Isoniazid toxicity: Difference between revisions

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==Management==
==Management==
*Focus on aggressive supportive care and hemodynamic stabilization
*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]]===
===[[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
*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
Line 43: Line 44:
*May not be effective but will activate the GABA receptors and halt seizure activity
*May not be effective but will activate the GABA receptors and halt seizure activity
==='''[[Pyridoxine]]'''===
==='''[[Pyridoxine]]'''===
*'''Known INH quantity''' ingested treat with with a '''1:1 ingested isoniazid:administered pyridoxine''' dose ratio  
*'''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
*'''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>


*'''Children''' - start 70-300mg/kg and increase until seizure resolves<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
 
*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
*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]]===
===[[Hemodialysis]]===

Latest revision as of 00:58, 19 January 2022

Background

  • Isoniazid (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 on aggressive supportive care and hemodynamic stabilization with early pyridoxine administration
  • Pyridoxine does not reverse hepatic injury that can result from chronic toxicity.[3]

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)[4]
  • 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. [5]

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. ↑ 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.
  2. ↑ Gent, WL et al. Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients. Eur J Clin Pharmacol (1992) 43: 131-136.
  3. ↑ Farrell G. Drug induced hepatic injury. J. Gastroenterol. Hepatat. 1997; 12:S242l-S50
  4. ↑ Minns, A. et al. Isoniazid-Induced Status Epilepticus in a Pediatric Patient After Inadequate Pyridoxine Therapy. Pediatric Emergency Care. 2010:26(5)380-381
  5. ↑ Santucci, K. et al. Acute isoniazid exposures and antidote availability. Pediatric Emergency Care. 1999;15:99-101.
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