Download Drugs Used In Peptic Ulcer and Eradication Therapy

INDEX
Description
Page no :
Section 1
Introduction
1.1 Definition
1.2 Types Of Peptic Ulcer
1.3 Prevalence of Peptic Ulcer
1.4 Pathophysiology
1.4.1 Defensive factors
1.4.2 Aggressive factors
Section 2 Peptic Ulcer Disease
2.1 Signs and symptoms
2.2 Causes
2.3 Risk increases with: both in DU and GU
2.4 Appropriate Health care
2.5 Possible major complications
2.6 Diet
2.7 General measures
2.8 Surgery
2.9 Inestigations
A) Fibreoptic endoscopy
B) Barium contrast Radiography
C) Secretary tests and Serum Gastrin Levels
Section 3 Aim of Treatment
3.1 Gastric Oulet Obstruction
3.2 Penetration
3.3 Perforation
Section 4 Drugs used in management of Ulcers
4.1 neutralizing agent
4.1.1 antacids
A) Mechanism of action
B) Clinical uses
C) Dosage
D) Pharmacokinetics
E) Adverse reaction and precaution
F) Drug interaction
G) Patient instruction
H) Trade name
4.2 Antisecratory agent
4.2.1 Histamine H2 receptor blockers
A) Regulation of Acid Secretion
B) Mechanism of action
C) Clinical uses
D) Dosage
E) Patient instruction
F) clinical uses
G) Pharmacokinetics
H) Adverse reaction and precaution
I) Drug interaction
J) Trade name.
4.2.2 Gastric acid proton pump inhibitors
A) mechanism of HCL transport
B) mechanism of action of PPIs
C) Dosage
D) Clinical uses
E) patient instruction
F) Pharmacokinetics
G) adverse reaction and precaution
H) drug interaction
I) Trade name
4.2.3 Selective antimuscarinic agent
4.3 Mucosal protective agents
4.2.4 chelates and complexes
4.2.4.1
sucralfate
A) mechanism of action
B) dosage
C) patient instruction
D) pharmacokinetics
E) adverse reaction and precaution
F) Drug interactions
G) Trade name
4.2.4.2
colloidal Bismuth Sulphate
A) mechanism of action
B) dosage
C) pharmacokinetics
D) adverse reaction
E) uses
F) trade names
4.3.2 Carbenoxolone
A) mechanism of action
B) Dosage
C) Adverse reaction and precaution
D) Drug interactions
E) Parameters to monitor
F) Uses
G) Trade name
4.2.5 Prostagladin analogue
A) mechanism of action
B) dosage
C) pharmacokinetics
D) adverse reaction and precaution
E) drug interaction
F) patient instructions
G) uses
H) trade name
Section 5 Helicobacter pylori Infection
A) Introduction
B) what are helicobacter pylori ?
C) Prevalence
D) Detection of H.P
E)Causes
F) Eradication therapy
G) Dosage
I) Patient instruction
J) Illnesses caused.
Section 6 Future direction
Section 7 Conclusion
ACKNOWLEDGMENTS
Sincere gratitude was extended to project supervisor Dr.Asim Ahmed, for
the continuous follow up, constructive criticism, and valuable comments.
The author is indebted to Dr. Rafeeq Abu Shaaban from the Pharmaceutics
department, to the support, encouragement and fruitful accompaniment,
through out the training and presentation of this project.
The author wishes to express special gratitude and thanks to those contributing in
this revolutionary, distinctive and advanced Hospital pharmacy training 1: namely
Dr. Dana Sallam and the staff of New Medical Center Hospital.
Finally the Author wishes to express the heartfelt thanks to Dr Abdul Mola in
charge of the central training committee for furnishing the entire clinical pharmacy
services as far as this term is concerned.
______________________________________Section 1 Introduction
General Introduction:
1.1 Definition:
Peptic ulcer disease (PUD) is a chronic inflammatory condition of a heterogeneous group
of ulcerative disorders in the upper gastrointestinal tract (G.I) that require acid and pepsin
for their formation. Ulcers differ from superficial mucosal erosions in that they extend
deeper into the muscularis mucosa.
1.2 Types Of Peptic Ulcer:

Duodenal Ulcer occurring in the duodenal bulb (first few centimeters of the
duodenum)

Gastric Ulcer occurring along the lesser curvature of the stomach.

Helicobacter pylori (Hp) associated ulcers. (Chronic ulcers)

NSAIDs associated ulcers. (Chronic ulcers)

Stress ulcers (acute ulcers)
Uncommon ulcers are associated with Zollinger-Ellison syndrome, radiation,
chemotherapy and vascular insufficiency.
1.3 Prevalence of Peptic Ulcer:

DU occurs in both sexes but more predominant in males. Mainly after age of 40.

Common in low social economic group

2 % of GU is malignant where as DU are nerve cancerous.

GU occurs in both sexes and all ages.

Deaths in people over the age of 75 years associates with the widespread use of
NSAIDs.

Age trends for ulcer occurrence reveal declining rates in younger men,
particularly duodenal ulcer, and increasing rates in older women. Most the PU
cases can be managed without drugs.
1.4 Pathophysiology:
Without protection, the stomachs own hydrochloric acid and pepsin would eat away at
the stomach wall. In order to protect itself the stomach tissue employs a number of
defense and repair factors and an imbalance between the Gastric mucosal defense and
countervailing aggressive force leads to the ulcer formation.
1.4.1 Defensive factors: (stomach self - protection)
i.
Secretion of mucus by surface epithelial cells (which is the first line of defense).
It protects underlying cells and acts as a lubricant layer between the mucosa and
its contents .It also forms a mucus layer that impedes hydrogen ion back diffusion
(the permeability of hydrogen ions from the stomach lumen into the gastric
mucosa).
ii.
Columnar epithelial cells, which line the stomach and duodenum, secrete a
protective layer of mucus that impedes the movement of acid and pepsin from
lumen to mucus. These cells also secrete bicarbonate to create a pH gradient from
very acidic at the luminal surface of the mucus layer to nearly neutral at the
surface of the underlying mucosa. In the duodenum, neutralization of acid is aided
by pancreatic and bleary bicarbonate.
iii.
Rapid gastric epithelial regeneration and when injured , migrating gastric pit cells
are immediately available to restore the damaged surface epithelium.
iv.
The dense network of capillaries underlying the surface epithelium of the stomach
and duodenum ensures a high rate of mucosal blood flow that provides the rapid
removal of any substances that may have breached the epithelial barrier, as well
as supplying oxygen and nutrients. The reactive hyperemia that follows epithelial
damage helps protect the mucosa from toxic
v.
substances and provides additional buffering capacity in the presence of acid
back-diffusion.
vi.
Endogenous PGE2, produced in gastric and duodenal mucosal cells, stimulate
mucus and bicarbonate secretion, maintain mucosal blood flow and participate in
epithelial restitution and cell growth.
NOTE: In the absence of mucous, acid would begin to attack the first layer of stomach
tissue. Normally this would not be a problem because the first layer of stomach tissue is
constantly being shed. But if the inner lining is destroyed faster then it can be replaced an
ulcer may develop. With enough acidity and continued absence of mucous, the ulcer may
grow deep enough to reach the underlying blood flow. When that happens, the ulcer is
said to have perforated the stomach wall, allowing stomach acid and pepsin can directly
act on the tissue underneath. At this point the person with the perforation would be in
considerable danger .If the acid reaches an artery, death may occur without prompt
medical attention.
1.4.2 Aggressive factors:
i.
The parietal or oxyntic cells are located in the mucosa of the fundus and body of
the stomach. When stimulated, they secrete acid into the gastric lumen through
the secretory canaliculi. Three major endogenous substances acetylcholine,
histamine, and gastrin, stimulate specific receptors on the parietal cell to secrete
acid. The neurocrine pathway delivers acetylcholine released from postganglionic
vagal neurons in the stomach. The paracrine pathway delivers histamine released
by mucosal mast or (ECL) Enterochromaffin- like cells. The endocrine pathway
delivers gastrin from antral and duodenal G cells.
ii.
Pepsin elaboration; Acid (parietal cell) + Pepsinogen (chief cell) lie in the gland
in the stomach lining  they convert Pepsinogen (inactive) to  Pepsin (active),
in presence of acid.
iii.
Helicobacter pylori infection.
iv.
Refluxed bile salts.
v.
Cigarette smoking is clearly associates with a higher incidence of PUD, although
the underlying mechanism is uncertain.
vi.
Alcohol in high concentration is associated with acute gastric mucosal damage
and upper GI bleeding, Diet (eating irregularity), NSAIDs Caffeine is a gastric
stimulant, which is responsible in increasing gastric acid.
vii.
Physical and psychological stress, which may predispose selected patients to PUD
or alter the degree of pain or disability that results from an ulcer.
viii.
ix.
Gastro esophageal reflux
Genetic factors and blood group O. (the gene for blood group O is associated with
an increased incidence in DU).
x.
People who drink their tea and coffee very hot are mostly to develop PUD than
those who have their drinks cooler.
_____________________________________________Section 2
Peptic Ulcer Disease .
An ulcer in the duodenum, which causes symptoms similar to those of stomach ulcer
(gastric ulcer). Where as ulcer that develops in the stomach lining is known as gastric
ulcer.
2.1 Signs and symptoms:
a) Epigastric pain, is the most common symptom of DU and GU with following
characteristics:

Burning, gnawing feeling that lasts 30 min to 3 hours; the pain is often interpreted
as heartburn in (DU), indigestion of hunger.

