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4TH
GaIT C.
ProfesSor
Department
.md
COLOGY
1'11.0.
Integra tin> Biology nd Pharmacology
Graduate s . : h+o. of Biomedical Scie,c{'s
i\ssl stanl for Education Programs
Medical School at Houston
Dm'i d Loose, 1'11.0.
Associate ""'1"'"'
Department . Integrated [l iology and Pharmacology
ilnd
Graduat(' Seh,,101 of Biomedical SciellCl's
of Medical School . .It Iioustoll
I
With sp,celat contributions by
Medilla IIshell, ,\I.D.
Will iam
Royal Oak,
Todd \.
William
Royal Oak,
.\J.D., 1'11.1).


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Third Edition,
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Rosenfeld, Ga ry C.
Pharmacology /
Kushell, Todd A.
p. ;
Includes index.
ISfiN-13:
Loose, David .
C. Rosenfeld, Dav d S. Loose; with special contributions by Medina
I. ted.
(alk. paper) I. Pharmacology-Examinations, questions, etc. l.
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This conci se
and others
for !
tiuns of
the mual
lati on of
e to the Fourth Edition
of medical pharmacology is designed for medi cal students, dental students.
health care professions. It is intended primarily to help students prepare
such as the Un ited States Medical Licensing Examination Step 1
examinations. This book presents condensed and succinct descrip-
and current BoorddJi ven i nformation pertaining to pharmacology without
-j details. 11 is not rneant to be a for the comprehensive presen
and difficult (oncepts found in standard pharmacology l{?xtS.
The fourth - ion begins with a chap: er devoted to the general principles of action, fol-
lowed concerned with dLlgs acting on the maj or body systems. Other chapters
discuss a " ergots, antiinflamnatory and Immunosuppressive agents, drugs used to
treat anemias disorders of hemos asis, infeCl ious diseases, ca nccr. and tOXicology.
Each indudes a presentali)n of specific drugs with a discussion of their general
propert ies, n ism of action, pharmacologic effects, thcrapeutic uses, and ad,'crsc effects.
A drug li sl, and figures surnmaTizc essential drug information included in all chapters,
Clinical ly USMLEstyle rfview questions and answers with cxplanations follow
each chapter help st udents assess their understa nding of the information, Similarl y, a com
prehen:.i,"e comisting of USMLE-stylc questi ons is included at the end of the
book. serve. as a self-a.\scssment tool to help determine their fund
of knowledge diagnose any weakr esses in pharmacology.
current drug infurmat ic'il
review tests feat ure updatr.-d questions
2colo! ""'"" summarize (sscntial lnformation for qukk recall

Drug !iSH

Addiltonal comprehellSi\-e examination questions and explanatIons
Gary C. Rosl'lI{,eld, PII.o.
Dm'ill S. i (K)\C, Pl!.lJ.
v
Acknowledgments
The aullmrs a ' knowledge and thank our for their .'IUppor! allll contributions to
thi s boo!.. and our medical students fo)r being OUf hars hest
vii
Contents
Preface v
Acknowledgn cnts vii
1 Gener I Principles of [)rug Action ......... . . .. . .. . . . . .. 1
I. D( se-Response Relation ;hips 1
II . 0 g Absorption 6
III . Dr g Dist ribution 9
IV. Dr g Elimi nation and Tt' rmi nat ion of Action 10
V. Bl )tramformal ion (Met,bolism) of Drugs 11
VI. E --ret lon of Drug.. \.;
VII . P rmacokinct in. 16
Re , iew cs t 19
2 Drugs cting on the Autonomic Nervous System .... 25
I. TI Peripheral Efferent Nervous System 2S
II . Pa asympat homimetit: Crug.. 10
III . :V1 scari ni c Receptor Antagonists .15
IV. G< nglionic-Blocking On. gs 3 7
V. Sk 'leta! Muscle Relaxanl'i 37
VI . Sy npathomimetic 42
VII . A energic Ikceptor Antlgonhls 47
Review r e:<ol 53
3 Drugs cling on the System ................ . . ... 60
I. Oi retics 60
II . N ndiuretic Inhi bi tors o Tubular Transpurt 66
Review cst 69
Drugs cting on the Cardiovascular System . . . . . .. . ... 73
I. ' nh Used to Treat Congestive Ileart J:ailure (CHF) 73
II . AI Dmgs 79
III. A ia ngi nal Agenh 81
IV. A ihypertcnsin' 86
v. Dr Igs that Lower Plasma Li pids 92
Review est 96
ix
X
5 Drugs
on the Central Nervous System .......... 101
I.
.. Drugs 101
II. .. (Neuroleptic) Drugs 106
III. Drugs ItO
IV. I1 S
V. Analgesics dnd Ant,lgonists L 16
VI . Drugs and Drugs Used to Treat Alzhdnll' r's Dise<lSl' 123
VII . 12.
VIII . 1JO
IX. ns
X. 117
Review 148
6 Ergots, Antiinflammatory Agents,
and Apnts IS3
I. and Anti histamines 153
II. and Seroto nin A ltagonists 157
Ill. 1 S9
IV.
V.
VI.
VII .

161
Antiinflammatory Drugs (:-.JSAIDs) 164
Used for Gout 171
VIII .
Imnilm''''' PI'''''''''' Agent -, 172
177
7 u,eo in Anemia and Disorders of Hemostasis .... 180
Used in the Treat me It of ISO
Act ing o n \-fyelo id (ells 184
III. USN in Hemostat ic )iso rders 184
Review 192
8 Drugs
on the Gast rointestinaJ Tract ........... 197
I. and Ant iemet ics 197
II . and Appet it" En hancers 199
III. f or Upper Gas :rointestinai !"ract 200
IV. Agents 205
V. Used to Disso lve Gallstones 20:5
VI.
