Isoniazid toxicity: Difference between revisions
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==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]] | |||
Latest revision as of 00:58, 19 January 2022
Background
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
- ↑ 1.0 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.
- ↑ Farrell G. Drug induced hepatic injury. J. Gastroenterol. Hepatat. 1997; 12:S242l-S50
- ↑ Minns, A. et al. Isoniazid-Induced Status Epilepticus in a Pediatric Patient After Inadequate Pyridoxine Therapy. Pediatric Emergency Care. 2010:26(5)380-381
- ↑ Santucci, K. et al. Acute isoniazid exposures and antidote availability. Pediatric Emergency Care. 1999;15:99-101.