Transcript Arthritis Medications Part I - St. Joseph's Health Care London

Arthritis Medications
Part I
Dr. Sherry Rohekar
May 13, 2010
Overview
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Nonsteroidal antiinflammatories
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Steroids
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Local
Systemic
Osteoporosis medications
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COX-1 vs COX-2 inhibition
Bisphosphonates
Complementary and alternative medications for arthritis
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Glucosamine for OA
Nonsteroidal Antiinflammatories
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Caroxylic acids
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Proprionic acids
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Piroxicam, phenylbutazone
Napthylkanones
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Meclofenamate, mefenamic acid
Enolic acids
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Indomethacin, tolmentin, sulindac, diclofenac, etodolac
Fenamates
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Ibuprofen, naproxen, fenoprofen, flurbiprofen, oxaprozin
Acetic acid derivatives
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ASA, salalate, diflunisal, choline magnesium trisalicylate
Nabumetone
Selective COX-2 inhibitors
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Celecoxib
Nonsteroidal Antiinflammatories
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Mechanism of action
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Prostaglandin-mediated
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Inhibit cyclooxygenase (COX), which goes on to
catylize the formation of prostaglandins
(inflammatory mediators)
Nonprostaglandin-mediated
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NSAIDs insert into biological membranes and
disrupt cell functions
Nonsteroidal Antiinflammatories
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Variability of response
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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
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Nonsteroidal Antiinflammatories
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Drug interactions
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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
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Adverse effects with non-selective NSAIDs:
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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
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Who is at increased risk of GI toxicity?
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Age > 65
Previous stomach ulcer
Patients taking other blood thinners (i.e.
warfarin)
Selective COX-2 Inhibitors
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Two isoforms of COX: COX-1 and COX-2
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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
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Most NSAIDs inhibit both COX-1 and COX2
Selective COX-2 inhibitors: celecoxib
(Celebrex), rofecoxib (Vioxx), valdecoxib
(Bextra)
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200-300 x increased selectivity for COX-2 over
COX-1
Comparable analgesia to nonselective
NSAIDs, but superior gastroprotection
Steroids (Prednisone)
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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
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Side effects of oral prednisone
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General: weight gain, Cushingoid appearance
Skin: thinning and easy bruising, acne,
hypertrichosis, striae
Ocular: early cataract formation, glaucoma,
exophthalmos, central serous
chorioretinopathy
Prednisone
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Side effects of oral prednisone
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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
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Side effects of oral prednisone
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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
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Side effects of oral prednisone
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Endocrine: hyperglycemia, worsened DM,
HONK, DKA, hypothalamic-pituitary-adrenal
insufficiency
Infection: increased infection, neutrophilia,
infection post vaccination with live vaccine,
opportunistic infection, shingles
Bisphosphonates
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Most popular type of drug used to treat
and prevent osteoporosis
Inhibit bone resorption
Complicated to take:
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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
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Response to therapy
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Serial BMDs looking for stable or improving
measurements
Inadequate response suggest poor
compliance, inadequate GI absorption,
inadequate calcium/vitamin D intake,
secondary disease
Bisphosphonates
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Adverse events
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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
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Adverse events
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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
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Risk about 1:10 000 to 1:100 000 patient-years
Bisphosphonates
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Adverse events
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Theoretically, could caused paradoxical
increase in bone fragility due to
oversuppression of bone turnover
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Cases of atypical fracture (sub-trochanteric
fracture)
CAM For Osteoarthritis:
Glucosamine
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Technical aspects:
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A hexosamine sugar
Mechanism of action:
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Acts as a building block for glycosaminoglycans
(GAGs) and proteoglycans
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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
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Cochrane Review includes a metaanalysis
containing 20 RCTs
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Last update February 2005
65% of trials had an association with Rotta Pharm, an
Italian manufacturer of glucosamine sulfate (GS)
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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
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Recent RCT published in NEJM that examined
1583 patients with symptomatic knee OA
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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
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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
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Adverse events:
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Theoretical possibility that glucosamine could alter
glucose homeostasis
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Theoretical possibility of increased proteoglycan
synthesis in arterial cell walls
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Could contribute to the development of atherosclerosis
Shown to accelerate the toughness and the
growth rate of the nails
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Has not occurred in any of the clinical trials
Questionable clinical significance
Glucosamine extracted from chitin
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Source are shells of crustaceans
Should not be used in those with shellfish allergy
Towheed et al., Cochrane Library 2006.
CAM For Osteoarthritis:
Glucosamine
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Summary:
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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
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Clegg et al., NEJM 2006;354:795-808.
Towheed et al., Cochrane Library 2006.
Any questions?