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| ==Background==
| | #REDIRECT[[Isoniazid toxicity]] |
| *INH used for latent and active [[Tuberculosis|TB]] treatment
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| ===Toxicology===
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| *Isoniazid’s metabolites restrict the conversion of pyridoxine to pyrodoxal-5’-phosphate and binds to pyridoxine, facilitating its excretion in the urine
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| *Loss of pyridoxine leads to decreased GABA synthesis due to the decreased function of glutamic acid decarboxylase (GAD)
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| *Anion-gap acidosis likely results from lactic acid buildup as a consequence of persistent seizure activity
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| *Finally come due to decreased catecholamine synthesis secondary to pyridoxine depletion
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| ===Toxic Dose===
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| *2-3g ingested can lead to symptoms, 10-15g can lead to death<ref name="Haddad">Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th Ed. Chapter 55: Isoniazid.</ref>
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| ===Pharmacology===
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| *Absorbed via GI tract (small intestine), peak concentrations at 1-2 hours after ingestion
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| *Volume of Distribution: 0.6L/kg
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| ===Metabolism===
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| *Clearance of 46mL/min, metabolized by acetylation.
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| **T<sub>1/2</sub> for fast acetylators = 70 minutes
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| **T<sub>1/2</sub> for slow acetylators = 3 hours
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| ===Excretion===
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| *Via kidneys with levels successfully measured in urine<ref name="Haddad"></ref>
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| ==Clinical Features==
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| ===Signs and Symptoms===
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| *[[Seizure]]
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| *[[Metabolic Acidosis]]
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| *[[Coma]]
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| *Signs and symptoms can appear 30 minutes after ingestion, with more severe symptoms including persistent seizures, metabolic acidosis, and coma
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| *Hepatotoxicity
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| **Most common side effect and more frequent with slow acetylators, the elderly, and those with preexisting liver disease
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| **Approximately 20% of patients on isoniazid therapy can have elevated liver enzymes
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| **Treatment is stopped when levels reach three times the upper limit of normal with symptoms or five times the limit of normal without<ref name="Haddad"></ref><ref>Gent, WL et al. Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients. Eur J Clin Pharmacol (1992) 43: 131-136.</ref>
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| ==Diagnosis==
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| *Seizures refractory to conventional treatment are hallmarks of isoniazid toxicity
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| *Clinical history is extremely important in evaluating for isoniazid toxicity (i.e. dosing history, duration of treatment, estimated dose taken)
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| *Elevated anion-gap metabolic acidosis with elevated lactate in the appropriate clinical setting AND refractory seizures should raise suspicion
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| *INH levels can be measured but results may not immediately be available <ref name="Haddad"></ref>
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| ==Management==
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| *Focus is on aggressive supportive care and hemodynamic stabilization Focuses mainly on management of symptoms and stabilization of patient.
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| ===Activated Charcoal===
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| *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
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| ===Benzos===
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| *May not be effective but will activate the GABA receptors and halt seizure activity
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| ===Pyridoxine===
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| *'''Known INH quantity''' ingested treat with with a '''1:1 ingested isoniazid:administered pyridoxine''' dose ratio
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| *'''Unknown INH quantity''' ingested treat with empiric 5g of pyridoxine can be administered
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| *'''Children''' - 1gm/kg regardless of age <ref>Minns, A. et al. Isoniazid-Induced Status Epilepticus in a Pediatric Patient After Inadequate Pyridoxine Therapy. Pediatric Emergency Care. 2010:26(5)380-381</ref>
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| *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
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| *Pyridoxine administration may temporarily worsen the metabolic acidosis
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| *Hemodialysis can clear lactate and isoniazid from the bloodstream effectively and can be used as a final measure to increase clearance if needed. <ref name="Haddad"></ref>
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| ==Disposition==
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| *Patient will likely require admission and potentially ICU care for continued monitoring and evaluation
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| *If the patient has active [[TB]] also keep in respiratory isolation
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| ==See Also==
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| *[[Seizure (Peds)]]
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| *[[Seizures]]
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| *[[Antidotes]]
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| ==References==
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| <references>
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| [[Category:Toxicology]]
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