INH toxicity: Difference between revisions
Neil.m.young (talk | contribs) No edit summary |
Neil.m.young (talk | contribs) (format and small edits) |
||
Line 2: | Line 2: | ||
*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 | *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 | ||
**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 | **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 | *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=== | ||
* | *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 | ||
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 | *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 | ||
Revision as of 03:50, 18 August 2015
Background
- 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 Cite error: Invalid
<ref>
tag; refs with no name must have content[2]
Diagnosis
- 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 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 - 1gm/kg regardless of age [3]
- 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. [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
<references>
- ↑ 1.0 1.1 1.2 1.3 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.
- ↑ Minns, A. et al. Isoniazid-Induced Status Epilepticus in a Pediatric Patient After Inadequate Pyridoxine Therapy. Pediatric Emergency Care. 2010:26(5)380-381