Dr. Shikha Sachdeva Assistant Professor MMCP,MMDU

1. Drugs usedin Bronchial Asthma
Dr. Shikha Sachdeva
Assistant Professor
MMCP,MMDU

2. Bronchial Asthma
• Asthma as an inflammatory illness
• Accounting 5000 deaths/ year in USA
• Asthma is common disorder and it is characterized by airway
inflammation and hyperresponsiveness to stimuli that produce
bronchoconstriction. These stimuli include cold air, exercise, a
wide variety of allergens and emotional stress.
– Extrinsic asthma: It is mostly episodic, less prone to status
asthmaticus.
– Intrinsic asthma: It tends to be perennial, status asthmaticus is
more common.

3. Pathophysiology
of asthma

4. Bronchial Asthma: Treatment
approaches
• Prevention of antigen antibody reaction: Avoidance of
antigen, hyposensitization
• Neutralization of IgE: Omalizumab
• Suppression of inflammation and bronchial hyper reactivity:
Corticosteroids
• Prevention of release of mediators: Mast cell stabilizers
• Antagonism of released mediators: Leukotriene
antagonists, antihistamines, platelet aggravating factor (PAF)
antagonist
• Blocked of constrictor neurotransmitter: Sympathomimetics
• Directly acting bronchodilators: Methylxanthines

5. Classification
• Bronchodilators
– β Sympathomimetics:
Salbutamol, Terbutaline, Bambuterol, Salmeterol, Formoterol,
Ephedrine.
– Methylxanthines: Theophylline (anhydrous), Aminophylline, Choline
theophyllinate, Hydroxyethyl theophylline, Theophylline ethanolate of
piperazine, Doxophylline.
– Anticholinergics (muscarnic receptor antagonist): Ipratropium
bromide, Tiotropium bromide.
• Leukotriene antagonists: Montelukast, Zafirlukast.
• Mast cell stabilizers: Sodium cromoglycate, Ketotifen.
• Corticosteroids
– Systemic: Hydrocortisone, Prednisolone and others.
– Inhalational: Beclomethasone dipropionate, Budesonide, Fluticasone
propionate, Flunisolide, Ciclesonide.
• Anti-lgE antibody: Omalizumab

6. Bronchodilators
Stimulates
2-adrenergic
receptors of bronchi
2-agonists
Anticholinergic
drugs
Smooth
muscle
relaxation
reduce tonus
of vagus
Methylxanthines
inhibit phosphodiesterase
2-agonists: treatment of
acute asthmatic attacks
Muscarinic antagonist: Less
useful in asthma, used for
treat COPDs
Methylxanthines: Long-term/
prevent bronchoconstriction

7. Sympathomimetics
• The selective β2 agonist is the primary bronchodilators used in the
treatment of asthma/ acute asthmatic attacks.
• β2 adrenergic receptor agonists stimulates the beta receptor, increasing
the cAMP concentration in smooth muscle and causing
bronchodilatation. It also increase the conductance of large Ca2+-
sensitive K+ channels in airway smooth muscle, leading to membrane
hyperpolarization and relaxation.
• The selective β2 agonist relax the bronchial smooth muscle without
affecting cardiac function. In higher doses selective β2 agonist
increasing the heart rate by stimulating the cardiac β1-receptor. The
selective β2 agonist produce hypertension to patient those receiving
digitalis.
• Types:
– Long-acting β2 adrenergic receptor agonists (Salmeterol;
formoterol)
– Short-acting β2 adrenergic receptor
(albuterol, levalbuterol, metaproterenol, terbutaline, and
pirbuterol)
agonists

8. Sympathomimetics
• Salbutamol:
– Selective β2 agonists with less cardiac side effects
– Inhaled salbutamol produce bronchodililation within 5-min and the action
lasts for 2-4 h.
– Used for acute asthmatic attack. Not suitable for prophylaxis
– Side effect: Palpitation, restlessness, nervousness, throat irritation and
ankle edema.
– Metabolism: metabolized in gut; oral bioavailability is 50%.
– Duration of action: oral salbutamol acts 4-6 h.
– Dose: 2-4 mg/ oral; 0.25- 0.5 mg/ i,.p., or s.c.,; 100-200 μg/ inhalation
• Terbutaline:
– Similar to salbutamol; regular use dose not reduce bronchial hyper-reactivity
– Dose: 5 mg/ oral; 0.25 mg/ i,.p., or s.c.,; 250 μg/ inhalation
Cont
.,

