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Antiemetic Serotonin 5-HT3 Receptor Blockers

Editor: John V. Ashurst Updated: 11/21/2022 8:38:00 PM


Selective serotonin receptor (5-HT3) antagonists block serotonin both peripherally, on gastrointestinal (GI) vagal nerve terminals, and centrally in the chemoreceptor trigger zone. This blockade results in powerful antiemetic effects. Currently, there are four 5-HT3 receptor antagonists on the market: ondansetron, granisetron, dolasetron, and palonosetron, which are FDA-approved for the prevention of nausea and vomiting in children and adults related to chemotherapy use, radiation therapy, and the effects of postoperative anesthesia. Dolasetron is also indicated for the treatment of postoperative nausea and vomiting in children and adults.[1] There are several formulations providing clinicians and patients many options for effective dose administration. The most common adverse effects include headaches, fatigue, and constipation. Rarely, 5-HT3 receptor antagonists can cause QTc prolongation if administered concomitantly with other QTc-prolonging medications or in patients with a history of congenital long-QT syndrome.[2] There is also documentation of cases of serotonin syndrome in susceptible patient populations. There is also the concern for masking symptoms of bowel obstruction in the elderly or postoperative patient. An overdose of 5-HT3 receptor antagonists is rare, and there is no fatal dose established. Treatment is mainly supportive in these cases. Overall, select serotonin receptor antagonists are an effective antiemetic class with a wide therapeutic index and mild side effect profile.[3]

Adult FDA-Approved Indications

  • Prevention of chemotherapy-induced nausea and vomiting
  • Prevention of radiation therapy-induced nausea and vomiting
  • Prevention of postoperative nausea and vomiting

Adult Non-FDA-Approved Indications

  • Treatment of postoperative nausea and vomiting
  • Nausea and vomiting during pregnancy, severe or refractory

Pediatric FDA-Approved Indications

  • Prevention of chemotherapy-induced nausea and vomiting
  • Prevention of postoperative nausea and vomiting

Three 5-HT3 receptor antagonists are currently approved for use in the United States: ondansetron, granisetron, and palonosetron. Dolasetron has been discontinued in the US market.

Mechanism of Action

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Mechanism of Action

Selective serotonin receptor (5-HT3) antagonists block serotonin both peripherally on vagal nerve terminals in the gastrointestinal (GI) system and centrally in the chemoreceptor trigger zone in the area postrema of the fourth ventricle, resulting in powerful antiemetic effects.


5-HT3 receptor antagonists come in a variety of formulations offering multiple routes of administration.[4] These include oral tablets, orally disintegrating tablets, oral soluble film, oral solution, intramuscular injection, intravenous injection, subcutaneous injection, and transdermal patch.[5][6]

Some common dosing and administration regimens are as follows: (note, this list is not exhaustive)

  • Ondansetron: 
    • For nausea and vomiting prophylaxis, chemotherapy-related:
      • IV: (moderately to highly emetogenic chemo): 0.15 mg/kg/dose every 4 hours for 3 doses, max 16 mg per dose. Start 30 minutes before chemo.
      • PO: (highly emetogenic chemo): 24 mg once 30 minutes before chemo; do not cut or chew ODT dose forms.
      • PO: (moderately emetogenic chemo): 8 mg every 8 hours for two doses, then 8 mg every 12 hours until one or two days following chemo completion. Start 30 minutes before chemo and do not cut, crush or chew ODT dosage forms.
    • Nausea and vomiting prophylaxis, post-operative: 4 mg IM for one dose.
    • Nausea and vomiting prophylaxis, X-ray therapy (XRT) related (total body): 8 mg PO for one dose, given 1 to 2 hours before each therapy fraction; do not cut, crush or chew ODT dosage forms.
  • Granisetron:
    • Nausea and vomiting prophylaxis, chemotherapy-related: 10 mg IV 30 minutes before chemo; oral dose within 1 hour before chemo. Alternately, 2 mg PO once or 1 mg PO every 12 hours for two doses.
    • Nausea and vomiting prophylaxis, XRT-related: 2 mg orally for a single dose; start within one hour of XRT.
    • Nausea and vomiting prophylaxis, post-operative: 1 mg IV for a single dose.
  • Palonosetron:
    • Nausea and vomiting prevention, chemo-related: 0.25 mg IV for one dose, started 30 minutes before chemo.
    • Nausea and vomiting prophylaxis, post-operative: 0.075 mg IV for a single dose, started immediately prior to anesthesia induction.

