5-HT3 antagonist
5-HT3 receptor antagonist | |
---|---|
A04AA | |
Biological target | 5-HT3 receptor |
Clinical data | |
Drugs.com | Drug Classes |
Consumer Reports | Best Buy Drugs |
External links | |
MeSH | D058831 |
Legal status | |
In Wikidata |
The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 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 exceptions 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.
Medical uses
5-HT3 antagonists are most effective in the prevention and treatment of
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
Available agents
- Glaxo around 1984. Its efficacy was first established in 1987, in animal models,[10][11] and it was extensively studied over the following years.[12] 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 drugin the United States. Ondansetron may be given several times daily, depending on the severity of symptoms.
- Tropisetron was also first described in 1984.[13] 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 was developed around 1988.[14] 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).[15] It is taken once daily.
- Dolasetron was first mentioned in the literature in 1989.[16] 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 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.[17] Palonosetron was approved by the FDA in 2003,[18] 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.[19]
- Ramosetron is only available in Japan and certain Southeast Asian countries as of 2008.[20] 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.[21] In animal studies, ramosetron was also effective against irritable bowel syndrome-like symptoms.[22]
Certain
Adverse effects
There are few
All 5-HT3 antagonists have been associated with
Pharmacology
Mechanism of action
The 5-HT3 receptors are present in several critical sites involved in emesis, including
Pharmacokinetics
All 5-HT3 antagonists are well-absorbed and effective after oral administration,
Comparative pharmacology
Despite that the 5-HT3 receptor antagonists share their
Because of this, patients who are resistant to one
Drug
|
Chemical nature |
Receptor antagonists | T1/2 (h)
|
Metabolism | Dose |
---|---|---|---|---|---|
Ondansetron | Carbazole derivative | 5-HT3 receptor antagonist and weak 5-HT4 antagonist | 3.9 hours | CYP1A1/2, CYP2D6, CYP 3A3/4/5 | 150 μg/kg |
Granisetron | Indazole | 5-HT3 receptor antagonist | 9–11.6 hours | CYP3A3/4/5 | 10 μg/kg |
Dolasetron | Indole | 5-HT3 receptor antagonist | 7–9 hours | CYP 3A3/4/5, CYP2D6 | 600 – 3000 μg/kg |
Palonosetron | Isoquinoline | 5-HT3 receptor antagonist; highest affinity for 5-HT3 receptor in this class | 40 hours | CYP1A2, CYP2D6, CYP3A3/4/5[32] | 0.25 mg dose |
Ramosetron | Benzimidazole derivative | 5-HT3 receptor antagonist | 5.8 hours | 300 μg/kg | |
Tropisetron[30] | Indole | 5-HT3 receptor antagonist | 5.6 hours | CYP 3A3/4/5, CYP2D6 | 200 μg/kg |
Vortioxetine (Trintellix) | Indole | 5-HT3 receptor antagonist Antidepressant | 66h | CYP 2D6/ 2A6/CYP2B6/CYP2C8/9, CYP2C19 | 5 mg, 10 mg, 20 mg doses |
History
The history of the 5-HT3 receptor antagonists began in 1957, when John Gaddum and Zuleika P. Picarelli at the University of Edinburgh proposed the existence of two serotonin receptor subtypes, the M and D receptors (thus named because their function could be blocked by morphine and dibenzyline respectively).[33] The 5-HT3 receptor was later found to correspond to the M receptor.[34] In the 1970s, John Fozard found that metoclopramide and cocaine were weak antagonists at the 5-HT3 (5-HT-M) receptor. Fozard and Maurice Gittos later synthesized MDL 72222, the first potent and truly selective 5-HT3 receptor antagonist.[35][36] The antiemetic effects of metoclopramide were found to be partially because of its serotonin antagonism.[30]
While Fozard was investigating cocaine analogues, researchers at Sandoz identified the potent, selective 5-HT3 receptor antagonist ICS 205-930 from which the first marketed selective 5-HT3 receptor antagonists ondansetron and granisetron were developed, and approved in 1991 and 1993 respectively.[35][37] Several compounds related to MDL 72222 were synthesized which eventually resulted in approval of tropisetron in 1994 and dolasetron in 1997.[37] A new and improved 5-HT3 receptor antagonist, named palonosetron, was approved in 2003.[37] The development of selective 5-HT3 receptor antagonists was a dramatic improvement in the
Development
5-HT3 receptor antagonists or serotonin
Drug design
Experiments have shown evidence that the ligand-binding site is located at the interface of two adjacent subunits.
