Drugs For Tuberculosis Isoniazid

Isoniazid (nydrazid, others) remains the primary drug for tuberculosis. All patients with disease caused by sensitive strains should receive the drug if they can tolerate it.

antibacterialactivityand mechanism of action

Isoniazid is bacteriostatic for "resting" bacilli but bactericidal for dividing microorganisms. Isoniazid is a prodrug that is converted by mycobacterial catalase-peroxidase into an active metabolite. It inhibits biosynthesis of mycolic acids—long, branched lipids that are attached to a unique polysaccharide in the mycobacterial cell wall. Mycolic acids are unique to mycobacteria. The target of the isoniazid derivative is enoyl-ACP reductase of fatty acid synthase II, which converts unsaturated to saturated fatty acids in mycolic acid biosynthesis.

bacterial resistance

Isoniazid resistance most commonly results from mutations in catalase-peroxidase that decrease its activity, preventing conversion of the prodrug isoniazid to its active metabolite. Mutations in genes involved in mycolic acid biosynthesis also cause resistance.

Isoniazid monotherapy leads to resistance. This resistance typically develops after a few weeks of therapy but can vary. Approximately 1 in 106 tubercle bacilli will be genetically resistant to isoniazid; since tuberculous cavities may contain as many as 109 microorganisms, it is not surprising that isoniazid selects for resistant bacteria. The incidence of primary resistance to isoniazid in the U.S. is estimated at 8% of isolates but may be much higher in Asian and Hispanic immigrants, large urban areas, and border communities.

absorption, distribution, and excretion Isoniazid is readily absorbed after oral or parenteral administration. Isoniazid diffuses readily into all body fluids and cells. The drug achieves significant quantities in pleural and ascitic fluids; concentrations in the cerebrospinal fluid (CSF) with inflamed meninges are similar to those in the plasma. Isoniazid penetrates well into caseous material and persists in therapeutic concentrations.

From 75 to 95% of a dose of isoniazid is excreted in the urine within 24 hours, mostly as metabolites. The main excretory products in humans result from acetylation (acetylisoniazid) and hydrolysis (isonicotinic acid).

Slow and rapid inactivators (acetylators) of isoniazid differ in the polymorphic arylamine A-acetyltransferase type 2 (NAT2); in the U.S., the incidence of "slow acetylators" is ~50%. The serum t1/2 in fast acetylators is 1 hour versus 2-5 hours in slow acetylators, resulting in serum isoniazid levels in fast acetylators that are 30-50% of those in slow acetylators. Because isoniazid is relatively nontoxic, sufficient drug can be administered to fast acetylators to achieve a therapeutic effect. Hepatic insufficiency also increases drug concentrations, and dosage reduction is recommended for slow acetylators in this setting. Slow acetylators rarely may accumulate toxic concentrations if their renal function is impaired.

CONHNH., ISONIAZID

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