Proton pump inhibitors – new molecules, new knowledge

Czech version

Authors: J. Špičák; K. Chmelová
Authors‘ workplace: Klinika hepatogastroenterologie, Transplantcentrum, IKEM, Praha
Published in: Kardiol Rev Int Med 2016, 18(1): 67-75
Category: Cardiology Review

Overview

Proton pump inhibitors (PPI) are the primary medication in the treatment of acid-related diseases. All proton pump inhibitors are weak bases selectively metabolised in an acid environment which block the function of active proton pumps. Proton pump inhibitors provide efficient treatment for gastroesophageal reflux disease, Helicobacter pylori, functional dyspepsia and NSAID gastropathy. PPI may be helpful in patients with eosinophilic oesophagitis. PPI of the first generation comprise omeprazole, pantoprazole and lansoprazole, the second one is represented by esomeprazole and rabeprazole. Proton pump inhibitors differ in pharmacokinetic properties but these differences do not necessarily have clinically relevant consequences. Generally, second generation proton pump inhibitors provide a faster onset of effect, longer gastric secretion inhibition, and specifically the effect of rabeprazole is less dependent on the method of administration and has less influence on the function of cytochrome P450. The effect of proton pump inhibitors, particularly the first generation, is modified by the genetic variety of the CYP2C19 enzyme and is significantly lower in rapid metabolisers. Proton pump inhibitors are very safe and immediate complications are rare. They can cause progression of gastritis in Helicobacter infection. In spite of causing hypergastrinemia, they do not have malignant potential. Their long-term administration is associated with an increased risk of pelvis and hip fractures, community-acquired pneumonia, and clostridium infection. They decrease the effect of antiaggregant therapy with clopidogrel, and increase the risk of recurrent cardiovascular events. This effect is not proven in prasugrel. We cannot expect any potential progression in developing new molecules or PPI formulas. The instructions for patients are usually not clearly presented and often lack important information.

Keywords:
proton pump inhibitors – omeprazole – lansoprazole – pantoprazole – rabeprazole – esomeprazole – side effects – interactions

Sources

1. Huang JQ, Hunt RH. Pharmacological and pharmacodynamic essentials of H2-receptor antagonists and proton pump inhibitors for the practicing physicians. Best Practis Res Clin Gastroenterol 2001; 15: 355– 370.

2. Martínek J, Lukáš M. Inhibitory protonové pumpy – up to date. Gastroent Hepatol 2011; 65: 231– 242.

3. Andersson T, Weidolf L. Stereoselective disposition of proton pump inhibitors. Clin Drug Investig 2008; 28: 263– 279.

4. Morelli G, Chen H, Rossiter B et al. An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastrin acid suppression of rabeprazole extended-realise with omeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers. Aliment Pharmacol Ther 2011; 33: 845– 854. doi: 10.1111/ j.1365-2036.2011.04580.x.

5. Chiba N, De Gara CJ, Wilkinson JM et al. Speed of healing and symptom relief in grade II to IV gastroesopohageal reflux disease: a metaanalysis. Gastroenterology 1997; 112: 1798– 1810.

6. Vakil N, Fennerty MB. Direct comparative trials of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and peptic ulcer disease. Aliment Pharmacol Ther 2003; 18: 559– 568.

7. Maiti R, Jaida J, Israel J et al. Rabeprazole and esomeprazole in mild-to-moderate erosive gastroesophageal reflux disease: a comparative study of efficacy and safety. J Pharmacol Pharmacother 2011; 2: 150– 157. doi: 10.4103/ 0976-500X.83278.

8. Maret-Ouda J, Brusselaers N, Lagergren J. What is the most effective treatment for severe gastro-oesophageal reflux disease? BMJ 2015; 350: 3169. doi: 10.1136/ bmj.h3169.

9. de Jonge PJ, Spaander MC, Bruna MJ et al. Acid suppression and surgical therapy for Barrett's oesophagus. Best Pract Res Clin Gastroenterol 2015; 29: 139– 150. doi: 10.1016/ j.bpg.2014.11.005.

10. Jachimski P, Maqbool S, Bhat YM et al. Control of acid and duodenogastroesophageal reflux (DGER) in patients with Barrett's esofagus. Am J Gastroenterol 2015; 110: 1143– 1148. doi: 10.1038/ ajg.2015.161.

11. Sheikh I, Waghray A, Waghray N et al. Consumer use of over-the-counter proton pump inhibitors in patients with gastroesophageal reflux disease. Am J Gastroenterol 2014; 109: 789– 794. doi: 10.1038/ ajg.2013.421.

