Mechanism of the anti-emetic 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-hydroxytryptamine (5-HT) at 5-HT3 receptors on vagal afferent neurons 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.
Tyers
M B
MB
Glaxo Group Research Limited, Ware, UK.
Freeman
A J
AJ
D000932:Antiemetics; D001933:Brain Stem / Q000503:physiopathology; D004064:Digestive System / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D017294:Ondansetron; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists; D014839:Vomiting / Q000503:physiopathology*
D000932:Antiemetics; D007093:Imidazoles; D012702:Serotonin Antagonists; D012701:Serotonin; D017294:Ondansetron