Antiemetics and Prokinetic Drugs

Antiemetics and Prokinetic Drugs

1. Physiology of emesis — the substrate for antiemetic action

• Vomiting (emesis) is a complex, coordinated protective reflex that rids the upper gut of toxic/noxious substances; nausea is the accompanying aversive sensation that conditions future avoidance (an unconditioned aversive stimulus for learning) (G&G 14e Ch.54, p.1099–1100).
• The reflex is coordinated by a central emesis ("vomiting") centre — a loosely organised neuronal region in the lateral reticular formation of the medulla, adjacent to the chemoreceptor trigger zone and nucleus tractus solitarius; it integrates with cranial nerves VIII and X and the respiratory, salivatory and vasomotor centres (G&G 14e Ch.54, p.1100; Katzung 16e Ch.62, p.1169).
• Four major afferent inputs converge on the vomiting centre (Katzung 16e Ch.62, pp.1169–70; KDT 8e Ch.48, pp.709–10):
  • Chemoreceptor trigger zone (CTZ) — located in the area postrema at the floor of the fourth ventricle; it lies outside the blood–brain barrier, so it samples blood- and CSF-borne emetogens (drugs, toxins, metabolites, hormones). Rich in D₂, 5-HT₃, M₁, NK₁, CB₁, opioid µ receptors.
  • Vagal and spinal (splanchnic) afferents from the GIT — densely express 5-HT₃ receptors; mucosal irritation (chemotherapy, radiation, distension, gastroenteritis) releases 5-HT from enterochromaffin (EC) cells, activating 5-HT₃ on vagal afferents → impulses to NTS and CTZ.
  • Vestibular apparatus (via cranial nerve VIII) — mediates motion sickness; rich in muscarinic M₁ and histamine H₁ receptors; relays largely via the cerebellum.
  • Higher cortical centres — mediate vomiting from psychiatric disorders, stress, noxious sensory stimuli (bad odour/sight/pain), and anticipatory nausea/vomiting (e.g. before a repeat cisplatin cycle) (KDT 8e Ch.48, p.709).
• The NTS (nucleus tractus solitarius) is the key relay for visceral afferents; it is rich in receptors for enkephalin, histamine, ACh and 5-HT₃ (G&G 14e Ch.54, p.1100).
• Mediator detail: cytotoxic drugs, radiation and GI irritants release 5-HT from EC cells acting on 5-HT₃ receptors on extrinsic primary afferent neurones (PAN) of the enteric nervous system; large releases can spill 5-HT into the circulation to reach the CTZ. 5-HT is not the only mediator — substance P (NK₁) and other peptides participate (KDT 8e Ch.48, p.709).
• Brain centres for nausea differ from those for emesis — nausea is processed in higher regions (insular, anterior cingulate, orbitofrontal, somatosensory, prefrontal cortices); consequently most antiemetics are relatively poor at preventing nausea even when they abolish vomiting (G&G 14e Ch.54, p.1100).
• Mechanics of the emetic act: nausea is accompanied by reduced gastric tone/peristalsis; in the emetic response the fundus, body of stomach, oesophageal sphincter and oesophagus relax, the glottis closes, while the duodenum and pyloric stomach contract retrogradely; rhythmic contraction of diaphragm + abdominal muscles then compresses the stomach and ejects contents. Conditions inhibiting gastric emptying predispose to vomiting (KDT 8e Ch.48, p.709).