Anti-ulcer drugs

Professor Glenda Gillies

Learning Objectives

Identify the factors that impinge on the development of peptic ulcer disease.

Explain why antibiotics feature prominently in the treatment of peptic ulcer

disease.

Using named examples, explain, with the use of a clearly labelled diagram,
the mechanisms by which proton pump inhibitors and histamine (H2)
receptor antagonists promote the healing of gastric ulcers

Explain why misoprostol may be used in the treatment of iatrogenic peptic

ulcer disease.

Explain the mechanisms by which sucralphate and bismuth chelate are

thought to be useful anti-ulcer drugs.

List two examples of triple therapy for peptic ulcer disease.

Explain the term gastroesophageal reflux disease and how it may be

treated.

Overview:
Treatment of gastric & duodenal ulcers

Background - physiology and pathology of the

gastrointestinal barrier
Drugs
1. Antacids
2. Inhibitors of gastric acid secretion
Triple
3. Cytoprotective drugs
therapy
4. Antibiotics and triple therapy

Peptic ulcer disease

duodenal:gastric 4:1

Area of damage to the inner lining of

- the stomach (gastric ulcer)
or
- Upper part of the duodenum
(duodenal ulcer)

Pain at mealtimes,
when gastric acid
is secreted

Pain relieved by
a meal as pyloric
sphincter closes;
pain 2-3h after a
meal

Imbalance of factors which protect or damage gastointestinal

barrier

Physiology: The integrity of the

gastrointestinal mucosal barrier is
important in maintaining a disease free
state.
Protective factors lubricate ingested food and
protect the stomach and duodenum from attack
by acid and enzymes:
1.
2.
3.

mucous from gastric mucosa creates gastrointestinal

mucosal barrier
HCO3- ions trapped in mucous generate a pH of 6-7 at
mucosal surface
locally produced prostaglandins stimulate mucous and
bicarbonate production (paracrine action) and inhibit
gastric acid secretion

Physiology: The integrity of the

gastrointestinal mucosal barrier is
important in maintaining a disease free
state.
Other factors which are needed to convert food
into a thick semi-liquid paste (chyme) have the
potential to damage the mucosal barrier:
1.

acid secretion from parietal cells of the oxyntic glands

in the gastric mucosa

2.

pepsinogens from the chief cells which can erode the

mucous layer

Mucus secreting cells cover

the surface of the stomach

Parietal (oxyntic) cell in human stomach

(pink staining)

Pathogenesis: not fully understood

Factors which may cause damage to mucosal
gastrointestinal barrier
Increased acid and/or decreased bicarbonate
production
Decreased thickness of mucosal layer
Increase in pepsin type I
Decreased mucosal blood flow
Infections with Helicobacter pylori (discovered 1982)

Pathogenesis: not fully understood

Risk factors:
- genetic predisposition,
- stress,
- diet, alcohol, smoking

Prevalence:
- 1:10 of the population in developed countries

Endoscopy
Normal stomach
Duodenal ulcer

Gastric ulcer

Aims of drug treatments

- eliminate cause of mucosal

damage
- promote ulcer healing

Drug targets
Neutralise gastric acid
Drugs
1. Antacids
Prevent gastric acid production
2. Inhibitors of gastric acid secretion
Promote healing
3. Cytoprotective drugs
4. Antibiotics and triple therapy
Eradicate H. pylori

1. Antacids

mainly salts of Na+, Al3+ and Mg2+

Sodium bicarbonate has rapid effects
Aluminium hydroxide and magnesium trisilicate have
slower actions

neutralise acid, raises gastric pH, reduces

pepsin activity
taken orally; primarily used for non-ulcer
dyspepsia
may be effective in reducing duodenal ulcer
recurrence rates

2. Inhibitors of gastric acid secretion

2.1. Proton pump inhibitors

2.2. Histamine type 2 (H2) receptor
antagonists
2.3. Anti-muscarinics

CONTROL OF GASTRIC ACID SECRETION

Parietal cell
oxyntic cell
Membrane of the canaliculus

Vesicles
storing the
H+/K+ ATPase
pump

Human stomach
(pink staining)

Enterochromaffin/mastlike cells close to parietal

cells in stomach
Endocrine cells
of mucosa

Local
cells
PLASMA

K+
STOMACH LUMEN

PARIETAL CELL
H+/K+ ATPase pump

H+
150mM HCl produced by active transport system

ACh(M)
Enterochromaffin/mastlike cells close to parietal
cells in stomach
Vagus +
enteric
neurones
PLASMA

Endocrine cells
of mucosa

Local
cells

H2

ACh(M)

K+
LUMEN

PARIETAL CELL
H+/K+ ATPase pump

H+
150mM HCl produced by active transport system

ACh(M)
Enterochromaffin/mastlike cells close to parietal
cells in stomach
Vagus +
enteric
neurones
PLASMA

H2

ACh(M)

