ReviewPharmacological mechanisms of 5-HT3 and tachykinin NK1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting
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Chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting (CINV) is a common and distressing consequence of cytotoxic chemotherapies and a major reason for non-compliance with cancer treatment (Feyer and Jordan, 2011). CINV can be acute if it occurs within the first 24 h after chemotherapy administration or delayed if the symptoms persist beyond 24 h; the terms acute and delayed are approximations and do not provide a clear distinction of where acute emesis ends and delayed emesis begins. However, the terminology
5-HT3 receptor antagonists
Miner and Sanger in the mid 1980s were the first to report that a selective 5-HT3 receptor antagonist could attenuate cisplatin-induced emesis in ferrets (Miner and Sanger, 1986). Cytotoxic chemotherapies are toxic to enterochromaffin cells lining the upper small intestine causing free radical generation and serotonin release. Serotonin binds to 5-HT3 receptors on vagal afferents thus contributing sensory inputs that cause emesis (Fig. 1). The antiemetic effect of 5-HT3 receptor antagonists is
Tachykinin NK1 receptor antagonists
In an effort to further optimize antiemetic therapy, aprepitant, a drug belonging to a new class of antiemetic was introduced in 2003. Aprepitant counteracts the activity of SP, the preferred ligand at NK1 receptors. These receptors are located in the gut, the area postrema and the nucleus tractus solitarius; all areas involved in the emetic reflex. Like serotonin, SP is released by emetogenic chemotherapies but it appears to act largely on receptors that are centrally located. Consequently, NK1
Molecular pharmacology of 5-HT3 receptor antagonists: a direct comparison among ondansetron, granisetron and palonosetron
Palonosetron, a 5-HT3 receptor antagonist came to the market in 2003, the same year aprepitant was introduced; unlike first generation 5-HT3 receptor antagonists, palonosetron was found to be effective in preventing both acute and delayed CINV (Aapro et al., 2006, Eisenberg et al., 2003, Gralla et al., 2003, Saito et al., 2009). The effect of palonosetron on delayed emesis was initially received with skepticism by the clinical community. There was no apparent reason why one 5-HT3 receptor
Current studies and future possibilities
Current guidelines for patients receiving highly emetogenic chemotherapy recommend the use of a 5-HT3 receptor antagonist, dexamethasone and a NK1 receptor antagonist (Basch et al., 2011, Ettinger et al., 2011, Roila et al., 2010). Palonosetron is recommended by the National Comprehensive Cancer Network (NCCN) as the preferred 5-HT3 receptor antagonist for both high and moderate emetic risks to patients following intravenous chemotherapies to prevent emesis (Ettinger et al., 2011). The American
Acknowledgments
We thank Silvia Sebastiani and Silvia Olivari Tilola from Helsinn Healthcare for their help with the making of Table 2 and Fig. 6.
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2023, Biochemical PharmacologyA Practical 5-Step Approach to Nausea and Vomiting
2022, Mayo Clinic ProceedingsCitation Excerpt :Long-term use is limited by potential extrapyramidal adverse effects (akathisia, parkinsonism, and tardive dyskinesia) that may be irreversible.6,18 Neurokinin 1 receptor antagonists work by alleviating the emetic effects of substance P and are Food and Drug Administration approved for the treatment of CINV.19 Of note, there are limited studies directly comparing the effectiveness of these various antiemetic agents.
Nausea and Vomiting
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2021, Journal of Controlled ReleasePhase 3 Study of Palonosetron IV Infusion Vs. IV Bolus for Chemotherapy-Induced Nausea and Vomiting Prophylaxis After Highly Emetogenic Chemotherapy
2020, Journal of Pain and Symptom ManagementCitation Excerpt :Palonosetron (PALO) is a pharmacologically and clinically distinct second-generation 5-HT3RA13,14 approved for the prevention of MEC-related and HEC-related CINV as a single 0.25-mg 30-second IV bolus15,16 or as a single 0.50-mg capsule.16 The unique pharmacologic characteristics that differentiate PALO from first-generation oral 5-HT3RAs (such as ondansetron, granisetron, and dolasetron) are longer half-life (approximately 40 hours), higher receptor-binding affinity (approximately 30-fold), ability for allosteric interactions and positive cooperativity with 5-HT3 receptors, capacity to induce receptor internalization, and inhibition of 5-HT3 and NK1 receptor cross talk.13 Altogether, these properties may extend the antiemetic effect of PALO, allowing for a convenient single-dose schedule per chemotherapy cycle and with a favorable safety profile (reviewed in the study by Navari17), compared with first-generation 5-HT3RAs, which require multiple-dose administration per chemotherapy cycle.9
Vomiting and Nausea
2020, Pediatric Gastrointestinal and Liver Disease, Sixth Edition