Isoniazid adverse effects /toxicity

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. 

The severe fiver dysfunction also seemed to be more common in slow metabofizers, and it was proposed that this due to a deficiency in detoxication of a metabolite. Monitoring patients with fiver function tests is one way to avoid this adverse effect. There may be other factors as well as the acetylator phenot5rpe that are important, such as other drugs being taken at the same time. Excessive and sustained alcohol intake may also be a factor, as this is quite commonly associated with the occurrence of tuberculosis. Apart from weakening the fiver it will also increase the amount of the enzyme that produces the toxic metabolite of isoniazid. 

A study found that aminosalicylic acid significantly increased the plasma levels of isoniazid at 4 and 6 hours after administration by 32% and 114%, respectively in fast acetylators of isoniazid, and by 21% and 39%, respectively in slow acetylators. The half-life of isoniazid was increased from 1.32 to 2.89 hours in fast acetylators and from 3.05 to 4.27 hours in slow acetylators (see Genetic factors , (p.4), for more information about acetylator status). The effects were probably due to the inhibition of isoniazid metabolism by aminosalicylic acid. There seem to be no reports of isoniazid toxicity arising from this interaction, but the manufacturers of isoniazid warn that adverse effects are more likely in the presence of aminosalicylic acid. ... 

The mechanism of isoniazid-induced neurotoxicity is believed to be reduced concentrations of GABA by inhibition of pyridoxine (vitamin Be) metabolism. Human studies describing white matter changes in isoniazid toxicity have also corroborated a potential toxic effect on myelin. Rapid resolution of diffusion-restricted lesions in this patient suggested a similar process of intramyeUnic edema. In addition, the half-Ufe of isoniazid was 3.9 hours, suggestive of the slow acetyla-tor phenot, with increased susceptibility to adverse effects of isoniazid. 

Rifampicin toxicity is becoming of greater importance in the treatment of leprosy. Several studies have recently been reported in which rifampicin was used in combination with Isoprodian, a combination of dapsone, isoniazid and prothionamide. The commonest adverse effects observed on this combination are gastrointestinal disturbances and mild hepatitis, manifested either as abnormalities in biochemical parameters or clinically by jaundice. One case of exfoliative dermatitis was reported from a trial carried out in South India (35 ). 

Careful monitoring and the addition of pyridoxine to isoniazid have reduced the number of adverse drug effects in tuberculosis. Awareness of potentially severe hepato-toxic reactions is vital, because hepatic failure may be a devastating and often fatal condition. Fulminant hepatic failure caused by rifampicin, isoniazid, or both has been described (2). 

For recent skin-test converters of all ages, the risk of active TB outweighs the risk for drug toxicity.Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid should receive pyridoxine (vitamin Bg) 10-50 mg daily to reduce the incidence of central nervous system (CNS) effects or peripheral neuropathies. All patients who receive treatment of LTBl should be monitored monthly for adverse drug reactions and for possible progression to active TB. 

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