Pharmacotherapy in bronchial asthma and recent advances in treatment of bronchial asthma

1. 1
Dr. Resu Neha Reddy, MD Pharmacology, 3rd year PG
PHARMACOTHERAPY OF
BRONCHIAL ASTHMA

2. CASE STUDY
2
 A 32 year old female patient
presented to the ER with
acute dyspnoea, dry cough &
wheeze, she gave history of
recurrent similar attacks in
the past, she admitted
increasing symptoms with
exercise & dust exposure,
how would you approach this
case?

3. OBJECTIVES
3
 INTRODUCTION
 HISTORY OF ASTHMA
 TRIGGERS/RISK FACTORS
 PATHOPHYSIOLOGY OF BRONCHIAL ASTHMA
 VARIOUS ROUTES AND DELIVERY DEVICES
 PHARMACOTHERAPY
 RECENT ADVANCES

4. INTRODUCTION
4
 Asthma was recognized as early as Ancient Egypt.
 The word “asthma” is from the Greek which means
“difficulty in breathing” or “to stay awake in order to
breathe”.
 It often begins in childhood.
EPIDEMIOLOGY :
 300 million people suffer from asthma worldwide.
 30 million asthmatics are in India.
 WHO - India has the largest number of asthma deaths
in the world, contributing to 22.3% of all global
asthma deaths.

5. CELEBRITIES WITH ASTHMA
5

6. HISTORY
6
Hippocrates (~400 BC)
 First to use the term “Asthma” for panting and
laborious breathing.
 Relationship between the environment and
respiratory disease.

7. HISTORY
7
 Physicians used Belladonna as remedy for respiratory illness.
 The dried & crushed herbs were heated & smoke was inhaled
 provide relief.
 S/E: Dry mouth, Tachycardia, Dilated pupil, nausea & excitation

8. HISTORY
8
 Galen(130-201AD)- asthma due to bronchial
obstruction –treated with owl’s blood in wine
 Rene Laennec using the stethoscope he invented
 For the first time asthmatic wheezes could be
heard.

9. HISTORY
9
 In mid 19th century, Asthma cigarettes made of “herbal
preparations containing Atropine-like alkaloids” were used.
 By 1985 asthma cigarettes were removed from shelves of all
U.S. Stores
 Many options of inhalers  introduction of first Pressurised
metered dose inhaler(pMDI)

10. 10
 1905 - Epinephrine was referred in the treatment
 1950 - Oral corticosteroids
 1960 - Inhaled corticosteroids and selective beta2
agonists
HISTORY
 1980 - Over-prescription of
bronchodilator led to an
epidemic of asthma deaths

11. PHYSIOLOGY OF AIRWAY
SMOOTH MUSCLE CONTRACTION
11
Involuntary responses of airway smooth muscle regulated
ANS
↓
↓ ↓
SYMPATHETIC PARASYMPATHETIC
ADRENERGIC TONE CHOLINERGIC TONE
beta 2 adrenergic receptors M3 receptors
↓ ↓
BROCHODILATATION BRONCHOCONSTRICTION
(Beta 2 agonists) (Anticholinergics)

12. 12
 Asthma is reversible airway obstruction 2° to bronchial
hyper-reactivity, airway inflammation, mucous plugging, and
smooth muscle hypertrophy.
 Often diagnosed in childhood or early adulthood but can
present later.
 Manifests with attacks of (worsening night/ early morning)
 breathlessness,
 cough,
 wheezing,
 chest tightness &
 sibilant rales more expressed on breathing-out
ASTHMA - DEFINITION

13. TRIGGERS
13
 Allergic reactions to plants, foreign bodies in the air way.
 The allergens are divided into:
• Communal
• Industrial
• Pharmacological
• Occupational
• Natural

14. 14
House-dust mites which live in
carpets, mattresses and
upholstered furniture
Domestic insects
& animals
e.g.cockroach,
dog
Tobacco smoke
during active or
passive smoking
aerosols and synthetic
detergents
СOMMUNAL

15. 15
Industrial - Nitric, carbonic, sulphuric oxides,
formaldehyde, ozone, industrial emissions.
Pharmacological - enzymes, antibiotics, vaccines, serums.
Occupational - Dust of stock buildings, mills, weaving-mills,
book depositories etc.
Natural - Food components, plant pollen (especially
ambrosia, wormwood and goose-foot pollen)
and different viral infections.
TRIGGERS/ RISK FACTORS

