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Indications of proton pump inhibitors

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Indications of proton pump inhibitors

  1. 1. Indications of Proton Pump Inhibitors Samir Haffar M.D. Assistant Professor of Gastroenterology Al-Mouassat University Hospital – Damascus – Syria
  2. 2. Carl Schwartz: 1910
  3. 3. Strategies used during the 20th century for counteracting action of gastric acid Inflexion occurs during the 1980s with introduction of drugs inhibiting gastric acid secretion Dı az-Rubio M. Drugs 2005 ; 65 (Suppl. 1) : 1 – 6.
  4. 4. “Potent acid inhibition” • pH > 4 1000-fold ↓ H concentration in stomach Reduced the pepsin activity • At least 16 h No clear evidence to 16 h as cut-off Used in many studies Described arbitrarily as maintaining an intragastric pH > 4 for at least 16 h out of every 24 h
  5. 5. 0 20 40 60 80 100 Maximum pepsin activity (%) 1 2 3 4 Gastric juice pH pH 4 is a critical threshold for gastric pepsin activity Adapted from Berstad 1970
  6. 6. H2RA or PPIs? No indications for H2RA in present day digestive diseases, perhaps with the exception of Gomollón1 F & Calvet X . Drugs 2005; 65 Suppl. 1: 25 – 33. • Management of occasional heartburn Possibly in association with an antacid • Exceptional patient who is allergic to all PPIs
  7. 7. PPIs are one of the most frequently prescribed classes of drug in the world because of:  High level of efficacy  Low toxicity  Reduced cost  Lack of alternative therapies
  8. 8. Sales of PPI & H2RA in USA & Italy United States Italy Corleto VD. Aliment Pharmacol Ther 2001 ; 15 : 1555 – 1561. Sales of PPI reach > 50% of entire market of gastric antisecretory drugs in both countries by 1998
  9. 9. Six available PPIs Generic name Trade name Daily dose Route Delayed release PPIs Omeprazole Losec® – Prilosec® 20 mg Oral Lanzoprazole Lanzor – Prevacid® 30 mg Oral – IV Pantoprazole Protonix® 40 mg Oral – IV Rabeprazole Aciphex® – Pariet® 20 mg Oral Esomeprazole Nexium® 40 mg Oral – IV Are all PPIs the same? Immediate release PPIs OMP Na bicarbonate Zegerid Oral
  10. 10. Intragastric pH control in patients with GERD Katz PO. Rev Gastroenterol Disord. 2003; 3(2): 59 - 69. Gain from 20% to 40% is achieved when comparing esomeprazole with other PPIs
  11. 11. Helpful facts on the use of PPIs • Take twice daily for first 2 – 3 days of therapy Steady state is not reached for a couple of days • First dose should be before breakfast • Second dose, if used, should be before dinner • Not likely to be effective when used as required Wolfe MM, Sachs G. Gastroenterology 2000; 118: S9 -S31.
  12. 12. Hierarchy of intragastric pH control • PPI once a day • PPI once a day plus H2RA • PPI bid • PPI bid + H2RA
  13. 13. Indications of potent acid inhibition  GERD: need more acid inhibition than PU  Helicobacter Pylori eradication  Peptic ulcer: gastric – duodenal – bleeding PU  Prevention & treatment of NSAID-induced lesions  Functional Dyspepsia  ↑Gastric acid : ZES - mastocytosis - retained antrum
  14. 14.  PPIs & GERD
  15. 15. Healing rates in erosive esophagitis 4 –12week of treatment Meta-analysis of > 2000 patients assessing 4 - 12week healing rates in patients with erosive esophagitis Chiba N et al. Gastroenterology. 1997; 112: 1798 - 1810.
  16. 16. Healing rates of erosive esophagitis according to LA Grade Richter et al. Am J Gastroenterol 2001; 96 : 656 – 665. P = 0.001
  17. 17. Maintenance of healing of erosive esophagitis Lauritsen K et al. Aliment Pharmacol Ther. 2002;17:333-341.
