Antisecretory
agent
Contents
Antisecretory agent
• H2-receptor antagonist
– Mechanism
– Pharmacological
action
– ADR
– ADME
– Uses
• Proton
pump inhibitors
– Mechanism
– Pharmacological
action
– ADR
– ADME
– Uses
Objectives
At the end of this
lecture, student will be able to
• Explain
the pharmacology of H2-receptor antagonist
• Describe
the pharmacology of proton pump inhibitors
H2 receptor antagonist
E.g. Cimetidine, ranitidine,
nizatidine, famotidine
• First class of highly effective
drugs for acid-peptic disease
• The H2 antagonists
are competitive antagonists of histamine at the parietal cells H2 receptor
• They suppress the normal secretion
of acid by parietal cells and the meal-stimulated secretion of acid
MOA
• Inhibits gastric acid secretion, as
well as pepsin and gastrins output
• It also blocks the activity of cytochrome
P-450 which might explain proposals for use
• Cimetidine binds to an H2-receptor
located on the basolateral membrane of the gastric parietal cell, blocking
histamine effects
• This competitive inhibition results in reduced
gastric acid secretion and a reduction in gastric volume and acidity
Pharmacological
actions:
• Cimetidine and all other H2
antagonists block histamine-induced gastric secretion, cardiac stimulation
• The only significant in vivo action
of H2 blockers is marked inhibition of gastric secretion
• The H2 blockers have antiulcerogenic
effect
• Gastric ulceration due to stress and drugs
(NSAIDs,cholinergic, histaminergic) is prevented uterine relaxation (in rat)
and bronchial relaxation
• Cimetidine has antiandrogenic action (displaces
dihydrotestosterone from its cytoplasmic receptor), increases plasma prolactin
and inhibits degradation of estradiol by liver
• High doses given for long periods
have produced gynaecomastia
• Loss of libido
• Decrease in sperm count
ADME
• Cimetidine is adequately absorbed
orally
• Absorption is not interfered by
presence of food in stomach
• Crosses placenta reaches milk
• 2/3 of a dose is excreted unchanged
in urine
S/E:
• Headache, dizziness, bowel upset,
dry mouth,rashes
• CNS effects like confusional state,
restlessness,convulsions and coma have occurred infrequently in elderly
patients
• Release histamine
Drug
Interactions
• Isoenzymes and reduces hepatic blood
flow
• Inhibits the metabolism of many
drugs so that they can accumulate to toxic levels, e.g. theophylline,phenytoin,
carbamazepine
• Antacids reduce absorption of all H2
blockers
• Ketoconazole absorption is decreased
by cimetidine
Ranitidine
Ranitidine has a furan ring H2 blocker, it has several desirable features
compared to cimetidine About 5 times more potent than cimetidine
• Pharmacokinetic profile and t½ of
2–3 hr is similar to cimetidine
• No antiandrogenic action, does not
increase prolactin secretion
• Lesser permeability into the brain
MOA
• Ranitidine is a competitive,
reversible inhibitor of the action of histamine at the histamine H2 receptors
found in gastric parietal cells
• This results in decreased gastric
acid secretion and gastric volume, and reduced hydrogen ion concentration
Famotidine
• Famotidine, thiazole ring containing H2 blocker
which binds tightly to H2 receptors
• Longer duration of action
elimination t½ of 2.5–3.5 hr 5–8 times more potent than ranitidine
• Antiandrogenic action is absent
• The oral bioavailability of
famotidine is 40–50% and it is excreted by the kidney
Therapeutic uses
• Duodenal ulcer
• Gastric ulcer
• Stress ulcers and gastritis
• Zollinger-Ellison syndrome
• Gastroesophageal reflux disease
(GERD)
• Prophylaxis of aspiration pneumonia
Ranitidine Vs Cimetidine
• Ranitidine, a new H2-receptor
blocking antihistamine
• Pharmacokinetically similar to cimetidine, but
its potency is about eightfold greater
• The clinical response to ranitidine is more
prolonged, largely because of potency and not kinetic advantage
• Ranitidine for 6 to 25 months is not
associated with hepatic or hematologic toxicity or alterations of serum gastrin
levels
• Ranitidine can adequately inhibit
acid secretion in patients with gastric hypersecretory disorders
• Safe at high doses, does not cause
the antiandrogen side effects frequently seen with high doses of cimetidine
Proton pump inhibitors
a) Reversible
Omeprazole(OMEZ) , Rebaprazole
b) Irreversible
Lansoprazole,
Pantoprazole, Laminoprazole
Omeprazole
• Omeprazole It is the prototype
member of substitute
benzimidazoles which inhibit the final common step in gastric acid secretion
inactive at neutral pH
• React covalently with SH groups of
the H+K+ATPase enzyme and inactivate it
MOA
• Omeprazole is a selective and irreversible
proton pump inhibitor
• It suppresses stomach acid secretion
by specific inhibition of the H+/K+-ATPase system found
at the secretory surface of gastric parietal cells
• The duration of inhibition is up to
72 hours
ADME
• Oral absorption of omeprazole is
~50%,
• Bioavailability of all PPIs is
reduced by food
• Metabolised in liver by CYP2C19 and
CYP3A4
• No dose modification
• Antisecretory action increases on
daily dosing to reach a plateau after 4 days
Therapeutic uses
• Peptic ulcer
• Gastroesophageal reflux disease
(GERD)
• Zollinger-Ellison syndrome
• Stress ulcers
• Bleeding peptic ulcer
• Aspiration pneumonia
S/E
• Nausea
• Loose stools
• Headache
• Abdominal pain
• Muscle and joint pain
• Dizziness
• Leucopenia
• Hepatic dysfunction
• Gynaecomastia and erectile dysfunction
Drug interaction
• Clarithromycin inhibits omeprazole metabolism and increases its plasma
concentration
• Omeprazole inhibits oxidation of
certain drugs: diazepam, phenytoin and warfarin levels may be increased
Esomeprazole
• It is the S-enantiomer of omeprazole
• Higher oral bioavailability and to
produce better control of intragastric pH than omeprazole in GERD patients
because of longer t½
Lansoprazole
• More potent than omeprazole but similar in
properties. Inhibition
• of H+ K+ ATPase by lansoprazole
• It has higher oral bioavailability,
faster
• Onset of action and slightly longer
t½ than omeprazole.
Pantoprazole
• Newer H+ K+ ATPase inhibitor,
similar in potency and clinical efficacy to omeprazole
• More acid stable and has higher oral
bioavailability.
• Available for i.v. Administration
• Lower affinity for cytochrome P450
than omeprazole
• Risk of drug interactions is minimal
Summary
• H2
blockers competitively blocks the binding of histamine to H2
receptors.
• H2
blockers, are a class
of medications that block the action of histamine at
the histamine H2 receptors of the parietal
cells in the stomach
• Decreases the production of stomach acid
H2antagonists can be used in the treatment
of dyspepsia peptic ulcer and gastroesophageal reflux
disease
• PPIs irreversibly inhibits the H+/K+
ATPase (the proton pump), the terminal step in the acid secretory pathway
• Both basal and stimulated gastric
acid secretion is reduced
• Oral administration is the most
common route of administration, although some injectable preparations are
available
