Neurotoxicity isoniazid

Shah BR, Santucci K, Sinert R, Steiner P. Acute isoniazid neurotoxicity in an urban hospital. Pediatrics 1995 95(5) 700-4. 

N-acetyltransferase (NAT2) Isoniazid, hydralazine, sulfonamides, amonafide, procainamide, dapsone, caffeine Hypersensitivity to sulfonamides, amonafide toxicity, hydralazine-induced lupus, isoniazid neurotoxicity... 

Isoniazid Adults S mg/kg (300 mg) Children 1 0-1 S mg/kg (300 mg) Asymptomatic elevation of aminotransferases, clinical hepatitis, fatal hepatitis, peripheral neurotoxicity, CNS system effects, lupus-like syndrome, hypersensitivity, monoamine poisoning, diarrhea LFT monthly in patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of drug Dosage adjustments may be necessary in patients receiving anticonvulsants or warfarin... 

Increased risk of hydralazine-induced lupus, increased levels of isoniazid with an increased risk of neurotoxicity, increased risk of bladder cancer in individuals exposed to aromatic amines Increased risk of serious toxicity to mercaptopurine and azathioprine... 

Ethionamide is an analog of isoniazid and also inhibits mycolic acid synthesis. Its usefulness is limited by the rapid development of resistance. It can cause intense gastric pain and, like isoniazid, may also be neurotoxic. 

Pyridoxine is indicated in vitamin B deficiency, for the treatment of some pyridoxine responsive anemia s and for isoniazid-induced neuropathy. It may relieve symptoms of pellagra when niacin fails. Long-term administration of large doses may produce neurotoxicity manifesting itself in progressive peripheral sensory neuropathy. 

Alder S, Zbinden G (1973) Use of pharmacological screening tests in subacute neurotoxicity studies of isoniazid, pyridoxine HC1 and hexachlorophene. Agents Actions 3 233-243... 

Siskind MS, Thienemann D, Ku hn L. Isoniazid-induced neurotoxicity in chronic dialysis patients report of three cases and a review of the literature. Nephron 1993 64(2) 303-6. 

The addition of pyridoxine to usual doses of isoniazid of 5 mg/kg/day in adults and 8-10 mg/kg/day in children markedly reduces neurotoxicity (9). Adherence to therapy is improved by prescribing combined tablets containing 20 mg of pyridoxine per 100 mg of isoniazid. In otherwise healthy people, prescription of pyridoxine is not mandatory. However, it should be routinely given to malnourished patients and those predisposed to neuropathy (for example pregnant women, elderly people, and people with diabetes, alcoholism, or uremia) (7). 

Synthetic chemicals with neurotoxic potential (Table 2) are most commonly encountered in the form of prescription (ethambutol, isoniazid, vincristine)... 

Other neurotoxic substances (isoniazid, metronidazole, dapsone, vincristine, pyridoxine, stavidine, zalcitabine, and others)... 

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. 

Are more likely to experience isoniazid-induced neurotoxicity... 

With respect to neurotoxins, there are a number of industrial chemicals (acrylamide, n-hexane, methyl n-butyl ketone, cresyl phosphate), pharmaceuticals (nitrofuradantoin, isoniazid), and pesticides (leptophos, Kepone ) which have been associated with neuropathic effects in humans (for reviews, see References 107,123, 124). Subchronic exposure studies in rodents and other animals such as cats have been used to identify and study the mechanism of action of neurotoxic chemicals which produce paralysis and behavioral changes in exposed animals. Studies are currently underway to evaluate the relative sensitivities of behavioral tests and morphological assays of peripheral and central nervous system axon morphology for detecting the earliest signs of chemically induced neuropathies. " ... 

Isoniazid may precipitate convulsions, usually in patients with known seizure disorders. Optic neuritis also has occurred. Muscle twitching, dizziness, ataxia, paresthesias, stupor, and potentially fatal encephalopathy are other manifestations of neurotoxicity. A number of mental abnormalities may appear, including euphoria, transient memory inpairment, loss of self-control, and psychosis. 

Some limited evidence siu esitsi that vincristine neurotoxicity may possibly be increased by isoniazid. 

This report is consistent with another much earlier report of two patients who also developed peripheral neurotoxicity when they were given vincristine after starting to take isoniazid and pyridoxine, the cumulative doses of vincristine being 11 mg and 11.2 mg, respectively, and of a case of severe neurotoxicity with an overdose of isoniazid and high-dose vincristine. ... 

The most significant side effects associated with isoniazid are hepatotoxicity and neurotoxicity (Jnawali and Ryoo, 2013). These side effects remain a prime reason for discontinuation of treatment with INH (Basoulis et al., 2012). Studies show that 10—20% of patients treated with INH have a tendency to have hepatotoxicity (Basoulis et al., 2012). 

Nervous system The adverse effects of antituberculosis drugs on the nervous system have been reviewed [1 ]. Isoniazid is most often associated with nervous system reactions, most prominently peripheral neuropathy, psychosis, and seizures. Optic neuropathy can occur with ethambutol and ototoxicity and neuromuscular blockade with aminoglycosides. Cycloserine can cause psychosis and seizures, and the psychosis in particular limits its use. Fluoroquinolones are rare causes of seizures and delirium. Significant neurotoxicity has not been documented with newer forms of therapy under development. 

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. 

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