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= &gt;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&ndash;25&nbsp;mg/kg daily, or * 50&ndash;70&nbsp;mg/kg three times a week. The [[British Thoracic Society]] guidelines are for 1.5&nbsp;g daily for patients weighing less than 50&nbsp;kg, and 2&nbsp;g daily for patients weighing 50&nbsp;kg or more. Pyrazinamide is a [[generic drug]] and is available in a wide variety of presentations. Pyrazinamide tablets are usually 500&nbsp;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&ndash;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&ndash;70&nbsp;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]] [[de:Pyrazinamid]] [[nl:Pyrazinamide]]