CYTOPROTECTIVE AGENTS

IN
PEPTIC ULCER DISEASE
Moderator – Dr. Sunita Gupta(Professor)
Presenter – Dr. Gaurav Singh(PGY2)

Department of General Medicine, MMIMSR

ANATOMY & DEFINITION

ULCER is disruption in mucosal integrity till Muscularis Mucosa

layer. It involves all the layers of mucosa.
Whereas an erosion is called when only upper layers of mucosa is
involved. It is a partial thickness defect.(surface epithelium and
lamina propria)
Blood vessels are in submucosal layer and hence dreadful
complication of bleeding exist in case of ulcer.
PHYSIOLOGY OF ACID SECRETION
 PEPTIC ULCER
 Peptic ulcers are defects in the gastric or duodenal mucosa that
extend through the muscularis mucosa layer of mucosa.

 The superficial portion of the gastric and duodenal mucosa exists

in the form of a gel layer, which is impermeable to acid and
pepsin. Some gastric and duodenal cells secrete bicarbonate,
which aids in buffering acid that lies near the mucosa.
Prostaglandins E (PGE) have protective role, because PGE increases
the production of both bicarbonate and the mucous layer.
 The defensive mechanisms include tight intercellular junctions,
mucus, bicarbonate, mucosal blood flow, cellular restitution, and
epithelial renewal.
 Aggressive factors, such as nonsteroidal anti-inflammatory drugs
(NSAIDs), H pylori infection, alcohol, bile salts, acid, and pepsin,
can alter the mucosal defense by allowing back diffusion of
hydrogen ions and subsequent epithelial cell injury.
ETIOLOGY OF PEPTIC ULCER
1. H.Pylori infection
2. Severe Physiological Stress(SRMD)
3. Drugs – NSAIDs, Aspirin, Corticosteroids,
Bisphosphonates, Chemotherapeutic
agents, potassium supplements.
4. Lifestyle factors – SMOKING AND ALCOHOL
5. Raised Intracerebral pressures.
6. Hypersecretory states
7. Genetic factors
8. Comorbid Illnesses like anemia, depression
 ETIOLOGY OF PEPTIC ULCER
 H PYLORI INFECTION - The prevalence is as high as 80% in some parts
of India. It’s most common manifestation is peptic ulcer disease,
particularly duodenal ulcer, which outnumbers gastric ulcers ratio
being between 8:1 and 30:1.
PATHOPHYSIOLOGY- Tumor necrosis factor alpha and specific products
of H. pylori, such as ammonia, release gastrin from G cells. It also
diminishes mucosal expression of somatostatin.

 SEVERE PHYSIOLOGIC STRESS – Stress Related Mucosal Disease(SRMD)

seen in patients who are in critical care settings(ICCU, CCU, POST-OP)
PATHOPHYSIOLOGY are –
a) Shock-induced reduction in gastro-intestinal blood flow, causing
mucosal ischemia and reperfusion injury(ROS), resulting in necrosis
of the apical mucosal cells.
b) Increased gastric acidity (increased histamine release, vagal
stimulation and increased production of glucocorticoids),
c) Changes in the mucosal barrier (e.g. gastro-duodenal reflux).
 ETIOLOGY OF PEPTIC ULCER
 DRUGS – NSAIDs As many as 30% of adults taking NSAIDs have GI
adverse effects which also includes peptic ulcer.
Mechanism - Inhibition of COX in the gastrointestinal tract leads
to a reduction of prostaglandin secretion.

 LIFESTYLE FACTORS –
SMOKING - reduces gastric mucosal blood flow
ALCOHOL(ethanol) lowers antioxidant levels by increasing purine
degradation that leads to increased O2- radical production and
ROS-mediated increased lipid peroxidation.

 RAISED INTRACEREBRAL PRESSURES - Brain tumors, traumatic

head injury, infections etc can cause increased intracranial
pressure and lead to overstimulation of the vagus nerve, resulting
in increased secretion of gastric acid may occur which leads to
gastro-duodenal ulcer formation known as Cushing's ulcer.
 DEFINITION OF CYTOPROTECTION
 Cytoprotection is defined as ability of a
pharmacological agent to provide protection
to cells against harmful agents.

 It’s types are –

1. Gastroprotection (Today’s topic)

2. Chemoprotection
3. Cardioprotection
4. Neuroprotection
5. Hepatoprotection
MECHANISMS OF GASTROPROTECTION
1) Increase MUCUS production
2) Increase BLOOD FLOW throughout the lining of
the gastrointestinal tract.
3) Increase BICARBONATE secretion
4) Forming a COATING that protects the ulcerated
tissue
5) Decrease gastric MOTILITY
6) Scavenging of FREE RADICALS
7) Decrease release of endogenous mediators of
gastric injury
8) Stimulation of cellular growth and repair
GASTROPROTECTIVE AGENTS
1. Sucralfate
2. PGE analogues like Misoprostol
3. Colloidal bismuth subcitrate
4. Rebamipide (NEW)
5. Carbenoxolone(NEW)
6. Nocloprost (obsolete)
7. Triletide(obsolete)
 SUCRALFATE
 It is Aluminium salt of sulfated sucrose.
 MOA - polymerizes at pH < 4(no antacids) by cross linking of molecules
and strongly adheres to ulcer base for around 6 hours and acts as
physical barrier to ulcer from acid, pepsin, bile.
 Also inhibit hydrolysis of mucosal proteins
 Stimulation of local production of PGs and EGF.

