SEROTONIN 5-HT3 RECEPTOR ANTAGONISTS
ALOSETRON, DOLASETRON, GRANISETRON, ONDANSETRON, PALONOSETRON
Serotonin 5-HT3 Receptor Antagonists
The serotonin type 3 (5-HT3) receptor antagonists are potent antiemetics used for prevention of postsurgical or chemotherapy induced nausea and vomiting and for some agents as therapy of diarrhea-predominant irritable bowel syndrome. The 5-HT3 receptor antagonists are associated with a low rate of transient serum enzyme elevations during therapy, but have been only rarely implicated in cases of clinically apparent liver injury.
The 5-HT3 receptor antagonists act to block the effects of serotonin on specific receptors that are found most frequently in the gastrointestinal tract and the central nervous system. The antiemetic effects appear to be the result of both central and peripheral inhibition of serotonin activity, with a decrease in vagal activity as well as interruption of pathways in the chemoreceptor trigger zone and solitary tract nucleus of the brainstem. 5-HT3 receptor antagonists in clinical use for treatment of nausea and vomiting in the United States include (with brand name and year of approval) granisetron (Kytril: 1994), dolasetron (Anzemet: 1997), ondansetron (Zofran: 1999), and palonosetron (Aloxi: 2003). All except palonosetron are also available in generic forms. These four 5-HT3 receptor antagonists are approved for prevention of nausea and vomiting after major surgery, chemotherapy or radiation therapy. They are sometimes used off-label to treat severe nausea and vomiting including that from hyperemesis gravidarum and acute gastroenteritis. They are not effective for motion sickness. These agents are generally given intravenously before or at the time of chemotherapy or surgery, but are also available as oral tablets, capsules and solutions, but are usually given for 1 to 3 days only. Common side effects include headache, fatigue, dizziness and constipation.
Alosetron (al oh’ se tron) is a 5-HT3 receptor blocker, but was developed and used largely for management of diarrhea-predominant irritable bowel syndrome rather than as an antiemetic. Its introduction in the 1990s however, was followed by cases of severe, even life-threatening, constipation which led to its withdrawal in 2000. Alosetron was reintroduced in 2002 with restrictions on its availability and limitation to women with severe diarrhea-predominant irritable bowel syndrome. Alosetron is available as 0.5 and 1.0 mg tablets generically and under the brand name Lotronex. The typical initial dose in adults is 0.5 mg twice daily, which can be increased to 1 mg twice daily if it is well tolerated. Side effects include abdominal pain and constipation, which can be severe resulting in intestinal obstruction, ileus, impaction and ischemic colitis. Patients treated with alosetron must be enrolled in a prescribing program and have regular monitoring for side effects.
Dolasetron (doe las’ e tron) is a 5-HT3 receptor blocker used as an antiemetic to prevent nausea and vomiting postoperatively or after cancer chemotherapy. It was first approved in 1997 and is available as tablets of 50 and 100 mg and as a solution for injection in single or multidose vials (20 mg/mL) under the brand name Anzemet. As with most 5-HT3 receptor blockers, the dose varies by mode of administration, indication and expected severity and duration of nausea. Side effects include headache, fatigue, diarrhea and dizziness. Dolasetron can prolong the QTc interval and is susceptible to drug-drug interactions.
Granisetron (gra nis’ e tron) is a 5-HT3 receptor blocker used as an antiemetic to prevent nausea and vomiting postoperatively or after cancer chemotherapy. Introduced in 1993, granisetron is available as tablets of 1 mg and as a solution for injection in single or multidose vials (1 mg/mL) generically and under the brand name Kytril. A transdermal patch of granisetron for prevention of chemotherapy associated nausea and vomiting is also available (Sancuso). As with other 5-HT3 receptor blockers, the dose varies by mode of administration, indication and expected severity and duration of nausea. Side effects of granisetron can include headache, fatigue, diarrhea and dizziness.
Ondansetron (on dan’ se tron) is a 5-HT3 receptor blocker that was developed as an antiemetic and was introduced in 1993, the first of this class of anti-emetic agents. The current indications are for prevention of nausea and vomiting postoperatively or after cancer chemotherapy. Ondansetron is available as tablets of 4, 8, 16 and 24 mg and as a solution for injection in single or multidose vials (2 mg/mL) in multiple generic forms and under the brand name Zofran. As with other 5-HT3 receptor blockers, the dose varies by mode of administration, indication and expected severity and duration of nausea. Side effects include headache, fatigue, diarrhea and dizziness. Ondansetron can prolong the QTc interval.
Palonosetron (pal” oh noe’ se tron) is a 5-HT3 receptor blocker that was developed as an antiemetic and introduced in 2003. The current indications are prevention of nausea and vomiting postoperatively or after cancer chemotherapy. Palonosetron is available as capsules of 0.5 mg and as a solution for injection in single or multidose vials (0.05 mg/mL) generically and under the brand name Aloxi. As with other 5-HT3 receptor blockers, the dose varies by mode of administration, indication and expected severity and duration of nausea. Side effects include headache, fatigue, diarrhea and dizziness. Palonosetron has not been shown to prolong the QTc interval.