Pain is usually in the upper abdomen, but occasionally below the breastbone.

Many patients with DU describe a typical nocturnal pain that awakens them at
night. Since 60% of gastric acid is secreted at night.

Ulcer related pain in DU often occurs 1-3 hours after meals and is usually relieved
by food.

In GU, food may precipitate or accentuate ulcer pain (30 min)

Pain usually diminishes or disappears during treatment; recurrence of pain after
healing usually indicates a recurrent ulcer.
b) Loss of appetite usually In GU, less occurs in DU.
c) Recurrent vomiting mainly in GU
d) Blood in the stool
e) Nausea mainly in GU
f) Anemia
2.2 Causes:

An ulcer is more likely to develop in anxious, tense or worried person.

Patients with DU have an elevated mass of Gastric parietal cells and increased
acid secretions, irregular living habits, bacterial infection.

Also some disease state associated with an increased risk of peptic ulcer disease
includes cirrhosis, chronic pulmonary disease, renal failure, and renal
transplantation.

Additional, but rare, miscellaneous causes include radiation or chemotherapyinduced, vascular insufficiency (crack, cocaine), and duodenal obstruction.
2.3 Risk increases with: both in DU and GU
i.
Family history of ulcers
ii.
Stress
iii.
Improper diet, irregular meal times
iv.
Smoking
v.
Excess alcohol and caffeine consumption, which increases acid secretion.
vi.
Long-term usage of NSAIDs cortisone, which impairs mucosal defense.
2.4 Appropriate Health care:
i.
Doctors treatment
ii.
Hospitalization (in complicated states) during the initial treatment.
iii.
Psychotherapy or counseling (GU).
iv.
Self care after diagnosis
2.5 Possible major complications:
i.
Perforation (erosion of the ulcer through the stomach or duodenal wall), pain of
perforation is usually sudden and severe with mortality higher for GU than DU.
DU may penetrate the pancreas, biliary tract, or liver.
ii.
Hemorrhage (when the acid or ulcer breaks a blood vessels), anemia
iii.
Mechanical obstruction is caused by scarring or edema of the duodenal bulb and
can lead to delayed gastric emptying. Symptoms usually occur over several
months and include nausea, vomiting and weight loss.
iv.
Extensive peptic ulcer disease, with increased likelihood of stomach cancer.
Malignant change of ulcer in GU
2.6 Patient advice :
i.
Eat small frequent meals for at least 2 weeks
ii.
Don’t drink alcohol, after recovery; don’t drink more than 1 or 2 alcoholic drinks
a day.
iii.
Avoid caffeine and any hot spicy food that seems to make symptoms worse.
iv.
Check stool daily for bleeding
v.
Sharp sudden persistent stomach pain despite treatment.
vi.
Check for bloody vomit
vii.
Diarrhea begins which may be caused by antacids
viii.
You are usually weak pale, due to anemia
2.7 Surgery:
i.
Here one fifth of the patient require surgery; Mastectomy. Indication for presence
of complication and less often-elective operation. (Du)
ii. Indicated when risks and discomfort of ulceration are greater than surgery (DU) and
(GU)
ii.
In (GU) one half of the patient’s vagactomy (cutting out of the vagus nerve
which is responsible for stimulation of the acid production), required, if the
conservative treatment fails.
iii.
In (GU) indication for elective operation include slowly healing or unhealed ulcer
(malignant).
2.8 Investigations:

Initial investigations:
i.
Full blood count
ii.
Faecal occult bloods
Evidence of anemia or GI blood loss will prompt more detailed investigations.
A) Fibreoptic endoscopy
i.
Facilitates early biopsy of potentially malignant gastric ulcers in GU.
ii.
Allow biopsy for detection of H.pylori.
iii.
DU could be detected from other acid-peptic diseases.
iv.
It detects more than 90% of peptic ulcer
B) Barium contrast Radiography
When do we use it?
i.
If endoscopies is not available
ii.
Is the preferred method for patient with advanced ISH or COAD, since the
catheter is irritant
iii.
It detects 30 % of peptic ulcer.
C) Secretary tests and Serum Gastrin Levels recommended in patients unresponsive to
therapy or for cases which hypersecretory disease are suspected.
___________________________________________________Section 3
3. Aim of the treatment:
i.
To relive the symptoms e.g. pain, vomiting and improve quality of life.
ii.
Accelerate healing of the ulcer.
iii.
Prevent further complications like hemorrhage, Perforation, Penetration.
Prevent recurrence by the maintenance treatment, its important that we don’t use
iv.
proton pump inhibitor, since it causes complete inhibition of acid, (achlohydria)
there for this leads to no digestion of food, no absorption and finally leading to
weakness and diarrhea.

