1) Asthma is a chronic inflammatory airway disease characterized by recurrent episodes of breathlessness, wheezing, coughing and chest tightness. 2) Pharmacotherapy includes relievers like beta-2 agonists for acute symptoms and controllers like inhaled corticosteroids to control underlying inflammation. 3) Other controller options include leukotriene modifiers, theophylline, mast cell stabilizers and monoclonal antibody omalizumab for severe asthma.

1. Pharmacotherap
y of Asthma
28/10/2012

2. What is Bronchial Asthma?
 Chronic inflammatory airway disease associated with
increased airway responsiveness and reversible airway
obstruction.
 It can present at any age; majority of cases diagnosed in
childhood
 Most of them become asymptomatic by adolescence
 Disease severity rarely progresses; patients with severe
asthma have it at the onset.

3. Clinical Features
Recurrent episodes characterized by:
 Breathlessness
 Wheezing
 Coughing- especially at night or early morning
 Tightness in the chest
 Hyperinflation
 Increased mucus production

4. Risk factors
Endogenous
• Atopy
• Genetic
predisposition
• Obesity
• Early infections
Environmental
• Indoor allergens
• Outdoor allergens
• Occupational
sensitizers
• Passive smoking

5. Triggers
 Allergens
 Respiratory tract infection
 Exercise
 Stress
 Cold Air
 Drugs- Aspirin
 Other irritants- SO2 , Household sprays

6. Pathophysiology

7. Pathophysiology

8. Diagnosis
 Spirometry
 Reduced FEV1, FEV1/FVC ratio, and PEF
 Reversibility - >12% or 200 ml increase in FEV1 15 min after
an inhaled short-acting beta 2-agonist
 Airway Responsiveness - increased AHR measured by
methacholine or histamine challenge - reduces FEV1 by 20%
 Chest X ray- Usually normal; may show hyperinflation
 Skin prick test – May be positive but not helpful in diagnosis

9. Drug Therapy
• Beta 2 agonists
• Anticholinergics
• Methylxanthines
Relievers
• Corticosteroids
• Mast cell stabilizers
• Anti Leukotrienes
• Biological Agents- Omalizumab
Controllers

10. β2 Agonists
Classified as:
 SABAs(short acting)- Salbutamol, Terbutaline,
Levalbuterol, Fenoterol, Pirbuterol, Metaproterenol
 LABAs(Long acting) - Salmeterol, Formoterol
 Ultra LABA: Indacaterol (as yet not approved for
asthma)

11. Mechanism of action

12. Why are some β2 agonists long acting?
DIFFUSION
MICROKINETIC
MODEL

13. Other actions
 Acute anti-inflammatory effects by:
 Inhibition of mast cell mediator release
 Inhibition of plasma exudation and airway edema
 Increased mucus secretion and enhanced mucociliary
clearance
 Reduction in airway cholinergic nerve transmission
 Chronic inflammation not affected- Rapid
downregulation of inflammatory cell β2 receptors
No effect on airway hyper-responsiveness

14. SABAs
 Albuterol, levalbuterol, terbutaline
 Rapid onset of action with effects lasting for 3-6 hrs
 Inhaled from pMDI or DPI; very few systemic ADRs
 DOC for acute asthma symptoms and exacerbations
and for preventing EIA
 Regular, long-term use of SABA not recommended;
used on ‘as required’ basis.
 SABA >2 days a week indicates inadequate control

15. LABAs
 Salmeterol, Formoterol
 Formeterol: faster onset of action
 Duration of action: 12 hrs; given BD
 Do not control underlying inflammation and increase
mortality in asthmatics
 NOT TO BE USED AS MONOTHERAPY
 Used as an adjunct to ICS therapy in persistent asthma
 May be used before exercise to prevent EIA
 Dose: Salmeterol- 50μg BD; Formeterol- 12μg BD

