ASTHMA

Khurram Aamir
Pharm-D MPhil
Pharmacology & Toxicology

INTRODUCTION
Asthma is the chronic inflammatory
disorder of airways in which many
cells and cellular elements like mast
cells, eosinophils, T lymphocytes,
macrophages, neutrophils, and
epithelial cells are ivolved.
Inflammation causes recurrent
episodes of wheezing,
breathlessness, chest tightness, and
coughing particularly at night and in

INTRODUCTION
Airway obstruction occur due to
contraction of smooth muscles of
bronchioles
Smooth muscles hypertrophy and
hyperplasia
Inflammatory cells infiltration
Oedema
Goblet cells and mucous gland
hyperplasia
Protein deposition including collagen

RISK FACTORS
Potential triggers for the inflammatory
process include
Allergy
Viral respiratory infection
Gastro-oesophageal reflux disease
Irritants such as tobacco smoke, air
pollutants, and occupational dust, gases
and chemicals non specific stimuli such
as cold air exposure and exercise.

PATHOPHYSIOLOGY
Studies during last 35 years have
revealed 2 principle mechanisms
T helper cell pathway
IgE mediated mechanism
Both these mechanisms leads to
inflammation of the airways and
leads to obstruction of airways.

T HELPER CELL MEDIATED PATHWAY

T helper type 2 cells release
cytokines that include IL-4, IL-5, IL-9,
and IL-13 all of which contribute to
various manifestations of allergic
inflammation and disease.
IL-4 and IL-13 predominantly act
directly on airway smooth muscles
and
epithelium
to
elicit
hypersensitivity reaction, enhanced
glycoprotein
production,
and

MECHANISMS

IgE MEDIATED
PATHWAY

Type 1 or immediate hypersensitive response is

mediated by IgE an antibody isotype produced
by B cells activated by IL-4.
Circulating IgE captured by IgE Receptors
present on effector immune cells such as mast
cells, basophils, eosinophils and other airway
cells.
Upon
binding
cellular
activation
and
degranulation occur and variety of toxic
inflammatory
mediator
release
which
ultimately cause obstruction.

DIAGNOSIS
The diagnosis of asthma is based on
History
Physical examination
Supportive diagnostic testing

HISTORY
The presence of one or more of the
following characteristic symptoms is
suggestive for asthma
Wheeze
Chest tightness
Shortness of breath
Cough

HISTORY
Asthma is specially likely if any of the
following applies
Symptoms are recurrent or seasonal
Symptoms are worse at night or in early
morning
Symptoms are triggered by exercise or
other irritants
Symptoms are rapidly relieved by short
acting bronchodilators

EXAMINATION
Examine chest for hyperinflation and wheeze
Also look sign for allergic rhinitis which commonly
co-occurs with asthma because its presence will
affect management.
Wheeze is suggestive but not diagnostic for asthma
Absence of physical
diagnosis of asthma

signs

does

not

exclude

Crackles on chest auscultation indicate an alternate

or concurrent diagnosis

DIAGNOSTIC TESTING
Spirometry
It helps you to diagnose asthma and
assess asthma control
Assess change in airflow limitation
Measure

degree

of

airflow

limitations

compared with predicted normal airflow

HOW TO PERFORM
Sit upright with feet firmly on floor and do not
lean forward
Breathe in until lungs feel absolutely full
Form a good seal around mouthpiece
Blast air out as fast and hard as possible and for
as long as possible until the lungs are completely
empty
Repeat test until you obtain reproducible and
acceptable measures

INTERPRETING SPIROMETRY
Airflow limitation is judged to be reversible if
either of the following applies:
Baseline FEV > 1.7L and post bronchodilator
FEV at least 12% higher than baseline
Baseline FEV 1.7L and post bronchodilator
FEV at least 200ml higher than baseline

SPIROMETER

Management and Treatment

Non pharmacological treatment
Patient education and teaching of selfmanagement skills should be done
Avoidance of known allergenic triggers can
improve symptoms, reduce medication
use, and decrease BHR.
Environmental triggers (animals) should
be avoided in sensitive patients and those
who smoke should be encouraged to stop

