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    Hevi Milda Lestari

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    The document discusses drug metabolism, which is the process by which drugs are chemically converted in the body by enzymes. It covers topics like the location of metabolism mainly in the liver, the two phases of metabolism, and factors that can affect metabolism like genetics, environment, drug interactions, and an individual's drug dosage regimen.

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    Hevi Milda Lestari

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    Hevi MeeLda Lestari
    36 views36 pages
    The document discusses drug metabolism, which is the process by which drugs are chemically converted in the body by enzymes. It covers topics like the location of metabolism mainly in the liver, the two phases of metabolism, and factors that can affect metabolism like genetics, environment, drug interactions, and an individual's drug dosage regimen.

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    The document discusses drug metabolism, which is the process by which drugs are chemically converted in the body by enzymes. It covers topics like the location of metabolism mainly in the liver, the two phases of metabolism, and factors that can affect metabolism like genetics, environment, drug interactions, and an individual's drug dosage regimen.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    36 views36 pages

    Hevi Milda Lestari

    Uploaded by

    Hevi MeeLda Lestari
    The document discusses drug metabolism, which is the process by which drugs are chemically converted in the body by enzymes. It covers topics like the location of metabolism mainly in the liver, the two phases of metabolism, and factors that can affect metabolism like genetics, environment, drug interactions, and an individual's drug dosage regimen.

    Copyright:

    Attribution Non-Commercial (BY-NC)
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    of 36

    Metabolism

    By : Hevi Milda Lestari 0811013158

    ELIMINATION
    The irreversible removal of drug from the body by all routes of elimination Metabolism Excretion

    METABOLISM
    Biotransformation The process by which the drug is chemically converted in the body to a metabolite Enzymatic Non Enzymatic (ester hydrolysis)

    Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products. Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs.

    Drug molecules are processed by enzymes evolved to cope with natural compounds Drug may have actions increased or decreased or changed Individual variation genetically determined May be several routes of metabolism May not be what terminates drug action May take place anywhere BUT liver is prime site Not constant - can be changed by other drugs; basic of many drug-drug interactions

    metabolism is what the body does to the drug

    Location of Metabolism
    Mainly: Liver Kidney Lung Small Intestine Skin GI mucosal cells Microbiological flora in the distal portion of the ileum & large intestine

    LIVER
    the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation

    Clearance
    The process of drug elimination from the body or from the single organ without identifying the individual processes involved. The volume of fluid cleared of drug from the body per unit of time (mL/min)

    BIOTRANSFORMATION REACTIONS
    Any structural change in a drug molecule may change its activity Active drug to inactive metabolite
    Amphetamine Phenylacetone

    Active drug to active metabolite


    Codeine Morphine

    Inactive drug to active metabolite


    Hetacillin PCT Ampicllin

    Active drug to reactive intermediate


    Reactive metabolite

    REACTIONS
    Phase I - changes drugs and creates site for phase II oxidation (adds O) eg. Microsomes (P450); reduction; hydrolysis (eg. by plasma esterases) others More polar metabolites A-synthetic reactions Phase II - couples group to existing (or phase I formed) conjugation site glucuronide (with glucuronic acid) sulphate others Conjugation Synthetic reactions Much more polar metabolites

    OH

    O-SO3

    Phase I

    Phase II

    Phase I
    Occurs first Introduce or expose a functional group on drug mol Oxygen into phenyl group of phenylbutazone by aromatic hydroxylation to form oxyphenbutazone Codeine is demethylated to form morphine Hydrolysis of ester Aspirin to form Salicylic Acid

    Phase I
    Oxidation
    Aromatic hydroxylation Side chain hydroxylation N-, O-, and S-dealkylation Deamination Sulfooxidation, N-oxidation N-hydroxylation Azoreduction Nitroreduction Alcohol dehydrogenase Ester hydrolysis Amide hydrolysis

    Reduction

    Hydrolysis

    Hydroxylation -CH2CH3 -CH2CH2OH Oxidation -CH2OH -CHO -COOH


    N-de-alkylation -N(CH3)2

    - NHCH3 + CH3OH

    Oxidative deamination -CH2CHCH3


    |

    -CHCOCH3

    NH3

    NH2

    Phase II
    Salicylic Acid with glycine to form salicyluric acid Salicylic Acid with glucoronic acid to form salicylglucoronide Conjugating reagents Derived from biochemical compounds involved carbohydrate, fat, and protein metabolism

    CONJUGATIONS

    -OH, -SH, -COOH, -CONH with glucuronic acid to give glucuronides -OH with sulphate to give sulphates -NH2, -CONH2, aminoacids, sulpha drugs with acetyl- to give acetylated derivatives -halo, -nitrate, epoxide, sulphate with glutathione to give glutathione conjugates all tend to be less lipid soluble and therefore better excreted (less well reabsorbed)

