Airway Pharmacology

Question 1

How are drugs effective but not ‘cure’?

Answer 1

1. Reduce airway smooth muscle contraction
2. Reduce mucus secretion
3. Reduce allergic inflammation of airways
4. Reduce sensitivity to irritating stimuli (cough)

But the drugs don’t resolve the causes of inflammation, reverse airway or repair damage to tissues.

Question 2

How can we treat airway smooth muscle contraction?

Answer 2

Use of bronchodilators. They are used in asthma as contraction of smooth muscles plays a big role in obstruction:

1. Beta-2 adrenergic receptor agonists (mainly used for asthma):
   a. short acting e.g salbutamol (so works to dilate when the attack is happening)
   b. long acting e.g salmeterol - used as an add on, preventer treatment, in combination with corticosteroids (without corticosteroids, use of LABAs increase the risk of sudden death) twice a day
   c. ultra long acting e.g indacaterol
2. Long acting muscarinic receptor antagonist
3. Phosphodiesterase inhibitors e.g theophylline (has a low therapeutic window so not really used)

Question 3

How do bronchodilators work?

Answer 3

Relax smooth muscles, increase luminal area, reduce resistance, increase airflow

Question 4

How do LAMA’s work?

Answer 4

They are muscarinic antagonists which prevent the effects of acetylcholine on airway smooth muscle. Blocking of these receptors reduces the levels on airway smooth muscle contraction in situations where acetylcholine plays a big role in contraction. But acetylcholine doesn’t play that much role in airway smooth muscle contraction which is why LAMAs are less effective as bronchodilators.

LAMAs are used to treat chronic bronchitis ; as an add on, preventer therapy in asthma.

LAMAs are also helpful in reducing mucus secretion and inhibiting coughs.

Question 5

How do inflammatory mediators induce airway smooth muscle contraction?

Answer 5

1. Mediator e.g Ach or prostaglandins bind to the M3 receptor which is positively coupled to phospholipase C via Gaq/11
2. Phospholipase C breaks down PIP2 to DAG and IP3. IP3 binds to calcium ion channel receptors in the ER, releasing calcium ions.
3. Calcium ions then bind to calmodulin which activates myosin light chain kinase.
4. Myosin light chain kinase phosphorylates myosin at the light chain at serine 19, activating it, increasing ATPase activity and ATP binding affinity. This allows muscle contraction.

Look through pharmacology muscle contraction lecture.

Question 6

How do muscarinic antagonists work?

Answer 6

Inhibit acetylcholine binding to the receptor so that the muscle can’t contract.

Question 7

How can we treat airway inflammation?

Answer 7

We can inhibit different cells or mediators, preventing them from causing inflammation.

Question 8

Why are beta 2 agonists so effective?

Answer 8

Because there are lots of beta 2 receptors in airways. There are much fewer beta 1 receptors in the airways.

Question 10

How do beta-2 receptor agonists work to induce relaxation?

Answer 10

1. Agonist e.g salbutamol binds to beta-2 receptor which is positively coupled to adenylate cyclase via Gas
2. Adenylate cyclase converts ATP to cAMP which activates PKA
3. PKA causes reduced calcium ion release from intracellular stores
4. So can’t bind to troponin —> relaxation

Question 11

Give examples of drugs that can prevent inflammation

Answer 11

1. Glucocorticoids (fluticasone)
2. Leukotriene inhibitors (montelukast) for asthma - block the receptor by with leukotriene mediators bind to cause inflammatory effects on tissues
3. Biologics (omalizumab) for asthma - inhibit a specific pro-protein e.g IgE or IL-4 involved in inflammatory pathway
4. Mast cell stabilisers (sodium cromoglicate) for asthma and allergies - prevent degranulation of mast cells
5. PDE4 inhibitors (roflumilast) for COPD - inhibits cAMP metabolism

Question 12

What are corticosteroids?

Answer 12

They refer to glucocorticoids.
They are used as preventer medication to reduce airway inflammation. So they are used even when you don’t have an asthma attack.