VII .
Enzyme Hepl acements 20:5
A that Act on the LmH'r Gast rointestinal Tract 206
Review 210
9 Drugs
on the Pulmonary System ............... 214
I. 10 to Pulmonary l)isorders 2 14
II. Used to Treat Asthma and Other Bronchial I)isorders 21 S
III. Used to Treat Rhi nit S and Cough 220
Re view 223
10 Drugs
on the Endoc;rine System ................ 225
I. Recepto<s 22:
II. The 225
Ill. The.
IV. Th('
229
, Pituitary :!31
c ot\, F. :,\'TS xi
V.
!rugs Acting on the G'Jnadai and Reproductive Sys tem 232
VI . h e Adrenal Cortex 2-11
VII. he Thyroid 245
VIII. - he Pancreas and GlueJsc 2-1 7
IX. he Calcium Ho meost.lt ic System 252
x. I eti noie Aci d and Deri ' ati ves 256
Revie Test 260
11 Dru Used in Treatm.ent of Infectious Diseases ... . .... 262
I. l l fcc tioLLS Di sease Tht' lapy 262
II. ntibacterials 263
III . . ntimycobacterial Age1b 276
IV. f nti fungal Agent s
v. ntiparasit ic Drugs 282
VI. I nti viral Drugs 2R6
Rcvie Test 293
12 Cane r Chemotherapy ........................... . .... 298
I. r rinciples of Cancer Chemotherapy 29S
II . lkylat ing Agents 299
III . t nt imetabolites 30:;
IV. atural l'rodm1s 1[6
V. I iscellaneous Agents 308
VI . . ewid Hormones and 4..ntagonists and Rel at ed Drugs 3 t 1
VIT. d junct Agents 313
Revie ' Test 315
13 'foxi logy . . . . ................... . ..... . . . . . . .. ..... 320
I. I inci ples ami Tl'rminology 320
II , ir Pollutanb 322
III . S )Ivents 324
IV. J lsec ticides and lIerbi Cldes 324
V. F Jlll igants and Rodenticides .326
VI . r avy Metal POisoning and Ma nagrml' nt
VII. l rug Poison ing 330
Revic Test 333
Com rehensive Exami nation ............... , .. . . . .. . . 335
lode .. ... .... ..... .. . . .. . . . . 353
I
)
I
General Principles
of Drug Action
Relati onships
.\ (' fh 1\ are producl'd by alteJing t he normal funclions of and in t he body
via orl\' of fou general mechanisms:
I. /1111'1 <14 i OIl IIi'" rn, p/on, n,lturally occurring target th,lt mediate th'
cffe('l s )f endogenous physiolo!,iC suu)tanoc's such as neurotrallSmitters and
a. figu e 1-1 illustrat t:'s the four majm ela s)e) of drug-receptor intl' TKtions. using specific
cxar lples of endogenous li gands.
(1) .iga nd-acti\'atcd ion dlannels. Figure J-IA illustrat es aC{,I)' lcholi ne interacting
ilh a n icotinic receptor ttlat b a nonspecific Na' (K' tr<lmmembranc ion channt'!.
teract ion of a moltlllie :If acetylcholine wit h each subunit of Ihe channel produces
conformational change that permits the passage of Na' and K'. Ot her ch,mnels that
re targets for include SpKifK Cab and K chan neb.
(2) ;-pro l cin--<oupled rcctplOrs (Fig. l -I B- lJ). G-protcitl-(: oll pled reu!ptors com
ose the largest of receptors. The receptors al l have 7 tra nsmembrane scg-
lents, 3 intracellular 10Jps, and an intracellul,H tarboxy-terminal tail. The bio-
glc activit} of the r{'('ertors is rnaliated via interaction with a number o f G (GTP
I inding)-proteins .
1) Ga,-coupled receptors. Figure I-IB il lustrat es a B-adn.': IH.Kef)Wr, which when
<Ktivated h} ligand linding (e,g., epi nephrine) eXChanges GDP for GTI'. Thi s
the migrat on of Get., (Gu,"m"l"'o,,) and its int eraction with adenylyl
t}"dase rAC). Cru.,-bound AC the pnxh,il"lion of cAMl' from ATP; cAMP
activates protein kin;.se 1\ , whirh acts to phosphorylate and acti-
vate a number of effe ctor proteins. The [iy dimer may also :Ktivate some efte<:-
Hydrolysis of GTP bound to the Go. to GOP terminates the signal.
) GOI
I
(G1nhobowr,)-i.:ouplet.l rt'Ccptors (Fig. I- IC). Ligand binding (e.g., somat ostatin),
to Gu; (Ga,nIub,,,,,, )<Ol pl ed ft'(eptors, simi larly .\(hangt'!> G'I I' for li DI', but Go,
adenylyl ere asc, leading to reduced cAMl' prOOuftion.
{-l (and GIl)-coupletl ft'ceptors (Fig. 1-1.D). (and G,,) int eract with ligand
(e .g., serotonin )-,Kti " ated recept ors and increa se the 3cth ity of phospholi -
pa'ie C (PLC). PLe: cI 'aves the membrane phosphOlipid phosphatidylinmitol
(Pil l) to diacylglycerol (DAG) and inositoll,4,S-triphosphate
(II'; ). lJAG protein kinase C. which can subsequently phosphoryl ate
and acti\aie a n umb. 'f of cellula r prot eins; II'. cau'ies the release of Ca
2
from
the endoplasmic ret iculum int o the cyt oplasm, where it can activat e many
cellular processes.
