Postoperative and postradiation nausea and vomiting—5-HT3-receptor antagonists are used to prevent or treat postoperative nausea and vomiting. Because of adverse effects and increased restrictions on the use of other antiemetic agents, 5-HT3-receptor antagonists are increasingly used for this indication. They are also effective in the prevention and treatment of nausea and vomiting in patients undergoing radiation therapy to the whole body or abdomen.
The 5-HT3-receptor antagonists are well-tolerated agents with excellent safety profiles. The most commonly reported adverse effects are headache, dizziness, and constipation. All four agents cause a small but statistically significant prolongation of the QT interval, but this is most pronounced with dolasetron. Although cardiac arrhythmias have not been linked to dolasetron, it should not be administered to patients with prolonged QT or in conjunction with other medications that may prolong the QT interval (see Chapter 14). Serotonin syndrome has been reported in patients taking 5-HT3-receptor antagonists in combination with other serotonergic drugs (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]; see Chapter 30).
No significant drug interactions have been reported with 5-HT3receptor antagonists. All four agents undergo some metabolism by the hepatic cytochrome P450 system, but they do not appear to affect the metabolism of other drugs. However, other drugs may reduce hepatic clearance of the 5-HT3-receptor antagonists, altering their half-life.
Corticosteroids (dexamethasone, methylprednisolone) have anti-emetic properties, but the basis for these effects is unknown. The pharmacology of this class of drugs is discussed in Chapter 39. These agents appear to enhance the efficacy of 5-HT3-receptor antagonists for prevention of acute and delayed nausea and vomiting in patients receiving moderately to highly emetogenic chemotherapy regimens. Although a number of corticosteroids have been used, dexamethasone, 8–20 mg intravenously before chemotherapy, followed by 8 mg/d orally for 2–4 days, is commonly administered.
Neurokinin 1 (NK1)-receptor antagonists have antiemetic properties that are mediated through central blockade in the area postrema. Aprepitant, netupitant, and rolapitant (all oral formulations) are highly selective NK1-receptor antagonists that cross the blood-brain barrier and occupy brain NK1 receptors. They have no affinity for serotonin, dopamine, or corticosteroid receptors. Netupitant (300 mg) is available only as a combination product with palonosetron (0.5 mg). Fosaprepitant is an intravenous formulation that is converted within 30 minutes after infusion to aprepitant.
The oral bioavailability of aprepitant is 65%, and the serum half-life is 12 hours. Netupitant and rolapitant have longer half-lives (90 and 180 hours, respectively), allowing single-dose administration. All three agents are metabolized by the liver, primarily by the CYP3A4 pathway.