SlideShare a Scribd company logo
1 of 79
Download to read offline
BETA 2-AGONISTS




                  Piyawadee Lertchanaruengrith, MD
                                       30/09/2011
Topic outlines
   Structure & Function Relationship
   Non-bronchodilator Actions of β2–Adrenergic
    Agonist
   Clinical Applications
   Safety issues
   β2–Adrenergic Agonist in Asthma Guidelines
Structure & Function Relationship
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.
Modification of
    3,4- hydroxyl
group on benzene ring




    Prolonged
  bronchodilator
      action


    Sorkness CA. In Middleton’s Allergy: Principles and Practice; 2009:1485-1503.
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.
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.
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.
Mechanisms of Actions




         Johnson M. Paediatric respiratory reviews 2001;2:57-62.
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.
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.
Non-bronchodilator Actions of
β2–Adrenergic Agonist
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.
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.
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.
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.
β2-receptor Desensitization




                   Johnson M. JACI 2006;117:18-24.
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.
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.
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.
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.
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.
• 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.
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.
Clinical Applications
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
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.
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
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
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
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
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
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
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.
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.
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.
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.
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.
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.
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.
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.
1   2       3       4




    Pauwels RA, et al. NEJM 1997;337:1405-11.
• 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.
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.
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.
Bisgaard H, et al. Chest 2006;130:1733-43.
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.
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.
SFC is as effective as FP, at half the dose of ICS


           de Bilc J. et al. Pediatr Allergy Immunol 2009;20:763-71.
   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.
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.
% ACD
-F 64.2%
-C 59.6%
-M 52.5%




           Sorkness C, et al. JACI 2007;119:64-72.
Sorkness C, et al. JACI 2007;119:64-72.
• 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.
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.
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.
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.
Safety issues
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.
Nelson H, et al. Chest 2006;129:15-26.
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.
Seretide
Salmeterol
Formoterol
Symbicort




             Kramer JM. NEJM 2009;360(16):1592-5.
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.
Chowdhury BA, Pan GD. NEJM 2010;362(13):1169-71.
Asthma guidelines: β2-agonist
• EPR 3: 2007
• GINA 2010

• GINA under five

• PRACTALL
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
Beta 2 agonists
Beta 2 agonists
Beta 2 agonists
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
2009




     SABAs are the most effective bronchodilators
and the preferred reliever treatment in children ≤ 5 years.

   LABAs cannot be recommended in this age group.
2010
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
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
Children > 2 years of age




Bacharier LB, et al. Allergy 2008;63:5-34.
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
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.
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
Thank you
for your attention

More Related Content

What's hot

Seminar on LABA & SABA: By RxvichuZ! ;)
Seminar on LABA & SABA: By RxvichuZ! ;)Seminar on LABA & SABA: By RxvichuZ! ;)
Seminar on LABA & SABA: By RxvichuZ! ;)RxVichuZ
 
Beta adrenergic blockers
Beta adrenergic blockersBeta adrenergic blockers
Beta adrenergic blockersKarun Kumar
 
Benzodiazipines
Benzodiazipines  Benzodiazipines
Benzodiazipines havalprit
 
Drugs used for cough
Drugs used for coughDrugs used for cough
Drugs used for coughBPKIHS
 
Pharmacological management of heart failure
Pharmacological management of heart failurePharmacological management of heart failure
Pharmacological management of heart failureNaser Tadvi
 
Beta blockers - pharmacology
Beta blockers - pharmacologyBeta blockers - pharmacology
Beta blockers - pharmacologyPARUL UNIVERSITY
 
Drugs for treatment of Diabetes Mellitus
Drugs for treatment of Diabetes MellitusDrugs for treatment of Diabetes Mellitus
Drugs for treatment of Diabetes MellitusNaser Tadvi
 
Cephalosporins - Pharmacology
Cephalosporins - Pharmacology Cephalosporins - Pharmacology
Cephalosporins - Pharmacology Areej Abu Hanieh
 
