Ver el código de «Isoniazid toxicity»

==Background==
*[[Isoniazid]] (INH) used for latent and active [[Tuberculosis|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<ref name="Haddad">Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th Ed.  Chapter 55: Isoniazid.</ref>
===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<sub>1/2</sub> for fast acetylators = 70 minutes
**T<sub>1/2</sub> for slow acetylators = 3 hours
===Excretion===
*Via kidneys with levels successfully measured in urine<ref name="Haddad"></ref>

==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<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>

==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 <ref name="Haddad"></ref>

==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.<ref>Farrell G. Drug induced hepatic injury. J. Gastroenterol. Hepatat. 1997; 12:S242l-S50</ref>
===[[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)<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>

*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. <ref>Santucci, K. et al. Acute isoniazid exposures and antidote availability. Pediatric Emergency Care. 1999;15:99-101.</ref>

===[[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>

==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==
*[[Seizure (Peds)]]
*[[Seizures]]
*[[Antidotes]]

==References==
<references/>
[[Category:Toxicology]]