Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions.

Narrator - ?  00:11
This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:31
Welcome to HelixTalk episode 194 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is five ht, three receptor antagonists for nausea and vomiting, an in depth drug class review.

Dr. Khyati Patel  00:44
So similar to some of the drug class review episodes we have in past, Dr. Kane, we're going to talk about the pharmacology, the indication, the adverse effects, some of the unique characteristics of agents, and how they kind of separate from, you know, one another.

Dr. Sean Kane  00:58
I would say that most people have probably heard of ondansetron (Zofran). This is the first 5‑HT3 receptor antagonist that made it to the US market, and that was way back in 1991 so kind of an older drug class, if you think about it.

Dr. Khyati Patel  01:11
Yeah, and I believe we have a few more agents, so they kind of all end in the last letters of "-setron." So there we have granisetron (Kytril). We have dolasetron (Anzemet). We have palonosetron (Aloxi), and that was like the latest one in the market,

Dr. Sean Kane  01:27
and that was 2003 so still, it's been two decades since the last one, but we're still getting new data on these five HT three receptor antagonists, and we'll kind of go through kind of their role in therapy throughout today's episode before we get there, we have to kind of talk about understanding how the drug works, the drug targets and the pathophysiology of nausea and vomiting. Yeah.

Dr. Khyati Patel  01:49
And so, Dr. Kane, I teach this topic in the GI series of therapy, and there are quite a few other agents, so I get to spend such a little time. So I think this kind of a in depth review is really helpful, but in general, kind of talking about the pathophysiology, you know, our body ingest, or we ingest any toxic stimuli. So it could be a substance like alcohol, could be a drug like chemotherapy, or something foul smelling like a natural stimuli, right? Or a sensation. Maybe it's anxiety, maybe it's pain, maybe it's vertigo, like a motion, and that will trigger certain receptors that are innervated with neurotransmitters like the five, HT three or NK, one, dopamine, histamine. And these receptors then release these corresponding neurotransmitters or substances that ends up impacting the chemoreceptor trigger zone, CTZ, we call it. And once that happens, that kind of triggers the vomiting center. There is actually a place in the brain called vomiting Center, which then kind of signals the peripheral organs, such as the stomach, the intestine, the esophageal sphincter, the diaphragm, and then you you feel the contractions of So, feeling of nausea, and if the content of the stomach comes out, that's what we define as vomit. Yeah.

Dr. Sean Kane  03:04
So, Dr. Patel, as you mentioned, 5‑HT3 is a serotonin receptor subtype. So let's talk a little bit more about what's going on with that. Enterochromaffin cells line your GI tract, and they are responsible for releasing serotonin, also called 5‑HT or 5‑hydroxytryptamine, and that gets released from these cells in response to noxious stimuli or injury. And you mentioned several different things; chemo and radiation are what we're going to focus on today. But it could also be that you overate and that releases serotonin, or hey, you got some spoiled food—whatever it is these cells are responsible for releasing serotonin, and then the process continues from there.

Dr. Khyati Patel  03:46
And really the job of the serotonin is to improve peristalsis and increase that GI motility. And it also helps to secrete more water and chloride into the GI tract, and this increases the volume, aka, could also result in diarrhea,

Dr. Sean Kane  04:05
and this is a feature, right? So if you just ingested something that is toxic to your GI tract, that wants to move it along as quickly as possible, and one way to do that is diarrhea, but the other way is for you to vomit it up as well, right? Yeah, so then when that serotonin gets released, there's two places that it can act. On the periphery. You have five HT three receptors. So serotonin is five HT. The five HT three receptors are a subtype of that serotonin receptor, and they sit on your vagus afferent nerve in the GI tract. So this is kind of the pathway from the GI tract to the brain to tell the brain, hey, there's something going on here. So what will happen is that those five HT three receptors on the vagus nerve sends a signal to the brain saying, hey, it's time for nausea and vomiting. And the part of the brain that it actually innervates is called the NTS, the nucleus tractus solitarius, and it sits inside the blood brain barrier. So that means that most substances that are in your blood. Can't get to this part of the brain, but then this is part of that vomiting center that we talked about. So peripherally, the vagus nerve is receiving the serotonin. It sends a signal to that NTS part of the brain that then innervates and triggers the vomiting center of your brain. And then

Dr. Khyati Patel  05:15
there's that central mechanism, and again, the five HT three is going to trigger the chemo receptor Trigger Zone, the CTZ zone we talked about, and that's also then connected to the vomiting center. This one is kind of sitting outside of the blood brain barrier, and so it's going to be directly impacted by the five ht, three other toxins and drugs, and the vomiting center is going to do its job.

