Role of corticosteroids in acute

asthma

Need for a corticosteroid treatment in asthma

Ideal treatment
Corticosteroids
Regular Controllers

Traditional
treatment
Occasional
Relievers

Need for a corticosteroid treatment in acute asthma

Systemic corticosteroids are considered in the management of all
but mildest exacerbations of asthma.
Both oral & IV steroids appear to have equivalent effects.
Extremely effective in reducing airway inflammation.
Corticosteroids given in moderate to high doses:
Speed resolution of exacerbations
Reduce admissions
Improve pulmonary function.
Corticosteroids are the most effective drugs to
suppress airway inflammation
Global Initiative for Asthma (GINA) 2009

Need for a corticosteroid treatment

Early intervention alters the chronic progressive nature of the
disease.
May play a key role in the reduction of permanent lung
damage.
Reduces the airway inflammation by:
Potent vasoconstriction activity in airway
Decrease activation & recruitment of inflammatory cells
Decrease secretion from mucus glands
Prevent leakage from endothelial cells

Clinics in chest medicine, vol 21, no. 2. June 2002

Anti-inflammatory
effects

Ann Intern Med. 2003;139:359-370.

Systemic Corticosteroids
Require between 6 to 24 hours to improve pulmonary function.
Dose response relationship is difficult to prove.
Even single short courses of SCS may cause HPA axis
suppression which rapidly returns to normal. But; markers of
bone metabolism can remain abnormal for several weeks.
There is striking inconsistency in the use of SCS to treat acute
asthma.
Chest 2006; 130:13011311
Clin Cornerstone 4 (6) :1-17, 2002
Expert Rev Clin Immunol 4 (6):723-729, 2008
Curr Opin Allergy Clin Immunol 3 (3): 169-175, 2003

Do we have other options?

Inhaled corticosteroids
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.
GINA 2009

Nebulised corticosteroids
Can effectively be used in:
Chronic severe asthma
Very effective in all patients with acute asthma
Rapid effects: 1-2 hrs to produce therapeutic effects
Topical effect: vasoconstriction in airway mucosa
A potential alternative to SCS in acute asthma not requiring
hospitalization.
In steroid dependent asthmatics to reduce the maintenance dose of oral
steroids thereby reducing the risk of adverse effects.
Chest 2006; 130:13011311
Clin Cornerstone 4 (6) :1-17, 2002
Expert Rev Clin Immunol 4 (6):723-729, 2008
Curr Opin Allergy Clin Immunol 3 (3): 169-175, 2003

Nebulization therapy is useful when Acute attacks of Asthma /COPD

Immediate relief is required
High doses of bronchodilators and steroids are to be given along
with the oxygen supply.
Patient is critical / unconscious
Unable to co-ordinate with inhaled devices like MDI/ DPI
Patients do not respond to regular treatment

Why nebulization?
Useful in acute symptoms of Asthma and COPD
Most convenient way to give optimal dose and targeted drug
delivery
Oxygen can be supplied along with the high dose drugs
Can be used in infants , children and elderly
Home management of severe conditions when patient is unable to
co-ordinate with inhalation devices
Intravenous drug delivery can lead to increased risk of side effects

 Require minimal patient cooperation and coordination

Do not require propellants
Aerosol generated has a high fine-particle fraction resulting
in highly efficient delivery

Guideline Recommendation
The combination of high dose inhaled corticosteroids and salbutamol
in acute asthma results in
Greater bronchodilation than salbutamol alone
Greater benefit than the addition of systemic corticosteroids
Reduced hospitalizations, especially for patients with more severe
attacks

GINA 2009

Why rapid effects with inhaled

corticosteroids?

A different mechanism of
action

Genomic action
of steroids

Phospholipase A2

Proc Am Thorac Soc 2004;1:255-63

European J Pharmacology 2008;585:483-91

New Engl J Med 2005;353:1711-23

Non-Genomic
action of steroids

Steroid S
Membrane
Receptor ?

Cell

Steroid
Receptor ?

Nucleus DNA

Ion
Channel
s?
Enzymes ?
Transporters ?
eNO ?

Genomic vs. Non genomic

Flohale respules

Fluticasone propionate
Topically active glucocorticosteroid
Derived from the 17-carbothioate series
of androstane analogues
Halogenated with two fluorines
substituted at positions 6 and 9
This helps to increase the potency

High lipophilicity
Increased deposition in the lung
Slower release from the lung/ lipid compartment
Longer pulmonary residence time
Prolonged exposure of drug to receptor
Increased anti inflammatory effect

Lipophilicity - Fluticasone >BDP>Budesonide

300 times more than budesonide
3 times more than BDP

High anti-inflammatory activity

Lipophilicity

Fluticasone

Budesonide

300

High lipophilicity of fluticasone so ensures high antiinflammatory activity

Vasoconstrictor
Potency

Fluticasone

Budesonide

Higher vasoconstrictor potency of fluticasone ensures higher

topical activity at half the dose of budesonide.

