Osteoarthritis (OA)

  • General
    • Degenerative joint disease
    • No known cure
  • Therapeutic objectives
    • reduce pain
    • improve joint mobility
    • limit functional impairment
  • Management
    • Patient education
      • lose weight
        • lessen burden of weight-bearing joints
        • exercise
    • Non-medicinal & rebilitative
      • exercises
        • range-of-motion
        • muscle-strengthening
      • braces, orthotics, assistive devices
      • appropriate footwear
      • occupational therapy
    • Pharmacotherapy
      • Oral
        • NSAIDs
        • COX2 selective inhibitors
        • glucosamine
      • Intra-articular injection
        • Glucocorticoids
        • Hyaluronic acid
      • Topical
        • NSAIDs
    • Surgery

Rheumatoid arthritis (RA)

  • Therapeutic objectives
    • Pain relief
    • Reduce inflammation
    • Control disease activity
      • prevent/slow joint damage
      • prevent loss of function
      • improve quality of life
        • correct/compensate mechanical & structural abnormalities by assistive devices
    • Induce a remission (if possible)
      • a state of absence of chronic disease
  • Therapeutic measures
    • Pharmacologic
      • NSAIDs
        • reduce joint pain & swelling
        • pharmacologic actions
          • analgesic
          • antipyretic
          • anti-inflammatory
      • Glucocorticoids
      • Drugs that suppress the rheumatoid disease process
        • Disease-modifying anti rheumatic drug (DMARDs)
        • Biologic response modifiers

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NSAIDs

  • pharmacologic actions
    • analgesic
    • antipyretic
    • anti-inflammatory
  • pharmacology
    • Inhibits COX-1 & COX-2
      • reduce production of prostaglandins
      • analgesic, antipyretic, anti-inflammatory
  • Side effects
    • Inhibition of COX-1 in gastric epithelial cells
      • gastic ulcer/bleeding
    • Inhibition of COX-1 & 2 in kidney
      • interfere with regulation of renal blood flow
      • nephrotoxicity
    • Inhibit platelet TXA2 formation
      • prevent platelet aggregation
      • Increased cardiovascular thrombotic risk
      • but can be used as anti-thrombosis
  • Classification (based on potency)
    • Moderate potency
      • Fenamates
        • mefenamic acid
      • Propionic acids
        • naproxen
        • ibuprofen
        • ketoprofen
      • Paraaminophenol derivative
        • acetaminophen
        • paracetamol
    • High potency
      • Salicylates
        • aspirin
        • diflunisal
      • Acetic acids & derivatives
        • indomethacin
        • sulindac
        • etodolac
        • diclofenac sodium
      • Oxicams
        • piroxicam
        • meloxicam
      • Pyrazolones
        • phenylbutazone
      • COX-2 selective inhibitor
        • Celecoxib
        • valdecoxib
        • meloxicam
  • Therapeutic uses
    • Analgesic, Antipyretic, Anti-inflammatory
    • Closure of patent ductus arteriosus
      • in neonates
      • indomethacin
    • Dysmenorrhea
      • COX2 inhibitors
    • Systemic mastocytosis
      • due to prostaglandin released from mast cells
        • induce vasodilation & hypotension
      • prevented by NSAIDs
    • Bartter’s syndrome
      • excessive productionof renal prostaglandins
    • Prevention of colon cancer
  • Contraindication
    • Aspirin in children <16 yo
      • risk of Reye’s syndrome
  • Adverse effects
    • Gastric/intestinal ulceration
    • Increased bleeding time
      • prevent formation of platelet-TXA2
    • Renal dysfunction
      • decrease RBF & GFR
      • renal insufficiency
      • hyperkalemia
      • proteinuria
    • Salt & water retention
      • oedema
      • hypertensive
      • antagonize the action of anti-hypertensives
    • Hypersensitivity
      • rashes
      • urticaria
      • vasomotor rhinitis
      • angioneurotic oedema
      • bronchial asthma (aspirin)
    • Abnormal liver function tests
    • During pregnancy
      • prolongation of gestation
        • delay labour
      • early closure of ductus arteriosus
        • fetal distress
  • Choice of NSAIDs
    • based on side effects
    • risks of upper GI side effects
      • Phenylbutazone
        • highest risk
      • Ibuprofen
        • lowest risk
    • do not use more than 1 oral NSAIDs simultaneously
  • COX-2 inhibitors (NSAIDs)
    • as effective as older NSAIDs
    • lower incidence of upper GI ulceration
      • for patients with high risk of GI ulceration
      • no difference in bleeding
    • more expensive
    • Higher rate of thrombotic events
      • non-fatal myocardial infarction
      • non-fatal strokes
  • Acetaminophen & paracetamol
    • Inhibits COX-3
    • analgesic & antiypyretic effects
    • metabolised in liver
      • through glucoronic acid conjugation
      • small % undergo cytochrome P450 mediated N-hydroxylation
        • forming highly reactive intermediate
      • associated with hepatotoxicity in large doses
    • half life of 2 hours
    • no risk of upper GI ulceration & bleeding
    • effective for osteoarthritis
      • less for inflammatory arthritis

