- 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
- 2-3g ingested can lead to symptoms, 10-15g can lead to death
- Absorbed via GI tract (small intestine), peak concentrations at 1-2 hours after ingestion
- Volume of Distribution: 0.6L/kg
- Clearance of 46mL/min, metabolized by acetylation.
- T1/2 for fast acetylators = 70 minutes
- T1/2 for slow acetylators = 3 hours
- Via kidneys with levels successfully measured in urine
Signs and Symptoms
- Metabolic Acidosis
- Signs and symptoms can appear 30 minutes after ingestion, with more severe symptoms including persistent seizures, metabolic acidosis, and coma
- 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
- 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 
- Focus on aggressive supportive care and hemodynamic stabilization with early pyridoxine administration
- Pyridoxine does not reverse hepatic injury that can result from chronic toxicity.
- 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
- May not be effective but will activate the GABA receptors and halt seizure activity
- 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. 
- Can clear lactate and isoniazid from the bloodstream effectively and can be used as a final measure to increase clearance if needed. 
- 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
- Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th Ed. Chapter 55: Isoniazid.
- Gent, WL et al. Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients. Eur J Clin Pharmacol (1992) 43: 131-136.
- Farrell G. Drug induced hepatic injury. J. Gastroenterol. Hepatat. 1997; 12:S242l-S50
- Minns, A. et al. Isoniazid-Induced Status Epilepticus in a Pediatric Patient After Inadequate Pyridoxine Therapy. Pediatric Emergency Care. 2010:26(5)380-381
- Santucci, K. et al. Acute isoniazid exposures and antidote availability. Pediatric Emergency Care. 1999;15:99-101.