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Pantoloc a

The document summarizes information about Pantoprazole, a proton pump inhibitor used to treat acid-related gastrointestinal disorders. It discusses conditions like GERD, dyspepsia, gastritis, and peptic ulcers. It provides details on the anatomy of the stomach and mechanisms involved in acid regulation. Pantoprazole works by inhibiting the hydrogen-potassium ATPase enzyme system, thereby reducing acid secretion in the stomach. The drug is indicated for treatment of acid-related disorders and improves patients' quality of life.

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Introduction MUP introduces the most efficient treatment for Acid Related Disorders Proton Pump Inhibitor PANTOLOC pantoprazole
PANTOPRAZOLE Prof. Dr. Aly Taha
PANTOPRAZOLE PROTON PUMP INHIBITOR PPI O-CH F2 O C H3 N H3CO S N + N O Na
Main Indications Acid Related Disorders of GIT
GIT Acid Related Disorders Dyspepsia GERD* Erosive Esophagitis Barrett’s Esophagus Gastritis PUD Gastric Ulcer Duodenal Ulcer * GERD: Gastro-Esophageal Reflux Disease
Medical Background Quick Review
General Anatomy of the Stomach
Detailed Anatomy of the Stomach Located on the left side of the body, under the diaphragm, the stomach is a muscular, saclike organ that connects the esophagus and small intestine through the duodenum. Its main function is to break down food. Cells in the stomach lining secrete enzymes, hydrochloric acid, and other chemicals to continue the digestive process begun in the mouth and produce mucus to keep these substances from digesting the lining itself.
ACID Related Disorders of GIT Responding to PPI Treatment Note : Acid Related Disorders will be abbreviated (ARD)
GIT Acid Related Disorders GERD Dyspepsia Gastritis Gastric Ulcer Duodenal Ulcer
* Gastro Esophageal Gastric Duodenal Reflux Disease Ulcer Ulcer Dyspepsia Peptic GERD* Ulcer ACID RELATED DISORDERS Adeno- Erosive Carcinoma Esophagitis Barrett’s Esophagus
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 antacids Nocturnal: 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 GERD Population Untreated Duodenal Ulcer Angina Pectoris Mild Heart Failure Normal Female Normal Male 60 70 80 90 100 110 Deminas, Scand J Gastroentrol; 1993 Psychological Well Being Index (PGWBI)
Acid Related GIT Diseases & QOL Mean PGWB score Normal Population Best 132 100 90 80 70 Worst 22 Esophagitis Gastric Duodenal Negative Gastritis/ ulcer ulcer endoscopy duodenitis PGWB = Psychological Well Being
Dyspepsia
Dyspepsia Dyspepsia is a condition of impaired or painful digestion resulting from failure of some phase of the normal digestive process. It is a common disorder (up to 25% of Population) with negative impact on patient quality of life (QOL) It can be defined as “persistent or recurrent abdominal pain or abdominal discomfort centered in the upper abdomen”.
Possible Causes Of Dyspepsia The 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 Dyspepsia Symptoms 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
Gastritis Acute : Caused by NSAIDs or Alcohol. May be associated with mucosal ulceration. 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 Ulcer specially when H. pylori colonization is present Psychological stress may also be involved in the development of gastritis.
GERD
GERD Gastro-Esophageal Reflux Disease Is A Common Condition That Results From The Reflux Of Gastric Material Through The Lower Esophageal Sphincter (LES) Into The Esophagus Or Oropharynx, Causing Symptoms And/Or Injury To Esophageal Tissue. The Term Encompasses Both Symptoms And Patho-physiologic Changes To The Esophageal Mucosa, Which Occur As A Result Of Exposure Of The Distal Esophagus To Acidic Gastric Contents After Episodes Of Gastro-esophageal Reflux. GERD Is Typically Chronic, Generally Non- progressive, But Some Cases Are Associated With Complications Of Increasing Severity And Significance.
Clinical Overview of GERD GERD Is A Dysmotility Problem With A Broad Clinical Spectrum. Has High Prevalence Rate. Greatly Affects Quality of Life (QOL). Acid Related Complicated Esophageal Manifestations Are The Real Danger Of The Disease. Extra Esophageal Problems Are Equally Dangerous.
