Airway Control Flashcards
Give some background on asthma pathophysiology.
Mucosal oedema + bronchoconstriction + mucus plugging
All lead by Th2-driven inflammation
Which leads to bronchial hyperresponsiveness
And might be the reason for airway remodelling.
What happens in terms of airway remodelling in asthma?
Mucous gland hyperplasia Subepithelial fibrosis Epithelium desquamation Airway wall thickening Increased smooth muscle mass
Where do the airway control drugs target?
Smooth muscle dysfunction (^contraction+^Cytokine)
Beta-2 agonist
- Short-acting BA: Salbutamol
- Long-acting BA: Formoterol
Inflammation(immune cells(T cells/mast cells/eosinophils)
Steroids (CS)
Inhaled CS: Budesonide
Oral CS: Prednisolone `
How is asthma a heterogeneous disease?
Pathologically
- Eosinophilic versus neutrophillic inflammation
Symptom patterns and triggers of exacerbations
Response to treatment
What are the 5 steps to asthma management?
Step 1: Mild intermittent asthma Step 2: Regular preventer therapy Step 3: Add-on therapy Step 4: Persistent poor control Step 5: Continuous or frequent use of oral steroids
Describe step one in terms of asthma therapy.
Mild intermittent asthma
Short-acting beta2-agonists
(Salbutamol, terbutaline)
Used for symptom relief through reversal of bronchoconstriction
Prevention of bronchoconstriction i.e. on exercise
Short-acting B2-agonists should only be used on an as-required basis
If used regularly, they reduce asthma control
What is the mechanism of action of Beta2-agonists?
They act on B2 adrenoceptors in airway smooth muscle
This leads to an increase in cAMP and leads to more PKA which leads to
Relaxation
and
Inhibition of agonist-induced contraction
There are other links and this pathway isn’t well known
What are some different classes of B2-agonists?
Fast onset, short duration: - Inhaled terbutaline - Inhaled salbutamol Fast onset, long duration: - Inhaled formoterol Slow onset, long duration - Inhaled salmeterol - (Oral bambuterol) (not used) Slow onset, slow duration (Not used anymore) - Oral terbutaline - Oral salbutamol - Oral formoterol
What are some side effects of B2-agonist?
Adrenergic
Tachycardia
Palpitations
Tremor
Describe step 2 in terms of asthma therapy.
Regular preventer therapy
Inhaled corticosteroids
Start when:
- Using B2-agonists >3 times/week
- Symptoms >3 times/week
- Waking at least once a week
- Exacerbation requiring oral steroids in last two years
Why are inhaled corticosteroids used in asthma treatment?
They work to reduce inflammation
Improve symptoms
Improve lung function
Reduce exacerbations
Prevent death
How do inhaled steroids get into systemic circulation?
Through absorption from lungs and being swallowed and then gut absorption, and what is left after first pass metabolism
Beclomethasone absorbed through gut and lungs
Budesonide and fluticasone undergo extensive first-pass metabolism
What is the relevance of eosinophilic asthma and non-eosinophilic asthma?
Patients with eosinophilic asthma have a better treatment response to inhaled steroids than non-eosinophilic patients
Describe step 3 in terms of asthma therapy.
Add on therapy
BUT before initiating a new drug therapy
- Re-check patient’s medication compliance
- Check inhaler technique
- Eliminate trigger factors
First choice - long-acting B2-agonists (formoterol, salmeterol)
Add-in LAB2A when patients not controlled on 400mcg/day ICS
What are the advantages to long-acting B2-agonists?
Reduce asthma exacerbations
Improve asthma symptoms
Improve lung function
(Not anti-inflammatory on their own, and must always be prescribed in conjunction with an inhaled steroid)
Name some combined LAB2As and ICSs.
Twice daily: Budesonide/formoterol Beclomethasone/formoterol Fluticasone/formoterol Fluticasone/salmeterol
Once daily:
Fluticasone furoate/vilanterol
What is the rationale for combining LABA and ICS in single inhaler?
Ease of use Compliance 1 versus 2 prescriptions to worry about Potentially cheaper Safety
What are some alternative step 3/4 add-ons?
High dose ICS
Leukotriene receptor antagonists
Theophylline
Tiotropium
How do leukotriene receptor agonists work?
Montelukast, Zafirlukast
LTC4 release by mast cells and eosinophils can induce bronchoconstriction, mucus secretion and mucosal oedema and promote inflammatory cell recruitment
LRAs block the effect of cysteinyl leukotrienes in the airways at the CysLT1 receptor
Some anti-asthma activity but only useful in about 15% patients as add-on therapy
What are some side effects of leukotriene receptor antagonists?
Angioedema Dry mouth Anaphylaxis Arthralgia Fever Gastric disturbances
Rarely a problem in clinical practice
No important drug interactions
What are methylxanthines?
Theophylline aminophylline
Antagonise adenosine receptors
Inhibit phosphodiesterase - increase cAMP - unlikely to be relevant in vivo
AS with LTRAs, often poorly efficacious
Narrow therapeutic window
Frequent side effects - nausea, headache, reflux
Potentially life-threatening toxic complications - arrhythmias, fits
Important drug interactions - levels increased by CYP450 inhibitors
e.g. erythromycin, ciprofloxacin
Tell me about long acting anticholinergics (LAMAs) in airway control treatment.
Tiotropium bromide (SPIRIVA)
Long-acting once daily anti-cholinergic
Licensed for COPD and severe asthma (step4/5)
Reduces exacerbations in both COPD and asthma, small improvements in lung function and symptoms
Side effects:
Dry mouth
Urinary retention
Glaucoma (more of a risk with nebulisation of ipratropium)
Name some LAMAs licensed for COPD only
Aclidinium (twice daily)
Umeclidinium
Glycopyrronium
Name some LABA/LAMA combinations licensed for COPD only.
Tiotropium/Olodaterol
Aclidinium/formoterol (twice daily)
Umeclidinium/vilanterol
Glycopyrronium/indacaterol
