• 26 May 2020
  • 17 min
  • 26 May 2020
  • 17 min

What and when should you prescribe for vomiting and nausea? Jo Cheah interviews Akshay Athavale about this sickly problem. Read the full article in Australian Prescriber.

Transcript

Welcome to the Australian Prescriber Podcast. Australian Prescriber, independent, peer-reviewed, and free.

Hi, my name is Jo Cheah, and welcome to the Australian Prescriber Podcast. Today, joining me on the episode, is Dr Akshay Athavale. Akshay is an advanced trainee in clinical pharmacology at the Royal Prince Alfred Hospital in Sydney. Welcome, Akshay.

Hi Jo, thanks for having me on.

Thanks for joining us. To get started, I just wanted to know what prompted you to write an article about antiemetic drugs.

The idea about the article was actually my wife's idea. She's a GP in the community and encounters a lot of issues with which antiemetics can be prescribed safely for which groups of patients. She thought it would probably be a good topic that would need to be covered, so here we are.

Great, you've got some firsthand feedback from doctors in the community, that's really good. To start off, can you briefly describe the pathophysiology of nausea and vomiting?

Sure. Originally, from a physiological standpoint, vomiting is designed to be a protective mechanism to try and expel harmful compounds that are ingested by the body. They can also reflect various types of medical conditions, including viral or bacterial gastroenteritis, obviously pregnancy or inner ear disturbance, as well as representing adverse effects from multiple medications.

The mechanism of nausea involves the higher centres in the brain, the cerebral cortex, as well as predominantly what they call the vomiting centre in the medulla, in the brainstem. They have complex pathways between the cerebral cortex, the vomiting centre in the brainstem and the gastrointestinal tract, all of which are connected by the autonomic nervous system. There are a number of neurotransmitters that modulate the response that occurs. These include histamine, dopamine, serotonin, and neurokinin. They all interact in a fairly complex way, in order to trigger nausea and vomiting.

In regards to the antiemetic drug classes, what are they, and briefly, what are their mechanisms of action?

That's a good question. There are a number of different drug classes that we can use to manage nausea and vomiting, most of them tend to target the neurotransmitters that I mentioned just a little bit earlier. The more common antiemetics that we're all familiar with would probably be the dopamine antagonists, the best known of those would probably be the metoclopramide and the domperidone.

Metoclopramide works through blocking the dopamine receptors centrally, in the brainstem and cortex, and in what they call the chemoreceptor trigger zone, as well as blocking those receptors in the gastrointestinal tract. Domperidone, on the other hand, while it's still a dopamine antagonist, only blocks the dopamine receptors in the gastrointestinal tract or the periphery, rather than crossing the blood brain barrier and having any central effects.

There are other dopamine antagonists that I guess we don't classically think of as antiemetics necessarily. These include things like droperidol, which is very commonly used for sedative benefits, and haloperidol, which is often used for the same purpose. Even less commonly, we wouldn't really think of atypical antipsychotics such as olanzapine as being a really useful antiemetic, but it has been shown to be quite effective and also works through blocking the dopamine receptors.

The next class would be serotonin antagonists. Everyone's very familiar with these now, ondansetron would be the most well known. They block the serotonin 3 receptors in the chemoreceptor trigger zone and in the gastrointestinal tract.

Some of the more older antiemetics, such as antihistamines, doxylamine or cyclizine, block the histamine 1 receptor in the nucleus tractus solitarius, which is a nucleus within the vomiting centre in the medulla. Importantly, they can also have anticholinergic effects, and certain antihistamines, like promethazine, can also block dopamine receptors. The anticholinergics like hyoscine, which is very commonly used for vestibular causes of nausea and vomiting, block the muscarinic receptors in the vestibular nuclei, the vomiting centre and in the cerebral cortex itself.

Corticosteroids such as dexamethasone are actually very effective antiemetics, but we don't really see much of their use outside of a chemotherapy palliative care population. They reduce the amount of prostaglandins that are synthesised and released. They also increase the gastrointestinal receptors’ sensitivity to blockade by coadministration of serotonin antagonists, like ondansetron.

Some of the newer antiemetics which have fairly limited use at the moment include the neurokinin 1 antagonist. They block those NK1 receptors, both in the peripherally and in the central nervous system, and their use is predominantly limited to chemotherapy-related nausea and vomiting.

The cannabinoid-based drugs are gaining a lot of popularity and there's a lot of discussion about when they should be used. They tend to modulate the effect of all the other neurotransmitters that we talked about through activation of the cannabinoid 1 receptor, which is an inhibitory receptor. At the moment, they're not registered for use as dedicated antiemetics, but they can be used based on a special access program.

