Pharmacology of Peptic Ulcer Disease - GBV · Pharmacology of Peptic Ulcer Disease ... D....

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Pharmacology of Peptic Ulcer Disease Contributors S.B. Benjamin, G.M.A. Borsch, S.H. Caldwell, E.L. Cattail M.J. Collen, J. Doppman, D.E. Fleischer, J.D. Gardner D.Y. Graham, A. Guglietta, D. Hollander, C.W. Howden R.H. Hunt, R.T. Jensen, D.A. Johnson, J.H. Lewis, P.N. Maton R.W. McCallum, L.S. Miller, R.V. Nardi, I.Parikh J.W. Rademaker, A.M. Rosen, G. Sachs, A. Tarnawski J. Van Dam, B. Wallmark, M.M. Wolfe, P.N. Yakshe Editors Martin J. Collen and Stanley B. Benjamin f Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest

Transcript of Pharmacology of Peptic Ulcer Disease - GBV · Pharmacology of Peptic Ulcer Disease ... D....

Pharmacologyof PepticUlcer DiseaseContributors

S.B. Benjamin, G.M.A. Borsch, S.H. Caldwell, E.L. CattailM.J. Collen, J. Doppman, D.E. Fleischer, J.D. GardnerD.Y. Graham, A. Guglietta, D. Hollander, C.W. HowdenR.H. Hunt, R.T. Jensen, D.A. Johnson, J.H. Lewis, P.N. MatonR.W. McCallum, L.S. Miller, R.V. Nardi, I.ParikhJ.W. Rademaker, A.M. Rosen, G. Sachs, A. TarnawskiJ. Van Dam, B. Wallmark, M.M. Wolfe, P.N. Yakshe

Editors

Martin J. Collen and Stanley B. Benjamin

f

Springer-VerlagBerlin Heidelberg New York London ParisTokyo Hong Kong Barcelona Budapest

Contents

CHAPTER 1

Pharmacology of the Parietal CellG. SACHS, P.N. MATON, and B. WALLMARK. With 14 Figures 1

A. Introduction 1B. Anatomy of Gastric Mucosa • • • 1C. Secretion by the Stomach 3

I. General 3II. Secretion and Absorption by Surface Epithelial Cells 5

D. Gastric Barrier 5E. Agents Thought to Affect Gastric Barrier Function 9

I. Sucralfate 9II. Prostaglandins 9

III. Bismuth Compounds 10F. Ion Transport by the Parietal Cell 10

I. Apical Surface 10II. Basal Lateral Surface . . 12

III. Stimulation of Acid Secretion 12IV. Mechanism of Parietal Cell Stimulation 13

G. Receptor Antagonists 15I. Muscarinic Antagonists 15

II. H2 Antagonists 15H. Mechanism of Gastric Proton Pump 16

I. Transport by ATPase 16II. Reaction Cycle 17

III. Structure of Gastric H+,K+-ATPase 19J. Inhibitors of H+,K+-ATPase 20

I. Omeprazole 211. Effects on Acid Secretion 212. Duration of Action 223. Mechanism of Action 22

II. Reversible H+,K+-ATPase Inhibitors 27III. Clinical Use of Pump Inhibitors 30

References 31

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CHAPTER 2

Epidermal Growth FactorR.V. NARDI, A. GUGLIETTA, and I. PARIKH, With 6 Figures 37

A. Introduction 37B. Perspective on Growth Factors 37C. Perspective on Mucosal Disease 38D. EGF Structure 41E. Structure-Activity Relationships 41F. Biological Effects 42G. Gastrointestinal Activity 45

I. Developmental Effects of EGF 45II. Gastric Acid Secretion 46

III. Trophic Effects 47H. Conclusion 48References 50

CHAPTER 3

Gastrin and Other Peptide HormonesJ. VAN DAM and M.M. WOLFE. With 6 Figures 55

A. Introduction 55B. The Molecular Heterogeneity of Gastrin 55C. Gastrin Release 57D. Autonomic Control of Gastrin Release 60E. Bombesin-Like Peptides 62F. Somatostatin 64G. Mechanism of Gastrin-Induced Gastric Acid Secretion 69H. Gastrin and Peptic Ulcer Disease 72J. Hypergastrinemic Syndromes 74K. Conclusion 77References 77

