IS2 GI Disorders HANDOUT Winter 2024-25 PDF

PHID 1502 – Integrated Sequence 2 – Winter Quarter 2024 February 4 & 7, 2025 Pathophysiology, Pharmacological Treatment of Gastrointestinal Disorders Required Reading: Katzung 15th ed, Chapter 62 Recommended Reading: Harrison’s Principle of Inte...

PHID 1502 – Integrated Sequence 2 – Winter Quarter 2024 February 4 & 7, 2025 Pathophysiology, Pharmacological Treatment of Gastrointestinal Disorders Required Reading: Katzung 15th ed, Chapter 62 Recommended Reading: Harrison’s Principle of Internal Medicine 21st ed, Chapter 323, 324, 326, 327 Pathophysiology of Disease: An Introduction to Clinical Medicine 8th ed, Chapter 13 Recommended Reading: Goodman & Gilman 14th ed, Chapters 53,54,55 Molly Yao, Ph.D., M.S. Professor 623-572-3575 Glendale Hall 236-10 [email protected] © MWU 2024 Dr. Yao 1  Learning Objectives Identify factors that induce onset of GERD Be familiar with pharmacological treatment options of GERD Describe pathophysiology of H. pylori-, gastrinoma-induced PUD  Predict changes in mediator(s) in terms of gastric acid, gastrin, histamine somatostatin, etc. Describe pathophysiology of NSAIDs-induced PUD  Specify benefits provided by prostaglandins Describe mechanism of action (MOA), adverse drug reactions (ADR), drug interaction, contraindication of drugs used to treat GERD and PUD  Describe activation process of PPI List clinical manifestations of IBD  Recognize those common in both forms of IBD and unique symptom(s) present in Crohn’s Disease Describe mechanism of action (MOA), adverse drug reactions (ADR), drug interaction, contraindication of drugs used to treat IBD, IBS.  Associate mechanism with pharmacokinetics of cytostatic agents used to treat IBD 2  Review: Cell Types in Gastric Pits Fundus Body/Corpus Antrum Cell Type Location Secretion Parietal cells Body HCl, intrinsic factor Chief cells Body Pepsinogen gastric digestive juice Mucous neck cells Antrum Mucus, HCO3- Enterochromaffin-like Body, in the vicinity Histamine cells (ECL cells) of parietal cells regulatory factors to control secretion of G cells Antrum Gastrin gastric digestive juice D cells Antrum Somatostatin 3  Review: Control of Gastric Acid Secretion Somatostatin Somatostatin Fasting Ach, Gastrin Feasting High gastric [H+] Low gastric Inhibitory Pathways [H+] Proton pump Stimulate Inhibit 4 CCK: cholecystokinin  Review: Control of Gastric Acid Secretion Stimulation of gastric acid secretion Acetylcholine (Ach) from vagus nerve stimulates parietal cells  acid secretion Low gastric [H+] stimulates G cells  gastrin from G cells stimulates parietal cells  acid secretion Ach & gastrin stimulate ECL cells  histamine from ECL cells stimulates parietal cells  acid secretion Inhibition of gastric acid secretion High gastric [H+] stimulates D cells  somatostatin  Inhibit parietal cells  acid secretion inhibits G cells  gastrin release  reduce in stimulation of parietal cells and ECL cells  acid secretion Inhibit ECL cells  histamine release  reduce in stimulation of parietal cells  acid secretion High gastric [H+] stimulates prostaglandin receptor on the parietal cells  acid secretion 5  Acid-Peptic Disorders Imbalance between protective factors (mucus, HCO3-, prostaglandins, mucosal blood flow, growth factors) and damaging factors (H+, pepsin, pancreatic enzymes, bile acids, H. pylori infection, NSAIDs, psychologic stress, smoking, alcohol consumption, etc.)  