Autonomic regulation of the airways

Question 1

regulation of airways smooth muscle tone

Answer 1

• Regulated by the autonomic nervous system – contractile signals cause increase in intracellular calcium in smooth muscle, which activates actin-myosin contraction
• Regulated by inflammation

Question 2

ACOS

Answer 2

asthma and COPD overlap syndrome

Question 3

discovery of the autonomic nervous system

Answer 3

• In 1860s, muscarine was shown to mimic the actions of nervous activation and atropine to oppose these actions
• 1905: Langley showed nicotine activated the neuromuscular junction and curare opposed this activation
• 1920s: vagal nerve stimulation slowed the heart and released a transferrable chemical that could slow (frog) hearts

Question 4

autonomic nervous system

Answer 4

• The peripheral autonomic nervous system divides into sympathetic and parasympathetic branches, which typically have opposing effects
• The autonomic nervous system conveys all outputs from the CNS to the body, except for skeletal muscular control
• Two nerves in series, the pre- and post-ganglionic fibres
• The parasympathetic ganglia are near their targets with short post-ganglionic nerves, whereas the sympathetic ganglia are near the spinal cord with longer post-ganglionic fibres

Question 5

parasympathetic bronchoconstriction

Answer 5

• The dominant neurological bronchoconstrictor response is mediated by the parasympathetic nervous system
• 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

excessive bronchoconstriction

Answer 6

• Narrows the airway in asthma and in COPD (and in some other inflammatory airways disorders like bronchiectasis)
• Therefore, 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 7

SAMA (short acting muscarinic antagonist)

Answer 7

• Ipratropium bromine (Atrovent) can be used as inhaled treatment to relax airways in asthma and COPD
• Less widely used since long acting muscarinic antagonists (LAMAs) were developed which are more effective bronchodilators
• Ipratropium is still used in high dose in nebulisers as part of acute management of severe asthma and COPD (though beta agonists are more effective bronchodilators)

Question 8

LAMAs (long acting muscarinic antagonists)

Answer 8

• Have long duration of action (many hours), often given o.d. (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 9

the sympathetic nervous system

Answer 9

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

Question 10

SABAs and LABAs

Answer 10

• 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 11

adverse effects of beta 2 agonists

Answer 11

• 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 12

drug deposition

Answer 12

• 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 13

fundamentals of treatment

Answer 13

• Concordance with therapy is poor
• Inhaler education is key
• Device selection is vital

Question 14

goals of treatment

Answer 14

• Most patients have poor control
• Aim to improve control
• Address important issues for patient (exercise, for example)
• Maximum relief of symptoms for minimum side effects

Question 15

immediate management

Answer 15

• Oxygen up to 60% (CO2 retention not usually a problem)
• Salbutamol neb 5 mg (±ipratropium neb 0.5mg)
• Prednisolone 30-60 mg (±hydrocortisone 200mg iv)
• Magnesium or aminophylline i.v. (bolus/load)