Pharmacological gastroprotection: Indications, possibilities and risks

The article is an analytical review of the concept of pharmacological gastroprotection. The authors emphasize that the integrity of the gastric mucosa is maintained due to a complex balance between the factors of aggression (hydrochloric acid, pepsin, NSAIDs, H. pylori) and protection (mucus, bicarbonates, prostaglandins, adequate microcirculation, mucosal regeneration). The main mechanisms of damage to the gastric mucosa are listed and a classification of protective factors is given. The terms “cytoprotection” and “gastroprotection” are considered. It is substantiated that true gastroprotection is defined as a pharmacological enhancement of the protective properties of the mucosa, and not the suppression of acid aggression. In this regard, proton pump inhibitors (PPIs), which remain the “gold standard” for the prevention of dangerous complications (bleeding, perforation), do not belong to true gastroprotectors, since they act on the aggression factor. The criteria for assessing the risk of gastrointestinal bleeding and the approach to prescribing gastroprotectors are presented. The authors classify bismuth preparations, misoprostol and rebamipide as true drugs with proven gastroprotective properties. However, each of them has serious limitations: the risk of bismuth accumulation with long-term use, pronounced side effects of misoprostol (diarrhea, abortive effect) and an insufficiently strong evidence base for rebamipide for widespread use. The key problem of clinical practice is the low frequency of gastroprotection use even among high-risk patients (elderly age, taking anticoagulants and NSAIDs, ulcer history), for whom it is indicated first and foremost. The main conclusion of the work is that classical gastroprotection has given way to antisecretory therapy not because of inefficiency, but because of the simplicity, predictability and strong evidence base of PPIs in preventing life-threatening complications. A paradigm shift will require the development of a new drug with clear advantages over existing standard therapy.

1. Kolotilova ML, Ivanov LN. Neurosis and genetic theory of etiology and pathogenesis of ulcer disease. Annals of Russian Academy of Medical Sciences. 2014;69(7-8):10–16. (In Russ) https://doi.org/10.15690/vramn.v69i7-8.1104.

2. Rashina OV, Churnosov MI. Multi-Factor etiopathogenesis of gastric and duodenal peptic ulcer disease. Experimental and Clinical Gastroenterology. 2021;192(8):154–159. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-192-8-154-159.

3. Sánchez-Mendoza ME, Arrieta J, Navarrete A. Role of Prostaglandins, Nitric oxide, Sulfhydryls and Capsaicin-sensitive Neurons in Gastroprotection of Stigmasterol and β-Sitosterol. Natural Product Communications. 2008;3(4):505–510. https://doi.org/10.1177/1934578X0800300406.

4. Marakhouski Y, Rubens J. Gastroprotection without Gastric Acid Suppression, Mini Review and Personal Experience. Int J Biomed Res Prac. 2023;3(1):1–7. https://doi.org/10.26717/BJSTR.2023.51.008042.

5. Kanno T, Moayyedi P. Who Needs Gastroprotection in 2020? Curr Treat Options Gastro. 2020;18(4):557–573. https://doi.org/10.1007/s11938-020-00316-9.

6. Lanas A, García-Rodríguez LA, Arroyo MT, Gomollón F, Feu F, Gonzalez-Perez A et al. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut. 2006;55(12): 1731–1738. https://doi.org/10.1136/gut.2005.080754.

7. Yusuf S, Zhao F, Metha SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494–502. https://doi.org/10.1056/NEJMoa010746.

8. Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL. Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release. Proc Natl Acad Sci U S A. 2001;98(11):6470–6475. https://doi.org/10.1073/pnas.111150798.

9. Ruff CT, Guigliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–962. https://doi.org/10.1016/S0140-6736(13)62343-0.

10. Leontiadis GI, Molloy-Bland M, Moayyedi P, Howden CW. Effect of comorbidity onmortality in patients with peptic ulcer bleeding: systematic review and metaanalysis. Am J Gastroenterol. 2013;108(3):331–345. https://doi.org/10.1038/ajg.2012.451.

11. Brzozowski T, Konturek PC, Konturek SJ, Brzozwska I, Pawlik T. Role of prostaglandins in gastroprotection and gastric adaptation. J Physiol Pharmacol. 2005;56(5):33–55. Available at: https://pubmed.ncbi.nlm.nih.gov/16247188/.

