Serotonin 5-HT3 Receptor Antagonists

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Information about 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. 

Liver safety of Serotonin 5-HT3 Receptor Antagonists

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.  

Mechanism of action of Serotonin 5-HT3 Receptor Antagonists

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. 

Clinical use of Serotonin 5-HT3 Receptor Antagonists

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. 

Side effects of Serotonin 5-HT3 Receptor Antagonists

Common side effects include headache, fatigue, dizziness and constipation

List of Serotonin 5-HT3 Receptor Antagonists

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.

Antidiarrheal agents

Antidiarrheal agents include bulk forming agents, hydroscopic agents, bile acid resins, bismuth, inhibitors of intestinal motility, non-absorbed antibiotics and hormones. Bulk forming agents include methylcellulose; hydroscopic agents include pectin and kaolin; bile acid resins are cholestyramine, colestipol and colesevalam; inhibitors of intestinal motility include opioids such as diphenoxylate and loperamide. Antibiotics include rifamycin and rifaximin which are non-absorbed and are used for travelers' diarrhea. Hormones with antidiarrheal activity include octretide and somatostatin. Most antidiarrheal agents are active locally in the small intestine and colon and are largely not absorbed. Some, however, have been implicated in rare causes of liver injury (senna, cascara, cholestyramine). Telotristat is a relatively new agent that inhibits the synthesis of serotonin and is used specifically for the diarrhea of carcinoid syndrome.

Antiemetics are a diverse group of medications that act at different points in the pathways that regulate nausea and vomiting. These include antihistamines, anticholinergic agents, phenothiazines, serotonin type 3 receptor blockers, centrally acting benzamides, cannabinoid receptor agonists, substance P antagonists and miscellaneous.

Anticholinergic Agents

Antihistamines

Cannabinoid Receptor Agonists

Serotonin 5-HT3 Receptor Antagonists

Substance P/Neurokinin 1 Receptor Antagonists

Miscellaneous

Acid peptic disease/antiulcer agents that include antacids, the histamine type 2 receptor blockers (H2 blockers), and the proton pump inhibitors (PPIs). These agents are some of the most commonly taken medications and are very well tolerated, most being available both by prescription and over-the-counter. While many of these drugs are approved for use in duodenal and gastric ulcer disease, their major use is for acid reflux and indigestion.

Histamine H2 Receptor Antagonists (H2 Blockers) Cimetidine, Famotidine, Nizatidine, Ranitidine

Proton Pump Inhibitors

Cathartics, laxatives or agents for constipation include bulk forming agents, osmotic agents, stool wetting agents, nonspecific stimulants, prokinetic agents and agents that increase fluid secretion. Many of these therapies are not systemically absorbed and none are considered particularly hepatotoxic. Naldemedine and naloxegol are opioid antagonists and are used to treat the constipation associated with opioid use.

Inflammatory bowel disease encompasses several disorders, most commonly ulcerative colitis and Crohn colitis. Agents can be classified as 5-aminosalicyclic acid (5-ASA) based agents, immunosuppressive drugs, antitumor necrosis factor agents, corticosteroids, antibiotics and miscellaneous.

5-Aminosalicyclic Acid (5-ASA) Derivatives

Immunosuppressive Agents

Tumor Necrosis Factor Antagonists

Miscellaneous

Irritable Bowel Syndrome Agents Antimuscarinics/Antispasmodics [See Anticholinergic agents

Prokinetic Agents - See Serotonin 5-ht4 receptor agonists Alosetron, Cisapride, Domperidone, Linaclotide, Lubiprostone, Metoclopramide, Plecanatide, Prucalopride, Tegaserod

Other

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