54.1 Asthma and its Pharmacology Flashcards
(41 cards)
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.
