mode of action

Last reviewed 04/2022

Aspirin causes modification of the cyclooxygenase activity of prostaglandin synthase by permanent acetylation of the protein.

There are two isoenzymes of prostaglandin synthase:

• type 1:
• this is constitutively expressed on platelets
• involved in platelet aggregation
• cyclo-oxygenase activity irreversibly blocked by aspirin - aspirin reacts with the binding site of COX-1 and results in selective and irreversible acetylation of serine reside 529. Platelets lack the ability to synthesise COX-1 de novo and therefore the effects of aspirin last for the life of the platelet (8-10 days)
• the effects of aspirin are cumulative so that on repeated low-dose administration more than 95% of platelet COX-1 activity is suppressed after seven days of treatment

• type 2:
• only expressed in response to inflammation
• inhibition of this isoenzyme results in the analgesic and anti-inflammatory effects of aspirin
• cyclooxgenase activity is modified by aspirin

The beneficial effects of aspirin, such as analgesia and the reduction of platelet adhesion are due to the block in prostaglandin production. For the latter, aspirin inhibits the production of pro-thrombotic thromboxane A2 in platelets and anti-thrombotic prostacyclin in endothelial walls. However, the effect on platelets occurs at a lower concentration of aspirin than that on endothelial cells; also, endothelial cells can resynthesise arachidonic acid metabolites whereas platelets cannot.

The unwanted side-effect of gastric irritation is probably due to reduced production of prostacyclin, a vasodilator which is important in maintaining a good blood supply to the gastric mucosa.