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Arthritis Medications Part I

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Arthritis Medications Part I Powered By Docstoc
					Arthritis Medications
         Part I

   Dr. Sherry Rohekar
      May 13, 2010
                          Overview
   Nonsteroidal antiinflammatories
       COX-1 vs COX-2 inhibition
   Steroids
       Local
       Systemic
   Osteoporosis medications
       Bisphosphonates
   Complementary and alternative medications for arthritis
       Glucosamine for OA
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
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 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
         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, pre-
        existing 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
            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.
             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?