Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases.
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.
AstraZeneca R&D, 431 83 Mölndal, Sweden. kjell.andersson@astrazeneca.com
Kjell
K
Andersson
Enar
E
Carlsson
D000818:Animals; D000863:Antacids / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism*; D005764:Gastroesophageal Reflux / Q000188:drug therapy; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D010295:Parietal Cells, Gastric / Q000378:metabolism; D010437:Peptic Ulcer / Q000188:drug therapy; D011188:Potassium / Q000378:metabolism; D054328:Proton Pump Inhibitors
D000863:Antacids; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D054328:Proton Pump Inhibitors; D011188:Potassium