Section VI - Drugs Affecting Gastrointestinal Function

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The term acid-peptic disorders encompasses a variety of relatively specific medical conditions in which injury by gastric acid (and activated pepsin) is thought to play an important role. These disorders include gastroesophageal reflux disease (GERD), benign "peptic" ulcers of the stomach and duodenum, ulcers secondary to the use of conventional nonsteroidal antiinflammatory drugs (NSAIDs), and ulcers due to the rare Zollinger-Ellison syndrome.

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Section VI. Drugs Affecting Gastrointestinal Function Chapter 37. Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease Overview The term acid-peptic disorders encompasses a variety of relatively specific medical conditions in which injury by gastric acid (and activated pepsin) is thought to play an important role. These disorders include gastroesophageal reflux disease (GERD), benign "peptic" ulcers of the stomach and duodenum, ulcers secondary to the use of conventional nonsteroidal antiinflammatory drugs (NSAIDs), and ulcers due to the rare Zollinger-Ellison syndrome. It appears that exposure of the involved tissue to acid is essential to the development of clinical symptoms in most instances of these diseases. Control of gastric acidity is therefore a cornerstone of therapy in these disorders, even though this approach may not address the fundamental pathophysiological process. Mankind has lived with peptic ulcers since ancient times. Perhaps the first description of this malady is the one inscribed on the pillars of the temple of Aesculapius at Epidaurus from around the fourth century B.C.: "A man with an ulcer in his stomach. He incubated and saw a vision; the god seemed to order his followers to seize and hold him, that he might incise his stomach. So he fled, but they caught and tied him to the doorknocker. Then Asklepios opened his stomach, cut out the ulcer, sewed him up again, and loosed his bonds." Many prominent people have suffered from indigestion and ulcers, including the Roman emperor Marcus Aurelius, whose death has been attributed by some to a perforated ulcer and whose physician was none other than Galen himself. Acid neutralization was recognized as effective treatment more than 12 centuries ago by Paulus Aeginata, who prescribed a mixture of Samian and Lemnian earths and milk, not unlike the milk- antacid regimens of the mid-twentieth century (Smith and Rivers, 1953). Since then, of course, considerable advances in understanding the pathogenesis and in the treatment of acid-peptic conditions have occurred, culminating in the discovery of Helicobacter pylori and proton pump inhibitors. We now know that eradication of H. pylori effectively promotes healing of peptic ulcers and prevents their recurrence in most cases. Proton pump inhibitors have become the drugs of choice in promoting healing from erosive esophagitis and peptic ulcer disease because of their ability to nearly completely suppress acid production. Although several clinical challenges still need to be met in this area, it is reasonable to conclude that the battle against the ravages of gastric acid is finally turning in our favor. This chapter covers some of the principal therapeutic agents in this area and strategies for their use. Physiology of Gastric Secretion Gastric acid secretion is a complex, continuous process controlled by multiple central (neural) and peripheral (endocrine and paracrine) factors. Each factor attributes to a common final physiological event—the secretion of H+ by parietal cells, which are located in the body and fundus of the stomach. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all play important roles in the regulation of acid secretion (Figure 37–1). Their respective specific receptors (M3, H2, CCK2 receptors) have been anatomically and/or pharmacologically localized to the basolateral membrane of the parietal cell. Two major signaling pathways are present within the parietal cell: the cyclic AMP–dependent pathway and the Ca2+–dependent pathway. Histamine uses
the first pathway, while gastrin and ACh exert their effect via the latter. The cyclic AMP–dependent pathway results in phosphorylation of parietal-cell effector proteins and the Ca2+–dependent pathway leads to an increase in cytosolic Ca2+. Both pathways activate the H+,K+–ATPase (the proton pump). The H+,K+–ATPase consists of a large -subunit and a smaller -subunit. This pump generates the largest ion gradient known in vertebrates, with an intracellular pH of about 7.3 and an intracanalicular pH of about 0.8. Figure 37–1. Physiological and Pharmacological Regulation of Gastric Secretions: The Basis for Therapy of Peptic Ulcer Disease. This schematic shows the interactions among an endocrine cell that secretes histamine [enterochromaffin-like (ECL) cell], an acid-secreting cell (parietal cell), and a cell that secretes the cytoprotective factors mucus and bicarbonate (superficial epithelial cell). Physiological pathways are in solid black and may be stimulated (+) or inhibited (–). Physiological agonists stimulate transmembrane receptors: muscarinic (M) and nicotinic (N) receptors for acetylcholine (ACh); CCK2, gastrin (and cholecystokinin) receptor; H2, histamine (HIST) receptor; EP3, prostaglandin E2 receptor. Actions of drugs are indicated by dashed lines. A blue X indicates a point of pharmacological antagonism. A light blue dashed line and arrow indicate a drug action that mimics or enhances a physiological pathway. Drugs currently used in treating peptic ulcer disease and discussed in this chapter are shown in dark blue. NSAIDs are nonsteroidal antiinflammatory drugs such as aspirin and are ulcerogenic. and indicate possible input by cholinergic postganglionic fibers. shows neural input from the vagus nerve. See the text for detailed descriptions of these pathways and of therapeutic interventions. The most important structures in the central nervous system (CNS) involved in central stimulation
of gastric acid secretion are the dorsal motor nucleus of the vagal nerve (DMNV), the hypothalamus, and the nucleus tractus solitarius (NTS). Efferent fibers originating in the DMNV descend to the stomach via the vagus nerve and synapse with ganglion cells of the enteric nervous system (ENS). ACh release from postganglionic vagal fibers can stimulate directly gastric acid secretion through a specific muscarinic cholinergic receptor subtype, M3, located on the basolateral membrane of the parietal cells. The CNS probably modulates the activity of the ENS with ACh as its main regulatory neurotransmitter. The CNS generally is thought of as the main contributor to the initiation of gastric acid secretion in response to the sight, smell, taste, and anticipation of food ("cephalic phase"). ACh also indirectly affects the parietal cell through the stimulation of histamine release from the enterochromaffin-like (ECL) cells in the fundus and the stimulation of gastrin release from the G cells in the gastric antrum. Histamine is released from ECL cells through multifactorial pathways and is a critical regulator of acid production through the