L12 - Anti-inflammatories - Antiheumatoids Flashcards
Rheumatoid arthritis affects?
Half a million-people affected by it in the UK
Affects 3x more women than men
Rheumatoid arthritis age of onset
40-60
There is a juvenile onset form
Rheumatoid arthritis risk factors
Environmental - smoking
Genetic
Rheumatoid arthritis symptoms
Inflammation of the synovium - increases risk of cardiovascular disease and therefore death
Swelling of the joints
Pain and stiffness
Poor sleep
Rheumatoid arthritis - cells and mediators that activate inflammation
Proinflammatory cytokines
Rheumatoid arthritis - cells and mediators that activate inflammation -proinflammatory cytokines
IL1 and TNF alpha
Lead to recruitment and activation of other cells
- Influx of inflammatory cells leads to joint damage
- Leads to activation of osteoclast and fibroblasts
- Release metalloproteinases which lead to joint damage
Rheumatoid arthritis - cells and mediators that inhibit inflammation - 5-aminosalicylic acid
Free radical scavenger to decrease damage produce by neutrophils
Rheumatoid arthritis - cells and mediators that inhibit inflammation
Glucocorticoids and ciclosporin
Immunosuppressants - methotrexate
5-aminosalicylic acid
DMARDs
Rheumatoid arthritis - cells and mediators that inhibit inflammation - glucocorticoids and ciclosporin
Inhibit transcription of proinflammatory cytokines
Rheumatoid arthritis - cells and mediators that inhibit inflammation - immunosuppressants - methotrexate
Inhibit induction phase of inflammatory response
Inhibit transcription of immune cells (Th1 which activate macrophages)
Methotrexate – is an antagonist to folic acid which can become a problem
Glucocorticoids and ciclosporin method of action
- Glucocorticoids enter cells and bind to receptors
- Receptors translocate into nucleus and regulate gene transcription
- Ciclosporin block activation of calcineurin
- Cyclophilin binds to calcineurin phosphatase
- Ca binds to calcineurin to activate it
- Calcineurin targets NFkappaB – a transcription factor
- This dephosphorylates NFkappaB which can them move into the nucleus
- From there it controls transcription of genes that promote inflammation
What are biopharmaceuticals? - humanized therapeutic monoclonal antibodies
Humanized therapeutic monoclonal antibodies to target inflammatory mediators
- Neutralize action of soluble or membrane bound proinflammatory cytokines
- FC portion of antibody has got the sequence of the human antibody (not seen as foreign)
What are biopharmaceuticals? - soluble receptor proteins
Soluble receptor proteins for the inflammatory mediators
Bind to cytokine preventing it interacting with its receptor
Asthma affects?
5.4 million in the UK
Causes of asthma
Inflammation of the airways
Bronchial hyper reactivity – sensitised to the triggers
Reversible airway obstruction
Anti-asthmatic drugs
Bronchodilators – salbutamol
Polymorphisms in b2 adrenoceptors – linked to reduced efficacy of bronchodilators
Anti-inflammatories– prednisolone, omalizumab
Sources of allergens - inhaled materials
Plant and mould spores
Dander of domestic animals
Faeces of small animals
Sources of allergens - injected materials
Insect venoms
Vaccines and drugs
Therapeutic proteins
Sources of allergens - ingested material
Food and drugs
Sources of allergens - contacted materials
Plant leaves
Industrial products made from plants
Metals
Synthetic chemicals
Examples of IgE mediated hypersensitivity
Asthma, allergic rhinitis, eczema, urticaria, food allergy, systemic anaphylaxis
IgE mediated hypersensitivity method
IgE antibodies produced against allergen
Individual becomes sensitised within 2-3 weeks
IgE antibodies bind tightly to IgE Fc receptors on
- Mast cells on skin and mucous surfaces
- Basophils in blood
- Activated eosinophils
Mast cells
They are key mediators of Type 1 hypersensitivity reactions
They are full of granules that contain mediators (IgE)
Role of IgE is to fight parasitic infections - in some individuals activated wrongly
Respiratory allergy - allergic rhinitis
Allergen activates mast cells in nasal mucosa and conjunctivae
Nasal congestion, sneezing, allergic conjunctivitis
Respiratory allergy - allergic asthma
Allergen activates mast cells in lower respiratory tract
Respiratory allergy - allergic asthma early phase
Reversible airways obstruction
Inflammation
Increased numbers of mast cells in bronchi which mediate these effects
Respiratory allergy - allergic asthma late phase
Cytokines –> leukocyte infiltration (especially eosinophils)
Inflammation
Asthma is associated with?
Over activity of Th2 cells
TH2 cells activate cells that make the IgE antibodies through release of cytokines
Control asthma through controlling the release of these cytokines
Susceptibility to allergy - genetic
IgE production
Specific allergens
Hyper-responsiveness
Gender and age-relate
Susceptibility to allergy - environmental
Level allergen
Nutrition
Pollutants
Family size
Immediate hypersensitivity reaction
5-10 minutes after re-exposure to allergen
Cross linking of IgE by allergen on mast cell surface triggers release of inflammatory mediators
- Smooth muscle contraction
- Increases vascular permeability
- Mucous secretion
- Platelet activation
- Stimulation of nerve endings
- Recruitment and activation of eosinophils
When are cytokines and chemokines secreted?
During immediate phase and set the scene for the last phase of asthma attach
What to use to counteract symptoms of cytokines and chemokines?
Inhalers Antihistamines Inhibit production of cytokines Biological molecules – directly interfere with IgE and cytokine receptor signalling - Very expensive
Pathology associated with inflammation of the airways
Dilated blood vessels Thickened basement membrane Mucus plug with eosinophils and desquamated epithelial cells Hypertrophied smooth muscle Infiltration of inflammatory cells Oedema
Unwanted side effects of chronic steroid use
Euphoria Buffalo jump Hypertension Thinning of skin Muscle wasting Intercranial hypertension Cataracts Moon face with red cheeks Increased abdominal fat/obesity Easy bruising Poor wound healing Avascular necrosis of femoral head Increased susceptibility to infection Osteoporosis
