ntezoI ) , a pyr azi noi soqui nol i ne der i vat i ve, i s a
synt het i c het erocycl i c ant hel mi nt i c.
1. Mechani sm of act i on i s not known pr eci sel y. Thi abendazol e i s shown t o
i nhi bi t t he hel mi nt h-speci f i c enzyme, f umar at e reduct ase. Thi abendazol e
al so demonst r at es ant i -i nf l ammat or y, ant i pyr et i c, and anal gesi c ef f ect s.
2. Spect rum of acti vi t y. Ì t i s act i ve agai nst most i nt est i nal nemat odes,
i ncl udi ng Ancyl ost oma br azi l i ense (dog and cat hookwor m), A. duodenal e
( hookwor m) , A. l umbr i coi des ( r oundwor m), E. vermi cul ar i s (pi nwor m), N.
amer i canus (hookwor m), St r ongyl oi des st ercoral i s ( t hr eadwor m) , T.
t r i chi ur a ( whi pwor m), T. spi ral i s, and Toxocar a cani s and Toxocar a cat i
( dog and cat roundwor ms) .
3. Therapeut i c uses. Thi abendazol e i s used f or t he t reat ment of
st r ongyl oi di asi s ( t hr eadwor m i nf ect i on) , cut aneous l ar va mi grans (cr eepi ng
er upt i on) , and vi sceral l ar va mi gr ans. Ì t i s used f or t he t r eat ment of
unci nar i asi s (hookwor m), N. ameri canus, A. duodenal e, t r i chur i asi s
( whi pwor m) , and ascari asi s ( l ar ge r oundwor m) when more speci f i c t her apy
i s unavai l abl e or f urt her t r eat ment i s r equi red wi t h a second agent .
4. Precauti ons and moni t ori ng ef f ect s
a. Adverse ef f ect s of t hi abendazol e ar e usual l y mi l d and t r ansi ent ,
occur ri ng 3- 4 hr af t er t he dr ug has been admi ni st er ed and l ast i ng f or 2-8 hr .
b. Most common r eact i ons i ncl ude anor exi a, nausea, vomi t i ng, and
di zzi ness.
c. Gi ddi ness, sei zur es, ver t i go, parest hesi as, and psychi c di st ur bances may
al so occur , but l ess f requent l y.
d. Ì f hypersensi t i vi t y devel ops, t he drug shoul d be di scont i nued. Er yt hema
mul t i f or me (i ncl udi ng St evens-Johnson syndrome) has been r epor t ed.
5. Si gni f i cant i nteracti ons. Ser um xant hi ne l evel s (t heophyl l i ne and
caf f ei ne) may i ncr ease.
G. I vermecti n ( St romect oI )
1. Mechani sm of act i on. Ì ver mect i n pot ent i at es t he i nhi bi t or y ef f ect s of v-
ami nobut yr i c aci d ( GABA) i n vari ous nemat odes and art hropods, r esul t i ng i n
par al ysi s and deat h of t he or gani sms.
2. Spect rum of acti vi t y. Thi s agent i s act i ve agai nst S. st er cor al i s
( i nt est i nal f or ms onl y) and O. vol vul us ( i mmat ur e f or ms onl y) . Ì t i s al so
usef ul f or t r eat ment of i nf ect i ons wi t h A. l umbr i coi des, E. ver mi cul ar i s, M.
ozzar di , T. t ri chi ur a, and W. bancr of t i .
3. Therapeut i c uses
a. Ì vermect i n i s usef ul f or t r eat ment of i nf ect i ons wi t h t he parasi t es l i st ed i n
VÌ Ì Ì . G. 2.
b. Two st udi es demonst rat ed t hat i ver mect i n was more ef f ect i ve t han
al bendazol e f or t r eat ment of st rongyl oi di asi s.
c. Ì vermect i n i s of t en f avor ed over di et hyl car bamazi ne ci t r at e owi ng t o i t s
l ess severe adver se ef f ect pr of i l e.
4. Precauti ons and moni t ori ng ef f ect s,
a. May cause a Mazzot ti reacti on (see VÌ Ì Ì . D. 4. b) t hat i s l ess severe t han
wi t h di et hyl car bamazi ne ci t rat e.
b. Repor t s of ser i ous and possi bl y f at al encephal opat hy have occurr ed i n
pat i ent s wi t h concomi t ant L. l oa i nf ect i on
c. Ot her adver se ef f ect s i ncl ude edema, di zzi ness, headache, r ash, and GÌ
di st ur bances.
d. Counsel pat i ent s t o t ake i ver mect i n wi t h wat er .
H. Prazi quant eI ( Bi I t ri ci de)
1. Mechani sm of act i on. Pr azi quant el i ncreases cel l membr ane
per meabi l i t y i n suscept i bl e hel mi nt hs, wi t h l oss of i nt racel l ul ar cal ci um and
par al ysi s of t hei r muscul at ur e. Vacuol i zat i on and di si nt egrat i on of t he
schi st osome t egument r esul t , f ol l owed by at t achment of phagocyt es t o t he
par asi t e and deat h.
P. 978


2. Spect rum of acti vi t y. Pr azi quant el i s act i ve agai nst t r emat odes ( f l ukes) ,
i ncl udi ng al l Schi st osoma spp. and Cl onorchi s si nensi s, Opi st horchi s
vi ver ri ni , Fasci ol a hepat i ca (l i ver f l ukes) , Par agoni mus ut er obi l at eral i s,
Par agoni mus west er mani ( l ung f l ukes) , Met agoni mus yokogawai ,
Fasci ol opsi s buski , and Het er ophyes het erophyes ( i nt est i nal f l ukes) .
3. Therapeut i c uses. Prazi quant el i s act i ve i n t reat i ng al l t ypes of
schi st osomi asi s t hat are pat hogeni c t o humans; cl onor chi asi s and
opi st hor chi asi s ( Chi nese and sout heast Asi an l i ver f l ukes); many ot her
t ypes of i nf ect i ons i nvol vi ng i nt est i nal , l i ver , and l ung f l ukes; and
cest odi asi s ( t apewor m) i nf ect i ons.
4. Precauti ons and moni t ori ng ef f ect s
a. Tr eat ment of ocul ar cyst i cer cosi s i s cont r ai ndi cat ed because parasi t e
dest r uct i on wi t hi n t he eyes may cause i r r eparabl e l esi ons.
b. Ì n general , adverse ef f ect s ar e gener al l y mi l d and wel l t ol erat ed. Ì t i s
di f f i cul t t o di f f erent i at e bet ween ef f ect s caused by t he pr azi quant el ver sus
ef f ect s demonst r at ed by dyi ng parasi t es.
c. The most common si de ef f ect s ar e t r ansi ent and may i ncl ude mal ai se,
headache, di zzi ness, and abdomi nal di scomf or t .
d. Pr azi quant el may i mpai r act i vi t i es t hat requi r e ment al al er t ness.
P. 979


STUDY QUESTIONS
Di rect i ons for quest i ons 1- 12: Each of t he quest i ons, st at ement s, or
i ncompl et e st at ement s i n t hi s sect i on can be cor rect l y answer ed or
compl et ed by one of t he suggest ed answer s or phr ases. Choose t he best
answer .
1. I soni azi d i s a pri mary ant i t ubercuI ar agent that
( A) r equi res pyr i doxi ne suppl ement at i on.
( B) may di scol or t he t ears, sal i va, ur i ne, or f eces or ange red.
( C) causes ocul ar compl i cat i ons t hat ar e r eversi bl e i f t he drug i s
di scont i nued.
( D) may be ot ot oxi c and nephr ot oxi c.
( E) shoul d never be used because of hepat ot oxi c pot ent i al .
Vi ew Answer 1. The answer i s A[ see V. B. 2. d. (5)] . 2. AI I of t he
f oI I owi ng f act ors may i ncrease the ri sk of nephrot oxi ci t y f rom
gent ami ci n therapy except whi ch one?
( A) age > 70 year s
( B) pr ol onged courses of gent ami ci n t her apy
( C) concur r ent amphot eri ci n B t herapy
( D) t r ough gent ami ci n l evel s < 2 mg/ mL
( E) concur r ent ci spl at i n t her apy
Vi ew Answer 2. The answer i s D[ see] . 3. I n whi ch of t he f oI I owi ng
groups do aI I f our drugs warrant caref uI moni tori ng for drug- reI ated
sei zures i n hi gh- ri sk pat i ents?
( A) peni ci l l i n G, i mi penem, amphot er i ci n B, met roni dazol e
( B) peni ci l l i n G, chl or ampheni col , t et r acycl i ne, vancomyci n
( C) i mi penem, t et racycl i ne, vancomyci n, sul f adi azi ne
( D) cycl oser i ne, met r oni dazol e, vancomyci n, sul f adi azi ne
( E) met r oni dazol e, i mi penem, doxycycl i ne, er yt hromyci n
Vi ew Answer 3. The answer i s A[ see I I . E. 1. e. ( 2); I I . J. 5. d. ( 2);] . 4. AC
i s a 34- year- oI d maI e admi t t ed wi t h a di agnosi s of peri t oni t i s. CuI t ures
are posi t i ve for Bact eroi des f ragi l i s, Enterococcus f aecal i s, and
St aphyl ococcus aureus. Whi ch of t he f oI I owi ng wouI d be t he best i ni ti aI
t herapy t o recommend?
( A) t el i t hr omyci n
( B) qui nupr i st i n/ dal f opri st i n
( C) t i gecycl i ne
( D) t r i met hopr i m/ sul f amet hoxazol e
( E) kanamyci n
Vi ew Answer 4. The answer i s C[ see] . 5. TJ i s a 45- year- oI d f emaI e
present i ng wi t h an Enterobact er aerogenes bact eremi a wi th a I ow- grade
f ever ( 101. 6°F) . The most appropri at e management of her f ever wouI d
be t o
( A) gi ve acet ami nophen 1000 mg oral l y ever y 6 hr .
( B) gi ve aspi ri n 650 mg or al l y ever y 4 hr .
( C) gi ve al t er nat i ng doses of aspi r i n and acet ami nophen ever y 4 hr .
( D) wi t hhol d ant i pyr et i cs and use t he f ever cur ve t o moni t or her
r esponse t o ant i bi ot i c t her apy.
( E) use t epi d wat er bat hs t o r educe t he f ever .
Vi ew Answer 5. The answer i s D[ see] . 6. BC has an upper
respi rat or y i nf ect i on. Two years ago, she experi enced an epi sode of
bronchospasm af ter peni ci I I i n therapy. Current cuI tures are posi t i ve for
a st rai n of St rept ococcus pneumoni ae that i s sensi t i ve t o aI I of the
f oI I owi ng drugs. Whi ch of t hese drugs wouI d be t he best choi ce for thi s
pat i ent ?
( A) amoxi ci l l i n/ cl avul anat e
( B) t el i t hr omyci n
( C) ampi ci l l i n
( D) cef acl or
( E) l oracar bef
Vi ew Answer 6. The answer i s B[ see I I . K. 12] . 7. AI I of t he
f oI I owi ng drugs are appropri ate t herapi es f or a I ower uri nar y t ract
i nf ecti on owi ng t o Pseudomonas aerugi nosa except
( A) norf l oxaci n.
( B) t r i met hopr i m- sul f amet hoxazol e.
( C) ci pr of l oxaci n.
( D) t obramyci n.
( E) met henami ne mandel at e.
Vi ew Answer 7. The answer i s B[ seeand] . P. aerugi nosa. 8. BT i s a
43- year- oI d f emaI e seen by her pri mar y- care physi ci an f or a mi I d
st aphyI ococcaI ceI I uI i t i s on the arm. Whi ch of t he f oI I owi ng regi mens
wouI d be appropri at e oraI t herapy?
( A) di cl oxaci l l i n 125 mg ever y 6 hr
( B) vancomyci n 250 mg ever y 6 hr
( C) met hi ci l l i n 500 mg ever y 6 hr
( D) cef azol i n 1 g ever y 8 hr
( E) peni ci l l i n V 500 mg ever y 6 hr
Vi ew Answer 8. The answer i s A[ see] . P. 980


9. RC i s a 33- year- oI d maI e wi t h a hi st or y of HI V f or 10 years who now
present s wi th Mycobact eri um avi um-i nt racel l ul are (MAI ) . Whi ch of t he
f oI I owi ng drugs has demonst rat ed i n vi t ro acti vi t y agai nst MAI ?
( A) dapt omyci n
( B) cl ar i t hr omyci n
( C) er yt hromyci n base
( D) cl oxaci l l i n
( E) mi nocycl i ne
Vi ew Answer 9. The answer i s B[ see I I . D. 6. a-b] . Toxopl asma
gondi i Crypt ospori di um10. AI I of t he f oI I owi ng st at ements
regardi ng pent ami di ne i set hi onat e are t rue except whi ch one?
( A) Ì t i s i ndi cat ed f or t r eat ment or pr ophyl axi s of i nf ect i on owi ng t o
Pneumocyst i s cari ni i .
( B) Ì t may be admi ni st ered i nt r amuscul ar l y, i nt r avenousl y, or by
i nhal at i on.
( C) Ì t has no cl i ni cal l y si gni f i cant ef f ect on ser um gl ucose.
( D) Ì t i s ef f ect i ve i n t he t r eat ment of l ei shmani asi s.
Vi ew Answer 10. The answer i s C[ see] . P. cari ni i . 11. RE i s a 23-
year- oI d maI e wi t h a hi st or y of i nf I uenza A i nfect i ons. An out break of
i nf I uenza A has j ust been report ed i n hi s communi t y, and he i s
exhi bi t i ng i ni t i aI sympt oms of t he i nfecti on. Whi ch agent wouI d be t he
most usefuI to t reat RE?
( A) ci dof ovi r
( B) f amci cl ovi r
( C) osel t ami vi r
( D) f oscar net
( E) r i bavi r i n
Vi ew Answer 11. The answer i s C[ see] . 12. Dr. Jones request s your
heI p i n prescri bi ng a prot ease i nhi bi t or for hi s pat i ent . He has heard
t hat not aI I agents are the same and asks f or your recommendat i on as
t o whi ch agent wouI d be I east I i keI y t o cause the pat i ent ' s choI esteroI
t o i ncrease. Whi ch agent wouI d you recommend?
( A) saqui navi r
( B) r i t onavi r
( C) i ndi navi r
( D) nel f i navi r
( E) at azanavi r
Vi ew Answer 12. The answer i s E[see] . Di rect i ons f or questi ons
13- 14: The quest i ons and i ncompl et e st at ement s i n t hi s sect i on can be cor r ect l y
answer ed or compl et ed by one or more of t he suggest ed answer s. Choose t he
answer , A- E.
13. Drugs usuaI I y act i ve agai nst peni ci I I i nase-produci ng St aphyl ococcus
aureus i ncI ude whi ch of t he foI I owi ng?
( I ) pi peraci I I i n- t azobactam
( I I ) amoxi ci I I i n-cI avuI anat e
( I I I ) naf ci I I i n
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 13. The answer i s E(I , I I , I I I ) [ seeand] . S. aureus14. Ant i vi raI
agents t hat are act i ve agai nst cyt omegaI ovi rus ( CMV) i ncI ude whi ch of t he
f oI I owi ng?
( I ) ganci cI ovi r
( I I ) f oscarnet
( I I I ) acycI ovi r
A i f I onI y i s cor rect
B i f I I I onI y i s cor r ect
C i f I and I I ar e cor r ect
D i f I I and I I I are cor rect
E i f I , I I , and I I I ar e cor rect
Vi ew Answer 14. The answer i s C( I and I I ) [ seeand] . Di rect i ons for
questi ons 15- 17: Each descr i pt i on l i st ed i n t hi s sect i on i s most cl osel y associ at ed
wi t h one of t he f ol l owi ng dr ugs. The drugs may be used mor e t han once or not at
al l . Choose t he best answer , A- E.
15. I t may be admi ni stered once per day f or t he t reatment of uri nar y t ract
i nf ecti ons.
A cl of azi mi ne
B i t r aconazol e
C l omef l oxaci n
D neomyci n
Vi ew Answer 15. The answer i s C[ see] . 16. I t may cause pi nk t o browni sh
ski n pi gmentat i on wi t hi n a few weeks of i ni t i ati on of t herapy.
A cl of azi mi ne
B i t r aconazol e
C l omef l oxaci n
D neomyci n
Vi ew Answer 16. The answer i s A[ see I I . J. 9] . Mycobact eri um17. Co-
admi ni st rat i on wi t h astemi zoI e or terf enadi ne may I ead t o I i f e- t hreat eni ng
cardi ac dysrhyt hmi as.
A cl of azi mi ne
B i t r aconazol e
C l omef l oxaci n
D neomyci n
Vi ew Answer 17. The answer i s B[ see] . P. 981


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see V. B. 2. d. (5) ] .
Ì soni azi d i ncreases t he excr et i on of pyr i doxi ne, whi ch can l ead t o per i pheral
neuri t i s, par t i cul ar l y i n poor l y nouri shed pat i ent s. Pyr i doxi ne (a f or m of vi t ami n B6)
def i ci ency may cause convul si ons as wel l as t he neuri t i s, i nvol vi ng synovi al
t ender ness and swel l i ng. Tr eat ment wi t h t he vi t ami n can rever se t he neuri t i s and
pr event or cure t he sei zur es.
2. The answer i s D [ see Ì Ì . B. 4. b] .
Tr ough serum l evel s < 2 mg/ mL ar e consi der ed appr opr i at e f or gent ami ci n and are
r ecommended t o mi ni mi ze t he r i sk of t oxi ci t y f r om t hi s ami nogl ycosi de. Because
ami nogl ycosi des accumul at e i n t he proxi mal t ubul e of t he ki dney, nephrot oxi ci t y can
occur .
3. The answer i s A [ see I I . E. 1. e. ( 2) ; I I . J. 5. d. (2) ; Ì Ì Ì . B. 4. b; Ì V. C. 3. c] .
Sei zur es have been at t r i but ed t o t he use of peni ci l l i n G, i mi penem, amphot er i ci n B,
and met r oni dazol e. Sei zur es are especi al l y l i kel y wi t h hi gh doses i n pat i ent s wi t h a
hi st or y of sei zures and i n pat i ent s wi t h i mpai red dr ug el i mi nat i on.
4. The answer i s C [ see Ì Ì . K. 13] .
Al t hough act i ve agai nst var i ous gr am- posi t i ve and negat i ve organi sms, t i gecycl i ne i s
onl y agent approved f or t he t r eat ment of i nt ra- abdomi nal i nf ect i ons caused by t hese
or gani sms.
5. The answer i s D [ see I . H. 1] .
The f ever cur ve i s usef ul f or moni t or i ng a pat i ent ' s r esponse t o ant i mi crobi al
t her apy. Ant i pyr et i cs can be used t o r educe hi gh f ever i n pat i ent s at ri sk f or
compl i cat i ons ( e. g. , sei zur es) or , i n some cases, t o make t he pat i ent mor e
comf ort abl e.
6. The answer i s B [ see Ì Ì . K. 12] .
Amoxi ci l l i n and ampi ci l l i n ar e al l peni ci l l i ns and shoul d be avoi ded i n pat i ent s wi t h
hi st ori es of hypersensi t i vi t y t o ot her peni ci l l i n compounds. Al t hough t he ri sk of
cr oss- react i vi t y wi t h cephal ospor i ns ( e. g. , cef acl or , l or acarbef ) i s now consi dered
l ow, most cl i ni ci ans avoi d t he use of t hese agent s i n pat i ent s wi t h hi st ori es of t ype Ì
hyper sensi t i vi t y r eact i ons ( e. g. , anaphyl axi s, bronchospasm, gi ant hi ves) .
7. The answer i s B [ see Ì Ì . E. 4; Ì Ì . H. 3. a and b; Ì Ì . Ì . 2. a; Ì Ì . Ì . 3. a; Ì Ì . J. 7] .
Nor f l oxaci n, ci pr of l oxaci n, t obr amyci n, and met henami ne mandel at e achi eve ur i ne
concent r at i ons hi gh enough t o t r eat uri nar y t r act i nf ect i ons caused by P.
aer ugi nosa. Tr i met hopri m- sul f amet hoxazol e i s not usef ul f or t r eat i ng i nf ect i on
caused by t hi s organi sm, al t hough t he combi nat i on i s usef ul f or t r eat i ng cer t ai n
ot her uri nar y t r act i nf ect i ons.
8. The answer i s A [ see Ì Ì . C; Ì Ì . E. 1. c. (3) ; Ì Ì . E. 2. b; Ì Ì . J. 8] .
Al t hough vancomyci n, met hi ci l l i n, and cef azol i n have excel l ent act i vi t y agai nst
st aphyl ococci , t hey ar e not ef f ect i ve or al l y f or syst emi c i nf ect i ons. Vancomyci n i s
pr escri bed oral l y f or i nf ect i ons l i mi t ed t o t he gast r oi nt est i nal t r act , but because i t i s
poorl y absorbed or al l y, i t i s not ef f ect i ve f or syst emi c i nf ect i ons. Most hospi t al - and
communi t y- acqui red st aphyl ococci ar e cur r ent l y resi st ant t o peni ci l l i n. Thus of t he
dr ugs l i st ed, t he most appr opri at e drug f or or al t her apy of st aphyl ococcal cel l ul i t i s i s
di cl oxaci l l i n.
9. The answer i s B [ see I I . D. 6. a-b] .
Cl ar i t hr omyci n, an al t er nat i ve t o er yt hr omyci n, has demonst r at ed i n vi t r o act i vi t y
agai nst MAÌ . Cl ari t hromyci n i s al so used agai nst Toxopl asma gondi i and
Cr ypt ospor i di um spp. , and i t i s more act i ve t han er yt hr omyci n agai nst st aphyl ococci
and st rept ococci . Vancomyci n and cl oxaci l l i n ar e used t o t reat st aphyl ococci and
st r ept ococci , but has no demonst r at ed act i vi t y ver sus MAÌ .
10. The answer i s C [ see Ì V. D] .
Pent ami di ne i set hi onat e i s i ndi cat ed f or bot h t r eat ment and pr ophyl axi s of i nf ect i on
f r om P. cari ni i . Ì t can be admi ni st er ed i nt r amuscul ar l y, i nt r avenousl y, or by
i nhal at i on. Ì nhal at i on may pr oduce br onchospasm. Bl ood gl ucose shoul d be
car ef ul l y moni t ored because pent ami di ne may produce ei t her hypergl ycemi a or
hypogl ycemi a.
P. 982


11. The answer i s C [ see VÌ Ì . B. 9] .
Ci dof ovi r , f amci cl ovi r , and f oscar net have l i t t l e or no i n vi vo act i vi t y agai nst
i nf l uenza A. Ri bavi ri n has some act i vi t y but i s a second-l i ne agent f or i nf l uenza A
and i s mai nl y i ndi cat ed f or t r eat ment of hepat i t i s C i n combi nat i on wi t h i nt er f eron.
Osel t ami vi r i s an agent t hat demonst rat es act i vi t y agai nst i nf l uenza A and B. Ì t i s
i ndi cat ed f or t he prophyl axi s and t r eat ment of i nf l uenza i nf ect i ons.
12. The answer i s E [ see VÌ Ì . C. 5. b. ( 3). ( b) ] .
The maj ori t y of pr ot ease i nhi bi t ors cause hyperl i pi demi a. At azanavi r does not cause
t hi s adver se ef f ect and may be pref er red i n cer t ai n cl i ni cal si t uat i ons.
13. The answer i s E ( I , I I , I I I ) [ see Ì Ì . E. 2, 3 and 4] .
Pi peraci l l i n and amoxi ci l l i n each i ncl ude a 8- l act amase i nhi bi t or . These
combi nat i ons of f er act i vi t y agai nst S. aureus si mi l ar t o t hat of t he peni ci l l i nase-
r esi st ant peni ci l l i ns, such as naf ci l l i n.
14. The answer i s C ( I and I I ) [ see VI I . B. 1; VÌ Ì . B. 7 and 8] .
Onl y ganci cl ovi r and f oscar net ar e act i ve agai nst CMV i nf ect i ons. These agent s ar e
vi r ust at i c and ar r est DNA synt hesi s by i nhi bi t i ng vi r al DNA pol ymerase. Foscarnet i s
a br oad-spect r um ant i vi ral agent and i s used i n pat i ent s wi t h ganci cl ovi r resi st ance.
Acycl ovi r i s not cl i ni cal l y usef ul f or t he t reat ment of CMV i nf ect i ons because CMV i s
r el at i vel y resi st ant t o acycl ovi r i n vi t r o.
15. The answer i s C [ see Ì Ì . H. 3. c] .
Lomef l oxaci n may be admi ni st er ed dai l y f or t r eat i ng ur i nar y t ract i nf ect i ons.
Enoxaci n i s anot her f l uoroqui nol one used t o t reat ur i nar y t ract i nf ect i ons. Compar ed
t o ot her f l uor oqui nol ones, nei t her l omef l oxaci n nor enoxaci n i mpr oves t he spect r um
of act i vi t y.
16. The answer i s A [ see I I . J. 9] .
Because cl of azi mi ne cont ai ns phenazi ne dye, i t can cause pi nk t o br own ski n
pi gment at i on. Thi s change i n pi gment at i on occurs i n 75%- 100% of pat i ent s t aki ng
cl of azi mi ne, and i t occurs wi t hi n a f ew weeks of t he i ni t i at i on of t her apy. The
di scol orat i on of ski n has r epor t edl y l ed t o sever e depressi on and even sui ci de i n
some pat i ent s. Cl of azi mi ne i s used i n t he t r eat ment of l epr osy and sever al at ypi cal
Mycobact eri um i nf ect i ons.
17. The answer i s B [ see Ì Ì Ì . E. 5. d] .
Admi ni st rat i on of i t r aconazol e or ket oconazol e wi t h ast emi zol e or t er f enadi ne may
i ncrease t he l evel of ast emi zol e or t er f enadi ne, whi ch can l ead t o l i f e- t hreat eni ng
dysr hyt hmi as and deat h. Ì t r aconazol e, whi ch i s an i mi dazol e, i s a f ungi st at i c agent .
Speci f i cal l y, i t r aconazol e can be t aken or al l y t o t r eat asper gi l l osi s i nf ect i ons and
ot her deep f ungal i nf ect i ons, such as bl ast omycosi s, cocci di oi domycosi s,
cr ypt ococcosi s, and hi st opl asmosi s.

44
Infectious Diseases
PauI F. Souney
Ant hony E. Zi mmermann
Li nda M. Spooner
I. PrincipIes of Anti-Infective Therapy
A. Def i ni t i on. Ant i -i nf ect i ve agent s t r eat i nf ect i on by suppr essi ng or
dest r oyi ng t he causat i ve mi cr oor gani sms÷bact eri a, mycobact eri a, f ungi ,
pr ot ozoa, or vi r uses. Ant i - i nf ect i ve agent s der i ved f r om nat ur al subst ances
ar e cal l ed ant i bi ot i cs; t hose pr oduced f r om synt het i c subst ances ar e cal l ed
ant i mi cr obi al s. These t wo t erms are now used i nt er changeabl y.
B. Ì ndi cat i ons. Conf i r m t he presence of i nf ect i on by compl et i ng a caref ul
hi st or y and physi cal exami nat i on, searchi ng f or si gns and sympt oms of
i nf ect i on as wel l as pr edi sposi ng f act ors. Ant i -i nf ect i ve agent s shoul d be
used onl y when
1. A si gni f i cant i nf ect i on has been di agnosed or i s st r ongl y suspect ed
2. An est abl i shed i ndi cat i on f or pr ophyl act i c t herapy exi st s
C. Gr am st ai n, mi cr obi ol ogi cal cul t ur i ng, and suscept i bi l i t y t est s shoul d be
per f or med bef or e ant i - i nf ect i ve t her apy i s i ni t i at ed. Test mat eri al s must be
obt ai ned by a met hod t hat avoi ds cont ami nat i on of t he speci men by t he
pat i ent ' s own f l or a.
1. Gr am st ai n. Per f or med on al l speci mens except bl ood cul t ur es, t he gram
st ai n hel ps i dent i f y t he cause of i nf ect i on i mmedi at el y. By det er mi ni ng i f t he
causat i ve agent i s gr am posi t i ve or gr am negat i ve, t he t est al l ows a bet t er
choi ce of drug t herapy, par t i cul ar l y when an ant i - i nf ect i ve r egi men must
begi n wi t hout del ay.
a. Gr am- posi t i ve mi cr oorgani sms st ai n bl ue or pur pl e.
b. Gr am- negat i ve mi cr oor gani sms st ai n r ed or r ose- pi nk.
c. Fungi may al so be i dent i f i ed by gram st ai n.
2. Mi cr obi ol ogi cal cul t ures. To i dent i f y t he speci f i c causat i ve agent ,
speci mens of body f l ui ds or i nf ect ed t i ssue are col l ect ed f or anal ysi s.
3. Suscept i bi l i t y t est s. Di f f erent st r ai ns of t he same pat hogeni c speci es may
have wi del y var yi ng suscept i bi l i t y t o a part i cul ar ant i - i nf ect i ve agent .
Suscept i bi l i t y t est s det ermi ne mi cr obi al suscept i bi l i t y t o a gi ven dr ug and
t hus can be used t o pr edi ct whet her t he drug wi l l combat t he i nf ect i on
ef f ect i vel y.
a. Mi cr odi l ut i on met hod. The dr ug i s di l ut ed ser i al l y i n vari ous medi a
cont ai ni ng t he t est mi cr oor gani sm.
( 1) The l owest dr ug concent r at i on t hat pr event s mi cr obi al growt h af t er 18-
24 hr of i ncubat i on i s cal l ed t he mi ni mum i nhi bi t or y concent r at i on ( MÌ C) .
( 2) The l owest dr ug concent r at i on t hat r educes bact er i al densi t y by 99. 9%
i s cal l ed t he mi ni mum bact eri ci dal concent r at i on (MBC) .
( 3) Br eakpoi nt concent rat i ons of ant i bi ot i cs are used t o char act er i ze
ant i bi ot i c act i vi t y: The i nt er pret i ve cat egor i es ar e suscept i bl e, moderat el y
suscept i bl e ( i nt er medi at e) , and resi st ant . These concent r at i ons ar e
det ermi ned by consi deri ng pharmacoki net i cs, ser um and t i ssue
concent r at i ons f ol l owi ng nor mal doses, and t he popul at i on di st ri but i on of
MÌ Cs of a gr oup of bact er i a f or a gi ven dr ug.
b. Ki rby- Bauer di sk di f f usi on t echni que. Thi s t est i s l ess expensi ve but l ess
r el i abl e t han t he mi cr odi l ut i on met hod; however , i t pr ovi des qual i t at i ve
suscept i bi l i t y i nf or mat i on.
( 1) Fi l t er paper di sks i mpr egnat ed wi t h speci f i c dr ug quant i t i es ar e pl aced
on t he surf ace of agar pl at es st r eaked wi t h a mi cr oor gani sm cul t ur e. Af t er
18 hr, t he si ze of
P. 914

a cl ear i nhi bi t i on zone i s det er mi ned; dr ug act i vi t y agai nst t he t est st r ai n i s
t hen cor r el at ed t o zone si ze.
( 2) The Ki r by- Bauer t echni que does not rel i abl y pr edi ct t herapeut i c
ef f ect i veness agai nst cert ai n mi croorgani sms ( e. g. , St aphyl ococcus aur eus,
Shi gel l a) .
D. Choi ce of agent . An ant i -i nf ect i ve agent shoul d be chosen on t he basi s
of i t s phar macol ogi cal proper t i es and spect r um of act i vi t y as wel l as on
var i ous host ( pat i ent ) f act ors ( Fi gur e 44-1) .
1. Phar macol ogi cal proper t i es i ncl ude t he drug' s abi l i t y t o r each t he
i nf ect i on si t e and t o at t ai n a desi r ed l evel i n t he t ar get t i ssue.
2. Spect r um of act i vi t y. To t r eat an i nf ect i ous di sease ef f ect i vel y, an ant i -
i nf ect i ve drug must be act i ve agai nst t he causat i ve pat hogen. Suscept i bi l i t y
t est i ng or cl i ni cal exper i ence i n t reat i ng a gi ven i nf ect i on may suggest t he
ef f ect i veness of a par t i cul ar dr ug.
3. Pat i ent f act ors. Sel ect i on of an ant i - i nf ect i ve dr ug regi men must t ake
var i ous pat i ent f act or s i nt o account t o det ermi ne whi ch t ype of dr ug shoul d
be admi ni st er ed, t he corr ect dr ug dosage and admi ni st r at i on r out e, and t he
pot ent i al f or adverse dr ug ef f ect s.
a. Ì mmunol ogi cal st at us. A pat i ent wi t h i mpai r ed i mmune mechani sms may
r equi r e a drug t hat r api dl y dest roys pat hogens ( i . e. , bact eri ci dal agent )
r at her t han one t hat merel y suppresses a pat hogen' s gr owt h or r epr oduct i on
( i . e. , bact er i ost at i c agent ) .
b. Pr esence of a f or ei gn body. The ef f ect i veness of ant i -i nf ect i ve t herapy i s
r educed i n pat i ent s who have prost het i c j oi nt s or val ves, cardi ac
pacemaker s, and vari ous i nt er nal shunt s.
c. Age. A dr ug' s phar macoki net i c pr oper t i es may var y wi del y i n pat i ent s of
di f f er ent ages. Ì n ver y young and ver y ol d pat i ent s, dr ug met abol i sm and
excr et i on commonl y decrease. El derl y pat i ent s al so have an i ncr eased r i sk
of suf f er i ng ot ot oxi ci t y when recei vi ng cer t ai n ant i bi ot i cs.
d. Under l yi ng di sease
( 1) Pr eexi st i ng ki dney or l i ver di sease i ncreases t he ri sk of nephr ot oxi ci t y
or hepat ot oxi ci t y duri ng t he admi ni st rat i on of some ant i bact er i al dr ugs.
( 2) Pat i ent s wi t h cent r al ner vous syst em ( CNS) di sor der s may suf f er
neurot oxi ci t y (mot or sei zur es) dur i ng peni ci l l i n t her apy.
( 3) Pat i ent s wi t h neur omuscul ar di sor der s ( e. g. , myast heni a gr avi s) ar e at
i ncreased r i sk f or devel opi ng neur omuscul ar bl ockade dur i ng
ami nogl ycosi de or pol ymyxi n B t her apy.
e. Hi st or y of dr ug al l ergy or adver se drug r eact i ons. Pat i ent s who have had
pr evi ous al l er gi c or ot her unt owar d r eact i ons t o a par t i cul ar ant i bi ot i c have
a hi gher r i sk of exper i enci ng t he same react i on dur i ng subsequent
admi ni st rat i on of t hat drug. Except i n l i f e- t hr eat eni ng si t uat i ons, pat i ent s
who have had seri ous al l er gi c react i ons t o peni ci l l i n, f or exampl e, shoul d
not recei ve t he dr ug agai n.
f . Pr egnancy and l act at i on. Because drug t herapy duri ng pr egnancy and
l act at i on can cause unwant ed ef f ect s, t he mot her ' s need f or t he ant i bi ot i c
must be wei ghed agai nst t he dr ug' s pot ent i al harm.
( 1) Pr egnancy can i ncrease t he r i sk of adverse dr ug ef f ect s f or bot h mot her
and f et us. Al so, pl asma dr ug concent rat i ons t end t o decr ease i n pr egnant
women, reduci ng a drug' s t her apeut i c ef f ect i veness.
( 2) Most drugs, i ncl udi ng ant i bi ot i cs, appear i n t he br east mi l k of nur si ng
mot hers and may cause adver se ef f ect s i n i nf ant s. For exampl e,
sul f onami des may l ead t o t oxi c bi l i r ubi n accumul at i on i n a newborn' s br ai n.
g. Genet i c t r ai t s
( 1) Sul f onami des may cause hemol yt i c anemi a i n pat i ent s wi t h gl ucose- 6-
phosphat e dehydr ogenase ( G6PD) def i ci ency.
( 2) Pat i ent s who r api dl y met abol i ze dr ugs (i . e. , rapi d acet yl at ors) may
devel op hepat i t i s when recei vi ng t he ant i t uber cul ar drug i soni azi d.
E. Empi ri c t herapy. Ì n ser i ous or l i f e-t hr eat eni ng di sease, ant i - i nf ect i ve
t her apy must begi n bef ore t he i nf ect i ng or gani sm has been i dent i f i ed. Ì n
t hi s case, t he choi ce of dr ug ( or dr ugs) i s based on cl i ni cal exper i ence,
suggest i ng t hat a par t i cul ar agent i s ef f ect i ve i n a gi ven set t i ng.
P. 915



Figure 44-1. Approach to management oI
inIection.
P. 916


1. A br oad- spect r um ant i bi ot i c usual l y i s t he most appropri at e choi ce unt i l
t he speci f i c or gani sm has been det ermi ned.
2. Ì n al l cases, cul t ure speci mens must be obt ai ned bef ore t herapy begi ns.
F. Mul t i pl e ant i bi ot i c t her apy. A combi nat i on of dr ugs shoul d be gi ven onl y
when cl i ni cal exper i ence has shown such t her apy t o be more ef f ect i ve t han
si ngl e- agent t her apy i n a par t i cul ar set t i ng. A mul t i pl e- agent r egi men can
i ncrease t he r i sk of t oxi c dr ug ef f ect s and, i n a f ew cases, may r esul t i n
dr ug ant agoni sm and subsequent t herapeut i c i nef f ect i veness. Ì ndi cat i ons
f or mul t i pl e-agent t herapy i ncl ude
1. Need f or i ncr eased ant i bi ot i c ef f ect i veness. The syner gi st i c ( i nt ensi f i ed)
ef f ect of t wo or mor e agent s may al l ow a dosage r educt i on or a f ast er or
enhanced dr ug ef f ect .
2. Tr eat ment of an i nf ect i on caused by mul t i pl e pat hogens (e. g. , i nt ra-
abdomi nal i nf ect i on)
3. Pr event i on of pr ol i f er at i on of dr ug- r esi st ant or gani sms (e. g. , dur i ng
t r eat ment of t ubercul osi s)
G. Dur at i on of ant i - i nf ect i ve t her apy. To achi eve t he t her apeut i c goal , ant i -
i nf ect i ve t her apy must cont i nue f or a suf f i ci ent dur at i on.
1. Acut e uncompl i cat ed i nf ect i on. Tr eat ment gener al l y shoul d cont i nue unt i l
t he pat i ent has been af ebr i l e and asympt omat i c f or at l east 72 hr .
2. Chroni c i nf ect i on ( e. g. , endocar di t i s, ost eomyel i t i s) . Tr eat ment may
r equi r e a l onger dur at i on ( 4- 6 weeks) wi t h f ol l ow- up cul t ur e anal yses t o
assess t herapeut i c ef f ect i veness.
H. Moni t or i ng t herapeut i c ef f ect i veness. To assess t he pat i ent ' s r esponse
t o ant i -i nf ect i ve t herapy, appropri at e speci mens shoul d be cul t ur ed and t he
f ol l owi ng par amet ers moni t or ed.
1. Fever cur ve. An i mport ant assessment t ool , t he f ever cur ve may be a
r el i abl e i ndi cat i on of response t o t herapy. Def er vescence usual l y i ndi cat es
f avor abl e r esponse.
2. Whi t e bl ood cel l (WBC) count . Ì n t he i ni t i al st age of i nf ect i on, t he
neut rophi l count f rom a per i pheral bl ood smear may r i se above nor mal
( neut r ophi l i a), and i mmat ur e neut r ophi l f or ms ( "bands¨ ) may appear ( "l ef t
shi f t ¨ ) . Ì n pat i ent s who ar e el derl y, debi l i t at ed, or suf f eri ng over whel mi ng
i nf ect i on, t he WBC count may be nor mal or subnor mal .
3. Radi ogr aphi c f i ndi ngs. Smal l ef f usi ons, abscesses, or cavi t i es t hat
appear on radi ographs i ndi cat e t he f ocus of i nf ect i on.
4. Pai n and i nf l ammat i on ( as evi denced by swel l i ng, er yt hema, and
t ender ness) may occur when t he i nf ect i on i s super f i ci al or wi t hi n a j oi nt or
bone, al so i ndi cat i ng a possi bl e f ocus of i nf ect i on.
5. Er yt hrocyt e sedi ment at i on r at e ( ESR or "sed r at e¨ ) . Large el evat i ons i n
ESR ar e associ at ed wi t h acut e or chroni c i nf ect i on, par t i cul arl y
endocar di t i s, chr oni c ost eomyel i t i s, and i nt ra- abdomi nal i nf ect i ons. A
nor mal ESR does not excl ude i nf ect i on; more of t en, ESR i s el evat ed as a
r esul t of noni nf ect i ous causes such as col l agen vascul ar di sease.
6. Serum compl ement concent r at i ons, par t i cul arl y t he C3 component , ar e
of t en r educed i n ser i ous i nf ect i ons because of consumpt i on dur i ng t he host
def ense process.
Ì . Lack of t her apeut i c ef f ect i veness. When an ant i bi ot i c dr ug r egi men f ai l s,
ot her drugs shoul d not be added i ndi scr i mi nat el y or t he r egi men ot her wi se
changed. Ì nst ead, t he si t uat i on shoul d be reassessed and di agnost i c ef f or t s
i nt ensi f i ed. Causes of t her apeut i c i nef f ect i veness i ncl ude t he f ol l owi ng:
1. Mi sdi agnosi s. The i sol at ed or gani sm may have been mi si dent i f i ed by t he
l abor at or y or may not be t he causat i ve agent f or i nf ect i on (e. g. , t he pat i ent
may have an unsuspect ed i nf ect i on) .
2. Ì mproper dr ug regi men. The dr ug dosage, admi ni st rat i on rout e, dosi ng
f r equency, or durat i on of t herapy may be i nadequat e or i nappr opr i at e.
3. Ì nappr opr i at e choi ce of ant i bi ot i c agent . As di scussed i n Ì . D, pat i ent
f act or s and t he phar macol ogi cal pr oper t i es and spect r um of act i vi t y of a
gi ven dr ug must be consi dered when pl anni ng ant i - i nf ect i ve dr ug t herapy.
P. 917


4. Mi cr obi al r esi st ance. By acqui ri ng r esi st ance t o a speci f i c ant i bi ot i c,
mi cr oor gani sms can sur vi ve i n t he drug' s presence. Many gonococcal
st r ai ns, f or i nst ance, now r esi st peni ci l l i n. Drug r esi st ance i s part i cul ar l y
common i n geogr aphi cal ar eas i n whi ch a speci f i c dr ug has been used
excessi vel y ( and per haps i mproper l y) .
5. Unreal i st i c expect at i ons. Ant i bi ot i cs are i nef f ect i ve i n cer t ai n
ci rcumst ances.
a. Pat i ent s wi t h condi t i ons t hat r equi re sur gi cal dr ai nage f requent l y cannot
be cur ed by ant i - i nf ect i ve dr ugs unt i l t he drai n has been r emoved. For
exampl e, t he presence of necr ot i c t i ssue or pus i n pat i ent s wi t h pneumoni a,
empyema, or r enal cal cul i i s a common cause of ant i bi ot i c f ai l ur e.
b. Fever shoul d not be t reat ed wi t h ant i - i nf ect i ve dr ugs unl ess i nf ect i on has
been i dent i f i ed as t he cause. Al t hough f ever f r equent l y si gni f i es i nf ect i on, i t
somet i mes st ems f rom noni nf ect i ous condi t i ons (e. g. , drug react i ons,
phl ebi t i s, neopl asms, met abol i c di sor der s, ar t hr i t i s) . These condi t i ons do
not respond t o ant i bi ot i cs. One except i on t o t hi s posi t i on i s neut r openi c
cancer pat i ent s; such pat i ent s wi t h no si gns or sympt oms of i nf ect i on ot her
t han f ever ar e wi del y t reat ed wi t h ant i mi cr obi al agent s.
6. Ì nf ect i on by t wo or mor e t ypes of mi cr oor gani sms. Ì f not det ect ed
i ni t i al l y, an addi t i onal cause of i nf ect i on may l ead t o t her apeut i c f ai l ure.
J. Ant i mi cr obi al pr ophyl axi s f or sur ger y
1. Def i ni t i on. Ant i bi ot i c pr ophyl axi s i s a shor t cour se of ant i bi ot i c
admi ni st er ed bef ore t here i s cl i ni cal evi dence of i nf ect i on.
2. Gener al consi der at i ons
a. Ti mi ng. The ant i bi ot i c shoul d be admi ni st er ed t o ensure t hat appr opr i at e
ant i bi ot i c l evel s are avai l abl e at t he si t e of cont ami nat i on bef or e t he
i nci si on. Ì ni t i at i on of pr ophyl axi s i s of t en at i nduct i on of anest hesi a, wi t hi n
1 hr or j ust bef ore t he sur gi cal i nci si on. Thi s ensur es peak serum and
t i ssue ant i bi ot i c l evel s.
b. Durat i on. Pr ophyl axi s shoul d be mai nt ai ned f or t he durat i on of surger y.
Long sur gi cal pr ocedur es ( e. g. , > 3 hr ) may r equi r e addi t i onal doses. Ther e
i s l i t t l e evi dence t o suppor t cont i nuat i on of pr ophyl axi s beyond 24 hr.
c. Ant i bi ot i c spect r um shoul d be appr opr i at e f or t he usual pat hogens.
( 1) Ì n general , f i rst -gener at i on cephal ospori ns ( e. g. , cef azol i n) ar e t he
dr ugs of choi ce f or most pr ocedur es and pat i ent s. These agent s have an
appropr i at e spect r um, a l ow f r equency of si de ef f ect s, a f avor abl e hal f - l i f e,
and a l ow cost .
( 2) Vancomyci n i s a sui t abl e al t ernat i ve i n peni ci l l i n- sensi t i ve pat i ent s and
i n si t uat i ons i n whi ch met hi ci l l i n- r esi st ant S. aur eus i s a concern.
d. Rout e of admi ni st r at i on. Ì nt r avenous ( Ì V) or i nt r amuscul ar ( Ì M) r out es ar e
pr ef er r ed t o guar ant ee good serum and t i ssue l evel s at t he t i me of i nci si on.
II. AntibacteriaI Agents
A. Def i ni t i on and cl assi f i cat i on. Used t o t r eat i nf ect i ons caused by bact er i a,
ant i bact eri al agent s f al l i nt o several maj or cat egor i es: ami nogl ycosi des,
car bapenems, cephal ospor i ns, er yt hr omyci ns, peni ci l l i ns (i ncl udi ng vari ous
subgr oups) , sul f onami des, t et r acycl i nes, f l uoroqui nol ones, met r oni dazol e
( see V. C. 2. b) , uri nar y t ract ant i sept i cs, and mi scel l aneous ant i -i nf ect i ves
( Tabl e 44- 1).
B. Ami nogl ycosi des. These dr ugs, cont ai ni ng ami no sugar s, are used
pr i mar i l y i n i nf ect i ons caused by gr am- negat i ve ent er obact eri a and i n
suspect ed sepsi s. They have l i t t l e act i vi t y agai nst anaer obi c and f acul t at i ve
or gani sms. The t oxi c pot ent i al of t hese dr ugs l i mi t s t hei r use. Maj or
ami nogl ycosi des i ncl ude ami kaci n ( Ami ki n) , gent ami ci n ( Garamyci n),
kanamyci n, neomyci n, net i l mi ci n, st rept omyci n, and t obramyci n ( Nebci n).
1. Mechani sm of act i on. Ami nogl ycosi des are bact er i ci dal ; t hey i nhi bi t
bact er i al pr ot ei n synt hesi s by bi ndi ng t o and i mpedi ng t he f unct i on of t he
30S ri bosomal subuni t . (Some ami nogl ycosi des al so bi nd t o t he 50S
r i bosomal subuni t . ) Thei r mechani sm of act i on i s not f ul l y known.
P. 918


P. 919


P. 920


P. 921


P. 922


P. 923


Table 44-1. Some Important Parameters of Anti-Infective Drugs
Agent
Elimination
Route Half-Life
Administrat
ion Route
Common
Dosage Range
(Adults)
Aminoglycosides

Amikacin Renal 2-3 hr IV. IM 15
mg/kg/da
y. (once
daily
dose)

Gentamicin Renal 2 hr IV. IM 3
mg/kg/da
y
(standard
dose); 6-7
mg/kg/da
y (once
daily
dose)

Kanamycin Renal 2-4 hr Oral.
IV
15 mg/kg
every 8-
12 hr

Neomycin Renal 2-3 hr Oral.
topical
50-100
mg/kg/da
y (oral);
10-15
mg/day
(topical)

Netilmicin Renal 2-7 hr IV. IM 3-6
mg/kg/da
y

Streptomycin Renal 2-3 hr IM 15
mg/kg/da
y
a


Tobramycin Renal 2-5 hr IV. IM 3
mg/kg/da
y
(standard
dose); 6-7
mg/kg/da
y. (once
daily
dose)
Carbapenems

Doripenem Renal 1 hr IV 500 mg
every 8 hr
Imipenem Renal 1 hr IV 250 mg-1
g every 6
hr
Ertapenem Renal 4 hr IV. IM 1 g/day

Meropenem Renal 1.5 hr IV. IM 0.5-2 g
every 8 hr
Cephalosporins
First-generation
CeIadroxil Renal 1.5 hr Oral 1-2 g/day

CeIazolin Renal 1.4-2.2
hr
IV 250 mg-1
g every 8
hr

Cephalexi
n
Renal 0.9 1.3
hr
Oral 250-500
mg every
6 hr

Cephapirin Renal
(H)
0.6-0.8
hr
IV. IM 500 mg-2
g every 4-
6 hr

Cephradin
e
Renal 1.3 hr Oral.
IV
250-500
mg every
6 hr
Second-generation

CeIaclor Renal
(H)
0.8 hr Oral 250-500
mg every
8 hr

CeImetazo Renal 72 min IV 2 g every
le 6-12 hr

CeIotetan Renal 2.8-4.6
hr
IV. IM 1-2 g
every 12
hr


CeIoxitin Renal 0.8 hr IV 1-2 g
every 6-8
hr


CeIprozil Renal 78 min Oral 250-500
mg every
12-24 hr


CeIuroxim
e
Renal 1.5-2.2
hr
IV. IM 750 mg-
1.5 g
every 8 hr


LoracarbeI Renal 1 hr Oral 200 mg
every 12
hr or 400
mg/day

Third-generation

CeIixime Renal 3-4 hr Oral 400
mg/day


CeIdinir Renal 1.7-1.8
hr
Oral 300 mg
every 12
hr


CeIoperaz
one
Hepatic 1.6-2.4
hr
IV 2-4 g
every 12
hr


CeIotaxim
e
Renal
(H)
1.5 hr IV 1-2 g
every 6-8
hr


CeIpodoxi
me
Renal 2.5 hr Oral 100-400
mg every
12 hr


CeItazidim
e
Renal 1.8 hr IV. IM 1-2 g
every 8-
12 hr


CeItibuten Renal 2.5 hr Oral 400
mg/day


CeItizoxi
me
Renal 1.7 hr IV 1-2 g
every 8-
12 hr


CeItriaxon
e
Renal 8 hr IV. IM 1-2 g/day

Fourth-generation

CeIepime Renal 2-2.3
hr
IV. IM 1-2 g
every 8-
12 hr

Erythromycins and other macrolides

Azithromycin Hepatic 68 hr Oral 250
mg/day


Clarithromycin Renal 3-7 hr Oral 250-500
mg every
12 hr


Dirithromycin Hepatic 8 hr Oral 500
mg/day


Erythromycin base
estolate.
Hepatic 1.2-2.6
hr
Oral 250-500
mg every

ethylsuccinate. and
stearate
6 hr

Erythromycin
gluceptate and
lactobionate
IV 0.5-2 g
every 6 hr
Natural penicillins

Penicillin G Renal
(H)
0.5 hr Oral.
IV. IM
200.000-
500.000
U every
6-8 hr


Penicillin V Renal 1 hr Oral 500 mg-2
g/day


Penicillin G
procaine
Renal 24-60
hr
IM 300.000-
600.000
U/day


Penicillin G
benzathine
Renal 24-60
hr
IM 300.000-
600.000
U/day

Penicillinase-resistant penicillins

Cloxacillin Renal
(H)
0.5 hr Oral 250-500
mg every
6 hr


Dicloxacillin Renal
(H)
0.5-0.9
hr
Oral 500 mg-1
g/day


Methicillin Renal
(H)
0.5-1
hr
IV. IM 1-2 g
every 4-6
hr


NaIcillin Hepatic
(R)
0.5 hr Oral.
IV. IM
0.25-2 g
every 6 hr


Oxacillin Renal
(H)
0.5 hr Oral.
IV. IM
500 mg-2
g every 4-
6 hr 500-
875 mg
every 12
hr

Aminopenicillins

Amoxicillin Renal
(H)
0.9-2.3
hr
Oral 250-500
mg every
8 hr


Amoxicillin/clavula
nic acid
Renal 1 hr Oral 250-500
mg every
8 hr


Ampicillin Renal
(H)
0.8-1.5
hr
Oral.
IV. IM
250 mg-2
g every 4-
6 hr


Ampicillin/sulbacta
m
Renal 1-1.8
hr
IV. IM 1.5-3 g
every 6 hr

Extended-spectrum penicillins

Mezlocillin Renal
(H)
0.6-1.2
hr
IV. IM 1-3 g
every 4-6
hr


Piperacillin Renal
(H)
0.8-1.4
hr
IV. IM 1-1.5
mg/kg
every 6-
12 hr

Piperacillin/tazobact Renal 0.7-1.2 IV 3.375 g
am hr every 6 hr

Ticarcillin Renal 0.9-1.5
hr
IV. IM 1-3 g
every 4-6
hr


Ticarcillin/clavulani
c acid
Renal 1-1.5
hr
IV 3.1 g
every 4-6
hr

Sulfonamides

SulIacytine Renal 4-4.5
hr
Oral 250 mg
every 6 hr


SulIadiazine Renal
(H)
6 hr Oral.
IV
2-4 g/day


SulIamethoxazole Hepatic
(R)
9-11 hr Oral 1-3 g/day


SulIisoxazole Renal
(H)
3-7 hr Oral.
IV
2-8 g/day


SulIamethizole Renal Oral 0.5-1 g
every 6-8
hr

Tetracyclines

Demeclocycline Renal 10-17
hr
Oral 300 mg-1
g/day


Doxycycline Hepatic 14-25
hr
Oral.
IV
100-200
mg every
12 hr


Minocycline Hepatic 12-15
hr
Oral.
IV
100-200
mg every
12 hr


Oxytetracycline Renal 6-12 hr Oral.
IM
250-500
mg every
6 hr 250-
500 mg
q.i.d. or
300
mg/day in
1 or 2
divided
doses


Tetracycline
b
Renal 6-12 hr Oral.
IV. IM
1-2 g/day

Fluoroquinolones

CiproIloxacin Renal
(H)
5-6 hr IV 200-600
mg every
12 hr


Enoxacin Renal
(H)
3-6 hr Oral 200
mg/day-
400 mg
every 12
hr


GemiIloxacin Fecal (R) 4-12 hr Oral 320 mg
once daily


LomeIloxacin Renal 6.35-
7.77 hr
Oral 400
mg/day


LevoIloxacin Renal 8 hr IV.
Oral
250-500
mg every
24 hr


MoxiIloxacin Hepatic 12 hr Oral 400 mg
once daily


OIloxacin Renal 5-7.5
hr
Oral 100
mg/day-
400 mg

Urinary tract antiseptics

Cinoxacin Renal 1-1.5
hr
Oral 250 mg
every 6 hr
or 500 mg
every 12
hr


FosIomycin Renal/Iec
al
5.7 hr Oral One
packet (3
g) in 90-
120 mL
water × 1
dose


Methenamine
hippurate and
mandelate
Renal 1-3 hr Oral 0.5-2 g
q.i.d.
Nalidixic acid Renal 8 hr Oral 4 g/day

NitroIurantoin Renal 0.3-1
hr
Oral 5-7
mg/kg/da
y

NorIloxacin Hepatic 3-4 hr Oral 400 b.i.d.
Miscellaneous anti-infectives

Atovaquone Fecal 50-84
hr
Oral 750 mg
b.i.d. × 21
days


Aztreonam Renal 1.7 hr Oral.
IV
50-100
mg/kg/da
y


Clindamycin Hepatic 2-4 hr Oral.
IM. IV
300-900
mg every
6-8 hr


CloIazimine Hepatic 70
days
Oral 50-100
mg/day


Dapsone Hepatic
(R)
28 hr Oral 50-100
mg/day


Daptomycin Renal 8 hr IV 4
mg/kg/da
y


Lincomycin Hepatic
(R)
4.4-6.4
hr
IV. IM 600 mg-1
g every 8-
12 hr


Linezolid Renal 4-6 hr Oral.
IV
600 mg
every 12
hr


Mupirocin Renal 19-35
min
Topical Apply
every 8-
12 hr


Quinupristin/dalIopr
istin
Hepatic 1
hr/0.4-
0.5 hr
IV 7.5 mg/kg
every 8 hr

RiIaximin Fecal 6 hrs Oral 200 mg
t.i.d.


Spectinomycin Renal 1.2-2.8
hr
IM 2-4 g
(single

dose)

Telithromycin Hepatic
(R)
10 hr Oral 800
mg/day


Tigecycline Biliary
(R)
42 hr IV 100 mg
load. 50
mg every
12 hr


Trimethoprim Renal
(H)
8-15 hr Oral 100-200
mg/day


Vancomycin Renal 6-8 hr Oral.
IV
500 mg
every 6 hr

Antifungal agents

Amphotericin B Unknow
n
24 hr IV 1-1.5
mg/kg/da
y


AnidulaIungin Fecal (R) 40-50
hr
IV Candidem
ia: 200
mg day 1.
then 100
mg/day


Esophage
al
candidiasi
s: 100 mg
day 1.
then 50
mg/day


CaspoIungin Hepatic 9-11 hr IV 70 mg on
day 1.
then 50
mg q.d.


Fluconazole Renal 22-37
hr
IV.
Oral
100-800
mg/day


Flucytosine Renal 6 hr Oral 50-150
mg/kg/da
y


GriseoIulvin Hepatic
(R)
9-24 hr Oral 300-375
mg/day


Itraconazole Hepatic 24-42
hr
Oral 200-600
mg/day


Ketoconazole Hepatic/I
ecal
3.3 hr Oral 200-400
mg/day
b.i.d


MicaIungin Hepatic 11-17
hr
IV Esophage
al
candidiasi
s: 150
mg/day


HSCT
prophylas
is: 50
mg/day


Miconazole Hepatic 20-24
hr
Oral 200-400
mg/day


Nystatin Fecal Oral 500.000-
1.000.000
U t.i.d.


Posaconazole Fecal/ren
al
35 hrs Oral 200 mg
t.i.d.

TerbinaIine Hepatic 11-16 Oral 250
(R) hr mg/day

Voriconazole Hepatic 6 hr IV.
Oral
IV: 6
mg/kg
every 12
hr × 2
doses.
then 4
mg/kg
every 12
h; oral:
200 mg
every 12
h Ior ~ 40
kg. 100
mg every
12 h Ior ·
40 kg

Antiprotozoal agents

Atovaquone Hepatic 67 hr Oral 750 mg
b.i.d.


Chloroquine Renal/Iec
al
72-120
hr
IM.
Oral
Depends
on disease


Diloxanide Renal IM 500 mg
t.i.d.


EIlornithine Renal 3 hr IV 100
mg/kg/do
se every 6
hr


Fansidar Renal 100-
231 hr
Oral 1 tablet
every
week

HaloIantrine Hepatic 3-4 Oral 500 mg
days every 6 hr
× 3 doses;
repeat in
7 days

Renal 72-120
hr
Oral 310 mg
every
week


Hydroxychloro
quine


Iodoquinol Fecal Oral 650 mg
t.i.d. Ior
20 days


MeIloquine Hepatic 15-33
days
Oral 1250 mg
single
dose


Metronidazole Hepatic
(R)
6-14 hr Oral.
IV
250-500
mg every
6-8 hr


Nitazoxanide Hepatic 1-1.6
hr
Oral 100-200
mg b.i.d.
based on
age


Paromomycin Fecal Oral 25-35
mg/kg/da
y


Pentamidine Renal 6-9 hr IM. IV.
inhalati
on
IV. IM: 3-
4 mg/kg
every
day;
inhalation
: 300 mg
every 4

weeks

Primaquine Hepatic 3.7-9.6
hr
Oral 15 mg
(base)/da
y


Pyrimethamine Renal 111 hr Oral 25 mg
every
week


Quinacrine

5 days Oral 100
mg/day


Quinine Renal 12 hr Oral 325 mg
b.i.d.


Tinidazole Hepatic
(R)
13.2 hr Oral 2 g q.d. ×
1-3 days

Antitubercular agents

Aminosalicylic acid Renal 1 hr Oral 150
mg/kg
daily
(maximu
m 12
g/day)


Capreomycin Renal 4-6 hr IM 15
mg/kg/da
y to 1
g/day
maximum


Cycloserine Renal 10 hr Oral 15-20
mg/kg
(maximu
m 1
g/day)


Ethambutol Hepatic 3.3 hr Oral 15-25
mg/kg/da
y


Ethionamide Hepatic 3 hr Oral 500 mg-1
g/day


Isoniazid Hepatic 1-4 hr Oral.
IV
5-10
mg/kg
daily
(maximu
m dose ÷
300 mg)


Pyrazinamide Hepatic 9-10 hr Oral 15-30
mg/kg
daily
(maximu
m 2
g/day)


RiIampin Hepatic 2-3 hr Oral.
IV
10 mg/kg
(up to 600
mg) q.d.


RiIabutin Hepatic 45 hr Oral 300 mg
q.d.


RiIepentine Hepatic 13.9 hr
(active
metabo
lite
\13.4
hr)
Oral 600 mg
every 3
days

Antiviral agents

Abacavir Hepatic 1.5 hr Oral 300 mg
b.i.d. or
600 mg

every day

AdeIovir Renal 7.5 hr Oral 10 mg
every day


Acyclovir Renal 2.2 hr Oral.
IV.
topical
IV: 5-10
mg/kg
every 8
hr; oral:
200-800
mg 3-5 ×
daily
(dependin
g upon
indication
)


Amantadine Renal 17 hr Oral 100 mg
b.i.d. or
200 mg
every day


Amprenavir Hepatic 7-10 hr Oral 1200 mg
b.i.d.
(caps)


Atazanavir Hepatic 7 hr Oral 400 mg
every day


CidoIovir Renal 6.5 hr IV 5 mg/kg
week × 2
(induction
); 5
mg/kg
every 2
weeks
(maintena
nce)


Darunavir Hepatic 15 hr Oral 600 mg
plus 100

mg
ritonavir
b.i.d.

Delavirdine Hepatic
(R)
2-11 hr Oral 400 mg
t.i.d.


Didanosine Renal 1.5 hr Oral > 60 kg:
400 mg
every day
(EC
caps); ·
60 kg:
250 mg
every day
(EC caps)


Emtricitabine Renal 10 hr Oral 200 mg
every day
(caps)


EnIuvirtide n/a 3.8 hr SC 90 mg
b.i.d.


Entecavir Renal 128-
149 hr
Oral 0.5 mg
every
day. or 1
mg every
day in
patients
with
lamivudin
e
resistance


EIavirenz Hepatic 40-55
hr
Oral 600 mg at
bedtime


Famciclovir Renal 2-2.3
hr
Oral 250-500
mg every
8-12 hr


Fosamprenavir Hepatic 7.7 hr Oral 1400 mg
b.i.d.


Foscarnet Renal 3-6 hr IV 90 mg/kg
every 12
hr × 14-
21 days
(CMV
induction)
; 90
mg/kg
every day
(CMV
maintena
nce)


Ganciclovir Renal 2.9 hr IV 5 mg/kg
every 12
hr
(induction
) × 14-21
days; 5
mg/kg
every day
(maintena
nce)


4.8 hr Oral 1000 mg
t.i.d.
(aIter
induction)


Indinavir Hepatic 1.4-2.2
hr
Oral 800 mg
every 8 hr


Lamivudine Renal 3-7 hr Oral 150 mg
b.i.d. or
300 mg
daily


Lopinavir/ritonavir Hepatic 4.4-6.1
hr
Oral 200
mg/50 mg

per tab (2
tablets
b.i.d.)

Maraviroc Hepatic 14-18
hr
Oral 150-600
mg b.i.d..
dependin
g upon
concomit
ant
medicatio
ns


NelIinavir Hepatic 3.5-5
hr
Oral 1250 mg
b.i.d.


Nevirapine Renal
(H)
25-30
hr
Oral 200 mg
every day
× 14
days. then
200 mg
b.i.d.


Oseltamivir Renal 6-10 hr Oral 75 mg
b.i.d.
(treatment
); 75 mg
every day
(prophyla
xis)


Raeltegravir Hepatic 9 hr Oral 400 mg
b.i.d.


Ribavirin Renal 298 hr Oral 800-1200
mg daily.
divided
into 2
doses

Rimantadine Renal 25 hr Oral 100 mg
b.i.d.

Ritonavir Hepatic 3-5 hr Oral 100-400
mg daily.
divided in
1 or 2
doses (as
booster
agent
with other
PIs)


Saquinavir Hepatic 13 hr Oral 1000 mg
(Invirase)
plus 100
mg
ritonavir
b.i.d.


Stavudine Renal 1.5 hr Oral > 60 kg:
40 mg
every 12
hr; · 60
kg: 30 mg
every 12
hr


Telbivudine Renal 40-49
hr
Oral 600 mg
every day


TenoIovir Renal 10-14
hr
Oral 300 mg
daily


Tipranavir Hepatic 6 hr Oral 500 mg
plus 200
mg
ritonavir
b.i.d.


Valacyclovir Renal 2.5-3.6
hr
Oral 0.5-1 g
every day

or b.i.d.
or t.i.d.

Valganciclovir Renal 4 hr Oral 900 mg
b.i.d. × 21
days
(induction
). 900 mg
every day
(maintena
nce)


Zalcitabine Renal 1-3 hr Oral 0.75 mg
t.i.d.


Zanamivir Renal 2.5-5.1
hr
Inhalati
on
(Diskha
ler)
2
inhalation
s (10 mg)
b.i.d.
(treatment
); 10 mg
every day
(prophyla
xis)


Zidovudine Renal
(H)
1.5-3.1
hr
Oral 300 mg
b.i.d.


IV 2 mg/kg
over 1 hr.
then 1
mg/kg/hr
until cord
clamping
(intrapart
um
perinatal
prophylax
is Ior
pregnant
women)

Anthelmintics

Albendazole Hepatic 8-12 hr Oral 400-800
mg daily


Diethylcarbamazine Renal 8 hr Oral 25
mg/day
Ior 3
days. then
50
mg/day
Ior 5
days. then
100
mg/day
Ior 3
days. then
150
mg/day
Ior 12
days


Ivermectin Hepatic 16-35
hr
Oral 150-200
mcg/kg ×
1 dose


Mebendazole Hepatic 8 hr Oral 100 mg
b.i.d. × 3
consecuti
ve days


Praziquantel Hepatic 0.8-3
hr
Oral 60-75
mg/kg in
3 divided
doses on
the same
day


Pyrantel Hepatic Oral 11 mg/kg
(maximu
m ÷ 1 g)
as a

single
dose

Thiabendazole Hepatic Oral Dose
based
upon
weight
chart in
prescribin
g
inIormati
on. 100
lb: 1 g
b.i.d. 125
lb: 1.25 g
b.i.d. ~
150 lb:
1.5 g
b.i.d.

CMJ. cytomegalovirus; EC cap. enteric-coated capsule; H. additional
signiIicant hepatic elimination; HSCT. hematopoietic stem cell transplant;
IM. intramuscular; IJ. intravenous; PIs. protease inhibitors R. additional
signiIicant renal elimination; SC. subcutaneous.

a
Dosage applies to inIections other than tuberculosis; Ior tuberculosis.
dosage is 1 g/day.

b
Intravenous agent withdrawn Irom U.S. market.


P. 924


2. Spect r um of act i vi t y
a. St rept omyci n i s act i ve agai nst bot h gram-posi t i ve and gr am- negat i ve
bact er i a. However , wi despr ead r esi st ance t o t hi s dr ug has rest r i ct ed i t s use
t o t he or gani sms t hat cause pl ague and t ul ar emi a, gram-posi t i ve
st r ept ococci (gi ven i n combi nat i on wi t h peni ci l l i n) , and Mycobact er i um
t ubercul osi s ( gi ven i n combi nat i on wi t h ot her ant i t ubercul ar agent s, as
descr i bed i n VÌ . C. 2) .
b. Ami kaci n, kanamyci n, gent ami ci n, t obr amyci n, neomyci n, and net i l mi ci n
ar e act i ve agai nst many gr am- negat i ve bact er i a (e. g. , Pr ot eus, Ser r at i a,
and Pseudomonas organi sms).
( 1) Gent ami ci n i s act i ve agai nst some St aphyl ococcus st rai ns; i t i s mor e
act i ve t han t obramyci n agai nst Ser rat i a organi sms.
( 2) Ami kaci n i s t he broadest spect r um ami nogl ycosi de wi t h act i vi t y agai nst
most aer obi c gram-negat i ve baci l l i as wel l as many anaer obi c gram-
negat i ve bact eri al st r ai ns t hat resi st gent ami ci n and t obramyci n. Ì t i s al so
act i ve agai nst M. t ubercul osi s and Mycobact eri um avi um-i nt racel l ul ar e
( MAÌ ) .
( 3) Tobr amyci n may be mor e act i ve agai nst Pseudomonas aerugi nosa t han
gent ami ci n.
( 4) Net i l mi ci n may be act i ve agai nst gent ami ci n- resi st ant or gani sms; i t
appears t o be l ess ot ot oxi c t han ot her ami nogl ycosi des.
( 5) Neomyci n, i n addi t i on t o i t s act i vi t y agai nst such gr am- negat i ve
or gani sms as Escheri chi a col i and Kl ebsi el l a pneumoni ae, i s act i ve agai nst
sever al gr am- posi t i ve organi sms ( e. g. , S. aur eus) . P. aer ugi nosa and most
st r ept ococci ar e now neomyci n resi st ant .
3. Ther apeut i c uses
a. St rept omyci n i s used t o t r eat pl ague, t ul aremi a, acut e brucel l osi s ( gi ven
i n combi nat i on wi t h t et r acycl i ne), bact er i al endocar di t i s caused by
St r ept ococcus vi ri dans (gi ven i n combi nat i on wi t h peni ci l l i n) , and
t ubercul osi s ( gi ven i n combi nat i on wi t h ot her ant i t ubercul ar agent s, as
descr i bed i n VÌ . C. 2) .
b. Gent ami ci n, t obr amyci n, ami kaci n, and net i l mi ci n ar e t herapeut i c f or
ser i ous gr am- negat i ve baci l l ar y i nf ect i ons ( e. g. , t hose caused by
Ent erobact er , Ser r at i a, Kl ebsi el l a, and P. aer ugi nosa), pneumoni a ( gi ven i n
combi nat i on wi t h a cephal ospor i n or peni ci l l i n) , meni ngi t i s, compl i cat ed
ur i nar y t r act i nf ect i ons, ost eomyel i t i s, bact er emi a, and per i t oni t i s.
c. Neomyci n i s used f or pr eoper at i ve bowel st eri l i zat i on; hepat i c coma (as
adj unct i ve t herapy) ; and, i n t opi cal f orm, f or ski n and mucous membr ane
i nf ect i ons (e. g. , bur ns) .
4. Pr ecaut i ons and moni t or i ng ef f ect s. Ami nogl ycosi des can cause ser i ous
adver se ef f ect s. To prevent or mi ni mi ze such pr obl ems, bl ood drug
concent r at i ons and bl ood ur ea ni t rogen ( BUN) and ser um cr eat i ni ne l evel s
shoul d be moni t ored dur i ng t her apy.
a. Ot ot oxi ci t y. Ami nogl ycosi des can cause vest i bul ar or audi t or y damage.
The r el at i ve ot ot oxi ci t y i s as f ol l ows:
st r ept omyci n = kanamyci n > ami kaci n = gent ami ci n = t obramyci n >
net i l mi ci n
( 1) Gent ami ci n and st r ept omyci n cause pri mar i l y vest i bul ar damage
( mani f est ed by t i nni t us, ver t i go, and at axi a) . Such damage may be bi l at eral
and i r r eversi bl e.
( 2) Ami kaci n, kanamyci n, and neomyci n cause mai nl y audi t or y damage
( heari ng l oss) .
( 3) Tobr amyci n can r esul t i n bot h vest i bul ar and audi t or y damage.
b. Nephr ot oxi ci t y. Because ami nogl ycosi des accumul at e i n t he proxi mal
t ubul e, mi l d r enal dysf unct i on devel ops i n up t o 25% of pat i ent s recei vi ng
t hese dr ugs f or several days or mor e. Usual l y, t hi s adver se ef f ect i s
r ever si bl e. Use of once-dai l y admi ni st r at i on ( ODA) has been r epor t ed i n t he
l i t er at ur e t o be as ef f ect i ve and l ess nephrot oxi c t han t r adi t i onal dosi ng.
( 1) Neomyci n i s t he most nephr ot oxi c ami nogl ycosi de; st rept omyci n i s t he
l east nephr ot oxi c. Gent ami ci n and t obr amyci n are nephrot oxi c t o
approxi mat el y t he same degree.
( 2) Ri sk f act ors f or i ncr eased nephr ot oxi c ef f ect s i ncl ude t he f ol l owi ng:
( a) Pr eexi st i ng r enal di sease
( b) Pr evi ous or pr ol onged ami nogl ycosi de t her apy
( c) Concur r ent admi ni st rat i on of anot her nephr ot oxi c dr ug
( d) Ì mpai r ed r enal f l ow unr el at ed t o r enal di sease ( e. g. , f rom hypot ensi on,
sever e hepat i c di sease)
P. 925


( 3) Tr ough l evel s > 2 µg/ mL f or gent ami ci n and t obr amyci n and > 10 µg/ mL
f or ami kaci n are associ at ed wi t h nephr ot oxi ci t y.
c. Neur omuscul ar bl ockade. Thi s pr obl em may ari se i n pat i ent s r ecei vi ng
hi gh- dose ami nogl ycosi de t her apy.
( 1) Ri sk f act ors f or neuromuscul ar bl ockade i ncl ude t he f ol l owi ng:
( a) Concur r ent admi ni st rat i on of a neur omuscul ar bl ocki ng agent or an
anest het i c
( b) Pr eexi st i ng hypocal cemi a or myast heni a gr avi s
( c) Ì nt r aperi t oneal or r api d Ì V dr ug admi ni st r at i on
( 2) Apnea and r espi r at ory depr essi on may be r ever sed wi t h admi ni st r at i on
of cal ci um or an ant i chol i nest erase.
d. Hypersensi t i vi t y and l ocal r eact i ons ar e r are adver se ef f ect s of
ami nogl ycosi des.
e. Ther apeut i c l evel s
( 1) Gent ami ci n and t obr amyci n peak at 6- 10 µg/ mL f or t r adi t i onal dosi ng;
when usi ng t he ODA met hod, t he peak i s 16- 20 µg/ mL or 8- 10 t i mes t he
MÌ C of t ar get ed bact er i a. Thei r t rough l evel i s 0. 5- 1. 5 µg/ mL f or t radi t i onal
or once- dai l y r egi mens.
( 2) Ami kaci n peaks at 25- 30 µg/ mL. The t r ough l evel i s 5-8 µg/ mL.
5. Si gni f i cant i nt eract i ons
a. Ì V l oop di uret i cs can resul t i n i ncr eased ot ot oxi ci t y.
b. Ot her ami nogl ycosi des, cephal ot hi n, ci spl at i n, amphot er i ci n B, and
met hoxyf l ur ane can cause i ncr eased nephr ot oxi ci t y when gi ven concur rent l y
wi t h st r ept omyci n.
C. Car bapenems. These agent s ar e 8- l act ams t hat cont ai n a f used 8-l act am
r i ng and a 5-membered ri ng syst em t hat di f f er s f rom peni ci l l i ns i n bei ng
unsat urat ed and cont ai ni ng a car bon at om i nst ead of a sul f ur at om. The
cl ass has a broader spect r um of act i vi t y t han do most 8-l act ams. Former l y
known as t hi enamyci n, i mi penem (Pr i maxi n) was t he f i rst carbapenem
compound i nt r oduced i n t he Uni t ed St at es, f ol l owed by meropenem
( Mer r em) and, most recent l y, er t apenem ( Ì nvanz) and dori penem ( Dor i bax) .
Because i t i s i nhi bi t ed by r enal di pept i dases, i mi penem must be combi ned
wi t h ci l ast at i n sodi um, a di pept i dase i nhi bi t or ( ci l ast at i n i s not requi r ed wi t h
t he ot her s because t hese ar e not sensi t i ve t o r enal di pept i dase) .
1. Mechani sm of act i on. Car bapenems ar e bact eri ci dal , i nhi bi t i ng bact eri al
cel l wal l synt hesi s.
2. Spect r um of act i vi t y. These dr ugs have t he broadest spect r um of al l 8-
l act am ant i bi ot i cs. The gr oup i s act i ve agai nst most gr am- posi t i ve cocci
( i ncl udi ng many ent er ococci ) , gr am- negat i ve r ods ( i ncl udi ng many P.
aer ugi nosa st r ai ns) , and anaer obes. Thi s cl ass has good act i vi t y agai nst
many bact eri al st r ai ns t hat r esi st ot her ant i bi ot i cs. Er t apenem has a
nar r ower spect rum of act i vi t y t han t he ot her car bapenems. Ì t has l i t t l e or no
act i vi t y agai nst P. aer ugi nosa and Aci net obact er . These 8-l act am ant i bi ot i cs
r esi st dest ruct i on by most 8-l act amases.
3. Ther apeut i c uses. Carbapenems ar e most val ued i n t he t r eat ment of
sever e i nf ect i ons caused by dr ug- r esi st ant or gani sms suscept i bl e t o t hese
agent s. These agent s are ef f ect i ve agai nst ur i nary t r act and l ower
r espi r at or y i nf ect i ons, i nt r a- abdomi nal and gynecol ogi cal i nf ect i ons, and
ski n, sof t - t i ssue, bone, and j oi nt i nf ect i ons.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Carbapenems may cause nausea, vomi t i ng, di ar r hea, and
pseudomembranous col i t i s.
b. Sei zur es, di zzi ness, and hypot ensi on may devel op; sei zures appear l ess
f r equent l y wi t h mer openem or ert apenem (1. 5% of pat i ent s recei vi ng
i mi penem ver sus 0. 5% of t hose r ecei vi ng mer openem or er t apenem) .
c. Pat i ent s who are al l ergi c t o peni ci l l i n or cephal ospori ns may suf f er cross-
sensi t i vi t y react i ons dur i ng car bapenem t herapy.
D. Cephal ospor i ns. These agent s ar e known as 8- l act am ant i bi ot i cs
because t hei r chemi cal st r uct ur e consi st s of a 8-l act am r i ng adj oi ned t o a
t hi azol i di ne r i ng. Cephal ospor i ns gener al l y are cl assi f i ed i n f our maj or
gr oups based mai nl y on t hei r spect r um of act i vi t y ( Tabl e 44-2) .
1. Mechani sm of act i on. Cephal ospor i ns ar e bact er i ci dal ; t hey i nhi bi t
bact er i al cel l wal l synt hesi s, reduci ng cel l wal l st abi l i t y and t hus causi ng
membr ane l ysi s.
P. 926


Table 44-2. Classification of Cephalosporins
First
Generation Second Generation Third Generation
Fourth
Generation
CeIadroxil
(DuriceI.
UltraceI)
a

CeIazolin
(AnceI.
KeIzol)
Cephalexin
(KeIlex)
a

Cephapirin
(CeIadyl)
Cephradine
(Anspor.
VeloseI)
a

CeIaclor (Ceclor)
a

CeImetazole
(ZeIazone)
CeIotetan (CeIotan)
b

CeIoxitin (MeIoxin)
CeIuroxime(ZinaceI)
CeIuroxime axetil
(CeItin)
a

CeIprozil (CeIzil)
a

LoracarbeI
(Lorabid)
a

CeIdinir
(OmniceI)
a

CeIixime
(Suprax)
a

CeIoperazone
(CeIobid)
CeIotaxime
(ClaIoran)
CeIpodoxime
proxetil
(Vantin)
a

CeItazidime
(Fortex.
TaziceI.
Tazidime)
CeItibuten
(Cedax)
a

CeItizoxime
(CeIizox)
CeItriaxone
(Rocephin)
CeIditoren
(SpectraceI)
a

CeIepime
(Maxipime)
a
Oral agent.

b
Discontinued in the U.S. market 2005.

2. Spect r um of act i vi t y
a. Fi r st - generat i on cephal ospor i ns ar e act i ve agai nst most gr am- posi t i ve
cocci ( except ent er ococci ) as wel l as ent er i c aer obi c gr am-negat i ve baci l l i
( e. g. , E. col i , K. pneumoni ae, Prot eus mi rabi l i s) .
b. Second- gener at i on cephal ospori ns are act i ve agai nst t he or gani sms
cover ed by f i rst - generat i on cephal ospori ns and have ext ended gram-
negat i ve coverage, i ncl udi ng 8- l act amase- produci ng st rai ns of Haemophi l us
i nf l uenzae.
c. Thi rd- generat i on cephal ospor i ns have wi der act i vi t y agai nst most gram-
negat i ve bact eri a, f or exampl e, Ent er obact er , Ci t r obact er , Ser r at i a,
Pr ovi denci a, Nei sser i a, and Haemophi l us organi sms, i ncl udi ng 8-l act amase-
pr oduci ng st rai ns.
d. Four t h- generat i on cephal ospor i ns i ncl ude cef epi me ( Maxi pi me) , whi ch i s
t he f i rst member of t hi s gr oup t o be mar ket ed. However , i t s desi gnat i on as
a f our t h-gener at i on cephal ospor i n i s debat abl e. Cef epi me i s hi ghl y r esi st ant
t o 8- l act amases and has a l ow pr opensi t y f or sel ect i on of 8-l act am- resi st ant
mut ant st rai ns. Ì t shows evi dence of gr eat er act i vi t y ver sus gr am- posi t i ve
cocci , Ent erobact er i aceae, and Pseudomonas t han t hi r d-gener at i on
cephal ospori ns.
e. Each gener at i on of cephal ospori n has shi f t ed t owar d i ncr eased gr am-
negat i ve act i vi t y but has l ost act i vi t y t owar d gr am- posi t i ve or gani sms.
Four t h- generat i on agent s have i mproved act i vi t y t owar d gr am-posi t i ve
or gani sms over t hi r d-gener at i on agent s.
3. Ther apeut i c uses
a. Fi r st - generat i on cephal ospor i ns commonl y ar e admi ni st er ed t o t reat
ser i ous Kl ebsi el l a i nf ect i ons and gram-posi t i ve and some gr am- negat i ve
i nf ect i ons i n pat i ent s wi t h mi l d peni ci l l i n al l er gy. These agent s al so are
used wi del y i n peri oper at i ve prophyl axi s. For most ot her i ndi cat i ons, t hey
ar e not t he pr ef er red dr ugs.
b. Second- gener at i on cephal ospori ns are val uabl e i n t he t reat ment of
ur i nar y t r act i nf ect i ons resul t i ng f r om E. col i or gani sms, acut e ot i t i s medi a,
si nusi t i s, and gonococcal di sease caused by or gani sms t hat resi st ot her
agent s.
( 1) Cef acl or ( Cecl or ) i s usef ul i n ot i t i s medi a and si nusi t i s i n pat i ent s who
ar e al l er gi c t o ampi ci l l i n and amoxi ci l l i n. Cef pr ozi l ( Cef zi l ) and l oracar bef
( Lor abi d) are second- gener at i on cephal ospori ns t hat can be admi ni st er ed
t wi ce dai l y but of f er no i mport ant spect rum di f f erences.
( 2) Cef oxi t i n ( Mef oxi n) i s t herapeut i c f or mi xed aer obi c- anaer obi c
i nf ect i ons, such as i nt r a-abdomi nal i nf ect i on. The cef ot et an ( Cef ot an)
spect rum i s si mi l ar but t hi s agent can be gi ven t wi ce dai l y.
( 3) Cef ur oxi me ( Zi nacef ) i s commonl y admi ni st ered f or out pat i ent
communi t y- acqui red pneumoni a.
c. Thi rd- generat i on cephal ospor i ns penet r at e t he cerebrospi nal f l ui d ( CSF)
and t hus ar e val uabl e i n t he t r eat ment of meni ngi t i s caused by such
or gani sms as meni ngococci , pneumococci , H. i nf l uenzae, and ent er i c gram-
negat i ve baci l l i .
P. 927


( 1) These agent s al so are used t o t r eat sepsi s of unknown or i gi n i n
i mmunosuppr essed pat i ent s and t o t r eat f ever i n neut ropeni c
i mmunosuppr essed pat i ent s ( gi ven i n combi nat i on wi t h an ami nogl ycosi de) .
( 2) Thi r d-gener at i on cephal ospor i ns ar e usef ul i n i nf ect i ons caused by many
or gani sms r esi st ant t o ol der cephal ospori ns.
( 3) These agent s ar e f r equent l y admi ni st er ed as empi r i c t herapy f or l i f e-
t hr eat eni ng i nf ect i on i n whi ch r esi st ant or gani sms are t he most l i kel y cause.
( 4) Ì ni t i al t her apy of mi xed bact er i al i nf ect i ons ( e. g. , sepsi s) commonl y
i nvol ves t hi r d- gener at i on cephal ospor i ns.
d. The f our t h- generat i on agent , cef epi me, i s approved f or t reat ment of
ur i nar y t r act i nf ect i ons, uncompl i cat ed ski n and ski n st r uct ur e i nf ect i ons,
pneumoni a, and empi ri c use i n f ebr i l e neut r openi c pat i ent s. Cef epi me has a
spect rum of act i vi t y si mi l ar t o t hi r d-gener at i on agent s but i s more r esi st ant
t o some 8- l act amases.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Because al l cephal ospor i ns ( except cef oper azone) ar e el i mi nat ed r enal l y,
doses must be adj ust ed f or pat i ent s wi t h renal i mpai rment .
b. Cr oss- sensi t i vi t y wi t h peni ci l l i n has been r eport ed i n up t o 10% of
pat i ent s recei vi ng cephal ospor i ns. Mor e r ecent i nf or mat i on i ndi cat es t hat
t r ue cr oss- r eact i vi t y i s rar e.
c. Cephal ospor i ns can cause hyper sensi t i vi t y r eact i ons si mi l ar t o t hose
r esul t i ng f r om peni ci l l i n (see Ì Ì . E. 1. e. ( 1)) . Mani f est at i ons i ncl ude f ever ,
macul opapul ar rash, anaphyl axi s, and hemol yt i c anemi a.
d. Ot her adver se ef f ect s i ncl ude nausea, vomi t i ng, di ar r hea, superi nf ect i on,
nephr ot oxi ci t y, and Cl ost r i di um di f f i ci l e-i nduced col i t i s; wi t h cef oper azone,
cef met azol e, and cef ot et an ( and f ormerl y moxal act am and cef amandol e) ,
bl eedi ng di at heses may occur . Bl eedi ng can be rever sed by vi t ami n K
admi ni st rat i on.
e. Cephal ospori ns may cause f al se- posi t i ve gl ycosur i a resul t s on t est s
usi ng t he copper r educt i on met hod.
f . Cef t r i axone now cont rai ndi cat ed i n newbor ns recei vi ng concur rent
admi ni st rat i on of cal ci um- cont ai ni ng sol ut i ons or pr oduct s due t o r i sk of
f at al preci pi t at i on i n l ungs and ki dneys. New war ni ng added al so st at i ng
t hat cef t r i axone and Ì V cal ci um- cont ai ni ng sol ut i ons shoul d not be
admi ni st er ed wi t hi n 48 hour s of each ot her .
5. Si gni f i cant i nt eract i ons
a. Pr obeneci d may i mpai r t he excr et i on of cephal ospor i ns ( except
cef t azi di me) , causi ng i ncr eased cephal ospor i n l evel s and possi bl e t oxi ci t y.
b. Al cohol consumpt i on may r esul t i n a di sul f i r am- t ype r eact i on i n pat i ent s
r ecei vi ng cef met azol e, cef ot et an, and cef oper azone.
c. Ami nogl ycosi des or l oop di uret i cs may cause addi t i ve t oxi ci t y when
admi ni st er ed wi t h cephal ot hi n.
d. Pl asma concent rat i ons of cef acl or ext ended- rel ease t abl et s, cef di ni r, and
cef podoxi me may be r educed by coadmi ni st r at i on wi t h ant aci ds.
e. H2-ant agoni st s may r educe pl asma l evel s of cef podoxi me and
cef ur oxi me.
f . Ì r on suppl ement s and i r on- f or t i f i ed f oods reduce absorpt i on of cef di ni r by
80% and 30%, respect i vel y.
E. Er yt hr omyci ns. The chemi cal st ruct ur e of t hese macrol i de ant i bi ot i cs i s
charact eri zed by a l act one ri ng t o whi ch sugars ar e at t ached. Er yt hr omyci n
base and t he est ol at e, et hyl succi nat e, and st ear at e sal t s ar e gi ven oral l y;
er yt hr omyci n l act obi onat e and gl ucept at e are gi ven par ent eral l y.
1. Mechani sm of act i on. Er yt hr omyci ns may be bact er i ci dal or
bact er i ost at i c; t hey bi nd t o t he 50S ri bosomal subuni t , i nhi bi t i ng bact er i al
pr ot ei n synt hesi s.
2. Spect r um of act i vi t y. Er yt hr omyci ns ar e act i ve agai nst many gr am-
posi t i ve or gani sms, i ncl udi ng st r ept ococci ( e. g. , St r ept ococcus
pneumoni ae) , and Cor ynebact eri um and Nei sser i a speci es as wel l as some
st r ai ns of Mycopl asma, Legi onel l a, Tr eponema, and Bor det el l a. Some S.
aur eus st rai ns t hat r esi st peni ci l l i n G ar e suscept i bl e t o er yt hr omyci ns.
3. Ther apeut i c uses
a. Er yt hromyci ns ar e t he pr ef er r ed drugs f or t he t r eat ment of Mycopl asma
pneumoni ae and Campyl obact er i nf ect i ons, Legi onnai r es di sease,
chl amydi al i nf ect i ons, di pht her i a, and pert ussi s.
P. 928


b. Ì n pat i ent s wi t h peni ci l l i n al l er gy, er yt hr omyci ns are i mpor t ant
al t er nat i ves i n t he t reat ment of pneumococcal pneumoni a, S. aur eus
i nf ect i ons, syphi l i s, and gonor r hea.
c. Er yt hr omyci ns may be gi ven pr ophyl act i cal l y bef or e dent al pr ocedur es t o
pr event bact er i al endocar di t i s.
4. Pr ecaut i ons and moni t or i ng par amet er s
a. Gast r oi nt est i nal ( GÌ ) di st ress (e. g. , nausea, vomi t i ng, di ar rhea,
epi gast r i c di scomf or t ) may occur wi t h al l er yt hr omyci n f or ms and ar e t he
most common adverse ef f ect s.
b. Al l ergi c r eact i ons ( r are) may pr esent as ski n er upt i ons, f ever , and
eosi nophi l i a.
c. Chol est at i c hepat i t i s may ari se i n pat i ent s t reat ed f or 1 week or l onger
wi t h er yt hr omyci n est ol at e; sympt oms usual l y di sappear wi t hi n a f ew days
af t er dr ug t her apy ends. Ther e have been i nf r equent repor t s of
hepat ot oxi ci t y wi t h ot her sal t s of er yt hromyci n.
d. Ì M i nj ect i ons of more t han 100 mg produce sever e pai n per si st i ng f or
hours.
e. Tr ansi ent heari ng i mpai r ment may devel op wi t h hi gh-dose er yt hr omyci n
t her apy.
5. Si gni f i cant i nt eract i ons
a. Er yt hromyci n i nhi bi t s t he hepat i c met abol i sm of t heophyl l i ne, r esul t i ng i n
t oxi c accumul at i on.
b. Er yt hromyci n i nt er f er es wi t h t he met abol i sm of di goxi n, cort i cost eroi ds,
car bamazepi ne, cycl ospor i n, and l ovast at i n, possi bl y pot ent i at i ng t he ef f ect
and t oxi ci t y of t hese dr ugs.
c. Cl ar i t hr omyci n ( Bi axi n) may pot ent i at e oral ant i coagul ant s ( moni t or
pr ot hr ombi n t i me) , i ncr ease cycl ospor i ne l evel s wi t h i ncr eased t oxi ci t y, and
i ncrease di goxi n and t heophyl l i ne l evel s.
d. Co-admi ni st r at i on of cl ar i t hr omyci n and ci sapr i de may i ncrease ri sk of
ser i ous car di ac ar r hyt hmi as; coadmi ni st rat i on i s cont r ai ndi cat ed.
e. Sudden deat hs have been repor t ed when cl ar i t hr omyci n was added t o
ongoi ng pi mozi de t her apy; co- admi ni st r at i on i s cont r ai ndi cat ed.
6. Al t er nat i ves t o er yt hr omyci n
a. Cl ar i t hr omyci n, azi t hromyci n (Zi t hr omax) , and di r i t hr omyci n ( Dynabac)
ar e semi synt het i c macr ol i de ant i bi ot i cs. These expensi ve but wel l - t ol erat ed
al t er nat i ves t o er yt hromyci n ar e admi ni st er ed once dai l y.
( 1) Cl ar i t hr omyci n
( a) Spect r um of act i vi t y. Cl ar i t hr omyci n i s more act i ve t han er yt hr omyci n
agai nst st aphyl ococci and st r ept ococci . Ì n addi t i on t o act i vi t y agai nst ot her
or gani sms cover ed by eryt hr omyci n, i t i s al so act i ve i n vi t r o agai nst MAÌ ,
Toxopl asma gondi i , and Cr ypt ospor i di um spp.
( b) Ther apeut i c uses. Thi s agent i s i ndi cat ed f or t he prevent i on of
Mycobact eri um avi um compl ex ( MAC) i nf ect i on and i s usef ul i n ot i t i s medi a,
si nusi t i s, mycopl asmal pneumoni a, and phar yngi t i s. Cl ari t hromyci n i s al so
used wi t h pr ot on pump i nhi bi t or s ( PPÌ s) f or Hel i cobact er pyl ori er adi cat i on.
( 2) Azi t hr omyci n
( a) Spect r um of act i vi t y. Azi t hr omyci n i s l ess act i ve t han er yt hr omyci n
agai nst gram- posi t i ve cocci but mor e act i ve agai nst H. i nf l uenzae and ot her
gr am- negat i ve organi sms. Azi t hr omyci n concent rat es wi t hi n cel l s, and
t i ssue l evel s are hi gher t han serum l evel s.
( b) Ther apeut i c uses. Thi s agent i s usef ul i n nongonococcal ur et hri t i s
caused by chl amydi a, l ower r espi r at or y t r act i nf ect i ons, ( MAC) i nf ect i on and
pr ophyl axi s, phar yngi t i s, pel vi c i nf l ammat or y di sease, and l egi onnai r es'
di sease. Azi t hromyci n i s al so i ndi cat ed f or pedi at r i c use.
( 3) Di ri t hromyci n i s i ndi cat ed f or t he t r eat ment of acut e exacer bat i ons of
chr oni c br onchi t i s, phar yngi t i s and t onsi l l i t i s caused by St r ept ococcus
pyogenes, and uncompl i cat ed ski n and ski n st r uct ur e i nf ect i ons caused by
S. aureus.
F. Peni ci l l i ns
1. Nat ur al peni ci l l i ns. As wi t h cephal ospor i ns and al l ot her peni ci l l i ns,
nat ural peni ci l l i ns ar e 8-l act am ant i bi ot i cs. Among t he most i mpor t ant
ant i bi ot i cs, nat ural peni ci l l i ns are t he pr ef er r ed dr ugs i n t he t reat ment of
many i nf ect i ous di seases.
a. Avai l abl e agent s
( 1) Peni ci l l i n G sodi um and pot assi um sal t s can be admi ni st ered or al l y,
i nt ravenousl y, or i nt ramuscul arl y.
P. 929


( 2) Peni ci l l i n V ( Pen- Vee K) , a sol ubl e dr ug f or m, i s admi ni st ered or al l y.
( 3) Peni ci l l i n G procai ne and peni ci l l i n G benzat hi ne are reposi t or y drug
f or ms. Admi ni st er ed i nt ramuscul ar l y, t hese i nsol ubl e sal t s al l ow sl ow dr ug
absor pt i on f rom t he i nj ect i on si t e and t hus have a l onger durat i on of act i on
( 12- 24 hr) .
b. Mechani sm of act i on. Peni ci l l i ns are bact er i ci dal ; t hey i nhi bi t bact er i al
cel l wal l synt hesi s i n a manner si mi l ar t o t hat of t he cephal ospor i ns.
c. Spect r um of act i vi t y
( 1) Nat ur al peni ci l l i ns are hi ghl y act i ve agai nst gr am-posi t i ve cocci and
agai nst some gr am- negat i ve cocci .
( 2) Peni ci l l i n G i s 5- 10 t i mes mor e act i ve t han peni ci l l i n V agai nst gram-
negat i ve or gani sms and some anaer obi c organi sms.
( 3) Because nat ural peni ci l l i ns ar e r eadi l y hydr ol yzed by peni ci l l i nases ( 8-
l act amases) , t hey are i nef f ect i ve agai nst S. aur eus and ot her or gani sms
t hat r esi st peni ci l l i n.
d. Ther apeut i c uses
( 1) Peni ci l l i n G i s t he pref er red agent f or al l i nf ect i ons caused by peni ci l l i n-
suscept i bl e S. pneumoni ae organi sms, i ncl udi ng
( a) Pneumoni a
( b) Ar t hr i t i s
( c) Meni ngi t i s
( d) Peri t oni t i s
( e) Peri car di t i s
( f ) Ost eomyel i t i s
( g) Mast oi di t i s
( 2) Peni ci l l i ns G and V ar e hi ghl y ef f ect i ve agai nst ot her st r ept ococcal
i nf ect i ons, such as phar yngi t i s, ot i t i s medi a, si nusi t i s, and bact er emi a.
( 3) Peni ci l l i n G i s t he pref er red agent i n gonococcal i nf ect i ons, syphi l i s,
ant hrax, act i nomycosi s, gas gangrene, and Li st eri a i nf ect i ons.
( 4) Admi ni st ered when an or al peni ci l l i n i s needed, peni ci l l i n V i s most
usef ul i n ski n, sof t - t i ssue, and mi l d respi rat or y i nf ect i ons.
( 5) Peni ci l l i n G procai ne i s ef f ect i ve agai nst syphi l i s and uncompl i cat ed
gonor r hea.
( 6) Used t o t r eat syphi l i s i nf ect i ons out si de t he CNS, peni ci l l i n G
benzat hi ne al so i s ef f ect i ve agai nst gr oup A8-hemol yt i c st rept ococcal
i nf ect i ons.
( 7) Peni ci l l i ns G and V may be used pr ophyl act i cal l y t o pr event
st r ept ococcal i nf ect i on, rheumat i c f ever , and neonat al gonor r hea
opht hal mi a. Pat i ent s wi t h val vul ar heart di sease may r ecei ve t hese drugs
pr eoper at i vel y.
( 8) Ther e i s emergi ng r esi st ance t o peni ci l l i n G by S. pneumoni ae i n some
ar eas of t he Uni t ed St at es. The al t ernat i ve t her apy i s vancomyci n.
e. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Hypersensi t i vi t y react i ons. These occur i n up t o 10% of pat i ent s
r ecei vi ng peni ci l l i n. Mani f est at i ons range f rom mi l d r ash t o anaphyl axi s.
( a) The rash may be ur t i car i al , vesi cul ar , bul l ous, scarl at i ni f orm, or
macul opapul ar . Rar el y, t hr ombopeni c purpura devel ops.
( b) Anaphyl axi s i s a l i f e-t hr eat eni ng r eact i on t hat most commonl y occurs
wi t h par ent eral admi ni st rat i on. Si gns and sympt oms i ncl ude sever e
hypot ensi on, bronchoconst r i ct i on, nausea, vomi t i ng, abdomi nal pai n, and
ext r eme weakness.
( c) Ot her mani f est at i ons of hyper sensi t i vi t y r eact i ons i ncl ude f ever,
eosi nophi l i a, angi oedema, and serum si ckness.
( d) Bef or e peni ci l l i n t herapy begi ns, t he pat i ent ' s hi st or y shoul d be
eval uat ed f or r eact i ons t o peni ci l l i n. A posi t i ve hi st or y pl aces t he pat i ent at
hei ght ened r i sk f or a subsequent r eact i on. Ì n most cases, such pat i ent s
shoul d r ecei ve a subst i t ut e ant i bi ot i c. ( However , hyper sensi t i vi t y r eact i ons
may occur even i n pat i ent s wi t h a negat i ve hi st or y. )
( 2) Ot her adver se ef f ect s of nat ural peni ci l l i ns i ncl ude GÌ di st ress (e. g. ,
nausea, di ar rhea), bone mar row suppr essi on ( e. g. , i mpai r ed pl at el et
aggregat i on, agr anul ocyt osi s) , and super i nf ect i on. Wi t h hi gh- dose t her apy,
sei zures may occur, par t i cul arl y i n pat i ent s wi t h r enal i mpai rment .
f . Si gni f i cant i nt eract i ons
( 1) Pr obeneci d i ncr eases bl ood l evel s of nat ural peni ci l l i ns and may be
gi ven concur r ent l y f or t hi s pur pose.
P. 930


( 2) Ant i bi ot i c ant agoni sm occurs when er yt hr omyci ns, t et r acycl i nes, or
chl or ampheni col i s gi ven wi t hi n 1 hr of t he admi ni st r at i on of peni ci l l i n. The
cl i ni cal si gni f i cance of such ant agoni sm i s not cl ear .
( 3) Wi t h peni ci l l i n G procai ne and benzat hi ne, pr ecaut i on must be used i n
pat i ent s wi t h a hi st or y of hypersensi t i vi t y react i ons t o peni ci l l i ns because
pr ol onged react i ons may occur . Ì nt r avascul ar i nj ect i on shoul d be avoi ded.
Pr ocai ne hyper sensi t i vi t y i s a cont rai ndi cat i on t o t he use of procai ne
peni ci l l i n G.
( 4) Parent er al product s cont ai n ei t her pot assi um (1. 7 mEq/ mi l l i on uni t s) or
sodi um ( 2 mEq/ mi l l i on uni t s) .
2. Peni ci l l i nase- resi st ant peni ci l l i ns. These peni ci l l i ns ar e not hydrol yzed by
st aphyl ococcal peni ci l l i nases ( 8-l act amases) . These agent s i ncl ude
met hi ci l l i n, naf ci l l i n, and t he i soxazol yl peni ci l l i ns÷cl oxaci l l i n, di cl oxaci l l i n
( Dynapen) , and oxaci l l i n.
a. Mechani sm of act i on (see Ì Ì . E. 1. b)
b. Spect r um of act i vi t y. Because t hese peni ci l l i ns r esi st peni ci l l i nases, t hey
ar e act i ve agai nst st aphyl ococci t hat pr oduce t hese enzymes.
c. Therapeut i c uses
( 1) Peni ci l l i nase- resi st ant peni ci l l i ns ar e used sol el y i n st aphyl ococcal
i nf ect i ons resul t i ng f r om or gani sms t hat r esi st nat ur al peni ci l l i ns.
( 2) These agent s ar e l ess pot ent t han nat ur al peni ci l l i ns agai nst or gani sms
suscept i bl e t o nat ural peni ci l l i ns and t hus make poor subst i t ut es i n t he
t r eat ment of i nf ect i ons caused by t hese organi sms.
( 3) Naf ci l l i n i s excr et ed by t he l i ver and t hus may be usef ul i n t r eat i ng
st aphyl ococcal i nf ect i ons i n pat i ent s wi t h renal i mpai r ment .
( 4) Oxaci l l i n, cl oxaci l l i n, and di cl oxaci l l i n ar e most val uabl e i n l ong- t erm
t her apy of ser i ous st aphyl ococcal i nf ect i ons ( e. g. , endocar di t i s,
ost eomyel i t i s) and i n t he t r eat ment of mi nor st aphyl ococcal i nf ect i ons of t he
ski n and sof t t i ssues.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) As wi t h al l peni ci l l i ns, t he peni ci l l i nase- resi st ant gr oup can cause
hyper sensi t i vi t y r eact i ons (see Ì Ì . E. 1. e. ( 1) ).
( 2) Met hi ci l l i n may cause nephr ot oxi ci t y and i nt erst i t i al nephr i t i s.
( 3) Oxaci l l i n may be hepat ot oxi c.
( 4) Compl et e cross- resi st ance exi st s among t he peni ci l l i nase- r esi st ant
peni ci l l i ns.
e. Si gni f i cant i nt eract i ons. Probeneci d i ncreases bl ood l evel s of t hese
peni ci l l i ns and may be gi ven concur r ent l y f or t hat pur pose.
3. Ami nopeni ci l l i ns. Thi s peni ci l l i n gr oup i ncl udes t he semi synt het i c agent s
ampi ci l l i n and amoxi ci l l i n ( Amoxi l ) . Because of t hei r wi der ant i bact eri al
spect rum, t hese drugs are al so known as br oad-spect r um peni ci l l i ns.
a. Mechani sm of act i on (see Ì Ì . E. 1. b)
b. Spect r um of act i vi t y. Ami nopeni ci l l i ns have a spect rum t hat i s si mi l ar t o
but br oader t han t hat of t he nat ur al and peni ci l l i nase-r esi st ant peni ci l l i ns.
Easi l y dest royed by st aphyl ococcal peni ci l l i nases, ami nopeni ci l l i ns ar e
i nef f ect i ve agai nst most st aphyl ococcal or gani sms. Agai nst most bact er i a
sensi t i ve t o peni ci l l i n G, ami nopeni ci l l i ns ar e sl i ght l y l ess ef f ect i ve t han t hi s
agent .
c. Therapeut i c uses. Ami nopeni ci l l i ns are used t o t r eat gonococcal
i nf ect i ons, upper respi rat or y i nf ect i ons, uncompl i cat ed ur i nar y t r act
i nf ect i ons, and ot i t i s medi a caused by suscept i bl e or gani sms.
( 1) For i nf ect i ons r esul t i ng f rom peni ci l l i n- r esi st ant organi sms, ampi ci l l i n
may be gi ven i n combi nat i on wi t h sul bact am ( Unasyn) .
( 2) Amoxi ci l l i n i s l ess ef f ect i ve t han ampi ci l l i n agai nst shi gel l osi s.
( 3) Amoxi ci l l i n i s mor e ef f ect i ve agai nst S. aureus, Kl ebsi el l a, and
Bact er oi des f ragi l i s i nf ect i ons when admi ni st ered i n combi nat i on wi t h
cl avul ani c aci d÷amoxi ci l l i n/ pot assi um cl avul anat e ( Augment i n) because
cl avul ani c aci d i nact i vat es peni ci l l i nases.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Hypersensi t i vi t y react i ons may occur (see Ì Ì . E. 1. e. ( 1) ) .
( 2) Di ar r hea i s most common wi t h ampi ci l l i n.
( 3) Ì n addi t i on t o t he urt i car i al hypersensi t i vi t y r ash seen wi t h al l
peni ci l l i ns, ampi ci l l i n and amoxi ci l l i n f requent l y cause a gener al i zed
er yt hemat ous, macul opapul ar r ash. ( Thi s occur s i n 5%- 10% of pat i ent s
r ecei vi ng ampi ci l l i n. )
e. Si gni f i cant i nt eract i ons (see Ì Ì . E. 2. e)
P. 931


4. Ext ended- spect r um peni ci l l i ns. These agent s have t he wi dest
ant i bact eri al spect rum of al l peni ci l l i ns. Al so cal l ed ant i pseudomonal
peni ci l l i ns, t hi s gr oup i ncl udes t he carboxypeni ci l l i n ( e. g. , t i carci l l i n) and
t he ur ei dopeni ci l l i ns (e. g. , mezl oci l l i n, pi per aci l l i n) .
a. Mechani sm of act i on (see Ì Ì . E. 1. b)
b. Spect r um of act i vi t y. These dr ugs have a spect r um si mi l ar t o t hat of t he
ami nopeni ci l l i ns but al so ar e ef f ect i ve agai nst Kl ebsi el l a and Ent er obact er
spp. , some B. f r agi l i s organi sms, and i ndol e- posi t i ve Pr ot eus and
Pseudomonas or gani sms.
( 1) Ti car ci l l i n i s act i ve agai nst P. aer ugi nosa. Combi ned wi t h cl avul ani c
aci d ( Ti ment i n) , t i carci l l i n has enhanced act i vi t y agai nst organi sms t hat
r esi st t i carci l l i n al one.
( 2) Pi peraci l l i n i s mor e act i ve t han t i car ci l l i n agai nst Pseudomonas
or gani sms.
( 3) Pi peraci l l i n and t azobact am ( Zosyn) . Tazobact am i s a 8- l act amase
i nhi bi t or t hat expands t he spect r um of act i vi t y t o i ncl ude some or gani sms
not sensi t i ve t o pi per aci l l i n al one ( i f r esi st ance i s t he r esul t of 8- l act amase
pr oduct i on) , i ncl udi ng st rai ns of st aphyl ococci , Haemophi l us, Bact eroi des,
and Ent erobact er i aceae. General l y, t azobact am does not enhance act i vi t y
agai nst Pseudomonas.
c. Therapeut i c uses. Ext ended-spect rum peni ci l l i ns ar e used mai nl y t o t reat
ser i ous i nf ect i ons caused by gram-negat i ve organi sms ( e. g. , sepsi s;
pneumoni a; i nf ect i ons of t he abdomen, bone, and sof t t i ssues) .
Pi peraci l l i n/ t azobact am i s ef f ect i ve i n t he t r eat ment of nosocomi al
pneumoni a.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Hypersensi t i vi t y react i ons may occur (see Ì Ì . E. 1. e. ( 1) ) .
( 2) Ti car ci l l i n may cause hypokal emi a.
( 3) The hi gh sodi um cont ent of t i car ci l l i n may pose a danger t o pat i ent s
wi t h heart f ai l ur e ( HF) .
( 4) Al l i nhi bi t pl at el et aggr egat i on, whi ch may resul t i n bl eedi ng.
e. Si gni f i cant i nt eract i ons (see Ì Ì . E. 2. e)
G. Sul f onami des. Der i vat i ves of sul f ani l ami de, t hese agent s wer e t he f i rst
dr ugs t o prevent and cure human bact er i al i nf ect i on successf ul l y. Al t hough
t hei r cur r ent usef ul ness i s l i mi t ed by t he i nt roduct i on of more ef f ect i ve
ant i bi ot i cs and t he emergence of resi st ant bact eri al st rai ns, sul f onami des
r emai n t he drugs of choi ce f or cer t ai n i nf ect i ons. The maj or sul f onami des
ar e sul f adi azi ne, sul f amet hoxazol e, sul f i soxazol e, and sul f amet hi zol e.
1. Mechani sm of act i on. Sul f onami des are bact er i ost at i c; t hey suppr ess
bact er i al gr owt h by t r i gger i ng a mechani sm t hat bl ocks f ol i c aci d synt hesi s,
t her eby f orci ng bact eri a t o synt hesi ze t hei r own f ol i c aci d.
2. Spect r um of act i vi t y. Sul f onami des are broad-spect rum agent s wi t h
act i vi t y agai nst many gram- posi t i ve or gani sms (e. g. , S. pyogenes, S.
pneumoni ae) and cer t ai n gr am- negat i ve or gani sms ( e. g. , H. i nf l uenzae, E.
col i , P. mi r abi l i s) . They al so are ef f ect i ve agai nst cer t ai n st r ai ns of
Chl amydi a t r achomat i s, Nocardi a, Act i nomyces, and Baci l l us ant hraci s.
3. Ther apeut i c uses
a. Sul f onami des most of t en are used t o t reat ur i nar y t r act i nf ect i ons caused
by E. col i , i ncl udi ng acut e and chr oni c cyst i t i s, and chr oni c upper uri nar y
t r act i nf ect i ons.
b. These agent s have val ue i n t he t r eat ment of nocardi osi s, t r achoma and
i ncl usi on conj unct i vi t i s, and dermat i t i s herpet i f or mi s.
c. Sul f adi azi ne may be admi ni st ered i n combi nat i on wi t h pyr i met hami ne t o
t r eat t oxopl asmosi s.
d. Sul f amet hoxazol e may be gi ven i n combi nat i on wi t h t ri met hopr i m
( Bact ri m) t o t r eat such i nf ect i ons as Pneumocyst i s car i ni i pneumoni a,
Shi gel l a ent eri t i s, Ser rat i a sepsi s, ur i nar y t ract i nf ect i ons, r espi r at or y
i nf ect i ons, and gonococcal ur et hr i t i s ( see Ì Ì . J. 7. c). Ì t i s t he drug of choi ce
i n t he t r eat ment of St enot r ophomonas mal t ophi l i a.
e. Sul f i soxazol e i s somet i mes used i n combi nat i on wi t h er yt hr omyci n
et hyl succi nat e t o t reat acut e ot i t i s medi a caused by H. i nf l uenzae
or gani sms. For t he i ni t i al t r eat ment of uncompl i cat ed ur i nar y t ract
i nf ect i ons, sul f i soxazol e may be gi ven i n combi nat i on wi t h phenazopyr i di ne
f or r el i ef of sympt oms of pai n, bur ni ng, or urgency.
f . Pr ophyl act i c sul f onami de t her apy has been used successf ul l y t o pr event
st r ept ococcal i nf ect i ons and rheumat i c f ever r ecur r ences.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Sul f onami des may cause bl ood dyscr asi as ( e. g. , hemol yt i c anemi a÷
par t i cul arl y i n pat i ent s wi t h G6PD def i ci ency, apl ast i c anemi a,
t hr ombocyt openi a, agranul ocyt osi s, and eosi nophi l i a) .
P. 932


b. Hypersensi t i vi t y react i ons t o sul f onami des probabl y r esul t f r om
sensi t i zat i on and most commonl y i nvol ve t he ski n and mucous membr anes.
Mani f est at i ons i ncl ude var i ous t ypes of ski n r ash, exf ol i at i ve dermat i t i s, and
phot osensi t i vi t y. Dr ug f ever and ser um si ckness al so may devel op.
c. Cr yst al l uri a and hemat ur i a may occur , possi bl y l eadi ng t o uri nar y t r act
obst r uct i on. ( Adequat e f l ui d i nt ake and ur i ne al kal i ni zat i on can prevent or
mi ni mi ze t hi s r i sk. ) Sul f onami des shoul d be used caut i ousl y i n pat i ent s wi t h
r enal i mpai rment .
d. Li f e-t hr eat eni ng hepat i t i s caused by drug t oxi ci t y or sensi t i zat i on i s a
r ar e adverse ef f ect . Si gns and sympt oms i ncl ude headache, nausea,
vomi t i ng, and j aundi ce.
e. AÌ DS pat i ent s have i ncr eased f requency of cut aneous hypersensi t i vi t y
r eact i ons t o sul f amet hoxazol e.
5. Si gni f i cant i nt eract i ons. Sul f onami des may pot ent i at e t he ef f ect s of
phenyt oi n, oral ant i coagul ant s, and sul f onyl ur eas.
H. Tet r acycl i nes. These br oad- spect r um agent s ar e ef f ect i ve agai nst cert ai n
bact er i al st rai ns t hat r esi st ot her ant i bi ot i cs. Nonet hel ess, t hey ar e t he
pr ef er r ed dr ugs i n onl y a f ew si t uat i ons. The maj or t et r acycl i nes i ncl ude
demecl ocycl i ne ( Decl omyci n) , doxycycl i ne ( Vi br amyci n) , mi nocycl i ne
( Mi noci n), and chl or t et r acycl i ne.
1. Mechani sm of act i on. Tet r acycl i nes ar e bact er i ost at i c; t hey i nhi bi t
bact er i al pr ot ei n synt hesi s by bi ndi ng t o t he 30S r i bosomal subuni t .
2. Spect r um of act i vi t y. Tet r acycl i nes ar e act i ve agai nst gram- negat i ve and
gr am- posi t i ve or gani sms, spi r ochet es, Mycopl asma and Chl amydi a
or gani sms, ri cket t si al speci es, and cer t ai n prot ozoa.
a. Pseudomonas and Pr ot eus organi sms are now r esi st ant t o t et racycl i nes.
Many col i f or m bact er i a, pneumococci , st aphyl ococci , st rept ococci , and
Shi gel l a st r ai ns are i ncreasi ngl y r esi st ant .
b. Cr oss- r esi st ance wi t hi n t he t et r acycl i ne group i s ext ensi ve.
3. Ther apeut i c uses
a. Tet r acycl i nes ar e t he agent s of choi ce i n ri cket t si al ( Rocky Mount ai n
spot t ed f ever) , chl amydi al , and mycopl asmal i nf ect i ons; amebi asi s; and
baci l l ar y i nf ect i ons (e. g. , chol era, br ucel l osi s, t ul ar emi a, some Sal monel l a
and Shi gel l a i nf ect i ons).
b. Tet r acycl i nes ar e usef ul al t er nat i ves t o peni ci l l i n i n t he t r eat ment of
ant hrax, syphi l i s, gonor rhea, Lyme di sease, nocar di osi s, and H. i nf l uenzae
r espi r at or y i nf ect i ons.
c. Or al or t opi cal t et r acycl i ne may be admi ni st er ed as a t r eat ment f or acne.
d. Doxycycl i ne i s hi ghl y ef f ect i ve i n t he prophyl axi s of " t ravel er ' s di ar rhea¨
( commonl y caused by E. col i ) . Because t he drug i s excr et ed mai nl y i n t he
f eces, i t i s t he saf est t et r acycl i ne f or t he t r eat ment of ext r ar enal i nf ect i ons
i n pat i ent s wi t h r enal i mpai rment .
e. Demecl ocycl i ne i s used commonl y as an adj unct i ve agent t o t r eat t he
syndr ome of i nappropri at e ant i di uret i c hormone (SÌ ADH) secret i on.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. GÌ di st r ess ( e. g. , di ar rhea, abdomi nal di scomf or t , nausea, anor exi a) i s a
common adverse ef f ect of t et r acycl i nes. Thi s pr obl em can be mi ni mi zed by
admi ni st er i ng t he dr ug wi t h f ood or t empor ari l y decr easi ng t he dosage.
b. Ski n r ash, ur t i car i a, and gener al i zed exf ol i at i ve dermat i t i s si gni f y a
hyper sensi t i vi t y r eact i on. Rar el y, angi oedema and anaphyl axi s occur .
c. Cr oss- sensi t i vi t y wi t hi n t he t et r acycl i ne group i s common.
d. Phot ot oxi c r eact i ons (sever e ski n l esi ons) can devel op wi t h exposur e t o
sunl i ght . Thi s r eact i on i s most common wi t h demecl ocycl i ne and
doxycycl i ne.
e. Tet r acycl i nes may cause hepat ot oxi ci t y, par t i cul arl y i n pr egnant women.
Mani f est at i ons i ncl ude j aundi ce, aci dosi s, and f at t y l i ver i nf i l t rat i on.
f . Renal l y i mpai r ed pat i ent s may exper i ence a si gni f i cant i ncr ease i n BUN
secondar y t o cat abol i c ef f ect s of t et racycl i nes.
g. Tet r acycl i nes may i nduce permanent t oot h di scol or at i on, t oot h enamel
def ect s, and r et ar ded bone growt h i n i nf ant s and chi l dren.
h. Use of out dat ed and degr aded t et r acycl i nes can l ead t o renal t ubul ar
dysf unct i on, possi bl y r esul t i ng i n r enal f ai l ure.
i . Mi nocycl i ne can cause vest i bul ar t oxi ci t y ( e. g. , at axi a, di zzi ness, nausea,
vomi t i ng).
j . Ì V t et racycl i nes are i r r i t at i ng and may cause phl ebi t i s.
P. 933


5. Si gni f i cant i nt eract i ons
a. Dai r y pr oduct s and ot her f oods, i r on prepar at i ons, and ant aci ds and
l axat i ves cont ai ni ng al umi num, cal ci um, or magnesi um can cause r educed
t et r acycl i ne absor pt i on. Absorpt i on of doxycycl i ne i s not i nhi bi t ed by t hese
f act or s.
b. Met hoxyf l ur ane may exacer bat e t he t et r acycl i nes' nephr ot oxi c ef f ect s.
c. Bar bi t ur at es and phenyt oi n decr ease t he ant i bi ot i c ef f ect i veness of
t et r acycl i nes.
d. Demecl ocycl i ne ant agoni zes t he act i on of ant i di uret i c hormone ( ADH)
and may be gi ven as a di ur et i c i n pat i ent s wi t h SÌ ADH.
Ì . Fl uoroqui nol ones are agent s r el at ed t o nal i di xi c aci d÷see Ì Ì . Ì . 1. c;
Ì Ì . 2. c. (1) ; Ì Ì . 4. c. ( 1) ÷and i ncl ude ci pr of l oxaci n ( Ci pr o) , enoxaci n ( Penet r ex) ,
l omef l oxaci n ( Maxaqui n), norf l oxaci n ( Noroxi n) , of l oxaci n ( Fl oxi n) ,
moxi f l oxaci n ( Avel ox) , l evof l oxaci n ( Levaqui n) , and gemi f l oxaci n (Fact i ve) .
They ar e bact er i ci dal f or gr owi ng bact eri a.
1. Mechani sm of act i on. Fl uor oqui nol ones i nhi bi t DNA gyr ase.
2. Spect r um of act i vi t y. Fl uor oqui nol ones ar e hi ghl y act i ve agai nst ent er i c
gr am- negat i ve baci l l i , Sal monel l a, Shi gel l a, Campyl obact er, Haemophi l us,
and Nei sser i a.
a. Ci pr of l oxaci n has act i vi t y agai nst P. aerugi nosa, but t he f l uor oqui nol ones
as a group have var i abl e act i vi t y agai nst non- P. aer ugi nosa. Ci pr of l oxaci n
i s act i ve agai nst some anaerobes; i t has moder at e act i vi t y agai nst M.
t ubercul osi s.
b. Gr am- posi t i ve or gani sms ar e l ess suscept i bl e t han gr am- negat i ve
or gani sms but usual l y are sensi t i ve, except f or Ent er ococcus f aecal i s and
met hi ci l l i n- r esi st ant st aphyl ococci .
c. Of l oxaci n has t he gr eat est act i vi t y agai nst Chl amydi a.
3. Ther apeut i c uses ( Tabl e 44-3)
a. Nor f l oxaci n i s i ndi cat ed f or t he oral t r eat ment of uri nar y t r act i nf ect i ons,
uncompl i cat ed gonococcal i nf ect i ons, and prost at i t i s.
b. Ci pr of l oxaci n, of l oxaci n, and l evof l oxaci n ar e avai l abl e or al l y and
i nt ravenousl y. Ci prof l oxaci n i s appr oved f or use i n uri nar y t r act i nf ect i ons;
l ower r espi rat or y i nf ect i ons; si nusi t i s; bone, j oi nt , and ski n st r uct ure
i nf ect i ons; empi ri c use i n f ebr i l e neut r openi c pat i ent s; t yphoi d f ever ;
ur et hr al and cer vi cal gonococcal i nf ect i ons; and i nf ect i ous di ar rhea.
Of l oxaci n i s appr oved f or use i n l ower r espi rat ory i nf ect i ons, uncompl i cat ed
gonococcal and chl amydi al cer vi ci t i s and ur et hr i t i s, ski n and ski n st r uct ure
i nf ect i ons, pr ost at i t i s, and uri nar y t r act i nf ect i ons.
c. Lomef l oxaci n, l evof l oxaci n, and enoxaci n ar e appr oved f or t he t reat ment
of uri nar y t r act i nf ect i ons. Lomef l oxaci n, moxi f l oxaci n, and l evof l oxaci n ar e
al so used i n l ower r espi rat or y i nf ect i ons.
d. Moxi f l oxaci n i s appr oved f or t he t r eat ment of compl i cat ed i nt ra-
abdomi nal i nf ect i ons but shoul d not be used f or ur i nar y t r act i nf ect i ons.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Occasi onal adver se ef f ect s i ncl ude nausea, dyspepsi a, headache,
di zzi ness, i nsomni a, cardi ac QT pr ol ongat i on, art hr opat hy, t endoni t i s, CNS
ef f ect s, phot osensi t i vi t y, and hypogl ycemi a.
Table 44-3. Quinolone Agents Classified by Generation
Agent
Spectrum of
Coverage Site of Infection
First-
generation
Cinoxacin
(Cinoxacin.
Cinobac)
Gram
negatives
Urinary tract
Enoxacin (Penetrex)

Nalidixic acid
(NegGram)


NorIloxacin
(Noroxin)

Second-
generation
LomeIloxacin
(Maxaquin)
Gram
negatives
Urinary tract

CiproIloxacin
(Cipro)
Systemic.
urinary tract

OIloxacin (Floxin)

Systemic.
urinary tract
Third-
generation
LevoIloxacin
(Levaquin)
Gram
negatives
Systemic.
urinary tract

MoxiIloxacin
(Avelox)
Atypicals Systemic only

P. 934


b. Ì nf r equent adverse ef f ect s i ncl ude rash, ur t i cari a, l eukopeni a, and
el evat ed l i ver enzymes. Cr yst al l uri a occurs wi t h hi gh doses at al kal i ne pH.
c. The FDA has added a bl ack box war ni ng about t he i ncr eased ri sk of
devel opi ng t endi ni t i s and t endon r upt ur e i n pat i ent s t aki ng t hi s cl ass of
medi cat i ons.
5. Si gni f i cant i nt eract i ons
a. Ci pr of l oxaci n has been shown t o i ncr ease t heophyl l i ne l evel s. Var i abl e
ef f ect s on t heophyl l i ne l evel s have been repor t ed f r om ot her members of
t he gr oup. Ì n pat i ent s requi ri ng f l uoroqui nol ones, t heophyl l i ne l evel s shoul d
be moni t ored.
b. Ant aci ds and sucr al f at e and di val ent or t ri val ent cat i ons such as i r on
si gni f i cant l y decr ease t he absorpt i on of f l uor oqui nol ones.
c. Fl uor oqui nol ones may i ncr ease pr ot hrombi n t i mes i n pat i ent s recei vi ng
war f ar i n.
d. Concur r ent use wi t h nonst er oi dal ant i - i nf l ammat or y drugs ( NSAÌ Ds) may
i ncrease t he r i sk of CNS st i mul at i on (sei zures).
e. Fl uoroqui nol ones may pr oduce prol onged QT i nt er val when admi ni st ered
wi t h ci sapr i de and ant i arr hyt hmi c agent s. Some f l uor oqui nol ones ( i . e. ,
gat i f l oxaci n, moxi f l oxaci n) shoul d be avoi ded i n pat i ent s wi t h known
pr ol ongat i on of t he QTC i nt er val , wi t h uncor rect ed hypocal cemi a, or who
ar e recei vi ng cl ass Ì A or cl ass Ì Ì Ì ant i ar r hyt hmi c dr ugs.
f . Some f l uor oqui nol ones have been r epor t ed t o enhance t he ef f ect s of oral
ant i coagul ant s.
g. Hypergl ycemi a and hypogl ycemi a have been repor t ed i n pat i ent s
r ecei vi ng qui nol ones and an ant i di abet i c agent . Bl ood gl ucose moni t or i ng i s
r ecommended i n such pat i ent s.
h. Di danosi ne shoul d be admi ni st er ed at l east 4 hr af t er gat i f l oxaci n.
J. Uri nar y t r act ant i sept i cs. Concent r at i ng i n t he r enal t ubul es and bl adder ,
t hese agent s exer t l ocal ant i bact eri al ef f ect s; most do not achi eve bl ood
l evel s hi gh enough t o t reat syst emi c i nf ect i ons. However , some new
qui nol one der i vat i ves, such as ci pr of l oxaci n and of l oxaci n, are val uabl e i n
t he t r eat ment of cert ai n i nf ect i ons out si de t he uri nar y t r act ( see Ì Ì . H. 3. b) .
1. Mechani sm of act i on
a. Met henami ne i s hydrol yzed t o ammoni a and f or mal dehyde i n aci di c ur i ne;
f or mal dehyde i s ant i bact er i al agai nst gram-posi t i ve and gr am- negat i ve
or gani sms. Mandel i c and hi ppuri c aci ds, wi t h whi ch met henami ne i s
combi ned, provi de suppl ement ar y ant i bact er i al act i on.
b. Ni t r of ur ant oi n i s bact er i ost at i c; i n hi gh concent r at i ons, i t may be
bact er i ci dal . Presumabl y, i t di sr upt s bact er i al enzyme syst ems.
c. Qui nol ones. Nal i di xi c aci d and i t s anal ogs and deri vat i ves÷oxol i ni c aci d,
nor f l oxaci n, ci noxaci n, ci pr of l oxaci n, and ot hers÷i nt er f ere wi t h DNA gyr ase
and i nhi bi t DNA synt hesi s dur i ng bact eri al r epl i cat i on.
d. Fosf omyci n t r omet hami ne i s bact eri ci dal i n t he uri ne at t herapeut i c
doses. The bact er i ci dal act i on i s because of i t s i nact i vat i on of t he enzyme
enol pyr uvyl t r ansf erase, t her eby bl ocki ng t he condensat i on of ur i di ne
di phosphat e- N-acet yl gl ucosami ne wi t h p- enol pyruvat e, one of t he f i r st st eps
i n bact er i al cel l wal l synt hesi s.
2. Spect r um of act i vi t y
a. Met henami ne i s act i ve agai nst bot h gram-posi t i ve and gr am- negat i ve
or gani sms ( e. g. , Ent er obact er , Kl ebsi el l a, Pr ot eus, P. aerugi nosa, S.
aur eus).
b. Ni t r of ur ant oi n i s act i ve agai nst many gram-posi t i ve and gr am- negat i ve
or gani sms, i ncl udi ng some st rai ns of E. col i , S. aur eus, Pr ot eus,
Ent erobact er , and Kl ebsi el l a.
c. Qui nol ones ( see Ì Ì . H)
( 1) Nal i di xi c aci d and oxol i ni c aci d are act i ve agai nst most gr am- negat i ve
or gani sms t hat cause uri nar y t r act i nf ect i ons, i ncl udi ng P. mi r abi l i s, E. col i ,
Kl ebsi el l a, and Ent er obact er or gani sms. These drugs ar e not ef f ect i ve
agai nst Pseudomonas organi sms.
( 2) Nor f l oxaci n i s act i ve agai nst E. col i , Ent er obact er, Kl ebsi el l a, Prot eus,
P. aerugi nosa, S. aur eus, Ci t robact er , and some St r ept ococcus or gani sms.
( 3) Ci noxaci n i s act i ve agai nst E. col i , Kl ebsi el l a, P. mi r abi l i s, Prot eus
vul gari s, Pr ot eus mor gani i , Ser rat i a, and Ci t robact er or gani sms.
3. Ther apeut i c uses
a. Met henami ne and ni t rof ur ant oi n ar e used t o prevent and t r eat ur i nar y
t r act i nf ect i ons.
P. 935


b. Qui nol ones ar e admi ni st er ed t o t r eat ur i nar y t ract i nf ect i ons; some al so
ar e used i n such di seases as ost eomyel i t i s and respi rat or y t r act i nf ect i ons.
c. Fosf omyci n i s i ndi cat ed f or t r eat ment of uncompl i cat ed ur i nar y t ract
i nf ect i on ( acut e cyst i t i s) i n women caused by suscept i bl e st rai ns of E. col i
or E. f aecal i s.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Met henami ne may cause nausea, vomi t i ng, and di ar r hea; i n hi gh doses,
i t may l ead t o ur i nar y t ract i r r i t at i on (e. g. , dysuri a, f r equency, hemat ur i a,
al bumi nuri a). Ski n r ash al so may devel op.
b. Ni t r of ur ant oi n may cause var i ous adverse ef f ect s.
( 1) GÌ di st r ess ( e. g. , nausea, vomi t i ng, di ar r hea) i s rel at i vel y common.
( 2) Hypersensi t i vi t y react i ons t o ni t rof urant oi n may i nvol ve t he ski n, l ungs,
bl ood, or l i ver ; mani f est at i ons i ncl ude f ever , chi l l s, hepat i t i s, j aundi ce,
l eukopeni a, hemol yt i c anemi a, gr anul ocyt openi a, and pneumoni t i s.
( 3) Adverse CNS ef f ect s i ncl ude headache, ver t i go, and di zzi ness.
Pol yneur opat hy may devel op wi t h hi gh doses or i n pat i ent s wi t h r enal
i mpai rment .
c. Qui nol ones
( 1) Nal i di xi c aci d and oxol i ni c aci d may cause nausea, vomi t i ng, abdomi nal
pai n, urt i cari a, pr uri t us, ski n rash, f ever , eosi nophi l i a, and CNS ef f ect s,
such as headache, di zzi ness, conf usi on, ver t i go, dr owsi ness, and
weakness.
( 2) Ci noxaci n may i nduce nausea, vomi t i ng, di ar rhea, headache, i nsomni a,
ski n rash, pr ur i t us, and ur t i cari a.
5. Si gni f i cant i nt eract i ons
a. The ef f ect s of met henami ne ar e i nhi bi t ed by al kal i ni zi ng agent s and are
ant agoni zed by acet azol ami de.
b. Ni t r of ur ant oi n absor pt i on i s decr eased by magnesi um- cont ai ni ng
ant aci ds. Ni t rof ur ant oi n bl ood l evel s ar e i ncr eased and ur i ne l evel s
decreased by sul f i npyr azone and probeneci d, l eadi ng t o i ncr eased t oxi ci t y
and reduced t herapeut i c ef f ect i veness.
c. Qui nol ones
( 1) Ci noxaci n ur i ne l evel s are decreased by probeneci d, r educi ng
t her apeut i c ef f ect i veness.
( 2) Nor f l oxaci n i s rendered l ess ef f ect i ve by ant aci ds.
K. Mi scel l aneous ant i bact er i al agent s
1. Azt r eonam ( Azact am) . Thi s agent was t he f i rst commer ci al l y avai l abl e
monobact am ( monocycl i c 8- l act am compound) . Ì t r esembl es t he
ami nogl ycosi des i n i t s ef f i cacy agai nst many gr am- negat i ve or gani sms but
does not cause nephrot oxi ci t y or ot ot oxi ci t y. Ot her advant ages of t hi s drug
i ncl ude i t s abi l i t y t o pr eser ve t he body' s normal gr am-posi t i ve and
anaer obi c f l or a, act i vi t y agai nst many gent ami ci n- r esi st ant or gani sms, and
l ack of cr oss-al l er geni ci t y wi t h peni ci l l i n.
a. Mechani sm of act i on. Azt r eonam i s bact er i ci dal ; i t i nhi bi t s bact eri al cel l
wal l synt hesi s.
b. Spect r um of act i vi t y. Thi s drug i s act i ve agai nst many gr am- negat i ve
or gani sms, i ncl udi ng Ent er obact er and P. aer ugi nosa.
c. Therapeut i c uses. Azt r eonam i s t her apeut i c f or ur i nar y t ract i nf ect i ons,
sept i cemi a, ski n i nf ect i ons, l ower r espi r at or y t r act i nf ect i ons, and i nt r a-
abdomi nal i nf ect i ons resul t i ng f r om gram- negat i ve or gani sms. Ì ncreased
i nci dence of P. aerugi nosa resi st ant t o azt r eonam have been r epor t ed.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Azt r eonam somet i mes causes nausea, vomi t i ng, and di ar r hea.
( 2) Li ver enzymes may i ncr ease t ransi ent l y duri ng azt r eonam t herapy.
( 3) Thi s drug may i nduce ski n r ash.
2. Chl or ampheni col . A ni t r obenzene der i vat i ve, t hi s dr ug has br oad act i vi t y
agai nst r i cket t si a as wel l as many gr am-posi t i ve and gr am- negat i ve
or gani sms. Ì t al so i s ef f ect i ve agai nst many ampi ci l l i n- r esi st ant st rai ns of H.
i nf l uenzae.
a. Mechani sm of act i on. Chl orampheni col i s pri mar i l y bact eri ost at i c,
al t hough i t may be bact er i ci dal agai nst a f ew bact er i al st r ai ns.
b. Spect r um of act i vi t y. Thi s agent i s act i ve agai nst r i cket t si a and a wi de
r ange of bact er i a, i ncl udi ng H. i nf l uenzae, Sal monel l a t yphi , Nei sser i a
meni ngi t i di s, Bor det el l a per t ussi s, Cl ost r i di um, B. f r agi l i s, S. pyogenes, and
S. pneumoni ae.
P. 936


c. Therapeut i c uses. Because of i t s t oxi c si de ef f ect s, chl or ampheni col i s
used onl y t o suppr ess i nf ect i ons t hat cannot be t r eat ed ef f ect i vel y wi t h
ot her ant i bi ot i cs. Such i nf ect i ons t ypi cal l y i ncl ude
( 1) Typhoi d f ever
( 2) Meni ngococcal i nf ect i ons i n cephal ospori n-al l er gi c pat i ent s
( 3) Seri ous H. i nf l uenzae i nf ect i ons, par t i cul ar l y i n cephal ospor i n- al l ergi c
pat i ent s
( 4) Anaer obi c i nf ect i ons ( e. g. , t hose ori gi nat i ng i n t he pel vi s or i nt est i nes)
( 5) Anaer obi c or mi xed i nf ect i ons of t he CNS
( 6) Ri cket t si al i nf ect i ons i n pr egnant pat i ent s, t et r acycl i ne- al l er gi c pat i ent s,
and renal l y i mpai r ed pat i ent s
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Chl or ampheni col can cause bone mar r ow suppr essi on ( dose- rel at ed)
wi t h r esul t i ng pancyt openi a; r arel y, t he dr ug l eads t o apl ast i c anemi a ( not
r el at ed t o dose) .
( 2) Hypersensi t i vi t y react i ons may i ncl ude ski n rash and, i n ext r emel y r are
cases, angi oedema or anaphyl axi s.
( 3) Chl or ampheni col t herapy may l ead t o gray baby syndrome i n neonat es
( especi al l y premat ure i nf ant s) . Thi s danger ous r eact i on, whi ch st ems par t l y
f r om i nadequat e l i ver det oxi f i cat i on of t he drug, i s mani f est ed by vomi t i ng,
gr ay cyanosi s, r api d and i r r egul ar respi r at i ons, vasomot or col l apse, and i n
some cases deat h.
e. Si gni f i cant i nt eract i ons
( 1) Chl or ampheni col i nhi bi t s t he met abol i sm of phenyt oi n, t ol but ami de,
chl or propami de, and di cumarol , l eadi ng t o pr ol onged act i on and i nt ensi f i ed
ef f ect of t hese dr ugs.
( 2) Phenobarbi t al shor t ens chl or ampheni col ' s hal f - l i f e, t hereby r educi ng i t s
t her apeut i c ef f ect i veness.
( 3) Peni ci l l i ns can cause ant i bi ot i c ant agoni sm.
( 4) Acet ami nophen el evat es chl orampheni col l evel s and may cause t oxi ci t y.
3. Cl i ndamyci n ( Cl eoci n). Thi s agent has essent i al l y repl aced l i ncomyci n,
t he dr ug f r om whi ch i t i s der i ved. Ì t i s used t o t reat ski n, respi rat or y t r act ,
and sof t - t i ssue i nf ect i ons caused by st aphyl ococci , pneumococci , and
st r ept ococci .
a. Mechani sm of act i on. Cl i ndamyci n i s bact er i ost at i c; i t bi nds t o t he 50S
r i bosomal subuni t , t hereby suppr essi ng bact er i al pr ot ei n synt hesi s.
b. Spect r um of act i vi t y. Thi s agent i s act i ve agai nst most gr am- posi t i ve and
many anaer obi c organi sms, i ncl udi ng B. f ragi l i s.
c. Therapeut i c uses. Because of i t s marked t oxi ci t y, cl i ndamyci n i s used
onl y agai nst i nf ect i ons f or whi ch i t has pr oven t o be t he most ef f ect i ve drug.
Typi cal l y, such i nf ect i ons i ncl ude abdomi nal and f emal e geni t ouri nar y t r act
i nf ect i ons caused by B. f r agi l i s.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Cl i ndamyci n may cause rash, nausea, vomi t i ng, di ar rhea, and
pseudomembranous col i t i s as evi denced by f ever, abdomi nal pai n, and
bl oody st ool s.
( 2) Bl ood dyscr asi as ( e. g. , eosi nophi l i a, t hrombocyt openi a, l eukopeni a) may
occur .
e. Si gni f i cant i nt eract i ons. Cl i ndamyci n may pot ent i at e t he ef f ect s of
neuromuscul ar bl ocki ng agent s.
4. Dapsone. A member of t he sul f one cl ass, t hi s dr ug i s t he pri mar y agent
i n t he t r eat ment of al l f orms of l epr osy.
a. Mechani sm of act i on. Dapsone i s bact er i ost at i c f or Mycobact er i um
l eprae; i t s mechani sm of act i on probabl y resembl es t hat of t he
sul f onami des.
b. Spect r um of act i vi t y. Thi s drug i s act i ve agai nst M. l eprae; however , drug
r esi st ance devel ops i n up t o 40% of pat i ent s. Dapsone al so has some
act i vi t y agai nst P. cari ni i or gani sms and t he mal ar i al parasi t e Pl asmodi um.
c. Therapeut i c uses
( 1) Dapsone i s t he drug of choi ce f or t r eat i ng l epr osy.
( 2) Thi s agent may be used t o t reat dermat i t i s herpet i f ormi s, a ski n
di sor der .
( 3) Mal opr i m, a dapsone- pyr i met hami ne pr oduct , i s val uabl e i n t he
pr ophyl axi s and t reat ment of mal ar i a.
( 4) Dapsone, wi t h or wi t hout t r i met hopr i m, i s used f or pr ophyl axi s of P.
car i ni i pneumoni a i n pat i ent s wi t h AÌ DS.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Hemol yt i c anemi a can occur wi t h dai l y doses > 200 mg. Ot her adverse
hemat ol ogi cal ef f ect s i ncl ude met hemogl obi nemi a and l eukopeni a.
P. 937


( 2) Nausea, vomi t i ng, and anor exi a may devel op.
( 3) Adverse CNS ef f ect s i ncl ude headache, di zzi ness, ner vousness,
l et har gy, parest hesi as, and psychosi s.
( 4) Dapsone occasi onal l y r esul t s i n a pot ent i al l y l et hal mononucl eosi s-l i ke
syndr ome.
( 5) Paradoxi cal l y, t hi s drug somet i mes exacer bat es l eprosy.
( 6) Ot her adver se ef f ect s i ncl ude ski n rash, per i pheral neuropat hy, bl ur red
vi si on, t i nni t us, hepat i t i s, and chol est at i c j aundi ce.
e. Si gni f i cant i nt eract i ons. Probeneci d el evat es bl ood l evel s of dapsone,
possi bl y r esul t i ng i n t oxi ci t y.
5. Cl of azi mi ne i s phenazi ne dye wi t h ant i mycobact eri al and ant i -
i nf l ammat or y act i vi t y.
a. Mechani sm of act i on. Cl of azi mi ne appears t o bi nd pr ef er ent i al l y t o
mycobact eri al DNA, i nhi bi t i ng r epl i cat i on and gr owt h. Ì t i s bact er i ci dal
agai nst M. l eprae, and i t appears t o be bact er i ost at i c agai nst MAÌ .
b. Spect r um of act i vi t y. Cl of azi mi ne i s act i ve agai nst vari ous mycobact eri a,
i ncl udi ng M. l eprae, M. t ubercul osi s, and MAÌ .
c. Therapeut i c uses. Cl of azi mi ne i s used t o t r eat l eprosy and a var i et y of
at ypi cal Mycobact er i um i nf ect i ons.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Pi gment at i on (pi nk t o br owni sh) occurs i n 75%- 100% of pat i ent s wi t hi n a
f ew weeks. Thi s ski n di scol or at i on has l ed t o sever e depressi on (and
sui ci de) .
( 2) Ur i ne, sweat , and ot her body f l ui ds may be di scol ored.
( 3) Ot her ef f ect s i ncl ude i cht hyosi s and dr yness of ski n (8%- 28%) , r ash and
pr ur i t us ( 1%- 5%) , and GÌ i nt ol er ance ( e. g. , abdomi nal / epi gast ri c pai n,
di ar rhea, nausea, vomi t i ng) i n 40%-50% of pat i ent s. Cl of azi mi ne shoul d be
t aken wi t h f ood.
6. Dapt omyci n ( Cubi ci n) i s a uni que l i popept i de ant i bi ot i c wi t h cl i ni cal
act i vi t y i n t he t reat ment of r esi st ant gr am- posi t i ve i nf ect i ons.
a. Mechani sm of act i on. Dapt omyci n i s bact eri ci dal ; unl i ke ot her ant i bi ot i cs,
i t bi nds t o t he bact eri al cel l membrane, causi ng depol ar i zat i on of t he
membr ane pot ent i al l eadi ng t o i nhi bi t i on of RNA, DNA, and prot ei n
synt hesi s.
b. Spect r um of act i vi t y. Thi s drug i s act i ve agai nst vancomyci n-suscept i bl e
E. f aeci um and S. aureus ( i ncl udi ng met hi ci l l i n- resi st ant st rai ns) as wel l as
ot her aer obi c gr am- posi t i ve bact er i a.
c. Therapeut i c uses. Dapt omyci n i s i ndi cat ed f or t he t r eat ment of
compl i cat ed ski n and ski n st r uct ure i nf ect i ons and S. aur eus bact er emi a. Ì t
i s not i ndi cat ed f or t he t reat ment of pneumoni a.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Repor t ed si de ef f ect s ar e gener al l y mi l d and sel f -l i mi t i ng and i ncl ude
const i pat i on, abnor mal l i ver f unct i on t est s, and renal f ai l ur e.
( 2) Cases of myal gi a and/ or muscl e weakness, exacer bat i ons of myast heni a
gr avi s, and i ncr eases i n cr eat i ne phosphoki nase ( CPK) have been report ed.
7. Li nezol i d ( Zyvox) i s a synt het i c oxazol i di none t hat has cl i ni cal use i n t he
t r eat ment of i nf ect i ons caused by aerobi c gr am- posi t i ve bact eri a.
a. Mechani sm of act i on. Li nezol i d i s bact eri ost at i c agai nst Ent er ococci and
St aphyl ococci , and bact er i ci dal agai nst St r ept ococci . Li nezol i d bi nds t o t he
23S ri bosomal RNA of t he 50S subuni t and t hus i nhi bi t s prot ei n synt hesi s.
b. Spect r um of act i vi t y. The dr ug i s act i ve agai nst vancomyci n- r esi st ant
Ent erococcus f aeci um and S. aureus (met hi ci l l i n- suscept i bl e and -r esi st ant
st r ai ns) as wel l as ot her aer obi c gram-posi t i ve bact eri a.
c. Therapeut i c uses. Li nezol i d i s i ndi cat ed f or t r eat ment of i nf ect i ons
caused by vanco-myci n- resi st ant E. f aeci um, nosocomi al pneumoni a caused
by met hi ci l l i n-suscept i bl e and - resi st ant st r ai ns of S. aureus, communi t y-
acqui red pneumoni a caused by peni ci l l i n-suscept i bl e st r ai ns of S.
pneumoni ae, and ski n and ski n st r uct ure i nf ect i ons owi ng t o t hese
or gani sms.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Saf et y dat a ar e l i mi t ed. Adverse ef f ect s general l y ar e mi nor (e. g. ,
gast r oi nt est i nal compl ai nt s, headache, r ash).
( 2) Thr ombocyt openi a or a si gni f i cant r educt i on i n pl at el et count has been
r eport ed ( 2. 4%) and i s rel at ed t o dur at i on of t herapy. Moni t or pl at el et s i n
pat i ent s wi t h r i sk of bl eedi ng, preexi st i ng t hrombocyt openi a, pl at el et
di sor der s ( i ncl udi ng t hose
P. 938

caused by concurr ent medi cat i ons) and i n pat i ent s r ecei vi ng l i nezol i d
l ast i ng l onger t han 2 weeks.
( 3) Myel osuppr essi on owi ng t o di rect bone mar row suppr essi on has been
r eport ed r ar el y.
e. Si gni f i cant i nt eract i ons. Pat i ent s r ecei vi ng concomi t ant t her apy wi t h
adr ener gi c or serot onergi c agent s or consumi ng mor e t han 100 mg of
t yr ami ne a day may exper i ence an enhancement of t he dr ug' s ef f ect or
ser ot oni n syndrome.
8. Qui nupr i st i n/ dal f opri st i n ( Syner ci d) i s an i nt r avenous st rept ogr ami n
ant i bi ot i c composed of t wo chemi cal l y di st i nct compounds.
a. Mechani sm of act i on. Qui nupr i st i n bi nds t o t he 50S subuni t , and
dal f opri st i n bi nds t i ght l y t o t he 70S ri bosomal part i cl e.
b. Spect r um of act i vi t y. Syner ci d has act i vi t y agai nst St aphyl ococci spp. ,
i ncl udi ng r esi st ant st rai ns. Thi s combi nat i on has bet t er act i vi t y agai nst E.
f aeci um t han Ent er ococcus f aecal i s and i s al so act i ve agai nst some gr am-
negat i ve or gani sms and anaer obes; act i vi t y has not been shown agai nst
Ent erobact er i aceae.
c. Therapeut i c uses. Ì t i s used f or t reat ment of vancomyci n- r esi st ant E.
f aeci um ( VREF) bact er emi a and ski n and ski n st ruct ur e i nf ect i ons caused
by S. aur eus and S. pyogenes.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Repor t ed si de ef f ect s ar e gener al l y mi l d and i nf usi on r el at ed: pai n,
er yt hema, or i t chi ng at t he i nf usi on si t e; i ncr eases i n pul se and di ast ol i c
pr essure; headache; nausea or vomi t i ng; and di arr hea. Ì t may i ncr ease l i ver
f unct i on t est s sl i ght l y.
( 2) Dr ug i nt eract i ons ar e a r esul t of cyt ochr ome P450 3A4 i nhi bi t i on.
Pot ent i al dr ug i nt er act i ons i ncl ude cycl ospori n, ni f edi pi ne, and mi dazol am.
( 3) Concomi t ant use of medi cat i ons t hat may prol ong QTc i nt er val shoul d be
avoi ded.
( 4) Mi l d t o l i f e-t hr eat eni ng pseudomembr anous col i t i s has been r epor t ed.
9. Ri f axi mi n. Ì s a semi -synt het i c ant i bi ot i c t hat i s st ruct ur al l y r el at ed t o
r i f amyci n.
a. Mechani sm of act i on. Ì t i nhi bi t s bact eri al RNA synt hesi s by bi ndi ng t o t he
bet a-subuni t of bact eri al DNA- dependent RNA pol ymer ase.
b. Spect r um of act i vi t y. Thi s non-syst emi cal l y absor bed dr ug has act i vi t y
agai nst bot h ent er ot oxi geni c and ent er oaggregat i ve st r ai ns of Escher i chi a
col i .
c. Therapeut i c uses. Ri f axi mi n i s used i n t he t r eat ment of Tr avel er ' s
di ar rhea wi t h noni nvasi ve st r ai ns of E. col i . Hi gh r esi st ance rat es have
been r epor t ed af t er 5 days of t r eat ment .
d. Pr ecaut i ons and moni t or i ng ef f ect s. Because of i t s l i mi t ed syst emi c
absor pt i on, adver se ef f ect s ar e f ew but i ncl ude const i pat i on, vomi t i ng,
f l at ul ence and headache.
10. Spect i nomyci n. An ami nocycl i t ol agent r el at ed t o t he ami nogl ycosi des,
t hi s ant i bi ot i c i s usef ul agai nst peni ci l l i n- r esi st ant st rai ns of gonor r hea.
a. Mechani sm of act i on. Spect i nomyci n i s bact er i ost at i c; i t sel ect i vel y
i nhi bi t s pr ot ei n synt hesi s by bi ndi ng t o t he 30S r i bosomal subuni t .
b. Spect r um of act i vi t y. Thi s agent i s act i ve agai nst vari ous gr am- negat i ve
or gani sms.
c. Therapeut i c uses. Spect i nomyci n i s used onl y t o t r eat gonococcal
i nf ect i ons i n pat i ent s wi t h peni ci l l i n al l er gy or when such i nf ect i on st ems
f r om peni ci l l i nase-pr oduci ng gonococci ( PPNG) .
d. Pr ecaut i ons and moni t or i ng ef f ect s. Because spect i nomyci n i s gi ven onl y
as a si ngl e-dose Ì M i nj ect i on, i t causes f ew adverse ef f ect s. Nausea,
vomi t i ng, urt i car i a, chi l l s, di zzi ness, and i nsomni a occur r arel y.
11. Tel i t hromyci n ( Ket ek) i s t he f i r st of a new cl ass of ant i mi crobi al s cal l ed
t he ket ol i des. Ì t i s an oral semi synt het i c der i vat i ve of er yt hr omyci n.
a. Mechani sm of act i on. Tel i t hromyci n may be bact eri ci dal or bact er i ost at i c;
i t i nhi bi t s bact eri al prot ei n synt hesi s.
b. Spect r um of act i vi t y. Thi s drug i s act i ve agai nst many aer obi c and
anaer obi c gr am- posi t i ve or gani sms, i ncl udi ng mul t i drug- resi st ant S.
pneumoni ae, some gr am- negat i ve or gani sms as wel l as at ypi cal pat hogens.
c. Therapeut i c uses. Tel i t hr omyci n i s i ndi cat ed f or t he t r eat ment of mi l d t o
moder at e communi t y- acqui r ed pneumoni a onl y. The FDA r emoved t he
pr evi ous 2 approved i ndi cat i ons and added a bl ack box war ni ng.
P. 939


d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) GÌ ef f ect s ( i ncl udi ng di ar rhea, nausea, and vomi t i ng) wer e t he most
common si de ef f ect s f ol l owed by di zzi ness and vi sual di st ur bances (such as
di pl opi a and bl ur r ed and abnor mal vi si on); ser i ous l i ver t oxi ci t y has been
r eport ed.
( 2) Cr oss-sensi t i vi t y wi t h t he ot her macr ol i des occurs.
( 3) Concomi t ant use of dr ugs or condi t i ons t hat may pr ol ong t he QTc
i nt er val shoul d be avoi ded.
( 4) Cont r ai ndi cat ed i n pat i ent s wi t h myast heni a gravi s, hepat i t i s, or
j aundi ce.
e. Si gni f i cant i nt eract i ons
( 1) Co-admi ni st r at i on of t el i t hromyci n wi t h ei t her ci sapri de or pi mozi de i s
cont r ai ndi cat ed.
( 2) Concomi t ant admi ni st r at i on of dr ugs met abol i zed by cyt ochr ome P450
3A4 i n pat i ent s wi t h t el i t hr omyci n shoul d be cl osel y moni t or ed.
( 3) Pat i ent s on bepr i di l , mesor i dazi ne, t er f enadi ne, t hi ori dazi ne, or
zi pr asi done shoul d not be pr escr i bed t el i t hr omyci n owi ng t o t he hi gh
pot ent i al f or t oxi ci t y.
( 4) Thi s agent has a hi gh pot ent i al t o i nt eract wi t h many drugs. Check
pr oduct i nf ormat i on f or t he most cur rent i nt er act i on i nf ormat i on.
12. Ti gecycl i ne ( Tygaci l ). An i nt ravenous gl ycyl cycl i ne ant i bi ot i c devel oped
as a semi synt het i c anal ogue of t et racycl i ne wi t h a br oad spect r um of
act i vi t y.
a. Mechani sm of act i on. Ti gecycl i ne i s bact eri ost at i c; i t i nhi bi t s bact eri al
pr ot ei n synt hesi s by r ever si bl y bi ndi ng t o t he 30S r i bosome subuni t .
b. Spect r um of act i vi t y. The dr ug i s act i ve agai nst vancomyci n-suscept i bl e
E. f aecal i s, met hi ci l l i n- resi st ant S. epi der mi di s, and S. aureus (met hi ci l l i n-
suscept i bl e and - resi st ant st r ai ns) as wel l as some gr am- negat i ve aer obes
and anaer obes.
c. Therapeut i c uses. Ti gecycl i ne i s i ndi cat ed f or t he t r eat ment of
compl i cat ed i nt r a- abdomi nal i nf ect i ons caused by E. col i , vancomyci n-
suscept i bl e E. f aecal i s, S. aureus (met hi ci l l i n- suscept i bl e st r ai ns onl y) and
B. f r agi l i s. Al so i ndi cat ed f or t he t reat ment of compl i cat ed ski n and ski n
st r uct ur e i nf ect i ons caused by E. f aecal i s ( vancomyci n- suscept i bl e st rai ns) ,
S. pyogenes and S. aur eus (met hi ci l l i n-suscept i bl e and - resi st ant st r ai ns).
d. Pr ecaut i ons and moni t or i ng ef f ect s.
( 1) Saf et y dat a ar e l i mi t ed. Si de ef f ect s ar e general l y mi l d wi t h GÌ
di st ur bances÷f or exampl e, nausea ( 22%-35%) and vomi t i ng ( 13%- 19%)÷
t he most commonl y r epor t ed. The mechani sm of t hese r eact i ons i s
uncer t ai n.
( 2) May cause permanent di scol or at i on of t he t eet h si mi l ar t o t he
t et r acycl i nes.
( 3) Caut i on i n pat i ent s wi t h a hi st or y of hypersensi t i vi t y r eact i ons t o
t et r acycl i nes.
( 4) Phot ot oxi c r eact i ons, pancr eat i t i s, and i ncr eases i n BUN may occur .
e. Si gni f i cant i nt eract i ons. Cl osel y moni t or t he pr ot hr ombi n t i me or
i nt er nat i onal sensi t i vi t y i ndex ( Ì NR) i n pat i ent s on war f ar i n dur i ng
concomi t ant admi ni st rat i on of t i gecycl i ne.
13. Tr i met hopri m. A subst i t ut ed pyri mi di ne, t r i met hopri m i s most commonl y
combi ned wi t h sul f amet hoxazol e ( a sul f onami de di scussed i n Ì Ì . F) i n a
pr epar at i on cal l ed cot r i moxazol e. However , i t may be used al one f or cer t ai n
ur i nar y t r act i nf ect i ons.
a. Mechani sm of act i on. Tr i met hopri m i nhi bi t s di hydr of ol at e r educt ase, t hus
bl ocki ng bact er i al synt hesi s of f ol i c aci d.
b. Spect r um of act i vi t y
( 1) Tr i met hopr i m i s act i ve agai nst most gr am-negat i ve and gr am- posi t i ve
or gani sms. However , dr ug r esi st ance may devel op when t hi s drug i s used
al one.
( 2) Tr i met hopr i m-sul f amet hoxazol e i s act i ve agai nst a vari et y of organi sms,
i ncl udi ng S. pneumoni ae, N. meni ngi t i di s, and Cor ynebact eri um di pht her i ae;
some st r ai ns of S. aureus, St aphyl ococcus epi der mi di s, P. mi r abi l i s,
Ent erobact er , Sal monel l a, Shi gel l a, Ser r at i a, and Kl ebsi el l a spp. ; and E.
col i .
( 3) The t ri met hopri m-sul f amet hoxazol e combi nat i on i s synergi st i c; many
or gani sms r esi st ant t o one component are suscept i bl e t o t he combi nat i on.
c. Therapeut i c uses
( 1) Tr i met hopr i m may be used al one or i n combi nat i on wi t h
sul f amet hoxazol e t o t r eat uncompl i cat ed ur i nar y t r act i nf ect i ons caused by
E. col i , P. mi rabi l i s, and Kl ebsi el l a and Ent er obact er organi sms.
( 2) Tr i met hopr i m-sul f amet hoxazol e i s t her apeut i c f or acut e gonococcal
ur et hr i t i s, acut e exacerbat i on of chr oni c bronchi t i s, shi gel l osi s, and
Sal monel l a i nf ect i ons.
P. 940


