GASTROINTESTINAL

DRUGS

Dr. Mariam Yousif

PHARMACOLOGY & TOXICOLOGY DEPARTMENT
)27/1/2007(
 OBJECTIVES
I. Peptic ulcer
* Definition & Pathophysiology
* Therapeutic strategies
* Drug treatment
A. Antimicrobial therapy )treatment of H. pylori(
B. Drugs that inhibit or neutralize gastric acid secretion
1. Proton-Pump Inhibitors )PPI(
2. H2-receptor antagonists
3. Antacids
C. Cytoprotective agents
II. Antiemetic Drugs
III. Laxatives )Purgatives(
1. Bulk Laxatives
2. Osmotic Laxatives
3. Faecal Softeners
4. Stimulant Purgatives

IV. Antidiarrhoeal agents

1. Antimotility agents
2. Adsorbents
 I. Peptic Ulcer

A peptic ulcer
is an open sore Location of peptic ulcers
or raw area in
the lining of the
stomach
(gastric) or the
upper part of
the small
intestine
(duodenal).
Peptic ulcer is
the most
common
chronic illness
of the digestive
system , it
recurs and
affects at least
10% of the
population in
developed
countries. Peptic ulcer seen under endoscopy
Pathophysiology
Peptic ulcer results when the normal balance of
factors that damage or protect the
gastrointestinal mucosal barrier is disturbed.
Infection of the gastric mucosa with Helicobacter
pylori is generally considered a major cause.

Other factors: An imbalance between mucosal-

damaging mechanisms )acid and pepsin( and
mucosal-protecting mechanisms )mucus,
bicarbonate, local synthesis of PGE2 and I2, and
nitric oxide(.
NSAIDs: decrease synthesis of PGs, abrogate
mucosal protecting mechanisms.
 Therapeutic Strategies For Treatment Of Peptic
Ulcer

To balance the aggressive factors )Helicobacter

pylori infection, gastric acid secretion( against
defensive or cytoprotective factors )bicarbonate
secretion, mucus secretion, prostaglandins(.

The goals of therapy are relief from pain,

promotion of healing and prevention of recurrence.
 Gastric acid secretion by parietal cells of the gastric
mucosa is controlled by acetylcholine, histamine,
prostaglandins E2 and I2; and gastrin.

 The binding of acetylcholine, histamine or gastrin

results in the activation of a H+/K+-ATPase proton
pump that secretes HCl into the lumen of the stomach.

 Prostaglandins E2 and I2 diminish gastric acid

production.
Acid secretion from the parietal cell. )a( Gastrin )G( and acetylcholine )Ach( stimulate the parietal
cell directly to increase acid secretion, and also stimulate the enterochromaffin-like )ECL( cells to
secrete histamine, which then acts upon the H2 receptors of the parietal cell )b(. The H+/K+ ATPase
pump in tuberovesicles, which fuse with the canalicular membrane upon stimulation and release
H+ into the lumen; Cl- is transported into the lumen by a separate carrier system. The parietal cell
also has receptors for PGE2 and their stimulation inhibits acid secretion.
The important approaches in the treatment:

1. To eradicate the bacterial infection )most

important(.

2. To reduce gastric acid secretion or neutralize it.

3. To provide agents that protect the gastric

mucosa from damage.
A. Eradication of Helicobacter pylori infection
)antimicrobial therapy(

 H. pylori is a gram-negative rod that colonizes the

mucus on the luminal surface of the gastric epithelium.

 H. pylori infection causes inflammatory gastritis and

is a putative contributor to peptic ulcer disease and
gastric lymphoma.
Helicobacter Pylori )HP( Closely Associated with the Disease
In 1983, researchers in Australia discovered a bacterium residing in the stomach of
patients with chronic gastritis )inflammation of the stomach(. Further studies showed
that this bacterium, subsequently called Helicobacter pylori )fig. 2(, was found in at
least 90 per cent of patients suffering from peptic ulcers. The bacteria protect
themselves from the high acidity in the stomach by producing 'urease' in the gastric
mucosa, which is an enzyme that metabolizes urea and neutralizes gastric acid. They
also elaborate various toxic substances which induce inflammation and cause cell
damage in the stomach and the duodenum.

Helicobacter pylori seen under an

electronic microscope
 Optimal therapy of patients with peptic ulcer
disease )both duodenal and gastric ulcers( who
are infected with H. pylori requires antimicrobial
treatment.

 Eradication of H. pylori reduces ulcer

recurrence rates.
 A variety of regimes that constitute 'triple
therapy' are utilized as 'best' therapy
)combination therapy(
Metronidazole or amoxicillin plus clarythromycin
plus omeprazole [a PPI )proton pump inhibitor(]

Given twice daily for 14 days

- Single agent therapy of H. pylori infections has

proven less effective )20-40% eradication rates(
 -Eradication rate is greater than 90% with the
triple regime.
-A two-week course of triple therapy is chosen
based on efficacy and cost.
- Elimination of the bacillus can produce long-
term remission of ulcers.

