Autonomic Regulation Of Airways

Question 1

Regulation of airways tone

Answer 1

Airway smooth muscle is regulated, and can thus contract and relax to regulate airway diameter

Clearly important in obstructive lung diseases, e.g. asthma and COPD

Question 2

Autonomic nervous system

Answer 2

2 neurons separated by the autonomic ganglion

Question 3

Ganglion in sympathetic system

Answer 3

In the sympathetic system, the ganglion is within a chain adjacent to the spinal cord

Question 4

Ganglion in parasympathetic system

Answer 4

In the parasympathetic system, the ganglion is within or very close to the effector organ

Question 5

Parasympathetic bronchoconstriction

Answer 5

Vagus nerve neurons terminate in the parasympathetic ganglia in the airway wall
Short post-synaptic nerve fibres reach the muscle and release acetylcholine (ACh), which acts on muscarinic receptors of the M3 subtype on the muscle cells
This stimulates airway smooth muscle constriction

Question 6

What subtype of receptor does ACh act on

Answer 6

Muscarinic receptors of the M3 subtype on muscle cells

Question 7

Asthma and COPD parasympathetic bronchoconstriction

Answer 7

Narrows the airway in asthma and in COPD

Inhibition of the parasympathetic nervous system will be beneficial

Drugs that do this in the airway block the M3 receptor, and are called anti-cholinergics or anti-muscarinics

Question 8

Antimuscarinics

Answer 8

Ipratropium bromide (Atrovent) can be used as inhaled treatment to relax airways in asthma and COPD, but is a short acting antimuscarinic (SAMA)

SAMA less widely used since long acting muscarinic antagonists (LAMAs) were developed

Ipratropium is still used in high dose in nebulisers as part of acute management of severe asthma and COPD

Question 9

LAMAs

Answer 9

Have long duration of action (many hours), often given once daily (tiotropium)

Increase bronchodilatation and relieve breathlessness in asthma and COPD

Seem to reduce acute attacks (exacerbations) as well

Have other benefits, e.g. on parasympathetic regulation of mucus production

Question 10

Sympathetic regulation of lungs

Answer 10

Sympathetic NS Regulates the fight-and-flight response

Nerve fibres release noradrenaline which activates adrenergic receptors, of which there are two main types (alpha/beta)

Nerve fibres in humans mainly innervate the blood vessels, but airway smooth muscle cells have adrenergic receptors (beta)

Activation of beta2 receptors on the airway smooth muscle causes muscle relaxation (by activating adenylate cyclase, raising cyclic AMP)

Question 11

Activation of which receptors causes relaxation of airway smooth muscles

Answer 11

Beta2 receptors

Question 12

What do sympathetic nerve fibres release

Answer 12

Noradrenaline

Question 13

What do parasympathetic nerve fibres release

Answer 13

Acetylcholine

Question 14

SABAs and LABAs

Answer 14

Short-acting (salbutamol) and long-acting (formoterol, salmeterol) beta2 agonists are valuable drugs
Given with steroids in asthma, often without steroids in COPD
Often given with LAMA in COPD
Acute rescue of bronchoconstriction
Prevention of bronchoconstriction
Reduction in rates of exacerbations

Question 15

Adverse effects of beta2-agonists

Answer 15

Raising cAMP may activate Na/K exchange pump driving cellular influx of potassium
Tachycardia (cardiac side effects)
Hyperglycaemia: loss of insulin sensitivity, increased liver glucose release

Question 16

Drug deposition

Answer 16

Particle size is main factor that governs deposition
1-10 µm size generally in the range of respiration

Other factors:
device (e.g. MDI, DPI)
flow rate
underlying disease
regional differences in lung ventilation

Question 17

Immediate management

Answer 17

Oxygen if needed to maintain oxygen saturations 94 – 98%
Salbutamol nebuliser 5 mg
Ipratropium nebuliser 0.5mg
Prednisolone 30-60 mg (±hydrocortisone 200mg iv)
Magnesium or aminophylline i.v. (bolus/load)

Question 18

Bronchoconstriction flow diagram

Answer 18

Vagus nerve —> ACh —> M3 receptors —> Gq activation —> airway smooth muscle contracts

Question 19

Bronchodilation flow diagram

Answer 19

T2-4 sympathetic chain —> Noradrenaline—> beta-2 adrenergic receptors —> Gs activation—> airway smooth muscle relaxes

Question 20

A 23 year old patient is admitted with shortness of breath and a severe wheeze.

Which of these factors will cause bronchodilation?

Answer 20

Adrenaline

Adrenaline causes bronchodilation, by binding to β 2 -receptors in the smooth muscle of the bronchioles and causing their relaxation.

Question 21

Factors associated with Bronchoconstriction

Answer 21

Beta-Blockers
Cold dry air
Histamine release
Parasympathetic stimulation

Question 22

How does the sympathetic nervous system cause bronchodilation

Answer 22

Adrenaline binds to beta-2 receptors that are coupled with Gs proteins
Leads to adenylyl cyclase activation and increased cAMP
Causes a decrease in intracellular calcium leading to bronchodilation

Question 23

How does parasympathetic stimulation cause Bronchoconstriction

Answer 23

ACh binds to M3 receptors coupled to Gq protein
Phospholipase C is activated and catalyses breakdown of the membrane phospholipids into diacylglycerol and inositol triphosphate
IP3 binds to ligand-gated calcium channels causing calcium release and Bronchoconstriction