Physiology and Pharmacology of Gastric Motility and Gastric Acid production

1. Physiology and Pharmacology of Gastric Motility and Gastric Acid production 10 m 10 m Professor John Peters E-mail j.a.peters@dundee.ac.uk TEMs of resting (left) and stimulated (right) parietal cells from piglet stomach from: Handbook of Physiology – The Gastrointestinal System III (1989). Cell biology of hydrochloric acid secretion. Forte, J.G and Soll, A.

2. Learning Objectives Following this lecture, students should be able to: • Draw a diagram showing how HCl is produced and how this is regulated • List the products of the gastric glands • Describe the 3 phases of gastric secretion and the nature of their controls • Describe the role of peristalsis and the pyloric sphincter in the controlled emptying of the stomach contents • State how emptying is affected by the volume and composition of the food in the stomach • Appreciate the overall mechanism by which acetylcholine, histamine and gastrin enhance the activity of the H+/K+ATPase (‘proton pump’) to promote the secretion of HCl • Understand the importance of mucosal-protecting mechanisms in the prevention of ulcer formation and how such defence may be compromised by NSAIDs and chronic infection of the gastric antrum with H. pylori • Understand how drug treatment aims to promote ulcer healing • Appreciate how commonly prescribed drugs that suppress acid secretion [e.g. proton pump inhibitors (PPIs) and H2 receptor antagonists] exert their actions noting any adverse effects • Appreciate the role of mucosal strengtheners and antacids in the treatment of peptic ulcer • Be aware of combination therapies of antibiotics and PPIs in the treatment of peptic ulcer • Give examples of drugs that are used to increase gastric motility and their uses

3. Secretions of the Gastric Glands OM Gastric pit PGA Mucosa Chief cell pepsinogen Gastric gland G cell Gastrin Parietal cell Hydrochloric acid Intrinsic factor Enterochromaffin- like cell Histamine D cell Somatostatin Pyloric gland area (PGA) antrum Oxyntic mucosa (OM) fundus and body

4. Functions of the Gastric Secretions Oxyntic mucosa • HCl • Activates pepsinogen to pepsin • Denatures protein • Kills most (not all) micro-organisms ingested with food • Pepsinogen • Inactive precursor of the peptidase, pepsin. Note: pepsin once formed activates pepsinogen (autocatalytic) • Intrinsic factor • Binds vitamin B12 allowing absorption in terminal ileum • Histamine • Stimulates HCl secretion • Mucus • Protective Pyloric gland area • Gastrin • Stimulates HCl secretion • Somatostatin • Inhibits HCl secretion • Mucus • Protective

5. Secretion of HCl by the Gastric Parietal Cell (Present in gastric glands of the oxyntic mucosa) Lumen of gastric pit H+ Cl- K+ K+ CO2 + H2O H+ CA H2CO3- Cl- Na+ HCO3- HCO3- Plasma Na+ K+ channel Cl- channel Canaliculus Cl-/HCO3- antiporter Na+/K+ ATPase H+/K+ ATPase (proton pump) CA = Carbonic anhydrase N.b. Not all transport processes are illustrated

6. Regulation of Hydrochloric Acid Secretion from the Gastric Parietal Cell Pyloric gland area Cholinergic nerve (postganglionic parasympathetic) D CELL G CELL Somatostatin Gastrin PARIETAL CELL Cl- Cl- Inhibits between meals M3 ACh K+ K+ G Blood vessel H2 K+ K+ + G G H+ H+ Histamine + ACh M1 + P P ECL CELL Oxyntic mucosa PGE2 Gastrin (CCK2) receptor Prostaglandin receptor M1/3 H2 Histamine receptor Muscarinic M1 or M3 ACh receptor H2

7. Secretagogues Cause Trafficking of the H+/K+ATPase http://mcb.berkeley.edu/labs/forte/morphol.html H+ H+ Canaliculus H+ Extended microvillus H+ H+ M3 H+ M3 H+ ACh H+ G G + Gastrin H2 H2 Histamine Tubulovesicle Resting state of the parietal cell – H+/K+ATPase is largely within cytoplasmic tubulovesicles Stimulated state of the parietal cell – H+/K+ATPase traffics to the apical membrane taking residence in extended microvilli