Complication Of PUD:
3.1 Gastric Outlet Obstruction
Narrowing of the lumen in the region of a peptic ulcer, the usual cause of gastric outlet
obstruction may result from spasm, acute inflammation and edema, muscle hypertrophy,
or contraction of scar tissue.
3.1.1 Symptoms:
The primary symptom, persistent emesis, is large volume and free of bile, often
containing food recognized as having been eaten 12 to 24 hours earlier. Pain, which may
be due to vigorous peristalsis as the stomach attempts to overcome the obstruction, tends
to be more constant than previous ulcer pain and may be relieved by vomiting. Patients
may be dehydrated and anorexic and are usually constipated.
Treatment:
a) Endoscopic Dilatation:
An ulcerated, stenotic pyloric channel is usually less than 5 mm in diameter, compared to
the normal 10 to 20 mm. The considerable experience with endoscopic dilatation of
esophageal strictures has now been applied to dilatation of the pylorus in combination
with medical treatment of the ulcer disease.
b) Surgery:
Operative intervention should be considered only after appropriate correction of fluid and
electrolyte abnormalities and a trial of medical treatment. The most popular operation is
vagotomy and a drainage procedure.
3.2 Penetration:
It is Defined as erosion of an ulcer through the entire thickness of the stomach or
duodenal wall without leakage of digestive contents into the peritoneal cavity,
penetration, or confined perforation, occurs through dense, fibrous adhesions into
adjacent structures It may involve the pancreas (the most common site for both gastric
and duodenal ulcers), gastrohepatic omentum, biliary tract, liver, greater momentum,
mesocolon, or colon. Treatment: Penetrating ulcers usually respond to therapy with
H2-receptor antagonists or acid pump blockers.
3.3Perforations:
A peptic ulcer is said to have perforated when it extends through the muscle wall and
serosa of the gastrointestinal tract, establishing communication between the lumen and an
adjacent space or structure. If extension through the wall is sealed by surrounding
structures before outflow of luminal contents occurs, the ulcer is said to have penetrated.
Treatment: Immediate management of a perforated ulcer includes alleviation of shock,
correction of electrolyte abnormalities, and relief of pain. Nasogastric suction is one of
the mainstays of treatment. If Non-operative management is considered, the tube should
be placed in the most dependent part of the stomach under fluoroscopic control.
Parenteral broad-spectrum antibiotics, to cover both aerobes and anaerobes, are also
necessary. Finally, eradication of Helicobacter pylori should be considered in all patients.
__________________________________________________Section 4
Drugs used in management of Ulcers:
Ulcer healing drugs are classified into:
4.1) Neutralizing agents:
4.1.1 Antacids
4.2) Antisecretory agent :
4.2.1 Histamine H-2 receptor blockers
4.2.2 Gastric acid proton pump inhibitors.
4.2.3 Selective Antimuscarinic agent ex, prienzepine and Tricyclic antidepressants.
THESE ARE NO LONGER USED
4.3) Mucosal protective agents:
4.3.1 Chelate and Complexes
4.3.1.1 Sucralfate
4.3.1.2 Colloidal Bismuth Compounds:
4.3.2Carbenoxolone
4.3.3 Prostagladin analogue.
4.1) Neutralizing agents:
4.1.1 Antacids
A) Mechanism of action.
Gastric antacids are weak bases that react with gastric hydrochloric acid to form a salt
and water. Their usefulness in peptic ulcer disease appears to lie in their ability to reduce
gastric acidity and, since pepsin is inactive in solutions above pH 4.0, to reduce peptic
activity.
B) Clinical uses of Antacids:
After a meal, gastric acid is produced at a rate of about 45 meq/h. A single dose of 156
meq of antacid given 1 hour after a meal effectively neutralizes gastric acid for 2 hours.
A second dose given 3 hours after eating maintains the effect for over 4 hours after the
meal. The dose response relationship of antacids is variable, depending on the gastric
secretary capacity (some individuals are “hyper secretors,” and some “hyposecretors” and
the rate at which the antacid is emptied from the stomach.
Antacids can be effective as per oral (PO) for symptomatic relief of indigestion, non ulcer
dyspepsia, epigastric pain in PUD or heart burn in gastroesophageal reflux disease.
C) Dosage:
In the best-controlled trial of duodenal ulcer therapy that would maximally neutralize
gastric acid throughout a 24-hour period, 140 meq of liquid antacid given 1 and 3 hours
after each meal and at bedtime accelerated the healing of duodenal ulcers. Additional
doses may be required up to once an hour. Different dosage of antacid is
required to achieve this degree of neutralizing capability, depending on the commercial
product used.
Missed Doses:
If your health care practitioner has told you to take this medicine on a regular schedule
and you miss a dose, take it as soon as possible. If it is almost time for your next dose,
skip the missed dose and return to your usual dosage schedule. Do not double doses.
Dosage forms:
1) Chewable tablets and capsules antacids are generally weak in their neutralizing
capability, and a large number of tablets would be required for this high-dose regimen.
They are not recommended for the treatment of active peptic ulcer.
2) Oral suspensions, liquid.
3) Oral powder
D ) Pharmacokinetics.
Onset and duration. Onset of acid neutralizing is immediate: duration is 30  10 min
in the fasted state and 1-3 hr if ingested after meals.
Fate. Antacid cat ions are absorbed to varying degrees. Sodium is highly soluble and
readily absorbed; calcium absorption is generally less than 30%, but may decrease with
increasing age, intake, achlorhydria, and estrogen loss at menopause; magnesium is
generally about 30 % absorbed, but percent absorption may vary inversely with intake;
aluminum is slightly absorbed. Calcium, magnesium and aluminum are excreted renally
with normal renal function. The unabsorbed portion is excreted in the feces.
E) Adverse Reactions and Precautions
Long term use of sodium –or calcium- containing antacids can cause systemic alkalosis
and fluid retension. Hypercalcemia may occur with ingestion of large amounts of
calcium carbonate; soluble antacids plus a diet high in milk products may result in milkalkali syndrome, which can lead to nephrolithiasis It also may cause stone kidney, muscle
calcification. Magnesium-containing antacids cause a dose-related laxative effect;
hypermagnesemia occurs in patients with renal impairment. Aluminum-containing
antacids cause dose-related constipation, especially in elderly. Prolonged administration
or large dosages of aluminum hydroxide or carbonate can result in hypophosphatemia,
particularly in the elderly and in alcoholics; encephalopathy has been reported in dialysis
patients receiving aluminum-containing antacids alone or with sucralfate.
Precautions. Avoid magnesium-containing products in renal impairment .Use others
with caution in patients with chronic renal failure or with fluid retention avoid those
containing large amounts of sodium, e.g magnesium trisilicate mixture (Gaviscon),
hypertension, or CHF. Because antacids are particulate and elevate intragastric pH.
Caution is recommended also in patients having appendicitis, gastrointestinal bleeding,
ulcerative colitis, or intestinal obstruction.
F) Drug interactions.
Antacids reduce the absorption of numerous drugs, the most important of which are
digoxin, oral iron (calcium carbonate, sodium bicarbonate, and possibly magnesium
trisilicate), isoniazide (aluminum containing), ketoconazole, oral quinolones, and oral
tetracyclines (di -and trivalent cations). Antacids may reduce salicylate levels and
increase quinidine levels because of urinary pH changes. Large dosages of calcium
antacids may produce hypercalcemia in the presence of thiazides. Sodium polystyrene
sulfonate resin can bind magnesium and calcium ions from the antacid in the gut ,
resulting in systemic alkalosis.
G). Patient instruction:
If the antacids do not relieve symptoms of indigestion, upset stomach, or heart within 2
weeks, contact your health care practitioner. Diarrhea may occure with magnesium,
therefore decrease the daily dosage, alternate dose with or switch to aluminum containing
antacids. Refrigerating liquid antacids may improve their palatability. Antacids may
interfere with other medications, therefore take other medications 1-2 hours before or
after antacids unless, otherwise directed. If tablets are used chew throughout before
swallowing and follow with a glass of water.
Parameters to Monitor.
Monitor for relief of dyspepsia, epigastric pain or heartburn and diarrhea or constipation.
Monitor serum phosphate during long-term use of aluminum –containing products in
patients with chronic renal impairment. Monitor for drug interactions
Notes.
Aggressive antacid therapy is at least as effective as the H2-receptor antagonists or
sucralfate when treating PUD or preventing stress related mucosal bleeding; however do
not use antacids as first line agents because large, frequent doses are inconvenient and
associated with an increased risk of adverse effect. Magaldrate is a chemical mixture of
magnesium and aluminum hydroxides. Although gastrin is stimulated by calcium, gastric
acid rebound with calcium containing antacids is of questionable clinical importance.
Activated dimeticone (simethicone) is added to an antacid since its highly effective
antiflatulent that act as dispersant of gas bubbles by reducing surface tension destroying
there by mucosal pockets of trapped gas, which causes distress. Aliginates added as
protectants against gastro-oesophageal reflux disease.
H) Trade names:
Non proprietary
Aluminum –magnesium hydroxide
Aluminum – magnesium and
simethicone
Sodium carbonate
4.2Gastric antisecretory drugs:
4.2) Antisecretory agent:
4.2.1. Histamine H-2 receptor blockers
Proprietary name
Maalox, Mucogel, Maalox plus
Moxal plus 
Roaids.
A) Regulation of Acid secretion:
Gastric acid secretion is produced in connection with meals, very weak during inter
digestive states; it is strongly stimulated by food uptake and even before, by anticipation
of this uptake. This anticipation is due to the existence of a “cephalic phase” which
integrates a variety of factors including metabolic stimuli whose effects are either
orexigenic, such as hypoglycemia, or anorexigenic (satiety signals). This phase involves
central nuclei (mainly the vagus nerve dorsomotor nucleus and the tractus solitaries
nucleus). Gastric emptying by food stimulates acid secretion by a local reflex initiated by
stomach distention. Gastrin secretion is activated by vagal stimulation and by luminal
peptones and amino acids. Then, acid secretion progressively decreases because of the
distension of the fundus, which provokes a central inhibitory reflex, of the acidification
of the antral lumen, which inhibits gastrin secretion, and of the arrival of nutrients into
the intestine, which stimulates the release of inhibitory peptides.
Parietal cell receptors: A histaminic H2-receptor is located at the basolateral
membrane of the parietal cell . Binding of histamine to the H2- receptor activates
adenylate cyclase and thereby CAMP production , via a stimulatory GTP dependent
protein. Also the parietal cell basolateral membrane also contains a muscarinic M3
(acetylcholine ) and a gastrin receptor .These two receptors cause an increase in
cytosolic Ca+2 concentration which through hydrolysis of membrane phosphoinositides
also leads to production of acid.The final common pathway is through the Proton pump
H+/K+ ATPase. Inhibitors of the activities of the first two secretagogues and of the proton
pump have been developed.
H2 - Receptor Antagonists :
B) Mechanism of action:
The four drugs used are Cimetidine, Ranitidine, and Famotidine and Nizatidine.
These agents are capable of over 90% reduction in basal, food stimulated, and nocturnal
secretion of gastric acid after a single dose. By competitively and reversibly binding to
the H2- Receptors on the parietal cell, diminishing cytosolic cyclic AMP production and
secretion of histamine stimulated gastric acid. An interaction between the cyclic AMP
and calcium pathways also results in partial inhibition of acetylcholine and gastrin
stimulated acid secretion.
C) Clinical Use:
Many trials have demonstrated their effectiveness in promoting the healing of duodenal
and gastric ulcers and preventing their recurrence .In patients with (GU) they are usually
given for 8 weeks. In addition they are important in the medical management of
Zollinger –Ellison syndrome and gastric hypersecretory states seen in systemic
mastocytosis.
D) Dosage:
Suppression of nocturnal acid secretion appears to be the most important determinant of
the rate of healing of duodenal ulcers.

