Block D Lecture 2 - Pharmacology of Asthma and COPD

Question 1

What are 3 differences between COPD and asthma?

Answer 1

COPD is not reversible with a bronchodilator treatment

COPD occurs in older patients

COPD is less responsive to inhaled corticosteroid treatment

(Slide 4)

Question 2

How do treatments for COPD change as symptoms worsen?

Answer 2

Acute symptoms - Short-Acting Beta-Agonists (SABA), short acting anti-cholinergic drugs such as ipratropium or both

Persistent symptoms - Long-Acting Beta-Agonists (LABA) or tiotropium (long acting anti-cholinergic)

Severe airflow obstruction - inhaled corticosteroid

(Slide 4)

Question 3

How do β2-adrenoceptors agonists help treat COPD?

Answer 3

They increase intracellular cAMP levels, which relaxes smooth muscle for symptomatic relief

(Slide 5)

Question 4

What is an example of a short acting and a long acting β2-adrenoceptor agonist?

Answer 4

Short Acting: Salbutamol

Long Acting: Salmeterol

(Slide 5)

Question 5

How do long-acting β2-adrenoceptor agonists work longer than short acting ones?

Answer 5

As they have lipophilic groups attached to them which interact with exo-sites on the receptor, locking them onto the receptor binding site, allowing them to bind to the receptor for longer.

(Slide 5)

Question 6

How do β2-adrenoceptor agonists work?

Answer 6

1. They activate Gs, which promotes the stimulation of adenylyl cyclase.
2. This enzyme catalyses the formation of cAMP.
3. cAMP activates protein kinase A

4a. PKA can inhibit Myosin Light Chain Kinase (MLCK), which is required for airway smooth muscle contraction, reducing smooth muscle airway contraction

4b. PKA can also promote calcium efflux via the calcium efflux pump, further preventing contraction

4c. PKA can inhibit the MAPK pathway by phosphorylating and inhibiting Raf-1 kinase

These effects all lead to smooth muscle relaxation, and therefore bronchodilation.

(Slide 7)

Question 7

Why are β2-adrenoceptor agonists relatively short acting?

Answer 7

Due to desensitisation

(Slide 8)

Question 8

What is desensitisation?

Answer 8

A loss in response to an agonist over time

(Slide 8)

Question 9

What is an example of a mechanism for desensitisation?

Answer 9

Phosphorylation of the occupied receptor by a specific receptor kinase, known as a G protein-coupled receptor kinase (GRK), which phosphorylate the receptor at specific threonine / serine residues.

This creates a binding site for β-arrestins, which block further G-protein coupling (turning off signalling), and promote receptor internalisation, meaning the receptor can no longer be activated since it is not on the surface

(Slide 8)

Question 10

Why do scientists believe that salmeterol triggers less desensitisation?

Answer 10

As it’s a partial agonist of β2-adrenoceptors, meaning less phosphorylation by the GRK, and therefore less internalisation of the receptor

(Slide 9)

Question 11

Other than bronchodilation, what are 3 other effects of β2-adrenoceptor agonists?

Answer 11

Answers Include:

Inhibition of inflammatory meditator and cytokine release - due to raising cAMP levels.

Increased vascular permeability

Increased ciliary beats - clears mucous

Inhibits cholinergic acetylcholine release, reducing cholinergic transmission

(Slide 10)

Question 12

What are 2 side effects of β2-adrenoceptor agonists?

Answer 12

Tachycardia

Tremors

Hypokalaemia (low potassium level due to the agonist stimulating the Na/K- pump)

Note: long acting beta agonists (LABAs) have a black box warning for asthma and can be problematic. Fine for COPD though

(Slide 12)

Question 13

What are Anti-Muscarinics used to treat and what can they be used in combination with?

Answer 13

Used more for COPD (especially when LABAs become less effective), but can also be used for asthma.

They can be used in combination with β2-adrenoceptor agonists

(Slide 14)

Question 14

What are 2 examples of anti-Muscarinics and what are their basic properties?

Answer 14

Ipratropium - non-selective muscarinic antagonist - short acting

Tiotropium - primarily acts on M3 receptors and lesser so on M1 - longer acting

(Slide 14)

Question 15

Why can Ipratropium cause problems by being a non-selective muscarinic inhibitor?

Answer 15

As it blocks M2 receptors, which usually act as a “brake” for muscarinic activity. Turning this off can cause acetylcholine accumulation

(Slide 15)

Question 16

Tiotropium is “functionally selective” for M3 receptors. What does this mean?

Answer 16

It binds to all muscarinic receptors with similar affinity, but most its effects are seen at M3 receptors

(Slide 16)

Question 17

What has a faster onset, Ipratropium or Tiotropium?

Answer 17

Ipratropium

(Slide 16)

Question 18

What are 2 effects of Tiotropium?

Answer 18

Relaxes airway smooth muscle (bronchodilator)

Reduces mucus production via blockage of M3 on mucosal glands

May reduce neutrophil migration

(Slide 18)

Question 19

How are glucocorticoids used to treat asthma and COPD?

Answer 19

They dampen down many aspects of inflammation which are linked with asthma and COPD. They are taken by inhalation and are used as a prophylactic (preventative) therapy.

