USMLE Step 1 Web Prep NSAIDs & Antiinflammatory Drugs

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Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Most NSAIDs are nonselective inhibitors of cyclooxygenases acting on both !"# 1 $ !"# % isofor&s for&ation of '(s $ thro&boxanes) !"# inhibition *n+erlies anti,yretic antiinfla&&atory $ anti,latelet actions of NSAIDs $ &*ch of the toxicity) As,irin -ASA. is the ,rototy,e an+ the only NSAID ca*sing irreversible inhibition of !"# for&ing a covalent bon+ via acetylation of a serine hy+roxyl near the active site) ASA actions are +ose/+e,en+ent)
SLIDE 2 of 9

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Acetylsalicylic acid (ASA, aspirin)

Anti,latelet: lo1 +ose irreversible

2xA% / ,ost/MI ,ro,hylaxis)

Analgesia: '( actions to sensiti3e ,eri,heral ,ain rece,tors to algesic &e+iators s*ch as 45 $ hista&ine) Anti,yresis: ,yrogens I6/1 '(7% lo1ers it bac: to nor&al in hy,erther&ia) te&,erat*re 8set/,oint9 / ASA selectins $ integrins

Anti/infla&&atory / high +oses via !"# % inhibition $ -,ro&oters of le*cocyte a+hesion.) ;rate eli&ination: 6o1 +ose <igh +ose t*b*lar secretion hy,er*rice&ia) *ricos*ria) t*b*lar reabsor,tion

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SLIDE

of 9

Aspirin! Acid"#ase $ Electrolyte %alance

&ig' () dose!

Mil+ *nco*,ling of oxi+ative ,hos,horylation lea+s to

res,iration

'!"

res,iratory al:alosis

renal co&,ensation toxicity)

<!">/ eli&ination <!">/ '!" .) In a+*lts this

%

co&,ensate+ res,iratory al:alosis -,< ? nor&al can be a stable con+ition in chil+ren *o)ic doses!

Inhibition of res,iratory center ,<

res,iration
%

'!"

res,iratory aci+osis -

<!">/ nor&ali3ation of '!" .@ ,l*s inhibition of 5rebs cycle $ severe A2'. &etabolic aci+osis 5A.)
SLIDE + of 9

*nco*,ling of oxi+ative ,hos,horylation hy,erther&ia $ hy,o:ale&ia 145705 >>> 0:10:4%

Ad,erse Effects of Aspirin

(I Irritation: gastritis *lcers blee+ing)

Salicylis&: tinnit*s vertigo hearing 4ronchoconstriction / exacerbation of asth&a) <y,ersensitivity: Btria+B of asth&a nasal ,oly,s $ rhinitis) Ceyes syn+ro&e -very rare. Anti,latelet: !hronic *se ,rothro&bin ti&e -high +ose.) renal +ysf*nction '(s. $ hy,oglyce&ia) effects of s*lfonyl*rea (I blee+ing

Dr*g interactions: ethanol hy,oglyce&ics $ 1arfarin

effects of *ricos*rics)
SLIDE - of 9

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Aspirin .,erdose $ /anagement

7xtensions of ,har&aco+yna&ics vaso&otor colla,se 1ith res,iratory $ renal fail*re) No anti+ote E &g&t) incl*+es gastric lavage -AF/ activate+ charcoal. ,l*s ventilatory s*,,ort an+ correction of aci+Fbase $ electrolyte i&balance hy,erther&ia $ +ehy+ration) *rine vol*&e $ al:alini3ation facilitates renal eli&ination) ASA +oses associate+ 1ith severe toxicity ? 150 &gF:g eG*ivalent to ingestion of 10g in a ,atient 1eighing 70 :g) In a chil+ -10/1% :g. 4/0 tablets can be life/ threateningH
SLIDE 0 of 9

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.t'er NSAIDs

Ceversible inhibitors of !"# 1 an+ !"# %) Analgesia: :etorolac > ib*,rofenFna,roxen > ASA (I irritation I ASA) Aci+Fbase +ysf*nction: &ini&al no effects on *ric aci+ eli&ination) Allergy: co&&on ,ossible cross/hy,ersensitivity 1ith ASA) !hronic *se: ne,hritis ne,hrotic syn+ro&e ac*te renal fail*re) Dr*g Interactions: activity of s*lfonyl*reas M2# $ 6iA -not ASA.) In <2N &ay activity of A!7Is loo, +i*retics $ beta bloc:ers) S,ecific toxicities: in+o&ethacin -he&atotoxicity. s*lin+ac -,ancreatitis. +iclofenac E he,atotoxicity)
SLIDE 1 of 9

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Selecti,e 2.3 2 In'i#itors !elecoxib $ rofecoxib at thera,e*tic +oses selectively ca*se reversible

inhibition of !"# %) No &ore effective as anti/infla&&atory agents@ &any actions G*ite si&ilar incl*+ing ,otential for ne,hrotoxicity an+ hy,ersensitivity) Main +ifferences: less gastrointestinal toxicity $ less anti,latelet actions) Increase ,rothro&bin ti&e -'2. 1hen *se+ 1ith 1arfarin $ &ay exert ,rotho&botic effects via inhibition of en+othelial cell f*nction) !elecoxib is cross/allergenic 1ith s*lfona&i+es)
SLIDE 4 of 9

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Acetaminop'en

No inhibition of !"# in ,eri,heral tiss*es $ insignificant antiinfla&&atory effects@ analgesic $ anti,yretic activity ? ASA ,robably +*e to inhibition of cyclooxygenases in the !NS)

!o&,arisons 1ith ASA no anti,latelet action) not i&,licate+ in Ceyes syn+ro&e) no effects on *ric aci+) not bronchos,astic) (I +istress is &ini&al at lo1/&o+erate +oses)
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SLIDE 9 of 9

Acetaminop'en &epatoto)icity

Metaboli3e+ by liver gl*c*ronyl transferase inactive conJ*gate) Minor ,ath1ay -via '450. for&ation of a reactive &etabolite -N/ acetylben3oG*inone i&ine. that is nor&ally inactivate+ by (S<) In "D stores of (S< are +e,lete+ toxic &etabolite ca*ses na*sea $ vo&iting ab+o&inal ,ain liver fail*re -centrilob*lar necrosis.) !hronic ethanol enhances liver toxicity via in+*ction of '450) Manage&ent: N/acetylcysteine ASA')