Bupropion

• Bupropion (amfebutamone)

Bupropion was approved for use as an antidepressant in the US in 1986, but was withdrawn from the market due to a high incidence of seizures occurring at therapeutic doses.(1) It was reintroduced in 1989 with a lower recommended maximum dose of 450 mg/day which lead to a therapeutic range of plasma concentrations of 50 - 100 microg/L.(2). In some countries only a modified release form is available. The main serious toxic effects in overdose are delirium and seizures, which are both very common. Occasionally fatal cardiac toxicity has been reported, always in the context of someone with significant CNS toxicity.

Bupropion is a monocyclic antidepressant whose primary mode of action is inhibition of neuronal uptake of noradrenaline and dopamine. It has minimal effects on re-uptake of serotonin. Its chemical structure is similar to amphetamines, however in therapeutic doses it has no stimulant effects in volunteers or patients with a history of amphetamine abuse.(3) Published animal data demonstrated predominantly neurological toxicity in acute poisoning, concordant with human experience.(4) Despite reports of ECG abnormalities in human overdose (see below), bupropion has very low potency at blocking cardiac conduction in vitro.(5)

Bupropion has no significant monoamine oxidase inhibitor activity or affinity for muscarinic, cholinergic, histamine or α1- or α2-adrenergic receptors. The mechanism of the high frequency of seizure is unclear.

Bupropion is well absorbed but has significant first-pass metabolism. Peak plasma concentrations occur around 2 h after ingestion of immediate release preparations. However, bupropion is more commonly available in a sustained release formulation with peak concentrations at 3–5 h.

It is approximately 80 - 85% plasma protein bound at therapeutic concentrations.(6) The volume of distribution is high, ranging from 10 - 20 L/kg and the median elimination half-life is 10 hours.(7)

Bupropion is predominantly metabolised in the liver. It has a number of metabolites with significant pharmacological activity (hydroxybupropion and threohydrobupropion) with higher plasma concentrations and elimination half-lives approximately double that of the parent compound.(7;8) The major enzyme involved in biotransformation is CYP2B6 but bupropion may significantly inhibit CYP2D6.(9)

The major manifestations in overdose with bupropion are neurological, in particular delirium and seizures are very common. Cardiac complications and death in and out of hospital may also occur.(11- 16) Overdoses involving ingestion of 8- 10 g of bupropion have produced fatalities.(13)

In a retrospective case series involving 58 bupropion overdoses (mean ingested dose 2310 mg (immediate release tablets)) the most common sequelae were neurological. Lethargy, tremors, vomiting and confusion were common. Seizures occurred in 21% from 1 to 8h post ingestion (mean ingested dose 3078mg). Mixed overdoses with benzodiazepines did not have a lower incidence of seizures. There were no fatalities and sinus tachycardia was the only significant cardiovascular effect.(10)

ECG changes have been reported after ingestions over 1.5 g.(12;17) Cardiac arrest has been reported to closely follow seizures.(14) Broad complex tachycardia and cardiac arrest in hospital have also been observed.(15;16)

These ECG changes including QRS widening appear to be due to blockage of intracellular gap junctions. Correction of acidosis may restore gap junction function and therefore intracellular communication.

Patients ingesting bupropion with abnormal ECGs (increased QRS duration) or seizure activity should be monitored until the ECG returns to normal.

This is most likely to be a problem in the setting of someone with delirium and seizures. The most common poisonings in Australia that would do this would be psychiatric or stimulant drugs, for example venlafaxine, amphetamines, tricyclic antidepressants, cocaine, ecstasy, MAO inhibitors, lithium, antihistamines, antipsychotic drugs.

Toxic effects may be delayed in onset, with the onset of seizures as late as 32 hours after ingestion of the SR preparation.(19;20) Patients should be considered to be at risk of seizures for at least 18 hours, and as long as they are symptomatic.

• IV access & fluids

Oral activated charcoal should be given to all patients ingesting more than 10 to 20 tablets of bupropion who present within 1 hour. Whole bowel irrigation should be considered in patients who have ingested more than 10 tablets of the extended release preparation. Pharmacobezoars have been observed post mortem in fatal bupropion SR overdose. A single dose of activated charcoal, followed by whole bowel lavage (polyethylene glycol solution) is generally appropriate for overdose of controlled release preparations of toxic drugs.(18) However bear in mind the high risk of sudden deterioration with seizures, and possible aspiration.

Cardiac effects
Treatment of tachy & bradyarrhythmias should be similar to that used in TCA poisoning with alkalinisation as the first line therapy.

Seizures
No specific antidote exists for bupropion overdose. Seizures should be managed with airway protection and benzodiazepines. Repeated seizures are common but status epilepticus (although reported) is not.(19) The use of sodium channel blocking drugs (e.g., phenytoin, carbamazepine) to control seizures might contribute to cardiotoxicity. Therefore, high dose benzodiazepines followed by barbiturates would be the preferred agents for refractory seizures.

There is no evidence of enhanced elimination with forced diuresis , urinary pH manipulation, haemodialysis or haemoperfusion.

Discharge after clinical toxicity has resolved. There are no specific long term sequelae.

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6- Dec-2014