9. Sympathomimetics
• Bambuterol:
– Biocarbamate ester of prodrug of terbutaline
– Slowly hydrolyzed in plasma and lung by pseudocholinesterase to release
the active drug over 24 h. It also reversely inhibits pseudocholinesterasein
a dose dependent manner.
– Used in chronic bronchial asthma in a singe evening dose of 10-20 mg/ oral.
• Salmeterol:
– First long acting selective β2 agonists with slow onset of action
– Twice daily for maintain the therapy/ nocturnal asthma, but not for acute
asthma
– Concurrent use of inhaled glucocorticoid with salmeterol is advised for
patient with persistent asthma.
– COPD: equivalent to inhaled anticholinergics in COPD. Reduce
breathlessness by abolishing the reversible component of airway
obstruction.
• Formoterol:
– Long acting selective β2 agonists which acts 12 h when inhaled.
– Compare to salmeterol it has a faster onset of action (with in 10 min)
Cont
.,

10. Methylxanthines
• Theophylline and its derivatives are most commonly used for the
treatment of COPD and asthma.
• Caffeine, theophylline and theobromine are naturally occurring
xanthine alkaloids which have qualitatively similar actions.
• Mechanism of action:
– Methylxanthines inhibits cyclic nucleotide phosphodiesterase (PDEs),
thereby preventing conversion of cAMP and cGMP to 5’-AMP and 5’-
GMP, respectively. Inhibition of PDEs will lead to an accumulation of
intracellular cAMP and cGMP. Bronchodilataion, cardiac stimulation
and vasodilatation occur when cAMP level rises in the concerned
cells. Theophylline and related methylxanthines are relatively
nonselective in the PDE subtypes inhibitor.
– Theophylline is a competitive antagonist at adenosine receptors.
Adenosine can cause bronchoconstriction in asthmatics and potentiate
immunologically induced mediator release from human lung mast
cells. Methylxanthines inhibits the adenosine action thereby casing
bronchodilataion.

11. Methylxanthines
• Mechanism of
action:
Bronchodilation
Bronchial tone
Muscarinic
antagonist
Acetylcholine
Adenosine
Theophylline
cAMP
ATP
AMP
Adenylyl cyclase
Phosphodiesterase (PDE)
Theophylline
Beta agonist

12. Methylxanthines
• Pharmacological action:
• CNS:
– Stimulant; affects higher center.
– Caffeine 150-200 mg produce a sense of wellbeing, alertness, beats
boredom, allays fatigue and improve performance and increase the motor
activity. Caffeine is more active than theophylline in producing these effects.
– Higher dose cause nervousness, restlessness, panic, insomnia and
excitements.
– Still higher dose cause tremors, delirium and convulsions. Theophylline is
more toxic than caffeine.
– Stimulates medullary vagal, respiratory and vasomotor centers.
– High dose: Vomiting and gastric irritation and CTZ stimulation.
Cont
.,

13. Methylxanthines
• Pharmacological action:
• CVS
– Stimulates the heart and increase force of contraction. Increase the heart
rate (direct action) but decrease it by vagal stimulation- net effect is
variable.
– Tachycardia; increased cardiac output; increased cardiac work
– High dose: cardiac arrhythmias
– Effect on blood pressure is variable and unpredictable. Usually a rise in
systolic and fall in diastolic BP is observed.
• Vasomotor center and direct cardiac stimulation- tends to raise BP
• Vagal stimulation and direct vasodilatation- tends to lower BP
• Smooth muscles:
– Relaxation
– Theophylline is more potent and slow, sustained dose related
bronchodilatation
– Increase vital capacity
– Direct action due to adrenergic stimulation
– Biliary spasm is relived, but the effects on intestines and urinary tract
is negligible.
Cont
.,

