Proton pump inhibitor

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In medicine, specifically gastroenterology, proton pump inhibitors (PPI) are medications that "inhibit H(+)-K(+)-exchanging atpase. They are used as anti-ulcer agents and sometimes in place of histamine H2 antagonists for gastroesophageal reflux disease."[1] They are also used to eradicate Helicobacter pylori, in combination with antibiotics.

Examples:

  • Esomeprazole. Available as generic.
  • Lansoprazole. Available as generic.
  • Omeprazole. Available as non-prescription in the United States.
  • Pantoprazole. Available as generic.
  • Rabeprazole

Metabolism

Proton pump inhibitors are metabolized by the CYP2C19 isoenzyme of cytochrome P-450. Lanzoprazole is the strongest inhibitor of CYP2C19,[2] This may be less true for pantoprazole and esomeprazole.[3] Pantoprazole is the strongest inhibitor of the CYP2C9 isoenzyme[2]

Effectiveness

Proton pump inhibitors may improve:

PPIs may reduce the risk of gastrointestinal hemorrhage among patients undering anticoagulation.[9]

Adverse effects

Proton pump inhibitors may be associated with spontaneous bacterial peritonitis.[10] Recent starting of these drugs may also be associated with pneumonia acquired in the community[11]or hospital[12]. These drugs may be associated with Clostridium difficile diarrhea[13], and fractures other than hip fractures[14].

Starting proton pump inhibitors in healthy volunteers may induce acid-related symptoms when PPIs are stopped[15] This is problematic considering how often PPIs are incorrectly prescribed.[16]

Proton pump inhibitors may induce acid-related symptoms in healthy volunteers after withdrawal, presumably due to rebound acid hypersecretion.[15]

Drug interactions

In the United States, the Food and Drug Administration has issued warnings regarding combining PPIs with clopidogrel.[17][18] Proton pump inhibitors (especially inhibitors other than pantoprazole[19]), which are metabolized by the CYP2C19 isoenzyme of cytochrome P-450, may[20] or may not[21] increase adverse cardiac events when given to patients taking clopidogrel for coronary heart disease.

Studies of drug interactions between PPIs and clopidogrel[22][23][24][19][20][21][25][26]
Trial Patients Intervention Comparison Outcome Results
PPI Control
COGENT Randomized controlled trial[22]
2010		 3,873 patients with an indication for dual antiplatelet
• 94% were anglo		 1,033 concurrent users of clopidogrel and PPIs
• all used omeprazole		 Placebo Serious cardiovascular disease
Odds ratio = 0.99; 95% CI, 0.68 - 1.44; P=0.96);
"There was no apparent cardiovascular interaction between clopidogrel"
Stockl et al Retrospective cohort study[23]
2010		 2,066 patients hospitalized for myocardial infarction or stent 1,033 concurrent users of clopidogrel and PPIs
• 64% used pantoprazole		 1,033 patients not taking PPIs Serious cardiovascular disease
Odds ratio = 1.64 (95% CI 1.16-2.32)
"Patients who received clopidogrel plus a PPI had a significantly higher risk of rehospitalization for MI or coronary stent placement than did patients receiving clopidogrel alone"
Tennessee Medicaid cohort study[24] 20,596 patients hospitalized for myocardial infarction, myocardial revascularization, or unstable angina pectoris 7593 concurrent users of clopidogrel and PPIs
• 62% used pantoprazole		 13003 patients not taking PPIs Serious cardiovascular disease
"Serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk"
Ontario nested case-control study[19] 13,636 subjects taking clopidogrel after myocardial infarction 782 subjects readmitted for myocardial infarction 2057 subjects not readmitted Rate of PPI usage other than pantoprazole Odds ratio = 1.40 (95% CI 1.10–1.77)
Cohort study from the VA Cardiac Care Follow-up Clinical Study[20] 8205 subjects with acute coronary syndrome 64% were taking PPIs:
• 0.2% used pantoprazole
• 50% received stents
• Probably < 50% used drug eluting stents[27]		 Subjects not taking PPIs Major vascular events 29.8% 20.8%
Odds ratio = 1.25 (95% CI: 1.11-1.41)
• "each 10% increase in the proportion of time taking clopidogrel plus PPI during follow-up was associated with a higher risk"
Cohort study taken from TRITON-TIMI 38 randomized controlled trials[21][28][29]
2 of 14 authors disclosed payments from AstraZenca, the maker of omeprazole and esomeprazole		 6795 subjects with acute coronary syndrome who were randomized to the clopidogrel arm of the trial 33% (4529) were taking PPIs at randomization:
• 2814 took PPIs for duration of study
• 41% used pantoprazole
• 94% received stents
• 47% received at least one drug eluting stent		 Subjects not taking PPIs Major vascular events 11.8% 12.2%
• Patients taking any PPI HR = 0.94, (95% CI 0.80–1.11)
• Patients taking any PPI for duration of study HR = 1.05 (95% CI 0.85–1.30)
• Results similar for each individual PPI
• Results also insignificant when restricted to analysis of patients with a reduced function allele
Medco cohort study[25] 16,718 subjects who took clopidogrel for 12 months after coronary stent 41% were taking PPIs:
• 24% used pantoprazole
• 100% received stents
• Unknown use of drug eluting stents		 Subjects not taking PPIs Major vascular events 24% to 29% 17.9%
• Pantoprazole HR=1.61 (pantoprazole had most GI bleeding)
• Esoprazole HR=1.57
• Lansoprazole HR=1.39
• Omeprazole HR=1.39
• Histamine H2 antagonists HR=1.14 (insignicant)
Danish cohort study[26] 56,406 subjects discharged after first-time myocardial infarction • 44% received clopidogrel
• 41% were taking PPIs:
• 30% of PPIs were pantoprazole		 Subjects not taking PPIs Cardiovascular deaths and rehospitalization for myocardial infarction or strokes 26.3% 18.6%
• Any PPI HR=1.29
• Clopidogrel was associated with more adverse outcomes among patients taking PPIs and patient not taking PPIs. The increase due to clopidogrel was the same in both groups.