16. TYPES OF ASTHMA
16
 Atopic asthma- Classical IgE mediated hypersensitivity,
allergen sensitization, from childhood, +ve family
history, skin test +ve
 Non-atopic asthma- No allergen sensitization, no such
history, skin test –ve, virus infection?
 Drug induced asthma- Sensitive to  Aspirin, NSAIDS
etc.
 Occupational asthma- Stimulants  fumes, organic &
chemical dusts(wood, cotton), gas(toluene), penicillin
products etc.
 Exercise induced asthma- begins after exercise & stops
after 30min, worsens in cold and dry climate.

17. PATHOGENESIS
17
 Inflammation
 Inflammatory mediators
 Airway remodeling
 Pathology

18. INFLAMMATION
18
 Allergic type of inflammation occurs
 From trachea to terminal bronchiole
 Predominantly in bronchi
 Cells involved in inflammation
 Mast cells
 Macrophages
 Dendritic cells
 Eosinophils
 Neutrophils
 T lymphocytes

19. IFLAMMATORY MEDIATORS
19
INFAMMATORY MEDIATORS ACTIONS
Histamine
PGD2
Cys-LT
Smooth m/s contraction,
Increased microvascular leakage,
Increased mucous secretion,
Chemo-attractant for inflammatory cells.
Cytokines IL-4, IL-5, IL-13  Allergic inflammation
IL-1beta, TNF-alpha  Inflammation amplification
TSLP  Chemo-attractant for Th2 cells
NO Act as relaxant
Vasodilatation  leakage
LTD4 Bronchoconstriction (1000 times > histamine )
Mucus hyper secretion, Capillary leakage,
Vasogenic edema
Once called slow reacting substance of anaphylaxis
(SRS-A)

20. AIRWAY REMODELING:-
20
 Irreversible narrowing of lumen
 Decline in lung function
 Smooth muscle hyperplasia
 Fibrosis
 Mast cells-
 Tryptase  smooth muscle mitogen  Hyperplasia
Hyper-responsiveness
 Proteases  Airway remodelling  Irreversible impairment of
pulm function

21. 21
TH cells and the origin of asthma
production of Ig G antibodies against allergen.
PHAGOCYTOSED
ALLERGEN
ANTIGEN
PRESENTING CELL
TH1 CELL ACTIVATION
NORMAL INDIVIDUALS

22. 22

23. 23

24. EARLY AND LATE PHASE
24
START -10-15 min
UPTO - 1-2 hrs
START - 3-4 hrs
UPTO - 6-12 hrs

25. 25

26. EXERCISE INDUCED ASTHMA
27

27. PATHOLOGY
28
 Chronic inflammation of lower airways
 Mucosal infiltration of activated eosinophils & T lymphocytes
 Thickening of basement membrane
 Goblet cell metaplasia
 Smooth muscle hypertrophy & thickening
 Shedding of epithelium
 Occlusion by mucosal plug
 Vasodilatation & leakage
 Angiogenesis
 Lung parenchyma not affected

28. 29
PATHOLOGY

29. LUNG VOLUMES & LUNG CAPACITIES
30

30. DIAGNOSIS
31
 Spirometry/PFT :
 Obstructive pattern i.e., reversible with SABA
 FEV1/FVC < 70%
 Decreased FEV1
 Normal/ Decreased FVC
 Increased RV & TLC
 Increase in FEV1 > 12% with SABA
 PFT normal between exacerbations

31. SPIROMETRY
32

32. 33
DIAGNOSIS

33. PEAK EXPIRATORY FLOW RATE
34

34. 35
 Methacholine challenge
 Tests for bronchial hyper-responsivness
 Useful when PFTs are normal  suspected ?
 Positive  > 20% decrease in FEV1
 Arterial blood gas (ABG)
 Chest x-ray (CXR)
 Normal appearance to hyperinflation
 Flattening of the diaphragm.
DIAGNOSIS

35. 36

36. DELIVERY DEVICES
37
1.Inhalational route
Administration of medication directly to the lung by
aerosol inhalation.
Devices –
 Small volume nebulizers
 pMDIs- pressurised metered dose inhaler
 Spacer chambers
 Dry powder inhalers
 Ultrasonic nebulizers
 Jet nebulizers

