Show the model answerAttempt it first — that is what makes it stick
5 marks
Mechanism of action for five named antiemetics
What earns the marksfive drugs
| The specific receptor | Not the family — the receptor itself |
|---|---|
| And its site | Central (CTZ, vomiting centre) or peripheral/vestibular |
| All five | Including dexamethasone, the weakest-answered |
| Drug | Receptor / target | Action | Site |
|---|---|---|---|
| Ondansetron | Serotonin (5-HT3) | Antagonist | Peripheral (vagal afferents in the gut) and central (CTZ) |
| Dexamethasone | Not a single defined receptor — mechanism not fully established | — | Central; proposed prostaglandin-synthesis inhibition, endorphin control, and an anti-inflammatory effect |
| Promethazine | Histamine (H1) | Antagonist | Central — area postrema, vomiting centre, vestibular nucleus |
| Metoclopramide | Dopamine (D2) antagonist, plus serotonin (5-HT4) agonist and 5-HT3 antagonist | Antagonist / agonist as above | CTZ (D2); its 5-HT4 agonism also drives its separate prokinetic action |
| Aprepitant | Neurokinin-1 (substance P) | Antagonist | Dorsal vagal complex — nucleus tractus solitarius and area postrema |
Commonly lost: 80% could give a mechanism, but full marks needed the specific receptor and its site, not the family. Dexamethasone was the weakest-answered of the five, and only about half identified aprepitant as an NK1 antagonist.
A full-marks answer states the mechanism, not just the drug class. Ondansetron is a carbazole structurally related to serotonin; blocking 5-HT3 receptors stops serotonin, released from gut enterochromaffin cells during chemotherapy, radiotherapy or surgical stimulation, from activating vagal afferents peripherally and the CTZ centrally — both steps use the same receptor, which is why one drug covers both sites. Promethazine, an H1 antagonist, blocks histamine receptors that sit alongside the vomiting centre, vestibular nucleus and area postrema; like most antiemetic antihistamines it also carries genuine anticholinergic activity that contributes independently to its antiemetic effect, which is worth naming as a second mechanism rather than H1 blockade alone. Metoclopramide’s antiemetic action is primarily D2 antagonism at the CTZ, but its full receptor pharmacology for full marks is three-part: D2 antagonism, 5-HT3 antagonism (which may contribute independently to the antiemetic effect), and 5-HT4 agonism — the last of which, together with a separate cholinergic action on the gut, drives its prokinetic effect rather than its antiemetic one, so the two actions should not be attributed to the same receptor. Aprepitant antagonises the neurokinin-1 receptor, a G-protein-coupled receptor whose ligand is substance P, at the dorsal vagal complex — the nucleus tractus solitarius and area postrema together — which is why it is described as potentiating ondansetron and dexamethasone rather than duplicating either.
5 marks
Adverse effects of prolonged steroid therapy
| System | Effect |
|---|---|
| Endocrine / metabolic | Hypothalamic–pituitary–adrenal axis suppression, hyperglycaemia, Cushingoid features, weight gain |
| Musculoskeletal | Osteoporosis and increased fracture risk, proximal myopathy, avascular necrosis |
| Gastrointestinal | Peptic ulceration, particularly with concurrent NSAID use |
| Immune | Immunosuppression — increased infection risk, impaired wound healing |
| Cardiovascular | Hypertension, fluid retention |
| Ophthalmic / dermatological | Cataracts, glaucoma; skin thinning and easy bruising |
| Psychiatric | Mood disturbance, insomnia |
If this came up in the viva
Viva points
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.
Metoclopramide and domperidone are both D2 antagonists. Why does only one of them cause extrapyramidal effects?
Answer
Metoclopramide crosses the blood–brain barrier and acts directly on central D2 receptors — the same property that produces its extrapyramidal and sedative effects. Domperidone shares the same D2-antagonist mechanism but does not cross the blood–brain barrier, so it is far less likely to cause them.