2. Respiratory System Flashcards
What characterises asthma?
-Reversible airflow obstruction
-Airway inflammation
-Airway hyperresponsiveness
What is obstruction in asthma caused by?
-Smooth muscle contraction
-Inflammation
-Oedema
-Mucous
-Airway structural changes
What are the main symptoms of asthma?
-Wheezing
-Chest tightness
-Dyspnea
-Cough
-Hypoxemia
Describe airway inflammation in asthma
-Eosinophils, mast cells, T-helper 2 (Th2) lymphocytes, and neutrophils infiltrate the airway walls
-Increased vascular permeability leads to swelling of the airway walls, forming oedema
-Goblet cell hyperplasia and submucosal gland hypertrophy lead to excessive mucus production
-Constriction in smooth muscle
Describe airway remodelling in asthma
-Subepithelial fibrosis reduces elasticity
-Epithelial damage may exacerbate hyperresponsiveness
-Smooth muscle hypertrophy and hyperplasia leads to thicker walls
Describe the immediate acute phase of asthma
-Eliciting agent of allergen or non specific stimulus
-Increases activity of mast cells (releasing spasmogens and chemokines/taxins)
-Spasmogens lead to bronchospasm
Describe the late acute phase of asthma
-Infiltration of chemokine/taxins leads to infiltration of cytokine TH2 cells and monocytes AND activation of inflammatory cells such as eosinophils
-Leads to mediators eg CysLTs, neuropeptides, NO, that contribute to airway inflammation and airway hypereactivity
-Also leads to EMBP and ECP release, leading to hyperreactivity
-These contribute to bronchospasm, wheezing and cough
Describe features the chronic phase of asthma
-Persistant inflammation
-Airway remodelling
-Airway hyperresponsiveness
-Obstruction and reduced lung function
Describe β2 adrenoceptor agonists as treatments for asthma
-Cause relaxation of airway smooth muscle by increasing cAMP through Gs physiological antagonists to bronchoconstrictors
-Either short or long acting β2 agonists
-Less systemic effects as most are directly inhaled
Give examples of β2 adrenoceptor agonists used to treat asthma
-Adrenaline: Non-selective ⍺, β1 and β2 effects
-Isoprenaline (isoproterenol): Selective β agonist, leading to bronchodilation and cardiac stimulation
Describe short acting β2 agonists used to treat asthma, and give examples
-Use as needed for acute episodes
-Inhaled, with relief within 5-10 minutes, with max effect within 30 minutes
-Duration lasts 3-5 hours
-eg Salbutamol, terbutaline
Describe longer acting β2 agonists used to treat asthma, and give examples
-Given regularly twice daily, slow onset so not appropriate for an acute episode
-12 hour duration
-Used as an adjunct to corticosteroids
-eg Salmeterol, formoterol
Give routes of administration for β2 agonists used to treat asthma
-Aerosol inhalation - metered-dose inhaler
-Inhalation of nebulised solution
-Inhalation of powder
-Oral (tablet or solution) administration
-Parenteral → IV, SC or IM injection
Give side effects associated with β2 agonists used to treat asthma
-Side effects are minimised with delivery via inhalation, but the following may occur:
-Muscle tremor at high doses
-Tachycardia
-Cardiac dysrhythmias
-Risk of paradoxical bronchospasm
What is SRS-A?
-Slow reacting substance of anaphylaxis
-Comprised of LTC₄ (Leukotriene C₄), LTD₄ (Leukotriene D₄), LTE₄ (Leukotriene E₄)
Describe the production of SRS-A compounds
-Activation of mast cells triggers arachidonic acid release
-5-lipoxygenase metabolizes arachidonic acid into LTC₄, which is then converted to LTD₄ and LTE₄.
Describe the action of SRS-A compounds in asthma
-Potent constrictors of bronchial smooth muscle
-Increase vascular leakage, mucus production
-Chemoattractants for eosinophils/basophils
Describe targets for therapies for asthma targeting SRS-A/Leukotrienes
-Conversion of Arachidonic acid to Leukotrienes: Inhibitors of 5-lipoxygenase
-Binding of leukotrienes to Cys-LT1 receptors: Leukotriene receptor antagonists
Give a 5-lipoxygenase inhibitor
Zileuton
Give some leukotriene receptor antagonists
-Zafirlukast
-Montelukast
Describe some issues with leukotriene modulators
-Weak anti inflammatory effects
-Weak bronchodilator
-Used in mild to moderate asthma: improve basal lung function and symptoms; indicated as
alternative to low dose ICS and/or add-on therapy
What may cause differences in responders vs non responders to leukotriene modulators?
May be due to polymorphisms in 5LOX, LTC4 synthase or CysLT1 receptors
Describe treatment of asthma with antimuscarinics
-Muscarinic (M3) receptor antagonist leads to bronchodilation and reduces mucous secretion
-Used as adjunct therapy to b2 agonists and steroids
-May increase mucociliary clearance through action on cilia of epithelial cell
-Main use in COPD
Describe SAMAs used to treat asthma
-Short acting Muscarinic antagonists
-Primarily used for acute symptom relief during an asthma attack or exacerbation.
-Often used as rescue inhalers.
-Slower onset (30-60 minutes)
-eg Ipratropium bromide
Describe LAMAs used to treat asthma
-Longer acting Muscarinic antagonists
-Primarily used for maintenance treatment of asthma, especially in moderate to severe asthma.
-Long-lasting effects, usually up to 24 hours.
-Slower onset >1 hour
-eg Tiotropium bromide
What are the side effects associated with SAMA and LAMAs for asthma?
Typical anticholinergic side effects
Describe glucocorticoids used to treat asthma
-Inhibit inflammatory response to injury and allergic disease
-Inhibit synthesis of inflammatory mediators, cytokines, cell chemoattractants, vasoactive agents
-Decrease inflammatory cell infiltration and proliferation, vascular permeability and mucus secretion
Describe inhaled corticosteroids used to treat asthma
-Effective in controlling chronic inflammation.
-Help reduce asthma symptoms (wheezing, coughing, shortness of breath).
-Reduces transcription and decreased formation of cytokines
-Preventative measure for exacerbations and hospitalizations.
-Minimal systemic side effects when used properly (low doses, correct inhalation technique).
-May up regulate β2 receptor expression
Give some adverse effects associated with inhaled corticosteroids for asthma
-Oropharyngeal candidiasis may occur, with spacers helping to prevent
-Inhaled corticosteroid show reduced systemic side effects but may still cause adrenal suppression and reduced bone mineral density when taken long term
Give examples of inhaled corticosteroids for asthma
-Beclometasone
-Budesonide
Describe oral corticosteroids used to treat asthma
-Fast-acting for controlling severe inflammation.
-Used in the management of acute asthma exacerbations or when ICS are not adequate
Give some adverse effects associated with oral corticosteroids for asthma
Prolonged corticosteroid therapy causes:
-Suppression of immune response to infection
-Cushing’s syndrome
-Osteoporosis
-Hyperglycaemia
-Muscle wasting
-Inhibition of growth in children
Describe IL5 blockers used in asthma
-Mepolizumab is a monoclonal antibody that binds to IL-5 and prevents it from interacting with its receptor on eosinophils.
