Pharmacology of acid suppression in the hospital setting: focus on proton pump inhibition

Abstract

The more potent and longer-lasting inhibition of gastric acid secretion provided by proton pump inhibitors (PPIs) as compared with histamine-2-receptor antagonists is caused in large part by differences in their mechanism of action. PPIs block histamine-2-, gastrin-, and cholinergic-mediated sources of acid production and inhibit gastric secretion at the final common pathway of the H+/K+ adenosine triphosphatase proton pump. In contrast, histamine-2-receptor antagonists cannot block receptor sites other than those mediated by histamine. It seems that the rapid loss of acid suppression activity by the histamine-2-receptor antagonists may be attributed to tolerance. Such tolerance has not occurred in patients receiving PPIs because these agents are irreversible inhibitors of the H+/K+ adenosine triphosphatase proton pump. For these reasons, patients who have acid-related disorders that require high levels of acid suppression do not respond well to intravenous histamine-2-receptor antagonists and would be excellent candidates for intravenous PPI therapy. Candidates for intravenous PPIs also include patients who cannot receive oral PPIs and those who may need the higher acid suppression therapy provided by the intravenous rather than the oral route. Clinical studies have demonstrated the efficacy of intravenous pantoprazole in maintaining adequate control of gastric acid output during the switch from oral to intravenous therapy in patients with severe gastroesophageal reflux disease or the Zollinger-Ellison syndrome. Intragastric administration of solutions prepared from oral PPIs has been used as an alternative to the intravenous route in critical care settings. However, decreased bioavailability may limit the value of intragastric delivery of PPIs because of the high frequency of gastric emptying problems in critically ill patients.

Figure 1.

Physiology of nocturnal gastric acid secretion. How histamine-2–receptor antagonists and proton pump inhibitors suppress gastric acid secretion. ECL, enterochromaffin-like; PACAP, pituitary adenylate cyclase–activating polypeptide; M, muscarinic. Adapted with permission from Modlin and Sachs (6).

Figure 2.

Binding of proton pump inhibitors to the H⁺/K⁺ adenosinetriphosphatase (ATPase) proton pump. This diagrammatic representation shows the activation of PPIs within the parietal cell secretory caniculus and covalent binding to this enzyme that is responsible for suppression of gastric acid production. Adapted with permission from Wolfe and Sachs (2).

Figure 3.

Maintenance of control of gastric acid output by intravenous (IV) pantoprazole in patients with severe gastroesophageal reflux disease during switch over from oral proton pump inhibitors. MAO, maximal acid output. Adapted with permission from Metz et al (41).

Figure 4.

Control of acid output in patients with Zollinger-Ellison syndrome by intravenous pantoprazole. Note that acid output is rapidly inhibited and remains controlled, below 10 mEq/hr. Adapted with permission from Lew et al (44).

Figure 5.

Maintenance of control of acid output in patients with Zollinger-Ellison syndrome who are switched from an oral proton pump inhibitor (PPI) to intravenous pantoprazole. Note the similar level of gastric acid output control. bid, twice a day. Adapted with permission from Metz et al (45).