Motility Pharmacology: Prokinetics and Antiemetics
Vomiting reflex pathways · Prokinetic agents · Antiemetic drug classes · Gastroparesis management
Vomiting Reflex: Four Afferent Inputs
Input 1
Chemoreceptor Trigger Zone
  • Outside blood-brain barrier
  • Blood-borne emetogenic agents, opioids, toxins
  • D2, 5-HT3, NK1 receptors
  • Target: dopamine antagonists, 5-HT3 antagonists, NK1 antagonists
Input 2
GI Vagal Afferents
  • Enterochromaffin cells release serotonin
  • Triggered by chemotherapy, mucosal injury, distension
  • Drives acute CINV (0–24 hours)
  • Target: serotonin 5-HT3 receptor antagonists
Input 3
Vestibular Nuclei
  • Motion sickness, labyrinthine disorders
  • Muscarinic M1 receptors
  • Target: scopolamine
Input 4
Cortical Centers
  • Anticipatory nausea, psychological triggers
  • Learned associations
  • Target: benzodiazepines, behavioral therapy
Prokinetic Agents
Drug Mechanism Key Advantage Key Risk / Limitation
Metoclopramide D2 antagonist (central + peripheral) Only FDA-approved agent for gastroparesis Tardive dyskinesia (irreversible); 12-week maximum; avoid in Parkinson disease
Domperidone D2 antagonist (peripheral only — P-gp substrate) No extrapyramidal effects QTc prolongation; not FDA-approved; expanded access only
Erythromycin Motilin receptor agonist Most potent prokinetic; useful for acute crisis Tachyphylaxis within weeks; CYP3A4 inhibitor; QTc risk
Antiemetic Drug Classes
5-HT3 Antagonists
Ondansetron, Palonosetron
  • Block vagal serotonin afferents + nucleus tractus solitarius
  • Acute CINV and postoperative nausea and vomiting
  • Ondansetron: QTc risk; IV dose ≤32 mg
  • Palonosetron: longer half-life, superior delayed CINV, no QTc risk
  • Adverse effects: constipation, headache
NK1 Antagonists
Aprepitant, Fosaprepitant
  • Block substance P at neurokinin 1 receptors
  • Delayed CINV (days 2–5 post-chemotherapy)
  • Aprepitant: moderate CYP3A4 inhibitor → reduce dexamethasone dose ~50%
  • Induces CYP2C9 → monitor international normalized ratio on warfarin
  • Netupitant + palonosetron: fixed-dose combination
Other Antiemetics
D2 Antagonists, Scopolamine, Dronabinol
  • Prochlorperazine / haloperidol: D2 blockade at chemoreceptor trigger zone; extrapyramidal risk
  • Dexamethasone: adjunct; +15–25% complete response with serotonin antagonists
  • Scopolamine patch: muscarinic M1 blocker; motion sickness; anticholinergic effects
  • Dronabinol: CB1 agonist; refractory CINV; Schedule III; dysphoria, sedation
Critical Rule — Metoclopramide

Maximum 12-week use for any indication. Document start date at prescription. Tardive dyskinesia is often irreversible. Do not prescribe to patients with Parkinson disease or prior tardive dyskinesia.