Recent advances in the pharmacotherapy of asthma and new therapies

1. Recent Advances in the Pharmacotherpy
of Asthma
Dr. Mohit Kulmi
Postgraduate resident
Department of Pharmacology
SAMC & PGI, Indore

2. History
• Asthma : derived from the Greek aazein, meaning "sharp breath.“
• In 450 BC. Hippocrates: more likely to occur in tailors, anglers,
and metalworkers.
• Six centuries later, Galen: caused by partial or complete bronchial
obstruction.
• 1190 AD, Moses Maimonides: wrote a treatise on asthma, describing
its prevention, diagnosis, and treatment
• 17th century, Bernardino Ramazzini: connection between asthma
and organic dust.
• 1901: The use of bronchodilators started.
• 1960s: inflammatory component of asthma was recognized and
anti-inflammatory medications were added to the regimens.

3. Simple Definition
It’s a reversible chronic inflammatory airway
disease which is characterized by bronchial
hyper-responsiveness of the airways to various
stimuli, leading to widespread
bronchoconstriction, airflow limitation and
inflammation of the bronchi causing symptoms of
cough, wheeze, chest tightness and dyspnoea.

4. • Bronchial asthma Patients with asthma experience:
• Attacks of severe dyspnea, coughing, and wheezing.
• Rarely, “status asthmaticus” - may prove fatal.
• Patients may be asymptomatic between the attacks.
• In some cases, the attacks are triggered by exercise and cold or by
exposure to an allergen, but often no trigger can be identified.
• There has been a significant increase in the incidence of asthma in
the world in the past three decades.

6. • Genetic factors
• Environmental factors
• House dust
• Mites
• Exposure to tobacco smoke,
• to animals, pollens, molds.
• Dietary changes
• junk food and fast food contain MSG
ETIOLOGY OF ASTHMA

7. Lack of exercise
• Less stretching of the airways
Occupational exposure
• Irritants in the workplace : chemicals, dusts, gases, moulds and
pollens.
• These can be found in industries such as baking, spray painting of
cars, woodworking, chemical production, and farming.

8. • Atopic diseases – eczema and allergic rhinitis.
• Maternal status – both physical and mental conditions like
anaemia and depression in the mother are associated with asthmatic
stress for the child.
• Early antibiotic use – babies who are given antibiotics may be
50% more likely to develop asthma by the age of six

9. Pathogenesis
• Complex, not fully understood
• Large numbers of cells, mediators are involved and vascular leakage
-activated by expose to allergens or several mechanism
Inflammation
• Eosinophils, T-lymphocytes, macrophages and mast cell
Remodeling
• Deposition of collagens and matrix proteins-damage
• Loss of ciliated columnar cells- metaplasia – increase no of
secreting goblet cells

10. Inflammation of
inner lining of
airways
Muscle around
airways tighten
Airways produce
mucus due to
inflammation
Pathogenesis

11. Bronchial inflammation
Environment factor Genetic prediposition
Bronchial hyperreactivity + trigger factors
Cough, Wheeze, Breathlessness, Chest tightness
Oedema
Bronchoconstriction
Mucus production
Airways narrowing

12. Early phase
• Inhaled Antigen
 Sensitised mast cells on the mucosal surface  mediator
release.
 Histamine  bronchoconstriction, increased vascular
permeability.
 prostaglandin D 2  bronchoconstriction, vasodilatation.
 Leucotriene C4,D4, E4  Increased vascular permeability,
mucus secretion and bronchoconstriction.
 Direct subepithelial parasympathetic stimulation 
bronchoconstriction.

13. Late phase
• Starts 4 to 8 hours later
• Mast cell release additional cytokine
• Influx of leukocytes(neutrophil,eosinophil)
• Eosinophils are particularly important- exert a variety of effect

14. Trigger
Eg.dust,pollen,
animal dander
TH2
cell
IL5
IL4
Eosino
phil
IgE B
cell
Mast
cell
IgE antibody
Mediators
Eg.Histamine,
leukotrines
Bronchospasm
Increase vascular permeability
Mucus production
Immediate phase
(minutes)
Late phase (hours)

15. Differrence between normal airway and airway in person with asthma
Narrowed
bronchioles
(muscles spasms)

17. Management of Chronic Asthma
Aims of management
• to recognize asthma
• to abolish symptoms
• to restore normal or best possible long term
airway function
• to reduce morbidity and prevent mortality

18. Approach of chronic asthma
• Education of patient and family
• Avoidance of precipitating factors
• Use of the lowest effective dose of convenient
medications minimizing short and long term
side effects.
• Assessment of severity and response to
treatment.

19. Medication
Bronchodilator drugs
•to relieve
bronchospasm and
improve symptoms.
Anti inflammatory
drugs
•to treat the airway
inflammation and
bronchial hyper-
responsiveness, the
underlying cause of
asthma, i.e. to prevent
attacks.

