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Detailed Anatomy of the StomachLocated on the left side of the body, under the diaphragm, thestomach is a muscular, saclike organ that connects theesophagus and small intestine through the duodenum. Its mainfunction is to break down food. Cells in the stomach liningsecrete enzymes, hydrochloric acid, and other chemicals tocontinue the digestive process begun in the mouth and producemucus to keep these substances from digesting the lining itself.
ACID Related Disorders of GIT Responding to PPI TreatmentNote : Acid Related Disorders will be abbreviated (ARD)
Spectrum of Overlapping GIT Symptoms Ulcer-Like Dysmotility-Like Epigastric Pain : Early satiety Nocturnal Postprandial bloating Fasting Nausea / Relieved by Vomiting food/antacids Pain Unrelieved Bleeding by food or antacidsNocturnal: Occurring by night Satiety: a state in which somebody has had enough or GERD-Like too much. Postprandial : after a meal, Heartburn especially an evening meal Regurgitation : bring Bloating : Swollen or Inflated undigested or partially Regurgitation digested food up from stomach to esophagus Chest pain
Diseased Conditions & Quality Of Life (QOL) Psychiatric Patients Untreated GERDPopulation Untreated Duodenal Ulcer Angina Pectoris Mild Heart Failure Normal Female Normal Male 60 70 80 90 100 110Deminas, Scand J Gastroentrol; 1993 Psychological Well Being Index (PGWBI)
Acid Related GIT Diseases & QOL Mean PGWB score Normal Population Best 132 100 90 80 70Worst 22 Esophagitis Gastric Duodenal Negative Gastritis/ ulcer ulcer endoscopy duodenitisPGWB = Psychological Well Being
Dyspepsia Dyspepsia is a condition of impaired orpainful digestion resulting from failure ofsome phase of the normal digestiveprocess. It is a common disorder (up to 25% ofPopulation) with negative impact onpatient quality of life (QOL) It can be defined as “persistent orrecurrent abdominal pain or abdominaldiscomfort centered in the upperabdomen”.
Possible Causes Of DyspepsiaThe Cause May Be Physical Or Emotional Upset Among The Physical Causes Are: Gastritis. Chronic Peptic Ulceration. GERD. Gallbladder Inflammation. Gastric Cancer. Drugs. Symptoms Of Possible Causes Often Overlap,Which Can Make Initial Diagnosis Difficult.
Symptoms Of DyspepsiaSymptoms May Include A Heavy Feeling in the Pit of the Stomach. Gas and Belching. Constipation. Diarrhea. Nausea. Heartburn.Headache or dizziness may accompany the discomfort.
Patients With Dyspepsia May Have Underlying Organic Lesions Reflux esophagitis Normal 23.9% 33.6% 2% Cancer 19.9% 20.8%Gastritis/duodenitis Peptic ulcer disease
Gastritis Acute : Caused by NSAIDs or Alcohol. May be associated with mucosalulceration. Chronic : Often associated with H. pylori colonization of mucosa.
Gastritis Gastritis is Acute or Chronic inflammation of the mucosal lining of the stomach In gastritis the inflammation may be marked by the erosion of surface cells of the mucosa, formation of granular nodules, and hemorrhage. In chronic gastritis, there is a growth of fibrous tissue on the lining. Weight loss and delayed emptying of the contents of the stomach may accompany the disease. Gastritis may develop into Gastric Ulcerspecially when H. pylori colonization is present Psychological stress may also be involved inthe development of gastritis.
GERD Gastro-Esophageal Reflux Disease Is A CommonCondition That Results From The Reflux Of GastricMaterial Through The Lower Esophageal Sphincter(LES) Into The Esophagus Or Oropharynx, CausingSymptoms And/Or Injury To Esophageal Tissue. The Term Encompasses Both Symptoms AndPatho-physiologic Changes To The EsophagealMucosa, Which Occur As A Result Of Exposure Of TheDistal Esophagus To Acidic Gastric Contents AfterEpisodes Of Gastro-esophageal Reflux. GERD Is Typically Chronic, Generally Non-progressive, But Some Cases Are Associated WithComplications Of Increasing Severity AndSignificance.
Clinical Overview of GERD GERD Is A Dysmotility Problem With ABroad Clinical Spectrum. Has High Prevalence Rate. Greatly Affects Quality of Life (QOL). Acid Related Complicated EsophagealManifestations Are The Real Danger OfThe Disease. Extra Esophageal Problems AreEqually Dangerous.