( 3) Tr i met hopr i m-sul f amet hoxazol e may be gi ven as pr ophyl act i c or
suppr essi ve t her apy i n P. car i ni i pneumoni a. Ì t i s t he dr ug of choi ce f or t he
t r eat ment of St enot r ophomonas mal t ophi l i a i nf ect i ons.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Most adver se ef f ect s i nvol ve t he ski n ( possi bl y f r om sensi t i zat i on) .
These i ncl ude rash, pr uri t us, and exf ol i at i ve dermat i t i s.
( 2) Rarel y, t ri met hopri m-sul f amet hoxazol e causes bl ood dyscrasi as ( e. g. ,
acut e hemol yt i c anemi a, l eukopeni a, t hrombocyt openi a,
met hemogl obi nemi a, agranul ocyt osi s, apl ast i c anemi a) .
( 3) Adverse GÌ ef f ect s i ncl udi ng nausea, vomi t i ng, and epi gast r i c di st r ess
gl ossi t i s may occur .
( 4) Neonat es may devel op ker ni ct er us.
( 5) Pat i ent s wi t h AÌ DS somet i mes suf f er f ever , rash, mal ai se, and
pancyt openi a dur i ng t r i met hopr i m t herapy.
14. Vancomyci n. Thi s gl ycopept i de dest r oys most gr am- posi t i ve or gani sms.
a. Mechani sm of act i on. Vancomyci n i s bact er i ci dal ; i t i nhi bi t s bact er i al cel l
wal l synt hesi s.
b. Spect r um of act i vi t y. Thi s drug i s act i ve agai nst most gr am- posi t i ve
or gani sms, i ncl udi ng met hi ci l l i n- r esi st ant st r ai ns of S. aureus and
Ent erococci .
c. Therapeut i c uses. Vancomyci n usual l y i s reserved f or ser i ous i nf ect i ons,
especi al l y t hose caused by met hi ci l l i n- r esi st ant st aphyl ococci . Ì t i s
par t i cul arl y usef ul i n pat i ent s who are al l ergi c t o peni ci l l i n or
cephal ospori ns. Typi cal uses i ncl ude endocar di t i s, ost eomyel i t i s, and
st aphyl ococcal pneumoni a.
( 1) Or al vancomyci n i s val uabl e i n t he t r eat ment of ant i bi ot i c- i nduced
pseudomembranous col i t i s caused by C. di f f i ci l e or S. aur eus ent er ocol i t i s.
Because vancomyci n i s not absor bed af t er oral admi ni st r at i on, i t i s not
usef ul f or syst emi c i nf ect i ons. Because of resi st ance, t he Cent ers f or
Di sease Cont r ol and Prevent i on ( CDC) recommend vancomyci n as t he
second choi ce t o met r oni dazol e f or C. di f f i ci l e i nf ect i ons.
( 2) Because 1 g provi des adequat e bl ood l evel s f or 7-10 days, Ì V
vancomyci n i s par t i cul ar l y usef ul i n t he t r eat ment of anephr i c pat i ent s wi t h
gr am- posi t i ve bact eri al i nf ect i ons.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Ot ot oxi ci t y may ari se; nephr ot oxi ci t y i s rar e but can occur wi t h hi gh
doses.
( 2) Vancomyci n may cause hypersensi t i vi t y react i ons, mani f est ed by such
sympt oms as anaphyl axi s and ski n rash.
( 3) Ther apeut i c l evel s peak at 20- 40 µg/ mL. The t r ough i s < 15 µg/ mL.
( 4) Red man' s syndr ome may occur . Thi s i s f aci al f l ushi ng and hypot ensi on
owi ng t o t oo r api d i nf usi on of t he dr ug. Ì nf usi on shoul d be over a mi ni mum
of 60 mi n f or a 1- g dose.
( 5) Ì V sol ut i ons ar e ver y i r r i t at i ng t o t he vei n.
e. Vancomyci n- resi st ant ent erococci . A f ew st r ai ns of vancomyci n- r esi st ant
ent erococci ar e suscept i bl e t o t ei copl ani n ( i nvest i gat i onal by Hoechst
Mar i on Roussel ) , l i nezol i d ( Zyvox) , or qui nupr i st i n/ dal f opr i st i n ( Syner ci d) .
These agent s may be usef ul f or mul t i pl e- drug- resi st ant E. f aeci um.
III. Systemic AntifungaI Agents
A. Def i ni t i on. These agent s t r eat syst emi c and l ocal f ungal (mycot i c)
i nf ect i ons÷di seases t hat r esi st t reat ment wi t h ant i bact er i al dr ugs.
B. Amphot er i ci n B (Fungi zone) . Thi s pol yene ant i f ungal ant i bi ot i c i s
t her apeut i c f or var i ous f ungal i nf ect i ons t hat f requent l y pr oved f at al bef ore
t he dr ug became avai l abl e. Ì t i s used i ncr easi ngl y i n t he empi r i c t r eat ment
of sever el y i mmunocompr omi sed pat i ent s i n cert ai n cl i ni cal si t uat i ons.
1. Mechani sm of act i on. Amphot eri ci n B i s bot h f ungi st at i c i n cl i ni cal l y
obt ai ned concent r at i ons and may be f ungi ci dal i n t he pr esence of
suscept i bl e organi sms. Ì t bi nds t o st er ol s i n t he f ungal cel l membrane,
t her eby i ncr easi ng membr ane per meabi l i t y and per mi t t i ng l eakage of
i nt racel l ul ar cont ent s. Ot her mechani sms may be i nvol ved as wel l .
P. 941


2. Spect r um of act i vi t y. Amphot eri ci n B i s a broad- spect r um ant i f ungal
agent wi t h act i vi t y agai nst Asper gi l l us, Bl ast omyces, Candi da spp.
( al bi cans, kr usei t r opi cal i s, and gl abrat a) , Cr ypt ococcus, Cocci di oi des,
Hi st opl asma, Paracocci di oi des, Phycomycet es ( mucor) , and Sporot hri x. Ì t i s
al so usef ul agai nst some pr ot ozoa such as Lei shmani a, Naegl er i a, and
Acant hamoeba.
3. Ther apeut i c uses. Amphot er i ci n B i s t he most ef f ect i ve ant i f ungal agent
i n t he t r eat ment of syst emi c f ungal i nf ect i ons, especi al l y i n
i mmunocompr omi sed pat i ent s.
a. Ì t i s t he t reat ment of choi ce f or pul monar y Asper gi l l us i nf ect i ons;
Bl ast omyces i nf ect i ons, whi ch are l i f e- t hreat eni ng wi t h AÌ DS or CNS
i nvol vement ; deep- organ i nf ect i ons wi t h Candi da; Cocci di oi des i nf ect i ons
wi t h severe pul monar y i nvol vement or wi t h di ssemi nat ed nonmeni ngeal
i mmunocompet ent or i mmunocompr omi sed pat i ent s; al l Cr ypt ococcus
i nf ect i ons; di ssemi nat ed Hi st opl asma i nf ect i ons i nvol vi ng CNS or
i mmunosuppr essed pat i ent s; Mal assezi a f urf ur f ungemi a; pul monar y and
ext r apul monar y Phycomycet es (mucor mycosi s); Peni ci l l i um mar nef f ei ; and
ext r acut aneous Sporot hri x.
b. Thi s agent may be used t o t reat cocci di oi dal ar t hr i t i s.
c. Topi cal pr epar at i ons ar e gi ven t o eradi cat e cut aneous and
mucocut aneous candi di asi s.
d. Ì t may be used as empi r i c t herapy i n f ebr i l e, neut r openi c pat i ent s.
e. Ì t i s used as secondary pr ophyl axi s of f ungal i nf ect i ons i n HÌ V-posi t i ve
pat i ent s, guar di ng agai nst recur r ence of i nf ect i on.
f . Ì t may be used pr ophyl act i cal l y i n neut r openi c cancer pat i ent s and bone
mar row t r anspl ant or sol i d- or gan t r anspl ant pat i ent s t o reduce t he i nci dence
of Aspergi l l us and Candi da i nf ect i ons.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Because amphot eri ci n B can cause
many seri ous adverse ef f ect s, i t shoul d be admi ni st er ed i n a hospi t al
set t i ng÷at l east dur i ng t he i ni t i al t her apeut i c st age. The adverse ef f ect s
ar e di vi ded i nt o i nf usi on r eact i ons and ot hers.
a. Ì nf usi on react i ons occur whi l e t he drug i s bei ng admi ni st ered and i ncl ude
f ever , shaki ng chi l l s, hypot ensi on, anor exi a, nausea, vomi t i ng, headache,
dyspnea, and t achypnea. Pr emedi cat i on wi t h acet ami nophen and
di phenhydr ami ne has been hel pf ul i n prophyl axi ng agai nst i nf usi on
r eact i ons. Ì n addi t i on, hydr ocor t i sone 10-50 mg may be added t o t he
i nf usi on as pr ophyl axi s agai nst i nf usi on- r el at ed react i ons. Meper i di ne 25-50
mg Ì V i s ef f ect i ve t r eat ment of act i ve shaki ng chi l l s/ ri gor s. Meper i di ne i s
al so ef f ect i ve i n prophyl axi s of ri gors.
b. Nephr ot oxi ci t y f requent l y occur s. Dosage adj ust ment or dr ug
di scont i nuat i on or changi ng t o a l i posomal amphot eri ci n B pr oduct may be
necessar y as renal i mpai r ment progresses.
c. El ect r ol yt e abnor mal i t i es, i ncl udi ng hypokal emi a, hypomagnesemi a, and
hypocal cemi a, are common. Moni t or and repl ace el ect r ol yt es as needed.
d. Normocyt i c, normochromi c anemi a wi l l devel op over l ong- t er m use (10
weeks) . Moni t or hemat ocr i t per i odi cal l y.
e. Br onchospasm, wheezi ng, and anaphyl axi s or anaphyl act oi d r eact i ons
have occur r ed. A t est dose of 1 mg of amphot er i ci n B i s of t en admi ni st ered
bef ore i nf usi on of l arge quant i t i es of t he dr ug.
f . Phl ebi t i s or t hr ombophl ebi t i s i s repor t ed wi t h convent i onal amphot eri ci n
B. Hepar i n ( 500- 1000 U) can be added t o t he i nf usi on t o ai d i n pr event i on.
g. CNS ef f ect s i ncl ude headache, peri pher al neur opat hy, mal ai se,
depressi on, sei zur e, myast heni a, and hal l uci nat i ons.
h. El evat ed l i ver t ransami nases, aspar t at e ami not r ansf erase ( AST) , al ani ne
ami not ransf er ase ( ALT) , al kal i ne phosphat ase, bi l i r ubi n, v-
gl ut amyl t r ansf er ase ( GGT) , and l act at e dehydrogenase (LDH) may occur .
i . Amphot eri ci n B par ent er al use shoul d be mi xed onl y i n dext r ose 5% i n
wat er ( D5W) and shoul d be prot ect ed f r om l i ght .
5. Si gni f i cant i nt eract i ons. Ot her nephr ot oxi c dr ugs (ami nogl ycosi des,
capreomyci n, col i st i n, ci spl at i n, cycl ospori ne, met hoxyf l ur ane, pent ami di ne,
pol ymyxi n B, and vancomyci n) may cause addi t i ve nephr ot oxi ci t y.
6. Amphot eri ci n B l i pi d compl ex ( Abel cet ) , amphot er i ci n B chol est erol
sul f at e compl ex ( Amphot ec) , and l i posomal amphot eri ci n B ( AmBi some)
of f er al t er nat i ve f ormul at i ons of amphot er i ci n B f or t he t r eat ment of sever e
f ungal i nf ect i ons i n pat i ent s who ar e i nt ol er ant of or whose di sease i s
r ef r act or y t o convent i onal t r eat ment .
P. 942


C. Echi nocandi ns. Thr ee echi nocandi ns are approved i n t he US:
capsof ungi n ( Canci das) , mi caf ungi n ( Mycami ne) and ani dul af ungi n ( Eraxi s) .
These agent s have a br oad spect rum of act i vi t y agai nst Candi da speci es
wi t h mi caf ungi n and ani dul af ungi n havi ng si mi l ar MÌ Cs t hat ar e gener al l y
l ower t han t he MÌ C of capsof ungi n.
1. Mechani sm of act i on. Caspof ungi n wor ks by causi ng f ungal cel l wal l
l ysi s. By bei ng a noncompet i t i ve i nhi bi t or of 8 ( 1, 3) synt hase, whi ch i s an
essent i al component of f ungal cel l wal l synt hesi s, i t causes osmot i c
i nst abi l i t y wi t hi n t he f ungus and f ungal cel l wal l l ysi s.
2. Spect r um of act i vi t y. Echi nocandi ns have f ungi ci dal act i vi t y agai nst
Candi da speci es and f ungi st at i c act i vi t y agai nst Aspergi l l us speci es. Al l
t hr ee agent s i n t hi s cl ass appear t o have good act i vi t y i n vi t r o f or most
i sol at es of Candi da speci es, i ncl udi ng t hose t hat ar e ei t her Amphot er i ci n-B
or f l uconazol e and i t r aconazol e- r esi st ant , such as C. gl abr at a.
3. Ther apeut i c uses. Al l t hr ee agent s ar e i ndi cat ed f or t he t r eat ment of
esophageal candi di asi s
a. Caspof unf i n and ani dul af ungi n ar e al so i ndi cat ed f or t he t r eat ment of
candi demi a and ot her i nf ect i ons caused by Candi da speci es, i ncl udi ng
i nt rabdomi nal abscesses and peri t oni t i s.
b. Caspof ungi n may al so be used f or t he t r eat ment of candi dal pl eur al
space i nf ect i ons, empi r i c t r eat ment of pr esumed f ungal i nf ect i ons i n
neut ropeni c pat i ent s, and t r eat ment of i nvasi ve aspergi l l osi s i n pat i ent s
r ef r act or y t o or i nt ol erant of ot her ant i f ungal s ( i . e. , amphot er i ci n B,
i t r aconazol e) .
c. Mi caf ungi n i s i ndi cat ed f or t he prophyl axi s of candi dal i nf ect i ons i n
pat i ent s i nder goi ng hemat opoi et i c st em cel l t ranspl ant at i on ( HSCT) .
4. Pr ecaut i ons and moni t or i ng ef f ect s. Al t hough t hi s cl ass has adver se
event s associ at ed wi t h i t s use, t he overal l t oxi ci t y pr of i l e i s si gni f i cant l y
bet t er t han t hat of amphot eri ci n B.
a. Ì nf usi on vei n compl i cat i ons (not def i ned by manuf act ur er ) and
t hr ombophl ebi t i s have been seen on i nf usi on of caspof ungi n.
b. Hemat ol ogi cal decreases i n hemogl obi n and hemat ocr i t may occur;
however , t he i nci dence does not di f f er f r om t hat of havi ng a f ungal di sease.
c. Headache may occur .
d. Sl i ght decreases i n ser um pot assi um may occur , but nowher e near t he
magni t ude of t hat caused by amphot er i ci n B.
e. Anor exi a, nausea, vomi t i ng, and di ar r hea have occur r ed.
f . Rar e i ncreases i n ser um cr eat i ni ne; however , t her e have been no
r eport ed cases of nephrot oxi ci t y.
g. Possi bl e sl i ght i ncreases i n ser um ami not r ansf er ases
h. Al l ergi c r eact i ons occur i n < 5% of pat i ent s and anaphyl axi s i n < 2% of
pat i ent s.
i . Pr egnancy cat egor y C embr yot oxi c r eact i ons have occur r ed i n ani mal s.
5. Si gni f i cant i nt eract i ons
a. When cycl ospori ne i s combi ned wi t h caspof ungi n, cl i ni cal l y si gni f i cant
r i ses i n ALT wer e obser ved. Ser um t ransami nases shoul d be moni t or ed, and
t hi s combi nat i on shoul d be avoi ded i n pat i ent s wi t h preexi st i ng l i ver
di sease.
b. When used i n combi nat i on, carbamazepi ne, nel f i navi r, nevi r api ne,
phenyt oi n, and ri f ampi n i ncr eases t he cl ear ance of caspof ungi n. Hi gher
doses of caspof ungi n ( 70 mg ever y day) shoul d be consi dered when t hi s
combi nat i on i s admi ni st er ed.
c. Tacrol i mus cl earance wi l l be i ncr eased when t he combi nat i on i s used;
moni t or t acr ol i mus ser um l evel s cl osel y.
D. Fl ucyt osi ne ( Ancobon) . Thi s f l uor i nat ed pyr i mi di ne usual l y i s gi ven i n
combi nat i on wi t h amphot er i ci n B.
1. Mechani sm of act i on. Fl ucyt osi ne penet r at es f ungal cel l s and i s
convert ed t o f l uor our aci l , a met abol i c ant agoni st . Ì ncor por at ed i nt o t he RNA
of t he f ungal cel l , f l ucyt osi ne causes def ect i ve prot ei n synt hesi s. Ì t i s ei t her
f ungi st at i c or f ungi ci dal , dependi ng on t he concent r at i on of t he drug.
2. Spect r um of act i vi t y. Thi s drug i s pr i mar i l y act i ve agai nst Cr ypt ococcus
and Candi da. Ì t i s most commonl y used i n conj unct i on wi t h amphot eri ci n B.
Fungal r esi st ance agai nst f l ucyt osi ne al one has been wel l document ed.
Fl ucyt osi ne may al so possess some act i vi t y agai nst chromomycosi s and
some st r ai ns of Aspergi l l us (i n vi t r o t est i ng onl y) .
P. 943


3. Ther apeut i c uses. Fl ucyt osi ne i s adj unct i vel y used wi t h amphot er i ci n B
f or sever e syst emi c i nf ect i ons (e. g. , sept i cemi a, endocardi t i s, pul monar y
and ur i nar y t ract i nf ect i ons, meni ngi t i s) . Use of f l ucyt osi ne al one i s not
r ecommended.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Frequent adverse ef f ect s i ncl ude GÌ i nt ol erance wi t h nausea, vomi t i ng,
and di ar r hea.
b. Occasi onal adver se r eact i ons ar e more sever e and i ncl ude mar r ow
suppr essi on wi t h l eukopeni a or t hrombocyt openi a ( dose r el at ed, especi al l y
wi t h r enal f ai l ur e or concur r ent amphot er i ci n B use) . Conf usi on, r ash,
hepat i t i s, ent erocol i t i s, headache, and phot osensi t i vi t y r eact i ons can al so
occur .
c. Rare react i ons i ncl ude hal l uci nat i ons, bl ood dyscrasi as wi t h
agr anul ocyt osi s and pancyt openi a, f at al hepat i t i s, anaphyl axi s, and anemi a.
d. Fl ucyt osi ne may cause a markedl y f al se el evat i on of ser um creat i ni ne i f
an Ekt achem anal yzer i s used.
5. Si gni f i cant i nt eract i ons. Benef i ci al drug i nt er act i ons occur wi t h
f l ucyt osi ne. Fl ucyt osi ne has demonst r at ed synergy wi t h amphot eri ci n B and
f l uconazol e agai nst Cr ypt ococcus and Candi da spp.
E. Gr i seof ul vi n ( Ful vi ci n). Pr oduced f r om Peni ci l l i um gr i seof ul vi n Di er ckx,
t hi s drug i s deposi t ed i n t he ski n, bound t o ker at i n.
1. Mechani sm of act i on. Thi s agent i s f ungi st at i c; i t i nhi bi t s f ungal cel l
act i vi t y by i nt erf eri ng wi t h mi t ot i c spi ndl e st r uct ure. Ì t s mechani sm of act i on
i s si mi l ar t o col chi ci ne.
2. Spect r um of act i vi t y. Gr i seof ul vi n i s act i ve agai nst vari ous st rai ns of
Mi cr osporum, Epi der mophyt on, and Tr i chophyt on.
3. Ther apeut i c uses. Gri seof ul vi n i s ef f ect i ve i n t i nea i nf ect i ons of t he ski n,
hai r, and nai l s ( i ncl udi ng at hl et e' s f oot , j ock i t ch, and ri ngwor m) caused by
Mi cr osporum, Epi der mophyt on, and Tr i chophyt on.
a. Gener al l y, t hi s agent i s gi ven onl y f or i nf ect i ons t hat do not r espond t o
t opi cal ant i f ungal agent s.
b. Gr i seof ul vi n i s avai l abl e onl y i n or al f orm.
c. Ì t possesses vasodi l at or y act i vi t y and may be used i n Raynaud di sease.
d. Ì t may be used t o t r eat gout .
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Gr i seof ul vi n rar el y resul t s i n ser i ous adver se ef f ect s. However , t he
f ol l owi ng pr obl ems have been r epor t ed.
( 1) Common: headache, f at i gue, conf usi on, i mpai r ed per f or mance, syncope,
and l et hargy, whi ch gener al l y r esol ve wi t h cont i nued use
( 2) Occasi onal : l eukopeni a, neut r openi a, and granul ocyt openi a
( 3) Rare: ser um si ckness, angi oedema, ur t i car i a, er yt hema, and
hepat ot oxi ci t y
b. The dosage depends on t he par t i cl e si ze of t he pr oduct : 250 mg of
ul t rami crosi ze ( Ful vi ci n P/ G) i s equi val ent i n t her apeut i c ef f ect s t o 500 mg
of mi cr osi ze ( Ful vi ci n U/ F) .
5. Si gni f i cant i nt eract i ons
a. Gr i seof ul vi n may i ncrease t he met abol i sm of war f ari n, l eadi ng t o
decreased prot hrombi n t i me.
b. Barbi t ur at es may r educe gr i seof ul vi n absor pt i on.
c. Al cohol consumpt i on may cause t achycar di a and f l ushi ng.
d. Or al cont racept i ves may cause amenor r hea or i ncreased breakt hrough
bl eedi ng.
F. Ì mi dazol es. The subst i t ut ed i mi dazol e deri vat i ves ket oconazol e ( Ni zoral ) ,
mi conazol e ( Moni st at ) , f l uconazol e ( Di f l ucan) , i t raconazol e ( Spor anox) ,
vor i conazol e ( Vf end) and posaconazol e ( Noxaf i l ) ar e val uabl e i n t he
t r eat ment of a wi de r ange of syst emi c f ungal i nf ect i ons.
1. Mechani sm of act i on. Ì mi dazol es i nhi bi t st er ol synt hesi s i n f ungal cel l
membr anes and i ncr ease cel l wal l permeabi l i t y; t hi s, i n t ur n, makes t he cel l
mor e vul ner abl e t o osmot i c pr essur e. These agent s ar e f ungi st at i c.
2. Spect r um of act i vi t y. These agent s are act i ve agai nst many f ungi ,
i ncl udi ng yeast s, dermat ophyt es, act i nomycet es, and some Phycomycet es.
P. 944


3. Ther apeut i c uses
a. Ket oconazol e, an oral agent , successf ul l y t r eat s many f ungal i nf ect i ons
t hat pr evi ousl y yi el ded onl y t o parent er al agent s.
( 1) Ì t i s t her apeut i c f or syst emi c and vagi nal candi di asi s, mucocandi di asi s,
candi dur i a, or al t hrush, hi st opl asmosi s, cocci di oi domycosi s,
chr omomycosi s, dermat ophyt osi s ( t i nea) , and paracocci di oi domycosi s.
( 2) Because ket oconazol e i s sl ow act i ng and requi r es a l ong dur at i on of
t her apy ( up t o 6 mont hs f or some chroni c i nf ect i ons) , i t i s l ess ef f ect i ve
t han ot her ant i f ungal agent s f or t he t reat ment of sever e and acut e syst emi c
i nf ect i ons.
b. Mi conazol e, pri mar i l y admi ni st er ed as a t opi cal agent , The par ent eral
f or m has been di scont i nued i n t he Uni t ed St at es. Ì t was a r el at i vel y t oxi c
f or mul at i on whi ch has been r epl aced by ot her members of t hi s cl ass ( e. g. ,
f l uconazol e) .
( 1) Topi cal mi conazol e i s hi ghl y ef f ect i ve i n vul vovagi nal candi di asi s,
r i ngwor m, and ot her ski n i nf ect i ons.
c. Fl uconazol e. Avai l abl e i n or al and parent er al f or ms, f l uconazol e can be
used agai nst syst emi c and CNS i nf ect i ons i nvol vi ng Cr ypt ococcus and
Candi da. Candi da or ophar yngeal i nf ect i on and esophagi t i s may al so be
t r eat ed wi t h f l uconazol e. Asper gi l l us, Cocci di oi des, and Hi st opl asma have
demonst r at ed i n vi t r o sensi t i vi t y.
d. Ì t raconazol e i s avai l abl e as an or al agent wi t h act i vi t y agai nst syst emi c
and i nvasi ve pul monar y asper gi l l osi s wi t hout t he hemat ol ogi cal t oxi ci t y of
amphot er i ci n B. Ot her deep mycot i c i nf ect i ons suscept i bl e t o i t r aconazol e
i ncl ude bl ast omycosi s, cocci di oi domycosi s, cr ypt ococcosi s, and
hi st opl asmosi s.
e. Vori conazol e. Vori conazol e i s avai l abl e as bot h an i nt r avenous and an
or al agent f or t he t r eat ment of f ungal i nf ect i ons i nvol vi ng i nvasi ve
asper gi l l osi s, Scedospori um api osper mum, and Fusari um spp. , i ncl udi ng
t hose speci es t hat ar e ref r act or y t o ot her t herapy.
f . Posaconazol e. Avai l abl e as an or al suspensi on i ndi cat ed f or t he
pr event i on of i nvasi ve i nf ect i ons caused by Asper gi l l us and Candi da
speci es i n pat i ent s r ecei vi ng HSCT or wi t h neut ropeni s. Posaconazol e may
al so be used t o t r eat i nvasi ve f ungal i nf ect i ons i n pat i ent s who have
pr evi ousl y f ai l ed or ar e i nt ol er ant t o ot her ant i f ungal s.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Ket oconazol e may cause nausea, vomi t i ng, di ar r hea, abdomi nal pai n,
and const i pat i on. Rar el y, i t l eads t o headache, di zzi ness, gynecomast i a,
and f at al hepat ot oxi ci t y.
b. Fl uconazol e commonl y causes GÌ di st urbances ( e. g. , nausea, vomi t i ng,
epi gast r i c pai n, di ar rhea) . Reversi bl e el evat i ons i n ser um ami not ransf erase,
exf ol i at i ve ski n r eact i ons, and headaches have been repor t ed.
c. Ì t r aconazol e may cause nausea, vomi t i ng, hyper t r i gl ycer i demi a,
hypokal emi a, rash, and el evat i ons i n l i ver enzymes.
d. Vori conazol e. Vi sual di st ur bances, f ever , r ash, vomi t i ng, nausea,
di ar rhea, headache, sepsi s, per i pher al edema, abdomi nal pai n, and
r espi r at or y di sor der s rarel y occur r ed. Li ver f unct i on t est abnormal i t i es have
occur r ed.
e. Posaconazol e. Most common adverse event s have been nausea and
headache. Rash, dr y ski n, t ast e di st ur bances, abdomi nal pai n, di zzi ness,
hypokal emi a, t hr ombocyt openi a, and f l ushi ng can occur . Posaconazol e can
cause abnormal i t i es i n l i ver f unct i on and has been associ at ed wi t h
pr ol ongat i on of t he QT i nt er val .
5. Si gni f i cant i nt eract i ons
a. Bot h ket oconazol e and mi conazol e may enhance t he ant i coagul ant ef f ect
of war f ar i n.
b. Ket oconazol e may ant agoni ze t he ant i bi ot i c ef f ect s of amphot er i ci n B.
c. Fl uconazol e has been shown t o el evat e ser um l evel s of phenyt oi n,
cycl ospor i ne, war f ar i n, and sul f onyl ur eas. Concurr ent hepat i c enzyme
i nducer s, such as ri f ampi n, have resul t ed i n i ncr eased el i mi nat i on of bot h
f l uconazol e and i t r aconazol e.
d. Coadmi ni st r at i on of i t raconazol e or ket oconazol e wi t h ast emi zol e or
t er f enadi ne may r esul t i n i ncr eased ast emi zol e or t er f enadi ne l evel s,
possi bl y l eadi ng t o l i f e-t hr eat eni ng dysrhyt hmi as and deat h.
e. Bot h ket oconazol e and i t raconazol e need t he pr esence of st omach aci d
f or adequat e absor pt i on. Use wi t h ant aci ds, H2- bl ockers, or prot on pump
i nhi bi t ors i s cont r ai ndi cat ed.
f . Concomi t ant use of i mi dazol e ant i f ungal agent s wi t h ci sapr i de may resul t
i n i ncr eased concent r at i ons of ci sapr i de, whi ch has been associ at ed wi t h
adver se car di ac event s such as t orsades de poi nt es l eadi ng t o sudden
deat h.
P. 945


g. Vori conazol e. Cyt ochrome P450 2C19 i s t he maj or enzyme i nvol ved i n
met abol i sm. Vori conazol e i nhi bi t s cyt ochr ome P450 2C19, 2C9, and 3A4.
Any medi cat i on t hat i s met abol i zed vi a t hese r out es may be af f ect ed, and
moni t ori ng of bl ood l evel s ( i f appr opr i at e) or cl i ni cal si gns and sympt oms i s
necessar y when t aki ng concomi t ant medi cat i ons.
h. Posaconazol e ser um l evel s ar e r educed by concurr ent admi ni st rat i on
wi t h ci met i di ne, phenyt oi n or ri f but i n; avoi d concommi t ant use i f possi bl e.
Posaconazol e may i ncrease concent r at i ons of cycl ospor i ne, t acr ol i mus,
r i f abut i n, mi dazol am, and phenyt oi n; dosage adj ust ment s may be requi r ed.
( 1) Food i ncr eases t he or al bi oavai l abi l i t y; t ake posaconazol e wi t h a f ul l
meal or l i qui d nut ri t i onal suppl ement
G. Nyst at i n ( Mycost at i n) . A pol yene ant i bi ot i c, nyst at i n has a chemi cal
st r uct ur e si mi l ar t o t hat of amphot er i ci n B.
1. Mechani sm of act i on. Nyst at i n i s f ungi ci dal and f ungi st at i c; bi ndi ng t o
st erol s i n t he f ungal cel l membr ane, i t i ncr eases membr ane permeabi l i t y
and permi t s l eakage of i nt r acel l ul ar cont ent s.
2. Spect r um of act i vi t y. Nyst at i n i s act i ve pri mar i l y agai nst Candi da spp.
3. Ther apeut i c uses
a. Thi s drug i s used pr i mar i l y as a t opi cal agent i n vagi nal and or al Candi da
i nf ect i ons.
b. Or al nyst at i n i s t herapeut i c f or Candi da i nf ect i ons of t he GÌ t ract ,
especi al l y oral and esophageal i nf ect i ons; because t he dr ug i s not readi l y
absor bed, i t mai nt ai ns good l ocal act i vi t y.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Or al nyst at i n occasi onal l y causes GÌ
di st r ess ( e. g. , nausea, vomi t i ng, di ar r hea) . Rar el y, hyper sensi t i vi t y
r eact i ons occur .
H. Ter bi naf i ne (Lami si l ) i s a synt het i c al l yl ami ne wi t h st r uct ur e and act i vi t y
r el at ed t o naf t i f i ne.
1. Mechani sm of act i on. Ter bi naf i ne i nhi bi t s squal ene monooxygenase,
l eadi ng t o an i nt er rupt i on of f ungal st erol bi osynt hesi s. Ter bi naf i ne may be
f ungi ci dal or f ungi st at i c, dependi ng on dr ug concent r at i on and speci es.
2. Spect r um of act i vi t y. Ter bi naf i ne has act i vi t y agai nst der mat ophyt i c f ungi
( Tr i chophyt on, Mi cr osporum, and Epi dermophyt on) , f i l ament ous f ungi
( Asper gi l l us), and di morphi c f ungi ( Bl ast omyces). Ì t may al so possess some
act i vi t y agai nst yeast s.
3. Ther apeut i c uses
a. Or al t erbi naf i ne i s usef ul agai nst i nf ect i ons of t he t oenai l and f i nger nai l
( onychomycosi s, t i nea ungui um) . Ti me t o cur e i s r educed over i mi dazol e
ant i f ungal s f or t hese i ndi cat i ons. Ì t i s usef ul i n pat i ent s who may not
t ol er at e t he adver se ef f ect pr of i l e of i mi dazol e ant i f ungal s.
b. Ì t i s al so used i n t i nea capi t i s and t i nea cor por i s i nf ect i ons.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Adverse ef f ect s i ncl ude t ast e or
ocul ar di st ur bances, sympt omat i c hepat obi l i ar y dysf unct i on, decr ease i n
l ymphocyt e count and neut r openi a, and ser i ous ski n r eact i ons.
IV. TopicaI AntifungaI Agents
A. Def i ni t i on. These agent s ar e f or t opi cal use f or f ungal i nf ect i ons.
B. Amphot er i ci n B (Fungi zone) i s avai l abl e as a 3% cr eam or l ot i on or an
or al suspensi on t hat i s not absor bed t hr ough t he GÌ t r act .
1. Mechani sm of act i on. See Ì Ì Ì . B. 1.
2. Spect r um of act i vi t y. See Ì Ì Ì . B. 2.
3. Ther apeut i c uses. Amphot er i ci n B i s used f or or ophar yngeal candi di asi s,
cut aneous and mucocut aneous candi dal i nf ect i ons, or as a l ocal i r r i gant f or
t he bl adder and i nt rapl eur al or i nt raper i t oneal areas.
P. 946


4. Pr ecaut i ons and moni t or i ng ef f ect s. Compar ed wi t h syst emi c
admi ni st rat i on, t he t opi cal f or mul at i ons have r el at i vel y l ow t oxi ci t y.
a. Dr y ski n and l ocal i r ri t at i on wi t h er yt hema, pruri t us, or bur ni ng, al ong
wi t h mi l d ski n di scol or at i on, has occur r ed wi t h t he l ot i on and cr eam.
b. Rash and GÌ ef f ect s (e. g. , nausea, vomi t i ng, st eat or r hea, di ar r hea) t end
t o occur wi t h t he suspensi on. Ì n addi t i on, t her e have been case r epor t s of
ur t i cari a, angi oedema, St evens- Johnson syndr ome, and t oxi c epi der mal
necrol ysi s.
C. But enaf i ne ( Ment ax) i s a synt het i c benzyl ami ne r el at ed t o t he al l yl ami ne
ant i f ungal agent s (naf t i f i ne, t er bi naf i ne) .
1. Mechani sm of act i on. But enaf i ne al t ers f ungal membr ane permeabi l i t y
and gr owt h i nhi bi t i on, i nt er f eres wi t h st er ol bi osynt hesi s by al l owi ng
squal ene t o accumul at e wi t hi n t he cel l , and may be f ungi ci dal i n cer t ai n
concent r at i ons agai nst suscept i bl e or gani sms such as t he dermat ophyt es.
2. Spect r um of act i vi t y. But enaf i ne i s act i ve agai nst Tr i chophyt on rubr um,
Tr i chophyt on ment agr ophyt es, Mi cr ospor um cani s, Spor ot hr i x schencki i ,
and yeast s i ncl udi ng Candi da par apsi l osi s and C. al bi cans.
3. Ther apeut i c uses. The 1% cr eam i s used i n dermat ophyt oses, i ncl udi ng
t i nea cor por i s, t i nea cr uri s, and t i nea pedi s.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Ì f cl i ni cal i mpr ovement of f ungal
i nf ect i on does not i mprove af t er t he t reat ment per i od, t he di agnosi s shoul d
be r eeval uat ed.
D. But oconazol e ( Mycel ex) i s an azol e ant i f ungal cr eam avai l abl e f or
vagi nal use.
1. Mechani sm of act i on. But oconazol e has f ungi st at i c act i vi t y agai nst
suscept i bl e organi sms. The drug i nt er f er es wi t h membrane per meabi l i t y,
secondar y met abol i c ef f ect s, and gr owt h i nhi bi t i on. But oconazol e cont ai ns
ant i bact eri al ef f ect s agai nst some gr am-posi t i ve or gani sms.
2. Spect r um of act i vi t y. But oconazol e i s act i ve agai nst dermat ophyt es
( Tr i chophyt on concent r i cum, T. ment agr ophyt es, T. r ubr um, Tr i chophyt on
t onsur ans, Epi der mophyt on f l occosum, M. cani s, Mi cr osporum gypseum) ,
yeast s ( C. al bi cans, C. gl abrat a), and some gr am- posi t i ve organi sms ( S.
aur eus, E. f aecal i s, and S. pyogenes) .
3. Ther apeut i c uses. A 2% cream i s used f or vul vovagi nal candi di asi s and
compl i cat ed, recur r ent vul vovagi nal candi di asi s.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Vul vovagi nal bur ni ng and i t chi ng ar e t he most common; however , t hei r
i nci dence i s l ow. Headache; i t chi ng of f i ngers; ur i nar y f r equency and
bur ni ng; and vul vovagi nal di schar ge, i r r i t at i on, sor eness, st i ngi ng, odor ,
and swel l i ng r ar el y occur.
b. But oconazol e may damage bi r t h- cont rol devi ces such as condoms and
di aphr agms, l eadi ng t o i nadequat e pr ot ect i on. Consi der al t ernat i ve met hods
of bi r t h cont rol .
c. Tampon use shoul d be avoi ded wi t h t he use of but oconazol e.
E. Ci cl opi rox ( Lopr ox) i s a synt het i c ant i f ungal agent t hat i s chemi cal l y
unr el at ed t o any ot her ant i f ungal agent . The et hanol ami ne cont ai ned i n
ci cl opi rox appears t o enhance epi dermal penet r at i on.
1. Mechani sm of act i on. Ci cl opi r ox causes i nt r acel l ul ar depl et i on of ami no
aci ds and i ons necessary f or nor mal cel l ul ar f unct i on.
2. Spect r um of act i vi t y. Ci cl opi r ox i s act i ve agai nst dermat ophyt es, yeast s,
some gr am- posi t i ve and gr am- negat i ve bact er i a, Mycopl asma, and
Tr i chomonas vagi nal i s. Speci f i cal l y, ci cl opi r ox has act i vi t y agai nst T.
ment agrophyt es, T. r ubrum, E. f l occosum, M. cani s, M. f ur f ur, and C.
al bi cans.
3. Ther apeut i c uses. Ci cl opi rox i s used t opi cal l y f or t he t reat ment of t i nea
pedi s, t i nea crur i s, t i nea corpori s, t i nea ver si col or ( f r om Mal assezi a) , and
cut aneous candi di asi s (moni l i asi s) f rom C. al bi cans.
P. 947


4. Pr ecaut i ons and moni t or i ng ef f ect s. Local i r r i t at i on mani f est ed by
er yt hema, pr uri t us, burni ng, bl i st er i ng, swel l i ng, and oozi ng has occur r ed. Ì f
t hi s occur s, ci cl opi rox shoul d be di scont i nued.
F. Cl i oqui nol ( f ormerl y i odochl or hydr oxyqui n) i s a t opi cal ant i f ungal i n a 3%
oi nt ment t hat can be used al one or i n combi nat i on wi t h hydrocor t i sone.
1. Mechani sm of act i on. Unknown
2. Spect r um of act i vi t y. Ì t i s act i ve agai nst dermat ophyt i c f ungi .
3. Ther apeut i c uses. Ì t i s used t opi cal l y agai nst t he f ol l owi ng:
a. Ti nea pedi s and t i nea cr uri s ( r i ngwor m i nf ect i ons)
b. Pr evi ousl y used t o t r eat di aper rash; however , i t i s no l onger
r ecommended, and use i n chi l dr en < 2 years of age i s cont r ai ndi cat ed
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Local i r r i t at i on, r ash, and sensi t i vi t y r eact i ons ar e common.
b. Syst emi c absorpt i on af t er t opi cal appl i cat i on may occur .
c. Hi gh doses of cl i oqui nol over l ong peri ods of t i me have been associ at ed
wi t h ocul ot oxi c/ neur ot oxi c ef f ect s, i ncl udi ng opt i c neuri t i s, opt i c at r ophy,
and subacut e myel oopt i c neuropat hy.
G. Cl ot ri mazol e ( Lot r i mi n) i s an azol e ant i f ungal agent t hat i s an i mi dazol e
der i vat i ve. Ì t i s rel at ed t o ot her azol e ant i f ungal agent s such as
but oconazol e, econazol e, ket oconazol e, mi conazol e, oxi conazol e,
sul conazol e, and t i oconazol e.
1. Mechani sm of act i on. Cl ot r i mazol e al t ers f ungal cel l membr ane
per meabi l i t y by bi ndi ng wi t h phosphol i pi ds i n t he membrane.
2. Spect r um of act i vi t y. Ì t i s act i ve agai nst yeast s, dermat ophyt es ( T.
r ubr um, T. ment agr ophyt es, E. f l occosum, M. cani s) , and some gr am-
posi t i ve bact er i a. At hi gher concent r at i ons, cl ot ri mazol e i nhi bi t s M. f ur f ur ,
Aspergi l l us f umi gat us, C. al bi cans, and some st rai ns of S. aureus, S.
pyogenes, Pr ot eus vul gar i s, and Sal monel l a. At ver y hi gh concent r at i ons,
cl ot r i mazol e has an ef f ect on Spor ot hr i x, Cr ypt ococcus, Cephal ospor i um,
Fusar i um, and T. vagi nal i s.
3. Ther apeut i c uses
a. The l ozenges, whi ch ar e admi ni st er ed 5 t i mes per day, are usef ul i n
t r eat i ng orophar yngeal candi di asi s. Lozenges ar e al so used f or pr i mar y
pr ophyl axi s of mucocut aneous candi di asi s i n HÌ V- i nf ect ed i nf ant s or
chi l dren wi t h severe i mmunosuppr essi on.
b. The cr eam, l ot i on, or sol ut i on i s used t o t r eat der mat ophyt oses,
super f i ci al mycoses, and cut aneous candi di asi s.
c. Ì nt r avagi nal dosage f or ms ar e usef ul i n t r eat i ng vul vovagi nal candi di asi s.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Cut aneous react i ons wi t h t opi cal admi ni st r at i on may i ncl ude bl i st er i ng,
er yt hema, edema, pr ur i t us, burni ng, st i ngi ng, peel i ng, ski n f i ssur es, and
gener al i r ri t at i on.
b. The vagi nal t abl et s are associ at ed wi t h mi l d bur ni ng, ski n r ash, i t chi ng,
vul val i r r i t at i on, l ower abdomi nal cr amps, bl oat i ng, sl i ght crampi ng, vagi nal
sor eness duri ng i nt ercour se, and an i ncrease i n ur i nar y f r equency.
c. Cr oss- sensi t i zat i on occurs wi t h i mi dazol e; however , i t i s unpredi ct abl e.
d. Abnormal l i ver f unct i on t est s ( el evat ed AST) have occur r ed i n pat i ent s
t aki ng t he l ozenges.
H. Econazol e ( Spect azol e) i s an azol e ant i f ungal agent t hat i s an i mi dazol e
der i vat i ve.
1. Mechani sm of act i on. Econazol e al t ers cel l membr anes and i ncr eases
per meabi l i t y ( l i ke many ot her azol e agent s).
2. Spect r um of act i vi t y. Econazol e i s act i ve agai nst dermat ophyt es, yeast s,
some gr am- posi t i ve bact er i a, and T. vagi nal i s.
3. Ther apeut i c uses
a. The 1% t opi cal cr eam, l ot i on, or sol ut i on i s usef ul i n t r eat i ng
der mat ophyt oses and cut aneous candi di asi s ( t i nea cor por i s and t i nea
cr uri s).
b. Econazol e i s al so used t o t r eat pi t yr i asi s (t i nea) ver si col or ( M. f ur f ur) .
P. 948


4. Pr ecaut i ons and moni t or i ng ef f ect s. Ì n general , t here i s a l ow i nci dence
of t oxi ci t y. Topi cal l y, a pat i ent may exper i ence bur ni ng, st i ngi ng
sensat i ons, prur i t us, and er yt hema ( af t er 2- 4 days) .
Ì . Gent i an vi ol et i s a dye t hat possesses t he abi l i t y t o ki l l f ungi , yeast s, and
some gr am- posi t i ve bact er i a.
1. Mechani sm of act i on. None known
2. Spect r um of act i vi t y. Gent i an vi ol et i s act i ve agai nst Candi da,
Epi der mophyt on, Cr ypt ococcus, Tr i chophyt on, and some St aphyl ococcus
spp.
3. Ther apeut i c uses. Ì t i s used t o t reat cut aneous C. al bi cans i nf ect i ons
( moni l i a or t hr ush) .
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Gent i an vi ol et may cause i r ri t at i on or sensi t i vi t y r eact i ons or possi bl y
ul cer at i on of t he mucous membranes. Ì f t he sol ut i on i s swal l owed,
esophagi t i s, l ar yngi t i s, or t r achei t i s may occur .
b. Ski n t at t ooi ng may occur i f gent i an vi ol et i s appl i ed t o gr anul at i on t i ssue.
c. Gent i an vi ol et shoul d not be used i n ar eas of ext ensi ve ul cer at i on.
d. Thi s drug i s a dye and wi l l st ai n cl ot hi ng.
J. Ket oconazol e ( Ni zoral ) i s an i mi dazol e- deri ved ant i f ungal drug t hat i s
avai l abl e t opi cal l y as a cr eam and a shampoo.
1. Mechani sm of act i on. See Ì Ì Ì . E. 1.
2. Spect r um of act i vi t y. See Ì Ì Ì . E. 2.
3. Ther apeut i c uses
a. The 2% t opi cal cr eam i s used i n t r eat i ng t i nea cor por i s, t i nea cr ur i s, and
t i nea pedi s caused by t he dermat ophyt es ( E. f l occosum, T. ment agrophyt es,
and T. rubr um) .
b. Ì t i s used f or cut aneous candi di asi s.
c. The 2% t opi cal cr eam or 2% shampoo may be used i n t reat i ng t i nea
ver si col or ( M. f ur f ur ) . Sel eni um- based shampoos may al so be usef ul i n t hi s
ar ea.
d. The 2% t opi cal cr eam i s usef ul agai nst sebor r hei c dermat i t i s. The 2%
shampoo i s usef ul i n reduci ng scal i ng caused by dandr uf f .
e. When combi ned wi t h a st er oi d, ket oconazol e i s usef ul i n t r eat i ng t he
f ol l owi ng: at opi c der mat i t i s, di aper r ash, eczema, f ol l i cul i t i s, i mpet i go,
i nt er t r i go, l i chenoi d dermat i t i s, and psori asi s.
f . An opht hal mi c suspensi on can be ext empor aneousl y prepar ed t o t r eat
f ungal kerat i t i s.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. React i ons f r om t he 2% t opi cal cream i ncl ude l ocal i r r i t at i on, prur i t us, and
st i ngi ng. Cont act der mat i t i s i s possi bl e and occurs wi t h ot her i mi dazol e
der i vat i ves.
b. The 2% shampoo may l ead t o i ncreased hai r l oss, i r ri t at i on, abnor mal
hai r t ext ur e, scal p pust ul es, dr y ski n, pr uri t us, and oi l i ness or dr yness of
hai r and scal p. Ì t may i n addi t i on st r ai ght en ot herwi se cur l y hai r .
K. Mi conazol e ( Moni st at ) i s an i mi dazol e-deri ved ant i f ungal drug t hat i s
avai l abl e t opi cal l y as a 2% aerosol , 2% aer osol powder , 2% cream, a ki t ,
2% powder and 2% t i nct ur e, 2% vagi nal cream, and 100 mg and 200 mg
vagi nal supposi t or i es.
1. Mechani sm of act i on. See Ì Ì Ì . E. 1.
2. Spect r um of act i vi t y. See Ì Ì Ì . E. 2.
3. Ther apeut i c uses. Mi conazol e i s advant ageous over ot her agent s such as
nyst at i n and t ol naf t at e i n t hat i t s act i vi t y cover s der mat ophyt es as wel l as
Candi da.
a. Topi cal use i s ef f ect i ve agai nst t i nea pedi s, t i nea cr uri s, and t i nea
cor por i s caused by dermat ophyt es ( T. ment agr ophyt es, T. r ubrum, and E.
f l occosum) .
b. Ì t i s al so ef f ect i ve agai nst t i nea versi col or f rom M. f ur f ur .
c. Li ke ot her i mi dazol e der i vat i ves, i t i s usef ul i n t r eat i ng cut aneous f ungal
i nf ect i ons.
d. The vagi nal cr eam and vagi nal supposi t or i es ar e ef f ect i ve i n t r eat i ng
vul vovagi nal candi di asi s.
P. 949


4. Pr ecaut i ons and moni t or i ng par amet er s
a. Topi cal cr eams have caused l ocal i r r i t at i on and burni ng.
b. Vagi nal pr eparat i ons have l ed t o vul vovagi nal bur ni ng, i t chi ng, i r r i t at i on,
pel vi c cr amps, vagi nal bur ni ng, headache, hi ves, and ski n r ash.
c. Ì f vul vovagi nal candi di asi s persi st s f or l onger t han 3 days, seek f ur t her
medi cal at t ent i on.
d. Tampons shoul d be avoi ded i n pat i ent s usi ng vagi nal supposi t or i es or
cr eam; sani t ar y pads shoul d be subst i t ut ed.
e. Vagi nal supposi t ori es ar e manuf act ur ed f r om a veget abl e oi l base t hat
may i nt eract wi t h l at ex pr oduct s. Avoi d usi ng di aphr agms or condoms
concur rent l y wi t h supposi t ori es. Seek an al t er nat i ve f orm of bi r t h cont r ol .
L. Naf t i f i ne ( Naf t i n) i s a synt het i c al l yl ami ne si mi l ar t o t er bi naf i ne. Ì t i s
avai l abl e as a 1% t opi cal cr eam and a 1% t opi cal gel .
1. Mechani sm of act i on. Naf t i f i ne i s f ungi st at i c and i nt erf eres wi t h st er ol
bi osynt hesi s by accumul at i ng squal ene i n t he f ungal cel l . Naf t i f i ne al so
possesses some l ocal ant i - i nf l ammat or y act i vi t y.
2. Spect r um of act i vi t y
a. Naf t i f i ne i s act i ve agai nst T. ment agr ophyt es, T. r ubr um, T. t onsur ans,
Tr i chophyt on ver r ucosum, Tr i chophyt on vi ol aceum, E. f l occosum,
Mi cr osporum audoui ni i , M. cani s, and M. gypseum.
b. C. al bi cans, Candi da kr usei , Candi da parapsi l osi s, and Candi da
t r opi cal i s ar e af f ect ed by naf t i f i ne; however , t he concent rat i ons of naf t i f i ne
var y f or Candi da ki l l i ng, dependi ng on t he speci es.
c. Ì n vi t ro act i vi t y has been demonst r at ed agai nst Asper gi l l us f l avus and
Aspergi l l us f umi gat us. Ot hers i ncl ude Spor ot hr i x schencki i , Cr ypt ococcus
neof or mans, Pet r i el l i di um boydi i , Bl ast omyces der mat i t i di s, and
Hi st opl asma capsul at um.
3. Ther apeut i c uses. Naf t i f i ne i s act i ve agai nst der mat ophyt oses and
cut aneous candi di asi s.
a. Ì t i s al so used t o t r eat t i nea cr uri s, t i nea pedi s, t i nea cor pori s, and t i nea
manus ( T. ment agr ophyt es, T. rubrum, T. ver r ucosum, T. vi ol aceum, E.
f l occosum, or M. cani s) .
b. Ì t i s al so usef ul i n t r eat i ng t i nea ungui um (onychomycosi s) .
4. Pr ecaut i ons and moni t or i ng ef f ect s. Tr ansi ent bur ni ng and st i ngi ng
M. Nyst at i n ( Mycost at i n) . A pol yene ant i bi ot i c, nyst at i n has a chemi cal
st r uct ur e si mi l ar t o t hat of amphot er i ci n B. Ì t i s avai l abl e as an oral
suspensi on, t abl et , l ozenge, t opi cal cream, oi nt ment , t opi cal powder , and
vagi nal t abl et .
1. Mechani sm of act i on. Nyst at i n i s f ungi ci dal and f ungi st at i c; bi ndi ng t o
st erol s i n t he f ungal cel l membr ane, i t i ncr eases membr ane permeabi l i t y
and permi t s l eakage of i nt r acel l ul ar cont ent s.
2. Spect r um of act i vi t y. Nyst at i n i s act i ve pri mar i l y agai nst Candi da spp.
3. Ther apeut i c uses. Thi s drug i s used pr i mari l y as a t opi cal agent i n
vagi nal and or al Candi da i nf ect i ons.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Ì r ri t at i on has occur red i n ext r emel y
r ar e i nst ances.
N. Oxi conazol e ( Oxi st at ) i s an i mi dazol e-deri ved ant i f ungal drug t hat i s
avai l abl e as a 1% t opi cal cr eam or 1% t opi cal l ot i on.
1. Mechani sm of act i on. See Ì Ì Ì . E. 1.
2. Spect r um of act i vi t y. See Ì Ì Ì . E. 2.
3. Ther apeut i c uses
a. The 1% cr eam or l ot i on i s usef ul i n t r eat i ng t i nea cr uri s, t i nea cor por i s,
t i nea manus, and t i nea pedi s f rom dermat ophyt es.
b. Oxi conazol e i s al so ef f ect i ve agai nst t i nea versi col or caused by M.
f ur f ur.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Adverse ef f ect s ar e rar e and are
conf i ned t o l ocal i r ri t at i on.
P. 950


O. Sul conazol e ( Exel derm) i s an i mi dazol e-der i ved ant i f ungal drug t hat i s
avai l abl e as a 1% t opi cal cr eam and a 1% t opi cal sol ut i on.
1. Mechani sm of act i on (see Ì Ì Ì . E. 1). The ant i bact er i al ef f ect s exer t ed by
sul conazol e ar e t hought t o be t he resul t of a di r ect physi cochemi cal ef f ect
on t he dest r uct i on of unsat ur at ed f at t y aci ds pr esent i n bact eri al cel l
membr anes.
2. Spect r um of act i vi t y
a. Sul conazol e has act i vi t y agai nst der mat ophyt es, i ncl udi ng E. f l occosum,
M. audoui ni i , M. cani s, M. gypseum, T. ment agrophyt es, T. rubr um, T.
t onsur ans, and T. vi ol aceum. Ì t al so has act i vi t y agai nst M. f ur f ur.
b. Sul conazol e al so has act i vi t y agai nst sel ect ed gr am- posi t i ve aer obes (S.
aur eus, S. epi dermi di s, St aphyl ococcus saprophyt i cus, E. f aecal i s,
Mi cr ococcus l ut eus, and Baci l l us subt i l i s) and anaer obes ( Cl ost r i di um and
Pr opi oni bact er i um acnes, Cl ost ri di um perf r i ngens, Cl ost ri di um t et ani , and
Cl ost r i di um bot ul i num) .
3. Ther apeut i c uses
a. The 1% t opi cal cr eam or 1% t opi cal sol ut i on i s usef ul i n t r eat i ng t i nea
cor por i s and t i nea crur i s.
b. The 1% t opi cal cr eam has been st udi ed f or use agai nst t i nea pedi s; t he
sol ut i on has not been eval uat ed f or t hi s i ndi cat i on.
c. The 1% cr eam i s usef ul agai nst t i nea versi col or ( M. f ur f ur ).
d. Ther e i s not an approved i ndi cat i on f or cut aneous candi di asi s; however ,
sul conazol e 1% i s as ef f ect i ve as mi conazol e 2% or cl ot r i mazol e 1% i n
t r eat i ng cut aneous candi di asi s.
e. Sul conazol e i s usef ul i n t reat i ng i nf ect i ons caused by bact er i a such as
i mpet i go ( S. pyogenes) and ect hyma ( S. aureus).
4. Pr ecaut i ons and moni t or i ng ef f ect s. Adverse r eact i ons i ncl ude l ocal
ef f ect s such as bur ni ng and i r r i t at i on, ski n edema, dr yness, scal i ng,
f i ssuri ng, cr acki ng, gener al i zed r ed papul es, and sever e eczema.
P. Ter bi naf i ne ( Lami si l AT) i s a synt het i c al l yl ami ne avai l abl e as a 1%
cr eam wi t h st ruct ur e and act i vi t y r el at ed t o naf t i f i ne.
1. Mechani sm of act i on. Ter bi naf i ne i nhi bi t s squal ene monooxygenase,
l eadi ng t o an i nt er rupt i on of f ungal st erol bi osynt hesi s. Ter bi naf i ne may be
f ungi ci dal or f ungi st at i c, dependi ng on dr ug concent r at i on and speci es.
2. Spect r um of act i vi t y. Ter bi naf i ne has act i vi t y agai nst der mat ophyt i c f ungi
( Tr i chophyt on, Mi cr osporum, and Epi dermophyt on) , f i l ament ous f ungi
( Asper gi l l us), and di morphi c f ungi ( Bl ast omyces). Ì t may al so possess some
act i vi t y agai nst yeast s.
3. Ther apeut i c uses. Ì t i s usef ul f or t i nea pedi s, t i nea corpori s, and t i nea
cr uri s.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Ì t can cause l ocal i r r i t at i on.
Q. Ter conazol e ( Ter azol - 7) i s an i mi dazol e- der i ved ant i f ungal drug t hat i s
avai l abl e as a 0. 4% and 0. 8% vagi nal cream and an 80- mg vagi nal
supposi t or y.
1. Mechani sm of act i on. Ì t i s f ungi ci dal agai nst C. al bi cans. Li ke ot her
i mi dazol e agent s, t er conazol e al t er s cel l ul ar membr anes, resul t i ng i n
i ncreased membr ane permeabi l i t y.
2. Spect r um of act i vi t y. Ì t i s act i ve agai nst dermat ophyt es; yeast s; and, at
hi gh concent r at i ons, gr am- posi t i ve and gr am-negat i ve bact eri a.
3. Ther apeut i c uses ar e f or compl i cat ed and uncompl i cat ed vul vovagi nal
candi di asi s.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Adverse r eact i ons i ncl ude burni ng,
pr ur i t us, i r r i t at i on, headache, body pai n, and pai n of f emal e geni t al i a.
R. Ti oconazol e ( Vagi st at - 1) i s an i mi dazol e- der i ved ant i f ungal drug t hat i s
avai l abl e as a 6. 5% vagi nal oi nt ment .
1. Mechani sm of act i on. Ti oconazol e i s f ungi ci dal agai nst C. al bi cans. Li ke
ot her i mi dazol e agent s, t i oconazol e al t ers cel l ul ar membranes, r esul t i ng i n
i ncreased membr ane permeabi l i t y.
P. 951


2. Spect r um of act i vi t y
a. Act i vi t y agai nst f ungi i ncl udes most st rai ns of Candi da and t he
der mat ophyt es. Ther e i s al so act i vi t y agai nst Asper gi l l us and C.
neof or mans.
b. Ti oconazol e i s act i ve agai nst t he f ol l owi ng aerobi c gram- posi t i ve
bact er i a: Gar dner el l a vagi nal i s, Cor ynebact eri um mi nut i ssi mum, E. f aecal i s,
S. aureus, S. epi der mi di s, and some St r ept ococci spp. Gram-negat i ve
bact er i a: i t i s act i ve agai nst H. pyl or i , Haemophi l us ducr eyi , Mor axel l a
cat ar r hal i s, Nei sser i a gonor r hoeae, and N. meni ngi t i di s.
c. Ot her or gani sms t hat t i oconazol e has act i vi t y agai nst ar e T. vagi nal i s,
Lymphogr anul oma venereum, and Chl amydi a t rachomat i s.
3. Ther apeut i c uses. Ti oconazol e i s used f or si mpl e and compl i cat ed
vul vovagi nal candi di asi s. Ot her uses have been expl or ed; however , t opi cal
cr eams f or use i n t hose scenari os are not avai l abl e i n t he Uni t ed St at es.
4. Pr ecaut i ons and moni t or i ng ef f ect s. Local i r r i t at i on has been mani f est ed
as vul vovagi nal burni ng, vagi ni t i s, and pr ur i t us.
S. Tol naf t at e ( Ti nact i n) i s avai l abl e t opi cal l y as a 1% aer osol , 1% powder ,
1% cr eam, and 1% sol ut i on.
1. Mechani sm of act i on. Ì t may di st or t hyphae and st unt mycel i al growt h i n
suscept i bl e f ungi .
2. Spect r um of act i vi t y. Tol naf t at e may be ei t her f ungi st at i c or f ungi ci dal t o
t he f ol l owi ng or gani sms: M. gypseum, M. cani s, M. audoui ni i , Mi crospor um
j aponi cum, T. rubr um, T. ment agr ophyt es, Tr i chophyt on schoenl ei ni i , T.
t onsur ans, E. f l occosum, Asper gi l l us ni ger , C. al bi cans, C. neof ormans, and
A. f umi gat us.
3. Ther apeut i c uses. Tol naf t at e i s used f or dermat ophyt oses and t i nea
ver si col or .
4. Pr ecaut i ons and moni t or i ng ef f ect s. Ther e may be sl i ght l ocal i r r i t at i on.
V. AntiprotozoaI Agents
A. Cl assi f i cat i on. These dr ugs f al l i nt o t wo mai n cat egori es: ant i mal ar i al
agent s, used t o t r eat mal ar i a i nf ect i on, and amebi ci des and
t r i chomonaci des, used t o t r eat amebi c and t r i chomonal i nf ect i ons.
B. Ant i mal ari al agent s. St i l l a l eadi ng cause of i l l ness and deat h i n t r opi cal
and subt r opi cal count r i es, mal ar i a r esul t s f rom i nf ect i on by any of f our
speci es of t he pr ot ozoal genus Pl asmodi um. Ant i mal ar i al agent s are
sel ect i vel y act i ve dur i ng di f f er ent phases of t he pr ot ozoan l i f e cycl e. Maj or
ant i mal ari al drugs i ncl ude chl oroqui ne ( Aral en) , hal of ant ri ne ( Hal f an) ,
hydr oxychl or oqui ne ( Pl aqueni l ), pri maqui ne, pyr i met hami ne ( Darapri m),
qui ni ne, and mef l oqui ne ( Lar i am). Ì n addi t i on, t wo combi nat i on br ands are
avai l abl e: sul f adoxi ne pl us pyr i met hami ne ( Fansi dar ) and at ovaquone pl us
pr oguani l ( Mal ar one) .
1. Mechani sm of act i on
a. Chl or oqui ne and hydroxychl or oqui ne bi nd t o and al t er t he proper t i es of
mi cr obi al and mammal i an DNA.
b. The mechani sm of act i on of pr i maqui ne, qui ni ne, Fansi dar , and
mef l oqui ne i s unknown.
c. Pyr i met hami ne i mpedes f ol i c aci d r educt i on by i nhi bi t i ng t he enzyme
di hydrof ol at e r educt ase.
2. Spect r um of act i vi t y
a. Chl or oqui ne and hydroxychl or oqui ne are suppr essi ve bl ood schi zont i ci dal
agent s and are act i ve agai nst t he asexual er yt hr ocyt e f or ms of Pl asmodi um
vi vax and Pl asmodi um f al ci parum and gamet ocyt es of P. vi vax, Pl asmodi um
mal ar i ae, and Pl asmodi um oval e.
b. Pr i maqui ne, a curat i ve agent , i s act i ve agai nst l i ver f orms of P. vi vax and
P. oval e and t he pr i mar y exoer yt hr ocyt e f orms of P. f al ci parum.
c. Pyr i met hami ne i s act i ve agai nst chl or oqui ne- resi st ant st rai ns of P.
f al ci par um and some st rai ns of P. vi vax.
d. Qui ni ne, a gener al i zed pr ot opl asmi c poi son, i s t oxi c t o a wi de r ange of
or gani sms. Ì n mal ar i a, t hi s dr ug has bot h suppr essi ve and cur at i ve act i on
agai nst chl or oqui ne- resi st ant st r ai ns.
P. 952


e. Fansi dar (sul f adoxi ne pl us pyr i met hami ne) i s a bl ood schi zont i ci dal agent
t hat i s act i ve agai nst t he er yt hr ocyt i c f or ms of suscept i bl e pl asmodi a. Ì t i s
al so act i veagai nst T. gondi i .
f . Mal ar one ( at ovaquone pl us pr oguani l ) i s act i ve agai nst t he er yt hrocyt i c
and exoer yt hr ocyt i c f orms of Pl asmodi um spp.
g. Mef l oqui ne i s a bl ood schi zont i ci dal agent t hat i s act i ve agai nst P.
f al ci par um (bot h chl or oqui ne- suscept i bl e and - r esi st ant st r ai ns) and P.
vi vax.
h. Hal of ant ri ne i s a bl ood schi zont i ci dal agent act i ve agai nst P. f al ci parum
and P. vi vax.
3. Ther apeut i c uses
a. Chl or oqui ne i s t he pref er r ed agent used t o suppr ess mal ari a sympt oms
and t o t ermi nat e acut e mal ari a at t acks r esul t i ng f r om P. f al ci par um and P.
mal ar i ae i nf ect i ons.
( 1) Ì t i s mor e pot ent and l ess t oxi c t han qui ni ne.
( 2) Except wher e dr ug- r esi st ant P. f al ci parum st rai ns are pr eval ent ,
chl or oqui ne i s t he most usef ul ant i mal ar i al agent .
b. Hydr oxychl oroqui ne i s used as an al t er nat i ve t o chl oroqui ne i n pat i ent s
who cannot t ol er at e chl or oqui ne or when chl oroqui ne i s unavai l abl e.
c. Pri maqui ne i s used t o cur e r el apses of P. vi vax and P. oval e mal ari a and
t o prevent mal ari a i n exposed per sons r et ur ni ng f r om regi ons wher e mal ari a
i s endemi c.
d. Pyr i met hami ne i s ef f ect i ve i n t he prevent i on and t reat ment of
chl or oqui ne- resi st ant st rai ns of P. f al ci parum. Ì t i s now used al most
excl usi vel y i n combi nat i on wi t h a sul f onami de or sul f one.
e. Qui ni ne
( 1) Qui ni ne sul f at e, an or al f or m, i s t herapeut i c f or acut e mal ar i a caused by
chl or oqui ne- resi st ant st rai ns.
( 2) Qui ni ne di hydrochl or i de, a par ent eral f or m, i s used i n sever e cases of
chl or oqui ne- resi st ant mal ar i a. (Ì t i s avai l abl e onl y f r om t he CDC. )
( 3) Qui ni ne i s al most al ways gi ven i n combi nat i on wi t h anot her ant i mal ari al
agent .
f . Fansi dar
( 1) Fansi dar i s used f or t he suppr essi on or pr ophyl axi s of chl or oqui ne-
r esi st ant P. f al ci par um mal ari a.
( 2) Ì t has been used f or t he prophyl axi s of P. cari ni i i nf ect i ons i n AÌ DS
pat i ent s unabl e t o t ol er at e cot ri moxazol e ( t r i met hopr i m-sul f amet hoxazol e).
g. Mef l oqui ne i s i ndi cat ed f or t he t reat ment of acut e mal ari a and t he
pr event i on of P. f al ci parum and P. vi vax i nf ect i ons.
h. Hal of ant ri ne i s i ndi cat ed f or t reat ment of mal ari a i n adul t s who can
t ol er at e oral medi cat i on and who have mi l d t o moder at e mal ar i a ( < 100, 000
par asi t es/ mm
3
) caused by P. f al ci parum or P. vi vax.
i . Mal ar one
( 1) Pr ophyl axi s of P. f al ci parum mal ari a, i ncl udi ng ar eas wher e chl or oqui ne
r esi st ance has been r epor t ed.
( 2) Tr eat ment of acut e, uncompl i cat ed P. f al ci parum mal ar i a. Thi s
combi nat i on has been shown t o be ef f ect i ve i n r egi ons wher e t he drugs
chl or oqui ne, hal of ant ri ne, mef l oqui ne, and amodi aqui ne may have
unaccept abl e f ai l ur e r at es, pr esumabl y because of dr ug r esi st ance.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Chl or oqui ne and hydroxychl or oqui ne
( 1) Because t hese drugs concent rat e i n t he l i ver , t hey shoul d be used
caut i ousl y i n pat i ent s wi t h hepat i c di sease.
( 2) Chl or oqui ne must be admi ni st er ed wi t h ext r eme caut i on i n pat i ent s wi t h
neurol ogi cal , hemat ol ogi cal , or sever e GÌ di sorder s.
( 3) Vi sual di st urbances, headache, ski n r ash, and GÌ di st r ess have been
r eport ed.
b. Pr i maqui ne
( 1) Thi s agent i s cont r ai ndi cat ed i n pat i ent s wi t h r heumat oi d ar t hri t i s and
l upus er yt hemat osus and i n t hose r ecei vi ng ot her pot ent i al l y hemol yt i c
dr ugs or bone mar r ow suppr essant s.
( 2) Pr i maqui ne may cause agranul ocyt osi s, gr anul ocyt openi a, and mi l d
anemi a. Ì n pat i ent s wi t h G6PD def i ci ency, i t may cause hemol yt i c anemi a.
( 3) Abdomi nal cr amps, nausea, vomi t i ng, and epi gast r i c di st r ess somet i mes
occur .
c. Pyr i met hami ne
( 1) Ì n hi gh doses, t hi s drug may cause agr anul ocyt osi s, megal obl ast i c
anemi a, apl ast i c anemi a, and t hrombocyt openi a.
P. 953


( 2) Er yt hema mul t i f or me ( St evens- Johnson syndrome), nausea, vomi t i ng,
and anor exi a may devel op duri ng pyr i met hami ne t her apy.
d. Qui ni ne
( 1) Qui ni ne i s cont r ai ndi cat ed i n pat i ent s wi t h G6PD def i ci ency, t i nni t us,
and opt i c neur i t i s.
( 2) Qui ni ne over dose or hyper sensi t i vi t y r eact i ons may be f at al .
Mani f est at i ons of qui ni ne poi soni ng i ncl ude vi sual and hear i ng
di st ur bances; GÌ sympt oms ( e. g. , nausea, vomi t i ng) ; hot , f l ushed ski n;
headache; f ever; syncope; conf usi on; shal l ow, t hen depressed, r espi r at i ons;
and cardi ovascul ar col l apse.
( 3) Qui ni ne must be used caut i ousl y i n pat i ent s wi t h at r i al f i bri l l at i on.
( 4) Renal damage and anur i a have been r epor t ed.
e. Fansi dar
( 1) Severe, somet i mes f at al , hyper sensi t i vi t y r eact i ons have occur r ed. Ì n
most cases, deat h r esul t ed f rom sever e cut aneous r eact i ons, i ncl udi ng
er yt hema mul t i f orme, St evens-Johnson syndr ome, and t oxi c epi der mal
necrol ysi s.
( 2) Adverse hemat ol ogi cal and hepat i c ef f ect s as seen wi t h sul f onami des
have been r epor t ed.
f . Mef l oqui ne
( 1) Concomi t ant use of mef l oqui ne wi t h qui ni ne, qui ni di ne, or 8- adr ener gi c
bl ockade may pr oduce el ect rocar di ographi c abnormal i t i es or cardi ac ar r est .
( 2) Concomi t ant use of mef l oqui ne and qui ni ne or chl or oqui ne may i ncrease
t he ri sk of convul si ons.
g. Hal of ant ri ne
( 1) Do not admi ni st er wi t h dr ugs known t o pr ol ong t he QTc i nt er val ;
i nt er act i on wi t h mef l oqui ne f ur t her pr ol ongs t he QTc i nt er val .
( 2) A sevenf ol d i ncr ease i n peak pl asma l evel and t hreef ol d i ncrease i n t he
ar ea under t he cur ve ( AUC) occur red when gi ven wi t h hi gh-f at f ood. Si mi l ar
i ncreases occur when doses are admi ni st er ed 2 hr af t er a meal . Admi ni st er
hal of ant r i ne on an empt y st omach.
h. Mal ar one
( 1) Concomi t ant admi ni st r at i on wi t h t et r acycl i ne has been associ at ed wi t h
40% reduct i on i n pl asma concent rat i ons of at ovaquone. Si mi l ar l y,
concur rent r i f ampi n i s known t o r educe at ovaquone l evel s by 50%.
( 2) Take mal ar one wi t h f ood or mi l k.
C. Amebi ci des and t ri chomonaci des. These agent s ar e cr uci al i n t he
t r eat ment of amebi asi s, gi ardi asi s, and t ri chomoni ases÷t he most common
pr ot ozoal i nf ect i ons i n t he Uni t ed St at es. The maj or amebi ci des i ncl ude
di l oxani de, i odoqui nol ( Yodoxi n) , met roni dazol e (Fl agyl ) , ni t azoxani de
( Al i ni a), par omomyci n ( Humat i n), qui nacr i ne, and t i ni dazol e ( Ti ndamax) .
1. Mechani sm of act i on
a. Di l oxani de, a di chl oroacet ami de der i vat i ve, i s amebi ci dal ; i t s mechani sm
of act i on i s unknown. ( Not avai l abl e commerci al l y but can be compounded
by Panorama Compoundi ng Phar macy, Van Nuys, CA÷per Medi cal Let t er
8/ 04. )
b. Met r oni dazol e i s a synt het i c compound wi t h di r ect amebi ci dal and
t r i chomonaci dal act i on; i t wor ks at bot h i nt est i nal and ext r ai nt est i nal si t es.
Ì t s mechani sm of act i on i nvol ves di sr upt i on of t he hel i cal st ruct ur e of DNA.
c. Ni t azoxani de i s desi gnat ed by t he U. S. Food and Drug Admi ni st r at i on
( FDA) as an orphan dr ug. Ì t s ant i pr ot ozoal act i vi t y i s bel i eved t o be t he
r esul t of i nt er f erence wi t h t he pyr uvat e: f er redoxi n oxi dor educt ase ( PFOR)
enzyme- dependent el ect r on t ransf er r eact i on essent i al f or ener gy
met abol i sm.
d. Qui nacr i ne i s an acri di ne deri vat i ve t hat i nhi bi t s DNA met abol i sm.
e. Ì odoqui nol i s a l umi nal or cont act amebi ci de t hat i s ef f ect i ve agai nst t he
t r ophozoi t es of Ent amoeba hi st ol yt i ca l ocat ed i n t he l umen of t he l ar ge
i nt est i ne.
f . Paromomyci n i s a poorl y absor bed amebi ci dal ami nogl ycosi de whose
mechani sm of act i on paral l el s ot her ami nogl ycosi des ( i . e. , pr ot ei n synt hesi s
i nhi bi t or ) . Ì t i s al so ef f ect i ve agai nst ent eri c bact er i a Sal monel l a and
Shi gel l a.
g. Ti ni dazol e pr eci se mechani sm of act i on i s unknown.
2. Spect r um of act i vi t y and t her apeut i c uses
a. Di l oxani de
P. 954


( 1) Thi s drug i s used t o t r eat asympt omat i c car r i er s of amebi c and Gi ar di a
cyst s.
( 2) Di l oxani de i s t her apeut i c f or i nvasi ve and ext r ai nt est i nal amebi asi s
( gi ven i n combi nat i on wi t h a syst emi c or mi xed amebi ci de) .
( 3) Di l oxani de i s not ef f ect i ve as si ngl e-agent t her apy f or ext r ai nt est i nal
amebi asi s.
b. Met r oni dazol e
( 1) Thi s agent i s t he pr ef er r ed dr ug i n amebi c dysent er y, gi ar di asi s, and
t r i chomoni asi s.
( 2) Met r oni dazol e al so i s act i ve agai nst al l anaerobi c cocci and gr am-
negat i ve anaer obi c baci l l i .
( 3) Thi s agent i s t he t reat ment of choi ce by t he CDC f or t he t r eat ment of C.
di f f i ci l e col i t i s i nf ect i ons owi ng t o t he emergi ng use of br oad- spect r um
ant i bi ot i cs. Thi s t her apy i s cost - ef f ect i ve.
c. Qui nacr i ne i s usef ul i n t he t r eat ment of gi ar di asi s and t apewor ms (see
VÌ Ì Ì . H. 2) .
d. Ì odoqui nol i s i ndi cat ed f or t r eat ment of i nt est i nal amebi asi s. Ì t i s act i ve
agai nst t he pr ot ozoa E. hi st ol yt i ca.
e. Ni t azoxani de i s i ndi cat ed f or t r eat ment of di arrhea caused by
Cr ypt ospor i di um par vum and Gi ar di a l ambl i a i n chi l dren.
f . Paromomyci n i s i ndi cat ed f or acut e and chr oni c i nt est i nal amebi asi s; i t i s
not usef ul f or ext r ai nt est i nal amebi asi s because i t i s not absor bed.
Par omomyci n has been used f or Di ent amoeba f ragi l i s, Taeni a sagi nat a,
Di pyl i di um cani num, and Hymenol epi s nana.
g. Ti ni dazol e i s a second- gener at i on synt het i c ni t r oi mi dazol e act i ve agai nst
t r i chomoni asi s, Gi ar di a duodenal i s/ G. l ambl i a, and E. hi st ol yt i ca.
3. Pr ecaut i ons and moni t or i ng ef f ect s
a. Di l oxani de r arel y causes seri ous adverse ef f ect s. Vomi t i ng, f l at ul ence,
and pr uri t us have been repor t ed.
b. Met r oni dazol e
( 1) The most common adver se ef f ect s of t hi s drug ar e nausea, epi gast r i c
di st r ess, and di ar rhea.
( 2) Met r oni dazol e i s carci nogeni c i n mi ce and shoul d not be used
unnecessar i l y.
( 3) Headache, vomi t i ng, met al l i c t ast e, and st omat i t i s have been report ed.
( 4) Occasi onal l y, neurol ogi cal r eact i ons ( e. g. , at axi a, per i pher al
neuropat hy, sei zures) devel op.
( 5) A di sul f i r am- t ype r eact i on may occur wi t h concur rent et hanol use.
c. Qui nacr i ne. See VÌ Ì Ì . H. 4.
( 1) Thi s drug f r equent l y causes di zzi ness, headache, nausea, and vomi t i ng.
Ner vousness and sei zures al so have been r epor t ed.
( 2) Qui nacr i ne shoul d not be t aken i n combi nat i on wi t h pri maqui ne because
t hi s may i ncr ease pr i maqui ne t oxi ci t y.
( 3) Qui nacr i ne shoul d be admi ni st er ed wi t h ext r eme caut i on i n pat i ent s wi t h
psori asi s because i t may cause mar ked exacer bat i on of t hi s di sease.
d. Ì odoqui nol may pr oduce opt i c neur i t i s or at r ophy or per i pheral
neuropat hy wi t h hi gh- dose, l ong- t er m use. Pr ot ei n- bound i odi ne l evel s may
be i ncreased dur i ng t reat ment and may i nt er f ere wi t h t he r esul t s of t hyr oi d
t est s f or 6 mont hs af t er t r eat ment . Ì odoqui nol shoul d not be used i n
pat i ent s who ar e hypersensi t i ve t o 8- hydroxy- qui nol one ( e. g. , i odoqui nol ,
i odochl orhydr oxyqui n) or i odi ne- cont ai ni ng agent s or i n pat i ent s wi t h
hepat i c di sor der s.
e. Paromomyci n may cause nausea, cr ampi ng, and di ar r hea at hi gh doses
( > 3 g/ day) . Ì nadver t ent absor pt i on t hr ough ul cerat i ve bowel l esi ons may
r esul t i n ot ot oxi ci t y or r enal damage.
f . Ni t azoxani de may cause abdomi nal pai n, di ar rhea, vomi t i ng, headache,
f l at ul ence, f ever , eye di scol or at i on, rhi ni t i s, and di scol ored ur i ne.
g. Ti ni dazol e may produce met al l i c t ast e, nausea, anor exi a, dyspepsi a,
vomi t i ng, weakness, di zzi ness, and headache.
D. Pent ami di ne i set hi onat e ( Pent am 300) i s an ar omat i c di ami de
ant i pr ot ozoal agent . Ì t can be admi ni st er ed i nt r amuscul arl y, i nt r avenousl y,
or by i nhal at i on.
1. Mechani sm of act i on i s not f ul l y under st ood, but i n vi t ro st udi es i ndi cat e
i nt er f erence wi t h nucl ear met abol i sm and i nhi bi t i on of DNA, RNA,
phosphol i pi d, and pr ot ei n synt hesi s.
2. Ther apeut i c uses
a. Pent ami di ne i s i ndi cat ed f or t he pr event i on and t r eat ment of i nf ect i ons
caused by P. car i ni i .
P. 955


b. Unl abel ed uses i ncl ude t r eat ment of t r ypanosomi asi s, vi scer al
l ei shmani asi s, and babesi osi s.
3. Pr ecaut i ons and moni t or i ng ef f ect s
a. Nephr ot oxi ci t y, br onchospasm, and cough ar e t he most common ef f ect s
pr oduced by i nt ravenous or i nhal ed pent ami di ne.
b. Severe hypot ensi on may occur af t er a parent eral dose of pent ami di ne.
Car di or espi rat or y ar r est can occur af t er a si ngl e r api d i nf usi on of t he dr ug.
c. Pai n, er yt hema, and t ender ness may occur af t er an Ì M admi ni st rat i on of
t he dr ug. Thi s can be mi ni mi zed by usi ng t he Z- t rack t echni que of dr ug
admi ni st rat i on. Phl ebi t i s may occur f ol l owi ng Ì V admi ni st r at i on.
d. Hypogl ycemi a may occur wi t h i ni t i al admi ni st rat i on of drug vi a t he Ì V, Ì M,
or i nhal at i onal r out e. Af t er t he pat i ent has been on t he dr ug f or a per i od of
t i me, hyper gl ycemi a wi l l r esul t . The ef f ect of t he dr ug may act ual l y i nduce a
r ever si bl e i nsul i n- dependent di abet es mel l i t us.
e. Leukopeni a and t hr ombocyt openi a, whi ch can be sever e, occur
occasi onal l y.
f . Pent ami di ne may r esul t i n el evat ed l i ver f unct i on t est s, AST, and ALT.
g. GÌ ef f ect s can al so occur , i ncl udi ng nausea, vomi t i ng, abdomi nal
di scomf or t , pai n, di ar r hea, and dysgeusi a.
h. Neur ol ogi cal ef f ect s can occur wi t h parent er al admi ni st rat i on and may
i ncl ude di zzi ness, t remors, conf usi on, anxi et y, i nsomni a, and sei zures.
i . Hypocal cemi a and f ever have al so been repor t ed and may be sever e at
t i mes.
E. At ovaquone ( Mepr on) i s a hydroxynapht hoqui none i ni t i al l y synt hesi zed
as an ant i mal ari al drug.
1. Mechani sm of act i on. At ovaquone bl ocks mi t ochondr i al el ect r on t ranspor t
at compl ex Ì Ì Ì of t he r espi r at or y chai n of prot ozoa, r esul t i ng i n i nhi bi t i on of
pyr i mi di ne synt hesi s.
2. Spect r um of act i vi t y. Ì t i s act i ve agai nst P. cari ni i , T. gondi i , C. par vum,
P. f al ci parum, Ì sospori di a, and Mi cr ospor i di a.
3. Ther apeut i c uses. At ovaquone i s used f or second-l i ne t reat ment of mi l d
t o moder at e P. cari ni i pneumoni a i n pat i ent s i nt ol er ant of cot r i moxazol e or
ot her sul f onami des or who are nonresponsi ve t o cot ri moxazol e.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Or al absor pt i on si gni f i cant l y i ncreases when admi ni st ered wi t h f ood
( especi al l y a hi gh- f at meal ) .
b. Rash, nausea, di ar r hea, headache, f ever , abdomi nal pai n, di zzi ness, and
el evat ed l i ver f unct i on t est s commonl y are r epor t ed.
5. Si gni f i cant i nt eract i ons. At ovaquone i s hi ghl y bound t o pl asma prot ei n. Ì t
shoul d be used wi t h caut i on when admi ni st er ed wi t h ot her hi ghl y prot ei n-
bound dr ugs wi t h a nar r ow t her apeut i c range.
F. Ef l or ni t hi ne HCl ( Orni dyl ) . Thi s i s an Ì V ant i prot ozoal agent . Ì t s act i vi t y
has been at t ri but ed t o t he i nhi bi t i on of t he enzyme or ni t hi ne decar boxyl ase.
1. Mechani sm of act i on. Thi s i s a speci f i c, enzyme- act i vat ed, i r rever si bl e
i nhi bi t or of or ni t hi ne decar boxyl ase.
2. Spect r um of act i vi t y and t her apeut i c uses. Ef l or ni t hi ne i s act i ve i n t he
t r eat ment of t he meni ngoencephal i t i c st age of Tr ypanosoma br ucei
gambi ense (sl eepi ng si ckness) .
3. Pr ecaut i ons and moni t or i ng ef f ect s
a. Myel osuppr essi on i s t he most f requent ser i ous si de ef f ect .
b. Sei zur es occur i n about 8% of t r eat ed pat i ent s.
c. Cases of heari ng i mpai r ment have been r eport ed.
VI. AntitubercuIar Agents
A. Def i ni t i on and cl assi f i cat i on. Dr ugs used t o t r eat t ubercul osi s suppr ess
or ki l l t he sl ow- gr owi ng mycobact eri a t hat cause t hi s di sease.
Ant i t uber cul ar agent s f al l i nt o t wo mai n cat egori es: f i r st - l i ne
P. 956

and second-l i ne drugs. Because t he causat i ve organi sms t end t o devel op
r esi st ance t o any si ngl e dr ug, combi nat i on dr ug t her apy has become
st andard i n t he t r eat ment of t uber cul osi s.
1. The i nci dence of t ubercul osi s i n t he Uni t ed St at es i s i ncreasi ng owi ng t o
shi f t s i n popul at i ons consi der ed t o be endemi c f or t uber cul osi s, t he r i se i n
HÌ V- posi t i ve pat i ent s, and dr ug resi st ance.
2. Agent s chosen f or t her apy must eradi cat e mycobact eri um. Fi rst - l i ne
agent s avai l abl e i ncl ude i soni azi d, et hambut ol , pyr azi nami de, r i f ampi n,
r i f abut i n, and r i f apent i ne. Combi nat i on chemot herapy i s essent i al . Agent s
showi ng t he l owest i nci dence of r esi st ance (i soni azi d, ri f ampi n) ar e usual l y
used i n combi nat i on wi t h pyr azi nami de or et hambut ol .
3. Choi ce of t her apy depends on many pat i ent and di sease f act or s ( e. g. ,
dur at i on of t her apy needed, l i kel i hood of dr ug r esi st ance, and HÌ V st at us) .
4. Tr eat ment choi ces based on CDC r ecommendat i ons ( Tabl e 44- 4) .
B. Fi rst -l i ne. These dr ugs, i soni azi d, et hambut ol , r i f ampi n, r i f abut i n,
r i f apent i ne, and pyr azi nami de usual l y of f er t he great est ef f ect i veness wi t h
t he l east t oxi ci t y; t hey are successf ul i n most t uber cul osi s pat i ent s. At l east
t hr ee t o f our drug combi nat i ons are recommended. The CDC recommends
dai l y t r eat ment wi t h i soni azi d, r i f ampi n, pyr azi nami de, and et hambut ol f or
t he i ni t i al phase of 2 mont hs, f ol l owed by a cont i nuat i on phase of i soni azi d
and ri f ampi n f or 4- 5 mont hs ( Tabl e 44-4) .
1. Et hambut ol ( Myambut ol ) i s a synt het i c wat er - based compound.
a. Mechani sm of act i on. Thi s drug i s bact er i ost at i c. Ì t s pr eci se mechani sm
of act i on i s unknown; however , i t has demonst rat ed act i vi t y onl y agai nst
suscept i bl e bact er i a act i vel y under goi ng cel l di vi si on.
b. Spect r um of act i vi t y and t her apeut i c uses. Et hambut ol i s act i ve agai nst
many M. t uber cul osi s st rai ns as wel l as many ot her mycobact er i al speci es.
However , dr ug r esi st ance devel ops f ai rl y r api dl y when i t i s used al one. Ì n
most cases, et hambut ol i s gi ven adj unct i vel y i n combi nat i on wi t h i soni azi d
or r i f ampi n f or t ubercul osi s. Ì t i s al so usef ul i n combi nat i on wi t h ot her
agent s such as cl ari t hromyci n or azi t hr omyci n and r i f abut i n i n t reat i ng MAC.
Table 44-4. Treatment for Active Tuberculosis
Initial Phase Continuation Phase
Rank Agent Dosage Agent Dosage
1 INH 7 days a week × 8 weeks INH/RIF 7 days a week
× 18 weeks
RIF or or

PZA 5 days a week × 8 weeks

5 days a week
× 18 weeks
EMB
2 INH
RIF
7 days a week × 2 weeks.
then 2 times a week × 6
weeks
INH/RIF 2 times a
week × 18
weeks
PZA or

EMP 5 days a week × 2 weeks.
then 2 times a week × 6
weeks

3 INH 3 times a week × 8 weeks INH/RIF 3 times a
week × 19
weeks
RIF
PZA
EMB
4 INH 7 days a week × 8 weeks INH/RIF 7 days a week
× 31 weeks
RIF or or

EMP 5 days a week × 8 weeks

5 days a week
× 31 weeks
or

2 times a
week × 31
weeks
EMB. ethambutol; INH. isoniazid; PZA. pyrazinamide; RIF. riIampin.
Adapted with permission Irom CDC guidelines Ior treatment oI tuberculosis
2003. MMWR 2003; 52 (RR11); 1-77.

P. 957


c. Precaut i ons and moni t or i ng ef f ect s. Rarel y, et hambut ol causes such
adver se ef f ect s as reversi bl e dose- rel at ed ( = 15 mg/ kg/ day) opt i c neur i t i s,
dr ug f ever , abdomi nal pai n, headache, di zzi ness, and conf usi on. Li ver
f unct i on t est s shoul d be per i odi cal l y moni t or ed. Vi sual t est i ng and r enal
f unct i on ( reduce dose wi t h i mpai rment ) shoul d al so be moni t or ed.
2. Ì soni azi d ( Nydr azi d) i s a hydr azi de of i soni cot i ni c aci d. The mai nst ay of
ant i t uber cul ar t her apy, t hi s dr ug shoul d be i ncl uded (i f t ol er at ed) i n al l
t her apeut i c regi mens.
a. Mechani sm of act i on. Ì soni azi d i s bact eri ost at i c f or r est i ng baci l l i and
bact er i ci dal f or r api dl y di vi di ng organi sms. Ì t s mechani sm of act i on i s not
f ul l y known; t he dr ug pr obabl y di sr upt s bact er i al cel l wal l synt hesi s by
i nhi bi t i ng mycol i c aci d synt hesi s.
b. Spect r um of act i vi t y. Ì soni azi d has act i vi t y onl y agai nst organi sms i n t he
genus Mycobact eri um. Mor e speci f i cal l y, i t has demonst r at ed act i vi t y
agai nst M. t uber cul osi s, Mycobact eri um bovi s, and sel ect st rai ns of
Mycobact eri um kansasi i .
c. Therapeut i c uses
( 1) The most wi del y used ant i t ubercul ar agent , i soni azi d shoul d be gi ven i n
combi nat i on wi t h ot her ant i t ubercul ar dr ugs ( such as r i f ampi n, et hambut ol ,
and pyr azi nami de) t o pr event drug resi st ance i n t ubercul osi s.
( 2) Tr eat ment of l at ent i nf ect i on (pr evi ousl y r ef er r ed t o as pr event i ve
t her apy of chemoprophyl axi s) . Ì soni azi d may be admi ni st ered al one f or up
t o 1 year i n adul t s or chi l dr en who have a posi t i ve t ubercul i n t est resul t but
l ack act i ve l esi ons.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) The most common adver se ef f ect s of i soni azi d ar e ski n r ash, f ever,
j aundi ce, and per i pher al neuri t i s.
( 2) Hepat i t i s, an occasi onal r eact i on, can be sever e and, i n some cases,
f at al . The ri sk of hepat i t i s i ncreases wi t h t he pat i ent ' s age and ri ses wi t h
al cohol abuse. Moni t or l i ver f unct i on t est s.
( 3) Bl ood dyscr asi as ( e. g. , agr anul ocyt osi s, apl ast i c or hemol yt i c anemi a,
t hr ombocyt openi a) may occur . Moni t or compl et e bl ood count ( CBC)
r out i nel y.
( 4) Adverse GÌ ef f ect s i ncl ude nausea, vomi t i ng, and epi gast ri c di st ress.
( 5) CNS t oxi ci t y may r esul t f r om pyr i doxi ne def i ci ency. Si gns and sympt oms
i ncl ude i nsomni a, rest l essness, hyper r ef l exi a, and convul si ons. Pyr i doxi ne
15- 50 mg/ day shoul d be admi ni st er ed t o pat i ent s t aki ng i soni azi d t o
mi ni mi ze t he peri pher al neuropat hy associ at ed wi t h i t s use (especi al l y i n
pat i ent s wi t h di abet es, HÌ V, uremi a, al cohol i sm, mal nut ri t i on, pregnancy, or
sei zure di sor der ) .
e. Si gni f i cant i nt eract i ons
( 1) Wi t h concur r ent phenyt oi n t herapy, bl ood l evel s of bot h phenyt oi n and
i soni azi d may i ncrease, possi bl y causi ng t oxi ci t y.
( 2) Al umi num-cont ai ni ng ant aci ds may r educe i soni azi d absor pt i on.
( 3) Concur r ent car bamazepi ne t herapy may i ncr ease t he r i sk of hepat i t i s.
( 4) Use of i soni azi d wi t h ot her ant i t uber cul ar agent s, such as cycl oser i ne or
et hi onami de, may cause addi t i ve ner vous syst em ef f ect s.
( 5) Ther e i s t he pot ent i al f or t he serot oni n syndr ome t o exi st when i soni azi d
i s used i n combi nat i on wi t h sel ect i ve ser ot oni n r eupt ake i nhi bi t or s or i n
pat i ent s t aki ng meper i di ne. Ì soni azi d has been shown t o have some
monoami ne oxi dase ( MAO) i nhi bi t i ng act i vi t y.
3. Ri f ampi n ( Ri mact ane) i s a compl ex macr ocycl i c agent .
a. Mechani sm of act i on. Thi s drug i s bact er i ci dal ; i t i mpai rs bact eri al RNA
synt hesi s by bi ndi ng t o DNA- dependent RNA pol ymer ase.
b. Spect r um of act i vi t y. Ri f ampi n has act i vi t y agai nst most mycobact eri al
st r ai ns. Ì n addi t i on, r i f ampi n has act i vi t y agai nst many ot her or gani sms,
i ncl udi ng N. meni ngi t i di s, S. aur eus, H. i nf l uenzae, Legi onel l a pneumophi l a,
and C. t r achomat i s.
c. Therapeut i c uses
( 1) Ì n r ecommended combi nat i ons f or t r eat ment of act i ve t uber cul osi s
( 2) Pr ophyl act i c r i f ampi n i s ef f ect i ve when admi ni st ered t o car ri ers of N.
meni ngi t i di s di sease and chemopr ophyl axi s of pat i ent s wi t h H. i nf l uenzae
t ype b or gani sms.
( 3) Ri f ampi n may be used i n combi nat i on wi t h dapsone f or t he t r eat ment of
l eprosy.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Seri ous hepat ot oxi ci t y may r esul t f rom r i f ampi n t her apy. Li ver f unct i on
t est s shoul d be r out i nel y conduct ed.
P. 958


( 2) Ì n r are cases, t hi s drug i nduces an i nf l uenza-l i ke syndr ome.
( 3) Ot her adver se ef f ect s i ncl ude ski n rash, dr owsi ness, headache, f at i gue,
conf usi on, nausea, vomi t i ng, and abdomi nal pai n.
( 4) Ri f ampi n col or s ur i ne, sweat , t ear s, sal i va, and f eces orange red.
e. Si gni f i cant i nt eract i ons
( 1) Ri f ampi n i nduces hepat i c mi cr osomal cyt ochrome P450 i soenzymes and
t hus may decr ease t he t her apeut i c ef f ect i veness of cor t i cost er oi ds,
war f ar i n, or al cont r acept i ves, qui ni di ne, di gi t oxi n, pr ot ease i nhi bi t or s ( PÌ s) ,
nonnucl eosi de r everse t ranscr i pt ase i nhi bi t or s, ket oconazol e, ver apami l ,
met hadone, oral ant i di abet i c agent s, cycl ospor i ne, dapsone,
chl or ampheni col , and bar bi t ur at es.
( 2) Pr obeneci d may i ncrease bl ood l evel s of r i f ampi n.
( 3) Ami nosal i cyl i c aci d may i mpai r absor pt i on of ri f ampi n secondar y t o
bent oni t e, an exci pi ent used i n pr eparat i on of ami nosal i cyl i c gr anul es.
f . The newer r i f amyci ns, r i f abut i n ( Mycobut i n) and r i f apent i ne ( Pri f t i n) may
be subst i t ut ed f or ri f ampi n i n speci al si t uat i ons, e. g. , i nt ol er ance or ser i ous
dr ug i nt er act i ons.
4. Ri f abut i n ( Mycobut i n) i s an ant i mycobact er i al agent t hat i s si mi l ar t o
r i f ampi n, wi t h act i vi t y agai nst bot h t ubercul ar and nont ubercul ar
mycobact eri al , and of f ers no cl ear advant age over r i f ampi n.
a. Mechani sm of act i on. Ì n addi t i on t o i t s ant i mycobact eri al act i vi t y agai nst
t ubercul ar and nont ubercul ar mycobact eri al , r i f abut i n has been repor t ed t o
i nhi bi t r everse t r anscr i pt ase and bl ock t he i n vi t ro i nf ect i vi t y and r epl i cat i on
of HÌ V.
b. Ther apeut i c uses. Ri f abut i n i s i ndi cat ed f or t he pr event i on of
di ssemi nat ed MAÌ compl ex di sease i n pat i ent s wi t h advanced HÌ V
i nf ect i ons.
c. Precaut i ons and moni t or i ng ef f ect s. The use of r i f abut i n has r esul t ed i n
mi l d el evat i on of l i ver enzymes and t hr ombocyt openi a.
d. Si gni f i cant i nt eract i ons
( 1) Ri f abut i n ant agoni zes and pot ent i al l y negat es t he i mmune r esponse
medi at ed by t he baci l l us Cal met t e- Guéri n ( BCG) vacci ne.
( 2) Ri f abut i n may i ncr ease t he cl earance of dr ugs by i nduci ng hepat i c
mi cr osomal enzymes, but does so t o a l esser ext ent t han r i f ampi n. The
concent r at i ons of t he f ol l owi ng drugs may be r educed whi l e t aki ng ri f abut i n:
cycl ospor i ne, zi dovudi ne, pr edni sone, di gi t oxi n, qui ni di ne, ket oconazol e,
pr ot ease i nhi bi t ors, pr opr anol ol , phenyt oi n, sul f onyl ur eas, and war f ari n.
Ser um cycl ospor i ne l evel s shoul d be moni t ored i n pat i ent s r ecei vi ng bot h
agent s.
5. Ri f apent i ne ( Pr i f t i n) i s a l ong-act i ng ri f amyci n-der i vat i ve and has a
si mi l ar pr of i l e of mi crobi ol ogi cal act i vi t y t o ri f ampi n. Ì t i s usual l y
admi ni st er ed once or t wi ce weekl y.
a. Mechani sm of act i on. Ri f apent i ne i s bact er i ci dal agai nst i nt r acel l ul ar and
ext r acel l ul ar M. t uber cul osi s at t herapeut i c l evel s.
b. Spect r um of act i vi t y and t her apeut i c uses. Ì ndi cat ed f or t reat ment of
pr i mar y t ubercul osi s. Ri f apent i ne shoul d al ways be used i n conj unct i on wi t h
< 1 ot her ant i t ubercul osi s drug t o whi ch t he i sol at e i s suscept i bl e.
c. Precaut i ons and moni t or i ng ef f ect s. Ri f apent i ne i nduces cyt ochr ome
P450 i soenzymes 3A4 and 2C8/ 9 r esponsi bl e f or i nact i vat i on of cer t ai n
cal ci um channel bl ocki ng agent s ( verapami l , di l t i azem, ni f edi pi ne) ,
ant i f ungal s (ket oconazol e, f l uconazol e, i t r aconazol e), sul f onyl ur ea
ant i di abet i c agent s, met hadone, cor t i cost er oi ds, car di ac gl ycosi des, cer t ai n
ant i ar r hyt hmi c agent s ( di sopyr ami de, mexi l et i ne, qui ni di ne, t ocai ni de) ,
qui ni ne, dapsone, chl orampheni col , cl ar i t hr omyci n, doxycycl i ne,
f l uor oqui nol ones, t r anscri pt ase i nhi bi t or cycl ospor i n, t acr ol i mus, and
war f ar i n. Concomi t ant use of r i f apent i ne wi t h t hese dr ugs may decr ease
pl asma concent r at i ons and dosage adj ust ment s may be r equi r ed.
6. Pyr azi nami de i s a pyrazi ne anal og of ni cot i nami de.
a. Mechani sm of act i on. Thi s drug i s bact er i ci dal and/ or bact eri ost at i c,
dependi ng on t he cel l concent r at i on achi eved.
b. Spect r um of act i vi t y and t her apeut i c uses. Pyrazi nami de i s a hi ghl y
speci f i c agent and has act i vi t y onl y agai nst M. t uber cul osi s. Pyr azi nami de
i s used as a pri mar y agent wi t h i soni azi d and r i f ampi n f or at l east 2 mont hs,
f ol l owed by i soni azi d and r i f ampi n.
c. Precaut i ons and moni t or i ng ef f ect s. Thi s agent may resul t i n
hepat ot oxi ci t y and, rar el y, hepat i c necrosi s r esul t i ng i n deat h. Anor exi a,
nausea, vomi t i ng, mal ai se, and f ever have
P. 959

been r epor t ed. Hyper uri cemi a may r esul t i n gout y exacer bat i ons. Bot h l i ver
f unct i on t est s and uri c aci d l evel s shoul d rout i nel y be moni t ored.
C. Second- l i ne agent s. These agent s i ncl ude ami nosal i cyl i c aci d ( Paser ) ,
capreomyci n ( Capast at ) , cycl oser i ne ( Ser omyci n), et hi onami de ( Tr ecat or -
SC) , qui nol ones ( ci prof l oxaci n, of l oxaci n, l evof l oxaci n, spar f l oxaci n) ,
st r ept omyci n and kanamyci n. Second- l i ne dr ugs ar e mai nl y subst i t ut ed or
added t o pref er r ed t her apy owi ng t o i nt ol er ance or drug resi st ance. These
agent s ar e l ess ef f ect i ve, mor e t oxi c, and ar e used i n combi nat i on wi t h
pr i mar y agent s.
1. Mechani sm of act i on
a. Ami nosal i cyl i c aci d i s bact er i ost at i c; i t pr obabl y i nhi bi t s t he enzymes
r esponsi bl e f or f ol i c aci d synt hesi s.
b. Cycl oser i ne can be bact eri ost at i c or bact er i ci dal , dependi ng on i t s
concent r at i on at t he i nf ect i on si t e; i t i mpai r s ami no aci d use, t her eby
i nhi bi t i ng bact er i al cel l wal l synt hesi s.
c. The mechani sm of act i on of capr eomyci n (bact er i ost at i c) , et hi onami de
( bact eri ci dal ) , and pyr azi nami de ( bact er i ci dal ) i s unknown.
2. Spect r um of act i vi t y and t her apeut i c uses. Second-l i ne ant i t uber cul ar
agent s ar e act i ve agai nst var i ous mi croor gani sms, i ncl udi ng M.
t ubercul osi s. These agent s gener al l y ar e reser ved f or pat i ent s wi t h
ext ensi ve ext r apul monary or dr ug- r esi st ant di sease or f or pat i ent s who
need r et r eat ment . These dr ugs ar e al most al ways admi ni st er ed i n
combi nat i on.
3. Pr ecaut i ons and moni t or i ng ef f ect s
a. Adverse ef f ect s of ami nosal i cyl i c aci d i ncl ude l eukopeni a,
agr anul ocyt openi a, t hr ombocyt openi a, hemol yt i c anemi a, mononucl eosi s-
l i ke syndr ome, mal ai se, j oi nt pai n, f ever, and ski n r ash.
b. Capr eomyci n and st rept omyci n are ot ot oxi c and nephrot oxi c; t hey shoul d
not be admi ni st er ed t oget her .
c. Cycl oser i ne may cause adverse CNS ef f ect s, i ncl udi ng headache,
sui ci dal and psychot i c t endenci es, hyper i r ri t abi l i t y, conf usi on, par anoi a,
and ner vousness.
d. Et hi onami de may i nduce nausea, vomi t i ng, ort host at i c hypot ensi on,
met al l i c t ast e, epi gast r i c di st r ess, and peri pher al neuropat hy.
e. St rept omyci n. See Ì Ì . B. 3.
D. Al t er nat i ve agent s
1. Ri f at er . A combi nat i on of ri f ampi n 120 mg, i soni azi d 50 mg, and
pyr azi nami de 300 mg i n one t abl et i s used i n pat i ent s expect ed t o have l ow
compl i ance wi t h t ubercul osi s dr ug t her apy. One di sadvant age i s t hat many
pat i ent s ar e requi r ed t o t ake as many as 5- 6 t abl et s dai l y, whi ch may
r educe compl i ance.
2. Qui nol ones. Ci pr of l oxaci n and l evof l oxaci n are used i n t uber cul osi s
t her apy. Levof l oxaci n i s pr ef er r ed owi ng t o i ncr eased ser um concent rat i ons.
Levof l oxaci n i s usual l y used i n combi nat i on wi t h ot her t ubercul osi s agent s
f or act i ve t r eat ment . For pr ophyl axi s, l evof l oxaci n i s combi ned wi t h
pyr azi nami de.
3. Macr ol i des. Cl ari t hromyci n and azi t hromyci n have shown l i mi t ed act i vi t y
agai nst M. t uber cul osi s.
VII. AntiviraI Agents
A. Def i ni t i on. These dr ugs t reat vi r al i nf ect i ons by af f ect i ng vi r al
r epl i cat i on. Because vi r uses l ack i ndependent met abol i c act i vi t y and can
r epl i cat e onl y wi t hi n l i vi ng host cel l s, ant i vi r al agent s t end t o i nj ur e host as
wel l as vi r al cel l s. Al t hough most ant i vi r al drugs ar e act i ve agai nst ei t her
DNA or RNA vi r uses, some (e. g. , adef ovi r , ri bavi r i n) ar e act i ve agai nst
bot h.
B. DNA vi r uses. Cur r ent l y appr oved ant i vi ral t herapi es agai nst t he
Her pesvi r i dae f ami l y of DNA vi r uses÷her pes si mpl ex vi r us 1 and 2 ( HSV- 1,
HSV- 2) , vari cel l a- zost er vi r us ( VZV) , cyt omegal ovi r us ( CMV) ÷ar e vi rust at i c
and ar r est DNA synt hesi s by i nhi bi t i ng vi r al DNA pol ymer ase. Many of t hese
agent s ar e pr odr ugs and r equi r e vi r al and host cel l ul ar enzymes ( e. g. ,
t hymi di ne, deoxyguanosi ne ki nase) t o phosphor yl at e t hem i nt o t he act i ve
t r i phosphat e f orm bef ore exer t i ng t hei r ant i vi r al act i vi t y. Hence, a common
mechani sm of resi st ance i s a def i ci ency or
P. 960

st r uct ur al al t erat i on i n vi r al t hymi di ne ki nase ( Tabl e 44-5) . Some of t hese
agent s al so demonst r at e act i vi t y agai nst RNA vi ruses, i ncl udi ng hepat i t i s C
and HÌ V.
Table 44-5. Activity of Various Anti-DNA Viral Agents
Agent HSV-1 HSV-2 VZV CMV Influenza
A
Influenza
B
Acyclovir
a
¹ ¹ ¹
Amantadine ¹
CidoIovir ¹
Famciclovir ¹ ¹ ¹
Foscarnet ¹ ¹ ¹ ¹
Ganciclovir
a
¹
Oseltamivir ¹ ¹
Rimantadine ¹
Valacyclovir
a
¹ ¹ ¹
Valganciclovir
a
¹
Zanamivir ¹ ¹
HSJ. herpes simplex virus. JZJ. varicella-zoster virus; CMJ.
cytomegalovirus.
a
Requires activation into
triphosphate Iorm.


1. Acycl ovi r ( Zovi r ax) i s a synt het i c acycl i c anal og of guanosi ne wi t h
act i vi t y agai nst var i ous her pes vi ruses.
a. Mechani sm of act i on. Acycl ovi r monophosphat e i s phosphor yl at ed t o t he
t r i phosphat e, wher e i t becomes i ncor porat ed i nt o vi r al DNA and i nhi bi t s
vi r al repl i cat i on.
b. Spect r um of act i vi t y. Thi s agent i s act i ve agai nst herpes vi r uses,
par t i cul arl y HSV- 1, HSV-2, VZV, and chi ckenpox ( var i cel l a) .
c. Therapeut i c uses
( 1) Acycl ovi r i s used t o t r eat i ni t i al and r ecur rent HSV- 1 and HSV-2
i nf ect i ons and f or acut e t r eat ment of her pes zost er ( shi ngl es) and
chi ckenpox. Ì t i s al so used oral l y f or l ong- t er m suppressi on of geni t al HSV
i nf ect i ons.
( 2) Thi s agent i s avai l abl e i n t opi cal , oral , and Ì V f or ms. Topi cal acycl ovi r i s
appl i ed di r ect l y on her pes l esi ons i n recur r ent her pes l abi al i s (col d sores).
Ì t i s not recommended f or use on geni t al her pes l esi ons due t o poor
ef f i cacy.
( 3) Acycl ovi r may be admi ni st er ed i nt ravenousl y i n t he t r eat ment of i ni t i al
and recur r ent mucocut aneous HSV i nf ect i on and VZV i nf ect i on i n
i mmunocompr omi sed pat i ent s, as wel l as i n t he t reat ment of HSV i nf ect i ons
t hat ar e di ssemi nat ed or af f ect t he cent ral ner vous syst em.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Or al acycl ovi r may i nduce nausea, vomi t i ng, di ar rhea, and headache.
( 2) Ì V admi ni st r at i on may cause dose- dependent r enal i mpai rment ,
cr yst al l i ne nephropat hy, neurol ogi cal ef f ect s ( e. g. , l et hargy, conf usi on,
t r emor s, agi t at i on, sei zur es, coma, obt undat i on) , hypot ensi on, rash, i t chi ng,
and phl ebi t i s at t he i nj ect i on si t e.
( 3) Local di scomf or t and pr ur i t us may r esul t f rom t opi cal admi ni st rat i on.
( 4) Acycl ovi r i s r emoved by hemodi al ysi s. Doses shoul d be adj ust ed i n
r enal i mpai rment and hemodi al ysi s.
e. Si gni f i cant i nt eract i ons. Probeneci d r educes t he r enal cl earance of
acycl ovi r , r esul t i ng i n i ncr eases i n acycl ovi r hal f - l i f e and serum
concent r at i on.
2. Adef ovi r di pi voxi l ( Hepsera) i s a phosphonat e nucl eot i de anal og wi t h
act i vi t y agai nst var i ous DNA and RNA vi r uses.
a. Mechani sm of act i on. Adef ovi r i s phosphor yl at ed t o t he act i ve
di phosphat e f orm by cel l ul ar ki nases. Ì t i s t hen i ncor por at ed i nt o vi ral DNA,
r esul t i ng i n t ermi nat i on of r epl i cat i on.
b. Spect r um of act i vi t y and t her apeut i c uses
( 1) Adef ovi r i s act i ve agai nst hepat i t i s B vi rus ( i ncl udi ng l ami vudi ne-
r esi st ant st rai ns), her pes vi r uses, and HÌ V.
( 2) However , adef ovi r i s approved f or use onl y f or t r eat ment of chroni c
hepat i t i s B i nf ect i on i n adul t s wi t h evi dence of act i ve vi r al r epl i cat i on wi t h
per si st ent l y el evat ed l i ver f unct i on t est s or hi st ol ogi cal l y act i ve di sease.
P. 961


c. Precaut i ons and moni t or i ng ef f ect s
( 1) Severe acut e hepat i t i s exacerbat i ons have occur red i n pat i ent s who
di scont i nue t her apy ( bl ack box war ni ng) . Ì f t herapy i s di scont i nued, l i ver
f unct i on t est s must be moni t or ed cl osel y.
( 2) Nephr ot oxi ci t y has been repor t ed wi t h adef ovi r , especi al l y i n pat i ent s
wi t h under l yi ng renal dysf unct i on or t hose t aki ng concomi t ant nephrot oxi ns
( bl ack box war ni ng) .
( 3) Ot her adver se ef f ect s i ncl ude r ash, GÌ di st urbances, headache, and
weakness.
( 4) Dose adj ust ment i s requi r ed f or r enal i nsuf f i ci ency.
3. Amant adi ne ( Symmet rel ) i s a synt het i c t ri cycl i c ami ne wi t h a uni que
chemi cal st r uct ur e si mi l ar t o ri mant adi ne. Ì t i s ef f ect i ve agai nst i nf l uenza A
vi r al i nf ect i on.
a. Mechani sm of act i on. Amant adi ne i nhi bi t s repl i cat i on of t he i nf l uenza A
vi r us by i nt er f er i ng wi t h vi r al at t achment and uncoat i ng.
b. Spect r um of act i vi t y and t her apeut i c uses
( 1) Due t o i ncr easi ng r at es of resi st ance, amant adi ne i s no l onger
r ecommended f or prophyl axi s or t r eat ment of i nf l uenza A vi r us.
( 2) Thi s drug may al so be used t o t r eat par ki nsoni sm as wel l as dr ug-
i nduced ext r apyr ami dal sympt oms.
c. Precaut i ons and moni t or i ng ef f ect s
( 1) The most pr onounced adverse ef f ect s of amant adi ne are at axi a,
ni ght mar es, and i nsomni a. Ot her CNS ef f ect s i ncl ude depr essi on,
conf usi on, di zzi ness, f at i gue, anxi et y, and headache. El derl y pat i ent s may
be at i ncreased r i sk of CNS adverse react i ons. Pat i ent s wi t h a hi st or y of
sei zures or psychi at r i c di sorders shoul d be moni t or ed cl osel y dur i ng
t her apy.
( 2) Ant i chol i ner gi c r eact i ons ( e. g. , dr y mout h, bl ur r ed vi si on) have been
r eport ed.
( 3) Dosage adj ust ment i s needed f or pat i ent s wi t h i mpai r ed r enal f unct i on.
4. Ci dof ovi r ( Vi st i de) i s a synt het i c acycl i c puri ne nucl eosi de phosphonat e
der i vat i ve.
a. Mechani sm of act i on. Ci dof ovi r di phosphat e suppr esses CMV r epl i cat i on
by sel ect i ve i nhi bi t i on of vi r al DNA synt hesi s.
b. Spect r um of act i vi t y. Ì n vi t r o act i vi t y has been demonst r at ed agai nst
CMV, VZV, Epst ei n- Bar r vi r us ( EBV) , and HSV- 1 and HSV-2. Cont rol l ed
cl i ni cal st udi es are l i mi t ed t o pat i ent s wi t h AÌ DS and CMV r et i ni t i s.
c. Therapeut i c use i ncl udes t he t reat ment , but not t he cure of , CMV r et i ni t i s
i n pat i ent s wi t h AÌ DS.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Avoi d usi ng t hi s dr ug i n pat i ent s wi t h ser um cr eat i ni ne > 1. 5 mg/ dL or
cr eat i ni ne cl ear ance ( CrCl ) > 55 mL/ mi n or i n pat i ent s who ar e recei vi ng (or
have r ecei ved i n t he past 7 days) nephr ot oxi c agent s.
( 2) Ci dof ovi r i s cont r ai ndi cat ed i n pat i ent s wi t h a hi st or y of sever e
hyper sensi t i vi t y t o probeneci d or sul f a-cont ai ni ng medi cat i ons.
( 3) The dose- l i mi t i ng t oxi ci t y of ci dof ovi r i s nephrot oxi ci t y; neut r openi a,
per i pheral neur opat hy, and di ar rhea are common adver se ef f ect s.
( 4) Pr obeneci d must be admi ni st er ed bef ore and af t er each ci dof ovi r dose.
The pat i ent must be hydrat ed wi t h 1 L of nor mal sal i ne bef or e i nf usi ng.
Ci dof ovi r i s avai l abl e onl y i n Ì V f orm.
5. Ent ecavi r ( Bar acl ude) i s a car bocycl i c anal og of guanosi ne used f or
t r eat ment of chr oni c hepat i t i s B i nf ect i on.
a. Mechani sm of act i on. Once phosphor yl at ed t o t he act i ve t ri phosphat e
f or m, ent ecavi r i nhi bi t s hepat i t i s B vi r al pol ymer ase and ul t i mat el y hal t s
hepat i t i s B DNA synt hesi s.
b. Spect r um of act i vi t y. Ent ecavi r exhi bi t s act i vi t y agai nst hepat i t i s B vi r us,
i ncl udi ng l ami vudi ne- resi st ant st r ai ns. Devel opment of HÌ V resi st ance t o
nucl eosi de r everse t r anscr i pt ase i nhi bi t ors i s possi bl e i f ent ecavi r i s used
wi t hout ant i r et rovi r al t reat ment i n HÌ V and hepat i t i s B vi r us co-i nf ect i on.
c. Therapeut i c uses
( 1) Ent ecavi r i s appr oved f or t r eat ment of chr oni c hepat i t i s B i nf ect i on i n
adul t s wi t h evi dence of act i ve vi r al r epl i cat i on and persi st ent el evat i ons i n
l i ver f unct i on t est s or hi st ol ogi cal l y act i ve di sease.
( 2) Ì t i s ef f ect i ve f or pat i ent s who have f ai l ed t reat ment wi t h l ami vudi ne
owi ng t o r esi st ance devel opment .
P. 962


( 3) Ent ecavi r i s not r ecommended f or use i n pat i ent s wi t h hepat i t i s B vi r us
i nf ect i on who ar e co- i nf ect ed wi t h HÌ V and are not r ecei vi ng ant i r et r ovi r al
t her apy.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Severe acut e exacerbat i ons of hepat i t i s B have been obser ved i n
pat i ent s who di scont i nue t herapy, necessi t at i ng cl ose moni t ori ng ( bl ack box
war ni ng) .
( 2) Common adverse ef f ect s i ncl ude di zzi ness, f at i gue, headache, and
nausea.
( 3) Dose adj ust ment i s requi r ed f or r enal i nsuf f i ci ency.
( 4) Counsel pat i ent s t o t ake ent ecavi r on an empt y st omach.
6. Famci cl ovi r ( Famvi r ) i s a pr odr ug of t he ant i vi r al agent penci cl ovi r .
a. Mechani sm of act i on. Famci cl ovi r i s rapi dl y phosphor yl at ed i n vi r us-
i nf ect ed cel l s by vi r al t hymi di ne ki nase t o penci cl ovi r monophosphat e.
Penci cl ovi r i s a compet i t i ve i nhi bi t or of vi r al DNA pol ymer ase and prevent s
vi r al repl i cat i on by i nhi bi t i on of herpes vi r us DNA synt hesi s.
b. Spect r um of act i vi t y and t her apeut i c uses
( 1) Famci cl ovi r has act i vi t y agai nst HSV- 1, HSV-2, and VZV. The dr ug i s
i ndi cat ed f or management of acut e her pes zost er ( shi ngl es) and or al and
geni t al her pes.
( 2) Ther apy must be pr ompt l y i ni t i at ed as soon as her pes zost er i s
di agnosed ( wi t hi n 48- 72 hr ) , at a dose of 500 mg ever y 8 hr f or 7 days.
c. Precaut i ons and moni t or i ng ef f ect s
( 1) Common adverse event s i ncl ude f at i gue, GÌ compl ai nt s ( nausea,
di ar rhea, vomi t i ng, const i pat i on) , and anor exi a. Headache i s al so commonl y
r eport ed.
( 2) Dose adj ust ment i s necessar y i n pat i ent s wi t h r enal dysf unct i on.
Famci cl ovi r i s removed by hemodi al ysi s.
7. Foscar net (Foscavi r ) i s a synt het i c pyr ophosphat e anal og t hat di r ect l y
i nhi bi t s enzymes i nvol ved i n vi r al DNA synt hesi s wi t hout i ncor por at i on i nt o
vi r al DNA. Ì t i s a br oad- spect r um ant i vi ral agent and i s an opt i on i n cases
of acycl ovi r or ganci cl ovi r r esi st ance.
a. Mechani sm of act i on
( 1) Vi ral DNA r epl i cat i on r equi r es t he addi t i on of deoxynucl eosi de
t r i phosphat es at t he end of t he DNA st rand by DNA pol ymer ase and t he
subsequent cl eavage of pyr ophosphat e f rom t he newl y at t ached nucl eot i de.
Foscarnet bi nds noncompet i t i vel y t o DNA pol ymer ase t o f orm an i nact i ve
compl ex and prevent s pyr ophosphat e cl eavage. Vi r al DNA chai n el ongat i on
i s t hus t er mi nat ed.
( 2) Foscar net i s al so act i ve agai nst HÌ V. Ì t i s a noncompet i t i ve, r eversi bl e
i nhi bi t or of HÌ V r everse t r anscri pt ase, t he enzyme r esponsi bl e f or
convert i ng vi r al RNA t o vi r al DNA.
b. Spect r um of act i vi t y and t her apeut i c uses. Foscar net has i n vi t ro act i vi t y
agai nst HSV- 1 and HSV-2, CMV, VZV, EBV DNA pol ymer ases, i nf l uenza
pol ymer ase, and HÌ V r ever se t r anscr i pt ase. Therapeut i cal l y, t he dr ug i s
used t o t reat CMV di sease as wel l as acycl ovi r - resi st ant HSV and VZV
i nf ect i ons.
( 1) Foscar net i s an al t ernat i ve t o ganci cl ovi r and val ganci cl ovi r f or
t r eat ment of CMV i nf ect i on i n i mmunocompr omi sed pat i ent s. Foscar net
causes l ess hemat ol ogi c t oxi ci t y t han ganci cl ovi r i n pat i ent s who have
r ecei ved al l ogenei c st em cel l t r anspl ant s. An i ni t i al i nduct i on t her apy l ast s
2- 3 weeks. Mai nt enance t her apy i s needed t o pr event r el apse.
( 2) Foscar net i s i ndi cat ed f or t he t reat ment of acycl ovi r - resi st ant
mucocut aneous HSV i n i mmunocompromi sed pat i ent s. Ì t i s not , however , a
cur e f or HSV i nf ect i ons.
( 3) Foscar net i s abl e t o cr oss t he bl ood- brai n bar r i er .
c. Precaut i ons and moni t or i ng ef f ect s
( 1) Ì V f oscar net i s hi ghl y nephr ot oxi c, causi ng acut e t ubul ar necrosi s. The
i nci dence of acut e renal f ai l ur e can be markedl y reduced i f adequat e
hydr at i on and dai l y moni t or i ng of ser um cr eat i ni ne and BUN ar e mai nt ai ned
t hr oughout t her apy.
( 2) Ot her common adverse ef f ect s i ncl ude el ect rol yt e abnor mal i t i es ( e. g. ,
hypocal cemi a, hypomagnesemi a, hypophosphat emi a and
hyper phosphat emi a, hypokal emi a) , anemi a, f ever, headache, and sei zur es.
( 3) Dose adj ust ment f or r enal dysf unct i on i s r equi r ed. Foscar net i s r emoved
by hemodi al ysi s.
( 4) Foscar net must be admi ni st ered usi ng an i nf usi on pump over at l east
1. 5- 2 hr . Do not admi ni st er t he drug as an Ì V bol us.
P. 963


d. Si gni f i cant i nt eract i ons
( 1) Concomi t ant nephrot oxi ns ( ami nogl ycosi des, amphot er i ci n B, et c. )
i ncrease t he r i sk of r enal t oxi ci t y.
( 2) Foscar net i s excl usi vel y el i mi nat ed by gl omerul ar f i l t r at i on; concur r ent
nephr ot oxi c agent s shoul d be avoi ded whenever possi bl e.
8. Ganci cl ovi r ( Cyt ovene) i s a synt het i c pur i ne nucl eosi de anal og t hat i s
approved f or t he t r eat ment and pr ophyl axi s of CMV i nf ect i ons i n
i mmunocompr omi sed pat i ent s (e. g. , HÌ V-posi t i ve pat i ent s, t r anspl ant
r eci pi ent s) .
a. Mechani sm of act i on. Af t er conver si on t o ganci cl ovi r t r i phosphat e,
ganci cl ovi r i s i ncor por at ed i nt o vi r al DNA, whi ch i nhi bi t s vi r al DNA
pol ymer ase, t her eby t ermi nat i ng vi r al r epl i cat i on.
b. Spect r um of act i vi t y. Ganci cl ovi r has i n vi t ro act i vi t y agai nst HSV-1 and
HSV- 2, VZV, EBV, and CMV ( owi ng t o i t s enhanced abi l i t y t o penet r at e host
cel l s).
c. Therapeut i c uses. Ì t i s i ndi cat ed f or t reat ment of CMV r et i ni t i s i n pat i ent s
wi t h HÌ V/ AÌ DS. Ì t i s al so used f or prophyl axi s of CMV i nf ect i on i n HÌ V-
posi t i ve pat i ent s ( secondar y pr ophyl axi s) and t r anspl ant r eci pi ent s at r i sk
f or CMV di sease.
( 1) Conver si on i nt o t he t r i phosphat e f or m i s great er i n i nf ect ed host cel l s,
even t hough dr ug penet rat i on occurs i n bot h uni nf ect ed and i nf ect ed cel l s.
( 2) Ì nhi bi t or y concent r at i ons f or t he vi r al DNA pol ymer ase ar e l ower t han
t hose f or t he host cel l ul ar pol ymerase.
( 3) Ì t i s avai l abl e i n oral and Ì V f or mul at i ons as wel l as an i nt r aocul ar
i mpl ant . Al t hough t he oral f or mul at i on i s appr oved f or pr event i on and
mai nt enance t r eat ment of CMV, i t s poor bi oavai l abi l i t y has l i mi t ed i t s use.
Val ganci cl ovi r has become t he dr ug of choi ce f or t hese i ndi cat i ons, owi ng
t o i t s markedl y i mproved bi oavai l abi l i t y.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Ganci cl ovi r has a bl ack box war ni ng concerni ng i ncreased pot ent i al f or
neut ropeni a, anemi a, and t hrombocyt openi a. Ì t i s al so t er at ogeni c,
carci nogeni c, and mut ageni c.
( 2) Adverse ef f ect s commonl y i ncl ude f ever, r ash, and GÌ di st ur bances.
Phl ebi t i s and pai n may occur at t he si t e of i nf usi on.
( 3) Because ganci cl ovi r i s cl ear ed by gl omer ul ar f i l t rat i on and t ubul ar
secr et i on, r enal f unct i on and adequat e hydr at i on shoul d be moni t ored.
Doses shoul d be adj ust ed i n cases of renal i mpai r ment and hemodi al ysi s.
( 4) Sol ut i ons of ganci cl ovi r ar e ext r emel y al kal i ne. Avoi d di r ect cont act wi t h
ski n.
e. Si gni f i cant i nt eract i ons
( 1) Pr obeneci d may i ncrease ganci cl ovi r concent r at i ons and possi bl y
t oxi ci t y.
( 2) Use of zi dovudi ne, azat hi opr i ne, or mycophenol at e mof et i l i n
combi nat i on wi t h ganci cl ovi r may r esul t i n neut ropeni a; caref ul moni t or i ng
of neut rophi l count i s r equi red when t hese are t aken concur r ent l y wi t h
ganci cl ovi r .
( 3) Ì mi penem-ci l ast at i n i n combi nat i on wi t h ganci cl ovi r may i ncr ease t he
pot ent i al f or sei zur es.
9. Osel t ami vi r ( Tami f l u) i s pharmacol ogi cal l y si mi l ar t o zanami vi r but
st r uct ur al l y di f f erent . Bot h of t hese agent s ar e i n a cl ass known as t he
neurami ni dase i nhi bi t ors and have a uni que mechani sm of act i on.
a. Mechani sm of act i on. Osel t ami vi r i s a prodrug t hat must be hydr ol yzed t o
osel t ami vi r car boxyl at e i n vi vo t o exer t i t s ant i vi ral act i vi t y. Ì t i s a pot ent
sel ect i ve i nhi bi t or of t he i nf l uenza vi r us enzyme, neurami ni dase. Ì nhi bi t i on
of t hi s enzyme prevent s vi r al repl i cat i on and spr ead t o ot her host cel l s.
b. Spect r um of act i vi t y. Thi s agent i s act i ve agai nst bot h i nf l uenza A and B
vi r uses.
c. Therapeut i c uses
( 1) Ì t i s appr oved f or t he sympt omat i c t r eat ment of i nf l uenza A and B
i nf ect i ons i n pat i ent s 1 year of age and ol der who pr esent wi t h sympt oms
wi t hi n 48 hr.
( 2) Osel t ami vi r has been shown t o decrease t he dur at i on of sympt oms by 1-
2 days i f t aken wi t hi n 48 hr of onset of vi r al sympt oms.
( 3) Ì t i s al so appr oved f or t he pr ophyl axi s of i nf l uenza i nf ect i ons i n pat i ent s
1 year of age and ol der. Not e: The i nf l uenza vi rus vacci ne i s st i l l t he gol d
st andard f or prophyl axi s.
( 4) Osel t ami vi r demonst rat es some act i vi t y agai nst st r ai ns of avi an
i nf l uenza, maki ng i t a possi bl e opt i on f or t r eat ment and pr ophyl axi s.
P. 964


d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) The most common adver se ef f ect s ar e nausea and vomi t i ng. Ther e have
been post mar ket i ng repor t s of sel f -i nj ur y and del i r i um ( most l y i n Japan)
among pedi at r i c pat i ent s. Cl ose moni t or i ng f or abnor mal behavi or i s
r ecommended.
( 2) Dosage adj ust ment s ar e requi r ed f or pat i ent s wi t h i mpai red r enal
f unct i on.
( 3) Cr oss-r esi st ance bet ween osel t ami vi r and zanami vi r has been repor t ed.
10. Ri bavi ri n ( Rebet ol , Copegus) i s a synt het i c nucl eosi de anal og.
a. Mechani sm of act i on. Ri bavi ri n may i nhi bi t RNA and DNA synt hesi s by
depl et i ng i nt r acel l ul ar nucl eot i de reser ves.
b. Spect r um of act i vi t y. Thi s agent i s act i ve i n vi t r o agai nst a br oad
spect rum of DNA and RNA vi r uses, i ncl udi ng i nf l uenza A and B, RSV,
her pes si mpl ex, and hepat i t i s C vi r us.
c. Therapeut i c uses. The aer osol i zed f or m of ri bavi r i n i s no l onger
r ecommended f or t r eat ment of RSV i n i nf ant s and chi l dr en, owi ng t o
i nconsi st ent cl i ni cal benef i t s obser ved i n cl i ni cal t r i al s. Combi nat i on
t her apy wi t h oral ri bavi r i n and subcut aneous i nt er f er on- q i s ef f ect i ve i n
t r eat ment of chr oni c hepat i t i s C.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) Common adverse ef f ect s of oral ri bavi r i n i ncl ude hemol yt i c anemi a and
GÌ di st urbances. Hemogl obi n and hemat ocri t shoul d be moni t or ed car ef ul l y,
especi al l y dur i ng t he f i rst 4 weeks of t reat ment .
( 2) Ri bavi r i n i s t er at ogeni c; i t s use i s cont rai ndi cat ed i n pr egnancy.
( 3) Ri bavi r i n shoul d be avoi ded i n pat i ent s wi t h a Cr Cl < 50 mL/ mi n.
( 4) Ri bavi r i n shoul d never be used as monot her apy i n t r eat ment of chroni c
hepat i t i s C.
11. Ri mant adi ne (Fl umadi ne) i s a synt het i c ant i vi r al agent and an q- met hyl
der i vat i ve of amant adi ne t hat bl ocks t he ear l y st ep i n t he r epl i cat i on of t he
i nf l uenza A vi rus.
a. Mechani sm of act i on. Ri mant adi ne i nhi bi t s t he ear l y vi ral repl i cat i on
cycl e, possi bl y i nhi bi t i ng t he uncoat i ng of t he vi r us. Ì t has t he same
mechani sm of act i on and spect rum of act i vi t y as amant adi ne.
b. Spect r um of act i vi t y and t her apeut i c uses
( 1) Due t o i ncr easi ng r at es of resi st ance, r i mant adi ne i s no l onger
r ecommended f or prophyl axi s or t r eat ment of i nf l uenza A vi r us.
( 2) Ì nf l uenza vacci nat i on i s t he met hod of choi ce f or prevent i on of i nf l uenza
i nf ect i on.
c. Precaut i ons and moni t or i ng ef f ect s
( 1) Ri mant adi ne may i ncr ease t he i nci dence of sei zur e i n pat i ent s wi t h
sei zure di sor der .
( 2) The most f requent adver se react i ons i ncl ude GÌ di st urbance ( e. g. ,
nausea, vomi t i ng, anor exi a) and CNS t oxi ci t y ( e. g. , i nsomni a, di zzi ness,
headache), whi ch ar e l ess t han t hose obser ved wi t h amant adi ne.
( 3) Dose reduct i ons ar e r ecommended i n pat i ent s wi t h hepat i c or r enal
dysf unct i on.
12. Tel bi vudi ne ( Tyzeka) i s a synt het i c t hymi di ne nucl eosi de anal og used
f or t reat ment of chr oni c hepat i t i s B i nf ect i on.
a. Mechani sm of act i on. Tel bi vudi ne i s phosphor yl at ed i nt o t he act i ve
t r i phosphat e f orm t hat i nhi bi t s hepat i t i s B vi r al DNA pol ymer ase, wi t h
ul t i mat e t ermi nat i on of t he DNA chai n and i nhi bi t i on of vi ral repl i cat i on.
b. Spect r um of act i vi t y.
( 1) Tel bi vudi ne exhi bi t s act i vi t y agai nst hepat i t i s B vi r us but not HÌ V.
( 2) Ther e i s a hi gh i nci dence of cross- resi st ance bet ween l ami vudi ne-
r esi st ant hepat i t i s B vi r us and t el bi vudi ne.
c. Therapeut i c uses.
( 1) Tel bi vudi ne i s i ndi cat ed f or t reat ment of chr oni c hepat i t i s B i nf ect i on i n
adul t s wi t h act i ve vi r al repl i cat i on and persi st ent el evat i ons i n l i ver f unct i on
t est s or hi st ol ogi cal l y act i ve di sease.
( 2) When compar ed wi t h l ami vudi ne, t el bi vudi ne pr oduced a gr eat er
vi r ol ogi c r esponse i n cont r ol l ed cl i ni cal t r i al s.
d. Pr ecaut i ons and moni t or i ng ef f ect s.
( 1) Ther e i s a bl ack box war ni ng regardi ng severe exacer bat i ons of
hepat i t i s B i n pat i ent s di scont i nui ng t her apy, r equi r i ng cl ose moni t ori ng.
P. 965


( 2) Common adverse ef f ect s i ncl ude el evat i ons i n creat i ne phosphoki nase,
headache, f at i gue, nausea, and vomi t i ng.
( 3) Dosage adj ust ment i s r equi r ed i n pat i ent s wi t h r enal i nsuf f i ci ency.
( 4) May be t aken wi t hout r egar d t o meal s.
13. Val acycl ovi r ( Val t r ex) i s t he L- val yl est er prodr ug of t he ant i vi r al agent
acycl ovi r .
a. Mechani sm of act i on. Val acycl ovi r i s rapi dl y conver t ed t o acycl ovi r .
Acycl ovi r i s sel ect i ve f or t he t hymi di ne ki nase enzyme, begi nni ng t he
conversi on of acycl ovi r t o acycl ovi r t ri phosphat e, st oppi ng t he r epl i cat i on of
her pes vi r al DNA.
b. Spect r um of act i vi t y and t her apeut i c uses
( 1) Val acycl ovi r i s act i ve agai nst HSV-1, HSV-2, and VZV.
( 2) Thi s agent i s used f or t he acut e t r eat ment of her pes zost er (shi ngl es) ,
her pes l abi al i s (col d sores) , and geni t al her pes i n i mmunocompet ent adul t s.
Ì t i s al so ef f ect i ve f or suppr essi on of r ecur rent epi sodes of geni t al her pes i n
i mmunocompet ent and HÌ V- i nf ect ed peopl e as wel l as reduct i on of
t r ansmi ssi on of geni t al her pes.
( 3) Advant ages over acycl ovi r i ncl ude oral dosi ng of onl y once t o t hr ee
t i mes dai l y and at t ai nment of hi gher pl asma concent r at i ons t han or al
acycl ovi r . A di sadvant age i s t hat t here i s no Ì V f or m avai l abl e.
c. Precaut i ons and moni t or i ng ef f ect s
( 1) Val acycl ovi r has caused t hrombot i c t hrombocyt openi c purpura/ hemol yt i c
ur emi c syndr ome i n i mmunocompr omi sed i ndi vi dual s, i ncl udi ng t hose wi t h
advanced HÌ V and t r anspl ant r eci pi ent s.
( 2) Begi n t her apy wi t hi n 72 hr of herpes zost er r ash onset .
( 3) Most commonl y r eport ed adverse react i ons are mi l d and i ncl ude nausea,
headache, and vomi t i ng. Dosage adj ust ment i s needed i n pat i ent s wi t h
r enal dysf unct i on.
14. Val ganci cl ovi r ( Val cyt e) i s t he L- val yl est er prodr ug of t he ant i vi ral
agent ganci cl ovi r .
a. Mechani sm of act i on. Val ganci cl ovi r i s convert ed i n vi vo t o ganci cl ovi r .
Af t er conver si on t o t he act i ve f orm, ganci cl ovi r t ri phosphat e, ganci cl ovi r i s
i ncor por at ed i nt o vi r al DNA, whi ch i nhi bi t s vi r al DNA pol ymer ase, t her eby
t er mi nat i ng vi ral repl i cat i on.
b. Spect r um of act i vi t y and t her apeut i c uses
( 1) For i n vi t ro act i vi t y, see VÌ Ì . B. 8. b.
( 2) Val ganci cl ovi r i s i ndi cat ed f or t he t r eat ment of CMV r et i ni t i s i n pat i ent s
wi t h AÌ DS and f or prevent i on of CMV af t er t r anspl ant at i on of ki dney, hear t ,
and ki dneypancr eas. Ì t i s not i ndi cat ed f or l i ver t r anspl ant r eci pi ent s, due t o
an i ncreased r i sk of t i ssue- i nvasi ve CMV as compar ed wi t h ganci cl ovi r .
( 3) The markedl y i mproved bi oavai l abi l i t y of val ganci cl ovi r over or al
ganci cl ovi r has resul t ed i n t he wi despread use of val ganci cl ovi r f or
t r eat ment and pr event i on of CMV di sease.
c. Precaut i ons and moni t or i ng ef f ect s
( 1) Same bl ack box war ni ngs as f or ganci cl ovi r .
( 2) Doses shoul d be adj ust ed i n cases of r enal i mpai r ment . Do not use i n
hemodi al ysi s pat i ent s; ganci cl ovi r must be used.
( 3) Onl y avai l abl e or al l y. Do not subst i t ut e doses of oral val ganci cl ovi r 1: 1
f or oral ganci cl ovi r ; t hey ar e not equi val ent .
( 4) A pot ent i al car ci nogen and t er at ogen; common adverse ef f ect s ar e t he
same as f or ganci cl ovi r .
( 5) Ì f t he t abl et i s br oken, avoi d cont act wi t h ski n owi ng t o t erat ogeni c and
carci nogeni c pot ent i al .
( 6) Be awar e of t he pot ent i al f or err ors as a r esul t of t he l ook-al i ke and
sound-al i ke names of val ganci cl ovi r and val acycl ovi r .
d. Si gni f i cant i nt eract i ons. Same as f or ganci cl ovi r ; see VÌ Ì . B. 8. e.
15. Zanami vi r ( Rel enza) i s t he f i rst of a cl ass of ant i vi r al agent s cal l ed
neurami ni dase i nhi bi t ors approved by t he FDA f or t he t r eat ment of i nf l uenza
A and B i nf ect i ons i n adul t s and chi l dren at l east 7 years of age. Ì t i s al so
i ndi cat ed f or prevent i on of i nf l uenza i n adul t s and chi l dr en at l east 5 years
of age.
a. Mechani sm of act i on. Zanami vi r i nhi bi t s repl i cat i on of t he i nf l uenza A and
B vi r uses by sel ect i ve i nhi bi t i on of t he i nf l uenza vi r us neur ami ni dase
enzyme.
b. Spect r um of act i vi t y. Thi s agent i s act i ve agai nst bot h t he i nf l uenza A
and B vi r uses. Ì t demonst r at es act i vi t y agai nst avi an i nf l uenza i n ani mal
st udi es.
P. 966


c. Therapeut i c uses
( 1) Ì t i s appr oved f or t he t r eat ment of uncompl i cat ed i nf l uenza A and B
i nf ect i on f or pat i ent s who have been sympt omat i c f or < 48 hr . Ì t i s al so
i ndi cat ed f or i nf l uenza prophyl axi s.
( 2) Zanami vi r i s appr oved f or or al i nhal at i on use onl y, usi ng t he Di skhal er
devi ce provi ded by t he manuf act ur er .
( 3) Zanami vi r may be consi dered f or pr event i on or t r eat ment of avi an
i nf l uenza.
( 4) Shown t o decrease dur at i on of sympt oms by approxi mat el y 1. 5 days i f
t aken wi t hi n 48 hr of onset of vi r al sympt oms.
d. Pr ecaut i ons and moni t or i ng ef f ect s
( 1) The use of zanami vi r i s gener al l y not recommended i n pat i ent s wi t h a
hi st or y of ast hma or chroni c obst ruct i ve pul monary di sease, owi ng t o t he
r i sk of bronchospasm and acut e decl i ne i n l ung f unct i on.
( 2) The most common adver se ef f ect s wer e mi l d and i ncl uded di ar rhea,
nausea, and vomi t i ng. The i nci dence of t hese was no di f f er ent t han
pl acebo.
( 3) Do not punct ur e t he Rot adi sk bl i st er unt i l i mmedi at el y bef ore
admi ni st er i ng t he dose t o ensure f ul l dosage. Manual dext er i t y r equi r ed f or
t hi s devi ce.
C. RNA vi r uses ( HÌ V)
1. Cur rent l y, si x cl asses of ant i ret r ovi r al agent s ar e appr oved. These dr ugs
ar e act i ve agai nst HÌ V and i ncl ude t he nucl eosi de r everse t r anscr i pt ase
i nhi bi t ors ( NRTÌ s) abacavi r , di danosi ne, emt ri ci t abi ne, l ami vudi ne,
st avudi ne, zal ci t abi ne, and zi dovudi ne; t he nucl eot i de r ever se t r anscri pt ase
i nhi bi t or ( Nt RTÌ ) t enof ovi r di sopr oxi l f umarat e; t he nonnucl eosi de rever se
t r anscri pt ase i nhi bi t ors (NNRTÌ s) del avi r di ne, ef avi r enz, nevi r api ne and
et r avi ri ne; and t he pr ot ease i nhi bi t or s ( PÌ s) amprenavi r , at azanavi r,
dar unavi r , f osamprenavi r, i ndi navi r , l opi navi r / ri t onavi r , nel f i navi r , r i t onavi r ,
saqui navi r , and t i pr anavi r ; t he f usi on i nhi bi t or enf uvi r t i de; t he ent r y i nhi bi t or
mar avi r oc; and t he i nt egr ase i nhi bi t or r al t egr avi r.
2. These agent s ar e vi r ust at i c and requi r e l i f el ong t her apy. They ar e
cur rent l y appr oved f or use i n vari ous combi nat i ons known as pot ent
combi nat i on ant i ret r ovi ral t her apy.
a. Appr opr i at e combi nat i ons i ncl ude t hose t hat have demonst r at ed ef f i cacy
and saf et y i n cont r ol l ed cl i ni cal t ri al s ( Tabl e 44-6) .
b. Monot her apy wi t h any si ngl e ant i r et rovi r al agent i s unaccept abl e i n t he
t r eat ment of HÌ V i nf ect i on owi ng t o rapi d devel opment of vi r al r esi st ance.
c. Bef ore desi gni ng a t r eat ment pl an, a mi ni mum of t wo CD4
+
cel l count s
and one HÌ V RNA l evel (vi r al l oad) shoul d be obt ai ned t o conf i rm t he i ni t i al
measurement s and det ermi ne i f t reat ment shoul d be i ni t i at ed. Af t er st ar t i ng
t her apy, r epeat t hese measur ement s i n 2- 8 weeks, f ol l owed by ever y 3- 4
mont hs t her eaf t er .
d. A mi ni mum of 1. 0- l og10 copi es/ mL decl i ne i n HÌ V RNA l evel s shoul d be
seen af t er t he f i rst 2- 8 weeks of t her apy f or cl i ni cal response; a subsequent
decrease t o undet ect abl e l evel s shoul d be achi eved by 16- 24 weeks.
3. Reverse t r anscr i pt ase i nhi bi t ors ar e cl assi f i ed as ei t her nucl eosi des or
nucl eot i des. These agent s ar e compet i t i ve i nhi bi t or s of rever se
t r anscri pt ase, whi ch l eads t o chai n t er mi nat i on when i ncorpor at ed i nt o t he
vi r al DNA chai n. They are i nact i ve unt i l phosphoryl at ed by human cel l ul ar
ki nases i nt o t he act i ve t ri phosphat e met abol i t e. Each agent has a
cor respondi ng t hr ee- l et t er acr onym as wel l as a br and name. Wi t h t he
except i on of abacavi r , each agent i n t hi s cl ass of ant i r et r ovi ral s r equi r es
dosage adj ust ment i n pat i ent s wi t h r enal dysf unct i on. Al l agent s i n t hi s
cl ass have a bl ack box war ni ng concer ni ng t he pot ent i al f or devel opment of
l act i c aci dosi s and severe hepat omegal y wi t h st eat osi s.
a. Abacavi r ( ABC; Zi agen) i s a synt het i c car bocycl i c nucl eosi de anal og
i ndi cat ed f or t he t reat ment of bot h adul t and pedi at r i c pat i ent s wi t h HÌ V.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Abacavi r i s appr oved f or use
i n adul t s and chi l dren < 3 mont hs of age onl y i n combi nat i on wi t h ot her
ant i r et rovi r al agent s.
( a) Abacavi r i s avai l abl e al one or co- f or mul at ed as a combi nat i on t abl et
wi t h l ami vudi ne and zi dovudi ne ( Tr i zi vi r ) whi ch i s dosed t wi ce dai l y.
( b) Abacavi r i s al so avai l abl e i n a combi nat i on t abl et wi t h l ami vudi ne
( Epzi com) whi ch i s dosed once dai l y.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s. Abacavi r has a bl ack box war ni ng
f or a l i f e- t hr eat eni ng hyper sensi t i vi t y r eact i on t hat can l ead t o deat h. Ì t
occurs i n appr oxi mat el y 5% of pat i ent s t aki ng t hi s drug, t ypi cal l y wi t hi n t he
f i r st 6 weeks of t herapy. Thi s r eact i on i nvol ves r espi rat or y sympt oms, f ever ,
r ash, and GÌ compl ai nt s. Reexposure f ol l owi ng t hese sympt oms can mi mi c
anaphyl axi s and may resul t i n deat h. Ther ef or e, rechal l enge i s
cont r ai ndi cat ed. A Medi cat i on Gui de descr i bi ng t hi s r eact i on shoul d be
di spensed wi t h each new pr escri pt i on and ref i l l of abacavi r- cont ai ni ng
pr oduct s. The HLA- B
*
5701 screeni ng t est shoul d be used pr i or t o i ni t i at i ng
t her apy t o r educe t he ri sk of t hi s r eact i on.
P. 967


Table 44-6. Department of Health and Human Services Guidelines for the Use of
Antiviral Agents in HIV-1-Infected Adults and Adolescents
When to begin treatment
Treat any patient with history oI AIDS deIining illness
Treat any patients with CD4
¹
cell count · 200/mm
3
or between 200-
350/mm
3

Treat patients who are pregnant. have HIV-associated nephropathy or those
co-inIected with hepatitis B virus (when treatment Ior hepatitis B is
indicated).
Note: The optimal time to start treatment in patients with CD4
¹
cell count ~
350/mm
3
is not well deIined.
Regimen selection
Selection oI a treatment regimen should be individualized Ior each patient
based on adverse eIIect proIiles. drug interactions. comorbidities. pill
burden. etc. PreIerred and alternative treatment regimens in previously
untreated patients are as Iollows:
To select an antiretroviral regimen. select one component Irom Column A
and one Irom Column B:
Column A (NNRTI or PI Options) Column B (Dual NRTI
Options)
PreIerr NNRT o PI PreIerr TenoIovir/em
ed
Compo
nents
I
EIavir
enz
a

r Atazanavir or
ritonavir
Fosamprenavi
r ¹ ritonavir
(b.i.d.)
Lopinavir/rito
navir (b.i.d.)
ed
Compo
nents
tricitabine or
abacavir/lami
vudine
Alterna
tive to
PreIerr
ed
Compo
nents
NNRT
I
Nevira
pine
b

o
r
PI
Atazanavir
Fosamprenavi
r
Fosamprenavi
r/ritonavir
(once daily)
Lopinavir/rito
navir (once
daily)
Saquinavir ¹
ritonavir
Alterna
tive to
PreIerr
ed
Compo
nents
Zidovudine/la
mivudine or
didanosine ¹
(emtricitabine
or
lamivudine)
Agents or combinations that should not be offered at any time
All monotherapies
2-NRTI regimens
Abacavir ¹ tenoIovir ¹ lamivudine as a triple NRTI regimen
TenoIovir ¹ didanosine ¹ lamivudine as a triple NRTI regimen
Saquinavir as the sole PI in a PI-based regimen
Zidovudine ¹ stavudine
Didanosine ¹ stavudine
Lamivudine ¹ emtricitabine
Atazanavir ¹ indinavir
2-NNRTI combination
Monitoring
BeIore initiating drug therapy. must obtain CD4
¹
cell count and plasma HIV
RNA levels plus complete blood count. chemistry. lipid proIile. liver
enzymes. and genotypic resistance testing
II HIV RNA does not reach undetectable levels (· 50 copies/mL) by 16-24
weeks. perIorm resistance testing. compliance assessment. and consider a
regimen change
NNRTI. nonnucleoside reverse transcriptase inhibitor; NRTI. nucleoside
reverse transcriptase inhibitor; PI. protease inhibitor.
a
Cannot be used in the Iirst trimester oI pregnancy or in women who wish to
conceive or are not using eIIective contraception.

b
Should not be initiated in women with pre-nevirapine CD4
¹
cell counts ~
250/mm
3
or men with pre-nevirapine CD4
¹
cell counts ~ 400/mm
3
owing to
high incidence oI hepatic adverse eIIects.

