Kaplan High-Yield Pharmacology PDF
Preview Kaplan High-Yield Pharmacology
Pharmacodynamics and pharmacokinetics Pharmacodynamics and Pharmacokinetics Matthew B. Wilkinson, PhD, M4 #$%&'"()&*)"(+,$$-"$."#/0)+)&/" PPHH0011-- !" Enzyme kinetics 1 Enzyme kinetics V = maximum reaction velocity for a given amount of enzyme max • Proportional to enzyme concentration Michaelis-Menten plot Substrate concentration [S] (mM) Kaplan Biochemistry 2011: Figures I-8-4 FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 PH01- 2 ME 3e: 55 Enzyme kinetics 2 Enzyme kinetics 1 Michaelis constant (K ): Substrate concentration required to reach half V = m max affinity • High K ! low affinity m • Low K ! high affinity m Michaelis-Menten plot Substrate concentration [S] (mM) Kaplan Biochemistry 2011: Figures I-8-4 FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 PH01- 3 ME 3e: 55 Enzyme kinetics 3 Enzyme kinetics 1 Michaelis constant (K ): Substrate concentration required to reach half V = m max affinity • High K ! low affinity m • Low K ! high affinity m V = maximum reaction velocity for a given amount of enzyme max • Proportional to enzyme concentration Lineweaver-Burk plot Kaplan Biochemistry 2011: Figure: I-8-5 FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 PH01- 4 ME 3e: 55 Enzyme inhibitors 1 Enzyme inhibitors Competitive inhibitors • Resemble substrate, bind at active site • Increasing substrate concentration can overcome inhibition • Decrease potency Non-competitive inhibitors • Typically bind at allosteric site, not near active site • Cannot be overcome with increased substrate concentration • Decrease efficacy Competitive inhibitor Non-competitive inhibitor Substrate Active site Allosteric site Enzyme Enzyme FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 PH01- 5 ME 3e: 55 Enzyme inhibitors 2 Enzyme inhibitors Competitive vs. Non-competitive inhibitors Competitive Non-competitive Resemble substrate Yes No Overcome with "substrate Yes No concentration Bind active site Yes No V No effect # max K " No effect m Pharmacodynamics #Potency #Efficacy Graphs cross? Yes No Non-competitive 1 / (velocity) Competitive No inhibitor Lineweaver-Burk plot 1 / (substrate concentration) FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228 PH01- 6 ME 3e: 55 Volume of distribution Volume of distribution total amount of drug in body Volume of distribution, V = (liters) d [drug] plasma Low V (4-8 L) mostly in blood d Mid V (12-14 L) mostly extracellular fluid d High V (>total body water) distributed in all tissues, non-fluid compartments (fat) d V of plasma protein bound drugs are altered in liver and kidney disease d • Hepatic disease: ! synthesis of plasma proteins • Renal diseases: Plasma proteins (and bound drugs) are excreted in the urine FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228 PH01- 7 ME 3e: 166 Drug clearance Drug clearance Rate of drug elimination Clearance (CI) = = V x k Plasma drug concentration d e • Clearance