The treatment of gastrointestinal (GI) clinical signs and definitive disease

Transcription

1 CE 452 V Vol. 24, No. 6 June 2002 Article #2 (1.5 contact hours) Refereed Peer Review KEY FACTS Xylazine is considered the drug of choice for stimulating emesis in cats, but it does not have consistent results in dogs. Serotonin antagonists are considered the most potent inhibitors of vomiting. H 2 -receptor antagonists ranitidine and nizatidine are also acetylcholinesterase inhibitors with prokinetic effects at the clinically recommended doses. Comments? Questions? compendium@medimedia.com Web: VetLearn.com Fax: Drug Therapies Used in Gastrointestinal Disease Oklahoma State University Susan M. Eddlestone, DVM, DACVIM ABSTRACT: Initial treatment of most gastrointestinal disorders in dogs and cats has traditionally been supportive and nonspecific. With the improved ability to diagnose many gastrointestinal disorders less invasively using endoscopy, serology, and fecal and rectal mucosal cytology, specific treatments can be applied earlier with marked improvement in clinical results. This article discusses the indications and uses of the most common treatments in small animal gastroenterology as well as newer therapies that are emerging and being received with favorable results. The treatment of gastrointestinal (GI) clinical signs and definitive disease in dogs and cats is often chosen based on the practitioner s knowledge and experience with treatments known to be effective. This article reviews the traditional treatment modalities and provides an introduction to newer therapies that are being used successfully to treat many GI disorders in dogs and cats. VOMITING REFLEX The emetic center, which is located in the medulla of the brain, coordinates all impulses that cause vomiting. The emetic center is protected by the blood brain barrier; therefore, input to this region occurs from the cerebral cortex (e.g., psychogenic vomiting, visual and olfactory stimuli), the limbic system (e.g., head injuries, increased intracranial pressure), the chemoreceptor trigger zone (CTZ), and peripheral impulses. Acetylcholine is the primary afferent neurotransmitter, mediating emesis from the higher centers with histamine acting as a secondary transmitter via H 1 receptors. Blood-borne chemicals stimulate the CTZ, which is located in the area postrema in the lateral walls of the third ventricle. Because this area does not have a complete blood brain barrier, it is more accessible to substances, drugs, or toxins present in the circulating blood than is the emetic center. Stimulation of the CTZ is initiated by dopaminergic receptors that respond to such agonists as dopamine, apomorphine hydrochloride, and serotonin (5-HT 3 ). Peripheral impulses originate in the pharynx and fauces and travel to the emetic center via cranial nerve IX. Other peripheral afferent impulses originate from stimulation in various organs and tissues via the sympathetic or vagal afferents (i.e., heart, stomach, duodenum, small intestine, liver, gallbladder, peritoneum, kidneys, ureter, urinary bladder, and uterus). 1

2 Compendium June 2002 Drug Therapy/GI Disease 453 Table 1. Emetic Drugs Drug Dose Comment 3% Hydrogen peroxide Dogs and cats: 5 10 ml PO, one to two Fatal aspiration of foam is possible in cats doses as needed Ipecac syrup Dogs: ml/kg PO; cats: Not to exceed 15 ml/dog; dogs and ml/kg PO (may cause toxicity and death) cats: dose may be repeated once but product must be removed via gastric lavage if vomiting does not occur Apomorphine hydrochloride Dogs: 0.04 mg/kg IV, mg/kg Not recommended for use in cats IM or SC, or 0.25 mg (conjunctival sac) Xylazine Cats: 0.44 mg/kg IM Not effective in dogs; emesis in cats should occur within 15 min; sedation lasts 1 2 hr EMETICS Emetics are used to induce vomiting in dogs and cats for early treatment of ingestion of noncorrosive toxins. Within the first 30 minutes to 1 hour after toxic ingestion, emetics can help eliminate the toxin from the stomach before they are absorbed in the small intestine. Emesis should never be induced in patients that are unconscious, experiencing a seizure, or having respiratory difficulty. Reflux emesis can be induced by instilling warm water (5 to 10 ml/kg) into the stomach via a stomach tube. This will dilute the toxin and initiate the vomiting reflex by stimulating peripheral receptors in the stomach that respond to distention. Gastric mucosa irritants can also induce the vomiting reflex peripherally. Orally administered hypertonic saline solution or table salt, 3% hydrogen peroxide solution, or ipecac syrup or powder (i.e., emetine) can be effective and administered at home prior to an emergency visit (Table 1). Ipecac in cats can be toxic, particularly with the administration of multiple doses that can be absorbed systemically. Hydrogen peroxide can foam and cause fatal aspiration in cats; therefore, it should be used with caution in this species. 1 Centrally acting drugs are more potent stimulants of the vomiting reflex. Apomorphine hydrochloride, an opioid and synthetic derivative of morphine, stimulates the CTZ by acting on dopamine receptors. 1 It is available as a powder inside a capsule and can be mixed in sterile water and given subcutaneously. The tablet form, which is more expensive, can be used in the conjunctival sac for quick absorption. Oral administration usually requires a much higher dose because of decreased oral bioavailability. 1 Likewise, giving subsequent doses does not improve the vomiting effect but may actually suppress the emetic center. Although considered only a mild CNS depressant, apomorphine hydrochloride should not be used in animals with depressed CNS conditions. Apomorphine hydrochloride is not recommended for use in cats because they need a higher dose to induce vomiting, and this can cause excitement and hyperactivity of the CNS. 1 Xylazine, an α 2 -agonist, is the drug of choice to stimulate emesis in cats. 1 Although it is used more commonly for its sedation/analgesic properties, it can be used at a lower dose to induce vomiting in cats. In dogs, xylazine is not as consistent at inducing emesis. There are no reports on the use of medetomidine, a drug with similar actions, to induce emesis in either species. ANTIEMETICS Vomiting occurs in dogs and cats as a result of many GI and non-gi disorders. Suppression of vomiting is indicated when the underlying cause is known and serves to prevent further metabolic alterations caused by the loss of fluid, gastric acids, and electrolytes. Although treatment of the underlying cause is always the primary objective, the use of antiemetics for the interim to prevent further debilitation is beneficial. Suppressing vomition is contraindicated in patients with pyloric or intestinal obstruction. Dopamine Antagonists Metoclopramide, a dopamine antagonist, blocks dopamine receptors at the CTZ 2 (Table 2). It is suspected that at higher doses, antagonism is at the 5-HT 3 receptors. This agent is reported to be 20 times more potent than phenothiazines, although this difference in efficacy has not been documented in dogs and cats. 3 Metoclopramide also has prokinetic effects, which may help minimize vomiting by increasing upper GI motility, increasing lower esophageal sphincter tone, decreasing pyloric sphincter tone, and promoting antegrade contraction of the gastric antrum. A side effect is CNS stimulation that presents as irritability or nervousness, particularly in cats. The antidote for this side effect is diphenhydramine hydrochloride

