Gastroduodenal ulceration and erosion (GUE) is a common problem in small and large animals, in association with physiologic stress (endogenous cortisol) or dietary management, or as a sequela of the administration of ulcerogenic drugs (see Gastrointestinal Ulcers in Small Animals and Gastrointestinal Ulcers in Large Animals).
In horses, GUE has been subdivided into equine gastric ulcer syndrome (EGUS)—a general all-encompassing term to describe erosive and ulcerative diseases of the stomach—as well as equine squamous gastric disease (ESGD) and equine glandular gastric disease (EGGD), which more specifically describe the affected region anatomically.
EGSD is associated primarily with management practices in the equine industry.
EGGD is believed to result from a breakdown of the normal defense mechanisms that protect the mucosa from acidic gastric contents and is associated with, for example, the administration of NSAIDs.
Antiulcerative drugs include antagonists that interact with stimulatory receptors (H2 receptor antagonists, muscarinic receptor antagonists, and gastrinergic receptor antagonists), agonists that interact with inhibitory receptors (somatostatin and prostaglandin E analogues), and irreversible inhibitors of H+,K+-ATPases (proton pump inhibitors). For a list of these drugs, see the table Antiulcerative Drugs.
Antiulcerative Drugs
Drug | Dosage |
|---|---|
Sucralfate | Cats: 250–500 mg, PO, q 8–12 h |
Dogs: 500–1000 mg, PO, q 6–8 h | |
Foals: 1–2 g, PO, q 6 h | |
Cimetidine | Dogs: 5–10 mg/kg, PO, q 6 h |
Horses: 4 mg/kg, IV, q 12 h; 18 mg/kg, PO, q 12 h | |
Ranitidine | Dogs: 0.5 mg/kg, PO, SC, or IV, q 12 h |
Horses: 1.3 mg/kg, IV, q 12 h; 11 mg/kg, PO, q 12 h | |
Famotidine | Dogs: 0.5–1 mg/kg, PO or IV, q 24 h |
Horses: 0.4 mg/kg, IV, q 12 h; 3 mg/kg, PO, q 12 h | |
Omeprazole | Dogs: 0.5–1 mg/kg, PO, q 24 h; loading dose of 1 mg/kg IV followed by 8 mg/kg/d as a constant-rate infusion (CRI) |
Horses: 4 mg/kg, PO, q 24 h for treatment; 2 mg/kg, PO, q 24 h to prevent recurrence; 1.0 mg/kg, IV, q 24 h as a loading dose, followed by 0.5 mg/kg, IV, q 24 h | |
Esomeprazole | Horses: 0.5 mg/kg, IV, q 24 h Dogs: 1 mg/kg, IV, q 24 h; 0.5–1.5 mg/kg, PO, q 24 h Cats: 1 mg/kg, IV, q 24 h; 0.5–1.5 mg/kg, PO, q 24 h |
Pantoprazole | Foals: 1.5 mg/kg, IV, q 24 h Dogs: 0.7–1 mg/kg, IV or PO, q 12–24 h Cats: 0.7–1 mg/kg, IV or PO, q 12–24 h |
Misoprostol | Dogs: 2–5 mcg/kg, PO, q 6–8 h |
Antacids Used to Treat Gastrointestinal Ulcers in Monogastric Animals
The common antacids are bases of aluminum, magnesium, or calcium (aluminum hydroxide, magnesium oxide or magnesium hydroxide, and calcium carbonate). These drugs neutralize stomach acid to form water and a neutral salt. They are usually not absorbed systemically. In addition to their acid-neutralizing ability, antacids decrease pepsin activity, binding to bile acids in the stomach and stimulating local prostaglandin (prostaglandin E1) production.
Over-the-counter antacid preparations are combinations of magnesium hydroxide and aluminum hydroxide; such combinations optimize the buffering capabilities of each compound and balance the constipating effect (from aluminum hydroxide) and the laxative effect (from magnesium hydroxide). Up to 20% of the magnesium can be absorbed after oral administration and can produce hypermagnesemia in animals with renal insufficiency.
