This document provides an overview of recent advances in asthma treatment. It discusses novel bronchodilators such as magnesium sulfate and potassium channel openers. Immunomodulatory therapies including anti-IgE therapy and specific immunotherapy are also covered. Newer anti-inflammatory drugs that target NF-kB and MAP kinase pathways are mentioned. The document concludes by briefly discussing miscellaneous approaches like cytokine modifiers, chemokine receptor antagonists, CRTH2 antagonists, and antioxidants.

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Recent advances in
Asthma treatment
Dr. Divya Krishnan
Calicut medical college

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CONTENTSCONTENTS
Introduction
Etiology
Pathogenesis
Diagnosis
Current management
Recent advances in treatment
Conclusion

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Common disease with enormous socioeconomic impact.
Prevalent in 10% of the world population.
 Can occur at any age with peak incidence in childhood.
Males affected more(childhood), Females affected more
in adults.
Asthma……………Asthma……………

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Clinical syndrome characterised by airway inflammation and
increased airway hyperresponsiveness that leads to recurrent
episodes of wheezing, shortness of breath, chest tightness and
cough.
Symptoms are associated with widespread but variable
bronchoconstriction that is at least partly reversible, either
spontaneously or with treatment.
Asthma……………….Asthma……………….

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Asthma-EtiologyAsthma-Etiology
A Atopy
Family history
Prematurity, abnormal lung function at birth
Aeroallergen exposures
Viral respiratory tract infections
Tobacco smoke
Air pollutants
Exercise
Cold air
Food additives
Drugs ( Beta blockers, Aspirin,
Bisphosphonates)
T
R
I
G
G
E
R
S

6. Etiological classification ofEtiological classification of
asthmaasthma
Extrinsic( atopic) asthma Intrinsic (non atopic)asthma
- History of atopy - No allergen identified
- Serum IgE raised - Serum IgE not raised
- Onset in childhood - Onset in adulthood
- Episodic type - Chronic type
Classification not popular now as it fails to define treatment
strategies
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7. Pathogenesis of asthmaPathogenesis of asthma
Immunological model of asthma pathogenesis
2 phases----early (bronchoconstriction) phase
late (inflammation and hyper-reactivity) phase
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8. Pathogenesis………Pathogenesis………
How it starts….?
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9. PathogenesisPathogenesis
Early phase reaction
Bronchoconstriction
start of late phase
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10. Pathogenesis……Pathogenesis……

11. PathogenesisPathogenesis
Role of neuronal pathways in asthma
Bronchial tone results due to a balance between
- Parasympathetic-bronchoconstriction
- Sympathetic - bronchodilatation
- NANC – releases neuropeptides (substance P, neurokinin A
causing bronchoconstriction and nitric oxide causing
bronchodilatation)
(NO also produced by iNOS besides being a neuropeptide)
Other mediators
Adenosine causes bronchoconstriction (A1 receptors on smooth
muscle)
Endothelins, Bradykinins and many more………. 11

12. Pathogenesis………Pathogenesis………
AIRWAY REMODELING

13. DiagnosingDiagnosing AsthmaAsthma
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Medical History
-Wheezing, dyspnoea, chest tightness, coughing
-Symptoms worse at night/early morning
-Symptoms exacerbated by known triggers
-Positive h/o atopy; family h/o asthma
Physical examination
-Rhonchi
-Hyperexpansion of thorax
-Associated atopic dermatitis/eczema

14. Diagnosing AsthmaDiagnosing Asthma
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Spirometry
- Decreased FEV1 , FEV1/FVC ratio, PEF
-Reversibility after inhalation of beta 2
agonist
->20% diurnal variation in PEF
Other tests
- Methacholine/histamine challenge test
- Total serum IgE levels/ blood eosinophils
- Skin tests for common allergens
- Exhaled NO test

