H2 receptor blockers, or H2 receptor antagonists (H2RAs), are a class of gastric acid-suppressing agents frequently used in a variety of gastric conditions. They are FDA-approved for short-term use in the treatment of uncomplicated gastroesophageal reflux disease (GERD), gastric or duodenal ulcers, gastric hypersecretion, and for mild to infrequent heartburn or indigestion. H2RAs may also be used off-label for stress ulcer prophylaxis, esophagitis, gastritis, gastrointestinal hemorrhage, or urticaria. H2RAs are also sometimes included in a multidrug regimen for Helicobacter pylori eradication.[1] Although antacids are generally considered first-line agents for heartburn during pregnancy, H2RAs are pregnancy category B with no known teratogenic effects and may be used if needed.[2] H2RAs have also shown to be safe for use in children or adolescents with mild or infrequent heartburn symptoms that do not respond to lifestyle changes.[3] The overall therapeutic effectiveness of H2RAs greatly depends on the severity of the gastric disease, dosage regimen, and duration of therapy. 

There are currently four FDA-approved H2RA agents for use in the United States available either over-the-counter (OTC) or by prescription only. Famotidine, ranitidine, and cimetidine are all available either OTC or by prescription, depending on the dose. Nizatidine is available by prescription only.

H2RAs decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and action of the endogenous ligand histamine. H2 blockers thus function as competitive antagonists. Normally, after a meal, gastrin stimulates the release of histamine from enterochromaffin-like cells, which then binds to histamine H2 receptors on gastric parietal cells and leads to gastric acid release. This increase in gastric acid release occurs through the activation of adenylate cyclase, which raises intracellular cAMP levels. cAMP then activates protein kinase A (PKA), which, among other functions, phosphorylates proteins involved in the movement of  H+/K+ ATPase transporters to the plasma membrane. The increase of H+/K+ ATPase transporters at the plasma membrane allows for the secretion of more acid from parietal cells.

By blocking the histamine receptor and thus histamine stimulation of parietal cell acid secretion, H2RAs suppress both stimulated and basal gastric acid secretion that is induced by histamine.[4] The onset of gastric relief provided by H2RAs is approximately 60 minutes with a duration of action that ranges from 4 to 10 hours, making them useful for the on-demand treatment of occasional symptoms. All H2RAs have similar efficacy in decreasing gastric acid secretion.[5]

H2RAs are well-absorbed after oral administration, and all H2RAs are available as a tablet for oral use. Ranitidine is also available as a capsule, oral solution, oral powder for suspension, or oral syrup. Nizatidine is also available as a capsule or an oral solution. Famotidine, one of the most commonly used agents, is available as a chewable tablet, oral powder for suspension, or as combination formulations containing calcium carbonate and magnesium hydroxide or ibuprofen. Of the H2RAs, famotidine and ranitidine are available as intravenous solutions for use in hospital settings.

H2RAs may be used as needed for gastric symptom relief or prophylactically 30 to 60 minutes before known food or beverage triggers. H2RAs may also be taken concomitantly with antacids if both quick relief of symptoms and a longer duration of action is desired. For best results, patients should take once-daily doses of H2RAs at bedtime. The more common twice-daily doses can be taken once in the morning and once in the evening.[5] Patients should not initially self-treat with H2RAs for longer than two weeks without consulting their primary care physician.

H2RAs are generally well-tolerated. Mild side effects may include headache, drowsiness, fatigue, abdominal pain, constipation, or diarrhea.[6] The use of H2RAs in patients with renal impairment, hepatic impairment, or who are over 50 years of age has correlated with central nervous system side effects such as delirium, confusion, hallucinations, or slurred speech. Cimetidine, in particular, is generally considered the most frequent cause of these symptoms, although similar effects have also occurred with ranitidine and famotidine.[7][8][9] 

Drug interactions with H2RAs may occur. As a result of the therapeutic increase in gastric pH, the absorption of drugs requiring an acidic environment for dissolution may be altered. Cimetidine is a potent cytochrome P450 (CYP450) enzyme inhibitor and should be avoided with other medications that are metabolized by CYP450 enzymes such as theophylline, selective serotonin reuptake inhibitors, or warfarin. Prolonged, high doses of cimetidine have also been linked to gynecomastia, reduced sperm count, and impotence in men and galactorrhea in women. This condition typically resolves with drug discontinuation. Today, clinicians generally avoid cimetidine as a therapeutic recommendation for gastric symptoms.[10] 

The use of H2RAs on a scheduled basis may result in tachyphylaxis or tolerance, which may limit their use as maintenance therapy for GERD symptoms. Tolerance to the effects of H2RAs can occur within 7 to 14 days of continued treatment. Intermittent, or as needed, use of H2RAs may help prevent the development of tachyphylaxis.[11]

Compared to proton pump inhibitors, H2RAs pose a minor risk for the development of bacterial overgrowth and infections.[12]

There are currently no absolute contraindications to H2RAs. However, they should not be used in patients with known hypersensitivity to any H2RA or other drug components. Patients should stop using OTC H2RAs if they are experiencing trouble or pain when swallowing food, vomiting with blood, or experiencing bloody or black stools and instead should seek appropriate medical attention.