B
o
c
Figure 1-1 Four m,liar
A. Acetylcholine i
[l'Captors. B. Epinephrine
(G",h,b<,C<"J-<..'oupil'd
ATP cAMP
ACh nicotinic receptor
-Ion channel
Na+ Acetylcholine
Epi lephrine
l5-adrenoreceptor coupled to Gas
Somatostatin
ATP
cAMP _ PKA
/\
Multiple cellular
effects
Somatostatin receptor
coupled to Gaj
Serotonin receptor
coupled to G
q
P1P2f'\
IP, +DAG
/ \
Ca
2
+ Activates
PKe
of drug-I('n:'ptor inter.Ktiam, with specific examples of l'mlog<.'num ligillids.
with a nilOtinic [('(cpIO! , I ligand-activated ion channel. IJ-O. (jprotdn ...... uupll'd
i Witll a GCI.,-coupled p-<1drenoceptur. C. jTlIl'[J(liOrl with J G()'
Serotonin interaction wLh a G" (and Gil l-coupled receptor. (Colltinucd)
\
,liuta.
,
""
""
G
\
:tlVates
PKe
E
I utin receptor
00
y y
F
HSP90 !
o A
I'RI",C!l' L1'5 OF DRU( , Acno:'\ 3
Ins Jlin receptor-activated tyrOSlr'le
kinase activity
Insulin
C>
po,
00 po,
y y
IRS f\
IRS - P0
4
\
PI3 K
\
AKT
I \
:Orlisol actIVatIOn of
9 ucocor1lcold receptor
0
Cortisol
:
\
"{
\
e
HSP90
Pol II
:

CoA
NA NA
Transcription
figure 1 1 t(, "imlt'n) E. In\ulin inlf'ral"ti. )11 with a trniUl' l in,IS('. F. COIIJ'101 interact ion
"ith an In\ .3r.'1 lar nudear R'O"pLor_
(3) ccptor-acthated t yrm inc l;:inaSel> (Fig. I- I E). Many growth-rt'l ated si gnal s
.g .. are mediated via m<;, mbr;mi..' rCCCplor\ that int ri nsi c tyrosine
nasI" acthLty iIIusl ral('d f{) r the renptor. Liga nd hi nding CillN'S confor-
t al ional changes in the n ccpt or; '>OfHe fl-'('eptor tyrosi m,' l,:inascs arc rnOllOmE'r:'> that
mcrilt> upon ligand hilK ing. The liga ndl-d recepto rs then aut ophosphorylatt> tyro-
4 URS
(4)
sine which recruits cytoplasmiC proteim to the plasma membrane where
aho tyrosine phosphor.dated and aClh'aled.
'n''''''t'",,, nudear receptor.; (Fig. l - lF). (e.g .. corliwl) for nuclear recep-
lipophilic and can diffuse rapidly IhrouRh the plasma membrane. In Ihe
of ligand. nuclear receptors are inaClh'e bccau\(' o f t heir inl eranion ,,-Uh
proteins such as heal -shock pro tei ns like IISP-90. Binding of ligand pro-
changes in the receptor t hai facili late of chaperones.
receptors in lo the nuclt-us, hetcfo- or homodilllt'li l Jtion of receptor" . md

interaction with tl e lJ:'\IA of tarRet genes. I>NA-bound nuclear rt"(:ep-

la rs to recruit a d iverse numix' r of prOteins called coacti\'alors. which suh-
act to increa'>C t ramcripUon of the target gene.
2. \lft'1<I1 i"" III <It I il'i/I "/ ! 1//1/1/," t y activation or inhibition of 111(' ell l-rllle's catalytic
activit y
3. III/illll'/.,/mii ! in which the dnlg. acting a nonfunctiona l analo),:ue of a naturally
interferes with m 'rmal metabolism
4. \"II'lh', iii" 'I
I or pIli ,;uil ;111,'. ,I< ti u/ /\ such those caused by antacids. osmotic
agents. and
II. II\(' ,l( r.Hkd rt"I)(1!l\e ,1111 " e,'press,s al1 individual ' s response to increasing doses of a
given dHl,g, a pharmacologic response is proportlon"l to the number of lereptors
"'Ith which a d I interacts (Fig. 1. The graded curve Includes the fol-
lowing
1. is graded; that is, it willl the dose lip to the
maximal of the system. ami it is often lIt'pirtt'd a func-l ion of Ihe logMithrn of
the dose (t o see the relat O \ ' {'T a " 'ide range of doses ).
2. II) is the that produces the half-lla.\;. imal response; the thrt'Shold doS<' is that which
:1.
noticeable effect .
I lltrill,i, ' /1 is t he ability of a drug to elici t a response.
a .
b,
Agonists
(I) Full
(2)
drugs
cap.lble o f bindi 19 to, and activating, a receptor.
OCCUP}' receptoT<; ,md have an activit y of I .
can ou;upy rl'lt'ptors but (annot el idt a ma.\ima l Such
I an intrinsic activitY ::l f less than 1 (Fig. l -.{; drug C).
",",g' <ni ' i' bind to the receptor Ul t do not initiat e a response; Ih.lt is. they block the
agonist or endogenous substance that works through the recepl or.
e"m,,,,tiliY' antagonists comb ne " 'ith the same site on the t('<eptor as the a),:onist
little or 110 efficacy and an intrinsit' activity of O. COrllpcliti\(' antagonists
>n"vb, iccYC"iblcor irreversible. Reversible, or equilibrium. competitive antagonists
"'" no' f"y"''''''y "OIm".,hift the dose- respome cucve for the agonist to the cight.
Intrinsic ac,;vt'y

log (drug dose)
rigun:' 1-2 GrJ,kd
flUV(-" .
Flgun." ) 1 Grad d do:;e.-r{"!;pome
for two ago! (A and Bl and
a <l 1/;()nist ( I.
