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Drugs Used for theManagement of Asthma
Jason X.-J. Yuan, M.D., Ph.D.
Professor of Medicine and Pharmacology
University of Illinois at Chicago
Institute for Personalized Respiratory MedicineDepartment of Medicine
(Section of Pulmonary, Critical Care, Sleep and Allergy )
Department of PharmacologyCenter for Cardiovascular Research
Katzung BG, Masters SB, Trevor AJ
Basic & ClinicalPharmacology 11e
Chapter 20: Drugs Used in Asthma(Homer A. Boushey and Bertram G. Katzung)
Reference
Leaning Objectives
Definition and basic pathology of asthma
Various cell types and mediators in the
pathogenesis of asthma
Rationale for the use of -agonist therapy(bronchodilation) and its side effects
Therapeutic actions of cromolyn (inhibitingmast cell degranulation), corticosteroids(anti-inflammation), and theophylline(bronchodilation and anti-inflammation)
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Definition of Asthma(What is Asthma?)
Physiologically characterized a) byincreased responsiveness of the tracheaand bronchi to various stimuli and b) bywidespread narrowing of the airways
Pathologically featured by airwaysmooth muscle contraction, mucosalthickening from edema and cellularinfiltration, an inspissation in the airwaylumen of abnormally thick, viscid plugsof mucus
Definition of Asthma
Asthma is a chronic inflammatorydisease of the airways
Hyper-responsiveness
Airway contraction (bronchospasm)
Inflammation
Airway/bronchial remodeling(thickening)
Asthma Therapy
Short-term Relievers:
Bronchodilators
-adrenoceptor agonists (e.g., isoproterenol)
Antimuscarinic agents (e.g., theophylline)
Long-term Controllers:
Anti-inflammatory Agents
Inhaled corticosteroid
Leukotriene antagonists
Inhibitors of mast cell degranulation (e.g.,cromolyn or nedocromil)
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Schematic Diagram of theDeposition of Inhaled Drugs
Delivery by inhalation results in the greatest local effect on airway smooth musclewith 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 m, 80-90% of the total dose ofaerosol is deposited in the mouth or pharynx.
Metered-dose inhaler (MDI)
Pathogenesis of Asthma(Immunological Model)
1) IgE antibodies bound to mast cells in airwaymucosa
2) On reexposure to antigens, antigen-antibodyinteraction on the surface of master cellstriggers release/synthesis of mediators (e.g.,histamine, tryptase, leukotrienes, and PGs)
3) Mediators (also including cytokines,interleukins) cause bronchial contraction(smooth muscle), vascular leakage, cellularinfiltration, mucus hyper-secretion
4) Inflammatory response
Conceptual Model for theImmunopathogenesis of Asthma
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Allergen causes synthesis ofIgE 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
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Hyperresponsiveness
Bronchospasm can be elicited by: Allergens (hypersensitivity to)
Non-antigenic stimuli (e.g., distilled water,exercise, cold air, sulfur dioxide, and rapidventilation) (nonspecific bronchialhyperreactivity )
Bronchial hyperreactivity is quantitated bymeasuring the fall in FEV1 (forced expiratoryvolume in 1 s) provoked by inhaling aerosolizedhistamine or methacholine (serially increasingconcentration)
Mechanisms of BronchialHyperreactivity
1) Inflammation of airway mucosa
2) Increased ozone exposure, allergen inhalation,& viral infection (causing airway inflammation)
3) Increased inflammatory cells (eosinophils,neutrophils, lymphocytes and macrophages)and increased products from these cells(causing airway smooth muscle contraction)
4) Sensitization of sensory nerves (afferent andefferent vagal nerves) in the airways
5) Cellular mechanisms in airway smooth musclecells and epithelial cells
Asthmatic Bronchospasm
Caused by a combination of:
Increased release/synthesis of contractile
mediators (mainly from master cells andinflammatory cells)
Enhanced responsiveness of airway smoothmuscle to these mediators
Afferent and efferent vagal nerves (e.g., cholinergicmotor fibers innervate M3 receptors on the smoothmuscle)
Airway smooth muscle cells
Airway epithelial cells
