Invictus Reviews

Antidepressants Toxicity

• Mel Herbert

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Dr. Sean Nordt delivers a comprehensive pharmacology lecture on antidepressants, their mechanisms, and the management of toxicity cases in emergency settings. The board-certified emergency physician, pharmacologist, and toxicologist walks through the complex pharmacology of psychiatric medications, focusing on their potentially deadly complications and how to recognize and treat them.

• Cyclic antidepressants cause toxicity through fast sodium channel blockade, leading to QRS widening and ventricular dysrhythmias
• Sodium bicarbonate is the cornerstone treatment for cyclic antidepressant toxicity, working by increasing pH and altering cardiac binding
• SSRIs and SNRIs have distinct adverse effect profiles, with SNRIs posing greater risk in overdose scenarios
• Bupropion overdose commonly causes seizures and QRS widening through cardiac gap junction blockade
• MAOIs can cause hypertensive crisis and severe serotonin syndrome, especially with tyramine-rich foods or drug interactions
• Serotonin syndrome is characterized by hyperreflexia and clonus, distinguishing it from neuroleptic malignant syndrome
• Treatment approaches differ for serotonin toxicity (benzodiazepines, cooling), NMS (supportive care), and malignant hyperthermia (dantrolene)
• Antiemetics like metoclopramide and promethazine can cause extrapyramidal effects treatable with anticholinergics


Speaker 1:

I've realized that I put this upside down. My rectum's up the top and it should be down the bottom, so I'll flip that later. Hey, let's talk about Invictus. The oral board review form of Invictus is called Encore, but it's actually going to come out first, which is funny, and that should be coming out in the next month or so. And then the written has turned out to be much bigger than we thought. We were having to bring more people into the studio, but it's coming along really nicely, with lots of questions, lots of written summaries. We've got a deal with rosh and it's going to be pretty spectacular.

Speaker 1:

And then it's going to be an ongoing discussion thing that we're going to do that maybe some of you are going to want to do for the rest of your life, because I believe that ER docs should be doing continuous board review. So I'm sorry it will be a little bit delayed. I thought by the end of the summer, but we're going to have to keep working at this for a few more months. So here he is, sean Nort, who is board-certified ER doc, who's also a pharmacologist, who also is a toxicologist, who's also got degrees in pain and palliative care. He is amazing and he's also a super nice guy. So this is the quality of the lectures that you're going to be getting on Invictus. Nobody, nobody, knows this stuff better than Sean. All right go.

Speaker 2:

Antidepressants Now, this is a really important group of medications to talk about because unfortunately, many of our patients do struggle with depression and they're going to be on these agents and they have an increased risk for potential self-harm. We're going to start with the cyclic antidepressants. Here's a question. A 35-year-old ingested 50 to 60 tablets of amitriptyline. Patients have tunded and intubated. They develop a wide, complex tachycardia and then resolve with sodium bicarbonate intravenous push. What is the mechanism of the cardiotoxicity causing this QRS widening? Is it fast sodium channel blockade? Is it muscarinic 2 receptor blockade? Is it L-type channel calcium channel blockade? Or is it histamine 1 receptor blockade, and the answer is fast sodium channel blockade? Or is it histamine one receptor blockade, and the answer is fast sodium channel blockade?

Speaker 2:

Cyclic antidepressants used to be very widely used. Now. They were very effective, but they had lots of adverse effects but also very high mortality risk if someone took too much or, let's say, an intentional ingestion. The way that they work in large part is they inhibit catecholamine reuptake and that includes norepinephrine and serotonin, and the serotonin increases the mood. Okay, the norepinephrine, if you've heard, when someone started on a antidepressant, particularly the cyclic antidepressants, you usually don't give them more than one week supply and and that's because they get sort of this boost of energy and the thought was, hey, they were so depressed before that they wouldn't even try to kill themselves, but now, particularly with that increase in norepinephrine and the serotonin, now they have the energy to actually harm themselves. So if you are in the position to prescribe this no more than seven days until they're stabilized on it, here's a bunch of different ones that are here. So the original ones are the tertiary ones, like amitriptyline. Nortriptyline is known as secondary, that is the metabolite of amitriptyline. Amipramine is tertiary, deciperamine is the metabolite of amipramine, and then you can see doxepine, all these other ones. The tertiaries are much more sedating. They have a lot more antihistaminic and anticholinergic effects than the other ones. But the nortriptyline and dicipramine absolutely do too.

