ANTIULCER DRUGS

WHAT IS ULCER??

Ulcer is a local defect or erosion of the surface of an organ/tissue produced by sloughing of

necrotic inflammatory tissue.

TYPES:

• Gastric ulcers: In Stomach

Peptic
• Duodenal Ulcers: In Duodenum Ulcers

• NSAID’s Induced ulcers: Due to decreased PG’s

• Zollinger Ellison Syndrome: Gastrin Tumor

• GERD: Gastro esophageal reflux disorder

• Due to Helicobacter pylori infections

INNERVATIONS AND HORMONES OF GIT:

I. Neuronal Control: Myenteric Plexus and Sub Mucous Plexus

II. Hormonal Control: Endocrine- Gastrin, Cholecystokinin (CCK)

Exocrine- HCl and Intrinsic Factor (IF)
Paracrine- Histamine and Somatostatin

VARIOUS GASTRIC SECRETIONS:

1. Chief cells - Prorenin or Pepsinogen
2. Parietal cells or Oxyntocic cells – HCl and Intrinsic Factor
3. Mucus Secreting cells- Mucus and HCO3- ions

Protecting Factors Damaging Factors

• Mucous • ACID
• HCO3- ions • PEPSIN
• Prostaglandin E2 & I2
• NO
• Somatostatin

GENESIS OF PEPTIC ULCERS:

1. Imbalance between the protective
factors and the damaging factors.
2. Infection due to H. pylori
infections.
STIMULI ACTING ON PARIETAL CELLS

1. GASTRIN (Stimulatory hormone)

2. ACETYLCHOLINE (Stimulatory NT)

3. HISTAMINE (Stimulatory local hormone)

4. PROSTAGLANDINS E2 & I2 (Inhibit acid secretion)

GASTRIN

• Is a peptide hormone synthesised in endocrine cells of the mucosa of the gastric

antrum and duodenum.

• Stimulation of the secretion of acid by the parietal cells.

• Also indirectly increases Pepsinogen secretion, stimulates blood flow and increases
gastric motility.

ACETYLCHOLINE

• Released from (e.g. vagal) neurons and stimulates specific muscarinic receptors on
the surface of the parietal cells and on the surface of histamine-containing cells.

HISTAMINE

• Acts on parietal cell H2 receptors

DRUGS USED TO INHIBIT OR NEUTRALISE GASTRIC ACID SECRETION

ANTACIDS

• These are used for symptomatic relief only.

• They directly neutralize acid, thus raising the gastric pH.

• Sufficient quantity for long enough, they can produce healing of duodenal ulcers but
are less effective for gastric ulcers.

• Mg2+ Salts- Diarrhoea

Mixtu
Al3+ Salts- Constipation re
• Magnesium hydroxide is an insoluble powder that forms magnesium chloride in
 the stomach. It does not produce systemic alkalosis, because Mg2+ is poorly absorbed
from the gut. Another salt, magnesium trisilicate, is an insoluble powder that reacts
slowly with the gastric juice, forming magnesium chloride and colloidal silica. This
agent has a prolonged antacid effect, and it also adsorbs pepsin.

• Aluminium hydroxide gel forms aluminium chloride in the stomach; when this
reaches the intestine, the chloride is released and is reabsorbed. Aluminium hydroxide
raises the pH of the gastric juice to about 4, and also adsorbs pepsin. Its action is
gradual, and its effect continues for several hours.

• Alginates or simeticone are sometimes combined with antacids. The former are
believed to increase the viscosity and adherence of mucus to the oesophageal mucosa,
forming a protective barrier (see also below), whereas the latter is a surface active
compound that, by preventing 'foaming', can relieve bloating and flatulence.

Clinical Uses:-

1. Dyspepsia
2. Symptomatic relief in peptic ulcer or (alginate) esophageal reflux.

HISTAMINE H2 RECEPTOR ANTAGONISTS

• Drugs in clinical use are Cimetidine, Ranitidine, Famotidine, and Nizatidine.

Pharmacokinetics:

• Cimetidine, Ranitidine, Famotidine undergo first pass hepatic metabolism resulting in

a bioavailability of about 50%.

• These are cleared by combination of hepatic metabolism, glomerular filtration and

renal tubular secretion.

• Orally well absorbed, i.v preparations are also available.

Pharmacodynamics:

• The histamine H2 receptor antagonists competitively inhibit histamine actions at all H2

receptors, but their main clinical use is as inhibitors of gastric acid secretion.

• Suppress basal and meal stimulated acid secretion. Pepsin secretion also falls with the
reduction in volume of gastric juice.

• They can inhibit histamine-, Gastrin- and acetylcholine-stimulated acid secretion.

 • H2 antagonists are especially effective at inhibiting Nocturnal acid secretion (which
mainly depends on Histamine), also have modest impact on meal stimulated acid
secretion.

• These are given twice daily, and duration of acid inhibition is less than 6hrs.

Clinical Uses:

1. GERD

2. Peptic Ulcer Disease

3. Nonulcer Dyspepsia

4. Prevention of bleeding from stress related gastritis

Adverse Effects:

1. Fatigue, Myalgia’s, Diarrhoea, dizziness, alopecia, transient rashes and

hypergastrinaemia have been reported.

2. Cimetidine inhibits

• binding of dihydrotestosterone to androgen receptors

• metabolism of estradiol

• increases serum prolactin levels

so when used for long duration or in high doses causes gynecomastia & impotence in men
and galactorrhes in women.