  18. 18. Underlying mechanisms for persistent heartburn despite treatment with PPIs Fass R & Sifrim D. Gut 2009 ; 58 : 295 – 309. 10 – 40 % of patients
  19. 19. Combined MII-pH of the esophagus Fass R & Sifrim D. Gut 2009 ; 58 : 295 – 309. Weakly acidic reflux Weakly alkaline reflux
  20. 20. Endoscopic images of eosinophilic esophagitis Linear furrows & adherent white exudatesConcentric rings Small calibre esophagus with stricture Mucosal laceration from diagnostic endoscopy
  21. 21.  PPIs & HP eradication
  22. 22. PPI & HP eradication • Single dose of PPIs reduces efficacy of HP eradication PPIs should be used at double the standard doses Exception of esomeprazole: 20mg bid is effective • No data available that might suggest one PPI to be preferable to another in this indication
  23. 23.  PPIs & peptic ulcers: Gastric – duodenal – bleeding
  24. 24. Medical therapy for gatric & duodenal ulcer • Removing injurious agent: NSAIDs or HP • Standard dose of PPI suffices • Double dose in some cases particularly in gastric ulcer • No comparative studies between various PPIs
  25. 25. Stage Characteristics Rebleeding I a Jet arterial bleeding 90 % Ib Oozing 50 % IIa Visible Vessel 25 – 30 % IIb Adherent clot 10 – 20% IIc Black spot in ulcer crater 7 – 10% III Clean base ulcer 3 – 5 % Forrest’s classification for PU bleeding
  26. 26. Forrest’s classification for bleeding PU III (clean base)II-b (adherent clot) II-a (visible vessel)I-b (oozing) II-c (black spot) I-a (arterial jet )
  27. 27. MA of PPI in UGI bleeding before endoscopy 4 RCTs – 1 512 patients • Excluding pts suspected of having variceal bleeding • Rebleeding OR 0.81; 95% CI (0.61–1.09) • Endoscopic tt at subsequent index endoscopy OR 0.93, 95% CI (0.53–1.64) • Surgery OR 0.96, 95% CI (0.68–1.35) • Mortality OR 1.12; 95% CI (0.72–1.73) Dorward S et al. Cochrane Database Syst Rev 2006;(4):CD005415.
  28. 28. PPI & bleeding PU * Barkun A et al. Ann Intern Med 2003 ;139 : 843 – 57. ** Leontiadis GI et al. Gastroenterol Clin N Am 2009 ; 38 : 199 – 213. *** Kaviani MJ et al. Aliment Pharmacol Ther 2003 ; 17 : 211 – 6. Controversial issues** • Dose No uniform consensus • Route Omeprazole 40 mg bid PO effective*** Consensus recommendations* • Initially 80 mg bolus • Followed by Infusion of 8 mg/hr for 72 hrs • After 72 h Equivalent to omeprazole 40 mg bid if oral intake is resumed
  29. 29. MA of PPIs in peptic ulcer bleeding 24 RCTs – 4373 patients included Leontiadis GI et al. Cochrane Database Syst Rev 2006;(1):CD002094. MortalityRebleeding – NNT 13
  30. 30.  PPIs & NSAIDs
  31. 31. Serious GI Events Clinical Ulcers Endoscopic Ulcers Relative Severity GI Symptoms Relative Frequency NSAID-related GI side effects
  32. 32. Choice between various NSAIDs dominated by uneasy application of ‘least harm principle’ balancing various potential adverse events
  33. 33. Risk factors for GI complications in NSAIDs users Ranked in terms of importance • Prior history of complicated ulcers • Concomitant use of anticoagulants • Multiple NSAID use, including low-dose aspirin • Prior history of uncomplicated ulcer • High NSAID dose (or use of piroxicam or ketorolac) • Age > 60 years • Severe illness • Helicobacter pylori infection • Concomitant use of corticosteroids
  34. 34. Prevention strategies of GI risk due to NSAIDs • Best way: avoid NSAID & substitute with acetaminophen • Use “safer” NSAID: C2SI, diclofenac, aceclofenac, ibuprofen • Avoid of NSAID with highest GI toxicity Ketorolac, piroxicam, ketoprofen • Use lowest effective dose for shortest period of time • Avoid concomitant therapy with Anticoagulants, corticosteroids, low-dose aspirin, APT • Eradicate HP infection in patients with prior ulcer history Sostres C et al Best Pract Res Clin Gastroenterology 2010 ; 24 : 121 – 132.
