Another study has suggested a link between proton pump inhibitors (PPIs) and cognitive decline. Use of a PPI for greater than 4.4 years was associated with 33% increased risk of dementia. Short-term use of PPIs was not associated with dementia.
One proposed mechanism involves amyloid beta (Aβ), a cardinal feature of Alzheimer's disease pathology. Lansoprazole (Prevacid) was shown to enhance Aβ production and inhibit Aβ degradation (Badiola et al, 2013).
H2-antihistamines (H2 blockers) such as ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid), and cimetidine (Tagamet) have NOT been linked to dementia or cognitive decline. However, H2 blockers are less effective than PPIs in reducing gastric acid.
In psychiatry, certain PPIs may cause problems related to pharmacokinetic interactions.
Omeprazole (Prilosec)
Class: Proton Pump Inhibitor (PPI)
Pronunciation: oh MEP ra zol
Mnemonic phrase / mascot: “Pry loose (Oh my!)”
FDA approved for:
❖ GERD
❖ Gastric ulcer
❖ Duodenal ulcer
❖ Hypersecretory conditions
❖ Helicobacter pylori infection
Used off-label for:
❖ Ulcer prophylaxis
Omeprazole (Prilosec) is a proton pump inhibitor (PPI) available over-the-counter. As a CYP2C19 inHibitor, it increases levels of certain SSRIs and benzodiazepines.
As a P-glycoprotein inhibitor, it can allow certain drugs (e.g., loperamide) into the CNS that would otherwise be quickly pumped outside the blood-brain barrier.
PPIs are used for the treatment of heartburn. They stop secretion of H+ ions (protons) into the gastric lumen by inhibiting the gastric parietal cell hydrogen-potassium ATPase, also known as the “proton pump”. Although PPIs have a short serum half-life of about 1 hour, they inhibit gastric acid secretion for 24 hours by irreversibly inhibiting the proton pump through a permanent covalent bond.
PPIs decrease gastric acid secretion up to 99%, making them substantially more effective than H2 receptor antagonists like ranitidine (Zantac) and famotidine (Pepcid). However, PPIs have been associated with risk of dementia, while H2 blockers have not.
PPIs are often taken longer than needed. If used for heartburn/GERD, they should be stopped after 4–8 weeks. An established risk of long-term PPI use is osteoporosis. Several studies have associated PPI use with cognitive decline. Other risks include hypomagnesemia and vitamin B12 deficiency.
Omeprazole and esomeprazole are more likely to cause relevant kinetic drug-drug interactions than other PPIs, as shown in the table below. Esomeprazole is the ‘Next omeprazole’ (Nexium).
There is no convincing evidence that any one PPI is more effective or better tolerated than the others. So, it is advisable to avoid omeprazole and esomeprazole to avoid interactions. For a prescription PPI, pantoprazole (Protonix) is preferred. For an OTC PPI, choose lansoprazole (Prevacid)—I like Lance’s Pants.
Dosing
PPIs should be taken 30 minutes before a meal; For GERD, the dose is 20 mg QD x 4–8 weeks; For gastric ulcer, the dose is 40 mg QD x 8 weeks; For Zollinger-Ellison syndrome (hypersecretory condition), substantially higher doses are needed; For erosive esophagitis, long-term treatment is needed; For helicobacter pylori infection, it is given BID as part of a multi-drug combo including (for instance) bismuth (Pepto-Bismol), tetracycline, and metronidazole.
Pharmacodynamic interactions
❖ Uncommonly, PPIs can cause hypomagnesemia, which could increase the risk of torsades when combined with QT-prolonging medications
Pharmacokinetic interactions
❖ Gastric alkalinizer
❖ CYP2C19 inHibitor
❖ CYP2C19 substrate (all PPIs)
– 2C19 ultrarapid metabolizers may need to take higher doses
– 2C19 poor metabolizers can take lower doses
An example of a relevant P-gp interaction involves the OTC opioid antidiarrheal loperamide (Imodium). Loperamide does not cause central opioid effects under normal circumstances. If the individual takes a potent P-gp inhibitor, megadose loperamide can stay in the brain long enough to cause euphoria. The P-gp inhibitor typically used the achieve this recreational effect is omeprazole (Prilosec).
Northuis, C., Bell, E., Lutsey, P., George, K. M., Gottesman, R. F., Mosley, T. H., ... & Lakshminarayan, K. (2023). Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study. Neurology.
Gomm, W., von Holt, K., Thomé, F., Broich, K., Maier, W., Fink, A., ... & Haenisch, B. (2016). Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA neurology, 73(4), 410-416.
Mehta, R., Kochar, B., Zhou, Z., Broder, J. C., Chung, P., Yang, K., ... & Chan, A. T. (2023). ASSOCIATION OF PROTON PUMP INHIBITOR USE WITH INCIDENT DEMENTIA AND COGNITIVE DECLINE IN OLDER ADULTS: A PROSPECTIVE COHORT STUDY. Gastroenterology.
Badiola, N., Alcalde, V., Pujol, A., Münter, L. M., Multhaup, G., Lleó, A., ... & Aloy, P. (2013). The proton-pump inhibitor lansoprazole enhances amyloid beta production. PloS one, 8(3), e58837.
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