- Filed under: Reflux
What Are H2 Blockers Really Bringing to the Table?
Dr. James Clark is an Assistant Professor in the Department of Otolaryngology-Head and Neck Surgery at Johns Hopkins and is the Medical Director of the Johns Hopkins Dysphagia and Deglutition Clinic. He specializes in the diagnosis and management of swallowing disorders, with a particular focus on deglutition issues related to head and neck cancer. His research is dedicated to developing innovative technologies for diagnosing and managing swallowing disorders.
Nearly 30% of Americans experience symptoms of gastroesophageal reflux disease (GERD) at least weekly.1 One of the stalwart treatments of GERD over the past 50 years has been histamine 2-receptor antagonists (H2RA or H2 blockers, commonly known as cimetidine [Tagamet], famotidine [Pepcid], or ranitidine [Zantac], for example). The introduction of these medicines in the late 1970s was revolutionary, as these were the first class of drugs specifically developed to reduce gastric acid secretion.2 Before the advent of H2 blockers, pharmacological interventions for reflux relied on cationic salts, commonly referred to as antacids. While antacids provide rapid relief, they do not reduce gastric acid and their effectiveness in managing GERD is limited by their short duration of action and the potential to cause
Although the introduction of H2 blockers in the 1970s was transformative, concerns quickly arose about diminishing efficacy of these medications over time with prolonged use.
hypercalcemia, metabolic alkalosis, and disruption of kidney function, i.e., milk-alkali syndrome. Although the introduction of H2 blockers in the 1970s was transformative, concerns quickly arose about diminishing efficacy of these medications over time with prolonged use.
It was recognized in the early 1980s that repeat dosing of H2 blockers was associated with decreased efficacy (a phenomenon known as tachyphylaxis); ie, the more you use it, the less it works. Despite occurring across the entire H2RA drug class, the precise mechanism for the tachyphylaxis remains poorly understood four decades later. What is now widely documented and understood is that the onset of H2RA tachyphylaxis is known to happen rapidly, with a measurable decrease in efficacy by just the second dose. The decline in effectiveness levels off around day three, at which point H2 blockers will have lost roughly a full quarter of their initial capacity to reduce gastric acid secretion. H2 blocker tachyphylaxis cannot be reversed by increasing the dose, and diminished efficacy remains in effect for over three days after treatment discontinuation.
Proton pump inhibitors (PPIs) are another class of acid-reducing medications that were introduced in the late 1980s. These medications provide more effective acid suppression than H2 blockers and are not affected by tachyphylaxis. PPIs maintain their clinical efficacy over time. It is for this reason that they are preferred by many clinicians to be the first line of treatment for persons with GERD. Nonetheless, the recent identification of various side effects with prolonged use of PPIs has reinvigorated interest in H2 blockers as a first step for reflux treatment. This makes understanding the role of H2RA tachyphylaxis of paramount and imminent importance.
Research has shown that after one week of adding H2RA, there is no statistical difference in acid suppression between PPI with or without a H2RA.4
The impact of H2RA tachyphylaxis (ineffectiveness) is most significant in managing reflux at night, when an individual lays down. The addition of bedtime H2RA for patients on PPIs with persistent nocturnal symptoms gained popularity after improved overnight intragastric pH control was demonstrated.3 That being said, research has shown that after one week of adding H2RA, there is no statistical difference in acid suppression between PPI with or without a H2RA.4 This brings into question the use of H2RAs as an addition to PPIs in individuals with nighttime GERD.
H2 blockers have been demonstrated to reduce esophageal sensation, presenting an opportunity for the clinical situation where there is no actual reduction in esophageal acid exposure despite reported symptomatic relief5 – meaning the esophagus continues to burn, but you just don’t know it.
Other factors should be considered when discussing the utility of H2 blockers in the treatment of GERD. H2RAs reduce gastric acid secretion by reversibly binding to histamine 2-receptors on parietal cells in the stomach; thereby preventing histamine from stimulating acid secretion. Histamine is, however, only one of three gastric acid secretagogues – meaning that H2RAs allow continued gastrin and acetylcholine-mediated stimulation of gastric acid secretion, resulting in an unintended physiological acidic imbalance in the stomach. Perhaps more alarmingly, H2 blockers have been demonstrated to reduce esophageal sensation, presenting an opportunity for the clinical situation where there is no actual reduction in esophageal acid exposure despite reported symptomatic relief5 – meaning the esophagus continues to burn, but you just don’t know it.
Recognizing the above limitations, the American College of Gastroenterology officially recommends against using H2RAs to manage GERD, except on an as-needed basis for breakthrough or occasional symptoms.6 Shockingly, despite such guidelines and the availability of alternative treatment options beyond antacids, H2RAs remain among the most commonly prescribed medications. This high utilization clearly illustrates a need for continued educational efforts to guide appropriate stewardship of GERD management, both in the clinician and patient populations, as we no longer should be settling for “good enough.”
When every seat at your table counts, it’s important to ask the question: What are H2 blockers really bringing to the table?
Referenced:
1. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871-880. doi:10.1136/gutjnl-2012-304269
2. MacLaren R, Kassel LE, Kiser TH, Fish DN. Proton pump inhibitors and histamine-2 receptor antagonists in the intensive care setting: focus on therapeutic and adverse events. Expert Opin Drug Saf. 2015;14(2):269-280. doi:10.1517/14740338.2015.986456
3. Peghini PL, Katz PO, Bracy NA, Castell DO. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol. 1998;93(5):763-767. doi:10.1111/j.1572-0241.1998.221_a.x
4. Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology. 2002;122(3):625-632. doi:10.1053/gast.2002.31876
5. Dhar A, Maw F, Dallal HJ, Attwood S. Side effects of drug treatments for gastro-oesophageal reflux disease: current controversies. Frontline Gastroenterol. 2020;13(1):45-49. doi:10.1136/flgastro-2019-101386
6. Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. Off J Am Coll Gastroenterol ACG. 2022;117(1):27. doi:10.14309/ajg.0000000000001538