Pharmacology of Asthma - Core Drugs & Case Study Flashcards
What are the 5 core drugs used in the treatment of asthma?
From Phase 1b
- Salbutamol
- Fluticasone
- Mometasone
- Budesonide
- Montelukast
What class are drugs with the suffix -sone or -ione?
Corticosteroids
What is the primary mechanism of action of salbutamol?
Agonist at the B2-receptor on airway smooth muscle cells
Activation reduces Ca2+ influx
This prevents smooth muscle contraction
What is the drug target for salbutamol?
Beta-2 (B2) adrenergic receptor
aka B2 adrenoreceptor
What is the primary site of action for salbutamol?
Airway (bronchial) smooth muscle
What are the main side effects associated with use of salbutamol?
Palpitations/agitation
Tachycardia/arrythmias
Hypokalaemia (at higher doses)
What is the half life of salbutamol?
2.5-5hrs
Salbutamol is a short acting beta agonist (SABA)
Why can cardiac effects be seen with use of salbutamol?
Beta-2 selectivity is not absolute so cardiac (beta-1) effects can be seen
What can cause hypokalaemia with use of salbutamol?
Hypokalaemia can be caused via an effect on sodium/potassium ATPase
Hypokalaemia is a side effect associated with use of salbutamol.
Use of what type of medication can exacerbate this effect?
Co-administration with corticosteroids can exacerbate this hypokalaemia
What is the primary mechanism of action of Fluticasone?
Very powerful drug that has multiple actions on many different cell types
Fluticasone directly decreases inflammatory cells, e.g. eosinophils, monocytes, mast cells, macrophages, and dendritic cells
It reduces the (n) of these cells and also the (n) of cytokines they produce
E.G.
Binds glucocorticoid receptor on eosinophils
Action - stimulates GR
GR - promotes anti-inflammatory response, reduced IL-5 production
This reduces (n) of eosinophils + their produced cytokines, promotes eosinophil apoptosis etc.
What is the drug target for Fluticasone?
Glucocorticoid receptor
What are the main local side effects of Fluticasone?
Sore throat
Hoarse voice
Opportunistic oral infections
What are the main systemic side effects of Fluticasone?
Growth retardation in children Hyperglycaemia Decreased bone mineral density Immunosuppression Effects on mood
(Many others)
How do Fluticasone and Cortisol differ in affinity for the glucocorticoid receptor?
Fluticasone has greater affinity for the glucocorticoid receptor compared to cortisol
What is the oral bioavailability of Fluticasone?
Oral bioavailability <1%
Any systemic delivery of Fluticasone via the inhaled route is predominantly through the pulmonary vasculature.
Why is this?
Oral bioavailability <1%
What is the primary mechanism of action of Mometasone?
Very powerful drug that has multiple actions on many different cell types
Mometasone directly decreases inflammatory cells, e.g. eosinophils, monocytes, mast cells, macrophages, and dendritic cells
It reduces the (n) of these cells and also the (n) of cytokines they produce
What is the drug target for Mometasone?
Glucocorticoid receptor
What are the main local side effects of Mometasone?
Sore throat
Hoarse voice
Opportunistic oral infections
What are the main systemic side effects of Mometasone?
Growth retardation in children Hyperglycaemia Decreased bone mineral density Immunosuppression Effects on mood
(Many others)
How do Mometasone and Cortisol differ in affinity for the glucocorticoid receptor?
Mometasone has greater affinity for the glucocorticoid receptor compared to cortisol
What is the oral bioavailability of Mometasone?
Oral bioavailability <1%
Any systemic delivery of Mometasone via the inhaled route is predominantly through the pulmonary vasculature.
Why is this?
Oral bioavailability <1%
What is the primary mechanism of action of Budesonide?
Very powerful drug that has multiple actions on many different cell types
Mometasone directly decreases inflammatory cells, e.g. eosinophils, monocytes, mast cells, macrophages, and dendritic cells
It reduces the (n) of these cells and also the (n) of cytokines they produce
What is the drug target for Budesonide?
Glucocorticoid receptor
What are the main local side effects of Budesonide?
Hoarse voice
Opportunistic oral infections
What are the main systemic side effects of Budesonide?
Growth retardation in children Hyperglycaemia Decreased bone mineral density Immunosuppression Effects on mood
(Many others)
How does budesonide compare in potency to fluticasone and mometasone?
Less potent than fluticasone and mometasone
What is the primary mechanism of action of Montelukast?
Antagonism of CysLT1 leukotriene receptor on eosinophils, mast cells and airway smooth muscle cells
Decreases eosinophil migration, bronchoconstriction and inflammation induced oedema
What is the drug target of Montelukast?
CysLT1 leukotriene receptor
What is the primary mechanism of action of Montelukast?