12. Tang HL, Li Y, Hu YF et al. Effects of CYP2C19 loss--of-function variants on the eradication of H. pylori infection in patients treated with proton pump inhibitor-based triple therapy regimens: A meta-analysis of randomized clinical trials. PLoS One 2013; 8: e62162. doi: 10.1371/ journal.pone.0062162.

13. Tielemans MM, Eikendal T, Jansen JB et al. Identification of NSAID users at risk for gastrointestinal complications. Drug Saf 2010; 33: 443– 453. doi: 10.2165/ 11534590-000000000-00000

14. Iwamoto J, Saito Y, Honda A et al. Clinical features of gastroduodenal injury associated with long-term low dose aspirin therapy. World J Gastroenterol 2013; 19: 1673– 1682. doi: 10.3748/ wjg.v19.i11.1673.

15. Lanza FI, Chan FK, Quigley EM et al. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009; 104: 728– 738. doi: 10.1038/ ajg.2009.

16. Washio E, Esaki M, Maehata Y et al. Proton pump inhibitors increase incidence od nonsteroidal anti--inflammatory drug-induced small bowel injury: A randomized, placebo-controlled trial. Clin Gastroenterol Hepatol 2015; S1542-3565(15)01489-5. doi: 10.1016/ j.cgh.2015.10.022.

17. Liu B, Liu S, Yin A et al. Risks and benefits of stress ulcer prophylaxis in adult neurocritical care patients: a systematic review and metaanalysis of randomized controlled trials. Critical Care 2015; 19: 409. doi: 10.1186/ s13054-015-1107-2.

18. Jian Z, Li H, Race NS et al. Is the Era of intravenous proton pump inhibitors coming to an end in patients with bleeding peptic ulcers? Meta-analysis of the published literature. Br J Clin Pharmacol 2015. [Ahead of print]. doi: 10.1111/ bcp.12866.

19. Fords A, Moayyedi P. Current guidelines for dyspepsia management. Dig Dis 2008; 26: 225– 230. doi: 10.1159/ 000121351.

20. Liacouras CA, Furuta GT, Hirano et al. Eosinophilic esophagitis: updated konsensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128: 3– 20. doi: 10.1016/ j.jaci.2011.02.040.

21. Vazquez-Elizondo G, Ngamruengphong S, Khrisna M et al. The outcome of patients with oesophageal eosinophilic infiltration after an eight-week trial of a proton pump inhibitor. Aliment Pharmacol Ther 2013; 38: 1312– 1319. doi: 10.1111/ apt.12513.

22. Lucendo AJ, Arias A, Molina-Infante J. Efficacy of Proton pump inhibitor drugs for inducing clinical and histologic remission in patients with symptomatic esophageal eosinophilia: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2016; 14: 13– 22. doi: 10.1016/ j.cgh.2015.07.041.

23. Molina-Infante J, Rodriguez-Sanchez J, Martinek J et al. Long-term loss of response in proton pump inhibitor-responsive esophageal eosinophilia is uncommon and influenced by cyp2c19 genotype and rhinoconjunctivitis. Am J Gastroenterol 2015; 11: 1567– 1575. doi: 10.1038/ ajg.2015.314.

24. Lodato F, Azzyaroli F, Turco L et al. Adverse effects of proton pump inhibitors. Best Pract Res Clin Gastroenterol 2010; 24: 193– 201. doi: 10.1016/ j.bpg.2009.11.004.

25. Fiocca R, Mastracci L, Attwood SE et al. Gastric exocrine and endocrine cell morfology under prolonged acid inhibition therapy: results of 5-year follow-up in the LOTUS trial. Aliment Pharmacol Ther 2012; 36: 959– 971. doi: 10.1111/ apt.12052.

26. Thomson AB, Sauve MD, Kassam N et al. Safety of long-term use of proton pump inhibitors. World J Gastroenterol 2010; 16: 2323– 2330.

27. Yu EW, Bauer SR, Bain PA et al. Proton pump inhibitors and risk of fractures: a meta-analylsis of 11 internbational studies. Am J Med 2011; 124: 519– 526. doi: 10.1016/ j.amjmed.2011.01.007.

28. Zhou B, Huang Y, Li H et al. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 2015. In press.

29. Yang SD, Chen Q, Wei HK et al. Bone fracture and the interaction between bisphosphonates and proton pump inhibitors: a meta-analysis. Int J Clin Exp Med 2015; 8: 4899– 4910.

