2CaseA 34-year-old woman who presents to her physician with the chief complaint of a 4-month history of hard pellet-like stools and difficulty when passing stoolsShe states that she constantly feels bloated and has taken to wearing loose-fitting clothing because she cannot tolerate anything tight around her abdomenShe states that she was diagnosed with “spastic colon” in college and thinks she remembers hearing the physician talking about IBS as a diagnosisShe has been able to tolerate the minimal symptoms until about 6 months ago when she began to notice some bloating and a decrease in the number of bowel movements per week
3Contd.She attributes the worsening symptoms to increased stress at work and her recent enrollment in an evening MBA program.Prior to 6 months ago, she states that she averaged about five stools a week. She estimates that she has had one or two bowel movements a week for the past month.She complains of straining to pass her stools and states that she has to get up 30 minutes earlier in the morning to allow for an attempt to pass a stool.She also states that the abdominal pain is not limited to when she passes a stool. She complains of abdominal pain and bloating almost continuously throughout the day for the past 2 months, although her symptoms are somewhat alleviated by passing a “good stool
4Contd.She also states that the symptoms are worse when she has midterms or finals or when she needs to complete a major college writing assignment.She does not remember having any gastroenteritis symptoms in the past year, and she has never eaten yogurt.She resumed taking psyllium powder 3 months ago but could not stand the taste and wasn’t sure how much it was helping.She thought about trying FiberCon but didn’t know if it would help her symptoms since both psyllium and FiberCon are laxatives.She switched to sorbitol solution, but she says it tastes too sweet and doesn’t seem to help
6What is Irritable Bowel Syndrome(IBS)? A group of functional bowel disordersChronic abdominal complaints without a structural or biochemical causeConstitutes a major health problem with gastrointestinal (GI) symptomsThe cause of IBS is unknown.Affects up to ~20 % adults in the industrialized worldThe condition is more frequent in women.The direct medical costs of IBS are ~ $ US 8 billion in the US each year.
8Symptoms of IBS Abdominal discomfort and pain Bloating, mucous in stools, diarrhea, constipation, or alternating diarrhea and constipationDepression, anxiety or stressIBS can be subdivided intoDiarrhea-predominant (IBS-D)Constipation-predominant (IBS-C)Alternating diarrhea and constipation
12Patient Counseling and Dietary Alterations Reassurance and careful explanation of the functional nature of the disorderhow to avoid obvious food precipitants are important first steps
13Antispasmodicsanticholinergic drugs may provide temporary relief for symptoms such as painful cramps related to intestinal spasmpostprandial pain is best managed by giving antispasmodics 30 min before mealsbelladonna alkaloidsSome physicians prefer to use synthetic anticholinergics such as dicyclomine that have less effect on mucous membrane secretions and therefore produce fewer undesirable side effects
14Mebeverin (colofac®)an antispasmodic with a direct action on the smooth muscle of the gastrointestinal tract135 mg three times daily by mouth before meals100 mg three times daily has also been usedA modified-release preparation is also available, taken as 200 mg twice daily
15Continuing… 25 mg for those aged 3 to 4 years 50 mg for those 4 to 8 years100 mg for those 8 to 10 years135 to 150 mg for those over 10 years
16Adverse Effects and Precautions adverse effects appear raregastrointestinal disturbancesdizziness, headache, insomnia, anorexia, and decreased heart rate have been reportedrash, urticaria, and angioedema
17CONSTIPATION-PREDOMINANT DISEASE dietary fiber may be beneficialPatients should be instructed to begin with 1 tablespoonful of fiber with 1 meal daily and gradually increase the dose to include fiber with 2 and 3 meals a day until the desired outcome is achievedFor patients unable to tolerate dietary bran, bulking agents such as psyllium may be substitutedLaxative use is not encouraged in these patients, and it should only be used in the smallest dose for the least amount of time in cases of severe constipationThe 5-HT4 agonist tegaserod is the first therapy approved by the FDA specifically for the treatment of constipation-predominant form
18Serotonin is important in gut function GI disorders may be related toan imbalance of serotonin in the gutan improper reaction of the digestive system to serotonina faulty communication network between serotonin in the gut and the brain and spinal cord.Serotonin plays a major role in modulating intestinal movement and perception of pain. Helps to soften stools by releasing water.
19Serotonin (5-hydroxytryptamine, 5HT) A monoamine neurotransmitterFound in cardiovascular tissue, the peripheral nervous system, blood cells, and the CNS95 % resides in the GI tractSerotonergic neurons secrete 5HTThe function of serotonin is exerted upon its interaction with specific receptors.14 distinct families of 5HTreceptors; 5HT1, 5HT2, 5HT3 and ….
