The major ways in which the stomach is protected against acid injury include the physical and biochemical characteristics of gastric mucus, the tight epithelial cell junctions, prostaglandin production, bicarbonate secretion and rapid turnover of cells. Mucus is produced by surface mucosal cells in the gastric glands containing oxyntic and chief cells, which in turn secrete hydrochloric acid and pepsinogen, respectively. The surface mucosal cells also secrete bicarbonate, which is dependent on the blood flow to the mucosa, as well as serum bicarbonate concentrations and the acid productivity of oxyntic cells. Prostaglandins are responsible for stimulating the bicarbonate secretion from mucosal cells. The bicarbonate-rich mucus layer neutralizes hydrogen ions and leads to the formation of carbonic acid, which is then converted by carbonic anhydrase to form carbon dioxide and water for excretion.

If there is failure of the bicarbonate-mucus layer, intracellular bicarbonate protects the epithelial cells against acid back-diffusion. Proton pump exchanges on the basolateral epithelial membrane also protect against increasing intracellular acid. The epithelial cells are rapidly renewed, with surface mucous cells migrating from the wall of the crypts to the tips in as little as three days. When the stomach is exposed to acidic stimulants, there is localized hyperemia caused by increased mucosal blood flow. This in turn increases the bicarbonate-rich mucus secretion locally and protects against further damage.

Pathophysiologically, the most commonly implicated causes in veterinary medicine are decreased mucosal blood flow, abolition of surface prostaglandins, over-whelming gastric acid secretion or loss of the tight junctions due to inflammatory or neoplastic change.

Drugs used for gastric protection are classified according to their mechanism of action as non-systemic antacids, prostaglandin analogue(s), diffusion barriers, histamine-receptor (type 2) antagonists and proton-pump inhibitors (PPI). Anecdotally, the use of PPIs in veterinary practice has increased dramatically in the past decade and appears to have increased in popularity above that of histamine receptor antagonists.

Antacids are available as over the counter products, usually marketed to treat gastric reflux. The use of antacids leads to rebound gastric hypersecretion and they have no place in veterinary medicine. Misoprostol is a prostaglandin analogue, and as such should be used very carefully due to its potential to cause abortion. The only support beneficial use of misoprostol is prophylactically in dogs prior to high-dose aspirin administration.

The most well-known diffusion barrier is sucralfate, which is a complex of sucrose octasulfate and aluminium hydroxide that in the presence of acid dissociates into these two components. Sucrose octasulfate will polymerise into a sticky, viscous, yellow-white gel that is strongly anionic and electrostatically binds to cationic tissue proteins of ulcerated mucosa. The ulcerated site covered by this gel is then protected from backwards diffusion of hydrogen ions. Sucralfate also has additional cytoprotective roles that may involve mucosal synthesis of protective prostaglandins, secretion of mucus and bicarbonate, and increases in epidermal growth factor. It has little effect on stomach acidity. Although frequently cited as useful in the treatment of gastroesophageal reflux and esophagitis, there is no compelling evidence to support its use in veterinary practice. Additionally, the tablet formulation may not dissolve sufficiently to be useful in dogs, so if available the liquid formulation is preferable.

H2-receptor antagonists competitively inhibit H2-receptors in the gastric parietal cells and cause approximately 70–90% reduction in gastric acid production and a corresponding decline in pepsin production. H2 antagonists have significant popularity in human medicine, and in many countries are sold over the counter. Despite differences in the degree of gastric acid inhibition between the different drugs of this group, no studies have shown one to be superior to the other in a clinical setting. There is no advantage to giving these drugs in place of PPIs in truly indicated cases, and there is no indication that concurrent administration with PPIs will improve therapeutic outcomes.

As PPIs are the most effective group of drugs (and most widely used) to treat gastric ulceration, it is important to understand their mechanisms of actions and potential side effects. Proton pump inhibitors covalently bond to and irreversibly inhibit the proton pump (H+-K+-ATPase) that exists on the luminal surface of the parietal cell. New proton pumps are continuously formed, so the pharmacological effect is not permanent. All afferent pathways that culminate in the basal or stimulated secretion of hydrogen ions from the parietal cell (gastrin, histamine and acetylcholine) are inhibited. The two drugs from this class most commonly utilised in small animal medicine are omeprazole and pantoprazole.

These drugs should be given on an empty stomach as the presence of ingesta will decrease oral bioavailability. Studies have shown that twice daily dosing is most effective, and tablets should not be split or crushed. Long-term use of proton pump inhibitors (>8 weeks) may lead to increased levels of gastrin from the inhibition of negative feedback pathways, although this has not been documented to date in dogs or cats. Likewise, there is concern that rebound gastric hypersecretion can occur if the drug is used long-term (more than 3–4 weeks) and suddenly stopped. Therefore, current recommendations are to taper the dosage by 25–50% per week.

One of the major concerns of the use of PPI in people is the associated dysbiosis that may occur. In the intensive hospital setting, this has major implications in terms of nosocomial infection and ventilator-associated pneumonia. Some authors also associate the increase in Clostridia difficile associated diarrhea with the increased use of PPIs. Although not studied extensively in dogs, one study has shown an increase in total duodenal bacterial counts and quantitative changes in healthy dogs given omeprazole for two weeks. This raises concerns about long-term effects of PPIs in dogs and cats, particularly if administered when not clinically indicated.

In 2018, a consensus statement about the use of gastric protective agents was published by the American College of Veterinary Internal Medicine. In this review, the authors felt the evidence for the use of PPIs in dogs and cats overall was poor, and much less compelling than the human guidelines. However, the indications for PPIs does closely mirror that of the human situation, and can be summarized as below:

Indications for use of PPIs:

• Gastroduodenal ulceration and erosion, regardless of cause

Uncertain whether indication for use of PPIs at this stage:

• Stress-related mucosal disease (potentially beneficial in sled dogs)
• Reflux esophagitis

No indication for use of PPIs:

• Gastritis without erosion/ulceration
• Hepatic disease without erosion/ulceration
• Renal disease (IRIS stage 1–3)
• Pancreatitis, without gastric erosion/ulceration
• Non-Helicobacter pylori Helicobacter
• Thrombocytopenia-induced bleeding
• Spinal cord injury (intervertebral disc disease)
• Anorexia, vomiting, diarrhea

As can be seen, the clinical situations when PPIs are truly indicated are few and should be reserved for when there is documented or strongly suspected gastroduodenal ulceration. This will be in cases of iron deficiency anemia, melena or hematemesis (when there is no cause of coagulopathy). The need to be cautious with PPI usage is strengthened by the fact that the GI microbiome is altered when used. In addition, as gastric acid production is almost abolished, drugs that require an acidic environment to be active should not be administered concurrently.

References

1.  Marks SL, Kook PH, Papich M, et al. ACVIM consensus statement: support for rational administration of gastrointestinal protectants to dogs and cats. J Vet Intern Med. 2018;32:1823–1840.

2.  Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol. 2012;5:219–232.

3.  Garcia-Mazcorro JF, Suchodolski JS, Jones KR, et al. Effect of the proton pump inhibitor omeprazole on the gastrointestinal bacterial microbiota of healthy dogs. FEMS Microbiol Ecol. 2012;80:624–636.

4.  Mansfield C, Hyndman T. Section V. Chapter 46 - gastric cytoprotective agents. In: Washabau R, ed. Textbook of Veterinary Gastroenterology. 1st edition. Philadelphia, PA: Elsevier; 2012.