Drugs Used for the Drugs Used for the Management of AsthmaManagement of Asthma

Jason X.-J. Yuan, M.D., Ph.D.Jason X.-J. Yuan, M.D., Ph.D.

Professor of Medicine and Professor of Medicine and PharmacologyPharmacologyUniversity of Illinois at ChicagoUniversity of Illinois at Chicago

Institute for Personalized Respiratory MedicineDepartment of Medicine

(Section of Pulmonary, Critical Care, Sleep and Allergy )Department of Pharmacology

Center for Cardiovascular Research

Katzung BG, Masters SB, Trevor AJKatzung BG, Masters SB, Trevor AJ

Basic & Clinical Basic & Clinical Pharmacology 11ePharmacology 11e

Chapter 20Chapter 20: Drugs Used in Asthma : Drugs Used in Asthma (Homer A. Boushey and Bertram G. Katzung)(Homer A. Boushey and Bertram G. Katzung)

ReferenceReference

Leaning ObjectivesLeaning Objectives

Definition and basic pathology of asthmaDefinition and basic pathology of asthma

Various cell types and mediators in the Various cell types and mediators in the pathogenesis of asthmapathogenesis of asthma

Rationale for the use of Rationale for the use of ββ-agonist-agonist therapy (therapy (bronchodilationbronchodilation) and its side ) and its side effectseffects

Therapeutic actions of Therapeutic actions of cromolyncromolyn ( (inhibiting inhibiting

mast cell degranulationmast cell degranulation), ), corticosteroidscorticosteroids ((anti-inflammationanti-inflammation), and ), and theophyllinetheophylline ((bronchodilation and anti-inflammationbronchodilation and anti-inflammation))

Definition of Asthma Definition of Asthma (What is Asthma?)(What is Asthma?) PhysiologicallyPhysiologically characterized characterized aa)) by by

increased responsiveness of the trachea increased responsiveness of the trachea and bronchi to various stimuli and and bronchi to various stimuli and bb)) by by widespread narrowing of the airwayswidespread narrowing of the airways

PathologicallyPathologically featured by airway featured by airway smooth muscle contraction, mucosal smooth muscle contraction, mucosal thickening from edema and cellular thickening from edema and cellular infiltration, an inspissation in the infiltration, an inspissation in the airway lumen of abnormally thick, viscid airway lumen of abnormally thick, viscid plugs of mucus plugs of mucus

Definition of AsthmaDefinition of Asthma

Asthma is a chronic inflammatory Asthma is a chronic inflammatory disease of the airwaysdisease of the airways

Hyper-responsivenessHyper-responsivenessAirway contraction (bronchospasm)Airway contraction (bronchospasm)InflammationInflammationAirway/bronchial remodeling Airway/bronchial remodeling (thickening)(thickening)

Asthma TherapyAsthma Therapy

Short-term Relievers:Short-term Relievers:BronchodilatorsBronchodilators

– ββ-adrenoceptor agonists (e.g., isoproterenol)-adrenoceptor agonists (e.g., isoproterenol)– Antimuscarinic agents (e.g., theophylline)Antimuscarinic agents (e.g., theophylline)

Long-term Controllers:Long-term Controllers:Anti-inflammatory AgentsAnti-inflammatory Agents

– Inhaled corticosteroidInhaled corticosteroid– Leukotriene antagonistsLeukotriene antagonists– Inhibitors of mast cell degranulation (e.g., Inhibitors of mast cell degranulation (e.g.,

cromolyn or nedocromil)cromolyn or nedocromil)

Schematic Diagram of the Deposition of Inhaled Drugs

Delivery by inhalation results in the greatest local effect on airway smooth muscle with the least systemic toxicity. Aerosol deposition depends on particle size, breathing pattern, airway geometry. Even with particles in the optimal size range of 2-5 μm, 80-90% of the total dose of aerosol is deposited in the mouth or pharynx.