37. 38
Small volume nebulizers
Dry powder inhalers
Spacer chambers
Jet nebulizers
pMDI Ultrasonic nebulizers

38. PARTICLE SIZE
39
 Size of the particle determines the site of deposition in the
respiratory tract  Aerosol
 Large particles settle out in the upper airways
 Smaller particle remain suspended and are exhaled
 Optimum size to settle in airways2-5µm MMAD
(mass median aerodynamic diameter)
 Pressurized aerosol-
 Drug is dissolved in a low boiling point liquid in a canister
under pressure .
 Vehicle liquid - chloroflurocarbon
 RECENT  Hydrofluoroalkanes (HFAs)
 Advantages- ozone friendly , more potent .

39. Deposition of inhaled drugs
40

40. OTHER ROUTES
41
 ORAL ROUTE
 Reserved for patients unable to use inhaler
 Beta 2 agonist
 Methyl xanthines
 Corticosteroids
 Leukotriene receptor antagonist
 PARENTERAL ROUTE
 Beta 2 agonist
 Methyl xanthines
 Corticosteroids
 omalizumab

41. PHARMACOTHERAPY
42

42. DRUGS FOR BRONCHIAL ASTHMA
43
1.Sympathomimetics:
 Nonselective
 Epinephrine,
 Ephedrine,
 Isoprenaline,
 Orciprenaline (Metaproterenol)
 Selective beta 2 agonist
 Albuterol(salbutamol)
 Terbutaline
 Salmetrol, Formoterol, Eformoterol,
 Bambterol, Indacaterol, Oladaterol

43. 44
2.Anticholinergics /antimuscarinics
 Short acting(SAMA)
 Ipratropium Bromide ,oxitropium bromide
 Long acting (LAMA)
 Tiotropium,
 Glycopyrrinium,
 Aclidinium,
 Umeclidinium
DRUGS FOR BRONCHIAL ASTHMA

44. 45
3.Methylxanthines
 Theophylline,aminophyline,
 diprophylline,
 choline theophyllinate,doxophylline
4.Corticosteroids
 Oral :
prednisone, prednisolone, methylprednisolone,
dexamethasone, betamethasone
 Parenteral :
hydrocortisone, methylprednisolone
 Inhalational:
Beclomethasone,fluticasone,budesonide,flunisolide,
ciclesonide,triamcinalone ,mometasone
DRUGS FOR BRONCHIAL ASTHMA

45. 46
5.Mast cell stabilisers
Sodium cromoglycate (cromolyn sodium)
Nedocromil
6.Leukotriene modulators
5-lipoxygenase inhibitor- zileuton
7.Cysteinyl leukotriene receptor antagonists-
Zafirlukast, montelukast, iralukast, pranulukast
8.Monoclonal IgE Antibody
Omalizumab
9. Miscellaneous
Nitric oxide donors
DRUGS FOR BRONCHIAL ASTHMA

46. 47
Control/ treat chronic inflammation
Prevent future attacks
Long term control
Prevent airway remodelling
Rescue medication to treat acute
Quick relief of symptoms
Used during acute attacks
Action last  4-6hrs

47. AIMS OF ASTHMA THERAPY
48
 Minimal (ideally no)chronic symptoms including
nocturnal
 Minimal (infrequent)exacerbations
 No emergency visits
 Minimal (ideally no)use of a required β2 agonist
 No limitations on activities , including exercise.
 Peak expiratory flow circadian variation<20%
 (Near) normal peak expiratory flow
 Minimal (0r no) adverse effects from medicine

48. BRONCHODILATORS
49
 Sympathetic β2 adrenergic agonists (sympathomimetics)
 Anticholinergics (muscarinic receptor antagonists)
 Methylxanthines

49. Β2 ADRENERGIC AGONISTS
50
 Catechol ring consists
hydroxyl groups in 3 and 4
position of the benzene ring
 Substituition at the
terminal amine group confers
beta2 selectivity
 Eg. Albuterol(salbutamol)
and terbutaline

50. 51
 Beta 2 agonists not rapidly metabolised by
COMT  modification of the catechol rings
prevents methylation at 3 hydroxyl position
by COMT
 MAO  substituition at the amine group
confers resistance to MAO
Β2 ADRENERGIC AGONISTS

