OVERVIEW OF ASTHMA

MANAGEMENT

Dr. Noor Aliza Bte Md. Tarekh.

Chest physician, HSAJB.
Asthma:
epidemiology / pathology
 Epidemiology
 Common disease
 In Malaysia, prevalence of asthma :
Primary school children : 13.8%
Children aged 13-14 : 9.6%
Adults : 4.1%
 Higher prevalence in rural (4.5%),
compared to urban areas (4.0%)
 Asthma definition
 chronic inflammatory disorder of the airways

 infiltration of mast cells, eosinophils and lymphocytes

 wheeze, cough, chest tightness and shortness of breath

 symptoms vary over time and in severity

 widespread, variable and reversible airflow limitation

 airway hyperresponsiveness

GINA Guidelines 1998

 Comparisons of asthma &
COPD
Asthma COPD
Patho-  CD 4+ lymphocytes  CD 8+ lymphocytes
physiology:
chronic  eosinophils  macrophages
inflammation  mast cells  neutrophils

Vary over time and in Persistent and progressive

Clinical severity over time
history:  cough  cough
symptoms
 wheeze  sputum
 chest tightness  breathlessness
 breathlessness  wheeze
Asthma and COPD

Asthma COPD
population population

10% of patients
have both
conditions
 Modern view of
asthma Allergen

Macrophage/
dendritic cell Mast cell

Th2 cell Neutrophil

Eosinophil
Mucus plug
Epithelial shedding
Nerve activation

Subepithelial
fibrosis
Plasma leak
Sensory nerve
Oedema activation
Vasodilatation Cholinergic
Mucus New vessels reflex
hypersecretion
Hyperplasia Bronchoconstriction
Hypertrophy / hyperplasia

Barnes PJ
 Inflammatory processes

Barnes PJ Epidemiology / pathology

Asthma - an inflammatory
disease
Normal Asthma
 Increased loss of FEV1 in asthma
Height-adjusted FEV1 (L)

Male non-smokers

p <0.001

No asthma (n = 5480)
Asthma (n = 314)

Age (years)

Lange P et al, NEJM 1998 Epidemiology / pathology

 Risk factors that lead to
asthma development
Predisposing Factors Contributing Factors
 atopy  respiratory infections
 small size at birth
 diet
Causal Factors
 air pollution
 indoor allergens – outdoor
– dust mites
– indoor
– animal dander
– cockroach  smoking
– fungi – passive
 outdoor allergens – active
– pollens
– fungi
 occupational sensitisers

GINA Guidelines 1998

Common occupational
agents
 flour / grain dust (bakery)

 paint, glue or plastic fumes

 soldering flux

 natural rubber latex

 wood dust
Asthma:
diagnosis
Asthma diagnosis

 history and pattern of symptoms

 physical examination
 measurements of lung function
- reversibility test
- diurnal variability
 evaluation of allergic status
Is it asthma?

 symptoms - vary over time and in

severity:
 cough
 wheeze
 breathlessness
 chest tightness
 symptoms occur or worsen at night or
after exposure to trigger
 colds “go to the chest” or take >10
days to clear
Ask about triggers
Symptoms can occur or worsen in the presence of:

Others
Allergens
 exercise
 animal dander
 viral infection
 dust mites  smoke

 pollen  changes in temperature

 fungi  strong emotional expression

 aerosol chemicals
 drugs (NSAIDs, ß-blockers)
 Reversible and variable airflow
limitation
 Reversibility of airways’ obstruction
 increased PEF >15% 15-20 minutes after inhaling ß2-
agonist

 Variability of airways’ obstruction

 PEF varies between morning and evening
>20% in patients taking bronchodilator
>10% in patients not taking bronchodilator

 Exercise-induced airways’ obstruction

 decreased PEF >15% after 6 minutes of exercise

GINA Guidelines 1998

Peak flow measurement

The best of three PEF measurements is compared with the

normal predicted for that individual based on age, height and
sex.
Importance of long-term
peak flow measurements

 establishes diagnosis and treatment

 assesses severity of an exacerbation
 assesses response to treatment
 evaluates how well asthma is controlled
 alerts patient to need for possible
change in treatment
 PEF curves
PEF (L / min)

Before bronchodilator
After bronchodilator

Day
Morning Evening

Diagnosis
‘Clinical’ exacerbation
PEF

Mild attack

Acute severe
attack

Exacerbation

Days

An acute severe attack of asthma refers to the onset of symptoms

severe enough to require emergency treatment
FEV1 measurement
 FEV1 curves
Volume