CHAPTER 4

The Role of Essential Fatty Acids in Gastric and Duodenal Protectionand Ulcer TherapyD. HOLLANDER and A. TARNAWSKI. With 2 Figures 89

A. Cytoprotection and Prostaglandins 89I. Definition of Cytoprotection 89

II. Mucosal Sites of Cytoprotection 891. Protection of the Mucosal Microvasculature 902. Direct Protection of Gastric Mucosal Cells 90

III. Metabolism of Natural and Synthetic Prostaglandins 90

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B. Arachidonic Acid Cascade and Prostaglandin Synthesisby Gastric and Duodenal Mucosa 92

I. Arachidonic Acid Cascade 92II. Sources of Arachidonic Acid from Mucosal Pools 92

III. Control of Mucosal Prostaglandin Synthesis 92C. Dietary Sources of Arachidonic and Linoleic Acids 93

I. Food Sources 93II. Absorption of Dietary Essential Fatty Acids 93

III. Distribution of Absorbed Essential Fatty AcidsBetween Organs 94

IV. The Requirement for Detergents for the Intestinal or GastricAbsorption of Essential Fatty Acids 94

D. Gastric Mucosal Synthesis of Endogenous Prostanoidsfrom Dietary Essential Fatty Acids 95

I. The Requirement for Detergents for Absorption of DietaryEssential Fatty Acids into the Gastric Mucosa • • 95

II. The Requirement for Direct Gastric Mucosal Contact withSolubilized Essential Fatty Acids for Mucosal Protection . . . 95

III. Generation of Prostanoids by the Gastric Mucosafrom Solubilized Essential Fatty Acids 96

E. Gastric Mucosal Protection by Solubilized EssentialFatty Acids 96

I. Angiogenic Effect of Essential Fatty Acids 98F. Dietary Intake of Essential Fatty Acids 98

I. Animal Studies 98II. Human Intake of Dietary Essential Fatty Acids and Its

Relationship to Peptic Ulcer Disease . 99G. Potential Therapeutic Advantages of Dietary Essential Fatty Acids

Over the Synthetic Prostaglandins 101I. Effect of Short-Term Treatment with Dietary Essential Fatty

Acids on the Human Gastric Mucosa • . . . 102H. Summary and Conclusion 103References 103

CHAPTER 5

Helicobacter pyloriG.M.A. BORSCH and D.Y.GRAHAM. With 1 Figure 107

A. Introduction 107B. Clinical Relevance of Helicobacter pylori 107

I. Frequency in the General Population and Association withChronic Gastritis and Peptic Ulcer Disease 107

II. Causation 1091. Chronic Gastritis 1092. Peptic Ulcer Disease 110

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C. Attempts to Eradicate Helicobacter pylori 112I. Natural History 113

II. Eradication of Helicobacter pylori Infections 113III. Methods to Confirm Eradication of Helicobacter pylori

Infections 114IV. Bismuth Salts 115V. Antimicrobials as Monotherapy 118

VI. Drug Combinations 1211. Triple Drug Combinations 1212. Double Drug Combinations 123

VII. Toxicity of Antimicrobials and Bismuth Salts 126VIII. Experimental Therapeutic Approaches 128

D. Eradication oi Helicobacter pylori and Peptic Ulcer Disease . . . . 130I. Effect on Gastritis 130

II. Effect on Healing of Duodenal Ulcers 130III. Effect on Relapse Rates of Duodenal Ulcers . . . . . . . . 132IV. Effect on Relapse Rates of Gastric Ulcers 135

E. Whom to Treat and What to Expect? 135F. Summary and Conclusions 136References 138

C H A P T E R 6

Development of a New Gastric Antisecretory Drug for Clinical UseC.W. HOWDEN and R.H. HUNT 149

A. General Considerations 149B. Etiology and Pathophysiology of Peptic Ulcer 149C. Scope for Pharmacological Intervention 151D. Clinical Development of a New Antisecretory Drug

for Peptic Ulcer 151I. Phase I : 151

II. Phase II 151III. Phase III 156IV. Phase IV 157

References 157

CHAPTER 7

Therapeutic Use of Omeprazole in Man: Pharmacology, Efficacy,Toxicity, and Comparison with H2 Receptor AntagonistsP.N. MATON,G. SACHS, and B. WALLMARK. With 4 Figures 159