    Phase II
    Glucuronidation Sulfation by Amino acid conj Acetylation Methylation Glutathione conj by Glucuronic acid Sulfate by Glycine by Acetyl CoA by CH3 by glutathione

    Other (non-microsomal) reactions


    Hydrolysis in plasma by esterases (suxamethonium by cholinesterase) Alcohol and aldehyde dehydrogenase in cytosolic fraction of liver (ethanol) Monoamine oxidase in mitochondria (tyramine, noradrenaline, dopamine, amines) Xanthene oxidase (6-mercaptopurine, uric acid production) enzymes for particular drugs (tyrosine hydroxylase, dopa-decarboxylase etc)

    Factors affecting biotransformation


    race (CYP2C9; warfarin (bleeding) phenytoin (ataxia) Losartan (less cleared but less activated as well); also fast and slow isoniazid acetylators, fast = 95% Inuit, 50% Brits, 13% Finns, 13% Egyptians). age (reduced in aged patients & children) sex (women slower ethanol metabilizers) species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); biotransformation route can change clinical or physiological condition other drug administration (induction (not CYP2D6 ) or inhibition) food (charcoal grill ++CYP1A)(grapefruit juice --CYP3A) first-pass (pre-systemic) metabolism

    Inhibitors and inducers of microsomal enzymes


    INHIBITORS cimetidine prolongs action of drugs or inhibits action of those biotransformed to active agents (prodrugs) INDUCERS barbiturates, carbamazepine shorten action of drugs or increase effects of those biotransformed to active agents BLOCKERS acting on non-microsomal enzymes (MAOI, anticholinesterase drugs)

    Hepatic Elimination
    K = km + ke The rate constant of elimination (k) = firstorder rate constatn for metabolism (km) + the first-order rate constant for excretion (ke)

    Clinical Focus
    The overall el half life (t1/2) of a drug is 2 hr (k=0.347/hr, km=0.104/hr. If the renal excretion pathway becomes impaired as in the case of certain kidney disorders, then less or none drug will be excreted renally & hepatic metabolism may become the primary drug el route. K = km + ke, but ke = 0, thus k = km. T1/2 = 0.693/k. t1/2 = 0.693/0.104= 6.7 hr

    Variation of Biotransformation Enzymes in Humans


    Genetics Factors Environmental Factors & Drug Interactions Physiologic Conditions Drug Dosage Regimen

    Genetics Factors
    Genetic different within population Racial differences among different populations
    Environmental Factors & Drug Interactions Enzyme induction Enzyme inhibition Physiologic Conditions
    Age Gender Diet/Nutrition Pathophysiology

    Drug Dosage Regimen

    Route of drug administration Dose dependence (nonlinear) pharmacokinetics.

    Pharmacogenetics

    Genetic differences in drug elimination INH N-acetylation Rapid & slow acetylation Slow acetylation neurotoxicity The differences is referred to as genetic polymorphism.

    Genetic Polymorphism
    Procainamide acetylated Hydralazin acetylated Glucose-6-phosphate-dehydrogenase deficiency, which is observed in approximately 10% of black Americans Phenytoin, EM & PM (Efficient & Poor Metabolizer) Propranolol, difference among Chinese population

    Drug Interactions Involving Drug Metabolism


    The enzymes involved in the metabolism of drugs may be altered by: Diet Co-administration of other drugs & chemicals

    Enzyme induc
    A drug or chemical-stimulated increase in enzyme activity usually due to an increase in the amount of enzyme present Examples: Phenobarbital Carbamazepine Rifampicin Benzopyren (Smoking) Chlordane (Insecticide)

    Enzyme Inhibition
    May be due to substrate competition or due to direct inhibition of drug metabolizing enzyme, particularly one of several of the cytochrome P-450 enzymes. Examples: Fluoxetine decrease the clearance of IMI due to its inhibitory effect of hydroxylation.

    Inhibition
    Inhibitors PCT Cimetidine Example EtOH Result Increased hepatotoxicity Warfarin Prolongation of prothrombin time Carbamazepine Decreased Carbamazepine clearance

    Erythromycin

    Induction
    Inducers of drug metabolism Carbamazepine Example Result

    PCT

    Increased PCT metabolism

    Rifampin

    Methadone

    Increased methadone metabolism

    First Pass Effect


    Routes of administration may affects the metabolic rate A drug given parenterally, transdermally, or by inhalation may distribute within the body prior to metabolism by the liver

    First Pass Effect


    In contrast, drugs given orally are normally absorbed in the duodenal segment of the small intestine and transported via the mesenteric vessels to the hepatic portal vein & then to the liver prior to the systemic circulation.

    First Pass Effect


    Drugs that are highly metabolized by the liver or by the intestinal mucosal cells demonstrate poor systemic availability when given orally. This rapid metabolism of an orally administered drug prior to reaching the general circulation is termed FPE or presystemic elimination

    Thank You

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