7.1 Airway Control Flashcards
Asthma can be defined as more than one of what 4 symptoms?
- wheeze
- breathlessness
- chest tightness
- cough
Give the 4 characteristic features of Asthma
- Variable airflow obstruction
- Airway hyper-responsiveness
- Airway inflammation
- Airway remodelling
The inflammatory response in Asthma is driven by what type of cell?
What are the 3 effects this has on the airways?
Th2 cells which leads to:
- mucosal oedema
- bronchoconstriction
- mucus plugging
Smooth muscle dysfunction in asthma leads to what 2 things?
1) increased contraction
2) increased cytokines and chemokines
Give 5 features of ‘airway remodeling’ seen in Asthma
1) Mucus gland hyperplasia (+goblet cells)
2) Subepithelial fibrosis
3) Epithelium desquamation (epithelial damage)
4) Airway wall thickening and SM thickening
5) Increased BM thickness
Give 4 types of immune cells that are raised in Asthma
1) Th2 cells (CD4+)
2) Mast cells
3) Eosinophils
4) Neutrophils
Asthma is considered a heterogeneous disease, what does this mean?
There are many patterns of Asthma which vary in their:
- Pathology- eosinophil vs neutrophil inflammation
- Symptom patterns + triggers of exacerbations
- Response to treatment
What is meant by the ‘stepwise management of asthma’ in adults
A prinicipal applied to prevent ‘over-treatment’
It is very easy to start patients on medications but very difficult to step them down
Give 5 aims of asthma control
1) minimal symptoms during day and night
2) minimal need for reliever medication
3) no exacerbations
4) no limitation of physical activity
5) normal lung function (FEV1 and/or PEF >80% predicted or best)
Before initiating a new drug therapy for Asthma, what 3 things must we consider
1) check compliance with existing therapies
2) check inhaler technique
3) eliminate trigger factors
What catagory of Asthma begins at step 1 on the treatment ladder
Mild intermittent asthma
What treatment is used in Step 1 treatment + 2 examples
Are these ‘relievers’ or ‘preventers’?
Inhaled short-acting β2-agonists
- eg salbutamol, terbutaline
Function to reverse and prevent bronchoconstriction i.e. on exercise and are therefore ‘relievers’
What is the main target of short acting β2-agonists
Main target is airway smooth muscle
+ potentially inhibits mast cell degranulation (with intermittent use ONLY)
How does effect on mast cells differ in intermitent vs regular use of β2-agonists
What must we therefore advise patients?
Intermittently ➞ inhibits mast cell degranulation
Regular use ➞ increased mast cell degranulation in response to allergens
MUST advise patients to use ONLY as-required as regular use will reduce asthma control
Does increasing dose of β2-agonists provide more airway relaxation? Why?
No because saturation of β2-agonist pathway occurs very easily. There is not enough substrate to cope with an increased lode of drug
Give the MoA of β2-agonists on airway SM
Give the 4 classes of β2-agonists and include:
- Speed of onset
- Duration of action
- 1-2 examples for each
Formoterol has a ______ onset of action similar to ______
rapid, salbutamol
Give 4 β2-agonist side effects
- Tachycardia
- Palpitations
- Tremor
- Anxiety
(+ many other adrenergic effects)
What is Step 2 in Asthma treatment?
Are these ‘relievers’ or ‘preventers’?
Regular preventer therapy through use of Inhaled corticosteroids
What 4 criteria are required to transition from step 1 to step 2 treatment in Asthma?
1) using β2-agonist ≥3 times/week
2) Symptoms ≥3 times/week
3) Waking up in the morning wheezy ≥1 time/week
4) Exacerbation requiring oral steroids in last 2 years
What is the main target of corticosteroids?
Inflammation
Give 4 positive effects of corticosteroids
1) Improve symptoms
2) Improve lung function
3) Reduce exacerbations
4) Prevent death
Give the MoA of corticosteroids
CS bind glucocorticoid receptor causing downregulation of inflammation through:
1) transactivation ➞ regulates Annexin 1 which inhibits leukocyte inflammation events
2) transrepression ➞ upregulates the inhibtor of NF-κB
What is the chemical basis for potency and topical selectivity of inhaled GCS
The lipophilic substituents on D-ring. This determines how long the molecule remains in the intended target organ
Highly lipophilic ➞ long acting
Less lipophilic ➞ short acting
Lipophilic substituents on GCS lead to what 3 key properties?
