Gastric Acid DisordersEffective treatmentusing Rabeprazol      Dr Anshu P Gokarn       MBBS, MD(Pharmacology)
How my talk is structuredPart 1  1.     Physiology of Gastric acid secretion  2.     Overview of Gastric Acid-Related     ...
Gastric Acid Disorders        Effective treatment         using Rabeprazol                        Part I                  ...
How my talk is structured  1.    Physiology of Gastric acid secretion  2.    Overview of Gastric Acid-Related        Disor...
Stomach  Main Functions   Storage   Preparing the chyme for digestion in the    small intestine   Absorption of water a...
StomachDr Anshu P Gokarn             6
StomachTypes of Gland (located in gastric mucosa): Cardiac Glands Pyloric glands (many G cells) Oxyntic glands (most a...
Stomach Cells                    Surface Mucous Cell                                                     Gastric Pit      ...
Types of Cells  Parietal cells   most distinctive cells in stomach (HCl &    intrinsic factor)  Chief cells   pepsinogen...
Types of Cells  G Cells: Gastrin (hormone) ---> HCl secretion  D Cells: Somatostatin (antrum)  Enterochromaffin-like cell:...
Types of CellsDr Anshu P Gokarn                    11
Gastric juices   HCl (hydrochloric acid)   Pepsinogen   Electrolytes   Intrinsic factor   Mucus (mucus gel layer)    ...
Gastric motility  Functions    1. Allows the stomach to serve as       reservoir    2. Breaks food to small particles and ...
Gastric motility   Reservoir part       fundus + 1/3 corpus                    (tonic contraction)   Antral pump       2...
Gastric motility       Anatomic Regions         Functional Motor                                   RegionsDr Anshu P Gokar...
Mixing & emptying of gastric contents     Gastric contents may remain unmixed (1h)     Fat takes a longer time for empty...
Mixing & emptying of gastric contentsDr Anshu P Gokarn                    17
Constriction of pyloric sphincterDr Anshu P Gokarn                       18
Constriction of pyloric sphincter  Hormones promote constriction   1. CCK   2. Secretin   3. Gastrin   4. GIP  Sympathetic...
Regulation of gastric emptying       Acidity (stomach)   Secretin        antral      contraction      Fat (monoglycerides)...
Dr Anshu P Gokarn   21
Gastric reservoir Functions:  To maintain a continuous compression  To accommodate the received food with   out signific...
Relaxation in gastric reservoir     Receptive relaxation      - triggered by swallowing reflex     Adaptive relaxation  ...
Gastric juices  HydroChloric Acid (HCl) Secretion   Secreted by parietal cells       Fundus       BodyDr Anshu P Gokarn...
Gastric juices – HCl SecretionDr Anshu P Gokarn                      25
HCl Secretion (cont) Mechanism of HCl production:  H/K ATPase  Inhibited by: omeprazole  H/K pump depends on [K]out  [...
Neural & Hormonal Control of Gastric             Secretion   Vagus nerve (neural effector)   Gastrin (hormonal effector)...
Neural & Hormonal Control of Gastric             SecretionDr Anshu P Gokarn                   28
Neural & Hormonal Control of Gastric             SecretionDr Anshu P Gokarn                   29
Phases of Acid Secretion  Cephalic phase(30%):          Smelling, Chewing and swallowing          Stimulates parietal G-...
Regulation of Acid SecretionDr Anshu P Gokarn                      31
Inhibition of Acid Secretion Inhibitory hormones (Enterogastrones):  Somatostatin (D-cells) in antrum  Secretin (S-cells...
Mechanism of gastric acid secretion                                         HCI                                           ...
Activation of H1K ATPaseDr Anshu P Gokarn                      35
How my talk is structured  1.    Physiology of Gastric acid secretion  2.    Overview of Gastric Acid-Related        Disor...
Gastric acid plays a central role in  NSAID-associated gastroduodenal damage    PROTECTIVE                        Acidic  ...
Helicobacter pyloriDr Anshu P Gokarn                         38
Infection with H. pylori results in an           acute inflammatory reaction                                              ...
How my talk is structured  1.    Physiology of Gastric acid secretion  2.    Overview of Gastric Acid-Related        Disor...
Gastroesophageal reflux diseaseDr Anshu P Gokarn                          42
Gastroesophageal reflux disease                    Gastroesophageal reflux                    disease (GERD) is a chronic,...
Gastroesophageal reflux disease                       An approximated 2% of                       the   adult   population...
Complications of GERD   Barrett’s esophagus   Esophageal strictures   Carcinomas                              Barrett’s...
Guidelines for management of GERD   Lifestyle modification should be initiated and    continued throughout the course of ...
Guidelines contd.   Chronic proton pump inhibitor therapy is an    effective and appropriate form of maintenance    thera...
How my talk is structured  1.    Physiology of Gastric acid secretion  2.    Overview of Gastric Acid-Related        Disor...
Proton pump inhibitors  Proton-pump inhibitors (PPIs) - pronounced and long-    lasting reduction of gastric acid producti...
