Drugs Used for the Management of Asthma

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Drugs Used for the Management of Asthma
Institute for Personalized Respiratory
Medicine Department of Medicine (Section of
Pulmonary, Critical Care, Sleep and Allergy
) Department of Pharmacology Center for
Cardiovascular Research

• Jason X.-J. Yuan, M.D., Ph.D.
• Professor of Medicine and Pharmacology
• University of Illinois at Chicago

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Reference

• Katzung BG, Masters SB, Trevor AJBasic
  Clinical Pharmacology 11e
• Chapter 20 Drugs Used in Asthma (Homer A.
  Boushey and Bertram G. Katzung)

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Leaning Objectives

• Definition and basic pathology of asthma
• Various cell types and mediators in the
  pathogenesis of asthma
• Rationale for the use of ß-agonist therapy
  (bronchodilation) and its side effects
• Therapeutic actions of cromolyn (inhibiting mast
  cell degranulation), corticosteroids
  (anti-inflammation), and theophylline
  (bronchodilation and anti-inflammation)

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Definition of Asthma (What is Asthma?)

• Physiologically characterized a) by increased
  responsiveness of the trachea and bronchi to
  various stimuli and b) by widespread narrowing of
  the airways
• Pathologically featured by airway smooth muscle
  contraction, mucosal thickening from edema and
  cellular infiltration, an inspissation in the
  airway lumen of abnormally thick, viscid plugs of
  mucus

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Definition of Asthma

• Asthma is a chronic inflammatory disease of the
  airways
• Hyper-responsiveness
• Airway contraction (bronchospasm)
• Inflammation
• Airway/bronchial remodeling (thickening)

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Asthma Therapy

• Short-term Relievers
• Bronchodilators
• ß-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 the Deposition of Inhaled
Drugs
Metered-dose inhaler (MDI)

• 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.

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Pathogenesis of Asthma(Immunological Model)

1. IgE antibodies bound to mast cells in airway
   mucosa
2. On reexposure to antigens, antigen-antibody
   interaction on the surface of master cells
   triggers release/synthesis of mediators (e.g.,
   histamine, tryptase, leukotrienes, and PGs)
3. Mediators (also including cytokines,
   interleukins) cause bronchial contraction (smooth
   muscle), vascular leakage, cellular infiltration,
   mucus hyper-secretion
4. Inflammatory response

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Conceptual Model for the Immunopathogenesis of
Asthma
Cytokines activate eosinophils/ neutrophils
releasing ECP/MBP proteases, PAF, and cause late
reaction
Bronchoconstriction, vascular leakage, cellular
infiltration
On reexposure to allergens, antigen-antibody
interaction causes release of mediators
Allergen causes synthesis of IgE which binds to
mast cells Allergen activates T-cells
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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 rapid
  ventilation) (nonspecific bronchial
  hyperreactivity )
• Bronchial hyperreactivity is quantitated by
  measuring the fall in FEV1 (forced expiratory
  volume in 1 s) provoked by inhaling aerosolized
  histamine or methacholine (serially increasing
  concentration)

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Mechanisms of Bronchial Hyperreactivity

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 and
   efferent vagal nerves) in the airways
5. Cellular mechanisms in airway smooth muscle cells
   and epithelial cells

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Asthmatic Bronchospasm

• Caused by a combination of
• Increased release/synthesis of contractile
  mediators (mainly from master cells and
  inflammatory cells)
• Enhanced responsiveness of airway smooth muscle
  to these mediators
• Afferent and efferent vagal nerves (e.g.,
  cholinergic motor fibers innervate M3 receptors
  on the smooth muscle)
• Airway smooth muscle cells
• Airway epithelial cells

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Mechanisms of Inhaled Irritant-mediated Bronchial
Constriction
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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

ACh
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Asthmatic Bronchospasm

• Treated by drugs that
• Reduce the amount of IgE bound to mast cells
  (anti-IgE antibody)
• Prevent mast cell degranulation (cromolyn,
  ß-agonists, calcium channel blockers)
• Block the action of released mediators
  (anti-histamine, leukotriene receptor blockers)
• Inhibit the effect of acetylcholine (ACh)
  released from vagal motor nerves (muscarinic
  antagonists)
• Directly relax airway smooth muscle
  (theophylline, ß-agonists)

