Arthritis Medications Part I Dr. Sherry Rohekar May 13, 2010

Arthritis MedicationsArthritis MedicationsPart IPart I

Dr. Sherry RohekarDr. Sherry Rohekar

May 13, 2010May 13, 2010

OverviewOverview

Nonsteroidal antiinflammatoriesNonsteroidal antiinflammatories COX-1 vs COX-2 inhibitionCOX-1 vs COX-2 inhibition

SteroidsSteroids LocalLocal SystemicSystemic

Osteoporosis medicationsOsteoporosis medications BisphosphonatesBisphosphonates

Complementary and alternative medications for Complementary and alternative medications for arthritisarthritis Glucosamine for OAGlucosamine for OA

Nonsteroidal Nonsteroidal AntiinflammatoriesAntiinflammatories

Caroxylic acidsCaroxylic acids ASA, salalate, diflunisal, choline magnesium trisalicylateASA, salalate, diflunisal, choline magnesium trisalicylate

Proprionic acidsProprionic acids Ibuprofen, naproxen, fenoprofen, flurbiprofen, oxaprozinIbuprofen, naproxen, fenoprofen, flurbiprofen, oxaprozin

Acetic acid derivativesAcetic acid derivatives Indomethacin, tolmentin, sulindac, diclofenac, etodolacIndomethacin, tolmentin, sulindac, diclofenac, etodolac

FenamatesFenamates Meclofenamate, mefenamic acidMeclofenamate, mefenamic acid

Enolic acidsEnolic acids Piroxicam, phenylbutazonePiroxicam, phenylbutazone

NapthylkanonesNapthylkanones NabumetoneNabumetone

Selective COX-2 inhibitorsSelective COX-2 inhibitors CelecoxibCelecoxib


Mechanism of actionMechanism of action Prostaglandin-mediatedProstaglandin-mediated

Inhibit cyclooxygenase (COX), which goes on Inhibit cyclooxygenase (COX), which goes on to catylize the formation of prostaglandins to catylize the formation of prostaglandins (inflammatory mediators)(inflammatory mediators)

Nonprostaglandin-mediatedNonprostaglandin-mediated NSAIDs insert into biological membranes NSAIDs insert into biological membranes

and disrupt cell functionsand disrupt cell functions


Variability of responseVariability of response Different NSAIDs will work differently in Different NSAIDs will work differently in

each patienteach patient If a patient fails one class of NSAIDs, can If a patient fails one class of NSAIDs, can

try anothertry another Trial of about two weeks reasonable, if used Trial of about two weeks reasonable, if used

at maximal anti-inflammatory doseat maximal anti-inflammatory dose Toxicities can also vary between classes, to Toxicities can also vary between classes, to

some degreesome degree


Drug interactionsDrug interactions Important interactions with phenytoin and Important interactions with phenytoin and

warfarin (increased biologic effect)warfarin (increased biologic effect) Combination of platelet dysfunction with Combination of platelet dysfunction with

NSAIDs and warfarin-induced NSAIDs and warfarin-induced anticoagulation can increase risk for anticoagulation can increase risk for serious bleedingserious bleeding

NSAIDs may interfere with ASAs antiplatelet NSAIDs may interfere with ASAs antiplatelet effect if you are taking both at same timeeffect if you are taking both at same time


Adverse effects with non-selective NSAIDs:Adverse effects with non-selective NSAIDs: Gastrointestinal toxicity: dyspepsia, PUD, bleedingGastrointestinal toxicity: dyspepsia, PUD, bleeding Acute renal failure: due to renal vasoconstriction or direct Acute renal failure: due to renal vasoconstriction or direct

toxicitytoxicity Cardiovascular: Worsening HTN, fluid retentionCardiovascular: Worsening HTN, fluid retention Liver: elevation of transanimases; increased risk for those Liver: elevation of transanimases; increased risk for those

with RA or SLEwith RA or SLE Lungs: bronchospasm, worsening of asthma (especially in Lungs: bronchospasm, worsening of asthma (especially in

those with chronic sinusitis and nasal polyps), pulmonary those with chronic sinusitis and nasal polyps), pulmonary infiltrates with eosinophiliainfiltrates with eosinophilia

