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Pharmacokinetic (II) 2021-2022  3-METABOLISM (biotransformation) What is biotransformation means chemical alteration of the metabolism? drug in the body  Patterns of biotransformation 1. Phase-I reactions (Nonsynthetic reac...

Pharmacokinetic (II) 2021-2022  3-METABOLISM (biotransformation) What is biotransformation means chemical alteration of the metabolism? drug in the body  Patterns of biotransformation 1. Phase-I reactions (Nonsynthetic reactions): Conversion of the parent drug to more polar metabolites by - Oxidation ( e.g. Barbiturates ) - Reduction ( e.g. Choramphenicol ) - Hydrolysis ( e.g. Procaine ) 2.Phase-II reactions (synthetic or conjugation reactions): involve coupling between the drug or its metabolites and an endogenous substrate ( e.g. glucuronic acid, sulfuric acid, acetic acid, amino acid ). important conjugation reactions are: - Glucuronide conjugation e.g. chloramphenicol - Sulfate conjugation e.g. Steroids - Glycine conjugation e.g. Aspirin - Acetylation e.g. Sulfonamides - Methylation e.g. Histamine  Enzyme Induction  Consequences of microsomal enzyme induction 1. Decreased intensity and / or duration of action of drugs that are inactivated by metabolism, e.g. failure of contraception with contraceptives. 2. Increased intensity of action of drugs that are activated by metabolism, e.g. Acute paracetamol toxicity is due to one of its metabolites- toxicity occurs at lower doses in patients receiving enzyme inducers. ( hepatic necrosis ). 3. Tolerance- if the drug induces its own metabolism (autoinduction), e.g. carbamazepine, rifampin. 4. Some endogenous substrates (steroids, bilirubin) are also metabolized faster. 5. Intermittent use of an inducer may interfere with adjustment of dose of another drug prescribed on regular basis, e.g. Oral anticoagulants(Warfarin).  Possible uses of enzyme induction 1.Congenital nonhaemolytic jaundice: It is due to deficient glucuronidation of bilirubin; phenobarbitone hastens clearance of jaundice. 2. Cushing's syndrome: Phenytoin may reduce the manifestations by enhancing degradation of adrenal steroids. 3. Chronic poisonings: by faster metabolism of the accumulated poisonous substance. 4. Liver diseases.  Drugs that inhibit drug metabolizing enzymes Allopurinol Omeprazole Erythromycin Ketoconazole Enzyme Ciprofloxacin Inhibition isoniazid The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation phenobarbitone aspirin isoprenaline propanalol lidocaine hydrocortisone sulbutamol  4- Excretion What is excretion is the passage out of systemically excretion ? absorbed drug  Methods to prolong the action of the drugs ( to reduced the frequent administration ) 1) By prolonging absorption from site of administration. 2) By increasing plasma protein binding. 3) By retarding rate of metabolism. 4) By retarding renal excretion. Drugs, that are contraindicated by lactating mothers: *Sulfonamides, Tetracycline, Chloramphenicol ,Isoniazid. *Morphine, Sedative, hypnotic drugs(Diazepam). *Phenothiazines, Lithium. *Antithyroid drugs, radioactive iodine. *Senna and related purgatives, metronidazole. *Anticancer drugs , corticosteroids. Clearance: is the theoretical volume of plasma from which the drug is completely removed in unit time CL= Rates of elimination Concentration of drug (in blood or plasma) Half life ( t ½ ): Is the time, it takes for the plasma concentration or the amount of drug in the body to be reduced to 50%. Steady state: ( about 5x of t ½ ) Drug administrated = Drug eliminated