From the Guidelines
Proton Pump Inhibitors (PPIs) work by blocking the final step of acid production by inhibiting hydrogen potassium ATPase in gastric parietal cells.
Mechanism of Action
- The mechanism of action of PPIs involves the inhibition of the hydrogen potassium ATPase enzyme system at the secretory surface of the gastric parietal cell [ 1 ].
- This inhibition prevents the formation of gastric acid, thereby reducing the acidity of the stomach.
- The potential mechanisms of benefit of PPIs also include stimulation of platelet aggregation and stabilization of fibrin clots by raising the gastric pH [ 1 ].
Clinical Use
- PPIs are commonly used for the treatment and prevention of acid-mediated upper gastrointestinal conditions, such as gastroesophageal reflux disease (GERD), peptic ulcers, and Zollinger-Ellison syndrome.
- They are also used for the prevention of NSAID-related gastric and duodenal ulcers, and for the treatment of Helicobacter pylori infection [ 1 ].
Important Considerations
- The use of PPIs has been linked to a number of adverse events, and de-prescribing of PPIs is an important strategy to lower pill burden while reducing real costs and theoretical risks [ 1 ].
- Higher doses of PPIs may be required in patients with complicated disease, such as gastrinoma patients with gastric acid hypersecretion-associated symptoms [ 1 ].
From the Research
Mechanism of Action of Proton Pump Inhibitors (PPIs)
- The mechanism of action of PPIs involves inhibition of the H-K-adenosine triphosphatase enzyme present in the parietal cells of the gastric mucosa 2.
- PPIs irreversibly inhibit proton pump (H+/K+ ATPase) function, making them the most potent gastric acid-suppressing agents in clinical use 3.
- The inhibition of gastric H/K adenosine triphosphatase via covalent binding to the cysteine residues of the proton pump provides the most potent acid suppression available 4.
- The therapeutic mechanism of action of PPIs, such as omeprazole, involves formation of a disulfide linkage to cysteine residues in the H+/K+ ATPase pump on gastric secretory cells, resulting in inhibition of acid secretion in the stomach 5.
Key Aspects of PPI Mechanism
- PPIs effectively alleviate acid-peptic symptoms and facilitate healing of inflamed or ulcerated mucosa by inhibiting gastric acid secretion 2.
- The covalent linkage between the sole sulfur group of omeprazole and selected cysteine residues of the pump protein results in inhibition of acid secretion in the stomach 5.
- PPIs may interact with non-canonical target proteins (non-pump molecules) resulting in unexpected pathophysiological effects, and may bind to multiple proteins and form highly stable complexes that are not dependent on disulfide linkages between the drug and protein targets 5.