Vasomotor reversal of dale
Vasomotor reversal of daleVasomotor reversal of dale
Vasomotor reversal of dalepavithra vinayak
 
Pharmacology of corticosteroids
Pharmacology of corticosteroidsPharmacology of corticosteroids
Pharmacology of corticosteroidsMayur Chaudhari
 

What's hot (20)

Seminar on LABA & SABA: By RxvichuZ! ;)
Seminar on LABA & SABA: By RxvichuZ! ;)Seminar on LABA & SABA: By RxvichuZ! ;)
Seminar on LABA & SABA: By RxvichuZ! ;)
 
Bronchodilators
BronchodilatorsBronchodilators
Bronchodilators
 
Corticosteroids
CorticosteroidsCorticosteroids
Corticosteroids
 
Beta adrenergic blockers
Beta adrenergic blockersBeta adrenergic blockers
Beta adrenergic blockers
 
Skeletal muscle relaxants
Skeletal muscle relaxantsSkeletal muscle relaxants
Skeletal muscle relaxants
 
Opioid analgesic
Opioid analgesicOpioid analgesic
Opioid analgesic
 
Sympathomimetic
SympathomimeticSympathomimetic
Sympathomimetic
 
Anti-cholinergic Drugs
Anti-cholinergic DrugsAnti-cholinergic Drugs
Anti-cholinergic Drugs
 
Benzodiazipines
Benzodiazipines  Benzodiazipines
Benzodiazipines
 
Alpha blockers
Alpha blockersAlpha blockers
Alpha blockers
 
Drugs used for cough
Drugs used for coughDrugs used for cough
Drugs used for cough
 
Antiemetics
AntiemeticsAntiemetics
Antiemetics
 
Pharmacological management of heart failure
Pharmacological management of heart failurePharmacological management of heart failure
Pharmacological management of heart failure
 
Beta blockers - pharmacology
Beta blockers - pharmacologyBeta blockers - pharmacology
Beta blockers - pharmacology
 
Beta blockers
Beta blockers Beta blockers
Beta blockers
 
Drugs for treatment of Diabetes Mellitus
Drugs for treatment of Diabetes MellitusDrugs for treatment of Diabetes Mellitus
Drugs for treatment of Diabetes Mellitus
 
Skeletal Muscle Relaxants
Skeletal Muscle RelaxantsSkeletal Muscle Relaxants
Skeletal Muscle Relaxants
 
Cephalosporins - Pharmacology
Cephalosporins - Pharmacology Cephalosporins - Pharmacology
Cephalosporins - Pharmacology
 
Vasomotor reversal of dale
Vasomotor reversal of daleVasomotor reversal of dale
Vasomotor reversal of dale
 
Pharmacology of corticosteroids
Pharmacology of corticosteroidsPharmacology of corticosteroids
Pharmacology of corticosteroids
 

Viewers also liked

AP Biology - The stages of cellular respiration, Ch. 7
AP Biology - The stages of cellular respiration, Ch. 7AP Biology - The stages of cellular respiration, Ch. 7
AP Biology - The stages of cellular respiration, Ch. 7Stephanie Beck
 
Chapter 7 metabolism and energy
Chapter 7 metabolism and energyChapter 7 metabolism and energy
Chapter 7 metabolism and energySyeda Hussaini
 
11.19.08: Ventilation/Perfusion Matching
11.19.08: Ventilation/Perfusion Matching11.19.08: Ventilation/Perfusion Matching
11.19.08: Ventilation/Perfusion MatchingOpen.Michigan
 
anatomy-lecture-3-thoracic-wall-1-slides
anatomy-lecture-3-thoracic-wall-1-slidesanatomy-lecture-3-thoracic-wall-1-slides
anatomy-lecture-3-thoracic-wall-1-slidesForensic Pathology
 
Community acquired pneumonia 2015
Community acquired pneumonia  2015Community acquired pneumonia  2015
Community acquired pneumonia 2015samirelansary
 
