1. DISTINGUISHED
PARTICIPANTS

2. In the Name of Allah the Most Gracious, the Most Merciful

3. MODERN TRENDS IN THE
MANAGEMENT OF BRONCHIAL
ASTHMA
Summary
Airway inflammation is recognized as the most critical
component of asthma, and this may be present even in
the absence of severe symptoms. Present day therapy
comprises bronchodilators i.e. B-agonists, t heophylline
and anticholinergic, and anti inflammatory drugs i.e.
Corticosteroids, Leukotrein Inhibitors and cromolyn.
Inhaled corticosteroids and Leukotrein Inhibitors, are the
first-line therapy both to prevent and control symptoms.
In recommended dosages these medications are safe
and well tolerated.

4. Definitions:
Asthma is a complex and heterogeneous disorder
characterised by:
a) Reversible airway constriction
b) Airway inflammation and
c) Airway hyper-responsiveness to a wide variety of
stimuli.
In asthma, there is paroxysmal bronchospasm, mucosal
oedema, mucus hypersecretion, inflammatory infilterates in
the bronchial wall,bronchial epithelial damage and
desquamation, and glandular hypertrophy. The degree of
bronchial hyper-responsivences is related to the extant of
inflammation in airways.

5. Histopatholoqic Findings in Asthma:
Airway inflammation is exhibited even in patients
with mild disease as seen in the following:-
1) Denudation (Damage) of airway epithelium and
its shedding.
2) Deposition of collagen beneath the basement
membrane (thicking of basement membrane).
3) Mast Cell degranulation
4) Oedema
5) Inflammatory Cell infiltration
 Eosinophils
 Lymphocytes

6. Triggers of Asthma:
1. Allergic - Immunological mechanisms plays important
part.
2. Non-allergic -without immunological mechanism.
i) Infections
ii) Aspirin
Iii) Exercise
iv) Irritants
v) Occupational Exposures,
vi) Emotional Upset.
Both groups exhibit hyper reactive airways.

7. AIR-WAYS RESPONSE TO INHALED ANTIGEN
IN ASTHMA,
Fig-1

8. Inflammatory Cells:
1. Mast Cells
2. Eosinophils
3. Epithelial Cells

9. Inflammatory Mediators:-
Contribute to various features of asthmatic response.
------
Br: constriction, Microvascular leakage & mucus secretion.
----- PG D2 and leukotrienes contribute to B.H.
----- P.A.F. (Lipid Mediator)
Stimulates
a. Adhesion of Eosi: to vascular endothelium
b. Release of Basic Proteins from Eosino.
Epithelial Damage/Shedding
Loss of Protective Epi. relaxing factor
Bronchial Hyper responsiveness
Exposes sensory nerves
----- Triggered More readily

10. Inflammatory Cells Involved in Asthma:-

11. Clinical Features of Asthma:-
MILD MODERATE SEVERE
Symptoms Intermittent Chronic Continuous
brief symptoms >2 times/week
< 1-2 times/week
Activity/ Normal Affected Affected &
Sleep Limited
Nocturnal < 1-2 times/month > 2 times / month Frequent
Asthma
Symptoms
Between Asymptomatic +/- Frequent
Exacerbations exacerbations
PEFR or FEV 1 > 80% predicted 60 - 80 % of < 60% predicted
predicted
PEFRorFEVI < 20% 20-30% > 30%
Variability
B-Agonists --- + ++
daily requirement

12. Management of Asthma:-
Control of Asthma means:-
1. Minimal chronic symptoms including nocturnal
symptoms
2. Minimal exacerbations.
3. Minimal or no need for B2 agonists.
4. Normal activities, including exercise, can be
undertaken.
5. PEF circadian variation < 20%
6. Near Normal PEF.
7. Minimal or no adverse effects from medication.
Asthma may be mild, moderate or severe.

