Drugs in Respiration Flashcards
How are the airways innervated?
Parasympathetic nerves arise in the brain stem and travel to the lung via the vagus nerve and synapse at the parasympathetic ganglia (embedded in the airway wall) to give rise to post ganglionic fibres
These short post ganglionic fibres innervate submucosal glands, airway smooth muscle and possibly tracheobronchial vasculature
What do the parasympathetic nerves cause and how?
Bronchoconstriction and mucus secretion via the release of ACh which acts on M3 receptors
What is the purpose of M2 receptors on nerve terminals?
Act via a feedback mechanism to reduce the release of ACh
What would inhibition of M2 receptors cause?
Would enhance ACh release and thus cause bronchoconstriction
What would inhibition of M3 receptors cause?
Would prevent the binding on ACh in turn preventing bronchoconstriction and mucus secretion
The best muscarinic antagonists would be?
Selective for M3 receptors
What is the involvement of sympathetic nerves?
Innervate tracheobronchial blood vessels and glands, but not human airway smooth muscle
β2-adrenoceptors are, however, abundantly expressed on human airway smooth muscle
At a cellular level, how does activation of M3 receptors regulate airway smooth muscle?
ACh acting via M3 receptors increases intracellular calcium
Calcium then interacts with calmodulin to form Ca-Cam complex
This activates myosin light chain kinase (MLCK)
MLCK phosphorylates myosin
This allows it to interact with actin and causes airway muscle contraction
At a cellular level, how does activation of β2-adrenoceptors regulate airway smooth muscle?
Activation stimulates adenylyl cyclase leading to increased cAMP production
cAMP phosphorylates PKA which phosphorylates several proteins
All of which act to reduce intracellular calcium
Lowering of intracellular calcium reduces the activity of MLCK, reduces myosin phosphorylation and causes airway muscle relaxation
What is asthma?
Asthma is airway inflammation caused by hyperresponsiveness to a stimuli (allergen, cold, exercise) which causes bronchoconstriction and increased mucus secretion
It is recurrent but reversible airway obstruction
What is the usual age of onset of asthma vs. COPD?
Childhood vs. middle age
What are the usual triggers/causes of asthma vs. COPD?
Allergens, exercise vs. smoking
What is the degree of airway reversibility in asthma vs. COPD?
Reversible (except status asthmaticus) vs. partially reversible
What is status asthmaticus?
A very severe and potentially fatal form of asthma that may not be reversible
What are the time course of symptoms in asthma vs. COPD?
Episodic vs. gradually progressive
What is the inflammatory cell involved in asthma vs. COPD?
Eosinophils vs. neutrophils
What is COPD?
Characterised by chronic inflammation of the airways, lung tissue and pulmonary blood vessels as a result of exposure to inhaled irritants such as tobacco smoke
At a cellular level, how does smoking cause COPD?
In response to microbial infection or cigarette smoke, lung epithelial cells release factors that activate neutrophils
Inflammatory cells such as neutrophils, CD8+ T-cells, B cells and macrophages accumulate
When activated, these cells initiate an inflammatory cascade which triggers the release of inflammatory mediators such as TNF-α, IFN-γ, MMP-6, MMP-9 and IL’s
These inflammatory mediators sustain the inflammatory process and cause elastin degradation and emphysema
Epithelial cells and macrophages also release transforming growth factor-β (TGFβ), which stimulates fibroblast proliferation resulting in fibrosis in the small airways
What does MMP stand for in the inflammatory mediators MMP-6 and MMP-9?
Matrix-metalloproteinases
What effect does the chronic inflammation in COPD have?
Leads to various structural changes which further perpetuate airflow limitation
What is intrinsic asthma?
A non-seasonal, non-allergic form of asthma
Usually first occurs later in life than allergic asthma
Chronic and persistent rather than episodic
What is the difference between allergic asthma and intrinsic asthma?
In allergic asthma, you have higher levels of circulating IgE Intrinsic asthma is triggered by various non-allergic factors like stress, cold or dry air, smoke, anxiety, viruses or infections
At a cellular level, what happens in the immediate phase of asthma?
Immediate phase (i.e. initial response to allergen) occurs abruptly and is mainly caused by spasm of the bronchial smooth muscle Allergen interaction with mast cell fixed IgE causes release of histamine, leukotriene B4 and prostaglandin All of these are bronchoconstrictors Other inflammatory mediators, interleukins, macrophage inflammatory protein-1α and TNF-α, are also released Various chemotaxins and chemokine attract leukocytes, particularly eosinophils and mononuclear cells, into the area for late phase
At a cellular level, what happens in the late phase of asthma?
May be nocturnal
Progressing inflammatory reaction which initiated during the immediate phase and largely due to the influence of Th2 lymphocytes
The inflammatory cells include activated eosinophils
These release cysteinyl leukotrienes and toxic proteins
The toxic proteins cause damage and loss of epithelium
Other mediators involved include adenosine (acting on the A1 receptor), induced NO and neuropeptides
What are the toxic proteins involved in the late phase of asthma called?
Eosinophil cationic protein
Major basic protein
Eosinophil derived protein
What are bronchodilators?
Relax bronchial smooth muscle
Can be short-acting or long-acting
Include β2-agonists, antimuscarinics, PDE inhibitors
