PHARMACOLOGY OF GASTRIC ACIDITY, PEPTIC

ULCERS, AND GASTROESOPHAGEAL REFLUX

DISEASE
lUMEN
• The secretion of H+ by parietal cells. Neuronal
(acetylcholine, ACh), paracrine (histamine), and
endocrine (gastrin) factors all regulate acid secretion
• In parietal cells, the cyclic AMP and the Ca2+-
dependent pathways activate H+,K+-ATPase (the
proton pump), which exchanges hydrogen and
potassium ions across the parietal cell membrane.
 Gastric Defenses Against Acid
• The extremely high concentration of H+ in the gastric
lumen requires robust defense mechanisms to
protect the esophagus and the stomach
 lower esophageal sphincter, which prevents reflux of
acidic gastric contents into the esophagus
 secretion of a mucus layer that protects gastric
epithelial cells
 Mucus production is stimulated by prostaglandins E2
and I2, which also directly inhibit gastric acid
secretion by parietal cells
PROTON PUMP INHIBITORS (PPIs)
• The most potent suppressors of gastric acid
secretion are inhibitors of the gastric H+,K+-
ATPase (proton pump)
• Omeprazole
• Esomeprazole
• Lansoprazole
• Pantoprazole
• rabeprazole
 H2-RECEPTOR ANTAGONISTS
• The long history of safety and efficacy with the
H2-receptor antagonists eventually led to their
availability without a prescription

• The H2-receptor antagonists inhibit acid

production by reversibly competing with
histamine for binding to H2 receptors on the
basolateral membrane of parietal cells
• Cimetidine : king OF CYP INHIBITION
• Ranitidine dISCONT
• Famotidine : 10, 20, 40 MG
• Nizatidine

These drugs are less potent than proton pump

inhibitors but still suppress 24-hour gastric
acid secretion by about 70%
• Can be taken as OTC, also as IV .
• The H2-receptor antagonists are rapidly
absorbed after oral administration, with peak
serum concentrations within 1 to 3 hours.
Absorption may be enhanced by food or
decreased by antacids, but these effects
probably are unimportant clinically.
• Unlike proton pump inhibitors, only a small
percentage of H2-receptor antagonists are
protein-bound

• The H2-receptor antagonists generally are well

tolerated, with a low (<3%) incidence of
adverse effects
• Side effects include diarrhea, headache,
drowsiness, fatigue, muscular pain, and
constipation
• The major therapeutic indications for H2-
receptor antagonists:
 Promote healing of gastric and duodenal
ulcers
 To treat uncomplicated GERD
 Prevent the occurrence of stress ulcers
 TOLERANCE AND REBOUND

• Tolerance to the acid-suppressing effects of H2-

receptor antagonists is well described
• May account for a diminished therapeutic effect
with continued drug administration
• Secondary hypergastrinemia to stimulate histamine
release
• Proton pump inhibitors, despite even greater
elevations of endogenous gastrin, do not cause this
phenomenon, probably because their site of action
is distal to the action of histamine on acid release
 AGENTS THAT ENHANCE MUCOSAL
DEFENSE
• Prostaglandin Analogs: Misoprostol,
CYTOTEC®
• SUCRALFATE
• ANTACIDS
 Prostaglandin Analogs: Misoprostol

• Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the

major prostaglandins synthesized by the gastric mucosa
• Since NSAIDs diminish prostaglandin formation by
inhibiting cyclooxygenase, synthetic prostaglandin
analogs offer a logical approach to reducing NSAID-
induced mucosal damage
• Misoprostol is rapidly absorbed after oral
administration, require multiple dosing
• Cause diarrhea and cramps
• The degree of inhibition of gastric acid secretion by
misoprostol is directly related to dose
 SUCRALFATE
• Sucralfate consists of the octasulfate of sucrose to
which Al(OH)3 has been added
• Produce a viscous, sticky polymer that adheres to
epithelial cells and ulcer craters for up to 6 hours after a
single dose.
• The use of sucralfate to treat peptic acid disease has
diminished in recent years
• Since it is activated by acid, sucralfate should be taken on
an empty stomach 1 hour before meals
• The most common side effect of sucralfate is
constipation
 ANTACIDS
• Antacids largely have been replaced by more effective
and convenient drugs
• Although sodium bicarbonate effectively neutralizes
acid, it is very water-soluble and rapidly absorbed from
the stomach, and the alkali and sodium loads may pose a
risk for patients with cardiac or renal failure
• CaCO3 rapidly and effectively neutralizes gastric H+,
but the release of CO2 from bicarbonate- and
carbonate-containing antacids can cause belching,
nausea, abdominal distention, and flatulence.
Calcium also may induce rebound acid secretion,
necessitating more frequent administration.
• Combinations of Mg2+ (rapidly reacting) and
Al3+ (slowly reacting) hydroxides provide a
relatively balanced and sustained neutralizing
capacity and are preferred
 TRIPLE REGIMEN
• Clarithromycin/ Levofloxacin
• Amoxicillin
• PPI (rabeprazole)