A. Introduction 159B. Pharmacology 159

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I. General 159II. Plasma Concentrations 160

III. Inhibition of Acid Secretion . 161IV. Other Actions of Omeprazole 162

1. Effect on Secretion of Intrinsic Factor and Vitamin B12

Absorption 1622. Effect on Pepsin 1623. Effects on Motility 1634. Effects on Gastric Endocrine Function 163

C. Therapeutic Trials in Acid-Peptic Diseases 164I. Overview 164

II. Duodenal Ulcer 1651. Effect of Different Doses of Omeprazole 1652. Comparative Studies of Omeprazole and H2 Receptor

Antagonists 1673. Relapse After Stopping Omeprazole Therapy . . . . . . 1694. Omeprazole Treatment for Ulcers Resistant

to H2 Receptor Antagonists 170III. Gastric Ulcer 171

1. Noncomparative Studies of Omeprazole 1712. Comparative Studies of Omeprazole and Ranitidine . . . . 1723. Relapse After Stopping Omeprazole Therapy . . . . . . 1734. Omeprazole Treatment for Ulcers Resistant

to H2 Receptor Antagonists 173IV. Reflux Esophagitis 174

1. Effect of Different Doses of Omeprazole 1742. Comparative Studies of Omeprazole and H2 Receptor

Antagonists 1753. Relapse After Stopping Omeprazole Therapy 1764. Omeprazole Treatment for Reflux Esophagitis Resistant to H2

Receptor Antagonists . . 176V. Zollinger-Ellison Syndrome 177

VI. Side-Effects and Toxicity 180D. Probable Role of Omeprazole in Acid-Peptic Diseases 181References 181

CHAPTER 8

Hypothesis of Peptic Ulcer: A Modern Classificationof a Multifactorial DiseaseS.H. CALDWELL and R.W. MCCALLUM. With 3 Figures 189

A. Introduction 189B. Histopathology of Peptic Ulcer 190

I. Ulcer Histology 190

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II. Gastritis - Definitions 1911. Endoscopic Gastritis 1912. Histologic Gastritis 191

C. Schwarz's Balance 192I. Mucosal Defenses 193

1. Measurement of the Barrier 1932. The Mucus Gel and pH Gradient 1933. Mucosal Healing 1944. Mucosal Bloodflow 1945. Other Mechanisms of Defense 195

II. Aggressive Factors 1951. Hydrogen Ion 1952. Aspartic Proteinases 1963. Bile Acids 1974. Oxygen Free Radicals 198

III. Risk Factors as Modifiers of Mucosal Defense 1981. Blood Groups 1982. Tobacco Use 198

IV. Regulation of Mucosal Defenses: Prostaglandins andEpidermal Growth Factor 1991. Role of Prostaglandins in Mucosal Defense 1992. Epidermal Growth Factor and Other Factors 200

D. Classification of Peptic Ulcer Disease 201E. Drug-Induced Ulcer Disease 202

I. Nonsteroidal Anti-Inflammatory Drugs and Aspirin 2021. Mechanisms of NSAID-Induced Injury 2032. Lesions Associated with NSAID Ingestion 2043. Helicobacter pylori and NSAID Ingestion 205

II. Drug-Induced Ulcers - Alcohol 2051. Mechanisms of Injury 2052. Ethanol ad Ulcers 206

III. Drug-Induced Ulcers - Steroids 2061. Corticosteroids and Ulcers 2062. Effects of Corticosteroids on the Mucosa 207

F. Helicobacter pylori and Peptic Ulcer 2071. Helicobacter pylori 2072. The Effect of Helicobacter pylori on the Mucosa and

the Host Response 2083. Helicobacter pylori-Associated Gastroduodenal Ulcers . . 209

G. Ulcers Associated with Hypersecretory States 213H. Malignant Ulcers 215J. Other Types of Chronic Relapsing Peptic Ulcer 215K. Acute Mucosal Stress Ulceration 216L. Summary 216References 218

