recent advances in asthma in brief

1. 1

2. BRONCHIAL ASTHMA
PHARMACOLOGY AND RECENT ADVANCES
Dr Pranesh Pawaskar
FYR
Dept. Of Pharmacology.
L.T.M.M.C. SION, MUMBAI - 400022.
DATE -13/08/2016. 2

3. 3

4. DEFINITION
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.
4

5. HISTORY
 Bronchial asthma was recognized in ancient
Egypt and was treated by drinking
an incense mixture known as Kyphi.
 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.
5

6. EPIDEMIOLOGY
6

7. EPIDEMIOLOGY
• The most recent revised global estimate of asthma suggests that as
many as 334 million people have asthma, and that the burden of disability
is high.
• Approximately 250,000 people die per year from the disease
• Recognized as a major public health problem since the 1970s.
7

8. RISK FACTORS
8

9. 9

10. 10

11. STATUS ASTHMATICUS
11

12. 12

13. 13

14. HISTOPATHOLOGY
• Bronchi filled with mucus • Normal vs asthmatic bronchiole
14

15. SPIROMETRY
• Spirometry is the single best test for asthma.
• If the FEV1 measured by this technique improves more than
12% following administration of a bronchodilator such
as salbutamol, this is supportive of the diagnosis.
• Single-breath diffusing capacity can help differentiate asthma
from COPD.
15

16. OTHER TESTS
• METHACHOLINE CHALLENGE TEST : Involves the inhalation of increasing
concentrations of a substance that causes airway narrowing in those
predisposed.
• If negative it means that a person does not have asthma; if positive, however,
it is not specific for the disease
• PEAK EXPIRATORY FLOW RATE : Is variable than spirometry hence not
recommended for diagnosis. 16

17. TYPES OF BRONCHIAL ASTHMA
Intrinsic Asthma
• It tends to be perennial.
• Status asthmaticus is more
common.
Extrinsic Asthma
• It is mostly episodic.
• Less prone to status asthmaticus.
17

18. DIFFERENTIAL DIAGNOSIS
18

19. CLASSIFICATION
• The National Asthma Education And Prevention (NAEP) program has
classified asthma as:
1. Intermittent.
2. Mild Persistent.
3. Moderate Persistent.
4. Severe Persistent.
19

20. CLINICAL CLASSIFICATION
Severity
Symptom
frequency
Night time
symptoms
%FEV1 of
predicted
FEV1
Variability
SABA use
Intermittent ≤2/week ≤2/month ≥80% <20% ≤2 days/week
Mild persistent >2/week 3–4/month ≥80% 20–30% >2 days/week
Moderate
persistent
Daily >1/week 60–80% >30% daily
Severe
persistent
Continuously
Frequent
(7×/week)
<60% >30% ≥twice/day
20

21. TREATMENT
21

22. 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. 22

23. DRUGS USED FOR ASTHMA
• 1. Bronchodilators.
- Beta 2 sympathomimetics.
- Methylxanthines.
- Anticholinergics.
• 2. Leukotriene antgonists.
• 3. Mast cell stabilizers.
• 4. Corticosteroids.
- Systemic.
- Inhalational.
• 5. Anti-IgE antibody.
23

24. CLASSIFICATION
SHORT ACTING
• Short-acting Beta2-adrenoceptor
Agonists (SABA), such as Salbutamol
are the first line treatment.
• Anticholinergic Medications, such
as Ipratropium bromide.
• Older, less selective Adrenergic
Agonists, such as inhaled Epinephrine.
LONG ACTING
• Corticosteroids are most effective
treatment available for long-term
control.
• Long-acting beta-adrenoceptor
agonists (LABA) such
as salmeterol and formoterol.
• Leukotriene receptor antagonists (such
as montelukast and zafirlukast.
• Mast cell stabilizers such as cromolyn
sodium 24

