4. Classification of β2-agonists
CATECHOLAMINE NON-CATHECHOLAMINE
Ephedrine Short-acting non-selective:
Metaproterenol, Fenoterol
Epinephrine
Isoproterenol
Short-acting selective:
Albuterol, Terbutaline
Long-acting selective:
Formoterol, Salmeterol,
Arformoterol, Carmoterol,
Indacaterol
Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
5. Modification of
3,4- hydroxyl
group on benzene ring
Prolonged
bronchodilator
action
Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
6. Increasing the
bulk of side chain
β2-adrenergic
specificity
Increasing duration
of bronchodilation
Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
7. β2-adrenoreceptor
Long arm of chromosome 5
G protein-coupled
receptors
Distribution
Widely distributed in lung,
with high levels in central
lung and alveolar region
Airway smooth muscle,
epithelial cells, endothelial
cells, type II cells
Mast cell, eosinophil,
monocyte, alveolar
macrophage, dendritic cells
Johnson M. JACI 2006;117:18-24.
8. Intracellular signaling pathway
GTP
Phosphorylate key
regulatory proteins
ATP that control muscle tone
-Inhibition of Ca2+ release from intracellular store
-Reduction of membrane Ca2+ entry
-Sequestration of intracellular Ca2+
Relaxation of airway smooth muscle Johnson M. JACI 2006;117:18-24.
10. Summary of Structure
and Function Relationship
ALBUTEROL FORMOTEROL SALMETEROL
Lipophilicity Hydrophilic Moderately Most lipophilic
lipophilic
Onset of action Fast Fast Delayed
Duration of action Short Long Long
β2-agonist potency Partial agonist Full agonist Partial agonist
(Efficacy & receptor (= Terbutaline) (= Isoproterenol, (Less than albuterol)
affinity) Fenoterol)
Mechanism of action Accesses active site Forms a depot in Rapidly diffuses into
directly from the cell membrane and cell membrane to
aqueous progressively leach active site
extracellular out Exosite
compartment (Duration-dose (Duration-dose
dependent) independent)
Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
11. Summary of Pharmacologic Attributes
of Selected β2-agonists
β2-agonists Selectivity ratio Onset of action Duration of action
(β1:β2 receptors) (minutes) (hours)
Isoprenaline 1:1 2-5 < 20 minutes
Albuterol 1:1375 2-3 4-6
Fenoterol 1:120 2-4 4-6
Terbutaline nd 2-4 4-6
Salmeterol 1:85000 30 > 12
Formoterol 1:120 2-3 > 12
Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
13. Non-bronchodilator actions
1. Increased mucociliary clearance
- Increased ion & water secretion, ciliary beat frequency
- “Conflicting data; ? Clinical importance”
2. Suppression of microvascular permeability
- 16 normal subjects histamine inhalation followed by sputum induction by 4.5%
hypertonic saline inhalation formoterol 18 mcg or placebo sputum β2-
macroglobulin
- At 30 minutes after formoterol, the effect of histamine was reduced by 50%
compared with placebo.
3. Inhibition of cholinergic neurotransmission
4. Protection of respiratory epithelium against bacteria
Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
14. Non-bronchodilator actions
5. Inhibition of mediator release: basophil, mast cell, lung tissue
- In vitro: Salmeterol blocks release of histamine, LTC4, LTD4, PGD2 from normal
human lung tissues which were sensitized by serum of allergic donors
- In vitro: Salmeterol blocks TNF- α from human skin mast cell
6. Inhibition of function:
- Eosinophil – In vitro: Salmeterol reduces plasma ECP after allergen challenge
- Macrophage/DC - In vitro: Salbutamol inhibits production of IL-12
- T lymphocyte – In vitro: Salmeterol inhibits production of IFN-γ & IL-4
- Bronchial epithelial cells – In vitro: Formoterol + Budesonide inhibit production of
GM-CSF & IL-8
* However, SABA & LABA should not be replaced ICS in terms of anti-
inflammatory action *
Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
15. Non-bronchodilator actions
7. Priming the glucocorticoid receptor
- Mitogen-activated protein kinases (MAPKs) pathway – result of prolonged
stimulation of β2–adrenergic receptor
Barnes PJ. Eur Respir J 2007;29:587-95.