Metered-dose inhaler (MDI)

Pathogenesis of Pathogenesis of AsthmaAsthma((Immunological ModelImmunological Model))1)1) IgE antibodies bound to mast cells in airway IgE antibodies bound to mast cells in airway

mucosa mucosa

2)2) On reexposure to antigens, antigen-On reexposure to antigens, antigen-antibody interaction on the surface of antibody interaction on the surface of master cells triggers release/synthesis of master cells triggers release/synthesis of mediators (e.g., histamine, tryptase, mediators (e.g., histamine, tryptase, leukotrienes, and PGs)leukotrienes, and PGs)

3)3) Mediators (also including cytokines, Mediators (also including cytokines, interleukins) cause bronchial contraction interleukins) cause bronchial contraction (smooth muscle), vascular leakage, cellular (smooth muscle), vascular leakage, cellular infiltration, mucus hyper-secretioninfiltration, mucus hyper-secretion

4)4) Inflammatory responseInflammatory response

Conceptual Model for the Immunopathogenesis of Asthma

1

2

3

4

Allergen causes synthesis of IgE which binds to mast cells;Allergen activates T-cells

On reexposure to allergens, antigen-antibody interactioncauses release of mediators

Bronchoconstriction, vascularleakage, cellular infiltration

Cytokines activate eosinophils/neutrophils releasing ECP/MBPproteases, PAF, and causelate reaction

1

2

3

4

3

HyperresponsivenessHyperresponsiveness

Bronchospasm can be elicited by:Bronchospasm can be elicited by:Allergens (hypersensitivity to)Allergens (hypersensitivity to)Non-antigenic stimuli (e.g., distilled water, Non-antigenic stimuli (e.g., distilled water, exercise, cold air, sulfur dioxide, and rapid exercise, cold air, sulfur dioxide, and rapid ventilation) (“ventilation) (“nonspecific bronchial nonspecific bronchial hyperreactivityhyperreactivity” )” )

Bronchial hyperreactivity is quantitated by Bronchial hyperreactivity is quantitated by measuring the fall in FEVmeasuring the fall in FEV11 (forced expiratory (forced expiratory volume in 1 s) provoked by inhaling volume in 1 s) provoked by inhaling aerosolized histamine or methacholine aerosolized histamine or methacholine (serially increasing concentration)(serially increasing concentration)

Mechanisms of Mechanisms of Bronchial Bronchial HyperreactivityHyperreactivity1)1) Inflammation of airway mucosaInflammation of airway mucosa

2)2) Increased ozone exposure, allergen Increased ozone exposure, allergen inhalation, & viral infection (causing airway inhalation, & viral infection (causing airway inflammation)inflammation)

3)3) Increased inflammatory cells (eosinophils, Increased inflammatory cells (eosinophils, neutrophils, lymphocytes and macrophages) neutrophils, lymphocytes and macrophages) and increased products from these cells and increased products from these cells (causing airway smooth muscle contraction)(causing airway smooth muscle contraction)

4)4) Sensitization of sensory nerves (afferent and Sensitization of sensory nerves (afferent and efferent vagal nerves) in the airwaysefferent vagal nerves) in the airways

5)5) Cellular mechanisms in airway smooth muscle Cellular mechanisms in airway smooth muscle cells and epithelial cellscells and epithelial cells

Asthmatic Asthmatic BronchospasmBronchospasm

Caused byCaused by a combination of: a combination of: Increased release/synthesis of Increased release/synthesis of

contractile mediators (mainly from contractile mediators (mainly from master cells and inflammatory cells) master cells and inflammatory cells)

Enhanced responsiveness of airway Enhanced responsiveness of airway smooth muscle to these mediatorssmooth muscle to these mediators

Afferent and efferent vagal nerves (e.g., Afferent and efferent vagal nerves (e.g., cholinergic motor fibers innervate Mcholinergic motor fibers innervate M33 receptors on the smooth muscle)receptors on the smooth muscle)

Airway smooth muscle cellsAirway smooth muscle cells Airway epithelial cellsAirway epithelial cells

Mechanisms of Inhaled Irritant-mediated Bronchial Constriction

1

CNS Inhaled irritants can cause bronchoconstriction by:

(1) Triggering release of chemical mediators from response cells (e.g., mast cells, eosinophils, neutrophils)

(2) Stimulating afferent receptors to initiate reflex bronchoconstriction (via acetylcholine, ACh) or to release tachykinins (e.g., substance P) that directly stimulate smooth muscle contraction

