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 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.
Sachs
G
G
Department of Medicine and Physiology, Wadsworth VA Hospital, Los Angeles, California 90073, USA.
Shin
J M
JM
Briving
C
C
Wallmark
B
B
Hersey
S
S
D000595:Amino Acid Sequence; D000818:Animals; D001562:Benzimidazoles / Q000009:adverse effects / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology* / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry / Q000378:metabolism; D016480:Helicobacter pylori / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D011188:Potassium / Q000037:antagonists & inhibitors; D054328:Proton Pump Inhibitors; D013272:Stomach Diseases / Q000201:enzymology / Q000382:microbiology
D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium