DEPARTMENT OF PHARMACOLOGY AND THERAPEUTIC UNIVERSITAS SUMATERA UTARA
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1 METABOLISME dr. Yunita Sari Pane DEPARTMENT OF PHARMACOLOGY AND THERAPEUTIC UNIVERSITAS SUMATERA UTARA
2 Pharmacokinetic absorption distribution BIOTRANSFORMATION elimination
3 Intravenous Administration Oral Administration Metabolism Liver Intestines ti
4 GI: Biliary-Fecal Route liver blood bile gall bladder Enterohepatic cycle GI track
5 GI: Biliary-Fecal Route lipid soluble drugs have prolonged effects
6 Oral Drugs enter stomach: highly acidic environment absorbed by GI tract into portal circulation of the liver first-pass effect
7 First Pass Effect pass through liver before reaching circulation undergo metabolism by liver
8 Biotransformation chemical alteration of drug
9 Biotransformation change size lipid solubility charge or polarity
10 Sites of biotransformation liver: greatest activity others intestines, kidneys, brain, & plasma
11 Factors Affecting Biotransformation
12 Age very young less developed enzyme system less developed blood brain barrier very old decreased GI absorption decreased renal clearance
13 Disease altered liver enzymes liver disease most decrease enzymes some may increase
14 Disease other diseases that decreased liver enzymes hypothyroid hypoxemia malnutrition
15 Other genetic alterations or defects in enzymes metabolize drug more slowly or more rapidly
16 Biotransformation
17 Decreased Activity it of Liver Enzymes decreased rate of biotransformation can result in toxic effects
18 Metabolism (Biotransformation) Two effects Transformation to less active metabolite Enhancement of solubility Liver = primary site Liver disease Slows metabolism Prolongs effects
19 Hepatic First-Pass Metabolism Affects orally administered drugs Metabolism of drug by liver before drug reaches systemic circulation Drug absorbed into portal circulation, must pass through h liver to reach systemic circulation May reduce availability of drug
20 Elimination Elimination Excretion Drug Metabolism (Biotransformation)
21 Drug Metabolism The chemical modification of drugs with the overall goal of getting g rid of the drug Enzymes are typically involved in metabolism Drug Metabolism More polar Excretion (water soluble) Drug
22 ABSORPTION METABOLISM ELIMINATION Phase I Phase II Drug Conjugate Drug Drug metabolite with Conjugate modified activity Inactive drug Conjugate metabolite Drug Lipophilic Hydrophilic
23 METABOLISM REACTION I. PHASE - I - Oxidation : Morphin, acetaminophen - Reduction : Chloramphenicol, Clonazepam - Hydrolisis i : Aspirin, i Lidocain i
24 METABOLISM REACTION II. PHASE- II - Conjugation : Morphin (process glucuroridation), INH (process acetilation), etc.
25 Sites of Drug Metabolism Metabolism occurs in many tissues E.g. brain, kidney, lung But mostly in the liver because all of the blood in the body passes through the liver.
26 Consequences Of Metabolism Drug metabolism!= Drug inactivation The metabolite may have Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties
27 METABOLISM KINETIC 1.First order kinetic if drugs lower doses metabolism rapidly. 2Z 2.Zerro order kinetic if drugs higher doses metabolism slowly.
28 The Most Important Enzymes Microsomal cytochrome P450 monooxygenase family of enzymes, which oxidize drugs Act on structurally unrelated drugs Metabolize the widest range of drugs.
29 Alteration in first pass metabolism (note: high clearance drug have > 30% extraction from hepatic blood (F < 0.7)) a drug that inhibits hepatic metabolism will increase bioavailability of high clearance drug (provided it is metabolised by the enzyme(s) inhibited) and vice-versa versa
30 Examples: cimetidine inhibits CYP450s, therefore doubles oral propranolol bioavailability phenytoin induces enzymes, therefore decreases felodipine bioavailability acute alcohol intake inhibits a CYP, therefore amitriptiline bioavailability is higher
31 Enzyme Inhibition (drugs that reduce hepatic blood flow also inhibit metabolism of high clearance drugs) if this metabolic route is a major pathway of elimination, drug kinetics will change (increase Css and T(1/2)) and therefore drug response will change enzyme inhibition is immediate, and on cessation of inhibitor, reversion to normal is immediate
32 examples: metronidazole decreases clearance of warfarin by 40% cimetidine decreases clearance of phenytoin by 35% propranolo decreases clearance of lignocaine by 50% (by reducing hepatic blood flow) omeprazole decreases clearance of warfarin
33 examples with regards to enzymes other than cytochrome P450s example 1: allopurinol l is a xanthine oxidase inhibitor (used as an anti-gout t agent) also inhibits metabolism of cytotoxic agent 6- mercaptopurine (6-MP) therefore concurrent use of allopurinol and 6-MP leads to elevated plasma levels of 6-MP and toxicity
34 example 2: disulfiram inhibits aldehyde dehydrogenase therefore is used to give alcoholics a nasty "aldehyde reaction" when they take alcohol
35 Alteration of liver blood flow: for high first pass clearance drugs only, a fall in liver blood flow will cause a clear reduction in systemic clearance example: lignocaine toxicity can occur when patients are given a beta-blocker blocker which reduces liver blood flow
36 Importance Toxic drugs may accumulate Useful drugs may have no benefit because doses are too small to establish therapy A drug can be rapidly metabolized.
37
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