3 454 Small Animal/Exotics Compendium June 2002 Table 2. Antiemetic Drugs Drug Dose Comment Metoclopramide Dogs and cats: mg/kg PO or Use lower doses with renal failure; SC q8h, 0.02 mg/kg IV q1h, or 1 2 common side effects are anxiety and mg/kg/day IV by CRI restlessness in dogs and cats Domperidone Dogs and cats: mg/kg IM or Not available in the United States IV q12h or 2 5 mg/kg PO q12h Ondansetron Dogs and cats: mg/kg SC q8h, No side effects are known; further mg/kg q12 24h PO, 0.5 mg/kg investigation is needed in dogs and cats IV load, or 0.5 mg/kg IV infusion q1h Dolasetron Dogs and cats: to prevent nausea or Can be combined with metoclopramide vomiting 0.6 mg/kg/day IV or PO; for optimal prevention of chemotherapyvomiting 1 mg/kg/day IV or PO induced nausea and vomiting in dogs and cats Chlorpromazine Dogs: mg/kg IM or SC q6 8h, May cause sedation 3.3 mg/kg PO q6 8h; cats: 0.5 mg/kg IM or SC q6 8h, mg/kg/day PO Prochlorperazine Dogs: mg/kg IM q8 12h May cause sedation in dogs and cats or 1 mg/kg PO q12h; cats: 0.13 mg/kg IM q12h or 0.5 mg/kg PO q12h with food Trifluoperazine Dogs and cats: 0.03 mg/kg IM q12h May cause sedation in dogs and cats Cyclizine hydrochloride Dogs and cats: 4 mg/kg IM q8h For vestibular disease induced emesis Meclizine hydrochloride Dogs <10 kg: 2 10 mg/kg/day PO; For vestibular disease induced emesis dogs >10 kg: 2 6 mg/kg/day PO; cats: 4 mg/kg/day PO Diphenhydramine hydrochloride Dogs and cats: 2 5 mg/kg PO q6 8h, For vestibular disease induced emesis 2 mg/kg IM or IV (slowly) q12h CRI = constant-rate infusion. (1 mg/kg IV) in dogs and cats. 4 Contraindications are GI hemorrhage and obstruction. Other dopamine antagonists that have been available but less commonly used are domperidone and the butyrophenone derivatives haloperidol and droperidol. Domperidone, which is similar to metoclopramide in activity, is currently not available in the United States for use in dogs and cats. The butyrophenones cause potent tranquilizer side effects and seizures in preepileptic patients. Serotonin Antagonists Serotonin antagonists, also known as 5-HT 3 antagonists, are a relatively new class of antiemetic drug that blocks stimulation at the CTZ and in the intestine to prevent vomiting. 5 The neurotransmitter serotonin acts by increasing the secretion of acetylcholine at distal ganglia, thereby stimulating the CTZ to induce vomiting. Serotonin antagonists block this mechanism and are considered the most potent inhibitors of vomiting. They are particularly useful for preventing vomiting induced by chemotherapy, parvovirus, and causes that are resistant to other therapies. 5-HT 3 antagonists that are available include ondansetron, tropisetron, granisetron, azesetron, and dolasetron. Ondansetron and dolasetron have been reported to be very effective in both dogs and cats 6 ; however, the high cost of these drugs limits their use to chemotherapy patients or patients unresponsive to other medications. Side effects have not been reported in dogs and cats; however, indepth study of these drugs in companion animals have not been published. Phenothiazines Phenothiazines control vomiting by inhibiting the CTZ as a result of their antidopaminergic and antihistaminergic effects. 2 Phenothiazine derivatives used as antiemetics in small animals include chlorpromazine, prochlorperazine, triflupromazine, perphenazine, trifluoperazine, and mepazine. Side effects associated with phenothiazines are sedation, hypotension caused by peripheral α blockade, and seizures in preepileptic patients. Glucocorticoids Glucocorticoids are used in human medicine to con-

4 Compendium June 2002 Drug Therapy/GI Disease 455 Table 3. Antisecretory Drugs Drug Dose Comment Cimetidine Dogs and cats: 5 10 mg/kg PO q6 8h Give IV dose slowly over min or 10 mg/kg IV q6h in dogs and cats; cytochrome P450 microsomal enzyme inhibitor Ranitidine Dogs and cats: mg/kg PO, No serious side effects reported IV, IM, or SC q8 12h Famotidine Dogs and cats: mg/kg PO No serious side effects reported or IV q12 24h Nizatidine Dogs: 5 mg/kg/day PO No serious side effects reported Omeprazole Dogs: mg/kg/day PO Achlorhydria, diarrhea, and transient fluctuations in liver enzymes reported trol vomiting, although the exact mechanism of action is not understood. These agents may have a synergistic effect when used with other antiemetics, such as metoclopramide, particularly when used in chemotherapy patients. Because of the side effects of gastric, duodenal, and colonic ulceration, the use of glucocorticoids for vomiting is not recommended. Barbiturates and Benzodiazepines Barbiturates (e.g., phenobarbital) and benzodiazepines (e.g., diazepam) are sedatives that are used to control psychogenic and behavioral vomiting by acting on the higher centers of the brain. This type of vomiting, however, is not well documented in veterinary medicine. Anticholinergics Anticholinergics (e.g., atropine) are centrally acting antiemetics that block cholinergic transmission as well as muscarinic receptors in the emetic center. Many anticholinergics (e.g., glycopyrrolate, propantheline, meth-