P. 968


( 4) Si gni f i cant i nt eract i ons. Al cohol i ncr eases abacavi r ' s AUC by 41%.
b. Di danosi ne ( ddÌ ; Vi dex) , a synt het i c pur i ne anal og, i nhi bi t s HÌ V
r epl i cat i on and has a l onger i nt racel l ul ar hal f -l i f e ( > 20 hr ) t han zi dovudi ne
( 7 hr ).
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Di danosi ne i s appr oved f or
t he t r eat ment of adul t s and chi l dren onl y i n combi nat i on wi t h ot her
ant i r et rovi r al agent s.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Di danosi ne can cause r eversi bl e peri pher al neur opat hy and acut e,
pot ent i al l y l et hal pancr eat i t i s ( bl ack box war ni ng) . Ser um t r i gl ycer i des
shoul d be moni t ored, and di danosi ne shoul d be wi t hhel d when i ni t i at i ng
pot ent i al pancreat i t i s- i nduci ng agent s ( e. g. , Ì V pent ami di ne, sul f onami des) .
Tr ansi ent l y el evat ed serum amyl ase may not r ef l ect pancreat i t i s.
( b) Ot her adver se ef f ect s i ncl ude headaches, di ar r hea, nausea, and
hyper uri cemi a (because di danosi ne i s cat al yzed t o uri c aci d) .
( c) Di danosi ne i s avai l abl e i n an ent eri c coat ed capsul e or buf f ered or al
t abl et f ormul at i on t o pr event degr adat i on at aci di c pH. Ì t must be t aken on
an empt y st omach.
( d) Do not use i n combi nat i on wi t h st avudi ne or zal ci t abi ne because of
addi t i ve pot ent i al f or t oxi ci t y.
( e) Do not use t he combi nat i on regi men of di danosi ne and t enof ovi r i n
t r eat ment naï ve pat i ent s, owi ng t o hi gh rat es of ear l y vi r ol ogi c f ai l ure.
( 4) Si gni f i cant i nt eract i ons. Pancr eat i t i s- i nduci ng dr ugs, al cohol , and t hose
known t o cause per i pheral neuropat hy shoul d not be used wi t h di danosi ne.
Ri bavi ri n shoul d not be co- admi ni st ered wi t h di danosi ne.
c. Emt r i ci t abi ne ( FTC; Emt r i va) i s a synt het i c nucl eosi de anal og st ruct ural l y
r el at ed t o l ami vudi ne wi t h act i vi t y agai nst HÌ V i nf ect i on.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Emt r i ci t abi ne i s i ndi cat ed f or
use i n HÌ V- i nf ect ed adul t s and chi l dren i n combi nat i on wi t h ot her
ant i r et rovi r al agent s. Ì t i s avai l abl e by i t sel f or as a combi nat i on t abl et wi t h
t enof ovi r ( Tr uvada) and as a combi nat i on t abl et wi t h t enof ovi r and ef avi renz
( At r i pl a) . Al t hough i t demonst rat es act i vi t y agai nst hepat i t i s B vi r us, i t i s
not approved f or use i n t r eat ment of t hi s i nf ect i on.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Adverse ef f ect s most commonl y obser ved i n cl i ni cal t r i al s wer e mi l d-
moder at e and i ncl ude headache, r ash, di ar rhea, and nausea.
Hyper pi gment at i on of t he pal ms or sol es may occur .
( b) Seri ous acut e exacerbat i ons of hepat i t i s B have been document ed i n
HÌ V/ hepat i t i s B co-i nf ect ed pat i ent s who di scont i nued t her apy wi t h
emt ri ci t abi ne (bl ack box war ni ng) ; t her ef or e, l i ver f unct i on t est s shoul d be
moni t ored f or several mont hs af t er di scont i nuat i on.
( 4) Si gni f i cant i nt eract i ons. None have been i dent i f i ed.
d. Lami vudi ne (3TC; Epi vi r ) i s a synt het i c nucl eosi de anal og wi t h act i vi t y
agai nst HÌ V and hepat i t i s B vi rus.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Lami vudi ne i s i ndi cat ed f or
use i n HÌ V- posi t i ve adul t s and chi l dren > 3 mont hs of age i n combi nat i on
wi t h ot her ant i ret r ovi r al agent s. Ì t i s al so used i n a l ower dosage f or t he
t r eat ment of chr oni c hepat i t i s B i n pat i ent s wi t h act i ve l i ver i nf l ammat i on
and evi dence of hepat i t i s B vi ral repl i cat i on.
( a) Lami vudi ne i s avai l abl e al one or wi t hi n a t wi ce dai l y combi nat i on t abl et
cont ai ni ng l ami vudi ne, zi dovudi ne and abacavi r (Tr i zi vi r ) .
( b) Lami vudi ne i s al so avai l abl e as a combi nat i on t abl et wi t h abacavi r
( Epzi com) and zi dovudi ne ( Combi vi r) .
P. 969


( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Repor t ed adverse react i ons ar e mi nor and i ncl ude headache, f at i gue,
and GÌ r eact i ons such as nausea, vomi t i ng, and di ar r hea. CNS t oxi ci t y
i ncl udes neur opat hy, di zzi ness, and i nsomni a. Lab t est abnor mal i t i es such
as neut r openi a and el evat i ons i n l i ver enzymes have al so been repor t ed.
( b) Do not use i n combi nat i on wi t h zal ci t abi ne owi ng t o ant agoni sm of
ef f ect s.
( c) Lami vudi ne has t he same bl ack box war ni ng regardi ng acut e
exacer bat i ons of hepat i t i s B as emt r i ci t abi ne ( see VÌ Ì . C. 3. c).
( 4) Si gni f i cant i nt eract i ons. Co- admi ni st rat i on wi t h cot r i moxazol e resul t s i n
i ncreased l ami vudi ne l evel s. No dose adj ust ment i s requi r ed.
e. St avudi ne (d4T; Zer i t ) i s a synt het i c t hymi di ne nucl eosi de anal og t hat i s
act i ve agai nst HÌ V.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. St avudi ne i s i ndi cat ed f or use
i n combi nat i on wi t h ot her ant i r et r ovi r al agent s i n adul t s and chi l dren of al l
ages.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) The maj or t oxi ci t y wi t h st avudi ne i s a dose rel at ed but r eversi bl e
per i pheral neur opat hy occur ri ng i n up t o 21% of pat i ent s.
( b) Ot her adver se ef f ect s i ncl ude headache, r ash, di ar rhea, nausea, and
vomi t i ng.
( c) Fat al epi sodes of pancr eat i t i s have been report ed.
( 4) Si gni f i cant i nt eract i ons. Do not use i n combi nat i on wi t h zi dovudi ne or
zal ci t abi ne.
f . Tenof ovi r di soproxi l f umar at e ( TDF; Vi r ead) i s an acycl i c nucl eosi de
phosphonat e di est er anal og ( nucl eot i de) wi t h ant i vi r al act i vi t y agai nst HÌ V
and hepat i t i s B vi rus.
( 1) Mechani sm of act i on. Tenof ovi r ( a pr odr ug) i s r api dl y hydr ol yzed by
pl asma est er ases t o t enof ovi r , wi t h subsequent conver si on t o t he act i ve
t enof ovi r di phosphat e. Not e: Nt RTÌ s are act i ve as t he di phosphat e, unl i ke
t he NRTÌ s, whi ch r equi re conver si on t o t he t r i phosphat e.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Tenof ovi r i s approved f or use
i n combi nat i on wi t h ot her ant i r et r ovi r al agent s f or t he t r eat ment of HÌ V i n
adul t s. Ì t i s al so avai l abl e as a once dai l y combi nat i on t abl et cont ai ni ng
t enof ovi r and emt r i ci t abi ne ( Tr uvada) and t enof ovi r , emt r i ci t abi ne, and
ef avi r enz ( At ri pl a) .
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Mi nor adver se ef f ect s have been r epor t ed i n cl i ni cal t ri al s. These
i ncl ude compl ai nt s of di ar r hea, vomi t i ng, and nausea.
( b) Addi t i onal adverse ef f ect s obser ved duri ng post mar ket i ng sur vei l l ance
i ncl ude acut e renal f ai l ure and decreases i n bone mi ner al densi t y.
( c) Tenof ovi r has t he same bl ack box war ni ng t hat emt ri ci t abi ne has f or
pat i ent s wi t h concomi t ant hepat i t i s B ( see VÌ Ì . C. 3. c) .
( d) Dose adj ust ment i s requi r ed f or r enal i nsuf f i ci ency.
( 4) Si gni f i cant i nt eract i ons
( a) Tenof ovi r i ncr eases di danosi ne serum concent r at i ons, necessi t at i ng a
dose r educt i on of di danosi ne.
( b) Tenof ovi r decr eases ser um concent rat i ons of at azanavi r . When t hese 2
agent s ar e used t oget her , r i t onavi r must be added t o t he r egi men.
g. Zal ci t abi ne (ddC; Hi vi d) i s a synt het i c pyr i mi di ne nucl eosi de anal ogue
t hat i s act i ve agai nst HÌ V.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Zal ci t abi ne i s no l onger
r ecommended as a component of i ni t i al combi nat i on t her apy of HÌ V owi ng t o
i t s severe adver se ef f ect pr of i l e. The manuf act urer di scont i nued i t s
pr oduct i on i n 2006.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) The maj or cl i ni cal t oxi ci t y of zal ci t abi ne i s peri pher al neur opat hy, whi ch
occurs i n up t o 35% of pat i ent s and may be pot ent i al l y di sabl i ng.
( b) Ot her adver se ef f ect s i ncl ude pancr eat i t i s, st omat i t i s, car di omyopat hy,
and hypersensi t i vi t y react i ons.
( c) Do not use i n combi nat i on wi t h l ami vudi ne, st avudi ne, or zi dovudi ne.
( 4) Si gni f i cant i nt eract i ons
( a) Dr ugs t hat have t he pot ent i al t o cause per i pher al neur opat hy shoul d be
avoi ded. These i ncl ude chl orampheni col , ci spl at i n, dapsone, di danosi ne,
di sul f i r am, hydr al azi ne, i soni azi d, met roni dazol e, ni t rof urant oi n, phenyt oi n,
r i bavi ri n, and vi ncr i st i ne.
P. 970


( b) Zal ci t abi ne t r eat ment shoul d be i nt err upt ed when a drug wi t h t he
pot ent i al t o cause pancreat i t i s i s i ni t i at ed ( i . e. , pent ami di ne) .
( c) Do not t ake wi t h magnesi um- , cal ci um- , or al umi num-cont ai ni ng
ant aci ds.
( d) Ci met i di ne and probeneci d may i ncr ease zal ci t abi ne l evel s, causi ng
i ncreased zal ci t abi ne t oxi ci t y.
h. Zi dovudi ne ( AZT; Ret rovi r ) i s a synt het i c t hymi di ne anal og. Thi s agent
was t he f i rst avai l abl e drug f or t he t r eat ment of HÌ V i nf ect i on.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses
( a) Zi dovudi ne i s i ndi cat ed i n t he t r eat ment of adul t s and chi l dren > 6
weeks of age f or t he t r eat ment of HÌ V.
( b) Ì t i s i ndi cat ed f or t he pr event i on of mat er nal - f et al HÌ V t ransmi ssi on.
( c) Zi dovudi ne i s avai l abl e as or al capsul es, t abl et s, and sol ut i on as wel l as
an Ì V sol ut i on.
( d) Or al zi dovudi ne i s al so avai l abl e as a co- f ormul at i on wi t h l ami vudi ne
( Combi vi r ) and wi t h l ami vudi ne and abacavi r ( Tr i zi vi r ) .
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Zi dovudi ne can cause sever e bone mar r ow suppressi on, i ncl udi ng
macr ocyt i c anemi a and neut r openi a af t er t he f i rst f ew weeks t o mont hs of
t her apy. The ri sk i s i ncr eased i n pat i ent s wi t h pr eexi st i ng bone mar row
suppr essi on or who ar e t aki ng concomi t ant medi cat i ons t hat cause bone
mar row suppr essi on.
( b) Er yt hropoi et i n can be consi dered as an adj unct i ve t her apy i n pat i ent s
wi t h zi dovudi ne- i nduced anemi a, i n cases f or whi ch i t cannot be
di scont i nued.
( c) Ot her adver se ef f ect s i ncl ude headache, mal ai se, sei zur es, anxi et y,
f ever , and r ash.
( d) Pr ol onged use may l ead t o sympt omat i c myopat hy.
( 4) Si gni f i cant i nt eract i ons
( a) Cot ri moxazol e, at ovaquone, val proi c aci d, met hadone, and pr obeneci d
may i ncrease zi dovudi ne concent rat i ons, causi ng i ncr eased ri sk of
zi dovudi ne t oxi ci t y.
( b) Ot her cyt ot oxi c dr ugs, such as ganci cl ovi r, dapsone, and i nt erf er on- q,
can cause addi t i ve bone mar row suppr essi on.
( c) Ri bavi ri n, r i f abut i n, and ri f ampi n may decrease l evel s of zi dovudi ne.
4. Nonnucl eosi de r everse t r anscr i pt ase i nhi bi t or s. The NNRTÌ cl ass bi nds
di r ect l y t o and pr oduces a noncompet i t i ve i nhi bi t i on of t he HÌ V r everse
t r anscri pt ase, l eadi ng t o chai n t ermi nat i on. These agent s are i ndi cat ed f or
use i n adul t s and pedi at ri c pat i ent s i n combi nat i on wi t h ei t her NRTÌ s or
possi bl y PÌ s. Ef avi r enz i s consi der ed a pr ef er red NNRTÌ , wher eas t he
ot hers ar e curr ent l y r ecommended as al t er nat i ves. NNRTÌ - based regi mens
pr ovi de pot ent ant i vi r al act i vi t y wi t h l ess pi l l burden t han many PÌ -based
r egi mens. Al l NNRTÌ s may cause r ash and hepat ot oxi ci t y; pat i ent s shoul d
be moni t ored cl osel y f or t hese adverse ef f ect s.
a. Del avi r di ne ( Rescri pt or )
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Del avi rdi ne i s approved f or
use i n adul t s i n t he t r eat ment of HÌ V i n combi nat i on wi t h ot her ant i ret r ovi ral
agent s. Ì t s use has f al l en out of f avor owi ng t o i t s t hr ee t i mes dai l y dosi ng
schedul e.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Ì n cl i ni cal t r i al s, 4. 3% of pat i ent s di scont i nued del avi r di ne because of
r ash. Cases of St evens-Johnson syndrome have been r epor t ed.
( b) Ot her adver se ef f ect s i ncl ude headache and nausea.
( 4) Si gni f i cant i nt eract i ons
( a) The concent r at i ons of t he f ol l owi ng medi cat i ons ar e gr eat l y i ncreased by
del avi r di ne and must be avoi ded: al pr azol am, mi dazol am, t r i azol am,
si mvast at i n, l ovast at i n, ri f abut i n, and ci sapr i de.
( b) Decr eased del avi r di ne concent r at i ons resul t when i t i s admi ni st ered wi t h
St . John' s wor t , carbamazepi ne, phenobar bi t al , phenyt oi n, or ri f ampi n.
Concomi t ant use shoul d be avoi ded.
( c) Because del avi r di ne r equi r es an aci di c GÌ t ract f or opt i mal absor pt i on,
i t s use i s cont r ai ndi cat ed wi t h prot on pump i nhi bi t ors and H2- r ecept or
ant agoni st s.
b. Ef avi r enz ( Sust i va)
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
P. 971


( 2) Spect r um of act i vi t y and t herapeut i c uses. Ef avi r enz i s approved f or use
i n combi nat i on wi t h ot her ant i r et r ovi r al agent s f or t he t r eat ment of HÌ V
i nf ect i on i n adul t s and pedi at r i c pat i ent s ( < 3 year s of age) . Ì t s advant age
over ot her NNRTÌ s i s once- dai l y dosi ng. Ì t i s avai l abl e al one or as a
combi nat i on t abl et wi t h t enof ovi r and emt r i ci t abi ne ( At ri pl a) .
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Most common adver se ef f ect s ar e CNS- r el at ed ( 52%) , i ncl udi ng
i nsomni a, di zzi ness, drowsi ness, ni ght mares, and hal l uci nat i ons,
necessi t at i ng bedt i me dosi ng t o mi ni mi ze t hese ef f ect s. These ef f ect s
t ypi cal l y subsi de af t er 2-4 weeks of t r eat ment .
( b) Owi ng t o i t s t er at ogeni c ef f ect s, ef avi r enz shoul d be avoi ded i n t he f i rst
t r i mest er of pr egnancy and i n women of chi l dbear i ng pot ent i al who wi sh t o
concei ve.
( c) Ot her adver se ef f ect s i ncl ude rash, i ncr eased t r ansami nases, and GÌ
di st ur bances.
( 4) Si gni f i cant i nt eract i ons
( a) Ef avi r enz i nduces and i nhi bi t s t he cyt ochr ome P450 3A4 i soenzyme
syst em. Ì t shoul d not be used concomi t ant l y wi t h ci sapri de, mi dazol am,
t r i azol am, or ergot deri vat i ves.
( b) St . John' s wor t decreases ef avi renz concent rat i ons and shoul d be
avoi ded.
( c) Ef avi r enz decr eases met hadone concent r at i ons by 60%; pat i ent s shoul d
be moni t ored f or opi at e wi t hdr awal and have t hei r doses t i t r at ed
accor di ngl y.
c. Et ravi r i ne (Ì nt el ence)
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Et r avi r i ne i s i ndi cat ed f or use
i n combi nat i on wi t h at l east t wo addi t i onal ant i r et r ovi r al agent s i n
t r eat ment - exper i enced adul t s who demonst r at e vi r al repl i cat i on and
document ed resi st ance t o ot her NNRTÌ s. Ì t i s not f or use i n t reat ment - naï ve
pat i ent s.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s.
( a) Adverse ef f ect s i ncl ude nausea and r ash.
( b) Si nce f ood i ncr eases t he absorpt i on of et r avi ri ne by 50%, i t shoul d be
t aken f ol l owi ng a meal .
( 4) Si gni f i cant i nt eract i ons.
( a) Et ravi r i ne i nduces and i nhi bi t s a var i et y of cyt ochrome P450
i soenzymes. Ì t shoul d not be used concomi t ant l y wi t h carbamazepi ne,
phenobar bi t al , phenyt oi n, unboost ed PÌ s, at azanavi r / r i t onavi r,
f osampr enavi r / ri t onavi r , t i pranavi r/ r i t onavi r , or ot her NNRTÌ s.
( b) St . John' s wor t and ri f ampi n decr ease et r avi ri ne concent r at i ons and
shoul d be avoi ded.
( c) Et ravi r i ne may decr ease ser um concent r at i ons of met hadone; pat i ent s
shoul d be moni t ored cl osel y.
d. Nevi rapi ne (Vi r amune) was t he f i rst NNRTÌ appr oved f or use by t he FDA
f or t he t r eat ment of HÌ V i nf ect i on.
( 1) Mechani sm of act i on. See VÌ Ì . C. 3.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Nevi r api ne i s i ndi cat ed i n
combi nat i on wi t h ot her ant i ret r ovi ral s i n adul t and pedi at r i c ( < 2 mont hs ol d)
HÌ V pat i ent s.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Nevi rapi ne has t he hi ghest i nci dence of St evens-Johnson syndrome of
al l NNRTÌ s.
( b) Sympt omat i c hepat i t i s, i ncl udi ng f at al hepat i c necr osi s, has been
obser ved wi t h nevi rapi ne ( bl ack box war ni ng). The f r equency of t hi s
adver se ef f ect i s i ncr eased i n women wi t h pr e- nevi r api ne CD4
+
count s >
250 cel l s/ mm
3
and men wi t h CD4
+
count s > 400 cel l s/ mm
3
. Nevi r api ne
shoul d not be i ni t i at ed i n t hese pat i ent s.
( c) Ot her adver se ef f ect s i ncl ude f ever , nausea, and headache.
( d) To decr ease t he f r equency of adverse ef f ect s, a 2- week dose escal at i on
i s requi r ed.
( 4) Si gni f i cant i nt eract i ons
( a) Nevi rapi ne i nduces cyt ochrome P450 3A4, r esul t i ng i n decreased
concent r at i ons of caspof ungi n, ket oconazol e, i t r aconazol e, oral
cont r acept i ves, and pr ot ease i nhi bi t ors.
P. 972


( b) Use of r i f ampi n and St . John' s wor t shoul d be avoi ded, as t hey decrease
t he serum concent rat i ons of nevi r api ne.
( c) Met hadone concent r at i ons decr ease si gni f i cant l y wi t h nevi r api ne, of t en
necessi t at i ng a dose i ncrease.
5. Pr ot ease i nhi bi t or s. The PÌ s compet i t i vel y i nhi bi t t he vi r al pr ot ease
enzyme, pr event i ng t he enzyme f rom cl eavi ng t he gag and gag- pol
pol yprot ei ns necessar y f or vi r i on pr oduct i on. PÌ s ar e used i n combi nat i on
wi t h ot her ant i ret r ovi r al agent s, i ncl udi ng ot her PÌ s, t o suppr ess HÌ V
r epl i cat i on. Al l of t he PÌ s ar e cyt ochrome P450 i nhi bi t ors; ri t onavi r i s t he
most pot ent i nhi bi t or. Al l PÌ s ar e cont r ai ndi cat ed wi t h numer ous dr ugs,
i ncl udi ng si mvast at i n, l ovast at i n, r i f ampi n, ci sapr i de, pi mozi de, mi dazol am,
t r i azol am, ergot s, and St . John' s wor t . Concomi t ant t her apy wi t h
ant i epi l ept i c dr ugs, er ect i l e dysf unct i on dr ugs, and azol e ant i f ungal s must
be under t aken wi t h caut i on. Owi ng t o t he wi de arr ay of dr ug i nt er act i ons
wi t h PÌ s, al ways assess medi cat i on pr of i l es car ef ul l y f or drug i nt er act i ons
bef ore i ni t i at i on.
a. Ampr enavi r ( Agenerase)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Ampr enavi r i s no l onger
r ecommended f or use i n t r eat ment regi mens f or HÌ V due t o i t s
di scont i nuat i on i n l at e 2007.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s.
( a) Use of t he oral sol ut i on i n pregnant women, chi l dr en < 4 years ol d, and
pat i ent s wi t h hepat i c or renal i nsuf f i ci ency i s cont r ai ndi cat ed owi ng t o t he
pr opyl ene gl ycol vehi cl e ( bl ack box war ni ng) .
( b) Because amprenavi r i s a sul f onami de, t he pot ent i al f or cr oss- sensi t i vi t y
t o ot her sul f onami des exi st s.
( c) Adver se ef f ect s i ncl ude hyper l i pi demi a, hypergl ycemi a, f at
mal di st ri but i on, rash, and GÌ di st ur bances.
( d) Dosage adj ust ment i s r equi r ed f or hepat i c i nsuf f i ci ency.
( 4) Si gni f i cant i nt eract i ons (see VÌ Ì . C. 5). Ampr enavi r decreases met hadone
concent r at i ons, possi bl y r equi r i ng a met hadone dose i ncr ease t o prevent
wi t hdr awal .
b. At azanavi r ( Reyat az)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect r um of act i vi t y and t herapeut i c uses. At azanavi r i s a component of
pr ef er r ed and al t er nat i ve PÌ - based r egi mens f or HÌ V. Ì t i s dosed once dai l y.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s.
( a) At azanavi r may pr ol ong t he PR i nt er val and possi bl y cause f i r st - degr ee
AV bl ock. El ect r ocardi ogr am ( ECG) shoul d be moni t or ed.
( b) Ot her adver se ef f ect s i ncl ude f at mal di st ri but i on, hypergl ycemi a, and
i ndi r ect hyper bi l i r ubi nemi a. Ì n cont r ast t o t he ot her PÌ s, at azanavi r appear s
t o be devoi d of ef f ect s on l i pi ds.
( c) Dose adj ust ment i s requi r ed f or hepat i c i nsuf f i ci ency.
( 4) Si gni f i cant i nt eract i ons (see VÌ Ì . C. 5). At azanavi r i s t he most pr obl emat i c
of al l PÌ s i n t erms of dr ug i nt er act i ons.
( a) Ì f used i n combi nat i on wi t h ef avi r enz or t enof ovi r , l ow- dose r i t onavi r
must be admi ni st er ed concomi t ant l y.
( b) Because at azanavi r requi r es an aci di c GÌ t ract f or opt i mal absorpt i on,
concomi t ant use of pr ot on pump i nhi bi t or s i s cont r ai ndi cat ed. Ì f ot her aci d
suppr essant s ar e used wi t h at azanavi r , t he doses must be separ at ed by as
much t i me as possi bl e ( up t o 12 hr apart ) .
c. Darunavi r ( Prezi st a)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5
( 2) Spect r um of act i vi t y and t herapeut i c uses. Dar unavi r i s t he newest PÌ t o
r ecei ve FDA appr oval f or t he t r eat ment of HÌ V. Ì t s use i s l i mi t ed t o hi ghl y
t r eat ment - exper i enced pat i ent s or pat i ent s wi t h HÌ V r esi st ance mut at i ons.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Darunavi r must be co- admi ni st er ed wi t h ri t onavi r
( b) Because dar unavi r cont ai ns a sul f onami de moi et y, cross- r eact i vi t y may
occur i n sul f a-al l er gi c pat i ent s.
( c) Adver se ef f ect s i ncl ude nausea, i ncreased amyl ase, hepat ot oxi ci t y,
hyper l i pi demi a, hyper gl ycemi a, and rash.
( 4) Si gni f i cant i nt eract i ons. See VÌ Ì . C. 5.
d. Fosampr enavi r ( Lexi va)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5. Fosampr enavi r i s t he pr odr ug of
amprenavi r .
P. 973


( 2) Spect r um of act i vi t y and t herapeut i c uses. Fosampr enavi r has l ar gel y
r epl aced ampr enavi r because of i t s i mpr oved dosi ng conveni ence. Ì t i s
r ecommended as one of t he pr ef er r ed component s i n PÌ -based r egi mens f or
i ni t i al t reat ment of HÌ V.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Fosamprenavi r may be dosed once dai l y i n t r eat ment naï ve pat i ent s. PÌ -
exper i enced pat i ent s r equi r e t wi ce dai l y dosi ng. Ì n most cases,
f osampr enavi r i s admi ni st er ed wi t h l ow dose r i t onavi r .
( b) Adverse ef f ect s ar e t he same as t hose wi t h ampr enavi r ( see
VÌ Ì . C. 5. a. (3) . b, c and d).
( 4) Si gni f i cant i nt eract i ons (see VÌ Ì . C. 3). Ì f used i n combi nat i on wi t h
ef avi r enz, f osampr enavi r must be admi ni st er ed wi t h a boost er dose of
r i t onavi r .
e. Ì ndi navi r ( Cri xi van)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Ì ndi navi r , i n combi nat i on wi t h
r i t onavi r , i s no l onger r ecommended as part of r egi men f or pat i ent s
r ecei vi ng i ni t i al t r eat ment f or HÌ V due t o a hi gh i nci dence of nephr ol i t hi asi s.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Because i ndi navi r may cause nephr ol i t hi asi s (ki dney st ones) , pat i ent s
shoul d be i nst ruct ed t o dr i nk at l east 1. 5 L of wat er dai l y t o prevent t hi s
adver se ef f ect .
( b) Ì ndi navi r can cause i ndi rect hyperbi l i rubi nemi a. Combi nat i on t her apy
wi t h at azanavi r i s not r ecommended owi ng t o t he pot ent i al f or addi t i ve
ef f ect s.
( c) Ot her adver se ef f ect s i ncl ude hypergl ycemi a, hyper l i pi demi a, f at
mal di st ri but i on, headache, and GÌ i nt ol er ance.
( d) Dose adj ust ment i s requi r ed f or hepat i c i nsuf f i ci ency.
( 4) Si gni f i cant i nt eract i ons (see VÌ Ì . C. 5). Vi t ami n C i n doses > 1 g dai l y
decreases i ndi navi r concent r at i ons. Caut i on pat i ent s not t o exceed t he
r ecommended dai l y al l owance f or vi t ami n C.
f . Lopi navi r / ri t onavi r ( Kal et r a)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Thi s pr oduct i s avai l abl e as a
co- f or mul at i on of l opi navi r wi t h a " boost er ¨ dose of r i t onavi r , whi ch i nhi bi t s
l opi navi r met abol i sm and r esul t s i n hi gher serum concent r at i ons.
Lopi navi r/ r i t onavi r i s a pr ef er red PÌ used i n i ni t i al PÌ - based r egi mens owi ng
t o i t s pot ency and conveni ent dosi ng.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Lopi navi r / r i t onavi r was recent l y r ef or mul at ed as a f i l m- coat ed t abl et t hat
does not requi r e r ef ri gerat i on. Ì t i s al so avai l abl e as an or al sol ut i on
cont ai ni ng 42% al cohol .
( b) Adverse ef f ect s i ncl ude GÌ i nt ol er ance, hyperl i pi demi a, hyper gl ycemi a,
f at mal di st ri but i on, and pancreat i t i s.
( 4) Si gni f i cant i nt eract i ons. See VÌ Ì . C. 5.
( a) Lopi navi r / r i t onavi r decr eases met hadone concent r at i ons, possi bl y
necessi t at i ng a met hadone dose i ncrease t o pr event opi at e wi t hdr awal .
( b) Concomi t ant admi ni st r at i on wi t h vor i conazol e i s cont rai ndi cat ed
because of t he ri sk of decr eased vor i conazol e ef f i cacy.
( c) Dosi ng vari es due t o dr ug i nt er act i ons wi t h concomi t ant use of
ef avi r enz, nevi r api ne, f osampr enavi r , or nel f i navi r . Be sure t o check
appropr i at e r ef er ences f or proper dosi ng.
g. Nel f i navi r ( Vi r acept )
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Nel f i navi r i s a possi bl e
component of an al t ernat i ve PÌ - based regi men f or i ni t i al t reat ment of adul t s
wi t h HÌ V i nf ect i on. Unl i ke t he ot her PÌ s, i t i s never used i n combi nat i on wi t h
r i t onavi r . Ì t i s not general l y r ecommended due t o i nf er i or vi r ol ogi c ef f i cacy.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Di ar r hea i s commonl y r epor t ed wi t h nel f i navi r. Thi s can of t en be
managed wi t h ant i di ar r heal s.
( b) Ot her adver se ef f ect s are si mi l ar t o t hose wi t h l opi navi r / ri t onavi r .
( c) Use caut i on wi t h l ook- al i ke, sound- al i ke names ( nel f i navi r and
nevi r api ne) .
( 4) Si gni f i cant i nt eract i ons (see VÌ Ì . C. 5. ) Nel f i navi r decr eases met hadone
concent r at i ons, necessi t at i ng i ncreased moni t ori ng and dose adj ust ment i f
i ndi cat ed.
h. Ri t onavi r ( Nor vi r)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
P. 974


( 2) Spect r um of act i vi t y and t herapeut i c uses. Ri t onavi r i s r ar el y used as
t he sol e PÌ i n a PÌ - based r egi men owi ng t o i t s poor t ol erabi l i t y and hi gh pi l l
bur den when admi ni st ered i n f ul l doses. Al t er nat i vel y, i t i s used i n l ow
doses as a phar macoki net i c boost i ng agent wi t h ot her PÌ s. Because i t i s
such a pot ent cyt ochr ome 450 enzyme i nhi bi t or , ri t onavi r markedl y
i ncreases t he serum concent r at i ons of ot her PÌ s, r esul t i ng i n hi gher
concent r at i ons wi t h i mproved vi r al suppr essi on.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Capsul es shoul d be ref r i ger at ed bef or e di spensi ng. Capsul es t hen may
be st ored at room t emper at ure f or up t o 30 days.
( b) Or al sol ut i on shoul d not be ref r i gerat ed.
( c) Adver se ef f ect s i ncl ude GÌ i nt ol er ance, ci r cumor al par est hesi as,
hyper l i pi demi a, hyper gl ycemi a, f at mal di st r i but i on, i ncreased l i ver f unct i on
t est s, and t ast e per ver si on.
( 4) Si gni f i cant i nt eract i ons (see VÌ Ì . C. 5). Many dr ug i nt er act i ons occur wi t h
r i t onavi r because i t i s such a pot ent i nhi bi t or of so many cyt ochr ome P450
i soenzymes. Al ways r ef er t o pr oper resources t o assess f or dr ug
i nt er act i ons.
i . Saqui navi r ( Ì nvi rase)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect r um of act i vi t y and t herapeut i c uses. Use of saqui navi r wi t hout
boost er doses of ri t onavi r i s not r ecommended because of t he poor
bi oavai l abi l i t y of saqui navi r .
( 3) Pr ecaut i ons and moni t ori ng ef f ect s
( a) Saqui navi r i s avai l abl e as a hard gel capsul e and t abl et ( Ì nvi rase) and
was pr evi ousl y avai l abl e as a sof t gel capsul e ( For t ovase) . The var i ous
dosage f orms are not bi oequi val ent and cannot be used i nt erchangeabl y.
( b) The sof t gel capsul e f or mul at i on i s no l onger manuf act ur ed ( ef f ect i ve
Febr uar y 2006).
( c) Adver se ef f ect s ar e si mi l ar t o l opi navi r / ri t onavi r .
( 4) Si gni f i cant i nt eract i ons. See VÌ Ì . C. 5.
j . Ti pr anavi r ( Apt i vus)
( 1) Mechani sm of act i on. See VÌ Ì . C. 5.
( 2) Spect r um of act i vi t y and t herapeut i c uses. The use of t i pranavi r i s
l i mi t ed t o hi ghl y t r eat ment - exper i enced pat i ent s wi t h HÌ V who ar e r esi st ant
t o ot her PÌ s as wel l as t o ot her cl asses of ant i r et rovi r al s.
( 3) Pr ecaut i ons and moni t ori ng ef f ect s.
( a) Owi ng t o t he poor bi oavai l abi l i t y of t i pranavi r, i t must be co-
admi ni st er ed wi t h ri t onavi r .
( b) Capsul es must be ref r i gerat ed. Once di spensed, t hey ar e st abl e at r oom
t emper at ure f or up t o 60 days.
( c) Ti pranavi r has been associ at ed wi t h cl i ni cal hepat i t i s and f at al hepat i c
decompensat i on ( bl ack box war ni ng) . Li ver f unct i on t est s shoul d be
moni t ored cl osel y, especi al l y i n pat i ent s wi t h under l yi ng l i ver di sease.
( d) Rarel y, t here have been repor t s of f at al and nonf at al i nt r acrani al
hemor r hage wi t h t i pr anavi r ( bl ack box war ni ng) .
( e) Because t he st r uct ure of t i pr anavi r cont ai ns a sul f onami de moi et y,
cr oss- react i vi t y may occur i n sul f a- al l er gi c pat i ent s.
( f ) Ot her adver se ef f ect s i ncl ude rash, hyperl i pi demi a, hyper gl ycemi a, and
f at mal di st ri but i on.
( 4) Si gni f i cant i nt eract i ons (see VÌ Ì . C. 5). Loperami de may decrease
t i pranavi r concent r at i ons.
6. Fusi on i nhi bi t or s. Enf uvi r t i de ( T- 20; Fuzeon) i s t he f i r st and onl y member
of t hi s cl ass of ant i r et r ovi r al s.
a. Mechani sm of act i on. Enf uvi r t i de i nhi bi t s t he ent r y of HÌ V i nt o CD4
+
cel l s
by i nt er f eri ng wi t h t he f usi on of vi r al and cel l ul ar membr anes.
b. Spect r um of act i vi t y and t her apeut i c uses. Enf uvi r t i de i s pr i mari l y used i n
hi ghl y t r eat ment - exper i enced pat i ent s wi t h ext ensi ve vi ral resi st ance. Ì t i s
not recommended f or use as i ni t i al t her apy i n t r eat ment -nai ve pat i ent s, as i t
has not been st udi ed i n t hi s popul at i on.
c. Precaut i ons and moni t or i ng ef f ect s
( 1) Enf uvi r t i de i s i nj ect ed subcut aneousl y t wi ce dai l y. Local i nj ect i on si t e
r eact i ons occur i n al most al l pat i ent s, i ncl udi ng pai n, r edness, prur i t us, and
nodul es.
P. 975


( 2) Ot her adver se ef f ect s i ncl ude hyper sensi t i vi t y r eact i ons and i ncreased
r at e of bact eri al pneumoni a.
( 3) No dose adj ust ment i s necessar y f or r enal i mpai rment .
d. Si gni f i cant i nt eract i ons. There are no si gni f i cant drug i nt er act i ons wi t h
enf uvi rt i de.
7. Ent r y i nhi bi t or . Mar avi r oc ( Sel zent r y) i s t he f i rst and onl y member of t hi s
cl ass of ant i ret r ovi ral t her apy.
a. Mechani sm of act i on. Mar avi r oc i s a chemoki ne r ecept or 5 ( CCR5)
cor ecept or ant agoni st . Ì t bi nds t o t he CCR5 recept or on t he CD4 cel l
membr ane, pr event i ng ent r y of t he vi r us i nt o t he cel l .
b. Spect r um of act i vi t y and t her apeut i c uses. Mar avi r oc i s used al ong wi t h
ot her ant i ret r ovi ral s onl y i n hi ghl y t reat ment - exper i enced adul t pat i ent s who
ar e i nf ect ed wi t h HÌ V t hat bi nds t o t he CCR5 recept or .
c. Precaut i ons and moni t or i ng ef f ect s.
( 1) Hepat ot oxi ci t y was obser ved dur i ng cl i ni cal t ri al s wi t h maravi r oc ( bl ack
box war ni ng) . Thi s may be preceded by a syst emi c al l er gi c r eact i on.
Pat i ent s shoul d be eval uat ed i mmedi at el y i f ei t her occurs.
( 2) Use caut i on i n pat i ent s wi t h l i ver di sease or car di ovascul ar ri sk f act ors.
( 3) Adverse ef f ect s i ncl ude cough, r ash, f ever , muscul oskel et al sympt oms,
di zzi ness, and abdomi nal pai n.
( 4) Not r ecommended f or use i n pat i ent s wi t h renal i nsuf f i ci ency unl ess no
al t er nat i ve opt i on i s avai l abl e.
d. Si gni f i cant i nt eract i ons.
( 1) Dosi ng f or mar avi r oc var i es dependi ng upon concomi t ant medi cat i ons
t hat i nt er act :
( a) When used wi t h cyt ochr ome P450 i nhi bi t ors, such as PÌ s ( except
t i pranavi r/ r i t onavi r ) , del avi r di ne, ket oconazol e, i t raconazol e, and
cl ari t hr omyci n, admi ni st er maravi r oc 150 mg t wi ce dai l y.
( b) When used wi t h cyt ochr ome P450 i nducer s ( such as car bamazepi ne,
phenobar bi t al , phenyt oi n, ef avi r enz, and r i f ampi n) wi t hout a st r ong
cyt ochr ome P450 i nhi bi t or , admi ni st er mar avi r oc 600 mg t wi ce dai l y.
( c) When used wi t h ot her medi cat i ons, i ncl udi ng t i pranavi r/ r i t onavi r ,
nevi r api ne, NRTÌ s, and enf uvi r t i de, admi ni st er mar avi r oc 300 mg t wi ce
dai l y.
( 2) Concomi t ant admi ni st r at i on wi t h St . John' s wor t i s not r ecommended
due t o reduct i on i n mar avi r oc serum concent r at i ons.
8. Ì nt egr ase i nhi bi t or . Ral t egr avi r (Ì sent ress) i s t he f i rst and onl y member of
t hi s cl ass of ant i r et r ovi ral t her apy.
a. Mechani sm of act i on. Ral t egr avi r i nhi bi t s t he vi r al enzyme i nt egr ase,
t her eby pr event i ng t he i nsert i on of HÌ V genet i c mat er i al i nt o t he CD4 cel l
genome and hal t i ng t he vi r al repl i cat i on pr ocess.
b. Spect r um of act i vi t y and t her apeut i c uses. Ral t egr avi r i s used al ong wi t h
ot her ant i ret r ovi ral s onl y i n t r eat ment -exper i enced adul t pat i ent s who
demonst r at e resi st ant st rai ns of HÌ V.
c. Precaut i ons and moni t or i ng ef f ect s.
( 1) Si nce el evat i ons i n cr eat i ne ki nase, al ong wi t h myopat hy and
r habdomyol ysi s, may occur wi t h r al t egravi r , use wi t h caut i on i n pat i ent s
who ar e r ecei vi ng concomi t ant medi cat i ons t hat may cause t hese adverse
ef f ect s.
( 2) The most common adver se ef f ect s i ncl ude nausea, di arr hea, headache,
and f ever .
d. Si gni f i cant i nt eract i ons. Ri f ampi n decreases t he ser um concent r at i on of
r al t egr avi r and shoul d be used wi t h caut i on.
VIII. AntheImintics
A. Def i ni t i on. These dr ugs are used t o r i d t he body of wor ms ( hel mi nt hs).
These agent s may act l ocal l y t o r i d t he GÌ t ract of wor ms or wor k
syst emi cal l y t o eradi cat e wor ms t hat ar e i nvadi ng or gans or t i ssues.
B. Mebendazol e ( Vermox) i s a synt het i c benzi mi dazol e-der i vat i ve
ant hel mi nt i c.
1. Mechani sm of act i on. Mebendazol e i nt erf er es wi t h r eproduct i on and
sur vi val of hel mi nt hs by i nhi bi t i ng t he f or mat i on of mi crot ubul es and
i r r eversi bl y bl ocki ng gl ucose upt ake, t hereby depl et i ng gl ycogen st or es i n
t he hel mi nt h.
2. Spect r um of act i vi t y. Mebendazol e i s act i ve agai nst var i ous nemat odes
t hat ar e pat hogeni c t o humans, i ncl udi ng Ancyl ost oma duodenal e (common
hookwor m) , Ascar i s l umbr i coi des
P. 976

( r oundwor m) , Capi l l ar i a phi l i ppi nensi s ( Phi l i ppi ne t hreadwor m) , Ent erobi us
ver mi cul ar i s (pi nwor m) , Necat or amer i canus ( Amer i can hookwor m) , and
Tr i churi s t r i chi ur a ( whi pwor m) .
3. Ther apeut i c uses. Mebendazol e i s used f or t he t r eat ment of si ngl e or
mi xed i nf ect i ons wi t h t he hel mi nt hs l i st ed i n VÌ Ì Ì . B. 2. Ì mmobi l i zat i on and
subsequent deat h of hel mi nt hs are sl ow, wi t h compl et e GÌ cl ear ance up t o 3
days af t er t her apy.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Ì n cases of massi ve i nf ect i on, abdomi nal pai n, nausea, and di ar r hea
associ at ed wi t h expul si on of or gani sms may resul t .
b. Myel osuppr essi on ( neut r openi a and t hrombocyt openi a) can occur wi t h
hi gh doses (40-50 mg/ kg/ day) .
c. Ì f t he pat i ent i s not cur ed i n 3 weeks, ret r eat ment i s necessar y.
5. Si gni f i cant i nt eract i ons. Agent s t hat may r educe t he ser um
concent r at i ons and subsequent ef f i cacy of mebendazol e i ncl ude
car bamazepi ne and phenyt oi n.
C. Al bendazol e ( Al benza) i s a synt het i c benzi mi dazol e-der i vat i ve
ant hel mi nt i c.
1. Mechani sm of act i on. See VÌ Ì Ì . B. 1.
2. Spect r um of act i vi t y. Al bendazol e i s act i ve agai nst Taeni a sol i um ( pork
t apewor m) and Echi nococcus gr anul osus ( dog t apewor m) .
3. Ther apeut i c uses. Al bendazol e i s used t o t r eat par enchymal
neurocyst i cercosi s i n combi nat i on wi t h cor t i cost er oi ds as wel l as cyst i c
hydat i d di sease (bef or e and af t er sur gi cal removal of t he di sease).
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. The dr ug shoul d be admi ni st ered wi t h a f at t y meal t o achi eve opt i mal
absor pt i on.
b. Hepat ot oxi ci t y occurs i n 16% of pat i ent s; l i ver f unct i on t est s ever y 2
weeks ar e recommended whi l e t aki ng al bendazol e.
c. Rarel y, l eukopeni a, t hr ombocyt openi a, granul ocyt openi a, pancyt openi a,
and agranul ocyt osi s occur . A CBC shoul d be checked ever y 2 weeks whi l e
t aki ng al bendazol e.
D. Di et hyl car bamazi ne ci t r at e ( Het razan)
1. Mechani sm of act i on. Di et hyl carbamazi ne ci t rat e i s a synt het i c organi c
compound hi ghl y speci f i c f or sever al common par asi t es.
2. Spect r um of act i vi t y. Thi s agent i s act i ve agai nst Wucher er i a bancr of t i ,
Onchocerca vol vul us, Brugi a mal ayi , Mansonel l a per st ans, Mansonel l a
ozzar di , Ascar i s l umbr i coi des, and Loa l oa.
3. Ther apeut i c uses. Di et hyl car bamazi ne ci t r at e i s used f or t he t reat ment of
Bancrof t ' s f i l ari asi s, onchocer ci asi s, ascari asi s, and l oi asi s. Ì t i s avai l abl e
di r ect l y f r om t he manuf act urer f or compassi onat e use onl y.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Pat i ent s t r eat ed f or W. bancrof t i i nf ect i on of t en pr esent wi t h headache
and gener al mal ai se. Sever e al l ergi c phenomena i n conj unct i on wi t h a ski n
r ash have been repor t ed.
b. Pat i ent s t r eat ed f or onchocer ci asi s present wi t h prur i t us, f aci al edema,
and syst emi c sympt oms secondar y t o t he i nf l ammat or y r esponse caused by
pat hogen deat h (known as a Mazzot t i r eact i on). Sever e react i ons may be
not ed af t er a si ngl e dose. For t hi s reason, i vermect i n i s used t o t reat
onchocerci asi s.
c. Chi l dr en who ar e under nour i shed or are suf f eri ng f r om debi l i t at i ng
ascar i asi s i nf ect i on may exper i ence gi ddi ness, mal ai se, nausea, and
vomi t i ng af t er t r eat ment . Ot her dr ugs ar e avai l abl e t o t r eat Ascar i s
( mebendazol e and al bendazol e) .
E. Pyr ant el ( Pi n- Ri d) i s a pyr i mi di ne- der i vat i ve ant hel mi nt i c.
1. Mechani sm of act i on. Pyr ant el i s a depol ar i zi ng neur omuscul ar bl ocki ng
agent t hat causes a spast i c par al ysi s of t he hel mi nt h.
2. Spect r um of act i vi t y. Pyr ant el i s act i ve agai nst A. l umbr i coi des
( r oundwor m) , E. ver mi cul ar i s (pi nwor m), A. duodenal e (hookwor m) , N.
ameri canus (hookwor m), and Tr i chost r ongyl us ori ent al i s ( hai r wor m).
3. Ther apeut i c uses. Pyrant el i s used f or t he t r eat ment of r oundwor m,
pi nwor m, and hookwor m i nf ect i ons.
P. 977


4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Most commonl y report ed r eact i ons i ncl ude anor exi a, nausea, vomi t i ng,
di ar rhea, headache, and r ash.
b. A si ngl e dose may be mi xed wi t h f ood, mi l k, j ui ce, or t aken on an empt y
st omach.
F. Thi abendazol e ( Mi nt ezol ) , a pyr azi noi soqui nol i ne deri vat i ve, i s a
synt het i c het erocycl i c ant hel mi nt i c.
1. Mechani sm of act i on i s not known preci sel y. Thi abendazol e i s shown t o
i nhi bi t t he hel mi nt h-speci f i c enzyme, f umar at e reduct ase. Thi abendazol e
al so demonst r at es ant i -i nf l ammat or y, ant i pyr et i c, and anal gesi c ef f ect s.
2. Spect r um of act i vi t y. Ì t i s act i ve agai nst most i nt est i nal nemat odes,
i ncl udi ng Ancyl ost oma br azi l i ense (dog and cat hookwor m), A. duodenal e
( hookwor m) , A. l umbr i coi des ( r oundwor m), E. vermi cul ar i s (pi nwor m), N.
ameri canus (hookwor m), St r ongyl oi des st ercoral i s ( t hr eadwor m) , T.
t r i chi ur a ( whi pwor m), T. spi ral i s, and Toxocar a cani s and Toxocar a cat i
( dog and cat roundwor ms) .
3. Ther apeut i c uses. Thi abendazol e i s used f or t he t reat ment of
st r ongyl oi di asi s ( t hr eadwor m i nf ect i on) , cut aneous l ar va mi grans (cr eepi ng
er upt i on) , and vi sceral l ar va mi gr ans. Ì t i s used f or t he t r eat ment of
unci nar i asi s (hookwor m), N. ameri canus, A. duodenal e, t r i chur i asi s
( whi pwor m) , and ascari asi s ( l ar ge r oundwor m) when more speci f i c t her apy
i s unavai l abl e or f urt her t r eat ment i s r equi red wi t h a second agent .
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Adverse ef f ect s of t hi abendazol e ar e usual l y mi l d and t r ansi ent ,
occur ri ng 3- 4 hr af t er t he dr ug has been admi ni st er ed and l ast i ng f or 2-8 hr .
b. Most common react i ons i ncl ude anor exi a, nausea, vomi t i ng, and
di zzi ness.
c. Gi ddi ness, sei zures, ver t i go, parest hesi as, and psychi c di st ur bances may
al so occur , but l ess f requent l y.
d. Ì f hypersensi t i vi t y devel ops, t he drug shoul d be di scont i nued. Er yt hema
mul t i f or me (i ncl udi ng St evens-Johnson syndrome) has been r epor t ed.
5. Si gni f i cant i nt eract i ons. Ser um xant hi ne l evel s ( t heophyl l i ne and
caf f ei ne) may i ncr ease.
G. Ì ver mect i n (St r omect ol )
1. Mechani sm of act i on. Ì ver mect i n pot ent i at es t he i nhi bi t or y ef f ect s of v-
ami nobut yr i c aci d ( GABA) i n vari ous nemat odes and art hropods, r esul t i ng i n
par al ysi s and deat h of t he or gani sms.
2. Spect r um of act i vi t y. Thi s agent i s act i ve agai nst S. st ercoral i s (i nt est i nal
f or ms onl y) and O. vol vul us ( i mmat ure f or ms onl y) . Ì t i s al so usef ul f or
t r eat ment of i nf ect i ons wi t h A. l umbr i coi des, E. ver mi cul ari s, M. ozzar di , T.
t r i chi ur a, and W. bancrof t i .
3. Ther apeut i c uses
a. Ì vermect i n i s usef ul f or t r eat ment of i nf ect i ons wi t h t he parasi t es l i st ed i n
VÌ Ì Ì . G. 2.
b. Two st udi es demonst rat ed t hat i ver mect i n was more ef f ect i ve t han
al bendazol e f or t r eat ment of st rongyl oi di asi s.
c. Ì vermect i n i s of t en f avor ed over di et hyl car bamazi ne ci t r at e owi ng t o i t s
l ess severe adver se ef f ect pr of i l e.
4. Pr ecaut i ons and moni t or i ng ef f ect s,
a. May cause a Mazzot t i r eact i on (see VÌ Ì Ì . D. 4. b) t hat i s l ess sever e t han
wi t h di et hyl car bamazi ne ci t rat e.
b. Repor t s of ser i ous and possi bl y f at al encephal opat hy have occurr ed i n
pat i ent s wi t h concomi t ant L. l oa i nf ect i on
c. Ot her adverse ef f ect s i ncl ude edema, di zzi ness, headache, r ash, and GÌ
di st ur bances.
d. Counsel pat i ent s t o t ake i ver mect i n wi t h wat er .
H. Pr azi quant el ( Bi l t r i ci de)
1. Mechani sm of act i on. Pr azi quant el i ncr eases cel l membrane per meabi l i t y
i n suscept i bl e hel mi nt hs, wi t h l oss of i nt r acel l ul ar cal ci um and par al ysi s of
t hei r muscul at ur e. Vacuol i zat i on and di si nt egr at i on of t he schi st osome
t egument resul t , f ol l owed by at t achment of phagocyt es t o t he par asi t e and
deat h.
P. 978


2. Spect r um of act i vi t y. Pr azi quant el i s act i ve agai nst t r emat odes ( f l ukes),
i ncl udi ng al l Schi st osoma spp. and Cl onorchi s si nensi s, Opi st horchi s
vi ver r i ni , Fasci ol a hepat i ca (l i ver f l ukes) , Par agoni mus ut er obi l at eral i s,
Par agoni mus west er mani ( l ung f l ukes) , Met agoni mus yokogawai ,
Fasci ol opsi s buski , and Het er ophyes het erophyes ( i nt est i nal f l ukes) .
3. Ther apeut i c uses. Prazi quant el i s act i ve i n t reat i ng al l t ypes of
schi st osomi asi s t hat are pat hogeni c t o humans; cl onor chi asi s and
opi st hor chi asi s ( Chi nese and sout heast Asi an l i ver f l ukes); many ot her
t ypes of i nf ect i ons i nvol vi ng i nt est i nal , l i ver , and l ung f l ukes; and
cest odi asi s ( t apewor m) i nf ect i ons.
4. Pr ecaut i ons and moni t or i ng ef f ect s
a. Tr eat ment of ocul ar cyst i cer cosi s i s cont r ai ndi cat ed because parasi t e
dest r uct i on wi t hi n t he eyes may cause i r r eparabl e l esi ons.
b. Ì n general , adverse ef f ect s ar e gener al l y mi l d and wel l t ol erat ed. Ì t i s
di f f i cul t t o di f f erent i at e bet ween ef f ect s caused by t he pr azi quant el ver sus
ef f ect s demonst r at ed by dyi ng parasi t es.
c. The most common si de ef f ect s ar e t r ansi ent and may i ncl ude mal ai se,
headache, di zzi ness, and abdomi nal di scomf or t .
d. Pr azi quant el may i mpai r act i vi t i es t hat requi r e ment al al er t ness.
P. 979


STUDY QUESTIONS
Di r ect i ons f or quest i ons 1- 12: Each of t he quest i ons, st at ement s, or
i ncompl et e st at ement s i n t hi s sect i on can be cor rect l y answer ed or
compl et ed by one of t he suggest ed answer s or phr ases. Choose t he best
answer .
1. I soni azi d i s a pri mary ant i t ubercuI ar agent that
( A) r equi res pyr i doxi ne suppl ement at i on.
( B) may di scol or t he t ears, sal i va, ur i ne, or f eces or ange red.
( C) causes ocul ar compl i cat i ons t hat ar e r eversi bl e i f t he drug i s
di scont i nued.
( D) may be ot ot oxi c and nephr ot oxi c.
( E) shoul d never be used because of hepat ot oxi c pot ent i al .
Vi ew Answer 1. The answer i s A[ see V. B. 2. d. (5) ] . 2. AI I of t he
f oI I owi ng f act ors may i ncrease the ri sk of nephrot oxi ci t y f rom
gent ami ci n therapy except whi ch one?
( A) age > 70 year s
( B) pr ol onged courses of gent ami ci n t her apy
( C) concur r ent amphot eri ci n B t herapy
( D) t r ough gent ami ci n l evel s < 2 mg/ mL
( E) concur r ent ci spl at i n t her apy
Vi ew Answer 2. The answer i s D[ seeÌ Ì . B. 4. b] . mgmL3. I n whi ch of
t he f oI I owi ng groups do aI I f our drugs warrant carefuI moni tori ng f or
drug- reI at ed sei zures i n hi gh- ri sk pat i ent s?
( A) peni ci l l i n G, i mi penem, amphot er i ci n B, met roni dazol e
( B) peni ci l l i n G, chl or ampheni col , t et r acycl i ne, vancomyci n
( C) i mi penem, t et racycl i ne, vancomyci n, sul f adi azi ne
( D) cycl oser i ne, met r oni dazol e, vancomyci n, sul f adi azi ne
( E) met r oni dazol e, i mi penem, doxycycl i ne, er yt hromyci n
Vi ew Answer 3. The answer i s A[ see I I . E. 1. e. ( 2) ;
I I . J. 5. d. ( 2) ;Ì Ì Ì . B. 4. b] . 4. AC i s a 34- year- oI d maI e admi t t ed wi t h a
di agnosi s of peri toni ti s. CuI t ures are posi ti ve f or Bacteroi des f ragi I i s,
Ent erococcus faecaI i s, and StaphyI ococcus aureus. Whi ch of t he
f oI I owi ng wouI d be t he best i ni t i aI therapy t o recommend?
( A) t el i t hr omyci n
( B) qui nupr i st i n/ dal f opri st i n
( C) t i gecycl i ne
( D) t r i met hopr i m/ sul f amet hoxazol e
( E) kanamyci n
Vi ew Answer 4. The answer i s C[ seeÌ Ì . K. 13] . 5. TJ i s a 45- year- oI d
f emaI e present i ng wi t h an Enterobact er aerogenes bacteremi a wi th a
I ow-grade f ever (101. 6°F) . The most appropri ate management of her
f ever wouI d be to
( A) gi ve acet ami nophen 1000 mg oral l y ever y 6 hr .
( B) gi ve aspi ri n 650 mg or al l y ever y 4 hr .
( C) gi ve al t er nat i ng doses of aspi r i n and acet ami nophen ever y 4 hr .
( D) wi t hhol d ant i pyr et i cs and use t he f ever cur ve t o moni t or her
r esponse t o ant i bi ot i c t her apy.
( E) use t epi d wat er bat hs t o r educe t he f ever .
Vi ew Answer 5. The answer i s D[ seeÌ . H. 1]. 6. BC has an upper
respi rat or y i nf ect i on. Two years ago, she experi enced an epi sode of
bronchospasm af ter peni ci I I i n therapy. Current cuI tures are posi t i ve for
a st rai n of St rept ococcus pneumoni ae that i s sensi t i ve t o aI I of the
f oI I owi ng drugs. Whi ch of t hese drugs wouI d be t he best choi ce for thi s
pat i ent ?
( A) amoxi ci l l i n/ cl avul anat e
( B) t el i t hr omyci n
( C) ampi ci l l i n
( D) cef acl or
( E) l oracar bef
Vi ew Answer 6. The answer i s B[ see I I . K. 12]. 7. AI I of the foI I owi ng
drugs are appropri at e therapi es for a I ower uri nar y t ract i nf ect i on
owi ng t o Pseudomonas aerugi nosa except
( A) norf l oxaci n.
( B) t r i met hopr i m- sul f amet hoxazol e.
( C) ci pr of l oxaci n.
( D) t obramyci n.
( E) met henami ne mandel at e.
Vi ew Answer 7. The answer i s
B[ seeÌ Ì . E. 4Ì Ì . H. 3. aandbÌ Ì . Ì . 2. aÌ Ì . Ì . 3. a]. P. aerugi nosa. 8. BT i s a 43-
year- oI d f emaI e seen by her pri mar y- care physi ci an f or a mi I d
st aphyI ococcaI ceI I uI i t i s on the arm. Whi ch of t he f oI I owi ng regi mens
wouI d be appropri at e oraI t herapy?
( A) di cl oxaci l l i n 125 mg ever y 6 hr
( B) vancomyci n 250 mg ever y 6 hr
( C) met hi ci l l i n 500 mg ever y 6 hr
( D) cef azol i n 1 g ever y 8 hr
( E) peni ci l l i n V 500 mg ever y 6 hr
Vi ew Answer 8. The answer i s A[ seeÌ Ì . C] . P. 980


9. RC i s a 33- year- oI d maI e wi t h a hi st or y of HI V f or 10 years who now
present s wi th Mycobact eri um avi um-i nt raceI I uI are (MAI ) . Whi ch of t he
f oI I owi ng drugs has demonst rat ed i n vi t ro acti vi t y agai nst MAI ?
( A) dapt omyci n
( B) cl ar i t hr omyci n
( C) er yt hromyci n base
( D) cl oxaci l l i n
( E) mi nocycl i ne
Vi ew Answer 9. The answer i s B[ see I I . D. 6. a-b] . ToxopI asma
gondi i Cr ypt ospori di um10. AI I of t he f oI I owi ng st at ements
regardi ng pent ami di ne i set hi onat e are t rue except whi ch one?
( A) Ì t i s i ndi cat ed f or t r eat ment or pr ophyl axi s of i nf ect i on owi ng t o
Pneumocyst i s cari ni i .
( B) Ì t may be admi ni st ered i nt r amuscul ar l y, i nt r avenousl y, or by
i nhal at i on.
( C) Ì t has no cl i ni cal l y si gni f i cant ef f ect on ser um gl ucose.
( D) Ì t i s ef f ect i ve i n t he t r eat ment of l ei shmani asi s.
Vi ew Answer 10. The answer i s C[ seeÌ V. D] . P. cari ni i . 11. RE i s a 23-
year- oI d maI e wi t h a hi st or y of i nf I uenza A i nfect i ons. An out break of
i nf I uenza A has j ust been report ed i n hi s communi t y, and he i s
exhi bi t i ng i ni t i aI sympt oms of t he i nfecti on. Whi ch agent wouI d be t he
most usefuI to t reat RE?
( A) ci dof ovi r
( B) f amci cl ovi r
( C) osel t ami vi r
( D) f oscar net
( E) r i bavi r i n
Vi ew Answer 11. The answer i s C[ seeVÌ Ì . B. 9] . 12. Dr. Jones
request s your heI p i n prescri bi ng a prot ease i nhi bi tor f or hi s pat i ent .
He has heard that not aI I agent s are t he same and asks f or your
recommendat i on as t o whi ch agent wouI d be I east I i keI y t o cause the
pat i ent ' s choI est eroI t o i ncrease. Whi ch agent wouI d you recommend?
( A) saqui navi r
( B) r i t onavi r
( C) i ndi navi r
( D) nel f i navi r
( E) at azanavi r
Vi ew Answer 12. The answer i s E[ seeVÌ Ì . C. 5. b. (3). ( b) ] . Di r ect i ons f or
quest i ons 13- 14: The quest i ons and i ncompl et e st at ement s i n t hi s sect i on
can be cor r ect l y answered or compl et ed by one or mor e of t he suggest ed
answer s. Choose t he answer , A- E.
13. Drugs usuaI I y act i ve agai nst peni ci I I i nase-produci ng
St aphyI ococcus aureus i ncI ude whi ch of the foI I owi ng?
( I ) pi peraci I I i n- t azobactam
( I I ) amoxi ci I I i n-cI avuI anat e
( I I I ) naf ci I I i n
A i f Ì onl y i s cor r ect
B i f Ì Ì Ì onl y i s corr ect
C i f Ì and Ì Ì ar e cor r ect
D i f Ì Ì and Ì Ì Ì ar e cor rect
E i f Ì , Ì Ì , and Ì Ì Ì ar e cor rect
Vi ew Answer 13. The answer i s E( I , I I , I I I ) [ seeÌ Ì . E. 23and4]. S.
aureus14. Ant i vi raI agent s t hat are act i ve agai nst
cyt omegaI ovi rus ( CMV) i ncI ude whi ch of the foI I owi ng?
( I ) ganci cI ovi r
( I I ) f oscarnet
( I I I ) acycI ovi r
A i f Ì onl y i s cor r ect
B i f Ì Ì Ì onl y i s corr ect
C i f Ì and Ì Ì ar e cor r ect
D i f Ì Ì and Ì Ì Ì ar e cor rect
E i f Ì , Ì Ì , and Ì Ì Ì ar e cor rect
Vi ew Answer 14. The answer i s C( I and I I ) [seeVÌ Ì . B.
1VÌ Ì . B. 7and8] . Di r ect i ons f or quest i ons 15- 17: Each descri pt i on
l i st ed i n t hi s sect i on i s most cl osel y associ at ed wi t h one of t he f ol l owi ng
dr ugs. The dr ugs may be used more t han once or not at al l . Choose t he
best answer , A- E.
15. I t may be admi ni stered once per day f or t he t reatment of uri nar y
t ract i nf ect i ons.
A cl of azi mi ne
B i t r aconazol e
C l omef l oxaci n
D neomyci n
Vi ew Answer 15. The answer i s C[ seeÌ Ì . H. 3. c] . 16. I t may cause pi nk
t o browni sh ski n pi gment at i on wi t hi n a f ew weeks of i ni t i at i on of
t herapy.
A cl of azi mi ne
B i t r aconazol e
C l omef l oxaci n
D neomyci n
Vi ew Answer 16. The answer i s A[ see I I . J. 9]. Mycobacteri um17. Co-
admi ni st rat i on wi t h astemi zoI e or terf enadi ne may I ead t o I i f e-
t hreat eni ng cardi ac dysrhyt hmi as.
A cl of azi mi ne
B i t r aconazol e
C l omef l oxaci n
D neomyci n
Vi ew Answer 17. The answer i s B[ seeÌ Ì Ì . E. 5. d] . P. 981


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see V. B. 2. d. ( 5)] .
Ì soni azi d i ncreases t he excr et i on of pyr i doxi ne, whi ch can l ead t o
per i pheral neur i t i s, par t i cul ar l y i n poorl y nour i shed pat i ent s. Pyri doxi ne (a
f or m of vi t ami n B6) def i ci ency may cause convul si ons as wel l as t he
neuri t i s, i nvol vi ng synovi al t ender ness and swel l i ng. Tr eat ment wi t h t he
vi t ami n can r everse t he neuri t i s and pr event or cur e t he sei zur es.
2. The answer i s D [ see Ì Ì . B. 4. b] .
Tr ough serum l evel s < 2 mg/ mL ar e consi der ed appr opr i at e f or gent ami ci n
and ar e r ecommended t o mi ni mi ze t he r i sk of t oxi ci t y f rom t hi s
ami nogl ycosi de. Because ami nogl ycosi des accumul at e i n t he proxi mal
t ubul e of t he ki dney, nephr ot oxi ci t y can occur .
3. The answer i s A [ see Ì Ì . E. 1. e. ( 2) ; Ì Ì . J. 5. d. ( 2); Ì Ì Ì . B. 4. b; Ì V. C. 3. c] .
Sei zur es have been at t r i but ed t o t he use of peni ci l l i n G, i mi penem,
amphot er i ci n B, and met r oni dazol e. Sei zur es ar e especi al l y l i kel y wi t h hi gh
doses i n pat i ent s wi t h a hi st or y of sei zures and i n pat i ent s wi t h i mpai red
dr ug el i mi nat i on.
4. The answer i s C [ see Ì Ì . K. 13] .
Al t hough act i ve agai nst var i ous gr am- posi t i ve and negat i ve organi sms,
t i gecycl i ne i s onl y agent approved f or t he t r eat ment of i nt r a-abdomi nal
i nf ect i ons caused by t hese or gani sms.
5. The answer i s D [ see Ì . H. 1] .
The f ever cur ve i s usef ul f or moni t or i ng a pat i ent ' s r esponse t o
ant i mi cr obi al t herapy. Ant i pyr et i cs can be used t o r educe hi gh f ever i n
pat i ent s at ri sk f or compl i cat i ons ( e. g. , sei zur es) or , i n some cases, t o
make t he pat i ent mor e comf or t abl e.
6. The answer i s B [ see Ì Ì . K. 12] .
Amoxi ci l l i n and ampi ci l l i n ar e al l peni ci l l i ns and shoul d be avoi ded i n
pat i ent s wi t h hi st ori es of hypersensi t i vi t y t o ot her peni ci l l i n compounds.
Al t hough t he ri sk of cr oss- r eact i vi t y wi t h cephal ospori ns (e. g. , cef acl or ,
l or acarbef ) i s now consi der ed l ow, most cl i ni ci ans avoi d t he use of t hese
agent s i n pat i ent s wi t h hi st or i es of t ype Ì hypersensi t i vi t y react i ons ( e. g. ,
anaphyl axi s, br onchospasm, gi ant hi ves) .
7. The answer i s B [ see Ì Ì . E. 4; Ì Ì . H. 3. a and b; Ì Ì . Ì . 2. a; Ì Ì . Ì . 3. a; Ì Ì . J. 7] .
Nor f l oxaci n, ci pr of l oxaci n, t obr amyci n, and met henami ne mandel at e achi eve
ur i ne concent r at i ons hi gh enough t o t reat ur i nar y t r act i nf ect i ons caused by
P. aerugi nosa. Tr i met hopr i m- sul f amet hoxazol e i s not usef ul f or t reat i ng
i nf ect i on caused by t hi s or gani sm, al t hough t he combi nat i on i s usef ul f or
t r eat i ng cer t ai n ot her ur i nar y t r act i nf ect i ons.
8. The answer i s A [ see Ì Ì . C; Ì Ì . E. 1. c. ( 3) ; Ì Ì . E. 2. b; Ì Ì . J. 8] .
Al t hough vancomyci n, met hi ci l l i n, and cef azol i n have excel l ent act i vi t y
agai nst st aphyl ococci , t hey ar e not ef f ect i ve or al l y f or syst emi c i nf ect i ons.
Vancomyci n i s prescr i bed or al l y f or i nf ect i ons l i mi t ed t o t he gast roi nt est i nal
t r act , but because i t i s poor l y absor bed or al l y, i t i s not ef f ect i ve f or
syst emi c i nf ect i ons. Most hospi t al - and communi t y- acqui r ed st aphyl ococci
ar e cur rent l y r esi st ant t o peni ci l l i n. Thus of t he dr ugs l i st ed, t he most
appropr i at e drug f or or al t herapy of st aphyl ococcal cel l ul i t i s i s di cl oxaci l l i n.
9. The answer i s B [ see Ì Ì . D. 6. a- b] .
Cl ar i t hr omyci n, an al t er nat i ve t o er yt hr omyci n, has demonst r at ed i n vi t r o
act i vi t y agai nst MAÌ . Cl ar i t hromyci n i s al so used agai nst Toxopl asma gondi i
and Cr ypt ospori di um spp. , and i t i s more act i ve t han er yt hr omyci n agai nst
st aphyl ococci and st rept ococci . Vancomyci n and cl oxaci l l i n ar e used t o
t r eat st aphyl ococci and st r ept ococci , but has no demonst r at ed act i vi t y
ver sus MAÌ .
10. The answer i s C [ see Ì V. D] .
Pent ami di ne i set hi onat e i s i ndi cat ed f or bot h t r eat ment and pr ophyl axi s of
i nf ect i on f r om P. car i ni i . Ì t can be admi ni st er ed i nt r amuscul arl y,
i nt ravenousl y, or by i nhal at i on. Ì nhal at i on may produce br onchospasm.
Bl ood gl ucose shoul d be caref ul l y moni t ored because pent ami di ne may
pr oduce ei t her hyper gl ycemi a or hypogl ycemi a.
P. 982


11. The answer i s C [ see VÌ Ì . B. 9] .
Ci dof ovi r , f amci cl ovi r , and f oscar net have l i t t l e or no i n vi vo act i vi t y agai nst
i nf l uenza A. Ri bavi ri n has some act i vi t y but i s a second-l i ne agent f or
i nf l uenza A and i s mai nl y i ndi cat ed f or t r eat ment of hepat i t i s C i n
combi nat i on wi t h i nt erf eron. Osel t ami vi r i s an agent t hat demonst rat es
act i vi t y agai nst i nf l uenza A and B. Ì t i s i ndi cat ed f or t he prophyl axi s and
t r eat ment of i nf l uenza i nf ect i ons.
12. The answer i s E [ see VÌ Ì . C. 5. b. ( 3) . (b) ] .
The maj ori t y of pr ot ease i nhi bi t ors cause hyperl i pi demi a. At azanavi r does
not cause t hi s adverse ef f ect and may be pr ef er red i n cer t ai n cl i ni cal
si t uat i ons.
13. The answer i s E ( Ì , Ì Ì , Ì Ì Ì ) [ see Ì Ì . E. 2, 3 and 4] .
Pi peraci l l i n and amoxi ci l l i n each i ncl ude a 8- l act amase i nhi bi t or . These
combi nat i ons of f er act i vi t y agai nst S. aureus si mi l ar t o t hat of t he
peni ci l l i nase- r esi st ant peni ci l l i ns, such as naf ci l l i n.
14. The answer i s C ( Ì and Ì Ì ) [ see VÌ Ì . B. 1; VÌ Ì . B. 7 and 8] .
Onl y ganci cl ovi r and f oscar net ar e act i ve agai nst CMV i nf ect i ons. These
agent s ar e vi r ust at i c and ar r est DNA synt hesi s by i nhi bi t i ng vi ral DNA
pol ymer ase. Foscar net i s a br oad-spect rum ant i vi r al agent and i s used i n
pat i ent s wi t h ganci cl ovi r r esi st ance. Acycl ovi r i s not cl i ni cal l y usef ul f or t he
t r eat ment of CMV i nf ect i ons because CMV i s r el at i vel y r esi st ant t o acycl ovi r
i n vi t ro.
15. The answer i s C [ see Ì Ì . H. 3. c] .
Lomef l oxaci n may be admi ni st er ed dai l y f or t r eat i ng ur i nar y t ract i nf ect i ons.
Enoxaci n i s anot her f l uoroqui nol one used t o t reat ur i nar y t ract i nf ect i ons.
Compar ed t o ot her f l uoroqui nol ones, nei t her l omef l oxaci n nor enoxaci n
i mproves t he spect r um of act i vi t y.
16. The answer i s A [ see Ì Ì . J. 9] .
Because cl of azi mi ne cont ai ns phenazi ne dye, i t can cause pi nk t o br own
ski n pi gment at i on. Thi s change i n pi gment at i on occur s i n 75%- 100% of
pat i ent s t aki ng cl of azi mi ne, and i t occurs wi t hi n a f ew weeks of t he
i ni t i at i on of t her apy. The di scol orat i on of ski n has r epor t edl y l ed t o severe
depressi on and even sui ci de i n some pat i ent s. Cl of azi mi ne i s used i n t he
t r eat ment of l eprosy and several at ypi cal Mycobact eri um i nf ect i ons.
17. The answer i s B [ see Ì Ì Ì . E. 5. d] .
Admi ni st rat i on of i t r aconazol e or ket oconazol e wi t h ast emi zol e or
t er f enadi ne may i ncr ease t he l evel of ast emi zol e or t er f enadi ne, whi ch can
l ead t o l i f e- t hr eat eni ng dysr hyt hmi as and deat h. Ì t r aconazol e, whi ch i s an
i mi dazol e, i s a f ungi st at i c agent . Speci f i cal l y, i t r aconazol e can be t aken
or al l y t o t r eat asper gi l l osi s i nf ect i ons and ot her deep f ungal i nf ect i ons,
such as bl ast omycosi s, cocci di oi domycosi s, cr ypt ococcosi s, and
hi st opl asmosi s.

55
Thyroid Disease
John E. Janosi k
I. PHYSIOLOGY
A. Thyroi d hormone regul at i on
1. The t hyr oid gland synt hesi zes, st or es, and secret es hormones t hat ar e import ant
t o gr owt h, development , and t he met aboli c r at e. These hormones are t hyroxi ne (T4)
and t ri i odot hyroni ne (T3 ).
2. The t hyr oid gland also secret es cal ci t oni n, whi ch r educes bl ood cal ci um i on
concent r at ion.
3. Thyr oi d hor mone secr et i on and t r ansport ar e cont r ol l ed by t hyroi d- st imul at i ng
hormone (t hyrotropi n; TSH). TSH is r el eased by t he ant er ior pi t ui t ar y gl and, which
is t r iggered by t hyrot ropi n- rel easi ng hormone (TRH) , secr et ed f r om t he
hypot halamus.
a. The process pr oduces i ncr eased levels of t hyr oi d hor mone ( ci r culat ing f r ee T4
and f ree T3 ), which, i n t ur n, si gnal s t he pit uit ar y t o st op r eleasing TSH ( negat i ve
f eedback).
b. Conver sel y, low bl ood l evel s of f r ee hormone t ri gger pit uit ar y r elease of TSH,
whi ch st i mulat es t he t hyr oi d gland t o secr et e T4 and T3 unt i l f r ee hormone levels
r et ur n t o normal. At t hi s poi nt , t he pi t ui t ar y gl and ceases t o r el ease TSH, which
complet es t he f eedback loop ( Figur e 55- 1) .
c. Thi s homeost at ic mechani sm at t empt s t o maint ai n t he level of ci r culat i ng t hyr oid
hormone wi t hi n a nar r ow r ange.
B. Bi osynt hesi s ( Figur e 55- 2)
1. Essent ial t o synt hesis of t hyr oi d hormones i s di et ar y iodi ne, reduced t o i norgani c
i odi de, whi ch t he t hyr oid act i vel y ext r act s f r om t he pl asma t hr ough i odide t r apping
( i odi de pump) . Some of t his iodide i s st or ed wit hi n t he col l oi d; some di f f uses i nt o
t he lumen of t hyr oi d f ol l i cl es.

Figure 55-1. Thyroid hormone regulation loop.
This carefully balanced hormone regulation
system uses both positive (stimulating) and
negative (inhibiting) feedback to maintain
homeostasis. Disruption of any of these elements
can produce serious consequences, such as
myxedema crisis (under availability of thyroid
hormone) or thyroid storm (overabundance of
thyroid hormone). T
3
, triiodothyronine; T
4
,
thyroxine; TRH, thyroid-releasing hormone; TSH,
thyroid-stimulating hormone.
P. 1199



Figure 55-2. Biosynthesis of thyroid hormones.
The major products are thyroxine (T
4
) and
triiodothyronine (T
3
). These are formed in the
follicle cells of the thyroid gland by iodination of
tyrosine residues. Monoiodotyrosine and
diiodotyrosine residues are formed first. These
then react to form T
3
and T
4
.
P. 1200


2. I odi de is oxidi zed by per oxi dase and bound t o t yr osyl r esi dues wit hi n t he
t hyr oglobul i n mol ecule i n a pr ocess cal led organi f i cat i on.
a. The synt hesi s begins wit h iodide bi ndi ng t o t yrosi ne, f ormi ng monoi odot yrosi ne
( MI T) .
b. MI T t hen binds anot her iodi de t o f orm di i odot yrosi ne ( DIT).
c. Then, slowly, a coupl i ng r eact ion bi nds MI T and DI T, pr oduci ng T3 and T4 .
C. Hormone transport
1. Af t er TSH st i mulat ion of t he t hyr oid gland, T3 and T4 ar e cleaved f rom
t hyr oglobul i n and released int o t he cir culat ion.
2. When in t he ci r culat ion, t hyr oi d hormone is t r anspor t ed bound t o sever al plasma
pr ot ei ns, a pr ocess t hat
a. Helps pr ot ect t he hormone f rom pr emat ur e met abol ism and excr et ion
b. Pr olongs it s half - l i f e i n t he ci r culat ion
c. Al lows t he t hyr oid hormone t o r each i t s sit e of act i on
3. Most t hyr oi d hor mone is t r anspor t ed by t hyroxine- bi ndi ng gl obul i n ( TBG) .
Preal bumi n and al bumi n also ser ve as car ri er s.
D. Hormone metabol i sm
1. Per ipher al conver si on of T4 t o T3 occur s i n t he pit uit ar y gland, l i ver , and ki dneys
and account s f or about 80% of T3 gener at i on.
2. Dei odi nat i on account s f or most hormone degradat ion. The maj or st eps in t his
pr ocess are shown in Figur e 55- 3.
3. Deiodi nat ed hormones are excr et ed in f eces and uri ne.
4. Minor nondei odi nat ion pat hways of met aboli sm incl ude conj ugat ion wit h sulf at e
and gl ucur onide, deaminat ion, and decar boxylat ion.

Figure 55-3. Thyroxine metabolism—major steps
in the primary and alternative deiodination
pathways.
P. 1201


E. Hormone f unct i on. Al t hough t he ef f ect s of t hyr oi d hormones ar e known, t he
basic mechanisms pr oduci ng t hese ef f ect s el ude pr ecise def ini t ion; however , t hey
seem t o act i vat e t he messenger RNA (mRNA) t r anscr i pt i on pr ocess and can promot e
pr ot ei n synt hesis or ( i n excessi ve amount s) pr ot ein cat abolism. Thyroi d hormones
af f ect t he f ol lowi ng:
1. Gr owt h and development
2. Calor igenics by i ncr easing t he r at e of basal met aboli sm
3. Car di ovascul ar syst em by incr easi ng t he met abol i c r at e, whi ch i ncr eases blood
f low, car di ac out put , and heart r at e (may be r el at ed i n par t t o an incr eased t issue
sensit i vit y t o cat echolami nes)
4. The cent ral ner vous syst em (CNS) by i ncr easing or dimi ni shi ng cer ebr at ion
5. Musculat ur e by causi ng a f i ne t remor
6. Sleep by i nduci ng f at i gued wakef ul ness wi t h hypert hyr oi dism or somnolence wi t h
hypot hyr oi di sm
7. Lipid met abolism by st imulat i ng l ipid mobi l i zat i on and degradat ion
F. Thyroi d f unct i on st udi es ( Table 55- 1)
1. Serum t otal t hyroxi ne (TT4 )
a. Thi s t est pr ovides t he most dir ect r ef lect ion of t hyr oid f unct i on by i ndi cat i ng
hormone avai labi l it y t o t issues. Tot al ( f r ee and bound) T4 is det ermined by
r adioi mmunoassay, which i s sensit i ve and r api d.
b. Changes in t hyr oi d globul i n concent r at ion, part icular ly TBG, whi ch i ncr eases
dur i ng pregnancy, alt er t he t ot al concent r at i on of T4 and may pr oduce a misleadi ng
high or low t est r esul t .
c. However , t hese changes i n TBG do not af f ect t he concent r at i on of f r ee T4 .
Ther ef or e, t o cl ar if y t hyr oid f unct ion, eit her pr ot ei n- bi ndi ng ( T3 upt ake t est ) or f r ee
T4 must be measur ed.
d. An elevat ed TT4 level i ndi cat es hyper t hyr oidism; a decr eased TT4 level,
hypot hyr oi di sm. However, t he TT4 l evel in a eut hyr oid pat ient can be alt er ed by
ot her f act or s, such as pr egnancy or f ebr i l e i l l nesses ( whi ch elevat e t he TT4 ) ,
nephr ot i c syndr ome or cir r hosis ( which lower it ) , and var i ous dr ugs ( Table 55- 2) .
2. Serum t otal t ri i odot hyroni ne (TT3)
a. Thi s sensit ive and highl y speci f ic t est measur es t ot al ( f r ee and bound) T3 .
b. Ser um T3 and T4 usual l y r ise and f al l t oget her; however , hyper t hyr oi dism
commonl y causes a di spr oport i onat e r ise i n T3 , and t he TT3 can r ise bef or e t he TT4
level . Ther ef or e, TT3 i s usef ul f or ear ly det ect i on or t o r ule out hyper t hyr oidism.
Many of t he sympt oms associ at ed wi t h hyper t hyr oidi sm ar e t he r esul t of t he
elevat ed TT3 .
c. Thi s t est may not be diagnost ical l y si gnif icant f or hypot hyr oidism, in whi ch TT3
level s may f al l but st ay wi t hi n t he normal r ange. The TT3 may be l ow i n onl y 50% of
pat ient s wit h hypot hyr oidism.
Table 55-1. Test Results in Thyroid Disorders
Thyroid Function Test Hypothyroidism Hyperthyroidism
Serum resin triiodothyronine
uptake (RT
3
U)
|
(< 35%)
|
(> 45%)
Serum total thyroxine (TT
4
)
|
(< 5 µg/dL)
|
(> 12 µg/dLl)
Serum total triiodothyronine
(TT
3
)
|
(< 80 ng/dL)
|
(> 180 ng/dLl)
Free thyroxine index (FTI)
|
(< 5.5)
|
(< 10.5)
Serum thyrotropin (TSH) assay
a

|
(> 4.5
µU/mL)
|
(· 0.4 µU/mL)
b

|
, increased levels;

|
, decreased levels.

a
In clinical practice the third-generation test is commonly used with
sensitivity to detect 0.01-0.02 mIU/L.

b
Fourth-generation assays detect 0.001-0.002 mIU/L.

P. 1202


P. 1203


Table 55-2. Effects of Drugs on Thyroid Function Tests
Drug
Serum
T
4

Resin
T
3

Uptak
e
Free
Thyroxin
e Index
Serum
T
3

Serum
TSH Comment
p-
Aminosalicylic
acid
| n/
d
| n/
d
|
a
Antithyroid
effect, rarely,
with long-
term use
Aminoglutethim
ide (Cytadren)
| n/
d
n/d n/
d
|

Amiodarone
b
| n/
d
n/d | |
q
Inhibits
peripheral
conversion of
T
4
to T
3

Anabolic
steroids and
androgens
| | 0 |
a
n/
d
Decreased
serum TBG
Antithyroid
drugs
(propylthiouraci
l or
methimazole)
| | | | 0
or
|
TSH may
increase if
patient
becomes
hypothyroid
Asparaginase
(Elspar)
| | n/d |
a
|
a
Decreased
serum TBG
Barbiturates |
c
n/
d
| n/
d
n/
d
Stimulates T
4

metabolism
Calcium
carbonate
d

| n/
d
n/d 0 | Subclinical
signs of
hypothyroidis
m; separate
time of
ingestion of
calcium and
levothyroxine
Ciprofloxacin
e
| n/
d
n/d | | Clinical signs
of
hypothyroidis
m; separate
administratio
n by 6 hr.
Contraceptives,
oral
| | 0 | 0 TBG usually
increased
Corticosteroids 0
or
|
0
or
|
0 or
|
| | Usual doses
decrease
TBG; high
doses may
increase TBG
Danazol
(Danocrine)
| | 0
p
| 0
or
|
Decreased
serum TBG
Estrogens and
SERMs
g

| | 0 | 0 Increased
serum TBG
Ethionamide
(Trecator-SC)
| n/
d
|
a
n/
d
|
a
Antithyroid
effect
Fluorouracil
(Adrucil)
| | n/d | 0 Patients
clinically
euthyroid;
TBG
increased
Heparin, IV |
h
0
or
|
a
0 n/
d
FTI is
increased
| with some
measures
Hypoglycemics
(sulfonylureas)
0
i
0
i
0
i
n/
d
n/
d

Iodides,
inorganic
0 0 0 n/
d
n/
d

Iodides, organic 0 0 0 n/
d
n/
d

Levodopa and
levodopacarbid
opa (Sinemet,
Parcopa)
0 0 0 0 |
j


Levothyroxine
(Levothroid,
Levoxyl,
Synthroid,
Unithroid)
|s
k
,
l

|
or
0
or
|
k
,
l

0 or
|
k
,
l

|
or
0
k
,
l

|
or
0
k


Liothyronine
(Cytomel)
|
k
0
or
|
k

|
k
|
or
|
k
,
l

0
k


Liotrix
(Thyrolar)
0
k

or
|s
0
k
0
k
0
k
,
l

0
k


Lithium
carbonate
(Eskalith,
Lithobid)
0
or
|
0
or
|
0 or
|
0
or
|
0
or
|

Methadone
(Dolophine)
|s | 0 | 0 Increased
serum TBG
Mitotane
(Lysodren)
| 0 0
a
n/
d
n/
d

Nitroprusside
(Nitropress)
| n/
d
n/d n/
d
n/
d
Clinical
hypothyroidis
m
Oxyphenbutazo
ne and
phenylbutazone
(Butazolidin)
0
or
|
| | n/
d
|
a
May compete
with T
4
for
TBG binding,
rarely, overt
hypothyroidis
m and goiter
may occur
Perphenazine
(Trilafon)
| | | | 0
a


Phenytoin
(Dilantin)
| 0
or
|s
0 or
|s
| 0 Stimulates T
4

metabolism
and may
compete with
T
4
for TBG
binding
Propranolol
(Inderal)
0
or
|
m

0
n
n/d |
o
0

Raloxifene
g

(Evista)
| | 0 | 0 Increased
serum TBG
Resorcinol
(excessive
topical use)
| | | | |

Salicylates
(large doses)
| |S |
a
| 0
a
Compete
with T
4
for
TBG binding
Tamoxifen
g
| | 0 | 0 Increased
serum TBG
a
Effect deduced, not based on reported clinical evidence.

b
Data from Rae P, Farrar J, Beckett G, Toft A. Assessment of thyroid status
in elderly people. Br Med J 1993;307:177-180.

c
Patients requiring thyroid-replacement therapy have decreased serum
thyroxine when barbiturates are given.

d
Data from Singh N, Singh P, Hershman JM. Effect of calcium carbonate on
the adsorption of levothyroxine. JAMA 2000;283:2822-2825.

e
Data from Cooper JG, HarboeK, Frost SK, Skadberg O. Ciprofloxacin
interacts with thyroid replacement therapy. Br Med J 2005;330:1002.

f
May increase slightly but usually remains in the normal range.

g
Data from Siraj ES, Gupta MK, Reddy SK. Raloxifene causing
malabsorption of levothyroxine. Arch Intern Med 2003;163:1367-1370.

h
T
4
assay by competitive protein binding is spuriously increased, but T
4

radioimmunoassay is probably not affected. Free thyroxine measured by
dialysis may be increased.

i
May occasionally decrease serum T
4
and increase resin T
3
uptake.

j
Slight decrease in euthyroid patients; but in long-standing hypothyroid
patients, levodopa considerably decreases the elevated TSH.

k
In a patient on adequate doses for thyroid replacement.

l
Increased T
4
, FTI, and T
3
tend to return to normal after several months of
therapy with levothyroxine. After liothyronine, T
3
may be elevated 2 hr after
a dose and depressed 24 hr after a dose.

m
Increased T
4
levels are reported in one study, but not in others.

n
With short-term propranolol in hyperthyroid patients.

o
In euthyroid patients, the decreased serum T
3
returns to normal with
continued propranolol therapy.

p
Free thyroxine index may increase slightly but usually remains in the
normal range.

q
Data from Batcher EL, Tang XT, Singh BN, et al. Thyroid Function
Abnormalities during Amiodarone Therapy for Persistent Atrial Fibrillation.
Am J Med 2007;120:880-885. FTI, free thyroxine index; IV, intravenous;
n/d, no data; s, slight effect; SC, subcutaneous; SERMs, selective estrogen
receptor modulators; T
3
, triiodothyronine; T
4
, thyroxine; TBG, thyroxine-
binding globulin; TSH, thyroid-stimulating hormone; 0, no effect; |.
increased; |. decreased.

P. 1204


d. If t her e i s an abnormal i t y i n bi ndi ng pr ot ei ns, t his t est can yiel d t he same
mi sl eadi ng r esul t s as t he TT4 r eadi ngs. Ot her f act or s af f ect ing t est r esul t s i ncl ude
pr egnancy ( which i ncr eases TT3 l evel s) , malnut r i t ion or hepat ic or r enal di sease
( which lower TT3 l evels) , or var ious dr ugs ( Table 55- 2) .
3. Resi n t ri i odot hyroni ne upt ake (RT3U)
a. Thi s t est cl ar i f ies whet her abnormal T4 levels ar e t he r esult of a t hyr oid di sor der
or t o abnormal it ies i n t he bi ndi ng pr ot eins because i t eval uat es t he bindi ng capaci t y
of TBG.
b. If an abnormal amount ( hi gh or l ow) of t hyr oid hormone is present in t he bl ood,
t he RT3 U r esul t s change i n t he same di rect i on as t he alt er ed level—el evat ed i n
hyper t hyr oidi sm, decreased in hypot hyr oidism.
c. However , if abnormali t ies i n bi ndi ng pr ot eins under l ie t he abnormal levels of TT4,
TT3 , or bot h, t he RT3 U r esult s change i n t he opposi t e di rect i on—decr easing as
TBG i ncr eases, incr easi ng as TBG decr eases.
d. Sever al dr ugs can cause spur ious changes in t he RT3U ( Table 55-2).
4. Serum t hyrot ropi n (TSH) assays
a. Thi s t est is t he most sensi t i ve t est f or det ect ing t he hypot hyr oid st at e because
t he hypot halamic- pi t uit ar y axis compensat es ver y qui ckly f or even sl ight decreases
i n cir cul at i ng f r ee hormone by r eleasi ng more TSH. The TSH l evel s may be el evat ed
even bef or e low cir cul at i ng levels of TT4 ar e det ect able by di agnost ic t est ing.
b. The ear ly TSH assay used r adioimmunoassay (RI A) met hodology. The sensit i vi t y
of t he assay has impr oved si nce, movi ng t o t he use of monocl onal ant ibodies i n t he
lat e 1980s. Nomencl at ur e est abl ished by t he Amer ican Thyr oid Associ at i on ( ATA)
has classif i ed t he impr ovement in sensit i vi t y based on t he lower l i mit of det ect i on.
The new classif i cat ion f ol l ows a gener at i onal f ormat , as shown in Table 55- 3.
c. The cur r ent (t hir d- gener at i on) ser um TSH assay ( level of det ect i on 0. 01- 0. 02
mI U/ L) uses monoclonal ant i bodies r ef er r ed t o as immunor adiomet r ic or
immunomet r ic ( I MA) met hodology ( i nst ead of t he older r adioimmunoassay
t echniques) and demonst rat es gr eat er sensi t i vit y i n t he det ect ion of t hyr oid disease
t han older t est s.
d. This assay is usual l y used t o di agnose t hyr oid disease and monit or pat ient s
r eceivi ng r eplacement t her apy t o cont r ol over t r eat ment . ( Over t r eat ment —TSH < 0. 4
mI U/ L—may cont r ibut e t o excessi ve bone deminer al i zat i on ( r educed bone densit y) ,
elect r ocar diogr am [ ECG] changes, at r ial f ibr i l lat ion, or el evat ion of li ver f unct i on
t est s. )
e. The I MA t echnique is ver y sensit i ve. The f our t h- gener at ion I MA can det ect TSH
level s i n t he r ange of 0. 001- 0. 002 mIU/ L.
f . The t hir d- gener at i on I MA assays may also det ect subcl i ni cal t hyr oid di sease ( TSH
= 0. 1-0. 45 mIU/ L). Tr eat ment of subcl i nical hypot hyr oidism is cont r oversial because
t her e i s i nsuf f ici ent evi dence t o indi cat e a benef i t .
g. TSH levels may also be i nf l uenced by psychi at ri c i l l ness. Some st udies of
hospit al i zed pat ient s have r eport ed abnor mal ly hi gh or low TSH levels in ot her wi se
eut hyr oi d pat i ent s. Cur r ent f i ndings i n HI V-posi t i ve pat i ent s ar e uncer t ain; however ,
aut oi mmune t hyr oid disease appears t o be mor e pr evalent i n t hese pat ient s.
h. Ef f ect s of dr ugs on t he serum TSH ar e shown i n Tables 55- 2 and 55- 4.
5. Free t hyroxi ne i ndex ( FTI )
a. Thi s i s not a separ at e t est but r at her an est imat ion of t he f r ee T4 level t hr ough a
mat hemat ical i nt er pr et at ion of t he r elat ionship bet ween RT3 U and ser um T4 l evel s.

Table 55-3. Serum Thyroid-Stimulating Hormone Assay Nomenclature
Generation Lower Level of Detection
First (RIA method) 1-2 mIU/L
Second 0.1-0.2 mIU/L
Third 0.01-0.02 mIU/L
Fourth 0.001-0.002 mIU/L

P. 1205


P. 1206


P. 1207


Table 55-4. Medications Influencing Thyroid-Stimulating Hormone (TSH)
Levels
Agent Mechanisms
Potential
Clinical
Thyroid
Effect(s)
Effect on
TSH
Effect on
Other
Thyroid
Function
Tests Comments
Amioda
rone
Iodine
effects
(see
Iodine
below)
Clinical
or
subclinic
al
hypothyr
oidism;
subclinic
al
hyperthy
roidism
infreque
ntly
Hypothy
roidism
is
usually
detected
during
the first
3
months
after
starting
therapy;
continue
to detect
patients
at 6
months.
Overt
hypothyr
oidism
(TSH
>10
µU/mL)
has been
observed
at 6
months.
Mild
elevatio
ns (TSH
4.5-
10µU/m
L) have
been
observed
at 12
months.
Incre
ased
total
T
4

level
s
The
large
iodine
load
with the
administ
ration of
amiodar
one is
the
primary
contribut
or to the
drug
interacti
on.
Regions
where
patients
have
adequate
intake of
iodine in
their diet
have
been
associate
d with
higher
rates of
hypothyr
oidism.
Biochem
ical
changes
in
thyroid
Subclini
cal
hyperthy
roidism
(TSH
·0.35µU
/mL) has
been
observed
occasion
ally
function
noted in
a
majority
of
patients
on
therapy,
requirin
g
frequent
monitori
ng

Direct
inhibition
of T
4
to T
3

conversio
n

Incre
ased
free
T
4

level
s


Direct
toxic
effects on
thyroid

Incre
ased
rever
se T
3

level
s


Induction
of thyroid
autoimmu
nity
Hyperth
yroidism

Decr
eased
total
and
free
T
3


Calciu
m
carbona
te
Adsorptio
n of
levothyrox
ine to
calcium in
acid
environme
nt
Subclini
cal
hypothyr
oidism
Elevatio
n
Decr
ease
free
T
4

and
total
T
4


Ciprofl
oxacin
Decreases
absorption
of
levothyrox
ine
Hypothy
roidism
Elevatio
n
Decr
eased
thyro
id
horm
one
level
s
Clinical
hypothyr
oidism
detected
Cortico
steroids
Central
suppressio
n of TSH
release
Minimal
or none
Suppress
ion
Usua
lly
withi
n
norm
al
range
,
altho
ugh
total
T
4
,
free
T
4
,
T
3

reduc
ed,
and
rever
se T
3

incre
ased
from
basel
ine
Compen
satory
mechani
sms lead
to
normaliz
ation of
TSH
levels
with
chronic
exposure

Reduction
of thyroid
iodine
uptake


Inhibition
of T
4
to T
3

conversio
n


Reduction
of
thyroidbin
ding
globulin
levels

Dopami
ne and
dopami
ne
agonists
Central
suppressio
n of TSH
release
Minimal
or none
Suppress
ion
Nor
mal
or
decre
ased
horm
one
level
s
Prolonge
d use of
dopamin
e in high
doses
may
potentiat
e the
low
thyroxin
e state of
critical
illness
Dopami
ne
antagon
ists
Release of
central
TSH
inhibition
Minimal
or none
Elevatio
n
Usua
lly
norm
al
Effects
not well
characte
rized
Iodine Inhibition
of iodine
uptake
and
organificat
ion
Clinical
or
subclinic
al
hypothyr
oidism
Elevatio
n
Decr
eased
thyro
id
horm
one
level
s
Clinical
hypothyr
oidism
most
common
in those
with
underlyi
ng
organific
ation
defects,
such as
autoimm
une
thyroidit
is or
previous
radioiodi
ne
therapy;
iodine-
induced
hyperthy
roidism
is
generall
y
confined
to those
with
iodine
deficien
cy or
autoimm
une
thyroid
disease

Impairme
nt of
thyroid
hormone


Inhibition
of T
4
to T
3

conversio
n
Hyperth
yroidism
Suppress
ion
Eleva
ted
thyro
id
horm
one
level
s


Induction
of thyroid
autoimmu
nity

Interfer
on
Unclear;
likely
owing to
Hypothy
roidism
(silent
Elevatio
n
Decr
eased
thyro
No
apparent
direct
immunom
odulating
properties
and
stimulatio
n of
autoimmu
nity
thyroiditi
s, Graves
disease)
id
horm
one
level
s
influenc
e on
TSH
secretion
:
pretreat
ment
detectabl
e
antimicr
osomal
antibodi
es may
represen
t a risk
factor
for
interfero
n-
induced
thyroid
disease

Hyperth
yroidism
(with or
without
autoantib
odies)
Suppress
ion
Incre
ased
thyro
id
horm
one
level
s

Lithium
salts
Inhibition
of
iodothyro
nine
biosynthes
is
Clinical
or
subclinic
al
hypothyr
oidism
Elevatio
n
Nor
mal
or
decre
ased
thyro
id
horm
one
level
s
Some
sources
recomm
end
thyroid
function
testing
at 6-
month
intervals
while on
therapy

Reduction
of thyroid
iodine
concentrat
ion


Suppressi
on of
thyroid
hormone
release


Induction
of thyroid
autoimmu
nity

Radiogr
aphic
contrast
media
Iodine
effects
(See
Iodine
above)
Minimal
or none
Elevatio
n
Nor
mal
or
decre
ased
thyro
id
horm
one
level
s
Alteratio
ns are
maximal
3-4 days
after
administ
ration
and may
persist
for up to
2 weeks

Direct
inhibition
of T
4
to T
3

conversio
n

Eleva
tion
of
rever
se T
3

level
s

Raloxif
ene
Malabsorp
tion;
mechanis
m
unknown
Hypothy
roidism
Elevatio
n
Decr
eased
thyro
id
horm
one
Clinical
hypothyr
oidism
detected
level
s
Somato
statin
and
analogs
Central
suppressio
n of TSH
release
Minimal
or none
Suppress
ion
Usua
lly
norm
al
Effects
not well
characte
rized
T
3
, triiodothyronine; T
4
, thyroxine.

P. 1208


b. FTI val ues ar e elevat ed i n hyper t hyr oi dism, when TBG is low, and decr eased i n
hypot hyr oi di sm, when TBG is el evat ed.
c. Ef f ect s of dr ugs on FTI ar e shown i n Tabl e 55- 2.
G. St rat egi es and cost consi derat i ons f or t est i ng
1. The most f requent l y used and l east expensi ve t est s f or scr eeni ng ar e t he TT4
and t he RT3 U, which ar e used t o calcul at e t he FTI . A ser um TSH assay may also be
used, but at an addit ional cost ( Figur e 55- 4) .
2. Thyr oi d disease scr eening f or t he ot her wise gener al l y healt hy populat ion has
been shown t o not be cost -ef f ect i ve based on t he rat e of det ect ion and cost
associ at ed wit h massi ve scr eeni ng. However , wit h i ncr eased use and impr ovement s
i n t echnol ogy, cost s have been f al l i ng ( Figur e 55-5) .
3. The most appr opr iat e target popul at i on f or screeni ng i ncl udes elder ly pat ient s
hospit al i zed f or exacer bat ions of chr onic di seases or who ar e coi ncident al l y
diagnosed wi t h a chr onic
P. 1209

disease—f or exampl e, congest ive hear t f ail ur e (CHF) , r heumat oi d art hr i t is—ment al
st at us changes, or psychosoci al pr oblems.

Figure 55-4. Algorithm for using a sensitive
thyroid-stimulating hormone (TSH) assay as a
single test of thyroid function. The algorithm
assumes a clinically intact hypothalamic-pituitary
axis, absence of medications known to influence
TSH or other thyroid indices, and generally good
physical and psychiatric health. The TSH assay
should meet the American Thyroid Association
criteria for a sensitive assay and/or have a known
functional sensitivity limit at the second-
generation (0.1 mIU/L) level or greater. Close
follow-up, clinical observation for signs and
symptoms of hyperthyroidism or hypothyroidism
and repeated TSH determinations at intervals of 6
to 12 months. T
3
, trirodothyronine; T
4
, thyroxine.

Figure 55-5. Algorithm for the use of sensitive
thyroid-stimulating hormone (TSH) testing in
patients with nonthyroidal illness (NTI). The TSH
assay should meet the American Thyroid
Association criteria for a sensitive assay and/or
have a known functional sensitivity limit at the
second-generation (0.1 mIU/L) level or greater.
Medications known to alter TSH levels (i.e.,
corticosteroids, dopamine) must be considered
when interpreting results.
4. The ATA r ecommends a f r ee t hyr oxi ne ( FT4 ) and a sensit i ve TSH assay as t he
pr imar y l abor at or y t est s f or diagnosi ng t hyroid di sease. The sensit ive TSH assay i s
usef ul i n det ect ing pat ient s at r isk of r ecei vi ng an excess amount of t hyr oxi ne as
r eplacement t herapy.
II. HYPOTHYROIDISM.
The i nabi l i t y of t he t hyr oi d gland t o supply suf f i ci ent t hyr oi d hor mone r esult s i n
var yi ng degr ees of hypot hyr oidism f r om mil d, cl i ni cal l y i nsi gnif icant f orms t o t he l if e-
t hr eat eni ng ext r eme, myxedema coma.
A. Classi f i cat i on
1. Pri mary hypot hyroi di sm i s t he r esul t of
a. Gl and dest r uct i on or dysf unct i on caused by disease or medical t her apies ( e. g. ,
r adiat i on, sur gical pr ocedur es)
b. Fai l ur e of t he gl and t o devel op or congenit al i ncompet ence ( i. e. , cret i ni sm)
2. Secondary hypot hyroi di sm is t he r esult of a pi t ui t ar y di sor der t hat i nhibi t s TSH
secret ion. The t hyr oid gl and i s normal but l acks appr opr iat e st imulat ion by TSH.
3. Tert iary hypot hyroi di sm ref er s t o a condit i on i n whi ch t he pit ui t ar y- t hyr oid axis
is int act , but t he hypot halamus lacks t he abi l it y t o secr et e TRH t o st imulat e t he
pit uit ar y.
4. Subcl i ni cal hypot hyroi di sm r ef er s t o pat ient s wit hout cl i nical sympt oms, a
normal FT4 , and el evat ed TSH levels. Cur r ent ly t her e i s i nsuf f icient evi dence t o
suppor t t r eat ment because consequences of nont reat ment ar e mini mal.
B. Causes
1. Hashi mot o t hyroi di ti s, which is a chr onic lymphocyt i c t hyr oi dit i s t hat is
consider ed t o be an aut oimmune di sor der
2. Treatment of hypert hyroi di sm, such as r adioact ive i odi ne t her apy, subt ot al
t hyr oi dect omy, or admi nist r at ion of ant it hyr oi d agent s
P. 1210


3. Surgi cal exci si on
4. Goit er (enl ar gement of t he t hyr oi d gland)
a. Endemi c goit er result s f rom i nadequat e int ake of diet ar y i odi ne. This i s common
i n r egi ons wit h iodine- deplet ed soi l and i n ar eas of endemi c malnut r i t ion.
b. Sporadi c goi ter can f ol low i ngest ion of cert ain dr ugs or f oods cont ai ni ng
progoi tri n ( L-5- vi nyl- 2- t hi ooxazol idone) , whi ch is inact ive and conver t ed by
hydr ol ysi s t o goit r i n.
( 1) Goit r ins inhibit oxi dat ion of iodi ne t o i odide and pr event iodide f r om bindi ng t o
t hyr oglobul i n, t her eby decr easi ng t hyr oi d hor mone product ion.
( 2) Pr ogoit r i n has been i solat ed in cabbage, kale, peanut s, br ussel s spr out s,
must ar d, r ut abaga, kohlr abi , spi nach, caul if l ower , and hor ser adish.
( 3) Goi trogeni c drugs i ncl ude pr opyl t hi our aci l ( PTU) , i odides, phenylbut azone,
cobalt , and l i t hi um.
c. Less common causes i ncl ude acut e ( usual l y t raumat ic) and subacut e t hyr oi di t is,
nodules, nodul ar goi t er , and t hyr oid cancer .
C. Si gns and sympt oms
1. Ear ly cl i nical f eat ur es t end t o be somewhat vague: l et har gy, f at igue,
f orget f ul ness, sensit i vi t y t o cold, unexpl ai ned wei ght gai n, and const i pat ion.
2. Pr ogr essi vel y, t he char act er ist ic f eat ur es of myxedema emer ge: dr y, f laky,
i nelast i c skin; coar se hair ; slowed speech and t hought ; hoar seness; puf f y f ace,
hands, and f eet ; eyel id dr oop; hear i ng loss; menor r hagia; decr eased l ibido; and
slow r et ur n of deep t endon r ef l exes ( especial l y i n t he Achi l l es t endon). If unt r eat ed,
myxedema coma wi l l develop.
D. Laborat ory f i ndi ngs ( Table 55- 1)
E. Treatment goal is r eplacement t her apy usi ng or al agent s ( Tabl e 55- 5) .
Table 55-5. Thyroid Replacement Preparations
Preparation
(Trade Names) Advantage Disadvantage Comments Source
Desiccated
thyroid
(Thyroid
USP,
Thyroid
Strong,
Armour
Thyroid,
Thyrar, S-P-
T)
Low cost Some
preparation
s have
unpredicta
ble results;
inconsisten
t T
3
:T
4

ratio T
3

increases
adverse
effects
Contains T
3
;
some brands
are
standardized
by iodine
content
a

Porcine
,
bovine,
or
ovine
thyroid
glands
Liothyronine
(Cytomel)
Predictabl
e results;
useful for
myxedema
crisis
Lacks T
4
Usually
reserved for
myxedema
crisis
Synthet
ic
Liotrix
(Thyrolar)
Standardiz
ed
formulatio
n
T
3

increases
adverse
effects;
expensive
Fixed T
3
:T
4

ratio of 1:4;
metabolism
of T
4
to T
3

renders T
3

component
unnecessary
Synthet
ic
Levothyroxi
ne
b

(Levothroid,
Synthroid,
Levoxyl,
Unithroid)
Predictabl
e results,
intravenou
s
preparatio
n available
Expensive Agent of
choice; does
not contain
T
3
; all
preparations
may be
interchangea
ble
Synthet
ic
a
Iodine content and T
3
:T
4
ratio vary with species.

b
Generic formulations manufactured by Pharmaceuticals Basics for Geneva
Generics and Rugby have been shown to be bioequivalent to Synthroid and
Levoxyl. (Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of
generic and brand-name levothyroxine products in the treatment of
hypothyroidism. JAMA 1997;277:1205-1213.) T
3
, triiodothyronine; T
4
,
thyroxine.

P. 1211


F. Therapeut i c agent s
1. Desi ccat ed t hyroi d preparat i ons
a. At one t ime t he agent of choice, desiccat ed t hyr oid ( Armour Thyr oi d) has f allen
out of f avor since st andar dized synt het ic levot hyr oxi ne pr epar at i ons have become
avai l able.
b. Desi ccat ed t hyr oid pr epar at i ons ar e not consider ed bioequi valent ; t hey have
evidenced var yi ng amount s of act i ve subst ances. Alt hough t hey met est abl ished
Uni t ed St at es Phar macopei a (USP) cr i t er i a f or iodi ne cont ent , var iat ion i n act ivit y
was not ed. The cont ent assay, whi l e speci f ic f or i odi ne, was unable t o specif y t he
r at io of T3 t o T4, and t his r at io var ies wi t h t he ani mal sour ce. Por ci ne gl and
pr epar at i ons have a higher T3 t o T4 rat io t han t hose f r om ovi ne and bovi ne sour ces.
2. Fi xed-rat i o l i ot ri x (Thyrolar) preparat i ons. I n an ef f or t t o st andar di ze t he T3 t o
T4 r at io, subst ances t hat mimi c glandul ar cont ent wer e developed. However, t he T3
component pr oved unnecessar y ( because T4 i s met abol i zed t o T3 ) and even
disadvant ageous because of T3 - induced adverse ef f ect s ( e. g. , t r emor, headache,
palpi t at i ons, diar r hea) .
3. Levot hyr oxi ne
a. Pr edict able r esul t s and lack of T3 - i nduced side ef f ect s have made levot hyr oxi ne
( Levot hr oid, Synt hr oid, Levoxyl) t he agent of choi ce.
b. The t hree maj or brands of levot hyr oxi ne pr epar at i ons ( Levot hr oid, Synt hr oid,
Levoxyl) have been compared f or bi oequi valence and wer e shown t o be equi valent
i n pat ient s wit h hypot hyr oidism.
c. Recent st udies i n pat i ent s wit h hypot hyr oidi sm have compar ed brand and gener ic
f ormulat i ons of l evot hyr oxi ne, which i ncl ude Synt hr oi d, Levoxyl, and gener ic
f ormulat i ons manuf act ur ed by Pharmaceut ical Basics and sold by Geneva Gener ic
and Rugby. Bioequi valence has been demonst r at ed wit h t hese f ormul at i ons.
However, when swit chi ng f ormulat ions, it is r ecommended t o moni t or t he pat ient
closely because t her e may be some indi vidual pat ient var i abi l it y among f ormul at i ons
( Figur e 55- 6) .

Figure 55-6. Algorithm for management of
patients on levothyroxine therapy. TSH, tyroid-
stimulating hormone.
P. 1212


d. The average adul t mai nt enance dose i s 75- 150 µg/ day. The dose r ange has
been shown t o be 1. 5- 1. 7 µg/ kg/ day or an aver age of 1. 6 µg/ kg/ day f or ot her wise
healt hy adul t s.
e. El derl y or chroni cal l y i l l pat i ent s r equi r e an aver age dose of 50- 100 µg/ day,
whi ch is 25- 50 µg/ day less t han ot herwise healt hy adult s of t he same height and
wei ght .
f . Thyr oxi ne levels r et ur n t o normal wi t hi n a f ew weeks. Cli nical impr ovement begins
i n 2 weeks wit h f ul l r esol ut ion of signs and sympt oms of hypot hyr oidism by 3- 6
mont hs of t her apy.
g. TSH levels begin t o decr ease af t er st art i ng t hyr oi d r epl acement . TSH remai ns
elevat ed f or some t ime af t er T4 level s r et ur n t o normal. Gener al l y, TSH l evels r et ur n
t o normal af t er a minimum of 6-8 weeks, but may cont i nue t o f all over 6- 12 mont hs
( Figur e 55- 6) .
G. Precaut i ons and moni t ori ng ef f ect s
1. Adult pat i ent s wit h a hist or y of cardiac disease and elder l y pat ient s should begi n
t her apy wit h lower doses ( e. g. , 25 µg/ day of levot hyr oxi ne) . Af t er 2- 4 weeks, t he
dose should be incr eased gr adual ly t o an indi vi dual l y adj ust ed maint enance dose
( usual l y < 100 µg dai l y) .
2. Pat i ent s should be obser ved on init iat ion of t her apy f or possi ble cardiac
compl i cat i ons, such as angi na, pal pi t at i ons, or ar r hyt hmi as.
3. Ser um t hyr oi d l evel s should be monit or ed, part icul ar l y T4 , sensit i ve TSH and
RT3 U l evel s, and t he FTI . Ser um t hyr oxi ne t est s remain el evat ed dur i ng t he f i r st f ew
mont hs of t r eat ment even wit h t he pr esence of cl i ni cal sympt oms. Ser um t hyr oxi ne
t est s do not pr edict t he cl i nical st at e. Test ing is unnecessar y unless noncompl i ance
is suspect ed.
4. It is r ecommended t o monit or t he sensi t ive TSH t est 2- 6 mont hs af t er t he last
dose change. However, t his t est cont inues t o change f or up t o 1 year . Test ing ear l y
may resul t i n over t r eat ment . Ref er t o Figur e 55- 6 f or t he management of pat ient s on
levot hyr oxi ne t her apy.
5. Levot hyr oxi ne admi nist r at ion, par t i cular l y long- t erm t herapy, can i nduce
t hyr ot oxicosis; T4 l evel s can r ise even t hough t he dosage r emai ns unchanged.
Moni t or f or cli nical si gns of t hyr oid di sease.
6. Accel erat ed bone l oss has been associ at ed wit h over t r eat ment . Pat ient s
r eceivi ng r eplacement t her apy wit h low TSH val ues may have l ower bone miner al
densit y because excess hormone accel er at es t he r at e of remodel i ng ( r at e of
r epor pt ion > r at e of f or mat ion) and may cont r ibut e t o an incr eased i ncidence of
nont r aumat ic f r act ur e.
7. Drug i nt eract i ons
a. Chol est yrami ne (Quest ran) and col est i pol (Col est i d) , bi le acid sequest r ant s,
can cont r ibut e t o a decr ease in t hyroxi ne bioavai labi l i t y when admi nist er ed
concomi t ant l y. Bi l e acid sequest rant s should be administ er ed at l east 6 hr af t er or al
t hyr oxi ne t o r educe t he pot ent ial f or t hi s cl i nical l y si gnif icant dr ug int er act ion.
b. Cal ci um carbonate (Os-Cal , Tums) can r educe t hyroxi ne bioavai l abi l it y by
adsorpt i on i n an acid envir onment . These should be administ er ed separ at ely t o
avoid i nt er act ion.
c. Estrogens (Est r ace, Pr emar i n) and sel ect ive est rogen recept or modul at or s
(SERMs) t amoxif en ( Nolvadex) or r aloxif ene (Evist a) may cont r i but e t o lower levels
of FT4 and el evat ed TSH l evel s, r equir i ng an i ncr ease in levot hyr oxi ne dose.
d. Ral oxif ene has been shown t o cause malabsorpt ion of l evot hyr oxi ne when co-
admi ni st er ed r esult i ng i n hypot hyr oi dism. Absor pt ion st udies demonst r at ed t hat
separat i ng admini st r at ion t imes by ~ 12 hr f or t he t wo medicat i ons pr event s t he
i nt er act i on.
e. Ci prof l oxaci n (Cipr o) has been r epor t ed t o i nt er act wit h l evot hyr oxi ne when
gi ven t oget her, r esult i ng i n elevat ed TSH and r educed FT4 and FT3 levels.
Administ r at ion of t he dr ugs separ at ely, wit h a 6- hr int er val, r esult ed i n r api d
normal i zat ion of t he t hyr oid f unct ion t est s.
H. Myxedema coma is a l if e- t hreat eni ng compl icat i on wit h a hi gh mor t al it y r at e.
1. It is most common in el der l y pat ient s wi t h pr eexi st i ng, alt hough usual l y
undiagnosed, hypot hyr oi dism.
2. Preci pi tat i ng f act ors i nclude alcohol, sedat ive, or nar cot i c use; over use of
ant it hyr oid agent s; abr upt discont i nuat i on of t hyr oi d hor mone t her apy; inf ect ion;
exposur e t o col d t emper at ur es; and iat rogeni c i nsult owi ng t o radi at i on t her apy or
t hyr oi d sur ger y.
P. 1213


3. The pat ient usual l y decl i nes f r om pr of ound let har gy t o coma, hypot hermia, and a
signi f icant decr ease in r espir at or y r at e, pot ent ial l y leadi ng t o r espi r at or y f ai l ur e as
t he cr i si s pr ogr esses. Hypomet aboli sm pr oduces a f luid and elect r olyt e imbalance
t hat leads t o f l ui d r et ent ion and hyponat r emia. Cardi ac eff ect s i ncl ude decr eased
hear t r at e and cont r act i l it y, decr easing car diac out put .
4. Treatment consist s of r api d r est or at ion of T3 and T4 level s t o normal.
a. A loadi ng dose of levot hyr oxi ne 400- 500 µg is gi ven as an i nt r avenous ( I V) bolus.
Liot hyr oni ne ( Cyt omel ) , 25 µg, i s t hen given or al l y ever y 6 hr .
b. Tr eat ment is cont i nued unt i l impr ovement is not ed. Then l i ot hyroni ne is
discont i nued, and levot hyr oxi ne is changed t o t he oral pr epar at ion. A mai nt enance
dose is t hen det ermi ned ( see I I . F. 3) .
III. HYPERTHYROIDISM
is t he over abundance of t hyroi d hormone. Thyrotoxi cosi s i s t he gener al t erm
appl i ed t o over act i vi t y of t he t hyr oi d gland.
A. Graves di sease ( dif f use toxi c goit er)
1. The most common f orm of hyper t hyr oidism, Gr aves disease occur s pr imar i l y, but
not excl usivel y, i n young women.
2. The basi s of t his disease is an aut oimmune disorder in which ant ibodies bi nd t o
and act i vat e TSH r ecept or s, r esult i ng i n t he over pr oduct ion of t hyr oid hor mone.
a. These ant ibodies ar e t ermed l ong-act i ng t hyroi d st imul at ors ( LATS) because
t heir dur at ion of act i on ext ends beyond t hat of TSH. As TSH is onl y mimicked, not
over abundant , nei t her t est ing f or TSH nor at t empt s t o inf l uence it ar e pr oduct i ve.
b. Ant ibody t it er s of t en ar e elevat ed i n pat i ent s wit h Gr aves disease.
3. Si gns and sympt oms char act er ist ic of Gr aves disease incl ude
a. Di f f usely enlar ged nont ender goit er
b. Ner vousness, ir r it abi l it y, anxiet y, and i nsomnia
c. Heat int oler ance and pr of use sweat ing
d. Wei ght loss despi t e i ncr eased appet it e
e. Tr emor and muscle weakness
f . Palpi t at i ons and t achycar di a
g. Exopht halmos, st ar e, and l i d l ag ( sl ow upper li d cl osi ng)
h. Di ar r hea
i . Thr i l l or br ui t over t he t hyr oid
j . Per ior bit al edema
B. Pl ummer di sease ( t oxi c nodul ar goi t er)
1. Thi s f orm of t hyrot oxi cosi s i s l ess common t han Gr aves di sease. It s under l yi ng
cause remai ns unknown, but it s inci dence is highest in pat ient s > 50 year s of age,
and i t ar i ses usual l y f r om a l ong- st andi ng nont oxi c goit er.
2. The t hyr ot oxicosis is a r esul t of one or mor e adenomat ous nodules aut onomousl y
secret ing excessi ve t hyr oi d hor mone, which suppr esses t he r est of t he gland.
Scanni ng conf i r ms t he diagnosis if i t i ndi cat es t hat act ivit y and iodi ne upt ake ar e
conf i ned t o t he nodul ar mass, unl ess TSH i s i nt r oduced.
3. Si gns and sympt oms are essent ial l y t he same as f or Gr aves disease except t hat
one or mor e nodular masses ar e f ound, r at her t han dif f use gl andular enlar gement ,
and opht halmopat hy is usual l y absent . Cardi ac abnormal i t i es ( e. g. , CHF,
t achyar r hyt hmias) ar e commonl y seen wi t h Plummer di sease.
C. Less common f orms of hypert hyroi di sm
1. Jodbasedow phenomenon is an over pr oduct ion of t hyr oid hor mone f oll owi ng a
sudden, lar ge incr ease in iodi ne i ngest ion—t hr ough eit her a sudden rever sal of an
iodi ne- def i cient di et or t he i nt r oduct i on of iodide or iodi ne i n cont rast agent s or
dr ugs ( e. g. , t he ant iar r hyt hmi c agent amiodar one).
P. 1214


2. Fact i t i ous hypert hyroi di sm occur s wit h abusi ve i ngest ion of t hyr oid- r eplacement
agent s, usual l y i n a mi sgui ded ef f or t t o lose wei ght . Di agnosi s i s aided by t he
absence of glandular swel l i ng and of exopht halmos and t he lack of aut oimmune
act ivit y f ound i n Graves disease.
3. Subcl i ni cal hypert hyroi di sm r ef ers t o pat ient s wit hout cl i nical sympt oms, a
normal FT4 and FT3 and TSH l evel s bel ow t he lower li mit s of normal ( <0. 4 mIU/ L) .
Cur r ent l y t her e is i nsuf f i ci ent evidence t o suppor t t r eat ment because consequences
of nont r eat ment are mi ni mal.
D. Laborat ory f i ndi ngs ( Table 55- 1)
E. Treatment goal . Sympt omat i c rel i ef i s pr ovided unt i l def i nit i ve t r eat ment can be
ef f ect ed.
F. Therapeut i c agent s
1. 8- Adr energic bl ocki ng agent s—pr opr anolol
a. Pr opr anolol ( I nder al) r educes some of t he per i pher al manif est at i ons ( e. g. ,
t achycar dia, sweat ing, sever e t r emor , ner vousness) of hyper t hyr oidism.
b. I n addi t ion t o pr ovidi ng sympt omat ic r el ief , propr anolol i nhi bi t s t he per ipher al
conver sion of T4 t o T3 .
2. Ant i t hyroi d agent s—propyl t hi ouraci l (PTU) and met himazol e (Tapazol e)
a. Act i on. These agent s may help at t ai n r emi ssion t hr ough dir ect int er f erence wit h
t hyr oi d hor mone synt hesi s. Bot h agent s inhi bi t iodide oxidat ion and iodot hiour aci l
coupl i ng. I n addit i on, PTU ( but not met hi mazol e) diminishes per i pher al deiodi nat ion
of T4 t o T3 .
b. Therapeut i c uses of t hese dr ugs incl ude
( 1) Def i ni t i ve t reatment in which r emission is achieved
( 2) Adj unct i ve therapy wit h r adioact ive iodine unt i l t he r adi at i on t akes ef f ect
( 3) Preoperati ve preparat i on t o est abl i sh and mai nt ai n a eut hyr oid st at e unt i l
def ini t i ve sur ger y can be perf ormed
c. Dosages
( 1) Propyl t hi ouraci l
(a) For adul t s, t he init ial dose i s 300- 450 µg/ day i n t hr ee divided doses ( i. e. , 100-
150 µg ever y 8 hr) . Adult pat ient s wit h sever e disease may r equir e as much as 600-
1200 µg/ day ini t ial l y.
( b) The i ni t ial dose i s cont inued f or about 2 mont hs; t hen a maint enance dose of
100- 150 µg/ day is given, as a si ngl e dose or divided i nt o t wo doses.
( c) Maint enance t her apy is cont inued f or approxi mat ely 1 year , t hen gradual l y
discont i nued over 1- 2 mont hs whi l e t he pat ient i s moni t or ed f or signs of r ecur rent
hyper t hyr oidi sm. The pat ient may r emain i n r emissi on f or sever al year s. A r ecur r ent
episode of hyper t hyr oidism is most l i kely t o occur wit hi n 3- 6 mont hs of dr ug
discont i nuat ion.
( d) I f hyper t hyr oi di sm r ecur s af t er dr ug t her apy is st opped, t he agent shoul d be
r est art ed and alt er nat ive t her apy should be consi der ed (e. g. , t hyr oid gl and abl at ion
or r emoval ) .
( 2) Met himazol e
(a) The i nit ial dose r ange is 5-60 µg/ day i n t hr ee di vi ded doses, dependi ng on
disease severi t y. Af t er 2 mont hs of t her apy, a maint enance dose of 5-30 µg/ day is
i ni t iat ed.
( b) Mai nt enance t her apy is cont i nued f or appr oxi mat ely 1 year at which t i me t he
dr ug i s gr adual l y discont i nued, usual l y over 1- 2 mont hs.
d. Precaut i ons and moni t ori ng ef f ect s
( 1) Ser um t hyr oi d l evels and t he FTI shoul d be moni t or ed f or a r et ur n t o normal.
( 2) Goit er si ze should decr ease wit h r educed hormone out put .
( 3) The i ncidence of adverse ef f ect s i s < 1% wi t h PTU and < 3% wit h met hi mazole.
The adver se ef f ect s ar e simi lar f or t he t wo agent s.
(a) The most bot her some are dermatol ogi c reacti ons ( e. g. , r ash, ur t i car ia,
pr ur it us, hai r loss, ski n pigment at i on) . Ot her s incl ude headache, dr owsi ness,
par est hesi a, nausea, vomit i ng, ver t i go, neur i t is, l oss of t ast e, ar t hr algia, and
myal gi a.
( b) Severe adverse ef f ect s—agr anulocyt osis, granul ocyt openi a, t hr ombocyt openia,
dr ug f ever , hepat i t is, and hypopr ot hr ombi nemia—occur l ess f requent l y. Pat i ent s
r eceivi ng met himazol e who ar e > 40 year s ol d and ar e r eceivi ng doses above 40
µg/ day ar e at i ncr eased r isk of devel opi ng agr anulocyt osis. Pat ient s r eceivi ng
P. 1215

PTU who are > 40 years old ar e at i ncr eased r isk of devel opi ng agr anulocyt osis, but
no dose associat ion has been est abl ished.
3. Radi oact i ve i odi ne (RAI )
a. Act i on. The t hyr oi d gland pi cks up t he r adioact i ve el ement i odi ne- 131 (
13 1
I ) as it
would r egular iodi ne. The r adi oact ivi t y subsequent ly dest r oys some of t he cel ls t hat
would ot her wi se concent r at e iodine and pr oduce T4 , t hus decr easi ng t hyr oid
hormone pr oduct ion.
b. Advantages
( 1) Hi gh cure rat e—almost 100% f or pat ient s wit h Gr aves disease and onl y sl ight l y
less f or pat ient s wit h Pl ummer disease
( 2) Avoi ds surgi cal ri sks—such as adverse r eact ion t o anest het ics,
hypopar at hyr oidism, ner ve pal sy, bleedi ng, and hoar seness
( 3) Less expensi ve—avoi ds cost of hospit al i zat ion
c. Di sadvantages
( 1) Ri sk of delayed hypot hyr oi dism
( 2) Sl ight , t hough undocument ed, r isk of genet i c damage
( 3) Mult iple doses, whi ch may be r equir ed, may delay t her apeut i c ef f i cacy f or a long
per iod (many mont hs or a year ).
d. Dosage. A dose of 80- 100 mCi of
1 3 1
I per est imat ed gram of t hyr oi d gland is
r ecommended. Some pr ot ocols use lower dosages, but t hese may be less ef f ect ive,
r equir i ng r et r eat ment . When t he dose is hi gher , t her e i s a pot ent i al r isk t hat
hypot hyr oi di sm wi l l devel op.
e. Precaut i ons and moni t ori ng ef f ect s
( 1) Radi oiodi ne t her apy gener al l y is r eser ved f or pat ient s past t he chi ldbear i ng
year s because ef f ect s on f ut ur e of f spr ing ar e not known.
( 2) Response t o
1 3 1
I is har d t o gauge, and pat i ent s must be monit or ed ear ly f or
r ecur rence of hyper t hyr oi dism, and lat er f or hypot hyr oi dism, which may develop
even 20 year s or more af t er t her apy.
4. Subt otal thyroi dect omy. Par t ial r emoval of t he t hyr oid gland may be i ndicat ed i f
dr ug t herapy f ails or r adioact ive i odi ne is undesir abl e. This is a di f f icul t pr ocedur e,
but t he success r at e is hi gh and t he cur e r apid. Risks incl ude t hose ment ioned i n
I I I . F. 3. b. (2), pr eci pit at ing t hyr oi d st orm, and per manent post operat ive
hypot hyr oi di sm. The r isk of i nduci ng t hyr oid st orm can be minimized by obt aini ng a
eut hyr oi d st at e t hr ough use of ant it hyr oid agent s ( see I I I . F. 2) or pr opr anol ol ( see
I I I . F. 1).
G. Compl i cat i ons
1. Hypot hyroi di sm may occur iat rogenical l y or , it has been pr oposed, as a nat ur al
sequel t o Gr aves di sease.
2. Thyroi d st orm (t hyrot oxi c cri si s) is a sudden exacer bat ion of hyper t hyr oidism
caused by r api d r elease ( l eakage) of t hyr oid hormone. I t is i nvar iabl y f at al if not
t r eat ed r apidl y. I n t hi s cr isis, unchecked hyper met abol ism leads ult i mat el y t o
dehydr at ion, shock, and deat h.
a. Preci pi tat i ng f act ors i nclude t hyr oid t r auma or sur ger y, RAI t her apy, inf ect i on,
and sudden discont i nuat ion of ant it hyr oid t her apy.
b. Charact eri st i cs. I t is char act er ized by a TT4 l evel of 25- 30 µg/ dl , r apidl y r ising
f ever , t achycar dia dispr opor t i onat e t o t he f ever , and unexpl ai ned, pr onounced
r est lessness and t r emor.
c. Treatment
( 1) PTU, i n doses of 150- 250 µg oral l y ever y 6 hr , i s t he pr ef er red agent because
PTU blocks per ipher al deiodi nat i on of T4 t o T3 , wher eas met hi mazol e does not .
However, i f necessar y, met hi mazol e, 15 mg or al l y ever y 6 hr , can be used inst ead.
( 2) Propranol ol , i n doses of 20- 200 mg or al l y ever y 6 hr or 1- 3 mg int r avenousl y
ever y 4- 6 hr , should be administ er ed unless cont rai ndi cat ed ( e. g. , if t he pat ient has
CHF) .
( 3) Potassi um i odi de, in doses of 50- 100 mg ever y 12 hr, i s given ( af t er PTU) t o
mi nimi ze i nt r at hyr oidal iodine upt ake.
( 4) Ot her suppor t i ve t her apy incl udes r ehydr at ion, cooli ng, ant ibiot ics, r est , and
sedat ion.
P. 1216


STUDY QUESTIONS
Di rect i ons f or quest i ons 1- 16: Each of t he quest i ons, st at ement s, or incompl et e
st at ement s i n t his sect ion can be corr ect ly answer ed or compl et ed by one of t he
suggest ed answers or phr ases. Choose t he best answer .
1. What i s t he correct f ormul a t o use f or cal cul at i ng t he f ree t hyroxi ne i ndex
( FTI ) ?
( A) T4 × RT3U/ mean ser um RT3U
(B) T3 × T3 / mean ser um RT3 U
(C) T3 × RT3U/ mean ser um RT3 U
(D) T4 × RT3U × mean ser um RT3 U
(E) T3 × RT3U × mean ser um RT3 U
View Answer 1. The answer i s A[ see I . F. 15] . 2. What i s t he necessary
precursor besi des di etary i odi ne requi red f or thyroxi ne bi osynt hesi s?
( A) t r i i odot hyroni ne ( T3 )
(B) t hr eonine
(C) t yr osine
(D) t hyr ot r opin ( t hyr oid- st imulat ing hor mone)
(E) t hyr oxi ne- bindi ng gl obul i n ( TBG)
View Answer 2. The answer i s C[ see] . 3. Al l of t he f ol l owi ng condi t i ons are
causes of hypert hyroi di sm except
( A) Gr aves disease.
(B) Hashimot o t hyroidit is.
(C) t oxic mult inodul ar goi t er .
(D) t r i i odot hyr oni ne t oxicosis.
(E) Pl ummer disease.
View Answer 3. The answer i s B[ seeand4. Whi ch of t he f ol l owi ng
preparat i ons i s used t o at tai n remi ssi on of t hyrot oxi cosi s?
( A) pr opranolol
(B) l i ot r i x
(C) levot hyr oxi ne
(D) propylt hiour aci l
(E) desiccat ed t hyr oid
View Answer 4. The answer i s D[ seeand] . 5. The thyroi d gl and normal l y
secret es whi ch of t he f ol l owi ng subst ances i nt o t he serum?
( A) t hyr ot r opin- r el easi ng hor mone ( TRH)
(B) t hyr ot r opin ( t hyr oid-st i mulat ing hor mone)
(C) di iodot hyr oni ne ( DI T)
(D) t hyr oglobul i n
(E) t hyr oxi ne ( T4 )
View Answer 5. The answer i s E[ see] . 6. Al l of t he f ol l owi ng condi t i ons are
causes of hypot hyroi di sm except
( A) endemic goit er.
(B) sur gical exci sion.
(C) Hashimot o t hyr oidit is.
(D) goit r i n- i nduced iodi ne def i ci ency.
(E) Gr aves disease.
View Answer 6. The answer i s E[ see] . 7. Common t est s to moni tor pat i ent s
recei vi ng repl acement t herapy f or hypot hyroi di sm i ncl ude al l of t he f ol l owi ng
except
( A) t hyr ot r opin ( TSH) st imul at ion t est .
(B) ser um TSH assay.
(C) f r ee t hyr oxi ne index ( FTI ) .
(D) r esin t r i i odot hyr oni ne upt ake (RT3 U) .
(E) t ot al t hyr oxi ne ( TT4 ) .
View Answer 7. The answer i s A[ see] . 8. Whi ch of t he f ol l owi ng pairs of
preparat i ons has been st udi ed f or bi oequi val ence?
( A) Levoxyl —Thyr ol ar
(B) t hyr ogl obul i n
(C) Levot hr oid—Synt hr oid
(D) Cyt omel—Synt hroid
(E) desiccat ed t hyr oid—Ar mour Thyr oi d
View Answer 8. The answer i s C[ seeand] . 9. The i nhi bi t i on of pi t ui tary
t hyrot ropi n secret i on i s cont rol l ed by whi ch of t he f ol l owi ng?
( A) f r ee t hyr oxi ne ( T4)
(B) t hyr oid- r eleasi ng hor mone ( TRH)
(C) f r ee t hyr oxi ne index ( FTI )
(D) r everse t r i i odot hyr oni ne ( r T3 )
(E) t ot al t hyr oxi ne ( TT4 )
View Answer 9. The answer i s A[ see] . 10. Whi ch of t he f ol l owi ng agent s
has been shown t o i nt eract wi t h oral t hyroxi ne (T4) repl acement t herapy?
( A) pr opylt hiour aci l
(B) cholest yr amine
(C) t hyr ot r opin
(D) levot hyr oxi ne
(E) lovast at i n
View Answer 10. The answer i s B[ see] . P. 1217


11. What l aborat ory t est s are current l y recommended by t he Ameri can Thyroi d
Associ at i on t o diagnose t hyr oi d di sease?
( A) resin t r i i odot hyr oni ne upt ake (RT3 U) and t ot al t hyr oxi ne ( TT4 )
(B) t hyr ot r opin ( TSH) and f r ee t hyr oxi ne i ndex ( FTI )
(C) t ot al t hyr oxi ne ( TT4 ) and sensi t i ve TSH assay
(D) f r ee T4 and sensit i ve TSH assay
(E) f r ee T4 and RT3 U
View Answer 11. The answer i s D[ see] . 12. What pat i ent popul at i on shoul d
be screened f or t hyroi d di sease?
( A) hospit al i zed pat i ent s
(B) el der ly pat ient s wi t h chr onic disease
(C) el der ly hospit al i zed pat i ent s
(D) coll ege st udent s
(E) women > 20 year s ol d
View Answer 12. The answer i s B[ see] . 13. What i s t he average
replacement dose of l evot hyroxi ne f or an ot herwi se heal t hy adul t ?
( A) 25- 50 µg/ day
(B) 50- 100 µg/ day
(C) 75- 150 µg/ day
(D) 100- 200 µg/ day
(E) 200- 400 µg/ day
View Answer 13. The answer i s C[ see] . 14. What f act ors af f ect t he opt imal
replacement dose of l evot hyroxi ne?
( A) age, height , and weight
(B) dur at ion of hypot hyr oidism
(C) pret r eat ment t hyr oi d- st imul at i ng hor mone ( TSH) l evel
(D) presence of chr onic i l l ness
(E) Al l of t he above
View Answer 14. The answer i s E[ see] . 15. Whi ch of t he val ues represent s
t he l ower l evel of det ect i on f or t he f ourt h- generat i on sensi t i ve TSH assay as
est abl i shed by t he Ameri can Thyroi d Associ at i on?
( A) 0. 5-5 mIU/ L
(B) 1- 2 mIU/ L
(C) 0. 01-0. 02 mIU/ L
(D) 0. 001- 0. 002 mIU/ L
(E) 0. 0001- 0. 0002 mI U/ L
View Answer 15. The answer i s D[ seeand] . 16. I n whi ch of t he f ol l owi ng
cl i ni cal present at i ons shoul d t he TSH assay be used?
( A) populat ion scr eeni ng f or t hyr oi d disease
(B) scr eeni ng hospi t al i zed pat ient s
(C) pat ient s r eceivi ng t hyroid r eplacement af t er 6- 8 weeks of t her apy
(D) pat ient s who ar e HIV posit i ve
(E) scr eeni ng pat i ent s wit h psychiat r ic i l l ness
View Answer 16. The answer i s C[ see] . Di rect i ons f or quest i on 17: The
quest ion i n t his sect ion can be cor r ect ly answer ed or compl et ed by one or more of
t he suggest ed answer s. Choose t he answer, A-E.
17. A 62- year- ol d woman wit h a 5-year hi st ory of wel l managed hypot hyroi di sm
was recentl y start ed on ral oxif ene 60 mg dai l y i n t he morni ng f or t he
prevent i on of postmenopausal ost eoporosi s. Her t hyroi d di sease had been wel l
cont rol l ed on 150 µg l evot hyroxi ne (Synt hroi d) dai l y i n t he morni ng. Her TSH
has remai ned wi t hi n t he normal range whi l e on treatment. Her most recent TSH
of 2. 5 mIU/ L and normal FT4 val ues where not ed l ast year. She present s t oday
wi t h an el evat ed TSH 15. 5 mIU/ L af t er 4 mont hs of ral oxif ene t herapy and
sympt oms of hypot hyroi di sm. What change i n therapy woul d be best f or t hi s
pat i ent ?
( I ) repeat t he TSH t est and FT4 Test s
( I I ) i ncrease t he dose of l evot hyroxi ne t o 200 µg dai l y
( I I I ) swi t ch t he dosi ng of t he ral oxif ene t o t he eveni ng
A if I onl y is corr ect
B if I I I onl y i s corr ect
C if I and I I ar e corr ect
D if I I and I I I ar e cor r ect
E if I , I I , and I I I are corr ect
View Answer 17. The answer i s B( I I I) [ seeand] . P. 1218


Di rect i ons f or quest i on 18: The quest ion i n t his sect i on can be corr ect l y answer ed
by one of t he suggest ed answer s. Choose t he best answer .
18. A 69- year- ol d woman wit h hypertensi on and hypot hyroi di sm i s bei ng
t reat ed for a wound i nf ect i on. I n t he past, she was mai ntai ned on 125 µg
l evot hyroxi ne ( Levoxyl ) dai l y wi t h a normal TSH of 2. 0 mIU/ L. Af t er 6 weeks of
t reatment wi t h oral ci prof l oxaci n (500 mg twi ce a day) she complai ns of f at i gue
and sensi t i vi t y t o col d. Her serum TSH l evel was 14 mI U/ L and FT4 was bel ow
normal . What i s t he best management f or t hi s pat i ent .
( A) incr ease t he dose of levot hyr oxi ne
(B) swit ch t he pat ient f r om Levoxyl t o Synt hr oi d
(C) di scont i nue levot hyr oxi ne unt i l t he wound i s healed
(D) cont inue t her apy wit hout any changes
(E) separ at e t he admini st r at ion of cipr of l oxaci n and levot hyr oxi ne by at l east 6 hr
View Answer 18. The answer i s E[ seeandDi rect i ons f or questi on 19: The
quest ions i n t hi s sect i on can be corr ect l y answer ed or complet ed by one or more of
t he suggest ed answer s. Choose t he answer, A-E.
19. Whi ch of t he f ol l owi ng agent s have been shown to i nt eract wit h oral
t hyroxi ne (T4) replacement t herapy?
( I ) at enol ol
( I I ) cal ci um carbonat e
( I I I ) ci prof l oxaci n
( I V) l evot hyroxi ne
(V) ral oxi f ene
A if I onl y is corr ect
B if I V onl y i s corr ect
C if I and IV ar e cor rect
D if I , I I , I I I , and I V ar e corr ect
E if I I , I I I , and V ar e cor r ect
View Answer 19. The answer i s E( I , I I I , V) [ seeand] . 20. What i s t he ef f ect
of ami odarone t herapy on t hyroi d f unct i on?
( A) Pat ient s wi t h under l yi ng t hyr oi d dysf unct ion ar e at an incr ease r i sk of
developi ng hypot hyr oi dism wi t hi n 6 mont hs of t her apy
(B) Pat ient s wi t hout under l yi ng t hyr oid dysf unct i on r out i nel y devel op subcl i nical
hyper t hyr oidi sm wi t h amiodar one t herapy
(C) Amiodar one i nt er act s di r ect ly wi t h cir cul at i ng ser um t hyr ot r opi n
(D) Amiodar one has no ef f ect on t hyr oid f unct i on.
(E) None of t he above
View Answer 20. The answer i s A[ and] . P. 1219


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see I . F. 15] .
The FTI is a mat hemat ical i nt er pret at ion of t he r elat ionshi p bet ween t he r RT3 U and
T4 levels, compar ed t o t he mean populat ion val ue f or RT3 U. The FTI is cal culat ed
usi ng r eport ed val ues f or TT4 and RT3 U. The nor mal FTI val ue i n eut hyr oid pat i ent s
is 5. 5- 12.
2. The answer i s C [ see I . B] .
Biosynt hesis of t hyr oid hor mones begi ns wit h i odi de bi ndi ng t o t yr osine, which f orms
MI T. MI T bi nds anot her iodi de at om t o f or m DI T. When MI T and DI T are f ormed, a
coupl i ng r eact ion occur s, whi ch pr oduces T3 , T4 , rever se t r i iodot hyr oni ne ( r T3) , and
ot her by-pr oduct s.
3. The answer i s B [ see I I . B. 1; I I I . A and B]
Hashi mot o t hyr oidi t is ( chr onic l ymphocyt ic t hyr oidi t is) is a cause of hypot hyr oi dism.
The i nci dence of Hashi mot o t hyr oi di t is is 1%- 2%, and i t i ncr eases wi t h age. I t i s
mor e common in women t han i n men and mor e common in whi t es t han i n bl acks.
Ther e may be a f amil ial t endency. Pat ient s wi t h Hashimot o t hyr oi di t is have el evat ed
t it er s of ant i bodies t o t hyr oglobul i n: A t i t er < 1: 32 is seen i n > 85% of pat ient s. Two
var iant s of Hashi mot o t hyr oidi t is have been described: gl and f i br osi s and idiopat hi c
t hyr oi d at r ophy, which is most l ikely an ext ension of Hashimot o t hyroidit is.
4. The answer i s D [ see I I I . F. 1 and 2] .
I n hyper t hyr oi d pat i ent s, r emission of t hyr ot oxicosis is achieved wi t h PTU by t wo
mechanisms: ( 1) i nt er f er ence of iodi nat i on of t he t yr osyl r esidues, ul t imat ely
r educi ng pr oduct ion of T4 and ( 2) i nhi bit i on of peripher al conver sion of T4 t o T3 .
Pr opr anol ol is commonl y used as an adj unct t o PTU f or sympt omat ic management of
hyper t hyr oidi sm.
5. The answer i s E [ see I . A. 1] .
The maj or compounds secr et ed by t he t hyr oid gl and, af t er it s st imul at i on by
t hyr ot r opi n, are T3 and T4 . When r el eased f r om t he t hyr oid, T3 and T4 ar e
t r anspor t ed by pl asma pr ot eins—namel y TBG, t hyr oxi ne- bi ndi ng pr ealbumin, and
albumin.
6. The answer i s E [ see I I . B; I I I . A. 1] .
Gr aves di sease ( dif f use t oxic goit er ) is t he most common f orm of hyper t hyr oi dism. It
occur s most of t en i n women i n t he 3r d and 4t h decades of lif e. There is a genet ic
and f amil i al pr edisposit ion. The cause is l i nked t o an aut oi mmune r eact ion bet ween
immunoglobul i n G ( I gG) and t he t hyr oi d.
7. The answer i s A [ see I I . G. 3] .
The TSH st imul at i on t est measur es t hyr oi d t issue r esponse t o exogenous TSH. I t i s
not commonl y used t o monit or t hyr oid-r epl acement t her apy. I t may be usef ul i n t he
i ni t ial di agnosi s of hypot hyr oidism.
8. The answer i s C [ see I I . F. 3. b and c] .
Many br ands of levot hyr oxi ne ar e cur r ent ly avai labl e. Bot h gener ic and t rade name
pr epar at i ons have been st udied, wi t h an emphasi s on Levot hr oid and Synt hr oid. The
import ance of bi oequival ence becomes appar ent when pat i ent s have r eceived
dif f er ent br ands of levot hyr oxi ne and have exhi bi t ed changes in t her apeut ic
r esponse t o equival ent r eplacement doses.
9. The answer i s A [ see I . A. 3. a] .
An i ncr ease in t he blood level of t hyr oid hormone ( see cir culat i ng f ree T4 and f r ee
T3 ) signal s t he pi t ui t ar y t o st op r eleasi ng TSH. The f r ee f r act ion of T4 i s avai l able t o
bi nd at t he pit uit ar y r ecept ors.
10. The answer i s B [ see I I . G. 7] .
Eut hyr oid pat ient s r eceivi ng or al r eplacement t herapy have become hypot hyr oid
af t er concomit ant admi nist r at ion of bi le acid sequest r ant t her apy. I t appears t hat
bioavai l abi l it y is r educed as a r esult of administ er i ng t hese agent s at cl ose dosi ng
i nt er vals. I t is r ecommended t hat at least 6 hr pass bef or e admi nist r at ion of a bi l e
acid sequest r ant . I t would be pr ef er able t o select anot her nonbi le acid sequest r ant
when cl i nical l y possible.
11. The answer i s D [ see I. G. 4] .
The f ree T4 and t he ( t hi r d- gener at ion) TSH assay should be used onl y f or t he
diagnosis of pat ient s most l ikel y t o have t hyr oid disease based on cl i ni cal
pr esent at ion and r elat i ve r isk ( e. g. , age, sex, f ami l y hist or y) , not f or popul at ion
scr eeni ng. The t hir d- gener at ion TSH assay is also mor e commonly used t o monit or
r eplacement t herapy and t o minimize over t r eat ment and t he corr espondi ng r i sk of
acceler at ed bone loss.
P. 1220


12. The answer i s B [ see I. G. 3] .
Cost ver sus benef i t is cr it ical t o t he decisi on of choosi ng t o scr een ent ir e
populat i ons. Because t he f r equency of det ect ion has been proven t o be higher i n
elder l y pat ient s ( 2%- 5%) wit h chr onic di sease, t he relat i ve minor cost s associat ed
t o obt ain RT3 U and TT4 t o calcul at e a FTI ar e wort h t he cost . A ser um TSH assay
can be r eser ved f or pat ient s wi t h an abnormal FTI . Anot her consi der at i on is t o use
t he sensit i ve TSH assay f or di agnosi s i n place of t he ser um TSH assay at a higher
cost but wit hout t he necessit y of r et est ing. I f pat ient s admit t ed t o t he hospit al f or an
acut e il l ness wer e scr eened and t he result s wer e mi sl eadi ng, t hey may be
pr escr ibed inappr opr iat e t her apy because acut e il l ness may be associat ed wit h t he
t empor ar y ef f ect s causing abnormal t est r esult s.
13. The answer i s C [ see I I . F. 3. d] .
The aver age adult maint enance dose i s 75-150 µg/ day, which has been shown t o be
1. 5- 1. 7 µg/ kg/ day. The dose is usual l y adj ust ed i n i ncr ement s of 25- 50 µg/ day ever y
4 weeks. The t ot al dai l y dose used t o be 100-200 µg/ day, which r esul t ed in
over t reat ment af t er t he i nt r oduct ion of t he sensi t i ve TSH assay. Elder ly or
chr onical l y i l l pat i ent s r equi r e an aver age dose of 50- 100 µg/ day, which is 25- 50
µg/ day l ess t han ot her wi se heal t hy adult s of t he same height and wei ght .
14. The answer i s E [ see I I . F. 3. e] .
Elder ly or chr onical l y i l l pat ient s r equir e an aver age dose of 50- 100 µg/ day, whi ch is
25- 50 µg/ day less t han ot her wi se heal t hy adult s of t he same height and weight .
Because t he aver age dose f or r eplacement t her apy is bet ween 1. 5 and 1. 7
µg/ kg/ day, wei ght af f ect s t he t ot al dai l y dose.
15. The answer i s D [ see I. F. 4. e and f ] .
The Amer ican Thyr oid Associ at i on has est abl ished st andar d nomenclat ur e t hat
i ndicat es each t echnological improvement and t he abi l it y t o det ect l ower levels of
TSH usi ng monoclonal ant i bodi es. As t he sensit i vi t y of t he assay i mpr oves, t he
lower level of det ect ion is r epor t ed as a r ange in mil l i - I nt er nat i onal Uni t s per l it er .
The most sensit i ve t est is cur rent l y t he f our t h- gener at i on I MA, wit h a repor t ed lower
level of det ect ion of 0. 001-0. 002 mIU/ L. I n usual cl i nical pr act ice t he t hir d-
gener at i on I MA is most commonl y used, wit h sensi t i vit y in t he r ange of 0. 01- 0. 02
mI U/ L.
16. The answer i s C [ see I. F. 4. g; I I . 6; Figur e 55-6] .
The cur r ent t hi r d- gener at ion TSH assay is not i ndicat ed f or use in hospit al i zed
pat ient s who are not suspect ed t o have t hyr oi d di sease. St udi es have i ndicat ed t hat
abnormall y high or low TSH levels ar e det ect ed in eut hyr oi d hospi t al ized pat ient s.
Psychi at r ic i l l ness may also i nf l uence TSH l evel s.
17. The answer i s B (I I I ) [ see I I . G. 7; Tables 55- 2 and 55- 4] .
The pat i ent is most l i kely exper ienci ng a drug int er act i on bet ween r al oxif ene and
levot hyr oxi ne. The best choice is t o separ at e t he medicat ions by at l east 12 hr. A
r epeat of t he TSH assay wil l onl y conf ir m t he r esult s, which ar e si gnif icant l y
elevat ed. I ncr easi ng t he dose of levot hyr oxi ne may r esult i n over t r eat ment .
18. The answer i s E [ see I I . G. 7; Tables 55- 2 and 55- 4]
Thi s pat ient i s most l ikel y exper i enci ng a dr ug int er act ion bet ween l evot hyroxi ne
and cipr of l oxaci n when t aken concomit ant l y. Ther e i s no benef it t o swit chi ng t o
anot her br and of l evot hyr oxi ne or incr easi ng t he dose. The best solut ion is t o
separat e t he doses of cipr of loxaci n by 6 hr .
19. The answer i s E (I , I I I , V) [ see I I . G. 7; Tables 55- 2 and 55-4] .
Pat i ent s r ecei vi ng or al r eplacement t her apy who t ake calci um car bonat e
concomi t ant l y have been shown t o exper ience decr eased f r ee T4 and t ot al T4 l evel s
t hat r esult ed in an elevat ed TSH. The mechani sm appear s t o be adsor pt i on of
levot hyr oxi ne t o cal ci um car bonat e at acid pH level s, whi ch may r educe
bioavai l abi l it y. I t i s r ecommended t o separ at e t he t ime of ingest i on of each pr oduct
t o r educe t he chance of t hi s i nt er act ion. Cipr of l oxaci n and Raloxi f ene have al so
been shown t o int er act wit h levot hyr oxi ne when admi ni st er ed t oget her. Separat e
admi ni st r at ion t i mes by 6 hr f or cipr of l oxacin and by 12 hr f or r aloxi f ene.
20. The answer i s A [ Tables 55-2 and 55- 4] .
Pat i ent s r ecei vi ng amiodar one t her apy ar e at r i sk of developi ng hypot hyr oidism
especi al l y i f t her e is under lyi ng t hyr oid di sease. Amiodar one del i ver s hi gh levels of
iodi ne t o t he syst em cont r ibut i ng t o subcl i nical or cl i nical hypot hyr oidi sm mor e
of t en. Subcl i nical hyper t hyr oi dism has been observed r ar ely. Some pat ient s wit hout
under l yi ng t hyr oid disease may exper ience changes i n t hyr oid f unct ion whi l e
pat ient s wit h under l yi ng disease ar e mor e l ikel y t o pr esent wit h hypot hyr oidism.
Pat i ent s should be monit or ed cl osel y f or t hyr oid f unct ion when beginni ng
amiodar one t her apy.

