Medication History Guide-2

Comprehensive Guide to CYP450 Enzymes and Clinical Pharmacology 1. Introduction Cytochrome P450 (CYP450) enzymes are a large family of proteins encoded by P450 genes, playing a central role in the metabolism of the majority of drugs used in clinical practice. These enzymes help the body chemically modify and eliminate drugs, influencing therapeutic efficacy, toxicity, and overall patient outcomes. Approximately 90% of clinically relevant drugs are metabolized by six primary CYP450 enzymes: CYP3A4, CYP3A5, CYP2D6, CYP2C19, CYP2C9, and CYP1A2, with CYP3A4 and CYP2D6 being the most critical. Understanding these enzymes is essential for clinicians, as variations in their activity can result in significant differences in drug response between individuals and populations. 2. Genetic Polymorphism of CYP450 Enzymes Polymorphism refers to the genetic variations in CYP450 genes that result in enzymes with differing capacities to metabolize drugs. These genetic differences are a major factor in inter-individual variability in therapeutic outcomes and the risk of adverse effects. 2.1 CYP2D6 Phenotypes CYP2D6, responsible for metabolizing a broad range of drugs including beta-blockers, opioids, and antidepressants, exhibits four primary metabolic phenotypes: - Poor Metabolizers (PM) - Intermediate Metabolizers (IM) - Extensive Metabolizers (EM) - Ultrarapid Metabolizers (UM) Clinical Implications: - Poor Metabolizers: Reduced metabolism may lead to drug accumulation and toxicity. - Ultrarapid Metabolizers: Accelerated metabolism can result in sub-therapeutic drug levels, or, in the case of prodrugs, increased conversion to active metabolites causing toxicity. - Intermediate Metabolizers: Display a metabolism rate between PM and EM, potentially increasing susceptibility to adverse effects. Population Distribution: - PMs affect up to 10% of Caucasians and 30% of Chinese populations. - UMs are most common in North African, Ethiopian, and Arab populations (16–28%) but rare in East Asia (1%) and Western Europe (~5.5%). 2.2 Drug Examples • Propranolol: A beta-blocker metabolized by CYP2D6; PMs have higher plasma concentrations leading to bradycardia, hypotension, dizziness, or syncope. • Codeine: A prodrug activated to morphine by CYP2D6; UMs may experience overdose symptoms, while PMs may lack analgesic effect. • Nortriptyline: A tricyclic antidepressant metabolized by CYP2D6; IMs have higher drug levels and increased side effect risk, often requiring dose adjustments. 1 3. CYP450 Enzyme Substrates, Inducers, and Inhibitors 3.1 Substrates Substrates are drugs metabolized by CYP450 enzymes. Common examples include: - Statins Theophylline - Phenytoin - Warfarin - SSRIs (sertraline, citalopram, fluoxetine) - Amitriptyline - Codeine Caffeine 3.2 Inducers Inducers enhance CYP450 enzyme expression, accelerating drug metabolism and reducing therapeutic levels. Effects typically develop gradually and may take days to resolve after discontinuation. Examples: - Anticonvulsants: phenytoin, carbamazepine, phenobarbitone - Steroids: dexamethasone, prednisolone - Antibiotics: rifampicin, griseofulvin - Others: nicotine, alcohol, St John’s Wort Clinical Relevance: Inducers may cause treatment failure by lowering drug concentrations. Monitoring and dose adjustments may be required. 3.3 Inhibitors Inhibitors decrease CYP450 activity, slowing drug metabolism and increasing the risk of toxicity. The effects are often dose-dependent and appear rapidly. Examples: - Azoles: ketoconazole, fluconazole - Antibiotics: sulfonamides, metronidazole, ciprofloxacin, macrolides - Other agents: cimetidine, omeprazole, sodium valproate, grapefruit juice Clinical Cases: - St John’s Wort and Oral Contraceptives: Induces CYP3A4/3A5, reducing contraceptive efficacy and increasing risk of breakthrough bleeding; alternative contraception recommended. Miconazole and Warfarin: Inhibits CYP2C9, increasing warfarin plasma levels and INR, requiring dose adjustment and close monitoring for bleeding. 4. Clinical Considerations and Prescribing Implications • Polymorphisms: Influence dosing requirements and risk of adverse reactions. • Drug-Drug Interactions: Inducers and inhibitors must be considered when prescribing multiple drugs. • Population Variability: Ethnicity and genetic background affect prevalence of PM, IM, EM, and UM phenotypes. 5. Key Takeaways 1. CYP450 enzymes metabolize the majority of clinically used drugs. 2. CYP2D6 and CYP3A4 are the most significant enzymes in drug metabolism. 3. Genetic polymorphisms greatly affect individual drug response and toxicity. 2 4. Understanding enzyme substrates, inducers, and inhibitors is essential to avoid adverse effects and therapeutic failure. 5. Careful clinical monitoring and dose adjustment can improve patient safety and treatment efficacy. References 1. Lynch T, Price A. The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects. August 2007. 2. Zanger UM, Raimundo S, Eichelbaum M. CYP2D6: Overview and Update. November 2003. 3. Wong C, Lau E, Palozzi L, Campbell F. Pain Management in Children: From Codeine to Morphine. November 2012. 4. Ingelman-Sundberg M. Genetic Polymorphisms of CYP2D6: Clinical Consequences. October 2004. 5. Royal Pharmaceutical Society. Stockley’s Drug Interactions. 3