3. Blockade of cardiac H2 receptors may cause bradycardia & hypotension. (Rapid i.v
infusion)

4. Cimetidine also inhibits cytochrome P450, and can retard the metabolism (and thus
potentiate the action) of a range of drugs including oral anticoagulants and tricyclic
antidepressants. It can cause confusion in the elderly.

PROTON PUMP INHIBITORS

• Drugs in clinical use are Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole and

Esomeprazole.
• These are substituted Benzimidazoles.

Pharmacokinetics:

• Oral administration is the most common route of administration.

 • Omeprazole is given orally, but as it degrades rapidly at low pH it is
administered as capsules containing enteric-coated granules.

• It is absorbed and, from the blood, passes into the parietal cells and then into the
canaliculi. Although its half-life is about 1 hour, a single daily dose affects acid
secretion for 2-3 days.

Pharmacodynamics:

• Irreversibly inhibits the H+/K+ ATPase (the proton pump), inhibit both fasting and
meal stimulated secretion because they block the terminal step in the acid
secretory pathway, the proton pump.

Clinical Uses:

1. GERD

2. Peptic Ulcer Disease- H.pylori associated ulcers, NSAID’s associated ulcers,

prevention of rebleeding from peptic ulcers

3. Nonulcer Dyspepsia

4. Prevention of stress related mucosal bleeding

5. Gastrinoma and other Hypersecretory conditions

Adverse Effects:

• These are usually safe. Diarrhea, headache and abdominal pain are seen.
Somnolence, mental confusion, impotence, gynaecomastia, and pain in muscles
and joints have been reported.

• Acid is important in releasing vitamin B12 from food. Minor reduction in oral
Cyanocobalamin absorption occurs during PPI, leading to subnormal B12 levels
with prolonged therapy.

Drug Interactions:

• Omeprazole may inhibit metabolism of warfarin, diazepam and phenytoin.

• Esomeprazole may decrease metabolism of diazepam.

• Lansoprazole may enhance the clearance of theophylline.

 MUCOSAL PROTECTIVE AGENTS

SUCRALFATE

Pharmacokinetics:

• Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide. In

water or acidic solutions it forms a viscous, tenacious paste that binds selectively
to ulcers or erosions for up to 6 hours.

Pharmacodynamics:

• It is believed that the negatively charged sucrose sulfate binds to positively

charged proteins in the base of ulcers or erosion, forming a physical barrier that
restricts further caustic damage and stimulates mucosal prostaglandin and
bicarbonate secretion.

Clinical Uses:

• Sucralfate is administered in a dosage of 1 g four times daily on an empty stomach

(at least 1 hour before meals).

• Sucralfate (administered as a slurry through a nasogastric tube) reduces the

incidence of clinically significant upper gastrointestinal bleeding in critically ill
patients hospitalized in the intensive care unit

• Used for prevention of stress-related bleeding.

Adverse Effects:

• Constipation occurs in 2% of patients due to the aluminum salt.

• Should not be used for prolonged periods in patients with renal insufficiency.

PROSTAGLANDIN ANALOGS

Pharmacokinetics:

• Misoprostol, a methyl analog of PGE1, has been approved for gastrointestinal

conditions.

• Following oral administration, it is rapidly absorbed and metabolized to a

metabolically active free acid.
 • The serum half-life is less than 30 minutes; hence, it must be administered 3–4
times daily. It is excreted in the urine.

Pharmacodynamics:

• Misoprostol has both acid inhibitory and mucosal protective properties. It is

believed to stimulate mucus and bicarbonate secretion and enhance mucosal blood
flow.

• In addition, it binds to a prostaglandin receptor on parietal cells, reducing

histamine-stimulated cAMP production and causing modest acid inhibition.

Clinical Uses:

• Misoprostol reduces the incidence of NSAID-induced ulcers to less than 3% and

the incidence of ulcer complications by 50%. It is approved for prevention of
NSAID-induced ulcers in high-risk patients

Adverse Effects:

• Diarrhea and cramping abdominal pain occurs in 10–20% of patients.

• Misoprostol stimulates uterine contractions (see Chapter 18), it should not be used
during pregnancy or in women of childbearing potential unless they have a
negative serum pregnancy test and are compliant with effective contraceptive
measures. No significant drug interactions are reported.

COLLOIDAL BISMUTH COMPOUNDS

Pharmacokinetics:

• Bismuth subsalicylate

• Bismuth subcitrate, Tripotassium dicitratobismuthate and Bismuth dinitrate

are also available.

• Bismuth is absorbed, it is stored in many tissues and has slow renal excretion.

Pharmacodynamics:

• Bismuth probably coats ulcers and erosions, creating a protective layer against
acid and pepsin. It may also stimulate prostaglandin, mucus, and bicarbonate
secretion.
 • Bismuth has direct antimicrobial effects and binds enterotoxins, accounting for its
benefit in preventing and treating traveler's diarrhea. Bismuth compounds have
direct antimicrobial activity against H pylori.

Clinical Uses:

• For the nonspecific treatment of dyspepsia and acute diarrhea.

• Bismuth compounds have been used in multidrug regimens for the eradication of
H pylori infection.

Adverse Effects:

• All bismuth formulations have an excellent safety profile.

• Bismuth causes blackening of the stool, which may be confused with

gastrointestinal bleeding.

• Liquid formulations may cause harmless darkening of the tongue.

• Bismuth agents should be used for short periods only and should be avoided in
patients with renal insufficiency.

• Prolonged usage of some bismuth compounds may rarely lead to bismuth

toxicity, resulting in encephalopathy (ataxia, headaches, confusion, seizures).