Therapy of Gastrointestinal Ulcers - The Merck Veterinary Manual

Therapy of Gastrointestinal Ulcers

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 also Gastrointestinal Ulcers in Small Animals and Gastrointestinal Ulcers in Large Animals: Introduction). Helicobacter organisms, incriminated as the most frequent cause of ulcers in humans, appear to be involved in some cases of gastritis in animals (see Helicobacter Infection). Antiulcerative drugs are listed in Table: Antiulcerative Drugs.

Antacids:

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 aluminium 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 in small animals, they are not as popular as newer therapies.

Histamine (H₂)-receptor Antagonists:

Acid secretion by the parietal cells of the stomach is controlled by stimulation of 3 receptors: gastrin, muscarinic (cholinergic), and histamine (H₂). Normal acid secretion is from an interrelationship of all 3 receptors, but inhibition of a single receptor can effectively inhibit all acid secretion. H₂-receptor antagonists effectively block gastric acid secretion from parietal cells by blocking the H₂ receptor.

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, so it may be administered less frequently. Famotidine can be administered once daily. Oral bioavailability in horses for these drugs is only 10-30%, so large oral doses must be administered.

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 side effects. Dosage regimens are extrapolated from human dosages.

Omeprazole is a proton-pump inhibitor. It inhibits the sodium/potassium proton pump at the luminal surface of the parietal cell that secretes hydrogen ions into the gastric lumen. In dogs, a single dose inhibits acid secretion for 3-4 days, despite a relatively short plasma half-life. Omeprazole also reduces gastric acid production and allows healing of gastric ulcers in horses. A specific horse product has been developed, as oral bioavailability of the human omeprazole formulation is poor in horses. Its use in cats has not been reported. In humans, 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. Therefore, omeprazole is contraindicated for chronic therapy. Omeprazole is also a microsomal enzyme inhibitor (to a similar extent as cimetidine).

Misoprostol is a synthetic prostaglandin E₁ analog 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 is less efficacious than H₂-blockers for treatment of ulcers. Side 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.