Airway Control Flashcards
What do the T-helper cells 2 cause?
Secrete interleukins causing
- mucosal oedema
- bronchoconstriction
- mucus plugging
- airway remodelling
- bronchial hyperresponsiveness
What changes in airway remodelling?
Mucous gland hyperplasia Subepithelial fibrosis Epithelial desquamation Airway wall thickening Increased smooth muscle mass
How can asthma vary between individuals?
Pathologically - eg eosinophils vs neutrophil if inflammation
By symptom patterns
Triggers of exacerbation
How it responds to treatment
Which β2 agonists have a fast onset but are short acting?
Inhaled terbutaline
Inhaled salbutamol
Which β2 agonists have fast onset and long acting?
Inhaled formoterol
Which β2 agonists have a slow onset and short acting
Oral salbutamol
Oral terbutaline
Oral formoterol
Which β2 agonists are slow onset and long duration?
Inhaled salmeterol
Oral bambuterol
What are short-acting β2 agonists used for?
Symptom relief though reversal of bronchoconstriction
Prevention of bronchoconstriction eg on exercise
Why should short-acting β2 agonists only be used when required?
If used regularly, can reduce control of asthma
Mechanism of action of short-acting β2 agonists?
β adrenoceptors are coupled to Gs proteins
Activate adenylyl cyclase to convert ATP to cAMP
Increased cAMP activates PKA which phosphorylates L-type calcium channels, increasing calcium entry into cells
Leads to smooth muscle relaxation and inhibition of of agonist-induced contraction
What drives inflammation in asthma?
T-helper cell 2 which secrete interleukins
How do beta-2 agonists reduce bronchoconstriction?
Beta-adrenoceptors coupled to Gs proteins
Activate adenylyl cyclase to convert ATP to cAMP
Increased cAMP activates PKA which
-reduces intracellular Ca2+ concentration
-inhibits MCLK leading to dephosphorylation of myosin
= smooth muscle relaxation
How can beta-2 agonists potentially make asthma worse?
Regular use can increase mash cell degranulation in response to allergens
Side effects of short acting beta-2 agonists?
Tachycardia
Palpitations
Tremor
When are long-acting beta-2 agonists used?
In step 3 as an add-on therapy
- must check patient compliance
- check inhaler technique
- eliminate triggering factors
What is the first choice for a long-acting beta-2 agonist?
Formoterol or salmeterol
What is the onset time and duration of action for beta-2 agonists?
Formoterol works in 1-3 minutes
Salmeterol works in 10-20 minutes
Work for 12 hours
Benefits of long-acting β2 agonists?
Reduce asthma exacerbations
Improve symptoms
Improve lung function
What must long-acting β2 agonists be prescribed with?
An inhaled steroid as they do not have anti-inflammatory properties of their own
What are the different combination inhalers with a long-acting β2 agonist and steroid?
Budesonide/formoterol Beclomethasone/formoterol Fluticasone/formoterol Fluticasone/salmeterol Fluticasone furoate/vilanterol
Why are combined inhalers useful?
Better compliance and easy to use
Only one prescription
Cheaper than two inhalers
When are inhaled corticosteroids introduced?
Using β2 agonist 3 or more times a week
Have symptoms 3 or more times a week
Waking once or more a week
Exacerbation requiring oral steroids in last two years
Mechanism of action of inhaled corticosteroids?
Suppress gene transcription in a wide range of pro-inflammatory structural cells
This reduces infiltration of the lung by eosinophils and other cells that execute the exaggerated immune response
Increase expression of β2 receptors
Increase anti-inflammatory ILs which induce apoptosis in many inflammatory cells and reduce the number of mast cells in respiratory mucosa
Overall, reduce inflammation
Benefits of inhaled corticosteroids?
Improve symptoms
Improve lung function
Reduce exacerbations
Prevent death
When are optimum effects seen with inhaled corticosteroids?
Weeks/months after surgery
What proportion of inhaled corticosteroids are delivered to the lungs?
10-50%
What can reduce the amount of corticosteroid reaching the target site when inhaled?
