Anti Asthmatics, Asthma pathophysiology , Salbutamol, Aminophylline , Theophylline , beta agonist , Respiratory System , Bronchitis , Montelukast , Omalizumab , Corticosteroids , Dexamethasone , Cromolyn , Albuterol , Salmeterol , SABA/LABA , ASTHMA , Healthcare , Health and Medicines , Pharmacology & Therapeutics-I (Pharm D)

1. Anti-Asthmatic Drugs
(Pharmacology & Therapeutics-I)
Lecture By
Dr. Syed Baqir Raza Naqvi
(BSc, Pharm-D, M. Phil-Pharmacology)
Nazar College of Pharmacy
1

2. • Asthma is a chronic inflammatory disease of the airways characterized by
episodes of acute bronchoconstriction causing shortness of breath, cough,
chest tightness, wheezing, and rapid respiration.
• It is a disease characterized by increased responsiveness of
tracheobronchial tree (trachea, bronchi, bronchioles) to various stimulus &
wide spread narrowing of the airways i.e. bronchospasm.
• It is also called as reversible airways obstruction (RAO).
2
Asthma

3. 1. Early onset asthma
(Atopic or allergic asthma)
Types of Asthma
2. Late onset asthma
(Non atopic asthma)
3

4. 4

5. Clinical Features
Coughing
Shortness
of breath
Chest
tightness
wheezing
Contraction of airway’s
smooth muscles.
Mucosal thickening.
Inspissation (rendering dry
or thick) in airway’s lumen.
Abnormally thick viscid
plug of mucus.
Pathological Features
5

6. Inducers of Asthma
Smoke
• It is known that if parents smoke during 1st two years of
their child’s life, the child is likely to develop asthma.
Allergens
• 1. Aero allergens: House dust, smoke,
pollens, animal dander.
• 2. Ingestant allergens: Milk, fish, chocolates,
strawberries. 6

7. Triggers of Asthma
Exercise
• Running,
• Cycling,
• Laughing,
• Coughing etc.
Emotional
factors
• Pleasurable excitements in
children.
• Stress or worry in adults.
• Drugs like β-blockers
(propranolol).
7

8.  Asthmatic person has tendency to produce large amount of anti-
bodies in response to antigen.
 Mast cells are present in lungs, Ig-E become attached to mast cells.
 On subsequent exposure to the same antigen, antigen-antibody
reaction on the surface of mast cells takes place.
 As result mast cells release Leukotriene's i.e. LTC4, LTD4 and
Histamine (inflammation causing agents).
• As a result inflammation of respiratory tract occur leading to difficulty
in breathing, cough sneezing and chest congestion.
8
Pathogenesis of Asthma

9. 9
Pathophysiology of Asthma

10. Pathogenesis of Asthma
• Classic allergic asthma is mediated by the exposure of
sensitized Ig.E antibodies, bound to mast cells in airway
mucosa.
• Antigen-antibody reactions takes place on mast surface, that in
turns triggers both the release of mediators stored in mast cells
granules & synthesis of other mediators.
• These mediators diffused through out the airway wall &
causing narrowing, through muscles contraction, edema,
cellular infiltration (deposition of solution) & change in mucus. 10

11. 11
Pathophysiology of Asthma

12. Goals of therapy
1) The goals of asthma therapy are to decrease the intensity and
frequency of asthma symptoms and the degree to which the
patient is limited by these symptoms.
2) All patients need to have a “quick-relief” medication to treat
acute asthma symptoms.
3) Drug therapy for long term control of asthma is designed to
reverse and prevent airways inflammation.
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13. Classification of Anti Asthmatics
Bronchodilators
• 1. Sympathomimetic 2. Para-sympatholytic 3. Methyl Xanthine derivatives
Mast cell stabilizers
• 1. Ketotifen 2. Cromolyn
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Leukotriene modifiers
• 1. Montelukast 2. Zafirlukast
Corticosteroids
• 1. Beclomethasone 2. Dexamethasone 3. Prednisolone 4. Hydrocortisone

14. Non-selective α & β
stimulants
Non selective- β1 & β2
stimulants
Selective-β2
stimulants
• Ephedrine
• Adrenaline
• Isoprenaline
• Orciprenaline
• Salbutamol, Salmeterol
• Bambuterol, Procetrol
• Formoterol, Terbutaline
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Bronchodilators
1. Sympathomimetic

