Pyrazinamide

Pyrazinamide is a synthetic nicotinamide analogue and the main sterilising drug of the intensive phase, which allows treatment of drug-susceptible tuberculosis to be shortened from 9 months to 6. It acts on slowly dividing bacilli in acidic environments such as macrophage phagolysosomes and caseous foci. It is given for the first 2 months only. It is the most hepatotoxic first-line drug, and it causes hyperuricaemia and arthralgia.

Class. First-line antimycobacterial; sterilising agent.

Mechanism. A prodrug converted by the bacterial pyrazinamidase (pncA gene) to pyrazinoic acid, which disrupts membrane energetics and interferes with coenzyme A synthesis and trans-translation. pncA mutations cause resistance. Mycobacterium bovis is intrinsically resistant, which matters for tuberculosis acquired from unpasteurised milk.

Pharmacokinetics. Well absorbed orally, peak at 1 to 2 hours, half life 9 to 10 hours (longer in liver or kidney failure). Excellent cerebrospinal fluid penetration. Hepatic hydrolysis to pyrazinoic acid, then renal excretion; pyrazinoic acid blocks renal urate secretion.

Drug-susceptible tuberculosis (first line). - Adults: 25 mg/kg (range 20 to 30) orally once daily; usual 1.5 g daily under 50 kg and 2 g daily at 50 kg or over; maximum 2 g daily. - Children: 35 mg/kg (range 30 to 40) once daily. - Duration: first 2 months (intensive phase) only, with isoniazid, rifampicin and ethambutol. - Loading dose: none. Maintenance dose: none beyond the intensive phase. Titration: none.

Tuberculous meningitis. Same daily dose, 2 months of the intensive phase, within a regimen that continues rifampicin and isoniazid for a total of 9 to 12 months in adults (shorter in some paediatric regimens).

Drug-resistant tuberculosis (specialist). 25 mg/kg daily as a companion drug when the isolate is susceptible, with duration set by the individualised regimen.

Intermittent dosing. 35 mg/kg three times weekly (maximum 3 g) under direct observation only when daily dosing is impossible.

Contraindications. Severe liver damage, acute gout, porphyria and hypersensitivity. Caution in diabetes (glycaemic control becomes harder), chronic liver disease and alcohol dependence.

Serious adverse effects. Dose-related hepatotoxicity (cholestatic or hepatocellular, occasionally fatal), gouty arthritis, severe arthralgia, sideroblastic anaemia, thrombocytopenia and photosensitivity.

Common adverse effects. Asymptomatic hyperuricaemia (almost universal), arthralgia, anorexia, nausea and flushing.

Interactions. - Reduces the uricosuric effect of probenecid and sulfinpyrazone. - Lowers ciclosporin levels. - Combining it with rifampicin for latent infection caused severe liver injury, so that short regimen is not advised. - Additive hepatotoxicity with isoniazid, rifampicin, alcohol and antiretrovirals such as nevirapine.

Common prescribing errors. Continuing beyond 2 months, dosing on a fixed adult tablet count without weight bands, treating asymptomatic hyperuricaemia with allopurinol, and relying on it for M. bovis disease.

Special groups.

• Pregnancy: used in most high-burden settings as part of the four-drug regimen; where omitted, a 9-month regimen of isoniazid, rifampicin and ethambutol replaces it.
• Breastfeeding: compatible.
• Children: higher weight-based dose is tolerated.
• Older adults: greater hepatotoxicity risk; check liver tests early.
• Kidney impairment: with CrCl under 30 mL/min or on haemodialysis, give 25 to 35 mg/kg three times weekly, after dialysis.
• Liver impairment: avoid in active or severe disease; use a regimen without it in chronic liver disease.

Formulations. Tablets 500 mg and fixed-dose combination tablets; dispersible forms for children.

Administration. Once daily, with or without food; give with food for gastric upset. Dose by weight band.

Baseline. Liver tests (in all adults where available), weight, HIV status. Uric acid only if gout history.

Monitoring. Symptoms of hepatitis at each visit; liver tests at 2 and 4 weeks in at-risk patients. Treat joint pain with paracetamol or an NSAID where kidney function allows.

Stopping thresholds. ALT over three times the upper limit of normal with symptoms, or over five times without, stops all hepatotoxic antituberculosis drugs. Stop for severe gouty arthritis.

Referral and escalation. Refer for hepatitis, severe arthropathy, sideroblastic anaemia, or if M. bovis is suspected.