Lecture - Pharmacology (Asthma Intro)

Question 1

What is asthma in a pathology view point vs a physiology view point?

Answer 1

Pathologists think in terms of it being an airway inflammation (with the inflam cells, airway remodelling etc) whereas the physiologist think of it being a bronchial SM constriction (bs airwya hyper-responsiveness)

Question 2

What happens in asthma?

Answer 2

1. Contracted SM
2. BV infiltrated by immune cells
3. Inflam and swelling
4. Excess mucous

= DECREASED LUMEN DIAMETER

(In path: airway inflammation, bronchial oedema, bronchoconstriction, mucous secretion, epithelial shedding, ariway remodelling comprising of SM proliferation, subepithelial fibrosis, angiogenesis, mucous gland hyperplasia, etc)

Question 3

What’re the main goals of treatment for asthma?

Answer 3

Reduce symptoms using the minimum of medication

-this requires the pateint to self monitor their symptoms and adjust medication following a set treatment plan

Question 4

Asthma as an inflammatory illness:

What’re the two things that happen in response to the mediators and the activation of airways TH2 lymphocytes?

Answer 4

1. So the released mediators activate neural pathways provoking vagal efferent release of Ach onto smooth muscle and that results in bronchoconstriction
2. The airways TH2 lymphocte activation results in:
   - synthesis and released of cytokines
   - increase inflam cells recruited
   - increased IgE levels

Question 5

There are two forms of mediators in asthma that are made or released by the mast cell stimulation - what are they?

Answer 5

1. Pre-formed prior to mast cell stimulation:
   - these are stored in the cytoplasmic secretory granules of the mast cells and basophils
   - they are released during allergic or inflam reactions (like cross linking of the IgE receptors after allergen binds)
   - eg histamine etc
2. Synthesised at the time of mast cell stimulation
   - leukotrienes and prostanoids are formed because mast cells (and other inflam cells like neutrophils, macrophages etc) membranes break down (phospholipid breakdown by phospholipases) and this releases arachnodonic acid which either goes down the COX pahway to be modified into prostanoids or down the lipoxygenase pathway to be modified into leukotrienes.

Question 6

Now explain to me what leukotrienes do and why is LTB4 of most importance?

Answer 6

So these are formed when the arachdonic acid goes down the lipoxygenase pathway and leukotreienes are ‘slow reacting substance of anaphylaxis” because they:

• contract respiratory SM (bronchoconstriction)
• increase vascular permeability leading to inflam cell infiltration and lung oedema)

LTB4 is involved in ALL types of inflammation

-it had a chemotactic effect where it attracts inflam cells to the site and they all release toxic products and enzymes which can damage host’s own tissues

Question 7

What do proastanooids do and how can aspirin induce asthma?

Answer 7

So prostanoids are produced when arachidonic acid goes down the COX pathway. Two important examples of proastanoids is:

• prostaglandin PGD2: bronchoconstriction, vasodilation (so increased permeability for inflam ells)
• TXAa: bronchoconstriction

(these are similar effects to leukotrienes except LTB4 was also a chemotactant)

It’s impotant to note that prostaglandin E1 will negatively feedback and inhibit the lipozygenase pathway. Aspirin leads to blocking of the COX enzyme (so do other NSAIDs) and this will lead to increased activiation of lipozygenase pathway (since reduced PGE1 forming) so you have increased amounts of leukotreienes

Question 8

What things cause bronchial SM contraction and relaxation?

Answer 8

Three things at play:

To cause relaxation (bronchodilation - you have beta2 adrenergic agonist where the beta agonist binds to beta 2 adrengergic (Adrenalin) and this is a G protein coupled receptor so through the activity of adenylate cyclase, the concentration of cAMP will increase and produce protein kinase A which will lead to bronchodilation

To cause bronchoconstriction, there are two mechanisms

1 - Muscuranic receptor M3 will bind Ach and this is also a G protein coupled receptor and when Ach binds to this, it will trigger phospholipase C beta and produce IP3, which will increase Ca entry from the sarcoplasmic reticulum and you will get contraction in this airway cell

2 - Muscuranic M2 receptor will also bind to Ach and it will block the adendylate cyclase to inhibit the adrenergic relaxation pathway

We can make this contraction even worse if you increase CysLT receptor activation by cysteinyl leukotrienes (which are types of leukotrienes) and they will also increase IP3 which will increase Ca entry so produce SM contraction

Question 9

What’s the terapeutic approach to asthma?

Answer 9

Primary is to manage inflamamtion as underlying probelm and secondary is to reserve bronchodilators mainly for symptomatic use