16. Safety issues of LABA
 Trials comparing salmeterol with placebo found increased
mortality and exacerbations in salmeterol group
 Discontiuation of ICS after LABA results in increased markers
of inflammation
 Black box warning issued by FDA on all LABA
 Postulated mechanisms are:
 A direct deleterious effect on bronchial smooth muscle
 Maintenance of lung function despite worsening
inflammation; so that patients tend to delay seeking treatment
for an exacerbation

17. Adverse Effects
 Muscle tremor, palpitations- more common in
elderly patients
 Hypokalemia- clinically insignificant
 Metabolic effects(hyperglycemia)- seen after
large, systemic doses
 Tolerance- Although downregulation is seen
after chronic therapy, it does not affect efficacy
due to large receptor reserve in airways

18. Recent Advances
INDACATEROL:
 Inhaled once-daily β2 agonist
 Onset of action faster than salmeterol
 Duration of action ~ 24 hrs
 Has been approved only for COPD
 Clinical trials in asthma underway to test safety and
efficacy of once-daily combination of indacaterol with
mometasone
Cazzola M, Calzetta L, Matera MG. β(2) -adrenoceptor agonists: current and future direction. Br J Pharmacol.
2011 May; 163(1):4-17

19. Anticholinergics
 Ipratropium
 Tiotropium
 Oxitropium
M3 > M1
Prevent
cholinergic-nerve
induced:
Broncho-
constriction
Mucus secretion

20. Contd…
 Do not reduce mucociliary clearance
 Less effective than beta-2 agonists as they
inhibit only the cholinergic reflex component of
bronchoconstriction
 Hence used only as add-on drug
 Combined with β2-agonists in treating acute
severe asthma

21. Adverse effects
 Bitter taste
 Dryness of mouth
 Glaucoma- due to direct effect of nebulized drug
on the eye
 Paradoxical bronchoconstriction- due to
hypotonic nebulizer solution or additives like
benzalkonium chloride/ EDTA
 Urinary retention – common in elderly patients

22. Methylxanthines
AC
CAMP
β2
AMP
PDE
Bronchial tone
Contraction
Relaxation
Adenosine
Methylxantines

23. Anti-inflammatory action
 Increased secretion of IL-10
 Inhibits the translocation of the pro-inflammatory
transcription factor NK-κB into the nucleus
 Promotes apoptosis in eosinophils(in-vitro)
 Activates HDAC2 and enhances the effects of
glucocorticoids
 All these effects are seen at Cp < 10mg/L
 Clinically, low oral doses reduce leukocytic infiltration
into the airways and reduce the no. of eosinophils seen
in BAL and induced sputum of asthmatic patients

24. Clinically available compounds
 Theophylline
 Doxofylline- less potent adenosine receptor antagonist
 Enprofylline- no effect on adenosine receptors
 Aminophylline- ethylenediamine salt; increases its
solubility hence used for i.v. administration

25. Pharmacokinetics
 Therapeutic range is 5-15 mg/L
 Oral drug rapidly and completely absorbed
 Metabolized in liver by CYP1A2
 Dose has to be individualized because of:
 Different patients respond differently to the
drug
 Clearance varies among patients due to the
factors such as….

26. ….Factors affecting clearance
Increased clearance
Enzyme inducers- rifampin,
barbiturates
Smoking- which induces
CYP1A2
High-protein, low-carb diet
Barbequed meat
In children
Decreased clearance
Enzyme inhibitors- emycin,
ciprofloxacin
CCF, liver disease, pneumonia
Viral infection
High-carb diet
Old age
Dose reduced to half

27. Route of administration
Intravenous
 Aminophylline is used in dose of 6mg/kg over 20 min f/b
0.5 mg/kg/hr maintenance dose
 Indicated in acute severe asthma
 Associated with many adverse effects
 Hence, currently nebulized β2 agonists preferred over
i.v. aminophylline

28. Oral Preparations
 Immediate release formulations give wide fluctuations in
plasma levels(Cp)- NOT RECOMMENDED
 Sustained-release preparations: Absorbed at a constant
rate and provide steady Cp
 Twice daily therapy in dose of 8mg/kg is given
 Once-daily release preparations now available
 Single dose given at night for controlling nocturnal
asthma symptoms

