Anti-Inflammatory Drugs

  • Created by: LBCW0502
  • Created on: 25-01-19 11:00
Give examples of non-allergic inflammatory diseases
Arthritis (RA, OA-patients complain about treatment) - most common. Skin conditions (psoriasis). Inflammatory bowel disease
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Describe features of a normally functioning joint
Synovial fluid is smooth/clear with no cells. Smooth bone
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Describe features of an arthritic joint (1)
Cells in synovial fluid (neutrophils). Synovial fluid not as viscous (not as functional). Synovial membrane changes into inflammatory organ (growth of blood vessels, fibroblasts, release of inflammatory mediators, invade bone). Bone no longer smooth
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Describe features of an arthritic joint (2)
Nerves become sensitised due to damaged cartilage and bone. Cytokines help to break down bone and cartilage
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Describe the concerns over arthritis
40% of people 65+ years of age have a form of arthritis. 1% of total population suffers from RA (male:female, 1:3). 10% of GP consultations are arthritic complaints (number 1 disability in UK). Annual cost of £10.2 billion for NHS
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Describe features of managing RA (1)
Not fatal condition but reduces quality of life and patients experience pain. Aetiology of RA unknown (possible causes - bacterial infection, genetic link, humidity/cold). Cannot to stop RA being formed
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Describe features of managing RA (2)
Treatment directed towards - relief of symptoms, conservation/restoration of function in affect joints, suppression of active progressive disease, reduce morbidity
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Summarise features of mediators and arthritis
TNF alpha, IL-1, stimulate release of other mediators, effects of neutrophil release (high endothelial venule). Determine effects of osteoclasts/osteoblasts
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Outline the therapeutic pyramid in RA (1)
Patient education, physiotherapy, exercise/rest, NSAIDs. NSAIDs and analgesics. Immunosuppresants e.g. methotrexate or other DMARDS
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Outline the therapeutic pyramid in RA (2)
Add in more DMARDs or biologic. Steroids/short term/ADRs (flare up). Cytotoxics (usually used in cancer/ADRs). Biologics/biosimilars (want as first line/fewer side effects)
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Outline the therapeutic pyramid in RA (3)
Intra-articular steroid, IV, side effects/topical creams, NSAIDs, surgery (use later). Don't stop disease but manage it
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Describe features of NSAIDs
Most widely described. Most work by inhibiting COX (inhibit prostaglandin production). Analgesic, anti-inflammatory, anti-pyretic. (Paracetamol - not true NSAID, different mechanism, analgesic, not anti-inflammatory)
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Give examples of non-selective inhibitors
Naproxen, aspirin, ibuprofen, indomethacin (side effects - inhibit blood flow/mucus secretion/GI bleeding, problems with kidneys)
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Give examples of COX-2 selective inhibitors
Celecoxib, etoricoxib, rofecoxib, meloxicam (fewer side effects, cough - regulation of COX-2 in lungs)
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Describe features of COX inhibitors in patients with CV risk (ways to reduce side effects)
With oral NSAIDs - associated use of PPI to inhibit GI reflux due to excess acid (e.g. esomeprazole). Alternatively use prostaglandin analogues (e.g. misoprostol). Also, gradual increase in NSAID use via topically application (diclofenac)
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Give examples of anti-inflammatory steroids
Corticosteroids (e.g. hydrocortisone - in body/weakest). Glucocorticoids (dexamethasone/prenisolone, synthetic- more potent)
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What are the beneficial effects of anti-inflammatory steroids (multi anti-inflammatory activities)?
Inhibit arachidonic acid release, cytokine inhibition, down regulation of adhesion molecules, inhibition of enzyme induction (COX, NOS)
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What are the effects of anti-inflammatory steroids on immune response?
Inhibition of lymphocyte t-cell proliferation, induces apoptosis
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What are the side effects of anti-inflammatory steroids
Osteoporosis, diabetes, glaucoma, increases risk of infection, adrenal atrophy (organs become fibrous/not as functional)
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When are anti-inflammatory steroids appropriate for treatment?
Give for local flare ups or when waiting for other DMARDs to work (don't keep patient on them for long term/only if necessary). Decreased if given locally (intra-articular, highly effective). Concept of steroid sparing popular (due to side effects)
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Describe features of Disease Modifying Anti-Rheumatic Drugs (DMARDS)?
Suppress overactive immune and/or inflammatory systems to inhibit the damaging process. Most take effect over weeks/months. Often prescribed together as 'combination therapies'. May add NSAID and/corticosteroid with DMARD (until DMARD takes effect)
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What are the three subsets of DMARDS? (1)
Traditional DMARDs taken orally, broad immuno-suppressants, adverse effects common with most. Biologics/biosimilars, taken by self-injection/infusion (late 1990s), target specific mediators, well tolerated. Targeted DMARDs (newest) taken orally
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What are the three subsets of DMARDS? (2)
Target specific immune system signalling molecules
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Describe features of traditional DMARDs
Methotrexate. Several weeks for therapeutic effect. Need to monitor for side effects (blood count). Hydroxychloroquine (antimalarial). Sulfasalazine. Leflunomide. Azathoprine. D-penicillamine. Minocycline
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Describe features of methotrexate (1)
