Antituberculous Drugs

ISONIAZID

Isoniazid inhibits the phosphorylation of pyridoxine and chelates whatever pyridoxal phosphate remains. Because pyridoxal phosphate is a co-factor that is important to the GABA system, it has been hypothesized that the centrally diminished GABA activity may relate to the pathophysiology of isoniazid-induced seizures. In chronic toxicity, isoniazid predominantly inhibits the phosphorylation of pyridoxine to induce a peripheral neuropathy. ';'

The incidence of pyridoxine-associated polyneuropathy is 0.2 to 2 percent, and the clinical features include numbness and tingling of the feet with diminished or absent deep tendon reflexes and occasional optic neuropathy. Isoniazid-associated neuropathy can be prevented by concomitant administration of pyridoxine, 50 mg/day.y In patients not receiving pyridoxine, high-risk groups for neuropathy include slow acetylators, adults, alcoholics, malnourished individuals, and those receiving more than 5 mg/kg/day.

Acute isoniazid intoxication due to overdosage is associated with generalized seizures, ataxia, psychosis, and coma. Metabolic acidosis, hyperglycemia, and aciduria may accompany

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the acute neurological syndrome. Pyridoxine should be administered immediately, along with standard anticonvulsant and supportive measures. Because seizures are a complication of isoniazid therapy, the drug is not recommended for patients with pre-existing seizure disorder if another drug can be chosen. When isoniazid is required in patients who are already receiving phenytoin, the phenytoin dose has to be adjusted because isoniazid decreases its clearance. [i] , [3i]

More unusual isoniazid-related neurotoxic syndromes include drug-induced lupus with meningitis, psychosis, obsessive-compulsive disorder, and acute mania.

RIFAMPIN

Rifampin may induce an encephalopathy with features suggestive of a psychosis. Other rare adverse reactions are dizziness, headache, drowsiness, confusion, inability to concentrate, and ataxia. y Rarely, paresthesias and pain suggestive of peripheral neuropathy are reported. y

ETHAMBUTOL

Optic neuropathy has been associated with ethambutol treatment. This appears to be a demyelinating process, and the reason for the optic nerve's sensitivity to this drug is unknown. Symptoms are seen in as many as a third of patients taking doses of 35 mg/kg/day for 6 months. Doses of 25 mg/kg/day are safe for not more than 2 months, and the safe maintenance dose is 15 mg/kg/day. Toxicity is manifested by impairment of visual acuity, loss of color discrimination, constricted visual fields, and central and peripheral scotomata. The drug should be stopped at the first sign of visual change, and recovery can be anticipated, although it may take weeks to months.y Other side effects include mild peripheral neuropathy and a metallic taste in the oral cavity. y

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