5-HT3 Antagonist - Available Agents

Available Agents

• Ondansetron (trade name Zofran in most countries) was the first 5-HT₃ antagonist, developed by Glaxo around 1984. Its efficacy was first established in 1987, in animal models, and it was extensively studied over the following years. Ondansetron was approved by the U.S. Food and Drug Administration in 1991, and has since become available in several other countries, including the UK, Ireland, Australia, Canada, France and Brazil. As of 2008, ondansetron and granisetron are the only 5-HT₃ antagonists available as a generic drug in the United States. Ondansetron may be given several times daily, depending on the severity of symptoms.
• Tropisetron (trade name Navoban) was also first described in 1984. It is available in several countries, such as the UK, Australia and France, but not in the United States. The effects of tropisetron last up to 24 hours, so it only requires once-daily administration.
• Granisetron (trade name Kytril) was developed around 1988. It is available in the U.S., UK, Australia and other countries. Clinical trials suggest that it is more effective than other 5-HT₃ antagonists in preventing delayed CINV (nausea and vomiting that occur more than 24 hours after the first dose of chemotherapy). It is taken once daily.
• Dolasetron (U.S. trade name Anzemet) was first mentioned in the literature in 1989. It is a prodrug, and most of its effects are due to its active metabolite, hydrodolasetron, which is formed in the liver by the enzyme carbonyl reductase. Dolasetron was approved by the FDA in 1997, and is also administered once daily.
• Palonosetron (trade name Aloxi) is the newest 5-HT₃ antagonist to become available in the U.S. market. It is an isoquinoline derivative, and is effective in preventing delayed CINV. Palonosetron was approved by the FDA in 2003, initially for intravenous use. An oral formulation was approved on August 22, 2008 for prevention of acute CINV alone, as a large clinical trial did not show oral administration to be as effective as IV use against delayed CINV.
• Ramosetron (trade name Nasea) is only available in Japan and certain Southeast Asian countries as of 2008. It has higher affinity for the 5-HT₃ receptor than the older 5-HT₃ antagonists, and maintains its effects over two days; it is therefore significantly more effective for delayed CINV. In animal studies, ramosetron was also effective against irritable bowel syndrome-like symptoms.

Alosetron and cilansetron—the latter being developed by Solvay—are not antiemetics; instead, they are indicated in the treatment of a subset of irritable bowel syndrome where diarrhea is the dominant symptom. Alosetron was withdrawn from the U.S. market in 2000 due to unacceptably frequent severe side effects, and is only available through a restrictive program to patients who meet certain requirements.

Certain prokinetic drugs such as cisapride, renzapride and metoclopramide, although not 5-HT₃ antagonists proper, possess some weak antagonist effect at the 5-HT₃ receptor. Galanolactone, a diterpenoid found in ginger, is a 5-HT₃ antagonist and is believed to at least partially mediate the anti-emetic activity of this plant. Mirtazapine (trade name Remeron) is a tetracyclic antidepressant with 5-HT₃ antagonist effects and strong anti-emetic properties. Studies show mirtazapine as equally effective in treating chemotherapy-related nausea and vomiting as standard treatments; it is also cheaper and has fewer side effects than typical anti-emetics, and its antidepressant qualities may be an added benefit for cancer populations. Mirtazapine has also been used in the treatment of the motility disorder gastroparesis due to its anti-emetic effects. Olanzapine (trade name Zyprexa), an atypical antipsychotic with anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.