PharmacologyTier 1Medical Sciences concept

Chemotherapy-induced nausea and vomiting - neurotransmitter pathways (5-HT3, NK1, D2)

Core concept

Three anatomically distinct emetic inputs converge on the vomiting centre (nucleus tractus solitarius, medulla)

Trigger	Pathway	Receptors	Timing
Chemo in gut lumen	Enterochromaffin cells release 5-HT -> vagal afferent 5-HT3	5-HT3	Acute (<24 h)
Chemo in blood	Chemoreceptor trigger zone (area postrema, outside the BBB)	D2, 5-HT3, NK1	Acute
Central substance P	NTS and area postrema	NK1	Delayed (24-120 h)
Anticipatory	Cortical/limbic	GABA	Before the cycle
Vestibular	Vestibular nuclei	H1, muscarinic	Motion, opioids

The acute phase is serotonin; the delayed phase is substance P - and that dictates the drug choice
Aprepitant/fosaprepitant - NK1 receptor antagonists blocking substance P centrally; effective in both acute and delayed phases

Highly emetogenic (>90% risk): cisplatin, AC (anthracycline + cyclophosphamide), high-dose cyclophosphamide, dacarbazine
Moderate (30-90%): carboplatin, oxaliplatin, irinotecan, doxorubicin alone
Low: taxanes, gemcitabine, 5-FU, cetuximab
Minimal: bleomycin, vinca alkaloids, most checkpoint inhibitors

Prophylaxis by emetogenic risk

High: 5-HT3 antagonist + dexamethasone + NK1 antagonist (+/- olanzapine)
- Olanzapine 5-10 mg (multi-receptor D2, 5-HT2, H1, M1) adds substantial benefit, especially for delayed nausea
Moderate: 5-HT3 antagonist + dexamethasone (+ NK1 for carboplatin)
Low: dexamethasone or a single agent
Palonosetron - second-generation 5-HT3 antagonist, t-half ~40 h, covers the delayed phase better
Aprepitant is a moderate CYP3A4 inhibitor -> inc dexamethasone exposure (halve the dexamethasone dose), interacts with warfarin and the oral contraceptive
5-HT3 antagonists cause constipation and QT prolongation (IV ondansetron especially); dexamethasone causes insomnia, hyperglycaemia, agitation
Metoclopramide and prochlorperazine are D2 antagonists -> extrapyramidal reactions, particularly acute dystonia in the young

Prophylaxis is far more effective than rescue - once anticipatory nausea is established it is conditioned and hard to treat (benzodiazepine, lorazepam)
Match the antiemetic to the mechanism, not to habit
- Chemotherapy / metabolic (uraemia, hypercalcaemia, opioids) -> CTZ, use D2 or 5-HT3 antagonists
- Gastric stasis -> prokinetic metoclopramide (D2 antagonist + 5-HT4 agonist)
- Bowel obstruction -> haloperidol + octreotide; avoid prokinetics in complete obstruction
- Raised ICP -> dexamethasone
- Vestibular / motion -> H1 and antimuscarinic (promethazine, hyoscine), not ondansetron
Ondansetron does not work for vestibular or vestibular-opioid nausea - a common failure
Cannabinoids (nabilone) and dexamethasone remain second-line options

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