  35. 35. Patients at increased risk for NSAIDs GI toxicity High risk 1. History of complicated ulcer especially recent 2. Multiple (> 2 risk factors) HP is independent & additive risk factor & addressed separately ACG guidelines for prevention of NSAID-related ulcer complications . Am J Gastroenterol 2009 ; 104: 728 – 738. Moderate risk (1 – 2 risk factors) 1. Age > 65 years (OR 2.0 – 3.5) 2. High dose NSAID therapy (OR 8.0) 3. Previous history of uncomplicated ulcer 4. Concurrent use of aspirin 5. Concurrent use of corticosteroids (OR 2.0) 6. Concurrent use of anticoagulants (OR 3.0) Low risk No risk factors
  36. 36. Patients at increased risk for NSAIDs CV toxicity High risk Patients with risk factors for CV disease often receive prophylactic aspirin Arbitrarily defined as requirement for low-dose aspirin for prevention of serious CV events Low risk No risk factors
  37. 37. Prevention of NSAID-related ulcer complications Low GI risk Moderate GI risk High GI risk Low CV risk NSAID alone (least ulcerogenic at lowest dose) NSAID + PPI/misoprostol Alternative therapy or C2SI + PPI/misoprostol Patients with ulcer history: search for HP & if present eradicated Naproxen may have some cardioprotective properties ACG guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009 ; 104: 728 – 738. High CV risk Naproxen + PPI/misoprostol Naproxen + PPI/misoprostol Avoid NSAIDs & C2SI Use alternative therapy
  38. 38. GI safety of non-selective NSAIDs RR of different NSAIDs could differ 10-fold * Risk at higher doses (> 1.5 –2.4 g/d) comparable to others NSAIDs Br Med J 1996 ; 312 : 1563 – 1566. Lowest risk Ibuprofen * Diclofenac Moderate risk Indomethacin Naproxen Sulindac Aspirin Highest risk Azapropazone Tolmetin Ketoprofen Piroxicam Longer half-time
  39. 39. SENSAR software Appropriate use of NSAIDs in chronic rheumatic disease • 18 experts from 10 European countries • Published English-language literature from 1998 to 2008 • Method: Research & Development/UCLA(RAND/UCLA) • Three panel meeting: January, June, &November 2008 • 144 different patient profiles & 10 treatment options • Statement: Appropriate – Uncertain – Inappropriate • Coordinated by Center for Decision Analysis & Support • Supported by Pfizer Inc http://www.e-hims.com/Sensar/
  40. 40. European expert panel on appropriate use of NSAID Name Speciality Country 1- Gerd R Burmester Rheumatology Germany 2-Francis Berenbaum Rheumatology France 3- Ferdinand Breedveld Rheumatology The Netherlands 4- Maxime Dougados Rheumatology France 5- Emilio Martín Mola Rheumatology Spain 6- Ignazio Olivieri Rheumatology Italy 7- Josef Smolen Rheumatology Austria 8- Stefan Lohmander Orthopaedics Sweden 9- Luigi M Biasucci Cardiology Italy 10- Matthias Hermann Cardiology Switzerland 11- Tom MacDonald Cardiology and Clinical Pharmacology UK 12- Chris Hawkey Gastroenterology UK 13- Angel Lanas Gastroenterology Spain 14- Carmelo Scarpignato Gastroenterology and Clinical Pharmacology Italy 15- Adam Bajkowski Family Medicine UK 16- Peter Dieleman Family Medicine Belgium 17- Tony Mets Geriatrics Belgium 18- Nele Van Den Noortgate Geriatrics Belgium
  41. 41. http://www.e-hims.com/Sensar/
  42. 42. SENSAR software Appropriate use of NSAIDs in chronic rheumatic disease • Given complexity of data & to avoid oversimplification: Electronic tool may offer best opportunities as quick reference guide to panel results • In the complex and dynamic area of NSAID use: Such approach offer best chances of benefiting from perspective of both science & practice http://www.e-hims.com/Sensar/ Burmester G et al. Ann Rheum Dis 2011 ; 70 : 818 – 822.
