18.02.2 Isoniazid

Isoniazid has a similar structure to nicotinic acid, and because of this it causes inhibition of nicotinamide adenine dinucleotide (NAD) synthesis. Without NAD, there is inhibition of synthesis of mycolic acids, which are constituents of mycobacterial cell wall. As a result of preventing the synthesis of the mycobacterial cell wall, isoniazid is bactericidal in actively dividing cells but bacteriostatic in resting cells. Unfortunately, with continued use, resistance develops to isoniazid, and it loses effectiveness.

Unfortunately, isoniazid also has effects on the host. Isoniazid interferes with Vitamin B₆ (pyridoxime) metabolism, which makes the vitamin ineffective. Vitamin B₆ is required to maintain the integrity of peripheral nerves. By interfering with the Vitamin B₆ metabolism, isoniazid causes peripheral neuropathy. This serious adverse effect of isoniazid can be avoided by supplementation with Vitamin B6 tablets to avoid peripheral neuropathy. Isoniazid in metabolised by acetylation to hepatotoxic metabolite. There is a polymorphism of the acetylating enzyme and people can be either slow or fast acetylators. The slow acetylators will have higher plasma levels of isoniazid and will be at an increased risk of peripheral neuropathy but at decreased risk of hepatotoxicity compared to fast acetylators. In contrast, the fast acetylators have higher levels of the hepatotoxic metabolite (and the resulting toxicity). The fast acetylators will have lower plasma levels of isoniazid.