Continue.
Patient with acute severe asthma should

receive supplemental oxygen therapy to

maintain arterial oxygen saturation above
90%
Significant dehydration should be corrected
Urine

specific gravity may

therapy in young children

help guide

CLASSIFICATION

1. Bronchodilators
A. Bets 2 sympathomimetics
Salbutamol
Terbutaline
Bambuterol
Salmetrol
Formoterol
Ephidrine

B. METHYLXANTHINS
Theophylline
Aminophylline
Choline theophylinate
Hydroxyethyl theophylline
Doxyphylline

C. ANTICHOLINERGICS
Ipratropium bromide
Tiotropium bromide
2. Leukotriene
antagonist
Montelukast
Zafirlukast

3. Mast cell stabilizer

Sodium chromoglycate
Ketotifen
4. Corticosteriods
A. Systemic
B.
Inhaled
Hydrocortisone
Beclomethsone
Prednisolone
Budesonide

5. Anti-IgE antibody
Omalizumab
Sympathomimetics
Adrenergic drugs cause bronchodilation by
the stimulation of beta 2 receptors
Adrenergic drugs are the mainstay of
treatment of reversible airway obstruction
but should be cautiously used in
hypertensives and in those receiving
digitalis.

Salbutamol
A highly selective beta 2 agonist and selectivity
is further increased by inhaling the drugs
Inhaled salbutamol produces bronchodilation in
5 min and the action last for 2-4 hours.
It is used to terminate asthma attacks but not
suitable for round the clock prophylaxis.
Side effects are palpitation, restlessness,
nervousness, throat irritation and ankle edema.
Oral bioavailability 50% and acts for 4-6 hours.

Salmetrol
It is the first long acting selective beta 2 agonist
with a slow onset of action used by inhalation
on twice daily schedule for maintenance
therapy and for nocturnal asthma.
It is more beta 2 selective than salbutamol and
more lipophilic which probably accounts for its
longer action.
Clinical studies have shown concurrent use of
inhaled Salmetrol with inhaled glucocorticoid
produces effect equivalent to double dose of CS
alone.

Methyl Xanthins
Theophylline and its compounds have been
extensively used in asthma but are not
considered first line drugs anymore.
Theophylline is one of the three naturally
occurring methyl xanthine alkaloids caffeine,
theophylline and theobromine.
Mechanism of action : (a) release of calcium
from sarcoplasmic reticulum especially in
skeletal and cardiac muscle (b) inhibition of
phosphodiesterase (PDE) which degrades
cyclic nucleotides intracellularly.

Continue..
(c) blockade of adenosine receptors which acts as
a local mediator in CNS, CVS and other organscontract smooth muscles especially bronchial,
dilate cerebral blood vessels, depresses cardiac
pacemaker and inhibit gastric acid secretion.
Pharmacokinetics : it is well absorbed orally
and distributed in all tissues crosses placenta and
secreted in milk
50% plasma protein bound and extensively
metabolized in liver by demethylation and
oxidation.

Continue.
Only 10% excreted unchanged in urine. Its
elimination rate varies with age
At therapeutic concentrations, half life in
adult is 7-12 hours.
Children eliminate it much faster and
elderly eliminate it slowly
Theophylline metabolizing enzyme are
saturable so half life is prolonged with
higher doses.

Adverse effects
Theophylline has a narrow margin of safety
Dose dependent toxity starts from the upper
part of therapeutic concentration
Adverse effects are referable to GIT, CNS and
CVS
Children are more liable to develop CNS toxity.
Gastric pain, rectal inflammation and pain at
IM injection site
Syncope and sudden death due to sudden fall
in blood pressure and ventricular arrhythmias.

Anticholinergics
These drugs cause bronchodilation by blocking
cholinergic receptors and acts primarily in
larger airways.
Inhaled ipratropium bromide is less efficacious
than Sympathomimetics.
Patients of asthmatic bronchitis, COPD and
psychogenic
asthma
respond
better
to
Anticholinergics
They produce slower response than inhaled
Sympathomimetics and are better suited for
regular prophylactic use

Continue
Ipratropium 2-4 puffs 6 hourly or tiotropium 1

rotacap OD.
Combination of inhaled ipratropium with beta 2

agonist

produces

more

marked

and

longer

lasting bronchodilation and can be utilized in

severe asthma
Nebulized ipratropium mixed with salbutamol is

employed in refractory asthma.