Dr. Sean Kane  05:38
Yeah. So really, there's two ways that your vomiting center can be activated, and hopefully that makes sense, that we have drugs that are blocking that receptor either on the vagus nerve, so even though serotonin gets released from those cells in your GI tract, they don't bind to anything on the vagus nerve to send that signal to your brain. Or any serotonin that makes its way into the bloodstream doesn't hit that chemotherapy trigger zone because that serotonin is being blocked by this drug class called the Five HT receptor antagonist. So there's kind of two different ways that we can block serotonin from binding to its target receptor.

Dr. Khyati Patel  06:13
And then, when it comes to radiation, people may wonder, look at how radiation can trigger nausea and vomiting, and what radiation does is end up actually damaging those enterochromaffin cells. Right? The job of the radiation is to hit those highly multiplying cells, and these chromaffin cells are one of those. And so it kind of leads to a serotonin dump, like a large release of serotonin. And so that's why radiation could be related to nausea and vomiting, and that's why these drugs work for those who are on radiation therapy,

Dr. Sean Kane  06:45
I think most people who think about chemotherapy think about hair loss and then nausea and vomiting. But when it comes to nausea and vomiting, there's actually two kinds of nausea and vomiting that happens, or there's two stages, the acute chemotherapy induced nausea and vomiting, or CI NV stage, is the first 24 hours after getting chemo. So you get chemo, this peaks at about five to six hours after receiving chemo. But then during that 24 hour period is the acute phase, and then you also have delayed chemotherapy induced nausea and vomiting, which is one to seven days after chemo. And the pathophysiology is a lot different between the acute phase the first day, and then the one to seven days, or the delayed

Dr. Khyati Patel  07:23
phase, yeah, and there's actually three more chemo induced nausea and vomiting that can happen, but we're going to focus on this acute and delayed phase. And as you mentioned, you know, the pathophysiology is a little bit different, and so the 5‑HT3 receptor antagonist is going to focus on those acute onset of chemo induced nausea and vomiting, because this acute nature of nausea and vomiting is mediated by that serotonin release from the enterochromaffin cells versus the delayed one is mediated by other neurotransmitters, like that substance P or the NK‑1 receptor. And so we use different drugs to attack the delayed nausea and vomiting

Dr. Sean Kane  08:05
of chemo. So given all of that, given that the acute phase of chemo induced nausea and vomiting is primarily caused by serotonin with the five HT receptor, it shouldn't surprise the audience, and that when we give these five HT three receptor antagonists, we're, for the most part, only giving it on day one of chemo, or whenever chemo is received by the patient. We wouldn't give it, let's say on day two or three after chemo has been received, because then you're in the delayed chemotherapy induced nausea and vomiting area, as opposed to the acute phase. And most of our efficacy is based on that acute phase blocking serotonin.

Dr. Khyati Patel  08:41
Yeah. And if you look at some one getting chemotherapy, especially highly hematogenic chemotherapy, they're going to be on multiple different agents to control their nausea and vomiting. So in the acute phase, we see the five ht, three RAS. But then the delayed phase, you know, they pay really well with those NK, one receptor antagonist. In some cases, we bring the dexamethasone and then kind of give some other agents for breakthrough and stuff. So you may see five HT three RAS as part of the overall chemo induced nausea vomiting regimen.

Dr. Sean Kane  09:12
So Dr. Patel, all of the five ht, three receptor antagonists are FDA approved for acute nausea and vomiting from chemotherapy. Two of them that we'll talk about later are also approved for delayed chemotherapy induced nausea and vomiting, where it happens one to seven days after chemo, and then also two—ondansetron and granisetron—are also approved for radiation induced nausea and vomiting. But on top of all of that, we can also use this drug class for non chemo, non radiation, reasons that someone might have nausea and vomiting,

Dr. Khyati Patel  09:43
yeah, and more commonly, we get to see its use in post operative nausea and vomiting. And the acronym po NV is used the loss of trans is not used for this. But we will talk about why. That's the reason. And outside of this FDA approvals, you know there is, of course. And unlabeled, or, you know, non labeled, use of these agents as well. More commonly, if you have, like that, advanced nausea and vomiting or morning sickness of pregnancy, then we have seen the use of this agents as well, and some limited studies show that there is no risk of fetal harm there.

