Inhaled corticosteroids in acute asthma

1
Inhaled corticosteroidsin acute asthma

• Arzu Yorgancioglu
• Celal Bayar University Medical School
• Manisa

2
Disclosure of Interest
Contract research (institution) Astra-Zeneca,
Boehringer Ingelheim/ Pfizer, Sanofi-Aventis,
MSD,Novartis,Chiesi Advisory boards
Astra-Zeneca, Boehringer Ingelheim/ Pfizer,
AbdiIbrahim, UCB,Glaxo Smith Klein Lectures
Astra-Zeneca, Boehringer Ingelheim/ Pfizer, Glaxo
SmithKline, MSD, Sanofi-Aventis, Abdi Ibrahim,
Bilim, Novartis,UCB, Chiesi
3

• Established Management of Acute Asthma
• Systemic corticosteroids
• Bronchodilators
• Oxygen therapy
• ICS potential benefit ???

4
Outline

• Guidelines
• The rationale behind
• Mechanisms of steroid action
• Pharmacokinetics
• Adverse systemic effects
• Clinical data
• Acute worsenings
• Exacerbations
• The importance of dose and time
• Cost effectiveness
• Opposing points

5
GINA 2008

• ICS are effective as part of therapy for asthma
  exacerbations
• The combination of high-dose ICS
• salbutamol in acute asthma conferred
• greater benefit gt the addition of SCS
• across all parameters, hospitalizations,
• especially for patients with more severe attacks

6
NHLBI-EPR3

• Higher doses of ICS
• may be considered in ED
• Data are suggestive ,
• but further investigations with greater
• attention to dosing and severity level
• is required

7
MECHANISMS OF STEROID ACTION
8
Inhibits the synthesis of inflammatory proteins
by supression of the genes encode them
activation
4-12 h
supression
Engelbrecht Y Endocrinology
2003144412-422 Ito K J Exp Med
20062037-13
9
increase the synthesis of anti-inflammatory
proteins by activation of the genes encode them
Mak JCW Am J Physiol 19951241-46
10
Genomic Effects

• Genomic
• (implies the participation of cellular genome)
• The length of time between CS entry into the cell
  and the production of new proteins takes hours
  or days
• In concordance with the delay in clinical
  improvement (4 -12 h)
• The slowness of action is not surprising

11
Rapid Effects

• Some CS-induced effects (anesthesia)
• (only minutes after their application)
• Acute cardiovascular effects of aldosterone
• (after 5 min of its administration)
• Acutely decrease nasal itching in allergic
  rhinitis
• Cutaneus blanching by topical steroids in 2h

Selye H. Endocrinology 1942 30437453
Brown, P. H., Lancet 1991 337576580.
12
After a single dose of 2.4 mg of inhaled
budesonide

• at 6 h,
• an increase of FEV1 of 4
• a difference in airway eosinophils of 12,
• a significant change in the airway responsiveness

Gibson P , AJRCCM 1997155A289.
13
Acute Anti-inflammatory Effects of Inhaled
Budesonide in Asthma A Randomized Controlled
Trial
6h after a single dose 2,400 µg inh.
budesonide plt0.05
There may be another mechanism independant of
gene transcription process
Gibson P AJRRCM 200116032-36
14
Non-genomic effect

• Function by generating cAMP or protein kinases as
  a second set of messengers, produce a much faster
  responsewithin secs or mins mediated by
  receptors located in the cell membrane
• Membrane-binding sites for CS have been shown in
  ASM cells

Losel R,.Nat Rev Cell Biol 2003 44656
Horvath G, Am J Physiol Lung Cell Mol Physiol
2003 1011521158
15
GENOMIC EFFECT
NON-GENOMIC EFFECT
GR
CC
CC

R
DNA
Protein
Ca , K
mRNA
cAMP

Inflammation ?
Rodrigo GJ Arch Bronconeumol 200642 (10)533-40
16
SYNAPTIC SPACE
Sympathetic neuronal cell
Neuronal uptake (re-use)
CS ? airway blood flow by modulating
sympathetic control of vascular tone,
potentiating noradrenergic neurotransmission in
the airway vasculature.
Corticosteroids
Inhibit NA uptake
Norepinephrin

NA ?
EMT
? adrenoreceptör
CS-induced vasoconstruction
Extraneuronal uptake (metabolism)
Vascular smooth muscle cell
Horvath G, Wanner A. Eur Respir J 2006 27172187
17
Non-genomic effects on ASM