Detailed Etiologic Factors Involved in GERD Impaired Esophageal Impaired Salivary Acid Clearance Function Hiatal Hernia Impaired EsophagealTransient, Inappropriate Mucosal Relaxation of LES Defense Gastric Acid; Pepsin Secretion: Normal / Raised Reduced Resting Pyloric Tone of LESIncompetence;duodenogastric reflux Delayed Gastric Emptying Acidity Related Motility Related
Significance of Acid Reflux in GERDProlonged Dwell Time of Acid and Pepsin in Esophagus.Normal Gastric And Pepsin Output in Most Patients.Daytime Food-stimulated Acid Reflux May Be an Additive Factor in Some Patients.Nocturnal Reflux May Be a Factor in Severe Esophagitis, Stricture or Barrett’s Metaplasia.
Esophageal pH Monitoring Among Controls & Patients with Various Grades of GERD 25Total Time pH <4.0 (%) 21 20 18 15 15 10 7 5 3 0 Controls No Esophagitis Esophagitis Uncomplicated Complicated Barrett’s Barrett’s Source : Vaezi,MF et al : Gastroenterology, 1996; 111:1192-1199
The Clinical Spectrum of GERDPhysiological Symptomatic Complicated Esophagitis Reflux GERD Esophagitis Typical Atypical Complications Heartburn Chest pain Ulceration Regurgitation Dysphagia Erosion Cough Hemorrhage Asthma Stricture Laryngitis Barrett’s Eso. AdenocarcinomaSource : Peura DA, et al : Aliment Pharmacol Ther.; 19 Suppl 1: 77-80 (Feb 2004)
Barrett’s Esophagus Effect of Age Erosive Esophagitis Heartburn Alone Patients with GERD (%) 100 6 9 17 17 36 32 80 33 42 28 34 60 39 40 56 61 55 49 49 20 25 13 0 <30 30-39 40-49 50-59 60-69 >70 Age (y) Proportions of GERD Patients with Heartburn, ErosiveEsophagitis, and Barrett’s Esophagus According to Age Group.Jankowski J, Sharma P.: Aliment Pharmacol Ther 19 Suppl. 1: 54-9. (Feb 2004)
Summary of Symptoms & Manifestations of GERD Symptoms Manifestations Heartburn Esophageal Ulcer Regurgitation Erosive Esophagitis Dysphagia Peptic Stricture Belching Barrett’s Esophagus Odynophagia Esophageal Adenocarcinoma Manifestations of (GERD) are caused directly by contactbetween refluxed acidic gastric juice and the esophageal mucosa. Esophageal erosion & ulcerations result when epithelial cellssuccumb to the caustic effects of refluxed acid and pepsin.
Percent Prevalence of All GERD Symptoms HEARTBURN 83%Regurgitation 70% 4%Typical 7% odynophagiaSymptoms 8% 10% Belching 37% 30% 10% Nausea Chest Pain Dysphagia Abdominal Pain Respiratory Symptoms Castell, DO et al : Practical Gastroenterology , Feb 1999: 20-44
Hidden Complications of GERD Chronic, recurrent heartburn, dysphagia, hoarseness, etc. Erosive Esophagitis Reports of frequent episodes of heartburn, but no other symptoms Barrett’s Esophagus Mild intermittentheartburn, not seen by a physician GERD ICEBERG Esoph.Adeno- Carcinoma
The Pyramid of Diseases Associated with GERD Extra Esophagial0% Misc. Asthma ENT Chest Pain } Non-Erosive Reflux Dis. Erosive Esophagitis100%
What Is A PUD PUD is a Term Used to Refer to : Ulcer of Esophagus. Ulcer of Stomach. Ulcer of Duodenum. Definition It is an Erosion of the Mucosa True Ulcer Affects Deeper Lesions Extends Down into Sub-Mucosal Layersof the Gut Wall.
