Overview
This lecture focuses on aspirin’s chemical structure, unique mechanism among NSAIDs, clinical uses, and important precautions regarding its side effects.
History and Chemistry of Aspirin
- Aspirin belongs to the salicylic acid class of NSAIDs.
- Ancient remedies used willow and meadowsweet for fever, both containing salicin, a precursor to salicylic acid.
- Felix Hoffman synthesized aspirin (acetylsalicylic acid) in 1899 by adding an acetyl group to salicylic acid.
- The acetyl group distinguishes aspirin, enabling its unique effects compared to other NSAIDs.
Mechanism of Action
- Aspirin irreversibly inhibits cyclooxygenase (COX) enzymes by acetylating a serine residue in the active site.
- Acetylation permanently inactivates COX, requiring new enzyme synthesis for function to return.
- Other NSAIDs only reversibly inhibit COX by competing for the active site.
Clinical Effects and Platelet Function
- Low-dose aspirin prevents blood clotting by inhibiting pro-clotting prostaglandin TxA2 in platelets.
- Platelets cannot replace inactivated COX because they lack nuclei, so the effect lasts for the platelet’s lifespan (8-9 days).
- Vessel-lining cells can regenerate COX, maintaining production of anti-clotting prostaglandin PGI2.
- The shift in pro- and anti-clotting factors results in aspirin's blood-thinning effect.
Aspirin-Triggered Lipoxins and Anti-inflammatory Actions
- Aspirin-acetylated COX-2 can generate aspirin-triggered lipoxins (ATLs) like 15-epi-lipoxin-A4, enhancing anti-inflammatory effects.
- ATLs are epimers of natural lipoxins, differing only in one stereocenter.
Clinical Uses and Precautions
- Aspirin treats pain, fever, inflammation, and is used in low doses for heart disease and stroke prevention.
- Some patients, especially 10-25% of asthmatics, have hypersensitivity to aspirin.
- Aspirin is linked to Reye’s syndrome in children and young adults with viral illness, causing liver and brain swelling.
- Aspirin is avoided in children and young adults with viral fever; acetaminophen is preferred because it lacks this risk.
Key Terms & Definitions
- NSAID — Nonsteroidal anti-inflammatory drug, used to reduce pain, fever, and inflammation.
- Aspirin (acetylsalicylic acid) — An NSAID that irreversibly inhibits COX.
- COX (cyclooxygenase) — Enzyme making prostaglandins, central to inflammation and clotting.
- TxA2 (thromboxane A2) — Prostaglandin promoting blood clotting.
- PGI2 (prostacyclin) — Prostaglandin preventing blood clotting.
- Aspirin-triggered lipoxins (ATLs) — Anti-inflammatory molecules produced by aspirin-modified COX-2.
- Reye’s syndrome — Rare disorder causing swelling in the liver and brain, associated with aspirin use in children.
Action Items / Next Steps
- Review the mechanism of action for acetaminophen (Tylenol) in the next lecture.