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Emergency And Acute Medicine – Isoniazid Poisoning
Basics Description
Isoniazid (INH) toxicity results from interference with pyridoxine (vitamin B6) metabolism. INH complexes with and inactivates pyridoxal-5-phosphate, the active form of pyridoxine, and inhibits pyridoxine phosphokinase, preventing conversion to its active form. This leads to a net decrease in γ-aminobutyric acid (GABA) production, causing cerebral excitability and seizures. INH also inhibits lactate dehydrogenase, impairing conversion of lactate to pyruvate and contributing to profound anion gap metabolic acidosis. Free effects include mitochondrial dysfunction and impaired oxidative metabolism.
Chronic toxicity interferes with nicotinic acid (niacin) synthesis and may produce a pellagra-like syndrome after months of therapy. INH has some monoamine oxidase inhibitor–like effects, with rare reports of tyramine reactions, mania, depression, obsessive–compulsive symptoms, and psychosis. Pharmacokinetically, INH is rapidly absorbed with peak levels within 1–2 hours. It has a volume of distribution of 0.6 L/kg, low protein binding, hepatic acetylation, and renal excretion within 24 hours. Half-life is less than 1 hour in fast acetylators and 2–4 hours in slow acetylators.
Etiology
High-risk populations include immigrants, individuals experiencing homelessness, people with HIV infection, alcohol use disorder, and those of lower socioeconomic status. Slow acetylators are more prone to chronic toxicity. The estimated LD50 is 80–150 mg/kg. Ingestions less than 1.5 g typically cause mild toxicity, while ingestions of 10 g or more are often fatal.
Diagnosis: Signs and Symptoms
Acute toxicity primarily affects the nervous system and presents with altered mental status, seizures refractory to standard therapy, agitation, coma, dizziness, ataxia, hyperreflexia, slurred speech, hallucinations, and psychosis. Gastrointestinal symptoms include nausea and vomiting. Renal findings may include oliguria or anuria. Cardiovascular manifestations include hypotension, tachycardia, shock, and cyanosis. Metabolically, patients develop profound anion gap metabolic acidosis with elevated lactate and may be hyperthermic.
Chronic toxicity presents with peripheral neuropathy, optic neuritis or atrophy, insomnia, vertigo, psychosis, and features of pellagra. Hepatic involvement may include hepatitis or liver failure, along with anorexia, nausea, vomiting, and constipation.
Essential Workup
In the absence of a clear ingestion history, evaluation should focus on unexplained altered mental status, seizures, and metabolic acidosis.
Diagnosis Tests and Interpretation
Laboratory evaluation typically reveals severe metabolic acidosis on arterial blood gas. Serum chemistries show elevated anion gap acidosis and possible hyperglycemia. CBC may show leukocytosis and eosinophilia in acute toxicity, or agranulocytosis, hemolysis, anemia, and eosinophilia in chronic toxicity. Chest radiography may show evidence of tuberculosis or aspiration pneumonia. CT imaging or lumbar puncture may be required if the history is unclear.
Differential Diagnosis
The differential includes other toxicologic causes such as tricyclic antidepressants, salicylates, theophylline, methanol, ethylene glycol, lithium, carbon monoxide, and cyanide. Non-toxicologic causes include stroke, intracranial hemorrhage or mass, trauma, abscess, hypoglycemia, uremia, and thyrotoxicosis.
Treatment Prehospital
All prescription bottles and medications should be collected and transported with the patient for identification.
Initial Stabilization and Therapy
Initial management prioritizes airway, breathing, and circulation. Supplemental oxygen should be provided, and intubation performed if airway protection is required. Establish IV access, initiate cardiac monitoring, and administer isotonic fluids. For altered mental status, give naloxone, thiamine, and dextrose as indicated.
ED Treatment and Procedures
Pyridoxine (vitamin B6) is the specific antidote for INH toxicity. The goal dose is 1 g of pyridoxine for each gram of INH ingested, administered IV in divided doses every 2–3 minutes. If the amount ingested is unknown, give 5 g IV. Doses may be repeated after 20 minutes for refractory seizures or persistent coma. If IV pyridoxine is unavailable, tablets may be crushed and administered via nasogastric tube.
Seizure control relies on pyridoxine replacement; benzodiazepines are synergistic and should be used as needed. Phenytoin is ineffective and should not be used. After stabilization, gastric decontamination may be considered in life-threatening ingestions presenting within one hour, provided the airway is protected. Activated charcoal may be given at a 10:1 charcoal-to-drug ratio. Hemodialysis is reserved for persistent symptoms despite adequate therapy or in patients with renal insufficiency. Metabolic acidosis usually resolves after seizure control and does not routinely require bicarbonate therapy.
Medication
Supportive medications may include IV dextrose, benzodiazepines such as diazepam or lorazepam for seizures, naloxone if indicated, pyridoxine as the antidote, and thiamine.
Follow-Up Disposition
ICU admission is required for refractory seizures, severe acidosis, coma, or persistent altered mental status. Patients with unclear ingestion history, uncontrolled vomiting, or intentional overdose also require admission and toxicology consultation. Asymptomatic patients may be discharged after at least 6 hours of observation, as symptoms typically develop within 45 minutes to 2 hours.
Follow-Up Recommendations
Psychiatric evaluation is recommended for all intentional ingestions or suicidal patients.
Pearls and Pitfalls
Refractory seizures unresponsive to standard therapy are a key clue to INH poisoning. Severe lactic acidosis in a patient with seizures and altered mental status should raise suspicion for INH toxicity. Pyridoxine dosing should be gram-for-gram relative to INH ingestion, and additional doses may be given if seizures resolve but coma persists. Never paralyze an actively seizing patient without continuous EEG monitoring.