Ca2+

LUMEN

Endocrine cells
of mucosa

Local
cells

Adenylyl
cyclase

ATP
cAMP
Protein kinases
K+
H+/K+ ATPase pump

H+
150mM HCl produced by active transport system

PARIETAL CELL

ACh(M)

Enterochromaffin/mastlike cells close to parietal

cells in stomach
Vagus +
enteric
neurones
PLASMA

Endocrine cells
of mucosa

Local
cells

H2

ACh(M)

Ca2+

Adenylyl
cyclase

G
+

ATP
cAMP
Protein kinases
K+
H+/K+ ATPase pump
LUMEN

H+
150mM HCl produced by active transport system

Gastrin secreted
into bloodstream

Ca2+
PARIETAL CELL

ACh(M)

Enterochromaffin/mastlike cells close to parietal

cells in stomach
Vagus +
enteric
neurones
PLASMA

Endocrine cells
of mucosa

Local
cells

PGE2

ACh(M)

Ca2+

H2
Adenylyl
cyclase

G
+

ATP
cAMP
Protein kinases
K+
H+/K+ ATPase pump
LUMEN

H+
150mM HCl produced by active transport system

Gastrin secreted
into bloodstream

Ca2+
PARIETAL CELL

2.1. Proton pump inhibitors (PPIs)

e.g. OMEPRAZOLE,
inhibits basal and stimulated gastric acid secretion
from the parietal cell by >90%

PPIs: mechanism of action

PPIs are irreversible inhibitors of the H+/K+

ATPase
inactive at neutral pH
as it is a weak base it accumulates in the
cannaliculi of parietal cells; this concentrates its
action there and prolongs its duration of action
(2-3 days) and minimises its effect on ion pumps
elsewhere in the body

PPIs: uses
uses
component of triple therapy
peptic ulcers resistant to H2 antagonists
reflux oesophagitis
orally active; administered as enteric coated
slow-release formulations
unwanted effects - rare

2.2. Histamine type 2 (H2) receptor

antagonists

e.g. CIMETIDINE, RANITIDINE,

inhibits gastric acid secretion by approximately
60% and are less effective at healing ulcers than
PPIs

Sir James Whyte Black, OM, FRS. FRSE, FRCP

(14 June 1924 21 March 2010)
Scottish doctor and pharmacologist; Nobel Laureate

1964
Developed Propranolol
1972
Discovered histamine type-2 (H2)
receptors and their antagonist,
cimetidine; established a new principle in
the treatment of peptic ulcer
1988
awarded the Nobel Prize for Medicine or
Physiology in 1988 for these discoveries
2008
The Medical Futures Innovation Awards
for Lifetime Achievement

H2 receptor antagonists
orally administered, well absorbed
unwanted effects rare
>90% recurrence within 1 year after initial healing

ACh(M)

Enterochromaffin/mastlike cells close to parietal

cells in stomach
Vagus +
enteric
neurones
PLASMA

Endocrine cells
of mucosa

Local
cells

PGE2

ACh(M)

Ca2+

H2
Adenylyl
cyclase

G
+

ATP
cAMP
Protein kinases
K+
H+/K+ ATPase pump
LUMEN

H+
150mM HCl produced by active transport system

Gastrin secreted
into bloodstream

Ca2+
PARIETAL CELL

2.3. Antimuscarinics

Little use as anti-ulcer drugs

ACh(M)

Enterochromaffin/mastlike cells close to parietal

cells in stomach
Vagus +
enteric
neurones

Endocrine cells
of mucosa

Local
cells

Gastrin secreted
into bloodstream
PLASMA

PGE2

ACh(M)

Ca2+

H2

Adenylyl
cyclase

Ca2+

ATP

cAMP

Protein kinases
K+
LUMEN
150mM HCl produced by active transport system

H+

H+/K+ ATPase pump

3. CYTOPROTECTIVE DRUGS

These drugs enhance mucosal

protection mechanisms and/or build a
physical barrier over the ulcer
3.1 Sucralfate
3.2. Bismuth chelate
3.3. Misoprostol

3.1 Sucralfate: a polymer containing

aluminium hydroxide and sucrose octasulphate

How does it act?

acquires a strong negative charge in an acid

environment
binds to positively charged groups in large
molecules (proteins, glycoproteins) resulting in
gel-like complexes
these coat and protect the ulcer, limit H+
diffusion and pepsin degradation of mucus
increases PG, mucous and HCO3- secretion
and reduces the number of H. pylori

Sucralfate:

What are its side effects?

most of orally administered drug remains in g.i.t.
may cause constipation
reduces absorption of some other drugs (eg.
antibiotics and digoxin)

3.2. Bismuth chelate

acts like sucralfate

used in triple therapy (resistant cases)

3.3. Misoprostol

a stable prostaglandin analogue

mimics the action of locally produced PG
to maintain the gastroduodenal mucosal
barrier

ACh(M)