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Basic Pharmacology of Agents for Treatment of
Asthma

• The drugs mostly used for management of asthma
  are
• ß-Adrenoceptor agonists
• Used as short-term relievers or bronchodilators
• Inhaled corticosteroids
• Used as long-term controllers or
  anti-inflammatory agents

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Basic Pharmacology of Agents for Treatment of
Asthma

• Symathomimetic Agents (ß-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 (sodium nitroprusside)

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Basic Pharmacology(Sympathomimetic Agents)

• Adrenergic Receptors (adrenoceptors)
• a-receptors (a1, a2)
• ß-receptors
• ß1, heart muscle (causing increased heart
  rate/contractility) kidney (causing renin
  release)
• ß2, airway smooth muscle (causing
  bronchodilation) GI smooth muscle, cardiac
  muscle, skeletal muscle, vascular smooth muscle
• ß3, adipose tissue (causing lipolysis, increasing
  fatty acids in the blood)

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Bronchodilation is Promoted by Increased cAMP
Bronchodilation
ß-agonists
AC, adenylyl cyclase
cAMP
Bronchial tone
Theophylline
Acetylcholine
Adenosine
Muscarinic antagonists
Theophylline
Bronchoconstriction
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Basic Pharmacology(Sympathomimetic Agents)

• Mechanisms of Action
• Activation of ß-adrenergic receptor
• ß1 and ß2 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

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Molecular Action of ß2-agonists to Induce Airway
Smooth Muscle Relaxation
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Basic Pharmacology(Sympathomimetic Agents)

• Non-selective ß-Adrenoceptor Agonists (ß1 and
  ß2)
• Epinephrine
• Injected subcutaneously or inhaled as a
  microaerosol, rapid action (15 min)
• Ingredient in non-prescription inhalants
• Ephedrine
• Oral intake, long-lasting action, obvious central
  effects (used less frequently now)
• Isoproterenol
• Inhaled as a microaerosol, rapid action (5 min)

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Basic Pharmacology(Sympathomimetic Agents)

• Selective ß2-Adrenoceptor Agonists (most widely
  used ß-agonists for the treatment of asthma)
• Terbutaline, Metaproterenol, Albuterol,
  Pirbuterol, Levalbuterol, Bitolterol
• Inhalation from a metered-dose inhaler
• Bronchodilation is maximal by 30 min and persists
  for 3-4 hrs
• Salmeterol, Formoterol
• Long-acting ß2 agonists (12 hrs or more)
• High lipid solubility (into smooth muscle cells)
• Interact with inhaled corticosteroids to improve
  asthma control

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Basic Pharmacology(ß-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

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Basic Pharmacology(Corticosteroids)

• Mechanism of Action
• Anti-inflammatory effect mediated by inhibiting
  production of inflammatory cytokines
• Inhibition of the lymphocytic, eosinophic airway
  mucosal inflammation of asthmatic airways
• Reduce bronchial reactivity
• Reduce the frequency of asthma exacerbations if
  taken regularly
• No relaxant effect on airway smooth muscle
• Potentiate the effect of ß-agonists

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Basic Pharmacology(Corticosteroids)

• Administration
• Inhaled (aerosol treatment is the most effective
  way to decrease the systemic adverse effects,
  e.g., lipid-soluble beclomethasone, budesonide,
  flunisolide, fluticasone, triamcinolone)
• Oral and parenteral (e.g., intravenous infusion)
  use is reserved for patients who require urgent
  treatment (nonresponders to bronchodilators)

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Clinical Pharmacology(Corticosteroids)

• Side Effects
• Dysphonia
• Oropharyngeal candidiasis (an opportunistic
  mucosal infection caused by the fungus )
• Both can be reduced by mouth rinsing with water
  after inhalation

vocal cords
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Effect of Corticosteroids on Inflammatory and
Structural Cells in the Airway
1) Anti-inflammation 2) Reducing bronchial
reactivity
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Cellular Mechanism of anti-inflammatory Action of
Corticosteroids in Asthma
GR, glucocorticoid receptor
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Basic Pharmacology(Methylxanthine Drugs)

