MedSurg Nursing - The New NSAIDs: Cox-2 Inhibitors
Nonsteroidal anti-inflammatory drugs (NSAIDS) are the most widely used medications in the world, with an estimated 30 million people taking an NSAID each day (James, 1999). Millions of dollars are spent each year on this class of drug in over-the-counter (OTC) and prescription forms. Four commonly used OTC NSAIDS are aspirin, ibuprofen (Motrin[R], Advil, Nuprin[R]), naproxen (Aleve[R]), and ketop[R]ofen (Orudis[R]). Prescription NSAIDS include indomethacin (Indocin[R]), diclofenac (Arthrotec[R], Voltaren[R]), ketorolac (Toradol[R]), piroxicam (Feldene[R]), and sulindac (Clinoril[R]). NSAIDS are widely recommended for various disorders such as fever, headache, arthritis, dysmenorrhea, postoperative dental pain, and musculoskeletal injury. Aspirin and ibuprofen are particularly ubiquitous ingredients used in numerous OTC preparations for various conditions from back pain to migraine headache. Patients with arthritis have been among the most frequent users of NSAIDS. The NSAIDs have long been prescribed as first-line treatment in rheumatoid arthritis (RA) and osteoarthritis (OA) (Singh & Ramey, 1998).
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Although clinically effective antipyretic, analgesic, and anti-inflammatory agents, NSAIDs can be accompanied by deleterious side effects. Long-term use has been associated with gastrointestinal and renal complications. Gastrointestinal (GI) ulceration, also known as “NSAID gastropathy,” has been the most significant adverse effect. NSAID-related GI side effects such as peptic ulcer and upper GI bleeding are responsible for 200,000 to 400,000 hospitalizations and 16,500 deaths annually (Lanza & Members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology, 1998; Singh, 1998).
The anti-inflammatory and adverse effects of NSAIDS stem from their ability to inhibit prostaglandins (PGs) — a family of chemical mediators which can be both protective and noxious to the body. Prostaglandins have different actions depending on the type of ceils which emit them and the conditions under which they are liberated.
Arachidonic acid, the parent molecule of prostaglandins, is a constituent of the cell membrane. This molecule is transformed into PGs via the cyclo-oxygenase enzyme pathway. When activated, prostaglandins (PGs) have positive and negative effects on the body. On the negative side, PGs cause the pain, edema, fever, and vasodilation of inflammation. They can trigger painful uterine smooth muscle contractions and stimulate platelet aggregation. Positively, PGs stimulate gastrointestinal mucus secretion which forms a protective barrier against ulceration. They also influence the maintenance of adequate renal perfusion through specific vasodilating effects on kidney vessels (Masferrer, Isakson, & Siebert, 1996). Therefore, generalized inhibition of prostaglandins, the key action of NSAIDS, comes with benefits and risks. NSAID suppression of PGs alleviates the fever, swelling, redness, and pain of inflammatory conditions. NSAIDS also relieve the uterine cramping of dysmenorrhea, and aspirin can specifically suppress platelet aggregation which can lead to cardiovascular thrombus formation. However, this broad inhibition of prostaglandins also simultaneously suppresses gastrointestinal mucosal protection — a major drawback of NSAID use. Severe gastrointestinal irritation, peptic ulcer, and gastrointestinal bleeding are the major problems associated with NSAID use.
Recent advances in understanding the inflammation cascade have led to the discovery of new kinds of NSAIDs. In the past, prostaglandins were thought to arise from a single cyclo-oxygenase (cox) pathway. In 1990, it was discovered that there are at least two forms of the cyclo-oxygenase enzyme — cox-1 and cox-2 (Vane & Botting, 1998). It followed that two cyclo-oxygenase pathways actually produce prostaglandins from arachidonic acid. The cox-1 pathway produces the majority of “protective or homeostatic prostaglandins” which stimulate gastric mucus secretion, enhance kidney vasodilation, and platelet aggregation. Cox-2 mainly produces the “inflammatory prostaglandins” that contribute to pain, edema, and stimulation of inflammatory mediators. The discovery of these two distinct enzymes and pathways led to the creation of selective NSAIDS which precisely strike the “inflammatory prostaglandins” — cox-2 inhibitors. Cox-2 inhibitors do not target the cox-1 pathway which yield the “protective/homeostatic prostaglandins.” Therefore, cox-2 inhibitors do not affect gastric mucus secretion, decrease kidney perfusion, or inhibit platelet aggregation (Andrews, Wallace, & Davis, 1999; Noble, King, & Olutade, 2000) (see Figure 1).
[Figure 1 ILLUSTRATION OMITTED]
Based on the detailed understanding of the cyclooxygenase pathways in inflammation, new NSAIDs are being developed which selectively target the cox-2 pathway. Meloxicam, celecoxib, and rofecoxib have 100-fold selectivity toward inhibiting the cox-2 pathway and are now available. Valdecoxib, parecoxib, and deracoxib are 1,000-fold selective for the cox-2 pathway and are in clinical trials (Davies & McLachlan, 2000). With the property of selective cox-2 inhibition, new NSAIDs have less side effects than older NSAIDs.
