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Talk given to Medical Representatives and Doctors in a promotion for a Rebeprazole preparation - Rablet

Talk given to Medical Representatives and Doctors in a promotion for a Rebeprazole preparation - Rablet

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Talk on gastic disorders and rabeprazole Presentation Transcript

  • 1. Gastric Acid DisordersEffective treatmentusing Rabeprazol Dr Anshu P Gokarn MBBS, MD(Pharmacology)
  • 2. How my talk is structuredPart 1 1. Physiology of Gastric acid secretion 2. Overview of Gastric Acid-Related Disorders 3. Gastroesophageal Reflux Disease 4. Drugs used in GERD – proton pump inhibitorsPart 2 5. RabeprazolDr Anshu P Gokarn 2
  • 3. Gastric Acid Disorders Effective treatment using Rabeprazol Part I Dr Anshu P Gokarn MBBS, MD(Pharmacology)Dr Anshu P Gokarn 3
  • 4. How my talk is structured 1. Physiology of Gastric acid secretion 2. Overview of Gastric Acid-Related Disorders 3. Gastroesophageal Reflux Disease 4. Drugs used in GERD – proton pump inhibitors 5. RabeprazolDr Anshu P Gokarn 4
  • 5. Stomach Main Functions  Storage  Preparing the chyme for digestion in the small intestine  Absorption of water and lipid-soluble substances (alcohol and drugs)Dr Anshu P Gokarn 5
  • 6. StomachDr Anshu P Gokarn 6
  • 7. StomachTypes of Gland (located in gastric mucosa): Cardiac Glands Pyloric glands (many G cells) Oxyntic glands (most abundant, found in fundus and corpus)Dr Anshu P Gokarn 7
  • 8. Stomach Cells Surface Mucous Cell Gastric Pit (Ioveola) Isthmus Mucous Neck Cell Neck Panetal Cell Oxyntic Gland Endocrine Cell Chief Cell BaseDr Anshu P Gokarn 8
  • 9. Types of Cells Parietal cells  most distinctive cells in stomach (HCl & intrinsic factor) Chief cells  pepsinogen Mucus neck cells: - HCO3- - MucusDr Anshu P Gokarn 9
  • 10. Types of Cells G Cells: Gastrin (hormone) ---> HCl secretion D Cells: Somatostatin (antrum) Enterochromaffin-like cell: HistamineDr Anshu P Gokarn 10
  • 11. Types of CellsDr Anshu P Gokarn 11
  • 12. Gastric juices  HCl (hydrochloric acid)  Pepsinogen  Electrolytes  Intrinsic factor  Mucus (mucus gel layer) pH ~4Dr Anshu P Gokarn 12
  • 13. Gastric motility Functions 1. Allows the stomach to serve as reservoir 2. Breaks food to small particles and mix it with gastric juice 3. Empties gastric contents at a controlled rateDr Anshu P Gokarn 13
  • 14. Gastric motility  Reservoir part fundus + 1/3 corpus (tonic contraction)  Antral pump 2/3 corpus + antrum & pylorus (phasic contraction)Dr Anshu P Gokarn 14
  • 15. Gastric motility Anatomic Regions Functional Motor RegionsDr Anshu P Gokarn 15
  • 16. Mixing & emptying of gastric contents  Gastric contents may remain unmixed (1h)  Fat takes a longer time for empty  Liquids are emptied easier and first  Major mixing activities are in the antrum  RetropulsionDr Anshu P Gokarn 16
  • 17. Mixing & emptying of gastric contentsDr Anshu P Gokarn 17
  • 18. Constriction of pyloric sphincterDr Anshu P Gokarn 18
  • 19. Constriction of pyloric sphincter Hormones promote constriction 1. CCK 2. Secretin 3. Gastrin 4. GIP Sympathetic innervationDr Anshu P Gokarn 19
  • 20. Regulation of gastric emptying Acidity (stomach) Secretin antral contraction Fat (monoglycerides) CCK, GIP gastric emptying Hyperosmotic solutions gastric emptying Amino acids G cells Gastrin contraction of sphincterDr Anshu P Gokarn 20
  • 21. Dr Anshu P Gokarn 21
