Pyrazinamide, adverse reaction

Hepatotoxicily is the principal adverse reaction seen witii pyrazinamide use Symptoms of hepatotoxicily may range from none (except for slightly abnormal hepatic function tests) to a more severe reaction such as jaundice Nausea, vomiting, diarrhea, myalgia, and rashes also may be seen. 

Alternative dosing Alternatively, a twice weekly dosing regimen (50 to 70 mg/kg twice weekly based on lean body weight) has been developed to promote patient compliance on an outpatient basis. In studies evaluating the twice weekly regimen, doses of pyrazinamide in excess of 3 g twice weekly have been administered without an increased incidence of adverse reactions. 

C. Pyrazinamide is known to cause hyperuricemia and precipitate gouty arthritis. Pyrazinamide-induced gouty arthritis does not respond to uricosuric therapy with probenecid but may respond to acetylsalicylic acid. Cycloserine (A) can cause headaches, confusion, tremors, and seizures, possibly secondary to low levels of magnesium in the cerebrospinal fluid cycloserine should be avoided in patients with epilepsy and mental depression. It is not associated with hyperuricemia. Thiacetazone (B) is an antibiotic that is rarely used in tuberculosis. The most common adverse reactions are general rashes and GI intolerance. Its use is not associated with hy-... 

The combination of pyrazinamide plus levofloxacin is first-line treatment for multidrug-resistant latent tuberculosis. In 17 Canadian patients there were important adverse reactions affecting the musculoskeletal and central nervous systems hyperuricemia, gastrointestinal effects, and dermatological effects were also common (3). This combination may be used with careful monitoring for adverse effects. 

Therapy for drug-sensitive pulmonary tuberculosis consists of isoniazid (5 mg/kg, up to 300 mg/day), rifampin (10 mg/tcg/day, up to 600 mg daily), pyrazinamide (15-30 mg/kg/day or a maximum of 2 g/day), and a fourth agent, typically either ethambutol (usual adult dose cf 15 mg/kg once per day) or streptomycin (1 g daily). The streptomycin dose is reduced to 1 g twice weekly after 2 months. Pyridoxine, 15-50 mg/day, also should be included for most adults to minimize adverse reactions to isoni(K,id. Isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin are given for 2 months isoniazid and rifampin are then continued for 4 more months. Doses in children are isoniazid, 10 mg/kg/day (300 mg maximum) rifampin, 10-20 mg/kg/day (600 mg maximum) pyrazinamide, 15-30 mg/kg/day (2 g maximum). Isoniazid, rifampin, and ethambutol are considered safe during pregnancy. 

Hepatotoxicity is the most important adverse effect of antituberculosis drug therapy. Isoniazid, rifampicin, and pyrazinamide are the main culprits. There is wide variability in the risk of hepatotoxic reactions reported from different parts of the world or in different populations (for example African-American women in the postpartum period) (SEDA-24, 353). 

Liver damage is the most common adverse effect of pyrazinamide (6). It varies from asymptomatic alteration of hver function detectable only by laboratory tests, through a mild syndrome characterized by fever, anorexia, malaise, hver tenderness, hepatomegaly, and splenomegaly, to more serious reactions with clinical jaundice, and finally the rare form with progressive acute yellow atrophy and death. As most patients take a combined regimen of pjrazinamide with isoniazid and rifampicin, it is difficult to determine which of the three drugs causes the hepatotoxicity it could be due to a combined effect (7). As with isoniazid and rifampicin, hepatic function should initially be monitored every few weeks. 

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