Anti-emetic Drugs — Vomiting Pathways, Receptor Classes and Drug of Choice by Situation

The chemoreceptor trigger zone (CTZ) lies in the area postrema, on the dorsal surface of the medulla oblongata in the floor of the fourth ventricle. Here the blood-brain barrier is permeable, so the CTZ can detect emetic toxins in both blood and CSF. It relays this information to the neighbouring nucleus tractus solitarius (NTS) and on to the vomiting centre (StatPearls — Chemoreceptor Trigger Zone).

The CTZ is only one input. The vomiting centre also receives signals from the gastrointestinal tract (vagal afferents, which also end in the NTS), the vestibular system, and higher centres in the cortex and thalamus. Modern physiology describes the 'vomiting centre' not as one nucleus but as loosely organised medullary neurons driven in sequence by a central pattern generator.

StatPearls groups anti-emetics by mechanism: serotonin (5-HT3) antagonists, glucocorticoids, anticholinergics, NK1 antagonists, dopamine antagonists, cannabinoids and antihistamines, with benzodiazepines and others as adjuncts.

Gastric irritation or cell damage — the classic example is cytotoxic chemotherapy — makes the gut release serotonin, which stimulates 5-HT3 receptors on vagal afferent terminals; the signal travels to the NTS and triggers vomiting. Ondansetron blocks 5-HT3 receptors both peripherally (vagal terminals) and centrally (area postrema); StatPearls notes that the peripheral action is thought to be the predominant mechanism.

• Approved uses of ondansetron: prevention of chemotherapy-induced, radiation-induced and postoperative nausea and vomiting. Pregnancy use is off-label.
• Palonosetron is the second-generation drug with higher binding affinity for the 5-HT3 receptor. All 5-HT3 antagonists prevent acute chemotherapy-induced vomiting; ondansetron and palonosetron also help with delayed vomiting.
• Commonest adverse effects: headache, fatigue, constipation.
• QT prolongation is dose-dependent. The FDA warned about a single 32 mg IV dose of ondansetron; 16 mg IV is the maximum recommended single dose.
• Labelling also warns of serotonin syndrome when combined with other serotonergic drugs (SSRIs, SNRIs, MAOIs).
• Ondansetron is metabolised by CYP3A4, CYP2D6 and CYP1A2; patients with high CYP2D6 activity respond less.

Metoclopramide blocks central and peripheral D2 receptors in the CTZ. It is also a 5-HT3 antagonist (at higher doses) and a 5-HT4 agonist, so it is a prokinetic: it raises lower oesophageal sphincter tone, relaxes the pylorus and duodenal bulb, and speeds gastric emptying. FDA-approved uses are nausea and vomiting with GERD and diabetic gastroparesis.

Domperidone blocks peripheral D2 receptors only (Australian Prescriber). Because it does not readily cross the blood-brain barrier, dystonic reactions are rare — which is why it is preferred for gastrointestinal symptoms in Parkinson disease, where centrally acting D2 blockers worsen the disease. Its downside is the heart: arrhythmias, sudden death and cardiac arrest were reported with high intravenous doses, and oral doses above 30 mg/day need caution, especially in patients older than 60.

Droperidol and haloperidol (butyrophenones) are effective anti-emetics but have fallen out of favour because of dose-dependent QT prolongation. Phenothiazines such as prochlorperazine are available orally, IV and rectally; their extrapyramidal effects mirror those of metoclopramide.

Motion sickness arises from a sensory conflict between visual, vestibular and somatosensory input. The vestibular nuclei feed the vomiting centre through histamine H1 and muscarinic synapses, so the drugs that work are antihistamines (promethazine, cyclizine, meclizine, dimenhydrinate) and anticholinergics (hyoscine).