For active ulcers, Cimetidine (least potent) can be given in Adult (oral) doses of
400-600 mg twice daily (with breakfast) or 800 mg at bedtime (benign gastric and
duodenal ulceration) for at least 4 weeks. (6 weeks in gastric ulceration, 8 weeks in ulcer
associated with continued NSAID). Children over 1 year, 25-30mg/kg daily in divided
doses. In slow intravenous infusion 200 mg given over at least 5 minutes; may be
repeated every 4-6 hours

Ranitidine and nizatidine can be given in Adult (oral) dosage of 150 mg twice
daily or 300 mg at night (benign gastric and duodenal ulcerations) for 4 to 8 weeks (more
potent) maintenance therapy therapy of 150 mg at night. For child (peptic ulcer) 2-4
mg/kg twice daily. By intravenous infusion for short –term use in peptic ulcer hospital
inpatients as alternative to oral route in ranitidine give 50mg diluted to 20 ml, and given
at least 2 minutes; in nizatidine 10 mg / hour, not recommended in child.

Famotidine (most potent) can be given at 20 mg (orally) daily as maintenance
therapy at bedtime or 40 mg at night for 4-8 weeks. Child it is not recommended.
Dosage forms:
1)
Capsules, tablets
2)
Syrup, suspension.
3)
Effervescent tablets
4)
Injection (IM, IV infusion).
Dosage:
Indication
PO for short
term ttt of active
duodenal ulcer
(4-8 weeks)
PO for
maintenance of
healed duodenal
ulcer
PO for short
term ttt of active
benign gastric
Cimetidine
300 mg qid.
400mg bid
Famotidine Nizatidine
20 mg bid or 150 mg bid
40 mg hs
or 300 mg
hs
Ranitidine
150 mg bid
or 300 mg
hs
400 mg hs
20 mgs hs
150 mg hs
150 mg hs
300 mg qid
20 mg bid or 150 mg bid
or 800 mg hs 40 mg hs
or 300 mg
hs
150 mg bid
or 300 mg
hs
ulcer (6-8
weeks)
PO for maint.
Healed of GU
400 mg hs
20 mg hs
150 mg hs
150 mg hs
Missed Doses;
If you miss a dose, take it as soon as possible .If it is almost time for your next dose, skip
the missed dose and return to your usual dosage schedule. Do not double doses.
E) Patient Instructions.
Cigarette smoking may decrease the effectiveness of H2-Receptor antagonists in peptic
ulcer disease. Discontinue or decrease smoking or avoid smoking after the last dose of
the day, since ulcers will fail to heal with 4 weeks of conventional therapy. Antacids may
be used as needed for relief of epigastric pain. Even though ulcer symptoms may
improve, continue treatment for the duration of therapy unless instructed otherwise. If
symptomatic relief is not obtained in 2 weeks with over the counter medication, contact
you health care practitioner. Report any bleeding, vomiting, or sever esophageal or
abdominal pain. Take tablet or liquid, swallow with liquid.
Parameters To Monitor:
Improvement in epigastric pain or heartburn. In patients receiving IV doses of cimetidine
(2.4g/day) or ranitidine (400 mg/day), it is advisable to monitor serum transaminases
routinely throughout the duration of IV therapy. Measure the intragastric pH periodically
and monitor for potential drug interactions.
F) Clinical Uses:
Indications systemic mastocytosis, Zollinger-Ellison syndrome, aspiration prophylaxis,
duodenal ulcer, dyspepsia, esophagitis, gastric ulcer, gastroesophageal reflux disease
(GERD), Helicobacter pylori multiple endocrine adenoma syndrome, NSAID-induced
ulcer prophylaxis pyrosis, (heartburn) stress, gastritis prophylaxis.
G) Pharmacokinetics :
Onset; all agents have an oral onset of 1 hour and an IV onset of 15 min.
Cimetidine
Famotidine
41  4%
ug/L
70 5 %
Fate oral
60  20 %
bioavailablity
ug/L
Excreted
75%
unchanged in
urine
T.5 normal
1.9  0.4 hr 3  0.5 hr
T.5 anuric
20 + hr
4.5  0.5
H) Adverse reactions and Precaution :
Nizatidine
Ranitidine
95  5%; 75 % 55  25 %
ug/L failure
70%
70 5 %
1.4  0.2 hr
7.2  1.3 hr
2  0.4 hr
7  3 hr
In general the H2-receptor antagonist are safe and well tolerated, when used in
recommended therapeutic doses for the treatment of PUD.Adverse reactions are generally
mild. The most frequent adverse events occur in 1-7% of patients and include, headache,
diarrhea, constipation, dizziness, drowsiness and fatigue. Reversible confusional states,
depression, agitation and other CNS manifestations
may occur occasionally.Rare cases of fatal hepatic disease with and without jaundice
have been reported with cimetidine and ranitidine. Cardiac arrhythmias, tachycardia, and
hypotension may occur following rapid IV bolus administration of cimetidine or
ranitidine, bradycardia with both oral and IV administration of these drugs. Negative
inotropic effect has been noted following oral administration of famotidine in healthy
subjects and patients with CHF. Hematological reactions occur occasionally with all H2
receptor antagonists, and include leukopenia, neutropenia, thrombocytopenia and they
may cause mild but reversible increase in fasting serum gastrin.
Gynecomastia develops in less than 1% of all men receiving cimetidine , but in 4% of
men treated for pathologic hypersecretory states as a long prolonged high dose treatment.
Dose dependent increases with serum prolactin concentrations with cimetidine and
ranitidne. Hyperuricemia with nizatidine.. Ranitidine and cimetidine may cause
alopecia.
Precautions: Pregnancy, lactation, dosage adjustment may be required in severe renal
and /or hepatic failure. H2-receptor antagonist may mask symptoms of gastric cancer;
particular care is required in those whose symptoms change and in those who are middleaged or over. Don’t take it if you are allergic to H2-receptor antagonist.
I) Drug interactions:
The potential drug interactions exist with the entire H2-receptor antagonist, they
may:
1)
Alter the bioavailablity of orally administered drugs as a consequence of
increating intragastric pH.ex ketoconazole.
2)
They bind reversibly to hepatic cytochromes P450 and decrease the hepatic
clearance of drugs that undergo phase I metabolism of ethanol.
3)
Inhibit gastric mucosal alcohol dehydrogenase thereby influencing the mucosal
metabolism of ethanol.
4)
Decrease the renal clearance of drugs by inhibiting their renal tubular secretion.
Numerous drug interactions has been reported with cimetidine, important drug
interaction exist with drugs of narrow therapeutic index e.g. (theophyline, phenytoin,
warfarin), metabolic interaction with cimetidine may be dose dependent. Antacids
Decreases absorption of ranitidine if taken simultaneously.
Famotidine and nizatidine no effect on hepatic drug metabolism.
Possible Interaction With Other Substances:
Interacts
Combined effect
with
Alcohol
Caffeine
drinks
Food
Tobacco
No interaction expected, but alcohol may slow body’s
recovery. Best to avoid
May increase acid secretion and delay healing
Enhanced effectiveness, protein rich foods should be water in
moderation to minimize secretion of stomach acid.
Reverses cimetidine effect. Tobacco may slow body’s
recovery. Best to avoid it.
Notes:
In general, the H2- receptor antagonists are similar in efficacy when conventional dosages
are prescribed for the treatment of gastric and duodenal ulcer and for maintenance of
healing of duodenal ulcer. The H2 -antagonists is often used in combination with a
number of antibiotics to eradicate Helicobacter pylori in peptic ulcer disease. Usual
dosages of H2-receptor antagonists are less effective than MISOPROSTOL or proton
pump inhibitors in preventing NSAID –induced gastric ulcer. However high doses of
FAMOTIDINE may be effective in preventing and healing NSAID-induced gastric and
duodenal ulcers.
Intermittent admiistration or continuous infusion of IV cimetidine, ranitidine or
famotidine is more effective than preventing upper GI bleeding in critically ill patients.
J) Trade names:
Non Proprietary
Name
Cimetidine
Famotidine
Proprietary Name
Tagamet , Dyspamet, Apo-Cimetidine , Peptol
,Novocimetidine
Pepcid , Famotec
Nizatidine
Ranitidine
Axid
Ranitidine, Zantac, Rantag
4.2.2 Proton Pump Inhibitors:
A) Mechanism of HCL transport:
The parietal cells, located in parietal or oxyntic glands of the gastric fundus and corpus,
have been identified as the source of gastric acid secretion .The molecule responsible for
secretion, gastric H+,K+-ATPase, or the gastric acid pump, which is found in large
quantity only in the gastric parietal cells, uses the chemical energy of ATP to transport
hydrogen protons from thecell's cytoplasm into its secretory canaliculi. The outward H+
transport is accompanied by an inward transport of potassium (one H+ for one K+) from
the canaliculus. Then K+ and Cl- enter the canaliculi, via either a K+,Cl- transporter or
K+ and Cl- channels present in the canaliculi membrane. The pump reabsorbs the K+ in