Anatomy of thorax /certified fixed orthodontic courses by Indian dental academy
Anatomy of thorax /certified fixed orthodontic courses by Indian dental academy Anatomy of thorax /certified fixed orthodontic courses by Indian dental academy
Anatomy of thorax /certified fixed orthodontic courses by Indian dental academy Indian dental academy
 
Respiration biochemistry
Respiration   biochemistryRespiration   biochemistry
Respiration biochemistrysvenwardle
 
Fluid and electrolyte balances and imbalances
Fluid and electrolyte balances and imbalancesFluid and electrolyte balances and imbalances
Fluid and electrolyte balances and imbalanceskatherina Rajan
 

Viewers also liked (19)

AP Biology - The stages of cellular respiration, Ch. 7
AP Biology - The stages of cellular respiration, Ch. 7AP Biology - The stages of cellular respiration, Ch. 7
AP Biology - The stages of cellular respiration, Ch. 7
 
blood supply of lungs
blood supply of lungsblood supply of lungs
blood supply of lungs
 
Chapter 7 metabolism and energy
Chapter 7 metabolism and energyChapter 7 metabolism and energy
Chapter 7 metabolism and energy
 
thorax intercostal space
thorax intercostal spacethorax intercostal space
thorax intercostal space
 
Cephalosporins
CephalosporinsCephalosporins
Cephalosporins
 
Mcq abd thorax
Mcq abd thoraxMcq abd thorax
Mcq abd thorax
 
Pathology of Respiratory System Disorders
Pathology of Respiratory System DisordersPathology of Respiratory System Disorders
Pathology of Respiratory System Disorders
 
11.19.08: Ventilation/Perfusion Matching
11.19.08: Ventilation/Perfusion Matching11.19.08: Ventilation/Perfusion Matching
11.19.08: Ventilation/Perfusion Matching
 
anatomy-lecture-3-thoracic-wall-1-slides
anatomy-lecture-3-thoracic-wall-1-slidesanatomy-lecture-3-thoracic-wall-1-slides
anatomy-lecture-3-thoracic-wall-1-slides
 
Anatomy mcqs thorax
Anatomy mcqs thoraxAnatomy mcqs thorax
Anatomy mcqs thorax
 
Vagus nerve
Vagus nerveVagus nerve
Vagus nerve
 
Spinal Nerve
Spinal NerveSpinal Nerve
Spinal Nerve
 
Community acquired pneumonia 2015
Community acquired pneumonia  2015Community acquired pneumonia  2015
Community acquired pneumonia 2015
 
Pneumonia Diagnosis and treatment
Pneumonia Diagnosis and treatmentPneumonia Diagnosis and treatment
Pneumonia Diagnosis and treatment
 
Mycobacterium
MycobacteriumMycobacterium
Mycobacterium
 
ABG Interpretation
ABG InterpretationABG Interpretation
ABG Interpretation
 
Anatomy of thorax /certified fixed orthodontic courses by Indian dental academy
Anatomy of thorax /certified fixed orthodontic courses by Indian dental academy Anatomy of thorax /certified fixed orthodontic courses by Indian dental academy
Anatomy of thorax /certified fixed orthodontic courses by Indian dental academy
 
Respiration biochemistry
Respiration   biochemistryRespiration   biochemistry
Respiration biochemistry
 
Fluid and electrolyte balances and imbalances
Fluid and electrolyte balances and imbalancesFluid and electrolyte balances and imbalances
Fluid and electrolyte balances and imbalances
 

Similar to Beta 2 agonists

Pharmacotherapy of bronchial asthma
Pharmacotherapy of bronchial asthma Pharmacotherapy of bronchial asthma
Pharmacotherapy of bronchial asthma HIMANSHUKUMAR822
 
Management of Bronchial asthma
Management of Bronchial asthmaManagement of Bronchial asthma
Management of Bronchial asthmaAsif Hussain
 
Pharmacotherapy of asthma
Pharmacotherapy of asthmaPharmacotherapy of asthma
Pharmacotherapy of asthmaTabindah Hesam
 