Gold standard. Most widely used (disease modifying agent for RA). Works in 30% of patients. Acceptable safety, low cost, steroid sparing. Can be mixed with other anti-inflammatories. Better if used in early disease (used in young and old)
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Describe features of methotrexate (2)
Several weeks to work (unlike NSAIDs). Dosing - 7.5-15 mg once weekly, higher doses in early RA are not associated with a better clinical outcome
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Describe the mechanism of action of methotrexate (1)
Folate antagonist (widely used anti-metabolite in cancer chemotherapy). Low dose used. Decreases production of purines/pyrimidines (ATP/AMP, polyamines) and interferes with DNA synthesis
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Describe the mechanism of action of methotrexate (2)
May act with other mechanisms (administer folate - decreases adverse effects without affecting anti-inflammatory effects). Suppressor of NF-kappa B activation. Inhibition of t-cell and macrophage activation
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Describe the mechanism of action of methotrexate (3)
Generally anti-inflammatory (decreases pro-inflammatory cytokines). Inhibits endothelial adhesion molecule activation (suppresses and helps cardiovascular protection). Increases adenosine release (mainly beneficial)
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Describe the mechanism of action of methotrexate (4)
Adenosine thought to reduce cell activation (via increase cAMP)
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Describe the mechanism of action of methotrexate (5)
Toxicity/adverse effects, monitor. Cytopenia (bone marrow deficits), infection, intestinal, liver function, administer folate
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What are biologics?
Antibodies - large size, complex structure
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How are biological products different? - small molecule drugs
Small molecule drugs - low mwt, organic/chemical synthesis, fewer critical processes, well-characterised, known structure, homogeneous drug substance, usually not immunogenic
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How are biological products different? - biological products
High mwt, made with live cells/organisms (inherent/contamination risk), many critical process steps, less easily characterised, structure may/may not be completely defined or known, heterogenous mixtures (variants), often immunogenic
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Give examples of biologics
Anti-TNF antibodies (infliximab, adalimumab etc.). Soluble TNF receptor construct (etanercept). Used when 2-3 DMARDs failed. Effective for 30% of cases, less successful in follow up treatments, expensive, can be given as co-treatments (e.g. NSAIDs)
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Describe features of established therapy and inhibition of TNF alpha
Antibodies collect TNF - prevent inflammation, tissue damage, deformities/disability, pain, stiffness, swelling, tenderness (diagrams)
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Describe features of cytokines as biologics (1)
IL-1 antibodies/receptor antagonist (anakira - not beneficial, cannakinumab - effective in juvenile (14-15 yrs, age) arthritis, effective in atherosclerosis). IL-6 blocker (tocilizumab, roActemra - used on non-responders to anti TNF or methotrexate)
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Describe features of cytokines as biologics (2)
IL-17 receptor antagonist - psoriatic arthritis
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Describe features of cell based biologics
Rituximab (MabThera - removes antibody-producing white blood cells, B-cells, also used in MS). Abatacept/Orencia (inhibits action of T cells and reduces damaging effects)
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Describe features of biosimilars
Available but very expensive (2009), possible to treat a few. Biologic medical product. Almost identical copy of an original product. May be manufactured by a different company. Cheaper (by 40%), UK NHS has been keen to use them
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Describe features of newer targeted DMARDs
Approved in 2017. Janus kinase inhibitors (JAK inhibitors) e.g. baricitnib (Pfizer), oral daily, cheaper than biologics, moderately-severely active RA, used when other DMARDs not tolerated, acts to inhibit cell signalling (e.g. t-cells)
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Describe features of apremilast
Oral, inhibits activity of phosphodiesterase type-4 (PDE4). Suppresses pro-inflammatory mediator synthesis and promotes anti-inflammatory mediators. Psoriatic arthritis (with DMARDs or alone). Good for patients intolerant to DMARDs
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Summarise features of RA treatment using traditional methods
Treat symptoms (pain, swelling), less aggressive, treat steroids, surgery when RA gets worse
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Summarise features of RA treatment using modern methods
Limit joint destruction, early aggressive treatment. Methotrexate used early (including elderly and young). Combination therapy. Increasing use of biologics/biosimilars
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Describe features of the important of adherence in RA (1)
DMARD (e.g. methotrexate) takes several weeks to work. Perceptions about disease/treatment (willingness - manage actual side effects). Benefits - less pain/stiffness, fewer flares, reduction in joint damage, improved quality of life
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Describe features of the important of adherence in RA (2)
Unintentional - elderly patients/blood tests, forget to take medications (leads to bad adherence). Chronic inflammatory disease - more problematic
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Card 2

Front

Describe features of a normally functioning joint

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Synovial fluid is smooth/clear with no cells. Smooth bone

Card 3

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Describe features of an arthritic joint (1)

Back

Preview of the front of card 3

Card 4

Front

Describe features of an arthritic joint (2)

Back

Preview of the front of card 4

Card 5

Front

Describe the concerns over arthritis

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