Arthritis Medications Part I

1. Arthritis MedicationsPart I Dr. Sherry Rohekar May 13, 2010

2. Overview • Nonsteroidalantiinflammatories • COX-1 vs COX-2 inhibition • Steroids • Local • Systemic • Osteoporosis medications • Bisphosphonates • Complementary and alternative medications for arthritis • Glucosamine for OA

3. Nonsteroidal Antiinflammatories • Caroxylic acids • ASA, salalate, diflunisal, choline magnesium trisalicylate • Proprionic acids • Ibuprofen, naproxen, fenoprofen, flurbiprofen, oxaprozin • Acetic acid derivatives • Indomethacin, tolmentin, sulindac, diclofenac, etodolac • Fenamates • Meclofenamate, mefenamic acid • Enolic acids • Piroxicam, phenylbutazone • Napthylkanones • Nabumetone • Selective COX-2 inhibitors • Celecoxib

5. 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

6. 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

7. 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

8. 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

10. Nonsteroidal Antiinflammatories • Who is at increased risk of GI toxicity? • Age > 65 • Previous stomach ulcer • Patients taking other blood thinners (i.e. warfarin)

11. 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)

13. Selective COX-2 Inhibitors • Most NSAIDs inhibit both COX-1 and COX-2 • 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

15. 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 . . .

16. 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

17. 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

18. Zerikly RK et al. (2008) Cyclic Cushing syndrome due to an ectopic pituitary adenomaNat Clin Pract Endocrinol Metab doi:10.1038/ncpendmet1039

19. 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, pseudotumourcerebri

20. 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

21. 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

23. 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

24. 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

25. 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, pre-existing dental disease • Risk about 1:10 000 to 1:100 000 patient-years

27. Bisphosphonates • Adverse events • Theoretically, could caused paradoxical increase in bone fragility due to oversuppression of bone turnover • Cases of atypical fracture (sub-trochanteric fracture)

29. 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.

31. 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.

32. Glucosamine vs. placebo - Pain CAM For Osteoarthritis:Glucosamine Towheed et al., Cochrane Library 2006.

33. WOMAC Function Subscale CAM For Osteoarthritis:Glucosamine Towheed et al., Cochrane Library 2006.

34. Mean Joint Space Width CAM For Osteoarthritis:Glucosamine Towheed et al., Cochrane Library 2006.

35. Compared to NSAID - Pain Compared to NSAID - Toxicity CAM For Osteoarthritis:Glucosamine Towheed et al., Cochrane Library 2006.

36. 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.

37. 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.

38. CAM For Osteoarthritis:Glucosamine • Adverse events: • Theoretical possibility that glucosamine could alter glucose homeostasis • Has not occurred in any of the clinical trials • 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 • 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.

39. 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.

40. Any questions?