Proton pump inhibitors            End of Part – I     any questions ?Dr Anshu P Gokarn             58
Gastric Acid Disorders        Effective treatment         using Rabeprazol                 Part II             Dr Anshu P ...
How my talk is structuredPart 1  1.     Physiology of Gastric acid secretion  2.     Overview of Gastric Acid-Related     ...
MODERN ZENDr Anshu P Gokarn                61
Rabeprazole  • Novel Proton pump inhibitor  • Acid suppression with once-daily dosing  • Consistent symptom control  • Sig...
Chemistry      Substituted benzimidazole sulfoxide       Empirical Formula C18H20N3NaO3S       Molecular weight   381.43D...
Structure activity relationship  • Produrg  • Transformed at low pH to a more reactive     species, a Sulfenamide.  • Sulf...
Reduced side effect profile  • Irreversible disulphide bond with the enzyme      (ATPase)  • Binding to the Proton Pumps i...
   Pyridine nitrogen and the nitrogen near        benzimidazole 2-position – responsible for        the activity of rabep...
Pharmacokinetics        Peak plasma levels occur 2-5 hours         after oral administration        Oral bioavailability...
Rapid onset of action   Rapid dissociation to active tetracyclic    sulfenamide.1   Faster Rate of inhibition of proton ...
Faster acid inhibition       To produce the same degree of inhibition                       Rabeprazole takes 5 minutes   ...
Activation time    Activation time                  At pH 5.1,the    (minutes)                                    activati...
Increases gastric mucin        Omeprazole reduces gastric mucin and         prevents mucin synthesis        Lansoprazole...
Antisecretory potency of Rabeperazole                   Vs Omeprazole   Significantly greater                     decreas...
Faster onset of antisecretory activity than                                      Omeprazole                       800Intra...
Most Patients Treated With Rabeprazole ReportedDay And Night time Symptom Relief After One Day    No. of patients treated...
Rabeprazole                              Short Course Therapy•Calabreseincluding azithromycin usedaeither at the initiatio...
Advantage over H2 antagonists       Intrinsically                         greater                   reduction            ...
Increases Collagen regeneration     Does not suppress collagen regeneration      unlike H2 receptor antagonists     Does...
Pharmacological advantages         over older PPI’s     More potent than other PPI’s     Faster onset of action due to q...
Pharmacological advantages over               older PPI’s contd…   Greater increase in mucin synthesis.   Significantly ...
Does not alter prostaglandin levels       Increases prostaglandin synthesis       Prevents                 stress       ...
Indications     Duodenal ulcer     GERD     Gastric ulcer     Reflux oesophagitis     Zollinger- Ellison Syndrome   ...
Consistent symptomatic                                  relief      More           consistent                symptomatic ...
Nocturnal symptom relief         Greater reduction in frequency and severity          of symptoms especially nighttime he...
Higher rate of healing     Higher healing rates as compared to      omeprazole     Significantly greater improvement in ...
Healing Rates of Ulcerative GERD with different                       doses of rabeprazole compared to placebo            ...
Rabeprazole Vs Omeprazole               in healing of Duodenal ulcer               100   % HEALING                80      ...
Rabeprazole Vs Ranitidine  in management of active duodenal ulcer disease            90            80            70       ...
Improvement in symptoms of                                gastric ulcer                       100                         ...
Intrinsic Anti H. pylori activity     Highly effective inhibitor of gastric acid      secretion in subjects infected with...
Potential novel agent for        Clarithromycin resistant H. pylori               (CRPH) eradication.   Thioether derivati...
Triple therapy for eradicating H.pylori     4-day triple therapy in combination with      clarithromycin and amoxicillin ...
Rabeprazole vs. Omeprazole  1.       Rapid onset of H+K+ATPase inhibition than           omeprazole,  2.       Greater eff...
Rabeprazole vs. Omeprazole     3.      More consistent symptom relief     4.      Faster rate of healing     5.      Lower...
Rabeprazole vs. Omeprazole                           contd.       6. Two to ten fold greater antisecretory            acti...
Rabeprazole vs. Omeprazole                          contd.    8.        Irreversibly                         inhibits     ...
Rabeprazole vs. Esomeprazole        Esomeprazole 40 mg results in 10%-15% higher         healing rates in GERD patients, ...
Rabeprazole vs.                     Esomeprazole       Lower        incidences   of   Drug-Drug        interactions     ...
Rabeprazole Vs Lansoprazole        Comparable                          Ulcer              healing                 rates  ...
Cure Rates of H.pylori infection with                                             Lansoprazole and Rabeprazole            ...
Safety profile     Similar short term side effect profile to      other PPIs     Safe for long-term use.     Serious si...
Well tolerated     Very well tolerated as compared to      omeprazole                                         and        ...
Dosage and administration                                            For GERD  Adults:  Usual dosage: 20mg/day  Route of a...
For pathological hyper secretory       conditions including Zollinger-Ellison                     syndrome  Adults:  Usual...
Maximum dosage limits    Adults:     GERD, Duodenal ulcer, Gastric ulcer: 40 mg qd     Zollinger-Ellison Syndrome: 120mg ...
