Block D Lecture 2 - Pharmacology of Asthma and COPD Flashcards
What are 3 differences between COPD and asthma?
COPD is not reversible with a bronchodilator treatment
COPD occurs in older patients
COPD is less responsive to inhaled corticosteroid treatment
(Slide 4)
How do treatments for COPD change as symptoms worsen?
Acute symptoms - Short-Acting Beta-Agonists (SABA), anti-cholinergic drugs such as ipratropium or both
Persistent symptoms - Long-Acting Beta-Agonists (LABA) or tiotropium
Severe airflow obstruction - inhaled corticosteroid
(Slide 4)
How do β2-adrenoceptors agonists help treat ?
They increase intracellular cAMP levels, which relaxes smooth muscle for symptomatic relief
(Slide 5)
What is an example of a short acting and a long acting β2-adrenoceptor agonist?
Short Acting: Salbutamol
Long Acting: Salmeterol
(Slide 5)
How do long-acting β2-adrenoceptor agonists work longer than short acting ones?
As they have lipophilic groups attached to them which interact with exo-sites on the receptor, locking them onto the receptor binding site.
(Slide 5)
How do β2-adrenoceptor agonists work?
- They activate Gs, which promotes the stimulation of adenylyl cyclase.
- This enzyme catalyses the formation of cAMP.
- cAMP activates protein kinase A
4a. PKA can inhibit Myosin Light Chain Kinase (MLCK), which is required for 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 MPK pathway by phosphorylating and inhibiting Raf-1 kinase
(Slide 7)
Why are β2-adrenoceptor agonists relatively short acting?
Due to desensitisation
(Slide 8)
What is desensitisation?
A loss in response to an agonist over time
(Slide 8)
What is a mechanism for desensitisation?
Phosphorylation of the occupied receptor by a specific receptor kinase, known as a G protein-coupled receptor kinase (GRK).
This leads to receptor internalisation, meaning the receptor can no longer be activated since it is not on the surface
(Slide 8)
Why do scientists believe that salmeterol triggers less desensitisation?
As it’s a partial agonist of β2-adrenoceptors, meaning less phosphorylation by the GRK, and therefore less internalisation of the receptor
(Slide 9)
Other than bronchodilation, what are 3 other effects of β2-adrenoceptor agonists?
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)
What are 2 side effects of β2-adrenoceptor agonists?
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)
What are Anti-Muscarinics used to treat and what can they be used in combination with?
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)
What are 2 examples of anti-Muscarinics and what are their basic properties?
Ipratropium - non-selective muscarinic antagonist - short acting
Tiotropium - primarily acts on M3 receptors and lesser so on M1 - longer acting
(Slide 14)
Why can Ipratropium cause problems by being a non-selective muscarinic inhibitor?
As it blocks M2 receptors, which usually act as a “brake” for muscarinic activity. Turning this off can cause acetylcholine accumulation
(Slide 15)
Tiotropium is “functionally selective” for M3 receptors. What does this mean?
It binds to all muscarinic receptors with similar affinity, but most its effects are seen at M3 receptors
(Slide 16)
What has a faster onset, Ipratropium or Tiotropium?
Ipratropium
(Slide 16)
What are 2 effects of Tiotropium?
Relaxes airway smooth muscle (bronchodilator)
Reduces mucus production via blockage of M3 on mucosal glands
May reduce neutrophil migration
(Slide 18)
How are glucocorticoids used to treat asthma and COPD?
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)
What are the standard oral and intravenous glucocorticoid steroids used to treat asthma and COPD?
Oral: Prednisolone
Intravenous: Hydrocortisone and Methylprednisolone
(Slide 19)
What is the mechanism of action of glucocorticoids in treating asthma?
- They bind to glucocorticoid receptors (GRs) which are bound to hsp90, causing hsp90 to dissociate
- The GRs then translocate to the nucleus, where they regulate gene transcription by binding to glucocorticoid response elements (GREs) on DNA
- Positive (+GRE) and Negative (-GRE) Glucocorticoid Response Elements exist inside the nucleus. Glucocorticoids bind to the positive and upregulate anti-inflammatory genes
- These include lipocortin-1 which inhibits Phospholipase A₂, reducing prostaglandin and leukotriene synthesis, and increase β2-adrenoceptor transcription, increasing bronchodilation.
- Glucocorticoids also interfere with the activation of pro-inflammatory genes by blocking NF-κB and AP-1 transcription factors, leading to downregulation of pro-inflammatory cytokines and adhesion molecules, reducing inflammation
(Slide 20)
What does lipocortin-1 inhibiting phospholipase A2 (PLA2) result in?
- Inhibiting PLA2 means arachidonic acid (the precursor for eicosanoids) isn’t released from membrane phospholipids
- This means many eicosanoids, such as prostaglandins or leukotrienes cannot be produced.
- 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)
Why do glucocorticoids and β2-adrenoceptor agonists synergise so well together when treating asthma or COPD?
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)
What do B4, C4 and D4 leukotrienes do?
B4 - neutrophil chemoattractant
C4 and D4 - cause bronchoconstriction, increased bronchial activity, mucosal edema and mucous hypersecretion
(Slide 25)
What is an example of a D4 leukotriene receptor antagonist?
Answers Include:
Zafirlukast
Montelukast
(Slide 25)
What is the enzyme involved in leukotriene synthesis?
5-lipoxygenase (5-LOX)
(Slide 25)
What is zileuton?
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)
What is aspirin-induced asthma?
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)
What is a major side effect of zileuton and zafirlukast?
Liver toxicity (less for zafirlukast)
(Slide 25)
What is the mechanism of action of montelukast and zafirlukast?
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)
What are xanthines used for?
Mainly for asthma but can also be used for COPD
(Slide 28)
State an example of a xanthine.
Answers Include:
Theophylline
Profylline
(Slide 28)
What are the 2 mechanisms of action of xanthines?
- 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
- 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 MPK pathway
(Slides 28 and 29)
Are antibodies used for COPD or asthma?
Mostly for asthma, less frequently used for COPD
(Slide 33)
What is an example of an antibody used to treat asthma / COPD?
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)
