Nonsteroidal
Antiasthma Agents
I.
Clinical Indication for Nonsteroidal Antiasthma Agents
a.
Prophylactic management (control) of mild persistent asthma
II.
Identification of Nonsteroidal Antiasthma Agents
|
Drug |
Brand Name |
Formulation and Dose |
|
Cromolyn sodium |
Intal |
MDI: 800 mcg/puff Adults and children ≥
5 yr: 2 puffs qid |
|
|
|
SVN: 20 mg/ampule Adults and children ≥
2 yr: 20 mg ampule qid |
|
Nedocromil sodium |
Tilade |
MDI: 1.75 mg/puff Adults and children ≥
6 yr: 2 puffs qid |
|
Zafirlukast |
Accolade |
Tablets: 10 mg Children 5-11 yr: 1
tab bid |
|
|
|
Tablets: 20 mg Adults and children ≥
12 yr: 1 tab bid |
|
Montelukast |
Singulair |
Tablets: 10 mg Adults and children ≥
15 yr: 1 tab q evening |
|
|
|
Chewable Tablets: 5
mg Children 6-14 yr: 1
tab q evening |
|
|
|
Chewable Tablets: 4
mg Children 2-5 yr: 1
tab q evening |
|
|
|
Oral Granules: 4 mg Children 12
mos.-2yr: 1 pouch q evening |
|
Zileuton |
Zyflo |
Tablets: 600 mg Adults and children ≥
12 yr: 1 tab qid |
III.
Mechanisms of Inflammation in Asthma
a.
Forms of Asthma
i.
Extrinsic (Allergic) Asthma
1.
caused by stimuli that cause an antigen-antibody reaction
a.
atopy - a tendency to develop allergies, usually inherited
b.
antigen - a substance that causes antibody production and/or
cellular immunity
c.
antibody - a serum protein (globulin) modified to combine
and react with a specific antigen
i.
also called immunoglobulins (IgE)
2.
associated with younger subjects
ii.
Intrinsic (Non-allergic) Asthma
1.
caused by non-allergic stimuli
a.
exercise
b.
cold air
c.
emotion and stress
2.
there is no antigen - antibody reaction
3.
these stimuli can cause both mediator release and vagal
reflex
4.
associated with older children and adults
b.
Components of Asthma
i.
The acute asthma attack
1.
resolves spontaneously or with treatment
ii.
A hyper-responsiveness of the airways to various stimuli
iii.
Persistent inflammation in the airways
c.
Consequences of an Extrinsic or Intrinsic Asthma Attack
i.
Chemical mediators and enzymes are released to act on target
tissues in the airways
ii.
Inflammatory cells are recruited and activated in the
airways
iii.
Airway inflammation results in
1.
bronchoconstriction
2.
airway inflammation
3.
mucus secretion and obstruction
4.
airway wall remodeling
d.
The Immunological (Allergic) Response
i.
Initiated by the interaction of T lymphocytes with an
antigen (virus, fungus, dust mites)
ii.
Activation of T lymphocytes results in production of IgE by B
lymphocytes
iii.
Antigen specific IgE binds to effector cells such as mast
cells
iv.
Further exposure to the antigen results in the release of
chemical mediators of inflammation from the mast cells (degranulation)
1.
Prostaglandins
2.
Leukotrienes
3.
Proteases
4.
Histamine
5.
Platelet-activating factor (PAF)
6.
Cytokines
a.
tumor necrosis factor-α (TNF-
α)
b.
interleukin-4 (IL-4)
v.
This cascade of mediators causes an inflammatory response
1.
Vascular leakage
2.
Bronchoconstriction
3.
Mucus secretion
4.
Mucosal swelling
vi.
T lymphocytes also release mediators which cause
accumulation and activation of eosinophils
vii.
Eosinophils also release chemicals that damage the airways
e.
The Non-Allergic Response
i.
Nonspecific stimuli (noxious substances) can stimulate
sensory receptors in the airway and cause reflex bronchoconstriction
1.
fog
2.
sulfur dioxide
3.
cold air
ii.
