Airway Pharmacology

Question 1

in respiratory diseases, what are drugs used for?

Answer 1

treat or reduce the severity of symptoms:

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

Question 2

what are drugs not as effective at doing?

Answer 2

Resolving the underlying cause of the pathology:

1. resolving the actual causes of excessive inflammation
2. reversing tissue remodelling
3. repairing damage that has already occurred

Question 3

What aspects of acute airway pathology can be treated with drugs?

Answer 3

• contraction of smooth muscle
• excess mucus secretion
• oedema/swelling
• irritation of sensory neurons (cough)

Question 4

name a treatment for airway smooth muscle contraction and how it works:

Answer 4

bronchodilators, which act by relaxing airway smooth muscle cells

-in order to get bronchodilation you need to get the individual smooth muscle cells that make up the smooth muscle tissue to relax, which means the circumference of the airway is bigger

Question 5

name the 3 types of bronchodilators:

Answer 5

1. Beta-2 adrenergic receptor agonists
2. Long-acting muscarinic receptor antagonists
3. Phosphodiesterase inhibitors

Question 6

how are the different classes of beta-2 adrenergic receptor agonists differentiated?

Answer 6

duration of action

Question 7

what are the different classes of beta-2 adrenergic receptor agonists?

Answer 7

o Short-acting (SABA) e.g. salbutamol
-the first-line therapy in asthma and are administered when required as reliever therapy (e.g. when the patient experiences an acute asthma attack) by metered-dose inhaler

o Long-acting (LABA) e.g. salmeterol

• usually used with chronic asthma, take it every day on a regular basis instead of just when an attack occurs
• used as an add-on, preventer treatment in combination with inhaled corticosteroids (this is because there is evidence that the use of LABAs without corticosteroids increases the risk of sudden death) in metered-dose inhalers, with twice daily, continual dosing

o Ultra-long acting (ultra-LABA) e.g. indacaterol

Question 8

explain how long-acting muscarinic receptor antagonists (LAMAs) work and give an example:

Answer 8

o widely used to treat chronic bronchitis in COPD patients, and as an add-on, preventer therapy in asthma
o they are dosed on a daily, continual basis via metered-dose inhalers
e.g. tiotropium

Question 9

explain how phosphodiesterase inhibitors work:

Answer 9

o These tend to not be used anymore as they have a very narrow therapeutic window
-ie. a very small difference between a dose having a good effect and a dose having a very negative effect

o Also, they just aren’t as effective as beta-2 agonists

e.g. theophylline

Question 10

what do inflammatory mediators induce?

Answer 10

ASMC (aortic smooth muscle cell) contraction

Question 11

how do inflammatory mediators induce ASMC contraction?

Answer 11

• mediators bind to specific receptors (GPCR) -activation of receptors triggers intracellular pathways
• Increased calcium mobilisation from the SR, leading to muscle contraction
• also, more sensitivity of the contractile machinery to the Ca2+.

Question 12

how do bronchodilator drugs work?

Answer 12

bronchodilator drugs act by binding to a specific receptor or enzyme expressed by ASM cells and inducing an intracellular change which interrupts the contractile process (thereby causing relaxation)

Question 13

explain how Beta-2 agonists cause ASMC relaxation:

Answer 13

Beta-2 adrenergic receptor activation induces ASMC relaxation via AC & PKA:

The Beta-2 agonist binds to Beta-2 adrenoceptor

There is a signalling cascade, which starts with the activation of the enzyme Adenylyl cyclase

AC catalyses the conversion of ATP into cAMP (an intracellular signalling molecule)

Leads to PKA which reduces the level of contraction- how?

PKA phosphorylates different proteins leading to decreased Ca2+ mobilisation and sensitivity, causing muscle relaxation

Question 14

how do muscarinic receptor antagonists relax ASMCs?

Answer 14

Muscarinic receptor antagonists relax ASMCs by inhibiting the contractile effects of ACh at the M3 receptor

These drugs work by inhibiting a mediator that will cause contraction- they block these receptors that Ach normally bind to (GPCR’s that cause the contraction, eg. M3)

Antagonism of the M3 receptor on airway smooth muscle cells prevents the contractile actions of Ach, promoting relaxation

Question 15

what is an important target of drugs used to treat these airway diseases?

Answer 15

the inflammatory process

Question 16

What are the necessary steps needed for inflammation to come about?

Answer 16

-you need proliferation of the particular immune cells involved
-you need antibody production, which then leads to ab cross linking and degranulation
(degranulation = particular allergen binds to antibody on mast cell)
-in order for proliferation to occur in one place and also infiltrate tissue, the immune cells need to gain access to the blood stream, and then leave the blood stream at a particular tissue location (eg. airways)
-in order to get to a particular location within a tissue the immune cell has to go through chemotaxis and follow a particular concentration gradient

Question 17

list some key drugs used in diseases of the airways and which disease they target:

Answer 17

1. Glucococorticoids, asthma
2. Leukotriene inhibitors, asthma
3. Biologics, asthma
4. Mast cell stabilisers, asthma
5. PDE4 inhibitors, COPD

Question 18

how do leukotriene inhibitors work?

Answer 18

Leukotriene receptor antagonists block the receptor by which LT mediators produce inflammatory effects on immune cells + tissue

Question 19

how do biologics work?