Deposited in upper airway
Swallowed
What is given for an acute exacerbation of asthma?
Oral steroids - 40mg prednisolone
ADRs of inhaled corticosteroids?
Low due to poor systemic absorption and metabolised pre-systemically
Spacers also reduce effects such as croaky voice, sore throat and thrush
Which patients have a better response to inhaled corticosteroids?
This with eosinophilic asthma rather than non-eosinophilic
What is used in step 1 asthma treatment?
Mild intermittent asthma
-β2 short acting agonist prn
What is used in step 2 management of asthma?
Regular preventer therapy
-add inhaled steroids 200-800mcg a day
What is done in step 3 in management of asthma?
Add inhaled long-acting β2 agonist
- if needed, increase dose of inhaled steroid to 800mcg a day
- if no response, stop LABA and increase dose of inhaled steroid to 800mcg a day. If not enough, trial other therapies eg leukotriene receptor antagonist or SR theophylline
What happens in step 4 asthma management?
Persistent, poor control
Consider trials of
-increasing inhaled steroid to 2000mcg/day
-addition of fourth drug eg leukotriene receptor antagonist, SR theophylline, β2 agonist tablet
What is done in step 5 management of asthma?
Continuous/frequent use of oral steroids
- use daily steroid tablet at the lowest dose providing adequate control
- maintain high dose of inhaled steroid at 2000mcg/day
- consider other treatments to minimise use of steroid tablet
- refer for specialist care
Name some leukotriene receptor antagonists
Montelukast
Zafirlukast
How do leukotriene receptor antagonists work?
LTC4 is released 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 CysLT1 receptors
Side effects of leukotriene receptor antagonists?
Angioedema Dry mouth Anaphylaxis Fever Gastric disturbances
Name some methylxanthines
Theophylline
Aminophylline
Mechanism of action of methylxanthines?
Antagonise adenosine receptors
Inhibit phosphodiesterase leading to increase in cAMP (but unlikely to be relevant in vivo)
Problems with methylxanthines?
Poorly efficacious
Narrow therapeutic window
Frequent ADRs - some potentially life threatening
DDIs
ADRs of methylxanthines?
Nausea, headache, reflux
Arrhythmias and fits
DDIs with methylxanthines?
Get increased levels with CYP450 inhibitors such as erythromycin and ciprofloxacin
Name some long-acting anti-cholinergics
Tiotropium bromide
What is tiotropium bromide used for?
COPD and asthma
Used once a day to reduce exacerbations
Can improve lung function and symptoms
Side effects of long-acting cholinergics?
Dry mouth
Urinary retention
Glaucoma
How does anti-IgE work?
Prevents IgE binding to high affinity IgE receptor
Therefore, cannot bind to IgE already bound to receptor, so cannot cross-link IgE and activate mast cells
What is the ideal size of particles for inhaled drugs and why? What happens if they are too big or too small?
1-5 micron particles - settle in small airways
Too big, deposited in mouth and oropharynx
Too small, inhaled to alveoli without being deposited in lungs
What happens once asthma is controlled?
Stepping down of therapy to ensure patients are not receiving a higher dose than is necessary
What are the criteria for severe acute asthma?
Any one of these features Unable to complete sentences Pulse at or above 110 bpm Resp rate at or above 25 bpm Peak flow 33-50% of best or predicted Plus any one of some life-threatening features
What are the life threatening features for severe acute asthma?
Low PEF Low oxygen sats (below 92) High CO2 >4.5kPa Silent chest Cyanosis Feeble respiratory effort Hypotension, bradycardia, arrhythmia Exhaustion, confusion, coma
When is mechanical ventilation required in a severe acute asthma attack?
If PaCO2 rises above 6kPa
Treatment of severe acute asthma?
High flow oxygen - need to keep O2 94-98%
Nebulised salbutamol
Oral prednisolone - 40mg/day for 10-14 days
If not responding, nebuliser ipratropium bromide
If no improvement, IV aminophylline
What is ipratropium bromide?
An anti-cholinergic
- bronchodilation develops more slowly than adrenergic agonists
- response may last up to 6 hours