51. 52

52. MECHANISM OF ACTION
53

53. Bronchodilators
Selective beta2 agonist drugs
54
 Short acting beta2 agonists (SABA)
 Salbutamol(albuterol)
 Terbutaline
 Remiterol
 Fenoterol
 Pirbuterol
 Bitoterol
BRONCHODILATORS OF CHOICE IN ACUTE SEVERE ASTHMA

54. SHORT ACTING BETA2 AGONISTS
55
Inhaled bronchodilators for symptom relief & acute Bronchodilation
Albuterol (Salbutamol) Asthma, COPD, EIA
Inhaled: 180 μg (2puffs) 4-6 hrly
Nebulized:2.5mg 6-8 hrly, 5-15min
Oral: 2-4mg 6-8 hrly
Levalbuterol Bronchodilator
Inhaled (MDI nebulizer)
Pirbuterol 400 μg (2puffs) 4-6 hrly
Inhaled (MDI nebulizer)

55. LONG ACTING BETA 2 AGONISTS
(LABA)
56
 Salmetrol, Formoterol, Eformoterol, Bambterol
 Bulky substituition in the aliphatic chain, moderate
liphophilicity, keeps drug close to receptors –slow
release
 Formetrol and salmetrol > 12hours
 Ultra long acting beta agonist
Indacaterol ,oladaterol, vilanterol > 24 hours
Approved only for treatment of COPD

56. LONG-ACTING Β2 AGONISTS
57
Add-on therapy to ICSs in asthma; can be used alone in COPD
Formoterol • Asthma as add-on to ICS
• Maintenance and treatment of severe COPD
• Inhaled: 12 μg (contents of 1 capsule) every 12 h
• Nebulized 20 μg in 2 mL, twice per day
Arformoterol
Salmeterol
Indacaterol
Olodaterol
• Arformoterol for severe COPD
• Maintenance treatment for COPD
• Arformoterol, nebulized, 15 μg in 2 mL BD
• Salmeterol, inhaled 50 μg twice daily
• Indacaterol, inhaled (DPI) 75 once daily
• Olodaterol, inhaled 2.5 once daily

57. LONG ACTING Β2 AGONIST LABA
58
 Prolonged broncho-dilatation during sleeping
hours
 Useful in the management of exercise induced
bronchospasm and nocturnal episodic asthma
 In asthma patients LABAs should never be used
alone it should always be combined with ICS to
treat the underlying inflammation.

58. ADVERSE EFFECTS :
59
 Systemic administration involves a larger dose of
medication.
 Greater potential for side effects
 Tremor, tachycardia ,palpitations ,gastrointestinal upset,
anxiety and headache
 Alteration in serum electrolytes
 Decreased potassium magnesium and phosphates
 Increasing the arrhythmogenic effects

59. Selective beta2 agonist drugs
60
 Patients on hemodialysis, develop acutely dangerous hyperkalemia
benefit from iv or aerosal administration of albuterol due to its potassium
lowering effect .
LONG TERM SAFETY
 Terbutaline only bronchodilator that can be safely used in pregnancy
 Fenoterol –rise in asthma deaths in 1990s newzealand
 Mortality due to LABA use is related to lack of
concomitant use of ICS
 Combination inhaler to be used

60. Anticholinergics /antimuscarinics
6161
Asthma treated by smoking “Asthma cigerrets”
 Datura stramontium– the active ingredient is anticholinergic
belladonna alkaloid.
M3 receptors

61. ANTICHOLINERGICS /ANTIMUSCARINICS
INHALED AS BRONCHODILATORS
Ipratropium bromide
Albuterol/ipratropium
combination
• Inhaled, 2 puffs (17 μg/puff)
3–4 times/day
• Combination albuterol 103
μg/ipratropium
18 μg/puff; 2 puffs 4 times
daily
 Largely replaced by LAMAs
 Avoid spraying in eyes
 Adverse effects include dry
mouth, tachycardia, urinary
retention, glaucoma
 Combination with albuterol
may be used as a reliever
Tiotropium Bromide 2.5 μg via oral inhalation (2
puffs of 1.25 μg/
actuation) once daily
 Caution in patients with
urinary retention or glaucoma
history
Umeclidinium bromide Inhaled (DPI) 62.5 μg (1 puff)
once daily
Aclidinium bromide Inhaled (DPI) 400 μg (1 puff)
twice daily
Glycopyrrolate Inhaled (DPI) 1 capsule (15.6
μg) inhaled twice daily