16. β2-receptor Desensitization
Down-regulation of receptor after constant
association with agonist molecule
Autoregulatory process
Develops over days or weeks
Mechanisms
Uncoupling of receptor from adenylate cyclase
Internalization of uncoupled receptor
Downregulation
Johnson M. JACI 2006;117:18-24.
18. β2-receptor Desensitization
Downregulation
A net loss of cellular receptors
Several mechanisms that are independent of
receptor phosphorylation receptor degradation
Transcriptionof β2–receptor gene is required to
restore the membrane receptor
Hours of agonist exposure
Johnson M. JACI 2006;117:18-24.
19. β2-receptor Desensitization
Effects of β2-receptor Desensitization
Decreased in unwanted receptor stimulation
Tremor: decreases after 2 weeks
Palpitation
Hyperglycemia, hypokalemia
? Loss of bronchodilator response
Johnson M. JACI 2006;117:18-24.
20. Salmeterol
Objective: To determine whether regular use of salmeterol reduces the emergency
effectiveness of albuterol
Patient ≥ 17 years, asthma with acute attack, 2 groups (match)
1. Using salmeterol for chronic asthma control (57)
2. Not using salmeterol for chronic asthma control (57)
Intervention & 1st : Albuterol 2.5 mg NB every 20 minutes x 3 doses (33 each)
control 2nd: Albuterol 5.0 mg NB every 20 minutes x 3 doses (24 each)
Primary outcome Change of PEF % predicted before & after each aerosol
Korosec M, et al. Am J Med 1999; 107:209-13.
21. P = 0.13
46% 62%
58%
P < 0.001
39% Salmeterol vs control Salmeterol vs control
P = 0.37 P = 0.81
Korosec M, et al. Am J Med 1999; 107:209-13.
22. Formoterol
FACET
Objective: To evaluate the effects of adding inhaled formoterol to both lower and
higher doses of the inhaled glucocorticoid budesonide
Patient 852 patients with asthma (FEV1 at baseline ≥ 50%) at least 6
months, 18-70 years, treat with ICS
Intervention & Run-in period: BUD 800 µg BID x 4 wk
control Random to 4 groups:
1. BUD 100 µg BID x 1 year
2. BUD 100 µg BID + Formoterol 12 µg BID x 1 year
3. BUD 400 µg BID x 1 year
4. BUD 400 µg BID + Formoterol 12 µg BID x 1 year
Primary outcome Rates of severe and mild exacerbations of asthma per patient per
year
Pauwels RA, et al. NEJM 1997;337:1405-11.
23. • Formoterol groups, am PEF was higher during the first days
of treatment than subsequently (i.e., after day 3; P <.001)
• ? Limited tolerance to bronchodilating effect of formoterol during the
early phase of regular treatment little or no clinical significance.
Pauwels RA, et al. NEJM 1997;337:1405-11.
24. LABAs: Desensitization
Occurs in Formoterol, but not Salmeterol
FACET study
Little or no clinical significance
ICSs did not prevent tolerance
Hypothesis?
Agonist occupancy: Full (Formoterol), Partial
(Salmeterol)
Salmeterol may maintain functional –receptor through
persistent elevation of gene transcription.
Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
26. Clinical Applications
SABAs
Regular schedule or as-needed
LABAs
Monotherapy or combination with ICSs
Reduction or stop ICSs if LABAs were added
Add-on LABAs or double dose ICSs
ICS + LABAs or ICS + Montelukast
27. BAGS
Objective: To compare the effects of regularly scheduled use of inhaled albuterol
with those of albuterol used only as-needed
Patient 255 mild asthma patients (12-55 years, FEV1 ≥ 70%, PC20 ≤ 16
mg/ml), no ICS for 6 weeks
Intervention & Run-in period: no ICS x 6 weeks
Control
Albuterol MDI 2 puff qid daily (µg/d) + as-needed x 16 weeks
(126/116)
Placebo MDI 2 puff qid daily + Albuterol as-needed x 16 weeks
(129/114)
Withdrawal period: Placebo X 4 weeks
Primary outcome Morning peak expiratory flow
Drazen JM et al. NEJM 1996;335:841-7.