refers to the volume of blood totally cleared of drug per unit time • Units: • Rate of drug elimination: (mass)/(units of time) • Plasma drug concentration: (mass)/(volume of plasma) • Elimination rate constant (k ): t-1 e • Renal clearance: • Clearance: • Equals glomerular filtration rate (GFR) when there is no reabsorption, secretion, or plasma protein binding • Inulin and creatinine clearance are used to estimate GFR • Protein-bound drugs are not cleared • Clearance = (free fraction) x GFR FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228 PH01- 8 ME 3e: 166 Drug half-life Drug half-life • A1$%&'"$."21/")'"'*3/4".$5"*&"*1$%&'"$."05%6")&"',/"7$08"'$"+,*&6/"78"$&/",*-." 0.7 x V d t = 1/2 Clearance • Half-life relates to both a decrease in plasma concentration via elimination or an increase in plasma concentration via drug infusion • Steady state is reached in 4-5 half-lives with continuous infusion n t1/2 1 t1/2 2 t1/2 3 t1/2 4 t1/2 5 t1/2 [drug] 50 % 75 % 87.5 % 93.75 % 96.9 % FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228 PH01- 9 ME 3e: 166 " Loading and maintenance doses Loading and maintenance doses Loading dose C blood plasma conc. p Cl clearance • Large initial dose given to fill up V d • Can increase plasma concentration in less than 4-5 half-lives F bioavailability V x C d p LD = F Maintenance dose • Given to maintain constant blood plasma levels • Lowered if hepatic/renal function is impaired Cl x C p MD = F Bioavailability (F) F = 1 for IV infusion • Fraction of administered drug that reaches systemic circulation • Some drugs fail to be absorbed, or are metabolized before reaching circulation FA 2012: 259.2 • FA 2011: 233.1 • FA 2010: 229 PH01- 10 ME 3e: 167 Drug elimination Drug elimination Zero order elimination • Constant amount of drug eliminated with time • Phenytoin, aspirin, ethanol 100 mg ! 90 mg ! 80 mg ! 70 mg ! ! First order elimination • Constant fraction of drug eliminated with time • Most drugs follow first-order kinetics 100 mg ! 50 mg ! 25 mg ! 12.5 mg ! ! (cid:52)(cid:70)(cid:68)(cid:85)(cid:74)(cid:80)(cid:79)(cid:3)(cid:42) (cid:3)(cid:79)(cid:3)(cid:3)(cid:40)(cid:70)(cid:79)(cid:70)(cid:83)(cid:66)(cid:77)(cid:3)(cid:49)(cid:83)(cid:74)(cid:79)(cid:68)(cid:74)(cid:81)(cid:77)(cid:70)(cid:84) (cid:52)(cid:70)(cid:68)(cid:85)(cid:74)(cid:80)(cid:79)(cid:3)(cid:42) (cid:3)(cid:79)(cid:3)(cid:3)(cid:40)(cid:70)(cid:79)(cid:70)(cid:83)(cid:66)(cid:77)(cid:3)(cid:49)(cid:83)(cid:74)(cid:79)(cid:68)(cid:74)(cid:81)(cid:77)F(cid:70)A(cid:52)(cid:84) 2(cid:70)01(cid:68)2(cid:85):(cid:74) (cid:80)2(cid:79)60(cid:3).(cid:42)1 (cid:3) (cid:79) (cid:3)•(cid:3) (cid:40) (cid:70)F(cid:79)A (cid:70)2(cid:83)0(cid:66)11(cid:77)(cid:3): (cid:49) 2(cid:83)3(cid:74)3(cid:79).