Basics Description
Isoniazid (INH) toxicity results from interference with pyridoxine (vitamin B6) metabolism. INH complexes with and inactivates pyridoxal-5-phosphate, the active form of pyridoxine, and inhibits pyridoxine phosphokinase, preventing conversion to its active form. This leads to a net decrease in γ-aminobutyric acid (GABA) production, causing cerebral excitability and seizures. INH also inhibits lactate dehydrogenase, impairing conversion of lactate to pyruvate and contributing to profound anion gap metabolic acidosis. Free effects include mitochondrial dysfunction and impaired oxidative metabolism.
Chronic toxicity interferes with nicotinic acid (niacin) synthesis and may produce a pellagra-like syndrome after months of therapy. INH has some monoamine oxidase inhibitor–like effects, with rare reports of tyramine reactions, mania, depression, obsessive–compulsive symptoms, and psychosis. Pharmacokinetically, INH is rapidly absorbed with peak levels within 1–2 hours. It has a volume of distribution of 0.6 L/kg, low protein binding, hepatic acetylation, and renal excretion within 24 hours. Half-life is less than 1 hour in fast acetylators and 2–4 hours in slow acetylators.
Etiology
High-risk populations include immigrants, individuals experiencing homelessness, people with HIV infection, alcohol use disorder, and those of lower socioeconomic status. Slow acetylators are more prone to chronic toxicity. The estimated LD50 is 80–150 mg/kg. Ingestions less than 1.5 g typically cause mild toxicity, while ingestions of 10 g or more are often fatal.
Diagnosis: Signs and Symptoms
Acute toxicity primarily affects the nervous system and presents with altered mental status, seizures refractory to standard therapy, agitation, coma, dizziness, ataxia, hyperreflexia, slurred speech, hallucinations, and psychosis. Gastrointestinal symptoms include nausea and vomiting. Renal findings may include oliguria or anuria. Cardiovascular manifestations include hypotension, tachycardia, shock, and cyanosis. Metabolically, patients develop profound anion gap metabolic acidosis with elevated lactate and may be hyperthermic.
Chronic toxicity presents with peripheral neuropathy, optic neuritis or atrophy, insomnia, vertigo, psychosis, and features of pellagra. Hepatic involvement may include hepatitis or liver failure, along with anorexia, nausea, vomiting, and constipation.
Essential Workup
In the absence of a clear ingestion history, evaluation should focus on unexplained altered mental status, seizures, and metabolic acidosis.
Diagnosis Tests and Interpretation
Laboratory evaluation typically reveals severe metabolic acidosis on arterial blood gas. Serum chemistries show elevated anion gap acidosis and possible hyperglycemia. CBC may show leukocytosis and eosinophilia in acute toxicity, or agranulocytosis, hemolysis, anemia, and eosinophilia in chronic toxicity. Chest radiography may show evidence of tuberculosis or aspiration pneumonia. CT imaging or lumbar puncture may be required if the history is unclear.
Differential Diagnosis
The differential includes other toxicologic causes such as tricyclic antidepressants, salicylates, theophylline, methanol, ethylene glycol, lithium, carbon monoxide, and cyanide. Non-toxicologic causes include stroke, intracranial hemorrhage or mass, trauma, abscess, hypoglycemia, uremia, and thyrotoxicosis.
Treatment Prehospital
All prescription bottles and medications should be collected and transported with the patient for identification.
Initial Stabilization and Therapy
Initial management prioritizes airway, breathing, and circulation. Supplemental oxygen should be provided, and intubation performed if airway protection is required. Establish IV access, initiate cardiac monitoring, and administer isotonic fluids. For altered mental status, give naloxone, thiamine, and dextrose as indicated.
ED Treatment and Procedures
Pyridoxine (vitamin B6) is the specific antidote for INH toxicity. The goal dose is 1 g of pyridoxine for each gram of INH ingested, administered IV in divided doses every 2–3 minutes. If the amount ingested is unknown, give 5 g IV. Doses may be repeated after 20 minutes for refractory seizures or persistent coma. If IV pyridoxine is unavailable, tablets may be crushed and administered via nasogastric tube.
Seizure control relies on pyridoxine replacement; benzodiazepines are synergistic and should be used as needed. Phenytoin is ineffective and should not be used. After stabilization, gastric decontamination may be considered in life-threatening ingestions presenting within one hour, provided the airway is protected. Activated charcoal may be given at a 10:1 charcoal-to-drug ratio. Hemodialysis is reserved for persistent symptoms despite adequate therapy or in patients with renal insufficiency. Metabolic acidosis usually resolves after seizure control and does not routinely require bicarbonate therapy.
Medication
Supportive medications may include IV dextrose, benzodiazepines such as diazepam or lorazepam for seizures, naloxone if indicated, pyridoxine as the antidote, and thiamine.
Follow-Up Disposition
ICU admission is required for refractory seizures, severe acidosis, coma, or persistent altered mental status. Patients with unclear ingestion history, uncontrolled vomiting, or intentional overdose also require admission and toxicology consultation. Asymptomatic patients may be discharged after at least 6 hours of observation, as symptoms typically develop within 45 minutes to 2 hours.
Follow-Up Recommendations
Psychiatric evaluation is recommended for all intentional ingestions or suicidal patients.
Pearls and Pitfalls
Refractory seizures unresponsive to standard therapy are a key clue to INH poisoning. Severe lactic acidosis in a patient with seizures and altered mental status should raise suspicion for INH toxicity. Pyridoxine dosing should be gram-for-gram relative to INH ingestion, and additional doses may be given if seizures resolve but coma persists. Never paralyze an actively seizing patient without continuous EEG monitoring.
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