Continuing Education Activity

H2 receptor blockers, or H2 receptor antagonists (H2RAs), are a class of gastric acid-suppressing agents frequently used in various gastric conditions. They are FDA-approved for short-term use in treating uncomplicated gastroesophageal reflux disease (GERD), gastric or duodenal ulcers, gastric hypersecretion, and 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. 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. The overall therapeutic effectiveness of H2RAs greatly depends on the severity of gastric disease, dosage regimen, and duration of therapy. This activity describes the indications, contraindications, and use of H2 blockers and highlights the interprofessional team's role in promoting their safety.

Objectives:

• Identify the mechanism of action of H2 blockers.
• Describe the adverse effects of H2 receptor blockers.
• Review the indications of H2 blockers.
• Outline some interprofessional team strategies for improving care coordination and communication to advance the safety of H2 blockers and improve outcomes.

Indications

H2 receptor blockers, or H2 receptor antagonists (H2RAs), are a class of gastric acid-suppressing agents frequently used in various gastric conditions. They are FDA-approved for short-term use in treating uncomplicated gastroesophageal reflux disease (GERD), gastric or duodenal ulcers, gastric hypersecretion, and mild to infrequent heartburn or indigestion. H2 receptor antagonists may also be used off-label for stress ulcer prophylaxis, esophagitis, gastritis, gastrointestinal hemorrhage, or urticaria. These drugs 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, H2 receptor antagonists are pregnancy category B with no known teratogenic effects and may be used if needed.[2] H2RAs have also been 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 three FDA-approved H2RA agents for use in the United States available either over-the-counter (OTC) or by prescription only. Famotidine and cimetidine are available either OTC or by prescription, depending on the dose. Nizatidine is available by prescription only. Ranitidine was previously available but has been withdrawn in the United States and suspended in Europe and Australia for carcinogen contamination during manufacturing.[4][5]

Mechanism of Action

H2RAs decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and activity of the endogenous ligand histamine. H2 blockers thus function as competitive antagonists. Normally, after a meal, gastrin stimulates histamine release 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 induced by histamine.[6] 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.[7]

Administration

H2 receptor antagonists are well-absorbed after oral administration, and all H2RAs are available as a tablet for oral use. 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 in combination formulations containing calcium carbonate and magnesium hydroxide or ibuprofen. Of the H2RAs, famotidine is available as an intravenous solution for use in hospital settings.

H2 receptor antagonists 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 are 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.[7] Patients should not initially self-treat with H2RAs for longer than two weeks without consulting their primary care physician.

Adverse Effects

H2 receptor antagonists are generally well-tolerated. Mild side effects may include headache, drowsiness, fatigue, abdominal pain, constipation, or diarrhea.[8] 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 is generally considered the most frequent cause of these symptoms, although similar effects have also occurred with famotidine.[9][10][11] 

Drug interactions with H2 receptor antagonists may occur. As a result of the therapeutic increase in gastric pH, the absorption of drugs requiring an acidic environment for dissolution may become altered. Cimetidine is a potent cytochrome P450 (CYP450) enzyme inhibitor and should be avoided with other medications 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.[12] 

Using H2 receptor antagonists on a scheduled basis may result in tachyphylaxis or tolerance, limiting 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, H2RAs may help prevent the development of tachyphylaxis.[13]

Compared to proton pump inhibitors, H2RAs pose a minor risk for developing bacterial overgrowth and infections.[14]

Contraindications

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. Instead, they should seek appropriate medical attention.

Monitoring

Patients using H2RAs should be monitored for endoscopic improvement and decreased gastric symptoms to assess the clinical effectiveness and need for therapy adjustments. Patients should also be monitored for adverse effects and possible drug interactions, especially when taking cimetidine.

H2RAs are eliminated by a combination of hepatic and renal metabolism. Famotidine and nizatidine require dose adjustment for patients with a creatine clearance of less than 50 mL/min, while cimetidine doses should be reduced for patients with a creatine clearance of less than 30 mL/min. The half-life of cimetidine may become prolonged in patients with hepatic impairment, but for all H2RAs, no dose adjustments are required for hepatic impairment unless also accompanied by renal impairment.

Rarely, QT-prolongation or central nervous system effects have been observed in patients with impaired renal function whose dose was not properly adjusted. Famotidine use requires caution during renal impairment and in combination with other QT-prolonging medications or conditions. Elderly patients should also be monitored for central nervous system side effects such as dizziness or confusion that may result from decreased drug clearance.[15]

Toxicity

H2 receptor antagonists have a broad therapeutic index and, therefore, severe toxicity is rare. Toxicities of H2RAs may be associated with inhibition of H2 receptors in the myocardium and central nervous system. Central nervous system depression, hypotension, and bradycardia have rarely been reported and usually involve the rapid intravenous infusion of an H2RA. Treatment for toxicities related to H2RA use may include decontamination with gastric lavage or activated charcoal, discontinuation of the drug, and supportive care measures. 

Enhancing Healthcare Team Outcomes

Many healthcare professionals prescribe H2 blockers, and there are also agents in the class available over the counter. While these drugs are relatively safe, they may produce severe adverse effects when combined with other CNS drugs. Patient education by the pharmacist, nurse, and clinician, working as an interprofessional healthcare team, is key to preventing toxicity and driving improved patient outcomes when using H2 receptor blocking therapy. Pharmacists would do well to check for drug interactions and even inquire of patients in the retail setting if they encounter a patient purchasing H2 receptor antagonists as an over-the-counter option. Patients should be advised not to combine these agents with other CNS drugs/alcohol and refrain from taking them for prolonged periods.[16]