Non-adrenergic
non-cholinergic (NANC) excitatory nerves
1.
Activation of
C-fibers by noxious substances cause afferent impulses to the CNS with reflex
parasympathetic activity
a.
constriction
of airway smooth muscle
b.
increased
mucous gland secretion
c.
vasodilation
d.
increased
vascular permeability (leaky vessels)
e.
increased
mucociliary activity
IV.
Cromolyn-Like (Mast Cell Stabilizing) Agents
a.
Cromolyn Sodium (Intal)
i.
FDA approved for general use: 1982
ii.
Mode of action
1.
inhibits mast cell degranulation
2.
exact mode of action not completely understood
iii.
Clinical Indications
1.
Prophylactic management of bronchial asthma
2.
Prevention of exercise-induced bronchospasm
iv.
Clinical Application
1.
Not for use in acute bronchospasm
a.
no bronchodilating effect
2.
may take as long as 2 to 4 weeks for improvement in symptoms
v.
Dosage Forms
1.
DPI (Spinhaler)
a.
original form
b.
dry powder in a capsule
2.
Solution for Nebulization
3.
MDI
4.
Eye Drop Solution
5.
Nasal Solution
vi.
Side Effects
1.
Dry powder
a.
throat irritation
b.
hoarseness
c.
dry mouth
d.
cough
e.
chest tightness
2.
Solution
a.
cough
b.
nasal congestion
c.
wheezing
d.
sneezing
e.
nasal itching
f.
epistaxis
vii.
Clinical Efficacy
1.
Spinhaler
a.
Effective as a treatment for approximately 70% of all
patients
2.
MDI strength
a.
Provides better protection against exercise induced asthma, with
a longer duration of protection
b.
Nedocromil Sodium (Tilade)
i.
FDA approved for general use: 1992
ii.
Mode of Action
1.
Inhibits the activation and activity of multiple
inflammatory cells
a.
mast cells
b.
eosinophils
c.
airway epithelial cells
d.
sensory neurons
iii.
Clinical Indication
1.
Prophylactic management of mild to moderate asthma in adults
and children ≥ 6 years of age
iv.
Clinical Application
1.
Not for use in acute bronchospasm
a.
no bronchodilating effect
2.
optimal control of asthma symptoms depends on regular use
v.
Dosage Form
1.
MDI
vi.
Side Effects
1.
Unpleasant taste
2.
Headache
3.
Nausea
4.
Vomiting
5.
Dizziness
vii.
Clinical Efficacy
1.
Adults
a.
Shown to provide equal or better control of mild to moderate
asthma compared to theophylline but with much better therapeutic index
b.
Shown to be of potential use in reducing high-dose inhaled
steroid use
2.
Children
a.
Significant improvement in daily peak flow and a reduction
in daily bronchodilator use in stable mild asthma
V.
Antileukotriene Agents
a.
Zafirlukast (Accolate)
i.
FDA approved for general use: 1996
ii.
Mode of Action
1.
Acts as an antagonist at leukotriene receptors (LTD4, LTE4)
preventing the inflammatory response of airway contractility, vascular
permeability, and mucus secretion
iii.
Clinical Indication
1.
Indicated for the prophylaxis and chronic treatment of
asthma in individuals ≥ 5 years of age
iv.
Clinical Application
1.
Evidence of being effective in preventing
bronchoconstriction and other asthmatic airway responses
2.
Effective against leukotriene-induced bronchoconstriction
caused by allergens, exercise, aspirin and cold air
v.
Dosage Forms
1.
10 mg oral tablet
2.
20 mg oral tablet
vi.
Side Effects
1.
headache
2.
nausea
3.
diarrhea
4.
generalized and abdominal pain
5.
infection (primarily respiratory)
6.
hepatic insufficiency (rare)
vii.
Drug Interactions
1.
warfarin – increased prothrombin time (PT)
2.
theophylline – decreased plasma level
3.
aspirin – increases plasma level of zafirlukast
b.
Zileuton (Zyflo)
i.
FDA approved for general use: 1997
ii.
Mode of Action
1.
