CHAPTER 2-88: ISONIAZID (INH)

INTRODUCTION

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

MECHANISM OF TOXICITY

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%. 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.

   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 (see also Table II–66).

TOXIC DOSE

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.

CLINICAL PRESENTATION

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 ...