62. METHYL XANTHINES
63
HISTORICAL NOTE :
 William withering recommended coffee made very
strong as a remedy for asthma
 Caffeine  methylxamthine
THEODORE ROOSEVELTWILLIAM WITHERING

63. 64
 Inhibition of Phosphodiesterases
 Adenosine receptor antagonism
 Interleukin 10 release
 Effects on gene transcription
 Effects on apoptosis
 Histone deacetylase activation
THEOPHYLLINE
MECHANISM OF ACTION
Therapeutic plasma concentration 5-15 mg /L

64. 65
1. Inhibition of PDEs
 Theophylline is a
nonselective PDE inhibitor
 Effect minimal - within the
therapeutic range
 Elevation of cellular cAMP
and cGMP
THEOPHYLLINE
MECHANISM OF ACTION

65. 66
 Adenosine receptor antagonism :
 At therapeutic concentrations
 Adenosine bronchoconstriction - histamine and LTs.
 Side effects - cardiac arrhythmias and seizures.
 Interleukin 10 release:
 Broad spectrum of anti-inflammatory effects - secretion is reduced in asthma.
 Effect may be mediated via PDE inhibition
 Effects on gene transcription:
 Prevents the translocation of the pro-inflammatory transcription factor NF-κB into the
nucleus  reducing the expression of inflammatory genes, at high concentrations.
 Effects on apoptosis:
 Prolonged survival of eosinophils and neutrophils due to reduction in apoptosis
reduction in the antiapoptotic protein Bcl-2
Induces apoptosisneutrophils- viaA2A receptors antagonism
 T lymphocytes via PDE inhibition
THEOPHYLLINE
MECHANISM OF ACTION

66. THEOPHYLLINE
MECHANISM OF ACTION67
 Histone deacetylase activation.
 Recruitment of HDAC2 by GRs switches off inflammatory
genes.

67. EFFECT OF THEOPHYLLINE
68

68. SIDE EFFECTS OF THEOPHYLLINE
AND MECHANISMS
69
SIDE EFFECT PROPOSED MECHANISM
Nausea & vomiting PDE4 inhibition
Headaches PDE4 inhibition
Gastric discomfort PDE4 inhibition
Diuresis A1 receptor antagonism
Cardiac arrhythmias PDE3 inhibition, A1 receptor
Epileptic seizures A1 receptor antagonism
Consumption of more than 9 cups per day  arrhythmias

69. FACTORS AFFECTING CLEARANCE OF
THEOPHYLLINE70
 Increased clearance
 Enzyme induction (mainly CYP1A2) by coadministered drugs (e.g.,rifampicin,
barbiturates, ethanol)
 Smoking (tobacco, marijuana) via CYP1A2 induction
 High-protein, low-carbohydrate diet
 Barbecued meat
 Childhood
 Decreased clearance
 CYP inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol,
fluvoxamine, zileuton, zafirlukast)
 Congestive heart failure
 Liver disease
 Pneumonia
 Viral infection and vaccination
 High-carbohydrate diet, Old age

70. NARROW THERAPEUTIC INDEX
71

71. CORTICOSTEROIDS
72
 NOT BRONCHODILATOR
 Used in inflammatory lung diseases
 All corticosteroids are active in asthma when
given systemically (Prednisone, Prednisolone,
Dexamethasone)
 Substitution at 17ᾳ ester position increases
topical absorption active by inhalation
(beclomethasone, triamcinalone, flunisolide,
budesonide etc…)

72. 73

73. 74
MECHANISM OF ACTION

74. MECHANISM OF ACTION
75
 Most effective anti-inflammatory agents used in
asthma therapy
 Reduce eosinophils and mast cells in airways
 Reduce activated T lymphocytes
 Activate anti-inflammatory genes - Mitogen
activated protein kinase phosphatase1
 Increased expression of beta 2 receptors

