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INH toxicity
From WikEM
Contents
Background
- 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[1]
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.
- T1/2 for fast acetylators = 70 minutes
- T1/2 for slow acetylators = 3 hours
Excretion
- Via kidneys with levels successfully measured in urine[1]
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[1][2]
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 [1]
Management
- Focus is on aggressive supportive care and hemodynamic stabilization Focuses mainly on management of symptoms and stabilization of patient.
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 can be administered
- Children - start 70-300mg/kg and increase until seizure resolves[3]
- IV Infusion rate is 0.5 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
- Hemodialysis can clear lactate and isoniazid from the bloodstream effectively and can be used as a final measure to increase clearance if needed. [1]
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
See Also
References
- ↑ 1.0 1.1 1.2 1.3 1.4 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.
- ↑ Minns, A. et al. Isoniazid-Induced Status Epilepticus in a Pediatric Patient After Inadequate Pyridoxine Therapy. Pediatric Emergency Care. 2010:26(5)380-381