15. 2. Para-
simpatholytics
Atropine
Ipratropium
3. Methyl
xanthine
derivatives
Theophylline
Aminophylline
15
Bronchodilators
• Disodium
chromoglycate
• Ketotifen
Mast cell
stabilizers
• Montelukast
• Zafirlukast
Leukotriene
ant agonistics
• Beclomethasone
• Dexamethasone
• Prednisolone
Cortico-
steroids

16. 16

17. Ephedrine
• Ephedrine is an alkaloid obtained from Ephedra plant.
• Its chemical structure is similar to adrenaline. It is a powerful
bronchodilator & is highly effective on treating pulmonary disease i.e.
bronchitis & bronchial asthma.
• It is commonly called Ma huang in china.
17
1. Bronchodilators
A. Sympathomimetic

18. Mechanism of Action
(Ephedrine)
• Ephedrine stimulates both alpha & beta receptors.
• Bronchodilators effect is achieved when the drug stimulates the
Beta2 receptors present in cell membrane of bronchial cells.
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19. 19
1. IN LUNGS: In bronchial cell membrane there is an enzyme (Adenyl
cyclase). When β2 receptors activated, they stimulate the adenyl cyclase.
• This activated adenyl cyclase catalyzes the ATP, present in cytoplasm of cell
to form cyclic 3,5-AMP.
• This resulting cyclic 3,5-AMP is responsible for Broncho dilation.
2. ON HEART: Ephedrine also causes vasoconstriction b/c it also stimulates
alpha receptors of heart, so B.P. is increased.
• It also causes increased heart rate due to stimulation of β1 receptors.

20. Adverse effects
• Common adversities includes nausea,
sweating, anxiety, nervousness and
significant adverse effects includes;
• CNS; confusion, agitation, insomnia.
• CVS; Tachycardia, Hypertension.
• Renal; Urinary retention (due to closure
of internal sphincter of bladder).
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Clinical Uses
1. Used as nasal decongestant.
2. As a presser agent in spinal anesthesia
3. To treat stress incontinence (inability
to control excitory functions).
4. Also used in heart block.
5. It has long duration of action.

21. Salbutamol
• It is also called albuterol. It is the most widely used sympathomimetic
bronchodilator.
Mode of Action
• It is a selective β2-receptor agonist.
• It posses useful degree of selectivity towards B2-receptors, there by Producing its
bronchodilator effects.
• It stimulate the β2 receptor present in cell membrane of bronchial cell.
• when B2-receptor stimulated, it interns Stimulate adenyl cyclase which catalyzes ATP
in cytoplasm into cyclic 3,5-AMP in the presence of Mg+. (Broncho dilation occurs).
21
A. Sympathomimetic

22. Clinical Uses of Salbutamol
• Salbutamol is an effective treatment for bronchial asthma as it quickly
relief bronchospasm, associated with reversible airway obstruction.
• Specially used in sudden asthmatic attacks. (Short Acting Beta-Agonist {SABA}).
• Also effective for uterine muscles relaxation, thus is clinically used in
treatment of threatened abortion (complicated premature labor).
• Indicated in emphysema (abnormal enlargement of alveolar walls due
to accumulation of mucous or sputum).
22

23. Dosage forms
• Tablets; 2, 4, 8 mg
• Syrups: 2 mg/5 ml
• Injections; 2 mg/1ml
• Inhalations; 100 microgram/puff
• Dose: 1-2 puffs (3-4 times)
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Adverse effects:
• Common adversities includes headache,
nervousness, mild tremors and
significant adverse effects includes;
• CNS; dizziness, insomnia.
• CVS; Tachycardia, Hypertension,
palpitation (irregular heart beat).
• GIT; Nausea, vomiting & dryness of
oropharynx.

