5-HT₃ receptor antagonists, such as dolasetron, granisetron (Kytril), ondansetron (Zofran), and palonosetron (Axoli), are crucial in managing chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea. These drugs selectively block 5-HT₃ receptors in the visceral vagal and spinal afferent nerves, chemoreceptor trigger zone, and the vomiting center. They have a rapid onset of action and can be given as a single dose before chemotherapy. Ondansetron and granisetron, in particular, can prevent emesis in 50% to 60% of patients treated with the chemotherapy drug cisplatin (Platinol).

The liver extensively metabolizes these drugs, with excretion primarily via urine. Ondansetron requires dosage adjustments for hepatic insufficiency. These drugs do not inhibit dopamine or muscarinic receptors and do not affect esophageal or gastric motility. These antagonists are also effective in treating hyperemesis of pregnancy and upper abdominal irradiation-induced nausea. However, they may cause adverse effects, including constipation, diarrhea, headache, and lightheadedness. All of these drugs are associated with QT prolongation, especially when combined with other drugs and anesthetics, which can lead to cardiac arrest. They are also associated with serotonin syndrome when combined with other serotonergic drugs. However, their efficacy may be enhanced in combination therapy with corticosteroids, NK1 receptor antagonists, and dopamine D2 antagonists.