Isoniazid (INH, or isonicotinic hydrazide) is structurally related to nicotinic acid (niacin, or vitamin B3), nicotinamide adenosine dinucleotide (NAD), and pyridoxine (vitamin B6) (Fig. 58–1). The pyridine ring is essential for antituberculous activity. INH itself does not have direct antibacterial activity. It is a prodrug that undergoes metabolic activation by KatG, a catalase peroxidase in M. tuberculosis that produces a highly reactive intermediate,95,135 which in turn interacts with InhA, a mycobacterial enzyme that functions as an enoyl-acyl carrier protein (enoyl-ACP) reductase.92,93 InhA is required for the synthesis of very-long-chain lipids, mycolic acids (containing between 40 and 60 carbons) that are important components of mycobacterial cell walls.
The activated form of INH is stabilized by the pyridine ring. Enoyl-ACP reductase (InhA) catalyzes the NADH-dependent reduction of the double bonds in the growing fatty acid chain linked to acyl carrier proteins. This INH metabolite enters the binding site of InhA, where it reacts with the reduced form of nicotinamide adenine dinucleotide (NADH).95 The covalently linked INH-NADH complex remains bound to the active site of InhA, irreversibly inhibiting the enzyme.76,92
When therapeutic doses of 300 mg are administered orally, INH is rapidly absorbed, reaching peak serum concentrations typically within 2 hours.60,88,89 INH diffuses into all body fluids with a volume of distribution of approximately 0.6 L/kg and has negligible binding to serum proteins. After the drug penetrates infected tissue, it persists in concentrations well above those generally required for bactericidal activity.89
The primary metabolic pathway for INH is via N-acetylation via hepatic acrylamine N-acetyltransferase type 2 (NAT2) to acetylisoniazid, which may be (1) excreted by the kidney; (2) oxidized to hydroxylamine, a hepatotoxic metabolite via CYP2E1130; (3) directly hydrolyzed to hepatotoxic hydrazine; or (4) further metabolized by NAT2 to (somewhat hepatotoxic) acetylhydrazine, which may be further metabolized by NAT2 to nontoxic diacetylhydrazine. Hydrazine and (to a lesser extent) acetylhydrazine are oxidized by CYP2E1 to reactive metabolites, which induce oxidative stress or alter lipid metabolism, resulting in hepatic apoptosis or steatosis. The mechanisms and circumstances of hepatotoxicity are not clearly elucidated and are of continuing interest in research.130 Approximately 75% to 95% of INH is renally eliminated in the form of these hepatic metabolites within 24 hours of administration.49N-acetyltransferase-2 (NAT2) exhibits Michaelis-Menten kinetics but is genotypically polymorphic, and the activity of an individual’s enzymes is determined by an autosomal dominant inheritance pattern, with homozygous fast acetylators (FF), heterozygous fast acetylators (FS), and homozygous slow acetylators (SS). Patients are distinguishable phenotypically as fast, intermediate, and slow acetylators. Whereas the fast acetylation isoform is found in 40% to 50% of American whites and African Americans, the fast acetylator isoenzymes are found in 80% to 90% of Asians and Inuits.37 These isoforms are distinguishable by the following characteristics: (1) slow acetylators have less presystemic clearance, or first-pass effect, than do fast acetylators; (2) fast acetylators metabolize INH five to six times faster than slow acetylators; and (3) serum INH concentrations are 30% to 50% lower in fast acetylators than in slow acetylators. The elimination half-life of INH is approximately 70 minutes in fast acetylators, and 180 minutes in slow acetylators. Twenty-seven percent of INH is excreted unchanged in urine by slow acetylators compared with 11% excretion in fast acetylators. Slow acetylators are at increased risk of peripheral neuropathy and may require dose adjustments.117 The clearance of INH averages 46 mL/min.10,125 Additionally, a small portion of INH is directly hydrolyzed into isonicotinic acid and hydrazine, and this pathway is of greater quantitative significance in slow acetylators than in rapid acetylators. Although both hepatic microsomal oxidation by CYP2E1 of hydrazine or the acetylhydrazine intermediate into reactive intermediates have been proposed as causes of INH related hepatotoxicity, there is no significant association between variations in genetic polymorphisms and hepatotoxicity.44,81,121,130 There is increasing evidence that hydrazine is linked to direct hepatotoxicity as well as causing hepatotoxicity via an immune mediated, idiosyncratic mechanism.77Figure 58–2 illustrates the metabolism of INH.
