NSAIDs: What's new? (Proceedings)
General Pharmacology of NSAIDs
As their name implies, nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of inflammatory conditions, which are characterized by redness, swelling, heat, pain, and loss of function. Although the inflammatory response can be viewed as essentially protective and beneficial to the body, excessive inflammation in the face of progressive disease can promote the cycle of increasing damage and inflammation. In addition, the pain associated with inflammation can have adverse effects on patient welfare. The major indications for the administration of NSAIDs are analgesic, anti-inflammatory, and reduction of pyrexia. These indications generally involve symptomatic treatment of a primary problem. Indications for the use of NSAIDs as primary therapy in small animal patients include the prevention and treatment of thromboembolic disease and the adjunctive therapy of neoplasia. Of these indications, the greatest area of use and interest in NSAIDs during recent years has been in the reduction of pain. As the need for geriatric medicine has increased in prominence, there has been a commensurate rise in interest in the use of NSAIDs as palliative therapy for osteoarthritis.
Osteoarthritis involves the cycle of inflammation and damage, in which the underlying damage to chondrocytes and synovial cells results in localized inflammation. Inflammatory mediators, such as prostaglandins, leukotrienes, superoxides, and proteolytic enzymes, lead to decreased viscosity of synovial fluid, further damage to the joint, and increased inflammation. The original injury stimulates this process by liberating phospholipids from cellular membranes. Phospholipases act on the liberated phospholipids to form arachidonic acid, which is itself a substrate for two separate enzyme systems. Arachidonic acid can be metabolized by several isoforms of cyclooxygenase to form prostanoid metabolites, including prostaglandin E2 (PGE2), thromboxane (TXA2), prostacyclin (PGI2), and PGF2α. Alternatively, arachidonic acid can be metabolized by lipoxygenase to form leukotrienes, such as LTB4. All of these eicosanoids are inflammatory mediators that differ with respect to their physiological functions. As the various NSAIDs will inhibit different enzymes in the eicosanoid pathway, an understanding of the functions of each eicosanoid provide the foundation for the differential effects of NSAIDs. The prostanoid most commonly measured to assess the efficacy of NSAIDs is PGE2, which is vasodilatory, sensitizes nerves to pain, and is pyretic. Of the other prostanoids, thromboxane and prostacyclin oppose one another in activity, with thromboxane serving to stimulate vasoconstriction and platelet aggregation whereas prostacyclin exerts the opposite effects. The eicosanoid PGF2α primarily functions as a reproductive hormone, although it also exhibits vasoconstrictive effects. Arguably the best known inflammatory leukotriene is LTB4, which stimulates leukocyte chemotaxis, aggregation, and degranulation. In addition, LTB4 also increases vasodilation and permeability of capillaries, thus increasing redness and swelling. Although leukotrienes appear to play a role in the toxicities that can be associated with NSAID administration, they are also important mediators of hypersensitivity, such as in asthmatic diseases. Other inflammatory mediators, such as proteolytic enzymes and superoxides, contribute to localized lipid peroxidation and tissue destruction.