H2 subtype of receptor. ECL cells usually are found in close proximity to parietal cells. Histamine activates the parietal cell in a paracrine fashion; it diffuses from its release site to the parietal cell. Its involvement in gastric acid secretion (whether or not as the final, common, effector hormone) has been convincingly demonstrated by the inhibition of acid secretion with the use of H2-receptor antagonists. The ECL cells are the sole source of gastric histamine involved in acid secretion. Gastrin primarily is present in the antral G cells. As with histamine, the release of gastrin is regulated through multifactorial pathways involving, among other factors, central neural activation, local distention, and chemical components of the gastric content. Gastrin stimulates acid secretion predominantly in an indirect manner by causing the release of histamine from ECL cells; a less- important, direct effect of gastrin on parietal cells also is seen. Somatostatin, localized in the antral D cells, may inhibit gastrin secretion in a paracrine matter, but its exact role in the inhibition of gastric acid secretion remains to be defined. There appears to be a decrease in D cells in patients with Helicobacter pylori infection, and this may lead to excess gastrin production due to a reduced inhibition by somatostatin. Gastric Defense The stomach protects itself from damage by gastric acid through several mechanisms such as the presence of intercellular tight junctions between the gastric epithelial cells, the presence of a mucin layer overlying the gastric epithelial cells, the presence of prostaglandins in the gastric mucosa, and secretion of bicarbonate ions into the mucin layer. Prostaglandins E2 and I2 inhibit gastric acid secretion by a direct effect on the parietal cell mediated by the EP3 receptor (see section entitled "Prostaglandin Analogs: Misoprostol ," below). In addition, prostaglandins enhance mucosal blood flow and stimulate secretion of mucus and bicarbonate. Agents Used for Suppression of Gastric Acid Production Figure 37–1 provides the rationale and pharmacological basis for the classes of drugs currently used to combat acid-peptic diseases. The most commonly used agents at present are the proton pump inhibitors and the histamine H2-receptor antagonists. Proton Pump Inhibitors
Chemistry, Mechanism of Action, and Pharmacological Properties The most effective suppressors of gastric acid secretion undoubtedly are the gastric H+,K+–ATPase (proton pump) inhibitors. They are the most effective drugs used in antiulcer therapy and have found worldwide popularity over the past decade. Currently, there are several different proton pump inhibitors available for clinical use: omeprazole (PRILOSEC), lansoprazole (PREVACID), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX). They are -pyridylmethylsulfinyl benzimidazoles with different substitutions on the pyridine or the benzimidazole groups; their pharmacological properties are similar. Proton pump inhibitors are "prodrugs," requiring activation in an acid environment. These agents enter the parietal cells from the blood and, because of their weak basic nature, accumulate in the acidic secretory canaliculi of the parietal cell, where they are activated by a proton-catalyzed process that results in the formation of a thiophilic sulfenamide or sulfenic acid (Figure 37–2). This activated form reacts by covalent binding with the sulfhydryl group of cysteines from the extracellular domain of the H+,K+–ATPase. Binding to cysteine 813, in particular, is essential for inhibition of acid production, which is irreversible for that pump molecule. Proton pump inhibitors have profound effects on acid production. When given in a sufficient dose (e.g., 20 mg of omeprazole a day for seven days), the daily production of acid can be diminished by more than 95%. Secretion of acid resumes only after new molecules of the pump are inserted into the luminal membrane. Omeprazole also selectively inhibits gastric mucosal carbonic anhydrase, which may contribute to its acid suppressive properties. Figure 37–2. Proton Pump Inhibitors. A. Structures of four inhibitors of the gastric H+,K+–ATPase (proton pump). B. Conversion of omeprazole to a sulfenamide in the acidic canaliculi of the parietal cell. The other three proton pump inhibitors undergo analogous conversions. The sulfenamides interact covalently with sulfhydryl groups in the extracellular domain of the proton pump, thereby inhibiting its activity.
Pharmacokinetics Proton pump inhibitors are unstable at a low pH. The oral dosage forms ("delayed release") are supplied as enteric-coated granules encapsulated in a gelatin shell (omeprazole and lansoprazole) or as enteric-coated tablets (pantoprazole and rabeprazole). The granules dissolve only at an alkaline pH, thus preventing degradation of the drugs by acid in the esophagus and stomach. Proton pump inhibitors are rapidly absorbed, highly protein bound, and extensively metabolized in the liver by the cytochrome P450 system (particularly CYP2C19 and CYP3A4). Their sulfated metabolites are excreted in the urine or feces. Their plasma half-lives are about 1 to 2 hours, but their durations of action are much longer (see below). Chronic renal failure and liver cirrhosis do not appear to lead to drug accumulation with once-a-day dosing of the drugs. Hepatic disease reduces the clearance of
lansoprazole substantially, and dose reduction should be considered in patients with severe hepatic disease. The requirement for enteric coating poses a challenge to the routine use of oral proton pump inhibitors in critically ill patients or in patients unable to swallow adequately. Intravenous H2- receptor antagonists have been preferred in patients with contraindications to oral ingestion, but this picture is expected to change with the advent of intravenous preparations of proton pump inhibitors. Pantoprazole, a relatively more acid-stable compound, is the first such preparation to be approved in the United States. A single intravenous bolus of 80 mg can inhibit acid production by 80% to 90% within an hour, an effect that can last up to 21 hours. Therefore, once-daily dosing of intravenous proton pump inhibitors (in doses similar to those used orally) may be sufficient to achieve the desired degree of hypochlorhydria. The clinical utility of these formulations in the above situations will require further study but is expected to be equal to if not greater than that of intravenous H2-receptor antagonists. The requirement for acid to activate these drugs within the parietal cells has several important consequences. The drugs should be taken with or before a meal, since food will stimulate acid production by parietal cells; conversely, coadministration of other acid-suppressing agents such as H2-receptor antagonists may diminish the efficacy of proton pump inhibitors. Since not all pumps or all parietal cells are functional at the same time, it takes several doses of the drugs to result in maximal suppression of acid secretion. With once-a-day dosing, steady-state inhibition, affecting about 70% of pumps, may take 2 to 5 days (seeSachs, 2000). Achieving steady-state inhibition may be accelerated somewhat by more frequent dosing initially (e.g., twice daily). Since the binding of the drugs' active metabolites to the pump is irreversible, inhibition of acid production will last for 24 to 48 hours or more, until new enzyme is synthesized. The duration of action of these drugs, therefore, is not directly related to their plasma half-lives. Adverse Effects and Drug Interactions Proton pump inhibitors inhibit the activity of some hepatic cytochrome P450 enzymes and therefore may decrease the clearance of benzodiazepines, warfarin, phenytoin, and many other drugs. When disulfiram is coadministered with a protein pump inhibitor, toxicity has been reported. Proton pump inhibitors usually cause few adverse effects; nausea, abdominal pain, constipation, flatulence, and diarrhea are the most common side effects. Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported. Chronic treatment with omeprazole decreases the absorption of vitamin B12, but insufficient data exist to demonstrate whether or not this leads to a clinically relevant deficiency. Hypergastrinemia (>500 ng/liter) occurs in approximately 5% to 10% of long-term omeprazole users. Gastrin is a trophic factor for epithelial cells, and there is a theoretical concern that elevations in gastrin can promote the growth of different kinds of tumors in the gastrointestinal tract. In rats undergoing long-term administration of proton pump inhibitors, there has been development of enterochromaffin-like cell hyperplasia and gastric carcinoid tumors secondary to sustained hypergastrinemia; this has raised concerns about the possibility of similar complications in human beings. There are conflicting data on the risk and clinical implications of enterochromaffin-like cell hyperplasia in patients on long-term proton pump inhibitor therapy. These drugs now have a track record of more than 15 years of use worldwide, and no major new issues regarding safety have emerged (Klinkenberg-Knol et al., 1994; Kuipers and Meuwissen, 2000). There is as yet no reason to believe, therefore, that hypergastrinemia should be a trigger for discontinuation of therapy or that gastrin levels should be monitored routinely in patients on long-term proton pump inhibitor therapy.
However, the development of a hypergastrinemic state may predispose the patient to rebound hypersecretion of gastric acid following discontinuation of therapy. Proton pump inhibitors have not been associated with a major teratogenic risk when used during the first trimester of pregnancy; caution, however, is still warranted. Therapeutic Uses Proton pump inhibitors are used principally to promote healing of gastric and duodenal ulcers and to treat gastric esophageal reflux disease (GERD) that is either complicated or unresponsive to treatment with H2-receptor antagonists (see below). Proton pump inhibitors also are the mainstay in the treatment of Zollinger-Ellison syndrome. Therapeutic applications of proton pump inhibitors are further discussed later in this chapter, under "Specific Acid-Peptic Disorders and Therapeutic Strategies." Histamine H2-Receptor Antagonists The description of selective histamine H2-receptor blockade by Black in 1970 was a landmark in the history of pharmacology and set the stage for the modern approach to the treatment of acid-peptic disease, which until then had relied almost entirely on acid neutralization in the lumen of the stomach (seeBlack, 1993; Feldman and Burton, 1990a,b). Equally impressive has been the safety record of H2-receptor antagonists, a feature that eventually led to their availability without a prescription. Increasingly, however, these agents are being replaced by the more efficacious albeit more expensive proton pump inhibitors. Chemistry, Mechanism of Action, and Pharmacological Properties Four different H2-receptor antagonists are currently on the market in the United States: cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID) (Figure 37–3). Their different chemical structures do not alter the drugs' clinical efficacies as much as they determine interactions with other drugs and change the side-effect profiles. H2-receptor antagonists inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells. Figure 37–3. Structures of Histamine and H2-Receptor Antagonists.
The most prominent effects of H2-receptor antagonists are on basal acid secretion; less profound but still significant is suppression of stimulated (feeding, gastrin, hypoglycemia, or vagal stimulation) acid production. These agents thus are particularly effective in suppressing nocturnal acid secretion, which reflects mainly basal parietal cell activity. This fact has clinical relevance in that the most important determinant of duodenal ulcer healing is the level of nocturnal acidity. Therefore, duodenal ulcers can be healed with once-daily dosing of H2-receptor antagonists given between supper and bedtime. In addition, some patients with reflux esophagitis who are being treated with proton pump inhibitors may continue to produce acid at night (so-called nocturnal acid breakthrough) and could benefit from the addition of an H2-receptor antagonist at night. Pharmacokinetics H2-receptor antagonists are absorbed rapidly after oral administration, with peak serum concentrations reached within 1 to 3 hours. Unlike proton pump inhibitors, only a small percentage of H2-receptor antagonists is protein-bound. Small amounts (from
kidney by both filtration and renal tubular secretion. It is important to reduce doses of H2-receptor antagonists in patients with decreased creatinine clearance. Figure 37–4 provides a useful nomogram to guide the dosage adjustment for cimetidine when renal clearance is impaired. Hemodialysis and peritoneal dialysis clear only very small amounts of the drugs. Liver disease per se is not an indication for dose adjustment; however, in advanced liver disease with decreased renal clearance, reduced dosing is indicated (seeTable 37–1 and Appendix II for pharmacokinetic properties of these drugs). Figure 37–4. Relationship between Creatinine Clearance (CLCr), Cimetidine Elimination Clearance (CLE), and Appropriate Cimetidine Dose Reduction for Patients with Impaired Renal Function. (Adapted from Atkinson and Craig, 1990, with Permission.) All four H2-receptor antagonists are available in dosage forms for oral administration; intravenous and intramuscular preparations of cimetidine, ranitidine, and famotidine also are available. Therapeutic levels are achieved quickly after intravenous dosing and are maintained for several hours (4 to 5 hours for cimetidine, 6 to 8 hours for ranitidine, and 10 to 12 hours for famotidine). In clinical practice, these drugs can be given in intermittent boluses or by continuous infusion ( Table 37–2). Adverse Reactions and Drug Interactions The overall incidence of adverse effects of H2-receptor antagonists is low (