28. Morning PEF did not change significantly during the treatment period in
the scheduled or the as-needed treatment groups (P = 0.71)
As-needed use
Drazen JM et al. NEJM 1996;335:841-7
29. LABA Monotherapy vs Continued Therapy With ICS in
Patients With Persistent Asthma: A Randomized
Controlled Trial
SOC
Objective: To examine the effectiveness of salmeterol as replacement therapy in
patients whose asthma is well controlled by low-dose TA
Patient 164 patients, 12-65 years, well controlled persistent asthma
(FEV1 > 80%, PEF variability ≤ 20%) during a 6-week run-in
period of treatment with TA 400 µg BID
Intervention 1. Triamcinolone MDI 400 µg BID X 16 weeks (54)
2. Salmeterol MDI 42 µg BID X 16 weeks (54)
Control Placebo MDI 2 puffs BID X 16 weeks (56)
Primary outcome Change in morning PEF from the final week of the run-in period
(week 6) to the final week of the randomized treatment period
(week 22).
Lazarus SC, et al. JAMA 2001;285:2583-93
30. AM PEF, increased in salmeterol and triamcinolone groups
and decreased initially then increased in placebo group
(no statistically significant differences either within or among 3 groups)
Lazarus SC, et al. JAMA 2001;285:2583-93
31. P=.18 P=.29
P=.001 P=.003
P=.04
P=.004
Salmeterol group had more treatment
failures and asthma exacerbations
than the triamcinolone group Lazarus SC, et al. JAMA 2001;285:2583-93
32. P = .001
2.4%[0.0-10.6%]
Greater increases in
median sputum eosinophils
Patients with well-controlled persistent
asthma by low doses of TA cannot be
switched to salmeterol monotherapy
without risk of clinically significant loss
of asthma control
Monotherapy could not be
recommended in persistent asthma
−0.1%[−0.7% - 0.3%]
Lazarus SC, et al. JAMA 2001;285:2583-93
33. ICS Reduction and Elimination in Patients With SLIC
Persistent Asthma Receiving Salmeterol
Lemanske RF, Jr, et al. JAMA 2001;285;2594-603.
Objective: To determine whether ICS can be reduced or eliminated in patients with
persistent asthma after adding LABA
Patient: 175 patients, 12-65 years with persistent asthma that was uncontrolled (FEV1
≤ 80%, PEF variability >20%) during a 6-week run-in period of treatment with TA 400 µg BID
Intervention & Salmeterol induction phase (2 wk)
Control 1. TA 400 µg BID + Placebo BID (21) Group I
2. TA 400 µg BID + Salmeterol 42 µg BID(154) Group II
TA Reduction Phase (8 wk)
1. Group I: TA 200 µg BID + Placebo BID (19) Placebo-minus
2. Group II: TA 400 µg BID + Salmeterol 42 µg BID (74) Salmeterol-
plus
3. Group II: TA 200 µg BID + Salmeterol 42 µg BID (74) Salmeterol-
minus
TA Elimination Phase (8 wk)
1. Placebo-minus: Placebo TA + Placebo (18)
2. Salmeterol-plus: TA 400 µg BID + Salmeterol 42 µg BID (71)
3. Salmeterol-minus: Placebo TA + Salmeterol 42 µg BID (71)
Primary outcome: Time to asthma treatment failure in patients receiving salmeterol
34. Reduction phase: RR of treatment failure Elimination phase: RR of treatment failure
for patients in salmeterol-minus group in salmeterol-minus group compared with
compared with salmeterol-plus group was salmeterol-plus group was 4.3 (2.0-9.2), (P
2.2 (0.5-9.2) (P =.27) = .001)
ICSs could safely undergo 50% reduction
, but could not have ICSs eliminated
Lemanske RF, Jr, et al. JAMA 2001;285:2594-603.
