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.
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
Gastric pit
Secretions of the Gastric Glands
OM
Mucosa
PGA
Gastric gland
Chief cell
pepsinogen
G cell
Gastrin
D cell
Somatostatin
Enterochromaffinlike cell
Histamine
Parietal cell
Hydrochloric acid
Intrinsic factor
Pyloric gland area (PGA)
Oxyntic mucosa (OM)
antrum
fundus and body
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
Secretion of HCl by the Gastric Parietal Cell
(Present in gastric glands of the oxyntic mucosa)
Lumen of
H+ Cl+
K channel
gastric pit
K+
Cl- channel
Cl-/HCO3antiporter
Canaliculus
K+
CO2 + H2O
Na+/K+
ATPase
CA
Na+
H+/K+
ATPase
(proton pump)
CA = Carbonic
anhydrase
H+
H2CO3-
HCO3
-
Cl-
HCO3Na+
Plasma
N.b. Not all transport processes are illustrated
Regulation of Hydrochloric Acid Secretion from the
Gastric Parietal Cell
Pyloric gland area
D CELL
Somatostatin
Cholinergic nerve (postganglionic parasympathetic)
G CELL
Gastrin
PARIETAL CELL
Inhibits
between meals
ACh
Blood vessel
M3
Cl-
Cl-
G
K+
K
H2
K+
K+
H+
H+
+
+
G
+ Histamine
ACh
M1
Oxyntic
mucosa
G
+
P
ECL CELL
Gastrin (CCK2) receptor
M1/3 Muscarinic M or M ACh receptor
1
3
PGE2
P
Prostaglandin receptor
H2
H2 Histamine receptor
Secretagogues Cause Trafficking of the H+/K+ATPase
http://mcb.berkeley.edu/
labs/forte/morphol.html
H+
H+
Canaliculus
M3
H+
H+ H+
Extended
microvillus
H+
ACh
G
Gastrin
H2
M3
G
H+
H+
+
H2
Histamine
Tubulovesicle
Resting state of the parietal cell –
is largely within cytoplasmic
tubulovesicles
H+/K+ATPase
Stimulated state of the parietal cell –
traffics to the apical membrane
taking residence in extended microvilli
H+/K+ATPase
The Three Phases of Gastric Secretion
 Cephalic – before food reaches stomach
 Gastric – when food is in stomach
 Intestinal – after food has left stomach
ACh
-
D cell
+
+
Vagal
activation
+
Enteric
neurone
Enteric
neurone
GRP
+
+
G-cell
ACh
+
Enteric
neurone
Increased
secretion
ss
+
ECL cell
ss, somatostatin; GRP, gastrin releasing peptide
histamine
gastrin (in blood)
Enteric
neurone
ACh
Slight, smell, taste of food. Conditioned
reflexes, chewing, swallowing
Cephalic (‘in the head’) phase (prepares stomach to receive food)
+
Parietal
cell
+
+
Gastric phase – mechanical and chemical factors augment secretion
Via
mechanoceptors
ACh
-
Protein
digestion
products
D cell
+
+
+
Vagal
activation
+
+
Enteric
neurone
Enteric
neurone
GRP
+
+
+ +
G-cell
ACh
+
Enteric
neurone
Increased
secretion
ss
+
ECL cell
ss, somatostatin; GRP, gastrin releasing peptide
histamine
gastrin (in blood)
Enteric
neurone
ACh
Slight, smell, taste of food. Conditioned
reflexes, chewing, swallowing
Distension
+
Parietal
cell
+
+
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)
Drug Classes that Influence Acid Secretion
Muscarinic receptor
antagonists (e.g. pirenzepine)
block competitively
PARIETAL CELL
ACh X M3
X
Cl-
Cl-
G
K+
K+
H2
K+
K+
+
G
X
H+
+ Histamine
ACh X M1
Proton-pump inhibitors
(e.g. omeprazole) block
by covalent
modification
H+
+
PARACRINE
CELL
H2 histamine receptor
antagonists (e.g. ranitidine)
block competitively
P
PGE2
Cyclo-oxygenase
Arachidonic acid
X
NSAIDs (e.g.
aspirin) block
irreversibly
Protection of the Mucosa from Attack by HCl and Pepsin
H+
pH 2
H+
Hydrophobic
monolayer
pH
Gradient
pH 7
HCO3-
HCO3-
H+
H+
HCO3-
HCO3-
HCO3Mucus gel layer
Apical
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
Non-Steroidal Anti-inflammatory Drugs and Peptic Ulcer
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 (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
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
H. pylori
HCl
Pepsin
Submucosa
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
Drug treatment of peptic ulcer aims to promote ulcer healing by:
reducing acid secretion
increasing mucosal resistance
Eradicating H. pylori (see next slide)
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, gastrinproducing, tumour); Cushing’s ulcers (heightened vagal tone)]
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
4) antagonism of gastrin receptors (not utilized clinically)
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
• Concentration
(1000-fold)
Systemic
circulation
Plasma
• Two step activation
involving
protonation
• Cys-modification
• Inactivation of all
available pumps
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 ZollingerEllison syndrome
unwanted effects are uncommon but concerns have been raised
regarding long term treatment
Histamine H2 receptor antagonists;
e.g. ranitidine and cimetidine
 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
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
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)
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
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