Asthma Long Term Treatment

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

Triggers

Inflammation (–) (+) • •

Normal Bronchial hyperreactivity (-)

Symptoms (-)

• •

• •

•

•

• •

Asthma Bronchial hyperreactivity Symptoms (+)

Ca++ Histamin

Ag

Ig E

YY

Phospholipid

Methyl transferase

Phosphatidyl ethanolamine

Phosphatidyl choline

Phospho lipase A2 Ca++

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

Histamin ECF, NCF

Thromboxanes Prostaglandins TXA2 PGD PGF2α

Diagnosis Data

Analisis

Planning

Data:

Diagnosis

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

Volume (liters)

5 4 3

FEV1

FVC

2 1 0

1

2

3

4

5

6

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

93 %

•Used anti inflammation

25 %

•Used objective values

9%

•Inhaller tehnique (poor )

92 %

•Compliance

19 %

•Dose interval

17 %

PATIENT’S PROFILE

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

•More than one year

96 %

•Used anti inflammation

32 %

•Used objective values

7%

•Inhaller tehnique (poor )

89 %

•Compliance

23 %

•Dose interval

21 %

Reflected in Indonesian Asthma Market (IPMG Nov 2001)

5%

3% 1%

11%

4%

46%

5%

25%

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

World Asthma Market (IMS 2000) 1% 16%

30% 5%

6%

7%

35%

b2-agonist Xanthines NS Antiinflammatory Inhaled Steroid Anticholinergics Antileukotriene Other

Change paradigm of asthma To/

To/

Symptoms

Diseases

control

control

Anti Inflammations is the mainstay therapy

Inflammation

Controller

Bronchial hyperreactivity Reliever

Symptoms Pathogenesis of asthma

Natural History of Asthma

CURE

•UNCORRECT TREATMENT

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

c a m r Pha

? c i t e 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

e llin d o Rem g

Time

Era of Asthma management 1930th

: Xanthin

1960th

: Beta2-agonist

1970th

: Steroid inhallation

2000th

: Combination

2003th

: 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

1995 Inflammation

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

* salbutamol/albuterol (Ventolin ®)

(LABA)

* terbutaline (Bricasma®) * procaterol * fenoterol * orciprenaline, etc

•salmoterol

2

AGONIST:

•formoterol

ANTICHOLINERGIC:

XANTHINE:

* atropine sulfate

* theophylline

* ipratropium bromide, etc 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 Healthy Subjects Subjects

Asthma Asthma in in Remission 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

GINA 1998 (adapted) Current evidences

Moderate persisten t

Severe persisten t

Short-acting ß-agonists2 prn

ICS

LABA+ICS LABA+ICS

The rationale behind fixed combination therapy  To

increase adherence to controller

therapy  To

gain better control with less inhaled

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

Change in morning PEF (L/min)

Combinations once- or twice-daily dosing offers convenient than single dosing 35 30 25 20 15

p<0.001 both treatments vs. budesonide alone

10 5 0 -5 -10

0

10

20

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

30 40 50 Treatment days

60

Symbicort® 160/4.5 µg 1 inhalation bid

70

80

90

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 (

300

0

normal )

PEFR Monitoring: A Major Tool in Asthma Self-Management Chronic Diseases

Monitor

Hypertension

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

Subepithelial layer thickness (µm)

30

Airway Airway Remodelling Remodelling in in Asthma Asthma

25 20 15 10 5 rs = 0.581 p < 0.001

0

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:

RELIEVER

daily multiple medications

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

Step down when controlled

STEP 3: MODERATE PERSISTENT

CONTROLLER: daily medications

RELIEVER

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

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, GINA, Guidelines Guidelines 2002 2002

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

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