Section VI - Drugs Affecting Gastrointestinal Function docx

Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux DiseaseOverview The term acid-peptic disorders encompasses a variety of relatively

Section VI Drugs Affecting Gastrointestinal Function

Chapter 37 Agents Used for Control of Gastric Acidity and

Treatment of Peptic Ulcers and Gastroesophageal Reflux DiseaseOverview

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 thefourth 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 stillneed 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 theinitiation 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 pumpinhibitors 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 cysteinesfrom 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, whichmay 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

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 H2receptor antagonists have been preferred in patients with contraindications to oral ingestion, but thispicture 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 orall 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 thereforemay 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 pumpinhibitors 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 thatgastrin 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 thefirst 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 arefurther 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 thehistory 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 acidproduction 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 butstill 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 <10% to 35%) of these drugs undergo metabolism in the liver Both metabolized and unmetabolized products are excreted by the

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 (<3%) Side effects usually are minor and include diarrhea, headache, drowsiness, fatigue, muscular pain, and

constipation Less-common side effects include those affecting the CNS (confusion, delirium, hallucinations, slurred speech, and headaches), which occur primarily with intravenous

administration of the drugs Gynecomastia in men and galactorrhea in women may occur due to the binding of cimetidine to androgen receptors and inhibition of the cytochrome P450-catalyzed hydroxylation of estradiol Reductions in sperm count and reversible impotence have been reported

in men These effects are mainly seen with long-term use of cimetidine in high doses Several reports have associated H2-receptor antagonists with various cytopenias, including reductions in platelet count H2-receptor antagonists cross the placenta and are excreted in breast milk Although

no major teratogenic risk has been associated with these agents, caution is nevertheless warranted when they are used in pregnancy All agents that inhibit gastric acid secretion may alter the rate of

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; theyinhibit 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 reducingNSAID-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 anincrease 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.

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 evenmore 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 sodiumload 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 increasesgastric 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 hasunpredictable 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 normalpatients, 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 (CCK2 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 manypotentially 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 theirability 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 theesophageal 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 isbest 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 isrequired 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 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

"step-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 foresophageal 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 arevery 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 day course generally is preferred Finally, antibiotic resistance is increasingly being recognized as

14-an import14-ant factor in the failure to eradicate H pylori Antibiotic resist14-ance 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, bothsucralfate 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 isused 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

migrating motor complex when referring to the accompanying contractions) The MMC occurs in

the fasting (interdigestive) state, during which it helps sweep debris away (hence, it also is

sometimes called the intestinal "housekeeper") It consists of a series of four phasic activities, the most characteristic of which is phase III, consisting of clusters of rhythmic contractions that occupy short segments of the intestine for a period of 6 to 10 minutes before proceeding caudally One whole MMC cycle (all four phases) takes about 80 to 110 minutes before it repeats itself Cycling ofthe MMC occurs continually in continuously feeding animals but is interrupted in intermittently feeding animals such as human beings by another pattern of contractions (the fed pattern) This consists of high-frequency (12 to 15 per minute) contractions that are either propagated for short

segments (propulsive) or are irregular and not propagated (mixing) Propulsive activity in the intestine generally is considered to be synonymous with the term peristalsis (see below) Both these

patterns of movement are under the dominant control of the ENS, which is an autonomous

collection of nerves within the wall of the gastrointestinal tract The ENS programs iterative activitysuch as the MMC as well as coordinated peristaltic or mixing movements in response to input from both the local environment and the central nervous system The ENS is organized into two plexi

(connected networks of neurons): the myenteric(Auerbach's)plexus, found between the circular and longitudinal muscle layers, and the submucosal(Meissner's)plexus, found below the epithelium The

former is responsible for motor control, while the latter regulates secretion, fluid transport, and vascular flow