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CHAPTER 9

Nonulcer DyspepsiaD.A. JOHNSON 229

A. Introduction 229B. Definition 229C. Epidemiology 230D. Categories of Nonulcer Dyspepsia 231

I. Gastroesophageal Reflux-Like Dyspepsia 231II. Dysmotility-Like Dyspepsia 231

III. Ulcer-Like Dyspepsia 232IV. Aerophagia 232V. Idiopathic/Essential Dyspepsia 232

E. Pathophysiology 232I. Gastric Acid 232

II. Helicobacter pylori 234III. Motility •'•. . . 235IV. Psychosocial Factors 237V. Environmental Factors 238

F. Diagnostic Approach 239G. Treatment 242H. Prognosis 253J. Conclusions 254References 254

CHAPTER 10

The Natural History of Duodenal Ulcer Disease:Has It Been Altered by Drug Therapy?J.H. LEWIS 263

A. Introduction 263B. Incidence of Duodenal Ulcer - Historical Perspectives 263

I. Cohort Phenomena 265C. Recent Time Trends in the Incidence of Duodenal Ulcer 266D. Geographic Influences . 267E. Recent Trends in Hospitalization and Surgery

for Duodenal Ulcer 268F. Seasonal Variations in Duodenal Ulcer 270

I. Seasonal Variations Studied Endoscopically 272G. Natural History of Duodenal Ulcer - Pre-H2 Blocker Studies . . . 272

I. Scandinavian Studies 274II. European Studies 276

III. CURE Study 277

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H. Duodenal Ulcer Disease in the H2 Blocker Era 278I. How Long Does a Duodenal Ulcer Stay Healed

After Treatment? 279J. Role of Helicobacter pylori 280K Natural History of Untreated Ulcers 280L. Natural History of Unhealed Ulcers 281M. Can Drug Therapy Prevent Duodenal Ulcer Relapse? 282N. Other Agents for "Short-Term" Maintenance Therapy 285

I. Antacids 285II. Anticholinergics 285

III. Tricyclic Antidepressants 286IV. Sucralfate 286V. Bismuth 286

VI. Omeprazole 287O. How Long Should Maintenance Therapy Be Continued? 287

I. On-Demand Versus Intermittent Therapy 288P. Summary 289References 290

CHAPTER 11

Refractory Duodenal UlcerJ.W. RADEMAKER and R.H. HUNT 301

A. Introduction 301I. Definition 301

II. Adequate Treatment and Compliance 302III. Hypersecretory Disorders and Nonpeptic Ulcer Disease . . . 306

B. Factors Which Affect Healing and Recurrence 306I. Acid Hypersecretion 307

1. Parietal Cell Sensitivity 3082. Tolerance 3093. Rebound Hypersecretion 3104. Gastrin . . 3105. Clinical Significance . 311

II. Smoking . 311III. Nonsteroidal Anti-Inflammatory Drugs 312IV. Helicobacter pylori . 312V. Ulcer Morphology 313

C. Outcome of Refractory Duodena l Ulcer Trea tment Trials . . . . 313I. Acid Suppression 314

II. Mucosal Protective Agents 315III. Surgery 316

D . Management 316

Contents XIX

I. General Advice 317II. Specific Treatment 317

References 318

CHAPTER 12

Idiopathic Gastric Acid HypersecretionM.J. COLLEN. With 8 Figures 325

A. Introduction 325B. Method of Doing Gastric Analysis 327C. Definition of Idiopathic Gastric Acid Hypersecretion 328

I. Statistical Definition 328II. Functional Definition 328

D. Diseases Associated with Idiopathic Gastric Acid Hypersecretion . 331I. Gastroesophageal Reflux Disease . - ? . . . 332

II. Duodenal Ulcer Disease 332III. Gastric Ulcer Disease 333IV. Nonulcer Dyspepsia 333

E. Comparison of Idiopathic Gastric Acid Hypersecretion andZollinger-Ellison Syndrome 334

I. Characteristics 334II. Basal Acid Output, Maximal Acid Output, and Basal Acid

Output/Maximal Acid Output Ratio 336F. Helicobacter pylori Associated with Idiopathic Gastric Acid