2

1

ACh

Asthmatic Asthmatic BronchospasmBronchospasmTreated byTreated by drugs that: drugs that: Reduce the amount of IgE bound to mast cells Reduce the amount of IgE bound to mast cells

(anti-IgE antibody)(anti-IgE antibody)

Prevent mast cell degranulation (cromolyn, Prevent mast cell degranulation (cromolyn, ββ--agonists, calcium channel blockers)agonists, calcium channel blockers)

Block the action of released mediators (anti-Block the action of released mediators (anti-histamine, leukotriene receptor blockers)histamine, leukotriene receptor blockers)

Inhibit the effect of acetylcholine (ACh) released Inhibit the effect of acetylcholine (ACh) released from vagal motor nerves (muscarinic from vagal motor nerves (muscarinic antagonists)antagonists)

Directly relax airway smooth muscle Directly relax airway smooth muscle (theophylline, (theophylline, ββ-agonists)-agonists)

Basic Pharmacology of Basic Pharmacology of Agents for Treatment of Agents for Treatment of AsthmaAsthmaThe drugs mostly used for The drugs mostly used for management of asthma are:management of asthma are:

ββ-Adrenoceptor agonists-Adrenoceptor agonists– Used as “short-term relievers” or Used as “short-term relievers” or

bronchodilatorsbronchodilators

Inhaled corticosteroidsInhaled corticosteroids– Used as “long-term controllers” or Used as “long-term controllers” or

anti-inflammatory agentsanti-inflammatory agents

Basic Pharmacology of Basic Pharmacology of Agents for Treatment of Agents for Treatment of AsthmaAsthmaSymathomimetic Agents (Symathomimetic Agents (ββ-adrenoceptor agonists)-adrenoceptor agonists)Epinephrine, isoproterenol, salmeterol, formoterolEpinephrine, isoproterenol, salmeterol, formoterol

CorticosteroidsCorticosteroidsBeclomethasone, flunisolide, fluticasone, triamcinoloneBeclomethasone, flunisolide, fluticasone, triamcinolone

Methylxanthine DrugsMethylxanthine DrugsTheophylline, theobromine, caffeineTheophylline, theobromine, caffeine

Antimuscarinic AgentsAntimuscarinic AgentsIpratropium, atropineIpratropium, atropine

Cromolyn and Nedocromil Cromolyn and Nedocromil (inhibitors of mast cell degranulation)(inhibitors of mast cell degranulation)

Leukotriene InhibitorsLeukotriene InhibitorsZileuton, montelukast, zafirlukastZileuton, montelukast, zafirlukast

Other Drugs in the Treatment of Asthma:Other Drugs in the Treatment of Asthma:Anti-IgE monoclonal antibodies (omalizumab), calcium channel blockers Anti-IgE monoclonal antibodies (omalizumab), calcium channel blockers (nifedipine, verapamil), Nitric oxide donors (sodium nitroprusside) (nifedipine, verapamil), Nitric oxide donors (sodium nitroprusside)

Basic PharmacologyBasic Pharmacology((Sympathomimetic Sympathomimetic AgentsAgents)) Adrenergic Receptors Adrenergic Receptors

(adrenoceptors): (adrenoceptors): – αα-receptors (-receptors (αα1, 1, αα2)2)

– ββ-receptors-receptors ββ1, heart muscle (causing increased heart 1, heart muscle (causing increased heart

rate/contractility); kidney (causing renin rate/contractility); kidney (causing renin release)release)

ββ2, 2, airway smooth muscle (causing airway smooth muscle (causing bronchodilation)bronchodilation); GI smooth muscle, cardiac ; GI smooth muscle, cardiac muscle, skeletal muscle, vascular smooth muscle, skeletal muscle, vascular smooth muscle muscle

ββ3, adipose tissue (causing lipolysis, 3, adipose tissue (causing lipolysis, increasing fatty acids in the blood)increasing fatty acids in the blood)

Bronchodilation is Promoted by Increased cAMP

Bronchodilation

Bronchoconstriction

cAMP

Theophylline

Theophylline

Muscarinicantagonists

β-agonists

Acetylcholine Adenosine

Bronchial tone

+

_

Activate or increase

Inhibit ordecrease

AC, adenylyl cyclase

Basic PharmacologyBasic Pharmacology((Sympathomimetic Sympathomimetic AgentsAgents)) Mechanisms of ActionMechanisms of Action

