Review

Proton Pump Inhibitors: The Good, the Bad, and the Unwanted

Authors: Saman Chubineh, MD, John Birk, MD

Abstract

Proton pump inhibitors (PPIs) are one of the most commonly prescribed classes of medications in the United States. By inhibiting gastric H+/K+ adenosine triphosphatase via covalent binding to the cysteine residues of the proton pump, they provide the most potent acid suppression available. Long-term PPI use accounts for the majority of total PPI use. Absolute indications include peptic ulcer disease, chronic nonsteroidal anti-inflammatory drugs use, treatment of Helicobacter pylori, and erosive esophagitis. Although PPIs are generally considered safe, numerous adverse effects, particularly associated with long-term use have been reported. Many patients receiving chronic PPI therapy do not have clear indications for their use, prompting consideration for reduction or discontinuation of their use. This article reviews the indications for PPI use, the adverse effects/risks involved with their use, and conditions in which their use is controversial.

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References

1. The Henry J. Kaiser Family Foundation. Follow the pill: Understanding the U.S. commercial pharmaceutical supply chain. http://www.kff.org/rxdrugs/upload/follow-the-pill-understanding-the-u-s-commercial-pharmaceutical-supply-chain-report.pdf. Published March 2005. Accessed August 10, 2012.
 
2. Massoomi F, Savage J, Destache CJ. Omeprazole: a comprehensive review. Pharmacotherapy1993; 13: 46–59.
 
3. Lew EA. Pharmacokinetic concerns in the selection of anti-ulcer therapy. Aliment Pharmacol Ther 1999; 13 (5 suppl): 11–16.
 
4. Norman A, Hawkey CJ. What you need to know when you prescribe a proton pump inhibitor. Frontline Gastroenterol 2011; 2: 199–205.
 
5. Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs 2003; 63: 2739–2754.
 
6. Horn J. Understanding the pharmacodynamic and pharmacokinetic differences between proton pump inhibitors—focus on pKa and metabolism. Aliment Pharmacol Therapeut Symp 2006; 2: 340–350.
 
7. Boparai V, Rajagopalan J, Triadafilopoulos G. Guide to the use of proton pump inhibitors in adult patients. Drugs 2008; 68: 925–947.
 
8. Kirchheiner J, Glatt S, Fuhr U, et sl. Relative potency of proton-pump inhibitors—comparison of effects on intragastric pH. Eur J Clin Pharmacol 2009; 65: 19–31.
 
9. Holt S, Howden CW. Omeprazole. Overview and opinion. Dig Dis Sci 1991; 36: 385–393.
 
10. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration meta-analysis of randomized controlled trials. Mayo Clin Proc 2007; 82: 286–296.
 
11. Ramakrishnan K, Salinas RC. Peptic ulcer disease. Am Fam Phys 2007; 76: 1005–1012.
 
12. Cheatum D, Arvanitakis C, Gumpel M, et sl. An endoscopic study of gastroduodenal lesions induced by nonsteroidal anti-inflammatory drugs. Clin Ther 1999; 21: 992–1003.
 
13. Lanza FL, Chan FK, Quigley EM. Practice parameters committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009; 104: 728–738.
 
14. Yeomans ND, Tulassay Z, Juhasz L, et sl. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998; 338: 719–726.
 
15. Hawkey CJ, Krrasch AJ, Szczepanski L, et sl. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-inflammatory drugs. Omeprazole vs. Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998; 338: 727–734.
 
16. Chan FK, Wong VW, Suen BY, et sl. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet 2007; 369: 1621–1626.
 
17. Gisbert JP, Khorrami S, Carballo F, et sl. H. pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Cochrane Database Syst Rev 2004; 2: CD004062.
 
18. Ford AC, Delaney BC, Forman D, et sl. Eradication therapy for peptic ulcer disease inHelicobacter pylori positive patients. Cochrane Database Syst Rev 2006; 2: CD003840.
 
19. Katz PO, Ginsberg GG, Hoyle PE, et sl. Relationship between intragastric acid control and healing status in the treatment of moderate to severe erosive esophagitis. Aliment Pharmacol Ther 2007; 25: 617–628.
 
20. Armstrong D. Gastric pH—the most relevant predictor of benefit in reflux disease. Aliment Pharmacol Ther 2004; 20: 19–26.
 
21. Triadafilopoulos G. Proton pump inhibitors for Barrett’s oesophagus. Gut 2000; 46: 144–146.
 
22. Peters FT, Ganesh S, Kuipers EJ, et sl. Endoscopic regression of Barrett’s oesophagus during omeprazole treatment; a randomized double blind study. Gut 1999; 45: 489–494.
 
23. Horwhat JD, Baroni D, Maydonovitch C, et sl. Normalization of intestinal metaplasia in the esophagus and esophagogastric junction: incidence and clinical data. Am J Gastroenterol 2007; 102: 497–508.
 
24. Charlot M, Ahlehoff O, Norgaard ML, et sl. Proton pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use. Ann Intern Med 2010; 153: 378–386.
 
25. van Boxel OS, van Oijen MG, Hagenaars MP, et sl. Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study. Am J Gastroenterol 2010; 105: 2430–2437.
 
26. Angiolillo DJ, Gibson CM, Cheng S, et sl. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther 2011; 89: 69–74.
 
27. Gremmel T, Steiner S, Seidinger D, et sl. The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by five different platelet function tests. J Cardiovasc Pharmacol 2010; 56: 532–539.
 
28. Bianchi LK, Burke CA, Bennett AE, et sl. Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2008; 6: 180–185.
 
29. Modlin IM, Lye KD, Kidd M. A 50-year analysis of 562 gastric carcinoids: small tumor or larger problem? Am J Gastroenterol 2004; 99: 23–32.
 