56
Renal Failure
Andrew L. Wi l son
I. ACUTE RENAL FAI LURE
A. Def i ni t i on. Acut e r enal f ai l ur e ( ARF) is t he sudden, pot ent ial l y r ever si bl e
i nt er r upt ion of kidney f unct i on, r esult i ng i n r et ent i on of nit r ogenous wast e pr oduct s
i n body f lui ds.
B. Classi f i cat i on and et i ol ogy. ARF is classif i ed accor di ng t o it s cause.
1. Prerenal ARF st ems f r om impair ed renal per f usion, which may r esul t f r om:
a. Reduced art er ial blood vol ume [ e. g. , dehydrat i on, hemor r hage, vomi t ing,
diar r hea, ot her gast r oint est inal ( GI ) f luid loss]
b. Ur i nar y l osses f r om excessi ve di ur esis
c. Decreased car diac out put [ e. g. , f r om congest ive heart f ai l ur e (CHF) or per i car dial
t amponade]
d. Renal vascul ar obst r uct i on ( e. g. , st enosi s)
e. Sever e hypot ension
2. I nt rarenal ARF ( i nt ri nsi c or parenchymal ARF) r ef l ect s st ruct ur al kidney
damage r esult i ng f r om any of t he f ol lowi ng condit i ons.
a. Acut e t ubul ar necrosi s ( ATN), t he leadi ng cause of ARF, may be associ at ed
wit h:
( 1) Exposur e t o nephr ot oxic aminogl ycosi des, anest het ics, pest icides, or ganic
met als, and r adi opaque cont r ast mat er i als
( 2) I schemi c i nj ur y ( e. g. , sur ger y, ci r culat or y col l apse, sever e hypot ension)
( 3) Pi gment ( e. g. , hemol ysis, myoglobi nur i a)
b. Acut e glomer ulonephr i t is
c. Tubul ar obst r uct i on, as f r om hemol yt i c r eact ions or ur i c aci d cr yst als
d. Acut e i nf l ammat i on ( e. g. , acut e t ubuloi nt er st it i al nephr i t is, papi l lar y necr osi s)
e. Renal vascul it is
f . Mal i gnant hyper t ension
g. Radi at i on nephr it is
3. Post renal ARF r esult s f r om obst r uct i on of ur i ne f low anywher e along t he ur i nar y
t r act . Causes of post r enal ARF i ncl ude:
a. Ur et er al obst r uct ion, as f r om cal cul i, ur ic aci d cr yst als, or t hr ombi
b. Bl adder obst r uct ion, as f r om calcul i , t hr ombi , t umor s, or inf ect ion
c. Ur et hr al obst r uct ion, as f r om st r ict ur es, t umors, or prost at ic hyper t r ophy
d. Ext r i nsic obst ruct ion, as f rom hemat oma, inf lammat or y bowel disease, or
acci dent al sur gical l igat i on
C. Pat hophysi ol ogy. ARF pr ogresses in t hr ee phases.
1. I ni t i at i ng phase
a. The i nit iat i ng phase i s def i ned as t he t ime bet ween t he renal i nsult and t he poi nt
at which ext r ar enal f act ors no longer rever se t he damage caused by t he obst r uct ion
or ot her cause of ARF. This phase may not be wel l- def i ned cl i ni cal l y and may
escape not ice or diagnosis.
b. Uri ne out put may drop markedly t o 400 mL/ day or l ess ( ol i guri a). I n some
pat ient s, uri ne out put f all s bel ow 100 mL/ day (anuri a). Oligur ia may l ast only hour s
or as l ong as 4- 6 weeks. However , i t has been shown t hat 40%- 50% of ARF pat i ent s
ar e not ol igur ic or anur i c.
c. Ni t rogenous wast e product s accumulat e i n t he blood.
( 1) Azot emia r ef lect s ur ea accumulat ion due t o impair ed glomer ul ar f i lt r at ion and
concent r at ing capacit y.
( 2) Ser um cr eat i ni ne concent r at ion, sul f at e, phosphat e, and or ganic acid levels
cl i mb r api dl y.
d. The serum sodi um concent rat i on f al ls below normal f rom i nt r acel l ular f luid
shif t i ng and di l ut ion.
P. 1222


e. Hyperkal emia occurs due t o t he accumulat i on of or ganic acids (met abol ic
acidosis) . I f pot assium int ake is not rest r i ct ed or body pot assi um i s not removed,
hyperkalemi a r esult s. Wit hout t r eat ment , hyperkal emia may lead t o neur omuscular
depr ession and par al ysis, i mpai r ed car di ac conduct i on, arr hyt hmi as, r espir at or y
muscl e par alysi s, cardiac ar r est , and ult i mat ely deat h.
2. Mai nt enance phase
a. Thi s phase begins when ur i ne out put r i ses above 500 mL/ day—t ypical l y af t er
sever al days of ol igur ia. A r i se in ur i ne out put or a “di ur et ic r esponse” may not be
seen i n non- ol igur i c pat i ent s. I ncr eased ur inar y out put does not si gnal r ecover y of
r enal f unct i on.
b. Ur i ne out put r i ses i n i ncr ement s of sever al mil l i l i t er s t o 300- 500 mL/ day. Ur ine
out put may doubl e f r om day t o day in t he i ni t ial r ecover y per i od.
c. Azot emi a and associat ed labor at or y f indi ngs may per sist unt i l ur i ne out put
r eaches 1000- 2000 mL/ day.
d. The mai nt enance phase car r i es a r isk of f luid and elect r olyt e abnormal it ies, GI
bleedi ng, i nf ect ion, and r espi r at or y f ai l ur e.
3. Recovery phase. Dur i ng t he r ecover y phase, renal f unct ion gr adual l y r et ur ns t o
normal. Most r ecover ed r enal f unct ion appears i n t he f ir st 2 weeks; however ,
r ecover y of r enal f unct ion may cont inue f or a year. Residual impair ment may per si st
i ndef i ni t el y.
D. Cl i ni cal eval uat i on
1. Physi cal f i ndi ngs. I nit ial l y, ARF causes azot emia and, in 50%-60% of cases,
ol i gur ia. Lat er, elect r olyt e abnormal it ies and ot her sever e syst emi c ef f ect s occur .
a. Uri ne out put t ypi cal l y i s l ow, f r om 20- 500 mL/ day. Complet e anur ia is r ar e.
b. Si gns and sympt oms of hyperkal emi a, r esult i ng f r om met abol ic acidosis and
r educed pot assium excr et ion by impair ed kidneys, i ncl ude:
( 1) Neur omuscular depr essi on ( e. g. , par est hesi as, muscle weakness, par al ysis)
( 2) Di ar r hea and abdomi nal dist ent ion
( 3) Sl ow or ir r egular pulse
( 4) El ect rocar di ogr aphic changes wi t h pot ent ial car di ac ar r est
c. Uremia, caused by excessi ve nit r ogenous wast e ret ent ion, leads t o nausea,
vomi t ing, diar r hea, edema, conf usion, f at igue, neur omuscul ar i r r it abi l it y, and coma.
d. Metabol i c aci dosi s, a common compl icat i on of ARF, is evidenced by:
( 1) Det er i or at ion of ment al st at us, obt undat i on, coma, and l et har gy
( 2) Depr essed car diac cont r act i l it y and decr eased vascul ar r esi st ance, leadi ng t o
hypot ensi on, pulmonar y edema, and vent r i cular f ibr i l lat ion
( 3) Nausea and vomit i ng
( 4) Respir at or y abnormal it i es ( e. g. , hyper vent i lat i on, Kussmaul' s r espir at ion)
e. Hyperphosphat emia ar i ses f rom decr eased phosphat e excr et ion. I t is gener al l y
not seen in ARF.
( 1) As ser um phosphat e r i ses, hypocalcemi a r esul t s f r om t he f ormat i on of i nsol uble
calci um phosphat e compl exes.
( 2) The si gns and sympt oms r elat e t o r esult ant hypocalcemia and met ast at ic sof t -
t issue cal ci f icat i on.
( 3) Manif est at i ons of hypocalcemia incl ude:
(a) Neur omuscular ir r i t abi l i t y, cr amps, spasms, and t et any
( b) Hypot ension
( c) Sof t -t i ssue cal cif icat ion
( d) Ment al st at us changes ( e. g. , conf usi on, mood changes, l oss of i nt el lect and
memor y)
( e) Hyper act i ve deep-t endon r ef l exes and Tr ousseau' s and Chvost ek' s si gns
(f ) Abdomi nal cr amps
( g) St r i dor and dyspnea
f . Hyponatremia result s f r om dil ut i on and i nt r avascular f luid shif t s dur ing t he
di ur et i c phase of ARF. Physi cal f i ndi ngs i ncl ude l et har gy, weakness, seizur es,
cognit i ve impairment , and possi ble r educt i on in level of consciousness.
g. I nt ravascul ar vol ume depl et i on, suggest ing prerenal fai l ure, may cause:
( 1) Flat j ugul ar venous pulses when t he pat i ent l i es supi ne
( 2) Ort host at ic changes in bl ood pr essur e and pul se
( 3) Poor skin t ur gor and dr y mucous membr anes
P. 1223


h. Ot her f i ndi ngs suggest i ng prerenal f ai l ure i ncl ude:
( 1) An abdominal br uit , possibl y i ndicat i ng r enal ar t er y st enosis
( 2) I ncr eased par adoxus, suggest i ng per icar dial t amponade
( 3) I ncr eased j ugular venous pr essur e, pulmonar y r ales, and a t hir d hear t sound,
signal i ng CHF
i . Post renal f ai l ure caused by obst r uct ed ur inar y f low may mani f est it self in:
( 1) A supr apubi c or f lank mass
( 2) Bl adder di st ent ion
( 3) Cost overt ebr al angle t ender ness
( 4) Pr ost at e enlar gement
2. Di agnost i c test resul t s
a. Uri nal ysi s i ncl udes an examinat i on of sedi ment ; ident if i cat ion of pr ot eins,
gl ucose, ket ones, blood, and nit r i t es; and measurement of ur inar y pH and ur ine-
specif i c gr avit y ( concent r at i on) or osmolal it y ( di l ut ion) . Pr ior admi ni st r at ion of
f lui ds, diur et ics, and changes i n ur inar y pH may conf ound accur at e diagnosis, usi ng
ur inal ysis.
( 1) Uri nary sedi ment exami nat i on
(a) Few cast s and f ormed element s ar e f ound i n pr er enal ARF.
( b) Pi gment ed cel l ular cast s and r enal t ubul ar epi t hel ial cel ls appear wi t h ATN.
( c) Red blood cell and whit e blood cel l cast s gener al l y r ef lect i nf l ammat or y di sease.
( d) Lar ge number s of br oad whit e cel l cast s suggest chr onic r enal f ai l ur e.
( 2) The pr esence of blood in t he ur i ne ( hemat uria) or pr ot eins ( prot ei nuri a)
i ndicat es r enal dysf unct i on.
( 3) Uri ne- specif i c gravi t y r anges f r om 1. 010- 1. 016 i n ARF.
( 4) Uri ne osmol al i t y t ypi cal l y r ises i n pr er enal ARF due t o i ncr eased secr et i on of
ant idi ur et ic hormone.
b. Measurement of uri ne sodi um and creat i ni ne l evel s can help cl assif y ARF.
( 1) I n prerenal ARF, t he ur ine cr eat i ni ne concent r at ion i ncreases, and ur ine sodi um
level decreases.
( 2) I n i nt rarenal ARF r esult i ng f r om ATN, t he ur i ne cr eat ini ne concent r at ion
decreases, and t he ur ine sodi um level i ncreases.
c. Creat i ni ne cl earance, an index of t he gl omerul ar f i l trat i on rate (GFR), al l ows
est imat ion of t he number of f unct ioni ng nephr ons; decr eased creat ini ne clear ance
i ndicat es r enal dysf unct i on. A t i med ur i ne col lect i on shoul d be used t o calculat e
GFR i n acut e r enal f ai l ur e.
d. Bl ood chemi st ry pr ovides an i ndex of renal excr et or y f unct ion and body
chemist r y st at us. Findi ngs t ypical of ARF i ncl ude:
( 1) I ncr eased blood ur ea nit r ogen (BUN)
( 2) I ncr eased ser um cr eat ini ne concent rat ion
( 3) Possi ble i ncr ease in hemogl obin and hemat ocr it val ues due t o dehydr at ion
( 4) Abnormal ser um elect r olyt e val ues
(a) Ser um pot assi um l evel above 5 mEq/ L
( b) Ser um phosphat e level above 2. 6 mEq/ L ( 4. 8 mg/ dl)
( c) Ser um calci um l evel below 4 mEq/ L ( 8. 5 mg/ dl) , ref l ect ing hypocalcemia. ( The
ser um cal ci um level must be cor relat ed wit h t he ser um al bumi n l evel . Each r ise or
f al l of 1 g/ dl of ser um albumin beyond i t s normal range i s r esponsible f or a
corr esponding i ncr ease or decrease in ser um cal ci um of appr oximat ely 0. 8 mg/ dl . A
below-normal ser um al bumin level may r esult i n a decept ively low ser um calci um
level . )
( d) Ser um sodium level bel ow 135 mEq/ L, ref lect i ng hyponat r emia
( 5) Abnormal art er ial blood gas values [ pH bel ow 7. 35, bicar bonat e concent r at i on
(HCO
-
3) below 22] , r ef lect i ng met abol i c aci dosi s
e. Renal f ai l ure i ndex (RFI ) is t he r at io of ur i ne sodium concent r at ion t o t he ur ine-
t o-ser um cr eat ini ne r at i o. The RFI helps det ermine t he et i ol ogy of ARF. Typical l y,
t he RFI is less t han 1 i n pr erenal ARF or acut e gl omer ul onephr i t is ( a cause of
i nt r ar enal ARF) . The RFI i s gr eat er t han 2 i n post r enal ARF and i n ot her int r ar enal
causes of ARF.
f . El ectrocardi ography (ECG) may show evi dence of hyperkalemi a—t hat is, t al l,
peaked T waves; wi deni ng QRS complexes; prol onged PR int er val, progressi ng t o
decr eased ampli t ude and di sappear ing P waves; and, ult i mat el y, vent ri cular
f ibr i l l at ion and car diac ar r est .
P. 1224


g. Radi ographi c f i ndi ngs
( 1) Ul trasound may det ect upper ur i nar y t r act obst r uct i on.
( 2) Ki dney, uret er, or bladder radi ography may r eveal:
(a) Ur i nar y t ract calcul i
( b) Enlar ged kidneys, suggest ing ATN
( c) Asymmet r ical kidneys, suggest i ng uni l at er al renal ar t er y disease, ur et er al
obst r uct ion, or chr onic pyelonephr it is
( 3) Radi onucl i de scan may reveal:
(a) Bi lat er al dif f erences in renal per f usion, suggest ing ser i ous r enal disease
( b) Bi lat er al di f f erences i n dye excr et ion, suggest i ng par enchymal di sease or
obst r uct ion as t he cause of ARF
( c) Di f f use, sl ow, dense radi onucl i de upt ake, suggest ing ATN
( d) Pat chy or absent r adionucl i de upt ake, possibl y i ndicat i ng sever e, acut e
glomer ulonephr it is
( 4) Comput ed t omography ( CT) scan may pr ovide bet t er visual i zat i on of an
obst r uct ion.
h. Renal bi opsy may be perf ormed i n select ed pat i ent s when ot her t est r esul t s are
i nconcl usi ve.
E. Treatment obj ect i ves
1. Corr ect r eversible causes of ARF, pr event i ng or mini mi zi ng f ur t her r enal damage
or compl icat ions.
a. Di scont inue nephr ot oxic dr ugs; r emove ot her nephr ot oxi ns t hrough di al ysis or
gast r i c l avage f or poi soni ngs.
b. Tr eat under l yi ng i nf ect i on.
c. Remove any ur inar y t r act obst r uct ions.
2. Corr ect and mai nt ai n pr oper f luid and elect r ol yt e balance. Mat ch f l ui d,
elect r olyt e, and nit r ogen i nt akes t o ur i ne out put .
3. Tr eat body chemist r y al t er at ions, especial l y hyperkalemia and met abol ic acidosis,
when pr esent . Tr eat ment may i ncl ude r enal dial ysis.
4. Impr ove ur i ne out put .
5. Tr eat syst emi c mani f est at ions of ARF.
F. Therapy
1. Conservat i ve management alone may suf f i ce i n uncompl icat ed ARF.
a. Fl ui d management
( 1) Flui d i nt ake should mat ch f luid losses. Sensi bl e l osses ( i. e. , ur i ne, st ool, t ube
dr ainage) and i nsensi bl e l osses ( i . e. , skin, r espi r at or y t r act ) of 500- 1000 mL/ day
should be i ncl uded in f l ui d bal ance calcul at i ons.
( 2) Volume over load should be avoided t o mi ni mi ze t he r isk of hyper t ension and
CHF.
( 3) The pat ient should be wei ghed dai l y t o det ermi ne f l uid vol ume st at us.
b. Di etary measures
( 1) Because cat abol ism accompanies r enal f ai l ur e, t he pat ient should r ecei ve a
hi gh- cal ori e, l ow-prot ei n di et . Such a diet hel ps t o:
(a) Reduce r enal workl oad by decr easing pr oduct ion of end product s of pr ot ein
cat abol ism t hat t he kidneys cannot excr et e
( b) Prevent ket oacidosis
( c) Al leviat e manif est at ions of ur emia ( e. g. , nausea, vomit i ng, conf usion, f at igue)
( 2) I f edema or hyper t ensi on is pr esent , sodium i nt ake shoul d be r est r ict ed.
( 3) Pot assi um int ake must be limi t ed in most pat i ent s. Fr ui t s, veget ables, and salt
subst it ut es cont aini ng pot assium should be l imit ed or avoided.
2. Management of body chemi stry al t erat i ons
a. Treatment of hyperkal emia
( 1) Di al ysi s may be used t o t r eat acut e, l if e- t hr eat eni ng hyper kal emia (see I I . F. 7).
( 2) Cal ci um chl ori de or cal ci um gl uconat e
(a) Mechani sm of acti on and t herapeut i c ef f ects. Cal ci um chl or ide or cal ci um
gl uconat e r eplaces and maint ai ns body calci um, count er act ing t he cardi ac ef f ect s of
acut e hyperkal emia.
P. 1225


( b) Admi ni st rat i on and dosage. When used t o r ever se hyperkalemia- i nduced
car diot oxi cit y, calci um chl or i de is gi ven i nt r avenousl y, as 5- 10 mL of a 10% sol ut i on
( 1. 4 mEq Ca
2+
/ mL) admini st er ed over 2 mi nut es. Doses of up t o 20 mL of a 10%
sol ut ion ar e saf e when gi ven slowl y. Anot her 10- 20 mL of a 10% solut ion placed i n a
lar ger f lui d vol ume and admi nist er ed sl owl y may f ol low t he i nit ial dose. Cal ci um
gl uconat e is admini st er ed as 10 mL of a 10% solut ion ( 1 g) over 2- 5 mi nut es. This
may be repeat ed a second t ime.
( c) Precaut i ons and moni t ori ng ef f ect s
( i ) I nt ravenous ( I V) cal ci um is cont r ai ndicat ed i n pat i ent s wit h vent r icular f ibr i l l at i on
or r enal cal cul i.
( i i ) The i nf usion r at e shoul d not exceed 0. 5 mL/ min. Pat ient s shoul d r emain
r ecumbent f or about 15 minut es af t er inf usi on.
( i i i ) The ECG shoul d be moni t or ed dur i ng calci um gl uconat e t her apy.
( i v) Calcium gluconat e should not be mi xed wit h sol ut ions cont ai ni ng sodi um
bicar bonat e because t his can lead t o pr ecipit at ion.
( v) Adverse ef f ect s incl ude hypot ensi on, t ingl i ng sensat ions, and r enal calcul us
f ormat ion.
( d) Si gni f i cant i nt eract i ons. Cal ci um may cause i ncr eased digit al is t oxi ci t y when
admi ni st er ed concur r ent ly wit h digi t al is pr eparat i ons.
( 3) Sodi um bi carbonat e may be gi ven as an emer gency measur e f or sever e
hyperkalemi a or met abol i c acidosis.
(a) Mechani sm of act i on and t herapeut i c ef f ect. IV sodi um bicar bonat e r est or es
bicar bonat e t hat t he r enal t ubules cannot reabsorb f r om t he glomer ular f i lt r at e and
i ncr eases art er ial pH. This r esult s in a shif t of pot assium int o cel ls and r educes
ser um pot assium concent rat ion.
( b) Onset of act i on i s 15- 30 mi nut es.
( c) Admi ni st rat i on and dosage
( i ) Sodium bi car bonat e is admini st er ed int r avenousl y.
( i i ) The dosage is calcul at ed as f ol lows:
[ 50% of body wei ght (kg)] × [ desir ed ar t er i al bicar bonat e (HCO
-
3) - act ual HCO
-
3]
One ampule ( 50 mEq) may be given int r avenousl y over 5 minut es.
( d) Precaut i ons and moni t ori ng ef f ect s
( i ) To avoid sodi um and f lui d over load, sodium bi car bonat e must be gi ven
caut i ousl y. Half of t he pat ient ' s bicar bonat e def i ci t is replaced over t he f ir st 12
hour s of t her apy.
( i i ) Sodium bi car bonat e may pr ecipi t at e cal ci um salt s i n I V solut ions and should not
be mi xed i n t he same i nf usion f l uid.
( i i i ) Ar t er ial blood gas values and ser um elect r olyt e l evel s shoul d be moni t or ed
closely dur i ng sodi um bi car bonat e t her apy.
( 4) Regul ar i nsul i n wi t h dextrose
(a) Mechani sm of act i on and t herapeut i c ef f ect. The i nsul i n causes an
i nt r acel l ular shi f t of pot assium. The combinat ion of i nsul i n wit h dext r ose deposit s
pot assi um wi t h gl ycogen i n t he l i ver , r educi ng t he ser um pot assi um.
( b) Onset of act i on i s 15- 30 mi nut es.
( c) Admi ni st rat i on and dosage. Regul ar i nsul i n ( 10 uni t s in 500 mL of 10%
dext r ose) is administ er ed int r avenousl y over 60 mi nut es.
( d) Precaut i ons and moni t ori ng ef f ect s
( i ) The ser um glucose level shoul d be moni t or ed dur i ng t her apy.
( i i ) The pat ient shoul d be assessed f or signs and sympt oms of f l uid over load.
( 5) Sodi um pol yst yrene sul f onat e (SPS)
(a) Mechani sm of act i on. SPS is a pot assi um-r emovi ng r esin t hat exchanges
sodium ions f or pot assium ions i n t he i nt est ine (1 g of SPS exchanges 0. 5- 1 mEq/ L
of pot assi um). The SPS is di st r i but ed t hroughout t he int est i nes and excr et ed in t he
f eces.
( b) Therapeut i c ef f ect . Admi nist er ed as an adj unct i ve t r eat ment f or hyperkal emi a,
SPS r educes pot assium levels i n t he ser um and ot her body f l ui ds.
( c) Onset of act i on of oral l y admi ni st er ed SPS is 2 hour s; ef f ect s are seen i n 1
hour when SPS is administ er ed as a r et ent ion enema.
P. 1226


( d) Admi ni st rat i on and dosage
( i ) SPS is usual l y administ ered or all y, alt hough it may be given t hr ough a
nasogast r i c t ube. The or al dose is 15- 30 g in a suspensi on of 70% sor bit ol,
admi ni st er ed ever y 4-6 hour s unt i l t he desir ed t her apeut i c ef f ect is achi eved.
( i i ) When or al or nasogast r i c admi nist r at ion is not possible due t o nausea, vomi t ing,
or par alyt ic i leus, SPS may be given by r et ent i on enema. The r ect al dose is 30- 50 g
i n 100 mL of sor bit ol as a warm emulsion, admi ni st er ed deep int o t he si gmoid colon
ever y 6 hour s. Administ r at i on may be done wi t h a r ubber t ube t hat i s t aped in pl ace
or via a Fol ey cat het er wit h a bal loon i nf lat ed di st al t o t he anal sphi nct er .
( e) Precaut i ons and moni t ori ng ef f ect s
( i ) The pat ient ' s ser um el ect r ol yt e levels shoul d be moni t or ed closely dur i ng SPS
t her apy. Sodium, chlor ide, bicar bonat e, and pH shoul d be monit or ed in addi t ion t o
pot assi um.
( i i ) SPS t her apy usual l y cont i nues unt i l t he ser um pot assi um l evel dr ops t o bet ween
4 and 5 mEq/ L.
( i i i ) The pat ient should be assessed r egular ly f or signs of pot assi um depl et ion,
i ncl udi ng ir r it abi l it y, conf usion, car di ac ar r hyt hmias, ECG changes, and muscle
weakness.
( i v) SPS exchanges sodium f or pot assium, so sodi um over load may occur duri ng
t her apy. Pat i ent s wit h hyper t ension or CHF shoul d be closely monit or ed.
( v) For or al admi ni st r at ion, SPS should be mixed onl y wit h wat er or sor bit ol. Or ange
j ui ce, which has a high pot assi um cont ent , should not be used because i t decr eases
t he ef f ect iveness of t he SPS. For rect al administ r at i on, SPS should be mixed onl y
wit h wat er and sor bi t ol , never wi t h mi ner al oi l .
( vi ) Adverse ef f ect s of SPS incl ude const ipat ion, f ecal impact ion wi t h r ect al
admi ni st r at ion, nausea, vomit i ng, and diar r hea.
( vi i ) SPS should not be used as t he sole agent in t he t r eat ment of sever e
hyperkalemi a; ot her agent s or t herapi es should be used i n conj unct ion wi t h t hi s
agent .
(f ) Si gni f i cant i nt eract i ons. Magnesi um hydr oxide and ot her nonabsorbable
cat iondonat i ng laxat i ves and ant acids may decr ease t he ef f ect iveness of pot assi um
exchange by SPS and may cause syst emi c alkal osis.
b. Treat ment of metabol i c aci dosi s. Sodium bi car bonat e may be gi ven i f t he
ar t er ial pH is below 7. 35 [ see I . F. 2. a. ( 3)] .
c. Treatment of hyperphosphat emia
( 1) IV cal ci um is f ir st - l i ne t her apy f or severe l if e- t hr eat ening hyper phosphat emi a.
Calci um r educes t he ser um phosphor us concent r at i on by chelat ion.
( 2) Oral cal ci um salt s bi nd di et ar y phosphor us i n t he GI t r act .
( 3) Sevel amer is a non- i oni c pol ymer t hat binds diet ar y phosphor us i n t he GI t r act .
( 4) Di al ysi s may be used t o t r eat acut e, l if e- t hr eat eni ng hyper phosphat emi a
accompani ed by acut e hypocalcemia ( see I I . F. 7). I t is al so perf ormed when vol ume
over l oad is pr esent .
( 5) Al umi num hydroxi de ( an al uminum-cont ai ni ng ant acid)
(a) Mechani sm of act i on and t herapeut i c ef f ect. Al uminum binds excess
phosphat e in t he i nt est i ne, t her eby reduci ng phosphat e concent r at ion.
( b) Onset of act i on i s 6- 12 hour s.
( c) Admi ni st rat i on and dosage. Al umi num hydr oxi de is administ er ed or al ly as a
t ablet or suspensi on. For t he t r eat ment of hyper phosphat emia, 0. 5- 2 or 15-30 mL of
suspensi on is administ er ed t hr ee or f our t imes dai l y wi t h meals.
( d) Precaut i ons and moni t ori ng ef f ect s
( i ) Al uminum hydr oxide may cause const ipat i on and anor exia.
( i i ) Ser um phosphat e levels should be monit or ed because al uminum hydr oxi de can
cause phosphat e depl et i on.
( i i i ) Al umi num hydr oxi de can cause cal ci um r esorpt i on and bone deminer al i zat i on.
d. Treat ment of hypocal cemi a. I mmedi at e t reat ment i s necessar y if t he pat ient has
sever e hypocalcemia, as evidenced by t et any.
( 1) Cal ci um gl uconat e [ see I . F. 2. a. ( 2) ]
(a) Mechani sm of act i on and t herapeut i c ef f ect. This dr ug r eplaces and maint ai ns
body calci um, r ai si ng t he ser um calci um l evel immediat el y.
P. 1227


( b) Admi ni st rat i on and dosage. When used t o r ever se hypocalcemi a, calci um
gl uconat e is admini st er ed i nt r avenousl y in a dosage of 1- 2 g over a per iod of 10
mi nut es, f oll owed by a slow i nf usion ( over 6- 8 hour s) of an addit ional 1 g.
( c) Precaut i ons, moni t ori ng ef f ect s, and si gni f i cant i nt eract i ons [ see
I . F. 2. a. ( 2). ( c), ( d) ]
( 2) Oral cal ci um salt s. Calci um car bonat e, chlor i de, gl uconat e, or lact at e may be
gi ven by mout h when or al i nt ake is permit t ed or i f t he pat i ent has rel at i vel y mi ld
hypocalcemia. The usual adult dosage is 4- 6 g/ day gi ven i n t hr ee or f our di vided
doses.
e. Treatment of hyponat remia
( 1) Moder at e or asympt omat ic hyponat r emia may r equi r e onl y f l ui d rest ri ct i on.
( 2) Sodi um chl ori de may be given f or sever e sympt omat ic hyponat r emi a ( i . e. , a
ser um sodium level below 120 mEq/ L).
(a) Mechani sm of act i on and t herapeut i c ef f ect. Sodium chl or i de r eplaces and
maint ai ns sodi um and chl or ide concent r at i on, t hereby i ncr easing ext r acel l ular
t onicit y.
( b) Admi ni st rat i on and dosage
( i ) A 3% or 5% sodi um chl or ide sol ut ion may be admi nist er ed by slow I V i nf usi on.
The amount of sol ut ion needed is calcul at ed f r om t he f oll owi ng equat ion:
(Normal ser um sodi um level - act ual ser um sodium l evel ) × t ot al body wat er
( i i ) Typi cal l y, 400 mL or less i s admi nist er ed.
( c) Precaut i ons and moni t ori ng ef f ect s
( i ) Hyper t onic sodi um chl or i de must be administ ered ver y slowl y t o avoi d cir cul at or y
over l oad, pul monar y edema, or cent r al pont i ne demyel i nat i on.
( i i ) Ser um elect r olyt e level s must be monit or ed f requent ly dur i ng t herapy.
( i i i ) Excessi ve i nf usion may cause hyper nat r emi a and ot her ser ious elect r ol yt e
abnormali t ies and may wor sen exist i ng aci dosi s. I nf usi on r at es should not exceed
0. 5 mEq/ kg/ hr.
3. Management of syst emi c manif est at i ons
a. Treatment of f l ui d overl oad and edema. As wat er and sodi um accumulat e i n
ext r acel l ular f lui d dur i ng ARF, f luid over l oad and edema may occur . Di uret i cs and
dopami ne may be given t o reduce f lui d vol ume excess and edema. Tr eat ment shoul d
be ini t iat ed as soon as possible af t er ol igur i a begi ns. Manni t ol or a l oop di uret i c
may be used; t hiazi de di ur et ics ar e avoi ded i n r enal f ai l ur e because t hey ar e
i nef f ect i ve when cr eat i ni ne cl ear ance is less t han 25 mL/ mi n, and t hey may wor sen
t he pat ient ' s cl i ni cal st at us.
( 1) St ep 1. Loop ( hi gh- cei l i ng) di uret i cs. These agent s incl ude f urosemi de,
bumetani de, t orsemi de and et hacryni c aci d. Loop diur et i cs ar e mor e pot ent and
f ast er- act ing t han t hiazide diur et i cs.
(a) Mechani sm of act i on and t herapeut i c ef f ects. Loop di ur et ics i nhibit sodium
and chl or ide r eabsor pt ion at t he l oop of Henl e, promot ing wat er excr et i on.
( b) Onset of act i on f or an or al dose is 1 hour ; sever al mi nut es f or an IV dose.
Dur at ion of act i on f or an or al dose i s 6- 8 hour s; 2- 3 hour s f or an I V dose.
( c) Admi ni st rat i on and dosage
( i ) Furosemi de, t he most commonl y used loop di ur et ic, usual l y i s admi ni st er ed
i nt r avenousl y i n pat i ent s wit h ARF t o hast en t he t her apeut ic ef f ect . The dose i s
t it r at ed t o t he pat ient ' s needs; t he usual i ni t ial dose is 1-1. 5 mg/ kg. If t he f ir st dose
does not pr oduce a ur ine out put of 10- 15 mL wit hi n 20- 30 minut es, a dose of 2- 3
mg/ kg i s admi nist er ed; if t he desi r ed r esponse st i l l does not occur, a dose of 3- 6
mg/ kg i s admi nist er ed 20- 30 minut es af t er t he second dose.
( i i ) Bumetani de may be given t o pat ient s who are unr esponsi ve or al ler gic t o
f ur osemide. The usual dosage, administ er ed i nt r avenousl y or int r amuscul ar l y i n t he
t r eat ment of ARF, is 0. 5- 1 mg/ day; however , some pat ient s may r equir e up t o 20
mg/ day. A second or t hir d dose may be gi ven at i nt ervals of 2- 3 hour s. When
bumet anide is gi ven or al l y, t he dosage i s 0. 5- 2 mg/ day, repeat ed up t o t wo t imes, i f
necessar y, at int er vals of 2- 3 hour s.
( i i i ) Et hacryni c aci d is l ess commonl y used t o t r eat ARF because ot ot oxi ci t y
( somet i mes ir r eversi ble) is associat ed wit h i t s use. It may be gi ven i nt r avenousl y
( slowly over sever al minut es) in a dose of 50- 100 mg. The usual or al dosage is 50-
200 mg/ day; some pat i ent s may r equi r e up t o 200 mg t wice dai ly. Et hacr ynic aci d
can be saf el y gi ven t o pat ient s who may have a sulf onami de
P. 1228

al l er gy, which would pr ecl ude t hem f r om t her apy wi t h f ur osemide or t orsemi de.
( i v) Torsemi de may also be given t o pat ient s unr esponsi ve t o or all er gi c t o
f ur osemide. The usual dose is 20 mg, admi ni st er ed int r avenousl y. Doses may be
i ncr eased by doubl i ng up t o 200 mg; 10- 20 mg of t orsemi de is equi pot ent t o 40 mg
of f ur osemi de or 1 mg bumet ani de. Tor semide of f er s bet t er bioavai labi l i t y compar ed
t o ot her loop diur et ics; however , it i s consider abl y more expensive.
( d) Precaut i ons and moni t ori ng ef f ect s
( i ) Loop di ur et ics must be used caut i ousl y because t hey may cause over di ur esi s
leadi ng t o ort host at ic hypot ension, f l uid and el ect r ol yt e abnormal it ies, incl udi ng
vol ume depl et i on and dehydr at ion, hypocalcemia, hypokal emia, hypochl or emia,
hyponat r emi a, hypomagnesemi a, and t r ansient ot ot oxicit y, especial l y wi t h r api d I V
i nj ect ion.
( i i ) Ser um elect r olyt e level s should be monit or ed f r equent ly and t he pat ient
assessed r egular l y f or signs and sympt oms of elect rol yt e abnormal it ies.
( i i i ) Bl ood pr essur e and pul se r at e should be assessed dur i ng di ur et ic t her apy.
( i v) GI r eact i ons i nclude abdominal pai n and discomf ort , diar r hea (wit h f ur osemide
and et hacr ynic acid) , and nausea ( wit h bumet anide) .
( v) Bl ood glucose levels shoul d be moni t or ed i n diabet ic pat ient s r eceivi ng loop
di ur et i cs because t hese agent s may cause hyper gl ycemi a and impair ed glucose
t oler ance.
( vi ) Pat i ent s who ar e al lergic t o sulf onamides may be hyper sensit ive t o bumet anide
and f ur osemi de.
( vi i ) Fur osemide and et hacr yni c acid may cause agr anul ocyt osis.
( e) Si gni f i cant i nt eract i ons
( i ) Ami nogl ycosi de ant i bi ot i cs may pot ent iat e ot ot oxicit y when administ er ed wi t h
any l oop di ur et i c.
( i i ) Nonst eroi dal ant i - i nf lammat ory drugs (NSAIDs) may hamper t he diur et i c
r esponse t o f ur osemi de and bumet ani de; probeneci d may hamper t he di ur et ic
r esponse t o bumet anide.
( i i i ) Et hacr yni c acid may pot ent iat e t he ant icoagul ant ef f ect s of warf ari n.
( 2) St ep 2. Manni t ol , an osmot i c di ur et i c, i s a non- r eabsor bable polysacchar i de.
(a) Mechani sm of act i on and t herapeut i c ef f ect. Mannit ol i ncr eases t he osmot i c
pr essur e of t he glomer ul ar f i lt r at e; f lui d f r om int erst i t ial spaces i s dr awn i nt o bl ood
vessel s, expandi ng plasma vol ume and mai nt ai ni ng or i ncr easing t he ur ine f l ow.
Thi s dr ug may be given t o pr event ARF in hi gh- r isk pat i ent s, such as t hose
under going sur ger y or suf f er ing f r om sever e t r auma or hemol yt ic t r ansf usion
r eact i ons.
( b) Onset of act i on i s 15- 30 mi nut es. Dur at ion of act ion i s 3- 4 hour s.
( c) Admi ni st rat i on and dosage. Mannit ol i s avai l able i n sol ut i ons, r angi ng f r om
5%-25%. For t he t r eat ment of oli gur ic ARF or t he pr event i on of ARF, t he usual
i ni t ial dose is 12. 5-25 g, administ er ed i nt r avenousl y; t he maximum dai ly dosage is
100 g, administ er ed i nt r avenously. The exact concent r at ion of t he sol ut ion is
det ermined by t he pat ient ' s f l ui d r equir ement s.
( d) Precaut i ons and moni t ori ng ef f ect s
( i ) Manni t ol is cont r aindi cat ed in pat ient s wi t h anur ia, pulmonar y edema or
congest ion, sever e dehydr at ion, and int r acr ani al hemor r hage (except dur ing
cr ani ot omy) .
( i i ) Manni t ol may cause or wor sen pulmonar y edema and cir cul at or y over load. I f
signs and sympt oms of t hese pr oblems devel op, t he i nf usi on should be st opped.
( i i i ) Ot her adver se ef f ect s of mannit ol i ncl ude f lui d and elect r olyt e abnormal it i es,
wat er int oxicat ion, headache, conf usion, bl ur r ed vi si on, t hi r st , nausea, and
vomi t ing.
( i v) Vit al signs, ur i ne out put , dai l y wei ght , car diopul monar y st at us, and ser um and
ur ine sodi um and pot assi um l evel s should be moni t or ed dur ing manni t ol t her apy.
( v) Mannit ol solut ions wi t h undissol ved cr yst al s shoul d not be administ er ed.
4. Di al ysi s. I f t he above st r at egies f ai l, hemodial ysi s or per i t oneal dial ysis may be
necessar y i n ARF pat i ent s who develop anur ia, acut e f l ui d over load, sever e
hyperkalemi a, met abol ic acidosis, or a BUN level above 100 mg/ dl. For a discussion
of dialysis, see I I . F. 7.
P. 1229


II. CHRONIC KIDNEY DI SEASE
A. Def i ni t i on. Chr onic kidney disease ( CKD) is t he pr ogressi ve, ir r ever sible
det er i or at ion of r enal f unct ion. Usual l y r esult i ng f r om long- st andi ng disease, CKD
somet imes der ives f r om ARF t hat does not r espond t o t reat ment .
B. Classi f i cat i on and pat hophysi ol ogy
1. CKD is def i ned as kidney damage or GFR <60 mL/ min/ 1. 73 m2 f or <3 mont hs.
Kidney damage is def ined as pat hological abnor mal i t ies or marker s of damage,
i ncl udi ng abnormali t ies i n blood or ur ine t est s or i magi ng st udies. CKD has r ecent ly
been r eclassif i ed as st ages I-V t o denot e t he sever it y of r enal impairment .
Gener all y, CKD, if l ef t unt r eat ed, pr ogr esses at a pr edict able, st eady r at e f r om
st age I t hr ough st age V.
a. Stage 1 is def ined as kidney damage wit h a normal or i ncr eased GFR. The
corr esponding GFR in st age I CKD i s usual l y >90 mL/ min/ 1. 73 m2.
b. Stage 2 is def i ned as kidney damage or a mil dl y decr eased GFR ( 60- 89
mL/ min/ 1. 73 m2).
c. Stage 3 si gnif ies moderat e r educt ions i n GFR (30- 59 mL/ min/ 1. 73 m2).
d. Stage 4 connot es a GFR of 15- 29 mL/ mi n/ 1. 73 m2.
e. Stage 5 is ki dney f ai lur e or a GFR of <15 mL/ mi n/ 1. 73 m2.
2. As CKD pr ogr esses, nephr on dest r uct ion wor sens, leadi ng t o det er i or at ion i n t he
kidneys' f i lt r at ion, r eabsor pt ion, and endocr ine f unct i ons.
3. Renal f unct i on t ypical l y does not diminish unt i l about 75% of kidney t issue i s
damaged. Ult i mat ely, t he kidneys become shr unken, f ibr ot i c masses.
C. Et i ol ogy. Causes of CKD i n adul t s i ncl ude:
1. Di abet i c nephropat hy
2. Hyper t ension
3. Gl omerulonephr it i s
4. Polycyst ic kidney disease
5. Long- st andi ng vascular di sease ( e. g. , r enal ar t er y st enosis)
6. Long- st andi ng obst r uct i ve ur opat hy ( e. g. , r enal calcul i)
7. Exposur e t o nephr ot oxic agent s
D. Cl i ni cal eval uat i on
1. Physi cal f i ndi ngs. Si gns and sympt oms, which vary wi dely, do not appear unt i l
r enal i nsuf f iciency pr ogr esses t o r enal f ai l ur e.
a. Metabol i c abnormal i t i es i ncl ude loss of t he abi l it y t o maint ai n sodi um,
pot assi um, and wat er homeost asi s, l eadi ng t o hyponat r emi a or hyper nat r emia,
based on r elat ive sodi um or wat er int ake. Hyperkalemi a i s uncommon unt i l end-
st age di sease. Fl uid over load, edema, and CHF may become a pr obl em unl ess f l ui d
i nt ake i s closel y managed. As renal f ai l ur e pr ogr esses, t he i nabi l it y t o excr et e acid
and maint ai n buf f er capacit y leads t o met abol ic acidosis ( see I . D. 1. b, d, g, h).
Calci um and phosphat e met abol i sm i s alt er ed due t o hyper parat hyr oidism.
b. Neurol ogi cal mani f estat i ons i ncl ude shor t at t ent ion span, loss of memor y, and
l ist lessness. As CKD progr esses, t hese advance t o conf usion, st upor, sei zur es, and
coma. Neuromuscul ar f i ndi ngs i nclude per ipher al neur opat hy; pai n, i t chi ng, and a
bur ni ng sensat i on, part icul ar l y i n t he f eet and legs. Pat ient s may appear
i nt oxicat ed. I f di al ysis is not st art ed af t er t hese abnormali t ies occur, mot or
i nvol vement begi ns, i ncl udi ng l oss of deep-t endon r ef lexes, weakness, and f inal l y,
quadr ipl egia.
c. Cardi ovascul ar probl ems incl ude ar t er i al hyper t ension, per i pher al edema, CHF,
and pul monar y edema. Uremi c per i car di t is is now i ncr easi ngly i nf r equent as a r esult
of ear l y dial ysi s.
d. GI manif estat i ons i ncl ude hi ccups, anor exi a, nausea, vomit i ng, const i pat ion,
st omat i t is, and an unpl easant t ast e in t he mout h. CKD pat i ent s have an incr eased
i ncidence of ul cer s, pancr eat it i s, and diver t i cul osi s.
P. 1230


e. Respi rat ory probl ems i ncl ude dyspnea when CHF i s pr esent , pulmonar y edema,
pleur i t ic pai n, and ur emi c pleur i t is.
f . I nt egumentary f i ndi ngs t ypi cal l y i ncl ude pal e yel lowi sh, dr y, scal y skin; sever e
it chi ng; ur emic f r ost ; ecchymoses; pur pur a; and br it t l e nai l s and hai r .
g. Muscul oskel et al changes r ange f r om muscl e and bone pain t o pat hologi cal
f r act ur es and calcif icat i ons i n t he br ain, hear t , eyes, j oint s, and vessel s. Sof t -t issue
calcif icat i on and r enal ost eodyst rophy may occur .
h. Hemat ol ogi cal di st urbances i ncl ude anemia. The signs and sympt oms of anemia
ar ise f r om l ack of epoet i n alf a and r educed l i f e span of r ed blood cel l s, i ncludi ng:
( 1) Pall or of t he ski n, nai l beds, palms, conj unct i vae, and mucosa
( 2) Abnormal br uisi ng or ecchymoses, and ur emic bl eedi ng due t o plat elet
i nact i vat ion
( 3) Dyspnea and angina pect or is
( 4) Ext r eme f at igue
2. Di agnost i c test resul t s
a. Creat i ni ne cl earance may r ange f r om 0- 90 mL/ min, r ef lect ing r enal impairment .
b. Bl ood t est s t ypical l y show:
( 1) El evat ed BUN and ser um cr eat i ni ne concent r at ion
( 2) Reduced ar t er ial pH and bicar bonat e concent rat i on
( 3) Reduced ser um cal ci um level
( 4) I ncr eased ser um pot assium and phosphat e levels
( 5) Possi ble r educt i on i n t he ser um sodium level
( 6) Normochr omic, normocyt ic anemi a ( hemat ocr it 20%- 30%)
c. Uri nal ysi s may reveal gl ycosur ia, pr ot ei nur ia, er yt hr ocyt es, leukocyt es, and
cast s. Speci f ic gr avi t y is f i xed at 1. 010.
d. Radi ographi c f i ndi ngs. Kidney, ur et er, and bl adder radi ogr aphy, I V pyel ogr aphy,
r enal scan, r enal ar t er iogr aphy, and nephr ot omogr aphy may be perf ormed.
Typical l y, t hese t est s r eveal smal l ki dneys ( less t han 8 cm in lengt h) .
E. Treatment obj ect i ves
1. Impr ove pat ient comf ort and pr olong l i f e.
2. Tr eat syst emi c mani f est at ions of CKD.
3. Corr ect body chemi st r y abnormal it i es.
F. Therapy. Management of t he CKD pat ient i s gener al l y conser vat i ve. Diet ar y
measur es and f lui d r est r ict ion r el ieve some sympt oms of CKD and may incr ease
pat ient comf ort and pr olong l if e unt i l di al ysis or r enal t r ansplant at ion i s r equir ed or
avai l able ( see I . F. 1. a, b).
1. Treatment of edema. Angi ot ensi n- convert i ng enzyme ( ACE) i nhi bi t ors and
di uret i cs may be given t o manage edema and CHF and t o i ncr ease ur i ne out put .
a. ACE i nhi bi t ors—capt opri l , enalapri l , l i si nopri l , f osi nopri l —ar e widel y used t o
delay pr ogr essi on of CKD because t hey hel p pr eser ve renal f unct ion and t ypical l y
cause f ewer adverse ef f ect s t han ot her ant ihyper t ensi ve agent s (see Chapt er 39).
They al so decr ease pr ot ei nur ia and nephr ot ic syndr ome.
b. Di uret i cs. An osmot i c di ur et i c, a loop diur et ic, or a t hiazide- l ike di ur et ic may be
gi ven.
( 1) Osmot i c and l oop di uret i cs. See I . F. 3. a. ( 1), ( 2) f or inf ormat ion on t he use of
t hese dr ugs i n r enal f ai l ur e.
( 2) Thi azi de- l i ke di uret i cs. Met olazone is t he most commonl y used t hiazide
di ur et i c i n CKD.
(a) Mechani sm of act i on and t herapeut i c ef f ect. Met ol azone r educes t he body' s
f lui d and sodium volume by decr easi ng sodium r eabsorpt ion i n t he dist al convolut ed
t ubul e, t her eby incr easi ng ur i nar y excr et ion of f lui d and sodium.
( b) Admi ni st rat i on and dosage. Met ol azone is gi ven or al l y at 5- 20 mg/ day; t he
dose is t it r at ed t o t he pat i ent ' s needs. Due t o it s l ong hal f - l if e, met olazone may be
gi ven ever y ot her day. Fur osemide and met olazone act syner gi st i cal l y. Combinat ion
use i s common, and met ol azone should be admi ni st er ed 30 minut es bef or e
f ur osemide t o achieve t he opt imal di uret ic ef f ect .
( c) Precaut i ons and moni t ori ng ef f ect s
( i ) Met olazone should not be given t o pat ient s wi t h hyper sensit i vi t y t o sul f onamide
der ivat ives, i ncludi ng t hi azi des.
P. 1231


( i i ) To avoid noct ur ia, t he dai l y dose should be gi ven i n t he mor ni ng.
( i i i ) Met olazone may cause hemat ol ogical r eact i ons, such as agranulocyt osis,
aplast ic anemi a, and t hr ombocyt openia.
( i v) Flui d volume depl et i on, hypokalemia, hyper ur icemia, hyper glycemia, and
impair ed glucose t ol er ance may occur dur i ng met olazone t her apy.
( v) Met ol azone may cause hyper sensit i vi t y r eact i ons, i ncl udi ng vascul it is and
pneumoni t is.
( d) Si gni f i cant i nt eract i ons
( i ) Diazoxi de may pot ent iat e t he ant ihyper t ensive, hyper gl ycemi c, and
hyper ur i cemi c ef f ect s of met ol azone.
( i i ) Col est i pol and chol est yrami ne decrease t he absorpt ion of met olazone.
2. Treatment of hypert ensi on. Ant i hypert ensi ve agent s may be needed i f bl ood
pr essur e becomes dangerousl y high as a r esult of edema and t he high r eni n l evel s
t hat occur i n CKD. Ant i hypert ensi ve t her apy shoul d be init i at ed i n t he l owest
ef f ect ive dose and t i t r at ed accor di ng t o t he pat ient ' s needs.
a. ACE i nhi bi t ors—capt opri l , enalapri l , l i si nopri l , f osi nopri l —as above in I I . F. 1. a
( see also Chapt er 39).
b. Di hydropyri di ne cal ci um-channel bl ockers, incl udi ng amLodi pi ne and
f el odi pi ne, have simi lar ef f ect s and may be used i nst ead of ACE inhi bit or s.
c. ß- Adrenergi c bl ockers, incl udi ng propranol ol and at enol ol , r educe blood
pr essur e t hr ough var ious mechanisms ( see Chapt er 39).
d. Ot her ant i hypertensi ve agent s are somet imes used in t he t reat ment of CKD,
i ncl udi ng q- adr ener gi c dr ugs, cl oni di ne, and vasodi lat or s, such as hydral azi ne
( see Chapt er 39).
3. Treatment of hyperphosphat emia i nvol ves admini st rat ion of a phosphat e binder ,
such as alumi num hydr oxide or calci um car bonat e ( see I. F. 2. c).
4. Treatment of hypocal cemia
a. Oral cal ci um sal t s [ see I . F. 2. d. ( 2) ]
b. Vi tami n D
( 1) Mechani sm of act i on and t herapeut i c ef f ect. Vi t ami n D promot es i nt est inal
calci um and phosphat e absorpt i on and ut i l i zat i on and, t hus, i ncr eases t he ser um
calci um concent rat i on.
( 2) Choi ce of agent . For t he t reat ment of hypocal cemi a i n CKD and ot her r enal
disor der s, cal ci t ri ol ( vit ami n D3, t he act ive f orm of vi t ami n D) i s t he pr ef er r ed
vit amin D suppl ement because of it s gr eat er ef f i cacy and r el at i vel y shor t dur at i on of
act ion. Ot her si ngle- ent it y pr epar at i ons i ncl ude di hydr ot achyst er ol, er gocal ci f er ol,
and cal ci f ediol . Newer vit amin D analogues i nclude doxer cal ci f er ol and par ical cit ol.
( 3) Admi ni st rat i on and dosage. Calcit r iol is gi ven or al l y or via I V; t he dose is
t it r at ed t o t he pat ient ' s needs ( 0. 5- 1 mg/ day may be ef f ect ive) .
( 4) Precaut i ons and moni t ori ng ef f ect s
(a) Vi t ami n D admi nist r at ion may be danger ous in pat ient s wi t h r enal f ai l ur e and
must be used wi t h ext r eme caut ion.
( b) Vi t amin D t oxici t y may cause a wide r ange of signs and sympt oms, i ncl udi ng
headache, di zzi ness, at axia, convulsi ons, psychosis, sof t - t i ssue cal ci f icat ion,
conj unct i vi t is, phot ophobia, t inni t us, nausea, di arr hea, pr ur it us, and muscle and
bone pain.
( c) Vi t ami n D has a nar r ow t herapeut ic i ndex, necessi t at i ng f r equent measur ement
of BUN and ser um ur ine cal ci um and pot assium level s.
5. Treatment of ot her syst emi c manif estat i ons of CKD
a. Treatment of anemia incl udes administ r at i on of i r on ( e. g. , f err ous sul f at e) , f olat e
supplement s, and epoet i n alf a.
( 1) Sever e anemia may war r ant t r ansf usi on wit h packed red blood cel l s.
( 2) Epoet in alf a st i mulat es t he pr oduct i on of r ed cel l pr ogenit or s and t he product ion
of hemogl obi n. I t al so accel er at es t he r elease of ret icul ocyt es f rom t he bone
mar r ow.
(a) An init i al dose of epoet i n alf a i s 50- 100 U/ kg i nt r avenousl y or subcut aneousl y
t hr ee t imes a week. The dose may be adj ust ed upwar d t o eli ci t t he desir ed
r esponse.
( b) Epoet in al f a works best i n pat ient s wit h a hemat ocr i t below 30%. Dur ing t he
i ni t ial t r eat ment , t he hemat ocr i t increases 1%-3. 5% in a 2- week per iod. The t arget
P. 1232

hemat ocr i t is 33%- 35%. Maint enance doses ar e t it r at ed based on hemat ocr i t af t er
t hi s l evel is r eached.
( c) Epoet in alf a t her apy should be t empor ar i l y st opped if hemat ocr it exceeds 36%.
Addit i onal side ef f ect s i ncl ude hyper t ension i n up t o 25% of pat i ent s. Headache and
malaise have been r eport ed.
( d) The ef f ect s of epoet i n alf a ar e dependent on a r eady supply of ir on f or
hemogl obin synt hesi s. Pat i ent s who do not r espond should have ir on st or es
checked. This i ncl udes ser um i r on, t ot al ir on- bi ndi ng capacit y, t r ansf err i n
sat ur at ion, and ser um f err it i n. I r on supplement at ion should be i ncr eased as
i ndicat ed.
( 3) Dar bepoei t i n is a new epoet in al f a analogue. I t s advant age is a pr olonged
plasma half - l if e, t hus al lowi ng it t o be admi nist er ed once weekly or biweekly.
( 4) I nt r avenous ir on pr oduct s may be given t o r eplet e i r on st or es. Thi s r out e is
pr ef err ed t o or al supplement at i on due t o low or al bioavai l abi l it y and GI i nt ol er ance.
I r on dext r an is commonl y used; however , i t is associat ed wit h hypot ension and
anaphylaxi s. Newer ir on pr oduct s incl ude sodi um f err i c gluconat e and i r on sucr ose,
whi ch ar e bet t er t ol er at ed and can be inf used more rapidly compar ed t o ir on
dext r an. Pat i ent s wit h sever e ir on def i ci ency may r eceive up t o a t ot al of 1 g of an
ir on prepar at ion over sever al days. The r at e of i nf usi on depends on t he pr epar at ion
used.
b. Treat ment of GI di st urbances
( 1) Ant iemet i cs help cont r ol nausea and vomit i ng.
( 2) Docusat e sodium or met hylcel l ul ose may be used t o prevent const ipat i on.
( 3) Enemas may be gi ven t o remove blood f r om t he GI t r act .
c. Treatment of ski n probl ems. An ant ipr ur i t ic agent , such as di phenhydr amine,
may be used t o al leviat e it chi ng.
6. Management of body chemi stry abnormal i t i es ( see I . F. 2)
7. Di al ysi s. When CKD progresses t o end- st age renal disease and no longer
r esponds t o conser vat i ve measur es, l ong- t erm di al ysis or r enal t r ansplant at ion i s
necessar y t o prolong l i f e.
a. Hemodi al ysi s is t he pr ef err ed dial ysis met hod f or pat i ent s wit h a r educed
per it oneal membr ane, hyper cat abol i sm, or acut e hyperkalemi a.
( 1) This t echni que i nvol ves shunt i ng of t he pat i ent ' s bl ood t hr ough a di al ysis
membr anecont aini ng uni t f or di f f usion, osmosis, and ult r af i l t r at i on. The blood is
t hen r et ur ned t o t he pat i ent ' s cir culat ion.
( 2) Vascular access may be obt ai ned vi a an ar t er i ovenous f ist ula or an ext er nal
shunt .
( 3) The pr ocedur e t akes onl y 3- 8 hour s; most pat i ent s need t hr ee t r eat ment s a
week. Wit h proper t rai ni ng, pat ient s can per f orm hemodi al ysis at home.
( 4) The pat ient r eceives hepar i n dur i ng hemodial ysis t o pr event cl ot t i ng.
( 5) Var ious complicat i ons may ar ise, incl udi ng clot t ing of t he hemof i lt er ,
hemor r hage, hepat i t is, anemi a, sept i cemia, car di ovascular pr obl ems, air embol ism,
r apid shif t s in f l uid and elect r ol yt e balance, i t chi ng, nausea, vomit i ng, headache,
sei zur es, and alumi num ost eodyst r ophy.
b. Peri t oneal di al ysi s is t he pr ef err ed dial ysis met hod f or pat i ent s wit h bl eedi ng
disor der s and car diovascul ar disease.
( 1) The per it oneum i s used as a semi permeabl e membr ane. A plast i c cat het er
i nser t ed i nt o t he per it oneum pr ovides access f or t he di al ysat e, which dr aws f luids,
wast es, and el ect r olyt es acr oss t he per i t oneal membr ane by osmosis and di f f usion.
( 2) Per it oneal di al ysis can be car r ied out i n t hr ee dif f er ent modes.
(a) I nt ermit tent peri t oneal di al ysi s is an aut omat i c cycl i ng mode last i ng 8- 10
hour s, per f ormed t hr ee t imes a week. This mode al lows ni ght t ime t r eat ment and is
appr opr iat e f or working pat i ent s.
( b) Cont i nuous ambul at ory perit oneal di al ysi s i s per f ormed dail y f or 24 hour s
wit h f our exchanges dai l y. The pat i ent can r emain act ive dur i ng t he t r eat ment .
( c) Cont i nuous cycl i c peri t oneal dial ysi s may be used if t he ot her t wo modes f ai l
t o impr ove cr eat ini ne cl ear ance. Di al ysis t akes pl ace at night ; t he last exchange i s
r et ai ned i n t he per it oneal cavi t y dur i ng t he day, t hen dr ai ned t hat eveni ng.
( 3) Advantages of per it oneal di al ysis i ncl ude a lack of ser ious compl icat i ons,
r et ent i on of normal f l ui d and el ect r ol yt e balance, si mpl i ci t y, r educed cost , pat i ent
i ndependence, and a r educed need ( or no need) f or hepar in admi nist r at ion.
( 4) Compl i cat i ons of peri t oneal dial ysi s i ncl ude hyper gl ycemi a, const ipat ion, and
i nf l ammat ion or inf ect ion at t he cat het er sit e. Also, t his met hod car r i es a high r isk of
per it onit i s.
P. 1233


8. Renal t ranspl antat i on. Thi s sur gi cal procedur e al lows some pat ient s wi t h end-
st age r enal di sease t o l i ve normal and, in many cases, longer l i ves.
a. Hi st ocompat i bi l i t y must be t est ed t o mi ni mi ze t he r isk of t ransplant rej ect ion
and f ai lur e. Human l eukocyt e ant igen (HLA) t ype, mixed l ymphocyt e r eact i vi t y, and
blood gr oup t ypes ar e det ermi ned t o assess hi st ocompat ibi l it y.
b. Renal t r ansplant mat er i al may be obt ai ned f rom a li vi ng donor or a cadaver .
c. Three t ypes of graf t rej ect i on can occur .
( 1) Hyperacut e ( immedi at e) rej ect i on r esult s in graf t l oss wit hi n mi nut es t o hour s
af t er t r anspl ant at i on.
(a) Acut e ur ine f l ow cessat ion and bl uish or mot t led kidney discolor at i on ar e
i nt r aoperat ive si gns of hyper acut e r ej ect ion.
( b) Post oper at ive mani f est at ions i ncl ude kidney enl ar gement , f ever, anur ia, l ocal
pai n, sodi um r et ent ion, and hyper t ension.
( c) Tr eat ment f or hyper acut e r ej ect i on is immediat e nephr ect omy.
( 2) Acut e rej ect i on may occur 4- 60 days af t er t r ansplant at ion.
( 3) Chroni c rej ect i on occur s mor e t han 60 days af t er t r ansplant at i on.
(a) Si gns and sympt oms incl ude low- gr ade f ever , i ncr eased pr ot einur ia, azot emia,
hyper t ensi on, ol igur ia, weight gai n, and edema.
( b) Tr eat ment may incl ude alkyl at i ng agent s, cycl ospor ine, ant i l ymphocyt e globul i n,
and cort i cost er oids. I n some cases, nephr ect omy is necessar y.
d. Compl i cat i ons i ncl ude:
( 1) I nf ect i on, di abet es, hepat it i s, and leukopenia, r esult i ng f rom immunosuppr essive
t her apy
( 2) Hypert ension, r esult i ng f r om var ious causes
( 3) Cancer (e. g. , lymphoma, cut aneous mal i gnanci es, head and neck cancer,
leukemia, colon cancer )
( 4) Pancr eat i t is and ment al and emot ional disor der s ( e. g. , suicidal t endencies,
sever e depression, brought on by st er oi d t herapy)
P. 1234


STUDY QUESTIONS
Di rect i ons: Each of t he number ed it ems or incomplet e st at ement s i n t his sect ion i s
f ol l owed by answer s or by compl et i ons of t he st at ement . Sel ect t he one let t er ed
answer or complet ion t hat is best in each case.
Quest i ons 1- 5 A 48- year- ol d black man has a hist or y of mil d t o sever e
hyper t ensi on. His hyper t ensi on has been poor ly cont r ol led wi t h enalapr i l and
hydr ochlor ot hiazi de. On pr ior vi si t s, hi s blood pr essur e cont r ol has var ied and
seems t o cor respond wi t h a lack of compl iance wi t h his t reat ment regimen. The
pat ient st at es t hat he occasi onal l y f or get s his pi l l s or does not t ake t hem when he i s
f eel ing “ okay. ” The pat ient ' s hist or y does not incl ude diabet es mell it us or hear t
disease. He complet ed a 14- day cour se of clar i t hr omyci n f or an upper r espir at or y
i nf ect ion i n t he past mont h and has r et ur ned t o t he cli nic f or f ol low- up r eview of t he
i nf ect ion and hi s hyper t ensi on t her apy.
On t his vi si t , t he pat ient complai ns of di zzi ness, loss of ener gy, incr eased f requency
of ur inat i on, and edema of t he lower ext remit i es. His physi cal exami nat i on r eveals
an over weight man wit h a st andi ng blood pr essure of 175/ 100 mm Hg, moder at e
edema of t he ankl es, and a sl i ght t hi r d hear t sound. Labor at or y r esult s incl ude
blood ur ea ni t r ogen (BUN) of 45 mg/ dl , ser um cr eat i ni ne concent r at ion of 3. 7 mg/ dl ,
ser um cal ci um of 5. 3 mg/ mL, ser um pot assium of 6. 3 mg/ mL, and a hemat ocr it of
25. Ser um ir on, t ot al i r on- bi ndi ng capacit y, t ransf er r in sat ur at ion, and ser um f err it i n
ar e normal. Mi cr oscopi c ur i ne and chemi cal anal yses r eveal mi l d pr ot einur i a and a
specif i c gr avit y of 1. 010.
1. The hi st ory, physi cal exami nat i on, laborat ory val ues, and current si gns and
sympt oms suggest t hat t he pat i ent has whi ch of t he f ol l owi ng condi t i ons?
( A) Acut e r enal f ai lur e br ought on by a nephr ot oxi c dr ug (clar i t hr omycin, enalapr i l )
(B) Acut e r enal f ai lur e r esult i ng f rom r enal obst r uct ion by a kidney st one
(C) Acut e r enal f ai lur e pr ecipit at ed by sever e dehydr at ion
(D) Chr onic r enal f ai l ur e r esult i ng f r om hypert ensi on
View Answer 1. The answer i s D[] . 2. Treatment of t he pat i ent ' s f l ui d
ret ent i on and edema shoul d begi n wi t h al l of the f ol l owi ng EXCEPT
( A) rest r i ct i on of f lui d i nt ake
(B) t herapy wit h f ur osemi de or met ol azone
(C) t r eat ment of hyper t ension using a 8- blocker or angiot ensi n- conver t ing enzyme
i nhibit or
(D) di git al i s gl ycosi de t her apy if congest ive hear t f ai l ur e is pr esent
(E) hemodial ysi s
View Answer 2. The answer i s E[] . 3. The most l i kel y cause of t he anemia
seen i n t hi s pat i ent i s
( A) ur i nar y blood loss
(B) vit ami n B12 def iciency
(C) ir on def i ci ency
(D) decr eased r ed cel l l if e span and a def i ci ency of epoet in al f a
View Answer 3. The answer i s D[] . 4. Thi s pat i ent' s sympt oms seemed t o
appear suddenl y and may resul t f rom hi s hi st ory of uncont rol l ed hypertensi on.
Whi ch st at ement best descri bes hypert ensi on?
( A) A maj or cause of chr onic r enal f ai l ur e
(B) A maj or cause of acut e renal f ai l ur e
(C) A maj or cause of bot h chr oni c and acut e renal f ail ur e
(D) Onl y seen i n pat ient s whose r enal f ai l ur e has caused excessi ve f l uid r et ent ion
View Answer 4. The answer i s A[] . 5. When shoul d peri t oneal dial ysi s or
hemodial ysi s be consi dered t o treat t hi s pat i ent ' s renal f ai l ure?
( A) As soon as possible t o pr event f ur t her compli cat ions r esul t ing f r om decreased
r enal f unct i on
(B) Onl y when r enal f unct i on has decr eased t o a poi nt wher e f l ui d and el ect r ol yt e
st at us cannot be maint ai ned usi ng conser vat ive measur es
(C) On an i nt ermit t ent basi s as t he sit uat i on demands
(D) Onl y i f t he pat i ent is a ki dney t r ansplant candi dat e
View Answer 5. The answer i s B[] . 6. Acut e renal f ai l ure ( ARF) may be
caused by al l of t he f ol l owi ng EXCEPT
( A) acut e t ubular necr osis ( ATN) due t o dr ug t herapy ( e. g. , aminogl ycosi des,
cont r ast media)
(B) sever e hypot ension or cir culat or y col lapse
(C) decr eased car diac out put , as f r om congest ive hear t f ail ur e
(D) hemol ysis and myoglobi nur ia
(E) hyper kal emia
View Answer 6. The answer i s E[ and] . P. 1235


7. Lif e- t hreat eni ng cardiac arrhyt hmias due t o hyperkal emia shoul d be t reated
wi t h
( A) calci um chlor ide or calci um gluconat e int r avenousl y
(B) di goxi n or ot her di git al i s pr eparat ions
(C) loop di ur et ics t o r apidl y el imi nat e pot assium
(D) sodi um pol yst yr ene sul f onat e (SPS)
View Answer 7. The answer i s A[] . 8. Al umi num hydroxi de i s used t o treat
hyperphosphat emi a associ ated wi th renal f ai l ure. Chroni c use of al umi num
hydroxi de may cause al l of t he f ol l owi ng condi t i ons EXCEPT
( A) phosphat e deplet ion
(B) calci um r esorpt ion and bone demi ner al i zat ion
(C) anor exia and const ipat ion
(D) f luid r et ent i on
View Answer 8. The answer i s D[ and] . 9. The di uret i c of choi ce f or t he
i ni t i al t reatment of a pat i ent wi t h ei ther acut e or chroni c renal f ai l ure ( ARF,
CKD) whose creat i ni ne cl earance i s bel ow 25 mL/ mi n i s
( A) hydr ochl or ot hi azide
(B) bumet anide
(C) f ur osemide
(D) et hacr yni c aci d
View Answer 9. The answer i s C[] . 10. Epoet i n alfa i s used commonl y t o
t reat t he anemia associ at ed wit h chroni c renal f ai l ure (CKD) . Whi ch of t he
f ol l owi ng condi t i ons l i mi t s t he ef f ect i veness of epoet i n alf a?
( A) A pat i ent ' s al ler gy t o epoet in al f a
(B) Deplet ion of i r on st or es, r equir i ng or al or par ent er al supplement at ion
(C) The i nef f ect iveness of epoet in al f a, as 30% of pat ient s do not respond
(D) The anemia of chr onic r enal f ai l ur e is not due t o a l ack of epoet in alf a, so
epoet in alf a wi l l not amel iorat e.
View Answer 10. The answer i s B[ ] . P. 1236


ANSWERS AND EXPLANATIONS
1. The answer i s D [ I I . D. 1] .
The f l uid and elect r olyt e st at us of t he pat ient descr ibed in t he case, combined wit h
t he ur i ne- specif i c gr avit y, l ack of cr yst als or cast s i n t he ur i ne, and t he complai nt of
f at i gue, suggest chr oni c r enal f ai lur e resul t i ng f rom uncont r ol l ed hyper t ension or an
unknown cause. The ant ibiot ic t her apy ( clar it hr omyci n) and ant i hyper t ensi ve dr ug
( enalapr i l) ar e not nephr ot oxi c, and t he pat ient ' s blood pr essure and f luid st at us do
not indicat e a pr er enal cause.
2. The answer i s E [ I I . F. 1, 2] .
Al l of t hese measur es ar e i ndi cat ed as i ni t ial t her apy f or t he t r eat ment of edema and
f lui d r et ent ion due t o chr oni c r enal f ai l ur e except hemodial ysis, which shoul d be
r eser ved unt i l mor e conser vat ive measur es ar e t r i ed.
3. The answer i s D [ I I . D. 1. h] .
Ther e is no evidence of f r ank bl ood l oss. The decr eased hemat ocr i t and t he cl i nical
signs i ndi cat e t he anemi a of chr oni c r enal f ai l ur e due t o t he shor t ened r ed blood
cel l l if e span. Decr eased epoet i n alf a is t he cause.
4. The answer i s A [ I I . C. 2] .
Syst emi c long- st andi ng high blood pr essur e is t he second most common cause of
chr onic r enal f ai l ur e (CKD). Onl y malignant hyper t ension can cause acut e r enal
f ai l ur e ( ARF), which is not common. High blood pressur e is common af t er
subst ant ial r enal damage has occur r ed in bot h CKD and ARF, but i t does not occur
as t he f i rst or onl y manif est at i on.
5. The answer i s B [ I I . F. 7] .
Dial ysis shoul d be consider ed when t he pat i ent ' s r enal f unct ion has decr eased t o a
poi nt wher e conser vat i ve measur es ar e inef f ect i ve. Per it oneal di al ysis and
hemodi al ysis have associat ed compl icat i ons and mor bidit y, so int ermit t ent or ear l y
use of t hese t herapies i s not indicat ed. Pat ient s can be mai nt ained on di al ysis f or
ext ended per iods, so el igibi l it y f or t r ansplant is not r equir ed.
6. The answer i s E [ I . B. 1- 3] .
Hyperkal emia is a si gn of acut e and chr onic r enal f ai l ur e, r esult i ng f r om t he
decr eased renal f unct ion and changes i n acid- base balance.
7. The answer i s A [ I . F. 2. a] .
I nt r avenous cal ci um chl or ide or gluconat e i s used t o t r eat pot assium- induced
ar r hyt hmias. Digoxi n i s not indicat ed. Loop diur et i cs and sodium polyst yr ene
sulf onat e (SPS) do not have a si gnif icant enough ef f ect on pot assium in a short
per iod t o t r eat a l if e- t hr eat eni ng ar r hyt hmi a. SPS and l oop di ur et ics, al ong wi t h
dial ysi s, may be consider ed t o r emove pot assi um i n t he shor t t erm, pr event i ng t he
r ecur rence of arr hyt hmias.
8. The answer i s D [ I . F. 2. c. ( 5). ( d) . ( i ) , ( ii ) and ( i i i) ] .
Common ef f ect s of t he sust ai ned use of al umi num- cont aini ng ant acids i ncl ude
phosphat e depl et i on, calci um r esor pt i on, bone deminer al i zat i on, anor exia, and
const ipat i on. Fl uid r et ent ion does not r esult f r om t he use of ant acids cont aini ng
al uminum hydr oxide.
9. The answer i s C [ I . F. 3. a. ( 1). ( c) ] .
Fur osemide i s t he di ur et ic of choice f or t he init ial t r eat ment of a pat i ent wit h eit her
acut e or chr onic r enal f ai l ure ( ARF, CKD) whose cr eat ini ne clear ance is below 25
mL/ min. A t hiazi de di ur et ic has l it t l e ef f ect at a creat ini ne clear ance bel ow 25
mL/ min. Bumet ani de, t or semi de, and et hacr yni c aci d ar e appr opr iat e onl y if t he
pat ient i s al ler gi c t o f ur osemi de or i f r epeat ed doses of f ur osemi de ar e inef f ect ive.
10. The answer i s B [ I I . F. 5. a. ( 2) . ( d) ] .
Epoet i n alf a is widel y used and highl y ef f ect i ve i n t r eat ing t he anemi a associat ed
wit h chr onic r enal f ai l ur e (CKD) . Few r eport s of pat ient s r ef ract or y t o epoet in al f a
t her apy have appear ed i n medi cal l i t er at ur e. However , t he deplet ion of ir on st ores
wi l l not al low t he f ormat ion of r ed blood cel l s, even i n t he pr esence of appr opr i at e
amount s of epoet i n alf a. Al l CKD pat ient s receivi ng epoet in alf a r equir e some ir on
supplement at ion, and most pat ient s r equir e par ent eral i r on t o achieve suf f ici ent
suppl i es t o cont inue devel opi ng hemoglobi n over t he t erm of t heir i l l ness.

57
Cancer Chemotherapy
Judy Chase
I l a Maewal
I. PRINCIPLES OF ONCOLOGY.
The t erm cancer r ef ers t o a het erogeneous group of diseases caused by an
impairment of t he normal f unct ioni ng of genes, which leads t o genet i c damage.
A. Charact eri st i cs of cancer cel l s. Cancer cell s ar e also r ef er r ed t o as t umor s, or
neoplasms. Tumor s ar i se f r om a singl e abnor mal cel l , which cont i nues t o divide
i ndef i ni t el y. Uncont r ol led gr owt h, abi l it y t o invade local t issues, and abi l it y t o
spr ead, or metast asi ze, ar e char act er ist ics of cancer cel ls.
1. Carci nogenesi s. The mechanism of how cancer s occur is t hought t o be a
mult i st age, mult if act or ial pr ocess t hat i nvol ves bot h genet i c and envir onment al
f act ors.
a. I ni t i at i on. The f ir st st ep invol ves t he exposur e of normal cel ls t o a carci nogen,
pr oduci ng genet ic damage t o a cell .
b. Promot i on. The envi r onment becomes alt er ed t o al l ow pr ef er ent i al gr owt h of
mut at ed cel l s over normal cel l s. The mut at ed cel l s become cancer ous.
c. Progressi on. I ncr eased prol i f er at ion of cancer cell s al l ows f or invasi on i nt o l ocal
t issue and met ast asis.
2. Types of cancer. Tumor s can be beni gn or mal i gnant . Beni gn t umor s ar e
gener al l y slow gr owi ng, resemble normal cel ls, are l ocal i zed, and are not harmf ul .
Mal i gnant t umors of t en pr ol if er at e mor e r api dl y, have an at ypical appear ance,
i nvade and dest roy sur roundi ng t issues, and are harmf ul i f lef t unt r eat ed. Mal i gnant
cancer s are f ur t her cat egor ized by t he locat ion f rom wher e t he t umor cel ls ar i se.
a. Sol i d t umors. Carci nomas ar e t umors of epit hel i al cel ls. These i ncl ude speci f ic
t issue cancer s ( e. g. , l ung, colon, br east ). Sarcomas i ncl ude t umors of connect i ve
t issue such as bone ( e. g. , ost eosar coma) or muscl e ( e. g. , leiomyosar coma).
b. Hemat ol ogi cal mal i gnanci es. Lymphomas are t umor s of t he lymphat i c syst em
and i ncl ude Hodgkin and non- Hodgki n l ymphomas. Leukemias ar e t umors of bl ood-
f orming element s and ar e classif i ed as acut e or chr onic, myeloi d or lymphoi d.
B. I nci dence. Cancer is t he second l eadi ng cause of deat h in t he Unit ed St at es.
The l i f et i me pr obabi l i t y of devel opi ng cancer is > 30%. The est imat ed i ncidences of
new cancer s and cancer -r el at ed deat hs by si t e are given i n Fi gur e 57- 1. The most
common cancer s are br east , prost at e, l ung, and color ect al. The leadi ng cause of
cancer deat h is l ung cancer .
C. Cause. Many f act or s have been implicat ed in t he ori gi n of cancer. Some of t hese
f act ors ar e as f ol lows:
1. Vi ruses, i ncludi ng Epst ein- Bar r vi r us (EBV), hepat it is B vir us ( HBV) , and human
papi l lomavi r us ( HPV)
2. Envi ronmental and occupat i onal exposures, such as ioni zi ng and ult r aviol et
r adiat i on and exposur e t o chemical s, i ncludi ng vi nyl chl or ide, benzene, and
asbest os
3. Lif est yl e f act ors, such as hi gh- f at , low- f iber di et s and t obacco and et hanol use
4. Medi cat i ons, i ncl udi ng alkylat i ng agent s and i mmunosuppr essant s
5. Genet i c f act ors, incl udi ng i nher it ed mut at i ons, cancer - causing genes
( oncogenes), and def ect ive t umor -suppr essor genes
D. Det ect i on and diagnosi s ar e cr it ical f or t he appr opr iat e t reat ment of cancer.
Ear l ier det ect ion may impr ove response t o t r eat ment .
P. 1238



Figure 57-1. Cancer incidence and deaths.
Leading cancer sites for estimated new cases and
deaths by gender in the United States, 2007
estimates.
a
Excludes basal and squamous cell skin
cancers and in situ carcinomas except urinary
bladder. [Adapted with permission from Jemal A,
Murray T, Ward E, et al. Cancer statistics, 2007.
CA Cancer J Clin 2007;57:43-66.]
1. Warni ng si gns of cancer have been out l i ned by t he Amer ican Cancer Societ y.
a. Change in bowel or bl adder habi t s
b. A sor e t hat does not heal
c. Unusual bleedi ng or di schar ge
d. Thickeni ng or lump in t he br east or elsewher e
e. I ndi gest ion or dif f icult y swal lowi ng
f . Obvious change i n a wart or mole
g. Nagging cough or hoar seness
2. Gui del i nes f or screeni ng asympt omat ic people f or t he pr esence of cancer have
been est abl i shed by t he Amer ican Cancer Societ y, t he Nat ional Cancer I nst it ut e,
and t he U. S. Pr event ive Healt h Ser vices Task For ce. Because many cancer s do not
pr oduce si gns or sympt oms unt i l t hey have become lar ge, t he goal of scr eening i s t o
det ect cancers ear ly, when t he disease is cur able, and t o reduce mor t al it y. The
dif f er ent set s of gui del i nes var y sl ight l y i n t hei r r ecommendat i ons f or age and
f r equency of scr eeni ng pr ocedur es. Table 57- 1 provides t he Amer ican Cancer
Societ y' s r ecommendat ions f or scr eeni ng.
3. Tumor markers are biochemical i ndicat or s of t he pr esence of neoplast i c
pr ol if er at i on det ect ed i n ser um, plasma, or ot her body f luids. These t umor marker s
may be used init i al l y as scr eeni ng t est s, t o r eveal f urt her inf ormat ion af t er abnor mal
t est r esult s, or t o moni t or t he ef f icacy of t her apy. Elevat ed levels of t hese markers
ar e not def init i ve f or t he pr esence of
P. 1239

cancer because l evel s can be elevat ed in ot her beni gn and malignant condit i ons,
and f alse- posit i ve r esult s do occur . Exampl es of some commonl y used marker s
i ncl ude
Table 57-1. American Cancer Society's Recommendations for the Early
Detection of Cancera
Cancer Site Population Starting
Age
Tests or Procedures
Breast Women 20+ Breast self-examination
20+ Clinical breast examination
40+ Mammography
Colorectal Men and
Women
50+ Fecal occult blood test or fecal
immunochemical test
50+ Flexible sigmoidoscopy
50+ Colonoscopy
50+ Double-contrast barium enema
Prostate Men 50+ Digital rectal examination
50+ Prostate-specific antigen
Cervix Women 18+ Pap (Papanicolaou) test
a
In average-risk, asymptomatic people.
Adapted with permission from Smith RA, Cokkinides V, Eyre HJ, et al.
American Cancer Society guidelines for the early detection of cancer. CA
Cancer J Clin 2005;55:31-44.

a. Car cinoembr yonic ant igen ( CEA) f or col or ect al cancer
b. q- Fet opr ot ein ( AFP) f or hepat ocel l ular carci noma
c. Pr ost at e- speci f ic ant igen ( PSA) f or pr ost at e cancer
4. Tumor bi opsy. The def ini t ive t est f or t he pr esence of cancerous cel ls is a biopsy
and pat hol ogical examinat i on of t he bi opsy speci men. Sever al t ypes of pr ocedur es
ar e used in t he pat hol ogical anal ysis of t umor s, i ncl udi ng evaluat i ng t he
mor phol ogical f eat ur es ( appear ance) of t he t issue and cel ls, looking f or cel l - sur f ace
marker s, and cyt ogenet ic eval uat ion f or speci f ic chr omosomal abnormal it ies.
5. Imagi ng st udi es, such as x- r ays, CT scans, MRI , and posit r on- emissi on
t omogr aphy (PET) , may be used t o aid i n t he di agnosis or locat ion of a t umor and t o
moni t or response t o t r eat ment .
6. Ot her laborat ory t est s commonly used f or cancer di agnosi s i ncl ude complet e
blood count s (CBCs) and blood chemist r ies. A CBC measur es t he level s of t he t hr ee
basic blood cel ls—whit e cel ls, red cel l s, and plat elet s.
a. The CBC wil l of t en i ncl ude an ANC ( absolut e neut r ophi l count ) whi ch measur es
t he absolut e number of neut r ophi ls in your whi t e blood count . The ANC is calcul at ed
by mul t ipl yi ng t he whit e bl ood count (WBC) × t ot al neut r ophi ls ( segment ed
neut r ophi ls% + segment ed bands%) × 10 = ANC. Segment ed neut r ophi ls are of t en
l ist ed as “ pol ys” and segment ed bands ar e i mmat ur e “ pol ys. ”
E. Stagi ng i s t he cat egor i zi ng of pat ient s accor di ng t o t he ext ent of t heir disease.
The st age of t he disease i s used t o det ermine pr ognosis and t reat ment . Two
dif f er ent st aging syst ems ar e widel y empl oyed f or t he st agi ng of neoplasms.
1. TNM cl assi f i cat i on
a. T indicat es t umor size and is classif ied f r om 0 t o 4, wit h 0 i ndicat ing t he absence
of t umor .
b. N i ndicat es t he presence and ext ent of r egional l ymph node spr ead and is
classi f ied f r om 0 t o 3, wit h 0 indicat i ng no r egi onal l ymph node invol vement and 3
i ndicat i ng ext ensi ve i nvol vement .
c. M i ndicat es t he pr esence of dist ant met ast ases and i s be classi f ied as 0 ( f or
absence) or 1 (f or pr esence of dist ant met ast ases) .
d. For exampl e, T2N1M0 i ndicat es a moder at e- si ze t umor wi t h l imit ed nodal di sease
and no dist ant met ast ases.
2. AJCC st aging, developed by t he Amer ican Joi nt Commit t ee on Cancer, cl assi f ies
cancer s as st ages 0- IV. An assi gned TNM t r anslat es i nt o a st age. A high number
i ndicat es lar ger t umors wit h ext ensi ve nodal i nvol vement and/ or met ast asi s.
Gener all y, high number s also indicat e a worse prognosis. Ther e ar e specif i c st aging
cr it er ia f or each t umor t ype.
P. 1240


F. Survi val depends on t he t umor t ype, t he ext ent of di sease, and t he t herapy
r eceived. Alt hough some pat ient s are f ree of al l det ect able disease, not al l pat ient s
ar e cur ed. Oncologist s pr ef er t o use t he t erm compl et e response or remi ssi on t o
i ndicat e a pat ient wit h no evidence of di sease af t er t r eat ment . Thi s i s not a synonym
f or cur e. For some slow- gr owing t umor s, t hese di sease- f r ee peri ods may ext end f or
10- 15 year s af t er t he i nit ial r emission. However , a number of pat ient s who have
achieved compl et e r emission may r elapse.
II. CELL LIFE CYCLE.
Knowledge of t he cel l l if e cycle and cel l cycle ki net ics i s essent i al t o t he
under st anding of t he act ivit y of chemot her apy agent s in t he t r eat ment of cancer
( Figur e 57- 2) .
A. Phases of t he cel l cycl e
1. M phase, or mi t osi s, i s t he phase i n which t he cell di vides i nt o t wo daught er
cel ls.
2. G1 phase, or postmi tot i c gap, is when RNA and t he pr ot eins r equir ed f or t he
special i zed f unct ions of t he cell ar e synt hesi zed i n pr epar at i on f or DNA synt hesis.
3. S phase is t he phase i n which DNA synt hesis and r epl icat i on occur s.
4. G2 phase, or t he premi t ot i c or post synt het i c gap, i s t he phase in whi ch RNA
and t he enzymes t opoisomer ase I and I I ar e pr oduced t o pr epar e f or dupl icat i on of
t he cell .
5. G0 phase, or resti ng phase, i s t he phase i n which t he cell is not commit t ed t o
di vision. Cel l s i n t his phase are gener al l y not sensi t ive t o chemot her apy. Some of
t hese cel l s may reent er t he act ivel y di vi di ng cel l cycl e. I n a pr ocess cal led
recrui tment , some chemot her apy r egimens ar e desi gned t o enhance t his r eent r y by
kil l i ng a lar ge number of act ivel y dividi ng cel ls.
B. Cel l growt h ki net i cs. Several t erms descr ibe cel l gr owt h ki net ics.
1. Cel l growt h f racti on is t he pr oport ion of cel ls i n t he t umor dividi ng or pr epar i ng
t o divide. As t he t umor enlar ges, t he cell gr owt h f r act ion decr eases because a
lar ger pr oport ion of cell s may not be able t o obt ai n adequat e nut r i ent s and blood
suppl y f or repl icat i on.
2. Cel l cycl e t ime i s t he aver age t ime f or a cel l t hat has j ust complet ed mit osis t o
gr ow and again di vi de and agai n pass t hr ough mit osis. Cel l cycle t ime is speci f ic f or
each i ndivi dual t umor .

Figure 57-2. The cell cycle. The cell growth
cycle, emphasizing the relationship between
proliferating cell populations. [Reprinted with
permission from Lenhard RE Jr., Osteen RT,
Gansler T, et al., eds. The American Cancer
Society's Clinical Oncology. Atlanta, American
Cancer Society, 2001.]
P. 1241



Figure 57-3. The gompertzian growth curve.
During the early stages of its development, a
tumor grows exponentially. But as a tumor
enlarges, its growth slows. By the time a tumor
becomes large enough to cause symptoms and be
clinically detectable, the majority of its growth
has already occurred and is no longer exponential.
[Reprinted with permission from Lenhard MJ Jr.,
et al., eds. The American Cancer Society's
Clinical Oncology. Atlanta, American Cancer
Society, 2001.]
3. Tumor doubl i ng t i me is t he t ime f or t he t umor t o double in si ze. As t he t umor
get s l ar ger, it s doubl i ng t ime get s l onger because it cont ains a smal ler pr opor t i on of
act ivel y di vidi ng cel l s owing t o rest r i ct i ons of space, nut r ient avai labi l it y, and bl ood
suppl y.
4. The gompert zian growt h curve i l l ust r at es t hese cel l gr owt h concept s ( Figur e 57-
3) .
C. Tumor cel l bur den i s t he number of t umor cell s i n t he body.
1. Because of t he lar ge number of cel l s r equir ed t o pr oduce sympt oms and be
cl i ni cal l y det ect abl e ( appr oximat el y 10
9
cells) , t he t umor may be i n t he plat eau
phase of t he growt h curve by t he t ime i t is det ect ed.
2. The cel l ki l l hypot hesi s st at es t hat a cer t ain per cent age of t umor cel ls wi l l be
kil led wi t h each cour se of cancer chemot her apy.
a. As t umor cel ls are kil l ed, cell s i n G0 may be recr ui t ed i nt o G1 , r esul t i ng i n t umor
r egrowt h.
b. Thus r epeat ed cycles of chemot her apy are r equir ed t o achieve a complet e
r esponse or r emi ssion ( Figur e 57- 4) .
c. The per cent age of cel ls ki l led depends on t he chemot her apy dose.
3. I n t heor y, t he t umor bur den would never reach absolut e zer o because only a
per cent age of cell s ar e kil led wit h each cycl e. Less t han 10
4
cell s may depend on
el i mi nat ion by t he host ' s immune syst em.
D. Chemot her apeut ic agent s may be classif i ed accor di ng t o t heir rel i ance on cel l
cycl e ki net i cs f or t heir cyt ot oxi c ef f ect . Combinat ions of chemot her apy agent s t hat
ar e act ive i n dif f er ent phases of t he cell cycle may r esul t i n a gr eat er cel l ki l l. A cel l
cycl e classif i cat ion of some commonl y used chemot her apeut ic agent s is given i n
I I . D. 1. a, b, c and d.
1. Phase- speci f i c agent s ar e most act ive against cel ls t hat are i n a speci f ic phase
of t he cel l cycl e. These agent s are most ef f ect ive agai nst t umors wi t h a high gr owt h
f r act ion. Theor et ical l y, by administ er i ng t hese agent s as cont i nuous i nt r avenous
i nf usions or by mult i pl e r epeat ed doses, i t may i ncr ease t he l i kel i hood of hit t i ng t he
maj or it y of cel ls i n t he specif ic phase at any one t i me. Ther ef or e, t hese agent s ar e
also consider ed schedule-dependent agent s. Examples ar e as f ol lows:
P. 1242



Figure 57-4. Chemotherapy and tumor cell
survival. Relationship between tumor cell
survival and chemotherapy administration. The
exponential relationship between chemotherapy
drug dose and tumor cell survival dictates that a
constant proportion, not number, of tumor cells is
killed with each cycle of treatment. In this
example, each cycle of drug administration
results in 99.9% (3 log) cell kill, and 1 log of cell
regrowth occurs between cycles. The broken line
indicates what would occur if the last cycle of
therapy were omitted. Despite complete clinical
remission of disease, the tumor would ultimately
recur. [Reprinted with permission from Lenhard
MJ Jr., et al., eds. The American Cancer Society's
Clinical Oncology. Atlanta, American Cancer
Society, 2001.]
a. M phase: mit ot i c i nhibi t or s (e. g. , vi nca alkal oids, t axanes)
b. G1 phase: aspar agi nase, pr edni sone
c. S phase: ant imet aboli t es
d. G2 phase: bleomycin, et oposide
2. Phase- nonspeci f i c agent s ar e ef f ect i ve whi l e cel ls ar e in t he act ive cycl e but do
not r equi r e t hat t he cell be i n a par t icular phase. These agent s gener al l y show mor e
act ivit y agai nst slow- gr owing t umor s. They may be admini st er ed as singl e bol us
doses because t heir act i vi t y i s i ndependent of t he cell cycl e. These dr ugs ar e also
consider ed dose- dependent agent s. Examples ar e alkylat i ng agent s and ant it umor
ant ibi ot i cs.
3. Cel l cycl e-nonspeci f i c agent s ar e ef f ect i ve i n al l phases, i ncludi ng G0 .
Exampl es ar e carmust i ne, lomust ine, and r adiat ion.
III. CHEMOTHERAPY
A. Obj ect i ves of chemot herapy
1. A cure may be sought wit h aggr essive t her apy f or a pr olonged per iod of t i me t o
er adicat e al l disease. For l eukemias, t his cur at ive appr oach may consist of
r emissi on i nduct i on, at t empt ing t he maximal cel l ki l l, f ol lowed by consol idat ion
t her apy t o er adicat e al l cl i nical l y undet ect able di sease and t o lower t he t umor cel l
bur den bel ow 10
3
, at which l evel host i mmunol ogi cal def enses may keep t he cel ls i n
cont r ol.
2. If t he goal is pal l i at i on, chemot her apy may be gi ven t o decr ease t umor size,
cont r ol gr owt h, and r educe sympt oms. Pal l i at ive t her apy is usual l y gi ven when
complet e er adicat ion of t he t umor i s consider ed unl ikel y or t he pat ient r ef uses
aggr essive t her apy.
P. 1243


3. Adj uvant chemot her apy is gi ven af t er mor e def i nit i ve t her apy, such as sur ger y,
t o el imi nat e any r emaini ng disease or undet ect ed micromet ast asis.
4. Neoadj uvant chemot her apy i s given t o decr ease t he t umor bur den bef or e
def ini t i ve t her apy, such as sur ger y or r adiat ion.
5. Sal vage chemot her apy i s given as an at t empt t o get a pat i ent int o r emissi on,
af t er pr evious t her apies have f ai led.
B. Chemot herapy dosi ng may be based on body wei ght , body surf ace ar ea (BSA) ,
or ar ea under t he concent r at i on ver sus t ime cur ve ( AUC) . BSA is most f requent l y
used because it provides an accur at e compar ison of act ivit y and t oxicit y acr oss
species. I n addit i on, BSA cor rel at es wit h cardi ac out put , whi ch det ermi nes renal and
hepat ic bl ood f l ow and t hus af f ect s dr ug el i mi nat i on.
C. Dosi ng adj ustment s may be r equi r ed f or kidney or l i ver dysf unct ion t o pr event
t oxicit y.
D. Combi nat i on chemot herapy is usual l y mor e ef f ect i ve t han si ngle- agent t herapy.
1. When combini ng chemot her apy agent s, f act ors t o consi der incl ude
a. Ant i t umor act ivit y
b. Di f f er ent mechani sms of act ion
c. Minimal ly over lappi ng t oxi cit i es
2. The r easons f or administ er i ng combi nat ion chemot her apy i ncl ude:
a. Overcomi ng or prevent i ng r esist ance
b. Cyt ot oxicit y t o r est ing and di vidi ng cel l s
c. Biochemical enhancement of ef f ect
d. Rescue of normal cel l s
3. Dosi ng and schedul i ng of combi nat ion r egimens ar e i mpor t ant because t hey ar e
designed t o all ow r ecover y of normal cel ls. These r egimens gener al ly ar e gi ven as
shor t cour ses of t her apy i n cycles.
4. Acronyms of t en ar e used t o desi gnat e chemot her apy r egimens. For exampl e,
CMF r ef er s t o a combinat i on of cyclophosphamide, met hot rexat e, and f luor our aci l
used i n t he t r eat ment of breast cancer.
E. Admi ni st rat i on
1. Rout es of administ r at ion var y, alt hough i nt r avenous ( I V) administ r at i on is
empl oyed most commonl y.
2. Ot her admi ni st r at ion t echniques i ncl ude or al, subcut aneous, int r at hecal , int r a-
ar t er ial , i nt r aper i t oneal, i nt r avesical, cont i nuous I V inf usion, bol us I V i nf usion, and
hepat ic ar t er y inf usion.
3. Dr ugs t hat may be given i nt rat hecal l y ar e met hot r exat e and cyt ar abi ne. Dr ugs
should not be administ er ed by t he int r at hecal r out e wit hout specif ic i nf ormat ion
suppor t i ng i nt r at hecal administ r at i on. Deat hs have occur r ed when vi ncr ist ine and
ot her dr ugs have been administ er ed by t he i nt r at hecal r out e. Caut ion shoul d be
used i n t he prepar at ion and del i ver y of dr ugs t o be used in t hi s manner .
4. Pr oduct s wit h di f f erent f ormulat ions, incl udi ng l i posomal or pegyl at ed agent s
( e. g. , li posomal doxor ubici n, pegf i lgr ast im) , ar e bei ng used t o decr ease f r equency
of administ r at ion and/ or reduce t oxici t ies.
F. Response t o chemot herapy is def i ned i n a number of ways and does not always
corr el at e wit h pat ient sur vi val.
1. Compl et e response ( CR) i ndi cat es disappear ance of al l cl i nical , gr oss, and
mi croscopic disease.
2. Part i al response (PR) indicat es a > 50% r educt i on i n t umor si ze, last i ng a
r easonabl e per iod of t ime. Some evidence of di sease r emai ns af t er t her apy.
3. Response rate (RR) i s def i ned as CR + PR.
4. Stabl e di sease i ndicat es t umor t hat nei t her grows nor shr inks signi f icant ly ( <
25% change i n si ze) .
P. 1244


5. Progressi on or no response af t er t her apy is def ined by a > 25% i ncr ease i n
t umor si ze or t he appear ance of new lesi ons.
G. Fact ors af f ect i ng response t o chemot herapy
1. Tumor cel l het erogenei t y. Lar ge t umor s have complet ed mul t iple cel l divisi ons,
r esul t i ng i n sever al mut at i ons and genet i cal l y di ver se cel ls.
2. Drug resi st ance. The Gol di e-Col dman hypothesi s st at es t hat genet ic changes
ar e associat ed wit h dr ug r esist ance, and t he pr obabi l i t y of r esi st ance incr eases as
t umor si ze i ncr eases. The hypot hesis assumes t hat at t he t ime of diagnosi s, most
t umors possess r esist ant clones. The most wel l -st udi ed mechani sm of resist ance
i nvol ves t he mdr (mult i dr ug r esi st ance) gene, whi ch codes f or membrane- bound P-
gl ycopr ot ein. P- glycopr ot ei n ser ves as a channel t hr ough whi ch cel l ular t oxi ns ( i. e. ,
chemot her apeut ic agent s) may be excr et ed f rom t he cel l .
3. Dose i nt ensi t y is def ined as a specif i c dose del i ver ed over a speci f ic per iod of
t ime. Occasional l y, t he f ul l dose cannot be given or a cycle is delayed owi ng t o
compli cat ions or t oxicit i es. Subopt i mal doses have resul t ed i n r educed r esponse
r at es and sur vi val . Dose densi t y i nvol ves shor t eni ng t he usual i nt er val bet ween
doses t o maxi mi ze t he dr ug ef f ect s on t he t umor gr owt h kinet i cs.
4. Pat i ent - specif i c f act ors such as poor f unct i onal st at us, impai r ed or gan f unct ion,
or concomit ant diseases may compr omise how a chemot her apy r egimen is gi ven and
af f ect how t he pat i ent r esponds t o t reat ment .
IV. CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS
A. Al kylat i ng agent s wer e t he f ir st group of ant i neoplast i c agent s. The prot ot ype of
t hi s class is mechlor et hamine, or ni t rogen mustard, which was resear ched as a
chemical war f ar e agent . Alkylat i ng agent s cause cr oss- li nki ng and abnormal base
pair ing of DNA st r ands, which i nhi bi t r epl icat ion of t he DNA. This mechani sm i s
known as al kylat i on. These ar e phase- nonspecif i c agent s. Exampl es of al kylat ing
agent s and t hei r t oxicit i es ar e li st ed i n Table 57- 2.
B. Most of t he ant i t umor ant i bi ot i cs are obt ained f r om organisms of t he
St r ept omyces genus. These agent s may act by eit her alkylat ion (mit omyci n) or
i nt ercal at i on. I nt er calat ion i s t he pr ocess by whi ch t he dr ug sl i des bet ween DNA
base pair s and inhibit s DNA synt hesis. These ar e phase- nonspecif ic agent s.
Exampl es of ant it umor ant i bi ot ics and t heir t oxi ci t ies ar e l ist ed in Table 57- 2.
C. Ant i metabol i t es ar e st r uct ur al analogs of nat ur al l y occurr i ng subst r at es f or
biochemi cal r eact ions. They i nhibi t DNA synt hesi s by act ing as f alse subst it ut i ons i n
t he product ion of nucl ei c aci ds. These ar e S phase- speci f ic agent s. Examples of
ant imet abol i t es and t heir t oxi ci t ies ar e l ist ed in Tabl e 57- 2.
D. Mi t ot i c i nhi bi t ors. The vi nca alkaloids ar r est cel l divisi on by pr event i ng
mi crot ubul e f ormat ion. The t axanes pr omot e mi crot ubule assembly and st abi l i zat ion,
t hus pr ohibit i ng cel l division. These are M phase-specif ic agent s. Exampl es of t hese
agent s and t hei r t oxicit i es ar e li st ed i n Table 57- 2.
E. Topoi somerase i nhi bi t ors i nhi bit t he enzymes t opoisomer ase I or I I . The
t opoisomer ases ar e necessar y f or DNA repl icat ion and RNA t r anscr ipt ion. These ar e
G2 phase-specif ic agent s. Examples of t hese agent s and t heir t oxi cit ies ar e l ist ed in
Table 57- 2.
F. Enzymes. Aspar aginase is an enzyme t hat causes t he degr adat ion of t he
essent i al amino acid aspar agi ne t o aspart i c aci d and ammoni a ( Table 57- 2). Unl i ke
normal cel ls, t umor cel ls lack t he abi l it y t o synt hesi ze aspar agine. Thi s i s a G1
phase- specif ic agent .
G. Protei n t yrosi ne ki nase i nhi bi t ors. I mat inib mesyl at e is a select i ve t yr osi ne
kinase i nhi bit or t hat causes apopt osis or arr est of growt h in cel ls expr essi ng t he
Bcr - Abl oncopr ot ei n ( Table 57- 2). Bcr - Abl is t he pr oduct of a specif ic chr omosomal
abnormali t y ( Phi l adel phia chr omosome), which is pr esent in vi rt ual l y al l pat i ent s
wit h chr onic myelogenous leukemi a (CML). It i s t he f ir st approved ant i neoplast ic
agent desi gned t o have t ar get ed enzyme act ivit y. Er lot i ni b i s a select ive i nhi bi t or of
epidermal gr owt h f act or recept or (EGFR) t yr osine kinase. EGFR i s a cell sur f ace
r ecept or t hat is over expr essed i n cert ain sol i d t umor s. The bi ndi ng of t he EGFR
r ecept or t o i t s l igand act i vat es t yr osi ne ki nase, which t hen st imul at es cel l
pr ol if er at i on and gr owt h of t he t umor. Er lot ini b bl ocks t he t yr osi ne ki nase signal i ng
cascade and i nhi bi t s cancer cel l gr owt h. These agent s ar e also known as t arget ed
agent s because t hey af f ect specif i c r ecept ors t o i nduce cancer cel l deat h.
P. 1245


P. 1246


P. 1247


Table 57-2. Cancer Chemotherapeutic Agents by Mechanism of Action and
Toxicities
Drug Toxicities
Alkylating agents
Altretamine
(hexamethylmelamine)
Nausea and vomiting, myelosuppression,
paresthesias, CNS toxicity
Busulfan Myelosuppression, pulmonary fibrosis,
aplastic anemia, skin hyperpigmentation
Carmustine (BCNU) Delayed myelosuppression, nausea and
vomiting, hepatotoxicity
Chlorambucil Myelosuppression, pulmonary fibrosis,
hyperuricemia
Carboplatin Myelosuppression, nausea and vomiting,
peripheral neuropathy, ototoxicity
Cisplatin Nephrotoxicity, nausea and vomiting,
peripheral neuropathy, myelosuppression,
ototoxicity
Cyclophosphamide Myelosuppression, hemorrhagic cystitis,
immunosuppression, alopecia, stomatitis,
SIADH
Dacarbazine (DTIC) Myelosuppression, nausea and vomiting,
flulike syndrome, hepatotoxicity, alopecia,
flushing
Estramustine Myelosuppression, ischemic heart disease,
thrombophlebitis, hepatotoxicity, nausea
and vomiting
Ifosfamide Myelosuppression, hemorrhagic cystitis,
somnolence, confusion
Lomustine (CCNU) Delayed myelosuppression, nausea and
vomiting, hepatotoxicity, neurotoxicity
Mechlorethamine Myelosuppression, nausea and vomiting,
phlebitis, gonadal dysfunction
Melphalan Myelosuppression, anorexia, nausea and
vomiting, gonadal dysfunction
Oxaliplatin Sensory peripheral neuropathy, nausea and
vomiting, diarrhea, mucositis,
transaminase elevations, alopecia
Procarbazine Myelosuppression, nausea and vomiting,
lethargy, depression, paresthesias,
headache, flulike syndrome
Streptozocin Renal toxicity, nausea and vomiting,
diarrhea, altered glucose metabolism, liver
dysfunction
Temozolomide Myelosuppression, nausea and vomiting,
fatigue, headache, peripheral edema
Thiotepa Myelosuppression, nausea and vomiting,
mucositis, skin rashes
Antitumor antibiotics
Bleomycin Pneumonitis, pulmonary fibrosis, fever,
anaphylaxis, hyperpigmentation, alopecia
Dactinomycin Stomatitis, myelosuppression, anorexia,
nausea and vomiting, diarrhea, alopecia
Daunorubicin Myelosuppression, cardiotoxicity,
stomatitis, alopecia, nausea and vomiting
Doxorubicin Myelosuppression, cardiotoxicity,
stomatitis, alopecia, nausea and vomiting
Epirubicin Myelosuppression, nausea and vomiting,
cardiotoxicity, alopecia
Idarubicin Myelosuppression, nausea and vomiting,
stomatitis, alopecia, cardiotoxicity
Mitomycin C Myelosuppression, nausea and vomiting,
anorexia, alopecia, stomatitis
Mitoxantrone Myelosuppression, cardiotoxicity,
alopecia, stomatitis, nausea and vomiting
Valrubicin Urinary frequency, dysuria, hematuria,
bladder spasm, incontinence, cystitis (For
intravesical bladder administration)
Antimetabolites
Azacytidine Myelosuppression, nausea and vomiting,
diarrhea, constipation, injection site pain,
muscle aches, fatigue, edema, dizziness
Capecitabine Diarrhea, stomatitis, nausea and vomiting,
hand-foot syndrome, myelosuppression
Cladribine (2Cda) Myelosuppression, fever, rash
Cytarabine (Ara-C) Myelosuppression, nausea and vomiting,
diarrhea, stomatitis, hepatotoxicity, fever,
conjunctivitis, CNS toxicity
Decitabine Myelosuppression, petechiae, fatigue,
diarrhea, constipation, hyperglycemia,
myalgias/arthralgias, rash, edema
Fludarabine Myelosuppression, nausea and vomiting,
fever, malaise, pulmonary infiltrates
Floxuridine Hepatotoxicity, gastritis, mucositis
5-Fluorouracil Stomatitis, myelosuppression, diarrhea,
nausea and vomiting, cerebellar ataxia
Gemcitabine Myelosuppression, fever, flu-like
syndrome, rash, mild nausea and vomiting
Hydroxyurea Myelosuppression, mild nausea and
vomiting, rash
6-Mercaptopurine Myelosuppression, nausea and vomiting,
anorexia, diarrhea, cholestasis
Methotrexate Mucositis, myelosuppression, pulmonary
fibrosis, hepatotoxicity, nephrotoxicity,
diarrhea, skin erythema
Nelarabine Neurologic toxicities disorders,
somnolence, hypoesthesia, and seizures),
thrombocytopenia, anemia, and
neutropenia, fatigue, and nausea
Pemetrexed Myelosuppression, edema, fatigue, nausea
and vomiting, diarrhea, mucositis, skin
rash
Pentostatin Nephrotoxicity, CNS depression,
myelosuppression, nausea and vomiting,
conjunctivitis
6-Thioguanine Myelosuppression, hepatotoxicity,
stomatitis
Mitotic inhibitors
Docetaxel Myelosuppression, fluid retention,
hypersensitivity, paresthesias, rash
alopecia
Ixabepilone Peripheral sensory neuropathy,
neutropenia, fatigue, myalgia, arthralgia,
stomatitis, hypersensitivity reactions,
anorexia
Paclitaxel Myelosuppression, peripheral neuropathy,
alopecia, mucositis, anaphylaxis, dyspnea
Vinblastine Myelosuppression, paralytic ileus,
alopecia, nausea, stomatitis
Vincristine Peripheral neuropathy, paralytic ileus,
SIADH
Vinorelbine Peripheral neuropathy, myelosuppression,
nausea and vomiting, hepatic dysfunction
Topoisomerase inhibitors
Etoposide Myelosuppression, nausea and vomiting,
diarrhea, fever, hypotension with infusion,
alopecia
Irinotecan Myelosuppression, diarrhea, nausea and
vomiting, anorexia
Teniposide Myelosuppression, nausea and vomiting,
alopecia, hepatotoxicity, hypotension with
infusion
Topotecan Myelosuppression, fever, flulike
syndrome, nausea and vomiting
Enzymes
Asparaginase Allergic reactions, nausea and vomiting,
liver dysfunction, CNS depression,
hyperglycemia
Pegasparaginase Hypersensitivity reactions, hepatotoxicity,
fever, nausea and vomiting
Protein tyrosine kinase inhibitors
Dasatinib Pleural and pericardial effusions, diarrhea,
myelosuppresion, gastrointestinal
hemorrhage, rash
Erlotinib (OSI-774) Acneiform rash, diarrhea, nausea, pruritus,
fatigue, eye irritation
Imatinib mesylate (STI-571) Myelosuppression, hepatotoxicity, fluid
retention, nausea, diarrhea
Lapatinib Diarrhea, rash, nausea, fatigue, anemia,
left ventricular and liver dysfunction
Nilotinib Rash, headache, nausea, fatigue,
thrombocytopenia, neutropenia
Sorafenib Hand-and-foot syndrome, fatigue,
hypertension, rash/desquamation, diarrhea
Sunitinib Hand-and-foot syndrome, skin and hair
discoloration, fatigue, diarrhea,
hypothyroidism, hypertension, left
ventricular dysfunction,
mucositis/stomatitis, nausea
Temsirolimus Hyperglycemia, hypophosphatemia,
anemia, hypertriglyceridemia, rash,
diarrhea, mucositis/stomatitis
Histone deacetylase inhibitors
Vorinostat Thrombocytopenia, anemia, diarrhea,
nausea/vomiting, hyperglycemia
Miscellaneous
Tretinoin (all-trans retinoic
acid, ATRA)
Leukocytosis, arrhythmias, headache,
nausea and vomiting, scaling of skin,
ATRA syndrome (fever, dyspnea, weight
gain, pulmonary infiltrates)
Arsenic trioxide Arrhythmias, hyperleukocytosis, nausea
and vomiting, diarrhea, abdominal pain,
APL differentiation syndrome (fever,
dyspnea, weight gain, pulmonary
infiltrates)
Bexarotene (Targretin R) Hyperlipidemia, pancreatitis,
hypothyroidism, hypercalcemia,
leukopenia, peripheral edema, rash
Bortezomib (Velcade R) Fatigue, peripheral neuropathy,
myelosuppression, hypotension,
arthralgias, diarrhea, nausea and vomiting,
headache, fever
Lenalidomide Myelosuppression, thromboembolic
events, bacterial infection, fatigue,
diarrhea
Thalidomide Fatigue; headache; numbness in hands,
feet, arms, and legs; constipation;
increased risk for thrombotic events
Hormonal agents
Adrenocorticoids Fluid retention, hyperglycemia,
hypertension, infection
Dexamethasone

Methylprednisolone
Prednisone

Estrogens Fluid retention, feminization, uterine
bleeding, nausea and vomiting,
thrombophlebitis
Diethylstilbestrol

Estradiol

Progestins Weight gain, fluid retention, feminization,
cardiovascular effects
Medroxyprogesterone
Megestrol acetate

Antiestrogens Hot flashes, nausea and vomiting, altered
menses
Fulvestrant
Tamoxifen

Toremifene

Estrogen agonist/antagonist
Raloxifene Hot flashes, arthralgias, flu-like syndrome
Aromatase Inhibitors Rash, electrolytes disturbance, drowsiness,
nausea, anorexia
Aminoglutethimide
Anastrozole

Exemestane
Letrozole

Androgens
Testosterone
Methyltestosterone
Fluoxymesterone
Masculinization, amenorrhea,
gynecomastia, nausea, water retention,
changes in libido, skin hypersensitivity,
hepatotoxicity
Antiandrogens
Bicalutamide
Flutamide
Nilutamide
Hot flashes, decreased libido, impotence,
diarrhea, nausea and vomiting,
gynecomastia, hepatotoxicity
LHRH Analogs
Leuprolide
Goserelin
Hot flashes, menstrual irregularity, sexual
dysfunction, edema
LHRH antagonist Hypersensitivity reactions, hypotension,

Abarelix syncope, hot flashes, breast enlargement,
prolongation of QT interval
APL, acute promyelocytic leukemia; ATRA, all-trans-retinoic acid; CNS,
central nervous system; LHRH, luteinizing hormone-releasing hormone;
SIADH, syndrome of inappropriate antidiuretic hormone.

P. 1248


H. Ot her mi scel l aneous agent s ar e l i st ed i n Tabl e 57- 2.
1. Tret i noi n (al l - t r ans r et inoi c acid; ATRA) is a r et inoi d der i ved f r om vit amin A,
used f or a specif ic f orm of acut e leukemi a, known as acut e pr omyelocyt i c leukemia
( APL), t o help cel ls dif f er ent iat e i nt o f unct ional l y mat ur e cel ls.
2. Arseni c t ri oxi de is an ant ineopl ast ic ar senic compound used f or APL t hat may
i nduce select i ve apopt osis of APL cel ls.
3. Bexarot ene is a select ive r et i noid X r ecept or (RXR) li gand used f or cut aneous T
cel l l ymphoma. Act i vat ion of t he r et inoi d r ecept ors leads t o r egulat ion of gene
expr ession and apopt osi s.
4. Bort ezomi b is a prot eosome i nhibi t or used in pat ient s wit h mult iple myeloma.
a. Pr ot eosomes are enzyme complexes t hat ar e responsible f or degr ading pr ot eins
t hat cont r ol t he cel l cycle.
b. Bort ezomib is specif i c i n t hat it i nt er f er es wit h t he degr adat i on of nucl ear f act or
k8 (NF- k8). NF- k8 i s r eleased f r om it s inhi bit or y par t ner pr ot ein and moves t o t he
nucleus. When t he inhi bit or y par t ner does not degr ade because of t he act i on of
bort ezomi b, NF- k8 is pr event ed f rom t r anscr i bi ng t he genes t hat pr omot e cancer
gr owt h.
5. Thal i domi de and Lenol i domi de ar e immunomodulat or y agent s wit h a var iet y of
mechanisms of act ion. They work as angiogenesi s i nhibi t or s by i nt er f er i ng wit h t he
gr owt h of new blood vessels needed f or t umor gr owt h and sur vi val. They i nhibit t he
pr oduct i on of t umor necr osis f act or q ( TNF-q) product ion, causes oxidat i ve damage
t o DNA, and help st i mulat e human T cel ls. They can be used as t r eat ment f or
mult i ple myeloma i n combinat i on wit h dexamet hasone.
I . Hormones are a cl ass of het erogeneous compounds t hat have a var i et y of ef f ect s
on cel ls. Table 57- 2 l ist s some of t he most commonl y used hormonal agent s i n
cancer t her apy.
J. Bi ol ogi cal response modif i ers alt er or enhance t he pat ient ' s i mmune syst em t o
f ight cancer or t o lessen t he side ef f ect s of t he cancer t r eat ment . Exampl es ar e
gi ven i n Tabl e 57- 3.
P. 1249


Table 57-3. Biological Agents Used in Oncology
Agent Indications Toxicity
Cytokine
Interferon-u -2a,
-2b (Roferon-
AR, Intron A)
Malignant melanoma,
chronic myelogenous
leukemia, hairy-cell
leukemia, Kaposi
sarcoma, chronic
hepatitis B and C,
follicular lymphoma
Flulike syndrome,
anorexia, depression,
fatigue
Interleukin 2
(aldesleukin,
Proleukin)
Renal cell carcinoma,
malignant melanoma
Chills, fever, dyspnea,
pulmonary congestion,
edema, nephrotoxicity,
hypotension, mental
status changes, anemia,
thrombocytopenia,
diarrhea, nausea and
vomiting
Interleukin 11
(oprelvekin,
Neumega)
Thrombocytopenia Fluid retention,
peripheral edema,
dyspnea, tachycardia,
atrial arrhythmias,
dizziness, blurred vision
Filgrastim (G-
CSF,
Neupogen)
Decrease
incidence/duration of
neutropenia,
hematopoietic stem-cell
mobilization
Bone pain, fever,
malaise
Pegfilgrastim
(Neulasta)
Decrease
incidence/duration of
neutropenia
Bone pain, fever,
malaise
Sargramostim
(GM-CSF,
Leukine)
Acceleration of myeloid
recovery, BMT failure or
engraftment delay,
induction for acute
myelogenous leukemia,
hematopoietic stem cell
mobilization, myeloid
reconstitution after BMT
Bone pain,
arthralgia/myalgia,
chills, fever, rash, first-
dose reaction
(hypotension,
tachycardia, dyspnea)
Epoetin u
(erythropoietin,
Epogen, Procrit)
Anemia associated with
chronic renal failure,
cancer chemotherapy or
HIV treatments,
reduction of blood
transfusions in surgery
patients
Hypertension, headache,
arthralgias
Darbepoetin u
(Aranesp)
Anemia associated with
chronic renal failure,
chronic renal
insufficiency, cancer-
and chemotherapy-
associated anemia
Hypertension, myalgia,
headache, fever,
tachycardia, nausea
Monoclonal antibody
Alemtuzumab
(Campath R)
B cell chronic
lymphocytic leukemia
Infusion-related fevers,
chills, rash, hypotension,
shortness of breath,
nausea and vomiting,
opportunistic infections,
neutropenia,
thrombocytopenia
Bevacizumab
(Avastin R)
Metastatic colorectal
cancer, non-small cell
lung cancer
(nonsquamous)
Hypertension,
proteinuria, GI
perforation, thrombotic
events, impaired wound
healing
Cetuximab
(Erbitux R)
Metastatic colorectal
cancer
Acneiform rash, infusion
related reactions, fatigue,
nausea and vomiting,
diarrhea
Gemtuzumab
ozogamicin
(Mylotarg R)
Acute myeloid leukemia Infusion-related fever,
chills, nausea and
vomiting, headache,
hypotension,
myelosuppression,
hepatotoxicity,
hypersensitivity
Ibritumomab
tiuxetan
(Zevalin R)
Non-Hodgkin lymphoma Infusion-related fevers,
chills, rigors,
hypersensitivity,
hypotension,
myelosuppression
Panitumumab EGFR-expressing,
metastatic colorectal
carcinoma with disease
progression on or
following
fluoropyrimidine-,
oxaliplatin-, and
irinotecan-containing
chemotherapy regimens.
Transient acneiform skin
rash, erythema, dry skin,
skin fissures/exfoliation,
diarrhea
Rituximab
(Rituxan R)
Non-Hodgkin lymphoma Hypersensitivity,
infusion-related fevers,
chills, rigors,
hypotension
Tositumomab
(Bexxar R)
Non-Hodgkin lymphoma Hypersensitivity
reactions, fever, chills,
myelosuppression,
especially
thrombocytopenia, rash,
nausea and vomiting,
diarrhea
Trastuzumab
(Herceptin R)
Breast cancer Infusion-related fevers,
chills, cardiac
dysfunction including
dyspnea, cough,
peripheral edema,
nausea and vomiting,
hypersensitivity,
hypotension, diarrhea
Immunotoxin
Denileukin
diftitox (Ontak
R)
Cutaneous T cell
lymphoma
Acute hypersensitivity,
including hypotension,
dyspnea, rash, chest
pain, tachycardia,
vascular leak syndrome,
dizziness, nausea and
vomiting, diarrhea
BMT, bone marrow transplant; G-CSF, granulocyte colony-stimulating
factor; GI, gastrointestinal; GM-CSF, granulocyte-macrophage colony-
stimulating factor.

P. 1250


1. Cyt oki nes ar e solubl e f act ors secr et ed or released by cell s t hat af f ect t he
act ivit y of ot her cel ls and/ or t he secr et ing cel l i t self . These agent s gener all y act as
r egulat ory or hemat opoiet ic gr owt h f act ors.
2. Monocl onal ant i bodi es ar e r ecombi nant ant ibodi es designed t o ident if y cancer -
specif i c ant i gens, bind t o t he ant i gens on t he pat i ent ' s cancer cel l s, and al low t he
pat ient ' s i mmune syst em t o el imi nat e t hose cell s.
a. Some monoclonal ant ibodies ar e being conj ugat ed t o ant it umor agent s or
r adioi sot opes ( e. g. , gemt uzumab ozogamicin, ibr it umomab t i uxet an) t o hel p t ar get
cyt ot oxic t her apy t o t he t umor cel l s.
b. Anot her example of a monocl onal ant ibody i s bevaci zumab, whi ch t ar get s and
i nhibit s vascular endot hel ial gr owt h f act or (VEGF). VEGF is an import ant r egulat or
of t he gr owt h and sur vi val of blood vessels known as angi ogenesis. Bevacizumab
works by inhi bit i ng angi ogenesis and, t her ef or e, i nhibit ing t he bl ood suppl y t o t he
t umor.
c. Ot her monoclonal ant ibodies ar e list ed in Tabl e 57- 3.
3. Immunot oxi ns. Deni leuki n dif t it ox i s a f usi on pr ot ei n composed of di pht her ia
t oxi n and i nt er leuki n 2 ( I L- 2) . I t i s designed t o di r ect t he cyt oci dal act i on of
dipht her ia t oxi n t o cel ls wit h t he I L- 2 r ecept or on t heir sur f ace. This f orm of t her apy
is able t o bypass t he need f or a f unct ioni ng i mmune syst em, which may be def ect ive
i n many cancer pat i ent s.
V. TOXICITIES OF CHEMOTHERAPY AGENTS.
Chemot her apeut i c agent s ar e most t oxi c t o r apidl y pr ol if er at ing cel ls. The t i ssues
most commonl y af f ect ed ar e t hose of t he mucous membr anes,
P. 1251

ski n, hair , gast r oint est i nal ( GI ) t r act , and bone mar r ow. Of t hese, bone mar r ow
t oxicit y can be t he most l if e- t hr eat eni ng.
A. Bone marrow suppressi on i s t he most common dose- li mi t i ng si de ef f ect of
cancer t her apy.
1. Compl i cat i ons
a. I nf ect i ons. Whit e bl ood cel ls ar e most af f ect ed owing t o t hei r short lif e span ( 6-
12 hr ).
( 1) A si gnif icant decr ease in t he whit e bl ood cel l count , par t icul ar l y a neut r ophi l
count < 500/ mm
3
( neut ropeni a), predi sposes t he pat ient t o devel opment of ser ious
i nf ect ions.
( 2) The usual signs and sympt oms of i nf ect ion may be absent , and f ever may be t he
onl y i ndicat or (f ebri l e neut ropeni a) .
( 3) Col ony- st imul at i ng f act ors—f or example, granul ocyt e col ony- st imul at i ng
f actor (G-CSF) and granul ocyt e-macrophage col ony- st i mul at i ng f act or (GM-
CSF) —may be used t o st imulat e neut r ophi l pr oduct ion and lessen t he degr ee and
dur at i on of neut r openia.
b. Bl eedi ng. Pl at elet s have an i nt ermedi at e lif e span of 5-10 days. Decr eased
plat el et s ( t hrombocyt openi a) can also occur f rom chemot her apy, which can lead t o
bleedi ng and may r equir e plat el et t r ansf usions.
c. Anemia and f at i gue secondar y t o cancer chemot her apy may also occur . I t
gener al l y does not occur as quickl y as ot her bone marr ow t oxicit i es because of t he
long l if e span of r ed bl ood cel ls ( about 120 days). Human recombi nant
eryt hropoi et i n ( e. g. , epoet in q, dar bepoet i n q) may be used t o i ncr ease
hemogl obin, decr ease t r ansf usion r equir ement s, and decrease f at igue.
2. The t ime course of myelosuppr essi on var ies wit h t he chemot her apy r egimen. I n
gener al, t he onset of myelosuppr ession i s 7- 10 days af t er t he chemot her apy has
been admini st er ed. The lowest point of t he count s, cal led t he nadi r, i s usual l y
r eached in 10- 14 days. Recovery of count s usual l y occur s in 2- 3 weeks.
3. A pat ient ' s count s must be suf f i ci ent l y recovered bef or e r eceivi ng subsequent
chemot her apy cycl es. Gener al l y, t he neut r ophi l count must be > 1, 500/ mm
3
and t he
plat el et count > 100, 000/ mm
3
bef ore t he pat i ent receives addi t ional chemot her apy.
4. The ext ent of myel osuppr ession i s r elat ed t o t he chemot herapy agent s used and
doses gi ven. Dr ugs t hat can cause sever e myelosuppr ession incl ude car must ine,
cyt ar abi ne, daunor ubici n, doxor ubici n, and pacl i t axel .
5. Some chemot her apy agent s cause l it t l e or no myelosuppr ession. These i ncl ude
asparaginase, bleomyci n, and vi ncr ist i ne.
B. Dermat ol ogi cal t oxi ci ty
1. Al opeci a is t he l oss of hair associat ed wit h chemot her apy. Not all agent s cause
alopeci a, and hai r loss may be part i al or complet e. Chemot her apy agent s t hat
commonl y cause alopeci a i ncl ude cyclophosphamide, doxor ubici n, mechl or et hami ne,
and pacl it axel.
2. Dr ugs associ at ed wi t h necr osi s of t i ssue ar e cal led vesi cant s. Local necrosi s
may resul t f r om ext ravasat i on of vesicant chemot her apy dr ugs out side t he vei n
dur i ng t heir admi ni st r at ion. Vesicant agent s incl ude dact i nomycin, daunor ubi ci n,
doxor ubici n, idar ubici n, mechl or et hamine, mi t omyci n, vinbl ast ine, vi ncr ist ine, and
vi nor elbi ne.
a. Most vesi cant ext r avasat ions pr oduce immedi at e pai n or burni ng. However , a
delayed r eact ion may occur hour s or weeks l at er. Si gnif i cant t issue i nj ur y, incl udi ng
ulcer at ion or necr osis, may r equir e pl ast ic sur gery i nt er vent ion.
b. The treatment of ext r avasat i ons var ies, dependi ng on t he vesicant . Heat or cold
packs and chemical s such as hyaluroni dase or dimet hyl sulf oxi de ( DMSO) may be
used.
3. Cancer chemot her apy can also cause ski n changes such as dr yness and
sensit i vit y t o sunl ight . Exampl es are f l uor our aci l and met hot rexat e.
C. GI t oxi ci t i es ar e f r equent l y exper i enced by pat ient s r eceivi ng chemot her apy.
1. Nausea and vomi t i ng ar e of t en t he most dist ressi ng t oxi ci t ies f r om t he pat i ent ' s
per spect ive. However, t his side ef f ect can gener al l y be pr event ed, or bet t er
cont r ol led, wit h t he use of cur r ent ly avai labl e ant i emet ics.
a. Sever e vomit i ng can r esul t i n dehydr at ion, elect r olyt e imbalances, and
esophageal t ear s and may cause t he pat ient t o discont i nue t her apy.
P. 1252


b. Nausea and vomit i ng may be acut e, delayed, or ant i ci pat ory in nat ur e.
Ant i emet ics should be used pr ophylact i cal l y t o prevent t he occur r ence of nausea
and vomit ing, part i cular l y wit h chemot herapeut i c agent s t hat have a high
emet ogenic r isk.
c. Table 57-4 l ist s commonl y used chemot herapeut i c agent s and t heir emet ogenic
pot ent ial on a scale of 1- 5.
( 1) The emet ogenic pot ent ial of combinat ions of chemot her apy agent s can be
est imat ed by ident if yi ng t he most emet ogenic agent i n t he combi nat ion.
( 2) The cont ri but ion of t he ot her agent s can t hen be evaluat ed by usi ng t he
f ol l owi ng guidel i nes:
(a) Level 1 agent s do not cont r ibut e t o t he emet ogenicit y of t he regimen.
( b) Addi ng one or mor e level 2 agent s incr eases t he emet ogenicit y t o one l evel
higher t han t he most emet ogeni c agent in t he combinat ion.
( b) Addi ng level 3 or 4 agent s incr eases t he level of emet ogenicit y by one level per
agent .
d. The occurr ence of nausea and vomi t i ng is inf l uenced by t he emet ogeni ci t y of t he
chemot her apeut ic agent or combi nat ion of agent s, t he chemot her apeut ic dose, t he
met hod of admi ni st r at ion, and indi vi dual pat ient char act er ist ics.
2. St omat it i s i s a gener al i zed i nf lammat ion of t he oral mucosa or ot her ar eas of t he
GI t ract . Because of t he rapi d t ur nover of epit hel i al cel l s i n t he GI t r act , t hi s i s a
common si t e of t oxi ci t y.
a. Si gns and sympt oms incl ude er yt hema, pain, dr yness of t he mout h, bur ni ng or
t ingl i ng of t he lips, ulcer at i ons, and bleedi ng.
b. Chemot her apy agent s associat ed wit h st omat it i s incl ude capeci t abine,
f luor our aci l , and met hot r exat e.
c. Time course. St omat it is usual l y appears wi t hi n a week af t er t he of f endi ng agent
is admi ni st er ed, and resol ves i n 10- 14 days.
d. Consequences of st omat it i s i ncl ude i nf ect i on of t he ulcer at ed ar eas, i nabi l it y t o
eat , pain r equi r i ng opioid anal gesi cs, and subsequent decr eases i n chemot her apy
doses.
Table 57-4. Emetogenic Potential of Cancer Chemotherapeutic Agents
Level 5: Very
Highly
Emetogenic
Level 4: Highly
Emetogenic
Level 3:
Moderately
Emetogenic
Level 2: Low
Emetic Risk
Level 1:
Very Low
Emetic Risk
Carmustine
> 250
mg/m
2

Cisplatin >
50 mg/m
2

Cyclophosp
hamide >
1500 mg/m
2

Dacarbazine
Mechloretha
mine
Streptozocin
Carmustine
< 250
mg/m
2

Cisplatin <
50 mg/m
2

Cyclophosp
hamide 750-
1500 mg/m
2

Cytarabine >
1000 mg/m
2

Dactinomyci
n
Doxorubicin
> 60 mg/m
2

Lomustine
Melphalan
(intravenous
> 50 mg/m
2
)
Methotrexat
e > 1000
mg/m
2

Procarbazin
e
Temozolomi
de
Thiotepa >
15 mg/m
2

Carboplatin
Cyclophosp
hamide <
750 mg/m
2

Cytarabine <
1000 mg/m
2

Daunorubici
n
Doxorubicin
< 60 mg/m
2

Idarubicin
Ifosfamide
Methotrexat
e 250-1000
mg/m
2

Mitoxantron
e
Temozolami
de
Melphalan >
50 mg/m
2

Docetax
el
Etoposid
e
Fluorour
acil
Gemcita
bine
Irinoteca
n
Methotr
exate
50-250
mg/m
2

Mitomy
cin
Paclitax
el
Thiotepa
< 15
mg/m
2

Topotec
an
Pemetre
xed
Asparagi
nase
Bleomyc
in
Capecita
bine
Chloram
bucil
Dasatini
b
Decitabi
ne
Erlotinib
Gemtuzu
mab
Hydroxy
urea
Lenalido
mide
Methotre
xate
<50mg/
m
2

Melphal
an (oral)
Nelarabi
ne
Rituxima
b
Sorafeni
b
Sunitinib
Thalido
mide
Thiogua
nine
Trastuzu
mab
Vinblasti
ne
Vincristi
ne
Vinorelb
ine

P. 1253


e. Topi cal and l ocal anal gesi cs i n t he f orm of mout hr inses ar e commonl y used and
can hel p wi t h mout h and t hr oat pai n.
3. Ot her GI t oxi cit ies i ncl ude di arrhea ( e. g. , i r inot ecan, f luor our aci l ) , const i pat i on
( e. g. , vincr ist i ne) , anorexia, and tast e changes.
D. Tumor l ysi s syndrome (TLS) may occur in hemat ologi cal malignancies such as
leukemia and l ymphoma, i n which t her e i s a high t umor cel l bur den or r api dl y
gr owing t umor s. Owi ng t o t he spont aneous l ysis of cel l s f r om t r eat ment wit h
chemot her apy, cel l l ysis causes r elease of i nt r acel l ul ar pr oduct s, incl udi ng ur i c
acid, pot assium, and phosphat e, which can lead t o renal f ai l ur e and cardi ac
ar r hyt hmias. Thi s may be prevent ed by gi vi ng i nt r avenous hydr at ion, by al kal ini zi ng
t he ur i ne, and by gi vi ng agent s such as al l opuri nol or rasburi case (El i t ek) t o
decr ease ur ic aci d.
E. Hypercal cemi a may occur in pat ient s wi t h sol i d or hemat ol ogic mali gnanci es and
can of t en be t he pr esent ing sign of mal i gnancy. The maj or cause of hyper cal cemia
is incr eased ost eoclast i c bone r esorpt ion, which i s gener all y caused by t he r elease
of parat hyr oid hormone- relat ed pr ot ei n ( PTHrP) by t he t umor cel ls. Common
pr esent i ng sympt oms incl ude ment al st at us changes, f at igue and muscle weakness,
pol yur ia, polydi psia, nausea and vomit i ng. Tr eat ment incl udes aggr essive hydr at ion
wit h normal sal i ne, calci ur i c t her apy which consist s of calci t oni n, and
bisphosphonat es such as pamidr onat e ( Ar edia) or zoledr oni c aci d ( Zomet a).
F. Chi l l s and f ever may occur af t er t he admi nist r at ion of some chemot herapy and
biological agent s. This f ever general l y can be dif f er ent i at ed f rom f ever owing t o
i nf ect ion because of it s t empor al r elat ionshi p t o chemot her apy administ r at i on. This
r eact i on is commonly associat ed wit h bl eomycin, cyt ar abine monocl onal ant ibodies,
and I L- 2.
G. Pul monary t oxi ci t y is gener all y i r r ever sible and may be f at al.
1. Si gns and sympt oms ar e shor t ness of breat h, nonpr oduct i ve cough, and low-
gr ade f ever. I n some cases, t he r isk of pul monar y t oxicit y i ncr eases as t he
cumulat i ve dose of t he dr ug incr eases ( e. g. , bleomyci n) .
2. Chemot herapeut i c agent s associat ed wi t h pul monar y t oxi cit y i nclude bleomyci n,
busulf an, carmust ine, and mit omycin.
H. Cardiac t oxi ci ty may manif est as an acut e or chr onic pr oblem.
1. Acut e changes ar e gener al l y t r ansi ent el ect r ocar diogr aph abnormal it ies t hat may
not be cl inical l y signi f icant .
2. Chroni c cardiac t oxi ci t y i s i r r ever sible congest ive hear t f ai l ur e. Ri sk f act ors
i ncl ude chest i r r adiat ion and hi gh cumul at i ve doses of car diot oxi c chemot her apy.
3. Chemot herapy agent s t hat ar e associ at ed wit h chr onic car di ot oxici t y i nclude
daunor ubici n, doxor ubi ci n, epi r ubici n, i dar ubici n, and mi t oxant r one. Dexrazoxane i s
a car diopr ot ect ive agent t hat may be used wit h doxor ubi ci n t o help pr event or
lessen it s t oxi c ef f ect s t o t he heart .
I . Hypersensi t i vi t y react i ons may occur wit h any chemot her apy agent . Li f e-
t hr eat eni ng r eact ions, incl udi ng anaphylaxi s, appear t o be mor e common wit h
asparaginase, car boplat in, cisplat i n, et oposide, pacl i t axel , and t eniposide.
J. Neurot oxi ci t y may occur wit h syst emi c or int r at hecal chemot her apy.
1. Vincr ist i ne i s associ at ed wit h aut onomi c and peri pheral neuropat hies. Pat ient s
may exper ience gai t di st ur bances, numbness and t i ngl i ng of hands and f eet , and
loss of deep-t endon r ef lexes. I nt r at hecal administ r at i on of vi ncr ist i ne r esult s i n f at al
neur ot oxicit y.
2. Peri pheral neuropathy and ot ot oxi ci t y are common dose- l imi t ing t oxi ci t ies of
cisplat i n. Sensory neur opat hies, causi ng t i ngl i ng or numbi ng of t he hands and f eet ,
may be associat ed wit h capecit abi ne, oxal i plat i n, and pacl it axel.
3. Hi gh doses of cyt arabine may pr oduce cerebell ar toxi ci t y t hat mani f est s init ial l y
as loss of eye- hand coor dinat i on and may pr ogr ess t o coma.
P. 1254


4. Arachnoi di t i s has been associat ed wit h int r at hecal admi nist r at ion of cyt ar abine
and met hot rexat e.
K. Hemorrhagi c cyst i t i s is a bl adder t oxicit y t hat i s seen most commonly af t er
admi ni st r at ion of cyclophosphami de and i f osf amide. Acrol ei n, a met abol it e of t hese
agent s, is t hought t o cause a chemical i r r it at ion of t he bladder mucosa, r esult i ng i n
bleedi ng. Prevent i ve measur es incl ude aggr essive hydr at i on wit h subsequent
f r equent ur i nat i on, and t he administ r at i on of t he ur oprot ect ant mesna. Mesna act s
by bi ndi ng t o acr ol ei n and pr event ing it f r om cont act i ng t he bladder mucosa.
L. Renal t oxi ci t y may mani f est by elevat ions i n ser um cr eat ini ne and blood ur ea
nit r ogen (BUN) as wel l as elect r olyt e abnormali t ies. Nephr ot oxicit y is associat ed
wit h ci splat i n, if osf amide, met hot r exat e, and st r ept ozoci n. I nt r avenous hydr at ion is
used t o pr ot ect t he kidneys f r om t he nephr ot oxi c ef f ect s of ci splat i n. Osmot ic
di ur esis wit h mannit ol may also hel p r educe t he i ncidence of cisplat i n
nephr ot oxi ci t y.
M. Hepat ot oxi ci t y may manif est as elevat ed li ver f unct ion t est s, j aundice, or
hepat it is. Aspar agi nase, cyt arabine, mer capt opur i ne, and met hot r exat e ar e known t o
cause hepat ic t oxicit y.
N. Secondary mal i gnanci es, such as sol id t umors, lymphomas, and leukemi as, may
occur many year s af t er chemot her apy or r adi at i on. Ant i neoplast ic agent s known t o
possess a high car cinogenic r isk incl ude cyclophosphami de, et oposide, melphal an,
and mechlor et hamine.
O. Chemot herapy may cause i nf ert i l i t y, whi ch may be t emporar y or permanent .
Cyclophosphami de, chlor ambuci l, mechl or et hami ne, mel phal an, and pr ocar bazi ne
ar e associat ed wit h a signi f icant inci dence of i nf er t il i t y i n males and f emales.
VI. OTHER THERAPEUTIC MODALITIES
A. Surgery may be diagnost ic ( bi opsy, explor at ory lapar ot omy, second- look) or
t her apeut ic (t umor debul ki ng or r emoval ) . Sur ger y i s of t en combined wit h
chemot her apy and/ or r adiat ion.
B. Radi at i on t herapy invol ves high doses of ioni zi ng r adi at i on di r ect ed at t he
cancer ous t i ssue. Radi at ion may be combi ned wit h sur ger y and/ or chemot her apy.
Dependi ng on t he ar ea of t he body being ir r adiat ed, adverse react i ons may i ncl ude
st omat i t is, nausea and vomit i ng, di ar r hea, and myelosuppr ession.
C. Hematopoi et i c st em- cel l transpl antat i on invol ves i nt r avenous i nf usion of st em
cel ls f r om a compat i bl e donor t o a r ecipient f oll owi ng high- dose chemot her apy. I t i s
used f or t r eat ment of di seases i nvol vi ng t he bone marr ow or immune syst em and t o
al l ow f or administ r at i on of hi gh- dose chemot her apy or r adiat i on f or t umor s resist ant
t o st andar d doses. St em cel l s can be obt ai ned f r om bone marr ow or per ipher al
blood.
1. I n aut ol ogous t r ansplant s, st em cells ar e obt ained f rom t he pat ient , preser ved,
and l at er r ei nf used i nt o t he same pat i ent . Al l ogenei c t r ansplant s i nvol ve t wo
separat e indi vi duals. Cel ls ar e obt ained f r om a mat ched donor and t hen i nf used i nt o
a separ at e pat ient .
2. Tr ansplant - r elat ed compl icat i ons i ncl ude hepat i c venooccl usi ve di sease (VOD),
acut e and chr onic gr af t versus host disease (GVHD) , inf ect ion, and pul monar y
compli cat ions.
P. 1255


STUDY QUESTIONS
Di rect i ons f or quest i ons 1- 14: Each of t he quest i ons, st at ement s, or incompl et e
st at ement s i n t his sect ion can be corr ect ly answer ed or compl et ed by one of t he
suggest ed answers or phr ases. Choose t he best answer .
1. The t op f our most commonl y diagnosed cancers i ncl ude al l of t he f ol l owi ng
except
( A) lung.
(B) pr ost at e.
(C) colon and r ect um.
(D) t hyr oid.
(E) br east .
View Answer 1. The answer i s D[ see] . 2. Whi ch st at ement regardi ng phase-
speci f i c chemot herapeut i c agent s i s correct ? They
( A) ar e most ef f ect i ve i n one phase of t he cell cycl e.
(B) ar e ef f ect ive in al l phases of t he cel l cycle.
(C) are only ef f ect ive in G0 phase.
(D) incl ude t he alkylat i ng agent s.
(E) incl ude t he ant it umor ant i biot ics.
View Answer 2. The answer i s A[ seeand] . 3. Body surf ace area (BSA) i s
used i n cal cul at i ng chemot herapy doses because
( A) BSA is an i ndi cat or of t umor cell mass.
(B) BSA cor r elat es wit h car diac out put .
(C) BSA corr el at es wit h gast r oint est i nal t r ansit t i me.
(D) t he Nat ional Cancer I nst it ut e r equi r es t hat BSA be used.
(E) t he U. S. Food and Dr ug Administ r at i on ( FDA) r equi res t hat BSA be used.
View Answer 3. The answer i s B[ see] . 4. The rat ional e f or combi nat i on
chemot herapy i ncl udes al l of t he f ol l owi ng except
( A) bi ochemical enhancement of ef f ect .
(B) rescue of normal cells.
(C) over comi ng or pr event i ng r esist ance.
(D) bi ochemical nul l if i cat ion of ef f ect .
(E) cyt ot oxic t o bot h r est ing and di vidi ng cel l s.
View Answer 4. The answer i s D[ see] . 5. Al l of t he f ol l owi ng chemot herapy
agent s can be admi ni st ered i nt rat hecal l y except
( A) met hot r exat e.
(B) cyt ar abine.
(C) hydr ocort i sone.
(D) t hi ot epa.
(E) vi ncr ist i ne.
View Answer 5. The answer i s E[ see] . 6. Whi ch of t he f ol l owi ng
chemot herapeut i c agent s i s cl assi f i ed as an alkyl at i ng agent ?
( A) cyclophosphami de
(B) et oposide
(C) mechl or et hamine
(D) pacl it axel
(E) cyclophosphami de and mechlor et hami ne
View Answer 6. The answer i s E[ see IV. A. 1] . 7. Whi ch of t he f ol l owi ng
chemot herapy agent s act s by i nt ercalat i on?
( A) vi ncr ist i ne
(B) paclit axel
(C) doxor ubici n
(D) vi ncr ist i ne and pacl it axel
(E) t opot ecan
View Answer 7. The answer i s C[ see IV. B. 1] . 8. How do ant i metabol i t es
exert t hei r cyt otoxi c ef f ect?
( A) inhi bit i ng DNA synt hesis by sl i di ng bet ween DNA base pai r s
(B) inhi bit i ng RNA synt hesis by sl i di ng bet ween RNA base pai r s
(C) act ing as f al se met aboli t es in t he micr ot ubul es
(D) act ing as f al se subst i t ut ions i n t he pr oduct ion of nucl ei c aci ds
(E) pr omot i ng micr ot ubule assembl y and st abil i zat ion
View Answer 8. The answer i s D[ see] . 9. Al l of t he f ol l owi ng chemot herapy
agent s work t hrough af f ect i ng mi crot ubul e f unct i on except
( A) docet axel.
(B) vi nblast i ne.
(C) mit oxant r one.
(D) vi ncr ist i ne.
(E) vi nor el bi ne.
View Answer 9. The answer i s C[ see] . 10. Hormonal agent s t hat are usef ul
i n t he t reatment of cancer i ncl ude
( A) t amoxif en.
(B) pr ednisone.
(C) f lut ami de.
(D) t amoxif en and f l ut ami de.
(E) t amoxif en, pr edni sone, and f lut amide.
View Answer 10. The answer i s E[ see] . P. 1256


11. When does t he neut rophi l nadi r associ ated wi t h chemot herapy agent s
general l y occur?
( A) dur ing admi nist r at ion of t he chemot her apy
(B) 1- 2 days af t er t her apy
(C) 10- 14 days af t er t her apy
(D) 1 mont h af t er t her apy
(E) when t he plat elet count begins t o r i se
View Answer 11. The answer i s C[ see] . 12. St omat i t i s i s charact eri zed by
al l of t he f ol l owi ng si gns and sympt oms except
( A) headache.
(B) er yt hema.
(C) bl eedi ng.
(D) ul cer at i ons.
(E) dr yness of mout h.
View Answer 12. The answer i s A[ see] . 13. Whi ch of t he f ol l owi ng
st atement s descri bes hemorrhagi c cyst i t i s? I t
( A) is caused by excr et ion of t umor cell br eakdown pr oduct s.
(B) is associat ed wit h i f osf ami de or cycl ophosphamide administ r at i on.
(C) is caused by t he administ r at i on of mesna.
(D) can be pr event ed or t r eat ed wit h acr olei n.
(E) can be t r eat ed wi t h gr anulocyt e colony- st i mul at ing f act or (G-CSF).
View Answer 13. The answer i s B[ see V. J] . 14. All of t he f ol l owi ng
chemot herapy agent s are vesi cant s except
( A) doxor ubici n.
(B) mechl or et hamine.
(C) vi ncr ist i ne.
(D) met hot rexat e.
(E) idar ubi ci n.
View Answer 14. The answer i s D[ see] . Di rect i ons f or quest i ons 15- 19:
Each agent in t hi s sect i on is most closel y associat ed wit h one of t he f ol l owi ng
adver se ef f ect s. Each ef f ect i s used only once. Choose t he best answer, A-E.
15. Vi ncri st i ne
A car di ot oxici t y
B hyper sensi t i vit y
C di ar r hea
D gast roint est i nal hemor r hage
E const i pat ion
View Answer 15. The answer i s E[ see] . 16. I ri not ecan
A car di ot oxici t y
B hyper sensi t i vit y
C di ar r hea
D gast roint est i nal hemor r hage
E const i pat ion
View Answer 16. The answer i s C[ see] . 17. Doxorubi ci n
A car di ot oxici t y
B hyper sensi t i vit y
C di ar r hea
D gast roint est i nal hemor r hage
E const i pat ion
View Answer 17. The answer i s A[ see] . 18. Pacl i taxel
A car di ot oxici t y
B hyper sensi t i vit y
C di ar r hea
D gast roint est i nal hemor r hage
E const i pat ion
View Answer 18. The answer i s B[ see] . 19. Bl eomyci n
A car di ot oxici t y
B hyper sensi t i vit y
C di ar r hea
D gast roint est i nal hemor r hage
E const i pat ion
View Answer 19. The answer i s D[ see] . Di rect i ons f or quest i ons 20- 24:
Each of t he quest ions, st at ement s, or incomplet e st at ement s i n t his sect ion can be
corr ect ly answer ed or complet ed by one of t he suggest ed answer s or phr ases.
Choose t he best answer.
For quest i ons 20- 22: P. A. is a 60- year- old man who has r ecent l y been diagnosed
wit h st age I IB lung cancer . Af t er his case was eval uat ed, it was deci ded t hat he
would under go sur gi cal r esect ion of t he pr imar y t umor and t hen r eceive
chemot her apy wit h car bopl at i n and docet axel.
20. What t ype of chemot herapy i s P. A. recei vi ng?
( A) adj uvant
(B) salvage
(C) neoadj uvant
View Answer 20. The answer i s A[ see] . 21. What si de ef f ect s woul d you
counsel P. A. about ?
( A) nausea and vomit i ng
(B) per ipher al neur opat hy
(C) hemor r hagic cyst it i s
(D) A and B
(E) B and C
View Answer 21. The answer i s D[ see] . 22. P. A. recei ved carbopl at i n and
docetaxel and has an appoi ntment i n cl i ni c 1 week af ter compl et i ng
chemot herapy to check hi s CBC and el ect rol ytes. Hi s WBC = 2. 7, Pol ys = 12%,
and Bands = 2%. What i s P. A. ' s ANC?
( A) 324
(B) 54
(C) 378
(D) 2700
View Answer 22. The answer i s C[ see I. C. 6] . P. 1257


23. If P. A. has recurrence of hi s l ung cancer aft er t herapy wi t h carbopl at i n and
docetaxel , whi ch targeted agent may be consi dered f or second- l i ne t herapy?
( A) doxor ubici n
(B) busulf an
(C) cyclophosphamide
(D) er l ot i nib
(E) bl eomyci n
View Answer 23. The answer i s D[ see] . 24. What si de ef f ect s are
associ at ed wi t h erl ot i ni b use?
( A) Acneif orm r ash
(B) Diar r hea
(C) Per ipher al neur opat hy
(D) A and B
(E) Hypert ension
View Answer 24. The answer i s D[ see] . P. 1258


ANSWERS AND EXPLANATIONS
1. The answer i s D [ see I . B] .
Pr ost at e cancer i s t he most common cancer in men, br east cancer i s t he most
common cancer i n women, f oll owed by l ung, t hen colon and r ect um f or bot h men and
women.
2. The answer i s A [ see I I . D. 1, 2 and 3] .
Phase-speci f ic agent s are most act i ve in one specif i c phase of t he cel l cycle. These
agent s have no act i vit y against cel ls i n G0 , t he r est ing phase. Examples of phase-
specif i c agent s incl ude t he mit ot ic i nhibit or s, aspar aginase, t he ant imet abol it es, and
et oposi de.
3. The answer i s B [ see I I I . B] .
BSA cor relat es wi t h cardiac out put , which det ermines r enal and hepat ic blood f low
and t hus af f ect s dr ug el i minat ion.
4. The answer i s D [ see I I I . D. 2] .
Combinat ion chemot her apy has been developed t o have maximal cyt ot oxi ci t y t o
t umor cells and minimal t oxicit y t o normal cel ls. The dr ugs ar e dosed and scheduled
such t hat maxi mal cel l ki l l occur s, whi le spar i ng normal cel l s as much as possible.
Combinat ion r egi mens of t en cont ain agent s wit h di f f er ent spect r ums of t oxi ci t y.
5. The answer i s E [ see I I I . E. 3] .
I nt r at hecal l y admi nist er ed vi ncr ist i ne i s f at al. Al l syr i nges of vi ncr ist i ne must be
label ed “ Fat al if gi ven i nt r at hecal ly. For int r avenous use onl y. ”
6. The answer i s E [ see I V. A. 1] .
Cyclophosphami de and mechlor et hami ne ar e ni t r ogen must ar ds, a subgr oup of t he
alkylat i ng agent s. Et oposide is a t opoi somerase I I i nhibi t or , and pacl i t axel is a
mi t ot i c i nhibit or .
7. The answer i s C [ see I V. B. 1] .
Doxor ubi ci n i s an ant i t umor ant ibiot ic t hat i nhibi t s DNA synt hesis by i nt er calat ion.
Vincr i st i ne and pacl i t axel ar e mit ot ic i nhibit or s t hat act on mi cr ot ubule assembl y.
Topot ecan inhi bit s t opoisomer ase I .
8. The answer i s D [ see IV. C] .
Ant i met abol it es ar e st r uct ur al analogs of nat ur all y occurr ing subst r at es f or
biochemi cal r eact ions. They i nhibi t DNA synt hesi s by act ing as f alse subst it ut i ons i n
t he product ion of DNA.
9. The answer i s C [ see IV. D] .
Docet axel is a t axane, which works by promot i ng microt ubule assembl y and
st abi l i zat i on, r esult i ng i n i nhibi t ion of cel l di vi si on. Vincr i st i ne, vi nblast i ne, and
vi nor elbi ne ar e vinca alkaloids, which wor k by pr event i ng mi cr ot ubule f ormat ion.
Mi t oxant r one is an ant i t umor ant ibiot i c, whi ch wor ks by DNA int er cal at i on.
10. The answer i s E [ see VI ; Tabl e 57-2] .
Tamoxi f en is an ant i est r ogen used i n t he t r eat ment of br east cancer. Pr edni sone is
used f or it s ant i l ymphocyt ic pr oper t ies in t he t r eat ment of non- Hodgkin l ymphoma.
Fl ut ami de is an ant iandr ogen used i n t he t r eat ment of pr ost at e cancer.
11. The answer i s C [ see V. A. 2] .
Bone mar row suppr ession, par t i cular l y of t he neut r ophi l s, usual l y is t he most
pr of ound 10- 14 days af t er chemot her apy.
12. The answer i s A [ see V. C. 2] .
St omat it i s, or mucosi t is, is an i nf lammat i on of t he mucous membr anes, par t icul ar l y
t he oral mucosa. Al t hough t he sympt oms gener al l y ar e li mi t ed t o t he mout h and
t hr oat , st omat i t is may af f ect any par t of t he gast roi nt est inal t r act , pot ent ial l y
causi ng diar r hea and anal f issur es.
P. 1259


13. The answer i s B [ see V. J] .
Hemor r hagic cyst i t is r esul t s f r om ir r i t at i on of t he li ni ng of t he bladder by acr ol ei n, a
met abolit e of if osf amide and cyclophosphamide. Mesna may be used t o i nact i vat e
t he acr ol ei n, t hus pr event i ng hemor r hagi c cyst it is.
14. The answer i s D [ see V. B. 2] .
Vesicant chemot herapy agent s may cause l ocal necr osi s i f ext r avasat ed out side t he
vei n. Doxor ubici n, i dar ubici n, mechl or et hami ne, and vi ncr ist ine ar e all cl assi f ied as
vesi cant s.
15. The answer i s E [ see V. C. 3; V. E-G] .
16. The answer i s C [ see V. C. 3; V. E-G] .
17. The answer i s A [ see V. C. 3; V. E-G] .
18. The answer i s B [ see V. C. 3; V. E-G] .
19. The answer i s D [ see V. C. 3; V. E-G] .
Car diot oxicit y is associat ed wit h cumulat i ve doses of doxor ubici n and ot her
ant it umor ant i biot ics. Hyper sensit i vi t y f r om pacl it axel may be t he r esult of it s
Cr emophor di l uent . Sever e di ar r hea, r equi r i ng t r eat ment wit h at r opine, is associat ed
wit h ir i not ecan. Pulmonar y t oxi ci t y i s associ at ed wit h cumul at i ve doses of
bleomyci n. Sever e const ipat ion and par alyt ic i leus is associat ed wit h t he use of
vi ncr ist ine.
20. The answer i s A [ see I I I . A. 3] .
Recei vi ng chemot her apy af t er pot ent i al l y cur at i ve sur ger y is known as adj uvant
chemot her apy.
21. The answer i s D [ see Table 57-2] .
Nausea and vomit i ng are common side ef f ect s of car boplat i n and docet axel.
Pr emedi cat ions wit h ant i - nausea medicat i ons ar e gi ven bef or e t hese chemot her apy
agent s ar e given. Per ipher al neur opat hy can commonl y be seen wit h docet axel.
Pat i ent s need t o be counseled about t hi s and f ol l owed up on t his adver se event on
r out i ne cl i nic vi si t s. I f lef t unt r eat ed sever e, di sabl i ng neur opat hy can r esult .
Hemor r hagic cyst i t is is an adver se event of some of t he alkyl at i ng agent s incl udi ng
if osf amide and cyclophosphamide, but not car boplat i n.
22. The answer i s C [ see I . C. 6] .
The ANC is calcul at ed by mult ipl yi ng t he WBC × t he t ot al neut r ophi ls ( segment ed
neut r ophi l% + segment ed band %) × 10. 2. 7 × ( 12% + 2%) × 10 = 378.
23. The answer i s D [ see IV. G] .
Er lot i ni b i s an agent t ar get ed f or t he epidermal growt h f act or r ecept or t yr osine
kinase. Busulf an and cyclophosphami de ar e al kyl at ing agent s t hat ar e non cel l cycl e
specif i c. Bleomyci n and doxor ubicin ar e ant it umor ant ibi ot i cs t hat i nt er calat e wit h
DNA and ar e phase non- specif ic agent s.
24. The answer i s D [ see Table 57-2] .
Er lot i ni b can cause acnief orm r ash, diar rhea, nausea, pr ur it i s, f at igue, and eye
ir r it at ion.

58
Pain Management
Al an F. Kaul
I. INTRODUCTION
A. Def i ni t i ons
1. Pai n is an unpl easant sensor y and emot ional exper i ence t hat i s associ at ed wit h
act ual or pot ent ial t issue damage or descr ibed i n t erms of such damage. I t i s a
subj ect ive, i ndi vidual exper ience t hat has physical, psychol ogical, and social
det erminant s. Ther e is no obj ect ive measur ement of pain. I n t he Unit ed St at es
alone, r ecur r ent or per si st ent pain is exper ienced by mor e t han 75 mil l ion
i ndi vidual s.
2. Acut e pai n last s > 30 days and occur s af t er muscle st r ains and t i ssue i nj ur y,
such as t r auma or sur ger y. The pai n i s usual l y sel f - l imit ing, decreasing wit h t ime as
t he inj ur y heals. I t i s descr ibed as a l i near pr ocess, wit h a beginni ng and an end.
I ncr eased aut onomi c ner vous syst em act ivit y of t en accompani es acut e pai n, causing
t achycar dia, t achypnea, hyper t ensi on, di aphor esi s, and mydr iasi s. I ncr eased anxi et y
also may occur .
3. Chroni c pai n is per si st ent or epi sodi c pain of a dur at ion or int ensi t y t hat
adver sely af f ect s t he f unct ion or wel l - bei ng of t he pat ient and can persist af t er t he
r esolut ion of an i nj ur y. Some def i ne it as last ing mor e t han 6 mont hs.
a. Chroni c nonmal i gnant pai n may be a compl i cat ion of acut e i nj ur y i n whi ch t he
heal i ng pr ocess does not occur as expect ed or may be caused by a disease such as
a r heumat ological di sor der (e. g. , ost eoar t hr it i s, r heumat oid art hr i t is, f ibr omyal gia) .
b. The el der l y ar e mor e l ikel y t o exper ience chr oni c pai n because of t he i ncr eased
pr evalence of degener at ive disor ders in t his age gr oup.
c. The pain is const ant , does not improve wit h t ime, and is descr ibed as a cycl ic
pr ocess ( vicious ci r cl e) .
d. Compar ed t o acut e pain, t her e is no l onger aut onomi c ner vous syst em st imulat ion
so t he pat i ent may not appear t o be in pai n. I nst ead, t he pat ient may be depr essed;
suf f er insomnia, weight l oss, and sexual dysf unct i on; and may not be able t o cope
wit h t he normal act ivit i es of dail y l i vi ng, i ncl udi ng f ami ly and j ob-r el at ed act ivit ies.
4. Chroni c cancer pai n occur s i n 60%- 90% of pat ient s wi t h cancer . I t s
char act er ist ics are simi lar t o t hose of chr onic nonmal i gnant pain. I n addi t ion t o
depr ession, pr omi nent char act er ist ics ar e f ear, anger, and agony. The cause of
chr onic cancer pain can be r elat ed t o t he t umor or cancer t her apy or can be
idi osyncr at ic. Tumor causes of pain i ncl ude bone met ast asis, compr ession of ner ve
st r uct ur es, occl usion of bl ood vessel s, obst r uct ion of bowel , or inf i lt r at ion of sof t
t issue.
5. Breakt hrough pai n i s t he int ermit t ent , t r ansit or y i ncr ease i n pai n t hat occur s at a
gr eat er int ensi t y over baseli ne chr oni c pai n. I t may have t empor al char act er i st i cs,
pr ecipit at i ng f act ors, and pr edi ct abi l it y.
6. Neuropat hi c pai n i s a r esult of an inj ur y or malf unct ion of t he ner vous syst em.
Excludi ng pat ient s wi t h a pr ogressi ve per ipher al neur opat hy or neur opat hic pai n
associ at ed wit h a cancer l esion, t i ssue damage is not ongoing. Neur opat hic pain is
descr ibed as achi ng, t hr obbi ng, bur ni ng, shoot i ng, st ingi ng and t ender ness or
sensit i vit y of t he skin.
B. Pri nci pl es of management
1. Comprehensi ve pai n assessment should det ermine t he char act er ist ics of t he
pat ient ' s pai n complai nt , cl ini cal st at us, and pain management hist or y.
a. Assessment of t he pain compl aint shoul d i ncl ude chr onol ogy and sympt omat ol ogy
of t he pr esent i ng compl ai nt such as inf ormat ion about onset , l ocat i on, i nt ensi t y,
dur at i on, qual it y, di st r i but ion, provocat ive f act or s, t empor al qual it ies, sever it y, and
pai n hist or y.
b. Assessment of cl i ni cal st at us should i ncl ude t he ext ent of under l yi ng t r auma or
disease. Also, t he pat ient ' s physical, psychologi cal, and social condit i ons should be
det ermined.
P. 1261


c. Assessment of pain management hist or y i ncl udes dr ug al l er gies, analgesic
r esponse, onset , dur at ion, and side ef f ect s.
2. Appropriat e pai n management target s should be est abli shed.
a. The pr imar y pain management goal i s t o impr ove pat ient comf ort .
b. For acut e pain management , i mpr oved comf ort can aid t he heal i ng and
r ehabi l it at i on pr ocess.
c. For chronic pai n, t he speci f ic obj ect i ves ar e t o br eak t he pain cycle ( i. e. , er ase
pai n memor y) and mini mi ze br eakt hr ough pain.
d. Ot her t ar get s f or chr onic pai n management incl ude impr ovement of general wel l -
bei ng, sleep, out look, sel f - est eem, act i vi t ies of dai l y l i vi ng, support , and mobil i t y.
3. I ndi vi dual i zed pai n management regi mens shoul d be det ermined and i nit iat ed
pr ompt ly.
a. The opt imal analgesic r egimen, incl uding dose, dosi ng i nt er val , and mode of
admi ni st r at ion, should be select ed.
b. Addi t ional pharmacologi cal adj unct s and nonpharmacol ogical t her apies shoul d be
added i f needed.
c. The most common r egimens f or acut e pai n i ncl ude i nt ermit t ent (as needed)
dosing, pat ient - cont r olled analgesia (PCA) , or epi dur al i nf usions wit h nar cot ic or
nonnar cot i c agent s.
d. Al t hough t he pr act ice i s cont r oversi al and of t en not i n t he best i nt er est s of
pat ient s, narcot i c use is of t en minimized or avoi ded f or chr oni c nonmal ignant pai n.
Pai n management special i st s are changing t his subopt imal pr act ice. Nonnar cot ic
analgesics and nonpharmacologi cal management usual l y ar e maxi mi zed.
e. For chronic cancer pain, an i ndi vidual i zed ar ound- t he- cl ock analgesic r egimen i s
est ablished, usi ng a long- act ing analgesic. An int ermi t t ent , as-needed r egimen f or
br eakt hr ough pai n, usi ng a shor t - act ing analgesic, is al so det ermined.
4. Moni t ori ng t he pain management r egi men and reassessment of t he pat ient ' s
pai n should occur on a cont i nuous, t imely basi s. Any changes i n anal gesi c, dose,
dosing i nt er val , or met hod of admi nist r at ion shoul d be not ed in t he pat ient ' s medical
r ecor d and car r ied out i n a t imely f ashion.
II. ANALGESICS
A. Nonnarcoti c anal gesi cs i ncl ude aspir i n; ot her sali cylat es; acet ami nophen;
nonst er oidal ant i- i nf lammat or y dr ugs (NSAI Ds) ; select i ve, cyclooxygenase 2 (COX-
2) inhi bi t or s; disease-modif yi ng ant i r heumat ic dr ugs (DMARDs); and t umor - necr osis
f act or q ( TNF-q) inhibit or s ( Table 58- 1). Aspir i n pr oduct s, acet aminophen, and some
low-dose NSAI Ds such as ibupr of en, ket opr of en, and napr oxen sodi um ar e avai l able
as over- t he- count er (OTC) pr oduct s.
1. Mechani sm of act i on. Sal icyl at es and NSAI Ds ar e pr ost aglandin i nhibit or s and
pr event peri pher al nocicept ion by vasoact i ve subst ances such as pr ost aglandins
and br adykini ns. Most NSAI Ds i nhibit bot h COX- 1, which pr oduces pr ost aglandi ns
t hat ar e beli eved t o be cyt opr ot ect i ve of t he st omach l i ni ng, and COX- 2, which
pr oduces prost agl andi ns r esponsible f or pai n and i nf lammat i on. Select ive COX- 2
i nhibit or s l ike cel ecoxib do not inhi bi t COX- 1. Adal imumab, et aner cept , and
i nf l i ximab act by bindi ng or capt ur ing excess TNF- q, one of t he domi nant cyt okines,
or pr ot eins, t hat pl ay an i mport ant r ol e i n t he i nf l ammat or y r esponse. The exact
mechanism of act ion of l ef l unomide, a novel dr ug used t o t r eat r heumat oid art hr it is,
is not compl et el y known but it is t hought t o inhi bit pyr imidi ne synt hesis.
2. Therapeut i c ef f ect s
a. The per ipher al l y act ing, nonnar cot i c analgesics have sever al ef f ect s in common.
These ef f ect s dist ingui sh t hese agent s f r om nar cot i c analgesics.
( 1) They ar e ant ipyr et ic.
( 2) They ar e ant i- i nf lammat or y ( except acet aminophen) .
( 3) Ther e i s a cei l i ng ef f ect t o t he analgesia.
( 4) They do not cause t ol er ance.
( 5) They do not cause physical or psychologi cal dependence.
b. The ef f i cacy of nonnar cot ics is compar ed t o aspi r i n. Most dr ugs ar e compar able
t o aspir i n; however , sever al NSAI Ds have shown a super ior ef f ect t o 650 mg of
aspir i n.
P. 1262


Table 58-1. Nonnarcotic Oral Analgesics and Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)
Drug
Adult Dose
Range (mg)
Dosing
Interval (hr)
Maximum
Dose/Day (mg)
Para-aminophenol derivatives
Acetaminophen (Tylenol) 325-1000 4-6 4000
Salicylates

Aspirin 325-1000 4-6 4000
Choline magnesium
trisalicylate (Trilisate) 1000-1500 12
3000
Diflunisal (Dolobid) 250-1000 8-12 1500
Salsalate (Disalcid) 500-1000 8 3000
Arylpropionic acid derivatives
Fenoprofen (Nalfon) 200 4-6 3200
Flurbiprofen (Ansaid) 50-100 6-12 300
Ibuprofen (Motrin) 300-800 6-8 3200
Ketoprofen (Orudis) 12.5-75 6-8 300
Naproxen (Naprosyn) 200-500 12 1250
Naproxen sodium
(Anaprox)
275-550 12 1375
Oxaprozin (Daypro) 600-1200 12 1200
Heteroaryl acetic acid derivatives
Diclofenac (Voltaren) 25-75 6-12 200
Ketorolac (intramuscular)
(Toradol) 15-60 6
120
Ketorolac (oral) 10 4-6 40
Tolmetin (Tolectin) 200-600 6-8 1800
Indole and indene acetic acid derivatives
Etodolac (Lodine) 200-400 6-12 1200
Indomethacin (Indocin) 25-50 8-12 200
Sulindac (Clinoril) 150-200 12 400
Anthranilic acid derivatives (fenamates)
Meclofenamate 50-100 4-6 400
Mefenamic acid (Ponstel) 250 6 1000
Alkanone derivatives
Nabumetone (Relafen) 1000 12-24 2000
Enolic acid derivatives (oxicams)
Piroxicam (Feldene) 20 24 20
Cyclooxygenase 2 (COX-
2) selective inhibitors

Celecoxib (Celebrex) 100-200 12-24 400
Disease-modifying antirheumatic drugs (DMARDs)
Leflunomide (Arava) 20 24 20
a

Biological response modifiers (tumor necrosis factor o inhibitors)
Adalimumab (Humira) 40 SC
injection
Every
other
week
TBD
Etanercept (Enbrel) 25 SC
injection
Once
weekly
50 SC
injection
Infliximab (Remicade) 3/kg IV.
infusion
Every 4-6
weeks
10/kg
a
Excludes loading dose of 100 mg/day for 3 days.

