pyrazinamide
Brand: PZA
Prototype Drug
Drug Class: nicotinamide analog antimycobacterial
Drug Family: antibiotic
Subclass: pyrazinamide prodrug
Organ Systems: infectious-disease
Mechanism of Action
Prodrug converted by mycobacterial pyrazinamidase/nicotinamidase to active pyrazinoic acid; uniquely active in acidic pH environments (within macrophage phagolysosomes), killing dormant organisms not targeted by other first-line agents; key for shortening TB regimens.
pyrazinoic acid (PZA metabolite) — targets fatty acid synthesis and disrupts membrane potential
Indications
- active tuberculosis (part of standard RIPE regimen for first 2 months — sterilizing phase)
Contraindications
- pyrazinamide hypersensitivity
- severe hepatic disease
- gout (relative)
Adverse Effects
Common
- hyperuricemia (universal)
- arthralgia/gout exacerbation
- GI upset
Serious
- hepatotoxicity (most hepatotoxic first-line TB drug)
- gout precipitation
- photosensitivity
Pharmacokinetics (ADME)
| Absorption | well absorbed orally (~90%); unaffected by food |
| Distribution | widely distributed; crosses BBB (CSF levels 87–105% of serum) |
| Metabolism | hepatic hydrolysis to pyrazinoic acid (active) then hydroxylation |
| Excretion | renal |
| Half-life | 9–10 hours |
| Onset | 1–3 hours |
| Peak | 1–2 hours |
| Duration | 24 hours |
| Protein Binding | 10–20% |
| Vd | moderate |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| uricosuric agents (probenecid) | pyrazinoic acid inhibits renal tubular secretion of uric acid; interferes with uricosuric effect | moderate |
| cyclosporine | reduced cyclosporine levels via hepatic enzyme interactions | moderate |
Nursing Considerations
- Baseline uric acid level is recommended; pyrazinamide universally raises uric acid — allopurinol or dose reduction may be needed if symptomatic gout develops.
- Monitor LFTs (AST, ALT, total bilirubin) monthly or more frequently in patients with pre-existing liver disease.
- Counsel patients to report joint pain (especially great toe) and skin rashes; advise adequate hydration.
- Used only for the initial 2-month sterilizing phase of TB therapy; discontinuation after month 2 is standard unless drug-resistant TB.
Clinical Pearls
- Pyrazinamide's unique ability to kill dormant, intracellular mycobacteria in the acidic phagolysosomal environment is the key reason that standard TB treatment was shortened from 18 months to 6 months when PZA was incorporated into the regimen.
- All three first-line hepatotoxic agents (isoniazid, rifampin, pyrazinamide) can cause drug-induced liver injury in the RIPE regimen; when all three are given together, the hepatotoxicity risk is additive.
Safety Profile
Pregnancy use-with-caution
Lactation use-with-caution
Renal Adjustment Required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
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