MILITARY PHARMACY AND MEDICINE

© Military Pharmacy and Medicine • 2012 • 4 • 35 – 50Jerzy Z. Nowak: Non-steroidal anti-inflammatory drugs (NSAIDs) in …Figure 1: Metabolizm of arachidonic acid (AA) with the aid of cyclooxygenases (COX) and lipoxygenases (LOX) and sites of actions of nonsteroidalanti-inflammatory drugs (NSAIDs), and glucocorticosteroids in comparison.NSAIDs inhibit COX activity (the COX-1 and COX-2 isoenzymes); depending on the drug the inhibitory effect on COX-1 and COX-2 is varied (COX-1 > COX-2, COX-2 > COX-1). Glucocorticosteroidsinhibit phospholipase A2 – PLA2 (this enzyme releases AA from the pool of membrane phospholipids, which makes the free AA a substrate for COX and LOX).The PLA2-related effect of glucocorticosteroids refers to rapid nongenomic action, which in fact involves an indirect mechanism via lipocortin-1 and EGF receptor-driven signalingpathway. However, the main anti-inflammatory and immunosuppressive effects of glucocorticosteroids, as well as their unwanted effects, result from the specific glucocorticosteroidreceptor-mediated genomic mechanisms involving trans-suppression or inhibition of the expression of genes encoding pro-inflammatory mediators (main therapeutic effect), and transactivation,i.e. stimulation of the expression of genes encoding various proteins with varied biological activity (most of the effects are unwanted).lipoxins (resulting from AA molecules undergoingtransformation by the activity of acetyl-COX-2, i.e.the enzyme acetylated with aspirin, ASA-COX2)[3]. One should also remember that AA is a constantingredient of membrane phospholipids and, in orderto become a substrate for COX, LOX and ASA-COX2it must be extracted from the phospholipid poolinto its free form, which is achieved by means of aspecific phospholipase A 2(PLA 2) enzyme [4]. Thisstep is the stage for anti-inflammatory activity ofglucocorticosteroids, where endogenous cortisol andits synthetic analogs, all of them used in medicine,inhibit the PLA 2activity, blocking the supply of theAA substrate for the synthesis of pro-inflammatorymediators, both COX-dependent (mostlyprostaglandins) and LOX-dependent (leukotrienes)(Fig. 1). It should be highli-ghted that the mainanti-inflammatory effects of glucocorticosteroidsare achieved by means of a receptor-dependentgenomic mechanism as a result of inhibition ofthe expression of genes encoding inflammatorymediators (transsuppression), while the adverseeffects of this class of drugs are due to activation ofthe transactivation mechanism.http://military.isl-journals.comThe findings of the Nobel Prize winners as mentionedin Introduction did not differentiate betweenindividual COX isoforms, as the secondisoenzyme, known as COX-2, was identified onlyas late as in early 1990s [6]. Experiments in dogtissues revealed the existence of a third COX isoform,COX-3, characterized by particular sensitivityto paracetamol. However, as soon becameevident, such paracetamol-sensitive COX-3 isoformis absent from human body, and the humanequivalent of dog COX-3 gene, present in sometissues, particularly the tissues of the centralnervous system (CNS) is an alternatively splicedvariant of COX-1, without preferential sensitivityto paracetamol, encoding a protein with theamino acid sequence different from that of COXand exerting no COX-like activity. Thus, contributionof COX-3 to the mechanism of action ofthe popular drug paracetamol in humans, as proposedby some authors, is not substantiated, asconfirmed by Kis [7] and the recent detailed analysesconducted by Hinz and Brune’s group [8] [2] .[2] The exact mechanism of action of paracetamol is unknown, despite thelong history of its use in pharmacology. Discovered more than 100 years agoand extensively used in medicine for more than half a century, paracetamol35