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 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

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.)

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

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

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)

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

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)

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

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

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

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

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

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

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

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

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

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)

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