25. BRONCHODILATORS
BETA SYMPATHOMIMETIC :-
• Cause Broncho-dilatation through βeta2 receptor stimulation → increased
CAMP formation in bronchial muscle cell → relaxation.
• Increased CAMP in mast cells and other inflammatory cells decreases
mediator release.
• Since β2 receptors on inflammatory cells desensitize quickly, the contribution
of this action is of short duration.(SABA)
• Mainstay of treatment of reversible airway obstruction.
25

26. • They are the most effective and fastest acting bronchodilators when
inhaled.
• Selective β2 agonists that are now used in asthma to minimize cardiac
side effects.
• Should be used cautiously in hypertensives, ischaemic heart disease
patients and in those receiving digitalis.
26

27. 27

28. 28

29. BRONCHODILATORS
29

30. SALBUTAMOL (ALBUTEROL):-
• Highly selective BETA-2 agonist ( inhaled is best )
• Action starts in 5 min. And lasts for 2-4 hours.
• Used to abort or terminate asthmatic attacks.
• Dose related side effect: muscle tremors.
• Palpitation, nervousness, throat irritation can also occur
• Bioavailability 50%
• Oral administration increases risk of side effects.
30

31. OTHER SYMPATHOMIMETICS:-
• Terbutaline: similar to salbutamol in properties and use.
• Bambuterol: prodrug of terbutaline. Release active drug for 24
hours, indicated in nocturnal and chronic bronchial asthma.
• Salmeterol: first long acting selective b2 agonist, more b2 selective,
superior action for COPD patients.
• Formeterol: faster action than salmeterol but active for 12 hrs
31

32. BRONCHODILATORS
METHYLXANTHINES:
• Theophylline and compounds extensively used in asthma but
are not first line drugs any more.
• On CNS it acts as stimulant. Primarily affect higher centers.
• On CVS it acts as a direct stimulant of heart. Increases force of
myocardial contractions, tachycardia. Effect on blood pressure
is unpredictable.
32

33. • On smooth muscles it acts as relaxant primarily on bronchial muscles.
• On kidney they act as mild diuretics.
• They enhance power of skeletal muscles, enhance pepsin secretion in
stomach.
• They increase BMR slightly, also decreases release of histamines from
mast cells.
33

34. 34

35. 35

36. THEOPHYLLINE:
• Well absorbed orally.
• Metabolised in liver by demethylation and oxidation by CYP1A2.
• Crosses placenta and is secreted in breast milk.
• Factors needed for dose reduction: age (0.6), CHF (0.6)
pneumonia (0.4), liver failure(0.2-0.4).
• Irritant property can lead to gastric pain.
36

37. • Agents enhancing metabolism- smoking, phenytoin, rifampicin,
phenobarbitone
• Agents inhibiting metabolism- erythromycin, ciprofloxacin, cimetidine,
OCP, allopurinol.
• Theophylline enhances effects of furosemide, digitalis, OHA.
• Theophylline decreases effects of phenytoin and lithium.
37

38. BRONCHODILATORS
ANTICHOLINERGICS:-
• Cause Broncho dilatation by blocking M3 receptors mediated constricted
tone.
• Act primarily on larger airways which receive vagal innervation.
• Less effective than sympathomimetic.
• When inhaled they are drug of choice for COPD.
38

39. MECHANISM OF ACTION OF
ANTICHOLINERGICS
39

40. IPRATROPIUM BROMIDE:-
• Short acting
• Patients with COPD (reflex cholinergic tone) and psychogenic asthma
responds to these better.
• Combination with sympathomimetics produce marked and longer lasting
action.
• Dry mouth , respiratory discomfort are the ADRs.
TIOTROPIUM BROMIDE:-
• Its longer acting.
• More effective than ipratropium. 40

41. LEUKOTRIENE ANTAGONIST
• Two drugs available.
• Both have similar actions and clinical utility.
• Montelukast and zafirlukast .
• Competitively block cysLT1 receptor mediated bronchoconstriction, mucus
secretion, vascular permeability and recruitment of eosinophils.
• Given for chronic bronchial asthma.
• Rapid oral absorption, liver metabolism and excretion into feces.
41

