Pharmacology of Asthma Flashcards
What are the 5 main asthma drugs?
- Salbutamol
- Fluticasone
- Mometasone
- Budesonide
- Montelukast
What is the primary mechanism of action of salbutamol?
Agonist at the β2 receptor on airway smooth muscle cells
Activation reduces Ca2+ entry and this prevents smooth muscle contraction
What is the drug target site for salbutamol?
Beta 2 (β2) adrenergic receptor
What are the main side effects of salbutamol?
Palpitations/ agitation
Tachycardia/ Arrythmias
Hypokalaemia (at higher doses)
What is some extra information about salbutamol?
Salbutamol is a short acting beta agonist (SABA)
It’s half life is 2.5 - 5hrs
Beta 2 selectivity is not absolute – as a result, cardiac (beta 1) effects can be seen
Hypokalaemia can be caused via an effect on sodium/ potassium ATPase - this can be exacerbated by coadministration with corticosteroids
What is the primary mechanism of action of fluticasone?
Very powerful drugs - multiple actions on many different cell types
Fluticasone directly reduces the number of inflammatory cells such as eosinophils, monocytes, mast cells, macrophages, and dendritic cells = reduces the number of cytokines they produce
What is the drug target site for fluticasone?
Glucocorticoid receptor
What are the main side effects of fluticasone?
Local side effects:
Sore throat, hoarse voice, opportunistic oral infections
Systemic side effects:
Growth retardation in children Hyperglycaemia Decreased bone mineral density Immunosuppression Effects on mood
What is some extra information about fluticasone?
Greater affinity for the glucocorticoid receptor compared to cortisol
Oral bioavailability <1%. Therefore, any systemic delivery via the inhaled route is predominantly through the pulmonary vasculature.
What is the primary mechanism of action of mometasone?
Very powerful drugs - multiple actions on many different cell types
Mometasone directly reduces the number of inflammatory cells such as eosinophils, monocytes, mast cells, macrophages, and dendritic cells = reduces the number of cytokines they produce
What is the drug target site for mometasone?
Glucocorticoid receptor
What are the main side effects of mometasone?
Local side effects:
Sore throat, hoarse voice, opportunistic oral infections
Systemic side effects:
Growth retardation in children Hyperglycaemia Decreased bone mineral density Immunosuppression Effects on mood
What is some extra information about mometasone?
Greater affinity for the glucocorticoid receptor compared to cortisol
Oral bioavailability <1%. Therefore, any systemic delivery via the inhaled route is predominantly through the pulmonary vasculature.
What is the primary mechanism of action of budesonide?
Very powerful drugs - multiple actions on many different cell types
Budesonide directly reduces the number of inflammatory cells such as eosinophils, monocytes, mast cells, macrophages, and dendritic cells = reduces the number of cytokines they produce
What is the drug target site for budesonide?
Glucocorticoid receptor
What are the main side effects of budesonide?
Local side effects:
Hoarse voice, opportunistic oral infections
Systemic side effects:
Growth retardation in children Hyperglycaemia Decreased bone mineral density Immunosuppression Effects on mood
What is some extra information about budesonide?
Oral bioavailability >10%. Therefore, inhaled budesonide will still result in some systemic absorption through the GI tract
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 = decreased eosinophil migration, broncho-constriction and inflammation induced oedema
What is the drug target site for montelukast?
CysLT1 leukotriene receptor
What are the main side effects of montelukast?
Mild side effects:
Diarrhoea
Fever
Headaches
Nausea or vomiting
Serious side effects:
Mood changes
Anaphylaxis
What is some extra information about montelukast?
For prophylaxis of exercise-induced bronchoconstriction, montelukast should be administered at least 2 hours before initiating exercise
Case Study: Katie Lucero
3F - brought to A&E by her parents due to difficulty in breathing. Whistle like wheeze when exhaling and occasionally coughing Slight temperature (38.2oC)
Further history and physical examination reveal nothing.
Few minor childhood infections but never been ill before, taken no other drugs than children’s ibuprofen
What are some further questions that can be asked by the doctor?
Is there a family history of asthma?
How often do symptoms occur?
Does coughing wake your child at night?
Do the symptoms accompany a cold or are they unrelated to colds?
How long do they last?
Has your child needed emergency care for breathing difficulties?
Does your child have any known pollen, dust, pet or food allergies?
Is your child exposed to cigarette smoke or other airborne irritants?
Answers to questions:
Family history of asthma? No family history
How often do symptoms occur? Mostly when she has a cold or other infection. Sometimes when it is very cold outside.
Does coughing wake your child at night? Actually, she has had a couple of episodes in the last few months.
Do the symptoms accompany a cold or are they unrelated to colds? They definitely are most common when she has a cold or other infection.
How long do they last? Has only ever been for a few minutes until today. This is definitely the worst. It’s been going for well over an hour now.
Has your child needed emergency care for breathing difficulties? No
Does your child have any known pollen, dust, pet or food allergies? No
Is your child exposed to cigarette smoke or other airborne irritants? No
What is the patient’s problem - what are the 4 differentials for asthma triggers and what does Katie most likely have?