exchange for H+ extrusion. The Cl- accumulates with the H+, resulting in the net
secretion of isotonic HCl.
B) Mechanism of action of Proton Pump Inhibitors :
Proton Pump Inhibitors (PPIs) are inactive substituted benzimidazoles that , when
protonated in the secretory canaliculi of the parietal cells forms A sulfhydryl bond which
, covalently bind to H+/K+ -ATPase. The PPIs produce a profound and prolonged
antisecretory effect that persists for several days and inhibit basal , nocturnal ,
pentagastrin , and food stimulated gastric acid secretion . Secrum gastrin levels increases
during treatment , but return to pretreatment levels within 1-2 weeks of discontinuing
therapy.
C) Dosage :
Indication
Lansoprazol
Omeprazole
PO for short term ttt
15mg/day
20mg/day
15mg/day
20 mg/day
PO for reduction of
Days 1-10 30mg
Days 1-14 40mg bid ,then
the risk of DU
bid or
Days15-28 20 mg ,Or Days 1-
of active (DU)(4-8
weeks)
PO for maintenance
of healed ( DU)
recurrence
10 ,40 mg bid then days 11-28
Days 1-14 30 mg
, 20 mg/day
bid or days 1-14 30
mg bid.
PO for short term ttt
30 mg/day
40 mg/day
15-30 mg/day
20-40 mg/day
of active benign
(GU)(4-8 weeks)
PO for maintenance
of healed (GU)
Pantoprazole IV and oral dosage is 40 mg once daily , dosage reduction is required in
hepatic insufficiency. Rabeprazole is a partially reversible H+/K+-ATPase inhibitor given
in a dose of 20 mg/day orally. The efficency and tolerability of pantoprazole and
rabeprazole are similar to those of omeprazole and lansoprazole .
They are not recommended in child.
Dosage forms :
1.
Omeprazole and lansoprazole are inactivated by gastric acid therefore the drugs
are administered orally in capsule , that contains pH-sensitive granules that release the
drug when the pH is higher than 6.
Upon dissolution of the capsule in the stomach the granules passes into the duodenum
where the drug is released and absorbed.
In patients who are unable to swallow the capsule , may be opened but the granules
should be administered in an acidic juice (orange juice) to avoid dissolution of the
protective coating.
2.
Pantoprazole is present in the form of Tablets , injection powder for
reconstitution.
3.
Rabeprazole is present in the form of Tablets.
Missed Doses :
If you miss a dose , take it as soon as possible .If it is almost time for your next dose ,
skip the missed dose and return to your usual dosage schedule. Do not double doses.
D) Clinical uses :
Omeprazole is indicated for short term therapy of gastroesophageal reflux disease, gastric
and duodenal ulcers, and gastric hypersecretory conditions including Zollinger-Ellison
syndrome, systemic mastocytosis, and multiple endocrine adenoma. Despite its potency,
omeprazole must be used in combination with antibiotics to be effective against
Helicobacter pylori.
E) Patient Instructions :
Swallow capsule whole or open the capsule and sprinkle the granules on apple or orange
juice , and take before meals. Swallow capsule or intact granules immediately
without chewing. The effectiveness of PPIs in peptic ulcer disease may be decreased by
cigarette smoking. Even though symptoms may improve , continue treatment for the
duration of therapy unless instructed otherwise.
Parameters to monitor :
Improvement in epigastric pain , or heart burn , however pain relief in peptic ulcer
disease does not correlate directly with endoscopic evidence of healing. Monitor for
potential drug interactions and adverse effects. Asses the indication , dosage and duration
of PPI therapy especially as it relates to the need for treatment beyond 16 weeks.
Consider monitoring serum vitamin B12 concentration every several years in patients on
long-term PPI therapy.
F) Pharmacokinetics :
i. Onset and duration .
Onset of antisecretory activity after multiple oral daily doses is within 1 hr for all PPIs.
Duration of antisecretory effect is dose dependent. Gastric acid inhibition increases with
repeated daily doses, reaching a plateau after several days. Gastric secretary activity
gradually returns to pretreatment levels 2-5 days after discontinuation. There is not
indication that rebound gastric acidity occurs.
ii. Serum levels .
Antisecretory effects correlates with AUC rather than serum levels. Inhibition of gastric
acid secretion continues after serum drug concentration have decrease below the limit of
detection, apparently caused by prolonged drug binding to parietal cell H+/K+-ATPase.
Fate
Lansoprazole Omeprazole Pantoprazole
Oral bioavailability
80%
65%
77%
Protein binding
97%
95%
98%
Excreted unchanged in urine Very little
Very little
Very little
t.5 healthy young adults
1.50.2 hr
0.75 0.25hr
0.662.06
t.5 healthy elderly
2.2 0.7 hr
1 hr
1.64 hr
G) Adverse reaction and Precaution:
The short and long term safety of lansoprazole appears to be similar to that of
omeprazole. Headache ,diarrhea , nausea , and dizziness , occur frequently. Constipation ,
fatigue malaise , muscle cramps , Stevens-Johnson syndrome, joint pain , myalgia ,
anxiety , skin rash , and taste perversion occur occasionally. Rarely gynecomastia ,
hemolytic anemia , thrombocytopenia , and psychic disturbances have been reported.
Rare cases of skin reactions overt hepatic failure , liver necrosis , pancreatitis , interstitial
nephritis and agranulocytosis have occurred with omeprazole .Rarely gastric polyposis
has occurred in patients receiving 20-24 mg of omeprazole for 12 months or longer. Long
term PPI use may reduce the absorption of protein bound vitamin B12.Adverse effects in
patients over 65 years of age are similar to that of younger patients. Pantoprazole also
causes fever , liver enzyme changes and raised triglycerides. Precautions : Pregnancy
, breast feeding , they should be used in caution with in patients with liver disease since
clearance of the drug can be prolonged. Proton pump inhibitors may mask symptoms of
gastric cancer particular care is required in those whose symptoms change and in those
over 65 years of age. Should not use PPIs in patients who are hypersensitive to such
product.
H) Drug interactions:
Elevations in gastric pH could increase the extent of absorption of ampicillin , and
decease the rate of extent of absorption of digoxin, itraconazole , iron salts, ketoconazole,
and other drugs or dosage forms that are pH dependent. Omeprazole pantoprazole
interacts selectively with hepatic enzyme , and may inhibit the metabolism of drugs , such
as some benzodiazepines (e.g. .diazepam), carbamezapine , cyclosporins , phenytoin , and
warfarin . They increase the hepatotoxicity of acteominophen or lead to an increased risk
of cancer in smokers. Lansoprazole they may increase theophylline clearance.
Possible interactions with other substances :
Interacts with
Combined effect
Alcohol
Decreased effect
Caffeine drinks
Decreased effect
Spicy food
Decreased effect
Tobacco
Decreased effect
Notes :
The PPIs are effective in preventing NSAID-induced gastric and duodenal ulcers and
appear to be superior to Misoprostol 200mg bid or ranitidine 150mg bid.When
prophylactic treatment with omeprazole 20 mg/day was compared with misoprostol 200
bid , omeprazole was associated with a lower relapse rate and was better tolerated than
misoprostol. Coadminstration of PPI with an H2 receptor antagonist is without
established benefit , the action of PPI many be compromised if administered .PPIs are
more cost effective than the h2 receptor antagonists when treating patients with severe
ulcers.
I) Trade names:
Non Proprietary name
Omeprazole
Lansoprazole
Pantoprazole
Rabeprazole sodium
Proprietary name
Losec®, Prilosec® Risek®
Heliclear®, Prevacid®,
Pantozol®
Pariet®
4.3 Mucosal Protective agents :
4.3.1 Chelate and Complexes
4.3.1.1 Sucralfate
A) Mechanism of action :
Sucralfate is an aluminum hydroxide salt of a sulfated disaccharide. It is only minimally
absorbed 3-5% from the GI tract. When exposed to acid , the sucralfate forms a viscous
adhesive that binds electrostatically to positively charged protein molecules in the ulcer
crater, forming a protective barrier that inhibits the back diffusion of hydrogen ions,
pepsin and bile salts. Adherence to the ulcer crater is enhanced at a pH 3.5 and it lasts for
up to 6 hours following oral administration.
Sucralfate inhibits pepsin , adsorbs bile salts , stimulates endogenous Prostaglandin’s and
EGF. Sucralfate does not have an action on the acid secretion.
B) Dosage :

PO for short term treatment of DU 1g qid on an empty stomach, 1 hr before meals
and at bedtime or 2g bid for 4-8 weeks.

PO for maintenance of healed DU 1g bid.

