Pharmacology of Airway diseases

Question 1

What are the 2 main mechanisms of action for treating airway disease?

Answer 1

Promote Bronchodilation (BAM)
Reduce tissue inflammation and allergy triggers (LeuGlu)

Question 2

How can you treat severe acute asthma? (O SHIT)

Answer 2

Oxygen
Salbutamol (beta 2 agonist)
Hydrocortisone (corticosteroid)
Ipratropium (antimuscarinic)
Theophylline (methylxantine)

Question 3

How does the nervous system regulate airway regulation? (i.e. parasymp and symp)

Answer 3

Sympathetic - drives bronchodilation (adrenergic fibres/ noradrenaline)
Parasymptathetic - drives bronchoconstriction (cholingergic/acetylcholine)

Question 4

Name the 4 ß2-adrenoreceptor agonists, which ones are short/long acting?

Answer 4

Salbutamol and Terbutaline (short-acting)

Salmeterol and Formoterol (long-acting)

Question 5

Describe how Beta2 agonists stimulate adrenergic responses in lungs.

Answer 5

Beta2 agonists (adrenaline/noradrenaline) bind to beta2 adrenergic receptors, activate Gs proteins, activate Adenylate cyclase enzyme, converts ATP to cAMP, activates PKA enzyme - reduces act. of myosin and contraction of muscles

Question 6

How does stimulation of PKA, cause bronchodilation?

Answer 6

Ca2+ packaged into vesicles
Reduced smooth muscle contraction
Inactivates MLCK (myosin light chain kinase)
Dephosphorylation of MLC

Question 7

What are the cellular targets and key side effects of ß2-adrenoreceptor agonists?

Answer 7

Bronchiolar smooth muscle cells

Tremor, tachycardia, cardiac arrhythmia

Question 8

How do Antimuscarinic Drugs (e.g. tiotropium) Block Acetylcholine Responses in Lungs?

Answer 8

Tiotropium binds to M3 Muscarinic receptors (usual agonist - acetylcholine), therefore doesn’t do the following:
activate Gq protein
activate PLC enzyme
activate IP3
Calcium release from intracellular stores
smooth muscle contraction
Therfore, no bronchoconstriction

Question 9

Name some antimuscarinics.

Answer 9

Ipratropium (short-acting)
Tiotropium (long-acting)
Glycopyrronium (long-acting)

Question 10

What are the cellular targets and key side effects of antimuscarinics?

Answer 10

Bronchiolar smooth muscle cells

Dry mouth, constipation, urinary retention

Question 11

What is the MoA of methylxantines?

Answer 11

Inhibit the Phosphodiesterase (PDE) enzyme, therefore sustains levels of cAMP.
(PDE inactivates cAMP)

Question 12

What are the common examples of methylxantines? what are its side effects?

Answer 12

Theophylline, Aminophylline

cardiac arrhythmias, seizures

Question 13

Name some common leukotriene receptor antagonists and their side effects.

Answer 13

Montelukast, Zafirlukast

Abdominal pain, headache

Question 14

What are the cellular and molecular targets of Leukotriene receptor antagonists?

Answer 14

Cellular: Eosonophils in the lung ( stop inflammation); bronchiolar smooth muscle cells (stop bronchospasm)
Molecular: Blockade of CysLT1 leukotriene receptors:
Reduce inflammatory responses in early & late phases of asthma
Additive effect when used with other drugs (e.g. inhaled glucocorticoids)
No evidence of effect on remodelling (chronic asthma)

Question 15

Name some glucocorticoids/corticosteroids and their cellular targets.

Answer 15

Beclomethasone (inhaled), Fluticasone (inhaled), Prednisolone (oral), Hydrocortisone (IV)
mmune cells of the lung, especially macrophages,
T-lymphocytes and eosinophils

Question 16

What are the molecular targets of glucocorticoids?

Answer 16

Intracellular glucocorticoid receptor (GR) - transcription factor
Activate GRs - changes exp of genes:
Suppression of pro-inflammatory mediators (e.g. TH2 cytokines such as IL-3, IL-5)
Expression of anti-inflammatory products (e.g. lipcortin-1, Secreted Leukocyte Peptidase Inhibitor (SLPI))

Question 17

What are the key side effects of glucocorticoids?

Answer 17

Moon face, weight gain (inc abdominal fat), osteoporosis, hyperglycaemia; throat infection with inhalers

Question 18

A 69 year old woman (Rachel) is using salbutamol inhaler as part of her treatment.
What class of drug is salbutamol?

Answer 18

Beta-2 agonist (or Beta-2 adrenergic receptor agonist)

Question 19

A 69 year old woman (Rachel) is using salbutamol inhaler as part of her treatment.
ii) Indicate THREE intracellular events stimulated within target cells upon exposure to salbutamol.

Answer 19

Activation of Gs G Protein
Activation of adenylate cyclase OR Generation of intracellular cAMP
Activation of Protein Kinase A
Reduced Activity of Myosin Light Chain Kinase
Dephosphorylation of Myosin Light Chain
Reduction in intracellular calcium levels

Question 20

A 69 year old woman (Rachel) is using salbutamol inhaler as part of her treatment.
iii) What cell type is primarily targeted by salbutamol and what is the overall physiological effect of this drug on the lung?

Answer 20

Airway smooth muscle cell (1 mark)

Smooth muscle relaxation OR airway dilatation (1 mark)