Pharmacology of Asthma Flashcards
What are the goals of asthma treatment?
1) Reducing impairment → reducing symptoms, maintaining normal activities and achieving near normal pulmonary function
2) Minimising risks associated with the disease e.g. asthma exacerbations which puts patients in hospital and adverse effects of medication e.g. steroids
What are the two classifications of pharmacological treatment for asthma?
1) Reliever - short term benefit
2) Controller - long term
How are asthmatic airways blocked?
Blockage with e.g. eosinophils or narrowing by inflammation
What is the first step in asthma treatment?
As needed reliever inhaler (blue) → SABA
Describe use of only as needed SABAs
- SABAs are highly effective for relief of asthma symptoms
- However there is insufficient evidence about the safety of treating asthma with SABA alone
- This option should reserved fr patients with infrequent symptoms (less than twice a month) of short duration, with no night waking due to asthma and with no risk factors for exacerbations
What is step 2 of asthma treatment?
Low dose controller (ICS to control inflammation first line) + as needed SABA
What is step 3 of asthma treatment?
One or two controllers (ICS/LABA) + as needed SABA
What is step 4 of asthma treatment?
Two or more controllers _ as needed SABA
Why is increasing the dose of medication past step 4 not a good idea?
Bc after this, even if you increases the dose a lot, it might make no difference and just have really bad side effects
What is step 5 of asthma treatment?
Higher level care and/or add on treatment
Why are bronchodilators quick relief?
Bc they relax smooth muscle
What are the two types of bronchodilators?
1) Selective beta 2 adrenoreceptor agonists (short and long acting)
2) Anticholinergic/muscarinic receptor antagonists (short and long acting)
How are bronchodilators given?
Inhaled (but SBAA can be given IV in intensive care)
What is an example of a short acting selective beta 2 adrenoreceptor agonists (SABA)?
Salbutamol → works within half an hour but effect is gone after 4h
What are some examples of long acting selective beta 2 adrenoreceptor agonists (LABA)?
Formoterol, salmeterol → last up to 12h
Vilanterol → lasts up to 24h (72h)
What is an example of a short acting anticholinergic/muscarinic receptor antagonist?
Ipratropium (bromide)
What are 2 examples of long acting anticholinergic/muscarinic receptor antagonist?
Tiotropium, umeclidinum
How do SABAs (salbutamol) work?
1) Salbutamol stimulates beta-2 adrenergic receptors (the prominent receptors in bronchial smooth muscle)
2) Stimulation of beta-2 receptors leads to activation of adenyl cyclase leading formation of cyclic AMP from ATP
3) High levels of cyclic AMP relaxes bronchial smooth muscle and also inhibits the release fo bronchoconstrictor mediators e.g. histamine and leukotrienes from mast cells in the airway
What happens to salbutamol in the body?
1) After inhalation, salbutamol reaches the lungs directly and acts within 3-5 minutes with a peak at 15-20 minutes
2) After oral administration, ~50% of salbutamol is absorbed from the gut with a slower onset of action, reaching a peak at ~2 hours after intake
What is the overall duration of action of salbutamol?
4-6 hours → buys time to get to hospital/GP, doesn’t treat asthma
How do anti-cholinergic/muscarinic receptor antagonists work?
Block effects of ACh released from cholinergic parasympathetic nerve fibres to smooth muscle and mucus glands → prevents airway smooth muscle contraction and mucus hypersecretion
(Less effective than BAAs at relaxing smooth muscle)
What are side effects of anti-cholinergic/muscarinic receptor antagonists?
Unusual but can include dry mouth, palpitations (bc anti-cholinergic), headache, dizziness, blurred vision → if it doesn’t help after two weeks, stop
What are the effects of tiotropium?
Increases FEV1 and reduces the risk of severe exacerbations
How does tiotropium work?
It attenuates IL-13-induced goblet cell metaplasia and potentially reduces mucus hypersecretion
Why does asthma required anti-inflammatory therapies in most patients?
Bc it is an inflammatory condition
What is the cornerstone of asthma management?
Inhaled corticosteroids (ICS) - brown inhaler
What are the effects of ICS therapy?
1) Reduces asthma symptoms
2) Increases lung function
3) Improve QoL
4) Reduces the risk of exacerbations, hospitalisations and death
How do corticosteroids work?
