Pharmacology of the Airways

Question 1

label the correct neurotransmitters

Answer 1

Question 2

activation of the parasympathetic nerves does what on the airways?
activation of the sympathetic nerves does what on the airways?

what are lung effectors cells found? (3)

Answer 2

activation of the parasympathetic nerves: constriction of the airways
activation of the sympathetic nerves: no functional evidence of direct innervation of airway smmoth muscle

lung effector cells:

• submucosal glands
• blood vessels
• airway smooth muscle

Question 3

describe the pathway for parasympathetic innervation that cauases airway smooth muscle constriction or relaxation

Answer 3

• preganglionic cell bodies: brain stem
• postganglionic cell bodies: walls of bronchi & bronchioles
• stimulation of postganglionic cholinergic fibres:
  a) Ach on M3 receptors: contraction of smooth muscle of aiways
• stimulation of postganglionic non-cholinergic fibres:
  a) NO released and causes relaxation of smooth muscle of airwys

Question 4

explain mechanism that occurs after Ach binds to M3 smooth muscles to cause ASM contraction

Answer 4

• Ach binds to M3 receptor
• causes IP₃ to be released
• IP₃ binds to IP₃ Receptor - IP₃R on ER
• causes Ca2+ released into cytoplasm
• increase in intracellular Ca2+ binds to calmodulin & myosin light chain kinase (MCLK)
• phosphorylaes light chain on myosin
• actin-myosin corss link occurs & SMC occurs

Question 5

what type of nerves cause bronchodilator effect?
what is the major NT? - where expressed from? (2)

Answer 5

bronchodilator nerves are nonadrenergic noncholinergnic (NANC)
major NT: Nitric Oxide, expressed in epithelial and nerve cells

Question 6

what type of airway remodelling occurs in:

a) asthma? (1)
b) COPD? (3)

what is FEV₁ like in asthma and?

Answer 6

a) asthma: bronchoconstriction (mucus secretion)
b) COPD: bronchoconstriction, mucus secretion, emphysemia

FEV₁ like in asthma: reduced, BUT WITH bronchodilators, can return to normal / good level of FEV1

Question 7

how do bronchodilators work (SAMA, LAMAS & SABA & LABAS)

Answer 7

airway smooth muscle cells have both M3 muscarinic receptors & beta2 adrenerginc receptors

SAMA & LAMA: block the binding of ACh to M3 muscarinic receptors - bring about smooth muscle relaxation

SABA & LAMA: activate beta2-adrenergic receptors - induce cascade of signalling events (see photo) = smooth muscle relaxation

Question 8

how can you manage asthma pharmcologically? - if gets worse etc?

Answer 8

SABA - used as a reliever to alleviate symptoms

- Regular preventers: low dose inhaled cortical steroids (ICS) (anti-inflamm drugs) - take for rest of life
still have symptoms?
- ICS & LABA (LABA as monotherapy can increase risk of mortality - so needs to be dual)
still have worsening symptoms?
- increased dose of ICS & other classses of drugs

Question 9

how do you manage COPD?
what is the first line of therapy?

0-1 moderate exacerbations (not in hosptital?)
>1 hosptial or >2 moderate exacerbations?

Answer 9

first line of therapy: LABA / LAMA

ICS shouldnt be used as first line, but certain patient pop.

Question 10

what are the treatment goals of inhaled corticosteroids?

Answer 10

reduce underyling inflammation !

Question 11

explain mechanism of action of inhaled cortical steroids in lungs

Answer 11

inhaled cortical steroids -> arrives @ lungs:

• cortical steroid crosses cytoplasm & binds to glucocorticoid receptor - activates into glucocorticoid response element (GRE)
• GRE binds to nucleus:
  a) encodes for anti-inflam. genes
  b) recruits machinery that leads to down regulation of gene expression of pro-inflam mediators: IL-6, TNF-a & CXCL8

Question 12

what is a major trigger for asthma? how do u test/

what are two ways that allergy can cause an effect?

Answer 12

• *- allergy - major trigger for athsma - e.g. dust, fungus**
• conduct a skin prick allergy test

- significant worldwide impact !!!

• sensitisation - allergen introduced for first time
• provocation -

Question 13

explain mechanism of action of allergic reaction due to a) sensitistaion b) provacation

Answer 13

allergic reaction driven by immune system:

_IgE mediated mechanism!!

• sensitisation: allergen introduced for first time_

a) allergen digested by antigen presenting cells
b) digested and presented by MHC Class II molecules
c) presented to T niave helper cells - promotes development of TH2 cells
d) produces IL-4 & IL-13
e) causes production of B cells
f) creates antibody: IgE - bind to mast cells = sensitised mast cells

- provacation: rexposure to allergen

a) antigen region of allergen is recognised - bound to IgE molecules
b) IgE cross link
c) causes mast cells degranulation
d) release of mast cell mediators - commonly histamine - (causes hayfever, asthma and dermititis) - drive inflammation

Question 14

which cells are activated in chronic inflammation of asthma & copd?

Answer 14

In asthmatic airways, activated mast cells/eosinophils and T helper 2 lymphocytes (Th2) are predominant.
In contrast, macrophages and neutrophils are important in COPD airways/lung.