In a 60-year-old man with hypertension and a prosthetic aortic valve who is taking lisinopril, amlodipine, and warfarin, which medication requires dose adjustment after initiating first‑line anti‑tuberculosis therapy?

Warfarin Requires Dose Adjustment

Warfarin (option C) is the medication that requires dose adjustment when initiating first-line anti-tuberculosis therapy, specifically due to rifampin's potent enzyme-inducing effects that significantly reduce warfarin's anticoagulant activity. 1

Mechanism of Drug Interaction

Rifampin, a cornerstone of first-line TB therapy, is a powerful inducer of hepatic enzymes that dramatically reduces serum levels of warfarin and other drugs metabolized in the liver. 1 This interaction decreases warfarin's effectiveness, placing this patient with a prosthetic aortic valve at substantial risk for thromboembolic complications including valve thrombosis, stroke, and systemic embolization—all potentially fatal outcomes. 1

The European Respiratory Society guidelines explicitly document that rifampin decreases serum levels of warfarin through hepatic enzyme induction. 1 This is not a minor interaction but rather a critical drug-drug interaction requiring immediate attention.

Clinical Significance in This Patient

This 60-year-old man faces particularly high stakes:

• Prosthetic aortic valve: Requires therapeutic anticoagulation (INR 2.5-3.5 typically) to prevent catastrophic valve thrombosis 2
• Starting rifampin: Will substantially reduce warfarin efficacy within days to weeks 1
• Risk of inadequate anticoagulation: Could result in valve thrombosis, stroke, or death—outcomes far more immediately life-threatening than tuberculosis progression 2

Management Algorithm

Immediate Actions (Week 1-2):

1. Increase INR monitoring frequency to 2-3 times weekly initially, as rifampin's enzyme-inducing effects begin within days 1, 2
2. Anticipate warfarin dose increases of 50-100% or more may be necessary 1
3. Do not wait for INR to drop before adjusting—proactive dose increases are safer than reactive management 2

Ongoing Management:

• Continue frequent INR monitoring (at least weekly) for the first month of TB therapy 2
• Once stable, can extend to every 2-4 weeks, but never beyond 4 weeks given the critical nature of anticoagulation in prosthetic valves 2
• Document baseline warfarin dose before TB therapy for reference when rifampin is eventually discontinued 1

Critical Pitfall to Avoid:

When TB therapy is completed and rifampin is stopped, warfarin's enzyme induction will reverse over 2-4 weeks, and the patient will become over-anticoagulated on the higher warfarin dose. 1 At that time, warfarin must be reduced (often back to near the original dose) with very frequent INR monitoring to prevent major bleeding. 2

Why Other Medications Don't Require Adjustment

• Lisinopril (option A): No significant interaction with rifampin or other first-line TB drugs 1
• Amlodipine (option B): While rifampin can reduce calcium channel blocker levels through enzyme induction, this rarely causes clinical problems requiring dose adjustment, and blood pressure can be monitored non-invasively 1
• Rifampin (option D): Standard dosing of 600 mg daily (or 10 mg/kg) is appropriate and does not require adjustment based on this patient's other medications 1

Additional Monitoring Considerations

Beyond warfarin adjustment, this patient requires:

• Hepatotoxicity monitoring: All three medications (lisinopril is not hepatotoxic, but isoniazid, rifampin, and pyrazinamide in the TB regimen are) can cause liver injury, with risk increased in patients over 60 years 1, 3
• Baseline and monthly liver function tests during the first 2-3 months of TB therapy 1, 4
• Immediate reporting of jaundice, dark urine, or persistent nausea 4

The combination of advanced age (60 years) increases risk of both TB drug hepatotoxicity and warfarin sensitivity, making this patient particularly high-risk and requiring meticulous monitoring. 1, 3