Arachidonic Acid Pathway

PGs are eicosanoid-compounds synthesised from arachadonic acid (normally found bound to cell membrane phospholipids). After injury, arachadonic acid (AA) is liberated from the cell membrane by the enzymatic action of phospholipase A₂ [PA₂]). Once liberated, free-AA may enter the cyclooxygenase (COX) pathway whereby COX enzymes transform AA into various PG’s. There are two broad categories of active COX: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues including gastrointestinal tract (GIT), platelets and kidney. COX-2 is mostly an inducible enzyme in response to injury (including endothelial injury) and inflammatory stimuli, and a major source of prostanoids. PGs have numerous effects, including acting as inflammatory mediators. Numerous PGs are also active in vascular tissue contributing to vasodilatation (PGI₂, PGE₂), vasoconstriction (PGF_2α, thromboxane A₂ [TxA₂]), platelet aggregation (TxA₂) and platelet inhibition (PGI₂).

Targeting the Arachadonic Acid Pathway

• Corticosteroids inhibit the phospholipase A₂ (PA₂)-mediated release of arachadonic acid from the cell membrane and down-regulate COX-2 expression (but not COX-1). However, steroids have not been shown to alter restenosis rates after treatment of vascular disease.
  
• Non-steroidal anti-inflammatory agents (NSAIDs) are reversible COX inhibitors (both COX-1 and COX-2), thus inhibiting PG synthesis. Induced COX-2 may be responsible for restenosis and platelet aggregation, and selective blockade of this isoform may inhibit this. However, inhibition of COX-2 is associated with increased rates of thrombosis (including coronary), thus prohibiting its use in vascular disease.

Platelet Aggregation