(15) Proton Pump Inhibitors

Antacid vs. PPI

Antacid
→ neutralizes acid already present

PPI
→ blocks proton pump
→ prevents more H⁺ entering stomach

Proton Pump

• Proton pump

  • H⁺/K⁺-ATPase

  • Located in parietal cells

  • Pumps H⁺ into stomach lumen

  • ↑ H⁺ → ↓ pH → ↑ acidity

Name the amino-acid residues on the gastric proton pump (aka Important Cysteines)

CYS813 and CYS822

CYS813 vs CYS822

CYS813

• closer to entrance

• reactive/unstable PPI hits it first

• GSH can reach it

  • attacks the disulfide linkage

  • removes the PPI from the pump

  • CYS813 gets its free SH back

  • proton pump becomes active again

  • An inactive/excretable GSH–PPI conjugate is formed.

• GSH can rescue pump

• → shorter duration

CYS822

• deeper

• more stable PPI can reach it

• GSH cannot reach it

• no rescue

• → longer duration

Glutathione Rescue - draw

How PPI Inhibits the Pump

• Activated/reactive PPI

  • cysteine SH → forms disulfide bond

• This makes the PPI:

  • covalently attached to the proton pump

  • Result: pump inhibited → cannot pump H⁺ into stomach lume

How PPI Inhibits the Pump - draw it

Potency + Duration Trend

• PPIs that reach 822 generally have:

  • higher potency

  • longer duration

• But professor said this is a general trend, not an absolute rule.

Fast vs slow PPIs

• Fast / more reactive → reacts at 813

• Slower / more stable → can reach 822

PPI structure

• All PPIs have the same general core:

  • pyridylmethyl – sulfinyl – benzimidazole

• Different R groups → change how quickly the PPI reacts.

PPI structure - draw

PPI activation idea

• PPIs are like prodrugs, but not technically prodrugs.

• Why?

  • Prodrug → needs metabolism

  • PPI → picks up H⁺ and chemically activates itself → no CYP activation needed

Henderson–Hasselbalch

For the basic PPI nitrogens:

pH − pKa = log [B]/[H:B]

• For a base:

  • B = unionized

  • H:B = ionized/protonated

• Important relationship:

  • pH < pKa → protonated/cationic form favored

  • pH > pKa → unionized form favored

Two Important PPI Nitrogens

Pyridine N1

• higher pKa

• stronger base

• picks up H⁺ first

Benzimidazole N3

• lower pKa

• weaker base

Two Important PPI Nitrogens - draw

At pH 1.5, what is the ionization state of the 2 important PPI nitrogens?

• Pyridine N1 → cationic (+)

  • pH < pKa1

• Benzimidazole N3 → un-ionized

  • pH > pKa2

PPI at pH 7.4

• fully unionized conjugate predominates

• The professor also initially says: both deprotonated

  • The important lecture idea is that once the drug has left the gastric pump environment, professor says its behavior there is no longer the main concern.

Two Monocationic Forms

• Bz–PyrH⁺

  • proton is on pyridine

  • predominates at pH 1.5

• BzH⁺–Pyr

  • proton is on benzimidazole

  • does NOT predominate

  • required for PPI activation

🔴 MEMORIZE THIS PAIR

Bz–PyrH⁺ = predominant

BzH⁺–Pyr = activation

Two Monocationic Forms - draw