**3. Histamine 2 receptor antagonists (H2RA)**

H2RAs consist of famotidine, ranitidine, cimetidine, and nizatidine [13]. Famotidine and cimetidine, available over the counter, are the only H2RAs currently available in the United States. The dosing and duration of these H2RAs are summarized in **Table 2** [13].

Ranitidine and nizatidine are no longer available in the United States. They were withdrawn from the market in April 2020 due to the detection of a carcinogenic agent N-nitrosodimethylamine (NDMA), in some available products [13]. NDMA is a probable human carcinogen and has been linked to multiple cancers, including kidney cancer, bladder cancer, and cancers of the digestive tract [14]. Higher concentrations of NDMA were found in older products and products stored above room temperature [14].

As food enters the stomach, the hormone gastrin is released, leading to histamine's release. Histamine binds to H2 receptors on parietal cells, activating adenylate cyclase


## **Table 2.**

*Dosing and duration of available H2RA.*

to increase cAMP within the cell [15]. Increase in intracellular cAMP leads to protein kinase A (PKA) activation, which phosphorylates proteins, leading to the H+/K+ ATPase releasing acid into the stomach [15]. H2RAs function by competitively inhibiting H2 receptors located on the outer surface of parietal cells in the stomach's inner lining [15, 16]. By blocking the H2 receptor, H2RAs prevent the downstream effect of the release of gastric acid into the stomach [15]. This mechanism of action leads to a decrease in stomach acidity, which helps relieve the symptoms of GERD. The H2RAs are considered interchangeable as all have shown equivalent efficacy at approved doses in clinical trials [15].

All H2RAs are available as oral tablets [15]. Famotidine comes in other formulations, including a chewable tablet, a powder for oral suspension, and a solution for intravenous administration [15]. Famotidine is also available in combination with calcium carbonate, magnesium hydroxide, and ibuprofen [15]. H2RA's therapeutic effect typically begins one hour after administration, and its effect can last between 4 and 10 hours [15].

H2RAs are metabolized in the liver and the kidneys, and dose adjustments are required for renal impairment [15]. Cimetidine dose adjustments are necessary for patients with a CrCl of less than 30 ml/min. For famotidine, a dose adjustment should be made for patients with a CrCl less than 50 ml/min, as QTc prolongation has been reported in patients with renal dysfunction [15].

H2RAs have a strong safety profile due to their wide therapeutic index [15]. Reported side effects of H2RAs include constipation, diarrhea, headache, dry mouth, and abdominal pain [15]. In patients over 50 and those with renal or hepatic dysfunction, central nervous system (CNS) side effects have been observed [15]. These include anxiety, depression, confusion, insomnia, disorientation, delirium, hallucinations, and agitation [17]. Compared to famotidine, cimetidine has shown to have more side effects which are attributed to its prolonged half-life. Additionally, it has been found to have weak anti-androgenic activity. Consequently, endocrine dysfunction has been reported with cimetidine use and includes symptoms such as decreased libido, gynecomastia, impotence, hyperprolactinemia, and galactorrhea [18]. These adverse effects are more likely to occur with high-dose therapy used in hypersecretory conditions and typically do not begin to appear until at least one month of treatment [18].

For patients in the hospital setting, those who are taking H2RAs and also recceing antibiotic therapy have been found to have an elevated risk for *Clostridioides difficile* infection [19]. Additionally, increasing evidence suggests a link between AST and community- and hospital-acquired pneumonia [20]. There have been several proposed mechanisms for this association [20]. A potential mechanism for this observation is that the stomach's acidic environment, which typically serves as a barrier against pathogens, is no longer effective due to the increased pH from AST. This