• ICS ? blood flow
• dose dependent
• (larger doses lead greater reductions)
• Transient
• (peaks 30 m, returning in 60-90m)
• Affected by baseline flow values
• (Greater baseline values lead greater
  reductions)
• Asthmatics mucosal blood flow (24-77) gt
  normals, Decrease greater in asthmatics

Kumar SD,. Am J Respir Crit Care Med 2000
161918921
18
direct relationship between the
ICS-induced airway blood flow decrease and
predrug airway blood flow
Simultaneous ICS bronchodilators Clinical
Significance
Kumar SD,Am J Respir Crit Care Med
2000161918921
19
Variables GENOMIC NONGENOMIC
Receptor location Cytoplasm Membrane
Onset Slow (h to d) Rapid ( s to min)
Actions Regulation of inflamatory gene transcription Inhibition of local catecholamines disposal
Target-effects Hyperperfusion ? Hyperpermeability? Leukocyte recruitment inhibition Hyperperfusion ?
Rodrigo G,Chest 20061301301-1311
20
Pharmacokinetics
21
ICS

• No differences in efficacy at equipotent doses
• Different formulations may exert different
  clinical activity
• Main variation is the side effect profile
• More consistent documentation in acute settings
  with Budesonide

Barnes NC Prim Care Resp J 200716(3)149-154
Corren J et al Ann Allergy Asthma Immunol 2001,
87405411
22
Lipophilic ICS less than optimal for the
treatment of acute airway obstruction

• Dissolution and lipophilicity
• Budesonide
• readily dissolved in human bronchial
  secretions
• rapidly absorbed irrespective of the site of
  deposition Fluticasone
• dissolution profile of lipophilic compounds
  different
• greater central deposition ,faster clearence
• commonest to show adrenocortical supression
• The rate of pulmonary absorption
• Mean absorption time Budesonide 0.8 h
• Fluticasone 5.9 h
• Absorption in asthmatics lt normal
• ( sp.fluticasone, less marked for BDP and Bud)

Volovitz B, Respir Med 2007 101, 685695
Barnes NC Prim Care Resp J 200716(3)149-154
23
Airway availability of fluticasone is severely
restricted by methacholine challenge designed to
decrease FEV1
when drug inhaled during bronchoconstriction,
plasma concentrations of fluticasone Lower
AUC
P0.003
Mortimer KJ Br J Clin Pharmacol.2007 64439-44
24
Comparative bronchial vasoconstrictive efficacy
of 3 ICSs in healthy volunteers and asthmatic
patients
higher potency of budesonide and fluticasone vs
BDP in asthmatics
More clinical importance in obstructed patients
BDP, FP , BUD Sagliklilarda 1, 3.3 ,
3.0 Astimlilarda 1, 1.9 , 2.7
Mendes ES, Eur Respir J 2003 21989-993
25
ADVERSE SYSTEMIC EFFECTS
26
Nebulized budesonide 1, 2 and 4 mg / Oral
prednisolone 5, 10 and 20 mg over 4 days

• Morning plasma cortisol
• Serum osteocalcin
• A significant dose-related suppression
• with prednisolone ,
• not with budesonide

Wilson AM, Chest 199811410227.
Rowe BH, Respir Med 20049827584.
27
Inhaled budesonide 200 and 800 ?g (pMDI and
spacer) /oral prednisolone 2.5 and 5 mg (7-10
days)

• Prepubertal school children
• A dose-related effect on osteocalcin
• for oral prednisolone but not for ICS
• Wolthers OD, et al Pediatr Pulmonol
  1993163416
• Smaller children 13 years
• Inh. budesonide no influence on serum or urinary
  cortisol or markers of bone turnover
• Hedlin G, . Acta Paediatr1999884851

28
Asthmatic children 1115 years old
received repeated bursts (less than 7
days) prednisone (12 mg/kg/day) for acute
exacerbations

• The adrenal dynamics
• (hypoglycemia and ACTH stimulation)
• Most children normal adrenal response,
• in those received more than 4 bursts /y
• a subnormal response

Dolan LM. J Allergy ClinImmunol 198780817 Abd
Al-Aziz AM ERS 2008 A4623
29

• Even short, intermitten courses of SCS have
  undesirable effects on bone metabolism
• The use of ICS may reduce this risk substantially
  

Hodsman AB, J Clin Endocrinol Metab
19917253040.
30
Clinical Data
31
ICS at acute worsenings
32
Doubling the dose of inhaled corticosteroids to
prevent asthma exacerbations randomised
controlled trial
No difference in Exacerbation rates or OS use
15
1 point
Harrison TW Lancet 2004363271-275
33
Doubling the dose of budesonide versus
maintenance treatment in asthma exacerbation
No difference
48 h
Fitzgerald JM Thorax 200459550-556
34
the use of short-termincreases in budesonide to
controlasthma worsening in patients already
receiving maintenance treatment with budesonide
100 ?g twice daily

