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. According to the Centers for Disease Control and Prevention, there were 10.4 million new cases of TB worldwide in 2015, with approximately 1.8 million TB-related deaths.¹ The total number of cases reported in the United States increased in 2015 to 9557 cases, after several years of decline from 1993 to 2014.¹ It remains the leading cause of death in HIV-infected individuals.¹

Isoniazid (INH) has for years been the first-line medical treatment against active tuberculosis as well as prophylactic therapy for latent TB/positive tuberculin skin test reactions. As such, toxic exposures to INH, including in children, still occur. The 2015 Annual Report of the American Association of Poison Control Centers’ National Poison Data System reported 145 INH exposures within the United States, 10 of which were in children younger than 5 years, and 38 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.

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

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 is approximately 70 minutes, compared to 180 minutes in slow acetylators.³ Following acetylation, the INH metabolites are excreted via the urine, with 75% to 95% of a single dose eliminated within 24 hours.³

INH can inhibit several cytochrome P450-mediated functions, such as demethylation, oxidation, and hydroxylation. INH has been associated with interactions with several drugs, including theophylline, phenytoin, warfarin, valproic acid, and carbamazepine.³ Adverse effects of these drugs result from elevated drug levels due to INH inhibition of their metabolism. Interactions with food (e.g., tyramine reactions) from its weak monoamine oxidase inhibitor activity have also been reported.

The process by which INH toxicity occurs is complex but includes two main mechanisms, which have the overall effect of depleting gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS). First, INH creates a functional deficiency of pyridoxine by inhibiting pyridoxine phosphokinase, the enzyme that converts pyridoxine to its active form, pyridoxal-5′-phosphate. Pyridoxal-5′-phosphate is a necessary cofactor in the conversion of glutamic acid to GABA. INH itself also combines with pyridoxine-5′-phosphate, forming inactive INH pyridoxal hydrazones, which are renally excreted.³

Second, INH inhibits the enzyme glutamic acid decarboxylase, which, along with pyridoxine-5′-phosphate, is also required for the synthesis of GABA. Depletion of GABA leading to increased CNS excitability is believed to be the etiology of INH-induced seizures (Fig. 124-1).