1

Drugs Used for the

Management of Asthma
Jason X.-J. Yuan, M.D., Ph.D.
Professor of Medicine and Pharmacology
University of Illinois at Chicago
Institute for Personalized Respiratory Medicine
Department of Medicine
(Section of Pulmonary, Critical Care, Sleep and Allergy )
Department of Pharmacology
Center for Cardiovascular Research
Katzung BG, Masters SB, Trevor AJ
Basic & Clinical
Pharmacology 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 (inhibiting
mast cell degranulation), corticosteroids
(anti-inflammation), and theophylline
(bronchodilation and anti-inflammation)
2
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
Definition of Asthma
Asthma is a chronic inflammatory
disease 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)
3
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 m, 80-90% of the total dose of
aerosol is deposited in the mouth or pharynx.
Metered-dose inhaler (MDI)
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
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 interaction
causes release of mediators
Bronchoconstriction, vascular
leakage, cellular infiltration
Cytokines activate eosinophils/
neutrophils releasing ECP/MBP
proteases, PAF, and cause
late reaction
1
2
3
4
3
4
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 FEV
1
(forced expiratory
volume in 1 s) provoked by inhaling aerosolized
histamine or methacholine (serially increasing
concentration)
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
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 M
3
receptors on the smooth
muscle)
Airway smooth muscle cells
Airway epithelial cells
5
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 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) released
from vagal motor nerves (muscarinic antagonists)
Directly relax airway smooth muscle (theophylline,
-agonists)
Basic Pharmacology of Agents
for Treatment of Asthma
The drugs mostly used for
management of asthma are:
-Adrenoceptor agonists
Used as short-term relievers or
bronchodilators
Inhaled corticosteroids
Used as long-term controllers or anti-
inflammatory agents
6
Basic Pharmacology of Agents
for 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 (sodium
nitroprusside)
Basic Pharmacology
(Sympathomimetic Agents)
Adrenergic Receptors (adrenoceptors):
-receptors (1, 2)
-receptors
1, heart muscle (causing increased heart
rate/contractility); kidney (causing renin
release)
2, airway smooth muscle (causing
bronchodilation); GI smooth muscle, cardiac
muscle, skeletal muscle, vascular smooth muscle
3, adipose tissue (causing lipolysis, increasing
fatty acids in the blood)
Bronchodilation is Promoted
by Increased cAMP
Bronchodilation
Bronchoconstriction
cAMP
Theophylline
Theophylline
Muscarinic
antagonists
-agonists
Acetylcholine Adenosine
Bronchial tone
+
_
Activate or
increase
Inhibit or
decrease
AC, adenylyl cyclase
7
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 Ca
2+
/CaM
AC5 and AC6 are inhibited by Ca
2+
/CaM
Increase in the formation of cAMP
Relaxation of airway smooth muscle
Molecular Action of
2
-
agonists to Induce Airway
Smooth Muscle Relaxation
Basic Pharmacology
(Sympathomimetic Agents)
Non-selective -Adrenoceptor
Agonists (
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 central
effects (used less frequently now)
Isoproterenol
Inhaled as a microaerosol, rapid action (5 min)
8
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 and
persists for 3-4 hrs
Salmeterol, Formoterol
Long-acting
2
agonists (12 hrs or more)
High lipid solubility (into smooth muscle cells)
Interact with inhaled corticosteroids to improve
asthma 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 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 -agonists
9
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)
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
Effect of Corticosteroids on
Inflammatory and Structural
Cells in the Airway
1) Anti-inflammation
2) Reducing bronchial reactivity
10
Cellular Mechanism of anti-
inflammatory Action of
Corticosteroids in Asthma
GR, glucocorticoid
receptor
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
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
11
Theophylline Affects Multiple
Cell Types in the Airway
Mechanisms of Theophylline-
mediated Bronchodilation
Bronchodilation
Bronchoconstriction
cAMP
Theophylline
Theophylline
Muscarinic
antagonists
-agonists
Acetylcholine Adenosine
Bronchial tone
+
_
Activate or
increase
Inhibit or
decrease
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) 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)
12
Antimuscarinic Agent-
mediated Bronchodilation
1
CNS
Atropine and Ipratropium
blocks bronchoconstriction
induced by vagal activity
ACh
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
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 D
4
receptors leads to
decreased action of leukotriene (zafirlukast,
montelukast)
Both inhibitors (used orally) decrease airway
responses to allergens and exercise
13
Effects of Leukotrienes on the
Airways and Their Inhibition by
Anti-leukotriene Drugs
LTC4 Receptor
Blockers
LT Synthesis
Inhibitors
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.
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 (inhibiting
mast cell degranulation), corticosteroids
(anti-inflammation), and theophylline
(bronchodilation and anti-inflammation)
14
Questions
Jason Yuan
312-355-5911 (office phone)
jxyuan@uic.edu (email)
COMRB 3131