11/19/2012. Comparison between PPIs G CELL. Risk ratio (95% CI) Patient subgroup. gastrin. S-form of omeprazole. Acid sensitive. coated.

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1 REGULATION OF GASTRIC ACID SECRETION Comparison between PPIs Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole gastrin G CELL + Acid sensitive Yes T1/ minutes Main elimination Enteric coated Acid stable Enteric coated S-form of omeprazole 1.5 hour 1 hour hour hour 70-80% renal 60-70% fecal 90% renal 70% renal 80% renal side effects abdominal arthralgia, pain, abdominal back pain, pain, cough, diarrhea, flu-like constipation apnea, convulsion, hematuria, hepatitis black tarry stool, eosinophilia, impotence headache, respiratory tract infection, diarrhea (4)Scott LJ Drugs 2oo2;62(7) (3)Cheer SM Drugs 2oo3;63(1) (2)CarswellCI Drugs 2001;61(15) (1)Matheson AJ Drugs 2001;61(12) Rationale use of PPI Symptom subgroup on efficacy of PPI therapy in FD DYSPEPSIA HP PEPTIC ULCER REFLUX ESOPHAGITIS UPPER GI BLEEDING NSAID ULCER Patient subgroup Reflux group Epigastric pain group Dysmotility group Overall (95% CI) Risk ratio Risk ratio (95% CI) 0.75 (0.66,0.88) 0.85 (0.79, 0.92) 1.02 (0.92, 1.13)) 0.87 (0.82, 0.92) Favors PPI therapy Favors placebo Moayyedi P and et al. Gastroenterology

2 Meta-analysis: analysis: PPI vs. H 2 RA therapy in FD Cochrane collaboration meta-analysis analysis of PPI treatment for FD Study Blum (23) 98/002 (26) Risk ratio (95% CI) 0.93 (0.84,1.03) 0.92 (0.71, 1.18) Overall (95% CI) 0.93 (0.84,1.02) Favors PPI Risk ratio Favors H2RA % weight Q=0.01, df=1, p= RCTs (3347 patients) Significant heterogeneity (P <0.0001) Risk Ratio = 0.87 ( ) RRR = 13% (95% CI = 4% to 20%) NNT = 10 (95% CI = 7 to 33) Moayyedi P and et al. Gastroenterology 2004 Moayyedi et al. Cochrane Database Syst Rev Rationale use of PPI DYSPEPSIA HP PEPTIC ULCER REFLUX ESOPHAGITIS UPPER GI BLEEDING NSAID ULCER Cytochrome P450 Families Family Subfamily Subtype CYP1 A 1A1, 1A2 CYP2 A 2A6 B 2B6 C 2C8, 2C9, 2C10, 2C18, 2C19 D 2D6 E 2E1 CYP3 A 3A3, 3A4, 3A5, 3A7 Chiba H: Chiryo1994: 76 (9); 2214 Hp eradication and PPI poor or rapid metabolizes 5-O-Desmethyl-omeprazole Omeprazole 3-Hydroxy-omeprazole Lansoprazole 5-Hydroxy-omeprazole Omeprazole hydroxysulphone Demethylatedrabeprazole Rabeprazole Rabeprazole Sulphone Omeprazole sulphone Hydroxy-lansoprazole nonenzymatic Rabeprazole thioether Pantoprazole Lansoprazole sulphone Dealkylated metabolite Pantoprazole sulphone sulfotransferase Pantoprazole sulfate Arrows indicate approximate contribution of CYP isoforms to each of the metabolic pathways. Ishizaki, T. and Horai, Y. : Aliment. PharmacolTher. 1999: 13 (Suppl.3); Furota T et al Drug Metabolism and pharmacokinetic