21. Drug Delivery
• The inhaled route is preferred for beta2-agonists and steroids as it
produces the same benefit with fewer side effects
• Inhaled medications exert their effects at lower doses
• MDI is suitable for most patients as long as the inhalation technique
is correct
• Alternative methods include spacer devices, dry powder inhalers and
breath-actuated MDI
• Nebulized route is preferred in the management of acute attacks

22. The Need for New Asthma Therapy
• 5-10% have uncontrolled asthma despite effective inhaled therapy.
• What we need
– Drugs with similar mechanism but less side effects
– New classes of drug to treat asthma
– New classes of drug that modify the course of the disease
• Improvement in understanding basic pathophysiology of asthma in
molecular level
– IgE in pathogenesis of asthma
– Cytokines and cell signalling
– Immunomodulating pathway

23. New Bronchodilators
• Ultra-long-acting beta-2 agonists
• Muscarinic receptor agonist
• Bitter taste receptor agonist

24. New Bronchodilators
• Bronchodilators use
– Relieving bronchoconstriction (short-acting)
– Preventing bronchoconstriction (long-acting beta-agonist or
LABA: formoterol, salmeterol – lasting 12 hrs)
• Ultra-LABAs in development (lasting > 24 hrs) for once-daily use
• Long-acting muscarinic receptor agonist (LAMA), e.g. tiotropium,
can be a useful add-on for severe asthma.
• Bitter taste receptor (TAS2R) agonist can cause bronchodilation.

25. Bitter Taste Receptor (TAS2R) Agonist
Bitter taste receptor agonist can cause bronchodilator via
G-protein-phosphatidylinositol phosphate pathway
resulting in activation of Ca-dependent K channel and
subsequent hyperpolarization of smooth muscle cell.

26. Magnesium sulphate
• Reduces cytosolic calcium in airway smooth muscles leading to
bronchodilatation
• Can be given by IV/nebulisation
• Useful as an additional drug to SABA in acute severe asthma
• Not suitable to be employed alone as clinical benefit is small
• Cheap, well tolerated with minor s/e like nausea and flushing

27. Potassium channel openers
• Potassium channel openers that open calcium activate large conductance
K+ channels in smooth muscles.
• Experimental evidence and preclinical models suggest that ATP-dependent
K(+) (K(ATP)) channel openers, big-conductance K(+) (BK(CA)) channel
openers, and intermediate-conductance K(+) (IK(CA)) channel blockers
may be the most effective agents for treating asthma and COPD.
• Modulation of potassium channels by these agents may produce beneficial
effects such as bronchodilation, a reduction in airways hyper-
responsiveness (AHR), a reduction in cough and mucus production and an
inhibition in airway inflammation and remodelling.
Calcium channel blockers
• Nifedipine, verapamil
• Prevent calcium entry into smooth muscle
• Inhibit stimuli induced bronchoconstriction but no effect on basal airway
caliber
• Bronchodilator effect less than SABA.

29. ANP
• Activates membrane guanylyl cyclase  cGMP 
bronchodilatation
• Bronchodilator effects comparable to SABA
• Useful for additional bronchodilatation in acute severe asthma
VIP analouges
• VIP binds to VPAC1 (smooth muscles of blood vessels) & VPAC2
(airway smooth muscles)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 analouge of VIP (RO25-1533) selectively stimulate
VPAC2 produces rapid bronchodilatation.

30. New Corticosteroids
• Designing new corticosteroids to decrease side
effects
• Dissociated steroids
• Nonsteroidal selective glucocorticoid receptor
agonists

31. • ICSs are the most effective anti-inflammatory therapy for asthma.
• Currently available ICSs can be absorbed from the lung, leading to
potential systemic side effects.
• New corticosteroids’ preferred properties
– Reduced absorption from the lungs
– Inactivated in the circulation
– Dissociated steroid (trans-activation vs cis-activation vs trans-
repression)
– Nonsteroidal selective glucocorticoid receptor agonist (SEGRA)

32. Transcription Mechanism of Corticosteroid
• Most of the anti-inflammatory effects of corticosteroid are due to
trans-repression of the pro-inflammatory gene.
• corticosteroid-GR complex is needed to attach to nuclear factor
leading to inhibition of gene expression.
• Dimerization of corticosteroid-GR complexes is needed for trans-
activation and cis-repression.
• Most of the side effects (osteoporosis, HTN, DM) of steroid are from
gene trans-activations.

34. Dissociated Steroid/SEGRA
• Dissociated steroid and selective glucocorticoid receptor agonist can
bind to glucocorticoid receptor and prevent dimerization. This will
prevent trans-activation and cis-repression of metabolic gene
products.
• However, trans-activation of anti-inflammatory protein will be
prevented leading to decreased anti-inflammatory effects.
• Mapracorat, Fosdagrocorat, Dagrocorat

36. Targeting Lipid Mediators
• Problems: More than 100 mediators are involved in the complex
inflammatory process in asthma.
• The only mediator antagonists available are cysteinyl-Leukotriene
CysLT1 receptor antagonists e.g. montelukast.
• 5’-lipooxygenase and 5’-lipooxygenase-activating protein inhibitors
are in development.

