Drugs Influencing the Airways Flashcards
what is Poiseuille’s Law?
what does it explain?
Poiseuille’s Law: describes the relationship between airflow, pressure gradient (Barometric pressure vs alveolar pressure) and resistance to airflow (combination of length of airways and radius of airways + viscosity of gas)
Pressure (P) = flow (V.) x resistance (R)
Flow = pressure / resistance
This equation suggests most resistance would be in smallest airways
BUT actually, highest resistance is in large airways (trachea > medium bronchi)
why is there higher resistance in the large airways?
This is due to the bifurcating nature of airways
Despite the radius of individual respiratory bronchioles being small there are a huge number of them → total cross-sectional area of them is much greater than the cross sectional area of the trachea
Diameter of trachea very large, but cross-sectional area is relatively small
where does majority of airway resistance reside?
Majority (80%) of airways resistance resides in upper airways: pharynx, larynx and airways with diameter >2 mm
Smaller airways <2 mm contribute about 20% of airway resistance
what does this graph show?
This graph shows the increases in total cross-sectional area the airway generation number increases.
This graph also shows that there is an inverse relationship between velocity of air and total cross-sectional area.
how is physiological control of airway diameter achieved?
Airways contain smooth muscle - allows radius of airway to be controlled physiologically
Contraction of smooth muscles –> bronchoconstriction
Relaxation of smooth muscles –> bronchodilation
The smooth muscle in the airway controlled by the ANS and also influenced by several other mechanisms
what are the different mechanisms that smooth muscle in the airway are controlled by?
Parasympathetic innervation
No sympathetic innervation
NANC innervation
Mast cells
Mechanical receptors
CO2
what does parasympathetic innervation of the smooth muscle of bronchi result in?
Parasympathetic innervation
Efferent parasympathetic preganglionic fibres run in vagus nerve to ganglia found in walls of airways
They stimulate ACh release from postganglionic fibres - stimulates muscarinic M3 receptors on smooth muscle
This causes contraction of smooth muscle → bronchoconstriction
There is 30% vagal tone to airways at rest
Muscarinic antagonist (atropine) will reduce airways resistance by 30% by antagonising this parasympathetic pathway
Occurs in healthy individual → system influences airway diameter at rest
Cigarette smoke will stimulate this system –> bronchoconstriction
This therefore increases airway resistance
what parts of the smooth muscle do not have sympathetic innervation?
However, β2-adrenoreceptors are found on airway smooth muscle
These are stimulated by circulating adrenaline (released by adrenal medulla)
Binding of adrenaline to this receptor results in smooth muscle relaxation –> bronchodilation
β2-receptor stimulation also inhibits the activity of mast cells found in the area
These mast cells usually release bronchoconstrictors –> Spasmogens e.g. histamine, platelet activating factor, leukotrienes.
β2-receptor stimulation also promotes muco-ciliary escalator activity in the airways
This is an important defensive mechanism for moving foreign particles up out of airways
β2-receptor agonists can therefore be a target for asthma treatment (see later)
what is NANC innervation and what does it innervate?
Non-adrenergic non-cholinergic arm of the ANS
Stimulation of this system results in relaxation of smooth muscle –> bronchodilation (decreases airway resistance)
Transmitters involved: VIP + NO
Another transmitter, substance P → causes bronchoconstriction
may have a role in precipitation of asthma.
what does stimulation of mast cells do?
Mast cells are present in high numbers in the airway walls
They are stimulated by allergens
Stimulation of mast cells result in degranulation
This is where Spasmogens are released from their contents e.g. histamine, platelet activating factor, leukotrienes
They cause bronchoconstriction
They contribute to pathology of asthma
Mast cells also release Chemotaxins which attract eosinophils and neutrophils which release further Spasmogens which have further effect leading to the longer term effects of asthma.
what different mechanical receptors do airways contain?
Airways contain several different types of mechanical receptors:
Stimulation of rapidly adapting receptors (RAR) by foreign bodies or chemical irritants initiates a reflex with afferent and efferent arms in the vagus
These result in contraction of smooth muscle –> bronchoconstriction
Stimulation of slowly adapting pulmonary stretch receptors (PSR) by stretch (e.g. large breath) –> bronchodilation
Found between smooth muscle of trachea and lower airway
Afferent fibres from these PSR are also found in vagus nerve
how does CO2 act on airway smooth muscle?
CO2 Acts directly on airway smooth muscle –> relaxation –> bronchodilation
This is an important mechanism to ensure good ventilation in all parts of lung:
They are important in matching ventilation to perfusion
CO2 will build up in under-ventilated areas of lung → bronchodilation - improves ventilation to these areas
what is the difference in airway resistance at residual volume and TLC?
what are the 2 reasons for this?
