Microbiology: Antimicrobial Action: Pyrazinamide has a bactericidal effect against Mycobacterium tuberculosis but appears to have no activity against other Mycobacteria or microorganisms in vitro. The MIC for M. tuberculosis is >20 mcg/mL at pH 5.6. It is almost completely inactive at neutral pH. Pyrazinamide is effective against persisting tubercle bacilli within the acidic intracellular environment of the macrophages. The initial inflammatory response to chemotherapy increased the number of organisms in the acidic environment. As inflammation subsides and pH increases, the sterilizing activity of pyrazinamide decreases. This pH-dependent activity explains the clinical effectiveness of pyrazinamide as part of the initial 8-week phase in short-course treatment regimens. In order to avoid inducing bacterial resistance when used alone, pyrazinamide should always be given together with other antituberculous drugs.
Pharmacokinetics: Pyrazinamide is readily absorbed from the GI tract. Peak serum concentrations occur about 2 hrs after an oral dose and have been reported to be about 35 mcg/mL after 1.5 g and 66 mcg/mL after 3 g. Pyrazinamide is widely distributed in body fluids and tissues and diffuses into the CSF. The t½ has been reported to be about 9-10 hrs. It is metabolized primarily in the liver by hydrolysis to the major active metabolite pyrazinoic acid which is subsequently hydroxylated to the major excretory product 5-hydroxypyrazinoic acid. It is excreted through the kidney mainly by glomerular filtration. About 70% of a dose appears in the urine within 24 hrs mainly as metabolites and 4-14% as unchanged drug. Pyrazinamide is excreted in breast milk.
All forms of pulmonary and extrapulmonary tuberculosis due to strains of Mycobacterium tuberculosis sensitive to pyrazinamide. When treating all forms of tuberculosis, pyrazinamide is used as part of multidrug regimens for the treatment of tuberculosis, primarily in the initial 8-week phase of short-course treatment.
Pyrazinamide is usually given daily or 3 times a week. Recommended oral doses for adults and children are up to 35 mg/kg body weight daily (maximum daily dose is 3 g) or 50 mg/kg 3 times a week, or 75 mg/kg twice weekly. In partial intermittent therapy, pyrazinamide is administered daily for the first 2 months with isoniazid and rifampicin. Afterwards, treatment with isoniazid and rifampicin will continue for the next 4 months.
Patients with liver damage, but if treatment is necessary, the dosage must be reduced.
Liver functions should be assessed before and regularly during treatment.
Caution should be observed in patients with impaired renal functions or a history of gout. Pyrazinamide should be discontinued, in the event of severe arthralgia or attack of gout.
Pyrazinamide should be used with caution in patients with diabetes mellitus, as their management may become more difficult.
Use in pregnancy & lactation: Pyrazinamide should not be given during pregnancy unless the potential benefit outweighs the potential risk to the fetus.
Pyrazinamide passes into the breast milk; the adverse effect on the infant are unknown. Therefore, the benefits and risks of nursing infant should be carefully considered.
Liver toxicity is the most serious side effect of pyrazinamide and it depends on the dosage, duration of treatment and concomitant therapy.
Other side effects are anorexia, nausea, vomiting, arthralgia, malaise, fever, sideroblastic anemia and dysuria. Photosensitivity and skin rashes have been reported on rare occasions.
Store at temperatures not exceeding 30°C.
J04AK01 - pyrazinamide ; Belongs to the class of other drugs used in the systemic treatment of tuberculosis.
Oral susp 250 mg/5 mL x 120 mL.