(cid:68)2(cid:74) (cid:81) •(cid:77) (cid:70) (cid:84) FA 2010: 229 PH01- 11 (cid:52)(cid:70)(cid:68)(cid:85)(cid:74)(cid:80)(cid:79)(cid:3)(cid:42) (cid:3)(cid:79)(cid:3)(cid:3)M(cid:40)E(cid:70) (cid:79)3(cid:70)e:(cid:83) (cid:66) 1(cid:77)6(cid:3)(cid:49)6 (cid:83)(cid:74)(cid:79)(cid:68)(cid:74)(cid:81)(cid:77)(cid:70)(cid:84) DrReanal exfcrteti on Not for Distribution Draft Not for Distribution Draft Not for Distribution Draft Not forP ERDMEATiIOsN tribution PERMEATION (cid:52)(cid:70)(cid:68)(cid:85)(cid:74)(cid:80)(cid:79)(cid:3)(cid:42) (cid:3)(cid:79)(cid:3)(cid:3)(cid:40)(cid:70)(cid:79)(cid:70)(cid:83)(cid:66)(cid:77)(cid:3)(cid:49)(cid:83)(cid:74)(cid:79)(cid:68)(cid:74)(cid:81)(cid:77)(cid:70)(cid:84)PERMEATION PERRMeEnATaIOl Nexcretion • Drug permeation is dependent on: • Drug permeation is dependent on: • Drug permeation is dependent on–: Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for • Drug permeation is dependent on: Dr a– Solufbilitty. A bilNity to diffuose thr–o tug Sho lluipbifdil ibtyiol.a Ayebrisli (tryli ptoid d sioffluuDsbei ltihtyr)o iusmg iihmo slspitp odirdrtu abgnisttl;a fyhoeorrr ws e(vliiepri,d bw saotleurb sioluiltuyb) iilsit iytm cpanoir itnaofnlut efonrc en permeation through aqueous most drugs; however, water so lub–i lit Syo claunb iilnitfylu. Aenbcileit py etrom deifaftuisoen t hthrorouughgh li paqidu beoiluayse rs (lipid solubility) is important for most drugs; however, water solubiplihtya sceasn. influence permeation through aqueous • Both iopnhizaseeds. (I) and noPniEonRizMedE (NA)T foIOrmmNso st drugs; however, water solubility can influence permeation through aqueous phases. – Concentration gradient. Diffusion down a concentration gradient—only free, phases. a re– f ilte Croendc entration gradien• t. DDi rfufug–s ipoen Cr odmnoewcaentni taor ncaot iinsoc nde negtprraeadntiidoennen tg.t rD aodinfife:unsti—ounno dinoolnyw ifznree dae ,cd ornucge fnotrrmatsio cno ngtrraidbiuetnet —to othnely c forneec,e ntration gradient. unionized drug forms con–tr ib Suote–l u tob C itlohinety cc.eo nAntbcraeilntiittoryna ttgioor andd igiferfnuadts.ei eD ntihtf.fruosuiognh d loipwind a b ciolanyceernst r(altiipoind g sroadluiebnitl—ityo)n ilys firmeep, ortant for • Only non-ionized forms are activelmy osut undniroiuongnizsize; edhd od dwrruueggv fefoorr,r mmwsas tcceoornn stt rroiiblbuu–ubt teei l t Sitotouy tr thfchaeae cnc eco oiannnrcefeclaneun taertnanrtadcitoe ivno ap ngse crgraumrdlaaideernaiietttn.yio.t .nIm tphorortuagnht waiqthu eroeguasr d to absorption of drugs into – Surface area and vascularity. Important with regard to absorption of drugs into secretethde o sry srteeambisco cribrceudl ation. Th e lpa–rh g–ae sr Se u Stshur.fera fsacucere af aarrceeeaa aa arnendad avvnaasdscc tuuhlleaa rrgiirttyey.a. tIIemmr ppttohhoreert tavsanyantss ttcw euwmiltiahtirhc ir t ecrygei,r agcraudrl dato tti ooa bnas.bo Tsrophrtepi oltanior gonef rod ftr hudegr sus uignsrt foian cteo a rea and the greater the vascularity, In –A N Cuotsnhtchetehlenl est ysrysatsettemiomincic cg cirirraccudulilaaettniiootnn. ..D TTihhfefeu llasariroggenetrhr tdeth hobeew es tsunture rfraaf acicsec o etah nraeecra eea anab ntasrodna rdttph ittoehi ongenr geg