Answer 19

mAb that block/inhibit a specific pro- protein (e.g. IgE or IL-4, IL-5, IL-13, etc.) involved in the inflammatory pathway.

Question 20

how do Mast cell stabilisers work?

Answer 20

Prevents degranulation of mast cells/sensory nerve activation

Question 21

how do PDE4 inhibitors work?

Answer 21

Inhibits cAMP metabolism

Intracellular signalling effects then lead to changes in protein expression and neutrophil responses

Question 22

what are corticosteroids used for?

Answer 22

used as preventer medication to reduce airway inflammation

Question 23

what can 2 groups are corticosteroids classified into? give examples

Answer 23

Inhaled corticosteroids
♣ Fluticasone
♣ Budesonide

Oral/systemic steroids
♣ Prednisone
♣ Dexamethasone

Question 24

what is the most effective and widely used drug for reducing allergic inflammation in asthma?

Answer 24

corticosteroids

Question 25

why would you use oral/systemic corticosteroids as opposed to inhaled ones?

Answer 25

if inhaled corticosteroids cannot cope with the level of inflammation

(The problem with this is that instead of the steroid just going to the airways, you’re just dumping it in the body, so it can get to other tissues which might not be a good thing)

Question 26

what is the problem with using systemic/oral corticosteroids?

Answer 26

instead of the steroid just going to the airways you’re just dumping it in the body, so it can get to other tissues which might not be a good thing

Question 27

what do corticosteroids affect and how do they do it?

Answer 27

the function of various immune and structural cells to reduce inflammation

do this by changing the expression of different proteins by cells that they work on. They work on TF’s within the DNA to change transcription and translation, hence affecting the amount of protein expressed

Question 28

explain the mechanism of steroids:

Answer 28

• the cortic.’s diffuse through the membrane and gain access to the cytosol as they are non-polar and have no charge (i.e. lipid soluble)
• binds to the corticosteroid receptor present within the cytosol of immune and structural cells
• binding of the drug to the nucleus activates it, and the receptor drug complex translocates to the nucleus
• when it arrives at nucleus it binds to particular regions within the DNA that codes for a particular gene and affects the level in which that gene is transcribed
• this changes the mRNA produced, the translation and transcription that occurs

Question 29

in order to have an anti-inflammatory effect, what 2 things can corticosteroids do?

Answer 29

• decrease the expression of pro-inflammatory proteins (cytokines associated with having an inflammatory effect)
• increase the expression of anti-inflammatory proteins (cytokines associated with having an anti-inflammatory effect)

Question 30

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

Answer 30

BENEFITS

• increase in quality of life (decrease in severity of the disease, decrease in symptoms)
• increase in life expectancy

ADVERSE EFFECTS

• decrease in quality of life
• increased risk of developing other diseases
• economic costs

Question 31

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

Answer 31

-it’s a way of reducing the side effects
-get less adverse effects when you inhale them rather than giving them orally, because
greater concentration of the drug will end up in the lungs/airways - why?
-the therapeutic effects are produced by the drug acting within the airway/lungs
-the adverse effects tend to be produced by the drug acting on other tissues of the body

-so, you can reduce the adverse effects by maximising the exposure to the lungs/airways and reduce exposure to the systemic circulation of the tissues

Question 32

how do beta-2 agonists induce side effects?

Answer 32

activating receptors in extra respiratory tissues

Question 33

beta-2 agonists are selective not specific - what does this mean?

Answer 33

this means that they will preferentially bind, but at a certain concentration more and more will gradually bind to other receptors

(in actual fact, at a sufficient concentration any drug will bind to any receptor)

Question 34

what is the dominant receptor expressed in the heart?

Answer 34

beta-1

Question 35

at normal concentrations which receptors does salbutamol act at?

Answer 35

acts at beta-2 receptors (and beta-1) on smooth muscle in the airway to cause bronchodilation

Question 36

at higher concentrations which receptors does salbutamol act at?

Answer 36

1. activates beta-1 receptors at the SAN and in myocardium
   - tachycardia, palpatations
2. activates beta-2 receptors expressed in other tissues like skeletal muscle
   - tremor, muscle growth

Question 37

what has a high risk of serious side effects?

Answer 37

long-term/high dose corticosteroid administration is associated with a high risk of serious side effects, particularly in susceptible individuals

Question 38

how is asthma pharmacotherapy administered?

Answer 38

in a step-wise manner

• move up a step to improve control as needed
• move down as possible to maintain minimal controlling step
• if the patient remains stable for a long time and the disease improves a bit, you can potentially move them down a step

Question 39

in asthma pharmacotherapy, whats the difference between drugs administered at higher and lower steps?

Answer 39

• the drugs used in higher steps tend to have more side effects, so it’s better to try the less strong drugs first to see if they work
• if not, then you can start to try stronger ones- only use them if you actually need them

Question 40

how is COPD therapy administered?

Answer 40

administered in a progressive (one direction) stepwise manner

move along as symptoms/dyspnoea worsen

1. smoking cessation
2. SABA
3. LAMA/LABA
4. add inhaled corticosteroids if exacerbation are frequent
5. add long term o2 therapy
6. surgical interventions (lung volume reduction surgery, transplantation