A 48-year-old woman on warfarin for atrial fibrillation is started on fluconazole for oesophageal candidiasis. Her INR rises from 2.5 to 8.2 within 5 days. Which is the most common mechanism responsible for this warfarin–fluconazole interaction?

Question

Accepted Answer

A. Inhibition of cytochrome P450 2C9, the major enzyme responsible for warfarin metabolism. ## Warfarin–Fluconazole Interaction: CYP2C9 Inhibition

**Key Point:** The most common mechanism of elevated INR when fluconazole is combined with warfarin is **inhibition of cytochrome P450 2C9 (CYP2C9)**, the major enzyme responsible for warfarin metabolism.

### Warfarin Metabolism

**High-Yield:** Warfarin is a racemic mixture of S- and R-enantiomers:
- **S-warfarin** (more potent): metabolized by **CYP2C9** (major pathway, ~80%)
- **R-warfarin** (less potent): metabolized by CYP3A4, CYP1A2, CYP2C19

### Fluconazole as a CYP2C9 Inhibitor

1. **Mechanism:**
   - Fluconazole is a **potent inhibitor of CYP2C9**
   - Blocks metabolism of S-warfarin (the more active enantiomer)
   - Leads to accumulation of warfarin → increased INR

2. **Onset and severity:**
   - Onset: 2–5 days (as seen in this case)
   - Severity: Significant (INR rose from 2.5 to 8.2)
   - Fluconazole is a **high-risk interacting drug** with warfarin

3. **Clinical consequences:**
   - Supratherapeutic INR → bleeding risk
   - Requires INR monitoring and possible warfarin dose reduction

### Comparison of Azole Antifungals and CYP Inhibition

| Azole | CYP2C9 Inhibition | CYP3A4 Inhibition | Warfarin Interaction Risk |
|-------|-------------------|-------------------|---------------------------|
| **Fluconazole** | **Potent** | Moderate | **High** |
| **Itraconazole** | Moderate | Potent | Moderate–High |
| **Ketoconazole** | Moderate | Potent | Moderate–High |
| **Miconazole** | Potent | Moderate | **High** |
| **Voriconazole** | Moderate | Potent | Moderate |

**Mnemonic:** **CYP2C9 = Warfarin's Highway** — Fluconazole blocks this major route, causing warfarin accumulation.

### Clinical Management

**Clinical Pearl:** When fluconazole must be used in a warfarin-treated patient:
- Monitor INR closely (every 2–3 days initially)
- Consider reducing warfarin dose by 30–50%
- Switch to alternative antifungal if possible (e.g., caspofungin, which has no CYP interactions)
- Educate patient on bleeding precautions

**Warning:** Do NOT assume all azoles have the same interaction potential — fluconazole and miconazole are particularly potent CYP2C9 inhibitors.

Answer

B. Displacement of warfarin from plasma albumin binding

Answer

C. Inhibition of cytochrome P450 3A4, reducing warfarin metabolism

Answer

D. Inhibition of warfarin absorption in the small intestine

A 48-year-old woman on warfarin for atrial fibrillation is started on fluconazole for oesophageal candidiasis. Her INR rises from 2.5 to 8.2 within 5 days. Which is the most common mechanism responsible for this warfarin–fluconazole interaction?

Explanation

Warfarin–Fluconazole Interaction: CYP2C9 Inhibition

Warfarin Metabolism

Fluconazole as a CYP2C9 Inhibitor

Comparison of Azole Antifungals and CYP Inhibition

Clinical Management

Practice similar questions

Join our NEET PG community

Azole	CYP2C9 Inhibition	CYP3A4 Inhibition	Warfarin Interaction Risk
Fluconazole	Potent	Moderate	High
Itraconazole	Moderate	Potent	Moderate–High
Ketoconazole	Moderate	Potent	Moderate–High
Miconazole	Potent	Moderate	High
Voriconazole	Moderate	Potent	Moderate