  • 22. Gastric reservoir Functions:  To maintain a continuous compression  To accommodate the received food with out significant gastric wall distention or pressureDr Anshu P Gokarn 22
  • 23. Relaxation in gastric reservoir  Receptive relaxation - triggered by swallowing reflex  Adaptive relaxation - triggered by stretch receptors (vago-vagal reflex) - lost in vagotomy - threshold of fullness and pain  Feedback relaxation - triggered by chyme in small intestineDr Anshu P Gokarn 23
  • 24. Gastric juices HydroChloric Acid (HCl) Secretion  Secreted by parietal cells Fundus BodyDr Anshu P Gokarn 24
  • 25. Gastric juices – HCl SecretionDr Anshu P Gokarn 25
  • 26. HCl Secretion (cont) Mechanism of HCl production:  H/K ATPase  Inhibited by: omeprazole  H/K pump depends on [K]out  [HCl] drives water into gastric content to maintain iso-osmolality  During gastric acid secretion: amount of HCO3- in blood = amount of HCl being secreted  Alkaline tideDr Anshu P Gokarn 26
  • 27. Neural & Hormonal Control of Gastric Secretion  Vagus nerve (neural effector)  Gastrin (hormonal effector)  Enterochromaffin-like cellsHistamine --- H2 receptor (parietal cells)  acid secretion  Cimetidine (H2 receptor blocker) peptic ulcer and gastroesophageal refluxDr Anshu P Gokarn 27
  • 28. Neural & Hormonal Control of Gastric SecretionDr Anshu P Gokarn 28
  • 29. Neural & Hormonal Control of Gastric SecretionDr Anshu P Gokarn 29
  • 30. Phases of Acid Secretion Cephalic phase(30%):  Smelling, Chewing and swallowing  Stimulates parietal G-Cells  GRP Gastric phase (60%):  gastric distention  proteins Intestinal phase (10%):  digested proteinsDr Anshu P Gokarn 30
  • 31. Regulation of Acid SecretionDr Anshu P Gokarn 31
  • 32. Inhibition of Acid Secretion Inhibitory hormones (Enterogastrones):  Somatostatin (D-cells) in antrum  Secretin (S-cells) in duodenum  Glucose-dependent insulinotropic peptide (GIP) in duodenumDr Anshu P Gokarn 32
  • 33. Mechanism of gastric acid secretion HCI HCl H Cl Protein Protein kinases K kinases Acid Ca2+ pump Ca2+ Cl Release of K Release of Ca2+ Ca 2+ from Ca2+ from intracellular Protein intracellular stores kinases stores cAMP ACh (M3) Gastrin Acetylcholine HistamineDr Anshu P Gokarn 33
  • 34. Activation of H1K ATPaseDr Anshu P Gokarn 35
  • 35. How my talk is structured 1. Physiology of Gastric acid secretion 2. Overview of Gastric Acid-Related Disorders 3. Gastroesophageal Reflux Disease 4. Drugs used in GERD – proton pump inhibitors 5. RabeprazolDr Anshu P Gokarn 36
  • 36. Gastric acid plays a central role in NSAID-associated gastroduodenal damage PROTECTIVE Acidic AGGRESSIVE FACTORS FACTORS environment Aspirin H. pylori Mucus layer and other Gastric Pepsin NSAIDs acid Ionic gradientBicarbonate layer Neutral environment ProstaglandinsSurface epithelial cells Mucosal blood supply Aspirin and other NSAIDs Prostaglandin Bicarbonate Mucus production productionproductionDr Anshu P Gokarn 37
  • 37. Helicobacter pyloriDr Anshu P Gokarn 38
  • 38. Infection with H. pylori results in an acute inflammatory reaction Epithelial cell O2 radicals IL-8 Proteolytic enzymes PolymorphDr Anshu P Gokarn 39
  • 39. How my talk is structured 1. Physiology of Gastric acid secretion 2. Overview of Gastric Acid-Related Disorders 3. Gastroesophageal Reflux Disease 4. Drugs used in GERD – proton pump inhibitors 5. RabeprazolDr Anshu P Gokarn 41
  • 40. Gastroesophageal reflux diseaseDr Anshu P Gokarn 42