They suppress Th2/type 2 airways inflammation → reduces the infiltration and activation of eosinophils, Th2 cells and other inflammatory cells
What do patients with elevated blood eosinophil levels experience?
A higher rate of exacerbations and lower asthma control
What is an example of a long acting ICS?
Fluticasone furoate
Describe fluticasone furoate (FF)
- FF is an ICS with enhanced affinity for the glucocorticoid receptor (fast association and slow dissociation) → results in a longer duration of action and prolonger retention in the lung
- This enables one-daily dosing → improves patient convenience and enhances adherence to treatment
What combination of medication is currently the only available once daily inhaler?
- FF/vilanterol → ICS/LABA combination inhaler licensed in asthma
What medication might you take as well if the preventer inhaler (ICS) is not working v well?
Leukotriene receptor antagonist (LTRA)
What is an example of an LTRA?
Montelukast
What are leukotrienes?
A group of potent arachidonic acid-derived inflammatory mediators
How do LTRAs work?
- The CysLT1 receptor mediates the bronchoconstrictive and pro-inflammatory effects of cysteinyl-leukotrienes
- Montelukast is a competitive antagonist of the CysLT1 receptor
Describe LTRAs
- Once daily oral administration → many patients prefer to take tablet than inhaler
- Likely to work best in a subgroup of asthma patients with aspirin exacerbated respiratory disease (AERD) bc they have increased production of cysteinyl-leukotrienes
- Side effects are rare but bad → headache, GI disturbances, nightmares
- Only works in 10-20% of patients with severe asthma, can’t rely on it
What is part of step 5 of asthma treatment?
Oral corticosteroids → excellent at controlling the inflammation fo asthma but at an expense
What is an example of an oral corticosteroid?
Prednisolone
How do oral corticosteroids work?
Get rids of eosinophils, relaxes smooth muscle and make salbutamol work better
What are the side effects of OCS?
Obesity, osteoporosis, diabetes, cataracts, reflux, glaucoma, skin disease, psychiatric
How do OCS lead to osteoporosis?
Inhibits osteoclasts so inhibits bone turnover
How are OCS prescribed?
As short term relief → short course, 40mg for 5 days
Which cytokine is largely involved in bronchoconstriction?
IL-13
Why do you need steroids for asthma treatment?
Bc salbutamol does not get rid of eosinophils and inflammation
What correlates with worse asthma and therefore what do biologics (MAbs) target?
More eosinophils → so target these by blocking IL-5
In an ideal world what would we give all patients who need/use OCS?
MAbs
What types of MAbs are used to treat asthma?
Anti IL-5
How effect are anti IL-5 Mabs?
They reduce asthma exacerbations by >50%
What are examples of anti IL-5 Mabs?
Mepolizumab, benralizumab, dupilumab (new, hoping will work for 20% of patients for who IL-5 targets doesn’t work
What is the central effector cell in asthma?
Eosinophils
What does IL-5 do?
IL-5 is critically involved in the synthesis, maturation, homing and activation of eosinophils
What does mepolizumab target?
Serum IL-5
What does benralizumab target?
IL-5 receptor
How do anti IL-5 Mabs work?
Both lead to a significant reduction in eosinophils, asthma exacerbations and systemic steroid exposure
What is benralizumab?
A humanised MAb that depletes blood eosinophils by specifically targeting IL-5a receptor on eosinophils and then recruits effector cells to APC
What increases response to IL-5 MAb treatment?
The higher the blood eosinophil count
What is another MAb used to treat asthma?
Anti-IgE MAb
What is an example of an anti-IgE Mab?
Omalizumab
How does omalizumab work?
1) Depletes IgE and disarms mast cells
2) This reduces allergen-induced mast cell activation, decreases expression of IgE high affinity receptors on mast cells and blocks effects of IgE on dendritic cells
3) This decreases exacerbation rates
Describe omalizumab
- Given by SC injection every 2-4 weeks, at a dose and frequency determined by body weight and serum IgE levels
- It is licensed for patients with evidence of atopy to perennial allergens
- It eliminates the seasonal peaks in asthma exacerbations
What combination of factors is most associated with exacerbations?
The combination of virus, allergy and exposure to a relevant antigen
What do anticholinergics offer?
Additional bronchodilation
What are side effects of biologics?
- Only available for 2-3 years in practice so don’t know long term effects
- On day of injection → skin reaction, fatigue, headache
- Slightly higher rate of pharyngitis and other infections
