Hepatotoxicity pyrazinamide

PYRAZINAMIDE Patients should have baseline liver functions tests to use as a comparison when monitoring liver function during pyrazinamide therapy. The nurse should monitor the patient closely for symptoms of a decline in hepatic functioning (ie, yellowing of the skin, malaise, liver tenderness, anorexia, or nausea). The primary health care provider may order periodic liver function tests. Hepatotoxicity appears to be dose related and may appear at any time during therapy. 

Pyrazinamide Adults Based on IBW 40-55 kg 1000 mg 56-75 kg 1500 mg 76-90 kg 2000 mg Children 15-30 mg/kg Hepatotoxicity, gastrointestinal symptoms (nausea, vomiting), non-gouty polyarthralgia, asymptomatic hyperuricemia, acute gouty arthritis, transient morbilliform rash, dermatitis Serum uric acid can serve as a surrogate marker for compliance FFTs in patients with underlying liver disease... 

Concurrent administration of rifampin is recommended at doses of 10 to 20 mg/kg/day (maximum 600 mg/day) for children and 600 mg/day for adults. The addition ofpyrazinamide (children and adults, 15 to 30 mg/kg/ day maximum in both, 2 g/day) to the regimen of isoniazid and rifampin is now recommended. The duration of concomitant pyrazinamide therapy should be limited to 2 months to avoid hepatotoxicity. 

Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebu-tol, and others. 

Treatment of latent tuberculosis infection (LTBI) with isoniazid (INH) is very effective in preventing persons infected with M. tuberculosis from developing tuberculosis, regardless of HIV-1 serostatus. Several recent studies have shown that rifampicin and pyrazinamide taken for 2 months is as effective as 6-12 months of INH for the prevention of active TBC in HIV-1 seropositive persons although more hepatotoxicity is seen. 

Hepatotoxicity is the major concern in 15% of pyrazinamide recipients. It also can inhibit excretion of urates, resulting in hyperuricemia. Nearly all patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is not recommended for use during pregnancy. 

Major adverse effects of pyrazinamide include hepatotoxicity (in 1-5% of patients), nausea, vomiting, drug fever, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy. Hyperuricemia may provoke acute gouty arthritis. 

Pyrazinamide (generic) is used primarily as an adjunct to other drugs in treating tuberculosis. This drug s mechanism of action against M. tuberculosis is unknown. Problems associated with pyrazinamide include hepatotoxicity and lower-extremity joint pain. 

Polypharmacy For example, NSAIDs if used with other hepatotoxic drugs increase the risk of hepatotoxicity. Isoniazid with rifampicin or pyrazinamide... 

A1 Sarraf, K.AA., Michielsen, P.P., Hanben, E.I., Lefebure, A., Ramon, A.M., van March, E.A., Pelckmans, P.A. Hepatotoxicity after a short course of low-dose pyrazinamide. Acta Gastro-Enterol. Belg. 1996 59 251-253... 

If liver damage occurs, isoniazid is probably an important factor and it should be stopped before rifampicin or pyrazinamide (8). Prediction of hepatotoxicity is possible (9). In a case-control study of 60 patients in India, conducted in order to identify features predicting hepatotoxicity, the body mass index was significantly lower (17.2 kg/m ) in patients who experienced hepatotoxicity than in controls (19.5 kg/m ) (10). 

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). 

There are mild to moderate increases in liver transaminases during treatment with rifampicin plus isoniazid in most patients. However, biochemical hepatitis is diagnosed when transaminase activities increase to more than four times the upper limit of the reference ranges on two occasions at least 1 week apart, or more than five times on any single occasion. This calls for withdrawal of all potentially hepatotoxic drugs (rifampicin, isoniazid, and pyrazinamide) until the enzymes return to the reference ranges. During this period, streptomycin plus etham-butol, with or without cycloserine and a fluoroquinolone, is recommended in seriously ill patients. 

There is continuing concern about the hepatotoxicity of the combination of pyrazinamide with rifampicin for the treatment of latent pulmonary tuberculosis. Among 148 who... 

There is a lack of consensus on the best re-treatment protocol for patients who develop hepatotoxicity during treatment with standard antituberculosis agents. Investigators from Turkey have reported a high risk of recurrence of hepatitis (in six of 25 patients) on re-introduction of all drugs in full doses after recovery from hepatitis (31). This risk was less when rifampicin and isonia-zid were re-introduced sequentially in increasing doses and when pyrazinamide was replaced by streptomycin. 

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. 

Side effects caused by isoniazid, rifampin, pyrazinamide, and ethambutol are common and can include hepatotoxic-ity, peripheral neuropathy, optic neuritis, and Gl side effects. All four agents can potentially be hepatotoxic, but this side effect is most frequently associated with isoniazid and rifampin. Peripheral neuropathy is most commonly associated with isoniazid, whereas optic neuritis is associated with ethambutol. The metabolism of isoniazid is genetically predetermined. Patients of Scandinavian, European, and African descent metabolize isoniazid slower (slow acetylators) and are therefore more predisposed to hepatotoxicity and peripheral neuropathy due to isoniazid. Fast acetylators include people of Asian or American Indian descent and are less predisposed to these adverse effects. 

Sarich TC, Yousseli M, 2hou T et al (1996) Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits. Arch Toxicol 70 835-840 Schaberg T, Rebhan K, Lode H (1996) Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J 9 2026-2030... 

Hepatotoxicity can occur with several antituberculous drugs including ethionamide, isoniazid, pyrazinamide and rifampicin and high alcohol consumption/chronic alcoholism has been reported to increase the risk. However, one study in patients with active tuberculosis taking rifampicin and pyrazinamide, found that of the 14 patients who developed hepatotoxicity, only 5 of these reported alcohol use (not quantified), and alcohol was not found to be associated with an increased risk of hepatotoxicity. Similarly, another study found that alcohol consumption was not a risk factor for antimycobacterial-induced hepatotoxicity. ... 

Lee AM, Mennone JZ, Jones RC, Paul WS. Risk factors for hepatotoxicity associated with rifampin and pyrazinamide for tiie treatment of latent tuberculosis infection experience from tiiree public healtii tuberculosis clinics. IntJ Tuberc Lung Dis (2002) 6, 995-1000. 

Isoniazid-induced fulminant liver failure occurred in a 16-year-old girl taking carbamazepine and clonazepam, within 5 days of starting isoniazid, rifampicin and pyrazinamide. She recovered with supportive measures and later tolerated the antiepileptics with concurrent rifampicin and pyrazinamide. Isoniazid hepatotoxicity has also occurred in a 74-year-old woman and a 10-year-old boy" taking carbamazepine, shortly after treatment with isoniazid, rifampicin, and ethambutol, with or without pyrazinamide, was started. 

A study from India (53 ) reported the results of an attempt to predict the onset of hepatotoxicity in patients receiving this compound. Sixty-nine patients were included, 38 of them receiving pyrazinamide 30 mg/kg body weight daily in combination with 1 g of streptomycin and 300 mg of isoniazid daily. Thirty-one patients received pyrazinamide 60 mg/kg body weight in combination with 1 g intramuscularly of streptomycin and 650 mg of isoniazid twice a week. The results of this study showed that abnormalities in serum enzymes indicative of hepatic dysfunction occurred in a large proportion of the patients in both treatment groups but did not progress to clinical hepatitis. In most cases the enzyme levels returned to normal with continued treatment. It... 

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