Module 48

Question 1

The first drugs used for the treatment of acid-peptic disorders were sodium bicarbonate and calcium carbonate. What are the drawbacks to the use of these agents?

Answer 1

• Sodium bicarbonate has a very short duration of action, and it represents a large sodium load that can result in congestive heart failure and edema in patients with marginal cardiac function.
  
  • The calcium in calcium carbonate actually stimulates acid production through an increase in gastrin production.
    ○ There is also the possibility that calcium carbonate will cause the mild/alkali syndrome leading to systemic alkalosis and kidney injury.
    Therefore, both of the agents produce a very short duration of symptom relief, but do nothing to treat ulcer disease and can cause significant side-effects.

Question 2

What is the mechanism by which omeprazole inhibits acid production? Instead of development of tolerance, omeprazole often becomes more effective with continued use. What is the mechanism of this increase in activity with continued use?

Answer 2

• The mechanism involves an acid catalyzed rearrangement that produces a chemically reactive species. The reactive product irreversibly inactivates the proton pump thereby leading to a decrease in the production of acid. Apparently this was found by accident. The reactive species is the sulfenic acid (-S-O-H).
  
  • The PPI has to get to the parietal cells, the cells that produce stomach acid and also activate the PPI. The PPI has to get to the parietal cells through the blood stream; almost nothing is absorbed directly in the stomach
  • Therefore, the PPI must first be absorbed from the intestine, but if the proton pump inhibitor is activated in the stomach by acid, the reactive sulfenic acid will react with something in the stomach such as food, and not be absorbed in the intestine to reach the parietal cells. With continued use, there is less acid in the stomach, less premature activation in the stomach, more drug reaching the parietal cells, and the PPI becomes more effective.

Question 3

It appears that the use of proton pump inhibitors (PPIs) increases at least one type of infection, which one?

Answer 3

iT has been reported that the use of PPIs increase the risk of C.diff infections and community-acquired pneumonia
- I think the first is real; stomach acid probably kills many of the C.diff before they reach the intestine, and lack of stomach acid is probably a risk factor
- But there is a major problem with the interpretation of the data related to pneumonia
The major use of PPIs is for the treatment of gastroesophageal reflux (GERD). But GERD leads to an increase in stomach and oral contents entering the lungs, and this increases the risk of pneumonia. This is another example where association does not prove causation, but this was not mentioned in the interpretation of the data

Question 4

What is the problem with using PPIs PRN?

Answer 4

• The use of PPIs leads to a feedback increase in the production of gastrin, and when patients stop taking a PPI there is a rebound in acid production
  
  • Therefore, once a patient starts taking a PPI it is difficult to stop, because when they do, the level of acid production is greater than before the patient started taking the PPI.

Question 5

The FDA issued a warning that patients using clopidogrel (Plavix) should avoid using omeprazole? What if the patient needs a PPI?

Answer 5

• Clopidogel is bioactivated by CYP2C19 to a reactive species that binds to and inhibits P2Y12, which is involved in platelet activation. Omeprazole is also metabolized by CYP2C19, and it is a competitive inhibitor of this enzyme; therefore, it inhibits bioactivation of clopidogrel and its therapeutic effect.
  
  • Several other PPIs such as rabeprazole are not metabolized by CYP2C19 so they are not a problem.
    In addition, the half-life of omeprazole is quite short so timing of the administration of the two drugs would also likely eliminate the problem. (Note that although the half-life of omeprazole is short, it duration of action is not because the inhibition of the proton pump is irreversible.) It also turns out that clopidogel is also bioactivated by CYP3A4 and therefore the interaction may not be as great as originally suspected.

Question 6

What other adverse event related to bones is associated with proton pump inhibitors?

Answer 6

• There appears to be a small increase in the risk of bone fractures in patients taking PPIs, possibly because of a decrease in calcium absorption.