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Arthritis Medications Part I Dr. Sherry Rohekar May 13, 2010 Overview Nonsteroidal antiinflammatories Steroids Local Systemic Osteoporosis medications COX-1 vs COX-2 inhibition Bisphosphonates Complementary and alternative medications for arthritis Glucosamine for OA Nonsteroidal Antiinflammatories Caroxylic acids Proprionic acids Piroxicam, phenylbutazone Napthylkanones Meclofenamate, mefenamic acid Enolic acids Indomethacin, tolmentin, sulindac, diclofenac, etodolac Fenamates Ibuprofen, naproxen, fenoprofen, flurbiprofen, oxaprozin Acetic acid derivatives ASA, salalate, diflunisal, choline magnesium trisalicylate Nabumetone Selective COX-2 inhibitors Celecoxib Nonsteroidal Antiinflammatories Mechanism of action Prostaglandin-mediated Inhibit cyclooxygenase (COX), which goes on to catylize the formation of prostaglandins (inflammatory mediators) Nonprostaglandin-mediated NSAIDs insert into biological membranes and disrupt cell functions Nonsteroidal Antiinflammatories Variability of response Different NSAIDs will work differently in each patient If a patient fails one class of NSAIDs, can try another Trial of about two weeks reasonable, if used at maximal anti-inflammatory dose Toxicities can also vary between classes, to some degree Nonsteroidal Antiinflammatories Drug interactions Important interactions with phenytoin and warfarin (increased biologic effect) Combination of platelet dysfunction with NSAIDs and warfarin-induced anticoagulation can increase risk for serious bleeding NSAIDs may interfere with ASAs antiplatelet effect if you are taking both at same time Nonsteroidal Antiinflammatories Adverse effects with non-selective NSAIDs: Gastrointestinal toxicity: dyspepsia, PUD, bleeding Acute renal failure: due to renal vasoconstriction or direct toxicity Cardiovascular: Worsening HTN, fluid retention Liver: elevation of transanimases; increased risk for those with RA or SLE Lungs: bronchospasm, worsening of asthma (especially in those with chronic sinusitis and nasal polyps), pulmonary infiltrates with eosinophilia Blood: aplastic anemia, neutropenia, platelet dysfunction CNS: aseptic meningitis, tinnitus Dermatologic: toxic epidermal necrolysis, Stevens-Johnson syndrome Nonsteroidal Antiinflammatories Who is at increased risk of GI toxicity? Age > 65 Previous stomach ulcer Patients taking other blood thinners (i.e. warfarin) Selective COX-2 Inhibitors Two isoforms of COX: COX-1 and COX-2 COX-1: gastric cytoprotection, vascular homeostasis, platelet aggregation, kidney function COX-2: expressed in brain, kidney, bone, female reproductive function Ideal NSAID would inhibit COX-2 (inflammation) without inhibiting COX-1 (and thus contributing to toxicity) Selective COX-2 Inhibitors Most NSAIDs inhibit both COX-1 and COX2 Selective COX-2 inhibitors: celecoxib (Celebrex), rofecoxib (Vioxx), valdecoxib (Bextra) 200-300 x increased selectivity for COX-2 over COX-1 Comparable analgesia to nonselective NSAIDs, but superior gastroprotection Steroids (Prednisone) Immunosuppressant corticosteroid that is a powerful antiinflammatory and immunosuppressant Chemically similar to cortisol, which is naturally produced by the adrenal glands Multiple steroids with multiple routes of administration: po, inhaled, im, iv . . . Prednisone Side effects of oral prednisone General: weight gain, Cushingoid appearance Skin: thinning and easy bruising, acne, hypertrichosis, striae Ocular: early cataract formation, glaucoma, exophthalmos, central serous chorioretinopathy Prednisone Side effects of oral prednisone Cardiovascular: hypertension, ischemic heart disease, heart failure, MI, stroke, arrythmias Lipids: elevated lipoprotein levels, peripheral insulin resistance, hyperinsulinemia GI: gastritis, ulcer formation, GI bleeding, visceral rupture, fatty liver, pancreatitis Renal: fluid retention, hypertension, hypokalemia Zerikly RK et al. (2008) Cyclic Cushing syndrome due to an ectopic pituitary adenoma Nat Clin Pract Endocrinol Metab doi:10.1038/ncpendmet1039 Prednisone Side effects of oral prednisone GU: menstrual irregularities, decreased fertility MSK: osteoporosis, osteonecrosis, muscle weakness, vertebral fractures CNS: euphoria, hypomania, depression, memory loss, akathisia, insomnia, depression, psychosis, pseudotumour cerebri Prednisone Side effects of oral prednisone Endocrine: hyperglycemia, worsened DM, HONK, DKA, hypothalamic-pituitary-adrenal insufficiency Infection: increased infection, neutrophilia, infection