Proton Pump Inhibitors (PPIs)

The Proton Pump

• the final step in gastric acid secretion in the parietal cell is ______ ______ ______.

• carried out by an enzyme ____/____-______ or the “proton pump” —> catalyzes the exchange of _______ ions for ______ ions in the stomach.

• exchange is stimulated by ______ messengers (Ca2+ and cAMP) from ______ activation (histamine, gastrin, acetylcholine)

• inhibitors of the pump will block both ______ and ______ secretion

• extrusion of protons

• H+/K+-ATPase, hydrogen, potassium

• secondary, GPCR

• basal, stimulated

What does this structure represent?

the backbone for PPIs

The final step in gastric acid secretion in parietal cells is mediated by:

H⁺/K⁺-ATPase

The proton pump exchanges which ions across the parietal cell membrane?

Na⁺ out / K⁺ in

Which messenger pathways stimulate activation of the proton pump?

Ca²⁺ and cAMP

Which signaling molecules stimulate gastric acid secretion via GPCRs?

Histamine, gastrin, acetylcholine

Proton pump inhibitors (PPIs) block:

Both basal and stimulated secretion

Which statement correctly describes the action of the gastric proton pump (H⁺/K⁺-ATPase)?

Pumps hydrogen ions into the stomach → increases proton concentration → decreases pH

Which statement best explains why proton pump inhibitors (PPIs) are more effective than H2-receptor antagonists in reducing gastric acid secretion?

H2 antagonists block stimulated gastric acid secretion, but PPIs inhibit the proton pump itself, blocking both basal and stimulated secretion.

Which statement best explains why older methods (e.g., atropine, proglumide, H₂ antagonists) are less effective than PPIs for reducing gastric acid?

They block only upstream stimulatory pathways (ACh, gastrin, histamine) and do not block the proton pump itself

The drug becomes acidic → increases solubility and dissolution

What happens if a PPI is formulated with HCl?

The drug becomes basic

Proton pump inhibitors are best described as:

Prodrugs activated in acidic environments

Where do PPIs become activated?

Secretory canaliculus of parietal cells

PPIs react with which functional group on the proton pump?

Thiol group

At neutral pH PPIs are:

Inactive, chemically stable, lipid-soluble, weak bases

How do PPIs reach the parietal cells?

From the bloodstream

Why do PPIs accumulate in the secretory canaliculi?

They become protonated and trapped

Parietal cell canaliculi are unique because they:

Have the lowest pH in the body

Once protonated, PPIs convert to:

Sulfenamide and sulfenic acid

PPIs bind to the pump by:

Covalent bond formation

PPIs convert to their active form fastest at:

Very low pH (acidic environment)

Why do PPIs require enteric coating?

To prevent premature activation in the acidic stomach

Where are PPIs absorbed after oral administration?

Small intestines

What happens as pH increases?

Conversion rate decreases

Why must PPIs avoid activation in the stomach?

They would be trapped and not reach parietal cells

Most drug absorption occurs in intestines because:

Larger surface area

PPIs irreversibly inhibit the H⁺/K⁺-ATPase by:

Covalently reacting with thiol groups on cysteine residues of the pump

At least ______ molecules of the PPI sulfenamide form must react with thiol groups on the H⁺/K⁺-ATPase to fully inhibit the pump.

two

Which cysteine residue is a key target on the H⁺/K⁺-ATPase for covalent binding by PPIs?

Cys-813

PPI specificity is primarily derived from:

Requirement for acidic conditions and trapping in the canaliculus

Trapping of the protonated PPI occurs in the:

Acidic secretory canaliculus adjacent to the enzyme

Omeprazole administration results in:

Permanent inhibition of H⁺/K⁺-ATPase in vivo

Acid secretion resumes only when:

New H⁺/K⁺-ATPase pumps are synthesized and inserted in the membrane

PPIs are formulated as:

Enteric-coated microcapsules or granules

Why are PPIs enteric-coated?

To prevent activation in the mouth and stomach

What happens if the enteric coating is disrupted in the mouth before swallowing?

Neutral pH releases drug prematurely

Premature release in the mouth or esophagus leads to:

Cyclization in the stomach lumen and drug inactivation

In which GI region do PPIs normally dissolve and absorb due to pH?

Duodenum (pH ~6.8)

Which statement best describes esomeprazole?

S-enantiomer of omeprazole

Phase I metabolism of PPIs typically includes:

O-dealkylation and sulfone formation

Phase II metabolism of PPIs primarily involves:

Glucuronidation

OTC PPIs like omeprazole should be used for a maximum of:

14 days

Why is long-term PPI use avoided without supervision?

Raises stomach pH, increasing infection risk

PPIs MOA

1. PPIs are prodrugs

   • Inactive at neutral pH

   • Lipid-soluble, weak bases → can cross membranes

2. Absorbed into the bloodstream and delivered to parietal cells

3. Diffuse into the secretory canaliculi

   • Only location in body with very low pH

4. Become protonated (acidic environment)

   • Acid activates them and causes them to become trapped in the canaliculus

5. Chemical rearrangement

   • Protonated parent drug → forms sulfenic acid and sulfenamide

6. Covalent binding

   • Sulfenamide reacts with thiol (–SH) groups on H⁺/K⁺-ATPase

   • Forms covalent disulfide bond

7. Permanent enzyme inactivation

   • Pump is irreversibly inhibited

   • Acid secretion stops

8. Recovery only when new pumps are made

   • Parietal cell must synthesize and insert new pumps into membrane

   • (Hence long duration despite short half-life in plasma)