Drugs Affecting Airway Structure & Function Flashcards
Give a general description of asthma.
Asthma
- A chronic inflammatory disorder of the airways
- Many cells and cellular elements play a role
- Chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing
- Widespread, variable, and often reversible airflow limitation
What are some Factors that Influence Asthma Development and Expression?
Host factors: - Genetic - atopy - airway hyperresponsiveness (These genes are independant of each other) - Gender (post puberty - more common in females; prepuberty - more common in males) - Obesity
Environmental Factors:
- Indoor allergens & Outdoor allergens
- Occupational sensitizers
- Tobacco smoke
- Air Pollution
- Respiratory Infections
- Diet
What are some cells and mediators involved in asthmatic responses?
- Inflammation occurs in the epithelium.
- Eosinophils release LTs and they are able to diffuse into the airway smooth muscle and act upon this tissue.
What are some pathophysiological responses associated with asthma?
- bronchospasm
- airway mucosal oedema
- mucus plugs in fatal asthma
- airway obstruction
What are some features of mucus plugs in fatal asthma?
- mucus plugging occurs in smaller airways
- the mucus plug occludes around 50% of the lumen which contributes to the narrowing of the airways and obstruction
- more difficult to reverse.
What are some treatment strategies to deal with airway obstruction in asthma?
Airway Smooth Muscle Shortening (narrowing of lumen) - Relievers
- Controllers
- Preventers
Bronchial Wall Oedema (swelling/ encroachment on lumen) & Mucus Hypersecretion (occlusion of lumen)
- Preventers
What is the Anatomical Distribution of Airway Smooth Muscle?
- A single band in the trachea (the cartilage in the trachea prevents it from being fully obstructed by smooth muscle shortening.
- arranged roughly, circumferentially, around the airways
- Beyond the trachea the smooth muscle is irregularly distributed in smaller intraparenchymal bronchi together with cartilage plates which disappear in later generations
- Parenchymal tethering/ Load; the activity of the airway is affected by breathing itself
- Not breathing deeply can cause an increase in airway reactivity
- Airways are not directly innervated by the sympathetic nervous system, instead being innervated by the parasympathetic cholinergic nerves.
Explain the concept of Load and Velocity of Contraction on airway smooth muscle.
Load on ASM is a determinant of how fast and how much shortening occurs
- load decreases during expiration causing - increase in airways resistance - increase likelihood of airways collapse - Velocity of contraction is a determinant of airways resistance during expiration - Unloaded muscle shortens faster - Stretch opposes shortening (consider cough, sigh, yawn and other manoeuvres that increase tidal volume and stretch)
The contractile mechanism involves:
- Increase in intracellular calcium
- Calcium binding to calmodulin
- Activation of myosin light chain kinase
- Myosin light chain phosphorylated - actomyosin ATPase activated
- Cross bridges between actin and myosin break and reform, sliding past each other resulting in overall cell shortening
How is intracellular calcium regulated?
- Regulation of intracellular calcium
↑ free [calcium]- voltage operated calcium channels
- Phospholipase C/ inositol trisphosphate (IP3) release from intracellular stores
↓ free [calcium]
- plasma Ca2+ ATPase - extrusion across plasma membrane - sarcoplasmic reticulum Ca2+ ATPase (SERCA) - uptake into internal stores
Explain dysfunctions in airway smooth muscle.
- ASM does not just constrict and relax, they are the source for some of the cytokines involved in the inflammation process.
- contributes to wall volume in airway remodelling and inflammation as well as contraction
– proliferation
– migration
– secretion of cytokines
– secretion of extracellular matrix proteins - They do this by secreting:
– growth factors e.g. PDGF, FGF, TGF β , VEGF
– cytokines e.g. IL-5, GM-CSF
– chemokines e.g. RANTES, eotaxin, CXCL8
– lipid mediators e.g. PGE2
– extracellular matrix components e.g. collagen - There is a potential for autocrine effects
Explain both short acting and long acting beta2 agonists in the treatment of asthma.
Relievers
Short Acting β2-adrenoceptor Agonists:
Short-acting - salbutamol, terbutaline (SABA)
- mainstay of acute bronchodilator therapy
Key features- short acting agents: rapid (2 - 5 min) onset β2-selective (very important) Adverse effects- tachycardia, tremor, hypokalemia
Other features- variable degrees of efficacy; Tolerance (measurable - may be important)
- Regular use controversial link to morbidity and mortality so now it is only used as required.
- β2-adrenoceptor agonists relax airway smooth muscle
Controllers
Long-acting β2-adrenoceptor agonists:
Salmeterol - slow onset, 12 hrs duration } LABA
Formoterol - rapid onset, 12 hrs duration } LABA
Indacaterol - rapid onset, 24 hrs duration - once-daily
Concern - equivalent to regular short-acting β2-agonists; monotherapy associated with increased morbidity/mortality
Results -
- reduce number of exacerbations - anti-inflammatory - benefit of chronic bronchodilatation - tolerance develops to bronchoprotective effects - indicated for prophylaxis only - Combined with inhaled GCS in single actuator
Explain the role of muscarinic receptor antagonists as preventors of asthmatic responses.
Preventers
Muscarinic Receptor Antagonists
- Prevent manifestations of reflex airway obstruction
- less effective than β2-agonists (in asthma), as or more effective in COPD
- Stimuli:
- irritant receptors - histamine
- c-fibres - tachykinins, bradykinin
- Initiating Responses:
- enhanced by viral infection/epithelial damage
- Efferent responses - cholinergic
- M3 muscarinic receptors on ASM
Ipratropium bromide - non selective (SAMA)
Tiotropium bromide- functionally M3-selective (LAMA) once daily
