Isoniazid (isonicotinic acid hydrazide) - The original TB killer

  • first-line drug (literally, the first drug a doctor will turn to) for the treatment and prophylaxis (prevention) of tuberculosis
  • converted by a catalase-peroxidase (enzyme that functions primarily to rapidly detoxify hydrogen peroxide) to an active metabolite that inhibits the synthesis of mycolic acids, which are a major and unique component of the cell walls of mycobacteria (bacteria belonging to the genus Mycobacterium)
    • mycolic acids provide mycobacteria with special cell walls that enable them to proliferate inside macrophages (and thus avoid the immune system) and increase their resistance to chemical damage (including damage mediated by hydrophobic antibiotics) and dehydration
  • inactivated mainly by N-acetyltransferase, a liver enzyme that comes in two flavours - slow and fast - such that some people metabolize isoniazid more quickly than others (rapid acetylators vs. slow acetylators)
    • approximately 90% of Asians are rapid acetylators, while it's about 1:1 rapid and slow acetylators in Caucasians and Blacks
  • inhibits CYP 3A4, one of the major drug metabolizing enzymes in the body, resulting in elevated levels of other drugs being taken concurrently that are metabolized by this enzyme (this is a type of drug-drug interaction)
  • somehow causes the depletion of pyridoxine (vitamin B6) stores in the body, which can result in peripheral neuropathy, skin lesions, and anemia
- Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.
- Marcinkeviciene JA, Magliozzo RS, Blanchard JS. Purification and characterization of the Mycobacterium smegmatis catalase-peroxidase involved in isoniazid activation. J Biol Chem. 1995 Sep 22;270(38):22290-5.

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