receptors present in vomiting centre and CTZ. 2. ANTIMETIC DRUGS AND HOW THEY WORK(receptor blockers)
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antiemetic drugs receptor sites vomiting center CTZ mechanism diagram
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Receptors in the Vomiting Centre and CTZ - Plus Antiemetic Drugs
Overview Diagram
PART 1: Receptors at Each Site
Vomiting Centre (VC)
- Location: Lateral medullary reticular formation (loosely organized neuronal network); interacts with cranial nerves VIII and X and the nucleus tractus solitarius
- Receptors present:
Receptor Type Muscarinic M1 Cholinergic Histamine H1 Histaminergic Neurokinin 1 (NK1) Substance P receptor Serotonin 5-HT3 Serotonergic
Chemoreceptor Trigger Zone (CTZ) / Area Postrema
- Location: Caudal end of the 4th ventricle (floor); circumventricular organ - outside the blood-brain barrier, so it directly samples blood and CSF for emetogenic chemicals
- Receptors present:
Receptor Type Dopamine D2 Dopaminergic (predominant) Opioid receptors mu, delta, kappa Serotonin 5-HT3 Serotonergic Neurokinin 1 (NK1) Substance P
Vestibular System (inputs to VC)
- Muscarinic M2 receptors
- Histamine H1 receptors
- (Key in motion sickness)
GI Tract / Vagal Afferents (peripheral inputs to VC and CTZ)
- Serotonin 5-HT3 receptors on vagal and splanchnic afferent nerves
- Enterochromaffin cells release 5-HT in response to mucosal damage, chemotherapy, radiation, distension
PART 2: Antiemetic Drugs and Their Receptor Mechanisms
1. 5-HT3 Receptor Antagonists (Setrons)
Drugs: Ondansetron, Granisetron, Dolasetron, Palonosetron (2nd gen), Tropisetron, Ramosetron
Mechanism: Block 5-HT3 receptors both centrally (VC + CTZ) and peripherally (vagal afferents in GI tract). The peripheral action is actually the dominant antiemetic effect - they prevent serotonin released from enterochromaffin cells from activating vagal afferents.
Uses: Chemotherapy-induced nausea & vomiting (CINV), post-operative N&V, radiation-induced N&V
Key facts:
- Do NOT block dopamine or muscarinic receptors
- 1st-gen agents (ondansetron, granisetron, dolasetron): half-life 4-9 hours; can prolong QT interval
- Palonosetron: half-life 40 hours, greater 5-HT3 affinity, effective for both acute and delayed CINV, does not prolong QT
2. Dopamine D2 Antagonists
Drugs: Metoclopramide, Domperidone (peripheral), Prochlorperazine, Haloperidol, Droperidol
Mechanism: Block D2 receptors in the CTZ, reducing CTZ stimulation of the vomiting centre. Metoclopramide also acts peripherally as a D2 antagonist (prokinetic). Domperidone acts only peripherally (does not cross BBB - fewer CNS side effects).
Uses: Medication-induced N&V, toxin-induced N&V, metabolic causes, gastroparesis
Adverse effects: Extrapyramidal symptoms (EPS) - dystonia, akathisia, tardive dyskinesia (from D2 blockade in basal ganglia)
3. H1 Antihistamines
Drugs: Dimenhydrinate, Meclizine, Cyclizine, Promethazine
Mechanism: Block H1 receptors in the vomiting centre and vestibular system. These agents are most effective when the emetic stimulus comes via the vestibular pathway.
Uses: Motion sickness, labyrinthine disorders (vestibular neuritis, Meniere's disease)
Limitation: Ineffective against substances that directly activate the CTZ
4. Muscarinic (M1/M2) Antagonists (Anticholinergics)
Drugs: Scopolamine (hyoscine), Hyoscine hydrobromide
Mechanism: Block muscarinic receptors in the vomiting centre (M1) and vestibular system (M2), reducing afferent input from the vestibular apparatus to the VC.
Uses: Motion sickness (transdermal patch is very effective), post-operative N&V
Limitation: Ineffective against CTZ-mediated vomiting
5. NK1 (Neurokinin-1) Receptor Antagonists
Drugs: Aprepitant, Fosaprepitant (IV prodrug), Netupitant, Rolapitant
Mechanism: Block NK1 receptors (substance P receptors) centrally in the area postrema (CTZ) and the vomiting centre. They cross the BBB and occupy brain NK1 receptors. Have NO affinity for serotonin, dopamine, or corticosteroid receptors.
Uses: Acute AND delayed CINV (especially with highly emetogenic chemotherapy); added to 5-HT3 antagonist + dexamethasone triple-drug regimen
Key facts: Combined NK1 + 5-HT3 + dexamethasone prevents acute emesis in 80-90% vs <70% without NK1 antagonist. Metabolized by CYP3A4 (important drug interactions).
6. Corticosteroids
Drugs: Dexamethasone, Methylprednisolone
Mechanism: Unknown - but they enhance the efficacy of 5-HT3 antagonists. Possibly involve prostaglandin inhibition or direct CNS effects.
Uses: Chemotherapy-induced N&V (combined with 5-HT3 antagonists and NK1 antagonists)
7. Cannabinoids
Drugs: Dronabinol (THC), Nabilone
Mechanism: Act on CB1 cannabinoid receptors in the CNS (brainstem and higher cortical areas), suppressing emetic pathways.
Uses: Chemotherapy-induced N&V (second-line)
8. Atypical Antipsychotics
Drugs: Olanzapine (blocks D2, 5-HT2, H1, muscarinic receptors), Mirtazapine
Mechanism: Broad receptor blockade across multiple pathways - D2, 5-HT2, H1, and muscarinic.
Uses: CINV (olanzapine 10 mg days 1-4 added to triple therapy reduces delayed emesis by 15-30%), chronic nausea/vomiting syndrome
Quick Summary Table
| Drug Class | Receptor Blocked | Key Site | Clinical Use |
|---|---|---|---|
| 5-HT3 antagonists (setrons) | 5-HT3 | CTZ + vagal afferents | CINV, PONV, radiation |
| D2 antagonists (metoclopramide, prochlorperazine) | Dopamine D2 | CTZ | Drug/toxin/metabolic N&V |
| H1 antihistamines (meclizine, dimenhydrinate) | H1 | VC + vestibular | Motion sickness |
| Anticholinergics (scopolamine) | M1/M2 | VC + vestibular | Motion sickness |
| NK1 antagonists (aprepitant) | NK1 | CTZ + VC | Delayed CINV |
| Corticosteroids (dexamethasone) | Unknown | CNS | Adjunct in CINV |
| Cannabinoids (dronabinol) | CB1 | CNS | CINV (2nd line) |
| Olanzapine | D2, 5-HT2, H1, M | Multiple | CINV |
Sources: Katzung's Basic & Clinical Pharmacology 16th Edition; Lippincott Illustrated Reviews Pharmacology; Harrison's Principles of Internal Medicine 22E; Rosen's Emergency Medicine
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