Pyrazinamide exhibits bactericidal activity in vitro only at a slightly acidic pH; this poses no problem since the drug kills tubercle bacilli residing in acidic phagosomes within the macrophage. The target of pyrazinamide is the mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis. Resistance develops rapidly if pyrazinamide is used alone.
absorption, distribution, and excretion
Pyrazinamide is well absorbed from the GI tract and widely distributed throughout the body, including the CNS, lungs, and liver. The plasma t/2 is 9-10 hours in patients with normal renal function. The drug is excreted primarily by glomerular filtration. Pyrazinamide is hydrolyzed to pyrazinoic acid and subsequently hydroxylated to 5-hydroxypyrazinoic acid.
Pyrazinamide is an important component of short-term (6-month) multiple-drug therapy of tuberculosis. The daily dose for adults is 15-30 mg/kg in a single oral dose. The maximum dose is 2 g/day, regardless of weight. Children should receive 15-30 mg/kg/day; daily doses also should not exceed 2 g. Pyrazinamide is safe and effective when administered twice or thrice weekly (at increased dosages).
Hepatic injury is the most serious side effect of pyrazinamide. Current regimens (15-30 mg/kg/day) are much safer than higher doses used previously. Prior to pyrazinamide administration, all patients should have liver function tests, which should be repeated at frequent intervals. If evidence of significant hepatic damage appears, therapy must be stopped. Pyrazinamide should not be given to individuals with any degree of hepatic dysfunction unless this is absolutely unavoidable.
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