Therapeutics of Obstructive Airway Disease Flashcards
Categories of drugs used to treat airflow obstruction?
Preventors (anti-inflammatory)
Relievers (bronchodilators and used acutely)
Describe importance of taking both medications
Treating acute smooth muscle twitching - bronchospasm - is not enough; the inflammation must also be treated
β2 agonists are relievers
Coritcosteroids are preventors
Patients often told to take blue inhaler when they need but, due to instantaneous relief, they do not take the brown inhaler
How is the problem of not taking corticosteroids being prevented?
Combination inhalers with both β2 agonists and corticosteroids (SMART therapy)
Can also have a longer duration of action
Describe the asthma treatment pyramid
For mild, intermittent and episodic asthma a reliever is give - short-acting β2-agonist (SABA) as needed
In order of increasing severity:
If SABA required > once a day, they also require a preventor - inhaled corticosteroid but cromones (cromoglycate) can also be given, to melt away mast cells
If still not controlled, ADD-ON drugs to ICS are given, like theophylline, a methyxanthine, Anti-IgE, Anti IL-5, LABA/LAMA, LTRA (leukotrience receptor antagonists)
If still uncontrolled, oral steroids (prednisolone is a cortisol analogue) can be given but tend not to be used long-term as bad side effects
Use of steroids in asthma?
Oral steroid (prednisolone) has a low therapeutic ratio and is only used for acute exacerbations - bad side effects like thin skin, fat deposits, etc Inhaled steroid (beclomethasone) has a higher therapeutic ratio and is used for maintenance therapy, as it is a local therapy and minimises systemic exposure
OPTIMISE DELIVERY TO LUNGS used a SPACER
Use of steroids in COPD?
Corticosteroids are used in COPD, to reduce exacerbations, but may cause pneumonia due to local immune suppression
How can prednisolone be integrated into asthma treatment?
Can be given to increase PEFR and then, after a few weeks, can be replaced with beclomethasone which keeps PEFR up at constant value
Benefits of using a spacer device with inhaled corticosteroids?
Spacer can avoid gagging caused by inhalation
Avoids coordination problems with metered dose inhaler
Reduces oropharyngeal and laryngeal side effects
Reduces systemic absorption from swallowed fraction
Acts as a holding chamber for aerosol
Reduces particle size and velocity
Improves lung deposition
Why is particle size important with ICS?
Particles must be small enough to get into lungs, past carina
If over 5 microns, too large
If over 2 microns, still too large but will still treat inflammation in some regions
Below 2 microns - greater distribution of ICS in lungs
Use of cromones in obstructive airway diseases?
Anti-inflammatory drugs used only in ASTHMA, LIKE CROMOGLYCATE
MAST CELL STABILISERS but have a weaker anti-inflammatory effect than steroids
Taken via inhaled route only (4 times a day, compliant with QID dosing) but are not used much due to POOR EFFICACY
Cromoglycate is effective in ATOPIC children
Describe the leukotriene synthesis pathway
Cell membrane phospholipid is converted to arachidonic acid, which is converted to LTA4 using 5-lipooxygenase + FLAP
LTA4 is converted to LTB4 (end of pathway)
LTA4 is converted to LTC4, which converts to LTD4 to LTE4
What are the cysteinyl LTs?
LTC4, LTD4, LTE4
LTD4 is the main pro-inflammatory mediator in asthma as they attract and recruit eosinophils
LTD4 produced by inflammatory cells, like mast cells and eosinophils
Role of leukotrienes in asthma?
LTD4 causes:
Oedema - capillaries leak fluid causing swelling
Contraction and proliferation of airway smooth muscle
Increased mucous secretion but decreased mucous transport
Eosinophil influx - release cationic proteins will cause epithelial cell damage
Sensory nerves (C-fibres) become exposed and thus hyper-sensitivity
Uses of leukotriene receptor antagonists?
Only used in ASTHMA for anti-inflammatory purposes, however less potent anti-inflammatory properties than ICS
Also, effective for EXERISE-INDUCED BRONCHOCONSTRICTION and allergic rhinitis (with anti-histamine)
Example is Montelukast - given via oral route, once daily and has a high therapeutic ratio
It is a 2nd line treatment and is a complimentary non-steroidal anti-inflammatory additive to inhaled steroid
Use of anti-IgEs?
Example is an anti-IgE monoclonal antibody - Omalizumab; inhibits binding to high-affinity IgE receptors and inhibits mediator release from basophils/mast cells
Has no effect on pulmonary function but does reduce exacerbations and steroid sparing
Injected every 24 hrs but is very expensive and so is only used for patients with raised IgE and severe persistent allergic asthma, despite max therapy
Examples of another monoclonal antibodies used for severe refractory asthma?
