1. Esophageal and Gastric Physiology Richmond Sy, MD FRCPC Division of Gastroenterology The Ottawa Hospital Sept. 8, 2015

2. Objectives  Describe the mucosal protective mechanisms of the esophagus and stomach.  Illustrate the role of the stomach in the digestion of food.  Explain the processes making up normal gastric secretion.  Summarize the regulatory mechanisms controlling gastric digestion, secretion and emptying.  Summarize the process of normal gastric contractility and emptying.

3. Gastric Anatomy

4. Functions of the Stomach  Motor  Reservoir  Mixing and grinding  Controlled emptying  Secretory  HCl secretion  Mucosal barrier  Pepsinogen secretion  Intrinsic factor

5. Main function of Gastric Motility  Accommodate meal (receive food via receptive relaxation)  Grind down solids (triturate) to chyme  Regulated emptying of stomach contents into the duodenum  The 3 major neuromuscular activities of the stomach  Receptive relaxation of the fundus  Recurrent peristaltic waves of the corpus and antrum  Antral peristaltic waves coordinated with antropyloroduodenal coordination

6. Gastric Electrophysiology  Gastric pacemaker is located along the greater curve at the proximal or mid corpus  Gastric slow waves originate at the interstitial cells of Cajal  Slow waves propagate in longitudinal and circumferential direction  Migrate towards the pylorus at 14mm/second  Coordinated propulsive peristaltic activity  Do not go pass the pylorus

7. Fasting Stomach  In fasted state, the motor activity of the stomach is known as the migratory motor complex (MMC)  MMC made of three sequences  Phase 1 – quiescence phase  Phase 2 – random and irregular contraction phase  Phase 3 – burst of uninterrupted phasic contractions that last 5 – 10 minutes (activity front)  Individual cycles last 1-2 hours  Activity front can migrate from the antrum to ileum  Stimulated by vagus nerve and motilin

8. Motor Response to a Meal  On initiation of swallowing, the gastric fundus relaxes to accommodate incoming food – mediated by the vagus nerve  Tone and phasic contractions are inhibited as meal enters the proximal stomach  Abolishes the cyclical MMC  Accommodation results in 2-3 fold increase in gastric volume  Leads to retention of food in stomach until it is distributed to the antrum

9. Liquid Meal  Trituration of the meal is accomplished with the propulsive force generated by the tonic contractions of the proximal stomach and the resistance of the antrum, pylorus and the duodenum  Liquids rapidly disperse through the stomach without a lag phase  Rate depends on volume, nutrient content and osmolarity  Empty nutrient liquids empty quickly  Rich nutrient liquids empty slower

10. Liquid Meal Total stomach emptying time Proximal stomach emptying time Distal stomach emptying time

11. Solid Meals  Solid meal emptying occurs in two phases  Initial lag phase  Linear emptying phase  Solid component initially held in proximal stomach  As liquid empties, the solid components move to antrum for trituration  Lag phase causes redistribution of solids  Restrict emptying of solid particles > 1mm

12. Solid Meals  The antrum and pylorus grinds down larger particles into smaller particles  Then empties in linear fashion with liquids  The lag phase depends on size and consistency of meal  For typical western diet, the lag phase is 60 minutes

13. Solid Meals Total stomach emptying time Proximal stomach emptying time Distal stomach emptying time

14. Antropyloric motility  Trituration is the function of coordinated contractions  High amplitude waves originate in proximal antrum  Propagate to pylorus  At the midantrum point, the pylorus is open permitting flow of liquids and liquefied solid particles  At the distal antrum, the terminal antral contraction closes the pylorus, promoting retropulsion of particles too large to exit the pylorus  Solid particles continue to move in and out of the antrum until it is broken down

15. Grinding and Emptying

16. Regulation of Gastric Emptying  Controlled by central and local neurohormonal control  Neuronal control includes:  Intrinsic myenteric plexus  Extrinsic postganglionic sympathetic fibers of the celiac plexus  Preganglionic parasympathetic fibers of the vagus nerve  Vagus afferents can be relaxatory and excitatory  Hormonal control via CCK  Relaxes fundic tone, decreases antral contraction and increase pyloric tone  Also other hormones (glucagon like polypeptide, peptide YY) can control gastric emptying

17. Enterogastric Reflexes Distension RELAXATION

18. Gastric Secretion Cell populations  Gastric epithelial cells  Mucus and HCO 3  Cells of the gastric glands  Cells of the lamina propria  Mast cells: histamine  Plasma cells: immunoglobulins  Neurocrine secretion  E.g. ACh, VIP, somatostatin

19. Functional Gastric Anatomy

20. Cells of the Gastric Glands Gland typeCell typeSecretory products CardiacMucousMucus, pepsinogen II Endocrinee.g. D cells: somatostatin OxynticMucousMucus, pepsinogens I and II ParietalHCl, intrinsic factor ChiefPepsinogen and Leptin Enterochromaffin-like cellsHistamine D cellsSomatostatin EnterochromaffinANP, serotonin, adrenomedullin PyloricMucousMucus, pepsinogens II G cellsGastrin enterochromaffinANP, Serotonin D cellsSomatostatin

21. The Oxyntic and Pyloric Gland

22. HCl Secretion Functions of gastric acid 1.Facilitate peptic hydrolysis of dietary proteins 2.Inactivate ingested microorganisms 3.Facilitate intestinal absorption of calcium, Vitamin B12 and iron