GI mucosal injury GastroEsophageal Reflux Disease (GERD) Peptic Ulcer Disease (PUD) Gastric Ulcer (GU) Duodenal Ulcer (DU) 6  Review: Defense Mechanism by Esophagus Esophageal epithelium Resistant to abrasion from food, sensitive to acid Defense Mechanism Lower esophageal sphincter (LES) or gastroesophageal sphincter (smooth muscle) a barrier between the stomach and esophagus stays tonically contracted = maintains elevated basal resting pressure, reducing the chance of reflux of acidic gastric contents into the esophagus Secretion of mucin & bicarbonate by the submucosal glands of the esophagus protect the esophageal wall from acid and enzymes in gastric juice lubricate the passage of food 7  Gastroesophageal Reflux Disease (GERD) Retrograde movement of gastric contents from stomach into esophagus causing inflammation of esophageal mucosa  reflex esophagitis Pathogenesis protective factors, damaging factors LES tone or abdominal pressure due to  Neural agents: α-adrenergic antagonists, β-adrenergic agonists, cholinergic antagonists  Foods: Fat, chocolate, peppermint, alcohol and tobacco use, caffeine  Others: obesity, pregnancy, delayed gastric emptying, gastric volume due to a large meal or gastric outlet obstruction (i.e. pyloric obstruction) and abnormal esophageal anatomy, e.g. Hiatal hernia Defects in mucosal defense mechanisms by irritant refluxates including gastric acid, pepsin, bile acids, pancreatic enzymes 8  GERD Pathophysiology of GERD Clinical Manifestations Heartburn Dysphagia due to obstruction of distal esophagus Hemorrhage or perforation Hoarseness, coughing, or 10 % wheezing Pneumonia 0.2-2 % Complication Barrett’s esophagus, a precursor lesion to cancer Treatment-Depend on severity TLC (Therapeutic life style changes) Therapy: Antacids, H2 blockers, proton pump inhibitors (PPI) 5-10% Antireflux surgery 9  Peptic Ulcer Disease (PUD) Peptic ulcer disease refers to chronic mucosal ulceration, a local defect or excavation of the mucosa that is produced by the sloughing (shedding) of inflamed necrotic tissue, affecting duodenum or stomach. Etiology of Ulcer protective factors, damaging factors H. Pylori infection NSAIDs Gastrinoma, called Zollinger-Ellison syndrome Stress-Related Mucosal Damage (SRMD) Crohn’s Disease (to be discussed in IBD section) Clinical Manifestations Chronic, mild, gnawing or burning abdominal or chest pain Complications GI tract bleeding: hematemesis or melena Life-threatening perforation and obstruction Gastric cancer 10  Pathophysiology of H. pylori Infection Motile  tunnel through, reside under the thick layer of alkaline mucus; preferentially settle in the antrum  gastritis Produce urease to break down urea into ammonia (NH3) and CO2  NH3 neutralizes acid, damages the epithelial cells, facilitates neutrophils infiltration  breath test using 13C-Urea  13CO2 Disrupt the tight junctions between surface mucosal cells 11 Pathophysiology of H. pylori-Induced PUD Fundus GU and DU Body GU Sustained H. pylori infection in the antrum  Antrum H. pylori disrupt the tight junctions between surface mucosal cells  H+ leaks into damaged mucosa  gastric H+ causes local gastrin secretion  gastrin stimulates more H+ production and hypertrophy of parietal cells and ECL cells  hypersecretion of H+ H. pylori inhibit somatostatin secretion  gastrin ? DU Excessive H+ delivered to the duodenum Gastric metaplasia in the duodenum due to high Inhibit acid exposure HCO3- secretion H. pylori infection spreads to the duodenum, inhibits HCO3- secretion 12  Pathophysiology of NSAIDs-Induced PUD Prostaglandins - Prostaglandin E2 (PGE2), prostacyclin I2 (PGI2) NSAIDs Non-selectively inhibit COX-1- mediated prostaglandins NSAIDs production  loss of GI mucosal integrity and repair (next slide) Direct or topical damage to Loss of GI mucosal mucosal epithelium by NSAIDs Anti-inflammation integrity and repair  via “ion trapping” (slide 15)  NSAIDs: inhibit COX-2- mediated prostaglandins production for anti- inflammation application 13  Pathophysiology of NSAIDs-Induced PUD Prostaglandins are critical in maintaining gastroduodenal mucosal integrity and repair  Effect when Maintain microcirculation prostaglandins Microcirculation stasis  ischemia are absent Effects on epithelial cells Specifically, on parietal cells, inhibit H+-K+ ATPase inhibits acid secretion  acid secretion Stimulate secretion of gastric mucin (physical barrier) and HCO3- (chemical barrier)  mucin, HCO3- secretion Replaced every 3 days Cell regeneration at large defects, cell proliferation-dependent Restitution: restore a damaged region via cell migration, cell proliferation- independent Cell proliferation-dependent, -independent repair and spontaneous healing do not exist. 