Mechanism of action of aspirin

Structure of COX-2 inactivated by Aspirin. In the active site of each of the two enzymes, Serine 516 has been acetylated. Also visible is the salicylic acid which has transferred the acyl group, and the heme cofactor.

There are at least two different cyclooxygenase isozymes: COX-1 (PTGS1) and COX-2 (PTGS2). Aspirin is non-selective and irreversibly inhibits both forms[2] (but is weakly more selective for COX-1[3]). It does so by acetylating the hydroxyl of a serine residue.[4] Normally COX produces prostaglandins, most of which are pro-inflammatory, and thromboxanes, which promote clotting. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the hope for reduction of gastrointestinal side-effects.[5]

However, several COX-2 selective inhibitors have subsequently been withdrawn after evidence emerged that COX-2 inhibitors increase the risk of heart attack (e.g., see the article on Vioxx). The underlying mechanism for the deleterious effect proposes that endothelial cells lining the microvasculature in the body express COX-2, whose selective inhibition results in levels of prostaglandin I2 (PGI2, prostacyclin) down-regulated relative to thromboxane (since COX-1 in platelets is unaffected). Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. As platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference between aspirin and the reversible inhibitors.

Prostaglandins are local chemical messengers that exert multiple effects including but not limited to the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. They are produced in response to the stimulation of phospholipids within the plasma membrane of cells resulting in the release of arachidonic acid (prostaglandin precursor).[6] Thromboxanes are responsible for the aggregation of platelets that form blood clots.

Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A₂ in platelets, producing an inhibitory effect on platelet aggregation.[7]

This antiplatelet property makes aspirin useful for reducing the incidence of heart attacks;[7] heart attacks are primarily caused by blood clots, and their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. A dose of 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.[8]

A side-effect of aspirin mechanism is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin.[9]

Aspirin has been shown to have three additional modes of action. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the intermembrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons.[10] In short, aspirin buffers and transports the protons, acting as a competitor to ATP synthase. When high doses of aspirin are given, aspirin may actually cause hyperthermia due 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 reduces leukocyte adhesion, which is an important step in immune response to infection. There is currently insufficient evidence to show that aspirin helps to fight infection.[11]

More recent data also suggests that salicylic acid and its derivatives modulate signaling through NF-κB.[12] NF-κB is a transcription factor complex that plays a central role in many biological processes, including inflammation.

Salicylates are derivatives of salicylic acid that occur naturally in plants and serve as a natural immune hormone and preservative, protecting the plants against diseases, insects, fungi, and harmful bacteria. Salicylates can also be found in many medications, perfumes and preservatives. Both natural and synthetic salicylates can cause health problems in anyone when consumed in large doses, but for those who exhibit salicylate sensitivity (also known as salicylate intolerance), even small doses of salicylate can cause adverse reactions.

Specifically, salicylate sensitivity refers to any adverse effect that occurs when a normal amount of salicylate is introduced into a person's body. People with salicylate intolerance are unable to consume a normal amount of salicylate without adverse effects.

Salicylate sensitivity differs from salicylism, which occurs when an individual takes an overdose of salicylates.[13] Salicylate overdose can occur in people without salicylate sensitivity, and can be deadly if untreated. For more information, see aspirin poisoning.

• History of aspirin