Adverse Effects

Most Common Adverse Reactions

  • Headache (9% to 27%)
  • Fatigue (9% to 13%)
  • Malaise (9% to 13%)
  • Constipation (6% to 11%)

One Percent to 10%

Drowsiness, sedation, dizziness, agitation, anxiety, paresthesia, the sensation of cold, pruritus, skin rash, diarrhea, gynecologic disease, urinary retention, transient increase (greater than two times) of serum aminotransferases, injection site reaction, hypoxia, fever[7]

Less Than 1%

Abdominal pain, accommodation disturbance, anaphylactoid reaction, anaphylaxis, angina pectoris, angioedema, atrial fibrillation, bradycardia, bronchospasm, bullous skin disease, cardiac arrhythmia, cardiorespiratory arrest, chest pain, chills, depression of ST-segment on ECG, dyspnea, dystonic reaction, ECG changes, extrapyramidal reaction, flushing, hepatic failure, hiccups, hypersensitivity reaction, hypokalemia, hypotension, ischemic heart disease, laryngeal edema, laryngospasm, liver enzyme disorder, mucosal tissue reaction, myocardial infarction, neuroleptic malignant syndrome, oculogyric crisis, palpitations, positive lymphocyte transformation test, prolonged QTc interval on ECG (dose-dependent), second-degree atrioventricular block, serotonin syndrome, shock, Stevens-Johnson syndrome, stridor, supraventricular tachycardia, syncope, tachycardia, tonic-clonic seizures, torsades de pointes, toxic epidermal necrolysis, transient blindness, transient blurred vision, urticaria, vascular occlusive events, ventricular premature contractions, ventricular tachycardia, weakness, xerostomia


5-HT3 receptor antagonists are FDA pregnancy category B. Available human studies examining early pregnancy conclude there is not a high risk of congenital malformations. There is a small increased risk of septal defects and cleft palate. Animal studies show no increased risk during early pregnancy. It is not known if 5-HT3 receptor antagonists are present in breast milk.


The major relative contraindications include the following:

  • Hypersensitivity to 5-HT3 receptor antagonists, or any components of the formulation, due to concern for cross-reactivity.
  • Concomitant use with apomorphine due to concern for a decreased level of consciousness and hypotension.[8]


Obtain baseline ECG in at-risk patient populations, along with monitoring sodium, potassium, calcium, and magnesium.


5-HT3 receptor antagonist use correlates with many dose-dependent increases in ECG intervals (PR, QRS, QTc, JT), usually occurring 1 to 2 hours after intravenous (IV) administration. When used in conjunction with other interval prolonging agents, there is the risk of arrhythmia development. Healthcare providers should observe caution with patients with a history of congenital long QT syndrome, ventricular arrhythmias, cardiac disease, electrolyte abnormalities, or with those who are receiving concomitant cardiotoxic chemotherapy.

Serotonin Syndrome

There are cases of fatal serotonin syndrome reported with 5-HT3 receptor antagonists, most often in the post-anesthesia setting or an infusion center. This condition appears to be from the concomitant use of serotonergic medications, such as SSRIs, e.g., fluoxetine, selective norepinephrine serotonin reuptake inhibitors (SNRIs), lithium, fentanyl, and mirtazapine. Patients require monitoring for signs of serotonin syndrome, including mental status changes, autonomic instability, tachycardia, labile blood pressure, diaphoresis, flushing, neuromuscular changes, GI symptoms, and/or seizures. If serotonin syndrome occurs, discontinue 5-HT3 receptor antagonists, and initiate supportive management.


Constipation is a commonly reported adverse effect with all formulations of 5-HT3 receptor antagonists, especially the use of tablets or extended-release subcutaneous injection; this can be compounded during pregnancy or for patient populations at risk for constipation. There is concern regarding the masking of symptoms of bowel obstruction with 5-HT3 receptor antagonist use and should not be a substitute for nasogastric suctioning—exercise caution in patients with recent abdominal surgery.


