For Asthma and COPD

8/12/2019 For Asthma and COPD

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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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2

3

4

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

1

2

3

4

3


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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

2

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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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


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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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

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