35. GOAL
Objective: To determine proportion of patients who achieved well-controlled
asthma with salmeterol/fluticasone combination compared with fluticasone alone
Patient 3421 patients, 12 years, asthma 6 months, reversibility of
15%, smoking pack years < 10 years, uncontrolled asthma 2
out of 4 weeks during run-in period
3 strata (ICS in 6 months prior to randomisation):
Stratum 1: Corticosteroid-naïve (S/F 550;F 548)
Stratum 2: 500 µg Beclomethasone or equivalent (S/F 578;F
585)
Stratum 3: >500 – 1000µg Beclomethasone or equivalent
(S/F 579;F 576)
Bateman ED, et al. AJRCCM 2004;170:836-44.
36. Study design for Strata 1 and 2
Phase I 8- week control assessment
Phase II 4- week control assessment
Seretide 50/500 &
oral prednisolone
Seretide 50/500
or FP 500
Seretide 50/250
or FP 250 Step 3
Seretide 50/100
or FP 100 Step 2
Step 1
Visit 1 2 3 4 5 6 7 8 9
Week -4 0 4 12 24 36 48 52 56
Bateman ED, et al. AJRCCM 2004;170:836-44.
37. Study design for Stratum 3
Phase I 8- week control assessment
Phase II 4- week control assessment
Seretide 50/500 &
oral prednisolone
Seretide 50/500
or FP 500
Seretide 50/250
or FP 250 Step 2
Step 1
Visit 1 2 3 4 5 6 7 8 9
Week -4 0 4 12 24 36 48 52 56
Bateman ED, et al. AJRCCM 2004;170:836-44.
38. 70% 78% 75%
71% 69% 62%
65% 60%
52% 47%
51%
33%
Well-controlled asthma: SFC versus FP
Phase I: stratum 1 p = 0.039, strata 2 and 3 p < 0.001
Cumulative phase I and phase II: stratum 1 p = 0.003, strata 2 and 3 p < 0.001
Bateman ED, et al. AJRCCM 2004;170:836-44.
39. Well Controlled Asthma
% of patients with a Seretide
Well-controlled week
100 FP
80 77%
60 68%
40
20
0
-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Week
All patients
Bateman ED, et al. AJRCCM 2004;170:836-44.
40. 50% 44%
40%
42%
28% 32% 29%
31%
16%
20% 19%
8%
Totally controlled asthma: SFC versus FP
Phase I: all strata p < 0.001
Cumulative phase I and phase II: all strata p < 0.001
Bateman ED, et al. AJRCCM 2004;170:836-44.
41. FACET
Objective: To evaluate the effects of adding inhaled formoterol to both lower and
higher doses of the inhaled glucocorticoid budesonide
Patient 852 patients with asthma (FEV1 at baseline ≥ 50%) at least 6
months, 18-70 years, treat with ICS
Intervention & Run-in period: BUD 800 µg BID x 4 wk
control Random to 4 groups:
1. BUD 100 µg BID x 1 year
2. BUD 100 µg BID + Formoterol 12 µg BID x 1 year
3. BUD 400 µg BID x 1 year
4. BUD 400 µg BID + Formoterol 12 µg BID x 1 year
Primary outcome Rates of severe and mild exacerbations of asthma per patient per
year
Pauwels RA, et al. NEJM 1997;337:1405-11.
43. • FEV1 increased significantly in all groups during the run-in period
• FEV1 increased further with the addition of formoterol
• The higher dose of budesonide was associated with a significantly higher
FEV1 than the lower dose
Patients who have persistent symptoms despite treatment with ICSs, the addition
of formoterol to BUD Increasing dose of ICSs might be a more appropriate
initial therapeutic step in patients with repeated severe exacerbations
Pauwels RA, et al. NEJM 1997;337:1405-11.
44. Objectives: To investigate whether budesonide/formoterol for maintenance and
reliever therapy could reduce asthma exacerbations.