Respiratory Drugs (for Asthma & COPD)
Respiratory Drugs (for Asthma & COPD)Respiratory Drugs (for Asthma & COPD)
Respiratory Drugs (for Asthma & COPD)MedicineAndHealth
 
Asthma and copd e000 1233730950067181-1
Asthma and copd e000 1233730950067181-1Asthma and copd e000 1233730950067181-1
Asthma and copd e000 1233730950067181-1guest62e4da
 
Resp drugs presesntation
Resp drugs presesntationResp drugs presesntation
Resp drugs presesntationmdduffy21
 
Asthma - Recent advances in treatment
Asthma - Recent advances in treatmentAsthma - Recent advances in treatment
Asthma - Recent advances in treatmentDivya Krishnan
 
Recent advances in drugs affecting autonomic nervous system dr jayesh vaghela
Recent advances in drugs affecting autonomic nervous system dr jayesh vaghelaRecent advances in drugs affecting autonomic nervous system dr jayesh vaghela
Recent advances in drugs affecting autonomic nervous system dr jayesh vaghelajpv2212
 
Management of Bronchial Asthma
Management of Bronchial AsthmaManagement of Bronchial Asthma
Management of Bronchial AsthmaPk Doctors
 
Bronchial asthma therapeutics and status asthmaticus
Bronchial asthma therapeutics and status asthmaticusBronchial asthma therapeutics and status asthmaticus
Bronchial asthma therapeutics and status asthmaticusDr Chinmaya Debasis Panda
 

Similar to Beta 2 agonists (20)

Pharmacotherapy of bronchial asthma
Pharmacotherapy of bronchial asthma Pharmacotherapy of bronchial asthma
Pharmacotherapy of bronchial asthma
 
642402 634249935653553750
642402 634249935653553750642402 634249935653553750
642402 634249935653553750
 
Management of Bronchial asthma
Management of Bronchial asthmaManagement of Bronchial asthma
Management of Bronchial asthma
 
Pharmacotherapy of asthma
Pharmacotherapy of asthmaPharmacotherapy of asthma
Pharmacotherapy of asthma
 
ANTI-ASTHMATICS
ANTI-ASTHMATICSANTI-ASTHMATICS
ANTI-ASTHMATICS
 
Bronchial asthma
Bronchial asthmaBronchial asthma
Bronchial asthma
 
Pharmacotherapy of asthma
Pharmacotherapy of asthmaPharmacotherapy of asthma
Pharmacotherapy of asthma
 
Respiratory Drugs
Respiratory DrugsRespiratory Drugs
Respiratory Drugs
 
Respiratory Drugs (for Asthma & COPD)
Respiratory Drugs (for Asthma & COPD)Respiratory Drugs (for Asthma & COPD)
Respiratory Drugs (for Asthma & COPD)
 
Asthma and copd e000 1233730950067181-1
Asthma and copd e000 1233730950067181-1Asthma and copd e000 1233730950067181-1
Asthma and copd e000 1233730950067181-1
 
Resp drugs presesntation
Resp drugs presesntationResp drugs presesntation
Resp drugs presesntation
 
Asthma - Recent advances in treatment
Asthma - Recent advances in treatmentAsthma - Recent advances in treatment
Asthma - Recent advances in treatment
 
Bronchial asthma in children
Bronchial asthma in childrenBronchial asthma in children
Bronchial asthma in children
 
Respiratory Drugs
Respiratory DrugsRespiratory Drugs
Respiratory Drugs
 
Respiratory Drugs
Respiratory DrugsRespiratory Drugs
Respiratory Drugs
 
Drugs for asthma
Drugs for asthmaDrugs for asthma
Drugs for asthma
 
Bronchial asthma - AHS by Gowtham sap
Bronchial asthma - AHS by Gowtham sapBronchial asthma - AHS by Gowtham sap
Bronchial asthma - AHS by Gowtham sap
 
Recent advances in drugs affecting autonomic nervous system dr jayesh vaghela
Recent advances in drugs affecting autonomic nervous system dr jayesh vaghelaRecent advances in drugs affecting autonomic nervous system dr jayesh vaghela
Recent advances in drugs affecting autonomic nervous system dr jayesh vaghela
 
