Anti Asthmatic Agents

Ana Marie R. Morelos, MD, DPPS

Asthma
One of the most common chronic
diseases worldwide and the
prevalence is increasing, especially
among children.
Fortunately asthma can be treated
and controlled

Asthma
Causes recurrent episodes of
wheezing
breathlessness
chest tightness
nocturnal coughing

Chronic inflammatory disorder of the

airways (3 cells)

Asthma
Increased airway responsiveness to
various stimuli (risk factors)

leading to widespread but variable

airflow obstruction
reversible spontaneously or with
treatment.

Asthma
Asthma attacks ( exacerbations) are
episodic but airway inflammation is
chronically present.
For many patients, medications must
be taken every day
To control symptoms
To improve lung function
To prevent attacks
To relieve acute symptoms: cough,
wheezing, chest tightness.

Risk Factors for Asthma

Host factors
Environmental factors

Exposure to allergens & viral infxns

Diet
Tobacco smoke
Socioeconomic status
Family size

Asthma Triggers

Viral infections of the resp. tract

Aeroallergens
Environmental tobacco smoke
Air pollutants

Asthma Triggers

Strong/noxious odors or fumes

Occupational exposure
Cold/Dry air
Exercise
Crying/laughter/hyperventilation
Co-morbid conditions

Asthma Pathogenesis (acute)

Early phase response: within 10-20 min
of airway exposure to the trigger allergen/antigen binds to the
IgE surface

activation of mast cells/macrophages

release of histamine and leukotrienes
contraction of airway smooth muscles
increased mucous secretion,
vasodilation and increased blood flow
microvascular leakage of plasma
thickening of airway walls

Asthma Pathophysiology (acute)

Late phase response
6-12hrs of allergen exposure
recruitment and activation of cells
(infiltration by neutrophils, eosinophils,
basophils, monocytes) cause further
mucus production, inflammation and
bronchospasm more wheezing

Asthma Pathophysiology
Studies on bronchial
hyperreactivity:
Release of mediators from mast
cells
Activation of neural or humoral
pathways leading to exaggeration
of responsiveness

Asthma Pathophysiology
chronic phase failure to interrupt
ongoing inflammatory cycle
non specific bronchial
hyperresponse leads to airway wall
remodeling :
unless treated early and
aggressively, airway remodeling can
cause irreversible reduced
pulmonary function

Asthma major types of drugs

Sympathomimetics
Beta 2 selective drugs
Glucocorticosteroids
Sodium chromoglycate
Methylxanthines
Antileukotrienes
Anticholinergics
Anti-IgE monoclonal antibodies

Routes of Drug Delivery

Inhaled Route
Oral
Parenteral

Asthma Medications
Inhaled medications
High therapeutic ratio :
high concentration of low doses
of the drug
delivered directly to the airways
potent therapeutic effects
few systemic side effect

Asthma Medications
Inhaled medications
Devices
Pressurized metered-dose
inhaler (pMDI)
Breath-actuated metereddose inhaler
Dry powder inhaler (DPI)
Nebulizer
Spacer (holding chamber)

MDI & spacer

Nebulizer

Nebulizer - mask

Nebulizer - mouthpiece

Asthma Medications
Oral medications
Higher doses
More systemic side effects
Reserved for patients unable to use
inhalers
For drugs that are ineffective via the
inhaled route

Parenteral medications
IV for severely ill
More side effects

Bronchodilators
2 Adrenergic agonists
(sympathomimetics)
Theophylline
(methylxanthine)

Anticholinergic agents
(muscarinic receptor antagonists)

2 Adrenergic agonists

Epinephrine non selective agonist

Albuterol/Salbutamol
Terbutaline
Salmeterol
Formoterol
MOA: bind to Beta2 receptors in
airway smooth muscle, activate Gadenylyl cyclase cAMP-PKA pathwaymuscle relaxation, decrease airway
resistance.

2 Adrenergic agonists
Side Effects
Muscle tremor
Tachycardia and palpitations
Hypokalemia
V/Q mismatch
Metabolic effects

2 Adrenergic agonists
Tolerance desensitization or
subsensitivity
Relative resistance of airway
smooth muscle responses to
desensitization may reflect the
large receptor reserve: >90% of
2 receptors may be lost without
any reduction in the relaxation
response.