– Activation of Activation of ββ-adrenergic receptor-adrenergic receptor ββ1 and 1 and ββ2 receptors 2 receptors G protein-coupled receptorG protein-coupled receptor

– Stimulation of adenylyl cyclase (AC)Stimulation of adenylyl cyclase (AC) Ten known ACs (AC1-AC10)Ten known ACs (AC1-AC10) AC1, AC3 and AC8 are activated by CaAC1, AC3 and AC8 are activated by Ca2+2+/CaM/CaM AC5 and AC6 are inhibited by CaAC5 and AC6 are inhibited by Ca2+2+/CaM/CaM

– Increase in the formation of cAMPIncrease in the formation of cAMP

– Relaxation of airway smooth muscleRelaxation of airway smooth muscle

Molecular Action of β2-agonists to Induce Airway Smooth Muscle Relaxation

Basic PharmacologyBasic Pharmacology((Sympathomimetic Sympathomimetic AgentsAgents)) ““Non-selective” Non-selective” ββ-Adrenoceptor -Adrenoceptor

Agonists (Agonists (ββ11 and and ββ22) )

– EpinephrineEpinephrine Injected subcutaneously or inhaled as a Injected subcutaneously or inhaled as a

microaerosol, rapid action (15 min)microaerosol, rapid action (15 min) Ingredient in non-prescription inhalantsIngredient in non-prescription inhalants

– EphedrineEphedrine Oral intake, long-lasting action, obvious Oral intake, long-lasting action, obvious

central effects (used less frequently now) central effects (used less frequently now)

– IsoproterenolIsoproterenol Inhaled as a microaerosol, rapid action (5 Inhaled as a microaerosol, rapid action (5

min) min)

Basic PharmacologyBasic Pharmacology((Sympathomimetic Sympathomimetic AgentsAgents)) Selective Selective ββ22-Adrenoceptor Agonists -Adrenoceptor Agonists

(most widely used (most widely used ββ-agonists for the treatment of -agonists for the treatment of asthma)asthma)

– Terbutaline, Metaproterenol, Albuterol, Terbutaline, Metaproterenol, Albuterol, Pirbuterol, Levalbuterol, BitolterolPirbuterol, Levalbuterol, Bitolterol

Inhalation from a metered-dose inhalerInhalation from a metered-dose inhaler Bronchodilation is maximal by 30 min and Bronchodilation is maximal by 30 min and

persists for 3-4 hrspersists for 3-4 hrs

– Salmeterol, FormoterolSalmeterol, Formoterol Long-acting βLong-acting β22 agonists (12 hrs or more) agonists (12 hrs or more) High lipid solubility (into smooth muscle cells)High lipid solubility (into smooth muscle cells) Interact with inhaled corticosteroids to improve Interact with inhaled corticosteroids to improve

asthma control asthma control

Basic PharmacologyBasic Pharmacology((ββ-adrenoceptor Agonists-adrenoceptor Agonists))

AdministrationAdministration– Inhalation (by aerosol)Inhalation (by aerosol)– Available orally and for injectionAvailable orally and for injection

Side EffectsSide Effects– Muscle tremorMuscle tremor– Tachycardia and palpitationsTachycardia and palpitations– Increased free fatty acid, glucose, Increased free fatty acid, glucose,

lactatelactate– V/Q mismatch due to pulmonary V/Q mismatch due to pulmonary

vasodilationvasodilation

Basic PharmacologyBasic Pharmacology((CorticosteroidsCorticosteroids)) Mechanism of ActionMechanism of Action

– Anti-inflammatory effect mediated by Anti-inflammatory effect mediated by inhibiting production of inflammatory inhibiting production of inflammatory cytokinescytokines

Inhibition of the lymphocytic, eosinophic airway mucosal inflammation of asthmatic airways

– Reduce bronchial reactivityReduce bronchial reactivity– Reduce the frequency of asthma Reduce the frequency of asthma

exacerbations if taken regularlyexacerbations if taken regularly– No relaxant effect on airway smooth No relaxant effect on airway smooth

musclemuscle– Potentiate the effect of Potentiate the effect of ββ-agonists-agonists