A useful, if somewhat simplistic, way to view the functional elements of the myenteric plexus is from the perspective of the peristaltic reflex Physiologically, peristalsis can be defined as a series

of reflexes in response to a bolus in the lumen of a given segment of the intestine, the ascending excitatory reflex resulting in contraction of the circular muscle on the oral side of the bolus and the descending inhibitory reflex resulting in relaxation on the anal side The net pressure gradient creates forward movement of the bolus Three neural elements, responsible for sensory, relay, and effector functions, are required to produce these reflexes (Figure 38–1) Luminal factors stimulate sensory elements in the mucosa, leading to a coordinated pattern of muscle activity This is under the direct control of the motor neurons of the myenteric plexus, which provide the effector

component of the peristaltic reflex These neurons receive input from both ascending and

descending interneurons (which constitute the relay system) and are of two broad types: excitatory and inhibitory The primary neurotransmitter of the excitatory motor neurons is acetylcholine (ACh), although tachykinins, coreleased by these neurons, also play a role The principal

neurotransmitter in the inhibitory motor neurons appears to be nitric oxide (NO), although

important contributions may be made by ATP, vasoactive intestinal peptide, and pituitary adenylyl cyclase–activating peptide (PACAP), which are variably coexpressed with nitric oxide synthase

Figure 38–1 The Neuronal Network Responsible for Initiation and Generation of the Peristaltic Reflex Mucosal stimulation leads to release of serotonin by

enterochromaffin cells (8), which excites the intrinsic primary afferent neuron (1), which then communicates with both ascending (2) and descending (3) interneurons in the local reflex pathways The reflex results in contraction at the

oral end via the excitatory motor neuron (6) and aboral relaxation via the inhibitory motor neuron (5) The migratory myoelectric complex (see text) is

shown here as being conducted by a different chain of interneurons (4) Another intrinsic primary afferent neuron with its cell body in the submucosa also is shown here (7) MP = myenteric plexus; CM = circular muscle; LM =

longitudinal muscle; SM = submucosa; Muc = mucosa (Adapted from Kunze and Furness, 1999 , with permission.)

It has become clear in recent years that the current view of nerve–muscle interaction within the gastrointestinal tract may be an oversimplification Evidence is accruing rapidly that another cell type, the interstitial cell of Cajal, may play a significant role in mediating neurogenic influence on gastrointestinal smooth muscle These cells are found in the muscle layer and are responsive to various nerve-derived neurotransmitters including NO, ACh, and substance P It appears that these cells may translate or modulate neuronal communication with the muscle, although the mechanismsresponsible for this have yet to be worked out.

Excitation-Contraction Coupling in Gastrointestinal Smooth Muscle

Control of tension in gastrointestinal smooth muscle is in large part dependent on the intracellular

Ca2+ concentration In general, there are two types of excitation-contraction coupling based on the type of mechanism responsible for changes in Ca2+ concentration Electromechanical coupling

requires changes in membrane potential, due to either an action potential or a slow wave, which in turn activate voltage-dependent Ca2+ channels to trigger an influx of Ca2+ Conversely,

hyperpolarization of the membrane is associated with relaxation of the muscle due to inhibition of action potentials or closure of voltage-dependent Ca2+ channels In smooth muscle, there are other

stimuli, usually of a chemical nature, that act via specific receptors and can produce changes in tension without necessarily first affecting membrane potential This is called pharmacomechanical coupling and also can be both excitatory and inhibitory in nature Excitatory receptors involved in

this mechanism often are linked to heterotrimeric G proteins such as those that can activate

phospholipase C, which produces diacylglycerol (DAG) and inositol trisphosphate (IP3) IP3 acts on specific receptors on the sarcoplasmic reticulum causing release of Ca2+, while DAG activates protein kinase C with subsequent phosphorylation (and modulation) of several important proteins, including ion channels, involved in the generation of muscle tone Inhibitory receptors also exist on

smooth muscle and generally act via cyclic AMP– and cyclic GMP–dependent kinases, which

phosphorylate proteins and channels and eventually lead to decreased intracellular Ca2+

concentrations As an example, NO is thought to induce relaxation via activation of guanylyl

cyclase, generation of cyclic GMP, and opening of several different types of K+ channels.