14  Pathophysiology of NSAIDs-Induced PUD NSAIDs “Ion trapping” Resolution for topical damage: Enteric-coated NSAIDs An acidic NSAID such as aspirin remains unionized within the acidic environment of the stomach Lipid-soluble NSAID diffuses across the cell membrane Aspirin in the stomach NSAID ionizes in the physiologically neutral pH in the mucosal epithelial cells and becomes trapped  H+ accumulate within the mucosal epithelial cell  cell lysis  epithelial damage Aspirin in the mucosal epithelial cell 15 Pathophysiology of Gastrinoma-Induced Ulcer, or Zollinger-Ellison syndrome Gastrinoma: gastrin secreting tumor located within duodenum, pancreas, stomach, bone, ovary, heart, liver, lymph nodes, etc. Gastrinoma gastrin (hypergastrinemia)  hypertrophy of ECL cells and parietal cells  histamine, H+ secretion with somatostatin  Endogenous somatostatin is not enough to suppress gastrin secretion from gastrinoma  FDA approved 177lutetium (Lu-177)-labeled somatostatin analogue for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors After PPIs, H2-blockers treatment  gastric H+, somatostatin but gastrin and histamine remain high 16  Stress-Related Mucosal Disease (SRMD) Most commonly in critically ill patients in the ICU with severe head trauma, intracranial disease, extensive burns, major surgery, sepsis with severe coagulopathy, or requiring mechanical ventilation More than 75% of critically ill patients develop endoscopically visible gastric lesions during the first 3 days of their illness Mucosal damage or lesion commonly in the body and fundus (acid- producing areas) Focal deep mucosal damage, higher risk of bleeding Causes Local ischemia mucosa Direct stimulation of vagal nerve submucosa H. pylori infection muscle Prophylaxis is key gastric anti-secretory agents - Spirt MJ. Stress-related mucosal disease (2003) PPI, H2 blockers Curr Treat Options Gastroenterol 6:135–145 17  Pharmacological Treatment Relieve symptoms, accelerate healing, reduce recurrence But NOT cure Agents to Reduce Gastric Acid Antacids Histamine H2 receptor antagonists (H2RA, H2 blocker) Proton Pump Inhibitors (PPI) Mucosal Protective Agents Prostaglandin Analog (Cytotec) Sucralfate (Carafate) 18  Antacids/Alginic acid Maalox: Al(OH)3 and Mg(OH)2 Mylanta: Al(OH)3, Mg(OH)2 and Simethicone Tums: CaCO3 Rolaids: CaCO3 and Mg(OH)2 MOA OH- + H+  H2O CO32- + 2H+  CO2 (gas) + H2O ADR CO2 (gas) - belching, abdominal distension Mg2+ - diarrheal effect Al3+, Ca2+ - constipation effect Drug interaction gastric pH affect absorption or solubility of other drugs, e.g., tetracycline, fluoroquinolones. 19  Gaviscon® Mixture of Antacids: CaCO3 + Mg2O8Si3 or MgCO3 + Al(OH)3 Gelling agent - sodium alginate (naturally occurring polysaccharide found in a particular seaweed) MOA Antacids - Neutralize excess gastric acid Sodium alginate - form a highly viscous layer on top of the gastric contents, acting as a strong protective barrier  prevents gastric contents from refluxing back up into the esophagus  If reflux occurs, this protective barrier laying over the esophageal mucosa prevents direct contact with gastric contents ADR CO2 (gas) - ? Na+ - may aggravate HTN, HF, marked renal failure 20 Inhibition of Histamine Ach, Gastrin Inhibitory Pathways X X X XGastric acid secretion is partially inhibited. Proton pump 21 Histamine H2 Receptor Antagonists (H2RA, H2 blockers) MOA Reversible competition with histamine for binding to H2 receptors on basolateral membrane of parietal cells (Tagamet) Suppress 24-hour gastric acid secretion by ~70% Effectively inhibit basal acid (nocturnal acid) secretion X (Zantac) Modest impact on meal-stimulated acid secretion Less potent vs. PPIs Quick onset vs. PPIs: < 1 hr (Pepcid) (Zantac 360) Duration of action up to 12 hr (Axid) 22  H2 Blockers Extremely safe Tolerance may develop ADR - common with high doses, prolonged use of Cimetidine Weak anti-androgenic effect  reversibly sperm count, impotence, gynecomastia Rare and reversible galactorrhea in women Contraindication Pregnancy, although no known harmful effects on fetus Drug Interaction - Cimetidine only inhibit CYP450 isoenzymes  half-life of other drugs, e.g., Warfarin (anti-coagulant)  risk of ? reduce activation of prodrug Clopidogrel (anti-platelet) risk of ? 