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. 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. 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. 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. 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.
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. 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. 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.
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.
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.
Compared to proton pump inhibitors, H2RAs pose a minor risk for the development of bacterial overgrowth and infections.
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.
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, ranitidine, and nizatidine all require dose adjustment for patients with a creatine clearance less than 50 mL/min, while cimetidine doses should be reduced for patients with a creatine clearance 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.
H2RAs 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 involved 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.
Many healthcare professionals prescribe H2 blockers. While the drugs are relatively safe, when used in combination with other CNS drugs, they may produce severe adverse effects. Patient education by the pharmacist, nurse, and physician is key to preventing toxicity. Patients should be advised not to combine these agents with other CNS drugs/alcohol and refrain from taking them for prolonged periods.
|||Pappa KA,Williams BO,Payne JE,Buaron KS,Mussari KL,Ciociola AA, A double-blind, placebo-controlled study of the efficacy and safety of non-prescription ranitidine 75 mg in the prevention of meal-induced heartburn. Alimentary pharmacology [PubMed PMID: 10215730]|
|||Servey J,Chang J, Over-the-Counter Medications in Pregnancy. American family physician. 2014 Oct 15 [PubMed PMID: 25369643]|
|||Mattos ÂZ,Marchese GM,Fonseca BB,Kupski C,Machado MB, ANTISECRETORY TREATMENT FOR PEDIATRIC GASTROESOPHAGEAL REFLUX DISEASE - A SYSTEMATIC REVIEW. Arquivos de gastroenterologia. 2017 Dec [PubMed PMID: 28954042]|
|||MacFarlane B, Management of gastroesophageal reflux disease in adults: a pharmacist's perspective. Integrated pharmacy research [PubMed PMID: 29892570]|
|||Pettit M, Treatment of gastroesophageal reflux disease. Pharmacy world [PubMed PMID: 16341949]|
|||Pinto-Sanchez MI,Yuan Y,Bercik P,Moayyedi P, Proton pump inhibitors for functional dyspepsia. The Cochrane database of systematic reviews. 2017 Mar 8 [PubMed PMID: 28271513]|
|||von Einsiedel RW,Roesch-Ely D,Diebold K,Sartor K,Mundt C,Bergemann N, H(2)-histamine antagonist (famotidine) induced adverse CNS reactions with long-standing secondary mania and epileptic seizures. Pharmacopsychiatry. 2002 Jul [PubMed PMID: 12163986]|
|||Hamano T,Takano A,Miyao S,Teramoto J, Reversible adverse effects on the CNS induced by histamine H2 receptor antagonists. European neurology. 1998 [PubMed PMID: 9635477]|
|||Werbel T,Cohen PR, Ranitidine-Associated Sleep Disturbance: Case Report and Review of H2 Antihistamine-Related Central Nervous System Adverse Effects. Cureus. 2018 Apr 3 [PubMed PMID: 29872595]|
|||Humphries TJ,Merritt GJ, Review article: drug interactions with agents used to treat acid-related diseases. Alimentary pharmacology [PubMed PMID: 10491725]|
|||Fox RK,Muniraj T, Pharmacologic Therapies in Gastrointestinal Diseases. The Medical clinics of North America. 2016 Jul [PubMed PMID: 27235617]|
|||Untersmayr E, Acid suppression therapy and allergic reactions. Allergo journal international. 2015 Dec [PubMed PMID: 28603686]|
|||Ben-Joseph R,Segal R,Russell WL, Risk for adverse events among patients receiving intravenous histamine2-receptor antagonists. The Annals of pharmacotherapy. 1993 Dec [PubMed PMID: 8305790]|
|||Carroll C,Hassanin A, Polypharmacy in the Elderly-When Good Drugs Lead to Bad Outcomes: A Teachable Moment. JAMA internal medicine. 2017 Jun 1; [PubMed PMID: 28437544]|