Isoniazid (INH) is metabolised primarily by N-acetyltransferase 2 (NAT2). A patient is a slow acetylator. Which adverse effect is they at GREATEST risk of, and why?

• A Lupus-like syndrome; slow acetylators accumulate hydralazine and INH, stimulating autoimmunity
• B Peripheral neuropathy; accumulated free INH competitively inhibits pyridoxal kinase, depleting active vitamin B6 ✓
• C Hepatotoxicity from acetylhydrazine; fast acetylators convert INH to acetylhydrazine which is hepatotoxic
• D Drug-induced haemolytic anaemia from reactive metabolites

Explanation

Slow NAT2 acetylators accumulate unacetylated INH at higher plasma concentrations. Free INH and its hydrazone metabolites compete with pyridoxal-5'-phosphate (active vitamin B6) for binding to pyridoxal kinase and also form hydrazones with PLP, inactivating it. This causes functional B6 deficiency manifesting as peripheral neuropathy (sensorimotor, typically stocking-glove). Slow acetylators are at higher risk than fast acetylators for INH peripheral neuropathy. Pyridoxine (vitamin B6) supplementation prevents this. Lupus-like syndrome with INH and hydralazine is related to drug-induced lupus but is not the greatest risk in slow acetylators specifically. Fast acetylators, paradoxically, have greater hepatotoxicity risk from acetylhydrazine.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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