Current Treatment of Irritable Bowel Syndrome

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The goal of IBS treatment is to provide rapid, sustained, global relief of the multiple symptoms of IBS with a single, effective, well-tolerated agent. However, because of the complexity and overlap of the neural circuitry of the gut and CNS and potential occurrence of multiple pathophysiological disturbances, it has proved difficult to identify a single optimal therapeutic target. The choice of therapy has traditionally been based on the primary bowel symptom. Because of the multiplicity of symptoms associated with IBS, patients often need to use a variety of agents to achieve relief. Traditional treatment approaches rely on a combination of dietary changes, bulking agents, laxatives, antispasmodics, antidiarrheal agents, and antidepressants. These therapies, in general, target individual symptoms and therefore do not address the multiple-symptom complex.142 Clear-cut evidence for their use in patients with IBS is lacking. An evidence-based review of IBS therapies concluded that, although bulking agents, antidiarrheals, and tricyclic antidepressants (TCAs) relieved constipation, diarrhea, and abdominal pain, respectively, these agents did not provide global relief from multiple symptoms of this disorder.5 The single-symptom approach often leaves many patients dissatisfied, leading to the use of multiple agents, frequent switching of medications, repeated doctor visits, and increased medical costs.143 Furthermore, some treatments may have adverse effects that mimic IBS symptoms.

The use of serotonergic agents in patients with IBS is based on the critical role played by 5HT in maintaining normal motor, sensory, and secretory functions of the gut. Through their pharmacological action on serotonin receptors, serotonergic modulators can target multiple IBS symptoms. Two agents in this class are currently approved for clinical use, and others are in late-stage trials. Tegaserod 1, a partial agonist of 5HT4, has been demonstrated to be efficacious against the symptoms of abdominal pain, bloating, and constipation in patients with IBS-C. Alosetron 2 is a 5HT3 antagonist that has proved effective in relieving abdominal pain, discomfort, and fecal urgency in patients with IBS-D.

The lack of a standardized treatment algorithm for patients with IBS poses a challenge with regard to optimal treatment. In general, the agent of choice depends on the severity of symptoms, response to traditional agents, and degree to which IBS symptoms are affecting daily life. The clinical pharmacology and potential place in therapy of single-symptom and multiple-symptom treatment options are discussed next and summarized in Table 3.5>59>134>143-152

6.29.5.1 Drugs Targeting the Multiple-Symptom Complex of Irritable Bowel Syndrome

6.29.5.1.1 Serotonergic agonists and antagonists

As discussed, 5HT is a common and key element linking the pathophysiological abnormalities observed in patients with IBS: altered GI motility, altered intestinal secretion, and visceral hypersensitivity. Although numerous serotonin receptor subtypes have been identified in the GI tract, the 5HT3 and 5HT4 subtypes have been studied most widely, primarily due to the availability of agents for clinical use. The critical role played by serotonergic mechanisms in GI function and dysfunction led to the clinical development and approval of two medications for the treatment of IBS: tegaserod, a 5HT4 agonist, and alosetron, a 5HT3 antagonist.

6.29.5.1.1.1 Tegaserod

5HT4 receptors are unique in that they provide both excitatory and inhibitory influences on the GI tract with relevance to the treatment of disorders involving the multiple symptoms associated with dysmotility and visceral hypersensitivity. Their activation results in facilitation of peristalsis and secretion through the release of neurotransmitters involved in the ENS75 and inhibition of visceral sensitivity via inhibition of extrinsic afferent nerves that transmit sensory information from the gut to the spinal cord.40'54 5HT4 agonists thus act via multiple mechanisms to treat the multiple symptoms associated with IBS.

Tegaserod 1 is a partial 5HT4 agonist, the first in a novel class of drugs, the aminoguanidole indoles.60,153-155 Tegaserod is approved by the Food and Drug Administration (FDA) for the short-term (up to 12 weeks) treatment of women with IBS-C.5 It also recently has been approved by the FDA for the treatment of women and men younger than 65 years with chronic idiopathic constipation.156 The promotility and secretory actions of tegaserod have been confirmed in clinical pharmacology studies, which demonstrate that tegaserod accelerates overall GI transit, promotes gastric emptying, enhances the peristaltic reflex, increases fasting gastric compliance, and enhances fluid secretion in healthy subjects.59 Similarly, in patients with IBS-C, tegaserod increases orocecal and proximal colon transit.157