References

  1. ↑ Anonymous (2024), Proton pump inhibitor (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. ↑ 2.0 2.1 Li XQ, Andersson TB, Ahlström M, Weidolf L (2004). "Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities.". Drug Metab Dispos 32 (8): 821-7. PMID 15258107.
  3. ↑ Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B (January 2009). "Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel". Am. Heart J. 157 (1): 148.e1–5. DOI:10.1016/j.ahj.2008.09.017. PMID 19081411. Research Blogging.
  4. ↑ Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D (2006). "Pharmacological interventions for non-ulcer dyspepsia.". Cochrane Database Syst Rev (4): CD001960. DOI:10.1002/14651858.CD001960.pub3. PMID 17054151. Research Blogging. Review in: Evid Based Med. 2007 Jun;12(3):79
  5. ↑ van Pinxteren B, Numans ME, Bonis PA, Lau J (2006). "Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease.". Cochrane Database Syst Rev 3: CD002095. DOI:10.1002/14651858.CD002095.pub3. PMID 16855986. Research Blogging.
  6. ↑ Pace F, Tonini M, Pallotta S, Molteni P, Porro GB (2007). "Systematic review: maintenance treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken 'on-demand'.". Aliment Pharmacol Ther 26 (2): 195-204. DOI:10.1111/j.1365-2036.2007.03381.x. PMID 17593065. Research Blogging. Review in: Evid Based Med. 2007 Dec;12(6):177 Review in: ACP J Club. 2007 Nov-Dec;147(3):69
  7. ↑ Bardhan KD, Müller-Lissner S, Bigard MA, Bianchi Porro G, Ponce J, Hosie J et al. (1999). "Symptomatic gastro-oesophageal reflux disease: double blind controlled study of intermittent treatment with omeprazole or ranitidine. The European Study Group.". BMJ 318 (7182): 502-7. PMID 10024259. PMC PMC27748.
  8. ↑ Khan M, Santana J, Donnellan C, Preston C, Moayyedi P (2007). "Medical treatments in the short term management of reflux oesophagitis.". Cochrane Database Syst Rev (2): CD003244. DOI:10.1002/14651858.CD003244.pub2. PMID 17443524. Research Blogging.
  9. ↑ Massó González EL, García Rodríguez LA (2008). "Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study.". Aliment Pharmacol Ther 28 (5): 629-37. DOI:10.1111/j.1365-2036.2008.03780.x. PMID 18616644. Research Blogging.
  10. ↑ Bajaj JS, Zadvornova Y, Heuman DM, et al. (May 2009). "Association of proton pump inhibitor therapy with spontaneous bacterial peritonitis in cirrhotic patients with ascites". Am. J. Gastroenterol. 104 (5): 1130–4. DOI:10.1038/ajg.2009.80. PMID 19337238. Research Blogging.
  11. ↑ Sarkar M, Hennessy S, Yang YX (2008). "Proton-pump inhibitor use and the risk for community-acquired pneumonia.". Ann Intern Med 149 (6): 391-8. PMID 18794558.
  12. ↑ Herzig SJ, Howell MD, Ngo LH, Marcantonio ER (2009). "Acid-suppressive medication use and the risk for hospital-acquired pneumonia.". JAMA 301 (20): 2120-8. DOI:10.1001/jama.2009.722. PMID 19470989. Research Blogging.
  13. ↑ Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA (2010). "Proton pump inhibitors and risk for recurrent Clostridium difficile infection.". Arch Intern Med 170 (9): 772-8. DOI:10.1001/archinternmed.2010.73. PMID 20458084. Research Blogging.
  14. ↑ Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE et al. (2010). "Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative.". Arch Intern Med 170 (9): 765-71. DOI:10.1001/archinternmed.2010.94. PMID 20458083. Research Blogging.
  15. ↑ 15.0 15.1 Reimer C, Søndergaard B, Hilsted L, Bytzer P (2009). "Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy.". Gastroenterology 137 (1): 80-7, 87.e1. DOI:10.1053/j.gastro.2009.03.058. PMID 19362552. Research Blogging. Cite error: Invalid <ref> tag; name "pmid19362552" defined multiple times with different content