8. The Three Phases of Gastric Secretion • Cephalic – before food reaches stomach • Gastric – when food is in stomach • Intestinal – after food has left stomach Cephalic (‘in the head’) phase (prepares stomach to receive food) Enteric neurone D cell ACh Increased secretion ss - - Slight, smell, taste of food. Conditioned reflexes, chewing, swallowing Enteric neurone Enteric neurone Parietal cell Vagal activation gastrin (in blood) G-cell GRP ACh + + + + + + + + + + Enteric neurone ECL cell ACh histamine ss, somatostatin; GRP, gastrin releasing peptide

9. Gastric phase – mechanical and chemical factors augment secretion Viamechanoceptors Distension Protein digestion products Enteric neurone D cell ACh Increased secretion ss - - Slight, smell, taste of food. Conditioned reflexes, chewing, swallowing Enteric neurone Parietal cell Vagal activation gastrin (in blood) G-cell GRP Enteric neurone ACh + + + + + + + + + + + + + + Enteric neurone ECL cell ACh histamine ss, somatostatin; GRP, gastrin releasing peptide

10. Intestinal phase – includesfactors originating from the small intestine that switch off acid secretion • The same factors that reduce gastric motility also reduce gastric secretion • As the stomach empties, the stimuli for secretion become less intense • Secretion of somatostatin resumes (low pH in stomach lumen, as occurs between meals, drives secretion)

11. G P Drug Classes that Influence Acid Secretion Muscarinic receptor antagonists (e.g. pirenzepine) block competitively Proton-pump inhibitors (e.g. omeprazole) block by covalent modification PARIETALCELL X M3 ACh Cl- Cl- G K+ K+ X K+ H2 K+ + X H+ H+ Histamine + X M1 ACh + PARACRINE CELL PGE2 NSAIDs (e.g. aspirin) block irreversibly Cyclo-oxygenase X H2 histamine receptor antagonists (e.g. ranitidine) block competitively Arachidonic acid

12. Protection of the Mucosa from Attack by HCl and Pepsin H+ H+ pH 2 Hydrophobic monolayer HCO3- HCO3- HCO3- HCO3- pH Gradient H+ HCO3- H+ Mucus gel layer Apical pH 7 Surface mucous cells Na+ Basolateral H+ Gastric blood flow • Locally produced prostaglandins (PGE2 and PGI2): • reduce acid secretion • increase mucus and bicarbonate secretion • increase mucosal blood flow

13. Peptic ulcer refers to any ulcer in an area where the mucosa is exposed to hydrochloric acid and pepsin (stomach, duodenum) Development of peptic ulcer is associated with a shift in the balance between mucosal-damaging and mucosal-protecting mechanisms Stomach ulcer Non-Steroidal Anti-inflammatory Drugs and Peptic Ulcer • Non-steroidal anti-inflammatory drugs (NSAIDs; e.g.aspirin) reduce prostaglandin formation (COX 1 inhibition) and may trigger: • gastric ulceration • Bleeding • Note: COX2-selective inhibitors may avoid this problem but are associated with increased risk of myocardial infarction and stroke – several withdrawn • Gastric damage due to long-term NSAID treatment can be prevented with a stable PGE1 analogue (i.e.misoprostol) • inhibits basal and and food-stimulated gastric acid formation • maintains (or increases) secretion and mucus and bicarbonate

14. Peptic Ulcer and Drug Treatment Development of peptic ulcer is incompletely understood, but one important factor is chronic infection of the gastric antrum with the bacterium, Helicobacter pylori HCl Pepsin Submucosa Submucosa H. Pylori, protected in mucus gel, secretes agents causing a persistant inflammation that weakens the mucosal barrier Breakdown of mucosal barrier damages the mucosal cell layer and leaves the submucosa (and deeper layers) subject to attack by HCl and pepsin H. pylori • Drug treatment of peptic ulcer aims to promote ulcer healing by: • reducing acid secretion • increasing mucosal resistance • Eradicating H. pylori (see next slide)

15. Drugs that Reduce Acid Secretion Drugs that reduce gastric acid secretion are used in the treatment of: • peptic ulcer • gastro-oesophageal reflux disease (GORD; inappropriate relaxation of lower oesophageal sphincter allowing reflux of acid gastric contents into the oesophagus and subsequent tissue damage – oesophagitis) • Acid hypersecretion [e.g.Zollinger-Ellison syndrome (a rare, gastrin-producing, tumour); Cushing’s ulcers (heightened vagal tone)] Mechanisms of anti-secretory activity include: inhibition of the proton-pump • competitive antagonism of histamine H2 receptors • competitive antagonism of muscarinic M1 and M3 ACh receptors antagonism of gastrin receptors (not utilized clinically)

