Isoniazid toxicity

Reviewed and revised 8 April 2014

OVERVIEW

• isoniazid toxicity, like other hydrazines, primarily cause life-threatening seizures and lactic acidosis through depletion of vitamin B6
• the antidote is pyridoxine

BASIC TOXICOLOGY

Toxicodynamics

• hydrazines like isoniazid decreased pyridoxal 5-phosphate levels (by inhibiting formation, binding and inactivating free P5P and increasing rate of P5P elimination)
• P5P is vitamin B6
• P5P is a cofactor in >100 enzyme reactions, including conversion of glutamate to GABA
• thus hydrazines cause GABA depletion resulting CNS excitation and seizures
• lactic acidosis results from seizures and from impaired conversion of lactate to pyruvate

Toxicokinetics

• rapid and complete oral absorption
• peak levels at 1-2 hours
• hepatic metabolism via acetylation or cytochrome P450 mediated hydrolysis
• half life varies from 1-4 hours depending on whether the patient is a ‘fast’ or ‘slow’ acetylator

RISK ASSESSMENT

Toxicity is rapid (30 min to 2 hours) and predictable

• >1.5g (20mg/kg) – symptoms may develop
• >3g (40mg/kg) – seizures, metabolic acidosis, coma
• >10g (130 mg/kg) – always lethal without treatment

CLINICAL FEATURES

• dizziness, blurred vision, photophobia, nausea and vomiting
• tachycardia, mydriasis, dysarthria, ataxia and hyperreflexia
• rapid confusion, coma, seizures, lactic acidosis in large overdoses
• seizures are usually generalised tonic-clonic in nature, and may resolve spontaneously then recur rapidly
• complications of prolonged seizures

INVESTIGATIONS

• screening ECG and paracetamol
• lactate and HAGMA on ABD
• isoniazid levels are rarely available, and only have a potential role in retrospectively confirming the diagnosis

MANAGEMENT

Resuscitation

• attend to ABCs
• treat seizures with benzodiazepines (high doses may be needed), escalate to barbiturates and give pyridoxine as soon as available (See below)
• prepare for and perform intubation in the event of prolonged seizures

Supportive care and monitoring

Decontamination

• only give activated charcoal after securing the airway by intubation

Enhanced elimination

• hemodialysis is not indicated even though it removes isoniazid because it is too slow

Antidote

• pyridoxine is indicated for isoniazid-induced seizures
• give 1g pyridoxine for each gram of isonizid ingested up to a maximum of 5g (70mg/kg in children) – give 5g IV if isonizid dose is unknown
• give as slow infusion of 0.5g/min until seizures stop
• also used for toxicity from other hydrazines e.g. Gyromitra mushrooms, rocket fuel (give 25mg/kg slow IV bolus initially); and as an adjunct in ethylene glycol toxicity (give 50mg IV q6h)
• 50% oral bioavailability and VD of 0.6L/kg, undergoes rapid extra-hepatic metabolism
• peripheral neuropathy from high chronic oral dosing of pyridoxine does not occur from acute treatment of an overdose
• only comes in 50mg vials!
• role of prophylactic isoniazid in asymptomatic overdoses is controversial

Disposition

• observe asymptomatic overdoses for 6 hours, then discharge if remain well and no treatment required
• symptomatic patients required HDU/ ICU admission