Dr. Sean Kane  10:18
There's also two New England Journal of Medicine articles looking at using these five ht, three reception tagnus For gastroenteritis in kids presenting to the emergency department. One study was they gave it in the ED. Another study, they gave them six doses after they went home from the emergency department, and it was really effective

Dr. Khyati Patel  10:36
for that. Yeah, and then last, but not least, because ondansetron is just so commonly used. You basically use it for any kind of nausea and vomiting that's not differentiated, right? So, again, this is not specifically studied, but it kind of becomes, you know, if your over‑the‑counter regimens or your dietary modifications didn't do that job, which is usually that first line, you know, options for us, people do tend to go for ondansetron. Again, it doesn't always work for all mechanisms. So if we think about motion sickness, right, some of those agents that treat motion sickness related nausea and vomiting are over the counter, but because these are different neurotransmitters or agents involved, such as histamine or muscarinic receptors at play, the 5‑HT3 receptor antagonists are not going to do anything for that pathway.

Dr. Sean Kane  11:28
So then, in terms of how these are given for chemo, these are always given on the day that chemo is received. Most chemo regimens are something like on day one and eight and 21 you get chemo. So that would mean on days one, eight and 21 you're going to get a five HTT receptor antagonist, so you're not going to give it typically on days that you don't receive chemo. And then, from a dosage form perspective, we primarily have oral and IV, and surprisingly, they're both equally effective, which you would think that IV would be more effective, but assuming everything is dosed appropriately. There's actually no difference in efficacy. And we'll talk about some other dosage forms in a bit. And then when you give it, these are best used preventatively. So once that serotonin is released, if you don't have that five HT three receptor blocker on board, then you're going to not as get as good of efficacy. So just like with motion sickness, prevention is way better than once you already get sick for oral, you're going to give this 30 to 60 minutes before chemo or for IV, 30 minutes before, and almost always as part of like, a bigger plan where you're getting other stuff as part of your therapy to prevent emesis, but also other things that you might receive because of the type of chemo that you're getting.

Dr. Khyati Patel  12:38
Yeah, I get to see this on the outpatient side. I don't work at an infusion center, Dr. Kane, but therapy plans, it's like an epic term. That's the database that we use. And thankfully, because of this, order sets are developed you if you enter, for example, a cisplatin based chemotherapy regimen, it will automatically include some of these, you know, nascent monitoring remedies in there already. And I think we, we are talking about this, because when it comes to chemotherapy and cancer treatment in general, pharmacists play a huge role in managing this palliative conditions such as nausea and vomiting. And so that's where the importance of knowing the agents and differentiating them kind of comes to, comes to, comes to a play, and we talked about radiation induced nausea and vomiting, where these drugs are used, and it's slightly different on how it's given. For those who are receiving radiation therapy, they're going to get it on each day they get the radiation dose, and radiation regimens are a little bit different. Patient may receive like five days of radiation, and then give them a couple days on the weekend to recover, and that may continue for multiple weeks. And so some patients may be on these agents for, you know, all of those days they receive radiation.

Dr. Sean Kane  13:54
So then, you know, Dr. Patel, anytime I think about a drug class, I always ask myself, you know, do the guidelines have a preference for is one drug better than the other within a given class. So if you look at chemotherapy induced nausea and vomiting, there are three guidelines that are the primary guidelines, and they kind of all say pretty similar things. So we have these reference but one is ASCO, the American society of clinical oncology. We have ESMO, the European Society for medical oncology, and then NCCN, which is the National Comprehensive Cancer Network. The first two are linked in our show notes. I'm just going to say it's a little bit annoying the NCCN guidelines, you have to create a free account and then answer questions about yourself to be able to have access to it, versus the other ones are published in journals that are open access. So I think it's annoying when guidelines kind of hide behind a sign up like that, but there are three guidelines out there that are available that all basically say very similar things.

Dr. Khyati Patel  14:48
And usually, I mean, we kind of mentioned when you know these five HT receptor antagonists are given, but in terms of your moderate or high hematogenic potential chemo. Therapy. These will be given as part of a larger regimen. So something for the acute those are your five, eight treaty receptor agonist. They're going to get another agent or two for your delayed Natura and vomiting as well.

