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  • Isoniazid toxicity (INH) should be considered in any patient with metabolic acidosis and seizures refractory to conventional therapy.
  • Altered sensorium, slurred speech, ataxia, coma, and seizures can occur rapidly after ingestion of INH ingestion.
  • INH has a half-life of approximately 180 minutes in slow acetylators and 70 minutes in fast acetylators.
  • INH toxicity is associated with a profound metabolic acidosis and increased lactate levels.
  • The antidote for INH overdose is pyridoxine (B6), given in a gram-for-gram dose to the amount of INH ingested. With ingestions involving unknown quantities, 70 mg/kg (up to a total of 5 gram) of pyridoxine should be given IV and repeated if seizures continue.

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For the last several decades, INH has been used as a first-line treatment against active tuberculosis (TB) and as prophylactic therapy for positive tuberculin skin test reactions. Globally, the burden of TB continues to be enormous. The World Health Organization reported an estimated 9.2 million new cases of TB in 2006, an increase from 9.1 million cases in 2005.1 Within the United States, the 2005 Annual Report of the Poison Control Centers Toxic Exposure Surveillance System reported 354 INH exposures, of which 76 were in children younger than 6 years, and 127 cases in children between the ages of 6 and 19 years.2 A high index of suspicion of INH toxicity by the health care provider, coupled with prompt, aggressive treatment, is needed to prevent morbidity and mortality in the overdose scenario.

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Isoniazid, or isonicotinic acid hydrazide, is an antimycobacterial agent whose mechanism of action is thought to be the disruption of mycolic acid synthesis, which is essential to the mycobacterial cell wall. The pyridine ring is a critical component of its antituberculous activity. Structurally, INH is similar to the metabolic cofactors nicotinic acid (niacin), nicotinamide-adenosine dinucleotide (NAD), and pyridoxine (vitamin B6). Ninety percent of ingested INH is readily absorbed from the gastrointestinal tract, with serum concentrations usually peaking within 2 hours. Peak cerebrospinal fluid levels reach approximately 10% of serum levels. INH is highly water-soluble, with an apparent volume of distribution of 0.6 L/kg. It exhibits less than 10% protein binding.3

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Metabolic degradation of INH is complex and occurs primarily by hepatic acetylation. The ability to inactivate INH by acetylation via the enzyme N-acetyltransferase is genetically determined in an autosomal dominant fashion. Slow acetylators are autosomal recessive for the acetylation gene. Fifty to sixty percent of Caucasians and blacks are slow acetylators, while up to 90% of Asians and Inuits are rapid inactivators.3,4 The effectiveness of the drug is not significantly affected by the rate of acetylation, although slow acetylation can lead to higher peak plasma concentrations, potentially increasing the risk for toxic side effects. The elimination half-life in fast acetylators is approximately 70 minutes, compared to 180 minutes in slow acetylators.3,4 Following acetylation, the INH metabolites are excreted into the urine, with 50% to ...

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