|Systematic (IUPAC) name|
|Half-life||9 to 10 hours|
|Mol. mass||123.113 g/mol|
| (what is this?)
The abbreviations PZA and Z are standard, and used commonly in the medical literature.
Dosing and presentation
- 20–25 mg/kg daily, or
- 50–70 mg/kg three times a week.
The British Thoracic Society guidelines are for 1.5 g daily for patients weighing less than 50 kg, and 2 g daily for patients weighing 50 kg or more.
Pyrazinamide is a generic drug, and is available in a wide variety of presentations. Pyrazinamide tablets are usually 500 mg and form the bulkiest part of the standard tuberculosis treatment regimen. Pyrazinamide tablets are so large, some patients find them impossible to swallow: pyrazinamide syrup is an option for these patients.
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.
Pyrazinamide is routinely used in pregnancy in the UK and the rest of the world; the WHO recommend its use in pregnancy; and there is extensive clinical experience to show that it is safe. In the U.S., pyrazinamide is not used in pregnancy, citing insufficient evidence of safety. Pyrazinamide is removed by haemodialysis and therefore doses should always be given at the end of a dialysis session.
Pyrazinamide is only used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis. It is never used on its own. It has no other indicated medical uses. In particular, it is not used to treat other mycobacteria; Mycobacterium bovis and Mycobacterium leprae are innately resistant to pyrazinamide. Pyrazinamide is used in the first two months of treatment to reduce the duration of treatment required. Regimens not containing pyrazinamide must be taken for nine months or more.
Mechanism of action
Pyrazinamide diffuses into M. tuberculosis, where the enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid. Under acidic conditions, 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.
Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids although this has been discounted. It was also suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I. Pyrazinoic acid binds to the ribosomal protein S1 (RpsA) and inhibits trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.
Mutations in the pncA gene, which encodes a pyrazinamidase, is responsible for the appearance of most pyrazinamide resistant M. tuberculosis strains. A few pyrazinamidase resistant strains with mutations in the rpsA gene have also been identified.
The most common (approximately 1%) side effect of pyrazinamide is joint pains (arthralgia), but this is not usually so severe that patients need to stop taking the pyrazinamide. Pyrazinamide can precipitate gout flares by decreasing renal excretion of uric acid. 
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. In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis. 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)
- American Thoracic Society, Centers for Disease Control, Infectious Diseases Society of America (2003). "Treatment of Tuberculosis". Am J Respir Crit Care Med 167 (602–662).
- Hong Kong Chest Service, Medical Research Council (1981). "Controlled trial of four thrice weekly regimens and a daily regimen given for 6 months for pulmonary tuberculosis". Lancet 1 (8213): 171–4. doi:10.1016/S0140-6736(02)95623-0. PMID 6109855.
- Centers for Disease Control and Prevention (2000). "Targeted tuberculin testing and treatment of latent tuberculosis infection". MMWR 49 (RR–6): 31–32. PMID 10881762.
- Spaia S, Magoula I, Tsapas G, Vayonas G (2000). "Effect of pyrazinamide and probenecid on peritoneal urate transport kinetics during continuous ambulatory peritoneal dialysis". Perit Dial Int 20 (1): 47–52. PMID 10716583.
- Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T (January 2004). "Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion". J. Am. Soc. Nephrol. 15 (1): 164–73. doi:10.1097/01.ASN.0000105320.04395.D0. PMID 14694169.
- Zhang Y, Mitchison D (January 2003). "The curious characteristics of pyrazinamide: a review". Int. J. Tuberc. Lung Dis. 7 (1): 6–21. PMID 12701830.
- Zimhony O, Cox JS, Welch JT, Vilchèze C, Jacobs WR (2000). "Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis" (abstract). Nature Medicine 6 (9): 1043–47. doi:10.1038/79558. PMID 10973326.
- Boshoff HI, Mizrahi V, Barry CE (2002). "Effects of Pyrazinamide on Fatty Acid Synthesis by Whole Mycobacterial Cells and Purified Fatty Acid Synthase I". Journal of Bacteriology 184 (8): 2167–72. doi:10.1128/JB.184.8.2167-2172.2002. PMC 134955. PMID 11914348.
- Zimhony O, Vilcheze C, Arai M, Welch J, Jacobs WR pi. Pyrazinoic acid and its n'Propyl Ester Inhibit Fatty Acid Synthase I in Replicating Tubercle Bacilli. Antimicrob Agents Chemother. 2007 51 752-754
- Ngo SC., Zimhony O, Chung WJ Sayahi, H, Jacobs WR. and JT. Welchpi. Inhibition of Isolated Mycobacterium tuberculosis Fatty Acid Synthase I by Pyrazinamide Analogs. Antimicrob Agents Chemother AntimicrobAgents Chemother. 2007; 1 2430-5
- Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE et al. (2011). "Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis". Science 333 (6049): 1630–1632. doi:10.1126/science.1208813. PMID 21835980.
- Scorpio A, Zhang Y (1996). "Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus". Nature Medicine 2 (6): 662–7. doi:10.1038/nm0696-662. PMID 8640557.
- East and Central African/Medical Research Council Fifth Collaborative Study (1983). "Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 9-month) for pulmonary tuberculosis". Tubercle 64 (3): 153–166. doi:10.1016/0041-3879(83)90011-9. PMID 6356538.
- British Thoracic Society (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". Br J Dis Chest 78 (4): 330–336. doi:10.1016/0007-0971(84)90165-7. PMID 6386028.
- American Thoracic Society; CDC; Infectious Diseases Society of America. (2003 Jun 20). "Treatment of tuberculosis.". MMWR Recomm Rep 52 ((RR-11)): 1-77. PMID 12836625.
- Yee D et al. (2003). "Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis". Am J Resp Crit Care Med 167 (11): 1472–7. doi:10.1164/rccm.200206-626OC. PMID 12569078.
- Kushner, S.; Dalalian, H.; Sanjurjo, J. L.; Bach, F. L.; Safir, S. R.; Smith, V. K.; Williams, J. H. (1952). Journal of the American Chemical Society 74 (14): 3617. doi:10.1021/ja01134a045.