The last class of antiemetics would be considered the benzodiazepines, lorazepam is probably the drug that's used most commonly. Benzodiazepines increase the activity of the GABAA chloride channel and that has a couple of effects. One, it helps in reducing anxiety for patients. That can often result in reductions in nausea and vomiting, but it also functions to suppress the activity of dopamine in that chemoreceptor trigger zone.

While all these drugs have one identified mechanism of action, they all act across a number of neurotransmitter systems and a number of receptor systems to alleviate nausea and vomiting.

Thank you, that was very informative. For the listeners out there, there's a very clear table in the article that Akshay has written looking at the mechanisms of action. You've already mentioned it a little bit that, depending on what neurotransmitters or receptors that these drugs are targeting, that can effect the side-effect profiles. If you want to discuss the key side effects per drug class, what are the things that we should actually be counselling our patients on, if we were handing out these drugs to them?

Absolutely. It's really important to think about side effects for any drug that we are prescribing or dispensing. We'll go through them in the same way that they're defined in the article.

Dopamine antagonists, mainly your metoclopramides, domperidone, and things like droperidol and haloperidol, the main side effects that we worry about are the extrapyramidal side effects, the movement-related side effects that occur from blocking the dopamine receptors, sometimes triggering an almost parkinsonian type of presentation. The other major side effects to consider, particularly for haloperidol and droperidol, would be effects on the electrocardiogram, on the ECG, and that would be prolongation of the QT interval.

There's been a lot of debate about whether these drugs actually prolong the QT interval on the ECG or not. Overwhelmingly, it doesn't seem like they have a particularly significant effect, but there are a number of reports in the medical literature about cardiac arrhythmias and prolonged QT intervals on the ECG. It is something to bear in mind, particularly in patients who do have underlying cardiac disease.

The other thing to think about is the off-target effects, the effects that these dopamine antagonists have on other receptor systems. Often, you can see that in the form of antihistaminergic effects. Patients might have sedation, they might have antiadrenergic effects, so they might have hypotension. They may also have anticholinergic effects through inhibition of the muscarinic receptors. The anticholinergic effects are particularly important in older patients, who are susceptible to those side effects in particular. These can include things like urinary retention, confusion and visual changes, so really important to identify who your population is and look at whether they're at risk of developing these side effects or not.

Serotonin antagonists, the most well-known adverse effect would be fairly severe constipation. They're also associated with a dose-dependent lengthening of the QT interval on the ECG. It's important to point out that most of these QT effects are actually related to intravenous administration of these drugs rather than oral administration, particularly in children. While there are a number of reports of cardiac arrhythmia and sudden deaths, these have all occurred in situations where the kids have either had underlying cardiac disease, electrolyte abnormalities, and they've been given repetitive intravenous doses rather than the oral dose, which certainly seems to be much safer.

The neurokinin antagonist, the main side effects to that really would be constipation and fatigue. Fatigue can be quite significant, particularly given that these drugs are used in patients with cancer, who are suffering from chemotherapy-induced nausea and vomiting, so they often tend to be fairly tired, fatigued or lethargic to begin with. These medications can add to that and make that worse.

Antihistamines, such as doxylamine or cyclizine, the main side effects to really consider would be sedation. Often, that's actually a desirable side effect and that's part of the reason why people sometimes take those medications. The other big class would be the anticholinergic side effects. Again, in the elderly populations in particular, there's a risk of increasing confusion, urinary retention, increasing risk of falls. Using these drugs should be carefully weighed against the risk of developing those side effects.

The anticholinergic drugs themselves, such as hyoscine, their main adverse events are anticholinergic, as I just described for the antihistamine. The corticosteroids such as dexamethasone, with acute use of these drugs, the things to consider would be acute mood changes, euphoria or dysphoria, hyperglycaemia. That's particularly important in patients who are diabetic or have difficulty to control diabetes. Then, more chronically, the adverse events can include hypertension, weight gain and osteoporosis.

Thanks Akshay. You were mentioning in your answer before, making sure we choose the right patient populations. In which patients are the drugs that you've mentioned most effective?

Absolutely. It's a bit of a two-part question, in terms of which drugs are most effective, cause you need to consider which drugs are most effective and which drugs are safe in that particular population.

The primary example would be in pregnancy or in first trimester of pregnancy. Metoclopramide and antihistamines, such as doxylamine, are commonly used and they're considered category A medications for pregnancy. However, increasingly, we're seeing more and more use of oral serotonin antagonists like ondansetron, but it's more used as a second-line agent. While we consider the drug to be fairly safe, it is important to remember that there are some studies that show that there is a slightly increased risk of developing malformations, such as oral clefts.