FEV1

Normal subject

Asthmatic (after bronchodilator)

Asthmatic (before bronchodilator)

1 2 3 4 5
Time (sec)

Note: Each FEV1 curve represents the highest of three repeat measurements
FEV1 and FVC provide a useful guides to the degree of airflow obstruction at
diagnosis and in the evaluation of the effectiveness of anti-asthma drugs.
Diagnostic challenges in
adults
 heart failure
 COPD
 angina
 bronchiectasis
 lung cancer
 ‘Clinical’ classification of severity

Clinical features before treatment

Symptoms Night-time PEF
symptoms

STEP 4 Continuous <60% predicted

Severe Frequent
persistent
Limited physical Variability >30%
activity
STEP 3 Daily >60% - <80%
Moderate Use β2-agonist daily >1 time a week predicted
persistent
Attacks affect activity Variability >30%
STEP 2
>1 time a week >80% predicted
Mild persistent >2 times a month
but <1 time a day Variability 20-30%

STEP 1 <1 time a week

Intermittent >80% predicted
Asymptomatic and <2 times a month
normal PEF between Variability <20%
attacks

Asthma severity is graded, in the GINA guidelines, according to the frequency of symptoms,
occurrence of symptoms at night, and PEF measurement before treatment.
‘Real-life’ classification of severity

 Many doctors classify asthma severity

based on treatment given rather than
treatment needed

 mild asthma is usually more severe than

many doctors and patients realise

 patients adjust lifestyle to suit asthma

severity: limited expectations rather than
optimal quality of life
 Treatment goal: take
control of asthma
 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

GINA Guidelines 1998

 Treatment
strategy
 identify and avoid triggers that make asthma
worse
 achieve control by selecting appropriate
medication
 treat asthma attacks promptly and
effectively
 educate patients to manage their condition
 monitor and modify asthma care to maintain
effective long-term control

GINA Guidelines 1998

Pharmacological therapy

Relievers Controllers
 inhaled
fast-acting  inhaled corticosteroids
ß2-agonists  inhaled long-acting ß -
2
 inhaled anticholinergics agonists
 inhaled cromones

 oral anti-leukotrienes

 oral theophyllines

 oral corticosteroids
 RELIEVERS MEDICATION

 Quickrelief medicine or rescue

medicine.

 Rapid acting bronchodilators that act to

relieve bronchoconstriction.
ROUTE OF ADMINISTRATION
 INHALATION
 Pressurized metered dose inhalers ( MDI)
 MDI-plus-spacer
 Breath actuated MDI
 Dry powder inhalers
 Nebulised

 ORAL

 PARENTERAL
Classes of ß2-agonists
Speed of
onset RESCUE MEDICATION

fast onset, long duration M

inhaled terbutaline A
fast inhaled salbutamol inhaled formoterol I
N
T
E
N
oral terbutaline A
inhaled salmeterol N
slow oral salbutamol oral bambuterol C
oral formoterol E
Duration
short long of action
Inhaled formoterol belongs to a new class of bronchodilator, in that
it has both a long duration and fast onset of effect.
 Short-acting inhaled B-agonist
 Use intermittently to control
episodes of bronchoconstriction
 Avoid regular scheduled use if
possible
 An increase use is an indication of
deteriorating control
 LONG ACTING β2 AGONIST

 Mechanism of action:
 Bronchodilator
 Enhance mucociliary clearance
 Modulate mediators release from mast cells and
basophils

 Example : Inhaled : Salmeterol , formeterol

Oral : Bambuterol
Salbutamol SR
Terbutaline SR
Clenbuterol
 LONG ACTING β2 AGONIST

 Inhaled β2 Agonists have fewer side effects than

oral formulations.

 Side-effects : tachycardia, palpitations, tremors,

anxiety, headache and hypokalaemia.
Differences between ß2-agonists

 chemical structure

 pharmacological properties:
 mode of action in the ß2-receptor region
 potency
 efficacy (ie full / partial agonism)
 selectivity
 CONTROLLER MEDICATIONS

 Are medications taken daily on a long term

basis that are useful in getting and keeping
persistent asthma under control.
 Prophylactic, preventive or maintenance
medications
 Include
 Inhaled glucocorticosteroids
 Systemic glucocorticosteroids
 Theophylline
 Long acting inhaled β2 agonist
 Long acting oral β2 agonist
 Leukotriene modifiers
 GLUCOCORTICOSTEROIDS
 Mechanisms of action :

