Side Effects of Long‐Term Proton Pump Inhibitor Use: A Review

Haastrup, Peter; Thompson, Wade; Søndergaard, Jens; Jarbøl, Dorte Ejg

doi:10.1111/bcpt.13023

Cited by 140 publications

(152 citation statements)

References 69 publications

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“…A similar practice of inappropriate prescription of acid suppressants is commonplace in veterinary medicine. Judicious use of acid suppressants is warranted, considering recent studies documenting adverse effects of long‐term PPI supplementation in people and animals …”

Section: Introductionmentioning

confidence: 99%

ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats

Marks

Kook

Papich

et al. 2018

Veterinary Internal Medicne

102

177

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The gastrointestinal (GI) mucosal barrier is continuously exposed to noxious toxins, reactive oxygen species, microbes, and drugs, leading to the development of inflammatory, erosive, and ultimately ulcerative lesions. This report offers a consensus opinion on the rational administration of GI protectants to dogs and cats, with an emphasis on proton pump inhibitors (PPIs), histamine type‐2 receptor antagonists (H2RAs), misoprostol, and sucralfate. These medications decrease gastric acidity or promote mucosal protective mechanisms, transforming the management of dyspepsia, peptic ulceration, and gastroesophageal reflux disease. In contrast to guidelines that have been established in people for the optimal treatment of gastroduodenal ulcers and gastroesophageal reflux disease, effective clinical dosages of antisecretory drugs have not been well established in the dog and cat to date. Similar to the situation in human medicine, practice of inappropriate prescription of acid suppressants is also commonplace in veterinary medicine. This report challenges the dogma and clinical practice of administering GI protectants for the routine management of gastritis, pancreatitis, hepatic disease, and renal disease in dogs and cats lacking additional risk factors for ulceration or concerns for GI bleeding. Judicious use of acid suppressants is warranted considering recent studies that have documented adverse effects of long‐term supplementation of PPIs in people and animals.

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Section: Introductionmentioning

confidence: 99%

ACVIM consensus statement: Support for rational administration of gastrointestinal protectants to dogs and cats

Marks

Kook

Papich

et al. 2018

Veterinary Internal Medicne

102

177

View full text Add to dashboard Cite

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“…Inhibitory effects of PPIs have also been observed in the renal collecting duct, in osteoclast resorptive pits and on lysosomal enzymes . The short‐term use of PPIs causes only mild side effects, whereas long‐term exposure has been associated with osteoporosis and bone fractures . In fact, since 2010, all manufacturers of PPIs in the USA are required by the Food and Drugs Agency (FDA) to label the drugs with a warning about possible hip, wrist and spine fractures when used in high doses or for an extended period of time (>1 year)…”

Section: Introductionmentioning

confidence: 99%

“…9,10 The short-term use of PPIs causes only mild side effects, whereas long-term exposure has been associated with osteoporosis and bone fractures. [11][12][13][14][15][16] In fact, since 2010, all manufacturers of PPIs in the USA are required by the Food and Drugs Agency (FDA) to label the drugs with a warning about possible hip, wrist and spine fractures when used in high doses or for an extended period of time (>1 year). 17 Lysosomes are acidic organelles (pH 3.5) with membrane proton pumps.…”

mentioning

confidence: 99%

Lansoprazole inhibits the cysteine protease legumain by binding to the active site

Bosnjak

Solberg

Hemati

et al. 2019

Basic Clin Pharma Tox

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Proton pump inhibitors (PPIs) are prodrugs used in the treatment of peptic ulcer diseases. Once activated by acidic pH, the PPIs subsequently inhibit the secretion of gastric acid by covalently forming disulphide bonds with the SH groups of the parietal proton pump, that is the H+/K+‐ATPase. Long‐term use of PPIs has been associated with numerous adverse effects, including bone fractures. Considering the mechanism of activation, PPIs could also be active in acidic micro‐environments such as in lysosomes, tumours and bone resorption sites. We suggested that the SH group in the active site of cysteine proteases could be susceptible for inhibition by PPIs. In this study, the inhibition by lansoprazole was shown on the cysteine proteases legumain and cathepsin B by incubating purified proteases or cell lysates with lansoprazole at different concentrations and pH conditions. The mechanism of legumain inhibition was shown to be a direct interaction of lansoprazole with the SH group in the active site, and thus blocking binding of the legumain‐selective activity‐based probe MP‐L01. Lansoprazole was also shown to inhibit both legumain and cathepsin B in various cell models like HEK293, monoclonal legumain over‐expressing HEK293 cells (M38L) and RAW264.7 macrophages, but not in human bone marrow‐derived skeletal (mesenchymal) stem cells (hBMSC‐TERT). During hBMSC‐TERT differentiation to osteoblasts, lansoprazole inhibited legumain secretion, alkaline phosphatase activity, but had no effects on in vitro mineralization capacity. In conclusion, lansoprazole acts as a direct covalent inhibitor of cysteine proteases via disulphide bonds with the SH group in the protease active site. Such inhibition of cysteine proteases could explain some of the off‐target effects of PPIs.

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“…Because these drugs usually cause few adverse effects, they are usually available over‐the‐counter in many countries and there is an overall impression that their use is relatively not risky. In fact, possible adverse effects induced by PPIs include increased susceptibility to bacterial infections, deficient absorption of micronutrients, hypergastrinaemia and its consequences, dementia and kidney diseases . While these drugs are usually regarded as safe drugs, a number of studies have shown a variety of pleiotropic effects associated with the use of PPIs, which may be attributable to interactions of PPIs with other relevant biological mechanisms not directly associated with suppression of gastric acid secretion.…”

mentioning

confidence: 99%