PROTON PUMP INHIBITORS Flashcards
1
Q
How can too much acid in the stomach be treated ? and how is this done ?
A
- Too much acid in the stomach can be treated with PPIs
- These increase the pH in the stomach by acting on the proton pump
2
Q
Proton pump inhibitors are used for the prevention and treatment of acid-related conditions such as:
A
- GERD (Gastro esophageal reflux disorder)
- Peptic ulcer
- Zollinger Ellison syndrome
- Barrett’s oesophagus (premalignant condition leading to cancer)
3
Q
Explain how the proton pump works specifically in parietal cells ?
A
- Pumps protons out of the parietal cell and potassium ions back in
- Requires energy - provided by hydrolysis of ATP to ADP, catalysed by ATPase
4
Q
What is the proton pump also called ?
A
H+/K+-ATPase
5
Q
Explain the chloride ions and HCl in the proton pump ?
A
- Chloride ions depart through a separate ion channel
- HCl is formed in the canaliculus
6
Q
How do the potassium ions exit the parietal cell ?
A
As counterions for the chloride ions and are pumped back in
7
Q
What can proton pump inhibitors act as ?
A
- Act as prodrugs
- Activated by strongly acidic conditions found in the canaliculae of parietal cells
8
Q
Design of Omeprazole (Losec)?
A
- The lead compound
- Originally an antiviral drug
- Inhibits gastric acid secretion
- Liver toxicity due to the thioamide group - Modify the imidazole ring
- Increase in activity due to the benzimidazole ring - Drug metabolism studies
- Timoprazole formed by metabolism of H124/26
- Timoprazole is the active drug
- Pyridinylmethylsulfinyl benzimidazole structure
- Side effect - inhibits iodine uptake by the thyroid gland - Substituents varied on the benzimidazole ring
- Substituents were varied to get the right balance of potency chemical stability and synthetic accessibility
- Omeprazole was found to have the best balance
9
Q
Explain Esomeprazole (Nexium) ?
A
- Omeprazole has an asymmetric centre
- The S-enantiomer has better potency and pharmacokinetic profile
- Example of chiral switching