1) very high affinity for the GCS receptor
2) increased uptake and dwell time in tissue on local application
3) rapid inactivation by hepatic biotransformation following systemic absorption
When corticosteroids are inhaled what are the 2 routes absorption occur via
Give an Asthma drug which is absorbed through gut and lungs
Beclomethasone (corticosteroid)
Give 2 Asthma drugs which undergo extensive first-pass metabolism
Budesonide and fluticasone
At high doses what can be said about ALL Inhaled CS?
ALL have the potential to produce systemic side- effects
What is Step 3 in Asthma treatment?
Add on therapy
When should you consider transitioning from Step 2 to Step 3 treatment?
When patients Asthma exacerbations are not being controlled even at 400μg/day ICS
ie flat ICS dose-response curve
What is the first choice drug class for step 3 treatment?
Incl 2 examples and state which is preffered and why
Long-acting b2-agonists (LABA)
Eg. formoterol, salmeterol ➞ formoterol preffered because it is must faster acting
How does mean morning PEF change when transitioning from step 2 to 3?
At step 2 on ICS, increasing dosage does not have any effect on mean morning PEF
In step 3, with the addition of formoterol, an increase in mean morning PEF is seen
Give 3 positive effects of LABAs
1) Reduce asthma exacerbations
2) Improve asthma symptoms
3) Improve lung function
Why must we always prescribe LABAs in conjunction with an ICS
Because they are not anti-inflammatory on their own
Give 2 examples of combined inhalers containing both an ICS and a LABA
(incl how often they must be taken)
Twice daily:
- Budesonide/formoterol
- Beclomethasone/formoterol
- Fluticasone/formoterol
- Fluticasone/salmeterol
Once daily:
- Fluticasone furoate/vilanterol
Give 4 benefits of LABA + ICS in single inhaler compared to 2 seperate inhalers
- Ease of use
- Compliance
- 1 versus 2 prescriptions to worry about
- Potentially cheaper than 2 individual inhalers
- Safety
What is SMART therapy?
Symbicort Maintenance and Reliever Therapy
combination treatment of an ICS and LABA in one inhaler for both maintenance and reliever therapy ➞ budesonide/formoterol
List 3 advantages studies have shown regarding use of SMART
- fewer patients with severe exacerbations
- sustained improvements in morning PEF
- less reliever use with Symbicort SMART
When should we consider transitioning from step 3 to step 4?
For persistant poor control
What is Step 4 treatment in Asthma?
1) Increasing dose of ICS
2) Additon of a another drug alongside current treatment
Give 3 drugs which can be added for step 4 treatment
1) Leukotriene receptor antagonists (LRA)
2) Methylxanthines
3) Long acting anti-muscarinics e.g tiotoprium (LAMAs)
Why are LRA’s and Theophylline kess clinically indicated?
Both poorly efficacious
Give 2 examples of Leukotriene receptor antagonists
Montelukast and Zafirlukast
Give the target/MoA of LRAs
LTC4 release by mast cells and eosinophils can induce bronchoconstriction, mucus secretion, mucosal oedema and promote inflammatory cell recruitment
LRAs block the effect of cysteinyl leukotrienes in the airways at the CysLT1 receptor
Give 4 side effects of LRA’s
- Angioedema
- Dry mouth
- Anaphylaxis
- Arthralgia
- Fever
- Gastric disturbances
Give 2 examples of Methylxanthines
Theophylline and Aminophylline
Give the MoA of Methylxanthines
Antagonise adenosine receptors through inhibition of phosphodiesterase ➞ increase cAMP
Give 5 issues with use of Theophylline
- Poorly efficacious
- Narrow therapeutic window
- +++ side-effects (nausea, headache, reflux)
- Potentially life-threatening toxic complications (arrhythmias, fits)
- Impt DDIs
Give an important DDI experienced with Methylxanthines + 2 drug examples
levels increased by CYPP450 inhibitors
eg. erythromycin, ciprofloxacin
Give one example of a long acting anticholinergic + another condition it can also be used to treat
Tiotropium bromide (SPIRIVA)
Reduces exacerbations in COPD and asthma ➞ small improvements in lung function and symptoms
Compare the effect of anti-cholinergics to adrenergic agonists
Bronchodilation develops more slowly and less intense than adrenergic agonists
Response may last up to 6 hours.
