Classification of antiemetics

This chapter is relevant to Section O2(iii) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "Describe the pharmacology of drugs with anti-emetic activity". This is an important topic for pre-exam revision, as between these, and the drugs influencing gastric fluid pH and volume, one would easily cover 60% of the total gastrointestinal SAQs from the CICM Part One exam. Historical examples have included:

Beyond being able to classify them with examples, the candidates are directed to memorise as many facts as possible about ondansetron and metoclopramide, because these keep coming up in the written exam. Though the college has never actually asked trainees to compare these agents side by side, that time must surely be at hand.

In summary:

Several major classes of antiemetics:

  • Dopamine (D2) antagonists:
    • Phenothiazines (promethazine), which also have potent activity against muscarinic, H1, 5-HTand dopamine receptors
    • Butyrophenones (droperidol), which have slightly less potent anticholinergic and antihistamine effects 
    • Benzamides (metoclopramide), which have a prokinetic effect related to indirect cholinergic activity
  • Anticholinergic (antimuscarinic): 
    • Hyoscine, atropine (purely antimuscarinic)
    • Phenothiazines and butyrophenones also have strong antimuscarinic effect
  • 5-HT3 antagonists: 
    • ondansetron and granisetron are pure, high-affinity 5-HT3 antagonists
    • Phenothiazines and butyrophenones also have strong 5-HT3 antagonist effects
  • Antihistamines: 
    • Cyclizine and prochlorperazine have mainly anti-H1 effects
    • Most centrally acting H1 antagonists also have potent antimuscarinic activity
  • NK-1 antagonists: 
    • aprepitant 
  • Many miscellaneous agents:
    • dexamethasone
    • propofol
    • cannabinoids
    • benzodiazepines
    • pyridoxine (Vit B6)

A comparison of ondansetron and metoclopramide:

Name Ondansetron Metoclopramide
Class 5-HT3 receptor antagonist Dopamine receptor antagonist
Chemistry Carbazole Benzamide
Routes of administration Oral, IV, IM, s/c, sublingual Oral, IV, IM, s/c
Absorption Rapidly and completely absorbed, bioavailability ~ 60% Rapidly and completely absorbed, bioavailability ~ 80%
Solubility pKa 7.4, sparingly soluble in water pKa 9.27, highly water soluble
Distribution VOD= 2.5L/kg, 70-76% protein bound VOD = 3.5L/kg; minimally protein-bound (13-22%)
Target receptor 5-HT3 serotonin receptor antagonist - which are ligand-gated cation channels and which mainly conduct depolarising sodium and potassium currents D2 dopamine receptor antagonist (Gi-protein coupled);
also has activity as a muscarinic agonist (mainly peripherally)
Metabolism 95% of the dose is cleared by hepatic oxidative metabolism Undergoes some hepatic metabolism, mainly by CYP 2D6
Elimination Clearance is almost completely hepatic; only some minimal amount is eliminated by the kidneys About 20-50%of the drug dose is eliminated unchanged
Time course of action Half life is about 3.8 hours; duration of effect is about 4-8 hours Half-life is about 4-6 hours, but the duration of antiemetic effect is only 1-2 hours
Mechanism of action Main mechanism of antiemetic activity is the antagonism of 5-HT3 ligand-gated cation channels at the chemoreceptor trigger zone. No anticholinergic or antidopaminergic effects, and therefore no effects on gastric motility or nausea related to vertigo Antiemetic/antinausea effect is mainly exerted by the antidopaminergic effects centrally. Side effects (eg. dystonic reaction and galactorrhoea) are also mainly antidopaminergic. Prokinetic effects are mainly due to the peripheral muscarinic agonist effects
Clinical effects - Antiemetic effects
- constipation
- QT prolongation
- Headache, potentiation of migraine
- Increased lower oesophageal sphincter tone
- increased gastric emptying rate
- risk of dystonic reaction, especialy with children under 10
- Galactorrhoea due to dopamine antagonist effects
Single best reference for further information Naylor et al, 1992 Albibi et al, 1983

For the pharmacology of antiemetics, Singh et al, 2015 would probably be the best free article, mainly because it only spends about a paragraph on each class, and from the look of previous SAQs we can surmise that this is enough. However, metoclopramide and ondansetron have received a lot of attention in past papers, and the savvy candidate will have a detailed familiarity with their properties. Markham & Sorkin, 1993, is suggested for ondansetron, and Albibi & McCallum (1983) for metoclopramide.

