PHARMACOTHERAPY OF BRONCHIAL ASTHMA

By:
Dr. FAZEEL ZUBAIR AHMED
FINAL YEAR PG,
PHARMACOLOGY
1 TO THE PRESENT DAY
ASTHMA HAS PUZZLED AND CONFUSED PHYSICIANS FROM THE TIME OF HIPPOCRATES
 OVERVIEW
DEFINITION OF ASTHMA
GRADING OF ASTHMA
CLASSIFICATION OF ANTI ASTHMATICS
MECHANISMS OF ACTION
2 AGONISTS
ANTI CHOLINERGICS
METHYLXANTHINES
CORTICOSTEROIDS
MAST CELL STABILIZERS
LEUKOTREINE MODULATORS
ANTI IgE ANTIBODY
MISCELLANEOUS
TREATMENT STRATEGY

2
 DEFINITION

A disease caused by hyper-

responsiveness of the tracheobronchial
tree to various stimuli, which results in
episodic narrowing and inflammation of
the airways.

Tabers cyclopedic medical dictionary. 21st ed.

3
 GRADING OF ASTHMA SEVERITY

SYMPTOMS

NOCTURNAL AWAKENINGS

NTERFERENCE WITH DAILY ACTIVITY

Usually not affected

 CLASSIFICATION OF ANTI-ASTHMATIC AGENTS
1. BRONCHODILATORS 2. LEUKOTREINE ANTAGONISTS
a. Beta2 Agonists Montelukast.
Salbutamol.
3. MAST CELL STABILIZERS
b. Anti cholinergics Sodium cromoglycate.
Ipratropium bromide.
4. CORTICOSTEROIDS
c. Methyl-Xanthines a. Inhalation : Budesonide.
Theophylline. b. Systemic: Hydrocortisone.
Mechanisms Of
Action
OVERVIEW

6
Mechs. Of Action
SELECTIVE 2
AGONISTS
SALBUTAMOL

8
 SELECTIVE 2 AGONISTS
Eg: Salbutamol, Terbutaline, Salmeterol, Formoterol, Bambuterol.

Bronchodilators provide rapid symptomatic relief but do not

control disease process, hence are often termed as Relievers.
2 agonists are currently the mainstay of bronchodilator therapy.
Relax bronchial smooth muscle and also inhibit release of
chemical mediators from mast cells.

PHARMACOKINETICS
Salbutamol, terbutaline are short acting (t=2-4hrs);
Salmeterol, bambuterol, formoterol are long acting (t=12hrs)
 SELECTIVE 2 AGONISTS Contd

THERAPEUTIC USES:
Inhaled salbutamol is Drug Of Choice for terminating acute
attack of bronchospasm.
Due to their 2 selectivity they do not have cardiac stimulating
action in therapeutic doses.

Salmeterol, Formoterol are used for treating nocturnal asthma

or for round the clock prophylaxis of asthma.

DOSE (salbulatmol):
2 puffs every 46 hours or as needed.
90 mcg/puff, 200 puffs/canister.
 SELECTIVE 2 AGONISTS Contd

ADVERSE DRUG REACTIONS:

Minimal on inhalation.
On oral administration
Tremors, restlessness, nervousness, ankle edema,
palpitation, tachycardia (in high doses)
Desensitization of beta2 receptors on prolonged use.

Terbutaline is only safe bronchodilator in pregnancy

Aerosol preparations contain FLUOROCARBON

propellants.
Fluorocarbons sensitize myocardium to toxic effects of
Catecholamines (in high doses).
 ANTI-
CHOLINERGICS
IPRATROPIUM BROMIDE

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 ANTI-CHOLINERGICS

Eg: Ipratropium, Oxitropium, Tiotropium.

Available as aerosol preparations.

Less effective than 2 agonists.
Decrease mucus secretion
Have less drying effect on mucus.

PHARMACOKINETICS:
Poorly absorbed from bronchial mucosa.
Does not cross BBB and devoid of CNS effects.
 ANTI-CHOLINERGICS Contd

THERAPEUTIC USES:
Inhaled Ipratropium is better suited for regular prophylaxis.

Ipratropium in combination with salbutamol gives good results in

asthma and has longer duration of action than when either drug
used alone. Used as aerosol or with nebulization.

Patients of Asthmatic bronchitis, COPD and Psychogenic asthma

respond better to anticholinergics.

DOSE (ipratropium):
23 puffs every 6 hours.
17 mcg/puff, 200 puffs/canister

ADVERSE EFFECTS:
Bad taste and dryness of mouth
after inhalation.
METHYLXANTHIN
ES
THEOPHYLLINE

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 METHYL XANTHINES
Eg: Theophylline, Aminophylline, Diprophylline, Acebrophylline.

