Anti-secretory & Anti-ulcer Agents

Dr. Vinod Tiwari

IIT (BHU), Varanasi
Email: vtiwari.phe@iitbhu.ac.in
 Clinical Manifestations of
Gastric Ulcer

 Epigastric burning or aching pain

 Episodes of remission and exacerbation
 Nausea, vomiting, bloating, and weight loss occur
 Erosions followed by perforation in GIT
 G.I. bleeding and possible hemorrhage (20 to 25% of
patients)
 The mortality rate among the elderly patients undergoing
surgery for perforated PU is as high as 12-47%
 Stomach

 Plays a pivotal role in the digestion of foods that we eat

 Releases gastric juice (including hydrochloric acid, pepsin,
and bile salts) required for digestion of food
 This organ can resist to a large variety of noxious factors:
hydrochloric acid, refluxed bile salts, alcohol, and wide
range of temperatures and osmolality
 This high resistance is provided by mucosal lining of the
stomach and its ability to quickly repair on damage
 Peptic Ulcer Disease (PUD)
Definition
Peptic ulcers: are chronic lesions that occur in any portion of
the gastrointestinal tract and occurs as a result of breaching of
the mucosal layer due to aggressive action of acid-peptic juices
Peptic ulcers are produced by an imbalance between the
Aggressive and Protective factors in the GIT
 Aggressive factors: Gastric HCl, Pepsin, H. Pylori,
NSAIDS, Smoking
Protective factors: gastro-intestinal mucosa, PG’s,
Bicarbonate
 Anatomy of Stomach

Gastric ulcer: the

ulcer that occurs in the
stomach lining
Duodenal ulcer: most
often seen in first portion
of duodenum (>95%)
 Physiology of gastric acid secretion

Gastrin-expressing cells (G cells); Enterochromaffin-like cells (ECL cells);

Parietal cells; Somatostatin (SST) cells
 Pepsin & Pepsinogen

 Hyperacidity in the stomach is one of the essential

factor for gastric ulcer to occur
 Pepsinogen is activated to pepsin in presence of HCl
and a pH of 2 to 3
 Secreted HCl by parietal cells has a pH of 0.8
 pH reaches 2 to 3 after mixing with stomach contents
 At pH level 3.5 or more, stomach acid is neutralized (At
this pH, pepsin has little or no proteolytic activity)
 Gastric Mucosa

 Surface mucosa of stomach is renewed about every 3

days
 Mucosa can continually repair itself except in extreme
instances
 Mucosal barrier prevents back diffusion of acid from gastric
lumen through mucosal layers to underlying tissue
 If this mucosal barrier is impaired, back diffusion can occur
Erosion of Mucosal Barrier
Peptic ulcer disease
Etiology of PUD

A) Normal
B) Increased Attack
*Hyperacidity
*Pepsin
*NSAIDs
C) Weak defense
*Helicobacter pylori
*Stress, drugs, smoking
 Mucosal defense mechanisms:
Protective Forces

 Bicarbonate secretion
 Mucous secretion
 Tight adherence between epithelial cells to prevent any
acid leakage to the inside
 Good blood supply to the mucosa
 Renewal of damaged epithelial cells
Imbalance between protective vs
hostile factors
Protective factors vs. hostile factors
 Causes of Peptic Ulcer

The causes of peptic ulcer disease include the following:

1) Infection with the bacteria Helicobacter pylori: occurs in 80 to 95% of
patients with peptic ulcer disease. H. pylori infection impairs the protective
mechanisms of the G.I. tract against low pH and digestive enzymes and
leads to ulceration of the mucosa.
2) Stress: Emotional, trauma, surgical (leads to Increase acidity)
3) Injury or death of mucus-producing cells (Foveolar cells)
4) Excess acid production in the stomach: The hormone gastrin stimulates
the production of acid in the stomach; therefore, any factors that increase
gastrin production will in turn increase the production of stomach acid.
5) Drugs: Chronic use of aspirins and NSAIDs, or Corticosteroids
 Helicobacter pylori

 Most common infection in the world (20%) No acid

 10% of men, 4% women develop PUD No ulcer
 Positive in 70-100% of PUD patients
OLD TESTAMENT

No HP No ulcer

NEW TESTAMENT
 Helicobacter pylori
 Gram negative, Spiral bacilli
 Do not invade cells – only mucous
 Breakdown urea - ammonia
 Break down mucosal defense
 Chronic Superficial inflammation
 Role of H. Pylori infection in the
pathogenesis of peptic ulcer