Classification of antiemetics

Here is a list of antiemetics, arrayed according to their class and year of their commercial availability:

Drug Year of availability Reference
Antimuscarinic agents (M1 receptors)
Atropine Hoary antiquity Kovac, 2000 - p.132
Hyoscine (scopolamine) Kassel et al, 2018
Dopamine antagonists (D2 receptors)
Prochlorperazine 1956 Olver et al, 1989
Levomepromazine 1966 Skinner et al, 1999
Droperidol 1970 White, 2002
Domperidone 1979 Brogden et al, 1982
Metoclopramide 1980 Gralla, 1983
Olanzapine 2003 Srivastava et al, 2003
Antihistamines (H1 receptors)
Cyclizine 1947 Gan et al, 1994
Promethazine 1951 Adelman et al, 1959
Hydroxizine 1956 Simons et al, 1984
Steroids
Dexamethasone 1961 Liu et al, 1998
5-HT3 receptor antagonists
Ondansetron 1991 Markham & Sorkin, 1993
Granisetron 1993 Yarker & McTavish, 1994
Neurokinin-I antagonists
Aprepitant 2003 Curran & Robinson, 2009
Antiemetics with unclear mechanism of action
Propofol 1989 Borgeat & Stirnemann, 1998
Benzodiazepines Antiquity Triozzi et al, 1988
Cannabinoids Prehistory Plasse, 2002
Pyridoxine (Vitamin B6) 1939 Matok et al, 2014
Barbiturates 1934 Krebs et al, 1985
Isopropyl alcohol vapour Impossible to say Beadle et al (2016)

There is a lot of overlap in the antihistamine / anticholinergic / dopamine antagonist groups, because many of those drugs are extremely "dirty" and have appreciable antiemetic effects exerted by each of these mechanisms (for example promethazine). Instead of carefully dissecting the pharmacokinetics and pharmacodynamics of each substance, short notes on each class will be offered here, as well as links to a monograph dealing with the use of that substance as an antiemetic. For the reader who needs a compendium of such short notes but is understandably reluctant to recognise the authority of an unreliable non-peer-reviewed online resource, an excellent anaesthesia-focused paper by Lyons and Ballisat (2016) is available for free and covers all the usual suspects. 

  • Anticholinergic antiemetics are mainly represented by hyoscine, a tropane alkaloid which, prior to its role in anaesthesia was enjoying a rich career improving the party atmosphere for medieval witches and loosening the tongues of captured criminals (although occasionally also loosening other things). Theoretically one could also use atropine, but practically the effective antiemetic dose tended to also cause an undesirable and persistent tachycardia, which is why you never really see this. The most interesting feature of hyoscine and its ilk is the long duration of action: the vestibular effects, for example, are said to last for days, which makes it an attractive solution for motion sickness. As hallucinations and disinhibition are undesirable in perioperative medicine, most people will not see these agents used as antiemetics. However there are many drugs that are said to exert their effect by means of other receptor systems which also happen to have strong anticholinergic effects (eg. the phenothiazine class). Speaking of which:
  • Dopamine antagonists come in three main classes:
    • Phenothiazines, known for their dirtiness, which are equally good at blocking dopamine, serotonin, acetylcholine and histamine receptors, and which could therefore be correctly described as "broad spectrum antiemetics". Of these, the ones best known are probably prochlorperazine (often marketed as "Stemetil") and levomepromazine, which is favoured by the palliative medicine community. Promethazine, sold as "Phenergan", is usually marked as an antihistamine, and chlorpromazine is sold as an antipsychotic, but they could just as easily be classified as an antiemetics. Their dirtiness is the main advantage - it makes them equally effective at managing the nausea of cancer chemotherapy and of vertigo, for example. They also tend to be long-lasting; levomepromazine can hang around for up to 30 hours.
    • Butyrophenones, only fractionally cleaner, are also drugs that were originally marketed as antipsychotics and which were discovered to have a potent antiemetic effect. Of these, droperidol has a slower and longer duration of action when given IM, which has made it somewhat more popular with the perioperative medicine crowd. However, haloperidol has a more immediate onset of antiemetic effect. Both of them are still relatively short-acting when given IV - the antiemetic and sedative effects wear off over a couple of hours, making them more suitable for day procedures, where you do not wish to send the patient home to their family in a stuporous zombie state.
    • Benzamides are the cleanest D2 dopamine receptor antagonists, which has made them more popular. Metoclopramide is probably the most popular member of this group, but there are others - for example alizapride and  cisapride are also benzamides, and one could theoretically group domperidone with these drugs,  because it is mechanistically related (even though technically it's a  4-aminopiperidine derivative). Lacking in anticholinergic and antihistamine side-effects, these drugs are much more popular as antiemetics, and have a narrower spectrum of activity. However, unlike the phenothiazines and butyrophenones, they have the effect of promoting gastrointestinal motility, instead of anticholinergically inhibiting it. 
  • Antihistamines used as antiemetics include some phenothiazines (such as promethazine) as well as diphenhydramine, doxylamine, meclizine and cyclizine (which are piperazines). Most of them have substantial central anticholinergic side-effects, to the point where cyclizine was withdrawn from the market for a period of time because of recreational abuse potential. 
  • Serotonin (5-HT3) antagonists act on the chemoreceptor trigger zone and gastrointestinal tract. They are the drugs with the most direct effect on the central processing of nausea, and the least effect on the mechanical process of vomiting. If anything, they tend to have an inhibitory effect on gut motility. They are all carbazole chemicals, numerous (ondansetron, granisetron, dolasetron, tropisetron, ramosetron and palonosetron) and all very similar from a pharmacokinetic/pharmacodynamic standpoint.

