Asthma & Its Pathophysiology related Mechanism

1. Integrative Inflammation Pharmacology of
Asthma
Presented by
Dhanesh Ajay Gaikwad
M. Pharm, 2nd Sem, Reg No: 200604022
Department of Pharmacology, MCOPS, MAHE, Manipal

2. Manipal College of Pharmaceutical Sciences - MAHE Manipal
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Content
Bronchial Asthma – Introduction & Causes,
Symptoms
Types of Bronchial Asthma
Pathogenesis Of Asthma
Approaches To Treatment
Drugs used to treat asthma
Conclusion
References

3. Bronchial Asthma – Introduction, Causes & Symptoms
Bronchial asthma is a chronic inflammatory airway disease
in which inflammatory agents causing reversible and
periodic airway constriction leading to symptoms like
wheeze, cough, breathlessness, chest tightness etc.
Bronchial asthma was officially named as specific
respiratory disorder by Hippocrates in 450 BC
Epinephrine was first referred to in the treatment of asthma
in 1905.
Oral corticosteroids began to be used for this condition in
the 1950s while inhaled corticosteroids and selective Short
Acting Beta Agonist came into wide use in the 1960s.
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Fig1: https://www.indiamart.com/proddetail/bronchial-
asthma-treatment-service-14538004173.html

4. Asthma affects about 8% of the population.
It is the commonest chronic disease in children in economically
developed countries and is also common in adults
Bronchial Asthma- Hyperresponsiveness of tracheobronchial smooth
muscle to variety of stimuli.
This result into- Narrowing of air tube, ↑ secretion of mucosal
oedema and mucus plugging.
Asthma
1}Obstructive lung disease
2} Inflammatory disease
Medication used to treat asthma act in one of two ways-
1] By relaxing Bronchial smooth muscle
2] By preventing and reducing inflammation
4
Fig 2: William W. Busse,
The Relationship of Airway Hyperresponsiveness and Airway
Inflammation: Airway Hyperresponsiveness in Asthma: Its
Measurement and Clinical Significance, Chest, Volume 138, Issue
2, Supplement, 2010, Pages 4S-10S,

5. Asthma: Symptoms & Causes
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Fig 3: bkallergy.com/what-causes-asthma/

6. Manipal College of Pharmaceutical Sciences - MAHE Manipal
Types of asthma
Extrinsic Asthma Intrinsic Asthma
It is called as Atopic, Immunologic, Allergic,
Eosinophilic asthma.
It is called as Non-atopic, Non-immunologic,
Non-allergic, Non-eosinophilic asthma.
It is mostly occurred in Young patient: Child or
Teenagers
It is mostly occurred in Adult patient: 35 or
over age
Its triggering agents are Pollens, Animal dander,
Dust particles, Mold.
Its triggering agents are: Respiratory infections,
Exercise, Inhalation of fumes i.e., like cigarette
smoke, chemicals, dust & cold air.
IgE dependent: Specific IgE increased in blood IgE independent: Specific IgE not increased in
blood
Skin prick test positive for common allergens Skin prick test negative for common allergens
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• The pathogenesis of asthma involves both genetic and environmental factors.
• In the asthma mainly two main phase are: An immediate phase & A late [ or delayed ] phase.
• Due to the allergens in asthma as activated T cells, with a T-helper (Th)2 profile of cytokine
production in their bronchial mucosa.
• Then also increase the eosinophils specially in the mucus and tissue part of bronchioles &
increases the goblet cell also.
• In the lamina propria a layer present in bronchiole that also thicker due to increase in mast cells,
neutrophile & T-helper cell, & finally increase in size of smooth muscle.
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8. • Allergen interact with dendritic cell &
CD4+ T cell.
• Th0 lymphocyte → Th2 lymphocyte ↑
1. Production of B cell or plasma cell and
release immunoglobulins ( IgE ).
2. IL-5 → promote differentiation &
activation of eosinophils.
3. IL-4 & IL- 13 → induce expression of
IgE receptors.
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T-Lymphocytes in allergic asthma
Fig4: Rang HP, Ritter JM, Flower RJ, Henderson G. Rang &
Dale’s Pharmacology, International Edition. 9th ed. Churchill
Livingstone; 2020 page no: 373.