IV, intravenous; SC, subcutaneous; TBD, to be determined.

( 1) Di f l unisal ( 500 mg)
( 2) I bupr of en ( 200- 400 mg)
( 3) Napr oxen sodi um ( 550 mg)
( 4) Ket opr of en ( 25- 50 mg)
c. The newer cl asses of dr ugs, in gener al , have not been compar ed t o aspi r i n.
P. 1263


3. Cl i ni cal use
a. Gener al l y, t he nonnar cot ic analgesi cs ar e used oral l y t o manage mi ld t o moder at e
pai n.
( 1) They ar e par t icular l y suit ed f or acut e pain of skel et al muscle ( ort hopedic) or or al
( dent al) or igi n.
( 2) They ar e used t o t r eat pain and inf lammat ion associat ed wi t h ost eoart hr it i s and
r heumat oid art hr i t is.
( 3) They ar e used in chr onic pai n and can have an addi t ive ef f ect wit h nar cot ic
analgesics.
( 4) They also may be ef f ect ive i n managi ng pai n owi ng t o bone met ast ases.
b. The NSAI D ket or olac is admini st er ed int r amuscular ly and i s usef ul i n moderat e t o
sever e pai n, par t icular l y in cases in which nar cot i cs ar e undesir abl e ( e. g. , wit h dr ug
addict s, excessi ve nar cot i c sedat ion, r espir at or y depr ession) .
c. The NSAI D di cl of enal epolami ne is avai lable as a t opical pat ch ( Flect or Pat ch
®
)
f or t r eat ment of st r ains, spr ai ns, and cont usions. One pat ch i s appli ed t o t he most
pai nf ul ar ea t wi ce a day (should not be appl ied t o damaged or non- int act skin) .
d. Pat ient s may var y i n t hei r r esponse and t ol er ance t o nonnar cot ic analgesi cs. I f a
pat ient does not r espond t o t he maxi mum t her apeut i c dose, t hen an al t er nat e NSAI D
should be t r ied. Likewi se, i f a pat ient exper i ences side ef f ect s wit h one dr ug, t hen
anot her agent should be t r ied.
e. Sever al dr ugs ( e. g. , dif l uni sal, chol i ne magnesi um t r isal icyl at e, naproxen,
celecoxi b, l ef l unomide, et anercept , inf l i ximab, and adal imumab) have long half - l i ves
and, t heref or e, may be admini st er ed l ess f requent l y.
f . The cost of nonnar cot ic analgesics i s highl y var i able and shoul d be consider ed
when an agent is select ed. Pharmacot her apy wit h t he COX- 2 i nhibi t or celecoxib, t he
newer DMARDs like l ef l unomide or TNF-q inhi bit or s i s signi f icant l y mor e expensi ve
t han older agent s.
4. Adverse ef f ect s
a. Gastroi nt est i nal (GI ) ef f ect s. Most nonnar cot i c analgesics cause GI sympt oms
secondar y t o pr ost aglandi n i nhibit ion. At normal doses, acet aminophen and chol i ne
magnesium t r isal icyl at e pr oduce minimal GI upset . Because of t hei r mechani sm of
act ion, t he COX- 2 inhibit or s have a GI t oxicit y si milar t o pl acebo. Adal imumab,
et aner cept , inf l i ximab, and lef lunomide have been associ at ed wit h GI side ef f ect s
i ncl udi ng nausea, abdominal pai n, dyspepsia, const i pat ion, vomi t ing, hemat ochezia,
i nt est inal obduct i on, i nt est inal per f orat ion, pancr eat it i s, per i t onit i s, pept ic ulcer , and
diar r hea.
( 1) The most common GI sympt om is dyspepsia, but ulcer at ion, bleedi ng, or
perf or at ion can occur .
( 2) Pat ient s most pr edisposed t o sever e GI ef f ect s incl ude t he elder l y, pat ient s wit h
a hist or y of ul cer s or chr oni c disease, and t hose who smoke or use alcohol .
( 3) To minimize GI ef f ect s, t he lowest possible analgesic dose shoul d be used.
Aspir i n, avai l abl e as ent er i c- coat ed product s, may minimi ze GI upset . Combi nat ion
t her apy wit h a GI “pr ot ect ant ” ( e. g. , ant aci d, H2 - ant agonist , sucr al f at e, misoprost ol)
may be needed.
b. Hemat ol ogi cal eff ect s. Most nonnar cot i c anal gesics inhibit plat elet aggr egat i on.
The ef f ect i s pr oduced by r eversible i nhibit ion of pr ost aglandi n synt het ase. Aspir i n
is an ir r ever si ble i nhi bit or . Acet aminophen and chol i ne magnesi um t r i sal icyl at e lack
ant ipl at elet ef f ect s. TNF- q i nhibit or s have been associat ed wit h anemi a, apl ast ic
anemia, leukopenia, neut r openia, pancyt openia, and t hr ombocyt openia. Lef l unomide
has been associ at ed wit h anemia and ecchymosis.
( 1) The ef f ect of t he NSAI Ds cor rel at es t o t he pr esence of an ef f ect ive ser um
concent r at ion.
( 2) Use of ant icoagul ant s (e. g. , hepar i n, war f ar in [ Coumadin] is r el at i vel y
cont r aindicat ed in combi nat ion wi t h aspir i n or NSAI Ds.
c. Renal ef f ect s. NSAI Ds can pr oduce r enal dysf unct ion. Et aner cept has not been
shown t o af f ect r enal f unct ion.
( 1) The mechani sm of NSAI D- induced r enal dysf unct i on i ncl udes pr ost agl andi n
i nhibit ion, int er st it ial nephr i t is, impair ed r eni n secr et ion, and enhanced t ubul ar
wat er / sodium r eabsorpt ion.
( 2) Many r isk f act or s have been impl icat ed, incl udi ng congest ive hear t f ai l ur e
(CHF), chr onic r enal f ai l ur e (CRF), cir r hosis, dehydr at ion, di ur et ic use, and
at her oscler ot i c disease in elder ly pat ient s.
P. 1264


( 3) Renal dysf unct ion i s commonl y mani f est ed as abr upt onset ol igur i a wi t h
sodium/ wat er r et ent i on. The ef f ect r ever ses af t er discont i nuat i on of t he NSAI D.
d. Mal i gnanci es and l ymphoprol if erat i ve di sorders
Agent s t hat block TNF may af f ect host def enses agai nst mal ignancies because TNF
medi at es inf lammat ion and modul at es cell ular immune r esponse. Lymphomas have
occur r ed mor e f r equent l y i n pat i ent s r eceivi ng TNF- blocking agent s t han i n cont r ols.
e. I nf ect i ons. Opport uni st i c and ser i ous i nf ect i ons l eadi ng t o sepsis and deat h have
been associat ed wit h lef l unomi de and t he TNF- bl ocki ng agent s.
f . Mi scel l aneous ef f ect s
( 1) Even i n normal doses, acet ami nophen can cause hepat ot oxi ci t y i n pat ient s wit h
l i ver disease or chr onic al cohol i sm. Hepat ot oxicit y has al so been r epor t ed wit h t he
use of al l NSAI Ds i ncl udi ng t he COX- 2 select ive i nhibit or s. Lef lunomi de and
i nf l i ximab have also been shown t o cause t r ansi ent elevat ions in l i ver f unct i on t est s
such as aspart at e ami not r ansf er ase ( AST) —ser um gl ut amic- oxal oacet ic
t r ansaminase (SGOT)—and alani ne aminot r ansf erase ( ALT) —ser um gl ut amic-pyr uvic
t r ansaminase (SGPT)
( 2) Some pat ient s exhibi t acut e hyper sensit i vit y react ions t o aspir in. Manif est at ions
i ncl ude ei t her a r hinit i s or ast hma pr esent at ion or a t r ue al ler gic r eact ion ( e. g. ,
ur t i car ia, wheal s, hypot ensi on, shock, syncope). A cr oss- sensit i vit y t o ot her NSAI Ds
may develop.
( 3) Some NSAI Ds pr oduce cent r al ner vous syst em (CNS) ef f ect s, incl udi ng impai r ed
ment at i on, headaches, and at t ent i on def icit disor der .
( 4) Lef l unomide has r eceived a black box warni ng because of it s Cat egor y X
pr egnancy war ni ng. I t has al so been associat ed wi t h weight loss, al opecia, r ash,
and anemia.
( 5) TNF- blocking agent s have been associ at ed wit h r eact ions at t he inj ect ion sit e
and aut oant ibody pr oduct i on.
( 6) As of Apr il 2005, t he U. S. Food and Dr ug Admi ni st r at ion ( FDA) i ssued a black
box warni ng f or celecoxi b, a select ive COX- 2 i nhibi t or , because if it s l i nk t o an
i ncr eased r isk f or car diovascular event s ( heart at t ack and st r oke) Thi s i ncr eased
r isk has been demonst r at ed t o be a dr ug class ef f ect f or al l NSAI Ds, excl udi ng
aspir i n. Celecoxib is al so cont raindi cat ed in pat ient s wi t h sulf onami de al ler gy.
5. Drug i nt eract i ons. Salicylat es have t wo cli nical l y signi f icant dr ug int er act i ons.
a. Oral ant i coagul ant s. Aspi r i n should be car ef ul l y moni t or ed, if used, in
ant icoagulat ed pat ient s because it inhibit s pl at elet f unct ion and can cause gast r i c
mucosal damage. Thi s can signif i cant l y i ncr ease t he r isk of bl eedi ng i n
ant icoagulat ed pat ient s. Al so, doses of > 3 g/ day of aspir i n pr oduces
hypopr ot hr ombi nemi a. Chol i ne magnesium t r isal icylat e or acet ami nophen can be
used if a nonnar cot ic is needed in an ant i coagul at ed pat ient .
b. Met hot rexate. Sal icyl at es may enhance t he t oxi cit y of met hot rexat e. The pr i mar y
mechanism is blockage of met hot rexat e r enal t ubular secr et ion by sal i cylat es. The
r esul t ant met hot rexat e t oxi ci t y has been r eport ed as pancyt openi a or hepat ot oxicit y.
Sal icylat es shoul d be avoided in pat i ent s r eceivi ng met hot r exat e.
c. TNF- bl ocki ng agent s. Anaki nr a (Ki ner et ), a r ecombi nant i nt er leukin 1 ( I L- 1)
r ecept or ant agonist , has been obser ved t o cause an i ncr eased r isk of ser ious
i nf ect ions as neut r openia when used concomi t ant l y wi t h et aner cept i n pat i ent s wit h
r heumat oid art hr i t is. Consequent l y, i t s use i s not r ecommended concomit ant ly wi t h
any TNF- blocking agent .
B. Narcot i c anal gesi cs i nclude t he opioid dr ugs (Table 58- 2) . Because of t heir
abuse pot ent ial , opioids ar e classi f ied as cont r oll ed dr ugs. Special r egul at i ons
cont r ol t hei r pr escr ibi ng.
1. Mechani sm of act i on
a. Endogenous opi at es af f or d t he body sel f - pain- r el i evi ng mechanisms. These
endogenous pept ides incl ude t he endor phi ns, enkephal i ns, and dynor phi ns.
b. Exogenous opiat es ar e classif i ed as agoni st s (st imul at e opiat e r ecept ors),
ant agonist s ( displ ace agonist s f r om opiat e r ecept or s) , and mixed opiat es (agoni st -
ant agonist or part ial agonist act i ons) .
c. Opiat e recept or s are locat ed i n t he br ain and spi nal cor d. Several t ypes of opi at e
r ecept or s have been ident if ied, i ncl udi ng µ, k, ô, o, and s.
d. St imul at i on of µ r ecept ors pr oduces t he char act er i st i c nar cot ic (morphi ne- l ike)
ef f ect s.
( 1) Anal gesi a
( 2) Miosi s
( 3) Euphori a
( 4) Respir at or y depression
( 5) Sedat ion
P. 1265


Table 58-2. Some Commonly Used Opioid Analgesics
Drug
Parenteral Dose
(mg)
a

Oral Dose
(mg)
a

Duration
(hr)
Morphine 10 60 4-7
Morphine (CR) (MS Contin) n/a n/a 12-24
Hydromorphone (Dilaudid) 1.3 7.5 4-6
Oxymorphone (Numorphan) 1 — 4-6
Levorphanol (Levo-
Dromoran)
2 4 4-7
Methadone (Dolophine) 10 20 4-6
Meperidine (Demerol) 75 300 3-6
Fentanyl (Sublimaze) 0.1 — 1-2
Fentanyl transdermal
(Duragesic)
n/a n/a 48-72
Codeine 130 200 4-6
Hydrocodone
b
— 5-10 4-5
Dihydrocodeine
b
— 32 4-5
Oxycodone
b
— 5-10 4-5
Oxycodone (CR)
(OxyContin)
n/a 12-24
Propoxyphene (Darvon) — 65-100 4-6
Nalbuphine (Nubain) 10 — 4-6
Butorphanol (Stadol) 2 — 4-6
Dezocine (Dalgan) 10 — 4-7
a
Doses equivalent to 10 mg intramuscular or subcutaneous morphine

b
Doses for moderate pain not necessarily equivalent to 10 mg morphine.

CR, controlled release; n/a, not applicable.

( 6) Physi cal dependence
( 7) Br adycar dia
e. The specif ic mechani sm (cent r al and spinal) of opi at e agonist is al t er at ion of t he
ef f ect s of nocicept ive neur ot r ansmit t er s, possi bl y nor epi nephr i ne or serot onin.
2. Cl i ni cal use
a. Opioid analgesics ar e used f or t he management of moder at e t o sever e pain
( acut e or chr onic pai n) of somat i c or viscer al or igi n.
b. The use of narcot ics should be indi vidual i zed f or each pat ient . The opt imal
analgesic dose var i es f r om pat ient t o pat i ent . Each analgesic r egimen should be
t it r at ed by i ncr easi ng t he dose up t o t he appear ance of l i mit i ng adver se ef f ect s.
Changing t o anot her anal gesi c shoul d occur onl y af t er an adequat e t her apeut ic t r ial.
c. The appr opr i at e r out e of admi ni st r at ion should be select ed f or each pat ient .
( 1) Oral admi ni st rat i on i s t he pr ef err ed r out e, par t i cular l y f or pat ient s wit h chr oni c,
st abl e pai n. Cont r oll ed- r el ease mor phi ne and oxycodone t ablet s ar e avai l able f or
convenience i n cont r oll i ng cont i nuous pai n, part icular ly i n t hose pat i ent s wit h
cancer .
( 2) I nt ramuscul ar and subcut aneous admi ni st rat i on ar e ver y commonl y used i n
t he post oper at ive per i od. Fl uct uat ions i n absor pt i on may occur , par t icular l y i n
elder l y or cachect ic pat ient s.
( 3) I nt ravenous ( I V) bol us admi ni st rat i on has t he most r api d, pr edict able onset of
ef f ect .
( 4) IV i nf usi on i s used t o t i t r at e pain r el ief r apidl y, part icular l y i n pat i ent s wit h
unst abl e chr oni c pai n. Mor phine i s most commonl y used, of t en wi t h suppl ement al I V
bol us doses f or br eakt hr ough pai n. A mechanical i nf usion device i s necessar y.
( 5) IV PCA i s most of t en used f or acut e post operat i ve pai n. I t pr oduces prompt
analgesia wit h minimal si de ef f ect s because small doses ( e. g. , 1- 2 mg mor phi ne)
ar e del iver ed at f r equent i nt er vals ( e. g. , ever y 10 min) . I t al l ows pat ient cont r ol of
pai n management . Mor phine and meper i di ne ar e t he most commonl y used agent s. A
mechanical i nf usion device and pr oper l y t r ained pat ient and st af f ar e necessar y.
( 6) Epi dural and i nt rat hecal admi ni st rat i on ar e used f or acut e post oper at i ve pai n
and ear l y management of chr onic cancer pain. Al l dr ugs used epidur al l y or
i nt r at hecal l y must be preser vat i ve f r ee because of t he neur ot oxi cit y of par abens and
benzyl al cohol when administ er ed via t hese r out es. I nt r at hecal doses ar e gener all y
1/ 10 of t he cor responding dr ug' s epidur al dose.
P. 1266


Table 58-3. Epidurally Administered Preservative-Free Opioids: Intermittent
Dosing
Drug Dose (mg)
Onset of
Action
(min)
Time to
Peak
Effect
(min)
Duration of
Action
(hr)
Morphine 5-10 25 60 12-24
Fentanyl 0.1 5-10 20 6
Meperidine 50-
100
5-10 15-30 7
Hydromorphone 1 10-15 20 12
Buprenorphine
(Subutex)
0.3 30 40-60 8-9

(a) Low opi at e doses st imul at e spinal opiat e r ecept or s and r educe t he amount of
nar cot ic r eachi ng t he br ain. This r esul t s in delayed or mini mal ef f ect s such as
sedat ion, nausea, and respi rat or y depr ession. The opiat e dist r ibut i on t hat causes
such ef f ect s depends on t he sit e of spinal i nj ect ion, wat er solubi l it y of t he opiat e,
and vol ume inf used. For example, af t er lumbar admi nist r at ion of a mor e wat er -
sol uble opiat e (mor phi ne) , sever e r espir at or y depr ession can be obser ved 12- 24 hr
af t er init ial dosi ng.
( b) Local si de ef f ect s of i nt r at hecal opi at e admini st rat i on ar e it chi ng and ur i nar y
r et ent i on. Depending on t he opi at e used and t he t ype of pain bei ng t r eat ed,
i nt ermit t ent doses or cont inuous i nf usi ons ( via a mechanical i nf usion device) can be
used ( Tabl es 58-3 and 58- 4).
( 7) Rectal admi ni st rat i on i s an al t er nat i ve f or pat ient s unable t o t ake or al
nar cot ics. Gener al ly, poor absor pt ion r esult s in an unr el iabl e analgesic r esponse. I t
is an unaccept able r out e of administ r at ion f or many pat ient s.
( 8) Transdermal admi ni st rat i on is an al t er nat i ve f or pat ient s wit h chr oni c pai n who
ar e unable t o t ake or al nar cot ics. A cont r ol led- r elease pat ch is avai lable f or
f ent anyl . Sl ow onset requi r es addi t ional analgesi a when st art ing t r eat ment . The
dur at i on of analgesia is 48- 72 hr per pat ch. A sl ow r educt ion of ef f ect f ol l ows
r emoval of t he pat ch and r equir es 24-36 hr of monit or i ng.
d. Pat ient s who have chr onic pain or acut e pain t hat is const ant t hr oughout t he day
should r ecei ve r egul ar l y scheduled ( ar ound- t he- cl ock) doses of nar cot ics.
( 1) Long- act i ng opiat es ( e. g. , cont rol l ed- r elease mor phi ne and oxycodone) ar e
pr ef er abl e.
( 2) A supplement gi ven as needed may be necessar y t o manage br eakt hr ough pai n,
f or which shor t -act i ng opiat es ( e. g. , immediat e- r elease mor phi ne, hydr omor phone)
ar e pr ef er abl e. I f f requent supplement s ar e r equi r ed, t hen t he ar ound- t he- cl ock
r egimen should be adj ust ed based on morphi ne equi valent s ( Tabl e 58- 2) .
e. Alt hough t he anal gesi a and side ef f ect s of opiat es are qual it at ivel y simi l ar ,
i ndi vidual pat ient s may r espond di f f er ent l y. Analgesic select ion is based on:
( 1) Pat ient ' s past analgesia exper ience
( 2) Need f or a rapi d onset of ef f ect
( 3) Pr ef er ence f or a l ong ( or shor t ) dur at ion of act ion
( 4) Pr ef er ence f or a part icular mode of del i ver y
( 5) Pr ef er ence f or a part icular dosage f orm
(a) Cont rol l ed- r elease mor phi ne or oxycodone f or a long dur at i on of act ion ( 8- 12 hr )
may be pr ef erable t o opi at es wit h long half - l i ves ( e. g. , met hadone, levor phanol ) ,
whi ch can accumul at e and cause over dose sympt oms (e. g. , r espir at or y depression) .
Table 58-4. Epidurally Administered Preservative-Free Opioids: Continuous
Infusion
Drug
Initial Bolus Dose
(mg)
Infusion Concentration
(mg/mL)
Rate
(mg/hr)
Morphine 2 0.05-0.25 0.2-1.5
Fentanyl 0.05-0.1 0.005-0.025 0.02-
0.15
Meperidine 50-100 10-20 5-20
Hydromorphone 0.5-1 0.02-0.05 0.15-
0.3

P. 1267


( b) Tr ansdermal f ent anyl can be used f or pat i ent s who are unabl e t o swal low.
( c) Rect al supposit or ies can be used f or pat ient s who ar e unabl e t o swal l ow. They
ar e avai lable f or mor phi ne, hydr omor phone, and oxymor phone.
( d) Concent r at ed hydr omor phone i nj ect i on ( 10 mg/ mL) can be used f or cachect ic
pat ient s who r equir e subcut aneous i nj ect i ons and in pat ient s whose inj ect ion
vol umes must be minimized.
( 6) I ndi vi dual sensit i vit y t o side ef f ect s, which i ncl udes nausea, euphor i a, sedat ion,
and r espir at or y depr essi on
(a) Par t ial agoni st s or mixed agonist - ant agonist s may be pr ef er able f or acut e pain
management in pat i ent s at r isk f or r espi r at or y depr ession secondar y t o opiat e
agonist s. These agent s shoul d not be used in pat ient s who have r eceived chr onic
doses of opi at es because wit hdr awal sympt oms wi l l occur .
( b) Epidur al administ r at i on may be pr ef erable f or cr i t ical l y i l l pat i ent s at r i sk f or
r espir at or y depr ession secondar y t o syst emic narcot i c admi nist r at ion.
3. Adverse ef f ect s. Al l nar cot i cs can pr oduce a var iet y of si de ef f ect s t hat r ange
f r om bot her some t o lif e- t hr eat eni ng.
a. Const i pat i on occur s as a result of decreased i nt est i nal t one and per ist al si s.
Ther e is a pat i ent var iabi l it y, but gener all y most pat ient s exper i ence const i pat ion
af t er several days of t her apy. Const i pat ion may be more bot her some wit h cert ain
t ypes of opiat es ( e. g. , codeine) . I t may occur sooner and be more pr oblemat ic i n
hospit al i zed or bedr idden pat ient s or in pat ient s who have r eceived anest hesi a or
dr ugs wit h ant i chol i ner gi c ef f ect s. Prophylaxis wi t h a laxat ive/ st ool sof t ener
combinat i on ( e. g. , bisacodyl/ docusat e (Gent l ax- S) and di et ar y counsel i ng ar e
war r ant ed f or pat i ent s who need chr oni c opi at e t her apy.
b. Nausea and vomi t i ng occur owi ng t o cent ral st i mulat ion of t he chemor ecept or
t r igger zone. I t i s mor e problemat i c wit h one- t i me or int ermit t ent par ent er al dosi ng
f or acut e pain. Occasi onal l y, pat ient s r equi r e concomit ant t her apy wit h an
ant iemet ic ( e. g. , hydr oxyzi ne, pr ochl or per azi ne) ; however , t hese agent s may add t o
t he sedat ive ef f ect s of opi at es.
c. Sedat i on is a dose-r el at ed ef f ect but somet imes is enhanced by concomi t ant use
of ot her dr ugs wit h sedat ing ef f ect s ( e. g. , benzodi azepi nes, ant iemet ics). Most
chr onic pai n pat ient s become t ol er ant t o t his ef f ect , but occasional l y t he addi t ion of
a CNS st imul ant , such as dext roamphet ami ne or met hyl pheni dat e, is needed.
( 1) Pat ient s st art ing t her apy wi t h nar cot ics shoul d be war ned about dr ivi ng or
oper at ing machi ner y.
( 2) Sedat ion may be a sign of excessive dosi ng or accumulat ion. However , sedat i on
should not be conf used wi t h physiol ogical sleep i n pat ient s who have pai n- cont r ol
dif f icult i es. Pat ient s in pai n of t en develop i nsomni a. When pai n i s br ought under
cont r ol by appr opr iat e nar cot ic t it r at i on, t he pat i ent i nit ial l y may sleep f or sever al
hour s.
d. Respi rat ory depressi on is t he most ser ious adver se ef f ect accompanyi ng
nar cot ic over dose. Respir at or y depr essi on may be a si gn of an excessi ve dose,
accumul at ion of l ong hal f - l i ved opiat es ( e. g. , met hadone, levor phanol ) , or
accumul at ion of act ive mor phi ne met aboli t es in r enal f ai l ur e pat i ent s.
( 1) Respir at or y r at e should be car ef ul l y moni t or ed i n pat i ent s recei vi ng I V or
epidur al opiat es, in neonat es, in elder l y pat ient s, and i n pat ient s r eceivi ng ot her
dr ugs t hat cause r espir at or y depr essi on.
( 2) The opiat e ant agoni st s, nal oxone and nal mef ene, are administ er ed i nt r avenousl y
t o r everse l if e- t hr eat eni ng r espi r at or y depr ession. Use of naloxone or nal mef ene
(Revex) in an opi at e- dependent pat ient ( e. g. , a chr oni c cancer pai n pat i ent ) can
pr ecipit at e opiat e wi t hdr awal.
e. Ant i chol i nergi c ef f ect s, such as dr y mout h and ur i nar y r et ent ion, can be
bot her some f or some pat ient s.
f . Hypersensi t i vi t y r eact ions, such as i t chi ng owi ng t o hist ami ne r el ease, can occur
secondar y t o opiat e use, part icular l y wit h epidur al or int r at hecal administ r at i on.
Wheals somet i mes occur at t he sit e of mor phi ne i nj ect ion. These r eact ions do not
r epresent t r ue al ler gy.
g. CNS exci tat i on, such as myoclonus and ot her sei zur e- l ike act ivit y, can be
pr oduced wi t h t he use of meper idi ne in r enal f ai l ur e. These sympt oms have also
been obser ved in pat ient s wit h nor mal r enal f unct i ons who r eceive hi gh doses of
meper idi ne ( e. g. , < 800 mg/ day of int r amuscular meper idi ne) . The accumulat ion of
t he met abol it e normeper idi ne is t he cause.
P. 1268


4. Drug i nt eract i ons
a. Nar cot i cs have addit i ve CNS depr essant ef f ect s when used i n combi nat ion wi t h
ot her dr ugs t hat also are CNS depr essant s ( e. g. , al cohol, anest het ics,
ant idepr essant s, ant i hi st amines, bar bi t ur at es, benzodiazepi nes, phenot hiazi nes) .
b. Nar cot ics, par t icular l y meper idi ne, can cause sever e r eact ions such as
exci t at i on, sweat i ng, r i gi dit y, and hyper t ension i n pat i ent s r ecei vi ng monoami ne
oxidase ( MAO) inhibit or s. Meper idine shoul d be avoi ded and ot her nar cot ics st ar t ed
at l ower doses in pat ient s being t r eat ed wit h MAO i nhibit or s.
5. Tol erance means t hat i ncr easi ng doses of opiat e ar e needed t o maint ai n
analgesia. Toler ance usual l y develops t o t he anal gesi c, sedat ive, and euphor ic
ef f ect s of opioids, but not t o t he pupi l l ar y- const r i ct i ng and const ipat i ng ef f ect s. This
is usual l y obser ved as a decr easi ng dur at i on of analgesia i n chr onic pai n pat ient s.
The addit ion of an NSAI D may help delay or pr ovi de adequat e anal gesi a i n t olerant
pat ient s.
6. Dependence. The use of opiat es f or chr onic pai n may r esult in physical
dependence, such t hat t he abr upt discont inuat ion of t he opi at e r esul t s in t he
development of wit hdr awal sympt oms.
a. Wit hdrawal sympt oms incl ude anxiet y, ir r it abi l it y, i nsomnia, chi l l s, sal i vat i on,
r hinor r hea, diaphor esis, nausea, vomit i ng, GI cr amping and di ar r hea, and
pi l oer ect ion.
( 1) The appear ance and i nt ensit y of wit hdr awal sympt oms var y accor ding t o t he
half - l i f e of t he opi at e. For exampl e, t he wit hdr awal sympt oms af t er discont i nuat i on
of chr onic met hadone may t ake sever al days t o develop and may be l ess int ense
t han t hose of wit hdr awal f rom mor phi ne owi ng t o it s shor t er half - l i f e.
( 2) The development of t oler ance may be associat ed wi t h wit hdr awal sympt oms.
( 3) The use of nal oxone or a par t ial agonist - ant agoni st such as pent azoci ne i n a
pat ient r eceivi ng chr oni c opi at e t her apy pr oduces acut e wit hdr awal .
b. The development of physi cal dependence seen in chr onic pai n pat ient s i s not t he
same as psychologi cal dependence or addict ion. Al so, t he dr ug- seeki ng behavi or
obser ved i n many acut e pain pat ient s ( i. e. , f r om post oper at ive pai n) i s not a sign of
addict ion, but r at her a need f or adequat e pai n r el i ef . St udies suggest t hat t he
addict i ve r at es f or l ong- t erm t reat ment of noncancer pai n ar e low in pat ient s wi t hout
a pr ior hist or y of addict ion. The anal gesi c needs of t his t ype of pat ient shoul d be
r eassessed and usual l y necessi t at es incr easing t he dose of opiat e, changi ng t o a
longer dur at ion dr ug, changi ng t o a PCA, or adding an analges ic adj unct .
C. Tramadol (Ul tram) is an or al, cent r all y act i ng anal gesi c wi t h weak opi at e
act ivit y. I t has not been placed i n a cont r ol led dr ug schedul e.
1. Mechani sm of act i on
a. Tr amadol is a synt het ic ami nocycl ohexanol t hat binds t o opiat e r ecept or s,
i nhibit i ng nor epi nephr i ne and serot oni n.
b. The anal gesi c ef f ect s are part i al l y ant agonized by naloxone.
2. Cl i ni cal use
a. Tr amadol is used f or moder at e t o moder at el y sever e pai n.
b. The r ecommended dosage i s 50-100 mg ever y 4- 6 hr , up t o a maximum of 400
mg/ day.
c. At maximum dosage, t r amadol appears no more ef f ect ive t han acet aminophen-
codeine combinat ions.
3. Adverse ef f ect s
a. GI ef f ect s incl ude nausea, const ipat i on, and dry mout h.
b. CNS ef f ect s incl ude di zzi ness, headache, sedat ion, and sei zur es ( overdose).
c. Di aphoresi s
4. Drug i nt eract i ons
a. Tr amadol can i ncr ease t he sedat i ve ef f ect of al cohol and hypnot ics.
b. Tr amadol i nhi bit s monoamine upt ake and shoul d not be used wit h MAO i nhi bi t or s.
c. Tr amadol used wi t h select i ve ser ot oni n r eupt ake inhi bit or s (SSRI s) and ot her
agent s t hat i ncr ease ser ot oner gi c act ivit y can cause “ ser ot oni n syndr ome, ” which is
char act er ized by i r r it abi l it y, anxiet y, CNS excit at i on, and myoclonus.
D. Adj uvant anal gesi cs
Adj uvant analgesi cs ar e dr ugs whose init i al FDA appr oved i ndicat ion was f or a
condit ion ot her t han pai n. Ot her classes of dr ugs af f ect nonopi at e pain pat hways
and may be usef ul i n cer t ain t ypes of pai n ( e. g. , neur opat hi c pai n) . These dr ugs
of t en ar e used wit h ot her anal gesi cs and some may help manage narcot i c side
ef f ect s ( Table 58- 5) .
P. 1269


Table 58-5. Analgesic Adjuncts
Class Drugs Indications
Tricyclic
antidepressants
Amitriptyline (Elavil),
desipramine (Norpramin),
doxepin (Sinequan),
imipramine (Tofranil)
Neurogenic pain;
chronic pain
complicated by
depression or insomnia
Anticonvulsants Gabapentin (Neurontin),
pregabalin (Lyrica),
carbamazepine (Tegretol),
clonazepam (Klonopin),
phenytoin (Dilantin),
valproate (Depakote),
Lancinating
neurogenic pain (e.g.,
trigeminal neuralgia,
phantom limb pain,
post-trauma
neurogenic pain)
Neuroleptics Fluphenazine (Prolixin),
haloperidol (Haldol),
prochlorperazine
(Compazine)
Refractory neurogenic
pain; pain complicated
by delirium or nausea
(prochlorperazine)
Corticosteroid Dexamethasone
(Decadron)
Pain from neural
infiltration; pain
associated with bony
metastases
Antihistamine Hydroxyzine (Atarax,
Vistaril)
Pain complicated by
anxiety or nausea
Benzodiazepines Alprazolam (Xanax),
lorazepam (Ativan)
Pain complicated by
anxiety or muscle
spasm
Amphetamines Dextroamphetamine
(Dexedrine),
methylphenidate (Ritalin)
For excessive opiate-
induced sedation in
chronic pain patients

1. Neuropat hi c pai n agent s i nclude ant i convul sant s ( e. g. , gabapent i n, pr egabal in,
lamot r igi ne, carbamazepi ne) , syst emi c l ocal anest het i c agent s—f or example, 5%
l idocai ne ( Lidoder m) pat ch—and t r icycl ic ant idepr essant s—such as, amit r i pt yl i ne,
nor t r ipt yl i ne, and desi pr amine. Gabapent i n and syst emi c l ocal anest het i c agent s are
consider ed f i r st - l ine t her apy i n t r eat i ng pol yneur opat hi es.
a. Mechani sm of act i on.
( 1) Gabapent i n and pr egabal i n may r el i eve neur opat hic pai n by t he pr esynapt ic
bi ndi ng of t he q- 2- ô subuni t of volt age- sensit i ve calci um channels.
( 2) Pr egabali n may also modulat e t he r el ease of t he sensor y neur opept ide
subst ance P.
( 3) Lamot r igi ne and carbamazepi ne ar e bel ieved t o block sodi um channel s at t he
sit e of ect opi c dischar ge of damaged ner ves.
( 4) The use of l ocal anest het ics al lows f or local pai n r el ief wi t hout syst emic t oxi cit y,
specif i cal l y by bi ndi ng t o t he sodium channel s i n t he damaged ner ves.
( 1) I t is hypot hesized t hat TCAs obt ai n t hei r anal gesi c ef f ect s as a r esult of sodium
channel blockade at t he sit e of ect opi c dischar ge i n t he per ipher al ner ves.
( 6) Al l of t hese agent s ar e r ecommended t o aid in t he r educt i on of neur onal
hyper exci t abi l i t y, whet her i t is per ipher al l y or cent r al l y.
b. Cl i ni cal use
( 1) Dat a ar e avai lable t o gi ve guidance on which agent s t o use t o t r eat neur opat hic
pai n, but t hey do not predict which agent wi l l pr ovi de r el i ef f or each indi vidual
pat ient ' s pai n.
( 2) Typical l y, a treatment al gori t hm may recommend:
(a) Fi rst l i ne
( i ) Gabapent in
( i i ) Pr egabal i n
( i i i ) 5% l idocai ne pat ches
( i v) TCAs
( b) Second l i ne
( i ) Ot her ant i convul sant s ( l amot r igi ne or car bamazepine)
( i i ) Ot her ant i depr essant s ( bupr opion, cit alopr am, par oxet i ne, venlaf axi ne,
imipr amine)
( c) Ot her
( i ) Capsaici n, clonidi ne
P. 1270


c. Adverse ef f ect s. t he most common adver se event s associ at ed wit h
ant iconvulsant s ar e di zzi ness, headaches, and drowsi ness. Lamot r igi ne has been
associ at ed wit h t he devel opment of St evens- Johnson syndr ome (SJS). I t is
r ecommended t hat lamot r i gi ne be t it r at ed up every 2 weeks t o mini mize t he
occur r ence of SJS.
E. Mi scel l aneous agent s
1. Capsai ci n, a component of r ed pepper s, causes t he r elease of subst ance P f r om
sensor y ner ve f i ber s, r esul t i ng i n pr ol onged cut aneous pain t r ansmi ssion, hist ami ne
r elease, and er yt hema because of r ef lex vasodi l at i on. Repeat ed l ocal appl i cat ion
deplet es t he per ipher al sensor y C- ner ve f i ber of subst ance P, r esult ing i n pai n
i nhibit ion. Topical capsaici n cr eam 0. 025% or 0. 075% has been shown t o be usef ul
i n t r eat ing j oint pain and t ender ness i n pat i ent s wit h ar t hr it i s. Ot her uses may
i ncl ude t r eat ing diabet ic neur algia, r ef lex sympat het ic dyst r ophy, t r i gemi nal
neur algi a, not algia par est het i ca, psor i asis and psor alen ( P) , and l ong- wave
ult r aviol et r adi at i on ( UVA) i nduced ski n pai n, and post her pet ic neur al gia. Local
t oxicit y may incl ude bur ni ng, st i ngi ng, er yt hema, pr ur i t us, and superf icial ski n
ulcer s.
2. Gl ucosami ne sul f ate and chondroi t i n sul f ate have been used wit h i ncr easi ng
f r equency i n t he t r eat ment of degener at ive j oint disease. Glucosamine sulf at e
appear s t o act as a subst r at e f or and st imulant t o t he biosynt hesis of
gl ucosaminogl ycans and hyal ur oni c aci d f or f orming pr ot eoglycans f ound i n t he
st r uct ur al mat r i x of j oint s. Chondr oit i n sul f at e pr ovides addit ional subst r at es f or t he
f ormat ion of heal t hy j oint mat r i x. Shor t - t erm si de ef f ect s associat ed wit h
gl ucosamine i ncl ude GI pr oblems, dr owsiness, skin r eact ions, and headache.
Fur t her r esear ch i s needed t o val idat e t heir r oles.
F. Nonpharmacol ogi cal pai n management . Ot her t her apeut ic modal it i es f or pai n
management incl ude cognit ive behavi or al i nt er vent i ons and physi cal met hods.
These modal it i es ar e appr opr iat e f or int er est ed pat ient s, pat i ent s exper ienci ng
anxi et y wit h t hei r pai n, pat ient s who have incomplet e r eli ef f r om analgesic t her apy,
and pat i ent s who need t o avoi d or r educe anal gesi c use ( e. g. , t hose wi t h chr onic
nonmal ignant pai n) .
1. Cogni t i ve behavi oral i nt ervent i ons i ncl ude educat ion and i nst r uct ion, simpl e
r elaxat ion, bi of eedback, and hypnosi s.
2. Physi cal met hods i ncl ude acupunct ur e, physi cal t her apy, compr ession gloves,
or t hot i c devices, heat and cold appl icat i ons, massage, exer ci se, rest ,
immobi l i zat ion, and t r anscut aneous elect r i cal ner ve st imulat ion ( TENS).
P. 1271


STUDY QUESTIONS
Di rect i ons f or quest i ons 1- 7: Each of t he quest ions, st at ement s, or i ncomplet e
st at ement s i n t his sect ion can be corr ect ly answer ed or compl et ed by one of t he
suggest ed answers or phr ases. Choose t he best answer .
1. An emaciat ed 69- year- ol d man wit h advanced i noperabl e t hroat cancer i s
hospi t al i zed f or pai n management. He i s recei vi ng a morphi ne sol ut i on ( 40 mg
oral l y) every 3 hr f or pai n. He complai ns of dysphagi a and t he f requency wit h
whi ch he must take morphi ne. An appropri at e anal gesi c al ternat i ve f or t hi s
pat i ent woul d be
( A) changi ng t o a cont r ol led- r elease or al mor phi ne.
(B) incr easi ng t he dose of t he or al mor phi ne sol ut ion.
(C) changi ng t o int r amuscul ar met hadone.
(D) changi ng t o t r ansdermal f ent anyl .
(E) decr easi ng t he f r equency of or al mor phi ne administ r at ion.
View Answer 1. The answer i s D[ see] . For quest i ons 2- 3: A 52- year- old
woman wi t h a diagnosis of ovar ian cancer pr esent s wit h complai nt s of pain. Her
pai n was r easonably wel l cont r ol led wit h t wo capsules of oxycodone ever y 4 hr unt i l
2 weeks ago, at which poi nt she was hospit al i zed f or pain cont r ol . She was placed
on meper idi ne ( 75 mg) ever y 3 hr but st il l compl ai ned about pai n. Her meper idi ne
dosage was i ncr eased t o 100 mg ever y 2 hr .
2. At t hi s dosage of meperi di ne, t he pat i ent i s l i kel y t o experi ence
( A) excel l ent pai n r el ief .
(B) respir at or y depr ession.
(C) worseni ng r enal f unct i on.
(D) myocl onic seizur es.
(E) excessi ve sedat i on.
View Answer 2. The answer i s D[ see] . 3. An appropriat e next st ep i n t hi s
pat i ent ' s t herapy woul d be t o
( A) add a nonst er oidal ant i - i nf lammat or y dr ug (NSAI D) .
(B) di scont i nue t he meper idine and conver t her t o a cont r olled- r elease or al
mor phi ne or oxycodone.
(C) cont inue t he pr esent meper i di ne dosage because she wi l l event ual l y get r el i ef .
(D) decr ease t he meper idi ne dose t o avoid side ef f ect s.
(E) consi der hypnosis or r el axat i on t echniques.
View Answer 3. The answer i s B[ see] . 4. A 20- year- ol d vi ct i m of a mot or
vehi cl e acci dent i s 3 days post surgery f or ort hopedi c and i nt ernal i nj uri es. He
has been i n severe pai n and was placed on a regi men of i nt ramuscul ar
morphi ne (5-10 mg) every 4 hr as needed f or pai n. A pai n consul t ant start s t he
pat i ent wi t h a 20-mg i nt ravenous morphi ne l oadi ng dose and t hen begi ns a
cont i nuous i nt ravenous morphi ne i nf usi on wi th as- needed morphi ne boost ers.
About 2 hr af t er t hi s regi men i s st art ed, t he pat i ent i s asl eep. The nurse i s
concerned and cal l s t he physi ci an. The physi ci an shoul d
( A) call f or a psychiat r ic consult .
(B) administ er nal oxone.
(C) exami ne t he pat i ent and r econf irm t he dosage and moni t or i ng par amet ers.
(D) add an inj ect able nonst er oi dal ant i - i nf l ammat or y dr ug ( NSAI D).
(E) add an amphet amine.
View Answer 4. The answer i s C[ see] . P. 1272


5. Pot ent ial adverse eff ect s associ at ed wit h aspi ri n i ncl ude al l of t he f ol l owi ng
except
( A) gast r oi nt est i nal ulcer at ion.
(B) renal dysf unct ion.
(C) enhanced met hot r exat e t oxicit y.
(D) car di ac ar r hyt hmi as.
(E) hyper sensi t ivit y ast hma.
View Answer 5. The answer i s D[ see] . 6. Al l of t he f ol l owi ng f act s ar e true
about nonst eroi dal ant i - i nf lammat ory drugs (NSAIDs) except whi ch one?
( A) They ar e ant i pyr et ic.
(B) Ther e is a cei l i ng ef f ect t o t heir analgesia.
(C) They can cause t ol er ance.
(D) They do not cause dependence.
(E) They ar e ant i - i nf lammat or y.
View Answer 6. The answer i s C[ see] . 7. Whi ch of t he f ol l owi ng narcot i cs
has t he l ongest durat i on of ef f ect ?
( A) met hadone
(B) cont r ol led- r el ease mor phi ne
(C) levor phanol
(D) t r ansdermal f ent anyl
(E) di hydr omor phone
View Answer 7. The answer i s D[ see] . Direct i ons f or quest i ons 8- 10: The
quest ions and incomplet e st at ement s in t his sect ion can be corr ect ly answer ed or
complet ed by one or more of t he suggest ed answer s. Choose t he answer, A-E.
8. Agent s t hat are saf e t o use i n a pat i ent wi t h bl eedi ng probl ems i ncl ude
( I ) chol i ne magnesi um tri sal i cyl at e
( I I ) acet ami nophen
( I I I ) ket orolac
A if I onl y is corr ect
B if I I I onl y i s corr ect
C if I and I I ar e corr ect
D if I I and I I I ar e cor r ect
E if I , I I , and I I I are corr ect
View Answer 8. The answer i s C( I , I I) [ see] . 9. Whi ch of t he f ol l owi ng drugs
bi nd or capt ure excess TNF- o?
( I ) adal i mumab
( I I ) et anercept
( I I I ) l ef l unomi de
A if I onl y is corr ect
B if I I I onl y i s corr ect
C if I and I I ar e corr ect
D if I I and I I I ar e cor r ect
E if I , I I , and I I I are corr ect
View Answer 9. The answer i s C( I , I I) [ see] . 10. Lef l unomi de has been
associ at ed wi t h
( I ) di arrhea.
( I I ) al opeci a.
( I I I ) anemia.
A if I onl y is corr ect
B if I I I onl y i s corr ect
C if I and I I ar e corr ect
D if I I and I I I ar e cor r ect
E if I , I I , and I I I are corr ect
View Answer 10. The answer i s E( I , I I , I I I ) [ see] . P. 1273


ANSWERS AND EXPLANATIONS
1. The answer i s D [ see I I . B. 2. c. ( 8) ] .
Pat i ent s wit h t hroat cancer of t en cannot t ake oral analgesi cs. The pat ient descr ibed
i n t he quest ion i s also havi ng pai n dif f icult i es wit h an ever y 3- hr r egimen.
Tr ansdermal f ent anyl is a good alt er nat i ve because, af t er t i t r at ion, excel lent
analgesia can be pr oduced wit hout usi ng or al or par ent eral agent s. Also, t he
f r equency of analgesic use may be decr eased when t i t r at ion has occur red.
2. The answer i s D [ see I I . B. 3. g] .
3. The answer i s B [ see I I . B. 2. c. ( 1) ; I I . B. 2. d. ( 1)] .
Myocl onic sei zur es can occur af t er f r equent , high- dose meper idi ne owing t o t he
accumul at ion of t he met abolit e, normeper idi ne. Bot h oxycodone and meper idi ne
have shor t dur at i ons of ef f ect . I n t he chr onic pai n pat ient , an around- t he- cl ock
r egimen, usi ng a cont r ol led- r eleased oral morphi ne, woul d be an appropr iat e
alt er nat i ve. Wit h t it r at ion, t he pat ient shoul d have good pain r el ief wit h an ever y 8-
t o 12- hr r egimen.
4. The answer i s C [ see I I . B. 3. c] .
A pat ient suf f er ing f rom pain cannot sl eep pr oper l y. When t he pain is adequat ely
cont r ol led, t he pat ient may sl eep i ni t ial l y f or many hour s. This usual l y is not
over sedat i on owi ng t o t he narcot i c. These pat i ent s should be monit or ed cl osel y
( e. g. , r espir at or y r at e) , and ot her sedat i ng dr ugs shoul d be el imi nat ed. Usual ly, no
ot her i nt er vent ion is needed.
5. The answer i s D [ see I I . A. 4] .
Aspir i n has sever al adver se ef f ect s and dr ug int er act i ons. However, cardiac
ar r hyt hmias ar e not induced by aspi r i n.
6. The answer i s C [ see I I . A. 2] .
Unl i ke t he opi at es, NSAI D use i s not associat ed wit h t he development of t ol er ance.
7. The answer i s D [ see Table 58- 2] .
Tr ansdermal f ent anyl is a cont r ol led- r elease dosage f orm t hat is ef f ect ive f or up t o a
72- hr per i od. Al l of t he ot her dr ugs li st ed i n t he quest ion ar e ef f ect ive f or per iods of
1- 8 hr .
8. The answer i s C ( I , I I ) [ see I I . A. 4. b] .
Unl i ke aspir in and NSAI Ds, acet ami nophen and chol i ne magnesium t r isal i cylat e l ack
ant ipl at elet ef f ect s. Ther ef ore, t hey ar e saf e t o use f or pat ient s wi t h bleedi ng
pr oblems.
9. The answer i s C ( I , I I ) [ see I I . A. 1] .
Adal imumab, et anercept , and inf l i ximab act by bi ndi ng or capt ur i ng excess TNF- q,
one of t he dominant cyt okines or pr ot ei ns t hat play an i mport ant r ole i n t he
i nf l ammat or y r esponse. The exact mechanism of act ion of lef lunomide, a novel dr ug
used t o t r eat r heumat oid art hr it is, i s not compl et el y known but i t is t hought t o i nhibit
pyr imidi ne synt hesis.
10. The answer i s E (I , I I , I I I ) [ see I I . A. 4. a; I I . A. 4. d. ( 4) ] .
Lef lunomi de has been associat ed wit h weight l oss, diar r hea, nausea, alopecia, r ash,
anemia, and t r ansi ent elevat ions i n l i ver f unct i on t est s.

59
Nutrition and the Hospitalized Patient
Robert A. Quercia
Kevi n P. Keat i ng
I. NUTRITIONAL PROBLEMS IN HOSPITALIZED
PATIENTS
A. I nci dence. I t has been est i mat ed t hat 30%- 50% of pat i ent s admi t t ed t o hospit als
have some degr ee of mal nut r it i on. As many as 75% of pat ient s under go a
det er i or at ion of nut r it i onal st at us whi l e hospi t al i zed.
B. Def i ni t i ons
1. Mal nut ri t i on is a pat hological st at e, r esult i ng f r om a r el at i ve or absolut e
def iciency or excess of one or more essent ial nut r ient s.
2. Marasmus i s a chr oni c disease t hat develops over mont hs or year s as a r esult of
a def i ci ency i n t ot al calor i c i nt ake. Depl et i on of f at st or es and skelet al pr ot ein
occur s t o meet met abol ic needs. Mar asmi c pat ient s ar e general l y not
hypermet abol ic and ar e able t o pr eser ve t hei r vi scer al prot ein compart ment as
det ermined by measur ement s of ser um albumin, pr eal bumin, and t r ansf err in.
a. Mar asmus is a wel l- adapt ed f orm of malnut r it ion, and despi t e a cachect ic
appear ance, immunocompet ence, wound heal i ng, and t he abi l it y t o handle shor t -
t erm st r ess are gener al l y wel l pr eser ved.
b. Nut r it i onal suppor t i n t hese pat ient s shoul d be i ni t iat ed caut iousl y because
aggr essive r epl et i on can r esul t i n sever e met aboli c di st ur bances, such as
hypokalemi a and hypophosphat emi a.
3. Kwashi orkor is an acut e pr ocess t hat can develop wi t hi n weeks and i s
associ at ed wit h vi scer al pr ot ei n depl et i on and i mpair ed immune f unct ion. I t is t he
r esul t of poor pr ot ein int ake wit h adequat e t o sl i ght l y i nadequat e cal or i c i nt ake; t hus
pat ient s usual l y appear well nour ished. A hypermet abol ic st at e ( e. g. , t r auma,
i nf ect ion) combined wit h pr ot ei n depr ivat i on can r apidl y develop i nt o a sever e
kwashior kor mal nut r it i on char act er ized by hypoal bumi nemi a, edema, and impair ed
cel l ular immune f unct i on.
a. I n hospi t al i zed pat ient s, t he devel opment of kwashior kor has been i mpli cat ed in
poor wound heal i ng, gast r oi nt est i nal ( GI ) bleedi ng, and sepsi s.
b. Aggressi ve nut r it i onal suppor t t o repl et e pr ot ein st ores and decr ease mor bidit y
and mor t al it y is i ndicat ed when t he di agnosi s of kwashi or kor is made.
4. Mi xed marasmi c kwashi orkor is a sever e f orm of pr ot ein- calor i e mal nut r i t ion
t hat usual l y develops when a marasmi c pat ient i s subj ect ed t o an acut e
hypermet abol ic st ress, such as t rauma, sur ger y, or i nf ect i on.
a. Thi s condi t ion r esult s in deplet i on of f at st ores, skelet al muscle prot ein, and
viscer al pr ot ein.
b. Because of t he marked immune dysf unct ion t hat develops i n t hi s st at e, vigor ous
nut r it ional suppor t i s i ndicat ed.
II. NUTRITIONAL ASSESSMENT AND METABOLI C
REQUIREMENTS
A. Nut ri ti onal assessment . The most commonl y used t ool s f or nut r it ional
assessment ar e as f ol lows:
1. Subj ect i ve gl obal assessment (SGA) r eli es heavi l y on t he pat ient ' s hist or y.
a. SGA t akes int o account :
P. 1275


( 1) Recent wei ght change
( 2) Di et hist or y
( 3) Type and lengt h of sympt oms af f ect i ng nut r it i onal st at us ( e. g. , nausea, vomi t ing,
diar r hea)
( 4) Funct i onal st at us
( 5) Met abol ic demands of t he cur r ent disease pr ocess
( 6) Gross physi cal signs
(a) St at us of subcut aneous f at
( b) Evidence of muscl e wast ing
( c) Pr esence or absence of edema and ascit es
b. Pat ient s ar e t hen classif i ed as being wel l nour i shed or moder at el y or severely
malnour ished.
2. Mi ni Nutri t i onal Assessment ( MNA) similar t o t he SGA, val i dat ed in el der ly
pat ient s
a. MNA t akes i nt o account :
( 1) Loss of appet it e
( 2) Wei ght loss
( 3) Mobil it y
( 4) Psychol ogical/ physical st r ess
( 5) Neur o- psychol ogical pr oblems
( 6) BMI
b. Pat ient is t hen assessed as being at no or incr eased nut r it i onal r isk. I f at
i ncr eased r isk a f ul l nut r it ional assessment is under t aken
3. Vi sceral Prot ei n Markers ( VPM) can be indi cat ors of prot ein deplet ion i f r esult s
ar e subnormal.
a. Most commonl y used VPM ar e:
( 1) Al bumin
( 2) Pr eal bumin ( t r anst hyr et i n)
( 3) Tr ansf er r in
( 4) Ret inol - bi ndi ng pr ot ei n
4. Total l ymphocyt e count —an i ndicat or of immune compet ence—subnormal levels
can be an indicat or of mal nut r it ion.
5. Ant hropomorphi cs—skin- f old measur ement s
a. Values <5t h percent i le can be indicat or s of f at and pr ot ein deplet i on
b. Most commonl y used:
( 1) Tr iceps
( 2) Bi ceps
( 3) Subscapul ar
( 4) Supr ail i ac
6. Mul t if act orial Prognost i c I ndi cat ors
a. Pr ognost i c Nut r i t ional I ndex ( PNI ) is der ived f rom a f ormula t hat at t empt s t o
quant if y a pat ient ' s r i sk of developi ng oper at ive compli cat ions based on a vari et y of
marker s of nut r it i onal st at us incl uding:
( 1) Vi scer al pr ot ein markers
( 2) Ant hr opomor phics
( 3) Immune compet ence
b. Pr ognost i c I nf lammat or y Nut r i t ional I ndex ( PI NI) i s simi l ar t o t he PNI but adds t he
i nf l ammat or y marker s alpha 1 aci d glycopr ot ein and c- react ive pr ot ein.
7. Body composi t i on anal ysi s assesses nut r i t ional st at us by measur ing and
compar ing t he r at ios of var i ous body compart ment s.
a. Bi oel ect ri cal impedance. The r esist ance t o an elect r i cal curr ent is used t o
calculat e lean body mass. The equipment i s r el at i vel y i nexpensi ve and easy t o use.
The r esult s are inaccur at e i n cr it i cal l y i l l pat i ent s and pat i ent s wit h f l uid and
elect r olyt e abnormal it ies.
b. Dual - energy x- ray absorpt i omet ry (DEXA) . The dif f er ent ial at t enuat i on of x- r ays
is used t o measur e f at and lean body mass. The equi pment is expensi ve, and
r esul t s ar e af f ect ed by hydr at i on st at us.
c. Total body pot assi um est imat es lean body mass by usi ng a whole body count er
t o measur e a pot assium i sot ope concent r at ed in l ean t issue. This met hod of body
composi t ion analysis is i mpract ical and avai lable at onl y a f ew cent er s.
P. 1276


d. Total body water est imat es lean body mass f rom deut er i um t ot al body wat er
measur ement s. This t echni que i s cl i nical l y impr act ical.
e. I n vi vo neut ron act i vat i on anal ysi s. Unl i ke ot her t echniques, t hi s anal ysis
di vides t he body int o sever al compart ment s. Thi s t echnique r equi r es a signi f icant
dose of radiat ion and is avai lable at only a f ew r esearch cent ers.
8. Test s of physi ol ogi cal f unct i on at t empt t o quant it at e malnut r i t ion based on t he
decr ease i n muscle st r engt h caused by amino acid mobi l i zat ion.
a. Maximum vol unt ary gri p st rengt h i s measur ed wit h isoki net i c dynamomet r y. The
r esul t s cor relat e wel l t o t ot al body prot ei n. Thi s t est r equir es pat ient cooper at ion.
b. El ect ri cal st i mul at i on of t he ul nar nerve measur es cont r act il e f unct ion of t he
adduct or poll ici s muscle. This t echni que does not r equir e vol unt ar y pat i ent ef f ort
and i s i nexpensi ve and easy t o do. I t s pr ognost i c rel i abi l it y i s st i l l under eval uat i on.
B. Metabol i c requi rement s
1. Energy requi rement s ar e det ermined as nonprot ei n cal ori es ( NPCs). I t is
import ant t o avoid excess cal or ies t o mi nimi ze compl icat i ons of nut r i ent del i ver y and
t o opt imize nut r i ent met abol i sm. Ener gy requi r ement s can be det ermi ned by t he
f ol l owi ng t hr ee met hods.
a. I ndi rect cal orimet ry or measured energy expendi t ure ( MEE) i s t he most
accur at e met hod of det ermini ng calor ic r equi r ement s.
( 1) Oxygen ( O2) consumpt ion and car bon dioxi de (CO2 ) product ion ar e measur ed
dir ect ly.
( 2) Ener gy expendit ur e is r elat ed dir ect l y t o oxygen consumpt ion and is calculat ed
f r om t hese measur ement s.
( 3) A r espi r at or y quot ient (RQ) can al so be obt ained f r om an MEE and is def ined as
t he r at i o of t he amount of CO2 pr oduced t o t hat of O2 consumed dur i ng t he cour se of
oxidat ion of body f uels. The oxidat ion of car bohydr at e r esult s i n an RQ of 1. 0—t hat
is, as much CO2 is produced as O2 is consumed. The oxidat i on of f at produces
signi f icant ly less CO2 and r esult s in an RQ of 0. 7. Normal mi xed subst r at e oxidat i on
r esul t s i n an RQ of 0. 8-0. 9.
( 4) The pr ovi si on of excess car bohydr at e cal or i es causes t heir conver si on t o f at
( l ipogenesis) . Li pogenesi s pr oduces signi f icant ly mor e carbon di oxide t han oxidat i on
does. This can r esul t i n an RQ > 1. 0, which i s consist ent wi t h over f eeding. The
det erminat ion of RQ can, t heref or e, indi cat e pat t er ns of subst r at e use.
b. Est imat ed energy expendi t ure (EEE) f ir st r equi r es t he cal culat ion of t he basal
energy expendi t ure (BEE) f rom t he Harri s- Benedi ct equat i on; t he BEE i s t hen
mult i pl i ed by appr opr iat e st r ess and act ivit y f act or s.
( 1) Men: BEE = 66. 5 + [ 13. 8 × wei ght (kg) ] + [ 5 × hei ght (cm)] - [ 6. 8 × age ( years)]
( 2) Women: BEE = 655 + [ 9. 6 × wei ght (kg) ] + [ 1. 8 × height ( cm)] - [ 4. 7 × age
( year s) ]
( 3) St ress f act ors: uncomplicat ed sur ger y 1. 00- 1. 05, per it onit is 1. 05- 1. 25, and
sepsis or mult i ple t r auma 1. 25- 1. 5
( 4) Act i vi t y f act ors: bedr est 0. 95- 1. 10 and ambul at ion 1. 10- 1. 30
c. Si mpl e nomogram. The least accur at e met hod of est imat i ng cal or ic
r equir ement s, t hi s t echnique is based on t he pat i ent ' s wei ght i n ki logr ams. I t is
usef ul when t he ot her met hods cannot be used. Pat i ent s wit h mild t o moder at e
degr ees of st ress r equir e appr oximat ely 25- 30 kcal/ kg/ day, wher eas t he sever ely
st ressed pat i ent ( e. g. , a pat i ent wit h maj or bur ns) may r equi r e 35 kcal / kg/ day or
mor e.
2. Prot ei n ( ni t rogen) requi rement s can be det ermined by a number of t echniques,
but ni t r ogen balance det erminat i ons and nomogr ams appear t o be t he most
pr act i cal.
a. Ni t rogen bal ance t echni ques. The pr act it ioner det ermines t he pat ient ' s ni t r ogen
out put and develops a nut r it ional suppor t pr ogr am i n which t he pr ot ei n admi nist er ed
r esul t s i n a ni t r ogen i nput t hat exceeds losses.
( 1) Ni t r ogen balance = 24- hr ni t r ogen i nt ake - 24-hr nit r ogen out put .
( 2) A 24- hr nit r ogen i nt ake = 24- hr t ot al pr ot ein i nt ake ÷ 6. 25 (appr oximat ely 16% of
pr ot ei n is composed of ni t r ogen) .
( 3) A 24- hr nit r ogen out put = [ 24- hr ur i ne ur ea ni t r ogen (UUN) × 1. 25 + 2, wher e
1. 25 account s f or non- UUN l osses ( e. g. , ammonia, cr eat i ni ne) and 2 account s f or
non- ur i ne nit r ogen losses ( e. g. , ski n, f eces). Tot al ur i nar y nit r ogen ( TUN)
det erminat ions
P. 1277

ar e cur r ent ly avai labl e i n some cent ers. Because TUN is a mor e accur at e met hod of
assessi ng ur i nar y nit r ogen l osses, it shoul d be used when avai l able i n place of a
24- hr UUN × 1. 25 when calculat i ng a nit r ogen balance.
( 4) A posi t ive nit r ogen bal ance of 3- 6 g i s t he goal .
( 5) This met hod cannot be used i n r enal l y i mpair ed pat i ent s.
b. Nomogram met hod. Thi s met hod est imat es prot ei n needs based on l ean body
wei ght . Pr ot ei n r equir ement s are 1. 5- 2. 0 g pr ot ei n/ kg/ day f or hospi t al i zed pat ient s.
c. Nonprot ei n cal ori e t o ni t rogen (NPC: N) rat i o. An NPC: N r at io of 125- 150: 1
gener al l y has been r ecommended f or t he mi ldl y t o moder at ely st r essed pat ient t o
achieve opt i mal nit r ogen r et ent i on and pr ot ein synt hesis. I n t he severely st r essed
pat ient , some st udies i ndicat e t hat r at ios as low as 85: 1 may be ef f ect i ve.
3. Essent i al f att y aci ds (EFAs) ar e t hose polyunsat ur at ed f at t y aci ds t hat cannot
be synt hesi zed by humans. EFAs af f ect i mmune responses by i nf l uenci ng ener gy
pr oduct i on, ei cosanoid synt hesi s, and cel l membrane f luidi t y. They al so af f ect levels
of ar achidoni c aci d i n l ymphocyt es—especi al l y monocyt es, macrophages, and
pol ymor phonuclear neut r ophi ls (PMNs). Linoleic acid, an omega- 6 polyunsat ur at ed
f at t y aci d (PUFA) , is t he pr i ncipal EFA f or humans. q-Li nolenic acid, an omega- 3
PUFA, al so cannot be synt hesi zed i n vi vo; it s met abol i c signi f icance i n humans
cont i nues t o be invest igat ed. I t mi ght be a condit i onal l y essent i al f at t y aci d.
a. Def iciency st at es of l i nol ei c aci d ar e char act er ized by diar r hea, dermat it i s, and
hair loss.
b. The cur r ent ly avai labl e l i pi d emulsions have a high l i nolei c aci d cont ent .
c. Pr ovidi ng 4%- 7% of a pat i ent ' s calor ic r equi r ement s as l i nolei c acid f rom l ipi d
emul si on pr event s t he development of essent ial f at t y acid def iciency.
4. Vi tami ns ar e essent i al f or proper subst rat e met abol ism. Accept ed dai ly
al l owances f or or al admi nist r at ion have been est abl i shed. The FDA recent l y
approved a new mul t i vi t ami n preparat i on f or adul t s r ecei vi ng parent eral
nut ri t i on (PN).
a. Vi tami n A (f at solubl e) . Normal st or es can l ast up t o 1 year but ar e rapidly
deplet ed by st r ess. Vi t ami n A has essent i al f unct i ons i n vision, gr owt h, and
r eproduct ion. Recommended or al i nt ake is 2500- 5000 IU/ day. The recommended
requi rement i s 3300 IU/ day i n PN f ormul at i ons.
b. Vi tami n D (f at sol ubl e) . I n conj unct ion wi t h par at hormone and cal ci t oni n, vi t ami n
D helps r egulat e calci um and phosphor ous homeost asi s. Recommended or al i nt ake
is 100- 400 IU/ day. The PN requi rement i s 200 I U/ day.
c. Vi tami n E (f at solubl e) appears t o f unct i on as an ant i oxi dant , inhi bit ing t he
oxidat ion of f r ee unsat ur at ed f at t y acids. Recommended dai l y or al al lowances ar e
12- 15 IU/ day. The requi rement i n PN f ormul at i ons i s 10 I U/ day. The pr esence of
pol yunsat ur at ed f at t y acids i ncr eases t he requir ement f or vit amin E, which needs t o
be consider ed wit h t he use of l ipid syst em PN.
d. Vi tami n K (f at sol ubl e) plays an essent ial r ole i n t he synt hesi s of clot t ing f act or s.
The suggest ed or al i nt ake is 0. 7-2. 0 mg/ day. The recommended PN requi rement i s
150 µg/ day.
e. Vi tami n B1 (t hi ami ne; wat er sol uble) f unct ions as a coenzyme in t he
phosphogluconat e pat hway and as a st r uct ur al component of ner vous syst em
membr anes. The devel opment of it s def iciency st at e ( i . e. , acut e per nicious ber iber i
wit h hi gh out put car diac f ai l ur e) is wel l descr i bed i n pat i ent s on PN receivi ng
i nadequat e t hiami ne r eplacement . A pr olonged def iciency st at e can cause Wer nicke
encephal opat hy. Recommended doses are 0. 5 mg/ 1000 oral calor i es/ day and 6
mg/ day i n PN f ormul at i ons.
f . Vi tami n B2 ( ri bof lavi n; wat er soluble) f unct ions as a coenzyme in oxidat i ve
phosphor ylat ion. Essent ial l y, no i nt r acel l ular st ores ar e maint ai ned. Oral
r equir ement s ar e 1. 3-1. 7 mg/ day. The requi rement i n PN f ormul at i ons i s 3. 6
mg/ day.
g. Vi tami n B3 ( ni aci n; wat er soluble) f unct ions as a coenzyme in oxidat ive
phosphor ylat ion and bi osynt het i c pat hways. Pell agr a is t he wel l - descr ibed
def iciency st at e. Or al r equir ement s ar e 14. 5- 19. 8 mg/ day. The recommended PN
requi rement i s 40 mg/ day.
h. Vi tami n B5 ( pant ot heni c aci d; wat er soluble) . The f unct ional f orm of vit ami n B5
is coenzyme A, which i s essent i al t o all acyl at ion react i ons. Oral r equir ement s ar e
5- 10 mg/ day. I nt r avenous ( I V) requir ement s ar e 10- 29 mg/ day.
i . Vi tami n B6 ( pyri doxi ne; wat er sol uble) f unct ions as a coenzyme in a var i et y of
enzymat i c pat hways. Def iciency st at es ar e accent uat ed by some medicat i ons,
i ncl udi ng
P. 1278

isoni azi d, peni ci l lami ne, and cycloser ine. Or al r equir ement s ar e 1. 5- 2. 0 mg/ day.
The recommended PN requi rement i s 6. 0 mg/ day.
j . Vi tami n B7 (bi ot i n; wat er soluble) f unct ions i n car boxyl at i on r eact i ons. I t is
synt hesi zed by i nt est inal f l or a; t heref or e, def i ci ency st at es ar e r ar e. The
requi rement i n PN f ormul at i ons i s 60 µg/ day.
k. Vi tami n B9 (f ol i c aci d; wat er sol uble) is invol ved in a var i et y of bi osynt het i c
r eact i ons and ami no acid conver si ons. Fol at e cof act or s ar e necessar y f or pur i ne
and pyr i mi di ne ( DNA) synt hesis. St or es usual l y last 3- 6 mont hs; however , r api d
deplet ion i s seen wit h met aboli c st r ess. Def iciency of vit amin B1 2 causes def iciency
i n f olat e. A megaloblast i c anemia is cl assic i n t he def iciency st at e. Def i ci ency of
f ol i c acid i n a pr egnant mot her can cause neur al t ube def ect s i n t he f et us. Or al
r equir ement s ar e 200- 400 µg/ day. The recommended requi rement i n PN
f ormulat i ons i s 600 µg/ day.
l . Vi tami n B12 ( cyanocobalami n; wat er solubl e) has a var iet y of met abolic and
biosynt het ic f unct ions. Because of lar ge st or es, def i ci ency st at es can t ake years t o
develop. Megaloblast i c ( per nicious) anemi a i s one manif est at i on of def iciency.
Anot her manif est at i on of def iciency i s per i pher al neur opat hy because B1 2 is
r esponsible f or biosynt hesi s of t he i nsul at i on sheet on ner ves cal led myel i n. Or al
r equir ement s ar e 2 µg/ day. The requi rement i n PN f ormul at i ons i s 5. 0 µg/ day.
5. Trace mi neral def i ci ency may develop dur i ng PN because of r educed i nt ake,
i ncr eased use, decr eased plasma bindi ng, or incr eased excr et i on.
a. Iron i s necessar y f or hemoglobi n and myoglobi n pr oduct i on and i s a necessar y
cof act or i n a var i et y of enzymat ic r eact ions. Def ici ency i s classical l y demonst rat ed
by a hypochr omic, microcyt ic anemia as wel l as by t he development of immune
def iciency. Oral r equir ement s ar e 16- 18 mg/ day. I V r equi r ement s ar e 0. 5- 1. 0
mg/ day.
b. Zi nc is necessar y f or DNA and RNA synt hesis and is a necessar y cof act or i n a
var iet y of enzymat ic r eact ions. Zi nc def iciency r esul t s in impair ed wound heal i ng,
gr owt h r et ardat ion, hai r loss, dermat it is, diar r hea, anor exia, and gl ucose
i nt oler ance. Pat ient s at high r isk f or developi ng zi nc def iciency ar e t hose wit h long-
t erm st eroid t her apy, mal absor pt ion syndr omes, f i st ulas, sepsis, and maj or sur ger y.
Or al r equir ement s ar e 10- 15 mg/ day. I V r equir ement s ar e 3. 0- 5. 0 mg/ day.
c. Copper is necessar y f or heme synt hesis, elect ron t r anspor t , and wound heal i ng.
Def i ci ency t hat develops dur i ng PN usual l y manif est s as anemia, leukopenia, and
neut r openi a. Or al r equir ement s ar e 30 µg/ kg/ day. I nt ravenous requi rement s are
0. 5- 1. 5 mg/ day.
d. Manganese is i nvol ved i n pr ot ei n synt hesis and possibly gl ucose use. Or al
r equir ement s ar e 0. 7-22 mg/ day. I nt ravenous requi rement s are 150-300 µg/ day.
e. Sel eni um is impor t ant in ant i oxidant r eact ions. Def i ci ency dur ing PN has been
associ at ed wit h muscl e pai n and car diomyopat hy. I nt ravenous r equi r ement s ar e 40-
60 µg/ day.
f . I odi ne is a component of t he t hyr oi d hor mones. Def i ci ency manif est s as a goi t er .
Recommended int ake i s 1 µg/ kg/ day.
g. Chromi um is i mport ant in gl ucose use and pot ent i at es t he ef f ect of insul i n. Si gns
of def i ci ency incl ude hyper gl ycemia and abnormal glucose t oler ance. Or al
r equir ement s ar e 70- 80 µg/ day. I nt r avenous ( I V) maint enance r equir ement s are
0. 14- 0. 2 µg/ kg/ day ( 10- 15 µg/ day). Suggest ed I V requi rement s f or def i ci ency and
severe gl ucose i nt ol erance are 150- 200 µg/ day.
h. Mol ybdenum is essent ial t o xant hi ne oxidase. Oral r equir ement s ar e 2. 0
µg/ kg/ day.
III. METHODS OF SUPPORT
A. PN i s also cal led t otal parent eral nut ri t i on (TPN) and hyperal i mentat i on. It i s
used t o meet t he pat i ent ' s nut r it i onal r equir ement s when t he ent eral r out e cannot
accompl i sh t his.
1. I ndi cat i ons. When t he ent eral r out e cannot be used because of dysf unct ion or
disease st at es ( e. g. , acut e pancr eat i t is, i nf lammat or y bowel disease, complet e
bowel obst r uct ion) , PN is inst i t ut ed.
2. I ni t i at i on of PN shoul d be under t aken wit hin 1- 3 days i n moder at ely t o severel y
malnour ished pat i ent s when t he i nadequacy of ent er al suppor t i s ant ici pat ed f or
mor e t han 5- 7
P. 1279

days. I n heal t hy or mildl y malnour ished pat ient s, PN should be init iat ed wit hi n 5- 7
days if ent eral suppor t has not been i nit iat ed.
3. Rout es of admi ni st rat i on
a. A central venous rout e is used wi t h hyper t oni c PN f ormul at i ons ( i . e. , dext r ose
concent r at ions > 10%) . Most commonl y, dext r ose concent r at i ons of 25% ar e used
cent r al ly, and t he osmolar it y exceeds 2000 mOsm/ L. Such highl y osmolar solut ions
must be i nf used i nt o a l ar ge- diamet er cent r al vei n (e. g. , super i or vena cava) , wher e
t hey ar e r apidl y di l ut ed by high f low r at es.
b. A peri pheral venous rout e can be used when t he dext r ose concent rat ion is 10%
or less.
( 1) Solut ions wit h 10% dext r ose, amino acids, elect rolyt es, and t race miner als have
a result i ng osmol ar it y of 900- 1000 mOsm/ L. Higher osmolar i t y is associat ed wit h a
higher inci dence of t hr ombophl ebit is.
( 2) The maj or r eason f or use of t he cent r al venous PN r at her t han t he per i pher al
r out e i s t he development of t hr ombophl ebi t is. Mai nt ai ni ng t he osmolal it y of t he
per ipher al PN solut ion < 900 mOsm/ kg and pr ef erabl y bet ween 600 and 800
mOsm/ kg wi t h int r avenous l ipi d emul si on admi ni st er ed concur r ent ly over 24 hr
mi nimi zes t he inci dence of t hr ombophl ebi t is. Al so, t he devel opment of new
per ipher al f i nebor e cat het er s made f r om pol yur et hane or si l i cone has been shown t o
be si gnif icant ly less t hr ombogenic. I n addi t ion, t he use of l ow- dose hepar in ( 1
unit / mL) and hydr ocort isone ( 5 mg/ L) del i ver ed in t he PN solut ions has been shown
t o pr ot ect agai nst t hr ombophl ebit is.
( 3) Gl yceryl tri ni t rate pat ches ( 5 mg), when appl ied over t he ar ea wher e t he t ip of
t he cat het er is expect ed t o l ie, have been shown t o si gnif i cant l y r educe per ipher al
PN inf usion f ai l ur e caused by phlebit i s. Wit h t he use of t his new cat het er t echnology
and new t echniques f or inf usi on, it i s now f easi bl e t o administ er per i pher al PN in
select ed pat i ent s f or short -t erm t her apy ( 7-10 days) wi t h a low inci dence of
per ipher al vei n t hr ombophl ebit is.
4. NPC sources
a. Dextrose monohydrat e i s t he f orm of dext r ose used f or par ent er al
admi ni st r at ion. I t yi el ds 3. 4 kcal/ g. I t i s t he component i n PN f ormul as t hat
cont r i but es t he most t o osmolar it y. I t i s avai l able commer ci al l y i n concent r at ions up
t o 70%.
b. I nt ravenous l i pi ds ar e commercial l y avai labl e as 10% or 20% emulsions der ived
f r om soybean oil ( I nt r al ipi d) or a combi nat ion of soybean oi l and saf f l ower oi l
( Liposyn I I ) .
( 1) Bot h t he 10% and 20% emul si ons ar e isot oni c ( 280 and 340 mOsm/ L,
r espect i vely) and can be admi ni st er ed via t he per ipher al vei n wit h a l ow i ncidence
of phl ebit is; t hese emulsi ons pr ovi de 1. 1 and 2. 0 kcal/ mL, r espect ivel y. They
cont ai n 1. 2% egg yolk phosphol ipi ds as t he emul si f yi ng agent and 2. 25%- 2. 5%
gl ycer ol t o make t he emulsions isosmot i c.
( 2) Lipi d emul sions can be given as part of t he dai l y NPC requir ement or 2- 3 t imes
per week t o pr event essent i al f at t y aci d def i ci ency. Bot h t ypes of l i pid emulsion
cont ai n part icles of 0. 4-0. 5 µm, which pr event s t he use of 0. 22 µm bact er i al
r et ent i on f i lt er s.
5. Prot ei n ( ni t rogen) source. Synt het i c crystal l i ne ami no aci ds ar e cur r ent ly
used as t he nit r ogen sour ce i n PN f ormulat ions.
a. These f ormulat i ons are avai l abl e commerci al l y wi t hout el ectrol ytes and
dextrose i n concent rat i ons of 5. 5% (Travasol ) , 8. 5% (Travasol ) , 10% ( Ami nosyn
I I , Travasol ) , 15%. ( Ami nosyn I I , Cl i ni sol ) and 20% (Prosol ) .
b. These f ormulat ions yiel d 4 kcal/ g.
c. These sol ut ions gener al l y cont ai n a mixt ur e of f r ee essent ial and nonessent i al L-
amino aci ds.
d. Special i zed amino aci d f ormulat ions ar e avai l able f or speci f ic di sease st at es.
6. Syst ems of PN
a. Gl ucose system PN
( 1) Def i ni t i on. The gl ucose syst em PN is a par ent er al f ormul at i on i n whi ch dext r ose
is used excl usi vel y as t he NPC sour ce. Nit r ogen i s pr ovi ded as cr yst all i ne ami no
acids. Elect rolyt es, vit ami ns, and t race miner als ar e added t o t he f ormulat ion as
needed.
P. 1280


( 2) Admi ni st rat i on. The gl ucose syst em PN f ormulat ions usual l y have dext r ose
concent r at ions of 25% or gr eat er and must be admi ni st er ed by t he cent r al venous
r out e. These f ormul at ions ar e also r ef err ed t o as t wo- in- one f ormulat ions because
t he dext r ose and ami no acids ar e usual l y mi xed i n one cont ai ner wit h el ect r ol yt es,
vit amins, and t race miner als.
(a) Because of t he high dext r ose concent r at ion, i nit i al admi ni st r at ion should be at
low hour ly r at es ( e. g. , 50 mL/ hr ) and incr eased gradual l y over 24 hr t o avoid
hyper gl ycemia ( > 200 mg/ dL) .
( b) To avoid r eact i ve hypoglycemia ( < 70 mg/ dL), discont i nuat i on should be gr adual
over several hour s.
( c) Lipi d emul sions shoul d be admi ni st er ed f or essent i al f att y aci d replacement i n
a dose t hat pr ovides 4%- 7% of r equir ed cal or ies as l inol ei c aci d. Thi s can be
accompl i shed by t he admi ni st r at ion of 250 mL of 20% or 500 mL of 10% emulsion,
t wo t o t hr ee t imes weekl y.
b. Li pi d syst em PN
( 1) Def i ni t i on. The l ipi d syst em PN i s a par ent er al f ormulat ion i n which l i pi d is
admi ni st er ed dai l y t o provide a subst ant i al pr oport ion of t he NPC. Ni t r ogen is
pr ovi ded as cr yst al l i ne ami no acids. Elect r olyt es, vit amins, and t race miner als ar e
added t o t he f ormul at i on as needed.
( 2) Admi ni st rat i on. The l ipid syst em PN is administ er ed per i pher al l y when t he
dext r ose concent r at i on is less t han or equal t o 10% and cent ral l y when t he dext r ose
concent r at ion is mor e t han 10%.
(a) Pi ggyback met hod. The sol ut i on wit h ami no acids, dext r ose, elect r olyt es, t r ace
mi ner al s, and vit ami ns is i nf used concur r ent l y wi t h a separ at e bot t le of lipid
emul si on t hr ough a Y si t e on t he int r avenous admi ni st r at ion set .
( b) Total nut ri ent admi xt ure ( TNA) met hod—t hree- i n- one, al l- i n- one. Lipids, amino
acids, dext r ose, elect r olyt es, t r ace miner als, and vi t amins ar e mixed i n one
cont ai ner and administ er ed by t he cent r al or per i pher al r out e, depending on
dext r ose concent r at i on.
( i ) Advantages incl ude simpl if i cat ion of administ r at i on and decr eased t r ai ni ng t ime
f or home PN pat ient s.
( i i ) Di sadvantages i nclude t he i nabi l it y t o inspect f or par t i culat e mat t er in t he
opaque admixt ur e, t he i nabi l it y t o use 0. 22- µm bact er ial r et ent ion f i lt er s, and
st abi l it y pr oblems.
( i i i ) Because t he pr esence of lipid emulsion i n TNAs obscur e t he pr esence of a
pr ecipit at e and may pr esent a l i f e- t hr eat eni ng hazar d t o pat i ent s, t he U. S. Food and
Dr ug Admi ni st r at ion ( FDA) suggest s t hat t he piggyback met hod be used t o
admi ni st er li pid emulsion. I f a TNA i s deemed medical l y necessar y, t hen speci f ic
admi xt ur e guidel i nes r ecommended by t he FDA shoul d be f ol lowed. Also, a part icle
f i lt er ( i. e. , 1. 2 µ) shoul d be used wit h TNA admini st rat i on.
( c) Li pi d dosage
( i ) Li pid calor ies should not exceed 60% of t ot al dai l y cal or ies, incl udi ng pr ot ei n
calor i es.
( i i ) Maximum dosage of l ipids f or adult s is 2. 5 g/ kg/ day.
( i i i ) Baseli ne and weekly ser um t r igl ycer ides must be moni t or ed i n pat i ent s on l ipid
syst em PN.
( 3) Adverse ef f ect s of lipids ar e uncommon. The most f r equent adverse ef f ect s
i ncl ude f ever, chi l ls, sensat ion of warmt h, chest pai n, back pai n, vomit i ng, and
ur t i car ia ( over al l i ncidence < 1%). Sever e hypoxemia has been r epor t ed wit h r apid
i nf usion of lipid emulsion.
7. Addi t i ves
a. El ect rol yt es. PN f ormulat i ons must incl ude adequat e amount s of sodi um,
magnesium, calci um, chlor ide, pot assi um, phosphor us, and acet at e. The
i nt r acel l ular “ anabol ic” el ect rolyt es—pot assium, magnesium, and phosphat e—ar e
essent i al f or pr ot ein synt hesis. Requi r ement s vary widel y, dependi ng on a pat ient ' s
f lui d and elect r olyt e l osses; r enal , hepat ic, and endocr i ne st at us; acid- base
balance; met abol ic r at e; and t ype of PN f ormula used. The el ect r olyt e composit i on
of t he PN f ormula must be adj ust ed t o meet t he needs of t he i ndividual pat ient .
b. Vi tami ns and t race mi neral s. Vi t ami ns ar e usual l y added t o PN solut i ons i n t he
f orm
P. 1281

of commerci al l y avai l able mult i vi t ami n prepar at ions. Cur r ent ly, t her e is a new adul t
mult i ple vit ami n i nf usi on f or mula avai lable ( I nf uvit e Adul t , MVI - Adul t ) t hat meet s t he
r ecent ly amended r equir ement s of t he FDA f or adul t par ent er al mult i vi t amins.
( 1) The new FDA requir ement s ar e based on t he pr ior mul t i vit ami n f ormul at i on
r ecommended by t he Nut r it i on Advi sor y Gr oup of t he Depar t ment of Foods and
Nut r i t ion of t he Amer ican Medical Associ at i on ( NAG- AMA) but wit h i ncr eased
dosages of vit amins B1, B6 , C, and f oli c aci d and t he addit i on of vit amin K.
( 2) The FDA also appr oved t he same mult i vi t amin f ormulat ion wit hout vi t amin K
( MVI- 12; mul t ivit amin i nf usion wit hout vit amin K) f or t hose pat i ent s who r eceive
war f ar in- t ype ant icoagulant t her apy. Because of st abi l it y pr oblems, one vial of
I nf uvi t e Adult and MVI- Adult cont ai ns vit ami ns A, D, E, B1 , B2, B3 , B5, B6, and K.
MVI - 12 cont ai ns t he same vi t ami ns i n one vial wi t hout vi t amin K. The second vial f or
bot h pr epar at ions cont ai ns vit ami ns B12 , biot i n, and f ol i c acid.
( 3) Tr ace mi ner als may be added indi vi dual l y or as a commer cial ly avai l abl e
mult i element preparat ion. Pr ecise r equir ement s f or t race miner als have yet t o be
det ermined.
c. I nsul i n may be r equi r ed f or pat ient s r eceivi ng PN f ormulat i ons ( especi al l y
gl ucose syst em PN) t o mai nt ai n bl ood gl ucose levels < 200 mg/ dL. I f insul i n is
r equir ed, it is best pr ovided by t he addit i on of an appr opr i at e amount of r egul ar
i nsul i n t o t he PN f ormul at i on at t he t ime of admi xt ur e. Alt hough a small amount of
i nsul i n ( 5- 10 U per bag) may be adsor bed t o t he cont ai ner and t ubi ng, such l osses
can be over come by appr opr iat e t i t r at i on of t he dose. The addi t i on of insul i n t o t he
PN f ormulat ion has t he advant age of changes in t he r at e of PN inf usion bei ng
aut omat ical l y accompanied by appr opr i at e changes in t he r at e of i nsul i n i nf usi on.
d. Mi scel l aneous drugs. A number of medicat i ons have been successf ul l y admi xed
wit h PN f ormul at i ons f or cont inuous i nf usion. The H2- r ecept or ant agoni st s ar e t he
most common dr ugs used i n t his way. The r out i ne addi t ion of medicat i ons t o PN
f ormulat i ons r emai ns cont r oversial because of :
( 1) Quest i ons of stabi l i t y over t he wi de r ange of PN component concent r at i ons
( 2) Possi ble t herapeuti c i nadequacy or t oxicit y secondar y t o PN rat e changes and
loss of peak and t rough levels
( 3) I ncr eased pot ent ial f or wast e wit h dose changes
8. Compl i cat i ons wit h t he use of PN can be ser ious and pot ent ial l y l if e- t hr eat eni ng
but can be avoi ded by car ef ul management . Compl i cat ions can be di vi ded i nt o
mechanical, i nf ect i ous, and met abol i c.
a. Mechani cal compl icat i ons gener al l y r elat e t o t he cent r al venous cat het er or i t s
placement and incl ude pneumot hor ax, cat het er occl usi on, and venous t hr ombosis.
b. I nf ect i ous compl icat ions usual l y ar e r elat ed t o t he cent r al venous cat het er. Thi s
l i ner elat ed sepsis is secondar y t o mult i ple cat het er manipul at i ons, cont ami nat ion
dur i ng inser t ion, or cont ami nat ion dur i ng r out i ne maint enance. Hyper gl ycemi a and
I V li pids al so have been i mplicat ed. Mai nt ai ni ng blood sugar s < 200 mg/ dL has been
shown t o si gnif icant ly r educe sept ic compl icat i ons i n cer t ain subset s of pat ient s.
c. Metabol i c compl icat i ons ar e t he most common. These i ncl ude hyper gl ycemia,
hypogl ycemia, hypokal emia, hypomagnesemi a, hypophosphat emia, met abol i c
acidosis, r espi r at or y acidosis, pr er enal azot emia, and zi nc def iciency. A t r ansient
self - l i mi t ed hepat i c dysf unct ion i s also seen wit h l ong- t erm PN.
B. Ent eral nut ri t i on (EN). Use of t he GI t r act t o achieve t ot al nut r it i onal suppor t or
part ial suppor t in combi nat ion wi t h t he par ent er al r out e shoul d be at t empt ed
whenever possi ble i n t he f ace of inadequat e or al i nt ake. Theor et i cal advant ages
i ncl ude mai nt enance of normal digest ion, absor pt ion, and gut mucosal bar r ier
f unct i on.
1. Cont rai ndi cat i ons t o EN incl ude compl et e int est i nal obst r uct ion, hi gh- out put
i nt est inal f ist ulas, severe acut e pancr eat i t is, sever e acut e i nf l ammat or y bowel
disease, and sever e di ar r hea.
2. Rout es of admi ni st rat i on. Tube f eedings can be administ er ed via nasogast r ic,
nasoduodenal , nasoj ej unal, gast r ost omy, and j ej unost omy t ubes.
3. EN f ormulat i ons can be classif ied as bei ng st andar d ( complet e) or modul ar .
a. Standard f ormulas gener al l y cont ai n car bohydr at es, f at s, vit amins, t r ace
mi ner al s, and a ni t r ogen sour ce. They ar e f ur t her classif i ed accordi ng t o t heir
nit r ogen sour ce.
P. 1282


( 1) Monomeri c f ormul as cont ain cr yst al l i ne ami no aci ds as t heir ni t r ogen sour ce.
These f ormul as ar e usual l y market ed commer ci al l y f or specif ic i ndi cat ions ( e. g. ,
i leus, pancr eat i t is, hepat ic coma).
( 2) Short- chai n pept i de f ormulas cont ain dipept i des and t r ipept ides f r om
hydr ol yzed pr ot ein or de novo synt hesis as t hei r nit r ogen sour ce. They ar e cur r ent l y
market ed f or t he met abol ical l y st r essed pat i ent .
( 3) Pol ymeri c f ormul as cont ai n eit her i nt act pr ot ei ns or pr ot ei n hydr ol ysat es as
t heir nit r ogen sour ce. Most pat ient s can be managed wit h t hese f ormulas.
b. Modul ar f ormul as consist of separ at e modules of speci f ic nut r i ent s t hat can be
combined or admi ni st er ed separ at el y. They ar e used f or suppl ement al use or t o
cust om design an EN f ormula t o meet a specif ic cl i nical si t uat ion.
( 1) Carbohydrate modul es di f f er in t he t ype of car bohydr at e pr esent ( e. g. ,
pol ysacchar ides, disacchar i des, monosacchar i des) .
( 2) Prot ei n modul es cont ai n eit her i nt act pr ot ei n, hydr ol yzed pr ot ein, or cr yst all i ne
amino aci ds.
( 3) Fat modules cont ai n eit her long- chai n t r igl ycer ides ( LCTs) pr epar ed f r om
veget able oi ls or medium- chai n t ri gl ycer i des ( MCTs) prepared f r om coconut oil.
MCTs ar e mor e wat er sol uble and mor e easil y absor bed t han LCTs. (Bypassi ng t he
i nt est inal l act eal and l ymphat i c syst em, MCTs ar e t r ansport ed di r ect ly t o t he port al
syst em. ) MCTs ar e, however, r el at i vely expensive and cont ain no essent ial f at t y
acids.
4. Compl i cat i ons. The t wo most common compl i cat ions of EN ar e diar r hea and
impr oper t ube placement .
a. Di arrhea i n pat i ent s r ecei vi ng EN i s usual l y secondar y t o concomit ant
admi ni st r at ion of medicat ion ( e. g. , ant ibiot i cs and sor bi t ol - cont ai ni ng l i qui ds) .
I nf ect ious causes shoul d be eli mi nat ed ( e. g. , Cl ost ri di um di f f i ci l e) , af t er whi ch
ant idi ar r heal medicat ions may be benef i cial. Reduci ng t he r at e or concent r at ion may
also be ef f ect ive.
b. A f eedi ng t ube i mproperl y placed i nt o t he t r acheobr onchial t r ee can have
disast r ous consequences. Tube f eedings shoul d never be i nit i at ed wit hout
r adiol ogical ver if icat ion of t ube posit ion.
c. Aspi rat i on
IV. MONITORING SUPPORT
A. PN. I n addit i on t o appr opr iat e gener al medi cal and nur si ng car e, pat i ent s
r eceivi ng PN i nit i al l y r equir e dai l y and weekly labor at or y moni t or i ng t o assess
nut r it ional pr ogr ess and met abol ic st at us.
1. El ect rol yt es
a. I nit i al l y, potassi um, sodi um, and chl ori de should be det ermined dai l y.
Pot assi um is used i nt r acel l ular l y; t hus hypokal emia is not an uncommon f i ndi ng.
b. Cal ci um, magnesi um, and phosphat e are pr imar i l y i nt r acel l ul ar elect r olyt es,
ser um l evels of which become depl et ed duri ng pr ot ein synt hesis. Ser um levels
gener al l y do not f al l as r api dl y as pot assi um; t heref or e, moni t or i ng t wo t o t hr ee
t imes a week is r ecommended init ial l y unt i l t he pat i ent is st abi l i zed, t hen weekly
t her eaf t er .
c. Bi carbonat e should be monit or ed t o assess acid- base balance. Hyperchlor emic
met abolic acidosis may devel op i n pat ient s on PN. This imbalance can be cor r ect ed
by pr ovi di ng t he pot assium and sodi um as acet at e (conver t ed t o bicar bonat e in t he
ser um) r at her t han as t he chlor i de salt . Af t er init i al cor r ect ion, provision of one half
t he sodi um and pot assium r equi r ement s as t he acet at e salt and one half as t he
chlor i de salt may be benef icial.
2. Serum gl ucose shoul d be moni t or ed dai ly, part icular l y i n cent r al gl ucose
syst ems. Mai nt aini ng a blood gl ucose concent r at ion bet ween 100- 200 mg/ dL is
gener al l y r ecommended.
3. Wei ght s obt ained on a dai ly or ever y ot her day basis t r ack opt i mum lean body
wei ght gain of 0. 25- 0. 50 lb/ day. Weight gai n i n excess of 0. 5 lb/ day gener al l y
i ndicat es f lui d over load or f at deposi t ion.
4. Vi sceral prot ei ns ( e. g. , al bumi n, pr ealbumi n, t ransf er r in) ar e import ant
i ndicat or s of t he adequacy of nut r it ional suppor t .
P. 1283


a. Al bumi n is usef ul i n t he i nit ial assessment of nut r it ional st at us, but i t s long half -
l if e ( 18-21 days) l imit s it s ut il i t y as a short -t erm marker of nut r it ional r epl et i on.
b. Preal bumi n has a shor t half - l if e ( 2- 3 days) and is a mor e sensi t i ve and ear ly
i ndicat or of t he adequacy of nut r it ional suppor t . I t s ser um val ue is f al sel y el evat ed
i n r enal f ai l ur e.
c. Transf erri n has an int ermedi at e half - l if e ( 7- 10 days) , whi ch makes weekly
moni t or i ng usef ul. Tr ansf err i n may be f al sel y el evat ed i n i r on- def iciency st at es.
d. Ret i nol - bi ndi ng prot ei n has an ult r a-short hal f - li f e ( 12 hr s). Values ar e af f ect ed
by i nj ur y and met abol ic st r ess.
5. Serum creat i ni ne and bl ood urea ni t rogen (BUN) shoul d be obt ained at least
weekl y. Evi dence of r enal i mpai rment may r equir e modi f icat i on of t he PN f ormul a.
Elevat ion of t he BUN in t he absence of r enal impair ment may be secondar y t o t he
PN f ormula ( e. g. , excess nit r ogen, low NPC: N rat i o) and appr opr i at e adj ust ment s
need t o be made.
6. Li ver f unct i on t est s—aspar t at e ami not r ansf erase ( AST) , alani ne
aminot r ansf erase ( ALT) , al kal i ne phosphat ase, l act at e dehydr ogenase ( LDH) , and
bi l ir ubi n—r equir e basel i ne and per iodi c moni t or i ng because of pot ent ial t oxi ci t y f r om
t he PN f ormul at i on ( i. e. , f at t y inf i lt r at ion of t he l i ver ). Abnormal l i ver f unct ion
st udi es may necessi t at e changes in t he PN f ormulat ion.
7. Serum tri gl yceri des should be measur ed f or a baseli ne and weekl y t her eaf t er f or
pat ient s on l i pid syst em PN. I t is not necessar y t o moni t or t r igl ycer i des on a weekly
basis f or pat ient s r eceivi ng l ipi ds t wo t o t hr ee t imes per week f or essent ial f at t y acid
r eplacement .
8. A 24- hr UUN should be obt ai ned weekl y t o det ermine nit r ogen balance f or
pat ient s in whom ni t r ogen r equir ement s are uncert ai n. These ar e usual l y hi ghl y
st ressed, severel y i l l, or inj ur ed pat ient s in an i nt ensive car e unit ( ICU) set t ing.
9. Serum i ron l evels shoul d be obt ained weekly t o det ermine def iciency and t o
al l ow appr opr iat e i nt er pr et at ion of ser um t ransf er ri n levels.
B. EN generall y r equir es l ess i nt ense labor at or y monit ori ng. Specif i c l abor at or y
guidel i nes f or monit or i ng EN support var y f r om i nst it ut ion t o inst it ut ion.
V. SUPPORT OF SPECIFIC STATES
A. Condi t i onal l y essent i al nut ri ent s
1. Gl utami ne. Because of it s inst abi l i t y, gl ut ami ne is cur r ent ly not a component of
commer cial l y avai lable st andar d PN amino acid sol ut ions and is f ound i n f r ee f orm
i n r elat i vel y f ew EN f ormulas. A r el at i ve def iciency has been shown t o occur i n
cr it ical i l l ness. I t is known t o be used as a pr i mary f uel sour ce by ent erocyt es and
may exer t a t rophic ef f ect on t he gut mucosa. It i s most widel y used as a PN
component f or bone marr ow t r ansplant pat ient s and shor t gut syndr ome. Gl ut ami ne-
cont ai ni ng dipept i des t hat ar e st able and highl y sol uble ar e being i nvest igat ed as a
sour ce of glut ami ne i n PN. At pr esent , gl ut ami ne must be added t o t he PN solut ion
at t he t ime of compounding. I ncr easi ng evidence suppor t s glut ami ne
supplement at ion i n cr it ical i l l ness, however opt imum r out e, t iming and dosi ng have
yet t o be def init i vely det ermined.
2. Argi ni ne has been shown exper iment al l y and cl i ni cal l y t o enhance immune
f unct i on. EN f ormulas enr iched wit h argi ni ne ar e avai l able commer ci al l y. Recent l y
t he ef f icacy of exogenousl y administ er ed ar gini ne t o subset s of cr it ical l y i l l pat ient s
has come int o quest ion. Opt imum dosi ng i n ot her pat ient popul at i ons i s st il l
undet ermined.
3. Ant i oxi dant f ormulat i ons. Oxidant product ion occur s as part of t he normal
i nf l ammat or y r esponse and has been impl i cat ed in r eperf usion i nj ur y. The body also
pr oduces ant ioxidant def enses t o l i mi t oxidant damage t o healt hy t issue. These
def enses rely on adequat e i nt ake of diet ar y nut r ient s, such as t he sulf ur - cont ai ni ng
amino aci ds, vit amin E, vit ami n C, seleni um, and zi nc. Sever al i nvest igat or s bel ieve
pr ovi sion of t hese nut r ient s shoul d be an ear ly pr i or it y i n cr it ical l y i l l pat ient s.
Opt imum doses r emain cont r over sial.
4. Tyrosi ne, cyst ei ne, and tauri ne ar e eit her absent or pr esent in low
concent r at ions i n commer cial l y avai lable PN f ormul as. They ar e bel ieved t o be
condit ional l y essent ial amino aci ds by some invest i gat or s.
P. 1284


5. Omega- 3 pol yunsat urat ed f at ty aci ds ar e deri ved f r om f ish oi ls and ar e
cur r ent ly f ound i n some EN f ormul at i ons. These f at t y acids have been shown
exper iment al l y t o enhance i mmune r esponse, pr ot ect agai nst t umor growt h, and
i nhibit some of t he pr oinf lammat or y ef f ect s of omega- 6 f at t y aci ds. I n addi t ion, t hey
have been shown t o l ower car di ovascul ar r isk f act or s by decr easing plat elet
act ivat i on, lower i ng bl ood pr essur e, and r educi ng t r i gl ycer ides. However, wel l -
cont r ol led cl i ni cal t r ials in humans are needed t o conf ir m t he benef i ci al ef f ect s of
immunomodulat i on seen i n animal models.
B. Nut ri ti onal support f or renal f ai l ure. The goal of nut r it ional suppor t in acut e
r enal f ai l ur e ( ARF) is t o meet t he pat i ent ' s NPC requir ement s whi le mi nimi zi ng
vol ume, prot ein load, and pot ent ial el ect r olyt e i mbal ance.
1. PN f ormulat i ons used in ARF ar e low- ni t r ogen, high- calor ic densit y f ormul as
( e. g. , 2% amino aci d/ 47% dext r ose), r esult i ng i n NPC: N r at ios of appr oximat el y
500: 1.
2. Commercial renal f ai l ure f ormul at i ons ( e. g. , Nephr Amine, RenAmi n, Aminosyn
RF) , cont aini ng pr i mar i l y essent i al amino aci ds, have shown no cl i nical advant age
over l ess expensi ve, l ow- concent r at ion st andar d amino aci d f ormul at i ons.
3. Standard gl ucose syst em f ormulat i ons ( 4. 25% ami no acid/ 25% dext r ose) can
gener al l y be used in r enal f ai l ur e pat i ent s who are being dial yzed on a r egular
basis. Thi s f ormul at i on is part icul ar l y usef ul i n sever el y malnour ished pat i ent s
because i t can pr ovi de adequat e pr ot ei n t o at t ai n posit i ve nit r ogen balance, whi ch is
not possible wit h r enal f ai l ur e PN.
4. Moni t ori ng transf erri n is a more sensit ive and accur at e viscer al pr ot ei n marker
compar ed t o albumi n and pr eal bumi n f or assessi ng nut r i t ional pr ogr ess i n t hese
pat ient s.
5. Ent eral f ormulat i ons t hat are l ow i n nit r ogen and cal or ie dense ( 1. 7-2. 0
NPC/ mL) ar e avai labl e f or pat ient s wi t h r enal f ai l ur e.
C. Nut ri ti onal support f or hepati c f ai l ure. Pat ient s wi t h hepat ic f ai l ur e have
alt er ed pr ot ein met abol ism, r esult i ng i n decr eased ser um levels of br anched- chai n
amino aci ds ( i. e. , l euci ne, isol euci ne, val i ne) and i ncr eased l evel s of ar omat ic
amino aci ds ( i. e. , phenylalani ne, t yr osine, t r ypt ophan) , met hi oni ne, and gl ut ami ne.
A simi lar ami no acid pr of i l e can exist i n t he cer ebr ospi nal f l uid ( CSF) and i s t hought
t o cont r ibut e t o hepat ic encephalopat hy. Fl ui d and el ect rolyt e dist ur bances are
f r equent l y associ at ed wi t h hepat ic f ai l ur e as well .
1. PN f ormulat i ons enr iched i n br anched- chai n amino aci ds (36%) and l ow i n
ar omat ic ami no acids ( e. g. , Hepat Ami ne) impr ove ment al st at us in pat ient s wi t h
alt er ed ser um amino acid prof iles and hepat ic encephal opat hy. However , st udi es
have not demonst r at ed def init i ve cl i ni cal dif f erences i n mor bi dit y and mort ali t y wit h
t hese expensi ve f or mulat ions compared t o st andar d f ormul as.
2. Adequat e NPC wit h a 20- 40 g/ day pr ot ein load ( e. g. , 2% ami no acid/ 25%
dext r ose) is an alt er nat ive appr oach t o t he use of hepat ic f ail ur e amino acid
f ormulat i ons. Pr ot ein load can be l iber al i zed slowl y as long as ment al st at us does
not det er i or at e.
3. EN f ormulat i ons (e. g. , Hepat ic- Aid I I ) enr i ched wit h br anched- chai n amino acids
and l ow i n ar omat ic amino acids ar e commer ci al l y avai lable f or pat ient s wit h hepat i c
f ai l ur e.
D. Nut ri ti onal support f or respi rat ory fai l ure. The t ype and amount of subst r at e
admi ni st er ed as NPC can have an ef f ect on a pat i ent ' s vent i lat or y st at us.
Overf eedi ng wit h r esult ant l ipogenesis and i ncr eased carbon dioxi de pr oduct ion can
be a cause of r espir at or y acidosis and/ or i ncr eased mi nut e vent i lat ion and,
t her ef or e, should be avoided. Even i n t he presence of appropr i at e amount s of NPC
admi ni st er ed as car bohydr at e, t he normal carbon dioxi de load gener at ed by
gl ycolysis may be excessi ve f or t he pat i ent wit h under l yi ng pulmonar y dysf unct ion—
f or exampl e, chr onic obst r uct ive pul monar y di sease (COPD).
1. PN l i pi d syst em f ormul at i ons ( e. g. , 4. 25% ami no acid/ 15% dext r ose wi t h dai l y
l ipid emul si on) , wher e t he l i pid component const i t ut es 40%- 50% of t he t ot al NPC,
may be benef icial i n r educi ng t he vent i lat or y demands i n r espir at or y f ai l ur e pat ient s
because l ipol ysis gener at es less carbon dioxide t han gl ycol ysis.
2. EN f ormulat i ons cont aini ng similar amount s of f at can be pr epar ed f r om st andar d
EN f ormulas wit h t he use of l ipid modules ( i. e. , MCT oi l , cor n oi l ) . More expensi ve
commer cial pulmonary f ormul as ar e also avai labl e.
P. 1285


3. Oxepa, a low- car bohydr at e ent er al f or mula cont aini ng ant ioxidant s,
eicosapent aenoi c acid, and v- li nol enic acid, is cur r ent l y avai l able f or adult
r espir at or y dist ress syndr ome ( ARDS). I t modul at es t he phosphol ipi d f at t y acid
composi t ion of inf lammat or y cel l membr anes, decr eases t he synt hesis of t he
pr oinf l ammat or y ei cosanoids of l ung i nj ur y, and at t enuat es endot oxi n- i nduced
i ncr eases i n pulmonar y microvascular pr ot ein per meabi l it y. Limit ed st udi es have
shown some impr ovement in car diopulmonar y hemodynami cs and respi r at or y gas
exchange i n ARDS.
E. Nut ri t i onal support f or cardiac f ai l ure. The goal in t hese pat i ent s i s t o meet
met abolic needs whi le r est r ict i ng f l ui d and sodi um i nt ake.
1. PN f ormulat i ons t hat pr ovide pr ot ein and cal or i es i n as hi gh a concent r at ion as
possible i s t he goal of nut r it ional t her apy. Thi s can be accompl i shed wit h bot h
cent r al gl ucose or lipid syst em PN f ormulat ions ( e. g. , 5% amino acid/ 35% dext r ose;
7% ami no acid/ 21% dext r ose/ 20% l ipi d emulsion) .
2. Serum el ectrol yt e moni t ori ng and adj ust ment ar e imper at ive i n car diac f ai l ur e
pat ient s r eceivi ng PN, par t icular l y when pot ent di ur et ics ar e used concur r ent l y.
3. EN f ormulat i ons wit h hi gh nut r ient densit y ar e avai lable f or oral suppl ement at ion
or t ube f eedings. I nf usion of ent er al t ube f eedings shoul d begin at one t hir d t o one
half t he st rengt h, wit h a gr adual i ncr ease in concent r at ion, whi l e maint ai ni ng a slow
i nf usion r at e (30-50 mL/ hr ) t o avoi d r apid i ncreases i n f l ui d load, car diac out put ,
hear t r at e, and myocar dial oxygen consumpt ion.
F. Nutri t i onal support i n pancreat i t i s. Severe acut e pancreat i t is is a
hyper cat abol ic st at e t hat wi t hout nut r it i onal suppor t render s t he pat ient a poor
sur gi cal candidat e and at incr eased r isk of i nf ect ion. The goal of nut r it ional suppor t
i n sever e acut e pancreat it is is t o r est t he pancr eas by l imit i ng exocr i ne st i mulat ion
whi l e pr ovidi ng adequat e nut r i t ion.
1. PN is gener al l y f avor ed over EN t o achieve t hi s goal i n t he ear l y phases of
pancr eat it i s. Lipid syst em PN has been shown t o be saf e and ef f ect ive when
admi ni st er ed t o t hese pat i ent s, pr ovi ded t her e is no concur r ent hyper l ipidemia; in
f act , i t may be val uable i n t he pat i ent wit h r ecalci t r ant hyper gl ycemia.
2. EN, usi ng chemical l y def ined ( el ement al) , l ow- f at f ormul as admini st er ed int o t he
j ej unum, r esult s in minimal pancr eat ic st imulat i on and has been used saf ely i n t hese
pat ient s.
G. Nut ri t i onal support i n st ress/ cri t i cal care. I n hypermet abolic cr it ical l y i l l
pat ient s, al t er at ions i n subst r at e use, t he devel opment of condit ional nut r i ent
def icienci es, and modul at i on of t he immune r esponse pr ovide t he rat i onal e f or
specif i c nut r i t ional f ormulat ions.
1. I n cr it i cal i l l ness, br anched- chai n amino acids ( i . e. , i soleuci ne, l euci ne, val i ne)
ar e r eleased f r om skelet al muscl e f or pr ot ein synt hesis and as an ener gy subst r at e.
PN f ormulat ions enr iched in br anched- chai n ami no acids ( 45%)—f or example,
Fr eAmine HBC, Br anchAmi n, Aminosyn- HBC—have been made avai lable wit h t he
r at ionale t hat , bei ng t he pr ef err ed f uel sour ce in t hi s pat i ent populat ion, i t woul d
enhance pr ot ein synt hesis, decr ease pr ot ei n cat abol i sm, and impr ove t he pat ient ' s
cl i ni cal out come. However , t hese more expensive branched- chai n amino aci d
f ormulat i ons have not been shown t o f avor abl y i nf l uence cl i nical out comes i n
cr it ical l y i l l pat i ent s.
2. Ent er al f ormulat ions ar e curr ent l y bei ng pr oduced ( e. g. , Impact , Per at ive) wi t h
var ious amount s of t he condit i onal l y essent i al nut r ient s of cr i t ical i l l ness and
immunomodulat or y subst r at es ( e. g. , omega- 3 pol yunsat ur at ed f at t y acids, ar gi ni ne,
gl ut ami ne) . Cl i nical st udies of t he abi l it y of t hese f ormul as t o impr ove out comes in
cr it ical i l l ness have been mi xed.
3. Hypergl ycemi a and i nsul i n resi st ance are common occurr ences i n cr it i cal l y i l l
pat ient s. Recent dat a i nvol vi ng mechani cal l y vent i lat ed pat i ent s i n t he sur gi cal
i nt ensi ve car e uni t who r eceived i nt ensive i nsul i n t her apy t o mai nt ai n bl ood glucose
level s bet ween 80 and 110 mg/ dL showed a signi f icant r educt ion i n mort al it y when
compar ed t o mor e convent ional t her apy of mai nt ai ni ng blood gl ucose l evel s bet ween
180 and 200 mg/ dL. The gr eat est r educt i on i n mor t alit y was associat ed wit h deat hs
caused by mult iple or gan f ai l ur e wi t h a pr oven sept ic f ocus. These dat a point out
t he import ance of st r ivi ng f or a t ight glucose cont r ol i n cr it ical l y i l l pat ient s on PN
whi l e avoidi ng t he compl i cat ions of hypogl ycemi a.
P. 1286


4. Thermal i nj ur y is one of t he most hypermet abol ic condit ions obser ved i n t he
cr it ical care set t ing.
a. Met hods f or est i mat ing t he calor ie r equi r ement s in t hi s pat i ent populat ion ar e
conf l ict ing owi ng t o di f f er ences i n bias and pr ecision. One of t he mor e accur at e
unbiased met hods repor t ed f or est imat i ng ener gy requir ement s in t hermal inj ur y is
Kcal = ( 1000 kcal × BSA) + ( 25 × %BSAB)
wher e BSA i s body sur f ace ar ea and BSAB i s body sur f ace ar ea bur ned.
b. Pr ot ein r equir ement s in t hermal l y i nj ur ed pat i ent s are hi gh at 2-2. 5 g/ kg/ day
because of t he si gnif icant degr ee of cat abol ism associ at ed wit h t hi s i nj ur y.
c. The i ncr eased dermal losses of nit r ogen f r om t heir bur n wounds r ender s t he use
of t he convent ional nit r ogen bal ance f ormulas less accur at e i n assessing nit r ogen
r equir ement s especi al l y wit h t hermal inj ur i es > 40% of BSA. The UUN plus t he
i nsensibl e l oss f act or can dif f er signif i cant l y f r om t ot al ni t r ogen losses i n t his
pat ient popul at i on.
H. Nut ri ti onal support i n pregnancy. Nut r i t ional suppor t in pr egnancy can have a
signi f icant af f ect on f et al out come. Wei ght gain t hr oughout pr egnancy i s t he pr imar y
i ndicat or of t he adequacy of t he nut r it i onal st at e of mot her and chi ld. A wei ght gain
of 11. 5- 16. 0 kg shoul d be t he desi r ed goal i n women wi t h normal pr epr egnancy body
mass i ndex. PN and EN have bot h been used successf ul l y dur i ng pregnancy, wi t h
bot h modalit i es demonst r at i ng adequat e mat er nal weight gai n, appr opr iat e f et al
gr owt h, and t erm deli ver y. The cal or ies r equi red t o achieve appr opr iat e weight gai n
t hr oughout t he ent ir e pr egnancy per t he Wor ld Healt h Or gani zat i on
r ecommendat ions ar e an addit i onal 300 kcal/ day above t he est imat ed basal ener gy
expendit ur e ( based on t he pr egr avi d weight ) dur i ng al l t r imest er s. The
r ecommended dai ly pr ot ein i nt ake dur i ng a normal pr egnancy is appr oxi mat ely 1
g/ kg/ day. Thi s amount repr esent s t he normal r ecommended dai l y al lowance f or
f emales plus an addit i onal 10 g/ day. I n pr egnant pat i ent s wit h moder at e t o sever e
st ress, bot h cal or ies and pr ot ein r equi r ement s need t o be adj ust ed in t he same
manner as f or ot her hypermet abol ic nonpr egnant pat ient s.
1. PN gl ucose syst em and lipid syst em f ormul at i ons can bot h be used successf ul l y
t o meet t he nut r ient requir ement s of pr egnant pat ient s. PN is most commonly used
dur i ng pregnancy i n pat i ent s wit h sever e hyper emesis gr avi dar um.
2. Essent ial f at t y acids (EFAs) ar e r equir ed by bot h mot her and f et us. They ar e
necessar y f or pr ost aglandin synt hesi s and normal f et al l ipi d development . The
pr ovi sion of at least 4. 5- 7. 0% of cal or i e r equir ement s as EFAs has been est imat ed
t o meet t he mini mum r equir ement s dur i ng pr egnancy.
3. The dai l y vi tami n requi rement s i n a normal pregnancy based on t he 1999
diet ar y r ef er ence int akes (DRI ) can be met wi t h t he par ent eral vit amin i nf usion
I nf uvi t e Adult and MVI- Adult . I f MVI- 12 is used as t he par ent er al vi t amin
pr epar at i on, an addi t ional 65 ug of vit amin K needs t o be added t o t he dai l y PN
f ormulat i on t o meet t he dai l y DRI r equir ement s.
4. Pr ealbumin appears t o be t he pr ef er r ed biochemical marker t o assess pr ot ein
st at us i n pr egnancy because albumi n i s f alsel y depr essed and t r ansf err i n is f alsely
elevat ed i n pr egnant pat ient s.
5. EN may be usef ul dur ing pr egnancy f or pat ient s wit h l ess sever e hyper emesis
gr avi dar um. The composi t ion of polymer i c f ormul as shoul d be adequat e f or meet ing
t he nut r it i onal r equir ement s of most pr egnant pat i ent s.
6. Blood gl ucose levels shoul d be kept at appr oxi mat ely 100 mg/ dL dur ing pr olonged
cont i nuous PN or EN inf usi on because chr onical l y elevat ed mat er nal gl ucose l evel s
can r esult i n f et al anomal i es, increased r i sk of miscarr iages, and st i l l bi r t h.
I . Nut ri t i onal suppor t i n i nf l ammatory bowel di sease ( IBD). IBD i s associ at ed
wit h wei ght loss, hypoalbumi nemi a, anemia, el ect r ol yt e imbal ance, and
vit amin/ miner al def iciencies ( especi al l y zi nc)
1. PN has no r ol e as pr imar y t her apy
2. PN has a r ole wit h hi gh out put f i st ulae
3. Polymer i c and element al ent er al f ormulas seem equal l y t ol er at ed.
P. 1287


J. Nutri t i onal support i n short bowel syndrome (SBS) . A loss of bowel f r om
r esect ion or dysf unct ion can r esult i n r educed absor pt i on of f lui d, elect r olyt es,
macr o and micr onut r i ent s. Specif ic def i ci encies are rel at ed t o t he r egi ons of l ost
absorpt i on ( e. g. , f ree wat er and ir on def i ci ency ar e associat ed wi t h j ej unal l oss,
vit amin B12, bi l e sal t and f at sol uble vi t amin def i ciency ar e associat ed wit h i l eal
loss) . Compli cat ions i ncl ude dehydr at i on; weight l oss; def iciencies of el ect r ol yt es,
mi ner al and t race element s; met abol ic bone disease; cholel it hi asis; nephr ol it hiasi s;
gast r i c aci d hyper secr et ion and D- l act ic acidosis. I nt est i nal adapt at ion begi ns t o
occur af t er r esect ion and is pr omot ed by ent er al f eedi ng.
1. PN not uncommonly r equir ed f or t he shor t t erm, and is usual l y r equir ed f or t he
long t erm in massive smal l bowel r esect i on.
2. Hyper secr et ion of gast r ic acid should be t r eat ed wit h H2- blocker s.
3. D- l act ic acidosis i s caused by f erment at i on of an i ncr eased carbohydr at e load
del i ver ed t o t he colon. Tr eat ment is ai med at decreasing ent er al car bohydr at es.
4. Fat sol uble vi t ami ns should be monit or ed and replaced.
5. St ool vol ume should be monit or ed and t r eat ed wit h ant i - diar r heal agent s if
gr eat er t han 2 l it ers/ day.
6. Or al cal ci um and magnesi um suppl ement at ion needed when ent er al f eedi ng
achieved.
7. I nt est i nal adapt at ion i n pat i ent s wit h massi ve resect i on may be
hast ened/ i mpr oved by t he pr ovision of gl ut amine (ent er al and/ or par ent er al )
r ecombinant human gr owt h hormone and hi gh- car bohydr at e, low- f at f eeds.
K. Nut ri ti onal support i n bariat ri c surgery. Bar i at r ic sur ger i es ar e divi ded i nt o
r est r ict ive ( ver t ical banded gast r oplast ies and si l ast ic r ing ver t ical gast r oplast ies),
r est r ict ive/ malabsor pt ive (Roux- en- Y gast r ic bypass) and mal absor pt i ve pr ocedur es
( bi l iopancr eat ic di ver si on) . Since r est ri ct i ve pr ocedur es r et ain t he use of t he ent ir e
gast r oint est inal t r act , nut r it ional def i ci enci es ar e less common t han i n mal absor pt i ve
pr ocedur es. The pr imar y nut r ient s af f ect ed by bariat r ic sur ger y incl ude:
1. Ir on—one of t he most f r equent def i ciencies af t er bar iat r ic sur ger y. Occur s in bot h
r est r ict ive and mal absor pt ive pr ocedur es. Def ici ency is secondar y t o r educed ar eas
of absor pt ion i n t he smal l bowel wit h malabsor pt i ve pr ocedur es and r educed
pr oduct i on of hydr ochlor ic acid i n t he st omach f or bot h t ypes of bar iat r ic
pr ocedur es. The r esul t is a reduct ion i n i r on r educed t o t he absor bable f err ous
st at e. Pr event i on/ t r eat ment i s wi t h or al ir on suppl ement at ion combined wit h ascor bic
t o aci di f y t he st omach and f acil i t at e absor pt ion.
2. Vit ami n B12 def iciency—common af t er gast r ic bypass sur ger y. Absor pt i on is
dependent on int r i nsi c f act or pr oduced i n t he par i et al cel ls of t he st omach and
hydr ochlor ic acid is r equi r ed t o cleave vi t amin B12 f r om prot ein f oodst uf f s in t he
st omach. Prevalence af t er Roux- en- Y pr ocedur e is est imat ed at 12% t o 33%.
Pr event ion/ t r eat ment : or al B 12 f ormulat ions of 350- 1000 mcg/ day or mont hl y
i nj ect ions of 2000 mcg in t hose pat i ent s who do not respond t o t he or al
supplement s.
3. Fol at e def iciency—less f r equent t han B12 def i ci ency. Folat e absor pt i on occur s
pr ef er ent i al l y i n t he proxi mal i nt est ines but wit h adapt at ion af t er gast r ic bypass
sur ger y absorpt i on can occur t hr oughout t he smal l bowel. Pr event ion/ t r eat ment : 1
mg f olat e PO/ day.
4. Thi amine def i ci ency—uncommon. Seen wit h post oper at ive hyper emesis
syndr omes. Pr event i on: 50- 100 mg IV or I M t hiami ne at 6 weeks post op in pat i ent s
wit h hyper emesi s.
5. Zi nc—depends on f at absor pt i on. Def iciency observed wi t h malabsor pt ive
sur ger y. St andar d dai l y suppl ement at ion of zi nc i s recommended af t er
malabsor pt ive sur ger y.
6. Seleni um def i ci ency and a l if e- t hr eat eni ng car di omyopat hy have been r epor t ed i n
pat ient s af t er malabsor pt ive sur ger y. Suppl ement at ion of seleni um at 40- 80mcg/ day
is r ecommended in pat ient s under goi ng malabsorpt ive bar iat r i c sur ger y.
7. Fat sol uble vi t ami ns ( A, D, E, K) —Malabsorpt ive bar iat r ic sur ger y r esul t s in a high
i ncidence of vi t ami n A, D and K def iciency wit h al t er ed cal ci um met abol ism ( vi t amin
E, t o a l esser ext ent ) . Pat ient s under goi ng malabsor pt ive sur ger y r equir e long- t erm
annual measur ement s of f at - soluble nut r ient s. Ther e i s no pr oven r egimen f or
vit amin supplement at i on af t er malabsor pt ive sur ger y but lif e- long dai l y
supplement at ion of f at sol uble vi t amins has been r ecommended at t he f ol lowi ng
dosages: 10, 000 I U vi t ami n A; 1200 IU vit amin D; 300 mcg vit ami n K, and 1800 mg
calci um cit r at e.
P. 1288


VI. TECHNICAL ASPECTS OF PN PREPARATIONS
A. PN f ormul a prepar at ion is per f ormed asept i cal l y i n t he pharmacy under a lami nar
f low hood t hat f i lt er s t he ai r , r emovi ng ai r bor ne par t icles and micr oor gani sms.
B. Compat i bi l i t y of t he var ious component s of PN f or mulat ions is det ermi ned by
sever al f act or s, incl udi ng t heir concent r at i on, solut ion pH, t emper at ur e, and t he
or der of admixt ur e. The most common compat ibi l i t y concer n is i n r egar d t o t he
addit i on of calci um and phosphat e salt s t o PN sol ut i ons.
C. Af t er admixt ur e of t he var i ous component s, t he PN sol ut ion should be vi sual l y
i nspect ed f or pr eci pi t at e or part icul at e mat t er . Af t er l abel i ng and f i nal checki ng, t he
PN solut ion should be ref r i ger at ed unt i l del i ver y t o t he nur sing unit .
D. A st at ist ical l y val id, cont i nuous st eri l i t y t est i ng program shoul d be an essent ial
component of qual it y cont r ol i n pr epar ing PN solut ions.
VII. HOME PARENTERAL NUTRITI ON (HPN)
has become a widely accept ed and usef ul t echnique f or pr ovi si on of complet e
nut r it ional r equir ement s i n t he home set t ing. When used appropr i at ely, t his modali t y
benef it s t he pat i ent medical l y and psychological l y, wit h a decreased cost t o t he
healt hcar e syst em.
A. I ndi cat i ons f or HPN incl ude shor t bowel syndr ome, sever e inf lammat or y bowel
disease, r adi at i on ent er i t is, ent er ocut aneous f ist ulae, and select ed mal i gnanci es.
B. Candi dat e sel ect i on r equir es a mul t idisci pl i nar y appr oach t o det ermi ne if t he
pat ient and f ami ly can assume t he r esponsibi l i t y and t rai ni ng needed f or saf e and
successf ul HPN.
C. Admi ni st rat i on. HPN is inf used t hr ough a cent r al venous Sil ast ic cat het er ( e. g. ,
Hickman, Br oviac) , whi ch al lows f or pr olonged PN wit h low cl ot t i ng and inf ect ion
r at es. The PN solut ion is gener al l y i nf used over a 12- t o 15- hr per i od at night . This
t ype of cycl i ng pr ogram al lows t he pat ient t o be f r ee f r om t he inf usion pump dur ing
t he day, al lowi ng f or a more normal l i f est yle.
D. Cl i ni cal moni t ori ng and f ol low- up ar e done per i odical l y, dependi ng on t he needs
of t he indi vidual pat ient . Long-t erm HPN pat i ent s gener al l y ar e seen by t he
physician on a mont hl y basi s af t er ini t ial st abi l i zat ion.
VIII. MISCELLANEOUS
A. Sol ubl e f i ber i s pr esent i n some commercial l y avai labl e EN f ormulas. Thi s f iber
is f erment ed by normal lar ge i nt est i nal f lor a t o shor t - chai n f at t y acids t hat are used
by colonocyt es as a f uel sour ce. These short -chai n f at t y acids also seem t o have a
t r ophi c ef f ect on t he lar ge int est i nal mucosa.
B. Growt h f actors. The use of r ecombi nant human gr owt h hormone, insul i n- l ike
gr owt h f act or , and anaboli c st er oids, in combinat i on wi t h nut r i t ional suppor t t o
impr ove ni t r ogen balance and reduce hospi t al lengt h of st ay in sel ect pat ient
populat i ons, is cur r ent ly under i nvest igat i on. To dat e, r ecombinant gr owt h hormone
(Humat r ope) i s avai l able f or nut r it ional suppor t in chi l dr en wit h cyst ic f ibr osis, sickle
cel l anemia, and t halassemia and i n adult s wi t h AI DS-r elat ed cachexi a. Oxandr olone
is a synt het i c anabol ic st eroid wit h FDA appr oval f or i ncr easi ng weight gain i n
pat ient s wit h chr oni c i nf ect i on, maj or surger y, and severe t rauma. I t also has
est ablished ef f i cacy i n alcohol i c cir r hosis ( impr oved sur vi val and l i ver f unct ion) ,
bur ns ( improved ni t r ogen balance, wound heal i ng, and weight gai n) , and in AI DS
cachexia ( impr oved wei ght gain) . Usual dose is 2. 5- 20 mg or all y ( 80 mg in alcohol ic
cir r hosis) i n divided doses dai ly f or up t o 4 weeks.
P. 1289


STUDY QUESTIONS
Di rect i ons: Each of t he quest ions, st at ement s, or incomplet e st at ement s in t his
sect i on can be corr ect l y answer ed or complet ed by one of t he suggest ed answers or
phr ases. Choose t he best answer .
1. A 32- year- ol d wel l - nouri shed man i nvol ved i n a mot or vehi cl e acci dent was
admi tt ed t o t he surgi cal i nt ensi ve care uni t wi th mul t i pl e l ong bone f ract ures
and abdomi nal i nj uri es wi t h no nut ri t i onal support f or 4 days. Thi s pat i ent i s
most l i kel y
( A) suf f er ing f r om moder at e t o severe kwashior kor mal nut r it i on.
(B) at low r isk f or hospi t al - acquir ed i nf ect i on and ot her compl i cat ions.
(C) not suf f er ing f r om pr ot ein or calor i e malnut r it i on.
(D) suf f er ing f r om sever e mar asmus malnut r i t ion.
(E) not a candidat e f or aggr essi ve nut r it i onal support .
View Answer 1. The answer i s A[ see] . 2. A pat i ent i n the i nt ensi ve care
uni t on a vent i l at or was pl aced on a gl ucose syst em parent eral nut ri t i on (PN)
f ormulat i on provi di ng 2040 kcal / day and 98 g prot ei n/ day. A measured energy
expendi t ure ( MEE) of 2038 kcal and a respi ratory quot i ent (RQ) of 1. 1 were
subsequent l y obtai ned. Whi ch of t he f ol l owi ng i s correct based on t hi s
i nf ormat i on?
( A) The pat ient i s r eceivi ng adequat e glucose cal or ies, and an adj ust ment in t he
pr ogr am is not necessar y.
(B) The dai l y pr ot ei n i nt ake has t o be decr eased t o reduce t he pat i ent ' s RQ.
(C) The PN f ormulat ion shoul d be swi t ched t o a l i pi d syst em f ormulat ion t o reduce
t he car bon dioxide load.
(D) The pat i ent is r et ai ni ng oxygen f r om t he gl ucose calor ies i n t he PN f ormulat ion.
(E) Li pi d emulsion should be added t o t he cur r ent PN f ormul at i on t o enhance
l ipogenesis.
View Answer 2. The answer i sC [ see] . 3. Total nut ri ent admi xt ure (TNA)
( A) is mor e complicat ed t o admi nist er f or home par ent er al nut r it i on ( PN) pat i ent s.
(B) should be f i lt ered wit h a 1. 2-µ f i lt er .
(C) consist s of gl ucose, amino aci ds, elect r olyt es, and t r ace miner als mi xed i n one
cont ai ner .
(D) is t he met hod recommended by t he U. S. Food and Dr ug Admini st r at ion ( FDA) t o
admi ni st er li pid syst em PN.
(E) can be visual i zed f or part icul at e mat t er .
View Answer 3. The answer i s B[ see I I I . A. 6. b. (2) (b) . (i i i ) ] . 4. The cal ori e
requi rement s of a moderat el y hypermetabol i c hospi t al i zed pat i ent are best
est i mat ed by usi ng t he
( A) nomogr am met hod.
(B) ni t r ogen balance met hod.
(C) est imat ed ener gy expendit ur e (EEE) met hod.
(D) prognost ic nut r i t ional i ndex ( PNI ).
(E) subj ect ive gl obal assessment met hod.
View Answer 4. The answer i s C[ see] . 5. Li pi d syst em parent eral nut ri t i on
(PN)
( A) can be administ er ed by per ipheral vei n i f t he gl ucose concent r at ion is less t han
15%.
(B) requir es dai l y serum t r i glycer ide moni t or i ng.
(C) is cont r aindi cat ed in pat i ent s wit h elevat ed carbon dioxide level s.
(D) r equi r es dai l y l ipi d administ r at ion t o pr ovi de a por t ion of t he pat i ent ' s nonpr ot ein
calor i e r equir ement s.
(E) can be administ er ed wi t h a maximum l ipid dosage of 4. 5 g/ kg/ day.
View Answer 5. The answer i s D[ see] . 6. Commerci al parent eral nut ri t i on
(PN) f ormul at i ons f or hypermetabol i c crit i cal l y i l l pat i ents
( A) ar e enr iched i n br anched- chai n ami no acids and cont ai n l ow concent r at i ons of
ar omat ic ami no acids.
(B) cont ai n pr imar i ly essent ial amino acids.
(C) have not demonst r at ed a posi t ive cl i nical out come benef it i n t his pat ient
populat i on.
(D) are t he pr ef err ed PN f ormulat ion used i n t his cl i nical set t ing.
(E) ar e enr iched wit h ar gi ni ne t o enhance immune f unct i on.
View Answer 6. The answer i s C[ see] . 7. Whi ch of t he f ol l owi ng met hods of
parent eral nut ri t i onal support woul d be most appropriat e i n a severel y prot ei n
cal ori e mal nouri shed pat i ent wi t h acute renal fai l ure?
( A) 2% amino aci d/ 47% dext r ose.
(B) 4. 25% amino aci d/ 25% dext r ose.
(C) 4% essent ial amino aci d/ 47% dext r ose.
(D) 4. 25% amino aci d/ 25% dext r ose wit h dial ysis on a regul ar basis.
(E) 2% amino aci d/ 47% dext r ose/ 20% l ipid emulsi on.
View Answer 7. The answer i s D[ see] . P. 1290


8. Whi ch of t he f ol l owi ng stat ement s regardi ng t he moni tori ng of nut ri t i onal
support i s true?
( A) Preal bumi n i s not t he opt imal marker t o f ol low f or shor t -t erm nut r it ional
pr ogr ess.
(B) Tr ansf er r in is f al sel y depr essed i n pat i ent s wit h ir on def i ci ency.
(C) Albumi n i s f alsel y elevat ed in r enal f ai l ur e.
(D) A posit i ve ni t r ogen balance of 3-6 g of ni t r ogen dai l y i s opt imal .
(E) A weight gai n of 1. 5- 2 lb/ day i ndicat es opt imal lean body weight gain.
View Answer 8. The answer i s D[ see] . 9. Pat i ent s wit h end- st age l i ver
di sease
( A) gener al l y have i ncr eased l evel s of br anched- chai n amino aci ds and decreased
level s of ar omat ic ami no acids.
(B) should be placed on a low- br anched chai n, hi gh ar omat ic ami no acids par ent er al
nut r it ion ( PN) sol ut ion.
(C) can t ol er at e 20- 40 g prot ein/ day wit h a 2% st andar d amino aci d PN solut ion.
(D) r equi r e gl ut amine- enr i ched ami no acid solut ions.
(E) can t ol er at e st andar d gl ucose syst em f ormul at i ons 4. 25% ami no acid/ 25%
dext r ose wi t h r egular di alysis.
View Answer 9. The answer i s C[ see] . For quest i ons 10- 12: A 67- year- old
whi t e f emal e present ed t o t he at t endi ng physi cian wit h a 3-mont h hi st or y of
pr ogr essive dif f i cult y swal lowi ng and a 10-kg wei ght loss. She is curr ent ly 160 cm
t al l and weighs 50 kg. She has j ust under gone a dist al esophagect omy and pr oximal
gast r ect omy f or dist al esophageal cancer. At t he t i me of sur ger y, she had a f eeding
j ej unost omy t ube inser t ed.
10. The di et i cians who are adept at usi ng t he Harri s- Benedi ct equat i on have
gone home f or t he day, and t he surgeon cal l s you f or your best guess at what
t he hourl y goal rat e f or t hi s pat i ent shoul d be usi ng i sot oni c ent eral f ormula,
whi ch provi des 0. 85 nonprot ei n cal ori es ( NPCs) / mL. Your answer shoul d be
( A) 65 mL/ hr.
(B) 75 mL/ hr.
(C) 85 mL/ hr.
(D) 95 mL/ hr.
(E) 50 mL/ hr.
View Answer 10. The answer i s B[ see] . 11. The ent eral f ormul at i on t he
surgeon has sel ect ed i s enri ched wi t h f i sh oi l s. He i s hopi ng t hi s addi t i ve wi l l
( A) pr event di ar r hea.
(B) pr event dermat i t is.
(C) prevent hyper gl ycemi a.
(D) impr ove immune f unct ion.
(E) impr ove neur ol ogical f unct ion.
View Answer 11. The answer i s D[ see V. A. 5] . 12. On t he 5t h post operat i ve
day, t he f eedi ng j ej unost omy t ube becomes cl ogged and unusabl e. The pat i ent
wi l l be NPO an addi t i onal 5 days to ensure t he i nt egri t y of her surgi cal
anast omosi s. The most appropri at e course at thi s t i me i s
( A) st art t he pat ient on a l ipi d- based per ipher al par ent eral nut r it ion pr ogram.
(B) keep t he pat ient NPO and wit hout par ent er al nut r it ional suppor t .
(C) have a cent r al venous cat het er inser t ed, and init i at e a l ipid- based parent er al
nut r it ion pr ogr am.
(D) st art t he pat ient on a glucose- based per ipher al par ent er al nut r i t ional pr ogr am.
(E) have a cent r al venous cat het er inser t ed, and st art t he pat i ent on a high
br anched- chai n ami no acid par ent er al program.
View Answer 12. The answer i s A[ see] . For quest i ons 13- 14: RJ i s a 28-
year - old pr egnant woman. She i s i n t he 9t h week of her pr egnancy and is di agnosed
wit h hyper emesi s gravi dar um. Her pr egr avid wei ght was 57 kg, and her height i s 5
f t . , 5 in. She has lost 7 kg (12. 3%) dur i ng her pr egnancy. She was placed on a
cent r al gl ucose PN program.
13. Whi ch one of t he f ol l owi ng represent s t he best est imat e of her dai l y cal ori c
requi rement s?
( A) 1675 kcal
(B) 1790 kcal
(C) 2261 kcal
(D) 2062 kcal
(E) 1925 kcal
View Answer 13. The answer i s A[ see] . 14. MVI- 12 i s used as t he
parent eral vi t ami n preparat i on i n t he PN f ormul at i on. Whi ch of t he f ol l owi ng
vi t ami n( s) need t o be suppl ement ed i n t he dai l y PN f ormul at i on t o meet t he
dai l y requi rement s duri ng pregnancy?
( A) vit ami n K
(B) t hiami ne (B1 )
(C) f ol ic acid
(D) A and C
(E) pyr idoxi ne ( B6 )
View Answer 14. The answer i s A[ see] . P. 1291


For quest i ons 15- 17: A 55- year old male wit h mult ipl e t r aumat i c i nj ur ies and t ype I I
diabet es was admit t ed t o t he sur gical I CU. He was pl aced on mechanical vent i l at i on
and i nit i at ed on glucose syst em PN. Af t er 3 days of PN t her apy his bl ood gl ucose
level s have r anged f r om 250 t o 285 mg/ dL over t he past 24 hr wit h 80 U of i nsul i n/ L
i n his PN f ormulat i on. He is on no ot her insul i n suppl ement at ion at t his t ime.
15. The nut ri t i onal support servi ce recommends an i nsul i n dri p wi t h t he goal of
achi evi ng a bl ood gl ucose l evel of
( A) 180- 225 mg/ dL.
(B) 200- 215 mg/ dL.
(C) 80- 110 mg/ dL.
(D) 65- 100 mg/ dL.
(E) 70- 105 mg/ dL.
View Answer 15. The answer i s C[ see] . 16. What parent eral trace mi neral
t herapy may be an ef f ect i ve adj unct if t he i nsul i n dri p f ai l s t o achi eve t he
gl ucose l evel goal ?
( A) 20- 40 mg zi nc/ day
(B) 150- 200 µg chr omium/ day
(C) 0. 5- 1. 5mg copper / day
(D) 150- 400mcg manganese/ day
(E) 40- 60 µg sel eni um/ day
View Answer 16. The answer i s B[ see] . 17. Appropri at e i nsul i n cont rol i n
t hi s pat i ent sett i ng has been shown t o provi de whi ch of t he f ol l owi ng cl i ni cal
out comes?
( A) decr eased l engt h of t ime on t he vent i l at or
(B) signif i cant r educt ion i n mort al i t y
(C) decr eased dur at ion of PN t her apy
(D) a decr ease i n mult i ple or gan f ail ur e wit h a pr oven sept ic f ocus
(E) B and D
View Answer 17. The answer i s E[ see] . For questi ons 18- 19: A 35 year old
f emale wit h sever e morbid obesit y (BMI = 51 kg/ m2) of more t han 12 years' dur at ion
and r ef r act or y t o convent ional obesit y t r eat ment was ent er ed int o a bar i at r i c sur ger y
pr ogr am. The pat i ent under went a Roux- en Y- pr ocedur e wi t hout any maj or post -
oper at ive complicat ions.
18. The pat i ent was re-admitt ed t o t he hospi t al t hree mont hs af t er di scharge
wi t h i nt ol erance to sol i d and l i qui d f oods and per si st ent hyperemesi s. She al so
present ed wit h general i zed parat hesi a, ataxi s and mental conf usi on. Whi ch of
t he f ol l owi ng nut ri ent s i s most l i kel y def i ci ent i n t hi s pat i ent ?
( A) Seleni um
(B) Vi t amin D
(C) Cal ci um
(D) Thiami ne
(E) Vi t amin E
View Answer 18. The answer i s D[ see] . 19. Thi s pat i ent shoul d be placed
on whi ch of the f ol l owi ng nut ri ent suppl ement at i ons t o prevent pot ent ial
cardi omyopat hy.
( A) Folat e ( 1 mg/ day)
(B) Vi t amin B12 ( 350-1000 mcg/ day)
(C) Seleni um ( 40- 80 mcg)
(D) Vit amin A ( 10, 000 IU/ day)
(E) Vi t amin K ( 300 mcg/ day)
View Answer 19. The answer i s C[ see] . P. 1292


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see I . B. 3] .
A hypermet aboli c st at e ( e. g. , t r auma, inf ect ion) combined wi t h pr ot ein depr i vat ion
can r api dl y devel op i nt o a sever e kwashi or kor malnut r i t ion char act er ized by
hypoal bumi nemia, edema, and impair ed cel l ul ar i mmune f unct ion.
2. The answer i s C [ see V. D. 1] .
Even i n t he pr esence of appr opr iat e amount s of NPCs admi ni st er ed as
car bohydr at e, t he normal car bon di oxide load gener at ed by glycol ysi s may be
excessive f or t he pat ient wit h under l yi ng pulmonar y dysf unct i on. PN l ipi d syst em
f ormulat i ons, i n whi ch t he l i pid component const i t ut es 40%- 50% of t he t ot al NPCs,
may be benef icial i n r educi ng t he vent i lat or y demands i n r espir at or y f ai l ur e pat ient s
because l ipol ysis gener at es less carbon dioxide t han gl ycol ysis.
3. The answer i s B [ see I I I . A. 6. b. ( 2)( b) . ( i i i) ] .
A par t icle f i l t er ( i . e. , 1. 2 µ) should be used wi t h TNA administ r at ion.
4. The answer i s C [ see I I . B. 1] .
Ener gy r equir ement s ar e det ermined as nonpr ot ei n calor i es by indi r ect cal or imet r y,
est imat ed ener gy expendit ur e, and t he simple nomogr am met hod. The nomogr am
met hod is t he least accur at e met hod of est imat i ng cal or i c r equir ement s.
5. The answer i s D [ see I I I . A. 6. b. ( 1)] .
The l i pid syst em PN is a f or mulat ion i n which l ipi d i s administ er ed dail y t o pr ovide a
subst ant ial por t i on of t he NPCs.
6. The answer i s C [ see V. G. 1] .
PN f ormulat ions enr iched in br anched- chai n ami no acids have been made avai l able
wit h t he r at ional e t hat , being t he pr ef er red f uel sour ce in t his pat ient popul at i on, it
would enhance pr ot ein synt hesis, decr ease pr ot ei n cat aboli sm, and impr ove t he
pat ient ' s cl i nical out come. However, t hese mor e expensi ve br anched- chai n ami no
acid f ormulat ions have not been shown t o f avor abl y inf l uence cl i ni cal out comes i n
cr it ical l y i l l pat i ent s.
7. The answer i s D [ see V. B. 3] .
St andar d glucose syst em f ormulat ions ( 4. 25% amino aci d/ 25% dext r ose) can
gener al l y be used in r enal f ai l ur e pat i ent s who are being dial yzed on a r egular
basis. Thi s f ormul at i on is part icul ar l y usef ul i n sever el y malnour ished pat ient s
because i t can pr ovi de adequat e pr ot ei n t o at t ai n posit i ve nit r ogen balance, whi ch is
not possible wit h r enal f ai l ur e PN.
8. The answer i s D [ see I I . B. 2. a. ( 4) ] .
A posit ive nit rogen balance of 3- 6 g is t he goal.
9. The answer i s C [ see V. C. 2] .
Adequat e NPCs wit h a 20- 40 g/ day pr ot ein load ( e. g. , 2% amino aci d/ 25% dext r ose)
is an al t er nat i ve appr oach t o t he use of hepat ic f ai l ur e ami no acid f or mulat ions.
10. The answer i s B [ see I I . B. 1. c] .
Use t he nomogr am of 30 kcal / kg t o det ermi ne t he NPCs/ day, and divide t hat by t he
NPCs/ mL of t he ent eral f ormula t o det ermi ne t he vol ume of f ormul a per day, which
is di vided by 24 hr t o yi el d t he hour l y goal r at e.
11. The answer i s D [ see V. A. 5] .
Omega- 3 polyunsat ur at ed f at t y acids ar e der ived f r om f ish oi ls and ar e cur r ent ly
f ound i n some ent eral f ormulat ions. These f at t y acids have been shown
exper iment al l y t o enhance i mmune r esponse.
12. The answer i s A [ see I I I . A. 3. b] .
Wit h t he use of new cat het er t echnol ogy and new t echniques f or inf usion, it i s now
f easi ble t o admini st er per ipher al PN i n select ed pat i ent s f or shor t - t erm t her apy ( 7-
10 days) wi t h a low i nci dence of per i pher al vei n t hr ombophl ebit is. This met hod of
PN administ r at i on avoids t he pot ent ial of mor e ser ious compl icat i ons associ at ed
wit h cent r al venous r out e admini st r at ion.
P. 1293


13. The answer i s A [ see V. H] .
The est imat ed basal ener gy expendit ur e i s calcul at ed usi ng t he pr egravid wei ght i n
t he Harr i s- Benedict equat ion. An addit ional 300 kcal/ day i s added t o t he basal
ener gy expendit ur e t o pr ovide t he r equir ed cal or i es per day dur ing pr egnancy.
14. The answer i s A [ see V. H. 3] .
An addit i onal 65 µg of vi t amin K needs t o be added t o t he dail y PN f ormulat ion when
MVI - 12 is used as t he par ent er al vi t amin pr epar at ion t o meet t he dai l y r equi r ement s
dur i ng pregnancy.
15. The answer i s C [ see V. G. 3] .
Recent dat a invol vi ng cr it i cal l y i l l , mechanical l y vent i l at ed pat ient s in t he sur gical
i nt ensi ve car e uni t i ndi cat e i nt ensi ve i nsul i n t her apy t o mai nt ai n blood gl ucose
level s bet ween 80 and 110 mg/ dL.
16. The answer i s B [ see I I . B. 5. g] .
Suggest ed I V r equir ement s of chr omium f or def ici ency and sever e gl ucose
i nt oler ance are 150-200 µg/ day.
17. The answer i s E [ see V. G. 3] .
The gr eat est r educt i on i n mort ali t y i n pat i ent s maint ai ned on t ight i nsul i n cont r ol
was associat ed deat hs owi ng t o mult ipl e or gan f ail ur e wit h a pr oven sept i c f ocus.
18. The answer i s D [ see V. K. 4] .
Thi amine def iciency i s not common af t er bar iat r ic sur ger y but i s seen in pat ient s
wit h post - oper at ive hyper emesis syndr omes.
19. The answer i s C [ see V. K. 6] .
Sel eni um def ici ency and a l if e t hr eat ening car diomyopat hy have been r eport ed i n
pat ient s af t er malabsor pt ive sur ger y. Suppl ement at ion of seleni um at 40- 80 mcg/ day
is r ecommended in pat ient s under goi ng malabsorpt ive sur ger y.

