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, preventing nausea and vomiting by inhibiting the action of serotonin. This mechanism of action is supported by the study published in the Journal of the National Comprehensive Cancer Network in 2009 1, which discusses the development of 5-HT3–receptor antagonists, including ondansetron, as a significant advance in antiemetic therapy.

Key Points

• The study highlights that ondansetron, along with other 5-HT3 antagonists such as granisetron and dolasetron, has been shown to be effective in controlling acute chemotherapy-induced nausea and/or vomiting 1.
• Ondansetron's effectiveness in preventing acute emesis is well-documented, but it seems to be less effective in preventing delayed emesis compared to intravenous palonosetron 1.
• The medication's mechanism of action involves interrupting the pathway triggered by serotonin binding to 5-HT3 receptors, which normally triggers the vomiting reflex.
• Ondansetron has a favorable side effect profile due to its minimal effect on other serotonin receptor subtypes.
• The drug can be administered orally, intravenously, or as an orally disintegrating tablet, and it begins working within 30 minutes of administration.

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

The mechanism of action of ondansetron (Zofran) can be described as follows:

• Ondansetron is a highly potent and selective antagonist at 5-HT3 receptors 3, 4.
• It prevents emesis by antagonizing 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 4.
• The anti-emetic actions of ondansetron are thought to occur at two specific sites:
  • Centrally, in the area postrema/nucleus tractus solitarius (NTS) 3.
  • Peripherally, on vagus nerve terminals 3, 4.
• Ondansetron blocks nausea and vomiting by 5-HT3 receptor antagonism, which is essential for the initiation of the emetic reflex 4.

Key Findings

• Chemotherapy induces the release of 5-HT from enterochromaffin cells in the small intestine, stimulating vagal afferent nerves via 5-HT3 receptors 4.
• 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.
• Ondansetron has been shown to provide excellent control of nausea and vomiting in patients treated with cisplatin and other highly emetogenic drugs 5, 6, 7.