15. Clinical classification ofClinical classification of
AsthmaAsthma
Mild
intermittent
Mild
Persistent
Moderate
persistent
Severe
Persistent
Symptoms ≤ 2 times a week
Asymptomatic
between
exacerbations
Brief
exacerbations
>2 times a week
but <1 time a
day
Exacerbations
affect activity
Daily symptoms
Exacerbations≥2
times a week &
may last for days
Daily
symptoms
Limited
physical
activity
Frequent
severe
exacerbations
Night time
symptoms
≤ 2 times a
month
> 2 times a
month
> 1 per week Almost every
night
Lung function
FEV1
PEF variability
≥80% predicted
< 20%
≥80%
predicted
20-30%
>60-<80%
predicted
>30%
≤ 60%
predicted
>30%
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16. AsthmaAsthma exacerbationsexacerbations
Mild Moderate Severe Respiratory failure
(Status asthmaticus) imminent
- breathless at rest if
- talks in words drowsy
- respiratory rate >30/min
- loud wheeze no wheeze
- pulse >120/min bradycardia
- PEF < 60%
- Arterial O2 saturation<90%
- PaO2 < 6O ; PaCO2 > 45 mm of hg
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17. ManagementManagement
ofof
asthmaasthma
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18. Asthma Management GoalsAsthma Management Goals
Achieve & maintain symptom control
Maintain normal activity including exercise
Maintain pulmonary function as close to normal as possible
Prevent asthma exacerbations
Avoid adverse effects from asthma medications
Prevent asthma mortality
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19. Asthma managementAsthma management
Pharmacological measures Non pharmacological
measures
- Patient education
- Avoidance of triggers
- Avoid smoking
- Graded exercise training
- Psychological treatment
- Yoga, acupuncture, hypnosis
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20. Targets of drug actionTargets of drug action
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Suppression of inflammation and hyper-reactivity-steroids
Prevention of release of mediators from mast cells-mast cell
stabilizers
Antagonism of released mediators- LTRA
Blockade of constrictor neurotransmitter- anticholinergics
Mimicking dilator neurotransmitter- beta 2 agonists
Directly acting bronchodilator- methyl xanthines
+ new targets

21. Drugs for asthmaDrugs for asthma
Short term relievers Long term controllers
Immediate reversal of bronchospasm
but no effect on underlying
inflammation.
Used at the time of acute attacks
Short acting beta 2 agonists
Anticholinergics
Methyl xanthines
Control degree of inflammation and
bring about an improvement of overall
asthma control
Taken regularly on a long term basis.
Corticosteroids
Mast cell stabilizers
Long acting beta 2 agonists
Leukotriene modifiers
Methyl Xanthines
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22. Short term relieversShort term relievers
Short acting beta 2 agonists(SABA)
Salbutamol (albuterol), Terbutaline, Fenoterol, Remiterol,
Pirbuterol, Levalbuterol
- Beta 2 receptor agonism-bronchodilatation
- Given by inhalation/oral/parenteral
-S/E : Tachycardia, tremors, hypokalemia, decreased response on
long term use ( at higher inhaled dose or with oral and parenteral
dose)
-Levalbuterol considered to be more potent with less side effects
than racemic mixture – evidence from trials lacking
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23. Short term relieversShort term relievers
Anticholinergics
Ipratropium, Tiotropium
-Less effective than beta agonists
-Used as additional to beta 2 agonists in severe asthma
-S/E : Dry mouth, urinary retension
-Tiotropium has longer duration of action and doesn’t
inhibit M2 receptors
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24. Long term controllersLong term controllers
Corticosteroids
Inhaled Corticosteroids: Beclomethasone, Budesonide,
Fluticasone, Flunisolide, Ciclesonide
- Have high topical to systemic activity
-Reduce inflammation and hyperresponsiveness and improve all
indices of asthma control
-Peak effect seen after 5-7days. No role in acute episodes.
-S/E : sore throat, hoarseness of voice,
oropharyngeal candidiasis (local)
Mood changes, osteoporosis, growth retardation,
hyperglycemia, pituitary adrenal suppression(systemic effects a
high doses) 24