75. EFFECTS OF CORTICOSTEROIDS
76

76. INHALED CORTICOSTEROIDS
77
Maintenance treatment for asthma
Beclomethasone
dipropionate
(BDP)
 Orally bioavailable BDP  Beclomethasone
monopropionate
 Systemic effects: growth suppression, bruising, adrenal
suppression
Fluticasone
propionate
 Fewer systemic effects than BDP
Budesonide  Fewer systemic effects than BDP
 Used in children less than 8 who cannot use PDI
Ciclesonide  Least-systemic effects of all ICSs
 May be effective once daily
LOCAL: HOARSE VOICE, CANDIDIASIS

77. 78
Short course or oral maintenance for asthma (and COPD)
Prednisone
Prednisolone
Oral: 40–80 mg once
daily or divided dose
for 3–10 days for acute
exacerbation
Minimal dose for
maintenance
Prednisone converted to
prednisolone in the liver
 Bruising, weight gain, edema,
osteoporosis, diabetes, cataracts,
adrenal suppression
Hydrocortisone
succinate
IM/IV: 100–500 mg
every 12 h for acute
severe asthma
Only if patient not able to take
oral steroids
Methylprednisolone IV: 100–1000 mg for
acute severe asthma
Rarely indicated because of
steroid side effects
SYSTEMIC CORTICOSTEROIDS

78. SIDE EFFECTS OF CORTICOSTEROIDS
79
 LOCAL SIDE EFFECTS
 Dysphonia
 Oropharyngeal candidiasis
 Cough
 SYSTEMIC SIDE EFFECTS
 Adrenal suppression and insufficiency
 Growth suppression
 Bruising
 Osteoporosis
 Cataracts
 Glaucoma
 Metabolic abnormalities (glucose, insulin, triglycerides)
 Psychiatric disturbances (euphoria, depression)
 Pneumonia

79. MAST CELL STABILIZER
80
 Cromolyn sodium (sodium
cromoglycate) an egypytian
herbal remedy
 Nedocromil
 Ketotifen
Roger Altounyan

80. 81
MAST CELL STABILIZER
 Stabilises mast cells # Ca2+
influx into mast cells
 Inhalational
 Effective in blocking trigger
induced asthma, exercise,
occupational asthma
 Nasal spray or eye drops-
Allergic rhinoconjunctivitis

81. ANTILEUKOTRIENES (LEUKOTRIENE MODIFIERS)
ASTHMA MAINTENANCE
82

82. ANTILEUKOTRIENES
83
 Oral administration
 Useful in aspirin induced asthma
 Side effects
 Zileuton- liver toxicity
 Montelukast, zafirlukast- Churg-strauss syndrome
 A systemic vasculitis, worsening of asthma,
pulmonary infiltrates and eosinophilia

83. ANTI- IgE ANTIBODY - OMALIZUMAB
84
 Recombinant DNA-derived monoclonal antibody
 Selectively binds to human IgE & decrease binding
affinity of IgE to high-affinity IgE receptor (mast cells &
basophils)
 Reduce allergic response
 Moderate – severe allergic asthma
 High cost
 Limitations on dosage
 Limited clinical trial data
 NOT USED AS FIRST LINE THERAPY

84. 85
 SC administration
 Once in 2-4weeks
 Reduction in the
frequency and
severity of
exacerbations
 Also used in chronic
urticaria and peanut
allergy
ANTI- IgE ANTIBODY - OMALIZUMAB

85. 86
GLOBAL INITIATIVE FOR ASTHMA (GINA)

86. GLOBAL INITIATIVE FOR ASTHMA (GINA)
87

87. 88
REFRACTORY ASTHMA-
Poor control of asthma
Non compliance of Drugs
Treatment– low dose theophyline and ocs
ASPIRIN SENSITIVE ASTHMA-
Rhinohorea, conjuctival injection and wheezing
Treatment- ICS and Anti leukotrienes
PREGNANCY-
SABAs , ICS and Theophylline
SPECIAL CONSIDERATIONS

88. 89
RECENT ADVANCES IN THE
PHARMACOTHERAPY OF
BRONCHIAL ASTHMA

89. 90
ADVANCES IN STEROID

90. 91
SEGRA
SELECTIVE GLUCOCORTICOID RECEPTOR AGONIST
Mapracorat, Fosdagrocorat, Dagrocorat