Speaker 2:

The anticholinergic effect is from that muscarinic blockade. This is very distressing to patients because they'd have dry mouth, blurred vision, urinary retention, constipation, all these other things. They can get somnolent and that's from the histamine one blockade. And then the thing that we worry about with poisoning is not only that fast sodium channel blockade causing the QRS widening, but it also can cause hypotension because an alpha adrenergic blocker. So if someone's just even on this. Chronically they can get orthostatic hypotension, but this is something that we'll see in acute poisonings. So what are the toxicities that we see? Anti-muscarinic right, they can get confused. All the other things Alpha-adrenergic blockade that's the hypotension. Sodium channel blockade that's the QRS widening the ventricular dysrhythmias, and then the GABA antagonism is what causes the seizures. So how do they present? And if you've never seen one of these, they're pretty scary because the patient comes in, they're pretty awake, they might have some anticholinergic signs or symptoms and it's easy to focus on that, but that is the least of our worries. It's really the cardiotoxicity that we're going to worry about. But what happens is they're lethargic, they're obtunded, but then they have a seizure and they just go from like being wide awake or pretty awake and then they slip over and they have a seizure. When they seize, the pH drops and that makes the binding to the cardiac myocytes much better, and then they widen out their QRS and go into VT, and so you don't want them to have a seizure. So when I used to see these quite a bit, I used to actually prophylactically treat them with diazepam or lorazepam to minimize the chance of them having a seizure, and I always have boxes of sodium bicarbonate right at the bedside.

Speaker 2:

Now QTC prolongation can happen, particularly with chronic use, but almost never with any of these medications you have to worry about with acute poisoning. So the sodium channel blockade finds. What do we see on an ECG? You see sinus tachycardia. Very often that's from the anticholinergic effects. But you see a rightward axis. You see a prominent R wave in AVR and then you get the QRS widening. I always worry about a relative sinus bradycardia with QRS widening and, let's say, qt prolongation, because this does set them up for dysrhythmias torsade. This would be the rare case that you would see if they have QTC prolongation. But with QRS prolongation I do worry about that causing VT or V-Fib.

Speaker 2:

What are some common medications? So we're talking about cyclic antidepressants. Diphenhydramine can do it. Propranolol is a beta blocker but actually has sodium channel blockade effects, so you can see QRS widening. You can actually see seizures. Quinidine and quinine those are sodium channel blockers, 1a types, as is procainamide Cocaine. So cocaine is a local anesthetic, as well as the pathomimetic carbamazepine and the local anesthetics. So how are you going to treat any of these? I always say if you have anybody who has widened QRS and you think it's from some sort of ingestion or toxin, just treat with bicarb and worry about it later. So you're going to prevent the seizures, ideally with benzos.

Speaker 2:

Phenobarbital, phenitoin and other anticonvulsants do not work for drug-induced or medication-induced seizures If they are hypotensive. The sodium bicarbonate actually works pretty well for that. What it does is it increases the pH, it changes that binding at the cardiac myocytes and it also provides volume, but QRS widening. You'll hear different toxicologists use different numbers, generally greater than 100 or 120. And then, of course, if they're in a ventricular dysrhythmia, just give it Alpha agonists. You want to use direct acting agonists such as norepinephrine or phenylephrine Dopamine at least there's some concern that it might worsen it. We really don't use dopamine anymore, so it's almost a moot point. And of course, if they're hypotensive, just give them IV crystalloid. Intubate them early, particularly if they're starting to get uptundant. And fisostigmine is not recommended. It will reverse the anticholinergic effects, but it also is associated with increased mortality, increased ventricular dysrhythmias.

Speaker 2:

Ssris and SNRIs, or selective serotonin reuptake inhibitors or SSRIs serotonin norepinephrine reuptake inhibitors these are two classes of antidepressants that are widely used with distinct mechanism of action. Okay, so how do SSRIs work? Well, it's in the name, right? It's like they say what does it say on the tin? It does what it says it's on the tin. So it inhibits the reuptake of serotonin or 5-HT, and this is at the serotonin transporter and this increases serotonin at the synaptic cleft. And then there's all those agents, so fluoxetine, sertraline, peroxetine, those are the earlier ones and kind of not much happened to poisoning. They would get maybe a little tachycardia, they get a little somnolent, but then citalopram and escitalopram they can actually get sick. And then SNRIs, much more worrisome with acute poisonings. They inhibit both the reuptake of serotonin but also norepinephrine. Okay, and this is venlafaxine, desvenlafaxine and duloxetine.

Speaker 2:

What are some of the common adverse effects of SSRIs? They have, so remember, on Dancitron, and Dancitron is a 5-HT3 or serotonin blocker. So if you have excess serotonin you get GI disturbances like nausea, vomiting and diarrhea. Sexual dysfunction is a common one. Patients can gain weight, all right.