Prokinetic Agents

Prokinetic agents are medications that enhance coordinated gastrointestinal motility and transit of material in the gastrointestinal tract (Reynolds and Putnam, 1992; Tonini, 1996) These agents are pharmacologically and chemically diverse (Table 38–1) Although ACh, when released from primary motor neurons in the myenteric plexus, is the principal immediate mediator of muscle contractility, most of the clinically useful prokinetic agents in fact act "upstream" of this point These drugs may act at receptor sites on the motor neuron itself, or even more indirectly, on

neurons one or two orders removed from it (Figure 38–2) Direct activation of muscarinic receptors,

such as with the older cholinomimetic agents (see Chapter 7: Muscarinic Receptor Agonists and Antagonists), has not been a very effective strategy for treating gastrointestinal motility disorders, because contractions are enhanced globally in a relatively uncoordinated fashion, producing little or

no net propulsive activity By contrast, newer prokinetic agents enhance the release of acetylcholine

at the nerve muscle junction without apparently interfering with the normal physiological pattern and rhythm of motility Coordination of activity among the various segments of the gut, necessary for propulsion of luminal contents, therefore is maintained

Figure 38–2 Conceptual Model to Explain the Action of Prokinetic Agents In the center is shown the primary motor neuron in the myenteric plexus that

induces smooth muscle contraction via the release of acetylcholine (ACh) when

excited The activity of this motor neuron can be modulated by several other neurons: as shown here, nonadrenergic, noncholinergic (NANC) and

dopaminergic neurons are inhibitory, while cholinergic neurons are facilitatory

In turn the activity of the modulatory neurons can be affected by various neurotransmitters such as serotonin acting on specific receptor subtypes Agents such as bethanechol mimic the action of ACh at the neuromuscular junction

Other prokinetic agents act more indirectly via the modulation of motor neuron

activity and their connecting neurons Thus, the major effect of cisapride and

metoclopramide appears to be via the activation of 5-HT4 receptors (5-HT4R) on cholinergic facilitatory neurons Domperidone and metoclopramide can act as antagonists at dopamine D2 receptors (D2R) and thus antagonize inhibition of the motor neuron by dopamine also resulting in net facilitation of its activity

Antagonism of the 5-HT3 receptor (5-HT3R), as shown here, also should have a similar facilitatory effect by dampening the activity of the inhibitory neuron Thismechanism is probably of minor importance in the effects of known prokinetic

agents (see text for details).

Cholinergic Agents

Choline Derivatives

The effects of ACh on smooth muscle are mediated in large part by two types of muscarinic

receptors, M2 and M3 (see Chapter 7: Muscarinic Receptor Agonists and Antagonists), present in a 4:1 ratio Activation of these receptors results in an increase in intracellular Ca2+, an effect mediated

by inositol trisphosphate acting on internal calcium stores ACh itself is not used pharmacologicallybecause it affects all classes of cholinergic receptors (nicotinic and muscarinic) and is rapidly degraded by acetylcholinesterase Modifications of the structure of acetylcholine have led to

increased receptor selectivity and resistance to enzymatic hydrolysis and have yielded drugs such as

carbachol and bethanechol Bethanechol, once widely used, is now largely of historical importance

in gastroenterology In addition to its lack of real prokinetic efficacy (see above), the drug is further

limited by significant side effects resulting from its broad muscarinic effects on both contractility and secretion in the gastrointestinal tract and other organs These include bradycardia, flushing, diarrhea and cramps, salivation, and blurred vision

