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
Cromolyn sodium
Brand
Name
Intal
Nedocromil sodium Tilade
Zafirlukast
Accolade
Montelukast
Singulair
Zileuton
Zyflo
III.
Formulation and Dose
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
MDI: 1.75 mg/puff
Adults and children ≥ 6 yr: 2 puffs qid
Tablets: 10 mg
Children 5-11 yr: 1 tab bid
Tablets: 20 mg
Adults and children ≥ 12 yr: 1 tab bid
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
Tablets: 600 mg
Adults and children ≥ 12 yr: 1 tab qid
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 highdose 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
iii.
iv.
v.
vi.
vii.
contractility, vascular permeability, and mucus
secretion
Clinical Indication
1. Indicated for the prophylaxis and chronic treatment of
asthma in individuals ≥ 5 years of age
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
Dosage Forms
1. 10 mg oral tablet
2. 20 mg oral tablet
Side Effects
1. headache
2. nausea
3. diarrhea
4. generalized and abdominal pain
5. infection (primarily respiratory)
6. hepatic insufficiency (rare)
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
Oral administration
Disadvantages
Relatively limited anti-inflammatory
action limited to one mediator
pathway
Unknown long-term toxicity
Variable response – effective in about
50-70% of patients
No predictor of patients that will
respond
Safe with few side effects
Effective in aspirin
sensitivity
Systemic distribution
reaches the entire lung
through the circulation
Additive effect with inhaled Systemic drug exposure
steroids
May reduce steroid dose, or Generally not useful as monotherapy
prevent an increase in
steroid dose
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
ii.
iii.
iv.
v.
vi.
states
1. they are not indicated for acute relief or rescue therapy
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
These agents may not be optimal as mono-therapy in
persistent asthma
These agents may allow reduction of high-dose inhaled
corticosteroids or prevent an increase in the dose of inhaled
steroids
These agents reduce or prevent the need for oral
corticosteroids
These agents are safe and often effective choices in managing
a wide range of asthma severity