Proton pump inhibitor

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In medicine, 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."[1] They are also used as part of curative therapy for Helicobacter pylori, in combination with antibiotics.

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]

Adverse effects

Proton pump inhibitors may be associated with spontaneous bacterial peritonitis.[4] Recent starting of these drugs may also be associated with pneumonia acquired in the community[5] or hospital[6]. These drugs may be associated with Clostridium difficile diarrhea, and fractures.

Starting proton pump inhibitors in healthy volunteers may induce acid-related symptoms PPIs are stopped[7] This is problematic considering how often PPIs are incorrectly prescribed.[8]

Drug interactions

In the United States, the Food and Drug Administration has issued a warning regarding combining PPIs with clopidogrel.[9]

Studies of drug interactions between PPIs and clopidogrel[10][11][12][13]
Trial Patients Intervention Comparison Outcome Results
PPI Control
Ontario nested case-control study[10] 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[11] 8205 subjects with acute coronary syndrome 64% were taking PPIs:
• 0.2% used pantoprazole		 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[12][14][15]
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		 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
Medco cohort study[13] 16,718 subjects who took clopidogrel for 12 months after coronary stent 41% were taking PPIs:
• 24% used pantoprazole		 Subjects not taking PPIs Major vascular events 24% to 29% 17.9%
• Pantoprazole HR=1.61 (pantoprazole had most GI bleeding)
• Esooprazole HR=1.57
• Lansoprazole HR=1.39
• Omeprazole HR=1.39
• Histamine H2 antagonists HR=1.14 (insignicant)

Proton pump inhibitors (especially inhibitors other than pantoprazole[10]), which are metabolized by the CYP2C19 isoenzyme of cytochrome P-450, may[11] or may not[12] increase adverse cardiac events when given to patients taking clopidogrel for coronary heart disease.

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. ↑ 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.
  5. ↑ Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med. 2008 Sep 16;149(6):391-8. PMID 18794558
  6. ↑ Herzig SJ, Howell MD, Ngo LH, Marcantonio ER. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA. 2009 May 27;301(20):2120-8. PMID 19470989
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Anonymous. (2009) Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix)
  10. ↑ 10.0 10.1 10.2 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
  11. ↑ 11.0 11.1 11.2 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.
  12. ↑ 12.0 12.1 12.2 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.
  13. ↑ 13.0 13.1 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
  14. ↑ 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.
  15. ↑ 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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