Safe corticosteroid
Oral bioavailability

Fluticasone

Budesonide

< 1%

11%

Lesser oral bioavailability of fluticasone ensures

least systemic side effects, giving you the reason to
trust Flohale respules

Long Acting
Relative receptor
affinity

Fluticasone

Budesonide

1800

935

Higher affinity towards receptor of fluticasone increases uptake and

retention in airway tissue.
Thereby making Flohale respules a long acting corticosteroid

Nebulised Fluticasone
Clinical efficacy and safety

 Multi-centre, randomized, double-blind, parallel group design

N = 321
Aged 4-16 years old
Presented with an acute exacerbation of asthma
Randomly allocated to either
Nebulized FP (1 mg BID) or
Oral prednisolone for 7 days
Respir Med. 2000 Dec;94(12):1206-14.

Lung function
PEF (L/min)

Respir Med. 2000 Dec;94(12):1206-14.

FEV1 & FVC

(liters)

Respir Med. 2000 Dec;94(12):1206-14.

Morning & evening PEFR

Respir Med. 2000 Dec;94(12):1206-14.

Results
Both treatments reduced symptom scores to a
similar
extent.FP is at least as effective as oral
Nebulized

prednisolone in the treatment of an acute

The two treatments
were well
tolerated, and there
exacerbation
of asthma.
was no difference in the incidence of adverse
events.

Respir Med. 2000 Dec;94(12):1206-14.

Multicenter, randomized, double blind, double dummy,

parallel group study
N = 413
Mean age= 43 years
Primary outcome = treatment failure
PEF < 60%
Symptom score 3
Patient withdrawal
Fluticasone propionate (2 mg daily)
A short reducing course of oral prednisolone (starting at 40
mg / day and reducing by 5 mg every other day)

Thorax 1996;51: 1087-1092

Proportion of treatment
failure

A=FP
B= PDN
Thorax 1996;51: 1087-1092

Morning PEF

Thorax 1996;51: 1087-1092

Conclusion
There is no evidence of a significant difference in
efficacy between a reducing dose course of oral
prednisolone and high dose inhaled fluticasone
propionate in mild exacerbations of asthma which
do not require admission to hospital.

Thorax 1996;51: 1087-1092

 N=106
Mean age = 33.5 + 8.8 years
Randomly assigned to receive
Fluticasone (3 mg/hour) or
500 mg of intravenous hydrocortisone.

Am J Respir Crit Care Med. 2005 Jun 1;171(11):1231-6.

Fluticasone group showed 30.5 % greater improvements in PEF

compared with the hydrocortisone group.

Am J Respir Crit Care Med. 2005 Jun 1;171(11):1231-6.

Fluticasone group showed 46.4% greater improvements in

FEV1compared with the hydrocortisone group.

Am J Respir Crit Care Med. 2005 Jun 1;171(11):1231-6.

RESULTS
Fluticasone group showed higher rates of
patients who obtained the discharge
threshold.
Subjects treated with fluticasone showed a
significant decrease in hospitalization rate
(p = 0.05)
The use of repeated doses of inhaled fluticasone
was more effective than intravenous hydrocortisone
associated with an early improvement
Am J Respir Crit Care Med. 2005 Jun 1;171(11):1231-6.

 Locally delivered steroids by inhalers or

nebulizers have been shown in small trials to
be effective in acute asthma attack.
N = 73; Age = 17-75 years

IMAJ 2008;10:568571.

Objectives:
To determine the efficacy of nebulized compared to
systemic steroids in adult asthmatics admitted to the
emergency department following an acute attack.
Methods:
Adult asthmatics admitted to the ED were assigned in
random consecutive case fashion to one of three
protocol groups:

IMAJ 2008;10:568571.

Mean PEFR (% of predicted)

IMAJ 2008;10:568571.

IMAJ 2008;10:568571.

Conclusion
This study cohort showed the advantage of
nebulized steroid fluticasone vs. systemic
corticosteroids in adult asthmatics managed
in the ED following an acute attack.
Results suggest that nebulized steroids
should be used, either alone or in
combination with systemic steroids, to treat
adults suffering acute asthma attack.

IMAJ 2008;10:568571.

 N= 40
Mean age= 45 + 13 years
Duration= 24 month
Compared biological markers along with clinical &
functional parameters.
During attack, sputum was collected spontaneously or
by induction.
Pulmonary Pharmacology & Therapeutics 19 (2006) 353360

Results

FP is effective at least as well as P in reducing sputum eosinophilia

and in improving airway obstruction due to asthma exacerbation.

Pulmonary Pharmacology & Therapeutics 19 (2006) 353360

 Multicenter, randomized, single-blind, parallel group

design.
N= 168
Age= 4-15 years
randomly allocated to receive either nebulized FP
(250 mcg) or nebulized BUD (500 mcg) twice daily
for 10 days.
J Asthma. 2005 Jun;42(5):331-6

RESULTS

Improvement of morning PEF was

significantly higher in patients treated with
FP.