9. • Allergen interaction with mast cell-fixed IgE
→ release of histamine, leukotriene B4 &
prostaglandin (PG) D2 .
• IL-4, IL-5 & IL-13 macrophage
inflammatory protein-1alpha & ( TNF-
Alpha ).
• The late Phase or delayed phase may be
nocturnal.
• The inflammatory cells include activated
eosinophils.
• These release of cysteinyl leukotrienes, IL-
3, IL-5 & IL-8
• Toxic proteins eosinophil cationic protein,
major basic protein & eosinophile –derived
neurotoxin.
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Fig5: Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s
Pharmacology, International Edition. 9th ed. Churchill Livingstone;
2020 page no: 374.

10. Manipal College of Pharmaceutical Sciences - MAHE Manipal
Approaches To Treatment
1. Prevention of AG:AB reaction
2. Neutralisation of IgE
3. Suppression of inflammation
4. Prevention of release of mediators
5. Antagonism of released mediators
6. Blockade of constrictor neurotransmitter
7. Mimicking dilator neurotransmitter
8. Directly acting bronchodilators
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11. Manipal College of Pharmaceutical Sciences - MAHE Manipal
Drugs used to treat
Asthma
A. Bronchodilators
I. ꞵ-Adrenoreceptor agonists
II. Methylxanthines
III. Muscarinic receptor antagonists
IV. Cysteinyl leukotriene receptor antagonists
B. Anti-inflammatory agents
I. Corticosteroids
II. Mast-cell stabilizer
III. Anti-IgE treatment
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12. Bronchodilators
I. ꞵ-Adrenoreceptor agonists
• Primary effect in asthma → dilate
bronchi by direct action on → ꞵ2
adrenoreceptor of smooth muscle.
• ↓ mediator release from mast cells &
TNF-alpha release from monocytes,
↑ mucus clearance by an action on
cilia.
• Short acting agents: Salbutamol &
terbutaline
• Long acting agents: Salmeterol &
formoterol
• Unwanted effects: Tremor,
Tachycardia & Cardiac dysthymia.
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Fig 7: Golan DE, Rose HS, Armstrong EJ, Galanter JM, Arnaout RA,
Armstrong AW, et al. Principles of pharmacology: The pathophysiologic
basis of drug therapy 4th edition, Philadelphia, PA: Lippincott Williams
and Wilkins; 2017 page no: 885.

13. II. Methylxanthines
1. Adenosine-2 receptor antagonist→
↓Bronchoconstriction & ↓ potentiate
inflammatory mediators release
2. ↓ PDE → High level of cAMP, Smooth
muscle relaxation & ↓ IgE release of
mast cell mediator.
• Theophylline & Roflumilast- Blocks
PDE-4
• Unwanted effect: Insomnia,
nervousness, dysrhythmia.
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Fig 8: Tilley SL. Methylxanthines in asthma. Handb Exp Pharmacol.
2011;(200):439-56. Doi: 10.1007/978-3-642-13443-2_17. PMID:
20859807.

14. III. Muscarinic receptor
antagonists
• Bronchodilation→ anticholinergics →
bronchial smooth muscle.
• ↓ Mucus Secretion → anticholinergics
→ submucosal gland
• ↓ Airway inflammation→
anticholinergics → eosinophil,
macrophage, lymphocyte & neutrophil
• Ipratropium, tiotropium, glycopyrrolate.
• Unwanted effect: Bad taste, dryness of
mouth
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Fig:9 Gosens, R., & Gross, N. (2018). The mode of action of
anticholinergics in asthma. European Respiratory Journal,
1701247. doi:10.1183/13993003.01247-2017

15. IV. Cysteinyl leukotriene receptor
antagonists
• LTC4, LTD4, LTE4 → CysLT1 & CysLT2
• ↓ Respiratory mucosa & ↓ infiltrating
inflammatory cell.
• Lukast ↓ exercise-induced asthma & ↓
early and late response
• Montelukast & Zafirlukast→ CysLT1
• Zileuton→ 5-Lox Inhibitor
• Unwanted effects: Headache & GI
disturbances 15
Fig 10: Dempsey, O. J. (2000). Leukotriene receptor
antagonist therapy. Postgraduate Medical Journal, 76(902),
767–773. doi:10.1136/pgmj.76.902.767