  • 41. Gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) is a chronic, relapsing condition with associated morbidity and an adverse impact on quality of life. The disease is common, with an estimated lifetime prevalence of 25 to 35 percent.Dr Anshu P Gokarn 43
  • 42. Gastroesophageal reflux disease An approximated 2% of the adult population suffer from GERD all over the world. The incidence of GERD increases markedly after the age of 40.Dr Anshu P Gokarn 46
  • 43. Complications of GERD Barrett’s esophagus Esophageal strictures Carcinomas Barrett’s esophagus Gastric Cancer Esophageal strictures Dr Anshu P Gokarn 47
  • 44. Guidelines for management of GERD Lifestyle modification should be initiated and continued throughout the course of GERD therapy Antacids and over-the-counter acid suppressants are appropriate, initial patient- directed therapy for GERD. Acid suppression by PPIs which provide symptomatic relief and healing of esophagitisDeVault RK et al,The American Journal of Gastroenterology 1999:94(6): 1434-42Dr Anshu P Gokarn 52
  • 45. Guidelines contd. Chronic proton pump inhibitor therapy is an effective and appropriate form of maintenance therapy in many patients. Antireflux surgery, performed by an experienced surgeon, is a maintenance option for the patient with well-documented GERD. DeVault RK et al,The American Journal of Gastroenterology1999:94(6):1434-42Dr Anshu P Gokarn 53
  • 46. How my talk is structured 1. Physiology of Gastric acid secretion 2. Overview of Gastric Acid-Related Disorders 3. Gastroesophageal Reflux Disease 4. Drugs used in GERD 5. Proton Pump Inhibitors - RabeprazolDr Anshu P Gokarn 54
  • 47. Proton pump inhibitors Proton-pump inhibitors (PPIs) - pronounced and long- lasting reduction of gastric acid production Most potent inhibitors of acid secretion available. Largely superseded another group of pharmaceuticals called H2-receptor antagonists. Biological target Hydrogen potassium ATPaseDr Anshu P Gokarn 57
  • 48. Proton pump inhibitors End of Part – I any questions ?Dr Anshu P Gokarn 58
  • 49. Gastric Acid Disorders Effective treatment using Rabeprazol Part II Dr Anshu P Gokarn MBBS, MD(Pharmacology) 59Dr Anshu P
  • 50. How my talk is structuredPart 1 1. Physiology of Gastric acid secretion 2. Overview of Gastric Acid-Related Disorders 3. Gastroesophageal Reflux Disease 4. Drugs used in GERD – proton pump inhibitorsPart 2 5. RabeprazolDr Anshu P Gokarn 60
  • 51. MODERN ZENDr Anshu P Gokarn 61
  • 52. Rabeprazole • Novel Proton pump inhibitor • Acid suppression with once-daily dosing • Consistent symptom control • Significantly effective healing rates in erosive GERD. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6Dr Anshu P Gokarn 62
  • 53. Chemistry  Substituted benzimidazole sulfoxide Empirical Formula C18H20N3NaO3S Molecular weight 381.43Dr Anshu P Gokarn 63
  • 54. Structure activity relationship • Produrg • Transformed at low pH to a more reactive species, a Sulfenamide. • Sulfenamide reacts with thiol group on gastric (H+K+)-ATPase. Yun Hee jang, Hojing Kim; Quantam Chemical study of proton pump inhibiting activity of Substituted 2-Sunfinylbenimidazoles; Korean Jour. Of Med. Chem., VOl 2, No. 2, 1992Dr Anshu P Gokarn 64
  • 55. Reduced side effect profile • Irreversible disulphide bond with the enzyme (ATPase) • Binding to the Proton Pumps is partially reversible. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6Dr Anshu P Gokarn 65