GERD Pathogenesis Pathophysiology Clinical Manifestation
Esophageal Non- Pathologic Reflux
Esophagus Stomach Gastric Folds Lower Esophageal Sphincter (LES) Junction of Gastric & Esophageal Mucosa Pyloric Sphincter First Part of Duodenum
GERD: A Multi-Factorial Etiology Acidity Motility Factors Factors Increased Esophageal Acid Exposure Motility Impaired Dysfunctions Acid Clearance
GERD Main Etiological Processes
Detailed Etiologic Factors Involved in GERD Impaired Esophageal Impaired Salivary Acid Clearance Function Hiatal Hernia Impaired Esophageal Transient, Inappropriate Mucosal Relaxation of LES Defense Gastric Acid; Pepsin Secretion: Normal / Raised Reduced Resting Pyloric Tone of LES Incompetence; duodenogastric reflux Delayed Gastric Emptying Acidity Related Motility Related
Endoscopic Diagnosis of GERDs
Proportion of Subjects with Esophageal Motility Abnormalities 50 48 Patients (%) 40 30 26 21 20 9 10 0 Normal Normal Mild Severe Volunteers Esophagus/ Esophagitis Esophagitis GERD Source : Kahrilas, PJ et al : Gastroenterology, 1986; 91:897-904
Gastro Esophageal Reflux Mechanisms in Normal & GERD 1% 100% 5% Spontaneous 18% Reflux 80% Transient 17% Increase in 94% Intra- 60% Abdominal Pressure 40% 65% Transient Lower 20% Esophageal Sphincter Relaxations 0% NORMAL Volunteers GERD Patients Source : Kahrilas, PJ : Cleveland Clin. J Med.,; 70 (Suppl.5) :S4-S17 (Nov.2003)
Significance of Acid Reflux in GERD Prolonged 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 25 Total 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 GERD Physiological Symptomatic Complicated Esophagitis Reflux GERD Esophagitis Typical Atypical Complications Heartburn Chest pain Ulceration Regurgitation Dysphagia Erosion Cough Hemorrhage Asthma Stricture Laryngitis Barrett’s Eso. Adenocarcinoma Source : Peura DA, et al : Aliment Pharmacol Ther.; 19 Suppl 1: 77-80 (Feb 2004)
Atypical and Extra-Esophageal Manifestations of GERD Atypical Extra Esophageal Chest Pain Oral Pulmonary Epigastric Pain Dental Erosion Chronic Cough Nausea Asthma Aspiration Pulmonary Fibrosis Pharyngo-laryngeal Recurrent Pneumonia Hoarseness Posterior Laryngitis Globus Sensation Sore Throat Other Vocal Cord Irritation Sleep Abnormalities Vocal cord Polyps Sleep Apnea (?) Posterior Laryngitis Angina Malagelada JR : Aliment Pharmacol Ther 19 Suppl. 1: 43-48. (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, Erosive Esophagitis, 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 contact between refluxed acidic gastric juice and the esophageal mucosa. Esophageal erosion & ulcerations result when epithelial cells succumb to the caustic effects of refluxed acid and pepsin.
Percent Prevalence of All GERD Symptoms HEARTBURN 83% Regurgitation 70% 4% Typical 7% odynophagia Symptoms 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 intermittent heartburn, not seen by a physician GERD ICEBERG Esoph.Adeno- Carcinoma
The Pyramid of Diseases Associated with GERD Extra Esophagial 0% Misc. Asthma ENT Chest Pain } Non-Erosive Reflux Dis. Erosive Esophagitis 100%
Peptic Ulcer Diseases (PUD) PUD
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 Layers of the Gut Wall.
Gastric Mucosa G Cell : A Gastrine-secreting cell ECL Cell : (Entero-Chromaffin-Like Cell) A Histamine-secreting endocrine cell
Peptic Ulcer Esophageal Ulcer Gastric Ulcer Duodenal Ulcer Esophageal Ulcer Gastric Ulcer Duodenal Ulcer
ULCER movie
Peptic Ulcer Diseases Pathogenesis Increased ACID secretions and digestive enzymes erode gastric mucosa Helicobacter pylori plays a role Complications Hemorrhage, perforation peritonitis, scarring
Peptic Ulcer Complications Peptic Ulcers may lead to BLEEDING or PERFORATION emergency situations
PUD Risk Factors Social Factors Patho-Physiological Factors Life Style NSAID Mucosal Damage Smoking Hypo-Volemia Alcohol Hyper-secretion of Corticoids Stress Adrenaline hyper-secretion hypovolemia - 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 Microscopic H. 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 is rare among teenagers and uncommon with children. Gastric Ulcers are more likely to develop in people between 40-60. Duodenal Ulcers have an earlier peak incidence between ages of 25-50. Gastric Ulcers develop more in Women. Duodenal Ulcers occur more frequently in Men.
What Are The Symptoms Of Peptic Ulcers ? The Most Common Symptom Is Gnawing Or Burning Pain In The 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% of patients either with peptic ulcer or stress ulcer. Bacterial infection may occur & is accompanied by hemorrhage in about 10% of cases. Acute perforation may lead to 5% mortality rate mainly in the elderly. Pyloric stenosis (Gastric outlet obstruction) which results from fibrous changes, oedema or spasm (or a combination of all of them). It may be produced by an ulcer in the region of pylorus & the obstruct stomach may lead to nausea and vomiting. Early symptoms are often sensation of excessive and long-lasting ”fullness” after a small meal and continuous vomiting, therefore, it may cause dehydration.
How Can Peptic Ulcers Be Diagnosed ? Endoscopy Barium Meal X-Ray Acid Secretion Test. H. Pylori Tests.
