Irritable Bowel Syndrome (IBS)

Tachykinin Receptor Antagonists

The role of the neurokinins (tachykinins) — substance P, neurokinin A, and neurokinin B — in the pathogenesis of irritable bowel syndrome has been the subject of considerable investigation and debate within the scientific community. Many companies have taken an interest in this research area over the last decade, but no tachykinin receptor antagonists have yet reached the market.

IBS: Pathophysiology

The pathophysiology of irritable bowel syndrome (IBS) is heterogeneous, involving motor, central nervous system (CNS) and autonomic abnormalities, enhanced visceral sensitivity, and complex psychosocial factors. Patients with IBS may have alterations in gastrointestinal (GI) tract motility in response to both psychological and physical stimuli such as meals, balloon distention, and cholecystokinin, a hormone released from the small-bowel mucosa in response to the ingestion of fats and proteins. Fasting small-bowel motor functions are considerably different from normal in IBS patients.

Treatment of IBS. Antidepressants

The effectiveness of antidepressant medications in treating irritable bowel syndrome (IBS) may be attributable to several mechanisms including anticholinergic activity, central analgesic effect, and modulation of neurotransmitter activity or a combination of these actions. These agents tend to produce relief of symptoms sooner than a central steady state effect is achieved, and at times with lower doses than used to treat psychological disorders. Tricyclic antidepressants (TCAs) such as amitriptyline and desipramine traditionally have been the agents used as adjuncts to other symptomatic treatments in IBS.

Irritable Bowel Syndrome (IBS): Laxatives

Patients with constipation-predominant irritable bowel syndrome (IBS) are often advised to increase dietary fiber intake or use fiber supplements, also referred to as bulking agents. The rationale behind the use of fiber is based on its ability to decrease gastrointestinal (GI) transit time (for treatment of constipation) and to decrease intracolonic pressure (to lessen pain).

IBS: Presentation

Irritable bowel syndrome (IBS) is a chronic, nonspecific disorder that affects up to 20% of the US population. Altered bowel habits may include constipation, diarrhea, straining at the stool, and feelings of incomplete evacuation. Many patients also experience fatigue, pelvic pain, somatic pain disorders, and sexual dysfunction as well as urologic or gynecologic complaints.

Irritable Bowel Syndrome (IBS): Pharmacologic Treatments

Although non-pharmacologic therapy is often effective for the treatment of mild irritable bowel syndrome (IBS) symptoms, many patients who experience moderate-to-severe symptoms do not attain adequate relief and are given drug therapy. Pharmacologic therapy is symptom-specific and is intended for use in combination with lifestyle therapy. A review of the literature in 1988 concluded that trials involving IBS therapies were poorly designed and that no treatments had evident efficacy.

Renzapride

The agent was initially being developed by SmithKline Beecham, but Alizyme gained full ownership of the compound following SmithKline Beecham’s merger with Glaxo Wellcome. Patient recruitment for Phase III trials began in late 2005.

Irritable Bowel Syndrome

The irritable bowel syndrome is the most common of all digestive disorders, affecting nearly everyone at one time or another and accounting for up to 50% of patients referred to a gastroenterologic practice. Although characterized as a disorder of bowel motility, in many patients it is an exaggeration of normal physiologic responses. Numerous terms have been used to describe the syndrome (Table SYNONYMS FOR IRRITABLE BOWEL SYNDROME).

Treatment of IBS. Prokinetic Agents

Metoclopramide affects the gastrointestinal (GI) tract via cholinergic and dopaminergic action, which leads to relaxation of the esophageal and pyloric sphincters, increased gastric and duodenal peristalsis, and thus decreased transit time. This was the first prokinetic agent available with the potential to affect constipation-dominant irritable bowel syndrome (IBS).

Treatment of IBS. Antidiarrheal Agents

Morphine analogs such as diphenoxylate and codeine have been used for their antiperistaltic actions to counter frequent stools in irritable bowel syndrome (IBS). Although these medications are effective, the accompanying central nervous system (CNS) side effects, potential for addiction, and controlled-substance status make these less desirable in light of other agents, such as loperamide.

Antidepressants

Initially, the use of antidepressants was proposed for the large proportion of irritable bowel syndrome patients who also suffered from clinical depression, but it was subsequently discovered that antidepressants, independent of their mood-modulating effects, have neuromodulatory and analgesic properties that make them useful in treating irritable bowel syndrome itself. These effects are usually seen at dosages that are subtherapeutic for the treatment of psychiatric disorders, and they occur more quickly than mood elevation.

Irritable Bowel Syndrome (IBS): Tegaserod Maleate

The serotonin receptor subtype 4 (5-HT4) receptor is present in high concentrations throughout the gastrointestinal (GI) tract and appears to mediate the release of other neurotransmitters, such as substance P and CGRP. By acting as a partial agonist on the 5-HT4 receptor, tegaserod maleate may decrease abdominal pain and normalize altered GI function in patients who suffer from abdominal pain and constipation-predominant irritable bowel syndrome (IBS).

Treatment of IBS. Other meds

Benzodiazepines have been prescribed to treat anxiety contributing to and stemming from irritable bowel syndrome (IBS). Despite this, Farthing suggests that support for anxiolytics in the treatment of IBS has not been compelling enough to advocate their use.

Opioid Receptor Modulators

Opioids are a family of receptors and ligands that profoundly affect the neural circuits that modulate pain and motility in the gut. Both agonists and antagonists at the various opioid receptors represented in the periphery (kappa, mu, delta, and sigma) are under investigation for the treatment of irritable bowel syndrome. Pfizer has an agent in preclinical development (JO-2871, a sigma opioid receptor modulator and novel antidiarrheal), while both GSK (UK-321130, a delta opioid antagonist) and Eli Lilly (alvimopan, a mu receptor antagonist) have compounds in Phase I development for irritable bowel syndrome.

Irritable Bowel Syndrome (IBS): Antidepressants

Antidepressants were initially used for patients with irritable bowel syndrome (IBS) who reported significant depressive symptoms. Because it has been shown that antidepressants are useful in the treatment of pain due to neuromodulatory and analgesic properties, the use of these agents for IBS may be considered for patients with less severe symptoms. A recent meta-analysis concluded that tricyclic antidepressants (e.g., amitriptyline, desipramine) were generally more effective than placebo in the treatment of irritable bowel syndrome (IBS).

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

According 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.