Antacids frequently interfere with the GI absorption of concurrently administered drugs (eg, digoxin, tetracyclines, fluoroquinolones). Aluminum-containing antacids impair the absorption of phosphate. Because they are difficult to administer and require frequent dosing, they are not as popular as newer treatments.
Sucralfate as a Treatment for Gastrointestinal Ulcers in Monogastric Animals
Sucralfate is an antiulcerative drug that has a cytoprotective effect on GI mucosa. It dissociates in the acidic environment of the stomach to sucrose octasulfate and aluminum hydroxide. Sucrose octasulfate polymerizes to a viscous, sticky substance that creates a protective effect by binding to ulcerated mucosa. This binding prevents back-diffusion of hydrogen ions, inactivates pepsin, and adsorbs bile acid. In addition, sucralfate increases the mucosal synthesis of prostaglandins, which have a cytoprotective role. Because sucralfate is not absorbed, it has virtually no adverse effects. Dosage regimens are extrapolated from human dosages.
Although sucralfate is frequently administered to horses and small animals as a preventive or treatment for GUE, there is little evidence of its efficacy in animals, and it may alter the absorption of fluoroquinolones and tetracyclines. Sucralfate is inferior to proton pump inhibitors (PPIs) in the treatment of GUE. There is no clinical evidence of benefit from concurrent administration of sucralfate and H2 receptor antagonists or PPIs. Animals in renal failure may have increased aluminum absorption.
Histaminergic Receptor Antagonists Used to Treat Gastrointestinal Ulcers in Monogastric Animals
Histaminergic receptor-2 [H receptor] antagonists inhibit acid secretion by competitively blocking H2 receptors on parietal cells. Cimetidine, ranitidine, and famotidine are the commonly used H2 receptor antagonists.
Ranitidine is 3–13 times as potent as cimetidine (on a molar basis) in inhibiting gastric acid secretion. Famotidine is 20–150 times as potent as cimetidine. In humans, food tends to delay the absorption of cimetidine, has a minimal effect on ranitidine, and slightly enhances the absorption of famotidine. Some evidence suggests that cimetidine strengthens the gastric mucosal defenses against ulceration and enhances cytoprotection.
Cimetidine decreases the metabolism of other drugs (warfarin, phenytoin, lidocaine, metronidazole, theophylline) by inhibiting hepatic microsomal enzyme systems.
Unlike cimetidine, ranitidine only minimally (10%) inhibits the hepatic metabolism of some drugs. Famotidine seems to have no effect on the metabolism of other drugs. Antacids should be administered 1 hour before or after cimetidine to avoid interactions. Famotidine may be administered with antacids; ranitidine may be administered with low doses of antacids. Sucralfate may alter the absorption of cimetidine and ranitidine.
In horses, oral bioavailability for H2 receptor antagonists is only 10%–30%, so large oral doses must be administered. Cimetidine suppresses gastric acid secretion in dogs for 3–5 hours. Because ranitidine has a longer elimination half-life, it suppresses acid for up to 8 hours, and it may be administered less frequently.
Chronic H2 receptor antagonist administration results in pharmacological tolerance that is likely due to gastrin-induced upregulation of the synthesis of histamine, which then competes with the H2 receptor antagonist at the level of parietal cells. Abrupt discontinuation can lead to rebound gastric acid hypersecretion. Therefore, patients should be gradually weaned from longterm treatment.
Clinical evidence suggests that H2 receptor antagonists are inferior to PPIs in the treatment of GUE.
Proton Pump Inhibitors Used to Treat Gastrointestinal Ulcers in Monogastric Animals
Proton pump inhibitors (PPIs) irreversibly block the H+,K+-ATPase proton pump of the gastric parietal cell. They are administered in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (such as the parietal cell canaliculus) that have acidic environments. The inactive drug is protonated, rearranges into its active form, and irreversibly binds to and deactivates the proton pump.