42. • Side effect like headach and rashes.
• Few case of Chrug-strauss Syndrome have been noted.
• Metabolism occurs by CYP2C9.
• Use cautiously in case of pregnancy lactation and hepatic
impairment. 42

43. 43

44. MECHANISM OF ACTION
44

45. ZILEUTON:-
• Newer drug
• It is a 5-LOX inhibitor.
• Blocks LTC4/D4 as well as LTB4 synthesis.
• So prevents all LTB induced responses.
• Efficacy is similar to montelukast.
• Hepatotoxic
45

46. MAST CELL STABILIZER
SODIUM CROMOGLYCATE:-
• Synthetic chromone derivative.
• Inhibits mast cell degranulation.
• Chemotaxis of inflammatory cells is inhibited.
• It is not a bronchodilator hence cant be used in acute asthma attack.
• Used in bronchial asthma, allergic rhinitis, allergic conjunctivitis.
• Bronchospasm, throat irritation and cough occurs if taken as dry powder
inhalation. 46

47. KETOTIFEN:-
• An antihistaminic.
• Blocks H1 and blocks stimulation of immunogenic and inflammatory cells.
• Thus mediator release is reduced.
• Produces sedation.
• Dry mouth, dizziness, nausea, weight gain are side effects.
47

48. NEDOCROMIL
• Nedocromil sodium is a medication considered as mast cell stabilizer
which act to prevent wheezing, shortness of breath, and other breathing
problems caused by asthma.
• Nedocromil inhibits the degranulation of mast cells, prevents release of
histamine and tryptase.
• Prevents the synthesis of prostaglandins and leukotrienes.
48

49. 49

50. MECHANISM OF ACTION
50

51. CORTICOSTEROIDS
• Benefit by reducing bronchial hyperactivity by suppressing inflammation and
mucosal edema.
• They are not bronchodilators.
• Afford more complete and sustained symptomatic relief than bronchodilator
Improve airflow, reduce exacerbation Influence airway remodelling.
• Increases responsiveness of airway muscles to beta agonists
51

52. 52

53. 53

54. 54

55. SYSTEMIC STEROID THERAPY
• In case of severe chronic asthma not controlled by bronchodilators and
inhalational steroids.
• Status asthmaticus /acute exacerbation – start a high dose of rapidly
acting corticosteroids, shift to oral therapy 5-7 days after.
• COPD.- a short course of 1-3 week
55

56. INHALED STEROIDS
• High topical and low systemic activity. High first pass metabolism.
• Beclomethasone, budesonide, fluticasone are the examples.
• Indicated in all cases of persistent asthma when inhaled beta agonist are
daily required.
• Suppress inflammation airway, increases PEF rate.
• No role in status asthamaticus.
• Higher dose is required in case of COPD.
56

57. • Adverse effects – hoarseness of voice, dysphonia, sore throat,
oropharyngeal candidiasis.
• Minimised using a spacer, gargling.
• Other side effects - mood changes, osteoporosis, growth retardation in
children brusing, petechie, hyperglycaemia can occur
57

58. • Drugs used-
• Beclomethasone dipropionate
• Budesonide – non halogenated steroid
• Fluticccasone propionate- high potencylonger duration
• Flunisolide- seasonal and perennial rhinitis
58

59. ANTI IGE ANTIBODY
OMALIZUMAB:-
• Humanised monoclonal antibody.
• Administered subcutaneously.
• Neutralises free IgE without mast cell activation.
• It is found to reduce exacerbations.
• Resistant bronchial asthma.
• Expensive.
• Reserved for resistant asthma patients. 59