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Mechanisms of InhaledIrritant-mediated BronchialConstriction
1
CNSInhaled irritants can cause
bronchoconstriction by:
(1) Triggering release of chemicalmediators from response cells (e.g.,mast cells, eosinophils, neutrophils)
(2) Stimulating afferent receptors toinitiate reflex bronchoconstriction(via acetylcholine, ACh) or to releasetachykinins (e.g., substance P) thatdirectly stimulate smooth musclecontraction
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1
ACh
Asthmatic Bronchospasm
Treated by drugs that:
Reduce the amount of IgE bound to mast cells (anti-IgE antibody)
Prevent mast cell degranulation (cromolyn,-agonists, calcium channel blockers)
Block the action of released mediators (anti-histamine, leukotriene receptor blockers)
Inhibit the effect of acetylcholine (ACh) releasedfrom vagal motor nerves (muscarinic antagonists)
Directly relax airway smooth muscle (theophylline,-agonists)
Basic Pharmacology of Agentsfor Treatment of Asthma
The drugs mostly used formanagement of asthma are:
-Adrenoceptor agonists
Used as short-term relievers orbronchodilators
Inhaled corticosteroids
Used as long-term controllers or anti-inflammatory agents
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Basic Pharmacology of Agentsfor Treatment of Asthma
Symathomimetic Agents (-adrenoceptor agonists) Epinephrine, isoproterenol, salmeterol, formoterol
Corticosteroids Beclomethasone, flunisolide, fluticasone, triamcinolone
Methylxanthine Drugs Theophylline, theobromine, caffeine
Antimuscarinic Agents Ipratropium, atropine
Cromolyn and Nedocromil (inhibitors of mast cell degranulation)
Leukotriene Inhibitors Zileuton, montelukast, zafirlukast
Other Drugs in the Treatment of Asthma: Anti-IgE monoclonal antibodies (omalizumab), calcium channel
blockers (nifedipine, verapamil), Nitric oxide donors (sodiumnitroprusside)
Basic Pharmacology(Sympathomimetic Agents)
Adrenergic Receptors (adrenoceptors):
-receptors (1, 2)
-receptors
1, heart muscle (causing increased heartrate/contractility); kidney (causing reninrelease)
2, airway smooth muscle (causingbronchodilation); GI smooth muscle, cardiacmuscle, skeletal muscle, vascular smooth muscle
3, adipose tissue (causing lipolysis, increasing
fatty acids in the blood)
Bronchodilation is Promotedby Increased cAMP
Bronchodilation
Bronchoconstriction
cAMP
Theophylline
Theophylline
Muscarinicantagonists
-agonists
Acetylcholine Adenosine
Bronchial tone
+
_
Activate orincrease
Inhibit ordecrease
AC, adenylyl cyclase
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Basic Pharmacology(Sympathomimetic Agents)
Mechanisms of Action Activation of -adrenergic receptor
1 and 2 receptors
G protein-coupled receptor
Stimulation of adenylyl cyclase (AC)
Ten known ACs (AC1-AC10)
AC1, AC3 and AC8 are activated by Ca2+/CaM
AC5 and AC6 are inhibited by Ca2+/CaM
Increase in the formation of cAMP
Relaxation of airway smooth muscle
Molecular Action of 2-agonists to Induce AirwaySmooth Muscle Relaxation
Basic Pharmacology(Sympathomimetic Agents)
Non-selective -AdrenoceptorAgonists (1 and 2)
Epinephrine Injected subcutaneously or inhaled as a
microaerosol, rapid action (15 min)
Ingredient in non-prescription inhalants
Ephedrine
Oral intake, long-lasting action, obvious centraleffects (used less frequently now)
Isoproterenol
Inhaled as a microaerosol, rapid action (5 min)
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Basic Pharmacology(Sympathomimetic Agents)
Selective 2-Adrenoceptor Agonists(most
widely used -agonists for the treatment of asthma)
Terbutaline, Metaproterenol, Albuterol,Pirbuterol, Levalbuterol, Bitolterol
Inhalation from a metered-dose inhaler
Bronchodilation is maximal by 30 min andpersists for 3-4 hrs
Salmeterol, Formoterol
Long-acting2 agonists (12 hrs or more)
High lipid solubility (into smooth muscle cells)
Interact with inhaled corticosteroids to improveasthma control
Basic Pharmacology(-adrenoceptor Agonists)
Administration
Inhalation (by aerosol)
Available orally and for injection
Side Effects
Muscle tremor
Tachycardia and palpitations
Increased free fatty acid, glucose, lactate