5 456 Small Animal/Exotics Compendium June 2002 Table 4. Cytoprotective Drugs and Antacids Drug Dose Comment Aluminum magnesium hydroxide Dogs and cats: 2 10 ml PO q2 4h Preferred combination to avoid side effects Aluminum carbonate gel Dogs and cats: mg/kg PO Can cause diarrhea, nausea, GI upset, q8h with meals constipation, and hypophosphatemia Aluminum hydroxide Dogs and cats: mg/kg PO Binds bile salts and phosphorus; q8 24h with meals inactivates pepsin; can cause constipation Magnesium hydroxide Dogs: 5 30 ml PO q8 24h; Can cause diarrhea; avoid cats: 5 10 ml PO q8 24h magnesium-based products in patients with renal failure Calcium carbonate Dogs: mg/kg divided daily Can cause metabolic alkalosis, q8 12h PO hypercalcemia, calciuria, hypophosphatemia, and constipation Misoprostol Dogs and cats: 2 5 µg/kg PO q6 8h Prevents NSAID-induced gastric ulcers Sucralfate Dogs <15 kg: 1 /2-g tablet q6 8h; Give on empty stomach; give 2 hr dogs >15 kg: 1-g tablet q6 8h; before or after other drugs (may bind cats: 1 /4 - to 1 /2-g tablet q8 12h with other medications if administered together) scopolamine [not recommended for use in cats], and isopropamide) do not cross the blood brain barrier; therefore, they act peripherally. Peripheral actions that prevent vomiting are due to inhibition of afferent vagal stimulation, relaxation of smooth muscle, and inhibition of GI secretions. Unfortunately, the limiting effect is that they promote delayed gastric emptying and decreased intestinal motility, causing GI overdistention, which may in itself cause vomiting. They also inhibit the actions of such drugs as metoclopramide, cisapride, and opioids that are dependent on cholinergic activity in ganglia or smooth muscle. Because this inhibition limits their usefulness, anticholinergics are not usually recommended. 1 Antihistamines Antihistamines are used to control vomiting caused by motion sickness or inner-ear disease, which is mediated by the vestibular apparatus. Cyclizine hydrochloride, meclizine hydrochloride, or diphenhydramine hydrochloride may control vomiting for several hours. 2 Side effects of antihistamines include drowsiness and dry mouth. GASTRIC ANTISECRETORY DRUGS Gastric antisecretory drugs are most commonly used to treat gastric inflammation and ulceration (Table 3). Gastric ulceration caused by drugs, toxins, trauma, immune-mediated disease, or neoplasia may be treated by reducing the acidity of gastric secretions. Esophagitis caused by foreign bodies, ingestion of caustic substances, gastric reflux during anesthesia, and chronic vomiting are also treated by reducing gastric acidity and reflux of gastric fluid. H 2 -Receptor Antagonists H 2 -receptor antagonists (H 2 blockers), which are relatively inexpensive, are the most widely available drugs that reduce hydrogen ion content of gastric secretions and the amount of pepsin induced by other secretory enzymes. In addition, these drugs, particularly the newer ones (e.g., ranitidine, nizatidine), may also promote gastric prokinetic activity due to anticholinesterase properties. The potency and duration of action of H 2 blockers are rated as follows: Famotidine > ranitidine > cimetidine 2 Gastric motility potency studied in guinea pig muscle is rated as follows: Nizatidine = ranitidine > cimetidine > famotidine 7 Cimetidine inhibits the cytochrome P450 microsomal enzyme system in the liver and thus impairs the metabolism of other drugs and should be avoided in animals with liver disease or when being used with other medications that are metabolized by the liver. Rebound hypersecretion of gastric acid is believed to be the cause for relapse of gastroduodenal ulcers in humans when H 2 blockers are discontinued. 8 Most H 2 blockers are available over the counter, making dispensing and refilling them easy. Proton Pump Inhibitors Proton pump inhibitors are substituted benzimida-

6 Compendium June 2002 Drug Therapy/GI Disease 457 Table 5. Protectants and Adsorbents Drug Dose Comment Kaolin pectin Dogs and cats: 1 2 ml PO q2 6h Used for nonspecific treatment of diarrhea Bismuth subsalicylate Dogs: ml/kg PO q4 6h; cats: Cats should not receive frequent or 0.25 ml/kg PO q4 6h high doses because of possible salicylate toxicity Activated charcoal Dogs and cats: 1 4 g/kg PO slurry, as Best if used within the first hour of needed (1 g/5 ml water); 6 10 ml/kg PO ingestion; slurry and suspension are suspension, as needed more absorptive than tablets Cholestyramine Dogs: mg/kg PO q12h, Can cause hypochloremic acidosis, as needed steatorrhea, decreased fat-soluble vitamin absorption, and hypoproteinemia zoles and a new class of antisecretory drugs. They are potent antagonists of the H + /K + ATPase proton pump, which is the final step to secretion of hydrogen ions at the apex of the parietal (oxyntic) cell. Omeprazole is the most commonly used proton pump inhibitor in veterinary medicine and is reported to be 30 times more potent than the H 2 blocker cimetidine. 9 Omeprazole is formulated as encapsulated entericcoated granules that are dissolved in the alkaline contents of the small intestine. The drug is absorbed into the systemic circulation and concentrated in the acidic environment of the parietal (oxyntic) cell, where it is converted to the inhibitor drug. There is a lag period of 3 to 5 days for the drug to accumulate in the parietal cell before maximum effects are seen. After this time, low serum concentrations will maintain the effect with once-daily dosing. Omeprazole is considered superior to H 2 blockers in the treatment of

