Drug Metabolism Lecture Notes PDF

Drug metabolism objectives Phases of drug metabolism with examples Non-microsomal & microsomal enzymes with genetic variability First pass effect Mechanism of hepatic enzyme induction & enlist drugs that induce & drugs that inhibit hepatic metabolism. Assess drugs for which there a...

Drug metabolism objectives Phases of drug metabolism with examples Non-microsomal & microsomal enzymes with genetic variability First pass effect Mechanism of hepatic enzyme induction & enlist drugs that induce & drugs that inhibit hepatic metabolism. Assess drugs for which there are well defined, genetically determined differences in metabolism Hepatocyte showing the main components and transporters. D and Da are 2 different drugs that have different clearance pathways. (1) Drug D is uptaken by transporter then metabolized by phase I pathway to M (main metabolic product) followed by conjugation process by phase II enzymes and finally effluxed into biliary system by transporter. (2) In this scenario, drug Da is transported into the hepatocyte through OAT then pumped out by MDR1 without any chemical modification to the drug molecule. D, drug; Da, drug a; M, metabolite; MG, metabolite glucuronide. Drug-metabolizing enzymes and transporters in gut, enterocyte. The drug (D) is transported from gut into enterocyte and then to the circulation. Metabolite (Da) also can be affected by transporters either by efflux or uptake transports. Metabolism or Biotransformation of drugs Biotransformation means chemical alteration of the drug in the body. It is needed to convert nonpolar (lipid-soluble) compounds into polar (lipid insoluble) so that they are not reabsorbed in the renal tubules and are excreted. Most hydrophilic drugs, e.g. streptomycin, neostigmine, pancuronium,etc. are little biotransformed and are largely excreted unchanged. Sites for drug metabolism The primary site: liver Others are-kidney, intestine, lungs and plasma.  Biotransformation of drugs may lead to the following (i) Inactivation: Most drugs and their active metabolites are rendered inactive or less active, e.g. ibuprofen, paracetamol, lidocaine, chloramphenicol, propranolol (ii) Active metabolite from an active drug: Many drugs have been found to be partially converted to one or more active metabolite; the effects observed are the sumtotal of that due to the parent drug and its active metabolite(s)  Biotransformation of drugs may lead to the following (iii) Activation of inactive drug :Few drugs are inactive as such and need conversion in the body to one or more active metabolites. Such a drug is called a prodrug. The prodrug may offer advantages over the active form in being more stable, having better bioavailability or other desirable pharmacokinetic properties or less side effects and toxicity. Active drugs and Active metabolites Chloral hydrate - Trichloroethanol Morphine - Morphine-6-glucuronide Cefotaxime – Des acetyl cefotaxime Allopurinol- Alloxanthine Procainamide- N Acetyl procainamide Primidone- Phenobarbitone Diazepam- Desmethyl-diazepam,oxazepam Digitoxin- Digoxin Imipramine- Desipramine Amitriptyline- Nortriptyline Codeine- Morphine Spironolactone- Canrenone  PRODRUGS(Inactive to active) Levodopa- Dopamine Enalapril- Enalaprilat I a-Methyldopa- Alpha methyl norepinephrine Dipivefrine- Epinephrine Prednisone- Prednisolone Bacampicillin- Ampicillin Phases of Biotransformation Biotransformation reactions can be classified into: (a) Nonsynthetic / Phase I / Functionalization reactions: a functional group is generated or exposed. Metabolite may be active or inactive. (b) Synthetic/Conjugation/ Phase II reactions: metabolite is mostly inactive; except few drugs, e.g. glucuronide conjugate of morphine and sulfate conjugate of minoxidil are active. Phase I Oxidation Reduction Hydrolysis Cyclization Decyclization Phase II Glucuronide conjugation Sulphate conjugation Glycine conjugation Glutathione conjugation Ribonucleoside/nucleotide synthesis Acetylation methylation Drug metabolizing enzymes 1. Microsomal enzymes-- These are located on smooth endoplasmic reticulum (a system or microtubules inside the cell), primarily in liver, also in kidney, intestinal mucosa and lungs. The monooxygenases, cytochrome P 450, glucuronyl transferase, etc. are microsomal enzymes. They catalyse most of the oxidations, reductions, hydrolysis and glucuronide conjugation Microsomal enzymes are inducible by drugs, diet and other agencies. 