Dr. Sean Kane  15:13
So examples, the main two examples that come to my mind are cisplatin and cyclophosphamide. And the lists are pretty long in terms of highly amatogenic versus moderately amatogenic chemo, but those are the two that for NAPLEX reasons, I think I would definitely commit to memory of cisplatin and cyclophosphamide are highly imatogenic. And just to give a sense of what a patient might receive, if they're on a highly amatogenic regimen, they're going to get a four drug combo to control for nausea and vomiting from their chemo. They're going to get their five ht, three receptor antagonist on the day of chemo, they're going to get an NK one receptor antagonist on the day of chemo, and then for a couple days after that, they're going to get dexamethasone on the day of chemo, plus a couple days after that, and then olanzapine, which is Zyprexa, which is actually an anti psychotic given the day of chemo, and then a couple days after that. So again, just highlighting the five HT three receptor antagonist is only given on the day of chemo, and then all of the other drugs are given on the day of chemo, plus a couple days after chemo is given.

Dr. Khyati Patel  16:11
And then when you talk about that moderate hematogenic risk, we are looking at maybe two or three drug combos. So we do have the five HT three receptor antagonists, again, only on the day of the chemo, but dexamethasone can be given on the day of the chemo or a couple days after. And then this regimens may include NK, one receptor antagonist, again, that you know varies based on the chemotherapy agent in itself.

Dr. Sean Kane  16:36
And then for a low metagenic risk, we're just going to use one drug. So this could be a five HT three receptor antagonist on the day of chemo, or Metoclopramide, which is reglan on the day of chemo, or dexamethasone, which is a steroid on the day of chemo, and then for radiation induced nausea and vomiting, typically it's going to be a five HT three receptor antagonist with or without dexamethasone.

Dr. Khyati Patel  16:58
And this is the interesting part of the conversation. Dr. Kane is differentiating between all these five HT three receptor antagonists. So let's talk about if we see any efficacy differences when we utilize some of these agents we mentioned earlier.

Dr. Sean Kane  17:12
So if you look at the guidelines, basically, the guidelines don't have a preference, with a couple exceptions that we'll talk about. But essentially, the guidelines say, use a five HT three receptor antagonist. One exception is that the ESMO guidelines of the European guidelines, they do recommend specifically polynoceptron For oxaliplatin based moderate metagenic chemotherapy, which is a very specific regimen. But aside from that, one circumstance, they they don't have a strong preference. But as we'll talk about, polynosirtron has some benefits that I would argue probably should put it at a higher tier compared to the other five HT three receptor antagonists, but the guidelines don't have a strong preference,

Dr. Khyati Patel  17:51
and when we evaluate the efficacy of these agents, we are basing them off of couple of meta analysis that are linked in the show notes. So we're going to talk about when they were looked at for the chemo induced nausea and vomiting. We have a meta analysis for that, and then we have the post operative nausea and vomiting and the efficacy of these agents also via a meta analysis. So talking about the chemo induced nausea and vomiting meta analysis, that's the Mino and colleagues in 2016 they looked at acute nausea. So again, that definition is within that first 24 hours, and they found that all of those five HP receptor antagonists were equally effective.

Dr. Sean Kane  18:30
And just so we're clear, they do differentiate between nausea and then vomiting. Nausea just means that you feel sick. Vomiting is that you literally vomit stuff out of your stomach. And the meta‑analysis actually discriminates between the two, which I thought was interesting. So acute nausea, no difference; acute vomiting – in the first 24 hours, did you actually vomit? Dolasetron was the worst. So that was definitely worse than ondansetron, which was the typical comparator. Palonosetron was better than ondansetron, so palonosetron maybe being one of the better ones out there, and then all of the other ones were no different than each other. And we'll kind of see this pattern of evidence as we go through some of the other meta‑analyses. Generally speaking, palonosetron tends to have the best evidence, or is just as good. And then dolasetron tends to be the worst one out of the options that are available.

Dr. Khyati Patel  19:18
think about dull for Dola. You know, use it last effective. And then, when we then, they looked at the delayed nausea and vomiting, they did not separate. You know, nausea versus vomiting. They looked at all of it together. And that was defined as anywhere between 24 hours to seven seven days of instances of nausea and vomiting. And again, we discussed that based on the mechanism of delayed nausea and vomiting or pathophysiology or how it occurs, five h3 three receptor antagonists shouldn't really be effective for that. However, as we discussed, palonosetron did show better efficacy when it was compared with ondansetron. And so again, remember your palonosetron has a little bit effect on that delayed nausea and vomiting.