absorption and subsequent bioavailability of the H2-receptor antagonists (see"Antacids," below). Drug interactions with H2-receptor antagonists can be expected mainly with cimetidine, and these are an important factor in the preferential use of other H2-receptor antagonists. Cimetidine inhibits cytochrome P450 more so than do the other agents in this class (Table 37–1) and can thereby alter the metabolism and increase the levels of drugs that are substrates for the cytochrome P450 system. Such drugs include warfarin, phenytoin, certain -adrenergic receptor antagonists, quinidine, caffeine, some benzodiazepines, tricyclic antidepressants, theophylline, chlordiazepoxide, carbamazepine, metronidazole, calcium channel blockers, and sulfonylureas. Cimetidine can inhibit renal tubular secretion of procainamide, increasing the plasma concentrations of procainamide and of its cardioactive metabolite, N-acetylprocainamide. Special care should be taken with the concomitant use of other drugs whose metabolism can be altered by cimetidine and with the use of cimetidine in elderly patients with decreased creatinine clearance. Therapeutic Uses The major therapeutic indications for H2-receptor antagonists are for promoting healing of gastric and duodenal ulcers, for treatment of uncomplicated GERD, and for prophylaxis of stress ulcers. More information about the therapeutic applications of H2-receptor antagonists is provided in the section of this chapter entitled "Specific Acid-Peptic Disorders and Therapeutic Strategies." Prostaglandin Analogs: Misoprostol Chemistry, Mechanism of Action, and Pharmacological Properties Prostaglandin (PG)E2 and PGI2 are the major prostaglandins synthesized by the gastric mucosa; they inhibit acid production by binding to the EP3 receptor on parietal cells (seeChapter 26: Lipid- Derived Autacoids: Eicosanoids and Platelet-Activating Factor). Prostaglandin binding to the receptor results in inhibition of adenylyl cyclase and decreased levels of intracellular cyclic AMP. PGE also can prevent gastric injury by its so-called cytoprotective effects, which include stimulation of secretion of mucin and bicarbonate and improvement in mucosal blood flow; however, acid suppression appears to be its more critical effect (Wolfe et al., 1999). Although smaller doses than required for acid suppression may be protective for the gastric mucosa in laboratory animals, this has not been convincingly demonstrated in human beings. Since NSAIDs inhibit prostaglandin formation, the synthetic prostaglandins provide a rational approach to reducing NSAID-related mucosal damage. Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC) is a synthetic analog of prostaglandin E1 with an additional methyl ester group at C1 (resulting in an increase in potency and in the duration of the antisecretory effect) and a switch of the hydroxy group from C15 to C16 along with an additional methyl group (resulting in improved activity when given orally, increased duration of action, and improved safety profile). The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose; oral doses of 100 to 200 g produce significant inhibition of basal acid secretion (decreased by 85% to 95%) or food-stimulated acid secretion (decreased by 75% to 85%). Pharmacokinetics Misoprostol is rapidly absorbed and undergoes extensive and rapid first-pass metabolism (deesterification) to form misoprostol acid (the free acid), the principal and active metabolite of the drug. Some of this conversion may in fact occur in the parietal cells. After a single dose, inhibition of acid production can be seen within 30 minutes, peaks at 60 to 90 minutes, and lasts for up to 3
hours. Food and antacids decrease the rate of absorption of misoprostol, resulting in delayed and decreased peak plasma concentrations of misoprostol acid. The elimination half-life of the free acid, which is excreted mainly in the urine, is about 20 to 40 minutes. Adverse Effects The most frequently reported side effect of misoprostol is diarrhea, with or without abdominal pain and cramps, which can occur in up to 30% of patients. Diarrhea, which appears to be a dose- dependent response, is seen about 2 weeks after initiating therapy and often resolves spontaneously within a week. It can be severe, however, in some patients, requiring discontinuation. Misoprostol can cause clinical exacerbations in patients with inflammatory bowel disease (seeChapter 39: Agents Used for Diarrhea, Constipation, and Inflammatory Bowel Disease; Agents Used for Biliary and Pancreatic Disease) and hence should be avoided in these patients. Misoprostol is contraindicated during pregnancy, since it can cause abortion by increasing uterine contractility. Therapeutic Use Misoprostol currently is approved by the United States Food and Drug Administration (FDA) for use in preventing mucosal injury caused by nonsteroidal antiinflammatory drugs. Sucralfate Chemistry, Mechanism of Action, and Pharmacological Properties In the presence of acid-induced damage, pepsin-mediated hydrolysis of mucosal proteins contributes to mucosal erosion and ulcerations. This process can be inhibited by sulfated polysaccharides. Sucralfate ( CARAFATE ) consists of the octasulfate of sucrose to which aluminum hydroxide has been added. In an acid environment (pH < 4), it undergoes extensive cross-linking and polymerization to produce a viscous, sticky gel that adheres strongly to epithelial cells and even more strongly to ulcer craters for as long as 6 hours after a single dose. In addition to inhibition of hydrolysis of mucosal proteins by pepsin, sucralfate may have additional cytoprotective effects, including stimulation of local production of prostaglandin and epidermal growth factor (EGF). Sucralfate also binds bile salts, accounting for its use in some patients with esophagitis or gastritis in whom reflux of bile is thought by some to play a role in pathogenesis (the existence of such syndromes remains controversial). The role of sucralfate in the treatment of acid-peptic disease clearly has diminished in recent years. It still may be useful in the prophylaxis of stress ulcers (see below), where its use may be associated with a lower incidence of nosocomial pneumonia compared to acid-suppressing therapy with its tendency to promote gastric bacterial colonization. Since it is activated by acid, it is recommended that sucralfate be taken on an empty stomach one hour before meals rather than after; the use of antacids within 30 minutes of a dose of sucralfate should be avoided. Adverse Effects The most commonly reported side effect is constipation (2%). Small amounts of aluminum can be absorbed with the use of sucralfate, and special attention needs to be given to patients with renal failure, who are at risk for aluminum overload. Aluminum-containing antacids should not be used with sucralfate in patients with renal failure. Since sucralfate forms a viscous layer in the stomach, it may inhibit absorption of other drugs and change their bioavailability. These include phenytoin,
digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics. It is therefore recommended that sucralfate be taken at least 2 hours after the intake of other drugs. Antacids Although their use has been hallowed by tradition, antacids now are seldom part of regimens prescribed by physicians because of the availability of more effective and convenient drugs. Nevertheless, they continue to be used by patients for a variety of indications, and some knowledge of their pharmacological properties is essential for the medical professional. The usefulness of antacids is influenced by the rate of dosage-form dissolution, by their reactivity with acid, by physiological effects of the cation, by water solubility, and by the presence or absence of food in the stomach (seeTable 37–3 for a comparison of some commonly used antacid preparations). The very water-soluble NaHCO3 is rapidly cleared from the stomach and presents both an alkali and a sodium load. CaCO3 can neutralize HCl rapidly (depending on particle size and crystal structure) and effectively; however, it can cause abdominal distention and belching with acid reflux. Combinations of Mg2+ and Al3+ hydroxides provide a relatively fast and sustained neutralizing capacity. Magaldrate is a hydroxymagnesium aluminate complex that is rapidly converted in gastric acid to Mg(OH)2 and Al(OH)3, which are poorly absorbed and thus provide a sustained antacid effect with balanced effects on intestinal motility. Simethicone, a surfactant that may decrease foaming and hence esophageal reflux, is included in many antacid preparations. The presence of food alone elevates gastric pH to about 5 for approximately 1 hour and prolongs the neutralizing effects of antacids for about 2 hours. Alkalinization of the gastric contents increases gastric motility, through the action of gastrin. Al3+ can relax gastric smooth muscle, producing delayed gastric emptying and constipation, effects that are opposed by those of Mg2+. Thus, Al(OH)3 and Mg(OH)2 taken concurrently have relatively little effect on gastric emptying or bowel function. Because of its capacity to enhance secretion and to form insoluble compounds, CaCO3 has unpredictable effects on gastrointestinal motility. The release of CO2 from bicarbonate and carbonate-containing antacids can cause belching, occasional nausea, abdominal distention, and flatulence. Belching may cause exacerbation of gastroesophageal reflux. Antacids are cleared from the empty stomach in about 30 minutes and vary in the extent to which they are absorbed. Antacids that contain aluminum, calcium, or magnesium are less completely absorbed than are those that contain NaHCO3. In persons with normal renal function, the modest accumulations of Al3+ and Mg2+ do not pose a problem; with renal insufficiency, however, absorbed Al3+ can contribute to osteoporosis, encephalopathy, and proximal myopathy. About 15% of orally administered Ca2+ is absorbed, causing a transient hypercalcemia. Although not a problem in normal patients, the hypercalcemia from as little as 3 to 4 g per day can be problematic in patients with uremia. Absorption of unneutralized NaHCO3 will cause alkalosis. Neutralized antacids also may cause alkalosis by permitting the absorption of endogenous NaHCO3 spared by the addition of exogenous neutralizing equivalents into the gastrointestinal tract. These disturbances of acid-base balance by antacids usually are transient and clinically insignificant in persons with normal renal function. In the past, when large doses of NaHCO3 and/or CaCO3 were commonly administered with milk or cream for the management of peptic ulcer, the milk-alkali syndrome occurred frequently. This syndrome results from large quantities of Ca2+ and absorbable alkali; effects consist of hypercalcemia, reduced secretion of parathyroid hormone, retention of phosphate, precipitation of Ca2+ salts in the kidney, and renal insufficiency. Therapeutic regimens emphasizing the use of dairy products seldom are employed in current practice. By altering gastric and urinary pH, antacids may alter rates of dissolution and absorption, the
bioavailability, and renal elimination of a number of drugs. Al3+ and Mg2+ compounds also are notable for their propensity to adsorb drugs and to form insoluble complexes that are not absorbed. Unless bioavailability also is affected, altered rates of absorption have little clinical significance when drugs are given chronically in multiple doses. In general, it is prudent to avoid concurrent administration of antacids and drugs intended for systemic absorption. Most interactions can be avoided by taking antacids 2 hours before or after ingestion of other drugs. Other Agents Drugs That Suppress Acid Production The anticholinergic compounds pirenzepine and telenzepine (seeChapter 7: Muscarinic Receptor Agonists and Antagonists) can reduce basal acid production by 40% to 50% and have been used in countries other than the United States for many decades to treat patients with peptic ulcer. They are classically thought to be antagonists of the M1 cholinergic receptor and may act to suppress neural stimulation of acid production (the receptor on the parietal cell itself is of the M3 subtype). Because of their relatively poor efficacy and significant and undesirable anticholinergic side effects, their use is mainly of historical concern. Antagonists of the gastrin receptor on parietal cells (CCK 2 receptor) currently are under study. Cytoprotective Agents Rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]-propionic acid), is available as an antiulcer agent in parts of Asia. It appears to exert its cytoprotective effect by increasing prostaglandin generation in gastric mucosa as well as by scavenging reactive oxygen species. Ecabet (12-sulfodehydroabietic acid monosodium) is another antiulcer agent mainly used in Japan, which appears to increase the formation of PGE2 and PGI2. Carbenoxolone, a component of licorice root and a derivative of glycyrrhizic acid, has been used in Europe as an antiulcer compound for many years with modest efficacy. Its exact mechanism of action is not clear, but it may alter the composition and quantity of mucin. Unfortunately, it is a steroid congener, and its use may be limited by its significant mineralocorticoid activity. Bismuth compounds (seeChapter 39: Agents Used for Diarrhea, Constipation, and Inflammatory Bowel Disease; Agents Used for Biliary and Pancreatic Disease) may be as effective as cimetidine in patients with peptic ulcer. They have many potentially therapeutic effects in this regard. They bind to the base of the ulcer, promote mucin and bicarbonate production, and have significant antibacterial effects. They are an important component of many anti-Helicobacter regimens (see below). However, they are seldom used by themselves anymore, given the availability of more effective agents. Specific Acid-Peptic Disorders and Therapeutic Strategies Drugs that suppress gastric acid production have proven their efficacy in a variety of conditions in which acid plays a major role in injury to the gastrointestinal mucosa. In addition, these drugs also are employed in combination with antibiotics to treat infection with H. pylori (see"Treatment of Helicobacter pylori Infection," below). The success of these drugs is critically dependent upon their ability to keep intragastric pH above a certain level; the target pH varies to some extent with the disease being treated (Figure 37–5). The overall therapeutic strategy and role of various drugs in individual syndromes is discussed in the following sections (see also DeVault, 1999; Richardson et al., 1998; Sachs, 1997; Lew, 1999; Welage and Berardi, 2000; Wolfe and Sachs, 2000).