24. Terbutaline
• Like salbutamol it is one of the most popular
sympathomimetic bronchodilator and is highly safe.
Mode of Action: Same as salbutamol (Selective B2 agonist).
Adverse effects: Similar as salbutamol.
Clinical Uses
1. Highly effective in treatment of severe prolonged
asthma.
2. Used to reduce contraction in pre mature labor.
3. Indicated in chronic bronchitis & emphysema.
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Dosage forms
• Tablets; 2.5 mg
• Syrups: 1.5 mg/5 ml
• Injections; 0.5 /1ml
• Inhalations; 0.25 mg/puff
• Dose: 1-2 puffs (3-4 times)

25. 25
SABA’s
Vs.
LABA’s

26. • The anticholinergic agents block vagally mediated contraction of airway
smooth muscle and mucus secretion.
• Inhaled ipratropium (derivative of atropine), is not recommended for the
routine treatment of acute bronchospasm in asthma, as its onset is much
slower than inhaled slow acting Beta agonists (SABAs).
• However, it may be useful in patients who are unable to tolerate a Slow acting
Beta agonists (SABA) or patients with concomitant COPD.
• Ipratropium also has additional benefit when used with a SABA for the
treatment of acute asthma exacerbations in the emergency department.
• Adverse effects such as xerostomia and bitter taste are related to local
anticholinergic effects. 26
Ipratropium / Atropine
B. Parasympatholytics
Bronchodilators

27. Aminophylline/Theophylline
Aminophylline is one of the methyl
xanthine bronchodilator & consist of
86% anhydrous theophylline and
14% ethylene di amine.
Mode of Action
• Act as phosphodiesterase inhibitor.
27
Bronchodilators
C. Methyl xanthine
Derivatives

28. Mode of Action (Cont.)
• When B2-receptor is stimulated, it interns Stimulate adenyl cyclase which catalyzes ATP in
cytoplasm into cyclic 3,5-AMP in the presence of magnesium Mg+. This resulting cyclic 3,5-AMP
serves as bronchodilator.
• In the final stage Cyclic 3,5 AMP is inactivated to 5-AMP by an enzyme phsphodiesterase.
• Aminophylline inhibits the Phsphodiesterase & thus Cyclic 3,5-AMP level is maintained,
which promotes Broncho dilation & hence easier breathing.
• Cyclic 3,5-AMP also prevents influx of calcium ions inside cell, which also results in relaxation
of bronchial smooth muscles b/c Ca+ ions act as contractile element and causes contraction
of smooth muscles.
28

29. Clinical Uses
Bronchial Asthma
• Used in bronchial asthma & reversible bronchospasm associated with chronic bronchitis.
Chronic obstructive pulmonary disease (COPD)
• Aminophylline quickly improve pulmonary functions & relieves COPD symptoms.
29
Apnea (absence of breathing) in pre mature neonates
• Effective in apnea in premature neonates, during 1st few weeks of birth.
Left ventricular failure
• Effectively used to treat Left ventricular failure (LFV)

30. 30
Adverse effects:
• CNS; dizziness, insomnia, convulsions.
• CVS; Cardiac arrhythmia, palpitation
(irregular heart beat).
• GIT; Nausea, vomiting, anorexia and
abdominal pain.
Contra indications:
1. Patients suffering from cardiac
arrhythmia.
2. In epilepsy b/c it acts as CNS
stimulants.

31. Beclomethasone / Dexamethasone
31
• It is a synthetic inhalation glucocorticoids.
• It is not a bronchodilator but reduces the inflammation of the
airways.
Mode of action
• It acts to inhibit the inflammatory response in airways.
• Corticosteroids inhibit the release of arachidonic acid through
phospholipase A2 inhibition, from cell membrane & there by
inhibit the first step in the production of eicosanoids products
from arachidonic acid. (eicosanoids are responsible for airway
function abnormalities in asthmatic patients).
• It also potentiate the effect of beta adrenoreceptor agonists.
Cortico Steroids

32. Mode of action (Corticosteroids)
32

33. Clinical Uses of corticosteroids
Bronchial Asthma
• Beclomethasone has no direct effect on bronchial smooth muscles, however
they are potentially effective as initial therapy in the treatment of bronchial
asthma. It reduces the dependency of Beta2 agonists in asthma. (However it is
not effective for acute asthma attacks, b/c its beneficial effects appears after
5-7 days of its use.
COPD
• Beclomethasone is only given in advanced cases of COPD (Chronic COPD). It
shouldn't be given in acute/mild cases of this disease.
33

34. 34
Adverse effects:
Inhalation corticosteroids provides effective
inhalation therapy in asthma with no significant
adverse effects. Some common side effects
includes;
• Dyspnea (Altered voice production)
• Oral candidiasis (Fungal infection)
• Oral candidiasis can be prevented by using mouth
washes.
Dosage forms
• Becotide inhaler (by GSK)
(250 micrograms/puff)
• Dose: 400 micrograms in 2-3 or 4
divided doses.

