Respiratory pharmacology

Question 1

β2-adrenoceptor agonists

Answer 1

Salbutamol
Asthma
Cause bronchodilation through activation of Gs signalling.
cAMP activates PKA, which opens K+ channels, closing VGCCs and inhibiting MLCK, preventing constriction
Increased cAMP also prevents the release of histamine and decreases mucus secretion in goblet cells, increasing clearance

Question 2

Long-Acting Beta-2 Adrenoceptor Agonists (LABAs)

Answer 2

Salmeterol, formoterol, indacaterol
Asthma
Have long lipophilic chains that allow them to dissolve in the lipid bilayer and remain close to the receptor.

Question 3

Muscarinic antagonists

Answer 3

Examples: ipratropium, and the longer-acting tiotropium and aclidinium
Asthma
Block parasympathetic bronchoconstriction and inhibit mucus secretion
M3 receptors in the lungs are Gq-coupled
Inhibition of other receptors causes dry mouth and nausea/headache (M1), atrial fibrillation, tachycardia, palpitations (M2), and constipation and blurred vision (M3).

Question 4

Phosphodiesterase inhibitors - Roflumilast

Answer 4

PDEs break down cAMP, limiting the relaxation response - inhibitors prevent this, enhancing β2-AR agonist effects
Asthma
Roflumilast inhibits PDE4 in inflammatory cells - anti-inflammatory effect so can also be used in COPD

Question 5

Xanthines

Answer 5

Examples: theophylline, doxophylline and enprophylline
Asthma
PDE inhibitors, but action is mild
Anti-inflammatory
Antagonise adenosine receptors
Side effects: tremor, palpitations and nausea
Stimulate the CNS: overactivity can cause sleep disturbances

Question 6

Steroids

Answer 6

Inhaled: Beclomethasone, Budesonide, Ciclesonide, Fluticasone, Mometasone
Oral: Prednisolone
IV: Hydrocortisone
Asthma prevention
Act on glucocorticoid receptor to alter gene transcription
Activated genes: Annexin A1, β2-adrenoceptors. anti-inflammatory cytokines (IL-10 and IL-12).
Repressed genes: inflammatory cytokines ( IL-2/3/6, TNFα) enzymes (iNOS, COX-2) and peptides (endothelin-1), and chemokines
Annexin A1 (lipocortin) acts through formyl peptide receptors (FPRs) and inhibits the release of histamine from mast cells, and phospholipase A2 (PLA2), inhibiting PG and leukotriene synthesis.
Increased β2 transcription protects against downregulation.

Question 7

Cysteinyl-Leukotriene Receptor Antagonists

Answer 7

Examples: Montelukast, Zafirlukast
Leukotrienes stimulate mucus production, cause bronchoconstriction, affect airway remodelling, cause airway hyperresponsiveness and are linked to exercise-induced asthma.
CystLT1 antagonists block their actions

Question 8

Zileuton

Answer 8

Lipoxygenase inhibitor - blocks the synthesis of leukotrienes

Question 9

Omalizumab (Xolair)

Answer 9

Monoclonal antibody against IgE used in severe allergic asthma that cannot be controlled by steroids.
Prevents binding to mast cells and therefore degranulation.

Question 10

Cromones

Answer 10

Examples: sodium cromoglicate and nedocromil sodium
Thought to stabilise mast cells and prevent degranulation, possibly through enhanced action of annexin A1.
Exercise-induced asthma and allergic asthma