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What four drugs act against circulating proinflammatory cytokines?
- Infliximab: TNF-a monoclonal antibody
- Adalimumab: TNF-a monoclonal antibody
- Etanercept: TNF-a receptor
- Anakinra: IL-1 receptor antagonist
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What three drugs fall under the miscellaneous category? Give a quick synopsis of each.
- Penicillamine: last-ditch drug; bone marrow suppression
- Hydroxychloroquine: inhibits T-cells, WBCs and traps free radicals
- Sulphasalazine: COX inhibition, PG suppression
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What are the four cytotoxic drugs? Give a quick synopsis of each.
- Methotrexate: imitates dihydrofolate (blocks de novo purine synth)
- Azathioprine: PRPP synthetase/aminotransferase inhibitor (blocks de novo purine synth)
- Leflunomide: blocks dihydroorate dehydrogenase (RLS in de novo purine synth)
- Cyclosporine: calcineurin inhibitor (prevents T-cell proliferation)
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What is the therapeutic goal of anti-rheumatoid arthritis therapy?
To arrest the progress of the disease (remission) and to regulate the debilitating pain.
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What is the general therapeutic strategy for the three DMARD classes as a whole?
Almost always use anti-cytokines and miscellaneous in conjuction, and more commonly using cytotoxic tx as well. This prevents upregulation of inflammation and kills off rapidly dividing hematopoietic cells.
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What three types of cells produce IL-1 and TNF-α in rheumatoid arthritis?
- Dendritic cells
- Macrophages
- Synovial cells
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What are the 5 major roles of IL-1 in rheumatoid arthritis?
- Stimulates cytokine synthesis (PGE2, NO, metalloproteases)
- Endogenous pyrogen
- Augments T- and B-cell, and macrophage activation
- Stimulates cartilage destruction
- Stimulates integrin and selectin production in endothelium
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What are the 4 major roles of TNF-α in rheumatoid arthritis?
- Pro-inflammatory
- Cytotoxic
- Stimulates all leukocytes (proliferation, Ab production, etc)
- Stimulates cartilage destruction
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Infliximab: Give the structure, RoA, MoA, primary uses, and adverse effects
- Human/mouse chimeric IgG1 MAB
- RoA: IV @ 0, 2, and 6wks, then every 8
- MoA: binds soluble and transmembrane TNF-α
- Uses: Rheumatoid Arthritis, Crohn's, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis
- Adverse: hypersensitivity, infections (TB), hepatosplenic lymphoma (T-cell), heart failure
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Adalimumab: Give the structure, RoA, MoA, primary uses, and adverse effects
- fully humanized IgG1 MAB
- RoA: SQ every 14d by pen
- MoA: binds TNF-α; also reduces C-reactive protein, IL-6, RBC sedimentation, and MMP-1,-3
- Uses: Rheumatoid Arthrisits, ankylosing spondylitis, Crohn's, psoriasis
- Adverse: black box warning for opportunistic, fungal, and TB infection; exacerbates CHF; lupus-like
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Etanercept: Give the structure, RoA, MoA, primary uses, and adverse effects
- soluble recomb human TNF receptor fusion protein receptor
- RoA: weekly SQ by patient
- MoA: binds up all TNF-α,β, preventing inflammation
- Use: moderate to severe RA; psoriatic adn juvenile arthritis
- Adverse: hypersensitivity, autoantibodies, increase cancer risk; contra in sepsis
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Anakinra: Give the structure, RoA, MoA, primary uses, and adverse effects
- Recombinant IL-1 receptor antagonist
- RoA: daily SQ
- MoA: binds and antagonizes IL-1R, preventing IL-1 signal transduction
- Use: Rheumatoid Arthritis
- Adverse: infections, decreased WBCs, antibodies to drug
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Penicillamine: Give RoA, MoA, primary uses, and adverse effects
- RoA: orally; clinical efficacy takes months
- MoA: unknown
- Use: copper chelator for Wilson's disease; Rheumatoid Arthritis after other drugs fail
- Adverse: possibly fatal bone marrow suppression; cutaneous lesions; hypersensitivity rxn (fatal w/ Goodpastures)
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(Hydroxy)Chloroquine: Give the structure, RoA, MoA, primary uses, and adverse effects
- 4-aminoquinolines
- RoA: orally after meals; effect not until 4-12wk
- MoA: inhibits T-cell and leukocyte proliferation and movement; stabilizes lysosome membranes and traps free radicals
- Uses: Hydroxy - Rheumatoid Arthritis, SLE; chloroquine - prophylaxis and tx of P. vivax, ovale, and malariae
- Adverse: Irreversible retinal degeneration related to dose and frequency; hemolysis in G6PD deficiency
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Sulfasalazine: Give the structure, RoA, MoA, primary uses, and adverse effects
- Prodrug metabolized into mesalamine and sulfapyridine by GI flora
- RoA: oral
- MoA: inhibition of COX in the gut, lowering PG levels
- Uses: rheumatoid arthritis, ulcerative colitis
- Adverse: general GI; hypersensitivity; reversible leukopenia, thrombocytopenia, alopecia, stomatitis (remove tx)
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Methotrexate: Give the structure, RoA, MoA, primary uses, and adverse effects
- Folic acid lookalike
- RoA: oral, IV
- MoA: competitive reversible inhibition of dihydrofolate reductase, blocking THF production from dihydrofolate; prevents lymphoid cell proliferation
- Use: Anchor drug combined with others to tx RA; also anti-cancer
- Adverse: hepatotoxicity and fibrosis with long-term low dose tx
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Azathioprine: Give the class, RoA, MoA, primary uses, and adverse effects
- Antimetabolic cytotoxic drug that works in the S-phase
- RoA: oral; sometimes IV
- MoA: Prevents de novo purine synth by blocking PRPP synthetase and aminotransferase; also gets incorporated as a purine nucleotide into DNA
- Uses: Rheumatoid Arthritis (and other autoimmunes); antimalignant; immunosuppressive (blocks B/T cell prolif); prevent graft rejection; tx of typeIV hypersensitivity
- Adverse: bone marrow suppression; hepatotoxic -> cholestasis
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Leflunomide: Give the structure, RoA, MoA, primary uses, and adverse effects
- RoA: 100mg loading dose 3d, then daily 20mg
- MoA: blocks dihydroorate dehydrogenase, the rate-limiting enzyme of de novo pyrimidine synth, blocking B/T cell proliferation (depends on de novo)
- Uses: moderate/severe RA, psoriatic arthritis
- Adverse: GI tox, teratogenic, renal impairment
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Cyclosporine: Give the structure, RoA, MoA, primary uses, and adverse effects
- Fat-soluble cyclo-undecapeptide derived from fungus
- RoA: oral, IV, IM (lipid vehicle)
- MoA: binds and forms complex with cyclophilin-A, which in turn blocks calcineurin, a phosphatase that normally activates nuclear factor of activated T-cells (NF-AT) that would up-reg IL-2. Without this, naive T-cells can't proliferate, so they apoptose.
- Uses: rheumatoid arthritis; immunosuppression (prevention of graft rejection); tx of graft v host; psoriasis; glomerular nephritis
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