60
Immunosuppressive Agents in Organ
Transplantation
Davi d I . Mi n
I. ORGAN TRANSPLANTATION
A. Def i ni t i on: Repl acement of a diseased vit al or gan wit h a viabl e or gan f r om a
l i vi ng or cadaver donor . Sol id or gan t r ansplant at ion has become t he t herapy of
choice f or many pat i ent s wit h end- or gan f ail ur e ( i. e. , heart , l i ver , lung, and ki dney
disease) . However, it gener al l y r equir es immunosuppr ession t o overcome t he
immunologi cal bar r i er bet ween donor and r ecipient , except in syngenic ( i. e. , t wins)
or aut ologous t r anspl ant at i on.
B. Classi f i cat i on
1. Sol i d organ t ranspl antat i on
a. Lif e- savi ng t ranspl ant at i on ( e. g. , hear t , hear t -l ung, l ung, and l iver
t r ansplant at ion) . Ther e is no al t er nat i ve l i f e- sust ai ni ng met hod avai labl e
b. Non- l if e- savi ng t ranspl ant at i on ( i. e. , kidney, pancr eas, and cor nea
t r ansplant at ion) . Ther e ar e al t er nat i ve l i f e- sust ai ni ng met hods avai l able, such as
dial ysi s or ext er nal i nsul i n i nj ect ion. I n t hese cases, t r ansplant at ion wi l l impr ove t he
pat ient ' s qual it y of l i f e or long- t erm sur vi val signif i cant l y.
2. Hemat opoi et i c st em cel l ( bone mar row) transpl ant at i on is used mainl y f or
hemat ological mal i gnancy or aplast i c anemia.
II. GRAFT REJECTION
A. Transpl ant immunol ogy (see Chapt er 8)
1. Graf t rej ect i on. The body' s i mmune syst em r ecogni zes t he al logr af t ( t r anspl ant ed
or gan) as a f or eign ant i gen, and it i ni t iat es t he i mmune r esponse t o r emove or
dest r oy t he t r anspl ant ed gr af t . Thi s r eact ion is cal led “ r ej ect i on. ” The degr ee of t he
r eact i on depends on t he genet i c simil ar it i es or di f f erences bet ween t he or gan of t he
donor and t he immune syst em of t he r eci pient .
2. Hi st ocompat i bi l i t y. The ant igen det ermini ng t he compat ibi l it y bet ween t he donor
and t he recipi ent is cal l ed a hi st ocompat i bi l i t y ant i gen, t he gene bei ng locat ed on
chr omosome 6. I n many t r ansplant s ( e. g. , bone mar r ow or ki dney t r anspl ant ) , t his
hist ocompat ibi l it y mat chi ng i s an impor t ant f act or f or det ermini ng t he long- t erm
sur vi val of t he gr af t . However , mor e select i ve, pot ent i mmunosuppr ession may
al l eviat e t he impor t ance of t issue mat chi ng bet ween donor and r ecipient ( except i on:
i n hemat opoi et i c st em cell t r ansplant at ion, t he t issue mat chi ng is st i l l import ant ).
3. Ot her f act ors. Anot her gr oup of subst ances t hat al so pl ays an import ant r ole is
t he ABO bl ood group syst em of r ed blood cel l s. The donor and r ecipient must be
ABO- compat i ble; ot her wise, immediat e gr af t dest ruct ion occurs. Some pat ient s may
have pr ef ormed ant ibody f or unspeci f ied donor s because of mul t ipl e blood
t r ansf usions or ot her r eason. I n t his case, pat i ent s may dest r oy t he t r anspl ant ed
or gan immediat el y. To det ect t he pr ef ormed ant ibody, t he r eci pient ' s ser um wi l l be
t est ed immediat ely bef or e t he t r ansplant at ion ( cr oss-mat ch) .
B. Types of graf t rej ect i on
1. Types of graf t rej ect i on accordi ng t o t he t ime course
a. Hyperacut e rej ect i on. Immedi at e dest r uct i on ( wit hi n mi nut es or hour s) of t he
t r ansplant or gan by a pr ef ormed ant i body or compl ement syst em. Today, t hi s i s
ext r emely r ar e. I t occur s onl y i n an ABO-mismat ched or gan or a cr oss-mat ch
posit i ve ( pr ef ormed ant ibody) or gan. Ther e is no adequat e t r eat ment avai l able.
P. 1295


b. Acut e rej ect i on occur s wit hin a f ew days t o sever al mont hs af t er t ransplant at ion.
I t is mediat ed mai nl y by T- lymphocyt e ( acut e cell ular r ej ect ion) , but occasional l y, it
is medi at ed by ant ibody ( ant ibody medi at ed r ej ect i on) and t his r ej ect i on can be
r ever sible by st er oids or ant ibody t her apy such as mur omonab/ CD3 or ant it hymocyt e
globul i n ( acut e cel l ular r ej ect ion) or int r avenous i mmunoglobul i n ( I VI G) (ant ibody
medi at ed r ej ect ion) .
c. Chroni c rej ect i on occur s several mont hs t o sever al year s af t er t r ansplant at ion.
The exact mechani sm of t his r eact i on is unknown, but it i s t hought t o be mediat ed
by B- lymphocyt e ( ant ibody) , and t her e is no adequat e t r eat ment avai l able.
2. Graf t versus host , host versus graf t. I n most soli d or gan t ransplant s, r ej ect i on
occur s as t he host immune syst em rej ect s or at t acks t he t ransplant or gan ( host
ver sus gr af t ). However , in hemat opoiet ic st em cel l ( bone mar row) t r ansplant , t he
host i s gener al l y i mmune def i cient and t he t r ansplant ed gr af t is immune compet ent ,
whi ch at t r act s host t issues ( gr af t ver sus host ) .
III. PROPHYLAXIS AND TREATMENT OF GRAFT
REJECTION (Table 60-1)
A. Cal ci neuri n i nhi bi t ors
1. Cycl ospori ne (Neoral
®
, Sandi mmune
®
, Gengraf
®
, ot hers)
a. Mechani sm of act i on. Cycl ospor i ne bi nds an i nt r acel lular r ecept or , cycl ophi l i ne.
Thi s complex i nhibit s calci neur i n, an i nt r acel l ul ar phosphat ase, which i nvol ves
act ivat i on of t he promot er r egion f or t he gene- encodi ng cyt oki ne, such as
i nt er leukin- 2. Thi s r esult s i n i nhi bi t i ng T-cel l act i vat ion i n t he ear ly st age of immune
r esponse t o a f oreign ant igen such as a graf t .
b. Dosi ng and moni t ori ng. Cycl ospor ine pharmacokinet i cs is unpr edict able, and
many f act or s such as age, t ime af t er t r ansplant , di f f er ent or al f ormul at ion ( Neor al
®

or Sandimmune
®
), or dr ugs af f ect it . Or al bioavai l abi l i t y is about 30%. Gener all y, 8
mg/ kg/ day of or al cycl ospor ine as t wo divided doses is used in sol i d or gan
t r ansplant at ion and adj ust ed accor di ng t o t he blood l evel s. Ser um cr eat ini ne should
be monit or ed wit h t he blood levels of cycl ospor ine. The bl ood l evel s ar e usef ul i n
t he cl inical moni t or i ng.
c. Si de ef f ect s. Nephrot oxi ci ty is t he maj or si de ef f ect . Neur ot oxicit y and
hepat ot oxi ci t y ar e al so common. Hir sut ism and gingi val hyper plasia ar e also
cumbersome side ef f ect s. Numer ous dr ug int er act ions have been r epor t ed ( Tabl e
60- 2) .
2. Tacrol imus ( Prograf
®
)
a. Mechani sm of act i on. I t i s ver y simi l ar t o cyclospor i ne ( I I I . A. 1. a).
b. Dosi ng and moni t ori ng. Tacrol i mus pharmacoki net ics is also var iable, and or al
bioavai l abi l it y is about 25%. Bl ood l evel s ar e usef ul i n cl i nical moni t or i ng.
c. Si de ef f ect s. Nephrot oxi ci ty is t he maj or si de ef f ect . Neur ot oxicit y and
post t ransplant diabet es ar e mor e common t han wi t h cyclospor i ne.
B. Ant i metabol i t es
1. Azat hi opri ne ( Imuran
®
)
a. Mechani sm of act i on. I t i s conver t ed t o 6-mercapt opur i ne i n t he body and is a
nonspeci f ic pur i ne synt hesis i nhi bit or . I t i nt er f er es wit h DNA and RNA synt hesis so
t hat it may r educe bot h cel l - mediat ed and humor al immune responses.
b. Dosage and moni t ori ng. An i nit i al dose of 3- 5 mg/ kg/ day i s admi ni st er ed
pr eoper at ivel y. I mmedi at ely af t er t r anspl ant at ion, t he dose is usual l y t aper ed t o a
maint enance dose of 1- 3 mg/ kg/ day or t it r at ed t o t he pat i ent ' s whi t e blood cel l
(WBC) count . The WBC count i s gener al l y maint ai ned gr eat er t han 3000/ mm
3
.
c. Si de ef f ect s. Bone marrow suppressi on ( l eukopeni a, t hr ombocyt openia) is t he
maj or si de ef f ect . I n addit ion, xant hi ne oxi dase i nhi bit or al lopur i nol i nhibi t s
azat hiopr i ne met abol ism. When t hese dr ugs ar e used concur r ent ly, t he azat hi opr ine
dose should be reduced by 80%. Ot her wise, t he pat i ent may develop sever e
leukopeni a due t o azat hi opr i ne over dose.
2. Mycophenol i c aci d (Cel l Cept
®
, Myf ort i c
®
)
a. Mechani sm of act i on. Two f orms are avai l able. Mycophenolat e mof et i l
(Cel l cept
®
) i s a prodr ug, whi ch is conver t ed t o mycophenol ic acid i n t he body, which
is t he act ive f orm. Myf ort ic
®
is an ent er i c f ormul at i on of mycophenol ic aci d. I n t he
body, mycophenol i c acid i nhibit s de novo pur i ne synt hesi s pat hway by inhibit i ng
i nosi ne dehydr ogenase. As a r esult , it inhi bi t s DNA and RNA synt hesis i n t he
immune cel ls such as l ymphocyt es.
P. 1296


Table 60-1. Current Immunosuppressive Agents Used in Organ Transplantation
Classification Drug Usual Initial
Dose
Major Side
Effects
Monitoring
Calcineur
in
inhibitors
8
mg/kg/day
Nephrotoxi
city

Cyclosporine(
Neoral
®
,
Sandimmune
®
)

Neurotoxic
ity

Tacrolimus
(Prograft
®
)
0.1-0.3
mg/kg/day

Blood
concentr
ations
and
serum
creatinin
e
concentr
ations
Antimeta
bolites
Azathioprine
(Imuran
®
)
1.5-3
mg/kg/day
Bone
marrow
suppressio
n
WBC
count

Mycophenolat
e mofetil
(Cellcept
®
)
1 g twice
daily
Same as
above
Same as
above

Mycophenolic
acid sodium
(Myfortic
®
)
720 mg
twice daily


Methotrexate
(Rheumatrex
®
)
15 mg/m
2

on day 1,
10
mg/m
2
/day
on days 3,
6, and 11
Same as
above
Same as
above
mTOR
inhibitor
Sirolimus
(Rapamune
®
)
6-15 mg
loading
dose and
2-5 mg
once daily
Hyperlipid
emia,
leukopenia
and
thrombocyt
openia
Blood
concentr
ations
and
WBC,
platelet,
and lipid
profile
Alkylatin
g agent
Cyclophospha
mide
(Cytoxan
®
)
3-4
mg/kg/day
for 4 days,
followed
by
reduction
to 1
mg/kg/day
for
treatment
of
rejection
Hemorrhag
ic cystitis
WBC
count
Antibody
products
Muromonab/C
D3
(Orthoclone
OKT3
®
)
5 mg daily
for 7-14
days
Cytokine
release
syndromes
(flu-like
syndrome)
Signs
and
symptom
s, CD3 +
cell
count

Antithymocyt
e globulin
(Atgam
®
,
Thymoglobuli
n
®
)
15-20
mg/kg/day
for 7-14
days
(Atgam)
or 1.5
mg/kg/day
for 7-14
days
(Thymogl
obulin)
Leukopeni
a and
thrombocyt
openia
T-cell
count

Daclizumab
(Zenapax
®
)
1 mg/kg
(max. 100
mg), on
day 0, and
every 2
weeks for
a total of 5
doses
No
significant
side effects
reported
No
special
monitori
ng
required

Basiliximab
(Simulect
®
)
For adults,
2 doses of
20 mg
each (day
0 and day
4)
No
significant
side effects
reported
No
special
monitori
ng
required
Corticoste
roids
Prednisone
(Deltasone
®
)
or
methylprednis
olone
(Solumedrol
®
)
500 mg IV
on the day
of surgery
and
rapidly
tapering to
10 mg
daily at 1
Fluid
retention,
psychosis,
cataracts,
osteonecro
sis
Signs
and
symptom
s
month

P. 1297


Table 60-2. Major Drug Interactions of Cyclosporine and Tacrolimus with Other
Drugs and Their Management
Drugs Mechanism Effects Management
Antiepileptic drugs
Phenytoin
Phenobarbital

Carbamazepine
Increased
metabolism
by inducing
cytochrome
P450
enzyme
Cyclosporine
or tacrolimus
trough levels
drop within 48
hr after
initiation of
these drugs
Increase
cyclosporine
dose or
tacrolimus
with frequent
monitoring of
blood levels.
Valproic acid
does not
interfere
cyclosporin
or tacrolimus
levels
Rifampin or rifabutin Same as
above
Same as above
Nevirapine,
efavirenz
Increase
cyclosporine
dose or
tacrolimus
with frequent
monitoring of
blood levels.
St. John's Wort Same as
above
Same as above Avoid St.
John's wort
Azole antifungal agents
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Inhibition
of liver
cytochrome
P450
enzyme by
these drugs
Significant
increase of
cyclosporine or
tacrolimus
levels
Reduce
cyclosporine
or tacrolimus
dose with
frequent
monitoring of
levels
Macrolide antibiotics Same as
above.
Erythromycin

Clarithromycin
Inhibition
of liver and
GI
cytochrome
P450
enzyme
Increase AUC
(×2) and
cyclosporine or
tacrolimus
trough levels
(×2-3)

Calcium-channel
blockers
Same as
above
Same as above
Verapamil

Diltiazem
Reduce
cyclosporine
or tacrolimus
dose, or use
nifedipine or
isradipine
Nicardipine

Antiviral agents Same as
above
Same as above
Indinavir

Reduce
cyclosporine
or tacrolimus
dose
Ritonavir
Saquinavir

Grapefruit juice Inhibition
of GI
cytochrome
P450
enzyme
Increase AUC
and peak
concentrations
of cyclosporine
and possibly
tacrolimus, and
increase
variability of
blood levels
Avoid
grapefruit
juice

b. Dosi ng and moni t ori ng. A dose of 2 g/ day (Cel l cept
®
) or 1440 mg/ day
( Myf ort ic
®
) i s admi ni st er ed as t wo divided doses. The WBC and GI sympt oms shoul d
be monit or ed.
c. Si de ef f ect s. Bone marrow suppressi on ( l eukopeni a, t hr ombocyt openia) is t he
maj or si de ef f ect , as i n azat hiopr ine. I n addit i on, GI side ef f ect s are mor e common
t han wi t h azat hiopr i ne.
3. Met hot rexate. This agent is used mainl y i n aut oimmune di sease and prevent i ng
gr af t ver sus host di sease in hemat opoiet ic st em cel l t r ansplant pat ient s.
a. Mechani sm of act i on. I t pr event s di hydr of ol ic acid f r om conver t i ng t o
t et r ahydrof olic acid by i nhibi t i ng t he enzyme di hydr of olat e reduct ase. As a result ,
DNA and pr ot ei n synt hesis ar e i nhibi t ed.
P. 1298


b. Dosi ng and moni t ori ng. Dosage regimens in BMT pat ient s usual l y consist of 15
mg/ m2/ day on day 1 af t er t r ansplant and 10 mg/ m2/ day on days 3, 6, and 11 wi t h
ot her agent s such as cyclospor i ne.
c. Si de ef f ect s. Bone marrow suppressi on ( l eukopeni a, t hr ombocyt openia) is t he
maj or si de ef f ect as i n azat hiopr i ne. I n addit i on, di ar r hea and mucosit is ar e
common.
C. mTOR (mammarian Target of Rapamyci n) i nhi bi t or i s t he alkylat i ng agent
mainl y used f or BMT pat ient s. Rar ely i s i t used as a subst i t ut e agent f or
azat hiopr i ne i n sol i d or gan t r anspl ant at i on.
1. Si rol imus ( Rapamune
®
)
a. Mechani sm of act i on. Sir ol i mus binds int r acel l ular r ecept or, FKBP- 12 ( FK
bi ndi ng pr ot ei n- 12) . Thi s complex inhibit s t he mTOR, whi ch is a key regul at or y
kinase. This r esul t s i n i nhibit i ng T- cel l act ivat i on i n a l at er st age of immune
r esponse t o f or ei gn ant igen such as a gr af t .
b. Dosi ng and moni t ori ng. A dose of 2- 10 mg/ day i s admi nist er ed as a once-dai l y
dose. Usual l y, a loadi ng dose of 6- 15 mg wit h a mai nt enance dose of 2- 5 mg once
dai l y is used. Blood l evel s ar e usef ul i n cl i nical monit or i ng. The ser um l ipi d pr of i le,
WBC count , and GI sympt oms shoul d be moni t or ed.
c. Si de ef f ect s. Hyperl i pi demia is t he maj or side ef f ect . I n addit ion, l eukopenia,
t hr ombocyt openia, and GI side ef f ect s are common.
D. Al kylat i ng agent . Cycl ophosphami de is t he al kylat i ng agent mai nl y used f or
hemat opoiet ic st em cel l t r ansplant pat ient s. Rar el y, i t is used as a subst it ut e agent
f or azat hiopr i ne i n sol i d or gan t r ansplant at ion.
1. Mechani sm of act i on. I t i s conver t ed t o t he act ive met abol it e phosphor amide
must ar d in t he l i ver , which i nhibi t s t he cr oss- li nki ng of DNA, leadi ng t o cel l deat h.
2. Dosi ng and moni tori ng. Doses of cycl ophosphamide up t o 3- 4 mg/ kg/ day f or 4
days f ollowed by a reduct ion t o 1 mg/ kg/ day t o t r eat gr af t r ej ect i on. The dosage
should be t it r at ed t o mai nt ai n a WBC count great er t han 4000/ mm
3
.
3. Si de ef f ect s. Hemorrhagi c cyst i t i s and bone marrow suppressi on (l eukopeni a,
t hr ombocyt openia) . I n addi t ion, nausea, vomit i ng, and diar r hea ar e common.
E. Ant i body products
1. Muromonab CD3 (Ort hocl one OKT3
®
) is t he f i r st t her apeut ic mouse monocl onal
ant ibody pr oduced f or use in humans.
a. Mechani sm of act i on. OKT3 is a mouse Ì gG2q immunoglobul i n t hat binds t o t he
CD3 st r uct ur e on T- l ymphocyt es. Once OKT3 i s bound t o t he CD3 r egi on of T cel l s,
t hey l ose t he ant igen r ecognit ion f unct i on and cannot i ni t iat e t he rej ect i on pr ocess.
b. Dosi ng and moni t ori ng. The dosage is 5 mg/ day i nt r avenously f or 7- 14 days f or
pr event i on or t r eat ment of r ej ect ion. The CD3 + l ymphocyt e count s ar e monit or ed,
and i t is desi r able t hat CD + cel l be mai nt ai ned at less t han 30/ mm
3
. Gener al l y,
pr emedi cat ions such as acet aminophen, diphenhydr ami ne and cor t i cost er oid ar e
r equir ed t o reduce t he i nf usi on r el at ed side ef f ect s ( i . e. , f ever , chi l ls) .
c. Si de ef f ect s. Wit h t he f i r st f ew doses, t he pat ient wi l l develop sever e f l u- l i ke
sympt oms such as f ever , chi l ls, nausea, vomit i ng, and headache. The OKT3
st i mulat es T cel ls, and t hese sympt oms ar e caused by abr upt r elease of cyt okines
such as i nt er leuki n- 1, t umor - necrosis f act or- a, and i nt er leuki n- 6 f r om opsonized T
cel ls ( cyt oki ne r el ease syndr ome). It r equir es premedicat ions such as
acet aminophen, diphenhydr amine, and cort icost eroids t o r educe t hese side ef f ect s
bef or e OKT3 inj ect i on.
2. Ant i t hymocyte gl obul i n ( Thymogl obul i n
®
, Atgam
®
)
a. Mechani sm of act i on. I t i s a pur if i ed pol ycl onal immunoglobul i n f r om rabbit s
( Thymoglobul i n
®
) or horses ( At gam
®
), which bi nds t o t he human T cell s. However, i t
may have cr oss- r eact i vit y agai nst t he r ed bl ood cel ls, plat elet s, and gr anul ocyt es.
b. Dosi ng and moni t ori ng. The dosage is 1. 5 mg/ kg ( Thymogl obul i n
®
) or 15- 20
mg/ kg ( At gam
®
) i nf usion dai l y t hr ough a cent r al l i ne f or 7-14 days f or pr event ion or
t r eat ment of r ej ect ion. The T- l ymphocyt e count s ar e monit or ed and maint ai ned l ess
t han 100/ mm
3
. Gener all y, pr emedi cat ions such as acet aminophen, diphenhydr ami ne
and cort i cost er oid ar e r equi r ed t o reduce t he inf usion r elat ed si de ef f ect s ( i. e. ,
f ever , chi l l s) . For t he inf usion of t hese dr ugs, t he cent r al venous l i ne i s a pr ef er r ed
r out e r at her t han per ipher al vei n.
P. 1299


c. Si de ef f ect s. Ant it hymocyt e globul i n may cause f ever , chi l l s, er yt hema,
leukopeni a, t hr ombocyt openia, and anaphyl act ic react i on or ser um sickness.
3. Dacl i zumab ( Zenapax
®
)
a. Mechani sm of act i on. I t i s a mol ecul ar l y engi neer ed humanized immunoglobul i n
act ive agai nst int er leukin- 2 r ecept or (CD25, or Tac) t hat bi nds t o block t he
i nt er leukin- 2 r ecept or on t he surf ace of act ivat ed T- lymphocyt es, t hus pr event i ng T-
cel l act ivat ion and pr ol if erat ion.
b. Dosi ng and moni t ori ng. I t i s i ndicat ed onl y f or t he pr event i on of acut e r ej ect ion.
The usual r ecommended dosage is 1 mg/ kg (max. 100 mg) wi t hi n 24 hour s
post t ransplant at ion and ever y 2 weeks up t o 8 weeks ( a t ot al of 5 doses) .
c. Si de ef f ect s. Based on r esul t s of cli nical t r ials, no speci f ic saf et y monit or i ng is
r equir ed wit h dacl i zumab.
4. Basi l i xi mab (Simul ect
®
)
a. Mechani sm of act i on. I t i s a chimer ic (mur ine/ human) monoclonal ant ibody
( I gG1), pr oduced by r ecombinant DNA t echnology, t hat binds t o bl ock t he
i nt er leukin- 2 r ecept or on t he surf ace of act ivat ed T lymphocyt es, and as a r esult , i t
pr event s T-l ymphocyt e act ivat ion, t hus pr event ing acut e r ej ect ions.
b. Dosi ng and moni t ori ng. I t i s i ndicat ed onl y f or t he pr event i on of acut e r ej ect ion.
The usual r ecommended dosage f or t he adult pat i ent is 2 doses of 20 mg each at
day 0 and day 4 af t er kidney t r ansplant at ion. No special monit or i ng i s r equir ed.
c. Si de ef f ect s. Based on r esul t s of cli nical t r ials, no cyt okine r elease syndr omes
have been not i ced.
5. Ot her ant i body agent s
Alemt uzumab (Campat h- 1H
®
) or r et uxi mab (Rit uxan
®
) ar e i ndicat ed f or hemat ol ogic
mal iganancy and not appr oved f or t he organ t r ansplant at ion, but are occasional l y
used i n t he organ t r ansplant at ion f or pr event ion of acut e r ej ect i on or i nt r act able
ant ibody mediat ed rej ect i on.
F. Cort i cost eroi ds. Predni sone (Del t asone
®
) and met hyl predni sol one
(Sol umedrol
®
) ar e t he maj or cort icost er oid product s used f or t r ansplant pat i ent s.
1. Mechani sms of act i on. Cor t icost er oi ds have mult iple pharmacological ef f ect s in
var ious cel ls. Cort icost er oi ds bi nd wit h int r acel l ul ar gl ucocort i coid r ecept or s, which
r esul t s i n alt er i ng DNA and RNA t r anslat ion. As a r esult , cor t icost eroids cause a
r apid and prof ound drop in cir cul at i ng T l ymphocyt es. They have pot ent ant i -
i nf l ammat or y ef f ect s by inhi bit i ng ar achidonic aci d release and macr ophage
phagocyt osis.
2. Dosi ng and moni tori ng. They ar e used in bot h prevent i ng and t r eat ing graf t
r ej ect ion and acut e graf t versus host disease. I n gener al, pr ophylact ic doses in
sol id or gan t r anspl ant at i on ar e i n t he r ange of 1- 2 mg/ kg/ day and t aper ed over
mont hs t o 0. 1- 0. 3 mg/ kg/ day. I n t he case of t r eat ment , t he dosage i s 500 mg of
met hyl pr ednisolone I V f or 3- 5 days or 1- 2 mg/ kg/ day of oral pr ednisone, which
should be t aper ed r apidl y.
3. Si de ef f ect s. I n t he long- t erm, cort icost er oi ds cause more t roubl i ng side ef f ect s.
They i nclude psychological dist ur bances ( i. e. , euphor ia, depressi on) , adr enal axis
suppr essi on, hyper t ension, sodi um and wat er r et ent ion, myopat hy, impai r ed wound
heal i ng, incr eased appet i t e, ost eopor osis, hyper glycemia, and cat ar act s.
IV. COMPLICATIONS OF IMMUNOSUPPRESSION
A. I nf ect i ons
1. Ri sk. Tr anspl ant pat i ent s have a high r i sk of acquir i ng an inf ect ion due t o pat ient
f act ors such as di abet es mell it us, hepat it is, or uremia. I n addit ion,
immunosuppr essive agent s can cause var i ous ef f ect s, such as l eukopeni a,
l ymphopeni a, or T- cel l dysf unct ion, whi ch inhibit adequat e i mmune r esponse t o t he
i nf ect ion.
2. Time course. The r i sk of inf ect ion i s gr eat est dur i ng t he f i r st 3 mont hs af t er
t r ansplant at ion, when higher doses of i mmunosuppr ession ar e used, and agai n af t er
a rej ect i on episode i s t r eat ed. This r isk cor r elat es wit h t he over al l level of
immunosuppr ession.
3. Types of i nf ect i ons i ncl ude bact er ial, f ungal, vir al, and pr ot ozoan.
P. 1300


4. Prevent i on
a. Trimet hoprim- sul f amet hoxazol e (Bact r im
®
and ot her s). One singl e- or double-
st rengt h t ablet dai ly f or 6 mont hs signif i cant l y r educes Pneumocyst i s cari ni i
pneumoni a and bact er i al ur inar y t r act inf ect ion. Af t er 6 mont hs, t hr ee t imes a week
is ef f ect ive.
b. Herpes and Cyt omegal ovi rus ( CMV) i nf ect i on. Or al acyclovir ( 200 mg bid f or
normal r enal r enal f unct i on, wit h doses adj ust ed accor idn t o r enal f unct ion) f or
her pes pr ophylaxi s. For CMV pr ophylaxi s, var ious prophyxis can be used. High
doses of acyclovir ( 800 mg qi d f or normal renal f unct ion, wi t h doses adj ust ed
accor di ng t o renal f unct i on) , oral ganciclovir ( 1 g t id f or normal r enal f unct i on, wit h
doses adj ust ed according t o renal f unct ion) , valganci cl ovir ( Valcyt e
®
) 900 mg dail y,
or high- t it er CMV immunoglobul i n ar e ef f ect ive i n r educi ng t he i ncidence of CMV
i nf ect ion and i nvasi ve CMV disease.
c. Nyst at i n sol ut i on, cl ot rimazol e troche or f l uconazol e r educes or al candidiasis
( t hr ush) .
B. I ncreased ri sk of mal i gnancy
1. Cause. Cont i nuous immunosuppr ession i nt er f er es wit h normal i mmune
sur vei l l ance and f unct ion f or mal i gnancy. I n addit i on, some of t he
immunosuppr essive dr ugs may be dir ect l y carcinogenic or act ivat e oncogenic vir us,
such as Epst ei n- Barr vir us (EBV).
2. Charact eri st i cs. Cancer s t hat occur most f r equent l y i n t he gener al populat ion
( e. g. , lung, br east , colon) ar e not incr eased among t r anspl ant pat ient s. However ,
var ious cancer s uncommon i n t he gener al populat ion ar e of t en mor e pr eval ent i n
t r ansplant pat i ent s: lymphomas, squamous cel l car cinomas of t he l ip and skin,
Kaposi' s sarcoma, ot her sar coma.
3. Post t ranspl ant l ymphoprol if erat i ve di seases (PTLDs). The i ncidence of
l ymphoma appear s t o cor rel at e wit h t he i nt ensit y of immunosuppressi on. I t i s
especi al l y wel l document ed t hat T- cel l specif i c agent s, i ncludi ng OKT3,
cycl ospor i ne, and t acr oli mus, incr ease t he inci dence of lymphopr ol if er at i ve
diseases.
4. Treatment . I n case of nonvit al or gan t r ansplant , i mmunosuppr ession shoul d be
r educed or st opped. I f EBV-r elat ed lymphoma occur s, acycl ovir or ganciclovi r
t her apy appears t o be ef f ect ive; t he B- cel l- specif i c monoclonal ant ibody, r it uxi mab
(Rit uxan
®
) , is also used.
C. Hypert ensi on. Many immunosuppr essi ve agent s cause hyper t ension.
Cyclospor i ne and t acr ol imus clear ly i ncr ease t he ar t er ial blood pr essur e and
st er oi ds may exacer bat e hyper t ension af t er t r ansplant at ion f r om f luid and sodi um
r et ent i on. Tr eat ment usual l y r equir es t he use of mul t iple agent s, incl udi ng di ur et ics
and cal ci um- channel blocker s.
D. Postt ranspl ant di abet es mel l i t us. Many immunosuppr essi ve agent s incr ease
blood gl ucose levels. Cort icost er oids, cycl ospor i ne and t acr ol imus i ncr ease blood
gl ucose. Some pat ient s devel op a new onset di abet es af t er t r ansplant at ion, which
i ncr eases mor bidit y, mor t ali t y and r educes gr af t and pat ient sur vivals. Car ef ul
moni t or i ng of blood gl ucose and pat i ent counsel l i ng ar e essent i al .
P. 1301


STUDY QUESTIONS
Di rect i ons: Each of t he number ed it ems or incomplet e st at ement s i n t his sect ion i s
f ol l owed by answer s or by compl et i on of t he st at ement . Select t he one l et t ered
answer or complet ion t hat is best in each case.
1. S. M. , a 38- year- ol d, recei ved her l i vi ng rel ated ki dney t ranspl ant 2 mont hs
ago. At her cl i ni c vi si t t oday, she compl ai ned of t i redness, short ness of breat h
and pedal edema. Her serum creat i ni ne and BUN showed t he f ol l owi ng: serum
creat i ne 2. 2 mg/ dL, BUN 43 mg/ dL (1. 2 mg/ dL and 24 mg/ dL 4 weeks ago) and
tacrol i mus l evel s 3 ng/ mL (t herapeut i c range 5-15 ng/ mL). She was diagnosed
as acut e graft rej ect i on. She was admit ted t o the hospi t al and was t reat ed by
t hymogl obul i n. Whi ch of t he f ol l owi ng regardi ng t hymogl obul i n i s ( are) true?
I . I t i s a horse serum agai nst human B cel l s.
I I . I t i s an I L- 2 recept or antagoni st agai nst human T- cel l s.
I I I . I t i s a rabbi t i mmunogl obul i n agai nst human T-cel l s.
( A) I onl y
(B) I I I onl y
(C) I and I I
(D) I I and I I I
(E) I , I I and I I I
View Answer 1. The answer i s B[ I I I E 2] . 2. Af t er 7- day course of
t hymogl obul i n t herapy, S. T' s renal f unct i on i mproved by t hymogl obul i n
t reatment . Her t hymogl obul i n was compl et ed and her bl ood tacrol imus l evel
was 8 ng/ mL. She was di scharged t o her home. Several days l at er, she
devel oped diabet i c coma and sei zures. Her sei zures were cont rol l ed by IV
di azepam and t he l ocal physi ci an want ed to start phenyt oi n 200 mg dai l y as a
mai nt enance t herapy. Whi ch i s (are) appropriate advi ce( s) upon t hi s
prescri pt i on?
( A) Phenyt oi n wi l l r educe t acr ol imus met abol ism, so pl ease r educe t he t acroli mus
dose by 100% and check cycl ospor ine level t wice a week.
(B) Phenyt oi n wi l l i ncr ease t acr ol i mus met abol ism, so pl ease swit ch t acr ol imus t o
cycl ospor i ne.
(C) Phenyt oi n wi l l i ncr ease t acr ol imus met aboli sm, so pl ease swit ch pheyt oi n t o
valpr oic acid.
(D) Phenyt oi n wi l l not af f ect t acr oli mus met abol i sm, so cont i nue same dose of
t acr ol imus.
(E) Phenyt oi n wi l l r educe t acr ol imus met abol ism, so pl ease monit or t acr oli mus level
mor e f r equent l y.
View Answer 2. The answer i s C[] . 3. Si x mont h l at er, her renal f unct i on
was good wi th creat i ni ne 1. 6 mg/ dL and BUN 28 mg/ dL. Today her BP was
160/ 105. Whi ch of t he f ol l owi ng medi cat i on ( s) cont ri but e( s) t o her
hypert ensi on?
I . Tacrol imus
I I . Predni sone
I I I . Mycophenol at e mof et i l
( A) I onl y
(B) I I I onl y
(C) I and I I
(D) I I and I I I
(E) I , I I and I I I
View Answer 3. The answer i s C[] . 4. The physi ci an asked you whet her an
i mmunosuppressant , dacl i zumab ( Zenapax
®
) i s usef ul i n t reat i ng t hi s pat i ent' s
acut e rej ect i on. Whi ch of t he f ol l owi ng i s an appropriat e response?
( A) I t i s a humanized I gG pr oduct agai nst I L- 2 r ecept or and it is usef ul onl y i n
pr event i ng acut e r ej ect i on.
(B) I t i s a usef ul agent t o t r eat r ej ect i on, but chest x-r ay and moni t or i ng of pat ient ' s
f lui d st at us ar e r equir ed bef or e t hi s t her apy.
(C) I t i s usef ul, but pat ient ' s weight gai n shoul d be l ess t han 3% f rom t he dr y weight
bef or e t her apy
(D) I t i s a chimer al I gG wit h specif i ci t y agai nst I L-2 recept or and it is usef ul onl y f or
pr event i on of r ej ect ion.
(E) I t i s a humanized hor se serum against T- cel ls and it i s a new agent usef ul f or
pr event i on and t reat ment of r ej ect ion.
View Answer 4. The answer i s D[] . 5. Al l of t he f ol l owi ng are correct
regardi ng i nf ect i on prophyl axi s i n an organ transpl ant pat i ent EXCEPT
( A) Tr i met hopr ime- sul f amet hoxazol e f or Pneumocyt i s car i ni i pneumoni a pr ophylaxi s
(B) Nyst at in f or f ungal i nf ect ion
(C) Or al acyclovir f or her pes simplex
(D) Clot r imazole t r oche f or or al t hr ush
(E) Levof l oxaci n f or ur inar y t r act inf ect ion
View Answer 5. The answer i s E[] . P. 1302


6. A 16- year- ol d gi rl who had recei ved her transpl ant 2 years ago complai ned of
hai r growt h on her f ace and di d not want t o take her medi cat i ons any more.
Whi ch of t he f ol l owi ng i s (are) l i kel y cause of her probl em?
( A) cyclospor i ne
(B) t acrol imus
(C) prednisone
(D) azat hiopr i ne
(E) mycophenol i c acid
View Answer 6. The answer i s A[] . P. 1303


ANSWERS AND EXPLANATIONS
1. The answer i s B [ I I I E 2] .
Thymoglobul i n is an ant i body f r om r abbit against t he human t hymocyt es. This dr ug
can be used as a r ej ect ion pr event ion agent or a t r eat ment agent f or on- going
r ej ect ion. The dose f or r ej ect ion t r eat ment is 1. 5 mg/ kg dail y f or 7- 10 days. At gam
is a hor se ant ibody agai nst t he human t hymocyt es. Dacl izumab ( Zenopax) or
basi l i ximab (Simulect ) is an monoclonal ant i body agai nst an I L-2 r ecept or.
2. The answer i s C [ Tabl e 58- 2] .
Phenyt oin is a pot ent cyt ochr ome P450 enzyme i nducer, whi ch incr eases t acr ol i mus
met abolism. When t acr ol i mus is used concur r ent l y wi t h phenyt oi n, it i s necessar y t o
i ncr ease t acr oli mus dose by 500% in or der t o maint ai n t he t her apeut ic levels, whi ch
is ver y cost l y. Val pr oic acid is anot her ant iepi l ept ic agent , which does not int eract
wit h t acr ol imus. So i t is a good alt er nat i ve f or phenyt oi n i n t hi s case.
3. The answer i s C [ I I I . A. 1, F] .
Tacr ol imus and pr ednisone i ncr ease t he blood pressur e. Tacr olimus (Pr ogr af
®
)
pr omot es t he vasoconst r i ct i on and causes r enal dysf unct ion, which cont r i but es t o
hyper t ensi on. Pr ednisone ( Delt asone
®
) incr eases f l ui d and sodi um r et ent ion, whi ch
cont r i but es t o hyper t ension. Mycophenolat e mof et i l ( Cel lcept
®
) is an ant i met abol it e
i nhibit i ng DNA synt hesis and cel l pr ol i f er at ion. I t s si de ef f ect s incl ude leukopenia
and t hr ombocyt openia and does not cause hyper t ension.
4. The answer i s D [ I I I . E. 4. c] .
Dacli zumab ( Zenapax
®
) is a humani zed monoclonal ant ibody t hat di r ect s t o t he
i nt er leukin- 2 ( I L- 2) r ecept or on t he T cel ls. The bi ndi ng sit e of t his ant i body ( 10%) is
or iginat ed f r om mouse, but t he ot her par t is humani zed I gG ( 90%) . I nt er l euki n- 2 is
T- cel l gr owt h f act or, which i nit i at es T- cell pr ol if er at ion. The basi l i ximab opsoni zes
t hi s I L- 2 recept or, whi ch pr event s T- cel l gr owt h and pr ol if er at i on, whi ch is essent ial
f or t he graf t r ej ect ion pr ocess. Unl i ke OKT3 or ant it hymocyt e gl obul i n, it does not
show any ser i ous side ef f ect s, so it does not requir e pr emedi cat ions such as
acet ominophen, diphenhydr amine, and cort icost eroids bef or e it s administ r at i on.
5. The answer i s E [ IV. A] .
Al l except f or l evof l oxaci n ar e corr ect . Levof loxaci n is a br oad spect r um oral
qui nolone ant ibiot ic, whi ch is not appropr iat e f or a long t er m pr ophyl act ic r egimen.
6. The answer i s A [ I I I . A. 1] .
Facial hai r gr owt h ( hir sut ism) is one of t he cumber some side ef f ect s of
cycl ospor i ne, which may di scour age t he pat ient ' s compli ance.

61
Outcomes Research and
Pharmacoeconomics
Pet er K. Wong
Al an H. Mut ni ck
I. GENERAL CONCEPTS
A. Out comes research (OR) i s t he st udy of healt hcar e i nt er vent ions
( t r eat ment modal it ies such as dr ug t her api es, sur ger y, and pal l i at i ve
t her apy) , car e del i ver y pr ocesses, and healt hcar e qual it y t hat ar e evaluat ed
t o measur e t he ext ent t o whi ch opt imal and desi r able out comes can be
r eached. Normal l y, t he pur pose of OR i s t o assess t he val ue of a pr ogr am
or t her apy in quest i on.
1. The Economi c, Cl i ni cal , Humani st i c Out come (ECHO) model pr ovides
a f r amework f or compr ehensi ve eval uat i on of out comes. Thr ee areas of
out comes ident if i ed by Kozma and Reeder ( 1998) ar e economic out comes,
cl i ni cal out comes, and humani st i c out comes.
2. Out comes research met hodol ogi es i ncl ude r et r ospect i ve char t r eview,
pr ospect ive cl i ni cal t r ials, obser vat ional st udies, and comput er model i ng
st udi es.
3. Exampl es of out comes measures
a. Economic out comes incl ude acquisit ion cost s associat ed wi t h car e, l abor
cost s associat ed wi t h car e, cost s t o t r eat adver se dr ug r eact i ons, cost s of
t r eat ment f ail ur e, cost s of hospit al readmissi on, and cost s of emer gency
r oom and cl i nic visi t s.
b. Cl i ni cal out comes incl ude lengt h of hospit al st ay, adver se dr ug react ions,
hospit al r eadmi ssion, and deat h.
c. Humanist ic out comes i nclude pat ient sat isf act i on, f unct ional st at us as
measur ed by a val idat ed inst r ument , and qual it y- of - l if e assessment .
B. Pharmacoeconomi cs (PE) , a di vi si on of healt h economics, i s designed
t o pr ovide decision maker s wit h i nf ormat ion about t he value of t he dif f erent
pharmacot her apies. Accordi ng t o Boot man, Townsend, McGhan ( 2006), PE
r esear ch ident if i es, measur es, and compar es t he cost s ( resour ces
consumed) and consequences ( cl inical, economic, and humanist ic) of
pharmaceut i cal pr oduct s and ser vices.
II. COST
A. Def i ni t i ons
1. Total cost . Al l expenses t hat ar e di r ect ly and i ndir ect l y necessar y t o
pr ovi de a pr oduct or ser vice
2. Average cost . The aver age cost per unit of out put (t ot al cost divided by
quant it y)
3. Fi xed cost . Cost s t hat do not var y wi t h t he quant it y of out put f or a short -
r un pr oduct i on ( e. g. , r ent , f i xt ur es, f i xed sal ar y, depr eciat ion, admi nist r at ive
cost s)
4. Variabl e cost . Cost s t hat var y wit h t he level of out put ( e. g. , wages,
suppl i es)
5. Margi nal cost . The ext r a cost of produci ng one ext ra unit of out put
6. I ncremental cost. Addit ional cost s when compar i ng one alt er nat i ve t o
anot her
7. Di rect cost. Cost s dir ect ly r elat ed t o producing/ pr ovidi ng a specif i c
quant it y of ser vi ces or out put ( e. g. , sal ar y, dr ug cost and supply cost f or
t he provisi on of pharmacy ser vices)
P. 1305


8. I ndi rect cost. Cost s t hat are al locat ed t o t he ar ea(s) t hat
pr oduce/ pr ovide a specif i c quant it y of ser vi ces or out put ( e. g. , over head
cost )
9. Al l owabl e cost . A cost t hat i s el i gible t o claim f or pur poses of
r eimbursement as necessar y and r elevant t o t he del i ver y of a unit of out put
10. Opport uni t y cost . The cost of t he benef it of pur sui ng an alt er nat i ve
cour se of act ion
11. Operat i ng cost . Any cost t hat support s t he oper at ions t o pr ovide t he
out put
B. Cost and charge
1. The meani ng of t he t erm cost depends on t he per spect i ve f or t he
analysis. The f oll owi ng examples show dif f er ing per spect ives.
2. Pr ovider s may incl ude hospit al s, physician of f ices, or ambul at or y sur ger y
cent er s, and t he t erm cost means t he t ot al cost s f or pr ovidi ng t he specif ic
ser vi ce( s).
3. Payor s may i nclude insur ance compani es, Medi car e, or Medicaid, and t he
t erm cost means t he pr i ce t hat t hey have t o pay t o obt ai n t he ser vice ( i. e. ,
char ges by provider s) .
4. Charges do not equal t he payment t o provider s. Dependi ng on t he
cont r act ual t erms, many pr ovider s r eceive onl y a per cent age of t he char ges
f or payment . These ar e cal led discount ed char ges. Many pr ovider s t oday
r eceive a l ump sum amount of dol lar s f or each episode of car e, e. g. ,
diagnosis- r el at ed gr oups (DRGs) or case rat e payment . This may al so appl y
t o bot h inpat ient and out pat ient t r eat ment s.
5. Cont r act ual t erms ar e r ar ely r eviewed and var y wit h di f f er ent insur ance
carr iers. Thi s cr eat es addit i onal conf usion as t o t he cost s associat ed f or
var ious ser vices or t her apies.
6. A r ecogni zabl e way t o r esolve t hese hur dles i s t o use t he cost t o char ge
(RCC) r at io f or t he cost est imat ion. Mult i pl y t he RCC by t he pat ient ' s
char ge t o yield t he est imat ed cost . RCC can be obt ai ned f r om t he i ndi vi dual
hospit al' s Cent er s f or Medi car e and Medicai d Services (CMS) year ly cost
r epor t .
C. Basi c st eps i n assessi ng cost
1. Def ine t he unit s of ser vice or out put
2. Det ermi ne t he number of ser vice or out put unit s pr ovi ded
3. Det ermi ne cost dr i ver s of t hese unit s of ser vice or out put
4. Calcul at e t ot al cost s, dir ect or i ndir ect , r elat ed t o t he provision of t his
out put or ser vi ce
5. Calcul at e t he aver age cost and i ncr ement al cost
III. ELEMENTS OF A GOOD STUDY
A. Sound obj ect i ve( s) . The st udy has wel l- def ined obj ect ive( s) and
answer able quest ion( s) .
B. Perspect i ve( s) . Ther e is a def i ned per spect ive f or anal ysi s ( e. g. ,
pat ient , payor, provider , societ y) . I n many cases, st udy per spect i ve
det ermines t he cost - ef f ect i veness of an i nt er vent i on. Most of t he publ i shed
PE gui del i nes suggest t hat societ al per spect ive be consider ed as an
addit i onal per spect ive f or anal ysis.
C. Pat i ent popul at i on chosen must be wi t hin t he scope of analysi s. Pat i ent
select i on cr i t er i a t hat are t oo st r ingent pose a t hreat t o ext er nal val idit y.
Pat i ent select ion cr it er ia t hat ar e t oo l iber al ar e a t hr eat t o int er nal val idit y.
Consi der at i on is al so gi ven t o comor bidit y and mul t ipl e t r eat ment
modali t ies.
D. Possi bl e comparat ors and t hei r ef f ect i veness. Al l r elevant alt er nat i ves
f or compar i son ar e ident if ied. Chosen comparat or( s) should be r easonabl e
and i s t he cur r ent pr ef err ed st andar d t r eat ment . I n some i nst ances no
t r eat ment ( pl acebo) is consider ed as an al t er nat i ve.
P. 1306


E. Met ri cs f or cost s and consequences. Measur es chosen f or cost s and
consequences can af f ect t he r esul t s of t he analysis. Biases can be
i nt r oduced int o t he analysis if uni t s of measur es ar e not clear ly def i ned.
Thi s may pose a pr oblem wit h a mult icount r y st udy i n t he aggr egat ion of t he
f inal cost s and consequences because curr ency exchange r at es may
f luct uat e f rom t ime t o t ime.
F. I ncl usi on of rel evant cost s and consequences i n t he anal ysi s ar e
based on t he perspect i ve chosen. The comput at ion of cost s and
consequences shoul d be t r anspar ent t o r eader s. The key is r epr oduci bi l it y.
Readers should be able t o use t he publ i shed comput at ion met hods wi t h t he
local dat a t o val idat e t he f i ndi ngs.
G. A val i d data source. Dependi ng on t he design of t he st udy, dat a can
come f r om cl i nical t r ial s, obser vat ional st udies, heal t hcar e cl ai m dat abases,
char t r eviews, and epidemi ologi cal dat a. Each of t he sour ces of t hese dat a
wer e desi gned f or some ot her pur pose t han economic anal ysis. Limit at ions
ar e l ist ed in VI I I .
H. Di scount i ng f or cost s and consequences. Much di scussion has been
devot ed t o t he appr opr iat eness of discount i ng cost s and consequences as
wel l as t he discount r at e. The consensus at t his t i me is t o di scount bot h
cost s and consequences. The discount r at e normal l y i s t he opport unit y cost
of usi ng r esour ces. Many r esear cher s have used t he gover nment bond r at e.
Regar dless, t he r esear cher must of f er t he j ust if i cat ion f or t he chosen
discount r at e(s).
I . I ncremental anal ysi s pr ovides an insight on t he compar ison f or cost
gener at ed f r om one al t er nat i ve t o anot her alt er nat i ve, and t he addi t ional
benef it yielded f r om t he incr eased cost .
J. Sensi t i vi t y anal ysi s should i ncl ude al l t he pl ausi ble val ues and t heir
j ust if i cat ion f or t he key par amet ers.
K. Time hori zon of t he anal ysi s cover s t he f ul l dur at ion of t r eat ment f or
t he di sease pr ocess. For exampl e, t he t ime hor i zon f or t he cholest er ol -
lower ing agent ' s t r eat ment shoul d be t he lif e span f r om t he st ar t day of
t r eat ment t o t he end of l if e.
L. Appropr iat eness and comprehensi veness of present at i on and
di scussi on of t he st udy resul t s. Simi lar t o t he cl i nical st udi es, t he
pr esent at ion of st udy r esul t s should not be biased. I nt er vent i onal
alt er nat i ves and st udy l imit at ions must be addr essed. Gener al i zabi l i t y and
appl i cabi l it y ar e also discussed.
IV. PHARMACOECONOMIC METHODOLOGIES
A. Cost of i l l ness ( COI ) is t he eval uat ion and assessment of t he r esour ces
used i n t r eat ing an i l l ness. This t echni que is used t o obt ain t he basel i ne
cost inf ormat ion bef ore t he int r oduct ion of a new int er vent i on. Cost s ar e
measur ed in t erms of dol lar s. Li ke any PE anal ysi s, t he eval uat or needs t o
def ine t he anal ysi s per spect ive. A dif f erent per spect i ve wi l l change t he cost
st r uct ur e. For example, f r om a pat ient ' s per spect ive, t he cost of i l l ness wi l l
i ncl ude t he t r anspor t at ion t o and f r om t he t r eat ment sit e. Ti me dur at ion of
t he di sease can be cr it ical i n det ermini ng t he cost and may be a sour ce of
bias. No compar ison is made i n t his t ype of anal ysis.
B. Cost- benef i t anal ysi s ( CBA) is a t ool used t o det ermine pr ior it y f or t he
r esour ce al locat ion. The t echni que can be appl ied t o t he compar ison of
healt hcar e pr ogr ams and wi t h non- heal t hcar e pr ogr ams, such as social
wel f ar e pr ogr ams. For example, one can compare t he cost s and benef it s of
a cor onar y r isk f act or r educt ion pr ogr am and t he chi ldhood immuni zat i on
pr ogr am and t he domest ic vi ol ence pr event ion pr ogr am. Thi s t echnique
consist s of i dent i f yi ng al l of t he benef i t s t hat accrue f r om t he pr ogr am and
conver t i ng t hem i nt o dollar s i n t he year t hat t hey occur . The st ream of cost s
and benef i t s ar e t hen discount ed t o pr esent val ue at t he select ed discount
r at e. Net benef it is comput ed f or each pr ogr am and can t hen be compar ed
wit h ot her pr ogr ams.
C. Cost-mi ni mi zat i on anal ysi s ( CMA). The under lyi ng assumpt ion f or t his
t ype of anal ysi s assumes t hat consequences ar e equival ent . Ther ef ore, onl y
cost is compar ed. The cheapest
P. 1307

i nt er vent ion wi l l be chosen f or impl ement at ion. Equi valent out comes may
not necessar i ly be equal . One needs t o det ermine t he key out come of each
compar at or . For example, t wo dr ugs may have t he equi valent t her apeut ic
val ue but dif f er ent side ef f ect pr of iles. I n such cases, consequences may
not be equi valent , and t his t echni que i s not appr opr iat e. CEA should be
used i nst ead.
D. Cost- ef fect i veness anal ysi s ( CEA) is a t echni que t o assi st t he deci si on
maker i n ident if yi ng a pr ef er r ed choice among possibl e alt er nat i ves wi t hi n
simi lar consequences (e. g. , same t her apeut ic cat egor y) in t erms of healt h
impr ovement cr eat ed ( e. g. , l if e year gained, cl i nical cur es) . I t i s not t o be
used t o compar e dif f er ent consequences f or each alt er nat ive, such as blood
pr essur e r educt i on t o degree of cholest er ol lower i ng. Consequences can be
i nt ermediat e out comes or sur r ogat e out comes such as t he r eperf usi on t ime
of t he vessel af t er t hr ombol yt ic t her apy. Gener all y, t he i ncr ement al cost of
a pr ogram or an i nt ervent i on f r om a speci f ied perspect ive i s compar ed t o
t he incr ement al heal t h ef f ect s. An exampl e is t he cost per unit of blood
pr essur e r educt i on wit h each ant i hyper t ensi ve agent compar ed. The r esult s
of t he analysis nor mal l y ar e st at ed in t erms of cost per uni t of
ef f ect iveness.
E. Cost- ut i l i t y anal ysi s ( CUA) . Unl ike CEA, CUA measur es t he
consequences i n t erms of t he qual i t y- adj ust ed l i f e year (QALY) gained. The
r esul t s of t he anal ysis ar e normal l y expr essed as a cost per QALY. The
met r ic of QALY i ncor por at es bot h t he impr ovement in quant it y of l if e,
qual i t y of l if e, and t he pr ef er ence ( ut i l it y val ue) of t he heal t h st at e. Ther e
ar e t hr ee sour ces of obt aini ng ut i l it y val ues f or healt h st at es i n CUA:
j udgment t o est imat e t he ut i l i t y val ues, val ues f rom t he l i t er at ur e, or val ues
el i ci t ed f rom a sample of subj ect s. Common t echni ques f or el ici t i ng ut i l i t y
val ues ar e r at i ng scale ( vi sual anal og scal e) , st andar d gambl e, and t ime
t r adeof f . Five cir cumst ances have been summar ized t hat det ail when CUA
may be t he appr opr iat e t echnique t o apply.
1. When qual i t y of l if e is t he only out come
2. When qual i t y and quant i t y of l if e ar e heal t h out comes
3. When t he int er vent ion af f ect s bot h mort al it y and morbi dit y and a
combined unit of out come is desir ed
4. When t he int er vent ion bei ng compar ed has a wide r ange of pot ent ial
out comes and a common uni t of out come is needed
5. When t he obj ect i ve is t o compar e a gol d st andar d i nt er vent ion t hat
alr eady has t he cost per QALY. QALY i s calculat ed by mult i pl yi ng t he ut i l it y
val ues obt ai ned f or t he specif ic healt h st at e wit h t he quant i t y of l if e year s
spent in t hat specif ic healt h st at e. Compar i son can t hen be made f or t he
pr ogr am and i nt er vent ion.
F. Mul t i at tri but e ut i l i t y t heory ( MAUT) or anal ysi s ( MAUA) is anot her
t echnique f r equent l y used i n assessi ng ut i l it i es. I n t his si t uat ion, sever al
at t r i but es can be incl uded, such as cl ini cal ef f ect and f inancial ef f ect as
wel l as qual it y of li f e. I t is possible t o pr ef erent i al l y wei gh t he deci si on
based on what t he pr ior it ies ar e f or t he deci si on maker and t hen appl y t he
wei ght s t o ident if y t he most pref er able t herapy, ser vi ce, and so on. As
evidenced f r om t he f oll owi ng t hr ee exampl es, t he i ndi vidual ' s per spect ive
wi l l have a maj or ef f ect on t he f i nal decision made, based on t he l evel s of
pr ior it y chosen f or eval uat i on.
1. A physician may vi ew cl i ni cal out come t o r epr esent 70% of t he deci si on,
f ol l owed by pat ient ' s qual i t y of l i f e (20%), and l ast t he cost s ( 10%).
2. A hospit al administ r at or may view t he f i nancial out comes ( 70%) as a
maj or pr i or it y, f ol l owed by t he cl i nical out come (20%), and last t he qual it y
of l if e ( 10%) .
3. A pat ient wit h heal t h i nsur ance mi ght view t he cl i nical out come ( 45%)
and qual it y of li f e ( 45%) as t he t op pr ior i t ies and have mi nimal concer n f or
t he f inanci al out comes ( 10%) of such a deci si on.
G. Wi l l i ngness t o pay (WTP) t echnique is used t o assess t he per ceived
val ue or benef it of a pr oduct and ser vi ce. The WTP val ues can be obt ained
t hr ough t wo appr oaches:
1. I ndi r ect measur ement , which examines i n act ual payment s previous r eal -
wor ld decisions t hat involve t r ade- of f s bet ween money and expect ed
out comes
P. 1308


2. Di r ect measur ement , which uses sur vey met hods t o el icit st at ed dol l ar on
t he per ceived benef i t s. I n t his second approach, r esearcher s are seeking t o
pr ovi de suf f icient backgr ound i nf ormat i on t o cr eat e wi t hi n t he r espondent ' s
mi nd a hypot het ical market in which t he per son provides a j udgment of t he
val ue of t he pr oposed ser vice.
3. The chal lenge of usi ng cont i ngent val uat ion is t o pr esent wit hi n t he
quest ionnair e suf f i ci ent , clear ly or ganized inf ormat ion t o all ow t his
j udgment t o occur . Basi c f act s need t o be given at t he appr opr iat e t ime.
Unl i ke CBA, WTP t akes int o consider at ion t he psychological aspect s of t he
i l l ness as wel l as t he physi cal det er iorat ion. The use of WTP as an out come
measur e i s t heoret ical l y consist ent wit h welf ar e economics. I t also pr ovides
a means t o assign dol lar values t o healt h out comes.
V. DECISION ANALYSIS
is a syst emat i c appr oach t o decision making under condit i ons of
uncer t ai nt y. I t is a t ool f or helpi ng t he decision makers i dent i f y opt ions t hat
ar e avai lable, pr edi ct t he consequences and val ue of each opt i on based on
t he probabi l it i es assigned t o each opt i on, and choose t he opt i on t hat has
t he best payof f . Decision analysi s can be incor porat ed int o t he
pharmacoeconomics eval uat ion. St eps in per f orming a decision anal ysi s ar e
as f ol lows:
A. I dent i f y and bound t he deci si on. Al l t he gr ound r ul es such as anal ysis
per spect ive, compar at or s select i on, t ime span, and decision r ules ar e
ident i f ied and clar i f ied.
B. Devel op a deci si on t ree (Figur e 61- 1) . The decision maker wi l l st r uct ur e
t he deci si on i n t he f orm of a t ree wit h br anches f rom l ef t t o r i ght . Each
br anch i s a segment of a pat h t hat leads t o an out come. The pr ocess of
set t ing up t he t r ee helps t he decision maker put t hought s on paper and
pr ovi des an eval uat i on f or each opt ion t hat occur s.
C. Assess and assi gn probabi l i t i es. Probabil i t y r elat ed t o each br anch is
assessed and assigned. Pr obabi l it ies can be obt ai ned f r om t he publ i shed
l it er at ur e, an exper t panel , or cl i ni cal t r ials.

Figure 61-1. Decision tree with probabilities
included.
P. 1309



Figure 61-2. Completed decision tree after
averaging out and folding back.
D. Val ue out comes. For each of t he out come possi bi l it ies, assi gn a val ue.
Thi s can be i n t he f orm of monet ar y or ut i l it y val ues.
E. Cal cul at e t he expect ed val ue. Using t he averagi ng- out and f oldi ng- back
met hod, st art f r om t he r i ght and work backwar d t o t he lef t , and calcul at e t he
expect ed val ue by mult i pl yi ng t he out come val ue t o each assigned
pr obabi l it y ( Fi gur e 61- 2).
F. Choose t he pref erred course of act i on. Dependi ng on t he ground r ules
set in t he begi nni ng of eit her opt i mizat ion or mini mizat ion, choose t he best
cour se of act ion.
G. Perform a sensi t i vi t y anal ysi s. Assign dif f er ent val ues t o al l plausible
out comes and r esol ve t he decision t r ee t o i dent i f y t he r obust ness of t he
dat a and/ or r esul t s.
VI. PATIENT-REPORTED OUTCOMES (PRO).
PRO r ef er s t o any out comes based on dat a pr ovided by pat ient or pat i ent
pr oxy. I t i ncl udes healt h- r el at ed qual i t y of l if e dat a. PRO dat a can be
col lect ed dur ing t he cl i nical t r ial. Examples of PRO dat a incl ude pat i ent
sat isf act ion wit h t r eat ment and pr ovider s, f unct ional st at us, psychosocial
wel l - bei ng, t r eat ment compl iance/ adher ence, and disease sympt oms. Ther e
is a gr owi ng amount of int er est in addi ng PRO dat a int o t he dr ug- r evi ew and
evaluat ion pr ocess.
A. Healt h- related qual i t y of l if e (HRQOL). Alt hough qual it y of l if e f ocuses
on al l aspect s of l if e, HRQOL f ocuses onl y on a pat i ent ' s noncl i ni cal
i nf ormat i on such as f unct ional st at us, wel l - bei ng, per cept ion of healt h,
r et ur n t o work f r om an i l l ness, and ot her healt h out comes t hat ar e di r ect ly
af f ect by healt h st at us. St andardi zed quest ionnair es ar e used t o capt ur e
HRQOL dat a i n a var iet y of r esear ch set t i ngs. Dat a ar e obt ai ned ei t her by
t elephone i nt er view, self - admi nist r at ion, per sonal f ace-t o- f ace i nt er vi ew,
obser vat ion, or mail- i n sur vey. Such st andardized quest ionnai r es can al so
be divided i nt o gener al healt h st at us inst r ument s—f or example, , Shor t - Form
36 (SF- 36), Short - Form 12, SF-10 f or Chi ldr en, SF- 8 Heal t h Sur veys,
sickness impact prof i les ( SI P) —or disease- specif i c i nst r ument (e. g. , McGil l
Pai n I nvent or y, Beck Depr essi on Scale, Funct i onal
P. 1310

Li vi ng I ndex—Cancer ). The gener al healt h st at us i nst r ument s measur e t he
global healt h st at us, wher eas t he di sease- specif i c i nst r ument s t ar get t he
disease- speci f ic issues.
B. Short f orm surveys ar e t he most f r equent l y used gener al healt h st at us
i nst r ument s. Ther e ar e a var iet y of dimensi ons avai l able, dependi ng on t he
chosen shor t f orm inst r ument . The or iginal SF- 36 i ncl udes physical
f unct i ons, soci al f unct ions, emot ional r ole, physical r ol e, bodi ly pain,
ment al healt h, gener al healt h, and vi t al i t y. Ot her sur vey i nst r ument s may
cont ai n onl y some of t hese di mensions. I nt er est ed reader s can expl or e t he
t he f ol lowi ng Web si t e: www. qual it ymet r ic. com f or mor e inf ormat ion.
C. Psychomet ri c propert i es. Bef ore using any inst r ument , t he researcher
must under st and t he psychomet r ic pr oper t ies of t he chosen i nst r ument . The
psychomet ri c pr opert ies consist of t he rel iabi l i t y and val idi t y i nf ormat ion of
t he inst r ument . I n addi t ion, t he sensit i vi t y and specif icit y of t he inst r ument
ar e al so import ant .
1. Rel i abi l i t y is a measur e of consist ency. Can we repr oduce t he same
score under t he same condi t ions wit h t he same indi vidual? St at ist ical
met hods of measur i ng r el i abi l i t y ar e Cr onbach' s q, Pearson' s r coef f icient ,
and t he k st at ist ic.
2. Val i di t y is a measur e of accur acy. I s t he i nst r ument measur ing what i t is
supposed t o measur e? Types of val idit y ar e cont ent val idit y, const r uct
val idit y, cr it er ion val i di t y, and conver gent / di ver gent val idit y.
3. Use of t he i nst rument. The psychomet r ic proper t i es pr ecl ude “mi xi ng
and mat chi ng” sect i ons of est abl ished quest ionnai r es or sel ect ion of a
sect i on of an est abl i shed quest i onnair e f or admini st rat ion wi t hout
r ecali br at i ng t he i nst r ument ' s psychomet r ic pr oper t ies.
VII. MODELING STUDIES.
Mat hemat ical model i ng is widely used t oday in t he economi c eval uat ion of
medi cat ions and heal t hcar e t echnologies.
A. The goal f or model i ng i s t o assemble evidence of cost s and out comes in
a f orm t hat can pr oj ect long- t erm consequences. Model- based eval uat ions
ar e gr eat t ools f or healt hcar e deci si on maker s.
B. Mat hemat ical model s pr ovide t he cost - consequence est imat es t hat
cannot be r evealed by randomi zed cont r ol t r i al s or epidemiological st udies
because of t he dur at i on r equi r ed f or l ong- t erm st udies ( 10- 20 year s) .
C. Result s der ived f r om modeli ng assist deci si on maker s in making
i nf ormed decisions. However , t he qual it y of t he deci si on is based
complet el y on t he t r ut hf ul ness of t he pr oj ect ed r esult s, which i n t ur n
depends on t he input i nf ormat ion and assumpt ions imposed f or each model .
D. The I nt er nat ional Societ y of Pharmacoeconomi cs and Out comes
Research ( ISPOR) recommends t he f ol lowi ng cr it er ia f or assessi ng t he
qual i t y of models: model st r uct ur e, dat a used as i nput s f or t he model, and
model val idat ion.
1

VIII. 1997 FDA MODERNIZATION ACT, SECTION
114, HEALTH CARE ECONOMIC INFORMATION
A. “Healt h care economic inf ormat ion pr ovided t o a f ormular y commit t ee, or
ot her simil ar ent i t y, i n t he cour se of t he commit t ee or ent i t y carr yi ng out i t s
r esponsibi l i t i es f or t he sel ect ion of dr ugs f or managed care or ot her simi lar
or gani zat ions, shal l not be consi der ed t o be f al se or mi sl eadi ng under t his
par agr aph i f t he healt h car e economic inf ormat ion dir ect ly r elat es t o an
i ndicat i on appr oved … f or such dr ug and is based on compet ent and
r el i able scient i f ic evidence. ” ( Fr om t he FDA' s Moder ni zat ion Act of 1997,
ht t p: / / www. f da. gov/ cder/ guidance/ s830enr . t xt )
P. 1311


B. Healt h economic i nf ormat ion means any anal ysi s t hat ident if ies,
measur es, or compar es t he economic consequences incl udi ng t he cost s of
t he r epr esent ed healt h out comes, or t he use of a dr ug t o t he use of anot her
dr ug, or t o anot her healt hcar e int er vent ion, or t o no i nt er vent ion.
C. Key concept s of t he act
1. A venue f or t he pharmaceut i cal i ndust r y t o pr ovide OR and/ or PE
r esear ch st udies t o decision maker s
2. Economic inf ormat ion can be provided i n t he f orm of CMA, CBA, CUA,
COI , and cost qual it y of l if e.
3. Compet ent and r el iable sci ent if ic inf ormat ion pert ai ni ng t o an appr oved
i ndicat i on
4. St andard of compet ent and rel i abl e scient if i c i nf ormat i on has not been
addr essed.
IX. PRACTICAL ISSUES IN INTERPRETING OUTCOMES
RESEARCH AND PHARMACOECONOMIC STUDIES
A. Compari sons between economi c st udy and randomi zed cl i ni cal t rial s (RCTs)
1. Economic st udi es ar e car r i ed out in an obser vat ional envir onment , wher eas RCTs
depend on r igor ous exper iment al design wit h st r i ct incl usi on/ excl usion cr it er ia.
2. RCTs r el y on highl y cont r ol led and ar t if icial cl i nical set t ings t o demonst r at e
cl i ni cal ef f icacy. Cl inical and economic end point s of t he st udy may not be t he
same. I n addit ion, RCTs t end t o have addi t ional pr ot ocol cost s ( e. g. , ext r a t est s)
and i nf lat ed benef i t s ( e. g. , medicat ion compl iance, appropr iat eness of ut i l i zat i on) .
3. Economic st udi es have l ar ge sample si zes, wher eas RCTs ar e l imit ed t o a
r elat i vel y smal l sample si ze.
4. Economic st udi es ar e gener al izable t o t he broader pat ient popul at i on, wher eas
RCTs ar e l i mit ed t o t hose i ncl uded wi t hi n t he st r i ngent ent r y cr i t er i a, which mi ght
not r epr esent t he t ypical pat ient r eceivi ng t he t est ed t her apy.
B. Mul t i pl e count ri es' OR and PE st udi es
1. Ther e ar e signi f icant dif f er ences in physician pr act ice pat t er ns and car e- deli ver y
syst ems among di f f er ent count r ies.
2. Di f f er ent met hods of f undi ng healt hcar e and al l ocat i ng heal t h expendit ur es make
it almost impossibl e t o calculat e cost s.
3. Pat i ent s' concer ns and bel ief s ar e dif f er ent .
C. Budgetary const rai nt s. Decision making should not be solely based on t he
i nf ormat i on f r om t he PE anal ysis because most publ ished PE st udies do not impose
budget ar y const rai nt as par t of t he analysi s. Cost - ef f ect i ve does not equal
af f or dabl e. I n addit ion, one should also consider t he impl ement at ion cost s of t he
pr ogr am. I n many i nst ances, impl ement at ion cost s may exceed t he benef i t s or
ef f ect iveness of t he pr ogr am.
D. Reproduci bi l i t y
1. Of t en, owi ng t o j our nal space l imit at ion, l engt hy cost comput at i ons ar e el iminat ed
f r om t he publ i shed ar t i cl e. Such pr act i ce creat es an impossibl e audit i ng mechani sm
f or t he der ivat i on and comput at ion of cost s. Cr i t ical assessment of t his sect ion of
t he publ ished ar t icle is necessar y t o ensur e t he val idit y and r el iabi l it y of t he r esult s.
2. Model i ng i s an appr opr i at e met hod when t he disease and t r eat ment in quest i on
has a lengt hy t i me span and et hi cal di lemma of wit hdr awing t r eat ment . However,
assumpt i ons and i nput val ues t o t hese models are not t r anspar ent t o r eader s.
P. 1312


3. Bot h issues make it almost impossible t o r epr oduce t he st udy r esult s usi ng t he
local dat a.
E. Li mit at i ons of claim data st udi es. Clai m dat a are desi gned f or bil l i ng pur poses.
Ther e is no di f f erent iat i on bet ween comor bid condit i ons and complicat i ons in codi ng
dat a. Thi s can pose a pr oblem i n qual i t y benchmark st udies. I n addit i on, codi ng
pr act i ce may be dif f er ent f rom one i nst it ut ion t o anot her , a t hr eat t o r eli abi l i t y.
P. 1313


STUDY QUESTIONS
Di rect i ons: Each of t he quest ions, st at ement s, or i ncomplet e st at ement s in t his
sect i on can be corr ect l y answer ed or complet ed by one of t he suggest ed answers or
phr ases. Choose t he best answer .
1. The underl yi ng assumpt i on of cost -mi ni mi zat i on anal ysi s (CMA) i s
( A) calcul at i on of cost mi ni mi zat ion r at io.
(B) consequences ar e equi valent .
(C) cost s ar e equi valent .
(D) no mor e t han t wo compar at or s in any anal ysis.
View Answer 1. The answer i s B[ see] . 2. Whi ch one of t hese st at ement s i s
not t rue f or t he dif f erences between economi c st udi es and randomi zed cl i ni cal
t ri al s (RCTs) ?
( A) Gener al i zabi l it y and appl i cabi l it y of t he r esult s di f f er bet ween economic st udies
and RCTs.
(B) Cl i nical end poi nt and economic end point ar e ident ical .
(C) RCTs t end t o have i nf lat ed benef i t s and addit i onal pr ot ocol - dr iven cost s.
(D) Sample size of t he economic st udy i s nor mal l y lar ger t han in t he RCT.
View Answer 2. The answer i s B[ see] . 3. I n choosi ng an i nst rument t o
measure t he heal t h- relat ed qual i t y of l if e (HRQOL) , at t ent i on shoul d be pai d t o
( A) rel iabi l it y and val idit y of t he inst r ument .
(B) sensi t i vit y and specif icit y of t he i nst r ument .
(C) lengt h of t he i nst r ument .
(D) Al l of t he above
View Answer 3. The answer i s D[ seeand] . 4. I n choosi ng a st udy
perspect i ve, t he current pharmacoeconomi c (PE) gui del i nes have suggest ed
whi ch one of t he f ol l owi ng perspect i ves t o be i ncl uded?
( A) societ y
(B) payor s
(C) pat ient s
(D) provider s
View Answer 4. The answer i s A[ see] . 5. When i nt erpret i ng a mul t i nat i on
economi c cl i ni cal trial , what i ssue needs speci al att ent i on?
( A) cost comput at ions
(B) heal t hcar e f undi ng and cost - al locat ing mechanisms?
(C) pat ient s' var iat ions and bel ief s
(D) Al l of t he above
View Answer 5. The answer i s D[ seeand] . 6. Whi ch one of t hese
pharmacoeconomi c (PE) techni ques does not address bot h cost and
consequences?
( A) cost - benef it analysis
(B) cost - ef f ect iveness anal ysis
(C) cost - ut i l it y anal ysi s
(D) cost of il l ness
View Answer 6. The answer i s D[ see] . 7. Whi ch of t he f ol l owi ng i s an
exampl e of a cl i ni cal out come i ndi cat or?
( A) doll ar s spent t r eat i ng acut e myocar dial i nf ar ct ion
(B) resour ces used i n diagnosi ng t he pr esence of medical err or s
(C) dur at i on of hospit al i zat ion and mort al it y ver sus dischar ge rat e f or vent r i cul ar
f ibr i l l at ion pat i ent s t r eat ed wi t h amiodar one
(D) f unct ional capacit y of pat ient s t r eat ed wit h r amipr il i n t he pr esence of
car diovascular r isk f act ors
View Answer 7. The answer i s C[ see] . P. 1314


ANSWERS AND EXPLANATIONS
1. The answer i s B [ see IV. C] .
CMA assumes al l consequences compar ed ar e equi valent . For t his r eason, only t he
cost of each alt er nat i ve is compar ed. The least expensi ve al t er nat i ve wi l l be
chosen.
2. The answer i s B [ see I X. A] .
Cl inical and economic end poi nt s ar e gener al ly not equal. I n t he sequence of t he
st udy event s, ef f icacy should come bef ore ef f ect i veness.
3. The answer i s D [ see VI . C. 1, 2 and 3] .
Al l of t he charact er ist ics l ist ed r equir e at t ent ion.
4. The answer i s A [ see I I I . B] .
The societ al per spect ive must be incl uded. I t is cri t ical i n t he heal t hcar e
envi r onment t o i dent i f y t he per spect i ve f r om whi ch a decision i s bei ng made
because t hat perspect i ve di r ect l y af f ect s t he f i nal decision. The deci si on t o add a
high- cost , moderat ely ef f ect i ve t her apy f or t he t r eat ment of hospi t al i zed sept i c
pat ient s might be dif f er ent i f viewed f r om a hospit al f ormul ar y commit t ee ( in- house
budget ar y concer ns) t han f r om t he l ocal communi t y ( savi ng l i ves at what ever
expense) .
5. The answer i s D [ see I X. B. 1, 2 and 3] .
Al l of t he i ssues st at ed need special at t ent ion and play a maj or r ole in developi ng
mult i nat ion economic eval uat ions t o avoi d carr yi ng out a st udy, which when
complet ed cannot be gener al ized t o t he broad pat ient popul at ion.
6. The answer i s D [ see IV. A] .
The cost of i l l ness met hodology is carr ied out as an assessment of t he necessar y
r esour ces, whi ch wi l l be used t o t r eat a designat ed i l l ness. Resour ces ar e measur ed
i n t erms of dol lar s, and t her e ar e no compar at or gr oups in t he eval uat ion.
7. The answer i s C [ see I . A. 3. ] .
Cl inical out comes i ncl ude t he f ol lowi ng: lengt h of hospit al st ay, adver se dr ug
r eact i ons, hospit al r eadmi ssion, and deat h. These are def inable measur es of a
pat ient ' s r esponse t o a given t r eat ment , such as amiodar one used f or t he t reat ment
of vent r icular f ibr i l lat ion.

Appendix A
Prescription Dispensing Information and
Metrology
Prescriptions
PARTS OF THE PRESCRIPTION
A pr escr i pt ion is an or der f or medicat ion f or use by a pat ient t hat is issued by a
physician, dent ist , vet er inar i an, or ot her l icensed pr act it ioner who is aut hor i zed t o
pr escr ibe medicat ion or by t hei r agent via a col labor at ive pr act i ce agr eement . A
pr escr ipt ion i s usual l y wr it t en on a singl e sheet of paper t hat is commonl y impr int ed
wit h t he pr escr i ber ' s name, addr ess, and t el ephone number. A medi cat ion or der is
simi lar t o a pr escr i pt ion, but it is wr it t en on t he pat ient char t and i nt ended f or use
by a pat ient i n an i nst it ut ional set t i ng.
Al l pr escr ipt ions shoul d cont ai n accur at e and appr opr iat e i nf ormat i on about t he
pat ient and t he medicat ion t hat i s being prescr i bed. I n addit ion, a pr escr ipt ion or der
f or a cont rol l ed subst ance must cont ai n t he f ol lowi ng inf ormat ion:
Dat e of issue
Ful l name and addr ess of t he pat ient
Dr ug name, st r engt h, dosage f orm, and quant it y prescr i bed
Dir ect ions f or use
Name, addr ess, and Dr ug Enf or cement Agency ( DEA) number of t he
pr escr iber
Signat ur e of t he prescr i ber
A wr it t en pr escr ipt ion or der is r equir ed f or subst ances l ist ed in Schedul e I I .
Pr escr ipt i ons f or cont rol led subst ances list ed i n Schedul e I I ar e never r ef i l labl e.
Any ot her pr escr i pt ion t hat has no indi cat ion of r ef i l l s i s not r ef il lable.
Pr escr ipt i ons f or medi cat ions t hat are l ist ed in Schedules I I I , I V, and V may be
issued ei t her i n wr it i ng or or al ly t o t he pharmaci st . If aut hor i zed by t he pr escr i ber ,
t hese pr escr i pt i ons may be r ef i l led up t o f i ve t imes wi t hi n 6 mont hs of t he dat e of
issue. I f t he pr escr i ber wishes t he pat ient t o cont i nue t o t ake t he medicat ion af t er 6
mont hs or f ive r ef il l s, a new prescr ipt ion or der is r equi r ed.
THE PRESCRIPTION LABEL
I n addit i on t o t he name of t he pat i ent , t he pharmacy, and t he pr escr i ber , t he
pr escr ipt ion l abel should accur at ely ident if y t he medi cat ion and pr ovide dir ect ions
f or i t s use.
The label f or a prescr ipt ion or der f or a cont r olled subst ance must cont ain t he
f ol l owi ng i nf ormat ion:
Name and addr ess of t he phar macy
Ser i al number assi gned t o t he prescr i pt ion by t he pharmacy
Dat e of t he init i al f i l l i ng
Name of t he pat ient
Name of t he pr escr iber
Dir ect ions f or use
Caut ionar y st at ement s as r equir ed by l aw
*

AUXILI ARY LABELS
Auxi l i ar y, or caut ionar y, l abels pr ovide addit i onal i mport ant inf or mat ion about t he
pr oper use of t he medi cat ion. Exampl es i ncl ude “ Shake Well ” f or suspensi ons or
emul si ons; “ For Ext er nal Use Onl y” f or
P. 1316

t opical l ot i ons, solut ions, or cr eams; and “ May Cause Dr owsiness” f or medicat ions
t hat depress t he cent r al ner vous syst em. The i nf ormat ion cont ai ned on auxi l i ar y
label s should be br ought t o t he at t ent i on of t he pat ient when t he medicat i on is
dispensed. The pharmaci st should pl ace onl y appr opr iat e auxi l i ar y l abels on t he
pr escr ipt ion cont ai ner because t oo many labels may conf use t he pat ient .
BEFORE DISPENSING THE PRESCRIPTION
Doubl e- check t he accuracy of t he prescri pt i on. Provi de undi vi ded at t ent i on
when f i l l i ng t he prescri pt i on.
Check t he pat i ent i nf ormat ion ( e. g. , name, address, dat e of bi r t h, t el ephone
number) .
Check t he pat i ent pr of i le (e. g. , al ler gies, medical condit ions, ot her dr ugs,
i ncl udi ng over - t he-count er medi cat ions) .
Check t he dr ug ( e. g. , corr ect dr ug name, corr ect spel l i ng, appr opr iat e dr ug
f or t he pat ient ' s condi t ion) , and ver i f y t hat t her e ar e no known dr ug
i nt er act i ons. Always veri f y t he name of t he drug. Beware of drug names
t hat l ook al i ke ( see t able) .
Check t he dosage, incl udi ng t he dr ug st r engt h, t he dosage f or m ( e. g. ,
capsul e, l iquid, modif i ed r el ease), t he i ndi vi dual dose, t he t ot al dai l y dose,
t he dur at i on of t r eat ment , and t he uni t s (e. g. , mg, mL, t sp, t bsp).
Check t he l abel . Compare t he dr ug di spensed wit h t he pr escr i pt i on. Ver if y
t he Nat ional Dr ug Code (NDC) number. Ensur e t hat t he inf ormat ion i s
accur at e, t hat t he pat ient di r ect ions ar e accur at e and easi l y under st ood, and
t hat t he auxi l i ar y labels ar e appr opr iat e.
Provi de pat i ent counsel i ng. Be sure t hat t he pat i ent f ul l y underst ands
t he drug t reatment as wel l as any precauti ons.
Examples of Drugs with Similar Names
Brand name Celebrex Cerebyx Celexa
Generic
name
Celecoxib
capsules
Fosphenytoin
sodium injection
Citalopram
HCl
Manufacturer Searle Parke-Davis Forest
Indication Osteoarthritis and
rheumatoid
arthritis
Prevention and
treatment of
seizures
Major
depression

Dangerous or Confusing Abbreviations
Numer ous common abbr eviat ions and symbols have been associ at ed wit h err ors.
Det ai led l ist s of t hese can be f ound at t he websit es of t he I nst it ut e f or Saf e
Medi cat ion Pract ices ( ISMP) and Joint Commission f or t he Accr edit at ion of
Healt hcar e Or ganizat i ons ( JCAHO) at :
ht t p: / / www. ismp. org/ Tools/ abbr eviat i onsl ist . pdf .
ht t p: / / www. j caho. or g/ accr edi t ed + organi zat ions/ pat i ent + saf et y/ 06_dnu_l ist . pdf .
The JCAHO has cr eat ed a “Do Not Use” li st of abbr eviat ions t hat i t s accr edi t ed
or gani zat ions shoul d not al l ow t o be used.
[ black r i ght - point ing ar r owhead] “U” or “IU” f or uni t s: t he “U” has been
mi si nt er pr et ed as vari ous numbers such as zer o, f our ; ser ious harm has occur r ed
wit h i nsul i n and hepar i n as a r esult of conf usi on. For example, a pat ient r eceived 66
unit s of i nsul i n inst ead of 6 uni t s. The or der was wr i t t en f or “ 6u” of r egul ar i nsul i n
but was misi nt er pr et ed. The wor d “ unit s” shoul d be wr i t t en out i n f ul l .
[ black r i ght - point ing ar r owhead] “QD, Q. D, qd, q. d. ”: common abbrevi at ions f or dai l y
have been misint er pr et ed as “QID” or “ qi d” and over doses have occur r ed. “Dai l y”
should be wr it t en out i n f ul l.
[ black r i ght - point ing ar r owhead] “Q. O. D, QOD, qod”: common abbr evi at ions f or
ever y ot her day have been misi nt er pr et ed as QID ( f our t imes dai l y) . This should be
wr it t en out compl et el y as “ ever y ot her day. ”
P. 1317


[ black r i ght - point ing ar r owhead] Trai l i ng zero: when a dose is or der ed and f ol l owed
wit h a decimal point and a zer o, such as 2. 0 mg or 25. 0 mg, err ors can occur. The
decimal poi nt may be mi ssed and an over dose can occur . For example, Warf ar i n 2. 0
mg may be mi si nt er pret ed as 20 mg. Trai l i ng zer os should be avoi ded and t he dose
wr it t en wi t hout t he addit ional zer o, f or example War f ar in 2 mg r at her t han 2. 0 mg.
[ black r i ght - point ing ar r owhead] Lack of l eadi ng zero: a dr ug' s dose may be l ess
t han 1 mg, such as Di goxi n. Of t en t he dose may be wr it t en wit hout a leadi ng zer o,
such as Di goxi n . 25 mg, r at her t han as Di goxi n 0. 25 mg. Er ror s have occurr ed
because t he decimal poi nt is mi ssed. For exampl e, War f ar i n . 5 mg may be
i nt er pr et ed as Warf ar i n 5 mg. Leading zer oes shoul d be i ncl uded, so t he dose i s
wr it t en as “Digoxi n 0. 25 mg or Warf ar i n 0. 5 mg. ”
▶MS, MSO4, MgSO4: Abbrevi at i ons f or morphi ne sul f at e ( MS, MSO4) have been
conf used wi t h Magnesi um sul f at e ( MgSO4 ). It i s recommend t o wri t e out each
name i n f ul l rat her t han usi ng abbrevi at i ons: morphi ne sul f at e or magnesi um
sul f at e.
I n addi t i on t o t he above abbrevi at i ons, t here are numerous ot her hazardous
symbol s and abbrevi at i ons whi ch shoul d be revi ewed wit h caut i on when used
on prescri pt i ons. Exampl es i ncl ude:
▶“cc”: Of t en used i nst ead of “mL. ” This has been misi nt er pret ed as a “ 0” ( zer o).
Use “mL. ”
[ black r i ght - point ing ar r owhead] “µg”: Used f or “micr ogr ams, ” f or example,
Levot hyr oxi ne 250 µg. dai l y. The symbol has been mist aken f or “ mg. ” and over doses
have occur r ed. Best t o use “mcg. ” Or wr i t e out “micr ogr ams. ”
[ black r i ght - point ing ar r owhead] “<” or “ >”: Symbols f or “ less t han” (<) or “ great er
t han” ( >) have been mi st aken f or each ot her or misi nt erpret ed as numbers. Best t o
wr it e out as “ l ess t han” or “gr eat er t han. ”
[ black r i ght - point ing ar r owhead] “HCT”: An abbr evi at i on f or “ hydr ocort isone” has
been misi nt er pr et ed as “ hydr ochlor ot hiazi de. ” Best t o wr i t e name out complet el y.
[ black r i ght - point ing ar r owhead] “HCl ”: An abbr evi at ion f or “ hydr ochlor i c acid” has
been misi nt er pr et ed as “KCl” ( pot assi um chl or ide) . Best t o wr i t e out name
complet el y.
P. 1318


Common Abbreviations
Consi der able var iat ion occur s in t he use of capit al i zat i on, it al ici zat ion, and
punct uat ion i n abbr eviat ions. The f ol lowi ng l i st shows t he abbr eviat ions t hat ar e
most of t en encount er ed by pharmacist s.
Common Abbreviations
A, aa. , or aa
of each
a. c.
bef or e meals
ad
t o, up t o
a. d.
r ight ear
ad l i b.
at pleasur e, f reel y
a. m.
mor ni ng
amp.
ampule
ant e
bef or e
aq.
wat er
a. s.
lef t ear
asa
aspir i n
a. u.
each ear, bot h ears
b. i . d.
t wice a day
BP
Br it i sh Pharmacopoeia
BSA
body sur f ace ar ea
c. or c
wit h
cap. or caps.
capsul e
cp
chest pain
D. A. W.
dispense as wr i t t en
cc or cc.
cubic cent imet er
comp.
compound, compounded
di l .
di l ut e
D. C. , dc, or di sc.
discont i nue
di sp.
dispense
di v.
di vide, t o be divided
dl or dL
deci l it er
d. t. d.
gi ve of such doses
DW
dist i l l ed wat er
D5W
dext r ose 5% in wat er
el i x.
el i xi r
e. m. p.
as di r ect ed
et
and
ex aq.
i n wat er
f l or f l d
f lui d
f l oz
f lui d ounce
f t.
make
g or Gm
gr am
gal .
gal lon
GI
gast r oint est inal
gr or gr.
gr ain
gt t or gt t.
dr op, dr ops
H
hypodermic
h. or hr.
hour
h. s.
at bedt ime
I M
i nt r amuscular
i nj .
i nj ect ion
I V
i nt r avenous
I VP
i nt r avenous push
I VPB
i nt r avenous piggyback
K
pot assi um
l or L
l it er
l b.
pound
µ
Gr eek mu
M
mi x
m
2
or M
2

squar e met er
mcg, mcg. , or µg
mi crogram
mEq
mi l l i equi val ent
mg or mg.
mi l l i gr am
ml or mL
mi l l i l it er
µI or µL
mi crol it er
mi nim
N&V
nausea and vomi t ing
Na
sodium
N. F.
Nat i onal Formular y
No.
number
noct .
night , in t he ni ght
non rep.
do not r epeat
NPO
not hi ng by mout h
N. S. , NS, or N/ S
normal sal i ne
1/ 2 NS
half - st r engt h normal sal i ne
O
pi nt
o. d.
r ight eye, ever y day
o. l . or o. s.
lef t eye
OTC
over t he count er
o. u.
each eye, bot h eyes
oz.
ounce
p. c.
af t er meals
PDR
Physi ci ans' Desk Ref er ence
p. m.
af t er noon, eveni ng
p. o.
by mout h
Ppt
pr ecipit at ed
pr
f or t he r ect um
prn or p. r. n.
as needed
pt .
pi nt
pul v.
powder
pv
f or vaginal use
q.
ever y
q. d.
ever y day
q. h.
ever y hour
q. 4 hr.
ever y f our hour s
q. i . d.
f our t imes a day
q. o. d.
ever y ot her day
q. s.
a suf f ici ent quant i t y
q. s. ad
a suf f ici ent quant i t y t o make
R
r ect al
R. L. or R/ L
Ringer' s lact at e
pr escr ipt ion
s. or s
wit hout
Si g.
wr it e on label
sol .
sol ut ion
S. O. B.
shor t ness of br eat h
s. o. s.
if t her e is need ( once onl y)
ss. or ss
one- half
st at.
immediat el y
subc, subq, or s. c.
subcut aneousl y
sup. or supp
supposit or y
susp.
suspensi on
syr.
syr up
tab.
t ablet
tal .
such, such a one
P. 1319


tal . dos.
such doses
t bsp. or T
t ablespoonf ul
t . i . d.
t hr ee t imes a day
t r. or t i nct .
t inct ur e
t sp. or t.
t easpoonf ul
TT
t ablet t r it ur at es
U or u.
unit
u. d. or ut di ct.
as di r ect ed
ung.
oi nt ment
U. S. P. or USP
Uni t ed St at es Pharmacopoei a
w/ v
wei ght / vol ume
Metrology
THE METRIC, APOTHECARY, AND AVOIRDUPOIS
SYSTEMS
Metri c system
1. Basi c uni t s
Mass = g or gram
Length = m or meter
Volume = L or liter

1 cc (cubic centimeter) of water is approximately equal to 1
mL and weighs 1 g.

2. Pref i xes
kilo- 10
3
, or 1000 times the basic unit
hekto- 10
2
, or 100 times the basic unit
deka- 10
1
, or 10 times the basic unit
deci- 10
-1
, or 0.1 times the basic unit
centi- 10
-2
, or 0.01 times the basic unit
milli- 10
-3
, or 0.001 times the basic unit
micro- 10
-6
, or one-millionth of the basic unit
nano- 10
-9
, or one-billionth of the basic unit
pico- 10
-12
, or one-trillionth of the basic unit

Exampl es of t hese pr ef i xes i nclude mil l igr am (mg), whi ch equals one- t housandt h of
a gr am, and deci l i t er (dL), whi ch equals 100 mL, or 0. 1 L.
Apothecary system
1. Vol ume (f l ui ds or l i qui d)
60 minims () =
1 fluidrachm or fluidram (f ) or ( )
8 fluidrachms (480 minims) =
1 fluidounce (f or )
16 fluidounces = 1 pint (pt or 0)
2 pints (32 fluidounces) = 1 quart (qt)
4 quarts (8 pints) = 1 gallon (gal or C)

2. Mass (wei ght )
20 grains (gr) =
1 scruple ( )
3 scruples (60 grains) =
1 drachm or dram ( )
8 drachms (480 grains) =
1 ounce ( )
12 ounces (5760 grains) = 1 pound (lb)

Avoi rdupoi s system
1. Vol ume
1 fluidrachm = 60 min.
1 fluid ounce = 8 fl. dr.
= 480 min.
1 pint = 16 fl. oz.
= 7680 min.
1 quart = 2 pt.
= 32 fl. oz.
1 gallon = 4 qt.
= 128 fl. oz.

P. 1320


2. Mass (wei ght )
The gr ain is common t o bot h t he apot hecar y and t he avoi r dupois syst ems.
437. 5 gr ains ( gr) = 1 ounce ( oz)
16 ounces ( 7000 gr ai ns) = 1 pound ( lb)
CONVERSION
Exact equivalents
Exact equi valent s ar e used f or t he conver sion of speci f ic quant it ies i n
pharmaceut i cal f ormulas and pr escr ipt ion compoundi ng.
1. Lengt h
1 meter (m) = 39.37 in.
1 inch (in) = 2.54 cm.

2. Vol ume
1 ml = 16.23 minims ()
1 = 0.06 mL
1 f
= 3.69 mL
1 f
= 29.57 mL
1 pt = 473 mL
1 gal (U.S.) = 3785 mL

3. Mass
1 g = 15.432 gr
1 kg = 2.20 lb (avoir.)
1 gr = 0.065 g or 65 mg
1 oz (avoir.) = 28.35 g
1 (apoth.)
= 31.1 g
1 lb (avoir.) = 454 g
1 lb (apoth.) = 373.2 g

4. Ot her equi val ent s
1 oz (avoir.) = 437.5 gr
1 (apoth.)
= 480 gr
1 gal (U.S.) =
128 fl
1 fl (water)
= 455 gr
1 gr (apoth.) = 1 gr (avoir.)

Approxi mate equi val ents
Physici ans may use appr oxi mat e equi valent s t o pr escr ibe t he dose quant it ies usi ng
t he met r i c and apot hecar y syst ems of wei ght s and measur es, respect ivel y.
Household unit s ar e of t en used t o inf orm t he pat i ent of t he si ze of t he dose. I n view
of t he almost uni ver sal pr act i ce of usi ng an or dinar y househol d t easpoon t o
admi ni st er medicat i on, a t easpoon may be consider ed 5 mL. However, when
accur at e measur ement of a l iquid dose is r equir ed, t he USP r ecommends t he use of
a cal ibr at ed or al syr inge or dr opper.
1 fluid dram = 1 teaspoonful
= 5 mL
4 fluidounces = 120 mL
8 fluidounces = 1 cup
= 240 mL
1 grain = 65 mg
1 kg = 2.2 pounds (lb)


Appendix B
Common Prescription Drugs and Over-the-
Counter Products
The FDA Approved Drug Product s With Therapeutic
Equivalence Evaluation: The Orange Book
The Unit ed St at es Food and Dr ug Admi nist r at ion (FDA) publ ishes t he book,
Appr oved Dr ug Pr oduct s Wi t h Ther apeut i c Equi val ence Eval uat i on, of t en known as
t he Or ange Book. An elect r oni c ver sion of t he Orange Book is avai l able on t he
I nt er net at ht t p: / / www. f da. gov/ cder/ ob/ . Thi s book is al so r epr oduced by t he Uni t ed
St at es Pharmacopeial Convent ion, I nc. , in t he publ icat i on, USP DI , Vol ume I I I ,
Appr oved Dr ug Pr oduct s and Legal Requi r ement s.
The t ext s, which ar e publ ished annual l y, ident if y t he pr escr ipt ion and
nonpr escr i pt i on pr oduct s t hat ar e f ormall y appr oved by t he FDA on t he basis of
saf et y and ef f ect iveness. They also pr ovide t he FDA' s t herapeut ic equi valence
evaluat ions f or appr oved mult iple- sour ce pr escr ipt ion dr ug pr oduct s.
The Or ange Book i s a dr ug pr oduct select i on guide f or pharmacist s t o use when
dispensi ng a gener i c dr ug pr oduct as a subst i t ut e f or t he br and- name equi valent . A
f ew dr ug pr oduct s t hat wer e on t he market bef or e 1938 r eceived a “ gr andf at her ed”
FDA appr oval. These pr oduct s ar e assumed t o be saf e and ef f ect ive because of
t heir long usage ( e. g. , digoxi n t ablet s, phenobar bit al t abl et s) . These ol der pr oduct s
do not have t her apeut ic equi valence r at ings at t hi s t ime.
The Or ange Book uses var ious codes t o indicat e t her apeut ic equivalence. The f ir st
let t er “ A” desi gnat es dr ug product s t hat t he FDA consider s t her apeut i cal l y
equival ent t o a pharmaceut i cal l y equi valent dr ug pr oduct . These pr oduct s can be
saf el y subst it ut ed. The f ir st let t er “B” designat es dr ug product s t hat , f or var ious
r easons, t he FDA does not consi der bioequi valent t o t he pharmaceut i cal l y
equival ent dr ug pr oduct .
Therapeutic Equivalence Evaluation Codes
A Codes
Dr ug pr oduct s t hat t he FDA consi der s t her apeut ical l y equi val ent t o ot her
pharmaceut i cal l y equi valent pr oduct s
AA Products in conventional dosage forms that do not present
bioequivalence problems
AB Products that meet necessary bioequivalence requirements
AN Solutions and powders for aerosolization
AO Injectable oil solutions
AO Injectable aqueous solutions, and in certain instances, intravenous
nonaqueous solutions
AT Topical products

B Codes
Dr ug pr oduct s t hat t he FDA does not consider t her apeut ical l y equi val ent t o ot her
pharmaceut i cal l y equi valent pr oduct s at t his t ime
P. 1322


B
*
Drug products that require further FDA investigation and review to
determine therapeutic equivalence
BC Extended-release dosage forms (capsules, injectables, and tablets)
BD Active ingredients and dosage forms that have documented problems
with bioequivalence
BE Delayed-release oral dosage forms
BN Products in aerosol-nebulizer drug-delivery systems
BP Active ingredients and dosage forms that have potential problems with
bioequivalence
BR Suppositories or enemas that deliver drugs for systemic absorption
BS Drug products that have drug standard deficiencies
BT Topical products that have bioequivalence issues
BX Drug products for which the data are sufficient to determine therapeutic
equivalence

P. 1323


P. 1324


P. 1325


Top 200 Prescription Drugs by Trade Name and Generic Namea
Rank Trade Name Generic Name
1 Lortab Hydrocodone/acetaminophen
2 Synthroid Levothyroxine
3 Xanax Alprazolam
4 Potassium Chloride Potassium Chloride
5 Glucophage Metformin
6 Zestril/Prinivil Lisinopril
7 Ultram Tramadol
8 Lasix Furosemide
9 Lipitor Atorvastatin
10 Percocet Oxycodone/acetaminophen
11 Tenormin Atenolol
12 Toprol-XL Metoprolol succinate
13 Lopressor Metoprolol tartrate
14 Hydrochlorothiazide Hydrochlorothiazide
15 Coumadin Warfarin
16 Norvasc Amlodipine
17 Amoxil Amoxicillin
18 OxyContin Oxycodone ER
19 Zithromax and Zmax Azithromycin
20 Darvocet Propoxyphene/acetaminophen
21 Zoloft Sertraline
22 Zantac Ranitidine
23 Zocor Simvastatin
24 Lexapro Escitalopram
25 Nexium Esomeprazole
26 Seroquel Quetiapine
27 Proventil Albuterol
28 Singulair Montelukast
29 Plavix Clopidogrel
30 Deltasone Prednisone
31 Effexor XR Venlafaxine
32 Elavil Amitriptyline
33 Ativan Lorazepam
34 Neurontin Gabapentin
35 Glucotrol and
Glucotrol XR
Glipizide
36 Naprosyn and EC-
Naprosyn
Naproxen
37 Wellbutrin (SR, XL) Bupropion
38 Desyrel Trazodone
39 Prilosec Omeprazole
40 Dyazide Triamterene/hydrochlorothiazide
41 Flexeril Cyclobenzaprine
42 Duragesic Fentanyl transdermal system
43 Prozac Fluoxetine
44 Fosamax Alendronate
45 Vasotec Enalapril
46 Prevacid Lansoprazole
47 Lantus Insulin glargine
48 Premarin Conjugated estrogens
49 Lanoxin Digoxin
50 Valium Diazepam
51 Keflex Cephalexin
52 Paxil CR Paroxetine
53 Reglan Metoclopramide
54 Cardizem CD Diltiazem
55 Ambien Zolpidem
56 Celexa Citalopram
57 Advair Fluticasone/salmeterol
58 Zestoretic Lisinopril/hydrochlorothiazide
59 Vytorin Simvastatin/ezetimibe
60 Zyrtec Cetirizine
61 Fioricet Butalbital/acetaminophen/caffeine
62 Diflucan Fluconazole
63 Ortho Tri-Cyclen Ethinyl estradiol/norgestimate
64 Depakote ER Divalproex
65 Adderall XR Dextroamphetamine/amphetamine
66 Celebrex Celecoxib
67 Diovan Valsartan
68 Lotrel Amlodipine/benazepril
69 Allegra Fexofenadine
70 Klonopin Clonazepam
71 Augmentin XR Amoxicillin/clavulanate
72 Cymbalta Duloxetine
73 Risperdal Risperidone
74 Levaquin Levofloxacin
75 Aldactone Spironolactone
76 Lyrica Pregabalin
77 Zyloprim Allopurinol
78 Protonix Pantoprazole
79 Actos Pioglitazone
80 Dilantin Phenytoin
81 Kenalog Triamcinolone
82 Motrin Ibuprofen
83 Altace Ramipril
84 Coreg Carvedilol
85 Isoptin and Isoptin SR Verapamil
86 Estrace Estradiol
87 Catapres Clonidine
88 Soma Carisoprodol
89 Zetia Ezetimibe
90 Amaryl Glimepiride
91 Flomax Tamsulosin
92 Diovan-HCT Valsartan/hydrochlorothiazide
93 Humalog Insulin lispro
94 Flonase Fluticasone propionate
95 Tylenol with Codeine Acetaminophen/codeine
96 Aricept Donepezil
97 Mevacor Lovastatin
98 Accupril Quinapril
99 Miralax Polyethylene glycol 3350
100 MS Contin Morphine sulfate
101 Cozaar Losartan
102 Ditropan Oxybutynin
103 Detrol Tolterodine
104 TriCor Fenofibrate
105 Combivent Ipratropium/albuterol
106 Zyprexa Olanzapine
107 Crestor Rosuvastatin
108 Remeron Mirtazapine
109 Procardia and
Procardia XL
Nifedipine
110 Imdur Isosorbide mononitrate
111 Topamax Topiramate
112 Actonel Risedronate
113 Atrovent Ipratropium
114 Medrol Methylprednisolone
115 Tessalon Benzonatate
116 Ultracet Tramadol/acetaminophen
117 Sinequan Doxepin
118 Ritalin SR and LA Methylphenidate
119 Avandia Rosiglitazone
120 Cipro XR Ciprofloxacin
121 Bactrim or Septra Sulfamethoxazole/trimethoprim
122 Folic Acid Folic acid
123 Phenergan Promethazine
124 Macrodantin and
Macrobid
Nitrofurantoin
125 Pyridium Phenazopyridine
126 Hyzaar Losartan/hydrochlorothiazide
127 Dilacor XR Diltiazem
128 Vibramycin/Vibra-
Tabs
Doxycycline hyclate
129 Capoten Captopril
130 Tegretol Carbamazepine
131 Concerta Methylphenidate
132 Trileptal Oxcarbazepine
133 Evista Raloxifene
134 Glucovance Glyburide/metformin
135 Namenda Memantine
136 Cardura Doxazosin
137 NovoLog Insulin aspart
138 Flagyl Metronidazole
139 Nasonex Mometasone furoate
140 Restoril Temazepam
141 Micronase Glyburide
142 Xopenex Levalbuterol
143 Xalatan Latanoprost
144 Mycostatin Nystatin
145 Benicar Olmesartan
146 Alesse Ethinyl estradiol/levonorgestrel
147 Abilify Aripiprazole
148 DuoNeb Ipratropium/albuterol
149 Armour Thyroid Thyroid, dessicated
150 Ziac Bisoprolol/hydrochlorothiazide
151 Lotensin Benazepril
152 Phenobarbital Phenobarbital
153 Cleocin Clindamycin
154 Theophylline Theophylline
155 Pravachol Pravastatin
156 Lamictal Lamotrigine
157 Voltaren Diclofenac
158 Spiriva Tiotropium
159 Cogentin Benztropine mesylate
160 Mobic Meloxicam
161 Strattera Atomoxetine
162 Yasmin Ethinyl estradiol/drospirenone
163 Ortho-Novum 7/7/7 Ethinyl estradiol/norethindrone
164 Hytrin Terazosin
165 Avapro Irbesartan
166 Veetids Penicillin V
167 Lopid Gemfibrozil
168 Skelaxin Metaxalone
169 Inderal Propanolol
170 Zovirax Acyclovir
171 Benicar-HCT Olmesartan/hydrochlorothiazide
172 Adipex-P Phentermine
173 Bactroban Mupirocin
174 AcipHex Rabeprazole
175 Pepcid Famotidine
176 Imuran Azathioprine
177 Bentyl Dicyclomine
178 Clozaril Clozapine
179 Biaxin XL Clarithromycin
180 Methadone Methadone
181 Provera Medroxyprogesterone
182 Requip Ropinirole
183 Prempro Conjugated
estrogens/medroxyprogesterone
184 Lithonate & Lithotabs Lithium carbonate
185 Buspar Buspirone
186 Omnicef Cefdinir
187 Lunesta Eszopiclone
188 Relafen Nabumetone
189 Allegra-D Fexofenadine/pseudoephedrine
190 Niaspan Niacin
191 Bumex Bumetanide
192 Demadex Torsemide
193 Lotrisone Clotrimazole/betamethasone
194 Lomotil Diphenoxylate/atropine
195 Lactulose Lactulose
196 Monopril Fosinopril
197 Guaifenex PSE Guaifenesin/pseudoephedrine
198 Flovent Fluticasone propionate
199 Imitrex Sumatriptan
200 Antivert Meclizine
a
This table contains the top 200 prescription drugs dispensed through
independent, chain, food store, mass merchandiser, and deep discount
pharmacies. All forms of the same generic equivalent drug are grouped
together and listed under the brand name when appropriate. Rankings are
based on total number of prescriptions for August 2004 to August 2005, as
measured by SFI's Prescription Drug Audit. Insulin products are included in
the tally. Adapted with permission from Prescription Drug Cards, 23rd ed.
SFI Medical Publishing, 2007.

P. 1326


P. 1327


Top Over-the-Counter (OTC) Drugsa
Trade Name Drug Use
Abreva® Cold sore medication
Actifed® Allergy and cold relief
Advil® Analgesic
Afrin® Nasal decongestant
Aleve® Analgesic
ALternaGEL® Antacid
Anbesol® Oral cavity analgesic
Anusol® Hemorrhoidal agent
Azo Standard® UTI analgesic
Bayer® Aspirin Analgesic
Benadryl® Oral Allergy and cold relief
BEN-GAY® Topical analgesic
Betadine® Antiseptic
Bonine® Motion sickness medication
Bufferin® Analgesic
Caladryl® Topical antipruritic
Carmex® Cold sore medication
Cepastat® Oral cavity analgesic
Chlor-Trimeton® Allergy and cold relief
Chloraseptic® Oral cavity analgesic
Citrucel® Laxative
Claritin® Allergy and cold relief
Claritin-D® Allergy and cold relief
Colace® Stool softener
COLD-EEZE® Cold relief
Compound W® Keratolytic
Cortaid® Topical antipruritic
Debrox® Ear wax removal aid
Delsym® Cough suppressant
Dramamine® Motion sickness medication
Dulcolax® Laxative
Duofilm® Keratolytic
Emetrol® Antiemetic
Estroven® Menopause support
Excedrin® Analgesic
FiberCon® Laxative
Fungi-Nail® Topical antifungal
Gas-X® Antiflatulent
Gyne-Lotrimin® Vaginal antifungal
Herpecin-L® Cold sore medication
Imodium A-D® Antidiarrheal
Ivy Dry® Topical antipruritic
Lactaid® Digestive aid
Lactinex® Antidiarrheal
Lamisil® AT Antifungal
Listerine® Oral cavity antiseptic
Lotrimin AF® Topical antifungal
Maalox® & Maalox® Plus Antacid
Metamucil® Laxative
Midol® & Midol® PMS Analgesic
Monistat® Vaginal Vaginal antifungal
Motrin® IB Analgesic
Mucinex® (Adult) Expectorant
Mylanta® Antacid
Mylicon® Drops Antiflatulence
Myoflex® Topical analgesic
Naphcon® A Ophthalmic anti-allergy
NasalCrom® Allergy and cold relief
Neo-Synephrine® Nasal decongestant
Neosporin® Topical anti-infective
NicoDerm® CQ Smoking cessation aid
Nicorette® Smoking cessation aid
Nix® Pediculicide
Nizoral® Shampoo Topical antifungal
NoDoz® Analeptic
NyQuil® Cough and cold relief
Ocean® Nasal decongestant
Opcon-A® Ophthalmic anti-allergy
Orabase® Oral cavity analgesic
OralBalance® Oral moisturizer
Os-Cal® Essential mineral
Pamprin® Analgesic
PediaCare® Cough and cold relief
Pepcid® Complete Acid reducer
Pepcid-AC® Acid reducer
Pepto Bismol® Antidiarrheal
Peri-Colace® Stool softener plus laxative
Phillips' MOM® Laxative/antacid
Pin-X® Anthelmintic
Preparation H® Hemorrhoidal agent
Prilosec® OTC Acid reducer
RID® Pediculicide
Robitussin® (Adult) Cough relief
Rogaine® Hair growth stimulant
Salivart® Saliva substitute
Senokot® Laxative
Similasan Earache Relief® Earache relief
Slow-Mag® Essential mineral
Sominex® Sleeping aid
Sudafed® Allergy and cold relief
Tagamet HB 200® Acid reducer
Tavist® Allergy and cold relief
Tears Naturale® Artificial tears
Triaminic® Oral Cough and cold relief
Tums® Antacid
Tylenol® Analgesic
Tylenol® Allergy & Sinus Allergy and cold relief
Tylenol® Cold & Flu (Adult) Allergy and cold relief
Tylenol® PM Analgesic
Unisom® Sleeping aid
Zantac® OTC Acid reducer
Zicam® Cold Remedy Cold relief
Zilactin® and Zilactin-B® Cold sore medication
Zostrix® Topical analgesic
a
This table contains the top OTC drugs by pharmacist recommendation in
specific therapeutic classes.
Adapted with permission from Nonprescription Drug Cards, 6th ed. SFI
Medical Publishing, 2006.


Appendix B
Common Prescription Drugs and Over-the-
Counter Products
The FDA Approved Drug Product s With Therapeutic
Equivalence Evaluation: The Orange Book
The Unit ed St at es Food and Dr ug Admi nist r at ion (FDA) publ ishes t he book,
Appr oved Dr ug Pr oduct s Wi t h Ther apeut i c Equi val ence Eval uat i on, of t en known as
t he Or ange Book. An elect r oni c ver sion of t he Orange Book is avai l able on t he
I nt er net at ht t p: / / www. f da. gov/ cder/ ob/ . Thi s book is al so r epr oduced by t he Uni t ed
St at es Pharmacopeial Convent ion, I nc. , in t he publ icat ion, USP DI , Vol ume I I I ,
Appr oved Dr ug Pr oduct s and Legal Requi r ement s.
The t ext s, which ar e publ ished annual l y, ident if y t he pr escr ipt ion and
nonpr escr i pt i on pr oduct s t hat ar e f ormall y appr oved by t he FDA on t he basis of
saf et y and ef f ect iveness. They also pr ovide t he FDA' s t herapeut ic equi valence
evaluat ions f or appr oved mult iple- sour ce pr escr ipt ion dr ug pr oduct s.
The Or ange Book i s a dr ug pr oduct select i on guide f or pharmacist s t o use when
dispensi ng a gener i c dr ug pr oduct as a subst i t ut e f or t he br and- name equi valent . A
f ew dr ug pr oduct s t hat wer e on t he market bef or e 1938 r eceived a “ gr andf at her ed”
FDA appr oval. These pr oduct s ar e assumed t o be saf e and ef f ect ive because of
t heir long usage ( e. g. , digoxi n t ablet s, phenobar bit al t abl et s) . These ol der pr oduct s
do not have t her apeut ic equi valence r at ings at t hi s t ime.
The Or ange Book uses var ious codes t o indicat e t her apeut ic equivalence. The f ir st
let t er “ A” desi gnat es dr ug product s t hat t he FDA consider s t her apeut i cal l y
equival ent t o a pharmaceut i cal l y equi valent dr ug pr oduct . These pr oduct s can be
saf el y subst it ut ed. The f ir st let t er “B” designat es dr ug product s t hat , f or var ious
r easons, t he FDA does not consi der bioequi valent t o t he pharmaceut i cal l y
equival ent dr ug pr oduct .
Therapeutic Equivalence Evaluation Codes
A Codes
Dr ug pr oduct s t hat t he FDA consi der s t her apeut ical l y equi val ent t o ot her
pharmaceut i cal l y equi valent pr oduct s
AA Products in conventional dosage forms that do not present
bioequivalence problems
AB Products that meet necessary bioequivalence requirements
AN Solutions and powders for aerosolization
AO Injectable oil solutions
AO Injectable aqueous solutions, and in certain instances, intravenous
nonaqueous solutions
AT Topical products

B Codes
Dr ug pr oduct s t hat t he FDA does not consider t her apeut ical l y equi val ent t o ot her
pharmaceut i cal l y equi valent pr oduct s at t his t ime
P. 1322


B
*
Drug products that require further FDA investigation and review to
determine therapeutic equivalence
BC Extended-release dosage forms (capsules, injectables, and tablets)
BD Active ingredients and dosage forms that have documented problems
with bioequivalence
BE Delayed-release oral dosage forms
BN Products in aerosol-nebulizer drug-delivery systems
BP Active ingredients and dosage forms that have potential problems with
bioequivalence
BR Suppositories or enemas that deliver drugs for systemic absorption
BS Drug products that have drug standard deficiencies
BT Topical products that have bioequivalence issues
BX Drug products for which the data are sufficient to determine therapeutic
equivalence

P. 1323


P. 1324


P. 1325


Top 200 Prescription Drugs by Trade Name and Generic Namea
Rank Trade Name Generic Name
1 Lortab Hydrocodone/acetaminophen
2 Synthroid Levothyroxine
3 Xanax Alprazolam
4 Potassium Chloride Potassium Chloride
5 Glucophage Metformin
6 Zestril/Prinivil Lisinopril
7 Ultram Tramadol
8 Lasix Furosemide
9 Lipitor Atorvastatin
10 Percocet Oxycodone/acetaminophen
11 Tenormin Atenolol
12 Toprol-XL Metoprolol succinate
13 Lopressor Metoprolol tartrate
14 Hydrochlorothiazide Hydrochlorothiazide
15 Coumadin Warfarin
16 Norvasc Amlodipine
17 Amoxil Amoxicillin
18 OxyContin Oxycodone ER
19 Zithromax and Zmax Azithromycin
20 Darvocet Propoxyphene/acetaminophen
21 Zoloft Sertraline
22 Zantac Ranitidine
23 Zocor Simvastatin
24 Lexapro Escitalopram
25 Nexium Esomeprazole
26 Seroquel Quetiapine
27 Proventil Albuterol
28 Singulair Montelukast
29 Plavix Clopidogrel
30 Deltasone Prednisone
31 Effexor XR Venlafaxine
32 Elavil Amitriptyline
33 Ativan Lorazepam
34 Neurontin Gabapentin
35 Glucotrol and
Glucotrol XR
Glipizide
36 Naprosyn and EC-
Naprosyn
Naproxen
37 Wellbutrin (SR, XL) Bupropion
38 Desyrel Trazodone
39 Prilosec Omeprazole
40 Dyazide Triamterene/hydrochlorothiazide
41 Flexeril Cyclobenzaprine
42 Duragesic Fentanyl transdermal system
43 Prozac Fluoxetine
44 Fosamax Alendronate
45 Vasotec Enalapril
46 Prevacid Lansoprazole
47 Lantus Insulin glargine
48 Premarin Conjugated estrogens
49 Lanoxin Digoxin
50 Valium Diazepam
51 Keflex Cephalexin
52 Paxil CR Paroxetine
53 Reglan Metoclopramide
54 Cardizem CD Diltiazem
55 Ambien Zolpidem
56 Celexa Citalopram
57 Advair Fluticasone/salmeterol
58 Zestoretic Lisinopril/hydrochlorothiazide
59 Vytorin Simvastatin/ezetimibe
60 Zyrtec Cetirizine
61 Fioricet Butalbital/acetaminophen/caffeine
62 Diflucan Fluconazole
63 Ortho Tri-Cyclen Ethinyl estradiol/norgestimate
64 Depakote ER Divalproex
65 Adderall XR Dextroamphetamine/amphetamine
66 Celebrex Celecoxib
67 Diovan Valsartan
68 Lotrel Amlodipine/benazepril
69 Allegra Fexofenadine
70 Klonopin Clonazepam
71 Augmentin XR Amoxicillin/clavulanate
72 Cymbalta Duloxetine
73 Risperdal Risperidone
74 Levaquin Levofloxacin
75 Aldactone Spironolactone
76 Lyrica Pregabalin
77 Zyloprim Allopurinol
78 Protonix Pantoprazole
79 Actos Pioglitazone
80 Dilantin Phenytoin
81 Kenalog Triamcinolone
82 Motrin Ibuprofen
83 Altace Ramipril
84 Coreg Carvedilol
85 Isoptin and Isoptin SR Verapamil
86 Estrace Estradiol
87 Catapres Clonidine
88 Soma Carisoprodol
89 Zetia Ezetimibe
90 Amaryl Glimepiride
91 Flomax Tamsulosin
92 Diovan-HCT Valsartan/hydrochlorothiazide
93 Humalog Insulin lispro
94 Flonase Fluticasone propionate
95 Tylenol with Codeine Acetaminophen/codeine
96 Aricept Donepezil
97 Mevacor Lovastatin
98 Accupril Quinapril
99 Miralax Polyethylene glycol 3350
100 MS Contin Morphine sulfate
101 Cozaar Losartan
102 Ditropan Oxybutynin
103 Detrol Tolterodine
104 TriCor Fenofibrate
105 Combivent Ipratropium/albuterol
106 Zyprexa Olanzapine
107 Crestor Rosuvastatin
108 Remeron Mirtazapine
109 Procardia and
Procardia XL
Nifedipine
110 Imdur Isosorbide mononitrate
111 Topamax Topiramate
112 Actonel Risedronate
113 Atrovent Ipratropium
114 Medrol Methylprednisolone
115 Tessalon Benzonatate
116 Ultracet Tramadol/acetaminophen
117 Sinequan Doxepin
118 Ritalin SR and LA Methylphenidate
119 Avandia Rosiglitazone
120 Cipro XR Ciprofloxacin
121 Bactrim or Septra Sulfamethoxazole/trimethoprim
122 Folic Acid Folic acid
123 Phenergan Promethazine
124 Macrodantin and
Macrobid
Nitrofurantoin
125 Pyridium Phenazopyridine
126 Hyzaar Losartan/hydrochlorothiazide
127 Dilacor XR Diltiazem
128 Vibramycin/Vibra-
Tabs
Doxycycline hyclate
129 Capoten Captopril
130 Tegretol Carbamazepine
131 Concerta Methylphenidate
132 Trileptal Oxcarbazepine
133 Evista Raloxifene
134 Glucovance Glyburide/metformin
135 Namenda Memantine
136 Cardura Doxazosin
137 NovoLog Insulin aspart
138 Flagyl Metronidazole
139 Nasonex Mometasone furoate
140 Restoril Temazepam
141 Micronase Glyburide
142 Xopenex Levalbuterol
143 Xalatan Latanoprost
144 Mycostatin Nystatin
145 Benicar Olmesartan
146 Alesse Ethinyl estradiol/levonorgestrel
147 Abilify Aripiprazole
148 DuoNeb Ipratropium/albuterol
149 Armour Thyroid Thyroid, dessicated
150 Ziac Bisoprolol/hydrochlorothiazide
151 Lotensin Benazepril
152 Phenobarbital Phenobarbital
153 Cleocin Clindamycin
154 Theophylline Theophylline
155 Pravachol Pravastatin
156 Lamictal Lamotrigine
157 Voltaren Diclofenac
158 Spiriva Tiotropium
159 Cogentin Benztropine mesylate
160 Mobic Meloxicam
161 Strattera Atomoxetine
162 Yasmin Ethinyl estradiol/drospirenone
163 Ortho-Novum 7/7/7 Ethinyl estradiol/norethindrone
164 Hytrin Terazosin
165 Avapro Irbesartan
166 Veetids Penicillin V
167 Lopid Gemfibrozil
168 Skelaxin Metaxalone
169 Inderal Propanolol
170 Zovirax Acyclovir
171 Benicar-HCT Olmesartan/hydrochlorothiazide
172 Adipex-P Phentermine
173 Bactroban Mupirocin
174 AcipHex Rabeprazole
175 Pepcid Famotidine
176 Imuran Azathioprine
177 Bentyl Dicyclomine
178 Clozaril Clozapine
179 Biaxin XL Clarithromycin
180 Methadone Methadone
181 Provera Medroxyprogesterone
182 Requip Ropinirole
183 Prempro Conjugated
estrogens/medroxyprogesterone
184 Lithonate & Lithotabs Lithium carbonate
185 Buspar Buspirone
186 Omnicef Cefdinir
187 Lunesta Eszopiclone
188 Relafen Nabumetone
189 Allegra-D Fexofenadine/pseudoephedrine
190 Niaspan Niacin
191 Bumex Bumetanide
192 Demadex Torsemide
193 Lotrisone Clotrimazole/betamethasone
194 Lomotil Diphenoxylate/atropine
195 Lactulose Lactulose
196 Monopril Fosinopril
197 Guaifenex PSE Guaifenesin/pseudoephedrine
198 Flovent Fluticasone propionate
199 Imitrex Sumatriptan
200 Antivert Meclizine
a
This table contains the top 200 prescription drugs dispensed through
independent, chain, food store, mass merchandiser, and deep discount
pharmacies. All forms of the same generic equivalent drug are grouped
together and listed under the brand name when appropriate. Rankings are
based on total number of prescriptions for August 2004 to August 2005, as
measured by SFI's Prescription Drug Audit. Insulin products are included in
the tally. Adapted with permission from Prescription Drug Cards, 23rd ed.
SFI Medical Publishing, 2007.

P. 1326


P. 1327


Top Over-the-Counter (OTC) Drugsa
Trade Name Drug Use
Abreva® Cold sore medication
Actifed® Allergy and cold relief
Advil® Analgesic
Afrin® Nasal decongestant
Aleve® Analgesic
ALternaGEL® Antacid
Anbesol® Oral cavity analgesic
Anusol® Hemorrhoidal agent
Azo Standard® UTI analgesic
Bayer® Aspirin Analgesic
Benadryl® Oral Allergy and cold relief
BEN-GAY® Topical analgesic
Betadine® Antiseptic
Bonine® Motion sickness medication
Bufferin® Analgesic
Caladryl® Topical antipruritic
Carmex® Cold sore medication
Cepastat® Oral cavity analgesic
Chlor-Trimeton® Allergy and cold relief
Chloraseptic® Oral cavity analgesic
Citrucel® Laxative
Claritin® Allergy and cold relief
Claritin-D® Allergy and cold relief
Colace® Stool softener
COLD-EEZE® Cold relief
Compound W® Keratolytic
Cortaid® Topical antipruritic
Debrox® Ear wax removal aid
Delsym® Cough suppressant
Dramamine® Motion sickness medication
Dulcolax® Laxative
Duofilm® Keratolytic
Emetrol® Antiemetic
Estroven® Menopause support
Excedrin® Analgesic
FiberCon® Laxative
Fungi-Nail® Topical antifungal
Gas-X® Antiflatulent
Gyne-Lotrimin® Vaginal antifungal
Herpecin-L® Cold sore medication
Imodium A-D® Antidiarrheal
Ivy Dry® Topical antipruritic
Lactaid® Digestive aid
Lactinex® Antidiarrheal
Lamisil® AT Antifungal
Listerine® Oral cavity antiseptic
Lotrimin AF® Topical antifungal
Maalox® & Maalox® Plus Antacid
Metamucil® Laxative
Midol® & Midol® PMS Analgesic
Monistat® Vaginal Vaginal antifungal
Motrin® IB Analgesic
Mucinex® (Adult) Expectorant
Mylanta® Antacid
Mylicon® Drops Antiflatulence
Myoflex® Topical analgesic
Naphcon® A Ophthalmic anti-allergy
NasalCrom® Allergy and cold relief
Neo-Synephrine® Nasal decongestant
Neosporin® Topical anti-infective
NicoDerm® CQ Smoking cessation aid
Nicorette® Smoking cessation aid
Nix® Pediculicide
Nizoral® Shampoo Topical antifungal
NoDoz® Analeptic
NyQuil® Cough and cold relief
Ocean® Nasal decongestant
Opcon-A® Ophthalmic anti-allergy
Orabase® Oral cavity analgesic
OralBalance® Oral moisturizer
Os-Cal® Essential mineral
Pamprin® Analgesic
PediaCare® Cough and cold relief
Pepcid® Complete Acid reducer
Pepcid-AC® Acid reducer
Pepto Bismol® Antidiarrheal
Peri-Colace® Stool softener plus laxative
Phillips' MOM® Laxative/antacid
Pin-X® Anthelmintic
Preparation H® Hemorrhoidal agent
Prilosec® OTC Acid reducer
RID® Pediculicide
Robitussin® (Adult) Cough relief
Rogaine® Hair growth stimulant
Salivart® Saliva substitute
Senokot® Laxative
Similasan Earache Relief® Earache relief
Slow-Mag® Essential mineral
Sominex® Sleeping aid
Sudafed® Allergy and cold relief
Tagamet HB 200® Acid reducer
Tavist® Allergy and cold relief
Tears Naturale® Artificial tears
Triaminic® Oral Cough and cold relief
Tums® Antacid
Tylenol® Analgesic
Tylenol® Allergy & Sinus Allergy and cold relief
Tylenol® Cold & Flu (Adult) Allergy and cold relief
Tylenol® PM Analgesic
Unisom® Sleeping aid
Zantac® OTC Acid reducer
Zicam® Cold Remedy Cold relief
Zilactin® and Zilactin-B® Cold sore medication
Zostrix® Topical analgesic
a
This table contains the top OTC drugs by pharmacist recommendation in
specific therapeutic classes.
Adapted with permission from Nonprescription Drug Cards, 6th ed. SFI
Medical Publishing, 2006.


Appendix D
National And State Boards of Pharmacy
Contact Information
Thi s appendi x cont ai ns t he most r ecent cont act inf ormat ion f or t he nat i onal and
st at e boar ds of pharmacy. A cur rent list i ng of cont act i nf ormat i on f or st at e boar ds of
pharmacy is mai nt ained at t he Nat i onal Associ at i on of Boar ds of Pharmacy websit e,
ht t p: / / www. nabp. com. I n addit ion, cont act inf ormat ion f or al l t he pharmacy schools
i n t he Uni t ed St at es can be f ound at t he Amer i can Associat ion of Col leges of
Pharmacy Web sit e, www. aacp. or g.
Nat i onal Associ at i on of Boards of PharmacyCarmen A. Cat izoneExecut ive
Dir ect or 1600 Feehanvi l l e Dr iveMount Pr ospect , I L 60056Phone: 847/ 391- 4406Fax:
847/ 391-4502Web sit e: www. nabp. net
State Boards of Pharmacy Alabama Stat e Board of Pharmacy Loui se Fost er
JonesExecut i ve Secret ar y10 I nver ness Cent er , Suit e 110Bi rmingham, AL
35242Phone: 205/ 981-2280Fax: 205/ 981- 2330Web si t e: www. albop. comE-mai l:
lj ones@albop. com
Al aska Board of Pharmacy Sher Zi nnLi censi ng Examiner PO Box 110806Juneau,
AK 99811- 0806Phone: 907/ 465-2589Fax: 907/ 465- 2974Web sit e:
www. commer ce. st at e. ak. us/ occ/ ppha. ht mE-mail:
sher _zi nn@commer ce. st at e. ak. us(t hr ough t he Divisi on of Occupat ional Li censi ng)
Ari zona Stat e Board of Pharmacy Harlan WandExecut ive Dir ect or 4425 West Oli ve
Avenue, Sui t e 140Glendal e, AZ 85302- 3844Phone: 623/ 463- 2727Fax: 623/ 934-
0583Web sit e: www. pharmacy. st at e. az. usE-mai l: hwand@azsbp. com
Arkansas State Board of Pharmacy Charl es S. Campbel lExecut i ve Dir ect or 101
East Capi t ol , Suit e 218Lit t l e Rock, AR 72201Phone: 501/ 682- 0190Fax: 501/ 682-
0195Web sit e: www. arkansas. gov/ asbpE-mai l: char l i e. campbel l@arkansas. gov
Cal if or ni a State Board of Pharmacy Pat ri cia F. Harri sExecut i ve Of f icer 1625 Nort h
Market Boulevar d, N219Sacr ament o, CA 95834Phone: 916/ 574- 7900Fax: 916/ 574-
8618Web sit e: www. pharmacy. ca. gov/ E-mail: pat ricia_har r is@dca. ca. gov
Col orado Stat e Board of Pharmacy Susan L. WarrenPr ogr am Di r ect or 1560
Br oadway, Suit e 1310Denver , CO 80202- 5143Phone: 303/ 894- 7800Fax: 303/ 894-
7764Web sit e: www. dor a. st at e. co. us/ pharmacyE-mai l :
susan. war r en@dora. st at e. co. us
Connect i cut Commi ssi on of Pharmacy Mi chel l e Syl vest reDr ug Cont r ol Agent and
Boar d Administ r at orSt at e Of f ice Bui ldi ng, 165 Capit ol Avenue Room 147Har t f or d, CT
06106Phone: 860/ 713-6070Fax: 860/ 713- 7242Web si t e:
www. ct . gov/ dcp/ si t e/ def aul t . aspE-mai l: michel l e. syl vest r e@ct . gov
P. 1389


Delaware Stat e Board of Pharmacy Davi d W. DrydenExecut i ve Secr et ar yDivision
of Pr of essional Regulat ionCannon Buldi ng861 Sil ver Lake Boulevar d, Suit e
203Dover , DE 19904Phone: 302/ 744- 4526Fax: 302/ 739- 2711Web sit e:
www. dpr. del awar e. govE-mail: debop@st at e. de. us
Di st ri ct of Col umbia Board of Pharmacy Bonni e RampersaudExecut ive
Dir ect or 717 Four t eent h St r eet NW, Suit e 600Washi ngt on, DC 20005Phone: 202/ 724-
4900Fax: 202/ 727- 8471Web sit e: www. dcheal t h. dc. govE-mail :
gr aphel i a. r amseur@dc. gov
Fl ori da Board of Pharmacy Rebecca Post onExecut i ve Dir ect or 4052 Bald Cypr ess
Way, Bin #C04Tal lahassee, FL 32399-3254Phone: 850/ 245- 4292Fax: 850/ 413-
6982Web sit e: www. doh. st at e. f l. us/ mgaE- mai l: r ebecca_post on@doh. st at e. f l. us
Georgia Stat e Board of Pharmacy Syl vi a L. “Sandy” BondExecut i ve
Dir ect orPr of essi onal Li censing Boards237 Coli seum Dr i veMacon, GA 31217-
3858Phone: 478/ 207- 1640Fax: 478/ 207- 1660Web sit e:
www. sos. st at e. ga. us/ plb/ phar macyE-mai l: si bond@sos. st at e. ga. us
Guam Board of Exami ners f or Pharmacy Jane M. Di egoSecr et ar y f or t he Boar dPO
Box 2816Hagat na, GU 96932Phone: 671/ 735-7406 ext 11Fax: 671/ 735- 7413E-mai l:
j mdiego@dphss. govguam. net
Hawai i State Board of Pharmacy Lee Ann Teshi maExecut ive Of f i cerPO Box
3469Honol ul u, HI 96801Phone: 808/ 586- 2694Fax: 808/ 586- 2874Web si t e:
www. hawai i. gov/ dcca/ ar eas/ pvl/ boar ds/ pharmacyE-mai l: pharmacy@dcca. hawai i . gov
I daho Board of Pharmacy Ri chard MarkusonExecut i ve Dir ect or 3380 Amer icana
Ter r ace, Suit e 320Boi se, ID 83706Phone: 208/ 334- 2356Fax: 208/ 334- 3536Web si t e:
www. accessidaho. or g/ bop/ Emai l: rmarkuson@bop. st at e. id. us
I l l i noi s Department of Fi nanci al and Prof essi onal Regul at i on, Di vi si on of
Prof essi onal Regul at i on- Stat e Board of PharmacyKim Scott Pharmacy Boar d
Liaison320 West Washi ngt on, 3rd FloorSpr ingf iel d, I L 62786Phone: 217/ 782-
8556Fax: 217/ 782- 7645Web sit e: www. idf pr. comE-mai l :
PRFGROUP10@i df pr. com(t hr ough Depart ment of Pr of essi onal Regul at ion)
I ndi ana Board of Pharmacy Mart y Al l ai n, Di rectorDir ect or 402 West Washingt on
St r eet , Room W072I ndianapol is, I N 46204- 2739Phone: 317/ 234-2067Fax: 317/ 233-
4236Web sit e: ht t p: / / www. i n. gov/ pla/ bandc/ i sbp/ E-mai l : pl a4@pla. I N. gov
I owa Board of Pharmacy Exami ners Ll oyd K. JessenExecut i ve
Dir ect or/ Secr et ar y400 Sout hwest Eight h St r eet , Sui t e EDes Moi nes, I A 50309-
4688Phone: 515/ 281- 5944Fax: 515/ 281- 4609Web sit e: www. st at e. ia. us/ ibpeE-mai l:
Lloyd. j essen@ibpe. st at e. ia. us
Kansas St at e Board of Pharmacy Debra L. Bi l l i ngsl eyExecut i ve
Secr et ar y/ Dir ect or Landon St at e Of f i ce Bui l di ng, 900 Jackson, Room 560Topeka, KS
66612- 1231Phone: 785/ 296- 4056 Fax: 785/ 296- 8420Web sit e:
ht t p: / / www. kansas. gov/ pharmacyE-mai l : pharmacy@pharmacy. st at e. ks. us
Kent ucky Board of Pharmacy Mi chael A. Burl esonExecut i ve Di r ect orSpi ndlet op
Administ r at ion Bui l di ng, Sui t e 302, 2624 Resear ch Par k Dr i ve, Lexi ngt on, KY
40511Phone: 859/ 246-2820Fax: 859/ 246- 2823Web si t e: ht t p: / / pharmacy. ky. gov/ E-
mai l: mike. bur leson@ky. gov
P. 1390


Loui si ana Board of Pharmacy Mal colm J. BroussardExecut i ve Dir ect or 5615
Cor por at e Boulevar d, Sui t e 8EBat on Rouge, LA 70808-2537Phone: 225/ 925-
6496Fax: 225/ 925- 6499Web sit e: www. labp. comE-mai l: mbr oussar d@l abp. com
Mai ne Board of Pharmacy Geral di ne Bet t sBoar d Administ r at orDepart ment of
Pr of essi onal/ Fi nanci al Regulat ion35 St at e House St at ionAugust a, ME 04333Phone:
207/ 624-8689Fax: 207/ 624- 8637Hear ing I mpai r ed: 207/ 624- 8563PFR/ OLR Web si t e:
www. mai nepr of essional r eg. or gE-mai l: f or al l Licensi ng and Board Meet ing
I nf ormat i on/ I nqui r es and f or Appl icat ion packet s:
kell y. l. mclaughl i n@maine. govEnf orcement inquir i es:
gr egor y. w. cameron@maine. govAdminist r at i on and al l ot her I nquir i es:
ger aldi ne. l . bet t s@mai ne. gov
Maryl and Board of Pharmacy La Verne George NaeseaExecut i ve Dir ect or4201
Pat t erson AvenueBalt imore, MD 21215- 2299Phone: 410/ 764- 4755Fax: 410/ 358-
6207Web sit e: ht t p: / / www. dhmh. st at e. md. us/ pharmacyboar d/ E-mail :
I naesea@dhmh. st at e. md. us
Massachuset t s Board of Regi st rat i on i n PharmacyCharl es R. YoungExecut i ve
Dir ect or 239 Causeway St reet , 2nd FloorBost on, MA 02114Phone: 617/ 973- 0800Fax:
617/ 973-0983Web sit e: www. mass. gov/ dpl/ boards/ ph/ index. ht mE-mai l:
char l es. young@st at e. ma. us
Mi chi gan Board of Pharmacy Rae Ramsdel lDir ect or , Licensi ng Di vision611 West
Ot t awa, 1st Floor PO Box 30670Lansing, MI 48909- 8170Phone: 517/ 335- 0918Fax:
517/ 373-2179Web sit e: ht t p: / / www. mi chigan. gov/ heal t hl i censeEmai l :
r hr amsd@michi gan. gov
Mi nnesot a Board of Pharmacy Cody C. Wi bergExecut ive Di r ect or 2829 Uni ver si t y
Avenue SE, Sui t e 530Minneapol i s, MN 55414- 3251Phone: 612/ 617- 2201Fax:
612/ 617-2212Web sit e: ht t p: / / www. phcybr d. st at e. mn. usE-mai l:
Cody. Wiber g@st at e. mn. us
Mi ssi ssi ppi State Board of Pharmacy Leland McDi vi t t Execut i ve Dir ect or 204 Key
Dr ive, Suit e CMadi son, MS 39110Phone: 601/ 605- 5388 Fax: 601/ 605- 9546Web sit e:
www. mbp. st at e. ms. usE-mai l: l mcdivit t @mbp. st at e. ms. us
Mi ssouri Board of Pharmacy Kevi n E. Ki nkadeExecut ive Di r ect orPO Box
625Jef f er son Cit y, MO 65102Phone: 573/ 751- 0091Fax: 573/ 526-3464Web sit e:
ht t p: / / www. pr . mo. gov/ pharmaci st s. aspE-mai l: kevi n. kinkade@pr . mo. gov
Mont ana Board of PharmacyExecut i ve Di r ect or PO Box 200513301 Sout h Park
Avenue, 4t h Fl oorHel ena, MT 59620- 0513Phone: 406/ 841-2355Fax: 406/ 841-
2305Web sit e:
ht t p: / / mt . gov/ dl i/ bsd/ li cense/ bsd_boar ds/ pha_board/ boar d_page. aspE-mai l :
dl i bsdpha@st at e. mt . us
Nebraska Board of Pharmacy Becky Wi sel l Execut i ve Secr et ar yPO Box
94986Lincol n, NE 68509- 4986Phone: 402/ 471- 2118Fax: 402/ 471- 3577Web sit e:
www. hhs. st at e. ne. usE- mail : becky. wisel l@hhss. ne. gov
Nevada St at e Board of Pharmacy Larry L. Pi nsonExecut i ve Secr et ar y555 Double
Eagle Cir cui t , Suit e 1100Reno, NV 89521Phone: 775/ 850-1440Fax: 775/ 850-
1444Web sit e: ht t p: / / st at e. nv. us/ pharmacyE-mai l: pharmacy@govmail . st at e. nv. us
P. 1391


New Hampshi re Board of Pharmacy Paul G. Boi sseauExecut ive Secret ar y57
Regional Dr iveConcor d, NH 03301- 8518Phone: 603/ 271- 2350Fax: 603/ 271- 2856Web
sit e: www. nh. gov/ pharmacyE-mail: pharmacy. board@nh. gov
New Jersey Board of Pharmacy Joanne BoyerExecut i ve Dir ect or 124 Hal sey
St r eet Newark, NJ 07101Phone: 973/ 504- 6450Fax: 973/ 648- 3355Web sit e:
www. st at e. nj . us/ l ps/ ca/ boar ds. ht mE-mai l: boyerj @dca. lps. st at e. nj . us
New Mexi co Board of Pharmacy Wi l l i am HarveyExecut i ve Dir ect or / Chief Durg
I nspect or 5200 Oakl and NE, Suit e AAl buquer que, NM 87113Phone: 505/ 222-
9830Fax: 505/ 222- 9845Web sit e: www. st at e. nm. us/ pharmacyE-mail:
Wil l iam. Har vey@st at e. nm. us
New York Board of Pharmacy Lawrence H. Mokhi berExecut i ve Secr et ar y89
Washi ngt on Avenue, 2nd Floor WAlbany, NY 12234- 1000Phone: 518/ 474- 3817 ext .
130Fax: 518/ 473- 6995Web si t e: www. op. nysed. govE-mai l: pharmbd@mai l. nysed. gov
Nort h Carol i na Board of Pharmacy Jack W. Campbel l I VExecut i ve Dir ect orPO Box
4560Chapel Hi l l, NC 27515- 4560Phone: 919/ 942-4454Fax: 919/ 967- 5757Web sit e:
www. ncbop. or gE-mai l: j campbel l @ncbop. or g
Nort h Dakota Stat e Board of Pharmacy Howard C. Anderson Jr Execut i ve
Dir ect orPO Box 1354Bismar ck, ND 58502- 1354Phone: 701/ 328- 9535Fax: 701/ 328-
9536Web sit e: www. nodakpharmacy. comE-mai l: ndboph@bt i net . net
Ohi o Stat e Board of Pharmacy Wi l l i am T. Wi nsl eyExecut i ve Dir ect or 77 Sout h Hi gh
St r eet Room 1702Col umbus, OH 43215- 6126Phone: 614/ 466- 4143Fax: 614/ 752-
4836Web sit e: www. pharmacy. ohio. govE-mai l: exec@bop. st at e. oh. us
Oklahoma Stat e Board of Pharmacy Bryan H. Pot t erExecut ive Di r ect or4545
Li ncol n Boulevar d, Suit e 112Oklahoma Ci t y, OK 73105-3488Phone: 405/ 521-
3815Fax: 405/ 521- 3758Web sit e: www. pharmacy. ok. govE-mail:
pharmacy@pharmacy. ok. gov
Oregon St at e Board of Pharmacy Gary A. Schnabel Execut i ve Dir ect or 800
Nor t heast Or egon St reet , Suit e 150Port land, OR 97232Phone: 971/ 673-0001Fax:
971/ 673-0002Web sit e: www. phar macy. st at e. or. usE- mai l:
pharmacy. board@st at e. or. us
Pennsyl vani a Stat e Board of Pharmacy Melani e ZimmermanExecut i ve
Secr et ar yPO Box 2649Harr i sbur g, PA 17105- 2649Phone: 717/ 783-7156Fax:
717/ 787-7769Web sit e: www. dos. st at e. pa. us/ pharmE-mai l: st - phar macy@st at e. pa. us
Puerto Ri co Board of Pharmacy Madga Bouet Execut ive Dir ect or , Depar t ment of
Healt h, Boar d of PharmacyCal l Box 10200, Sant ur ce, PR 00908Phone: 787/ 724-
7282Fax: 787- 725- 7903E-mail : mbouet @sal ud. gov. pr
Rhode I sl and Board of Pharmacy Cat heri ne A. CordyExecut i ve Dir ect or3 Capit ol
Hi l l , Room 205Pr ovidence, RI 02908- 5097Phone: 401/ 222-2837Fax: 401/ 222-
2158Web sit e: www. heal t h. r i . gov/ hsr / prof essions/ pharmacy. phpE-mai l:
cat hyc@doh. st at e. r i. us
P. 1392


Sout h Carol i na Department of Labor, Li censi ng, and Regul at i on-Board of
PharmacyLeeAnn Bundri ckAdmi nist r at orKingst r ee Bui ldi ng110 Cent er view Dr i ve,
Sui t e 306Col umbia, SC 29210Phone: 803/ 896- 4700Fax: 803/ 896-4596Web sit e:
www. l l r onl i ne. com/ POL/ pharmacyE-mai l: bundr i ci @l lr . sc. gov
Sout h Dakota Stat e Board of Pharmacy Denni s M. JonesExecut ive Secret ar y4305
Sout h Louise Avenue, Suit e 104Si oux Fal ls, SD 57106Phone: 605/ 362- 2737Fax:
605/ 362-2738Web sit e: www. st at e. sd. us/ doh/ pharmacyE-mail :
dennis. j ones@st at e. sd. us
Tennessee Board of Pharmacy Terry Webb Gri nder I nt er i m Execut i ve
Dir ect or Tennessee Depar t ment of Commer ce and I nsur ance, Board of Phar macyDavy
Cr ocket t Tower, 2nd Fl oor 500 James Robert son PkwyNashvi l le, TN 37243-
1149Phone: 615/ 741- 2718Fax: 615/ 741- 2722Web sit e:
www. st at e. t n. us/ commerce/ boar ds/ pharmacyE-mai l: t err y. gr i nder @st at e. t n. us
Texas Stat e Board of Pharmacy Gay DodsonExecut i ve Dir ect or 333 Guadalupe,
Tower 3, Suit e 600Aust i n, TX 78701- 3942Phone: 512/ 305-8000Fax: 512/ 305-
8082Web sit e: www. t sbp. st at e. t x. usE-mai l: gay. dodson@t sbp. st at e. t x. us
Utah Board of Pharmacy Diana L. BakerBur eau Manager PO Box 146741Salt Lake
Cit y, UT 84114- 6741Phone: 801/ 530- 6179Fax: 801/ 530- 6511Web sit e:
ht t p: / / www. dopl . ut ah. gov/ E-mai l : dbaker @ut ah. gov(t hr ough Di vi si on of Occupat i onal
and Pr of essional Licensi ng)
Vermont Board of Pharmacy Peggy At ki nsBoar d Administ r at or Of f ice of
Pr of essi onal Regulat ion26 Ter r ace St r eet Mont peli er , VT 05609- 1106Phone:
802/ 828-2373Fax: 802/ 828- 2465Web si t e: www. vt pr of essionals. or gE-mai l:
pat ki ns@sec. st at e. vt . us
Vi rgi n I sl ands Board of Pharmacy Lydia T. Scot t Execut ive Assist ant Depart ment
of Heal t hSchneider Regi onal Cent er 48 Sugar Est at eSt . Thomas, VI 00802Phone.
340/ 774-0117Fax: 340/ 777- 4001E-mai l: lydia. scot t @usvi- doh. or g
Vi rgi ni a Board of Pharmacy El i zabet h Scott Russel l Execut i ve Dir ect or6603 West
Br oad St r eet , 5t h FloorRi chmond, VA 23230- 1712Phone: 804/ 662-9911Fax:
804/ 662-9313Web sit e: www. dhp. st at e. va. us/ pharmacy/ deaf aul t . ht m( or t hr ough
Depart ment of Heal t h Pr of essi ons at www. dhp. st at e. va. us)E-mai l:
scot t i. r ussel l@dhp. vir gi ni a. gov
Washi ngt on Stat e Board of Pharmacy St even M. SaxeExecut i ve Dir ect orPO Box
47863Olympi a, WA 98504- 7863Phone: 360/ 236- 4825Fax: 360/ 586- 4359Web si t e:
ht t ps: / / f or t ress. wa. gov/ doh/ hpqa1/ hps4/ pharmacy/ def aul t . ht mE-mai l :
St even. Saxe@doh. wa. gov
West Vi rgi ni a Board of Pharmacy Wi l l iam T. Dougl ass JrExecut i ve Dir ect or and
Gener al Counsel232 Capit ol St r eet Char lest on, WV 25301Phone: 304/ 558- 0558Fax:
304/ 558-0572Web sit e: ht t p: / / www. wvbop. com/ E-mai l : wdouglass@wvbop. com
P. 1393


Wi sconsi n Pharmacy Exami ni ng Board Tom RyanBur eau Dir ect or1400 East
Washi ngt onPO Box 8935Madison, WI 53708- 8935Phone: 608/ 266-2112Fax: 608/ 267-
0644Web sit e: ht t p: / / www. dr l. st at e. wi. us/ E-mail : t homas. r yan@dr l. st at e. wi . us
Wyomi ng Stat e Board of Pharmacy James T. CarderExecut i ve Dir ect or 632 Sout h
David St r eet Casper , WY 82601Phone: 307/ 234-0294Fax: 307/ 234- 7226Web sit e:
ht t p: / / pharmacyboard. st at e. wy. us/ E-mail: wybop@st at e. wy. us
Repr int ed wit h permissi on f r om Nat i onal Associ at i on of Boards of Pharmacy, Mount
Pr ospect , I L.

Appendix E
Budgeting for Drug Information Resources
Basic Library
References Cost
a


American Hospital Formulary Service
(AHFS) Drug Information
$ 239.00
Drug Facts and Comparisons $ 226.95
Handbook on Injectable Drugs $ 234.00

Handbook of Non-Prescription Drugs: An
Interactive Approach to Self-Care
$ 149.95
Martindale: The Complete Drug Reference $ 550.00
Nonprescription Product Therapeutics $ 94.95
Physicians' Desk Reference $ 94.95
Remington's Pharmaceutical Sciences $ 137.00
USP DI (three-volume set) $ 412.00
Additional Resources
References Cost
a

Drug-drug interaction

Drug Interactions Analysis and Management $ 210.00
Drug Interaction Facts $ 235.00
Evaluations of Drug Interactions $ 240.00
Herbal

PDR for Herbal Medicines $ 59.95
The Review of Natural Products $ 169.00
Natural Medicine Comprehensive Database $ 92.00

Natural Standard Herb and Supplement
Reference
$ 133.00
Internal medicine

Cecil Medicine $ 219.00
Harrison's Principles of Internal Medicine $ 137.75
Pediatrics

Pediatric Dosage Handbook $ 49.95
The Harriet Lane Handbook $ 54.95
Pharmacokinetics


Applied Biopharmaceutics and
Pharmacokinetics
$ 62.95
Clinical Pharmacokinetics $ 46.00
Concepts in Clinical Pharmacokinetics $ 66.00

Applied Pharmacokinetics and
Pharmacodynamics: Principles of
Therapeutic Drug Monitoring
$ 79.95
Pharmacology


Goodman and Gilman's The Pharmacological
Basis of Therapeutics
$ 140.00
Pregnancy/breast-feeding

Drugs in Pregnancy and Lactation $ 99.00
Therapeutics


Applied Therapeutics: The Clinical Use of
Drugs
$ 213.00

Pharmacotherapy: A Pathophysiologic
Approach
$ 206.00

Textbook of Therapeutics: Drug and Disease
Management
$ 213.00
CD ROM computer systems/programs

Clinical Pharmacology $ 5,800.00
Lexi-Comp Online $ 3,000.00
DataKinetics $ 1,225.00
Facts and Comparisons 4.0 (online) $ 2,000.00
Iowa Drug Information System $ 9,000+
IPA $ 3,000+
Medline $ 20,000+
MedTeach Patient Education Program $ 611.00
UPTODATE (stand alone) $ 1,611.93
Micromedex


Diseasedex Must contact
representative for price

Drugdex Must contact
representative for price

Poisindex Must contact
representative for price
Other Micromedex databases


CareNotes Must contact
representative for price

Drug-Reax Must contact
representative for price

Kinetidex Must contact
representative for price

Martindale: The Complete Drug Reference Must contact
representative for price

PDR Must contact
representative for price

P&T Quik Must contact
representative for price

Reprorisk Must contact
representative for price
Major Online Vendors
American Chemical Society

Dialog

EBSCO

Elsevier
Gale Group

National Library of Medicine
Ovid

OCLC First Search
ProQuest

ScienceDirect

Thomson

Wolters Kluwer
a
Costs are approximate and are based on 2007 figures. Costs vary depending
upon selection of format site versus individual license fees, concurrent users,
number of beds in facility, or number of students enrolled. Institutional
subscriptions are more expensive than individual subscriptions. It is important to
have the appropriate site license.



45
Seizure Disorders
Azi t a Razzaghi
I. INTRODUCTION
A. Def i ni t i ons
1. Sei zures ar e char act er i zed by an excessi ve, hyper synchr onous di schar ge of
cor t i cal neur on act i vi t y, whi ch can be measur ed by t he el ect r oencephal ogr am
( EEG) . Ì n addi t i on, t her e may be di st ur bances i n consci ousness, sensor y mot or
syst ems, subj ect i ve wel l - bei ng, and obj ect i ve behavi or ; sei zur es ar e usual l y br i ef ,
wi t h a begi nni ng and an end, and may pr oduce post sei zur e i mpai r ment .
2. Epi I epsy i s def i ned as a chr oni c sei zur e di sor der , or gr oup of di sor der s,
char act er i zed by sei zur es t hat usual l y r ecur unpr edi ct abl y i n t he absence of a
consi st ent pr ovoki ng f act or . The t er m epi l epsy i s der i ved f rom t he Gr eek wor d
meani ng " t o sei ze upon¨ or " t aki ng hol d of . ¨ Ì t was f i r st descr i bed by Hughl i ngs
Jackson i n t he 19t h cent ur y as an i nt er mi t t ent der angement of t he ner vous syst em
due t o a sudden, excessi ve, di sor der l y di schar ge of cer ebr al neur ons.
3. ConvuI si ons ar e vi ol ent , i nvol unt ar y cont r act i ons of t he vol unt ar y muscl es. A
pat i ent may have epi l epsy or a sei zur e di sor der wi t hout convul si ons.
B. CI assi f i cat i on. An al t er nat i ve sei zur e cl assi f i cat i on i s bei ng devel oped t hat i s
pur el y sympt om based. Thi s consi st s of f our cat egor i es: sensor i al ( aur as) ,
consci ousness, aut onomi c, and mot or . Al so, t he i nt er nat i onal l eague agai nst
epi l epsy i s est abl i shi ng a f our - l evel descr i pt i ve sei zur e cl assi f i cat i on based on
sympt oms, apat hophysi ol ogi cal sei zur e, an epi l ept i c syndr ome, and f unct i onal
di sabi l i t y. At pr esent , t her e ar e t wo syst ems of cl assi f i cat i on of sei zur e di sor der :
one i s based on t he sei zur e t ype and char act er i st i cs ( Tabl e 45- 1) , and t he ot her i s
based on t he
P. 984

char act er i st i cs of t he epi l epsy ( i ncl udi ng age at onset , et i ol ogi cal f act or s, and
f r equency) and char act er i st i cs of t he sei zur e (Tabl e 45- 2) .
Table 45-1. International Classification of Epileptic Seizures
I. Partial seizures (seizures beginning locally)
A. Simple partial seizures (consciousness not impaired)
1. With motor symptoms
2. With somatosensory or special sensory symptoms
3. With autonomic symptoms
4. With behavioral symptoms

B. Complex partial seizures (with impairment oI
consciousness)

1. Beginning as simple partial seizures and
progressing to impairment oI consciousness
a. Without automatisms
b. With automatisms
2. With impairment oI consciousness at onset
a. With no other Ieatures
b. With Ieatures oI simple partial seizures
c. With automatisms

C. Partial seizures (simple or complex). secondarily
generalized
II. Generalized seizures (bilaterally symmetric. without localized
onset)
A. Absence seizures
1. True absence seizures (petit mal)
2. Atypical absence seizures
B. Myoclonic seizures
C. Clonic seizures
D. Tonic seizures
E. Tonic-clonic seizures (grand mal)
F. Atonic seizures
III. Unclassified seizures
Reprinted Irom Commission on ClassiIication and Terminology oI the
International League against Epilepsy. Proposal Ior classiIication oI
epilepsies and epileptic syndromes. Epilepsia 1985;26:268-278.

1. Part i aI sei zures ar e t he most common sei zur e t ype, occur r i ng i n appr oxi mat el y
80% of pat i ent s wi t h epi l epsy.
Table 45-2. Classification of Epilepsies and Epileptic Syndromes
I. Localized-related (focal. local. partial) epilepsies and syndromes
A. Idiopathic (with age-related onset)

1. Benign childhood epilepsy with centrotemporal
spikes (rolandic epilepsy)
2. Childhood epilepsy with occipital paroxysms
B. Symptomatic

1. Chronic progressive epilepsia partialis continua oI
childhood

2. Syndromes characterized by speciIic modes oI
precipitation
3. Temporal lobe epilepsies
4. Frontal lobe epilepsies
5. Parietal lobe epilepsies
6. Occipital lobe epilepsies
C. Cryptogenic
II. Generalized epilepsies and syndromes
A. Idiopathic (with age-related onset)
1. Benign neonatal Iamilial convulsions
2. Benign neonatal convulsions
3. Benign myoclonic epilepsy in inIancy
4. Childhood absence epilepsy (pyknolepsy)
5. Juvenile absence epilepsy
6. Juvenile myoclonic epilepsy

7. Epilepsy with generalized tonic-clonic seizures on
awakening

8. Other generalized idiopathic epilepsies not deIined
above

9. Epilepsies with seizures precipitated by speciIic
modes oI activation
B. Cryptogenic or symptomatic (in order oI age)
1. West syndrome (inIantile spasms)
2. Lennox-Gastaut syndrome
3. Epilepsy with myoclonic-astatic seizures
4. Epilepsy with myoclonic absences
C. Symptomatic
1. Nonspecific etiology
a. Early myoclonic encephalopathy

b. Early inIantile epileptic encephalopathy
with suppression burst

c. Other symptomatic generalized epilepsies
not deIined above

2. Specific syndromes and generalized seizures
complicating other disease states
III. Epilepsies and syndromes undetermined whether focal or
generalized
A. With both focal and generalized seizures
1. Neonatal seizures
2. Severe myoclonic epilepsy in inIancy

3. Epilepsy with continuous spike waves during slow-
wave sleep

4. Acquired epileptic aphasia (Landau-KleIIner
syndrome)
a

5. Other undetermined epilepsies not deIined above
B. Without unequivocal generalized or focal features
IV. Special situations
A. Febrile convulsions
B. Isolated seizures or isolated status epilepticus

C. Seizures occurring only when there is an acute metabolic or
toxic event due to such Iactors as alcohol. drugs. eclampsia.
and nonketotic hyperglycemia
a
Believed to be a localized-related epilepsy.
Reprinted with permission Irom Bleck TP. Convulsive disorders: the use oI
anticonvulsant drugs. Clin Neuropharmacol 1990;1:198-209.

P. 985


a. CI i ni caI and EEG changes i ndi cat e i ni t i al act i vat i on of a syst em of neur ons
l i mi t ed t o par t of one cer ebr al hemi spher e t hat may spr ead t o ot her or al l br ai n
ar eas. Mani f est at i ons of t he sei zur es depend on t he si t e of t he epi l ept ogeni c f ocus
i n t he br ai n.
b. Par t i al sei zur es ar e subcl assi f i ed as si mpI e (usual l y uni l at er al i nvol vement ) or
compI ex ( usual l y bi l at er al i nvol vement ) . Ì mpai r ment of consci ousness i s a f eat ur e
of compl ex sei zur es. Consci ousness i s def i ned as t he degr ee of awar eness and
r esponsi veness of t he pat i ent t o ext er nal l y appl i ed st i mul i .
( 1) Si mpI e part i aI sei zures gener al l y do not cause l oss of consci ousness. Si gns
and sympt oms of si mpl e par t i al sei zur es may be pr i mar i l y mot or , sensor y,
somat osensor y, aut onomi c, or behavi or al . These si gns and sympt oms may hel p
pi npoi nt t he si t e of t he abnor mal br ai n di schar ge, f or exampl e, l ocal i zed numbness
or t i ngl i ng r ef l ect s a dysf unct i on i n t he sensor y cor t ex, l ocat ed i n t he par i et al l obe.
( a) Mot or si gns i ncl ude convul si ve j er ki ng, chewi ng mot i ons, and l i p smacki ng.
( b) Sensory and somat osensory mani f est at i ons i ncl ude par est hesi as and aur as.
( c) Aut onomi c si gns i ncl ude sweat i ng, f l ushi ng, and pupi l di l at i on.
( d) Behavi oraI mani f est at i ons, whi ch ar e somet i mes accompani ed by i mpai r ed
consci ousness, i ncl ude déj à vu exper i ences, st r uct ur ed hal l uci nat i ons, and
dysphasi a.
( 2) CompI ex part i aI sei zures ar e accompani ed by i mpai r ed consci ousness;
however , i n some cases, t he i mpai r ment pr ecedes or f ol l ows t he sei zur e. These
sei zur es have var i abl e mani f est at i ons.
( a) Pur posel ess behavi or i s common.
( b) The af f ect ed per son may have a gl assy st ar e, may wander about ai ml essl y, and
may speak uni nt el l i gi bl y.
( c) Psychomot or ( t emporal l obe) epi l epsy may l ead t o aggr essi ve behavi or ( e. g. ,
out bur st s of r age or vi ol ence) .
( d) Post i ct al conf usi on usual l y per si st s f or 1- 2 mi n af t er t he sei zur e ends.
( e) Aut omat i sm ( e. g. , pi cki ng at cl ot hes) i s common and may f ol l ow vi sual , audi t or y,
or ol f act or y hal l uci nat i ons.
2. GeneraI i zed sei zures ar e di f f use, af f ect i ng bot h cer ebr al hemi spher es.
a. CI i ni caI and EEG changes i ndi cat e i ni t i al i nvol vement of bot h hemi spher es.
( 1) Consci ousness may be i mpai r ed, and t hi s i mpai r ment may be t he i ni t i al
mani f est at i on.
( 2) Mot or mani f est at i ons ar e bi l at eral .
( 3) The i ct al EEG pat t er ns i ni t i al l y ar e bi l at er al and pr esumabl y r ef l ect neur onal
di schar ge, whi ch i s wi despr ead i n bot h hemi spher es.
b. Ther e ar e t hr ee t ypes of gener al i zed sei zur es.
( 1) I di opat hi c epi I epsi es have an age- r el at ed onset , t ypi cal cl i ni cal and EEG
char act er i st i cs, and a pr esumed genet i c or i gi n.
( 2) Sympt omat i c epi I epsi es ar e consi der ed t he consequence of a known or
suspect ed under l yi ng di sor der of t he cent r al ner vous syst em ( CNS) .
( 3) Crypt ogeni c epi I epsy r ef er s t o a di sor der f or whi ch t he cause i s hi dden or
occul t ; i t i s pr esumed t o be sympt omat i c, but t he causal f act or s ar e unknown. Ì t i s
age r el at ed, but of t en does not have wel l - def i ned cl i ni cal and EEG char act er i st i cs.
c. Si gns and sympt oms of gener al i zed sei zur es may be mi nor or maj or .
( 1) Absence ( pet i t maI ) sei zures pr esent as al t er at i ons of consci ousness
( absences) l ast i ng 10- 30 sec.
( a) St ar i ng (wi t h occasi onal eye bl i nki ng) and l oss or r educt i on i n post ur al t one ar e
t ypi cal . Ì f t he sei zur e t akes pl ace dur i ng conver sat i on, t he i ndi vi dual may br eak of f
i n mi dsent ence.
( b) Enur esi s and ot her aut onomi c component s may occur dur i ng absence sei zur es.
( c) Some pat i ent s exper i ence 100 or mor e absences dai l y.
( d) Onset of t hi s sei zur e t ype occur s f r om age 3 t o 16 year s; i n most pat i ent s,
absence sei zur es di sappear by age 40.
( 2) MyocI oni c ( bi I at eraI massi ve epi I ept i c myocI onus) sei zures pr esent as
i nvol unt ar y j er ki ng of t he f aci al , l i mb, or t r unk muscl es, possi bl y i n a r hyt hmi c
manner .
( 3) CI oni c sei zures ar e char act er i zed by sust ai ned muscl e cont r act i ons al t er nat i ng
wi t h r el axat i on.
P. 986


( 4) Toni c sei zures i nvol ve sust ai ned t oni c muscl e ext ensi on ( st i f f eni ng) .
( 5) GeneraI i zed ( grand maI ) t oni c- cI oni c sei zures cause sudden l oss of
consci ousness.
( a) The i ndi vi dual becomes r i gi d and f al l s t o t he gr ound. Respi r at i ons ar e
i nt er r upt ed. The l egs ext end, and t he back ar ches; cont r act i on of t he di aphr agm
may i nduce gr unt i ng. Thi s t oni c phase l ast s f or about 1 mi n.
( b) A cl oni c phase f ol l ows, mar ked by r api d bi l at er al muscl e j er ki ng, muscl e
f l acci di t y, and hyper vent i l at i on. Ì ncont i nence, t ongue bi t i ng, t achycar di a, and heavy
sal i vat i on somet i mes occur .
( c) Dur i ng t he post i ct al phase, t he i ndi vi dual may exper i ence headache, conf usi on,
di sor i ent at i on, nausea, dr owsi ness, and muscl e sor eness. Thi s phase may l ast f or
hour s.
( d) Some pat i ent s wi t h epi l epsy have ser i al gr and mal sei zur es, r egai ni ng
consci ousness br i ef l y bet ween at t acks. Ì n some cases, gr and mal sei zur es occur
r epeat edl y wi t h no r ecover y of consci ousness bet ween at t acks ( st atus epi I ept i cus) ;
t hi s di sor der i s di scussed i n Ì Ì Ì . A.
( 6) At oni c sei zures ( drop at t acks) ar e char act er i zed by a sudden l oss of post ur al
t one so t hat t he i ndi vi dual f al l s t o t he gr ound. They occur pr i mar i l y i n chi l dr en.
C. Epi demi oI ogy
1. Most common neuroI ogi caI di sorder
2. Epi l epsy has a pr eval ence of appr oxi mat el y 1% ( i . e. , 500, 000 cases per 50
mi l l i on per sons wor l dwi de) .
3. Ì n t he Uni t ed St at es, t he pr eval ence of epi l epsy i s 6. 42 cases per 1000 peopl e.
4. The onset of sei zur es i s gr eat est dur i ng t he 1st year of l i f e; t hi s pr obabi l i t y
decr eases each decade af t er t he 1st year unt i l age 60. Appr oxi mat el y 1 of 50
chi l dr en and 1 of 100 adul t s ar e af f ect ed.
5. Appr oxi mat el y 70% of peopl e wi t h epi l epsy have onl y one sei zur e t ype; t he
r emai nder have t wo or mor e sei zur e t ypes.
D. Cause. Some sei zur es ar i se secondar y t o ot her condi t i ons. However , i n most
cases, t he cause of t he sei zur e i s unknown.
1. Pri mary ( i di opat hi c) sei zures have no i dent i f i abl e cause.
a. Thi s t ype of sei zur e af f ect s about 75% of peopl e wi t h epi l epsy.
b. The onset of pr i mar y sei zur es t ypi cal l y occur s bef or e age 20.
c. Bi r t h t r auma, her edi t ar y f act or s, and unexpl ai ned met abol i c di st ur bances have
been pr oposed as possi bl e causes.
2. Secondary sei zures ( sympt omat i c or acqui red sei zures) occur secondar y t o an
i dent i f i abl e cause.
a. Di sor der s t hat may l ead t o secondar y sei zur es i ncl ude
( 1) Ì nt r acr ani al neopl asms
( 2) Ì nf ect i ous di seases, such as meni ngi t i s, i nf l uenza, t oxopl asmosi s, mumps,
measl es, and syphi l i s
( 3) Hi gh f ever ( i n chi l dr en)
( 4) Head t r auma
( 5) Congeni t al di seases
( 6) Met abol i c di sor der s, such as hypogl ycemi a and hypocal cemi a
( 7) Al cohol or dr ug wi t hdr awal
( 8) Li pi d st or age di sor der s
( 9) Devel opment al abnor mal i t i es
b. Age at sei zur e onset i s associ at ed wi t h speci f i c causes (Tabl e 45- 3) .
E. Pat hophysi oI ogy. Sei zur es r ef l ect a sudden, abnor mal , excessi ve neur onal
di schar ge i n t he cer ebr al cor t ex. Any abnor mal neur onal di schar ge coul d pr eci pi t at e
a sei zur e ( Fi gur e 45- 1) .
1. NormaI f i ri ng of neurons, whi ch usual l y or i gi nat e f r om t he gr ay mat t er of one or
mor e cor t i cal or subcor t i cal ar eas, r equi r es t he f ol l owi ng el ement s:
a. VoI t age-dependent i on channeI s ar e i nvol ved i n act i on- pot ent i al pr opagat i on or
bur st gener at i on.
P. 987


Table 45-3. Probable Causes of Recurrent Seizures by Age Group
Age at Seizure
Onset
Probable Cause of Seizure
Birth-1
month
Birth iniury or anoxia. congenital hereditary diseases. and
metabolic disorders
1-6 months As above. plus inIantile spasms
6 months-2
years
InIantile spasms. Iebrile convulsions. birth iniury or
anoxia. meningitis. and head trauma
3-10 years Birth iniury or anoxia. meningitis. cerebral vessel
thrombosis. and idiopathic epilepsy
10-18 years Idiopathic epilepsy and head trauma
18-25 years Idiopathic epilepsy. trauma. neoplasm. and withdrawal
Irom alcohol or drugs
35-60 years Trauma. neoplasm. vascular disease. and withdrawal Irom
alcohol or drugs
~ 60 years Vascular disease. neoplasm. degenerative disease. and
trauma

b. Neurot ransmi t t ers cont r ol neur onal f i r i ng, i ncl udi ng exci t at or y neur ot r ansmi t t er s,
acet yl chol i ne, nor epi nephr i ne, hi st ami ne, cor t i cot r opi n- r el easi ng f act ors ( CRFs) ,
i nhi bi t or y neur ot r ansmi t t er s, v- ami nobut yr i c aci d ( GABA) , and dopami ne; t her ef or e,
nor mal neur onal act i vi t y r equi r es adequat e i ons ( e. g. , sodi um, pot assi um, cal ci um);
exci t at or y and i nhi bi t or y neur ot r ansmi t t er s; and gl ucose, oxygen, ami no aci ds, and
adequat e syst emi c pH.
c. Peopl e wi t h epi l epsy may be genet i caI I y pr edi sposed t o a I ower sei zure
t hreshoI d.
d. A di encephaI i c nerve group t hat nor mal l y suppr esses excessi ve br ai n di schar ge
may be deaf f er ent at ed, hyper sensi t i ve, and vul ner abl e t o act i vat i on by var i ous
st i mul i i n i ndi vi dual s wi t h epi l epsy.

