54.1 Asthma and its Pharmacology Flashcards
What is asthma?
Heterogenous, non-progressive chronic inflammatory respiratory disease
*Various pathobiological mechanisms → different subtypes.
Different onsets, inflammation types, + responses to treatments.
What are asthma attacks?
Asthma attacks → recurrent acute exacerbations of episodic bronchoconstriction + mucus hypersecretion causing reversible airflow obstruction.
*Breathlessness, wheezing, + coughing.
What is type 2 asthma?
Type 2 asthma → type 2 inflammation.
CD4+ Th2 lymphocytes (+ innate lymphocytes) drive IgE production + secrete CKs IL-4/5/10 –recruit→ eosinophils/ basophils/ mast cells into airways.
E.g. early-onset allergic asthma/ late-onset eosinophilic asthma.
What is non-type 2 asthma?
Non-type 2 asthma → inflammation w/out T2 inflammatory markers.
Th1 + Th17, neutrophils, + proinflammatory CKs (e.g. IL-1beta/ IL-6/ TNF-alpha) involved.
E.g. neutrophil asthma
What is the same between non-type 2 and type 2 asthma?
All subtypes: ex/intrinsic factors drive exacerbation + production of bronchoconstrictors by mast cells.
E.g. histamine/ PD2/ LTC/ LTD4/ PAF
How can asthma be assessed?
NICE 2018 guidelines:
*Clinical setting → spirometry results assessing FEV1/FVC used in diagnosis + assessment of bronchodilator reversibility.
*Asthma –obstructive pulmonary disease→ ↑ airflow obstruction.
*↓ FEV1:FVC ratio (<0.7 usually - due to decrease in FEV1)
*Reversibility of airflow obstruction (assessment of bronchodilator response) = ↑ FEV1 >12% + > 200 ml.
What can be used to grade the severity of asthma exacerbations?
*PEFR (peak expiratory flow rate) → maximum flow rate generated during forced exhalation, starting from full inspiration.
*Used to grade severity of exacerbation (along w/ O2 saturation/ HR/ BP/ ABG)
What is the PERF grading for asthma?
- Moderate: PEFR> 50-75% of best (results <2 years ago)or predicted PEFR + no features of severe asthma
- Acute severe: PEFR 33-50% of best or predicted Or any of following: RR > 25/min, HR >11/ min or inability to complete sentences in one breath
- Life-threatening: PEFR <33% of best/predicted OR O2 saturation <92% OR altered consciousness, confusion, exhaustion, cyanosis, poor respiratory effort, cardiac arrhythmia
What is the acute management of someone hospitalised with asthma?
Acute management of someone hospitalised :
*hypoxic: give controlled supplementary O2.
*Treat with SABA
*poor initial response, consider adding other bronchodilators – ipratropium bromide or xanthines
*For all attacks: give corticosteroid prednisolone.
*Adjuvant, acutely in severe asthma attacks: magnesium sulphate: IV, some bronchodilator effect and membrane stabiliser
Why is FEV1 a truer indication of airway obstruction than PERF?
FEV1 is a dynamic measure of flow used that represents a truer indication of airway obstruction than PEFR (since reduced PEFR may be due to muscle weakness that improves maximal effort for exhalation)
How is therapeutic response to antiasthmatic drugs measured?
- FEV1 test
- Review symptoms
What is the diagnostic feature for asthma on a spirometer?
Decreased FEV1
What is the function of relivers?
to treat acute symptoms (shortness of breath/ wheezing/ coughing/ chest tightness) - also for COPD exacerbations
What are the different relievers available?
*SAMAs (Short-acting muscarinic receptor antagonists) → (e.g. ipratropium bromide)
*SABA (Short-acting beta-2 agonists) → (e.g. salbutamol/ terbutaline/ adrenaline)
*Xanthines → (e.g. IV-administered aminophylline or oral theophylline)
What is the mechanism by which beta-2 agonists cause bronchodilation?
Activate beta-2 receptors (GsPCRs)
Increases cAMP, activates PKA, activates MLCP (myosin light chain phosphatase) which dephosphorylates the myosin light chain so it cannot form actin-myosin cross bridges
What is the mechanism by which xanthines cause bronchodilation?
- Competitively inhibit PDE (which usually breaks down cAMP)
- Increased cAMP levels and/or cGMP –> relaxation (via PKA/PKG)
- ALSO block adenosine receptors which usually permit Ca2+ entry for contraction
What is the mechanism by which cholinergic receptor antagonists cause bronchodilation?