37. • Prostaglandin D2 is released from mast cells, Th2 cells and dendritic
cells.
– DP2 receptor (CRTh2)  chemotaxis of Th2 and eosinophil
– DP1 receptor  vasodilation, enhancing Th2 polarization
– Thromboxane receptor  airway smooth muscle constriction
• CRTh2 inhibitors: AMG-853 OC000459 and MK-2746
• DP1/DP2 inhibitors: in development
• PGD2 synthesis inhibitors: in development

38. Interleukin-4 and Interleukin-13
• Pitrakinra
– Mutated IL-4 (recombinant human IL-4 mutein)
– Blocking IL-4Rα, the common receptor for IL-4 and IL-13
– Reduces the late response to inhaled allergen in mild asthmatics
– Patients with high eosinophil count have a decrease in asthma
exacerbation on pitrakinra.

39. Interleukin-5
• IL-5 is important for eosinophilic inflammation.
• Mepolizumab is a blocking antibody to IL-5.
– Depletes eosinophil from the circulation and the sputum of
asthmatics
– Reduces exacerbation in patients with persistent sputum
eosinophilia despite high dose ICS but no improvement in lung
function.
• IL-5Rα blocker is currently studied.

40. Other Interleukins
• Anti-TNF-α
– No beneficial effect on lung function, symptoms, or
exacerbations
– Increased reports of pneumonia and cancer
• IL-17
– May be a target in severe asthma with neutrophillic
inflammation
• IL-10
– Broad spectrum of antiinflammatory effects
– Efficacy has not been demonstrated in asthma.
• IL-12 and Interferons
– Not effective and results in unacceptable side effects

41. Phosphodiesterase-4 inhibitors
• PDE 4 inhibitors have wide spectrum of anti-inflammatory effects –
inhibiting T cells, eosinophils, mast cells, airway smooth muscle
• Roflumilast – inhibitory effect on allergen-induced response similar
to low dose ICSs.
• Side effects: nausea/vomiting mediated through PDE4D while
PDE4B decreases inflammation.
• PDE-3 inhibitor can cause bronchodilation.
• Roflumilast can inhibit both the early and late phase response in
patients with mild allergic asthma.

43. Other novel anti-inflammatory drugs
• Adhesion molecule blockade
– Adhesion molecules play important role in recruitment of
inflammatory cells from the circulation to the airways.
• PPAR (peroxisome proliferator-activated receptor)-γ agonist
– Wide spectrum of anti-inflammatory effects
– Polymorphism of PPARγ gene is linked to increased risk of
asthma
– Rosiglitazone marginally improves lung function in smoking
asthmatics.
– Rosiglitazone 8 mg/day helps improve FEV1 and FEF in
smokers with asthma.

44. Anti-IgE therapy
• Omalizumab, monoclonal antibody that blocks IgE, is now used in
treatment of selected patients with severe asthma.
• More potent anti-IgE antibodies are in development.
• Low-affinity IgE receptor (FcεRII or CD23) antagonist seems to be
well tolerated and reduces IgE concentrations in patient with mild
asthma in a phase I study.

45. Mast cell Inhibitors
• Mast cell stabilizers
– Cromones (Sodium cromoglycate, nedocromil sodium)
– Furosemide
– Short-acting, not effective as long-term controllers
• Stem cell factor (SCF)
– Key regulator of mast cell survival
• Masitinib
– A potent tyrosine kinase inhibitor.
– Reduction in steroid use and symptoms in patients with severe
steroid-dependent asthma.
Syk kinase Inhibitors
• Spleen tyrosine kinase is involved in activation of mast cells and
other immune cells.
• Still in pre-clinical studies for asthma

46. Targeting Treg and Dendritic cells
• Specific immunotherapy increases Treg numbers and their
expression of IL-10  suppressed Th2 responses  decrease IgE
synthesis
• Several classes of drug have been shown to suppress myeloid
dendritic cell activation
– iloprost
– fingolimod
• In preclinical development

48. Bronchial thermoplasty
• Bronchial Thermoplasty, delivered by the Alair™ System, is a
treatment for severe asthma approved by the FDA in 2010
• It involves the delivery of controlled, therapeutic radiofrequency
energy to the airway wall,
• thus heating the tissue and reducing the amount of smooth muscle
present in the airway wall..

50. Conclusion
• With the understanding of pathogenesis of asthma new targets can
be found in the drug development.
• Future drugs will be associated with less side effects and toxicity.
• As of now the drugs in current use are possibly the best that can be
offered to a asthma patient.