23  Proton Pump (H+-K+ ATPase) Resting, or unstimulated Stimulated prominent cytoplasmic tubulovesicle membrane tubulovesicles along with apical membranes intracellular canaliculi transforms into a dense containing short microvillli network of apical intracellular along with parietal cell apical canaliculi containing long surface microvilli Location of Proton Pump Inactive: Active: in cytoplasmic on apical vesicles canaliculi surface Mitochondria generate high energy 24 Inhibition of Proton Pump (H+/K+ ATPase) Ach, Gastrin Inhibitory Pathways X 25  Proton Pump Inhibitors (PPIs) Dexlansoprazole Esomeprazole R-isomer of lansoprazole S-isomer of omeprazole H+-K+ ATPase H+-K+ ATPase H2O H+-K+ ATPase Trapped in canaliculi (long microvilli) Activated PPI forms covalent disulfide bond (IRREVERSIBLE) with sulfhydryl groups of active H+-K+ ATPase located on the apical surface of parietal cells 26  Proton Pump Inhibitors (PPIs) MOA PPI is activated by H+  cyclic sulfenamide trapped in canaliculi containing long microvilli  form covalent disulfide bond with sulfhydryl groups of active H+-K+ ATPase located on the apical surface of parietal cells  Inhibit basal & stimulated gastric acid production >95% after 1 week  Maintain gastric pH>4 even during postprandial acid surge Pharmacokinetics Prodrugs, activated at low pH Enteric-coated formula in sustained-release capsule to prevent premature activation in gastric lumen Short plasma half-life of 1.5 hr vs. prolonged duration of action of up to 24 hr 3-4 days daily medication to reach full acid-inhibiting potential  presence of pump in quiescence located in non-secreting vesicles 2-5 days to return normal full acid secretion after discontinuing the drug  synthesis of new H+-K+ ATPase requires at least 18 h, half-life of proton pump is ~ 50 h. 27  Proton Pump Inhibitors (PPIs) ADR Long-term use  suppressed H+ secretion  HypERgastrinemia  hypertrophy and hyperplasia of ECL cells, parietal cells  risk of acid hypersecretion following PPIs discontinuation Resolution: tapering of PPI or switching to H2 blocker HypOchlorhydria  bacterial overgrowth  risk of pneumonia and Clostridium difficile infection, N-nitroso compounds (carcinogenic) from ingested nitrates In H. pylori-positive individuals, chronic gastric inflammation may accelerate progression from atrophic gastritis and intestinal metaplasia to gastric cancer Drug Interactions gastric pH, affect bioavailability of other drugs, e.g., digoxin Omeprazole inhibits metabolism of Warfarin half-life of warfarin  ? PPIs reduce activation of prodrug Clopidogrel  ? 28  Misoprostol (Cytotec) Human gastric epithelial cells synthesize prostaglandins FDA approved to prevent and treat NSAID-induced gastric ulcers, not duodenal ulcer MOA Replace the missing endogenous prostaglandins to interact with prostaglandin receptor (EP3 receptors)  maintain microcirculation, effects on epithelial cells (slide 14) ADR Stimulate intestinal electrolyte and fluid secretion, intestinal motility  diarrhea, abdominal cramping pain  May worsen symptoms of Inflammatory Bowel Disease (IBD), Irritable Bowel Syndrome (IBS)  Avoid concomitant use of Mg2+-containing antacid Stimulate uterine contraction – used with Mifepristone (progesterone antagonist) for medical abortion Contraindication: pregnancy 29  Sucralfate (Carafate) Sucrose salt complexed to sulfated aluminum hydroxide MOA Form a viscous, sticky paste in acidic environment (pH