Veterinary Voice, August 2016 – GI Ulceration

Ben Nolan, DVM, PhD, DACVIM
 

Gastric acid secretion is an essential part of normal gastrointestinal function, but also can play a role in several different disease processes. Of particular concern is the development of gastroduodenal ulcers (Figure 1) and gastroesophageal reflux (Figure 2). The pathophysiology of these conditions can be complex, but in most cases the primary cause is an imbalance between gastric acid secretion and the innate defenses to counter the deleterious effects of acid. Gastric acid is in the form of HCl, which is produced by the parietal cells of the oxyntic (gastric) glands in the gastric fundus and body. Acid is released into the gastric lumen through the H+K+ATPase pumps located on the canalicular membrane of these cells. Secretion of HCl is stimulated by endocrine and neural signals, including gastrin, acetylcholine, and histamine (Figure 3). All three of these substances directly stimulate the parietal cell to release HCl, but gastrin has an additional action by stimulating enterochromaffin-like (ECL) cells to release histamine. ECL cells also reside in the oxyntic glands adjacent to parietal cells, and the release of histamine results in the secretion of additional HCl.
 
As with every other aspect of veterinary medicine, our knowledge regarding gastric ulceration and its treatment continues to evolve. While it is known that effective acid suppression is essential for the healing of gastric ulcers and is beneficial for esophagitis due to acid reflux, much less is known regarding the role of acid suppression in other diseases. Antacids have been recommended for a variety of conditions such as renal disease, hepatic disease, gastrointestinal disease, and pancreatitis. However, good evidence to support the use of these medications in any of these diseases is severely lacking. Prescribing antacids for gastrointestinal disease such as gastritis likely originated as an extrapolation from human medicine, in which gastritis and ulceration often result from infection with Helicobacter. Antacids in conjunction with antibiotics have been shown to be an effective therapy for this condition in people, but Helicobacter infection in dogs and cats is rare and not a common cause of gastritis. For other causes of gastritis, no study has demonstrated a benefit from antacid therapy. Similarly, there is a lack of evidence to justify the use of antacids in pancreatitis, renal disease, and hepatic disease unless ulcers are present. Despite this, antacids are still commonly prescribed for all of these diseases based on pathophysiologic reasoning. Some may argue that although there is no hard evidence supporting their use, this is the case for many therapies in veterinary medicine, and the use of antacids can be justified based on consideration of how disease morbidities may contribute to ulcer formation. This is a reasonable argument, but additional studies are needed to determine if there is truly a benefit or not. Also, if one does elect to use antacids, potential adverse effects must be taken into account. While the short-term use of these medications is generally safe, when used chronically in people side effects have included vitamin B12 deficiency, diarrhea, enteric infections (C. difficile), increased risk of hospital-acquired pneumonia, and potentially an increased risk of fractures. There is very limited data on the long-term use of antacids in cats and dogs, but one study showed that after 60 days of omeprazole therapy, 4/6 cats had an 8% or greater loss of bone mineral density. As with any medication, the potential benefit of an antacid must be weighed against the potential risk before initiating therapy.
 
As our knowledge regarding the appropriate use of antacids evolves, so is the way we are administering these medications. The two classes of antacids are H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). H2RAs inhibit gastric acid secretion by competitive antagonism of histamine H2 receptors on parietal cells. PPIs act by irreversibly binding H+K+ATPase pumps on the canalicular membrane of parietal cells. The H+K+ATPase pump is the last step in acid secretion for all pathways, making PPIs more effective for acid suppression compared to H2RAs. In human medicine the current recommendations for successful therapy of gastroduodenal ulceration and gastroesophageal reflux are to maintain an intragastric pH ≥3 for at least 75% of the day or ≥4 for 67% of the day, respectively. Although dogs and cats are not people, veterinary medicine has adopted these goals to help choose effective antacid therapy. Several studies have been completed in recent years that evaluated the relative efficacy of different antacids in meeting the intragastric pH goals described above. Bersenas et al (2005) compared the intragastric pH in healthy Beagles given ranitidine (2 mg/kg IV BID), famotidine (0.5 mg/kg IV BID), pantoprazole (1 mg/kg IV SID), omeprazole (1 mg/kg PO SID and BID), and saline placebo. Famotidine, omeprazole, and pantoprazole significantly suppressed gastric acid production compared to placebo, but ranitidine did not. Furthermore, omeprazole given at a dose of 1 mg/kg PO BID was the only regimen that achieved the goals for gastric pH listed above. Another study by Tolbert et al (2011) evaluated the effect of famotidine (1-1.3 mg/kg PO BID), omeprazole tablet (1.5-2.6 mg/kg PO SID), omeprazole reformulated paste (1.5-2.6 mg/kg PO SID), and placebo in healthy dogs. Both forms of omeprazole significantly increased intragastric pH compared to famotidine and placebo, and there was no significant difference between the omeprazole tablet and paste. The latter finding indicates that both forms can be used effectively in dogs. However, neither omeprazole regimen achieved the pH goals for optimal therapy of gastroduodenal ulcers or acid reflux. The study also found a waning effect of omeprazole after 12-24 hours, suggesting that BID dosing may be more effective. Notably, there was no significant difference between famotidine and placebo, calling into question the efficacy of famotidine.
 
A later study by Tolbert et al (2015) compared pantoprazole (1 mg/kg IV BID) with the combined therapy of pantoprazole and famotidine (1 mg/kg IV BID) in healthy dogs. The goal of this study was to evaluate the notion that a PPI should be combined with a H2RA for the first few days of therapy because there is a delay of potentially a few days for the full action of a PPI, while a H2RA acts immediately. This study found no significant difference between treatment groups in the mean percentage time that intragastric pH was ≥3 or ≥4 at any time point. Furthermore, the group treated with pantoprazole alone achieved the pH goals listed above for optimal treatment of acid-related disorders. Previous studies have shown that ~24 hours after receiving of dose of a PPI, inhibition of acid secretion is ~30% of maximal as not all H+K+ATPase pumps are inhibited, while full inhibition takes up to 4 days. However, the results of the Tolbert study indicate that the clinical efficacy of PPIs has a faster onset of action and concurrent treatment with a H2RA is not necessary.
 
The information presented above represents the most current information regarding when and how to suppress gastric acid production, and much progress has been made in the last decade regarding the most effective way to use antacids. It is important for practitioners to be aware of the most current recommendations for dose and frequency, as these will aid in providing the best patient care. However, our knowledge is still evolving and there are still many gaps that require additional research, particularly with regards to the role of acid suppression in conditions such as hepatic disease, renal disease, pancreatitis, and gastrointestinal disease.

Comments are closed.