Proton Pump Inhibitors: Can They Hurt Me?

Medication side effects are an unfortunate potential consequence of treating diseases. There are drug safety concerns in the management of gastrointestinal diseases related to stomach acid which include reflux, dyspepsia and peptic ulcer disease.

Gastroesophageal reflux disease (GERD) is a common disorder affecting approximately 10-20% of people in the western world. It occurs when stomach acid enters the esophagus and causes bothersome symptoms such as heartburn, food regurgitation and excessive burping. Reflux symptoms can be debilitating and are the most common reasons why patients visit gastroenterologists.

Acid blocking medications are the mainstay of GERD treatment and include antacids, histamine receptor blockers and proton pump inhibitors (PPIs). The gastric parietal cell holds the main targets of acid blockade including hydrogen and histamine receptors. It is displayed in the figure below.

PPIs effectively block the production of hydrochloric acid in the stomach and are the most potent acid blockers. They are also used to treat dyspepsia (abdominal pain), peptic ulcer disease (stomach and proximal bowel ulcers) and for prophylaxis in people taking NSAIDs (non-steroidal anti-inflammatories) which can cause ulcers.

There have been several studies evaluating the safety of PPIs. The potential side effects associated with short and long term use include, but are not limited to, atrophic gastritis, fundic gland polyps, infections, inadequate absorption of vitamins and nutrients and acute interstitial nephritis. PPIs can also interact with other medications and decrease their efficacy. These safety concerns will be briefly reviewed here.

Atrophic gastritis is a chronic inflammatory condition affecting the stomach which can develop as a result of chronic suppression of hydrochloric acid or hypochlorhydria. Atrophic gastritis might not cause symptoms but is usually diagnosed during an upper endoscopy (a test performed by a gastroenterologist to evaluate the stomach lining). Surveillance endoscopies are recommended.

The bacteria, Helicobacter pylori infects the stomach and is associated with atrophic gastritis and gastric cancer. H pylori eradication does not significantly decrease cancer risk and current guidelines do not recommend H pylori screening in patients who require long term PPIs.

An upper endoscopy, might also reveal small benign gastric polyps known as fundic gland polyps (FGPs). These polyps are usually found incidentally and are associated with chronic PPI use. They are not associated with malignancy and surveillance endoscopies are not required. FGPs usually resolve following discontinuation of PPIs.

Low levels of stomach acid create an environment for bacterial infections. The upper intestinal tract can become colonization by bacterial pathogens with chronic PPI use. There is an increased risk of community acquired pneumonia in patients on PPIs. Antibiotic treatment is recommended.

The acidic environment of the stomach protects us from harmful bacteria and people taking PPIs are at increased risk of acquiring diarrheal infections such as Clostridium dificile, Shigella, Salmonella and Campylobacter. Clostridium dificile infection is treatable with antibiotics. The other infections usually resolve without therapy.

Suppressing stomach acid not only predisposes us to infections but can also affect absorption of vitamins and nutrients. Hydrochloric acid is necessary for the optimal absorption of iron, vitamin B12, calcium and magnesium. Inadequate absorption can occur in the setting of hypochlorhydria and lead to varying degrees of deficiencies.

PPI induced iron deficiency is usually mild and vitamin B 12 deficiency is more common in the elderly. Annual vitamin B12 monitoring in patients on long term PPI is recommended.

Calcium malabsorption can adversely affect bone health and possibly increase the risk of hip fractures. However, this is thought to occur in people with at least one additional risk factor for fractures. Age-appropriate bone mineral density screening should be obtained in those thought to be at increased risk of fracture.

Low levels of magnesium are associated with long term PPI use. Experts recommend monitoring magnesium levels periodically especially in people who are on other medications which can further decrease magnesium levels such as Digoxin and diuretics.

Additionally, long term PPI use is associated with increased levels of the hormone, gastrin and this state of increase is called hypergastrinemia. Gastrin levels are increased reflexively as a result of acid suppression. Hypergastrinemia has been associated with a risk of carcinoid tumors of the stomach. This risk is low and screening by way of measuring gastrin levels and/or endoscopy are not recommended.

Long term PPI use can also injure the kidneys and cause acute interstitial nephritis. It is a hypersensitivity reaction which usually resolves with discontinuation of the PPI. There is no risk of chronic kidney disease.

PPIs can interact with other drugs and potentially reduce their efficacy. There are safety concerns related to concomitant use of the PPI, Omeprazole and antiplatelet agent, Clopidogrel (Plavix). Omeprazole and Plavix compete for the same metabolic pathway in the liver and the antiplatelet (blood thinning) effect of Plavix is reduced in people taking both medications. There is a slightly increased risk of in stent re-stenosis or blockage of coronary stents. Those on dual therapy should be closely monitored.

Finally, some pregnant women experience reflux symptoms during pregnancy and most PPIs are considered to be safe during pregnancy.

In summary, PPIs are very effective widely prescribed medications for the management of acid related diseases. The safety concerns related to both short and long term use are rare. PPI related risks and benefits should be carefully considered by the physician and patient prior to beginning therapy and frequently reviewed throughout the treatment course. The shortest duration of therapy and/or the lowest effective dose of PPI are recommended. PPIs are considered safe medications and are usually well tolerated by most.