The 5-HT3 receptor antagonists have been linked to occasional instances of serum enzyme elevations during therapy, but these are generally mild and asymptomatic, resolving rapidly. Because they are used at the time of surgery and with chemotherapy, instances of liver injury arising after their use have been reported, but other drugs or factors may have played a role in the published cases. The rate of serum enzyme elevations with 5-HT3 receptor antagonist therapy has ranged from 1% to 8% and has generally been no greater than that observed with placebo therapy. While moderate serum enzyme elevations during 5-HT3 receptor antagonist therapy have been described, there have been have been only rare and isolated reports of clinically apparent acute liver injury with jaundice attributed to these agents. The onset of injury has been within 1 to 2 weeks of exposure and the pattern of injury hepatocellular and without immunoallergic or autoimmune features. Instances of recurrence after re-exposure have been published. No instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been attributed to the 5-HT3 receptor antagonists.
Alosetron likelihood score: D (possible cause of clinically apparent liver injury).
Dolasetron likelihood score: E (unlikely cause of clinically apparent liver injury).
Granisetron likelihood score: E (unlikely cause of clinically apparent liver injury).
Ondansetron likelihood score: D (possible cause of clinically apparent liver injury).
Palonosetron likelihood score: E (unlikely cause of clinically apparent liver injury).
Mechanism of Injury
The 5-HT3 receptor blockers are metabolized in the liver, largely via the cytochrome P450 system, but appear to have a low potential for causing liver injury. All except alosetron are used in low doses for short periods of time which may account for their relative lack of hepatotoxicity.
Outcome and Management
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation. Clinically apparent liver injury due to the 5-HT3 receptor blockers is rare, generally mild and self-limited and frequently arises only after the agent is discontinued. Rechallenge with the same agent can lead to reoccurrence but in some instances patients have tolerated other 5-HT3 receptor blockers without reappearance of liver injury.
Serotonin 5-HT3 Receptor Antagonists
REPRESENTATIVE TRADE NAMES
Alosetron – Generic, Lotronex®
Dolasetron – Generic, Anzemet®
Granisetron – Generic, Kytril®
Ondansetron – Generic, Zofran®
Palonosetron – Aloxi®
Product labeling at DailyMed, National Library of Medicine, NIH
CHEMICAL FORMULAS AND STRUCTURE
Serotonin 5-HT3 Receptor Antagonists
Serotonin 5-HT3 Receptor Antagonists
References updated: 15 January 2018
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Wilde MI, Markham A. Ondansetron. A review of its pharmacology and preliminary clinical findings in novel applications. Drugs 1996; 52:773-94. PubMed Citation (Review of the structure, mechanism of action, pharmacokinetics, efficacy and safety of ondansetron as an antiemetic agent mentions that abnormalities of liver tests have been associated with ondansetron therapy and severe symptomatic jaundice has been reported in one case).
Chevallier B, Cappelaere P, Splinter T, Fabbro M, Wendling JL, Cals L, Catimel G, et al. A double-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy. Support Care Cancer 1997; 5: 22-30. PubMed Citation (Among 226 patients with cancer receiving cisplatin, 4% of 157 receiving dolasetron vs 1% receiving metoclopramide had liver test abnormalities during treatment).
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Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath A, Dukes GE, McSorley D, et al. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001; 161: 1733-40. PubMed Citation (Among 626 patients with diarrhea predominant IBS treated with either alosetron [1 mg] or placebo twice daily for 12 weeks, constipation was the most common adverse event [25% vs 5%] and "laboratory values were not significantly affected by alosetron treatment").
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Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to anti emetic agents or the 5-HT3 receptor blockers).
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Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. PubMed Citation (Among 624,673 adverse event reports in children between 2000 and 2006 in the WHO VigiBase, 1% were hepatic, but no 5-HT3 receptor blocker was listed among the 41 most commonly implicated agents).
Vergne-Salle P, Dufauret-Lombard C, Bonnet C, Simon A, Trèves R, Bonnabau H, Bertin P. A randomised, double-blind, placebo-controlled trial of dolasetron, a 5-hydroxytryptamine 3 receptor antagonist, in patients with fibromyalgia. Eur J Pain 2011; 15: 509-14. PubMed Citation (Among 60 patients with fibromyalgia treated with 4 monthly infusions of dolasetron or placebo, there were "no meaningful changes" in ALT, AST or Alk P levels; one patient on dolasetron developed rise in ALT to 4 times ULN that resolved within 3 weeks).
Schwartzberg L, Barbour SY, Morrow GR, Ballinari G, Thorn MD, Cox D. Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting(CINV). Support Care Cancer 2014; 22: 469-77. PubMed Citation (Analysis of 4 controlled trials comparing palonosetron to ondansetron, dolasetron and granisetron for prevention of nausea and vomiting after cancer chemotherapy found similar rates of adverse events 20-27%; ALT elevations in 0.2% and 2.1% of patients on palonosetron and 3.1% on other 5-HT3 receptor antagonists).
Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to antiemetics or 5-HT3 receptor blockers).
Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. PubMed Citation (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common implicated agents being nimesulide [n=53: 30%], cyproterone [n=18], nitrofurantoin [n=17], antituberculosis drugs [n=13] and flutamide [n=12: 7%]; antiemetics and metoclopramide were not listed).
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