Theophylline exerts:
Bronchodilatory and
(via PDE3 and cAMP in bronchial smooth muscle ),
Anti inflammatory effects
(via PDE4 in eosinophills and mast cells).
They also act by blocking adenosine receptors in
Bronchial smooth muscles (A1) and mast cells (A3)
 THERAPEUTIC USES:
Oral theophylline is combined with inhaled 2 agonists for
long term management of Asthma.

DOSE (Theophylline):
Starting dose 10 mg/kg/d upto 300 mg maximum;
(sustained release tablets)

NON ASTHMATIC USES

Dyspnoea associated with pulmonary edema due to CHF.
Aminophylline, as adjuvant with O2 and morphine used in
Paroxysmal dyspnoea associated with LVF.
Its safer to use iv aminophylline than iv adrenaline, if distinction
between bronchial asthma and cardiac asthma is doubtful.
 METHYL XANTHINES Contd

ADVERSE EFFECTS:
Narrow therapeutic window.
Nausea, vomiting.
Tremors, seizures, insomnia, agitation, diuresis, arrhythmia,
fever.

INTERACTIONS:
Enzyme inducers (rifampicin, phenytoin, carbamezapine,
phenobarbitone ) decrease theophylline levels.

Enzyme inhibitors (alcohol, cimetidine, erythromycin)

increase theophylline levels.
CORTICOSTEROI
DS
BUDESONIDE

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 CORTICOSTEROIDS
Eg: Inhalation : Beclomethasone, Fluticasone,
Budesonide.
Oral : Prednisolone, Methylprednisolone.
Parenteral : Hydrocortisone, Methylprednisolone

Often referred to as Controllers because they provide long

term
stabilization of symptoms due to their anti-inflammatory
effects.

MECHANISM OF ACTION
Inhibit release of PGs and LTs.
Produce eosinopenia thereby preventing release of
mediators from eosinophills.
They up-regulate 2 receptors in lung and leucocytes.
CORTICOSTEROIDS
 THERAPEUTIC USES:

Inhaled corticosteroids (budesonide) with inhaled 2

agonists are the First choice drugs for chronic asthma.
2 inhalations twice daily; 80 mcg/puff.

Oral corticosteroids (prednisolone) are prescribed after an

episode of acute attack for 7-10 days to prevent relapse.
7.560 mg OD

Parenteral corticosteroids are used in acute severe

asthma.
 CORTICOSTEROIDS Contd

ADVERSE EFFECTS:
INHALATION: Dryness of mouth, voice changes, oral
candidiasis.

ORAL: side effects are usually not observed as only short

acting
drugs are used and for brief period.
 MAST CELL
STABILIZERS
CROMOLYN SODIUM

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 MAST CELL STABILIZER
Eg: Sodium cromoglycate, Nedocromil sodium.

These are non bronchodilating, nonsteroidal drugs used for

asthma prohylaxis.
Available as inhalers. Cromolyn can also be taken with
nebulization.

MECHANISM OF ACTION:
They prevent degranulation and subsequent release of
chemical mediators from mast cells.
They stabilize mast cells by preventing trans-membrane
influx of Ca++ ions provoked by antigen IgE-antibody
reaction on mast cell membrane.
Also inhibit leucocyte activation and chemotaxis.
 MAST CELL STABILIZER Contd

THERAPEUTIC USES:
When taken regularly for prohylaxis they reduce the
need for bronchodilator / corticosteroid therapy.
Reserved for prophylaxis of chronic and seasonal
asthma.
Ineffective for acute attacks.

Also used in allergic rhinitis and allergic conjunctivitis.

DOSE:
Cromolyn : 2 puffs four times daily; 0.8 mg/puff
Nedocromil : 2 puffs four times daily; 1.75 mg/puff

ADVERSE EFFECTS:
These have least systemic absorption and are well
tolerated making them safe in children and elderly.
Throat irritation, dryness of mouth, mild headache may
 KETOTIFEN
Its a H1 antihistaminic with cromoglycate like action.
It inhibits activation of mast cells, macrophages,
eosinophills, lymphocytes and neutrophils.
Also inhibits release of mediators.

PHARMACOKINETICS:
Absorbed orally.
Bioavailabilty = 50%, undergoes first pass metabolism.
t1/2 = 22hours.
 THERAPEUTIC USE:
It reduces respiratory symptoms in 50% patients of asthma
but improvement in lung function is marginal.

Also used in atopic dermatitis, perennial rhinitis,

conjunctivitis, urticaria and food allergy.

DOSE:
1-2 mg po BD

ADVERSE EFFECTS:
Sedation, dry mouth, dizziness, weight gain.
LEUKOTRIENE
MODULATORS
ZAFIRLUKAST
ZILEUTON

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 LEUKOTRIENE MODULATORS
Eg: Zileuton, Zafirlukast, Montelukast, Pranlukast,
Iralukast.

Leukotrienes are inflammatory mediators. They cause

leukocyte recruitment, stimulate bronchoconstriction and
increase in capillary permeability pulmonary edema.

