| Systematic (IUPAC) name | |
|---|---|
| pyrazine-2-carboxamide | |
| Clinical data | |
| Trade names | Rifater |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682402 |
| Pregnancy cat. | C |
| Legal status | ? |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | >90% |
| Metabolism | Hepatic |
| Half-life | 9 to 10 hours |
| Excretion | Renal |
| Identifiers | |
| CAS number | 98-96-4 |
| ATC code | J04AK01 |
| PubChem | CID 1046 |
| DrugBank | APRD01206 |
| ChemSpider | 1017 |
| UNII | 2KNI5N06TI |
| KEGG | D00144 |
| ChEBI | CHEBI:45285 |
| ChEMBL | CHEMBL614 |
| Chemical data | |
| Formula | C5H5N3O |
| Mol. mass | 123.113 g/mol |
| SMILES | eMolecules & PubChem |
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Pyrazinamide is a drug used to treat tuberculosis. The drug is largely bacteriostatic, but can be bacteriocidal on actively replicating tuberculosis bacteria.
Contents |
The abbreviations PZA and Z are standard, and used commonly in the medical literature.
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).
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.
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.[2] Regimens not containing pyrazinamide must be taken for nine months or more.
Pyrazinamide in conjunction with rifampin is a preferred treatment for latent tuberculosis.[3]
Pyrazinamide is a potent antiuricosuric drug[4] and consequently has an off-label use in the diagnosis of causes of hyperuricemia and hyperuricosuria.[5] It acts on URAT1.[5]
Pyrazinamide is a prodrug that stops the growth of Mycobacterium tuberculosis.
M. tuberculosis has the enzyme pyrazinamidase which is only active in acidic conditions.[6] Pyrazinamidase converts pyrazinamide to the active form, pyrazinoic acid which accumulates in the bacilli. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids[7] although this has been discounted.[8] 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.[9] 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.[10] 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.[11]
Mutations in the pncA and rpsA genes are responsible for pyrazinamide resistance in M. tuberculosis.[11][12]
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.[13][14] 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.[15] 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.
Pyrazinamide can by synthesized from o-phenylenediamine and glyoxal:[16]
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