Other Agents That Suppress Motility

Smooth muscle relaxants such as organic nitrates and Ca2+ channel antagonists (see Chapter 31) often produce temporary, if partial, relief of symptoms in motility disorders such as achalasia, in which the lower esophageal sphincter fails to relax, resulting in a functional obstruction to the passage of food and severe difficulty in swallowing. Another approach relies on the use of botulinum toxin, injected in doses of 80—200 units directly into the lower esophageal sphincter via an endoscope. This agent inhibits ACh release from nerve endings (see Chapter 9) and can produce partial paralysis of the sphincter muscle, with significant improvements in symptoms and esophageal clearance. However, its effects dissipate over a period of several months, requiring repeated injections. Botulinum toxin also is being used increasingly in other GI conditions such as chronic anal fissures.

LAXATIVES, CATHARTICS, AND THERAPY FOR CONSTIPATION

OVERVIEW OF GI WATER AND ELECTROLYTE FLUX Fluid content is the principal determinant of stool volume and consistency; water normally accounts for 70-85% of total stool weight. Net stool fluid content reflects a balance between luminal input (ingestion and secretion of water and electrolytes) and output (absorption) along the length of the GI tract. The daily challenge for the gut is to extract water, minerals, and nutrients from the luminal contents, leaving behind a manageable pool of fluid for proper expulsion of waste material via the process of defecation. Normally ~8-9 L of fluid enter the small intestine daily from exogenous and endogenous sources (Figure 37-2). Net absorption of the water occurs in the small intestine in response to osmotic gradients that result from the uptake and secretion of ions and the absorption of nutrients (mainly sugars and amino acids), with only ~1—1.5 L crossing the ileocecal valve. The colon then extracts most of the remaining fluid, leaving ~100 mL of fecal water daily.

Under normal circumstances, these quantities are well within the range of the total absorptive capacity of the small bowel (~16 L) and colon (4—5 L). Neurohumoral mechanisms, pathogens, and drugs can alter these processes, resulting in changes in either secretion or absorption of fluid by the intestinal epithelium. Altered motility also contributes to this process, as the extent of absorption parallels transit time. With decreased motility and excess fluid removal, feces can become inspissated and impacted, leading to constipation. When the capacity of the colon to absorb fluid is exceeded, diarrhea will occur.

CONSTIPATION: GENERAL PRINCIPLES OF PATHOPHYSIOLOGY AND TREATMENT

Patients use the term constipation not only for decreased frequency, but also for difficulty in initiation or passage, passage of firm or small-volume feces, or a feeling of incomplete evacuation. Constipation has many reversible or secondary causes, including lack of dietary fiber, drugs, hormonal disturbances, neurogenic disorders, and systemic illnesses. In most cases of chronic constipation, no specific cause is found. Up to 60% of patients presenting with constipation will have normal colonic transit. These patients either have irritable bowel syndrome or define constipation in terms other than stool frequency. In the rest, attempts usually are made to categorize the underlying pathophysiology either as a disorder of delayed colonic transit because of an underlying defect in colonic motility, or less commonly, as an isolated disorder of defecation or evacuation (outlet disorder) due to dysfunction of the neuromuscular apparatus of the recto-anal region. Colonic motility is responsible for mixing luminal contents to promote absorption of water and moving them from proximal to distal segments by means of propulsive contractions. In any given patient, the predominant factor underlying constipation (propulsive vs. nonpropulsive colonic motility) often is not obvious. Consequently, the pharmacological approach to constipation remains empirical and nonspecific.

Constipation can be corrected by adherence to a fiber-rich (20—30 g daily) diet, adequate fluid intake, appropriate bowel habits and training, and avoidance of constipating drugs. Constipation related to medications can be corrected by use of alternative drugs where possible, or adjustment of dosage. If nonpharmacological measures alone are inadequate, they may be supplemented with bulk-forming agents or osmotic laxatives. When stimulant laxatives are used, they should be

FIGURE 37-2 The approximate volume and composition of fluid that traverses the small and large intestines daily.

Of the 9 L of fluid presented to the small intestine each day, 2-3 L are from the diet and the remainder are from secretions (salivary, gastric, pancreatic, and biliary). The absorptive capacity of the colon is 4-5 L/day.

FIGURE 37-2 The approximate volume and composition of fluid that traverses the small and large intestines daily.

Of the 9 L of fluid presented to the small intestine each day, 2-3 L are from the diet and the remainder are from secretions (salivary, gastric, pancreatic, and biliary). The absorptive capacity of the colon is 4-5 L/day.

administered at the lowest effective dosage and for the shortest period of time to avoid abuse. Habitual use of laxatives may lead to excessive loss of water and electrolytes; secondary aldosteronism may occur if volume depletion is prominent. Steatorrhea, protein-losing enteropathy with hypoal-buminemia, and osteomalacia due to excessive loss of calcium in the stool have been reported.

Laxatives are employed before surgical, radiological, and endoscopic procedures where an empty colon is desirable.

The terms laxatives, cathartics, purgatives, aperients, and evacuants often are used interchangeably. There is a distinction, however, between laxation (the evacuation of formed fecal material from the rectum) and catharsis (the evacuation of unformed, usually watery fecal material from the entire colon). Most of the commonly used agents promote laxation, but some are cathartics that act as laxatives at low doses.

Laxatives act by: (1) enhancing retention of intraluminal fluid by hydrophilic or osmotic mechanisms, (2) decreasing net absorption of fluid by effects on small- and large-bowel fluid and electrolyte transport, or (3) altering motility by either inhibiting segmenting (nonpropulsive) contractions or stimulating propulsive contractions. Based on their actions, laxatives can be classified as shown in Table 37-1; their known effects on motility and secretion are listed in Table 37-2. A variety of laxatives, both osmotic agents and stimulants, increase the activity of NO synthase and the biosynthesis of platelet-activating factor in the gut. Platelet-activating factor is a phospholipid proinflammatory mediator that stimulates colonic secretion and GI motility. Nitric oxide also may stimulate intestinal secretion and inhibit segmenting contractions in the colon, thereby promoting laxation. Agents that reduce the expression of NO synthase or its activity can prevent the laxative effects of castor oil, cascara, and bisacodyl (but not senna), as well as magnesium sulfate.

Laxatives also can be classed by the pattern of effects produced by the usual clinical dosage (Table 37-3).

Dietary Fiber and Supplements

Bulk, softness, and hydration of feces depend on the fiber content of the diet. Fiber resists enzymatic digestion and reaches the colon largely unchanged. Colonic bacteria ferment fiber to varying degrees, depending on its chemical nature and water solubility. Fermentation of fiber produces short-chain fatty acids that are trophic for colonic epithelium and increases bacterial mass. Although fermentation of fiber generally decreases stool water, short-chain fatty acids also may have a prokinetic effect, and increased bacterial mass may contribute to increased stool volume. Fiber that is not fermented can attract water and increase stool bulk. The net effect on bowel movement therefore varies with different compositions of dietary fiber (Table 37-4). In general, insoluble, poorly fermentable fibers, such as lignin, are most effective in increasing stool bulk and transit.

Bran, the residue left when flour is made from cereals, contains >40% dietary fiber. Wheat bran, with its high lignin content, is most effective at increasing stool weight. Fruits and vegetables contain more pectins and hemicelluloses, which are more readily fermentable and have less effect on stool transit. Psyllium husk, derived from the seed of the plantago herb, is a component of many commercial products for constipation (metamucil, others). Psyllium husk contains a hydrophilic mucilloid that undergoes significant fermentation in the colon, leading to an increase in colonic

Table 37-1

Classification of Laxatives

1. Luminally active agents a. Hydrophilic colloids; bulk-forming agents (bran, psyllium, etc.)

b. Osmotic agents (nonabsorbable inorganic salts or sugars)

c. Stool-wetting agents (surfactants) and emollients (docusate, mineral oil)

2. Nonspecific stimulants or irritants (with effects on fluid secretion and motility)

Diphenylmethanes (bisacodyl) Anthraquinones (senna and cascara) Castor oil

3. Prokinetic agents (acting primarily on motility)

5-HT4 receptor agonists Opioid receptor antagonists

Summary of Effects of Some Laxatives on Bowel Function

Small Bowel Colon
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