91. SIT - SINGLE INHALER THERAPY
92

92. RATIONAL OF ICS + LABA
93

93. SMART
Single Inhaler Maintenance and reliever therapy
94

94. DOXOFYLLINE
95
Novel xanthine bronchodilator
Mechanism of action
 Inhibition of PDE4,
 Decreased affinities
towards adenosine
A1 and A2 receptors,
Comparative Safety Profile

95. PHOSPHODIESTERASE INHIBITORS
96
PDE4 Inhibition elevate levels of
intracellular cAMP,
• suppress inflammatory cell
function
• inhibition of mucin production
• alterations in airway smooth
muscle tone

96. 97
ROFLUMILAST , CILOMILAST
Roflumilast
selective, long-acting inhibitor of the enzyme PDE-4
 Reduces release of cytokines
 Reduces migration and activation of immune cells
PHOSPHODIESTERASE INHIBITORS

97. Novel classes of bronchodilators
98
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.
DENATONIUM
CHLOROQUINE

98. 99
Novel classes of bronchodilators
MAGNESIUM SULFATE
MOA
Reduces cytosolic calcium in airway smooth muscle
bronchodilatation
USES
Useful as an additional drug to SABA in A/c severe
asthma can be given by IV/nebulisation
Side effects
Include flushing and nausea
Not suitable to be employed alone as clinical benefit is
small

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Novel classes of bronchodilators
POTASSIUM CHANNEL OPENERS
Potassium channel openers that open calcium activated large
conductance K+ channels in smooth muscle
CALCIUM CHANNEL BLOCKERS Nifedipine, verapamil
Prevent calcium entry into smooth muscle
Inhibit stimuli induced bronchoconstriction
ANP & RELATED PEPTIDE URODILATIN
Activates membrane guanylyl cyclasecGMP  bronchodilatation
Bronchodilator effects comparable to SABA.
Useful for additional bronchodilatation in Acute severe asthma

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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
 In patients it is rapidly metabolized and also has vasodilator Side
effects
 Stable analog of VIP (RO 25-1533) selectively stimulate VPAC2 
produces rapid bronchodilatation but effect is not prolonged
Novel classes of bronchodilators

101. IMMUNOMODULATORY THERAPIES
102
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 greater side effects and lesser
efficacy
2. Anti IgE therapy
3. Specific immunotherapy

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ANTICYTOKINES

103. 104

104. 105

105. 106

106. 107

107. CRTH2 ANTAGONISTS
108
OC459
CRTH2 (Chemo attractant Receptor-
homologous molecule expressed on
Th2 cells)
 GPCR expressed by Th2
lymphocytes, eosinophils, and
basophils.
 The receptor mediates the
activation and chemotaxis of these
cell types in response to
prostaglandin D2 (PGD2), produced
by mast cells.
 Contributes to the so-called “Th2
polarization”
reduction in total IgE concentration
decreasing sputum eosinophils

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Macrolides
Clarithromycin reported to be effective in many cases
asthma.
Causation of asthma linked to Chlamydia pneumonia or
mycoplasma pneumonia
Statins
Under evaluation in asthma therapy by AAAAI
It was observed that asthmatics with co-morbidities who
are on statins have 30% lower risk for ER visits &
hospitalizations due asthma than controls.
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.

109. NON PHARMACOLOGICAL TREATMENT
110
 Patient education
 Avoidance of triggers
 Avoiding smoking
 Graded exercise training
 Psychological treatment
 Yoga
 Accupuncture

110. WORLD ASTHMA DAY – MAY 7TH 2019
111

111. 112
Goodman & Gilman’sThe Pharmacological Basis of Therapeutics13th ed.
Bertram G Katzung Basic & Clinical Pharmacology 14th ed.
Rang & Dale’s Pharmacology 8th ed.
Lippincott’s Illustrated Reviews Pharmacology 5th ed.
KD Tripati Essentials of Medical Pharmacology 8th ed.
R S Satoskar Pharmacology and Pharmacotherapeutics 25th ed
Sharma & Sharma’s Principles of Pharmacology 3rd ed.
Bennett and Brown Clinical Pharmacology 10th Edition
Golan principles of pharmacology-3rd Edition
Harrison principles of internal medicine -19th Edition
Images - web
REFERENCES

112. 113
THANK
YOU