What is the mechanism of action of ondansetron (Zofran)?

From the Guidelines

Ondansetron works by blocking serotonin 5-HT3 receptors in the chemoreceptor trigger zone of the brain and in the gastrointestinal tract, effectively preventing nausea and vomiting by inhibiting serotonin from binding to these receptors. This mechanism of action is supported by the most recent and highest quality study available, which highlights the importance of 5-HT3 receptor antagonists in preventing acute chemotherapy-induced nausea and vomiting 1.

Mechanism of Action

The mechanism of action of ondansetron involves the selective antagonism of serotonin 5-HT3 receptors, which are located in the chemoreceptor trigger zone of the brain and in the gastrointestinal tract. Serotonin is released from enterochromaffin cells in the small intestine in response to various stimuli such as chemotherapy, radiation, or surgical procedures, which then activates vagal afferents via 5-HT3 receptors, triggering the vomiting reflex. By selectively antagonizing these receptors, ondansetron interrupts this pathway, making it particularly effective for managing chemotherapy-induced, radiation-induced, and postoperative nausea and vomiting.

Clinical Evidence

Clinical trials have demonstrated the efficacy of ondansetron in preventing acute nausea and vomiting induced by chemotherapy, with studies showing that it is equally effective as other 5-HT3 receptor antagonists such as granisetron and dolasetron 1. However, palonosetron has been shown to have a higher binding affinity for the 5-HT3 receptor and a longer half-life, making it more effective in preventing delayed emesis 1.

Formulations and Dosing

Ondansetron is available in various formulations, including oral tablets, orally disintegrating tablets, oral solution, and injectable forms, with typical adult dosing ranging from 4-8 mg administered every 8-12 hours depending on the indication 1. The choice of formulation and dosing schedule may depend on the specific clinical context and patient factors, such as the emetogenic potential of the chemotherapy regimen and the patient's medical history.

Comparison with Other Antiemetics

Ondansetron's selective action on 5-HT3 receptors gives it an advantage over older antiemetics, as it produces fewer side effects like sedation or extrapyramidal symptoms. However, the choice of antiemetic agent may depend on the specific clinical context and patient factors, such as the emetogenic potential of the chemotherapy regimen and the patient's medical history. Recent guidelines recommend the use of a combination of antiemetic agents, including a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone, for the prevention of acute and delayed nausea and vomiting induced by chemotherapy 1.

From the FDA Drug Label

1. 1 Mechanism of Action Ondansetron is a selective 5-HT 3receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT 3type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema It is not certain whether ondansetron’s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion increases after cisplatin administration in parallel with the onset of emesis The released serotonin may stimulate the vagal afferents through the 5-HT 3receptors and initiate the vomiting reflex.

The mechanism of action of ondansetron (Zofran) is as a selective 5-HT3 receptor antagonist. It works by blocking the action of serotonin at the 5-HT3 receptors, which are found in the vagal nerve terminals and the chemoreceptor trigger zone of the area postrema. This blocking action may help to prevent the vomiting reflex that is triggered by the release of serotonin from the enterochromaffin cells of the small intestine during cytotoxic chemotherapy. The exact site of action (central, peripheral, or both) is not certain 2. Key points about the mechanism of action of ondansetron include:

• Selective 5-HT3 receptor antagonist
• Blocks the action of serotonin at the 5-HT3 receptors
• May prevent the vomiting reflex triggered by chemotherapy
• Exact site of action is uncertain 2

From the Research

Mechanism of Action of Ondansetron

• Ondansetron is a highly potent and selective antagonist at 5-HT3 receptors, which are located at highest densities in the area postrema, nucleus tractus solitarius (NTS), and on afferent terminals of the vagus nerve 3.
• The anti-emetic actions of ondansetron are thought to be mediated by its ability to block nausea and vomiting by 5-HT3 receptor antagonism at two specific sites: centrally, in the area postrema/NTS, and peripherally on vagus nerve terminals 3.
• Chemotherapy induces the release of 5-HT from enterochromaffin cells in the small intestine, which stimulates vagal afferent nerves via 5-HT3 receptors, leading to emesis 4.
• Ondansetron prevents emesis by antagonizing the action of 5-HT at 5-HT3 receptors on vagal afferent neurons and in the central vomiting system, including the area postrema 4.
• The drug's anti-emetic activity is also attributed to its ability to block the initiation of the emetic reflex, preventing the recruitment of central mechanisms involving 5-HT3 receptors 4.

Sites of Action

• 5-HT3 receptors are found in the hind-brain vomiting system, including the area postrema, which is the site of the chemoreceptor trigger zone for emesis 4, 5.
• Ondansetron's action on 5-HT3 receptors in the GI tract and the brain contributes to its anti-emetic effects 5, 6.
• The drug's ability to antagonize 5-HT3 receptors in the chemoreceptor trigger zone and in the GI tract makes it an effective anti-emetic agent 6, 7.

Pharmacokinetics and Efficacy

• Ondansetron is well absorbed after oral administration, with peak plasma concentrations occurring approximately one hour after an oral dose and 6 to 20 minutes after an i.v. dose 6.
• The mean elimination half-life of ondansetron is approximately 3.5 hours in healthy volunteers, but it is extended in elderly patients 6, 7.
• Clinical trials have shown that ondansetron provides excellent control of nausea and vomiting in patients treated with cisplatin and other emetogenic chemotherapy agents 6, 7.