Differentials:
Infection induced asthma
Exercise induced asthma
Atopic (allergen-induced) asthma
NSAID induced asthma
For Katie:
Most likely to be viral infection triggered the asthma, as there are no known allergens
But she is young and this is her first presentation of asthma
What are the 2 stages of an asthma attack?
Early: Brochospasm
Late: Inflammation
What is the therapeutic objective for this Katie?
Short-term:
Reduce the symptoms - Improve cough / wheeze, reduce exacerbation
Treat underlying cause - treat the infection, improve raised temperature
Long-term:
Educate patient and parents how to manage the symptoms themselves - e.g. with an inhaler etc.
Reduce risk of further asthma attack
Reduce delayed phase of an asthma attack
Consider the NICE guidelines for the treatment of asthma in the under 5’s
What drug would you choose as your first treatment for Katie and what is the mechanism of action for this medication?
SABA - short acting beta agonist e.g. Salbutamol
Targets beta-2 adrenergic receptors
Located on the bronchiole smooth muscle cells
Acts as an agonist
Reduces Ca2+ entry and prevents smooth muscle contraction
Prevents bronchoconstriction = opens up the airways to reduce bronchospasm
SABA vs LAMA?
SABA = short acting beta agonist
LAMA = long acting muscarinic antagonist = causes bronchodilation
Katie is administered inhaled salbutamol (2.5mg; short acting beta 2 agonist) via an oxygen-driven nebulizer every 20mins and she recovers within an hour
On leaving hospital, she is prescribed salbutamol as a reliever therapy for future symptom relief. Katie is also provided with a spacer to help with delivery to the lungs
What is a nebuliser?
What is an inhaler?
And what is a spacer?
Nebuliser = transforms liquid medication into a mist, that is inhaled and allows the drug to directly hit the target site, automatic medication release
Inhaler = dried powder format rather than mist
Spacer = holds the medicine in place so you can breathe it in easier, allows for medicine delivery to be more effective. Lower percentage of the drug entering the mouth at once, so less medication is lost through exhalation
What are the 2 methods of administration of Salbutamol, and why do you think the inhalation route is preferred over the oral route?
Topical (inhalation) = via mouth into the lungs
Oral = ingestion, via mouth into the stomach
Inhalation = preferred due to direct delivery to the lungs and faster action, rather than oral, which takes a long time to travel through the system and may be broken down by the liver
Why is a nebuliser the best method for delivering the Salbutamol in an emergency situation?
Nebuliser - delivers medication as a mist, automatically
Requires less co-ordination than inhalers
Therefore a patient who may not be able to use an inhaler, the nebuliser = delivered to patients of all ages, and only requires normal breathing pattern
What are the advantages of a nebuliser?
Many drug solutions
Can deliver combinations
Minimal patient cooperation required
Can deliver to patient of all ages
Evidence suggests that only 20% of the inhaled dose of salbutamol (or any inhaled drug) penetrates deep enough into the lungs to be able to influence lung function (e.g. reduce breathlessness)
What do you think happens to the other 80% of inhaled salbutamol?
Some of the salbutamol goes down the oesophagus instead of the trachea
Poor inhaler technique / use
Some of the salbutamol absorbed by the mucus membranes in the oral cavity into systemic circulation
Exhalation of some of the salbutamol
Muco-ciliary clearance = salbutamol that enters the lungs is removed
Salbutamol absorbed within the systemic circulation of the lungs
3 years later, Katie takes salbutamol and inhaled fluticasone propionate (50ug/dose from a metered dose inhaler) during periods of exacerbation
Asthma may result in eosinophilic inflammation. Fluticasone proprionate is a corticosteroid that can target cells involved in the pathophysiology of asthma, including eosinophils
What is the mechanism of action of fluticasone propionate in terms of reducing eosinophilic inflammation?
Fluticasone acts on the glucocorticoid receptors
Located on immune cells, e.g. eosinophils
When fluticasone acts on these receptors, it reduces the inflammatory process by primarily reducing inflammatory mediators such as chemokines, IL-4, IL-5 released by the immune cells
How does fluticasone relate to Katie?
Viral infections = trigger eosinophils = trigger asthma
5 years later, Katie still utilizes salbutamol and fluticasone. She can still get quite breathless during hockey games. Bad bout of breathlessness recently. Montelukast works within this pathway
She hadn’t felt well on that day and had took some ibuprofen that morning before school
The NICE guidelines suggests montelukast (5mg orally, once daily)
What is the mechanism of action for montelukast and why might it be particularly useful for NSAID (Non-steroidal anti-inflammatory drug)-induced asthma?
NSAID induced asthma = overactivation of leukotrienes
NSAIDs block cyclooxygenase activity, leads to build up of arachidonic acid, which increases leukotriene production, which causes increased bronchoconstriction
So the Montelukast:
Targets and blocks the leukotrienes, C4, D4, E4
On phospholipid membranes
Causes reduced bronchoconstriction
