Transcript Physiological stimulants of gastric acid secretion

TREATMENT OF PEPTIC
ULCERS & CONTROL
OF GASTRIC ACIDITY
Prof. Riad Agbaria
Microscopic Anatomy of the Stomach
Four secretory epithelial cells:
1- Mucous cells: secrete an alkaline mucus that protects
the epithelium against shear stress and acid
2- Parietal cells: secrete hydrochloric acid!
3- Chief cells: secrete pepsin, a proteolytic enzyme
4- G cells: secrete the hormone gastrin
5-Entrochromaffin-Like Cells (ECL)- HISTAMINE
Physiological and pharmacological regulation of gastric secretions: the basis for
therapy of peptic ulcer disease.
Physiological stimulants of
gastric acid secretion:
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
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
Physiologic inhibitiongastric acid release:
Factors that inhibit gastric acid secretion
include:
– hyperglycemia
– hypertonic fluids
– duodenal fat
– duodenal acid
– intragastric pH = 3; partial inhibition
– intragastric pH < or = 1.5; complete blockade
of gastrin release
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
Peptic Ulcer Disease
Pathogenic Factors: Peptic ulcer disease
Peptic ulcer disease:
an imbalance
between aggressive
factors (gastric acid
and pepsin) and
protective factors
(gastric mucus,
bicarbonate,
prostaglandins)
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 proteolyticallyactive pepsins
Pepsinogen classification:
– Direct correlation between pepsinogen I
serum concentrations and maximal gastric
acid secretion
Pharmacological
Management of Ulcer Disease
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
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.
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)
1: Proton Pump Inhibitors:
The most effective suppressors of gastric acid secretion
Physiological and pharmacological regulation of gastric secretions: the basis for
therapy of peptic ulcer disease.
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
Proton Pump Inhibitors:
 Omeprazole (Prilosec), 20mg
 Lansoprazole (Prevacid), 30mg
 Rapeprazole 20mg
All given daily before breakfast
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 ZollingerEllison syndrome (Gastrinomas that cause secretion of
large amounts of acids)
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.
Inhibitory effect of omeprazole on secretion of gastric acid.
H2 receptor antagonists
Physiological and pharmacological regulation of gastric secretions: the basis for
therapy of peptic ulcer disease.
Role of histamine:
–Gastric mucosa contains large
amounts of histamine in:
mast cell cytoplasmic granules
enterochromaffin-like cells (ECL)
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
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
H2 Receptor Antagonists
Effective inhibitor of stimulated and NONstimulated 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)
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
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)
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)
(Tagament)
Side effects
antiandrogenic
Reduction of sperm
Inhibition of P450
(Zantac)
SAMALL
INHIBITION
OF p450
(Pepcid)
blood dyscrasias
(Axid)
blood dyscrasias
Effect of cimetidine on betazole-stimulated secretion of acid (upper
panel) and of pepsin (lower panel) in human beings.
H2 antagonist therapeutic use
Promoting healing if Gastric & Duodenal
Ulcer
Prophylaxis of stress ulcers
Gastroesophagal reflux Disease (GERD)
Anticholinergic drugs:
Atropine
Telenzepine (M1 antag)
Pirenzepine (M1 antag)
Physiological and pharmacological regulation of gastric secretions: the
basis for therapy of peptic ulcer disease.
Muscarinic cholinergic antagonists can
reduce basal secretion of gastric acid by
40% to 50%; stimulated secretion is
inhibited to a lesser extent.
Anticholinergic drugs:
Atropine: not as effective as H2 receptor
blockers
– Side effects:
dryness of mouth
blurred vision
urinary retention
cardiac arrhythmias
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.
Pirenzepine & telenzepine: Side effects
dry mouth
blurred vision
Constipation,
may limit the utility of these
drugs.
Helicobacter Pylori:
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.
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
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
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
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.
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.
Drawbacks of triple therapy:
patient compliance (two-week treatment:
200 tablets)
Side effects
Antacids
Magnesium hydroxide
Aluminum hydroxide
Calcium carbonate
Antacids: neutralizing HCl
Most widely used: mixture of aluminum hydroxide and magnesium
hydroxide (neutralizes HCl)
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
Coating Agents:
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
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
Prostaglandins:
Physiological and pharmacological regulation of gastric secretions: the basis for
therapy of peptic ulcer disease.
Prostaglandins: Mechanism of action
reduction in basal and stimulated gastric
acid secretion; enhanced mucosa
resistance to injury (PGE1/PGE2).
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
Misoprostol: therapeutic use
Although prostaglandin analogs remain secondline 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.
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.
THE END