Hypersecretion 338G. Therapy for Idiopathic Gastric Acid Hypersecretion 340H. Other Data on Idiopathic Gastric Acid Hypersecretion 344

I. Basal Acid Output in Children 344II. Basal Acid Output in Other Disorders 344

J. Conclusions 345References 346

CHAPTER 13

Zollinger-Ellison Syndrome:Advances in Diagnosis and ManagementL.S. MILLER, J.D. GARDNER, J. DOPPMAN, and R.T. JENSEN.With 15 Figures 349A. Introduction 349B. Pathophysiology 349C. Clinical Features 350

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D. Provocative Tests 353E. Differential Diagnosis of Disorders with Increased Basal Acid

Output and Increased Fasting Gastrin Concentration 355F. Medical Therapy 358

I. H2 Receptor Antagonists 3591. General 3592. Absorption and Excretion of H2 Receptor Antagonists . . 3613. Studies in Patients with Zollinger-Ellison Syndrome . . . 3614. Potency 3645. Onset of Action 3646. Duration of Action 3647. Failure 3668. Safety 3669. Use 367

10. Use of Parenteral H2 Receptor Antagonists 368II. Omeprazole 369

1. General 3692. Absorption, Metabolism, and Excretion 3693. Onset of Action 3714. Duration of Action 3715. Potency 3726. Failure 3727. Use 3728. Safety 375

III. Anticholinergic Agents 375IV. Prostaglandins 377V. Somatostatin or SMS 201-995 378

VI. Gastrin Receptor Antagonists 379G. Surgical Therapy 379H. Tumor Localization . . . 382J. Treatment of Metastatic Disease 388References 391

CHAPTER 14

The Pathophysiology and Treatment of Gastroesophageal Reflux DiseaseS.B.BENJAMIN. With 3 Figures 401

A. Introduction .' 401B. The Nosology of Reflux 401C. Why Do Humans Reflux? 402D. Variability of Tissue Response to Reflux 405E. Sequelae of Gastroesophageal Reflux 407F. Extraesophageal Manifestations of Reflux 408

Contents XXI

G. Testing in Gastroesophageal Reflux 410H. Treatment of Gastroesophageal Reflux 411J. Surgery in Gastroesophageal Reflux 412K Management in Real Life 4i3L. Summary 414References 414

CHAPTER 15

Endoscopy in the Evaluation and Treatment of Acid-Peptic DiseaseP.N. YAKSHE and E.L. CATTAU. With 7 Figures 417

A. Introduction 417B. Accuracy 417C. Safety . 418D. Uncomplicated Acid-Peptic Disease 418

I. Endoscopy as the Initial Diagnostic Modality 418II. Endoscopy Following a Radiologic Procedure 419

1. Negative Upper Gastrointestinal Series 4192. Gastric Ulcer 4193. Duodenal Ulcer 420

III. Biopsy and Cytology 420IV. Disease Follow-up 421

E. Gastrointestinal Bleeding from Acid-Peptic Disease 421I. Guidelines for Intervention 421

II. Stigmata of Bleeding 422III. Endoscopic Hemostasis 425

1. Electrocoagulation 4252. Photocoagulation 4293. Heater Probe . . . 4334. Chemical Injection 4345. Comparison of Hemostatic Modalities . 437

F. Gastric Outlet Obstruction 437G. Summary 438References 439

CHAPTER 16

Videoendoscopy and Digital ImagingA.M. ROSEN and D.E. FLEISCHER 445

A. Introduction 445B. Charge-Coupled Devices and Videoendoscopy - How They Work . 446

I. Background 446

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II. CCD Function 446III. Image Transfer 447IV. Microprocessor Function 448V. Color 449

1. Background 4492. Videoendoscopic Color Reproduction 449

VI. Technical Evaluation 450VII. Clinical Use 452

C. Practical Benefits and Advantages of Videoendoscopy 452I. Image Storage, Retrieval, and Transfer 452

II. Teaching/Other 453D. Special Applications 454

I. Measurement of Lesion Size 454II. Real-Time Image Analysis 454

III. Image Modification 455IV. Chromoscopy and Infrared Imaging • • • 455V. Mucosal Hemodynamics 456

VI. Videoenteroscopy 457E. The Future 457References 458

Subject Index 463