Blood: aplastic anemia, neutropenia, platelet dysfunctionBlood: aplastic anemia, neutropenia, platelet dysfunction CNS: aseptic meningitis, tinnitusCNS: aseptic meningitis, tinnitus Dermatologic: toxic epidermal necrolysis, Stevens-Dermatologic: toxic epidermal necrolysis, Stevens-

Johnson syndromeJohnson syndrome


Who is at increased risk of GI Who is at increased risk of GI toxicity?toxicity? Age > 65Age > 65 Previous stomach ulcerPrevious stomach ulcer Patients taking other blood thinners (i.e. Patients taking other blood thinners (i.e.

warfarin)warfarin)

Selective COX-2 InhibitorsSelective COX-2 Inhibitors

Two isoforms of COX: COX-1 and COX-Two isoforms of COX: COX-1 and COX-22 COX-1: gastric cytoprotection, vascular COX-1: gastric cytoprotection, vascular

homeostasis, platelet aggregation, kidney homeostasis, platelet aggregation, kidney functionfunction

COX-2: expressed in brain, kidney, bone, COX-2: expressed in brain, kidney, bone, female reproductive functionfemale reproductive function

Ideal NSAID would inhibit COX-2 Ideal NSAID would inhibit COX-2 (inflammation) without inhibiting COX-1 (inflammation) without inhibiting COX-1 (and thus contributing to toxicity)(and thus contributing to toxicity)

Selective COX-2 InhibitorsSelective COX-2 Inhibitors

Most NSAIDs inhibit both COX-1 and Most NSAIDs inhibit both COX-1 and COX-2COX-2

Selective COX-2 inhibitors: celecoxib Selective COX-2 inhibitors: celecoxib (Celebrex), rofecoxib (Vioxx), (Celebrex), rofecoxib (Vioxx), valdecoxib (Bextra)valdecoxib (Bextra) 200-300 x increased selectivity for COX-2 200-300 x increased selectivity for COX-2

over COX-1over COX-1 Comparable analgesia to nonselective Comparable analgesia to nonselective

NSAIDs, but superior gastroprotectionNSAIDs, but superior gastroprotection

Steroids (Prednisone)Steroids (Prednisone)

Immunosuppressant corticosteroid that Immunosuppressant corticosteroid that is a powerful antiinflammatory and is a powerful antiinflammatory and immunosuppressantimmunosuppressant

Chemically similar to cortisol, which is Chemically similar to cortisol, which is naturally produced by the adrenal naturally produced by the adrenal glandsglands

Multiple steroids with multiple routes of Multiple steroids with multiple routes of administration: po, inhaled, im, iv . . .administration: po, inhaled, im, iv . . .

PrednisonePrednisone

Side effects of oral prednisoneSide effects of oral prednisone General: weight gain, Cushingoid General: weight gain, Cushingoid

appearanceappearance Skin: thinning and easy bruising, acne, Skin: thinning and easy bruising, acne,

hypertrichosis, striaehypertrichosis, striae Ocular: early cataract formation, Ocular: early cataract formation,

glaucoma, exophthalmos, central serous glaucoma, exophthalmos, central serous chorioretinopathychorioretinopathy


Side effects of oral prednisoneSide effects of oral prednisone Cardiovascular: hypertension, ischemic heart Cardiovascular: hypertension, ischemic heart

disease, heart failure, MI, stroke, arrythmiasdisease, heart failure, MI, stroke, arrythmias Lipids: elevated lipoprotein levels, peripheral Lipids: elevated lipoprotein levels, peripheral

insulin resistance, hyperinsulinemiainsulin resistance, hyperinsulinemia GI: gastritis, ulcer formation, GI bleeding, GI: gastritis, ulcer formation, GI bleeding,

visceral rupture, fatty liver, pancreatitisvisceral rupture, fatty liver, pancreatitis Renal: fluid retention, hypertension, Renal: fluid retention, hypertension,

hypokalemiahypokalemia

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


Side effects of oral prednisoneSide effects of oral prednisone GU: menstrual irregularities, decreased GU: menstrual irregularities, decreased

fertilityfertility MSK: osteoporosis, osteonecrosis, MSK: osteoporosis, osteonecrosis,

muscle weakness, vertebral fracturesmuscle weakness, vertebral fractures CNS: euphoria, hypomania, depression, CNS: euphoria, hypomania, depression,

memory loss, akathisia, insomnia, memory loss, akathisia, insomnia, depression, psychosis, pseudotumour depression, psychosis, pseudotumour cerebricerebri