Methylxanthines

Theophylline
Doxofylline
Aminophylline

Methylxanthines
MOA

Phosphodiesterase inhibition
Adenosine receptor antagonism
Interleukin-10 release
Reduce expression of inflammatory
genes during gene transcription
Promotion of apoptosis in eosinophils
and neutrophils
Histone deacetylase activation

Methylxanthines
Theophylline side effects

Nausea and vomiting

Headaches
Gastric discomfort
Diuresis
Cardiac arrhythmias
Epileptic seizures
Behavioral disturbance and learning
difficulties in children

Methylxanthines
Clinical Uses
IV aminophylline for those nonresponders/intolerant of 2 agonists
Theophylline added to agonist for
more adequate bronchodilation
Theophylline added to inhaled
corticosteroid for better symptom
control and lung function (vs doubling
the dose of inhaled steroid)

Muscarinic Cholinergic Antagonists

Atropine
Ipratropium bromide

Muscarinic Cholinergic Antagonists

MOA
Inhibit the effect of
acetylcholine at muscarinic
receptors
Relax airway smooth muscle
Decrease mucus secretion

Muscarinic Cholinergic Antagonists

Clinical Use as bronchodilator
Atropine IV
Bronchodilation > tachycardia

Ipratropium bromide - inhalation

Can be delivered in high doses
Poorly absorbed into the circulation
Does not readily enter the CNS
For pt intolerant of inhaled 2 agonists
Combined with salbutamol
enhanced bronchodilation for acute
severe asthma

Muscarinic Cholinergic Antagonists

Side Effects
Very few because generally well
tolerated
Systemic side effects uncommon
Bitter taste of inhaled Ipratropium
May precipitate glaucoma in elderly:
direct effect of nebulized drug on
eye, therefore should nebulize with
mouthpiece not face mask.
Urinary retention in elderly

Corticosteroids

Prednisone
Prednisolone
Hydrocortisone
Methylprednisolone
Beclomethasone
Budesonide
Fluticasone
Triamcinolone

Corticosteroids
MOA
Enter target cells and bind to GR
(glucocorticoid receptors) in the
cytoplasm
Steroid-GR complex enters the nucleus
and repress transcription factors that
activate inflammatory genes anti
inflammatory effect of steroids

Corticosteroids
Anti-inflammatory effects in asthma
Inhibit the formation of cytokines IL, TNF,
GM-CSF (secreted by T lymphocytes,
macrophages, mast cells)
Decrease eosinophil survival apoptosis
Prevent and reverse the increase in
vascular permeability due to inflammatory
mediators resolution of edema
Inhibit mucus secretion by airway
submucosal glands

Corticosteroids
Inhaled steroids
Act locally on the airway mucosa
May be absorbed from airway and
alveolar surface
May be deposited in oropharynx,
swallowed, absorbed from the gut
Use of spacer chamber; mouth rinsing
and discarding the rinse reduce
oropharyngeal deposition and
absorption

Corticosteroids
Systemic Steroids
IV steroids - acute asthma, if lung
function is <30% , if no significant
improvement with nebulized 2 agonist
Oral steroids acute exacerbations,
short course, single dose in am (diurnal
pattern)

Corticosteroids
Local side effects (inhaled steroids)
Dysphonia
Oropharyngeal candidiasis
Cough

Systemic side effects

Adrenal suppression/insufficiency
Growth suppression, Bruising, Osteoporosis,
Cataracts, Glaucoma
Metabolic abnormalities
Psychiatric disturbances
Pneumonia

Leukotriene Pathway Inhibitors

Montelukast
Pranlukast
Zafirlukast
Zileuton

Leukotriene Pathway Inhibitors

MOA
inhibition of 5-lipoxygenase,
thereby preventing leukotriene
synthesis
zileuton

inhibition of the binding of LTD4 to

its receptor on target tissues,
thereby preventing its action
Zafirlukast
Montelukast

Leukotriene Pathway Inhibitors

Clinical Uses
Inhibit bronchoconstrictor effects of
LTD4. allergens, exercise, cold air,
aspirin
Add-on therapy for pts poorly controlled
by ICS
Prevent exercise induced asthma
Effective in tablet form
Most prescribed: Montelukast OD
dosing, taken without regard to meals,
approved for 2yrs & above

Leukotriene Pathway Inhibitors

Adverse Events
Liver toxicity Zileuton
Churg-Strauss syndrome ?
rare vasculitis that affects the heart,
peripheral nerves, and kidney and is
associated with increased circulating
eosinophils and asthma.