oarretfae adtrth eiteerh nedth trv—eua sgvco.ausnlcaluryil tafyrr, ietey,, In A Nutshell •I n AIIon Nn Aiuz teNsdthuh tefesolh lrbemeltlste or fi sd trhueg aabrseo r“tprtaiopnp eodfu ”t nhinei o tdnhtrheiuz egbe .bedet ttdeterrr ui sigs t thfhoeer amabbsssoo crropptntiiootrnni• b oouff I tttoehhn eet io dzdar rtutuhigoge.n. concentration gradient. For Weak Acids and Weak For fFW• i loterra aI–Wokt e neA ai Mczkia daAtsnic oiyadn nsd dar unWdge sWa aker aek w eak a cFBioadrs–s e W o•s re• St a whIukoee IrnAoa fscinkazyii daczsbsteata iet aosaimenonrsdne i acaWn caedian rckcda un vl aeatxsiicosutn il.na T reihitteyh .el arI m–rng openr Moi ortahtnnaeiynz estdud rw ruofigrat shc ea r raeerg weaaer adak nt aodc iatdhbsse oo grr rpwetaeiaoteknr b otahfs eeds v rauansgdcs u cilanantr oiet xyi,s t in either nonionized or BIoansiezesd = Water soluble In A Nu•Bt sahseDeBsalrlsuegss itohnaitz eadre f owrmeask i na caind se:q•u IoilniIbi oz re nidu it mz=h–a e–,Wt d iba Mioeote Miepnnoatretn nianszeniyoezrdy lde udi idnd bsrf g rulofetuo grhogrmsnems a saatsr rh iebiene ns w w oapaenerHnaap kek eto q qiaafouucc tiiniihllddii bbesso rrooefii unrurt mvhmwwiere,e, o adaitddknoheker pmne bpube iaepezangsnneKsed.eddstias n iaa fn(gaonntg nrdhdo mdo en c n acspt nahHtinn hee expaea itxHnps itwH s eoithnq foii u ntcefhiih ltteei hhbi tteeherhnr iee euvn nrmimo rvnonoi,o nrildooenmencnipeouimznenleenteid zdnai esonit dn r5da g0 on %ord n i othnei zpeHd aonfd t h5e0 %en vnioronniomneiznetd a)nd FBoars eWseakI oAncizIioednds•i z=ae ndWB dt=ah a tWWeer rbaep sitatKeourkla ur s abo(llttueehbsele ,p mHe atht owthre icNxhao –ntteh io,en a Mimzseopadnli re=tiyhcn t Luhe,di lpep er i dpuKi sKgsa o5a s(l 0u(ta%htbrhleee e i p owpHnHei az aaekttd waw achhniiiddcchhs 5 ott0 hh%ree w m–mne oooanllOkeeic ocnbunullayeilezs tiee shidss 5e )5a 0n0n%o%d ni oicioonanninziie zzedeexd dai ns(atudn ni d5nc0 h5%e0ai%rt nhgoe endnro)i on nfnoiooirnznmeiidoz )oendfi z)ae ddr uogr crosses biomembranes. Nonionized = Lipid soluble Ionized = NWonaN tioeonrn i–szioeo ndlui Oz=be ndlLe li=yp iLdthi pseiod ln usooblnlueibolenized (uncha r gitohe–dn e–) i pzOfoeKOndranml y fl( yo tto hrthfhme eae n spndo Hoirnnuni gioaao ntcnn riwi zozeeeshqdsdiue c(s(ihuu lbinn bitocchrhhmie aua rermmgmg–eeo ,dbd ld)r)eT a efcfonhpoureeremls meni.o doi nosfi i nfz5a age 0dd %dro ufrnou gi r gotcm hrncoe riiso zsspe sebsHdsee bst at oibenofrimd o tr mhee5mne0e abm%elrlnyab vnn reiaeoxrsnocn.erniseo.mtendeiz nbeted ca)anudse it is water soluble. Nonionize• d =D Lriup–gi ds sTtohhlauet b iaolerneiz wede afokr mba isse bse: t ter– r en Oa–lnl –yl yTe xThtchher eeei t oienondoni zinbzeeiedocd anf fouoirszrmeem di t i i ss(i s ubb wenettacttteeherrar rr rseegonnelaaudlllbl)yyl e feeo.xxcrcrmreet etoeddf b abe ecdacruauusegs e ict iritso iwss swaetsae rtbe srio oslumobluelebm.leb.ranes. Kaplan Pharmacology 2011: Figure I-1-3 • Amphetamines – The ionized form is better renally excreted because it is water