16. are absorbed from the GI tract and delivered via the systemic circulation to the secretory canaliculi of the stomach where accumulation, activation (to a sulfenamide) and covalent modification of lumenalsulphydryl groups of the membrane inserted proton-pump occurs • Concentration (1000-fold) • Two step activation involving protonation • Cys-modification • Inactivation of all available pumps Systemic circulation Plasma Proton-pump inhibitors (PPIs); e.g.omeprazole • inhibit the active (i.e.membrane inserted) H+/K+-dependent ATPase (proton-pump) – note pumps in tubulovesicles are not inhibited • are basic prodrugs that are inactive at neutral pH, but which change conformation in a strongly acidic environment (i.e. the canaliculus)

17. Proton-pump inhibitors (PPIs); e.g.omeprazole(continued) • inhibition of acid secretion (typically 10-14 hr duration after a single dose before breakfast) greatly exceeds plasma half-life [for most PPIs e.g. lansoprazole, pantoprazole, rabeprazole 1 to 1.5 hr – tenatoprazole is an exception]. • timing of dosing is important – drug must be present in plasma at an effective concentration whilst proton pumps are active • are effective orally once daily (q.d.) (as a capsule containing enteric-coated granules). However, not all pumps are inactivated and nocturnal acid breakthrough (NAB) may occur • full effect is only achieved after repeated dosing • are used in treatment of peptic ulcer (particularly when associated with H. pylori), GORD and are the drugs of choice in Zollinger-Ellison syndrome • unwanted effects are uncommon but concerns have been raised regarding long term treatment

18. Histamine H2 receptor antagonists; e.g.ranitidine and cimetidine Muscarinic ACh receptor antagonists; e.g. pirenzepine Have been used for the treatment of peptic ulcer in the past but are now obsolete Gastrin receptor antagonists; e.g. proglumide Are useful experimental tools, but have no clinical uses • act as competitive (reversible) antagonists of H2 receptors • completely block the histamine-mediated component of acid secretion and reduce secretion evoked by gastrin and ACh • are effective against basal and stimulated gastric acid production • are effective once/twice daily by oral administration • unwanted effects (of ranitidine) are rare • are used in the treatment of peptic ulcer and reflux oesophagitis

19. Mucosal Strengtheners Sucralfate – a complex of aluminium hydroxide and sulphated sucrose • requires an acid environment for activation – releases aluminium to acquire a strong negative charge • binds to the ulcer base (positively charged proteins) and forms complex gels with mucus – provides a mucosal barrier against acid and pepsin • increases mucosal blood flow, mucus, bicarbonate and prostaglandin production • administered orally Bismuth chealate • has mucosal strengthening actions similar to sucralfate • is toxic towards H. pylori - used in combination with antibiotics and histamine H2 antagonists (ranitidine) to promote eradication of the bacterium and ulcer healing • administered orally (in combination with ranitidine)

20. Antacids Act to neutralize gastric acid and inhibit peptic activity, e.g. • Magnesium hydroxide – forms MgCl2 in the stomach • Magnesium trisilicate - forms MgCl2 and colloidal silica (which binds pepsin) in the stomach Magnesium salts cause diarrhoea • Aluminium hydroxide – forms AlCl3 in the stomach Aluminium salts cause constipation Antacids are used in the symptomatic relief of peptic ulcer and in dyspepsia

21. Combination Therapies in the Treatment of Peptic Ulcer Aim to promote ulcer healing and prevent relapse by the eradication of H. pylori • Numerous combinations exist, examples include: • Omeprazole + clarithromycin + amoxycillin • Omeprazole + clarithromycin + metronidazole Drugs That Increase Motility Domperidone – increases tone of the lower oesophageal sphincter, increases gastric emptying and enhances duodenal peristalsis Used in GORD and disorders of gastric emptying (e.g.gastroparesis associated with diabetic neuropathy) Metoclopramide – greatly increases the rate of gastric Used in GORD and disorders of gastric emptying