TREATMENT OF PEPTIC ULCERS

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TREATMENT OF PEPTIC ULCERS CONTROL OF GASTRIC
ACIDITY
Prof. Riad Agbaria
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Microscopic Anatomy of the Stomach
Four secretory epithelial cells 1- Mucous
cells secrete an alkaline mucus that protects
the epithelium against shear stress and acid2-
Parietal cells secrete hydrochloric acid!3-
Chief cells secrete pepsin, a proteolytic
enzyme4- G cells secrete the hormone
gastrin 5-Entrochromaffin-Like Cells (ECL)-
HISTAMINE
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Physiological and pharmacological regulation of
gastric secretions the basis for therapy of
peptic ulcer disease.
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Physiological stimulants of gastric acid
secretion
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Physiological stimulants of gastric acid
secretion

• Major physiologic stimulus food intake -- three
  phases
• cephalic phase
• gastric acid secretion responds to anticipation
  of food, sight, smell, taste
• gastric phase
• stimulation of mechanical and chemical gastric
  wall receptors by luminal contents.
• intestinal phase
• gastrin release (small amount) release of other
  peptides that stimulate gastric acid secretion

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• Food constituents
• Coffee (both caffeine containing and caffeine
  free) stimulates gastric acid secretion by
  stimulating gastric release
• Beer and wine stimulation of gastric acid
  secretion

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Physiologic inhibition- gastric acid release

• Factors that inhibit gastric acid secretion
  include
• hyperglycemia
• hypertonic fluids
• duodenal fat
• duodenal acid
• intragastric pH 3 partial inhibition
• intragastric pH lt or 1.5 complete blockade of
  gastrin release

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• Basolateral parietal cells membranes contain
  receptors for
• histamine-- stimulation gastric acid secretion
• gastrin-- stimulation gastric acid secretion
• acetylcholine-- stimulation gastric acid
  secretion
• prostaglandins --inhibition of gastric acid
  secretion
• somatostatin -- inhibition of gastric acid
  secretion

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Peptic Ulcer Disease
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Pathogenic Factors Peptic ulcer disease

• Peptic ulcer disease an imbalance between
  aggressive factors (gastric acid and pepsin) and
  protective factors (gastric mucus, bicarbonate,
  prostaglandins)

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Role of pepsin in peptic ulcer disease

• Secreted gastric acid plus effects of pepsin
  promote tissue injury
• Gastric acid promotes cleavage of pepsinogen
  (inactive) to proteolytically-active pepsins
• Pepsinogen classification
• Direct correlation between pepsinogen I serum
  concentrations and maximal gastric acid secretion
  

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Pharmacological Management of Ulcer Disease
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Pharmacological Management of Ulcer Disease

• Overview
• Peptic ulcer stomach or duodenal mucosal lesion
  -- acid and pepsin major pathogenic roles
• Classification of peptic ulcer
• Duodenal (DU)
• Gastric (GU)
• Major causative factor bacterium Helicobacter
  pylori
•  Helicobacter pylori risk factor for
• gastric cancer
• certain types of gastric lymphoma

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Gastric Physiology

• Gastric mucosa acid secretion
• Oxidative phosphorylation dependent secretion by
  parietal cells.
• Parietal cells found in mucosal glands
• of the body and fundus of the stomach.

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Regulation of gastric acid secretion

• Many factors chemical, neural, hormonal
• stimulation
• Gastrin-most potent stimulant
•  Activation of postganglionic vagal fibers
  (muscarinic cholinergic parietal cells receptor
  activation)

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1 Proton Pump Inhibitors
The most effective suppressors of gastric acid
secretion
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Physiological and pharmacological regulation of
gastric secretions the basis for therapy of
peptic ulcer disease.
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Proton Pump

• Parietal cells H ion secretion depends on a
  H,K-ATPase pump-- promoting H K exchange
• H,K-ATPase located in apical membraneto and
  tubulovesicular apparatus of parietal cells
• Luminal surface of the membrane enzyme exposed
  to gastric luminal acid

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Proton Pump Inhibitors

• Omeprazole (Prilosec), 20mg
• Lansoprazole (Prevacid), 30mg
• Rapeprazole 20mg
• All given daily before breakfast

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Proton Pump Inhibitors Mechanism of Action

• Omeprazole (Prilosec) and lansoprazole (Prevacid)
  inhibit the proton pump, effectively irreversibly
  -- requiring synthesis of new enzyme protein
• Omeprazole and lansoprazole approved for
  treatment of
• Duodenal ulcer
•  may be used in conjunction with triple therapy
• Erosive esophagitis
• Gastric acid hypersecretory states, including
  Zollinger-Ellison syndrome (Gastrinomas that
  cause secretion of large amounts of acids)

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Proton Pump Inhibitors Side effects

• Long acting (irreversible)
• Hypergastrinemia because no acids, Bacteria may
  enter to the body
• In rats omeprazole cause tumors in GI.

