Discovery of the mechanism In 1971, British pharmacologist John Robert Vane, then employed by the Royal College of Surgeons in London, showed<unk>  suppressed the production of prostaglandins and thromboxanes. For this discovery he was awarded the 1982 Nobel Prize in Physiology or Medicine, jointly with Sune Bergström and Bengt Ingemar Samuelsson. Prostaglandins and thromboxanes<unk> 's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX; officially known as prostaglandin-endoperoxide synthase, PTGS) enzyme required for prostaglandin and thromboxane synthesis.<unk>  acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the PTGS enzyme (Suicide inhibition). This makes<unk>  different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors. Low-dose<unk>  use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8–9 days). This antithrombotic property makes<unk>  useful for reducing the incidence of heart attacks in people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack. 40mg of<unk>  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<unk>  are required to attain further inhibition. Prostaglandins, local hormones produced in the body, have diverse effects, 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 caused primarily by blood clots, and low doses of<unk>  are seen as an effective medical intervention to prevent a second acute myocardial infarction. COX-1 and COX-2 inhibition At least two different types of cyclooxygenases, COX-1 and COX-2, are acted on by<unk> .<unk>  irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally produces prostanoids, most of which are proinflammatory.<unk> -modified PTGS2 (prostaglandin-endoperoxide synthase 2) produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs, COX-2 inhibitors (coxibs), have been developed to inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal side effects. Several COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn from the market, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack and stroke. Endothelial cells lining the microvasculature in the body are proposed to 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 anticoagulative effect of PGI2 is removed, increasing the risk of thrombus and<unk> ociated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new PTGS once<unk>  has irreversibly inhibited the enzyme, an important difference with reversible inhibitors. Furthermore,<unk> , while inhibiting the ability of COX-2 to form pro-inflammatory products such as the prostaglandins, converts this enzyme's activity from a prostaglandin-forming cyclooxygenase to a lipoxygenase-like enzyme:<unk> -treated COX-2 metabolizes a variety of polyunsaturated fatty acids to hydroperoxy products which are then further metabolized to specialized proresolving mediators such as the<unk> -triggered lipoxins,<unk> -triggered resolvins, and<unk> -triggered maresins. These mediators possess potent anti-inflammatory activity. It is proposed that this<unk> -triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of<unk> . Additional mechanisms<unk>  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.<unk>  buffers and transports the protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of<unk>  seen with lower doses. In addition,<unk>  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 is an important step in the immune response to infection; however, evidence is insufficient to show<unk>  helps to fight infection. More recent data also suggest salicylic acid and its derivatives modulate signalling through NF-κB. NF-κB, a transcription factor complex, plays a central role in many biological processes, including inflammation.<unk>  is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In 2012, salicylic acid was found to activate AMP-activated protein kinase, which has been suggested as a possible explanation for some of the effects of both salicylic acid and<unk> . The acetyl portion of the<unk>  molecule has its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level.<unk>  is able to acetylate several other targets in addition to COX isoenzymes. These acetylation reactions may explain many hitherto unexplained effects of<unk> .
Aspirin
Clopidogrel
Warfarin
Ticagrelor
Ticlopidine
Palladin
Heparin
Tafamidis