• for 7 days at the first sign of an asthma
• exacerbation
• (defined as a 30 fall in PEFR on 2 consecutive
  days)
• the addition of budesonide 800 ?g daily at the
  onset of worsening was beneficial

Doubling not enough
Foresi A, Chest 20001174406.
35
Could immediate use of combination effect the
exacerbations ??
Worsening of asthma
INFLAMMATION
-15
-5
-10
5
0
10
15
Days before and after exacerbation
Tattersfield et al AJRCCM 1999
Partridge MR BMC Pulm Med 6132006
36
Clinical trials with combination inhalers
containing formoterol and budesonide used both
rescue and maintenance(9) (ngt25.000)
STEAM6 m vs ICS
Rabe 2006
STEP12 m vs. ICS
Scicchitano 2004
STAY12 m vs. ICS and Symbicort
OByrne 2005
COSMOS12 m vs. sal/flu
Vogelmeier 2005
SMILE12 m vs. Symbicort LABA or Symbicort
or SABA
Rabe 2006
COMPASS12 m vs. Symbicort or sal/flu
Kuna 2006
SOLO/CHAMPION6 m vs. best conv.
Sears 2006
AHEAD 6 m vs. sal/flu
Bousquet 2007
EOS 12 m vs.ICS (biopsy Eos)
37
SMILE
12-month double blind parallel All on
(BudForm) 160/4.5 µg x 2 maintanence
(Budesonide- Formoterol) Terbutalin 0.4 mg
n1141
Run-in
(Budesonide- Formoterol) Terbutalin 0.4mg rescue
R
(Budesonide- Formoterol) Formoterol 4.5 µg
n1140
(Budesonide- Formoterol) (Budesonide-
Formoterol) 160/4.5 µg n1113
n3394
Visit 1 2 3 4
5
6 Month -0.5 0 1
4 8
12
Rabe et al. Lancet 2006 368 74453
38
Severe exacerbations
Terbutalin
Severe ex. Patients ()
(Budesonide- Formoterol)
Formoterol
BudForm
25
20
Plt0.001
15
45?
27 ?
10
Benefit of Budesonide component
5

0
0
180
300
360
120
240
60
Days after randomisation
Rabe et al. Lancet 2006 368 74453
39
Morning PEF improvement
Morning PEF (L/min)
? morning PEF (L/min)
plt0.001
372
p0.004
20
15.3
364
15
10.6
356
10
7.9
Terbutalin
348
Formoterol
(Budesonid- Formoterol)
5
BudForm
340
0
(Bud - Form) Terbutalin
(Bud - Form) Formoterol
(Bud - Form) (Bud-Form)
0
40
120
200
280
360
Days after randomisation
Rabe et al. Lancet 2006 368 74453
40
SMILE

• Budesonide component of
• budesonide formoterol as needed
• results additional reductions
• related to the timing of ICS
• taken as needed
• (might supplement tissue concentrations at a
  time when the concentration remaining from the
  scheduled maintenance dose is suboptimum)

Rabe et al. Lancet 2006 368 74453
41
The greater the exacerbation risk, the greater
the benefit of budesonide/formoterol
AHEAD Study
Bousquet J, Respir Med 2007 101 (12) 2437-46
42
MECHANISMS

• Early increase in anti-inflammatory treatment
• Effect of high-dose budesonide on eosinophilic
  inflammation
• Effect of formoterol on neutrophilic inflammation
• (exacerbations)
• Complete protection by combination
• Non-genomic effects of as-needed budesonide
• (rapid vasoconstriction)

Bousquet J, Respir Med 2007 101 (12) 2437-46
43
ICS at exacerbations
44
Inhaled budesonide in the management of acute
worsenings and exacerbations of asthma A review
of the evidence
Volovitz B Respiratory Medicine (2007) 101,
685695
45
Rapid Effects of Inhaled Corticosteroids in Acute
AsthmaAn Evidence-Based Evaluation

• 17 studies on the early (1-4h) clinical impact of
  ICS in ED
• Moderate-severe asthmatics
• 3 BDP,1 Dex., 3 Flunis.,3 Flut.,8 Bud. (10
  nebulization)
• 8 ICS vs pla
• 3 ICSSS vs SCS
• 6 ICS vs SCS
• MD ? 3 doses at ? 30 m intervals
• SD ? 2 doses at ? 30m or ? 1 or more doses at
  gt30 m intervals