Acetylcholinesterase Inhibitors

These drugs inhibit the degradation of ACh by its esterase (see Chapter 8: Anticholinesterase Agents), thereby allowing ACh to accumulate at sites of release Neostigmine has been shown to be useful in some gastroenterological disorders, particularly those associated with colonic

pseudoobstruction and paralytic ileus (Ponec et al , 1999)

for the treatment of gastrointestinal disorders is the relief of emesis by antagonism of dopamine receptors in the chemoreceptor trigger zone (CTZ) Examples of such agents traditionally have included metoclopramide and domperidone However, it has become clear that the major

mechanism of the prokinetic effect of metoclopramide involves activation of serotonin receptors,

with antagonism of dopamine receptors playing a minor role (see below) Domperidone, on the

other hand, appears to have a predominantly antidopaminergic effect It is not available for use in the United States but has been used elsewhere in the world and has modest prokinetic activity (Barone, 1999) Although it does not readily cross the blood-brain barrier (hence, patients are spared the risk of extrapyramidal side effects), domperidone still can exert effects on those parts of the central nervous system (CNS) that do not possess this barrier, such as those regulating emesis, temperature, and prolactin release (dopamine inhibits prolactin release) Other D2-receptor

antagonists currently are being explored, and with some promise, as prokinetic agents, including

levosulpiride, the levoenantiomer of sulpiride.

actions appear to be mediated principally via 5-HT3 and 5-HT4 receptors, which are present on inhibitory and excitatory interneurons that synapse with cholinergic primary motor neurons (Figure 38–2) Thus, antagonism of the 5-HT3 receptor on inhibitory interneurons is expected to enhance the responsiveness of the motor neurons, an effect that also can be achieved by agonists of the 5-

HT4 receptor on excitatory interneurons Most of the currently useful prokinetic agents, including

cisapride and metoclopramide, are considered to act predominantly as agonists at 5-HT4 receptors (Briejer et al , 1995)

Cisapride

Cisapride (PROPULSID) is a substituted piperidinyl benzamide that appears to stimulate 5-HT4

receptors and increase adenylyl cyclase activity within neurons Until recently, it was one of the most commonly used prokinetic agents for a variety of disorders, particularly gastroesophageal reflux disease (GERD) and gastroparesis Its beneficial effects in GERD are thought to result from

an increase in lower esophageal sphincter pressure, acceleration of gastric emptying (and hence decreased intragastric pressure), and possibly from improvements in esophageal peristalsis In several trials, cisapride has been shown to be as effective as the histamine H2-receptor antagonists

ranitidine or cimetidine in patients with GERD However, in general, prokinetic agents by

themselves are seldom considered adequate for the treatment of clinically significant GERD (see

Chapter 37: Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and

Gastroesophageal Reflux Disease) Although they may be useful additives to a regimen involving

H2-receptor antagonists for patients with severe symptoms, the availability of the more efficacious

proton pump inhibitors (see Chapter 37: Agents Used for Control of Gastric Acidity and Treatment

of Peptic Ulcers and Gastroesophageal Reflux Disease) has made such combination therapy largely unnecessary Clinically, one of the greatest needs for prokinetic agents is in patients with delayed gastric emptying Cisapride accelerates gastric emptying for both solids and liquids and improves symptoms in patients with gastroparesis due to a variety of causes As a "true" prokinetic agent, it

acts via enhancement of coordinated antroduodenal contractions However, like metoclopramide

(see below), it seldom normalizes gastric emptying, and relief of symptoms usually is only modest

The efficacy of cisapride in other functional bowel diseases such as nonulcer dyspepsia is unclear, although this drug has been used empirically for many of these patients Similarly, although it has demonstrable effects on the small bowel and colon in experimental preparations, cisapride's

usefulness in patients with paralytic ileus, intestinal pseudoobstruction, and chronic constipation have not been established with any certainty

Cisapride is no longer generally available in the United States The drug is available only through

an investigational, limited-access program to patients who have failed all standard therapeutic modalities and who have undergone a thorough diagnostic evaluation, including an

electrocardiographic evaluation The main reason for withdrawal of cisapride from the open market has been its potential for serious cardiac adverse effects (Tonini et al , 1999) The drug has been shown to block selectively the rapid component of the delayed rectifying K+ current, which leads to

a lengthening of the action potential and QT interval on the electrocardiogram Serious cardiac

arrhythmias and deaths from ventricular tachycardia, ventricular fibrillation, torsades de pointes,

and QT prolongation have been reported in patients taking cisapride, particularly when used with other drugs that inhibit cytochrome P450 3A4 These include antibiotics such as erythromycin,

clarithromycin, and troleandomycin; antidepressants such as nefazodone; antifungals such as

fluconazole, itraconazole, and ketoconazole; and HIV protease inhibitors such as indinavir and

ritonavir

Metoclopramide

Chemistry and Pharmacological Effects

Metoclopramide (REGLAN) and other substituted benzamides are derivatives of para-aminobenzoic

acid and are structurally related to procainamide The chemical structure of metoclopramide is shown below

