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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, in addition to binding to pyridoxine phosphate and facilitating its excretion in the urine. The loss of pyridoxine leads to decreased GABA synthesis due to the decreased function of glutamic acid decarboxylase (GAD). The decrease in GABA synthesis leads to seizures that are refractory to conventional treatment (i.e. benzodiazepines). The anion-gap metabolic acidosis that accompanies isoniazid toxicity likely results from lactic acid buildup as a consequence of persistent seizure activity. Coma is the final characteristic symptom seen in isoniazid toxicity, likely 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 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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| ==Work up==
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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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| ==Treatment==
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| *Focus is on aggressive supportive care and hemodynamic stabilization Focuses mainly on management of symptoms and stabilization of patient. 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. Benzodiazepines can substitute in for the missing GABA and help control seizure activity. Ventilatory support may be necessary for patients who cannot protect their airway.
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| *Pyridoxine- Intravenous pyridoxine is also integral in the treatment of isoniazid overdose, with a 1:1 ingested isoniazid:administered pyridoxine dose ratio, if the dose is known. If the ingested isoniazid dose is unknown, 5g of pyridoxine can be administered initially, with follow up doses given until seizures resolve. Sources note the composition of intravenous pyridoxine can have an acidic pH, resulting in an initial worsening of the acidosis. Finally, 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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| *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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| *Rate - slow IV infusion at approximately 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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| ==Disposition==
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| *Patient will likely require admission and potentially ICU care for continued monitoring and evaluation.
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| ==Source==
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| Goldfrank's Toxicologic Emergencies -INH Poisoning
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| <references>
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| [[Category:Tox]]
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