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36 Cards in this Set
- Front
- Back
- 3rd side (hint)
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A range of DMARDS were all superior than placebo doing what |
Reducing erosions |
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DMARDS are —— in onset and ——- are needed to control pain |
Slow Nsaids |
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Name some glucocorticoids |
Dexamethasone Prednisolone |
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How do glucocorticoids supress all aspects of the inflammatory response |
Reduce vascular permeability Vasoconstrict Inhibit fibroblast activity Inhibit white cell accumulation and activity |
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Whats some of the mechanisms of glucocorticoids |
Act intracellularly Modify transcription Increase interest in non-genomic effects mediated by membrane-bound receptors |
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How does glucocorticoids modify transcription |
By induction or repression |
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Name the pathway for glucocorticoids |
Glucocorticoid enters the cell and binds to glucocorticoid receptor GRα Glucocorticoid receptor complex- migrates to the nucleus, binds to GRE and activates transcription Protein synthesis- annexin-1 (lipocortin) |
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What does annexin-1 do(1) |
Inhibits PLA2, (phospholipase a2)inhibiting production of arachidonic acid and therefore a range of inflammatory mediatorus |
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What are some other actions of annexin-1(2) |
Inhibits neutrophil accumulation Inhibits macrophage accumulation in joint Inhibits macrophage phagocytosis Inhibits production of cytokines by macrophages |
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What inflammatory mediators do glucocorticoids inhibit synthesis of |
Arachidonic acid metabolites Nitric oxide (via iNOS) Inflammatory cytokines (e.g TNF-a, IL-1,IL-8, IL-12) Chemokines Adhesion molecules |
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What happens with the NFkb pathway(1) |
Cytokine binds to receptor on the membrane and the release of NFkb this goes on into the nucleus and makes mrna for the synthesis of cytokines, COX-2, iNOS and chemokines |
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and what happens with the nfkb pathway being blocked?(2) |
Glucocorticoid binding to its receptor inhibits nfkb and other transcription factors |
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Whats a problem with corticosteroids and what do we then do |
Huge side effects we do corticosparing-combinations of different drugs with different side effects to allow not as bad side effects |
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Whats some other DMARDS |
Sulphazaline, gold salts, penicillin derivatives |
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How does sulphasalazine becomes the active agent and how could it not work |
Sulphasalazine to mesalazine which is the active agent Sulphasalazine to sulphapyridine which is absorbed metabolised then secreted |
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Whats the adverse effects of sulphasalazine |
Rashes, Gastro-intestinal intolerance Especially in patients with RA -leucopenia -neutropenia Thrombocytopenia Penia-loss of cells |
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What are the mechanisms of action of methotrexate |
Inhibits dihydrofolate reductase Stimulates release of adenosine |
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What are the mechanisms of action of methotrexate |
Inhibits dihydrofolate reductase Stimulates release of adenosine |
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Explain one of methotrexates mechanisms of action: Inhibits dihydrofolate reductase |
Therefore inhibits purine/pyrimidine synthesis, DNA synthesis and cell proliferation, including T-cell and B-cell populations, osteoclasts and fibroblasts |
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Explain one of methotrexates mechanism of action Stimulates the release of adenosine |
Adenosine has potent anti inflammatory effects through A2a and A3 receptors |
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What is methotrexate |
A first line drug in treating rheumatoid arthritis Highly effective in a significant proportion of patients |
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Why dont we like using DMARDs |
Not 100% sure on how they work and have a lot of side effects |
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What kind of cytokines can u target for the disease RA |
Il-17, IL-6, IL-23, TGF-b, TNFa, IFN-y, IL-1 |
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What are the 2 forms of TNF-α And how do you get one from the other |
Membrane-bound TNFα Soluble TNFα TACE(TNFα converting enzyme converts membrane bound TNF TO soluble tnf |
TACE(TNFα converting enzyme converts membrane bound TNF TO soluble tnf |
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What are the two TNFα receptors and whats their characteristics |
TNFR-1 and TNFR2 Share structural similarity in extracellular domain Intracellular domain differences Different signalling pathway |
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What happens when TNFR-1 is activated |
Apoptosis |
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What happens when TNFR-1 is activated |
Apoptosis |
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What about TNFR-2 receptor |
Through the nfkb pathway into the nucleus to cause transcription |
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What are the transcription products of tnfα signalling (TNFR2) |
TNFα IL-1β Upregulation of adhesion molecules(icam vcam) Cytokines that further enhance immune responee activators of inflammatory pathways |
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How is structure of infliximab (tnf antibody) different? |
Chimeric antibody Need a antibody that binds well but its a mouse antibody so need to make it as much as a human antibody as possible (humanised) so it wont cause a a response |
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Whats infliximabs mechanism of action |
Binds and neutralizes both soluble and membrane bound TNFα and inhibits further activity |
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What are other postulated mechanisms of actions of infliximab |
Antibody dependent cell mediated cytotoxicity Lysis of TNFα expressing cells through complement activation |
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How is infliximab administered and dose |
By intravenous infusion For RA patient 3mg/kg single dose followed by additional 3mg/kg doses 2 and 6 weeks after first dose Then maintenence dose is 3mg/kg every 8 weeks |
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What are some cytokine blocking agents |
Etanercept- soluble TNFa receptor fused to Fc domain of human IgG(mops up all tnf in the joint and gets rid of it) Anakinra Recombinant IL-1 receptor antagonist |
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What does abatacept do |
Target T cell activation Block interaction between the dendritic cells and T cells T cell doesn’t function well and starts to die |
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What does rituximab do |
Anti CD20 antibody expressed on b cells CD20 is expressed exclusively on B cells B cells nit only give rise to ab producing plasma cells but are highly effective APC Rituximab causes cytotoxicity so the B cell starts to die and could get opsonised and eated by other cells |
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