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Glucocorticoids

  • RA
    • low-dose oral glucocorticoids
    • relieve symptoms
    • slows rate of joint damage
  • Local injection

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  • Pharmacological actions
  1. anti-inflammatory & immunosuppression
  • suppress activation of T-cells, APC, macrophages
    • by cytokines
    • suppress production of cytokines
  • block PLA2
    • decrease release of chemical mediators of inflammation (from mast cells, eosinophils etc)
      • histamine
      • prostaglandins
      • leukotrienes
      • PAF
  • stabilize lisosomal membranes of neutrophils
    • prevent release of catabolic enzymes
      • acid phosphatase
  • increase synthesis of lipocortin
    • inhibit PLA
    • decrease prostacyclin
    • decrease capillary permeability
    • promote vasoconstriction
      • reduce inflammation
  • Carbohydrate, Protein & Fat metabolism
    • Increase serum glucose
      • increase insulin secretion
    • stimulate hormone sensitive lipase
      • lipolysis
    • increase insulin secretion stimulate lipogenesis, inhibit lipolysis
      • fat deposition on trunk
      • Cushing’s disease
  • Catabolic effect on lymphoid tissue, muscle & skin
  • Clinical uses
    • Replacement therapy in adrenal insufficiency
    • Anti-inflammatory & immunosuppressive
      • Allergy
      • bronchial asthma
      • RA, OA
      • organ transplantation
      • ARDS
      • malignancies
      • cerebral oedema
      • nephrotic syndrome
      • eye, skin disease
      • IBD
  • Special precautions
    • Check & monitor for:
      • hyperglycemia
        • glaucoma
        • cataract
        • hidden infections
      • BP
      • hypokalemia
      • peptic ulcer
      • osteoporosis
  • Contraindications
    • Patietns with
      • Diabetes mellitus
      • Glaucoma
      • Peptic ulcer disease
      • hypertension
        • with heart failure
      • TB
      • Varicella virus infection
      • Psychosis
      • Osteoporosis
  • Adverse effect
    • Cushing’s syndrome
    • Adrenal suppression
      • avoid sudden withdrawal
    • Immunosuppression
      • infection
    • Others
      • osteoporosis
      • hypertension
      • weight gain
      • fluid retention
      • hyperglycemia
        • cataracts
        • glaucome
      • skin fragility
      • premature atherosclerosis

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    Disease Modifying Anti-rheumatic Drugs (DMARDs)

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    • In RA
      • reduce/prevent joint injury
        • early use
      • preserve joint integrity & function
    • Advantages
      • economic
      • control symptoms in the long term
    • Disadvantages
      • no immediate analgesic effects
        • slow action: 8-12 weeks

