ASTHMA MANAGEMENT

LONG-TERM THERAPY

Inhalation therapy is the mainstay therapy

Gaps between treatment goal and the reality
THE GOAL
• • • • no chronic symptoms no asthma attacks no emergency visits no need for quick relief (as needed) ß2-agonist • normal physical activity including exercise • lung function as close to normal as possible • no adverse effects from medicine

THE REALITY
   

Frequent chronic symptoms Some asthma attacks Some emergency visits Excessive use of ß2-agonist as reliever Impaired physical activity including exercise Some “ups” and “downs” in lung function Frequent adverse effects from medicine

Pathogenesis of asthma

Pathogenesis of asthma
(NHLBI/WHO 1995)

Environmental risk factor

Inflammation

Symptoms
Airway hyperresponsiveness Airflow limitation

Triggers

Asthma is an inflammatory disease

Inflammation (–) (+)
Triggers
• • • • • • • • •

Normal
Bronchial hyperreactivity (-)

Asthma
Bronchial hyperreactivity Symptoms (+)

Symptoms (-)

Ig E

YY
Methyl transferase

Ag

Ca++ Histamin
Phosphatidyl ethanolamine Phosphatidyl choline

Phospholipid

Arachidonic acid lypoxygenase cyclooxygenase
5-HETE Leucotrienes LTB4 LTC4 LTD4 LTE4
Mediator release in asthma reactions

Phospho lipase A2 Ca++

Histamin ECF, NCF

Thromboxanes Prostaglandins TXA2 PGD PGF2α

Diagnosis Data

Analisis

Planning

Diagnosis

Data:
Batuk Sesak Mengi Keluarga asma Obat asma

Analisis
Asma Pem.Fisik Spirometri APE Tes Provokasi

Planning

FVC / KVP the total volume forcibly exhaled FEV1/ VEP1 the amount exhaled in the first second

6 5

Volume (liters)

4 3 2 1 0 1 2 3 4 5 6

FEV1

FVC

Time (sec)
Fig 2. Normal forced expiration curve

Peak Flow Meter /PEFR/APE

ASTHMA PROFILE

ASTHMA PROFILE IN THE WORLD
Globally, over 150 million people diagnosed with asthma Globally, over 180,000 people die from asthma each year Globally, the economic burden of asthma are estimated to be greater than TB and HIV/AIDS or combined Major factors contributing to asthma morbidity and mortality are underdiagnosis and inappropriate treatment

PATIENT’S ( Yayasan Asma Indonesia Wilayah SumateraUtara , 200, 93-95) PROFILE
•More than one year •Used anti inflammation •Used objective values •Inhaller tehnique (poor ) •Compliance •Dose interval 93 % 25 % 9% 92 % 19 % 17 %

( Yayasan Asma Indonesia Wilayah Sumatera Utara, 300, 96-99)

PATIENT’S PROFILE

•More than one year •Used anti inflammation •Used objective values •Inhaller tehnique (poor ) •Compliance •Dose interval

96 % 32 % 7% 89 % 23 % 21 %

Reflected in Indonesian Asthma Market (IPMG Nov 2001)

5%

3% 1%

11%

4%

46%

Inhaled b2-agonist Oral b2-agonist Xanthines NS Antiinflammatory Inhaled Steroid Anticholinergics Antileukotriene Other

5%

25%

World Asthma Market (IMS 2000)
1% 16%
b2-agonist Xanthines NS Antiinflammatory Inhaled Steroid Anticholinergics Antileukotriene Other

