Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists

Scand J Rheumatol Suppl. 2000;113:37-45. doi: 10.1080/030097400446625.


5-HT3-receptor antagonists are potent and highly selective competitive inhibitors of the 5-HT3-receptor with negligible affinity for other receptors. They are rapidly absorbed and penetrate the blood-brain barrier easily. 5-HT3-receptor antagonists are metabolized by diverse subtypes of the cytochrome P450-system, metabolites are excreted mainly in urine. Half-lifes in healthy subjects vary from 3-4 hours (ondansetron, granisetron) to 7-10 hours (tropisetron, hydrodolasetron). 5-HT3-receptor antagonists do not modify any aspect of normal behaviour in animals or induce remarkable changes of physiological functions in healthy subjects. They are well tolerated over wide dose ranges, most common side effects in clinical use are headache and obstipation. Clinical efficacy was first established in chemotherapy-induced emesis. In this indication, 5-HT3-receptor antagonists set a new standard regarding efficacy and tolerability. Further established indications are radiotherapy-induced and post-operative emesis. Antiemetic efficacy results from a simultaneous action at peripheral and central 5-HT3-receptors. Other peripheral actions include reduction of secretion and diarrhea caused by increased intestinal serotonin content (e.g. in carcinoid syndrome), a limited antiarrhythmic activity and a reduction of experimentally induced pain. CNS effects comprise anxiolysis, attenuation of age-associated memory impairment, reduction of alcohol consumption in moderate alcohol abuse and an antipsychotic effect in patients with parkinson psychosis. In migraine, 5-HT3-receptor antagonists show moderate efficacy, as well. Repeatedly demonstrated efficacy of 5-HT3-receptor antagonists in patients suffering from fibromyalgia raises the question for the mechanism of action involved. Ligand binding at the 5-HT3-receptor causes manifold effects on other neurotransmitter and neuropeptide systems. In particular, 5-HT3-receptor antagonists diminish serotonin-induced release of substance P from C-fibers and prevent unmasking of NK2-receptors in the presence of serotonin. These observations possibly provide an approach for the causal explanation of favourable treatment results with 5-HT3-receptor antagonists in fibromyalgia.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Anti-Arrhythmia Agents / pharmacology
  • Anti-Arrhythmia Agents / therapeutic use
  • Antiemetics / pharmacokinetics
  • Antiemetics / pharmacology
  • Antiemetics / therapeutic use*
  • Humans
  • Receptors, Serotonin / physiology*
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists / pharmacokinetics
  • Serotonin Antagonists / pharmacology*
  • Serotonin Antagonists / therapeutic use*


  • Anti-Arrhythmia Agents
  • Antiemetics
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists