THE NEUROHUMORAL CONTROL OF THE
AIRWAYS AND BRONCHODILATOR DRUGS
Dr Stuart M Wilson
EFFECTS OF THE AUTONOMIC
TRANSMITTERS ON THE AIRWAYS
Parasympathetic division
Innervates bronchial
smooth muscle and
submucosal glands
Stimulation causes:
Sympathetic division
No innervation of bronchial
smooth muscle, but supplies
submucosal glands and smooth
muscle of blood vessels
Stimulation causes:
 bronchial smooth muscle
contraction
 bronchial smooth muscle relaxation (via
2-adrenoceptors activated by adrenaline
released from the adrenal gland)
 increased mucus secretion
 decreased mucus secretion mediated
by 2-adrenoceptors activated by
neuronally released noradrenaline
Both effects are mediated by M3muscarinic ACh receptors activated
by ACh released from the vagus
nerve
 increased mucociliary clearance
mediated by 2-adrenoceptors activated
by neuronally released noradrenaline
Asthma
Affects 5-10% of the population in industrialized countries
Is a recurrent and reversible (in the short
term) obstruction to the airways in
response to substances (or stimuli) that:
 are not necessarily noxious
 normally do not affect non-asthmatic
subjects
Causes of attacks are numerous:
allergens (in atopic individuals)
exercise (cold, dry air)
respiratory infections (e.g. viral)
smoke, dust, environmental pollutants etc.
Acute severe asthma (status asthmaticus) is a medical emergency
and can be fatal (~2000 deaths per annum in the U.K.)
Asthma - intermittent attacks of bronchoconstriction cause:
cough
wheezing
difficulty in breathing
Chronic asthma involves pathological changes to the bronchioles that
result from long standing inflammation (
= inflammatory cells)
1. increased mass of
smooth muscle
2. accumulation of
interstitial fluid
(oedema)
3. increased secretion
of mucus
4. epithelial damage
(exposing sensory
nerve endings)
1
2
2
Non-asthmatic
3
4
Chronic asthmatic
Airway narrowing by inflammation and bronchoconstriction increase
airway resistance decreasing FEV1 and PEFR
BRONCHIAL HYPERRESPONSIVENESS IN ASTHMA
Epithelial damage, by exposing sensory nerve endings, contributes
to increased sensitivity of the airways to bronchoconstrictor
influences (termed bronchial hyperresponsiveness)
Fall in FEV1 (%)
Demonstrated in provocation tests with inhaled bronchoconstrictors
(spasmogens) such as methacholine (muscarinic ACh receptor agonist) or
histamine
Patient with
Patient with
60
mild asthma
severe asthma
40
Normal
subject
20
0
Concentration of inhaled bronchoconstrictor (log scale)
IMMEDIATE AND DELAYED PHASES OF AN ASTHMA
ATTACK
In many individuals, an asthma attack comprises immediate (mainly
bronchospasm) and delayed (inflammatory reaction) phases
3.0
 Inhalation of
grass pollen
FEV1 (lires)
2.5
2.0
1.5
Early phase
(bronchospasm)
Late phase
(inflammation)
1.0
0
2
4
Time (hours)
6
8
DEVELOPMENT OF ALLERGIC ASTHMA (1)
Initial presentation of an antigen (e.g. dust mite protein or pollen) initiates an
adaptive immune response
Induction phase
Antigen presentation
APC
Antigen
Clonal expansion and maturation
IL-2
IL-4
+
+
T
CD4
Th0
Th1
_
IL-4
B
P
B
P
+
Th2
+
B
: major histocompatibilty complex class II
APC: antigen presenting cell
Th: T helper lymphocyte
B: B lymphocyte
P: plasma cell
IL: interleukin
DEVELOPMENT OF ALLERGIC ASTHMA (2)
Effector phase
IgE antibodies
(immunoglobulin)
IgE
IL-4
B
P
B
P
+
Th2
+
IgE
receptor
(Fc)
B
Storage
granule
Eosinophils (differentiate and activate in
response to IL-5 released fromTh2 cells)
Mast cells in airway tissue (express
IgE receptors in response to IL-4
and IL-13 released from Th2 cells)
DEVELOPMENT OF ALLERGIC ASTHMA (3)
Subsequent presentation
of antigen
ACTIVATED MAST CELL
Antigen
Cross links IgE receptors
Stimulates calcium entry
into mast cells evoking:
IgE Receptor
IgE
 release of secretory granules
containing histamine and the
production and release of other
agents (e.g. leukotrienes LTC4
and LTD4) that cause airway
smooth muscle contraction
 release of substances (e.g. LTB4)
that attract cells causing
inflammation (e.g. eosinophils)
into the area
Ca2+
Ca2+ channel
Chemotaxins
(LTB4)
Storage granule
Spasmogens
Histamine
Leukotrienes
(LTC4, LTD4)
DEVELOPMENT OF ALLERGIC ASTHMA (4)
Early phase
Delayed phase
Antigen
Infiltration
IgE Receptor IgE
Ca2+
Ca2+
Channel
Chemotaxins
(e.g. LTB4)
Storage granule
Spasmogens
Histamine
Leukotrienes
(LTC4, LTD4)
Proteins causing
epithelial damage
(airway irritation)
Eosinophils, Th2
cells, and
monocytes
Spasmogens
(LTC4, LTD4)
Smooth muscle contraction - bronchoconstriction
OVERVIEW OF DRUGS USED IN THE TREATMENT OF
ASTHMA
Symptomatic
(bronchodilators)
Prophylactic
(prevent
inflammation)
Anti-inflammatory
(resolve
inflammation)
Glucocorticosteroids
First line
First line
2-Adrenoceptor
agonists
Glucocorticosteroids
Second line
Second line
Muscarinic ACh
receptor antagonists
Xanthines
Cysteinyl leukotriene
receptor antagonists
Xanthines
Cromoglycates
DRUGS USED IN THE TREATMENT OF ASTHMA
Bronchodilators (1)
2-ADRENOCEPTOR AGONISTS - act as physiological antagonists of
all spasmogens
Molecular mechanism of airway smooth muscle relaxation
Airway smooth
muscle cell
AC
2-adrenoceptor
agonist
2
Key:
AC – adenylyl cyclase
ATP – adenosine triphosphate
cAMP – cyclic adenosine
monophosphate
PKA – protein kinase A
+
+
Gs
ATP cAMP
PKA
Relaxation
DRUGS USED IN THE TREATMENT OF ASTHMA
Bronchodilators (1 continued)
2-Adrenoceptor agonists – short acting agents (e.g. salbutamol)

