Basic Pharmacology Lecture (4) PDF

Basic Pharmacology Lecture (4) Basic Pharmacology Lecture (4) Pharmacokinetics of Drugs 3- Metabolism Prepared by Emad Al-Sheikh Lecturer of Pharmacology a...

Basic Pharmacology Lecture (4) Basic Pharmacology Lecture (4) Pharmacokinetics of Drugs 3- Metabolism Prepared by Emad Al-Sheikh Lecturer of Pharmacology and Toxicology Department Basic Pharmacology Lecture (4) Pharmacokinetics of Drugs ❑The term "pharmacokinetics" describes the movement of drugs inside the body, and is usually referred to as "What the body does to the drug". Basic Pharmacology Lecture (4) 3-Metabolism=Biotransformation ❑ These are chemical reactions that occur mainly in the liver. ❑ The aim of biotransformation reactions is to "convert lipophilic (lipid soluble) drugs into water-soluble (hydrophilic, ionized, or polar) metabolites to be easily excreted in urine. ❑ It is clear that water-soluble drugs do not undergo metabolism and are excreted "unchanged" in urine. ❑ On the other hand; lipophilic drugs-after filtration through the renal glomeruli-will undergo "reabsorption" by the renal tubular cells, making renal excretion of these drugs very slow. So, they are metabolized to be converted into water soluble form to promote their renal excretion. Basic Pharmacology Lecture (4) Phases of Biotransformation Reactions a) Phase-I Reactions: ❑These are "Non-Synthetic" reactions. ❑The drug undergoes either: oxidation, reduction, or hydrolysis. ❑Phase I reactions will result in one of the following: o Conversion of an active drug into an "inactive" metabolite. This is the most common result, e.g.: Basic Pharmacology Lecture (4) Phases of Biotransformation Reactions….. a) Phase-I Reactions…… o Conversion of an active drug into an "active" metabolite, e.g.: Basic Pharmacology Lecture (4) Phases of Biotransformation Reactions….. a) Phase-I Reactions:……. o Conversion of an "inactive" drug into an "active" metabolite and in this case the parent drug is known as a "prodrug", e.g. cortisone (inactive) is changed into cortisol=hydrocortisone (active), and enalapril (inactive) is metabolized into enalaprilate (active). Basic Pharmacology Lecture (4) Phases of Biotransformation Reactions….. a) Phase-I Reactions:….. ❑Very rarely; a toxic metabolite is formed, e.g. methyl alcohol (methanol) is metabolized by oxidation into formaldehyde which causes permanent blindness, being retinotoxic. ❑In addition, insecticides as Parathion and Malathion are oxidized into toxic Paraoxon and Malaoxon; respectively. Basic Pharmacology Lecture (4) Phases of Biotransformation Reactions….. b) Phase-II Reactions: ❑These are "Synthetic" or "Conjugation" reactions. ❑The drug or a metabolite resulting from phase I reaction is "conjugated" with an endogenous polar compound as glucuronic acid, sulphate, glycine, acetate, glutathione or methyl group. ❑Phase II reactions mostly result in drug inactivation, with some exceptions as morphine (active) which is partially converted into morphine 6-glucuronide (active metabolite), and minoxidil (inactive) is conjugated into minoxidil sulphate (active). Basic Pharmacology Lecture (4) Phases of Biotransformation Reactions….. b) Phase-II Reactions:…….. ❑N.B. most drugs are metabolized by phase-I reactions followed by phase II reactions, undergo phase I reaction only, or phase-II reactions only. ❑Few drugs as isoniazid is metabolized by conjugation (phase-II) followed by hydrolysis (phase I), i.e. there is "reversal of order of the phases". Basic Pharmacology Lecture (4) Sites of biotransformation reactions 1)The liver: it is the main site of drug metabolism. 2)The plasma: e.g. plasma cholinesterase (pseudo cholinesterase) is responsible for metabolism of some drugs as Succinylcholine. 3)Other sites: the lung, the kidney, the skin, and GIT. Basic Pharmacology Lecture (4) Types of enzymes responsible for biotransformation reactions Basic Pharmacology Lecture (4) Factors Affecting Hepatic Microsomal Enzyme activity….. 1) The effect of drugs 2) Age 3) Sex (Gender) 4) Pathological conditions 5) Genetic factors (Pharmacogenetics) Basic Pharmacology Lecture (4) Factors Affecting Hepatic Microsomal Enzyme activity 1) The effect of drugs: ❑Some drugs increase the activity of hepatic microsomal enzymes (HME) and are known as HME inducers or activators, whereas other drugs reduce or inhibit the activity of HME and are thus called HME inhibitors. ❑Examples of HME inducers: phenytoin, phenobarbitone, rifampicin, nicotine (tobacco smoking), testosterone (androgens), carbamazepine, griseofulvin, chronic alcohol ingestion, coffee and tea. Basic Pharmacology Lecture (4) Factors Affecting Hepatic Microsomal Enzyme activity….. 1) The effect of drugs: ❑ Examples of HME inhibitors: 1) Direct HME inhibitors: cimetidine, chloramphenicol, contraceptive pills (containing estrogen and/or progesterone), ketoconazole, erythromycin, fluroquinolones, allopurinol, grapefruit, omeprazole, sulphonamides, sodium valproate, MAO Inhibitors, isoniazid, and acute alcoholism. 2) Indirect HME inhibitors, which are either: o Drugs causing hepatic toxicity as carbon tetrachloride. o Drugs reducing hepatic blood flow as Propranolol and Cimetidine. Basic Pharmacology Lecture (4) Importance of HME induction 1. HME inducers increase their own metabolism (auto- induction), which may lead to tolerance and dependence, e.g., phenobarbitone, nicotine and chronic alcoholism. 2. HME inducers increase the metabolism of other drugs given at the same time leading to decreased activity of the other drugs. This requires increasing the dose of the other drugs. 3. Some HME inducers as phenytoin increase the metabolism of vitamins such as folic acid, vitamin K, and vitamin D; leading to megaloblastic anemia, hemorrhage, and osteomalacia; respectively. 4. HME inducers as phenobarbitone are used in treatment of mild hyperbilirubinemia in neonates as they induce conjugation of bilirubin. Basic Pharmacology Lecture (4) Importance of HME inhibitors ❑Administration of HME inhibitors with some drugs – as warfarin, digitalis, oral hypoglycemics and theophylline- may lead to increased plasma levels of such drugs even with therapeutic doses, which may lead to "toxicity". ❑That is why we should reduce the dose of warfarin, digitalis, oral hypoglycemics and theophylline if given with HME inhibitors. Basic Pharmacology Lecture (4) Factors Affecting Hepatic Microsomal Enzyme activity….. 2) Age: The activity of HME is lower in extremities of age, i.e. neonates (especially if premature) and old age, so they should be treated with lower doses than adults. 3) Sex (Gender): Male sex hormones (androgens) act as HME inducers whereas female sex hormones (estrogen and progesterone) act as HME inhibitors. This is an important cause why females receive lower doses than males (of the same age and weight). 4) Pathological conditions: Liver diseases as cirrhosis markedly reduce the activity of HME and the dose of drugs metabolized by these enzymes should be adjusted according to liver function tests. Cancer and starvation have the same effect on HME activity. Basic Pharmacology Lecture (4) Factors Affecting Hepatic Microsomal Enzyme activity….. 5) Genetic factors (Pharmacogenetics): ❑There is marked variation (polymorphism) in the enzyme activity among the population which influences drug action and toxicity. ❑In addition, genetic abnormalities may result in defective or abnormal enzymes; e.g. genetic defect in pseudocholinesterase enzyme greatly reduces metabolism –and increases the action- of succinylcholine (skeletal muscle relaxant) and may lead to "apnea". This abnormal drug response due to genetic defect is known as "idiosyncrasy". Basic Pharmacology Lecture (4) Basic Pharmacology Lecture (4)