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High-Yield Facts

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  • Isoniazid (INH) toxicity 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 INH ingestion.

  • INH toxicity is associated with profound metabolic acidosis and increased serum lactate.

  • The antidote for INH poisoning is pyridoxine (Vitamin B6). Administer an amount of pyridoxine equivalent to the amount of INH ingested on a gram-for-gram basis. If the ingested dose is unknown, administer 70 mg/kg(up to a total of 5.0 g) intravenously and repeat if seizures continue.

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Although efforts to decrease incidence rates and mortality from tuberculosis (TB) infections have made considerable progress in recent years, the burden of TB continues to be enormous. The World Health Organization reported an estimated 8.7 million new cases of TB and 1.4 million deaths in 2011.1 The main treatment, isoniazid (INH), has been used for the last several decades as the first-line medication against active tuberculosis and as prophylactic therapy for positive tuberculin skin test reactions. As such, toxic exposures to INH still occur. Within the United States, the 2011 Annual Report of the American Association of Poison Control Centers' National Poison Data System reported 249 INH exposures, of which 42 were in children younger than 5 years, and 69 cases in children between the ages of 6 and 19 years.2 A high index of suspicion for INH toxicity in cases of refractory seizures, coupled with prompt, aggressive treatment by the health care provider, is needed to prevent morbidity and mortality in the acute overdose scenario.

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Pharmacology

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Isoniazid, or isonicotinic acid hydrazide, is an antimycobacterial agent whose mechanism of action is believed to be the disruption of mycolic acid synthesis, a process essential to the mycobacterial cell wall. Structurally, INH is similar to the metabolic cofactors nicotinic acid (niacin), nicotinamide adenosine dinucleotide (NAD), and pyridoxine (vitamin B6). The pyridine ring is a critical component of its antituberculous activity. 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 acetylators.3 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 ...

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