What is thought to be the major mechanism of action of NSAIDs?
The major mechanism of action is thought to be the inhibition of cyclooxygenase (COX), causing a decrease in PG production. There are two main isoforms of COX—COX-1 and COX-2. They are similar in size, have 60% C-DNA homology, and have similar but slightly different active sites.
COX-1 gene is on chromosome 9 and lacks a TATA box and upstream transcriptional start sites. The transcriptional product (mRNA) of COX-1 expression is long-lived. These aspects suggest that the COX-1 gene is a “housekeeping gene” , with constitutive expression in the stomach, intestine, kidney, platelet, and other sites.
COX-2 gene is on chromosome 1 and contains a TATA box as well as upstream regions that serve as binding sites for multiple transcription factors. These transcription factors include nuclear factor kappa B (NF-κB), interleukin-6/CCAAT enhancer-binding protein, cAMP regulatory binding protein, activator protein 1, nuclear factor of activated T cells, and glucocorticoid receptors. The mRNA produced by transcription is short-lived; therefore, ongoing expression is dependent on continual stimulation. As such, the COX-2 gene is thought to be an inducible gene with increased expression in response to inflammatory states due to binding of upregulated transcription factors.
It is this understanding of the different roles of COX-1 and COX-2 that led to the development of specific COX-2 inhibitors. The hope was that analgesic and antiinflammatory NSAIDs could be made with little or no side effects. However, COX-2 is now known to be constitutively produced in sites such as the kidney, brain, bone, and endothelium, and plays an important role in vascular and thrombotic regulation.
What are the other mechanisms of action of NSAIDs?
Non-PG-mediated effects of the NSAIDs have been postulated, but the relative importance of each of these pathways in the clinical effectiveness of NSAIDs is uncertain. These effects include:
- Inhibitory effects on lipoxygenase products.
- Inhibition of superoxide formation.
- Inhibition of neutrophil aggregation, adhesion, and enzyme release.
- Inhibition of degradative enzymes.
- Inhibition of cytokine production by inhibiting NF-κB.
- Suppression of proteoglycan degradation in cartilage.