30%
5%

6%

7%

35%

Change paradigm of asthma
To/ Symptoms control To/ Diseases control

Anti Inflammations is the mainstay therapy

Inflammation

Controller

Bronchial hyperreactivity
Reliever

Symptoms
Pathogenesis of asthma

Natural History of Asthma

•UNCORRECT TREATMENT

CURE

CHRONIC ASTHMA AIRWAY REMODELLING

PERSISTENCE OF INFLAMMATION AIRWAY REMODELLING

CHRONIC ASTHMA

AIRWAY REMODELLING IN ASTHMA

•Desquamation of epithelium •Increase in airway smooth muscle •Vascular proliferation •Collagen deposition •Thickening of basement membrane •Increase in bronchial glands •Vascular congestion •Oedema formation •Cellular infiltration

Epithelial Damage

P Jeffery, in: Asthma, Academic Press 1998

AIRWAY REMODELLING IN ASTHMA

rmac Pha

etic ? okin
Eosinophil

Desquamation of epithelium

MBP, ECP
Epithelium

Thickening of basement membrane Increase in airway smooth muscle

Basement Membrane Thickening

P Jeffery, in: Asthma, Academic Press 1998

Smooth Muscle Hyperplasia

P Jeffery, in: Asthma, Academic Press 1998

Fatal Asthma

Jeffery, 1994

FE V

1

Symptom Exacerbatio n Symptom

lin odel Rem g

Time

Era of Asthma management
1930th 1960th 1970th 2000th 2003th : Xanthin : Beta2-agonist : Steroid inhallation : Combination : Single inhaler combination

Steroid depo ?

Evolving treatment options
Large use of short-acting ß2-agonists 1975 ICS treatment introduced 1972 Adding LAßA to ICS therapy
Kips et al, AJRCCM 2000 Pauwels et al, NEJM 1997 Greening et al, Lancet 1992 Single

inhaler therapy (Symbicort®) “Fear” of short-acting ß2-agonists

1980

1985 1990
Bronchospasm Inflammation

1995
Remodelling

2000

Controller: Anti inflammation Non steroid Steroid

• budesonide • sodium chromoglicate (Pulmicort®) (Intal®) (Inflamid®) • beclomethasone dipropionate • sodium nedocromil (Becotide®) • ketotifen • triamcinolone acetonide

Mild Asthma has Airway Inflammation ICS Reverses Inflammation
E BM E

BM

Pre and post 3 month treatment with BUD 600 µg bd

Laitinen, J Allergy Clin Immunol, 1992

Reliever
Bronchodilator
∀β
2

- agonist

• Xanthin •Anticholinergic

BRONCHODILATOR
Short Acting β
2

AGONIST (SABA):

Long Acting β (LABA)

2

AGONIST:

* salbutamol/albuterol (Ventolin ®) * terbutaline (Bricasma®) * procaterol * fenoterol * orciprenaline, etc
ANTICHOLINERGIC:

•salmoterol •formoterol

XANTHINE:

* atropine sulfate * ipratropium bromide, etc

* theophylline

OTHER SYMPHATOMIMETIC:

* ephedrine * adrenaline, etc

GINA guidelines 1998/2002: Focus on ICS and ß2-agonists
Mild Intermittent persisten t Moderate persisten t Severe persisten t

Short-acting ß2 prn ICS Long-acting ß2
Symbicort not specifically mentioned

Healthy Subjects Healthy Subjects

Asthma in Remission Asthma in Remission

Increased Membrane Basic Protein (MBP) positive area ( the red stain stai and epithelial shedding in the subject in clinical remission.

Van den Toom. AJRRCM 2001; 164: 2107-13

Guidelines on Asthma: Past and Current Trends
Mild Intermittent persisten t Moderate persisten t Severe persisten t

GINA 1998 (adapted) Current evidences

Short-acting ß-agonists2 prn

ICS

LABA+ICS LABA+ICS

The rationale behind fixed combination therapy
 To

increase adherence to controller gain better control with less inhaled

therapy
 To

steroid

ADULT PATIENTS & CAREGIVERS OF CHILDREN WITH ASTHMA WERE ASKED “WHY THEY DID NOT TAKE THEIR INHALED CORTICOSTEROID AS PRESCRIBED?”

