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Treatment of IBS. 5-HT3 Antagonists and 5-HT4 Agonists

Last updated on October 6, 2021

Treatment of IBS. 5-HT3 Antagonists and 5-HT4 AgonistsAccording to Birrer, 96% of serotonin is concentrated in the gastrointestinal tract. As a major neurotransmitter, it exerts an effect on gut smooth muscle in response to central and physical stimuli primarily via the 5-HT3 and 5-HT4 receptors, affecting contractility and relaxation. Serotonin receptor antagonists may ameliorate the abnormal stool frequency and consistency in diarrhea-predominant irritable bowel syndrome (IBS) by blocking stimulation of the peripheral and visceral sensory pathways or by reducing the gut’s response to nociceptive stimuli. This in turn may decrease resistance to distension and urgency to defecate. Conversely, agonists of 5-HT4 receptors in the gastrointestinal tract trigger peristalsis and may modulate visceral sensitivity.

Both ondansetron and granisetron, at higher than the standard antiemetic doses, have resulted in improvement in several diarrhea-predominant IBS symptoms. The effects noted were improved stool consistency and fewer episodes of pain, as well as decreases in bowel frequency and relief of flatulence, heartburn, and postprandial epigastric motility and discomfort. Neither agent is approved to treat symptoms associated with IBS in the United States.

Alosetron, a 5-HT3 receptor antagonist, yielded positive results in several studies treating female irritable bowel syndrome (IBS) patients with diarrhea-predominant disease. A study conducted by Camilleri et al evaluated alosetron administered at 1, 2, 4, and 8 mg twice daily in a cohort, two thirds of which were female patients. Adequate relief of pain and discomfort was significant for the intent-to-treat (ITT) females in the 2-mg/day group and was more significant in the 4-mg/day group. In the per-protocol population, a significant improvement was also noted in the 8-mg/day group.

Lower, nonsignificant responses occurred for male participants at all doses in both the ITT and per-protocol populations. Females taking 2 mg per day showed significant improvement in stool consistency and urgency by the first week and in stool frequency by the second week, effects not observed in the male patients at any dosage. Placebo effects for males were the same or higher than those for females. In a later dose-ranging study comparing the effectiveness of 0.1, 0.5, and 2 mg alosetron taken twice daily, Bardhan et al noted similar results in females at a dose of 2 mg twice daily, as well as the lack of response in male patients at all dosages.

Alosetron was approved in the US for the treatment of female patients with IBS with the recommended initial dosage of 1 mg twice daily. Although 2 mg taken twice daily resulted in higher resolution of pain, the incidence of constipation was noted to be higher in some studies. Constipation was the most frequently reported adverse effect; others included headache, anorexia, dizziness, nausea, flatulence, abdominal cramping, and discomfort. Alosetron did not alter the metabolism of theophylline or cisapride when administered concurrently. However, significant decreases in levonorgestrol and ethinyl estradiol levels were detected when alosetron was used with oral contraceptives with those components.

LotronexWhen alosetron (Lotronex) was approved in early 2000, the labeling included warnings regarding dose-related constipation and the occurrence of ischemic bowel. Subsequent postmarketing reports of not only ischemic colitis but also obstruction, perforation, impaction, and megacolon prompted the manufacturer to withdraw the medication from the market by November of that same year. The company was recently permitted to rerelease the medication, providing revisions to labeling were made and precautionary action was taken. The FDA mandated creation of a medication guide for the use of alosetron informing patients taking the medication of the possible adverse events, how to recognize symptoms, and when to seek medical attention.

Information was also made available to health care professionals and patients via the FDA’s Lotronex Web page, which includes common questions and answers. To prescribe alosetron, a physician must register in the prescribing program for the agent by signing the “Physician Attestation of Qualifications and Acceptance of Responsibilities.” In doing this, the prescriber attests to his or her credentials for diagnosing and treating irritable bowel syndrome (IBS) as well as his or her understanding of the adverse-event potential, and agrees to educate patients and monitor them appropriately.

Tegaserod is a partial agonist of the 5-HT receptor, with a high binding affinity for a 5-HT4 subtype that affects its action on the peristaltic reflex. Since the agent is a partial agonist, it produces a moderate, more balanced effect versus full agonists and is less likely to lead to tachyphylaxis. Two or 6 mg twice daily improve abdominal distention, bloating, and constipation. In one study dosages as low as 0.5 or 2 mg twice daily significantly decreased the number of days per month with bloating, pain, and constipation.

In a 12-month open-label trial assessing safety at doses of 4 or 12 mg daily, given 30 to 60 minutes before morning and evening meals, tegaserod was well tolerated. Patients were given 4 mg daily for the first month then titrated to 12 mg daily for the remainder of the trial period, if possible. The study allowed for continued use of stable doses of bulking agents, rescue medications for severe constipation, and loperamide for diarrhea. The most common adverse events were diarrhea, headache, abdominal pain, and flatulence, denoted as severe in 81/579 patients. No abnormalities in blood chemistries, hematologic tests, or electrocardiogram were noted.

In a review of phase III studies, Camilleri found that females in the studies showed a high response rate for relief of symptoms, improved bowel habits, and improvement in overall well-being. However, as with alosetron, male patients in the studies did not derive the same level of efficacy as their female counterparts.

Tegaserod is approved for the treatment of females suffering from constipation-dominant IBS. The maximum dosage is 6 mg orally twice daily, given before meals for four to six weeks. If patients respond, an additional four to six weeks of medication may be indicated; data is lacking for treatment beyond 12 weeks. One common adverse effect is transient diarrhea, which appears dose related and tends to normalize as treatment continues. Lower starting doses may also mitigate this effect. Other adverse effects are dizziness, nausea, vomiting, and persistent, more severe diarrhea with or without abdominal pain.

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