Irritable Bowel Syndrome (cont.)
Bhupinder Anand, MD
William C. Shiel Jr., MD, FACP, FACR
William C. Shiel Jr., MD, FACP, FACR
Dr. Shiel received a Bachelor of Science degree with honors from the University of Notre Dame. There he was involved in research in radiation biology and received the Huisking Scholarship. After graduating from St. Louis University School of Medicine, he completed his Internal Medicine residency and Rheumatology fellowship at the University of California, Irvine. He is board-certified in Internal Medicine and Rheumatology.
In this Article
Constipation is due to the slow transport (transit) of intestinal contents through the intestines, primarily the colon. This slow transit may be due to either abnormal function of the muscles of the entire colon or just the muscles of the anus and rectum.
The treatment of constipation in IBS usually begins with a trial of the supplements and medications that are used to treat constipation of any cause. In 2002, the FDA approved tegaserod (Zelnorm), the first drug designed specifically for the treatment of abdominal pain and constipation in women with IBS. However, in March of 2007, the FDA asked Novartis to suspend sales of tegaserod (Zelnorm) in the United States because a retrospective analysis of data by Novartis from more than 18,000 patients showed a slight increase in the incidence of cardiovascular events (heart attacks, strokes and angina) among patients on Zelnorm compared to placebo. The data showed that cardiovascular events occurred in 13 out of 11,614 patients treated with Zelnorm (0.11%), compared to one cardiovascular event in 7,031 (0.01%) placebo-treated patients. However, it is unclear whether Zelnorm actually causes heart attacks and strokes. Doctors and scientists will be scrutinizing the data further to determine the long-term safety of Zelnorm.
The mechanism whereby tegaserod reduces constipation is interesting. It is the contractions of the intestinal muscles that controls transit of food through the intestine. More contractions speed transit, fewer contractions slow transit. In constipated patients, contractions are fewer. One important chemical in the control of the contractions is serotonin. Serotonin is manufactured by the nerves in the intestine. It is released by the nerves and then travels to other nerves where it binds to receptors on the nerves. It is, in scientific terms, a "neurotransmitter" that allows nerves to communicate with each other. When it binds to receptors on nerves that control the contractions of intestinal muscles, serotonin can either promote or prevent contractions depending on the type of receptor it binds to. Binding to some types of receptors causes contractions, and binding to other types of receptors prevents contractions. The serotonin 5-HT4 receptor prevents contractions when serotonin binds to it. Tegaserod blocks the 5-HT4 receptor, prevents serotonin from binding to it, and thereby increases contractions of the intestinal muscles. The increased contractions speed the transit of intestinal contents. In addition, tegaserod reduces the sensitivity of the intestinal pain-sensing nerves and can thereby reduce the perception of pain.
In a randomized, double blind, placebo-controlled study involving more than 1000 patients (80% women) with constipation-predominant IBS, tegaserod was found to be more effective than placebo in increasing the frequency of stools, relieving abdominal pain and discomfort, and decreasing the sensation of bloating in women. (There were an insufficient number of men in the study to draw conclusions about the effectiveness of treatment in men.) The beneficial effects of treatment started during the first week of treatment and were sustained throughout the 12-week period of study.
Diarrhea was the only side effect in the tegaserod study. Diarrhea usually occurred early during treatment and resolved quickly even if the treatment was continued. There was no effect of tegaserod on blood counts, liver and kidney tests, electrocardiograms (EKG, ECG), blood pressure, pulse, and body weight. (A medication similar to tegaserod, called cisapride [Propulsid], which also promoted intestinal muscle contractions, was withdrawn from the market due to rare but potentially fatal effects on the electrical rhythm of the heart. So far, there have been no reports of rhythm disturbances related to tegaserod.) Patients with major liver or kidney disease should not take tegaserod. The safety of tegaserod in a fetus or nursing infants has not been studied and is unknown. Therefore, pregnant or nursing women should avoid tegaserod.
Linaclotide (Linzess) is an oral drug that is not absorbed from the intestine. It stimulates the cells lining the small intestine to secrete fluid into the intestine. The increase in fluid secretion leads to an increased number of bowel movements. In addition, when constipation is associated with the abdominal pain of IBS, the pain also is reduced. Although the improvement in pain may be due to the improvement in constipation, linaclotide has been shown also to reduce the sensitivity of intestinal pain nerves, and this mechanism of action also may account for the decrease in pain.
Linaclotide is moderately effective, and it's effectiveness depends on how a favorable response is defined. In the studies leading up to its approval, linaclotide was associated with a predefined response of an increase in bowel movements and a decrease in pain in approximately one-third (33%) of patients as compared with 17% of patients who received placebo. The response was better when pain and constipation were considered separately, with responses of approximately 50% for either.
The only common side effect of linaclotide is diarrhea. It should not be used in children below the age of six because of serious toxicity (death) to very young mice in animal studies, and should be avoided in children ages six through 17.
Reviewed by William C. Shiel Jr., MD, FACP, FACR on 9/18/2012
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