25. Corticosteroids contd……
Fluticasone -higher potency
- longer duration of action
- negligible systemic bioavailability
Ciclesonide – prodrug cleaved by esterases in bronchial epithelium
- oral bioavailability < 1%
- In circulation highly plasma bound thus decreasing
exposure of tissue cells to free active drug
Systemic steroids in asthma
-In severe persistent asthma not controlled by other drugs(oral
prednisolone)
-Status asthmaticus (iv hydrocortisone)
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26. Long term controllersLong term controllers
Long acting beta 2 agonists (LABA)
salmeterol, formoterol
-Highly lipid soluble drugs with longer duration of action
(>12hrs) than SABA.
-Salmeterol has slow onset of action but formoterol’s onset
of action is comparable to SABA.
-They do not have anti-inflammatory actions. Their best
use is as an add on to ICS in patients not controlled by ICS
alone. The combination is better than increasing the dose
of steroids in terms of symptom control and improvement
of lung function
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27. Long term controllersLong term controllers
Leukotriene modifiers
- lipoxygenase inhibitor- Zileuton (hepatotoxicity)
- LTRA – Montelukast, Zafirlukast
. Oral administration
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28. Stepwise management ofStepwise management of
asthmaasthma
Step 1
Mild
intermittent
asthma
Step 2
Mild persistent
asthma
Step 3
Moderate
persistent
asthma
Step 4
Severe
persistent
asthma
Step 5
Continuous use
of oral steroids
Inhaled short
acting beta 2
agonist as and
when needed
As needed short acting beta 2 agonist with regular controller therapy
Low dose
inhaled steroid
or
LTRA
Medium dose
steroid
Or
Low dose steroid
+
LABA/LTRA/Su
stained release
theophylline
Medium or high
dose steroid +
one or more of
the following
options:-
LABA
LTRA
Sustained release
theophylline
To step 3, add
oral steroids
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29. Management of acute severeManagement of acute severe
exacerbationsexacerbations
Parenteral steroid(hydrocortisone)
Nebulized salbutamol+ ipratropium
High flow humidified oxygen
Salbutamol/ terbutaline im or subcutaneously
Intubation & mechanical ventilation if needed.
Correct dehydration & acidosis with saline+ sodium
bicarbonate infusion
Antibiotics to treat chest infection
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30. Recent Advances inRecent Advances in
thethe treatment oftreatment of
asthmaasthma
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31. Why the search for newWhy the search for new
drugs??drugs??
Asthma has a complex pathogenesis—many putative
targets still remain to be explored
Patients not controlled even by oral steroids need an
alternative
A drug which can reduce the dose of steroids/replace it
without producing side effects of its own.
Asthma still remains an incurable disease though it can
be managed effectively.
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32. Newer approaches toNewer approaches to
treatmenttreatment
Novel class of bronchodilators
Immunomodulatory therapies
Newer anti-inflammatory therapies
Mediator antagonists
Miscellaneous approaches
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33. Novel class of bronchodilatorsNovel class of bronchodilators
1. Magnesium Sulphate
-Reduces cytosolic calcium in airway smooth muscle-
bronchodilatation
-Can be given by IV/nebulisation
-Useful as an additional drug to SABA in A/c severe asthma.
(more studies needed to document this)
- Not suitable to be employed alone as clinical benefit is small.
-Cheap, well tolerated with minor S/E like nausea & flushing
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34. Novel class of bronchodilatorsNovel class of bronchodilators
2. Potassium channel openers
Potassium channel openers that open calcium activated large
conductanceK+ channels in smooth muscles(maxi K+ channels)
better tolerated. ( Potassium channel openers that open ATP
dependent K+ channels donot produce bronchodilatation as expected
and also produce CVS side effects)
3. Calcium channel blockers – Nifedipine, verapamil
-Prevent calcium entry into smooth muscle
-Inhibit stimuli induced bronchoconstriction but no effect on basal
airway calibre.
-Bronchodilator effect less than SABA.
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Novel class of bronchodilatorsNovel class of bronchodilators
5. ANP & related peptide Urodilatin
-Activates membrane guanylyl cyclasecGMPbronchodilatation
-Bronchodilator effects comparable to SABA.
-Useful for additional bronchodilatation in A/c severe asthma
6. VIP analogs
-VIP binds to VPAC1(smooth muscles of blood vessels) &
VPAC2(airway smooth muscle)-couple to Gs --adenylyl
cyclase stimulated-smooth muscle relaxation
-VIP potent bronchodilator in vitro studies but in patients it is
rapidly metabolised and also has vasodilator S/E.
-More stable analog of VIP (RO 25-1533) selectively stimulate
VPAC2-produces rapid bronchodilatation but effect is not
prolonged