Endoscopy Large Chronic Duodenal Ulcer Gastric Ulcer which Eroded a Blood Vessel in Base of Ulcer
Therapeutic Approach to PUD : A Staged Approach Stage I Stage II Stage Lifestyle Modification Intensive III Surgery + Therapy : Endoscopy Antacids PPI and/or H2RA H2RAs PPI
Profile & Assessment of ARD Pharmacotherapy PANTOLOC MUP RANITOL MUP
Medical Therapies for ARD AGENTS Examples Mucosal Sucralfate, Sodium Protectors Alginate Acid Neutralizers (Antacids) Magaldrate, Carbonates Acid Suppressive Histamine H2 Antagonists, Agents Proton Pump Inhibitors
Medical Therapies for ARD AGENTS TARGET Mucosal Damaged Mucosa Protectors Acid Neutralizers Local Raising of (Antacids) Refluxate pH Inhibition of Acid Acid Suppressive Agents Production in Parietal Cells
Mechanism for Acid Production Parietal Cell HCl Proton Pump (H+ K+ ATPase) Cl- K+ H+ Acetylcholine Gastrin Histamine 2
Mechanism for Acid Inhibition PPI
PPIs : 2004 Omeprazole (OME) Lansoprazole (LAN) Pantoprazole (PAN) Rabeprazole (RAB) Esomeprazole (ESO)
OME LAN RAB PAN ESO Source : Maton PN : Cleveland Clinic J Med : 70 (Suppl.5) 851-870 (Jan 2004)
PPIs : Chemistry
PPIs : Pharmacology Are 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 h New steady state for acid secretion occurs in about 3 days.
ACTIVATION OF SUBSTITUTED BENZIMIDAZOLES Pantoprazole Sulfenic Acid Sulfenamide Inactivated Enzyme
PPIs : Pharmacology (cont.) Half-life for various PPI’s reported at 0.5-2.0 hours. Duration of action is related to time for regeneration of new pumps and activation of resting pumps & not to half-life. Efficacy allows 24-h acid suppression with once-daily dosing.
Use of PPI’s in GERD Relieve Symptoms Heal Esophagitis Prevent Recurrence Treat 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% Esophagitis Spechler SJ : Am J Med Sci 326:297-84, (Nov 2003)
Relation Between Duration of Suppression of Intragastric Acidity and Esophageal Acid Exposure Duration 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>4.0 Source : 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’s Patients 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 No Clinically 80% Yes 20% No
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PPIs : Pharmacokinetics Parameter Bio - Protein Half- Time to Avail - PPI Peak, h Binding Life, h ability % Omeprazole 30-40 0.5-3.5 95 0.5-1.0 Esomeprazole N/A 1.6 97 1.2-1.5 Pantoprazole 77 1.1-3.1 98 1.0-1.9 Lansoprazole 80 1.7 97 1.6 Rabeprazole 52 2-5 95-97 0.85-2.0 Source : 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 83 Esomeprazole 4.13 N/A N/A N/A N/A Pantoprazole 3.96 4.6 282 83 100 Lansoprazole 4.01 2.0 90 66 100 Rabeprazole 5.0 1.3 7.2 99 100 pKa 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 RAB Drug Cyclosporine Diazepam Digoxin Ketoconazole Phenytoin Theophylline Warfarin 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 of PANTOPRAZOLE to Cysteine Residues 813 & 822
Activation After 1 hour (%) 100 50 1 Parietal Cell 3 Lysosome 5 Acid Activation of PPI’s 7 Cytosol pH
Pantoprazole I.V. Injection PANTOPRAZOLE is more stable than OMEPRAZOLE or LANSOPRAZOLE, and particularly much more stable than RABEPRAZOLE, under neutral conditions or conditions that are mildly acidic (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)
Healing of Erosive GERD : 8 Weeks Treatment with PPI’s 100 90 91 92 91 90 20 mg 80 30 mg Healing Rate % 70 40 mg 60 20 mg 50 40 30 20 10 0 OME LAN PAN RAB Source : Caro, JJ et al: Clin Ther; 23: 998-1017 (2001)
Lansoprazole Pantoprazole Rabeprazole Esomeprazole 0.5 0.7 1.0 1.5 2.0 Favors Relative Risk Favors Omeprazole Other PPI Relative Risk of Endoscopic Healing at 8 Weeks for All Standard-Dose PPI’s Compated with Omeprazole 20 mg Source : Maton PN : Cleveland Clinic J Med : 70 (Suppl.5) 851-870 (Jan 2004)
Metabolic Pathways of PPIs 5-O-desmethyl 3-hydroxy 2C19 Esomeprazole 3A4 (major) 2C19 3A4 (remaining) Omeprazole 2C19 3A4 Hydroxy and Sulfone desmethyl Sulfone 5-hydroxy Lansoprazole 2C19 3A4 Not Hydroxy Sulfone Rabeprazole Cytochrome 2C19 mediated 3A4 Pantoprazole 2C19 3A4 Demethylated Thioether Sulfone Sulfone Demethylated
Metabolism of PPIs Metabolized by CYP2C19 & CYP3A CYP2C19 Exhibits Genetic Polymorphism Rabeprazole least affected by polymorphism as its major metabolic pathway is non- enzymatic (not Cytochrome Mediated) Genetic polymorphism is due to deficiency of 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 Esomeprazole Hydroxy & Sulphone Sulphone Desmethyl • 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
Clinical Limitations of PPIs NAB & Nocturnal Heartburn Achlorohydria & Bacterial Colonization Cost
24-Hours Intragastric pH Profile Placebo Omeprazole Pantoprazole pH INTRAGASTRIC 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 GERD Patients 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
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 Benefits Dose 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 Benefit PANTOLOC Doctor, this means that you: Your patients... is dosed can expect will find once daily in greater patient PANTOLOC easy all 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 Benefit PANTOLOC Doctor, this means that you: Your patients... Tablets are Can Tailor will Obtain Available in 20 Dosage to the the Greatest mg and 40 mg Needs of Your Relief with the Strengths Patients. least Amount of Drug. As 7 Tabs. Have the Ability or 14 Tabs. to Titrate Up & benefit from Down for ON-DEMAND Maximum Therapy Therapeutic Accuracy.
