Protein Pump Inhibitors

Question 1

What is the proton pump

Answer 1

Pumps protons out of the parietal cell and pumps K+ into the cell using ATP
HCl is formed in the canaliculis
K+ exit parietal cell as counter ions for Cl- and are then pumped back in
Separate potassium ion channel used for K+ ions leaving the cell

Question 2

PPI’s

Answer 2

Pantoprazole, Omeprazole, Esomeprazole, Lansoprazole and Rabeprazole

• Act as pro-drugs
• Activated in strong acidic conditions found in the canaliculis of parietal cells

Question 3

Omeprazole

Answer 3

• Competitive inhibitor
• Active inhibitor
• Reduce the anti-platelet effects of clopidogrel due to its selective inhibition of CYP2C19
• Racemic mixture of R/S enantiomer

Question 4

Pantoprazole

Answer 4

Paramethoxy allows better rotation

Diflouro - less electron donating

Question 5

Lansoprazole

Answer 5

Triflouromethoxy makes it electron withdrawing and oxygen lone pair allows better rotation

Question 6

Rabeprazole

Answer 6

1. Methoxypropoxy group para to Nitrogen makes it a much better donor electron donator
2. Lone pair allows rotation into a position when it can donate very well
3. Pyridine ring is more basic and more nucleophilic - more rapid activation of pro-drug

Question 7

PPI absorption

Answer 7

• Occurs in small intestine
• May have enteric/double coating
• Gets past acid in stomach in small intestine to be released
• Crosses the membrane entering the bloodstream
• Returns back to the stomach lining

Question 8

PPI mechanism of action

Answer 8

Blocks the final stage of all receptors (gastrin, muscarinic, H2R) by inhibiting H+K+ ATPase

• Crosses membrane to parietal cell as it is lipophilic enough
• Once PPI is protonated it cannot get out of the cell as it is too polar now
• Pro-drug is activated when proton from pyridine is transferred to benzimidazole ring (slow rate determining step)

Question 9

Spirodynium ion

Answer 9

• Very unstable

- 2 or more heterocyclic rings want to push each other off

Question 10

Sulfenic acid

Answer 10

More electrophilic

Question 11

Pyridinium sulfenimide

Answer 11

6 membered ring forms due to loss of water by a nucleophile attacking sulfur

Question 12

Glutathione

Answer 12

Reduces disulfide linkage and makes enzyme active again

• Cys822 is more effective as glutathione cannot reach there (irreversible inhibition)
• Omeprazole only inhibits Cys813 as it gets activated too quickly before it can reach Cys822
• This means it can only inhibit for 24 hours

Question 13

Omeprazole and CYP2C19

Answer 13

• Omeprazole inhibits CYP2C19 and it increases concentration of other drugs
• Rabeprazole is given as an alternative as it does not involve CYP2C19 and is enzyme non-dependent
• Can also give lansoprazole and pantoprazole

Question 14

Rebound acidity

Answer 14

Occurs when you stop taking PPI

• Due to overexpression of receptors
• Very common with h2ra
• Lower dose gradually

Question 15

Tenatoprazole

Answer 15

• Longer half-life
• Effective for GORD during night time acid
• Less basic = less likely to get protonated
• Can reach Cys822
• Irreversible inhibition
• Pro-drug activation much slower