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
    2. 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
    3. 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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1 COMMENT

  1. 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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