12. Castañeda AA, Kim YoS, Chang LK, Cui Ya, Mercer DW. Nitric oxide synthase inhibition negates bombesin-induced gastroprotection. Surgery. 2000;128(3):422–428. https://doi.org/10.1067/msy.2000.107982.

13. Samsonov АА, Golubev NN, Andreev NG, Shcherbakova NA. The protective barrier of the gastric mucosa and the possibility of drug cytoprotection. Spravochnik Poliklinicheskogo Vracha. 2018;6:40–48. (In Russ.) Available at: https://omnidoctor.ru/upload/iblock/026/0261e2d57b032bac9946575472d56fd1.pdf.

14. Mózsik G, Szolcsányi J, Rácz I. Gastroprotection induced by capsaicin in healthy human subjects. World J Gastroenterol. 2005;11(33):5180–5184. https://doi.org/10.3748/wjg.v11.i33.5180.

15. Filaretova L. The hypothalamic–pituitary–adrenocortical system: Hormonal brain–gut interaction and gastroprotection. Auton Neurosci. 2006;125(1-2):86–93. https://doi.org/10.1016/j.autneu.2006.01.005.

16. Hanaa MI, EL Moselhy MA, Abd-El-Rahim SR. Gastroprotective Potential Effects of Statins on Indomethacin-Induced Gastric Ulcers in Rats. Bull Egypt Soc Physiol Sci. 2009;29(1):213–228. https://doi.org/10.21608/besps.2009.36341.

17. Abrignani MG, Gatta L, Gabrielli D, Milazzo G, Vincenzo De Francesco, Leonardo De Luca et al. Gastroprotection in patients on antiplatelet and/or anticoagulant therapy: a position paper of National Association of Hospital Cardiologists (ANMCO) and the Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO). Eur J Intern Med. 2021;85:1–13. https://doi.org/10.1016/j.ejim.2020.11.014.

18. Yandrapu H, Sarosiek J. Protective Factors of the Gastric and Duodenal Mucosa: An Overview. Curr Gastroenterol Rep. 2015;17(6):24. https://doi.org/10.1007/s11894-015-0452-2.

19. Robert A. Cytoprotection by prostaglandins. Gastroenterology. 1979;77(4): 761–767. Available at: https://pubmed.ncbi.nlm.nih.gov/38173/.

20. Kurlander JE, Helminski D, Kokaly AN, Richardson CR, De Vries R, Saini SD, Krein SL. Barriers to Guideline-Based Use of Proton Pump Inhibitors to Prevent Upper Gastrointestinal Bleeding. Ann Fam Med. 2022;20(1):5–11. https://doi.org/10.1370/afm.2734.

21. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365(21):2002–2012. https://doi.org/10.1056/NEJMsa1103053.

22. Joo MK, Park CH, Kim JS, Park JM, Ahn JY, Lee BE et al. Clinical Guidelines for Drug-Related Peptic Ulcer, 2020 Revised Edition. Gut Liver. 2020;14(6):707–726. https://doi.org/10.5009/gnl20246.

23. Kamada T, Satoh K, Itoh T, Ito M, Iwamoto J, Okimoto T et al. Evidence-based clinical practice guidelines for peptic ulcer disease 2020. J Gastroenterol. 2021;56(4):303–322. https://doi.org/10.1007/s00535-021-01769-0.

24. Valgimigli M, Bueno H, Byrne RA, Collet J-P, Costa F, Jeppsson A et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213–260. https://doi.org/10.1093/eurheartj/ehx419.

25. Abrignani MG, Lombardo A, Braschi A, Renda N, Abrignani V. Proton pump inhibitors and gastroprotection in patients treated with antithrombotic drugs: A cardiologic point of view. World J Cardiol. 2023;15(8):375–394. https://doi.org/10.4330/wjc.v15.i8.375.