Basic PharmacologyBasic Pharmacology((CorticosteroidsCorticosteroids))

AdministrationAdministration– Inhaled (aerosol treatment is the most Inhaled (aerosol treatment is the most

effective way to decrease the systemic effective way to decrease the systemic adverse effects, e.g., lipid-soluble adverse effects, e.g., lipid-soluble beclomethasone, budesonide, beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone)flunisolide, fluticasone, triamcinolone)

– Oral and parenteral (e.g., intravenous Oral and parenteral (e.g., intravenous infusion) use is reserved for patients infusion) use is reserved for patients who require urgent treatment who require urgent treatment (“nonresponders” to bronchodilators) (“nonresponders” to bronchodilators)

Clinical PharmacologyClinical Pharmacology((CorticosteroidsCorticosteroids)) Side EffectsSide Effects

– DysphoniaDysphonia – Oropharyngeal candidiasis (Oropharyngeal candidiasis (an an

opportunistic mucosal infection caused by opportunistic mucosal infection caused by the fungus the fungus ))

Both can be reduced by mouth rinsing with Both can be reduced by mouth rinsing with water after inhalationwater after inhalation

vocal cords

Effect of Corticosteroids on Inflammatory and Structural Cells in the Airway

1) Anti-inflammation2) Reducing bronchial reactivity

Cellular Mechanism of anti-inflammatory Action of Corticosteroids in Asthma

GR, glucocorticoidreceptor

Basic PharmacologyBasic Pharmacology((Methylxanthine DrugsMethylxanthine Drugs)) Major methylxanthinesMajor methylxanthines

– TheophyllineTheophylline 1,3-dimethylxanthine1,3-dimethylxanthine Aminophylline (a theophylline-Aminophylline (a theophylline-

ethylenediamine complex)ethylenediamine complex) Dyphylline (a synthetic analog of Dyphylline (a synthetic analog of

theophylline)theophylline)

– TheobromineTheobromine 3,7-dimethylxanthine3,7-dimethylxanthine

– CaffeineCaffeine 1,3,7-trimethylxanthine1,3,7-trimethylxanthine

Inexpensive and can be taken orally

Basic PharmacologyBasic Pharmacology((Methylxanthine DrugsMethylxanthine Drugs)) Mechanisms of ActionMechanisms of Action

– BronchodilationBronchodilation Inhibition of phosphodiesterases (PDEs; e.g. Inhibition of phosphodiesterases (PDEs; e.g.

PDE4), which results in an increased level of PDE4), which results in an increased level of cAMP (and cGMP) causing airway smooth cAMP (and cGMP) causing airway smooth muscle relaxationmuscle relaxation

Inhibition of adenosine receptor on the Inhibition of adenosine receptor on the surface membrane (surface membrane (adenosine causes airway adenosine causes airway smooth muscle contraction and provokes smooth muscle contraction and provokes histamine release from master cellshistamine release from master cells))

– Anti-inflammationAnti-inflammation Inhibition of antigen-induced release of Inhibition of antigen-induced release of

histamine from lung tissuehistamine from lung tissue

Theophylline Affects Multiple Cell Types in the Airway

Mechanisms of Theophylline-mediated Bronchodilation

Bronchodilation

Bronchoconstriction

cAMP

Theophylline

Theophylline

Muscarinicantagonists

β-agonists

Acetylcholine Adenosine

Bronchial tone

+

_

Activate or increase

Inhibit ordecrease

cGMP

AC GC

PDE4 PDE5 Theophylline

AMP/GMP

ATP/GTP

PDE, phosphodiesterase

Basic PharmacologyBasic Pharmacology((Antimuscarinic AgentsAntimuscarinic Agents))

Mechanism of ActionMechanism of Action– Inhibits the effect of acetylcholine (ACh) Inhibits the effect of acetylcholine (ACh)

at muscarinic (M) receptorsat muscarinic (M) receptors Block airway smooth muscle contractionBlock airway smooth muscle contraction Decrease mucus secretion by blocking vagal Decrease mucus secretion by blocking vagal

activityactivity

Major Antimuscarinic AgentsMajor Antimuscarinic Agents– AtropineAtropine– Ipratropium bromideIpratropium bromide (a selective (a selective

quaternary ammonium derivative of atropine)quaternary ammonium derivative of atropine)