13. Management of Bronchial Asthma:-
a. Bronchodiators SOS
b. Anti Inflammatory Drugs
i) Steroid
ii) Anti Leukotriene

14. Bronchodilator Drugs:-
a. B-Adrenergic Agonist drugs.
b. Methylxanthines (Theophylline),
c. Anticholinergic Drugs.

15. B-adrenergic Agonist Drugs:-
Mode of Action:-
B-adrenergic agents —> stimulate enzyme adenyl cyclase —> which converts ATP into
cyclic AMP. This increase of cyclic AMP leads to activation of protein kinase A, which
inhibits the phosphorylation of myosin and lowers intracellular ionic calcium
concentration, resulting in relaxation. B-Adrenergic agonists relax smooth muscle of all
airways, from trachea to terminal bronchioles.
B-Adrenergic agonists may inhibit the release of mediators from mast cells in the airways
and release ofacetylcholine from postganglionic cholinergic nerves in the airways.
B-Adrenergic agonists do not inhibit either the late response to allergens or the
subsequent brochial hyper-responsiveness. These actions may be related to the fact
that B-Adrenergic agonists do not have an inhibitory effect on inflammatory cells that
have been implicated in both the late reponse and bronchial hyperresponsiveness.
Clinical Use:-
Sympathomimetics: L.A. = Long Acting
i) Salbutamol (Ventolin) ii) Terbutaline(Bricanyl)
iii) Fenoterol (Berotec) iv) Formoterol (L.A)
v) Salmeterol (L.A) vi) TulobuterolBreemax(L.A)
vii) Rimiterol(Pulmadil) viii) Porbuterol (Exirel)
ix) Reproterol (Bronchodil). x) Others

16. Methylxanthines Theophylline:
a. Mechanism of Action
b. Dosage and Clinical Use

17. Anti Inflammatory Drugs:-
1. Cortico Steroids
2. Cromolyn Sodium
3. Leukotreins Inhibitors

18. Corticosteroids:-
a. Effect on inflammatory & Airway Cells
b. Effect on Asthmatic Inflammation
c. Effect on Air-way Hyper Responsiveness

19. Inhaled steroids and Dosages:-
1. First Line Therapy for Chronic Asthma.
2. Steroids required to control asthma in majority of Adults
3. Doses upto 800 ug daily in adults and 400 ug daily in
children are safe.
4. Twice daily administration of inhaled steroids are quite
effective.
5. Orally administered steroids, such as prednisolone or
methylpredinsolone, are still required to control Asthma in
some patients, but then there is risk of side effects, with daily
dose exceeding 10 mg.

20. Guidelines for Oral Steroid Therapy are:-
1. Start with high doses for exacerbation (e.g. prednisolone
30-60 mg/day). Dose will depend upon extent of exacerbation, and
patient's oral maintenance dose.
2. After control of symptoms, tapper rapidly (within 5-7 days) to
baseline steroid dose.
3. For "Chronic" patients, try to keep daily dose of
prednisolone below 10 mg/day.
4. Give daily morning dose only. This will eliminate or reduce
the suppression of hypothalamic pituitary-adrenal axis (HPA axi).
5. Attempt alternate-day steroids if more than 7.5mg
prednisolone/day is required. Then "On" days initial dose is to
be 2-3 times.
6. Use beclomethasone dipropionate aerosol or otherinhaled
steroids alongwith for ultimately eliminating or
reducing dose of oral prednisolone.

21. Asthma Therapy:-
MILD MODERATE SEVERE
CORTICOSTEROIDS
Inhaled _ +200 to 1000 ug +800 to 1400
ug
Oral _ _ +
Parenteral _ _ +
CROMOLYN +/- +/- _
B-AGONISTS
Inhaled + +
+
Oral + + +
THEOPHYLLINE _ +SR + SR

22. Importance of Inflammation in Asthma
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and
Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes
of Health, 1998; Bjermer L Respir Med 2001;95:703-719.

23. Leukotrienes: Important in Early Asthma and Throughout
the Disease
Other inflammatory mediators
Leukotrienes
No Inflammation Asthma Inflammation
Adapted from Holgate ST, Peters-Golden M J Allergy Clin Immunol 2003;111(1 suppl):S1-S4; Holgate ST et al J Allergy
Clin Immunol 2003;111(1 suppl):S18-S36; Henderson WR Jr et al Am J Respir Crit Care Med 2002;165:108-116; Peters-
Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Varner AE, Lemanske RF Jr. In Asthma and
Rhinitis. Oxford, UK: Blackwell Science, 2000:1172-1185.