Metoclopramide is one of the oldest true prokinetic agents; its administration results in coordinated contractions that enhance transit Its effects are confined largely to the upper digestive tract, where

it increases lower esophageal sphincter tone and stimulates antral and small intestinal contractions

Despite having in vitro effects on the contractility of colonic smooth muscle, the drug has no

clinically significant effects on motility of the large bowel

Mechanism of Action

The mechanism of action of metoclopramide is complex (Figure 38–2) In general, agents of this class facilitate ACh release from enteric neurons, an action that may be mediated indirectly by several different mechanisms, including suppression of inhibitory interneurons by antagonism of 5-

HT3 receptors and stimulation of excitatory neurons via activation of 5-HT4 receptors In addition, metoclopramide is distinguished from agents such as cisapride by having both central and

peripheral antidopaminergic effects The former is responsible for its antinauseant and antiemetic

effects, while the latter contributes to its prokinetic activity by counteracting the inhibitory effects

of dopamine, mediated via dopamine D2 receptors, on cholinergic enteric neurons (Figure 38–2).Pharmacokinetics

Metoclopramide is absorbed rapidly after oral ingestion, undergoes sulfation and glucuronide conjugation by the liver, and is excreted principally in the urine, with a half-life of 4 to 6 hours Peak concentrations occur within about 1 hour after a single oral dose with a duration of action that lasts 1 to 2 hours

Therapeutic Use

Metoclopramide has been used in patients with GERD; it can produce symptomatic relief without necessarily promoting healing of associated esophagitis It is clearly less effective than modern acid-suppressive medications such as proton pump inhibitors or even histamine H2-receptor

antagonists and now rarely is used for treating GERD Metoclopramide is indicated more often in symptomatic patients with gastroparesis, in whom it may cause mild to modest improvements of gastric emptying Metoclopramide injection also can be used as an adjunctive measure in medical ordiagnostic procedures such as intestinal intubation or contrast radiography of the gastrointestinal tract Although it has been used in patients with postoperative ileus, its effects on improving transit

in disorders of small-bowel motility appear to be limited In general, its greatest utility lies in its ability to ameliorate the nausea and vomiting that often accompany gastrointestinal dysmotility syndromes This effect is mediated by dopamine-receptor antagonism within the chemoreceptor

trigger zone (see below) Metoclopramide also has been used in the treatment of persistent hiccups,

but its efficacy in this condition is equivocal at best

Metoclopramide is available in oral dosage forms (tablets and solution) and as a parenteral

preparation for intravenous or intramuscular use The usual oral dose range is 10 to 20 mg three times a day, 30 minutes before a meal The onset of action is within 30 to 60 minutes after an oral dose In patients with severe nausea, an initial dose of 10 mg can be given intramuscularly (onset of action 10 to 15 minutes) or intravenously (onset of action 1 to 3 minutes) Intravenous dosing for patients undergoing chemotherapy can be given as an infusion of 1 to 2 mg per kg of body weight, administered over at least 15 minutes, beginning 30 minutes before the chemotherapy is begun and repeated as needed every two or three hours Alternatively, a continuous intravenous infusion may

be given (3 mg per kg of body weight before chemotherapy, followed by 0.5 mg per kg of body weight per hour for eight hours) The usual pediatric dose for gastroparesis is 0.1 to 0.2 mg per kg

of body weight per dose, given 30 minutes before meals and at bedtime

Adverse Effects

The major side effects of metoclopramide, although rare, can be serious and include extrapyramidal

effects such as those seen with the phenothiazines (see Chapter 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania) Dystonias, usually occurring acutely after intravenousadministration, and parkinsonism-like symptoms, which may occur several weeks after initiation of therapy, generally respond to treatment (with anticholinergic or antihistaminic drugs) and are reversible after discontinuation of the drug Tardive dyskinesia also can occur with chronic

treatment (months to years) but may be irreversible Extrapyramidal effects appear to occur more commonly in children and young adults, particularly at higher doses Like domperidone and other

dopamine antagonists, metoclopramide also can cause galactorrhea, but this is infrequent

