Drug Metabolism.pptx

Drug Metabolism.pptx

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  1 By Dr. Faraza Javaid
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  METABOLISM Drug metabolism (biotransformation) Itis the chemical reactions which lead to the modification of drugs Sites of metabolism Hepatic: microsomes, mitochondria, cytoplasm Extrahepatic: lung, blood, skin, GIT, kidney 4
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  Metabolism may result: Inactivation of active drug, e.g. Lidocaine  Active metabolite from active drug e.g. Codeine to Morphine  Activation of inactive drug (prodrug) e.g. Levodopa to Dopamine 5
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  Why metabolismof drugsis required 6
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  Importance of Metabolism Makesdrug less lipid soluble or H2O soluble  easy excretion of drugs Alternative process  termination of biological activity 7
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  Drug Metabolizing Enzymes 1)Microsomal Enzymes Major role in metabolism Located in membrane of ER (liver, GIT, lungs, kidney) Collectively called as Cytochrome P450, Monoxygenase, Glucouronyl Transferase Cyt families (1,2,3….) & sub families (A,B,C,D…..) CYP: 1A2, 2A6, 2B6, 2C9, 2C18, 2C19 etc 8
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  Cytochrome P-450 Root word Family Sub-family Genenumber 450denotes their strong absorbance at 450 nm Superfamily of microsomes CYP3A4 is involved in metabolism of 50% drugs Nomenclature CYP3A4
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  Non-Microsomal Enzyme Present incytoplasm and mitochondria of liver cells Flavoprotein oxidase, Esterase, Amidases 10
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  Non Microsomal Metabolism Mitochondria: Mono-amineoxidase enzyme (MAO), Flavoprotein oxidase Cytoplasm: Alcohol dehydrogenase Blood (plasma): Estrases, Amidases Catechol-o methyltransferases(COMT) Intestinal Mucosa and Lumen: Glucouronidase, Asoreductases GIT mucosa: Monoamime oxidase (MAO), Sulphatase 11
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  Drug metabolizing bymicrosomal enzyme is called as substrate and chemical increasing or decreasing that enzyme is called as inducer or inhibitor respectively 12 Enzyme inducer Increase metabolism Decrease effect Dose should be increased T olerance
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  Enzyme Inhibitors Decrease Metabolism Predisposes toxicity
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  Phases of Metabolism 1)Phase-I 2) Phase-II 14
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  1) Phase-I reactions Makesdrugs more water soluble and less lipid soluble; catalyzed by microsomal enzymes Metabolite may be active or inactive by introducing or unmasking a functional group (OH, NH2, SH) 15
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  Reactions Oxidation Addition of O/-velycharged radical or removal of H/+vely charged radical Enzymes: Monooxygenases and Cyt P450 e.g. Barbiturates, Ibuprofen, PCM 16
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  Hydroxylation Addition of OHgroup e.g., Phenobarbitone, Warfarine, Chloramphenicol De-amination Removal of amino group e.g. Amphetamine, diazepam 17
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  Hydrolysis Addition of H2Omolecule e.g., Aspirin, procaine 18
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  Phase-II reactions Addition ofan endogenous water-soluble group (glucoUronic acid, acetic acid sulfuric acid) to parent drug or its oxidized metabolite Metabolite is mostly inactive, Conjugation of a drug or Phase 1 metabolite with an endogenous substrate.  Synthetic in nature  Nearly all conjugates are inert & H2O soluble  Phase-II-terminate biologic activity  Conjugates pass in urine or bile  Enzyme: transferases 19
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  Types of Phase-IIReactions i) Glucouronide conjugation Drugs + glucoronic acid (glucose) Enzyme: glucoronyl transferase e.g., chloramphenicol, aspirin, morphine, metronidazole, digoxin 20
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  ii) Acetylation Drug ormetabolite + acetyl group (acetyl Co A) Enzyme: acetyl transferase e.g., sulphonamides, isoniazid, clonazepam etc iii) Glycine conjugation Drug or metabolite + glycine Enzyme: Glycine transferase e.g., salicylic acid, benzoic acid, nicotinic acid, cinnamic acid, cholic acid etc 21
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  iv) Sulphate conjugation Drug+ sulphate group Enzyme: sulphotransferase e.g., methyldopa, paracetamol, estrone etc. v) Methylation Drug or metabolite + methyl group Enzyme: transmethylase e.g., DA, Ad, Hist, pyridine, thiouracil 22
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  Kinetics of Metabolism Activityof enzymes to work… or metabolism 1. 1st order Kinetics 2. Zero order Kinetics Relation b/w Plasma Drug Concentration and Rate of Drug Metabolism 24
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  1st Order Kinetics Ifwe Increase the Plasma Drug Concentration, the Rate of Drug Metabolism Increases. OR The rate of drug metabolism is proportional to drug concentration 25 V = Rate of Drug Metabolism = Vmax [C] Km
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  2nd Order Kinetics(Max capacity) If we Increase the Plasma Drug Concentration, the Rate of Drug Metabolism remains constant. OR The rate of drug metabolism becomes independent to drug concentration 26 V = Rate of Drug Metabolism = Vmax [C] = Vmax [C]
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  Half life (t1/2) Time required to reduce the plasma conc. half to its original value  It is a secondary P’kinetic parameter derived from two primary P’kinetic parameter  Vd and clearance (Cl)  Determines dosing interval and time required to reach steady state conc. t1/2 = (0.693 * Vd)/Cl
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  Factors which canaffect the metabolism… 29
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  1) Genetic factors Or   activity of metabolizing enzyme a) Succinylcholine Metabolized by pseudocholinestrase Metabolism of succinylcholine - d/c in individuals Toxic effect occur at therapeutic doses + prolonged paralysis of skeletal muscles occur 30
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  b) Isoniazid Deficiency ofacetyl transferases in some individuals (slow acetylators) Acetylation of isoniazid is slow 31
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  2) Food Charcoal broiledmeat, cruciferous vegetable = activity of CYP1A enzyme Grapefruit juice=inhibit CYP3A 32
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  3) Environment Industrial workersexposed = pesticides Rapid metabolism of some drugs 33
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  4) Age Drugs =greater + prolonged effects at age extremes b/c of slower metabolism Reduced activity of enzyme or reduced availability of endogenous cofactor = slower metabolism Newborn=weak system for biotransformation Premature infants cannot metabolize drugs Elderly people =  metabolism 34
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  6) Drugs Many drugsaffect rate of metabolism of others or their own due to enzyme induction of inhibition 35
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  Enzyme Inducers Enzyme inducer GGriseofulvin P Phenytoin R Rifampicin S Smoking Cell Carbamazepine Phone Phenobarbitone
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  Enzyme Inhibitors Enzyme inhibitors VitaminValproate K Ketoconazole Cannot Cimetidine Cause Ciprofloxacin Enzyme Erythromycin Inhibition Isoniazid
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  7) Disease Many diseasesaffect drug metabolism due to: Malnourishment or hepatic dysfunction Acute or chronic disease affecting liver architecture or function=affect metabolism of drugs E.g., alcoholic hepatitis, active or inactive alcoholic cirrhosis, hemochromatosis, chronic active hepatitis, biliary cirrhosis & active viral or drug induced hepatitis These conditions  microsomal oxidases 38