Pyrazinamide
2507339
225005485
2008-07-11T12:31:10Z
Arcadian
104523
/* Mechanism of Action */ fix typo
{{Drugbox|
|IUPAC_name = pyrazine-2-carboxamide
| image=Pyrazinamide.svg
| width=120
| CAS_number=98-96-4
| ATC_prefix=J04
| ATC_suffix=AK01
| ATC_supplemental=
| PubChem=1046
| DrugBank=APRD01206
| C = 5 | H = 5 | N = 3 | O = 1
| molecular_weight = 123.113 g/mol
| bioavailability= >90%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life= 9 to 10 hours
| excretion = [[Kidney|Renal]]
| pregnancy_category = C
| legal_status = ?
| routes_of_administration= Oral
}}
'''Pyrazinamide''' is a [[drug]] used to treat [[tuberculosis]] in afflicted patients. The drug is largely [[bacteriostatic]], but can be [[bacteriocidal]] on actively replicating tuberculosis [[bacteria]].
==Abbreviations==
The abbreviations '''PZA''' and '''Z''' are standard, and used commonly in the medical literature. The abbreviation '''P''' stands for [[penicillin]], or in the context of [[tuberculosis treatment]], stands for [[para-aminosalicylic acid]].
==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 that some patients find them impossible to swallow: pyrazinamide syrup is an option for these patients.
Pyrazinamide is also available as part of fixed dose combinations with other TB drugs such as [[isoniazid]] and [[rifampicin]] (''[[Rifater]]'' is an example).
==Pharmacokinetics==
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 [[World Health Organisation|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.<!--
--><ref name="">{{cite journal
| author=American Thoracic Society, Centers for Disease Control, Infectious Diseases Society of America
| title=Treatment of Tuberculosis
| journal=Am J Respir Crit Care Med
| year=2003
| volume=167
| issue=602–662 }}</ref> Pyrazinamide is removed by [[haemodialysis]] and therefore doses should always be given at the end of a dialysis session.
==Medical uses==
Pyrazinamide is only used in combination with other drugs such as [[isoniazid]] and [[rifampicin]] in the [[Tuberculosis treatment|treatment]] of ''[[Mycobacterium tuberculosis]]'' it is never used on its own. It has no other 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.<!--
--><ref name="MRC">{{cite journal | author=Hong Kong Chest Service, Medical Research Council | title=Controlled trial of four thrice weekly regimens and a daily regimen given for 6 months for pulmonary tuberculosis | journal=Lancet | volume=1 | issue=8213 | pages=171–4 | pmid=6109855 }}</ref> Regimens not containing pyrazinamide must be taken for nine months or more.
Pyrazinamide in conjunction with rifampin is a preferred treatment for [[latent tuberculosis]].<ref>{{cite journal | author=Centers for Disease Control and Prevention | title=Targeted tuberculin testing and treatment of latent tuberculosis infection | journal=MMWR | volume=49 | issue=No. RR-6 | pages=31–32 }}</ref>
==Mechanism of Action==
Pyrazinamide is a [[prodrug]] that stops the growth of ''[[Mycobacterium tuberculosis]]''. M. tuberculosis has the enzyme [[pyrazinamidase]] which is only active in [[acid]]ic conditions. Pyrazinamidase converts pyrazinamide to the active form, [[pyrazinoic acid]]. Pyrazinoic acid is thought to inhibit the enzyme [[fatty acid synthetase]] I, which is required by the bacterium to synthesise [[fatty acid]]s<!--
--><ref name="Zimhony2000">{{cite journal | author=Zimhony O, Cox JS, Welch JT, Vilchèze C, Jacobs WR | title=Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of ''Mycobacterium tuberculosis'' | journal=Nature Medicine | year=2000 | volume=6 | issue=9 | pages=1043–47 | pmid=10973326 | url=http://www.nature.com/nm/journal/v6/n9/abs/nm0900_1043.html;jsessionid=AFEEF16483CA23196C7729EBE644297C | doi=10.1038/79558 | format=abstract }}</ref> although this has been disputed. Mutations of the pyrazinamidase gene (''[[pncA]]'') are responsible for pyrazinamide resistance in ''M. tuberculosis''.<!--
--><ref name=Scorpio1996>{{cite journal | author=Scorpio A, Zhang Y | title=Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus | journal=Nature Medicine | year=1996 | volume=2 | pages=662–7 | pmid=8640557 | doi=10.1038/nm0696-662 }}</ref>
==Side effects==
The most common (approximately 1%) side effect of pyrazinamide is [[joint pain]]s (arthralgia), but this is not usually so severe that patients need to stop taking the pyrazinamide.<ref name="MRC1983">{{cite journal | author=East and Central African/Medical Research Council Fifth Collaborative Study | title=Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 9-month) for pulmonary tuberculosis | journal=Tubercle | year=1983 | volume=64 | pages=153–166 | pmid=6356538 | doi=10.1016/0041-3879(83)90011-9 }}</ref><ref name="BTS">{{cite journal | author=British Thoracic Society | title=A controlled trial of 6 months chemotherapy in pulmonary tuberculosis, final report: results during the 36 months after the end of chemotherapy and beyond | journal=Br J Dis Chest | year=1984 | volume=78 | issue=4 | pages=330–336 | pmid=6386028 }}</ref> The arthralgia can be distressing to patients, but is never harmful.
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.<!--
--><ref name="Yee2003">{{cite journal
| author=Yee D ''et al.''
| title=Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis
| journal=Am J Resp Crit Care Med
| volume=167
| issue=11
| year=2003
| pages=1472–7
| url=http://ajrccm.atsjournals.org/cgi/content/full/167/11/1472
| pmid=12569078
| doi=10.1164/rccm.200206-626OC }}</ref> 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]])
Other [[Adverse drug reaction|side effects]] include [[nausea]] and [[vomiting]], [[anorexia (symptom)|anorexia]], [[sideroblastic anemia]], [[skin rash]], [[urticaria]], [[itch|pruritus]], [[hyperuricemia]], [[dysuria]], [[interstitial nephritis]], [[malaise]]; rarely [[porphyria]], and [[fever]].
==Wikipedia articles==
*[[Tuberculosis]]
*''[[Mycobacterium tuberculosis]]''
*[[Tuberculosis treatment]]
==References==
{{reflist|2}}
{{Antimycobacterials}}
[[Category:Medical treatments]]
[[Category:Prodrugs]]
[[Category:Tuberculosis]]
[[Category:Pyrazines]]
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