Figure 45-1. Gross anatomy oI the brain. Clinical
maniIestation oI seizures depends on the area oI
the cortex that is aIIected and its Iunction. the
degree oI irritability. and the identity oI the
impulse.
P. 988


e. Dur i ng sei zur es, t here i s an i ncr eased use of ener gy, oxygen, and, consequent l y,
an i ncr eased pr oduct i on of car bon di oxi de. Because of t he l i mi t ed capaci t y t o
i ncr ease t he bl ood f l ow t o t he br ai n, t he bl ood suppl y may be oxygen def i ci ent . The
r at i o of suppl y t o demand decr eases when t he sei zur e epi sode i s pr ol onged, l eadi ng
t o i ncr eased i schemi a and neur onal dest r uct i on. Thus i t i s cr uci al t o di agnose
sei zur es and t r eat t hem as soon as possi bl e.
2. AbnormaI eI ect ri caI brai n act i vi t y occur r i ng dur i ng a sei zur e usual l y pr oduces
charact eri st i c changes on the EEG. Each par t of t he cor t i cal ar ea has i t s own
f unct i on, and t he cl i ni cal pr esent at i on of a sei zur e depends on t he si t e, t he degr ee
of i r r i t abi l i t y of t he ar ea, and t he i nt ensi t y of t he i mpul se.
3. Sei zur e act i vi t y may i ncl ude t hr ee maj or phases.
a. A prodrome may pr ecede t he sei zur e by hour s or days.
( 1) Changes i n behavi or or mood t ypi cal l y occur dur i ng t he pr odr ome.
( 2) Thi s phase may i ncl ude an aur a÷a subj ect i ve sensat i on, such as an unusual
smel l or f l ashi ng l i ght .
b. The i ct aI phase i s t he sei zur e i t sel f . Ì n some cases, i t s onset i s her al ded by a
scr eam or cr y.
c. The post i ct aI phase t akes pl ace i mmedi at el y af t er t he sei zur e.
( 1) Ext ensor pl ant ar r ef l exes may appear .
( 2) The pat i ent t ypi cal l y exhi bi t s l et har gy, conf usi on, and behavi or al changes.
F. CI i ni caI evaI uat i on
1. Hi story i ncl udes an eval uat i on of t he sei zur e, i ncl udi ng i nt er vi ews of t he
pat i ent ' s f ami l y and eyewi t ness account s t o est abl i sh
a. The f r equency and dur at i on of t he epi sodes
b. Pr eci pi t at i ng f act or s
c. The t i mes at whi ch epi sodes occur
d. The pr esence or absence of an aur a
e. Ì ct al act i vi t y
f . Post i ct al st at e
2. Physi caI and neuroI ogi caI exami nat i ons ar e t he t ool s wi t h whi ch t o i dent i f y an
under l yi ng cause t o r ul e out di seases t hat mani f est as sei zur es (Tabl e 45- 4) .
3. Laborat ory t est s may al so i dent i f y an under l yi ng cause.
a. Li ver and ki dney f unct i on t est s, compl et e bl ood count ( CBC) , ur i nal ysi s, and
ser um dr ug l evel s ( e. g. , ant i depr essant s and amphet ami nes may pr eci pi t at e
sei zur es) ar e necessar y.
b. Lumbar punct ur e may be r equi r ed f or evi dence of cer ebr ospi nal f l ui d ( CSF)
i nf ect i on f or pat i ent s wi t h a f ever who have sei zur es.
Table 45-4. Disorders That Mimic Epilepsy
Gastroesophageal reIlux Movement disorders
Breath-holding spells Shuddering attacks
Migraine

Paroxysmal
choreoathetosis
ConIusional Nonepileptic myoclonus
Basilar Tics and habit spasms

With recurrent abdominal pain
and cyclic vomiting
Psychological disorders

Sleep disorders (especially
parasomnias)
Panic disorder
Cardiovascular events Hyperventilation attacks
Pallid inIantile syncope Pseudoseizures
Vasovagal attacks Rage attacks
Vasomotor syncope
Arrhythmias
Reprinted with permission Irom Scheurer ML. Pedley TA: The evaluation
and treatment oI seizures. N Engl J Med 1990;323:1469. Copyright © 1990
Massachusetts Medical Society. All rights reserved.

P. 989


4. NeuroI ogi caI i magi ng studi es, i ncl udi ng MRÌ and/ or CT, compl ement
el ect r ophysi ol ogi cal st udi es and can i dent i f y st r uct ur al br ai n di sor der s ( anat omi cal
abnor mal i t i es) .
a. An MRÌ can det ect cer ebr al l esi ons r el at ed t o epi l epsy and shoul d be used i n al l
cases, especi al l y i n pat i ent s wi t h par t i al sei zur e, t o excl ude br ai n abnor mal i t i es.
b. Posi t r on-emi ssi on t omogr aphy ( PET), si ngl e- phot on emi ssi on CT ( SPECT) , and
st abl e xenon- enhanced x- r ay CT of f er f unct i onal vi ews of t he br ai n t o det ect
hypomet abol i sm or r el at i ve hypoper f usi on. PET and SPECT scans ar e not avai l abl e
i n al l i nst i t ut i ons.
c. EEG st udi es measur e t he el ect r i cal act i vi t y of t he br ai n. These st udi es hel p
i dent i f y f unct i onal cer ebr al changes under l yi ng st r uct ur al abnor mal i t i es and ar e
usef ul wi t h MRÌ f or pat i ent s consi der ed f or epi l epsy sur ger y.
( 1) An EEG i s usef ul f or cl assi f yi ng t he sei zur e or as an addi t i onal di agnost i c t ool ,
but t he EEG by i t sel f cannot r ul e sei zur es i n or out , because some pat i ent s wi t h
nor mal i nt er i ct al EEGs have sei zur e di sor der s.
( 2) The best t i me t o obt ai n an EEG i s dur i ng a sei zur e epi sode. EEG r ecor di ngs
done whi l e t he pat i ent i s asl eep can of t en r ecor d t he abnor mal act i vi t y; t her ef or e,
EEGs per f or med dur i ng a sl eep- i nduced st at e under nor mal condi t i ons or i n a
sl eepdepr i ved st at e can be mor e sensi t i ve f or maki ng a di agnosi s.
G. Treat ment obj ect i ves
1. To pr event or suppr ess sei zur es or r educe t hei r f requency t hr ough dr ug t her apy
2. To cont r ol or el i mi nat e t he f act or s t hat cause or pr eci pi t at e sei zur es
3. To pr event ser i ous consequences of sei zur es, such as anoxi a, ai r way occl usi on,
or i nj ur y, by pr ot ect i ng t he t ongue and pl aci ng a pi l l ow under t he vi ct i m' s head
4. To encour age a nor mal l i f est yl e and pr event t he pat i ent f rom f eel i ng l i ke or bei ng
t r eat ed as an i nval i d
5. Shor t - and l ong- t er m si de ef f ect s
6. Dr ug i nt er act i ons
II. THERAPY
A. Pri nci pI es of drug t herapy
1. Sei zure cont roI . Appr oxi mat el y 50% of pat i ent s wi t h epi l epsy achi eve compl et e
sei zur e cont r ol t hr ough dr ug t her apy. Ì n anot her 25%, dr ugs r educe t he f r equency of
sei zur es. Peopl e wi t h epi l epsy gener al l y r equi r e cont i nuous dr ug t her apy f or at l east
2 sei zur e- f ree year s bef or e t he dr ug di scont i nuat i on can be consi der ed.
2. I ni ti aI t reat ment
a. Bef or e ant i convul si ve dr ug t r eat ment i s i nst i t ut ed, t r eat abl e under l yi ng causes of
t he sei zur e act i vi t y shoul d be excl uded.
b. A si ngl e pr i mar y dr ug t hat i s most appr opr i at e f or t he sei zur e t ype must be
sel ect ed. Ì f t her e i s mor e t han one appr opr i at e pr i mar y dr ug, t hen age, sex, and
compl i ance of t he pat i ent must be consi der ed.
c. For pat i ent s wi t h newl y di agnosed epi l epsy, admi ni st er l ow doses f or a f ew days.
Pat i ent s may r espond t o a dosage t hat i s l ower t han t hat t r adi t i onal l y pr escr i bed
i ni t i al l y by t hei r physi ci ans, and t hi s may have i mpor t ant i mpl i cat i ons i n t er ms of
l i mi t i ng adver se ef f ect s. The i nci dence of adver se ef f ect s i ncr eases wi t h i ncr easi ng
dr ug l evel s, even when t he pl asma concent r at i ons ar e mai nt ai ned wi t hi n t he so-
cal l ed t her apeut i c or opt i mal r ange.
d. Bet ween one f our t h and one t hi r d of t he mai nt enance dose of a si ngl e medi cat i on
i s used t o begi n t her apy; i t i s t hen i ncr eased over 3- 4 weeks. The except i ons ar e
phenyt oi n and phenobar bi t al , whi ch can be st ar t ed wi t h t he l oadi ng or mai nt enance
dose. The dose shoul d be t i t r at ed unt i l sei zur e cont r ol or i nt ol er abl e si de ef f ect s
occur .
e. Wi t h t he i ni t i at i on of t her apy, bl ood concent r at i ons of medi cat i ons shoul d be
measur ed:
( 1) To est abl i sh t her apeut i c r anges and dosage r egi mens based on sympt omat i c
t oxi ci t y or sei zur e f r equency
( 2) To assess t he pat i ent ' s compl i ance wi t h t her apy
( 3) To cont r ol t he cor r el at i on among t he dose, bl ood l evel s, and cl i ni cal t her apeut i c
l evel s or t oxi ci t y
( a) Phenyt oi n f ol l ows nonl i near ki net i cs, as dr ug l evel s i ncr ease dr amat i cal l y ( mor e
t han onef ol d) wi t h onl y a smal l i ncr ease i n t he dose. However , bef or e t hi s t wof ol d
P. 990

i ncr ease i n dr ug l evel wi t h a smal l i ncr ease i n dose, t her e i s a pr edi ct abl e l i near
i ncr ease wi t h dose i ncr eases; f or t hi s r eason, i t i s r ecommended t o i ncr ease t he
dose i n smal l i ncr ement s t o be abl e t o pr edi ct when t he dr ug f ol l ows t he nonl i near
ki net i c. When t hi s happens, t hat means t he maxi mum r at e of hepat i c enzyme
cl ear ance i s r eached and t he body can no l onger cl ear t he dr ug as i t i s i nt r oduced
i nt o t he body.
( b) Ì f physi cal exami nat i on r eveal s a new onset of nyst agmus ( except wi t h
phenyt oi n, i n whi ch nyst agmus devel ops bef or e cl i ni cal i nt oxi cat i on) , at axi a, and
unst eady wi de gai t , t he next dose i ncr ease shoul d be mi ni mal .
( c) Ther e i s no j ust i f i cat i on f or i ncr easi ng dr ug dosage when a pat i ent ' s sei zur es ar e
f ul l y cont r ol l ed, even i f t he pl asma concent r at i on i s bel ow t he l ower l i mi t of t he
t her apeut i c r ange. Ì f t he pat i ent cont i nues t o have sei zur es wi t hout any evi dence of
adver se ef f ect s at a pl asma concent rat i on near t he t oxi c r ange, t her e are t wo
appr oaches:
( i ) Some cl i ni ci ans i ncr ease t he dosage accor di ng t o cl i ni cal r esponse up t o t he
hi ghest t ol er at ed l i mi t .
( i i ) Some cl i ni ci ans do not i ncr ease t he dosage because of t he l i kel i hood of
pr oduci ng adver se ef f ect s.
( d) Car bamazepi ne has an aut oi nduct i on met abol i sm pr oper t y, whi ch means t hat i f
t he dose i s i ncr eased t wof ol d, bl ood l evel s i ncr ease l ess t han t wof ol d because of
i ncr eased met abol i sm.
( 4) To det er mi ne t he f r ee dr ug l evel , whi ch i s hel pf ul i n pat i ent s who ar e i n t he
t her apeut i c r ange but have si de ef f ect s or no response. The pl asma pr ot ei n bi ndi ng
may be al t er ed i n t hese pat i ent s by some ot her di sease st at e or medi cat i on.
Because of t hi s al t er at i on, t her e i s mor e f r ee dr ug avai l abl e i n t he syst em t han t he
t ot al l evel shows, especi al l y wi t h phenyt oi n, val pr oi c aci d, and car bamazepi ne.
3. Paradoxi caI i nt oxi cat i on occurs when a hi gh concent r at i on of a si ngl e dr ug
causes an i ncr eased f r equency of sei zur es wi t hout cl assi cal adver se event s. Thi s i s
common wi t h hydant oi ns and car bamazepi ne. The pr oposed r eason i s t hat t hei r
ef f ect on t he cer ebel l um i s bl ocked at hi gh concent r at i ons. Management usual l y
r equi r es no mor e t han wi t hhol di ng enough doses of t he dr ug t o al l ow t he
concent r at i on t o dr i f t down.
4. When sei zur es cannot be cont r ol l ed, t her e are t wo opt i ons.
a. The i ni t i al dr ug can be subst i t ut ed wi t h anot her agent . Thi s i s accompl i shed by
gr adual l y di scont i nui ng t he i ni t i al dr ug whi l e si mul t aneousl y i ncr easi ng t he dosage
of t he second agent . Then t he dosage of t he second agent i s t i t r at ed up t o t he
mai nt enance l evel as t he i ni t i al agent i s gr adual l y di scont i nued. Ther e ar e t hr ee
mai n advant ages of gr adual subst i t ut i on:
( 1) Ì t al l ows eval uat i on of t he ef f ect s of i ndi vi dual dr ugs
( 2) Ì t r educes t he r i sk of t oxi ci t y
( 3) Ì t r educes t he r i sk of adver se drug i nt er act i ons
b. A second dr ug can be added. Combi nat i on t her apy i s r eser ved f or pat i ent s wi t h
sever e epi l epsy t o r api dl y cont r ol t he sei zur es. Rapi d cont r ol can be i mpor t ant f or
psychosoci al r easons as wel l as f or t he possi bi l i t y of a mor e f avor abl e pr ognosi s.
5. Long- t erm drug t reat ment . Most physi ci ans r evi ew t he pat i ent ' s condi t i on when
t he pat i ent has been sei zur e f r ee f or 2 year s. Thi s has i mpor t ant i mpl i cat i ons i n
chi l dr en because ear l y t er mi nat i on of t r eat ment has bet t er remi ssi on r at es compar ed
wi t h adul t s. Ì t i s r ecommended t o gr adual l y decr ease t he dose, over at l east 6
mont hs. The age of onset of epi l epsy, t he pr esence of an under l yi ng neur ol ogi cal
condi t i on, and any abnor mal EEGs shoul d be consi der ed.
6. Di seases and condi ti ons that aI t er ant i epi I ept i c drug- prot ei n bi ndi ngs
a. Li ver di sease
b. Hypoal bumi nemi a
c. Bur ns
d. Pr egnancy
e. Hi gh pr ot ei n- bi ndi ng dr ugs or ant i epi l ept i c agent s. (Most i mpor t ant i nt er act i ons
ar e di scussed under i ndi vi dual agent s. )
7. Medi cat i ons. Some medi cat i ons decr ease l evel s of phenyt oi n, car bamazepi ne,
phenobar bi t al , and pr i mi done by enhanci ng t hei r met abol i sm. These dr ugs al so
cause f al se decr eases i n t hyr oi d f unct i on t est s.
P. 991


a. Or al cont r acept i ves
b. Or al hypogl ycemi cs
c. Gl ucocor t i coi ds
d. Tr i cycl i c ant i depr essant s
e. Azat hi opr i ne
f . Cycl ospor i ne
g. Qui ni di ne
h. Theophyl l i ne
i . War f ar i n
j . Doxycycl i ne
k. Levodopa
8. Over vi ew of drug t herapy i n sei zure di sorder
a. Monot herapy. St ar t t he dr ug t her apy as si ngl e agent .
b. Dosage t reat ment . Use a l ow dose f or a f ew days. Pat i ent s wi t h newl y di agnosed
epi l epsy may r espond t o dosages t hat ar e l ower t han t hose pr escr i bed i ni t i al l y by
t hei r physi ci ans, and t hi s may have i mpor t ant i mpl i cat i ons i n t er ms of adver se
ef f ect s. The i nci dence of adver se ef f ect s i ncr eases wi t h i ncr easi ng dr ug dosage,
even when t he pl asma concent r at i on i s mai nt ai ned wi t hi n t he so- cal l ed t her apeut i c
or opt i mal range.
c. Drug moni tori ng. Ther e i s no j ust i f i cat i on f or i ncr easi ng dr ug dosage when a
pat i ent i s f ul l y cont r ol l ed, even i f t he pl asma concent r at i on i s bel ow t he l ower l i mi t
of t he t her apeut i c r ange. Ì f t he pat i ent cont i nues t o have sei zur es wi t hout any
evi dence of adver se ef f ect s at a pl asma concent rat i on near t he t oxi c r ange, t her e
ar e t wo appr oaches:
( 1) Some cl i ni ci ans i ncr ease t he dosage accor di ng t o cl i ni cal r esponse up t o t he
hi ghest t ol er at ed l i mi t .
( 2) Some cl i ni ci ans do not i ncr ease t he dosage because of t he l i kel i hood of
pr oduci ng adver se event s.
9. Adverse ef f ect s of ant i convuI si ve drugs
a. AI t ernat i on i n cogni t i on and ment at i on
( 1) Sedat i on and depressi on ar e t he most common sympt oms of overdose of
ant i convul si ve dr ugs, but t hey ar e di f f i cul t t o assess. For exampl e, bar bi t ur at es
commonl y cause depr essi on, wi t h pr i mi done bei ng t he wor st of f ender ; di azepam and
cl or azepat e ar e l ess l i kel y t o cause depr essi on. Bar bi t ur at es, cl onazepam, and
t r i met hadi one commonl y cause cogni t i ve i mpai r ment , r angi ng f r om sensat i on t o
conf usi on.
( 2) Exci t at i on can be a par adoxi cal ef f ect of bar bi t ur at es wi t h younger chi l dr en and
t he el der l y. For exampl e, f el bamat e can cause r est l essness and hyper act i vi t y.
b. Det eri orat i on of mot or perf ormance and pri mary coordi nat i on i ncl udes
t r embl i ng hands, st aggeri ng when r oundi ng cor ner s, and mi l d l i mb at axi a. Dr ugs
associ at ed wi t h t hese ef f ect s i ncl ude hydant oi ns, met hsuxi mi de, car bamazepi ne,
and pr i mi done. These ef f ect s ar e l ess common wi t h bar bi t ur at es and l amot r i gi ne and
ar e r ar el y seen wi t h gabapent i n.
c. Gast roi ntest i naI sympt oms i ncl ude nausea and vomi t i ng. Two pur posed
mechani sms i ncl ude
( 1) A l ocal ef f ect on t he st omach, as i n t he case of val pr oi c aci d; di val pr oex aci d,
however , has l ess i nci dence compar ed wi t h val pr oi c aci d. These sympt oms decr ease
i n i nci dence i f t he dr ug i s gi ven wi t h meal s.
( 2) A br ai nst em ef f ect , as i n t he cases of f el bamat e and car bamazepi ne. Nausea
and vomi t i ng caused by t hese dr ugs ar e associ at ed wi t h br ai nst em i nvol vement ;
t her ef or e, drug l evel s pl ay a r ol e i n t hese sympt oms. Admi ni st r at i on i n smal l er ,
mor e f r equent doses decr eases t he i nci dence of t hese sympt oms by l ower i ng t he
t r ansi ent peak concent r at i on.
d. Appet i t e and body wei ght . Few ant i convul sant s af f ect appet i t e separ at e f r om
nausea and vomi t i ng, i ncl udi ng anor exi a or i ncr eased appet i t e.
( 1) Drugs t hat cause anorexi a ar e f el bamat e, and t o a l esser ext ent ,
car bamazepi ne, et hosuxi mi de, and val pr oi c aci d.
( 2) Drugs t hat cause i ncreased appet i t e ar e val pr oi c aci d, and t o a l esser ext ent ,
car bamazepi ne.
e. Headache and di zzi ness
( 1) Di f f use headaches may be caused by et hosuxi mi de and, t o a l esser ext ent , by
met hsuxi mi de and f el bamat e.
P. 992


( 2) Di zzi ness seen i n associ at i on wi t h ant i convul sant s i s caused by a combi nat i on
of at axi a and l oss of eye movement coor di nat i on, whi ch i s par t of mot or coor di nat i on
sympt oms.
B. Speci f i c ant i sei zure agent s. Tabl e 45- 5 l i st s t he uses of ant i epi l ept i c
medi cat i ons based on sei zur e t ype. Tabl e 45- 6 l i st s cl assi f i cat i ons of ant i convul si ve
dr ugs. Tabl e 45- 7 l i st s dosage char act er i st i cs of ant i epi l ept i c medi cat i ons.
1. Carbamazepi ne (Tegret oI )
a. Mechani sms of act i on. Car bamazepi ne i s chemi cal l y r el at ed t o t r i cycl i c
ant i depr essant s. Ì t s mechani sm of act i on i s unknown i n t he t r eat ment of sei zur e
di sor der s, but i t i s t hought t o act by r educi ng pol ysynapt i c r esponses and bl ocki ng
t he post t et ani c pot ent i at i on.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) AduI t s and chi I dren > 12 years of age r ecei ve an i ni t i al or al dose of 200 mg
t wi ce dai l y. Thi s may be i ncr eased gr adual l y t o 800- 2000 mg dai l y ( usual l y gi ven i n
di vi ded doses) .
( 2) Chi I dren < 12 usual l y r ecei ve 10- 20 mg/ kg dai l y i n t wo or t hr ee di vi ded doses.
c. Precaut i ons and moni tori ng ef fect s
( 1) Car bamazepi ne shoul d be used wi t h caut i on i n pat i ent s wi t h bone mar r ow
depr essi on. A CBC shoul d be obt ai ned and pl at el et s measur ed t o det er mi ne
basel i ne l evel s bef or e t her apy, and l evel s shoul d be moni t or ed dur i ng t her apy.
Apl ast i c anemi a and agr anul ocyt osi s have been r epor t ed.
( 2) Tr i cycl i c ant i depr essant s shoul d be avoi ded i f t her e i s a hi st or y of
hyper sensi t i vi t y t o t r i cycl i cs. Monoami ne oxi dase ( MAO) i nhi bi t or s shoul d be
di scont i nued 2 weeks bef or e car bamazepi ne t her apy.
( 3) Car bamazepi ne shoul d be used caut i ousl y i n pat i ent s wi t h gl aucoma because of
i t s mi l d ant i chol i ner gi c ef f ect s.
( 4) Car bamazepi ne i s an enzyme i nducer ; t her ef or e, t he hal f - l i f e ( t
1/ 2
) decr eases
over 3- 4 weeks ( t
1/ 2
18-54 hr ; t
1/ 2
10- 25 hr ) ; f or maxi mal enzyme i nduct i on, l evel s
shoul d be r echecked t o avoi d br eakt hr ough sei zur es.
( 5) Car bamazepi ne i s met abol i zed i n t he l i ver t o 10- 11 epoxi de, whi ch al so has
ant i convul sant act i vi t y; car bamazepi ne may i nduce i t s own met abol i sm.
( 6) Pot ent i al f or dr ug i nt er act i on i n el der l y pat i ent s.
( 7) Adverse ef f ect s. The physi ci an shoul d be not i f i ed i f any of t he f ol l owi ng
adver se ef f ect s occur: j aundi ce, abdomi nal pai n, pal e st ool , dar kened ur i ne, unusual
br ui si ng and bl eedi ng, f ever , sor e t hroat , or an ul cer i n t he mout h. The most
common si de ef f ect s ar e di zzi ness, dr owsi ness, unst eadi ness, nausea, and
vomi t i ng.
Table 45-5. Uses of Antiepileptic Medications Based on Seizure Type
Drug Therapy
Seizure Type Choice 1 Choice 2 Choice 3 Choice 4
Simple
partial
Carbamaze
pine (alone
or
combinatio
n)
Phenytoin Primidone
Lamotrigin
e
Oxcarbaze
pine
Gabapenti
n.
levetiracet
am
Zonisamid
e
Complex
partial
Carbamaze
pine
Lamotrigin
e
Phenytoin Phenobarbi
tal
Zonisamid
e
Oxcarbaze
pine
Valproic
acid
Primidone
Topiramat
e
Tiagabine
Primary
generalize
d
Tonic-
clonic
Valproic
acid
Lamotrigin
e
Carbamaze
pine
Phenytoin
Valproic
acid
Phenobarb
ital
Topiramat
e
Tiagabine
Absence Lamotrigin
e.
a

ethosuximi
de
Zonisamide
. valproic
acid

Myocloni
c atonic
Valproic
acid
Valproic
acid
Clonazepa
m
Clonazepa
m
Zonisamid
e
a

Felbamate
a
(alone or
in
combinati
on)
Status
epilepticu
s
Diazepam Phenytoin Phenobarbi
tal
Psychom
otor
Phenytoin

a
Also indicated Ior treatment oI Lennox-Gastaut syndrome in children.

P. 993


Table 45-6. Anticonvulsive Drug Classification
Barbiturat
es
Hydantoi
ns
Succinimi
des
Sulfonami
des
Oxazolidin
ediones
Benzodiaze
pine
Miscellane
ous
Pheno
barbit
al
Phen
ytoin
Ethos
uximi
de
Zonis
amide
Param
ethadi
one
Clonaz
epam
Lamot
rigine
Primi
done
Meph
enyto
in
Meths
uximi
de
Trime
thadio
ne
Diazep
am
Felba
mate
Gabap
entin
Meph
obarbi
tal
Ethot
oin
Phens
uximi
de

Loraze
pam
Cloraz
epate
dipota
ssium
Prega
balin

Fosph
enyto
in
Carba
mazep
ine
Oxcar
bazepi
ne

Valpro
ic acid


Topira
mate


Tiagab
ine


Leveti
raceta
m

P. 994


Table 45-7. Dosages Characteristic of Antiepileptic Medications
Drug
Enzy
me
Induc
er
Enzym
e
Inhibit
or
Loadi
ng
Dose
Usual
Adult
Dose
(mg/da
y)
Half-
life (hr)
Therapeut
ic Range
of Total
Plasma
Concentra
tion
(µg/mL)
Major
Mode of
Eliminat
ion
Protei
n-
Bindin
g
Level
(º)
Carbama
zepine
¹/
-
- N
o
80
0-
20
00
11
a
-22
4-12 Hep
atic
7
5-
8
0
Phenytoi
n
¹/
-
- Y
es
30
0-
70
0
22-
72
1-2
(Ir
ee)
5-20 Hep
atic
9
0
Phenobar
bital
¹/
-
- Y
es
90-
30
0
10
0
15-40 Hep
atic
~
rena
l
4
0-
6
0
Primidon
e
¹/
-
- N
o
75
0-
30
00
15
a
.
b

5-12 Hep
atic
2
0-
2
5
Valproic
acid
¹/
-
¹ Y
es
10
00-
30
00
15-
20
50-
150
Hep
atic
7
5-
9
0
Ethosuxi
mide
¹/
-
- N
o
75
0-
10
00
30-
60
c

40-
100
Hep
atic
~
rena
l
0
Felbamat
e
¹/
-
¹ N
o
24
00
20-
23
30-
100
Hep
atic
~
rena
l
2
2-
2
5
Gabapen
tin
- - Y
es
90
0-
10
00
5-7 5-7 Ren
al
·
3
Lamotrig
ine
¹/
-
- N
o
20
0-
40
0
25
12.
6
d

70
e

2-6 Hep
atic
~
rena
l
5
5
Topiram
ate
¹/
-
- N
o
20
0-
40
0
15-
23
n/a Ren
al ~
hepa
tic
9-
1
5
Tiagabin
e
- - N
o
32-
56
6-8 n/a Hep
atic
9
6
Levetirac
etam
- - Y
es
50
0-
30
00
7 n/a Ren
al
·
1
0
Zonisami
de
- - N
o
10
0-
60
0
24-
50
n/a Hep
atic
4
0-
6
0
Oxcarba
zepine
¹/
-
¹ N
o
90
0-
18
00
4-9 n/a Hep
atic
4
0-
6
0
a
The halI-liIe decreases autometabolism aIter chronic use.

b
Metabolized in part to phenobarbital.

c
Lower range in children and higher range in adults.

d
Receiving other enzyme-inducing drugs.

e
Valproic acid slows the metabolism.

P. 995


( a) CNS ef f ect s. These i ncl ude di zzi ness, at axi a, and di pl opi a. Ì f di pl opi a and
at axi a ar e common and occur af t er a dose, t he schedul e coul d be adj ust ed t o
i ncl ude mor e f r equent admi ni st r at i on or a l ar ger pr opor t i on of t he dose at ni ght .
CNS si de ef f ect s may decr ease wi t h chr oni c admi ni st r at i on.
( b) Gast roi nt est i naI ( GI ) ef f ect s. These most commonl y i ncl ude nausea, vomi t i ng,
and anor exi a.
( c) Met aboI i c ef f ect s. Hyponat r emi a occur s af t er sever al weeks t o mont hs of
t her apy, and t he i nci dence i ncr eases wi t h age. The ant i di ur et i c hor mone ( ADH) l evel
may be l ow. Level s of 125- 135 mEq/ L wi t hout sympt oms shoul d be moni t or ed. Fl ui d
r est r i ct i on shoul d be i nst i t ut ed when l evel s decr ease t o < 125 mEq/ L wi t h or wi t hout
sympt oms. Anot her agent shoul d be used i f f l ui d dose r educt i on does not hel p or t he
sei zur es r ecur .
( d) Hemat opoi et i c ef f ect s. Apl ast i c anemi a i s r ar e. Thr ombocyt openi a and anemi a
have a 5% i nci dence, and t hey r espond t o a cessat i on of drug t her apy. Leukopeni a
i s t he most common hemat opoi et i c si de ef f ect : 10% of cases ar e t r ansi ent , and
about 2% of pat i ent s have per si st ent l eukopeni a but do not seem t o have i ncr eased
i nf ect i ons even wi t h whi t e bl ood cel l ( WBC) count s of 3000/ mL.
( e) Dermat oI ogi caI ef f ect s. Pr ur i t i c and er yt hemat ous r ashes, t he St evens- Johnson
syndr ome, and l upus er yt hemat osus have been r epor t ed.
d. Si gni f i cant i nt eract i ons
( 1) Ant i epi I ept i c drugs, such as phenyt oi n, pri mi done, and phenobarbi t aI ,
decr ease t he l evel of car bamazepi ne ( i ncr ease met abol i sm) .
( 2) VaI proi c aci d i ncr eases t he l evel of car bamazepi ne ( decr eases met abol i sm) .
( 3) Ot her medi cat i ons such as eryt hromyci n, i soni azi d, ci met i di ne,
propoxyphene, di I t i azem, and verapami I i ncr ease t he l evel of car bamazepi ne
( decr ease met abol i sm) .
( 4) Car bamazepi ne decr eases l evel s of caI ci um channeI bI ockers, i ncr easi ng i t s
own l evel .
( 5) Car bamazepi ne decr eases t he ef f ect of war f ar i n.
( 6) Ant i bi ot i cs i ncr ease t he l evel of car bamazepi ne.
( 7) Car bamazepi ne decr eases t r i cycl i c ant i depr essant l evel s.
2. Phenyt oi n ( Di I ant i n)
a. Mechani sm of acti on
( 1) Phenyt oi n i nhi bi t s t he spr ead of sei zur es at t he mot or cor t ex and bl ocks
post t et ani c pot ent i at i on by i nf l uenci ng synapt i c t r ansmi ssi on. Ther e i s an al t er nat i on
of i on f l uxes i n depol ar i zat i on, r epol ar i zat i on, and membr ane st abi l i t y phase and
al t er nat i ng cal ci um upt ake i n pr esynapt i c t er mi nal s.
( 2) Phenyt oi n i s ef f ect i ve f or t he t r eat ment of gener al i zed t oni c- cl oni c ( gr and mal )
sei zur es and f or par t i al sei zur es, bot h si mpl e and compl ex. Ì t i s not ef f ect i ve f or
absence sei zur es.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) The usual dai l y dose f or aduI t s i s 300- 700 mg, wi t h adj ust ment s made as
needed.
( a) Regul ar dai l y doses above 500 mg ar e poor l y t ol er at ed.
( b) A l oadi ng dose of 900 mg t o 1. 5 g may be gi ven i nt r avenousl y ( Ì V) . The i nf usi on
r at e shoul d not exceed 50 mg/ mi n. ( Al t er nat i vel y, an or al l oadi ng dose may be
gi ven. )
( 2) The usual dai l y dose f or chi I dren i s 4- 7 mg/ kg di vi ded ever y 12 hr . An Ì V
l oadi ng dose of 15 mg/ kg may be gi ven.
( 3) Phenyt oi n sodi um i s avai l abl e as capsul es and par ent er al sol ut i on. Phenyt oi n i s
avai l abl e as t abl et s and or al suspensi on.
c. Precaut i ons and moni tori ng ef fect s
( 1) Ì V phenyt oi n shoul d not be used i n pat i ent s wi t h si nus br adycar di a, si noat r i al
bl ock, second- and t hi r d- degr ee at r i ovent r i cul ar ( AV) bl ock, or Adams- St okes
syndr ome.
( 2) Phenyt oi n shoul d be used caut i ousl y i n pat i ent s wi t h myocar di al i nsuf f i ci ency
and hypot ensi on.
( 3) El i mi nat i on of phenyt oi n conver t s f r om f i r st - or der el i mi nat i on ( pr opor t i onal t o i t s
concent r at i on) t o zer o- or der el i mi nat i on ( a f i xed amount per uni t t i me) , usual l y at
hi gh t her apeut i c l evel s. The dai l y dose of phenyt oi n can be i ncr eased 100 mg dai l y
unt i l t her apeut i c bl ood l evel s ar e at t ai ned, af t er whi ch i ncr eases of 30- 50 mg wi l l
avoi d t wof ol d t o t hr eef ol d i ncr eases i n bl ood l evel s.
P. 996


( 4) Ì t i s necessar y t o measur e f r ee dr ug l evel s or cor r ect t he t ot al l evel when
al umi num l evel s ar e abnor mal or t he pat i ent has r enal f ai l ur e.
( 5) Pot ent i al f or dr ug i nt er act i on i n el der l y pat i ent s.
( 6) Adverse ef f ect s. The physi ci an shoul d be not i f i ed i f any of t he f ol l owi ng
adver se ef f ect s occur: swol l en or t ender gums, ski n r ash, nausea and vomi t i ng,
swol l en gl ands, bl eedi ng, j aundi ce, f ever , or sor e t hr oat ( i . e. , si gns of i nf ect i on or
bl eedi ng) .
( a) CNS ef f ect s i ncl ude at axi a ( l i mi t i ng si de ef f ect ) , dysar t hr i a, and i nsomni a.
Tr ansi ent hyper ki nesi a may f ol l ow Ì V phenyt oi n i nf usi on. Al cohol i c bever ages shoul d
be avoi ded whi l e on t hi s medi cat i on.
( b) GÌ ef f ect s most commonl y i ncl ude nausea and vomi t i ng. Phenyt oi n shoul d be
t aken wi t h f ood t o enhance absor pt i on and decr ease GÌ upset .
( c) Dermat oI ogi caI ef f ect s i ncl ude macul opapul ar r ashes somet i mes wi t h f ever,
St evens- Johnson syndr ome, and l upus er yt hemat osus. Gi ngi val hyper pl asi a may be
r educed by f r equent br ushi ng and appr opr i at e or al car e.
( d) Connect i ve t i ssue di sorders i ncl ude a coar seni ng of t he f aci al f eat ur es.
( e) Hemat opoi et i c ef f ect s i ncl ude t hr ombocyt openi a, l eukopeni a, and
gr anul ocyt openi a.
( f ) Mi sceI I aneous ef f ect s i ncl ude hyper gl ycemi a and i ncr eased body hai r .
d. Si gni f i cant i nt eract i ons
( 1) Ant i epi I ept i c drugs, such as carbamazepi ne, vaI proi c aci d, cI onazepam, and
phenobarbi t aI , decr ease t he l evel of phenyt oi n ( i ncr ease met abol i sm) .
( 2) Phenyt oi n i ncr eases t he conversi on of pri mi done to phenobarbi t aI ( i ncr eases
met abol i sm) .
( 3) Ot her medi cat i ons such as di suI f i ram, i soni azi d, chI orampheni coI , and
propoxyphene i ncr ease t he l evel of phenyt oi n ( decr ease met abol i sm) .
( 4) Dr ugs whose ef f i cacy i s i mpai r ed by phenyt oi n i ncl ude cort i cost eroi ds,
di gi t oxi n, doxycycI i ne, est rogens, f urosemi de, oraI contracept i ves, qui ni di ne,
ri f ampi n, t heophyI I i ne, vi t ami n D, and ent eraI nut ri t i onaI t herapy.
( 5) Coumari n and warf ari n ant i coagul ant s i ncr ease t he ser um phenyt oi n l evel s and
pr ol ong t he ser um hal f - l i f e of phenyt oi n by i nhi bi t i ng i t s met abol i sm.
( 6) Phenyt oi n decr eases t ri cycI i c ant i depressant l evel s.
( 7) Phenyt oi n i nt er act s wi t h di abet es and art hri t i s medi cat i ons.
3. Fosphenyt oi n ( Cerebyx)
a. Mechani sm of acti on
( 1) Wat er - sol ubl e pr odr ug of phenyt oi n. Ì t i s conver t ed t o phenyt oi n by t he
bl oodst r eam phosphat ases, wi t h a hal f - l i f e of about 8 mi n i n bot h adul t s and
chi l dr en.
( 2) Ì t i s i ndi cat ed f or pat i ent s who cannot t ake or al dr ugs, and i n t he acut e
t r eat ment f or st at us epi l ept i cus.
( 3) Admi ni st er ed vi a Ì V or i nt r amuscul ar ( Ì M) i nj ect i on
( 4) A dose conver si on t abl e shoul d be used t o conver t t he phenyt oi n dose t o
f osphenyt oi n.
( 5) Char act er i st i cs si mi l ar t o phenyt oi n
( 6) Advant ages
( a) Fosphenyt oi n i s an aqueous sol ut i on, unl i ke phenyt oi n, whi ch i s an al kal i ne
sol ut i on; t her ef or e, t her e i s no need t o add pr opyl ene gl ycol and et hanol t o t he
sol ut i on.
( b) Fosphenyt oi n causes l ess sof t - t i ssue i nj ur y at t he si t e of i nj ect i on. When
admi ni st er ed by Ì M i nj ect i on, i t i s compl et el y absor bed and has mor e pr edi ct abl e
ser um concent r at i on t han Ì M- i nj ect ed phenyt oi n.
4. VaI proi c aci d ( Depakot e)
a. Mechani sm of acti on
( 1) Ì ncr eases l evel s of GABA
( 2) Pot ent i at es a post synapt i c GABA r esponse by i nhi bi t i ng t he enzymat i c r esponse
f or t he cat abol i sm of GABA
( 3) Af f ect s t he pot assi um channel , cr eat i ng a di r ect membr ane- st abi l i zi ng ef f ect
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) For aduI t s, val pr oi c aci d i s admi ni st er ed or al l y i n a usual dose of 1000- 3000 mg
dai l y i n di vi ded doses.
P. 997


( 2) For chi I dren, val pr oi c aci d i s admi ni st er ed or al l y i n a dose of 15- 60 mg/ kg dai l y,
di vi ded i nt o t wo or t hr ee doses.
( 3) Medi cat i on shoul d be t aken wi t h f ood t o r educe GÌ upset .
( 4) Tabl et s or capsul es shoul d be swal l owed, not chewed, t o avoi d i r r i t at i on of t he
mout h and t hr oat .
c. Precaut i ons and moni tori ng ef fect s. Ther e ar e some r epor t s of hepat ot oxi ci t y
and i ncr eased l i ver f unct i on t est s, whi ch ar e most l y r ever si bl e. The sever i t y and
i nci dence of hepat ot oxi ci t y i ncr ease when t he pat i ent i s younger t han 2 year s of
age.
d. Adverse ef f ect s. Cont act t he physi ci an i f abdomi nal pai n, nausea, vomi t i ng, or
anoxi a occur s; t hese coul d be sympt oms of pancr eat i t i s.
( 1) CNS ef f ect s i ncl ude t r emor, at axi a, di pl opi a, l et har gy, dr owsi ness, behavi or al
changes, and depr essi on.
( 2) GÌ ef f ect s i ncl ude nausea and i ncr eased appet i t e. Ent eri c- coat ed di val pr oex
sodi um may r educe t hese si de ef f ect s.
( 3) Dermat oI ogi caI ef f ect s i ncl ude al opeci a and pet echi ae.
( 4) Hemat opoi et i c ef f ect s i ncl ude t hr ombocyt openi a, br ui si ng, hemat oma, and
bl eedi ng.
( 5) Hepat i c ef f ect s i ncl ude mi nor el evat i ons of aspar t at e ami not r ansf er ase ( AST) ,
al ani ne ami not r ansf er ase ( ALT), and l act at e dehydr ogenase ( LDH) .
( 6) Endocri ne ef f ect s i ncl ude decr eased l evel s of pr ol act i n, r esul t i ng i n i r r egul ar
menses, and secondar y amenor r hea.
( 7) Pancreat i c ef f ect s i ncl ude acut e pancr eat i t i s.
( 8) Met aboI i c ef f ect s i ncl ude hyper ammonemi a owi ng t o r enal or i gi n.
Di scont i nuat i on may be consi der ed i f l et har gy devel ops.
e. Si gni fi cant i nt eract i ons
( 1) Ant i epi I ept i c drugs
( a) Pri mi done decr eases val pr oi c aci d cl ear ance ( i ncr eases met abol i sm) .
( b) Phenobarbi t aI and phenyt oi n di spl ace pr ot ei n bi ndi ng, r esul t i ng i n an
i ncr eased t ot al phenyt oi n l evel and an i ncr ease or no change of f r ee phenyt oi n.
( c) CI onazepam i ncr eases CNS t oxi ci t y i n pat i ent s on val proi c aci d.
( 2) Ot her medi cat i ons
( a) Aspi ri n i ncr eases t he l evel of val pr oi c aci d.
( b) Warf ari n i nhi bi t s t he secondar y phase of pl at el et aggr egat i on.
( c) Ant aci ds i ncr ease t he l evel of val pr oi c aci d.
( 3) Laborat ory t est s
( a) Fal se- posi t i ve ur i ne ket one t est s may r esul t i n pat i ent s t aki ng val pr oi c aci d; t hus
pat i ent s wi t h di abet es must use caut i on when usi ng ur i ne t est s.
( b) Thyr oi d f unct i on t est s may be al t er ed by ant i epi l ept i c dr ugs.
5. Phenobarbi t aI (Lumi naI )
a. Mechani sm of acti on. Phenobar bi t al i ncr eases t he sei zur e t hr eshol d by
decr easi ng post synapt i c exci t at i on by st i mul at i ng post synapt i c GABA- A r ecept or
i nhi bi t or r esponses as a CNS depr essant .
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) For aduI t s, phenobar bi t al i s admi ni st er ed or al l y at 90- 300 mg dai l y ( i n t hr ee
di vi ded doses or as a si ngl e dose at bedt i me) .
( 2) Chi I dren t ypi cal l y r ecei ve 3- 6 mg/ kg dai l y i n t wo di vi ded doses. Adj ust ment i s
made as needed.
c. Precaut i ons and moni tori ng ef fect s
( 1) Phenobar bi t al pr oduces r espi r at or y depr essi on, especi al l y wi t h par ent er al
admi ni st r at i on.
( 2) Phenobar bi t al shoul d be used wi t h caut i on i n pat i ent s wi t h hepat i c di sease who
may need dose adj ust ment s.
( 3) Phenobar bi t al has sedat i ve ef f ect s i n adul t s and pr oduces hyper act i vi t y i n
chi l dr en.
( 4) Abr upt di scont i nuat i on of phenobar bi t al pr oduces wi t hdr awal convul si ons. Ì f t he
dr ug must be di scont i nued, anot her GABA- A agoni st ( e. g. , benzodi azepi ne,
par al dehyde) shoul d be subst i t ut ed.
( 5) Pot ent i al f or dr ug i nt er act i on i n el der l y pat i ent s.
( 6) Adverse ef f ect s. The physi ci an shoul d be not i f i ed i f any of t he f ol l owi ng
adver se ef f ect s occur: sor e t hr oat , mout h sor es, easy br ui si ng or bl eedi ng, and any
si gns of i nf ect i on.
P. 998


( a) CNS ef f ect s i ncl ude agi t at i on, conf usi on, l et har gy, and dr owsi ness. Pat i ent s
shoul d avoi d al cohol and ot her CNS depr essant s.
( b) Respi rat ory ef f ect s i ncl ude hypovent i l at i on and apnea.
( c) Cardi ovascuI ar ef f ect s i ncl ude br adycar di a and hypot ensi on.
( d) GÌ ef f ect s i ncl ude nausea, di ar r hea, and const i pat i on. Ì f GÌ upset i s
exper i enced, phenobar bi t al shoul d be t aken wi t h f ood.
( e) Hemat oI ogi caI ef f ect s i ncl ude megal obl ast i c anemi a af t er chr oni c use ( a r ar e
si de ef f ect ) .
( f ) Mi sceI I aneous ef f ect s i ncl ude ost eomal aci a and St evens- Johnson syndr ome,
bot h of whi ch ar e r ar e.
d. Si gni f i cant i nt eract i ons
( 1) Ant i epi I ept i c drugs, such as vaI proi c aci d and phenyt oi n, i ncr ease t he l evel
of phenobar bi t al ( decr ease met abol i sm) .
( 2) Ot her drugs such as acet azoI ami de, chI orampheni coI , ci met i di ne, and
f urosemi de i ncr ease t he l evel of phenobar bi t al ( decr ease met abol i sm) .
( 3) Ri f ampi n, pyri doxi ne, and ethanoI decr ease t he l evel of phenobar bi t al
( i ncr ease met abol i sm) .
6. Pri mi done ( MysoI i ne)
a. Mechani sm of acti on. Pr i mi done i s a met abol i t e of phenobar bi t al and
phenyl et hyl mal onami de ( PEMA) , whi ch has some ant i convul si ve ef f ect s. Ì t has dr ug
char act er i st i cs si mi l ar t o phenobar bi t al , wi t h some di f f er ences i n dose and hal f - l i f e.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) Pr i mi done has a short hal f - l i f e of 7 hr , whi ch may r equi r e t hr ee- t i mes dai l y
dosi ng.
( 2) Pr i mi done i s t ol er at ed bet t er i f st ar t ed at 50 mg at ni ght f or 3 days unt i l t he
t ar get dai l y dose i s r eached.
7. Ethosuxi mi de (Zaront i n)
a. Mechani sm of acti on
( 1) Et hosuxi mi de may i nhi bi t t he sodi um- pot assi um adenosi ne t r i phosphat ase
( Na
+
/ K
+
ATPase) syst em and t he r educed f or m of ni cot i nami de adeni ne di nucl eot i de
phosphat e ( NADPH) l i nked al dehyde r educt ase (whi ch i s necessar y f or t he f or mat i on
of v- hydr oxybut yr at e, whi ch i s associ at ed wi t h t he i nduct i on of absence sei zur es) .
( 2) Et hosuxi mi de r educes or el i mi nat es t he EEG abnor mal i t y; however , absence
sei zur es ar e t he onl y sei zur es i n whi ch t he nor mal EEG has cl i ni cal val ue ( i . e. ,
when t he EEG abnor mal i t y i s cor r ect ed, t he sei zur es ar e al so cont r ol l ed) .
( 3) Et hosuxi mi de i s a r el at i vel y beni gn ant i convul sant wi t h mi ni mum pr ot ei n bi ndi ng.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7) . Et hosuxi mi de i s usual l y gi ven or al l y i n
an i ni t i al dose of 500 mg dai l y i n aduI t s and oI der chi I dren and 250 mg dai l y i n
chi I dren ages 3- 6 years. The dose may be r ai sed by 250 mg ever y week t o a
maxi mum of 1. 5 g dai l y i n adul t s.
c. Precaut i ons and moni tori ng ef fect s
( 1) Bl ood dyscr asi as have been r epor t ed, maki ng per i odi c bl ood count s necessar y.
( 2) Ther e have been r epor t s of hepat i c and r enal t oxi ci t y; t hus per i odi c r enal and
l i ver f unct i on moni t or i ng i s necessar y.
( 3) Cases of syst emi c l upus er yt hemat osus have been r epor t ed.
d. Adverse ef f ect s
( 1) GÌ ef f ect s i ncl ude nausea and vomi t i ng. Smal l doses may l essen t hese ef f ect s.
Et hosuxi mi de shoul d be t aken wi t h f ood i f GÌ upset occur s.
( 2) Hemat opoi et i c ef f ect s i ncl ude eosi nophi l i a, gr anul ocyt openi a, l eukopeni a, and
l upus.
( 3) CNS ef f ect s i ncl ude dr owsi ness, bl ur r ed vi si on, f at i gue, l et har gy, hi ccups, and
headaches. Al cohol i c bever ages shoul d be avoi ded wi t h t hi s medi cat i on.
( 4) Psychi at ri c- psychoI ogi caI ef f ect s i ncl ude conf usi on and emot i onal i nst abi l i t y.
( 5) Dermat oI ogi caI ef f ect s i ncI ude pr ur i t us, phot osensi t i vi t y, ur t i car i a, and
St evens- Johnson syndr ome.
( 6) Geni t ouri nary ef f ect s i ncI ude i ncr eased f requency of ur i nat i on, vagi nal
bl eedi ng, r enal damage, and hemat ur i a.
( 7) Mi sceI I aneous ef f ect s i ncI ude per i or bi t al edema and muscl e weakness.
Pat i ent s shoul d al so be advi sed of t he r i sks of exposur e t o sunl i ght and ul t r avi ol et
l i ght .
P. 999


e. Si gni fi cant i nt eract i ons.
( 1) Ant i epi I ept i c drugs, such as carbamazepi ne, decr ease t he l evel of
et hosuxi mi de ( i ncr eases met abol i sm) .
( 2) VaI proi c aci d i ncr eases t he l evel of et hosuxi mi de ( decr eases met abol i sm) .
8. CI onazepam ( KI onopi n)
a. Mechani sm of acti on. Cl onazepam i s a pot ent GABA- A agoni st , but i t s ef f i cacy
decr eases over sever al mont hs of t reat ment .
b. Admi ni st rat i on and dosage
( 1) For aduI t s, cl onazepam i s an or al agent t hat may be gi ven i n an i ni t i al dose of
1. 5 mg dai l y di vi ded t wo or t hr ee t i mes. The dose may be i ncr eased t o a maxi mum
of 20 mg dai l y.
( 2) Chi I dren shoul d r ecei ve 0. 01- 0. 03 mg dai l y i n t wo or t hree doses. The dosage
may be i ncr eased t o a maxi mum of 0. 2 mg/ kg dai l y.
c. Precaut i ons and moni tori ng ef fect s
( 1) Pat i ent s wi t h psychoses, acut e nar r ow- angl e gl aucoma, and si gni f i cant l i ver
di sease shoul d use t hi s medi ci ne caut i ousl y.
( 2) Adverse ef f ect s
( a) CNS ef f ect s i ncl ude dr owsi ness, at axi a, and behavi or di st ur bances i n chi l dr en;
t hese may be cor r ect ed by dose r educt i on.
( b) Respi rat ory ef f ect s i ncl ude hyper sal i vat i on and br onchi al hyper secr et i on.
( c) Mi sceI I aneous ef f ect s i ncl ude anemi a, l eukopeni a, t hr ombocyt openi a,
r espi r at or y depr essi on, anor exi a, and wei ght l oss.
d. Si gni f i cant i nt eract i ons
( 1) Ant i epi I ept i c drugs, such as phenyt oi n, i ncr ease t he l evel of cl onazepam
( decr ease met abol i sm) .
( 2) Ot her drugs. Cl onazepam decr eases t he ef f i cacy of I evodopa and i ncr eases t he
ser um l evel of di goxi n.
9. FeI bamate ( FeI bat oI )
a. Mechani sm of acti on. A pr oposed mechani sm of act i on i s t hat t he dr ug i nt er act s
wi t h gl yci ne modul at or y si t e on N- met hyl - D- aspar t at e ( NMDA) r ecept or s. Bl ockade
of NMDA may cont r i but e t o neur opr ot ect i ve ef f ect s of f el bamat e. Fel bamat e i s used
as monot her apy or adj unct i ve t her apy or wi t hout secondar y gener al i zat i on i n adul t s
and gener al i zed sei zur es associ at ed wi t h Lennox- Gast aut syndr ome i n chi l dr en. The
U. S. Food and Dr ug Admi ni st r at i on ( FDA) r ecommended t hat use of f el bamat e be
r est r i ct ed t o onl y t hose pat i ent s who ar e r ef r act or y t o ot her medi cat i ons and i n
whom t he r i sk- benef i t r el at i onshi p war r ant s i t s use, because of sever e
hepat ot oxi ci t y.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) AduI t s and chi I dren > 14 year s of age
( 2) Monot her apy, i ni t i al l y 1. 2 g i n t hr ee t o f our doses dai l y. The dosage may be
i ncr eased i n 600- mg i ncr ement s ever y 2 weeks t o 2. 4 g dai l y based on cl i ni cal
r esponse and, t her eaf t er , 3. 6 g dai l y i f necessar y.
( 3) Adj unct i ve t her apy, 1. 2 g i n t hr ee t o f our doses dai l y, wi t h r educt i on of t he
dosage of ot her ant i epi l ept i c dr ugs by 20%- 33%. The dosage of f el bamat e may be
i ncr eased i n i ncr ement s of 1. 2 g at weekl y i nt er val s t o a maxi mum of 3. 6 g dai l y.
( 4) Conver si on t o monot her apy i ni t i al l y 1. 2 g dai l y i n t hr ee t o f our doses, wi t h
r educt i on of t he dosage of ot her ant i epi l ept i c dr ugs by 33% at week 3. The
f el bamat e dosage may be i ncr eased t o 3. 6 g dai l y, and ot her ant i epi l ept i c dr ugs
di scont i nued or dosage f ur t her r educed i n st epwi se f ashi on.
( 5) Chi l dr en 2- 14 year s of age wi t h Lennox- Gast aut syndr ome, as adj unct i ve
t her apy, i ni t i al l y 15 mg/ kg dai l y i n t hr ee t o f our doses. The dosage of ot her
ant i epi l ept i c dr ugs i s r educed by 20%. The amount of f el bamat e may be i ncr eased i n
i ncr ement s of 15 mg/ kg at weekl y i nt er val s t o 45 mg/ kg dai l y. Fur t her r educt i on i n
t he dosage of ot her ant i epi l ept i c dr ugs may be necessar y.
c. Precaut i on and moni t ori ng ef f ect s. Ther e ar e t wo ver y ser i ous t oxi c ef f ect s,
apl ast i c anemi a and l i ver f ai l ur e, whi ch l ead t o deat h f or some pat i ent s.
( 1) For apl ast i c anemi a, t he onset range f r om 5 t o 30 weeks of i ni t i at i on of t her apy.
Weekl y or bi weekl y CBCs ar e r ecommended i ni t i al l y.
( 2) For l i ver, t oxi ci t y t i me bet ween i ni t i at i on of t r eat ment and di agnosi s of t hese
cases r anges f r om 14 t o 257 days. Ì t i s r ecommended t hat l i ver f unct i on t est s be
per f or med bef or e i ni t i at i on of t her apy t o i dent i f y pat i ent s who have evi dence of
pr eexi st i ng
P. 1000

l i ver damage. Li ver f unct i on t est s shoul d al so be per f or med weekl y or bi weekl y. The
FDA r ecommends t hat t hi s dr ug be used onl y i n pat i ent s who ar e r ef r act or y t o ot her
medi cat i ons and i n whom t he r i sk- benef i t r el at i onshi p war r ant s i t s use.
( 3) Phot oal l er gy or phot ot oxi ci t y may occur ; pat i ent s shoul d t ake pr ot ect i ve
measur es agai nst exposur e t o ul t r avi ol et l i ght or sunl i ght .
( 4) Ì nst r uct pat i ent s t o st or e medi cat i on i n i t s own t i ght l y cl osed cont ai ner at r oom
t emper at ur e away f r om excessi ve heat , di r ect sunl i ght , and moi st ur e.
( 5) Adverse ef f ect s. Cont act t he physi ci an i f si gns of i nf ect i on ( e. g. , bl eedi ng or
br ui si ng) occur .
( a) Thi s dr ug has t he pot ent i al t o cause apl ast i c anemi a ( bone mar r ow) .
( b) The pat i ent shoul d be moni t or ed f or t hese t oxi ci t i es by CBCs and l i ver f unct i on
t est s weekl y or bi weekl y unt i l di scont i nuat i on of any si gn of t hese t oxi ci t i es occur s.
( c) CNS ef f ect s ar e i nsomni a, headache, anxi et y, hyper act i vi t y, and f at i gue.
( d) Cardi ovascuI ar ef f ect s ar e per i pher al edema, vasodi l at i on, hypot ensi on, and
hyper t ensi on.
( e) OcuI ar ef f ect s ar e di pl opi a and bl ur r ed vi si on.
( f ) GÌ ef f ects ar e anor exi a, wei ght decr ease, and nausea.
( g) Hemat oI ogi caI ef f ect s may i ncl ude l ymphadenopat hy, l eukopeni a, and
t hr ombocyt openi a.
( h) Met aboI i c/ nut ri t i on ef f ect s may i ncl ude hypokal emi a and hyponat r emi a.
d. Si gni f i cant i nt eract i ons
( 1) FeI bamat e and phenyt oi n. Fel bamat e causes an i ncr ease i n phenyt oi n pl asma
concent r at i on. Phenyt oi n doubl es f el bamat e cl ear ance, r esul t i ng i n 45% decr ease i n
f el bamat e l evel s.
( 2) FeI bamat e and carbamazepi ne. Fel bamat e causes a decr ease i n
car bamazepi ne l evel s and an i ncr ease i n car bamazepi ne met abol i t es. Ì n addi t i on,
car bamazepi ne causes a 50% i ncr ease i n f el bamat e cl ear ance, r esul t i ng i n a 40%
decr ease i n st eady- st at e t r ough l evel s.
( 3) FeI bamat e and vaI proi c aci d. Fel bamat e causes an i ncr ease i n val pr oi c aci d
l evel s, but val pr oi c aci d does not af f ect f el bamat e l evel s.
( 4) Adverse ef f ect s. Si gns and sympt oms associ at ed wi t h i ncr eased pl asma l evel
and t oxi ci t y ar e anor exi a, nausea, vomi t i ng, i nsomni a, and headache.
10. Gabapent i n ( Neuront i n)
a. Mechani sm of acti on. Ì t i s an anal og of GABA. Ì t i ncr eases GABA t ur nover , but i t
does not bi nd t o GABA or any ot her est abl i shed neur ot r ansmi t t er r ecept or . Ì t s
mechani sm of act i on i s cur r ent l y unknown, al t hough i t bi nds t o a speci f i c r ecept or i n
t he br ai n and i nhi bi t s vol t age- dependent sodi um cur r ent s. Ì t has been shown t o be
ef f ect i ve as an add- on dr ug i n pat i ent s wi t h par t i al sei zur e wi t h or wi t hout
secondar y gener al i zat i on.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) Pat i ent s > 12 years r ecei ve 900 mg t o 1. 8 g dai l y, admi ni st er ed as adj unct i ve
t her apy i n t hr ee di vi ded doses. Ti t rat i ng t o an ef f ect i ve dose nor mal l y can be
achi eved wi t hi n 3 days by i ni t i at i ng t her apy wi t h 300 mg and t hen i ncr easi ng t he
dose i n 300- mg i ncr ement s over t he next 2 days t o est abl i sh a dosage of 900 mg
dai l y i n t hr ee doses. Ì f necessar y, t he dosage may be i ncr eased t o 1. 8 g dai l y. To
mi ni mi ze pot ent i al si de ef f ect s, especi al l y somnol ence, di zzi ness, or f at i gue, t he
f i r st dose on day 1 may be admi ni st er ed at bedt i me.
( 2) Pat i ent s 3- 12 year s of age shoul d r ecei ve 10- 15 mg/ kg/ day i n 3 di vi ded doses up
t o 25- 50 mg/ kg/ day.
( 3) The dr ug i s pr i mar i l y excr et ed r enal l y; t her ef or e, t he dosage shoul d be adj ust ed
f or pat i ent s who have compr omi sed r enal f unct i on.
( 4) The dr ug does not bi nd t o pl asma pr ot ei n. Ther e are no si gni f i cant
phar macoki net i c i nt er act i ons wi t h ot her commonl y used ant i epi l ept i c dr ugs.
( 5) Ì f gabapent i n i s di scont i nued or an al t er nat e ant i convul sant medi cat i on i s added,
i t shoul d be done gr adual l y over a mi ni mum of 1 week.
c. Precaut i ons and moni tori ng ef fect s
( 1) The val ue of moni t or i ng bl ood concent r at i on has not been est abl i shed and woul d
not al t er bl ood concent r at i on of ot her ant i epi l ept i c dr ugs when used t oget her .
( 2) Ì t has a l ow l evel of t oxi c si de ef f ect s, whi ch i ncl ude somnol ence, di zzi ness,
at axi a, and mi ni mal i nt er act i on wi t h ot her dr ugs.
P. 1001


( 3) Gabapent i n i s usef ul i n pat i ent s who ar e t aki ng ot her medi cat i ons f or epi l epsy or
ot her chr oni c di seases. Ì t may be especi al l y usef ul f or el der l y pat i ent s.
( 4) Gabapent i n i s wel l absor bed or al l y; i t can be t aken wi t h or wi t hout f ood.
However , pat i ent s who have GÌ pr obl ems mi ght have pr obl ems wi t h absor pt i on.
( 5) Adverse ef f ect s. Common si de ef f ect s ar e somnol ence, di zzi ness, at axi a,
f at i gue, wei ght gai n and nyst agmus.
( a) CNS ef f ect s ar e somnol ence, di zzi ness, at axi a, and f at i gue.
( b) GÌ ef f ect s i ncl ude dyspepsi a, dr yness of mout h, const i pat i on, and i ncr eased
appet i t e.
( c) OcuI ar ef f ect s ar e di pl opi a, bl ur r ed vi si on, and nyst agmus.
d. Si gni f i cant i nt eract i ons
( 1) Ant aci ds and gabapent i n. Ant aci ds r educe t he bi oavai l abi l i t y of gabapent i n by
20%; gabapent i n coul d be t aken 2 hr af t er ant aci d use.
( 2) Ci met i di ne and gabapent i n. Ci met i di ne decr eases t he r enal excr et i on of
gabapent i n by 14% and consequent l y i ncr eases gabapent i n pl asma l evel s ( however ,
t hi s amount i s not cl i ni cal l y si gni f i cant ) .
( 3) OraI cont racept i ves and gabapent i n. Or al cont r acept i ves i ncr ease t he l evel of
nor et hi ndr one by 13%; t hi s amount may not be cl i ni cal l y si gni f i cant .
11. Lamot ri gi ne (Lami ct aI )
a. Mechani sm of acti on. Ì t s ant i epi l ept i c ef f ect i s si mi l ar t o t hat of phenyt oi n. Ì t s
ef f ect may be t he r esul t of i nhi bi t i on of vol t age- dependent sodi um cur r ent s and
r educt i on of sust ai ned r epet i t i ve neur onal act i vi t y. Ì t i s i ndi cat ed f or t he t r eat ment of
par t i al sei zur es and secondar y gener al i zed t oni c- cl oni c sei zur es t hat are not
cont r ol l ed wi t h ot her dr ugs. Ì t i s al so used t o t r eat Lennox- Gast aut syndr ome.
Lamot r i gi ne i s br oad spect r um, as wel l t ol er at ed as monot her apy, and pr obabl y t he
l east t er at ogeni c of t he f i r st - l i ne agent s. Ì t may aggr avat e sever e myocl oni c
epi l epsy.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) AduI t s (> 16 year s) , i ni t i al l y 50 mg/ day i n t wo di vi ded doses ( pat i ent s t aki ng
val pr oi c aci d shoul d be gi ven 25 mg ever y ot her day) , up t o 100 mg/ day ( up t o 25
mg dai l y wi t h val pr oi c aci d t r eat ment ) .
( 2) Chi I dren 2- 12 year s 0. 6 mg/ kg/ day i n t wo di vi ded dosed ( 0. 15 mg/ kg/ day on
val pr oi c aci d t r eat ment ) , up t o 1. 2 mg/ kg/ day ( up t o 0. 3 mg/ kg/ day wi t h val pr oi c aci d
t r eat ment ).
( 3) The smal l est avai l abl e chewabl e di sper si bl e t abl et i s 5 mg. Then, af t er 2 weeks,
i ncr ease by 0. 3 mg/ kg/ day i n one t o t wo di vi ded doses, up t o 200 mg/ day.
( 4) Swal l ow chewabl e di sper si bl e t abl et whol e, chewed, or i n di sper si ng wat er or
di l ut ed f r ui t j ui ce. Ì f chewed, consume a smal l amount of wat er or di l ut e f r ui t j ui ce t o
ai d i n swal l owi ng. To di sper se, add t he chewabl e di sper si bl e t abl et t o a smal l
amount of l i qui d ( 1 t easpoon or enough t o cover t he medi cat i on) . Appr oxi mat el y 1
mi n l at er , when t he t abl et i s compl et el y di sper sed, swi r l t he sol ut i on and consume
t he ent i r e quant i t y i mmedi at el y.
( 5) For pat i ent s t aki ng val pr oi c aci d, t he i ni t i al dose i s 50 mg dai l y f or 2 weeks,
f ol l owed by mai nt enance doses of 100- 200 mg dai l y i n t wo di vi ded doses.
( 6) Reduced cl ear ance i n t he el der l y necessi t at es dosage r educt i on.
( 7) Pat i ent s wi t h hepat i c i mpai r ment may r equi r e dosage r educt i on because of
r educt i on i n met abol i sm.
c. Precaut i ons and moni tori ng ef fect s
( 1) The val ue of moni t or i ng pl asma concent r at i on has not been est abl i shed.
( 2) Caut i on shoul d be used f or pat i ent s t aki ng t hi s dr ug. Ì t may adver sel y af f ect t he
pat i ent ' s met abol i sm or compl i cat e t he el i mi nat i on of t he drug because of r enal ,
hepat i c, or car di ac i mpai r ment .
( 3) Lamot r i gi ne bi nds t o mel ani n and can accumul at e i n mel ani n- r i ch t i ssue over
t i me. Per i odi c opht hal mol ogi cal moni t or i ng i s recommended.
( 4) Phot osensi t i zat i on (phot oal l er gy and phot ot oxi ci t y) pat i ent s shoul d t ake
pr ot ect i ve measur es agai nst exposur e t o ul t r avi ol et l i ght or sunl i ght .
( 5) Ser i ous r ashes r equi r i ng hospi t al i zat i on have been r epor t ed. The i nci dence of
r ashes, i ncl udi ng St evens- Johnson syndr ome, i s appr oxi mal l y 1% i n pat i ent s < 16
year s ol d and 0. 3% i n adul t s. Rar e cases of t oxi c epi der mal necr ol ysi s or r ash-
r el at ed deat h have occur r ed. Most r ashes occur wi t hi n 2- 8 weeks of i ni t i al
t r eat ment .
P. 1002


( 6) Adverse ef f ect s. The most common si de ef f ect s ar e di zzi ness, di pl opi a, at axi a,
bl ur r ed vi si on, nausea, dose- r el at ed r ash and vomi t i ng.
( a) CNS ef f ect s ar e headache, di zzi ness, and at axi a t i cs ( i n chi l dr en) .
( b) GÌ ef f ect s ar e nausea, vomi t i ng, di ar r hea, and dyspepsi a.
( c) OcuI ar ef f ect s ar e di pl opi a, bl ur r ed vi si on, and vi si on abnor mal i t y.
( d) Dermat oI ogi caI ef f ect s ar e pr ur i t us, and a rash may f or m si mi l ar t o t hat f ound
when usi ng phenyt oi n and car bamazepi ne. Ì n many cases, t he r ash di sappear s
dur i ng cont i nued t her apy, but 1%- 2% of pat i ent s wi t h t he r ash r epr esent a mor e
ser i ous al l er gi c r eact i on. Occasi onal l y, pat i ent s have devel oped t he St evens-
Johnson syndr ome. Concomi t ant use wi t h val pr oi c aci d may i ncr ease t he l i kel i hood
of ser i ous rash. The occur r ences of l i f e- t hr eat eni ng r ash t hat wer e r epor t ed
devel oped wi t hi n 2- 8 weeks f ol l owi ng t her apy; ot her cases of r ash have been
r epor t ed devel opi ng up t o 6 mont hs af t er t her apy. The i nci dence of r ash i s hi gher i n
chi l dr en t han i n adul t s.
( e) Monot her apy dur i ng pr egnancy f ound no t er at ogeni c ef f ect .
d. Si gni f i cant i nt eract i ons
( 1) Car bamazepi ne decr eases l amot r i gi ne concent r at i on by 70% and i ncr eases
car bamazepi ne l evel s.
( 2) Phenobar bi t al or pr i mi done decr eases l amot r i gi ne concent r at i on by 40%.
( 3) Val pr oi c aci d decr eases t he met abol i sm of l amot r i gi ne and ext ends i t s hal f - l i f e
t o 60 hr , whi ch necessi t at es a dose r educt i on.
12. Topi ramat e ( Topamax)
a. Mechani sm of acti on. Topi r amat e i s a der i vat i ve of f r uct ose. Ì t decr eases r api d
hi ppocampal neur onal f i r i ng, possi bl y because of sodi um- or cal ci um- channel
i nhi bi t i on. Ì t i s al so a weak car boni c anhydr ase i nhi bi t or and a sodi um- channel
bl ocki ng agent . Topi r amat e pot ent i at es t he act i vi t y of GABA. Ì t has been shown t o
be ef f ect i ve adj unct i ve t her apy f or par t i al sei zur e t r eat ment i n adul t s, t oni c- cl oni c
sei zur e, i nf ant i l e spasms, and Lennox- Gast aut syndr ome.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) AduI t s 17 year s and ol der , 25- 50 mg/ day, up t o 400 mg/ day i n t wo di vi ded
doses. Chi I dren 2- 16 year s, 1- 3 mg/ kg/ day, up t o 5- 9 mg/ kg/ day i n t wo di vi ded
doses.
( 2) Topi r amat e i s 80% bi oavai l abl e, and f ood does not af f ect i t s bi oavai l abi l i t y.
( 3) Dose adj ust ment i s necessar y f or pat i ent s wi t h r enal or hepat i c i mpai r ment s.
( 4) Enzyme- i nduci ng ant i convul si ve dr ugs can decr ease t opi r amat e l evel s, but
t opi r amat e has a si gni f i cant ef f ect on met abol i sm of ot her ant i convul si ve dr ugs.
( 5) Ì ni t i al t reat ment i s 50 mg dai l y, f ol l owed by t i t r at i on t o an ef f ect i ve dosage. Mor e
t han 400 mg dai l y has not been shown t o i mpr ove r esponse.
c. Precaut i on and moni t ori ng ef f ect s
( 1) Ì ncr eased i nci dence of ki dney st ones ( r enal cal cul us) i n ol der pat i ent s who
r ecei ved t hi s dr ug. Pat i ent s shoul d be advi sed t o i ncr ease i nt ake of f l ui ds whi l e
t aki ng t opi r amat e.
( 2) Par est hesi a i s a common si de ef f ect of anhydr ase i nhi bi t or s.
( 3) Adverse ef f ect s
( a) The physi ci an shoul d be not i f i ed i f any of t he f ol l owi ng adver se ef f ect s occur :
( i ) Br east pai n i n f emal es
( i i ) Nausea or t r emor, whi ch ar e dose- r el at ed si de ef f ect s.
( i i i ) Back pai n, chest pai n, dyspepsi a, or l eg pai n
( b) CNS ef f ect s most l y seen i n 600 mg/ day dose i ncl ude psychomot or sl owi ng,
di f f i cul t y wi t h concent r at i on and speech, somnol ence, f at i gue, ast heni a, wei ght l oss,
cogni t i ve di st ur bances and di f f i cul t i es, t r emor s, di zzi ness, at axi a, and headache.
( c) GÌ ef f ect s i ncl ude upset , such as nausea, vomi t i ng, and gast r oent eri t i s.
( d) Geni t ouri nary ef f ect s i ncl ude r enal cal cul i nephr o.
( e) Cardi ovascuI ar ef f ect s i ncl ude chest pai n, pal pi t at i on, and vasodi l at i on.
( f ) OcuI ar ef f ect s i ncl ude abnor mal vi si on, eye pai n, di pl opi a, and open angl e
gl aucoma.
( g) Hemat oI ogi caI ef f ect s i ncl ude anemi a, epi st axi s, l eukopeni a, and apl ast i c
anemi a.
( h) Ot her: met abol i caci dosi s, hypohi dr osi s ( i n chi l dr en)
P. 1003


d. Si gni f i cant i nt eract i ons
( 1) Phenyt oi n and car bamazepi ne wi l l i ncr ease cl ear ance.
( 2) Topi r amat e i ncr eases t he cl ear ance of ot her dr ugs t hat ar e cl ear ed by
cyt ochr ome P450.
13. Ti agabi ne (Gabi t ri I )
a. Mechani sm of acti on. Ti agabi ne i s desi gned t o act on t he i nhi bi t or y act i on of
GABA by bl ocki ng i t s upt ake, t her eby pr ol ongi ng i t s act i on af t er synapt i c r el ease. Ì t
i s i ndi cat ed as adj unct i ve t her apy f or par t i al sei zur es and secondar y gener al i zed
t oni c- cl oni c sei zur es.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) St art i ng dose of 4 mg dai l y f or 2 weeks may be i ncr eased 4- 8 mg weekl y
t her eaf t er , t o a mai nt enance dose of 32- 56 mg dai l y.
( 2) Maxi mum r ecommended dosage f or chi I dren i s 32 mg dai l y; maxi mum
r ecommended dosage f or aduI t s i s 56 mg dai l y.
( 3) A hi gh- f at meal decr eases t he r at e of t i agabi ne absor pt i on but does not af f ect
t he ext ensi on of absor pt i on. Ti agabi ne shoul d be t aken wi t h f ood.
c. Precaut i ons and moni tori ng ef fect s
( 1) Moder at el y sever e t o sever e generaI i zed weakness has been r epor t ed. Ì t
r esol ves i n al l cases af t er r educt i on i n dose or di scont i nuat i on of t her apy.
( 2) Opht haI mi c ef f ect s, as i ndi cat ed by ani mal st udi es, i ncl ude t he possi bi l i t y f or
r esi dual bi ndi ng t o r et i na and mel ani n bi ndi ng; t hi s f i ndi ng, however , has not been
conf i r med i n human st udi es. Per i odi c opht hal mol ogi cal moni t or i ng i s necessar y.
( 3) Dermat oI ogi caI ef f ect s i ncl ude t he possi bi l i t y of sever e r ash t o St evens-
Johnson syndr ome, as r epor t ed i n cl i ni cal st udi es.
( 4) Adverse ef f ect s
( a) CNS ef f ect s ar e conf usi on, di zzi ness, and f at i gue.
( b) GÌ ef f ect s ar e upset st omach, nausea, mout h ul cer at i on, and anor exi a.
d. Si gni f i cant i nt eract i ons. Phenobar bi t al , phenyt oi n, and car bamazepi ne wi l l
i ncr ease t i agabi ne cl ear ance.
14. Zoni sami de (Zonegran)
a. Mechani sm of acti on. Ì t i s not wel l known. Ì t may bl ock t he sensi t i ve sodi um
channel s and T- t ype cal ci um channel s. Ì t i s an ef f ect i ve agent f or r ef r act or y par t i al
sei zur e, gener al i zed sei zur e i ndi cat ed f or adj unct t her apy f or par t i al sei zur e f or
adul t s, i nf ant i l e spasm, mi xed sei zur e t ypes of Lennox- Gast aut syndr ome,
myocl oni c, and gener al i zed t oni c- cl oni c sei zur e.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) AduI t s and chi I dren > 16 year s of age, 100 mg dai l y; wi t hi n 2 weeks, i ncr ease
t o 200 mg/ dai l y i n 2- week bases, up t o 600 mg dai l y.
( 2) Can be t aken wi t h or wi t hout f ood.
c. Precaut i ons and moni tori ng ef fect s
( 1) May i ncr ease mean concent r at i on of ser um cr eat i ni ne and bl ood, ur ea, ni t r ogen;
r enal f unct i on shoul d be moni t or ed per i odi cal l y.
( 2) May i ncr ease ser um al kal i ne phosphat ase.
( 3) May pr oduce dr owsi ness.
( 4) Si de ef f ect s. The physi ci an shoul d be cont act ed i f sudden pai n or abdomi nal
pai n occur s or i f bl ood i n ur i ne i s det ect ed; t hese sympt oms coul d i ndi cat e a ki dney
st one. Ì ncr ease f l ui d i nt ake t o decr ease t he r i sk of st one f ormat i on. Al so, cont act
t he physi ci an i f f ever , sor e t hr oat , or al ul cer , or easy br ui si ng i s seen; t hese
sympt oms coul d be t he r esul t of a hemat oI ogi caI compI i cat i on.
( 5) Most commonl y r epor t ed adver se event s are somnoI ence, anorexi a, di zzi ness,
headache, nausea, aI I ergi c react i ons, agi t at i on, and wei ght I oss.
( a) CNS ef f ect s ar e at axi a, conf usi on, t r emor, and abnor mal t hi nki ng.
( b) Cardi ovascuI ar ef f ect s ar e pal pi t at i on, t achycar di a, and vascul ar i nsuf f i ci ency.
( c) Dermat oI ogi c ef f ect s ar e macul opapul ar r ash, acne al opeci a, and
phot osensi t i vi t y.
( d) Ot her ef f ect s ar e bl adder cal cul us, l eukopeni a, and hypohi dr osi s ( chi l dr en) .
d. Si gni f i cant i nt eract i ons
( 1) Zoni sami de i nduces I i ver enzymes by i ncr easi ng met abol i sm and t hrough
cl ear ance of zoni sami de and decr eases hal f - l i f e.
( 2) Food wi l l del ay absor pt i on but wi l l not af f ect t he bi oavai l abi l i t y of t he dr ug.
P. 1004


15. Levet i racet am ( Keppra)
a. Mechani sm of acti on. Ì t i s a pyr r ol i done der i vat i ve and i s chemi cal l y unr el at ed
t o ot her ant i epi l ept i c dr ugs. Ì t di spl ays i nhi bi t or y pr oper t i es i n t he ki ndl i ng model i n
r at s. Ì t i s used as adj unct i ve t her apy i n t he t r eat ment of par t i al sei zur e i n adul t
pat i ent s.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7) . St ar t i ng dose of 1000 mg/ day gi ven i n
t wo di vi ded doses may be i ncr eased ever y 2 weeks, t o a maxi mum of 3000 mg/ day.
c. Precaut i ons and moni tori ng ef fect s
( 1) Hemat oI ogi caI ef f ect s ar e mi nor , but t her e i s a st at i st i cal l y si gni f i cant decr ease
compar ed t o pl acebo i n t ot al mean RBC count , mean hemogl obul i n, and mean
hemat ocr i t .
( 2) Decr ease i n WBC count and neur ophi l count
( 3) Ì t al so causes dr owsi ness.
( 4) Si de ef f ect s. Most commonl y r epor t ed adver se event s ar e somnoI ence,
weakness ( ast heni a) , i nf ect i on, and di zzi ness.
( a) CNS ef f ect s ar e somnol ence, di zzi ness, depr essi on, and ner vousness.
( b) Cardi ovascuI ar ef f ect s ar e pal pi t at i on, t achycar di a, and vascul ar i nsuf f i ci ency.
( c) Respi rat ory ef f ect s ar e phar yngi t i s, r hi ni t i s, and i ncr eased cough.
( d) Mi sceI I aneous ef f ect s ar e weakness, headache, and i nf ect i on.
e. Si gni fi cant i nt eract i ons. Levet i racet am does not i nf l uence t he pI asma
concent rat i on of exi st i ng ant i epi l ept i c dr ugs, and ot her anti epi I ept i c drugs do not
i nf l uence t he phar macoki net i c ef f ect s of l evet i r acet am.
16. Oxcarbazepi ne ( Tri I ept aI )
a. Mechani sm of acti on. Thi s dr ug pr oduces bl ockade of vol t age- sensi t i ve sodi um
channel s, r esul t i ng i n st abi l i zat i on of hyper exci t ed neur al membr anes, i nhi bi t i on of
r epet i t i ve neur onal f i r i ng, and di mi nut i on of pr opagat i on of synapt i c i mpul ses. These
act i ons ar e t hought t o be i mpor t ant i n t he pr event i on of sei zur e spr ead i n t he i nt act
br ai n. Ì n addi t i on, i ncr eased pot assi um conduct ance and modul at i on of hi gh- vol t age
act i vat ed cal ci um channel s may cont r i but e t o t he ant i convul sant ef f ect s of t he dr ug.
b. Admi ni st rat i on and dosage ( Tabl e 45- 7)
( 1) Chi I dren 4- 16 year s, 8- 10 mg/ kg/ day t o 600 mg/ day as adj unct i ve t her apy and 8-
10mg/ kgday as monot her apy.
( 2) AduI t s, 600mg/ day as adj unct i ve t her apy and 1200mg/ day as monot her apy. A
dosage adj ust ment i s needed f or pat i ent s wi t h r enal f ai l ur e; no dosage adj ust ment i s
needed f or pat i ent s wi t h mi l d t o moder at e hepat i c i mpai r ment .
( 3) Can be t aken wi t h or wi t hout f ood.
c. Precaut i on and moni t ori ng ef f ect s
( 1) Cl i ni cal l y si gni f i cant hyponat remi a ( sodi um < 125 mmol / L) can devel op dur i ng
t her apy.
( 2) Si de ef f ect s
( a) Use of t hi s pr oduct have been associ at ed wi t h CNS ef f ect s such as cogni t i ve
sympt oms ( psychomot or sl owi ng, di f f i cul t concent r at i ng) .
( b) May r educe t he ef f i cacy of or al cont r acept i ve.
( 3) Adverse ef f ect s
( a) CNS ef f ect s ar e di zzi ness, somnol ence, headache, at axi a, f at i gue, and ver t i go.
( b) GÌ ef f ect s ar e vomi t i ng, nausea, and abdomi nal pai n.
( c) NeuromuscuI ar and skeI et aI ef f ect s are abnor mal gai t and t r emor .
( d) OcuI ar ef f ect s ar e Di pl opi a, nyst agmus, and abnor mal vi si on.
( e) Endocri ne and met aboI i c ef f ect s common i n el der l y i ncl ude hyponat r emi a ( l ow
l evel of sodi um i n t he bl ood) .
( f ) Dermat oI ogi c: r ash.
d. Si gni f i cant i nt eract i ons
( 1) Oxcar bazepi ne i nhi bi t s cyt ochrome P450 2C19 and i nduces cyt ochrome P450
3A4/ 5 wi t h pot ent i al l y i mpor t ant ef f ect s on pl asma concent rat i ons of ot her dr ugs.
( 2) Ser um concent r at i ons of phenyt oi n and phenobarbi t aI ar e i ncr eased.
( 3) Ì t decr eases oraI cont racept i ve ef f ect s, benzodi azepi ne, and cal ci um channel
bl ocker s.
( 4) Cr oss- sensi t i vi t y wi t h carbamazepi ne ( 25%- 30%) .
17. Less common drugs ar e l i st ed i n Tabl e 45- 8.
P. 1005


Table 45-8. Less Common Drugs Used in Practice
Drug
Labeled
Indication
Half-Life
(hr)
Total
Plasma
Concentr
ation
(mg/L)
Therape
utic
Range of
Adult
Dose
(mg/day
)
Usual
Mode of
Eliminat
ion
Major
Protei
n
Bindin
g
Level
Mephoba
rbital
• Grand
mal
• Petit
mal
• Gets
conve
rted to
pheno
barbit
al
• Indica
ted
when
pheno
barbit
al
must
be
decrea
sed
becau
se oI
excess
ive
drows
iness
• Hyper
excita
bility
• Mood
distur
bance
s
11-67 n/a 400
-
600
Liv
er
4
0-
6
0
Mepheny
toin
• Tonic-
clonic
• Psych
95
(activ
e
n/a 200
-
600
Liv
er ~
rena
9
0
omoto
r
• Status
epilep
ticus
• Used
with
pheny
toin;
togeth
er
more
sedati
ve
compa
red to
pheny
toin
alone
metab
olite)
l
Ethotoin • Tonic-
clonic
• Psych
omoto
r
• Used
as
secon
d-line
therap
y; less
toxic
and
less
eIIecti
ve
than
pheny
toin
(alone
or
combi
ned)
3-9
a
15-50 200
0-
300
0
Liv
er
N
/
A
Methsuxi
mide
• Absen
ce
• Does
not
precip
itate
tonic-
clonic
(comp
ared
to
other
succin
imides
)
2-40
b
n/a 120
0
Liv
er
n/
a
Phensuxi
mide
• Absen
ce
• Less
toxic
and
less
eIIecti
ve
compa
red to
other
succin
imides
8
b
n/a 100
0-
300
0
Uri
ne.
bile
n/
a
Parameth
adione
c

• Absen
ce
• UseIul
when
other
seizur
es
exist
with
absen
ce
seizur
e
n/a n/a 900
-
240
0
Liv
er ~
rena
l
n/
a
• Note.
Do
not
use
with
mephe
nytoin
Trimetha
dione
c

• Absen
ce
• UseIul
when
other
seizur
es
exist
with
absen
ce
seizur
e
• Note.
Do
not
use
with
mephe
nytoin
6-13
days
> 700 900
-
240
0
Liv
er
0
Pregabali
n
• Simpl
e
partial
seizur
e
6 n/a 150
-
600
Ren
al
0
a
At high doses. nonlinear kinetic like phenytoin.

b
Active metabolite.

c
Possible Ietal malIormation iI used during pregnancy.

P. 1006


18. Vagus ner ve st i muI at i on ( VNS)
a. Ì t i s used as adj unct i ve t her apy f or adul t s and chi l dr en >r 12 year s of age whose
par t i al sei zur es ar e r ef r act or y t o ant i epi l ept i c medi cat i ons.
b. A pr ogr ammabl e si gnal gener at or t hat i s i mpl ant ed i n t he pat i ent ' s l ef t upper
chest has a bi pol ar VNS l ead t hat connect s t he gener at or t o t he l ef t vagus ner ve i n
t he neck, a pr ogr ammi ng wand t hat uses r adi o- f r equency si gnal s t o communi cat e
noni nvasi vel y wi t h t he gener at or , and handhel d magnet s used by t he pat i ent or
car egi ver t o manual l y t ur n t he st i mul at or on or of f .
c. The i mpl ant at i on pr ocedur e usual l y l ast s 1 hr under gener al anest hesi a. Once
pr ogr ammed, t he gener at or wi l l del i ver i nt er mi t t ent st i mul at i on at t he desi r ed set t i ng
unt i l any addi t i onal pr ogr ammi ng i s ent er ed.
C. Surgery. Ì f sei zur es do not r espond t o dr ug t her apy, sur ger y may be per f or med
t o r emove t he epi l ept ogeni c br ai n r egi on. The most common i s cor t i cal exci si on
( l obect omy) . Bet ween 70% and 80% of pat i ent s who have ant er i or t empor al
l obect omy have f ewer sei zur es. Bet ween 30% and 40% pat i ent s who have f r ont al
l obect omy have f ewer sei zur es.
1. I ndi cat i ons f or sur ger y ar e i nt r act abl e or di sabl i ng sei zur es r ecur r i ng f or 6- 12
mont hs. Shoul d be consi der ed f or pat i ent s wi t h medi cal l y r ef r act or y sei zur es.
2. Ì n st ereot axi c surgery, t he sur geon uses t hree- di mensi onal coor di nat es t o gui de
a needl e t hr ough a hol e dr i l l ed i n t he skul l , t hen dest r oys abnor mal pat hways vi a
smal l i nt r acer ebr al i nci si ons.
3. Other surgi caI approaches i ncl ude t empor al l obe r esect i on, r emoval of t he
t empor al l obe t i p, and cer ebr al hemi spher ect omy.
III. CompIications
A. ConvuI si ve st at us epi I ept i cus. Thi s di sor der i s char act er i zed by r api d r epet i t i on
of gener al i zed t oni c- cl oni c sei zur es wi t h no r ecover y of consci ousness bet ween
sei zur es. Thi s l i f e- t hr eat eni ng condi t i on may per si st f or hour s or even days; i f i t
l ast s l onger t han 1 hr , sever e per manent br ai n damage may r esul t .
1. Causes of st at us epi l ept i cus i ncl ude poor t her apeut i c compl i ance, i nt r acr ani al
i nf ect i on or neopl asm, al cohol wi t hdr awal , dr ug over dose, and met abol i c i mbal ance.
2. Management
a. A pat ent ai r way must be mai nt ai ned.
b. Ì f t he cause of t he condi t i on i s unknown, dext r ose 50% i n wat er ( 25- 30 mL) i s
gi ven vi a Ì V i n case hypogl ycemi a i s t he cause.
c. Ì f t he sei zur es per si st , di azepam ( 10 mg) i s admi ni st er ed vi a Ì V at a r at e not
exceedi ng 2 mg/ mi n unt i l t he sei zur es st op or 20 mg has been gi ven.
d. Phenyt oi n or f osphenyt oi n i s t hen admi ni st er ed vi a Ì V no f ast er t han 50 mg/ mi n
t o a maxi mum dose of 11- 18 mg/ kg. Bl ood pr essur e i s moni t or ed t o det ect
hypot ensi on.
e. Ì f t hese measur es do not st op t he sei zur es, one of t he f ol l owi ng dr ugs i s gi ven.
( 1) Di azepam i s gi ven as an Ì V dr i p of 50- 100 mg di l ut ed i n 500 mL dext r ose 5% i n
wat er , i nf used at 40 mL/ hr unt i l t he sei zur es st op.
( 2) Phenobarbi t aI i s gi ven as an Ì V i nf usi on of 8- 20 mg/ kg no f ast er t han 100
mg/ mi n.
f . Ì f sei zur es cont i nue despi t e t hese measur es, one of t he f ol l owi ng st eps i s t hen
t aken.
( 1) ParaI dehyde i s gi ven vi a Ì V i n a dosage of 0. 10- 0. 15 mL/ kg di l ut ed t o a 4%
sol ut i on i n nor mal sal i ne sol ut i on.
( 2) Li docai ne i s gi ven i n an Ì V l oadi ng dose of 50- 100 mg, f ol l owed by an i nf usi on
of 1- 2 mg/ mi n.
( 3) GeneraI anest hesi a i s i nduced wi t h vent i l at or y assi st ance and neur omuscul ar
j unct i on bl ockade.
B. NonconvuI si ve st at us epi I ept i cus. Thi s condi t i on pr esent s as r epeat ed absence
sei zur es or compl ex par t i al sei zur es. The pat i ent ' s ment al st at e f l uct uat es;
conf usi on, i mpai r ed r esponses, and aut omat i sms ar e pr omi nent . I ni t i aI
management t ypi cal l y i nvol ves i nt r avenous di azepam. Compl ex par t i al st at us
epi l ept i cus may al so necessi t at e admi ni st r at i on of such dr ugs as phenyt oi n or
phenobar bi t al .
P. 1007


IV. Seizure Disorder and Pregnancy
A. Epi demi oI ogy. About 0. 5% of al l pr egnanci es occur i n women wi t h epi l epsy.
B. Preconcept i on counseI i ng. The r i sks f or mot her and f et us shoul d be di scussed,
i ncl udi ng t he r i sks of f et al mal f or mat i on associ at ed wi t h ant i epi l ept i c dr ugs and
ot her genet i c f act or s.
C. Drug t herapy
1. Ì f t he pat i ent i s sei zure f r ee f or at l east 2 year s, wi t hdr awal of t he dr ug shoul d be
consi der ed. Ì f ant i epi l ept i c dr ug t her apy i s necessar y, a swi t ch t o monot her apy
shoul d be made i f possi bl e.
2. Fi ve ant i epi l ept i c medi cat i ons have been used or st udi ed i n pr egnant pat i ent s:
car bamazepi ne, phenobar bi t al , phenyt oi n, pr i mi done, and val pr oi c aci d.
Monot her apy of l amot r i gi ne dur i ng pr egnancy f ound no t er at ogeni c ef f ect .
Congeni t al mal f or mat i ons associ at ed wi t h t hese dr ugs i ncl ude cr ani of aci al
abnor mal i t i es, car di ac def ect s, and neur onal t ube def ect s. Most of t he st udi es di d
not consi der pat er nal genet i c f act ors, envi r onment al f act or s, dr ug dosi ng, or
combi nat i on t her apy.
3. Ant i epi l ept i c dr ugs i nt er f er e wi t h f ol at e met abol i sm. Admi ni st r at i on of f ol i c aci d, 4
mg dai l y, and mul t i vi t ami ns decr eases t he r i sk of mal f or mat i on, especi al l y of t he
neur onal t ube.
4. Vi t ami n K, 10 mg per day f or t he l ast 1- 2 mont hs of gest at i on, wi l l hel p pr event
neonat al hemor r hage, especi al l y i n cases of phenyt oi n or phenobar bi t al use.
5. Sei zur e di sor der and or al cont r acept i ves. Gabapent i n, l amot r i gi ne, l evet i r acet am,
et hosuxi mi de, val pr oat e, zoni sami de and t i agabi ne do not af f ect t he ef f i cacy of or al
cont r acept i ves.
6. Sei zur e di sor der and t he el der l y popul at i on. The new gener at i on of ant i epi l ept i c
dr ugs such as l evet i r acet am and gabapent i n may be mor e usef ul owi ng t o l ow l evel s
of pr ot ei n bi ndi ng and saf er si de ef f ect s. Al so, t he newer agent s have l ess pot ent i al
f or dr ug i nt er act i ons t han agent s el i mi nat ed f r om t he l i ver.
D. Moni t ori ng
1. Fr ee ser um ant i epi l ept i c dr ug l evel s shoul d be moni t or ed mont hl y, i mmedi at el y
bef or e t he next dose; and t he dose shoul d be adj ust ed t o t he l owest dose pr ovi di ng
adequat e cont r ol .
2. Ser um q- f et opr ot ei n l evel s shoul d be checked, and ul t r asonogr aphy shoul d be
per f or med at 16 weeks of gest at i on t o eval uat e f or f et al neuronal t ube def ect s. An
al t er nat i ve t o t hese t est s i s amni ocent esi s, especi al l y i f t he mot her i s t aki ng
val pr oat e or car bamazepi ne.
3. Compr ehensi ve ul t r asonogr aphy shoul d be per f or med at 18 and 22 weeks of
gest at i on f or pat i ent s t aki ng ant i epi l ept i c dr ugs t hat cause car di ac anomal i es.
4. Ì nt r apar t um pl ans shoul d i ncl ude Ì V admi ni st rat i on of a shor t - act i ng
benzodi azepi ne. Ì f t here i s concer n about f et al or mat er nal r espi r at or y depr essi on,
admi ni st er i ng i nt r avenous phenyt oi n or i nt r amuscul ar phenobar bi t al shoul d be
consi der ed. Cl ot t i ng st udi es shoul d be per f or med, and 1 mg vi t ami n K shoul d be
gi ven t o t he i nf ant . Nur ses and physi ci ans shoul d be al er t ed f or possi bl e
hemor r hage of t he i nf ant and appr i sed t hat t he i nf ant may exper i ence ant i epi l ept i c
dr ug wi t hdr awal .
P. 1008


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one of t he suggest ed answer s or
phr ases. Choose t he best answer .
1. Phenyt oi n i s ef f ect i ve f or t he treat ment of aI I of t he f oI I owi ng t ypes of
sei zures except
( A) gener al i zed t oni c- cl oni c.
( B) si mpl e par t i al .
( C) compl ex par t i al .
( D) absence.
( E) gr and mal .
Vi ew Answer 1. The answer i s D[ see] . 2. Whi ch of t he f oI I owi ng
ant i convuI sant s i s contrai ndi cat ed i n pat i ent s wi th a hi story of hypersensi t i vi t y
t o t ri cycI i c ant i depressant s?
( A) phenyt oi n
( B) et hosuxi mi de
( C) acet azol ami de
( D) car bamazepi ne
( E) phenobar bi t al
Vi ew Answer 2. The answer i s D[ see] . 3. Whi ch ant i convuI si ve drug
requi res t herapeut i c moni t ori ng of phenobarbi t aI serum I eveI s as weI I as i t s
own serum I eveI ?
( A) phenyt oi n
( B) pr i mi done
( C) cl onazepam
( D) et hot oi n
( E) car bamazepi ne
Vi ew Answer 3. The answer i s B[ seeand] . 4. Whi ch ant i convuI si ve drug
t reat ment has a hi gher i nci dence of ki dney st ones?
( A) phenyt oi n
( B) car bamazepi ne
( C) t opi r amat e
( D) t i agabi ne
Vi ew Answer 4. The answer i s C[ see5. What are t he most common adverse
ef f ect s of ant i convuI si ve drugs?
( A) headache and di zzi ness
( B) gast r oi nt est i nal sympt oms
( C) al t er nat i on of cogni t i on and ment at i on
( D) adver se ef f ect s on appet i t e and body wei ght
( E) al l of t he above
Vi ew Answer 5. The answer i s E[ see- 9] 6. Whi ch ant i epi I ept i c drug has t he
I east ef f ect on the ef fi cacy of oraI cont racept i ves?
( A) phenyt oi n
( B) t i agabi ne
( C) gabapent i n
( D) l amot r i gi ne
( E) C and D
Vi ew Answer 6. The answer i s E[ see7. Whi ch of t he f oI I owi ng drugs couI d
cause hyponat remi a?
( A) car bamazepi ne
( B) phenyt oi n
( C) oxcar bazepi ne
( D) f el bamat e
( E) t opi r amat e
( F) A, C, and D
Vi ew Answer 7. The answer i s F[ see] . P. 1009


ANSWERS AND EXPLANATIONS
1. The answer i s D [ see Ì . B. 2. c. ( 1) ] .
Phenyt oi n ( di phenyl hydant oi n) i s t he most commonl y pr escr i bed hydant oi n f or
sei zur e di sor der s. Ì t i s one of t he pr ef er r ed dr ugs f or gener al i zed t oni c- cl oni c ( gr and
mal ) sei zur es and f or par t i al sei zur es, bot h si mpl e and compl ex. However , phenyt oi n
i s not ef f ect i ve f or absence ( pet i t mal ) sei zur es.
2. The answer i s D [ see Ì Ì . B. 1. c. ( 2) ] .
Car bamazepi ne i s st r uct ur al l y r el at ed t o t he t r i cycl i c ant i depr essant s ( e. g. ,
ami t r i pt yl i ne, desi pr ami ne, i mi pr ami ne, nor t r i pt yl i ne, pr ot r i pt yl i ne) and shoul d not be
admi ni st er ed t o pat i ent s wi t h hyper sensi t i vi t y t o any of t he t r i cycl i c ant i depr essant s.
3. The answer i s B [ see Ì Ì . B. 5 and 6] .
Pr i mi done' s ant i sei zur e act i vi t y may be par t l y at t r i but abl e t o phenobar bi t al . Ì n
pat i ent s r ecei vi ng pr i mi done, ser um l evel s of bot h pr i mi done and phenobar bi t al
shoul d be measur ed.
4. The answer i s C [ see Ì Ì . B. 12]
Ther e i s a hi gher i nci dence of ki dney st ones ( r enal cal cul us) wi t h t opi r amat e
admi ni st r at i on.
5. The answer i s E [ see Ì . B. 1, 2- 9]
Al t er nat i on i n cogni t i on and ment at i on, gast r oi nt est i nal sympt oms, appet i t e and
body wei ght , and headache and di zzi ness ar e al l common adver se ef f ect s of
ant i convul si ve dr ugs.
6. The answer i s E [ see Ì V. C. 5]
Gabapent i n and l amot r i gi ne do not i ncr ease t he met abol i sm of or al cont racept i ves t o
a cl i ni cal l y si gni f i cant l evel ; t her ef ore, t hey coul d be used wi t h or al cont r acept i ves.
7. The answer i s F [ see Ì Ì . B. 1; Ì Ì . B. 9; Ì Ì . B. 16] .
Car bamazepi ne, oxcar bazepi ne, and f el bamat e al l cause hyponat r emi a.

46
Parkinson Disease
Azi t a Razzaghi
I. DISEASE STATE AND PATHOLOGY
A. Def i ni t i on. Par ki nson di sease i s a sl owl y pr ogr essi ve degener at i ve neur ol ogi cal
di sease char act er i zed by t r emor , r i gi di t y, br adyki nesi a ( sl uggi sh neur omuscul ar
r esponsi veness) , and post ur al i nst abi l i t y. Par ki nson di sease was f i r st descr i bed by
Dr . James Par ki nson i n 1817 as " shaki ng pal sy. ¨
B. I nci dence
1. Ì t has a pr eval ence of 1- 2 per 1000 of t he gener al popul at i on and 2 per 100
among peopl e >65 year s.
2. Onset gener al l y occur s bet ween age 50 and 65; i t usual l y occur s i n t he 60s.
C. Pat hogenesi s. Parki nson di sease i s a neur odegener at i ve di sease associ at ed
wi t h depi gment at i on of t he subst ant i a ni gra and t he I oss of dopami nergi c i nput
t o t he basaI gangI i a ( ext r apyr ami dal syst em) ; i t i s char act er i zed by di st i nct i ve
mot or di sabi I i t y. The basal gangl i a ar e r esponsi bl e f or i ni t i at i ng, sequenci ng, and
modul at i ng mot or act i vi t y.
1. Ì n heal t hy i ndi vi dual s, dopami ne i s pr oduced by neur ons t hat pr oj ect f r om t he
subst ant i a ni gr a t o t he neost r i at um ( whi ch i ncl ude caudat e and put amen) and gl obus
pal l i dus. Ì n t hese ar eas, dopami ne act s as an i nhi bi t or y neur ot r ansmi t t er .
2. Lewy bodi es ar e wi despr ead but occur especi al l y i n t he basal gangl i a, br ai nst em,
spi nal cor d, and sympat het i c gangl i a.
3. Ì n Par ki nson di sease, t he l oss of dopami ne- pr oduci ng neur ons i n t he subst ant i a
ni gr a r esul t s i n an i mbal ance bet ween dopami ne, an i nhi bi t or y neur ot r ansmi t t er , and
t he exci t at or y neur ot r ansmi t t er acet yl chol i ne. Al t er at i ons i n t he concent r at i ons of
ot her neur ot r ansmi t t er s, such as norepi nephr i ne, ser ot oni n, and v- ami nobut yr i c aci d
( GABA) , ar e al so i nvol ved i n t he pat hophysi ol ogy of Par ki nson di sease ( Fi gur e 46-
1) .
D. Cause. Sever al f or ms of Par ki nson di sease have been r ecogni zed.
1. Pri mary ( i di opat hi c) Parki nson di sease
a. Thi s i s al so cal l ed cl assi c Par ki nson di sease or paraI ysi s agi t ans.
b. The cause i s unknown; and whi l e t r eat ment may be pal l i at i ve, t he di sease i s
i ncur abl e.
c. Most pat i ent s suf f er f r om t hi s t ype of par ki nsoni sm.
d. Hypot heses of neuronaI I oss i n i di opat hi c Par ki nson di sease ar e as f ol l ows:
( 1) Absorpt i on of hi ghI y pot ent neurot oxi ns ( envi ronment aI ) , such as car bon
monoxi de, manganese, sol vent s, and N- met hyl - 4- phenyl - 1, 2, 3, 6- t et r ahydr opyr i di ne
( MPTP) , whi ch i s a pr oduct of i mpr oper synt hesi s of a synt het i c her oi n- l i ke
compound. Exposur e t o t hese agent s, al one or i n combi nat i on wi t h t he neur onal l oss
of age, may be t he cause of Par ki nson di sease.
( 2) Exposure t o t he f ree radi caI s. Nor mal l y, dopami ne i s cat abol i zed by
monoami ne oxi dase ( MAO) . Hydr ogen per oxi de and pr oduct i on of f r ee r adi cal s÷
bot h t oxi c t o cel l s÷ar e pr oduct s of cat abol i sm. Pr ot ect i ve mechani sms, enzymes,
and f r ee r adi cal scavenger s, such as vi t ami ns E and C, pr ot ect cel l s f r om damage.
Ì t i s pr oposed t hat ei t her a decr ease i n t hese pr ot ect i ve mechani sms or an i ncr ease
i n t he pr oduct i on of dopami ne causes a dest r uct i on of t he neur ons by f r ee r adi cal s.
e. Genet i cs f act or s: Genes t hat l i nk t o Par ki nson di sease such as al pha- synucl ei n
and Par ki n ar e f ur t her bei ng st udi ed i n t r eat ment and di agnosi s of Par ki nson
di sease.
2. Secondary parki nsoni sm-f rom a known cause
a. Onl y a smal l per cent age of cases ar e secondar y, and many of t hese ar e cur abl e.
b. Secondar y par ki nsoni sm may be caused by dr ugs, i ncl udi ng dopami ne
ant agoni st s, such as t he f ol l owi ng:
P. 1011



Figure 46-1. Extrapyramidal system involved in
Parkinson disease. (Reprinted with permission
Irom Netter F. Ciba Collection of Medical
Illustrations. West Caldwell. NJ: Ciba Geigy
Pharmaceuticals. 1983:69.)
P. 1012


( 1) Phenot hi azi nes ( e. g. , chl or pr omazi ne, per phenazi ne)
( 2) But yr ophenones ( e. g. , hal oper i dol )
( 3) Reser pi ne
c. Poi soni ng by chemi cal s or t oxi ns may be t he cause; t hese i ncl ude
( 1) Car bon monoxi de poi soni ng
( 2) Heavy- met al poi soni ng, such as t hat by manganese or mer cur y
( 3) MPTP, a commer ci al compound used i n or gani c synt hesi s and f ound ( as a si de
pr oduct ) i n an i l l egal meper i di ne anal og
d. Ì nf ect i ous causes i ncl ude
( 1) Encephal i t i s ( vi r al )
( 2) Syphi l i s
e. Ot her causes i ncl ude
( 1) Ar t er i oscl er osi s
( 2) Degener at i ve di seases of t he cent r al ner vous syst em ( CNS) , such as
pr ogr essi ve supr anucl ear pal sy
( 3) Met abol i c di sor der s, such as Wi l son di sease
E. Si gns and sympt oms
1. Tremor
a. Tr emor may be t he i ni t i al compl ai nt i n some pat i ent s. Ì t i s most evi dent at r est
( rest i ng t remor) and wi t h l ow- f r equency movement . When t he t humb and f or ef i nger
ar e i nvol ved, i t i s known as t he pi I I - roI I i ng t remor. Bef or e pi l l s wer e made by
machi ne, phar maci st s made t abl et s ( pi l l s) by hand, hence t he name ( Fi gur e 46- 2) .
b. Some pat i ent s exper i ence act i on t remor ( most evi dent dur i ng act i vi t y) , whi ch
can exi st wi t h or bef or e t he r est i ng t r emor devel ops.
2. Li mb ri gi di t y i s pr esent i n al most al l pat i ent s. Ì t i s det ect ed cl i ni cal l y when t he
ar m r esponds wi t h a r at chet - l i ke ( i . e. , cogwheel i ng) movement when t he l i mb i s
moved passi vel y. Thi s i s owi ng t o a t r emor t hat i s super i mposed on t he r i gi di t y.
3. Aki nesi a or bradyki nesi a. Aki nesi a i s char act er i zed by di f f i cul t y i n i ni t i at i ng
movement s, and br adyki nesi a i s a sl owness i n per f or mi ng common vol unt ar y
movement s, i ncl udi ng
P. 1013

st andi ng, wal ki ng, eat i ng, wr i t i ng, and t al ki ng. The l i nes of t he pat i ent ' s f ace ar e
smoot h, and t he expr essi on i s f i xed ( masked f ace) wi t h l i t t l e evi dence of
spont aneous emot i onal r esponses ( Fi gur e 46- 3) .

Figure 46-2. Resting (or static) tremors.
(Adapted Irom Bates B. A Guide to Phvsical
Examination and Historv Taking. 5th ed.
Philadelphia: Lippincott. 1991:197.)

Figure 46-3. Masked Iace oI Parkinson disease.
(Adapted Irom Bates B. A Guide to Phvsical
Examination and Historv Taking. 5th ed.
Philadelphia: Lippincott. 1991:197.)
4. Gai t and posturaI di ff i cuI t i es. Char act er i st i cal l y, pat i ent s wal k wi t h a st ooped,
f l exed post ur e; a short , shuf f l i ng st r i de; and a di mi ni shed ar m swi ng i n r hyt hm wi t h
t he l egs. Ther e may be a t endency t o accel er at e or f est i nat e ( Fi gur e 46-4) .
5. Changes i n ment aI stat us. Ment al st at us changes, i ncl udi ng depr essi on ( 50%) ,
dement i a ( 25%) , and psychosi s, ar e associ at ed wi t h t he di sease and may be
pr eci pi t at ed or wor sened by dr ugs.
6. Uni f i ed Parki nson di sease rat i ng scaI e ( UPDRS)
a. To evaI uat e t he cI i ni caI ef fi cacy of ant i par ki nson dr ugs and t o moni t or di sease
progressi on, most i nvest i gat or s have used t he UPDRS.
( 1) The di sadvant ages associ at ed wi t h t he use of scal es f or r at i ng t he f unct i onal
and mot or di sabi l i t i es of pat i ent s wi t h Par ki nson di sease i ncl ude t he pot ent i al of
i nt er r at er var i abi l i t y and i mpr eci si on because of t he semi quant i t at i ve scor i ng.
( 2) The r esul t of t est i ng depends hi ghl y on t he st age of t he di sease, whet her t he
pat i ent i s bei ng eval uat ed dur i ng an on or of f per i od, and t he r el at i ve di st r i but i on of
t he i mpr ovement acr oss al l t he i t ems eval uat ed.
b. Part I of t he UPDRS i s an evaI uat i on of ment at i on, behavi or, and mood.
c. Part I I i s a seI f - report ed evaI uat i on of the act i vi t i es of dai I y I i vi ng ( ADLs) and
i ncl udes speech, swal l owi ng, handwr i t i ng, abi l i t y t o cut f ood, dr essi ng, hygi ene,
f al l i ng, sal i vat i ng, t ur ni ng i n bed, and wal ki ng.
d. Part I I I i s a cI i ni ci an-scored motor evaI uat i on.
( 1) Pat i ent s ar e eval uat ed f or speech, r est - t r emor f aci al expr essi on and mobi l i t y,
act i on or post ur al t r emor of hands, ri gi di t y, f i nger t aps, hand movement s, r api d
al t er nat i ve pr onat i on- supi nat i on movement of hands, l eg agi l i t y, ease of ar i si ng f r om
a chai r , post ur e, post ur al st abi l i t y, gai t , and br adyki nesi a.
P. 1014



Figure 46-4. Characteristic walk oI patients with
Parkinson disease. (Adapted Irom Bates B. A
Guide to Phvsical Examination and Historv
Taking. 5th ed. Philadelphia: Lippincott.
1991:553.)
( 2) Each i t em i s eval uat ed on a scal e of 0- 4.
( a) A rat i ng of 0 on t he mot or per f ormance eval uat i on scal e i ndi cat es normaI
perf ormance.
( b) A rat i ng of 4 on t he mot or per f ormance eval uat i on scal e i ndi cat es severeI y
i mpai red perf ormance.
e. Part I V i s t he Hoehn and Yahr st agi ng of sever i t y of Par ki nson di sease (Tabl e
46- 1) .
f . Part V i s t he Schwan and EngI and ADL scaI e.
Table 46-1. Stages of Parkinson Disease
Stage Characteristics
0 No clinical signs evident
I Unilateral involvement. including the maior Ieatures oI tremor.
rigidity. or bradykinesia; minimal Iunctional impairment
II Bilateral involvement but no postural abnormalities
III Mild to moderate bilateral disease. mild postural imbalance. but still
ability to Iunction independently
IV Bilateral involvement with postural instability; patient requires
substantial assistance
V Severe disease; patient restricted to bed or wheelchair unless aided
Reprinted with permission Irom Hoehn MM. Yahr MD. Parkinsonism:
Onset. progression. and mortality. Neurologv 1967;17:427.

P. 1015


F. Di agnosi s
1. Di agnosi s depends on cl i ni cal f i ndi ngs.
2. Test s ( i ncl udi ng i magi ng) ar e most of t en used t o rul e out an or i gi n of secondar y
Par ki nson di sease.
3. New t echnol ogi es÷f or exampl e, posi t r on- emi ssi on t omogr aphy ( PET) scan÷ar e
used t o vi sual i ze dopami ne upt ake i n t he subst ant i a ni gr a and basal gangl i a. The
PET scan measur es t he ext ent of neur onal l oss i n t hese ar eas.
4. A speci f i c f or m of si ngl e- phot on emi ssi on comput ed t omogr aphy ( SPECT) can be
hel pf ul f or di agnosi s of par ki nsoni an syndr omes and nonpar ki nsoni sm syndr omes,
par t i cul ar l y essent i al t r emor .
5. Ot her di seases t hat ar e si mi l ar t o Par ki nson di sease ar e mul t i pl e syst em at r ophy
( st r i at oni gr al degener at i on, ol i vopont ocer ebel l ar at r ophy, shy- dr agger syndr ome) ,
cor t i cobasal gangl i oni c degener at i on, and pr ogr essi ve supr anucl ear pal sy.
6. Ot her i nvest i gat i onal di agnost i c t ool s: ( i ) Tr anscr ani al ul t r asound, ( i i ) exai me
def i ci t s i n ol f act i on, and ( i i i ) det ect i on of ol i gomet r i c al pl a- synucel i n i n bl ood of
pat i ent s wi t h Par ki nson di sease.
G. Treat ment (Fi gur e 46- 5)
1. Nondrug t reat ment
a. Exerci se i s an i mpor t ant adj unct i ve t her apy and i s most benef i ci al . Al t hough
exer ci se does not hel p wi t h t he sympt oms of Par ki nson di sease, r egul ar f ocused
exer ci se, st ret chi ng, and st r engt heni ng act i vi t i es can have a posi t i ve ef f ect on
mobi l i t y and mood.
b. Nut ri t i on. Pat i ent s wi t h Par ki nson di sease ar e at i ncr eased r i sk of poor nut r i t i on,
wei ght l oss, and r educed muscl e mass. Exampl es of t he benef i ci al ef f ect s of pr oper
nut r i t i on i n t hi s gr oup of pat i ent s i ncl ude t he f ol l owi ng:
( 1) Suf f i ci ent f i ber and f l ui d i nt ake hel p pr event const i pat i on associ at ed wi t h
Par ki nson di sease and t he medi cat i ons used t o t r eat t he di sease.
( 2) Cal ci um suppl ement at i on hel ps mai nt ai n t he exi st i ng bone st r uct ur e.
( 3) Excessi ve di et ar y pr ot ei n i n t he l at e st ages of t he di sease causes er r at i c
r esponses t o l evodopa t her apy.
( 4) A l ar ge body of l i t er at ur e suppor t s t he pat hophysi ol ogi cal r ol e of ant i oxi dant s i n
t he neur opr ot ect i ve r ol e and decr ease i n pr ogr essi on i n Par ki nson di sease.
Pr oduct s such as q- t ocopher ol or vi t ami n, cr eat i ne, coenzyme Q10 act as
scavenger s of f r ee r adi cal whi ch ar e har mf ul t o cel l s.
2. Drug therapy f or sympt omat i c reI i ef . Tr eat ment i s di vi ded i nt o t wo gener al i zed
cat egor i es: sympt omat i c t her api es and pr event i ve or pr ot ect i ve measur es.
Neur opr ot ect i ve st r at egi es ar e used t o sl ow t he devel opment and pr ogr essi on of t he
di sor der .
H. Drug t reat ment : Neuroprot ect i ve t reat ment
1. MAO- B, such as sel egi l i ne and t ocopher ol ( vi t ami n E) , act s as a scavenger of
f r ee r adi cal s.
2. Dopami ne agoni st s ser ve as scavenger s of f r ee r adi cal s and decr ease dopami ne
t ur nover , whi ch r educes oxi dat i ve st ress. Dur i ng ear l y devel opment of t he di sease,
t her e ar e i ncr eases i n oxi dat i ve st r ess. Four cl asses of dr ugs ar e avai l abl e:
a. Ant i chol i ner gi cs ( f or r est i ng t r emor )
b. Pr ecur sor of dopami ne ( e. g. , car bi dopa/ l evodopa)
c. Di r ect - act i ng dopami ne agoni st s (e. g. , br omocr i pt i ne)
d. Ì ndi r ect - act i ng dopami ne agoni st s
( 1) Decr ease r eupt ake (e. g. , amant adi ne)
( 2) Decr ease met abol i sm ( e. g. , sel egi l i ne)
3. Drug therapy f or t reat i ng associ at ed sympt oms
a. Tri cycI i c ant i depressant s ar e used t o t r eat depressi on. They exhi bi t some
dopami ner gi c and ant i chol i ner gi c ef f ect s.
b. ß- BI ockers, especi al l y propranoI oI wi t h i t s hi gh l i pophi l i ci t y, benzodi azepi nes,
and pri mi done, ar e medi cat i ons used f or act i on t remor. Usual l y, pat i ent s show a
cl i ni cal r esponse i n l ow doses.
P. 1016



Figure 46-5. Management oI Parkinson disease.
P. 1017


c. Ant i hi st ami nes. Di phenhydr ami ne hydr ochl or i de has some mi l d ant i chol i ner gi c
ef f ect s and i s used f or sympt omat i c r el ease of mi l d t r emor ; because of i t s adver se
r eact i on i n t he CNS, i t shoul d be used wi t h caut i on i n t he el der l y.
4. GeneraI pri nci pI es of drug therapy
a. Ì f a pat i ent does not r espond t o an agent i n one cl ass, anot her cl ass shoul d be
t r i ed. St udi es show t hat some pat i ent s r espond t o one agent when t hey f ai l t o
r espond t o t he ot her .
b. Ther apy shoul d be st ar t ed wi t h a l ow dose and t i t rat ed up. Response usual l y i s
seen wi t hi n a f ew days af t er st ar t i ng t her apy.
c. Ì f a second agent i s added t o t he dr ug t her apy, t he dose of t he f i r st medi cat i on
shoul d be decr eased t o mi ni mi ze si de ef f ect s.
d. Dr ug t herapy shoul d never be di scont i nued suddenl y because wi t hdr awal may
exacer bat e t he sympt oms.
5. Def i ni ti ons concerni ng drug t herapy
a. Dyski nesi as/ dyst oni a ar e t ypi cal l y or al - f aci al movement s, gr i maci ng, or j er ky
and wr i t hi ng movement s of t he t r unk and ext r emi t i es. They ar e al ways r ever si bl e
wi t h ant i par ki nsoni an medi cat i ons, and t hey decr ease or di mi ni sh wi t h dose
r educt i on. Sympt oms of Par ki nson di sease may r eappear by r educi ng t he dose, and
i t i s t he cl i ni cal j udgment of t he physi ci an or t he pr ef er ence of t he pat i ent whet her
t o cont i nue wi t h t he dr ug r egi men or t ol er at e t he si de ef f ect s. Ther e ar e t hr ee t ypes
of dyski nesi as/ dyst oni a: peak dose dyski nesi a, bi phasi c dyski nesi as, and of f - per i od
dyst oni a. Al l coul d benef i t f r om sust ai ned- r el ease pr epar at i ons.
( 1) Peak- dose dyski nesi a
( a) Coul d be cor r ect ed wi t h sust ai ned- r el ease pr epar at i ons.
( b) Decr ease L- dopa dose, or add cat echol - O- met hyl t r ansf er ase ( COMT) i nhi bi t or .
( c) Add amant adi ne.
( d) Per f or m sur ger y.
( 2) Bi phasi c dyski nesi as
( a) Coul d be cor r ect ed wi t h sust ai ned- r el ease pr epar at i ons.
( b) Decr ease L- dopa dose and i ncr ease dopami ner gi c dose. Ì f sympt oms ar e st i l l
pr esent , a COMT i nhi bi t or shoul d be added.
( c) Amant adi ne may be hel pf ul .
( 3) Of f - per i od dyst oni a
( a) Decr ease L- dopa dose.
( b) Ì ncr ease dopami ner gi c dose.
b. On- of f ef f ect descr i bes osci l l at i ons i n r esponse ( at t he r ecept or si t e) and sudden
changes i n mobi l i t y f r om no sympt oms t o f ul l par ki nsoni an sympt oms i n a mat t er of
mi nut es. No di r ect r el at i onshi p bet ween t he on- of f ef f ect and dr ug l evel s has been
f ound. Usual l y, a second dr ug i s added t o t he t her apy r egi men t o cor r ect t he ef f ect .
Reduci ng t he dose of one dr ug and addi ng a second dr ug may al so be usef ul . Coul d
be managed by addi ng ent acapone, dopami ne agoni st , amant adi ne, or sel egi l i ne.
c. End-dose ef f ect , known al so as t he weari ng- of f ef f ect, occur s at a l at t er par t of
t he dosi ng i nt er val ; i t happens af t er a f ew year s of L- dopa t her apy. Reduce t he
si ngl e L- dopa dose and spr ead t he t ot al L- dopa dose over a l ar ger number of si ngl e
doses. Change t o a dopami ne agoni st and use a sust ai ned- r el ease f or mul at i on of L-
dopa. Coul d be managed by addi ng ent acapone, dopami ne agoni st , amant adi ne, or
sel egi l i ne.
d. Drug hoI i day. Long- t er m l evodopa use r esul t s i n downr egul at i on of dopami ne
r ecept or s. A dr ug hol i day al l ows st r i at al ni gr a dopami ne r ecept or s t o be
r esensi t i zed, al t hough cont r over sy exi st s r egar di ng t he consequences and t he
out come of t hi s hol i day.
6. Physi caI rehabi I i t ati on r est or es pat i ent s' physi cal f unct i on and i ndependence
t hr ough physi cal and occupat i onal t her apy. Such t her apy hel ps pat i ent s wi t h
managi ng bi g and smal l muscl e gr oups by f ocusi ng on mai nt ai ni ng coor di nat i on,
dext er i t y, f l exi bi l i t y, and r ange of mot i ons.
7. PsychoI ogi caI rehabi I i t at i on pr ovi des suppor t f or pat i ent s and t hei r f ami l i es.
Keep i n mi nd t hat pat i ent s wi t h Par ki nson di sease have a hi gh i nci dence of
depr essi on and t hat , i n l at er st ages of t he di sease, t hey devel op dement i a (Tabl e
46- 2) .
8. Secondary ef f ect s of Parki nson di sease i ncI ude
a. Cardi ovascuI ar ef f ect s, i ncl udi ng or t host at i c hypot ensi on and ar r hyt hmi a
b. Gast roi nt est i naI ef f ect s, i ncl udi ng const i pat i on and hyper sal i vat i on
c. Geni touri nary ef f ect s, i ncl udi ng i ncr eased ur i nar y f r equency and i mpot ence
P. 1018


Table 46-2. Overview of Parkinson Disease Management
Treatment Considerations
Stage Characteristics Physical Psychosocial
Early Fully Iunctional
May have
unilateral tremor.
rigidity
Preventive
exercise program
Education
InIormation
Early
middle
Symptoms
bilateral.
bradykinesia.
rigidity
Mild speech
impairment
Axial rigidity.
stooped posture.
stiIIness
Gait impairment
begins
Corrective
exercise program
Counseling
Support group
Monitor Ior
depression
Late
middle
All symptoms
worse but
independent in
ADLs
May need minor
assistance
Balance problems
Compensatory
and corrective
exercise
Speech therapy
Occupational
therapy
Caregiver issues
(medications.
mobility)
Monitor Ior
dementia
Late Severely disabled.
impaired
Dependent with
ADLs
Compensatory
exercise
Dietary concerns
Skin care
Hygiene
Pulmonary
Iunction
Dementia
Depression
ADLs. activities oI daily living.
Reprinted with permission Irom Custin TM. Overview oI Parkinson's disease
management. Phys Ther 1995;75: 363-373. This material is copyrighted. and
any Iurther reproduction or distribution is prohibited.

d. Cent raI ner vous syst em ef f ect s, i ncl udi ng hal l uci nat i ons, depr essi on, and
psychosi s. Coul d be t r eat ed wi t h r educi ng or el i mi nat i ng amant adi ne, sel egi l i ne,
ant i chol i ner gi cs, or dopami ne agoni st s.
9. Lat e di sabi I i ti es of Parki nson di sease can be di vi ded i nt o t wo gr oups.
a. Levodopa- reI at ed di sabi I i t i es, whi ch i ncl ude mot or f l uct uat i on, dyski nesi a,
neur opsychi at r i c t oxi ci t y, and r educed r esponse
b. Non- I evodopa- reI at ed di sabi I i t i es, whi ch i ncl ude cogni t i ve i mpai r ment ,
i nst abi l i t y r esul t i ng i n mor e f r equent f al l s, gai t di st ur bance, i ncont i nence,
dysphagi a, and speech di st ur bance
c. Lat e di sabi l i t i es management t her api es i ncl ude t he f ol l owi ng:
( 1) Mot or f I uct uat i on. Al t er i ng t he l evodopa dosage and t i mi ng, usi ng al t er nat i ve
means of l evodopa admi ni st r at i on, del i ver y, and absor pt i on; usi ng di r ect - act i ng
dopami ne agoni st s or exper i ment al agoni st s; al t er i ng met abol i sm of dopami ne and
l evodopa par ent al agoni st s; usi ng gl ut amat e ant agoni st s; and per f or mi ng f unct i onal
neur osur ger y
( 2) Mi sceI I aneous l at e di sabi l i t i es and management t her api es i ncl ude
( a) Uri nary urgency: oxybut yni n
( b) Uri nary ret ent i on: apomor phi ne
( c) Const i pat i on: f i ber , pol yet hyl ene gl ycol s
( d) Tenesmus: cl onazepam, apomor phi ne
( e) HypersaI i vat i on: ant i hi st ami ne, ant i chol i ner gi c
( f ) Dysphagi a: l i qui d l evodopa
( g) Sweat i ng cri ses: 8-bl ocker s, ant i chol i ner gi c agent s
( h) Dayt i me sI eepi ness: sel egi l i ne
( i ) Ni ght mares: ami t r i pt yl i ne, cl onazepam
( j ) Pani c at t acks and depressi on: l i qui d l evodopa, ami t r i pt yl i ne
( k) Ort host at i c hypot ensi on: domper i done, desmopr essi n
( I ) Dysphoni a: r educe l evodopa dosage, speech t her apy
( m) Pai n: ami t r i pt yl i ne, f l uvoxami ne
P. 1019


II. INDIVIDUAL DRUGS
A. Ant i choI i nergi c agent s ar e used f or mi l d sympt oms, pr edomi nant l y t r emor s.
1. Mechani sm of acti on. Thi s cl ass of dr ugs bl ocks t he exci t at or y neur ot r ansmi t t er
chol i ner gi c i nf l uence i n t he basal gangl i a. These dr ugs ar e mor e ef f ect i ve f or t r emor
and r i gi di t y t han f or br adyki nesi a and l ess ef f ect i ve f or post ur al i mbal ance.
2. Admi ni st rat i on and dosage ( Tabl e 46- 3)
3. Precaut i ons and moni tori ng ef fect s
a. Ant i chol i ner gi cs shoul d be used wi t h caut i on i n pat i ent s wi t h obst r uct ed
gast r oi nt est i nal ( GÌ ) or geni t our i nar y ( GU) t r act s, nar r ow- angl e gl aucoma, or sever e
car di ac di sease. Physi ci ans shoul d be not i f i ed i f a r api d hear t beat or eye pai n ar e
exper i enced. (Fr equent opht hal mol ogi cal vi si t s ar e r ecommended. )
b. The sedat i ve si de ef f ect s of ant i hi st ami nes may be benef i ci al i n some pat i ent s.
c. Al cohol and ot her CNS depr essant s shoul d be used wi t h caut i on.
d. Adverse ef f ect s of ant i chol i ner gi c t her apy i ncl ude t he f ol l owi ng:
( 1) Peri pheraI ant i choI i nergi c ef f ect s i ncl ude dr y mout h ( har d candi es may be
hel pf ul ) ; decr eased sweat i ng, r esul t i ng i n decr eased t ol er ance t o heat ; ur i nar y
r et ent i on; const i pat i on ( st ool sof t ener s may be hel pf ul ) ; i ncr eased i nt r aocul ar
t ensi on; and nausea. Because of pat i ent s' decr eased t ol er ance t o heat , t hese
agent s shoul d be used wi t h caut i on i n hot weat her . They shoul d al so be t aken wi t h
f ood t o mi ni mi ze GÌ upset .
Table 46-3. Dosage Range and Characteristics of Drug Treatment
Drug
Time to Peak
Concentration
(hr) Half-Life (hr)
Daily Dosage
Range (mg/day)
Anticholinergic agents
Benztropine n/a n/a 1-6
Biperiden 1-1.5 18.4-24.3 2-8
Procyclidine 1.1-2 11.5-12.6 6-20
Trihexyphenidyl 1-1.3 5.6-10.2 2-15
Ethopropazine n/a n/a 50-400
Dopamine agents
Carbidopa/levodopa 1 1-1.75 10/100-
200/2000
Carbidopa/levodopa.
sustained-release
2 ~standard
treatment
10/400-
25/1000. in
2-3 divided
doses
Amantadine 4-8 9.7-14.5 100-400
Bromocriptine 1-3 3-8 2.5-40
Selegiline 0.5-2 2-20.5 5-10
Selegiline Oral
Disintegrating table
*

1 1-3 hrs 0.5-1 mg
Rasagiline 1 1.3-3hrs 0.5-1mg
Non-ergot dopamine
agents

Pramipexole 1-2 (3-4
a
) 8-12
b
1.5-4.5. in 3
divided
doses
Ropinirole 1-2 (3-4
a
) 6 3-24. in 3
divided
doses
COMT inhibitor 0.5-4 70 0.5-6
Tolcapone 2 2-3 300-600
Entacapone 1 2-3 200-1600
Rotigotine 15-27 5-7 hrs 2-6mg
Apomorphine
hydrochloride iniection
(SC)
1 40 min 2-6mg
a
With Iood.

b
Over 65 years oI age.
COMT. catechol-O-methyltransIerase; n/a. not available.

*
avoids Iirst pass eIIect
SC: subcutaneous iniection

P. 1020


( 2) CNS ef f ect s i ncl ude di zzi ness, del i r i um, di sor i ent at i on, anxi et y, agi t at i on,
hal l uci nat i ons, and i mpai r ed memor y. The i nci dence of CNS ef f ect s i ncr eases i n
el der l y i ndi vi dual s.
( 3) Cardi ovascuI ar ef f ect s i ncl ude hypot ensi on and or t host at i c hypot ensi on.
4. Si gni fi cant i nt eract i ons
a. Si de ef f ect s may be pot ent i at ed by ot her dr ugs wi t h ant i chol i ner gi c act i vi t y such
as ant i hi st ami nes, ant i depressant s, and phenot hi azi nes.
b. Ant i chol i ner gi c agent s i ncr ease di goxi n l evel s.
c. When ant i chol i ner gi c agent s ar e t aken wi t h haI operi doI , t he f ol l owi ng occur s:
( 1) Schi zophr eni c sympt oms may i ncr ease.
( 2) Hal oper i dol l evel s may decr ease.
( 3) The sever i t y of ( not t he r i sk of ) t ar di ve dyski nesi a may i ncr ease.
d. When phenot hi azi nes ar e t aken wi t h ant i chol i ner gi c dr ugs, t he ef f ect s of t he
phenot hi azi nes decr ease and t he ant i chol i ner gi c sympt oms i ncr ease.
e. Pat i ent s on hi gh doses of ant i chol i ner gi cs combi ned wi t h I evodopa shoul d be
wat ched f or decr eased l evodopa act i vi t y because of a del ayed gast r i c empt yi ng
t i me.
B. Dopami ne precursor. Levodopa/ carbi dopa i s t he most ef f ect i ve dr ug f or
managi ng Par ki nson di sease; however , pr ol onged use decr eases i t s t herapeut i c
ef f ect s (t her e i s a decl i ne i n ef f i cacy af t er 3- 5 year s) and i ncr eases adver se dr ug
r eact i ons. Dopami ne does not cr oss t he bl ood- br ai n bar r i er ; t her ef or e, a pr ecur sor
i s used. Per i pher al conver si on of l evodopa t o dopami ne causes adver se r eact i ons
l i ke nausea, vomi t i ng, car di ac ar r hyt hmi as, and post ur al hypot ensi on. To decr ease
t he per i pher al conver si on and per i pher al adver se ef f ect s, a per i pher al dopa
decar boxyl ase i nhi bi t or ( car bi dopa) i s added t o l evodopa.
1. Mechani sm of acti on
a. Levodopa i s convert ed t o dopami ne by t he enzyme dopa decar boxyl ase, whi ch
el evat es CNS l evel s of dopami ne.
b. The sust ai ned- r el ease f or mul at i on i s desi gned t o rel ease t he dr ug over 4- 6 hr ,
t her eby i nhi bi t i ng var i at i on i n pl asma concent r at i on and decr easi ng mot or
f l uct uat i on "of f ¨ t i me or i mpr ovi ng over al l dose r esponse i n pat i ent s wi t h advanced
di sease.
2. Admi ni st rat i on and dosage ( Tabl e 46- 3)
a. Ì t i s necessar y t o gi ve at l east 100 mg dai l y of car bi dopa t o decr ease t he
i nci dence of t he per i pher al conver si on of l evodopa and GÌ si de ef f ect s (e. g. ,
nausea) and i ncr ease t he bi oavai l abi l i t y of l evodopa f or t he CNS.
b. Ì f car bi dopa i s gi ven i n a separ at e dosage f or m, t he dose of l evodopa can be
decr eased by 75%.
c. Ì f pat i ent s st i l l compl ai n of GÌ si de ef f ect s af t er combi nat i on l evodopa/ car bi dopa,
pl ai n car bi dopa can be gi ven.
d. Sust ai ned- r el ease pr epar at i ons ar e appr oxi mat el y 30% l ess bi oavai l abl e as
compar ed wi t h l evodopa/ car bi dopa. Because of t hi s l ower bi oavai l abi l i t y, t he dai l y
dosage shoul d be hi gher . Ì f a pat i ent i s r ecei vi ng a st andar d pr epar at i on and needs
t o be convert ed t o t he sust ai ned- r el ease dose, appr oxi mat el y 10% mor e l evodopa
shoul d i ni t i al l y be added t o t he dai l y dosage and at l east 3 days shoul d pass
bet ween i ncr eased dosages; t hen gradual l y i ncr ease t he l evodopa dose up t o 30%
of st andar d pr epar at i on.
e. Wi t h t he sust ai ned- r el ease pr epar at i on, t he peak pl asma concent r at i on i s l ower
and t he t r ough pl asma concent r at i on i s hi gher .
f . The sust ai ned- r el ease pr epar at i on coul d be di vi ded i n hal f at t he scored poi nt
onl y. The t abl et shoul d not be chewed or cr ushed.
g. When carbi dopa i s gi ven t o pat i ent s bei ng t reat ed wi t h l evodopa, gi ve t he t wo
dr ugs at t he same t i me, st ar t i ng wi t h no mor e t han 20% t o 25% of t he previ ous dai l y
dosage of l evodopa and i ni t i at i ng t her apy wi t h car bi dopa and l evodopa.
h. Long- t er m t r eat ment coul d l ead t o mot or f l uct uat i on and dyski nesi as, especi al l y
at hi gh doses.
3. Precaut i ons and moni tori ng ef fect s
a. Levodopa must be used wi t h caut i on i n pat i ent s wi t h nar r ow- angl e gl aucoma.
b. Levodopa may act i vat e a mal i gnant mel anoma i n pat i ent s wi t h suspi ci ous
undi agnosed ski n l esi ons or a hi st or y of mel anoma.
P. 1021


c. The ef f i cacy of l evodopa decl i nes wi t h l ong- t er m t her apy by desensi t i zi ng t he
r ecept or s or because of t he decr eased number of r ecept or s, r esul t i ng f r om t he
pr ogr essi on of t he di sease.
d. Adverse drug react i ons
( 1) GÌ ef f ect s i ncl ude anor exi a, nausea and vomi t i ng, and abdomi nal di st r ess.
Levodopa shoul d be t aken wi t h f ood t o mi ni mi ze st omach upset .
( 2) Cardi ovascuI ar ef f ect s i ncl ude post ur al hypot ensi on and t achycar di a.
( 3) MuscuI oskeI et aI ef f ect s i ncl ude dyst oni a or chor ei f or m muscl e movement .
( 4) CNS ef f ect s i ncl ude conf usi on, memor y changes, depr essi on, hal l uci nat i ons,
and psychosi s. Physi ci ans shoul d be not i f i ed i f any of t hese sympt oms occur .
( 5) Hemat oI ogi caI ef f ect s i ncl ude hemol yt i c anemi a, l eukopeni a, and
agr anul ocyt osi s ( r ar e) .
4. Si gni fi cant i nt eract i ons
a. Ant aci ds cause r api d and compl et e i nt est i nal l evodopa absor pt i on ( by decr easi ng
gast r i c empt yi ng t i me) .
b. Hydant oi n decr eases t he ef f ect i veness of l evodopa.
c. Met hi oni ne i ncr eases t he cl i ni cal si gns of Par ki nson di sease.
d. Met ocI oprami de i ncreases t he bi oavai l abi l i t y of l evodopa, whi ch decr eases t he
ef f ect s of met ocl opr ami de on gast r i c empt yi ng and on l ower esophageal pr essur e.
As a dopami ne bl ocker , i t may al so pr eci pi t at e par ki nsoni an sympt oms.
e. Fal se- posi t i ve r esul t s ar e seen wi t h t he Coombs t est .
f . The ur i c aci d t est i ncr eases wi t h t he cal or i met r i c met hod but not wi t h t he ur i case
met hod.
g. Hyper t ensi ve r eact i ons may occur i f l evodopa i s admi ni st er ed t o pat i ent s
r ecei vi ng MAO i nhi bi t ors and f urazoI i done. MAO i nhi bi t or s must be di scont i nued 2
weeks bef or e st ar t i ng l evodopa.
h. Admi ni st er i ng papaveri ne may decr ease t he ef f ect of l evodopa.
i . Tri cycI i c ant i depressant s decr ease t he r at e and ext ent of absor pt i on of
l evodopa; hyper t ensi ve epi sodes have been r epor t ed when l evodopa i s combi ned
wi t h t r i cycl i c ant i depr essant s.
j . Food decreases t he r at e and ext ent of absor pt i on and t r anspor t t o t he CNS
acr oss t he bl ood- br ai n bar r i er . A prot ei n- rest ri ct ed di et may al so hel p mi ni mi ze t he
" f l uct uat i ons¨ ( i . e. , t he decr eased r esponse t o l evodopa) at t he end of each day or
at var i ous t i mes of t he day.
C. Di rect - act i ng dopami ne agoni st s ar e cl assi f i ed as er got der i vat i ves ( such as
br omocr i pt i ne) and noner gol i nes ( such as pr ami pexol e and r opi ni r ol e) .
1. These agent s mi mi c dopami ne agoni st and r educe mot or f l uct uat i ons.
2. Dr ugs i n t hi s cl ass have a r ange of hal f - l i ves, and t he hal f - l i f e of any par t i cul ar
dr ug can var y among pat i ent s.
3. These dr ugs ar e not met abol i zed by t he oxi dat i ve pat hway and do not pr oduce
f r ee- r adi cal met abol i t es.
4. Dopami ne agoni st s may have a di r ect ant i oxi dat i ve ef f ect .
5. They t ake l onger t han L- dopa t o r each ef f ect i ve doses and r equi r e suppl ement ar y
L- dopa f or rel i ef of sympt oms af t er a var yi ng per i od of t i me.
6. Common si de ef f ect s ar e nausea and psychi at r i c si de ef f ect s si mi l ar t o L- dopa
such as hal l uci nat i ons and del usi ons; dyski nesi as ar e l ess common.
7. Ot her adver se ef f ect s ar e headache, nasal congest i on, er yt hr omel al gi a, pl eur al
and r et r oper i t oneal f i br osi s, pul monar y i nf i l t r at es, and vasospasm ( except wi t h t he
new, non- er got der i vat i ves such as ropi ni r ol e) .
8. Annual chest r adi ogr aphs have been r ecommended f or pat i ent s on hi gh- dose
t her apy wi t h br omocr i pt i ne t o det ect pl eur opul monar y changes.
9. New dopami ner gi c agoni st s ( non- er got der i vat i ves) cause post ur al hypot ensi on,
sl eep di st ur bances, per i pher al edema, const i pat i on, nausea, dyski nesi as, and
conf usi on.
10. Bromocri pti ne ( ParI odeI )
P. 1022


a. Mechani sm of acti on. Br omocr i pt i ne i s r esponsi bl e f or di r ect l y st i mul at i ng
post synapt i c dopami ne r ecept or s; i t i s most commonl y used as an adj unct t o
l evodopa t her apy i n pat i ent s:
( 1) Wi t h a det er i or at i ng r esponse t o l evodopa
( 2) Wi t h a l i mi t ed cl i ni cal r esponse t o l evodopa secondar y t o an i nabi l i t y t o t ol er at e
hi gher doses
( 3) Who ar e exper i enci ng f l uct uat i ons i n r esponse t o l evodopa
b. Admi ni st rat i on and dosage ( Tabl e 46- 3)
( 1) Ì ni t i al l y, pat i ent s ar e gi ven one hal f of a t abl et t wi ce dai l y, whi ch i s t hen
i ncr eased t o one t abl et t wi ce dai l y ever y 2- 3 days.
( 2) Pat i ent s' r esponses ar e ext r emel y var i abl e. Many pat i ent s show a dopami ne
ant agoni st r esponse at bot h l ow and hi gh doses, wi t h t he desi r abl e agoni st
r esponse i n t he mi dr ange.
( 3) Because post ur al hypot ensi on may r esul t f r om t he f i r st f ew doses of
br omocr i pt i ne, t he f i r st dose shoul d be admi ni st er ed wi t h t he pat i ent l yi ng down,
and sudden changes i n post ur e shoul d be avoi ded.
c. Precaut i ons and moni tori ng ef fect s
( 1) Br omocr i pt i ne may cause a f i r st -dose phenomenon t hat can t r i gger sudden
car di ovascul ar col l apse. Ì t shoul d be used wi t h caut i on i n pat i ent s wi t h a hi st or y of
myocar di al i nf ar ct i on or ar r hyt hmi as.
( 2) Ear l y i n t her apy, di zzi ness, dr owsi ness, and f ai nt i ng may occur , so pat i ent s
shoul d be caut i ous about dr i vi ng or oper at i ng machi ner y. A physi ci an shoul d be
not i f i ed i f t hese sympt oms appear .
( 3) Cardi ac dysrhyt hmi as. Pat i ent s on br omocri pt i ne wer e f ound t o have
si gni f i cant l y mor e epi sodes of at r i al pr emat ur e cont r act i ons and si nus t achycar di a.
( 4) Ot her adverse ef f ect s
( a) GÌ ef f ect s, i ncl udi ng anor exi a, nausea, vomi t i ng, and abdomi nal di st r ess, may
be decr eased by t aki ng br omocr i pt i ne wi t h f ood.
( b) Cardi ovascuI ar ef f ect s i ncl ude post ur al hypot ensi on ( t o whi ch t ol er ance
devel ops) and t achycar di a. Bl ood pr essur e must be moni t ored, par t i cul ar l y f or
pat i ent s t aki ng ant i hyper t ensi ve medi cat i on.
( c) PuI monary ef f ect s, i ncl udi ng r ever si bl e i nf i l t r at i ons, pl eur al ef f usi ons, and
pl eur al t hi ckeni ng, may devel op af t er l ong- t er m t r eat ment , so pul monar y f unct i on
shoul d be moni t or ed i n pat i ent s t r eat ed l onger t han 6 mont hs.
( d) CNS ef f ect s, i ncl udi ng conf usi on, memor y changes, depr essi on, and
hal l uci nat i ons, as wel l as psychosi s may be exacer bat ed by br omocr i pt i ne; t hus
pat i ent s wi t h psychi at r i c i l l nesses must be moni t or ed.
d. Si gni f i cant i nt eract i ons
( 1) A combi nat i on of ant i hypert ensi ve drugs and br omocr i pt i ne coul d decr ease
bl ood pr essur e.
( 2) Dopami ne ant agoni st s i ncr ease t he ef f ect of br omocr i pt i ne.
D. I ndi rect - act i ng dopami ne agoni st s
1. SeI egi I i ne ( EI depryI )
a. Mechani sm of acti on
( 1) MAO cat abol i zes var i ous cat echol ami nes ( e. g. , dopami ne, nor epi nephr i ne,
epi nephr i ne) , ser ot oni n, and var i ous exogenous ami nes ( e. g. , t yr ami nes) f ound i n
f oods ( e. g. , aged cheese, beer , wi ne, smoked meat ) and dr ugs. Lack of MAO i n t he
i nt est i nal t r act causes absor pt i on of t hese ami nes, cr eat i ng a hyper t ensi ve cr i si s.
MAO t ype A i s pr edomi nant l y f ound i n t he i nt est i nal t r act , and MAO t ype B i n t he
br ai n. They di f f er i n t hei r subst r at e speci f i ci t y and t i ssue di st r i but i on. Thi s
speci f i ci t y decr eases wi t h sel egi l i ne as t he dose i ncr eases. Most pat i ent s
exper i ence si de ef f ect s at doses of sel egi l i ne hi gher t han 30- 40 mg/ day.
( 2) Sel egi l i ne i s a sel ect i ve i nhi bi t or of MAO- B, whi ch pr event s t he br eakdown of
dopami ne sel ect i vel y i n t he br ai n at r ecommended doses.
( 3) Sel egi l i ne i s most commonl y used as an adj unct wi t h l evodopa/ car bi dopa when
pat i ent s exper i ence a " wear i ng- of f ¨ phenomenon; i t decr eases t he amount of of f
t i me and decr eases t he dose needed of l evodopa/ car bi dopa by 10% t o 30%.
( 4) Resul t s of some st udi es show t hat sel egi l i ne del ays t he t i me bef or e t r eat ment
wi t h a mor e pot ent dopami ner gi c dr ug l i ke l evodopa i s needed; t he pr oposed
mechani sm
P. 1023

of act i on i s t hat an oxi dat i on mechani sm cont r i but es t o t he emer gence and
pr ogr essi on of Par ki nson di sease.
b. Admi ni st rat i on and dosage ( Tabl e 46- 3) . Exceedi ng t he r ecommended dose of
10 mg/ day i ncr eases t he r i sk of l osi ng MAO sel ect i vi t y.
( 1) OraI capsuI e/ t abI et : 5mg ( maxi mum of 10 mg/ day)
( 2) OraI di si nt egrat i ng t abI et : 1. 25 mg dai l y may be i ncr eased up t o 2. 5 mg dai l y.
Di si nt egr at i ng t abl et s maxi mum of 2. 5 mg dai l y.
( 3) TransdermaI : 6 mg/ 24 h appl y upper t or sa, hi gh on t he out er sur f ace of t he
upper ar m, avoi d exposur e of appl i cat i on si t e t o ext er nal heat r esour ces. Excessi ve
heat wi l l i ncr ease absor pt i on
c. Precaut i ons and moni tori ng ef fect s
( 1) Hypert ensi ve cri si s ( see Ì Ì . D. 1. a. 1) .
( 2) Levodopa- associ at ed si de ef f ect s may be i ncr eased because t he i ncr eased
amount s of dopami ne r eact wi t h super sensi t i ve post synapt i c r ecept or s. Reduci ng
t he dose of l evodopa/ car bi dopa by 10% t o 30% may decr ease l evodopa si de ef f ect s.
( 3) Pat i ent s shoul d be educat ed about f oods and dr ugs cont ai ni ng t yr ami ne and t he
si gns and sympt oms of hyper t ensi ve r eact i ons.
( 4) CNS ef f ect s i ncl ude di zzi ness, conf usi on, headache, hal l uci nat i ons, vi vi d
dr eams, dyski nesi as, behavi or al and mood changes, and depr essi on. Pat i ent s who
exper i ence i nsomni a shoul d avoi d t aki ng t he dr ug l at e i n t he day.
( 5) Cardi ovascuI ar ef f ect s i ncl ude or t host at i c hypot ensi on, hyper t ensi on,
ar r hyt hmi a, pal pi t at i ons, si nus br adycar di a, and syncope.
( 6) GÌ ef f ect s i ncl ude nausea and abdomi nal pai n and I ead t o GÌ bI eedi ng, wei ght
l oss, poor appet i t e, and dysphagi a.
( 7) GU ef f ect s i ncl ude sl ow ur i nat i on, t r ansi ent noct ur i a, and pr ost at i c hyper t r ophy.
( 8) Dermat oI ogi caI ef f ect s i ncl ude i ncr eased sweat i ng, di aphor esi s, and
phot osensi t i vi t y.
( 9) Hepat i c ef f ect s i ncl ude mi l d and t r ansi ent el evat i ons i n l i ver f unct i on t est s.
d. CYP2B6 i nhi bi t ors may i ncrease I eveI of seI egeI i ne. AI so seI egi I i ne have
act i ve met aboI i t e ( n- desmet hyI seI egeI i neand amphet ami ne) exampI e of such
si gni fi cant i nt eract i ons are:
( 1) MAO i nhi bi t or s ar e cont r ai ndi cat ed wi t h meperi di ne and ot her opi oi ds.
Admi ni st r at i on wi t h opi oi ds shoul d be avoi ded. ( ser ot oni n syndr ome) . Deat h has
occurred af t er i ni t i at i on of seI egi I i ne short I y af ter di scont i nuati on of
f I uoxet i ne. At l east 5 weeks shoul d el apse bet ween di scont i nuat i on of f l uoxet i ne
and i ni t i at i on of sel egi l i ne. ( ser ot oni n syndr ome)
( 2) Rasagi l i ne: si mi l ar t o sel egi l i ne. The di f f er ent i s 5- t o 10- f ol d gr eat er pot ency,
hi gher or al absor pt i on. Unl i ke sel egi l i ne i t i s not met abol i t es t o amphet ami ne
der i vat i ves (see Tabl e 46- 3)
2. Amant adi ne ( Symmet reI )
a. Mechani sm of acti on. Amant adi ne i s an ant i vi r al agent ( used t o pr event
i nf l uenza) .
( 1) Amant adi ne i ncr eases dopami ne l evel s at post synapt i c r ecept or si t es by
decr easi ng pr esynapt i c r eupt ake and enhanci ng dopami ne synt hesi s and r el ease.
( 2) Ì t may al so have some ant i chol i ner gi c ef f ect s. Ì t decr eases t r emor, r i gi di t y, and
br adyki nesi a.
( 3) Ì t can be gi ven i n combi nat i on wi t h l evodopa as Par ki nson di sease pr ogr esses.
( 4) Cl i ni cal ef f ect s of amant adi ne can be seen wi t hi n t he f i r st f ew weeks of t her apy,
unl i ke t he ot her ant i par ki nsoni an medi cat i ons ( e. g. , car bi dopa/ l evodopa) , whi ch
need weeks t o mont hs t o show t hei r f ul l cl i ni cal ef f ect s.
b. Admi ni st rat i on and dosage ( Tabl e 46- 3)
( 1) Amant adi ne shoul d be st ar t ed at 100 mg/ day. Thi s may be i ncr eased t o 200- 300
mg/ day as a mai nt enance dose.
( 2) Pat i ent s exper i enci ng a decl i ne i n r esponse may benef i t f r om t he f ol l owi ng:
( a) Di scont i nui ng t he dr ug f or a f ew weeks, t hen r est ar t i ng i t
( b) Usi ng t he dr ug epi sodi cal l y, onl y when t he pat i ent ' s condi t i on most needs a
t her apeut i c boost
( 3) Amant adi ne i s al so avai l abl e i n l i qui d f or m f or pat i ent s wi t h dysphagi a.
c. Precaut i ons and moni tori ng ef fect s
( 1) Amant adi ne shoul d be used wi t h caut i on i n pat i ent s wi t h r enal di sease,
congest i ve hear t f ai l ur e ( CHF) , per i pher al edema, hi st or y of sei zur es, and ment al
st at us changes. Ì t may be necessar y t o modi f y dosages i n pat i ent s wi t h r enal
f ai l ur e.
P. 1024


