Histamine 2 Receptor Antagonists
Cimetidine, ranitidine, famotidine, and nizatidine reduce acid secretion by competing with histamine receptors on the parietal cell. They are most effective in controlling nocturnal, as compared with meal-related acid, secretion because the parietal cell may also be stimulated postprandially by acetylcholine and gastrin. All the H 2RAs are equally effective when used in proper doses, usually twice a day before meals. Clinical GERD trials show that heartburn, both day and night, can be significantly decreased by H 2RAs, when compared with placebo, although symptoms are rarely abolished. Trials and a metaanalysis found that the overall esophagitis healing rates with H 2RAs rarely exceeded 60% after up to 12 weeks of treatment, even when higher than standard doses were used. Healing rates differ in individual trials, depending primarily on the degree of esophagitis being treated: grade I and II esophagitis heals in 60% to 90% of patients, whereas grade III and IV heals in 30% to 50% of patients despite high-dose regimens.
Reflux symptoms associated with nocturnal gastric acid breakthrough during PPI therapy have been recognized. At bedtime, H 2RAs successfully eliminated this problem, suggesting a new indication for H 2RAs in the PPI era. However, this study used only a single evening dose and did not account for the tolerance that frequently develops to H 2RAs over weeks to months. This may impair the ability of chronic long-term nocturnal dosing of H 2RAs to eliminate acid breakthrough symptoms, but it suggests an important clinical role as medications used on an as-needed basis when lifestyle indiscretions may promote nocturnal symptoms. As a class of drugs, the H 2RAs are very safe, with a side effect rate (most of which are minor and reversible) of about 4%. There have been some concerns about drug interactions with these agents. Serum concentrations of phenytoin, procainamide, theophylline, and warfarin are altered after the administration of cimetidine and, to a lesser degree, ranitidine, whereas this interaction is not reported with the other two H 2RAs. The former concern that these agents could alter blood ethanol levels has been discounted.