  • 56.  Pyridine nitrogen and the nitrogen near benzimidazole 2-position – responsible for the activity of rabeprazole. Yun Hee jang, Hojing Kim; Quantam Chemical study of proton pump inhibiting activity of Substituted 2-Sunfinylbenimidazoles; Korean Jour. Of Med. Chem., VOl 2, No. 2, 1992 Dr Anshu P Gokarn 66
  • 57. Pharmacokinetics  Peak plasma levels occur 2-5 hours after oral administration  Oral bioavailability is approximately 52%.  Plasma elimination half life is 1-2 hoursDr Anshu P Gokarn 67
  • 58. Rapid onset of action Rapid dissociation to active tetracyclic sulfenamide.1 Faster Rate of inhibition of proton pump Faster and greater effect on the intragastric pH2. 1. Besancon M, Simon A, Sachs G, Shin JM,.Sites of reaction of th egastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem 1997;272(36):22438-22446c 2. Langtry HD, Markham A.Rabeprazole :A review of its use in acic related gastrointestinal disorders. Drugs 1999;58(4):725-742 68Dr Anshu P Gokarn
  • 59. Faster acid inhibition To produce the same degree of inhibition Rabeprazole takes 5 minutes Omeprazole takes 30 minutes, Lansoprazole takes 30 minutes, Pantoprazole takes 60 minutesBesancon M, Simon A, Sachs G, Shin JM,.Sites of reaction of th egastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem1997;272(36):22438-22446cDr Anshu P Gokarn 69
  • 60. Activation time Activation time At pH 5.1,the (minutes) activation time pH 1.2 1.3 is faster for pH 5.1 7.2 rabeprazole Percent inhibition of the H+/K+-ATPase compared to At 10 minutes other proton 100% At 45 minutes 100% pump inhibitors. Dr Anshu P Gokarn 70
  • 61. Increases gastric mucin  Omeprazole reduces gastric mucin and prevents mucin synthesis  Lansoprazole that has no effect on mucin,  Rabeprazole significantly increases gastric mucin. and thus rapid ulcer healing Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6Dr Anshu P Gokarn 71
  • 62. Antisecretory potency of Rabeperazole Vs Omeprazole Significantly greater decrease in intragastric acidity over the 24-hour period Significantly low Intragastric acidity at night and during 3 of 4 meal related periods American Pharmaceutical Assoc.,Special Report:The use of proton pump inhibitors in acid-peptic Disorders 1999Dr Anshu P Gokarn 72
  • 63. Faster onset of antisecretory activity than Omeprazole 800Intragastric acidity mmol.h/L 600 640 400 200 331 160 218 0 Rabeprazole Omeprazole Intragastric acidity -Day 1 Intragastric acidity- Day 8Dr Anshu P Gokarn 73
  • 64. Most Patients Treated With Rabeprazole ReportedDay And Night time Symptom Relief After One Day No. of patients treated : 2,500 Data presented at the American College of Gastroenterology (ACG) meeting, Oct 16 2000 significantly improved symptoms of both daytime and nighttime heartburn after the first day. 80 % patients with moderate to severe symptoms reported satisfactory symptom relief on day one for both daytime and nighttime heartburn. By day seven,  91.2 % patients reported satisfactory symptom relief for daytime heartburn,  91.7 percent reported satisfactory symptom relief for nighttime heartburn.** Dr Anshu P Gokarn 74
  • 65. Rabeprazole Short Course Therapy•Calabreseincluding azithromycin usedaeither at the initiation ofantibiotics et al. studied the effect of 3-day course of7 days of PPI therapy or at the conclusion of the PPI treatment.Cure Rate was:86% (antibiotics at the initiation of PPI therapy)88% (antibiotics at the end of PPI therapy)Calabrese C, DiFebo G, Areni A, Scialpi C, Biasco G, Miglioli M. Pantoprazole, azithromycin and tinitazole: short duration triple therapy foreradication of Helicobacter pylori infection. Aliment Pharmacol Ther. 2000;14(12):1613-1617. Dr Anshu P Gokarn 75