2. Non microsomal enzymes -- These are present in the cytoplasm and mitochondria of hepatic cells as well as in other tissues including plasma. The flavoprotein oxidases, esterases, amidase and conjugases are nonmicrosomal. Reactions catalysed are: Some oxidations and reductions, many hydrolytic reactions and all conjugations except glucuronidation. Drug metabolizing enzymes The nonmicrosomal enzymes show genetic polymorphism (acetyl transferase, pseudocholinesterase). Both microsomal and nonmicrosomal enzymes are deficient in the newborn, especially premature, making them more susceptible to many drugs, e.g. chloramphenicol, opioids. This deficiency is made up in first few months after birth. Important CYP isoenzymes in human CYP3A4/5:(50%) lnhibition of this isoenzyme by erythromycin, clarithromycin, ketoconazole,itraconazole is responsible for the important drug interaction with terfenadine, astemizole and cisapride which are its substrates. Verapamil, diltiazem, ritonavir and a constituent of grapefruit juice are other important inhibitors, while rifampicin,barbiturates and other anticonvulsants are the important inducers. CYP2D6:(20%)tricyclic antidepressants, selective serotonin reuptake inhibitors, many neuroleptics, antiarrhythmics,beta-blockers and opiates. Inhibition of this enzyme by quinidine, failure of conversion of codeine to morphine so that analgesic effect of codeine is lost.  CYP2C8/9:phenytoin, warfarin which are narrow safety margin drugs, as well as ibuprofen and tolbutamide. CYP2C19: Metabolizes > 12 frequently used drugs including omeprazole, lansoprazole. Rifampicin and carbamazepine are potent inducers of the CYP2C subfamily. CYP1A1/2: Theophylline metabolism. rifampicin and carbamazepine, polycyclic hydrocarbons,cigarette smoke and charbroiled meat are its potent inducers. CYP2E1:induction by alcohol Microsomal Enzyme Induction Many drugs, insecticides and carcinogens interact with DNA and increase the synthesis of microsomal enzyme protein, specially cytochrome P-450 and glucuronyl transferase. Different inducers are relatively selective for certain cytochrome P-450 enzyme families, e.g.: Anticonvulsants including phenobarbitone,rifampin, glucocorticoids induce CYP3A isoenzymes. Phenobarbitone also induces CYP2Bl and rifampin also induces CYP2D6. Isoniazid and chronic alcohol consumption induce CYP2E1. Polycyclic hydrocarbons like 3-methylcholanthrene and benzopyrene found in cigarette smoke, charcoalbroiled meat and industrial pollutants induce CYP1A isoenzymes. Other important enzyme inducers are: chloralhydrate, phenylbutazone, griseofulvin, DDT. Drugs that inhibit hepatic metabolism Inhibition of CYP isozyme activity is an important source of drug interactions that leads to serious adverse events. The most common form of inhibition is through competition for the same isozyme. Some drugs, however, are capable of inhibiting reactions for which they are not substrates ( ketoconazole), leading to drug interactions. For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. If these two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage. Cimetidine blocks the metabolism of theophylline, clozapine, and warfarin 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 oral contraceptive. 2. Increased intensity of action of drugs that are activated by metabolism. Acute paracetamol toxicity is due to one of its meta bolites- toxicity occurs at lower doses in patients receiving enzyme inducers. 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. Precipitation of acute intermittent porphyria: enzyme induction increases porphyrin synthesis by derepressing 8-aminolevulenic acid synthetase.  6. Intermittent use of an inducer may interfere with adjustment of dose of another drug prescribed on regular basis, e.g. oral anti coagulants,oral hypoglycaemics, antiepileptics, antihypertensives. Drug whose metabolism is significantly affected by enzyme induction are-phenytoin, warfarin,tolbutamide, imipramine, oral contraceptives,chloramphenicol, doxycycline, theophylline, griseofulvin,phenylbutazone. First pass(presystemic) metabolism This refers to metabolism of a drug during its passage from the site of absorption into the Systemic circulation. All orally administered drugs are exposed to drug metabolizing enzymes in the intestinal wall and liver (where they first reach through the portal vein). Attributes of drugs with high first pass metabolism: (a) Oral dose is considerably higher than sublingual or parenteral dose. (b) There is marked individual variation in the oral dose due to differences in the extent of first pass metabolism. (c) Oral bioavailability is apparently increased in patients with severe liver disease. (d) Oral bioavailability of a drug is increased if another drug competing with it in first pass metabolism is given concurrently, e.g. chlorpromazine and propranolol. Examples for drugs with genetically determined differences in metabolism 1- Succinylcholine(SCh) (neuromuscular-blocking drug) Succinylcholine is metabolised by succinylcholine esterase It is a very rapid process (Phase I Reaction) So, a single dose of sussinylcholine has an action of about ONLY 5 minutes Genetically 1:2500 has an abnormal form of this enzyme, that metabolises succinylcholine more slowly. So, duration of action of SCh is prolonged with muscular paralysis. Its a complication occurs in anasethesia 2- Isoniazid Metabolised by Phase II reactions by acetylation (conjugation) Genetically Some persons (and even some populations) are deficient in acetylation capacity and will have prolonged response to normal doses of these drugs Called slow acetylators Inherited as an autosomal recessive gene Thank you