Some dosage forms of 5-HT3 receptor antagonists may contain sodium benzoate/benzoic acid, which is a metabolite of benzyl alcohol. Large amounts of benzyl alcohol (greater than 99 mg/kg per day) have correlated with fatal neonatal “gasping syndrome,” which consists of metabolic acidosis, respiratory distress, gasping respirations, central nervous system (CNS) depression, renal failure, and hypotension. Caution is necessary when using these agents for patients with phenylketonuria, as orally disintegrating tablets contain phenylalanine. Clinicians should decrease the dosing of 5-HT3 receptor antagonists in patients with hepatic impairment due to the altered hepatic clearance and prolonged drug half-life.


Overdose is rare, and there is no fatal dose yet established. 5-HT3 receptor antagonists have a broad therapeutic index with mild side effects that occur infrequently. Treatment is primarily supportive. Monitor for the rare cases of ECG changes, ventricular arrhythmias, serotonin syndrome, and masked bowel ileus or bowel obstruction. Due to the unknown fatal dose and extremely rare documented cases of overdose causing significant morbidity or mortality, there is little commercial motivation or clinical need for antidote development.[9] Additionally, there are a few notable drug interactions with 5-HT3 antagonists with amiodarone, amisulpride, apomorphine, and bosentan.[10]

Enhancing Healthcare Team Outcomes

Clinicians frequently manage nausea and vomiting with the use of selective serotonin receptor (5-HT3) antagonists. Because these two symptoms are very common for patients, all healthcare professionals need to be familiar with these medications. Consequently, an interprofessional team approach is the most effective means to use these medications effectively.

The clinician (MD, DO, NP, PA) will order or prescribe these agents. It would be advantageous to include a pharmacist in the decision process, as they can perform medication reconciliation, verify dosing, and even suggest the optimal agent in class. Nurses will administer these drugs to inpatients and provide counsel on home administration to outpatients and monitor treatment effectiveness over time. These examples of interprofessional teamwork demonstrate how this approach leads to better healthcare outcomes for patients [Level 5]



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Level 3 (low-level) evidence


Kast RE, Foley KF. Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects. European journal of cancer care. 2007 Jul:16(4):351-4     [PubMed PMID: 17587360]


Paul M, Callahan R, Au J, Kindler CH, Yost CS. Antiemetics of the 5-hydroxytryptamine 3A antagonist class inhibit muscle nicotinic acetylcholine receptors. Anesthesia and analgesia. 2005 Sep:101(3):715-721. doi: 10.1213/01.ANE.0000160531.65953.77. Epub     [PubMed PMID: 16115980]

Level 3 (low-level) evidence


National Comprehensive Cancer Network (NCCN). NCCN antiemesis guidelines emphasize 'delayed' emesis, new 5-HT3 inhibitors, and NK-1 blockers. The journal of supportive oncology. 2004 Jul-Aug:2(4):366     [PubMed PMID: 15357520]


Hargreaves AC, Gunthorpe MJ, Taylor CW, Lummis SC. Direct inhibition of 5-hydroxytryptamine3 receptors by antagonists of L-type Ca2+ channels. Molecular pharmacology. 1996 Nov:50(5):1284-94     [PubMed PMID: 8913360]


Piechotta V, Adams A, Haque M, Scheckel B, Kreuzberger N, Monsef I, Jordan K, Kuhr K, Skoetz N. Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta-analysis. The Cochrane database of systematic reviews. 2021 Nov 16:11(11):CD012775. doi: 10.1002/14651858.CD012775.pub2. Epub 2021 Nov 16     [PubMed PMID: 34784425]

Level 1 (high-level) evidence


Martirosov KS, Grigor'ev IuG, Zorin VV, Borovkov MV. [Comparative experimental study of antiemetic action of latranum in radiation-induced vomiting and vomiting caused by apomorphine]. Radiatsionnaia biologiia, radioecologiia. 2003 Jan-Feb:43(1):60-4     [PubMed PMID: 12677660]

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Tabrizi S, Heidari S, Rafiei H. Investigation role of ondansetron on long QT interval among non-cardiac patients. Annals of medicine and surgery (2012). 2021 Nov:71():102971. doi: 10.1016/j.amsu.2021.102971. Epub 2021 Oct 19     [PubMed PMID: 34712483]


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