Methemoglobinemia has been reported occasionally in premature and full-term neonates receiving

Other Serotonin-Receptor Modulators

Ondansetron (see below), a commonly used antiemetic, also has modest gastric prokinetic activity,

which is attributed to its ability to act as an antagonist at 5-HT3 receptors It also may prolong colonic transit time, possibly by increasing colonic tone (Wilde and Markham, 1996) However, ondansetron does not appear to be a clinically useful prokinetic agent and is seldom if ever used in this capacity Other 5-HT-receptor modulators with much greater promise as prokinetic agents currently are under evaluation These drugs, which include tegaserod and prucalopride, are potent agonists at the 5-HT4 receptor and appear to have relatively selective effects on the colon

Prucalopride is a benzofuran derivative and a specific 5-HT4-receptor agonist that has been shown

to facilitate cholinergic neurotransmission It enhances colonic contractility in experimental

animals, and preliminary studies suggest that it accelerates colonic transit in human beings (Bouras

et al , 1999) Tegaserod is an amino guanidine-indole with selective and partial 5-HT4-receptor agonist activity (Scot and Perry, 1999) In addition to its prokinetic effects on the colon, tegaserod

also appears to reduce visceral sensitivity (see"Irritable Bowel Syndrome," below) and thus has therapeutic potential for patients with constipation-dominant irritable bowel syndrome Tegaserod (ZELMAC) may be approved by the United States Food and Drug Administration (FDA) in the near future

Motilin: Macrolides and Erythromycin

Chemistry, Pharmacological Effects, and Mechanism of Action

Motilin is a 22–amino acid peptide hormone found in the gastrointestinal M cells as well as in someenterochromaffin cells of the upper small bowel Motilin levels fluctuate in association with the MMC and appear to be responsible for the amplification, if not the actual induction, of phase III

MMC activity (see"Overview of Gastrointestinal Motility," above) In addition, motilin receptors are found on smooth muscle cells, and motilin is a potent contractile agent of the upper

gastrointestinal tract Research on the prokinetic effects of motilin has been stimulated by the demonstration that these effects can be mimicked by erythromycin, a discovery that was based on the frequent occurrence of gastrointestinal side effects with the use of this antibiotic (Otterson and Sarna, 1990; Reynolds and Putnam, 1992; Faure et al , 2000) Subsequent studies showed that erythromycin could induce phase III MMC activity in dogs and increase smooth muscle

contractility This property is shared to varying extents by other macrolide antibiotics (see Chapter 47: Antimicrobial Agents: Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents),

including oleandomycin, azithromycin, and clarithromycin In addition to its motilin-like effects,

erythromycin also may act via other poorly defined mechanisms, possibly involving cholinergic

facilitation (Coulie et al , 1998)

Erythromycin has a variety of effects on upper gastrointestinal motility, including increases in loweresophageal pressure and stimulation of gastric and small-bowel contractility By contrast, it appears

to have little or no effect on colonic motility

bowel This can be a disadvantage, but it has been exploited clinically to clear the stomach of undigestible residue such as plastic tubes or bezoars Erythromycin also has been of anecdotal benefit in patients with small-bowel dysmotility such as that seen in scleroderma, ileus, or

pseudoobstruction Rapid development of tolerance to erythromycin, possibly by downregulation ofthe motilin receptor, and its undesirable (in this context) antibiotic effects have limited the practical use of this drug as a prokinetic agent However, a variety of nonantibiotic synthetic analogs of erythromycin as well as peptide analogs of motilin currently are under evaluation; simulation of motilin's actions by these agents may represent a viable prokinetic option in the future