  • 66. Advantage over H2 antagonists  Intrinsically greater reduction in gastric acid secretion  Intrinsic specificity advantage (binds to proton pump) Yun Hee jang, Hojing Kim; Quantam Chemical study of proton pump inhibiting activity of Substituted 2-Sunfinylbenimidazoles; Korean Jour. Of Med. Chem., VOl 2, No. 2, 1992Dr Anshu P Gokarn 76
  • 67. Increases Collagen regeneration  Does not suppress collagen regeneration unlike H2 receptor antagonists  Does not delay healing of gastric lesions. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6Dr Anshu P Gokarn 77
  • 68. Pharmacological advantages over older PPI’s  More potent than other PPI’s  Faster onset of action due to quicker dissociation.  Complete inhibition of H+K+ATPase. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6Dr Anshu P Gokarn 78
  • 69. Pharmacological advantages over older PPI’s contd… Greater increase in mucin synthesis. Significantly greater anti H. pylori activity. Does not produce conformational changes in proton pump Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6Dr Anshu P Gokarn 79
  • 70. Does not alter prostaglandin levels  Increases prostaglandin synthesis  Prevents stress induced increase in gastric mucosal peptide –leukotriene Does not alter testosterone levels  No effect on steroidogenesis unlike omeprazole Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6Dr Anshu P Gokarn 80
  • 71. Indications  Duodenal ulcer  GERD  Gastric ulcer  Reflux oesophagitis  Zollinger- Ellison Syndrome  H. pylori eradication Rabeprazole, Clinical Pharmacology 2000, Customised monographDr Anshu P Gokarn 81
  • 72. Consistent symptomatic relief  More consistent symptomatic relief H2 receptor antagonists or other PPIs  Superior to omeprazole and ranitidine in prevention of symptoms in patients with healed GERD. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6Dr Anshu P Gokarn 82
  • 73. Nocturnal symptom relief  Greater reduction in frequency and severity of symptoms especially nighttime heartburn.  Significantly lower Intragastric acidity at night. 1  Nocturnal acid control consistent after 8 days of once daily doses.21. American Pharmaceutical Assoc.,Special Report:The use of proton pump inhibitors in acid-peptic Disorders 19992. Williams MP et al,Aliment Pharmacol Ther 1998 Nov;12(11):1079-89 Dr Anshu P Gokarn 83
  • 74. Higher rate of healing  Higher healing rates as compared to omeprazole  Significantly greater improvement in daytime pain. Dekkers CP, Beker JA, Thjodleifsson B, Gabryelewicz A, Bell NE, Humphries TJ. Ignatius Hospital, Breda, the Netherlands.Comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of active duodenal ulcer: a European multicentre study. Aliment Pharmacol Ther 1999 Feb;13(2):179-86Dr Anshu P Gokarn 84
  • 75. Healing Rates of Ulcerative GERD with different doses of rabeprazole compared to placebo 100 80 93 % healing rates 84 85 60 40 20 12 0 Rabeprazole Rabeprazole Rabeprazole Placebo 10 mg 20 mg 40 mg Cloud ML et al,Dig.Dis.Sci.1998;43;993-1000Dr Anshu P Gokarn 85
