Pyrazinamide

July 24, 2020 Rima Pharmacology 0

  • Pyrazinamide (PZA) is synthetic pyrazine analogue of nicotinamide. It is one of the key drugs included in therapeutic regimen to treat tuberculosis.
  • TB is an infectious disease caused by several species of mycobacteria including tuberculosis and M. bovis. It is world’s second commonest cause of death due to infectious disease after HIV/AIDS.
  • PZA was first synthesized in 1936 and its use as anti-tubercular drug was not known before 1952. It is included in World Health Organization’s List of Essential Medicines. It is also available as generic medicine.

 Mechanism of action and antibacterial activity of Pyrazinamide

Figure 1- Different proposed Mechanism of action of Pyrazinamide (PZA- Pyrazinamide, POA- Pyrazinoic acid) (Source- Zhnag et al, 2014)

 

  • Its precise mechanism of action is not clear.
  • Pyrazinamide is a prodrug which  enters M. tuberculosis by passive diffusion and gets converted to active compound pyrazinoic acid by nicotinamidaze/ pyrazinamidase (PZase) which inhibit bacterial synthesis of mycolic acid resulting in cellular damage.
  • It also targets energy production and translation of mycobacteria.
  • It exhibits bactericidal activity in vitro only at slight acidic pH. Hence, it kills tubercle bacilli residing in acidic phagosome within the macrophage (intracellular effect).
  • It is more active against old than actively growing cultures.

Resistance

  • Resistance develops rapidly if pyrazinamide is used alone.
  • Resistance in some strains may be due to lack of pyrazinamidase or nicotinamidase enzyme. In some strains, mutation of pncA gene encoding nicotinamidase/ pyrazinamidase may lead to pyrazinamide resistance.
  • M bovis and M. leprae are innately resistant to pyrazinamide. M. kansasii is also naturally resistant to pyrazinamide.

Pharmacokinetics of Pyrazinamide

  • It is well absorbed after oral administration. The peak plasma level reaches within 1-3 hours and drug can be detected up to 15 hours in plasma.
  • It is widely distributed throughout the body including CNS, lungs and liver. The concentration in CSF (Cerebrospinal Fluid) is equal to that of plasma level.
  • It is metabolized in liver and excreted through urine. Its half-life is 9-10 hours in patients with normal renal function.

Therapeutic Uses of Pyrazinamide

  • It is an important component of short-term (6 month) multiple drug therapy regimen for tuberculosis. It is used in combination with isoniazid, rifampicin and ethambutol.
  • PZA is effective against M. tuberculosis resistant to isoniazid and streptomycin. It is effective in killing non-replicative persisters that other TB drugs fail to kill. It is effective in treating both drug-susceptible and drug-resistant TB such as MDR-TB.
  • PZAplays important role in reducing TB relapse rates.
  • It has off-label use in diagnosis of hypouricemia and hypouricosuria.

Adverse effects

  • The most serious side effect associated with pyrazinamide is hepatic injury. Before starting therapy, liver function test should be performed.
  • Some people may experience metallic taste and sulfurous eructation. Some other side effects are nausea, vomiting, arthralgia, anorexia, malaise and mild skin rashes. It can also cause photosensitivity reaction rarely which can result in right-brown discoloration of exposed parts of the body.
  • It inhibits urate excretion and can precipitate gout flares.

Contraindications

  • It should be used with caution in patients with hepatic insufficiency.
  • Should be used with caution in patients with history of alcohol abuse.
  • It should be avoided in patients with active gout.

References

  1. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003; 7(1): 6-21.
  2. Stehr M, Elamin AA, Singh M. Pyrazinamide: the importance of uncovering the mechanisms of action in mycobacteria Expert Rev Anti Infect Ther. 2015; 13(5): 593-603.
  3. Zhang Y, Shi W, Zhang W, Mitchison D. Mechanisms of Pyrazinamide Action and Resistance. Microbiol Spectr. 2013; 2(4): 1–12.
  4. Njire M, Tan Y, Mugweru J, Wang C, Guo J, Yew WW et al. Pyrazinamide resistance in Mycobacterium tuberculosis: Review and update. Advances in Medical Sciences. 2016; 61(1): 63-71.
  5. Sun Z, Zhang Y. Reduced Pyrazinamidase Activity and the Natural Resistance of Mycobacterium kansasii to the Antituberculosis Drug Pyrazinamide. Antimicrob Agents Chemother. 1999; 43(3): 537–542.
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