Inhibits the enzyme responsible for leukotriene formation
2.
Effectively blocks the inflammatory response in asthma
iii.
Clinical Indication
1.
Indicated for the prophylaxis and chronic treatment of
asthma in individuals ≥ 12 years of age
iv.
Clinical Application
1.
Effective against asthma response to allergens, cold air and
aspirin
2.
Produces sustained improvements in lung function
a.
FEV1 increases 15-20%
b.
Allows reduction in beta agonist and inhaled steroid use
v.
Dosage Form
1.
600 mg oral tablet
vi.
Side Effects
1.
headache
2.
general pain
3.
abdominal pain
4.
loss of strength
5.
dyspepsia
6.
liver dysfunction
vii.
Drug
Interactions
1.
theophylline - increased plasma level
2.
warfarin - increased prothrombin time (PT)
c.
Montelukast (Singulaire)
i.
FDA approved for general use: 1998
ii.
Mode of Action
1.
Acts as an antagonist at leukotriene receptors (LTD4, LTE4)
preventing the inflammatory response of airway contractility, vascular
permeability, and mucus secretion
iii.
Clinical Indication
1.
Indicated for the prophylaxis and chronic treatment of
asthma in adults and children ≥ 12 months of age
2.
Indicated for the relief of symptoms of seasonal allergic
rhinitis in adults and children ≥ 2 years of age
iv.
Clinical Application
1.
Evidence of being effective in treating mild to moderate
asthma and exercise-induced bronchoconstriction
v.
Dosage Forms
1.
10 mg oral tablet
2.
5 mg chewable tablet
3.
4 mg chewable tablet
4.
4 mg oral granules
a.
Taken plain or mixed with a teaspoon of apple sauce,
carrots, rice or ice cream
vi.
Side Effects
1.
headache – most common
2.
influenza
3.
abdominal pain
vii.
Drug Interactions:
None
d.
Role of Antileukotriene Drugs in Asthma Management
i.
Protection Against Specific Asthma Triggers
1.
exercise-induced asthma
a.
protection varies from complete to very little
b.
no tolerance occurs
2.
aspirin-induced asthma
a.
treatment of choice
3.
allergen-induced asthma
a.
block early phase asthma response
b.
reduce airway obstruction in the late phase response
ii.
Chronic Persistent Asthma
1.
mild to moderate asthma
a.
improvement in lung function
b.
reduced need for rescue beta-agonist agents
c.
decrease in asthma symptoms including nocturnal symptoms
2.
moderate to severe asthma
a.
additive effect between antileukotrienes and inhaled
corticosteroids
i.
inhaled or oral doses may be reduced
e.
Advantages and Disadvantages of Antileukotriene Drug Therapy
in Managing Asthma
|
Advantages
|
Disadvantages |
|
Oral administration |
Relatively limited anti-inflammatory
action limited to one mediator pathway |
|
Safe with few side effects |
Unknown long-term toxicity |
|
Effective in aspirin sensitivity |
Variable response –
effective in about 50-70% of patients |
|
Systemic distribution reaches the entire
lung through the circulation |
No predictor of patients that will
respond |
|
Additive effect with inhaled
steroids |
Systemic drug exposure |
|
May reduce steroid dose, or
prevent an increase in steroid dose |
Generally not useful as
monotherapy |
|
Formulations approved for
pediatric dosing |
|
f.
Summary of Clinical Use of Antileukotriene Therapy
i.
Antileukotriene agents are prophylactic controller drugs
used in persistent asthma, including mild, moderate, and severe states
1.
they are not indicated for acute relief or rescue therapy
ii.
These agents may be tried as an alternative to inhaled
corticosteroids or cromolyn-like agents in mild persistent asthma requiring
more than as-needed ß2 agonists
iii.
These agents may not be optimal as mono-therapy in
persistent asthma
iv.
These agents may allow reduction of high-dose inhaled
corticosteroids or prevent an increase in the dose of inhaled steroids
v.
These agents reduce or prevent the need for oral
corticosteroids
vi.
These agents are safe and often effective choices in
managing a wide range of asthma severity