7 458 Small Animal/Exotics Compendium June 2002 Table 6. Motility-Modifier Drugs Drug Dose Comment Metoclopramide Dogs and cats: mg/kg PO or SC q8h LES, stomach, and small intestinal effects Domperidone Dogs and cats: mg/kg IM or IV q12h LES, stomach, and small intestinal effects; or 2 5 mg/kg PO q12h not currently available in the United States Cisapride Dogs: mg/kg PO q8 12h; cats: LES, stomach, small intestinal, and colon mg PO q8 12h effects Diphenoxylate Dogs: mg/kg or mg PO q8h; Narcotic that contains atropine to hydrochloride cats: mg/kg PO q12h or mg prevent abuse; controlled substance; PO q8 12h used to treat diarrhea Loperamide hydrochloride Dogs: mg/kg PO q8 12h; cats: Available over the counter due to lack of mg/kg PO q12 24h or blood brain barrier transmission; used mg/kg PO q12h to treat diarrhea Erythromycin Dogs and cats: mg/kg PO q8h Give after meals; LES, stomach, and small intestinal effects Ranitidine Dogs and cats: mg/kg PO, IV, IM, or Stomach, small intestinal, and colon effects SC q8 12h Nizatidine Dogs: 5 mg/kg/day PO Stomach, small intestinal, and colon effects Misoprostol Dogs and cats: 2 5 µg/kg PO q6 8h Colon effects; may be effective in refractory constipation LES = lower esophageal sphincter. esophageal and gastric inflammation and ulceration. Although the high cost of omeprazole may limit its use, the shorter recovery period and more successful outcome in severe cases may justify the expense. Side effects in animals are not reported when omeprazole is used less than 8 weeks. 10 CYTOPROTECTIVE DRUGS AND ANTACIDS Cytoprotective drugs are commonly used in patients to decrease gastric acidity (Table 4). Antacids Antacids chemically neutralize hydrochloric acid in the gastric lumen, resulting in the generation of chlorides, water, and carbon dioxide. Some formulations (e.g., aluminum hydroxide) may also bind bile salts and inactivate pepsin. Some products induce local synthesis of the mucosal protectants, prostaglandins, and sulfhydryls. The duration of action of antacids is usually about 1 to 2 hours and is extended when food is present because of increased gastric ph. Administration of these drugs with food is required every 4 to 6 hours to prevent a gastric acid rebound effect, which occurs because the increased ph in the antral lumen stimulates increased serum gastrin levels. Aluminum, magnesium, and calcium salts can be used alone or in combination. In addition to antacid properties, aluminum salts absorb bile acids and pepsin and stimulate local prostaglandin production; however, they may cause constipation. Aluminum salts also bind phosphate, thereby reducing phosphate absorption. They are often used to manage patients with renal failure but can cause hypophosphatemia with prolonged use. Products containing magnesium are better at raising the gastric ph than are aluminum products. Unabsorbed magnesium salts, however, act as a laxative and can cause diarrhea. Therefore, a combination of aluminum and magnesium is the preferred antacid. Calcium carbonate is a potent and fast-acting antacid, but prolonged use may cause metabolic alkalosis, gastric-acid rebound, hypercalcemia, calciuria with metastatic calcification and urolithiasis, hypophosphatemia, and constipation. 11 Misoprostol Other drugs that have antisecretory properties are prostaglandin analogues, but they are not as effective as H 2 blockers in decreasing intraluminal gastric ph. Misoprostol, a prostaglandin E 1 analogue, is an antisecretory drug as well as a cytoprotectant. Hydrochloric acid production is decreased by interaction with a basolateral membrane receptor, which decreases cyclic adenosine monophosphate, thus decreasing protein kinase activity and hydrogen ion concentration. 12 Misoprostol increases mucus and bicarbonate secretion and enhances the epithelialization of the mucosa and

8 Compendium June 2002 Drug Therapy/GI Disease 459 mucosal blood flow. Its major effect is the ability to promote gastroduodenal ulcer healing. Preventive therapy or treatment of NSAID-induced gastroduodenal ulceration is the primary indication, but misoprostol may also be helpful in treating GI ulcers of other causes. Sucralfate Sucralfate is an orally administered disaccharide aluminum hydroxide product that binds to the submucosa of an ulcerated lesion in the stomach and duodenum and protects the submucosa from acid, bile salts, and pepsin activity. Binding also prevents exudation of protein and electrolytes and stimulates production of prostaglandins, sulfhydryl ions, and oxygen radical scavengers, which are natural gastric mucosal protectants. Potential binding and inhibition of other drugs may occur when given with sucralfate; therefore, sucralfate should be given on an empty stomach at least 2 hours before or after other medications. PROTECTANTS AND ADSORBENTS Protectants are nonabsorbable compounds that line the GI mucosa and prevent irritation and erosion by potentially harmful substances (Table 5). Although commonly used for vomiting, protectants such as kaolin, pectin, bismuth salts, demulcents, and antacids generally do not work and often increase vomiting by causing stomach distention and irritation. Adsorbents physically bind chemicals to prevent their absorption and promote elimination in the feces. Commonly used products contain both absorbent and protective properties. Indications for these products in small animal medicine are limited, and studies showing efficacy are lacking. Kaolin Pectin Kaolin pectin is a demulcent and adsorbent that is used for the nonspecific treatment of diarrhea. Although improvement may be seen in the consistency of stools, kaolin pectin has not been shown to reduce stool volume or shorten the course of the disease, and fluid and electrolyte loss remains unchanged. 13 Bismuth Salts Bismuth salts are demulcents and lesser adsorbents. When given to rabbits experimentally, bismuth subcarbonate and subsalicylate have been shown to inhibit Escherichia coli and Vibrio cholerae enterotoxins when administered before or immediately after enterotoxins. 14 They have benefit in preventing enterotoxin-induced

