Antiemetic, Serotonin-5-HT3 Receptor Blockers

Article Author:
Jonathan Theriot
Article Editor:
John Ashurst
Updated:
7/3/2018 12:27:27 PM
PubMed Link:
Antiemetic, Serotonin-5-HT3 Receptor Blockers

Indications

Select serotonin receptor (5-HT3) antagonists block serotonin both peripherally, on gastrointestinal (GI) vagal nerve terminals, and centrally in the chemoreceptor trigger zone. This results in powerful antiemetic effects. Currently, there are four 5-HT3 receptor antagonists on the market, 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 FDA-approved for the treatment of postoperative nausea and vomiting in adults and children. There are a number of 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 QT prolongation if administered concomitantly with other QT-prolonging medications or in patients with a history of congenital, long-QT syndrome. There are also documented 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 no fatal dose has been established. Treatment is largely supportive in these cases. Overall, select serotonin receptor antagonists are an effective antiemetic class with a wide therapeutic index and mild side effect profile.

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
  • Treatment of postoperative nausea and vomiting (dolasetron)

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
  • Treatment of postoperative nausea and vomiting (dolasetron)

Four 5-HT3 receptor antagonists are currently approved for use in the United States: ondansetron, granisetron, dolasetron, and palonosetron.

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.

Administration

5-HT3 receptor blockers come in a variety of formulations offering multiple routes of administration. These include oral tablet, orally disintegrating tablet, oral soluble film, oral solution, intramuscular injection, intravenous injection, subcutaneous injection, and transdermal patch.

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 2 times) serum aminotransferases, injection site reaction, hypoxia, fever

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 Q-T 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

Pregnancy

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 blockers are present in breast milk.

Contraindications

The major relative contraindications include the following:

  • Hypersensitivity to 5-HT3 receptor blockers, 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.

Monitoring

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

Arrhythmia

5-HT3 receptor antagonists have been associated with many dose-dependent increases in ECG intervals (PR, QRS, QT/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

Fatal case reports of serotonin syndrome have been reported with 5-HT3 receptor antagonists, most often in the post-anesthesia setting. This is thought to be from the concomitant use of serotonergic medications, such as SSRIs, selective norepinephrine serotonin reuptake inhibitors (SNRIs), lithium, fentanyl, and mirtazapine. Patients should be monitored for signs of serotonin syndrome, including mental status changes, autonomic instability, neuromuscular changes, GI symptoms, and/or seizures. If serotonin syndrome occurs, 5-HT3 receptor antagonists should be discontinued, and supportive management should be initiated.

Constipation

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 in 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 used as a substitute for nasogastric suctioning. Exercise caution in patients with recent abdominal surgery.

Other

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 been associated with fatal neonatal “gasping syndrome,” which consists of metabolic acidosis, respiratory distress, gasping respirations, central nervous system (CNS) depression, renal failure, and hypotension. Caution should be taken in patients with phenylketonuria, as orally disintegrating tablets contain phenylalanine. The dosing of 5-HT3 receptor antagonists should be decreased in patients with hepatic impairment, due to the altered hepatic clearance and prolonged drug half-life.

Toxicity

Overdose is rare, and no fatal dose has been established. 5-HT3 receptor antagonists have a wide therapeutic index with mild side effects that occur infrequently. Treatment is largely 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.