H. pylori infection is present in almost all patients with

duodenal ulcers and 70% of cases with gastric ulcers.
Mechanism:
1. H. pylori secretes urease (generates ammonia) & protease
(breaks down glycoprotein in the gastric mucus)
2. Bacterial lipopolysaccharide attracts inflammatory cells
to the mucosa
3. Inflammation of the gastric mucosa
4. Chronically inflamed mucosa more susceptible to acid-
peptic injury and prone to peptic ulceration
 Classification of drugs used in Peptic Ulcer

A. Drugs that inhibit gastric acid secretion

1) Proton pump inhibitors: Omeprazole, Esomeprazole,
lansoprazole, Pantoprazole, Rabeprazole.
2) H2-receptor antagonists: Cimetidine, Ranitidine,
Famotidine, Roxatidine, Nizatidine
3) Antimuscarinic agents (anticholinergics): Pirenzepine,
Telenzepine, Propanthelin, Oxyphenonium.
4) Prostaglandin analogues: Misoprostol, Enprostil.
 Classification of drugs used in Peptic Ulcer

B. Drugs that neutralize gastric acid (Antacids): Sodium

bicarbonate, Sodium citrate and Aluminum hydroxide.
C. Ulcer protective: Sucralfate, and bismuth subcitrate (CBS)
D. Anti- H. pylori drugs: Amoxicillin, Tetracycline, Clarithromycin,
Metronidazole, Tinidazole
 Proton pump inhibitors: Omeprazole

It is a powerful inhibitor of gastric acid and can totally abolish HCL

secretion, both resting as well as that stimulated by food or
secretagogues, without much effect on pepsin, intrinsic factor, juice
volume and gastric motility.
Mechanism of action: Omeprazole is inactive at neutral pH, but at
pH< 5 it rearranges to two charged cationic forms ( a sulphenic acid
and a sulphenamide configurations) that react covalently with SH
groups of the H+ K+ ATPase enzyme
 H2 Antagonists

Discovery and development of histamine H2-blocking drugs by

Black and his colleagues in 1972 was a major breakthrough in the
treatment of gastric ulcers.
These are first class of highly effective drugs for acid-peptic disease,
but have been surpassed by PPIs.
Pharmacological actions
Cimetidine and all other H2 antagonists block histamine – induced
gastric secretion.
 Drugs that protect the mucosa

Colloidal Bismuth subcitrate: It is a colloidal bismuth compound,

water soluble but precipitates at pH < 5. Heals 60% ulcers at 4
weeks and 80-90% ulcers at 8 weeks.
Mechanism of action:
1. Increase gastric mucosal PGE2, mucus and HCO3 production.
2. Precipitate mucus glycoproteins and coat the ulcer base.
3. Detach and inhibit H. Pylori directly.
 Drugs that protect the mucosa

Sucralfate: is a basic aluminium salt of sulfated sucrose.

Mechanism of action: It polymerizes at pH < 4 by cross linking of
molecules, assuming a sticky gel like consistency.
It preferentially and strongly adheres to ulcer base, especially
duodenal ulcer and has been seen endoscopically that it remain
there for around 6 hrs.
It acts as a physical barrier preventing acid, pepsin and bile from
coming in contact with the ulcer base.
 Prostaglandin Analogue

Mechanism of action: PGE2 and PGI2 are produced in gastric mucosa

and appear to serve a protective role by inhibiting acid secretion and
promoting mucus as well as HCO3 secretion. In addition, PG inhibits
gastrin release & increase mucosal blood flow.
As compare to natural PG, Misoprostol (methyl-PGE1 ester) is a
longer acting synthetic PGE1 derivative which inhibits acid output
dose dependently.
Side effects: Diarrhoea, abdominal cramps, uterine bleeding, abortion
and need for multiple daily doses.
 Antacids
Substances which neutralize the gastric acid and raise pH of
gastric contents. Peptic activity is indirectly reduced if the pH
rises above 4, because pepsin is always secreted as a complex to
get it activated it need pH below 4-5. Optimum peptic activity
can be seen between pH 2 – 4.
 Antacids

Sodium Bicarbonate: Water soluble, acts instantaneously but the

duration of action is short.
It is a potent neutralizer and pH may rise above 7. However it has
several demerits
a) Produces CO2 in stomach leads to discomfort & belching
b) Increases sodium load: may worsen edema and CHF.
 Anti H. Pylori drugs
Antimicrobials that are used against H. Pylori infection are:
Amoxilcillin, clarithromycin, tetracycline and metronidazole.
Resistance develop rapidly, especially to
metronidazole/tinidazole and clarithromycin but amoxicillin
resistance has not been found.
Acid suppression by PPIs/H2 blockers enhances effectiveness of
anti-H. Pylori antibiotics and optimum benefits are obtained
when gastric pH is kept > 5 for at least 16-18 hrs per day.
Thank You