13.1 Pharmacology of asthma & COPD Flashcards
What is chronic asthma?
A common chronic inflammatory condition of the airways, associated with airway hyperresponsiveness and variable airflow obstruction. The most frequent symptoms of asthma are cough, wheeze, chest tightness, and breathlessness
What is acute asthma?
The progressive worsening of asthma symptoms, including breathlessness, wheeze, cough, and chest tightness. An acute exacerbation is marked by a reduction in baseline objective measures of pulmonary function, such as peak expiratory flow rate and FEV1
What are the treatment options for someone with asthma?
- SABA = short-acting beta2 agonist, e.g. salbutamol
- LABA = long-acting beta2 agonist, e.g., formoterol
- LTRA = leukotriene receptor antagonist, e.g., montelukast
- ICS = inhaled corticosteroids, e.g. budesonide
- Oral corticosteroids: e.g., prednisolone
- Biologics: e.g., mepolizumab
- Others: e.g., theophylline, tiotropium (methotrexate, cromoglycate)
Explain the pathophysiology of asthma
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BRONCHOSPASM (immediate phase)
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Reversible airflow obstruction
- Smooth muscle contraction → constriction of airways
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Reversible airflow obstruction
- Why?
- Genetic predisposition: → hyperresponsiveness
- Environmental triggers: allergens, pollution, smoking, drugs
→ IgE, histamine, leukotrienes, cytokines etc (INCREASE)
2. INFLAMATION (late phase)
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Reversible airflow obstruction
- ↑ exudate, mucus, oedema → narrowing of airways
(tumor = swelling)
- Why?
- Inflammatory cells/mediators in wake of immediate phase: • Th cells, eosinophils, IL-5, IL-4, IL-13 etc, etc…
Draw a normal airway (cross-section) vs airway in asthma
Describe these images and how you know?
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LEFT
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Subject no asthma
- Epithelium is intact; there is no thickening of the subbasement membrane, and there is no cellular infiltrate
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Subject no asthma
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RIGHT
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Patient with MILD ASTHMA
- Evidence of goblet-cell hyperplasia in the epithelial-cell lining. The sub-basement membrane is thickened, with collagen deposition in the submucosal area, and there is a cellular infiltrate
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Patient with MILD ASTHMA
Explain the role of IgE in allergic (atopic) asthma
- APC presents allergen to CD4+ T cell
- Leads to the development of Th0 cells
- This gives rise to Th2 cells
- Interactions between Th2 cells and B cells that are important in IgE synthesis. IL-4 and IL-13 (glucocorticoids inhibit these - cytokines) provide the first signal to activate B cells, which switch to the production of the IgE isotype. IgE antibody circulates in the blood, binding to high- (FcεRI) and low- (FcεRII) affinity receptors. After encounters with antigens, bound high-affinity IgE receptors induce the release of preformed and newly generated mediators. Mediators produce various physiological effects, depending on the target organ.
What are the roles of the drugs for asthma?
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Bronchodilators (mostly IMMEDIATE phase)
- β₂ agonists
- Theophylline
- LTRA
- Anti-muscarinics
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Anti-inflammatory (mostly LATE phase)
- Glucocorticoids
- Targeted biologics
Explain the class, pharmacology, physiology and clinical of salbutamol
- CLASS: Short-acting beta₂ agonist (SABA)
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PHARMACOLOGY:
- 1° target: β₂ adrenoceptor (GPCR)
- Activity: Partial agonist
- Selective: β₂ > β₁
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PHYSIOLOGY:
- β₂ present on smooth muscle cells (and mast cells etc…)
- Gs → ↑adenylyl cyclase →↑cAMP →↑PKA → s.m. relaxation
- Bronchodilation, tocolytic, vasodilation (in some vascular beds)
- (↑cAMP →↓degranulation of mast cells)
- Overdosing → ↑heart rate and force of contraction (β₁)
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CLINICAL:
- Airway obstructive disease
- Premature labour
- Performance enhancing
What does activation of Gs do to cardiac and smooth muscle?