Speaker 2:

Some of the serious effects is increased risk of bleeding. So if you were to do an L lumbar puncture and someone has SRS is on an SSRI, you want to at least pause and say do you really need to do this now? And the guidelines don't say that you can't do it. But just know that there's a lot of data to suggest or support that SSRIs do increase the risk of bleeding. And then of course, serotonin syndrome can happen. Snris some of the stuff is just common stuff like dizziness, dry mouth, sweating, sexual dysfunction, but this is the one that is much more dangerous and acute poisoning. So you can see hypertension but you see seizures much more commonly.

Speaker 2:

Serotonin syndrome can be seen as well as hepatotoxicity chronically here's a question A 22-year-old presents after a bupropion overdose. Certainly serotonin syndrome can be seen as well as hepatotoxicity chronically here's a question A 22-year-old presents. After a bupropion overdose Patient has a seizure witness en route. Which additional complication is likely?

Speaker 2:

Bradycardia, qtc prolongation, wide QRS and ventricular dysrhythmia or respiratory depression. The thing we worry most about in addition to seizures is a wide-curessant ventricular dysrhythmia with Brupropion. Brupropion it's used for so many things, of course major depressive disorder, but it's also used for seasonal affective disorder, smoking cessation, weight loss and this is a norepinephrine and dopamine reuptake inhibitor and this is much more serious than the SSRIs by far in poisonings. So with an acute ingestion we can see seizures and actually you can see seizures with just people being a little bit super therapeutic. You can see clonus myoclonus, hyperreflexia, hypotension, decrease in sodium. But the thing that we also worry about is QRS widening and this is not from sodium channel blockade, this is from cardiac gap junction. It blocks the intracellular communication. So you can use bicarbonate. Very often it doesn't work. So that's just something to know about. Intravenous lipid emulsion we'll talk about mostly when we talk about local anesthetic, systemic toxicity. But it has been used in cardiac arrest for bupropion poisoning.

Speaker 2:

Monamine oxidase inhibitors an old medication but very testable. So monamine oxidase breaks down catecholamines. It comes in two major types monamine oxidase A and monamine oxidase B. A is predominantly A for alimentary, a for alimentary, so it's mostly in the GI tract. So what happens? If you inhibit monamineoxidase type A and you eat tyramine foods which are biogenically active and usually get broken down in the gut, you can get clinical response to this. Monamineoxidase B B for brain. This is why they're used for Parkinson's disease.

Speaker 2:

The traditional monominoxidase inhibitors like phenylzine, trenosyphromine, bind irreversibly. Now these were super effective for treatment refractory depression. But they're just so risk of toxicity, particularly if someone takes an acute poison. They're rarely used. Of course the monom oxidase B are used for Parkinson's.

Speaker 2:

So let's just talk about common adverse effects of these, particularly the original types, the non-selective ones. So orthostatic hypotension, weight gain, sexual dysfunction, insomnia. But if someone takes a large amount they can get a hypertensive crisis. Or if they have remember, I mentioned about those tyrene foods and that's the aged cheese's red wine, because the tyramine now is biogenic and it can cause all these effects and then serotonin syndrome. This is really a class of medication that we worry particularly about serotonin syndrome and acute ingestions. As I mentioned, you can get hypertension, hyperthermia, seizures and coma and often that hypertension can be followed by hypotension. So there's a lot of drug-drug interactions.

Speaker 2:

Now we call it serotonin toxicity because serotonin toxicity or serotonin syndrome is very predictable. It's from an excess amount of serotonin. This is not idiosyncratic. So if you have somebody who's on multiple serotonergic agents such as meparidine, sympathomimetics, dextromethorphine, linezolid, cyclic antidepressants, ssris, snris, lithium, there's many others but that can increase the risk of serotonin toxicity or serotonin syndrome.

Speaker 2:

So monominoxidase inhibitors, if someone takes an acute ingestion you're going to see tachycardia. Hypertension may be delayed, followed by hypotension. Hyperthermia can be seen. They can have seizures. It's basically supportive care If they're hyperthermic, cool them. If they're hypertensive, we generally just kind of wait because you usually don't have to treat it because of the hypotension. You can give them IV fluids if they're not responsive, which they may not be a direct acting vasopressor, such as norepinephrine or phenylephrine.

Speaker 2:

Serotonin toxicity or serotonin syndrome, neuroleptic malignant syndrome, nms and malignant hyperthermia Clinically these are somewhat overlapping and can be hard to distinguish if they're all in your differential, but we're going to go through them. Neuromuscular findings. So serotonin toxicity is hyperreflexia and clonus. They can have rigidity but it's usually mild. Nms is where you can't move them and they have decreased reflexes. And malignant hyperthermia you should not see in the emergency department. This is generally in the OR or operating theater when someone is on an inhaled anesthetic and this is when they have generalized muscle rigidity, particularly masseter muscle rigidity. So let's go into these and I'll provide this table to you, but let's go into these in detail because they're very testable.