The other thing to consider in that particular population, using pregnancy as an example, is that a number of the drugs haven't actually been trialled in pregnancy-associated nausea and vomiting, so they may in fact be quite effective. We just don't know because we're not aware of their safety profile in pregnancy. With that said, some of the other more common indications, patients presenting with acute gastroenteritis, serotonin antagonists and dopamine antagonists tend to be the most effective drugs used. Serotonin antagonists have the added benefit of reducing gastrointestinal motility, so it may help to settle the gastroenteritis a little bit.

In terms of migraine-associated nausea and vomiting, dopamine antagonists, mainly metoclopramide, tends to be the drug of choice. The reason for that is, one, that it's got a reasonable antiemetic effect, but two, pharmacokinetic studies have shown that it actually can boost the effectiveness of certain non-steroidal anti-inflammatory medications, as well as paracetamol. You get a double benefit in boosting the analgesic effect of the drugs you're co-administering and also getting the benefit related to reducing nausea and vomiting.

In terms of the vestibular causes and motion sickness-associated nausea and vomiting, because acetylcholine and histamine tend to be the main neurotransmitters involved in those pathways, the antihistamines and anticholinergic drugs tend to be the most effective.

In patients who have chemotherapy-induced nausea and vomiting or radiation-induced nausea and vomiting, the choice or combination of drugs that you use depend on the chemotherapeutic drugs being used or the extent of radiation that the patient is being exposed to. In patients who are receiving chemotherapy that is very highly likely to induce nausea and vomiting, they usually tend to derive the most benefit from a combination of a serotonin antagonist, a neurokinin 1 receptor blocker and a corticosteroid, whereas those receiving treatment with a drug that's less likely to cause it can usually get away with a serotonin antagonist or a combination of just two of those three previously mentioned.

The postoperative and the opioid-induced nausea and vomiting, I'm going to lump together because they do get dealt in the same way and it is hard to tease them apart. In general, all of the antiemetic classes listed are effective. Some of the antiemetics, we can't access readily. For example, the neurokinin 1 inhibitors are effective for postoperative nausea and vomiting, but they're currently not listed under the PBS for that particular indication, so that limits their use. Otherwise, serotonin antagonists and dopamine antagonists, in particular droperidol, is very commonly used for postoperative nausea and vomiting.

Thank you. Just to finish up, at the start of the talk, you did mention a couple of ‘newer drugs’ that have been trialled and recommended to treat nausea and vomiting, such as atypical antipsychotics, like olanzapine or the cannabinoids. From your experience, what has the uptake been like for these medications for nausea and vomiting?

That's a really good question. In terms of the olanzapine, I've seen that used in relation to chemotherapy-induced nausea and vomiting, and it has actually been taken up in some guidelines for standard treatment of chemotherapy-induced nausea and vomiting. The problem with it at the moment, and the reason that it hasn't been taken up even more, is that when you look at the PBS criteria for prescribing olanzapine, chemotherapy-induced nausea and vomiting or nausea and vomiting in general aren't actually indications for PBS subsidy. As a result, prescribing it privately tends to be more expensive and that can sometimes limit its more widespread use.

The cannabinoids are a topic of hot debate. At the moment, in Australia, the cannabinoids are licensed for management of spasticity associated with multiple sclerosis. They can be accessed by special access for refractory nausea and vomiting in patients receiving chemotherapy, but usually they're reserved as a last-line treatment, after failure of the standard treatments.

One of the major problems with the use of cannabinoids in that population is that they haven't really been compared against the current standard of care. They haven't really been compared against serotonin antagonists and they may in fact have more side effects. One of the other major limiting factors about their use is the accessibility factor, there's reasonable amount of paperwork in order to get the medications. Often, prescribers and practitioners aren't familiar with the logistics of trying to acquire the particular medication, and oftentimes they just don't feel comfortable prescribing them, given that they have no personal experience with those medications.

One of the other newer ones, which would be the neurokinin inhibitors, they've been around for a little while now, but they're used fairly routinely for chemotherapy-induced nausea and vomiting. As I said before, they are quite effective for postoperative nausea and vomiting, but at the moment, their PBS listing criteria is for chemotherapy-induced nausea and vomiting only.

All right, thank you Akshay. That brings us to the end of the interview. Thanks again for joining us.

Thank you very much for having me, Jo.

[Music]

The comments made by the guests and hosts of the Australian Prescriber Podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Jo Cheah, thanks again for joining us on the Australian Prescriber Podcast.