PANTOLOC Features and Benefits Available in Various Package Forms 20 mg (7 or 14 TAB), 40 mg (7 or 14 TAB) Convenient for both Doctors and Patients
PANTOLOC Features and Benefits Elderly Patients Patients With Renal Impairment Patients With Hepatic Dysfunction
PANTOLOC Features and Benefits 60 Pantoprazole 92 40mg 83 88 Healing rates (%) 40 Omeprazole 20mg 20 Lansoprazole 0 30mg 8 weeks Pilotto et al; 1999
2 (heartburn & acid eructation) Score improvement 1.5 * 1 0.5 (n=120) 0 1 2 3 4 5 6 7 8 * p=0.012 days (median) Pantoprazole 40mg Omeprazole 20mg Scholten et al; 2000
PANTOLOC Features and Benefits 100 100 97 91 80 85 Symptom relief (%) 80 Pantoprazole 67 40mg 60 60 40 33 Lansoprazole 30mg 20 0 Epigastric Heartburn Acid Vomiting Pain Regurgitation Pilotto et al; 1999
For Peptic Ulcer Treatment For Erosive Esophagitis For H Pylori Eradication For Heartburn For Other Symptoms Associated with GERD For Maintenance of Healed Esophagitis and Peptic Ulcer On-Demand Therapy
PANTOLOC Summary PANTOLOC movie

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Pantoloc a

  • 2.
    Introduction MUP introduces themost efficient treatment for Acid Related Disorders Proton Pump Inhibitor PANTOLOC pantoprazole
  • 3.
    PANTOPRAZOLE Prof. Dr. Aly Taha
  • 4.
    PANTOPRAZOLE PROTON PUMP INHIBITORPPI O-CH F2 O C H3 N H3CO S N + N O Na
  • 5.
  • 6.
    GIT Acid RelatedDisorders Dyspepsia GERD* Erosive Esophagitis Barrett’s Esophagus Gastritis PUD Gastric Ulcer Duodenal Ulcer * GERD: Gastro-Esophageal Reflux Disease
  • 7.
    Medical Background Quick Review
  • 8.
  • 9.
    Detailed Anatomy ofthe Stomach Located on the left side of the body, under the diaphragm, the stomach is a muscular, saclike organ that connects the esophagus and small intestine through the duodenum. Its main function is to break down food. Cells in the stomach lining secrete enzymes, hydrochloric acid, and other chemicals to continue the digestive process begun in the mouth and produce mucus to keep these substances from digesting the lining itself.
  • 10.
    ACID Related Disordersof GIT Responding to PPI Treatment Note : Acid Related Disorders will be abbreviated (ARD)
  • 11.
    GIT Acid RelatedDisorders GERD Dyspepsia Gastritis Gastric Ulcer Duodenal Ulcer
  • 12.
    * Gastro Esophageal Gastric Duodenal Reflux Disease Ulcer Ulcer Dyspepsia Peptic GERD* Ulcer ACID RELATED DISORDERS Adeno- Erosive Carcinoma Esophagitis Barrett’s Esophagus
  • 13.
    Spectrum of OverlappingGIT 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 antacids Nocturnal: 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
  • 14.
    Diseased Conditions &Quality Of Life (QOL) Psychiatric Patients Untreated GERD Population Untreated Duodenal Ulcer Angina Pectoris Mild Heart Failure Normal Female Normal Male 60 70 80 90 100 110 Deminas, Scand J Gastroentrol; 1993 Psychological Well Being Index (PGWBI)
  • 15.
    Acid Related GITDiseases & QOL Mean PGWB score Normal Population Best 132 100 90 80 70 Worst 22 Esophagitis Gastric Duodenal Negative Gastritis/ ulcer ulcer endoscopy duodenitis PGWB = Psychological Well Being
  • 16.
  • 17.
    Dyspepsia Dyspepsiais a condition of impaired or painful digestion resulting from failure of some phase of the normal digestive process. It is a common disorder (up to 25% of Population) with negative impact on patient quality of life (QOL) It can be defined as “persistent or recurrent abdominal pain or abdominal discomfort centered in the upper abdomen”.
  • 18.
    Possible Causes OfDyspepsia The 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.
  • 19.