V/Q mismatch due to pulmonary
vasodilation
Basic Pharmacology(Corticosteroids)
Mechanism of Action
Anti-inflammatory effect mediated byinhibiting production of inflammatorycytokines
Inhibition of the lymphocytic, eosinophic airwaymucosal inflammation of asthmatic airways
Reduce bronchial reactivity
Reduce the frequency of asthmaexacerbations if taken regularly
No relaxant effect on airway smooth muscle
Potentiate the effect of -agonists
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Basic Pharmacology(Corticosteroids)
Administration Inhaled (aerosol treatment is the mosteffective way to decrease the systemicadverse effects, e.g., lipid-solublebeclomethasone, budesonide, flunisolide,fluticasone, triamcinolone)
Oral and parenteral (e.g., intravenousinfusion) use is reserved for patients whorequire urgent treatment (nonrespondersto bronchodilators)
Clinical Pharmacology(Corticosteroids)
Side Effects
Dysphonia
Oropharyngeal candidiasis (an opportunisticmucosal infection caused by the fungus )
Both can be reduced by mouth rinsing with waterafter inhalation
vocal cords
Effect of Corticosteroids onInflammatory and StructuralCells in the Airway
1) Anti-inflammation2) Reducing bronchial reactivity
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Cellular Mechanism of anti-inflammatory Action ofCorticosteroids in Asthma
GR, glucocorticoidreceptor
Basic Pharmacology(Methylxanthine Drugs)
Major methylxanthines
Theophylline
1,3-dimethylxanthine
Aminophylline (a theophylline-ethylenediaminecomplex)
Dyphylline (a synthetic analog of theophylline)
Theobromine
3,7-dimethylxanthine
Caffeine
1,3,7-trimethylxanthine
Inexpensive and can be taken orally
Basic Pharmacology(Methylxanthine Drugs)
Mechanisms of Action
Bronchodilation
Inhibition of phosphodiesterases (PDEs; e.g.PDE4), which results in an increased level ofcAMP (and cGMP) causing airway smooth musclerelaxation
Inhibition of adenosine receptor on the surfacemembrane (adenosine causes airway smoothmuscle contraction and provokes histaminerelease from master cells)
Anti-inflammation
Inhibition of antigen-induced release ofhistamine from lung tissue
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Theophylline Affects MultipleCell Types in the Airway
Mechanisms of Theophylline-mediated Bronchodilation
Bronchodilation
Bronchoconstriction
cAMP
Theophylline
Theophylline
Muscarinic
antagonists
-agonists
Acetylcholine Adenosine
Bronchial tone
+
_
Activate orincrease
Inhibit ordecrease
cGMP
AC GC
PDE4 PDE5 Theophylline
AMP/GMP
ATP/GTP
PDE, phosphodiesterase
Basic Pharmacology(Antimuscarinic Agents)
Mechanism of Action
Inhibits the effect of acetylcholine (ACh) atmuscarinic (M) receptors
Block airway smooth muscle contraction
Decrease mucus secretion by blocking vagalactivity
Major Antimuscarinic Agents
Atropine
Ipratropium bromide (a selective quaternaryammonium derivative of atropine)
Tiotropium (for COPD)
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Antimuscarinic Agent-mediated Bronchodilation
1
CNSAtropine and Ipratropium
blocks bronchoconstrictioninduced by vagal activity
ACh
Basic Pharmacology(Cromolyn & Nedocromil)
Mechanism of Action Blockade of chloride channels and calcium
channels in mast cells (and airway smoothmuscle cells), and inhibition of cellular activation
Inhibition of mast cell degranulation (inhibitinginflammatory response to allergens, exercise,cold air. Inhibition of eosinophils/neutrophils torelease inflammatory mediators
Inhibition of bronchial responsiveness (withlong-term treatment)
No bronchodilator or antihistamine activity
Basic Pharmacology(Leukotriene Inhibitors)
Mechanism of Action
Leukotriene causes bronchoconstriction,increased bronchial reactivity, mucosal edema,and mucus hypersecretion
Inhibition of 5-lipoxygenase on arachidonic acidleads to decreased synthesis of leukotriene(zileuton)
Blockade of leukotriene D4 receptors leads todecreased action of leukotriene (zafirlukast,montelukast)
Both inhibitors (used orally) decrease airwayresponses to allergens and exercise
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Questions
Jason Yuan
312-355-5911 (office phone)
[email protected] (email)
COMRB 3131