5-HT3 antagonist

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


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.[1]

The 5-HT3 antagonists may be identified by the suffix –setron,[2] and are classified under code A04AA of the WHO's Anatomical Therapeutic Chemical Classification System.

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,[3] although some authors have argued that oral administration may be preferred.[4] 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.[5]

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.[6][7]


A small, open-label trial carried out in 2000 found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia.[8][9] 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.[10]

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,[11][12] and it was extensively studied over the following years.[13] 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 2007, 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.[14] 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.[15] 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).[16] It is taken once daily.
  • Dolasetron (U.S. trade name Anzemet) was first mentioned in the literature in 1989.[17] 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.[18] Palonosetron was approved by the FDA in 2003,[19] and is currently only available for intravenous use, although oral formulations are in clinical trials.[18]

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.[20]

Certain medications such as cisapride, renzapride and metoclopramide, although not 5-HT3 antagonists proper, possess some weak antagonist effect at the 5-HT3 receptor.

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.[21] 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.[21] The clinical significance of these side effects is unknown.


All 5-HT3 antagonists are well-absorbed and effective after oral administration,[4][21] and all are metabolized in the liver by various isoenzymes of the cytochrome P450 system. They do not, however, inhibit or induce these enzymes.[21]

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 negligible affinity for other receptors, such as dopamine, histamine and muscarinic acetylcholine receptors.[21]


  1. de Wit R, Aapro M, Blower PR (2005). "Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients?". Cancer Chemother Pharmacol. 56 (3): 231–8. doi:10.1007/s00280-005-1033-0. PMID 15838653.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. World Health Organization (2006). Template:PDFlink. Geneva: WHO Press. Retrieved on 2007-05-15.
  3. Herrstedt J, Aapro MS, Roila F, Kataja VV (2005). Template:PDFlink Ann Oncol 16 Suppl 1: i77–9. PMID 15888767. doi:10.1093/annonc/mdi805
  4. 4.0 4.1 Lindley C, Blower P (2000). "Oral serotonin type 3-receptor antagonists for prevention of chemotherapy-induced emesis". Am J Health-Syst Pharm. 57 (18): 1685–97. PMID 11006796.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> Free full text with registration at Medscape
  5. Roila F, Fatigoni S (2006). "New antiemetic drugs" (PDF). Ann Oncol. 17 Suppl 2: ii96–100. doi:10.1093/annonc/mdj936. PMID 16608997.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  6. Stott JR, Barnes GR, Wright RJ, Ruddock CJ (1989). "The effect on motion sickness and oculomotor function of GR 38032F, a 5-HT3-receptor antagonist with anti-emetic properties". British journal of clinical pharmacology. 27 (2): 147–57. PMID 2523720.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  7. Levine ME, Chillas JC, Stern RM, Knox GW (2000). "The effects of serotonin (5-HT3) receptor antagonists on gastric tachyarrhythmia and the symptoms of motion sickness". Aviation, space, and environmental medicine. 71 (11): 1111–4. PMID 11086664.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  8. Zullino DF, Eap CB, Voirol P (2001). "Ondansetron for tardive dyskinesia". Am J Psychiatry. 158 (4): 657–8. PMID 11282718.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. Sirota P, Mosheva T, Shabtay H, Giladi N, Korczyn AD (2000). "Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia". Am J Psychiatry. 157 (2): 287–9. PMID 10671405.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> Free full text
  10. Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ (2006). "Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study". Schizophr Res. 88 (1–3): 102–10. doi:10.1016/j.schres.2006.07.010. PMID 16959472.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  11. Hagan RM, Butler A, Hill JM, Jordan CC, Ireland SJ, Tyers MB (1987). "Effect of the 5-HT3 receptor antagonist, GR38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of the rat brain". Eur. J. Pharmacol. 138 (2): 303–5. PMID 2442006.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  12. Costall B, Gunning SJ, Naylor RJ, Tyers MB (1987). "The effect of GR38032F, novel 5-HT3-receptor antagonist on gastric emptying in the guinea-pig". Br. J. Pharmacol. 91 (2): 263–4. PMID 2955843.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  13. See Eur J Cancer Clin Oncol 1989; 25 Suppl 1.
  14. Donatsch P, Engel G, Richardson BP, Stadler PA (1984). "A highly selective and potent antagonist at peripheral neuronal 5-hydroxy tryptamine receptors". Br J Pharmacol 81: 34P.
  15. Zussman BD, Clarkeson A, Coates PE, Rapeport WG (1988). "The pharmacokinetic profile of BRL 43694, a novel 5-HT3 receptor antagonist, in healthy male volunteers". Br J Clin Pharmacol 25: 107P.
  16. Aapro M (2004). "Granisetron: an update on its clinical use in the management of nausea and vomiting". Oncologist. 9 (6): 673–86. doi:10.1634/theoncologist.9-6-673. PMID 15561811.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> Free full text
  17. Sorensen SM, Humphreys TM, Palfreyman MG (1989). "Effect of acute and chronic MDL 73,147EF, a 5-HT3 receptor antagonist, on A9 and A10 dopamine neurons". Eur. J. Pharmacol. 163 (1): 115–8. PMID 2744086.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  18. 18.0 18.1 De Leon A (2006). "Palonosetron (Aloxi): a second-generation 5-HT(3) receptor antagonist for chemotherapy-induced nausea and vomiting". Proceedings (Baylor University. Medical Center). 19 (4): 413–6. PMID 17106506.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> PMC 1618755.
  19. "FDA Approves Aloxi (Palonosetron) For Treatment of Chemotherapy-Related Nausea and Vomiting" (Press release). Doctor's Guide Publishing Limited. July 28 2003. Retrieved 2007-05-15. Check date values in: |date= (help)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  20. GlaxoSmithKline (2005). Template:PDFlink. U.S. Food and Drug Administration. Retrieved on 2007-05-15.
  21. 21.0 21.1 21.2 21.3 21.4 "5-Hydroxytryptamine3 (5-HT3) Receptor Antagonists". Oregon State University College of Pharmacy. 2003. Retrieved 2007-05-15.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>



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