Antagonism of CysLT1 leukotriene receptor on eosinophils, mast cells and airway smooth muscle cells
Decreases eosinophil migration, decrease bronchoconstriction and reduce inflammation-induced oedema
What are the main serious side effects associated with using montelukast?
Mood changes
Anaphylaxis
Why would someone with asthma administer montelukast at least 2 hrs before initiating exercise?
For prophylaxis of exercise induced bronchoconstriction
What process is characteristic of the immediate phase of an asthma attack?
Mainly bronchospasm
What process is characteristic of the delayed phase of an asthma attack?
Inflammatory reaction
What does the management of asthma in children under 5yo require?
Careful and relatively frequent monitoring
What does the management of asthma in children under 5yo require?
Careful and relatively frequent monitoring
- Can help minimise asthma symptoms by following a written asthma action plan you develop with the child’s doctor to monitor symptoms and adjust treatment as necessary
A three year old child, newly diagnosed with asthma, has been prescribed salbutamol as a reliever therapy for future symptom relief.
She has also been provided with a spacer to help with delivery to the lungs.
Why do you think inhalation route is preferred over the oral route?
Local (inhalation) vs systemic (oral) administration: inhalation - directly to lungs where drug can interact with target
Much smaller doses given with inhaled administration of salbutamol vs oral administration because inhalation = local administration
Fewer side effects - some of drug will leak out into systemic circulation via local route (to lungs) BUT much less so than via oral route
A three year old child, newly diagnosed with asthma, has been prescribed salbutamol as a reliever therapy for future symptom relief.
She has also been provided with a spacer to help with delivery to the lungs.
What is the benefits of using a nebuliser with treatment?
Patient is 3yo —-> easier for her to receive full dose with nebuliser (she has to do less work)
If patient is having difficulty breathing, can add extra drugs to the mix + oxygen to help (all administered with help of nebuliser)
Katie (3yo) is brought to A&E by her parents as she’s having great difficulty breathing.
She is wheezing upon exhalation and is coughing occasionally. She also has a slight temperature.
Katie is administered inhaled salbutamol (2.5mg; SABA) via an oxygen-driven nebuliser every 20mins and she recovers within an hour.
Why do you think the nebuliser was the best method for delivering the salbutamol in this urgent situation?
Patient is 3yo —-> easier for her to receive full dose with nebuliser (she has to do less work)
If patient is having difficulty breathing, can add extra drugs to the mix + oxygen to help (all administered with help of nebuliser)
Advantages
- Many drug solutions
- Can deliver combinations
- Minimal patient co-operation needed
- Can deliver to all patient ages
- Concentration and dose can be modified
- Normal breathing pattern
Evidence suggests that only 20% an inhaled drug penetrates deep enough into the lungs to be able to produce an effect and influence lung function (e.g. reduce breathlessness).
What do you think happens to the other 80% of the inhaled drug?
- Breathed out (exhaled)
- Down oesophagus + into stomach - a huge amount gets swallowed (>80%)
(Oesophagus —along GI tract —> absorbed from gut —> liver etc.)
- Mucociliary clearance
- Some escapes into systemic circulation (because lungs = heavily vascularised so some will be absorbed from lungs - will diffuse out of lungs + go elsewhere)
- Some absorbed across mucus membranes of oral cavity + pharynx
What are the advantages of using a spacer when administering inhaled drugs?
Are there any disadvantages?
- Less drug exhaled
- Less drug passes down into stomach
- More gets into lungs
However
- Can contribute to loss as some drug can get trapped in spacer
What is the approximate proportion of inhaled drug that ends up in:
a) Inhaler device
b) mouth/throat
c) lungs
With vs Without a spacer?
What conclusions can you draw from this?
Without spacer:
a) ID - 10%
b) M/T - 81%
c) L - 9%
With spacer:
a) ID - 57%
b) M/T - 22%
c) L - 21%
With a spacer, more of the inhaled drug reaches the lungs where it can hopefully produce an effect
Like salbutamol, a significant proportion of inhaled fluticasone is actually swallowed. Despite this, the oral bioavailability (i.e. the proportion of drug that reaches the plasma VIA the gastrointestinal tract) is less than 1%.
Why is this the case?
Because of first pass metabolism/inactivation
The swallowed portion of the drug will pass from the gut to the liver where it’s bioavailability will be significantly reduced due to the metabolism it undergoes in this organ.
Why might monteklaust be particularly useful for NSAID (Non-steroidal anti-inflammatory drug)-induced asthma?
NSAIDs inhibit COX enzyme (cyclooxygenase), thromboxane production + production of some anti-inflammatory prostaglandins
In asthma - results in overproduction of leukotrienes = pro-inflammatory —-> some asthmatic patients react to this —-> can exacerbate asthma
Montelukast acts within same pathway but inhibits leukotriene production –> reducing inflammatory effect
