L9- Pharmacology of the immune system I

Question 1

What are the signs of inflammation?

Answer 1

• Rubor (redness)
• Calor (heat)
• Dolor (pain by direct action on pain sensitive nerve terminals)
• Tumor (swelling from oedema)

Question 2

How does the innate immune system respond to pathogens?

Answer 2

1. PAMPs on pathogen bind to TLR’s on macrophage and trigger release of IL1 and TNFalpha
2. Cytokines act on endothelial cells which express adhesion molecules.
3. Phagocytes (neutrophils) adhere to endothelium and migrate toward pathogen.
4. Opsonins mediate attachment to pathogen and phagocytosis occurs/bactericidal killing

Question 3

What drugs targets can be used in the innate immune system?

Answer 3

TLR’s could be a possible future drug target

Question 4

What drug targets can be used in the adaptive immune system?

Answer 4

Immunosuppressants and glucocorticoids can be used to target humoural and cell mediated immune responses

Question 5

How does allergy work?

Answer 5

• Allergen ingested and presented by APC’s on first exposure.
• This activates Th2 cells which release IL-4.
• IL-4 activates B cells which synthesise IgE antibody.
• This IgE antibody can bind to the allergen on subsequent exposure to activate mast cells (sensitised state)

Question 6

How do autoimmune diseases work?

Answer 6

When the immune system becomes directed
against the body’s own tissues.
Initial causative event is likely to be pathogen invasion against which an immune response occurs, but which expresses a protein with sequence similarity to endogenous proteins.

Question 7

What are corticosteroids?

Answer 7

Steroid hormones released from the adrenal gland cortex.
• Glucocorticoids regulate glucose metabolism e.g corticosterone
• Artificial corticosteroids are used in therapy

Question 8

What is the effect of corticosteroid drugs?

Answer 8

• Anti-inflammatory effects

* Inhibit/activate transcription of genes encoding proteins involved in the regulation of inflammation

Question 9

What are the short acting steroids?

Answer 9

Less than 24hrs
• Hydrocortisone (natural)
• Prednisone (prodrug of prednisolone)

Question 10

What are the intermediate acting steroids?

Answer 10

24-48hrs

• Triamcinolone

Question 11

What are the long acting steroids?

Answer 11

Over 48hrs

• Dexamethasone

Question 12

What are the side effects of steroids?

Answer 12

Cushings syndrome:
• Hypertension
• Poor wound healing
• Easy bruising
• Thin arms and legs

Question 13

How is short term immunosuppression achieved?

Answer 13

High dose corticosteroids by I/V, long term use has severe side effects.

Question 14

What is a drug used for short term immunosuppression?

Answer 14

Cyclophosphamide
• prodrug
• alkylates DNA and kills proliferating T/B cells
Severe side effects: hair loss, infertility, haemorrhagic cystitis

Question 15

How is long term immunosuppression achieved?

Answer 15

• Antibodies against T cell markers- Alemtuzumab
• Antibodies against IL-2 receptors on T cells- Baxiliximab
• mTor inhibitors- Sirolimus
• Inhibitors of B/T cell proliferation- Azathioprine

Question 16

What do mast cells do?

Answer 16

• Bind to IgE on allergen and activate
• Produce inflammatory cytokines
• Release inflammatory granules (histamine)
• Release membrane derived molecules e.g prostaglandins, leukotrienes

Question 17

Where is histamine found?

Answer 17

• Mast cells in tissues
• Basophils in blood
• Histaminergic neurons in CNS

Question 18

What does histamine do?

Answer 18

• Contraction of smooth muscle in bronchi and gut
• Dilatation of small arterioles
• Increased permeability of venules
• Sensitised nerve endings- itching

Question 19

What are the antagonists of the histamine H1 receptor?

Answer 19

H1 receptor is target of antihistamines
• original: mepyramine (non selective, crossed bbb)
• second gen: terfenadine (more selective but had cardiac effects)
• third gen: loratidine. fexofenadine