Mechanism of Action of NSAIDs
NSAIDs exert their therapeutic effects primarily through inhibition of cyclooxygenase (COX) enzymes, which blocks prostaglandin synthesis in peripheral tissues, resulting in anti-inflammatory, analgesic, and antipyretic effects. 1, 2
COX Enzyme Inhibition
NSAIDs inhibit two structurally distinct forms of the cyclooxygenase enzyme:
- COX-1: Constitutively expressed in normal cells, responsible for physiological functions
- COX-2: Primarily induced in inflammatory cells 2
The inhibition of these enzymes leads to decreased production of prostaglandins, which are mediators of:
Types of NSAIDs Based on COX Selectivity
Traditional/Non-selective NSAIDs:
COX-2 Selective Inhibitors (Coxibs):
Aspirin:
- Unique in that it irreversibly blocks COX enzymes
- Has cardioprotective effects not seen with other NSAIDs 2
Pharmacological Effects
Anti-inflammatory effects: Primarily through COX-2 inhibition, reducing production of inflammatory prostaglandins 4
Analgesic effects: By decreasing prostaglandin synthesis, which:
- Reduces sensitization of afferent nerves
- Diminishes the action of bradykinin in inducing pain 3
Antipyretic effects: Through inhibition of prostaglandin synthesis in the central nervous system 6
Clinical Implications of COX Inhibition
Gastrointestinal effects: COX-1 inhibition reduces protective prostaglandins in the GI tract, leading to potential ulceration and bleeding 2, 1
Cardiovascular effects: COX-2 inhibition without balanced COX-1 inhibition may increase cardiovascular risks by altering the thromboxane/prostacyclin balance 7
Renal effects: Both COX-1 and COX-2 are constitutively expressed in the kidney; inhibition can lead to sodium retention, reduced renal blood flow, and potential acute kidney injury in susceptible individuals 8
Platelet effects: COX-1 inhibition reduces thromboxane A2 production, affecting platelet aggregation 1
Important Clinical Considerations
The therapeutic benefit of NSAIDs comes from their anti-inflammatory properties, which provide superior pain control compared to simple analgesics like acetaminophen 2
COX-2 selective inhibitors were developed to maintain anti-inflammatory effects while reducing gastrointestinal toxicity, but may have increased cardiovascular risks 5, 7
Both COX-1 and COX-2 have physiological roles in various tissues, explaining the diverse side effect profile of NSAIDs 8, 9
Understanding this mechanism of action helps explain both the therapeutic benefits and adverse effects of NSAIDs, guiding appropriate clinical use and risk assessment for individual patients.