A 35-year-old man with newly diagnosed pulmonary tuberculosis is started on standard 4-drug therapy including isoniazid. He is a slow acetylator of isoniazid (genetic polymorphism in N-acetyltransferase). The structure marked **A** in the diagram is the target of isoniazid action. Which of the following adverse effects is this patient at HIGHEST risk of developing due to his slow acetylator phenotype?

Explanation

## Why "Peripheral neuropathy and hepatotoxicity due to prolonged drug accumulation" is right Isoniazid is metabolized by hepatic N-acetyltransferase, and individuals with slow acetylator phenotype have reduced drug clearance, leading to higher plasma concentrations and prolonged tissue exposure. This genetic polymorphism is the MOST IMPORTANT pharmacogenetic determinant of INH toxicity. Slow acetylators accumulate INH and its toxic metabolites, placing them at significantly higher risk of both hepatitis (the most serious INH adverse effect) and peripheral neuropathy (caused by INH-induced pyridoxine/B6 depletion). The clinical anchor directly states: "slow acetylators are at higher risk of peripheral neuropathy + hepatotoxicity." This is a well-established principle in TB pharmacotherapy and is emphasized in KD Tripathi and Murray textbooks. ## Why each distractor is wrong - **Acute hemolytic anemia due to G6PD enzyme deficiency**: While INH can cause hemolysis in G6PD-deficient patients, this is an independent pharmacogenetic risk (G6PD polymorphism, not N-acetyltransferase polymorphism) and is NOT specifically linked to slow acetylator status. The question stem specifies slow acetylator phenotype, not G6PD status. - **Drug-induced lupus with positive ANA and anti-histone antibodies**: Drug-induced lupus is a recognized but less common adverse effect of INH and is NOT specifically associated with slow acetylator phenotype. It occurs across all acetylator phenotypes and is not the primary toxicity risk in slow acetylators. - **Ototoxicity and eighth cranial nerve damage**: This is a characteristic adverse effect of streptomycin and second-line TB drugs (fluoroquinolones, aminoglycosides), NOT isoniazid. Ototoxicity is not an INH-related adverse effect and is unrelated to acetylator status. **High-Yield:** Slow acetylators of isoniazid → prolonged drug accumulation → hepatotoxicity + peripheral neuropathy; always give prophylactic pyridoxine (B6) 10–50 mg/day to high-risk slow acetylators (pregnancy, alcoholism, malnutrition, diabetes, HIV, elderly). [cite: KD Tripathi 9e Ch 56; Murray 9e]