GI ulceration is a common problem in small and large animals, in association with physiologic stress (endogenous cortisol), dietary management, or as a sequela of administration of ulcerogenic drugs (see Gastrointestinal Ulcers in Small Animals Gastrointestinal Ulcers in Small Animals Disruption and ulceration of the GI mucosal barrier can be a consequence of several drugs and diseases in small animals. The stomach and/or the duodenum are the primary sites of ulceration.... read more and see Gastrointestinal Ulcers in Large Animals Gastrointestinal Ulcers in Large Animals read more ). Helicobacter organisms, the most frequent cause of ulcers in people, appear to be involved in some cases of gastritis in animals (see Helicobacter Infection in Small Animals Helicobacter Infection in Small Animals Helicobacter spp are commonly isolated from the stomachs of dogs and cats, but their pathogenicity in pets is not clearly established. Diagnosis requires cytologic or histologic examination... read more ). Antiulcerative drugs include antagonists that interact with stimulatory receptors (histamine H2-receptor antagonists, muscarinic receptor antagonists, and gastrin receptor antagonists), agonists that interact with inhibitory receptors (somatostatin and prostaglandin E analogues), and irreversible inhibitors of H+/K+-ATPase (proton pump inhibitors). Antiulcerative drugs are listed in Antiulcerative Drugs Antiulcerative Drugs GI ulceration is a common problem in small and large animals, in association with physiologic stress (endogenous cortisol), dietary management, or as a sequela of administration of ulcerogenic... read more .
The common antacids are bases of aluminum, magnesium, or calcium (aluminum hydroxide, magnesium oxide or 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 (PGE1) 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 administration PO and can cause 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 absorption of phosphate. Because they are difficult to administer and require frequent dosing, they are not as popular as newer therapies.
Sucralfate is an antiulcerative drug that has a cytoprotective effect on GI mucosa. It disassociates in the acid 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 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 causes virtually no adverse effects. Dosage regimens are extrapolated from human dosages. Although sucralfate is frequently administered to horses and small animals as an ulcer preventive, there is little evidence of efficacy in animals, and it may prevent the absorption of truly useful drugs. Animals in renal failure may have increased aluminum absorption.
Cimetidine, ranitidine, and famotidine are the commonly used H2-receptor antagonists. Ranitidine is 3–13 times as potent on a molar basis as cimetidine in inhibiting gastric acid secretion. Famotidine is 20–150 times as potent as cimetidine. In people, food tends to delay the absorption of cimetidine, has minimal effect on ranitidine, and slightly enhances absorption of famotidine. Some evidence suggests that cimetidine strengthens the gastric mucosal defenses against ulceration and enhances cytoprotection. Cimetidine reduces the metabolism of other drugs (warfarin, phenytoin, lidocaine, metronidazole, theophylline) by inhibiting hepatic microsomal enzyme systems. Ranitidine interacts differently than cimetidine and only minimally (10%) inhibits hepatic metabolism of some drugs. Famotidine seems to have no effect on metabolism of other drugs. Antacids should be given 1 hr before or after cimetidine to avoid interactions. Famotidine may be given with antacids; ranitidine may be given with low doses of antacids. Sucralfate may alter absorption of cimetidine and ranitidine.
Cimetidine suppresses gastric acid secretion in dogs for 3–5 hr. Because ranitidine has a longer elimination half-life, it suppresses acid for up to 8 hr and it may be administered less frequently. Famotidine can be administered once a day. Oral bioavailability in horses for these drugs is only 10%–30%, so large oral doses must be administered.
Proton pump inhibitors (PPIs) irreversibly block the H+/K+-ATPase proton pump of the gastric parietal cell. They are given in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like 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 PPI is omeprazole. In dogs and horses, a single dose of omeprazole inhibits acid secretion for 3–4 days, despite a relatively short plasma half-life. This is because of accumulation of the drug in parietal cell canaliculi and the irreversible nature of proton pump inhibition. A specific equine product has been developed, because oral bioavailability of the human omeprazole formulation or compounded formulations is poor in horses. Although ulcers in horses will heal while on omeprazole therapy, they tend to recur once therapy is discontinued. Human formulations are used in dogs and cats. In people, adverse effects from suppression of gastric acid secretion include hypergastrinemia, which causes mucosal cell hyperplasia, hypertrophy of the gastric rugae, and eventually development of carcinoids. It has also been associated with acute renal failure and disorders of calcium homeostasis, including fractures associated with longterm use. Studies in rodents show that PPIs can exacerbate NSAID-induced intestinal damage from significant shifts in enteric microbial populations. Prevention or reversal of this dysbiosis may be an important clinical consideration for reducing the incidence and severity of NSAID enteropathy. Therefore, omeprazole is contraindicated for chronic therapy. Omeprazole is also a microsomal enzyme inhibitor (to a similar extent as cimetidine). For animals that cannot receive oral medications, IV injectable formulations approved for people (pantoprazole and esomeprazole) can be considered for use.
Acid rebound is an increase in gastric acid secretion above pretreatment levels after discontinuation of antiulcer therapy. Rebound is reported after the use of histamine H2-receptor antagonists and PPIs and is thought to be due to increased serum gastrin and/or upregulation of the H2-receptors. An increased gastrin level, or hypergastrinemia, is a secondary effect that occurs during chronic inhibition of gastric acid secretion, such as with longterm antiulcer therapy. Gastrin is the primary regulator of gastric acid secretion, which is mediated by histamine released by the enterochromaffin-like (ECL) cell. Increased plasma gastrin stimulates and upregulates ECL cells to produce and release more histamine to stimulate parietal cells. In addition, an increase in parietal cell mass may occur with the chronic use of H2-blockers or PPIs, and this may be an additional mechanism for increased acid secretion that occurs after discontinuation of therapy.
Misoprostol is a synthetic prostaglandin E1 analogue used in dogs to reduce the risk of GI ulcers induced by chronic NSAID therapy. 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 cellular proliferation and migration. Misoprostol is clinically effective in preventing GI bleeding and ulceration from NSAID therapy but not from methylprednisolone sodium succinate, and it is less efficacious than H2-receptor antagonists or PPIs for treatment of ulcers. Adverse effects of misoprostol are mainly limited to diarrhea and flatulence. Magnesium-containing antacids may aggravate the diarrhea. Misoprostol is contraindicated in pregnant dogs, because it can induce abortion.