Leukotrienes are synthesised from arachidonic acid via 5-

lipoxygenase, they act on cys-LT receptors and cause
bronchoconstriction.

Zileuton inhibits 5-lipoxygenase and blocks LT synthesis.

Zafirlukast , Montelukast, etc. block LT receptors.
CORTICOSTEROIDS
 LEUKOTRIENE MODULATORS Contd

THERAPEUTIC USES:
Used as adjuvants with inhaled corticosteroids in poorly
responding patients.
They reduce the dosage of 2 agonists and inhaled
corticosteroids for maintenance.

DOSE:
Montelukast - 10 mg po at bedtime.
Zafirlukast - 20 mg po BD
Zileuton - 600 mg po QID
 LEUKOTRIENE MODULATORS Contd

ADVERSE EFFECTS:
Zileuton causes hepatotoxicity. (withdrawn from many countries)
In rare cases, Zafirlukast and Montelukast have been
associated with Churg-Strauss syndrome (vasculitis,
eosinophilia, worsening of asthma).
MONOCLONAL ANTI -IgE
ANTIBODY
OMALIZUMAB

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 OMALIZUMAB
Novel approach. Its an Antibody To An Antibody

MECHANISM OF ACTION:
Recombinant humanized Monoclonal antibody targeted to
IgE, so the latter cannot bind to its receptors on mast cells
and basophils.
Omalizumab also inhibits activation of IgE already bound
to mast cells and prevents their degranulation.

THERAPEUTIC USES:
Indicated for asthmatic patients who are not adequately
controlled by inhaled corticosteroids.
Not suitable for acute attacks.
 OMALIZUMAB Contd

DOSE:
150375 mg sc every 24 weeks, depending on body
weight.

ADVERSE EFFECTS:
Redness and stinging sensation may occur on injection.

Very costly.
Rs 38,000/-
MISCELLANEOUS
DRUGS
NITRIC OXIDE DONORS.
CLARITHROMYCIN.

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 NITRIC OXIDE DONORS
NO on inhalation dilates pulmonary blood vessels and
relaxes bronchial smooth muscles.
It is considered NANC transmitter in upper airways.

Trials are underway for NO donors that can be used for

acute severe asthma and pulmonary hypertension.

N 30 201 is under Phase I trial by NitroMed.

 MACROLIDES
Chlamydia and mycoplasma infections have been
reported to be precipitating factors for asthma.
Several patients have been benefitted on being treated
with Macrolide.
However injudicious use of antibiotics MUST be avoided to
avoid problem of resistance.
TREATMENT
STRATEGY
__________________

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 INTERMITTE MILD SEVERE
MODERATE
NT

SABA: Short Acting 2 Agonist.

LABA: Long Acting 2 Agonist.
ICS : Inhalational Corticosteroids.
LTRA : Leukotriene Antagonists.
REATMENT OF STATUS ASTHMATICUS / ACUTE SEVERE ASTHM

Increasing chest tightness, wheezing, and dyspnea that is

not relieved by their usual medications.
Patient is unable to complete sentence and may become
cyanotic.
Rx
1. Inj. Hydrocortisone 100mg iv stat;
followed by 100-200 mg 4-8hrly infusion.

2. Nebulized salbutamol (2.5-5mg) + ipratropium bromide

(0.5mg)
Intermittent inhalations driven by O2.

3. Salbutamol 0.4mg im/sc.

4. Antibiotics for chest infections.

SUMMARY
______________

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 SUMMARY
Two main approaches towards treating asthma are-
Bronchodilation and Suppression of inflammation.
2 agoinists corticosteroids are used in emergency.
Anticholinergics, mast cell stabilizers, leukotriene
antagonists are suitable for prophylaxis and chronic asthma.
Omalizumab is a novel drug that inhibits IgE binding to mast
cells.
Macrolide supplementation can benefit asthma when
infection is confirmed.
Nitric oxide donors are being investigated for asthma
treatment.
 BIBLIOGRAPHY

1. Brunton LL, Chabner BA, Knollmann BC. Pulmonary Pharmacology.

Goodman and Gilmans the pharmacological basis of therapeutics. 12th ed.
New York: McGraw-Hill; 2012.
2. Wilson JW, Li X. Vessels: New targets for asthma treatment. Thorax.
2001;56:899900.
3. Sharma P, Halayko AJ. Emerging molecular targets for the treatment of
asthma. Indian journal of biochemistry and biophysics. Vol. 46: December
2009; 447-460.
4. Thomson NC, Chaudhuri R and Spears M. Emerging therapies for severe
asthma. BioMedCentral Medicine. 2011: 9;102.
5. Chessnut MS, Pendergast TJ, Tavan ET. In: Papadakis MA, McPhee SJ,
editors. Pulmonary disorders, CMDT 2013. 52nd ed. New York. McGraw Hill.
p242-260.
THANK Y OU

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