Give 3 side effects of long acting anticholinergics
- dry mouth
- urinary retention
- glaucoma (risk with nebulisation of ipratropium)
Give 2 other examples of LAMAs only used for COPD
What is Step 5 treatment in Asthma?
Continuous or frequent use of oral steroids
Use daily oral steroid tablets in additon to high dose ICS
(consider other treatments to minimise use of oral steroid tablets)
What is the MoA of oral steroid tablets?
Works by preventing IgE binding to high affinity IgE receptor (FceRI)
This means allergen cannot bind to IgE already bound to receptor, so cannot cross-link IgE and activate mast cells
Give 3 disadvantges of oral steroids?
- Strict criteria for use
- very expensive
- Does not work for EVERY asthmatic patient (may allow oral steroid tapering)
Give an example of an Anticholinergic and when it is most benefical to use
Iprotrapium bromide ( ATROVENT )
Useful add-on in acute severe/life-threatening asthma, or moderate exacerbation with poor response to initial therapy
Give 2 examples of non-steroidal immunosuppressants which may be considered in step 5 treatment
Methetrexate and Cyclosporin
(used in very specialized centres, and currently superceded by anti IgE therapy)
What are Asthma action plans and what is their purpose?
Every asthmatic should have a self-management plan with written instructions on when and how to step- up and step down treatment
Leads to better outcomes in terms of day-to-day control, frequency and severity of exacerbations
What is the importance of stepping down in treatment?
Once asthma is controlled stepping down is recommended. If it does not take place patients may receive a higher dose than is necessary
Patients should be maintained at the lowest possible dose of inhaled steroid
Why does particle size delivered by inhaler matter?
Highlight which is the ‘ideal’ size
10 micron ➞ deposited in the mouth and oropharynx
1-5 micron ➞ most effective as they settle in small airways
0.5 microns ➞ too small. Inhaled to alveoli and exhaled without being deposited in the lungs
Give 4 things things we MUST consider when prescribing Inhaler devices
1) can patient use device satisfactorily (if not find alternatives)
2) patient should be assessed on inhaler technique by a healthcare professional
3) medication must be titrated against clinical response to ensure optimum efficacy
4) re-assess inhaler technique as part of a structured clinical review
How do we define ‘moderate’ acute asthma in adults?
- Saturation >92% in air
- Pulse < 110
- Respiratory rate < 25
- Speech normal
- Wheeze + +
- PEFR > 75-50% predicted
How do we define ‘severe’ acute asthma in adults?
Any one of:
- Unable to complete sentences
- Pulse ≥ 110beats/min
- Respiration ≥25/min
- PEFR 33% - 50% of best or predicted
How do we define life-threatening Asthma?
Same criteria as acute severe + any one of:
- PEFR<33% predicted
- Saturation <92% on oxygen
- PaO2 < 8kPa
- Rising or ‘normal’ PaCO2 (4.6-6 kPa)
- Altered consciousness/hyper-aggressive
- Exhaustion
- Arrythmia
- Hypotension
- Cyanosis
- Silent chest
- Poor respiratory effort
Give the 3 key treatments of acute severe asthma
1) high flow 02 (aim to keep at ~ 94-98% sat)
2) nebulised salbutamol (continuous if necessary, oxygen driven)
3) oral prednisolone ~40 mg daily for 10-14 days
If main treatments of acute severe asthma are not responding what 2 things should be done next?
1) Add nebulised ipratropium bromide
2) consider IV aminophylline (BEWARE if taking oral theophylline b/c it shows non-linear PK)