  43. 43. Major GI bleeding in low dose aspirin 14 RCTs – over 57 000 patients McQuaid KR et all. Am J Med 2006 ; 119 : 624 – 638. Major GI bleeding: fatal – hospitalization – transfusion Low dose asipirin: 75 – 325 mg/day NNH during 1 year period: 833
  44. 44.  PPIs & dyspepsia
  45. 45. Functional dyspepsia • Persistent or recurrent pain or discomfort centered in the upper abdomen for more than 12 weeks in the preceding 12 months with no evidence of an organic disease that is likely to explain the symptoms • Divided into 4 symptom groups: Ulcer-like Reflux-like Dysmotility-like Unspecified
  46. 46. Alarm features in dyspepsia (red flags) • Age > 55 years with new-onset dyspepsia • Family history of UGI cancer • Unintended weight loss • Gastrointestinal bleeding • Progressive dysphagia or odynophagia • Unexplained iron-deficiency anemia • Persistent vomiting • Palpable mass or lymphadenopathy • Jaundice AGA technical review on evaluation of dyspepsia. Gastroenterology 2005 ; 129 : 1756 – 80. 
  47. 47. PPI versus placebo in uninvestigated dyspepsia MA of 4 RCTs AGA technical review on evaluation of dyspepsia. Gastroenterology 2005 ; 129 : 1756 - 80.
  48. 48. PPI versus placebo in nonulcer dyspepsia MA of 8 RCTs AGA technical review on evaluation of dyspepsia. Gastroenterology 2005 ; 129 : 1756 - 80.
  49. 49.  PPIs & Zollinger-Ellison syndrome
  50. 50. Suspicion of ZES • Refractory erosive esophagitis • Multiple peptic ulcers • Ulcers in distal duodenum or jejunum • Complicated ulcers • Recurrent ulcers after acid-reducing surgery • Ulcers associated with diarrhea • Family history of MEN-1
  51. 51. Diagnosis of ZES
  52. 52. Treatment of ZES • Surgery Gastrinoma enucleation Parietal cell vagotomy Total gastrectomy (abandoned) • PPI Control acid secretion in most patients Very high doses (eg, omeprazole 120mg/day) BAO < 10 mEq/h 1 hour before next dose < 5 mEq/h in prior gastric surgery Schubert ML & Peura D A. Gastroenterology 2008 ; 134 : 1842 – 1860.
  53. 53. Referrals & diagnosis of new cases of ZES in 2 centers after widespread use of PPIs Corleto VD. Aliment Pharmacol Ther 2001 ; 15 : 1555 – 1561.
  54. 54. Retained antrum syndrome Hauser SC et al. Mayo clinic gastroenterology & hepatology board review. Mayo Clinic Scientific Press, Rochester, USA, 3rd edition, 2008. Retained antral tissue with gastrin secreting cells
  55. 55. What dose of PPIs? Generic name Standard dose (mg/day) Refractory patient (mg/day) Omeprazole 20 mg 80 mg Lanzoprazole 30 mg 120 mg Pantoprazole 40mg 160 mg Rabeprazole 20 mg 80 mg Esomeprazole* 40 mg 80 mg * Therapeutic advantage of esomeprazole, which is less relevant in overall population, might be of more interest in refractory one
  56. 56. When Should the PPI be Given? 15 – 30 minutes before meal Before morning meal Reduces acid secretion more than given in the evening Does not affect nocturnal acid secretion Before mid-day meal More effective inhibition of nocturnal secretion If single daily-dose Before breakfast or mid-day meals If no response Divided doses: compliance problem Increased dose (more reasonable) Gomollo n F et al. Drugs 2005; 65 (Suppl 1) : 25 – 33.
