Review
Pharmacological mechanisms of 5-HT3 and tachykinin NK1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting

https://doi.org/10.1016/j.ejphar.2012.01.046Get rights and content

Abstract

Nausea and vomiting are among the most common and distressing consequences of cytotoxic chemotherapies. Nausea and vomiting can be acute (0–24 h) or delayed (24–72 h) after chemotherapy administration. The introduction of 5-HT3 receptor antagonists in the 90s was a major advance in the prevention of acute emesis. These receptor antagonists exhibited similar control on acute emesis but had no effect on delayed emesis. These findings led to the hypothesis that serotonin plays a central role in the mechanism of acute emesis but a lesser role in the pathogenesis of delayed emesis. In contrast, delayed emesis has been largely associated with the activation of neurokinin 1 (NK1) receptors by substance P. However, in 2003, a new 5-HT3 receptor antagonist was introduced into the market; unlike first generation 5-HT3 receptor antagonists, palonosetron was found to be effective in preventing both acute and delayed chemotherapy induced nausea and vomiting. Recent mechanistic studies have shown that palonosetron, in contrast to first generation receptor antagonists, exhibits allosteric binding to the 5-HT3 receptor, positive cooperativity, persistent inhibition of receptor function after the drug is removed and triggers 5-HT3 receptor internalization. Further, in vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT3 receptor. It appears that the crossroads of acute and delayed emeses include interactions among the 5-HT3 and NK1 receptor neurotransmitter pathways and that inhibitions of these interactions lend the possibility of improved treatment that encompasses both acute and delayed emeses.

Section snippets

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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