60. 60

61. 61

62. PHARMACOTHERAPY
62

63. 63

64. GINA MANAGEMENT OF BRONCHIAL
ASTHMA
64

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66. 66

67. 67

68. 68

69. BRONCHIAL
ASTHMA IN
PREGNANCY
69

70. RECENT
DRUGS
70

71. 71

72. ARFORMOTEROL:
• Long-acting β2 adrenoreceptor agonist (LABA).
• Generally indicated for the treatment of chronic obstructive pulmonary
disease (COPD).
• It is the active (r,r)-(−)-enantiomer of formoterol and was approved by
the united states food and drug administration (FDA) on october 6, 2006.
72

73. CARMOTEROL:
• Also known as TA-2005 and CHF-4226.
• Experimental ultra-long-acting βeta adrenoreceptor agonist (ultra-LABA).
• It is over 100 times more selective for bronchial muscle than myocardial tissue.
• Was in clinical trials before 2010 when it has been withdrawn from further
development based on evidence that the compound does not possess a
competitive profile. 73

74. INDACATEROL:-
• Ultra-long-acting beta-adrenoceptor agonist developed by novartis.
• It needs to be taken only once a day.
• It is delivered as an aerosol formulation through a dry powder inhaler.
• It is licensed only for the treatment of chronic obstructive pulmonary
disease (COPD).
• Long-term data in patients with asthma are thus far lacking. 74

75. • VILANTEROL:-
• Ultra-long-acting β2 adrenoreceptor agonist (ultra-LABA).
• Approved in may 2013 in combination with Fluticasone furoate.
75

76. OLODATEROL:-
• Ultra-long-acting β adrenoreceptor agonist (ultra-LABA)
• Olodaterol mimics the effect of epinephrine at β2 receptors in the lung,
which causes the bronchi to relax and reduces their resistance to airflow
• Olodaterol is substantially metabolized by glucuronidation
• 88% intrinsic activity compared to the gold standard isoprenaline.
• Olodaterol monotherapy was previously evaluated in four phase II studies
in asthma patients. Not yet approved for asthma treatment.
• Phase III studies planned for Olodaterol monotherapy in patients with
asthma. 76

77. LONG ACTING MUSCARINIC AGONIST:- (LAMA)
• There are emerging data from key clinical trials to show that LAMA may
confer bronchodilator effects and improved control when used in addition
to inhaled corticosteroid (ICS) alone or in conjunction with long acting β-
adrenoceptor agonists (LABA).
77

78. NVA237 (GYCOPYRRONIUM)
• Once-daily dry-powder formulation of the long-acting muscarinic
antagonist Glycopyrronium Bromide.
• Glycopyrronium bromide in COPD Airways Clinical Study 1 (GLOW1)
evaluated the efficacy, safety and tolerability.
• Provided rapid, sustained improvements in lung function, improvements
in dyspnoea, and health-related quality of life, and reduced the risk of
exacerbations and the use of rescue medication
78

79. CILOMILAST:-
• It is orally active and acts as a selective phosphodiesterase-4 inhibitor.
• Four clinical trials were identified evaluating the efficacy of Cilomilast, the
usual randomized, double-blind, and placebo-controlled protocols were
used.
• Cilomilast is a second-generation PDE4 inhibitor with anti-
inflammatory effects that target bronchoconstriction, mucus
hypersecretion, and airway remodelling associated with COPD. And
bronchial asthma. 79

80. • ROFLUMILAST:-
• Is a drug that acts as a selective, long-acting inhibitor of the enzyme
phosphodiesterase-4 (PDE-4).
• It has anti-inflammatory effects and is used as an orally administered drug for
the treatment of inflammatory conditions of the lungs.
• Its primary clinical use is in the prevention of exacerbations (lung attacks) in
severe COPD.
• Has an inhibitory effect on allergen-induced responses in asthma
• Side effects :- diarrhoea, weight decreased, nausea, headache, insomnia
80

81. • Prostaglandin (PG)D2 is released from mast cells, Th2 cells, and dendritic
cells and activates DP2-receptors, also known as chemoattractant
homologous receptor expressed on Th2 cells (CRTh2), which mediate
chemotaxis of Th2 cells and eosinophils.
• Many CRTh2 antagonists are now in clinical development for asthma,
including amg-853 oc000459 and mk-2746, which have shown early
clinical efficacy as oral treatments for asthma and rhinitis.
81

