Asthma Flashcards
What are the three characteristic pathological features of asthma?
Increased outflow obstruction/airway resistance, causing a wheeze.
Hyper-responsiveness of airways to allergens (i.e. Harmless antigen)
Airway remodelling, notably smooth muscle cell hyperplasia and hypertrophy.
What factors increase airway resistance during an asthma attack?
- mucus hyper-secretion
- epithelial cell shedding
- smooth muscle contraction
- inflammation resulting in oedema
Describe the distribution of sympathetic nervous innervation within the respiratory system.
The sympathetic system ultimately acts to improve airflow within the airways. SNS fibres innervate bronchial blood vessels and glands, however do not innervate bronchial smooth muscle.
However, receptors (B2) are present on airway smooth muscle, which responds to circulating adrenalin. Activation of these receptors reduces histamine release, increase mucocillary clearance and dilates airway smooth muscle.
Describe the distribution and function of the parasympathetic nervous system in the airways.
The PNS fibres innervate the bronchial glands, vasculature and smooth muscle of the airways, ultimately resulting is reduced airflow, increased muscular secretion and vasodilation. This branch of the autonomic nervous system is dominant at rest.
What is the pathophysiological difference between the immediate and late phase response in asthma?
The immediate response is a type I hypersensitivity reaction in which a sensitised individual has IgE cross linking on the surface of mast cells, resulting in degranulation and smooth muscle cell contraction, oedema and mucus secretion.
The late phase response is an example of a type IV hypersensitivity in which initial T-cell sensitisation occurs, with later activation upon exposure to antigen, resulting in cytokinemediates infiltration of lymphocytes, eosinophils and neutrophils. This results in mucus secretion, inflammation and epithelial shedding into mucus.
What is the difference between allergic and non-allergic asthma?
Allergic asthma is generally younger onset asthma in which patients response to allergens such as dust or pet hair, resulting in an IgE mediated allergic reaction in the airways.
Non-allergic asthma is more commonly adult onset and generally results from exposure to non-allergic stimuli, such as cold air, exercise or cigarette smoke.
What is meant by airway hyper-responsiveness?
Airway hyper-responsiveness is one of the three pathological features of asthma, along with outflow obstruction and airway remodelling.
It describes the ‘twitchy’ nature of the airways in which they are excessively responsive to stimuli such as histamine, or to exercise for instance. As a result, compared to normal airways they have a lower threshold to cause bronchoconstriction.
Outline the BTS guidelines for the treatment of asthma.
For mild intermittent asthma - short acting inhaled B2 agonist. (Reliever therapy)
Regular preventer therapy - low dose inhaled steroid
Add-on therapy - Long-acting B2 agonist (LABA), if no response, proceed to increased inhaled steroid dose.
Persistent poor control - increase inhaled steroid dose
Oral therapy - use low dose oral steroid in addition to inhaled steroid
The BTS guideline is designed such that a low dose of corticosteroid can be used throughout therapy, minimising the effects of long term high dose steroid.
Describe the two general classifications of pharmacological asthma treatment.
Reliever therapy - these are generally bronchodilators such as B2 agonists, M3 antagonists and methylxanthines.
Preventer therapy - these are generally anti-inflammatory agents, normally corticosteroids.
Name a short acting and a long acting B2 agonist used in teh treatment of asthma/COPD
SABA - salbutamol, terbutaline, fenoterol
LABA - salmeterol, formeterol
How do B2 agonists work in the treatment of asthma/COPD?
B2 receptors are distributed throughout bronchial smooth muscle, however are only responsive to circulating adrenaline and do not have neural innervation from the SNS. B2 agonists such as fenoterol or terbutaline work by activating these receptors, which work through a Gs system. This increases cAMP and activated PKA.
PKA has a number of role in the muscle cell. It can cause increased potassium efflux, resulting in hyperpolarizaiton; it causes inhibition of MLCK to inhibit muscle contraction; and it can reduce intracellular calcium by inhibiting ER release and by activating Na/Ca antiporters/Ca ATPase. The net result of this is bronchodilation.
They also act to reduce mast cell degranulation and on epithelial cells to increase mucocilary clearance
What are the adverse effects of B2 agonist therapy?
Because B2 receptors are part of the SNS, ADR involved excessive activation of these. Hence, side effects include a tremor (b2 at skeletal muscle), tachycardia (cross reactivity with b1 receptors on heart) and hypokalaemia (due to effect on Na/K active transporters)
How can b2 agonists be administered in the treatment of asthma?
In acute flare-ups salbutamol can be administered through inhalation of a powder of microparticles. It can also be given intravenously in an emergency, however this is associated with a greater risk of hypokalaemia.
The ultimate microparticle size is 1-5 microns, such that they can be widely distributed throughout the lungs.
What is the difference between. Short and long acting beta agonists (SABA vs LABA)?
SABAs can be taken in an acute flare-up of asthma and are the first line treatment in BTS asthma guidelines. They induce bronchodilation in minutes, however are only active for about 5 hours. They have a shorter half life.
LABA can be taken alongside corticosteroid therapy (not alone). They have a longer half life and so can last about 12 hours. Formoterol is long acting and has rapid onset. LABAs are often used for overnight therapy in nocturnal asthma, which is typical of more advanced or poorly controlled asthma, hence thy are step for in BTS guidelines.
Describe the mechanism of action of methyxanthines use in the treatment of asthma, naming two examples.
Examples are theophylline (oral) and aminophylline (IV equivalent).
Methylxanthines work by antagonising the adenosine receptor, present on bronchial smooth muscle which acts through a Gi system, decreasing cAMP. Its blockade resulting in an increase in cAMP and increased activity of PKA in inducing bronchodilation.