    DMARDs Agents

    • Methotrexate (MTX)
      • MOA
        • folic acid inhibitor
      • inhibits
        • lymphocyte proliferation
        • production of cytokines
        • rheumatoid factor
      • Interferes with neutrophil chemotaxis
        • reduces production of cytotoxins & free radicals
        • that damage synovial membrane & bone
        • effective in reducing signs & symptoms of RA
      • Highest efficacy
        • without excess toxicity on long term use
      • Taken orally/subcutaneously
      • Adverse effects
        • Most serious (but rare)
          • hepatic cirrchosis
          • interstitial pneumonitis
          • severe myelosuppression
        • Stomatitis, Mild alopecia, GI upset
          • related to folic acid antagonism
          • management: give folic acid
      • Contraindication
        • patients with pre-existing
          • liver disease
          • hepatic dysfunction
          • alcohol abuse
    • Leflunomide
      • MOA
        • block intracellular enzyme
          • needed for de novo pyrimidine synthesis
      • Actions
        • antiproliferative
        • anti-inflammatory
        • immunosuppressive
        • As effective as methotrexate
          • decrease signs & symptoms
          • decrease joint damage
      • Metabolism
        • converted to active metabolite in GI wall & liver
      • Onset of action
        • relatively fast (1-2 months)
        • sustained
      • Adverse effects
        • diarrhea
        • rashes
        • alopecia
        • elevation of liver enzymes
          • possible liver damage
        • Potent teratogen
          • discontinue & undergo cholestyramine washout before attempting conception
      • Monitor blood count & hepatic function
    • Sulfasalazine (SSZ)
      • Metabolism
        • reaches the colon
          • splits into 2 components by bacteria
          • important for action
      • Onset of action
        • as early as 1 month
      • Action
        • reduce
          signs & symptoms of RA
        • slow/halt radiolographic progression
      • Adverse effects
        • hypersensitivity
          • sulfa allergy
        • mild GI upset
        • mild cytopenia
      • Monitor blood every 1-3 months
      • Good alternative to methotrexate
        • for patients with liver disease
        • less toxic to liver
    • Hydroxychloroquine
      • MOA
        • reduces chemotaxis & phagocytosis of polymorphs
      • Onset
        • slow
      • Use for
        • milder RA
          • less effective than SSZ & MTX
          • but less toxic & better tolerated
      • Side effects
        • ocular toxicity*
          • maculopathy
          • scotoma
      • Monitor
        • baseline & annual ophthalmologic assessments
      • Stop therapy
        • if any impairement of vision
        • severe rash
    • Sodium aurothiomalate (Gold therapy)
      • Given Intramuscularly
        • after injection, do CBC & urine test for protein
      • Side effects
        • skin rash
        • stomatitis
        • flushing
        • hypotension
        • tachycardia

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    Biologic response modifiers

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    TNF-alpha blockers

    • Etanercept
      • recominant fusion protein (consist of)
        • soluble human TNF-receptor
        • human IgG1-Fc fragment
      • MOA
        • binds TNF-alpha in the circulation & in joint
          • prevent interaction with cell surface TNFa receptors
          • reduce TNF activity
          • clears TNFa from circulation
      • Used in combination with MTX
        • if MTX alone not enough
      • Onset
        • 1-4 weeks
      • Given subcutaneously
      • Very expensive
    • Infliximab/Adalimumab
      • MOA
        • Monoclonal antibody that binds TNFa
          • with high affinity & specificity
        • same mechanism as (above)
      • Used in combination with MTX (same)
      • Onset
        • days – weeks

    Adverse effects for TNFa blockers

    • Injection site
      • pain
      • swelling
      • itching
    • Serious infections
      • sepsis
      • death
    • Disseminated tuberculosis
      • reactivation of latent disease
      • screening for latent TB essential before treatment
    • Lymphoma
      • non-hodgkin’s lymphoma
      • RA itself is a risk
    • Do not use in patients with
      • demyelinating disease
      • congestive heart failure

    Other drugs

    • Anakinra
      • recombinant
        • non-glycosylated human IL-1Ra
      • MOA
        • inhibits binding of cytokine to IL-1 receptor
      • Used with DMARDs
      • Onset
        • 2-4 weeks
      • Given subcutaneously
      • Side effects
        • injection site reactions
        • serious infections
        • decreased white blood cell count
        • lymphoma
      • Combination of biologics not recommended
        • risk of infections increased if combine with TNFa inhibitors
      • Advantage
        • no case of TB reported
          • does not reactivate latent TB
    • Abatacept
      • MOA
        • inhibits activation of T cells
          • by blocking co-stimulatory signal
      • Given alone/with DMARDs
      • Side effects
        • risk of infection
          • URTI
    • Rituximab
      • MOA
        • targets lymphocytes
          • cause depletion of B cells
      • Given IV
      • Side effects
        • rashes
      • Advantage
        • does not reactivate TB
        • does not cause lymphoma

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    Algorithm for Rheumatoid arthritis

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    terri

    Terri is obsessed with making medical school as painless as possible. She studies and compiles medical school notes in a concise, easy-to-understand format. She also enjoys reading contributions by others. She is an investor in sustainability projects. Her ideal weekend is wine tasting and experimenting on bread-making. She has yet to master the art of Sourdough baking.

    1 Comment

    Joan · November 9, 2010 at 4:30 pm

    If you have advanced arthritis and recommend that the relief operation for a while but does not replace painkillers such as hydrocodone. This medication should be taken to control and that can lead to addiction.

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