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42 Cards in this Set
- Front
- Back
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DMARD's
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- Systemic, inflammatory disease that may develop at any age
- Involvement of synovial tissues - Progression often leads to destruction of cartilage and bone. - Probable pathological reaction of the immune system - Minimal time to see effect of DMARD is two weeks. |
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RA triggered by:
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- Genetic disposition
- Age related “wear and tear” - Hypothermia - Infection |
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RA shows:
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- Thickening of synovial lining
- New blood vessel development - Stimulation of inflammatory cell and prostanoid production - Influx of inflammatory cells into synovial fluid (T-lymphocytes) - Induction of inflammatory cascade |
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RA pathogenesis:
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T-lymphocytes:
Stimulates release of macrophages ↓ Release of inflammatory cytokines ↓ Release of enzymes causing connective tissue degradation and stimulation of B lymphocytes. Subsequent production of Rheumatoid Factor (RhF) |
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RA: Proinflammatory cytokines:
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Proinflammatory Cytokines:
TNF-α IL-1 IL-6 IL-17 Stimulation of synovial fibroblasts & release of matrix metalloproteinases |
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RA: Progression
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Synovial inflammation
↓ Cartilage destruction ↓ Bone Erosions ↓ Changes in joint integrity |
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RA: Joint
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Pic
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RA: Therapeutic Goals
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- Analgesia-pain relief
- Reduction of inflammation - Protection of articular structures - Maintain joint function - Control systemic involvement/infection (All Palliative) |
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RA: Treatment options
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NSAID’s
Glucocorticoids DMARD’s Biological Response Modifiers |
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RA: Therapeutic Goals of non DMARDs
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- NSAID’s to control initial inflammation and pain and prostaglandinds
- Low dose oral glucocorticoids to retard disease progression - Disease modifying antirheumatic drugs-first line therapy for patients with aggressive disease. - Combination regimen for optimal results and prevention of disease progression |
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RA: NSAIDs
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Acute relief of inflammatory symptoms by NSAID’s:
indomethacin diclofenac piroxicam ibuprofen And glucocorticoids: prednisone (DO NOT HALT PROGRESSIVE DESTRUCTION OF JOINTS) |
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RA: Timing of DMARD administration
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Initiation of disease modifying anti-rheumatic drugs (DMARD’s) within first 3 months of diagnosis.
↓ Single or combination DMARD ↓ Prevention of joint erosion. |
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RA: Do you use NSAIDs alone?
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Always combine with DMARD
NSAID’s will provide some analgesic relief and antiinflammatory benefits. Do not alter disease progression Inhibition of cyclooxygenase activity Reduction in inflammatory mediators May require “switch” to different NSAID. |
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RA: NAIDs help by inhibition of...
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inhibition of neutrophil activation
inhibition of leukotriene production inhibition of T & B cell proliferation Interference with membrane associated processes activity of NADPH oxidase in neutrophils and activity of phospholipase C in macrophages |
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RA: NSAIDs used:
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Ibuprofen (400mg – 800mg t.i.d)
Indomethacin (50mg b.i.d/t.i.d) Diclofenac (150mg – 200mg/d) Piroxicam (10mg – 20mg b.i.d) Sulindac (150mg -200mg b.i.d) Celecoxib ( 100mg b.i.d) Don't need to know doses. |
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RA: Glucocorticoids
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More efficient than NSAID’s for management of pain and stiffness
↓ 7.5mg prednisolone daily, significantly reduces occurrence and progression of erosions in patients with early RA. Intraarticular instillation (triamcinilone, methylprednisolone, betamethasone) into swollen joint avoids undesirable systemic effects |
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RA: Glucororticoids
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Continuous oral background therapy.
Large oral pulses Short courses of rapidly decreasing doses for disease flares As intraarticular injections As intravenous pulses during a flare As induction treatment at time of commencement of DMARD’s |
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RA: DMARDs overview.
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Anti-inflammatory actions in several connective tissue diseases.
Inhibition of wide variety of cytokines including interleukins, interferons and TNF. Slow-acting –may take months for their benefits to become apparent. No analgesic activity Used primarily for rheumatic disorders and where inflammation does not respond to cyclooxygenase inhibitors. Slows course of disease. |
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RA: DMARDs
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Methotrexate (Rheumatrex)
Hydroxycloroquine (Plaquenil) Sulfasalazine (Azulfidine) Leflunomide (Arava) |
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RA: Methotrexate Contraindications
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thrombocytopenia
immune compromised patients 100% contraindicated in pregnant and nursing women |
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Methotrexate: MOA
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Methotrexate:
Inhibition of dihydrofolate reductase Lymphocyte proliferation Chemotaxis RhF production Cytokine production DMARD of choice |
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Methotrexate: Course
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Methotrexate:
May alter course of disease by retarding progression to other uninfected joints. Use of NSAID’s should be continued unless remission occurs. Once weekly doses, until symptomatic improvement occurs (max- 20mg/week) + supplemental folic acid. Monotherapy or combination with other DMARD’s |
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Methotrexate: Side effects
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Methotrexate:
Counsel patients to avoid alcohol and take folic acid as directed Essential to monitor liver function. Serious adverse reactions : hepatotoxicity and pulmonary fibrosis. |
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DMARDs: Hydroxychloroquine
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- Antimalarial used for treatment of acute and chronic RA.
