## Drug Interaction: Warfarin and TMP-SMX ### Mechanism of Interaction **Key Point:** TMP-SMX is a potent inhibitor of CYP2C9, the primary enzyme responsible for the metabolism of the active S-enantiomer of warfarin. When CYP2C9 activity is reduced: 1. Warfarin clearance decreases 2. Plasma warfarin concentration rises 3. Anticoagulant effect intensifies 4. INR becomes supratherapeutic → bleeding risk ### Clinical Presentation in This Case The patient's INR rose from the therapeutic range (2.5–3.5) to 8.2 within 2 weeks of starting TMP-SMX, accompanied by: - Spontaneous bruising (petechiae/ecchymoses) - Haematuria (bleeding into urinary tract) Both are signs of over-anticoagulation. ### High-Yield Warfarin Interactions Table | Interacting Drug | Mechanism | Effect on INR | Clinical Action | |---|---|---|---| | TMP-SMX | CYP2C9 inhibition | ↑ INR (major) | Monitor INR closely; reduce warfarin dose | | Aspirin | Platelet inhibition + protein displacement | ↑ INR | Avoid if possible; if needed, use PPI | | Rifampicin | CYP2C9 induction | ↓ INR | Increase warfarin dose | | NSAIDs | Protein displacement + GI ulcer risk | ↑ INR | Avoid; use paracetamol | | Amiodarone | CYP2C9 inhibition | ↑ INR (major) | Reduce warfarin by 30–50% | **Clinical Pearl:** TMP-SMX is one of the most notorious warfarin potentiators in primary care. Always check INR 3–5 days after starting any CYP2C9 inhibitor in a patient on warfarin. ### Management 1. **Immediate:** Check INR; hold warfarin if INR > 9 or bleeding present 2. **Vitamin K:** Give 2.5–5 mg IV if INR > 9 without bleeding, or 10 mg IV if bleeding 3. **Fresh frozen plasma (FFP):** If life-threatening bleeding 4. **Antibiotic choice:** Consider switching to a non-interacting antibiotic (e.g., cephalosporin, fluoroquinolone) or reduce warfarin dose by 20–30% if TMP-SMX is essential [cite:KD Tripathi 8e Ch 12]
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