Bronchodilators

Question 1

Phases of asthma attack

Answer 1

initial bronchoconstriction mediated by mast cell degranulation, which contains PGD2, histamine, LTD, LCD, chemokine, cytokines.

In later phase, the chemokine and cytokines attract other immune cells to the area, increasing the inflammatory response. can occur hours later. More responsive to the allergen than before - sensitisation.

Question 2

B2-AR agonists effect on lung and secondary antiasthmatic mechanism

Answer 2

isoprenaline, salbutamol, salmeterol
Increase the FEV1, increase B2-AR mediated bronchodilation. Normal ROA is inhalation.

B2-ARs also innervate mast cells, with the increase of cAMP inhibiting the release of histamine.

Question 3

Desensitisation of B2-AR

Answer 3

Occurs following prolonged use. Internalisation of the receptor mediated by B-arrestin binding, which attracts Cathrin-coated vesicles which transport the receptor to endosomes. If drug is continued to be used, downregulation occurs, where the internalised receptor is degraded in lysosomes, and decreased receptor transcription

B-arrestin binds follow phosphorylation of the receptor by GRK (causes acute tachyphylaxis). Uncouples the G-protein and receptor.

Question 4

B2-AR adverse effects

Answer 4

tremor, palpitations, hypokalaemia

Question 5

PDE role in metabolism and exploitation

Answer 5

metabolises cAMP and cGMP. PDE4 most prevalent in lungs: cAMP metabolism.

Roflumilast inhibits PDE4 for the treatment of COPD. Reduces inflammation and potentates B-AR effects.

Question 6

mAChR antagonists mechanism for asthma/COPD and side effects

Answer 6

e.g., ipratropium (non-selective), tiotropium, aclinidium

M3 receptor predominant one in lungs. It is Gaq-coupled, increasing Ca2+, mediating contraction.

Dry mouth, nausea/headache, atria fibrillation, tachycardia, palpitations, constipation, blurred vision.

Question 7

Xanthines mechanisms and side effects

Answer 7

Theophylline, doxofylline, enprofylline.

Unknown mechanism. Some PDE inhibition, potential adenosine receptor antagonist.
Has anti-inflammatory properties.

Aminophyline is a mix of theophylline and ethylenediamine to improve solubility and thus efficacy

Tremor, palpitations, nausea, insomnia.

DDIs can occur with inhibition of metabolism by cimetidine and induction by smoking.