Proton pump inhibitors (PPIs), one of the most sold medications in the world, are a large class of drugs (Omeprazole, Pantoprazole, Esomeprazole, Lansoprasol, and Rabeprasol) that are prescribed for a variety of conditions like dyspepsia, gastroesophageal reflux disease, peptic ulcers, stress gastritis or ulcer prevention in high-risk situations, Zollinger-Ellison syndrome, Barrett’s esophagus as well as a part of the protocol for Helicobacter pylori eradication.

They are prescribed to reduce the acidity in the stomach, doing so by irreversibly inhibiting the hydrogen potassium adenosine triphosphate enzyme system (H+/K+ ATPase), targeting the gastric pump as it is the last step in gastric secretion into the stomach,  but seeing how stomach acid is really important for digesting proteins, Vitamin B, calcium as well as other nutrients, and far too less of it can cause a condition known as hypochlorhydria, that could evolve into intestinal metaplasia, that’s why the body eventually produces new proton pumps to replace the inhibited ones, a physiological process of cellular turnover, in order of restoring some of the acid production.

Despite their high efficiency, PPIs are associated with a large number of serious side effects, from increased gastrointestinal infection risk, bone fractures, diabetes mellitus, chronic kidney disease, and cardiovascular effects. But since it was first reported by Epstein et al in 2006, many studies have shown that PPIs could also be associated with hypomagnesemia, which in severe cases could lead to serious complications such as seizures, fatigue, arrhythmias, and muscle cramps, signs that should be recognized by physicians as potential effects to the long-term use of proton pump inhibitors.

Magnesium is an essential cation that is regulated in the body through intestinal and renal absorption and excretion as well as exchange with the bone. For the patients who use PPIs, hypomagnesemia is initially mild and could easily be missed because routine Mg2+ measurements are not usually performed during the PPI therapy, especially since these cases are often asymptomatic.

Even though the specific mechanism through which PPIs could cause hypomagnesemia has not yet been elucidated, there are some of the hypotheses that have been suggested by various studies throughout the years:

• The effect of PPIs on the small intestine: Magnesium is absorbed passively via paracellular transport which depends on the presence of Mg2+ as well as the permeability of the intestinal cells, both factors being compromised by proton pump inhibitors.
• Interfering with the active transport of magnesium through the proteins involved in Mg2+ uptake, TRPM6 and TRPM7 channels. This probability has also been linked to some genetic dispositions (TRPM6 mutations) that could make certain individuals more susceptible.
• PPIs increase the pH levels in the small intestine which causes a decrease in Magnesium solubility, making it harder for it to be absorbed in an alkaline environment.
• PPIs decrease the expression of certain proteins, such as claudins, that maintain permeability in intestinal cell junctions, which could lead to an eventual decrease in cell permeability for Magnesium.

PPI-induced hypomagnesemia has been described with several PPIs, and the substitution of one for another resulted in the recurrence of the symptoms. But in nearly all cases, magnesium levels returned to normal after stopping the treatment altogether.

Given the rising incidence of reported cases in the last years and the high severity of the manifestations of this disorder, physicians are urged to use PPIs only when they are needed, as well as keeping in mind that the longer the duration of the treatment, the higher the risks of this side effect occurring. It is also advised to check magnesium levels before prescribing PPIs, especially for patients who are also taking other hypomagnesemia-inducing medications like diuretics or digoxin, and suspect the proton pump inhibitor as a possible causing factor in front of some of the symptoms that had been mentioned above.

Toh JW, Ong E, Wilson R. Hypomagnesaemia associated with long-term use of proton pump inhibitors. Gastroenterol Rep (Oxf). 2015 Aug;3(3):243-53. doi: 10.1093/gastro/gou054. Epub 2014 Aug 19. PMID: 25138239; PMCID: PMC4527261.

Janett S, Camozzi P, Peeters GG, Lava SA, Simonetti GD, Goeggel Simonetti B, Bianchetti MG, Milani GP. Hypomagnesemia Induced by Long-Term Treatment with Proton-Pump Inhibitors. Gastroenterol Res Pract. 2015;2015:951768. doi: 10.1155/2015/951768. Epub 2015 May 4. PMID: 26064102; PMCID: PMC4434191.