Dr. Sean Kane  20:03
And then the other ones were looked at, but they weren't any better than any of the other ones out there. So then for post operative nausea and vomiting, we have a meta analysis by a Trico and colleagues from 2015 this one, similarly, you know, you have a bunch of studies where you have a 5‑HT3 receptor antagonist versus some other regimen, which could be placebo or another nausea‑and‑vomiting drug or whatever. So there's a lot of different comparisons in the article. All of the five ht, three receptor antagonists are better than placebo, which is not seen a lot, but you know, they were studied versus placebo, so at least we have that.

Dr. Khyati Patel  20:36
And then they also separated the evidence for vomiting versus nausea. And so when looking at the vomiting evidence, they found that granisetron was maybe a little bit better than ondansetron. And again, remember dolasetron – that had the worst when it was compared with granisetron or ondansetron.

Dr. Sean Kane  21:00
And then they also looked at nausea. And again, dolasetron was the worst. It was worse than granisetron and palonosetron. So really, again, the constant theme here is dolasetron probably not a great agent to use, generally speaking, least effective. And then for this one, for post‑op nausea and vomiting, palonosetron, for whatever reason, just hasn't been studied very much. So it's not that it is better or worse. We just don't have a lot of comparative data showing that it is, you know, head to head versus any of the other ones. Based on the chemotherapy data, it's better. But for post‑operative data, we just don't have enough to make a firm conclusion.

Dr. Khyati Patel  21:36
And then, when we talk about radiation induced nausea and vomiting efficacy, evidence of this use comes from a 2017 meta analysis. And again, these five h3 receptor antagonists were compared with many different agents like placebo or metoclopramide or combination of metoclopramide or dexamethasone. And they also looked at the complete control of vomiting versus complete control of nausea as those outcomes, and what they found is that the five h3 receptor antagonists were more effective than the agents we just mentioned in complete control of vomiting and nausea in patients who were getting either single fraction or multiple fraction radiation to the abdomen, pelvis region, if you think about it, that radiation killing the enterochromaffin cells, releasing all that serotonin that that's what leads to the nausea. And they also looked at whether adding dexamethasone did anything better. And yes, they found modest improvement when dexamethasone was added. And so generally, for the radiation induced nausea and vomiting regimen, we tend to see five ht, three RAS used with or without dexamethasone. Again, it depends on, is it a total body radiation versus, you know, it's just a small area of the body receiving it. Total Body radiations are a lot of higher dose of radiation. And what they found for this particular patient population that five h3 receptor antagonists are also more effective than some of the other agents they looked at, such as dopamine receptor agonists alone or in combination with dexamethasone, or even things like Lorazepam, which are normally used for anticipatory style, nausea and vomiting.

Dr. Sean Kane  23:24
So then in terms of our dosage forms, we just covered efficacy. Dosage forms are kind of interesting. So we have on Dan Citroen or Zofran, the OG of the five HT three receptor class. We have oral tablets, oral liquids, orally disintegrating tablets, and then an IV injection. So we have kind of a lot of a lot of different options. And as I mentioned, the oral are just as effective as the IV options.

Dr. Khyati Patel  23:47
And then granisetron comes in many different formulations. And based on the formulation, obviously the brand name is different. And the FDA approval is a slightly bit different as well. So as an oral tablet and IV injection, the brand name is Kytril, and the oral tablet is also FDA approved for radiation‑induced nausea and vomiting. It comes in a patch form called Sancuso. Usually this is applied – again, prevention works better – 24 to 48 hours prior to receiving chemo, and the patients are asked to keep this patch on for seven days. And this was again studied as part of multi‑day chemo regimens, and showed non‑inferiority when patients were taking oral granisetron on each day of the chemo. So the patch basically worked just as well as the oral one.

Dr. Sean Kane  24:32
You could imagine a patient might prefer if they're nauseous, to not have an oral product, as long as they apply the patch early enough, it's just as good as the oral right, which is great one last pull, tipping, yep. And then we also have another granisetron formulation. The brand name is sustal, and this is actually an extended release injection. And they use a polymer to basically deliver the drug once it's injected over a slower period of time. And this is FDA approved for both acute and delayed. Delayed chemotherapy induced nausea and vomiting, and it was non inferior to pull on a citron. So this is one of the two examples where we're using a five HT three receptor antagonist, and we'll still just give it on the day of therapy, but it has this extended release, and partially because that extended release, it may have some efficacy of that post 24 hour mark with delayed chemo induced nausea and vomiting.

