Pyrazinamide Flashcards
What is the mechanism of action of pyrazinamide (PZA)?
Pyrazinamide is a prodrug converted by mycobacterial pyrazinamidase (encoded by pncA) into pyrazinoic acid. This acid accumulates in the bacterium, acidifies the intracellular environment, disrupts fatty acid synthase (FAS-I), and inhibits mycobacterial fatty acid synthesis and cell membrane function. PZA is most effective in the acidic pH of phagolysosomes where TB resides.
How do TB bacteria develop resistance to pyrazinamide?
Resistance usually involves mutations in the pncA gene that reduce production of functional pyrazinamidase or alter its structure, preventing conversion of pyrazinamide to active pyrazinoic acid.
What is the role of pyrazinamide in TB therapy?
Pyrazinamide is a first-line TB drug included in the initial intensive phase of therapy (typically the first 2 months of RIPE therapy). Its sterilizing effect on intracellular organisms helps shorten therapy duration and is effective against semi-dormant TB in acidic environments.
Outline key pharmacokinetic features of pyrazinamide.
Pyrazinamide is well absorbed orally, distributes throughout the body including CSF, and is metabolized in the liver to active metabolites. Both the parent drug and metabolites are cleared renally, necessitating dose adjustment in renal impairment. It works best in acidic conditions (pH < 6).
What are the notable adverse effects of pyrazinamide?
The most notable adverse effect is hepatotoxicity, which can be dose-dependent and additive with other TB drugs. It can cause hepatitis and must be monitored (LFTs). Pyrazinamide also inhibits uric acid excretion, causing hyperuricemia, which can precipitate gout attacks or cause arthralgias. Other side effects include GI upset and rash.
When is pyrazinamide contraindicated or used with caution?
Avoid pyrazinamide in patients with acute gout and severe pre-existing liver disease. Use with caution in diabetic patients and always monitor liver enzymes. Pyrazinamide, part of the 4-drug TB treatment given to nonpregnant individuals, is generally not administered in pregnancy due to uncertain teratogenic properties and little contribution to overall TB treatment efficacy.
Is there a mnemonic for pyrazinamide’s side effects?
Think ‘PZA = Polyarthralgia, Zaps the liver, Acid (uric) elevation.’ This helps recall joint pains, hepatotoxicity, and hyperuricemia associated with pyrazinamide.