INDICATIONS AND DOSE –

Duodenal Ulcer -1 g PO q6hr initially;

followed by 1 g PO q12hr as
maintenance

Take on empty stomach 1 hour before

or 2 hours after meals

Stress Ulcer (Off-label) Prophylaxis -

1 g PO q6hr for 4-8 weeks
 ADR -Constipation (2%), hypophosphatemia, dry mouth,
hyperglycemia.
 Absorption - 5% (sucralfate is considered nonsystemic); sucrose
octasulfate, 5%; aluminum, 0.005%
 Onset: 1-2 hr
 Duration: Up to 6 hr
 Do not take antacids within 30 minutes of sucralfate dose
 CAUTIONS - Aluminum absorption is increased; so use with
caution in patients with CRF or on dialysis
Sucralfate will decrease the level/effect of digoxin by inhibition
of GI absorption. Applies only to oral form. Use Alternate Drug
or measure serum digoxin concentrations before initiating
concomitant drugs; continue monitoring and increase digoxin
dose by approximately 20% to 40% as necessary
 MISOPROSTOL (RX)
 Synthetic prostaglandin E1 analogue parent drug that is rapidly
deesterified to misoprostol acid (active metabolite) and replaces
protective prostaglandins consumed with therapies that inhibit
prostaglandin synthesis.
 Mechanism of Action –
1) Decreases intracellular cAMP and gastric acid secretion
2) Stimulation of mucin and bicarbonate secretion
3) Increase mucosal blood flow
4) Also reduces NSAID induced mucosal damage
 CAUTION - Significantly reduces degree of fat malabsorption in
patients with >10% fat malabsorption(duodenal bicarbonate
production), PREGNANCY (Category X)
 Absorption
 Onset: 2-3 hr (initial response for acid secretion)
 Duration: ≥3 hr (inhibition of acid secretion)
 Peak plasma time: Misoprostol acid (active metabolite), 14 min
 Indications and Dose –
1. NSAID-Induced Ulcer Prophylaxis -
200 mcg PO q6hr with food; may be decreased to 100 mcg
q6hr; last dose to be administered at bedtime. Should take
therapy for duration of therapy.
2. Stress Ulcer Prophylaxis (Off-label) -100-200 mcg PO q4-6hr

ADR -Diarrhea (14-40%), Abdominal pain (13-20%), Headache

(2%).

 Antacids reduce the bioavailability of misoprostol acid.

Magnesium-containing antacids may potentiate misoprostol-
induced diarrhea. If an antacid is needs, use an aluminum- or
calcium- containing antacids.
 Pregnancy category: X
REBAMIPIDE
 It is amino acid analogue of 2 quinolinone.

 Mechanism of action –
1. Increase gastric concentration of PGE2
2. Increase mucosal blood flow through enhanced
NO synthase activity
3. Free radical scavenging effect on ROS
4. Replacement of lost tissue through increased
expression of EGF and EGF receptors
5. Increase COX-2 by increasing gene expression
 INDICATIONS AND DOSE –
Gastric ulcers and Acute Gastritis
Dose – 100mg TDS
Duration – 4 to 8 weeks

Pharmacokinetics –
Good oral absorption, hepatic metabolism(CYP450),
very low drug interactions
ADR – constipation, bloating, diarrhoea, nausea and
vomiting

Price – 300 INR for 10 tablets, per day 100INR

COLLOIDAL BISMUTH
SUBCITRATE
CARBENOXOLONE
 Obtained from Glycyrrhiza(licorice)
 Structure similar to steroid
 Under research for cancer, metastasis

 Mechanism of Action –
1) Increase synthesis of Prostaglandins
2) Increase gastric mucous secretion
3) Decrease exfoliation and increase half life of gastric mucosal
cells
ADR – Mineralocorticoid like action(fluid retention, hypokalemia)
POLAPREZINC
 Triletide
 nocloprost
GINGKO BILOBA
 Duodenal ulcer rats without ginkgo significantly
decreased superoxide dismutase activity in the
duodenal mucosa and erythrocytes
 Duodenal ulcer rats without ginkgo significantly
increased plasma lipid peroxides.
 Ginkgo biloba extract can improve weight gain and
mucosal healing in duodenal ulcer rats by the actions of
cytoprotection and antioxidation.
CORCHORUS CAPSULARIS L. LEAVES

 The serum lipid parameters in ECC groups revealed

significant increase in glutathione peroxidase (GPx),
superoxide dilmutase (SOD) and catalase (CAT), and a
decrease in malondialdehyde (MDA). Significant
amelioration on pathological lesion score was found in
ECC groups compared with the control group (P<0.05).
The overall results indicate that ECC has protective
effects on ethanol-induced AGML in rats, which could be
associated with its antioxidant activity.
THANK YOU