PPIs and Potassium-Competitive Acid Blockers (PCABs)

What is important about this drug’s metabolism?

Metabolized by both CYP2C19 and CYP3A4

• Very variable between different patients

What is important about this drug’s metabolism?

Less susceptible to first-pass CYP2C19 metabolism

• More bioavailable and predictable than omeprazole

What are important SARs about this drug?

• Fluorination slows down oxidation metabolism by the CYPs

  • More stable and less variable

What is the SAR from the r-enantiomer?

Increases duration of action

Decreases interpatient variability

What is important about how this drug is formulated?

Uses dual delayed-release formulation to have prolonged action

What is the benefit of this drug compared to other PPIs?

Longer duration of action

• can be taken before or after a meal

Dual action allows pain relief during evening and night

Based on this table, which drug will have the fastest onset of action?

Rabeprazole (High pKa 1)

What is the main benefit of this drug compared to the other PPIs?

Spontaneously decomposes to activate

• little reliance on CYP2C19 metabolization

What is the SAR of this molecule?

Difluromethyl group decreases onset of action

3,4-dimethoxypyridine increases acid trapping

What is the benefit of this drug’s metabolites?

Less dependent on CYP metabolism

• IV and PO used in hospitals

Which PPIs have high dependence on CYP2C19?

Omeprazole

Lansoprazole

Dexlansoprazole

What PPIs have low CYP2C19 dependence?

Pantoprazole

Rabeprazole

What PPIs have a fast onset?

Lansoprazole

Rabeprazole (Fastest)

Which PPIs have a slow onset?

Pantoprazole

What are the issues related to PPI use?

Poor absorption

Some drugs and minerals need the acidic environment

Decrease Microbiota survivability

What vitamins / nutrients do PPI impact absorption of?

Vitamin B12

Magnesium

Calcium

Iron

What are the 2 adverse effects of B12 deficiency

Neural and cognitive problems

What are the 2 adverse effects of magnesium deficiency?

Muscle and heart issues

What are the 2 adverse effects of calcium deficiency?

Increase fracture risk and decreased bone density

What is the adverse effect of iron deficiency?

Anemia

What infections are people who use PPIs for the first time or are elderly at risk of?

C. diff and CAP (Community-acquired pneumonia)

What kidney problems arise in people using PPIs?

Acute interstitial nephritis

CKD (Irreversible if untreated)

What happens if you take PPIs for a long period of time?

Overstimulation of parietal cells

• Rebound acid secretion

  • Especially after stopping the drug

What type of drug is this?

Potassium-competitive acid blocker (PCAB)

How does this drug work?

Reversibly and competitively bind to H+/K+ ATPase

What are the 3 benefits of this drug?

Relief of symptoms independent of food intake

Less CYP metabolism

More effective at treating H.pylori infections