82. 82

83. • SETIPIPRANT:-
• Is a drug originally developed by Actelion which acts as a selective, orally
available antagonist of the Prostaglandin D2 receptor 2 (DP2)
• Initially researched as a treatment for allergies and inflammatory
disorders, particularly asthma.
• It failed to show sufficient advantages over existing drugs and was
discontinued from further development in this application
83

84. • FEVIPIPRANT:-
• Code name QAW039
• Drug being developed by novartis which acts as a selective, orally
available antagonist of the prostaglandin d2 receptor 2 (DP2 or CRTh2).
• As of 2016, it is in phase II clinical trials for the treatment of asthma.
84

85. • CICLESONIDE-
• A new ICS that is locally activated in the lower airway epithelium.
• Consequently with very low systemic bioavailability.
• Negligible risk of local or systemic side effects even for long-term high-
dose treatment.
• Cleaved by Esterases in bronchial epithelium.
85

86. • RAMATROBAN
• Is a thromboxane receptor antagonist.
• It is also a DP2 receptor antagonist.
• It has also been used for the treatment of asthma.
86

87. • MAPRACORAT
• Anti-inflammatory drug belonging to the experimental class of selective
glucocorticoid receptor agonists (SEGRAs)
• In clinical trials for the topical treatment of atopic dermatitis, inflammation
following cataract surgery, and allergic conjunctivitis.
87

88. • The enzyme 5-lipoxygenase (5'-LO) works through 5'lo-activating protein
(FLAP).
• Several novel 5'-LO and FLAP inhibitors are currently in clinical
development.
• Drugs like Meclofenamate Sodium and Zileuton.
88

89. CYTOKINE BLOCKADE
• Inhibition of another th2 cytokine interleukin (IL)-4 by using inhaled
soluble receptors proved to be disappointing, but there is continued
interest in blocking IL-13, a related cytokine that regulates
immunoglobulin E (IgE) formation, particularly in severe asthma.
• IL-4 and IL-13 signal through stat6 (signal transduction-activated
transcription factor), and small molecule inhibitors, such as as1517499,
have been developed that are active in a murine model of asthma.
89

90. PITRAKINRA:-
• A mutated form of IL-4 that blocks IL-4Rα.
• IL -4Rα The common receptor for IL-4 and IL-13, significantly reduces
the late response to inhaled allergen in mild asthmatics when given by
nebulization.
• Clinical trials are currently in progress.
90

91. • An antibody against the IL-5 receptor (IL-5Rα) is also being studied in
clinical trials.
• Inhaled antisense oligonucleotides that block the common β chain of IL-5
and granulocyte-macrophage colony-stimulating factor (GM-CSF)
receptors together with the chemokine receptor CCR3 (TPI ASM8) has a
small effect in reducing allergen responses and airway inflammation.
91

92. • Several uncontrolled or small studies suggested that anti-TNF therapies
(TNF blocking antibody Infliximab or soluble receptor Etanercept) may be
useful in reducing symptoms, exacerbations, and airway
hyperresponsiveness in patients with severe asthma.
• a recent large multicentre trial with an antibody Golimumab showed no
beneficial effect on lung function, symptoms, or exacerbations, and there
were increased reports of pneumonia and cancer.
92

93. • Recently agonists of Bitter taste receptors (TAS2R), including Quinine,
Chloroquine, And Saccharine, have been identified as a novel class of
Bronchodilator.
93

94. • Corticosteroids switch off inflammatory genes by recruiting the nuclear
enzyme histone deacetylase-2 (HDAC2) to the activated inflammatory
gene initiation site
• So that activators of this enzyme may also have anti-inflammatory effects
or may enhance the anti-inflammatory effects of corticosteroids.
94

