airway pharmacology

Question 1

Which aspects of respiratory disease can be effectively treated using drugs?

Answer 1

• Reduces airway smooth muscle contraction
• Reduce mucus contraction
• Reduce allergic inflammation of the airways
• Reduce sensitivity to irritating stimuli
• Treats/reduces severity of symptoms
• Reduces excess mucus secretion
• Treats oedema
Reduces irritation of sensory neurons (cough)

Question 2

How can we treat airway smooth muscle contraction?

Answer 2

BRONCHODILATORS
• Beta-2-adrenergic receptor agonist
→ SABA: salbutamol (short acting)
→ LABA: salmeterol (long acting)
→ Ultra-LABA: indacaterol (ultra long acting)
· Long acting muscarinic receptor antagonist: tiotropium
Phosphodiesterase inhibitors: theophylline

Question 3

Give one example of a SABA

hint: S + B

Answer 3

Salbutamol

Question 4

Give one example of a LABA

Answer 4

Salmeterol

Question 5

Give one example of ultra-LABA

Answer 5

Indacaterol

Question 6

What is the function of bronchodilators and briefly describe how this works

Answer 6

Treats airway smooth muscle contraction
Bronchodilators act by relaxing airway smooth muscle cells
Causes relaxation of the airway smooth muscle cells, this increases the luminal area = decreases resistance = increases flow

Question 7

Name 2 inflammatory mediators that induce airway smooth muscle contraction

Answer 7

cysLTs
ACh
PGs

Question 8

Describe how inflammatory mediators such as cysLTs cause airway smooth muscle contraction

Answer 8

Inflammatory (contractile) mediators bind to GPCR on the membrane of smooth muscle cells, activating an intracellular signalling pathway that increases the [Ca2+] = muscle contraction

Question 9

Describe how a beta-2-adrenergic agonist induces airway smooth muscle relaxation

Answer 9

Beta-2-agonist such as salbutamol interacts with beta-2-adrenoreceptors on the surface of airway smooth muscle cells. This receptor is coupled to adenylyl cyclase via Gs, therefore causing the conversion of ATP—>cAMP.
cAMP then activates protein kinase A, decreasing [Ca2+] = muscle relaxation.

Question 10

Muscarinic receptor antagonists can be used to treat airway smooth muscle contraction. Briefly explain how.

Answer 10

Muscarinic antagonists relax airway smooth muscle contractions by inhibiting the contractile effects of ACh at the M3 receptors on the surface of airway smooth muscle cells.

Question 11

What are some steps in the inflammatory process which could potentially be targeted with drugs to reduce inflammation?

Answer 11

· proliferation of the immune cells
· antibody production
· antibody-crosslinking and degranulation
· inflammatory mediator-receptor binding
· tissue infiltration from the bloodstream (adhesion molecule expression)
· apoptosis
· chemotaxis
· cytokine-receptor binding
cytokine production and release

Question 12

What are corticosteroids and what is their function?

Answer 12

Corticosteroids are used as preventer medication to reduce airway inflammation

Question 13

Give 3 examples of inhaled corticosteroids

Answer 13

1. Fluticasone
   
   2. Budesonide
2. Beclometasone

Question 14

Give 2 examples of oral/systemic steroids

Answer 14

1. Prednisone

2. Dexamethasone

Question 15

Glucocorticoids (corticosteroid) work by affecting the function of various immune cells in order to reduce inflammation. Name 5 cell types it can act on and the effect this has to reduce inflammation

Answer 15

1. Eosinophils: less numbers, less apoptosis
   
   2. T-lymphocytes: less cytokines
   3. Mast cells: less numbers, less apoptosis
   4. Macrophages: less cytokines
2. Dendritic cells: less numbers, less apoptosis

Question 16

Glucocorticoids (corticosteroid) work by affecting the function of various structural cells in order to reduce inflammation. Name 4 cell types it can act on and the effect this has to reduce inflammation