  • 76. Rabeprazole Vs Omeprazole in healing of Duodenal ulcer 100 % HEALING 80 98 93 60 69 62 40 20 0 After 2 weeks After 4 Weeks Rabeprazole 20 mg Omeprazole 20 mgDekkers CPM,et al, comparison of rabeprazole 20mg vs omeprazole 20mg in the treatment of active duodenal ulcer,Aliment PharmacolTher.1999;13;179-86Dr Anshu P Gokarn 86
  • 77. Rabeprazole Vs Ranitidine in management of active duodenal ulcer disease 90 80 70 60 50 % 40 30 20 10 0 Healing Rates Complete resolution Night time pain improvement in of pain severity overall well being Rabeprazole 20 mg OD Ranitidine 150 mg D Breiter JR et al. Am J Gastroenterol 2000 Apr; 95(4): 936-42Dr Anshu P Gokarn 87
  • 78. Improvement in symptoms of gastric ulcer 100 98 93 80 % symptom relief 84 60 68 69 61 40 20 0 Day pain After 2 Day pain after 4 Night pain after weeks weeks 4 weeks Rabeprazole 20 mg Omeprazole 20 mg Dekkers CP et al. Aliment Pharmacol Ther 1999 Jan; 13: 49-57Dr Anshu P Gokarn 88
  • 79. Intrinsic Anti H. pylori activity Highly effective inhibitor of gastric acid secretion in subjects infected with H. pylori. Inhibits Urease enzyme Irreversibly inhibits urease enzyme produced by H. pylori Thus exerts a potent antibacterial activity Ohara T, Goshi S, Taneike I, Tamura Y, Zhang HM, Yamamoto T..Inhibitory action of a novel proton pump inhibitor, rabeprazole, and its thioether derivative against the growth and motility of clarithromycin-resistant Helicobacter pylori. Helicobacter 2001 Jun;6(2):125-9Dr Anshu P Gokarn 90
  • 80. Potential novel agent for Clarithromycin resistant H. pylori (CRPH) eradication. Thioether derivative of Rabeprazole has the strongest inhibitory action against both the growth and motility of CRPH 1. Park JB, Imamura L, Kobashi K, Kinetic studies of H. pylori urease inhibition by a novel PPI, Rabeprazole, Biol Pharm Bull 1996 Feb;19:182-7Dr Anshu P Gokarn 91
  • 81. Triple therapy for eradicating H.pylori  4-day triple therapy in combination with clarithromycin and amoxicillin - highly effective  Well tolerated in patients with gastric and duodenal ulcer disease.  Eradication rate- 90%  Comparable with the established 7-day triple therapy regimens.Luth S, Teyssen S, Kolbel CB, Singer MV. Department of Medicine IV Gastroenterology/Hepatology), University Hospital ofHeidelberg at Mannheim.4-day triple therapy with rabeprazole, amoxicillin and clarithromycin in the eradication ofHelicobacter pylori in patients with peptic ulcer disease--A pilot study. Z Gastroenterol 2001 Apr;39(4):279-81, 284-5Dr Anshu P Gokarn 92
  • 82. Rabeprazole vs. Omeprazole 1. Rapid onset of H+K+ATPase inhibition than omeprazole, 2. Greater effect on intragastric pH after the first dose1. 3. More potent inhibitor of proton pump than omeprazole2. 1. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6 2. Langtray HD, Markham A. Rabeprazole:A review of its use in Acid related gastrointestinal disorders, Drugs 199;58(4):725-742Dr Anshu P Gokarn 94
  • 83. Rabeprazole vs. Omeprazole 3. More consistent symptom relief 4. Faster rate of healing 5. Lower potential for interaction with cytochrome P450 enzyme system- Lesser drug interactions • Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6 • Humphries TJ, Spera AC, Laurent L, Spanyers SA. Rabeprazole sodium (E3810) 20 mg daily does not affect the pharmacokinetics of Phenytoin sodium in normal volunteers, AM J Gastroenterol 1996;91:1914Dr Anshu P Gokarn 95