Figure 37–5. The relative success of treatment with a proton pump inhibitor (given once daily) and an H2-receptor antagonist (given twice daily) in obtaining an 18-hour elevation in intragastric pH to target levels of pH 3.0 for duodenal ulcer, pH 4.0 for gastroesophageal reflux disease (GERD), and pH 5.0 for H. pylori eradication with antibiotics. Twice-daily administration further improves the elevation in intragastric pH. (Adapted from Wolfe and Sachs, 2000, with permission.) Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) is common in the United States, where it is estimated that one in five adults has symptoms of heartburn and/or regurgitation at least once a week. Although most of these cases are not associated with significant damage to the esophageal lining, it is clear that, in some individuals, GERD can cause severe esophagitis with sequelae that include stricture formation and Barrett's metaplasia or Barrett's esophagus (replacement of squamous by columnar epithelium of varying degrees of specialization), which in turn is associated with a small but significant risk of adenocarcinoma. The incidence of GERD has been rising over the past several decades; so has the incidence of esophageal adenocarcinoma, particularly in white males. An association has been suggested between GERD symptoms and the incidence of esophageal adenocarcinoma (Lagergren et al., 1999). An increasing number of reports also link GERD and tracheopulmonary symptoms such as chronic laryngitis and asthma, although a cause-and-effect relationship is still somewhat controversial. Finally, it should be borne in mind that GERD is a chronic disorder that requires long-term therapy (DeVault, 1999). Although the pathophysiology of GERD has more to do with a disturbance of gastrointestinal motility (seeChapter 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome), most of the symptoms are due to the injurious effects of the acid-peptic refluxate on the esophageal epithelium. This provides the rationale for the current pharmacotherapeutic approach to treating this syndrome, which is based on suppression of gastric acid. Traditional prokinetic agents have been of limited efficacy, but more specific agents currently are being developed and may hold greater promise (Chapter 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome).
Treatment of Acute GERD Symptoms The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis. Proton pump inhibitors are clearly more effective than H2-receptor antagonists in achieving both of these goals. Healing rates after 4 weeks and 8 weeks of therapy with protein pump inhibitors are around 80% and 90%, respectively; healing rates with H2-receptor antagonists are 50% and 75%. Indeed, protein pump inhibitors are so effective that their empirical use has been advocated as a therapeutic trial in patients in whom GERD is suspected to play a role in the pathogenesis of symptoms. The "omeprazole test" involves giving omeprazole for a period of 12 weeks to patients with noncardiac chest pain. Expensive diagnostic tests are instituted only if such a trial fails ( Fass et al., 1998). Because of the wide clinical spectrum associated with GERD, the therapeutic approach is best tailored to the level of severity in the individual patient (Figure 37–6). In general, the optimal dose for each individual patient should be determined based upon symptom control. Only in patients with complicated GERD and/or Barrett's esophagus is documentation of complete acid control with 24-hour pH monitoring indicated. Figure 37–6. General Guidelines for Medical Management of Gastroesophageal Reflux Disease (GERD). *Only acid production–suppressing and acid- neutralizing medication included. (Adapted from Wolfe and Sachs, 2000, with permission.) Regimens for the treatment of GERD with proton pump inhibitors and histamine H2-receptor antagonists are listed in Table 37–4. Although some patients with mild GERD symptoms may be managed by nocturnal doses of H2-receptor antagonists, dosing two or more times a day generally is required. In patients with severe symptoms or extraintestinal manifestations of GERD, twice-daily dosing with a proton pump inhibitor may be needed. It has been shown, though, that nocturnal acid breakthrough can occur even with twice-daily proton pump inhibitor dosing in healthy subjects and that this can be controlled by the addition of an H2-receptor antagonist at bedtime (Peghini et al.,
1998). The clinical importance of this finding for GERD patients with poorly responsive symptoms to standard dosing of proton pump inhibitors needs further evaluation. A popular approach to GERD therapy, encouraged by managed-care companies, consists of a "step- up" regimen, beginning with an H2-receptor antagonist and only progressing to one of the proton pump inhibitors if symptoms fail to respond. While theoretically appealing, this approach carries the risk of delaying the resolution of symptoms and or healing and eventually may be counterproductive because of the higher costs associated with ineffective therapy. Antacids currently are recommended only for the patient with mild, infrequent episodes of heartburn. Their use, of course, is entrenched in the public mind, and it is rare for a patient with GERD not to have tried several of these medications before seeking medical help. In general, prokinetic agents (seeChapter 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome) seldom form the mainstay of treatment for GERD, particularly since questions have been raised about the safety of cisapride. It also is doubtful that there is any value in using them in combination with acid-suppressant medications (Vigneri et al., 1995). Maintenance Therapy of GERD Reflux esophagitis is a chronic disease with a high relapse rate after discontinuation of therapy. Acid suppressant drugs have been the mainstay of therapy. Again, "step-down" approaches are advocated by some, namely to try and maintain symptomatic remission by either decreasing the dose of the proton pump inhibitor or switching to an H2-receptor antagonist. However, many patients will maintain their requirement for proton pump inhibitors. Several studies suggest that proton pump inhibitors are better than H2-receptor antagonists for maintaining remission in reflux esophagitis (Hallerbäck et al., 1994; Vigneri et al., 1995). Therapy for Complications of GERD Strictures associated with GERD respond better to proton pump inhibitors than to H2-receptor antagonists; indeed, the use of proton pump inhibitors has been shown to reduce the requirement for esophageal dilation (Marks et al., 1994). Unfortunately, one of the other complications of GERD, Barrett's esophagus, appears to be more permanent, as neither acid suppression nor antireflux surgery has been shown convincingly to produce regression of metaplasia. The role of acid suppression by proton pump inhibitors as adjuvants in ablative therapy of Barrett's esophagus currently is under investigation. It also appears that a subgroup of GERD patients with extraesophageal symptoms such as asthma and laryngitis may respond to trials of proton pump inhibitors, usually given in higher doses and more frequently than for the usual heartburn sufferer. Peptic Ulcer Disease The pathophysiology of peptic ulcer disease is best understood in terms of an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, other peptides and growth factors) and aggressive factors (acid and pepsin). Patients with duodenal ulcer on average produce more acid than do control subjects, particularly at night (basal secretion). Although patients with gastric ulcers have normal or even lower acid production than control subjects, ulcers rarely if ever occur in the complete absence of acid ("no acid, no ulcer"). In these gastric ulcer patients, even the lower levels of acid can produce injury, presumably due to weakened mucosal defense and reduced bicarbonate production. Both H. pylori and exogenous agents such as nonsteroidal antiinflammatory drugs (NSAIDs) interact with these factors in complex ways, leading to an ulcer diathesis. Up to