26. Lazebnik LB, Alekseenko SA, Belova GV, Vyuchnova ES, Kashkina EI, Kokorin VN et al. Recommendations for prevention and treatment of Esophago-Gastro-Entero-Colopathies induced by non-steroid anti-inflammatory drugs (NSAIDs) – 2025. Experimental and Clinical Gastroenterology. 2024;(12):146–166. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-232-12-146-166

27. Thorsen K, Søreide JA, Kvaløy JT, Glomsaker T, Søreide K. Epidemiology of perforated peptic ulcer: age- and gender-adjusted analysis of incidence and mortality. World J Gastroenterol. 2013;19(3):347–354. https://doi.org/10.3748/wjg.v19.i3.347.

28. Rodríguez GLA, Ruigómez A, Hasselgren G, Wallander MA, Johansson S. Comparison of mortality from peptic ulcer bleed between patients with or without peptic ulcer antecedents. Epidemiology. 1998;9(4):452–456. https://doi.org/10.1097/00001648-199807000-00018.

29. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23): e574–e651. https://doi.org/10.1161/CIR.0b013e31823ba622.

30. Barkun AN, Almadi M, Kuipers EJ, Laine L, Sung J, Tse F et al. Management of nonvariceal upper gastrointestinal bleeding: guideline recommendations from the International Consensus Group. Ann Intern Med. 2019;171(11):805–822. https://doi.org/10.7326/M19-1795.

31. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008;118(18):1894–1909. https://doi.org/10.1161/CIRCULATIONAHA.108.191087.

32. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB et al. ACCF/ACG/AHA. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol. 2010;105(12):2533–2549. https://doi.org/10.1038/ajg.2010.445.

33. Lanza FL, Chan FKL, Quigley EMM. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104(3):728–738. https://doi.org/10.1038/ajg.2009.115.

34. Kumbhani DJ, Cannon CP, Beavers CJ, Deepak L Bhatt, Cuker A, Gluckman TJ et al. 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2021;77(5):629–658. https://doi.org/10.1016/j.jacc.2020.09.011.

35. Kanno T, Moayyedi P. Who needs gastroprotection in 2020? Curr Treat Options Gastroenterol. 2020;18(4):557–573. https://doi.org/10.1007/s11938-020-00316-9.

36. Medlock S, Eslami S, Askari M, Taherzadeh Z, Opondo D, de Rooij SE, Abu-Hanna A. Co-prescription of gastroprotective agents and their efficacy in elderly patients taking nonsteroidal anti-inflammatory drugs: a systematic review of observational studies. Clin Gastroenterol Hepatol. 2013;11(10):1259–1269.e10. https://doi.org/10.1016/j.cgh.2013.05.034.

37. Gomm W, von Holt K, Thome F, Broich K, Maier W, Fink A et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73(4):410–416. https://doi.org/10.1001/jamaneurol.2015.4791.

38. Cheung KS, Chan EW, Wong AYS, Chen L, Wong ICK, Leung WK. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut. 2018;67(1):28–35. https://doi.org/10.1136/gutjnl-2017-314605.

39. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open. 2017;7(6):e015735. https://doi.org/10.1136/bmjopen-2016-015735.

40. Simonov M, Abel EE, Skanderson M, Masoud A, Hauser RG, Brandt CA et al. Use of proton pump inhibitors increases risk of incident kidney stones. Clin Gastroenterol Hepatol. 2021;19(1):72–79.е21. https://doi.org/10.1016/j.cgh.2020.02.053.

41. Moayyedi P. Leaving no stone unturned in the search for adverse events associated with the use of proton pump inhibitors. Clin Gastroenterol Hepatol. 2021;19(1):41–42. https://doi.org/10.1016/j.cgh.2020.04.053.

42. Almario CV, Chey WD, Spiegel BM. Increased risk of COVID-19 among users of proton pump inhibitors. Am J Gastroenterol. 2020;115(10):1707–1715. https://doi.org/10.14309/ajg.0000000000000798.

43. Moayyedi P, Leontiadis GI. The risks of PPI therapy. Nat Rev Gastroenterol Hepatol. 2012;9(3):132–139. https://doi.org/10.1038/nrgastro.2011.272.

44. Moayyedi P, Eikelboom JW, Bosch J, Connolly SJ, Dyal L, Shestakovska O et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology. 2019;157(3):682–691.е2. https://doi.org/10.1053/j.gastro.2019.05.056.

