Pharmacology Lecture: Metabolism PDF

Pharmacology Metabolism LECTURE (6) Pharmaco-kinetics (2) DR. El-Sawy 0  Pharmacology...

Pharmacology Metabolism LECTURE (6) Pharmaco-kinetics (2) DR. El-Sawy 0  Pharmacology Metabolism ‫التكسري‬ Def: process of chemical alteration of drugs in the body. site:  Liver "major site of drug metabolism".  Other organs: Kidney. Lungs. GIT. Effect of enzymes on drug:: Convert of Into Example  The most common. Inactive Active drug  Termination of drug effect. metabolite  Prolongation of drug effect Active Active drug  Codeine  morphine. metabolite  L-dopa to dopamine Inactive drug Active (pro-drug) metabolite  Enalapril to enalaprilat Non-toxic Toxic  Paracetamol  N-acetyl benzo-quinone. drug metabolite aim :  Metabolism aims to convert lipid soluble drugs to water-soluble leading to: 1. Facilitate drug excretion in body water (urine, bile, milk, sweet) 2. Decrease tissue penetration & renal re-absorption because it is water- soluble. DR. El-Sawy 1  Pharmacology Metabolism Phase reaction Phase reactions Oxidation Conjugation Reduction Hydrolysis if drug is converted into water- Coupling of water-insoluble soluble compound by one of these molecule to water-soluble compound reactions, it does not need to enter (usually the glucuronic acid) to form phase II metabolism. water-soluble conjugate. Definition:  Most common reaction in which O2 is added to the drug or H+ is removed from the drug Principles: 1- By oxidizing enzymes → in microsomes of many organs especially liver 2- Microsomes are sub-cellular membranous vesicles in the smooth endoplasmic reticulum of cells 3- Primary of this enzyme system is cytochrome P450 enzyme (Cp450 or CYP450) 4- CP450 is family of many iso-enzymes formed of hemoproteins & concerned with catalyzing oxidation – reduction reactions → so called mixed function oxidases. DR. El-Sawy 2  Pharmacology Metabolism Microsomal liver enzyme inducers & inhibitors: Microsomal enzyme induction Microsomal enzyme inhibition  ↑ rate of metabolism of some drugs leading to ↓  ↓ rate of metabolism of some drugs leading to ↑ their serum levels and therapeutic failure. their serum levels and toxicity.  For acetaminophen, if metabolism is induced → mechanism ↑ toxic metabolite  Must ↑ dose of drug affected by metabolism  Opposite → ↓ dose except acetaminophen  Rifampicin:  Ciprofloxacin: accelerates metabolism of contraceptive Inhibits metabolism of warfarin → Clinical pills → failure of contraception. accumulation of warfarin and bleeding. examples  Phenotyoin:  Erythromycin: accelerate metabolism of cyclosporine A inhibit metabolism of theophylline → → graft rejection toxcicity of theophylline (arrythemia) DR. El-Sawy 3  Pharmacology Metabolism 1. Oxcarbazepine ‫اوكسا‬ 1. Cimetidine ‫سايم‬ 2. Carbamazepine ‫واكراي‬ 2. Allopurinol ‫اللو‬ 3. Quinolones 3. dexamethasone ‫وديكسا‬ ‫كني‬ (ciprofloxacin) 4. Omeprazole ‫وأويم‬ 4. Chloramphenicol ‫لكور‬ 5. Macrolides (erythro 5. Phenytoin ‫ماكرو‬ ‫ فينو‬2 ‫ألكي‬ & clarithro) Examples 6. Phenobarbitone 6. Lincosamides ‫لينكو‬ 7. Smoking & alcohol ‫بيدخنو ويسكرو‬ 7. Isoniazide ‫أيزو‬ 8. Azoles 8. Rifampin ‫يف الريف‬ ‫أزو‬ (ketoconazole) 9. Interferon ‫انرتفريو‬ 9. St. John's Wort ‫حشيشة سانت جون‬ 10. Ritonavir ‫زيتونه‬ 11. Grapefruit juice ‫جريب فروت‬ DR. El-Sawy 4  Pharmacology Metabolism done by  Soluble enzymes in cytoplasm or mitochondria.  Xanthine Oxidase: Converts xanthine to uric acid. Examples  Monoamine oxidase (MAO) Oxidizes catecholamines and serotonin. NB  less common than oxidation.  