35. • All three drugs are approved for the prevention of asthma symptoms.
• Should not be used when immediate Broncho dilation is required.
• Also shown efficacy for the prevention of exercise induced bronchospasm.
Pharmacokinetics
• Orally active, highly protein bound. Food impairs absorption of zafirlukast.
• The drugs are metabolized extensively by the liver.
• Zileuton and its metabolites are excreted in urine.
• Zafirlukast & Montelukast and their metabolites undergo biliary excretion.
35
Leukotriene Antagonists
Zileuton / Montelukast / Zafirlukast

36. 36
Pathophysiology of Leukotriene

37. 37
Mechanism of action

38. Leukotriene inhibitors
38

39. Mechanism of action
• Leukotriene (LT) B4 and cysteinyl leukotriene's (LTC4, LTD4, and LTE4) are products of the 5-
lipoxygenase pathway of arachidonic acid metabolism and part of the inflammatory cascade.
• 5-Lipoxygenase is found in mast cells, basophils, eosinophil and neutrophils.
• LTB4 is a potent chemo attractant for neutrophils and eosinophil's, whereas cysteinyl leukotriene's
constrict bronchiolar smooth muscle and promote mucus secretion.
• Zileuton is a selective inhibitor of 5-lipoxygenase, and prevents the formation of both LTB4.
• Zafirlukast and Montelukast are selective antagonists of the cysteinyl leukotriene-1 receptor,
they block the effects of cysteinyl leukotriene's, thus promoting Broncho dilation.
39

40. Adverse Effects
• Elevations in serum hepatic enzymes
(requires periodic monitoring and discontinuation
when enzymes exceed three to five times the upper
limit of normal).
• Headache.
• dyspepsia.
40

41. 41
Mast cell stabilizers

42. 42
Cromolyn
Omalizumab

43. Cromolyn / Nedocromil
Mechanism of Action
• Cromolyn sodium is a mast cell stabilizer.
• It is a prophylactic anti-inflammatory agent that
inhibits mast cell degranulation and release of
histamine.
• It is an alternative therapy for mild persistent asthma.
However, it is not useful in managing an acute asthma
attack, because it is not a bronchodilator.
• It has short duration of action so it requires dosing
three or four times daily, which affects adherence and
limits its use. 43
Cromolyn is available as a
nebulized solution for
use in asthma.
Mast cell stabilizers

44. Clinical Uses
Cromolyn sodium is a medication used to
manage ;
• Bronchial asthma.
• Allergic rhinitis.
• Certain allergic eye conditions such as
vernal conjunctivitis, keratitis, and kerato-
conjunctivitis, allergic rhino conjunctivitis.
44
Adverse effects
It has minor adverse
effects that include;
• Cough.
• Irritation.
• Unpleasant taste.

45. Omalizumab
• Omalizumab is a recombinant DNA-derived monoclonal antibody that selectively binds to human
immunoglobulin E (IgE).
• This leads to decreased binding of IgE to its receptor on the surface of mast cells and basophils,
thus limits the release of mediators of the allergic response.
• Omalizumab is indicated for the treatment of persistent asthma in patients who are poorly
controlled with conventional therapy. Its use is limited by the high cost, route of administration
(subcutaneous), and adverse effect profile.
• Adverse effects include serious anaphylactic reaction (rare), arthralgia, fever and rash.
Secondary malignancies have been reported.
45
Anti-IgE Monoclonal Antibodies

46. 46
Cromolyn
Omalizumab

47. Guidelines for the treatment of asthma. In all asthmatic patients, quick relief
is provided by a SABA as needed for symptoms.
*Eighty percent or more of predicted function
47
Ref. Book: Lippincott's page 384