30. Kieboom BC, Kiefte- de Jong JC, Eijgelsheim M et al. Proton pump inhibitors and hypomagnesemia in the general population: a population-based cohort study. Am J Kidney Dis 2015; 66: 775– 782. doi: 10.1053/ j.ajkd.2015.05.012.

31. Sharara Al, Chalhoub JM, Hammoud N et al. Low prevalence of hypomagnesemia in long-term recipients of proton pump inhibitors in a manage care cohort. Clin Gastroenterol Hepatol 2016; 14: 317– 321. doi: 10.1016/ j.cgh.2015.10.012.

32. Giuliano C, Wilhem SM, Kale-Pradhan PB. Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis. Expert Rev Clin Pharmacol 2012; 5: 337– 344. doi: 10.1586/ ecp.12.20.

33. Lambert AA, Lam JO, Paik JJ. Risk of community--acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PLoS One 2015; 10: e0128004. doi: 10.1371/ journal.pone.0128004.

34. Freeman R, Dabrera G, Lane C et al. Association between use of proton pump inhibitors and non-typhoidal salmonellosis identified following investigation into an outbreak of Salmonella Mikawasima in the UK, 2013. Epidemiol Infect 2015; 1: 1– 8.

35. Deshpande A, Pant Ch, Pasupuleti V et al. Association between proton pump inhibitor therapy and clostridium difficile in a meta-analysis. Clin Gast-roenterol Hepatol 2012; 10: 225– 233. doi: 10.1016/ j.cgh.2011.09.030.

36. Ogawa R, Echizen H. Drug-drug interactions profiles of proton pump inhibitors. Clin Pharmacokinet 2010; 8: 509– 533. doi: 10.2165/ 11531320-000000000-00000.

37. Drepper MD, Spahr L, Frossard JL.Clopidogrel and proton pumpo inhibitors – where do we stand in 2012? World J Gastroenterol 2012; 18: 2161– 2171. doi: 10.3748/ wjg.v18.i18.2161.

38. Roe MT, Armstrong PW, Fox KA et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization N Engl J Med 2012; 367: 1297– 1309. doi: 10.1056/ NEJMoa1205512.

39. Hsieh CF, Huang WF, Chiang YT et al. Effects of clopidogrel and proton pump inhibitors on cardiovascular events in patients with type 2 diabetes mellitus after drug-eluting stent implantation: a nationwide cohort study. PLoS One 2015; 10: e0135915. doi: 10.1371/ journal.pone.0135915.

40. Collet JP, Hulot JS, Abtan J et al. Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study. Eur J Clin Pharmacol 2014; 70: 1049– 1057. doi: 10.1007/ s00228-014-1710-1.

41. Chen J, Yuan YC, Leontiadis GI et al. Recent safety concerns with proton pump inhibitors. J Clin Gastroenterol 2012; 46: 93– 114. doi: 10.1097/ MCG. 0b013e3182333820.

42. Cardoso RN, Benjo AM, DiNicolantonio JJ et al. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis. Open Heart 2015; 2: e000248. doi: 10.1136/ openhrt-2015-000248.

43. Bhatt DL, Cryer BL, Contant CF et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363: 1909– 1917. doi: 10.1056/ NEJMoa1007964.

44. Hulot JS, Collet JP, Silvain J et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration. J Am Coll Cardiol 2010; 56: 134– 143. doi: 10.1016/ j.jacc.2009.12.071.

45. Uotani T, Sugimoto M, Nishino M et al. Ability of rabeprazole to prevent gastrin mucosal damage from clopidogrel and low doses of aspirin depends on CYP2C19. Clin Gasteroenterol Hepatol 2012; 10: 879– 885. doi: 10.1016/ j.cgh.2012.04.016.

46. El-Halabi MM, Zgheuib N, Mansour NM et al. CYP2C19 genetic polymorphism, rabeprazole and esomeprazole have no effect on the anti-platelet action of clopidogrel. J Cardiovasc Pharmacol 2013; 62: 41– 49. doi: 10.1097/ FJC.0b013e31828ecf44.

47. Agewall S, Cattaneo M, Collet JP et al. Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. Eur Heart J 2013; 34: 1708– 1713. doi: 10.1093/ eurheartj/ eht042.

48. DeVault KR, Talley NJ. Insights into the future of gastric acid suppression. Nat Rev Gastroenterol Hepatol 2009; 6: 524– 532. doi: 10.1038/ nrgastro.2009.125.

49. Sachs G, Shin JM, Hunt R et al. Novel approaches to inhibition of gastrin acid secretion. Curr Gastroenterol Rep 2010; 12: 437– 447. doi: 10.1007/ s11894-010-0149-5.