GF-NEIl\!: ('IUNCH'LES Of DRUG ACTIO); 5
Drug A Drug B
DrogC
ED50 (A) EDso (B) = EDso (C)
log (drug dose)
a intTease tht ED'i<'; tha is, more agoni st is required to dicit a r('<;pollSe in the
pr ',ence of the antagonist (I'ig. 1-4). Hccaust hightr of agonist ,all overcome
til ! inhibition, the maxim,!! response can obtai nl'd.
(2) N ncompetitive antagonists bind to the rccl'ptor a t a si te o ther than the agonist -
bi ding site (Fig. 1-5) and Pi t her preven t the from binding correctly or pre-
\ 1t it from activati ng the '('(ept or. Con<.<'quent ly, the effcct i\'(' amount of receptor
is educed. Recept ors unocl upied hy retain the same affmity for agonist ,
a t he ED,',(J is unchanged
4. ",,/, /III I" .11'11,\ reflect s t he relati ve amount of drug nceded 10 produce a gil'en response.
The pol cy of a d rug is determ ned by the affinity of a drug for its recept o r and t he
amount .f admi nistered drug thaI the r('Ceptar si te. The relat h'e potenry of a drug
can be d monstrated by comparir g the f.D'io) values of two fuJI agonbt); l he dnl g \\ ith t he
lower E is mo re potent. (for exampl(', in Fig. 1-3. drug A is more potellllhall drug H. )
S. , I" 1'f/1. ,., <If ,/ ,/111.,: is the maXIma l d ru)! eff('cI t hat can be achl('\'N.1 in a p.llit'nt under
a given s t of conditions. I:.fti.cacy may be .lffec\('(\ by stlt"h fanor) tilE' number of d rug-
f('Ceptor omplexes formed, the at ility of the drug 10 11\ "fe the receptor OIlC(' \t is hound.
and t he . atus of the target organ or reil.
6. \ '''I't' is t easured at the mid portion of the dose- rtspumt' runt. TIll' varifs for differ-
ent drug. and different responses. Steep inliil',!\(' that a change
in dose p oduces a large change ir
7. I ,,,ia/li/', refled.s the differenre , bttwetn illdividual s in r('spOrlSC to a given drug.
R. III( '''1.'' Ih illdt\ (1/) relates the desired thtrapt uti c tfftrt \(J toxicity; it is
dctl'rmin 'd using data provided b" the quantal cur\'\'. The therapeutic index
1 (gurl' 1_4 GrJ{ ed do\e- respoo\e
('UI'\'es iII ustrltlng he of COlll-
[It'tl l l\'p aIllJ$oni\
Drug X alone Drug X plus antagonist
MaJ;;mum response
unchanged
ED50 - Rtghl
Drug X dose (log scale)
6 BRS 1'11"","0"'1'''
Is dcflllcd a,
)X!pullltion 10

respome '
Dr J9 X alone
MaximuM response
DOJ9 X plus
al tagonlst
ED5Q unchanged
X dose (log scale)
FigUT{ 1-5
curyt's 111,' "ff, .. __ I,,,f "0"-
lOl11].X'ti ti n' antag:oni,I,.
the ratio o[ th" that pmduce, ,\ tU'I;ir l'ffl'ct in h,llf uf tile
Ill al the desi red effect in hall of I he populati on). Nu\(' that
i index should be ' vith caution In wilen tile qH,mtd l du'>t'-
tor the desirt'd and tox ( effects arc not )laralll'l.
I h< qU,IILI,LI [ rl'\jloLL\(' < Ul\ e (Fi gs. I 6'\ and J-6BJ rda les Ihe dosage of J drug to the fre-
quency with response will 'Jl"(ur within" population. r he may he an
(e.g. , t' tht'f do Of do not fall askep after h'1,:ei\' ing a \'<1.1-
live) or \Ome in tensity of cffl' c . Tht;' quanta I dose- rt'sponse OHve is ohtained via
tramformalioll o f tlata used for a frcquel c}' plot 10 rt;'flt'{' t the cumulat i\(' Ire-
quency of a tht' conted of Ihe quan tal doS<'- re'> pOflM> wn't', ED", indicates Ih ... dose
of drug t hat response in haH of til > populatioll . (Nolt' that th is differs from t he mean-
ing 01 EO", in a ' curve. )
II.
Omg absorpt ioo is
In many cases, a
bloodstream.
1ll0vemt'nt of a drug from it, Sit" of admillhlratiOIl illlo the blOO(htream.
must be aclO,S one or morC' bioklgi( to rearh the
\ 1)l'u).:, tl',Ill'I'.,rl
1. /lit/lllj,,,, of
illl<; bi o logic
Diffusion ca n
1'0" ml'mhr,llll''i
" I " drll.\'\ is tht' lTI)st (ommon and most important 1110d ... of tfdvt'rs-
1 drugs diffu',e paSSively down Ilwir cOlKl'ntra tion grMlient.
influenced by the lipid- wn ter partition cOl'ffident of the
ratio of solubility in ,m organic soh'ent to hi lily ill JI1 ,1<l\leO\lS soll!-
,en"'I' . ab<,orption incn2a,>t''> LS lipid solubility (pMtilion (tw!tiril' nt) innl'a,es.
also can intlut'nt't' d ffu sion include the fOl1lelll ration gradit'!lt of the
dnll<; cell memil ralll', and thl ' su rface area 01 the cell r)1el11br'HW.