Rodrigo, GJ Chest 2006 13013011311
46
ICS present early (1-2h) beneficial effect in
MD protocols
Rodrigo, GJ Chest 2006 13013011311
47
Hospital admission rate (2-4h)
Discharge rate (2-3h)
ICS
nongenomic effect
ICS
Rodrigo, GJ Chest 2006 13013011311
48
Comparison of Inhaled Fluticasone with
IntravenousHydrocortisone in the Treatment of
Adult Acute Severe Asthma

• 106 patients

500mg IV Hydrocortisone
Fluticasone 3000?g/h (MDI every 10m for 3 h)
Rodrigo G.AJRCCM 2005 171 12311236
49
Fluticasone group showed greater improvements
compared with the hydrocortisone group. (p 0.05).
35
46
Rodrigo G.AJRCCM 2005 171 12311236
50
More evident in patients with the most severe
obstruction (baseline FEV1lt 1 L) (p 0.001)
FEVgt1L
FEVlt1L
Rodrigo G.AJRCCM 2005 171 12311236
51
higher rates of patients with the discharge
threshold at 90, 120, and 150 minutes More
evident in patients with the most severe
obstruction
FEVgt1L
FEVlt1L

• ICS may have an immediate and nongenomic
  beneficial effect in acute asthma

Rodrigo G.AJRCCM 2005 171 12311236
52

• high repetitive doses of either budesonide or
  fluticasone with a 48-day protocol, effective
  control of acute asthma exacerbations in young
  children at home

Volovitz B Journal of Asthma, 45561567, 2008
53
Additional Issues (Preventing Relapses)

• ICSs can be as effective as oral
  glucocorticosteroids at preventing relapses
• Lee-Wong M et al.. Chest 2002122(4)1208-13.
• Nana A et al Asthma 199835(8)647-55.
• Patients discharged from the emergency department
  on prednisone and inhaled budesonide have a
  lower rate of relapse than those on prednisone
  alone
• Rowe B et al. JAMA 1999281(22)2119-26.37
• A high-dose of ICS (2.4 mg budesonide daily in
  four divided doses) achieves a relapse rate
  similar to 40 mg oral prednisone daily
• FitzGerald JM eta l. Am J Respir Crit Care Med
  2000.251

54
The importance of High Doses

• SCS have a dose -response curve. High doses, no
  change in efficacy but side effects ?
• Beneficial effect of ICS at doses at least 5
  times more than maintenance dose
• Atypical dose-response effect in ICS than SCS

Volovitz B Respiratory Medicine 2007101, 685695
55
Why Higher Doses

• High dose effects may involve non-genomic effect
  of ICS
• These genomic effects
• dose-dependant
• need intervals not longer than 30 min
• (ICS-induced vasoconstriction peaks 30-60min)

Rodrigo G AMJRRC 1998157698-703
56
8 RCTs comparing oral corticosteroids / ICS
Single doses or multiple doses in prolonged
intervals smaller effects or no differences
between groups

• Budesonide
• 2400 mg via nebulizer as three doses of 800 mg
  at 30-min intervals
• 2000 mg via nebulizer every 8 h,
• 1600 mg via DPI, via MDI with spacer
• as three 400 mg doses at 30-min intervals,
• Dexamethasone 1.5 mg/kg via nebulizer,
• Fluticasone 1000 mg via nebulizer twice daily.
• At least as effective as oralcorticosteroids
• in controlling acute asthma attacks
• in the emergency setting

• high doses and
• high frequency of administration
• BENEFICIAL

the most important fact not the total dose ,
but the relationship between dose and timing of
administration.
Edmonds ML, Cochrane Database Syst Rev 2005(4).
57
Not Increasing a Single Dose
58
But Repeated Multiple Doses
59
The Minimum Effective Doses

• Nebulized
• Fluticasone 500 Mg every 15 min
• Budesonide 800 Mg every 30 min
• MDI via spacer
• Budesonide 400 Mg every 30 min
• Greater doses (fluticasone 500 Mg every 10 min
  by MDI) generated larger benefits
• To be administered during a minimum of 90 min

Rodrigo GJ Chest 20061361301
60
The Issue of Inflammation
61
Acute Anti-inflammatory Effects of Inhaled
Budesonide in Asthma A Randomized Controlled
Trial
6 h later plt0.05
Gibson P AJRRCM 200116032-36
62
Inhaled fluticasone propionate (MDI) is
effective as well as oral prednisone in reducing
sputum eosinophilia during exacerbations of asthma
High-dose-ICS a valid alternative to SCS not
only an improvement in pulmonary function but
also a short-term control of the increased airway
inflammation
Franco A et al, Pulm Pharm Ther 200619 353360
63
Anti-inflammatory effects of high-dose inhaled
fluticasone 4,000 mg/day MDI / oral prednisone30
mg/day in asthma exacerbations