23. The Parietal Cell

24. Activation of the Parietal Cell 3 pathways: 1.Neurocrine: Acetylcholine, released from vagal efferences 2.Endocrine: Gastrin, released from antral G cells 3.Paracrine: histamine, released from mast cells and ECL cells

25. The Parietal Cell

26. Pathways of Activation of H+ Secretion  Mucosal nerves  Mediate cephalic phase and response to gastric distension  ACh:  Stimulates parietal cell  Stimulates gastrin release  inhibits somatostatin release

27. Pathways of Activation of H+ Secretion  Gastrin  Stimulated by:  Raised gastric pH  Amino acids  Gastric distension  ACh  Stimulates histamine release via ECL cells and mast cells  Stimulates parietal cell directly

28. Pathways of Inactivation of H+ Secretion  Luminal H+  Gastrin release is inhibited once gastric pH < 2.5 - 3  Somatostatin  Secretion is stimulated by gastric acid, gastrin and VIP  Inhibits histamine and gastrin release  Inhibits histamine-mediated activation of parietal cell

29. Pathways of Inactivation of H+ Secretion  Prostaglandins  Autocrine secretion from macrophages and endothelial cells of lamina propria  Inhibit histamine-related parietal cell activation  Inhibit gastrin-related histamine release  TGF-alpha  Vasoactive Intestinal Peptide (VIP)

30. Phases of Gastric Secretion 3 phases: 1.Cephalic 2.Gastric 3.Intestinal

31. Cephalic Phase  Vagally mediated stimulation of the parietal cell  Triggers:  Thought of food  Sight  Smell  Taste and mastication

32. Gastric Phase Distension Vaso-vagal and local reflexes Parietal cell activation High pH Peptides Caffeine Gastrin Mast cells ECL cells Histamine

33. Intestinal Phase Distension Hypertonicity Carbohydrates Fat Low pH Vago-vagal and local reflexes Somatostatin CCK (-) Pancreas HCO3- SECRETIN

34. Patterns of Acid Secretion

35. Gastric Mucosa

36. Gastric Mucosal Barrier  Mucous layer*  HCO3* t  Epithelial tight junctions  Mucosal blood flow* * Modulated by prostaglandins t Stimulated by ACh

37. Mucoprotective Mechanisms

38. Esophageal Protective Mechanisms  Why is esophagus not damaged by reflux of fluid from the acid environment of the stomach?  Esophageal Peristalsis  Contraction wave propagated down to the esophagus in response to swallowing and distention clear acid bolus  Saliva  pH of saliva is 6.4-7.8 which neutralizes acid  Esophageal submucosal glands  In response to acid reflux from the stomach submucosal glands secrete bicarbonate rich fluid that neutralizes acid  Tissue Factors  Esophageal epithelium with relatively “tight” limiting ionic movement  Esophageal stratified squamous epithelium is 25-30 cell layers thick  Na 2+ /H + as well as Cl - /HCO 3- transmembrane ion exchangers remove hydrogen from the cell allow bicarbonate to enter cell  In response to acid, blood flow increased to esophagus to clear H + and deliver HCO 3-

39. Pepsinogens PepsinogenPepsin Proteins Peptides Amino acids H+ Stimulate acid secretion Gastrin Ach Histamine Secretin Pepsin Inactivated at pH>4 Somatostatin Prostaglandins CCK _ +

40. Intrinsic Factor B12 – dietary protein B12 Dietary protein R-binder B12 - R R B12 IF B12 - IF H+, pepsin Pancreatic enzymes

41. Intrinsic Factor

42. Drugs Used in Acid-peptic Disorders  Acid-suppressive therapy  Proton pump inhibitors (PPI’s)  H2 receptor antagonists (H2RA’s)  Antacids  Prostaglandin analogs  Misoprostol  Prokinetics  Domperidone  Metoclopramide  Sucralfate and bismuth compounds

43. Acid-suppressive Therapy

44. H2 RA’s  4 types  Cimetidine, ranitidine, nizatidine, famotidine  Achieve ~70% acid suppression, especially nocturnal  Exceptional safety record  Side effects  Antiandrogenic effect, hematopoietic, CNS, hepatic, prolonged QT if rapid infusion, ?immunomodulator

45. PPI’s  6 types  Omeprazole, esomeprazole, lanzoprazole, dexlanzoprazole, pantoprazole, rabeprazole  Mechanism of action 1.Accumulation in the parietal cell 2.Activation of the PPI by protonation 3.Irreversible binding and inactivation of the H+/K+ ATPase Side-effects: diarrhea, headaches Drug interactions  Secondary to P450 metabolism  Secondary to achlorhydria

46. PPI’s – Practical Aspects  PPI’s cannot be activated outside the parietal cell  Importance of parietal cell activation  Timing of PPI intake  Timing of onset of action  Impact of concomitant inhibitors of parietal cell activity  Bond to H+/K+ ATPase is irreversible  Effects of chronic achlorhydria  Hypergastrinemia  Bacterial overgrowth

47. Parietal Cell and PPI Interaction

48. H2RA PPI Placebo

49. Objectives  Describe the mucosal protective mechanisms of the esophagus and stomach.  Illustrate the role of the stomach in the digestion of food.  Explain the processes making up normal gastric secretion.  Summarize the regulatory mechanisms controlling gastric digestion, secretion and emptying.  Summarize the process of normal gastric contractility and emptying.