Which of the following enzyme inhibitors is most likely to cause a significant increase in warfarin levels when co-administered, leading to increased bleeding risk?

Explanation

## Warfarin–Drug Interaction Mechanism **Key Point:** Warfarin is metabolized by hepatic cytochrome P450 enzymes, primarily CYP2C9. Inhibitors of CYP2C9 increase warfarin levels and prolong INR, while inducers decrease warfarin levels and reduce anticoagulation. ### Fluconazole (Correct Answer) Fluconazole is a potent **CYP2C9 inhibitor** that significantly reduces warfarin metabolism, leading to: - Elevated warfarin plasma concentration - Prolonged prothrombin time (PT) and increased INR - Increased bleeding risk (major interaction) - Requires warfarin dose reduction and close INR monitoring ### Why Other Options Are Wrong | Drug | Mechanism | Effect on Warfarin | |------|-----------|--------------------| | **Rifampicin** | CYP2C9 inducer | ↓ Warfarin levels; ↓ INR; loss of anticoagulation | | **Phenytoin** | CYP2C9 inducer | ↓ Warfarin levels; ↓ INR; reduced efficacy | | **Carbamazepine** | CYP2C9 inducer | ↓ Warfarin levels; ↓ INR; reduced efficacy | **High-Yield:** Azole antifungals (fluconazole, itraconazole, ketoconazole) and macrolide antibiotics (erythromycin, clarithromycin) are classic CYP2C9 inhibitors that increase warfarin effect. Enzyme inducers (rifampicin, phenytoin, carbamazepine, phenobarbital) decrease warfarin effect. **Clinical Pearl:** When a CYP2C9 inhibitor is started in a patient on warfarin, INR must be checked within 3–5 days and warfarin dose adjusted downward to prevent supratherapeutic INR and bleeding. **Mnemonic:** **SICKFACES.COM** — a classic mnemonic for drugs that increase warfarin effect (inhibitors). Fluconazole fits the **F** (Fluconazole/antifungals).