Nexium and PPIs side effects

Nexium (Esomeprazole) is part of a class of medications called proton pump inhibitors (PPIs) associated with many serious side effects. These drugs are used to treat several conditions associated with gastric hyperacidity by reducing the amount of acid produced by the stomach. Among the many indications of PPI, the treatment of peptic ulcers and gastroesophageal reflux disease (GERD) are the most common, although they’re often used to prevent gastric bleeding as pharmacological protectors during nonsteroidal anti-inflammatory drug (NSAID) therapy 1, 2. They’re sold in several countries as over the counter (OTC) drugs to treat dyspepsia and heartburn 3. However, these medicines are associated with a long list of dangerous side effects, some of which seem to be much more severe than simple nausea or a headache.


How PPIs work and why they’re so widely used

In order to understand why proton pump inhibitors such as omeprazole and esomeprazole and are dangerous, a brief explanation of their mechanism of action is required. A PPI acts by irreversibly blocking the H+ proton pump of the gastric parietal cells. Hydrochloric acid secretion can be reduced by up to 99%, so their effectiveness is significantly above any other similar antacid drug, such as H2-receptor antagonists (Zantac, Tagamet or Pepcid) 3, 4. However, the proton pump directly releases H+ ions into the stomach and is the last stage of gastric acid production and secretion. Although much less acid is secreted after PPIs are taken, many other stages of acid production are unaffected, and thus some of the other hormones involved in this process such as gastrin are not inhibited at all 4.


The unpredictable consequences and dangers of long-term use of PPIs

PPIs are among the most used and sold medications worldwide with almost 114 million prescriptions in 2009 (netting over $14 billion in sales) in just the United States 5. They’re generally seen as safe medications with very few drawbacks and contraindications on the short term. Their own safety was, however, the reason why these drugs became widely overprescribed and overused, as well as taken for an excessively long time for which they were never intended, nor tested for 6. Many people keep using them for years and years, actually suppressing their stomach acid production for unhealthy lengths of time with dire long-term consequences 7.


Gastric tumors and the effects of hypergastrinemia

The long-term suppression of acid secretion is called “hypochlorhydria,” which literally means “low levels of hydrochloric acid.” Hypochlorhydria stimulates gastric cells to release a hormone called gastrin, in the vain effort of increasing the amount of gastric acid back its normal levels 8. According to the results of an experiment published in the journal Gastroenterology, a daily 20 mg dose of Prilosec (Nexium’s “older brother”, a mirror drug) increases gastrin levels three to fourfold after just 1-2 months of use. Longer doses (40 mg) or longer treatments (3-12 months) however, increased gastrin levels as much as tenfold 9. The excess of gastrin (called “hypergastrinemia”) stimulates a mucous membrane of the stomach called the oxyntic mucosa. When cells from this layer start growing uncontrolled, however, they may evolve into dangerous stomach tumors 7, 8, 10. The long-term effects of hypergastrinemia are also still poorly understood and may have other consequences such as a rebound effect of excessive stomach acid production when patients stop taking these medications 6. It is also associated with an increased risk of cancer in selected patients affected by GERD11.


Nutritional issues: increased risk of bone fractures, anemia, and malabsorption

Gastric acid secretion is a physiological mechanism that affects the absorption of several nutrients in humans. Although hyperacidity may represent an issue for many individuals, long-term suppression of stomach secretion may exert a detrimental effect on our ability to absorb several substances such as iron, vitamin B12, Vitamin C, magnesium, and calcium. Malabsorption may lead to nutritional deficiencies, which is especially dangerous for the elderly and frail subjects.

To be absorbed, iron must undergo a conversion that requires the presence of ascorbic acid (Vitamin C) and a low gastric pH (i.e. a very acidic medium). PPIs inhibit cellular secretion of acid and ascorbic acid inside the stomach, and the absence of a proper acidic medium also causes Vitamin C introduced with diet to became unstable, further preventing its ability to help iron absorption. All these effects contribute to a potential iron deficiency anemia as well as restless leg syndrome in patients who take PPIs for longer timespans 12.

Vitamin B12 that is acquired from food is bound to a protein complex that must be cleaved before the vitamin itself could be absorbed. Stomach parietal cells produce a compound called “intrinsic factor” (IF) which can separate Vitamin B12 from the protein it’s bonded to, allowing its absorption. Intrinsic Factor requires a very acid environment to exert its action, but guess what? Both IF and acid secretions are inhibited by PPIs, thus preventing an optimal absorption of this nutrient. Vitamin B12 deficiency will eventually lead to pernicious anemia, also known as megaloblastic anemia 13.

