Antacid Therapy

Chapter 123

Antacid Therapy

Pathogenesis of Ulcer Disease

Ulcer disease results from an imbalance between gastric acid secretion and the gastric mucosal defense mechanisms. The pathogenesis is multifactorial. The amount of acid in gastric contents is determined by the rate of gastric acid secretion, the neutralization of acid by bicarbonate, the dilution by food and other digestive enzymes, and back diffusion of acid through the gastric mucosa. Gastric acidity plays a role in ulcerogenesis; human studies have established that the healing of acid-related disorders (gastric and duodenal ulcers and erosive esophagitis) is correlated highly with the degree of gastric acid suppression. These studies also have identified that the optimal degree of acid suppression varies with the underlying disease process. However, the degree of gastric acidity is not the only cause of mucosal injury: erosions and ulcers can occur in areas of anacidity. Other factors include increased bile reflux, decreased mucosal perfusion, and decreased delivery of bicarbonate to the protective mucous layer.

The key cell in gastric acid secretion is the parietal cell. The parietal cell secretes hydrogen ion via a H+/K+-ATPase pump. Based on gastric stimulation, the proton pump proceeds from an inactive to an active state such that over a period of hours, essentially all the ATPase molecules cycle through an acid-producing state. Secretion of hydrochloric acid is initiated via three systems: endocrine, neurocrine, and paracrine. These systems are mediated by three separate chemical messengers; gastrin, acetylcholine, and histamine, respectively.

The goals of antisecretory therapy are to reduce gastric acid secretion, prevent damage to the gastric mucosa, and allow regenerative mucosal mechanisms to prevail (Box 123-1).

Gastric Acid Suppressants

H2 Receptor Antagonists

Cimetidine, ranitidine, famotidine, and nizatidine are reversible H2-specific receptor antagonists that competitively inhibit binding of histamine, thereby reducing gastric acid secretion. Formulations are available for oral and parenteral administration (IV, IM, and SC). Intravenous continuous rate infusions have been used in human medicine but have not been investigated in veterinary medicine.

H2 receptor antagonists (H2RAs) differ in their potency (famotidine > ranitidine = nizatidine > cimetidine); however, clinically increased potency does not necessarily correlate to increased efficacy. In developmental studies using the dog model, H2RAs have been shown to have an effect on canine gastric pH, where they produce an effect on gastric acidity for 6 to 7 hours. Cimetidine, the first H2RA, because of its increased frequency of administration and its interaction with the cytochrome P450 system, has been replaced by later-generation H2RAs. Unfortunately, in the last decade, several veterinary studies have demonstrated underwhelming acid suppression with later-generation H2RAs in dogs. In one veterinary study investigating the effects of different H2RAs on gastric pH in healthy dogs, ranitidine at a clinically recommended dose (2 mg/kg IV q12h) offered no change in gastric pH compared with saline (Bersenas et al, 2005). Results using famotidine at 0.5 mg/kg IV (q12h) were also underwhelming. Famotidine’s ability to raise substantially intragastric pH in dogs is limited (Tolbert et al, 2011). Clinically, oral famotidine has been shown to be efficacious for reducing the severity but not the prevalence of gastric lesions in racing sled dogs when used as a preventive (Williamson et al, 2007). Attempts at increasing the dose or dosing frequency of famotidine also have failed to show an improved outcome. It is unlikely that famotidine at the commonly used dose of 0.5 mg/kg q12h is very effective, and the once-daily dosing that has been recommended previously may not be as effective as suggested.

Overall, the acid suppression provided by H2RAs at current veterinary doses is low. Some evidence suggests that famotidine should be selected over ranitidine for improved effect (Bersenas et al, 2005). Famotidine appears to help primarily animals that are at lesser risk for gastric lesions or are at risk for less severe gastric lesions. Famotidine remains an excellent drug for routine prophylaxis when cost is a concern or when an injectable drug is preferred.

In addition to the H2RAs antisecretory effects, some of these drugs have a prokinetic effect on gastrointestinal motility. Ranitidine and nizatidine have prokinetic properties mediated by inhibition of acetylcholinesterase activity.

The H2RAs are metabolized in the liver and excreted unchanged in urine. In renal failure the half-life is increased; therefore a decreased dose or decreased dosing frequency (q24h) is recommended. Otherwise H2RAs have minimal adverse reactions and are considered very safe in humans and small animals.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Antacid Therapy

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