**5.3 Potassium-competitive acid blockers (P-CABs)**

P-CABs have been developing for over the past 30 years [50]. Unlike PPIs, P-CABs directly inhibit gastric H+ /K+ -ATPase in a K<sup>+</sup> -competitive, reversible manner and can bind to both the active and inactive forms of the ATPase pump resulting in a faster and longer duration of anti-secretory effect [26, 50]. Side effects of P-CABs include increased risk for gastric infection, obstruction of nutrient absorption, and increased levels of gastrin in the blood [50]. Advantages of P-CABs over PPIs have a faster onset of action with the maximum therapeutic effect observed in less than 2 hours postadministration [50]. P-CABs have a longer half-life compared to PPIs [50]. P-CABs have a better acid inhibitory effect than PPIs, and certain P-CABs have an effect that promotes gastric motility [50]. There are only three P-CABs available in Asia, with only one pending approval in the USA and Europe [50]. Revaprazan was the firstapproved P-CAB in 2007 [50]. In South Korea and India, revaprazan is used to treat gastric ulcers, gastritis, and duodenal ulcers [50]. Revaprazan increases the percentage of time of pH > 4 in a dose-dependent manner [50]. In addition to suppressing acid, revaprazan has two more pharmacological effects: increased prostaglandin E2 and reduction in the production of leukotriene B4, which leads to gastroprotection [50]. However, the acid suppression ability and gastric pH > 4.0 holding time of revaprazan is not superior to conventional PPIs [26].

Vonoprazan fumarate has been approved in Japan since 2015 for treating gastroduodenal ulcers, healing and preventing erosive esophagitis, gastric protection in patients taking aspirin or NSAIDs, and eradicating *H. pylori* infection [50]. Vonoprazan can inhibit gastric proton pumps in neutral pH, unlike PPIs that need to be activated by an acidic environment [50]. It can be taken without regard to meals [50]. Vonoprazan is currently under phase III trial in the USA and Europe [50]. In healing erosive esophagitis, vonoprazan 20 mg compared to lansoprazole 30 mg showed similar results in healing when compared to lansoprazole [50]. In patients with non-erosive reflux disease, vonoprazan was studied at doses of 10 and 20 mg compared to placebo. Patients experienced less severe GERD symptoms with vonoprazan compared to placebo [50]. Safety concerns about the long-term use of vonoprazan have been raised because of the significant elevation of serum gastrin levels compared with conventional PPI therapy [26]. Increased incidence of gastric endocrine cell tumors in a nonclinical carcinogenicity study has been correlated with the increased serum gastrin level, but the impact on humans is still unknown [26].

Tegoprazan has been approved and available since July 2018 in South Korea for treating erosive esophagitis and non-erosive reflux disease [50]. In patients with erosive esophagitis, tegoprazan (50 or 100 mg) was compared to esomeprazole 40 mg for 8 weeks [50]. Results showed that both doses of tegoprazan were non-inferior [50]. Although not currently available in the United States, P-CABs may play a role in GERD management soon after FDA approval.