• Spirometry
• Induced sputum for differential cell counts,
• Albumin
• ?2-macroglobulin levels
• Blood eosinophils,
• Interleukin-5
• Granulocyte macrophage colony-stimulating factor
• before and at 2, 6 and 24 h after treatment

Belda J, Eur Respir J 2007 30 11431149
64
F
P
as effective as prednisone in reducing plasma
exudation, bronchial obstruction and symptoms

• faster and stronger effect
• in reducing airway inflammation

P
F
Belda J, Eur Respir J 2007 30 11431149
65
Cost/Benefit Ratio
66

• In Turkey
• Budesonide nebule 0.25 mcg 30.14 TL/ patient
  6.2 TL
• Budesonide nebule 0.5mcg 45.11 TL /patient
   4.51 TL
• Systemic steroid Prednol amp, 1mg/kg 60 mg  7.06
  TL
• The cost of a 2 week treatment in Italy
• 27.4 for fluticasone and 5.2 for P
• This higher cost should be compared with the
  potential benefit of this option (lower rate of
  recurrence of exacerbations )
• This could result in an advantage of the
  inhalation treatment

Franco AD.Pulm Pharm Ther 2006 19353360
67

• Cost ?? , significant factor in the use of such
  high-doses of ICS
• Further studies required to document their
  potential benefits, especially cost
  effectiveness, in acute asthma

68
Opposing points
69
Deposition of drug in exacerbation

• Bronchospasm, air trapping, hyperinflation
• Delivery to distal airways not easy
• Largely deposited in the central airway
• Inflammation largely involves small airways
• Potentially harmful, (may cause a delay)

direct relationship between the
ICS-induced airway blood flow decrease and
predrug airway blood flow The more obstructed,
the more benefit
Foresi A. Curr Opin Pulm Med 2003, 95256
70

• may fail due to the viral contribution
• (not controlled by ICS)
• Neutrophil, mediated acute asthma ?

Could overcome by concurrent use of Formoterol
Foresi A. Curr Opin Pulm Med 2003, 95256
71
The only opposing study
fluticasone with prednisone

• Better outcomes
• in FEV1 and the requirement for hospitalization
• Single dose
• The decision for hospitalization after 4h
• (the beginning of genomic effects)

Schuh S, et al. New Engl J Med 200034368994.
72
Cortisol Supression

• 8.51 mg relative potency ratio between oral P
  and inhaled fluticasone
• 2000 mg fluticasone correspond to 17 mg of oral
  P
• Equivalent side effects??

ICS over multiple days more suppressive than
single high doses 1600Mg budesonide treatment
not associated with cortisol suppression
Wilson AM,. Br J Clin Pharmacol
19994857985. Franco A.Pulm Phar Ther
2006(19)353-360
Volovitz B, et al.. J Allergy Clin Immunol
19981026059.
73
Review inhaled corticosteroids reduce
hospitaladmission and increase discharge rate
during the first 4 hours in the emergency
department for acute asthma
COMMENTARY
ICS more effective than placebo or systemic
corticosteroids

• For a significant number of patients initial high
  doses of ICS may be the treatment of choice
• More evidence is needed
• on the changes in pulmonary function,
• added effect over SCS,
• type of patients who can be prescribed without
  SCS

Boulet LP, Evid. Based Med. 20071275
74
Conclusion

• ICS
• high doses and multiple administrations
• Control exacerbations
• Decrease the admission rates
• equally or better than SCS

75
REVIEW ARTICLEInhaled Corticosteroids in the
Treatment of Asthma Exacerbations Essential
Concepts

• ICS should not, however, be viewed as replacing
  SCS , which are considered to be a first-line
  treatment for asthma.
• The goal, rather, should be to use ICS to
  achieve an additional and early nongenomic
  effect, which may be particularly beneficial to
  patients with severe asthma or showing a poor
  initial response.

Rodrigo G. Arch Bronconeumol. 200642(10)533-40
76
Conclusion

• Optimal dose
• dose frequency
• duration of treatment
• delivery technique
• the additive benefit when used with SCS
• still debated

77

• Current data Suggestive
• Further controlled trials will be required before
  the use of ICS could be widely recommended in
  acute asthma

78
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