Pharmacology of Airway Control Flashcards
Describe the pathophysiology of asthma
Th2-driven and eosinophilic inflammation leads to;
- Mucosal oedema
- Bronchoconstriction
- Mucus plugging
- Airway remodelling
- Smooth muscle dysfunction
- Bronchial hyperresponsiveness (airway remodelling also contributes to this)
What airway remodelling occurs in asthma?
- Mucous gland hyperplasia
- Subepithelial fibrosis
- Epithelium desquamation
- Airway wall thickening
- Increased smooth muscle mass
In what ways is smooth muscle dysfunction in asthma?
- Increased contraction and mass
- Increased cytokines and chemokines
What part of the asthma pathophysiology do ß2 antagonists act on?
The smooth muscle dysfunction
What part of the asthma pathophysiology do steroids act on?
Inflammation
In what respects is asthma a heterogenous disease?
- Pathologically
- Symptom pattern and triggers of exacerbations
- Response to treatment
What is meant by ‘good’ asthma control?
- Minimal symptoms during day and night
- Minimal need for reliever medication
- No exacerbations
- No limitation of physical activity
- Normal lung function
What constitutes normal lung function in asthma?
FEV1 and/or PEF >80% predicted
What should be aimed for regarding asthma control?
Early control, with stepping up or down as required
What should be considered before initiating a new drug therapy for asthma?
- Check compliance with existing therapies
- Check inhaler technique
- Eliminate trigger factors
What are the steps in asthma management?
- Short acting ß2 agonists as required
- Regular preventer
- a. Initial add on therapies - b. Additional add on therapies
- High dose therapies
- Continuous or frequent use of oral steroids
When should moving up a step on asthma management be considered?
If using three doses a week or more
Give two examples of short acting ß-agonists
- Salbutamol
- Terbutaline
How do short-acting ß2 agonists reduce the symptoms of asthma?
Through reversal of bronchoconstriction
When might short acting ß2-agonists be used preventatively?
On exercise
On what basis should short acting ß2-agonists be used?
Only on an as-required basis
What happens if short-acting ß2-agonists are used regularly?
They reduce asthma control
What is the mechanism of action of short acting ß2 agonists?
- Predominant action is on airway smooth muscle, preventing contracting
- Potentially inhibit mast cell degranulation if only used intermittently
How does regular use of ß2 agonists reduce asthma control?
Causes mast cell degranulation in response to allergens to increase
What are the classes of inhaled ß2 agonists?
- Fast onset, short action
- Fast onset, long action
- Slow onset, long action
Give two examples of fast onset, short action ß2 agonists
- Terbutaline
- Salbutamol
What are fast onset, short duration ß2 agonists used for?
Reliever medication
Give three examples of fast onset, long duration ß2 agonists
- Formoterol (12 hours)
- Olodaterol (24 hours)
- Indacaterol (24 hours)
Give two examples of slow onset, long duration ß2 agonists
- Salmetarol (12 hours)
- Vilanterol (24 hours)
What are the side effects of ß2 agonists?
Adrenergic activity, including tachycardia, palpitations, tremor
What kind of drugs are used in regular preventer therapy in step 2 of asthma management?
Inhaled corticosteroids
When should a regular preventer therapy be started in asthma?
- Using ß2 agonists 3 or more times a week
- Symptoms 3 or more times a week
- Waking 1 or more time a week
- Exacerbations requiring steroids in the last 2 years
What point in the asthma pathogenesis does corticosteroids act?
The initial inflammation
What are the advantages of the use of inhaled corticosteroids in asthma treatment?
- Improve symptoms
- Improve lung function
- Reduce exacerbations
- Prevent death
What is the result of the lipophilic substiuents on the D-ring of inhaled corticosteroids?
- A very high affinity for the GCS receptor
- Increased uptake and dwell time in tissue on local application
- Rapid inactivation by hepatic biotransformation following systemic absorption
How do inhaled drugs reach the systemic circulation?
