Common side effects include nausea, loss of appetite, muscle and joint pains, and rash.[2][4] More serious side effects include gout, liver toxicity, and sensitivity to sunlight.[2] It is not recommended in those with significant liver disease or porphyria.[3] It is unclear if use during pregnancy is safe but it is likely okay during breastfeeding.[3] Pyrazinamide is in the antimycobacterial class of medications.[2] How it works is not entirely clear.[2]
Pyrazinamide is used in the first 2 months of treatment to reduce the duration of treatment required.[7] Regimens not containing pyrazinamide must be taken for 9 months or more.
The most common (roughly 1%) side effect of pyrazinamide is joint pains (arthralgia), but this is not usually so severe that patients need to stop taking it.[10][11] Pyrazinamide can precipitate gout flares by decreasing renal excretion of uric acid.[12]
The most dangerous side effect of pyrazinamide is hepatotoxicity, which is dose-related. The old dose for pyrazinamide was 40–70 mg/kg daily and the incidence of drug-induced hepatitis has fallen significantly since the recommended dose has been reduced to 12–30 mg/kg daily. In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis.[13] It is not possible to clinically distinguish pyrazinamide-induced hepatitis from hepatitis caused by isoniazid or rifampicin; test dosing is required (this is discussed in detail in tuberculosis treatment)[citation needed]
Pyrazinamide is well absorbed orally. It crosses inflamed meninges and is an essential part of the treatment of tuberculous meningitis. It is metabolised by the liver and the metabolic products are excreted by the kidneys.[citation needed]
Pyrazinamide is routinely used in pregnancy in the UK and the rest of the world; the World Health Organization (WHO) recommends its use in pregnancy; and extensive clinical experience shows that it is safe. In the US, pyrazinamide is not used in pregnancy, citing insufficient evidence of safety.[14] Pyrazinamide is removed by haemodialysis, so doses should always be given at the end of a dialysis session.[medical citation needed]
Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid.[15] Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.[15][16]
Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesize fatty acids[17] although this has been discounted.[18][19] The accumulation of pyrazinoic acid was also suggested to disrupt membrane potential and interfere with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. However, since an acidic environment is not essential for pyrazinamide susceptibility and pyrazinamide treatment does not lead to intrabacterial acidification nor rapid disruption of membrane potential, this model has also been discounted.[20] Pyrazinoic acid was proposed to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation,[21] but more detailed experiments have shown that it does not have this activity.[22]
The current hypothesis is that pyrazinoic acid blocks synthesis of coenzyme A. Pyrazinoic acid binds weakly to aspartate decarboxylase (PanD), triggering its degradation.[23] This is an unusual mechanism of action in that pyrazinamide does not directly block the action of its target, but indirectly triggers its destruction.[citation needed]
Mutations in the pncA gene of M. tuberculosis, which encodes a pyrazinamidase and converts pyrazinamide to its active form pyrazinoic acid, are responsible for the majority of pyrazinamide resistance in M. tuberculosis strains.[24] A few pyrazinamide-resistant strains with mutations in the rpsA gene have also been identified.[21] However, a direct association between these rpsA mutations and pyrazinamide resistance has not been established. The pyrazinamide-resistant M. tuberculosis strain DHMH444, which harbors a mutation in the carboxy terminal coding region of rpsA, is fully susceptible to pyrazinoic acid and pyrazinamide resistance of this strain was previously associated with decreased pyrazinamidase activity.[25] Further, this strain was found to be susceptible to pyrazinamide in a mouse model of tuberculosis.[26] Thus, current data indicate that rpsA mutations are not likely to be associated with pyrazinamide resistance. Currently, three main methods of testing are used for pyrazinamide resistance: 1) phenotypic tests where a tuberculosis strain is grown in the presence of increasing concentrations of pyrazinamide, 2) measuring levels of pyrazinamidase enzyme produced by the tuberculosis strain, or 3) looking for mutations in the pncA gene of tuberculosis.[15] Concerns exist that the most widely used method for phenotypic resistance testing may overestimate the number of resistant strains.[27][28]
The abbreviations PZA and Z are standard, and used commonly in the medical literature, although best practice discourages the abbreviating of drug names to prevent mistakes.[medical citation needed]
Pyrazinamide is a generic drug, and is available in a wide variety of presentations. Pyrazinamide tablets form the bulkiest part of the standard tuberculosis treatment regimen. Pyrazinamide tablets are so large, some people find them impossible to swallow: pyrazinamide syrup is an option.[citation needed]
Pyrazinamide is also available as part of fixed-dose combinations with other TB drugs such as isoniazid and rifampicin (Rifater is an example).[citation needed]
Pyrazinamide was first discovered and patented in 1936, but not used against tuberculosis until 1952.[19] Its discovery as an antitubercular agent was remarkable since it has no activity against tuberculosisin vitro, due to not being active at a neutral pH, so would ordinarily not be expected to work in vivo.[29] However, nicotinamide was known to have activity against tuberculosis and pyrazinamide was thought to have a similar effect. Experiments in mice at Lederle and Merck confirmed its ability to kill tuberculosis and it was rapidly used in humans.[29]
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^"Controlled trial of four thrice-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis". Lancet. 1 (8213): 171–174. January 1981. doi:10.1016/S0140-6736(02)95623-0. PMID6109855.
^"Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis". Tubercle. 64 (3): 153–166. September 1983. doi:10.1016/0041-3879(83)90011-9. PMID6356538.
^British Thoracic Society (October 1984). "A controlled trial of 6 months' chemotherapy in pulmonary tuberculosis. Final report: results during the 36 months after the end of chemotherapy and beyond. British Thoracic Society". British Journal of Diseases of the Chest. 78 (4): 330–336. doi:10.1016/0007-0971(84)90165-7. PMID6386028.
^American Thoracic Society; CDC; Infectious Diseases Society of America (June 2003). "Treatment of tuberculosis"(PDF). MMWR. Recommendations and Reports. 52 (RR-11): 1–77. PMID12836625.
^Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D (June 2003). "Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis". American Journal of Respiratory and Critical Care Medicine. 167 (11): 1472–1477. doi:10.1164/rccm.200206-626OC. PMID12569078.
^Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. (February 2003). "American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis". American Journal of Respiratory and Critical Care Medicine. 167 (4): 603–662. doi:10.1164/rccm.167.4.603. PMID12588714.
^Scorpio A, Zhang Y (June 1996). "Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus". Nature Medicine. 2 (6): 662–667. doi:10.1038/nm0696-662. PMID8640557. S2CID8579133.
^Piersimoni C, Mustazzolu A, Iacobino A, Giannoni F, Santoro G, Gherardi G, et al. (December 2016). "Pyrazinamide susceptibility testing: proposed new standard with the BACTECTM MGITTM 960 system". The International Journal of Tuberculosis and Lung Disease. 20 (12): 1677–1680. doi:10.5588/ijtld.16.0360. PMID27931346.
^ abZhang Y, Mitchison D (January 2003). "The curious characteristics of pyrazinamide: a review". The International Journal of Tuberculosis and Lung Disease. 7 (1): 6–21. PMID12701830.