Pharmacological properties of antiemetics as a group

There are only a few interesting things one could say about the pharmacological properties of antiemetics as a class:

  • Oral formulations are available for all of them, even though it makes no sense to force a vomiting nauseous person to ingest a tablet.
  • Most of them have good oral bioavailability,  the exceptions being prochlorperazine and domperidone
  • They all have modest volumes of distribution, except domperidone which behaves a bit like amiodarone
  • They are all highly protein-bound, except for metoclopramide and hyoscine.
  • They are all metabolised by the liver. Of these, the only exception is metoclopramide, of which 20-50% is renally eliminated.
  • Their half-lives do not usually reflect the duration of their effect (for example, the effects of aprepitant last for 48 hours, but its half-life is 9-13 hours).
  • The vast majority of them prolong the QT interval. It would actually be easier to list the ones that don't do it: hyoscine, dexamethasone, benzodiazepines, cannabinoids, palonosetron (alone among the 5-HT3 antagonists), aprepitant, cyclizine and prochlorperazine (alone among the phenothiazines). 

Receptor activity of common antiemetics

From a detailed reading of the examiner comments for Question 23 from the first paper of 2016, it would appear that the expectations had included a regurgitation of some specific textbook table, where these drugs are arrayed according to their receptor activity, with the activity crudely described by the number of pluses and minuses in the column. The official college example looked something like this:

Drug H1 M D2 5-HT3
Promethazine ++++ ++ ++  
Scopolamine + ++++ +  
Metoclopromide + -- +++ ++
Droperidol + - +++ +
Ondansetron - - - ++++
Granisetron ++++ ++  ++  
Dexamethasone - - - -

A brief overview of the recommended books from the CICM syllabus document did not reveal any such table, and so it is impossible to guess which specific one the writer of this model answer was referring to. From the deadnaming of scopolamine, we can infer an American origin, but beyond that it is impossible to narrow the possibilities. It is however possible that it does not come from anywhere, as it is outrageously inaccurate. For example, granisetron is definitely not a "++++" histamine receptor blocker. Moreover it is not clear what exactly "+" means here; does it reflect receptor affinity, or an agonist effect? It can't possibly be agonist effect, because "scopolamine" is definitely not a "++++" muscarinic agonist, except then what do we make of the "-" signs?

Ok, so this specific table is garbage, but there are other, better ones. These sorts of tables are highly prevalent in review articles. Here are several examples from Tomassino (2012), Mannix (2006), Wallenborn & Kranke (2010), to show just what two minutes of Googling can dredge up:

receptor activity of antiemetics from Tomassino, 2012

Antiemetic receptor activity from Mannix, 2006

Antiemetic receptor activity from Wallenborn & Kranke (2010)

It is important to point out that the "+" and "-" symbols are not some sort of calibrated pharmacological scale. These tables are not meant to be scientific, and in fact one unifying feature of all of these is the lack of a reference at the bottom, pointing to some kind of supporting clinical or experimental data. Also, they can't possibly all be borrowing from the same source material, as each table has different "+" and "-" values for each drug, and moreover it appears that each publication had decided on its own scale and meaning for the "+" and "-".

