Discovery of the mechanism
In 1971, British pharmacologist John Robert Vane, then employed by the Royal College of Surgeons in London, showed that aspirin suppressed the production of prostaglandins and thromboxanes. For this discovery, he was awarded both a Nobel Prize in Physiology or Medicine in 1982 and a knighthood.
Suppression of prostaglandins and thromboxanes
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (PTGS) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the PTGS enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors.
Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks.40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.
Prostaglandins are local hormones produced in the body and have diverse effects in the body, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute myocardial infarction. An unwanted side-effect of the effective anti-clotting action of aspirin is that it may cause excessive bleeding.
PTGS1 [COX-1] and PTGS2 [COX-2] inhibition
There are at least two different types of cyclooxygenase: PTGS1 and PTGS2. Aspirin irreversibly inhibits PTGS1 and modifies the enzymatic activity of PTGS2. Normally PTGS2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified PTGS2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called PTGS2 selective inhibitors have been developed that inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal side effects.
However, several of the new PTGS2 selective inhibitors, such as Vioxx, have been withdrawn recently, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express PTGS2, and, by selectively inhibiting PTGS2, prostaglandin production (specifically PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as PTGS1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGI2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.
Additional mechanisms
Aspirin has been shown to have at least three additional modes of action. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons.In short, aspirin buffers and transports the protons. When high doses of aspirin are given, aspirin may actually cause fever owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. Additionally, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion, which is an important step in immune response to infection; however, there is currently insufficient evidence to show that aspirin helps to fight infection. More recent data also suggests that salicylic acid and its derivatives modulate signaling through NF-κB. NF-κB is a transcription factor complex that plays a central role in many biological processes, including inflammation.
Effects upon Hypothalamic-Pituitary-Adrenal Activity
Aspirin reduces the effects of vasopressin and increases those of naloxone upon the secretion of ACTH and cortisol by the hypothalamic-pituitary-adrenal axis. It has been suggested that this occurs through an interaction with endogenous prostaglandins and their role in regulating the HPA axis
