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H₂RA, because of its increased frequency of administration and its interaction with the cytochrome P450 system, has been replaced by later-generation H₂RAs.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.