1. THE NEUROHUMORAL CONTROL OF THE AIRWAYS AND BRONCHODILATOR DRUGS
Dr Stuart M Wilson

2. EFFECTS OF THE AUTONOMIC TRANSMITTERS ON THE AIRWAYS
Parasympathetic division
Innervates bronchial smooth muscle and submucosal glands
Sympathetic division
No innervation of bronchial smooth muscle, but supplies submucosal glands and smooth muscle of blood vessels
Both effects are mediated by M3-muscarinic ACh receptors activated by ACh released from the vagus nerve
Stimulation causes:
bronchial smooth muscle contraction
increased mucus secretion
increased mucociliary clearance mediated by 2-adrenoceptors activated by neuronally released noradrenaline
Stimulation causes:
bronchial smooth muscle relaxation (via 2-adrenoceptors activated by adrenaline released from the adrenal gland)
decreased mucus secretion mediated by 2-adrenoceptors activated by neuronally released noradrenaline

3. are not necessarily noxious Causes of attacks are numerous:
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:
allergens (in atopic individuals)
are not necessarily noxious
normally do not affect non-asthmatic subjects
Causes of attacks are numerous:
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.)

4. difficulty in breathing
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)
Non-asthmatic
Chronic asthmatic
1. increased mass of smooth muscle 1
2. accumulation of interstitial fluid (oedema) 2
3. increased secretion of mucus 3
4. epithelial damage (exposing sensory nerve endings) 4
Airway narrowing by inflammation and bronchoconstriction increase airway resistance decreasing FEV1 and PEFR

5. BRONCHIAL HYPERRESPONSIVENESS IN ASTHMA
Epithelial damage, by exposing sensory nerve endings, contributes to increased sensitivity of the airways to bronchoconstrictor influences (termed bronchial hyperresponsiveness)
Demonstrated in provocation tests with inhaled bronchoconstrictors (spasmogens) such as methacholine (muscarinic ACh receptor agonist) or histamine
Patient with severe asthma
Patient with mild asthma
Fall in FEV1 (%) 20 40 60
Concentration of inhaled bronchoconstrictor (log scale)
Normal subject

6. IMMEDIATE AND DELAYED PHASES OF AN ASTHMA ATTACK
In many individuals, an asthma attack comprises immediate (mainly bronchospasm) and delayed (inflammatory reaction) phases 2 4 6 8
Time (hours)
1.0
1.5
2.0
2.5
3.0
FEV 1
(lires)
Inhalation of grass pollen
Early phase (bronchospasm)
Late phase (inflammation)

7. DEVELOPMENT OF ALLERGIC ASTHMA (1) Clonal expansion and maturation
Initial presentation of an antigen (e.g. dust mite protein or pollen) initiates an adaptive immune response
Induction phase
Antigen presentation
Clonal expansion and maturation
Antigen
IL-2
IL-4
Th1 + + T
CD4
Th0 _
IL-4 B P
APC +
Th2 + B
APC: antigen presenting cell
: major histocompatibilty complex class II
Th: T helper lymphocyte
B: B lymphocyte
P: plasma cell
IL: interleukin B P

8. DEVELOPMENT OF ALLERGIC ASTHMA (2) IgE antibodies (immunoglobulin)
Effector phase
IgE antibodies (immunoglobulin)
IgE
IL-4 B P
IgE receptor (Fc) +
Th2 + B B P
Storage granule
Mast cells in airway tissue (express IgE receptors in response to IL-4 and IL-13 released from Th2 cells)
Eosinophils (differentiate and activate in response to IL-5 released fromTh2 cells)

9. DEVELOPMENT OF ALLERGIC ASTHMA (3)
Subsequent presentation of antigen
Cross links IgE receptors
Stimulates calcium entry into mast cells evoking:
ACTIVATED MAST CELL
Antigen
IgE
IgE Receptor
Ca2+ channel
Storage granule
Ca2+
Spasmogens
Histamine
Leukotrienes
(LTC4, LTD4)
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
Chemotaxins
(LTB4)
release of substances (e.g. LTB4) that attract cells causing inflammation (e.g. eosinophils) into the area

10. DEVELOPMENT OF ALLERGIC ASTHMA (4)
Early phase
Delayed phase
Infiltration
Antigen
Proteins causing epithelial damage
(airway irritation)
IgE
IgE Receptor
Ca2+
Ca2+
Channel
Eosinophils, Th2 cells, and monocytes
Chemotaxins
(e.g. LTB4)
Spasmogens
(LTC4, LTD4)
Spasmogens
Histamine
Leukotrienes
(LTC4, LTD4)
Storage granule
Smooth muscle contraction - bronchoconstriction

11. OVERVIEW OF DRUGS USED IN THE TREATMENT OF ASTHMA
Symptomatic (bronchodilators)
First line
2-Adrenoceptor agonists
Second line
Muscarinic ACh receptor antagonists
Cysteinyl leukotriene receptor antagonists
Xanthines
Prophylactic
(prevent inflammation)
First line
Glucocorticosteroids
Second line
Xanthines
Cromoglycates
Anti-inflammatory (resolve inflammation)
Glucocorticosteroids

12. 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 AC
2-adrenoceptor agonist
Airway smooth
muscle cell +
ATP
cAMP Gs + 2
PKA
Key:
AC – adenylyl cyclase
ATP – adenosine triphosphate
cAMP – cyclic adenosine monophosphate
PKA – protein kinase A
Relaxation

13. 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 usually administered by inhalation via metered dose/dry powder devices (lessens systemic effects) - oral and i.v. administration are also sometimes used
are ‘relievers’ taken as needed
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

14. 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!
The use of selective 2-adrenoceptor agonists reduces potentially harmful stimulation of cardiac 1-adrenoceptors. Non-selective agonists (e.g. isoprenaline) are redundant
The use of non-selective -adrenoceptor antagonists (e.g. propranolol) in asthmatic patients is contraindicated – risk of bronchospasm

15. 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
DRUGS USED IN THE TREATMENT OF ASTHMA Bronchodilators (2)
Molecular mechanism of airway smooth muscle contraction M3
Airway smooth
muscle cell
ACh Gq +
PLC
PIP2
IP3
Key:
PLC – phospholipase C
PIP2 – phosphatidylinositol bisphosphate
IP3 – inositol trisphosphate
Sarcoplasmic reticulum
Contraction
Ca2+
Action of ACh is blocked by muscarinic receptor antagonists

16. 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
Vagus
Smooth muscle
Irritant stimulus
Ipratropium
blocks transmission
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
more effective agents (e.g. tiotropium) with selectivity for M3 muscarinic receptors have recently been introduced

17. Why should tiotropium be superior to ipratropium?
Cholinergic synapse
Ca2+
Ca2+ _
ACh
Prejunctional inhibitory autoreceptor (activation by ACh inhibits further ACh release, non-selective antagonists increase release) M2
ACh M3 M3
Smooth muscle cell

18. X X X 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
LTB4
(chemotaxin)
Infiltration of eosinophils
Stimulation of mast cell
5-lipoxygenase
Arachidonic acid X
LTA4
LTC4 &
LTD4
LTC4 &
LTD4
Zileuton blocks
CysLT receptor antagonists block X X
Mast cell
activation
CysLT receptor activation and bronchoconstriction (early phase)
CysLT receptor activation and bronchoconstriction (delayed phase)

19. 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

20. 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