There was no evidence of HPA axis

J Asthma. 2005 Jun;42(5):331-6

Conclusion
A short course of nebulized FP has the
same effects as a double dose of nebulized
BUD, when either drug is added to
bronchodilator therapy in children with mild
asthma exacerbation.

J Asthma. 2005 Jun;42(5):331-6

Multinational, multicentre, randomized, active-controlled,

parallel-group study

N=205; 12 weeks

Age= 18-65 years

Moderate persistent asthma, randomized to either

Respir Med. 2003 Feb;97 Suppl B:S35-40

Respir Med. 2003 Feb;97 Suppl B:S35-40

Results
The two treatments were equally well
tolerated.
Fluticasone propionate 2,000 mcg / day, is
equally effective, with an acceptable
safety and tolerability profile, when used
in adult patients with moderate persistent
asthma.

Respir Med. 2003 Feb;97 Suppl B:S35-40

 Randomized, double-blind study,

Nebulized FP 2 mg BID (4 mg) vs. 0.5 mg BID (1 mg) with placebo
N= 301
Adult patients with oral steroid-dependent asthma.
Primary efficacy = reduction in daily oral steroid dose.
Secondary efficacy parameters
Daily diary card peak expiratory flow (PEF),
Day and night-time symptoms
Clinic lung function measurements
Safety was assessed by adverse event monitoring and serum cortisol levels.

Respir Med. 1999 Oct;93(10):689-99

*P=0.039 for FP 1 mg
+P=0.004 for placebo

After 12 weeks of treatment the adjusted mean reduction in

oral prednisolone was significantly greater in the FP 4 mg
group compared other groups.

Respir Med. 1999 Oct;93(10):689-99

*P=0.038 for FP 1 mg
+P<0.001 for placebo

A higher percentage of patients discontinued the use of oral

steroids with FP 4 mg compared with other groups.

Respir Med. 1999 Oct;93(10):689-99

PEFR improvement over 12

weeks

Respir Med. 1999 Oct;93(10):689-99

FEV1 improvement over 12

weeks

Respir Med. 1999 Oct;93(10):689-99

Other results

FP 4 mg resulted in a significantly higher percentage of days

when the patients were free from daytime (P = 0.036) and
night-time (P = 0.021) wheeze, compared with placebo.

Significantly fewer patients withdrew from the FP 4 mg group

compared with the other two groups.

All three treatments were well tolerated and the incidence of

adverse events was similar between the groups.

FP Nebuliser suspension at a daily dose of between 1 and 4 mg are a safe

and effective means of reducing the oral steroid requirement of patients
with chronic oral steroid dependent asthma

Respir Med. 1999 Oct;93(10):689-99

 The Inhaled Steroids in Obstructive Lung Disease in Europe

(ISOLDE) study in COPD
26% reduction in the yearly rate of exacerbations in patients
treated with FP compared to placebo.
Data support recommendations in the GOLD treatment
guidelines that ICS should be considered in patients with
moderate-to-severe COPD who experience recurrent
exacerbations.

Proportion of patients experiencing

1 corticosteroid-treated exacerbation/year in
placebo ( ) and fluticasone propionate treated ( ) patients

Summary
Fluticasone propionate 2 mg / day is
effective, with an acceptable safety and
tolerability profile, when used in adult
patients with moderate persistent asthma.
Nebulized fluticasone propionate is at least
as effective as oral prednisolone in the
treatment of acute exacerbation of asthma.
Nebulized fluticasone propionate is more
effective than intravenous hydrocortisone
and is associated with an early
improvement.

Summary
A short course of nebulized fluticasone
propionate has the same effects as a double
dose of nebulized BUD.
Nebulized fluticasone propionate at a daily
dose of between 1 and 4 mg are a safe and
effective means of reducing the oral steroid
requirement of patients with chronic oral
steroid dependent asthma.

HIGHLIGHTS
FP is first and the only nebulized corticosteroid
approved for acute exacerbations of asthma in children
4 to 16 years.
Associated with faster clinical improvement.
Option for treatment of mild acute asthma attacks not
requiring hospital admission.
Option for oral & IV steroids, in treatment of mildmoderate acute asthma.
Reduces dependence on oral steroids when used as
maintenance therapy.

INDICATIONS
Flohale respules
For prophylactic management of severe chronic
asthma in patients requiring high dose inhaled or
oral corticosteroid therapy.
On introduction of fluticasone propionate many
patients currently treated with oral corticosteroids
may be able to reduce significantly, or eliminate,
their oral dose.

DOSAGE AND ADMINISTRATION

Adults and adolescents over 16 years:
500-2,000 micrograms twice daily.
Volume of FLOHALE respules for nebulisation
Dosage in mg

0.5 mg / 2 ml

2 mg / 2 ml

0.25 mg

1 ml*

0.5 mg

2 ml

0.75 mg

3 ml

1 mg

1 ml

1.5 mg

1.5 ml

2 mg

2 ml

3 mg

3 ml

4 mg

2 respules

* To be mixed with 0.9 % saline to make up a volume of at least 2 ml

PACKSHOTS