24. Dual Pathways of Inflammation
Effects of the CysLT1 Receptor on
Inflammatory Cells
Lung Macrophage Eosinophils
Smooth-
muscle
cell
Monocytes PBMC
CysLT=cysteinyl leukotriene; PBMC=peripheral blood mononuclear cells
Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233.

25. Dual Pathways of Inflammation
Expression of the CysLT1 Receptor
CD19 LN5
B Lymphocyte Macrophage
Mast Cell M-CSF LTC4
Basophil LTD4
CysLT1R GM-CSF
LTE4
M-CSF, GM-CSF, IL-3 CD14
LTC4, LTD4, LTE4 Monocyte
IL5Rβ
IL-5
CD34+ IL-3 Neutrophil
Pluripotent GM-CSF
LTC4 CCR3
hemopoietic LTE4
LTD4
stem cell
T Cells Eosinophil
Represents the
CysLT1 receptor
CD4+
CD8+
Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233; Mellor et al Proc Natl Acad Sci USA 2001;98:7964-7969

26. Dual Pathways of Inflammation
Leukotrienes Are Powerful Inflammatory Mediators
CysLT Other Mediator
CysLT
receptor mediators receptor
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.

27. Dual Pathways of Inflammation
Actions of LTRAs
Leukotrienes are highly specific but catalyze
a massive inflammatory cascade
 Suppress many inflammatory mediators
 Suppress inflammatory processes
 Via the leukotriene pathway
 Via the steroid-sensitive pathway
LTRAs = leukotriene receptor antagonists
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.

28. Dual Pathways of Inflammation
Central Role of CysLTs in Asthma
Decreased Mucus Transport Cationic Protein Release,
Epithelial-Cell Damage
Airway
Epithelium
Eosinophil Sensory
Increased Influx Nerves
Mucus (C fibers)
Secretion
Contraction and
Edema CysLTs Proliferation
Blood
Vessel
Inflammatory Cells
Airway Smooth Muscle
(mast cells,
eosinophils)
Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:304-309.

29. Airway Inflammation Persisted Despite
Corticosteroid Use
In a clinical study of 74 patients
p<0.01
p<0.001
20,000
10,000 p<0.001
p<0.01
1,000
Eosinophil
× 103/g
sputum 100
10
1
Control ICS ICS OCS OCS ± ICS
group low-dose high-dose (n=10) (n=7)
(n=10) (n=15)
Mild to moderate Severe asthma
ICS=inhaled corticosteroids; OCS ± ICS=received oral corticosteroids with or without ICS
Adapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.

30. Dual Pathways of Inflammation
Long-Acting Beta2 Agonists Did Not Have Anti-inflammatory Effects
LTRA montelukast further reduced inflammation when
added to ICS
ICS + LABA + ICS + ICS +
Montelukast Montelukast LABA ICS
0
Change in
eosinophils
(× 106/L) –100
from run-in
–200 p<0.05
p<0.05
LABA = long-acting beta2 agonist
Adapted from Currie GP et al Am J Respir Crit Care Med (in press).

31. Dual Pathways of Inflammation
LTRA Montelukast Further Reduced Asthmatic Inflammation
Complementary therapy that targets dual pathways of
inflammation provided better control of inflammation
0.12 *
0.10
Eosinophil 0.08
counts
(change 0.06
from baseline
× 103/µl) 0.04
0.02
<1*
0
Placebo Montelukast Beclomethasone Montelukast
+
beclomethasone
Treatment group
*p<0.05 compared with beclomethasone
Adapted from LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868.

32. Dual Pathways of Inflammation
Montelukast Combined with a Steroid Affects the Dual
Pathways of Inflammation
CysLTs Steroid-sensitive
play a key role mediators
in asthmatic play a key role
inflammation in asthmatic
inflammation
Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients
Montelukast Inhaled steroids
blocks the block
effects of steroid-
CysLTs sensitive
mediators
DUAL PATHWAY
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy 2001;56(suppl 66):7-11.

