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
SYMPTOMS
NOCTURNAL AWAKENINGS
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Mechs. Of Action
SELECTIVE 2
AGONISTS
SALBUTAMOL
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SELECTIVE 2 AGONISTS
Eg: Salbutamol, Terbutaline, Salmeterol, Formoterol, Bambuterol.
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.
DOSE (salbulatmol):
2 puffs every 46 hours or as needed.
90 mcg/puff, 200 puffs/canister.
SELECTIVE 2 AGONISTS Contd
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ANTI-CHOLINERGICS
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.
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)
ADVERSE EFFECTS:
Narrow therapeutic window.
Nausea, vomiting.
Tremors, seizures, insomnia, agitation, diuresis, arrhythmia,
fever.
INTERACTIONS:
Enzyme inducers (rifampicin, phenytoin, carbamezapine,
phenobarbitone ) decrease theophylline levels.
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CORTICOSTEROIDS
Eg: Inhalation : Beclomethasone, Fluticasone,
Budesonide.
Oral : Prednisolone, Methylprednisolone.
Parenteral : Hydrocortisone, Methylprednisolone
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:
ADVERSE EFFECTS:
INHALATION: Dryness of mouth, voice changes, oral
candidiasis.
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MAST CELL STABILIZER
Eg: Sodium cromoglycate, Nedocromil sodium.
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.
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.
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.
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.
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INTERMITTE MILD SEVERE
MODERATE
NT
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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
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