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Physiology and Pharmacology of Gastric Motility and Gastric Acid production Professor John Peters TEMs of resting (left)

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Presentation on theme: "Physiology and Pharmacology of Gastric Motility and Gastric Acid production Professor John Peters TEMs of resting (left)"— Presentation transcript:

1 Physiology and Pharmacology of Gastric Motility and Gastric Acid production Professor John Peters E-mail 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. 10  m

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 H 2 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 Chief cell pepsinogen Gastric pit Gastric gland Mucosa Parietal cell Hydrochloric acid Intrinsic factor Enterochromaffin- like cell Histamine G cell Gastrin D cell Somatostatin Pyloric gland area (PGA) antrum Oxyntic mucosa (OM) fundus and body PGA OM

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 B 12 allowing absorption in terminal ileum  Histamine  Stimulates HCl secretion  Mucus  Protective  Mucus  Protective Pyloric gland area  Gastrin  Stimulates HCl secretion  Somatostatin  Inhibits HCl secretion

5 Secretion of HCl by the Gastric Parietal Cell (Present in gastric glands of the oxyntic mucosa) K+K+ K+K+ CO 2 + H 2 O HCO 3 - H+H+ H 2 CO 3 - CA Na + HCO 3 - Cl - H+H+ Plasma Lumen of gastric pit K + channel Cl - channel Cl - /HCO 3 - antiporter Na + /K + ATPase CA = Carbonic anhydrase H + /K + ATPase (proton pump) N.b. Not all transport processes are illustrated Canaliculus


7 G M3M3 H2H2 G M3M3 H2H2 H+H+ H+H+ H+H+ 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 ACh Gastrin Histamine Tubulovesicle Extended microvillus + Secretagogues Cause Trafficking of the H + /K + ATPase H+H+ H+H+ H+H+ H+H+ Canaliculus H+H+ labs/forte/morphol.html

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) Slight, smell, taste of food. Conditioned reflexes, chewing, swallowing ECL cell G-cell +  GRP D cell  ACh - -  ss Parietal cell +  histamine +  gastrin (in blood) + Increased secretion Vagal activation + Enteric neurone + Enteric neurone + + Enteric neurone +  ACh ss, somatostatin; GRP, gastrin releasing peptide Enteric neurone +  ACh

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

10 Intestinal phase – includes factors 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 PARIETAL CELL G M3M3 ACh + P H2H2 Arachidonic acid Cyclo-oxygenase NSAIDs ( e.g. aspirin) block irreversibly X X X PARACRINE CELL Histamine G + + ACh M1M1 X Muscarinic receptor antagonists ( e.g. pirenzepine) block competitively H 2 histamine receptor antagonists ( e.g. ranitidine) block competitively X Proton-pump inhibitors ( e.g. omeprazole) block by covalent modification Drug Classes that Influence Acid Secretion K+K+ K+K+ H+H+ H+H+ PGE 2 Cl - K+K+ K+K+

12 Locally produced prostaglandins (PGE 2 and PGI 2 ):  reduce acid secretion  increase mucus and bicarbonate secretion  increase mucosal blood flow pH Gradient Protection of the Mucosa from Attack by HCl and Pepsin H+H+ Na + HCO 3 - Basolateral Surface mucous cells Mucus gel layer HCO 3 - Apical H+H+ H+H+ Hydrophobic monolayer H+H+ H+H+ pH 7 pH 2 Gastric blood flow

13 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 PGE 1 analogue (i.e. misoprostol)  inhibits basal and and food-stimulated gastric acid formation  maintains (or increases) secretion and mucus and bicarbonate 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

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

15 Drugs that Reduce Acid Secretion Drugs that reduce gastric acid secretion are used in the treatment of: 4)antagonism of gastrin receptors (not utilized clinically)  Acid hypersecretion [e.g. Zollinger-Ellison syndrome (a rare, gastrin- producing, tumour); Cushing’s ulcers (heightened vagal tone)]  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)  peptic ulcer Mechanisms of anti-secretory activity include: 1)inhibition of the proton-pump 2)competitive antagonism of histamine H 2 receptors 3)competitive antagonism of muscarinic M 1 and M 3 ACh receptors

16 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)  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 lumenal sulphydryl groups of the membrane inserted proton-pump occurs Systemic circulation Plasma Concentration (1000-fold) Two step activation involving protonation Cys-modification Inactivation of all available pumps

17  are used in treatment of peptic ulcer (particularly when associated with H. pylori), GORD and are the drugs of choice in Zollinger- Ellison syndrome  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  unwanted effects are uncommon but concerns have been raised regarding long term treatment 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].  full effect is only achieved after repeated dosing  timing of dosing is important – drug must be present in plasma at an effective concentration whilst proton pumps are active

18  are used in the treatment of peptic ulcer and reflux oesophagitis 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  completely block the histamine-mediated component of acid secretion and reduce secretion evoked by gastrin and ACh Histamine H 2 receptor antagonists; e.g. ranitidine and cimetidine  act as competitive (reversible) antagonists of H 2 receptors  are effective against basal and stimulated gastric acid production  are effective once/twice daily by oral administration  unwanted effects (of ranitidine) are rare

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 Bismuth chealate  has mucosal strengthening actions similar to sucralfate  administered orally  increases mucosal blood flow, mucus, bicarbonate and prostaglandin production  binds to the ulcer base (positively charged proteins) and forms complex gels with mucus – provides a mucosal barrier against acid and pepsin  administered orally (in combination with ranitidine)  is toxic towards H. pylori - used in combination with antibiotics and histamine H 2 antagonists (ranitidine) to promote eradication of the bacterium and ulcer healing

20 Antacids Act to neutralize gastric acid and inhibit peptic activity, e.g.  Aluminium hydroxide – forms AlCl 3 in the stomach Aluminium salts cause constipation  Magnesium hydroxide – forms MgCl 2 in the stomach  Magnesium trisilicate - forms MgCl 2 and colloidal silica (which binds pepsin) in the stomach Magnesium salts cause diarrhoea 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

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