95. RECENT ADVANCES
• PPARγ AGONISTS
• Peroxisome proliferator-activated receptor gamma agonists have a wide
spectrum of anti-inflammatory effects, including inhibitory effects on
macrophages, T cells, and neutrophilic inflammation, and polymorphisms
of the PPARγ gene have been linked to increased risk of asthma.
• A PPARγ agonist Rosiglitazone gave a small improvement in lung
function in smoking asthmatic patients in whom inhaled corticosteroids
were ineffective,[67] and a modest (15%) reduction in late response to
inhaled allergen in mild asthmatics.
95

96. LUMILIXIMAB :-
• A monoclonal antibody that targets CD23.
• Is well tolerated and reduces IgE concentrations in patients with mild asthma.
• Clinical efficacy has not been reported.
• It is being investigated in phase I and II clinical trials for the treatment
of Chronic Lymphocytic Leukemia. 96

97. • Stem cell factor (SCF) is a key regulator of mast cell survival in the
airways.
• acts via the receptor c-kit on mast cells.
• blockade of SCF or c-kit is very effective in animal models of asthma
• suggesting that this pathway may be a good target for new asthma
therapies.
• Masitinib is a potent tyrosine kinase inhibitor that blocks c-kit (as well as
platelet-derived growth factor receptors) and provides some symptomatic
benefit in patients with severe asthma.
• more selective c-kit inhibitors are in development.
97

98. • SPLEEN TYROSINE KINASE (SYK) that is involved in activation of mast cells
and other immune cells and several small molecule SYK kinase inhibitors are in
development.
• An antisense inhibitor of SYK kinase is effective in an animal model of asthma.
• And the small molecule inhibitor R112 given nasally reduces nasal symptoms in
hay fever patients.
• More potent inhibitors, such as R343 and Bay 61–3606, are in development for
inhalation in asthma. 98

99. • New technology for delivering inhaled drugs by metered dose inhaler.
• Using the new hydrofluoroalkane propellant instead of the old
chlorofluorocarbon propellant.
• The modulate technology combines the use of hydrofluoroalkane
propellant (maintaining the drug in a solution that may be better nebulised
in ultrafine particles) and some improvement in the device (with slow
plume speed and better lung penetration).
• This new formulation has the potential for more effectively reaching the
smaller airways, an important target of treatment, especially in more
severe asthmatics. 99

100. • The 'Single-inhaler Maintenance And Reliever Therapy' has been
developed.
• A rapid-onset bronchodilator (e.g., Formoterol) and an ICS (e.g.,
Budesonide) at the time of the occurrence of asthma symptoms allows
the delivery of higher doses of ICS at very beginning stages of
exacerbations.
100

101. SOME HOME REMEDIES
101

102. 102

103. SOME AYURVEDIC MEDICATIONS
103

104. 104

105. 105

106. BRONCHIAL THERMOPLASTY
• Bronchial thermoplasty, delivered by the ALAIR system.
• Is a treatment for severe asthma approved by the FDA in 2010.
• Involving 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.
• This treatment has been shown to result in acute epithelial destruction with
regeneration observed in the epithelium, blood vessels, mucosa and nerves.
• However, airway smooth muscle has demonstrated almost no capacity
for regeneration, instead being replaced by connective tissue.
• The treatment has been shown to be safe and effective over at least five years. 106

107. 107

108. Benefits
• 32% reduction in asthma attacks
• 84% reduction in emergency room visits for respiratory symptoms
• 66% reduction in days lost from work, school, or other daily activities due
to asthma symptoms
• 73% reduction in hospitalizations for respiratory symptoms
108

109. FINALLY
• Educational activities going around world about Bronchial asthma.
• Development of some implementation plans at the regional or country level
have been done.
• New research is on going always. Newer medicines are showing good
results.
• This all has obtained consistent results in terms of a reduction of the
socioeconomic burden of the disease, with a high share from the patients
associated with improvement in HRQOL and reduction in disability due to
asthma.
• Still there is a much longer path to make world asthma free forever.
109

110. FAMOUS FACES WITH ASTHMA
110

111. 111

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