    Symptoms Of Dyspepsia SymptomsMay Include A Heavy Feeling in the Pit of the Stomach. Gas and Belching. Constipation. Diarrhea. Nausea. Heartburn. Headache or dizziness may accompany the discomfort.
  • 20.
    Patients With DyspepsiaMay Have Underlying Organic Lesions Reflux esophagitis Normal 23.9% 33.6% 2% Cancer 19.9% 20.8% Gastritis/duodenitis Peptic ulcer disease
  • 21.
  • 22.
    Gastritis Acute : Caused by NSAIDs or Alcohol. May be associated with mucosal ulceration. Chronic : Often associated with H. pylori colonization of mucosa.
  • 23.
    Gastritis Gastritisis 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 Ulcer specially when H. pylori colonization is present Psychological stress may also be involved in the development of gastritis.
  • 24.
  • 25.
    GERD Gastro-EsophagealReflux Disease Is A Common Condition That Results From The Reflux Of Gastric Material Through The Lower Esophageal Sphincter (LES) Into The Esophagus Or Oropharynx, Causing Symptoms And/Or Injury To Esophageal Tissue. The Term Encompasses Both Symptoms And Patho-physiologic Changes To The Esophageal Mucosa, Which Occur As A Result Of Exposure Of The Distal Esophagus To Acidic Gastric Contents After Episodes Of Gastro-esophageal Reflux. GERD Is Typically Chronic, Generally Non- progressive, But Some Cases Are Associated With Complications Of Increasing Severity And Significance.
  • 26.
    Clinical Overview ofGERD GERD Is A Dysmotility Problem With A Broad Clinical Spectrum. Has High Prevalence Rate. Greatly Affects Quality of Life (QOL). Acid Related Complicated Esophageal Manifestations Are The Real Danger Of The Disease. Extra Esophageal Problems Are Equally Dangerous.
  • 27.
    GERD Pathogenesis Pathophysiology Clinical Manifestation
  • 28.
  • 29.
    Esophagus Stomach Gastric Folds Lower Esophageal Sphincter (LES) Junction of Gastric & Esophageal Mucosa Pyloric Sphincter First Part of Duodenum
  • 30.
    GERD: A Multi-FactorialEtiology Acidity Motility Factors Factors Increased Esophageal Acid Exposure Motility Impaired Dysfunctions Acid Clearance
  • 31.
    GERD Main Etiological Processes
  • 32.
    Detailed Etiologic FactorsInvolved in GERD Impaired Esophageal Impaired Salivary Acid Clearance Function Hiatal Hernia Impaired Esophageal Transient, Inappropriate Mucosal Relaxation of LES Defense Gastric Acid; Pepsin Secretion: Normal / Raised Reduced Resting Pyloric Tone of LES Incompetence; duodenogastric reflux Delayed Gastric Emptying Acidity Related Motility Related
  • 33.
  • 34.
    Proportion of Subjectswith Esophageal Motility Abnormalities 50 48 Patients (%) 40 30 26 21 20 9 10 0 Normal Normal Mild Severe Volunteers Esophagus/ Esophagitis Esophagitis GERD Source : Kahrilas, PJ et al : Gastroenterology, 1986; 91:897-904
  • 35.
    Gastro Esophageal RefluxMechanisms in Normal & GERD 1% 100% 5% Spontaneous 18% Reflux 80% Transient 17% Increase in 94% Intra- 60% Abdominal Pressure 40% 65% Transient Lower 20% Esophageal Sphincter Relaxations 0% NORMAL Volunteers GERD Patients Source : Kahrilas, PJ : Cleveland Clin. J Med.,; 70 (Suppl.5) :S4-S17 (Nov.2003)
  • 36.
    Significance of AcidReflux in GERD Prolonged 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.
  • 37.
    Esophageal pH MonitoringAmong Controls & Patients with Various Grades of GERD 25 Total 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
  • 38.
    The Clinical Spectrumof GERD Physiological Symptomatic Complicated Esophagitis Reflux GERD Esophagitis Typical Atypical Complications Heartburn Chest pain Ulceration Regurgitation Dysphagia Erosion Cough Hemorrhage Asthma Stricture Laryngitis Barrett’s Eso. Adenocarcinoma Source : Peura DA, et al : Aliment Pharmacol Ther.; 19 Suppl 1: 77-80 (Feb 2004)
  • 39.
    Atypical and Extra-Esophageal Manifestations of GERD Atypical Extra Esophageal Chest Pain Oral Pulmonary Epigastric Pain Dental Erosion Chronic Cough Nausea Asthma Aspiration Pulmonary Fibrosis Pharyngo-laryngeal Recurrent Pneumonia Hoarseness Posterior Laryngitis Globus Sensation Sore Throat Other Vocal Cord Irritation Sleep Abnormalities Vocal cord Polyps Sleep Apnea (?) Posterior Laryngitis Angina Malagelada JR : Aliment Pharmacol Ther 19 Suppl. 1: 43-48. (Feb 2004)
  • 40.
    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, Erosive Esophagitis, and Barrett’s Esophagus According to Age Group. Jankowski J, Sharma P.: Aliment Pharmacol Ther 19 Suppl. 1: 54-9. (Feb 2004)
  • 41.