A standard dose of erythromycin used for gastric stimulation is 3 mg/kg intravenously or 200 to 250

mg orally every 8 hours However, a smaller dose (40 mg intravenously) may be more useful for small-bowel stimulation, where higher doses may actually retard motility (Medhus et al , 2000;

DiBaise and Quigley, 1999)

Miscellaneous Agents That Can Modulate Gastrointestinal Motility

Octreotide (SANDOSTATIN) is a long-acting somatostatin analog (see Chapters 39: Agents Used for Diarrhea, Constipation, and Inflammatory Bowel Disease; Agents Used for Biliary and Pancreatic Disease and 56: Pituitary Hormones and Their Hypothalamic Releasing Factors) that has complex effects on gastrointestinal motility, including inhibition of antral motor activity and colon tone (Camilleri, 1996) However, octreotide also can rapidly induce phase III MMC activity in the small bowel, and this induced phase III activity appears to last longer with faster contractions than those occurring spontaneously Octreotide can accelerate gastric emptying of mixed meals and,

paradoxically, prolong small-bowel and mouth-to-cecum transit time These opposing effects may limit its potential as a clinically useful prokinetic agent Nevertheless, its use has been shown to result in improvement in selected patients with scleroderma and small-bowel dysfunction Its greatest utility, however, may be with the "dumping syndrome" seen in some patients after gastric surgery and pyloroplasty In this condition, octreotide inhibits the release of hormones (triggered byrapid passage of food into the small intestine) that are responsible for several distressing local and systemic effects

The gastrointestinal hormone cholecystokinin (CCK) is released from the intestine in response to

meals and slows down gastric emptying Loxiglumide is a CCK1- (or CCK-A)–receptor antagonist that can improve gastric emptying and is being investigated in patients with gastroparesis

Specific Motility Disorders and Therapeutic Strategies

Gastrointestinal motility disorders are a complex and heterogeneous group of syndromes whose pathophysiology is at best incompletely understood (McCallum, 1999; Pandolfino et al , 2000)

This term also traditionally has included disorders such as irritable bowel syndrome (see below) and

noncardiac chest pain, where disturbances in pain processing or sensory function may be more important than any associated motor patterns As a group, these disorders cause a heavy burden of suffering, but therapeutic developments in this area have been erratic, with a paucity of truly

effective pharmacological agents In most instances, the treatment approach remains empirical and symptom-based Thus, prokinetic agents such as metoclopramide and cisapride have modest if any effects on gastric emptying in patients with gastroparesis and have only limited ability to improve symptoms (Koch, 1999; Sturm et al , 1999) Chronic constipation (Chapter 39: Agents Used for Diarrhea, Constipation, and Inflammatory Bowel Disease; Agents Used for Biliary and Pancreatic Disease) is another syndrome of dysmotility where physicians rely predominantly on a nonspecific therapeutic approach Clearly, with advances in understanding the physiology of gastrointestinal

motility and dysmotility, better and more specific drugs will become available Some of these, such

as newer serotonin-receptor antagonists, currently are under development and offer new hope for the treatment of some of these conditions

In some disorders of motility, effective treatment does not necessarily require a "neuroenteric" approach An example is that of GERD The pathophysiology of GERD is poorly defined but appears to involve a disturbance in the normal antireflux barrier composed of the lower esophageal sphincter (LES) and perhaps the diaphragmatic crura Transient lower esophageal sphincter

relaxations (tLESRs) are prolonged relaxations of the LES that occur in the absence of a swallow and appear to be the dominant factor in reflux in most patients By contrast, a low resting LES pressure by itself does not appear to be as important unless it is less than 10 mm Hg Anatomical factors such as hiatal hernia also can contribute to the impaired integrity of the antireflux barrier Other factors that may play a role are delayed gastric emptying, gastric distention, and poor

esophageal clearance due to impaired peristalsis Thus, it appears that GERD is predominantly the result of problems with gastrointestinal motility and is not generally associated with hypersecretion

of gastric acid Nevertheless, the damage to the esophagus is ultimately inflicted by acid, and the

most effective therapy for GERD remains the suppression of acid production by the stomach (see