Side effects of oral prednisoneSide effects of oral prednisone Endocrine: hyperglycemia, worsened Endocrine: hyperglycemia, worsened

DM, HONK, DKA, hypothalamic-pituitary-DM, HONK, DKA, hypothalamic-pituitary-adrenal insufficiencyadrenal insufficiency

Infection: increased infection, Infection: increased infection, neutrophilia, infection post vaccination neutrophilia, infection post vaccination with live vaccine, opportunistic infection, with live vaccine, opportunistic infection, shinglesshingles

BisphosphonatesBisphosphonates

Most popular type of drug used to treat Most popular type of drug used to treat and prevent osteoporosisand prevent osteoporosis

Inhibit bone resorption Inhibit bone resorption Complicated to take:Complicated to take:

First thing in the morning, on empty First thing in the morning, on empty stomach, with full glass of water; no food , stomach, with full glass of water; no food , drink, medications or supplements for 30-drink, medications or supplements for 30-60 minutes after; must remain standing for 60 minutes after; must remain standing for 30 minutes after30 minutes after


Response to therapyResponse to therapy Serial BMDs looking for stable or Serial BMDs looking for stable or

improving measurementsimproving measurements Inadequate response suggest poor Inadequate response suggest poor

compliance, inadequate GI absorption, compliance, inadequate GI absorption, inadequate calcium/vitamin D intake, inadequate calcium/vitamin D intake, secondary diseasesecondary disease

BisphosphonatesBisphosphonates Adverse eventsAdverse events

GI: reflux, esophagitis, esophageal ulcers, ? GI: reflux, esophagitis, esophageal ulcers, ? increased risk of esophageal cancerincreased risk of esophageal cancer

Metabolic: hypocalcemiaMetabolic: hypocalcemia MSK: severe MSK pain , potentially not MSK: severe MSK pain , potentially not

resolving with discontinuation (very rare)resolving with discontinuation (very rare) Renal: renal impairment, renal failure in those Renal: renal impairment, renal failure in those

with pre-existing renal diseasewith pre-existing renal disease Ocular: pain, blurred vision, conjunctivitis, Ocular: pain, blurred vision, conjunctivitis,

iritisiritis

BisphosphonatesBisphosphonates Adverse eventsAdverse events

Cardiovascular: atrial fibrillation (conflicting Cardiovascular: atrial fibrillation (conflicting data)data)

Osteonecrosis of the jaw: risk factors include Osteonecrosis of the jaw: risk factors include iv bisphosphonates, cancer, cancer iv bisphosphonates, cancer, cancer treatments, duration of exposure, dental treatments, duration of exposure, dental extractions, dental implants, poorly fitting extractions, dental implants, poorly fitting dentures, glucocorticoids, smoking, pre-dentures, glucocorticoids, smoking, pre-existing dental diseaseexisting dental disease

Risk about 1:10 000 to 1:100 000 patient-yearsRisk about 1:10 000 to 1:100 000 patient-years

http://www.flickr.com/photos/12271362@N00/311441953/


Adverse eventsAdverse events Theoretically, could caused paradoxical Theoretically, could caused paradoxical

increase in bone fragility due to increase in bone fragility due to oversuppression of bone turnoveroversuppression of bone turnover

Cases of atypical fracture (sub-trochanteric Cases of atypical fracture (sub-trochanteric fracture)fracture)

Technical aspects:Technical aspects: A hexosamine sugarA hexosamine sugar

Mechanism of action:Mechanism of action: Acts as a building block for glycosaminoglycans Acts as a building block for glycosaminoglycans