- Activation of Gs → ↑cAMP
- Cardiac muscle → ↑rate & ↑force
- Smooth muscle → ↓contraction → RELAXATION (Gi and Gq activation → smooth muscle contraction)
Explain the class, pharmacology, physiology, clinical of budesonide
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CLASS: Inhaled corticosteroid (ICS)
- Synthetic glucocorticoid
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PHARMACOLOGY:
- 1° target: Glucocorticoid receptor
- Activity: agonist
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PHYSIOLOGY:
- ↓ pro-inflammatory mediators
- ↑ anti-inflammatory mediators
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CLINICAL:
- Anti-inflammatory
- Immunosuppressive
Explain the class, pharmacology, physiology, clinical of monteluklast
- CLASS: Leukotriene receptor antagonist (LTRA)
-
PHARMACOLOGY:
- 1° target: CysLT₁ receptor (GPCR)
- Activity: competitive antagonist
- PHYSIOLOGY:
- LTs (e.g., LTC₄, LTD₄, LTE₄) are inflammatory mediators derived from arachidonic acid
- → smooth muscle contraction → vaso- & bronchoconstriction
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CLINICAL:
- Prophylaxis of asthma
Explain the 2 pathways of arachidonic acid & what can target this
Prostaglandins
- Membrane phospholipids
- Arachidonic acid
- (COX inhibitor prevents to prostaglandin G2 e.g. aspirin)
- Prostaglandin G2
- (COX inhibitor prevents to prostaglandin H2 e.g. aspirin)
- Prostaglandin H2 (cause inflammation etc)
Leukotrienes
- Membrane phospholipids
- Arachidonic acid
- (LOX = e.g. 5-LOX inhibitis to LTA4 - leukotrienes)
- Leukotriene A4 (LTA4)
- LTC4
- LTD4
- LTE4 (these causes bronchoconstriction)
Explain COX
COX = cyclo-oxygenase
- Bifunctional enzyme:
- Dioxygenase
- Peroxidase
- e.g. PGH₂ synthase
Explain leukotrienes
Leukotrienes
- LTC₄, LTD₄ & LTE₄ are cysteinyl leukotrienes
- Agonists at CysLT₁ & CysLT₂ receptors (GPCRs)
- Cause:
- Smooth muscle contraction
- Vascular permeability
- Leucocyte activation
What is COPD and explain it
- Disease of smokers
- Impairs normal lung defences → recurrent infections of airways (bronchitis) and alveoli (pneumonia)
- Inflammatory reaction → tissue destruction (emphysema)
- These patients usually have damaged cilia (hence, may not function correctly, wafting mucus as can’t do this leads to recurrent infections)
How can we give relief and prophylaxis to a patient with asthma?
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RELIEF
- Reverse bronchospasm
- Severe attacks
- Reduce mucus secretion
- Suppress airway oedema
Can do this by:
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Bronchodilators
- β₂ agonists (SA)
- Muscarinic antagonists
- Theophylline__
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Duration of action
- Short-acting e.g., salbutamol
- Long-acting • e.g., formoterol
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PROPHYLAXIS
- Prevent bronchospasm
- ↓ chronic inflammation
- ↓ airway remodelling
Can do this by:
-
Bronchodilators
- β₂ agonists (LA)
- Theophylline
- Montelukast
- Glucocorticoids (inhaled/oral)
- Anti-IgE therapies
- Anti-IL-5 therapies
What is the difference between asthma and COPD?
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ASTHMA is a chronic inflammatory condition producing airway obstruction (bronchospasm and inflammation)
- Drug treatment may address
- Symptoms = bronchodilators
- Underlying inflammatory mechanisms = prophylaxis
- Drug treatment may address
-
COPD is a chronic inflammatory condition producing airway obstruction (bronchitis) and alveolar breakdown (emphysema)
- Current treatments are poorly effective
- Smoking prevention essential for long-term public health
Which one is asthma and which one is COPD and label them
