Elsevier

Thrombosis Research

Volume 110, Issues 5–6, 15 June 2003, Pages 255-258
Thrombosis Research

Review Article
The mechanism of action of aspirin

https://doi.org/10.1016/S0049-3848(03)00379-7Get rights and content

Abstract

The therapy of rheumatism began thousands of years ago with the use of decoctions or extracts of herbs or plants such as willow bark or leaves, most of which turned out to contain salicylates. Following the advent of synthetic salicylate, Felix Hoffman, working at the Bayer company in Germany, made the acetylated form of salicylic acid in 1897. This drug was named “Aspirin” and became the most widely used medicine of all time. In 1971, Vane discovered the mechanism by which aspirin exerts its anti-inflammatory, analgesic and antipyretic actions. He proved that aspirin and other non-steroid anti-inflammatory drugs (NSAIDs) inhibit the activity of the enzyme now called cyclooxygenase (COX) which leads to the formation of prostaglandins (PGs) that cause inflammation, swelling, pain and fever. However, by inhibiting this key enzyme in PG synthesis, the aspirin-like drugs also prevented the production of physiologically important PGs which protect the stomach mucosa from damage by hydrochloric acid, maintain kidney function and aggregate platelets when required. This conclusion provided a unifying explanation for the therapeutic actions and shared side effects of the aspirin-like drugs. Twenty years later, with the discovery of a second COX gene, it became clear that there are two isoforms of the COX enzyme. The constitutive isoform, COX-1, supports the beneficial homeostatic functions, whereas the inducible isoform, COX-2, becomes upregulated by inflammatory mediators and its products cause many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis.

Section snippets

Early explanations for the action of aspirin

Before 1971, little was known about the real mechanism of action of aspirin-like drugs. They produced an anti-inflammatory effect that was qualitatively and quantitatively different from that of the anti-inflammatory steroids, and their analgesic action was of a different nature than that produced by opiates. Aspirin-like drugs are weak analgesics compared with “strong” narcotic analgesics like morphine. They are effective in clinical pain of low or moderate but not high intensity such as

Aspirin and the prostaglandin system

It was against this background of knowledge that the investigation of aspirin's action was taken over by prostaglandin (PGs) researchers. Piper and Vane [7] used isolated lungs perfused with Krebs' solution from sensitised guinea pigs. The purpose was to detect substances released during the anaphylactic reaction, including histamine and SRS-A, both of which had been known for many years as possible mediators of anaphylaxis.

They used the technique of continuous bioassay with the cascade

Correlation of anti-enzyme activity of aspirin with its therapeutic activity

The major importance of these findings was that they provided a simple explanation of the manner in which aspirin-like drugs exerted their therapeutic actions. When the reports were published in 1971, there was already evidence suggesting that PGE1 was an extremely potent pyretic agent in several species [16] and that PGE1 or PGE2 mimicked the inflammatory response when injected intradermally. PGs had also been detected in inflammatory exudates [17], so there were grounds for speculating that

Inhibition of cyclooxygenase

A homogeneous, enzymatically active cyclooxygenase (COX) or prostaglandin endoperoxide synthase (PGHS) was isolated in 1976 [19]. This membrane-bound hemoprotein and glycoprotein with a molecular weight of 72 kDa is found in greatest amounts in the endoplasmic reticulum of prostanoid-forming cells [20]. It exhibits COX activity that both cyclizes arachidonic acid and adds the 15-hydroperoxy group to form PGG2. The hydroperoxy group of PGG2 is reduced to the hydroxy group of PGH2 by a peroxidase

Discovery of COX-2 and COX-3

By the late 1980s, several reports appeared that the synthesis of PGHS could be stimulated by growth factors, tumour promoters, interleukin-1 [24], lipopolysaccharide and tumour necrosis factor. Interleukin-1 exerted its effect during the transcriptional rather than during the translational phase of induced synthesis of PGHS [25]. Induction of PGHS gene expression by serum factors occurred after approximately 2 h in mouse 3T3 cells, in which PGs are essential for cell division. These reports

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