Asthma & pharmacology Flashcards
Discuss asthma vs COPD
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What diseases may COPD describe?
Emphysema (destruction of alveolar walls, producing a small number of large alveoli)
Chronic bronchitis (long-standing inflammation and hence obstruction of the bronchi or bronchioles)
What can asthma attacks be divided into?
- immediate phase (0-3 hours) → bronchospasms manifest
- delayed phase (4-8h) → inflammation
What type of hypersensitivity reaction is asthma?
T1 → triggered by antigen (dust, smoke, pollen)
What happens in asthma following antigen exposure?
- antigen recognised and phagocytosed by resident DC n bronchioles
- present it of MHC molecules (largely MHCII exogenous pathway, but also MHCI va cross-presentation)
- activation of mainly CD4+ Y cells in secondary lymphoid tissue - especially Th2
- activated T cells release cytokines → stimulates inflammatory response
- IL-5 → eosinophil recruitment and activation
- IL-4 and IL-13 → class switching in B cells, changing the antibodies they produce from IgM to allergen-specific IgE
- B cells go to airways and secrete allergen-specific IgE → bind to mast cells & eosinophils, sensitising them for activation upon secondary exposure
In asthma, what happens upon secondary exposure to antigen?
- binding of these immune cell-bound antibodies causes cross-linking to occur → cell degranulation
- release of mediators (e.g. histamine, PGs, leukotrienes) → inflammation → mucus production & bronchoconstriction
Describe non-allergic asthma
Less well understood
- thought to be a more cel-mediated response to self-antigens, characterised by a Th1-skewed immune response
- could be neurally mediated (anxiety can trigger asthma attacks)
Describe acute phase of asthma
- bronchoconstriction & mucosal oedema and mucus hypersecretion
Describe delayed phase of asthma
- mast cell degranulation causes an influx of inflammatory cells - especially Th2, eosinophils
- the inflammation causes endothelial damage → eosinophils release toxic proteins (e.g. eosinophil cationic protein, major basic protein) which damage endothelium → increases hypersensitivity of the bronchioles and irritant receptors and C fibres are more accessible to irritant stimuli → predisposes patient to asthma
- Mucus hypersecretion → caused by PGs, leukotrienes and IL-3 → airway narrowing and traps irritants that could potentially elicit further attacks (occurs due to goblet cells hyperplasia)
- inflammatory exudate enters bronchiolar tissue → oedema → contributes further to airway collapse → trapping of air, reduction in compliance
Chronic effects of asthma
- thickening of bronchiolar walls and fibrosis
- hyperplasia and hypertrophy of the airway SM
- persistant eosinophilia → eosinophils become increasingly fragile (degranulate more quickly) → asthma attacks may get more frequent over time
Discuss eosinophilic asthma and non-eosinophilic asthma
- eosinophilic = high number of eosinophils
- non-eosinophilic = low eosinophils, but my have neutophils, mixed granulocyte inflammatory cells or may be very few inflammatory cells
What drugs can cause asthma/make it worse?
Aspirin - blocks COX and shifts to leukotriene production instead of PG
Beta blockers - blocks B2 → bronchoconstriction
What do eosinophils do in asthma?
- release leukotrienes (inflammatory mediators) and other cytokines
- can release proteases → these can damage the respiratory tract
Mechanism pathway for B2 agonists
- Gs → AC → cAMP → PKA → MLCK phosphorylation → decreased MLCK activity → decreased phosphorylation of myosin regulation light chain → relaxation
Describe B2 agonists
β2 agonists may be short-acting agonists (SABAs) or long-acting (LABAs).
- Salbutamol is a commonly prescribed SABA for acute relief
- LABAs (e.g. salmeterol) are typically used as maintenance treatment, often in combination
with anti-inflammatory treatments.
Describe side effects of beta agonists
facial flushing, tremor, palpitations, peripheral vasodilation, headache,
dry mouth, and anxiety, through action on systemic β receptors
These receptors are also susceptible to desensitisation – the activated βγ subunit of the
Gs-protein binds kinases, which phosphorylate serine and threonine residues of the
receptor, causing it to be blocked by β-arrestin before it is eventually internalised by the
cell
Describe phosphodiesterase inhibitors for asthma w/ examples
e.g. aminophylline or theophylline
Increase levels of cAMP in SM → same effect of B2 agonists
Adverse effects of phosphodiesterase inhibitors
- insomnnia, nervousness
- narrow therapeutic window - if too high can have serious effects → dysrhythmia, seizures
Describe LAMAs
Long acting muscarinic antagonists
example = ipratropium
Gq M3 → blocking SM contraction
Side effects of LAMAs
Few unwanted effects because they’re given by aerosol and is a highly polar
compound, so not well absorbed into the circulation hence generally safe, well-
tolerated
Describe steroids to treat asthma
e. g. beclomethasone
- inhibit phospholipase A2 (enzyme that converts membrane phospholipids to arachidonic acid), thus lowering the production of prostaglandins and leukotrienes
- also immunosuppressive at high doses → reduce production of pro-inflammatory cytokines, bronchorelaxation effects
Adverse effects of steroids
- risk of desensitisation
- immunosuppressive effect means that risk of infection is increased (oropharyngeal candidiasis)
- side effects: mild cushing’s like phenotype → truncal obesity, easy bruising, poor wound healing, muscle wasting, oedema, osteoporosis, moonface, hypertension
Also CNS effects → euphoria, depression, psychosis
Example of anti-leukotrienes
- e.g. zurfirlukast
List all drugs for asthma treatment
Bronchodilators: - B2 agonists - phosphodiesterase inhibitors - muscarinic antagonists Anti-inflammatories: - Steroids -leukotriene receptor antagonists
