Hepatotoxicity rifampicin

Interesting information stems from studies of the hepatotoxic effect of the concomitant administration of rifampicin, another antituberculostatic drug (and a potent inducer of cytochrome P450) often used in combination with isoniazid. Rifampicin alone is not hepatotoxic but increases significantly the incidence of hepatitis in patients simultaneously dosed with isoniazid. In human volunteers (6 slow and 8 rapid acetylators), daily administration of rifampicin increased the release of hydrazine from isoniazid [180], In slow acetylators, the proportion of the dose metabolized to hydrazine increased... 

Tayal, V. et al. (2007) Hepatoprotective effect of tocopherol against isoniazid and rifampicin induced hepatotoxicity in albino rabbits. Indian Journal of Experimental Biology, 45 (12), 1031-1036. 

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. 

Rifampicin can cause renal failure, transient disturbances of liver function tests, hyperbilirubinaemia or severe hepatotoxicity and other side-effects. Streptomycin can cause renal and ototoxicity. The combination of rifampicin and streptomycin increases the risk of streptomycin-induced renal failure. 

Rifampicin is an enzyme inducer and can increase the incidence and severity of isoniazid-induced hepatitis. Carbamazepine is an enzyme induction agent and interacts with isoniazid, increasing its hepatotoxicity. Isoniazid toxicity is associated with fast acetylator genotype. Although his phenotype was unknown, the interaction with carbamazepine increases risk of this toxicity. 

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

RIFAMPICIN PROTEASE INHIBITORS 1 levels of protease inhibitor. Risk of hepatotoxicity with saquinavir Induction of metabolism Avoid co-administration... 

Drug toxicity may be more likely. A patient who becomes enzyme-induced by taking rifampicin is more likely to develop liver toxicity after paracetamol overdose by increased production of a hepatotoxic metabolite. (Such a patient will also present with a deceptively low plasma concentration of paracetamol due to accelerated metabolism, see p. 287)... 

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... 

Enhanced hepatotoxicity of conventional antituberculosis regimens has been reported in recipients of orthotopic hver transplants, which is not unexpected, because of bouts of organ rejection (25). The authors recommended ofloxacin for these patients on the basis of favorable outcome in six cases. A conventional antituberculosis induction regimen was used initially until hepatotoxicity developed in all six patients. Thereafter they were treated with a combination of ofloxacin and ethambutol, with apparent cure in all. It should be noted that most of the patients took isoniazid + rifampicin for almost 2 months, which is the usual period when hepatotoxic reactions occur. Perhaps one should evaluate substitution of rifampicin with ofloxacin from the very beginning in order to minimize hepatotoxicity, as well as interference with ciclosporin leading to graft rejection noted in an earlier study (26). 

The use of ofloxacin instead of rifampicin in antituberculosis drug regimens for patients with underlying chronic hver disease has been reported to be associated with a significantly lower risk of hepatotoxicity (27). Similar observations have been reported among carriers of hepatitis B and hver transplant recipients by other investigators. 

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. 

Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R, Ito M, Yamamoto Y, Ogura T, Maeda K, Komuta K, Igarashi T, Azuma J. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis 2000 4(3) 256-61. 

When thionamides are used in combination with rifam-picin, hepatotoxicity is more common and severe (18,19). There was a 13% incidence of hepatotoxicity in patients with multibaciUary leprosy treated with dap-sone, rifampicin, and protionamide 10 mg/kg/day, and a 17% incidence in 110 patients treated with dapsone, rifampicin, and protionamide 5 mg/kg/day however, although the lower dose of protionamide did not reduce the incidence of hepatotoxicity, it did reduce its severity (20). Protionamide does not affect the pharmacokinetics of rifampicin (21). 

Halothane also reduces liver blood flow during anesthesia, and this could increase the release of potentially hepatotoxic halothane metabolites. The role of reduced halothane metabolites and inorganic fluoride, which may covalently link to liver macromolecules, has been stressed in keeping with this hypothesis is the observation of halothane hepatitis in patients who simultaneously take enzyme-inducing agents, for example barbiturates (41) or rifampicin (42). 

The severe hepatotoxicity in this case was probably due to induction of CYP3A4 by rifampicin, but rifampicin-induced liver damage could not be excluded. 

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. 

Rifampicin is rarely used as monotherapy. The risk of hepatotoxicity appears to be very low in patients with normal liver function, especially if rifampicin is given continuously. When given with isoniazid, rifampicin can cause a fulminant liver reaction. This may be attributable to enhancement of isoniazid hepatotoxicity as a result of enzyme induction by rifampicin. In some cases, jaundice occurred within 6-10 days after beginning isoniazid plus rifampicin (52). High serum transaminase activities, disturbances of consciousness, and centrilobular necrosis were found. All the patients recovered. 

Hepatotoxicity of combined therapy for leprosy has been reported in 39 patients treated with dapsone, pro-tionamide, and rifampicin. There were similar findings in 50 patients treated with dapsone, clofazimine, rifampicin, and protionamide. Deaths probably related to the drngs occurred in both groups after 3-4 months of treatment... 

However, in 531 eligible patients enrolled in a US Public Health Service Cooperative Trial of Short-Course Chemotherapy of Pulmonary Tuberculosis, of whom 58% were classified as alcoholic, although the alcoholics had more abnormal concentrations of aspartate transaminase before and during therapy, there was no significant difference between the alcoholics and non-alcoholics in the incidence of adverse reactions, including hepatotoxic reactions (92). The authors concluded that in the absence of clinically significant and persistent pretreatment abnormalities of hepatic function tests, rifampicin and isoniazid are not contraindicated in patients categorized as alcoholic. 

However, Roche Pharma have recommended that rifampicin should not be used in patients who are taking ritonavir + saquinavir, because of the results of a study in which 11 of 28 patients who took rifampicin 300 mg/day with ritonavir 100 mg bd + saquiniavir 1000 mg bd developed severe hepatotoxicity [http //www.fda.gov/medwatch/ safety/2005/Saquinavir-Rifampin deardoc Feb05]. 

Probenecid can increase the serum concentration of rifampicin this can reduce costs and hepatotoxicity in long-term therapy (124). Interactions of rifampicin with probenecid have been reviewed (105). 

Ji BH, Chen JK, Wang CM, Xia GA. Hepatotoxicity of combined therapy with rifampicin and daily prothiona-mide for leprosy. Lepr Rev 1984 55(3) 283-9. 

Linna O, Uhari M. Hepatotoxicity of rifampicin and isoniazid in children treated for tuberculosis. Eur J Pediatr 1980 134(3) 227-9. 

Thus, the importance of enzyme induction is that it may alter the toxicity of a foreign compound. This can have important clinical consequences and underlie drug interactions. Thus, the antitubercular drug rifampicin is thought to increase the hepatotoxicity of the drug isoniazid, and alcohol may increase susceptibility to the hepatotoxicity of... 

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