45. Kimmey MB, Lanas A. Review article: appropriate use of proton pump inhibitors with traditional nonsteroidal anti-inflammatory drugs and COX-2 selective inhibitors. Aliment Pharmacol Ther. 2004;(Suppl. 1):60–65. https://doi.org/10.1111/j.0953-0673.2004.01840.x.

46. Nardio RJ, Vender RJ, Herbert P.N. Overuse of acid-suppressive therapy in hospitalized patients. Am J Gastroenterol. 2000;95(11):3118–3122. https://doi.org/10.1111/j.1572-0241.2000.03259.x.

47. Cook D, Deane A, Lauzier F, Zytaruk N, Guyatt G, Saunders L et al. Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation. N Engl J Med. 2024;391(1):9–20. https://doi.org/10.1056/NEJMoa2404245.

48. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010;122(24):2619–2633. https://doi.org/10.1161/CIR.0b013e318202f701.

49. Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis. Crit Care Med. 2013;41(3):693–705. https://doi.org/10.1097/CCM.0b013e3182758734.

50. Seol SY, Kim MH, Ryu JS, Choi M-G, Shin D-W, Ahn B-O. DA-9601 for erosive gastritis Results of a double-blind placebocontrolled phase III clinical trial. World J Gastroenterol. 2004;10(16):2379–2382. https://doi.org/10.3748/wjg.v10.i16.2379.

51. Raskin JB, White RH, Jackson JE, Weaver AL, Tindall EA, Lies RB, Stanton DS. Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: a comparison of three regimens. Ann Intern Med. 1995;123(5):344–350. https://doi.org/10.7326/0003-4819-123-5-199509010-00004.

52. Taha AS, McCloskey C, McSkimming P, McConnachie A. Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2018;3(7):469–476. https://doi.org/10.1016/S2468-1253(18)30119-5.

53. Lazzaroni M, Sainaghi M, Porro GB. Non-steroidal anti-inflammatory drug gastropathy: clinical results with antacids and sucralfate. Ital J Gastroenterol Hepatol. 1999;31(1):S48–53. Available at: https://pubmed.ncbi.nlm.nih.gov/10379470/.

54. Chan FK, Sung JJ. Role of acid suppressants in prophylaxis of NSAID damage. Best Pract Res Clin Gastroenterol. 2001;15(3):433–445. https://doi.org/10.1053/bega.2001.0192.

55. Trukhan DI, Degovtsov EN, Novikov AY. Antacids in real clinical practice. Meditsinskiy Sovet. 2023;17(8):59–67. (In Russ.) https://doi.org/10.21518/ms2023-141.

56. Castañeda AA, Kim YS, Chang LK, Cui Y, Mercer DW. Nitric oxide synthase inhibition negates bombesin-induced gastroprotection. Surgery. 2000;128(3):422–428. https://doi.org/10.1067/msy.2000.107982.

57. Garcia-Rayado G. Navarro M, Lanas A. NSAID induced gastrointestinal damage and designing GIsparing NSAIDs. Expert Rev Clin Pharmacol. 2018;11(10):1031–1043. https://doi.org/10.1080/17512433.2018.1516143.

58. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ. 2002;325(7365):619. https://doi.org/10.1136/bmj.325.7365.619.

59. Rostom A, Muir K, Dubé C, Jolicoeur E, Boucher M, Joyce J et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane collaboration systematic review. Clin Gastroenterol Hepatol. 2007;5(7):818–828. https://doi.org/10.1016/j.cgh.2007.03.011.

60. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. New Engl J Med. 2005;352(11):1092–1102. https://doi.org/10.1056/NEJMoa050493.

61. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. New Engl J Med. 2005;352(11):1071–1080. https://doi.org/10.1056/NEJMoa050405.

62. Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: metaanalyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–779. https://doi.org/10.1016/S0140-6736(13)60900-9.

63. Jordan F, Quinn TJ, McGuinness B, Passmore P, Kelly JP, Smith CT et al. Aspirin and other nonsteroidal anti-inflammatory drugs for the prevention of dementia. Cochrane Database Syst Rev. 2020;4(4):CD011459. https://doi.org/10.1002/14651858.CD011459.pub2.