(GAGs) and proteoglycans(GAGs) and proteoglycans These are important components of articular cartilageThese are important components of articular cartilage Shown Shown in vitroin vitro and in animal studies to improve the and in animal studies to improve the

growth and healing of cartilagegrowth and healing of cartilage Inhibits matrix metalloproteinases and other enzymes Inhibits matrix metalloproteinases and other enzymes

that degrade cartilagethat degrade cartilage Inhibits inducible nitric oxide synthesisInhibits inducible nitric oxide synthesis Inhibits COX-2 production without affecting COX-1Inhibits COX-2 production without affecting COX-1

CAM For Osteoarthritis:CAM For Osteoarthritis:GlucosamineGlucosamine

Pavelka et al., Arch Intern Med 2002;162:2113-2123.

Cochrane Review includes a metaanalysis Cochrane Review includes a metaanalysis containing 20 RCTscontaining 20 RCTs Last update February 2005Last update February 2005 65% of trials had an association with Rotta 65% of trials had an association with Rotta

Pharm, an Italian manufacturer of glucosamine Pharm, an Italian manufacturer of glucosamine sulfate (GS)sulfate (GS)

15 of the studies showed clear benefit of GS over 15 of the studies showed clear benefit of GS over placeboplacebo

The 5 negative studies did not use the Rotta The 5 negative studies did not use the Rotta formulation of GS and were not associated with formulation of GS and were not associated with pharmaceutical companiespharmaceutical companies


Towheed et al., Cochrane Library 2006.



Glucosamine vs. placebo - Pain



WOMAC Function Subscale



Mean Joint Space Width



Compared to NSAID - Pain

Compared to NSAID - Toxicity

Recent RCT published in NEJM that Recent RCT published in NEJM that examined 1583 patients with symptomatic examined 1583 patients with symptomatic knee OAknee OA Randomized to glucosamine alone, chondroitin Randomized to glucosamine alone, chondroitin

alone, glucoamine + chondroitin, celecoxib, or alone, glucoamine + chondroitin, celecoxib, or placeboplacebo

Assignment was stratified according to the Assignment was stratified according to the severity of the OAseverity of the OA

Primary outcome was a 20% decrease in knee Primary outcome was a 20% decrease in knee pain from baseline to week 24pain from baseline to week 24


Clegg et al., NEJM 2006;354:795-808.


Clegg et al., NEJM 2006;354:795-808.

No difference No difference between placebo between placebo and glucosamine, and glucosamine, chondroitin, or chondroitin, or bothboth

Celecoxib Celecoxib significantly significantly better than better than placeboplacebo

**


Adverse events:Adverse events: Theoretical possibility that glucosamine could alter Theoretical possibility that glucosamine could alter

glucose homeostasisglucose homeostasis Has not occurred in any of the clinical trialsHas not occurred in any of the clinical trials

Theoretical possibility of increased proteoglycan Theoretical possibility of increased proteoglycan synthesis in arterial cell wallssynthesis in arterial cell walls

Could contribute to the development of atherosclerosisCould contribute to the development of atherosclerosis Shown to accelerate the toughness and the growth Shown to accelerate the toughness and the growth

rate of the nailsrate of the nails Questionable clinical significanceQuestionable clinical significance

Glucosamine extracted from chitinGlucosamine extracted from chitin Source are shells of crustaceansSource are shells of crustaceans Should not be used in those with shellfish allergyShould not be used in those with shellfish allergy


Summary:Summary: Though several RCTs have shown Though several RCTs have shown

glucosamine to be superior to placebo, glucosamine to be superior to placebo, there are serious methodological issuesthere are serious methodological issues

Most recent detailed RCT showed that Most recent detailed RCT showed that glucosamine did not improve OA of the kneeglucosamine did not improve OA of the knee

Note that this trial used glucosamine Note that this trial used glucosamine hydrochloridehydrochloride

Some have suggested that it is the sulfa moiety Some have suggested that it is the sulfa moiety in glucosamine sulfate that has clinical activityin glucosamine sulfate that has clinical activity



Clegg et al., NEJM 2006;354:795-808.

Any questions?Any questions?

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Arthritis Medications Part I Dr. Sherry Rohekar May 13, 2010