NSAIDs: choices and issues (Proceedings)


NSAIDs: choices and issues (Proceedings)

Nov 01, 2010

General Pharmacology of NSAIDs

As their name implies, nonsteroidal aniti-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 PGF2a. 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 PGF2a 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.

It is of particular pharmacological interest that there are two isoforms of cyclooxygenase that are differentially expressed in the tissues. Cyclooxygenase I (COX-1) is constitutively expressed in numerous tissues, including the platelets, vascular endothelial cells, gastrointestinal tract, and renal tubule. The prostanoid products of COX-1 include PGE2, which is associated with gastroprotective effects and renal homeostasis. Prostacyclin and thromboxane are also produced by COX-1. In contrast, COX-2 is classically considered to be the inducible isoform of cyclooxygenase, with its expression being increased by injury, and its products, such as PGE2, being primarily pro-inflammatory and associated with pathological effects. The activity of an NSAID can be measured by in vitro assays that yield the concentration of drug that inhibits COX enzyme activity by 50% as compared to the absence of drug (IC50). An agent with a low IC50 more potently inhibits COX than does a drug with a higher IC50. In addition to facilitating the comparison of different NSAIDs, the IC50 can be used to test how an NSAID affects different COX isoforms. The ratio of the IC50 for COX-2:COX-1 can be used to classify the activity of NSAIDs as nonselective, preferential, or selective for inhibition of COX-2. An agent with similar activity against both COX-1 and COX-2, such as aspirin, is nonselective for COX-2. A drug that much more potently inhibits COX-2 as compared to COX-1, such as deracoxib, is considered to be COX-2 selective. Agents that are intermediate in their inhibition of COX-2 as compared to COX-1, such as carprofen, are considered to be preferential inhibitors of COX-2. These designations are somewhat arbitrary and are highly dependent on the assay and the species being studied, but are useful for considering the spectrum of indications and side effects that are expected from each NSAID. Most of the classical side effects associated with NSAID use, such as gastrointestinal ulceration and renal disease, are primarily attributed to inhibition of constitutive COX-1. Therefore, COX-2 preferential and selective agents are associated with fewer of these classical side effects than are nonselective agents. This has allowed many dogs and cats that couldn't have tolerated anti-inflammatory doses of older NSAIDs, such as aspirin and ibuprofen, to tolerate the newer COX-2 selective and preferential agents. In addition, considerable research and development of COX-2 selective NSAIDs in human medicine has led to the development of similar compounds for veterinary use. Altogether, the greater safety of newer agents along with the explosion in research interest has resulted in the approval of many new NSAIDs expressly for veterinary use during the past ten years.