Isoniazid (INH), a hydrazide derivative of isonicotinic acid, is an inexpensive and effective treatment for tuberculosis. Acute INH overdose is a well-known cause of drug-induced seizures and metabolic acidosis. INH can cause hepatitis and peripheral neuropathy with chronic use.

1. Acute overdose. In the central nervous system, GABA is the predominant inhibitory neurotransmitter. Pyridoxal 5'-phosphate (the active form of vitamin B₆) is a necessary coenzyme in the synthesis of GABA. Isoniazid depletes vitamin B₆ by inhibiting pyridoxine phosphokinase, the enzyme that converts pyridoxine to its active form, pyridoxal 5'-phosphate. Isoniazid also reacts with pyridoxal 5'-phosphate to form an inactive complex that is renally excreted. This functional deficiency of pyridoxine in turn impairs the synthesis of GABA and increases susceptibility to seizures. INH may also inhibit the hepatic conversion of lactate to pyruvate, exacerbating the lactic acidosis resulting from seizures.
2. Chronic toxicity. The overall incidence of adverse effects from chronic INH use is approximately 5%.
   1. Peripheral neuropathy and optic neuritis are thought to be caused by pyridoxine deficiency. Peripheral neuropathy is the most common complication of chronic INH therapy and is more commonly seen in patients with comorbidities such as malnutrition, alcoholism, diabetes, and uremia. It presents in a stocking-glove distribution that progresses proximally. INH has also been associated with other CNS findings such as hallucinations, ataxia, psychosis, and coma.
   2. The most serious adverse effect of INH is hepatocellular necrosis. The mechanism of INH-induced hepatitis involves two pathways: an autoimmune mechanism that is thought to be idiopathic, and more commonly, direct hepatic injury by INH and its metabolites. Asymptomatic elevation of aminotransferases is common in the first few months of treatment.
3. Pharmacokinetics. Peak absorption occurs in 1-2 hours. The volume of distribution is 0.6-0.7 L/kg, with insignificant protein binding. INH is metabolized via the cytochrome P450 system, with 75-95% of metabolites renally eliminated. The half-life is 0.5-1.6 hours in fast acetylators and 2-5 hours in slow acetylators.

1. Acute ingestion of as little as 15-40 mg/kg can produce toxicity. Doses larger than this often cause seizures. Ingestion of 80-150 mg/kg is associated with increased mortality.
2. With chronic use, 10-20% of patients will develop hepatic toxicity when the dose is 10 mg/kg/d, but fewer than 2% will develop this toxicity if the dose is 3-5 mg/kg/d. Older persons are more susceptible to chronic toxicity.

1. After acute overdose, nausea, vomiting, slurred speech, ataxia, depressed sensorium, coma, respiratory depression, and seizures may occur rapidly (usually within 30-120 minutes). Profound anion gap metabolic acidosis (pH, 6.8-6.9) often occurs after only one or two seizures and is likely the result of lactic acidosis due to seizure activity. The lactate usually clears slowly, even after the seizure activity is controlled. Liver injury may occur after an acute overdose and may be delayed up to several days. Hemolysis may occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Rhabdomyolysis can be a complication of recurrent seizures. Coma may occur, which can last for 24-36 hours even after the resolution of seizures and acidemia. Patients with underlying seizure disorders are predisposed to seizures at lower doses.
2. Chronic therapeutic INH use may cause peripheral neuritis, hepatitis, hypersensitivity reactions including drug-induced lupus erythematosus, and pyridoxine deficiency. Hepatitis (aminotransferase concentrations greater than 2-3 times baseline) mandates temporary termination of therapy; however, INH may be restarted with close monitoring.

Is usually made by history and clinical presentation. INH toxicity should be considered in any patient with acute-onset seizures, especially if they are unresponsive to routine anticonvulsant medications and accompanied by profound metabolic acidosis.

1. Specific levels. INH usually is not detected in routine toxicology screening. Specific levels may be obtained but are rarely available or helpful for the management of acute overdoses.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, creatine kinase (CK), and arterial blood gases. In chronic INH use, hepatic aminotransferases should be regularly monitored.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat coma, seizures, and metabolic acidosis (p 36) if they occur. Administer diazepam, 0.1-0.2 mg/kg IV, for treatment of seizures.
2. Specific drugs and antidotes.
   1. Pyridoxine (vitamin B6) terminates INH associated seizures, metabolic acidosis, and reverses coma. If the amount of INH ingested is unknown, administer 5 g IV. If the amount is known, administer an equivalent amount of pyridoxine (in grams) to the ingested amount of INH (in grams). Persistent seizures may require repeat dosing. Many hospitals have insufficient supplies of pyridoxine required to treat a single large ingestion. Pyridoxine tablets may be crushed and administered with fluids via a nasogastric tube if the IV formulation is not available in sufficient quantities.
   2. Benzodiazepines should also be given with pyridoxine, as they may have a synergistic effect in terminating seizures. If no pyridoxine is available, high-dose diazepam (0.3-0.4 mg/kg) may be effective for status epilepticus. Barbiturates may also be effective in terminating seizures, but have a greater risk of causing respiratory depression.
   3. Note: Pyridoxine does not reverse hepatic injury in chronic INH use. However, it is effective in both prevention and treatment of chronic neurologic toxicity.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Consider gastric lavage for massive ingestions.
4. Enhanced elimination. Forced diuresis and hemodialysis have been reported to be successful but are unnecessary for most cases because the half-life of INH is relatively short and toxicity can usually be managed with pyridoxine and benzodiazepines. Symptoms generally resolve over a course of 8-24 hours.