bbs 20102011 slide metabolisme

8/3/2019 Bbs 20102011 Slide Metabolisme

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METABOLISMEMETABOLISME

DEPARTMENT OF PHARMACOLOGY AND THERAPEUTIC

UNIVERSITAS SUMATERA UTARA

dr. Yunita Sari Pane

Pharmacokinetic

absorption

distribution

BIOTRANSFORMATIONelimination


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Oral

Administration

Intestines

Liver

Intravenous

Administration

Metabolism

GI: BiliaryGI: Biliary--Fecal RouteFecal Route

liverliver

bilebile

gall bladdergall bladder

GI trackGI track

bloodblood

Enterohepatic cycleEnterohepatic cycle


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GI: BiliaryGI: Biliary--Fecal RouteFecal Route

lipid soluble drugs have prolongedlipid soluble drugs have prolongedeffectseffects

Oral DrugsOral Drugs

enter stomachenter stomach: highly acidic: highly acidic

environmentenvironment

absorbed by GI tract into portalabsorbed by GI tract into portalcirculation of the livercirculation of the liver

firstfirst--pass effectpass effect


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First Pass EffectFirst Pass Effect

pass throughpass throughliver beforeliver beforereachingreachingcirculationcirculation

undergoundergo

metabolismmetabolismby liverby liver

BiotransformationBiotransformation

chemical alteration of drugchemical alteration of drug


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changechange

sizesize

lipid solubilitylipid solubility

charge or polaritycharge or polarity

Sites of biotransformationSites of biotransformation

liver: greatest activityliver: greatest activity

othersothers

intestines, kidneys, brain, &intestines, kidneys, brain, &plasmaplasma


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Factors AffectingFactors Affecting


AgeAge

very youngvery young

less developed enzyme systemless developed enzyme system

less developed blood brainless developed blood brainbarrierbarrier

very oldvery old decreased GI absorptiondecreased GI absorption

decreased renal clearancedecreased renal clearance


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DiseaseDisease

altered liver enzymesaltered liver enzymes

liver diseaseliver disease

most decrease enzymesmost decrease enzymes

some may increasesome may increase

DiseaseDisease

other diseases that decreasedother diseases that decreasedliver enzymesliver enzymes

hypothyroidhypothyroid

hypoxemiahypoxemia

malnutritionmalnutrition


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OtherOther

genetic alterations or defects ingenetic alterations or defects inenzymesenzymes

metabolize drug more slowly ormetabolize drug more slowly ormore rapidlymore rapidly



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Decreased Activity of Liver EnzymesDecreased Activity of Liver Enzymes

decreased rate of biotransformationdecreased rate of biotransformation

can result in toxic effects

MetabolismMetabolism

(Biotransformation)(Biotransformation)

Two effectsTwo effects

Transformation to less activeTransformation to less activemetabolitemetabolite

Enhancement of solubilityEnhancement of solubility

Liver = primary siteLiver = primary site Liver diseaseLiver disease

Slows metabolismSlows metabolism

Prolongs effectsProlongs effects


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Hepatic FirstHepatic First--PassPass

MetabolismMetabolism

Affects orally administered drugsAffects orally administered drugs

Metabolism of drug by liverMetabolism of drug by liverbefore drug reaches systemicbefore drug reaches systemiccirculationcirculation

Drug absorbed into portalDrug absorbed into portalcirculation, must pass throughcirculation, must pass throughliver to reach systemic circulationliver to reach systemic circulation

May reduce availability of drugMay reduce availability of drug

EliminationElimination

Elimination

Drug Metabolism

(Biotransformation)

Excretion


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Drug MetabolismDrug Metabolism

The chemical modification of drugsThe chemical modification of drugswith the overall goal of getting ridwith the overall goal of getting ridof the drugof the drug

Enzymes are typically involved inEnzymes are typically involved inmetabolismmetabolism

DrugMetabolism More polar

(water soluble)

Drug

Excretion

ABSORPTION METABOLISM ELIMINATIONABSORPTION METABOLISM ELIMINATION

Phase I Phase IIPhase I Phase II

DrugDrug ConjugateConjugate

Drug metabolite with ConjugateDrug metabolite with Conjugatemodified activitymodified activity

DrugDrug

Inactive drug ConjugateInactive drug Conjugatemetabolitemetabolite

DrugDrug

LipophilicLipophilic HydrophilicHydrophilic


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METABOLISM REACTIONMETABOLISM REACTION

I. PHASEI. PHASE -- II

-- Oxidation : Morphin,Oxidation : Morphin,

acetaminophenacetaminophen

-- Reduction : Chloramphenicol,Reduction : Chloramphenicol,

ClonazepamClonazepam

-- Hydrolisis : Aspirin, LidocainHydrolisis : Aspirin, Lidocain

METABOLISM REACTIONMETABOLISM REACTION

II. PHASEII. PHASE-- IIII

-- Conjugation : MorphinConjugation : Morphin

(process glucuroridation),(process glucuroridation),

INH (process acetilation),INH (process acetilation),

etc.etc.


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Sites of Drug MetabolismSites of Drug Metabolism

Metabolism occurs in manyMetabolism occurs in manytissuestissues

E.g. brain, kidney, lungE.g. brain, kidney, lung

But mostly in the liver because But mostly in the liver because

all of the blood in the bodyall of the blood in the body

passes through the liver.passes through the liver.

