by Dan Rusyniak

Let me just get this out of the way, I hate bupropion (Wellbutrin™ ) with the “white-hot intensity of a thousand suns” (Hulu). There is nothing “Well” about this drug. It was first synthesized by Burroughs-Wellcome (no, you are not Wellcome) in 1966, and was first approved by the FDA in 1989 as an antidepressant. It was pulled off the market, however, as it was found in post-marketing studies to have a significantly higher rate of seizures (~0.4%) than other second-generation antidepressants. Not willing to leave ill enough alone, they reformulated the drug as a sustained release version that lowered its seizure incidence rate to a more acceptable 0.1%.

So why do I hate this drug? But before I go there, a brief digression. It is important that everyone reading this understands that I am writing from an odd perch. My perspective is skewed, as if I borrowed someone else’s glasses. As a medical toxicologist, I only see the problems drugs cause. No one is calling up the poison center and telling the specialist “hey, guess what, I’m taking Xyban and I haven’t smoked in 7 months!” When you work at Midas all mufflers are broken. Ok, back to why I don’t like this drug. First, let’s look at its structure (it is a tox blog, of course there are structures). All structures were modified from Wikipedia. This is the structure of methamphetamine. It is a classic phenethylamine. That is to say it has a phenyl group (blue) and an ethylamine group (yellow). Throw in two more CH3’s and you get methamphetamine. Just ask Jessie Pinkman, yo.

Now, this is the structure of methcathinone (beta-methylamino-propiophenone or ephedrone). You may notice (if you did, you should do a tox fellowship) that it is nearly identical in structure to methamphetamine, with the exception of the double-bonded oxygen (beta-ketone in red). That ketone group makes this structure a cathinone. If you take away one CH3 group from this structure you get a naturally occurring stimulant found in the plant Catha edulis (khat). It is perhaps best known as that stuff the Somali pirates chewed in the movie Captain Philips. 

Stay with me. . . only two more structures. 

This is the structure of mephedrone. It is a “popular” bath salt. You know bath salts as the stuff that causes users to eat people’s faces (now you're awake). What do you notice. . . YES!!! It is a cathinone. All bath salts are synthetic cathinones. 

What does any of this have to do with bupropion? Well let’s take a look at its structure. 

So that drug that we use for smoking cessation and is written like candy to treat depression, is a sustained release bath salt. This is why persons who take bupropion can have urine drug screams that are positive for amphetamines (Casey 2011 PMID:21191682). It is also why, unsurprisingly, overdoses of it can cause tachycardia, agitation, hypertension, and seizures. All of these drugs work similarly by blocking the reuptake of dopamine and norepinephrine. 

One of the main reasons I hate bupropion is because in overdose it is really, really bad. The two most concerning effects are seizures and cardiac toxicity. 

So, while it might be technically incorrect to say bupropion causes seizures, it is probably more accurate to say bupropion metabolites (especially 6-hydroxybupropion) cause seizures; at least that is true if you are a Swiss albino mouse (Silverstone 2008 PMID:18922171). Seizures can occur even in persons taking bupropion at therapeutic doses, so it is no surprise that in overdose it is a common event. The risk is dose-dependent. In overdoses involving more than 3g of bupropion, the question is not if the patient will seize, but rather when they will they seize. Bupropion is now the most common cause of seizure in overdose (Thundiyil 2007 PMID:18072153). Seizures can be single, multiple, or can evolve into status. Patients can develop seizures as the only sign of toxicity. Most, however, will develop tachycardia and altered mental status before they seize. So, if you have a bupropion overdose and the patient is tachycardic and goofy, don’t sit around and wait for seizures – prevent them! All of these patients (IMHO) need either benzodiazepines (pick your favorite flavor – lorazepam, diazepam, or midazolam are all fine) or a prophylactic load of phenobarbital (10 mg/kg). I like the later because phenobarbital sticks around longer than buproprion. I like to think of phenobarb as the “Lantus of seizure prophylaxis”. It can cause sedation, so be aware. If the patient already has profound CNS depression, you may have to intubate them. Seizures are one of the causes of death in these overdoses, so stop them before they happen. 

The kinetics of bupropion also stink. While the majority of seizures occur within 6 hours of ingestion, the sustained and extended release formulations can result in delayed onset of seizures –  like 12, 15, and 24 hours delayed (Starr 2009 PMID:19857406). This is why, in overdose situations, the poison center recommends that patients be watched for 24 hours, even if they are asymptomatic (sorry, but I didn’t make the drug). 

The second most concerning effect of bupropion overdose is cardiotoxicity. Like other antidepressants, bupropion can widen the QRS and prolong the QT, cause hypotension, and patients can develop arrhythmias, shock, and death. The effect on QRS was thought to be secondary to its effects at blocking fast sodium (Na⁺) channels in cardiac cells (Curry 2005 PMID:16183450). However, unlike TCA’s, the QRS widening effects of bupropion may not be responsive to boluses of sodium bicarb (Wills 2009 PMID:19114875). This led some investigators to study it in rat cardiac cells, where they showed that even at large doses bupropion does not block Na⁺ channels (Caillier 2012 PMID:21623902). Rather it seems to affect cardiac gap junctions. No, these are not a new type of multicultural blue jean. Gap junctions are kind of like the cardiac “Chunnel”. They connect adjacent cardiac cells. Not so the Queen can drink fine Bordeaux, but rather to allow for the movement of nutrients and electrical impulses between cells. They are critical to the heart contracting in a coordinated fashion (Rohr 2004 PMID:15094351). Blocking these gap junctions may decrease cardiac output and may be the underlying cause of refractory hypotension in severe cases (Shenoi 2011 PMID:21206256). The effects on QTc are, like many other antidepressants, from blocking cardiac potassium channels (Curry 2005 PMID:16183450). 

So how do you treat bicarb-resistant refractory cardiac shock? You use everything you got. Like any life-threatening ingestion, you start with GI decontamination. Charcoal? Whole Bowel? As all tox is local, I suggest you talk you your friendly neighborhood toxicologist on their preference (yes, I am copping out of getting into the whole decon controversy). I for one give charcoal to these patients if they are not an aspiration risk. For hypotension, you can start with norepinephrine, but as noted above it may not help if the problem is your cardiac gap junctions are blocked. If the QRS is wide, it is reasonable to try some boluses of sodium bicarb but again, gap junctions. Because it is fat soluble, overdoses of bupropion have been treated with lipid emulsion therapy (Sirianni 2008 PMID:17766009). While, I think this is a reasonable thing to try in severe overdoses, the jury is still out on its benefit (Chhabra 2018 PMID:28644682). Another option that has been employed is ECMO (Shenoi 2011 PMID:21206256). 

And if a sustained release drug that causes delayed onset of seizures and bicarb-resistant QRS prolongation isn’t enough to stoke your hatred, did I mention that it is also abused (PMID: 24778361)? You shouldn’t be surprised because, after all, it is a bath salt. And unlike those sold on the street, this one is labeled for human consumption. 

Skull image by Mathew MacQuarrie

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