Mechanism of action The 5-HT3 receptors are present in several critical sites involved in emesis, including vagal afferents, the solitary tract nucleus (STN), and the area postrema itself. Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. The 5-HT3 receptor<unk> s suppress vomiting and nausea by inhibiting serotonin binding to the 5-HT3 receptors. The highest concentration of 5-HT3 receptors in the central nervous system (CNS) are found in the STN and chemoreceptor trigger zone (CTZ), and<unk> s may also suppress vomiting and nausea by acting at these sites. The<unk> s are greatly selective and have little affinity for other receptors, such as dopamine, histamine and muscarinic acetylcholine receptors. Pharmacokinetics All<unk> s 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. Comparative pharmacology Despite that the 5-HT3 receptor<unk> s share their mechanism of action, they have different chemical structures and exhibit differences in affinity for the receptor, dose response and duration of effect. They are also metabolized in different ways, that is, different components of the cytochrome P450 (CYP) system predominate in the metabolism of the<unk> s. Because of this, patients who are resistant to one<unk>  might benefit from another. A correlation exists between the number of active CYP 2D6 alleles and the number of vomiting episodes by patients who receive treatment with cisplatin and ondansetron or tropisetron. Patients with multiple alleles tend to be unresponsive to the antiemetic drug and vice versa. + Comparative pharmacology of 5-HT3 receptor<unk>  Drug Chemical nature Receptor<unk> s T1/2 (h) Metabolism Dose Ondansetron Carbazole derivative 5-HT3 receptor<unk>  and weak<unk>  3.9 hours CYP1A1/2, CYP2D6, CYP 3A3/4/5 0.15 mg/kg Granisetron Indazole 5-HT3 receptor<unk>  9-11.6 hours CYP3A3/4/5 10 μg/kg Dolasetron Indole 5-HT3 receptor<unk>  7–9 hours CYP 3A3/4/5, CYP2D6 0.6–3 mg/kg Palonosetron Isoquinoline 5-HT3 receptor<unk> ; highest affinity for 5-HT3 receptor in this class 40 hours CYP1A2, CYP2D6, CYP3A3/4/5 0.25 mg x 1 dose Ramosetron Benzimidazole derivative 5-HT3 receptor<unk>  5.8 hours 300 μg/kg Tropisetron Indole 5-HT3 receptor<unk>  5.6 hours CYP 3A3/4/5, CYP2D6 200 μg/kg Vortioxetine (Trintellix) Indole 5-HT3 receptor<unk>  Antidepressant 66h CYP 2D6/ 2A6/CYP2B6/CYP2C8/9, CYP2C19 5 mg, 10 mg, 20 mg doses
5-HT3 antagonist
Opioid antagonist
Dopamine antagonist
Dopamine agonist
GABA reuptake inhibitor
Adenosine reuptake inhibitor
5-HT2C receptor agonist
NMDA receptor antagonist