The Pharmacology of the Gastric Acid Pump: The H+,K+ ATPase

Abstract

The gastric H+,K+ ATPase--the gastric acid pump--is the molecular target for the class of antisecretory drugs called the proton-pump inhibitors (PPIs). These compounds--omeprazole, lansoprazole, and pantoprazole--contain, as their core structure, 2-pyridyl methylsulfinyl benzimidazole. The H+,K+ ATPase is a heterodimer composed of a 1034-amino acid catalytic alpha peptide and a glycosylated 291-amino acid beta subunit. The alpha subunit probably contains 10 membrane-spanning sequences; the beta, a single transmembrane segment. The PPIs have a pKa of about 4.0; hence they accumulate only in the acidic secretory canaliculus of the stimulated parietal cell. Here they undergo conversion to a cationic sulfenamide, which then reacts with available cysteines on the extracytoplasmic face of the alpha subunit. Omeprazole reacts and forms disulfide bonds with cys813(822) and cys892; lansoprazole, with cys813(822), cys892, and cys321; and pantoprazole, with cys813 and -822. The antisecretory effect of the drugs reflects their short plasma half-life (approximately 60 min), the number of active pumps during that time, and the recovery of pumps following biosynthesis and reversal of inhibition. These drugs also show synergism with either amoxicillin or clari- thromycin in eradicating Helicobacter pylori, an organism shown to be important in duodenal and gastric ulcer disease. Their action is probably due to elevation of pH in the environment of the organism, rather than to any direct action.

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

“…PPIs exert their pharmacological action through irreversibly inhibiting H + /K + -ATPase proton pumps in the gastric parietal cells, and thus inhibiting gastric acid secretion [13,14]. …”

A comparison of esomeprazole and lansoprazole for control of intragastric pH in patients with symptoms of gastro‐oesophageal reflux disease

“…2 Proton pump inhibitors suppress gastric acid secretion through the inhibition of H + /K + adenosine triphosphatase in gastric parietal cells. 3 Intragastric acid suppression, measured as the number of hours in a 24-hour period that intragastric pH is maintained above 4.0, is used to compare the effects of PPIs [4][5][6] and is correlated with mucosal healing rates in erosive oesophagitis. 7 Esomeprazole is the S-isomer of omeprazole and the first PPI developed as a single isomer.…”

Clinical Impact of Probiotics among Patients Receiving Antibiotics with a High Risk of Acquiring Clostridium difficile Infection

“…PPIs are known to increase gastric pH levels via selectively and irreversibly inhibiting gastric hydrogen/potassium adenosine triphosphatase (H+/K+-exchanging ATPase). This enzyme is part of the 'proton pump' that performs the ultimate step in the acid secretory process [21]. One of the mechanism of PPI associated CDI is that PPIs raise the pH of gastric contents, thus interfering with the ability of gastric acid to kill C. difficile spores, leading to germination and outgrowth of spores [22].…”