Pharmacology of Asthma and COPD: bronchodilators Flashcards
In what locations of the respiratory system do asthma, bronchitis and COPD occur?
Asthma & bronchitis are a disease of the larger (>2mm) conducting airways: trachea, bronchi and bronchioles
COPD is a disease of the smaller airways (<2mm): respiratory bronchioles, alveolar ducts and alveolar sacs
Define COPD
COPD is characterised by airflow obstruction that is not fully reversible.
The airflow obstruction does not change markedly over several months and is usually progressive in the long term.
COPD is predominantly caused by smoking
Characteristic features of asthma?
- reversible obstruction (to a degree) of airways
- response to stimuli (temperature & pollution) that are not themselves noxious and do not affect non- asthmatic subjects
- inflammation
- increased broncuial hyper-responsivness to wide variety of stimuli
- bronchoconstriction
- mucus secretion
- oedema due to increased vascular permeability
What is bronchial hyperresonsiveness?
An increased sensitivity to a wide variety of airway narrowing stimuli.
What happens when an asthmatic inhales an antigen?
- House dust mice produce small circular pellets which can be inhaled from the air and respond to a an antigen expressed on the mast cells
- Cross-linking occurs resulting in degranulation of mast cells
- Mediators are released: histamine. prostaglandins, leukotrienes and cytokines e.g. interleukin
Effects of which include
- oedema due to increased vascular permeability in blood vessels
- bronchoconstriction
- increased mucus secretion
- increased cell recruitment e.g. eosionphils and T lymphocytes
- cilia in airways become damaged- can no longer clear out mucus- exposed to sensory nerves underneath- more stimulation of sensory nerves resulting in more bronchoconstriciton
Difference between healthy and asthmatic lungs viewed down a bronchoscope
A bronchoscope allows us to see down into the bifurcations of the airways.
Healthy lung
- wide, clear conducting airways
- lumen full of air allowing for clear access to alveoli
- clear visualisations of the bifurcations
Diseased lungs
- bifurcations are more obscured
- conducting airways are full of mucus
- red, inflamed airway walls
- oedema and vascular leakeage further compressing the airway
Describe the biology of the asthma cell
- damage to epithelial layer exposing sensory nerves underneath
- vascularisation
- vasodilatation
- plasma exudation resulting in oedema
- inflammatory cell infiltration
- mucus plug in airway lumen containing inflammatory cells and plasma exudate
- thickened basement membrane
How can lung function overtime in hospitals?
Can measure there forced expiratory volume in 1 second.
- can extract protein from house dust mice that cause the response and expose it in hospital conditions
- first exposure induces a sharp decrease in FEV1 as a result of histamine release causing airway contraction
- accounted mast cell surface IgE cross reacting with HDM antigen triggering histamine and leukotriene release- AIRWAY SMOOTH MUSCLE CONTRACTION
- recovers within the first hour
- 6 hours later, a secondary spontaenous fall in FEV1
- this is due to an increase in inflammatory cell recruitment (20%)
- in asthma this is predominantly eosinophils
what happens to the basement membrane of asthmatics?
The thickened reticular basement membrane is made up of myofibroblasts secreting collagen.
if the tissue is continously damaged, the tissue tried to repiar itself producing scar tissue- airway wall remodelling
disrupted epithelium, thicken reticular basement membrane, inflammatory cell infiltrate & eosinophils
Difference between asthmatic and healthy cilia?
In healthy lungs, the epithelial layer is covered in cilia and goblet cells. when mucus is secreted from goblet cells, the cilia sweep it up the airway to remove inflammatory cells, foreign material.
in asthma
- epithelium is continously damaged by exposure to allergen
- constant disruption of mucus results in thickening of the mucus triggered by materials secreted from degranulated eosinophils
- dagaed epothelium exposes sensory nerves underneath which respond to temperature,, humidity and irritants in the air
- exposure and stimulation of the nerves triggers mucus secretion and muscle contraction- HYPERRESPONSIVENESS
- constantlyl get degranulation of mast cells resulting in degradation of protective cilia layer
Medicinal plants used in the pharmacological treatment of asthma
- deadly nightshage (atropa belladonna)
- thorn apple (datura stramonium)
active ingrediant- anticholinergic alkaloids atropine, hyoscyamine and scopolamine
What is COPD?
- vast majority of COPD is caused by cigarette smoke- although polution is another culprit
- alveolar macropgaes make up 95% of resident inflammatory cells in the lungs. Normally, there to phagocytose infectious, toxic particles.
- cigarette smoke activates these cells and tries to phagocytose them. once acgivated, they secrete large amounts of cytokines and inflammatory mediators.
- unlike in asthma, IL-8 is secreted which specifically recruits neutrophils
- neutrophils secrete enzymes e.g. neutrophil elastase to degrade bacteria
- in smokers this is overwhelmed and these enzymes are secreted into the lung tissue resulting in lung tissue degradation
- overtime the alveoli structure becomes completely destroyed leading to empysema
- UNLIKE ASTHMA THIS IS DESTRUCTION OF THE PERIPHERAL AIRWAYS NOT THE CONDUCTING AIRWAYS
- outcome for the measurement of COPD in the clinic is the 6 minute walk test
Describe the pathology of COPD
In normal lung parenchyma, alveolar in terminal airways adjacent to pulmonary endothelial cells provide a minimal barrier for air/blood exchange
In chronic bronchitis, in the early stages, significant neutrophil recruiment inflaming the airways and secreting elastases.
in emphysema, continual secretion of proteases causes tissue destruction bringing about emphysema. Can no longer absrob oxygen which is why patients are given supplemental oxygen.
What is the effect of smoking on annual decline in FEV1?
All of us have a decline in lung function with increasing age
• When you smoke, you accelerate this decline in lung function.
- If you stop smoking (shown by the dotted line) the decline in lung function returns to the normal rate of decline
- Whilst stopping smoking can arrest the increased rate of decline, you cannot recover what has been lost as this is due to irreversible peripheral airway destruction
- Eventually this decline in lung function is incompatible with life triggering disability and ultimately premature death!
- All treatments we have for COPD are at best symptomatic, we cannot alter disease outcome
Drug pharmacological treatment of asthma
First step is to induce bronchodilation
BRONCHODILATORS
- Beta 2 adrenergic receptor agonists (short acting and long acting)
- muscarinic antagonists (indirect)
- xanthines (but not used acutely)
ANTI-INFLAMMATORY AGENTS
- glucocorticosteroids (inhaled)
- xanthines
- cromones (sodium cromoglicate, nedocromil sodium)
- leukotriene antagonists
- Anti-IgE
- Anti- IL-5
How do inflammatory mediators such as histamine cause smooth muscle contraction?
- Histamine released from allergen stimulated mast cells stimulate H1- histamine receptors
- H1 receptor activation mobilises calcium from the SR, increasing intracellular concentration of calcium
- Ca2+ binds to calmodulin (CaM)
- The Ca2+ bound CaM activates myosin light chain kinase (MLCK)
- MLCK phosphorylates light chains in the myosin heads and increases activation of myosin ATPase
- Active myosin crossbridges slide along actin filaments creating muscle tension INCREASING MUSCLE CONTRACTION
- histamine signalling also inactivates myosin light chain phosphatase (also increases contraction)
How do beta-2 agonists function as bronchodilators?
1) inhibit calcium release/ increase uptake into the SR
2) inhibits MLCK (via phosphorylation)
3) activates MLCP (disinhibition via phsophorylation of RhoA, phosphorylation MYPT1)
