from fundic glands (which is distinct from fundic gland polyposis); these polyps do not cause cancer and resolve when PPIs are discontinued. There is concern that use of PPIs may mask gastric cancers or other serious gastric problems. PPI use has also been associated with the development of microscopic colitis. Cardiovascular Associations of PPI use and cardiovascular events have also been widely studied but clear conclusions have not been made as these relative risks are confounded by other factors. PPIs are commonly used in people with cardiovascular disease for gastric protection when aspirin is given for its antiplatelet actions. An interaction between PPIs and the metabolism of the platelet inhibitor clopidogrel is known and this drug is also often used in people with cardiac disease. There are associations with an increased risk of stroke, but this appears to be more likely to occur in people who already have an elevated risk. One suggested mechanism for cardiovascular effects is because PPIs bind and inhibit dimethylargininase, the enzyme that degrades asymmetric dimethylarginine (ADMA), resulting in higher ADMA levels and a decrease in bioavailable nitric oxide. Cancer A 2022 umbrella review and meta-analysis of observational studies show that proton-pump inhibitor significantly increases the risk of four cancers. Other Associations have been shown between PPI use and an increased risk of pneumonia, particularly in the 30 days after starting therapy, where it was found to be 50% higher in community use. Other very weak associations of PPI use have been found, such as with chronic kidney disease, dementia and HCC. As of 2016, results were derived from observational studies, it remained uncertain whether such associations were causal relationships. Mechanism of action Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. Because the H,K-ATPase is the final step of acid secretion, an inhibitor of this enzyme is more effective than receptor antagonists in suppressing gastric acid secretion. All of these drugs inhibit the gastric H,K-ATPase by covalent binding, so the duration of their effect is longer than expected from their levels in the blood. Targeting the terminal step in acid production, as well as the