INH toxicity - Revision history

ClaireLewis: Redirected page to Isoniazid toxicity

2021-02-08T14:56:46Z

← Older revision		Revision as of 14:56, 8 February 2021
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	~~==Background==~~		#REDIRECT[[Isoniazid toxicity]]
	*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 is on aggressive supportive care and hemodynamic stabilization Focuses mainly on management of symptoms and stabilization of patient.
	~~===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 can be administered

	*'''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 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
	*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~~]]

Kxl328: /* References */

2019-04-27T17:40:28Z

References

← Older revision		Revision as of 17:40, 27 April 2019
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	==References==		==References==
	</~~references~~>		<references/>

	[[Category:Toxicology]]		[[Category:Toxicology]]

Kxl328: /* References */

2019-04-27T17:39:09Z

References

← Older revision		Revision as of 17:39, 27 April 2019
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	==References==		==References==
	<references>		</references>

	[[Category:Toxicology]]		[[Category:Toxicology]]

Neil.m.young: Text replacement - "==Diagnosis==" to "==Evaluation=="

2016-07-23T17:36:15Z

Text replacement - "==Diagnosis==" to "==Evaluation=="

← Older revision		Revision as of 17:36, 23 July 2016
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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>		**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>

	==~~Diagnosis~~==		==Evaluation==
	*Seizures refractory to conventional treatment are hallmarks of isoniazid toxicity		*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)		*Clinical history is extremely important in evaluating for isoniazid toxicity (i.e. dosing history, duration of treatment, estimated dose taken)

Neil.m.young: Text replacement - "0 mg" to "0mg"

2016-07-19T08:12:41Z

Text replacement - "0 mg" to "0mg"

← Older revision		Revision as of 08:12, 19 July 2016
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	*'''Unknown INH quantity''' ingested treat with empiric 5g of pyridoxine can be administered		*'''Unknown INH quantity''' ingested treat with empiric 5g of pyridoxine can be administered

	*'''Children''' - start 70-~~300 mg~~/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>		*'''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 0.5 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

Kxl328 at 23:01, 12 June 2016

2016-06-12T23:01:31Z

← Older revision		Revision as of 23:01, 12 June 2016
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	*'''Unknown INH quantity''' ingested treat with empiric 5g of pyridoxine can be administered		*'''Unknown INH quantity''' ingested treat with empiric 5g of pyridoxine can be administered

	*'''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>		*'''Children''' - start 70-300 mg/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 0.5 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

Carpenj: /* Pyridoxine */

2016-06-09T04:26:51Z

Pyridoxine

← Older revision		Revision as of 04:26, 9 June 2016
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	===Benzos===		===Benzos===
	*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 can be administered

Ostermayer: Text replacement - "Category:Tox" to "Category:Toxicology"

2016-03-22T16:22:46Z

Text replacement - "Category:Tox" to "Category:Toxicology"

← Older revision		Revision as of 16:22, 22 March 2016
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	<references>		<references>

	[[Category:~~Tox~~]]		[[Category:Toxicology]]

Neil.m.young at 03:52, 18 August 2015

2015-08-18T03:52:43Z

← Older revision		Revision as of 03:52, 18 August 2015
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	**Most common side effect and more frequent with slow acetylators, the elderly, and those with preexisting liver disease		**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		**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>		**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>

	==Diagnosis==		==Diagnosis==

Neil.m.young: format and small edits

2015-08-18T03:50:20Z

format and small edits

← Older revision		Revision as of 03:50, 18 August 2015
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	*INH used for latent and active [[Tuberculosis\|TB]] treatment		*INH used for latent and active [[Tuberculosis\|TB]] treatment
	===Toxicology===		===Toxicology===
	*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.		*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===		===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>		*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===
	==Pharmacology==
	*Absorbed via GI tract (small intestine), peak concentrations at 1-2 hours after ingestion		*Absorbed via GI tract (small intestine), peak concentrations at 1-2 hours after ingestion
	*Volume of Distribution: 0.6L/kg		*Volume of Distribution: 0.6L/kg
Line 21:		Line 23:
	*[[Metabolic Acidosis]]		*[[Metabolic Acidosis]]
	*[[Coma]]		*[[Coma]]
	*Signs and symptoms can appear 30 minutes after ingestion, with more severe symptoms including persistent seizures, metabolic acidosis, and coma.		*Signs and symptoms can appear 30 minutes after ingestion, with more severe symptoms including persistent seizures, metabolic acidosis, and coma

	*Hepatotoxicity		*Hepatotoxicity
	**~~most~~ common side effect and more frequent with slow acetylators, the elderly, and those with preexisting liver disease.		**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		**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>		**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>

	==Diagnosis==		==Diagnosis==
	*Seizures refractory to conventional treatment are hallmarks of isoniazid toxicity.		*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).		*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		*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>		*INH levels can be measured but results may not immediately be available <ref name="Haddad"></ref>

	==Management==		==Management==
	*Focus is on aggressive supportive care and hemodynamic stabilization Focuses mainly on management of symptoms and stabilization of patient.		*Focus is on aggressive supportive care and hemodynamic stabilization Focuses mainly on management of symptoms and stabilization of patient.
	===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
	===Benzos===		===Benzos===
	*~~Will~~ activate the GABA receptors and halt seizure activity.		*May not be effective but will activate the GABA receptors and halt seizure activity
	*Ventilatory support may be necessary for patients who cannot protect their airway
	===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
Line 47:		Line 48:
	*'''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>		*'''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>

	* 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.		*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~~. 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>		*Pyridoxine administration may temporarily worsen the metabolic acidosis
			*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==		==Disposition==
	*Patient will likely require admission and potentially ICU care for continued monitoring and evaluation.		*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		*If the patient has active [[TB]] also keep in respiratory isolation