Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Special Issue: Global Perspectives and Novel Technologies for Esophageal Diseases Concise Review Gastrointestinal pharmacology: practical tips for the esophagologist Carmelo Scarpignato, 1,2 Joshua A. Sloan, 3 David H. Wang, 4 and Richard H. Hunt 5 1 Department of Health Sciences, Faculty of Health Sciences, United Campus of Malta, Msida, Malta. 2 Faculty of Medicine, Chinese University of Hong Kong, ShaTin, Hong Kong. 3 Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland. 4 Division of Hematology and Oncology, UT Southwestern Medical Center and VA North Texas Health Care System, Dallas, Texas. 5 Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada Address for correspondence:Carmelo Scarpignato, MD, DSc, PharmD, MPH, FRCP (Lond), FACP, FCP, FACG, AGAF, FEBGH, Department of Health Sciences, Faculty of Health Sciences, United Campus of Malta, 56, Silema Road, Gzira n/a GRZ1634, Malta. scarpi@tin.it; carmelo.scarpignato@gmail.com Gastroesophageal refux disease (GERD) is primarily a motor disorder, and its pathogenesis is multifactorial. As a consequence, treatment should be able to address the underlying pathophysiology. Proton pump inhibitors (PPIs) are the mainstay of medical therapy for GERD, but these drugs only provide the control of symptoms and lesions without curing the disease. However, continuous acid suppression with PPIs is recommended for patients with Bar- rett’s esophagus because of their potential chemopreventive efects. In addition to the antisecretory activity, these compounds display several pharmacological properties, often overlooked in clinical practice. PPIs can indeed afect gastric motility, exert a mucosal protective efect, and an antioxidant, anti-infammatory, and antineoplastic activity, also protecting cancer cells from developing chemo- or radiotherapeutic resistance. Even in the third millennium, current pharmacologic approaches to address GERD are limited. Refux inhibitors represent a promise unfulflled, efective and safe prokinetics are lacking, and antidepressants, despite being efective in selected patients, give rise to adverse events in a large proportion of them. While waiting for new drug classes (like potassium-competitive acid blockers), reassessing old drugs (namely alginate-containing formulations), and paving the new avenue of esophageal mucosal protection are, at the present time, the only reliable alternatives to acid suppression. Keywords: GERD; Barrett’s esophagus; PPIs; P-CABs; alginate-containing formulations; NSAIDs; aspirin; chemopre- vention Current treatments for gastroesophageal reflux disease Gastroesophageal refux disease (GERD) is pri- marily a motor disorder, and its pathogenesis is multifactorial. 1 As a consequence, treatment should be able to address the underlying pathophysiology. Unfortunately, this is not the case with proton pump inhibitors (PPIs) that only provide a pallia- tive approach to the disease, targeting the stomach rather than the esophagus, where abnormal acid exposure is not secondary to gastric acid hyper- secretion, which has been documented in only a small subset of GERD patients. 1 Currently, the mainstay of medical therapy for GERD is the administration of PPIs. Their use can actually be diagnostic for GERD in the setting of typical symptoms of heartburn and regurgitation. 2 PPIs work by inhibiting proton pumps, which are activated during a meal. By irreversibly binding and inhibiting the pumps, these drugs signifcantly decrease gastric acid secretion, raise the intragastric pH, and reduce the symptoms of GERD. 3 Other therapeutic options act to either decrease acid production (histamine doi: 10.1111/nyas.14447 1 Ann. N.Y. Acad. Sci. xxxx (2020) 1–18 © 2020 New York Academy of Sciences.