  16. ↑ Wohlt PD, Hansen LA, Fish JT (2007). "Inappropriate continuation of stress ulcer prophylactic therapy after discharge.". Ann Pharmacother 41 (10): 1611-6. DOI:10.1345/aph.1K227. PMID 17848420. Research Blogging.
  17. ↑ Anonymous. (2009) Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix)
  18. ↑ Anonymous (11/17/2009) Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC)
  19. ↑ 19.0 19.1 19.2 Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV et al. (2009). "A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.". CMAJ 180 (7): 713-8. DOI:10.1503/cmaj.082001. PMID 19176635. PMC PMC2659819. Research Blogging. Review in: Ann Intern Med. 2009 Aug 18;151(4):JC2-13 Review in: Evid Based Med. 2009 Oct;14(5):154
  20. ↑ 20.0 20.1 20.2 Ho PM, Maddox TM, Wang L, et al. (March 2009). "Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome". JAMA 301 (9): 937–44. DOI:10.1001/jama.2009.261. PMID 19258584. Research Blogging.
  21. ↑ 21.0 21.1 21.2 O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y et al. (2009). "Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials.". Lancet 374 (9694): 989-97. DOI:10.1016/S0140-6736(09)61525-7. PMID 19726078. Research Blogging.
  22. ↑ 22.0 22.1 Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ et al. (2010). "Clopidogrel with or without omeprazole in coronary artery disease.". N Engl J Med 363 (20): 1909-17. DOI:10.1056/NEJMoa1007964. PMID 20925534. Research Blogging.
  23. ↑ 23.0 23.1 Stockl, Karen M.; Lisa Le, Armen Zakharyan, Ann S. M. Harada, Brian K. Solow, Joseph E. Addiego, Scott Ramsey (2010-04-26). "Risk of Rehospitalization for Patients Using Clopidogrel With a Proton Pump Inhibitor". Arch Intern Med 170 (8): 704-710. DOI:10.1001/archinternmed.2010.34. Retrieved on 2010-04-27. Research Blogging.
  24. ↑ 24.0 24.1 Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K et al. (2010). "Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study.". Ann Intern Med 152 (6): 337-45. DOI:10.1059/0003-4819-152-6-201003160-00003. PMID 20231564. Research Blogging.
  25. ↑ 25.0 25.1 Stanek EJ et al. (2009) A National Study of the Effect of Individual Proton Pump Inhibitors on Cardiovascular Outcomes in Patients Treated with Clopidogrel Following Coronary Stenting: The Clopidogrel Medco Outcomes Study Society for Cardiovascular Angiography and Interventions 2009 Annual Meeting
  26. ↑ 26.0 26.1 Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ et al. (2010). "Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study.". Ann Intern Med 153 (6): 378-86. DOI:10.1059/0003-4819-153-6-201009210-00005. PMID 20855802. Research Blogging.
  27. ↑ Ho PM, Fihn SD, Wang L, Bryson CL, Lowy E, Maynard C et al. (2007). "Clopidogrel and long-term outcomes after stent implantation for acute coronary syndrome.". Am Heart J 154 (5): 846-51. DOI:10.1016/j.ahj.2007.08.028. PMID 17967588. Research Blogging.
  28. ↑ Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al. (2009). "Cytochrome p-450 polymorphisms and response to clopidogrel.". N Engl J Med 360 (4): 354-62. DOI:10.1056/NEJMoa0809171. PMID 19106084. Research Blogging.
  29. ↑ Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S et al. (2007). "Prasugrel versus clopidogrel in patients with acute coronary syndromes.". N Engl J Med 357 (20): 2001-15. DOI:10.1056/NEJMoa0706482. PMID 17982182. Research Blogging.
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