80% to 90% of ulcers may be associated with H. pylori infection of the stomach. This infection may lead to impaired production of somatostatin by D cells and, in time, decreased inhibition of gastrin production, with a resulting higher acid production as well as impaired duodenal bicarbonate production. NSAIDs also are very frequently associated with peptic ulcers (in up to 60% of patients, particularly those with complications such as bleeding). Topical injury by the luminal presence of the drug appears to play a minor role in the pathogenesis of these ulcers, as evidenced by the fact that ulcers can occur with very low doses of aspirin (10 mg) or with parenteral administration of NSAIDs. The effects of these drugs are instead mediated systemically, with the critical element being suppression of the constitutive form of cyclooxygenase (COX)-1 in the mucosa and a consequent reduction in cytoprotective prostaglandins, PGE2 and PGI2. Although antacids have been used historically and have proven to be somewhat effective, their use is inconvenient because of the need for multiple daily doses. They also may be associated with undesirable side effects (see"Antacids," above). It is clear that drugs causing suppression of acid production form the mainstay of peptic ulcer treatment (Table 37–5). Individual settings for their use are discussed below. Uncomplicated Ulcers: Acute Symptoms and Healing Proton pump inhibitors promote more rapid relief of duodenal ulcer symptoms and more rapid healing than do H2-receptor antagonists (McFarland et al., 1990), although both classes of drugs are very effective in this setting. Complicated Ulcers: Acute Gastrointestinal Bleeding Acid-suppressive therapy has a long history of use in patients presenting to the hospital with signs of acute upper gastrointestinal bleeding and is almost routinely prescribed. The theoretical benefits of acid-suppressive agents in this setting include acceleration of healing of the underlying ulcer. In addition, clot formation is enhanced and its dissolution retarded at a high pH (Peterson and Cook, 1998). Isolated studies suggest an improved outcome with the use of omeprazole in certain populations of patients with ulcer-related bleeding (Khuroo et al., 1997). Despite such studies and the results of meta-analysis, the benefits from empiric acid-suppressive therapy in patients with acute gastrointestinal bleeding remain somewhat controversial. Although proton pump inhibitors are probably more effective than H2-receptor antagonists in this setting, the availability of intravenous preparations of H2-receptor antagonists has led to their widespread use. This practice probably will change with the recent introduction of intravenous proton pump inhibitors. Uncomplicated Ulcers: Maintenance Therapy and Prophylaxis with Acid-Suppressive Agents With the demonstration that H. pylori plays a major etiopathogenic role in the majority of peptic ulcers (see below), prophylaxis against relapses is focused on eliminating this organism from the stomach. Chronic acid-suppressive therapy, once the mainstay of ulcer prevention, now is used mainly in patients who are H. pylori–negative or, in some cases, in patients with life-threatening complications. Treatment of Helicobacter pylori Infection H. pylori, a gram-negative rod, has been associated with gastritis and subsequent development of gastric and duodenal ulcers, gastric adenocarcinoma and gastric B-cell lymphoma (Veldhuyzen and Lee, 1999). Because of its critical role in the pathogenesis of peptic ulcers in the majority of cases,
it has become standard care to eradicate this infection in patients with gastric or duodenal ulcers (Graham, 1997; Chiba et al., 2000). Such a strategy almost completely eliminates the risk of ulcer recurrence, provided patients are not taking NSAIDs. Eradication of H. pylori also is indicated in the treatment of MALT-lymphoma of the stomach, as this can regress significantly after such treatment. Treatment of H. pylori infection is not straightforward, however, and many important factors need to be considered in the choice of a treatment regimen (Graham, 2000) (Table 37–6). Single antibiotic regimens are ineffective in treating H. pylori infection and lead to resistance. In addition, a proton pump inhibitor or H2-receptor antagonist significantly enhances the effectiveness of regimens containing pH-dependent antibiotics such as amoxicillin or clarithromycin. Third, 10 to 14 days of treatment appear to be better than shorter treatment regimens; in the United States, a 14-day course generally is preferred. Finally, antibiotic resistance is increasingly being recognized as an important factor in the failure to eradicate H. pylori. Antibiotic resistance is a complex issue, with different underlying mechanisms and clinical implications. Clarithromycin resistance is related to ribosomal mutations that prevent the binding of the antibiotic and is an all-or-none phenomenon. On the other hand, metronidazole resistance is relative rather than absolute and may involve several different changes in the bacteria. Despite in vitro resistance, however, a 14-day quadruple drug regimen generally is effective therapy (Huang and Hunt, 1999). Whether or not H. pylori infection should be treated in patients with GERD is controversial. An argument has been made to treat all of these patients because of concerns about the development of atrophic gastritis with the use of acid-suppressive therapy in the setting of H. pylori infection. However, the magnitude of this risk is unclear. On the other hand, GERD symptoms and esophagitis have been reported to be worse after H. pylori eradication in patients with ulcers. This is felt to be a consequence of the improvement in H. pylori–related inflammation and increased acid secretion, which trigger the development of GERD symptoms in this subset of patients (O'Connor, 1999). H. pylori appears to play a minor role, if any, in the development of NSAID-induced ulcers, although its elimination probably is done routinely (Hawkey et al., 1998b). Similarly, although often practiced, eradication of H. pylori does not improve the clinical symptoms in patients with nonulcer dyspepsia (Talley et al., 1999). NSAID-Related Ulcers Chronic NSAID users have a 2% to 4% risk of developing a symptomatic ulcer, gastrointestinal bleeding, or even perforation (La Corte et al., 1999; Wolfe et al., 1999). Ideally, conventional NSAIDs should be discontinued if at all possible and/or replaced with a selective COX-2 inhibitor (seeChapter 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout). Nevertheless, healing of ulcers despite continued NSAID use is possible with the use of acid-suppressant agents, usually at higher doses and for a considerably longer duration than with standard regimens (e.g., 8 weeks or longer). Again, proton pump inhibitors are superior to H2-receptor antagonists and misoprostol in promoting healing of active ulcers (80% to 90% healing rates compared to 60% to 75%) as well as in preventing recurrence (while on NSAIDs) of both gastric ulcers (5% to 13%versus 10% to 16% recurrence rates) and duodenal ulcers (0.5% to 3%versus 4% to 10% recurrence rate) (Hawkey et al., 1998a; Lanza, 1998; Yeomans et al., 1998). Stress-Related Ulcers