  57. 57. PPI dose adjustment • Renal failure No repercussion on PPI elimination No need to adjust dosage • Liver failure Half-life increases to 4 – 8 h (nl: 1 h) Reduction of dosage • Aged patients No dosage adjustment usually Adjustment if hepatic or renal failure is added to advanced age Drugs 2005; 65 Suppl. 1
  58. 58. For how long? Indication Duration GERD Indefinite period of time or use on demand HP eradication 7 – 10 – 14 days Duodenal ulcer 4 wks – duration increased in refractory cases Gastric ulcer 8 wks – duration increased in refractory cases Bleeding PU IV PPIs for 72 hours (consensus) Gastroprotection As long as patient requires NSAIDs or ASA Dyspepsia Depend on symptomatic response ZES Indefinite period of time
  59. 59. Which PPIs?  Efficacy Esomeprazole (40mg/d) slightly more effective Useful in refractory ulcer Useful in difficult GERD: extent of lesion – Barrett’s  Interactions with other drugs Less interaction in rabeprazole & especially pantoprazole Clinical relevance probably minimal Dose adjustment in AVK, benzodiazepines, phenytoin  Cost considerations
  60. 60. Major metabolic pathways for various PPIs De Argila CM. Drugs 2005; 65 (Suppl. 1) : 97 – 104. Contribution of each isoenzyme represented by thickness of arrow Rabeprazole: Important non-enzymatic metabolism Pantoprazole sulfotransferase not saturable
  61. 61. PPI & clopidogrel co-therapy  Evaluate risk of PU & GI bleeding in dual APT  Administer PPI in patients at high risk Administer PPI in all patients with dyspepsia  Prefer pantoprazole or rabeprazole Weak inhibitors of CYP2C19 Pantoprazole considered the first choice PPI  Separate administration by 12 – 15 hours Half life of PPI 1 – 2 h & clopidogrel 4 – 6 h PPI before breakfast & clopidogrel after dinner Lettino M. Eur J Intern Med 2010 (in press).
  62. 62. Mechanisms of suboptimal PPIs response • Variable bioavailability of PPIs • PPIs taken at times other than just before a meal • Hypersecretors: uncommon • Genetic variations in CYP 450 2C19 enzyme: rapid metabolism • Eradication of H pylori: controversial • PPI resistance despite normal blood levels of drug Strongly suggesting genetic abnormality of proton pump Ramakrishnan A. et al. Gastrointest Endoscopy Clin N Am 2003; 13 : 57 – 68.
  63. 63. Overprescribing PPIs In a series of hospital inpatients in Michigan, USA • On admission 20% of patients taking PPI • During hospital stay Another 40% were prescribed PPI Mostly for prophylaxis • At discharge 50% of patients taking PPIs 90% of patients did not need PPIs unless having GERD in the past Ann Pharmacother 2006 ; 40 : 1261 – 6. PPIs are clearly being overused
  64. 64. Overprescribing PPIs • 2006 Expenditure on PPIs in England £425m Expenditure on PPIs in the world £7bn • 25-70% of pts taking PPIs have no appropriate indication • Money spent unnecessarily on PPIs each year England at least £100m Worldwide at least £2bn Bruzzi P. BMJ 2008 ; 336 : 2 – 3.
  65. 65. Conclusion The lowest effective dose of the cheapest drug for the shortest possible time Prescribing PPIs
  66. 66. Thank You

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