5-HT3 receptors in the gastrointestinal tract activate visceral afferent pain sensation via extrinsic sensory neurons from the gut to the spinal cord and central nervous system. Inhibition of afferent gastrointestinal 5-HT3 receptors may reduce unpleasant visceral afferent sensation, including nausea, bloating, and pain. Blockade of central 5-HT3 receptors also reduces the central response to visceral afferent stimulation. In addition, 5-HT3-receptor blockade on the terminals of enteric cholinergic neurons inhibits colonic motility, especially in the left colon, increasing total colonic transit time.
Alosetron is a 5-HT3 antagonist that has been approved for the treatment of patients with severe IBS with diarrhea (Figure 62–5). Four other 5-HT3 antagonists (ondansetron, granisetron, dolasetron, and palonosetron) have been approved for the prevention and treatment of nausea and vomiting (see Antiemetics); however, their efficacy in the treatment of IBS has not been determined. The differences between these 5-HT3 antagonists that determine their pharmacodynamic effects have not been well studied.
Alosetron is a highly potent and selective antagonist of the 5-HT3 receptor. It is rapidly absorbed from the gastrointestinal tract with a bioavailability of 50–60% and has a plasma half-life of 1.5 hours but a much longer duration of effect. It undergoes extensive hepatic cytochrome P450 metabolism with renal excretion of most metabolites. Alosetron binds with higher affinity and dissociates more slowly from 5-HT3 receptors than other 5-HT3 antagonists, which may account for its long duration of action.
Alosetron is approved for the treatment of women with severe IBS in whom diarrhea is the predominant symptom
FIGURE 62–5 Chemical structure of serotonin; the 5-HT3 antagonists ondansetron, granisetron, dolasetron, and alosetron; and the 5-HT4 partial agonist tegaserod.
(“diarrhea-predominant IBS”). Its efficacy in men has not been established. In a dosage of 1 mg once or twice daily, it reduces IBS-related lower abdominal pain, cramps, urgency, and diarrhea. Approximately 50–60% of patients report adequate relief of pain and discomfort with alosetron compared with 30–40% of patients treated with placebo. It also leads to a reduction in the mean number of bowel movements per day and improvement in stool consistency. Alosetron has not been evaluated for the treatment of other causes of diarrhea.
In contrast to the excellent safety profile of other 5-HT3-receptor antagonists, alosetron is associated with rare but serious gastrointestinal toxicity. Constipation occurs in up to 30% of patients with diarrhea-predominant IBS, requiring discontinuation of the drug in 10%. Serious complications of constipation requiring hospitalization or surgery have occurred in 1 of every 1000 patients. Episodes of ischemic colitis—some fatal—have been reported in up to 3 per 1000 patients. Given the seriousness of these adverse events, alosetron is restricted to women with severe diarrhea-predominant IBS who have not responded to conventional therapies and who have been educated about the relative risks and benefits.
Despite being metabolized by a number of CYP enzymes, alosetron does not appear to have clinically significant interactions with other drugs.