LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

The selective histamine type 2 receptor antagonists/blockers (H2 blockers) are widely used in the treatment of acid-peptic disease, including duodenal and gastric ulcers, gastroesophageal reflux disease and common heartburn. The four H2 blockers in current use are available by prescription as well as over-the-counter, and are some of the most widely used drugs in medicine. The H2 blockers are very well tolerated, but have been linked to rare instances of clinically apparent liver injury. The H2 receptor blockers act by binding to histamine type 2 receptors on the basolateral (antiluminal) surface of gastric parietal cells, interfering with pathways of gastric acid production and secretion. The selectivity of H2 blockers is of key importance, as they have little or no effect on the histamine type 1 receptors, which are blocked by typical antihistamines that are used to treat allergic reactions and have little effect on gastric acid production. The selective H2 blockers are less potent in inhibiting acid production than the proton pump inhibitors (which block the common, final step in acid secretion) but, nevertheless, suppress 24 hour gastric acid secretion by about 70%. The effect of H2 blockers is largely on basal and nocturnal acid secretion, which is important in peptic ulcer healing. The selective H2 blockers were first developed in the early 1990s by Sir James Black, who subsequently received the Nobel Prize for his work developing selective receptor antagonists for clinical use (including the beta blockers as well as the H2 blockers). The initial H2 blocker approved for use in the United States was cimetidine (1977), which was followed by ranitidine (1983), famotidine (1986), and nizatidine (1988). All four of these agents are available by prescription and as over-the-counter oral formulations. Intravenous and intramuscular forms are available for cimetidine, ranitidine and famotidine. The four H2 receptor blockers available in the United States have similar spectra of activity, side effects and clinical indications. These medications are extremely well tolerated and are used by a high proportion of the general population to treat peptic ulcer disease, heartburn, esophagitis, and miscellaneous minor upper gastrointestinal symptoms. Their listed indications are for treatment of gastric and duodenal ulcer and esophageal reflux disease, and to prevent stress ulcers. Side effects are uncommon, usually minor and include diarrhea, constipation, fatigue, drowsiness, headache and muscle aches. The H2 receptor blockers are metabolized in the liver by the cytochrome P450 system. Among the four agents, cimetidine is distinctive in its potent inhibition of the P450 system (CYP 1A2, 2C9 and 2D6), which can result in significant drug interactions. All four H2 receptor blockers have been implicated in rare cases of clinically apparent, acute liver injury. The most cases have been linked to ranitidine and cimetidine, but these two agents are also the most commonly used. The four H2 receptor blockers in clinical use are discussed separately, with references given after each.