36. Immunomodulatory therapiesImmunomodulatory therapies
1. Immunosuppressive therapy
- Considered when other treatments are unsuccessful or to reduce
the dose of oral steroids (in step 5)
-Methotrexate, Cyclosporine, Gold salts, IV immunoglobulin
-Not routinely employed due to greater side effects and lesser
efficacy
2.Anti IgE therapy
3. Specific immunotherapy
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37. Immunomodulatory therapiesImmunomodulatory therapies
Anti IgE therapy - Omalizumab
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- Humanized monoclonal antibody
- MOA: Neutralises IgE in circulation
Inhibits activation of IgE bound to
mast cells
Down regulates IgE receptors on mast
cells
-Route : S/c or IV every 2- 4 weeks
-Use : severe persistent extrinsic asthma who
are resistant to other forms of treatment.
Reduces exacerbations and requirement of
oral and inhaled steroids in them
-Drawback : high cost
-S/E : local reaction at inj. site
- rarely anaphylactic reaction

38. Immunomodulatory therapiesImmunomodulatory therapies
Specific immunotherapy
-Injection of low doses of allergen to cause desensitization
-Benefit in asthma not well documented
-Mechanism : induces secretion of anti-inflammatory cytokine(IL 10)
from regulatory helper T cells. This blocks co-stimulatory
transduction in T cells so that they are unable to react to allergens.
-Drawback : risk of anaphylaxis and local reactions
: time consuming therapy
-Better specific immunotherapy developed with:-
cloned allergen epitopes, T cell peptide fragments of allergens, DNA
vaccines composed of allergen complement DNA.
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39. Newer anti-inflammatoryNewer anti-inflammatory
drugsdrugs
NF-kB inhibitors
-NF is a transcription factor regulating inflammatory genes in asthma.
-NF degraded by inhibitory protein IkB. IkB is degraded by IB Kinase.
-Inhibitors of IB kinase in clinical trials.
-Drawback: susceptibility to infections when NF is inhibited.
Mitogen activated protein kinase inhibitors
-MAP kinase pathways involved in C/C inflammation
-SB203580, RW567657 block p 38 MAP kinase pathways
-These inhibit synthesis of inflammatory mediators but severe toxicity
reported.
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40. Newer mediator antagonistNewer mediator antagonist
Several mediators involved.
Inhibitors of bradykinin, PAF found to be disappointing in
asthma
No new mediator antagonists deserves mention
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41. Miscellaneous approachesMiscellaneous approaches
Cytokine modifiers
-IL5 plays pivotal role in eosinophilic inflammation
-Anti IL5 antibodies shown to decrease exacerbations in severe
asthma with eosinophilia.
-Antibodies against IL 4, 13 showed disappointing results
Chemokine receptor antagonist
-CCR3 antagonists tried in asthma expecting to block eosinophil
recruitment in the airways
-Results disappointing due to high degree of toxicity.
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42. Miscellaneous approachesMiscellaneous approaches
CRTH2 antagonists in development show promising results in
asthma
Endothelin antagonists may improve structural changes in
asthma. However not tested.
Antioxidants more potent than Vit C&E, N-Acetyl cysteine in
development as oxidative stress important in asthma.
Macrolide antibiotics like Clarithromycin reported to be
effective in many cases of c/c asthma. Causation of c/c asthma
linked to Chlamydia pneumonia or mycoplasma pneumonia
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43. ConclusionsConclusions
Newer drugs in the already available classes of drugs may be
better in certain respects when compared to their predecessors.
Among newer classes of drugs, none holds promise.
- Among bronchodilators-MgSO4, ANP, VIP analogs may be used
as additional drugs to SABA but seem to be less efficient than
SABA.
- Anti IgE therapy with Omalizumab holds promise but it is too
costly for the majority of patients to afford.
As of now, the drugs in current use are the possibly the best
that can be offered to a asthma patient.
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Thank