Stress ulcers are ulcers of the stomach or duodenum that usually occur in the context of a major systemic or CNS illness or trauma (ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis, 1999). The etiology of stress-related ulcers is somewhat different from that of other peptic ulcers and involves acid as well as mucosal ischemia. Reduction of gastric acidity to a pH above 5 appears to be important in preventing the activation of pepsin and subsequent mucosal injury. This can be achieved by any of the acid production–suppressing agents as well as antacids (Cook et al., 1998). Because of limitations on the use of oral drugs in many patients with stress-related ulcers, intravenous H2-receptor antagonists currently are the preferred agents and have been shown to reduce the incidence of gastrointestinal hemorrhage due to stress ulcers. Now that intravenous preparations of proton pump inhibitors are becoming available, it is possible that their use will prove to be equally if not more beneficial. There is a concern over the risk of pneumonia secondary to gastric bacterial colonization in an alkaline milieu, and this has led to the use of sucralfate slurries (via nasogastric tube), which also appears to provide reasonable prophylaxis against bleeding, but is more inconvenient. In a meta-analysis that compared H2-receptor antagonists with sucralfate and placebo as prophylactic agents for clinically important gastrointestinal bleeding, both sucralfate and H2-receptor antagonists were found to reduce the incidence of overt bleeding compared to placebo or no therapy. There was a trend toward a lower incidence of nosocomial pneumonia with the use of sucralfate, but later studies have not confirmed this finding (Cook et al., 1996). Zollinger-Ellison Syndrome Patients with this syndrome develop gastrinomas that drive the secretion of large amounts of acid. This can lead to severe gastroduodenal ulceration and other consequences of the uncontrolled hyperchlorhydria. Proton pump inhibitors are clearly the drugs of choice and are usually given at twice the dosage for routine ulcers, with the goal of therapy being to reduce acid secretion in the range of 1 to 10 mmol/hour. Nonulcer Dyspepsia This term refers to ulcer-like symptoms in patients who are without overt gastroduodenal ulceration (American Gastroenterological Association position statement, 1998). This may occur with gastritis (with or without H. pylori) or with NSAID use, but the pathogenesis of this syndrome remains unclear. Although empirical treatment with acid-suppressive agents is used routinely in patients with nonulcer dyspepsia, there is no convincing evidence of their benefit in controlled trials. This disorder is best regarded as a regional manifestation of the same general type of visceral hyperalgesia seen in patients with irritable bowel syndrome (seeChapter 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome). Prospectus Impressive advances have been made in the pharmacological treatment of acid-peptic disorders. These have been made possible largely by the availability of the proton pump inhibitors and the discovery of H. pylori and its role in acid-peptic disorders. Another, somewhat indirect contribution has been made by the new selective COX-2 inhibitors, which are expected to reduce significantly the incidence of NSAID-induced ulcers. New drug discovery in this area will address specific therapeutic problems such as bleeding from gastrointestinal ulcers. Other advances should result from a greater understanding of the pathophysiology of GERD. Such understanding may eventually lead to treatments that correct the underlying defect in antireflux sphincteric mechanisms and
provide alternatives to long-term treatment with acid-suppressive agents. For further discussion of gastroesophageal reflux disease and peptic ulcer and related disorders, seeChapters 273 and 274 in Harrison's Principles of Internal Medicine, 16th ed., McGraw-Hill, New York, 2005. Acknowledgment The authors wish to acknowledge Laurence R. Brunton, author of this chapter in the ninth edition of Goodman and Gilman's the Pharmacological Basis of Therapeutics, some of whose text has been retained in this edition. Chapter 38. Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome Overview "The longer I live, the more I am convinced that. . .half the unhappiness in the world proceeds from little stoppages, from a duct choked up, from food pressing in the wrong place, from a vexed duodenum or an agitated pylorus."—(Sydney Smith, 1771–1845) This chapter covers a variety of conditions that, variably and often inaccurately, have been labeled as disorders of gastrointestinal motility. These include specific diseases (such as achalasia), pathophysiologic syndromes (such as gastroparesis), and symptom complexes (dyspepsia, irritable bowel syndrome). Often, no overt structural abnormalities can be detected on clinical routine investigation of the patient, giving rise to the term "functional bowel disorders," which commonly is used to describe many of these conditions. However, this definition clearly is not static, and it changes with improvements in our ability to discover subtle but real biological derangements underlying these disorders. Further, although these conditions traditionally have been viewed as abnormalities in gastrointestinal motility or motor function (either excessive or ineffective), it is becoming increasingly clear that many of them may, in fact, represent primary abnormalities in sensory or afferent neuronal function. As a group, these disorders are poorly understood, and their treatment remains one of the major challenges in gastrointestinal pharmacology. This chapter also covers agents used for nausea and vomiting, an area where there has been considerably more therapeutic progress, matching the significant gains in knowledge about underlying neurophysiological mechanisms for these responses. Overview of Gastrointestinal Motility The gastrointestinal tract is in a state of continuous contractile (and secretory) activity. The control of these activities is complicated, with contributions by the muscle itself, the local nerves (i.e., the enteric nervous system, ENS), and the central nervous system (mediated via both autonomic and somatic innervation as well as humoral pathways) (see Kunze and Furness, 1999). However, most of the functions of the gut are autonomous and are controlled almost entirely by the ENS. Autonomous motor activity of the gut, best illustrated in the intestine, displays two broad patterns. One of these is the MMC (migrating myoelectric complex when referring to electrical activity and