Pharmacology of Asthma

Question 1

Where are the cell bodies of postganglionic fibres located?

Answer 1

walls of the bronchi and bronchioles

Question 2

Where are the cell bodies of preganglionic fibres located?

Answer 2

brainstem

Question 3

What does stimulation of postganglionic cholinergic fibres cause?

Answer 3

bronchial smooth muscle contraction mediated by M3 muscarinic ACh receptors on ASM cells
increased mucus secretion mediated by M3 muscarinic ACh receptors on gland (goblet) cells

Question 4

What does stimulation of postganglionic noncholinergic fibres cause?

Answer 4

bronchial smooth muscle relaxation mediated by nitric oxide (NO) and vasoactive intestinal peptide (VIP)

Question 5

What does stimulation of the sympathetic system cause?

Answer 5

Bronchial smooth muscle relaxation via b2-adrenoceptors (β2-ADR) on ASM cells activated by adrenaline released from the adrenal gland
Decreased mucus secretion mediated by b2-adrenoceptors on gland (goblet) cells
Increased mucociliary clearance mediated by b2-adrenoceptors on epithelial cells (mucociliary escalator)
Vascular smooth muscle contraction, mediated by α1-adrenoceptors on vascular smooth muscle cells

Question 6

Describe the mucocillary escalator? Where is it located?

Answer 6

sweeps invading microorganisms/particles upward to the oropharynx
Present between nose and bronchi

Question 7

How does contraction in smooth muscle occur?

Answer 7

o Intracellular level of Ca rises and the Ca binds to a protein (calmodulin) forming a complex.
o It is a regulatory protein, it binds to MLCK, making it active.
o The active MLCK phosphorylates the myosin active cross bridge
Therefore, we get cross bridges between actin and myosin and the fibres slide over each other to generate the ‘contraction’ force

Question 8

How does relaxation in smooth muscle occur?

Answer 8

o dephosphorylation of MLC by myosin phosphatase which has constitutive activity
o Activities of myosin light chain kinase (MLCK) and myosin phosphatase oppose each other
o In the presence of elevated intracellular Ca2+ the rate of phosphorylation exceeds the rate of dephosphorylation
o Relaxation thus requires return of intracellular Ca2+ concentration to basal level – achieved by primary and secondary active transport

Question 9

What long term changes in the bronchioles can be seen in chronic asthma patients?

Answer 9

1. increased mass of smooth muscle (hyperplasia and hypertrophy)
2. accumulation of interstitial fluid (oedema)
3. increased secretion of mucus
4. epithelial damage (exposing sensory nerve endings)
5. Sub-epithelial fibrosis

Question 10

Asthma is an immune imbalance, what does this mean?

Answer 10

imbalance between TH1 and TH2 lymphocyte mediated responses

Question 11

What are the two components of bronchial hyper responisveness?

Answer 11

1. hypersensitivity

2. hyper-reactivity

Question 12

What are the two phases of an asthma attack?

Answer 12

• Type 1 hypersensitivity reaction - Early phase (bronchospasm and acute inflammation)
• Type 4 hypersensitivity reaction - Late phase (bronchospasm and delayed inflammation)

Question 13

What controllers + preventors are used in asthma?

Answer 13

anti-inflammatory agents that reduce airway inflammation Glucocorticoids, Cromoglicate, Humanised monoclonal IgE antibodies (very expensive)

Question 14

When are relievers used?

Answer 14

acute attacks - act as bronchodilators

Question 15

What relievers are used in asthma?

Answer 15

Short acting b2-adrenoceptor agonists (SABAs)
Long acting b2- adrenoceptor agonists (LABAs)
CysLT1 receptor antagonists

Question 16

Name a SABA? and name its side effects?

Answer 16

Salbutamol
Fine tremor
- tachycardia, cardiac dysrhythmia and hypokalaemia can also occur

Question 17

Name some LABAs? and their indications?

Answer 17

Salmeterol + Formoterol
- good for nocturnal asthma because long acting
Not to be used as mono therapy

Question 18

Name some CysLT1 receptor antagonists? and their indications?

Answer 18

Montelukast + Zafirlukast

add on therapy against early and late bronchospasm in mild persistent asthma

Question 19

What is the mechanism of action of Xanthines?

Answer 19

inhibit isoforms of phosphodiesterases (which inactivate cAMP and cGMP) - second messengers that relax smooth muscle and perhaps exert an anti-inflammatory effect

therefore they increase levels of cAMP and cGMP

Question 20

Name a Xanthine?

Answer 20

Methylxanthines

Question 21

Name some synthetic derivatives of cortisol that are used as anti inflammatories in asthma?

Answer 21

beclometasone
budesonide
fluticasone

Question 22

What do Glucocosteroids do?

Answer 22

suppress the inflammatory component of asthma

(1) prevent inflammation and (2) resolve established inflammation