    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 contact between refluxed acidic gastric juice and the esophageal mucosa. Esophageal erosion & ulcerations result when epithelial cells succumb to the caustic effects of refluxed acid and pepsin.
  • 42.
    Percent Prevalence ofAll GERD Symptoms HEARTBURN 83% Regurgitation 70% 4% Typical 7% odynophagia Symptoms 8% 10% Belching 37% 30% 10% Nausea Chest Pain Dysphagia Abdominal Pain Respiratory Symptoms Castell, DO et al : Practical Gastroenterology , Feb 1999: 20-44
  • 43.
    Hidden Complications ofGERD Chronic, recurrent heartburn, dysphagia, hoarseness, etc. Erosive Esophagitis Reports of frequent episodes of heartburn, but no other symptoms Barrett’s Esophagus Mild intermittent heartburn, not seen by a physician GERD ICEBERG Esoph.Adeno- Carcinoma
  • 44.
    The Pyramid ofDiseases Associated with GERD Extra Esophagial 0% Misc. Asthma ENT Chest Pain } Non-Erosive Reflux Dis. Erosive Esophagitis 100%
  • 45.
  • 46.
    What Is APUD 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 Layers of the Gut Wall.
  • 47.
    Gastric Mucosa G Cell: A Gastrine-secreting cell ECL Cell : (Entero-Chromaffin-Like Cell) A Histamine-secreting endocrine cell
  • 49.
    Peptic Ulcer Esophageal Ulcer Gastric Ulcer Duodenal Ulcer Esophageal Ulcer Gastric Ulcer Duodenal Ulcer
  • 50.
  • 51.
    Peptic Ulcer Diseases Pathogenesis Increased ACID secretions and digestive enzymes erode gastric mucosa Helicobacter pylori plays a role Complications Hemorrhage, perforation peritonitis, scarring
  • 52.
    Peptic Ulcer Complications PepticUlcers may lead to BLEEDING or PERFORATION emergency situations
  • 53.
    PUD Risk Factors Social Factors Patho-Physiological Factors Life Style NSAID Mucosal Damage Smoking Hypo-Volemia Alcohol Hyper-secretion of Corticoids Stress Adrenaline hyper-secretion hypovolemia - a blood disorder consisting of a decrease in the volume of circulating blood Aggressive Factors Hyper Acid Production Hyper Pepsin Secretion Helicobacter pylori Colonization
  • 54.
    PUD Risk Factor H. pylori H. Pylori Microscopic H. Pylori Electron Microscopic
  • 55.
    Epidemiology of H.pylori World Wide Prevalence
  • 57.
    Association of Ulcerswith H. pylori Duodenal Ulcer Gastric Ulcer Pylori-Free Pylori Positive 25.0% Pylori Positive Pylori-Free 96.0% 4.0% 75.0%
  • 58.
    PUD Prevalence Who May Develop an Ulcer ? Ulcer can develop at any age, but it is rare among teenagers and uncommon with children. Gastric Ulcers are more likely to develop in people between 40-60. Duodenal Ulcers have an earlier peak incidence between ages of 25-50. Gastric Ulcers develop more in Women. Duodenal Ulcers occur more frequently in Men.
  • 59.
    What Are TheSymptoms Of Peptic Ulcers ? The Most Common Symptom Is Gnawing Or Burning Pain In The 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
  • 60.
    What Are TheComplications 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.
  • 61.
    What Are TheComplications Of Peptic Ulcers ? (2) Perforation of the gut wall may occur in 5% of patients either with peptic ulcer or stress ulcer. Bacterial infection may occur & is accompanied by hemorrhage in about 10% of cases. Acute perforation may lead to 5% mortality rate mainly in the elderly. Pyloric stenosis (Gastric outlet obstruction) which results from fibrous changes, oedema or spasm (or a combination of all of them). It may be produced by an ulcer in the region of pylorus & the obstruct stomach may lead to nausea and vomiting. Early symptoms are often sensation of excessive and long-lasting ”fullness” after a small meal and continuous vomiting, therefore, it may cause dehydration.
  • 62.
    How Can PepticUlcers Be Diagnosed ? Endoscopy Barium Meal X-Ray Acid Secretion Test. H. Pylori Tests.
  • 63.
    Endoscopy Large Chronic Duodenal Ulcer Gastric Ulcer which Eroded a Blood Vessel in Base of Ulcer
  • 64.
    Therapeutic Approach toPUD : A Staged Approach Stage I Stage II Stage Lifestyle Modification Intensive III Surgery + Therapy : Endoscopy Antacids PPI and/or H2RA H2RAs PPI
  • 65.
    Profile & Assessmentof ARD Pharmacotherapy PANTOLOC MUP RANITOL MUP
  • 66.
    Medical Therapies forARD AGENTS Examples Mucosal Sucralfate, Sodium Protectors Alginate Acid Neutralizers (Antacids) Magaldrate, Carbonates Acid Suppressive Histamine H2 Antagonists, Agents Proton Pump Inhibitors
  • 67.