29. Indications
 Steroid sparing effect: Addition of low dose theophylline
to ICS improves symptom control compared to doubling
the steroid dose
 Nocturnal asthma
 As add-on therapy: less effective than β2 agonists, but
preferred when cost is a limiting factor
 Acute asthma: Used only when patient not responding to
β2 agonists

30. Adverse Effects
 Plasma conc dependent; occur at Cp>15 mg/L
 Headache
 Nausea, vomiting
 Increased gastric acid secretion
 Diuresis
 Cardiac arrythmias
 Seizures
Due to
PDE4
inhibition
Due to A1
receptor
inhibition

31. Recent Advances
 Most of the adverse effects of theophylline are
due to systemic effects on PDE receptors.
 Based on this, roflimilast, an oral PDE4 inhibitor,
was tested in asthmatic patients but was
associated with gastric side effects
 Hence, inhaled selective PDE4 inhibitors are in
development(phase 2) for asthma treatment
Singh D, Petavy F, Macdonald AJ, Lazaar AL, O'Connor BJ. The inhaled phosphodiesterase 4 inhibitor
GSK256066 reduces allergen challenge responses in asthma. Respir Res. 2010 Mar 1;11:26.

32. Corticosteroids

33. Mechanism of action

34. Anti-Inflammatory action
 Reduce the number of inflm. cells in airway epithelium
and submucosa
 Induce eosinophil apoptosis
 Prevent and reverse the increase in vascular
permeability
 Decease mucus secretion
 Reduction in airway hyper-responsiveness and healing
 Only suppress inflammation and do not cure underlying
disease- recurrence seen after steroid withdrawal

35. Synergism between steroids and β2
agonists
 They interact with each other to potentiate their actions
 Steroids:
a) Increase transcription of β2 receptor gene in airway
mucosa
b) Prevent uncoupling of β2 receptors to Gs
c) Prevent downregulation of β2 receptors
 β2 agonists:
a) Enhance binding of GR to DNA
b) Increase in translocation of liganded GR to the nucleus

36. Inhaled corticosteroids
 Beclomethasone dipropionate
 Budesonide
 Fluticasone
 Ciclesonide
 Flunisolide
 Mometasone furoate
 Triamcinolone

37. Equipotent doses of ICS

38. Inhaled corticosteroids-PK

39. Adverse effects-Local
 Hoarseness and weakness of voice(dysphonia)-
due to atrophy of vocal cords
 Oropharyngeal candidiasis
 Cough- Common with MDI due to additives

40. How to reduce these?
 Use a large-volume spacer
device
 Rinsing mouth after use of
inhaler
 Switch to DPI if cough is
troublesome

41. Systemic ADRs
 Adrenal suppression
 Growth suppression
 Dermal thinning and bruising
 Osteoporosis
 Cataract, glaucoma
 Metabolic abnormalities

42. How to minimize these?
Budesonide,
Fluticasone
High first-pass
metabolism
Reduced systemic
bioavailability
Ciclesonide
Lung
esterases
Active metabolite
Low oral
bioavailability and
less systemic ADRs

43. Indications
 First line therapy for all patients of persistent
asthma(mild, moderate, severe)
 In intermittent asthma- use only when β2 agonist
(SABA) use is more than twice weekly
 Usually administered twice daily- maintain at lowest
possible dose that controls symptoms
 Dose: < 400 μg/d of beclomethasone or equivalent
 If >800 μg/d is required, use spacer device
 Growth suppression in children- usually not seen at
doses < 400 μg/d

44. Systemic steroids
 Oral steroids
 For patients not controlled on ICS
 Prednisolone: 30-40 mg/day usually gives maximal
benefit
 Maintenance dose: 10-15 mg/day
 Given as single dose in the morning: produces less
adrenal suppression (matches with diurnal variation)
 Alternate day treatment: Control of asthma is
suboptimal; hence not preferred

45. contd…
 Intravenous steroids
 In acute asthma where lung function is < 30% predicted
 DOC: Hydrocortisone as it has rapid onset of action
 Once control is achieved, switch over to oral
prednisolone 40-60 mg/day