PO for short-term treatment of active benign gastric ulcer 1g qid.
Dosage forms :
1.
Tab 1g
2.
Susp 100mg/ml
Missed doses :
If you miss a dose , take it as soon as possible .If it is almost time for your next dose ,
skip the missed dose and return to your usual dosage schedule .Do not double doses.
C) Patient instructions :
Take this drug with water on an empty stomach , 1 hour before each meal and at bedtime.
Antacid may be used as needed for pain relief , but DO NOT take them within 30 minutes
before or after sucralfate. Since they require an acid pH to be activated and so should not
be administered with antacid or H2-antagonist.Take potentially interacting drugs 2 hours
before sucralfate in order to avoid or minimize drug interactions. Even though symptoms
may decrease , continue treatment for the duration for therapy unless instructed
otherwise.
Parameters to monitor :
Improvement in epigastric pain or heart burn . Observe for constipation and signs of
aluminum toxicity in the elderly , in chronic renal failure , or in patients , receiving other
aluminum-containing drugs.Obtain serum phosphate, periodically, in patients , receiving
concurrent aluminum-containing drugs or with prolonged use.Monitor for potential drug
interactions.
D) Pharmacokinetics :
Onset and Duration :
Onset (attachment of sucralfate to ulcer site) is within 1 hr , duration is about 6 hours.Fate
, sucralfate is only minimally absorbed from the GI tract and is excreted primarily in the
feces. About 3-5% (primarily aluminum) is absorbed and excreted in
E) Adverse reaction and Precaution :
Adverse reaction are usually minor and occur in about 5% of patients. Constipation
occurs in about 2% of patients. Other effects , including diarrhea, nausea , gastric
discomfort, indigestion , dry mouth , rash , pruritus ,backache , dizziness , drowsiness,
vertigo , and a metallic taste occur occasionally .Aluminum accumulation and toxicity ,
including osteodystrophy , osteomalacia , encephalopathy , and seizures, have been
reported in patients with chronic renal failure. Hypophosphatemia may develop in
critically ill patients and those on prolonged sucralfate therapy.
Precautions :Use with caution in patients receiving other aluminum-containing drugs
or in chronic renal failure and dialysis.
F) Drug interactions :
Sucralfate may inhibit the absorption of drugs including digoxin , ketoconazole ,
levothyroxine , phenytoin, quinidine, oral quinolones, tetracyclines, theophylline and
warfarin. In most cases these interaction can be avoided if the drug is given 2 hr before
sucralfate administration.
Notes :
Sucralfate may overcome the negative effect of cigarette smoking on DU healing and
recurrence.It is effective in preventing stress-related mucosal bleeding .It is poorly
absorbed systemically (though risking blood levels have been documented in patients
with renal failure).
G) Trade names:
Non Proprietary name
Proprietary name
Sucralfate
Antepsin® Carafate®
4.3.1.2 Colliodal Bismuth Compounds :
A) Mechanism of action :
Bismuth salts are used to treat nausea , indigestion , diarrhea , gastritis and peptic ulcers .
They cause local gastroprotective effect , stimulation of endogenous prostaglandins , and
antimicrobial activity against Helicobacter pylori.Given alone , bismuth salts suppress
H.pylori but long term eradication requires combination therapy with antibiotics.Bismuth
subsalicylate is the bismuth salt used often and Ranatidine bismuth citrate is a complex of
ranitidine trivalent bismuth , and citrate.
B) Dosage :
PO for the control of nausea , abdominal cramps , and diarrhea 52.5mg qid to maximum
of 4.2 g/day.When given with antibiotics to eradicate H.pylori treatment is usually
limited to 1-2 weeks.
Dosage Forms:
1)
Suspension of (Bismuth subsalicylate) 17.5,35 mg/ ml
2)
Tab (ranitidine bismuth citrate (RBC ) 262 mg Tab 400 mg (containing ranitidine
150 mg and bismuth citrate 240 mg)
C) Pharmacokinetics:
Following oral administration , BSS(58% bismuth , 42% salicylate) is converted in the GI
tract to bismuth oxide and salicylic acid. Bismuth is less than 0.2% absorbed with more
than 99% of an oral dose excreted in feces. Over 90% of the salicylate dose is absorbed
and excreted in urine. Ranitidine bismuth citrate (RBC) dissociates in intragastric fluid to
ranitidine and soluble and insoluble forms of bismuth. Oral absorption of bismuth from
(RBC) is variable.
D) Adverse reactions:
BSS and bismuth derived from RBC may cause temporary darkening of the tongue and
stool .Use BSS with caution in children , in the elderly , in patients with renal impairment
, salicylate sensitivity or bleeding disorders , in those receiving high-dosage salicylate
therapy, or when potentially interacting medications are taken. Salicylic acid is less likely
than aspirin to cause gastric mucosal damage and blood loss. Prolonged BSS therapy and
the use of other salts have been associated with neurotoxicity.Bismuth concentrations
may be elevated in the elderly and patients with renal impairment because of decreased
renal elimination. RBC should not be used as a single agent for the treatment of active
duodenal or gastric ulcers.
E) Uses:
They are used in GU and DU and for eradication therapy in Helicobacter pylori as a
combination therapy with antibiotics.
F)Trade names:
Non proprietary name
Proprietary name
Tripotassium dicitratobismuthate De-Noltab , Tritec
4.3.2 Carbenoxolone:
A) Mechanism of action:
It is a synthetic derivative of glychrihizic acid (an agent extracted from liquorice) .The
mechanism of action of not clear but it is thought to involve an increase in the
production, secretion, and viscosity of intestinal mucus.
B) Dosage Forms:
1)
2)
Tablets, chewable
Liquid
Dosage:
1 tablet to be chewed 3 times daily after meals, and 2 at night for 6-12 weeks or 10 ml
liquid 3 times daily after meals and 20 ml at night for 6-12 weeks.
C) Adverse reactions and Precautions
It has major aldosterone- like side effect, hypertension, fluid retention and hypokalemia
which has limited its clinical usefulness. Muscle weakness, cardiac failure. Precautions
: In cardiac disease, hypertension, hepatic and renal disease, elderly over the age of 75
years. NOT recommended for children.
D) Drug Interactions:
The concurrent administration of spironolactone controls the fluid retention but also
abolishes the ulcer healing effect; the thiazide prevents sodium retention without
abolishing the beneficial effect in peptic disease.
E) Parameters to measure:
If it is used regular monitoring of weight, blood pressure, and electrolytes is advisable
during treatment.
F) Uses:
It is used for both DU and GU.
G) Trade name:
Non-proprietary name
Proprietary name
Carbenoxolone sodium Pyrogastrone®
4.3.3 Prostaglandins analogues:
A) Mechanism of action:
Misoprostol is a synthetic prostaglandin E1 analogue that inhibits gastric acid secretion
and enhances gastric mucosal defense. Antisecretory effect occur at doses of 200ug or
more .The gastric ulcer protective effect of misoprostol appears to plateau between 200ug
bid-tid, but no dose-response effect is apparent in preventing duodenal ulcer.
B) Dosage:
PO for GI protection during NSAID therapy, 200ug qid with food, if this dosage is not
tolerated, and 100-ug qid can be used. Lower-dosage regimens of misoprostol 200 ug tid
or bid appear similar in efficacy and better tolerated for protection against NSAIDinduced gastric and duodenal ulcers than 200 mg qid dosage. Dosage reduction is not
required in renal impairment, hepatic failure, or in the elderly.
Dosage Forms:
1)
Tab 100, 200ug. Misoprostol is also available in combination with diclofenac in
Arthrotec.
Missed Dose:
Take as soon as you remember up to 2 hours late. If more than 2 hours, wait for the next
scheduled dose (don’t double this dose).
C) Pharmacokinetics:
After oral administration, misoprostol is extensively absorbed and rapidly de-esterified to
the active drug, misoprostol acid. Peak serum concentrations of misoprostol acid are
reduced when the drug is taken with food. Plasma protein binding of misoprostol acid
<90%. Misoprostol acid undergoes further metabolism, but approximately 80% is
excreted unchanged in urine.
D) Adverse reactions:
Diarrhea is reported to occur within 2 weeks of initiating therapy in 14-40% of patients
on NSAIDS receiving 800 ug/day, and less frequently with 400-600ug/day. Diarrhea is
usually self-limiting and resolves in about 1 week with inflammatory bowel disease.
Abdominal pain occurs in 13-20% of patients on NSAIDs receiving Misoprostol 800
ug/day. Antacids (except those containing magnesium) may be used for abdominal pain
relief. Nausea, flatulence, headache, dyspepsia, vomiting, and constipation occur
occasionally. Women who receive misoprostol occasionally develop gynecological
disorders including cramping, or vaginal bleeding.
Precautions: It is contraindicated in pregnancy because of high risk of abortion. Warn
patients not to give Misprostol to other. Advise patients receiving concurrent