• Major methylxanthines
• Theophylline
• 1,3-dimethylxanthine
• Aminophylline (a theophylline-ethylenediamine
  complex)
• Dyphylline (a synthetic analog of theophylline)
• Theobromine
• 3,7-dimethylxanthine
• Caffeine
• 1,3,7-trimethylxanthine

Inexpensive and can be taken orally
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Basic Pharmacology(Methylxanthine Drugs)

• Mechanisms of Action
• Bronchodilation
• Inhibition of phosphodiesterases (PDEs e.g.
  PDE4), which results in an increased level of
  cAMP (and cGMP) causing airway smooth muscle
  relaxation
• Inhibition of adenosine receptor on the surface
  membrane (adenosine causes airway smooth muscle
  contraction and provokes histamine release from
  master cells)
• Anti-inflammation
• Inhibition of antigen-induced release of
  histamine from lung tissue

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Theophylline Affects Multiple Cell Types in the
Airway
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Mechanisms of Theophylline-mediated
Bronchodilation
ATP/GTP
Bronchodilation
ß-agonists
cAMP
cGMP
PDE, phosphodiesterase
Bronchial tone
Theophylline
Theophylline
AMP/GMP
Acetylcholine
Adenosine
Muscarinic antagonists
Theophylline
Bronchoconstriction
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Basic Pharmacology(Antimuscarinic Agents)

• Mechanism of Action
• Inhibits the effect of acetylcholine (ACh) at
  muscarinic (M) receptors
• Block airway smooth muscle contraction
• Decrease mucus secretion by blocking vagal
  activity
• Major Antimuscarinic Agents
• Atropine
• Ipratropium bromide (a selective quaternary
  ammonium derivative of atropine)
• Tiotropium (for COPD)

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Antimuscarinic Agent-mediated Bronchodilation
1
CNS
Atropine and Ipratropium blocks
bronchoconstriction induced by vagal activity
ACh
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Basic Pharmacology(Cromolyn Nedocromil)

• Mechanism of Action
• Blockade of chloride channels and calcium
  channels in mast cells (and airway smooth muscle
  cells), and inhibition of cellular activation
• Inhibition of mast cell degranulation (inhibiting
  inflammatory response to allergens, exercise,
  cold air. Inhibition of eosinophils/neutrophils
  to release inflammatory mediators
• Inhibition of bronchial responsiveness (with
  long-term treatment)
• No bronchodilator or antihistamine activity

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Basic Pharmacology(Leukotriene Inhibitors)

• Mechanism of Action
• Leukotriene causes bronchoconstriction, increased
  bronchial reactivity, mucosal edema, and mucus
  hypersecretion
• Inhibition of 5-lipoxygenase on arachidonic acid
  leads to decreased synthesis of leukotriene
  (zileuton)
• Blockade of leukotriene D4 receptors leads to
  decreased action of leukotriene (zafirlukast,
  montelukast)
• Both inhibitors (used orally) decrease airway
  responses to allergens and exercise

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Effects of Leukotrienes on the Airways and Their
Inhibition by Anti-leukotriene Drugs
LT Synthesis Inhibitors
LTC4 Receptor Blockers
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Basic Pharmacology(Other Drugs)

• Anti-IgE Monoclonal Antibodies
• Omalizumab (anti-IgE Mab)
• Calcium channel blockers
• Nifedipine, verapamil
• Nitric Oxide Donors
• Sodium nitroprusside (SNP)
• Possible Future Therapies
• Monoclonal antibody against to cytokines (e.g.,
  IL-4/-5/-8), antagonists of cell adhesion
  molecules, protease inhibitors, etc.

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Leaning Objectives

• Definition and basic pathology of asthma
• Various cell types and mediators in the
  pathogenesis of asthma
• Rationale for the use of ß-agonist therapy
  (bronchodilation) and its side effects
• Therapeutic actions of cromolyn (inhibiting mast
  cell degranulation), corticosteroids
  (anti-inflammation), and theophylline
  (bronchodilation and anti-inflammation)

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Questions

• Jason Yuan
• 312-355-5911 (office phone)
• jxyuan_at_uic.edu (email)
• COMRB 3131