Asthma

Question 1

What is asthma?

Answer 1

Chronic inflammatory disorder of the lungs characterised by:

• airway hyper-responsiveness which causes
• variable and reversible airflow obstruction.

Question 2

How does the inflammatory response in asthma cause bronchoconstriction?

Answer 2

1. Eosinophils accumulate - infiltrate bronchial smooth muscle - mucosal oedema - bronchoconstriction.
2. Release of cytotoxic mediators - damage respiratory epithelial layer - exposure of sensory nerves - bronchial hyper-responsiveness (smooth muscle spasms) - bronchoconstriction.
3. Mucus hyper-secretion - mucus plug blocks airways - bronchoconstriction.

Question 3

Suggest triggers for airway inflammation in asthma.

Answer 3

• Infection
• Allergens (pollen, dust, mould, etc.)
• Air pollution (cigarette smoke, chemicals)
• Cold air
• Exercise

Question 4

Describe the symptoms of asthma.

Answer 4

1. Recurrent, acute attacks of dyspnoea (difficulty breathing)
2. Chest tightness
3. Chronic/nocturnal cough
4. Wheeze

Question 5

How are the airways innervated by the autonomic nervous system?

Answer 5

• Major autonomic innervation is parasympathetic (cholinergic tissues).
• Very little sympathetic innervation, although there is a large population of non-innervated B2-adrenoRs on SM cells.

Question 6

Describe how bronchoconstriction is stimulated.

Answer 6

1. Stimulated parasympathetic nerves release ACh.
2. ACh binds to mAChRs (M3) on SM cells - SM contraction.
3. Lumen of airways narrow - increases resistance to airflow = bronchoconstriction.

Question 7

Describe how bronchodilation is stimulated.

Answer 7

1. F/F response or exercise activates sympathetic NS - adrenal medulla releases adrenaline/NA into bloodstream.
2. A/NA binds to B2-adrenoRs in airways - GDP for GTP exchange on Gs - alpha subunit dissociates.
3. G alpha activates AC - ATP to cAMP - 4 cAMP bind PKA.
4. Decreased intracellular [calcium] - decreased SM contraction - bronchodilation.

Question 8

Which drugs are used to prevent asthma attacks?

Answer 8

Anti-inflammatory drugs

1. Inhaled/oral glucocorticosteroids: downregulate genes involved in mediating inflammatory response and suppressing the immune system.
2. Leukotriene receptor antagonists: e.g. Montelukast blocks leukotriene D4 - major bronchoconstriction mediator.
3. Inhibitors of mediator release (e.g. Sodium cromoglicate)

Question 9

Which drugs are used to relieve asthma attacks?

Answer 9

Bronchodilators

1. mAChR antagonists (e.g. Ipratropium): bind to M3 Rs on bronchial SM, blocking ACh-induced bronchospasms and decreasing mucus secretion.
2. B2-adrenoR agonists: bind to B2 Rs on bronchial SM, causing bronchodilation and symptom release.
3. Xanthines: increase cAMP by inhibiting phosphodiesterase - SM relaxation - bronchodilation.

Question 10

When are short- and long-acting B2 adrenoR agonists used? Give an example of each.

Answer 10

• Short-acting B2-agonists (e.g. Salbutamol) used acutely to counter-act bronchochonstriction during an asthma attack.
• Longer-acting B2-agonists (e.g. Salmeterol) used at night to try and prevent a fall in peak flow in the morning, and as an add-on therapy in chronic asthma.

Question 11

Why do adrenoR agonists have a greater therapeutic effect in asthmatic patients than mAChR antagonists?

Answer 11

• mAChR only prevent bronchoconstriction brought on by the actions of the parasympathetic NS - not usually the cause of an asthma attack.
• adrenoreceptor agonists cause bronchodilation irrespective of the reason for bronchochonstriction.

Question 12

Where are B2-adrenoRs found in the airways?

Answer 12

Receptor density increases as airway diameter decreases.

Question 13

What is the drawback of using salmeterol?

Answer 13

Insoluble so cannot be delivered via IV line.

Question 14

What are the side effects of salbutamol and why do these occur?

Answer 14

• Increases chronotropy and inotropy, promotes vasoconstriction - angina.
• Is only 20-fold more selective for B2 Rs than B1 - also activates B1 in heart