9 460 Small Animal/Exotics Compendium June 2002 Table 7. Antimicrobials Drug Dose Indication Comment Ampicillin/ Dogs and cats: mg/kg Gram-positive bacteria, Disrupts normal GI flora amoxicillin PO, IM, or IV q6 8h anaerobes Cephalexin Dogs and cats: 22 mg/kg PO Gram-positive bacteria, Disrupts normal GI flora; give q8 12h some gram-negative bacteria; with food if vomiting occurs mucosal injury, sepsis Metronidazole Dogs and cats: mg/kg Bacterial overgrowth, Neurotoxicity at higher PO q8 12h anaerobes, IBD, Clostridium, doses; use one third of dose Giardia if liver disease is present Erythromycin Dogs and cats: 10 mg/kg PO q8h Campylobacteriosis Can cause GI upset Enrofloxacin Dogs: mg/kg PO or IM Gram-positive bacteria, gram- Can cause cartilage q12h; cats: 2.5 mg/kg PO or IM negative bacteria, sepsis defects in puppies (if given q12h >5 mg/kg) and possible blindness in cats Sulfasalazine Dogs: mg/kg PO q8h; IBD, colitis Can cause keratoconjunccats: 20 mg/kg or 250 mg PO q8h tivitis sicca; use with caution (three times), then q24h in cats because of possible salicylate toxicity Tetracycline Dogs and cats: 20 mg/kg PO q8h Bacterial overgrowth, Can cause liver toxicity, hydrochloride rickettsial diarrhea, sepsis GI upset, discolored teeth (in puppies), drug fever (in cats) Gentamicin sulfate Dogs and cats: 2.2 mg/kg IM, Sepsis Can cause nephrotoxicity; IV, or SC q12h do not use in dehydrated patients or those with renal disease Tylosin Dogs and cats: or Bacterial overgrowth, IBD Sprinkle on food; broad dose mg/kg PO q12h; range with wide safety 5 10 mg/kg PO q8 12h; margin; each gram contains 1 /4 1 tsp with food q8 12h 100 mg tylosin Trimethoprim Dogs and cats: 15 mg/kg PO Mucosal injury, gram-negative Immune disease (in liver, sulfonamide or SC q12h bacteria, Salmonella, coccidia bone marrow) is a possible reaction diarrhea but are not effective once clinical illness is apparent. Bismuth subsalicylate has been shown to have antiprostaglandin synthetase effects that enhance the ability to control diarrhea caused by the subsalicylate component. This compound should be used cautiously in cats because the subsalicylate is absorbed systemically and toxicity is associated with use of this drug in cats. 1 Activated Charcoal Activated charcoal, which is a commonly used adsorbent to treat intoxications from ingestion of harmful drugs or substances, absorbs the toxin in the gut and decreases the amount of toxin entering the systemic circulation. If the drug or toxin is eliminated by the liver and reabsorbed in the intestine, activated charcoal can absorb the toxin and increase the rate of elimination from plasma and tissues. Timing of treatment is important for maximal efficacy, and delays of even 30 minutes can decrease absorption substantially. Activated charcoal is available in readymade liquid, powder, or tablet form; the liquid and powder forms are more absorptive than the tablets. Cholestyramine Cholestyramine is the chloride salt of a basic anion exchange resin and acts by forming ionic bonds with acidic side chains. 13 This drug is known for its bile acid binding capacity and is used for bile acid induced diarrhea following resection of the ileum. Cholestyramine can interfere with intestinal absorption of drugs (e.g., chlorothiazide, phenylbutazone, phenobarbital, anticoagulants, thyroxine, digitalis) and can be used to treat intoxication. Side effects include hypochloremic

10 Compendium June 2002 Drug Therapy/GI Disease 461 acidosis, steatorrhea, decrease in fat-soluble vitamins, and hypoproteinemia (of an unknown mechanism). MOTILITY MODIFIERS Prokinetic therapy is indicated when there is either a primary or secondary effect of GI stasis (Table 6). Motility problems are often secondary to inflammatory, infiltrative, postobstructive, and postoperative conditions. Primary motility problems are most commonly seen as congenital or acquired megaesophagus and megacolon. Aging animals may also be predisposed to less than adequate motility secondary to common GI ailments caused by degeneration of their GI neuromuscular system. Differences in anatomy and physiology between species must be recognized. For example, the distal one third of the esophageal muscle in cats consists of smooth muscle compared with dogs, which have skeletal muscle throughout the esophagus. Therapies to improve motility in these varied situations depend on treatment of any underlying cause of GI stasis and then supplementation with prokinetic drugs until the underlying problem is resolved. Other more permanent conditions may require continual use of these drugs. Prokinetic drugs are categorized into classes based on their mechanism of action. Dopamine Antagonists Metoclopramide and domperidone, which are dopamine antagonists, inhibit peripheral and central dopamine receptors. 15 As previously discussed, these drugs are effective antiemetics because of the central inhibition of dopamine. The peripheral inhibition of dopamine is still not fully understood. These drugs may actually have other properties, such as serotonin inhibition and agonism (5-HT 3 and 5-HT 4 receptors), α 2 - and β 2 -adrenergic receptor inhibition, and indirect cholinergic effects, which make them prokinetics. The major effects of these drugs are in the lower esophageal sphincter, stomach, and upper small intestine (i.e., duodenum, jejunum). Serotonin Agonists Cisapride, a serotonin agonist, acts on the 5-HT 4 and 5-HT 2a (smooth muscle) receptors and is antagonistic to the 5-HT 1 /5-HT 3 receptors. 16 Cisapride exerts its potent effects in the lower esophageal sphincter, stomach, small intestine, and colon. It is considered to be superior to metoclopramide in the treatment of gastroesophageal reflux, delayed gastric emptying, ileus, and constipation. However, cisapride is no longer produced because of its association with fatal arrhythmias

11 462 Small Animal/Exotics Compendium June 2002 in humans. 17,18 Veterinarians must, therefore, consider using other classes of motility drugs that are available. Motilinlike Drugs Motilinlike drugs simulate the activity of the gut hormone motilin to induce motility in the GI tract. Erythromycin, a macrolide antibiotic, is also a motilinlike drug. When given at lower than microbially effective doses, erythromycin acts on the GI tract to stimulate migrating motility complexes and causes antegrade peristalsis similar to the actions induced by the endogenous hormone motilin. Direct action is believed to be via cholinergic and noncholinergic mechanisms in dogs. 19,20 These effects are seen in the lower esophageal sphincter, stomach, and small intestine. This drug is not effective in the colon because it does not induce colonic propulsive motility. 21 Its prokinetic effect in the stomach has been compared with that of cisapride and metoclopramide, and it appears to induce greater antral contractions in amplitude and frequency than those induced by cisapride and metoclopramide. 22 Erythromycin stimulates the interdigestive contractions of the migrating myoelectrical complex in the stomach and small intestine that usually occur during the fasted state. Therefore, when given to patients that have been fed, erythromycin may cause premature emptying of gastric solids into the small intestine, resulting in inadequate digestion and absorption of larger pieces of food. This may cause increased intestinal distress, thereby limiting its use. Acetylcholinesterase Inhibitors Acetylcholinesterase inhibitors (i.e., parasympathetics) are usually overlooked as a first-line therapy for motility disorders and are more commonly used for their antisecretory properties. Ranitidine and nizatidine are H 2 -receptor antagonists but are also acetylcholinesterase inhibitors that increase the amount of acetylcholine available to bind smooth muscle at the muscarinic cholinergic receptors in the GI tract. 23 Prokinetic effects occur at the clinically recommended doses used for antisecretory activity. Both ranitidine and nizatidine are comparable to cisapride in stimulating gastric motor activity and increasing the rate of gastric emptying, making them the preferred antisecretory drugs for treating gastric ulcers. 23,24 Ranitidine and nizatidine have the strongest motility effect in the stomach but may also be effective in the small intestine and colon. They have both been shown to increase feline colonic smooth muscle contraction. 25 Opioids Diphenoxylate hydrochloride, a meperidine derivative, and loperamide hydrochloride, a butyramide derivative, are used for their ability to act directly on the GI wall to increase the segmental contraction of the small and large bowel. Although not considered prokinetic drugs, they can help control diarrhea in dogs and cats because diarrhea is most commonly caused by hypomotility of the bowel. Benzamides Future prokinetic drugs that may become available soon in the United States are the new benzamide drugs. Tegaserod is from this new class of 5-HT 4 receptor agonists and is being evaluated in human clinical trials for its ability to increase colonic transit in patients with irritable bowel syndrome. 26 Potent prokinetic effects on canine colonic motility have been reported. 27 Gastric and intestinal effects have not been studied. Prucalopride is a potent partial benzamide agonist

12 Compendium June 2002 Drug Therapy/GI Disease 463 Table 8. Immune-Modulating Drugs Drug Dose Comment Metronidazole Dogs and cats: cholangitis 7.5 mg/kg Neurotoxicity at high doses or with liver PO q12 24h; bacterial overgrowth mg/kg function impairment PO q12 24h; stomatitis 15 mg/kg PO q12 24h; Giardia, IBD mg/kg PO q12 24h Prednisone Dogs and cats: 1 2 mg/kg PO q12h; Can cause polyuria/polydipsia, polyphagia, cats with eosinophilic enteritis: 2 3 mg/kg PO q12h gastric ulcers, Cushing s syndrome Azathioprine Dogs: 50 mg/m 2 (1 1.5 mg/kg) PO q24h for Can cause bone marrow suppression; CBC 2 wk, then every other day for maintenance; monitoring required; lag period of weeks cats: mg/kg PO q48h for full effect Cyclophosphamide Dogs: 50 mg/m 2 PO four times per wk; cats: half Can cause bone marrow suppression; CBC of a 25-mg tablet PO four times per wk monitoring required; can cause vomiting/ diarrhea and hemorrhagic cystitis (dogs) Chlorambucil Dogs: mg/kg PO q48h; cats: Can cause bone marrow suppression mg/kg PO q48 72h Tylosin Dogs and cats: or mg/kg PO q12h; Broad dose range with wide safety margin; 1 /4 1 tsp with food q8 12h; 5 10 mg/kg PO each gram contains 100 mg tylosin; sprinkle q8 12h on food Sulfasalazine Dogs: mg/kg PO q8h; cats: 20 mg/kg Can cause keratoconjunctivitis sicca; use or 250 mg PO q8h (three times), then q24h with caution in cats because of possible salicylate toxicity Mesalamine Dogs: mg/kg PO q6 8h May decrease tear production in dogs Olsalazine Dogs and cats: mg/kg PO q12 24h Not reported to decrease tear production in dogs at the 5-HT 4 receptor and is reported to stimulate colonic activity in dogs and cats and stimulate gastric emptying in dogs. 28 Other new benzamide prokinetic drugs such as mosapride citrate, cinitapride, clebopride, and renzapride are currently being developed and may become available in the United States in the future. 4 Misoprostol Misoprostol may be used in dogs and cats with refractory constipation by initiating giant migrating complex pattern and increasing colonic propulsive activity as reported in dogs. 29 ANTIMICROBIALS Use of antimicrobials to treat nonspecific gastroenteritis can cause more harm than good by negatively influencing the normal GI microflora. Misuse of antibiotics in animals with gastroenteritis can lead to disruption of the normal bacterial flora. This can cause increased bacterial colonization of the bowel and overgrowth of antibiotic-resistant pathogenic strains of bacteria (e.g., Clostridium perfringens, Clostridium difficile), which in turn can result in severe and chronic inflammation of the bowel. 30 Helicobacter pylori colonization occurs with high prevalence in the gastric mucosa of healthy as well as sick dogs and cats. 31 Infection causing clinical illness is not proven and is being investigated; indications for treatment are also being investigated. 32 Proper use of antimicrobials for specific GI diseases includes adjunct treatment for secondary bacterial overgrowth caused by exocrine pancreatic insufficiency or inflammatory bowel disease (IBD; Table 7). Other indications for use are primary bacterial overgrowth of the proximal small intestinal bowel and diarrhea induced by Salmonella, Campylobacter, Clostridium, or enterotoxigenic E. coli, with evidence of these organisms on fecal culture, fecal cytology, or fecal enterotoxin assay. Bacterial adherence to villi on histopathologic examination of intestinal biopsies is another indication for antimicrobial treatment. Patients with bloody vomitus or bloody diarrhea or that have severe mucosal injury and mucosal barrier breakdown should also be placed on antimicrobial therapy. This includes patients with parvovirus, hemorrhagic gastroenteritis, salmon poisoning disease, and postchemotherapy complications. Translocation of normal bacterial flora from the intestinal lumen and into the bloodstream can lead to septicemia and death, particularly in immunosup-

