Lecture 8 - Anti-inflammatory and immunosuppressant drugs

Question 1

What do anti-inflammatory drugs do?

Answer 1

Exert action to reduce inflammation - inflammatory conditions that are chronic

Question 2

What are examples of overactivity of the immune response?

Answer 2

• rheumatoid arthritis
• asthma & allergies

Question 3

What is rheumatoid arthritis?

Answer 3

• contains genetic component and seen 3 times more likely in women
  -associated with morning stiffness and disrupted sleep (leading to comorbidities)
• £4-5 billion a year spent by NHS on treating rheumatoid arthritis
• genetic and environmental components
• reduction volume of synovial fluid
• sensory nerves are becoming activated by inflammatory mediators, leading to pain signals being sent to the brain

Question 4

What is osteo arthritis?

Answer 4

inflammation and damage to joints, however caused by damage - e.g. mechanical use

Question 5

What is rheumatoid arthritis?

Answer 5

genetic conditions and chronic

Question 6

Are osteo arthritis and rheumatoid arthritis the same?

Answer 6

Distinct conditions and therefore treated distinctly - no cure just manage symptoms

Question 7

Explain how the inflammatory response is mediated

Answer 7

Activated TH1 cells (T cells) - initiate a bigger immune response –> activation of macrophages, fibroblasts and osteoclasts. All this communication is mediated by inflammatory mediators

Question 8

What are the inflammatory mediators involved?

Answer 8

Cytokine - IL-1
Cytokine - TNF-alpha

cytokines and chemokines are inflammatory mediators that activate immune cells. Chemokines attract more immune cells into the area and therefore grow the immune response. Activation of these cells and influx of immune cells leads damage to joints and erosion of cartilage and bone..

Question 9

What can drugs do?

Answer 9

• act on T cells
• act on cytokines and chemokines

Question 10

What are the 2 types of drugs used?

Answer 10

• Biological drugs - act on cytokines & chemokines
• DMARDS (disease modifying anti-rheumatoid drugs

Question 11

What are DMARDS (disease modifying anti-rheumatoid drugs)?

Answer 11

Their structures vary and lots of the time they are found by chance

• Methotrexate folic acid antagonist, cytotoxic and immunosuppressant activity (can also be used as a chemotherapeutic - due to ability to kill cells at high concentration)
• Sulfasalazine is a sulfa drug, also used for chronic inflammatory bowel disease. Bacteria in colon produce 5-aminosalicylic acid, which may act as free radical scavenger to decrease damage by neutrophils

Question 12

Explain how immunosuppressant drugs inhibit induction phase of inflammatory response

Answer 12

• initiated by TH1 cells (BAD)
  We can control TH1 cells as well as the other cells that the system. We can use drugs
• cyclosporin
• glucocorticoids

Question 13

What does cyclosporin do?

Answer 13

• widely used to prevent transplant rejection. Binds to cyclophilin - this is a cytosolic protein that controls the activity of a phosphatase (calcineurin)
• calcineurin is a phosphatase that removes phosphate from a transcription factor called NF-CAPA-B. This, in immune cells, when dephosphorylated, moves into the nucleus and initiates that transcription of inflammatory mediators, such as cytokines
• cyclosporin inhibits the phosphatase, which therefore prevents the transcription of cytokines, preventing an inflammatory response.

Question 14

What do glucocorticoids do?

Answer 14

exerts their actions by binding to nuclear receptors which themselves control transcription of certain cytokines

Question 15

What is the end result of drugs used?

Answer 15

Reduced production of the cytokines = reduced inflammatory response. This can have negative effects - become immunocompromised (due to their immune system being suppressed) - meaning they are susceptible to infections

• DMARDs are more specific
• osteoarthritis doesn’t use these drugs. They aren’t as effective, so it is assumed that is it different pathways.

Question 16

What is a biopharmaceutical - the new anticytokine/anti-inflammatory drugs?

Answer 16

Adalimumab - it is a humanised monoclonal antibody

Question 17

What are features of humanised monoclonal antibodies?

Answer 17

• high affinity and selectivity for target
• neutralise action of either soluble or membrane bound
• proinflammatory cytokines
• long half life

However very expensive and injected into joints

Question 18

What are 2 inflammatory respiratory diseases?

Answer 18

• COPD (chronic obstructive pulmonary disease)
• Asthma

Question 19

What are features of COPD (chronic obstructive pulmonary disease)?

Answer 19

• breathless, emphysema and eventually respiratory failure
• treatment is palliative, using B2 agonists, muscarinic antagonists, corticosteroids

Question 20

What are features of asthma?

Answer 20

• 5.4 million in UK (1/5 households)
• shortness of breath, especially breathing out, cough
• inflammation of the airways
• bronchial hyper-reactivity
  -reversible airways obstruction

Question 21

What are anti-asthmatic drugs?

Answer 21

• bronchodilators (salbutamol)
• polymorphisms in B2-adrenoceptors associated with reduced efficacy of bronchodilators
• anti-inflammatory agents (prednisolone & omalizumab)

Question 22

Explain how asthma attacks consist of 2 phases

Answer 22

Lungs become exposed to allergen. This leads to early phase - immediate response - bronchospasm. Hours later there is a second, more severe attack - late phase - difficulty breathing more severe and duration is longer.

Question 23

What are respiratory allergies?

Answer 23

Allergic rhinitis (e.g. hayfever) - allergen activates mast cells in nasal mucosa and conjunctivae. Nasal congestion, sneezing and allergic conjunctivitis

Allergic asthma - allergen activates mast cells in lower respiratory tract. ‘Early immediate phase’ reactions characterized by reversible airway obstruction, inflammation. Patient have increased numbers of mast cells in bronchi which mediate these effects.

‘Late phase’ reactions (approx. 50% patients)

Cytokines - leukocyte inflammation, results in tissue damage and airway remodelling.

Question 24

How is asthma associated with over-activity of Th2 cells?

Answer 24

Th2 cells are activated in asthma, meaning the response is completely different. Cytokines involved in signalling in this immune response is different - IL4, IL5 & IL13. These are important as, when Th2 cells become activated in the presence of these cytokines, they interact with B cells (cells that make antibodies), causing a ‘class-switch recombination’. This will lead to the production of IgE antibodies (of that allergen), which bind specifically to receptors on mast cells and on eosinophils.

Question 25

What are mast cells?

Answer 25

Tissue resident immune cells (guards of the door). They have IgE receptors to allow quick response.

Question 26

What are eosinophils?

Answer 26

are more circulating cells, but also may be accumulating. When activated, they secrete molecules that kill pathogens.

Question 27

What is allergic asthma associated with?

Answer 27

increased levels of IgE to specific allergens

Question 28

What are mast cells key mediators of?

Answer 28

Type 1 hypersensitivity reaction

Question 29

What is the natural role of IgE?

Answer 29

parasitic infections

Question 30

What are inflammatory mediators?

Answer 30

• smooth muscle contraction
• increased vascular permeability
• mucous secretion
• platelet activation
• stimulation of nerve endings
• recruitment and activations of eosinophils

Question 31

What do cytokines and chemokines secreted during immediate phase do?

Answer 31

They set the scene for the late phase of asthma attack

Question 32

Explain how the transcription of other mediators occur

Answer 32

This is where the role of the cytokines and chemokines take place, to bring in the rest of the immune system.

NF-CAPA-B - is only one of the transcription factors that gets activated in mast cells.

Then there is an influx cells. Occasionally a lot of activation of neutrophils. These 2nd phase reactions, where the inflammatory response is being amplified, that is dangerous. This is what is leading to long term damage to the lungs.

Question 33

What are unwanted side effects of chronic steroid use - e.g. glucocorticoids (reduce inflammation)?

Answer 33

• hump - back of neck
• cataracts (eye - lens become cloudy - blurred vision)
• hypertension
• increased abdominal fat
• easy bruising
• poor wound healing