Answer 16

1. Epithelial cells 
	Less cytokine mediators 
	2. Endothelial cells 
	Less leakage 
	3. Airway smooth muscle cells 
	More B2 receptors 
	4. Muscle glands 
	Less mucus secretion

Question 17

Describe the mechanism by which corticosteroids work to affect the function of various cell types in order to reduce inflammation

Answer 17

1. Corticosteroid diffuses through the membrane (of immune or structural cells) and bind to intracellular glucocorticoid receptors
   
   2. The drug-receptor complex translocates to the nucleus and binds to DNA to affect the transcription of the protein being made
      ○ They can decrease pro-inflammatory mediators expression
      ○ They can increase anti-inflammatory mediators expression
2. This therefore decreases the overall level of inflammation

Question 18

What considerations need to be made when using drugs to treat patients?

Answer 18

• Drug efficacy 
	→ Does it increase the quality of life?
	→ Does it lessen the symptoms?
	→ Does it lower the severity of the disease or resolve it?
	→ Does it increase life expectancy?
	• Adverse effects 
	→ Does it decrease quality of life?
	→ Does it increase the risk of developing other diseases?

Economic costs

Question 19

Why are drugs used in asthma typically administered by metered dose inhaler?

Answer 19

Decreases the extent and likelihood of adverse effects in respiratory diseases.
• 10-20% of inhaled drug is delivered directly to the airway/lungs producing therapeutic effect. Some of the inhaled drug goes into the systemic circulation to produce systemic side effects
80-90% of inhaled drug is swallowed and goes from the GI tract and is then absorbed into the liver/ In the liver, first pass effect occurs via hepatic enzymes such as cytochrome p450. The metabolised drug then enters the systemic circulation, going to other tissues such as the heart, brain and skeletal muscles to produce systemic side effects

Question 20

List some side effects of salbutamol

Answer 20

1. Tachycardia and palpitations
   Activates beta receptors expressed on SA node and myocardium
   
   2. Bronchodilation
      Acts on beta receptors expressed on airway smooth muscle
   3. Tremors and muscle growth
      Acts on beta receptors expressed on skeletal muscle

Question 21

List some side effects that long-term/ high-dose corticosteroid administration is associated with

Answer 21

• growth retardation
• skin ulcers
• candidiasis (infection with candida)
• hypercortisolism
• depression
• osteoporosis

Question 22

Describe the stepwise manner of asthma pharmacotherapy

Answer 22

Step 1:
	• SABA as required 
Step 2:
	• SABA as required 
	• ICS (inhaled corticosteroids)
Step 3:
	• SABA as required 
	• Increase dose of ICS (inhaled corticosteroids)
	• Add LABA 
	• Add LTRA, PDEi, etc 
Step 4:
	• SABA as required 
	• Max dose of ICS (inhaled corticosteroids)
	• Add LABA 
	• Add LTRA, PDEi, etc 
	• Add fourth drug 
Step 5:
	• SABA as required 
	• Max dose of ICS (inhaled corticosteroids)
	• Add LABA 
	• Add LTRA, PDEi, etc 
	• Add fourth drug 
	• Add oral CS 
	• Refer to specialist 
Consider Anti-IgE

Question 23

What is the difference between asthma pharmacotherapy and COPD therapy?

Answer 23

Asthma pharmacotherapy is administered in a stepwise manner, with you moving up a step to improve control as needed, and moving down as many steps as possible to maintain minimal control.

COPD therapy is administered in a progressive (in one direction) stepwise manner, with you moving up/ along as the symptoms and dyspnoea worsens.

Question 24

COPD therapy is administered in a progressive stepwise manner. Explain these steps

Answer 24

1. Smoking cessation, education and lifestyle/environment interventions
   
   2. Add SABA for exacerbations
   3. Regular long acting bronchodilators (LAMA/LABA)
   4. Add inhaled corticosteroids
   5. Add long term oxygen therapy
2. Surgical interventions (LVRS, transplantation)