Drug Interactions and Hepatic Microsomal Enzymes - PDF

Drug interactions involving Hepatic Microsomal Enzymes  Table of contents 01 Metabolism of drugs in human and phases of metabolism Hepatic microsomal 06 enzyme inducers and...

Drug interactions involving Hepatic Microsomal Enzymes  Table of contents 01 Metabolism of drugs in human and phases of metabolism Hepatic microsomal 06 enzyme inducers and examples on DDI 02 Hepatic microsomal enzymes and their function Hepatic microsomal 03 Factors affect hepatic microsomal enzyme 07 enzyme inhibitors and examples on DDI Drugs used in 04 Diseases affect hepatic microsomal enzymes preclinical and 08 clinical studies as 05 Foods affect hepatic microsomal enzymes hepatic microsomal enzymes inducers and inhibitors Introduction The liver is the largest internal organ in the body, playing a central role in metabolism, detoxification, and the synthesis of essential proteins. It regulates chemical levels in the blood and processes drugs and toxins to make them easier for the body to excrete. One of its critical functions is drug metabolism, primarily involving hepatic microsomal enzymes.  01 Metabolism Of Drugs In Human And Phases Of Metabolism Biotransformation Biotransformation is the process by which the body chemically modifies drugs to facilitate their elimination. This primarily occurs in the liver. The primary goal of metabolism is to make drugs more water-soluble so, they can be excreted via urine or bile. Phase I Modification Oxidation, Reduction, Hydrolysis Phase II Conjugation Glucuronidation, Sulfation, etc. Excretion Kidney, Bile, etc Phase I (Functionalization Reactions) Oxidation by CYP450 Reduction enzymes nitroreductases, Hydrolysis azoreductases esterases, amidases Phase II (Conjugation Reactions) Glucuronidation UDP-glucuronosyltransferases Acetylation R-OH (UGTs) R-O-CO-CH3 N-acetyltransferases (NATs) Sulfation (X)toxic compoun sulfotransferases (SULTs) d GST →GSH Glutathione conjugation glutathione-S-transferases GSH-X (GSTs)  02 Hepatic Microsomal Enzymes Hepatic Microsomal Enzymes What are they? A group of enzymes responsible for drug metabolism, mainly found in the smooth endoplasmic reticulum of liver cells. Function: They play a key role in Phase I metabolism, helping in oxidation, reduction, and hydrolysis of drugs. Most Important Enzyme System: The Cytochrome P450 (CYP450) system, which metabolizes over 75% of drugs. Major Microsomal Enzymes & Their Functions Cytochrome P450 (CYP450) Metabolizes most drugs. Flavin-Containing Monooxygenases (FMO): Breaks down drugs containing nitrogen, sulfur, or phosphorus (e.g., nicotine, ranitidine). Microsomal Epoxide Hydrolase (mEH) Converts epoxides into active metabolites (e.g., carbamazepine). UDP-Glucuronosyltransferases (UGTs) Helps in drug detoxification through glucuronidation (e.g., acetaminophen).  03 Factors Affect Hepatic Microsomal Enzyme Factors Affecting Hepatic Microsomal Enzymes (CYP450) Physiological Genetics Age, sex, and nutrition CYP gene variations affect influence enzyme function. drug metabolism speed, Aging reduces activity, while making some individuals diet (fasting or high-fat) metabolize drugs faster or affects CYP3A4 metabolism. slower. Disease Conditions Environmental Liver diseases (e.g., cirrhosis, Alcohol, smoking, pollutants, hepatitis, NAFLD) lower CYP and certain drugs can activity, slowing drug increase or decrease CYP metabolism and increasing enzyme activity, altering drug drug buildup. breakdown.  