Speaker 2:

So serotonin syndrome or serotonin toxicity, remember this is excess serotonin and this is usually from multiple medications and I have all of them there SSRIs, mris, monominoxidase inhibitors, snris whatever it is. This is excess serotonin and the onset is rapid, within minutes to hours. This is not over days, okay. Neuroleptic malignant syndrome this should not be seen in the emergency department. If you're seeing this in the emergency department routinely, I guarantee you're probably seeing serotonin toxicity. This actually takes one to three days. It's psychiatrists that see this. This is generally seen with dopamine antagonists such as haloperidol, spiridone, droperidol, and what happens is it's over one to three days and it's generally when the dose is being escalated Okay.

Speaker 2:

And then malignant hyperthermia. This should only be seen in the OR or operating theater, and this is inhaled volatile anesthetics, although it is described with succinylcholine as well. This is a mutation in the rianidine receptor and this is genetic in the rianidine receptor, and this is genetic. Okay. And what this is? It's causing the calcium to bind and people cannot move, and this is life-threatening. So this happens within minutes too.

Speaker 2:

So how are you going to treat these? Well, of course, any of these immediately stop the agent, okay. But if you find that they have hyperreflexia and clonus, start thinking about serotonin syndrome. Most toxicologists, including me, say if they don't have clonus, they pretty much don't have serotonin syndrome. If they have lead pipe rigidity, if this happened in the emergency department with bradyreflexia and they're on their appropriate medications for it, think about that. And then malignant hyperthermia Okay, but the treatment is going to be again discontinue everything Supportive care. Now they can all cause hyperthermia. So you want to going to actively cool them.

Speaker 2:

Benzos, benzos, you can't go wrong, particularly for serotonin syndrome and neuroleptic malignant syndrome. You can give it for malignant hyperthermia, but the only thing that's going to work for that is dantrolene. What dantrolene is working at the sarcolemma because this is a calcium problem For serotonin syndrome it's just supportive care, cool them. You might have to intubate them. Ciproheptadine is a serotonin antagonist. The problem is it's only oral and it takes hours to work. Little downside to giving it, but mostly supportive care. Neuroleptic malignant syndrome. It really is just supportive care to benzos. Now dantrolene some people will use. It's controversial. If somebody was on bromocryptine, let's say, and they abruptly discontinued it, you want to give them a bromocryptine or a mantidine, but again, malignant hyperthermia. You have to give dantrolene. That's the only thing that's going to work.

Speaker 2:

Serotonin, 5-ht3 receptor antagonists we use these every day, all day, particularly on Dancetron, of course, as Granicitron 2. They work by blocking 5-HT3 or serotonin in the gastrointestinal tract and the central nervous system at the chemoreceptor trigger zone. They have very minimal adverse effects. So patients are on these. Sometimes they'll have headaches, sometimes constipation. Now QT subrungation is that you hear all the time. Now this medication is used all day, every day and you really don't see torsade commonly, but it has been described, particularly when very high doses were used. But it is very testable for standardized exams.

Speaker 2:

Dopamine receptor antagonists, particularly D2 receptors this is metoclopramide, prochlorperazine, promethazine, droperidol. They block dopamine or D2 receptors in the chemoreceptor trigger zone. Now it is used for a lot of things Nausea, but they're actually very good at least in my opinion, but probably yours as well for migraine-associated headache and nausea. Gastroparesis, particularly metoclopramide, because it is a prokinetic agent. They have a lot more adverse effects than other antiemetics, particularly the extrapyramidal effects. Now dystonia and you've all seen this. But this is very distressing to the patients. Right, they'll come in with torticollis or have these other things. You'll give them an anticholinergic such as diphenhydramine Acesthesia is that feeling where they might pull out the IV.

Speaker 2:

As diphenhydramine Acesthesia is that feeling where they might pull out the IV. Or you're far amount on the car park or you need a parking lot because they just ran away. That is idiosyncratic. That is not improved with diphenhydramine. Generally it's just reassurance benzodiazepines for that they can cause sedation, qt seroprolungation. Really you don't have to worry as much as other medications. However, droperidol and haloperidol it is a boxed warning, so very testable. So just be careful. If someone had a prolonged QTC, maybe try trimethabenzamide or Tigan. That has really no effect on the QTC interval. And then tardive dyskinesia. This is generally seen with prolonged use.