Leukotriene antagonist
Cystenyl leukotriene are important mediators of
bronchial asthma
Two LT1 receptors antagonist Montelukast and
Zafirlukast are available
Both have similar action and clinical utility
They antagonize cysLT1 receptors mediated
bronchoconstriction, vascular permeability and
recruitment of eosinophils
Bronchodilation, reduced sputum eosinophils
count, suppression of bronchial inflammation and
hyper reactivity are noted in patients

Continue.
Certain patients are RESPONDERS and
certain are non responders to anti-LT
therapy.
These are indicated for prophylactic therapy
of mild to moderate asthma as alternative to
inhaled glucocorticoids
In severe asthma they may permit reduction
in steroid dose. However, they are not to be
used for terminating asthma episodes
They are effective in aspirin induced asthma.

Continue
Both are very safe drugs and produce few
side effects like headache and rashes and
few cases of Churg-Strauss syndrome are
reported.
They are well absorbed orally. Highly
plasma protein bound and metabolized by
CYP2C9 (montelukast also by CYP3A4)
Plasma half life of montelukast is 3-6 hours
while that of zafirlukast is 8-12 hours.

Zileuton
It is 5-LOX inhibitor, blocks LTC4/D4 as well
as LTB4 synthesis
It is therefore has the potential to prevent
all LT induced responses including those
exerted by activation of cysLT1 receptors
Clinical efficacy in asthma is similar to
montelukast
Duration of action is short and has
hepatotoxic potential so its use is restricted
now.

Mast cell stabilizer

Sodium chromoglycate
It is a synthetic chromone derivative which
inhibit degranulation of the mast cell
Release of mediators of asthma like histamine,
LTs, PAF and interleukin etc is restricted.
Chemotaxis of inflammatory cells is inhibited
Bronchospasm induced by allergens, irritants,
cold air and exercise may be prevented
AG:AB reaction is not interfered with it.

Continue
It is also not a bronchodilator and does not
antagonize constrictor action of histamine,
Ach, LTs. Therefore, it is ineffective if given
during asthmatic attack.
It is not absorbed orally and administered
as an aerosol through metered dose
inhaler delivering 1mg per dose
This is rapidly excreted unchanged in urine
and bile

Ketotifen
It is an antihistaminic with some chromoglycate
like action
Stimulation of immunogenic and inflammatory
cells and mediator release are inhibited
It is absorbed orally and bioavailability is 50%
due to first pass metabolism
It is largely metabolized and half life is 22 hours

Corticosteroids
These are not bronchodilators but they provide
benefit by reducing bronchial hyper reactivity,
mucosal edema and by suppressing inflammatory
response to AG-AB reaction
Systemic steroid therapy is used in severe chronic
asthma which is not controlled by bronchodilators
and inhaled steroids or when there are frequent
recurrences of increasing severity
Starts with prednisolone 20-60mg daily. Attempt
dose reduction 1-2 weeks of good control and
finally shift patient to inhaled steroid

Continue
It is also used in status asthmaticus in which
asthma attack is not responding to intensive
bronchodilator therapy
Inhaled steroids have high topical and low
systemic activity due to poor absorption and
rapid first pass metabolism
They are not considered necessary for patients
with mild and episodic asthma
They are indicated when inhaled beta 2 agonist
are required almost daily or the disease is not
only episodic.

Continue
Inhaled
steroids
suppress
bronchial
inflammation, increase peak expiratory
flow rate, reduce need for rescue beta 2
agonist inhalation and prevent episodes of
acute asthma

ANTI-IgE ANTIBODY
Omalizumab
It is humanized monoclonal antibody
against IgE
Administered i.v or s.c which neutralizes
free IgE in circulation without activating
mast cell and other inflammatory cells
In severe asthma Omalizumab has been
found to reduce exacerbations and steroid
requirement.
It is very expensive so its use is reserved
for resistant asthma patients.

PHARMACOTHERAPY
Beta 2 agonist
Short acting beta 2 agonist are effective in the
management of asthma
Aerosol administration enhance bronchoselectivity
and provide more rapid response and greater
protection against bronchospasm
Albuterol and other inhaled short acting beta2
agonist are indicated for treatment of intermittent
episodes of bronchospasm and treatment of choice
for the acute severe asthma
Regular treatment does not improve symptoms
control over as needed use

CONTINUE..
Formoterol and Salmetrol are inhaled long acting
beta2 agonist indicated as adjunct to long term
treatment for patients with symptoms who are
already

on

low

to

medium

dose

of

inhaled

corticosteroids
Long acting agents are ineffective for the treatment
of acute severe asthma because it takes 20 minutes
for onset and 1-4 hours for maximum effect

CONTINUE..
In acute severe asthma nebulization with
short acting beta2 agonist (albuterol) is
recommended for patients having poor
response to aerosolized beta 2 agents and in
patients with PEF or FEV values less than 30%
Drug of choice for EIB provide protection for
1-2 hours and long acting for 8-12 hours
In nocturnal attack long acting are preferred
over sustained release beta2 agonist and
theophylline

CORTICOSTEROIDS
CS

increase number

receptors

and

of

improve

beta2

adrenergic

responsiveness

on

stimulation and thus reducing mucus production

and hyper secretion, reducing BHR and airway
edema
Inhaled CS are effective long term treatment of

persistent asthma because of their potency and

effectiveness.