Metabolism of isoniazid (INH). INH metabolism occurs via enzyme N-acetyltransferase type 2 (NAT2), hydrolysis, and further oxidation via cytochrome P450 enzyme type 2E1 (CYP2E1) into both nontoxic and hepatotoxic metabolites. Hepatotoxicity is multifactorial and occurs directly via hepatotoxic metabolites and indirectly via induced apoptosis and steatosis. DHFR = dihydrofolate reductase; InhA = mycobacterial enoyl-acyl carrier protein reductase; KatG = mycobacterial catalase peroxidase.
Toxicokinetic data are nearly absent. Delayed absorption of INH has not been observed.104
INH induces a functional pyridoxine deficiency via two main mechanisms (Fig. 58–3) and culminates in refractory seizures because of a relative lack of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system, and an excess of glutamate, the primary stimulatory neurotransmitter in the central nervous system (CNS). The GABA-glutamate pathway constantly balances the stimulatory, epileptogenic effects of glutamate against the inhibitory, sedative hypnotic effects of GABA. Disruption of this homeostasis, with increased glutamate and insufficient GABA, is thought to be the etiology of INH-induced seizures.5
The effect of isoniazid on γ-aminobutyric acid (GABA) synthesis.
Pyridoxine is converted in vivo to an active form, pyridoxal-5′-phosphate, which serves as an important cofactor in many biotransformation reactions such as transamination, transketolation, and decarboxylation. INH metabolites inhibit the enzyme pyridoxine phosphokinase, which converts pyridoxine (vitamin B6) to its active form, pyridoxal-5′-phosphate, which is a required cofactor for many pyridoxine dependent enzyme systems in the body, including two enzymes that control GABA metabolism.25,59,79 Glutamic acid decarboxylase (GAD) catalyzes GABA synthesis from glutamate, and GABA aminotransferase degrades the inhibitory neurotransmitter. The inhibitory effects are greater on GAD, which leads to both decreased GABA and elevated glutamate concentrations.127
Pyridoxine depletion is also involved in a decrease in catecholamine synthesis and interferes with the synthesis of and/or reacts with NAD to form inactive hydrazone adducts, thereby disrupting cellular reduction/oxidation reactions.
Pyridoxine depletion is further compounded when INH directly reacts with pyridoxal phosphate to produce an inactive hydrazone complex that is renally excreted and thereby increases renal losses of this required cofactor.79,125 Urinary excretion of pyridoxine and its metabolites increases with increasing INH dose, reflecting the effect of INH on pyridoxine metabolism.
Structurally similar chemicals exert similar acute toxic effects. Monomethylhydrazine, a metabolite produced from gyromitrin isolated from the Gyromitra spp (“false morel”) mushroom, and the hydrazines used in liquid rocket fuel have a similar mechanism of action (Chap. 120).
Interactions with Other Drugs and Foods
Drug–drug interactions associated with INH are mediated through alteration of hepatic metabolism of several CYP enzymes. The majority of these interactions are inhibitory, with decreased CYP-mediated transformations, particularly demethylation, oxidation, and hydroxylation (Chap. 13). Clinically relevant adverse effects with elevated concentrations of theophylline (CYP1A2), phenytoin (CYP2C9/CYP2C19), warfarin (CYP2C9/CYP2C19), valproic acid, and carbamazepine (CYP3A4) are caused by decreased hepatic metabolism of these xenobiotics.33,106,131 The CYP2E1 cytochrome subtype, however, exhibits a complex response to INH; a therapeutic dose of INH induces expression of CYP2E1, but simultaneously binds, stabilizes, and inhibits its metabolic activity. Eventual dissociation of INH from the enzyme active site creates an increased intracellular concentration of CYP2E1 available to metabolize potential substrates. The formation of the acetaminophen (APAP) metabolite responsible for toxicity, NAPQI (N-acetyl-p-benzoquinoneimine), is catalyzed by CYP2E1. INH mediated effects in APAP-induced hepatotoxicity are uncertain because of differences in acetylator status (fast, slow) and variations in CYP2E1 activity.24,106
INH interacts with numerous foods. INH is a weak monoamine oxidase inhibitor; both tyramine reactions to foods (aged cheeses, wines) and serotonin toxicity from meperidine are reported in patients taking INH. Clinical effects include flushing, tachycardia, and hypertension.32,43,69,113 Furthermore, INH inhibits the enzyme histaminase, leading to exacerbated reactions after the ingestion of histamine in scombrotoxic fish.55,79,106Table 58–1 summarizes additional INH drug and food interactions.