Patient 341 children, 4-11 years, with asthma ≥ 6 months,
prebronchodilator FEV1 60-100% and 12% reversibility,
uncontrolled with ICS
Intervention & 1. SMART: BUD/Formoterol 80/4.5 µg OD + BUD/Formoterol
Control additional inhalations for symptom relief (≤ 7 as-needed
inhalation/day) x 12 months (118)
2. Fixed combination: BUD/Formoterol 80/4.5 µg OD +
Terbutaline 0.4 mg for rescue medication X 12 months (117)
3. Fixed-dose budesonide: BUD 320 µg OD + Terbutaline 0.4
mg for rescue medication x 12 months (106)
Primary outcome Time to first exacerbation
Bisgaard H, et al. Chest 2006;130:1733-43.
45. 38%
26%
14%
SMART significantly prolonged the time to first exacerbation
vs fixed-dose combination (p < 0.001) or fixed-dose budesonide (p = 0.02)
Bisgaard H, et al. Chest 2006;130:1733-43.
47. Objective: To compare efficacy and safety of salmeterol/fluticasone 50/100 µg BID
with fluticasone 200 µg BID in children uncontrolled on low dose ICS.
Patient 584 children,4–11 yrs, with a clinical history of asthma for at least 6
months, reversibility in FEV1 ≥ 15%, currently receiving BDP 400
µg/day or equivalent
Intervention & Run-in period: FP 100 µg BID x 4 wk not controlled ≥ 2 wk
Control Randomization
1. Salmeterol/fluticasone (SFC) 50/100 µg BID x 12 wk (160)
2. Fluticasone propionate (FP) 200 µg BID x 12 wk (161)
Primary outcome Mean change from baseline in morning PEF over 12 wk
de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
48. Mean change differences between 2 groups:
7.06±3.01 (95% CI 1.7-13.5)(p = 0.012)
de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
49. SFC is as effective as FP, at half the dose of ICS
de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
50. At least one adverse event
SFC: 87 (58%) subjects
FP: 86(56%) subjects
Most common: headache and nasopharyngitis
Serious adverse events
SFC group (2%): laryngotracheitis(1), asthma
exacerbation (1) and concussion (1)
FP group (2%): wound infection (1), asthma
exacerbation (1) and gastritis (1)
None of which were assessed as related to study
de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
51. PACT
Objective: To compare the effectiveness of fluticasone monotherapy, fluticasone +
salmeterol, and montelukast in achieving asthma control
Patient 285 children, 6-14 years, mild-moderate persistent asthma
symptoms, FEV1 ≥ 80%, PC20 ≤ 12.5 mg/mL, not on controller
medications ≥ 2 weeks before randomization
Intervention & Run-in period: Placebo + Albuterol MDI x 2-4 weeks
Control Randomization x 48 weeks
1. Fluticasone monotherapy: Fluticasone 100 µg BID (96)
2. PACT combination: Fluticasone 100 µg/salmeterol 50 µg in
morning and salmeterol 50 µg evening (94)
3. Montelukast monotherapy: Montelukast 5 mg in the
evening (95)
Primary outcome Percent of asthma control days during the 48-week treatment
period
Sorkness C, et al. JACI 2007;119:64-72.
54. • Improvements ACD: Both F & C > M
• FEV1, FEV1/FVC, max bronchodilator response, ENO: F > C
• Favor fluticasone monotherapy in treating Sorkness C, et al.
children with mild-moderate persistent asthma with FEV1 ≥ 80% JACI 2007;119:64-72.
55. BADGERS
Objectives: To assess frequency of differential responses to 3 step-up treatments
in children who had uncontrolled asthma while receiving low-dose ICSs
Patient 182 children, 6 -17 years, uncontrolled asthma while receiving
Fluticasone 100 µg BID
Intervention Triple-crossover study (random order) x 16 weeks:
& Control 1. ICS step-up: Fluticasone 250 µg BID
2. LABA step-up: Fluticasone 100 µg BID + Salmeterol 50 µg of a
BID
3. LTRA step-up: Fluticasone 100 µg BID + Montelukast 5 or 10 mg
OD
Primary Differential response:
outcome - Oral prednisone (Total prednisone received during the period was ≤180
mg)
- Asthma-control days (Annualized asthma-control days during the final
12 weeks was increased ≥ 31 days
- FEV1 (FEV1 at the end ≥ 5%)
Lemanske RF, Jr, et al. NEJM 2010;362:975-85.
