CYCLOOXYGENASE INHIBITORS bind reversibly or irreversibly to the enzyme cyclooxygenase (originally referred to as the prostaglandin synthase system or ‘prostaglandin H2 synthase’; (PGHS)-l and (PGHS)-2). Members of the prostaglandin family have a number of proinflammatory or hyperalgesic actions, and consequently many cyclooxygenase inhibitors are used as anthnflammatories and ANALGESICS.
Prostanoids are members of the eicosanoid family of phospholipid mediators, and are comprised of the thromboxanes and the prostaglandins, both of which are formed by the complex cyclooxygenase system. They share common precursors in the form of a series of unstable cyclic endoperoxides. The first stage of the transformation of arachidonic acid has the enzyme endoperoxide synthase oxygenate arachidonate, followed by cyclization to give a cyclic endoperoxide called PGG2. These reactions are inhibited by cyclooxygenase inhibitors. Subsequently, PGG2 is converted by a peroxidase action to PGH2. This is a common precursor for a number of different pathways, forming prostacyclin (by prostacyclin synthase), the various prostaglandins or thromboxanes (by thromboxane synthase). See THROMBOXANE SYNTHASE INHIBITORS. The conversion depends somewhat on the cell type. For instance, the conversion of PGH2 to thromboxane (by thromboxane synthase) is a prominent pathway in the blood platelets, whereas prostacyclin synthesis is predominant in the vascular endothelium. The eicosanoids are synthesized and released on demand. See PLATELET AGGREGATION INHIBITING AGENTS.
Cyclooxygenase inhibition is thought to underlie the mechanism of action of one of the two main groups of analgesics the non-stewidal antiinflammatory drugs (NSAIDs) — typified by aspirin. The NSAIDs vary in their spectrum of activity, differing in their ability to reduce inflammation, hyperalgesia, raised body temperature, and in some instances inhibit platelet aggregation. It is now believed that the rather different pharmacology can, in part, be accounted for by their different activities against two recently discovered cyclooxygenase isoenzymes. One, COX-1, is constitutively expressed; but the other, COX-2, is inducible. Individual NSAIDs have different ratios of activity against the two forms of the enzyme, and this accounts partly for their side-effects when used for a particular purpose. For most antiinflammatory uses, a relatively high activity against the induced enzyme is desirable — whereas for antiplatelet-aggregation purposes, high activity at the constitutive form is required. A main difference is that paracetamol (acetaminophen, USA) is an effective antipyretic, but has no appreciable antiinflammatory activity and its efficacy as an analgesic depends on the source of pain. Of the many other NSAID drugs, their use is determined in part by how well their side-effects — particularly gastrointestinal disturbances ranging from dyspepsia to serious haemorrhage — are tolerated. It appears that cytotoxicity in the stomach is in part a result of diminished prostanoid synthesis — which has adverse effects on the microcirculation of the gastric mucosa. Preparations are now available that combine a prostaglandin with an NSAID (e.g. misoprostol and naproxen). Details of agents such as diclofenac, ibuprofen, indomethacin, piroxicam etc. are given under NSAID ANALGESICS, ANTIINFLAMMATORY AGENTS and ANTIPYRETICS. An important action of aspirin, not shared with the majority of NSAIDs, is as a platelet aggregation inhibiting agent. The explanation seems to be that aspirin is relatively active at COX-1, irreversibly alkylating its active site. This reduces thromboxane A2 (TXA2) synthesis in platelets, and platelets cannot synthesize new enzyme, so activity does not return until new platelets are formed (which takes about a week). In contrast, the vascular endothelium is able to generate more enzyme; further, a higher concentration of aspirin is required in these cells. Thus aspirin may be given intermittently at low doses.