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Efficacy of Gastrointestinal Drugs: What Works in the Dog?�SOTAL
Robert Washabau 
United States
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State of the Art Lecture
Robert J. Washabau, VMD, PhD, Dipl. ACVIM
Dr. Washabau received his veterinary degree (VMD) from the University of Pennsylvania. He performed an internship in small animal medicine at the University of Pennsylvania, a small animal internal medicine residency at the University of California-Davis, and he was certified in Internal Medicine by the American College of Veterinary Internal Medicine. Dr. Washabau received the PhD degree for graduate studies in gastrointestinal physiology and biochemistry. Dr. Washabau is currently Associate Professor at the University of Pennsylvania School of Veterinary Medicine. His clinical and basic science interests are in small animal gastroenterology. Dr. Washabau is the recipient of several teaching awards, including the Norden Distinguished Teaching Award (1990 and 1995) and the Lindback Distinguished Teaching Award (1995). Dr. Washabau currently serves as the ACVIM Internal Medicine Specialty President, and as the Immediate Past President of the Comparative Gastroenterology Society.
I. Gastric Anti-Secretory Drugs
Diffusion Barriers
Sucralfate is a cytoprotective drug composed of sulfated sucrose and polyaluminum hydroxide. In the acidic environment of the stomach, sucralfate is extensively cross-polymerized to form a viscous gel that binds to the necrotic tissue proteins in an ulcer. In addition to acting as a diffusion barrier, sucralfate may have additional beneficial effects (e.g., stimulation of prostaglandin production, adsorption of bile salts, and inactivation of gastric pepsins). Sucralfate is an effective drug in treating gastric erosion/ulcer in human beings, but its efficacy in companion animals has never been rigorously demonstrated. Although there are no retrospective or prospective studies, use of the drug would seem to make sense based on human and experimental animal studies. Combination therapy (sucralfate + histamine H2 antagonist, or sucralfate + H+, K+ - ATPase inhibitor) is frequently employed, but there is still no good evidence that combination therapy is better than component therapy in companion animal medicine. Finally, if combination therapy is to be considered, in vitro studies of sucralfate activation and histamine H2 receptor antagonist absorption suggest that the two drugs should be administered independently. It is not clear whether this is important in vivo. Sucralfate has proven efficacy in the treatment of esophagitis in dogs and cats. Indeed, sucralfate is probably the most important drug consideration in the treatment of esophagitis.
Histamine H2 Receptor Antagonists
Histamine H2 receptor antagonists (e.g., cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion by antagonizing the histamine H2 receptor on gastric parietal cells. These agents have proven efficacy in treating gastric ulcer disease in companion animals. There is no convincing evidence, however, that one drug is more efficacious than another in the same classification. Famotidine and nizatidine are more potent than ranitidine, and ranitidine is more potent than cimetidine, but pharmacologic potency is probably not that important in animals (e.g., dogs and cats) with low basal acid secretion. In this classification of drugs, ranitidine and nizatidine have the additional advantage (or disadvantage) of stimulating gastric emptying and colonic motility. Ranitidine, for example, is useful in restoring normal gastric emptying patterns in an experimental canine gastric ulcer.
Acetylcholine M1 Receptor Antagonists
Cholinergic antagonists inhibit acid secretion by antagonizing the muscarinic cholinergic receptor on gastric parietal cells. Most of the currently available antagonists are nonselective, however, and should not be used as gastric anti-secretory agents. Pirenzepine and telenzepine, selective M1 cholinergic antagonists, inhibit cholinergically mediated gastric acid secretion without significant effects on other muscarinic receptors (M2, M3) that mediate GI, airway, and urinary bladder smooth muscle contraction. Thus, pirenzepine and telenzepine could be recommended in the therapy of gastric ulcer disease in companion animals. Telenzepine is more potent than pirenzepine in the dog; neither drug is available in the United States (Canada and Europe, only).
H+, K+ - ATPase Inhibitors
The substituted benzimidazoles (e.g., omeprazole, lansoprazole) inhibit gastric acid secretion by irreversibly binding the proton-transporting enzyme at the luminal surface of the parietal cell. Omeprazole, for example, inhibits gastric acid secretion in dogs for at least 24 hours after a single oral dose (0.7 mg/kg). Omeprazole is as effective as cimetidine in healing mechanically-induced ulcers, but omeprazole is more effective than cimetidine in healing aspirin-induced gastritis. Additional studies will be needed to determine the comparative efficacy of these drugs in treating other forms of gastritis and gastric ulcer. There is less clinical experience with lansoprazole at the present time, but the drug is without reported side effects in both cats and dogs. Lansoprazole appears to have pharmacologic potency and duration of action similar to omeprazole, and has no apparent additional advantages.