215HT3 receptors and its antagonists A ligand-gated cation channelPresent in the GI tractControl sensation, contraction of intestinal muscleRelease of fluid into the intestines5HT3 antagonistsSlow intestinal transitDecrease intestinal secretionsDecrease the water content of stoolDiminish colonic pain
225HT4 receptors and its agonists G-protein-coupled receptorPresent in the GI tractMediate both relaxation and contraction of circular smooth-muscle stripsInduces small bowel and to a lesser extent colonic fluid secretion5HT4 agonistsAccelerate gastric emptyingAccelerate small and large bowel transitIncrease stool water content
23Tegaserod in IBS-CThe first selective serotonin 5HT4 receptor partial agonist approved by FDA for the treatment of abdominal pain and constipation predominent IBS patientsBrand name is ZelnormTM by Novartis Pharmceu. Corp.
24How does tegaserod work? The exact mechanism of tegaserod’s action is not yet understood completely.Tegaserod binds with high affinity at 5HT4 receptors.The activation of 5HT4 receptors in GI tract stimulates the peristaltic reflex and intestinal secretionAs a result, contractions increase and the increased contractions speed the transit of digesting food and reverse constipation.Reduces the sensitivity of the intestinal pain-sensing nerves and reduces pain by inhibiting visceral sensitivity
25Tegaserod –a Promising Option Tegaserod is rapidly absorbed and metabolized.Effective in increasing the frequency of stools, relieving abdominal pain and discomfort, and decreasing the sensations of bloatingDiarrhea is an occasional side effectIs approved only for womenShould be prescribed under the guidance of a specialist
26DIARRHEA-PREDOMINANT DISEASE Avoidance of certain food products may be necessaryCaffeine, alcohol, and artificial sweeteners (sorbitol, fructose, and mannitol) are known to irritate the gut and produce a laxative effectHerbal medicines or teas often contain senna, which may produce diarrheaIn patients with disease persistence following dietary modification, loperamide may be used for episodic management of urgent diarrheaor in situations in which the patient wishes to avoid the possibility of an acute onset of symptoms
27Continuing…Loperamide decreases intestinal transit, enhances water and electrolyte absorption, and strengthens rectal sphincter toneCholestyramine may be useful in patients with diarrhea related to idiopathic bile acid malabsorption or following cholecystectomyDiarrhea-predominant IBS caused by excessive stimulation of the 5-HT3 receptor can be relieved by the drug alosetron
28Alosetron in IBS-DThe first drug is approved for female patients by FDABrand name is Lotronex® by Glaxo Smith KlineA potent and selective antagonist of the 5HT3 receptors
29How does alosetron works? The exact mechanism how alosetron relieves the symptoms of IBS-D is unknown.Serotonin in the intestines controls how pain is felt, contraction of intestinal muscle, and release of fluid into the intestines. An excessive release of or an excessive response to serotonin causes a pain and diarrhea.By blocking 5HT3 receptors, alosetron reduced pain and motor responses.
30Alosetron-New Drug for IBS Alosetron is rapidly absorbed and extensively metabolized.Effective in relieving pain, normalizing bowel frequency, and reducing urgencyIn November 2000 it was voluntarily withdrawn from the market due to severe GI adverse effects, including 113 reported cases of serious constipation and 8 cases of possible ischemic colitis and deathBecause this drug was highly effective in many patients, the FDA approved restricted use of alosetron in June 2002Alosetron is now available via an FDA-approved restricted use programIt is now indicated, in lower initial doses of 1 mg daily, for women with diarrhea-predominant symptoms of greater than 6 months’ duration that are not relieved by conventional therapy
31Antidepressant DrugsIn addition to their mood-elevating effects, antidepressent medications have several physiologic effects that may be beneficial in IBSIn a 2-month study of desipramine, abdominal pain improved in 86% of patients compared to 59% given a placeboAnother study of desipramine in 28 IBS patients showed improvement in stool frequency, diarrhea, pain, and depressionImprovements were observed mainly in diarrhea-predominant patientsThe beneficial effects of the tricyclic compounds in the treatment of IBS appear to be independent of their antidepression actionsThe therapeutic benefits for the bowel symptoms occur faster and at a lower dosage
32Cotinuing…paroxetine may be useful in constipation-predominant patientsA small placebo-controlled study of citalopram in IBS patients reported reductions in pain