Gastrointestinal Pharmacology

Drugs used for treatment acid related

disorders
Obejctives
• Regulation of gastric acid secreation
• Classiffication of drugs used in peptic ulcer
disease
• Mechanison of action, uses and adverse effects,
drug interactions of
 H2 antagonist
 Proton pump inhibitors
 antacids
Cytoprotective agents
 Regulation of Stomach Acid Release
• Parietal cells: (located in body and fundus of
stomach) are responsible for secretion of
hydrochloric acid and intrinsic factor (required for
vitamin B12 absorption).
The parietal cell contains receptors for gastrin,
acetylcholine (muscarinic, M3), and histamine (H2).
Neural release of acetylcholine and gastrin stimulates
release of acid from the parietal cells by activating the
H+/K+ (ATPase) pump via a Ca+2 dependent protein
kinase
• G cell: a type of endocrine cell (in the gastric antrum
and duodenum )that secret gastrin.

• The enterochromaffin-like (ECL) cells: in the fundus

of the stomach produce, store and secrete histamine
in response to acetylcholine and gastrin.
Gastrin and acetylcholine receptors are found on ECL
cells as well as on parietal cells.
Acetylcholine and gastrin induce histamine release from
enterochromaffin-like cells, which then stimulate the
H+/K+ ATPase pump (through stimulation of H2
receptors) on parietal cells.
In contrast to acetylcholine and gastrin, H2 receptors
stimulate the H+/K+ ATPase pump via activation of
adenylate cyclase to form cAMP and stimulate protein
kinase A. Protein kinase A induces fusion of
tubulovesicles within the canalicular membrane of the
parietal cell to release protons into the gastric lumen.

Basal Acid Output (BAO): Is the minimum amount

of gastric hydrochloric acid produced by an individual in
a given period (Normal adult volume is 2 to 5 mEq/hr)
Proton pump