CONTINUE..
Patients with moderate disease are treated with twice

daily dosing and patients with severe disease require

multiple daily dosing
Inflammatory response of asthma inhibit binding of

steroid receptors thus higher dose and frequency

require initially and then tapered down
Response to inhaled CS is delayed and symptoms

improve within 1-2 weeks and max improvement in 4-8

weeks

METHYLXANTHINS
Theophylline

appears

to

produce

bronchodilation by inhibiting phosphodiesterase

which reduce inflammation, decrease mast cell
mediator

release,

decrease

lymphocyte

proliferation and cytokine release

Methylxanthins are ineffective by aerosol and
must be taken systemically (oral or IV)

CONTINUE..
Sustained

release

theophylline

is

the

effective oral preparation

Theophylline

when

complexed

with

aminophylline is the preferred parental

product due to increase solubility
IV theophylline is also available

ANTICHOLINERGICS
Ipratropium bromide and tiotropium bromide
are competitive inhibitors of muscarinic receptors
Produce

bronchodilation

only

in

cholinergic

mediated bronchoconstriction
These are effective bronchodilators but not as
potent as beta 2 agonist
They attenuate but do not block exercise induced
asthma

CONTINUE..
Maximum

bronchodilation

by

aerosolized

ipratropium is achieved in 30-60 minutes as

compared to aerosolized beta 2 agonist 510minutes.
Duration of action is 4-8 hours
Indicated as adjunct therapy in severe acute

asthma in patients not responsive to beta 2

agonist alone

MAST CELL STABILIZERS

Cromolyn sodium and Nedocromil sodium
have beneficial effects that are believed to
result from stabilization of mast cell membrane
They inhibit response to allergen challenge as
well as EIB but do not cause dilation
Effective only by inhalation and Cromolyn
available as nebulizer solution

CONTINUE..
These drugs are indicated for mild to
persistent asthma in child and adult
regardless of etiology
Effectiveness comparable to theophylline or
leukotriene antagonist for persistent asthma
Improvement in 1-2 weeks max effect take
longer time
Initial regimen four times daily then reduced
to two times for Nedocromil and three times
for Cromolyn

LEUKOTRIENE MODIFIERS
Zafirlukast and Montelukast are oral leukotriene
receptor antagonists that reduce proinflammatory
and bronchoconstriction effect of leukotriene D4
They improve pulmonary function test, decrease
nocturnal

awakenings

and

improve

asthma

symptoms
Less effective in asthma than low dose inhaled CS

CONTINUE..
Not used to treat acute attacks and must be

taken on regular basis even during symptom

free period
Zileuton is an inhibitor of leukotriene synthesis.

Use of zileuton is limited due to potential for

elevated level of hepatic enzyme and increase
metabolism of some drugs metabolized by
CYP3A4 (theophylline, warfarin)

OMALIZUMAB
It is an anti IgE antibody approved for the
treatment of allergic asthma not well controlled
by oral or inhaled CS
Dosage is determined by the patient baseline
total serum IgE (IU/ml) and body weight
Because of its high cost it is only indicated as
step 5 or 6 care for patients who have allergies
and severe persistent asthma that is
inadequately controlled with combination of
high dose inhaled CS and long acting beta 2
agonist

Combination controller
therapy
Single inhaler combination products containing

fluticasone
Budesonide

propionate
and

and

Formoterol

Salmetrol
are

or

currently

available
Inhalers contains varied doses of steroids but

fixed dose of long acting beta 2 agonist

Addition of beta2 agonist allows 50% reduction

of inhaled CS

CONTINUE..
Combination

therapy

is

more

effective than high dose inhaled CS

alone
Leukotriene receptor antagonist are
also successful as additive therapy in
patients inadequately controlled on
inhaled CS alone