## Mechanism of Warfarin-Amiodarone Interaction **Key Point:** Amiodarone is a potent inhibitor of CYP2C9, the primary enzyme responsible for warfarin metabolism. This inhibition leads to decreased warfarin clearance, elevated plasma levels, and increased anticoagulant effect. ### Pharmacokinetic Basis Warfarin is metabolized by CYP2C9 (major) and CYP2C8 (minor). Amiodarone's inhibition of CYP2C9 causes: 1. Reduced warfarin metabolism 2. Increased warfarin half-life (from ~40 hours to >100 hours) 3. Accumulation of warfarin with repeated dosing 4. Supratherapeutic INR and bleeding risk **High-Yield:** This is a classic **Type A interaction** (pharmacokinetic, predictable, dose-dependent). The onset is gradual (3–7 days) because warfarin has a long half-life and INR reflects the cumulative effect. ### Clinical Management | Step | Action | |------|--------| | **Baseline** | INR 2.5 (therapeutic) | | **After amiodarone start** | INR rises to 5.2 (supratherapeutic) | | **Management** | Reduce warfarin dose by 30–50%; monitor INR every 2–3 days until stable | | **Monitoring** | Check INR at 3, 7, and 14 days after dose adjustment | **Clinical Pearl:** Amiodarone also has a very long half-life (~26–107 days), so the interaction persists even after stopping amiodarone; warfarin dose reduction must be maintained for weeks. **Mnemonic: CYP2C9 Inhibitors** — **A**midarone, **A**zoles (fluconazole, voriconazole), **A**cetaminophen (high-dose), **N**SAIDs, **S**ulfonamides, **S**tatins (some), **F**luoxetine, **C**imetidine. ### Why INR Rose - Warfarin effect is potentiated by reduced hepatic clearance - Mild epistaxis indicates bleeding tendency (INR >4 carries increased bleeding risk) - No dietary or absorption changes occurred [cite:KD Tripathi 8e Ch 13]
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