69 - Drugs that Remodel the Airways

Question 1

Drugs not effective for asthma or colds

Answer 1

Antihistamines

Question 2

Asthma definition 
1)
2)
3)
4)

Answer 2

1) Chronic inflammatory disorder of the airways
2) Many cells, cellular elements play a role
3) Chronic inflammation is associated with hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, coughing
4) Widespread, variable and often reversible airflow limitation

Question 3

Inflammation in asthma
1)
2)
3)

Answer 3

1) Inflammation of airway wall
2) Eosinophils present. Release cytotoxins
3) Desquamation

Question 4

What leads to desquamation in asthmatic inflammation

Answer 4

Eosinophils release toxic products that lead to epithelial cell apoptosis

Question 5

Cells recruited by activated mast cells
1)
2)

Answer 5

1) Eosinophils

2) Neutrophils

Question 6

Things affected by mast cells in inflammation 
1)
2)
3)
4)
5)
6)
7)
8)

Answer 6

1) Other cells (eosinophils, neutrophils)
2) Epithelial cells (shedding)
3) Subendothelial fibrosis
4) Sensory nerve activation
5) Blood vessels (oedema, plasma leak, vasodilation, angiogenesis)
6) Mucus secretion, hyperplasia
7) Cholinergic reflex
8) Airway smooth muscle

Question 7

Timeline of mucosal oedema in asthma
1)
2)
3)

Answer 7

1) Normal at 0 minutes
2) Closed at 10 minutes
3) Red, glistening, swollen at 30 minutes. From mucus secretion, oedema, vasodilation

Question 8

What can lead to fatal asthma?

Answer 8

Mucus plugs (can occlude 50% of lumen)

Question 9

Classes of drugs for treating asthma

Answer 9

Relievers, controllers, preventers

Question 10

Things that can lead to airway lumen occlusion
1)
2)
3)

Answer 10

1) Airway smooth muscle contraction
2) Bronchial wall oedema
3) Mucus hypersecretion

Question 11

Asthmatic processes that relievers, controllers and preventers can stop

Answer 11

Airway smooth muscle contraction

Question 12

Asthmatic processes that preventers can stop

Answer 12

Bronchial wall oedema, mucus hypersecretion

Question 13

Shape of airway smooth muscle

Answer 13

Single band around the trachea

Question 14

Why can the trachea resist collapse?

Answer 14

Horse-shoe shape of cartilage. Resists collapse from smooth muscle contraction

Question 15

Distribution of smooth muscle in airways

Answer 15

Irregularly distributed in smaller intraperenchymal bronchi, together with cartilage plates, which disappear in later generations.

Question 16

Effect of preventing deep breathing

Answer 16

Can lead to alveolar contraction.

Deep breathing leads to lower pressure in airways from movement of air. Reducing flow of air leads to increasing air pressure, which smooth muscle contracts against.

Question 17

Airway smooth muscle layout

Answer 17

Arranged roughly circumferentially around the airways in irregularly-distributed bands

Question 18

Determinant of airway resistance during expiration

Answer 18

Velocity of contraction

Question 19

Muscle that shortens faster

Answer 19

Unloaded muscle

Question 20

What opposes muscle shortening?

Answer 20

Stretch

Question 21

Contractile mechanism of airway smooth muscle 
1)
2)
3)
4)
5)

Answer 21

1) Increase in intracellular Ca2+
2) Ca2+ binds calmodulin
3) Calmodulin activates myosin light chain kinase activity
4) Myosin light chain kinase phosphorylates myosin light chain
5) Actomyosin ATPase activated, which allows crossbridge formation

Question 22

Arrangement of actin and myosin in smooth muscle

Answer 22

Irregular

Question 23

Mechanism of Ca2+ release into smooth muscle cells

Answer 23

1) Voltage-operated Ca2+ channel leads to PLC/IP3 activation, which leads to Ca2+ release from intracellular stores. Sarcoplasmic reticulum Ca2+ ATPase (SRCA) pumps pump Ca2+ into SR.