Dr. Khyati Patel  25:21
And we talked about the last atron Earlier, you know, kind of like the least efficacy agent Enzo met is the brand name. It is available as oral tablets only. We don't have any IV available for that. We talked about the efficacy of these agents for both the chemo induced nausea and vomiting as well as post operative nausea and vomiting. But interestingly enough, it's not FDA approved for post operative nausea and vomiting like it is for the chemo induced nausea and vomiting.

Dr. Sean Kane  25:50
Dr. Patel, I think we should just beat up dolasetron a little bit more. I don't know why anyone would ever use this product. It's only available orally. It only has one FDA indication, which was acute chemo‑induced nausea and vomiting; it's the least effective when compared to many of these other 5‑HT3 receptor antagonists. I just don't know why this is even on the market anymore. Yeah, but then that leads us to probably the most effective one, which is palonosetron (Aloxi). This has an FDA approval for acute chemotherapy‑induced nausea and vomiting, post‑operative nausea and vomiting, and also delayed chemotherapy‑induced nausea and vomiting. So it's hitting a lot of different FDA indications. What's interesting is that probably the reason why it's the most effective is that it has higher potency, so the doses are really small compared to the other 5‑HT3 receptor antagonists; it has a long half‑life, and that leads to better efficacy, because it's hitting the receptors better and for a longer period of time.

Dr. Khyati Patel  26:44
Yeah, so this is the reason why I would have some of that delayed nausea and vomiting benefit, and again, overall efficacy is either equal or better than other five h3 receptor antagonists. So this is going to be your kind of topping the chart, type of a five h3 receptor antagonist.

Dr. Sean Kane  27:00
And we don't have time to go into the pharmacology, but from a half life standpoint, it lasts way longer, 40 hours, versus about four to nine hours with the other agents. But then there's something called pseudo irreversible antagonist effect, which basically means that even when the drug leaves the body, it's still kind of holding on to some of those five HT three receptors and still providing that antagonist quality. So even though the drug Half Life means that it's not in your blood anymore, there's some data that it kind of holds onto the receptor for really long time, which, again, would confer more efficacy for a longer period of time.

Dr. Khyati Patel  27:34
And then, of course, these agents are also available in combination with other agents. So couple of combination agents to point out here are when they are available with the NK, one receptor antagonist. So they kind of all end in pittance. So netan and polynocitron is one combination NEPA, or brand name is kinzio. This was approved back in 2014 that netupitan Is your neurokinin, one receptor antagonist. This is usually used on that first day, but because it has a longer half light, we get to see good efficacy for that delayed nausea and vomiting.

Dr. Sean Kane  28:12
And then there's also an IV version of that combo product. This one is going to be fosnetupitant with palonosetron. It's IV, and it has the same brand name of Akynzeo. This was approved in 2018 and then fast mutipotent is just the pro drug version of the oral mutipotent. So it's working similarly. It's just the IV version as a pro drug. And then, as you mentioned, Dr. Patel, when you give this combo with the NK one plus the five ht, three receptor antagonists. You're giving this on day one of chemo, and you don't need to give it

Dr. Khyati Patel  28:44
after that. Yeah. Well, we extensively talked about the efficacy differences and like the formulation and availability differences. Let's kind of go over the safety concerns when it comes to, you know, these agents as well. So most commonly side effect wise, we get to see headache, constipation, diarrhea or dizziness. Again, depending on the study and the drug that we're looking at, the incident rates were either slightly higher or similar to placebo. So again, not not an overt concern

Dr. Sean Kane  29:17
here, and especially if you compare the side effect profile of this drug class versus metoclopramide, for example, there are a ton of side effects you're going to get with metoclopramide, like akathisia, where you get this inner restlessness or hypotension, or a variety of EPS‑type symptoms. Versus with this one, you really have to look hard to even come up with a side effect that is common enough that is different than placebo for most clinical trials. So these are pretty safe. The main thing that comes to most pharmacists mind is going to be Qt prolongation. So Qt prolongation is a risk factor for Torsades, which is a potentially fatal arrhythmia. So this is a rare but serious problem. And actually, when ondansetron first came to the market for chemo dose nausea and vomiting. The typical dose would be up to 32 milligrams per day, but because of the risk of Qt prolongation, the FDA now maxes it out at 16 milligrams per day. So lower dose, the risk is going to be lower with Qt prolongation. And then Dr. Patel I'm not joking about this, but dolasetron appears to have the worst QT prolongation risk in addition to its bad efficacy, and, you know, poor showing with FDA approvals. So again, another reason why I don't understand why this is still in the market, but you shouldn't use that, and the nice palonosetron actually has the lowest incidence of QTc prolongation. So another reason to really favor that one, in addition to its better efficacy.

