Drugs acting on respiratory system Drugs used for bronchial asthma Pharmacology III

1. Drugs used in the treatment of
Asthma
Sapana Jain
M. pharm, Quality Assurance

2. • The term asthma means “to stay awake in
order to breathe”
• Its chronic inflammatory disease in which
patient suffers from reversible episodes of
airway obstruction due to bronchial hyper
responsiveness.
• The symptoms are breathlessness, wheezing,
cough and chest tightness with worsening of
these symptoms at night.

3. • Its classified as extrinsic or intrinsic.
• If its associated with specific allergen like
pollen grain, then its called extrinsic asthma.
• Unlike this, when there is no identifiable
external factor ,then its called as instrinsic
asthma
• Extrinsic asthma is episodic while intrinsic
asthma is perennial

4. Pathophysiology of Asthma
• Antigens like pollen grains sensitize individuals by
promoting production of IgE type of antibodies which
remain circulating in the blood or are attracted to the
mast cells of nasal/ bronchial tissues and basophils.
• On subsequent exposure to same antigen, there is
antigen-antibody reaction on the surface of lung mast
cells causing release of mediators like histamine,
serotonin, PGD2 and leucotrienes like LTC4/LTD4.
• Both leucotrienes are powerful broncho- constrictors.

5. Pathophysiology of Asthma
• In the delayed phase, mast cells release
leucotrienes as LTB4 and cytokines like IL-4,IL-5
and IL-13
• Eosinophil ,basophils and alveolar macrophages
are rich in these mediators.
• There are few other mediators like adenosine,
neurokinin—A and platelet activating factor(PAF)
which together cause inflammation, increased
vascular permeability , chemotaxis of neutrophils,
and eosinophil bronchoconstriction and bronchial
hypersensitivity

6. Classification of anti –Asthamatic
drugs
• 1)Bronchodilators
 Selective B2 agonists like salbutamol
Non selective sympathomimetics like
Ephedrine
Anti cholinergic like Ipratropium
Methylxanthine like theophylline

7. 2)Corticosteroids
Orallly active Corticosteroids like prednisolone
Parenteral corticosteroids like Hydrocortisone
Inhalational Corticosteroids like beclomethasone
3)Mast cells stabilisers
Sodium cromoglycate
4) Leucotriene modulators
5-lipooxygense inhibotors like Zileuton
Cysteinyl Leucotriene – antagonist like Zafirlucast
• 5)Monoclonal antibodies like
Omlizumab

8. Mechanism of action

9. 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
increase the heart rate by stimulating the cardiac β1-receptor.
Types: –
A)Long-acting β2 adrenergic receptor agonists: (Salmeterol; formoterol)
B)Short-acting β2 adrenergic receptor agonists: (albuterol, levalbuterol,
metaproterenol, terbutaline, and pirbuterol )

10. 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

11. Sympathomimetics
• Bambuterol:
• Bicarbamate ester prodrug of terbutaline
• It also reversely inhibits pseudo cholinesterase in a dose dependent
manner.
• Used in chronic bronchial asthma in a single 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 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. – Compared to salmeterol it has a faster onset of action
(with in 10 min)

12. 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.

14. 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.

15. 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.
• 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
• Theophylline is more potent; caffeine has minimal actions.

16. 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)

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).

18. Methylxanthines-
• Theophylline
• 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
concentrations; dose should be reduced to 2/3.
• Theophylline reduce the effects of phenytoin, lithium. –
Theophylline enhance the effects of furosemide,
sympathomimetic, digitalis, oral anticoagulants and hypoglycemic.
• Indications:
Primarily used to treat chronic obstructive lung disorders and
asthma.
Also used to treat apnea

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 reduce the volume of
respiratory secretion.
• Less effective than sympathomimetic.
• Inhaled ipratropium/ tiotropium are choice of
bronchodilator choice in COPD.
• Triotropium produce longer duration of action than
ipratropium
• ADR: Dry mouth, respiratory tract discomfort

21. Leukotriene antagonists
Leukotriene antagonists :Montelukast, Zafirlukast
• Both are having similar action and clinical 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.
Dose: Montelukast 10 mg OD, Zafirlukast 20 mg BD

22. Corticosteroids
• Corticosteroids are not bronchodilator; benefit by
reducing bronchial hyper reactivity, mucosal edema
and by suppressing inflammatory response.
• 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 – Severe chronic asthma:
Not controlled by bronchodilator and inhaled
steroids. – Status asthmaticus/ acute asthma
exacerbation:

23. 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.

24. 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.

25. Mast cell stabilizers
• Uses:
• 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 patient s.
• Allergic conjunctivitis: Regular use as eye drops is beneficial in
some chronic cases
• 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

26. 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
first line therapy.

27. References
• K.D, Tripathi, Essentials of Medical
Pharmacology, Seventh edition