2. I)il/ll,j,,, Of tlr.1I "rt' lI("a l.. de,t (lh tn
a. Only Ihe of drug c II I diffUM> "(fOSS biologi c Il)('mhralles.
h, The dtgree of a weak dl id or bilse b determined hy Ihe pK nl Ill(" tim); all(l
pH of liS according to tht' lIt' ntierson-lIi1ssc lbal ch equation,
<I) . adtl, A,
H +A ,
pK + log(A- ]I(HA]. and
]I1I1A] = pH - pK
t he cOllct'ntlation \I f the prolonatcd, or unioni /('d. form of till' ,Kid
"the concentration of li re ionized, or unprot o nated. form.
"
,
40
<
, 30
!
,
20
10
0
A
2.3%
-
001
Gt:KERAL OF I"lRU(, ACTION 7
13.7"{,
i
13.7"1.
-
2.3%
.....
00.1 10 100 10000
Drug dose (log scale)
(97.7 + 2.3 '" 100%)
100 _ -_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_- - - --
(84 + 13.7 '"
--- -- -- -- -- -- -- -- ---
I{, A. ft'4u .... m-y
lion plot. ""um >r of individuals
IX'rccllIagl' 0 1 Ih populat ion) who n"-
\.jilin' lilt' InlllcalE I drug dose 10
all 1lli:lI1i(JI nsi'. As iIlmlf aled.
2 .. 1% of II .. , P"I ,Iil hon ' <'quirl' 0.01
10 .'"hi!.>i l Ill" 1J.7%
't'(j ulrt> 0 1 nd so on. H. Quanta!
Cl .\t'. TI'e tumulati n'
!llt m ...... r of indhi uals (as a percenugl'
of lIlt' pl.!pu[atiut ) who will rt'slxmd if
thi' i!ll\",II<'u do . of dmg is adminis
tered w tlw cnti 'population.
(2) I r a weak base, B,

80
20
B
pI! = pK + log [BlI[BH' ], a (1
log [Bl/[BH-l = pH - p)(
(SO + 34 '" 84%)
(16 + 34 '" SO"o)
_________ (23+137=1600)
(2.3"0)
.01 0.1 10 100 1000
Orug dose (log scale)
\ here HH is tilt' COTKl'n -ratiun of the protollatt'd form of the base, and B is the
ncentration of tht! unprotonatt'd form.
e Whe 1 the pK of a drug cquah the pH of th(> 50')(' ionizat ion O(curs; t hat
IS, l'l ual numbers of ionized and unioni7ed spC'Cies .:tre pn'st' ll t. A JOWl'T pK r(>fll;"{'h a
'er acid; a higher pK corresl>onds 10 a st ronSt.>r bast'.
J . Dru . wit h d ifferent pK valu( s will diffuse across .It different hiles.
C. rh(' H of t he biologic fluid i 1 which the d rug afl ('Ch t ile degree of ioniza-
t ion IIld. th(' rcfort' . the rate { f druK t ransport.
3. \,,' iI t fIIl/\fJj"" h an enl'rgy-dl'pcndcnt that ca n move a concen-
t ril l ion ' radient , as in protein-mediated transport syst e ms. /\cti\(' tramport (K'curs in
only 01 e d irl'(:tion and is sat ut ablc. It is usually the mode of for that
actively transported cldogenous substances such as sugars, ami no acids, and
nuclem des.
8
It
"'"
4.
5.
"
t.
2.
I i//'oI/i",
;,
bulk flow of solvent and solute t tHough \j)()re\, in the membrane.
wi th molenlles usua lly with a molecular " 'eight than 100) th<lt
pores. Some sumtamcs of greater molecular wdght, surh as (ert<lin pro-
filt ration
can 1)<1
loan be through mtercetiu ar channels. Concentration gradicnh afft'i.1 the r3te
of li ltrat lon.
I ,I,
" if",,, .. t .t" I"";"" is movement of <I ' ubstancc down a concent ration gradient_ Facilitated
medi<Itt'tI, a III saturable; it not requi re cn<'rgy.
'111\" PI ,a tlun
11/.// , is the most convenient, t'Conomk;II, .lIld common rou te of admin-
I safe for most hlratlon; it is
,.
Sites o f
( t )
(a)
(b)
(2)
(b)
I
and weak acids, which all: normillly un-ionized at the low
to 2) of gastric cQ11IeTlts, may bt' ab)orbed directly from the stomach.
bases and strong acids (PK = 2 to 3) are not normalJr absorbed from this
since they tend to be protonated at low pH.
small intt'stine is the primary site of ahsorption of most drugs bl'cause of
l<lrge surface area a':ross which including partially ionized weill-<
and may rJiffust.
nonnallyabwrllt"l.! more t'xtensi\,{'ly from the small intestine than from
even though the in testine has a higher pH (approximately 5).
b. The
leaches
lily of a lIrug is th,> fraction of drug by any that
unaltert'(1 lbioavallabillty = I for intravenous administ rat ion).
to the condit i()11 in whk h the plasma conc{,ll tralion VS. t ime pro-
formulations ale it entkaL files of
effect influenct'5 (h ug i1bsorption metabolism in the livcr or by (I) r he
biliary

the
."fter ahsorpt ion from Iht' :.tomar or small inl esti ne, a must
the Ii"er before rNching t he irt.ulat ion ;md its target site. If
of liver metabolic enzymes to inact lv;i tht' drug i:. great, only limited
. of active druK will escolpe the process. $om drugs ar .. metabolized so exten-
,;,,",, ' , f<"SUIt of hepatic met.li-olism during the Ii t p..l) th,1I it j)H'('lud<"S thdr use.
that may <lltef abs' Jrpti on from the cll or small intestine illclude (2)
th e
(,)
(b)
emptying time and Jassage of drug to thc in stine may be intluenced
and intestinal motility. 'r wd emptying t im\:' gen-
decreases till;' rate of a11sorptlon because the intcstine is the major ahsorp-
for orally adII ini5tert'd
(GI) blood flow plays an important role in lirug absorption
b I the concentration gradicnt across epi thelial rTlCrTl-
"rhe absorption of SIThlll, very lipid soluble molecules is "blood !low Ii Ill-
whereas high Iy polar Illolenllt') ,Ht' "blood flow independent."
