Institute for Personalized Respiratory Medicine
Department of Medicine
(Section of Pulmonary, Critical Care, Sleep and Allergy )
Department of Pharmacology
Center for Cardiovascular Research
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
Reference

Katzung BG, Masters SB, Trevor AJ
Basic & Clinical
Pharmacology 11e

Chapter 20: Drugs Used in Asthma
(Homer A. Boushey and Bertram G. Katzung)
Leaning Objectives




Definition and basic pathology of asthma
Various cell types and mediators in the
pathogenesis of asthma
Rationale for the use of β-agonist therapy
(bronchodilation) and its side effects
Therapeutic actions of cromolyn (inhibiting
mast cell degranulation), corticosteroids
(anti-inflammation), and theophylline
(bronchodilation and anti-inflammation)
1
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
– β-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)
2
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.


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
4
Cytokines activate eosinophils/
neutrophils releasing ECP/MBP
proteases, PAF, and cause
late reaction
3
3
Bronchoconstriction, vascular
leakage, cellular infiltration
3
2
2
4
On reexposure to allergens,
antigen-antibody interaction
causes release of mediators
1
1
Allergen causes synthesis of
IgE which binds to mast cells;
Allergen activates T-cells
3
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)
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 M3 receptors on the smooth
muscle)
Airway smooth muscle cells
Airway epithelial cells
4
Mechanisms of Inhaled
Irritant-mediated Bronchial
Constriction
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
1
2
1
ACh
Asthmatic Bronchospasm
Treated by drugs that:

Reduce the amount of IgE bound to mast cells (antiIgE antibody)

Prevent mast cell degranulation (cromolyn, βagonists, calcium channel blockers)

Block the action of released mediators (antihistamine, leukotriene receptor blockers)

Inhibit the effect of acetylcholine (ACh) released
from vagal motor nerves (muscarinic antagonists)

Directly relax airway smooth muscle (theophylline,
β-agonists)
Basic Pharmacology of Agents
for Treatment of Asthma
The drugs mostly used for
management of asthma are:

β-Adrenoceptor agonists
–

Used as “short-term relievers” or
bronchodilators
Inhaled corticosteroids
–
Used as “long-term controllers” or antiinflammatory agents
5
Basic Pharmacology of Agents
for Treatment of Asthma
Symathomimetic Agents (β-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):
–
α-receptors (α1, α2)
–
β-receptors



β1, heart muscle (causing increased heart
rate/contractility); kidney (causing renin
release)
β2, airway smooth muscle (causing
bronchodilation); GI smooth muscle, cardiac
muscle, skeletal muscle, vascular smooth muscle
β3, adipose tissue (causing lipolysis, increasing
fatty acids in the blood)
Bronchodilation is Promoted
by Increased cAMP
Bronchodilation
β-agonists
AC, adenylyl cyclase
cAMP
Bronchial tone
Acetylcholine
Muscarinic
antagonists
Theophylline
Adenosine
Theophylline
Bronchoconstriction
+ Activate or
increase
_
Inhibit or
decrease
6
Basic Pharmacology
(Sympathomimetic Agents)

Mechanisms of Action
–
–
Activation of β-adrenergic receptor

β1 and β2 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 β2agonists to Induce Airway
Smooth Muscle Relaxation
Basic Pharmacology
(Sympathomimetic Agents)

“Non-selective” β-Adrenoceptor
Agonists (β1 and β2)
–
Epinephrine


–
Ingredient in non-prescription inhalants
Ephedrine

–
Injected subcutaneously or inhaled as a
microaerosol, rapid action (15 min)
Oral intake, long-lasting action, obvious central
effects (used less frequently now)
Isoproterenol

Inhaled as a microaerosol, rapid action (5 min)
7
Basic Pharmacology
(Sympathomimetic Agents)

Selective β2-Adrenoceptor Agonists (most
widely used β-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 β2 agonists (12 hrs or more)
High lipid solubility (into smooth muscle cells)
Interact with inhaled corticosteroids to improve
asthma control
Basic Pharmacology
(β-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 β-agonists
8
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
9
Cellular Mechanism of antiinflammatory Action of
Corticosteroids in Asthma
GR, glucocorticoid
receptor
Basic Pharmacology
(Methylxanthine Drugs)

Major methylxanthines
–
Theophylline



–
Aminophylline (a theophylline-ethylenediamine
complex)
Dyphylline (a synthetic analog of theophylline)
Theobromine

–
1,3-dimethylxanthine
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
10
Theophylline Affects Multiple
Cell Types in the Airway
Mechanisms of Theophyllinemediated Bronchodilation
ATP/GTP
Bronchodilation
AC GC
β-agonists
cAMP cGMP
Bronchial tone
PDE, phosphodiesterase
PDE4 PDE5
Theophylline
Theophylline
AMP/GMP
Acetylcholine
Muscarinic
antagonists
Adenosine
Theophylline
+ Activate or
increase
_
Bronchoconstriction
Inhibit or
decrease
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)
11
Antimuscarinic Agentmediated Bronchodilation
CNS
Atropine and Ipratropium
blocks bronchoconstriction
induced by vagal activity
1
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 D4 receptors leads to
decreased action of leukotriene (zafirlukast,
montelukast)
–
Both inhibitors (used orally) decrease airway
responses to allergens and exercise
12
Effects of Leukotrienes on the
Airways and Their Inhibition by
Anti-leukotriene Drugs
LT Synthesis
Inhibitors
LTC4 Receptor
Blockers
Basic Pharmacology
(Other Drugs)

Anti-IgE Monoclonal Antibodies
–

–

Nifedipine, verapamil
Nitric Oxide Donors
–

Omalizumab (anti-IgE Mab)
Calcium channel blockers
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 β-agonist therapy
(bronchodilation) and its side effects
Therapeutic actions of cromolyn (inhibiting
mast cell degranulation), corticosteroids
(anti-inflammation), and theophylline
(bronchodilation and anti-inflammation)
13
Questions

Jason Yuan
– 312-355-5911 (office phone)
– jxyuan@uic.edu (email)
– COMRB 3131
14