Consequences Of MetabolismConsequences Of Metabolism

Drug metabolism != DrugDrug metabolism != Druginactivationinactivation

The metabolite may haveThe metabolite may have

EqualEqual activityactivity to the drugto the drug

NoNo oror reducedreduced activityactivity IncreasedIncreased activity (Prodrugs)activity (Prodrugs)

ToxicToxic propertiesproperties


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METABOLISM KINETICMETABOLISM KINETIC

1.First order kinetic1.First order kinetic

if drugs lower dosesif drugs lower doses

metabolism rapidly.metabolism rapidly.

2.Zerro order kinetic2.Zerro order kinetic

if drugs higher dosesif drugs higher doses

metabolism slowly.metabolism slowly.

The Most Important EnzymesThe Most Important Enzymes

Microsomal cytochrome P450Microsomal cytochrome P450monooxygenase family of enzymes,monooxygenase family of enzymes,which oxidize drugswhich oxidize drugs

Act onAct on structurally unrelatedstructurally unrelated drugsdrugs

Metabolize theMetabolize the widestwidest range ofrange ofdrugs.drugs.


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Alteration in first pass metabolismAlteration in first pass metabolism

(note: high clearance(note: high clearancedrug have > 30%drug have > 30%extraction from hepaticextraction from hepaticblood (F < 0.7))blood (F < 0.7))

a drug that inhibitsa drug that inhibitshepatic metabolism willhepatic metabolism willincrease bioavailability ofincrease bioavailability ofhigh clearance drughigh clearance drug(provided it is(provided it is

metabolised by themetabolised by theenzyme(s) inhibited) andenzyme(s) inhibited) andvicevice--versaversa

Examples:Examples:

cimetidine inhibits CYP450s,cimetidine inhibits CYP450s,therefore doubles oraltherefore doubles oralpropranolol bioavailabilitypropranolol bioavailability

phenytoin induces enzymes,phenytoin induces enzymes,therefore decreases felodipinetherefore decreases felodipinebioavailabilitybioavailability

acute alcohol intake inhibits aacute alcohol intake inhibits aCYP, therefore amitriptilineCYP, therefore amitriptilinebioavailability is higherbioavailability is higher


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Enzyme InhibitionEnzyme Inhibition

(drugs that reduce hepatic blood flow(drugs that reduce hepatic blood flowalso inhibit metabolism of highalso inhibit metabolism of highclearance drugs)clearance drugs)

if this metabolic route is a majorif this metabolic route is a majorpathway of elimination, drug kineticspathway of elimination, drug kineticswill change (increase Css and T(1/2))will change (increase Css and T(1/2))and therefore drug response willand therefore drug response willchangechange

enzyme inhibition is immediate, and onenzyme inhibition is immediate, and oncessation of inhibitor, reversion tocessation of inhibitor, reversion tonormal is immediatenormal is immediate

examples:examples:

metronidazole decreasesmetronidazole decreasesclearance of warfarin by 40%clearance of warfarin by 40%

cimetidine decreases clearancecimetidine decreases clearanceof phenytoin by 35%of phenytoin by 35%

propranolo decreases clearancepropranolo decreases clearanceof lignocaine by 50% (byof lignocaine by 50% (byreducing hepatic blood flow)reducing hepatic blood flow)

omeprazole decreases clearanceomeprazole decreases clearanceof warfarinof warfarin


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examples with regards to enzymes otherexamples with regards to enzymes other

than cytochrome P450sthan cytochrome P450s

example 1:example 1:allopurinolallopurinol

is a xanthine oxidase inhibitoris a xanthine oxidase inhibitor(used as an anti(used as an anti--gout agent)gout agent)

also inhibits metabolism ofalso inhibits metabolism ofcytotoxic agent 6cytotoxic agent 6--mercaptopurine (6mercaptopurine (6--MP)MP)

therefore concurrent use oftherefore concurrent use of

allopurinol and 6allopurinol and 6--MP leads toMP leads toelevated plasma levels of 6elevated plasma levels of 6--MPMPand toxicityand toxicity

example 2:example 2:disulfiramdisulfiram

inhibits aldehydeinhibits aldehydedehydrogenasedehydrogenase

therefore is used to givetherefore is used to givealcoholics a nasty "aldehydealcoholics a nasty "aldehyde

reaction" when they takereaction" when they takealcoholalcohol


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Alteration of liver blood flow:Alteration of liver blood flow:

for high first pass clearancefor high first pass clearancedrugs only, a fall in liver blooddrugs only, a fall in liver bloodflow will cause a clear reductionflow will cause a clear reductionin systemic clearancein systemic clearance

example:example:lignocaine toxicity canlignocaine toxicity canoccur when patients are given aoccur when patients are given a

betabeta--blocker which reducesblocker which reducesliver blood flowliver blood flow

ImportanceImportance

Toxic drugs may accumulateToxic drugs may accumulate

Useful drugs may have noUseful drugs may have nobenefit because doses are toobenefit because doses are toosmall to establish therapysmall to establish therapy

A drug can be rapidlyA drug can be rapidlymetabolized.metabolized.


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bbs 20102011 slide metabolisme

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