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Inhibitory effect of omeprazole on secretion of
gastric acid.
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H2 receptor antagonists
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Physiological and pharmacological regulation of
gastric secretions the basis for therapy of
peptic ulcer disease.
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Role of histamine

• Gastric mucosa contains large amounts of
  histamine in
• mast cell cytoplasmic granules
• enterochromaffin-like cells (ECL)

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H2 receptor antagonists

• H2 receptor antagonists competitively inhibit
  histamine action on H2 receptors, located on
• gastric parietal cells
• cardiac atrial cells
• uterine smooth muscle cells

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H2 receptor antagonists

• H2 receptor antagonists
• Cimetidine (Tagamet)
• Ranitidine (Zantac)
• Famotidine (Pepcid)
• Nizatidine (Axid)
• Inhibit
• basal acid secretion
• secretion in response to feeding, gastrin,
  histamine, hypoglycemia, or vagal stimulation

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H2 Receptor Antagonists

• Effective inhibitor of stimulated and
  NON-stimulated gastric acid secretion
• Cimetidine (Tagamet) -- reduces acid secretion
  responses to histamine, caffeine, hypoglycemia,
  gastrin
• Healing rates similar between antacids and H2
  receptor antagonists (compliance better with
  receptor blockers)

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H2 Antagonist Cimetidine (Tagamet)

• Side effects
• interaction with cytochrome P450 drug
  metabolizing system
• tender gynecomastia the two-week antiandrogenic
  effects (seen typically in Zollinger-Ellison
  disease patients following prolonged space or
  treatment with large doses. Due to pinding to
  androgen receptors and inhibition of P450 which
  catalyze hydroxylation of estradiol.
• Reduction of sperm count is reversible

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H2 Antagonist Ranitidine (Zantac)

• Ranitidine (Zantac)-- six times as potent as
  cimetadine in inhibiting gastric acid secretion
• NO antiandrogenic properties
• Side effect
• Smaller inhibitory effect on cytochrome P450
  system than cimetidine (Tagamet)

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H2 Antagonist Famotidine (Pepcid)

• Famotidine (Pepcid) and nizatidine (Axid) potent
  H2 receptor blockers
• Side effects rare blood dyscrasias and rare
  hepatotoxicity (similarto that seen with
  cimetadine and ranitidine)

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(Axid)
(Zantac)
(Tagament)
(Pepcid)
Side effects
antiandrogenic
SAMALL INHIBITION OF p450
blood dyscrasias
blood dyscrasias
Reduction of sperm
Inhibition of P450
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Effect of cimetidine on betazole-stimulated
secretion of acid (upper panel) and of pepsin
(lower panel) in human beings.
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H2 antagonist therapeutic use

• Promoting healing if Gastric Duodenal Ulcer
• Prophylaxis of stress ulcers
• Gastroesophagal reflux Disease (GERD)

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Anticholinergic drugs

• Atropine
• Telenzepine (M1 antag)
• Pirenzepine (M1 antag)

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Physiological and pharmacological regulation of
gastric secretions the basis for therapy of
peptic ulcer disease.
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• Muscarinic cholinergic antagonists can reduce
  basal secretion of gastric acid by 40 to 50
  stimulated secretion is inhibited to a lesser
  extent.

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Anticholinergic drugs

• Atropine not as effective as H2 receptor
  blockers
• Side effects
• dryness of mouth
• blurred vision
• urinary retention
• cardiac arrhythmias

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Pirenzepine telenzepine

• pirenzepine is equivalent to cimetidine in
  preventing the recurrence of ulcers.
• Both are hydrophilic and poorly penetrate the
  blood-brain barrier.
• Dose
• Pirenzepine, oral, 50 mg 2-3Xdaily.
• Telenzepine, oral, 3 mg/day.

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Pirenzepine telenzepine Side effects

• dry mouth
• blurred vision
• Constipation,
• may limit the utility of these drugs.

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Helicobacter Pylori
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What is Helicobacter pylori?

• H. pylori IS a bacterium causes chronic
  inflammation (gastritis) of the inner lining of
  the stomach in humans.
• the most common cause of ulcers worldwide.
• H. pylori infection is most likely acquired by
  ingesting contaminated food and water and through
  person to person contact.
• In the United States, 30 of the adult population
  is infected. (50 of infected persons are
  infected by the age of 60.)
• The infection is more common in crowded living
  conditions with poor sanitation.
• In countries with poor sanitation, 90 of the
  adult population can be infected.
• Infected individuals usually carry the infection
  indefinitely unless they are treated with
  medications to eradicate the bacterium.
• One out of every six patients with H. pylori
  infection will develop ulcers of the duodenum or
  stomach.
• H. pylori also is associated with stomach cancer
  and a rare type of lymphocytic tumor of the
  stomach called MALT lymphoma.