TABLE 58–1. Adverse Reactions and Drug Interactions of Antituberculous Drugs ||Download (.pdf) TABLE 58–1. Adverse Reactions and Drug Interactions of Antituberculous Drugs
|Drug ||Major Adverse Reactions ||Drug Interactions Clinical Effect ||Monitoring ||Comments |
|Isoniazid (INH) || |
Acute: seizures, acidosis, coma, hyperthermia, oliguria, anuria
Chronic: elevation of liver enzyme concentrations, autoimmune hepatitis, arthritis, anemia, hemolysis, eosinophilia, peripheral neuropathy, optic neuritis, vitamin B6 deficiency (pellagra)
Rifampin, PZA, ethanol: hepatic necrosis
Acetaminophen: hepatic necrosis
Warfarin: increased INR
Theophylline: tachycardia, vomiting, seizures, acidosis
Phenytoin: increased phenytoin concentrations
Carbamazepine: altered mental status
Meperidine: serotonin toxicity
Lactose: decreased INH absorption
Antacids: decreased INH absorption
Red wine/soft cheese: tyramine reaction
Fish (scombroid): flushing, pruritus
|Liver enzymes, ANA, CBC ||HIV enteropathy may decrease absorption; INH should not be given with lactose containing drug formulations because lactose can form hydrazones and lower INH concentrations |
|Rifampin || |
Acute: diarrhea, periorbital edema
Chronic: hepatitis, reddish discoloration of body fluids
Protease inhibitors: decreased serum concentration of protease inhibitor
Delavirdine: increased HIV resistance
Cyclosporine: graft rejection
Warfarin: decreased INR
Oral contraceptives: ineffective contraception
Methadone: opioid withdrawal
Phenytoin: higher frequency of seizures
Theophylline: decreased theophylline concentrations
Verapamil: decreased cardiovascular effect
|If administered with HIV antiretrovirals, viral titers should be followed. Liver enzymes; monitor serum concentrations of drugs (ie, phenytoin, cyclosporine) or clinical markers of efficacy (ie, INR) ||Interactions of rifampin with several HIV medications are very poorly described; changes in dosing or dosing interval for both rifampin and antiretroviral drugs may be required; teratogenic |
|Ethambutol ||Chronic: optic neuritis, loss of red-green discrimination, loss of peripheral vision || ||Visual acuity, color discrimination ||Contraindicated in children too young for formal ophthalmologic examination |
|Pyrazinamide (PZA) ||Chronic: hepatitis, decreased urate excretion ||INH: increased rates of hepatotoxicity (when extended courses or high dose pyrazinamide used) ||Liver enzymes ||Courses of therapy of ≤2 months are recommended |
|Cycloserine ||Chronic: depression, paranoia, seizures, megaloblastic anemia ||INH: increased frequency of seizures ||CBC, psychiatric monitoring || |
|Ethionamide ||Chronic: orthostatic hypotension, depression ||Cycloserine: may increase CNS effects ||Blood pressure, pulse, orthostasis || |
|para-Aminosalicylic acid ||Chronic: malaise, GI upset, elevated liver enzyme concentrations, hypersensitivity reactions, thrombocytopenia || ||Liver enzymes, CBC || |
|Capreomycin ||Chronic: hearing loss, tinnitus, proteinuria, sterile abscess at IM injection sites || ||Audiometry, kidney function tests || |
The use of INH in pregnancy is of concern because it is a class C drug, crosses the placenta, and produces umbilical cord serum concentrations comparable to maternal serum concentrations.13,14,61 Mammalian teratogen studies suggest that INH is not a human teratogen, although fetal deformities after acute overdose of INH are reported.70,125 Administration of INH to pregnant women was not associated with cancer in their offspring. Although INH readily enters breast milk, breastfeeding during therapy is considered acceptable.100,125
Clinical Manifestations of Isoniazid Toxicity
INH produces the triad of seizures refractory to conventional therapy, severe metabolic acidosis, and coma. These clinical manifestations may appear as soon as 30 minutes after ingestion.53,57,119 The case fatality rate of a single acute ingestion may be as high as 20%.15,18 Although vomiting, slurred speech, dizziness, and tachycardia may represent early manifestations of toxicity, seizures may be the initial sign of acute overdose.72 Seizures may occur after the ingestion of greater than 20 mg/kg of INH and invariably occur with ingestions greater than 35 to 40 mg/kg. Patients with underlying seizure disorders may develop seizures at lower doses.15 Hyperreflexia or hyporeflexia may herald INH induced seizures. Consciousness may return between seizures, or status epilepticus can occur.30,84 Because GABA, the primary inhibitory neurotransmitter, is depleted in acute INH toxicity, seizure activity may persist until GABA concentrations are restored even with anticonvulsant therapy.
