- Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is most commonly associated with gastrointestinal bleeding.
- NSAIDs work by inhibiting cyclooxygenase (COX) enzymes, which are crucial for the synthesis of prostaglandins.
- Prostaglandins play an important role in protecting the gastric mucosa by promoting mucus and bicarbonate secretion and maintaining adequate blood flow.

- When prostaglandin production is inhibited, this protective effect is lost, leading to increased risk of gastric irritation, ulcer formation, and bleeding.
- This risk is especially significant with prolonged use or higher doses of NSAIDs.

- While renal insufficiency can also occur due to decreased prostaglandin-mediated renal blood flow, it is less common than gastrointestinal bleeding as a long-term adverse effect.
- Hepatotoxicity is rare with most traditional NSAIDs and hypoglycemia is not linked to NSAID use.

Key Points:
- NSAIDs inhibit COX enzymes → ↓ prostaglandins
- Prostaglandins protect gastric mucosa → ↓ prostaglandins → ↑ risk of ulcers and bleeding
- Gastrointestinal bleeding is the most frequent serious long-term adverse effect
- Renal insufficiency may occur but is less common
- Hepatotoxicity and hypoglycemia are not typical NSAID-related problems

Reference: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition, Chapter on NSAIDs / Page 787