Serum transaminase isoniazid

Elevations of serum transaminase concentrations generally are not correlated with the residual capacity of the liver to metabolize drugs, so these markers cannot be used directly as guides for residual metabolic capacity. Hepatically cleared TB drugs include isoniazid, rifampin, pyrazinamide, ethionamide, and p-aminosalicylic acid.39 Ciprofloxacin is about 50% cleared by... 

Mild hepatic dysfunction, detected as an elevation in serum transaminases, is now well recognized as an adverse effect of isoniazid and occurs in 10% to 20% of patients. Possibly, as many as 1 % of these cases progress to severe hepatic damage, and it has been suggested that this latter, more severe form, of hepa to toxicity may have a different underlying mechanism. However, the greater incidence of hepatotoxicity reported in rapid acetylators has since been questioned. It seems that the incidence of the mild form of isoniazid hepatotoxicity is not related to the acetylator phenotype, but the incidence of the rarer, more severe form is more common in slow acetylators. 

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. 

Transient elevations of the serum transaminases occur in 12% to 15% of patients receiving isoniazid and usually occur within the first 8 to 12 weeks of therapy. Overt hep ato toxicity, however, occurs in only 1% of cases. Risk factors for hepatotoxicity include patient age, preexisting liver disease, excessive alcohol intake, pregnancy, and the postpartum state. Isoniazid also may result in neurotoxicity, most frequently presenting as peripheral neuropathy or, in overdose, as seizures and coma. Patients with pyridox-ine deficiency, such as pregnant women, alcoholics, children, and the malnourished, are at increased risk. Isoniazid may inhibit the metabolism of phenytoin, carbamazepine, primidone, and warfarin." Patients who are being treated with these agents should be monitored closely, and appropriate dose adjustments should be made when necessary. 

Mitchell et al. (1975) made a blind, prospective evaluation in 358 psychiatric patients during 1 year of tuberculosis prevention with isoniazid. Most of the patients who developed abnormal serum transaminases recovered completely while continuing their isoniazid therapy. No serum antibodies against isoniazid could be demonstrated and no correlation was found between the presence of antinuclear antibodies or elevated isoniazid plasma concentrations and the occurrence of hepatic injury. These data support the view that hepatotoxic metabolites of isoniazid may be responsible for the liver damage. 

On the other hand, functional liver damage with elevation of serum transaminases and bilirubin levels during therapy with the combination of isoniazid and rifampicin is observed more often in slow inactivators, in whom rifampicin activates the enzyme system, which disintegrates the drugs. Therefore in these cases there is an elevated hepatotoxicity of isoniazid due to the increased appearance of reactive intermediates (voN Oldershausen et al. 1978 Smith 1979 Smith et al. 1972 Pessayre et al. 1977 von Oldershausen 1976 Dengler and Eichelbaum 1977 Musch et al. 1982). Admittedly, some of these studies were carried out with relatively high doses of isoniazid (10 mg/kg/day). 

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