The 5-HT3 antagonists are a class of medications which 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.
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.
5-HT3 antagonists are ineffective in controlling motion sickness.
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.
- 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, it is the only 5-HT3 antagonist available as a generic drug in the United States. It is given one to three 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. It is an isoquinoline derivative, and is effective in preventing delayed CINV. Palonosetron was approved by the FDA in 2003, and is currently only available for intravenous use, although oral formulations are in clinical trials.
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 medications 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.
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 arrhythmias. 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.
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