Physiology of the parietal cell and therapeutic implications

The field of acid suppression has been advanced by therapeutics of increasing specificity for inhibiting gastric acid secretion. Particularly important are proton pump inhibitors (PPIs), which inhibit the activity of the gastric acid pump (H+,K(+)-adenosine triphosphatase), the final common step in gastric acid production. Histamine2-receptor antagonists, which act at an early stage of the acid secretion pathway, are less effective and are subject to intolerance. The PPIs are weak bases that undergo accumulation in the acidic space of the secreting parietal cell and are converted in acid to the active thiophilic form, which then forms disulfide bonds with key cysteines of the gastric acid pump. Pantoprazole differs from other PPIs in terms of its reaction with cysteine 822 in the pump and with cysteine 813, a common binding site for all PPIs. Both cysteines are in the sixth transmembrane segment, which is part of the ion transport pathway. This selective binding may have an impact on the dwell time of pantoprazole versus other PPIs because it is inaccessible to reducing agents, in contrast to cysteine 813. Pantoprazole is also very stable (has a slow rate of activation) at neutral pH values compared with other PPIs and has a relatively robust plasma concentration-time curve. These agents are important in the management of duodenal ulcers, nonsteroidal antiinflammatory drug-induced ulcers, gastroesophageal reflux disease, and dyspepsia, but basic pharmacokinetic and pharmacodynamic differences among them may affect clinical utility.