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Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Gastrointestinal Disorders

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Introduction to Normal Physiology

The gastrointestinal (GI) tract consists of the esopha-gus, stomach, small intestine, and colon. It processes ingested boluses of food and drink and expels waste material. Intervention by disease or pharmacological therapy may alter function of the GI tract.

INTRODUCTION TO NORMAL PHYSIOLOGY

The gastrointestinal (GI) tract consists of the esopha-gus, stomach, small intestine, and colon. It processes ingested boluses of food and drink and expels waste material. Intervention by disease or pharmacological therapy may alter function of the GI tract.

From the mid esophagus to the anus, smooth muscle surrounds the alimentary canal and is responsible for active movement and segmentation of intestinal con-tents. This smooth muscle, which lies in the muscularis propria, consists of a circular and a longitudinal layer of muscle.

From the gastric body to the colon, repetitive spon-taneous depolarizations originate in the interstitial cells of Cajal, from which they spread to the circular muscle layer and then to the longitudinal muscle layer. The rate of slow-wave contraction varies in different regions of the gastrointestinal tract, occurring approximately 3 per minute in the stomach, 12 per minute in the proximal in-testine, and 8 per minute in the distal intestine. The in-creased frequency of contraction in the proximal intes-tine forms a gradient of contraction, and intestinal contents are therefore propelled distally. Though the stomach has fewer spontaneous contractions than does the small intestine, there is normally no retrograde spread of a depolarization wave from duodenum to stomach.

The underlying intrinsic smooth muscle motility is modulated by neurohormonal influences. Afferent sen-sory neurons, extrinsic motor neurons, and intramural neurons innervate the gut. It also has mucosal sensory receptors for monitoring chemical, osmotic, or painful stimuli and muscle receptors to monitor degrees of stretch.

Both the parasympathetic and sympathetic nervous systems provide extrinsic gastrointestinal innervation. Parasympathetic stimulation increases muscle con-traction of the gut, while sympathetic stimulation in-hibits contractions. Stimulation of either α- or β- adrenoceptors will result in inhibition of contractions. The intramural nervous system consists of a myenteric (Auerbach’s) plexus between the circular and longitudi-nal muscle areas and a submucosal (Meissner’s) plexus between the muscularis mucosa and the circular muscle layers. These two plexuses contain stimulatory choliner-gic neurons.

Ingested liquids are rapidly emptied from the stom-ach into the intestine, while digestible solids are first mechanically broken down in the stomach by peristaltic contractions. Stimulation of osmotic, carbohydrate, and fat receptors in the small bowel inhibits gastric peri-staltic contractions and retards gastric emptying.

The small intestinal motility in the fed state consists of random slow-wave contractions that result in slow transit and long contact of food with enzymes and ab-sorptive surfaces. With fasting, an organized peristaltic wave, termed the interdigestive migrating motor com-plex, begins to cycle every 84 to 112 minutes. During the migrating motor complex, a peristaltic contraction ring travels from the stomach to the cecum at 6 to 8 cm per minute. In the stomach the contractions sweep against a widely patent pylorus, permitting the passage of undigestible solids. In the small intestine this is to clear the intestine of undigested material: it functions as an intestinal housekeeper. The migrating motor complex appears to correlate with motilin hormonal levels and is modulated by vagal innervation. Motilin is a 22–amino acid polypeptide released from the duode-nal mucosa as a regulator of normal GI motor activity. Exogenous motilin is a potent inducer of gastric motor activity.

Colonic motor function also has cyclic slow waves in the proximal colon. These contractions are primarily retrograde in the proximal colon, allowing segmenta-tion and liquid reabsorption. In the distal colon a propulsive mass movement occurs intermittently. This may be stimulated by food ingestion and is termed the gastrocolonic reflex.

Approximately 1 to 1.5 L of fluid is ingested per day, and coupled with secretions from the stomach, pan-creas, and proximal duodenum, approximately 8 L of chyme enters the jejunum per day. Reabsorption of 6 to 7 L occurs within the small bowel, leaving a residual of 1.5 L fluid, 90% of which is reabsorbed in the colon. This pattern of liquid reabsorption permits the elimination of fecal waste containing an average of 0.1 to 0.2 L fluid per day. Diarrhea occurs if there is an altered rate of in-testinal motility, if mucosal function or permeability is altered, or if the fluid load entering the colon over-whelms colonic reabsorption. Constipation may occur if intestinal movement is inhibited or if there is a fixed ob-struction.

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