Airway Pharmacology Flashcards
What aspects of acute airway pathology can be treated with drugs?
- contraction of smooth muscle
- excess mucus secretion
- oedema/ swelling
- irritation of sensory neurons (cough)
How can we treat airway smooth muscle contraction?
We can do that through bronchodilators. Some examples would be:
- β-2 adrenergic receptor agonists (these are split into short-acting (eg. salbutamol), long-acting (eg. salmeterol) and ultra long-lasting (eg. indacaterol)
- long-acting muscarinic receptor antagonists (eg. tiotropium)
- phosphodiesterase inhibitors (eg. theophylline)
How do bronchodilators generally act?
Bronchodilator drugs act by binding to a specific receptor or enzyme expressed by the airway smooth muscle cell and inducing an intracellular change which interrupts the contractile process (thereby causing relaxation of the smooth muscle).
By relaxing the muscle, we increase the luminal area, thus decreasing resistance and increasing flow.
How do β-2 adrenergic receptor agonists act?
The activation of β-2 adrenoreceptors increases the activation of Adenylyl Cyclase, an enzyme that catalyses the conversion of ATP to cAMP. The resulting increase in cAMP, in turn, activates Protein Kinase A, which phosphorylates multiple intracellular targets, ultimately decreasing intracellular calcium levels, inducing relaxtion.
How do phosphodiesterase inhibitors act?
Inhibition of phosphodiesterase reduces the breakdown of cAMP to AMP. The resulting increase in cAMP, in turn, activates Protein Kinase A, which phosphorylates multiple intracellular targets, ultimately decreasing calcium levels, inducing relaxation.
How do long-acting muscarinic antagonists act?
Antagonism of the M3 receptor on the airway smooth muscle cells prevents the contractile actions of Acetylcholine, promoting relaxation.
What are some steps in the inflammatory process which could potentially be targeted with drugs to reduce inflammation?
- proliferation of the immune cells
- antibody production
- antibody-crosslinking and degranulation
- inflammatory mediator-receptor binding
- tissue infiltration from the bloodstream (adhesion molecule expression)
- chemotaxis
- cytokine-receptor binding
- cytokine production and release
With leukotriene inhibitors (such as montelukast), what disease is it used against, and what is its mechanism of action?
It is used against asthma.
Leukotriene receptor antagonists block the receptor by which LT mediators produce inflammatory effects on immune cells and tissues.
With biologics (such as omalizumab), what disease is it used against, and what is its mechanism of action?
It is used against asthma.
These drugs are monoclonal antibodies that block or inhibit a specific pro-inflammatory protein (eg. IgE, IL-4, IL-5, IL-13, etc.) involved in the inflammatory cascade.
With mast cell stabilisers (such as sodium cromoglicate), what disease is it used against, and what is its mechanism of action?
It is used against allergies and asthma.
They prevent the degranulation of mast cells (not in asthma) and/or sensory nerve activation.
With PDE4 inhibitors (such as roflumilast), what disease is it used against, and what is its mechanism of action?
They are used against COPD.
They inhibit cAMP metabolism. Intracellular signalling effects then lead to changes in protein expression and neutrophil response (among other cells).
With corticosteroids (such as fluticasone), what disease is it used against, and what is its mechanism of action?
They are used against asthma.
They achieve their anti-inflammatory effect by binding to glucocorticoid receptors present within the cytosol of immune and structural cells (steroids are able to diffuse through cell membranes as they are lipid soluble).
The bound drug-receptor complex then migrates to the nucleus of the cell, where it binds to DNA and modulates transcription.
This has the knock-on effect of changing protein expression. By acting in this way, corticosteroids are able to increase pro-inflammatory mediators and decrease anti-inflammatory mediator expression in a wide variety of cell types, therefore shifting the balance and reducing the overall level of inflammation.
What considerations need to be made when using drugs to treat patients?
- drug efficacy
- adverse effects
- economic costs
Why are drugs used in asthma typically administered by a metered-dose inhaler?
In order to try and reduce the extent and likelihood of adverse effects in respiratory diseases, many drugs are delivered by inhalation via a metered-dose inhaler.
This has the advantage that the drug is applied directly to the target tissue (the airways/lungs) and so the greatest dose will be present at the site of action (and, in theory, the dose reaching the other tissues will be much lower and less likely to produce adverse effects).
List some side effects of salbutamol.
- it acts on the heart, causing tachycardia and palpitations
- it acts on the airway smooth muscle, causing bronchodilation (main effect, not side effect)
- it acts on skeletal muscle, causing tremors and muscle growth