(el and inactivati ng enlymes may destroy certain drugs. Enteric coat-
brea\.;dowll of t Iblets by the acid p! I of the stomach.
(d) with tood, ottl( T drugs, and other constit uents of the gastric milieu
)
influence absorption.
in oral preparat ions or spt'i. i'll formut;lIion of t hose prepa-
may alter abwrptioll .
,. includes thft"(' major intr(wcnous ( IV), intramuscular
(1M), and (SC). Parenl<'ral administration generally in more pre
dictabl e ' than oral administ ration.
a. Wit h IV , the drug is Inj<'Cted d irectly into tht: blOQ(btrea m (lOO'tJ bio-
available). represenh t be most rapid means of IIl t roducing drugs in to the body and
in the treatllltnt of emerlo:encies when absolut e control at dTug
a' Is essential.
GENERAL I'RINCIPLES OF DRUG ACTION 9
b. !loftt 1M and SC admi n ist ration, many drugs can enter thc capilla rics directly through
s" between endothelial cdls. Dt.<pot preparations for release may be admin
ister by 1M or SC rout es, t SOUle preparations may cause ir ritat ion il lld pain.
3. Orill" I "t /I,lmlllj\lruri oll
a. lnh alio n results in ral}id ahsorpti on of t he large surface area and rich blOlXl
y of t he alveoli. Inhalat ion is frequently used for gaseous ancsthetics, bu t it is gen
crall' not pract ical. In halation may be useful for drugs that act on the airways, such as
epin phri ne and glucocort icc ids, which are used to t rea t bronchial ast h ma.
b. Subl ngual administrat ion uscful for drugs \\ith hi gh fi rst -pass Illetaholism,
as n' roglycerin, sim.:e hepat ,c metabolism is bypassed.
c. Int r thecal administration i, useful for drugs that do not rtadily (ross t ht' blood- brain
barn r.
d. Reet I administration minimizes first-pilSS metabolislll ,llId !IIay bI; used to circum
vent the nausea and vomilmg that sometimes result from oral administration. Use of
rect admi n istration may be limited by il1("Oliveniel1("t:' or patient noncompliance.
e. Top' al administration is u', ed widely when a local effect is desired or 10 minimi ze
sys! mic effects, espcriall y ill dermatology .Hld ophthalmulogy. Preparations be
noni ri uting. Not e t hat drug' administered toplc,llly may somet imes produce systemic
effec s.
'iiI. Dru Distribution
Drug disrnbuti )fl is the movement of , drug from the 1 to Ihe various tissues of t he
body
\. ()I \ trihuti 11 IIf IS t he proces by which a drug leavcs I I bloodstream and enters the
ext racellular fl ids and A tlrug must di ffuSt! auoss cellular elllbranes if its site of act ion
is in t ract'"llular. In this case, lipid solubi lit y is import ant for effect i\ d istribut ion.
1. IIII/h'F" 1I< t' ,,/Mm,,1 0011
d. In m 'I tissul"S, drugs can leav! the Circulat io n readi ly by dlffusio across or between cap-
illaT) endothel ial cells. Thus. l he initiail"dte of d istri b ut ' n of a rug depends heavil y
on <XXI flow to various org;ms (brain, Jj\'er, kidney> muse c, . n > fa t , bone).
b. At e uilibrium, or st eady st at e, the alllOulli of drug in all organ b related to the mass
of t organ and its as well as to the properties of the specific drug.
Z. I "II/III. <II dhl ,UIII! iVII ( I .,) is tl e volume of total body fluid into which a drug "appears"
to distri ute. Volume of distribu1ion is determined by adrniniS1l'ring a known dose of drug
(cxpres >d in uni t s of mass) iTltwvl;'nously and measUring tlw initial plasma ('onrentration
in unit s of mass/volume):
V,I '= ambunt of drug administered (m/g)!inilial plasma concentration (mwL)
Volurtlt of distribution is expres ;ed in units of vo lume. In most cases, the "initial " plasma
concen ration, Co, is determinec by ext rapolation fromllle elimination phase (see IV).
a. Stan ard va lues of of fluid t'ompartmenu in un ave r<l)!e 70-kg adult are as fol -
lows plasma'" 3 liters; extracellular tluid = 12 lih: rs; and tutallKxly water'" 41 liters.
b. Fea res of volume of distrib...ltion:
(1) "values for most drugs do not their actual distri but ion in bodily flu-
i Is. The use of V" values prima rily conceptual; th;1\ is. dru/(s t hat distribute exten-
vcly have relatively Vd values and viCe
(2) j very low Vd \'a lue may indicatc extensive plasma protci n bindi ng oi the drug. A
\'ry h igh value may indi ;ate t hat the drug is bound to
(3) I mong o ther variabl es, rna)' be inOuenced by age, sex, weig ht, and disease
I rocesses (e.g. , edema, a,ci tes).
3. IhllS It describes when thc rciati\c of a drug in t he hod}' changes
wit h til Ie. This is usually seen with highly Jipophilk )tl("h thiopental that ini-
tially elter tissues with h igh bl(oo flow (e .g., the brain) and then quickly redistribute to
jth lower blood flow (e.g., skeletalmusde and ildipoSl' th)ue).