Prostaglandin E1 Analogues
Endogenously produced prostaglandins promote gastric mucosal defense mechanisms by inhibiting parietal cell acid secretion and by stimulating mucosal blood flow, bicarbonate secretion, mucus secretion, and epithelial cell renewal. Nonsteroidal anti-inflammatory drugs inhibit this endogenous prostaglandin production and place animals at increased risk for gastritis, gastric erosion, and gastric ulcer. Synthetic analogues of prostaglandin E1 (e.g., misoprostol) diminish the pathology produced by aspirin and other NSAIDs. Prophylaxis against gastric mucosal injury induced by NSAIDs thus is the primary indication for misoprostol. This group of drugs apparently does not have distinct advantages over histamine H2 receptor antagonists in treating ulcer not associated with NSAIDs.
II. Gastrointestinal Prokinetic Agents�Dopaminergic Drugs (e.g., Metoclopramide)
Lower Esophageal Sphincter Disorders
Metoclopramide increases pressure in the gastroesophageal sphincter and stimulates gastric emptying. Delayed gastric emptying promotes gastroesophageal reflux by increasing the gastric volume and pressure gradient. Thus, metoclopramide may be recommended in the therapy of gastroesophageal reflux.
Gastric Emptying Disorders
Metoclopramide was the drug of choice for treatment of delayed gastric-emptying disorders prior to the availability of cisapride. In addition to its central anti-emetic effect, metoclopramide increases the amplitude and frequency of antral contractions, inhibits fundic receptive relaxation, and coordinates gastric, pyloric, and duodenal motility, all of which result in accelerated gastric emptying. It is used at a dosage of 0.2 to 0.5 mg/kg body weight every eight hours, administered orally or parenterally. Continuous intravenous infusions can be administered at dosages of 0.01 to 0.02 mg/kg/hour or 1�2 mg/kg/day. The effects of metoclopramide on gastric emptying in the dog appear to be more important for liquids than for solids.
Small Bowel Motility Disorders
Metoclopramide is most effective when delayed gastric emptying is due to poor antropyloroduodenal coordination. Metoclopramide is less effective in the distal small intestine and colon.
Centrally-Mediated Emesis
The antiemetic effect of metoclopramide is due to dopamine D2 receptor antagonism at the chemoreceptor trigger zone. Metoclopramide inhibits vomiting secondarily through effects on motility.
III. Gastrointestinal Prokinetic Agents�Serotonergic Drugs (e.g., Cisapride, Prucalopride, Tegaserod)
Esophageal Disorders
Cisapride would appear to be a rational drug in the treatment of gastroesophageal reflux disease because it stimulates gastric emptying and increases gastroesophageal (GE) sphincter pressure. The incidence and prevalence of GE reflux in the dog and cat are unknown, although recent reports suggest that reflux esophagitis may be a common entity. The mechanisms for transient relaxation of the GE sphincter and GE reflux exist in these species, just as they do in human beings. Comparative studies have shown that cisapride is more potent than metoclopramide in stimulating gastric emptying and increasing GE sphincter pressure. Cisapride also stimulates distal esophageal peristalsis in those animal species (e.g., cat, human) in which the distal esophageal muscularis is composed of smooth muscle. The obvious exception is the dog, a species in which the entire esophageal body is composed of striated muscle. Cisapride should not be recommended for the treatment of canine megaesophagus.
Gastric Emptying Disorders
Delayed gastric emptying is now recognized to be an important cause of upper gastrointestinal tract signs, e.g., anorexia and vomiting, in dogs and cats. Delayed gastric emptying has been reported in animals recovering from gastric dilatation and volvulus, in infectious and inflammatory gastric diseases, and in experimental gastric ulcer. Dosages of cisapride in the range of 0.05�0.2 mg/kg enhance gastric emptying in dogs with normal gastric emptying. However, dosages in the range of 0.5�1.0 mg/kg are needed to enhance gastric emptying in dogs with delayed gastric emptying induced by α2-adrenergic agonists, dopamine, disopyramide, or antral tachygastria. Cisapride accelerates gastric emptying in dogs by stimulating pyloric and duodenal motor activity, by enhancing antropyloroduodenal coordination, and by increasing the mean propagation distance of duodenal contractions. Cisapride appears to be superior to metoclopramide and domperidone in stimulating gastric emptying.
