Inhaled corticosteroids in acute asthma

3. Inhaled corticosteroids in acute asthma

4. Dr. Ashraf El Adawy
Consultant Chest Physician
TB TEAM EXPERT – WHO
Mansoura- Egypt

5. Airway
inflammation
Airflow
obstruction
Bronchial
hyperresponsiveness
Symptoms
Asthma Pathophysiology
The tip of the iceberg

7. Asthma patients may experience exacerbations or crises, the intensity of which range from mild episodeswhich may even go unnoticed by the patientto extremely serious episodes that place a patient's life at risk and may even result in death (fatal or near-fatal asthma).
7

8. Severe asthma exacerbations are potentially life- threatening medical emergencies and treatment requires close supervision
The most relevant factor when deciding treatment, consequently, is the severity of an asthma crisis
8

9. life threatening asthma
Evidence
useful vs harmful

10. Basic treatment of acute asthma

11. Emergency Department and Hospital Management: Goals
1.Correction of significant hypoxemia
2.Rapid reversal of airflow obstruction
3.Reduction of likelihood of recurrence

13. Established Management of Acute Asthma
1.Oxygen therapy
2.Bronchodilators
3.Systemic corticosteroids
ICS potential benefit ???

14. MECHANISMS OF STEROID ACTION

15. The evidence indicates that the use of oral or parenteral corticosteroids reduces hospitalizations and improves lung function,can lead to control of airway inflammation and prevention of relapses
Systemic steroids are slow to take effect (6 to 12 hours) because they depend on complex cellular mechanisms (Genomic effect)

16. The evidence indicates that the use of oral or parenteral corticosteroids reduces hospitalizations and improves lung function,can lead to control of airway inflammation and prevention of relapses
Systemic steroids are slow to take effect (6 to 12 hours) because they depend on complex cellular mechanisms (Genomic effect)

17. Mechanism of Action for Steroid Hormones
Blood vessel Cell membrane Nucleus DNA Endoplasmic reticulum

18. Carrier protein
Steroid hormone
Mechanism of Action for Steroid Hormones

19. Steroid receptor
Mechanism of Action for Steroid Hormones

20. Transcription of mRNA
Mechanism of Action for Steroid Hormones

21. Mechanism of Action for Steroid Hormones
Translation of new protein
New protein produces change in cellular activity

23. Genomic Effects of CS The classic antiinflammatory effects implicate the activation or repression of multiple genes involved in the inflammatory process. Thus, SCS produce their effects on cells by activating glucocorticoid receptors that alter transcription through direct DNA binding or transcription factor inactivation. As a consequence, SCS increase the synthesis of antiinflammatory proteins, or inhibit the synthesis of many inflammatory proteins through suppression of the genes that encode them.

24. 24

28. β2-receptor IқB IL-10 Lipocortin
*Mak JCW Am J Physiol 1995;12:41-46
increase the synthesis of anti-inflammatory proteins by activation of the genes encode them

29. (4 h*)
(6-12 h)**
* Engelbrecht Y Endocrinology 2003;144:412-422
** Ito K J Exp Med 2006;203:7-13
Supression
Activation
4-12 h
Inhibits the synthesis of inflammatory proteins
by supression of the genes encode them

31. Systemic Glucocorticoids in acute severe asthma
Barnes PJ & Aldock IM. (2003) How Do Corticosteroids Work in Asthma? Ann Intern Med,.
This takes hours and hours and hours and hours

32. Biological Bases for the Effects of Corticosteroids
The classical anti-inflammatory action, in which corticosteroid molecules are diffused across the target cell membrane and bind with corticosteroid receptors in the cytoplasm .
The corticosteroid-receptor complex is then rapidly transported to the cell nucleus, where it binds to specific DNA sequences and changes the gene transcription mechanism so that messenger RNA molecule synthesis is activated, leading to the production of new proteins. Corticosteroids reduce inflammation, therefore, by increasing the synthesis of anti-inflammatory proteins

33. As the cell genome is involved in this mechanism, this anti-inflammatory effect is referred to as a genomic effect.
In terms of response, after the corticosteroid molecule enters the cell, hours or even days may elapse before significant quantities of new proteins are produced.
This explains the 6 to 12 hours' delay (demonstrated by clinical trials) in detecting the beneficial action of systemic corticosteroids.

34. 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)

35. Non-genomic effect
●Function by generating cAMP or protein kinases as a second set of messengers, produce a much faster response–within secs or mins– mediated by receptors located in the cell membrane
●Membrane-binding sites for CS have been shown in ASM cells
●cAMP, increase the cell permeability of a number of ions
Losel R,.Nat Rev Cell Biol 2003
Horvath G, Am J Physiol Lung Cell Mol Physiol 2003; 10:1152–1158

36. Protein
CC
GENOMIC EFFECT
NON-GENOMIC EFFECT
CC
R
Ca ,
K
cAMP
mRNA
DNA
GR
Inflammation 
Rodrigo GJ Arch Bronconeumol 2006;42 (10):533-40

37. More recently, however, it has been demonstrated that the corticosteroids have biological effects that are independent of the gene transcription process.
Most of the research on this nongenomic effect has been performed in the last 10 years
The nongenomic effects of corticosteroids, which function by generating cyclic adenosinmonophosphate or protein kinases as a second set of messengers, produce a much faster responsewithin seconds or minutesthat is mediated by receptors located in the cell membrane.