-Many patients can not tolerate metronidazole because

of its side effects.

Other combinations:
Clarythromycin, tetracycline and omeprazole
 -In resistant cases, a PPI is also used as part of
'quadruple therapy' with both amoxicilin and
clarythromycin plus metronidazole.

-Combinations of the H2 receptor antagonist

ranitidine with bismuth are also available, given
with clarythromycin.
Recommended regimens for H. pylorieradication
Acid suppressantAntibiotic
Amoxycillin Clarythromycin
Metronidazole
Esomeprazole ----- 1g twice daily 500mg twice daily
20mg twice daily ------ 500mg twice daily 400mg twice
daily

Lansoprazole----- 1g twice daily 500mg twice daily

30mg twice daily 1g twice daily ----- 400mg twice
daily
500mg twice daily 400mg twice -------
daily
Omeprazole ---- 1g twice daily 500mg twice daily
20mg twice daily 500mg 3 times daily ----- 400mg 3 times daily
500mg twice daily 400mg twice daily -------
 B. Drugs used to inhibit or neutralize
gastric acid secretion

.1)Proton-Pump Inhibitors )PPI

e.g.’s

Omeprazole

Lansoprazole
 .1)Proton-Pump Inhibitors )PPI

 Act by irreversible inhibition of the H+/K+-ATPase

)the proton pump(, the terminal step in the acid
secretory pathway.

 Administered orally as capsules containing enteric-

coated granules as degrade rapidly at low pH.
 Inhibit acid secretion by more than 90%. PPIs are more
effective at healing ulcers than H2 receptor antagonists.

 PPIs have a longer duration of action than H2 receptor

antagonists and are given once daily.
Their longer duration of action is due to their irreversible
inhibition of the H+/K+ ATPase pump.
 The clinical uses of Omeprazole include

a. Peptic ulcers resistant to H2-receptor

antagonists.
b. Reflux oesophagitis.
c. As one component of therapy for Helicobacter
pylori infection.
d. Zollinger-Ellison syndrome
A major cause of peptic ulcer, although far less common than H.pylori or
NSAIDS, is Zollinger-Ellison syndrome. A large amount of excess acid is
produced in response to the overproduction of the hormone gastrin, which in
turn is caused by tumors on the pancreas or duodenum. These tumors are
usually malignant, must be removed and acid production suppressed to relieve
the recurrence of the ulcers.
Drug interactions
Omeprazole inhibits cytochrome P-450 liver enzymes
and reduces the metabolism of drugs such as warfarin
and phenytoin.
2. H2- receptor antagonists
)e.g. Ranitidine, Cimetidine, Famotidine(

 Inhibit histamine actions at H2-receptors.

 Given orally and are well absorbed.

 Suppression of acid secretion is less than with a PPI

because only the histamine component is inhibited.
 Clinical use include peptic ulcer and reflux
oesophagitis.

Drug interactions
Cimetidine inhibits cytochrome P-450 liver enzymes and
reduces the metabolism of drugs such as warfarin and
phenytoin.
.3Antacids
 Weak bases that act by neutralizing gastric acid.

 The commonly used are salts of magnesium & aluminum

such as aluminum hydroxide or magnesium hydroxide
)milk of magnesia(.

 Used to relieve the pain and not to heal the ulcer.

 Usually advised to avoid concurrent administration of
antacids and other drugs.
 C.Drugs which protect the mucosa

 Cytoprotective compounds: enhance the

mucosal protection mechanisms and provide
a physical barrier over the surface of the ulcer.
.1Bismuth chelate
 Bismuth chelate or colloidal bismuth is used in
combination regimens to treat H. pylori involvement
in peptic ulcer.
 Has toxic effects on the H. pylori.
 Other actions: coating the ulcer base forming a
protective barrier and stimulating bicarbonate
secretion.
 Bismuth produces black tongue and stools.
 .2Sucralfate
A complex of aluminum hydroxide and sulphated sucrose.

 Forms complex gels with mucus, thus decrease the

degradation of mucus by pepsin.

Given orally.

 Forms a viscous paste in the acid environment of the

stomach, antacids reduce its efficacy.
 3. Misoprostol
- A stable analogue of prostaglandin E1.
- Inhibits gastric acid secretion, increases the secretion of
mucus and bicarbonate.
- Only used to prevent gastric damage that can occur with
chronic use of NSAIDs.
- Produces uterine contractions )abortifacient(,
contraindicated during pregnancy. Abuse to induce
abortion.
- Unwanted effects: diarrhoea and abdominal cramps.
Drug List

Amoxicillin
Clarythromycin
Ranitidine
Omeprazole
Antacids (Magnesium hydroxide, Aluminum
hydroxide), Bismuth chelate
Sucralfate
Misoprostol