Salicylate common aspirin products

During the nineteenth century, chemists had a good deal of success in isolating and purifying natural products from plant sources. Morphine was isolated as a pure compound from crude opium in 1804. Quinine was isolated from the bark of the cinchona tree in 1820 and was initially employed as a fever reducer. However, its effectiveness against malaria was soon discovered and it found an alternative highly important medical use. Sodium salicylate was isolated from the bark of the willow tree in 1821 and was also shown to have analgesic, antipyretic, and antiinflammatory properties. It took an additional 76 years, until 1897, to synthesize the acetyl derivative, acetylsalicyclic acid, commonly known as aspirin. 

The isolation of strychnine (1), morphine (2), atropine (3), colchicine (4), and quinine (5) in the early 1800s from the commonly used plants and their use for the treatment of certain ailments might constitute the early idea of pure compounds as drugs. E. Merck isolated and commercialized morphine (2) as the first pure natural product for the treatment of pain (1-3). Preparations of the Willow tree have been used as a painkiller for a long period in traditional medicine. Isolation of salicylic acid (6) as the active component followed by acetylation produced the semisynthetic product called Aspirin (7) that was commercialized by Bayer in 1899 for the treatment of arthritis and pain (4). 

The initial product resulting from the action of a lipoxygenase is a hydroperoxy acid. This is quickly followed by reduction to a hydroxyacid by peroxidase. Some common anti-inflammatory drugs have been shown to cause accumulation of 12-HPETE in platelets by inhibition of the enzymatic reduction into 12-HETE [186,188]. Among the drugs showing this effect are aspirin, indomethacin, sodium salicylate and phenylbutazone. 

Salicylate can be applied to the skin as un-ionized salicylic acid (normally for its keratolytic activity), as a salicylate salt (most commonly trolamine salicylate), as esters such as methyl salicylate and, rarely, as aspirin. In the form most often used in topical products, salicylates work primarily as rubefacients. Rubefacients are compoimds that work by counter-irritation. 

The salicylate compounds used topically share with aspirin the common metabolic breakdown product, free salicylate (see section on aspirin earlier in this text), which is primarily responsible for the toxicity observed. On average, 12-20% of the dose of methyl salicylate is absorbed through the skin. Methyl salicylate is readily hydrolyzed to salicylate, although some methyl salicylate is found in blood. Some unchanged methyl salicylate is excreted in urine as hydrolysis is relatively slow in humans. 

The acyl group from an ester can be transferred to another alcohol group via the process of transesterilication. Aspirin is the most widely used dmg in which the ester group is partly responsible for its mechanism of action. In common with the acetylcholine esterase inhibitors discussed below, the target is a serine residue in the enzyme cydooxygenase 1 (COX-1). However, in the case of aspirin the covalent modification of the enzyme is irreversible. Acetylation of COX-1 prevents the production of prostaglandin inflammatory mediators. The salicylate portion of the molecule also possesses anti-inflammatory aaion (Fig. 5.46). 

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