As a bactericidal agent, INH interferes with lipid and nucleic acid biosynthesis in the growing Mycobacterium organism. It is rapidly and nearly completely absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours [2]. The rate and extent of absorption are decreased by food. The volume of distribution of INH approximates total body water (0.67 ± 0.15 L per kg), with cerebrospinal fluid concentrations 90% of those of serum [3]. INH passes into breast milk and through the placental barrier. There is little protein binding.

Between 75% and 95% of an INH dose is metabolized in the liver within 24 hours by acetylation to acetylisoniazid and hydrolysis to isonicotinic acid and hydrazine [2]. Genetic variation in its metabolism significantly alters plasma concentration, elimination half-life, and toxicity [4]. The elimination half-life in rapid acetylators (e.g., Asians, Eskimos, and American Indians) is 0.5 to 1.5 hours, whereas it is 2 to 4 hours in slow acetylators (e.g., people of African descent and Caucasians) [5]. The elimination half-life can be prolonged in people with liver disease. Rapid acetylators excrete 2.5% of INH as unchanged drug, compared with 10% in slow acetylators [2]. In addition, slow acetylators may have a higher percentage of the dose metabolized to hydrazine, a potential hepatotoxin [6]. INH exhibits dose-dependent inhibition of the mixed-function oxidases CYP2C19 and CYP3A, increasing the risk of adverse drug reactions in slow acetylators during the coadministration of drugs metabolized by these enzymes (e.g., phenytoin, carbamazepine, and diazepam) [7].

The usual adult INH dose is 5 mg per kg per day (maximum, 300 mg). The dose is increased to 15 mg per kg (maximum, 900 mg) when INH is used in combination with other antitubercular drugs and administered twice weekly. Acute ingestion of 1.5 to 3.0 g in adults may be toxic, with 6 to 10 g uniformly associated with severe toxicity and significant mortality [8]. The pediatric INH dose is 10 to 15 mg per kg per day (maximum, 300 mg) and is increased to 20 to 30 mg per kg (maximum, 900 mg) when concurrent INH and other antitubercular drugs are administered twice weekly. When INH is used in combination with rifampin, limiting the INH dose to 10 mg per kg per day and the rifampin dose to 15 mg per kg per day may minimize hepatotoxicity in children [9]. In patients with preexisting seizure disorders, convulsions have occurred with doses as low as 14 mg per kg per day; 19 mg per kg per day resulted in seizures in a 7-year-old child [8].

Daily therapeutic INH doses produce peak serum concentrations between 1 and 7 μg per mL. Intermittent INH therapy may produce concentrations between 16 and 32 μg per mL. Serum INH concentrations in acute ingestions have ranged from 20 μg per mL to more than 710 μg per mL, with little correlation to severity of intoxication [10,11,12,13].

The central nervous system toxicity of INH and its metabolites is believed to be due to a decrease in the concentration of γ-aminobutyric acid, an inhibitory neurotransmitter that suppresses neuronal depolarization by opening chloride ionophores (Fig. 137.1). INH combines with pyridoxine (vitamin B₆) and is excreted in the urine as pyridoxal isonicotinylhydrazine [14]. It also competes with pyridoxine for pyridoxine kinase, the enzyme that converts pyridoxine to pyridoxal 5′-phosphate, the cofactor for glutamic acid decarboxylase–mediated conversion of glutamate to γ-aminobutyric acid [15]. In addition, INH inhibits glutamic acid decarboxylase activity. Its metabolism results in metabolites such as hydrazides and hydrazones, which inhibit pyridoxal 5′-phosphate and pyridoxine kinase, respectively [16].

INH causes a peripheral neuropathy that may be responsive to pyridoxine supplementation [17]. Wallerian degeneration of the myelin sheath and axon with blockade of fast axoplasmic transport is noted, with sensory nerves affected more than motor nerves [18,19,20,21,22]. Peripheral neuropathy is most commonly associated with chronic INH use in slow acetylators but may occur after acute massive overdose [23,24].

The mechanism of INH-induced hepatic injury is not understood. Hepatitis occurs in 0.1% to 1.1% of patients receiving INH, especially those with advanced age and alcohol consumption [25,26,27,28]. Concurrent rifampin therapy increases the incidence of hepatitis to 2.7% in adults and 6.9% in children [9,25,26,27,28]. It is unclear whether this effect is due to an influence of rifampin on INH metabolism or to the additive effect of two hepatotoxic drugs [28]. The histopathologic pattern of hepatic injury closely resembles viral hepatitis. Hypersensitivity seems unlikely, as rechallenge often fails to produce recurrence. Hepatic damage may be due to hydrazine metabolites of INH, covalently binding to liver macromolecules and producing necrosis [29]. Both rapid and slow acetylators have been described as having a greater risk for hepatotoxicity, although other researchers failed to find an association with acetylator status [26,30]. More recent work suggests that slow acetylators may be more susceptible to antitubercular drug–induced hepatitis and may develop more severe hepatotoxicity than do rapid acetylators [31].