Maximum dosage limits  Hepatic impairment  No dosage adjustment required  Renal impairment  No dosage adjustment is necess...
Overdose                                                             No experience to date with                          ...
Contraindications    Known            hypersensitivity   to   rabeprazole,    other              substituted       benzimi...
Precautions     Gastric cancer     Hepatic disease     Children     Elderly     Japanese (AUC values were seen to be ...
Pregnancy     No data is available in human      pregnancy.     Studies in rats and rabbits have revealed      no eviden...
Lactation     It is not known whether rabeprazole sodium      is excreted in human breast milk.     No studies in lactat...
Low potential for drug                     interactions     Not          complicated by clinically significant drug-     ...
Drug interactions     Cyclosporine: metabolism is inhibited     Digoxin: AUC and Cmax is increased     Warfarin: No int...
Salient Features    Rapid onset of action    Higher rate of healing    Consistent Symptomatic relief    Increases gast...
Salient Features    The conformation of pump not altered as done by     Omeprazole.    Brings acid production level back...
How my talk is structured  1.    Physiology of Gastric acid secretion  2.    Overview of Gastric Acid-Related        Disor...
Thank You  Queries ?anshu.gokarn@gmail.com
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Talk on gastic disorders and rabeprazole

  1. 1. Gastric Acid DisordersEffective treatmentusing Rabeprazol Dr Anshu P Gokarn MBBS, MD(Pharmacology)
  2. 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. 3. Gastric Acid Disorders Effective treatment using Rabeprazol Part I Dr Anshu P Gokarn MBBS, MD(Pharmacology)Dr Anshu P Gokarn 3
  4. 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. 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. 6. StomachDr Anshu P Gokarn 6
  7. 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. 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. 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. 10. Types of Cells G Cells: Gastrin (hormone) ---> HCl secretion D Cells: Somatostatin (antrum) Enterochromaffin-like cell: HistamineDr Anshu P Gokarn 10
  11. 11. Types of CellsDr Anshu P Gokarn 11
  12. 12. Gastric juices  HCl (hydrochloric acid)  Pepsinogen  Electrolytes  Intrinsic factor  Mucus (mucus gel layer) pH ~4Dr Anshu P Gokarn 12
  13. 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. 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. 15. Gastric motility Anatomic Regions Functional Motor RegionsDr Anshu P Gokarn 15
  16. 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. 17. Mixing & emptying of gastric contentsDr Anshu P Gokarn 17
  18. 18. Constriction of pyloric sphincterDr Anshu P Gokarn 18
  19. 19. Constriction of pyloric sphincter Hormones promote constriction 1. CCK 2. Secretin 3. Gastrin 4. GIP Sympathetic innervationDr Anshu P Gokarn 19
  20. 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. 21. Dr Anshu P Gokarn 21
  22. 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. 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. 24. Gastric juices HydroChloric Acid (HCl) Secretion  Secreted by parietal cells Fundus BodyDr Anshu P Gokarn 24
  25. 25. Gastric juices – HCl SecretionDr Anshu P Gokarn 25
  26. 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. 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. 28. Neural & Hormonal Control of Gastric SecretionDr Anshu P Gokarn 28
  29. 29. Neural & Hormonal Control of Gastric SecretionDr Anshu P Gokarn 29
  30. 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. 31. Regulation of Acid SecretionDr Anshu P Gokarn 31
  32. 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. 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. 34. Activation of H1K ATPaseDr Anshu P Gokarn 35
  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. 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. 37. Helicobacter pyloriDr Anshu P Gokarn 38
  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. 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. 40. Gastroesophageal reflux diseaseDr Anshu P Gokarn 42
  41. 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. 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. 43. Complications of GERD Barrett’s esophagus Esophageal strictures Carcinomas Barrett’s esophagus Gastric Cancer Esophageal strictures Dr Anshu P Gokarn 47
  44. 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. 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. 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. 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. 48. Proton pump inhibitors End of Part – I any questions ?Dr Anshu P Gokarn 58
  49. 49. Gastric Acid Disorders Effective treatment using Rabeprazol Part II Dr Anshu P Gokarn MBBS, MD(Pharmacology) 59Dr Anshu P
  50. 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. 51. MODERN ZENDr Anshu P Gokarn 61
  52. 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. 53. Chemistry  Substituted benzimidazole sulfoxide Empirical Formula C18H20N3NaO3S Molecular weight 381.43Dr Anshu P Gokarn 63
  54. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 87. Rabeprazole vs. Esomeprazole  Lower incidences of Drug-Drug interactions  Faster rate of H+K+ATPase inhibitionDr Anshu P Gokarn 99
  88. 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. 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. 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. 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. 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. 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. 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. 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. 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. 97. Contraindications Known hypersensitivity to rabeprazole, other substituted benzimidazoles (e.g.,lansoprazole, omeprazole)Dr Anshu P Gokarn 110
  98. 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. 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. 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. 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. 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. 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. 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. 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. 106. Thank You Queries ?anshu.gokarn@gmail.com
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