 Reduced airway inflammation

 Efficacy in improving lung function, decreasing

airways hyperresponsiveness, reducing
symptoms, reducing frequency and severity of
exacerbations and improving quality of life.
 GLUCOCORTICOSTEROID

 Inhaled : Beclomethasone
Budesonide
Fluticasone

 Oral : Prednisolone
Dexamethasone

 Parenteral : Hydrocortisone
Methylprednisolone
 Side effects
 Local effects –

 oropharyngeal candidiasis, dysphonia, upper airway

irritation
 How to prevent ? – Mouth washing after inhalation &

use of spacer

 Systemic adverse
 effects depends on the dose and potency of
glucocrticosteroids , absorption in the gut, first past
effect of liver.
 Systemic adverse effects include : skin thinning,

easy bruising, cataract, obesity, adrenal

suppression, hypertension, diabetes and myopathy.
Inhaled steroids are first line
maintenance therapy

Laitinen LA et al, J Allergy Clin Immunol 1992

 METHYLXANTHINES

 Mechanism of action:
Antiinflammatory effects &
bronchodilator.
 Side effects :
 GIT Symptoms – nausea, vomiting
 CVS Symptoms – tachycardia,
arrhythmias
 Drug interaction : Erythromycin,
cimetidine and rifampicin
 Anti-cholinergics
 Inhaled ipratropium bromide.

 Mechanism of action : Bronchodilator.

 Efficacy : Bronchodilator actions are less

potent than those of inhaled ß2-agonists,
slower onset of action which peaks 30 –
60 min.

 Side-effect : Dry mouth.

LEUKOTRIENE MODULATORS

 MECHANISM OF ACTION :
 Block the synthesis of all leukotrienes

 Example : montelukast ( Singulair ),

Zafirlukast
 STEP 4: SEVERE PERSISTENT Step
CONTROLLER: daily multiple down
medications RELIEVER when
• Inhaled steroid
• Long-acting bronchodilator • Inhaled ß2- controlle
• Oral steroid agonist p.r.n. d
Avoid or control triggers
STEP 3: MODERATE PERSISTENT • Patient
CONTROLLER: daily education
medications RELIEVER
• Inhaled steroid and long-acting essential at
bronchodilator • Inhaled ß2- every step
• Consider anti-leukotriene agonist p.r.n. • Reduce
Avoid or control triggers therapy if
controlled for
STEP 2: MILD PERSISTENT at least
CONTROLLER: daily 3 months
medications RELIEVER • Continue
• Inhaled steroid • Inhaled ß2-
• Or possibly cromone, oral monitoring
theophylline or anti-leukotriene agonist p.r.n.
Avoid or control triggers
STEP 1: INTERMITTENT

RELIEVER Step up
CONTROLLER: none
• Inhaled ß2- if not controlled
agonist p.r.n. (after check on
inhaler technique
Avoid or control triggers and compliance)
TREATMENT
GINA Guidelines 1998
 Step 1

Step 1: Intermittent asthma

Controller Reliever
 Inhaled β 2-agonist prn
(not more than 3x a week)
None required
 Inhaled β 2-agonist or
cromone prior to exercise
or allergen exposure

Avoid or control triggers

ICS should be prescribed
to asthmatic patients
requiring daily B-agonist use
If asthma symptoms are intermittent, then reliever therapy
alone is sufficient.
 Step 2

Step 2: Mild persistent asthma

Controller Reliever
 Daily inhaled corticosteroid  Inhaled β2-agonist prn
(200-500 µg), cromone, (but less than 3-4 times
sustained release theophylline,
or anti-leukotriene per day)

If still not controlled, particularly
nocturnal symptoms, increase
inhaled steroid (500-800 µg) or
add long-acting bronchodilator

Avoid or control triggers

It is often best to initiate an inhaled steroid early and at a high dose to

establish rapid control and then reduce the dose.
 Step 3

Step 3: Moderate persistent asthma

Controller Reliever
 Daily inhaled corticosteroid  Inhaled β2-agonist prn
> 500 µg (but less than 3-4 times
 Daily long-acting per day)
bronchodilator
 Consider anti-leukotriene

Avoid or control triggers

A long-acting inhaled β2-agonist is the first choice add on therapy to

inhaled steroids
 Step 4

Step 4: Severe persistent asthma

Controller Reliever
 Daily inhaled corticosteroid  Inhaled β2-agonist prn
800-2000 µg (but less than 3-4 times
 Daily long-acting per day)
bronchodilator
 Daily / alternate day oral
corticosteroid

