L12 - Anti-inflammatories - Antiheumatoids

Question 1

Rheumatoid arthritis affects?

Answer 1

Half a million-people affected by it in the UK

Affects 3x more women than men

Question 2

Rheumatoid arthritis age of onset

Answer 2

40-60

There is a juvenile onset form

Question 3

Rheumatoid arthritis risk factors

Answer 3

Environmental - smoking

Genetic

Question 4

Rheumatoid arthritis symptoms

Answer 4

Inflammation of the synovium - increases risk of cardiovascular disease and therefore death
Swelling of the joints
Pain and stiffness
Poor sleep

Question 5

Rheumatoid arthritis - cells and mediators that activate inflammation

Answer 5

Proinflammatory cytokines

Question 6

Rheumatoid arthritis - cells and mediators that activate inflammation -proinflammatory cytokines

Answer 6

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

Question 7

Rheumatoid arthritis - cells and mediators that inhibit inflammation - 5-aminosalicylic acid

Answer 7

Free radical scavenger to decrease damage produce by neutrophils

Question 8

Rheumatoid arthritis - cells and mediators that inhibit inflammation

Answer 8

Glucocorticoids and ciclosporin
Immunosuppressants - methotrexate
5-aminosalicylic acid
DMARDs

Question 9

Rheumatoid arthritis - cells and mediators that inhibit inflammation - glucocorticoids and ciclosporin

Answer 9

Inhibit transcription of proinflammatory cytokines

Question 10

Rheumatoid arthritis - cells and mediators that inhibit inflammation - immunosuppressants - methotrexate

Answer 10

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

Question 11

Glucocorticoids and ciclosporin method of action

Answer 11

1. Glucocorticoids enter cells and bind to receptors
2. Receptors translocate into nucleus and regulate gene transcription
3. Ciclosporin block activation of calcineurin
4. Cyclophilin binds to calcineurin phosphatase
5. Ca binds to calcineurin to activate it
6. Calcineurin targets NFkappaB – a transcription factor
7. This dephosphorylates NFkappaB which can them move into the nucleus
8. From there it controls transcription of genes that promote inflammation

Question 12

What are biopharmaceuticals? - humanized therapeutic monoclonal antibodies

Answer 12

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)

Question 13

What are biopharmaceuticals? - soluble receptor proteins

Answer 13

Soluble receptor proteins for the inflammatory mediators

Bind to cytokine preventing it interacting with its receptor

Question 14

Asthma affects?

Answer 14

5.4 million in the UK

Question 15

Causes of asthma

Answer 15

Inflammation of the airways
Bronchial hyper reactivity – sensitised to the triggers
Reversible airway obstruction

Question 16

Anti-asthmatic drugs

Answer 16

Bronchodilators – salbutamol
Polymorphisms in b2 adrenoceptors – linked to reduced efficacy of bronchodilators
Anti-inflammatories– prednisolone, omalizumab

Question 17

Sources of allergens - inhaled materials

Answer 17

Plant and mould spores
Dander of domestic animals
Faeces of small animals

Question 18

Sources of allergens - injected materials

Answer 18

Insect venoms
Vaccines and drugs
Therapeutic proteins

Question 19

Sources of allergens - ingested material

Answer 19

Food and drugs

Question 20

Sources of allergens - contacted materials

Answer 20

Plant leaves
Industrial products made from plants
Metals
Synthetic chemicals

Question 21

Examples of IgE mediated hypersensitivity

Answer 21

Asthma, allergic rhinitis, eczema, urticaria, food allergy, systemic anaphylaxis

Question 22

IgE mediated hypersensitivity method

Answer 22

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

Question 23

Mast cells

Answer 23

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

Question 24

Respiratory allergy - allergic rhinitis

Answer 24

Allergen activates mast cells in nasal mucosa and conjunctivae
Nasal congestion, sneezing, allergic conjunctivitis

Question 25

Respiratory allergy - allergic asthma

Answer 25

Allergen activates mast cells in lower respiratory tract

Question 26

Respiratory allergy - allergic asthma early phase

Answer 26

Reversible airways obstruction Inflammation Increased numbers of mast cells in bronchi which mediate these effects

Question 27

Respiratory allergy - allergic asthma late phase

Answer 27

Cytokines --> leukocyte infiltration (especially eosinophils) Inflammation

Question 28

Asthma is associated with?

Answer 28

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

Question 29

Susceptibility to allergy - genetic

Answer 29

IgE production Specific allergens Hyper-responsiveness Gender and age-relate

Question 30

Susceptibility to allergy - environmental

Answer 30

Level allergen Nutrition Pollutants Family size

Question 31

Immediate hypersensitivity reaction

Answer 31

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

Question 32

When are cytokines and chemokines secreted?

Answer 32

During immediate phase and set the scene for the last phase of asthma attach

Question 33

What to use to counteract symptoms of cytokines and chemokines?

Answer 33

``` Inhalers Antihistamines Inhibit production of cytokines Biological molecules – directly interfere with IgE and cytokine receptor signalling - Very expensive ```

Question 34

Pathology associated with inflammation of the airways

Answer 34

``` Dilated blood vessels Thickened basement membrane Mucus plug with eosinophils and desquamated epithelial cells Hypertrophied smooth muscle Infiltration of inflammatory cells Oedema ```

Question 35

Unwanted side effects of chronic steroid use

Answer 35

``` 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 ```