Selective 5-HT3-receptor antagonists have potent antiemetic properties that are mediated in part through central 5-HT3receptor blockade in the vomiting center and chemoreceptor
Central nervous system Gastrointestinal tract and heart Vestibular system Fourth ventricle Medulla oblongata Parasympathetic and motor efferent activity Vomiting center Chemoreceptor trigger zone H1 receptor M1 receptor NK1 receptor? (5-HT3 receptor) Vomiting center (nucleus of tractus solitarius) Chemoreceptors D2 receptor NK1 receptor? (5-HT3 receptor) Chemoreceptor trigger zone (area postrema) H1 receptor? M1 receptor Mechanoreceptors Chemoreceptors 5-HT3 receptor Cortex Thalamus Hypothalamus Meninges Cranialnerve IXorX
FIGURE 62–6 Neurologic pathways involved in pathogenesis of nausea and vomiting (see text). (Adapted, with permission, from Krakauer EL et al: Case records of the Massachusetts General Hospital. N Engl J Med 2005;352:817. Copyright copy; 2005 Massachusetts Medical Society. Reprinted, with permission, from
Massachusetts Medical Society.) trigger zone but mainly through blockade of peripheral 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. The antiemetic action of these agents is restricted to emesis attributable to vagal stimulation (eg, postoperative) and chemotherapy; other emetic stimuli such as motion sickness are poorly controlled.
Four agents are available in the USA: ondansetron, granisetron, dolasetron, and palonosetron. (Tropisetron is available outside the USA.) The first three agents (ondansetron, granisetron, and dolasetron, Figure 62–5) have a serum half-life of 4–9 hours and may be administered once daily by oral or intravenous routes. All three drugs have comparable efficacy and tolerability when administered at equipotent doses. Palonosetron is a newer intravenous agent that has greater affinity for the 5-HT3 receptor and a long serum half-life of 40 hours. All four drugs undergo extensive hepatic metabolism and are eliminated by renal and hepatic excretion. However, dose reduction is not required in geriatric patients or patients with renal insufficiency. For patients with hepatic insufficiency, dose reduction may be required with ondansetron.
5-HT3-receptor antagonists do not inhibit dopamine or muscarinic receptors. They do not have effects on esophageal or gastric motility but may slow colonic transit.
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Chemotherapy-induced nausea and vomiting—5-HT3receptor antagonists are the primary agents for the prevention of acute chemotherapy-induced nausea and emesis. When used alone, these drugs have little or no efficacy for the prevention of delayed nausea and vomiting (ie, occurring >24 hours after chemotherapy). The drugs are most effective when given as a single dose by intravenous injection 30 minutes prior to administration of chemotherapy in the following doses: ondansetron, 8 mg; granisetron, 1 mg; dolasetron, 100 mg; or palonosetron, 0.25 mg. A single oral dose given 1 hour before chemotherapy may be equally effective in the following regimens: ondansetron 8 mg twice daily or 24 mg once; granisetron, 2 mg; dolasetron, 100 mg. Although 5-HT3-receptor antagonists are effective as single agents for the prevention of chemotherapy-induced nausea and vomiting, their efficacy is enhanced by combination therapy with a corticosteroid (dexamethasone), NK1-receptor antagonist, and a dopamine D2 antagonist (antipsychotics; see below).
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