46. New developments
 Transrepression – anti-inflammatory activity
 Transactivation - Causes side effects
 Classical steroids cause both activation and repression
so that beneficial effects are accompanied by side
effects
 SEGRA(selective Glucocorticoid Receptor Agonists)-
Less effective in transactivation; selective anti-
inflammatory activity
 Mapracorat- Undergoing preclinical studies

47. Mast Cell Stabilizers
 Sodium cromoglycate, Ketotifen
 Inhibit degranulation of mast cells by triggers such as
exercise and pollen
 Inhibit eosinophil recruitment and decrease inflammatory
response
 Well tolerated; hence widely used earlier for treatment of
childhood asthma
 Have short duration of action and hence given QID by
inhalation
 Less effective than ICS- Rarely used in current
scenario

48. Anti-Leukotrienes

49. Indications
 Orally administered
 Improve lung function; however are less effective than
ICS in mild asthma
 Used as add-on therapy in patients not controlled on
ICS
 Can also be used in prophylaxis of exercise-induced
and aspirin-induced asthma
 Doses:
a. Montelukast: 10 mg OD
b. Zafirlukast: 20 mg BD

50. Adverse Effects
 Well tolerated
 Rarely can cause liver dysfunction: monitor liver
enzymes
 Churg-Strauss syndrome
 Headache, rashes

51. FLAP inhibitors

52. Omalizumab

53. Indications
 Reduces no. of exacerbations and improves control in
severe asthma
 Very expensive
 Reserved for use only in patients not controlled on
maximal doses of inhaled therapy and having serum IgE
within a specified range
 Administered as s.c. injection every 2-4 weeks
 ADR- anaphylaxis

54. Types of Inhalers
 Metered dose inhalers- use a pressurized inert gas (CFC used
earlier now replaced by HFA)
 “Metered“- amount of dose goes directly to the lungs
 Coordination during inhalation may be difficult
 Deposition of 50–80 % of actuated dose in oropharynx
 Breath actuated MDI- useful for patients unable to coordinate
inhalation
 Most common patient errors:
Forgetting to shake the canister, inhaling at the wrong time, or forgetting
To hold their breath

55. Spacer devices/ Holding chambers
Used with pMDIs that act as a reservoir
or holding chamber for the drug
Fitted with 1 way valve- to prevent
medication escape
At pateint end, mouthpiece can be
attached- for use in children
Advantages:
Decrease oropharyngeal deposition and decreased risk of
topical side effects
No need for coordination with breathing

56. Dry Powder Inhalers
 Delivers drug in the form of a dry powder
 Contains no propulsion system/gas
 Rely on force of patient’s inhalation to trigger delivery of a single
dose(patient-activated)
 Hence, insuficient inhalational flow rates may reduce drug delivery-
used only in older children & adults
 Different types are-
Accuhaler DiskhalerTurbohaler

57. Nebulizer
 Turn liquid form of the drugs into a
fine mist like an aerosol
 Done with the help of compressed
oxygen/compressed air (Jet
nebulizer/ Atomizer) OR
ultrasonic waves(ultrasonic
nebulizer)
 Drug delivered during tidal breathing
 Less dependent on patient coordination and effort
 Method of choice – In patients with breating fatigue and in severe
asthma where large doses of inhaled drugs need to be
administered

58. Approach to
Management of
Asthma

59. Four pronged approach
• Develop doctor-patient
relationship1
• Identify and reduce exposure to
risk factors2
• Assess, treat and monitor asthma3
• Manage asthma exacerbations4

60. Develop doctor-patient relationship
 Asthma self-management education is essential
 Begin at the time of diagnosis and continue through
follow-up care
 Involve all members of the health care team
 Provide all patients with a written asthma action plan
that includes two aspects:
 daily management
 how to recognize and handle worsening asthma

61. Identify and reduce exposure to risk
factors
 Clinician should evaluate potential role of allergens,
particularly indoor inhalant allergens
 Reduce, if possible, exposure to allergens to which the
patient is sensitized
 Avoid exposure to environmental tobacco smoke and
other respiratory irritants
 Avoid exertion outdoors when levels of air pollution are
high

62. contd…
 Avoid use of nonselective beta-blockers
 H/o sensitivity to aspirin or NSAIDs should be counseled
-risk of fatal exacerbations from these drugs
 Consider inactivated influenza vaccination for adults and
children more than 3 yrs of age who have severe
asthma.

