Show the model answerAttempt it first — that is what makes it stick
Mechanisms of action
Every antiemetic class, by receptor, site and example
What earns the marksthe full range
| No restriction here | Not limited to PONV, and no named drugs — cover every class |
|---|---|
| Name the receptor | And its site, for every drug offered as an example |
| Not just the class | The discipline the later, more specific versions reward |
| Class | Receptor | Site of action | Examples |
|---|---|---|---|
| 5-HT3 antagonists | Serotonin 5-HT3 | Peripheral — vagal afferents in the gut, activated by serotonin released from enterochromaffin cells; and central — the CTZ, the site of highest 5-HT3 receptor density | Ondansetron, tropisetron, granisetron, dolasetron, palonosetron |
| Anticholinergics | Muscarinic | Vestibular system, near the CRTZ | Hyoscine (used clinically); atropine (not used for PONV — cardiovascular effects); glycopyrrolate (no central effect — quaternary amine) |
| Antihistamines | Histamine H1, usually with genuine anticholinergic activity alongside | Area postrema, vomiting centre, vestibular nucleus, nucleus tractus solitarius | Cyclizine, dimenhydrinate, diphenhydramine, promethazine |
| Corticosteroids | No single defined receptor — mechanism not fully established | Central; proposed prostaglandin-synthesis inhibition, endorphin control, anti-inflammatory effect | Dexamethasone |
| Dopamine antagonists | Dopamine D2 (metoclopramide additionally 5-HT3 antagonist and 5-HT4 agonist) | CTZ | Phenothiazines (chlorpromazine, prochlorperazine, perphenazine), droperidol, domperidone, metoclopramide |
| NK1 antagonists | Neurokinin-1 (substance P) | Dorsal vagal complex — nucleus tractus solitarius and area postrema | Aprepitant, fosaprepitant |
| Adjuncts | Various — reduced dopamine synthesis/release (midazolam); CB1 (cannabinoids) | CRTZ / nucleus of the solitary tract | Midazolam, lorazepam, nabilone; sub-induction-dose propofol |
Read the question: This is the broadest form of the question — no mark allocation signals how much detail is wanted. Name the receptor and its site for every example, which is what the later versions of this question explicitly reward.
The mechanism, not just the class label, is what separates a complete answer from a superficial one. 5-HT3 antagonists such as ondansetron block the same receptor at two points in one reflex arc — peripherally, where serotonin released from gut enterochromaffin cells activates vagal afferents, and centrally at the CTZ — which is why a single drug class covers causes as different as chemotherapy-induced and postoperative nausea. Anticholinergics such as hyoscine block muscarinic receptors in the vestibular apparatus, the pathway responsible for motion-related nausea; being an uncharged tertiary amine, hyoscine crosses the blood–brain barrier and so also produces sedation and, in excess, the central anticholinergic syndrome, whereas glycopyrrolate’s permanently charged quaternary structure keeps it out of the CNS entirely. Antihistamines such as cyclizine block H1 receptors across the same brainstem territory as the vomiting centre and vestibular nuclei, and typically carry a genuine anticholinergic action alongside that contributes independently to their antiemetic effect. Corticosteroids have no confidently established single mechanism — state that plainly rather than inventing one, then give the proposed central prostaglandin-synthesis inhibition, endorphin control and anti-inflammatory explanations. Dopamine antagonists block D2 receptors at the CTZ; metoclopramide’s full receptor pharmacology for full marks is three-part — D2 antagonism, 5-HT3 antagonism and 5-HT4 agonism, with the last driving its separate prokinetic action rather than its antiemetic one. NK1 antagonists block substance P at the dorsal vagal complex and are described as potentiating ondansetron and dexamethasone rather than replacing them.
Side effects
Side effects, by class
What earns the marksby class
| Group by class | So each effect is tied to the receptor it follows from |
|---|
| Class | Side effects |
|---|---|
| 5-HT3 antagonists | Headache, flushing, constipation, QTc prolongation; transient rise in liver transaminases (reported in chemotherapy patients) |
| Anticholinergics | Dry mouth, sedation, mydriasis, tachycardia (atropine more than hyoscine); central anticholinergic syndrome with hyoscine and atropine only, not glycopyrrolate |
| Antihistamines | Sedation, dry mouth, blurred vision — the anticholinergic overlap |
| Corticosteroids | Perioperative hyperglycaemia, particularly in obese or diabetic patients, from a single dose; the effects of prolonged therapy (Cushingoid features, osteoporosis, immunosuppression, peptic ulceration) do not apply to single-dose antiemetic use |
| Dopamine antagonists | Extrapyramidal reactions (oculogyric crisis, akathisia, dystonia), sedation, hyperprolactinaemia, neuroleptic malignant syndrome (rare); QT prolongation with droperidol |
| NK1 antagonists | Headache, fatigue, constipation; caution with other CYP3A4-metabolised drugs |
If this came up in the viva
Viva points
Why can the CTZ be triggered by a circulating drug or toxin that never crosses the blood–brain barrier?
Answer
Because the CTZ lies in the area postrema, on the floor of the fourth ventricle, functionally outside the blood–brain barrier. It is rich in dopamine (D2) and serotonin (5-HT) receptors, so a circulating agent can activate it directly without needing to cross the barrier at all.
Are 5-HT3 antagonists effective for motion sickness?
Answer
No. They are effective for chemotherapy- and radiotherapy-induced nausea and vomiting and for PONV, but not for nausea and vomiting caused by vestibular stimulation or by dopamine agonists — those causes need a drug acting on a different receptor.
Diphenhydramine, dimenhydrinate, cyclizine and promethazine are H1 antagonists. Why do they also have meaningful antimuscarinic effects?
Answer
These agents have significant anticholinergic activity alongside H1 blockade, concomitantly blocking muscarinic receptors in the vestibular system — part of their antiemetic effect comes from this second mechanism, not from H1 blockade alone.
What is dexamethasone’s mechanism of action as an antiemetic?
Answer
It is not fully established. Proposed mechanisms include central inhibition of prostaglandin synthesis, control of endorphin release, and an anti-inflammatory effect that may reduce 5-HT release within the gut — say the mechanism is unsettled rather than assert one confidently.
Where do NK1 antagonists act, and on what ligand?
Answer
On the neurokinin-1 receptor, whose primary ligand is substance P, at the brainstem nuclei of the dorsal vagal complex — the nucleus tractus solitarius and area postrema.