4. 1I,/nit-" I ..
a.
d i \ I rilml itm
( 1 )
poorly
(2)
(3) Th'
b. Placental
( I )
with a
,
nature of the blood-brain barrier, ioni7cd o r polar drug5 distribute
including certlin chemotherapeuti c and toxillompounds,
must pass through, rather t han hctw('('n, ('ndot ileliai cells.
such as that resulling from meni ngiti s, Illay iI1CIt'ast' tht' ability of
solubl t' drugs to ,:ross t h(' blood-bra in barri er.
barrit'r may not b(' full y d('\elopcd at t he time of hirth.
drugs cross the pi, lcental oorrier more e,tsil y tha n pol ar drugs; drugs
less ttan 600 pass the placental barrier hett cr than largt'[
(2) Thl' that drugs administered to thl' mother may cross the placenta and
reach fetus is always an important consideration in therapy.
(3) Drug '''in' PC""'" (e.g., the P-glycoprotein transporter) transfer out of the
fetus.
1\ lIiudin;.: III \Irug\ pr"h'i m . Drugs in the plasma may in tl1(' free forlll or may
be bound to plasma plo",'oo>OT otht'r blood components, such as red blood ("' Is.
t. ("/1..,,,1/, ,/fill \ of /I/IIIII"'I"otri"
a. plasma protein binding is highly variable and fror virtually (jJt, to
mort: t han bound, depending Oil the spedfic drug. IHnding gener lIy rewrsible.
b. Only the drug diffuses through \:apillary walls; ('xtemlve hinding tards the ratt'
at which drug reaches its site of .Ktion and may prolong durat ion 0 etion.
c. proteins hind many di fferent drugs, whilt o thcr proteins hin Iyone
or a I number. 1;01 example, .erum albumin tends 10 b ind many acidic ugs,
while glycoprotein tends to lind many ba:.il" drugs.
d. There are if any, documented ehangl's in a drug's effect du(' to chang('s n I sma
protein bl'"'I'n".
\. \lnh,lrlL\rrl\ of 'dimin.Llion .lnd tl'rminalion pi O"llti(\ll
1. In most cases,
Inact ive (or
other
action of a drug is tC ' minatcd by enzyme-catalyzt'd conversion to an
artive) compound and/ or elimination from the body via the kidney or
2. drugs from the sitt' of a :tion may terminate the action of a drug, although
mple, the action of the anestll etic thiopental is termi-
)1 from Ihe hrain (where it initially accumulates as a result
solubility and the high blood now to that organ) to tilt' morl' poorly per-
B 1{.Ih tWill t he IJodl
I . F ir"of./, I , . . The eliminatior of most drugs at therapeutic doses
un the eonet'ntration of drug in the plasma. and is
of drug mul tiplied by a proportionality cOIutant:
from body (maSS/Time) = Constant x Dmg
l
" .. "" (mass/vol)
Because the eliminatio n is gi ven in unit!> of ma!>!>{lime and concentration is in unit s
of t ht' units of the consta 'l t arc volume/time. Th is constant Is referred to as
the IV C).
2. //"1" "1"./,., '"ull'l< ,. Infrequent ly, the rate of eliminati on of a drug is ;' zero-order. " In this
case, thie' by which the body eliminates the drug (e.g., metabolism by hepatic
enzymes, secretion in the kidne is saturated. The rate of drug elimination from
the body is constant and does not depend on plasma con centration.
L I:I'[R,\L PRINCI PI UI UlI. lX; 11
( It .n UH. t {( I ). Conceptually, clearance is a measure of the of the bod}' to remon ' a
drug. ).Iathcm tkally, clearance h the poportionality constant that the rate of drug elimi
nation 10 the )Iasma concentration of the drug. Thus, drugs with cl earance are rapidly
removed trom he body, and drugs with "low" clearance are removro Slowly. As noted in IV R, the
units of clearal (e arc volume/time.
I. \/ ', , if I( o rXlll1 dew,III<. is the c,lpaclty of an individual organ TO {'lil11in;lt e a drug. SpeCific
organ c ea rance may be dut to metaholism (e.g., "htpatic clearantC" by the liver) or exere-
li on (e . . , "rtnai clearance" by tlimination in the urine).
Rat( of elimination by organ " CL. """, x Drugpl.i..,.. pnf ..... ,,"'5'''
Cl ..... .. , :0 Rate of elimination t ..... , .. I_""" ... n <p>
2. I I I, .. ,. "til ( , ... m"". is the cap.lcity of the body to eliminate tht' tlnlg by all
r hl.! H:f e, whole hody clearanct is equal to the sum of all of Ihe organ clearanl'e
!I1l'chal bms by which the "Cliv( drug is eliminated from the body:
CL", ol< 1..,Jy '"' CL",g.>n I + CI , .. ,.,." + . , +
rh e ter 1 "dearancc" genera!ly to whole body clearance UT!
in t hi s
Rate f elimination from !xxI) .. CL
wholttw
, x Orug['lo"'"
and
CI. 0 Rate of elimination from
1. 1'/" IIIItl I" ,Iltmtl' h the as whole hody de .. r;ulcc, but I minology
1<' imes used Ix'Gtuse clearance may be viewed as the \'olu1ll t:' of pl' ('011 1 .. im
thl' am( unt of drug removed pe ' unit time (re<:al! thaI the unih of clearance are volurnt /
lime) . I not specified, this term t o the volume of plasma "cleared" 01 drug by al!
l)(x li Iy I lechanisms (Lt:'., whole hody cle,Hanct:'j , Thc term may be appl ied to clt:'aranct
by C organs; for examplt, renal plasma dtarance is the volunw of plasma contain-
the ITIlOunt of drug elimina1ed In the urine per unit time.