are first line treatment for mild, intermittent, asthma

are ‘relievers’ taken as needed

are usually administered by inhalation
via metered dose/dry powder devices
(lessens systemic effects) - oral and i.v.
administration are also sometimes used

act rapidly (often within 5 minutes) to relax bronchial smooth
muscle - relaxation persists for 4-6 hours

increase mucus clearance and decrease mediator release from
mast cells and neutrophils

have few adverse effects (due to systemic absorption) when
administered by the inhalational route, tremor being the most
common
DRUGS USED IN THE TREATMENT OF ASTHMA
Bronchodilators (1 continued)
2-Adrenoceptor agonists – longer acting agents (e.g. salmeterol)



are not recommended for acute relief of bronchospasm (can
be relatively slow to act)
are useful in noctural asthma
can be used as add-on therapy in asthma inadequately
controlled by other drugs (e.g. glucocorticosteroids)
NOTE!
1. The use of selective 2-adrenoceptor agonists reduces
potentially harmful stimulation of cardiac 1-adrenoceptors.
Non-selective agonists (e.g. isoprenaline) are redundant
2. The use of non-selective -adrenoceptor antagonists (e.g.
propranolol) in asthmatic patients is contraindicated – risk of
bronchospasm
DRUGS USED IN THE TREATMENT OF ASTHMA
Bronchodilators (2)
MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS - act as
pharmacological antagonists of bronchoconstriction caused by
smooth muscle M3 receptor activation in response to ACh
released from parasympathetic fibres
Molecular mechanism of airway smooth muscle contraction
PLC
Airway smooth
muscle cell
Action of ACh is
blocked by muscarinic
receptor antagonists
ACh
M3
+
+
Key:
PLC – phospholipase C
PIP2 – phosphatidylinositol bisphosphate
IP3 – inositol trisphosphate
Gq
PIP2
IP3
Sarcoplasmic reticulum
Ca2+
Contraction
DRUGS USED IN THE TREATMENT OF ASTHMA
Bronchodilators (2 continued)
Non-selective muscarinic ACh receptor antagonists (e.g. ipratropium)
 are delivered by the inhalational route
 have a delayed (>30 min) onset of action
 are second line drugs – used as an
adjunct to 2-adrenoceptor agonists
and glucocorticosteroids

relax bronchospasm caused by
irritant stimuli (irritants initiate a
vagal reflex that liberates ACh)

decrease mucus secretion

have no effect on the late
inflammatory stage
have few adverse effects


Ipratropium
blocks
transmission
Vagus
Irritant
stimulus
Smooth
muscle
more effective agents (e.g. tiotropium) with selectivity for M3
muscarinic receptors have recently been introduced
Why should tiotropium be superior to ipratropium?
Cholinergic synapse Ca2+
Ca2+
ACh
ACh
_
Prejunctional inhibitory
autoreceptor (activation by
ACh inhibits further ACh
release, non-selective
antagonists increase release)
M2
M3
M3
Smooth muscle cell
DRUGS USED IN THE TREATMENT OF ASTHMA
Bronchodilators (3)
CYSTEINYL LEUKOTRIENE (CysLT) RECEPTOR ANTAGONISTS - act as
competitive antagonists at the CysLT receptor. Cysteinyl
leukotrienes (LTC4 and LTD4) released from mast cells and
infiltrating eosinophils cause smooth muscle contraction, mucus
secretion and oedema
Stimulation of
Arachidonic
X mast cell
acid
5-lipoxygenase
Zileuton
blocks
LTB4
(chemotaxin)
LTA4
LTC4 &
LTD4
Mast cell
activation
Infiltration of
eosinophils
X
LTC4 &
LTD4
CysLT receptor
antagonists block
CysLT receptor
activation and
bronchoconstriction
(early phase)
X
CysLT receptor
activation and
bronchoconstriction
(delayed phase)
DRUGS USED IN THE TREATMENT OF ASTHMA
Bronchodilators (3 continued)
CysLT receptor antagonists (e.g. Montelukast & Zafirlukast)

are effective as add on therapy in mild persistent asthma and
in combination with other medications in more severe
conditions

are effective against antigen-induced and exercise-induced
bronchospasm

relax bronchial smooth muscle in response to LTC4 & LTD4,

are delivered by the oral route

are not recommended for relief of acute severe asthma
(bronchodilator activity < salbutamol)

are generally well tolerated
DRUGS USED IN THE TREATMENT OF ASTHMA
Bronchodilators (4)
XANTHINES (e.g. Theophylline and Aminophylline)

are present in coffee, tea and chocolate-containing beverages

have an uncertain molecular mechanism of action - might involve
inhibition of isoforms of phosphodiesterases that inactivate cAMP
and cGMP (second messengers that relax smooth muscle)

combine bronchodilator and anti-inflammatory actions (relax
bronchial smooth muscle, inhibit mediator release from mast
cells, increase mucus clearance)

are second line drugs used in combination with 2-adrenoceptor
agonists and glucocorticosteroids

are delivered by the oral route as sustained release preparations

have several adverse effects at therapeutic concentrations
including: nausea, vomiting abdominal discomfort and headache
– problematic because of numerous drug interactions –
mandates monitoring serum concentrations