Dr. Khyati Patel  30:40
So we are again, driving that point down. Don't use dolasetron, and palonosetron is going to be your higher‑efficacy choice. And if you are worried about patients who are on other QT‑prolonging drugs it might be a little bit more safe drug to consider, in general. The other thing I get to hear about is because it's a serotonin mechanism, Dr. Kane is serotonin syndrome, especially in those who might be on other serotonergic drugs.

Dr. Sean Kane  31:06
And this one is kind of a head scratcher for me. So it's a five HT three receptor antagonist. So typically, when we are blocking serotonin, you're not at risk for serotonin syndrome. It'd be, it feels like it should be the opposite. But the hypothesis here is that you know you're you're not reducing the serotonin you make. You're just blocking the receptor. So if you're blocking the receptor, that means serotonin can then go bind to the other subtypes, not the five ht, three subtypes. And maybe that would be the mechanism here. But, and we've actually included an article in our show notes, that maybe this is completely made up, that maybe there is no risk of serotonin syndrome and it's just confounders and other things that have made this suggestion. But we'll leave it up to the listeners in the show notes. It's Rojas Fernandez 2014 if you'd like to read more about it. But that particular article really is arguing that there is no serotonin syndrome and it's just by chance, where we've seen case report things back, yeah.

Dr. Khyati Patel  32:02
And as the case report authors kind of talk about confounders and other factors, maybe, maybe there were other serotonergic drugs that the patients were on which put them at a higher risk, and not necessarily these agents alone.

Dr. Sean Kane  32:15
So at least from my perspective, I would keep it on the radar, because if it was on the differential diagnosis and they are ready to get a large dose of an antiemetic, I would be a little bit cautious, but I'd also appreciate that maybe it's completely made up, and it's kind of a gray area, in my opinion.

Dr. Khyati Patel  32:32
Yeah, and these agents go through this metabolism via one, a, two, 2d, six and three, a, four. So you're, you know, thinking about those potential drug interactions if patient is on an inducing or inhibiting medication. So Dr

Dr. Sean Kane  32:45
Patel, let's go ahead and wrap up today's podcast. So a couple key points that come to my mind. One, there are four of these, serotonin subtype three or five. HT, through receptor antagonists on the market. We've got ondansetron, granicothetron, that nobody should use and then plonocotron. Mostly. These have been studied for acute chemotherapy induced nausea and vomiting and also post operative nausea and vomiting. But we've also used them extensively, off label for a variety of other indications related to nausea and vomiting as well, and

Dr. Khyati Patel  33:14
focusing on the chemo induced nausea and vomiting, these agents are given prior to chemotherapy, so depending on the formulation, 30 to 60 minutes before, on that first day, they're usually not given on subsequent day because they're not as effective for the delayed nausea and vomiting.

Dr. Sean Kane  33:31
Then Plano Citron has the longest Half Life, the best binding affinity to that five HT three receptor. And then, depending on the data and the setting and things like that, generally speaking, it's as good, if not better, than the other five ht, three receptor antagonists that are on the market.

Dr. Khyati Patel  33:47
And when it comes to safety issues, you know we we know that these agents may be connected to the QTC prolongation risk and may cause headache, dizziness, constipation and diarrhea, again, not to a greater degree than placebo, when it was compared, their association with increased risk of serotonin syndrome, as we discussed, might be controversial and not really supportive. From the

Dr. Sean Kane  34:11
mechanistic standpoint, Dr. Patel, we actually have six references in our show notes, which is a little bit more than we typically have. So for the listeners, if you're interested in seeing the meta analyzes, some of the clinical guidelines or any of the other articles that we mentioned. They're in our show notes at HelixTalk.com Again, this is episode 194 so with that, I'm Dr. Kane

Dr. Khyati Patel  34:32
and I'm Dr. Patel, and as always, study hard.

Narrator - Dr. Abel  34:35
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Narrator - ?  34:46
to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.