Management of Bronchial Asthma
Management of Bronchial AsthmaManagement of Bronchial Asthma
Management of Bronchial Asthma
 
Bronchial asthma therapeutics and status asthmaticus
Bronchial asthma therapeutics and status asthmaticusBronchial asthma therapeutics and status asthmaticus
Bronchial asthma therapeutics and status asthmaticus
 

More from Chulalongkorn Allergy and Clinical Immunology Research Group

More from Chulalongkorn Allergy and Clinical Immunology Research Group (20)

Cat and dog allergy and exotic pets 2024
Cat and dog allergy and exotic pets 2024Cat and dog allergy and exotic pets 2024
Cat and dog allergy and exotic pets 2024
 
Anti-interferon-gamma autoantibody associated immunodeficiency
Anti-interferon-gamma autoantibody associated immunodeficiencyAnti-interferon-gamma autoantibody associated immunodeficiency
Anti-interferon-gamma autoantibody associated immunodeficiency
 
DRESS syndrome.pdf
DRESS syndrome.pdfDRESS syndrome.pdf
DRESS syndrome.pdf
 
Wheat allergy.pdf
Wheat allergy.pdfWheat allergy.pdf
Wheat allergy.pdf
 
Indoor allergen avoidance.pdf
Indoor allergen avoidance.pdfIndoor allergen avoidance.pdf
Indoor allergen avoidance.pdf
 
Hymenoptera sting allergy.pdf
Hymenoptera sting allergy.pdfHymenoptera sting allergy.pdf
Hymenoptera sting allergy.pdf
 
AERD and NSAID hypersensitivity
AERD and NSAID hypersensitivityAERD and NSAID hypersensitivity
AERD and NSAID hypersensitivity
 
Food immunotherapy.pdf
Food immunotherapy.pdfFood immunotherapy.pdf
Food immunotherapy.pdf
 
Agammaglobulinemia.pdf
Agammaglobulinemia.pdfAgammaglobulinemia.pdf
Agammaglobulinemia.pdf
 
Histamine and anti histamines.pdf
Histamine and anti histamines.pdfHistamine and anti histamines.pdf
Histamine and anti histamines.pdf
 
Food-dependent, exercise-induced anaphylaxis
Food-dependent, exercise-induced anaphylaxis Food-dependent, exercise-induced anaphylaxis
Food-dependent, exercise-induced anaphylaxis
 
Beta-lactam allergy.pdf
Beta-lactam allergy.pdfBeta-lactam allergy.pdf
Beta-lactam allergy.pdf
 
Immunoglobulin therapy
Immunoglobulin therapyImmunoglobulin therapy
Immunoglobulin therapy
 
Local anesthetic drug allergy.pdf
Local anesthetic drug allergy.pdfLocal anesthetic drug allergy.pdf
Local anesthetic drug allergy.pdf
 
Iodinated contrast media Hypersensitivity
Iodinated contrast media HypersensitivityIodinated contrast media Hypersensitivity
Iodinated contrast media Hypersensitivity
 
Urticaria.pdf
Urticaria.pdfUrticaria.pdf
Urticaria.pdf
 
Serum sickness & SSLR
Serum sickness & SSLRSerum sickness & SSLR
Serum sickness & SSLR
 
Vaccine Hypersensitivity.pdf
Vaccine Hypersensitivity.pdfVaccine Hypersensitivity.pdf
Vaccine Hypersensitivity.pdf
 
HyperIgM syndrome.pdf
HyperIgM syndrome.pdfHyperIgM syndrome.pdf
HyperIgM syndrome.pdf
 
Hypersensitivity pneumonitis and occupational asthma
Hypersensitivity pneumonitis and occupational asthmaHypersensitivity pneumonitis and occupational asthma
Hypersensitivity pneumonitis and occupational asthma
 

Recently uploaded

SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdfHongBiThi1
 
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdfPAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdfDolisha Warbi
 
Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Peter Embi
 
EXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionEXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionkrishnareddy157915
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...Shubhanshu Gaurav
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu Medical University
 
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.aarjukhadka22
 
AORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectionAORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectiondrhanifmohdali
 
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfSGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfHongBiThi1
 
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdfCONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdfDolisha Warbi
 
How to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyHow to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyZurück zum Ursprung
 
Male Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondMale Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondSujoy Dasgupta
 
Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.kishan singh tomar
 
pA2 value, Schild plot and pD2 values- applications in pharmacology
pA2 value, Schild plot and pD2 values- applications in pharmacologypA2 value, Schild plot and pD2 values- applications in pharmacology
pA2 value, Schild plot and pD2 values- applications in pharmacologyDeepakDaniel9
 
Mental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil ThirusanguMental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil Thirusangu Medical University
 
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfSGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfHongBiThi1
 

Recently uploaded (20)

SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
 
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdfPAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
 
Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024
 
EXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionEXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung function
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu
 
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
 
AORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectionAORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissection
 
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfSGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
 
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdfCONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
 
Rheumatoid arthritis Part 1, case based approach with application of the late...
Rheumatoid arthritis Part 1, case based approach with application of the late...Rheumatoid arthritis Part 1, case based approach with application of the late...
Rheumatoid arthritis Part 1, case based approach with application of the late...
 
How to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyHow to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturally
 
Biologic therapy ice breaking in rheumatology, Case based approach with appli...
Biologic therapy ice breaking in rheumatology, Case based approach with appli...Biologic therapy ice breaking in rheumatology, Case based approach with appli...
Biologic therapy ice breaking in rheumatology, Case based approach with appli...
 
Male Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondMale Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and Beyond
 
Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.
 
pA2 value, Schild plot and pD2 values- applications in pharmacology
pA2 value, Schild plot and pD2 values- applications in pharmacologypA2 value, Schild plot and pD2 values- applications in pharmacology
pA2 value, Schild plot and pD2 values- applications in pharmacology
 
Mental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil ThirusanguMental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil Thirusangu
 
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfSGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
 
GOUT UPDATE AHMED YEHIA 2024, case based approach with application of the lat...
GOUT UPDATE AHMED YEHIA 2024, case based approach with application of the lat...GOUT UPDATE AHMED YEHIA 2024, case based approach with application of the lat...
GOUT UPDATE AHMED YEHIA 2024, case based approach with application of the lat...
 
American College of physicians ACP high value care recommendations in rheumat...
American College of physicians ACP high value care recommendations in rheumat...American College of physicians ACP high value care recommendations in rheumat...
American College of physicians ACP high value care recommendations in rheumat...
 

Beta 2 agonists

  • 1. BETA 2-AGONISTS Piyawadee Lertchanaruengrith, MD 30/09/2011
  • 2. Topic outlines  Structure & Function Relationship  Non-bronchodilator Actions of β2–Adrenergic Agonist  Clinical Applications  Safety issues  β2–Adrenergic Agonist in Asthma Guidelines
  • 3. Structure & Function Relationship
  • 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.
  • 9. Mechanisms of Actions Johnson M. Paediatric respiratory reviews 2001;2:57-62.
  • 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.
  • 17. β2-receptor Desensitization 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.
  • 42. 1 2 3 4 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.
  • 46. 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.
  • 52. % ACD -F 64.2% -C 59.6% -M 52.5% Sorkness C, et al. JACI 2007;119:64-72.
  • 53. 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.
  • 60. 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.
  • 62. Seretide Salmeterol Formoterol Symbicort Kramer JM. NEJM 2009;360(16):1592-5.
  • 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.
  • 64. Chowdhury BA, Pan GD. NEJM 2010;362(13):1169-71.
  • 65. Asthma guidelines: β2-agonist • EPR 3: 2007 • GINA 2010 • GINA under five • PRACTALL
  • 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.
  • 72. 2010
  • 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
  • 79. Thank you for your attention