- The swallowed fraction travels to GI tract and gets absorbed in the gut. It then travels to the liver, where some is inactivated in the ‘first pass’, and some active drug remains which then enters the systemic circulation
- Some is deposited in the lungs, and absorbed from the lungs into the systemic circulation
Give an example of an inhaled corticosteroid which is absorbed through the gut and lungs
Beclomethasone
Give two examples of inhaled corticosteroids that undergo extensive first pass metabolism
- Budesonide
- Fluticasone
Why is it important to consider lung absorption with inhaled corticosteroids?
Because lung absorption is still relavent, and high doses of all inhaled corticosteroids have the potenital to produce systemic side effects
Which patients have a better response to inhaled corticosteroids?
Patients with eosinophilic asthma have a better response than non-eosionophilic patients
What should be done before initiating a new drug therapy in asthma?
- Re-check patients medication compliance
- Check inhaler technique
- Eliminate trigger factors
What is the first choice of add on therapy in stage 3 of asthma management?
Long acting ß2 agonists, e.g. formoterol, salmeterol
When should a long-acting ß2 agonist be added to asthma therapy?
When a patient is not controlled on 400mcg/day inhaled corticosteroids
What is the usual dosage of formorerol?
12μg bd
How long is the onset of action of formoterol?
1-3 minutes
What is the duration of action of formoterol?
12 hours
What are the molecular properties of formoterol?
Moderately lipophilic
What is the usual dosage of salmeterol?
50μg bd
How long is the onset of action of salmeterol?
10-20 mins
What is the duration of action of salmeterol?
12 hours
What are the molecular properties of salmeterol?
Highly lipophilic
What are the advantages of long-acting ß2 agonists?
- Reduce asthma exacerbations
- Improve asthma symptoms
- Improve lung function
What must long-acting ß2 agonists always be prescribed in conjunction with?
An inhaled steroid, as they are not anti-inflammatory on their own
Give five examples of combined inhalers containing both an inhaled corticosteroid and a long-acting ß2 agonist, and how often they should be administered?
- Budesonide/formoterol, twice daily
- Beclomethasone/formoterol, twice daily
- Fluticasone/formoterol, twice daily
- Fluticasone/salmeterol, twice daily
- Fluticasone furoate/vilanterol, once daily
What are the advantages of combining a long acting ß2 agonist and an inhaled corticosteroid in one inhaler?
- Ease of use
- Improved compliance
- 1 versus 2 prescriptions to worry about
- Potentially cheaper than 2 individual inhalers
- Safer
Give 4 examples of alternative drug classes used in step 3/step 4 add ons for the management of asthma
- High dose inhaled corticosteroid
- Leukotriene receptor antagonists
- Methylxanthines
- Long acting anticholinergics
Give two examples of leukotriene receptor antagonists
- Montelukast
- Zafirlukast
How to leukotriene receptor antagonists help with asthma?
LTC4 release by mast cells and eosionophils 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.
How effective are leukotriene receptor antagonists?
They have some anti-asthma activity, but only useful in about 15% of patients as an add on therapy
What are the side effects of leukotriene receptor antagonists?
- Angiodema
- Dry mouth
- Anaphylaxis
- Arthralgia
- Fever
- Gastric disturbances
- Nightmares
Rarely a problem in clinical practice
What are the important drug interactions with leukotriene receptor antagonists?
None
Give two examples of methylxanthines?
- Theophylline
- Aminophylline
What is the mechanism of action of methylxanthines?
- Antagonise adenosine receptors
- Inhibit phosphodiesterase, and increase cAMP
What are the problems with methylxanthines?
- Often poorly efficacious
- Narrow therapeutic window
- Frequent side effects
- Potentially life-threatening toxic complications
- Important drug interactions
What are the side effects of methylxanthines?
- Nausea
- Headache
- Reflux
What are the potentially life threatening toxic complications possible with methylxanthines?
