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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
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
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)
What is the therapeutic goal of anti-rheumatoid arthritis therapy?
To arrest the progress of the disease (remission) and to regulate the debilitating pain.
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.
What three types of cells produce IL-1 and TNF-α in rheumatoid arthritis?
- Dendritic cells
- Synovial cells
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
What are the 4 major roles of TNF-α in rheumatoid arthritis?
- Stimulates all leukocytes (proliferation, Ab production, etc)
- Stimulates cartilage destruction
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
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
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
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
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)
(Hydroxy)Chloroquine: Give the structure, RoA, MoA, primary uses, and adverse effects
- 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
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)
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
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
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
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