( 2) Tol er ance usual l y devel ops wi t hi n 6- 12 mont hs. Ì f t ol er ance occur s, anot her dr ug
f r om a di f f erent cl ass can be added, or t he dose may be i ncr eased.
( 3) Pat i ent s shoul d be i nf or med about t he si de- ef f ect pr of i l e.
( a) Peri pheraI ant i choI i nergi c ef f ect s i ncl ude t hose ment i oned i n Ì Ì . A. 3. d. ( 1) .
( b) CNS ef f ect s i ncl ude sei zur es as wel l as t hose ment i oned i n Ì Ì . A. 3. d. ( 2) .
( c) Cardi ovascuI ar ef f ect s. Pat i ent s may devel op CHF. Per i odi c bl ood pr essur e
moni t or i ng and el ect r ocar di ogr ams ( ECGs) ar e necessar y i n pat i ent s wi t h
myocar di al i nf ar ct i on or ar r hyt hmi as.
( d) Dermat oI ogi caI ef f ect s i ncl ude I i vedo ret i cuI ari s, a di f f use r ose- col or mot t l i ng
of t he ski n, whi ch i s r ever si bl e on di scont i nuat i on of t he dr ug.
( e) Hemat oI ogi caI ef f ect s. Per i odi c compl et e bl ood count s (CBCs) shoul d be done
f or pat i ent s wi t h l ong- t er m t her apy.
( 4) RenaI f unct i on i mpai rment . Dose adj ust ment i s necessar y i n pat i ent s wi t h r enal
f unct i on i mpai r ment .
d. Si gni f i cant i nt eract i ons
( 1) Amant adi ne i ncr eases t he ant i chol i ner gi c ef f ect s of anti choI i nergi c drugs,
r equi r i ng a decr ease i n t he dosage of t he ant i chol i ner gi c dr ug.
( 2) HydrochI orot hi azi de pl us t ri amt erene decr eases t he uri nar y excr et i on of
amant adi ne and i ncr eases i t s pl asma concent r at i on.
E. Nonergot dopami ne agoni st s
1. Pr ami pexol e and r opi ni r ol e ar e i ndi cat ed f or bot h ear l y and advanced st ages of
Par ki nson di sease.
2. Bot h sel ect i vel y bi nd t o dopami ne r ecept or s and act i vat e t he D
2
- r ecept or but
have l i t t l e or no af f i ni t y t o t he D
1
- r ecept or . They have gr eat er af f i ni t y f or t he D
3
-
r ecept or t han f or t he D
2
- r ecept or . The i nci dence of adver se event s ( such as
pl eur opul monar y f i br osi s and r et r oper i t oneal f i br osi s, cor onar y vasoconst r i ct i on,
er yt hr omel al gi a, and Raynaud phenomenon) , i s l ow compar ed t o nonsel ect i ve
dopami ne agoni st s.
3. Non- ergot dopami ne agoni st s have a l ow pot ent i al f or t he devel opment of mot or
f l uct uat i ons and dyski nesi a.
a. Prami pexoI e ( Mi rapex)
( 1) Mechani sm of act i on
( a) D
2
subf ami l y of dopami ne r ecept or s. Pr ami pexol e f ul l y st i mul at es t he dopami ne
r ecept or s t o whi ch i t bi nds. Ì t s act i on may be r el at ed t o i t s capaci t y t o f unct i on as
an ant i oxi dant and oxygen f r ee- r adi cal scavenger .
( b) Pr ami pexol e al so has ant i depr essant act i vi t y i n moder at e depr essi on, whi ch may
be r el at ed t o i t s pr ef er ent i al bi ndi ng t o t he dopami ne D
1
- r ecept or subt ype.
( c) Long- act i ng dopami ne agoni st s appear t o have a l ower r i sk of i nduci ng abnor mal
movement s. Thei r use as i ni t i al t r eat ment i n ear l y Par ki nson di sease seems
war r ant ed, par t i cul ar l y f or t hose wi t h di sease onset at a younger age.
( 2) Admi ni st rat i on and dosage
( a) Ì ni t i al t reat ment : st ar t i ng dose of 0. 375 mg dai l y gi ven i n t hr ee di vi ded doses.
( b) Do not i ncr ease mor e f r equent l y t han ever y 5- 7 days.
( c) Mai nt enance t r eat ment : 1. 5- 4. 5 mg dai l y i n t hr ee di vi ded doses wi t h or wi t hout
l evodopa.
( d) When gi ven i n combi nat i on wi t h l evodopa, consi der r educt i on of l evodopa dose
by an aver age of 27% f r om basel i ne.
( e) Ti t r at e sl owl y t o bal ance benef i t s and si de ef f ect s, such as dyski nesi a,
hal l uci nat i ons, somnol ence, and dr y mout h.
( f ) May be t aken wi t h f ood t o r educe t he occur rence of nausea. Food decr eases t he
r at e of absor pt i on but not t he ext ent of absor pt i on.
( g) Dosage adj ust ment i s necessar y i n pat i ent s wi t h r enal f unct i on i mpai r ment .
( h) Weak pr ot ei n bound 15%
( i ) Not ext ensi vel y met abol i zed; >90% of t he dose i s excr et ed unchanged i n ur i ne.
( j ) Dose needs t o be decr eased by 25% i n t he el der l y.
( 3) Precaut i ons and moni t ori ng ef f ect s
( a) Dose r educt i on necessar y i n pat i ent s >65 year s, and i n pat i ent s wi t h r enal
f unct i on i mpai r ment or f ai l ur e
P. 1025


( b) Sympt omat i c hypot ensi on
( i ) Dopami ner gi c agent s appear t o i mpai r t he syst emi c r egul at i on of bl ood pr essur e,
whi ch r esul t s i n or t host at i c hypot ensi on.
( i i ) Moni t or i ng and educat i on of t he pat i ent i s necessar y, especi al l y dur i ng
doseescal at i on per i ods.
( c) Hal l uci nat or y ef f ect s ar e i ncr eased i n pat i ent s >65 year s of age wi t h ear l y or
advanced st ages of Parki nson di sease.
( d) Ot her ef f ect s i ncl ude nausea, i nsomni a, const i pat i on, di zzi ness, somnol ence, GÌ
si de ef f ect s, and vi sual hal l uci nat i ons. Sl eep at t ack by f al l i ng sl eep dur i ng act i vi t y
dai l y l i vi ng.
( 4) Si gni f i cant i nt eract i ons
( a) Ci met i di ne r educes r enal cl ear ance of pr ami pexol e.
( b) No i nt eract i on wi t h sel egi l i ne, pr obeneci d, or domper i done.
( c) When combi ned wi t h l evodopa, t he dosage of l evodopa must be decr eased by
27%.
b. Ropi ni roI e ( Requi p)
( 1) Mechani sm of act i on i s si mi l ar t o pr ami pexol e.
( 2) Admi ni st rat i on and dosage
( a) Ì ni t i al t reat ment : 0. 25 mg t hr ee t i mes dai l y
( b) Ti t r at e weekl y i ncr ement s.
( c) Af t er week 4, i f necessar y, dai l y dosage may be i ncr eased by 1. 5 mg/ day on a
weekl y basi s up t o 9 mg/ day, t o a t ot al of 24 mg/ day.
( d) Di scont i nue gr adual l y over a 7- day per i od. Decr ease t he f r equency of
admi ni st r at i on f r om t hr ee t i mes t o t wo t i mes dai l y f or 4 days, and t hen once dai l y f or
t he r emai nder of t he week.
( e) When gi ven i n combi nat i on wi t h l evodopa, consi der r educt i on of l evodopa dose.
( f ) May be t aken wi t h f ood t o r educe t he occur rence of nausea. Food decr eases t he
r at e of absor pt i on, but not t he ext ent of absor pt i on.
( g) Met abol i zed by t he l i ver ( cyt ochr ome P450 1A2) , and f i rst - pass ef f ect .
( h) Smoki ng i nduces t he l i ver met abol i sm.
( i ) Bet ween 30% and 40% pr ot ei n bound
( 3) Precaut i ons and moni t ori ng ef f ect s
( a) Syncope. Br adycar di a i s obser ved i n pat i ent s t r eat ed wi t h r opi ni r ol e. Most cases
occur wi t hi n t he f i r st 4 weeks of t her apy and ar e usual l y associ at ed wi t h a r ecent
i ncr ease of dose.
( b) Bi nds t o mel ani n- cont ai ni ng t i ssues l i ke t he eyes and ski n.
( c) Sympt omat i c hypot ensi on
( i ) Dopami ner gi c agent s appear t o i mpai r t he syst emi c r egul at i on of bl ood pr essur e,
whi ch r esul t s i n or t host at i c hypot ensi on.
( i i ) Moni t or i ng and educat i on of t he pat i ent i s necessar y, especi al l y dur i ng
doseescal at i on per i ods.
( d) Hal l uci nat or y ef f ect s ar e i ncr eased i n pat i ent s >65 year s of age wi t h ear l y or
advanced st ages of Parki nson di sease.
( e) Ot her si de ef f ect s i ncl ude nausea, di zzi ness, somnol ence, headache, f at i gue,
and abnor mal vi si on. Sl eep at t ack, by f al l i ng asl eep dur i ng act i vi t y dai l y l i vi ng.
( 4) Si gni f i cant i nt eract i ons
( a) Smoki ng i nduces t he l i ver met abol i sm, but t he af f ect of smoki ng on cl ear ance of
r opi ni r ol e has not been st udi ed.
( b) Ther e i s no i nt er act i on bet ween l evodopa, t heophyl l i ne, di goxi n, or
domper i done.
( c) Est r ogens decr ease t he cl ear ance of r opi ni r ol e by appr oxi mat el y 36%.
( d) Ci pr of l oxaci n i ncr eases r opi ni r ol e ar ea under t he cur ve ( AUC) by 84% and
maxi mum pl asma concent r at i on by 60%.
c. Roti goti ne ( Neupro)
( 1) Mechani sm of act i on: Noner gol i ne D
3
/ D
2
/ D
1
dopami ne agoni st , i t st i mul at es
dopami ne D
2
r ecept or s wi t hi n t he caudat e- put amen i n t he br ai n.
( 2) Admi ni st rat i on and dosage:
( a) St art at 2 mg/ 24 hour s, may be i ncr eased weekl y by 2 mg/ 24 hour s i f t ol er at ed
and i f addi t i onal t her apeut i c ef f ect i s needed.
P. 1026


( b) The l owest ef f ect i ve dose i s 4 mg/ 24 hour s.
( c) The hi ghest r ecommended dose i s 6 mg/ 24 hour s.
( 3) Precaut i ons and moni t ori ng:
( a) Si mi I ar Ropi ni roI e
( b) Wei ght gai n and f I ui d ret ent i on: due t o devel opment of per i pher al edema ( f l ui d
r et ent i on)
( c) AppI i cat i on- si t e react i ons: l ocal i zed er yt hema, edema, or pr ur i t us l i mi t ed t o
t he pat ch area
( d) SuI f i t e sensi t i vi t y: cont ai ns a sul f i t e t hat may cause al l er gi c- t ype r eact i ons,
i ncl udi ng anaphyl act i c sympt oms and l i f e t hr eat eni ng or l ess sever e ast hmat i c
epi sodes i n cer t ai n suscept i bl e per sons.
( 4) Drug i nt eract i ons. Dopami ne agoni st s ( eg, ant i psychot i cs, met ocl opr ami de)
may decr ease ef f i cacy of r ot i got i ne.
d. Apomorphi ne HydrochI ori de I nj ect i on SC ( Apokyn)
( 1) Mechani sm of act i on:
( a) st i mul at i ng of post synapt i c dopami ne D2- t ype r ecept or s wi t hi n Caudat e and
put amen i n br ai n
( b) Subcut aneous i nj ect i on i s i ndi cat ed f or acut e i nt er mi t t ent t r eat ment i f
hypomobi l i t y " of f ¨ epi sodes ( end of dose wear i ng, unpr edi ct abl e on/ of f epi sodes)
( 2) Admi ni st rat i on and dosage:
( a) Doses mor e t han 6 mg i s not r ecommended
( b) Dose shoul d be st ar t ed at 2 mg i ncr ease t o maxi mum of 6mg.
( c) Ì t shoul d be admi ni st r at ed at " of f ¨ st at e shoul d begi n t est dose at 2 mg wher e
bl ood pr essur e can be moni t or ed. Bl ood pr essur e shoul d be moni t or ed pr edose at
20, 40, and 60 mi nut es post dose st andi ng up.
( d) Ì f pat i ent devel oped or t host at i c hypot ensi on shoul d not r ecei ved Apomor phi ne
( e) Pat i ent s who have a si gni f i cant i nt er r upt i on i n t her apy ( mor e t han a week)
shoul d be r est ar t ed on a 0. 2 mL ( 2 mg) dose and gr adual l y t i t r at ed t o ef f ect .
( 3) Precaut i ons and moni t ori ng:
( a) Pr of ound hypot ensi on and l oss of consci ousness when gi ven wi t h 5HT3
ant agoni st cl ass ( i ncl udi ng ondanset r on, gr ani set r on)
( b) QT pr ol ongat i on and pot ent i al pr o- ar r hyt hmi a ef f ect . Pat i ent shoul d be moni t or ed
f or pal pi t at i on syncopy and si gns f or epi sode of t or sades de poi nt s.
( c) Sl eep at t ack, f al l i ng asl eep dur i ng dai l y act i vi t i es.
( d) Hal l uci nat i on
( e) SuI f i t e sensi t i vi t y: cont ai ns a sul f i t e t hat may cause al l er gi c- t ype r eact i ons,
i ncl udi ng anaphyl act i c sympt oms and l i f e- t hr eat eni ng or l ess sever e ast hmat i c
epi sodes i n cer t ai n suscept i bl e peopl e
( 4) Drug i nt eract i ons:
( a) 5HT3 ant agoni st such as ondanset r on, gr ani set r on, dol aset r on, pal onoset r on)
r esul t s i n hypot ensi on
( b) Ant i hyper t ensi ve medi cat i ons and vasodi l at or s whi ch may r esul t s i n hypot ensi on.
( c) Cont r ai ndi cat ed when used wi t h ot her dr ugs t hat have pot ent i al t o pr ol ong QT,
QTC i nt er val . Ì t i ncr eases r i sk of l i f e- t hr eat eni ng ar r hyt hmi as.
4. COMT i nhi bi tors
a. ToI capone ( Tasmar)
( 1) Mechani sm of act i on
( a) Tol capone i s a sel ect i ve and r ever si bl e i nhi bi t or of COMT and i s used as an
adj unct t o l evodopa/ car bi dopa t her apy.
( b) Tol capone i nhi bi t s COMT bot h per i pher al and cent r al l y.
( c) COMT i s t he mai n enzyme r esponsi bl e f or per i pher al and cent r al met abol i sm of
cat echol ami nes, i ncl udi ng l evodopa. Addi t i on of a COMT i nhi bi t or r esul t s i n t he
doubl i ng of t he el i mi nat i on hal f - l i f e of l evodopa and i n i ncr eased or al bi oavai l abi l i t y
of l evodopa by 40%- 50%.
( d) Tol capone i s i ndi cat ed as an adj unct t her apy t o car bi dopa/ l evodopa t her apy.
( 2) Admi ni st rat i on and dosage
( a) St art i ng dose of 100- 200 mg, t hree t i mes dai l y
( b) Usual dai l y dose of 200 mg, t hr ee t i mes dai l y
( c) Ì f pat i ent f ai l s t o show expect ed benef i t af t er 3 weeks of t r eat ment , di scont i nue
dr ug because of associ at ed r i sk of l i ver f ai l ur e. Rapi d wi t hdr awal or abr upt
r educt i on
P. 1027

dose coul d l ead t o hyper pyr exi a and conf usi on sympt oms such as hi gh f ever and
sever e r i gi di t y si mi l ar t o t hose i n neur ol ept i c mal i gnant syndr ome.
( 3) Precaut i ons and moni t ori ng
( a) Li ver t oxi ci t y. Hi gh r i sk of f at al l i ver f ai l ur e has been r epor t ed wi t h t ol capone.
Di scont i nue use i f subst ant i al benef i t i s not seen wi t hi n 3 weeks of commencement
of t her apy.
( b) Do not use i n pat i ent s wi t h l i ver di sease or i n pat i ent s who have t wo al ani ne
ami not r ansf er ase ( ALT) or aspar t at e ami not r ansf er ase ( AST) val ues great er t han
t he upper l i mi t of nor mal .
( c) Advi se pat i ent r egar di ng sel f - moni t or i ng f or l i ver di sease ( i . e. , cl ay- col or ed
st ool , j aundi ce, f at i gue, appet i t e l oss, or l et har gy) .
( d) Moni t or AST and ALT ever y 2 weeks f or t he f i r st year , t hen ever y 4 weeks f or
t he next 6 mont hs and ever y 8 weeks t her eaf t er.
( e) MAO and COMT ar e t wo maj or enzyme syst ems i nvol ved i n t he met abol i sm of
cat echol ami nes; combi nat i on of t ol capone wi t h a nonsel ect i ve MAO i nhi bi t or wi l l
r esul t i n i nhi bi t i on of t he pat hway r esponsi bl e f or nor mal cat echol ami ne met abol i sm.
( f ) Tol capone can be t aken concomi t ant l y wi t h a sel ect i ve MAO- B i nhi bi t or , such as
sel egi l i ne i n r ecommended dose of l ess or equal t o 10 mg/ day.
( g) Fi br ol i c compl i cat i ons, such as r et r oper i t oneal f i br osi s, pul monar y i nf i l t r at es or
ef f usi on or pl eur al t hi ckeni ng.
( 4) Ot her si de ef f ect s
( a) Ort host at i c hypot ensi on. Tol capone enhances l evodopa bi oavai l abi l i t y and,
t her ef or e, may i ncr ease t he occur r ence of or t host at i c hypot ensi on.
( b) Di ar r hea usual l y mani f est s wi t hi n 6- 12 weeks af t er admi ni st r at i on of t ol capone,
but can devel op as ear l y as 2 weeks af t er admi ni st r at i on. Di ar r hea nor mal l y
r esol ves af t er di scont i nuat i on of t he dr ug.
( c) Hal l uci nat i ons ar e somet i mes accompani ed by conf usi on, i nsomni a, and
excessi ve dr eami ng. Hal l uci nat or y ef f ect s usual l y occur af t er i ni t i at i on of t ol capone
and ar e usual l y r esol ved by decr easi ng t he dose of l evodopa.
( d) Tol capone may pot ent i at e t he dopami ner gi c si de ef f ect of l evodopa and may
cause or exacer bat e pr eexi st i ng dyski nesi a. Decr eased doses of l evodopa may or
may not al l evi at e t he sympt oms.
( e) Sever e cases of r habdomyol ysi s have been r epor t ed, whi ch pr esent as f ever ,
al t er nat i on of consci ousness, and muscul ar r i gi di t y.
( f ) Ot her s. Dyspepsi a, abdomi nal cr ampi ng, mi l d par est hesi a of t he l egs, and
t empor ar y di scol or at i on of ur i ne have al so been not ed but ar e not consi der ed
cl i ni cal l y i mpor t ant .
( g) Drug i nt eract i ons. Al t hough no dr ug i nt er act i on st udi es have been conduct ed,
concur r ent use of t ol capone and dr ugs t hat ar e met abol i zed by t he COMT syst em
( i . e. , met hyl dopa, dobut ami ne, apomor phi ne) shoul d be moni t or ed. Tol capone al so
has af f i ni t y f or t he cyt ochr ome P450 2C9 i soenzyme, si mi l ar t o war f ar i n.
Coagul at i on par amet er s shoul d be moni t or ed when t ol capone i s admi ni st er ed wi t h
war f ar i n.
b. Ent acapone ( Comt an)
( 1) Mechani sm of act i on
( a) Ent acapone i s a sel ect i ve and rever si bl e i nhi bi t or of COMT and per mi t s
addi t i onal l evodopa t o r each t he br ai n. Ì t does not have any ant i - Par ki nson ef f ect of
i t s own.
( b) Ì t act s onl y per i pher al l y by i nhi bi t i ng COMT.
( c) Ì t i mpr oves t he dur at i on of on t i me and decr eases t he durat i on of of f t i me.
( d) Ì t i s i ndi cat ed as an adj unct t o t hose on l evodopa/ car bi dopa t her apy who
exper i ence t he si gns and sympt oms of end- of - dose wear i ng- of f .
( 2) Admi ni st rat i on and dosage
( a) Dosage: 200 mg wi t h each dose of L- dopa up t o 8 t i mes dai l y wi t h a maxi mum
dose of 1600 mg dai l y.
( b) Rapi d wi t hdr awal coul d l ead t o emer gency si gns and sympt oms of Par ki nson
di sease such as hyper pyr exi a and conf usi on ( sympt oms r esembl i ng neur ol ept i c
mal i gnant syndr ome) .
( c) Levodopa + car bi dopa and Ent acapone: Avai l abl e i n 4 st rengt hs, each i n a 1: 4
r at i o of car bi dopa t o l evodopa and combi ned wi t h ent acapone 200 mg i n a st andar d-
r el ease f or mul at i on, 50, 100, 150, and 200 mg of Levodopa.
P. 1028


( 3) Precaut i ons and moni t ori ng ef f ect s
( a) MAO. COMT and MAO ar e t wo maj or enzymes i n t he met abol i sm of
cat echol ami nes. Do not use t oget her .
( b) Drugs met aboI i zed by COMT. Dr ugs t hat are met abol i zed by t hi s pat hway, such
as i sopr ot er enol , epi nephr i ne, nor epi nephr i ne, dopami ne, and dobut ami ne, as wel l
as met hyl dopa, may i nt er act and may r esul t i n i ncr eased hear t r at e, arr hyt hmi as,
and an excessi ve i ncr ease i n bl ood pr essur e.
( c) Hepat i c f unct i on i mpai rment . The maj or i t y of t he dr ug i s met abol i zed by t he
l i ver ; t her ef or e, use caut i on i n pat i ent s who have l i ver f unct i on abnor mal i t i es.
( d) Fi brot i c compI i cat i on. Cases of r et r oper i t oneal f i br osi s, pul monar y i nf i l t r at es,
pl eur al ef f usi on, and pl eur al t hi ckeni ng have been r epor t ed. These compl i cat i ons
may r esol ve when t he dr ug i s di scont i nued, but compl et e r esol ut i on may not al ways
occur .
( e) Bi I i ary excret i on. Ent acapone i s excr et ed by bi l e; t her ef or e, use caut i on wi t h
dr ugs known t o i nt erf er e wi t h bi l i ar y excr et i on, such as pr obeneci d, er yt hr omyci n,
and ampi ci l l i n.
( 4) Ot her si de ef f ect s. Dyski nesi a/ hyper ki nesi a, nausea, ur i ne di scol or at i on
( br owni sh or ange) , di ar r hea, and abdomi nal pai n
( 5) Drug i nt eract i ons. May i nt er act wi t h dr ugs t hat ar e met abol i zed by t he l i ver
cyt ochr ome P450.
III. SURGICAL TREATMENT.
Al l sur ger i es r equi r e needl e i nser t i on i nt o t he brai n, whi ch i n t ur n i ncr eases t he r i sk
of hemor r hage.
A. GI obus paI I i dus i nt ernus ( Gpi ) paI I i dot omy
1. Def i ni ti on. A pal l i dot omy ent ai l s t he sur gi cal r esect i on of par t s of t he gl obus
pal l i dus.
2. Advant ages. Ì mpr oves cont r al at er al dyski nesi a
3. Di sadvant ages. Ì ncr eased r i sk of damage t o ot her par t s of t he br ai n, i ncl udi ng
opt i c ner ve and i nt er nal capsul e, and r i sk of emot i onal , behavi or al , and cogni t i ve
def i ci t s
B. Deep- brai n st i muI at i on
1. Def i ni ti on. Hi gh- f r equency st i mul at i on t hat i nduces f unct i onal i nhi bi t i on of t ar get
r egi ons of t he br ai n by i mpl ant i ng an el ect r ode i nt o a t ar get si t e and connect i ng t he
l ead t o a subcut aneousl y pl aced pacemaker .
2. Advant ages. No dest r uct i ve l esi on i s f or med. St i mul at i on par amet er s can be
r eadj ust ed at any t i me t o i mpr ove ef f i cacy or decr ease adver se event s.
3. Di sadvant ages. Si de ef f ect s associ at ed wi t h equi pment ( such as l ead br eaks,
i nf ect i on, ski n er osi on, mechani cal mal f unct i on, and need f or bat t er y r epl acement ) .
Ot her si de ef f ect s i ncl ude par est hesi a l i mb dyst oni a, at axi a, i nt r acer ebr al
hemor r hage, sei zur e, and conf usi on.
C. Fet aI ni graI t ranspI ant at i on
1. Def i ni ti on. Ì mpl ant at i on of embr yoni c dopami ner gi c cel l s i nt o t he dener vat ed
st r i at um t o r epl ace degener at ed neur onal cel l s.
2. Advant ages. Ì mpl ant ed cel l s al l sur vi ve, and i nner vat i on of t he st r i at um i s
accompl i shed i n an or ganot ypi c manner . Does not necessi t at e maki ng a dest r uct i ve
l esi on.
3. Di sadvant ages. Opt i mal t r anspl ant var i abl es and t ar get si t e not def i ned. Al so
cl i ni cal st udi es showed devel opment at ypi cal dyski nesi as dur i ng of f per i od.
D. Use of genet i cal l y engi neer ed vi r uses ( Adeno- associ at ed vi r us, AAV) t o car r y
l evodopa- dopami ne conver t i ng enzyme ar omat i c L- ami no decar boxyl ase ( AADC) t o
i ncr ease ef f ect i veness of l evodopa, as r esul t decr ease doses of l evodopa and
subsequent l y decr ease dyski nesi as and ot her si de ef f ect s associ at ed wi t h l evodopa.
E. Neur onal r egener at i on: del i ver i ng ei t her gr owt h f act or s or st em cel l s t o pr oduced
dopami ne pr oduci ng neur ons.
P. 1029


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one of t he suggest ed answer s or
phr ases. Choose t he best answer .
1. Whi ch of t he f oI I owi ng drugs i s a cat echoI - O- met hyI t ransf erase ( COMT)
i nhi bi tor and has report s of f at aI I i ver t oxi ci t y wi t h i t ?
( A) Tol capone
( B) Ent acapone
( C) Rasagi l i ne
( D) Sel egi l i ne
Vi ew Answer 1. The answer i s A[ see] . 2. Levodopa i s associ at ed wi t h
whi ch of t he f oI I owi ng probI ems?
( A) Gast r oi nt est i nal si de ef f ect s
( B) Ì nvol unt ar y movement s
( C) Decl i ne i n ef f i cacy af t er 3- 5 year s
( D) Al l of t he above
Vi ew Answer 2. The answer i s D[ seeand] . 3. Amant adi ne has whi ch of t he
f oI I owi ng advant ages over I evodopa?
( A) Mor e r api d r el i ef over sympt oms
( B) Hi gher success r at e
( C) Bet t er l ong- t er m ef f ect s
Vi ew Answer 3. The answer i s A[ seeand] . 4. Whi ch drug i s a non- ergot
dopami ne agoni st and has a si de- ef f ect prof i I e di f ferent from t he rest of the
dopami nergi c agent s?
( A) Ent acapone
( B) Levodopa/ car bi dopa
( C) Ropi ni r ol e
( D) Sel egi l i ne
Vi ew Answer 4. The answer i s C[ seeand] . 5. Whi ch of t he f oI I owi ng
medi cat i ons i s i ndi cat ed as an adj unct t o carbi dopa/ I evodopa t herapy?
( A) Pr ami pexol e
( B) Br omocr i pt i ne
( C) Amant adi ne
( D) Tol capone
Vi ew Answer 5. The answer i s D[ see] . P. 1030


ANSWERS AND EXPLANATIONS
1. The answer i s A [ see Ì Ì . E. 4. a. ( 3) . ( a) ] .
Sever e cases of hepat ocel l ul ar i nj ur y÷i ncl udi ng f ul mi nant l i ver f ai l ur e, whi ch
causes deat h÷have been r epor t ed. Pat i ent s shoul d be moni t or ed and i nst r uct ed t o
l ook f or si gns of l i ver di sease such as cl ay- col or ed st ool , j aundi ce, f at i gue, l oss of
appet i t e, and l et har gy.
2. The answer i s D [ see Ì Ì . B. 3. c and d] .
Levodopa can cause GÌ si de ef f ect s such as nausea and vomi t i ng, par t i cul ar l y when
st ar t i ng t r eat ment . Bowel i r r egul ar i t y and gast r oi nt est i nal bl eedi ng can al so occur .
Wi t h l ong- t er m l evodopa t her apy, i nvol unt ar y chor ei f or m movement s can devel op,
and t he ef f i cacy of t he dr ug decl i nes. Ot her unwant ed ef f ect s of l evodopa i ncl ude
t achycar di a and car di ac ar r hyt hmi as, post ur al hypot ensi on, and psychi at r i c
di st ur bances such as conf usi on or depr essi on.
3. The answer i s A [ see Ì Ì . D. 2. a. ( 4) , Ì Ì . D. 2. c and d] .
Amant adi ne i s most ef f i caci ous wi t hi n t he f i r st f ew weeks, wher eas benef i t s f r om
l evodopa may not be seen f or weeks t o mont hs. Amant adi ne i s mor e benef i ci al t han
t he ant i chol i ner gi cs but i s l ess ef f ect i ve t han l evodopa. Unf or t unat el y, t he ef f i cacy
of amant adi ne decl i nes af t er 6- 12 mont hs of t her apy. The ef f i cacy of l evodopa
decl i nes af t er 3- 5 year s of t her apy.
4. The answer i s C [ see Ì Ì . E. 3. a and b] .
Non- er got dopami ne agoni st s, such as r opi ni r ol e, ar e i ndi cat ed f or bot h ear l y and
advanced st ages of Parki nson di sease. These dr ugs sel ect i vel y bi nd t o dopami ne
r ecept or s and act i vat e t he D
2
- r ecept or , but have l i t t l e or no af f i ni t y f or t he D
1
-
r ecept or . They have a gr eat er af f i ni t y f or t he D
3
- r ecept or t han f or t he D
2
- r ecept or .
The i nci dence of adver se event s ( e. g. , pl eur opul monar y f i br osi s and r et r oper i t oneal
f i br osi s, coronar y vasoconst r i ct i on, er yt hr omel al gi a, and Raynaud phenomenon) i s
l ow compar ed t o nonsel ect i ve dopami ne agoni st s. Non- er got dopami ne agoni st s
have a l ow pot ent i al f or t he devol vement of mot or f l uct uat i ons and dyski nesi s.
5. The answer i s D [ see Ì Ì . E. 4. a. ( 1) . ( d) ] .
Tol capone i s an i nhi bi t or of COMT enzyme used t o met abol i ze cat echol ami nes,
i ncl udi ng l evodopa. Ì t i s i ndi cat ed as an adj unct t her apy t o car bi dopa/ l evodopa
t her apy.

47
Schizophrenia
Rebekah R. Art hur Grube
I. INTRODUCTION
A. Schi zophreni a i s a maj or psychol ogi cal di sor der af f ect i ng appr oxi mat el y 1% of
t he popul at i on.
B. Ì t i s a di sease t hat can mar kedl y af f ect soci al and occupat i onal f unct i oni ng,
i nt er per sonal r el at i onshi ps, mor bi di t y, and mor t al i t y.
1. As many as 45% of t he homel ess popul at i on i n t he Uni t ed St at es suf f er f r om
schi zophr eni a.
2. Mor t al i t y r at es of pat i ent s wi t h schi zophr eni a ar e t wo t o f our t i mes hi gher t han
t he gener al popul at i on.
3. Sui ci de at t empt r at es f or pat i ent s suf f er i ng f rom schi zophr eni a r ange f r om 20% t o
42%, wi t h a success r at e of 10%.
C. The cost of schi zophr eni a on t he U. S. economy i s est i mat ed t o be $62. 7 bi l l i on
per year . One hal f of t hi s cost i s t he r esul t of i ndi r ect l osses, such as l ost wor k.
II. PATHOPHYSIOLOGY.
The act ual cause of schi zophr eni a i s uncer t ai n, however mul t i pl e t heor i es exi st ,
each of whi ch pr ovi des par t i al expl anat i ons. These i ncl ude genet i c t heor i es, t he
dopami ne t heor y, t he neur odevel opment al t heor y, and psychosoci al t heor i es.
A. Genet i c t heori es. A st r ong genet i c l i nk exi st s f or t he devel opment of
schi zophr eni a.
1. Schi zophr eni a occur s i n 1% of t he gener al popul at i on; however , t hi s i ncr eases t o
10% i f a f i rst - degr ee r el at i ve has a hi st or y of schi zophr eni a.
2. The r i sk of devel opi ng schi zophr eni a f ur t her i ncr eases t o 40% when bot h par ent s
have a hi st or y of schi zophr eni a.
3. Monozygot i c t wi ns have demonst r at ed a 48% r i sk of bot h t wi ns devel opi ng
schi zophr eni a i f one t wi n has t he di sease.
4. St udi es ar e ongoi ng t o l ocat e speci f i c genes l i nked t o t he devel opment of
schi zophr eni a.
B. Dopami ne t heory. Thi s t heor y post ul at es t hat dopami ne hyper act i vi t y i n t he
br ai n i s r esponsi bl e f or psychot i c sympt oms pr esent i n schi zophr eni a.
1. Whi l e dopami ne hyper act i vi t y i s pr esent i n t he mesol i mbi c pat hway, ot her ar eas
of t he br ai n, such as t he pr ef r ont al , f r ont al , and t empor al cor t i ces, have decr eased
dopami ne act i vi t y dur i ng acut e psychosi s.
a. Typi cal ant i psychot i cs bl ock dopami ne act i vi t y i n t he br ai n. Bl ockade of dopami ne
wi t h t hese agent s has not r esul t ed i n a r esponse f or al l pat i ent s.
b. The dopami ne t heor y has not been f ound t o be a compl et e expl anat i on f or
schi zophr eni a.
2. Ot her neur ot r ansmi t t er s t hought t o be i nvol ved i n schi zophr eni a i ncl ude 5-
hydroxyt rypt ami ne ( serot oni n; 5- HT) and gI ut amat e.
a. The r ol e of 5- HT i s l ar gel y evi denced by t he bl ockade of 5- HT wi t h t he newer
at ypi cal ant i psychot i cs.
b. The r ol e of gl ut amat e i s al so bei ng eval uat ed because one of i t s maj or f unct i ons
i s t o r egul at e dopami ne act i vi t y. Gl ut amat e def i ci ency has been f ound t o cause
si mi l ar ef f ect s t o t hat of dopami ne hyper act i vi t y.
C. NeurodeveI opment aI t heory. Thi s t heor y suggest s t hat schi zophr eni a occur s as
a r esul t of an i n ut er o di st ur bance dur i ng pr egnancy. Pot ent i al causes of t hi s
di st ur bance i ncl ude upper - r espi r at or y i nf ect i ons, obst et r i c compl i cat i ons, and
neonat al hypoxi a. St udi es exi st t hat l i nk
P. 1032

t hese pr enat al condi t i ons wi t h an i ncr eased r i sk of devel opment of schi zophr eni a;
however , t hi s t heor y cont i nues t o be eval uat ed.
D. Psychosoci aI t heori es. These t heor i es pr opose t hat si t uat i ons such as st ress,
poor i nt er per sonal ski l l s, conf l i ct i ng f ami l y communi cat i on, and var i ous
soci oeconomi c i nf l uences ar e l i nked t o t he devel opment of schi zophr eni a. Whi l e
t hese t heor i es have been unpr oved, such si t uat i ons can ser ve as t r i gger s f or t he
devel opment of t he di sease i n peopl e wi t h a pr edi sposi t i on.
III. DIAGNOSIS AND CLINICAL FEATURES
A. Schi zophr eni a i s di agnosed based on Di agnost i c and St at i st i cal Manual of
Ment al Di sor der s, 4t h ed. ( DSM-Ì V-TR) cr i t er i a.
1. A pat i ent must have at l east t wo of t he f ol l owi ng sympt oms: del usi ons,
hal l uci nat i ons, di sor gani zed speech, di sor gani zed or cat at oni c behavi or , and
negat i ve sympt oms.
2. The sympt oms shoul d be pr esent f or at l east 1 mont h, wi t h at l east 6 mont hs of
cont i nuous pr odr omal or r esi dual sympt oms.
3. At l east one ar ea of t he pat i ent ' s soci al or occupat i onal f unct i oni ng shoul d be
si gni f i cant l y af f ect ed.
4. Ot her condi t i ons causi ng si mi l ar sympt oms such as schi zoaf f ect i ve di sor der ,
mood di sor der s, subst ance abuse, and gener al medi cal condi t i ons shoul d be r ul ed
out .
B. Fi ve t ypes of schi zophr eni a exi st (Tabl e 47- 1) .
C. The cl i ni cal f eat ur es of schi zophr eni a ar e cat egori zed as posi t i ve, negat i ve, or
di sorgani zed sympt oms (Tabl e 47- 2) . The most common sympt oms ar e
haI I uci nat i ons and deI usi ons.
1. An haI I uci nat i on i s a per cept i on di st ur bance i n sensor y exper i ences of t he
envi r onment . Hal l uci nat i ons can be audi t or y, vi sual , ol f act ory, or t act i l e. Audi t or y
hal l uci nat i ons ar e most common.
Table 47-1. Types of Schizophrenia
Type Presentation
Catatonic Motor symptoms are most notable. The patient may
either demonstrate rigid immobility or excessive
purposeless movement. The patient may be silent and
withdrawn or may become loud and shout. Bizarre
voluntary movements such as posturing may also
occur. The patient may Iluctuate between the two
extremes.
Disorganized The patient tends to have disorganized speech and
behavior with a Ilat aIIect. Hallucinations and
delusions are not well Iormed and Iragmented. The
patient may also have bizarre mannerisms and
grimacing.
Paranoid The most common type oI schizophrenia. Patients are
usually preoccupied with paranoid delusions or
auditory hallucinations. Cognitive Iunction is usually
preserved; iI thought disorder is present. it does not
prevent description oI delusions or hallucinations.
Residual The patient does not have acute psychosis. but some
symptoms oI schizophrenia remain. Largely negative
symptoms are seen. such as Ilat aIIect. social
withdrawal. and loose associations. Prominent
delusions or hallucinations are not present.
UndiIIerentiated The patient meets the criteria Ior a diagnosis oI
schizophrenia but does not meet the criteria Ior a
speciIic type. or the patient may meet the criteria Ior
multiple types oI schizophrenia. No one type appears to
be dominant.

P. 1033


Table 47-2. Symptoms of Schizophrenia
Positive Symptoms Negative Symptoms Disorganized Symptoms
Delusions AIIective Ilattening Disorganized speech
Hallucinations Alogia Thought disorder
Combativeness Anhedonia Disorganized behavior
Insomnia Amotivation Poor attention
Apathy
Asocial behavior

2. A deI usi on i s an i ncor r ect or f al se bel i ef . Del usi ons can be r el i gi ous,
par anoi d/ per secut or y, gr andi ose, somat i c, i nf l uent i al , or sexual . Per secut or y or
par anoi d del usi ons ar e t he most common.
IV. RISK FACTORS.
Ri sk f act or s f or t he devel opment of schi zophr eni a i ncl ude a f ami l y hi st or y of
schi zophr eni a, any pot ent i al cause of f et al hypoxi c br ai n damage, hi st ory of bi r t h
compl i cat i ons, advanced age of mot her dur i ng pr egnancy, bi r t h dur i ng wi nt er
mont hs, subst ance abuse, si ngl e mar i t al st at us, l ower soci oeconomi c cl ass, ur ban
envi r onment , and envi r onment al st r ess.
V. TREATMENT GOALS AND OBJECTIVES.
Ther e i s curr ent l y no known cur e f or schi zophr eni a. Tr eat ment opt i ons i ncl ude
psychot herapy as wel l as pharmacot herapy. The goal s and obj ect i ves of t r eat ment
ar e as f ol l ows:
A. Mi ni mi ze sympt oms of schi zophr eni a
B. Ì mpr ove qual i t y of l i f e and soci al / occupat i onal f unct i oni ng
C. Pr event rel apse and hospi t al i zat i on
D. Mi ni mi ze adver se ef f ect s of medi cat i ons
E. Pr event sui ci de at t empt s or sel f - har m
VI. PHARMACOTHERAPY: ANTIPSYCHOTIC
MEDICATIONS
A. Two gener at i ons of ant i psychot i c medi cat i ons ar e avai l abl e f or t r eat ment : f i rst -
generat i on or t ypi caI ant i psychot i cs and second-generat i on or at ypi caI
ant i psychot i cs.
1. The choi ce of an appr opr i at e ant i psychot i c agent depends on t he pat i ent ' s
pr evi ous exper i ences wi t h ant i psychot i c medi cat i ons, adver se ef f ect s, t he pat i ent ' s
concomi t ant medi cal condi t i ons, medi cat i on i nt er act i ons, and t he pat i ent ' s
pr ef er ence.
2. Cur r ent Amer i can Psychi at r i c Associ at i on ( APA) gui del i nes r ecommend usi ng an
at ypi cal ant i psychot i c f i r st , owi ng t o l ess r i sk f or ext r apyr ami dal sympt oms ( EPS) .
Pat i ent s who pr ef er or have a hi st or y of r esponse t o t ypi cal ant i psychot i cs may f i r st
use t ypi cal ant i psychot i cs.
3. Response t o medi cat i ons i s not i mmedi at e, and maxi mal t r eat ment r esponse may
t ake 6 mont hs or l onger t o be seen.
4. Af t er a t r eat ment r esponse i s seen, pat i ent s shoul d be mai nt ai ned on t he cur r ent
t her apy f or a mi ni mum of 6 mont hs. Most pat i ent s wi l l r equi r e chr oni c t her apy,
because 80% of f i r st - epi sode pat i ent s who do not r ecei ve ant i psychot i c t r eat ment
wi l l r el apse wi t hi n 5 year s.
P. 1034


Table 47-3. Properties of Typical Antipsychotics
Agent
CPZ
a

Equivale
nt
Dose
Range
a

(mg/day
)
Sedatio
n EPS
Anticholiner
gic Side
Effects
Orthostati
c
Hypotensio
n
Chlorpromaz
ine
(Thorazine)
100 300
-
100
0
¹¹
¹
¹¹ ¹¹ ¹¹¹
TriIluoperazi
ne
(Stelazine)
5 5-
15
¹ ¹¹
¹
¹ ¹
Thioridazine
(Mellaril)
100 300
-
800
¹¹
¹
¹ ¹¹¹ ¹¹¹
Perphenazine
(TrilaIon)
10 16-
64
¹¹ ¹¹ ¹ ¹
Fluphenazine
(Prolixin)
2 5-
20
¹ ¹¹
¹
¹ ¹
Thiothixene
(Navane)
5 15-
50
¹ ¹¹
¹
¹ ¹¹
Haloperidol
(Haldol)
2 5-
20
¹ ¹¹
¹
¹ ¹
Molindone
(Moban)
10 30-
100
¹¹ ¹¹ ¹ ¹
Loxapine
(Loxitane)
10 30-
100
¹ ¹¹ ¹ ¹
a
Data Irom Lehman AF. Lieberman JA. Dixon LB. et al. Practice guideline
Ior treatment oI patients with schizophrenia. 2nd ed. Am J Psych
2004;161:1-56.
CPZ. chlorpromazine; EPS. extrapyramidal symptoms; ¹¹¹. high; ¹¹.
moderate; ¹. low.

B. Typi caI ant i psychot i c medi cat i ons ( Tabl e 47- 3)
1. Mechani sm of acti on. The ant i psychot i c ef f ect of t hese medi cat i ons i s pr i mar i l y
medi at ed t hr ough t he bl ockade of dopami ne r ecept or s. These agent s al so have
act i vi t y at hi st ami ne, muscar i ni c, and q- r ecept ors, al t hough t hese r ecept or s ar e not
r esponsi bl e f or desi r ed t her apeut i c act i vi t y.
2. Pot ency. Typi cal ant i psychot i c agent s ar e cl assi f i ed by t hei r pot ency f or t he
dopami ne r ecept or i nt o hi gh- , moder at e- , and l ow- pot ency ant i psychot i cs. Hi gh-
pot ency agent s have a hi gher af f i ni t y f or t he dopami ne r ecept or and ar e associ at ed
wi t h hi gher r i sk f or t he devel opment of EPS. Low- pot ency agent s have l ess af f i ni t y
f or dopami ne r ecept or s; and al t hough t hey have l ess r i sk f or causi ng EPS, t hey ar e
associ at ed wi t h mor e adver se ef f ect s f r om t hei r act i vi t y at hi st ami ne, muscar i ni c,
and q- r ecept or s.
3. Ef fi cacy. When dosed i n equi val ent doses, t he var i ous t ypi cal ant i psychot i cs
have si mi l ar ef f i cacy. Equi val ent doses ar e descri bed usi ng chI orpromazi ne ( CPZ)
equi vaI ent s (Tabl e 47- 3) . Typi cal ant i psychot i cs ar e t hought t o be as ef f ect i ve as
at ypi cal ant i psychot i cs f or posi t i ve sympt oms but ar e l ess ef f ect i ve f or negat i ve
sympt oms.
4. Adverse ef f ect s. Typi cal ant i psychot i cs ar e associ at ed wi t h sever al adver se
ef f ect s (Tabl es 47- 3 and 47- 4) .
a. The act i vi t y of t he var i ous t ypi cal ant i psychot i cs at t he dopami ne, q- , muscar i ni c,
and hi st ami ne r ecept or s ar e r esponsi bl e f or many of t he adver se ef f ect s of t hese
medi cat i ons ( Tabl e 47- 5) .
b. Ext rapyrami daI si de ef f ect s can occur wi t h al l t he t ypi cal ant i psychot i cs,
especi al l y wi t h hi gh- pot ency t ypi cal ant i psychot i cs. Four t ypes of ext r apyr ami dal
si de ef f ect s have been descr i bed: acut e dyst oni a, akat hi si a, pseudopar ki nsoni sm,
and t ar di ve dyski nesi a.
( 1) Acut e dyst oni a descr i bes sudden muscl e spasms t hat pr i mar i l y occur i n t he
eye, neck, f ace, and t hr oat muscl es.
( a) Types of acut e dyst oni a i ncl ude t or t i col l i s ( a muscl e spasm of t he neck causi ng
t he head t o be t wi st ed t o t he si de) , r et r ocol l i s (a muscl e spasm of t he neck causi ng
t he head t o be pul l ed back) , t r i smus ( a muscl e spasm of t he mout h causi ng t he j aw
t o be cl enched) , and ocul ogyr i c cr i si s ( a spasm of t he eye muscl es causi ng one or
bot h eyes t o become f i xed i n an upwar d gaze) .
P. 1035


Table 47-4. General Adverse Effects of Antipsychotics
Typical Antipsychotics Atypical Antipsychotics
Sedation Sedation
Anticholinergic eIIects Anticholinergic eIIects (clozapine.
olanzapine)
Blurred vision Orthostatic hypotension
Constipation Moderate to severe weight gain
Dry mouth Diabetes mellitus
Urinary retention Hypercholesterolemia
Extrapyramidal symptoms Hyperprolactinemia (risperidone)
Lowered seizure threshold Lowered seizure threshold
Orthostatic hypotension QT prolongation
Hyperprolactinemia Neuroleptic malignant syndrome
Moderate weight gain Extrapyramidal symptoms
QT prolongation Sexual dysIunction
Photosensitivity
Temperature dysregulation
Neuroleptic malignant
syndrome

Sexual dysIunction
Elevated liver enzymes

( b) Acut e dyst oni as can occur wi t hi n hour s of i ni t i at i ng t he medi cat i on or i ncr easi ng
t he dose. Thi s i s most common i n young men and i n pat i ent s usi ng hi gh doses of
hi gh- pot ency t ypi cal ant i psychot i cs.
( c) Management i ncl udes t he use of ant i chol i ner gi c agent s l i ke benzt r opi ne and
di phenhydr ami ne; i f i nef f ect i ve, benzodi azepi nes can al so be used. Pr event i on of
f ut ur e r eact i ons may be achi eved by decr easi ng t he dose of ant i psychot i c, usi ng
or al ant i chol i ner gi cs, or changi ng t her apy t o an at ypi cal ant i psychot i c.
( 2) Akat hi si a i s descr i bed as mot or r est l essness associ at ed wi t h i nt er nal agi t at i on
and f eel i ngs of havi ng t o move.
( a) Pat i ent s wi t h akat hi si a may pace or be unabl e t o si t st i l l . Thi s may occur wi t hi n
days t o a f ew mont hs af t er t he i ni t i at i on of t her apy or i ncr ease i n dose.
( b) Tr eat ment of akat hi si a i ncl udes dose r educt i on of t he ant i psychot i c, l i pophi l i c 8-
bl ocker s, benzodi azepi nes, or ant i chol i ner gi cs. Ther apy may al so be changed t o an
at ypi cal ant i psychot i c.
( 3) Pseudoparki nsoni sm cl i ni cal l y appear s si mi l ar t o i di opat hi c Par ki nson di sease,
and i ncl udes sympt oms l i ke shuf f l i ng gai t , mask- l i ke f ace, cogwheel r i gi di t y, and
r est i ng or pi l l - r ol l i ng t r emor .
( a) Thi s can occur wi t hi n 1- 3 mont hs af t er st ar t i ng t her apy or i ncr easi ng t he dose of
t he ant i psychot i c agent .
( b) Thi s i s t r eat ed by changi ng t o an at ypi cal ant i psychot i c, decr easi ng t he dose,
and/ or addi ng an ant i chol i ner gi c agent .
Table 47-5. Adverse Effects by Receptor Affinities
Receptor Antagonized Adverse Effects
Histamine Sedation
Weight gain
Dopamine Extrapyramidal symptoms
Hyperprolactinemia
Muscarinic Anticholinergic adverse eIIects
Cognitive impairment
Tachycardia
Alpha Orthostatic hypotension
ReIlex tachycardia
Serotonin Weight gain

P. 1036


( 4) Tardi ve dyski nesi a ( TD) usual l y does not occur unt i l t he pat i ent has been
t aki ng ant i psychot i cs f or a year or mor e. Ì t i s a movement di sor der t hat can occur i n
var i ous l ocat i ons of t he body, i ncl udi ng t he f ace, t ongue, hi ps, and ext r emi t i es.
( a) Movement s can be dyst oni c ( f i xed) or chor eoat het oi d ( r hyt hmi c) . Common
movement di sor der s i ncl ude t ongue chewi ng, l i p smacki ng, and r hyt hmi c movement s
of t he t r unk.
( b) TD may be i r r ever si bl e, so pat i ent s t aki ng ant i psychot i cs shoul d be moni t or ed
cl osel y f or t he appear ance of any movement di sor der s.
( c) Tool s such as t he Abnor mal Ì nvol unt ar y Movement Scal e ( AÌ MS) or Dyski nesi a
Ì dent i f i cat i on Syst em Condensed User Scal e ( DÌ SCUS) ar e avai l abl e t o assi st i n
moni t or i ng pat i ent s.
( d) Tr eat ment shoul d i ncl ude st oppi ng t he ant i psychot i c. Mul t i pl e agent s have been
used t o at t empt t o t r eat TD, al t hough none has been def i ni t i vel y pr oven t o be
ef f ect i ve. These i ncl ude vi t ami n E, benzodi azepi nes, bacl of en, and r eserpi ne.
c. NeuroI ept i c maI i gnant syndrome ( NMS) i s an uncommon but pot ent i al l y f at al
adver se ef f ect of ant i psychot i cs. Si gns and sympt oms i ncl ude f ever , sever e r i gi di t y,
al t er ed ment al st at us, unst abl e bl ood pr essur e, t achycar di a, i ncont i nence, el evat ed
cr eat i ne ki nase, and i ncr eased whi t e bl ood count .
( 1) NMS has a sudden onset , and shoul d pr ompt i mmedi at e di scont i nuat i on of al l
ant i psychot i cs.
( 2) Tr eat ment i ncl udes suppor t i ve car e and t he use of br omocr i pt i ne and/ or
dant r ol ene.
C. At ypi caI ant i psychot i c medi cat i ons ( Tabl e 47- 6)
1. Seven at ypi cal ant i psychot i cs ar e cur r ent l y on t he U. S. mar ket : cl ozapi ne
( Cl ozar i l ) , r i sper i done ( Ri sper dal ) , ol anzapi ne ( Zypr exa) , quet i api ne ( Ser oquel ) ,
zi pr asi done ( Geodon) , ar i pi pr azol e ( Abi l i f y) , and pal i per i done ( Ì nvega) .
2. The mechani sm of act i on f or at ypi cal ant i psychot i cs i s di f f er ent f r om t hat of t he
t ypi cal ant i psychot i cs. Wi t h t he except i on of ar i pi pr azol e, t he at ypi cal ant i psychot i cs
ar e dopami ne ant agoni st s but al so bl ock 5- HT
2A
- r ecept or s. They bl ock 5- HT t o a
gr eat er ext ent t han dopami ne. Ar i pi pr azol e i s a par t i al dopami ne and 5- HT
1A
- agoni st
and a 5- HT
2A
- ant agoni st .
3. Recept or af f i ni t y di f f er s f or t he var i ous at ypi cal ant i psychot i cs. Al l at ypi cal
ant i psychot i cs have act i vi t y at t he 5- HT
2A
- r ecept or and dopami ne r ecept or . Di f f er ent
agent s have di f f er ent act i vi t y f or hi st ami ne, q-, and muscar i ni c r ecept or s (Tabl e 47-
6) .
4. At ypi cal ant i psychot i cs have i ncr eased ef f i cacy f or negat i ve sympt oms compar ed
t o t ypi cal ant i psychot i cs. Wi t h t he except i on of cl ozapi ne, al l ant i psychot i cs ar e
t hought t o have si mi l ar ef f i cacy f or posi t i ve sympt oms. Cl ozapi ne has demonst r at ed
ef f i cacy f or t r eat ment - r ef r act or y schi zophr eni a.
5. Adverse ef f ect s. At ypi cal ant i psychot i cs di f f er f r om t ypi cal ant i psychot i cs i n t hei r
adver se ef f ect pr of i l e (Tabl e 47- 4) . Owi ng t o t hei r hi gher af f i ni t y f or 5- HT- r ecept ors
compar ed t o dopami ne r ecept or s, t hey ar e associ at ed wi t h l ess EPS and
hyper pr ol act i nemi a t han t ypi cal ant i psychot i cs. However , t hey have pr obl emat i c
adver se ef f ect s, whi ch l i mi t t hei r use (Tabl e 47- 6) .
a. At ypi cal ant i psychot i cs have been l i nked wi t h wei ght gai n, hyper l i pi demi a, and
hyper gl ycemi a. The r i sk f or t he devel opment of t hese met abol i c adver se ef f ect s
di f f er s among agent s.
b. A r ecent met a- anal ysi s of t he at ypi cal ant i psychot i cs demonst r at ed an i ncr eased
r i sk of deat h i n pat i ent s wi t h dement i a. At ypi cal ant i psychot i cs now car r y a bI ack
box warni ng caut i oni ng pr ovi der s agai nst the use of at ypi caI ant i psychoti cs i n
t he t reat ment of dement i a- reI at ed psychosi s. For mor e i nf or mat i on, ref er t o
Schnei der LS, Dager man KS, Ì nsel P. Ri sk of deat h wi t h at ypi cal ant i psychot i c dr ug
t r eat ment f or dement i a. JAMA 2005; 294: 1934- 1943.
6. Cl ozapi ne was t he f i rst at ypi cal ant i psychot i c t o be market ed i n t he Uni t ed
St at es, i s t he onl y ant i psychot i c wi t h no r i sk of EPS or TD and i s t he onl y
ant i psychot i c wi t h pr oven ef f i cacy f or t r eat ment -r ef r act or y schi zophr eni a. However ,
cl ozapi ne i s i ndi cat ed onl y i n pat i ent s who have f ai l ed t wo t o t hr ee ant i psychot i cs
( i ncl udi ng t ypi cal and at ypi cal ant i psychot i cs) because of i t s r i sk of agranul ocyt osi s.
Compl et e bl ood count ( CBC) must be moni t or ed at basel i ne, ever y week f or t he f i rst
6 mont hs of t her apy, ever y ot her week f or t he next 6 mont hs, and t hen ever y mont h
t her eaf t er . Cl ozapi ne may al so l ower sei zur e t hreshol d i n pat i ent s, especi al l y wi t h
hi gher doses. Cl ozapi ne shoul d be used wi t h caut i on i n pat i ent s at r i sk f or sei zur es
or wi t h a hi st or y of a sei zur e di sor der .
P. 1037


Table 47-6. Properties of Atypical Antipsychotics
Medication
Dose
Range
a

(mg/da
y)
Recept
or
Affinity
a

Sedatio
n EPS
Anticholine
rgic Effects
Orthostat
ic
Hypotensi
on
Weight
Gain
Clozapin
e
15
0-
60
0
D.
5-
HT
.
M.
H
1
.
u
¹¹
¹
0 ¹¹¹ ¹¹¹ ¹¹¹
Risperid
one
2-
8
D.
5-
HT
.
H
1
.
u
¹ ¹
to
¹
¹
0 ¹ ¹¹
Olanzapi
ne
10
-
30
D.
5-
HT
.
M.
H
1
.
u
¹¹ ¹ ¹¹ ¹ ¹¹¹¹
Quetiapi
ne
30
0-
80
0
D.
5-
HT
.
H
1
.
u
¹¹ ¹ 0 ¹¹ ¹¹
Ziprasido
ne
12
0-
20
0
D.
5-
HT
.
H
1
.
u
0 ¹ 0 0 0
Aripipraz
ole
10
-
30
D.
5-
HT
.
H
1
.
u
¹ ¹ 0 0 0
Paliperid
one
b

3-
12
D.
5-
HT
.
H1
. u
¹ ¹
to
¹
¹
0 ¹ unkno
wn
a
Data Irom Lehman AF. Lieberman JA. Dixon LB. et al. Practice guideline
Ior treatment oI patients with schizophrenia. 2nd ed. Am J Psych
2004;161:1-56. 5-HT. 5-hydroxytryptamine (serotonin); u. alpha; D.
dopamine; EPS. extrapyramidal symptoms; H
1
. histamine; M. muscarinic;
¹¹¹. high; ¹¹. moderate; ¹. low.

b
Data Irom Invega package insert. 2007. Titusville. NJ. Janssen. L.P.

P. 1038


7. Uni que f or mul at i ons of at ypi cal ant i psychot i cs ar e avai l abl e f or pat i ent s.
a. OraI I y di si nt egrati ng t abI et s. Ri sper i done and ol anzapi ne bot h ar e avai l abl e as
or al l y di si nt egr at i ng t abl et s, and are manuf act ur ed as Ri sper dal M t abl et s and
Zypr exa Zydi s t abl et s.
b. Parent eraI f ormuI at i ons. Zi pr asi done and ol anzapi ne ar e avai l abl e i n par ent er al
f or mul at i ons f or use i n acut el y agi t at ed pat i ent s wi t h schi zophr eni a.
( 1) Zi pr asi done may be gi ven as 10 or 20 mg i nt r amuscul ar l y. The 10- mg dose may
be r epeat ed i n 2 hr , and t he 20 mg dose may be r epeat ed i n 4 hr . The maxi mum
dai l y dose i s 40 mg.
( 2) Ol anzapi ne may be gi ven as 10 mg i nt r amuscul ar l y. The 10- mg dose may be
r epeat ed ever y 2 hr , up t o a maxi mum of 30 mg dai l y.
D. Rapi d t ranqui I i zat i on i s used f or acut el y psychot i c pat i ent s wi t h aggr essi on or
who ar e sever el y agi t at ed. Par ent er al t ypi cal or at ypi cal agent s may be used i n
t hese pat i ent s. Typi cal agent s avai l abl e i n a par ent er al f or m i ncl ude chl or pr omazi ne
( Thor azi ne) , f l uphenazi ne ( Pr ol i xi n) , and hal oper i dol ( Hal dol ) . As descr i bed ear l i er ,
avai l abl e at ypi cal agent s i ncl ude zi pr asi done and ol anzapi ne.
E. NoncompI i ant pat i ent s. Those pat i ent s wi t h a hi st or y of noncompl i ance or who
have f r equent hospi t al i zat i ons secondar y t o noncompl i ance may be candi dat es f or a
l ong- act i ng i nt r amuscul ar f or mul at i on of ant i psychot i c. Cur rent l y t hr ee opt i ons exi st :
hal oper i dol decanoat e, f l uphenazi ne decanoat e, and l ong- act i ng r i sper i done
( Ri sper dal Const a) .
1. HaI operi doI decanoat e i s gi ven i nt r amuscul ar l y ever y 3- 4 weeks. The st ar t i ng
dose shoul d be 10- 15 t i mes t he t ot al dai l y dose of or al hal oper i dol . Thi s equat i on i s
onl y a r ough conver si on, and t he l owest ef f ect i ve dose shoul d be gi ven. The f i r st
dose shoul d not exceed 100 mg, and subsequent doses shoul d not exceed 450 mg.
2. FI uphenazi ne decanoat e i s admi ni st er ed i nt ramuscul ar l y ever y 2- 3 weeks. The
st ar t i ng dose i s 1. 2- 1. 6 t i mes t he t ot al dai l y dose of or al f l uphenazi ne. The
maxi mum dose of f l uphenazi ne decanoat e i s 100 mg at any one t i me. The l owest
ef f ect i ve dose of t hi s f or mul at i on shoul d be used.
3. Long- acti ng ri speri done i s admi ni st er ed i nt ramuscul ar l y ever y 2 weeks. An
ef f ect i ve dose of or al r i sper i done shoul d f i r st be i dent i f i ed bef or e changi ng t o t he
l ong- act i ng f or mul at i on. Pat i ent s shoul d be st ar t ed at 25 mg ever y 2 weeks and
cover ed wi t h or al medi cat i ons f or 3 weeks af t er i ni t i at i on. Doses may be i ncr eased
t o a maxi mum of 50 mg ever y 2 weeks.
F. Ant i psychot i c agent s may be swi t ched f or sever al r easons, such as l ack of
ef f i cacy and adver se ef f ect s. When swi t chi ng ant i psychot i c agent s, t he or i gi nal
agent shoul d be t i t r at ed down whi l e t he new agent i s t i t r at ed up. Ì f changi ng f r om a
t ypi cal ant i psychot i c t o an at ypi cal ant i psychot i c secondar y t o EPS, ant i chol i ner gi c
agent s may be cont i nued unt i l t he t ypi cal agent i s compl et el y di scont i nued unl ess
t he new agent i s cl ozapi ne. Cl ozapi ne has hi gh ant i chol i ner gi c ef f ect s, t hus
addi t i onal ant i chol i ner gi c agent s woul d not be i ndi cat ed.
G. Adj unct i ve t herapy. Ì n pat i ent s wi t h par t i al or no r esponse t o t her apy af t er an
adequat e t r i al of an ant i psychot i c, a second ant i psychot i c shoul d be t r i ed. Af t er t he
f ai l ur e of t wo t o t hr ee ant i psychot i cs, t he pat i ent meet s t he cr i t er i a f or cl ozapi ne,
and i t s use shoul d be consi der ed. Augment at i on i s an opt i on f or t hose pat i ent s
unabl e t o t ake cl ozapi ne or wi t h par t i al / no r esponse. Cl ozapi ne has been st udi ed i n
combi nat i on wi t h t ypi cal and at ypi cal ant i psychot i cs. Ot her opt i ons f or augment at i on
i ncl ude mood st abi l i zer s, such as l i t hi um, val pr oi c aci d, and car bamazepi ne.
Ant i depr essant s have al so been used i n pat i ent s suf f er i ng f rom depr essi ve
sympt oms. El ect r oconvul si ve t her apy ( ECT) has al so been used as an adj unct i ve
t her apy i n pat i ent s wi t h par t i al or no r esponse t o ant i psychot i cs.
P. 1039


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one of t he suggest ed answer s or
phr ases. Choose t he best answer .
For quest i ons 1- 5: DG i s a 23- year - ol d f emal e commi t t ed t o t he i npat i ent
psychi at r i c war d by her par ent s. They st at e t hat she has r ecent l y been under a l ar ge
amount of st r ess f r om col l ege, and t hey have not i ced over t he past year t hat she
has become mor e wi t hdr awn f r om her f r i ends and soci al act i vi t i es. They al so st at e
t hat she anger s mor e easi l y t han she used t o as a chi l d, and t hi s mor ni ng t hey
f ound her wi t h a kni f e t ryi ng t o sl i t her wr i st s. DG st at es t hat t he voi ces keep t el l i ng
her she i s bad and t hat she shoul d ki l l her sel f . She does not admi t t o any vi sual
hal l uci nat i ons but descri bes mul t i pl e voi ces ( mal e and f emal e) t al ki ng t o her
cont i nuousl y t el l i ng her t hat she shoul d har m her sel f or t hat peopl e ar e out t o get
her . She keeps t el l i ng you t hat her par ent s ar e t r yi ng t o get r i d of her , and she
want s t o l eave. She appear s t o be a heal t hy young woman al t hough not i ceabl y
agi t at ed. Her medi cal hi st or y i s si gni f i cant onl y f or smoki ng one pack/ day si nce age
16. DG i s di agnosed wi t h schi zophr eni a.
1. Whi ch t ype of schi zophreni a i s DG I i keI y experi enci ng based upon her
present i ng si gns and sympt oms?
( A) cat at oni c
( B) di sor gani zed
( C) par anoi d
( D) r esi dual
Vi ew Answer 1. The answer i s C[ see] . 2. Whi ch of t he f oI I owi ng of DG' s
sympt oms i s best descri bed as a negat i ve sympt om of schi zophreni a?
( A) soci al wi t hdr awal
( B) audi t or y hal l uci nat i ons
( C) del usi ons
( D) agi t at i on
Vi ew Answer 2. The answer i s A[ see] . 3. The medi caI t eam deci des t o
i ni t i at e t reat ment for DG. Whi ch of t he f oI I owi ng ant i psychot i c medi cat i ons i s
t he best i ni t i aI t reat ment f or t hi s pat i ent ?
( A) hal oper i dol
( B) r i sper i done
( C) t hi or i dazi ne
( D) cl ozapi ne
Vi ew Answer 3. The answer i s B[ see] . 4. Whi ch of t he f oI I owi ng i s not a
pot ent i aI adverse ef f ect of t he medi cat i on seI ect ed for DG i n questi on 3?
( A) wei ght gai n
( B) pseudopar ki nsoni sm
( C) sedat i on
( D) ur i nar y r et ent i on
Vi ew Answer 4. The answer i s D[ see] . 5. DG i s st abi I i zed on t he medi cat i on
prescri bed and i s di scharged home. DG i s readmi t t ed i nt o t he psychi at ri c ward
1 year I at er f or audi tory and vi suaI haI I uci nat i ons secondary t o noncompI i ance
on her current t reat ment regi men. Whi ch of t he f oI I owi ng t reat ment opt i ons i s
most appropri at e f or DG at t hi s t i me?
( A) hal oper i dol decanoat e
( B) l ong- act i ng r i sper i done
( C) cl ozapi ne monot her apy
( D) adj unct i ve cl ozapi ne wi t h hal oper i dol
Vi ew Answer 5. The answer i s B[ seeandand] . For quest i ons 6- 8: TW i s a
52- year - ol d f emal e wi t h a hi st or y of schi zophr eni a and di abet es mel l i t us t ype 2. She
has been t r eat ed f or many year s wi t h hal oper i dol wi t h good r esponse; however , she
has r ecent l y devel oped l i p smacki ng and t ongue chewi ng.
6. What t ype of adverse ef f ect i s TW experi enci ng?
( A) akat hi si a
( B) acut e dyst oni a
( C) pseudopar ki nsoni sm
( D) t ar di ve dyski nesi a
Vi ew Answer 6. The answer i s D[ seeand] . 7. Whi ch of t he f oI I owi ng
medi cat i ons has been used t o t reat t he adverse ef f ect descri bed i n quest i on 6?
( A) vi t ami n E
( B) pr opr anol ol
( C) di phenhydr ami ne
( D) amant adi ne
Vi ew Answer 7. The answer i s A[ see] . P. 1040


8. Now that TW i s experi enci ng t hi s react i on, her heaI thcare provi ders want t o
change her t herapy t o a di f f erent ant i psychot i c. Whi ch of t he f oI I owi ng
ant i psychot i cs i s the best t reat ment opt i on f or her?
( A) ol anzapi ne
( B) r i sper i done
( C) quet i api ne
( D) f l uphenazi ne
Vi ew Answer 8. The answer i s C[ see] . 9. Whi ch of t he f oI I owi ng at ypi caI
ant i psychot i cs wouI d be t he I east I i keI y t o cause wei ght gai n?
( A) r i sper i done
( B) ol anzapi ne
( C) quet i api ne
( D) ar i pi pr azol e
Vi ew Answer 9. The answer i s D[ see] . 10. Whi ch of t he f oI I owi ng
st at ement s does not descri be a way i n whi ch at ypi caI anti psychot i cs di f f er
f rom t ypi caI ant i psychot i cs?
( A) At ypi cal ant i psychot i cs have a hi gher af f i ni t y f or ser ot oni n r ecept or s t han
dopami ne r ecept or s.
( B) At ypi cal ant i psychot i cs ar e mor e ef f i caci ous f or posi t i ve sympt oms t han t ypi cal
ant i psychot i cs.
( C) At ypi cal ant i psychot i cs ar e mor e l i kel y t o cause wei ght gai n and hyper l i pi demi a
t han t ypi cal ant i psychot i cs.
( D) At ypi cal ant i psychot i cs ar e l ess l i kel y t o cause ext r apyr ami dal sympt oms ( EPS)
t han t ypi cal ant i psychot i cs.
Vi ew Answer 10. The answer i s B[ seeand] . P. 1041


ANSWERS AND EXPLANATIONS
1. The answer i s C [ see Tabl e 47- 1] .
DG' s pr omi nent sympt oms i ncl ude wel l - f or med hal l uci nat i ons and del usi ons. These
hal l uci nat i ons and del usi ons ar e char act er i st i c of par anoi d schi zophr eni a. DG al so
does not meet t he cr i t er i a f or any ot her t ype of schi zophr eni a.
2. The answer i s A [ see Tabl e 47- 2] .
Soci al wi t hdr awal or asoci al behavi or i s a negat i ve sympt om of schi zophr eni a.
Hal l uci nat i ons, del usi ons, and agi t at i on ar e al l posi t i ve sympt oms of schi zophr eni a.
3. The answer i s B [ see VÌ . A. 2; VÌ . C. 1; VÌ . C. 6] .
The Amer i can Psychi at r i c Associ at i on cur r ent l y r ecommends usi ng at ypi cal
ant i psychot i cs f i rst over t ypi cal ant i psychot i cs, unl ess t he pat i ent has a pr ef er ence.
Hal oper i dol and t hi or i dazi ne ar e t ypi cal ant i psychot i cs. Cl ozapi ne shoul d be used
onl y f or t r eat ment r ef r act or y pat i ent s because of i t s adver se ef f ect pr of i l e.
4. The answer i s D [ see Tabl e 47- 4; Tabl e 47- 6] .
Ri sper i done has been associ at ed wi t h moder at e wei ght gai n, l ow t o moder at e r i sk of
EPS, and l ow r i sk of sedat i on. Ì t has not been associ at ed wi t h ant i chol i ner gi cs
ef f ect s such as ur i nar y r et ent i on.
5. The answer i s B [ see VÌ . A. 1 and 2, VÌ . E. 1, 2 and 3] .
DG has a hi st or y of r esponse wi t h r i sper i done; however , she i s exper i enci ng a
r el apse of sympt oms owi ng t o noncompl i ance. A l ong- act i ng f or mul at i on i s i ndi cat ed
t o assi st wi t h medi cat i on compl i ance. As she has not f ai l ed mul t i pl e ant i psychot i cs,
DG i s not a candi dat e f or cl ozapi ne or adj unct i ve cl ozapi ne. Long- act i ng r i sper i done
i s pr ef er r ed i n t hi s pat i ent over hal oper i dol decanoat e owi ng t o t he pat i ent ' s
r esponse hi st or y and i t s pr ef er abl e adver se ef f ect pr of i l e.
6. The answer i s D [ see VÌ . B. 4. b. (1) , ( 2), ( 3) and ( 4) ] .
TW i s exper i enci ng l i p smacki ng and t ongue chewi ng of a l at e onset , whi ch i s best
descr i bed as t ar di ve dyski nesi a.
7. The answer i s A [ see VÌ . B. 4. b. (4) . ( d) ] .
Vi t ami n E, benzodi azepi nes, bacl of en, and r eser pi ne have al l been used i n t he
t r eat ment of t ar di ve dyski nesi a, al t hough none has been def i ni t i vel y pr oven t o be
ef f ect i ve.
8. The answer i s C [ see Tabl e 47- 3; Tabl e 47- 6] .
Because TW i s exper i enci ng t ar di ve dyski nesi a, her t her apy shoul d be changed t o
an at ypi cal ant i psychot i c. Her medi cal hi st or y i s si gni f i cant f or t ype 2 di abet es
mel l i t us. Ol anzapi ne i s associ at ed wi t h a hi gh r i sk of causi ng wei ght gai n, and ot her
met abol i c sympt oms and shoul d not be used i n t hi s pat i ent . Ri sper i done has a l ow
t o moder at e r i sk of EPS. Ot her at ypi cal ant i psychot i cs, such as quet i api ne, t hat
car r y a l ower r i sk of EPS woul d be pr ef er abl e.
9. The answer i s D [ see Tabl e 47- 6] .
Ol anzapi ne has a hi gh r i sk of causi ng wei ght gai n. Ri sper i done and quet i api ne have
a moder at e r i sk of causi ng wei ght gai n. Ar i pi pr azol e i s associ at ed wi t h a l ow r i sk of
wei ght gai n.
10. The answer i s B [ see VÌ . C. 2, 3, 4 and 5. a; Tabl e 47- 4] .
At ypi cal ant i psychot i cs have a hi gher af f i ni t y f or ser ot oni n r ecept or s t han dopami ne
r ecept or s, wher eas t ypi cal ant i psychot i cs have no act i vi t y at ser ot oni n r ecept or s.
At ypi cal and t ypi cal ant i psychot i cs have si mi l ar ef f i cacy f or posi t i ve sympt oms of
schi zophr eni a; however , at ypi cal ant i psychot i cs have i ncr eased ef f i cacy agai nst
negat i ve sympt oms. At ypi cal ant i psychot i cs ar e mor e l i kel y t o cause si gni f i cant
wei ght gai n and hyper l i pi demi a and l ess l i kel y t o cause EPS t han t ypi cal
ant i psychot i cs.

48
Mood Disorders
Rebekah R. Art hur Grube
I. DEFINITION.
Mood di sorders ar e descr i bed as an el evat i on or depr essi on i n mood t hat per si st s
over a per i od of t i me and af f ect s t he abi l i t y of t he per son t o f unct i on. These
di sor der s ar e associ at ed wi t h si gni f i cant mor bi di t y, mor t al i t y, and f i nanci al cost .
Mood di sor der s can cause a 10- t o 20- f ol d i ncr ease i n sui ci de r at es and i mpai r
soci al and occupat i onal f unct i oni ng. Two common t ypes of mood di sor der s ar e
maj or depressi on and bi poI ar di sorder.
II. MAJOR DEPRESSION
A. Maj or depressi ve di sorder i s def i ned as a mood di sor der i n whi ch t he pat i ent
has one or mor e epi sodes of maj or depr essi on but has no hi st or y of mani a, mi xed,
or hypomani a epi sodes. Maj or depr essi ve epi sodes ar e descri bed i n Ì Ì . D.
B. Epi demi oI ogy
1. Depr essi on occur s i n 16. 2% of t he Uni t ed St at es popul at i on. Resul t s f r om r ecent
st udi es i ndi cat e t hat 6. 6% of t he popul at i on has exper i enced an epi sode i n t he pr i or
12 mont hs.
2. Depr essi on occur s mor e f r equent l y i n women t han men, wi t h women havi ng a
l i f et i me r i sk of 1. 7- 2. 7 t i mes hi gher t han men.
3. The hi ghest r i sk of depr essi on occur s i n adul t s bet ween t he ages of 25 t o 44
years, al t hough depr essi on may occur at any age.
C. Pat hophysi oI ogy. The pat hophysi ol ogy of depr essi on i s not compl et el y known,
however sever al t heor i es exi st : genet i c t heor i es, t he bi ogeni c ami ne t heor y, and t he
dysr egul at i on t heor y.
1. As wi t h many psychi at r i c di sor der s, a genet i c I i nk exi st s f or depr essi on. Peopl e
who have a par ent or si bl i ng wi t h a hi st or y of depressi on have a 1. 5- 3 t i mes gr eat er
r i sk f or devel opi ng depr essi on t han t he gener al popul at i on. Bet ween 8% and 18% of
pat i ent s wi t h maj or depr essi on have a par ent or si bl i ng wi t h a hi st or y of depr essi on.
2. The bi ogeni c ami ne t heory was or i gi nal l y descr i bed i n t he 1950s and i s t he
basi s f or past and cur r ent phar macol ogi cal t r eat ment opt i ons. Thi s t heor y suggest s
t hat depr essi on i s associ at ed wi t h decreased I eveI s of norepi nephri ne ( NE) , 5-
hydroxyt rypt ami ne ( serot oni n; 5- HT) , and dopami ne ( DA) i n t he brai n.
3. The dysreguI at i on t heory was devel oped af t er t he bi ogeni c ami ne t heor y and
suggest s t hat i mpai red homeost asi s of NE, 5-HT, and DA i n the brai n i s
associ at ed wi t h depr essi on r at her t han absol ut e l evel s of t hese neur ot r ansmi t t er s.
Thi s t heor y i n par t at t empt s t o expl ai n t he changes i n neur ot r ansmi t t er recept or
sensi t i vi t i es wi t nessed i n t he f i r st f ew weeks of phar macot her apy.
D. Di agnosi s and cI i ni caI f eat ures
1. Maj or depr essi ve epi sodes ar e di agnosed usi ng t he Di agnost i c and St at i st i cal
Manual of Ment al Di sor der s, 4t h ed. ( DSM- Ì V-TR) cr i t er i a. To meet t he cri t er i a f or a
maj or depr essi ve epi sode, pat i ent s shoul d exper i ence at l east f i ve or more
per si st ent sympt oms f or at l east 2 weeks. These sympt oms i ncl ude depr essed mood,
l oss of i nt er est or pl easur e i n act i vi t i es, change i n appet i t e, uni nt ent i onal wei ght
gai n or l oss, i nsomni a or excess sedat i on, psychomot or agi t at i on or r et ar dat i on,
decr eased ener gy or f at i gue, f eel i ngs of wor t hl essness or i nappr opr i at e gui l t ,
decr eased abi l i t y t o concent r at e, and r ecur r ent t hought s of sui ci de, deat h, or
sui ci de at t empt .
1

P. 1043


2. Sympt oms shoul d i mpai r soci al or occupat i onal f unct i oni ng and shoul d not be
r el at ed t o a gener al medi cal condi t i on or subst ance abuse.
3. Pat i ent s pr esent i ng wi t h excessi ve sedat i on ( hyper somni a) , i ncr eased appet i t e,
wei ght gai n, and agi t at i on ar e cl assi f i ed as exper i enci ng at ypi cal depr essi on.
E. Treat ment opt i ons. Thr ee t r eat ment opt i ons exi st f or t he t r eat ment of
depr essi on: pharmacot herapy, psychot herapy, and eI ect roconvuI si ve t herapy
( ECT) . The choi ce of whi ch t r eat ment opt i on or combi nat i on of t r eat ment opt i ons t o
use shoul d be pat i ent speci f i c and i nf l uenced by t he sever i t y of sympt oms and
pat i ent pr ef er ence.
1. Pharmacot herapy opt i ons ( anti depressant s) . Phar macot her apy can be used f or
mi l d t o sever e maj or depr essi on and pr oduces a r esponse i n 40%- 70% of pat i ent s.
Ant i depr essant s have si mi l ar ef f i cacy; however , t hey di f f er i n adver se ef f ect s,
mechani sm of act i on, medi cat i on i nt er act i ons, and cost . Ther ef or e, sel ect i on of
phar macol ogi c agent s f or pat i ent s shoul d be based on t he speci f i c sympt oms t he
pat i ent i s exper i enci ng, adver se ef f ect s of t he medi cat i ons, medi cat i on i nt er act i ons,
pat i ent pr ef er ence, and abi l i t y of pat i ent t o af f or d t he medi cat i on. Pat i ent s wi t h a
hi st or y of r esponse t o a par t i cul ar agent may r est ar t t hat agent i f desi r ed.
a. Monoami ne oxi dase i nhi bi tors (MAOI s) ( Tabl e 48- 1)
( 1) I ndi cat i ons. MOAÌ s have numer ous adver se ef f ect s and medi cat i on i nt er act i ons
and ar e i ndi cat ed onl y i n pat i ent s ref r act or y t o ot her ant i depr essant s. These agent s
al so have a r ol e i n pat i ent s pr esent i ng wi t h at ypi cal depr essi on.
( 2) Mechani sm of act i on. MOAÌ s i nhi bi t monoami ne oxi dase, whi ch i s r esponsi bl e
f or t he br eakdown of neur ot r ansmi t t er s such as DA, 5- HT, and NE. By bl ocki ng t hi s
enzyme, l evel s of t hese ami nes i ncr ease i n t he br ai n.
( 3) Adverse ef f ect s. MAOÌ s have numer ous adver se ef f ect s t hat l i mi t t hei r use.
These i ncl ude hyper t ensi ve cr i ses, ser ot oni n syndr ome, or t host at i c hypot ensi on,
per i pher al edema, wei ght gai n, and sexual dysf unct i on.
( a) Hypert ensi ve cri ses can occur when i ncr eased l evel s of sympat het i c ami nes,
such as NE, bui l d up i n t he body, whi ch can be t he r esul t of i ngest i on of t yr ami ne-
cont ai ni ng f oods l i ke wi ne and cheese or t he admi ni st r at i on of sympat homi met i c
agent s ( e. g. , decongest ant s) . Pat i ent s shoul d be counsel ed r egar di ng t he r i sk f or
dr ug and f ood i nt er act i ons when t aki ng MAOÌ s.
( b) Serot oni n syndrome can occur when l evel s of 5- HT become t oo hi gh, usual l y as
t he r esul t of t he use of mul t i pl e ser ot oner gi c agent s. MAOÌ s i n combi nat i on wi t h
sel ect i ve ser ot oni n- r eupt ake i nhi bi t or s, t r i cycl i c ami nes, serot oni n and
nor epi nephr i ne r eupt ake i nhi bi t or s, and any ot her agent wi t h ser ot oner gi c act i vi t y
can l ead t o ser ot oni n syndr ome. The cl i ni cal mani f est at i ons of ser ot oni n syndr ome
ar e gi ven i n Tabl e 48- 2.
b. Many t ri cycI i c ami nes ( TCAs) ar e commer ci al l y avai l abl e i n t he Uni t ed St at es
and can be cl assi f i ed as t er t i ar y and secondar y ( Tabl e 48- 3) .
( 1) I ndi cat i ons. Owi ng t o t hei r numer ous adver se ef f ect s, TCAs ar e not usual l y
i ndi cat ed f i r st - l i ne f or t he t r eat ment of depr essi on.
( a) TCAs may be consi der ed f or pat i ent s wi t h a hi st or y of r esponse t o TCAs,
pat i ent s r ef ract or y t o ot her medi cat i ons, or pat i ent s wi t h co- mor bi di t i es t hat mi ght
benef i t f r om TCAs, such as neur opat hi c pai n and mi gr ai nes.
( b) TCAs shoul d not be used i n pat i ent s wi t h sui ci dal i deat i ons and shoul d pr obabl y
be avoi ded i n pat i ent s wi t h car di ovascul ar condi t i ons, cl osed angl e gl aucoma,
ur i nar y r et ent i on, or sever e pr ost at e hyper t r ophy.
Table 48-1. Monoamine Oxidase Inhibitors
Agent
Starting
Dose
(mg/day
)
Dose
Range
a
(mg/day
)
Anticholinergi
c Effects
Sedatio
n
Weight
Gain
Phenelzine
(Nardil) 10 15-90 ¹¹ ¹¹
¹¹
¹
Isocarboxazid
(Marplan) 20 20-40 ¹¹ ¹¹ ¹¹
Tranylcypromin
e (Parnate) 10 10-40 ¹¹ ¹ ¹¹
Selegiline
(Emsam) patch 6 6-12 ¹¹ 0 ¹
a
For normal adults. Doses may need to be adiusted Ior elderly patients or
those with impaired renal or hepatic Iunction.
¹¹¹. high; ¹¹. moderate; ¹. slight.

P. 1044


Table 48-2. Signs and Symptoms of Serotonin Syndrome
Cognitive-Behavioral
Dysfunction
Autonomic Nervous System
Dysfunction
Neuromuscular
Dysfunction
ConIusion Diarrhea Myoclonus
Hypomania Shivering HyperreIlexia
Agitation Fever Tremor
Diaphoresis Seizure
Change in blood pressure Death
Nausea and vomiting

( 2) Mechani sm of act i on. TCAs pr oduce t hei r ant i depr essant ef f ect by i nhi bi t i ng t he
r eupt ake of 5- HT and NE. TCAs al so have ef f ect at q- adr ener gi c, hi st ami ne, and
chol i ner gi c r ecept or s. Ì ndi vi dual TCAs have di f f er ent af f i ni t i es f or t hese r ecept or s.
( 3) Adverse ef f ect s. Sever al adver se ef f ect s exi st f or TCAs and may di f f er bet ween
agent s, dependi ng on t hei r af f i ni t y f or q- adr ener gi c, chol i ner gi c, and hi st ami ne
r ecept or s ( Tabl e 48- 3) .
( a) Ter t i ar y TCAs have been associ at ed wi t h a hi gher ri sk of causi ng ant i chol i ner gi c
adver se ef f ect s ( bl ur r ed vi si on, const i pat i on, ur i nar y r et ent i on, dr y mout h) ,
sedat i on, wei ght gai n, and or t host at i c hypot ensi on t han secondar y TCAs.
( b) Addi t i onal adver se ef f ect s i ncl ude t achycar di a, QT pr ol ongat i on, car di ac
conduct i on abnor mal i t i es, decr eased sei zur e t hr eshol d, and sexual dysf unct i on.
TCAs may be l et hal when t aken as an over dose.
( c) Owi ng t o t hei r act i vi t y on ser ot oni n, TCAs have t he pot ent i al f or causi ng
ser ot oni n syndr ome when used i n combi nat i on wi t h ot her serot oner gi c agent s.
( 4) Medi cat i on i nt eract i ons. TCAs ar e subst r at es of var i ous cyt ochr ome P450
enzymes and l evel s can be af f ect ed by enzyme i nhi bi t or s and i nducer s.
c. SeI ect i ve serot oni n reupt ake i nhi bi t ors ( SSRI s) . Fi ve SSRÌ s ar e cur r ent l y
avai l abl e i n t he Uni t ed St at es f or t he t r eat ment of depr essi on (Tabl e 48- 4) :
f l uoxet i ne ( Pr ozac) , paroxet i ne ( Paxi l ) , ser t r al i ne ( Zol of t ), ci t al opr am (Cel exa) , and
esci t al opr am ( Lexapr o) . These medi cat i ons ar e consi der ed t o be f i r st l i ne f or t he
t r eat ment of depr essi on, and many ar e al so
P. 1045

i ndi cat ed f or anxi et y, pani c di sor der , post - t r aumat i c st r ess di sor der , and obsessi ve-
compul si ve di sor der .
Table 48-3. Tricyclic Amines
Agent
Dose
Range
a

(mg/day
)
Anticholinerg
ic Effects Sedation
Orthostatic
Hypotensio
n
Cardiac
Effects
Weight
Gain
Tertiary
amine

Amitriptyli
ne (Elavil)
50-
300
¹¹¹¹ ¹¹¹
¹
¹¹¹¹ ¹¹
¹
¹¹¹
¹
Doxepin
(Sinequan)
50-
300
¹¹¹ ¹¹¹
¹
¹¹ ¹¹ ¹¹¹
¹
Imipramine
(ToIranil)
50-
300
¹¹¹ ¹¹¹ ¹¹¹¹ ¹¹
¹
¹¹¹
¹
Trimiprami
ne
(Surmontil)
50-
300
¹¹¹¹ ¹¹¹
¹
¹¹¹ ¹¹
¹
¹¹¹
¹
Secondary
amine

Nortriptylin
e (Pamelor)
25-
150
¹¹ ¹¹ ¹ ¹¹ ¹
Desipramin
e
(Norpramin
)
50-
300
¹ ¹¹ ¹¹ ¹¹ ¹
Protriptylin
e (Vivactil)
10-
60
¹¹ ¹ ¹¹ ¹¹
¹
¹
a
For normal adults. Doses may need to be adiusted Ior elderly patients or
those with impaired renal or hepatic Iunction.
¹¹¹¹. very high; ¹¹¹. high; ¹¹. moderate; ¹. slight.

Table 48-4. Selective Serotonin Reuptake Inhibitors and Serotonin and
Norepinephrine Reuptake Inhibitors
Agent
Starting
Dose
(mg/day)
Dose Range
(mg/day) Half-Life
CYP450 Isoenzyme
Inhibition
Fluoxetine
(Prozac)
10-20 20-80; 90
mg
weekly
a

7-9
days
b

2D6. 2C9/19
(potent); 3A4
(mild)
Paroxetine
(Paxil)
10-20 20-60 21 hr 2D6 (potent)
Sertraline
(ZoloIt)
25-50 50-200 24 hr 2D6 (mild)
Citalopram
(Celexa)
10-20 20-60 35 hr 2D6 (mild)
Escitalopram
(Lexapro)
5-10 10-20 27-32
hr
2D6 (mild)
VenlaIaxine
(EIIexor)
75 150-375 11 hr 2D6 (mild)
Duloxetine
(Cymbalta)
40 40-60 9-19
hr
2D6 (moderate)
a
Fluoxetine can be given in a once-weekly Iormulation in patients stabilized
on Iluoxetine 20 mg daily; should be started 1 week aIter the last dose oI
Iluoxetine.

b
NorIluoxetine is an active metabolite oI Iluoxetine and has a halI-liIe oI 7-9
days. The halI-liIe oI Iluoxetine alone is 2-3 days.
CYP450. cytochrome P450.

( 1) Mechani sm of act i on. SSRÌ s exer t t hei r ant i depr essant ef f ect by bl ocki ng t he
r eupt ake of ser ot oni n.
( 2) Adverse ef f ect s
( a) SSRÌ s have been associ at ed wi t h nausea, vomi t i ng, i nsomni a, sedat i on, sexual
dysf unct i on, headache, agi t at i on, and t r emor .
( b) Par oxet i ne has al so been associ at ed wi t h ant i chol i ner gi c adver se ef f ect s, such
as bl ur r ed vi si on, dr y mout h, const i pat i on, and ur i nar y r et ent i on.
( c) These agent s have been associ at ed wi t h ser ot oni n syndr ome when used i n
combi nat i on wi t h ot her ser ot oner gi c agent s.
( 3) Many SSRÌ s ar e subst r at es and i nhi bi t or s of t he cyt ochr ome P450 syst em and
may i nt er act wi t h ot her medi cat i ons.
( 4) Abr upt di scont i nuat i on of SSRÌ s has been associ at ed wi t h wi t hdrawaI
sympt oms, such as ni ght mar es, vi vi d dr eams, t r emor , anxi et y, nausea, and poor
concent r at i on. Fl uoxet i ne has l i t t l e r i sk of causi ng syndr ome upon di scont i nuat i on,
l i kel y because of i t s l ong hal f - l i f e. Wi t h t he except i on of f l uoxet i ne, SSRÌ s shoul d be
sl owl y t aper ed when di scont i nued t o pr event t hi s syndr ome.
d. Serot oni n and norepi nephri ne reupt ake i nhi bi t ors ( SNRI s) (Tabl e 48- 4) . Two
SNRÌ s ar e cur r ent l y avai l abl e f or t he t r eat ment of depr essi on: venl af axi ne ( Ef f exor )
and dul oxet i ne ( Cymbal t a) . Dat a have shown t hese medi cat i ons t o have ef f i cacy f or
t he t r eat ment not onl y of depr essi on but al so of pai nf ul per i pher al neur opat hi es.
Dul oxet i ne car r i es a U. S. Food and Dr ug Admi ni st r at i on ( FDA) i ndi cat i on f or t he
t r eat ment of pai n i n di abet i c neur opat hy.
( 1) Mechani sm of act i on. SNRÌ s i nhi bi t t he r eupt ake of 5- HT and NE, t her eby
i ncr easi ng t hei r l evel s. These medi cat i ons di f f er f r om TCAs i n t hat t hey have l i t t l e
act i vi t y f or q- adr ener gi c, chol i ner gi c, or hi st ami ne r ecept or s.
( 2) Adverse ef f ect s. SNRÌ s have an adver se ef f ect pr of i l e si mi l ar t o t hat of t he
SSRÌ s. Common adver se ef f ect s i ncl ude nausea, headache, somnol ence, dr y mout h,
di zzi ness, sexual dysf unct i on, and i nsomni a. Venl af axi ne and dul oxet i ne have al so
been associ at ed wi t h el evat i ons of di ast ol i c bl ood pr essur e, par t i cul ar l y wi t h hi gher
doses.
( 3) Medi cat i on i nt eract i ons. Venl af axi ne and dul oxet i ne ar e bot h subst r at es f or t he
cyt ochr ome P450 i soenzyme syst em and ar e mi l d t o moder at e i nhi bi t or s of t he
i soenzyme 2D6 ( Tabl e 48- 4) . SNRÌ s shoul d not be used wi t h MAOÌ s or ot her
ser ot oner gi c agent s owi ng t o r i sk of ser ot oni n syndr ome.
e. Bupropi on (WeI I but ri n) (Tabl e 48- 5) .
( 1) The mechani sm of act i on f or bupr opi on i s not compl et el y under st ood.
Bupr opi on i s known t o i nhi bi t t he r eupt ake of dopami ne and t o a smal l er ext ent t he
r eupt ake of ser ot oni n and nor epi nephr i ne.
P. 1046


Table 48-5. Miscellaneous Antidepressants
Agent
Starting Dose
(mg/day)
Dose Range
(mg/day)
Cytochrome P450
Isoenzyme Inhibition
Bupropion
(Wellbutrin) 75-150 200-450 2D6
Mirtazapine
(Remeron) 15 30-45 Does not inhibit
Trazodone
(Desyrel) 50-100 150-600 Does not inhibit

( 2) Ì n addi t i on t o i t s i ndi cat i on f or depr essi on, bupr opi on i s al so i ndi cat ed f or
smoki ng cessat i on.
( 3) Common adverse ef f ect s associ at ed wi t h t he use of bupr opi on i ncl ude nausea,
vomi t i ng, and i nsomni a.
( a) Bupr opi on has been associ at ed wi t h l ess sexual dysf unct i on t han many ot her
ant i depr essant medi cat i ons, such as SSRÌ s.
( b) Bupr opi on has been associ at ed wi t h an i ncr eased r i sk f or sei zur es and i s
cont r ai ndi cat ed i n pat i ent s at r i sk f or sei zur es. Thi s i ncl udes pat i ent s wi t h t he
f ol l owi ng medi cal di sor der s: sei zure di sor der , hi st or y of anor exi a or bul i mi a, or
usi ng or wi t hdr awi ng f r om medi cat i ons such as al cohol or benzodi azepi nes. Doses >
450 mg shoul d not be used, and dose i ncr eases shoul d be gr adual .
f . Mi rt azapi ne ( Remeron) (Tabl e 48- 5) .
( 1) Mi r t azapi ne ant agoni zes q- adr ener gi c and 5HT
2, 3
- r ecept or s, causi ng an i ncr ease
i n l evel s of NE and 5- HT. Ì n addi t i on, mi r t azapi ne has act i vi t y at hi st ami ne( H)
r ecept or s.
( 2) Adverse ef f ect s f or mi r t azapi ne i ncl ude sedat i on, wei ght gai n, const i pat i on, dr y
mout h, and i ncr eased appet i t e. Sedat i on, i ncr eased appet i t e, and wei ght gai n can
be pr obl emat i c, par t i cul ar l y at l ower doses. Mi r t azapi ne has a l ower r i sk f or causi ng
sexual dysf unct i on as compar ed t o SSRÌ s.
g. Trazodone ( DesyreI ) (Tabl e 48-5) .
( 1) The mechani sm of act i on f or t r azodone i s not compl et el y under st ood, but i s
t hought t o be owi ng an i ncr ease i n 5- HT.
( 2) Tr azodone i s i ndi cat ed f or t he t r eat ment of depr essi on, al t hough i t i s not
f r equent l y used because of sedat i on. Ì t i s mor e f r equent l y used i n l ow doses as
adj unct i ve t r eat ment f or i nsomni a i n depr essed pat i ent s.
( 3) The most common adverse ef f ect s of t r azodone i ncl ude sedat i on, nausea, and
or t host at i c hypot ensi on. Tr azodone has r ar el y been associ at ed wi t h pr i api sm and
QT pr ol ongat i on.
h. Nef azodone ( Serzone) . Nef azodone i s a medi cat i on st r uct ur al l y si mi l ar t o
t r azodone. Ì t was consi der ed t o be f i r st l i ne f or t r eat ment of depr essi on; however ,
r ecent r epor t s of hepat ot oxi ci t y have l i mi t ed i t s use and l ed t o a bI ack box warni ng
f or possi bl e l i ver f ai l ur e l eadi ng t o deat h.
( 1) Nef azodone i nhi bi t s 5- HT2-r ecept or s and bl ocks t he r eupt ake of NE and 5- HT.
( 2) Adverse ef f ect s. Common adver se ef f ect s f or nef azodone i ncl ude dr y mout h,
nausea, const i pat i on, ort host at i c hypot ensi on, and sedat i on. The most sever e
adver se ef f ect associ at ed wi t h nef azodone i s hepat i c f ai l ur e.
( a) Repor t ed r at es by t he FDA est i mat e 1 case of l i ver f ai l ur e r esul t i ng i n deat h or
t r anspl ant per 250, 000- 350, 000 pat i ent - year s.
( b) No known pr edi cat or s f or t he devel opment of l i ver f ai l ur e ar e avai l abl e. Ì f
nef azodone i s used, l i ver f unct i on enzymes shoul d be moni t or ed r out i nel y.
( c) The gener i c pr oduct i s st i l l avai l abl e, al t hough br and name nef azodone was
wi t hdr awn f r om t he U. S. mar ket i n 2004.
( 3) Nef azodone i s hi ghl y pr ot ei n bound and i s an i nhi bi t or of cyt ochr ome P450
i soenzyme 3A4, l eadi ng t o t he pot ent i al f or mul t i pl e dr ug- dr ug i nt er act i ons.
2. Durat i on of t reat ment . Tr eat ment i s di vi ded i nt o t hr ee phases: acut e phase,
cont i nuat i on phase, and mai nt enance phase.
a. The acute phase begi ns wi t h t he i ni t i at i on of t her apy unt i l r emi ssi on i s r eached,
t ypi cal l y l ast i ng bet ween 6 and 12 weeks.
b. The conti nuati on phase begi ns af t er r emi ssi on i s r eached and t ypi cal l y l ast s
bet ween 6 and 9 mont hs. Medi cat i on f r om t he acut e phase i s cont i nued dur i ng t hi s
phase t o pr event r el apse of depr essi on.
P. 1047


c. A mai nt enance phase i s used i n pat i ent s wi t h a hi gh r i sk of r ecurr ence of
depr essi on, such as t hose wi t h a hi st or y of mul t i pl e epi sodes of depr essi on, hi st or y
of sui ci dal t hought s, and sever e depr essi on. These pat i ent s shoul d r ecei ve
mai nt enance t r eat ment f or 2- 3 year s, and many may r ecei ve l i f e- l ong t her apy.
3. Admi ni st rat i on and dosage
( a) Ant i depr essant s ar e usual l y st ar t ed at l ow doses and sl owl y t i t r at ed up t o r each
t ar get doses over a per i od of a f ew weeks t o pr event adver se r eact i ons. Cl i ni cal
r esponse det er mi nes i f t he dose shoul d be f ur t her t i t r at ed. Whi l e f ul l ef f ect s may not
be seen f or 4- 6 weeks, of t en some si gns and sympt oms of depr essi on such as
i nsomni a may r esol ve mor e r api dl y. Pat i ent s must r ecei ve maxi mum t ol er at ed doses
f or 4- 6 weeks wi t hout r esponse t o be cl assi f i ed as i nef f ect i ve.
( b) Ì f pat i ent s r ecei ve onl y a par t i al or no r esponse, ot her ant i depr essant s may be
consi der ed. When changi ng t o anot her ant i depr essant agent , caut i on shoul d be
used t o pr event ser ot oni n syndr ome. These gui del i nes shoul d be f ol l owed i f
changi ng t o or f r om a MAOÌ :
( 1) A 2- week washout per i od shoul d be obser ved when changi ng t o a MAOÌ f r om an
ant i depr essant wi t hout a l ong hal f - l i f e and when changi ng f r om a MAOÌ t o anot her
ant i depr essant .
( 2) A 5- week washout per i od shoul d be obser ved when changi ng t o a MAOÌ f r om an
ant i depr essant wi t h a l ong hal f - l i f e, such as f l uoxet i ne.
4. Augment at i on of t herapy. When pat i ent s f ai l t o f ul l y or par t i al l y r espond t o t wo
or mor e medi cat i ons, augment at i on of ant i depressant t her apy wi t h anot her agent
may be consi der ed.
( a) Li t hi um and t hyr oi d hor mone have been used f or augment at i on of ant i depr essant
medi cat i ons. Li t hi um augment at i on i s cur r ent l y pr ef er r ed over t hyr oi d augment at i on.
( b) Dual ant i depr essant augment at i on has al so been used. Agent s t hat have been
used i ncl ude bupr opi on, TCAs, and mi r t azapi ne.
5. Sui ci de ri sk. Ri sk of sui ci de i s al ways a concer n i n pat i ent s suf f er i ng f r om a
maj or depr essi ve epi sode. Ì n adol escent s and chi l dr en, r ecent st udi es have shown a
l i nk bet ween ant i depr essant use and r i sk of i ncr eased sui ci dal t hought s and act i ons.
Because of t hi s i ncr eased r i sk, t he FDA has now i ssued a bI ack box warni ng f or al l
ant i depr essant s t hat an i ncr ease i n sui ci dal t hought s and act i ons may occur wi t h
t her apy and t hat adol escent s and chi l dr en r ecei vi ng t hi s t her apy shoul d be cl osel y
moni t or ed.
III. BIPOLAR DISORDER
A. Def i ni t i on. Bi pol ar di sor der or mani c depr essi on i s a syndr ome i n whi ch pat i ent s
suf f er f r om epi sodes of mani a and depr essi on. Mani a i s an unusual l y el evat ed mood
and i s descr i bed i n gr eat er det ai l i n Ì Ì Ì . D. 1.
B. Epi demi oI ogy
1. Bi pol ar Ì and Ì Ì di sorder s af f ect 3. 7%- 3. 9% of t he U. S. popul at i on. Ì n pat i ent s
pr esent i ng wi t h depr essi on, 21%- 49% of pat i ent s have bi pol ar di sor der .
2. Bi pol ar Ì di sor der occur s equal l y i n men and women al t hough bi pol ar Ì Ì di sor der
t ends t o occur mor e commonl y i n women.
3. Al t hough pat i ent s may pr esent wi t h bi pol ar di sor der at any age, most pat i ent s
have an aver age age of onset of 21 year s, wi t h peak onset occur r i ng bet ween t he
ages of 15 and 24 years.
4. Sui ci de occur s i n 10%- 15% of pat i ent s wi t h bi pol ar Ì di sor der .
C. Pat hophysi oI ogy. As wi t h many psychi at r i c di sor der s, t he pat hophysi ol ogy f or
bi pol ar di sor der i s not compl et el y under st ood, al t hough many t heor i es exi st .
1. A posi t i ve f ami l y hi st or y i s pr esent i n 80%- 90% of pat i ent s wi t h bi pol ar di sor der .
Ther ef or e, genet i cs i s bel i eved t o pl ay a r ol e i n i t s pat hophysi ol ogy, al t hough a
di r ect genet i c l i nk has not been di scover ed.
P. 1048


2. Li ke maj or depr essi on, bi pol ar di sor der i s bel i eved t o be caused by an i mbaI ance
of neurot ransmi t t ers. However , i n bi pol ar di sor der , t he neur ot r ansmi t t er l evel s
f l uct uat e and may be si mi l ar or r ever sed, dependi ng on t he pat i ent ' s cur r ent cl i ni cal
pr esent at i on.
a. A mani c epi sode i s bel i eved t o r esul t f r om el evat i ons i n NE.
b. Depr essi on has been associ at ed wi t h a decr ease i n NE.
3. A dysr egul at i on of v- ami nobut yri c aci d ( GABA) may pl ay a r ol e i n bi pol ar
di sor der . A def i ci ency i n GABA, an i nhi bi t or y neur ot r ansmi t t er , may l ead t o mani a
caused by unopposed exci t at or y neur ot r ansmi t t er s, such as DA and NE.
4. Ì ncr eased and decr eased l evel s of caI ci um i n t he cer ebr ospi nal f l ui d ( CSF) have
been det ect ed i n depr essed and mani c i ndi vi dual s, r espect i vel y. Changes i n t he
ext r acel l ul ar and i nt r acel l ul ar cal ci um l evel s, whi ch can af f ect t he exci t abi l i t y of
neur ons, may be a f act or i n emot i onal var i at i ons and swi t ches f r om depr essi on t o
mani a.
5. Recent r esear ch has f ocused on G prot ei ns and t hei r ef f ect s on mood
st abi l i zat i on. G pr ot ei ns ar e i nvol ved i n si gnal t r ansduct i on and act i vat i on of second
messenger syst ems f or var i ous neur ot r ansmi t t er s, l i ke NE, 5- HT, and DA.
a. The cur r ent t heor y pr oposes t hat hyper act i ve G pr ot ei ns cause mood i nst abi l i t y;
and by nor mal i zi ng G pr ot ei ns, mood st abi l i t y wi l l occur .
b. G pr ot ei ns and gl ut amat e may al so pl ay a r ol e i n t he l ong- t er m pot ent i at i on and
cycl i ng of mood di sor der s.
( 1) Gl ut amat e bi ndi ng t o G pr ot ei ns l i nked t o N- met hyl - D- aspar t at e ( NMDA)
r ecept or s may be i nvol ved i n l ong- t er m pot ent i at i on.
( 2) Ser ot oni n and NE ar e i nvol ved i n bi pol ar i l l ness, but t he cycl i ng and l ong- t er m
pot ent i at i on may be medi at ed by gl ut amat e and t he medi cat i ons t hat af f ect t he
gl ut amat e syst em.
6. Psychosoci aI and physi caI st ressors have been pr oposed t o t r i gger ear l y
epi sodes of bi pol ar di sor der , al t hough t hese st r essor s may or may not t r i gger l at er
epi sodes. These l at er epi sodes and cycl i c epi sodes ar e t hought t o be caused by
i ncr eased sensi t i vi t y or el ect r ophysi ol ogi c ki ndl i ng of t he brai n.
D. Di agnosi s. Bi pol ar di sor der i s di agnosed usi ng DSM- Ì V-TR cr i t er i a. The
sympt oms shoul d i mpai r soci al or occupat i onal f unct i oni ng and shoul d not be r el at ed
t o a gener al medi cal condi t i on or use of a subst ance.
1. Mani a i s descr i bed as at l east a 1- week per i od of a cont i nuousl y el evat ed or
i r r i t abl e mood, al t hough shor t er dur at i ons of sympt oms ar e accept abl e i f t he pat i ent
i s hospi t al i zed. Ì n addi t i on t o el evat ed mood, t he pat i ent shoul d exper i ence at l east
t hr ee of t he f ol l owi ng sympt oms: el evat ed sel f - est eem or grandi ose i deat i ons,
r educed need f or sl eep, pr essur ed speech, r aci ng t hought s or f l i ght of i deas, easi l y
di st r act ed, psychomot or agi t at i on, and excessi ve i nvol vement i n hi gh r i sk act i vi t i es.
2

2. Hypomani a has si mi l ar sympt oms t o t hat of mani a; however , sympt oms ar e not
as sever e. Hypomani a i s di agnosed by an el evat ed mood pr esent f or at l east 4 days,
wi t h at l east t hr ee of t he same sympt oms as descr i bed f or mani a. These sympt oms
shoul d not i nt er f er e wi t h soci al or occupat i onal f unct i oni ng and shoul d not cause
hospi t al i zat i on.
2. A mi xed di sorder i s di agnosed when t he cr i t er i a f or bot h mani a and a maj or
depr essi ve epi sode ar e met ever y day f or near l y 1 week, af f ect s soci al and
occupat i onal f unct i oni ng, and i s not caused by a gener al medi cal condi t i on or
subst ance.
3. Bi pol ar di sor der may be cl assi f i ed i nt o bi pol ar Ì di sor der , bi pol ar Ì Ì di sor der ,
cycl ot hymi a, and r api d cycl i ng.
a. Bi poI ar I di sorder. Pat i ent s ar e cl assi f i ed wi t h bi pol ar Ì di sor der wi t h a hi st or y of
at l east one mi xed or mani c epi sode and at l east one maj or depr essi ve epi sode.
b. Bi poI ar I I di sorder. Pat i ent s ar e cl assi f i ed wi t h bi pol ar Ì Ì di sor der wi t h a hi st or y
of at l east one epi sode of hypomani a and one maj or depr essi ve epi sode but have
never exper i enced mani a or a mi xed epi sode.
P. 1049


c. CycI ot hymi c di sorder. Pat i ent s ar e cl assi f i ed wi t h cycl ot hymi c di sor der wi t h at
l east a 2- year hi st or y of mul t i pl e epi sodes of hypomani a and depr essi ve sympt oms.
These pat i ent s have never met f ul l cr i t er i a f or a maj or depr essi ve or mani c epi sode.
d. Rapi d cycI i ng. Pat i ent s t hat exper i ence at l east f our depr essi ve, mani c,
hypomani c, or mi xed epi sodes wi t hi n a 12- mont h per i od of t i me ar e descr i bed as
r api d cycl i ng.
E. CI i ni caI course. The cour se of bi pol ar di sor der i s var i abl e and pat i ent speci f i c.
1. Pat i ent s f r equent l y pr esent wi t h epi sodes of depr essi on. Pat i ent s pr esent i ng wi t h
depr essi on shoul d al ways be quest i oned f or a hi st or y of si gns and sympt oms of
mani a.
2. Epi sodes var y i n l engt h and sever i t y; however , t hey may l ast f r om days t o mont hs
i f unt r eat ed.
3. The dur at i on of t i me bet ween epi sodes var i es. Commonl y, 4 year s or mor e may
separ at e t he f i r st and second epi sode but subsequent epi sodes ar e mor e f r equent .
Unt r eat ed pat i ent s may exper i ence 10 or mor e epi sodes dur i ng t hei r l i f e.
4. The management of t hi s di sor der can be compl i cat ed by mi xed epi sodes, r api d
cycl i ng, and subst ance abuse.
F. Treat ment opt i ons
1. Pharmacot herapeut i c opt i ons. Mood st abi l i zer s have hi st or i cal l y been t he
mai nst ays of t her apy f or bi pol ar di sor der . Agent s i ncl ude l i t hi um ( Eskal i t h,
Li t honat e, Li t hobi d) , val pr oi c aci d ( Depakene, Depakot e) , and car bamazepi ne
( Tegr et ol , Car bat r ol , Equet r o) . Recent l i t er at ur e has suppor t ed t he use of at ypi cal
ant i psychot i cs as monot her apy or adj unct i ve t r eat ment s i n bi pol ar mani a. Agent s f or
t he t r eat ment of depr essi ve epi sodes i n pat i ent s wi t h bi pol ar r emai ns mor e l i mi t ed,
wi t h r ecent dat a emer gi ng f or l amot r i gi ne ( Lami ct al ) , quet i api ne ( Ser oquel ) , and
ol anzapi ne- f l uoxet i ne ( Symbyax) . The 2005 Texas Ì mpl ement at i on of Medi cat i on
Al gor i t hms updat e f or t he t r eat ment of bi pol ar Ì di sor der i s summar i zed i n Tabl e 48-
6.
a. Li thi um i s a f i rst - l i ne agent f or t he acut e and mai nt enance t r eat ment of mani a
and hypomani a. Ì t i s al so f i r st - l i ne f or t he mai nt enance t r eat ment of mi xed epi sodes
and i s usef ul as adj unct i ve t r eat ment i n depr essi ve epi sodes.
( 1) Li t hi um i s avai l abl e as l i t hi um car bonat e and l i t hi um ci t r at e. Li t hi um car bonat e i s
avai l abl e as r egul ar ( Eskal i t h) , cont r ol l ed- r el ease ( Eskal i t h CR) , or ext ended
r el ease ( Li t hobi d) t abl et s and l i t hi um ci t r at e ( Li t honat e) i s avai l abl e as syr up.
( 2) Pharmacoki net i cs
( a) Bet ween 60% and 100% of l i t hi um i s absor bed f r om t he gast r oi nt est i nal t r act .
The ext ent of absor pt i on i s not af f ect ed by f ood. The r at e of absor pt i on var i es,
dependi ng on t he f or mul at i on.
( i ) Li t hi um ci t r at e syr up r eaches peak concent r at i ons i n 15- 60 mi n.
( i i ) Ì mmedi at e- r el ease t abl et s and capsul es peak i n 1- 3 hr .
( i i i ) Ext ended- r el ease t abl et s have peak concent r at i ons i n 4- 12 hr .
( b) Li t hi um i s di st r i but ed i nt o t ot al body wat er and penet r at es many body t i ssues,
such as t he t hyr oi d, bone, and br ai n. Li t hi um i s not hi ghl y pr ot ei n bound.
Table 48-6. Algorithms for Treatment of Bipolar I Disorder
Type of Episode
Monotherapy Options First-
Line
Monotherapy Options
Second-Line
Acute mania Lithium. VPA. aripiprazole.
quetiapine. risperidone.
ziprasidone
Olanzapine. CBZ
Acute mixed VPA. aripiprazole.
quetiapine. risperidone.
ziprasidone
Olanzapine. CBZ
Acute depressive Lamotrigine or lamotrigine
plus anti-manic
Quetiapine.
olanzapine-
Iluoxetine
Maintenance
mania or mixed
Lithium. VPA. or
lamotrigine
Olanzapine
Depression Lamotrigine plus anti-manic
or lamotrigine
CBZ. carbamazepine; JPA. valproic acid.
Adapted Irom Suppes T. Dennehy EB. HirschIeld RM. et al. The Texas
implementation oI medication algorithms: Update to the algorithm Ior
treatment oI bipolar I disorder. J Clin Psychiatry 2005;66:870-886.

P. 1050


( c) Li t hi um i s el i mi nat ed pr i mar i l y t hr ough t he ki dneys. Ì t i s f i l t er ed by t he gl omer ul i
i n t he ki dneys and i s al so cl ear ed by r enal t ubul ar r eabsor pt i on. Changes i n r enal
f unct i on can si gni f i cant l y af f ect t he cl ear ance of l i t hi um.
( 3) The mechani sm of act i on f or l i t hi um i s cur r ent l y unknown, al t hough sever al
t heor i es exi st .
( a) Li t hi um i s t hought t o hel p cor r ect desynchr oni zed bi ol ogi cal r hyt hms i n pat i ent s
wi t h bi pol ar di sor der .
( b) Li t hi um may af f ect membr ane st abi l i zat i on.
( c) Li t hi um may augment homeost asi s by enhanci ng t he f unct i on of secondar y
messenger syst ems, especi al l y cycl i c adenosi ne monophosphat e ( cAMP) , cycl i c
guanosi ne monophosphat e ( cGMP) , and phosphat i dyl i nosi t ol .
( d) Li t hi um can i nhi bi t NE r el ease and accel er at e i t s met abol i sm.
( e) Li t hi um may decr ease r ecept or sensi t i vi t y and i ncr ease pr esynapt i c r eupt ake of
NE and 5- HT.
( 4) Li t hi um has a narrow t herapeut i c i ndex, wi t h a t her apeut i c r ange of 0. 5- 1. 2
mEq/ L. Toxi ci t y i s associ at ed wi t h l evel s > 1. 5 mEq/ L. Pat i ent s pr esent i ng wi t h
acut e mani a gener al l y r equi r e l evel s i n t he hi gher end of t he t her apeut i c r ange t han
t hose on mai nt enance t her apy.
( a) Pat i ent s ar e gener al l y st ar t ed on 300 mg t wo t o t hr ee t i mes dai l y of l i t hi um and
t i t r at ed up by 300 mg i ncr ement s as needed t o achi eve t her apeut i c ef f ect s and
mi ni mi ze t oxi ci t y.
( b) Pat i ent - speci f i c f act or s shoul d be consi der ed when deci di ng t he appr opr i at e
i ni t i al dose of l i t hi um, such as age, wei ght , and r enal f unct i on.
( c) Ser um concent r at i ons may be moni t or ed 3 days af t er i ni t i at i on t her apy or
changi ng doses. Level s shoul d be obt ai ned 12 hr af t er t he dose, usual l y i n t he
mor ni ng bef or e t he f i r st dose of t he day.
( 5) CI i ni caI response. Cl i ni cal r esponse may be seen wi t hi n 2 weeks af t er l i t hi um
i ni t i at i on f or t he t r eat ment of acut e mani a. When used i n depr essi on, r esponses may
not occur f or 4- 6 weeks.
( 6) Precaut i ons and adverse ef f ect s
( a) Li t hi um has an absol ut e cont r ai ndi cat i on i n pat i ent s exper i enci ng acut e r enal
f ai l ur e or women i n t hei r f i r st t r i mest er of pr egnancy.
( b) Li t hi um has t he f ol l owi ng r el at i ve cont r ai ndi cat i ons: r enal i mpai r ment ,
car di ovascul ar di sease, dehydr at i on, pr egnancy, sei zur e di sor der , and t hyr oi d
di sease.
( c) Li t hi um has numer ous adverse ef f ect s (Tabl e 48- 7) . Cer t ai n adver se ef f ect s
i ndi cat e t oxi ci t y. Ì f t oxi ci t y occur s, l i t hi um shoul d be i mmedi at el y di scont i nued, t he
pat i ent shoul d be pr oper l y hydr at ed, st omach cont ent s shoul d be empt i ed wi t h
gast r i c l avage, and i f sever e t oxi ci t y occur s ( l evel < 3 mEq/ L) , hemodi al ysi s may be
i ndi cat ed.
( 7) Many medi cat i ons and di sease st at es may af f ect l i t hi um l evel s i n t he body
( Tabl e 48- 8) .
( a) Use of l i t hi um wi t h ant i psychot i cs or benzodi azepi nes may i ncr ease t he r i sk f or
CNS t oxi ci t y, especi al l y i f used t oget her l ong t er m.
( b) Use of l i t hi um wi t h medi cat i ons t hat can i ncr ease 5- HT may cause ser ot oni n
syndr ome.
Table 48-7. Adverse Effects of Lithium
Early Onset Long-Term Use Toxicity
Gastrointestinal upset Weight gain Severe drowsiness
Nausea Altered taste Coarse hand tremor
Polydipsia Decreased libido Muscle twitching
Nocturia Hypothyroidism Seizures
Dry mouth Rash Choreoathetosis
Hand tremor Acne Vomiting
Leukocytosis Psoriasis ConIusion
Polyuria Alopecia Vertigo

P. 1051


Table 48-8. Factors That Change Lithium Concentrationsa
Increase Lithium Levels Decrease Lithium Levels
Angiotensin-converting enzyme
inhibitors
Angiotensin II receptor blockers
Nonsteroidal anti-inIlammatory
drugs
Thiazides
Dehydration
Renal dysIunction
Sodium loss
Fluoxetine
Acetazolamide
Methylxanthines (e.g.. theophylline.
caIIeine)
Osmotic diuretics
Pregnancy (third trimester)
Sodium supplements
Urine alkalinizers (ex. sodium
bicarbonate)
a
Not an all-inclusive list.

b. VaI proi c aci d ( VPA) i s i ndi cat ed i n t he acut e and chr oni c t r eat ment of mani a,
hypomani a, mi xed di sor der s, and r api d cycl i ng. Ì t i s al so used as adj unct i ve
t r eat ment i n depr essi ve epi sodes ( Tabl e 48- 6) .
( 1) Mechani sm of act i on. The mechani sm of act i on f or VPA i s not ent i r el y known.
Ef f i cacy f or VPA i s t hought t o be r el at ed t o i t s abi l i t y t o i ncr ease l evel s of GABA.
( 2) Many f ormuI at i ons exi st f or VPA. VPA i s f or mul at ed as val pr oi c aci d
( Depakene) i n capsul es and syr up, as di val pr oex i n del ayed- r el ease t abl et s
( Depakot e) and ext ended- r el ease t abl et s ( Depakot e ER) , and as val pr oat e i n
i nt r avenous sol ut i on ( Depacon) .
( 3) VPA i s gener al l y i ni t i at ed at doses of 20 mg/ kg/ day gi ven i n di vi ded doses f or
i npat i ent s and 250 mg t hr ee t i mes dai l y f or out pat i ent s. The cur r ent t herapeut i c
r ange ( 50- 125 µg/ mL) was or i gi nal l y descr i bed f or t he t r eat ment of sei zur e di sor der s
and has not been est abl i shed f or ef f i cacy i n bi pol ar di sor der . However , t hi s r ange
can st i l l be usef ul t o mi ni mi ze t oxi ci t i es and assess compl i ance.
( a) Level s may be f i r st obt ai ned af t er 4- 5 days of t her apy. These val ues shoul d be
r epr esent at i ve of t r ough val ues and ar e f r equent l y obt ai ned i n t he mor ni ngs bef or e
t he f i r st dose of medi cat i on.
( b) Pat i ent s t hat ar e t r eat ed f or 4- 6 weeks wi t h VPA concent r at i ons of 80- 120 µg/ mL
wi t hout cl i ni cal r esponse may be cl assi f i ed as f ai l ur es of VPA t her apy.
( 4) Adverse ef f ect s. Common adver se ef f ect s of VPA i ncl ude nausea, vomi t i ng,
dyspepsi a, sedat i on, el evat ed l i ver enzymes, hai r l oss, and t r emor. Less f r equent
adver se ef f ect s i ncl ude t hr ombocyt openi a, l eukopeni a, pancr eat i t i s, wei ght gai n,
and l i ver f ai l ur e. VPA has al so been associ at ed wi t h pol ycyst i c ovar i an syndr ome i n
women of chi l d- bear i ng age.
( a) Gast r oi nt est i nal adver se ef f ect s may be mi ni mi zed by l ower i ng t he dose or by
usi ng di val pr oex f or mul at i ons i nst ead of val pr oi c aci d or sodi um val pr oat e.
( b) Li ver f unct i on t est s and compl et e bl ood count s shoul d be moni t or ed at basel i ne,
ever y mont h f or t he f i rst 2 mont hs of t her apy, and t hen ever y 6- 12 mont hs
t her eaf t er .
( 5) Medi cat i on i nt eract i ons. VPA has t he pot ent i al f or mul t i pl e dr ug i nt er act i ons.
VPA i s hi ghl y pr ot ei n bound i n t he body, t hus l evel s can i ncr ease i n t he pr esence of
anot her medi cat i on t hat i s hi ghl y pr ot ei n bound. VPA i s al so a subst r at e and
i nhi bi t or of t he cyt ochr ome P450 i soenzyme 2C9 and can pot ent i al l y el evat e l evel s
of ot her medi cat i ons t hat ar e met abol i zed vi a t hi s i soenzyme.
c. Carbamazepi ne ( CBZ) i s i ndi cat ed i n t he t r eat ment of bi pol ar di sor der and i s
consi der ed t o be a second- l i ne agent owi ng t o i t s numer ous adver se ef f ect s and
medi cat i on i nt er act i ons ( Tabl e 48- 6) .
( 1) The mechani sm of act i on f or CBZ i s not compl et el y known; however , i t s
ef f i cacy i n bi pol ar di sor der i s t hought t o be t he r esul t of i t s ef f ect s on GABA and G
pr ot ei nl i nked second messenger syst ems, such as cAMP.
( 2) CBZ shoul d be i ni t i at ed at doses of 200- 600 mg/ day gi ven i n di vi ded doses and
i ncr eased by 200 mg/ day t o usual doses of 800- 1000 mg/ day.
P. 1052


( a) A t her apeut i c r ange of 4- 12 µg/ mL has been descr i bed f or sei zur e di sor der s.
Whi l e cor r el at i on bet ween t hi s r ange and ef f i cacy have not been f ul l y est abl i shed
f or bi pol ar di sor der , i t i s used t o mi ni mi ze adver se ef f ect s.
( b) Level s may be obt ai ned 5- 7 days af t er i ni t i at i ng t her apy. Level s shoul d
cont i nued t o be obt ai ned i n t he f ol l owi ng f ew weeks because CBZ concent r at i ons
wi l l decr ease i n t he body once aut oi nduct i on occur s.
( c) Pat i ent s who ar e t r eat ed f or 4- 6 weeks wi t h CBZ concent r at i ons of 6- 12 µg/ mL
wi t hout cl i ni cal r esponse may be cl assi f i ed as f ai l ur es of CBZ t her apy.
( 3) Adverse ef f ect s. CBZ i s associ at ed wi t h numer ous adver se ef f ect s, many of
whi ch ar e dose r el at ed.
( a) Fr equent adver se ef f ect s i ncl ude di zzi ness, dr owsi ness, at axi a, f at i gue, bl ur r ed
vi si on, di pl opi a, nyst agmus, conf usi on, headache, nausea, vomi t i ng, di ar r hea, and
dyspepsi a. The gast r oi nt est i nal adver se ef f ect s of CBZ ar e of t en dose r el at ed.
( b) Addi t i onal adver se ef f ect s i ncl ude r ash, l eukopeni a, t hr ombocyt openi a,
hyponat r emi a, el evat i on i n l i ver enzymes, and wei ght gai n.
( c) Sever e i di osyncr at i c r eact i ons may al so occur , i ncl udi ng agr anul ocyt osi s,
apl ast i c anemi a, sever e t hr ombocyt openi a, l i ver f ai l ur e, St evens- Johnson syndr ome,
and pancr eat i t i s.
( d) Compl et e bl ood count s, l i ver f unct i on t est s, t hyr oi d t est s, and el ect r ol yt es
shoul d be moni t or ed at basel i ne and ever y 3- 6 mont hs.
( 4) Medi cat i on i nt eract i ons. CBZ i s an i nducer of many hepat i c enzymes
r esponsi bl e f or met abol i sm of medi cat i ons and, t her ef or e, has numer ous medi cat i on
i nt er act i ons. Or al cont r acept i ve l evel s i n t he body can be decr eased i n pat i ent s
t aki ng CBZ. Al t er nat i ve f or ms of cont r acept i on shoul d be used i n pat i ent s t aki ng
CBZ. CBZ can al so i nduce i t s own met abol i sm ( aut oi nduct i on) . Decr eases i n CBZ
l evel s i n t he body may be seen af t er 3- 30 days of t her apy. CBZ l evel s shoul d be
moni t or ed and adj ust ed accor di ngl y.
d. Lamot ri gi ne i s i ndi cat ed i n t he t reat ment of bi pol ar di sor der , pr i mar i l y i n pat i ent s
pr esent i ng wi t h depr essi on (Tabl e 48- 6) .
( 1) The mechani sm of act i on f or l amot r i gi ne i s not compl et el y under st ood. Ì t i s
cur r ent l y t hought t o be r el at ed t o i t s abi l i t y t o decr ease r el ease of gl ut amat e and
aspar t at e by bl ocki ng sodi um channel s.
( 2) Owi ng t o t he r i sk of rash, l amot r i gi ne shoul d be i ni t i at ed at l ow doses ( 25
mg/ day) and sl owl y i ncr eased by 25 mg ever y 1- 2 weeks. Lamot r i gi ne shoul d be
admi ni st er ed t wi ce dai l y i n doses > 50 mg. Pat i ent s who ar e t aki ng l amot r i gi ne wi t h
VPA shoul d decr ease t he dose by hal f owi ng t o a si gni f i cant medi cat i on i nt er act i on.
( 3) Common adverse ef f ect s i ncl ude di zzi ness, di pl opi a, nausea, vomi t i ng, r ash,
phot osensi t i vi t y, at axi a, headache, and bl ur r ed vi si on. Rashes may be sever e and
l i f e- t hr eat eni ng such as St evens- Johnson r ash, and pat i ent s shoul d i mmedi at el y
di scont i nue t he medi cat i on i f a r ash appear s.
e. At ypi caI ant i psychot i cs have r ecent l y been t he subj ect of mul t i pl e st udi es i n t he
t r eat ment of bi pol ar di sor der . These medi cat i ons ar e i ndi cat ed i n t he t r eat ment of
bi pol ar di sor der (Tabl e 48- 6) . For i nf or mat i on r egar di ng dosi ng, adver se ef f ect s,
and mechani sm of act i on see Chapt er 47. Ol anzapi ne i s avai l abl e i n a f or mul at i on
wi t h f l uoxet i ne ( Symbyax) and i s appr oved f or depr essi ve epi sodes i n bi pol ar
di sor der .
f . Addi t i onaI ant i convuI sant s
( 1) Gabapent i n has been eval uat ed i n t wo t r i al s f or i t s use i n acut e mani a and has
not been shown at t hi s t i me t o i mpr ove sympt oms. Ì t i s not i ndi cat ed f or
monot her apy i n bi pol ar di sor der but may be used as adj unct i ve t her apy t o assi st
wi t h sympt oms such as anxi et y.
( 2) Oxcarbazepi ne i s a medi cat i on st r uct ur al l y si mi l ar t o car bamazepi ne but wi t h
f ewer adver se ef f ect s. Ì t i s post ul at ed t o have si mi l ar t her apeut i c ef f ect s i n bi pol ar
di sor der t o car bamazepi ne; however , st udi es demonst r at i ng i t s ef f i cacy ar e l i mi t ed.
Ì t cur r ent l y i s r ecommended onl y i n combi nat i on wi t h ot her mood st abi l i zer s.
g. Ant i depressant s shoul d be used caut i ousl y i n pat i ent s wi t h bi pol ar di sor der
because of t he r i sk of i nduci ng mani a. When possi bl e, pat i ent s shoul d be r ecei vi ng
mood st abi l i zer s at goal doses bef or e i ni t i at i ng ant i depr essant s and shoul d be
caut i ousl y moni t or ed. Bupr opi on and par oxet i ne have been associ at ed wi t h l ess r i sk
of i nduci ng mani a t han ot her ant i depr essant s and may be pr ef er abl e.
2. Treat ment durat i on/ phases. The t r eat ment of bi pol ar di sor der i s st r uct ur ed
si mi l ar l y t o t hat of depr essi on wi t h acut e, cont i nuat i on, and mai nt enance phases.
Mai nt enance t r eat ment i s
P. 1053

st r ongl y r ecommended f or al l pat i ent s wi t h bi pol ar di sor der , especi al l y t hose wi t h a
f ami l y hi st or y.
3. Treat ment augment at i on
a. Pat i ent s wi t h no or par t i al r esponse t o monot her apy may r ecei ve combi nat i on
t her apy wi t h t wo agent s. Agent s t hat can be combi ned i ncl ude l i t hi um; VPA; and t he
at ypi cal ant i psychot i cs ol anzapi ne, quet i api ne, r i sper i done, and zi pr asi done.
At ypi cal ant i psychot i cs, i f used, shoul d be combi ned wi t h ei t her VPA or l i t hi um and
not combi ned wi t h anot her at ypi cal ant i psychot i c.
b. For depr essi ve epi sodes, l amot r i gi ne may be combi ned wi t h anot her mood
st abi l i zer as f i r st - l i ne t her apy and t he ol anzapi ne- f l uoxet i ne combi nat i on pr oduct i s
a second- l i ne opt i on.
4. Treat ment opti ons i n pregnancy
a. Mul t i pl e agent s used i n t he t r eat ment of bi pol ar di sor der have been associ at ed
wi t h bi r t h def ect s.
( 1) Li t hi um, VPA, and CBZ ar e pr egnancy cat egor y D medi cat i ons.
( 2) Li t hi um has been associ at ed wi t h bi r t h def ect s, pr i mar i l y i n t he f i r st t r i mest er .
( 3) VPA and CBZ shoul d be used dur i ng pr egnancy onl y i f t he benef i t s out wei gh t he
r i sks. Ì f t he deci si on i s made t o use t hese medi cat i ons dur i ng pr egnancy, f ol i c aci d
shoul d be gi ven t o mi ni mi ze t he r i sk of def ect s.
( 4) Lamot r i gi ne and oxcar bazepi ne ar e pr egnancy cat egor y C medi cat i ons.
P. 1054


STUDY QUESTIONS
Di rect i ons: Each of t he quest i ons, st at ement s, or i ncompl et e st at ement s i n t hi s
sect i on can be cor r ect l y answer ed or compl et ed by one of t he suggest ed answer s or
phr ases. Choose t he best answer .
1. Whi ch of t he f oI I owi ng st at ement s about depressi on i s t rue?
( A) The i nci dence of depr essi on i s gr eat er i n men t han i n women.
( B) Depr essi on occur s most f r equent l y i n adul t s bet ween t he ages of 60 and 85
year s.
( C) Depr essi on has no genet i c l i nk.
( D) Depr essi on i s di agnosed usi ng t he DSM- Ì V- TR cr i t er i a.
Vi ew Answer 1. The answer i s D[ seeand] . 2. A pat i ent wi t h maj or
depressi on shouI d recei ve ant i depressant t herapy f or at I east
( A) 2 weeks.
( B) 6 weeks.
( C) 2 mont hs.
( D) 6 mont hs.
Vi ew Answer 2. The answer i s D[ see] . For quest i ons 3- 4: A 36- year - ol d
woman pr esent s wi t h a 2- mont h hi st or y of depr essed mood, anhedoni a, i ncr eased
appet i t e, wei ght gai n, hyper somnol ence, and sui ci dal i deat i on. Thi s i s t he pat i ent ' s
f i r st epi sode of maj or depr essi on.
3. Whi ch of t he f oI I owi ng anti depressant s wouI d be most appropri at e i n t he
t reat ment of t hi s pat i ent ?
( A) ami t r i pt yl i ne
( B) ser t r al i ne
( C) phenel zi ne
( D) mi r t azapi ne
Vi ew Answer 3. The answer i s B[ seeand] . 4. Whi ch of t he f oI I owi ng i s not a
pot ent i aI adverse ef f ect of t he medi cat i on seI ect ed for t he pat i ent i n quest i on
3?
( A) sexual dysf unct i on
( B) nausea
( C) ur i nar y r et ent i on
( D) i nsomni a
Vi ew Answer 4. The answer i s C[ see] . 5. Whi ch of t he f oI I owi ng
medi cat i ons wouI d most I i keI y exacerbat e a preexi sti ng sei zure di sorder?
( A) venl af axi ne
( B) t r azodone
( C) bupr opi on
( D) par oxet i ne
Vi ew Answer 5. The answer i s C[ see] . 6. A pat i ent who has recei ved
ci t aI opram 40 mg/ day for 2 weeks f or the t reat ment of maj or depressi on
compI ai ns that the medi cat i on i s not worki ng and wouI d I i ke t o be swi t ched t o
another agent . What i s t he appropri at e recommendat i on?
( A) Pr ovi de t he pat i ent wi t h some i nf or mat i on on monoami ne oxi dase i nhi bi t or s
( MAOÌ s) and cal l t he physi ci an t o r ecommend swi t chi ng t he pat i ent t o phenel zi ne.
( B) Encour age t he pat i ent t o cont i nue wi t h t he cur r ent r egi men, and i nf or m hi m or
her t hat i t may t ake 4- 6 weeks bef or e t he f ul l r esponse i s evi dent .
( C) Recommend addi ng l i t hi um t o augment t he cur r ent r egi men.
( D) Recommend swi t chi ng t o mi r t azapi ne because of t her apeut i c f ai l ur e wi t h
ci t al opr am.
Vi ew Answer 6. The answer i s B[ see I I . E. 3. a- b] . 7. A pat i ent di agnosed
wi t h depressi on was unsuccessf uI I y t reat ed wi t h f I uoxet i ne. FI uoxet i ne was
di scont i nued, and 14 days I at er, t he pat i ent st art ed t herapy wi t h pheneI zi ne.
Then, 3 days af t er pheneI zi ne was st art ed, t he pat i ent present ed wi t h
hyperref I exi a, f ever, eI evat ed bI ood pressure, confusi on, and di arrhea. What i s
t he most I i keI y cause of t hi s cI i ni caI present at i on?
( A) ser ot oni n syndr ome
( B) ser ot oni n wi t hdr awal syndr ome
( C) hyper t ensi ve cr i si s
( D) neur ol ept i c mal i gnant syndr ome
Vi ew Answer 7. The answer i s A[ see I I . E. 3. b;] . P. 1055


8. A pat i ent present s wi t h pressured speech, i nabi I i t y t o sI eep for 72 hr, bi zarre
dress, i nappropri at e makeup, and grandi ose deI usi ons that i nt erf ere wi th soci aI
f unct i oni ng. Whi ch of t he f oI I owi ng i s t he most I i keI y di agnosi s?
( A) depr essi on
( B) eut hymi a
( C) hypomani a
( D) mani a
Vi ew Answer 8. The answer i s D[ see] . 9. Whi ch of t he f oI I owi ng
medi cat i ons wouI d be consi dered f i rst - I i ne monot herapy f or an acute epi sode
of mani a?
( A) gabapent i n
( B) l i t hi um
( C) l amot r i gi ne
( D) hal oper i dol
Vi ew Answer 9. The answer i s B[ see] . 10. Whi ch of t he f oI I owi ng i s the
appropri at e t herapeut i c range for I i thi um i n the t reat ment of mani a?
( A) 0. 4- 0. 6 mEq/ L
( B) 0. 6- 1. 5 mEq/ L
( C) 1. 0- 2. 0 mEq/ L
( D) 0. 5- 1. 2 mEq/ L
Vi ew Answer 10. The answer i s D[ see] . 11. Whi ch of the foI I owi ng mood
st abi I i zers wouI d be most appropri at e i n a pat i ent wi t h I i ver di sease?
( A) l i t hi um
( B) val pr oi c aci d
( C) car bamazepi ne
( D) none of t he above
Vi ew Answer 11. The answer i s A[ seeand] . 12. A 32- year- oI d, 70- kg man
di agnosed wi t h bi poI ar I di sorder i s bei ng t reat ed wi th vaI proi c aci d ( VPA) .
Whi ch of t he f oI I owi ng i s a reasonabI e I oadi ng dose for VPA i n t hi s pat i ent ?
( A) 250 mg t wi ce a day
( B) 500 mg t wi ce a day
( C) 250 mg t hr ee t i mes a day
( D) 500 mg t hr ee t i mes a day
Vi ew Answer 12. The answer i s D[ see] . 13. Whi ch of the foI I owi ng f actors
may i ncrease I i t hi um concent rat i on?
( A) caf f ei ne
( B) osmot i c di ur et i cs
( C) i ncr eased f l ui d i nt ake
( D) nonst er oi dal ant i - i nf l ammat or y dr ugs
Vi ew Answer 13. The answer i s D[ see] . P. 1056


ANSWERS AND EXPLANATIONS
1. The answer i s D [ see Ì Ì . B, C and D] .
The DSM- Ì V-TR cr i t er i a pr ovi de t he di agnost i c gui del i nes f or psychi at r i c di sor der s.
Depr essi on occur s mor e of t en i n women t han i n men and i n adul t s bet ween t he ages
of 25 and 44. A hi gher i nci dence of depr essi on occur s among pat i ent s wi t h a
posi t i ve f ami l y hi st or y, suppor t i ng a genet i c l i nk.
2. The answer i s D [ see Ì Ì . E. 2] .
Pat i ent s shoul d r ecei ve ant i depr essant t her apy t hr ough t he cont i nuat i on phase,
whi ch i s gener al l y 6- 9 mont hs.
3. The answer i s B [ see Ì Ì . E. 1. a, b and c; Ì Ì . E. 1. f ; Tabl e 48- 1; Tabl e 48- 3] .
Ser t r al i ne, an SSRÌ , i s a good f i r st - l i ne agent , par t i cul ar l y i n pat i ent s who woul d
benef i t f r om t he st i mul at or y si de ef f ect s. Ami t r i pt yl i ne and mi r t azapi ne woul d not be
good al t er nat i ves because of t hi s pat i ent ' s hyper somnol ence and wei ght gai n. Ì n
addi t i on, a TCA ( ami t r i pt yl i ne) i s not r ecommended i n pat i ent s at r i sk f or sui ci de.
Al t hough some aspect s of t hi s pat i ent ' s depr essi on may be consi der ed at ypi cal , an
MAOÌ woul d not be sel ect ed as f i r st - l i ne t her apy, gi ven t hat i t i s t he pat i ent ' s f i r st
epi sode of depr essi on.
4. The answer i s C [ see Ì Ì . E. 1. c. ( 2) ] .
Ser t r al i ne has been associ at ed wi t h nausea, sexual dysf unct i on, and i nsomni a.
Ser t r al i ne does not expr ess ant i chol i ner gi c act i vi t y and woul d, t her ef or e, not cause
ur i nar y r et ent i on. Of t he SSRÌ s, onl y par oxet i ne has been associ at ed wi t h causi ng
ant i chol i ner gi c adver se ef f ect s.
5. The answer i s C [ see I I . E. 1. e. ( 3) ( b) ] .
Al t hough al l ant i depr essant s can l ower t he sei zur e t hr eshol d, bupr opi on i s
cont r ai ndi cat ed i n pat i ent s wi t h sei zur e di sor der . Bupr opi on i s speci f i cal l y
cont r ai ndi cat ed i n pat i ent s wi t h a sei zur e di sor der . Par oxet i ne was associ at ed wi t h
a 0. 1% i nci dence of sei zur es dur i ng cl i ni cal t r i al s. Sei zur e associ at ed wi t h
venl af axi ne occur s i nf r equent l y ( 1/ 100 t o 1/ 1000 pat i ent s) . The over dosage of
t r azodone may be associ at ed wi t h sei zur es; but at nor mal doses, t r azodone i s not
t hought t o al t er t he sei zur e t hr eshol d.
6. The answer i s B [ see I I . E. 3. a- b] .
An ant i depr essant must be gi ven at t he maxi mum t ol er at ed dose f or 4- 6 weeks
bef or e i t i s consi der ed a t her apeut i c f ai l ur e; t her ef or e, t he best r ecommendat i on i s
t o cont i nue wi t h t he cur r ent r egi men f or at l east 2 mor e weeks. MAOÌ s ar e r eser ved
f or r ef r act ory depr essed pat i ent s and ar e not i ndi cat ed i n t hi s pat i ent scenar i o.
Li t hi um i s an appr opr i at e augment at i ve agent but i s not i ndi cat ed unt i l t he pat i ent
has f ai l ed t wo or t hr ee di f f er ent ant i depr essant t r i al s.
7. The answer i s A [ see I I . E. 3. b; Tabl e 48- 2] .
Ser ot oni n syndr ome may r esul t when st ar t i ng an MAOÌ i mmedi at el y af t er anot her
agent t hat i ncr eases ser ot oni n l evel s. Gener al l y, a 2- week washout per i od i s
r ecommended; however , f l uoxet i ne r equi r es a 5- week washout per i od because of
nor f l uoxet i ne ( act i ve met abol i t e) .
8. The answer i s D [ see Ì Ì Ì . D. 1] .
The cl i ni cal pr esent at i on descr i bed i s consi st ent wi t h mani a. Hypomani a gener al l y
does not i mpai r f unct i oni ng. Eut hymi a i mpl i es nor mal mood, wher eas depr essi on
t ypi cal l y i nvol ves mor e neur oveget at i ve sympt oms.
9. The answer i s B [ see Tabl e 48- 6] .
Li t hi um i s consi der ed t o be f i r st - l i ne monot her apy f or euphor i c mani a. Gabapent i n
has demonst r at ed ut i l i t y as a mood st abi l i zer but i s consi der ed onl y an adj unct i ve
t her apy. Lamot r i gi ne i s an ant i convul sant t hat cur r ent l y has dat a suppor t i ng i t s use
i n depr essi ve epi sodes of bi pol ar di sor der , but not as f i rst - l i ne monot her apy f or
mani a. Hal oper i dol i s a t r adi t i onal ant i psychot i c t hat may be used par ent er al l y t o
manage acut e agi t at i on but i s not appr opr i at e as f i r st - l i ne monot her apy.
10. The answer i s D [ see Ì Ì Ì . F. 1. a. (4) ] .
The t her apeut i c r ange of l i t hi um i s 0. 5- 1. 2 mEq/ L. When usi ng l i t hi um i n t he
t r eat ment of acut e mani a, t he upper end of t he t her apeut i c r ange i s t ypi cal l y used.
11. The answer i s A [ see Ì Ì Ì . F. 1. a. (6) and ( 7) ; Ì Ì Ì . F. 1. b. ( 4); Ì Ì Ì . F. 1. c. ( 3). ( b) ; Tabl e
48- 7] .
Li t hi um i s not known t o cause hepat i c dysf unct i on, nor i s i t met abol i zed vi a t he
l i ver . However , bot h val pr oi c aci d and car bamazepi ne can i mpai r l i ver f unct i on.
P. 1057


12. The answer i s D [ see Ì Ì Ì . F. 1. b. (3) ] .
The appr opr i at e l oadi ng dose f or VPA i n acut e mani a i s 20 mg/ kg/ day; t her ef or e, i n
t hi s pat i ent , t he appr opr i at e l oadi ng dose i s 1400 mg/ day. Thi s equat i on
appr oxi mat es t he need f or t he pat i ent , and i t i s appr opr i at e t o r ound up t o avai l abl e
dosage f or ms.
13. The answer i s D [ see Tabl e 48- 8] . Caf f ei ne, osmot i c di ur et i cs, and i ncr eased
f l ui d i nt ake al l decr ease l i t hi um concent r at i ons. Nonst er oi dal ant i - i nf l ammat or y
dr ugs decr ease r enal bl ood f l ow and decr ease l i t hi um cl ear ance, r esul t i ng i n
i ncr eased l i t hi um concent r at i ons.

49
Asthma and Chronic Obstructive PuImonary
Disease
Roy A. PI easant s
I. ASTHMA
A. Def i ni t i on. Ast hma i s a chr oni c i nf l ammat or y di sor der of t he ai r ways. Ì t i nvol ves
compl ex i nt er act i ons bet ween many cel l s ( e. g. eosi nophi l s, mast cel l s) and
i nf l ammat or y medi at or s ( e. g. i nt er l euki ns, l eukot r i enes) t hat r esul t i n i nf l ammat i on,
obst r uct i on ( par t i al l y or compl et el y r ever si bl e af t er t r eat ment or r esol ves
spont aneousl y) , i ncr eased ai r way r esponsi veness ( i . e. , hyper r esponsi veness) , and
epi sodi c ast hma sympt oms ( see Ì . G. 1) . Neut r ophi l s may pl ay an i mpor t ant r ol e i n
some ast hma exacer bat i ons.
B. CI assi f i cat i on. Ast hma sever i t y cl assi f i cat i ons accor di ng t o t he 2007 exper t
panel r epor t of t he Nat i onal Hear t , Lung, and Bl ood Ì nst i t ut e i ncl ude mi I d
i nt ermi tt ent ast hma i n addi t i on t o mi I d, moderat e, and severe persi st ent ast hma
( Tabl e 49- 1) . The ast hma gui del i nes hi ghl i ght t hat di sease sever i t y i s used t o
i ni t i at e t her apy and ast hma cont r ol shoul d be used t o moni t or t her apy. The 2007
Gui del i nes have al so been modi f i ed t o i ncor por at e domai ns of bot h di sease r i sk and
i mpai r ment t o det er mi ne di sease sever i t y. The gui del i nes def i ne i mpai r ment as t he
f r equency and i nt ensi t y of sympt oms and f unct i onal l i mi t at i ons t he pat i ent i s
cur r ent l y i s exper i enci ng or has r ecent l y exper i enced. Ri sk i s def i ned as t he
l i kel i hood of ast ma exacer bat i ons, pr ogr essi ve decl i ne i n l ung f unct i on ( or f or
chi l dr en l ung gr owt h) , or adver se ef f ect s f r om medi cat i ons. A pat i ent ' s sever i t y
cl assi f i cat i on pl ays an i mpor t ant r ol e i n det er mi ni ng t he most appr opr i at e
phar macot her apeut i c appr oach and i s det er mi ned by:
1. Sympt oms ( shor t - act i ng B- agoni st use, noct ur nal sympt oms)
2. Ì nt erf er ence wi t h nor mal dai l y act i vi t y
3. Lung f unct i on ( spi r omet r y t o det er mi ne FEV1 and FVC)
4. Fr equency of exacer bat i ons
C. I nci dence. Ì n 2002, accor di ng t o CDC dat a, appr oxi mat el y 31 mi l l i on Amer i cans
had ever been t ol d t hey had ast hma dur i ng t hei r l i f et i me. Ì n 2002, 20 mi l l i on peopl e
i n t he U. S. had ast hma ( ~7% of popul at i on) .
1. Ì t has been est i mat ed t hat 8. 3% mi l l i on chi l dr en age 18 year s and younger have
ast hma.
2. Ast hma i mpr oves i n many chi l dr en as t hey age; 50% appear t o have " out gr own¨
ast hma by t hei r mi d- t eens. However , i t i s i ncor rect t o consi der t hat t hese i ndi vi dual s
no l onger have ast hma, because many event ual l y have a r et ur n of sympt oms.
3. Si xt y per cent of ast hmat i cs have at l east one ast hma f l ar e each year
4. Al t hough deat h f r om ast hma r emai ns uncommon, deat h r at es had been i ncr easi ng
i n r ecent year s but appear t o have r eached a pl at eau. Ì n 1999, t her e wer e 4657
deat hs at t r i but ed t o ast hma. The most common cause of deat h i s bel i eved t o be
i nadequat e assessment of t he sever i t y of ai r way obst r uct i on by ei t her pr act i t i oner or
pat i ent , l eadi ng t o subopt i mal t her apy.
5. The cost t o soci et y of ast hma i s subst ant i al . Ì n 2000 al one, i t i s est i mat ed t hat
di r ect cost s r el at ed t o ast hma exceeded $8. 1 bi l l i on. These cost s i ncl ude $2. 4
bi l l i on f or medi cat i ons and $3. 5 bi l l i on f or hospi t al i zat i ons. Ì ndi r ect cost s of ast hma
ar e est i mat ed at $4. 6 bi l l i on. Acut e car e vi si t s ( e. g. , hospi t al i zat i ons) account f or
t he maj or i t y of heal t hcar e cost s f or ast hma.
D. Cause. Pr eci pi t at i ng f act or s of an acut e ast hma exacer bat i on may i ncl ude t he
f ol l owi ng:
1. Al l er gens ( e. g. , pol l en, house dust mi t e, ani mal dander , mol d, cockroaches, f ood)
a. Concur r ent pr edi sposi t i on t o al l er gy i s hi ghl y pr eval ent i n pat i ent s wi t h ast hma,
especi al l y chi l dr en.
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Table 49-1. ClassiIication oI Asthma Severity
b. For exampl e, al l er gi c r hi ni t i s i s r epor t ed i n 45% of pat i ent s wi t h ast hma
compar ed t o 20% of t he gener al popul at i on.
2. Occupat i onal exposur es ( e. g. , chemi cal i r r i t ant s, f l our , wood, t ext i l e dust s)
3. Vi r al r espi r at or y t r act i nf ect i ons
4. Exer ci se
5. Emot i ons ( e. g. , anxi et y, st r ess, har d l aught er or cr yi ng)
6. Exposur e t o i rr i t ant s ( e. g. , st r ong odor s, chemi cal s, f umes)
7. Envi r onment al exposur es ( e. g. , weat her changes, col d ai r , sul f ur di oxi de,
ci gar et t e smoke)
8. Dr ugs
a. React i ons t o dr ugs may occur as a r esul t of hyper sensi t i vi t y or as an ext ensi on of
t he phar macol ogi cal ef f ect .
b. Pr obl emat i c dr ugs i ncl ude
( 1) Aspi r i n and ot her nonst er oi dal ant i - i nf l ammat or y dr ugs such as i bupr of en ( not e:
cycl ooxygenase 2 i nhi bi t or s ar e not r ecommended f or use i n aspi r i n- sensi t i ve
ast hma pat i ent s)
( 2) Ant i adr ener gi c and chol i ner gi c dr ugs ( e. g. , 8- adr ener gi c bl ocker s, bet hanechol )
( 3) Medi cat i ons ( or f oods) t hat cont ai n t ar t r azi ne, sul f i t es, benzal koni um chl or i de,
and ot her pr eser vat i ves
( 4) Exci pi ent s i n i nhaI ed drugs t hat are deri vat i ves of I egumes ( soybeans) i n
peanut aI I ergi c pat i ent s. E. g. oI ei c aci d
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E. Pat hoI ogy. On post mor t em exami nat i on of pat i ent s wi t h ast hma, t he f ol l owi ng
char act er i st i cs have been i dent i f i ed:
1. Hyper t r ophy of smoot h muscl e
2. Ai r ways cont ai ni ng pl ugs consi st i ng of i nf l ammat or y cel l s and t hei r debr i s,
pr ot ei ns, and mucus
3. Ì nf l ammat or y cel l ul ar i nf i l t r at e wi t h vasodi l at i on, denuded ai r way epi t hel i um, and
mi cr ovascul ar l eakage
4. Vasodi l at i on of t he vascul at ur e
5. Denuded ai r way epi t hel i um
6. Mi cr ovascul ar l eakage
7. Col l agen deposi t i on i n basement membr anes
F. Pat hophysi oI ogy ( Fi gur e 49- 1)
1. Maj or cont ri buti ng processes
a. I nf I ammat ory ceI I s ( i . e. , mast cel l s, eosi nophi l s, act i vat ed T cel l s, macr ophages,
and epi t hel i al cel l s) secr et e medi at or s and i nf l uence t he ai r ways di r ect l y or vi a
neur al mechani sms.
b. Ai rway obst ruct i on i s r esponsi bl e f or many of t he cl i ni cal mani f est at i ons of
ast hma.
( 1) Sever i t y of obst r uct i on i s var i abl e and bel i eved t o be a r esul t of
br onchoconst r i ct i on, ai rway wal l edema, mucus pl ug f or mat i on, ai r way r emodel i ng,
smoot h muscl e hyper t r ophy, and hyper pl asi a.
( 2) Ai r way obst r uct i on r educes vent i l at i on t o some l ung r egi ons, whi ch causes a
vent i l at i on/ per f usi on ( V/ Q) i mbal ance t hat l eads t o hypoxemi a. Thi s i s r ef l ect ed by a
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r educt i on i n t he par t i al pr essur e of ar t er i al oxygen ( PaO
2
) obser ved i n moder at e t o
sever e exacer bat i ons.

Figure 49-1. The pathophysiology oI asthma.
c. Hyperresponsi veness, an exagger at ed r esponse t o cer t ai n st i mul i , i s an
i mpor t ant f eat ur e of ast hma and appear s t o cor r el at e wi t h cl i ni cal sever i t y and
medi cat i on r equi r ement s. Ì ncr eased l evel s of i nf l ammat or y medi at or s and i nf i l t r at i on
by i nf l ammat or y cel l s ar e t hought t o be t he pr i mar y mechani sms r esponsi bl e f or
ai r way hyper r esponsi veness.
d. Ai rway i nf I ammat i on i s cr uci al t o devel opment of ast hma and cont r i but es t o
ai r way hyper r esponsi veness, ai r f l ow obst r uct i on, r espi r at or y sympt oms, and di sease
chr oni ci t y. Ì nf l ammat or y cel l s and t hei r medi at or s ar e r esponsi bl e f or al t er ed
mucoci l i ar y f unct i on, epi t hel i al di sr upt i on r angi ng f r om mi nor ci l i ar y l oss t o sever el y
denuded epi t hel i um, i ncreased ai r way per meabi l i t y ( t o i nhal ed al l er gens, i r r i t ant s,
and i nf l ammat or y medi at or s) , and r educed cl ear ance of i nf l ammat or y medi at or s.
( 1) Acut e i nf l ammat i on i s associ at ed wi t h ear l y r ecr ui t ment of cel l s t o t he ai r way.
( 2) Subacut e i nf l ammat i on i s associ at ed wi t h r ecr ui t ed and r esi dent cel l act i vat i on,
r esul t i ng i n mor e per si st ent i nf l ammat i on.
( 3) Chr oni c i nf l ammat i on i s associ at ed wi t h per si st ent cel l damage and ongoi ng
r epai r , r esul t i ng i n ai r way abnor mal i t i es t hat may become per manent .
e. Al t er at i on i n autonomi c neuraI cont roI al so cont r i but es t o obst r uct i on.
( 1) El evat ed par asympat het i c t one and r ef l ex br onchoconst r i ct i on may occur as a
r esul t of i ncr eased chol i ner gi c sensi t i vi t y or a change i n muscar i ni c r ecept or
f unct i on.
( 2) Ì ncr eased smoot h muscl e r esponsi veness may be t he r esul t of smoot h muscl e
hyper t r ophy. Exposur e of t he ner ve endi ngs, caused by i nf l ammat i on, may al so
cont r i but e.
f . Ai rway remodeI i ng can r esul t f r om per si st ent i nf l ammat i on f r om chr oni c ast hma.
The r esul t i ng damage can yi el d per manent ai r way abnor mal i t i es because of
subbasement membr ane col l agen deposi t i on and f i br osi s. Hyper t r ophy of t he ai r way
smoot h muscl e i s anot her f or m of t i ssue r emodel i ng i n ast hma. These event s may
occur even i n t he f ace of mi l d di sease but ai r way r emodel i ng does not necessar i l y
occur i n al l ast hma pat i ent s.
2. Sequenci ng of event s i n ast hma
a. Tri ggeri ng. I n an aI I ergi c ast hma pati ent, af t er exposur e t o an al l er gi c t r i gger ,
t he ant i gen bi nds t o i mmunogl obul i n E (Ì gE) , whi ch i s at t ached t o act i vat ed mast
cel l s. Nonal l er gi c f act or s ( e. g. , aspi r i n, vi r al i nf ect i ons) may al so f unct i on as
t r i gger s. Vi ral i nf ect i ons ser ve as an i mpor t ant cause of wor sened ast hma.
b. Ear l y and l at e r esponses
( 1) The earI y ast hmat i c response begi ns wi t hi n 30 mi n of t ri gger exposur e ( usual l y
onl y sever al mi nut es af t er exposur e) and r esol ves wi t hi n 2 hr . Thi s r esul t s i n
const r i ct i on of t he ai r way smoot h muscl es, br onchospasm, and subsequent l y ast hma
sympt oms. Thi s r esponse can be bl ocked by t he admi ni st r at i on of shor t - act i ng 8-
agoni st s ( al but er ol [ Vent ol i n, Pr ovent i l ] , bi t ol t er ol [ Maxai r ] or l eval but er ol
[ Xopenex] ) .
( 2) The I at e ast hmat i c response i nvol ves a second decl i ne i n l ung f unct i on
t ypi cal l y 4- 8 hr af t er t he i ni t i al t r i gger exposur e. The ear l y ast hma r esponse does
not necessar i l y pr ogr ess i nt o t he l at e ast hmat i c r esponse. The l at e ast hmat i c
r esponse, pr i nci pal l y an i nf l ammat or y r esponse, i s char act er i zed by per si st ent
ai r f l ow obst r uct i on, ai r way i nf l ammat i on, and bronchi al hyper r esponsi veness. The
r esponse may l ast sever al days, and br onchi al hyper r eact i vi t y may per si st f or
sever al weeks. Thi s r esponse can be bl ocked by t he admi ni st r at i on of
cor t i cost er oi ds÷i nhal ed st er oi ds such as budesoni de ( Pul mi cor t ) and l eukot r i ene
modi f i er s such as mont el ukast ( Si ngul ai r ) or cr omones ( i . e. , cr omol yn sodi um ( Ì nt al )
or nedocr omi l (Ti l ade) .
G. CI i ni caI evaI uat i on
1. Physi caI f i ndi ngs
a. Ì n asympt omat i c pat i ent s, physi cal f i ndi ngs of ast hma ar e of t en not p