Long-term PPIs use has also been associated with an increased risk of bone fractures. Previously, it was theorized that hypochlorhydria could impair calcium absorption. However, more recent studies pointed out that this mechanism is not related to osteoporosis risk 14. Nonetheless, PPIs treatment is still linked with an increased risk of hip, wrist, and spinal fractures so significant, that the FDA added a new warning label about this potential side effect in March 2011 15. PPIs may act directly by inhibiting proper bone turnover, making bones denser but more brittle at the same time, thus making them more prone to fractures 14. Vitamin B12 deficiency is also associated with weakened bone strength 16.

PPIs may also negatively affect the absorption of magnesium, leading to hypomagnesemia 17. Although the mechanism through which magnesium absorption is impaired has not been yet clarified, its effects can be readily measured. Patients with low serum magnesium levels suffer from symptoms such as fatigue, muscle cramps, and arrhythmias (irregular heartbeat), as well as reduced bone strength 13.


Increased risk of infections, pneumonia, and diarrhea

The principal function of the gastric hydrochloric acid is to break the food we eat into simpler molecules so we can absorb its nutrients 18. However, it does more than, as it’s one of the principal barriers used by humans to defend themselves from bacterial and viral infections. The low pH of the gastric juice is, in fact, able to sterilize the content that reaches the digestive tract by killing most of the organisms that live in food. A reduction in acidity increases the risk of local gastrointestinal infections, as well as systemic ones such as pneumonia 19. Proton pump inhibitors can increase the risk of small intestinal bacterial overgrowth (SIBO) by 50% because they suppress the gastric acid barrier 20. This may, in turn, lead to dire consequences such as enteritis and a life-threatening form of acute diarrhea caused by Clostridium difficile bacteria 21, 22.

In patients with hypochlorhydria, bacteria and viruses from the oral cavity will start colonizing the upper gastrointestinal tract. Pathogens can also ascend from the colonized stomach up the esophagus, and reach the trachea and the respiratory system. A study from the Journal of American Medical Association showed an almost doubled risk of pneumonia in patients under PPI treatment. Although other acid-suppressive drugs such as H2-receptor antagonists also showed a similarly increased risk, albeit to a lower extent, PPIs were the only ones for which a dose-response relationship could be observed 23.


The potential risk of chronic kidney disease and the Nexium lawsuits

A newer study published in the JAMA Internal Medicine journal on February 2016, showed that the risk of chronic kidney disease (CKD) is 20 percent to 50 percent higher in patients under treatment with proton pump inhibitors. Higher doses were also linked with higher risks, suggesting that a direct correlation between risk and dosage may be traced. Researchers analyzed data from 10,482 total subjects and found that other antacid drugs such as H2-receptor antagonists were not associated with this risk increase 24. Chronic kidney disease is a condition characterized by the gradual loss of renal function, which may eventually progress to kidney failure, leaving no treatment option other than either dialysis (artificial filtering) or kidney transplant 25. Nexium itself was linked with several cases of acute interstitial nephritis, a dangerous complication which may also progress to CKD if the medication is not promptly suspended and treatment is administered 26, 27. In December 2014, the FDA issued a warning about acute interstitial nephritis during treatment with esomeprazole, even if the mechanism of this adverse reaction is still unknown 28. Since then, many people started filing lawsuits against AstraZeneca claiming the pharmaceutical company failed to warn the public of the serious threat of an increased risks of kidney damage.


Risk of cardiovascular diseases and heart attacks

Last, but not least, a recent large study called PLOS ONE showed that PPIs could be linked with an increased risk of cardiovascular diseases 29. Scientists investigated a theory they explained in their previous report, that demonstrated how PPIs could alter the vascular endothelium at a molecular level 29. According to their theory, PPIs may inhibit the production of a substance with critical vasoprotective effects within the human body. In their subsequent huge study, the research team analyzed data coming from 2.9 million patients and compared the effects of PPIs to those of the H2-receptor antagonists. Their findings showed an estimated increase in heart attack risk of 16 to 21 percent in patients under treatment with PPIs, providing substantial evidence that these drugs may adversely impact vascular function 29, 30.


Article by Dr. Claudio Butticè, Pharm.D.

Published: 2016/07/28
Last Updated: 2016/08/28