Serotonin 5-HT3-receptor antagonists: pharmacokinetics,
MOA, indications and adverse effects Pharmamotion
Serotonin 5-HT3-receptor antagonists: pharmacokinetics, MOA,
indications and adverse effects
Posted: 25 Aug 2009 06:23 AM PDT
This posts 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
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
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:
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 Antineoplastic Antineoplastic
receptor antagonists Therapy of High Therapy of Moderate
Emetic Risk Emetic Risk
Dolasetron Oral: 100 mg IV: Oral: 100 mg
100 mg or 1.8 mg/kg
IV: 100 mg or 1.8
Granisetron Oral: 2 mg Oral: 2 mg
IV: 1 mg or 0.01 mg/ IV: 1 mg or 0.01
Ondansetron Oral: 24 mg Oral: 16 mg (8 mg
IV: 8 mg or 0.15 mg/
kg IV: 8 mg or 0.15
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.
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)
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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