Isoniazid liver damage

Mefabo//sm - The half-life of INH is widely variable and dependent on acetylator status. Isoniazid is primarily acetylated by the liver this process is genetically controlled. Fast acetylators metabolize the drug about 5 to 6 times faster than slow acetylators. Several minor metabolites have been identified, one or more of which may be reactive (monoacetylhydrazine is suspected), and responsible for liver damage. The rate of acetylation does not significantly alter the effectiveness of INH. However, slow acetylation may lead to higher blood levels of the drug, and thus to an increase in toxic reactions. 

Isoniazid can induce a wide variety of potentially serious adverse reactions. Some hepatotoxicity can manifest itself as transient elevations of liver enzymes and this occurs in 10-20% of patients. Progressive and potentially fatal liver damage is age dependent with a very low incidence below the age of... 

Isoniazid and iproniazid are chemically similar drugs having different pharmacological effects they may both cause liver damage after therapeutic doses are given. Isoniazid is still widely used for the treatment of tuberculosis, but iproniazid is now rarely used as an antidepressant. 

Both these substituted hydrazine drugs may cause liver damage after therapeutic doses. With isoniazid, a mild hepatic dysfunction may occur in 10% to 20% of patients and a more severe type in less than 1%. Both isoniazid and iproniazid yield hydrazine metabolites (acetylhy-drazine and isopropylhydrazine, respectively), which are responsible for the hepatotoxicity after activation by cytochrome P-450. Isoniazid undergoes acetylation, which in humans is polymorphic. Slow acetylators are more at risk from the hepatotoxicity because acetylhy-drazine is detoxified by acetylation. 

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. In the bacterium it is converted to isonicotinic acid, which is membrane impermeable and hence likely to accumulate intracellularly. Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation. Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin B6 (pyridoxine), and liver damage. 

A number of features of isoniazid hepatotoxicity can be interpreted by reference to the metabolic scheme shown in Figure 16.6. First/ phenotypic slow ace ty la tors are more prone to liver damage than are rapid acetylators (Table 16.3) (30). Not only were hydrazine plasma concentrations higher in slow acetylators than in rapid acetylators treated with isoniazid for 14 days (31)/ hut, in another study/ urine excretion of hydrazine was higher in slow than in rapid acetylatorS/ whereas urine excretion of... 

Adverse effects. Isoniazid is in general well tolerated. The most severe adverse effect is liver damage which may range from moderate elevation of hepatic enzymes to severe hepatitis and death. It is probably caused by a chemically reactive meta-bolite(s), e.g. acetylhydrazine. Most cases develop within the first 8 weeks of therapy and liver function tests should be monitored monthly during this period at least. 

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). 

Liver damage usually appears 1-2 months after the start of therapy. In children, raised liver enzymes are common during the first few months of treatment, but withdrawal is seldom necessary. A careful watch should be kept for early symptoms of isoniazid-induced hepatitis, such as malaise, fatigue, nausea, and epigastric distress. The dangers of continuing isoniazid after the onset of symptoms of toxicity have been highlighted (30). The earhest symptoms of isoniazid toxicity should be clearly described to the patient, particularly to hepatitis B carriers, who may be more susceptible to hepatotoxicity (26). 

Timbrell JA, Wright JM. Urinary metabolic profile of isoniazid in patients who develop isoniazid-related liver damage. Hum Toxicol 1984 3(6) 485-95. 

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. 

Isoniazid causes peripheral neuropathy and liver damage (centrilobular necrosis). The liver damage is caused by a metabolite, acetylhydrazine whereas the peripheral neuropathy is caused by the parent drug interacting with pyridoxal phosphate and thereby interfering with the metabolism of vitamin B6. The genetic factor acetylator phenotype is important in both types of toxicity. Thus... 

The incidence of severe progressive liver damage due to isoniazid is said to be higher in those who drink alcohol regularly. The clinical effects... 

A 21 -year-old woman who had heen taking isoniazid 300 mg for 6 months took 3.25 g of paracetamol for abdominal cramping. Within about 6 hours she developed marked evidence of liver damage (prolonged prothrombin time, elevated ammonia, transaminases, hyperbilirubinaemia). ... 

The reasons for the hepatotoxicity are not fully understood but rifampicin or isoniazid alone can cause liver damage by their own toxic action. One suggestion is that the rifampicin alters the metabolism of isoniazid, resulting in the formation of hydrazine, which has proven to be hepatotoxic. Higher plasma levels of hydrazine are said to occur in slow acetylators of isoniazid, but one study failed to confirm that this is so. There has certainly been at least one fatality caused by this combina-tion. The manufacturers of rifampicin advise that caution is particularly needed in patients with impaired liver function, the elderly, malnourished patients, and children under two years of age. After baseline LFTs, further tests are only needed if fever, vomiting, or jaundice occur, or if the patient deteriorates. However, the manufacturers of isoniazid suggest that liver function tests should be reviewed regularly in patients on combined treatment. ... 

Allergic reactions are rare. Polyneuropathy is not caused by hypersensitivity, and can be prevented and if need be treated by administration of vitamin B5. In cases of existing liver damage isoniazid may be an additional burden, because it is metabolized in this organ. Some cases of liver damage by isoniazid are clinically difficult to differentiate from virus hepatitis (Garibaldi et al. 1972 Thomas et al. 1979). 

There are two forms of liver damage after isoniazid ... 

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. 

Warrington et al. (1978) found that the lymphocyte transformation test was positive after stimulation with isoniazid, isonicotinic acid, and conjugates of these compounds in 95% of patients who developed isoniazid hepatitis. Healthy controls and isoniazid patients who did not develop liver damage showed a negative test. There was no correlation between the degree of lymphocyte transformation and the severity of liver damage. The appearance of liver damage after isoniazid seems to depend on the presence of cellular hypersensitivity to this medicament. 

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). 

Asmar B, Maqbool S, Dajani AS (1981) Hematologic abnormalities after oral trimethoprim-sulfamethoxazole therapy in children. Am J Dis Child 135 1100 Assem ESK, Ndoping N, Nicholson H, Wade JR (1969) Liver damage and isoniazid allergy. Clin Exp Immunol 5 439... 

Other such enzyme deficiencies have been revealed through an individual s adverse reaction to drugs. More than 90% of Orientals are genetically rapid N-acetylators of isoniazid (6.12), whereas only 40% of black or white citizens of the United States showed this trait (Kalow, 1962). Rapid acetylators produce acetylhydrazine, which can cause liver damage. The same inheritance controls the acetylation (deactivation) of the sulphonamide antibacterials. The rise of intraocular pressure when glucocorticoids are placed in the eye is another pharmacogenetic effect. Low and high responses are shown by 66% and 5%, respectively, of a sample white population. 

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