Nonsteroidal anti-inflammatory drugs (NSAIDs)
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drug class for ones suffering from pain, fever, and inflammation. Daily, over 30 million aspirin or non-aspirin NSAIDs are being consumed consciously or unconsciously.
Currently, Aspirin™ has been a widely utilized pharmaceutical for 123 years and is appointed as the progenitor of NSAIDs. The origin of aspirin or non-aspirin NSAIDs is based on serendipitous discoveries in ancient times. In the journey to the past, it could be seen that Sumerians used to apply the salicylate-containing willow leaves (Salix species) to treat the inflammatory rheumatic disease.
The importance of the willow leaf could be also noted in the Ebers Papyrus (1534 B.C.) against inflammatory symptoms. Years later, the Greek physician Hippocrates (400 B.C.) suggested the use of leaves and bark extracts of the Salix plants for the relief of pain and fewer. Moreover, a number of the report recorded by Pliny the Elder (23 CE), Dioscorides (40 CE), and Galen (129 CE) regarding the medicinal potency of these substances have been transmitted from generation to generation.
Those pre-record paved the way for the clinical application of willow bark extract on 50 patients with agues or fever in the 17th century. Accordingly, the results of trials were presented by Edward Stone who is the first author exhibiting the healing potency of willow bark as an antipyretic in a scientific manner.
Owing to the developments in the fields of chemistry, the isolation of the active ingredient of willow called “salicin” was carried out by German pharmacologist Joseph Buchner in the mid-late 19th century. A few years later, Italian chemists, Raffaele Piria found a way to extract the salicylic acid, which is the primary compound for the synthesis of aspirin from salicin, and purified it.
In 1958, German chemist Hermann Kolbe and his assistant Rudolf Wilhelm Schmitt achieved a significant breakthrough in the chemical synthesis of salicylic acid. As a result of its production with industrial scale, synthetic salicylates were examined by several clinical trials in the same years. The effectiveness of the compound encouraged further studies for the development of salicylate derivatives with diminished adverse effects. In the Bayer’s lab (1897), pharmaceutical chemist Felix Hoffmann discovered the reaction conditions yielding acetylsalicylic acid.
This pure, stable, and cheap compound was patented by Bayer AG and manufactured in tablet form named Aspirin™. Although years have passed, approximately 100 billion standard aspirin tablets are still being marketed each year due to its potent anti-inflammatory, antipyretic, and antiplatelet therapeutic actions. Both clinical outcomes and the success of the aspirin in the pharmaceutical industry led to the development of further samples of NSAIDs. Eventually, drugs such as phenylbutazone, indomethacin, ibuprofen hit the markets in the pre-prostaglandin era.
COXs As Biological Target of NSAIDs
The basic action mode of NSAIDs is based on repressing the release of PGs and thromboxane (TxA) by inhibiting the action of COX enzymes. When Hemler et al. identified the constitutive COX enzyme, also termed prostaglandin H synthase (PGHS) in 1976 for the first time, it was not known the existence of COX isoforms. In the late 1980s– early 1990s, a second isoform of the enzyme (COX-2) was identified, isolated, and cloned. Both COX isoforms share a common role in arachidonic acid (AA) metabolism in which bioactive PG species are synthesized from arachidonate. They have not only similarities in the function, but the comparative analysis of these genes also revealed almost 60-65% amino-acid identity with each other in the same species and 85-90% similarity among different species. Another common feature of COXs is their subcellular locations: they are found mainly on the membranes of the luminal side of the endoplasmic reticulum (ER), besides, COX-2 is also found on the membrane of the nucleus.
The main differences between these isoenzymes are their expression levels and tissues in which they are expressed in the body. The COX-1 is constitutively expressed in various tissues at low levels for the maintenance of the synthesis of physiologically important prostanoids which are essential for the gastrointestinal cytoprotection, regulation of renal blood flow, improved organ perfusion as well as a healthy pregnancy. In contrast, the expression of COX-2 is induced and up- regulated in cells (mainly monocytes, macrophages, synovial microvessel endothelial cells, chondrocytes, and osteoblasts) by several stimulants including bacterial endotoxins, pro- inflammatory cytokines, and growth factors. Sustained activation of COX- 2 is associated with the exaggerated production of inflammation and pain-related PGs.
Understanding the Reasons For Adverse Effects of NSAIDs
The production of the PGs and TxAs depends on the presence of AA in the site of action. When an inflammatory signal comes to the cell, the enzymes called secretory and cytoplasmic Phospholipases A2, which balance the eicosanoid levels, are activated to convert the membrane-bound arachidonate into free AA. The release of AA induces COX pathways in which these molecules are oxygenated by COXs to yield prostaglandin G2. Immediately after, this molecule is catalyzed by peroxidase into prostaglandin H2 which is a substrate for the cell-specific enzymes to generate bioactive PG species PGD2, PGE2, PGF2α, prostacyclin (PGI2), and thromboxane A2 (TxA2) as shown in Figure.