Antisecretory agent

H2 Blockers

Contents �

Antisecretory agent

• H₂-receptor antagonist
• Mechanism
• Pharmacological action
• ADR
• ADME
• Uses

Contents

Antisecretory agent

• Proton pump inhibitors
• Mechanism
• Pharmacological action
• ADR
• ADME
• Uses

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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

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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

H₂ receptor antagonist cont..

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

H₂ receptor antagonist cont..

Pharmacological actions

• 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

H₂ receptor antagonist cont..

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

H₂ receptor antagonist cont..

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

H₂ receptor antagonist cont..

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

H₂ receptor antagonist cont..

• 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

H₂ receptor antagonist cont..

• 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

H₂ receptor antagonist cont..�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

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Ranitidine Vs Cimetidine cont..

• 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

1. Reversible

Omeprazole(OMEZ) , Rebaprazole

2. Irreversible

Lansoprazole, Pantoprazole, Laminoprazole

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Proton pump inhibitors cont..

• 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

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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

Proton pump inhibitors cont..

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

Proton pump inhibitors

Therapeutic uses

• Peptic ulcer
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome
• Stress ulcers
• Bleeding peptic ulcer
• Aspiration pneumonia

Proton pump inhibitors cont…

S/E

• Nausea
• Loose stools
• Headache
• Abdominal pain
• Muscle and joint pain
• Dizziness
• Leucopenia
• Hepatic dysfunction
• Gynaecomastia and erectile dysfunction

Proton pump inhibitors cont…

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

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Proton pump inhibitors cont…

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.

Proton pump inhibitors cont…

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

Summary

• 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