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Helicobacter pylori

• Helicobacter pylori a principal role in peptic
  ulcer pathogenesis
• H. pylori
• causes active, chronic gastritis
• Bacterial protein products appear damaging
• Proteases and phospholipases produced by H.
  pylori degrade glycoprotein-lipid mucus layer
  complex

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Management of H. pylori infection

• Management of H. pylori infection clinical
  consequences
• 15 relapse rate for duodenal ulcer following H.
  pylori eradication
• 75 relapse rate for duodenal ulcer following
  treatment with H2 receptor blockers only

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Drug Treatment for H. pylori

• Patients with documented duodenal ulcers (upper
  GI contrast radiography or endoscopy) -- treat
  for H. pylori Drugs include
• bismuth compounds
• amoxicillin
• tetracycline (Achromycin)
• clarithromycin (Biaxin)
• metronidazole (Flagyl)
• omeprazole (Prilosec), lansoprazole (Prevacid)
• H2 antagonists

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Bismuth compounds Mechanism of Action

• Mechanism of Action
• cytoprotective effects
• compounds bind to the ulcer base, stimulating
  mucus and prostaglandin production
• antibacterial effect inhibition of proteolytic,
  lipolytic, and urease activities
•  In monotherapy bismuth compounds eradicate H.
  pylori in about 20 of patients
• Bismuth compounds in combination with antibiotics
  eradicate H. pylori in up to 95 of patients.

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• Most successful protocol triple therapy
• bismuth compounds
• metronidazole (Flagyl)
• amoxicillin or tetracycline (Achromycin)
• Triple therapy (two weeks) plus H2 blocker
  therapy (six weeks) is also a recommended
  protocol
• Further increase in the rate of H. pylori
  eradication may be accomplished by the addition
  of omeprazole (Prilosec) to the regimen.

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• Drawbacks of triple therapy
• patient compliance (two-week treatment 200
  tablets)
• Side effects

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Antacids

• Magnesium hydroxide
• Aluminum hydroxide
• Calcium carbonate

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Antacids neutralizing HCl

• Most widely used mixture of aluminum hydroxide
  and magnesium hydroxide (neutralizes HCl)

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Antacids side effects

• Aluminum hydroxide
• constipation
• systemic phosphate depletion (weakness, malaise,
  anorexia)
• Magnesium hydroxide
• loose stools
• ionic magnesium stimulates gastric release ("acid
  rebound")
• Calcium carbonate
• milk-alkali syndrome with elevation of
• serum calcium, phosphate, urea, creatinine,
  bicarbonate levels
• may result in renal calcinosis
• Systemic alkalosis may occur

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Coating Agents
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Coating Agents Sucralfate (Carafate)

• Sucralfate (Carafate)-complex polyaluminum
  hydroxide salt of sucrose sulfate
• highly polar antacid pH binds to ulcer bed
  (granulation tissue, not to gastric or duodenal
  mucosa)
• decreases proton diffusion to the ulcer base
• may increase endogenous tissue prostaglandins and
  may bind epidermal growth factors and other
  growth factors-- improving mucosal defense

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Coating Agents Colloidal bismuth

• Colloidal bismuth -- bismuth-protein coagulant
• may protect also from pepsin and acid digestion
• may inhibit pepsin activity
• prevents proton diffusion into the ulcer
• Stimulates gastric mucosal secretion of
  protective agents
• Colloidal bismuth only class of antiulcer drugs
  that can eradicate H. pylori and cure associated
  gastritis

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Prostaglandins
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Physiological and pharmacological regulation of
gastric secretions the basis for therapy of
peptic ulcer disease.
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Prostaglandins Mechanism of action

• reduction in basal and stimulated gastric acid
  secretion enhanced mucosa resistance to injury
  (PGE1/PGE2).

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Misoprostol (CYTOTEC),

• misoprostol is moderately effective in treating
  duodenal and gastric ulcers.
• inhibits gastric acid secretion and is higher
  than the dose needed to produce cytoprotective
  effects (enhanced secretion of mucus and HCO3-).
• Dose 200 mg, four times daily with food

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Misoprostol therapeutic use

• Although prostaglandin analogs remain second-line
  agents in the treatment of peptic ulcer, they are
  valuable as cytoprotective agents in patients who
  require NSAIDS agents.
• Misoprostol is used for the prevention of gastric
  ulcer disease induced by NSAIDS in patients who
  must take aspirin-like drugs for the treatment of
  arthritis or other diseases and who are at high
  risk for complicated gastric ulcer disease.

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Misoprostol Side Effects

• Diarrhea in up to 30 of patients at therapeutic
  doses, a side effect that may limit its use
  somewhat.
• Some abdominal cramping also may occur.
• These compounds are potential abortifacients and
  should NOT be used in women who are pregnant or
  in whom conception is a possibility.

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THE END