DMARDs and treatment of gout

===Lecture Details===
Wayne Hodgson; Week 9 MED1022; Pharmacology
===Lecture Content===
RA is two times more common in females, smoking has a strong link as does weight, exercise. Pain and inflammation management can be with simple analgesics, NSAIDs (non-selective or COX 2 selective) eg ibuprofen or meloxicam, steroids (prednisolone) which are better for short term use (can cause Cushing's). Cons of NSAID therapy are that it does not prevent disease progression, GI toxicity common, there are renal complications and hepatic dysfunction, CV complications. Steroids can cause disease progression, discontinuation is often unsuccessful, Cushingoid appearance, steroid induced osteopaenia and skin thinning. NSAIDs/steroids provide symptomatic relief in RA. Loss of function is permanent within about 3 years of onset of RA if treated with these.
SAARDs= DMARDs (disease modifying anti-rheumatic drugs). Are potent and often toxic, most take 6-8 weeks to become effective. They retard the progression of disease. Combination therapy can be used, they are quite aggressive. Time from administration to benefit varies, methotrexate takes 1-3 months, sulfalazine also 1-3. Methotrexate is first line, good against joint destruction, is a folate antagonist which blocks purine synthesis. Is an anchor drug used with other DMARDs. Has acceptable toxicity. Leflunomide is similar to methotrexate, blocks pyrimidine synthesis. Sulfalazine is a synthetic drug, reduces lymphocyte function. Is an alternative to methotrexate. Hydrochloroquinine has major adverse effects (retinopathy). They slow disease progression, improve functional disability, decrease pain, interferes with inflammatory processes, retards development of joint erosions. Combination regimen does not increase toxicity levels, long-term outcome, superior efficacy to DMARD regimen in recent clinical trials. Methotrexate/sulfalazine/hydroxychloroquinine; cyclosporine/methotrexate; leflunomide/methotrexate.
Cytokines are LMW proteins, released by immune system, binds to TRK to alter gene expression, actions are local/synergistic. IL-1 activates monocytes/macrophages, induces fibroblast proliferation (synovial pannus formation), activates chondrocytes (cartilage breakdown), activates osteoclasts (bone resorption). Biologic agents are directed against specific cytokines or cell surface molecule. Anti-cytokines include eternacept, infliximab (anti-TNFa MAB). TNF-a inhibitors prevent binding of TNFa to TNF on inflammatory cells. Basiliximab is directed against IL-2.
RA management should have early use of DMARDs, frequent follow-up, rapid escalation of therapy, use of biologic agents in those that fail to respond to DMARDs, proper use of low dose glucocorticoids.
Metabolic disease (gout)- hyperuricemia and intermittent attacks of arthritis. Hyperuricemia is failure of balance between production/secretion of uric acid (no precipitation/formation of crystals). There is overproduction or impaired renal excretion of purines. Doesn't require treatment unless symptoms are evident. Causes arthritis due to deposition of urate crystals in synovium. There are primary (familial) and secondary causes. Allopurinol reduces uric acid synthesis, probenecid increases uric acid excretion, colchicine inhibits migration of leukocytes into joint and general anti-inflammatory and analgesic effects. Acute is colchicine, NSAIDs. Allopurinol is use of drug of choice for chronic use, inhibits uric acid synthesis, is a competitive xanthine oxidase inhibitor, converted to alloxanthine (non-competitive inhibitor).
Probenecid is uricosuric- increases excretion by blocking reabsorption. Has possible interactions with other drugs due to competition at proximal tubule. Colchicine reduces leukocyte migration to site of inflammation.
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