August 11, 2015 - NSAID, PPI, H2A, Antacid

Question 1

COX-1

Answer 1

Cytoprotective prostaglandin synthesis.

Inhibition of COX-1 may lead to ulcers and bleeding.

Question 2

COX-2

Answer 2

Inflammatory prostaglandin synthesis.

Inhibition of COX-2 leads to reduced inflammation, pain, and fever.

Question 3

Topic Effects of NSAIDs

Answer 3

“Trapping Theory”

Most NSAIDs are weak organic acids. They are non-ionized and lipid-soluble in the stomach. They diffuse across the mucosal cell membranes into the cytoplasm (which is a neutral pH), become ionized and lipid-insoluble. They then become trapped and accumulate within the cells, causing cellular injury.

Question 4

NSAIDs and PPIs

Answer 4

NSAIDs can be combined with PPIs to lower the risk of gastric ulcer disease (GUD). Lowering the pH of the stomach reduces injury to the mucosa.

Question 5

Antacids

Answer 5

Are weak bases which neutralize gastric acid. They also inhibit the formation of pepsin (as pepsinogen is converted to pepsin at a low pH).

Used to relieve occasional heartburn and/or acid indigestion.

Question 6

Potential Adverse Effects of Antacids

Answer 6

• Constipation
• Diarrhea
• Sodium overload, alkalosis
• Distension, discomfort, belching (CO₂-producing agents)
• Kidney stones (rare)
• Osteoporosis in aluminum-containing agents (rare)

Question 7

Anti-Secretatory Agents

Answer 7

Include H₂As and PPIs

These agents reduce gastric acid secretion.

Question 8

H₂A Drug Interactions

Answer 8

H₂As inhibit CYP-P450 which inhibits the metabolism of many drugs.

Question 9

Types of PPIs

Answer 9

There are currently six of them…

1. Esomeprazole
2. Dexlansoprazole
3. Lansoprazole
4. Omeprazole
5. Pantoprazole
6. Rabeprazole

All of them work extremely similarly. They are the most effective drugs in anti-ulcer therapy.

Question 10

PPI Mechanism of Action

Answer 10

The drugs are inactive at a neutral pH, but when the pH drops below 5, they rearrange to their activated form and irreversibly bind to and inactivates H⁺/K⁺ ATPase proton pumps which inhibits acid secretion by parietal cells. Acid secretion only resumes with the synthesis of new enzymes.

Question 11

Frequency of Prescribed PPIs

Answer 11

PPIs are one of the most frequently prescribed drugs in the world because of…

1. High level of efficacy
2. Low toxicity
3. Reduced cost
4. Lack of alternative therapies

Question 12

Threshold for Gastric Pepsin Activity

Answer 12

pH 4

After you cross the pH of 4 threshold, gastric pepsin activity drops from around 90% down to about 40%. This is important in the healing of ulcers, as you do not want pepsin (a protease) digesting the clotting factors or the blood clot.