L3. Drugs Affecting Airway Structure and Function 1

Question 1

Define Asthma

Answer 1

Asthma is a chronic inflammatory disorder of the airways due to airway hyper-responsiveness. It is characterised by bronchospasms and increased mucous production leading to a decrease/narrowing of the airways.

Question 2

How does atopic asthma develop?

Answer 2

A type 1 hypersensitivity. Which is the increase of IgE and Th2 response in reaction to environmental allergens with acute and late phase reactions.

Question 3

What are the major host and environmental factors in asthma?

Answer 3

Genetic atopy or airway hyper-responsiveness. Age and gender. Environmental: Allergens, occupational sensitisers, tobacco, air pollution, respiratory infections and diet.

Question 4

What are the key features of the inflammation that occurs in asthma?

Answer 4

Eosinophilic response that releases cytokines and toxins that cause apoptosis of the epithelium and degradation of the airway and a loss of fluid. Destruction of the airway increases the access of the allergen to the underlying tissue.
Mast cell activation leads to oedema and vasodilation and mucous secretion in this inflammation narrowing the lumen and causing bronchospasming.

Question 5

What is the anatomical distribution of airway smooth muscle?

Answer 5

Initially in the trachea, there is a single band of smooth muscle. In smaller bronchi, smooth muscle becomes irregularly distributed in a HELICAL fashion where contraction leads to airway narrowing.

Question 6

How are airway smooth muscles controlled?

Answer 6

Parasympathetic, cholinergic control

There is indirect sympathetic innervation via adrenaline on b2 receptors (no nerve, a hormonal supply)

Question 7

How does airway reactivity change?

Answer 7

Normal breathing has normal airway reactivity - no sensation of obstruction. When a person is forced to not breath deeply for a long period of time the airway reactivity INCREASES. The absence of the deep breath forces the perception that the muscles are contracted (sensed obstruction). The deep breaths/stretching of the muscle is important to prevent hypercontractile)

Question 8

Why does airflow resistance through the airways increase on expiration?

Answer 8

The small airways are physically attached to the parenchyma (the alveoli). During inspiration the alveoli are expanded and pull on the airways. Thus resistance is low as the airways are pulled open. During expiration alveoli are relaxed and offer little pull on the airway walls and thus there is a higher resistance to airflow with more likelihood of airway collapse. (The diameter is smaller).

Question 9

Define load and Describe the relationship between the load on airway smooth muscle and the velocity of their contraction

Answer 9

Load is the work that requires to be done by the smooth muscle in order to achieve contraction.
An unloaded muscle contracts faster and more forcefully

Question 10

Describe the load and velocity of contraction through the respiratory cycle. And thus the concept of gas trapping

Answer 10

Load is higher in inspiration because the alveoli pull the airways open and so contraction needs to bigger to close it. In expiration the load decreases thus muscle contraction is faster in expiration.
The respiratory cycle occurs every 2-3 seconds and because in expiration, the load is less and the contraction is faster, there is more difficulty getting air out than in (gas trapping)

Question 11

What are the triggers for airway smooth muscle contraction? What are the triggers for relaxation?

Answer 11

Contraction: Histamine, Cysteinyl leukotrienes (300x more potent than histamine), Ach
Relaxation: Adrenaline, Prostacyclins and PGE2

Question 12

What is the pathway that leads to airway smooth muscle contraction?

Answer 12

The triggers cause the activation of voltage gated Calcium channels which increase the level of calcium. This increases the release of calcium from SR stores by phospholipase C and Inositol triphosphate (IP3).
Calcium binds to calmodulin and activates myosin light chains (phosphorylated) and produces cross bridges and contraction

Question 13

What are the 2 mechanisms for decreasing intracellular calcium after contraction has been achieved?

Answer 13

1. Plasma Ca ATP-ase extrudes the calcium out of the cell. It leaves under the drive/gradient formed by the Na-K-ATPase
2. Sarcoplasmic Reticulum Ca-ATPase (SERCA) uptakes calcium back into the SR

Question 14

How does the calcium concentration affect the smooth muscle?

Answer 14

Increased calcium oscillations leads to the effects of contraction in the cell. The extent to which the calcium concentrations rise and fall and the frequency and amplitude of waves determines the events of myosin light chain activation

Question 15

What are the calcium sensitising pathways in airway smooth muscle contraction?

Answer 15

These pathways make the calcium more effective by inhibiting the deactivation process.
Myosin light chain phosphates usually inhibits myosin light chain activation. The Rho kinase and protein kinase C pathways block the inhibition.

Question 16

What is the role of protein kinase A in airway smooth muscle contraction?

Answer 16

A major regulating system that activates the phosphates and turns the contractile mechanisms off.

Question 17

Apart from relaxation and constriction, what are the major functions of airway smooth muscle?

Answer 17

Contributes to the wall volume in the airway: contributes to airway remodelling and thus inflammation by secretion of factors: GF, Cytokines, Chemokines, Lipid mediators, ECM components like collagen.

Question 18

What are the reliever medications in asthma? What are some examples

Answer 18

These are the short acting beta-2-adrenoreceptor agonists (SABA)
Eg. salburamol, terbualine

Question 19

How to the reliever [SABA] medications work and how quickly?

Answer 19

They start acting rapidly (2-4 minutes) and last for 2-4 hours. They are beta-2 selective (very important in only targeting the airways) and relax smooth muscle by binding a Gs protein that reduces the oscillation of calcium waves.
They activate adenylate cyclase, increase cAMP, activates PKA and activates the inhibitory phosphates.
It also indirectly acts on SERCA by inhibiting the action of IP3 receptors - diminishes the repsonse caused by histamine/muscarine or CysLT.

Question 20

What are the side effects of the SABA drugs?

Answer 20

The side effects are minimised by using the drug locally but can include: tachycardia, tremor, hypokalaemia and tolerance.

Question 21

What are the main controllers of asthma medications and when are they used?
What are some examples?

Answer 21

These are the long acting beta-2-adrenoreceptor agonists (LABA) and the are used prophylatically to produce a background level of bronchial tone.
EXAMPLE: Salmeterol and Formoterol (LABAs) The Indacaterol is a 24 hr duration once daily one

Question 22

How do they act? What are the issues with its use?

Answer 22

They act the same way as the SABAs (act within seconds) and are able to reduce the number of exacerbations (anti-inflammatory effects) by causing chronic vasodilations.
They have the same side effects as SABAs with an induced risk of Tolerance development and thus LABAs are not available as monotherapy. It is combined with low dose glucocorticoids.

Question 23

What are the preventors in asthma? What are some examples?

Answer 23

These are the muscarinic receptor antagonists and they prevent manifestations of any REFLEX airway obstruction. They are stimulated by irritants like histamine and bradykinins, viral infections or epithlial damage.

The Short and Long acting muscarinic antagonists (SAMA and LAMA). These bind to the muscarinic receptors to prevent ACh binding to the M3 receptors (usually activated by irritation).
SAMA: Ipatropium bromide (nonselective)
LAMA: Tiotropium bromide (M3 selective)
These confer less bronchodilation than beta 2 agonists and are used more commonly in COPD than in asthma.