33. Dual Pathways of Inflammation
Airway Inflammation Correlated with Lung Function and
Clinical Control
PEFR Daily symptom
FEV1 variability score
0
–0.2
rS
–0.4 –0.36
–0.43
–0.49 –0.51
–0.51 –0.52
–0.6
Absolute eosinophil counts
ECP concentrations
FEV1 = forced expiratory volume in one second; PEFR = peak expiratory flow rate; rS = Spearman’s rank coefficient of
correlation; ECP = eosinophilic cationic protein
Adapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.

34. Leukotriene Inhibitor:-
Montelukast

35. Leukotriene Inhibitor:-
Montelukast 5mg / 10mg Tablets
(Montelukast) blocks cystienyl, receptors in human airways
inhibiting LTD4 leukotriene attachment to these
receptors leading to:
1. Minimized airway odema (Bronchial
smooth muscles relaxation)
2. Minimized mucus secretion (By inhibiting
the inflammation process)
(Montelukast) Provides significant relief from symptoms
of allergic rhinitis while also conferring a benefit for asthma in
patients with both allergic rhinitis and asthma.
(Montelukast) administered once daily improved efficacy
was well tolerated in pediatric patients with chronic persistent
asthma establishing itself as a valuable treatment option to current
asthma therapies in 6 to 14 years old patients.

36. Others:
1. Cromolyn Sodium
2. Ketotifen
3. Methotraxate
4. Gold

37. ACUTE SEVERE ASTHMA
–
LIFE THREATENING

38. Clinical
1. Increased dyspnoea, fatigue, and stage of
exhaustion.
2. Altered mental state; cannot complete sentences.
3. Increased bronchodilator needs.
4. History of previous severe asthma attack.
5. Recent upper respiratory tract infection – viral or
bacterial.
6. A more persistent obstruction due to mucus
impaction.

39. Signs & Criteria
1. Cyanosis
2. Pulse rate > 120/minute
3. Pulses paradoxus greater than 18-20 mmHg.
4. Silent chest
5. PEFR below 100/L minute or PEVI less than 0.5L, and failure to
improve with bronchodilators.
6. PaO2< 60 mmHg.
7. PacO2 > mmHg.
8. Low blood pH.
9. Low serum Potassium.
10. ECG – P Pullmonate.

40. Possible Complications.
1. Mucus Plugging.
2. Tension pneumothorax or
pneumoperitoneum.
3. Pulmonary oedema.
4. Massive pulmonary collaspe.
5. Arrhythmias.
6. Hypovolemia.

41. ACUTE SEVERE ASTHMA
–
LIFE THREATENING
ATTACK IN ADULTS

42. TREATMENT
1. I.V. route established.
2. Oxygen by mask 6 L/min. & continue.
3. High dose of Beta2 – agonist given & repeat every 20 minutes
during 1st hour – preferably by nebulizer (10-15 puffs by spacer if
nebulizer not available) – Repeat 4 hourly.
4. Salbutamol subcut :/I.V.
5. Oral prednisolone 30-60 mg or I.V. hydrocortisone 200 mg. &
repeat 4 hourly.
6. Slow I.V. aminophylline 250 mg. (if not taken orally)
7. Arrange hospialization.
8. If danger of imminent arrest – mechanical ventalation/oxygen
mask +.

43. Conclusion:-
Summary
Targeting Dual Pathways of Inflammation Improves Asthma
control
1. Drug Inhalation is better than oral Administration
2. Mild Asthmatics-Inhaled B2-Adrenergic against may be enough.
3. Chronic Asthma-Anti Inflammatory Therapy must be introduced
earlier.
4. Cys LTs and steroid-sensitive mediators are two important
pathway of inflammation in asthma
5. Corticosteroids do not block the leukotriene-mendiated pathway
of inflammation
6. Treating dual pathways of inflammation in the airway of
asthmatic patients may provide better control of inflammation
and effective asthma control