At residual volume, airway resistance is very high
At TCL air way resistance is very low
Airway resistance decreases steeply as lung volume increases from RV to TLC
2 reasons for this:
Radial traction
Alveolar interdependence
what is radial traction?
In the lungs the airways are embedded in lung parenchyma (connective tissue)
Parenchyma acts as a splint to hold airways open
During inspiration, lung inflation stretches parenchyma fibres
This causes an increase in radial traction which causes an increase in the diameter of airways, therefore there is a decrease in airway resistance
At rest, this is what stops airway resistance increasing too much at FRC (FRC somewhere between RV and TLC) keeps it low.
what is Alveolar interdependence?
Alveolar interdependence: Neighbouring alveoli share walls –> adjacent alveoli will help keep each other open
Mechanical tethering of the alveoli with the small conducting airways keeps smallest conducting airways (with thicker walls than alveoli) open
During inspiration, each alveolus inflates itself - this pulls on conducting airways keeping them open. It also helps keep other alveoli open as well.
This helps lower airway resistance.
how does COPD affect airway resistance compared to someone w/o it?
Effect of lung volume on airway resistance during normal tidal breathing (from FRC) is very little as lung volume does not increase very much so airway resistance does not change much (moving up and down red line a little bit)
COPD causes a breakdown of the alveoli walls which causes a loss of radial traction and mechanical tethering which help to keep airways open. This causes increase airways resistance
explain pharmacological control of airway diameter in asthma: bronchodilators
Asthma: episodes of bronchoconstriction –> airway diameter decreases –> airway resistance increasing which therefore makes it difficult to breathe
People suffering from asthma have bronchial hyperactivity due to inflammation of airway mucosa –> the mucosa will be infiltrated by inflammatory cells and thickened
Therefore during exacerbations (asthma attack):
Inflammatory cells release mediators (Spasmogens) –> contraction of bronchial smooth muscle –> bronchoconstriction –> increase in airway resistance
Spasmogens also cause an increase in airway secretions which cause narrowing of the lumen causing further increased air way resistance.
what does the pharmacological treatment of asthma target?
Target either:
Bronchoconstrictor component of disease
Or Inflammatory/immune component
what does stimulation of β2-receptors on airway smooth muscle do?
Stimulation of β2-receptors on airway smooth muscle –> bronchodilation
The most prescribed anti-asthma drug are β2-agonists
Agonists (A or NA) binding stimulates these GPCRs via AC/cAMP/PKA pathway:
Ligand binding activates adenylyl cyclase, ↑ [cAMP] inside cell → activates protein kinase A → phosphorylation of proteins controlling intracellular Ca2+ concentration → decrease Ca2+ inside cells allows smooth muscle to relax
β2-receptors also found on inflammatory/immune cells
Therefore, agonists also decrease inflammation by inhibiting action of these cells
what is the most prescribed β2-agonist?
Most prescribed β2-agonist is Salbutamol:
Inhaled using inhaler
short-acting;
Side effects include: tachycardia, tremor and most seriously airway hyper-responsiveness (due to increase in airway sensitivity to noxious stimuli which can lead to tolerance to drug)
name other β2-agonists and their function
Other β2-agonists are Salmeterol/Terbutaline:
slower onset
long-acting –> not for help with relief of acute asthma attack
Terbutaline is only one safe during pregnancy
what are methylxanthines?
mechanism of action?
examples?
Methylxanthines (another group of bronchodilators)
Oral administration
They are PDE (phosphodiesterase) inhibitors
↑ cAMP by inhibiting phosphodiesterase (PDE) →SM relaxation –> bronchodilation
↑ [cAMP] inside cell → activates protein kinase A → phosphorylation of proteins controlling intracellular Ca2+ concentration → ↓ Ca2+ inside cells allows smooth muscle to relax
Also reduce inflammation by inhibiting action of immune/inflammatory cells
Example: Theophylline/aminophylline:
Oral administration
Narrow therapeutic window - doses above this cause serious side effects including headache, restlessness, abdominal symptoms, arrhythmias
therefore clinical use has decreased for use in asthma
what do anti-cholinergic/muscarinic antagonists do?
They block the bronchoconstriction action of ACh (released from postganglionic parasympathetic nerve fibres)
Ipratropium (analogue of atropine):
Inhaled
By using inhalation as a route of administration we can target the specific muscarinic receptors at the right organs.
It is quaternary nitrogen in structure which prevents systemic absorption and therefore decreases systemic side effects than if we were to use atropine (e.g. dry mouth, cough on administration, altered taste).
Ipratropium also used in COPD patients combined with salbutamol
what does pharmacological treatment of airway inflammation in asthma target?
People who have asthma have inflammation in their airways
Pharmacological treatment of inflammation in airways will target the inflammatory processes and immune cells which contribute to inflammation of airways.
