Section VI - Drugs Affecting Gastrointestinal Function docx

Section VI. Drugs Affecting Gastrointestinal Function Chapter 37. Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease Overview The term acid-peptic disorders encompasses a variety of relatively specific medical conditions in which injury by gastric acid (and activated pepsin) is thought to play an important role. These disorders include gastroesophageal reflux disease (GERD), benign "peptic" ulcers of the stomach and duodenum, ulcers secondary to the use of conventional nonsteroidal antiinflammatory drugs (NSAIDs), and ulcers due to the rare Zollinger-Ellison syndrome. It appears that exposure of the involved tissue to acid is essential to the development of clinical symptoms in most instances of these diseases. Control of gastric acidity is therefore a cornerstone of therapy in these disorders, even though this approach may not address the fundamental pathophysiological process. Mankind has lived with peptic ulcers since ancient times. Perhaps the first description of this malady is the one inscribed on the pillars of the temple of Aesculapius at Epidaurus from around the fourth century B.C.: "A man with an ulcer in his stomach. He incubated and saw a vision; the god seemed to order his followers to seize and hold him, that he might incise his stomach. So he fled, but they caught and tied him to the doorknocker. Then Asklepios opened his stomach, cut out the ulcer, sewed him up again, and loosed his bonds." Many prominent people have suffered from indigestion and ulcers, including the Roman emperor Marcus Aurelius, whose death has been attributed by some to a perforated ulcer and whose physician was none other than Galen himself. Acid neutralization was recognized as effective treatment more than 12 centuries ago by Paulus Aeginata, who prescribed a mixture of Samian and Lemnian earths and milk, not unlike the milk- antacid regimens of the mid-twentieth century (Smith and Rivers, 1953). Since then, of course, considerable advances in understanding the pathogenesis and in the treatment of acid-peptic conditions have occurred, culminating in the discovery of Helicobacter pylori and proton pump inhibitors. We now know that eradication of H. pylori effectively promotes healing of peptic ulcers and prevents their recurrence in most cases. Proton pump inhibitors have become the drugs of choice in promoting healing from erosive esophagitis and peptic ulcer disease because of their ability to nearly completely suppress acid production. Although several clinical challenges still need to be met in this area, it is reasonable to conclude that the battle against the ravages of gastric acid is finally turning in our favor. This chapter covers some of the principal therapeutic agents in this area and strategies for their use. Physiology of Gastric Secretion Gastric acid secretion is a complex, continuous process controlled by multiple central (neural) and peripheral (endocrine and paracrine) factors. Each factor attributes to a common final physiological event—the secretion of H + by parietal cells, which are located in the body and fundus of the stomach. Neuronal (acetylcholine, ACh), paracrine (histamine), and endocrine (gastrin) factors all play important roles in the regulation of acid secretion (Figure 37–1). Their respective specific receptors (M 3 , H 2 , CCK 2 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 Ca 2+ –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 Ca 2+ –dependent pathway leads to an increase in cytosolic Ca 2+ . 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); CCK 2 , gastrin (and cholecystokinin) receptor; H 2 , histamine (HIST) receptor; EP 3 , prostaglandin E 2 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, M 3 , located on the basolateral membrane of the parietal cells. The CNS probably modulates the activity of the ENS with ACh as its main regulatory neurotransmitter. The CNS generally is thought of as the main contributor to the initiation of gastric acid secretion in response to the sight, smell, taste, and anticipation of food ("cephalic phase"). ACh also indirectly affects the parietal cell through the stimulation of histamine release from the enterochromaffin-like (ECL) cells in the fundus and the stimulation of gastrin release from the G cells in the gastric antrum. Histamine is released from ECL cells through multifactorial pathways and is a critical regulator of acid production through the H 2 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 H 2 -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 E 2 and I 2 inhibit gastric acid secretion by a direct effect on the parietal cell mediated by the EP 3 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 H 2 -receptor antagonists. Proton Pump Inhibitors Chemistry, Mechanism of Action, and Pharmacological Properties The most effective suppressors of gastric acid secretion undoubtedly are the gastric H + ,K + –ATPase (proton pump) inhibitors. They are the most effective drugs used in antiulcer therapy and have found worldwide popularity over the past decade. Currently, there are several different proton pump inhibitors available for clinical use: omeprazole (PRILOSEC), lansoprazole (PREVACID), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX). They are -pyridylmethylsulfinyl benzimidazoles with different substitutions on the pyridine or the benzimidazole groups; their pharmacological properties are similar. Proton pump inhibitors are "prodrugs," requiring activation in an acid environment. These agents enter the parietal cells from the blood and, because of their weak basic nature, accumulate in the acidic secretory canaliculi of the parietal cell, where they are activated by a proton-catalyzed process that results in the formation of a thiophilic sulfenamide or sulfenic acid (Figure 37–2). This activated form reacts by covalent binding with the sulfhydryl group of cysteines from the extracellular domain of the H + ,K + –ATPase. Binding to cysteine 813, in particular, is essential for inhibition of acid production, which is irreversible for that pump molecule. Proton pump inhibitors have profound effects on acid production. When given in a sufficient dose (e.g., 20 mg of omeprazole a day for seven days), the daily production of acid can be diminished by more than 95%. Secretion of acid resumes only after new molecules of the pump are inserted into the luminal membrane. Omeprazole also selectively inhibits gastric mucosal carbonic anhydrase, which may contribute to its acid suppressive properties. Figure 37–2. Proton Pump Inhibitors. A. Structures of four inhibitors of the gastric H + ,K + –ATPase (proton pump). B. Conversion of omeprazole to a sulfenamide in the acidic canaliculi of the parietal cell. The other three proton pump inhibitors undergo analogous conversions. The sulfenamides interact covalently with sulfhydryl groups in the extracellular domain of the proton pump, thereby inhibiting its activity. Pharmacokinetics Proton pump inhibitors are unstable at a low pH. The oral dosage forms ("delayed release") are supplied as enteric-coated granules encapsulated in a gelatin shell (omeprazole and lansoprazole) or as enteric-coated tablets (pantoprazole and rabeprazole). The granules dissolve only at an alkaline pH, thus preventing degradation of the drugs by acid in the esophagus and stomach. Proton pump inhibitors are rapidly absorbed, highly protein bound, and extensively metabolized in the liver by the cytochrome P450 system (particularly CYP2C19 and CYP3A4). Their sulfated metabolites are excreted in the urine or feces. Their plasma half-lives are about 1 to 2 hours, but their durations of action are much longer (see below). Chronic renal failure and liver cirrhosis do not appear to lead to drug accumulation with once-a-day dosing of the drugs. Hepatic disease reduces the clearance of lansoprazole substantially, and dose reduction should be considered in patients with severe hepatic disease. The requirement for enteric coating poses a challenge to the routine use of oral proton pump inhibitors in critically ill patients or in patients unable to swallow adequately. Intravenous H 2 - receptor antagonists have been preferred in patients with contraindications to oral ingestion, but this picture is expected to change with the advent of intravenous preparations of proton pump inhibitors. Pantoprazole, a relatively more acid-stable compound, is the first such preparation to be approved in the United States. A single intravenous bolus of 80 mg can inhibit acid production by 80% to 90% within an hour, an effect that can last up to 21 hours. Therefore, once-daily dosing of intravenous proton pump inhibitors (in doses similar to those used orally) may be sufficient to achieve the desired degree of hypochlorhydria. The clinical utility of these formulations in the above situations will require further study but is expected to be equal to if not greater than that of intravenous H 2 -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 H 2 -receptor antagonists may diminish the efficacy of proton pump inhibitors. Since not all pumps or all parietal cells are functional at the same time, it takes several doses of the drugs to result in maximal suppression of acid secretion. With once-a-day dosing, steady-state inhibition, affecting about 70% of pumps, may take 2 to 5 days (seeSachs, 2000). Achieving steady-state inhibition may be accelerated somewhat by more frequent dosing initially (e.g., twice daily). Since the binding of the drugs' active metabolites to the pump is irreversible, inhibition of acid production will last for 24 to 48 hours or more, until new enzyme is synthesized. The duration of action of these drugs, therefore, is not directly related to their plasma half-lives. Adverse Effects and Drug Interactions Proton pump inhibitors inhibit the activity of some hepatic cytochrome P450 enzymes and therefore may decrease the clearance of benzodiazepines, warfarin, phenytoin, and many other drugs. When disulfiram is coadministered with a protein pump inhibitor, toxicity has been reported. Proton pump inhibitors usually cause few adverse effects; nausea, abdominal pain, constipation, flatulence, and diarrhea are the most common side effects. Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported. Chronic treatment with omeprazole decreases the absorption of vitamin B 12 , but insufficient data exist to demonstrate whether or not this leads to a clinically relevant deficiency. Hypergastrinemia (>500 ng/liter) occurs in approximately 5% to 10% of long-term omeprazole users. Gastrin is a trophic factor for epithelial cells, and there is a theoretical concern that elevations in gastrin can promote the growth of different kinds of tumors in the gastrointestinal tract. In rats undergoing long-term administration of proton pump inhibitors, there has been development of enterochromaffin-like cell hyperplasia and gastric carcinoid tumors secondary to sustained hypergastrinemia; this has raised concerns about the possibility of similar complications in human beings. There are conflicting data on the risk and clinical implications of enterochromaffin-like cell hyperplasia in patients on long-term proton pump inhibitor therapy. These drugs now have a track record of more than 15 years of use worldwide, and no major new issues regarding safety have emerged (Klinkenberg-Knol et al. , 1994; Kuipers and Meuwissen, 2000). There is as yet no reason to believe, therefore, that hypergastrinemia should be a trigger for discontinuation of therapy or that gastrin levels should be monitored routinely in patients on long-term proton pump inhibitor therapy. However, the development of a hypergastrinemic state may predispose the patient to rebound hypersecretion of gastric acid following discontinuation of therapy. Proton pump inhibitors have not been associated with a major teratogenic risk when used during the first trimester of pregnancy; caution, however, is still warranted. Therapeutic Uses Proton pump inhibitors are used principally to promote healing of gastric and duodenal ulcers and to treat gastric esophageal reflux disease (GERD) that is either complicated or unresponsive to treatment with H 2 -receptor antagonists (see below). Proton pump inhibitors also are the mainstay in the treatment of Zollinger-Ellison syndrome. Therapeutic applications of proton pump inhibitors are further discussed later in this chapter, under "Specific Acid-Peptic Disorders and Therapeutic Strategies." Histamine H 2 -Receptor Antagonists The description of selective histamine H 2 -receptor blockade by Black in 1970 was a landmark in the history of pharmacology and set the stage for the modern approach to the treatment of acid-peptic disease, which until then had relied almost entirely on acid neutralization in the lumen of the stomach (seeBlack, 1993; Feldman and Burton, 1990a,b). Equally impressive has been the safety record of H 2 -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 H 2 -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. H 2 -receptor antagonists inhibit acid production by reversibly competing with histamine for binding to H 2 receptors on the basolateral membrane of parietal cells. Figure 37–3. Structures of Histamine and H 2 -Receptor Antagonists. The most prominent effects of H 2 -receptor antagonists are on basal acid secretion; less profound but still significant is suppression of stimulated (feeding, gastrin, hypoglycemia, or vagal stimulation) acid production. These agents thus are particularly effective in suppressing nocturnal acid secretion, which reflects mainly basal parietal cell activity. This fact has clinical relevance in that the most important determinant of duodenal ulcer healing is the level of nocturnal acidity. Therefore, duodenal ulcers can be healed with once-daily dosing of H 2 -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 H 2 -receptor antagonist at night. Pharmacokinetics H 2 -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 H 2 -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 H 2 -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 (CL Cr ), Cimetidine Elimination Clearance (CL E ), and Appropriate Cimetidine Dose Reduction for Patients with Impaired Renal Function. (Adapted from Atkinson and Craig, 1990, with Permission.) All four H 2 -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 H 2 -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 H 2 -receptor antagonists with various cytopenias, including reductions in platelet count. H 2 -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 H 2 -receptor antagonists (see"Antacids," below). Drug interactions with H 2 -receptor antagonists can be expected mainly with cimetidine, and these are an important factor in the preferential use of other H 2 -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 H 2 -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 H 2 -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)E 2 and PGI 2 are the major prostaglandins synthesized by the gastric mucosa; they inhibit acid production by binding to the EP 3 receptor on parietal cells (seeChapter 26: Lipid- Derived Autacoids: Eicosanoids and Platelet-Activating Factor). Prostaglandin binding to the receptor results in inhibition of adenylyl cyclase and decreased levels of intracellular cyclic AMP. PGE also can prevent gastric injury by its so-called cytoprotective effects, which include stimulation of secretion of mucin and bicarbonate and improvement in mucosal blood flow; however, acid suppression appears to be its more critical effect (Wolfe et al. , 1999). Although smaller doses than required for acid suppression may be protective for the gastric mucosa in laboratory animals, this has not been convincingly demonstrated in human beings. Since NSAIDs inhibit prostaglandin formation, the synthetic prostaglandins provide a rational approach to reducing NSAID-related mucosal damage. Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE 1 ; CYTOTEC) is a synthetic analog of prostaglandin E 1 with an additional methyl ester group at C1 (resulting in an increase in potency and in the duration of the antisecretory effect) and a switch of the hydroxy group from C15 to C16 along with an additional methyl group (resulting in improved activity when given orally, increased duration of action, and improved safety profile). The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose; oral doses of 100 to 200 g produce significant inhibition of basal acid secretion (decreased by 85% to 95%) or food-stimulated acid secretion (decreased by 75% to 85%). Pharmacokinetics Misoprostol is rapidly absorbed and undergoes extensive and rapid first-pass metabolism (deesterification) to form misoprostol acid (the free acid), the principal and active metabolite of the drug. Some of this conversion may in fact occur in the parietal cells. After a single dose, inhibition of acid production can be seen within 30 minutes, peaks at 60 to 90 minutes, and lasts for up to 3 [...]... 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... (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)... and this has led to the use of sucralfate slurries (via nasogastric tube), which also appears to provide reasonable prophylaxis against bleeding, but is more inconvenient In a meta-analysis that compared H2-receptor antagonists with sucralfate and placebo as prophylactic agents for clinically important gastrointestinal bleeding, both sucralfate and H2-receptor antagonists were found to reduce the incidence... 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... 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... 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... center is a complex response and is described in the text 5-HT3-Receptor Antagonists Chemistry, Pharmacological Effects, and Mechanism of Action Ondansetron (ZOFRAN) is the prototypical drug in this class; since its introduction in the early 1990s, it and other 5-HT3-receptor antagonists have become some of the most widely used drugs for chemotherapy-induced emesis (Gregory and Ettinger, 1998; Hesketh,... used to treat chemotherapy-induced nausea was metoclopramide, a D2-receptor antagonist acting on the CTZ In recent years, an additional mechanism involving 5-HT3-receptor antagonism has been found (see above) The prokinetic effects of metoclopramide may contribute to its effectiveness in chemotherapy-induced nausea Domperidone is another D2-receptor antagonist with antinauseant and prokinetic effects... (TRANSDERM-SCOP) Its principal utility is in the prevention and treatment of motion sickness, although it has been shown to have some activity in postoperative nausea and vomiting as well In general, anticholinergic agents have no role in chemotherapy-induced nausea For a detailed discussion of these drugs, see Chapter 7: Muscarinic Receptor Agonists and Antagonists Dronabinol Dronabinol (delta-9-tetrahydrocannabinol;... lipid-soluble compound that is readily absorbed after oral administration; its onset of action occurs within an hour, and peak levels are achieved within 2 to 4 hours It undergoes extensive first-pass metabolism with limited systemic bioavailability after single doses (only 10% to 20%) Both active and inactive metabolites are formed in the liver, the principal example of the former being 11-OH-delta-9-tetrahydrocannabinol . 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 Section VI. Drugs Affecting Gastrointestinal Function Chapter 37. Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease Overview The. provide a rational approach to reducing NSAID-related mucosal damage. Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE 1 ; CYTOTEC) is a synthetic analog of prostaglandin E 1 with an additional