H2 antagonists and PPIs

What is the mechanism of action of H2 receptor antagonists?

They competitively inhibit histamine H2 receptors on gastric parietal cells, reducing acid secretion.

Why was cimetidine associated with CNS side effects?

It is lipophilic, crosses the blood-brain barrier, and causes confusion, depression, and anxiety, especially in the elderly

What replaced cimetidine to reduce CNS side effects?

Ranitidine, which is less lipophilic and does not cross the BBB, leading to fewer CNS adverse effects.

What are key side effects and risks of H2-receptor antagonists?

• CNS effects

• Sexual dysfunction

• Inhibition of CYP450 enzymes → drug interactions

• Can mask symptoms of gastric cancer

What is the mechanism of action of PPIs?

PPIs irreversibly inhibit the K+ ATPase (proton pump) in gastric parietal cells, preventing acid synthesis

Why are PPIs considered prodrugs?

PPIs are inactive in the bloodstream. They are activated in the acidic environment of the stomach's parietal cells.

Describe the activation process of a PPI inside the parietal cell

• diffuses into parietal cell canaliculi

• Protonation in acidic pH traps the drug

• Acid catalysis forms an active drug

• Forms covalent disulphide bonds with proton pump → irreversible inhibition

What are the advantages of PPIs over H2 antagonists?

• More potent

• Longer duration

• Irreversible inhibition

• Target-specific activation (only in acid-producing cells)

What are the disadvantages and side effects of long-term PPI use?

• Hypomagnesemia

• Increased risk of bone fractures (calcium malabsorption)

• Infections (e.g., C. difficile, pneumonia)

How do PPIs accumulate selectively at their target site?

Due to pH-dependent activation, they activate only in the acidic canaliculi, leading to site-specific action.

What are important prescribing considerations with PPIs?

• Take 30–60 minutes before food

• Use lowest effective dose

• Monitor in long-term users for electrolyte imbalance, B12 deficiency, and bone health

Compare the onset and duration of action for H2 antagonists vs PPIs

• H2 antagonists: Faster onset, shorter duration, reversible

• PPIs: Slower onset, longer duration, irreversible

When should an H2 antagonist be used instead of a PPI?

• For mild symptoms

• When rapid relief is needed