The most widely used oral PPI is omeprazole. In dogs and horses, a single dose of omeprazole inhibits acid secretion for 3–4 days, despite a relatively short plasma elimination half-life. The reason the effect lasts a few days is that the drug accumulates in the parietal cell canaliculi and proton pump inhibition is irreversible.
A specific equine product has been developed because oral bioavailability of the human omeprazole formulation or compounded formulations is poor in horses. Equine studies show significant differences between the healing response of ESGD and EGGD after omeprazole treatment, supporting the conclusion that gastric acid is important in the development of ESGD but plays a lesser role in the development of EGGD. Although ESGD ulcers in horses do heal while omeprazole is being administered, the ulcers tend to recur after treatment is discontinued. Because the equine-approved formulation of omeprazole is only an oral formulation, IV formulations of human-approved PPIs (omeprazole, esomeprazole, pantoprazole) have been used in adult horses and foals when oral administration is not suitable.
Human formulations are used in dogs and cats.
In humans, adverse effects from the suppression of gastric acid secretion include hypergastrinemia, which leads to mucosal cell hyperplasia, hypertrophy of the gastric rugae, and eventually development of carcinoids. Use of PPIs has also been associated with acute renal failure and disorders of calcium homeostasis, including fractures associated with longterm use of PPIs. Studies in rodents show that PPIs can exacerbate NSAID-induced intestinal damage from marked shifts in enteric microbial populations. Prevention or reversal of this dysbiosis may be an important clinical consideration for decreasing the incidence and severity of NSAID enteropathy. Therefore, omeprazole is contraindicated for longterm treatment.
Omeprazole is also a microsomal enzyme inhibitor (to an extent similar to that of cimetidine).
For patients that cannot receive oral medications, IV formulations approved for humans (pantoprazole and esomeprazole) can be considered.
Rebound Gastric Acid Hypersecretion in Monogastric Animals
Rebound gastric acid hypersecretion is an increase in gastric acid secretion above pretreatment concentrations after discontinuation of antiulcer treatment. Rebound gastric acid hypersecretion is reported after the use of H2 receptor antagonists and PPIs and is thought to be due to increased serum gastrin or upregulation of the H2 receptors. An increased gastrin concentration, or hypergastrinemia, is a secondary effect that occurs during chronic inhibition of gastric acid secretion, such as with longterm gastrointestinal ulcer treatment. Gastrin is the primary regulator of gastric acid secretion, which is mediated by histamine released by enterochromaffin-like cells. Increased plasma gastrin stimulates and upregulates enterochromaffin-like cells to produce and release more histamine to stimulate parietal cells. In addition, with the chronic use of H2 receptor antagonists or PPIs, which may be an additional mechanism for increased acid secretion after treatment is discontinued. Therefore, following prolonged use (> 3–4 weeks), administration should be tapered off.
Misoprostol as a Treatment for Gastrointestinal Ulcers in Monogastric Animals
Misoprostol is a synthetic prostaglandin E1 analogue used in dogs to decrease the risk of GI ulcers induced by longterm treatment with NSAIDs. Misoprostol suppresses gastric acid secretion by inhibiting the activation of histamine-sensitive adenylate cyclase. It has a cytoprotective effect from stimulation of bicarbonate and mucus secretion, increased mucosal blood flow, decreased vascular permeability, and increased cell proliferation and migration.
Misoprostol is clinically effective in preventing GI bleeding and ulceration from NSAID treatment in small animals but not from treatment with methylprednisolone sodium succinate, and it is overall less efficacious than are H2 receptor antagonists or PPIs for the treatment of GUE. Some evidence supports the efficacy of misoprostol in the treatment of horses with EGGD.
Adverse effects of misoprostol are limited mainly to diarrhea and flatulence. It is an abortifacient, and clients should be warned to handle the drug with caution.
