From the Guidelines
Aspirin works primarily by irreversibly inhibiting cyclooxygenase (COX) enzymes, which are responsible for producing prostaglandins and thromboxanes from arachidonic acid, with the most recent and highest quality study supporting this mechanism being from 2012 1.
Mechanism of Action
The mechanism of action of aspirin involves the inhibition of COX-1 and COX-2 enzymes, which are responsible for converting arachidonic acid into prostaglandin H2, an intermediate in the inflammatory cascade. This inhibition reduces the production of prostaglandins that mediate pain, fever, and inflammation, explaining aspirin's analgesic, antipyretic, and anti-inflammatory effects.
- Aspirin's inhibition of COX-1 in platelets blocks the formation of thromboxane A2, which normally promotes platelet aggregation and vasoconstriction.
- Since platelets cannot synthesize new COX enzymes, this antiplatelet effect lasts for the platelet's entire 7-10 day lifespan, making aspirin effective for preventing blood clots at low doses (typically 81-325 mg daily) 1.
- At higher anti-inflammatory doses (650-1000 mg), aspirin also inhibits COX-2, which is induced during inflammation, as supported by a study from 2009 1.
Key Points
- Aspirin's dual inhibition mechanism explains why it is effective for multiple conditions ranging from pain relief to cardiovascular protection.
- The antiplatelet effect of aspirin is saturable at doses in the range of 75 to 100 mg, as would be expected from human studies of platelet COX-1 inactivation, as noted in a study from 2007 1.
- Alternative or additional mechanisms of action for aspirin are possible, such as an anti-inflammatory effect, but they are unlikely to be important at the low doses of aspirin that are effective in preventing blood clots.
From the Research
Mechanism of Action of Aspirin
The mechanism of action of aspirin (acetylsalicylic acid) is primarily attributed to its ability to inhibit cyclooxygenase (COX) enzymes, which are responsible for the production of prostaglandins and thromboxanes 2, 3, 4. Aspirin acts as a non-selective COX inhibitor, targeting both COX-1 and COX-2 isoforms, although it has a higher potency for COX-1 inhibition 3.
Inhibition of COX Enzymes
- Aspirin inhibits COX-1 by acetylating serine-529, preventing the access of arachidonic acid to the catalytic site of the enzyme, resulting in an irreversible inhibition of platelet-dependent thromboxane formation 3.
- Aspirin also inhibits COX-2 activity, although to a lesser extent than COX-1, which contributes to its anti-inflammatory effects 2, 4.
Effects on Platelet Function
- Aspirin's inhibition of COX-1 in platelets reduces thromboxane A2 synthesis, leading to decreased platelet aggregation and an anti-thrombotic effect 3, 4.
- The optimum dose of aspirin for anti-thrombotic effects can vary depending on the specific condition being treated, with lower doses (e.g., 100 mg/day) sufficient for coronary circulation and higher doses required for cerebral and peripheral circulation 3.
Other Mechanisms
- Aspirin may also inhibit the expression of COX-2 protein through interference with the binding of CCAAT/enhancer binding protein beta (C/EBPbeta) to its cognate site on the COX-2 promoter/enhancer 4.
- At suprapharmacological concentrations, aspirin may inhibit NF-kappaB-mediated gene transcription, providing additional anti-inflammatory effects 4.
Clinical Applications
- Aspirin's mechanism of action contributes to its use in various clinical applications, including the prevention of cardiovascular disease, colorectal cancer, and neurologic ailments, although the decision to use aspirin should be guided by careful consideration of the risks and benefits 5.