56. 54%
32%
P = 0.004
52%
34%
P = 0.02
Similar
LABA vs LTRA: LABA vs ICS:
Relative probability Relative probability
of best response 1.6 of best response 1.7
(1.1-2.3);p = 0.004 1.7 (1.2-2.4);p=0.002
Lemanske RF, Jr, et al. NEJM 2010;362:975-85.
57. BADGERS
Higher childhood ACT scores (> 19) predict best
response to LABA step-up
Race
Hispanic & non-hispanic white: best response to
LABA
Black: best response to LABA or ICS equally
LABA step-up was significantly more likely to
provide the best response.
Lemanske RF, Jr, et al. NEJM 2010;362:975-85.
59. SMART
Objectives: To compare the safety of salmeterol xinafoate or placebo added to
usual asthma care
Patient 26,355 patients, > 12 years, asthma (Clinical judgment), no LABA,
no β-blocker
Intervention Salmeterol MDI 42 µg BID + Usual care x 28 weeks
Control Placebo MDI BID + Usual care + Usual care x 28 weeks
Primary outcome Respiratory-related deaths, or life-threatening experiences
Nelson H, et al. Chest 2006;129:15-26.
61. Asthma history and current nocturnal symptoms
indicate greater disease severity at baseline
in the African-American subgroup
Nelson H, et al. Chest 2006;129:15-26.
63. FDA Committee 2008
Age group Single agent Combination
4-11 years • Benefits did not • Benefits outweighed the risks
outweigh the risks (paucity of for salmeterol/fluticasone (Slim
randomized majority)
data)
Adolescent • Benefits did not out- • Adult: Benefits of combi-
& adult weigh the risks nation products outweighed the
• Label risks (unanimously for Advair
- Against using LABAs as &with 1 abstention for
monotherapy Symbicort)
- LABAs should be added to • Adolescent: Benefits
ICSs only when ICSs alone outweighed the risks for both
proved inadequate for Products (Substantial majority)
asthma control
Kramer JM. NEJM 2009;360(16):1592-5.
66. SABAs are the most effective medication for relieving acute
bronchospasm.
Therapy of choice for relief of acute symptoms and prevention of EIB.
Regularly scheduled, daily, chronic use of SABA is not recommended.
Increasing use of SABA treatment or using SABA >2 days a week for
symptom relief (not prevention of EIB) generally indicates inadequate
control of asthma.
SABA
70. LABAs are not to be used as monotherapy for long-term control.
LABAs are used in combination with ICSs for long-term control and
prevention of symptoms in moderate or severe persistent asthma (≥ step
3 care in children ≥ 5 years of age and adults) -- ? increased risk of
severe exacerbations associated with the daily use of LABA.
- For patients ≥5 years of age who have moderate persistent asthma
or asthma inadequately controlled on low-dose ICS increasing the
ICS dose = adding LABA.
- For patients ≥5 years of age who have severe persistent asthma or
asthma inadequately controlled on step 3 care combination of
LABA and ICS is the preferred therapy.
LABA may be used before exercise to prevent EIB.
The use of LABA for the treatment of acute symptoms is not currently
recommended.
LABA
71. 2009
SABAs are the most effective bronchodilators
and the preferred reliever treatment in children ≤ 5 years.
LABAs cannot be recommended in this age group.
73. GINA 2010
SABAs LABAs
Drug of choice for relief bronchospasm LABAs should not be used as
during exacerbation monotherapy
Prevention of EIB Most effective when combined with
ICSs
Preferred treatment when medium dose
of ICSs alone fails to achieve control
LABAs + ICSs may also be used to
prevent EIB and may provide longer
protection than SABAs
74. Treatment of choice for intermittent and acute asthma episodes in
children, very young children and for preventing EIB.