Asthma Medications
Reliever (Rescue)
Work quickly to treat attacks or
relieve symptoms
Beta 2 agonists, anticholinergics,
theophylline, epinephrine

Controller
Keep sx and attacks from starting
Steroids, cromolyn, long acting Beta 2
agonists, sustained release theophylline,
antileukotrienes, omalizumab

Controller Medications
Glucocorticoids
Inhaled: Budesonide, Fluticasone,
Beclomethasone, Triamcinolone
Tab/Syrup:Hydrocortisone,Methylprednisolone, Prednisolone, Prednisone

Sodium cromoglycate
Cromolyn

Sustained-release Methylxanthines
Theophylline, Aminophylline

Controller Medications
Long-acting 2-agonists
(-adrenergics/sympathomimetics)
Inhaled: Formoterol, Salmeterol
Sustained-release tabs: Salbutamol,
Terbutaline

Antileukotrienes
Montelukast, Pranlukast, Zafirlukast,
Zileuton

Controllers: Glucocorticoids
Inhaled steroids
Beginning dose depends on severity
titrated down over 2-3mos
Side effects:( high doses)
Potential but small risk of side effects is
well balanced by efficacy
Prevent oral candidiasis

Controllers: Glucocorticoids
Tablets/Syrups
Daily control: lowest effective dose 540mg prednisone equivalent in am
Acute attacks:
4060mg daily in 1-2divided doses young
children: 1-2mg/kg/day
Long-term use: SE/coexisting
conditions worsened by oral steroids
alternate day a.m. dosing less toxic
Short-term use: 3-10day bursts prompt
control

Controllers: Cromolyn
MDI 2-4 inhalations tid/qid
nebulizer 20mg tid/qid
Minimal side effects
coughing on inhalation
May take 4-6 wks for maximum
effects

Controllers:
Sustained-release Methylxanthines
10mg/kg/day in 2 divided doses
max: 800mg
Nausea and vomiting
higher doses: seizure, tachycardia,
arrhythmia
Requires theophylline level
monitoring

Controllers:
Long-acting 2 Agonist
Inhaled
1-2 puffs bid
Fewer/less significant side effects
Adjunct to anti-inflammatory tx
Best combined with low-medium doses
of inhaled glucocorticosteroids

Controllers:
Long-acting 2 Agonist
Sustained-release tablets
For adolescents
Salbutamol 3-6mg/kg/day
Terbutaline 10mg q 12h

SE: tachycardia, anxiety, tremors,

headache, hypokalemia

Controllers: Antileukotrienes
Bronchodilator and anti-inflammatory
Reduce exercise induced, aspirin
induced and allergen induced
bronchoconstriction
No significant adverse effects

Reliever Medications
Short-acting 2-agonist
Inhaled/tab/syrup: Albuterol, Fenoterol,
Metaproterenol,Salbutamol, Terbutaline

Anticholinergics
Ipratropium bromide

Short-acting theophylline
Aminophylline

Epinephrine injection

Relievers:
Short-acting 2 agonist
Prn symptomatic use and pretx
before exercise: 2puffs MDI
Asthma attack: 4-8puffs q 2-4h
may administer q 20min x 3
SE: tachycardia, tremor, headache,
irritability, hyperglycemia, hypoK
(inhaled less SE)
DOC for acute bronchospasm
Overuse

Relievers: anticholinergics
4-6 puffs MDI q 6h or nebulize q 20
min x 3
SE: minimal mouth dryness or bad
taste in mouth
May provide additive effects to 2
agonist but slower onset of action
Alternative for those intolerant to 2
agonists

Relievers: Aminophylline
7mg/kg loading dose over 20min then
0.4mg/kg/hr continuous infusion
SE: nausea, vomiting headache
higher doses: seizure, tachycardia,
arrhythmia
Requires theophylline level
monitoring

Relievers: Epinephrine
1:1000 solution ( 1mg/ml) 0.01mg/kg
up to 0.3-0.5mg q 20min x 3
Similar effects as 2 agonists
SE: hypertension, fever, vomiting,
hallucinations
In general, not recommended for
treating asthma attacks if selective
2 agonists are available

Have a nice day!