Though maddening from an educational perspective, this is actually a positive sign for the trainees. If they are expected to produce some sort of unscientific qualitative scale "to convey an understanding to the examiners", the scale itself can't possibly matter. Any random arrangement of pluses and minuses would have been sufficient (just look at the college answer!)

Indications for specific antiemetics

Specific indications and use cases for these drugs can be discussed in terms of their receptor effects, except only in the broadest and simplest sense, considering how little we know about the neurology of nausea and vomiting. The majority of these recipes are not especially scientific, in the sense that they did not originate from any physiologically plausible explanation of drug action - rather they come from observations and clinical trials,  i.e. we found what works in certain cases, and then reverse-engineered the neurotransmitter systems involved.  The article on the practical uses of antiemetics by Flake et al (2004) was the most succinct summary of these suggested indications:

  • Vertigo-related nausea, as well as motion sickness, are mediated by the acetylcholine and histamine systems of the vestibular apparatus, and therefore respond well to the anticholinergic and antihistamine antiemetics. As the result, they are less effective at reducing nausea and vomiting from visceral afferents.
  • Toxin-related nausea, such as nausea related to chemotherapy, can target the chemoreceptor trigger zone directly; 5-HT3 antagonists then interfere with serotonergic neurotransmission between the CTZ and the central pattern generator, preventing this sort of "central" nausea and vomiting.
  • Visceral nausea from intestinal sources appears to be mediated mainly by serotonergic neurotransmission, and is therefore most responsive to 5-HT3 antagonists. 
  • Migraine-related nausea seems to respond best to dopamine antagonists such as metoclopramide.
  • Hyperemesis gravidarum is perhaps the most difficult to treat among all the causes of nausea, the Latin name lending this condition a Harry Potter curse sort of vibe. The neurotransmitter pathways involved are difficult to reconstruct, as no single agent seems to be uniformly or reliably effective, and patients often end up sampling a selection of second-line agents before moving onto really toxic drugs like dexamethasone.
  • Post-operative nausea and vomiting seems to be related to the direct effects of anaesthetic agents on the chemoreceptor trigger zone, because 5-HT3 antagonists seem to be effective in controlling it. Dopamine antagonists are also used, though metoclopramide and droperidol consistently test poorly in clinical trials against ondansetron. 

The gastrointestinal effects of metoclopramide

These probably need to be discussed in slightly greater detail, not only because this drug is a common prokinetic, but also because these exact effects were the subject of  Question 23 from the first paper of 2012. The level of detail required for this answer was surprising. The examiners listed the following points in their comments:

"...lowers pressure threshold for occurrence of intestinal peristaltic reflex, reduces intestinal muscle fatigue, enhances frequency and amplitude of longitudinal muscle contraction, coordinates gastric, pyloric and duodenal activity to improve GI motility, mechanism of action appears to depend on intramural cholinergic  neuron, acts primarily by augmenting release of ACh and perhaps by inhibition of 5-HT release, increases lower oesophageal sphincter pressure, relaxes the pyloric sphincter and antagonize the inhibitory neurotransmitter, dopamine."

Let's unpack that. One might jump to the conclusion that this pile of facts must have come from some sort of textbook, but in fact looking at the usual suspects (Stoelting, Goodman & Gillman, Rang & Dale, Peck & Hill) does not reveal the source for this information.  The only resources that seem to contain this information are ancient articles like Albibi & McCallum (1983) and Harrington et al (1983). To summarise the contents of these papers, these are the things metoclopramide does to the gastrointestinal tract:

  • Oesophageal effects:
    • Increased amplitude of oesophageal perstaltic contractions (though not every study is able to demonstrate this effect)
    • Increased resting tone of the lower gastro-oesophageal sphincter (a short-term effect, lasting approximately one hour)
  • Gastric effects:
    • Accelerates gastric emptying, including the scenarios of diabetic and post-operative gastroparesis - this is described by the college as "appears to depend on intramural cholinergic neuron". In actual fact it appears to be an indirect effect, where metoclopramide enhances the acetylcholine release from suitable nerve endings (Sanger, 1985)
    • Increased antral contractions
    • Improved "antroduodenal coordination" (Lee & Kuo, 2010)
  • Intestinal effects
    • Increases the peristaltic activity of the upper small intestine

References

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Kassel, Lynn, et al. "Scopolamine use in the perioperative patient: a systematic review." AORN journal 108.3 (2018): 287-295.

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