Objectives for Lecture on Peptic Ulcer Disease By

Objectives for Lecture on Peptic Ulcer Disease • By the end of this class students will be able to: – List the causes of peptic ulcer disease from most common to least common – Identify the cause of peptic ulcer disease from history and diagnostic tests – Choose appropriate therapy based on the etiology of the condition – Describe the pharmacotherapies of peptic ulcer disease caused by H. pylori infection and NSAIDs and explain the rationale for these therapies – Explain the mechanism by which each drug cures or improves the symptoms of peptic ulcer disease

Gastric Ulcer

Peptic Ulcer Disease • Lesions of the gastric or duodenal mucosa 3 mm in diameter that extend through the muscularis mucosa • In North America, 90% occur in duodenum; in Asia, the great majority are in the gastric mucosa • Affects 11 -14% of men and 8 -11% of women at some time in their lives, 4. 5 million people in the USA annually • Symptom: burning pain that – is felt anywhere from the navel to the sternum – lasts for a few minutes to many hours – is worse when the stomach is empty and is relieved temporarily by eating or by taking an antacid or acid-reducing medication – flares at night – comes and goes for a few days or weeks

Peptic Ulcer Disease - Etiology • Infection with Helicobacter pylori – 60 -65% of duodenal and gastric ulcers in North America today (90% of duodenal ulcers, 70% of gastric ulcers in the 1980 s) – One out of 6 infected persons develops an ulcer – Thought to be spread by contaminated food and water and exchange of GI fluids – Declining due to improved sanitation and antibiotic therapy • Use of NSAIDs (~5%) • Tumors that cause hypersecretion of gastric acid (Zollinger -Ellison), other GI disorders (<1%) • Idiopathic – A growing contribution ( 30% in North America) as infection with H. pylori declines – Causes are unclear. Patients with an idiopathic ulcer tend to be older, sicker, and experience bleeding episodes more frequently. Many were “cured” of a previous ulcer caused by H. pylori or NSAID use. Probably related to fragile mucosa.

J. Robin Warren and Barry Marshall

Helicobacter pylori in the gastric mucosa

Helicobacter pylori • A microaerophilic spiral-shaped Gram-negative rod • Named and associated with ulcers and chronic gastritis by Warren (1979 -1981) • Cultured and sensitivity to bismuth demonstrated by Marshall (1982) • Patients treated successfully with bismuth + antibiotics by Marshall (1984) • H. pylori demonstrated to cause illness in humans by Marshall (1984) • Marshall/Warren theory accepted (1985 -1994), honors roll in (1994 - ) • Marshall/Warren awarded Nobel Prize in Medicine (2005)

Peptic Ulcer Disease and H. pylori - Diagnosis • Ulcer diagnosed from endoscopy and/or upper GI series – 5% are malignant • H. pylori infection diagnosed by – Biopsy (demonstrate breakdown of urea by H. pylori urease in the sample). Most accurate test for diagnosis; seldom used for monitoring therapy. – Breath test (ingest 13 C-urea, exhale 13 C-CO 2). Accurate for diagnosis and monitoring therapy, but expensive. – Serology (detect circulating antibody to H. pylori). Most cost effective test for diagnosis, but not as accurate as others. Not useful for monitoring therapy. – Stool antigen (detect H. pylori in feces with an antibody-based test). Useful for diagnosis and monitoring therapy. More cost effective than the breath test and more accurate than serology.

How Does H. pylori Cause Peptic Ulcer Disease?

Eradication of Helicobacter pylori • Optimal antibiotic therapy eradicates H. pylori and cures H. pylori-associated peptic ulcer disease in 85% of patients • Many H. pylori isolates are resistant to once-effective antibiotics and resistant strains emerge rapidly • At least two synergistic antibiotics must be used for maximal efficacy • Bismuth preparation may be added to improve efficacy, but it cannot substitute for a conventional antibiotic • Suppression of gastric acid secretion with a PPI speeds healing and improves the efficacy of amoxicillin. PPIs also have some toxicity toward H. pylori, but cannot substitute for a conventional antibiotic.

Triple Therapy – First-Line (where H. pylori resistance to metronidazole > to clarithromycin) • Amoxicillin – Cell wall inhibitor. Modest efficacy when used by itself. • Clarithromycin – Protein synthesis inhibitor. Normally a bacteriostatic drug, but amoxicillin damages the bacterial cell wall allowing a bactericidal concentration of clarithromycin to accumulate intracellularly. • PPI • Continue for 14 days • Note: Substitute metronidazole (source of intracellular free radicals in anaerobic and microaerophilic bacteria) for amoxicillin in patients with penicillin allergy.