3 Hp eradication and PPI poor or rapid metabolizes RM IM PM Hp eradication and PPI poor or rapid metabolizes Influence of PharmacogeniticPolymorphism on Proton Pump Inhibitor-based Therapies P< 0.06 RM n= % (CI :64.4% %) AUC for PPI (ng-hr/ml IM n=127 PM n=46 Total n= % (CI:80.4%- 97.3%) 97.8% (CI:88.5% 99.9%) 80.0% (CI:82.2% 90.3%) P< P< 0.2 P< OPZ 20 mg LPZ30 mg RPZ 20 mg FurotaT et al. Drug Metabolism and pharmacokinetic Eradication rate (%) Hp eradication rates achieved by triple therapy (PPI/Amoxy/Clarithromycin) for the difference FurotaT et al Drug Metabolism and pharmacokinetic 2005 Hp eradication and PPI poor or rapid metabolizes Rationale use of PPI Cure rates of H.Pylori infection by treatment with high doses of a PPI plus amoxicillin Regimen Cure rates % (PP) Reference OPZ 40 mg 3 times daily + AMPC 750 mg three times daily for 2 weeks 91% (92) OPZ 40 mg 4 times daily + AMPC 750 mg 4 times daily for 2 weeks LPZ 30 mg 4 times daily + AMPC 500 mg 4 times daily for 2 weeks RPZ 10 mg 4 times daily + AMPC 500 mg 4 times daily for 2 weeks 83.3 % 96.7% 100.0% (93) (85) (68, 80) DYSPEPSIA HP PEPTIC ULCER REFLUX ESOPHAGITIS UPPER GI BLEEDING NSAID ULCER PP = per protocol analysis, OPZ = omeprazole, LPZ = lanzoprazole, RPZ = rabeprazole Furota T et al Drug Metabolism and pharmacokinetic 2005 Diagnostic test for GERD Tests Sens / spec Limitation Recommendation Barium esophagus Upper GI endoscopy 24 hour ph monitoring Very low 20% of healthy subject show barium reflex 30 50% 50% of GERD No mucosal injury Sens 79 96% Spec % Normal in 25% of erosive esophagitis and 50% in NERD GERD with dysphagia Grading erosive esophagitis, etect complication, Barrett s Confirmation test PPI test in typical GERD Dosage Omeprazole mg Lansoprazole 60 mg Rabeprazole 40 mg Esomeprazole 40 mg Duration 7 28 days Sensitivity % Depend on dose, Duration Specificity 35 73% And gold standard test (s) Esophageal manometry NO ROLE 3

4 Inclusion Consultation n = 31 Advertisement n = 59 Symptom scores and the prevalence of reflux symptoms at baseline GERD n = 41 PPI test + n = 58 No GERD n = 17 Eligible for inclusion N = 90 PPI test n = 74 GERD n = 5 Unanalysable n = 16 Refused participation n = 2 Failed catheter insertion n = 1 Intolerance catheter n = 3 No symptoms during ph study n = 9 Achlorhydria n = 1 PPI test - n = 9 No GERD n = 4 Missing n = 7 Annen MC. Aliment Pharmacol Ther Reflux symptoms Heartburn Regurgitation Epigastric burning Acid taste Chest pain Epigastric pain CI, Confidence interval Symptoms prevalence (%) Symptom score, mean (95% CI) Total Total ( ) ( ) ( ) ( ) ( ) ( ) AnnenMC. Aliment PharmacolTher Sensitivity and specificity of the symptoms scored at baseline calculated with SAP as reference standard Reflux symptoms Sensitivity Specificity (%) 95% CI (%) 95% CI Heartburn Regurgitation Epigastric Burning Acid taste Chest pain Epigastric pain AnnenMC. Aliment PharmacolTher Typical LSM plus Standard dose PPI 4 wk Symptoms free Stop Symptoms suggestive of GERD No No symptom Symptom Recurrent symptoms Atypical Alarm *Exclude other condition Yes Dysphagia Odynophagia Frequent vomiting GI bleed / anemia Weight loss LSM plus Double dose PPI 2 wk (consider 4-12 wks for atypical GERD) Maintain for at least 4 wks On-demand/Continuous Rx Symptom Symptom No improvement within 12 wks Alarm symptoms EGD/ Re-evaluation Algorithm Uninvestigated Typical Reflux Symptoms Alarm features present Alarm features absent GERD: Initial Management Symptom-based diagnosis ~60% NERD Symptoms PPI therapy 4 wks and review at 2 to 4 wks Symptoms respond Alarm Risk symptoms assessment Endoscopy ~35% Non-erosive reflux disease RE Refer for EGD, 24 ph and H.pylori test Frequent relapses, or Alarm features Stop PPI at least 1 wk On demand therapy Trial of stopping PPI Restart PPI Relapse Empirical therapy ~95% of patients in primary care Treatment failure ~5% Reflux esophagitis CRD Complicated reflux disease 2006 Asia Pacific Consensus on the Management of GERD Labenz, Malfertheiner. World J Gastroenterol