corticosteroids or anticoagulants, to report bleeding vomiting, severe abdominal pain, and
diarrhea.
E) Drug interactions :
Misprostol does not affect the hepatic cytochrome P450 microsomal enzyme system, nor
does it interfere with the beneficial effects of NSAIDs in rheumatoid arthritis.
Possible Interaction With Other Substances:
Interacts with
Alcohol
Caffeine
Tobacco
Combined effect
Decreases misoprostol effect. Avoid
Decreases misoprostol effect. Avoid
Decreases misoprostol effect. Avoid
F) Patient instructions:
The tablets swallow with liquid .If you can’t swallow whole, crumble tablet and take with
liquid or food. Take on empty stomach mean 1 hour before or 2 hours after eating.
G)Clinical uses:
Prevents development of stomach ulcers in persons taking nonsteroidal, antiinflammatory analgesic (NSAID’s), including asprin.
H)Trade names:
Non proprietary name Preparatory name
Misoprostol
Cytotec®
__________________________________________________Section 5
5.1 The role of Helicobacter Pylori:
A) Introduction:
Associations are now established with chronic atrophic gastritis, peptic ulcer, and
Helicobacter pylori. The organism's effect apparently reflects its ability to induce a
chronic inflammatory response, which can result in gastric or duodenal ulceration and, in
some susceptible individuals, to gastric carcinoma. Helicobacter pylori, whose only
natural host is the human, is restricted mainly to the gastric antral surface, where a
number of specialized virulence (maintenance) factors allow it to flourish, while causing
minimal harm to its host.
B) What are Helicobacter pylori?
Helicobacter pylori (H. pylori) are a spiral-shaped bacterium that is found in the gastric
mucous layer or adherent to the epithelial lining of the stomach. H. Pylori causes more
than 90% of duodenal ulcers and up to 80% of gastric ulcers. He majority of patients
were given long-term medications, such as H2 blockers, and more recently, proton pump
inhibitors, without a chance for permanent cure. These medications relieve ulcer-related
symptoms, heal gastric mucosal inflammation, and may heal the ulcer, but they do NOT
treat the infection. When acid suppression is removed, the majority of ulcers, particularly
those caused by H. pylori, recur. Since we now know that most ulcers are caused by H.
pylori, appropriate antibiotic regimens can successfully eradicate the infection in most
patients, with complete resolution of mucosal inflammation and a minimal chance for
recurrence of ulcers.
Pathogenesis:
Once H. pylori is safely ensconced in the mucus, it is able to fight the stomach acid that
does reach it with an enzyme it possesses called urease. Urease converts urea, of which
there is an abundant supply in the stomach (from saliva and gastric juices), into
bicarbonate and ammonia, which are strong bases. This creates a cloud of acid
neutralizing chemicals around the H. pylori, protecting it from the acid in the stomach.
The reaction of urea hydrolysis (urea is broken down to ammonia and carbon dioxide) is
shown below. This reaction is important for diagnosis of H.pylori by the breath test.
C=O (NH2) 2 + H+ + 2H2O ---urease---> HCO3- + 2(NH4+)
Another defense H. pylori has is that the body's natural defenses cannot reach the
bacterium in the mucus lining of the stomach. The immune system will respond to an H.
pylori infection by sending white cells, killer T cells, and other infection fighting agents.
However, these potential H. pylori eradicators cannot reach the infection, because they
cannot easily get through stomach lining. They do not go away either, though, and the
immune response grows and grows. Polymorphs die, and spill their destructive
compounds (super oxide radicals) on stomach lining cells. Extra nutrients are sent to
reinforce the white cells, and the H. pylori can feed on this. Within a few days, gastritis
and perhaps eventually a peptic ulcer results. It may not be H. pylori itself which causes
peptic ulcer, but the inflammation of the stomach lining; i.e. the response to H. pylori.
C) Prevalence:
The rate of infection increases with age, so it occurs more often in older people. H.pylori
affects about 20% of persons below the age of 40 years, and 50% of those above the age
of 60 years. H.pylori is uncommon in young children. Low social-economic status
predicts H.pylori infection. Immigration is responsible for isolated areas of high
prevalence in some Western countries. In developing countries most adults are infected.
The majority of duodenal ulcers (> 90%) are caused by H.pylori. Non-H. Pylori duodenal
ulceration is generally the result of Zollinger-Ellison (ZE) syndrome or, less often, of
NSAID use. Acquisition occurs in about 10% of children per annum between the ages of
2 and 8 years so that most are infected by their teens.
D) Detection of Helicobacter pylori: [Laboratory Tests]
Who should be tested for H. pylori ?
Persons with active gastric or duodenal ulcers or documented history of ulcers should be
tested for H. pylori, and if found to be infected, they should be treated. To date, there has
been no conclusive evidence that treatment of H. pylori infection in patients with nonulcer dyspepsia is warranted. Testing for and treatment of H. pylori infection are
recommended following resection of early gastric cancer and for low-grade gastric
MALT lymphoma. Retesting after treatment maybe prudent for patients with bleeding or
otherwise complicated peptic ulcer disease. Treatment recommendations for children
have not been formulated. A specialist should evaluate pediatric patients who require
extensive diagnostic work-ups for abdominal symptoms.
Helicobacter pylori can be detected by one of three different tests:
1) Blood tests / Serology (Blood tests such as the enzyme-linked immunosorbent assay
(ELISA) and quick office-based tests identify and measure H. pylori antibodies. The
body produces antibodies against H. pylori in an attempt to fight the bacteria. The
advantages of blood tests are their low cost and availability to doctors. The disadvantage
is the possibility of false positive results in patients previously treated for ulcers since the
levels of H. pylori antibodies fall slowly.
2) Urea- Breath tests (UBT), it measure carbon dioxide in exhaled breath. Patients are
given a substance called urea with carbon to drink. Bacteria break down this urea and the
carbon is absorbed into the blood stream and lungs and exhaled in the breath. By
collecting the breath, doctors can measure this carbon and determine whether H. pylori is
present or absent. Breath tests are highly specific (98%) and very sensitive (95%). They
can indicate eradication of H. pylori 4 weeks after antibiotic treatment, at a time when
antibody tests will still read positive.
3) Saliva Test which is not generally available, rapid tests using salivary and /or gingival
IgG and IgA secretions have been evaluated for detection of H. pylori. Less accurate than
the best serum ELISA methods, these tests may be equal to rapid office tests, are simpler,
and may be particularly appropriate for children
4) The final method of detecting H. pylori by tissue test or what is known as Endoscopy
based test, (a visual exam of the stomach through a thin, lighted, flexible tube), the
physician can remove small bits of tissue from the stomach wall through the tube. The
tissue can then be examined under a microscope for the presence of H. pylori by campy
lobacter-likeorganism (CLO) test. A major advantage of endoscopy is its capacity to
detect also mucosal lesions, such as gastritis and duodenitis
There are three types of test for detection:
1) The rapid urease test detects the enzyme urease, which is produced by H. pylori.
2) A histology test allows the doctor to find and examine the actual bacteria.
3) A culture test involves allowing H. pylori to grow in the tissue sample.
E) Causes of Helicobacter pylori:
H. Pylori are believed to be transmitted orally. Many researchers think that H, pylori is
transmitted orally by means of fecal matter through the ingestion of waste tainted food or
water. In addition, it is possible that H. pylori could be transmitted from the stomach to
the mouth through gastro-esophagal reflux (in which a small amount of the stomach's
contents is involuntarily forced up the esophagus) or belching, common symptoms of
gastritis. The bacterium could then be transmitted through oral contact. Iatrogenic spread
through contaminated endoscopes has been documented but can be prevented by proper
cleaning of equipment.
F) Eradication therapy of Helicobacter Pylori:
The short-term goals of peptic ulcer therapy are to resolve symptoms and heal the ulcer.
The long-term goal is to prevent recurrence, thereby reducing morbidity, mortality, and
health-care cost. With the discovery and elucidation of the causativerole of Helicobacter
pylori in peptic ulcer disease and the development of treatments that eradicate the
organism, the disease can now be cured.
When should H.pylori infection be treated?