Quadruple Therapy – Backup (first-line where H. pylori resistance to clarithromycin > to metronidazole) • Tetracycline – Protein synthesis inhibitor • Metronidazole – Source of intracellular free radicals • Bismuth subsalicylate (Pepto-Bismol) or bismuth citrate – Toxic to H. pylori and protects stomach lining from acid • PPI • Continue for 14 days

H. pylori-Associated Tumors • Gastric carcinoma – H. pylori infection leads to chronic gastritis, epithelial cell hyperplasia, increased risk of malignant transformation – Increases risk 3 to 5 -fold • MALT (mucosa-associated lymphoid tissue) lymphoma – Low-grade type of B cell non-Hodgkin’s lymphoma (extranodal marginal zone B cell lymphoma) – Lymphoid tissue normally absent from the stomach – Inflammation of gastric mucosa causes development of MALT-type lymphoid tissue – B lymphocytes stimulated to replicate by constant presence of bacteria – In some people, lymphoid cells undergo malignant transformation. Transformation to a more aggressive form in <10% of cases. – Eradication of H. pylori induces tumor regression in 50 -70% of cases.

Oxyntic (Acid-Producing) Gland

Secretory Products of Oxyntic Glands • Parietal cells – HCl • Solubilizes food, extracts metals from food • Converts pepsinogen to pepsin • Disinfects – Intrinsic factor • Absorption of vitamin B 12 • Mucous cells – Mucus and bicarbonate • Protect the gastric mucosa from chemical/mechanical damage • Chief cells – Pepsinogen • Enterochromaffin-like (ECL) cells – Histamine • G cells (Pyloric glands) – Gastrin

Regulation of Gastric Acid Secretion PPI

Proton Pump Inhibitors (PPIs)

Proton Pump Inhibitors (PPIs) Mechanism of Action • Irreversible inhibitors of H+/K+-ATPase (proton pump). 95% suppression of acid production. • Complex mechanism – Enter parietal cell from the circulation – Accumulate in the acidic secretory canaliculi because they are weak bases – Activated by proton-catalyzed process to thiophilic sulfenamide or sulfenic acid – Activated form binds irreversibly to cysteine residues from the extracellular domain of the pump – Conversion to active form ceases when p. H rises to 4 -5 • Because they are destroyed by acid, PPIs are formulated in enteric-coated capsules. Absorption is entirely from the small intestine.

Proton Pump Inhibitors (PPIs)

Proton Pump Inhibitors (PPIs) Clinical Uses • Because they reduce gastric acid secretion more effectively than any other class of drugs, they have become the mainstays of therapy to – Promote healing of gastric and duodenal ulcers – Treat gastroesophageal reflux disease (GERD) – Treat Zollinger-Ellison syndrome

Proton Pump Inhibitors (PPIs) Adverse Effects • Remarkably safe when used for a short time, as in triple and quadruple therapy for peptic ulcer disease • Increasing reports of adverse effects when used chronically – Infection of stomach with E. coli, Clostridium difficile, and other lower-GI bacteria – Nosocomial pneumonia – Increased incidence of fractures related to hypocalcemia

H 2 Blockers

H 2 Blockers

H 2 Blockers • Competitive antagonists at the H 2 histamine receptor on parietal cell. Blocks stimulation of acid production by histamine. • Less effective than PPIs; reduce acid secretion by 60% • Most prominent effect is on basal acid secretion. Reduces nocturnal acid secretion effectively if taken during the evening. • Used today to suppress less serious symptoms of peptic ulcer disease and GERD and when PPI is undesirable; generally second-line

Sucralfate • Sucrose octasulfate + Al(OH)3 • Polymerizes at p. H <4 into viscous sticky gel that adheres to mucosa and especially to ulcer crater • Protects mucosa from acid and pepsin • As effective in promoting ulcer healing as H 2 blockers

Antacids

NSAID-Induced Ulcers • Diagnosed mainly in persons who use large doses to treat arthritis and other chronic inflammatory conditions, but less frequently even in persons who use aspirin for thrombotic prophylaxis • 3 -4. 5% of chronic NSAID users have clinically-significant upper GI events

How Do NSAIDs Cause Ulcers?

Prevention/Healing of NSAID-Induced Ulcers • Use the lowest effective dose. Minimize/avoid aspirin if possible (except for thrombotic prophylaxis) • Combine with PPI (80 -90% success) • Combine with misoprostol (analog of prostaglandin E 1) (60 -75% success) – – Inhibition of acid secretion Stimulation of mucus and bicarbonate secretion Increased mucosal blood flow Diarrhea, uterine contraction possibly leading to abortion • Use celecoxib (COX-2 inhibitor) – Cardiovascular risk

Misoprostol