Diseases Affect Hepatic Microsomal Enzymes Diseases Affecting Hepatic Microsomal Enzymes Acute Liver Injury Genetic Liver Diseases )cirrhosis, hepatitis( )acetaminophen toxicity( Disorders reduce enzyme activity, disrupts enzyme CYP450 mutations alter slowing drug metabolism. function. drug metabolism. Endocrine Infections Alcoholism Disorders )HIV, TB) & Cancer impact liver enzyme Modify enzyme activity, Thyroid imbalances function. affecting drug affect enzyme activity. breakdown.  Hepatic Microsomal Enzyme Inducers Hepatic Microsomal Enzyme Inducers What are they? Substances that increase liver enzyme activity (mainly CYP450), speeding up drug metabolism and reducing drug effectiveness. Common inducers include certain anticonvulsants: Phenytoin Carbamazepine Phenobarbital Rifampicin Chronic alcohol consumption Drug-Drug Interactions Strongest Moderate to strong Weaker Rifampicin Carbamazepine Phenytoin Warfarin Oral Contraceptives Theophylline Lowers anticoagulant Reduces effectiveness, Reduces asthma drug effect, risk of clots. risk of pregnancy. effectiveness.  Hepatic Microsomal Enzyme Inhibitors Hepatic Microsomal Enzyme Inhibitors What are Substances that inhibit liver enzymes 01 they? (mainly CYP450), slowing down drug metabolism. ❑ Block enzyme activity, How do preventing drug breakdown. 02 they ❑ Increase drug levels in the blood. ❑ Prolong drug effects and raise work? toxicity risk. Common Ketoconazole 03 Inhibitors: Erythromycin Cimetidine Drug-Drug Interactions Strongest Moderate to strong Weakest Ketoconazole Cimetidine Erythromycin Warfarin Warfarin Theophylline Higher warfarin levels, Reduced theophylline Slower warfarin metabolism, increased bleeding risk clearance, risk of toxicity increased anticoagulant effect Effect of Drugs on Hepatic Microsomal Enzymes Hepatic microsomal enzymes (CYP450) play a key role in drug metabolism Some drugs can: ❑ Induce enzymes → Speed up metabolism, Impact on Pharmacokinetics lower drug levels. Affects drug levels → Requires monitoring. ❑ Inhibit enzymes → Changes drug effectiveness & toxicity risk → Adjust doses Slow metabolism, accordingly. increase drug levels. Monitoring is essential for safe & effective drug use.  Hepatic Microsomal Enzyme Inducers ❖ increase liver enzyme activity → Faster drug metabolism. ❖ Can reduce drug effectiveness. Drug Induced Enzyme(s) Preclinical/Clinical Study Notes Used in tuberculosis; strong inducer affecting many Rifampin CYP3A4, CYP2C9, CYP2C19 CYP2C8 drugs. Phenobarbital CYP2B6, CYP3A4, CYP2C9 Classic inducer in epilepsy treatment. Phenytoin CYP3A4, CYP2C9, CYP2C19 Induces metabolism of anticoagulants and steroids. Induces CYP1A2, affecting caffeine and theophylline Omeprazole CYP1A2 metabolism.  Hepatic Microsomal Enzyme Inhibitor ❖ Reduce liver enzyme activity (CYP450), slowing drug metabolism. ❖ raising the risk of toxicity. Drug Inhibited Enzyme(s) Preclinical/Clinical Study Notes MAO inhibitors block the enzyme, increasing drug Phenelzine CYP2C8 levels and side effect risk. Leukotriene receptor antagonists rely on CYP2C8; Montelukast CYP2C8 inhibitors may lower metabolism and efficacy. Chemotherapeutics need CYP2B6; inhibitors may Thiotepa CYP2B6 reduce effectiveness. Antiplatelet drugs rely on CYP2B6 for activation; Clopidogrel CYP2B6 inhibition reduces their effectiveness, requiring careful monitoring.. THANKS DO YOU HAVE ANY QUESTIONS? [email protected] +91 620 421 838 yourwebsite.com CREDITS: This presentation template was created by Slidesgo, Slidesgo including icons by Flaticon and infographics & images by Freepik Flaticon Freepik Please keep this slide for attribution 26  Thanks Do you have any questions? [email protected] +91 620 421 838 yourwebsite.com Slidesgo CREDITS: This presentation template was created by Slidesgo, including icons Flaticon Freepik by Flaticon and infographics & images by Freepik Please keep this slide for attribution