Enterochromaffin/mastlike cells close to parietal

cells in stomach
Vagus +
enteric
neurones

Endocrine cells
of mucosa

Local
cells

Gastrin secreted
into bloodstream
PLASMA

PGE2

ACh(M)

Ca2+

H2

Adenylyl
cyclase

Ca2+

ATP

cAMP

Protein kinases
K+
LUMEN
150mM HCl produced by active transport system

H+

H+/K+ ATPase pump

Misoprostol
May be co-prescribed with oral non-steroidal antiinflammatory drugs (NSAIDs) when used
chronically
NSAIDs block the COX enzyme required for PG
synthesis from arachidonic acid
Therefore, there is a reduction in the natural
factors that inhibit gastric acid secretion and
stimulate mucus and HCO3- production

3.3. Misoprostol

Unwanted effects
diarrhoea, abdominal cramps, uterine
contractions
do not use in pregnancy

4. ANTIBIOTICS
to eliminate Helicobacter pylori (Gramnegative bacterium)
1982 H.pylori was discoverd as a new bacterium associated with
~100% of duodenal ulcers and ~80% of gastric ulcers
Barry J. Marshall and J. Robin Warren

Significant resistance to findings

Marshall drank a bacterial culture of H.pylori and became seriously ill,
with endoscopic investigations confirming dangerous inflammation of
stomach lining.
Successfully treated with antibiotics
Findings were not accepted until 1994, at NIH consensus conference,
Washington DC

Barry J. Marshall receiving his Nobel Prize from His

Majesty the King Carl XVI Gustaf of Sweden at the
Stockholm Concert Hall, 10 December 2005.

Barry J. Marshall and J. Robbin Warren

Summary
This year's Nobel Laureates in
Physiology or Medicine made the
remarkable and unexpected discovery
that inflammation in the stomach
(gastritis) as well as ulceration of the
stomach or duodenum (peptic ulcer
disease) is the result of an infection of
the stomach caused by the bacterium
Helicobacter pylori.

Helicobacter pylori

Gastric biopsy
Immunohistochemical stain

Scanning
electron
micrograph

Inclusion of antibiotics along with inhibitors of gastric

acid secretion or cytoprotective agents in the treatment
of peptic ulcers reduces relapse rates from >90% to
<15%
Patients were treated
with ranitidine for 610 weeks to attain
healing of their ulcer
One group also
received antibiotic
treatment for 12 days,
while the other
received placebo
Endoscopy was
performed at intervals
after healing to
determine recurrence
Hentschel, E New England Journal of Medicine 1993, 328: 308-12
of disease.

Rationale :

50-80% of population worldwide are

chronically infected (low grade infections
cause gastritis)
10-20% of which go on to develop peptic ulcer
disease or neoplasia (mechanisms unknown genetic/virulence of strain)
almost 100% of patients with duodenal ulcer
and 80-90% with gastric ulcer are infected
Current therapy aims for 90% eradication
within 7-14 days

Triple therapy is currently best practice

in treating peptic ulcer disease

A single antibiotic is not sufficiently

effective - partly due to development of
resistance

Example 1

metronidazole (active against anaerobic bacteria

and protozoa) or amoxycillin (broad spectrum
antibiotic), depending on pattern of local
resistance
clarithromycin
antibiotics with a macrolide structure; inhibits
translocation of bacterial tRNA)
proton pump inhibitor (PPI)
improves antibiotic efficiency possibly by
increasing gastric pH which improves stability
and absorption

Example 2
H2 receptor antagonists
clarithromycin
Bismuth
Example 3
Metronidazole
amoxycillin
bismuth

3 problems associated with triple therapy

compliance
development of resistance [vaccinations may
soon be available]
adverse response to alcohol, especially with
metronidazole (interferes with alcohol metabolism)

Gastroesophageal Reflux disease (GERD)

Stomach and duodenal contents reflux into the

oesophagus (oesophagitis)
- occasional and uncomplicated GERD
- heart burn, may treat by self medication with
antacids and H2 antagonists
- chronically may progress to pre-malignant mucosal
cells and potentially oesophageal adenocarcinoma

 treat with PPIs (drugs of choice) or H2

antagonists (less effective)
combine with drugs that increase gastric
motility and emptying of the stomach eg. DA2
receptor antagonists (metoclopramide)

Key Points

Identify the 3 main protective factors in maintaining the integrity of the upper GI tract and
prevent ulceration

Explain the role of antibiotics in the treatment if H. Pyloi and why this bacterium is significant
in ulcer formation

Explain using named examples, the mechanism of action of proton pump inhibitors and H2
antagonists in healing ulcers with the aid of a diagram

Describe the mechanism of action of misprostol and its use in treatment of iatrogenic peptic
ulcers

Explain the mechanism of action of sucralfate and bismuth chelate in preventing peptic
ulceration

Explain the term GORD (gastroesopageal reflux disease) and the role of H2 antagonists and
PPIs in its treatment with examples