  • 84. Rabeprazole vs. Omeprazole contd. 6. Two to ten fold greater antisecretory activity.1 7. Significantly increases the production of gastric mucin2. 1. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6 2. Takiuchi H, Asada S, Umegaki E et al. Effects of proton pump inhibitors, omeprazole, lansoprazole and E-3810, on th egastrin mucin. 10th World Congress of Gastroenterology; 1994 OctDr Anshu P Gokarn 96
  • 85. Rabeprazole vs. Omeprazole contd. 8. Irreversibly inhibits the enzyme urease produced by H. pylori 9. Potent anti-H.pylori activity 1. Bell NE, Humpries TJ, Comparision of fasting gastric levels in 634 patients treated with either rabeprazole 20 mg or omeprazole 20mg once daily in 3 double blind therapeutic trials, Gasteroenterology 197;112(4) Suppl:A 70 2. Park JB, Imamura L, Kobashi K, Kinetic studies of H. pylori urease inhibition by a novel PPI, Rabeprazole, Biol Pharm Bull 1996 Feb;19:182-7Dr Anshu P Gokarn 97
  • 86. Rabeprazole vs. Esomeprazole Esomeprazole 40 mg results in 10%-15% higher healing rates in GERD patients, compared to 20 mg omeprazole racemate. Same difference is found when the 20 & 40 mg omeprazole racemate are compared to each other. The chiral PPI prodrug is converted by acid into an achiral cyclic sulfenamide which only then reacts with the proton pump. Therefore no pharmacodynamic argument in favour of any single enantiomer formulation of any PPI.Kromer W. Relative efficacies of gastric proton-pump inhibitors on a milligram basis: desired and undesired SH reactions. Impact ofchirality. Scand J Gastroenterol Suppl 2001;(234):3-9Dr Anshu P Gokarn 98
  • 87. Rabeprazole vs. Esomeprazole  Lower incidences of Drug-Drug interactions  Faster rate of H+K+ATPase inhibitionDr Anshu P Gokarn 99
  • 88. Rabeprazole Vs Lansoprazole  Comparable Ulcer healing rates with Lansoprazole 30 mg  Lower potential for drug interactions  Earlier and better symptom relief American Pharmaceutical Assoc.,Special Report:The use of proton pump inhibitors in acid-peptic Disorders 1999Dr Anshu P Gokarn 100
  • 89. Cure Rates of H.pylori infection with Lansoprazole and Rabeprazole 88 87 Percent cure rates 87 85.6 86 LAC 85 84 82.7 RAC 83 R1/2AC 82 81 80 Cure rates Key: LAC: Lansoprazole 30mg bid with amoxicillin and clarithromycin RAC:Rabeprazole 20mg bid with amoxicillin and clarithromycin R1/2AC:10mg bid with amoxicillin and clarithromycin Miwa H et al,Efficacy of reduced dosage of rabeprazole in PPI/AC therapy for Helicobacter pylori infection: comparison of 20 and 40 mg rabeprazole with 60 mg lansoprazole.Dig Dis Sci 2000 Jan;45(1):77-82Dr Anshu P Gokarn 101
  • 90. Safety profile  Similar short term side effect profile to other PPIs  Safe for long-term use.  Serious side effects rare Welage SL,Journal of the American Pharmaceutical association 1999:40:1Dr Anshu P Gokarn 103
  • 91. Well tolerated  Very well tolerated as compared to omeprazole and H2-receptor antagonists.  No dose adjustments required for special populations Thjodleifsson and Cockburn,Alimentary Pharmacology & Therapeutic 1999 ; 13 s5 ; 17Dr Anshu P Gokarn 104
  • 92. Dosage and administration For GERD Adults: Usual dosage: 20mg/day Route of administration: Oral Frequency of administration: Once daily Rabeprazole, Clinical Pharmacology 2000, Customised monographDr Anshu P Gokarn 105
  • 93. For pathological hyper secretory conditions including Zollinger-Ellison syndrome Adults: Usual Dosage: 60mg/day (Dosage should be adjusted based on clinical response and should be continued as clinically indicated. Doses up to 100 qd or 60 mg bid have been administered). Duration of therapy: some patients with Zollinger-Ellison Syndrome have been treated continuously for up to one year. Rabeprazole, Clinical Pharmacology 2000, Customised monographDr Anshu P Gokarn 106
