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Pharmacological Management of Gastro-Esophageal Reflux Disease: an Update of the State-Of-The-Art

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Pharmacological Management of Gastro-Esophageal Reflux Disease: an Update of the State-Of-The-Art Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Pharmacological Management of Gastro-Esophageal Reflux Disease: An Update of the State-of-the-Art Vincenzo Savarino 1 Abstract: Gastro-esophageal reflux disease (GERD) is a highly prevalent, chronic disorder, Elisa Marabotto1 whose knowledge remains limited and the management of these patients changes continu­ Patrizia Zentilin 1 ously. This review provides a summary of the most recent advancements in the pathogenesis Maria Giulia Demarzo1 of this disease and the new drugs introduced into the market to overcome some of the unmet Nicola de Bortoli2 needs of traditional therapies. Nowadays, the most fruitful diagnostic examinations are 24- hour impedance-pH monitoring, which allows us to separate true NERD from esophageal Edoardo Savarino 3 functional disorders and high-resolution manometry, which helps to exclude the existence of 1Department of Internal Medicine (DIMI), motility disorders sharing the same symptoms of GERD. Proton pump inhibitors (PPIs) University of Genoa, Genoa, Italy; 2Department of Translational Research remain the first-choice therapy in the treatment of GERD, but a consistent proportion of these and New Technologies in Medicine and patients continue to experience symptoms despite their intake. These cases pertain mainly to Surgery, University of Pisa, Pisa, Italy; the subpopulation with non-erosive reflux disease (NERD) and represent very challenging 3Department of Surgery, Oncology and Gastroenterology, University of Padova, clinical situations, because it is mandatory to understand the reasons for PPI failure. The Padova, Italy management of these difficult patients requires necessarily to test them and avoid the use of empiric treatments that are often unsuccessful, costly and potentially dangerous. Recently, several new drugs have been used to increase the defensive properties of this mucosa with promising results in randomized clinical trials. Keywords: medical management of GERD, proton pump inhibitors, potassium competitive acid blockers, PPI-refractory patients, esophageal mucosal resistance, mucosal protective agents, bile acid sequestrant drug Introduction Gastroesophageal reflux disease (GERD) is defined as “a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications”.1 Typical esophageal symptoms include heartburn and regurgitation and, more rarely, chest pain and dysphagia. Extra-esophageal symptoms or signs with an established association with GERD on the basis of population-based studies are chronic cough, hoarseness, asthma and dental erosions. However, these symp­ toms have potential etiologies other than GERD and, in the absence of concomitant typical GERD symptoms, the causal role of reflux remains difficult to prove. GERD complications are mainly represented by mucosal injury, the most common being reflux esophagitis, strictures, Barrett’s esophagus and adenocarcinoma. The prevalence of GERD is high in Western countries and ranges from 13% to 20% in the USA and from 9.8% to 18% in Europe, while it is lower in Asia 2 Correspondence: Vincenzo Savarino (2.5–4.8%). Obesity, increasing age, a family history of reflux disease and chronic Department of Internal Medicine (DIMI), consumption of certain drugs (nitrates, calcium antagonists, benzodiazepines, etc.) University of Genoa, Genoa, Italy 3–5 Email [email protected] are significant risk factors. Drug Design, Development and Therapy 2021:15 1609–1621 1609 © 2021 Savarino et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Savarino et al Dovepress GERD is a chronic disease with phases of recurrence Pathophysiology of GERD and remission overtime, but it can be considered a benign GERD is due to multiple mechanisms and motor altera­ 6 disorder from a prognostic point of view. tions predominate, as shown in Figure 1. The anti-reflux The aim of this review is to provide a summary of the barrier is thought to consist of the intrinsic pressure of the most recent studies on the unmet needs and the pharma­ lower esophageal sphincter (LES), the extrinsic compres­ cological management of GERD with particular attention sion of the LES by crural diaphragm and the acute angle of to the new molecules that have enriched our therapeutic His. There are three prevalent mechanisms of reflux: tran­ armamentarium. A computerized (PubMed databases) lit­ sient LES relaxations (TLESRs), LES hypotension and erature research was performed with focus on the last five anatomical disruption of the esophago-gastric junction years (2016–2020). We used the following terms: (EGJ), that is hiatus hernia.7 “GERD”, “GORD”, “gastroesophageal reflux disease TLESRs represent the most important mechanism of treatment or therapy” “functional heartburn”, “reflux reflux in healthy subjects and in a very large part of GERD hypersensitivity”, “PPI-refractory GERD”, “PPI failure”, patients; they occur during swallows to allow the passage “impedance-pH monitoring”, “esophageal pH-metry”, of a bolus from the esophagus into the stomach and are “Bravo system”, “high resolution manometry”, “proton also induced by secondary peristalsis, which starts from pump inhibitors”, “PPIs”, “H2 antagonists”, “potassium mid esophagus as effect of a vago-vagal reflex commen­ competitive acid blockers”, “P-CABs”, “GABAb agonists, cing with activation of gastric receptors primarily placed anti-depressants”, “pain modulators”, “esophageal muco­ in the sub-cardiac region. Therefore, the primary stimulus sal integrity”, “esophageal mucosal resistance”, “esopha­ which triggers a TLESR is gastric distension, often due to geal mucosal protective drugs”, “alginates”, “hyaluronic gastric air or the presence of meal and this explains why acid”, “esophageal medical devices”, “add-on therapy to TLESRs are mainly a postprandial phenomenon.8 PPIs”. We critically reviewed all full-text papers, including A second mechanism is LES hypotension and episodes clinical trials, systematic reviews and meta-analyses, pub­ of free reflux are observed only when the LES pressure is lished in English language. The number of clinical trials lower than 5 mmHg measured by manometry. This we considered in this review was 19 and that of systematic mechanism is particularly frequent in patients with reviews was 14. scleroderma.9 Figure 1 The complex pathogenesis of GERD. 1610 http://doi.org/10.2147/DDDT.S306371 Drug Design, Dev elopment and Therap y 2021:15 DovePress Dovepress Savarino et al As third factor, the presence of hiatal hernia favors with GERD, particularly in those with non-erosive reflux gastroesophageal reflux by increasing the severity of eso­ disease (NERD), who do not present mucosal lesions at phageal acid exposure. It alters the position of LES with endoscopy.16,17 Indeed, the presence of dilated intercellu­ respect to the crural diaphragm because these two impor­ lar spaces (DIS) is common in patients with true NERD tant factors of the anti-reflux barrier are no longer and reflux hypersensitivity (RH) because of the presence coupled.10 of an impaired mucosal barrier.18 In patients with NERD it In addition to the above mechanisms, an impaired has been shown that microscopic esophagitis, including esophageal clearance of refluxate may prolong the con­ DIS, is significantly lower in controls (15%) and in tact time with the mucosa of the distal part of the patients with functional heartburn (FH) (13%) than in esophagus and this contributes to generate symptoms or patients with RH (65%) and in those with excess of acid to damage the epithelium. Primary (swallow-induced) (77%).19 and secondary (distension-induced) peristalses are the main clearance events to clear the refluxate. Esophageal Phenotypic Presentation of GERD motility disorders occur in about 30% of patients with At the end of the second millennium erosive esophagitis GERD, with ineffective esophageal motility being the (EE) was identified with GERD, but in the last two dec­ most prevalent alteration.11 Although less relevant, also ades we have realized that patients with esophagitis repre­ chemical clearance due to bicarbonates contained in sal­ sent only a minority (25–30%) of the entire spectrum of iva is decreased in GERD.12 Recently, the relevance of this disease, because about 70–75% of them pertain to the esophageal clearance has been shown even in neonates, NERD phenotype, that is patients with typical reflux where it enables to predict the response to PPI therapy. symptoms and devoid of any esophageal lesion visible at In a study by Nobile et al13 a more efficient and rapid endoscopy.20 Two large population-based epidemiological esophageal clearance assessed by impedance-pH moni­ studies have demonstrated that the rate of endoscopy- toring was significantly associated with a positive clin­ negative cases can be as high as 75%.21,22 ical response to anti-reflux therapy with omeprazole Current pathophysiological
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