All patients with proven gastric or duodenal ulcers who are infected with
H.pylori.

Patients with previously proven recurrent duodenal ulcers who are currently
requiring maintenance anti ulcer therapy.

For management of the small number of peptic ulcers in children a definitive
endoscopic and microbiological diagnosis is advisable.
G) How are H. pylori Peptic Ulcers treated?
H. Pylori peptic ulcers are treated with drugs to kill the bacteria, to reduce stomach acid,
and to protect the stomach lining. Antibiotics are used to kill the bacteria. Treatment
usually involves a combination of antibiotics, acid suppressors, and stomach protectors.

Three-drug regimens that contain a Proton Pump inhibitor plus two antibiotics
may be taken for 7 to 10 days rather than 14days to minimize adverse effects and enhance
compliance, however eradication rates may be lower, especially with the 1-week
regimen.

Four –drug regimens of bismuth subsalicylate, metronidazole, and tetracycline or
amoxicillin and an antisecretory drug are effective and have lower drug cost, but are
associated with a high frequency of adverse effect (up to 70%) and medication noncompliance. Unfortunately, patients may find triple therapy complicated because it
involves taking as many as 20 pills a day. Also, the antibiotics used in triple therapy
may cause mild side effects such as nausea, vomiting, diarrhea, dark stools, and
metallic taste in the mouth, dizziness, headache, and yeast infections in women.
(Most side effects can be treated with medication withdrawal.)

An antisecretory drug should be included when the patient has an active ulcer in
order to provide rapid relief of symptoms and enhance ulcer healing .

Extending antisecretory drug therapy beyond the 7-14 days of antimicrobial
therapy should be considered in ulcer patients with a history of ulcer complication who
remain symptomatic upon cessation of the antimicrobial regimen.

The selection of the eradication regimen should be individualized and based on
efficacy, tolerability, drug interaction potential, antibiotic resistance, cost and the
likelihood of compliance.

Antibiotics should not be used for longer than 2 weeks.
If treatment fails a different antibiotic regimen should be considered.
NOTE that: ampicillin should not be substituted for amoxicillin, doxycycline should
not be substituted for tetracycline, an H2-antagonist should not be substituted for a proton
Pump inhibitor, and bismuth salts should not be interchanged. When eradicating H.pylori,
omeprazole 20 mg and lansoprazole 30 mg are interchangeable.
i. Antimicrobial Monotherapy
Helicobacter pylori are sensitive to a wide variety of antibiotics in vitro, but not in vivo.
Results using single antibiotics have been uniformly disappointing; some antibiotics are
inactivated or destroyed at the acid pH of gastric juice, whereas others, such as the
nitroimidazoles, which should work at low pH, are ineffective as mono therapy because
they induce bacterial resistance. Others suppress but do not eradicate H. pylori.
ii. Triple Antimicrobial Therapy:
Because of metronidazole's propensity to induce resistant organisms, it is combined with
a bismuth compound, which substantially reduces the development of resistance, as well
as exerting a direct toxic effect on the organism. Deposition of bismuth into H. pylori's
outer membranes and within degraded bacteria causes ultra structural damage within
approximately 2hours after dosing with BSS. This triple antibiotic regimen consists of
10 to 14 days of:

BSS two tablets qid

Metronidazole 250 mg qid
The regimen's major disadvantage is the challenge to patient compliance of having to
take 16 pills daily for up to 2 weeks. Tetracycline 500 mg qid.
iii. Antisecretory/Antimicrobial Therapy : Four antisecretory /antimicrobial
regimens designed for both ulcer healing and eradication of H. pylori have been
approved.

Omeprazole plus clarithromycin

Ranitidine bismuth citrate (RBC) plus clarithromycin

Bismuth triple therapy plus ranitidine
 Lanzoprazole plus clarithromycin and amoxicillin.
iv. Omeprazole/Clarithromycin: The inclusion of an acid pump inhibitor offers
the advantage of:

Rapid symptom relief

The highest rate of ulcer healing (87% to 100%).
v. Ranitidine Bismuth Citrate/Clarithromycin : According to the
manufacturer's labeling, the regimen's:

H. pylori eradication rates range from 73% to 84%

Ulcer healing rates are 71% to 75%.

21% in the RBC/clarithromycin group

40% in the clarithromycin only group
 86%, RBC only
vi. Bismuth Triple Therapy/Ranitidine:

At 6 months—4% for the combination; 85% for ranitidine alone

At 12 months—9% vs 95%

At 2 years—12% vs 95%.
This triple therapy/ranitidine regimen is, to date, the least expensive of the approved
antisecretory / antimicrobial combination treatments.
H) Dosage:
Drugs
Dose
Frequency Duration Efficacy
Side
effects
Clarithromycin 500mg
Bid
10-14
Good-
days
excellent
Medium
Metronidazole
500mg
Bid
Omeprazole
20 mg
Bid
Clarithromycin 500mg
Bid
Amoxicillin
1g
Bid
Omeprazole
20 mg
Bid
Amoxicillin
1g
Bid
Metronidazole
500mg
Bid
Omeprazole
20mg
Bid
BSS (bismuth)
525mg
Qid
Metronidazole
250mg
Qid
Tetracycline
500mg
Qid
H2antagonist
Conventional
10-14
Good-
Low-
days
excellent medium
14 days
Good
Medium
14 days
Good-
Medium-
excellent high
ulcer heal
dosage for
28 days
Clarithromycin 500mg
Tid
14 days
Ranitidine
400 mg
Bid
28 days
Clarithromycin 500mg
Tid
14 days
Omeprazole
Qid
Fair –
LOW-
good
medium
Fair-
LOW –
good
medium
Bismuth
chelate
NOTE:
40 mg
Studies has shown Pantroprazole based simple safe triple therapy with clarithromycin
and amoxycillin is more effective than same omeprazole based Triple therapy in H-pylori
Eradication, and with appropriate antibiotics is more effective than the quadruple therapy
containing Ranitidine, Bismuth and Antibiotic in the Eradication of H-pylori and Healing
of Ulcers. Pantoprazole raises the pH  5 for 14.43 hr, and enhances antibiotic efficacy at
stable pH  5.Drug interactions with pantoprazole are negligible therefore it can be used
instead of omeprazole.
I) Patient Instructions:
Patient should be instructed to take all their medication (except PPIs) with meals and at
bed time (if necessary) , PPIs should be taken prior to eating and a full glass of water
should be taken to reduce the potential risk of esophageal irritation and ulceration that
may be induced by tetracycline.
J) What illness does H.pylori cause ?
Most persons who are infected with H. pylori never suffer any symptoms related to the
infection; however, H. pylori cause chronic active, chronic persistent, and atrophic
gastritis in adults and children. Infection with H.pylori also causes duodenal and gastric
ulcers. Infected persons have a 2- to 6-fold increased risk of developing gastric cancer
and mucosal-associated-lymphoid-type (MALT) lymphoma compared
with their uninfected counterparts. The role of H. pylori in non-ulcer dyspepsia remains
unclear.
Long-term consequences of H. pylori infection: Recent studies have shown an
association between long-term infection with H. pylori and the development of gastric
cancer. Gastric cancer is the second most common cancer worldwide; it is most common
in countries such as Columbia
How to prevent H. pylori infection : Since the source of H. pylori is not yet
known, recommendations for Avoiding infection has not been made. In general, it is
always wise for Persons to wash hands thoroughly, to eat food that has been properly
Prepared, and to drink water from a safe, clean source. We now know that nine out of ten
peptic ulcers are caused by an infection with the bacterium, Helicobacter pylori and not
by stress or spicy foods as previously thought. Curing the infection with antibiotics
shortens ulcer-healing time and significantly reduces the ulcer recurrence rate compared
with traditional ulcer therapies such as acid-reduce in medications. H. Pylori infection
can usually be cured with a two-week regimen of antibiotics. In more than 80 percent of
patients, the ulcer is cured and does not recur.
___________________________________________________Section 6
Future Directions:
Three new approaches to prevention and treatment of H. pylori are currently being
studied:

An oral vaccine composed of recombinant urease and Escherichia coli heat-labile
toxin as a mucosal adjuvant, which has demonstrated both prophylactic and
therapeutic qualities against Helicobacter felis in mice.

A potential vaccine using recombinant heat-shock protein, another H. pylori
antigen, which when fed to mice protected them against challenge with H. felis.

An orally administered, naturally occurring carbohydrate that mimics epithelial
bacterial adhesion ligands, thus inhibiting and reversing the adherence of H.
pylori organisms to gastric epithelial cells, currently in a phase II clinical trial.
The discovery of H. pylori as a gastrointestinal pathogen has had a profound effect on
current concepts of peptic ulcer disease pathogenesis. Evidence presented led to the
following conclusions:

Ulcer patients with H. pylori infection require treatment with antimicrobial agents
in addition to antisecretory drugs whether on first presentation with the illness or on
recurrence.

The value of treatment of nonulcer dyspepsia patients with H. pylori infection
remains to be determined.

The interesting relationship between H. pylori infection and gastric cancers
requires further exploration.
___________________________________________________Section 7
Conclusion
I conclude that a patient with PUD , should first undergo symptomatic treatment and then
if , symptoms still persist then the underlying cause should be noted , by further
investigations. Should also , state whether the ulcer is benign or malignant and avoid
any of the aggressive factors which induces the peptic ulcer disease .If after and
endoscopic investigation and outcome was that patient has Helicobacter pylori infection
then a triple therapy would be an appropriate and effective treatment.
Biography
References:




Basic Pathology 6th edition by Kumar ,Robbins and Cotran.
Basic and Clincal Pharmacology by Katzung.
BNF 39 March 2000
Handbook Gastroenterology (international diagnostic review)
 Drugs of Today , Prous science
 Drug facts and comparisons
 Clinical drug data