Anti-inflammatories II Flashcards
What is rheumatoid arthritis?
Inflammation of the synovium of the joints
With autoimmune components
What are the risk factors of rheumatoid arthritis?
Smoking
Genetics
What are the symptoms of rheumatoid arthritis?
- Swelling of the joints and pain
- Poor sleep is associated
- Can by symmetrical or not
- Can spread to other parts of the body
What is the inflammatory reaction underlying rheumatoid arthritis?
1) Activation of TH1 (T-cells)
2) Leads to activation of MACROPHAGES, which infiltrate the area and secrete CYTOKINES
3) Leads to the recruitment activation of other cells at the area of inflammation
4) All the cells together cause erosion of the cartilage and bone - causing joint damage
What are the cytokines released by macrophages in the lead up to rheumatoid arthritis?
Pro-imflammatory cytokines:
1) IL-1
2) TNF-alpha
What are the cells recruited by cytokines in the lead up to rheumatoid arthritis?
1) Fibroblasts
2) Osteoclasts
What do fibroblasts do?
Try to resolve tissue damage BUT by doing so can cause damage - by lots of deposition of extracellular matrix proteins
What drugs can decrease the level of damage in rheumatoid arthritis?
Describe them
DMARDs:
1) Methotrexte
- Large structure
- Folic acid antagonist
- Cytotoxic and immunosuppressant activity
2) Sulfasalazine
- Has a sulphate group
3) Drugs with metal ions
- Free radical scavengers to reduce tissue damage
What are immunosuppresants?
Drugs which lower the bodys ability to reject transplanted tissues
What do imminosupressants do?
How?
Inhibit the induction phase of an inflammatory response:
- Work directly at the level of the immune cells to suppress their activity and inhibit the transcription of proinflammatory cytokines
What is ciclosporin and what does it do?
An immunosupressant drug with helps to supress transplant rejection
What is the normal action in the cell, regarding cyclophilin and nf kappa b?
1) Cyclophillin usually binds to calcineurin
2) Calcineurin binds to Ca released in immune reactions - activating the calcineuin
3) Calcineurin (a phosphatase) removes phosphatase from nf kappa b (a transcription factor found in many cells)
4) Dephosphorylated nf kappa b can move into the nucleus and control the transcription proinflammatory cytokines
How does ciclosphorin work?
1) Binds to cyclophilin
2) Blocks the activation of calcineurin
3) Nf kappa b remains in the cytosol
4) Pro-inflammatory response is reduced and some cytokine production is inhibited
Which drugs repress transcription of pro-inflammatory mediators in immune cells?
Ciclosphorin
Glucocoricoids
How do glucocorticoids work?
Enter cells and translocate into the NUCLEUS - regulate at the level of transcription of pro-inflammatory mediators
What is a ‘cytokine’ and what can they do?
What are examples of cytokines?
ANY protein or polypeptide MEDIATORS which are synthesised or released by cells of the immune system during INFLAMMATION
They can act DIRECTLY on cells or AMPLIFY inflammation by inducing the formation of OTHER inflammatory mediators
Examples:
IL-1
IL-2
TNF-alpha
TGF-beta
How can new drugs be developed that are more effective than glucocoticoids or ciclosphorin?
What are these new drugs called?
Can be developed to target SPECIFIC cytokines
Biopharmaceuticals
How do biopharmaceuticals delivered?
They are INJECTED
What molecules are biopharmaceuticals?
Peptides
How do biopharmaceuticals work?
They are SPECIFICALLY directed to pro-inflammatory cytokines with high affinity
What is a type of biopharmaceutical and how does it work?
Humanised monoclonal antibodies:
- Bind to TNF alpha released from macrophages
- Preventing it from activating other cell types which cause tissue damage
Why is is important that the Fc region of a humanised monoclonal antibody is the equivalent to that of a human antibody?
To prevent rejection
So that they are treated like normal antibodies
Why mimic the soluble receptors made for cytokines by the body?
To bind up cytokines and prevent them from binding to their receptors
What causes asthma?
Chronic inflammation of the airways
Why do the symptoms of asthma become greater overime?
- Airways become sensitised
- Smooth muscle controlling the airways expand and become more sensitive to triggers
(Bronchial hyper-activity becomes greater overtime)
What are the treatments of asthma?
1) Salbutamol (bronchodilator)
2) Glucocorticoids (anti-inflammatory agent)
What causes a resistance to salbutamol?
1) Overuse of inhalers causing de-sensitisation of the receptors
2) Polymorphisms in the Beta-2 adrenoreceptors causing a reduction in efficacy of salbutamol
What is the pathology of asthma?
1) Atopic trigger (allergen)
2) Airways constricted upon exposure, due to immune cells accumulating in the airways
3) Stronger response several hours later - inflammatory response
- Cytokines released
What can the 2nd stage of asthma lead to?
Irreversible damage to the airways
What are 4 common sources of INHALED allergens?
1) Mold spores
2) Plant pollen
3) Faeces of dust mites
4) Animal fur
What is hayfever classified as?
Asthma
What kind of drugs are used to treat asthma and why?
Similar to drugs which are used to treat inflammation in other parts of the body
As asthma is classified as inflammation of the upper airways
What determines what allergic disease you will have?
How the allergen gets into the body
What ways can allergens get into the body?
1) Inhalation
2) Injection
3) Ingestation
4) Contact
Examples of allergens which can be injected?
Venoms
Vaccines/drugs
Examples of allergens which can be ingested?
Food
Orally administered drugs
Examples of allergens which can be contacted?
Plant leaves (eg. stinging nettles)
Metals
Synthetic chemicals in industrial products
How is it tested if you have an allergy?
Asthma?
Inject allergens underneath the skin
If have asthma - will also have a reaction to these allergens underneath the skin
What is igE-mediated hypersensitivity?
Allergies
What antibodies are produced against allergens?
igE class
What are examples of allergies?
1) Asthma
2) Hayfever
3) Eczema
4) Hives
5) Food allergy
6) Systemic anaphylaxis
What is the ‘scientific name’ for hayfever?
Allergic rhinitis
Describe the igE-mediated response to allergens
1) Individual has compromised barriers combined with genetic predisposition
2) Allergen gets into the body and is recognised as foreign
3) Individual becomes sensitised (2-3 weeks) and has lots of igE to that particular allergen
4) IgE antibodies bind specifically and tightly to igE Fc receptors on:
- Mast cells (skin and mucus surfaces)
- Basophils (blood)
- Activated eosionophils (circulating immune cells
5) When RE-EXPOSED to an the same allergen:
- Cross-linking of IgE by allergen on mast cell surfaces
- Triggers the release of INFLAMMATORY mediators
What are they key mediators in type 1 hypersensitivity reactions?
Mast cells
What is the NORMAL function of mast cells?
To release granules when activated to fight PARASITIC INFECTIONS
In hayfever, where are the mast cells activated?
UPPER airways
In allergic asthma, where are the mast cells activated?
LOWER airways
What is the ‘early-phase’ reactions of allergic asthma characterised by?
What causes this?
Characterised by:
- REVERSIBLE airway obstruction and inflammation
Caused by:
- Increased number of mast cells in the bronchi
- Release of HISTAMINE and PROSTANOIDS from these mast cells
What percentage of patients with allergic asthma suffer from a ‘late-phase’ reaction?
50%
What happens in the ‘late-phase” of allergic asthma?
1) Activation of mast cells causes recruitment and activation of further immune cells to the area - causes INFLAMMATION
2) These immune cells make DAMAGING mediators
3) Cytokines cause LEUKOCYE infiltration (esp. of eosinophils)
What happens if the ‘late-phase’ of allergic asthma is not controlled?
Leads to chronic asthma and tissue damage
What cells is asthma associated with?
How is this different to rheumatoid arthritis?
Overactivity of TH2 cells
In RA - TH1 cells involved
What do TH2 cells do?
Activate cells that make the igE antibodies through the release of cytokines
How is asthma treated and how is the late phase reaction controlled?
By controlling the synthesis of cytokines
For example, with glucocorticoids
What are pro-inflammatory mediators?
Mediators which PROmote inflammation
What are genetic factors which can alter the susceptibility to allergy?
IgE production
Gender
Age
Hyper-responsiveness
What are environmental factors which can alter the susceptibility to allergy?
Nutrition
Pollutants
Family sizes
What do inflammatory mediators cause to happen?
1) Smooth muscle contraction
2) Increased vascular permeability
3) Mucous secretion
4) Platelet aggregation
5) Stimulation of nerve endings
6) Recruitment and activation of eosinophils
What is the pathology associated with inflammation of the airways? (characteristics)
1) Thickened basement membrane
2) Mucus with eosinophils
3) Infiltration of inflammatory cells
4) Odema (swelling)
What are new therapies for treating asthma?
1) Humanises antibodies and soluble receptors to IgE and cytokines
2) PGD2 receptor antagonists
3) Inhibitors of immune cells and mast cell signalling
What are humanised antibodies for soluble receptors for IgE?
Omalizumab
What are humanised antibodies for soluble receptors for cytokines?
Biopharmaceuticals
Do all DMARDs have the same action?
No
What do DMARDs do?
Reduce symptoms of a disease AND slow disease progression
