Proton Pump Inhibitors

CHEMISTRY, MECHANISM OF ACTION, AND PHARMACOLOGY The most potent suppressors of gastric acid secretion are inhibitors of the gastric H+,K+-ATPase (proton pump) (Figure 36-2A). In typical doses, these drugs diminish the daily production of acid (basal and stimulated) by 80-95%. Five proton pump inhibitors are available for clinical use: omeprazole (PRILOSEC, rapinex, zegerid) and its S-isomer, esomeprazole (nexium), lansoprazole (prevacid), rabeprazole (aciphex), and pantoprazole (protonix). These drugs have different substitutions on their pyridine and/or benzimidazole groups but are remarkably similar in their pharmacological properties. Omeprazole is a racemate; the S-isomer, esomeprazole (S-omeprazole), is eliminated less rapidly than R-omeprazole, which theoretically provides a therapeutic advantage because of the increased t1/2. All proton pump inhibitors have equivalent efficacy at comparable doses.

Proton pump inhibitors are prodrugs that require activation in an acid environment. After absorption into the systemic circulation, the prodrug diffuses into the parietal cells of the stomach and accumulates in the acidic secretory canaliculi. Here, it is activated by proton-catalyzed formation of a tetracyclic sulfenamide (Figure 36-2), trapping the drug so that it cannot diffuse back across the

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