13 464 Small Animal/Exotics Compendium June 2002 pressed patients. Choosing the proper antibiotic therapy should be based on the known sensitivity of the antibiotic to the normal bacterial flora of the GI tract or the specific bacterial pathogen, if known. Stomach microflora has a transient population of clostridia, streptococci, lactobacilli, E. coli, and spirochetes. 33 The proximal small intestinal bowel has low numbers of gram-positive bacteria, including streptococci and lactobacilli. Anaerobes and gram-negative bacteria are the predominate organisms in the distal small intestinal bowel and colon, with over 90% of anaerobic bacteria (i.e., Bacteroides, clostridia, lactobacilli) comprising the colonic environment. 33 Other considerations when choosing an antibiotic include using a bactericidal drug for severe hemorrhagic diarrhea or for immunosuppressed patients; using drugs that can be given by parenteral route in patients that are vomiting, septic, or unconscious; choosing an antibiotic based on culture and sensitivity results when available; and being aware of toxic side effects (e.g., nephrotoxicity of an aminoglycoside in dehydrated animals). IMMUNE-MODULATING DRUGS Inflammatory or immune-mediated diseases of the bowel are treated by immunosuppressive therapy. In dogs and cats, IBD is the most commonly diagnosed disease by endoscopic biopsy or surgical biopsy of the GI tract. Treatment is directed at reducing the inflammation and implementing a controlled diet (Table 8) Drugs that can effectively help decrease the inflammatory response in the GI tract are metronidazole, salicylates, prednisone, azathioprine, cyclophosphamide, chlorambucil, and potentially cyclosporine. 36 Tylosin, a macrolide-like antibiotic used for bacterial overgrowth, has also been reported to be effective in some patients with IBD, although the exact mechanism of action is unknown. 36 It is available in a powder and can be sprinkled on the animal s food. Metronidazole Metronidazole is an antibiotic with sensitivity to anaerobic bacteria, although it does not cause detrimental alteration of normal bacterial flora. It also has immunemodulating properties that suppress cell-mediated responses, is an antiprotozoal, and has positive effects on brush-border enzyme levels and the uptake of nutrients by the intestine (e.g., glucose, amino acids). 37 It is unknown which of its actions is responsible for its efficacy in treating IBD. Metronidazole can be effective in mild cases of IBD and provide good control. In moderate to severe cases, it can be used as a combination therapy with lower doses of prednisone. Salicylates Sulfasalazine, a salicylate, is used specifically for inflammation of the colon and is the treatment of choice for chronic colitis. This drug contains sulfapyridine and 5-aminosalicylate joined by an azo bond that is separated in the colon. The 5-aminosalicylate component, which acts as a local suppressor of inflammation, is an NSAID that inhibits cyclooxygenase and lipoxygenase activity inhibiting prostaglandin and leukotriene synthesis. In mild to moderate cases of colonic IBD, this drug can be beneficial when used alone. In more severe cases, this drug should be used in combination with metronidazole or prednisone. Side effects include anorexia, vomiting, diarrhea, and keratoconjunctivitis sicca (which can lead to corneal ulceration); in cats, anemia has been reported. Preparations of 5-aminosalicylate without the sulfapyridine component (mesalamine, olsalazine) may prevent keratoconjunctivitis sicca and are commonly used in human medicine for long-term treatment. 38 However, mesalamine may decrease tear production in dogs.

14 466 Small Animal/Exotics Compendium June 2002 Corticosteroids Prednisone is a corticosteroid that is a rapid and potent suppressor of the cell-mediated response and the humoral response. Corticosteroids are considered the treatment of choice in cases of moderate to severe IBD (lymphocytic plasmacytic) and are usually effective when metronidazole is not. Side effects include gastric, duodenal, or colonic ulceration and iatrogenic hyperadrenocorticism. Dexamethasone should be avoided because of its prolonged effects on the hypothalamic pituitary axis. Prednisone can be given daily and then tapered to alternate-day maintenance therapy when clinical signs resolve. Patients that have severe side effects on alternate-day therapy can be given an alternative therapy alone or in combination with lowered doses of prednisone. Budesonide, a corticosteroid that is given orally and has topical effects in the small and large bowel with minimal systemic absorption, has been used successfully in humans with ulcerative colitis. 39 It is currently being investigated for its use in dogs with IBD. Azathioprine, a suppressor of the antigeninduced lymphocyte transformation, is a commonly used alternative. Azathioprine can be given alone or in combination with lower doses of prednisone. It is usually given daily for 2 weeks and then tapered to every other day. Side effects include anorexia, vomiting, diarrhea, and bone marrow suppression. Mild bone marrow suppression is common and not of great concern. Although rare, severe suppression occurs more commonly in cats than in dogs and is most often seen early in the treatment protocol. 36 Pancreatitis and hepatotoxicity have also been reported. 36 Patient monitoring with routine complete blood cell count analysis is indicated. Chemotherapeutic Agents Patients with severe and refractory IBD may respond to cyclophosphamide. Cyclophosphamide is a chemotherapeutic agent that is a potent immunosuppressor. 36 Side effects include vomiting, diarrhea, sterile hemorrhagic cystitis (in dogs), and bone marrow suppression. It is given daily for 4 consecutive days and then discontinued for 3 days each week, making this drug easier than azathioprine to administer to cats. The patient must be monitored closely with routine complete blood cell count analyses. Chlorambucil is an oral chemotherapeutic drug with cytotoxic effects similar to those of cyclophosphamide (although not as potent) but may be helpful in some refractory cases of IBD. 36 Side effects of bone marrow suppression are minimal when using chlorambucil compared with cyclophosphamide, and GI signs are usually eliminated by alternate-day dosing. Cyclosporine, a T-cell suppressor drug available in oral preparation, has not been studied in dogs and cats with IBD but has been shown to be an effective treatment in humans with severe, unresponsive IBD. 36 Although it is very expensive, cyclosporine has been used to treat other immune-mediated diseases in dogs and cats and could be considered in severe cases. Side effects include vomiting, diarrhea, pancreatitis, and bone

15 Compendium June 2002 Drug Therapy/GI Disease 467 marrow suppression. It is paramount to monitor closely for these side effects, and the drug should be withdrawn if these effects occur. Measuring serum cyclosporine levels is recommended to achieve therapeutic levels and avoid toxicity. It is available in a micropulverized compound because of reportedly poor oral absorption. Bioavailability of oral doses varies with individual patients. REFERENCES 1. Boothe DM: Small Animal Clinical Pharmacology and Therapeutics. Philadelphia, WB Saunders Co, 2001, pp Boothe DM: Gastrointestinal pharmacology. Vet Clin North Am Small Anim Pract 2: , Burrows CF: Metoclopramide. JAVMA 183: , Dowling PM: Life after cisapride: Prokinetic drugs for small animals. Vet Med 95(9): , Sanwald-Ducray P, Dow J: Prediction of the pharmacokinetic parameters of reduced-dolasetron in man using in vitro in vivo and interspecies allometric scaling. Xenobiotica 27(2): , Ogilvie G: Dolasetron: A new option for nausea and vomiting. JAAHA 36: , Parkman HP, Pagaw AP, Ryan JP: Ranitidine and nizatidine stimulate antral smooth muscle contractility via excitatory cholinergic mechanisms. Dig Dis Sci 43: , El-Omar E, Banerjee S, Wirz A, et al: Marked rebound acid hypersecretion after treatment with ranitidine. Am J Gastroenterol 91: , Lampkin TA, Ouelleet D, Hak LJ, et al: Omeprazole: A novel antisecretory agent for the treatment of acid-peptic disorders. Ann Pharmacother 24: , Jenkins CC, Denovo RC: Omeprazole: A potent antiulcer drug. Compend Contin Educ Pract Vet 13(10): , Guilford WG, Strombeck DR: Chronic gastric disease, in Guilford WG, Center SA, Strombeck DR, et al (eds): Strombeck s Small Animal Gastroenterology, ed 3. Philadelphia, WB Saunders Co, 1996, pp Wolfe MM, Soll AH: The physiology of gastric acid secretion. N Engl J Med 319: , Wilke JR, Turner JC: The use of adsorbents to treat gastrointestinal problems in small animals. Semin Vet Med Surg Small Anim 2(4): , Ericsson CD, Evans DG, Dupont HL, et al: Bismuth subsalicylate inhibits activity of crude toxins of Escherichia coli and Vibrio cholerae. J Infect Dis 136: , Hall JA, Washabau RJ: Gastrointestinal prokinetic therapy: Dopaminergic antagonist drugs. Compend Contin Educ Pract Vet 19(2): , FitzSimons H: Pharm profile: Cisapride. Compend Contin Educ Pract Vet 21(4): , Dowling PM: Life after cisapride: Prokinetic drugs for small animals. Vet Med 95(9): , Tonini M, DePonti F, Di Nucci A, Crema F: Review article: Cardiac adverse effects of gastrointestinal prokinetics. Aliment Pharmacol Ther 13(12): , Peeters TL: Erythromycin and other macrolides as prokinetic agents. Gastroenterology 105: , Hall JA, Washabau RJ: Gastrointestinal prokinetic therapy: Motilinlike drugs. Compend Contin Educ Pract Vet 19(3): , Inatomi N, Satoh T, Satoh H, et al: Comparison of the motor-stimulating action of EM523, an erythromycin derivative and prostaglandin F2 (alpha) in conscious dogs. Jpn J Pharmacol 63: , Itoh Z, Nakaya M, Suzuki T, et al: Erythromycin mimics exogenous motilin in gastrointestinal contractile activity in the dog. Am J Physiol 247:G688 G694, 1984.

16 468 Small Animal/Exotics Compendium June Mizumoto A, Fujimura M, Iwanaga Y, et al: Anticholinesterase activity of histamine H 2 -receptor antagonists in the dog: Their possible role in gastric motor activity. J Gastrointest Motil 2(4): , Ueki S, Seiki M, Yoneta T, et al: Gastroprokinetic activity of nizatidine, a new H 2 -receptor antagonist and its possible mechanism of action in dogs and rats. J Pharmacol Exp Ther 264(1): , Washabau RJ, Pitts M, Hasler A, et al: Nizatidine and ranitidine stimulate feline colonic smooth muscle contraction (abstract). Proc ACVIM:739, Prather CM, Camilleri M, Zinsmeister AR, et al: Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 118: , Nguyan A, Camilleri M, Kort LJ: SD2HTF919 stimulates canine colonic motility and transit in vivo. J Pharmacol Exp Ther 280: , Briejer MR, Ghoos E, Eelen J, et al: Serotonin 5H mediates the R induced changes in contractile patterns in the canine colon. Gastroenterology 112:A705, Washabau RT: What s new in gastrointestinal prokinetic therapy? Proc 19 th ACVIM: , Jergens AE: Rational use of antimicrobials for gastrointestinal disease in small animals. JAAHA 30: , Yamasaki K, Suematsu H, Takahashi T: Comparison of gastric lesions in dogs and cats with and without gastric spiral organisms. JAVMA 212(4): , Simpson K, Neiger R, DeNovo R, Sherding R: The relationship of Helicobacter spp. infection to gastric disease in dogs and cats. J Vet Intern Med 14: , Strombeck D: Microflora of the gastrointestinal tract and its symbiotic relationship with the host, in Guilford WG, Center SA, Strombeck DR, et al (eds): Strombeck s Small Animal Gastroenterology, ed 3. Philadelphia, WB Saunders Co, 1996, pp Leib MS, Hiler LA, Roth L, et al: Plasmacytic-lymphocytic colitis in the dog. Semin Vet Med Surg 4: , Nelson RW, Stookey LJ, Kazacos E: Nutritional management of idiopathic chronic colitis in the dog. J Vet Intern Med 2: , Guilford WG: Idiopathic inflammatory bowel disease, in Guilford WG, Center SA, Strombeck DR, et al (eds): Strombeck s Small Animal Gastroenterology, ed 3. Philadelphia, WB Saunders Co, 1996, pp Sanyal SN, Jamba L, Channan M: Effect of the antiprotozoal agent metronidazole (Flagyl) on absorptive and digestive functions of the rat intestine. Ann Nutr Metab 36: , Brzezinski A, Rankin GB, Seidner DL, et al: Use of old and new oral 5- aminosalycylic acid formulations in inflammatory bowel disease. Cleve Clin J Med 62(5): , Filip B, Schmit A, D Haens G, et al: Budesonide in collagenous colitis: A double-blind placebo-controlled trial with histologic follow-up. Gastroenterology 122:20 25, ARTICLE #2 CE TEST The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from the Auburn University College of Veterinary Medicine. Choose the best answer to each of the following questions; then mark your answers on the postage-paid envelope inserted in Compendium. 1. Which of the following emetics acts on α 2 receptors and is considered the emetic of choice in cats? a. apomorphine d. warm water b. xylazine e. saline c. hydrogen peroxide