16. Anti-inflammatory agents
I. Corticosteroids - Glucocorticoids
• ↓ Inflammatory cytokine release → Th2
cytokines & ↓ Prostaglandins, Leukotriene
• ↓ Eosinophilic & Lymphocytic infiltration of
lung
• Supress inflammatory response to AG:AB
reaction
• Beclometasone, budesonide, fluticasone,
mometasone, ciclesonide
• Unwanted effect: Oropharyngeal candidiasis,
adrenal suppression
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Fig 11: Goodman LS, Gilman A. Goodman and Gilman's the
pharmacological basis of therapeutics. 13th ed. Limbird LE, editor.
New York, NY: McGraw-Hill; 2018. page no: 737.

17. II. Mast-cell stabilizer
• ↓ Histamine release from mast cell
• ↓ Reduce Immediate & late phase
asthmatic response
• ↓ Bronchial hyper-reactivity
• Cromoglicate & Nedocromil
• Unwanted effect: Headache, diarrhoea
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Fig 12: Finn, D. F., & Walsh, J. J. (2013). Twenty-first century
mast cell stabilizers. British Journal of Pharmacology, 170(1),
23–37. doi:10.1111/bph.12138

18. III. Anti-IgE treatment
• Blocks the binding of IgE to receptors
• Mast cells, macrophages, T & B
lymphocytes
• Preventing their activation by allergens
• Use ONLY in patients with moderate to
severe persistent asthma
• Omalizumab
• It is expensive
• Unwanted effect: Rash, fever, headache
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Fig 13:
https://tmedweb.tulane.edu/pharmwiki/doku.php/treatment_of
_asthma

19. Manipal College of Pharmaceutical Sciences - MAHE Manipal
• In the finally conclude that asthma is chronic respiratory condition that mainly identified by
breathing difficulty, chest tightness & wheezing.
• The medications used to manage asthma long term are symptom preventers and symptom
controllers.
• Many of medications are used in combination for its better effect on patient.
• Avoid those factors that must be triggers asthma.
• Chronic asthma conditions affect patient physical, psychological and social wellbeing.
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20. Manipal College of Pharmaceutical Sciences - MAHE Manipal
References
• Dempsey, O. J. (2000). Leukotriene receptor antagonist therapy. Postgraduate Medical Journal,
76(902), 767–773. doi:10.1136/pgmj.76.902.767.
• Finn, D. F., & Walsh, J. J. (2013). Twenty-first century mast cell stabilizers. British Journal of
Pharmacology, 170(1), 23–37. doi:10.1111/bph.12138.
• Goodman LS, Gilman A. Goodman and Gilman's the pharmacological basis of therapeutics. 13th ed.
Limbird LE, editor. New York, NY: McGraw-Hill; 2018. page no: 737.
• Golan DE, Rose HS, Armstrong EJ, Galanter JM, Arnaout RA, Armstrong AW, et al. Principles of
pharmacology: The pathophysiologic basis of drug therapy 4th edition, Philadelphia, PA: Lippincott
Williams and Wilkins; 2017 page no: 885.
20

21. Manipal College of Pharmaceutical Sciences - MAHE Manipal
• Gosens, R., & Gross, N. (2018). The mode of action of anticholinergics in asthma. European
Respiratory Journal, 1701247. doi:10.1183/13993003.01247-2017.
• Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s Pharmacology, International
Edition. 9th ed. Churchill Livingstone; 2020 page no: 373,374.
• William W. Busse, The Relationship of Airway Hyperresponsiveness and Airway Inflammation:
Airway Hyperresponsiveness in Asthma: Its Measurement and Clinical Significance, Chest,
Volume 138, Issue 2, Supplement, 2010, Pages 4S-10S
• Tilley SL. Methylxanthines in asthma. Handb Exp Pharmacol. 2011;(200):439-56. Doi:
10.1007/978-3-642-13443-2_17. PMID: 20859807.
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22. Manipal College of Pharmaceutical Sciences - MAHE Manipal
Thank You
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