– Tiotropium (for COPD)Tiotropium (for COPD)

Antimuscarinic Agent-mediated Bronchodilation

1

CNS Atropine and Ipratropium blocks bronchoconstriction induced by vagal activity

ACh

Basic PharmacologyBasic Pharmacology((Cromolyn & NedocromilCromolyn & Nedocromil)) Mechanism of ActionMechanism of Action

– Blockade of chloride channels and calcium Blockade of chloride channels and calcium channels in mast cells (and airway smooth channels in mast cells (and airway smooth muscle cells), and inhibition of cellular muscle cells), and inhibition of cellular activation activation

– Inhibition of mast cell degranulationInhibition of mast cell degranulation (inhibiting (inhibiting inflammatory response to allergens, exercise, inflammatory response to allergens, exercise, cold air. Inhibition of eosinophils/neutrophils to cold air. Inhibition of eosinophils/neutrophils to release inflammatory mediators release inflammatory mediators

– Inhibition of bronchial responsiveness (with Inhibition of bronchial responsiveness (with long-term treatment)long-term treatment)

– No bronchodilator or antihistamine activityNo bronchodilator or antihistamine activity

Basic PharmacologyBasic Pharmacology((Leukotriene InhibitorsLeukotriene Inhibitors))

Mechanism of ActionMechanism of Action– Leukotriene causes bronchoconstriction, Leukotriene causes bronchoconstriction,

increased bronchial reactivity, mucosal increased bronchial reactivity, mucosal edema, and mucus hypersecretionedema, and mucus hypersecretion

– Inhibition of 5-lipoxygenase on arachidonic Inhibition of 5-lipoxygenase on arachidonic acid leads to decreased synthesis of acid leads to decreased synthesis of leukotriene (leukotriene (zileutonzileuton))

– Blockade of leukotriene DBlockade of leukotriene D44 receptors leads receptors leads to decreased action of leukotriene to decreased action of leukotriene ((zafirlukast, montelukastzafirlukast, montelukast) )

– Both inhibitors (Both inhibitors (used orallyused orally) decrease ) decrease airway responses to allergens and exercise airway responses to allergens and exercise

Effects of Leukotrienes on the Airways and Their Inhibition by Anti-leukotriene Drugs

LTC4 ReceptorBlockers

LT SynthesisInhibitors

Basic PharmacologyBasic Pharmacology((Other DrugsOther Drugs)) Anti-IgE Monoclonal AntibodiesAnti-IgE Monoclonal Antibodies

– Omalizumab (anti-IgE Mab)Omalizumab (anti-IgE Mab)

Calcium channel blockersCalcium channel blockers– Nifedipine, verapamilNifedipine, verapamil

Nitric Oxide DonorsNitric Oxide Donors– Sodium nitroprusside (SNP)Sodium nitroprusside (SNP)

Possible Future TherapiesPossible Future Therapies– Monoclonal antibody against to cytokines Monoclonal antibody against to cytokines

(e.g., IL-4/-5/-8), antagonists of cell adhesion (e.g., IL-4/-5/-8), antagonists of cell adhesion molecules, protease inhibitors, etc. molecules, protease inhibitors, etc.

Leaning ObjectivesLeaning Objectives

Definition and basic pathology of asthmaDefinition and basic pathology of asthma

Various cell types and mediators in the Various cell types and mediators in the pathogenesis of asthmapathogenesis of asthma

Rationale for the use of Rationale for the use of ββ-agonist-agonist therapy (therapy (bronchodilationbronchodilation) and its side ) and its side effectseffects

Therapeutic actions of Therapeutic actions of cromolyncromolyn ( (inhibiting inhibiting

mast cell degranulationmast cell degranulation), ), corticosteroidscorticosteroids ((anti-inflammationanti-inflammation), and ), and theophyllinetheophylline ((bronchodilation and anti-inflammationbronchodilation and anti-inflammation))

QuestionsQuestions

Jason Yuan Jason Yuan – 312-355-5911 (office phone)312-355-5911 (office phone)– jxyuan@uic.edu (email) (email)– COMRB 3131COMRB 3131