Peptic Ulcer Diseases Pathogenesis Increased ACID secretions and digestiveenzymes erode gastric mucosa Helicobacter pylori plays a role Complications Hemorrhage, perforation peritonitis, scarring
Peptic Ulcer ComplicationsPeptic Ulcersmay lead toBLEEDING orPERFORATIONemergencysituations
PUD Risk Factors Social Factors Patho-Physiological Factors Life Style NSAID Mucosal Damage Smoking Hypo-Volemia Alcohol Hyper-secretion of Corticoids Stress Adrenaline hyper-secretionhypovolemia - a blood disorder consisting of a decrease in the volume of circulating blood Aggressive Factors Hyper Acid Production Hyper Pepsin Secretion Helicobacter pylori Colonization
PUD Risk Factor H. pylori H. Pylori MicroscopicH. Pylori Electron Microscopic
Epidemiology of H. pylori World Wide Prevalence
Association of Ulcers with H. pylori Duodenal Ulcer Gastric Ulcer Pylori-Free Pylori Positive 25.0%Pylori Positive Pylori-Free 96.0% 4.0% 75.0%
PUD Prevalence Who May Develop an Ulcer ? Ulcer can develop at any age, but it israre among teenagers and uncommon withchildren. Gastric Ulcers are more likely to developin people between 40-60. Duodenal Ulcers have an earlier peakincidence between ages of 25-50. Gastric Ulcers develop more in Women. Duodenal Ulcers occur more frequently inMen.
What Are The Symptoms Of Peptic Ulcers ?The Most Common Symptom Is Gnawing Or Burning Pain InThe Abdomen Between The Breast Bone And The Naval Bone. Stomach Ulcer Pain Often Occurs After Meals. It May Last From Few Minutes to Few Hours. May be Relieved by Taking Antacids. Duodenal Ulcer Pain Occurs Between Meals (Hunger Pain). It Occurs Also by Night and in the Early Morning. Pain is Relieved by Eating or by Taking Antisecretory. Stress Ulcer Is Silent , Asymptomatic Ulcer, But is Life Threatening
What Are The Complications Of Peptic Ulcers ? (1)Bleeding Due to Deep Ulcer or Erosions.Minor Bleeding Occurs Rarely, But May Be Sufficient to Cause Anemia Over a Period of Time.Hemorrhage Occurs in The Sub-mucosal Layer Where a Large Vessel is Eroded.15-20% of Patients with Peptic Ulcer Experience an Episode of Hemorrhage.The Blood May Appear In The Vomits or in the Stools and Some Patients May be Shocked.
What Are The Complications Of Peptic Ulcers ? (2) Perforation of the gut wall may occur in 5% ofpatients either with peptic ulcer or stress ulcer. Bacterial infection may occur & is accompaniedby hemorrhage in about 10% of cases. Acute perforation may lead to 5% mortality ratemainly in the elderly. Pyloric stenosis (Gastric outlet obstruction) whichresults from fibrous changes, oedema or spasm (or acombination of all of them). It may be produced by an ulcer in the region ofpylorus & the obstruct stomach may lead to nauseaand vomiting. Early symptoms are often sensation of excessiveand long-lasting ”fullness” after a small meal andcontinuous vomiting, therefore, it may causedehydration.
How Can Peptic Ulcers Be Diagnosed ? Endoscopy Barium Meal X-Ray Acid Secretion Test. H. Pylori Tests.
Endoscopy Large Chronic Duodenal Ulcer Gastric Ulcer whichEroded a Blood Vessel in Base of Ulcer
Therapeutic Approach to PUD : A Staged ApproachStage I Stage II Stage LifestyleModification Intensive III Surgery + Therapy : Endoscopy Antacids PPI and/or H2RA H2RAs PPI
Medical Therapies for ARD AGENTS TARGET Mucosal Damaged Mucosa ProtectorsAcid Neutralizers Local Raising of (Antacids) Refluxate pH Inhibition of AcidAcid Suppressive Agents Production in Parietal Cells
PPIs : PharmacologyAre substituted benzimidazoles ProDrugs.They are concentrated & activated in the parietal cell canalicular lumen by conversion to sulfenamides in the presence of acid.Bind irreversibly to cysteine residues and inactivate H+, K+ ATPase (proton pump).Inhibit only active pumps.A new pump is regenerated in about 24 hNew steady state for acid secretion occurs in about 3 days.
ACTIVATION OF SUBSTITUTED BENZIMIDAZOLESPantoprazole Sulfenic Acid Sulfenamide Inactivated Enzyme
PPIs : Pharmacology (cont.) Half-life for various PPI’sreported at 0.5-2.0 hours. Duration of action is related totime for regeneration of new pumpsand activation of resting pumps ¬ to half-life. Efficacy allows 24-h acidsuppression with once-daily dosing.
