A 48-year-old woman with hepatic cirrhosis (Child-Pugh score 10) is prescribed warfarin 5 mg daily for atrial fibrillation. Her INR after 5 days is 4.8 (therapeutic range 2–3). She has normal renal function. Which pharmacokinetic mechanism best explains her exaggerated response to warfarin?

Explanation

## Warfarin Pharmacokinetics in Hepatic Disease ### Warfarin Metabolism - **Site:** Hepatic (CYP2C9, CYP2C8, CYP3A4) - **Clearance:** Entirely hepatic; renal excretion is minimal - **Normal t½:** 36–42 hours - **In cirrhosis:** t½ may extend to 80+ hours ### Why INR is Elevated | Parameter | Normal Liver | Cirrhotic Liver | |-----------|--------------|----------------| | **CYP450 activity** | Normal | ↓↓ (enzyme induction loss, hepatocyte necrosis) | | **Clotting factor synthesis** | Normal | ↓ (reduced hepatic protein synthesis) | | **Warfarin clearance** | High | Low | | **Warfarin half-life** | 36–42 h | 80+ h | | **Sensitivity to warfarin** | Standard | Exaggerated | ### Dual Mechanism of Exaggerated Response 1. **Reduced metabolism:** Cirrhotic liver has fewer functional hepatocytes and reduced CYP450 activity → warfarin accumulates 2. **Reduced clotting factor synthesis:** Cirrhosis impairs synthesis of vitamin K-dependent factors (II, VII, IX, X) → baseline INR already elevated, warfarin effect amplified **Clinical Pearl:** Cirrhotic patients require lower warfarin doses and more frequent INR monitoring. Initial dosing should be conservative (2–3 mg/day).