PDP-Isoniazid Mechanism of Action

Pharmacology: Isoniazid is a bactericidal agent active only against organisms of the genus Mycobacterium, specifically, M. tuberculosis, M. avium intracellulare, M. bovis and some strains of M. kansasii. It is a highly specific agent, ineffective against other microorganisms. The mode of action is unknown, but the drug is firmly bound to actively growing, sensitive tubercle bacilli and does not affect these organisms when they are in the metabolic resting state.
When used alone in the treatment of tuberculosis, resistant strains emerge very rapidly; when combined with other tuberculostatic drugs; the emergence of resistant strains may be delayed or prevented. When isoniazid is used alone in the prophylaxis of tuberculosis, the development of resistance does not appear to be a major problem.
Pharmacokinetics: Isoniazid is rapidly and almost completely absorbed, when administered either orally or i.m. and peak blood levels are reached in about 1 to 2 hours. Bioavailability is reduced when isoniazid is administered with food. It diffuses readily into all body fluids (including cerebrospinal, pleural, and ascitic), tissues, organs and excreta (saliva, sputum and feces). The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. Isoniazid is < 10% bound to plasma proteins.
Isoniazid is metabolized by the liver mainly by acetylation and dehydrazination. The N-acetylhydrazine metabolite is believed to be responsible for the hepatotoxic effects seen in patients treated with isoniazid. The rate of acetylation is genetically determined. Approximately 50% of Blacks and Caucasians are slow inactivators; the majority of Inuits and Orientals are rapid inactivators. The half-life in fast acetylators is 1 to 2 hours while in slow acetylators it is 2 to 5 hours. Elimination is largely independent of renal function; however, the half-life may be prolonged in liver disease. The rate of acetylation has not been shown to significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood concentrations with chronic administration of the drug and thus, to an increase in toxic reactions. Isoniazid and its metabolites are excreted in the urine with 75 to 95% of the dose excreted in 24 hours. Small amounts are also excreted in saliva, sputum and feces. Isoniazid is removed by hemodialysis and peritoneal dialysis.