A patient receiving ethionamide within an MDR-TB regimen develops lethargy, weight gain and bradycardia. TSH is elevated with low free T4. Which statement best explains this drug's behaviour?
- A It is a prodrug activated by KatG, and hypothyroidism results from iodide uptake inhibition
- B It inhibits ATP synthase directly, and hypothyroidism is an idiosyncratic autoimmune effect
- C It is activated by the ethA monooxygenase, inhibits InhA, and commonly causes hypothyroidism especially when combined with PAS ✓
- D It inhibits DNA-dependent RNA polymerase, and hypothyroidism occurs only in fast acetylators
Correct answer: C. It is activated by the ethA monooxygenase, inhibits InhA, and commonly causes hypothyroidism especially when combined with PAS
Explanation
Ethionamide (and prothionamide) is a prodrug activated by the bacterial flavoprotein monooxygenase encoded by ethA. The active metabolite inhibits InhA, the same enoyl-ACP reductase target as isoniazid, so low-level inhA promoter mutations confer cross-resistance to both drugs. Hypothyroidism is a well recognised cumulative toxicity, markedly more frequent when ethionamide is given with para-aminosalicylic acid. Activation by KatG belongs to isoniazid, not ethionamide.
Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th ed.
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