 45% said they just forgot  42% said that they felt
well
Stahl AJRCCM, 2002

Combinations once- or twice-daily dosing offers convenient than single dosing
Change in morning PEF (L/min)

35 30 25 20 15 10 5 0 -5 -10 0 10 20 30 40 50 Treatment days 60 70 80 90
p<0.001 both treatments vs. budesonide alone

Symbicort® 160/4.5 µg 2 inhalations od
Buhl et al, Am J Respir Crit Care Med 2001

Symbicort® 160/4.5 µg 1 inhalation bid

budesonide 200 µg 2 inhalations od

Combination therapy
Symbicort®
Budesonide + Formoterol

Seretide®
Fluticasone + Salmoterol

The Beginning of Treatment

Exacerbation

The beginning of treatment

?

Stable condition

Peak flow meter

Objective value

600-700 (

normal )

300

0

PEFR Monitoring: A Major Tool in Asthma Self-Management
Chronic Diseases Hypertension Monitor Blood pressure

Diabetes

Serum glucose

Asthma

PEFR

THE GOALS FOR SUCCESSFUL MANAGEMENT OF ASTHMA
( NHLBI / WHO, 1995)

• Achieve and maintain control of symptoms •Prevent asthma exacerbations • Maintain pulmonary function as close to normal levels as posible •Maintain normal activity levels, including exercise •Avoid adverse effect for asthma medications •Prevent development of irreversible airflow limitation •Prevent asthma mortality

MANAGEMENT
•ANTI INFLAMMATION, FIRST LINE, EARLY •BRONCHODILATOR, OBJECTIVE VALUE • MEDICINE , SELECTIVE •TIME, PROPERLY • TECHNIQUE, PROPERLY •REHABILITATION, DO •TRIGGER FACTORS, AVOID

THANK YOU

30

Subepithelial layer thickness (µm)

Airway Remodelling in Airway Remodelling in Asthma Asthma

25 20 15 10 5 0 rs = 0.581 p < 0.001

0

2

4

6

8

10

12

Asthma severity score Correlation between subepithelial layer thickness and asthma severity score in 34 asthmatic patients.
Chetta CHEST 1997; 111:362-67

GINA 2002
Systemic Glucocorticosteroid (Parenteral)
Systemic glucocorticosteroid speed resolution of exacerbations and should be considered integral to the management of all but the mildest exacerbation, especially if:
• The initial rapid acting inhaled ß2-agonist dose has failed to achieve lasting improvement • The exacerbation developed even though the patient was already taking oral glucocorticosteroid • Previous exacerbations required oral glucacorticosteroid

Intravenous administration may be considered if IV access is desirable. In patients being discharge from the emergency departement, intramuscular administration may be helpful, specially if there are concerns about compliance.

STEP 4: SEVERE PERSISTENT

CONTROLLER:
daily multiple medications

RELIEVER

•Inhaled ß2• Inhaled steroid agonist • Long-acting p.r.n. bronchodilator Avoid • Oral steroid or control triggers

Step down when controlled

STEP 3: MODERATE PERSISTENT

CONTROLLER: daily medications

• Inhaled steroid and •Inhaled ß2long-acting agonist bronchodilator p.r.n. • Consider anti-or control triggers Avoid leukotriene

RELIEVER

Patient education essential at every step Reduce therapy if controlled for at least 3 months Continue monitoring

STEP 2: MILD PERSISTENT

CONTROLLER: daily medications

• Inhaled steroid • Or possibly cromone, oral theophylline or anti-leukotriene

RELIEVER
•Inhaled ß2agonist p.r.n.

Avoid or control triggers STEP 1: INTERMITTENT
CONTROLLER: none

RELIEVER
•Inhaled ß2agonist p.r.n.

Avoid or control triggers TREATMENT
GINA, Guidelines 2002 GINA, Guidelines 2002

Step up if not controlled (after check on inhaler technique and compliance)

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