- Arrythmias
- Fits
What are the important drug interactions with methylxanthines?
Levels increased by cytochrome P450 inhibitors, e.g. erythromycin, ciprofloxacin
What long-acting anticholinergic is used in asthma?
Tiotropium bromide
How often is tiotropium bromide given?
Once daily
What is the effect of tiotropium bromide?
- Reduces exacerbations (does the same for COPD)
- Small improvements in lung function and symptoms
What does tiotropium bromide have relatively selectivity for?
M3 muscarinic receptors
What are the side effects of tiotropium bromide?
- Dry mouth
- Urinary retention
- Glaucoma
What medications are used in step 5 of asthma management?
- Oral steroids
- Biological therapies
What dose of oral steroids is given in asthma?
Usually need 10mg o.d. or more for maintenance therapy
Give two examples of biological therapies used in asthma
- Anti-IgE
- Anti-IL5
Give an example of an anti-IgE drug
Omalizumab
What are the criteria for the use of anti-IgE therapy?
Strict criteria, e.g. atopy, IgE within strict range
What are the advantages of anti-IgE therapy?
- Potentially reduces exacerbation rates in patients not controlled on oral steroids
- May allow oral steroid tapering
How do anti-IgE drugs work to treat asthma?
Prevents IgE binding to high affinity IgE receptor
What is the result of anti-IgE medications not being able to bind to IgE already bound to the receptor?
It cannot cross link IgE and activate mast cells
Give two examples of anti-IL5 therapies
- Mepolizumab
- Reslizumab
How do anti-IL5 therapies work in asthma?
They reduce peripheral blood and airway eosionophil numbers
When is anti-IL5 therapy most effective?
- In reducing the rate of severe asthma exacerbations
- If >3 exacerbations/year with blood eos >0.3x109/L in the last year
What should every asthmatic have?
A self management plan, with written instructions on when and how to step-up and step-down treatment
What are the advantages of asthmatic self-management plans?
Leads to better outcomes in terms of day-to-day control, frequency, and severity of exacerbations
When is stepping down recommended?
Once asthma is controleld
Why is stepping down recommended once asthma is controlled?
Because if stepping down does not take place, patients may recieve a higher dose than is necessary
What happens to 10 micron particles when they are deposited via inhaled devices?
They are deposited in the mouth and oropharyx
What happens to 1-5 micron particles when they are delivered by an inhaler device?
They are the most effective, as they settle in small airways
What happens to 0.5 micron particles when they are delivered via inhaler devices?
They are inhaled to alveoli, and exhaled without being deposited in the lungs
What should be done when a patient is unable to use an inhaler device satisfactorily?
An alternative should be found
Who should assess a patients ability to use their inhaler?
A competent healthcare professional
What needs to be done to ensure optimum efficacy when using inhaler devices?
The medication needs to be titrated against clinical response
What is the diagnostic criteria of severe asthma in adults?
- Unable to complete sentences
- Pulse > 110/min
- Respiration >25/min
- Peak flow 33-50% of best/predicted
What features suggest that asthma is life threatening?
- PEF <33%
- sPO2 <92
- PaO2 <8kPa
- PaCO2 >4.5kPa
- Silent chest
- Cyanosis
- Feeble respiratory effort
- Hypotension
- Bradycardia
- Arrythmia
- Exhaustion
- Confusion
- Coma
How should severe acute asthma be treated?
- High flow oxygen
- Nebulised salbutamol
- Oral prednisolone 40mg/day for 10-14 days
- If moderate exacerbation not responding, or acute severe/life threatening, add neulised ipratropium bromide
- Consider IV aminophylline if no improvement, and life threatening features not responding to treatment
What oxygen saturations should be aimed for in the treatment of acute severe asthma?
94-98%
What is ipratropium bromide?
A quaternary anti-cholinergic agent
How does iprotrapium bromide differ to other adrenergic agonists?
- Bronchodilation develops more slowly and less intense
- Response may last up to 6 hours