post vaccination with live vaccine, opportunistic infection, shingles Bisphosphonates Most popular type of drug used to treat and prevent osteoporosis Inhibit bone resorption Complicated to take: First thing in the morning, on empty stomach, with full glass of water; no food , drink, medications or supplements for 30-60 minutes after; must remain standing for 30 minutes after Bisphosphonates Response to therapy Serial BMDs looking for stable or improving measurements Inadequate response suggest poor compliance, inadequate GI absorption, inadequate calcium/vitamin D intake, secondary disease Bisphosphonates Adverse events GI: reflux, esophagitis, esophageal ulcers, ? increased risk of esophageal cancer Metabolic: hypocalcemia MSK: severe MSK pain , potentially not resolving with discontinuation (very rare) Renal: renal impairment, renal failure in those with pre-existing renal disease Ocular: pain, blurred vision, conjunctivitis, iritis Bisphosphonates Adverse events Cardiovascular: atrial fibrillation (conflicting data) Osteonecrosis of the jaw: risk factors include iv bisphosphonates, cancer, cancer treatments, duration of exposure, dental extractions, dental implants, poorly fitting dentures, glucocorticoids, smoking, preexisting dental disease Risk about 1:10 000 to 1:100 000 patient-years Bisphosphonates Adverse events Theoretically, could caused paradoxical increase in bone fragility due to oversuppression of bone turnover Cases of atypical fracture (sub-trochanteric fracture) CAM For Osteoarthritis: Glucosamine Technical aspects: A hexosamine sugar Mechanism of action: Acts as a building block for glycosaminoglycans (GAGs) and proteoglycans These are important components of articular cartilage Shown in vitro and in animal studies to improve the growth and healing of cartilage Inhibits matrix metalloproteinases and other enzymes that degrade cartilage Inhibits inducible nitric oxide synthesis Inhibits COX-2 production without affecting COX-1 Pavelka et al., Arch Intern Med 2002;162:2113-2123. CAM For Osteoarthritis: Glucosamine Cochrane Review includes a metaanalysis containing 20 RCTs Last update February 2005 65% of trials had an association with Rotta Pharm, an Italian manufacturer of glucosamine sulfate (GS) 15 of the studies showed clear benefit of GS over placebo The 5 negative studies did not use the Rotta formulation of GS and were not associated with pharmaceutical companies Towheed et al., Cochrane Library 2006. CAM For Osteoarthritis: Glucosamine Glucosamine vs. placebo - Pain Towheed et al., Cochrane Library 2006. CAM For Osteoarthritis: Glucosamine WOMAC Function Subscale Towheed et al., Cochrane Library 2006. CAM For Osteoarthritis: Glucosamine Mean Joint Space Width Towheed et al., Cochrane Library 2006. CAM For Osteoarthritis: Glucosamine Compared to NSAID - Pain Compared to NSAID - Toxicity Towheed et al., Cochrane Library 2006. CAM For Osteoarthritis: Glucosamine Recent RCT published in NEJM that examined 1583 patients with symptomatic knee OA Randomized to glucosamine alone, chondroitin alone, glucoamine + chondroitin, celecoxib, or placebo Assignment was stratified according to the severity of the OA Primary outcome was a 20% decrease in knee pain from baseline to week 24 Clegg et al., NEJM 2006;354:795-808. CAM For Osteoarthritis: Glucosamine * * No difference between placebo and glucosamine, chondroitin, or both Celecoxib significantly better than placebo Clegg et al., NEJM 2006;354:795-808. CAM For Osteoarthritis: Glucosamine Adverse events: Theoretical possibility that glucosamine could alter glucose homeostasis Theoretical possibility of increased proteoglycan synthesis in arterial cell walls Could contribute to the development of atherosclerosis Shown to accelerate the toughness and the growth rate of the nails Has not occurred in any of the clinical trials Questionable clinical significance Glucosamine extracted from chitin Source are shells of crustaceans Should not be used in those with shellfish allergy Towheed et al., Cochrane Library 2006. CAM For Osteoarthritis: Glucosamine Summary: Though several RCTs have shown glucosamine to be superior to placebo, there are serious methodological issues Most recent detailed RCT showed that glucosamine did not improve OA of the knee Note that this trial used glucosamine hydrochloride Some have suggested that it is the sulfa moiety in glucosamine sulfate that has clinical activity Clegg et al., NEJM 2006;354:795-808. Towheed et al., Cochrane Library 2006. Any questions?