    Medical Therapies forARD AGENTS TARGET Mucosal Damaged Mucosa Protectors Acid Neutralizers Local Raising of (Antacids) Refluxate pH Inhibition of Acid Acid Suppressive Agents Production in Parietal Cells
  • 68.
    Mechanism for AcidProduction Parietal Cell HCl Proton Pump (H+ K+ ATPase) Cl- K+ H+ Acetylcholine Gastrin Histamine 2
  • 69.
  • 70.
    PPIs : 2004 Omeprazole(OME) Lansoprazole (LAN) Pantoprazole (PAN) Rabeprazole (RAB) Esomeprazole (ESO)
  • 71.
    OME LAN RAB PAN ESO Source : Maton PN : Cleveland Clinic J Med : 70 (Suppl.5) 851-870 (Jan 2004)
  • 72.
  • 73.
    PPIs : Pharmacology Aresubstituted 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 h New steady state for acid secretion occurs in about 3 days.
  • 74.
    ACTIVATION OF SUBSTITUTED BENZIMIDAZOLES Pantoprazole Sulfenic Acid Sulfenamide Inactivated Enzyme
  • 75.
    PPIs : Pharmacology(cont.) Half-life for various PPI’s reported at 0.5-2.0 hours. Duration of action is related to time for regeneration of new pumps and activation of resting pumps & not to half-life. Efficacy allows 24-h acid suppression with once-daily dosing.
  • 76.
    Use of PPI’sin GERD Relieve Symptoms Heal Esophagitis Prevent Recurrence Treat Complications Chest Pain Benign Esophageal Stricture Respiratory Symptoms Oropharyngeal Symptoms Barrtett’s Esophagus Heal Esophagus Prevent Progression to dysphagia or adenocarcinoma
  • 77.
    Clinical Efficiency ofPPI’s in GERD Eliminate Symptoms 90% Heal Esophageal Lesions 90% Manage of Prevent Complications 80% Maintain Remission in Erosive 80% Esophagitis Spechler SJ : Am J Med Sci 326:297-84, (Nov 2003)
  • 78.
    Relation Between Durationof Suppression of Intragastric Acidity and Esophageal Acid Exposure Duration 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>4.0 Source : Bell et al: Digestion; : 51 (Suppl.) :59 (1992)
  • 79.
    Healing Rates ofEsophagitis 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)
  • 80.
    PPI’s versus H2RA’sin Erosive Esophagitis 100 PPI’s Patients 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)
  • 81.
    PPIs : AreThey All The Same ? Pharmacologically No Clinically 80% Yes 20% No
  • 82.
    _ +
  • 83.
    PPIs : Pharmacokinetics Parameter Bio - Protein Half- Time to Avail - PPI Peak, h Binding Life, h ability % Omeprazole 30-40 0.5-3.5 95 0.5-1.0 Esomeprazole N/A 1.6 97 1.2-1.5 Pantoprazole 77 1.1-3.1 98 1.0-1.9 Lansoprazole 80 1.7 97 1.6 Rabeprazole 52 2-5 95-97 0.85-2.0 Source : Vanderhoff BT & Tahbour R: Am Fam Physician ; 66: 273-280 (2002)
  • 84.
    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 83 Esomeprazole 4.13 N/A N/A N/A N/A Pantoprazole 3.96 4.6 282 83 100 Lansoprazole 4.01 2.0 90 66 100 Rabeprazole 5.0 1.3 7.2 99 100 pKa Influences : Accumulation in Parietal Cells, Acid Stability & Activation Rates Source : Johnson, S: Alim Pharmacol Ther; 14: 1249-1258 (2000)
  • 85.
    PPIs : Drug-DrugInteractions PPI OME ESO PAN LAN RAB Drug Cyclosporine Diazepam Digoxin Ketoconazole Phenytoin Theophylline Warfarin Clinically Significant Clinically Insignificant Reported but not well documented Source : Welage L et al : J Am Pharm Assoc; 40: 52-63 (2000)
  • 86.
    Specific Binding Sitesof PANTOPRAZOLE to Cysteine Residues 813 & 822
  • 87.
    Activation After 1hour (%) 100 50 1 Parietal Cell 3 Lysosome 5 Acid Activation of PPI’s 7 Cytosol pH
  • 88.
    Pantoprazole I.V. Injection PANTOPRAZOLE is more stable than OMEPRAZOLE or LANSOPRAZOLE, and particularly much more stable than RABEPRAZOLE, under neutral conditions or conditions that are mildly acidic (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)
  • 89.
    Healing of ErosiveGERD : 8 Weeks Treatment with PPI’s 100 90 91 92 91 90 20 mg 80 30 mg Healing Rate % 70 40 mg 60 20 mg 50 40 30 20 10 0 OME LAN PAN RAB Source : Caro, JJ et al: Clin Ther; 23: 998-1017 (2001)
  • 90.
    Lansoprazole Pantoprazole Rabeprazole Esomeprazole 0.5 0.7 1.0 1.5 2.0 Favors Relative Risk Favors Omeprazole Other PPI Relative Risk of Endoscopic Healing at 8 Weeks for All Standard-Dose PPI’s Compated with Omeprazole 20 mg Source : Maton PN : Cleveland Clinic J Med : 70 (Suppl.5) 851-870 (Jan 2004)
  • 91.
