1. Drugs used in Bronchial Asthma
Dr. S. Parasuraman, M.Pharm., Ph.D.,
Senior Lecturer, Faculty of Pharmacy
AIMST

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. Chronic obstructive pulmonary diseases (COPD)
• Incudes chronic bronchitis and emphysema
– chronic bronchitis: cough associated with inflammation of the
bronchioles
– Emphysema: permanent destruction and enlargement of the airspaces
distal to the bronchioles
• COPDs results airway obstruction, dyspnea, ↓ blood O2
concentrations and ↑blood CO2 concentrations.
• Risk factor of COPD: Smocking and old age
• Treatment: Bronchodilators and long time oxygen therapy.
Antibiotics can be used to treat acute exacerbations caused by
bacterial infections.

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

6. 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

7. 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

8. 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 heard 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 agonists
(albuterol, levalbuterol, metaproterenol, terbutaline, and pirbuterol )

9. 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.,

10. 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 mannor.
– 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.,

11. 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.

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

13. 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.,

14. 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.
– Theophylline is more potent; caffeine has minimal actions.
Cont.,

15. 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.,

16. 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.,

17. Pharmacological actions
of Methyl xanthines
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
Vegas stimulation: ↓ BP
Vasomotor center : ↑ BP
Smooth muscle
Relaxation
Lungs vital capacity- increased
Biliary spasm: relieved
Kidney
Mild diuretics (Inhibiting reabsorption of Na+ & H2O)
Increase the renal blood flow
Increase the g.f.r.
Mast cell
Inhibit the release of histamine
Stomach
Enhance the secretion of acid, Pepsin
Metabolism
Increase BMR
It has variable physiological actions

18. 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 rat various 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.

19. 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

20. 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.,

21. 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

22. 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

23. Leukotriene antagonists
• Mechanism of action of leukotriene antagonist, antiinflammatory drugs
Cont.,
Bronchoconstriction, I
nflammation, increase
d mucus
Bronchoconstriction, Infla
mmation, Pain
Block by steroidal
antiinflammatory
drugs
Block by nonsteroidal
antiinflammatory
drugs
Block by
Leukotriene
antagonists

24. 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 contorted by bronchodilator and inhaled steroids.
– Status asthmaticus/ acute asthma exacerbation: ‘’’

25. 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
– Sever chronic asthma: Not contorted by bronchodilator and inhaled steroids.
– Status asthmaticus/ acute asthma exacerbation: ‘’’

26. 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.

27. 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 congestion
Adverse effect (Ketotifen):
Generally well tolerated
Sedation and dry mouth
Dizziness, nausea and weight gain

28. 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.