(19) Acid-related drugs II: proton pump inhibitors

PROTON PUMP INHIBITORS (PPIs)

Main Idea

• strongest acid-suppressing drugs discussed because they block the FINAL step of acid secretion.

• They block: H⁺/K⁺-ATPase = proton pump

• PPIs suppress both:

  • fasting/nighttime acid

  • meal-stimulated acid

H2 blocker →

PPI →

H2 blocker → blocks only the histamine pathway

PPI → blocks the final common pathway

PPI

formulation

• Drug - Omeprazole (Prilosec)

• PPIs ARE ACID-LABILE PRODRUGS

  • Acid-labile = acid can destroy the drug

  • Prodrug = must be activated before it works

• The drug must survive the stomach FIRST before it can eventually block stomach acid.

PPI

MECHANISM

• enteric coating protects it in the stomach

• coating dissolves in the more alkaline intestine

• drug is absorbed into blood

• travels back to stomach parietal cells

• enters acidic secretory canaliculi and becomes activated and trapped there

• binds H⁺/K⁺-ATPase and irreversibly blocks proton pump

• ↓ gastric acid secretion

  
  

PPI

Irreversible inhibition

once that proton pump is blocked, that pump stays blocked.

PPI

PK

• Short time in blood + irreversible pump binding = acid suppression lasts ~24 hours

• New pumps must be made

  • → acid secretion returns over about 3–4 days

• Maximal PPI effect builds after about 3–4 days of daily use.

• Mainly metabolized by liver

  • Severe liver dysfunction may require dose consideration

• No renal dose adjustment generally needed

PPI

admin

• Take on an EMPTY STOMACH 30–60 minutes before breakfast

• Food can decrease PPI bioavailability.

Explain what happens when taking PPI before meals

• Take PPI and PPI gets absorbed

• eat meal and meal activates proton pump

• PPI is ready to block the active pumps

PPI USES

overview

• MAIN PPI USES

  • GERD, especially erosive GERD.

  • Peptic ulcer disease

  • H. pylori

  • NSAID-associated ulcers

• Clinical uses

  • GI BLEEDING

  • Stress-ulcer prophylaxis

  • Zollinger-Ellison syndrome

PPI USES

GERD

Take PPI

→ ↓ stomach acid

→ less acidic reflux

→ allows injured esophagus to heal

For PPI used for GERD, what is frequency?

Most → once daily

Some → need BID

PPI USES

Peptic ulcer disease

• PPIs provide:

  • strong acid suppression

  • faster healing than H2 blockers

• usual healing time with PPI treatment:

  • duodenal ulcer ≈ 4 weeks

  • gastric ulcer ≈ 6–8 weeks

PPI USES

H. pylori

• Take PPI

  • → raises gastric pH

  • → improves antibiotic activity

• Used with antibiotics to eradicate H. pylori.

• Stop PPI about 2 weeks before testing to confirm eradication.

PPI USES

NSAID-associated ulcers

• NSAIDs

  • → ↓ protective prostaglandins

  • → ↑ ulcer risk

• PPI

  • → ↓ acid

  • → helps prevent/heal ulcers

• If NSAID must continue, the slide says PPI is more reliable than an H2 blocker.

Clinical uses

GI BLEEDING

• Very acidic stomach → platelets do not aggregate well, so poor control over GI bleeding

• PPI

  → ↓ acid

  → ↑ stomach pH (pH >6)

  → ↑ clot formation

  → helps control GI bleeding

Clinical uses

Stress-ulcer prophylaxis

• Critically ill / severe stress

  • → risk of stress ulcers

  • → PPI can be used to reduce acid and prevent bleeding.

Clinical uses

Zollinger-Ellison syndrome

• Gastrinoma → ↑ gastrin → massive ↑ acid secretion

• PPI blocks the final proton pump → strongly suppresses the excess acid

LONG-TERM PPI RISKS

• fracture risk, especially discussed in older adults

• vitamin/mineral problems, especially B12 and magnesium

• infections

• kidney problems

• rebound acid secretion

LONG-TERM PPI RISKS

Infection risk

• Normally: stomach acid helps protect against microorganisms

• PPI

  → ↓ acid barrier

  → ↑ infection risk

LONG-TERM PPI RISKS

PPI can increase the risk of what infections?

• C. difficile

• pneumonia, especially hospitalized/critically ill patients

PPI + dementia/Alzheimer’s

Evidence inconclusive (the confidence interval crossed 1) → PPI not proven to increase dementia/Alzheimer’s risk

PPI DRUG INTERACTIONS

main reasons PPIs cause DDIs.

1. PPI changes stomach pH

2. Some PPIs can block CYP enzymes, especially CYP2C19.

PPI DRUG INTERACTIONS

PPI changes stomach pH

• PPI

  • → ↓ stomach acidity

  • → some drugs are absorbed less

• Important example:

  • ketoconazole → ↓ absorption

  • Also listed:

    • itraconazole

    • atazanavir

PPI DRUG INTERACTIONS

Some PPIs can block CYP enzymes, especially CYP2C19. What PPI have reduced interactions with CYP?

P + R = Pretty Reduced CYP interactions

• Pantoprazole

• Rabeprazole

skip

PPI DRUG INTERACTIONS

Example we spoke about

• Clopidogrel = prodrug that needs CYP2C19 to become active.

• Some PPIs block CYP2C19

  • → less clopidogrel gets activated

  • → ↓ antiplatelet effect

• PPIs of concern:

  • omeprazole

  • esomeprazole

  • lansoprazole

  • dexlansoprazole

• If a PPI is needed: → pantoprazole or rabeprazole = less CYP2C19 inhibition