Anti-IL4 - Dupilumab
Anti-IL5 - Mepoluzimab and Reslizumab
Anti-IL13 - Lebrikizumab
Anti-TH2 cytokines are in development
Use of β2-agonists?
Stimulate bronchial smooth muscle β2 receptors, so increased cAMP
Used in asthma (ICS/LABA combo) and in COPD (ICS/LABA combo or LAMA/LABA combo)
Can be used in SMART therapy as combination inhalers:
Fluticasone/Salmeterol
Budesonide/Formoterol
Beclometasone/Formoterol
High nebulised doses given in acute attacks
Types of β2 agonists?
Short-acting - Salbutamol
Long-acting - Salmeterol, formoterol, indaceterol, vilanterol, oladaterol
Describe β2 agonists and their effects
High therapeutic ratio when given via inhaled route
With LABAs, down-regulation and tachyphylaxis (acute, rapid decrease in response to a drug after its administration)
Systemic β2 effects when given systemically/high inhaled doses (tachycardia, fine tremor by acting on β1 and β2 receptors elsewhere)
Types of muscarinic (cholinergic receptors) and what they do?
M1 receptors - enhance cholinergic reflex
M2 receptors - inhibit acetylcholine release
M3 receptors - mediate bronchoconstriction and mucous secretion
How do anti-cholinergics (muscarinic receptor antagonists) work?
Block post-junctional end plate M3 receptors
Given via inhaled route ONLY and have a high therapeutic ratio
Examples of anti-cholinergics?
Long acting, Tiotropium, Aclidinium, Glycopyrronium, Umeclidinium
Uses of anti-cholinergics?
Used MOSTLY IN COPD - reduce exacerbations, on its own or as LAMA/LABA combo: Glycopyrronium/Indacaterol Aclidinium/Formoterol Umeclidinium/Vilanterol Tiotropium/Olodaterol
Also, used in ASTHMA as triple therapy at step 4, as ADD-ON to ICS/LABA
High nebulised doses of Ipratropium are used in acute COPD and in acute asthma
Uses of methylxanthines?
Used in ASTHMA and COPD and have a low therapeutic ratio (have p450 drug interaction along with erythromycin)
Example, oral Theophylline for maintenance therapy
Used as ADD-ON to inhaled steroid as complimentary non-steroidal anti-inflammatory
IV (Aminophylline) - acute attacks
Are non-selective phosphodiesterase inhibitors, so increase cAMP and are also adenosine antagonists
Uses of PDE4 (phosphodiesterase 4) inhibitors?
Example is Roflumilast (oral tablet)
Anti-inflammatory use in COPD ONLY; have a minimal effect on FEV1
Reduces exacerbations when ADDED-ON to LABA/LAMA
Rarely used but an be used as add-on to LABA/LAMA in frequent exacerbations, instead of ICS
Adverse effects of PDE4 inhibitors?
Nausea
Diarrhoea
Headache
Weight loss
Uses of mucolytics?
Example is oral Carcocisteine and Erdosteine
Reduce sputum viscosity and aid sputum expectoration and reduce exacerbations IN COPD
Rarely used - ONLY AS ADD-ON TO OTHER TREATMENTS
Aims of treatment of chronic asthma?
Abolish symptoms Minimise β2 use Normalise FEV1 Reduce PEF variability Reduce exacerbations Prevent long-term airway remodelling
How can asthma symptoms be reduced?
Avoid triggers
Suppress inflammatory cascade with inhaled corticosteroids +/- non-steroidal anti-inflammatory therapy (like Theophylline, anti-LT, cromoglycate)
Stabilise smooth muscle with LABA/LAMA - only once optimal anti-inflammatory therapy is in place
Treatment of acute asthma?
Oral prednisolone or iv hydrocortisone
Nebulised high dose salbutamol +/- nebulised ipratropium =/- iv aminophylline/magnesium
60% O2
ITU assisted mechanical intibated ventilation is falling PaO2 and rising PaCO2 - never use respiratory stimulant
Stages of COPD progression?
At risk
Symptomatic
Exacerbations
Respiratory failure
Interventions for COPD?
Smoking cessation (does no restore lost FEV1 but subsequent loss rate may return to normal)
Disease management
Pulmonary rehabilitation
Other options
How to monitor COPD progression?
Monitor FEV1
Monitor symptoms
Describe disease in smokers vs non-smokers
FEV1 falls over lifetime, accelerates with age
Non-smokers and non-susceptible smokers lose FEV1 slowly and almost never develop clinically significant airflow obstruction
Susceptible smokers develop airflow obstruction, becoming disabling or even fatal
Treatment of acute COPD?
Nebulised high-dose salbutamol + ipratropium
Oral prednisolone
Antibiotic (amoxycillin/doxycycline) if infection
24-28% O2 against PaO2/PaCO2
Physio to aid sputum expectoration
ITU intubated assisted ventilation only is there is a reversible component, like pneumonia
