Serotonin 5-HT3-receptor antagonists: pharmacokinetics, MOA, indications and adverse effects

This post overviews the general characteristics, pharmacokinetics, mechanism of action, dosing, indications and adverse effects profile of serotonin 5-HT3-receptor antagonists. These drugs are being increasingly used for the prevention of chemotherapy induced nausea and vomiting (CINV), as well as antiemetic prophylaxis of post-operative and post-radiation nausea and vomiting.

General characteristics and pharmacokinetics

All 5-HT3 antagonists are identified by the suffix -setron, according to the WHO’s Anatomical Therapeutic Chemical Classification System.

The following are  5-HT3  antagonists serum half- lives:

  • Dolasetron (Anzemet): 7-9 hours.
  • Granisetron (Kytril, generic) 9-11 hours.
  • Ondansetron (Zofran, generic): 3.9 hours.
  • Palonosetron (Aloxi): 40 hours.
  • Tropisetron (Navoban):  7.3 hours. Not available in the United States.

At equivalent doses for the prevention of acute emesis, 5-HT3 serotonin receptor antagonists have equivalent safety and efficacy and can be used interchangeably.

These drugs are metabolized in the liver and are eliminated by renal and hepatic excretion. In spite of this, dose adjustment is not  required in geriatric patients or patients with renal insufficiency.  Dose reduction may be required when giving ondansetron to patients with hepatic insufficiency.

Mechanism of Action

Chemotherapy causes emesis through effects at a number of sites. When antineoplastic agents are administered, 5-hydroxytryptamine (5-HT) is released from the upper small intestine enterochromaffin cells,  5-HT activates 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. These afferent fibers have projections to the  nucleus tractus solitarius (NTS) and the area postrema (AP).

Source: Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008 358: 2482-2494

Selective 5-HT3-receptor antagonists antiemetic properties are mediated through central (vomiting center, chemoreceptor trigger zone) and peripheral (intestinal and spinal) 5-HT3 receptor blockade.  This mechanism explains why their clinical use is limited to situations that produce vagal stimulation (eg. surgery) and chemotherapy.


Chemotherapy-induced nausea and vomiting  (CINV)

According to the 2006 update of the American Society of Clinical Oncology Guideline for Antiemetics in Oncology,  5-HT3-receptor antagonists are considered one of the classes of drugs with highest therapeutic index.  When used alone, these drugs have little or no efficacy for the prevention of delayed nausea and vomiting (ie, occurring  24 hours after chemotherapy).

These drugs are most effective when given as a single dose by intravenous injection 30 minutes prior to administration of chemotherapy in the following schedules:

Dose and Schedule of Antiemetics to Prevent Emesis Induced by Antineoplastic Therapy
5-HT3 serotonin receptor antagonists Antineoplastic Therapy of High Emetic Risk Antineoplastic Therapy of Moderate Emetic Risk
Dolasetron Oral: 100 mg IV: 100 mg or 1.8 mg/kg Oral: 100 mg

IV: 100 mg or 1.8 mg/kg

Granisetron Oral: 2 mg

IV: 1 mg or 0.01 mg/kg

Oral: 2 mg

IV: 1 mg or 0.01 mg/kg

Ondansetron Oral: 24 mg

IV: 8 mg or 0.15 mg/kg

Oral: 16 mg (8 mg twice daily)

IV: 8 mg or 0.15 mg/kg

Palonosetron IV: 0.25 mg IV: 0.25 mg

Oral: 5 mg

Tropisetron Oral or IV: 5 mg IV: 5 mg

Post-operative nausea and post-radiation nausea and vomiting

According to a recent meta-analysis, 5HT3 antagonists are superior to metoclopramide, droperidol, and dimenhydrinate in the pharmacologic prophylaxis of postoperative nausea and vomiting. Recently, the FDA added a boxed warning to metoclopramide because of an increased risk of tardive dyskinesia. Due to this and other restrictions on antiemetic agents, 5-HT3-receptor antagonists are gaining more acceptance for this clinical use.

Adverse effects

These drugs are generally very well tolerated, frequent adverse effects are: constipation or diarrhea, headache, and light-headedness. According to experimental data, these agents have shown to induce minor electrocardiographic changes. It is recommended not to administer dolasetron to patients with prolonged QT or with drugs that may prolong the QT interval.

References and further reading

Katzung, B. “Basic & Clinical Pharmacology”, 10th Edition. Mc Graw Hill Medical: 2007

Kris MG, Hesketh PJ, Somerfield MR, Petra F, Clark-Snow R, Koeller JM, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol (2006) 24:2932–47

Gregory E, Ettinger D. 5-HT3 Receptor Antagonists for the Prevention of Chemotherapy-Induced Nausea and Vomiting. Drugs 1998 Feb; 55 (2): 173-189.

Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008 358: 2482-2494

Martin J, Kim M. Meta-analysis of pharmacologic prophylaxis of postoperative nausea and vomiting in adults: 5HT3 antagonists, dexamethasone, droperidol, metoclopramide, dimenhydrinate, or combinations? Ital J Public Health 2005; 2: 273.

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