Microsomal reaction: Nitroreductase (chloramphenicol) Types  Non-microsomal reduction: Carbonyl reductase (naloxone). Type  Mainly non-microsomal (in plasma, tissues, & body fluids).  Nonspecific estrases Acetylcholine metabolism by cholinesterase. Examples  Peptidases: Insulin metabolism by insulinase. Note If drug is water soluble from the start, it does not need metabolism & excreted unchanged. DR. El-Sawy 5  Pharmacology Metabolism Definition: Coupling of a drug or its metabolite to endogenous substrate (usually glucuronic acid) to form a conjugate, which is water-soluble easily excreted in urine or bile. Types of endogenous substrates & conjugation reactions:  It is most common conjugation reaction  Activated glucuronic acid is Conjugated to: Drugs. Metabolites. Glucuronide  Glucuronide conjugates are inactive and rapidly excreted in conjugation urine or bile. (microsomal)  Glucuronide conjugates secreted in bile can be hydrolyzed by intestinal bacteria and free drug can be reabsorbed again (enterohepatic circulation) →↑duration of drug action e.g. estrogen pills a. Glutathion conjugation → using glutathione (acetaminophen, ethacrynic acid). Other b. Glycine conjugation → using Glycine (salicylic acid). conjugation reactions c. Methylation → using methyl group (COMT for (Non- noradrenaline). microsomal) d. Acetylation → using acetic acid (isoniazide, salicylic acid). e. Sulfation by sulfotransferase (steroid hormones) DR. El-Sawy 6  Pharmacology Metabolism DR. El-Sawy 7  Pharmacology Metabolism Note Breakthrough Pregnancy : Contraceptive pills contain estrogen, which is metabolized by glucuronide conjugation and excreted in bile conjugate. Intestinal bacteria hydrolyze this conjugate to form free estrogen again which is reabsorbed and attain long duration of action (so contraceptive pills are given once daily). If the woman took contraceptive pills with broad-spectrum antibiotics (kills the intestinal bacteria), estrogen will lose its long duration of action and pregnancy can occur. This drug interaction between antibiotics & estrogen pills is debated strongly & only proven for rifampin antibiotic & its derivative rifabutin (through enzyme induction) DR. El-Sawy 8  Pharmacology Metabolism  Metabolism of drugs at the site of administration before Def reaching systemic circulation as: A- Oral route: Gut first-pass metabolism: 1. Gastric acidity destroy benzyl penicillin. 2. Digestive enzymes digest hormones as insulin 3. COMT in Intestinal mucosa metabolize L-dopa. Sites & examples Hepatic first-pass metabolism: 4. Morphine & H2-blockers, B.B., Nitrates b- Lung after inhalation c- SC after topical skin application: e.g. insulin by proteolytic enzymes (abnormal) 1. ↑ drug dose if first pass effect is partial e.g. 5mg propranolol IV = 100mg oral 2. Use other routes if the first pass effect is complete How to avoid e.g. SL, inhalation, or i.v. e.g. sub-lingual nitroglycerin in acute angina instead of oral , to avoid first pass metabolism in liver, which delay drug effect DR. El-Sawy 9  Pharmacology Metabolism Factors affecting drug metabolism Genetic factors  Acetylation status (fast & slow)  Decrease vitamins & amino acids (needed for Malnutrition metabolism)  May decrease metabolism: Age (extremes) Elderly Children < 6 months  Cause impaired hepatic enzymes & decrease amino Liver dis. & LCF acids  Reduced drug metabolism → clearance decrease & hepatic enzyme longer t1/2 → ↓ drug dose inducers or  Increased drug metabolism → clearance increase & inhibitors shorter t1/2 → ↑ drug dose DR. El-Sawy 10