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Add Strokes to the Scary List of PPI Side Effects

The list of serious PPI side effects keeps expanding. Add strokes and heart attacks to several other complications like infections, fractures and dementia.

Proton pump inhibitors like esomeprazole, lansoprazole or omeprazole are the most popular treatments for heartburn and reflux disease. It is estimated that 15 million Americans spend $10 billion on such drugs annually. The FDA considers these medications so safe that it has approved drugs like Nexium, Prevacid and Prilosec for over-the-counter sale. But new PPI side effects are still being discovered.

PPIs and Strokes:

Danish researchers analyzed medical records of more than 244,000 adults. They found that those taking PPIs were 21 percent more likely to experience a stroke over the following six years. The higher the dose, the greater the risk.

Why Pharmacologists Love Dose Response Curves:

Pharmacologists like to use the term “dose response curve” to mean that the more you take of something the greater the likelihood there will be an effect. A baby aspirin (81 mg) does not cause a lot of stomach upset for most people. Two aspirin pills, however, increase the likelihood of heartburn. Someone who takes six aspirin tablets four times a day will be at even greater risk for complications. That’s a dose response curve. Another way to think of it is alcohol. One glass of wine won’t make many people drunk. Three glasses might get you close to the legal limit. Five glasses over two hours could get your arrested for driving under the influence.

Here is what the researchers found with PPIs. It was reported at the meetings of the American Heart Association Meetings in New Orleans (Nov. 2016). A high dose (over 80 mg) of pantoprozole (Protonix) produced a 94 percent increased risk of a clotting stroke compared with people not taking an acid-suppressing drug. Patients who took 40 mg of omeprazole experienced a 40 percent increased risk.

When side effects go up as the dose is raised, that’s pretty convincing evidence. It is not, however, proof positive. This was an epidemiological study so cause and effect have not been established. The investigators suggest a follow-up clinical trial to confirm the results. In the meantime, patients are urged to take PPIs only for serious digestive disorders for as short a period of time as possible.

How Plausible Is This New Complication?

Stroke is not the only cardiovascular complication of PPIs. A prior study published in the journal PLoS One (June 10, 2015) reported a linkage between these heartburn drugs and heart attacks. There is even a proposed mechanism.

The Law of Unintended Consequences:

PPIs block an ATPase enzyme (a proton pump) that prevent the stomach lining from making hydrochloric acid. Gastroenterologists like to think that is a good thing. But it turns out PPIs are not so selective.

That is not the only enzyme the drugs affect. They also interfere with another enzyme (DDAH). This enzyme is important for cardiovascular health. When it is inhibited, wheels are set into motion that lead to a cascade of events that may have unexpectedly harmful vascular effects (Circulation, Aug 20, 2013). Another critical enzyme, nitric oxide synthase is indirectly affected. This enzyme is essential for making…you guessed it…nitric oxide. This compound is essential for dilating blood vessels and keeping them flexible. Without enough nitric oxide on board you end up with what doctors call “endothelial dysfunction.”

We call this the law of unintended consequences. Push on the balloon in one place and it just may bulge somewhere else. If nitric oxide levels drop there could be an increased risk for both heart attacks and strokes.

Other Scary PPI Side Effects

In recent years there have been a surprising number of serious adverse reactions linked to proton pump inhibitors. Here is a partial list:

  • Infections (pneumonia, Clostridium difficile, aka C. diff)
  • Kidney damage (chronic kidney disease)
  • Heart attacks and vascular calcification
  • Dementia, Alzheimer’s disease
  • Malabsorption of nutrients (calcium, magnesium, zinc, vitamin B12)
  • Weakened bones, osteopenia, osteoporosis, fractures
  • Blood disorder (thrombocytopenia, anemia, iron deficiency)

Popular Proton Pump Inhibitors

  • Dexlansoprazole (Dexilant)
  • Esomeprazole (Nexium)
  • Esomeprazole plus naproxen (Vimovo)
  • Lansoprazole (Prevacid)
  • Omeprazole (Prilosec)
  • Omeprazole plus sodium bicarb (Zegerid)
  • Pantoprazole (Protonix)
  • Rabeprazole (Aciphex)

The People’s Pharmacy Bottom Line:

PPIs are not the super safe drugs we once imagined. If an herb or a dietary supplement were found to have half the side effects of PPIs, the FDA and most health professionals would be demanding its removal from the market.

Although such drugs can be beneficial for many patients, we suspect that they are over prescribed. We also think that the FDA’s decision to make them available without medical supervision was short sighted. We think that over-the-counter sale of PPIs should be reconsidered.

No one should ever stop a PPI suddenly or without medical supervision. Rebound hyperacidity can cause unbearable heartburn symptoms.

People who would like to learn more about other ways to deal with indigestion may find our Guide to Digestive Disorders of interest.



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About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.”.
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