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Emergency and Acute Medicine – Isoniazid poisoning
Isoniazid (INH) poisoning results from disruption of normal vitamin B6–dependent neurotransmitter metabolism. INH complexes with and inactivates pyridoxal-5-phosphate, the active form of pyridoxine, and inhibits pyridoxine phosphokinase, preventing conversion of pyridoxine to its active form. This leads to decreased production of γ-aminobutyric acid (GABA), causing cerebral excitability and refractory seizures. INH also inhibits lactate dehydrogenase, impairing conversion of lactate to pyruvate and contributing to profound anion gap metabolic acidosis. Chronic toxicity interferes with niacin synthesis and may cause a pellagra-like syndrome after months of therapy. Rare neuropsychiatric effects include mania, depression, obsessive–compulsive symptoms, and psychosis. INH is rapidly absorbed, with peak levels in 1–2 hours, has low protein binding, and is renally excreted after hepatic acetylation. Toxicity is more severe in slow acetylators.
High-risk populations include immigrants, homeless individuals, patients with HIV, alcohol use disorder, and those of lower socioeconomic status. Slow acetylators are more prone to chronic toxicity. Ingestions less than 1.5 g usually cause mild toxicity, whereas ingestions of 10 g or more are often fatal.
Acute toxicity typically presents with neurologic findings, most notably seizures that are refractory to standard anticonvulsant therapy, along with altered mental status, agitation, coma, ataxia, hyperreflexia, hallucinations, and psychosis. Gastrointestinal symptoms include nausea and vomiting. Cardiovascular manifestations include hypotension, tachycardia, shock, and cyanosis. Metabolic findings are dominated by severe anion gap metabolic acidosis with elevated lactate and hyperthermia. Chronic toxicity presents with peripheral neuropathy, optic neuritis or atrophy, vertigo, psychosis, insomnia, and gastrointestinal or hepatic injury including hepatitis and liver failure.
Initial evaluation should focus on any patient with unexplained refractory seizures, altered mental status, or severe metabolic acidosis. Laboratory studies typically show profound metabolic acidosis on arterial blood gas, elevated anion gap, hyperglycemia, and leukocytosis in acute toxicity. Chronic toxicity may show agranulocytosis, anemia, hemolysis, and eosinophilia. Imaging is guided by clinical presentation, with chest radiography sometimes suggesting underlying tuberculosis and helping evaluate aspiration.
Management begins with airway, breathing, and circulation stabilization, supplemental oxygen, IV access, cardiac monitoring, and bedside glucose assessment. The specific antidote is pyridoxine (vitamin B6). The recommended dose is 1 g of pyridoxine for every gram of INH ingested; if the amount ingested is unknown, administer 5 g IV. Pyridoxine may be repeated if seizures or coma persist. If IV pyridoxine is unavailable, crushed tablets may be given via nasogastric tube. Benzodiazepines are used adjunctively for seizure control, but phenytoin is ineffective. Gastric decontamination with activated charcoal may be considered after stabilization, and gastric lavage is reserved for life-threatening ingestions presenting within one hour with a protected airway. Hemodialysis may be considered for persistent symptoms or renal failure. Acidosis generally resolves once seizures are controlled and does not usually require aggressive bicarbonate therapy.
Patients with refractory seizures, severe acidosis, coma, or unclear ingestion history require ICU admission. Asymptomatic patients may be discharged after a minimum of six hours of observation. Psychiatric evaluation is required for intentional ingestions.
Key pitfalls include failure to recognize INH poisoning in patients with seizures refractory to standard therapy and severe lactic acidosis. Pyridoxine should be given gram for gram relative to the suspected ingestion, and additional doses may be required if coma persists. Never paralyze a seizing patient without continuous EEG monitoring.
Isoniazid (INH) poisoning results from disruption of normal vitamin B6–dependent neurotransmitter metabolism. INH complexes with and inactivates pyridoxal-5-phosphate, the active form of pyridoxine, and inhibits pyridoxine phosphokinase, preventing conversion of pyridoxine to its active form. This leads to decreased production of γ-aminobutyric acid (GABA), causing cerebral excitability and refractory seizures. INH also inhibits lactate dehydrogenase, impairing conversion of lactate to pyruvate and contributing to profound anion gap metabolic acidosis. Chronic toxicity interferes with niacin synthesis and may cause a pellagra-like syndrome after months of therapy. Rare neuropsychiatric effects include mania, depression, obsessive–compulsive symptoms, and psychosis. INH is rapidly absorbed, with peak levels in 1–2 hours, has low protein binding, and is renally excreted after hepatic acetylation. Toxicity is more severe in slow acetylators.
High-risk populations include immigrants, homeless individuals, patients with HIV, alcohol use disorder, and those of lower socioeconomic status. Slow acetylators are more prone to chronic toxicity. Ingestions less than 1.5 g usually cause mild toxicity, whereas ingestions of 10 g or more are often fatal.
Acute toxicity typically presents with neurologic findings, most notably seizures that are refractory to standard anticonvulsant therapy, along with altered mental status, agitation, coma, ataxia, hyperreflexia, hallucinations, and psychosis. Gastrointestinal symptoms include nausea and vomiting. Cardiovascular manifestations include hypotension, tachycardia, shock, and cyanosis. Metabolic findings are dominated by severe anion gap metabolic acidosis with elevated lactate and hyperthermia. Chronic toxicity presents with peripheral neuropathy, optic neuritis or atrophy, vertigo, psychosis, insomnia, and gastrointestinal or hepatic injury including hepatitis and liver failure.
Initial evaluation should focus on any patient with unexplained refractory seizures, altered mental status, or severe metabolic acidosis. Laboratory studies typically show profound metabolic acidosis on arterial blood gas, elevated anion gap, hyperglycemia, and leukocytosis in acute toxicity. Chronic toxicity may show agranulocytosis, anemia, hemolysis, and eosinophilia. Imaging is guided by clinical presentation, with chest radiography sometimes suggesting underlying tuberculosis and helping evaluate aspiration.
Management begins with airway, breathing, and circulation stabilization, supplemental oxygen, IV access, cardiac monitoring, and bedside glucose assessment. The specific antidote is pyridoxine (vitamin B6). The recommended dose is 1 g of pyridoxine for every gram of INH ingested; if the amount ingested is unknown, administer 5 g IV. Pyridoxine may be repeated if seizures or coma persist. If IV pyridoxine is unavailable, crushed tablets may be given via nasogastric tube. Benzodiazepines are used adjunctively for seizure control, but phenytoin is ineffective. Gastric decontamination with activated charcoal may be considered after stabilization, and gastric lavage is reserved for life-threatening ingestions presenting within one hour with a protected airway. Hemodialysis may be considered for persistent symptoms or renal failure. Acidosis generally resolves once seizures are controlled and does not usually require aggressive bicarbonate therapy.
Patients with refractory seizures, severe acidosis, coma, or unclear ingestion history require ICU admission. Asymptomatic patients may be discharged after a minimum of six hours of observation. Psychiatric evaluation is required for intentional ingestions.
Key pitfalls include failure to recognize INH poisoning in patients with seizures refractory to standard therapy and severe lactic acidosis. Pyridoxine should be given gram for gram relative to the suspected ingestion, and additional doses may be required if coma persists. Never paralyze a seizing patient without continuous EEG monitoring.
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