MECHANISM OF THE ANTIEMETIC ACTIVITY OF 5-HT3 RECEPTOR ANTAGONISTS

Ondansetron, a potent and highly selective 5-HT3 receptor antagonist, prevents emesis following chemotherapy by antagonising the action of 5-hydroxy-tryptamine (5-HT) at 5-HT3 receptors on vagal afferent neurones that innervate the gastrointestinal tract and 5-HT3 receptors in the central vomiting system. Evidence suggests that chemotherapy induces the release of 5-HT from enterochromaffin cells in the small intestine. This stimulates vagal afferent nerves via 5-HT3 receptors. Information is then relayed, via the vagus nerve, to the central vomiting system. 5-HT3 receptors are also found in the hind-brain vomiting system including the area postrema (the site of the chemoreceptor trigger zone for emesis). Therefore, following chemotherapy, 5-HT activates 5-HT3 receptors at 2 sites to induce emesis. Clinical data showing that a single dose of ondansetron prevents acute emesis suggest that it is important to block the initiation of the emetic reflex. This may prevent the recruitment of central mechanisms involving 5-HT3 receptors.