Physiology and Pharmacology of Gastric Motility and Gastric Acid production

Professor John PetersE-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.

10 m10 m

Learning ObjectivesFollowing 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

Secretions of the Gastric Glands

Chief cellpepsinogen

Gas

tric

pit

Gas

tric

gla

nd

Mu

cosa

Parietal cellHydrochloric acid

Intrinsic factor

Enterochromaffin-like cell

Histamine

G cellGastrin

D cellSomatostatin

Pyloric gland area (PGA)antrum

Oxyntic mucosa (OM)fundus and body

PGA

OM

Functions of the Gastric SecretionsOxyntic 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

Mucus Protective

Pyloric gland area Gastrin Stimulates HCl secretion Somatostatin Inhibits HCl secretion

Secretion of HCl by the Gastric Parietal Cell (Present in gastric glands of the oxyntic

mucosa)

K+

K+

CO2 + H2O

HCO3-

H+

H2CO3-

CA

Na+

Na+

HCO3-

Cl-

Cl-H+

Plasma

Lumen of gastric pitK+ channel

Cl- channel

Cl-/HCO3-

antiporter

Na+/K+ ATPase

CA = Carbonic anhydrase

H+/K+ ATPase (proton pump)

N.b. Not all transport processes are illustrated

Canaliculus

G Gastrin (CCK2) receptor

Muscarinic M1 or M3 ACh receptor H2 Histamine receptor

P Prostaglandin receptor

M1/3 H2

Regulation of Hydrochloric Acid Secretion from the Gastric Parietal Cell

PARIETAL CELL

ECL CELL

HistamineG

G

+

+

M3

GastrinG CELL

ACh

ACh

+

P

Blood vessel

Cholinergic nerve (postganglionic parasympathetic)

H2

M1

PGE2

Cl-Cl-

K+K+

H+H+

K+K+

Pyloric gland area

Oxyntic mucosa

D CELLSomatostatin

Inhibits between meals

G

M3

H2

G

M3

H2

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+

Canaliculus

H+

http://mcb.berkeley.edu/labs/

forte/morphol.html

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)

Slig

ht, s

mel

l, ta

ste

of fo

od. C

ondi

tione

d re

flexe

s, c

hew

ing,

sw

allo

win

g

ECL cell

G-cell+

GR

P

D cell

AC

h -

-

ss

Parietal cell

+

histamine

+

gas

trin

(in

blo

od

)

+

Increased secretion

Vagal activation

+

Entericneurone

+

Entericneurone

++

Entericneurone

+

AC

h

ss, somatostatin; GRP, gastrin releasing peptide

Entericneurone

+ACh

Slig

ht, s

mel

l, ta

ste

of fo

od. C

ondi

tione

d re

flexe

s, c

hew

ing,

sw

allo

win

g

ECL cell

G-cell+

GR

P

D cell

AC

h -

-

ss

Parietal cell

+

histamine

+

gas

trin

(in

blo

od

)

+

Increased secretion

Vagal activation

+

Entericneurone

+

Entericneurone

++

Entericneurone

+

AC

h

ss, somatostatin; GRP, gastrin releasing peptide

Entericneurone+ ACh

Distension

+ +

Protein digestion products

+

Via mechanoceptors

+

Gastric phase – mechanical and chemical factors augment secretion

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)

PARIETAL CELL

G

M3ACh

+

P

H2

Arachidonic acid

Cyclo-oxygenaseNSAIDs (e.g. aspirin) block irreversibly

X

X

X

PARACRINE CELL

HistamineG

+

+ACh M1X

Muscarinic receptor antagonists (e.g. pirenzepine)

block competitively

H2 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+

H+ H+

PGE2

Cl-Cl-

K+K+

Locally produced prostaglandins (PGE2 and PGI2):

reduce acid secretionincrease mucus and bicarbonate secretionincrease mucosal blood flow

pH Gradient

Protection of the Mucosa from Attack by HCl and Pepsin

H+

Na+

HCO3-

Basolateral

Surface mucous

cells

Mucus gel layer

HCO3- HCO3

- HCO3-HCO3

-

ApicalH+ H+

Hydrophobic monolayer

H+ H+

pH 7

pH 2

Gastric blood flow

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 ulcerationBleedingNote: 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 formationmaintains (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

Drug treatment of peptic ulcer aims to promote ulcer healing by:reducing acid secretionincreasing mucosal resistanceEradicating 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 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

Drugs that Reduce Acid SecretionDrugs 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 H2 receptors

3) competitive antagonism of muscarinic M1 and M3 ACh receptors

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

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

are used in the treatment of peptic ulcer and reflux oesophagitis

Muscarinic ACh receptor antagonists; e.g. pirenzepineHave been used for the treatment of peptic ulcer in the past but are now obsolete

Gastrin receptor antagonists; e.g. proglumideAre 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 H2 receptor antagonists; e.g. ranitidine and cimetidine

act as competitive (reversible) antagonists of H2 receptors

are effective against basal and stimulated gastric acid production

are effective once/twice daily by oral administration

unwanted effects (of ranitidine) are rare

Mucosal Strengtheners

Sucralfate – a complex of aluminium hydroxide and sulphated sucroserequires 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 H2 antagonists (ranitidine) to promote eradication of the bacterium and ulcer healing

AntacidsAct to neutralize gastric acid and inhibit peptic activity, e.g.

Aluminium hydroxide – forms AlCl3 in the stomach

Aluminium salts cause constipation

Magnesium hydroxide – forms MgCl2 in the stomach

Magnesium trisilicate - forms MgCl2 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

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