Salbutamol, terbutaline, and formoterol have a favorable safety and
efficacy profile in patients aged 2–5 years
Bacharier LB, et al. Allergy 2008;63:5-34. SABA
75. Children > 2 years of age
Bacharier LB, et al. Allergy 2008;63:5-34.
76. Add-on controller therapy to ICS for partially controlled or uncontrolled
asthma.
Efficacy is not well documented in children in contrast to adults, and use
should be evaluated carefully.
Safety concerns suggest that use should be restricted to add-on
therapy to ICS when indicated.
Combination products of LABA and ICS may be licensed for use in
children over 4–5 years, however, the effect of LABAs or combination
products has not yet been adequately studied in young children under
4 years.
Bacharier LB, et al. Allergy 2008;63:5-34. LABA
77. Take-home messages
Catecholamine structure has been modified to
achieve greater β2 selectivity and a better
pharmacologic profile.
Non-bronchodilator actions can be beneficial
in the treatment of asthma, including
glucocorticoid receptor priming.
SABAs are the drugs of choice for treating
acute asthma symptoms and exacerbations
and for preventing EIB.
78. Take-home messages
LABAs are useful in combination with inhaled
corticosteroids for long-term control of asthma
but should not be used as monotherapy.
Further studies are needed to definitively
determine whether the addition of LABAs to
ICSs increases the risk of serious asthma
outcomes
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Corticosteroids to beta- increase the transcription of the b2-receptorgene increased expression of b2-receptors at the cellsurface (human lung in vitro and in the nasal mucosa in vivo after application of a topicalnasal corticosteroid (effect with in a few hours)Preventdownregulation of pulmonary b2-receptors and tolerancethat occurs after prolonged b2-agonist administration Reverse the uncoupling of b2-receptors that occurs afterexposure to b2-agonists -This suggests that treatment withinhaled corticosteroids may prevent the development oftolerance to LABA. -Thus, b2-agonists maypreserve the response to b2-agonists in mast cells andneutrophils, which would normally rapidly develop tachy-phylaxis in response to b2-agonists. This would be relevant inthe use of budesonide/formoterol as rescue therapy as theacute effects of formoterol and mast cells and neutrophils maybe preserved by the maintenance treatment with inhaledbudesonide.
ไม่เท่ากับ tachyphylaxisซึงคือ ยา x ไปแทนที่ยา Y ที่symp n endings
No differences between LOS, admission rate, no of return visit
Regular treatment with formoterol combined withbudesonide did not cause any long-term loss of con-trol of asthma. There were no signs of worsening ofdisease or tolerance to the effects of medication withregard to any clinical or functional variable exam-ined, except for a decrease in the effect of formo-terol on peak expiratory flow in the morning afterthe first two days of treatment. The
FACET: ICS ไม่ prevent?
placebo vstriamcinolone, P,.001; for salmeterolvstriamcinolone, P=.004; and for placebo vssalmeterol, P=.18placebo vstriamcinolone, P=.003; forsalmeterolvstriamcinolone, P=.04; and for placebo vssalmeterol, P=.29
นอกจากนี้ SF ดีกว่า F: exacerbation, QOL, symptom-free day, achieve well และ total control ไวและที่ steroid ขนาดต่ำกว่า, change morning PEF มากกว่า
morning PEF 70% of baseline on 2 consecutive days;treatment with oral steroids; an increase in inhaled corticosteroids [via a separate inhaler] and/or otheradditional treatment; or hospitalization/ED treatment)
Best add-on therapy giving effective response
PC20, FeNo, Genotype Arg/Arg (เดิมว่าLABA ดี) – not predict
A for ≥12 years of age, B for 5–11 years of ageEIB: but duration of action does not exceed 5 hours with chronic regular use,disguise poorly controlled persistent asthma
A for ≥12 years of age, B for 5–11 years of ageEIB: but duration of action does not exceed 5 hours with chronic regular use,disguise poorly controlled persistent asthma