38. More recent research has centered on the nongenomic effects of inhaled corticosteroids on the airways, most particularly on mucosal blood flow in both asthmatic and healthy subjects.
These studies show that there is a significant increase in mucosal blood flow in asthmatic patients compared to healthy subjects, and that inhaled steroids has the effect of reducing flow by causing vasoconstriction.
The reduction is transient, however, reaching a peak 30 minutes after administration of the corticosteroid and returning to baseline values after 90 minutes

39. inhaled corticosteroids can present early therapeutic effects (after minutes of its administration) suggesting a different mechanism of action of topical character (Rapid nongenomic effect) This rapid response suggests a topical effect (airway mucosa vasoconstriction).

40. Blood flow reduction in the airway mucosa is a consequence of the acute vasoconstrictive effect of ICS on the smooth muscle of mucosal blood vessels (Rapid nongenomic effect).

41. Acute corticosteroid effects produced on the smooth muscle cell in airway mucosal blood vessels.

42. Vascular smooth muscle cell
Sympathetic neuronal cell
-
Corticosteroids
Norepinephrin
Neuronal uptake (re-use)
Extraneuronal uptake (metabolism)
EMT
 adrenoreceptör
Inhibit NA uptake
NA 
CS-induced vasoconstruction
Horvath G, Wanner A. Eur Respir J 2006; 27:172–187
SYNAPTIC SPACE
CS  airway blood flow
by modulating sympathetic control of vascular tone,
potentiating noradrenergic
neurotransmission in the airway vasculature.

43. The sympathetic nerve endings that form synapses with smooth muscle cells release norepinephrine to the synaptic space, where it binds to the α - receptors of the muscle cells, causing the muscles to contract.
There are a number of mechanisms that control the quantity of norepinephrine released to the synaptic space and, consequently, the extent of receptor stimulation.

44. In one mechanism, some of the neurotransmitter molecules are taken back up into the presynaptic nerve terminal so that they can be reused at a later stage.
In a second mechanism, norepinephrine is taken up in the muscular postsynaptic endings, where it is metabolized by intracellular enzymes such as monoaminoxidase and catechol-O- methyltransferase.
44

45. Corticosteroids inhibit the second of these norepinephrine uptake mechanisms, by allowing neurotransmitters to accumulate in the synaptic space and stimulate the α -receptors.
This in turn, leads to vasoconstriction of the smooth muscles of mucosal blood vessels (Rapid nongenomic effect)..

47. 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%) > normals, Decrease greater in asthmatics
Kumar SD,. Am J Respir Crit Care Med 2000; 161:918–921

49. 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 Angiogenesis
Hyperperfusion 
Rodrigo G,Chest 2006

52. Inhaled Corticosteroids in the Treatment of Asthma Exacerbations: Essential Concepts
Dr. G.J. Rodrigo
Arch Bronconeumol. 2006

53. Conclusions:
Data suggests that ICS present early beneficial effects (1 to 2 h) when they were used in multiple doses administered in time intervals < 30 min over 90 to 120 min.
The nongenomic effect is a possible candidate (CHEST 2006)

54. Conclusions
According to recent studies on the topical nongenomic effects of inhaled corticosteroids on the increased mucosal blood flow experienced by asthma patients, corticosteroids cause vasoconstriction by enhancing norepinephrine action during synapsis between sympathetic endings and smooth muscle cells in the mucosal vasculature.
 This has the effect of reducing blood flow and airway obstruction, and the result is a rapid increase in spirometric values and improvement in clinical variables.
Nonetheless, it must be remembered that even though the effect is rapid, it is also transient, depends on the dose administered, and increases in direct proportion to blood flow.

55. The nongenomic effect occurs within minutes, is transient, is dose-dependent, and is proportional to the initial hyperperfusion level.
Inhaled corticosteroids should, essentially, be administered frequently and in high doses in order to maintain the effect, most particularly in patients with severe obstruction.
55

56. The vasoconstrictive effect is not specific, it is more potent with budesonide and fluticasone than with beclomethasone. These factors should be taken into consideration in regard to rational use of inhaled corticosteroids to treat asthma exacerbations.
Inhaled corticosteroids should be used concurrently with bronchodilators and should be administered frequently, at short intervals and at high doses in order to maintain the effect over time
Multiple doses of inhaled corticosteroids administered at short intervals (10 to 30 minutes) result in early benefits (1 to 2 hours) in spirometric and clinical variables, irrespective of the initial severity of the asthma.