Biot nsformation etabolismLof Drugs_
-\. (,c11u,11 pi lpl' rlic<;
I. Bi otran ormation is a major for tJrug elimination; drugs undergo bio-
transfor nation, or meta holism, " fter they cnter the body. Biolramfor1l1ation, which
oducts metabolites that Ire more polar t hil n the parent drug, usually tt:'rmi nalcs I h('
pharma ologit' action of the part nt drug and. txcretion, r('moval of the dnlg
fro m til body. Howcvcr, Other {tmSCCjllcnces arE' possible. notably afit'r phase i reactiom,
ind udi simililr or different pharmil('oiogic activity, or toxicologic activit y.
2. Many d undergo severa l sequential biotransformation reacliom. Bio transformation
is catal} .ed by specific en1.yrno! systems, which may also catal },1e Ihe lllt:'tabolislll of
t' ndogel ous substances such as slt:'roid hormones.
:I. Th\, Ii\' ( is the major sit e of hi )transformati on, although may undergo
blOt ran . ormation primarily or 2xtensivt'ly in other
4. lhomlll 'ormation of drugs is viuiablt: and can be afferted by T11ilny il1cluding
pri or a( ministration of the drug in qut:'stion o r of ot her drugs; diet; hormonal status;
disease (e.g., decreased in cardiac and pulmonary age and devl'lop
1l1t:lltal tatus (thc very t'lderly ,lnd V('fy young may he more Sl'llsitive to drugs, in part.
hccause of decreascd or undcnloped I('wb of drug-mctabulilill/ol enzymes); and liver
fun cti o (i n of liver damagt, dosage adjustmertts mily be requirro for dru/ols
l'Iimindt largely via this route)
5. onsequenccs of biotransformation indude the production of inaclh'c metaho-
lit es (n1l st common), metabolite, with increa'>t:'U or decrea<,ed pOtendt's, wit h
12 ,"S 1'1I.',RM" ec' l o<iY
"
cent pharmacologic;: cUons, toxic or active met aholites from
inactive p
6. Metabolites olten more polar than the parent increased polarity may
lead to a ' rapid rate o f clearance X'cause of possible by acid or base carriers
in the '"'n,,,1 it may also lead 10 deCieased tubular reabsorption.
.It._ III hi ot r.lIl slur mati o n na(
I. /,/,,'\, I ti o ,',',J< tilm, joval\"{' enzyme-catalyzed biotra nsformation o f the
drug any conjugations. I real'lions indmh.' oxi dat ions, reductions, and
they frequently introduce a fum.1ional KrouP (e.g .. -011 ) that sel"es
3!. the at live for sequential conjugation in a phase II reaction.
2. 1'/1,1\, 1/' ,\ ,,, 1,,,,,,. j nm t i(ll/\ include conjugati o n react ions, v\'hich involn' the enzymt' -
catalyn' d of a dmg (or drug mt'taboHtc) with an t'TldogeTlous sub<; tance.
Phase 11 require a functional group-an active center-as tht' si tt' of conjugation
with th\' sub,lanct'. 11 readiom require t'nt'rgy indirectly for tht'
thesis of carriers," the form of the endogenous substamc in the conjuga-
tion reaction UDP-glucuronate).
( I lll\rnn ",,,,I,,,,,, phaR I fI:,H li , ' n, Include cytochrome 1'-1,.50,
aldt'hyde deaminases, esterases, amidases, and epoxlde hydratases.
c. phase II biotransform' ltion reacti o ns include glucuronyl (gl u-
curonidt' conj (sulfa!t' wnjugatioll), tram,Kylast's lamino acid wnjuga-
t ion), methylases, and g utathione transferase. These enzymes are present in
in plasma. Subcellular locat ions include cytosol, mitochondria.
I Only t hose enzymes loca ted In the endoplasmil reticulum are inducible
hy
I . (.(11<11/ lilt
a. Gcncrdl . (Table I-I )
b.
c.
(I) P-4S0 monooxygenase plays a central i n drug biotransfomlation.
12)
(3)
(4)
() )
numilcr of families tatl!a,t HI in mamma ls) of cytOChrome P ... 50 (ahhrcn-
"I:VI''' ) en7yme'\ exists, e.ch member o f cat alyzes the bi otransforma-
unique spectrum of drugs, with sonl(- overl ap in the subs;t rate specifi ci ties.
is the one InO"t ill\'olHd in J reactions.
T l'-4S0 families ar' referred to using an arahic numeral, e.g., CPl ,
C.g.,
Each family has a numilcr of denot ed hy an upper case letter,
Cl'''''.A CYP2H, etc. The inllividual em:ynlCs within each subfamily arc denoted
by
(vtOll
1
,lIld '
numeral, e.g, C:YP:V, 1. CYP:iA2, ctc.
, 1'-450 catalyzes Ill,merous reactions, Including aromatic and aliphatiC
i ; dealkylations .Jt nitrogen, sulfur, and oxygen atoms; heteroatom
at nitrogen and sulfur atoms; reductions al nitrogen atoms; and ester
hydrolysis.
T'," b [espomible for up to half of the total cytcx:hrome P-4S0 in
"'I' ""d :"':0,,"'" for approximately S09() of the of clinically unpor-
. CYP3A4 is a partin lally ilbundant enzymt>. tant
The
cillc
ot her
loca ti on of cytoclrome P-4S0 liver, whkh t he spe
1 i and t h.' highest total activity, but It is aho found in many
including the adrenals, oVarjes and teslis, and t issues invol\"ed in
and nit tabolism. The enzyme's suocellular locat ion is the
reticulum. l.ipit membrane locat ion facilitates t he metabolism of
drugs.
of reaction
(I) In o\"Crall reaction, the crug is OXidi7ed and oxygen is reduced to water.
equivalents are provi ded by n iCOti namide adenine dinucleotide phos-
and generation of thiS cofactor is coupled to cyt ochrome P-450
\