H/K
ATP
ase
Ach-R G-R

Mechanism of acid production

Mucus production:
• Produced by mucus-secreting cells
• Also produce bicarbonate, which becomes trapped in
the mucus layer
• Prostaglandins E2 and I2 inhibit acid secretion(by
inhibition of adenyl cyclase), but stimulate mucus
and bicarbonate secretion, and dilate mucosal blood
vessels.
• The majority of upper GI disorders are acid-related
diseases in which gastric acid plays an important role
in their development which include; dyspepsia,
peptic ulcer disease (PUD), gastroesophageal reflux
disease (GERD), and upper GI bleeding.
• Peptic ulcer disease affects approximately 10% of the
population of western countries. The incidence of
duodenal ulcer (DU) is four to five times higher than
that of gastric ulcer (GU).
 Although the pathogenesis of peptic ulcer disease is
not fully understood, several major causative factors
are recognized:
• Nonsteroidal anti-inflammatory drug (NSAID) use
• Infection with Helicobacter pylori,
• Increased hydrochloric acid secretion, and
• Inadequate mucosal defense against gastric acid.
 Drugs used to treat peptic ulcer
disease
A. Antimicrobial agents
Patients with peptic ulcer disease (both duodenal and
gastric ulcers) who are infected with H. pylori require
antimicrobial treatment.
Successful eradication of H. pylori (80-90 percent) is
possible with various combinations of antimicrobial
drugs, either:
. Triple therapy: consisting of a PPI with either
metronidazole or amoxicillin plus clarithromycin
or
. Quadruple therapy: bismuth subsalicylate plus
metronidazole plus tetracycline plus a PPI,
They are administered for a 2-week course. This
usually results in a 90 percent or greater eradication
rate.
B. PPI (proton pump inhibiters):
PPIs bind to the H+/K+-ATPase enzyme system
(proton pump) of the parietal cell and effectively
inhibite acid secreation. e.g: omeprazole,
lansoprazole, rabeprazole, pantoprazole,and
esomeprazole.
These agents are prodrugs, absorbed and transported
to the parietal cell canaliculus converted to the active
form, reacts with a cysteine residue of the H+/K+-
ATPase, forming a stable covalent bond and
irreversibly inactivate the proton pump (which is the
final step in the secretion of gastric acid).
Pharmacokinetics:
• They are effective orally,
• bioavailability is decreased 50% by food therefore
should be administered approximately 1 hour before
a meal, so that the peak serum concentration
coincides with the maximal activity of proton pump
secretion.
• They have a short serum half-life of about 1.5 hours,
but the duration of acid inhibition lasts up to 24
hours.
due to the irreversible inactivation of the proton
pump, about 18 hours needed for the enzyme to be
resynthesized.
Therapeutic uses:
• PPIs are superior over the H2 antagonists for
suppressing acid production and healing peptic ulcers
• Long-term treatment of Zollinger-Ellison
syndrome(pathologic conditions in which a gastrin-
producing tumor causes hyper secretion of HCl).
• They are approved for the treatment of GERD.
Adverse effects:
The PPIs are generally well tolerated.
normally acid is important in releasing vitamin B12 from
food, but long-term treatment with PPIs may lead to
subnormal B12 levels.
C. H2receptor antagonists
• Prescription of H2-blockers has declined markedly
with the advent of proton pump inhibitors.
• Four H2antagonists are in clinical use: cimetidine,
ranitidine, famotidine,and nizatidine.They potently
inhibit (greater
than 90%)basal, food-stimulated, and nocturnal
secretion of gastric acid.
• Pharmacodynamics:
They act selectively and competitivly on H2 receptors
and they are fully reversible. these agents reduce the
intracellular concentrations of cyclic adenosine
monophosphate (cAMP) and, thereby, secretion of
gastric acid.
cimetidine, ranitidine, and famotidine undergo first-
pass hepatic metaolism resulting in a bioavailability
of approximately 50%. Nizatidine has little first-pass
and a bioavailability of almost 100%.
• H2antagonists are cleared by liver and kidney. but
nizatidine is eliminated principally by the kidney.
• Dose reduction of H2antagonsts is required in
patients with moderate to severe renal (and possibly
severe hepatic) insufficiency and in elderly.
• cimetidine inhibits cytochrome P450 and thus
potentiate the action of several drugs (for example,
warfarin, diazepam, phenytoin, quinidine,
carbamazepine, theophylline, and imipramine)
resulting in serious adverse clinical effects.
Therapeutic uses:
• they are used for peptic ulcers,
• Acute stress ulcer they are usually injected
intravenously
• and used in Gastroesophageal reflux disease(GERD)
However,PPIs are now used preferentially in the
treatment of this disorder.
Adverse Effects:
• H2antagonists are extremely safe drugs.
• Side effects include diarrhea, headache, fatigue,
muscular pain, and constipation. Other CNS
effects (confusion, hallucinations)
• Cimetidine: can also cause male sexual
dysfunction and gynecomastia.
• Ranitidine has minimal side effects
D. Prostaglandins:
• Misoprostol binds to a prostaglandin receptor on
parietal cells, reducing histamine-stimulated cAMP
production and causing modest acid inhibition and
stimulates secretion of mucus and bicarbonate
(cytoprotective effect).
• Misoprostol with PPIs, are used for prevention of
gastric ulcers induced by NSAIDs . It is less effective
than H2 antagonists and the PPIs for acute treatment
of peptic ulcers.
• misoprostol produces uterine contractions and is
contraindicated during pregnancy. Dose-related
diarrhea and nausea are the most common adverse
effects and limit the use of this agent.
E. Antimuscarinic agents (anticholinergic agents)
A cholinergic antagonist, such as pirenzipine or
dicyclomine , can be used in the management of
peptic ulcer disease and Zollinger-Ellison syndrome,
particularly in patients who are refractory to standard
therapies.
However, its many side effects (for example, cardiac
arrhythmias, dry mouth, constipation, and urinary
retention) limit its use.
F. Mucosal Protective Agents
Both mucus and epithelial cell-cell tight junctions
restrict back diffusion of acid and pepsin.
Epithelial bicarbonate secretion establishes a pH
gradient within the mucous layer( in which the pH
ranges from 7 at the mucosal surface to 1–2 in the
gastric lumen). Blood flow carries bicarbonate and vital
nutrients to surface cells.
Mucosal prostaglandins appear to be important in
stimulating mucus and bicarbonate secretion and
mucosal blood flow.
A number of agents that potentiate these mucosal
defensive mechanisms are known as cytoprotective
compounds
• 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. forming a physical barrier that restricts
further gastric damage and stimulates mucosal
prostaglandin and bicarbonate secretion.
Because it requires an acidic pH for activation,
sucralfate should not be administered with H2
antagonists or antacids. It heals duodenal ulcers, but
does not prevent NSAID-induced ulcers, nor does it
heal gastric ulcers.
• Bismuth subsalicylate: this compound effective in
healing peptic ulcers. In addition to their
antimicrobial actions, they coat the ulcer base inhibit
the activity of pepsin, increase secretion of mucus.
Unwanted effects include nausea and vomiting, and
blackening of the tongue and feces.
• Bismuth subsalicylate: this compound
effective in healing peptic ulcers. In addition
to their antimicrobial actions, they coat the
ulcer base inhibit the activity of pepsin,
increase secretion of mucus.

• Unwanted effects include nausea and

vomiting, and blackening of the tongue and
feces.
G. Antacids:
Antacids are weak bases that react with gastric
acid to form water and a salt and cause:
1. Partial neutralization of gastric acid within the
gastric lumen.
2. Inhibition of pepsin activity within the gastric
lumen, secondary to decrease in gastric pH
because pepsin is inactive at a pH greater than 4.
Antacids are very quick acting and modestly
elevate intra-gastric pH within minutes, but their
duration of action is short (about 30 minutes on an
empty stomach).
Commonly used antacids are:
• NaHCO3: Can lead to systemic alkalosis and high
sodium load with high doses.
• Mg(OH)2:Can cause diarrhea and loose stools
when used alone, also it may cause Hyporeflexia,
hypotension, and cardiac arrest
• Al(OH)3: When used alone can cause
constipation, it may lead to oesteodystrophy,
encephalopathy, and Hypophosphatemia with
chronic use, contraindicated in uremic patients.
• CaCO3: reacts with HCl to form CO2 and CaCl2
and is a commonly used preparation.
Contraindications
1.Hypertension, heart failure
2. Renal disease
Drug interaction
• Alkalinization of gastric contents can change the
bioavailability of a large number of drugs: iron,
tetracyclines, digoxin, prednisolone, propranolol,
quinidine, antimuscarinics
• Ions in antacids can chelate with drugs,
forming insoluble complexes e.g.
Quinolones with Ca2+, Mg2+,or Al3-
Tetracyclines with Ca2+
• Also, alkalinization of urine alters the urinary
excretion of many drugs
It increases excretion of phenobarbital,
methotrexate, salicylate