14. Methylxanthines
• Pharmacological action:
• Kidney
– Mild diuretics
– Inhibiting tubular reabsorption of Na+ and water
– Increasing vascular blood flow and g.f.r.
– Theophylline is more potent; caffeine has minimal actions.
• Skeletal muscles:
– Caffeine enhance contractile power. In high dose it increases release of
Ca+ from sarcoplasmic reticulum by direct action.
– Twitch response at low doses.
– Caffeine facilitates neuromuscular transmission by increasing Ach release.
• Stomach:
– Enhance secretion of acid and pepsin
– Gastric irritation (more with theophylline)
Cont
.,

15. Methylxanthines
• Pharmacological action:
• Metabolism
– Increase BMR.
– Plasma free fatty acid levels are increased.
• Mast cells and inflammatory cells:
– Theophylline inhibits the release of histamine and other mediators form
mast cells and active inflammatory cells.
Cont
.,

16. CNS
Stimulation
Increase motor activity
Improve the performance
CVS
Stimulate the heart
Increase the force of contraction
High dose: cardiac arrhythmias
BP:effect is variable
Stimulation of
Vegasstimulation: ↓ BP
Vasomotor center : ↑ BP
Smooth muscle
Relaxation
Lungsvital capacity- increased
Biliary spasm:relieved
Mast cell
Inhibit the releaseofhistamine
Stomach
Enhancethe secretion of acid, Pepsin
Kidney
Mild diuretics(Inhibiting reabsorption of Na+& H2O)
Increase the renal bloodflow
Increase the g.f.r.
Metabolism
Increase BMR
Pharmacological actions
of Methyl xanthines
It has variable physiological actions

17. Methylxanthines- Theophylline
• Pharmacokinetics:
– Absorption: Absorbed orally; rectal absorption form suppositories is erratic.
– Distribution: All tissues; cross BBM; crosses placenta and is secreted in
milk; 50%
plasma protein bound
– Metabolism: Metabolized in liver (CYPP1A2) by demethylation and
oxidation.
– Excretion: Excreted in urine; 10 % of total administration excreted
unchanged
form. Elimination rate varies considerably with age (age dependent excretion).
– Adult t1/2 is around 7-12 h. Children elimination is much faster (t1/2 3-5 h); In
premature infants has prolonged t1/2 (24-36 h).
– In higher dose pharmacokinetics changes form first order to zero order.

18. Methylxanthines- Theophylline
Cont
.,
• Adverse effects:
– Narrow margin safety
– CVS and CNS stimulant; ADRs not dependent to dose; GIT distress
– Children are more liable to developed CNS toxicity
– Rapid i.v injection cause- precordial pain, syncope and sudden death
Bronchodilatation

19. Methylxanthines- Theophylline
• Interactions:
– Theophylline metabolism decreased by
smoking, phenytoin, rifampicin, phenobarbitone and charcoal broiled meat
meal., which increases the parenthesis.
– Erythromycin, ciprofloxacin, cimetidine, oral contraceptives and allopurinol
inhibits CYP1A2 and increasing the theophylline plasma concentraction; dose
should be reduced to 2/3.
– Theophylline reduce the effects of phenytoin, lithium.
– Theophylline enhance the effects of
furosemide, sympathomimetics, digitalis, oral anticoagulants and
hypoglycemics.
• Indications:
– Primarily used to treat chronic obstructive lung disorders and asthma.
– Also used to treat apnea
Cont
.,

20. Anticholinergics
Ipratropium/ tiotropium (derivative of
atropine)
• Parasympathetic activation/ release of ACh cause bronchoconstriction
and increase mucus secretion.
• Blocking the action of ACh by anticholinergic drugs produce
bronchodilation and also reduce the volume of respiratory secretion.
• Less effective than sympathomimetic.
• Inhaled ipratropium/ tiotropium are choice of bronchodilator choice in
COPD.
• Tritropium produce longer duration of action than ipratropium
• ADR: Dry mouth, respiratory tract discomfort

