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The 5-HT3 antagonists are a class of medications that act as receptor antagonists at the 5-hydroxytryptamine-3 receptor (5-HT3 receptor), a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain.With the notable exception of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

The 5-HT3 antagonists may be identified by the suffix –setron, and are classified under code A04AA of the WHO's Anatomical Therapeutic Chemical Classification System.


In 1957, J.H. Gaddum of the University of Edinburgh and Zuleika P. Picarelli of the Escola Paulista de Medicina published a landmark paper proposing the existence of two subtypes of serotonin receptor, the M and D receptors (thus named because their function could be blocked by morphine and Dibenzyline respectively). The 5-HT3 receptor was later found to correspond to the M receptor. In the 1970s, John R. Fozard reported that metoclopramide and cocaine were weak antagonists at the 5-HT3 (5-HT-M) receptor. Fozard later identified a tropane derivative, codenamed MDL 72222, as the first potent and truly selective 5-HT3 receptor antagonist. The antiemetic effects of metoclopramide where found to be partially due to its serotonin antagonism.

While Fozard was investigating cocaine analogues, workers at Sandoz identified a potent, selective 5-HT3 antagonist codenamed ICS 205-930, from which the first 5-HT3 antagonists to enter clinical use, ondansetron and granisetron, were developed. Several compounds related to MDL 72222 were later synthesized, eventually leading to tropisetron (approved in 1994) and dolasetron (1997).

Therapeutic uses

5-HT3 antagonists are most effective in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV), especially that caused by highly emetogenic drugs such as cisplatin; when used for this purpose, they may be given alone or, more frequently, with a glucocorticoid, usually dexamethasone. They are usually given intravenously, shortly before administration of the chemotherapeutic agent, although some authors have argued that oral administration may be preferred.The concomitant administration of a NK1 receptor antagonist, such as aprepitant, significantly increases the efficacy of 5-HT3 antagonists in preventing both acute and delayed CINV.

The 5-HT3 antagonists are also indicated in the prevention and treatment of radiation-induced nausea and vomiting (RINV), when needed, and postoperative nausea and vomiting (PONV). Although they are more effective at controlling CINV—where they stop symptoms altogether in up to 70% of people, and reduce them in the remaining 30%—, they are just as effective as other agents for PONV.

Current evidence suggests that 5-HT3 antagonists are ineffective in controlling motion sickness. A randomized, placebo-controlled trial of ondansetron to treat motion sickness in air ambulance personnel showed subjective improvement, but it was not statistically significant.


A small, open-label trial carried out in 2000 found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia.The study's patients also showed significant improvement in the disease's symptoms; a later double-blind, randomized controlled trial also found ondansetron to significantly improve schizophrenia symptoms when used as an adjunct to haloperidol, and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol.

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 Japanmarker 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.

Adverse effects

There are few side effects related to the use of 5-HT3 antagonists; the most common are constipation or diarrhea, headache, and dizziness. Unlike antihistamines with antiemetic properties such as cyclizine, 5-HT3 antagonists do not produce sedation, nor do they cause extrapyramidal effects, as phenothiazines (such as prochlorperazine) sometimes do.

All 5-HT3 antagonists have been associated with asymptomatic electrocardiogram changes, such as prolongation of the PT and QTc intervals and certain arrhythmia. The clinical significance of these side effects is unknown.


All 5-HT3 antagonists are well-absorbed and effective after oral administration, and all are metabolized in the liver by various isoenzymes of the cytochrome P450 system. They do not, however, inhibit or induce these enzymes.

Mechanism of action

As their name implies, 5-HT3 antagonists prevent serotonin from binding to 5-HT3 receptors. Such receptors are present mostly on the ends of afferent branches of the vagus nerve, which send signals directly to the brain's vomiting center in the medulla oblongata, and in the chemoreceptor trigger zone of the brain, which receives "input" from nausea-inducing agents in the bloodstream and communicates with the vomiting center. By preventing activation of these receptors, 5-HT3 antagonists interrupt one of the pathways that lead to vomiting.

The 5-HT3 antagonists are greatly selective, and have little affinity for other receptors, such as dopamine, histamine and muscarinic acetylcholine receptors.

See also



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