The precise mechanisms by which 5HT4 agonists act as promotility agents are well defined (see Section 6.29.2). 5HT4 receptors are located presynaptically on terminals of IPANs and interneurons, and, in this position, their activation results in an enhancement, or amplification, of peristaltic neurotransmission via increased release of additional neurotransmitters (e.g., ACh and CGRP).45,52,62-66

A similar enhancement of reflexes in secretomotor circuits of the ENS is thought to underlie the prosecretory effect of tegaserod.63,64 However, the demonstration of increased chloride ion and fluid secretion from isolated rat colonocytes suggests an additional action based upon the epithelium itself.68

The mechanisms by which tegaserod relieves abdominal pain and discomfort in patients with IBS are not as well defined. Peripheral 5HT4-mediated mechanisms appear to mediate visceral sensation and perception, and preclinical studies are beginning to reveal the visceroanalgesic properties of tegaserod. A feline model showed a direct action of tegaserod on the extrinsic spinal afferents innervating the colon.72,73 These findings were confirmed by using an in vitro isolated rat colorectal inferior splanchnic nerve preparation.74 Perceptions of fullness, urge to defecate,

Table 3 Select characteristics of current treatments for patients with IBS1

5,59,134,143-152,156,18

Drug class/agents

Mechanism of action

Place in therapy for IBS

Potential adverse effects/ limitations

Bulking agents

Natural (derivatives of agar, psyllium, kelp, plant gums, ispaghula husk) Synthetic (methylcellulose, carboxymethylcellulose)

Laxatives

* Long-chain carbohydrates swell in intestinal fluid

* Lead to softer bulkier stools

* Promote peristalsis and eases intestinal transit

Initial treatment of patients with IBS-C

May aggravate abdominal pain or bloating. Not recommended for patients with these symptoms or diarrhea

May hinder absorption of concurrently administered drugs

Stimulant laxatives (bisacodyl, senna, danthron, ricinoleic acid)

Osmotic laxatives (magnesium salts, lactulose, sorbitol, polyethylene glycol)

Stool softeners (docusate)

Antidiarrheal agents

Opioid agonists (loperamide, diphenoxylate-atropine, codeine)

Stimulate motility via nonspecific local irritation or a selective action on the intramural nerve plexus of intestinal smooth muscle

* Increase intraluminal water content through an osmotic effect

* Cause distension of the bowel and stimulate colonic peristalsis

Facilitate uptake of intestinal fluids by fecal contents and softening of stools

Stimulate m-opiate receptors in enteric nervous system Inhibit peristalsis Increase fluid absorption secondary to prolonged intestinal transit Increase basal and sphincter pressure

Tricyclic antidepressants

(TCAs) (amitriptyline, desipramine, clomipramine, doxepin, trimipramine)

Selective serotonin reuptake inhibitors (SSRIs) (fluvoxamine, luvoxamine, sertraline, paroxetine)

Block reuptake of norepinephrine and serotonin and exhibit anticholinergic activity Modulate sensorimotor activity and GI transit Reduce pain

Selective blockade of serotonin reuptake

Initial therapy in patients with IBS-C

Treatment of symptoms of IBS-C not improved with fiber

Value in IBS-C not yet established

Loperamide is used in the treatment of patients with IBS-D

Potential adverse effects include severe cramping, fluid loss, malabsorption, and hypokalemia

Abdominal cramping, flatulence, diarrhea

Abdominal cramping and diarrhea

Diphenoxylate-atropine and codeine cross the blood-brain barrier Codeine may cause dependence

Treatment of patients with moderate to severe IBS when pain is prominent or other therapies have failed May be more effective in patients with IBS-D Treatment of psychiatric comorbidity

Alternative treatment in patients with IBS and abdominal pain after failure of TCAs or with intolerability to TCAs

May be preferred in patients with IBS-C

Superior to TCAs in treating coexisting panic, anxiety, or obsessive disorder Treatment of older patients

Potential adverse effects include fatigue, somnolence, dry mouth, urinary retention May aggravate constipation; hence, use in patients with IBS-C or IBS-A is not recommended

High rate of discontinuation because of adverse effects Fewer adverse effects and better safety than TCAs Potential adverse effects include insomnia, night sweats, weight loss, and sexual dysfunction More likely than TCAs to cause diarrhea m m m m m m m m m m m m m m m m m m m m m m continued

Table 3 Continued

Drug class/agents Mechanism of action Place in therapy for IBS Potential adverse effects/

limitations

Table 3 Continued

Benzodiazepines

Antianxiety effect

Treatment of patients with IBS

a

Potential for physical

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