Chapter 37: Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and

Gastroesophageal Reflux Disease) Neither metoclopramide nor cisapride by itself is particularly effective in this condition However, a new approach currently under investigation relies on the suppression of tLESRs and may hold promise This can be achieved by CCK1-receptor antagonists (such as loxiglumide), GABA agonists (such as baclofen), and inhibitors of nitric oxide synthesis

By contrast with the above, some motility disorders are treated by agents that reduce contractility These include disorders such as achalasia, in which the LES fails to relax, resulting in a functional obstruction to the passage of food and severe difficulty in swallowing Smooth muscle relaxants

such as organic nitrates and calcium channel antagonists (see Chapter 32: Drugs Used for the Treatment of Myocardial Ischemia) often can lead to temporary if partial relief of symptoms A

more recent approach relies on the use of botulinum toxin, injected directly into the LES via an endoscope, in doses of 80 to 200 U This potent agent (see Chapter 9: Agents Acting at the

Neuromuscular Junction and Autonomic Ganglia) causes inhibition of release of ACh from nerve endings and can produce partial paralysis of the sphincter muscle, with significant improvements in symptoms and esophageal clearance (Pasricha et al , 1995) However, its effects wear off over a period of several months, requiring repetitive injections It also is being used increasingly in other gastrointestinal conditions such as chronic anal fissures (Hoogerwerf and Pasricha, 1999)

In addition to organic nitrates and calcium channel antagonists, other agents that decrease smooth muscle contractility include the traditional anticholinergic agents ("spasmolytics" or

"antispasmodics"), which often are used in patients with irritable bowel syndrome (see below).

Current and investigational pharmacological approaches to disorders of gastrointestinal motility are summarized in Table 38–2

Antinausea and Antiemetic Agents

Nausea and Vomiting

The act of emesis and the sensation of nausea that accompanies it generally are thought to be protective reflexes that serve to rid the stomach and intestine of toxic substances and prevent their further ingestion Vomiting is a complex process and consists of a preejection phase (gastric

relaxation and retroperistalsis), retching (rhythmic action of respiratory muscles preceding vomitingand consisting of contraction of abdominal, intercostal, and diaphragmatic muscles against a closed glottis), and ejection (intense contraction of the abdominal muscle and relaxation of the upper esophageal sphincter) All this is accompanied by multiple autonomic phenomena including

salivation, shivering, and vasomotor changes During prolonged episodes, marked behavioral changes including lethargy, depression, and withdrawal may occur The process appears to be coordinated by a central emesis center in the lateral reticular formation of the mid-brainstem

adjacent to the CTZ in the area postrema (AP) at the bottom of the fourth ventricle and the nucleus tractus solitarius (NTS) of the vagus nerve The lack of a blood-brain barrier allows the CTZ to monitor blood and cerebrospinal fluid constantly for toxic substances and to relay information to the emesis center to trigger nausea and/or vomiting The emesis center also receives information

from the gut, principally by the vagus nerve (via the NTS) but also by splanchnic afferents Two

additional inputs of importance to the emesis center come from the cerebral cortex (particularly in anticipatory nausea or vomiting) and the vestibular apparatus (in motion sickness) In turn, the center sends out efferents to the nuclei responsible for respiratory, salivary, and vasomotor activity

as well as to both striated and smooth muscle involved in the act The CTZ has high concentrations

of serotonin (5-HT3), dopamine (D2), and opioid receptors, while the NTS is rich in enkephalin, histamine, and cholinergic receptors and also contains 5-HT3 receptors As can be imagined, a variety of neurotransmitters are involved in this complex process (Andrews et al , 1998; Rizk and Hesketh, 1999); an understanding of their nature has allowed a rational approach to the