Antisecretory agent

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