Block parasympathetic nerve reflexes that usually cause airways to tighten –> bronchospasm
Via M3 receptors
What are some adverse effects of beta-2 agonists?
- Result from systemic absorption
- Tremor
- Tachycardia
- Cardiac dysrhythmia
- Also - desensitisation when used too much; may lose effect when most needed
What are some adverse effects of cholinergic receptor antagonists?
- Wider inhibition of parasympathetic NS
- Inhibition of secretions - e.g. mouth dryness, reduced gastric acid secretion
- Skin flushing
- Dizziness, nausea
- Tachycardia
What are some adverse effects of xanthines?
- Due to PDE inhibition: nausea, vomiting, headaches, gastric discomfort
- Due to adenosine receptor antagonism: diuresis, epileptic seizures
- Due to both: cardiac arrhythmias
When are relievers sufficient?
For mild asthma, relievers usually sufficient to keep asthma under control + achieve reversibility of airflow obstruction
What are controllers?
Controllers → to slow progression of disease. For individuals w/ poorly control of asthma.
*Regular use of controllers + maintenance therapy targeting underlying inflammation in airways that contributes to pathogenesis
*Over time → prevents asthma attacks + symptoms w/ aim of achieving more adequate long-term control.
What are some controllers?
*Immunomodulatory corticosteroids → (e.g. beclomethasone/ prednisolone)
*LABAs (Long-acting beta-2 agonists) → (e.g. salmeterol)
*Leukotriene receptor antagonists → (e.g. zafirlukast/ montelukast)
Combination of LABAs + immunomodulatory corticosteroids shown to best improve asthma control - why is this?
ICS ↑ gene transcription of beta-2 Rs → helps protect against ↓-reg of Rs in association w/ long-term beta-agonist use.
What is the mechanism of corticosteroids to treat asthma?
- Corticosteroids inhibit the synthesis and action of the enzyme phospholipase A2 which is required for the synthesis of both prostaglandins and leukotrienes.
- They also suppress transcription of many cytokines.
- Thus, the corticosteroids inhibit acute inflammation.
What are some adverse effects of corticosteroids?
- Higher risk of infection
- Mood changes
- Fluid retention, weight gain
- Easy bruising
- Muscle wasting, weakness
- Fat redistribution
- Osteoporosis
- Think CUSHING’S disease; excess corticosteroids
Do bronchodilators affect the underlying disease?
No, they just reduce symptoms
What is COPD?
Progressive, irreversible disease caused by chronic alveolar damage leading to a remodelling of the airways and sustained decreases in gas exchange
What are some triggers for asthma?
Allergens - like pollen
Antigens
Exercise
Cold air
Anxiety
What are the two types of bronchodilators in terms of duration of effect?
Short-acting: stop asthma attack
Long-acting: constant bronchodilation so symptoms of an acute attack are less severe
What happens to mucus in an asthma attack?
Becomes progressively more viscous (due to increasing sympathetic nervous activity)
Overall production increases
What is a cellular change caused by asthma over time?
Airway epithelial desquamation
What is airway epithelial desquamation?
The shedding of airway epithelial cells
What is given as a beta-2 agonist in extreme acute cases?
Adrenaline
What is the difference in duration of asthma vs COPD symptoms?
Asthma: short, acute attacks
COPD: more constant, chronic symptoms
Which drugs are able to treat eosinophilic but not non-eosinophilic asthma?
- Corticosteroids
- Inhibitors of type 2 inflammation
Which other symptom makes bronchoconstriction and the accompanying symptoms worse? How?
Inflammatory oedema
Makes lungs even more stiff and tight –> harder to breathe (worsened dyspnoea)
Which symptoms do asthma and COPD share?
- Cough
- Chest tightness
- Wheezing
- Dyspnea
Why is obstruction worse on exhalatation in asthma?
- Lung scaffolding collapses to become smaller on exhalation than inhalation
- Air is trapped in alveoli - so becomes more difficult to empty them (rather than inhale)
What is COPD caused by?
Often due to exposure to noxious chemicals (e.g. cigarette smoke) → Triggers abnormal inflammation
*More destructive, irreversible pathology compared to asthma.
CD8+ Tcells induce neutrophils + macrophages to produce abundance of proteases → emphysema
Elastase → degrades lung elastin
Inflammatory leukocytes → ↑ destructive oxidants
*COPD affects both airways + lung parenchyma
Asthma → only airways.
What can be used to treat COPD?
Relievers
*Corticosteroid resistance in COPD large problem