30. Hodgson N, Koniaris LG, Livingstone AS, et sl. Gastric carcinoids: a temporal increase with proton pump inhibitor introduction. Surg Endosc 2005; 19: 1610–1612.
 
31. Sandvik AK, Brenna E, Waldum HL, et sl. The pharmacological inhibition of gastric acid secretion—tolerance and rebound. Aliment Pharmacol Ther 1997; 11: 1013–1018.
 
32. Waldum HL, Qvigstad G, Fossmark R, et sl. Rebound hypersecretion of acid from a physiological, pathophysiological and clinical point of view. Scand J Gastroenterol 2010; 45: 389–394.
 
33. Dial MS. Proton pump inhibitor use and enteric infections. Am J Gastroenterol 2009; 104 (2 suppl): S10–S16.
 
34. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008; 149: 391–398.
 
35. Sultan N, Nazareno J, Gregor J. Association between proton pump inhibitors and respiratory infections: a systematic review and meta-analysis of clinical trials. Can J Gastroenterol 2008; 22: 761–766.
 
36. Gray SL, LaCroix AZ, Larso J, et sl. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women. Arch Intern Med 2010; 170: 765–771.
 
37. Targownik LE, Lix LM, Metge CJ, et sl. Use of proton pump inhibitors and risk of osteoporotic fractures. CMAJ 2008; 179: 319–326.
 
38. Recker RR. Calcium absorption and achlorhydria. N Engl J Med 1985; 313: 70–73.
 
39. O’Connell MB, Madden DM, Murray AM, et sl. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 2005; 118: 778–781.
 
40. Gray SL, LaCroix AZ, Larson J, et sl. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women. Arch Intern Med 2010; 170: 765–771.
 
41. Yu EW, Blackwell T, Ensrud KE, et sl. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 2008; 83: 251–259.
 
42. Targownik LE, Lix LM, Leung S, et sl. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010; 138: 896–904.
 
43. Food and Drug Administration. Drug safety communication: low magnesium levels can be associated with long-term use of proton pump inhibitor drugs (PPIs). www.fda.gov/drugs/drugsafety/ucm245011.htm. Published March 2, 2011. Accessed March 8, 2012.
 
44. Cundy T, Mackay J. Proton pump inhibitors and severe hypomagnesaemia. Curr Opin Gastroenterol 2011; 27: 180–185.
 
45. Falk GW, Fennerty MB, Rothstein RI. AGA Institute technical review on the use of endoscopic therapy for gastroesophageal reflux disease. Gastroenterology 2006; 131: 1315–1336.
 
46. Gaddam S, Wani S, Ahmed H, et sl. The impact of pre-endoscopy proton pump inhibitor use on the classification of non-erosive reflux disease and erosive oesophagitis. Aliment Pharmacol Ther 2010; 32: 1266–1274.
 
47. Dean BB, Gano AD Jr, Knight K, et sl. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol 2004; 2: 656–664.
 
48. Lee ES, Kim N, Lee SH, et sl. Comparison of risk factors and clinical responses to proton pump inhibitors in patients with erosive oesophagitis and non-erosive reflux disease. Aliment Pharmacol Ther 2009; 30: 154–164.
 
49. Hiyama T, Matsuo K, Urabe Y, et sl. Meta-analysis used to identify factors associated with effectiveness of proton pump inhibitors against non-erosive reflux disease. J Gastroenterol Hepatol2009; 24: 1326–1332.
 
50. Talley NJ, Axon A, Bytzer P, et sl. Management of uninvestigated and functional dyspepsia: a working party report for the World Congresses of Gastroenterology, 1998. Ailment Pharmacol Ther1999; 13: 1135–1148.
 
51. Moayyedi P, Delaney BC, Vakil N, et sl. The efficacy of proton pump inhibitors in nonulcer dyspepsia: a systematic review and economic analysis. Gastroenterology 2004; 127: 1329–1337.
 
52. Allescher HD, Bockenhoff A, Knapp G, et sl. Treatment of non-ulcer dyspepsia: a meta-analysis of placebo-controlled prospective studies. Scand J Gastroenterol 2001; 36: 934–941.
 
53. Khan M, Santana J, Donnellan C, et sl. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007; 2: CD003244.
 
54. Hatlebakk J, Katz P, Kuo B, et sl. Nocturnal gastric acidity and acid breakthrough on different regimens of omeprazole 40 mg daily. Aliment Pharmacol Ther 1998; 12: 1235–1240.
 
55. Forgacs I. Overprescribing proton pump inhibitors. BMJ 2008; 336: 2–3.
 
56. Heidelbaugh JJ, Goldberg KL, Inadomi JM. Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. Am J Manag Care 2010; 16: e228–e234.
 
57. Gerson LB, Robbins AS, Garber A, et sl. A cost-effectiveness analysis of prescribing strategies in the management of gastroesophageal reflux disease. Am J Gastroenterol 2000; 95: 395–407.
 
58. Jensen RT, Gardner JD. Gastrinoma. In: Go VLW, DiMagno EP, Gardner JD, et al. (eds): The Pancreas: Biology, Pathobiology and Disease. New York: Raven Press; 1993, 931–978.
 
59. Corleto VD, Annibale B, Gibril F, et sl. Does the widespread use of proton pump inhibitors mask, complicate and/or delay the diagnosis of Zollinger-Ellison syndrome? Aliment Pharmacol Ther 2001; 15: 1555–1561.
 
60. Ellison EC, Sparks J. Zollinger-Ellison syndrome in the era of effective acid suppression: are we unknowingly growing tumors? Am J Surg 2003; 186: 245–248.