• Hyoscine (scopolamine) is described by StatPearls as the most effective agent for motion sickness, acting as a non-selective antimuscarinic that inhibits input to the vestibular nuclei. Its FDA-approved indications are motion sickness and PONV; the commonest form is a transdermal patch, used prophylactically.
• Hyoscine contraindications: hypersensitivity to belladonna alkaloids and angle-closure glaucoma (mydriasis can precipitate it).
• Antihistamines cause sedation and anticholinergic effects (dry mouth, blurred vision, constipation, worsening of narrow-angle glaucoma). Meclizine is used mainly for motion sickness and vertigo.
• Promethazine also blocks D2 receptors. Children younger than 2 years are at increased risk of respiratory depression, and the injection carries a boxed warning for tissue necrosis and gangrene.
• Diphenhydramine and dimenhydrinate are about as effective as dexamethasone and droperidol for preventing PONV (StatPearls).

Aprepitant is a highly selective antagonist of the neurokinin-1 (NK1) receptor, whose natural ligand is substance P. NK1 receptors are found in both the central and peripheral nervous system. Aprepitant is given orally; fosaprepitant is its IV prodrug. It is metabolised mainly by CYP3A4, and is itself a dose-dependent inhibitor and inducer of CYP3A4 — the source of its drug interactions.

For highly emetogenic chemotherapy, StatPearls gives a standard regimen of aprepitant 125 mg orally 1 hour before chemotherapy on day 1 and 80 mg on days 2 and 3, combined with a 5-HT3 antagonist and dexamethasone.

• Dexamethasone — mechanism not clearly understood; proposed actions include reduced prostaglandin synthesis and changes in blood-brain barrier permeability. Short courses cause mainly insomnia and mood change. Widely studied in chemotherapy and PONV.
• Cannabinoids (dronabinol, nabilone) — modest benefit; vertigo, hypotension and dysphoria limit use. A systematic review found them better than placebo but not better than prochlorperazine.
• Olanzapine is now recommended as part of first-line management of highly emetogenic chemotherapy (Australian Prescriber).
• Benzodiazepines (lorazepam) reduce anxiety and anticipatory vomiting as adjuncts.

Nausea and vomiting affect up to 90% of women in the first trimester. Hyperemesis gravidarum is the severe end — persistent vomiting with weight loss (often more than 5% of pre-pregnancy weight), dehydration, ketonuria and electrolyte disturbance. StatPearls summarises the ACOG stepped regimen:

1. First line: pyridoxine (vitamin B6) alone or combined with doxylamine (an antihistamine).
2. Second line (added): antihistamines such as dimenhydrinate or diphenhydramine; dopamine antagonists such as prochlorperazine or promethazine.
3. Third line (added): metoclopramide, ondansetron or trimethobenzamide.
4. Inpatient: IV fluids, IV anti-emetics, and thiamine with IV multivitamins to prevent Wernicke encephalopathy.

• Do not give metoclopramide when vomiting may be from bowel obstruction — StatPearls also warns not to overlook surgical emergencies (obstruction, perforation, appendicitis) when treating nausea empirically.
• Dopamine antagonists are listed as contraindicated in children under 2 years or under 9 kg, and should be avoided in Parkinson disease.
• An acute dystonic reaction to metoclopramide is a classic vignette: young patient, oculogyric crisis or torticollis hours after an anti-emetic.

• Site of action — the CTZ lies in the area postrema, floor of the fourth ventricle, outside an effective blood-brain barrier.
• Drug of choice — chemotherapy (5-HT3 + NK1 + dexamethasone), motion sickness (hyoscine), pregnancy (pyridoxine-doxylamine), Parkinson disease (domperidone).
• Mechanism match — aprepitant = NK1/substance P; ondansetron = 5-HT3; metoclopramide = D2 block + 5-HT4 agonism; hyoscine = muscarinic.
• Adverse effect — EPS with metoclopramide; QT with ondansetron and domperidone; tardive dyskinesia boxed warning.
• Contraindication — metoclopramide in GI obstruction and phaeochromocytoma; hyoscine in angle-closure glaucoma.