5-HT3 receptor antagonists | Binding affinity (Kd, Ki, K50) | Species |
---|---|---|
Tropisetron | 11 nM | Human |
Granisetron | 1.44 nM | Human |
Ondansetron | 4.9 nM | Human |
Palonosetron | 31.6 nM | Rat cerebral cortex, rabbit ileal myenteric plexus, guinea-pig ileal plexus |
Dolasetron | 20.03 nM | NG 108-15 |
Metoclopramide (non-selective) | 355 nM | Human |
Cocaine | 2.45-83 nM | Rat-rabbit |
Pharmacophore scaffold
Chemical structures of the first generation 5-HT3 receptor antagonist can be categorized to three main classes[30]
- Carbazole derivatives (ondansetron)
- Indazoles(Granisetron)
- Indoles (Tropisetron and Dolasetron)
The first-generation 5-HT3 receptor antagonist (ondansetron,
Pharmacophore
The
Structure-activity relationship
5-HT3 receptor antagonists share the same
Ondansetron is a
A methyl- group appears to be as effective functionally as a chlorine in the R position (see fig. 6). The
Research
A small, open-label trial carried out in 2000 found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia.[50][51] The study's patients also showed
See also
References
- S2CID 27576150.
- KiB). Geneva: WHO Press. Retrieved on 2007-05-15.
- PMID 15888767.
- ^
- PMID 16608997.
- PMID 2523720.
- PMID 11086664.
- PMID 17679566.
- ^ Dula D, Rosenbach S (2006). "A randomized clinical trial comparing ondansetron with placebo in aeromedical personel with motion sickness". Paper presented at the annual meeting of the National Association of EMS Physicians, Registry Resort, Naples, FL, January 19–21, 2006. Retrieved on April 25, 2009.
- PMID 2442006.
- PMID 2955843.
- ^ See Eur J Cancer Clin Oncol 1989; 25 Suppl 1.
- ^ 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.
- ^ 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.
- PMID 15561811. Free full text
- PMID 2744086.
- PMID 17106506.
- ^ "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.
- ^ Waknine, Yael (September 4, 2008). "FDA Approvals: Nplate, Aloxi, Vidaza". Medscape. Archived from the original on December 2, 2008. Retrieved 2008-09-04. Freely available with registration.
- ^ Abridged prescribing information - Nasea (MIMS Philippines)[permanent dead link]. Retrieved on June 13, 2008.
- PMID 12532186.
- S2CID 29179265.
- KiB). U.S. Food and Drug Administration. Retrieved on 2009-07-30.
- University of Colorado at Denver and Health Sciences Center School of Pharmacy. Retrieved on 2007-10-25.
- PMID 2054863.
- ^ ]
- PMID 16959934.
- ^ a b c d e "5-Hydroxytryptamine3 (5-HT3) Receptor Antagonists" (PDF). Oregon State University College of Pharmacy. 2003. Archived from the original (PDF) on 2013-03-13. Retrieved 2007-05-15.
- ^ ISBN 978-0-07-142280-2.
- ^ S2CID 23209789.
- PMID 19086255.
- S2CID 71759860.
- PMID 13460238.
- ^ PMID 18761359.
- ^ ISBN 978-0-8493-5463-2.
- ^ Galvan, M.; Gittos, M.; Fatmi, M. (October 1996). "DISCOVERY OF 5-HT3 RECEPTOR ANTAGONISTS AND DOLASETRON MESILATE". EJHP Journal (6): 10–11. Archived from the original on 2011-07-20. Retrieved 2010-01-06.
- ^ .
- ^ S2CID 20464189.
- ^ S2CID 24133545.
- S2CID 30877434.
- S2CID 36985954.
- PMID 22873819.
- ^ PMID 17073663.
- ^ PMID 16999973.
- ^ PMID 2342053.
- ^ PMID 1992112.
- PMID 8879547.
- PMID 17391967.
- PMID 8246239.
- PMID 11282718.
- PMID 10671405. Free full text
- S2CID 24911372.
- Pasricha, Pankaj J. (2006). "Treatment of Disorders of Bowel Motility and Water Flux; Antiemetics; Agents Used in Biliary and Pancreatic Disease". In Laurence Brunton; John Lazo; Keith Parker (eds.). ISBN 978-0-07-142280-2.
- Hillier, Keith; Robert J. Naylor (2006). "Drugs and the Gastrointestinal System". In Clive Page; Brian Hoffmann; Michael Curtis; Michael Walker (eds.). Integrated Pharmacology (3rd ed.). Mosby. ISBN 978-0-323-04080-8.