- USES: Isoniazid is an agent used for the treatment of mycobacterium species infection including M. tuberculosis. PHARMACOLOGY: Isoniazid interferes with enzymes that help produce mycobacterial cell walls. TOXICOLOGY: Isoniazid causes a functional deficiency of pyridoxine by increasing its elimination and decreasing its conversion to the active form. The resulting deficiency of pyridoxine leads to decrease in GABA formation. EPIDEMIOLOGY: Uncommon exposure which can result in significant morbidity and death. MILD TO MODERATE TOXICITY: Vomiting, slurred speech, dizziness, and tachycardia. These signs may represent early signs of toxicity which may then progress, rather than mild toxicity. SEVERE TOXICITY: Seizures, which are classically intractable to traditional treatment, severe lactic acidosis, coma, hyperthermia, rhabdomyolysis, renal failure, and hypotension may occur. Elevations in hepatic enzymes to fulminant hepatic failure (rare) have developed in overdose. Persisting dementia has also been reported following acute overdose. ADVERSE EFFECTS: Peripheral neuropathy is the most common side effect of isoniazid and is often preceded by paresthesias of the hands and feet. The side effects appear to be dose-related and occur more in the malnourished, patients with risk factors for neuritis (eg, alcoholism, diabetes), and in patients who are slow-inactivators. Other neurotoxic effects (uncommon) include seizures, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis. Isoniazid can cause an idiosyncratic hepatitis with therapeutic use. Toxicity can range from mild asymptomatic elevation of transaminases to fulminant hepatic failure. The following adverse effects have also been reported following therapeutic use of isoniazid: Nausea, vomiting, epigastric distress, pancreatitis, agranulocytosis, hemolytic, sideroblastic, or aplastic anemia, thrombocytopenia, eosinophilia, hypersensitivity reactions, fever, rash, anaphylactic reactions, lymphadenopathy, vasculitis, pyridoxine deficiency, pellagra, hyperglycemia or hypoglycemia, metabolic acidosis, gynecomastia, rheumatic syndrome, and systemic lupus erythematosus-like syndrome.
Range of Toxicity:
- TOXICITY: Doses of 20 to 40 mg/kg have resulted in seizures. Doses of 80 to 150 mg/kg will produce seizures and may cause death. Acute ingestion of 2 to 3 grams in an adult is potentially toxic while 10 to 15 grams is frequently associated with death if untreated. THERAPEUTIC: ADULTS: The normal therapeutic dose of INH is 5 mg/kg/day to a maximum of 300 mg/day OR 15 mg/kg orally 2-3 times a week (maximum 900 mg/day). PEDIATRICS: 10 to 15 mg/kg orally once daily (maximum 300 mg/day) OR 20 to 40 mg/kg orally 2-3 times a week (maximum 900 mg/day) in combination with other antitubercular agents.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Adult patients who present within 2 hours after a large ingestion should be given a prophylactic dose of pyridoxine. Intravenous access should be established and the patient should be placed in a resuscitation-ready room. Seizures may be the presenting sign of ingestion and represent a more severe poisoning. MANAGEMENT OF SEVERE TOXICITY: Intractable seizures are the hallmark of severe isoniazid ingestions. Following adequate airway, respiratory, and circulatory support, primary treatment is aimed at terminating seizure activity. The patient should receive intravenous pyridoxine on a gram for gram basis of isoniazid ingested or 5 grams empirically for unknown doses. Standard anticonvulsant therapy is likely to be of marginal benefit as sole treatment, but benzodiazepines or barbiturates may act synergistically with pyridoxine and should be administered as well. Sodium bicarbonate can be administered for severe metabolic acidosis. Coma should be treated with standard supportive care. Administration of pyridoxine may reverse isoniazid-induced coma. Initially treat hypotension with 0.9% NaCl at 10 to 20 mL/kg. If necessary, add dopamine or norepinephrine.
- Decontamination: PREHOSPITAL: Because of the risk of seizures and aspiration, prehospital decontamination should generally be avoided. HOSPITAL: Activated charcoal and orogastric lavage should be used with caution because of the risk of seizures and subsequent risk of pulmonary aspiration. They should only be used in patients who present soon after an ingestion and who have adequate airway protection.
- Airway management: Patients who are comatose or with altered mental status generally need tracheal intubation and mechanical respiratory support.
- Antidote: Pyridoxine can be used to reverse the isoniazid-induced pyridoxine deficiency, which can terminate seizures and may be helpful in reversing isoniazid-induced coma. Treatment is on a gram-for-gram basis for the amount of isoniazid ingested, up to a maximum of 5 grams, or an empiric dose of 5 grams for an unknown ingestion in an adult. The pediatric dose is 70 mg/kg. The exact dosing regimen has not been established. For patients actively seizing, pyridoxine can be given at a rate of 0.5 g/min until the seizures stop or 5 g has given. The remainder can then be given over 1 to 4 hours. If seizures persist after the first dose, a second dose should be given. Oral pyridoxine can be administered via nasogastric tube if intravenous supplies are exhausted, but there is no data demonstrating the utility of oral pyridoxine for severe isoniazid toxicity. Benzodiazepines and/or barbiturate should also be administered to patients with seizures secondary to isoniazid overdose.
- Monitoring of patient: Isoniazid blood concentrations may be measured but are not clinically helpful in an acute setting. Monitor serum electrolytes, serum lactate, and venous or arterial blood gases. In patients with seizure, monitor renal function. Monitor CBC and liver enzymes in symptomatic patients. Monitor creatinine kinase if seizures are prolonged. An EEG may be necessary to rule out status epilepticus.
- Enhanced elimination procedure: Hemodialysis can eliminate isoniazid but is rarely indicated.
- Patient disposition: HOME MANAGEMENT: Patients who intentionally ingest isoniazid should be referred to a health care facility. Asymptomatic unintentional ingestions of less than 20 mg/kg can be watched at home. OBSERVATION CRITERIA: If patients are asymptomatic after 6 hours, they can be discharged after appropriate psychiatric clearance. ADMISSION CRITERIA: Patients with persistently altered mental status, abnormal vital signs, or seizures should be admitted. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.