ToxCard: Bupropion

Authors: Breeanna Lorenzen, MD (Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center); Christine Murphy, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Anthony Spadaro MD, (@TSpadaro91, Fellow in Medical Toxicology, Rutgers NJMS); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 17-year-old female with past medical history of prior suicide attempt, presents to the emergency department around noon after taking six bupropion sustained release 300 mg tablets (three at midnight and three at four AM). The patient’s mother believes the patient thought the pills were acetaminophen, and she was taking them for abdominal pain. Vitals on arrival included a temperature of 98.7°F, heart rate of 142 bpm, blood pressure of 114/66 mmHg, respiratory rate of 24 breaths/min, and oxygen saturation of 100% on room air. On exam, the patient has mydriasis, a fine tremor in both hands, and two beats of non-sustained clonus in her lower extremities. She is also noted to be agitated and hallucinating.

Questions:

1. What are the clinical manifestations of bupropion overdose?
2. How is bupropion overdose treated?
3. How long should a patient be observed after a bupropion overdose?

Background:

• Bupropion is used increasingly as an antidepressant and is used for weight management, smoking cessation, ADHD and eating disorders.
  • In 2020, bupropion was the 18^th most-prescribed medication in the USA.¹
  • In addition to intentional overdoses, there are multiple case studies of abuse (ingestion, insufflation, injection).² Bupropion has had street names including: “wellies” “dubs” “barnies” and “poor man’s cocaine.”
• Bupropion is a beta-keto amphetamine (a substituted cathinone like amphetamine and bath salt derivatives).³
• Bupropion blocks the reuptake of dopamine and norepinephrine, as well as antagonizes acetylcholine at nicotinic receptors.³
• Bupropion also inhibits cardiac gap junctions, leading to QRS widening, and inhibits delayed rectifier potassium channels, which can cause QTc prolongation.³
• Formulations:³
  • Bupropion hydrochloride (Wellbutrin)
    • Instant release (IR): 100 mg three times daily (max 450 mg/day, single dose max 150mg)
    • Sustained release (SR): 150 mg twice a day (max 400 mg/day, single dose max 200 mg)
    • Extended release (ER/XL): 300 mg daily (max 450 mg/day)
  • Bupropion hydrochloride SR and naltrexone (Contrave)
  • Bupropion hydrobromide XL (Aplenzin)
  • Bupropion-Dextromethorphan (Auvelity)
• The therapeutic dose is 150-450 mg/day.^3,4
• Pharmacokinetics:
  • Bupropion has a large volume of distribution and moderate protein binding. Bupropion demonstrates first pass metabolism with three metabolites.^3,4
    • Hydroxybupropion is the most active metabolite. ⁵
    • Bupropion is metabolized by CYP2B6 to hydroxybupropion. Additionally, even though it is not metabolized by CYP2D6, it can inhibit its function leading to elevated doses of drugs that are metabolized by this enzyme, such as dextromethorphan.^3,4
  • Time to peak serum concentrations: IR 1.5 hours, SR 3 hours, XL 5 hours. However, in overdose, it takes longer to reach peak levels.³
  • Mean elimination half-life in therapeutic use is 21 hours.³ This is slow!

Clinical Presentation:

Mild toxicity:

• Sympathetic activation: tachycardia, hypertension, tremor, myoclonic jerking, and GI symptoms.^3,6
• Can see delirium/hallucinations and agitation, likely due to a combination of anticholinergic and stimulant effects.
• Bupropion lowers the seizure threshold and even at therapeutic doses patients can have seizures.⁶

Severe toxicity:

Seizures:

• It is unclear if seizures are caused by bupropion or the active metabolite, hydroxybupropion.
• Seizures can occur spontaneously or follow a prodrome of agitation, tremor, hallucinations, or cardiac effects (primarily tachycardia).⁶
  • In one study, almost all patients who went on to develop seizures had tachycardia prior to the seizure.³
• Seizures are dose-dependent.⁶ Risk for seizure increases with ingestions of 3 g, while seizures are almost universal with ingestions of 6 g or more.⁶
  • In children, a single pill can cause significant toxicity with 16 mg/kg being the lowest ingested dose associated with a seizure in children.⁶
• Onset of seizures can occur rapidly after insufflation but are often delayed following an ingestion.
  • Seizures can occur up to 24 hours with ingestion of the XL formulation. Twenty-four percent of seizures occur > 8 hours after ingestion.⁶
• Fifty percent of patients will have additional seizures if they have had one, and status epilepticus can develop with large ingestions.⁶
• Video electroencephalogram (EEG) may be helpful to differentiate between myoclonic jerks and seizures.

