Potassium-Competitive Acid Blockers (P-CABs): Are They Finally Ready for Prime Time in Acid-Related Disease?

Richard H Hunt, Carmelo Scarpignato, Richard H Hunt, Carmelo Scarpignato

Abstract

The need for new acid suppressing agents with improved pharmacology and superior antisecretory effects to address unmet clinical needs in acid-related disorders has been evident for over a decade. Recent new antisecretory drugs (IR-omeprazole and MR-dexlansoprazole) only provide a small incremental advance in control of acid secretion over the delayed-release proton pump inhibitors. Vonoprazan (a new potassium-competitive acid blocker) displays more potent and extended 24 h acid suppression and preliminary Japanese trials translate this into meaningful clinical benefits in gastro-esophageal reflux disease and Helicobacter pylori eradication. We review the vonoprazan information to date and the indications, benefits, and concerns of more effective therapeutic control of acid secretion.

Figures

Figure 1
Figure 1
Role of K+ in the H+, K+, ATPase functioning, and potassium-competitive interaction of P-CABs with the proton pump. For details see Scarpignato et al. Left Panel: although it can also be activated by NH4+in vitro, the proton pump is highly selective for K+. In common with many other cells, the level of K+ in the parietal cell is higher than that in the plasma. The higher intracellular K+ level is dependent on H+, K+-ATPase. This enzyme, located on the basolateral membrane of the cell, exchanges intracellular H+ for extracellular K+. The level of K+ within the cell is also regulated by K+ channels, which allow ion movement across the basolateral membrane. These channels have a particularly important role in generating negative cell membrane potential. Given the importance of the cation for enzyme function, agents that compete with the binding of K+ are able to block acid secretion. P-CABs inhibit H+, K+ -ATPase by binding ionically to the enzyme and thus prevent its activation by the K+ cation. As these molecules are larger than K+, it is likely that they compete by preventing the access of the cation to its binding site rather than occupying the ion-binding site directly. Conversely from PPIs, P-CABs block gastric H+, K+-ATPase by reversible and K+-competitive ionic binding. Right Panel: PPIs are pro-drugs, which are weak bases that concentrate in the parietal cell canaliculus, where they undergo a proton-catalyzed, three-step process to generate the active sulfenamide. This moiety interacts covalently with sulfhydryl groups on cysteine residues in the transmembrane domains of the gastric H+, K+-ATPase and thereby inhibits the enzyme. Since a P-CAB concentrates in the parietal cell canaliculi, it is instantaneously protonated. It then binds ionically to the gastric H+, K+-ATPase and inhibits acid secretion. P-CAB, Potassium-Competitive Acid Blocker; PPIs, proton pump inhibitors.

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