Use of PPI’s in GERDRelieve SymptomsHeal EsophagitisPrevent RecurrenceTreat Complications Chest Pain Benign Esophageal Stricture Respiratory Symptoms Oropharyngeal Symptoms Barrtett’s Esophagus Heal Esophagus Prevent Progression to dysphagia or adenocarcinoma
Clinical Efficiency of PPI’s in GERD Eliminate Symptoms 90% Heal Esophageal Lesions 90% Manage of Prevent Complications 80% Maintain Remission in Erosive 80% EsophagitisSpechler SJ : Am J Med Sci 326:297-84, (Nov 2003)
Relation Between Duration of Suppression of Intragastric Acidity and Esophageal Acid ExposureDuration Intraesophageal pH<4.0 16 The longer the period of time 14 that the intragastric pH is above 4, the lower the percentage of (% of Total Time) 12 time that there is contact between gastric acid and 10 esophageal mucosa 8 6 4 2 0 1 3 5 7 9 11 13 15 17 19 21 Duration Intragastric pH>4.0Source : Bell et al: Digestion; : 51 (Suppl.) :59 (1992)
Healing Rates of Esophagitis During pH Control% Patients Healed 100 80 60 40 r = 0.87 20 0 2 4 6 8 10 12 14 16 18 20 22 Duration Intragastric pH > 4.0 (hr/24 hr) Bell, NJV et al Digestion , 51 (Suppl.1) :59-67 (1992)
PPI’s versus H2RA’s in Erosive Esophagitis 100 PPI’sPatients Healed (%) 80 H2RA’s 60 40 Placebo 20 0 Week 0 Week 2 Week 4 Week 6 Week 8 Week 10 Chiba, N. et al Gastroenterology, 112:1798-1810 (1997)
PPIs : Are They All The Same ? Pharmacologically NoClinically 80% Yes 20% No
PPIs : Pharmacokinetics Parameter Bio - Protein Half- Time to Avail -PPI Peak, h Binding Life, h ability %Omeprazole 30-40 0.5-3.5 95 0.5-1.0Esomeprazole N/A 1.6 97 1.2-1.5Pantoprazole 77 1.1-3.1 98 1.0-1.9Lansoprazole 80 1.7 97 1.6Rabeprazole 52 2-5 95-97 0.85-2.0Source : Vanderhoff BT & Tahbour R: Am Fam Physician ; 66: 273-280 (2002)
PPIs : Pharmacodynamics Parameter Activation Time, min. % Inhibition of pKa ATPase PPI At pH 1.2 At pH 5.1 At 10 min. At 45 min.Omeprazole 4.13 2.8 84 47 83Esomeprazole 4.13 N/A N/A N/A N/APantoprazole 3.96 4.6 282 83 100Lansoprazole 4.01 2.0 90 66 100Rabeprazole 5.0 1.3 7.2 99 100pKa Influences : Accumulation in Parietal Cells, Acid Stability & Activation Rates Source : Johnson, S: Alim Pharmacol Ther; 14: 1249-1258 (2000)
PPIs : Drug-Drug Interactions PPI OME ESO PAN LAN RABDrugCyclosporineDiazepamDigoxinKetoconazolePhenytoinTheophyllineWarfarin Clinically Significant Clinically Insignificant Reported but not well documented Source : Welage L et al : J Am Pharm Assoc; 40: 52-63 (2000)
Specific Binding Sites ofPANTOPRAZOLE to Cysteine Residues 813 & 822
Activation After 1 hour (%) 100 501 Parietal Cell3 Lysosome5 Acid Activation of PPI’s7 CytosolpH
Pantoprazole I.V. Injection PANTOPRAZOLE is more stablethan OMEPRAZOLE or LANSOPRAZOLE,and particularly much more stable thanRABEPRAZOLE, under neutralconditions or conditions that are mildlyacidic (pH ~3.5 to pH ~7.4) PANTOPRAZOLE, therefore, is the most suitable PPI to produce in intravenous form.Source : Maton PN : Cleveland Clinic J Med : 70 (Suppl.5) 851-870 (Jan 2004)
Metabolism of PPIsMetabolized by CYP2C19 & CYP3ACYP2C19 Exhibits Genetic Polymorphism Rabeprazole least affected by polymorphismas its major metabolic pathway is non-enzymatic (not Cytochrome Mediated) Genetic polymorphism is due to deficiencyof CYP2C19 in some populations : 3% Caucasians & Africans; 12-15% Asians.Stereo-Selective Metabolism
Alteration in Metabolism & Clearance With Repeated Dosing of Esomeprazole FIRST DOSE REPEATED DOSING Esomeprazole Esomeprazole CYP2C19 CYP3A CYP3A Esomeprazole EsomeprazoleHydroxy & Sulphone SulphoneDesmethyl • The Inhibition of CYP2C19 by the sulphone metabolite of esomeprazole lasts > 24 h • This causes progressive inhibition of clearance of succeding daily doses of esomeprazole
