Proton-pump Inhibitors Drug Interactions and Long Term Side Effects

Proton-pump inhibitors (PPIs) are a class of medications for the treatment of heartburn and acid-related disorders. On one hand, Proton-pump Inhibitors have long-lasting acid suppression effect, and alter the pH of the stomach, on the other hand,  PPIs are mainly metabolized by CYP2C19 and CYP3A4 in the body, and have varying degrees of inhibitory effects on CYP2C19, CYP3A4, p-glycoprotein and other transporters. It is necessary to pay attention to Proton-pump Inhibitors Drug Interactions and Long Term Side Effects before using it.

Drug Interaction of Proton-pump Inhibitors

Tyrosine kinase inhibitors (TKIs)

• Mechanism of action:The dissolution of some TKIs is pH-dependent, and the combined use of PPIs may result in reduced absorption and reduced bioavailability by 35% to 47%.
• Suggestion: It is recommended that gefitinib, dasatinib, and erlotinib be avoided in combination with PPIs if possible.

Citalopram or escitalopram

• Mechanism of action:Both omeprazole and esmeprazole can inhibit the activity of CYP2C19, resulting in an increase in the blood concentration of citalopram by 35.3% and 32.8%, and an increase in blood concentration of escitalopram by 93.9% and 81.8%.
• Suggestion: When combined with omeprazole or esomeprazole, the maximum dose of citalopram is 20 mg a day, and the dose of escitalopram should be reduced by 50%.

Cilostazol

• Mechanism of action: Omeprazole inhibits the activity of CYP2C19, resulting in an increase in the AUC value of cilostazol and its active metabolite by 26% and 69%.
• Suggestion: When cilostazol is used in combination with omeprazole, the dose of cilostazol should be reduced to 50 mg once, twice a day.

Warfarin

• Mechanism of action:Different PPIs have different degrees of inhibition on CYP2C19, which participates in the metabolism of PPIs (except ilaprazole) and warfarin at the same time. So PPIs may interfere with the metabolism of warfarin and enhance its anticoagulation effect and bleeding risk,
• Suggestion:Pay attention to monitor INR and prothrombin time when PPIs are used in combination with warfarin.

Mycophenolate mofetil

• Mechanism of action:PPIs increase the pH value in the stomach and reduce the absorption and bioavailability of mycophenolate mofetil, which may lead to acute rejection.
• Suggestion: PPIs and mycophenolate mofetil should be used with caution. Enteric solvent-based mycophenolate mofetil can be used to reduce the influence of PPIs on its absorption.

Methotrexate

• Mechanism of action: PPIs may block the efflux of methotrexate, resulting in high doses of methotrexate and increase the toxicity.
• Suggestion: Patients using high-dose methotrexate should consider temporarily discontinuing PPIs or using replacement therapy.

Long Term Size Effects of Proton-pump Inhibitors

Vitamin B12 deficiency

• Mechanism:  Gastric acid is closely related to the absorption of vitamin B12. Patients with long-term use of PPIs have a higher risk of vitamin B12 deficiency.
• Suggestion: For elderly patients with poor systemic nutrition, it is recommended to monitor the serum vitamin B12 level.

Hypomagnesemia

• Mechanism: Hypomagnesemia is a rare and serious adverse reaction of PPIs, which may be related to the following factors: 1) The suppression of acid by gastric acid leads to a decrease in the expression of genes and proteins related to magnesium transport; 2) PPIs  affect the bypass pathway of magnesium absorption. 3) PPIs reduce the amount of magnesium ions that can be used by the body and increase the excretion of magnesium from feces.
• Suggestion:It is recommended to regularly monitor the blood magnesium concentration in patients when prescribing long-term PPIs, and should not be combined with other drugs that may cause hypomagnesemia. For patients diagnosed with hypomagnesemia, use magnesium preparations and stop PPIs if necessary.

 Iron deficiency

• Mechanism: Gastric acid helps the separation of iron salts from food and increase iron absorption. PPIs inhibit gastric acid and may affect iron absorption.
• Suggestion: Long-term prescription of PPIs should be carefully prescribed for elderly patients or malnourished patients. It is recommended that hemoglobin levels of patients who have used PPIs for more than one year and have symptoms of suspected anemia should be tested. Patients with iron deficiency should evaluate the benefits and risks of continuing to use PPIs.

Osteoporosis and fracture

• Mechanism: PPIs cause alkalinization of the gastric environment, which can impair calcium absorption and bone density. PPIs can also inhibit osteoclast-mediated bone resorption.
• Suggestion: For patients with high calcium requirements and high fracture risk, it is recommended to pay attention to blood calcium, parathyroid hormone, bone mineral density and other indicators when using PPIs.

Intestinal infection

• Mechanism: Long-term application of PPIs makes the gastric environment alkalinize and reduce gastric acid barrier function, leading to bacterial colonization in the stomach and excessive growth of intestinal flora, increasing the risk of intestinal infection.
• Suggestion:For elderly patients with immune deficiencies or chronic underlying diseases, the benefits and risks of long-term PPIs treatment should be envaluated before using it. When patients have fatal intestinal infections without indications for emergency acid suppression therapy, do not use PPIs anymore.

Pneumonia

• Mechanism: PPIs change the internal environment, causing bacteria to colonize and overproduce in the stomach, increasing the risk of lung infection; PPIs reduce the activity of neutrophils and natural killer cells, reduce human immune function, and increase the risk of infection .
• Suggestion: The elderly are high-risk groups of pneumonia and gastroesophageal reflux disease. High-dose and long-term use of PPIs should be avoided as much as possible.

Dementia

• Studies have shown that long-term use of PPIs can cause cognitive impairment and increase the risk of dementia. The mechanism may be related to PPIs causing β-amyloid protein abnormalities and vitamin B12 deficiency.