63. Asthma Treatment
 In children upto 4 yrs of age:
 Diagnosis is difficult
 Long term therapy considered in patients who had 4 or
more wheezing episodes alongwith atopic
dermatitis/family h/o of asthma
 Inhaled ICS(budesonide, fluticasone) in low doses are
safe even for extended periods
 LABA- Salmeterol is approved for use
 Montelukast can be given as chewable tablets

64. contd..
 Delivery devices
 MDI plus valved holding chamber (VHC) with a face mask
 Nebulizer with a face mask
 Holding the mask or open tube near the infant’s nose and
mouth, is not appropriate
 If there is a clear and positive response for at least 3 months,
step down in therapy should be attempted to identify the
lowest dose
 If clear benefit is not observed within 4–6 weeks the therapy
should be discontinued and alternative diagnoses

65. In children 5-11 yrs of age
 Physical activity at play is an essential part of a child’s
life
 Full participation in physical activities should be
encouraged
 Manage moderate or severe exacerbations due to viral
RTI, with a short course of oral systemic
corticosteroids

66. Patients > 12 yrs old and adults
Achieving Control Of Asthma
 Assess asthma severity
 Select T/t that corresponds to the patient’s level of asthma
severity
 At a follow up visit after starting T/t, asthma is not well
controlled ,then T/t should be advanced to the next step

67. Adjusting Therapy
 Once therapy is selected T/t decisions are based on the
level of the patient’s asthma control
 Step up one step for pts whose asthma is not well
controlled
 Pts with very poorly controlled asthma, consider
increasing by two steps, a course of oral
corticosteroids, or both
 Regular follow up visits (1-6 months) depending on
severity

69. Special Considerations

70. Exercise-induced bronchospasm
 Pretreatment before exercise-
 Inhaled beta2-agonists- prevent EIB in more than 80 percent
 SABA use may be helpful for 2–3 hours
 LABAs can be protective up to 12 hours
 LTRAs can attenuate EIB in up to 50 percent of patients
 Cromolyn or nedocromil taken shortly before exercise is an
alternative

71. Contd..
 Frequent, severe EIB indicates poorly controlled
asthma- Consider long-term control therapy
 A warm up period before exercise may reduce the
degree of symptoms
 A mask or scarf over the mouth may attenuate cold-
induced EIB

72. Surgery and Asthma
 Attempts made to improve lung function preoperatively
 Short course of oral systemic corticosteroids may be
required
 For patients who have received oral systemic
corticosteroids during the past 6 months and for pts on a
long-term high dose of ICS
 100 mg hydrocortisone every 8 hours i.v during the
surgical period & reduce dose rapidly within 24 hours
after surgery

73. Pregnancy and Asthma
 Asthma increases risk of preterm birth, IUGR and
perinatal mortality.
 NEVER WITHHOLD TREATMENT
 Monitoring of asthma status during prenatal visits
 Albuterol is the preferred SABA because it has an
excellent safety profile
 ICS are the preferred treatment for long-term control
medication
 Budesonide is the preferred ICS because more data
are available

74. Bronchial Thermoplasty
 Catheter introduced through a
bronchoscope
 It delivers thermal energy to the
airway wall to reduce excess
smooth muscle
 Increases symptom-free days,
improves PEFR and reduces the
use of reliever medicines.
 FDA approval obtained in 2010
for treatment of severe asthma.
Cho JY. Recent Advances in Mechanisms and Treatments of Airway Remodeling in Asthma: A Message from the Bench Side to
the Clinic. Korean J Intern Med 2011; 26:367-383

75. THANK YOU