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-HT3 and 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 effectsSingle 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.
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.
There are only a few interesting things one could say about the pharmacological properties of antiemetics as a class:
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:
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. Clearly, any random arrangement of pluses and minuses would have been sufficient (just look at the college answer!)
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:
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:
Lyons, Samantha, and Ben Ballisat. "Antiemetic drugs: pharmacology and an
overview of their clinical use" Update in Anaesthesia 31 (2016).
Flake, Zachary A., Robert Scalley, and Austin G. Bailey. "Practical selection of antiemetics." American family physician 69.5 (2004): 1169-1174.
Sanger, Gareth J., and Paul LR Andrews. "A history of drug discovery for treatment of nausea and vomiting and the implications for future research." Frontiers in pharmacology 9 (2018): 913.
Kovac, Anthony L. "Prevention and treatment of postoperative nausea and vomiting." Drugs 59.2 (2000): 213-243.
Pearn, J., and J. Thearle. "The history of hyoscine." Histoire des sciences medicales 17.Spec 2 (1982): 257-261.
Kassel, Lynn, et al. "Scopolamine use in the perioperative patient: a systematic review." AORN journal 108.3 (2018): 287-295.
Krebs, Hans‐B., et al. "Combination antiemetic therapy in cisplatin‐induced nausea and vomiting." Cancer 55.11 (1985): 2645-2648.
Beadle, Kenneth Lee, et al. "Isopropyl alcohol nasal inhalation for nausea in the emergency department: a randomized controlled trial." Annals of emergency medicine 68.1 (2016): 1-9.
Olver, Ian N., et al. "A dose finding study of prochlorperazine as an antiemetic for cancer chemotherapy." European Journal of Cancer and Clinical Oncology 25.10 (1989): 1457-1461.
Skinner, Jenny, and Andrew Skinner. "Levomepromazine for nausea and vomiting in advanced cancer." Hospital Medicine 60.8 (1999): 568-570.
White, Paul F. "Droperidol: a cost-effective antiemetic for over thirty years." (2002): 789-790.
Loeser, Edward A., et al. "Comparison of droperidol, haloperidol and prochlorperazine as postoperative anti-emetics." Canadian Anaesthetists’ Society Journal 26.2 (1979): 125-127.
Brogden, R. N., et al. "Domperidone." Drugs 24.5 (1982): 360-400.
Gralla, Richard J. "Metoclopramide." Drugs 25.1 (1983): 63-73.
Srivastava, Manish, et al. "Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer." Journal of pain and symptom management 25.6 (2003): 578-582.
Gan, T. J., R. Collis, and M. Hetreed. "Double-blind comparison of ondansetron, droperidol and saline in the prevention of postoperative nausea and vomiting." BJA: British Journal of Anaesthesia 72.5 (1994): 544-547.
Adelman, Milton H., et al. "Promethazine hydrochloride in surgery and obstetrics." Journal of the American Medical Association 169.1 (1959): 5-7.
Simons, F. Estelle R., Keith J. Simons, and Evelyn M. Frith. "The pharmacokinetics and antihistaminic of the H1 receptor antagonist hydroxyzine." Journal of Allergy and Clinical Immunology 73.1 (1984): 69-75.
Liu, K., C. C. Hsu, and Y. Y. Chia. "Effect of dexamethasone on postoperative emesis and pain." British journal of anaesthesia 80.1 (1998): 85-86.
Markham, Anthony, and Eugene M. Sorkin. "Ondansetron." Drugs 45.6 (1993): 931-952.
Yarker, Yvonne E., and Donna McTavish. "Granisetron." Drugs 48.5 (1994): 761-793.
Curran, Monique P., and Dean M. Robinson. "Aprepitant." Drugs 69.13 (2009): 1853-1878.
Borgeat, A., and H. R. Stirnemann. "Antiemetic effect of propofol." Der Anaesthesist 47.11 (1998): 918-924.
Triozzi, Pierre L., David Goldstein, and John Laszlo. "Contributions of benzodiazepines to cancer therapy." Cancer investigation 6.1 (1988): 103-111.
Plasse, Terry. "Antiemetic effects of cannabinoids." Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential (2002): 165-80.
Matok, Ilan, et al. "Studying the antiemetic effect of vitamin B6 for morning sickness: pyridoxine and pyridoxal are prodrugs." The Journal of Clinical Pharmacology 54.12 (2014): 1429-1433.
Schaefer, Travis S., and Patrick M. Zito. "Antiemetic Histamine H1 Receptor Blockers." (2018).
Sanger, G. J. "Effects of metoclopramide and domperidone on cholinergically mediated contractions of human isolated stomach muscle." Journal of pharmacy and pharmacology 37.9 (1985): 661-664.
Harrington, R. A., et al. "Metoclopramide." Drugs 25.5 (1983): 451-494.
Lee, Allen, and Braden Kuo. "Metoclopramide in the treatment of diabetic gastroparesis." Expert review of endocrinology & metabolism 5.5 (2010): 653-662.