    Metabolic Pathways ofPPIs 5-O-desmethyl 3-hydroxy 2C19 Esomeprazole 3A4 (major) 2C19 3A4 (remaining) Omeprazole 2C19 3A4 Hydroxy and Sulfone desmethyl Sulfone 5-hydroxy Lansoprazole 2C19 3A4 Not Hydroxy Sulfone Rabeprazole Cytochrome 2C19 mediated 3A4 Pantoprazole 2C19 3A4 Demethylated Thioether Sulfone Sulfone Demethylated
  • 92.
    Metabolism of PPIs Metabolizedby CYP2C19 & CYP3A CYP2C19 Exhibits Genetic Polymorphism Rabeprazole least affected by polymorphism as its major metabolic pathway is non- enzymatic (not Cytochrome Mediated) Genetic polymorphism is due to deficiency of CYP2C19 in some populations : 3% Caucasians & Africans; 12-15% Asians. Stereo-Selective Metabolism
  • 94.
    Alteration in Metabolism& Clearance With Repeated Dosing of Esomeprazole FIRST DOSE REPEATED DOSING Esomeprazole Esomeprazole CYP2C19 CYP3A CYP3A Esomeprazole Esomeprazole Hydroxy & Sulphone Sulphone Desmethyl • 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
  • 95.
    Clinical Limitations ofPPIs NAB & Nocturnal Heartburn Achlorohydria & Bacterial Colonization Cost
  • 96.
    24-Hours Intragastric pHProfile Placebo Omeprazole Pantoprazole pH INTRAGASTRIC 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)
  • 97.
    Elimination of NABin GERD Patients 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)
  • 98.
  • 99.
    PANTOLOC Features and Benefits Efficacy Allows 24-h Acid Suppression With Once-Daily Dosing Patient Convenience Ensures Compliance Assured Cure of Ulcers
  • 100.
    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
  • 101.
    PANTOLOC Features and Benefits Dose Linearity in the Range 10-80 mg Consistency of Repeated Doses Continuous, Un-Interrupted Daily Relief of Symptoms Omeprazole & Esomeprazole exhibit NONLINEAR Dose Response
  • 102.
    PANTOLOC Features and Benefits Absolute Bioavailability 77% High Blood Level Concentration Maximum Activity Achieved Omeprazole (30-40%) ; Rabeprazole (52%)
  • 103.
    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
  • 104.
    PANTOLOC Features and Benefits pKa 3.96 Stable at Blood pH The ONLY PPI with I.V. Injection Form
  • 105.
    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)
  • 106.
    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
  • 107.
    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
  • 108.
    PANTOLOC Features and Benefits Feature Physician Benefit Patient Benefit PANTOLOC Doctor, this means that you: Your patients... is dosed can expect will find once daily in greater patient PANTOLOC easy all dosage compliance. to take. forms Will find Won’t have to PANTOLOC easy to take their prescribe. medication to work. Cost-effective therapy.
  • 109.
    PANTOLOC Features and Benefits Feature Physician Benefit Patient Benefit PANTOLOC Doctor, this means that you: Your patients... Tablets are Can Tailor will Obtain Available in 20 Dosage to the the Greatest mg and 40 mg Needs of Your Relief with the Strengths Patients. least Amount of Drug. As 7 Tabs. Have the Ability or 14 Tabs. to Titrate Up & benefit from Down for ON-DEMAND Maximum Therapy Therapeutic Accuracy.
  • 110.
    PANTOLOC Features and Benefits Available in Various Package Forms 20 mg (7 or 14 TAB), 40 mg (7 or 14 TAB) Convenient for both Doctors and Patients
  • 111.
    PANTOLOC Features and Benefits Elderly Patients Patients With Renal Impairment Patients With Hepatic Dysfunction
  • 112.
    PANTOLOC Features and Benefits 60 Pantoprazole 92 40mg 83 88 Healing rates (%) 40 Omeprazole 20mg 20 Lansoprazole 0 30mg 8 weeks Pilotto et al; 1999
  • 113.
    2 (heartburn & acid eructation) Score improvement 1.5 * 1 0.5 (n=120) 0 1 2 3 4 5 6 7 8 * p=0.012 days (median) Pantoprazole 40mg Omeprazole 20mg Scholten et al; 2000
  • 114.
    PANTOLOC Features and Benefits 100 100 97 91 80 85 Symptom relief (%) 80 Pantoprazole 67 40mg 60 60 40 33 Lansoprazole 30mg 20 0 Epigastric Heartburn Acid Vomiting Pain Regurgitation Pilotto et al; 1999
  • 115.
    For Peptic UlcerTreatment For Erosive Esophagitis For H Pylori Eradication For Heartburn For Other Symptoms Associated with GERD For Maintenance of Healed Esophagitis and Peptic Ulcer On-Demand Therapy
  • 120.
    PANTOLOC Summary PANTOLOC movie