Kaplan High-Yield Pharmacology

31 Pages·00.837 MB·English

by  Kaplan

Pharmacodynamics and pharmacokinetics
Pharmacodynamics and
Pharmacokinetics
Matthew B. Wilkinson, PhD, M4
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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