57. In Acute Asthma,
Addition of Pulmicort nebulising suspension to
Nebulised bronchodilator results in
Improved PEFR
More discharged patients
PEF(L/min)
PEFR after 60 mins.
Discharged after 60 mins.
% of discharged patients
***
***
Pulmicort neb. susp.
Plus neb. Bronchod.
Neb. bronchodilator
***
P < 0.005
Ref. Bautista MS et al Eur Respire J 1994

58. Inhaled budesonide in the management of acute worsenings and exacerbations of asthma: a review of the evidence.
The efficacy seems to benefit from high doses given repeatedly during the initial phase of an acute exacerbation..
The current evidence base revealed encouraging results regarding the efficacy of the ICS budesonide in patients with wheeze and acute worsening of asthma
Respir Med. 2007 Apr

59. Budesonide inhalation suspension in acute asthma
Five-day course of budesonide inhalation suspension is as effective as oral prednisolone in the treatment of mild to severe acute asthma exacerbations in adults
CONCLUSION:
Budesonide inhalation suspension may be an alternative treatment of acute asthma exacerbation in adults who are at risk for systemic corticosteroids.
Pulm Pharmacol Ther. 2011 Apr

60. -1.6
-1.2
-0.8
-0.4
0
Symptom score
(change from baseline)
B
P
Pulmicort Respules
Wheeze
Shortness
of breath
Prednisolone
Pulmicort Respules
Prednisolone
Higenbottam et al. BioDrugs 2000;14:247–254
24 hours
48 hours
*
*p < 0.05
*
PulmicortNS ® in severe asthma exacerbations in adults – symptoms
14 mg every 8 hrs
240 mg at 0, 24 and 48 hrs
www.sinagroup.net
*

61. 0
0.4
0.8
24 hours
48 hours
FEV1 (change from baseline)
Higenbottam et al. BioDrugs 2000;14:247–254
Pulmicort Respules
(4 mg every 8 hours)
Prednisolone
(40 mg at 0, 24 and 48 hours)
Pulmicort NS in severe asthma exacerbations in adults – FEV1

62. 0
100
90
80
70
60
50
40
30
20
10
Pulmicort
Prednisolon
Endobroncheal Dose mg/ml
Bai et al. ATS 2001
Pulmicort
Respules
(4 mg TID)
Prednisolone
(60 mg / day)
ICS & PO steroid in acute asthma Local & systemic concentration
www.sinagroup.net
Systemic Dose mg/ml
100
90
80
70
60
50
40
30
20
10
0

63. Pulmicort Respules
Prednisolone
12
10
8
6
4
2
Relapse rate %
P = NS
FitzGerald JM et al. 2001
10 days after treatment initiation
www.sinagroup.net
Pulmicort® Respules® in severe asthma exacerbations in adults – on relapse rate

64. Pulmicort NS
Prednisolone
0.24
0.22
0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0
Absolute change in FEV1 (L)
Pulmicort® Respules® as an alternative to oral steroids in acute paediatric asthma
*
*p<0.01 vs baseline
Matthews et al. Acta Paediatr 1999;88:835–840
24 hr after treatment initiation

66. 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 > the addition of SCS
across all parameters, hospitalizations,
especially for patients with more severe attacks

67. Additional Issues (Preventing Relapses)
●ICSs can be as effective as oral glucocorticosteroids at preventing relapses
Lee-Wong M et al.. Chest 2002;122(4)
Nana A et al Asthma 1998
●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.
●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 1999

68. 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 2007;101, 685–695

69. 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 1998

70. 8 RCTs comparing oral corticosteroids / ICS
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 oral corticosteroids
in controlling acute asthma attacks
in the emergency setting
Edmonds ML, Cochrane Database Syst Rev 2005
High doses and
high frequency of administration
BENEFICIAL
Single doses or multiple doses in prolonged intervals smaller effects or no differences between groups
The most important fact not the total dose , but the relationship between dose and timing of administration.

71. Conclusion
ICS
high doses and multiple administrations
●Control exacerbations
●Decrease the admission rates
equally or better than SCS

72. Inhaled Corticosteroids in the Treatment of Asthma Exacerbations: Essential Concepts
ICS may have an immediate and nongenomic beneficial effect in acute asthma
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. 2006

73. Ann Thorac Med 2009; 4(4): 216-233

74. •Cost ?? , significant factor in the use of such high-doses of ICS
●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
Cost/Benefit Ratio

75. Corticosteroids are not bronchodilators
Effective as a part of therapy for asthma exacerbations.
Targeted delivery
Evidence for greater bronchodilation when beta agonists used along with ICS.
Can be as effective as OCS in preventing relapses.
Less dosages required to produce therapeutic effect compared to OCS.
75
Nebulised corticosteroids
GINA 2008

77. 77