THE PHARMACOLOGY OF THE GASTRIC-ACID PUMP - THE H+,K+ ATPASE

The gastric H+,K+ ATPase-the gastric acid pump-is the molecular target for the class of antisecretory drugs called the proton-pump inhibitor s (PPIs). These compounds-omeprazole, lansoprazole, and pantoprazole-c ontain, as their core structure, 2-pyridyl methylsulfinyl benzimidazol e. The H+,K+ ATPase is a heterodimer composed of a 1034-amino acid cat alytic a peptide and a glycosylated 291-amino acid beta subunit, The a lpha subunit probably contains 10 membrane-spanning sequences; the bet a, a single transmembrane segment. The PPIs have a pK(a) 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 extracy toplasmic face of the alpha subunit. Omeprazole reacts and forms disul fide bonds with cys813(822) and cys892; lansoprazole, with cys813(822) , cys892, and cys321; and pantoprazole, with cys813 and -822. The anti secretory effect of the drugs reflects their short plasma half-life (s imilar to 60 min), the number of active pumps during that time, and th e recovery of pumps following biosynthesis and reversal of inhibition. These drugs also show synergism with either amoxicillin or clari- thr omycin in eradicating Helicobacter pylori, an organism shown to be imp ortant in duodenal and gastric ulcer disease. Their action is probably due to elevation of pH in the environment of the organism, rather tha n to any direct action.