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Clinical Pharmacology of A nti-inflammatory Agents. RHEUMATIC DISEASES. Rheumatic diseases (rheumatism) are painful conditions that affect millions. These diseases cause inflammation, swelling, and pain in the joints or muscles.
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RHEUMATIC DISEASES • Rheumatic diseases (rheumatism) are painful conditions that affect millions. These diseases cause inflammation, swelling, and pain in the joints or muscles. • Some rheumatic diseases like osteoarthritis are the result of "wear and tear" to the joints. Other rheumatic diseases, such as rheumatoid arthritis, happen when the immune system goes haywire; the immune system attacks the linings of joints, causing joint pain, swelling, and destruction.
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Therapeutic Strategies • The treatment of patients with inflammation involves two primary goals: first, the relief of symptoms and the maintenance of function, which are usually the major continuing complaints of the patient; and second, the slowing or arrest of the tissue-damaging process.
NSAIDs Propionic acid derivatives • Ibuprofen • Naproxen • Fenoprofen • Ketoprofen • Flurbiprofen • Oxaprozin Acetic acid derivatives • Indomethacin • Sulindac • Etodolac • Ketorolac • Diclofenac (Safety alert by FDA) • Nabumetone
NSAIDs Enolic acid (Oxicam) derivatives • Piroxicam • Meloxicam • Tenoxicam • Droxicam • Lornoxicam • Isoxicam Fenamic acid derivatives ( Fenamates ) • Mefenamic acid • Meclofenamic acid • Flufenamic acid • Tolfenamic acid
NSAIDs Selective COX-2 inhibitors (Coxibs) • Celecoxib (FDA alert) • Rofecoxib (withdrawn from market) - increased cardiovascular thrombotic events • Valdecoxib (withdrawn from market) - increased cardiovascular thrombotic events • Parecoxib FDA withdrawn • Lumiracoxib TGA cancelled registration • Etoricoxib FDA withdrawn • Firocoxib used in dogs and horses Sulphonanilides • Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity) Others • Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX inhibitor
The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. The cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. Inflammation
The discovery of two cyclooxygenase isoforms (COX-1 and COX-2) led to the concept that the constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy. Cyclooxygenase isoforms
The more an NSAID blocks COX-1, the greater is its tendency to cause ulcers and promote bleeding. Butcelecoxib (Celebrex), blocks COX-2 and has little effect on COX-1, and is therefore further classified as a selective COX-2 inhibitor. Selective COX-2 inhibitors cause less bleeding and fewer ulcers than other NSAIDs.
Choice of NSAID • All NSAIDs, including aspirin, are about equally efficacious with a few exceptions—tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for ankylosing spondylitis. • Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the gastrointestinal and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin or tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in these analyses.
Choice of NSAID (cont’d) • For patients with renal insufficiency, nonacetylated salicylates may be best. Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs. The relatively expensive, selective COX-2 inhibitor celecoxib, is probably safest for patients at high risk for gastrointestinal bleeding but may have a higher risk of cardiovascular toxicity. Celecoxib or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in patients at highest risk for gastrointestinal bleeding; in this subpopulation of patients, they are cost-effective despite their high acquisition costs. • The choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (eg, other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no best NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person.
CORTICOSTEROIDSMost of the known effects of the glucocorticoids are mediated by widely distributed glucocorticoid receptors
