Isoniazid toxicity

Background

• Isoniazid (INH) used for latent and active TB treatment

Toxicology

• Isoniazid’s metabolites restrict the conversion of pyridoxine to pyrodoxal-5’-phosphate and binds to pyridoxine, facilitating its excretion in the urine
• Loss of pyridoxine leads to decreased GABA synthesis due to the decreased function of glutamic acid decarboxylase (GAD)
• Anion gap acidosis likely results from lactic acid buildup as a consequence of persistent seizure activity
• Finally come due to decreased catecholamine synthesis secondary to pyridoxine depletion

Toxic Dose

• 2-3g ingested can lead to symptoms, 10-15g can lead to death

Pharmacology

• Absorbed via GI tract (small intestine), peak concentrations at 1-2 hours after ingestion
• Volume of Distribution: 0.6L/kg

Metabolism

• Clearance of 46mL/min, metabolized by acetylation.
  • T_1/2 for fast acetylators = 70 minutes
  • T_1/2 for slow acetylators = 3 hours

Excretion

• Via kidneys with levels successfully measured in urine

Clinical Features

Signs and Symptoms

• Seizure
• Metabolic Acidosis
• Coma
• Signs and symptoms can appear 30 minutes after ingestion, with more severe symptoms including persistent seizures, metabolic acidosis, and coma

• Hepatotoxicity
  • Most common side effect and more frequent with slow acetylators, the elderly, and those with preexisting liver disease
  • Approximately 20% of patients on isoniazid therapy can have elevated liver enzymes
  • Treatment is stopped when levels reach three times the upper limit of normal with symptoms or five times the limit of normal without

Evaluation

• Seizures refractory to conventional treatment are hallmarks of isoniazid toxicity
• Clinical history is extremely important in evaluating for isoniazid toxicity (i.e. dosing history, duration of treatment, estimated dose taken)
• Elevated anion-gap metabolic acidosis with elevated lactate in the appropriate clinical setting AND refractory seizures should raise suspicion
• INH levels can be measured but results may not immediately be available

Management

• Focus on aggressive supportive care and hemodynamic stabilization with early pyridoxine administration
• Pyridoxine does not reverse hepatic injury that can result from chronic toxicity.

Activated Charcoal

• If ingestion occurred within an hour of presentation, activated charcoal with cathartics may be necessary to restrict absorption and to facilitate excretion via the GI tract

Benzos

• May not be effective but will activate the GABA receptors and halt seizure activity

Pyridoxine

• Known INH quantity ingested - treat with with a 1:1 ingested isoniazid:administered pyridoxine dose ratio
• Unknown INH quantity ingested - treat with empiric 5g of pyridoxine
• Children - start 70mg/kg (max 5 gm)

• IV infusion rate is 1 g/min until the seizures stop or the maximum dose is reached. Remainder of dose infused over 4 to 6 hours
• Pyridoxine administration may temporarily worsen the metabolic acidosis
• If seizures persist repeat dosing is encouraged based on initial dosing.
• Oral tablets may be only form of pyridoxine available at many hospitals. The tablets can be crushed and administered with fluids via a nasogastric tube while arranging for transfer.

Hemodialysis

• Can clear lactate and isoniazid from the bloodstream effectively and can be used as a final measure to increase clearance if needed.

Disposition

• Patient will likely require admission and potentially ICU care for continued monitoring and evaluation
• If the patient has active TB also keep in respiratory isolation

Medication Dosing

• Pyridoxine Gram-for-gram of INH ingested (empiric: 5 g) IV at 1 g/min — Infuse at 1 g/min until seizures stop; remainder over 4-6 hr
• Pyridoxine 70 mg/kg IV at 1 g/min (max 5 g) — 1:1 ratio with INH if known quantity ingested

See Also

• Seizure (Peds)
• Seizures
• Antidotes