Small Bowel Motility Disorders
Cisapride stimulates jejunal spike burst migration, jejunal propulsive motility, and antropyloroduodenal coordination following intestinal lipid infusion in the dog. Thus, cisapride would appear to have a rational place in the treatment of post-operative ileus and intestinal pseudo-obstruction.
�Colonic Motility Disorders
The effects of many of the gastrointestinal prokinetic agents (e.g., metoclopramide, domperidone, and erythromycin) are limited to the proximal gastrointestinal tract. Unlike these agents, cisapride also stimulates colonic motility. Cisapride would appear to have a rational place in the treatment of idiopathic constipation. Disruption of the normal colonic motility patterns results in constipation in domestic cats. Cisapride improves colonic motility in cats that are mildly or moderately affected with idiopathic constipation; cats with long-standing hypomotility and dilation are usually less responsive.
Cis-platinum-Induced Emesis
Cisapride antagonizes 5-HT3 receptors and inhibits vomiting associated with cis-platinum chemotherapy. The potency of cisapride's 5-HT3 anti-emetic effect (ED50 = 0.6 mg/kg IV; ED100 = 2.6 mg/kg IV) is less than its 5-HT4 prokinetic effect. Thus, cisapride could be recommended as an antiemetic agent for the cancer chemotherapy patient only if other 5-HT3 antagonists (e.g., ondansetron) are not immediately available.
New Drugs
Two new 5-HT4 agonist drugs, prucalopride and tegaserod, are slated for marketing in 2001 or 2002. These drugs may provide suitable alternatives for countries in which cisapride has been removed from the marketplace.
IV. Gastrointestinal Prokinetic Agents�Motilin-Like Drugs (e.g., Erythromycin)
Lower Esophageal Sphincter Disorders
�Erythromycin increases the pressure of the gastroesophageal sphincter, and should be useful in the treatment of gastroesophageal reflux and reflux esophagitis.
Gastric Emptying Disorders
Erythromycin accelerates gastric emptying by inducing antral contractions similar to phase III of the interdigestive state. Contractions associated with phase III usually occur only during the fasting state, and they clear the stomach of indigestible solids. With erythromycin, the accelerated gastric emptying of solids occurs at the expense of gastric sieving during the fed state. Food that is inadequately triturated (> 0.5 mm) empties into the duodenum. If delayed gastric emptying is contributing to clinical signs, then emptying the stomach of retained solids may be beneficial. The recommended anti-microbial dosage of oral erythromycin in dogs and cats is 10�20 mg/kg every eight hours. The prokinetic dosage is much lower at 0.5�1.0 mg/kg every eight hours.
Small Bowel Motility Disorders
Erythromycin induces contractions that originate in the gastric antrum and migrate to the duodenum, jejunum, and terminal ileum. Erythromycin may be useful in the treatment of post-operative ileus.
V. Gastrointestinal Prokinetic Agents�Acetylcholinesterase Inhibitors
(e.g., Nizatidine and Ranitidine)
Nizatidine Antisecretory Activity
Nizatidine is a competitive, reversible antagonist of histamine H2-receptors, particularly those in parietal cells. Competitive antagonism of histamine H2-receptors with nizatidine effectively reduces gastric acid secretion. H2-receptor antagonists are used clinically in the treatment of gastric ulcerations. Nizatidine is a newer H2-receptor antagonist with a potency similar to that of ranitidine. The current recommended oral dosage of nizatidine (2.5-5.0 mg/kg/day) is derived from studies of gastric acid secretion in Heidenhain pouch dogs.
Nizatidine Prokinetic Activity
Nizatidine stimulates gastric emptying and colonic contractions at gastric antisecretory dosages mainly through its anti-cholinesterase (AChE) activity. Nizatidine significantly increases gastric emptying and colonic motility, whereas other H2-receptor antagonists (e.g., cimetidine, famotidine) have no such effect.
Ranitidine Antisecretory Activity
The H2-receptor antagonists, including ranitidine, competitively inhibit histamine-induced gastric acid secretion by the parietal cell. The recommended anti-secretory dosage of ranitidine for dogs and cats is 1�2 mg/kg orally every eight to twelve hours.
Ranitidine Prokinetic Activity
�Ranitidine stimulates gastrointestinal motility mainly through its anti-cholinesterase (AChE) activity. Gastric ulcers are considered a cause of defective gastric propulsion in dogs. Treatment with ranitidine would be beneficial not only by inhibiting gastric acid secretion but also by accelerating gastric emptying. Therefore, ranitidine-like nizatidine, has efficacy not found with some of the other H2-receptor antagonists in the stimulation of gastrointestinal motility.
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