- Inhibit lymphocyte function - Stabilize lysosomal membranes - Reduce chemotaxis and phagocytosis. - Reduce production and release of IL-1 |
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Hydroxychloroquine: Half life
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Long elimination half-life (3-4 days)
↓ 4-6 months for steady state concentrations ↓ Delayed effect (6 months!!) |
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DMARDs: Sulfasalazine
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- Converted in intestine to sulfapyradine (antibacterial) and mesalamine (antiinflammatory).
- Inhibition of prostaglandin production. - Metabolites highly distributed. - Limited use due to significant GI side effects. (do not use in GI comp ptn) - Side effects: GI discomfort, nausea, vomiting, - Commence with low dose. - Therapeutic effect takes up to 2 months. |
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DMARDs: Leflunomide
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Inhibition of mitochondrial dihydroorotate dehydrogenase
↓ Inhibition of T-lymphocyte response to inflammatory stimuli. - Metabolized to active metabolite (Half-life-19 days). - Commence with loading dose followed by maintenance dose |
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Leflunomide: Combination
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- May be used in combination with methotrexate (high risk of hepatotoxicity).
- Contraindicated in hepatic dysfunction. - Must monitor liver function |
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RA: Biological Response Modifiers
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Indicated as combination regimen with DMARD therapy or replacement therapy in patients with DMARD failure
- Should not be used in immunocomprimised ptns - Used in ptns who failed convetional Dmard therapy |
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Biological Response Modifiers:
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TNF Antagonists:
Etanercept (Enbrel) Infliximab (Remicade) Adalimumab (Humira) IL-1 Receptor Antagonist: Anakinra (Kineret) |
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Biological Response Modifiers: Costimulation blockers, Anti-CD20 monoclonal antibody
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Costimulation Blockers:
Abatacept (Orencia) Anti-CD20 Monoclonal Antibody: Rituximab (Rituxan) |
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Biological Response Modifiers: SE
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Can get injection site reaction. May be delayed.
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Etanercept: Prevents binding of TNF-alpha to receptors
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Etanercept:
- Prevents binding of TNF to receptors - SC administration twice weekly. - Elimination half-life: 5 days. - Highly effective as monotherapy. - Symptomatic improvement in 1-4 weeks - May be combined with DMARD. (except Anakinra). - Adverse reactions include injection site reactions, headache, dizziness (all BRMs) |
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Infliximab: Soaks up TNF-alpha
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- IgG1 monoclonal antibody
- Binds to soluble and bound TNF-α - Combination regimen with methotrexate. - IV infusion 4 to 8 weeks. - Elimination half-life: 9 days. - Symptomatic relief within 1-4 weeks. - Adverse reactions include headache, pain, nausea fever, dizziness, rash. |
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Adalimumab: Prevents binding of TNF with receptors.
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- Prevents binding of TNF with receptors.
- Lysis of TNF expressing cells. - Reduction of TNF-α production by macrophages. - SC administration every 2 weeks. - Half-life: 10-20 days. - Symptomatic relief within 1 week. - Monotherapy or combination with DMARD. - Adverse reactions include, infections, fever, rash. |
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Anakinra: Prevent IL-1 receptor binding
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- Recombinant form of IL-1 receptor antagonist.
- Prevention of IL-1 receptor binding. - Daily SC administration. - Half-life: 4-6h - Monotherapy or combination with DMARD. - Contraindicated with TNF antagonists - Adverse reactions include infections, headache, nausea, diarrhea. |
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Abatacept: Blocks T-cell signaling and T-cell activation
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- Blocks T-cell signaling and T-cell activation.
- Lack of response to antigen. - IV administration over 30 mins every 4 weeks. - Half-life: 13 days - Monotherapy or combination with DMARD. - Contraindicated with TNF-antagonists and anakinra. - Adverse reactions include headache, dizziness, anaphylaxis. |
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Rituximab: Causes Depletion of B-lymphocytes
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- Causes rapid and sustained depletion of B-lymphocyte.
- Administered IV over 4 hours, then at 2 weeks. - Half-life: 60-150h - Therapeutic effects last for at least 40 weeks after initial treatment. - Indicated as monotherapy or in combination with methotrexate. |
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Rituximab: antihypertensive therapy should be withheld 12 hours.
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- Adverse effects include, angioedema, fatigue, nausea,vomiting, headache, hypotension, bronchospasm, rash, urticaria.
- Antihypertensive therapy should be withheld 12 hours prior to administration of rituximab. |
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Considerations with BRMs
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- Must consider risk of infection with biological response modifiers!!
- Contraindicated in patients with acute, serious infection. - Contraindicated in immunocompromised patients and those with tuberculosis. |
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RA: AGGRESSIVE therapy
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Early diagnosis of rheumatoid arthritis and prognosis (RhF & Radiography)
↓ DMARD’s + NSAID’s ↓ Low-dose systemic Corticosteroids if required ↓ If inadequate response after 3 months change/add DMARD’s or consider biologics. Arrest progression and prevent permanent joint damage |
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Flow chart for RA drugs
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Pic
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