pyrazinamide
antitubercular agent· Brands: Tebrazid, ZinamidePO
Mechanism of action
Pyrazinamide is a prodrug that is converted by mycobacterial pyrazinamidase into pyrazinoic acid, the active form. Pyrazinoic acid disrupts fatty acid synthetase I and interferes with membrane transport, causing damage to the mycobacterial cell and inhibiting growth. It is active only against Mycobacterium tuberculosis, particularly organisms in acidic environments such as within macrophages, and is most effective in the first two months of treatment.
Pharmacokinetics
Pyrazinamide is rapidly and well absorbed from the gastrointestinal tract after oral administration. It is widely distributed throughout the body, including into cerebrospinal fluid. It is extensively metabolised in the liver, primarily by hydrolysis to pyrazinoic acid, which is then oxidised to inactive metabolites. The parent drug has a half-life of approximately 9 to 10 hours. Excretion is mainly renal, with about 70% of a dose eliminated in the urine as metabolites and unchanged drug. Dosage adjustment may be needed in severe renal impairment.
Indications & dosing
Active tuberculosis (in combination with other antitubercular drugs)
Usually given in the intensive phase for the first 2 months; max 2 g per day.
- adult · PO: 20–30 mg/kg once daily · Usually given in the intensive phase for the first 2 months; max 2 g per day.
Active tuberculosis (in combination with other antitubercular drugs)
Weight-based dosing; same as adults; maximum 2 g per day.
- pediatric · PO: 20–30 mg/kg once daily · Weight-based dosing; same as adults; maximum 2 g per day.
Contraindications & precautions
- Severe hepatic impairment · Pyrazinamide is hepatotoxic; avoid in patients with severe liver disease or acute liver failure.
- Hypersensitivity to pyrazinamide or any component of the formulation · Allergic reactions such as rash, fever, or drug-induced hepatitis have been reported.
- Acute gout · Pyrazinamide elevates serum uric acid; may precipitate or worsen gout flares.
- Monitor liver function tests (ALT, AST) before and during therapy, especially in patients with pre-existing liver disease.
- Monitor serum uric acid levels in patients with gout or at risk of hyperuricaemia; consider alternative therapy if levels rise significantly.
- Use with caution in patients with diabetes mellitus as pyrazinamide may impair glycaemic control.
- Use with caution in patients with porphyria as pyrazinamide can precipitate acute porphyric attacks.
Adverse effects
- Hepatotoxicityserious
- Hyperuricaemia
- Nausea and vomiting
- Arthralgia
- Rash
- Fever
Renal & hepatic adjustment
- eGFR 0–30: Reduce dose, for example to 25 mg/kg three times per week
- Hepatic impairment (mild): No adjustment required; monitor liver function tests
- Hepatic impairment (moderate): Use with caution; consider reducing dose or using an alternative agent
- Hepatic impairment (severe): Avoid; use an alternative antitubercular agent (avoid)
Monitoring, pregnancy & toxicity
- Liver function tests (ALT, AST) · Baseline and at least monthly during therapy
- Serum uric acid · Baseline and if hyperuricaemia or gout symptoms develop
- Clinical assessment for hepatotoxicity (jaundice, dark urine, nausea) · At each patient visit
- Pregnancy: Pyrazinamide may be used during pregnancy when indicated for tuberculosis. Evidence suggests it is not associated with teratogenic effects; therefore, it can be given if tuberculosis requires treatment.
- Toxicity: Hepatotoxicity: elevated transaminases, jaundice, liver failure · Discontinue pyrazinamide and monitor liver function. Provide supportive care; consider alternative antitubercular therapy.
- Toxicity: Hyperuricaemia: elevated uric acid, gouty arthritis, arthralgia · Reduce dose or discontinue if severe. Manage with allopurinol or colchicine if symptoms of gout occur.
- Toxicity: Gastrointestinal upset: nausea, vomiting, abdominal discomfort · Administer with food; consider reducing dose if symptoms persist.
- Toxicity: Rash and fever: maculopapular rash, fever · Withdraw drug; treat mild rash with antihistamines. For severe reactions, consider desensitisation.
Clinical notes
Pyrazinamide is used as part of short-course intensive therapy for tuberculosis, always in combination with other antitubercular drugs to prevent resistance. Doses are given orally once daily, usually for the first two months of treatment. Hepatotoxicity is the major dose-limiting adverse effect, so liver function tests should be monitored. Hyperuricaemia and gout may occur due to inhibition of uric acid clearance, and arthralgia is common. Other adverse effects include nausea, rash, and fever. It is generally avoided in pregnant women unless considered necessary, and is contraindicated in severe hepatic disease. Review local guidelines for susceptibility testing and use in multidrug-resistant tuberculosis.
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BNF; local formulary