Question 24

Cystenyl-leukotriene potency relative to histamine

Answer 24

300x more potent than histamine

Question 25

Timeframe of cystenyl-leukotriene release compared to histamine

Answer 25

Cys-leukotrienes are released over a longer period than histamine

Question 26

Most important chemical mediator in asthma

Answer 26

Cystenyl-leukotriene (more potent than histamine, released over a longer period)

Question 27

Bronchodilating factors
1)
2)
3)

Answer 27

1) PGE2
2) Adrenaline
3) PGI2

Question 28

Bronchoconstricting factors 
1)
2)
3)
4)

Answer 28

1) ACh
2) HA
3) LTC4
4) LTD4

Question 29

Things that can activate myosin light chain phosphatase

Answer 29

Protein kinase A

Question 30

Things that can prevent myosin light chain phosphatase activity

Answer 30

Rho kinase, protein kinase C

Question 31

Processes that can lead to airway narrowing in asthma
1)
2)
3)

Answer 31

1) Acute inflammation
2) Chronic inflammation
3) Airway remodelling

Question 32

Things, other than contraction, that airway smooth muscle can do
1)
2)
3)
4)

Answer 32

1) Proliferation
2) Migration
3) Secretion of cytokines (can secrete some cytokines at a greater rate than immune cells)
4) Secretion of ECM (leads to airway remodelling)

Question 33

Examples of smooth muscle released factors
1)
2)
3)
4)
5)

Answer 33

1) Growth factors
2) Cytokines (IL-5, GM-CSF)
3) Chemokines (IL-8, eotaxin)
4) Lipid mediators (PGE2)
5) ECM proteins (collagen)

Question 34

Effect of a bronchodilator on an asthmatic FEV1

Answer 34

Should return to normal, very close to normal quickly

Question 35

Ways to measure airway hyperresponsiveness

Answer 35

Challenge with histamine, methacholine.

Amount of chemical that leads to a 20% decrease in FEV1 correlates with severity of asthma.

Question 36

How long does it take to reverse hypersensitivity in an asthmatic?

Answer 36

About 12 months free of allergens

Question 37

Key features of relievers

Answer 37

Short acting agents.  Rapid onset (2-5 minutes).
Beta2 selective (beta2 adR agonists)

Question 38

Side effects of beta2 agonists

Answer 38

Tachycardia, tremor, hyperkalaemia

Question 39

Examples of short-acting beta-adR agonists

Answer 39

Salbutamol, terbutaline.

Question 40

Effect of short-acting beta2 adR over time

Answer 40

Desensitisation (common for GPCR agonists).

If used according to prescribed dose, this shouldn’t be a problem

Question 41

How are beta2-adR agonists administered?

Answer 41

Metered inhalers.

Inhaled into lungs, or ingested, and drug on upper airways washed off with mouthwash

Question 42

Receptor that leads to release of Ca2+ from SR

Answer 42

IP3 receptor

Question 43

Effect of beta-2 adR stimulation on smooth muscle
1)
2)
3)
4) 
5)

Answer 43

1) GPCR leads to adenyl cyclase activation
2) Increasing cAMP activates PKA
3) PKA stimulates SERCA, inhibits IP3R
4) PKA also activates myosin light chain phosphatase, inhibits myosin light chain kinase.
5) Muscle relaxation

Question 44

Effect of ACh on smooth muscle
1)
2)
3)
4)

Answer 44

1) Muscarinic ACh receptor stimulated
2) PLC cleaves PIP2 to IP3
3) IP3 binds IP3R on SR, leads to Ca2+ release from SR
4) Muscle contraction

Question 45

Examples of long-acting beta agonist

Answer 45

Formoterol, salmeterol, indacaterol

Question 46

Examples of controllers

Answer 46

Long-acting beta2 adR agonists

Question 47

How are controllers administered?

Answer 47

Prophylactically

Question 48

Slow onset, long acting beta2 adR agonist

Answer 48

Salmeterol

Question 49

Rapid onset, long acting beta2 adR agonists

Answer 49

Formoterol, indacaterol

Question 50

Duration of salmeterol, formoterol

Answer 50

12 hours (administered twice daily)

Question 51

Duration of indacaterol

Answer 51

24 hours (administered once daily)

Question 52

Worrying association with long-acting beta2 adR use

Answer 52

Monotherapy associated with increased morbidity and mortality.
Tolerance, if beta2 adR always activated by beta2 adR agonists

Question 53

Combination that long-acting beta2 adR agonists are always prescribed in

Answer 53

With inhaled glucocorticoids (LABA and GCS coformulated)

Question 54

Example of a muscarinic antagonist for smooth muscle

Answer 54

Ipatropium bromide (short acting)
Tiotropium bromide (long acting)