Acute INH toxicity is often associated with seizures and an anion gap metabolic acidosis associated with a high serum lactate concentration. Typically, arterial pH ranges between 6.80 and 7.30, although survival in the setting of an arterial pH of 6.49 was reported.53 Paralyzed animals poisoned with INH do not develop elevated lactate concentrations, a finding that suggests the lactate arises from intense muscular activity.25,85
In acute severe INH toxicity, coma may last as long as 24 to 36 hours and persist beyond both the termination of seizures and the resolution of acidemia. The cause of coma is unknown.11,53Additional sequelae from acute INH toxicity include rhabdomyolysis, kidney failure, hyperglycemia, glycosuria, ketonuria, hypotension, and hyperthermia.4,8,19,86,125,126
Chronic therapeutic INH use is associated with a variety of adverse effects. Overall incidence of adverse reactions to INH is estimated to be 5.4%,49 the most serious of which is hepatocellular necrosis.39 Although asymptomatic elevation of aminotransferases is common in the first several months of treatment, laboratory testing may reveal the onset of hepatitis up to one year after starting INH therapy. In 1978, after several deaths among patients receiving INH therapy, the US Public Health Service reported the incidence of clinically evident hepatitis as 1% of those taking INH; of that subgroup, 10% died, for an overall mortality rate of 0.1%.17,66 Research performed since the resurgence of TB, however, identified a considerably lower rate of hepatotoxicity. Clinically manifest hepatitis occurred in only 11 patients in a population of 11,141 persons receiving INH and close monitoring, yielding an incidence of 0.1%.83 Additional studies suggest that the death rate from INH hepatotoxicity is only 0.001% (two of 202,497 treated patients).98 Hepatotoxicity is associated with chronic overdose, increasing age, comorbid conditions such as malnutrition, and combinations of antituberculous drugs that may serve as cytochrome inducers. Overt hepatic failure often occurs if INH therapy is continued after the onset of hepatocellular injury in both adults and children.35,36,50,74,110,129 The incidence of hepatitis is two to four times higher in pregnant women than in nonpregnant women.41
Isoniazid induced hepatitis can arise via two pathways.35,132 The first involves an immunologic mechanism resulting in hepatic injury that is thought to be idiopathic.103,125 The association of hepatitis with lupus erythematosus, hemolytic anemia, thrombocytopenia, arthritis, vasculitis, and polyserositis supports an immunologic process.102,125 However, symptoms commonly found in autoimmune disorders such as fever, rash, and eosinophilia are usually absent with drug induced lupus erythematosus, and rechallenge with INH often fails to provoke recurrence of hepatocellular injury.35,102,132 The second, more common mechanism involves direct hepatic injury by INH or its metabolites. The metabolites believed responsible for hepatic injury are acetylhydrazine and hydrazine (Fig. 58–2).44,81,120
Peripheral neuropathy and optic neuritis are known adverse drug effects of chronic INH use. Neurotoxicity is probably caused by pyridoxine deficiency aggravated by the formation of pyridoxine-INH hydrazones.37 Peripheral neuropathy, the most common complication of INH therapy, presents in a stocking-glove distribution that progresses proximally. Although primarily sensory in nature, myalgias and weakness may occur.111 Peripheral neuropathy is generally observed in severely malnourished, alcoholic, uremic, or diabetic patients; it is also associated with slow acetylator status, an effect that leads to increased INH concentrations and, consequently, increased pyridoxine depletion.46 Optic neuritis may occur with INH therapy, usually concurrent with other medications such as ethambutol or etanercept, and presents as decreased visual acuity, eye pain, and dyschromatopsia; visual field testing may reveal central scotomata and bitemporal hemianopsia.47,57,64 INH is also associated with such findings of CNS toxicity as ataxia, psychosis, hallucinations, and coma.1,9,45,97
Acute INH toxicity is a clinical diagnosis that may be inferred by history and confirmed by measuring serum INH concentrations.105 Acute toxicity from INH is defined as a serum INH concentration greater than 10 mg/L one hour after ingestion, greater than 3.2 mg/L 2 hours after ingestion, or greater than 0.2 mg/L six hours after the ingestion.84 Because serum INH concentration measurements are not widely available, clinicians cannot rely on serum concentrations to confirm the diagnosis or initiate therapy. Because of the risk of hepatitis associated with chronic INH use, hepatic aminotransferases should be regularly monitored after therapy is started. In critically ill patients, serum should be assessed for acidemia, kidney function, creatine phosphokinase (CPK), and urine myoglobin indicating rhabdomyolysis and possible kidney failure.