24-Hours Intragastric pH Profile Placebo Omeprazole Pantoprazole pHINTRAGASTRIC ACIDITY (mmol/L) M Nocturnal Acid 0 M M Breakthrough 1 80 2 60 3 40 4 20 5 0 6 0800 1200 1600 2000 2400 0400 0800 Time of Day M Meal Source : Castell DO: Medscape ; Prog.118: 1-60 (Jan 2004)
Elimination of NAB in GERDPatients with NAB Eliminated (%) 45 41% 40 35 30 25 18% 18% 20 15 9% 10 5 0 PPI bid PPI am PPI +H2RA PPI /8h Source : Ours TM et al: Am J Gastroenterol ; 98: 545-550 (2003)
PANTOLOC Features and Benefits Efficacy Allows 24-h Acid Suppression With Once-Daily Dosing Patient Convenience Ensures Compliance Assured Cure of Ulcers
PANTOLOC Features and Benefits Efficacy in Controlled Clinical Trials ~90% : Eliminates Symptoms Heals Lesions Manages or Prevents Complications Maintains Remission Ensures Achievement of Therapeutic Results Rapid & Enhanced Cure of Ulcers
PANTOLOC Features and BenefitsDose Linearity in the Range 10-80 mg Consistency of Repeated Doses Continuous, Un-Interrupted Daily Relief of Symptoms Omeprazole & Esomeprazole exhibit NONLINEAR Dose Response
PANTOLOC Features and Benefits Absolute Bioavailability 77% High Blood Level Concentration Maximum Activity Achieved Omeprazole (30-40%) ; Rabeprazole (52%)
PANTOLOC Features and Benefits pKa 3.96 Rapid Activity Only at pH 1.2 of the Parietal Cell Selectivity of Action to Proton Pump Only No Side-Effects at Liposome or Cytosol Sites
PANTOLOC Features and Benefits pKa 3.96 Stable at Blood pH The ONLY PPI with I.V. Injection Form
PANTOLOC Features and Benefits Lack of Any Clinically Significant Drug-Drug Interactions No Effect on Other Drugs’ Metabolism Due to Low Interaction with CYP1A Safe Co-Administration of Other Drugs Except Ketoconazole, Contrasted with : Omeprazole and Rabprazole (Many D-D Interactions) Lansoprazole and Esomeprazole (more D-D Interactions)
PANTOLOC Features and Benefits Specific Binding Sites of Pantoprazole to Cysteine Residues 813 & 822 of ATPase Specific Block of Proton Channel Maximum Efficiency of Proton Pump Inhibition
PANTOLOC Features and Benefits Has Least Effect On The ECL Cells Than Other PPI Does Not Cause Gastric Atrophy or Metaplasia Safe on Prolonged Administration
PANTOLOC Features and Benefits Feature Physician Benefit Patient BenefitPANTOLOC Doctor, this means that you: Your patients... is dosed can expect will findonce daily in greater patient PANTOLOC easyall dosage compliance. to take.forms Will find Won’t have to PANTOLOC easy to take their prescribe. medication to work. Cost-effective therapy.
PANTOLOC Features and Benefits Feature Physician Benefit Patient BenefitPANTOLOC Doctor, this means that you: Your patients... Tablets are Can Tailor will ObtainAvailable in 20 Dosage to the the Greatestmg and 40 mg Needs of Your Relief with theStrengths Patients. least Amount of Drug. As 7 Tabs. Have the Abilityor 14 Tabs. to Titrate Up & benefit from Down for ON-DEMAND Maximum Therapy Therapeutic Accuracy.
PANTOLOC Features and Benefits Available in Various Package Forms20 mg (7 or 14 TAB), 40 mg (7 or 14 TAB) Convenient for both Doctors and Patients
PANTOLOC Features and BenefitsElderly PatientsPatients With Renal ImpairmentPatients With Hepatic Dysfunction
PANTOLOC Features and Benefits 60 Pantoprazole 92 40mg 83 88 Healing rates (%) 40 Omeprazole 20mg 20 Lansoprazole 0 30mg8 weeks Pilotto et al; 1999
For Peptic Ulcer Treatment For Erosive Esophagitis For H Pylori EradicationFor HeartburnFor Other SymptomsAssociated with GERD For Maintenance of HealedEsophagitis and Peptic UlcerOn-Demand Therapy