Avoid or control triggers

Patients with severe persistent asthma are often poorly controlled

despite using combinations of all available controller medications.
Summary of GINA
guidelines 1998
 gain control

 step up if control is not achieved and sustained

 step down if control is sustained for at least 3

months

 review treatment every 3-6 months

Future?
stepping up and down should involve both LAßA and ICS
Asthma:
rationale for adding
LAßA to ICS therapy
 THE FACET STUDY

 A total of 825 adult patients with moderate-to-

severe asthma were randomised into 4 treatment
groups based on bid doses as follows :
- budesonide 100 ug bid + placebo
- budesonide 100 ug bid + formorterol 9 ug bid
- budesonide 400 ug bid + placebo
- budesonide 400 ug bid + formorterol 9 ug bid
 Adding formoterol to budesonide
reduces rate of severe exacerbations
1 Increasing Pulmicort® dose: p <0.001
Adding Oxis®: p = 0.014
Exacerbations / patient / year

Pulmicort® 800 vs. Pulmicort® 200 + Oxis®: p = 0.031

0.5

0
Pulmicort®  Pulmicort® 100 µg bid Pulmicort®  Pulmicort® 400 µg bid
100 µg bid + Oxis® 9 µg bid 400 µg bid + Oxis® 9 µg bid

Pauwels et al, NEJM 1997

 Adding formoterol to
budesonide
90
improves FEV1
85
% predicted

80

Pulmicort®  Pulmicort® 100 µg bid
75 100 µg bid + Oxis® 9 µg bid
Pulmicort®  Pulmicort® 400 µg bid
400 µg bid + Oxis® 9 µg bid

70
-1 0 1 2 3 6 9 12
Months

Pauwels et al, NEJM 1997

 Adding formoterol to
budesonide
30
improves
20
morning PEF
10
L / min

-10
Pulmicort®  Pulmicort® 100 µg bid
-20 100 µg bid + Oxis® 9 µg bid
Pulmicort®  Pulmicort® 400 µg bid
400 µg bid + Oxis® 9 µg bid
-30
0 1 2 3 6 9 12
Months

Pauwels et al, NEJM 1997

Synergy between formoterol
and budesonide
Why add formoterol to budesonide?

Functional activity Budesonide Formoterol

Suppresses + ө
inflammation

Bronchodilates airways - +
Reduces AHR + +
Prevents progressive
airway damage
+ -
ө mast cell stabilising effect, reduces plasma exudation / inflammatory mediator release
Budesonide is highly effective at suppressing inflammation in the airway wall,
formoterol exerts a complementery action through stabilising mast cells and
reducing plasma exudation and inflammatory mediator realease.
 Why add formoterol to budesonide?
Cellular activity Formoterol Budesonide

Acts via cortico. + -

receptors

Activates cortico. - +
receptors
- +
Acts via ß2-receptors
+ -
Activates ß2-receptors

Budesonide and formoterol also mutually activate each others’

receptors.
 Summary on synergy

Corticosteroids increase β2- receptor synthesis,

reduce β2- receptor downregulation and prevent
inflammatory processes from uncoupling β2-
receptor.
Β2-agonists prime glucocorticoid receptors for
activation by corticosteroids, enhancing their anti-
inflammatory activity and resulting in an apparent
increase in potency.
 Conclusion

 There is a synergistic effect on

treatment when these agents are combined.

 The combination of these agents also

makes the treatment simpler for the patient,
which may improve compliance.

 Co-formulated products are generally less

expensive than giving the two constituents
separately.
Management of Asthma in Pregnancy.

 Management of asthma during

pregnancy should be aggressive.

 Cooperation between the resp.

physician and obstetrcian
throughout pregnancy for women
with severe asthma.
Beta2 agonists.
 There is no evidence of a teratogenic risk.

Ipratopium bromide / Sodium cromoglycate.

 Safe for use during pregnancy.

Salmeterol/formoterol.
 Have not been tested extensively in
pregnant women.
Theophyllines.
 May aggravate the nausea and gastroesophageal
reflux.
 May cause transient neonatal tachycardia and
irritability.

Inhaled corticosteroids.
 Has good safety profile in pregnancy.

 Experience with fluticasone in pregnancy is limited.

Anti-leukotrienes.
 No data is available on the use of this agent in
pregnant women.
Oral corticosteroids.
 Sometimes necessary for severe asthma but usually
only for short periods.
 An increased risk of cleft palate has been reported in
animals given huge doses.

Breastfeeding.
 Should be continued in women with asthma.

In general, asthma medications are safe during

pregnancy and lactation and the benefits outweigh
any potential risks to the foetus and baby.