  • 94. Maximum dosage limits Adults: GERD, Duodenal ulcer, Gastric ulcer: 40 mg qd Zollinger-Ellison Syndrome: 120mg qd Elderly: GERD, Duodenal ulcer, Gastric ulcer:40 mg qd Zollinger-Ellison Syndrome: 120mg qd Adolescents and Children: Safe and effective use has not been established. Rabeprazole, Clinical Pharmacology 2000, Customised monographDr Anshu P Gokarn 107
  • 95. Maximum dosage limits Hepatic impairment No dosage adjustment required Renal impairment No dosage adjustment is necessary Intermittent haemodialysis  Extensively protein bound  Not readily haemodialysable Rabeprazole, Clinical Pharmacology 2000, Customised monographDr Anshu P Gokarn 108
  • 96. Overdose  No experience to date with deliberate overdose.  Dosages of up to 120mg/day have been well tolerated. Product details, Pariet , Eisai, http://www.eisai.co.uk/pariet.htmDr Anshu P Gokarn 109
  • 97. Contraindications Known hypersensitivity to rabeprazole, other substituted benzimidazoles (e.g.,lansoprazole, omeprazole)Dr Anshu P Gokarn 110
  • 98. Precautions  Gastric cancer  Hepatic disease  Children  Elderly  Japanese (AUC values were seen to be 50-60% greater) Rabeprazole, Clinical Pharmacology 2000, Customised monographDr Anshu P Gokarn 111
  • 99. Pregnancy  No data is available in human pregnancy.  Studies in rats and rabbits have revealed no evidence of impaired fertility or harm to the foetus  Contraindicated during pregnancy.Dr Anshu P Gokarn 112
  • 100. Lactation  It is not known whether rabeprazole sodium is excreted in human breast milk.  No studies in lactating women have been performed.  Excreted in rat mammary secretions.  Should not be used during breast feeding.Dr Anshu P Gokarn 113
  • 101. Low potential for drug interactions  Not complicated by clinically significant drug- drug interactions with medications metabolized by CYP 2C19 Humphries TJ, Spera AC, Laurent L, Spanyers SA. Rabeprazole sodium (E3810) 20 mg daily does not affect the pharmacokinetics of Phenytoin sodium in normal volunteers, AM J Gastroenterol 1996;91:1914Dr Anshu P Gokarn 114
  • 102. Drug interactions  Cyclosporine: metabolism is inhibited  Digoxin: AUC and Cmax is increased  Warfarin: No interaction  Antacids: Not clinically significant  Theophylline: No interaction  Diazepam: No interaction Rabeprazole, Clinical Pharmacology 2000, Customised monographDr Anshu P Gokarn 115
  • 103. Salient Features Rapid onset of action Higher rate of healing Consistent Symptomatic relief Increases gastric mucin, Heals mucosa No effect on Steroidogenesis or endocrine functions Dr Anshu P Gokarn 116
  • 104. Salient Features The conformation of pump not altered as done by Omeprazole. Brings acid production level back to normal baseline within 2 days as compared to 4 days with Omeprazole Intrinsic anti H.pylori action Low potential for drug interactions Prevents stress induced increase in gastric mucosal peptide – leukotriene content without altering mucosal prostaglandin level. Dr Anshu P Gokarn 117
  • 105. How my talk is structured 1. Physiology of Gastric acid secretion 2. Overview of Gastric Acid-Related Disorders 3. Concluding Remarks Gastroesophageal Reflux Disease 4. Drugs used in GERD – protein pump inhibitors 5. RabeprazolDr Anshu P Gokarn 118
  • 106. Thank You Queries ?anshu.gokarn@gmail.com