Potassium-competitive acid blockade: A new therapeutic strategy in acid-related diseases

Abstract

Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either prevent stimulation of the parietal cell (H₂ receptor antagonists, H₂RAs) or inhibit gastric H⁺,K⁺-ATPase (e.g., proton pump inhibitors, PPIs). Of the 2 approaches, the inhibition of the final step in acid production by PPIs provides more effective relief of symptoms and healing. Despite the documented efficacy of the PPIs, therapeutic doses have a gradual onset of effect and do not provide complete symptom relief in all patients. There is scope for further improvements in acid suppressive therapy to maximize healing and offer more complete symptom relief. It is unlikely that cholecystokinin₂ (CCK₂, gastrin) receptor antagonists, a class in clinical trials, will be superior to H₂RAs or PPIs. However, a new class of acid suppressant, the potassium-competitive acid blockers (P-CABs), is undergoing clinical trials in GERD and other acid-related diseases. These drugs block gastric H⁺,K⁺-ATPase by reversible and K⁺-competitive ionic binding. After oral doses, P-CABs rapidly achieve high plasma concentrations and have linear, dose-dependent pharmacokinetics. The pharmacodynamic properties reflect the pharmacokinetics of this group (i.e., the effect on acid secretion is correlated with plasma concentrations). These agents dose dependently inhibit gastric acid secretion with a fast onset of action and have similar effects after single and repeated doses (i.e., full effect from the first dose). Animal studies comparing P-CABs with PPIs suggest some important pharmacodynamic differences (e.g., faster and better control of 24-hr intragastric acidity). Studies in humans comparing PPIs with P-CABs will help to define the place of this new class in the management of acid-related diseases.

Introduction

By the 19th century, gastric acid was known to be important in many physiological processes, such as protein digestion and the absorption of calcium and iron. Alongside these functions, sterilization of food is now also recognized as a vital function of gastric acid. Over time, awareness of its central role in the etiology of peptic ulcer disease (PUD), and more recently, gastroesophageal reflux disease (GERD), has also grown. This knowledge, together with an increased understanding of the physiology of acid production, directed the search for therapies in these diseases through inhibition of gastric acid secretion. However, until just under 30 years ago, patients with acid-related diseases had to rely on antacids, atropine, and other interventions (e.g., behavioral) for the relief of symptoms. The treatment of PUD was challenging and, apart from surgery, employed largely ineffective approaches that included a bland diet, antacids, and anticholinergics. Although antacids, and other approaches such as dietary changes and sucralfate, provide a degree of relief from the symptoms of GERD, healing of erosions was very difficult to achieve except with high and frequent doses of antacids (Grove et al., 1985).

The emergence of H₂ receptor antagonists (H₂RAs) in the 1970s represented the first major advance in the treatment of GERD and PUD, as they provided better symptom control and allowed higher healing rates compared with antacids. However, these agents have a relatively short duration of action, their effect is diminished by meal-stimulated secretion, and tolerance to their antisecretory effect can develop. Other approaches used to treat GERD (e.g., prokinetics, sucralfate) have generally not met expectations.

The first proton pump inhibitor (PPI), omeprazole, was approved for use in 1988 (Lindberg et al., 1990) and was the forerunner of a more effective class of agents than H₂RAs. PPIs provide superior symptom relief and achieve higher healing rates in GERD and PUD than do H₂RAs (Chiba et al., 1997, Van Pinxteren et al., 2001, Salas et al., 2002). Despite the undoubted efficacy of PPIs, there are still areas in which they could be improved upon (e.g., faster and better symptom control and more rapid healing). The quest for better therapy has driven research into other acid-suppressive treatments. This review examines the development and properties of current and potential treatments to suppress acid production, with particular emphasis on the potassium-competitive acid blocker (P-CAB) class.