The antidote for INH induced neurologic dysfunction is pyridoxine (Antidotes in Depth: A14). Pyridoxine rapidly terminates seizures, corrects metabolic acidosis, and reverses coma. The efficacy of pyridoxine is correlated with the administered dose; one study identified recurrent seizures in 60% of patients who received no pyridoxine and in 47% of those who received 10% of the ideal pyridoxine dose, and no seizures in patients who received the full dose of pyridoxine.124 To treat acute toxicity, the pyridoxine dose in grams should equal the amount of INH ingested in grams, with a first dose of up to 5 g intravenously in adults. Unknown quantities of ingested INH warrant initial empiric treatment with a pyridoxine dose of no more than 5 g (pediatric dose,: 70 mg/kg to a maximum of 5 g). Pyridoxine should be administered at a rate of 1 g every 2 to 3 minutes. Seizures that persist beyond administration of the initial dose should receive an additional similar dose of pyridoxine.6
Hospital pharmacies may stock insufficient quantities of intravenous (IV) pyridoxine to treat even a single patient with a large INH ingestion.101 In the event that IV formulations are unavailable in sufficient quantities, pyridoxine tablets may be crushed and administered with fluids via a nasogastric tube.101
Conventional anticonvulsants, although generally used as first line therapy, demonstrate variable effectiveness in terminating INH induced seizures. Benzodiazepines may be used to potentiate the antidotal efficacy of pyridoxine, particularly if optimal doses of the antidote are unavailable. The benzodiazepines act synergistically with pyridoxine, as well as possessing inherent GABA agonist activity, but they may be ineffective as the sole treatment of acute INH poisoning because of their reliance on GABA to exert their activity.26,27,57,124 Phenytoin has no intrinsic GABAergic effect and is not recommended as therapy for patients with INH-induced seizures.57,84,96 Barbiturates that have potent GABA agonist activity are expected to be as effective as the benzodiazepines, although the risk of respiratory depression is greater with this class of anticonvulsant. The efficacy of propofol in terminating INH induced seizures has not been evaluated in humans.
Although hemodialysis has been used to enhance elimination of INH in acute overdose, with clearance rates reported as high as 120 mL/min, hemodialysis is rarely indicated for initial management unless associated with kidney failure.19,125
Asymptomatic patients who present to the emergency department within 2 hours of ingestion of toxic amounts of INH should receive prophylactic administration of 5 g of oral or IV pyridoxine. This recommendation is based on the observation that INH reaches its peak serum concentration within 2 hours of ingestion of therapeutic doses. Asymptomatic patients may be observed for a 6 hour period for signs of toxicity. Acute toxicity is unlikely to manifest more than 6 hours beyond ingestion.
Gastrointestinal (GI) decontamination should be performed by administering activated charcoal only in patients who are awake and able to comply with therapy.109 Late GI decontamination with activated charcoal will probably be ineffective in preventing toxicity because delayed absorption has not been observed.104 Orogastric lavage is relatively contraindicated unless the patient is intubated because of the risk of seizures.
Hepatitis (defined as aminotransferase concentrations more than two to three times baseline) resulting from therapeutic INH administration mandates termination of therapy; malnourished patients may require nutritional support. After resolution of liver injury, INH may be restarted, provided aminotransferase concentrations are closely monitored, with reassessment in six weeks or any time the patient experiences nausea, vomiting, or abdominal discomfort.35,110 Pyridoxine does not reverse hepatic injury; consequently, surveillance for and recognition of hepatocellular injury remains essential. Cases of hepatitis refractory to medical therapy may require liver transplantation.38,54,129
Isoniazid produces an axonopathy caused by pyridoxine depletion and manifests as peripheral neuropathies, cerebellar findings, and psychosis. Neurotoxicity is commonly treated with as much as 50 mg/d of oral pyridoxine, although doses as low as 6 mg/d appear to be effective.1,9,97,114 Because of its effectiveness in preventing neurologic toxicity, pyridoxine is often used concurrently with INH therapy.