Asthma Flashcards
True/false, asthma is an irreversible obstruction to the airways in response to substances (or stimuli)
False, asthma is a reversible obstruction to the airways in response to substances to stimuli and can be relieved by drugs
What are some causes of asthma attacks?
- Allergens (in atopic individuals)
- Exercise (cold, dry air)
- Respiratory infections (eg. viral)
- Smoke, dust, environmental pollutants
Symptoms of asthma attacks
- Tight chest
- wheezing
- difficulty in breathing
- cough
In chronic asthma, which pathological changes to the bronchioles are a result of long standing inflammation?
- Increased mass of smooth muscle (hyperplasia and hypertrophy)
- Accumulation of interstitial fluid (oedema)
- Increased secretion of mucous
- Epithelial damage (exposing sentry nerve endings)
- Sub-epithelial fibrosis
Airway narrowing by inflammation and bronchoconstriction increase airway resistance, what does it decrease?
FEV1 and PEFR
What can be used as a diagnostic test for asthma?
can measure FEV levels and measure PEFR (pre respiratory flow rate)
Which pathological change contributes to hypersensitivity of the airways?
Epithelial damage exposing nerve endings
What are two components of Bronchial Hyper-responsiveness?
- Hypersensitivity
- Hyper-reactivity
What are the two phases of an asthma attack?
- Early phase (bronchospasm and acute inflammation)
- Late phase (bronchospasm and delayed inflammation)
Which type of Th is produced by atopic individuals? and what does it involve?
Th2, the immune response is antibody-mediated and involves IgE as it is due to an allergy to antigens
Which type of Th is produced by non-atopic individuals? and what does it involve?
Th1, the response is cell-mediated, involving IgG and macrophages
What does Th1 proliferation suppress?
Th2 production
What do Th2 cells mature and do with B cells?
Th2 cells mature proliferate and make physical contact with plasma B cells, this results in maturation and proliferation of B cells to plasma cells, and they produce immunoglobulin
Which interleukins do Th2 cells release and allow mast cells to express IgE receptors?
IL-4 and IL-13
Which interleukin is released from Th2 cells that signal for eosinophils to differentiate and activate?
IL-5
What is stimulated upon the cross-linkage of IgE receptors?
Stimulates (i) calcium entry into mast cells (ii) release of Ca2+ from intracellular stores
What does calcium entry into mast cells and release of calcium from intracellular stores invoke?
- The release of secretory granules containing preformed histamine and the production and release of other agents (e.g. leukotrienes LTC4 and LTD4) that cause airway smooth muscle contraction
- release of substances [e.g. LTB4 and platelet-activating factor (PAF) and prostaglandins (PGD2)] that attract cells causing inflammation (e.g. mononuclear cells and eosinophils) into the area
What is the treatment for an acute asthma attack?
SABAs (Beta2 agonists)
When should an individual start controller-preventor therapy?
If they have more than 2 asthma attacks a week
Which drug can be used to treat both acute and prolonged asthma?
Methylxanthines
What do Beta2-adrenoceptor agonists act as?
They act as physiological antagonists of all spasmogens
What are the different classes of Beta2-adrenoceptor agonists?
- Short acting (SABA)
- Long-acting (LABA)
- Ultra long-acting (ultra-LABA)
Examples of SABA
salbutamol aka albuterol, terbutaline
Examples of LABA
salmeterol, formoterol
What should LABA always be co-administered with?
LABAs must always be co-administered with a glucocorticoid
What do Cysteinyl leukotriene (CysLT1) receptor antagonists do?
They act competitively at the CysLT1 receptor. CysLTs (LTC4, LTD4 and LTE4) derived from mast cells and infiltrating inflammatory cells cause smooth muscle contraction, mucus secretion and oedema
How are CysLT1 receptor antagonists administered?
Orally
True/false, Methylxanthines are first line drugs used in combination with beta2-adrenoceptor agonists and glucocorticoids
False, Methylxanthines are second line drugs
How are Methylxanthines administered?
Orally
Why is the inhalational route of glucocorticoid administration favoured in the treatment of mild, or moderate, asthma?
They are preferably delivered by the inhalational route to minimise adverse systemic effects
Glucocorticoid Effects upon Gene Transcription
- Glucocorticoids increase transcription of genes encoding anti-inflammatory proteins and decrease transcription of genes encoding inflammatory proteins. Transcription of genes encoding other proteins is also affected
- Glucocorticoids recruit histone deacetylases (HDACs) to activated genes and switch off gene transcription
- Expression of inflammatory genes is associated with acetylation of histones by histone acetyltransferases (HATs). Acetylation ‘unwinds’ DNA from histones allowing transcription
Clinical uses of glucocorticoids in Asthma?
- Glucocorticoids suppress the inflammatory component of asthma – (1) prevent inflammation and (2) resolve established inflammation
Common adverse effects of glucocorticoids (due to deposition of steroid in the oropharynx) are:
- dysphonia (hoarse and weak voice)
- oropharyngeal candidiasis (thrush)
What are cromones?
They are second line drugs now infrequently used prophylactically in the treatment of allergic asthma (particularly children)
Molecular mechanism of cromones?
They have an uncertain molecular mechanism of action that includes a weak anti-inflammatory effect . A decrease in the sensitivity of irritant receptors associated with sensory C-fibres that trigger exaggerated reflexes and reduction of cytokine release are potential mechanisms
Molecular mechanism of cromones?
They have an uncertain molecular mechanism of action that includes a weak anti-inflammatory effect . A decrease in the sensitivity of irritant receptors associated with sensory C-fibres that trigger exaggerated reflexes and reduction of cytokine release are potential mechanisms
Example of monoclonal antibodies that act against IgE
omalizumab
Example of monoclonal antibodies that are directed at IL-5
mepolizumab