Cardiotoxicity:

• Overdose can cause prolonged QRS and QTc intervals.^3,8
• Ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation have been reported.
• Cardiogenic shock and hypotension can occur (systolic heart failure with reduced ejection fraction.)^10,12
• Refractory shock or malignant arrhythmias occur in < 5% of patients.⁶

Diagnosis:

• Bupropion toxicity is a clinical diagnosis – diagnosis is primarily based on history and physical exam.
• There are no lab tests that can confirm bupropion exposure in a clinically relevant time frame.
  • Due to its phenylethylamine structure, there can be some cross-reactivity with the amphetamine screens (e.g., EMIT II immunoassay).³
• Always get an EKG to assess for cardiotoxicity, including widened QRS and prolonged QTc, although this may not be evident right away.
• If there is a high suspicion or uncertainty regarding co-ingestion, consider obtaining acetaminophen and salicylate levels.

Management:

• There is no antidote, and treatment is primarily supportive.
• Activated charcoal can be considered following intentional overdoses or larger accidental overdoses.³
  • Multiple doses of activated charcoal may be needed (especially in massive overdoses).
  • Remember patients must be able to protect their airway/be intubated and have active bowel sounds.
• Whole bowel irrigation:³
  • Not routinely performed and limited evidence to support improved outcome in general.
  • Can consider in massive overdose, especially of SR or XL formulations.
  • Patient must have bowel sounds and a secure airway (protecting their own airway or intubated).
• Seizures:^3,7
  • Benzodiazepines are first line in management once a seizure occurs.
  • Second-line agents include barbiturates or propofol.
  • Avoid phenytoin as it works as a sodium channel blocker which may lead to an increased risk of cardiotoxicity.
    • Additionally, in one murine study, phenytoin did not prevent seizures induced by bupropion.³
• Cardiotoxicity³
  • All patients need an EKG and cardiac monitoring.
  • QRS > 100 msec can give sodium bicarbonate 1-2 mEq/kg IV boluses.
    • This may not always work in patients with bupropion toxicity, due to bupropion’s effects on the cardiac gap junction likely causing prolonged QRS as opposed to sodium channel blockade.
    • Sodium bicarbonate may still be worth giving especially if it isn’t clear bupropion was ingested or there is concern for polypharmacy with another xenobiotic that blocks sodium channels.
  • For prolonged QTc, optimize electrolytes: calcium, magnesium, and potassium.
    • If > 500 msec give 2 grams magnesium IV in adults, 50 mg/kg up to 2 grams in pediatric patients and observe closely for the development of dysrhythmias.
  • Consider lidocaine for associated dysrhythmias.⁸
  • Consider intravenous lipid emulsion (ILE) for cardiotoxicity not responsive to other treatments.^9-12
    • Do not use this prophylactically in bupropion overdoses.
  • Other
    • Norepinephrine or epinephrine are preferred vasopressors when needed.³
    • Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been successful for refractory cardiogenic. ^3,13
    • Isolated cases of bupropion overdose mimicking brain death have been reported with one patient having burst suppression on their EEG that resolved within 36 hours. ^3,14
      • Give patients plenty of time (a minimum of five half-lives of bupropion) to metabolize and clear the drug if pursuing brain death testing.
      • Understand that toxicokinetics in large overdoses may prolong drug absorption and elimination kinetics.
• Disposition
  • Following intentional overdose, observe for at least 16 hours post-IR ingestion and 24 hours following SR/XL ingestion.
  • Symptoms, including any vital sign abnormalities (especially tachycardia,) must be completely resolved before discharge/medical clearance.^6,15
  • Discuss cases of overdose, including pediatric exploratory ingestions, with a medical toxicologist or your local poison center.

Case Follow-up:

The patient required a dose of lorazepam in the emergency department. Her initial EKG showed sinus tachycardia with a QRS of 86 msec and QTc of 414 msec. She was admitted on a cardiac monitor with serial EKGs every four hours. She required one further dose of lorazepam and observation for greater than 24 hours due to continuing hallucinations and tachycardia. Once these resolved and she was medically cleared, she was evaluated by psychiatry for her suicidal ideation.