Editor's Notes

  1. OH ที่ 3,4 เป็นที่ที่COMT มาทำงานคือย่อย catecholamineReposition OH group ไปที่ 3,5 เปลี่ยนตำแหน่งที่ 3 จาก OH เป็นกลุ่มอื่น
  2. ส้ม = แทนที่isopropyl group ด้วยอย่างอื่นเหลือง = เพิ่มขนาด terminal amino group เป็น lipophilic side chain (salmet &gt; ) ป้องกันโดน MAO มาทำลาย  เพิ่ม duration of axn
  3. 413 aa residue, 46500 kDa7 transmembrane-spanning alpha helix, 3 intracellular loopRed: bindingGreen: polymorphismBlue: couplingPink: desensitizationOrange: downregulationAWsm m พบ receptor ประมาณ 30-40000 /cell
  4. Note: beta2-rec activated MAPK จะไปเติม P ให้ GR  prime GR ให้ไวต่อ steroid-dependent activationนอกจากนี้ยังเพิ่ม translocation GR เข้า nucleus ผ่าน C/EBP alpha
  5. Active site อยู่ใน lipid bilayerดังนั้น molecular structure ของยา จึงเป็นตัวกำหนด ว่ายาจะจับ receptor ยังไง Albuterol: ชอบน้ำ ผ่าน extracellular aqueous compartment ไปจับ active site โดยตรง  onset เร็ว แต่ก็ re-equilibrate คือจับ recอ่อนและกระจายกลับ microcirculation เร็ว จึงออกฤทธิ์สั้น 4-6 ชั่วโมงFormoterol: ชอบไขมันกลางๆ ถูก uptake เข้า cell membrane  depot แล้วค่อยๆปล่อยมาจับ active site ออกฤทธิ์ยาว 12 ชั่วโมง (conc dependent) : ก็ยังมีบางส่วน อยู่ใน aqueous phase นอกเซลล์ จึง onset เร็ว Salmeterol: ชอบไขมันที่สุด เข้าไปส่วนใหญ่อยู่ใน cell membrane ภายใน 1 นาที แล้วค่อยขยายไปด้านข้างเข้า active site ถูกปล่อยช้ากว่า จึง onset ช้ากว่า F และยาอื่น: interxnระหว่าง side chain ของมันที่ยาวมากๆ กับ exosite (บริเวณ aaที่เกลียดน้ำมาก อยู่ใน domain ที่ 4)  ทำให้ยาไม่หลุดจาก rec  ออกฤทธิ์นาน (conc independent)0
  6. Majority: intermediate agonist พอมี receptor เยอะ จะกลายเป็น full agonistF &gt; 80% rec activation
  7. 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.
  8. ไม่เท่ากับ tachyphylaxisซึงคือ ยา x ไปแทนที่ยา Y ที่symp n endings
  9. ระยะสั้น คือสีแดงPKAและหรือ ARK ไปเติม P ให้ receptor  receptor จับ B-arrestin  ทำให้ไม่มี receptor จับกับ stimulated Gs protein  limit receptor functionชั่วคราว หายในเวลาเป็นนาทีหลังเอา agonist ออกระยะกลางReceptor ถูก sequestration เข้า cell  เหลือน้อยบน cell surface เข้ามาก็จะถูกเอา P ออก หายในเวลาเป็นชั่วโมงหลังเอา agonist ออก
  10. No differences between LOS, admission rate, no of return visit
  11. 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
  12. FACET: ICS ไม่ prevent?
  13. 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
  14. นอกจากนี้ SF ดีกว่า F: exacerbation, QOL, symptom-free day, achieve well และ total control ไวและที่ steroid ขนาดต่ำกว่า, change morning PEF มากกว่า
  15. 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)
  16. Best add-on therapy giving effective response
  17. PC20, FeNo, Genotype Arg/Arg (เดิมว่าLABA ดี) – not predict
  18. 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
  19. 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
  20. - Tremor ลดใน 2 wkหลังให้ต่อเนื่อง (dose-limiting effect)