Side Effects of PPI Use

Introduction to PPIs

Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by glands in the lining of your stomach. Omeprazole a type of PPI is among the top 10 most prescribed drugs in the United States. They are first-line treatments prescribed for;

1. Esophagitis

2. Non-erosive reflux disease/GERD

3. Peptic ulcer disease

4. Prevention of nonsteroidal anti-inflammatory drug-induced ulcers

5. Zollinger-Ellison Syndrome

6. Part of the triple therapy regimen for Helicobacter pylori infections

Types of PPIs

1. Omeprazole

2. Esomeprazole

3. Lansoprazole

4. Dexlansoprazole

5. Pantoprazole

6. Rabeprazole

Mechanism of Action

Ultimately, PPIs function to decrease acid secretion in the stomach. These drugs are activated in the acidic environment of the stomach by acting on the parietal cells of the stomach which contain the H+/K+ ATPase enzyme, the proton pump, that PPIs block to inhibit stomach acid production.

PPIs have 90 minutes active action, because of this short half-life, only 70% of the pump enzymes are inhibited. It takes about 2 to 3 days for PPIs to reach steady state of stomach acid inhibition. About 20% of proton pumps are newly synthesised over a 24-hour period, and there may be greater pump synthesis at night than during the day. This may explain why some people experience increase heartburn and reflux at night, affecting their sleep.

Side Effects

It is accepted that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use can lead to adverse side effects such as rebound, infections and conditions related to nutritient deficiencies.

Side effects associated with the use of proton pump inhibitors (Yibirin et al, 2021).

Gastrointestinal Infections

PPI use has been linked with increased risk of Clostridium difficile infections and Small Intestinal Bowel Overgrowth (SIBO). The acidic nature gastric juice kills bacteria to prevent bacterial colonisation and infection. Studies have shown when stomach acid production is inhibited this increased the risk of altered intestinal flora and susceptibility to gastrointestinal infections (Yibirin et al, 2021).

Liver disease

Chronic PPI use of more than 12 months has been linked with increased risk of cirrhosis-related complications such as hepatic encephalopathy, spontaneous bacterial peritonitis, and liver cancer (Yibirin et al, 2021). The mechanism of liver injury associated with PPI use, is not completely understood, although researchers observed that proton pump inhibition leads to intestinal bacterial overgrowth and an altered intestinal flora, which may lead to increased concentrations of several potentially harmful substances passing through the liver. PPIs are broken down in the liver; therefore, patients with liver disease may be at risk for increased liver toxicity (Yibirin et al, 2021).

Fracture risk

Retrospective studies have suggested a relationship between long-term PPI dose dependent use and decreased bone mineral density, leading to an increase in fracture risk, especially hip fractures. The risk appears to be higher in patients with a risk factor for osteoporosis. The proposed mechanism that link long-term PPI-based therapy with decreased bone mineral density is low stomach acid secretion and low pH. Stomach acid production and cidity play an important role in the intestinal absorption of calcium from ingested food (Yibirin et al, 2021).

Vitamin B12 malapsortion

Suppression of gastric parietal cells inhibit adequate stomach acid and IF production, subsequently affecting absorption of vitamin B12 leading to potential vitamin b12 deficiency. Food-bound vitamin B12 enters the stomach, along with salivary R-binder protein molecule. Vitamin B12 absorption requires gastric pariatial cells to produce stomach acid production to breakdown food to release vitamin B12 to bind to salivary R-binder and to produce a second vitamin B12–binding protein, intrinsic factor (IF). The R binder–B12 complex and unbound IF then enter the small intestine where the R binder is hydrolysed by pancreatic enzymes and vitamin B-12 is released for absorption in the terminal ileum (Miller, 2018).

Iron deficiency

Chronic use of PPI have been associated with iron deficiency and iron deficiency anaemia through suppression of stomach acid. Haem ferrous (Fe2+) and non-haem ferric (Fe3+) iron are bound to animal and plant protein that require adequate stomach acid to breakdown protein to release iron for absorption. Ferrous iron (Fe2+) requires low pH of stomach acid to convert ferric iron (Fe3+) to ferrous iron (Fe2+) for absorption (Tran et al, 2019).

Rebound Acid Secretion 

PPIs can increase the levels of gastrin, which in turn leads to increased proliferation of Enterochromaffin-like (ECL) cells. ECL cells produce histamine to stimulate parietal cells to activate their H+/K+ ATPase and produce acid into the stomach. PPI suppression of parietal cell production creates feedback mechanism for the body to increase gastrin to stimulate proliferation of ECL cells to activate stomach acid. When PPI is discontinued after prolonged use, it has been shown in some cases to result in acid levels higher than before the initiation of PPIs. This effect has been referred to as rebound acid secretion (Helgadottir & Bjornsson, 2019)

Nutritional Therapy to Address PPI Adverse Effects

For those that are on long-term PPI use for acid reflux/GERD and have concerns about rebound then nutrititional therapy can be the appropriate complementary approach weaning you off PPIs without experiencing dibilitating acid reflux rebound.

If you suspect a gut infection such as SIBO or a nutrient deficiency then nutrititional therapy can get to the root cause of your acid reflux/GERD and address gut infections and deficiencies.

Learn about the Reverse Reflux Naturally 90-Day Nutrition & Wellness Programme for a 1:1 personalised programme.

Unsure if this programme is suitable for you? Book a free 30 minute health review to ask your questions.

References:

1. Helgadottir, H., & Bjornsson, E. S. (2019). Problems Associated with Deprescribing of Proton Pump Inhibitors. International journal of molecular sciences, 20(21), 5469. https://doi.org/10.3390/ijms20215469

2. Miller J. W. (2018). Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications. Advances in nutrition (Bethesda, Md.), 9(4), 511S–518S. https://doi.org/10.1093/advances/nmy023

3. Tran-Duy, A., Connell, N. J., Vanmolkot, F. H., Souverein, P. C., de Wit, N. J., Stehouwer, C. D. A., Hoes, A. W., de Vries, F., & de Boer, A. (2019). Use of proton pump inhibitors and risk of iron deficiency: a population-based case-control study. Journal of internal medicine, 285(2), 205–214. https://doi.org/10.1111/joim.12826

4. Shin, J. M., & Sachs, G. (2008). Pharmacology of proton pump inhibitors. Current gastroenterology reports, 10(6), 528–534. https://doi.org/10.1007/s11894-008-0098-4

5. Yibirin, M., De Oliveira, D., Valera, R., Plitt, A. E., & Lutgen, S. (2021). Adverse Effects Associated with Proton Pump Inhibitor Use. Cureus, 13(1), e12759. https://doi.org/10.7759/cureus.12759