Clinical Pearls:

• Bupropion blocks the reuptake of both dopamine and norepinephrine.
• Seizures can be seen at even therapeutic doses.
• Due to extended-release formulations, presentation of clinical effects, especially seizures, can be delayed. For extended-release preparations must observe for 24 hours AND until symptoms have resolved (this may be > 24 hours).
• Bupropion can cause cardiotoxicity and ventricular arrhythmias. Place on cardiac monitoring and get frequent EKGs. Wide QRS (> 100msec) may not resolve with sodium bicarbonate boluses due to bupropion’s inhibition of cardiac gap-junctions.
• Consider ILE and VA ECMO for severe cardiotoxicity.

References:

1. The Top 200 Drugs of 2020. https://clincalc.com/DrugStats/Top200Drugs.aspx. Accessed 12/18/2022.
2. Lewis JC, Sutter ME, Albertson TE, Owen KP, Ford JB. An 11-year review of bupropion insufflation exposures in adults reported to the California Poison Control System. Clin Toxicol (Phila). 2014;52(9):969-72.
3. Wu P, Juurlink D. Bupropion. In: Brent J, et al. Eds (2017). Critical Care Toxicology. 2^nde Cham:Springer Nature. p 965-974.
4. Wellbutrin XL [package insert]. Manufactured by Bausch Health US, Steinbach, Canada. 2022. https://pi.bauschhealth.com/globalassets/BHC/PI/WellbutrinXL-PI.pdf. Accessed 12/18/2022.
5. Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations. Clinical Therapeutics. 2005;27 (11):1685–1695.
6. Starr P, Klein-Schwartz W, et al. Incidence and onset of delayed seizures after overdoses of extended-release bupropion. Am J Emerg Med. 2009;27(8):911-5.
7. Shah AS, Eddleston M. Should phenytoin or barbiturates be used as second-line anticonvulsant therapy for toxicological seizures? Clin Toxicol (Phila). 2010; 48(8):800-5
8. Robinson S. Treatment of status epilepticus and prolonged QT after massive intentional bupropion overdose with lidocaine. American Journal of Emergency Medicine. 2022; 55:232.e3-232.e4
9. Livshits Z, Feng Q, Chowdhury F, et al. Life-threatening bupropion ingestion: is there a role for intravenous fat emulsion? Basic Clin Pharmacol Toxicol. 2011; 109: 418-422.
10. Sirianni AJ, Osterhoudt KC, Calello DP, Muller AA, Waterhouse MR, Goodkin MB, Weinberg GL, Henretig FM. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med. 2008 Apr;51(4):412-5, 415.e1. doi: 10.1016/j.annemergmed.2007.06.004. Epub 2007 Sep 4. PMID: 17766009.
11. Fulton LV, Fabich RA Jr, Bhatta J, Fletcher B, Leininger K, Lienesch K, Rodriguez TA, Coyner JL, Johnson AD, O’Sullivan J. Comparison of Resuscitative Protocols for Bupropion Overdose Using Lipid Emulsion in a Swine Model. Mil Med. 2016 May;181(5):482-7. doi: 10.7205/MILMED-D-15-00218. PMID: 27136657.
12. Gosselin S, Hoegberg L, Hoffmann R, et al. Evidence-based reommendations on the use of intravenous lipid emulsion therapy in poisoning. Clinical Toxicol. 2016;54(10):899-923.
13. Heise CW, Skolnik AB, Raschke RA, Owen-Reece H, Graeme KA. Two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno-arterial extracorporeal membrane oxygenation. J Med Toxicol. 2016;12(3):301-4. doi: 10.1007/s13181-016-0539-7. PMID: 26856351
14. Stranges D, Lucerna A, Espinosa J, et al. A Lazarus effect: A case report of Bupropion overdose mimicking brain death. World J Emerg Med. 2018;9(1):67-69. doi:10.5847/wjem.j.1920-8642.2018.01.011
15. Stewart E, Grewal K, Hudson H, Thompson M, Godwin J. Clinical characteristics and outcomes associated with bupropion overdose: a Canadian perspective. Clinical Toxicol. 2020;58(8):837-842.