soluble. Weak Acid R–COOH R–COO– + H+ Weak Acid R– C:O" OH WWWeaeekaa kkA AAccicdiidd " ;"9 R–RRC––OCCOOO–OO +HH H + (croRsR–seC–sCO mOOeO–m +–b +Hra H+ne+s) (better cleared) (crosses membWraneeask) Acid R (b–eCttOerO clHea red) R–COO– + H+ ((ccrroosssseess mmeemmbbrraanneess)) ( b(betettetre rc lcelaeraerde)d) (crosses membranes) (better cleared) Weak Base R–NH+ R–NH + H+ W eak Base (betRte –r:N "cHlea+3 r W e de) akW WBeaaeksa ekB Ba9saes; e " ( b(cer(t(oRbtbRsee–es–rtRettNR Ntesce– –rHlHrmN eN cca2+eHlH3l erem+ ae a++33 rrdb H eer)dd+a ))n e s) ( c((rc(corbrRosoeRs–sRtesstN–ssee– NeHsrmN sHmc2 eHlm m+e2e a2m +e3bHr mr+e bH+ad rnbH)+ae rns+a)ens)es) (crosses m2embranes) FA 2012: 260.2 • FA 2011: 233.3 • FA 2010: 229 PH01- 12 CGlacaleaaacmnlucciuictdttmnuuse ibifllpinoyoocahigssnancaee itgalule o mtimrCsotpih a moua.el atmsTr ohcefhrenytefeie.uccitaraal le a ablit fnctoomoie dlrhibaez,e se,e spc eoastm icae CGlacalenaa acmndlucciui ctdttmnuuse ibifllpinoyoocahigssnancaee itgalule o mtiCGlacalemrCsaaotpaicmnh alucc miuoua.ictdtel t mnuuaset msTri CGlacaleohbifllaacpiefnahoyoorcmncealnuccytehfiuigiessnicetdtanc.uctcmintuuasee e aitriaalgal bliuflellp ien ao aoyoobl mticamrithC sotfigncssnpitoanchomo aaee mioeitua. gale dlu lle r hao itbmsaT mtire mrzoh,Csotcefpe ihsreh ,eaenyte m foua.speieecl .u c citatemsTarr oaaaloh lcefe hasr abletnytmeitf f eiienct.uocomcoictaaireaal l de lren ah aibblaeizt , fncetdo omseoM,eie sp d% Nonionized Formlc r hibeaEezoa,e ses,et m sp 3ic caeoaee nst8642m: i dca 0000e1 n 6d6 CGlacaleaaacmnlucciuictdttmnuuse ibifllpinoyoocahigssnancaee itgalule o mtimrCsotpih a moua.el atmsTr ohcefhrenytefeie.uccitaraal le a ablit fnctoomoie % Nonionized Form dlrhibaez,e se,e spc % Nonionized Formeoa% Nonionized Formstm8642ww ibaca0000ae eenc s8642aadi8642de0000 kk0000 –2 Renal Clearance of Drug –1pH –0 pKa+% Nonionized Form1wwbawwbaeewwacbaasaaeei8642cadeeceskkaai0000+sdaaiekkde2kk Renal Clearance of DrugRenal Clearance of DrugRenal Clearance of Drug wwbaaeecsaaidekk Renal Clearance of Drug –2 –1 0 F+i1gure+ I2-1-2. D––e22gre–e–1 1of Io00nizat+i+1o1n a+n+2d2 Clea–r2ance– 1 0 +1 +2 Versus pH DpeHv –ia ptiKoan from pKa pH – pKa pH – pKa pH – pKa Figure I-1-2. Degree of IonizationF aignudr Ce lIe-a1r-a2n. cDee gree of Ionization and Clearance Figure I-1-2. Degree of IonizationF aignudr eC lIe-1a-r2a.n Dceeg ree of Ionization and Clearance Versus pH Deviation from pKa Versus pH Deviation from pKa Versus pH Deviation from pKa Versus pH Deviation from pKa 4 4 4 4 4 Biotransformation 1 Biotransformation • Occurs in the liver • Conversion of lipid soluble drugs into water soluble metabolites " # renal excretion • Two forms of drug metabolism: Phase 1 and 2 Phase I: • Three mechanisms of metabolization: Oxydation, reduction, and hydrolysis • Cytochrome P450 enzymes: • Located in smooth endoplasmic reticulum of the liver (to lesser extent GI, lungs, kidneys • Require O2 and NADP • Mechanisms of cytochrome P450 enzyme metabolism: • Reduction • Oxidation • Hydroxylation and dealkylation FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4 PH01- 13 ME 3e: 167 Cytochrome P-450 interactions Cytochrome P-450 interactions Inducers Inhibitors Quinidine HIV protease inhibitors Barbiturates Isoniazid (INH) St. John’s wort Sulfonamides Phenytoin Cimetidine Rifampin Ketoconazole Griseofulvin Grapefruit juice Carbamazepine Omeprazole Chronic alcohol use Chloramphenicol Glucocorticoids Marcolides Ritonavir FA2012 273 • FA 2011: 245.2 • FA 2010: 241.2 PH01- 14 ME 3e: 167 Biotransformation 2 Biotransformation Phase I Metabolism • Leads to polar, water-soluble metabolites • Non-cytochrome P450 enzyme metabolism • Mechanisms of metabolism: • Hydrolysis: Addition of H 0 to drugs to assist metabolism 2 • Esterase • Amiidase • Monoamine oxidase: Metabolizes amines • Endogenous amines: Dopamine, norepinephrine, serotonin • Exogenous amines: Tyramine • Alcohol metabolism FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4 PH01- 15 ME 3e: 167 Biotransformation 3 Biotransformation Phase II Metabolism • Conjugation of functional groups to a drug • Converts polar molecules to inactive molecules " # renal excretion • Mechanisms of metabolism: • Acetylation • Glucuronidation • Sulfation • Methylation • Glutathione conjugation FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4 PH01- 16 ME 3e: 167 Potency vs. efficacy 1 Potency vs. efficacy Potency: measure of how much drug required to give desired effect typically expressed as EC - concentration that gives 50% of max. response 50 Efficacy: maximal effect that a drug can produce B = full agonist A = partial agonist (low efficacy) with high potency C = partial agonist with low potency Kaplan Pharmacology 2011: Figure I-2-2 FA 2012: 261.1 • FA 2011: 233.5 • FA 2010: 229 PH01- 17 ME 3e: 168 Potency vs. efficacy 2 Potency vs. efficacy Competitive Antagonists acy nse Potency: # Effic spo e Efficacy: no effect R % Non-competitive Antagonists Potency: no effect Efficacy: # log [drug] Partial Agonist Potency e Acts at same site as agonist, but lower efficacy s n Can have higher or lower potency than agonist po s e R % >" Full agonist <" =" Partial agonist log [drug] FA 2012: 261.2 • FA 2011: 234.1 • FA 2010: 230 PH01- 18 ME 3e: 168 Physiologic antagonists Physiologic antagonists Substrate that produces opposite effect of an agonist, but acts through different receptor/pathway Example: "-adrenergic Agonist Bronchoconstriction Bronchodilation Muscarinic Agonist FA 2012: n/a • FA 2011: 234.2 • FA 2010: n/a PH01- 19 ME 3e: n/a Therapeutic index Therapeutic index Measure of drug safety. Higher therapeutic index indicates safer drug. median dose that produces toxic or lethal effect LD 50 TI = = median dose required to produce therapeutic effect ED 50 LD - lethal dose ED - effective dose Kaplan Pharmacology 2011: Figure I-2-5 FA 2012: 261.3 • FA 2011: 234.3 • FA 2010: 230 PH01- 20 ME 3e: 168
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