21. Leukotriene antagonists
Montelukast, Zafirlukast
• Both are having similar action and clincial utility
• Block the cys-leukotrienes C4, D4 and E4 (LTC4, LTD4, LTE4)
• Alternative for inhaled glucocorticoids
• Prophylactic therapy for mild, moderate asthma; not used for
terminating asthma.
• Both are very safe drugs and ADRs are few (headache, rashes);
eosinophilia and neuropathy are infrequent. Few cases Churg-
Strauss syndrome (vasculitis with eosinophilia) have been
reported.
• Dose: Montelukast 10 mg OD, Zafirlukast 20 mg BD

22. Leukotriene antagonists
• Mechanism of action of leukotriene antagonist,
antiinflammatory drugs
Cont
.,
Bronchoconstriction,
Inflammation,
increase d mucus
Bronchoconstriction,
Infla
mmation, Pain
Block by
steroidal
antiinflammato
ry drugs
Block by
nonsteroidal
antiinflammatory
drugs
Block by
Leukotriene
antagonists

23. Corticosteroids
• Corticosteroids are not bronchodilator; benefit by reducing
bronchial hyperreactivity, mucosal edema and by suppressing
inflammatory.
• Inhaled glucocorticoids are partially absorbed and because of
their systemic AEs oral glucocorticoids are usually reserved for
patients with severe persistent asthma.
• Systemic steroid therapy
– Sever chronic asthma: Not controlled by bronchodilator and inhaled
steroids.
– Status asthmaticus/ acute asthma exacerbation: ‘’’

24. Corticosteroids
Inhaled steroids
• High topical and low systemic activity (due to poor absorption/
fast pass metabolism).
• Inhaled steroids are not recommended for patient with mild or
episodic asthma. High dose inhaled steroids are beneficial for
advanced COPD with frequent exacerbations.
• Systemic steroid therapy
– Severe chronic asthma: Not controlled by bronchodilator and inhaled
steroids.
– Status asthmaticus/ acute asthma exacerbation: ‘’’

25. Mast cell stabilizers
Sodium cromoglycate, Ketotifen
• Inhibits degranulation of mast cell by trigger stimuli and prevent
the release of histamine, LTs, PAF, interleukins etc. from mast
cells. Inhibition of mediator release by cromolyn is through
blockade of calcium influx in mast cells.
• Long time therapy reduce cellular inflammatory response.
• It is not histamine antagonist/ bronchodilator- ineffective in
asthmatic attack.
• Pharmacokinetic:
– Not absorbed orally. It is administered as an aerosol through metered dose
inhaler delivering 1 mg per dose; 2 puffs 4 times a day
– Not popular- production of cough and bronchospasm because of
particulate nature of the inhalation.
– Small fraction of the inhaled drug is absorbed systemically and
excreted unchanged form in urine and bile.

26. Mast cell stabilizers
• Use:
– Bronchial asthma: Sodium Cromoglycate is used as a long term
prophylactic in patients not adequately controlled by inhaled
bronchodilators. Alternative for inhaled steroids in mild to moderate
asthma but not severe cases.
– Allergic rhinitis: Cromoglycate is not nasal decongestant, regular
prophylactic use as a nasal spray produces symptomatic improvement in
many patients.
– Allergic conjunctivitis: Regular use as eye drops is benificial in some
chronic cases
Cont
.,
Adverse effect
(cromoglycate):
Bronchospasm
Throat irritation
Cough,
headache
Arthralgia, rashes and
dysuria Rarely nasal
Adverse effect
(Ketotifen):
Generally well tolerated
Sedation and dry mouth
Dizziness, nausea and weight
gain

27. Anti-lgE antibody: Omalizumab
• recombinant DNA-derived monoclonal antibody
• Selectively binds to human immunoglobulin E (IgE) and decrease
binding affinity of IgE to the high-affinity IgE receptor on the surface of
mast cells and basophils, reduce allergic response.
• Omalizumab may be particularly useful for treatment of moderate to
severe allergic asthma in patients who are poorly controlled with
conventional therapy.
• Due to the high cost of the drug, limitations on dosage, and limited
clinical trial data, it is not currently used as firstline therapy.