5 Summary: Therapy of GERD Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture Uninvestigated, Mild EE or NERD PPI Initial Treatment 4 weeks Severe EE, Frequent attacks or Slow PPI response Objective To determine the association between PPI therapy and risk of hip fracture Design Setting, and Patients A nested case-control study was conducted using the General Practice Research Database ( in the United Kingdom PPI On demand PPI Maintenance There were hip fracture cases and controls Unsatisfactory response Yang YX. JAMA. 2006;296(24): Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture Summary: Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture - The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% CI). - The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI; P<.001). - The strength of the association increased with increasing duration of PPI therapy *AOR for 1 year, 1.22 (95% CI) 2 years, 1.41 (95% CI) 3 years, 1.54 (95% CI) 4 years, 1.59 (95% CI) P<.001 for all comparisons Yang YX. JAMA. 2006;296(24): Yang YX. JAMA. 2006;296(24): PPI and risk of Community acquired Pneumonia Population based study from Furen,Denmark CAP and control subjects (age,sex match) Diagnosis confirmed by x-ray and microbiological samples Logistic regression analysis Association Between Exposure to Proton Pump Inhibitors (PPIs) or Histamine 2 -Receptor Antagonists (H 2 RAs) and Community- Acquired Pneumonia (CAP) 5

6 Stratum-Specific Specific Odds Ratios (ORs) for the Association Between Current Use of Proton Pump Inhibitors (PPIs) and Community- Acquired Pneumonia (CAP) Association Between the Use of Proton Pump Inhibitors (PPIs) and Community-Acquired Pneumonia (CAP), Subgroup Analysis Within Modified End Points Subgroup of cases X-Ray positive CAP (n = 3942) X-Ray negative CAP (n = 3700) Fatal CAP (n = 692) Streptococcal CAP (n = 776) Airborne pathogen demonstrated (n = 1639) No airborne pathogen demonstrated (n = 6003) Cases, Exposed / Unexposed 432/ / /563 51/725 91/ /5277 Summary Risk of C. difficilediarrhea diarrhea among hospital in patients with PPI Adjusted ORs >84 First Ever PPI Prescription, Days before index date The adjusted odds ratio (OR) Associating PPI and CAP was 1.5( ). Association was strong for younger group(<40 year-old) :2.3( ) Recent treatment with PPI <7 days had strong correlation:5( ) Relative risk of Clostridium difficile diarrhea in relation to use of PPIS in cohort of 1187 patients Who received antibiotics while in hospital Variable Total no. of cases of C.difficile diarrhea Ward Surgical Medical Antibiotic exposure 1 antibiotic 2 antibiotics >3 antibiotics High-risk antibiotic Single-use antibiotic Cefazolin Any quinolonet Vancomycin Any second-or-thirdgeneration cephalosporin No. of cases of diarrhea / total no. with risk factor (%) Patients taking PPIs 55/591 (9.3) 13/287 (4.5) 42/294 (14.3) 24/261 (9.2) 8/146 (5.5) 23/184 (12.5) 16/181 (8.8) 6/54 (11.1) 9/47 (19.1) 3/91 (3.3) 1/12 (8.3) Patients not taking PPIs 26/596 (4.4) 4/301 (1.3) 22/295 (7.5) 10/333 (3.0) 3/150 (2.0) 13/113 (11.5) 14/173 (8.1) 1/84 (1.2) 3/44 (5.8) 2/103 (1.9) 1/13 (7.7) RR (95% CI) 2.1 ( ) 3.4 ( ) 1.9 ( ) 3.1 ( ) 2.8 ( ) 1.1 ( ) 1.1 ( ) 9.2 ( ) 2.8 ( ) 1.7 ( ) 1.1 ( ) Sandra Dial et al CMAJ 2004;171(1)33-8 Risk of C. difficilediarrhea diarrhea among hospital in patients with PPI 1187 inpatients received antibiotics. 81 developed AAC Summary: Risk of C. difficile diarrhea among hospital in patients with PPI Factors associated with C.difficile diarrhea in cohort of 1187 patients given antibiotics while in hospital Factor Unadjusted OR (95% CI) Adjusted OR (95% CI) Type of antibiotic and history of taking PPI and H2 blockers were recorded and PPI use (v. no acid suppressive therapy) H2 blocker (v. no acid suppressive therapy) >3 antibiotics (v. < 3) 2.1 ( ) 0.4 ( ) 2.4 ( ) 2.1 ( ) 1.1 ( ) 2.1 ( ) analysed Medical ward (v. surgical ward) 4.5 ( ) 4.1 ( ) Sandra Dial et al CMAJ 2004;171(1)33-8 Sandra Dial et al CMAJ 2004;171(1)33-8 6