Can be oral steroids or intravenous.

(Slide 19)

Question 20

What are the standard oral and intravenous glucocorticoid steroids used to treat asthma and COPD?

Answer 20

Oral: Prednisolone

Intravenous: Hydrocortisone and Methylprednisolone

(Slide 19)

Question 21

What is the mechanism of action of glucocorticoids in treating asthma?

Answer 21

1. They bind to glucocorticoid receptors (GRs) which are bound to hsp90, causing hsp90 to dissociate
2. The GRs then translocate to the nucleus, where they regulate gene transcription by binding to glucocorticoid response elements (GREs) on DNA
3. Positive (+GRE) and Negative (-GRE) Glucocorticoid Response Elements exist inside the nucleus. Glucocorticoids bind to the positive and upregulate anti-inflammatory genes
4. These include lipocortin-1 (annexin-1) which inhibits Phospholipase A₂, reducing prostaglandin and leukotriene synthesis, and increase β2-adrenoceptor transcription, increasing bronchodilation.
5. Glucocorticoids also interfere with the activation of pro-inflammatory genes by binding to NF-κB and AP-1 transcription factors, leading to downregulation of pro-inflammatory cytokines and adhesion molecules, reducing inflammation

(Slide 20)

Question 22

What does lipocortin-1 inhibiting phospholipase A2 (PLA2) result in?

Answer 22

1. Inhibiting PLA2 means arachidonic acid (the precursor for eicosanoids) isn’t released from membrane phospholipids
2. This means many eicosanoids, such as prostaglandins or leukotrienes cannot be produced.
3. This prevents leukotrienes from producing their effects and causing bronchoconstriction, increased mucus production, recruitment & activation of immune cells and airway edema, in turn reducing all of these

(Slide 22)

Question 23

Why do glucocorticoids and β2-adrenoceptor agonists synergise so well together when treating asthma or COPD?

Answer 23

As they regulate 2 different pathways which can contribute to inflammation, leading to a bigger effect on cellular response.

glucocorticoids also increase β2-adrenoceptor expression

Salbutamol also increases glucocorticoid receptor expression via increasing its half life

(Slide 24)

Question 24

What do B4, C4 and D4 leukotrienes do?

Answer 24

B4 - neutrophil chemoattractant

C4 and D4 - cause bronchoconstriction, increased bronchial activity, mucosal edema and mucous hypersecretion

(Slide 25)

Question 25

What is an example of a leukotriene (CysLT1) receptor antagonist?

Answer 25

Answers Include: Zafirlukast Montelukast (Slide 25)

Question 26

What is the enzyme involved in leukotriene synthesis?

Answer 26

5-lipoxygenase (5-LOX) (Slide 25)

Question 27

What is zileuton?

Answer 27

A 5-lipoxygenase (5-LOX) inhibitor which is used to reduce the frequency of asthma exacerbations (worsening of a disease, or an increase in symptoms) Particularly effective in aspirin-induced asthma (Slide 25)

Question 28

What is aspirin-induced asthma?

Answer 28

Aspirin-induced asthma (AERD) is a type of asthma that worsens after taking aspirin or other NSAIDs due to increased leukotriene production resulting from COX-1 inhibition. It is characterised by bronchoconstriction, nasal polyps (non-cancerous growths in the nose), and chronic rhinosinusitis (the inflammation or infection of the sinuses and nasal cavity) (Slide 25)

Question 29

What is a major side effect of zileuton and zafirlukast?

Answer 29

Liver toxicity (less for zafirlukast) (Slide 25)

Question 30

What is the mechanism of action of montelukast and zafirlukast?

Answer 30

They bind to and inhibit CysLT1 receptors, which C4, D4 and E4 leukotrienes bind to. This prevents leukotrienes from exerting their harmful effects on the airway, thereby reducing bronchoconstriction, inflammation, and mucus production. (Slide 26)

Question 31

What are xanthines used for?

Answer 31

Mainly for asthma but can also be used for COPD (Slide 28)

Question 32

State an example of a xanthine.

Answer 32

Answers Include: Theophylline Profylline (Slide 28)

Question 33

What are the 2 mechanisms of action of xanthines?

Answer 33

1. Adenosine receptor antagonist - they block the inhibitory effects of adenosine upon adenylyl cyclase through its receptors, and allow intracellular cAMP to accumulate and promote airway smooth muscle relaxation 2. Phosphodiesterase inhibitor - blocks reduction in intracellular cAMP and again promotes airway smooth muscle relaxation Note: cAMP also activates protein kinase A (PKA), which can inhibit MCLK, promote calcium efflux and inhibit the MAPK pathway (Slides 28 and 29)

Question 34

Are antibodies used for COPD or asthma?

Answer 34

Mostly for asthma, less frequently used for COPD (Slide 33)

Question 35

What is an example of an antibody used to treat asthma / COPD?

Answer 35

Answers Include: Tralokinumab or lebrikizumab (both anti-IL-13) Dupilimab (anti-IL-4 and anti-IL-13) Mepoluzimab (anti-IL-5) Omalizumab (anti-IgE antibody) (Slide 33)