Pyrazinamide

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.

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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 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.^[1] 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 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.^[2] Regimens not containing pyrazinamide must be taken for nine months or more.

Pyrazinamide must not be used to treat latent tuberculosis because the rate of liver toxicity is unacceptably high.

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 acidic conditions. Pyrazinamidase converts pyrazinamide to the active form, pyrazinoic acid. Pyrazinoic acid inhibits the enzyme fatty acid synthetase I, which is required by the bacterium to synthesise fatty acids.^[3] Mutations of the pyrazinamidase gene (pncA) are responsible for pyrazinamide resistance in M. tuberculosis.^[4]

Side effects

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.^[5][6] The arthralgia can be distressing to patients, but is never harmful.

The most dangerous side effect of pyrazinamide is hepatitis, 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.^[7] 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 side effects include nausea and vomiting, anorexia, sideroblastic anemia, skin rash, urticaria, pruritus, hyperuricemia, dysuria, interstitial nephritis, malaise; rarely porphyria, and fever.

Wikipedia articles

• Tuberculosis
• Mycobacterium tuberculosis
• Tuberculosis treatment

References

1. ^ 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).
2. ^ Hong Kong Chest Service, Medical Research Council. "Controlled trial of four thrice weekly regimens and a daily regimen given for 6 months for pulmonary tuberculosis". Lancet 1 (8213): 171–4. PMID 6109855.
3. ^ Zimhony O, Cox JS, Welch JT, Vilchèze C, Jacobs WR (2000). "Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis". Nature Medicine 6 (9): 1043–47. PMID 10973326.
4. ^ 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: 662–7. PMID 8640557.
5. ^ 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: 153–166. PMID 6356538.
6. ^ 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. PMID 6386028.
7. ^ 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. PMID 12569078.