Question 13

Give examples of inhaled corticosteroids

Answer 13

1. Fluticasone
2. Budesonide
3. Beclometasone

Question 14

Give examples of oral/systemic steroids

Answer 14

1. Prednisone
2. Dexamethasone

Oral/systemic steroids are only used when the inhaled ones don’t very well. They cause greater adverse effects that’s why they’re only used when the inhaled ones don’t work as well.

Inhaled ones still work well because most it goes straight to the airway and becomes concentrated there.

Question 15

How do corticosteroids work?

Answer 15

1. Reduce eosinophil numbers by apoptosis
2. Cause less cytokines to be produced
3. Reduced numbers of macrophages
4. Reduced numbers of dendritic cells
5. Reduced cytokines mediators for epithelial cells
6. Reduced endothelial cell leak
7. Increased activity of B2 receptors in airway smooth muscle
8. Reduced mucus secretion from mucus gland

Question 16

What is the mechanism of corticosteroids?

Answer 16

1. Corticosteroid diffuses through phospholipid bilayer of immune cells and structural cells
2. Corticosteroid binds to intracellular glucocorticoid receptor, activating the receptor
3. This drug-receptor complex moves to nucleus and binds to DNA, affecting transcription
4. Increase or decrease expression depending on the gene e.g increasing anti-inflammatory genes expression; decreasing pro-inflammatory genes expression
5. Then you you have translation of gene into protein

Question 17

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

Answer 17

Benefits: 
High drug efficacy
Increased quality of life
Reduced symptoms 
Reduced disease severity
Increased life expectancy 

Costs:
Adverse effects such as decreased quality of life and increased risk of developing other diseases.

Question 18

Give reasons how drugs can induce adverse effects

Answer 18

1. By interacting excessively with target. E.g opioids suppress cough at mild doses by inhibiting neural function in brainstem. However, higher doses causes respiratory depression and risk of death
2. By interacting with targets expressed in other tissues (‘off-target effects’) - either the primary target is present in other tissues or the drug binds to multiple targets. E.g beta 2 agonists act on beta 2 receptors in the airways which is good but they can also bind to beta 1 and beta 2 receptors in the heart causing cardiac side effects.

Question 19

Give the beta 2 agonist (e.g Salbutamol) side effects

Answer 19

1. Bind to beta 1 and beta 2 receptors in SA node and myocardium causing tachycardia and palpitations
2. Bind to beta 1 receptors in airways (as well as beta 2 receptors- beta 2 has a way bigger effect here)
3. Bind to beta 2 and beta 1 receptors (mainly beta 2) in skeletal muscle causing tremor and muscle growth

Question 20

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

Answer 20

Less adverse effects if inhaled because if it’s taken orally/systemically, it more easily affects other tissues as well as airways
Inhaled = most of it will go to the airway. Only some of it will go to systemic and reach other tissues
Systemically = goes into bloodstream and only some of that goes to airways. Has first pass metabolism and can reach other tissues

Question 21

What is long term/high dose corticosteroid administration associated with?

Answer 21

Can cause skin ulcers, candidiasis, depression, hypercortisolism, growth retardation, osteoporosis

Question 22

Why are drugs used in asthma administered in step wise manner?

Answer 22

To reduce risk of side effects to the minimal level possible for the degree of care required to control symptoms

Question 23

How is asthma pharmacology administrated?

Answer 23

Step 1: SABA
Step 2: Add ICS (inhaled corticosteroids)
Step 3: Add LABA, increase ICS dose
Step 4: Max ICS dose, add fourth drug
Step 5: Add oral CS, refer to specialist

The further the step, the greater the side effects. So only move up steps if it’s not working

Question 24

What is the asthma therapy?

Answer 24

Typically involves using inhaled SABA for acute episodes with daily doses of inhaled corticosteroids added to reduce underlying inflammation if symptoms aren’t controlled adequately.

Question 25

How is COPD therapy administrators?

Answer 25

COPD is a progressive condition meaning you get worse and worse so you have to go up steps over time.

Step 1: ending smoking, lifestyle/environmental interventions
Step 2: SABA for exacerbations
Step 3: LAMA/LABA
Step 4: Add inhaled corticosteroids if exacerbations are frequent
Step 5: Add long term oxygen therapy
Step 6: surgical interventions e.g transplants