Asthma
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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 Pathophysiology: chronic inflammation Clinical history: symptoms
Asthma
COPD
CD 4+ lymphocytes
CD 8+ lymphocytes
eosinophils
macrophages
mast cells
neutrophils
Vary over time and in severity
Persistent and progressive over time
cough
cough
wheeze
sputum
chest tightness
breathlessness
breathlessness
wheeze
Asthma and COPD
Asthma population
COPD population
10% of patients have both conditions
Modern view of asthma
Allergen
Macrophage/ dendritic cell
Mast cell
Th2 cell
Neutrophil Eosinophil
Mucus plug
Nerve activation
Plasma leak Oedema
Mucus hypersecretion Hyperplasia
Barnes PJ
Vasodilatation New vessels
Epithelial shedding
Subepithelial fibrosis Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy / hyperplasia
Inflammatory processes
Barnes PJ
Epidemiology / pathology
Asthma - an inflammatory disease Normal
Asthma
Height-adjusted FEV1 (L)
Increased loss of FEV1 in asthma 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
Causal Factors indoor – – – –
allergens
dust mites animal dander cockroach fungi
outdoor – –
allergens
pollens fungi
occupational GINA Guidelines 1998
sensitisers
infections small size at birth diet air pollution – –
outdoor indoor
smoking – –
passive active
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
Variability of airways’ obstruction
increased PEF >15% 15-20 minutes after inhaling ß2agonist
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 (L / min)
PEF curves
Before bronchodilator After bronchodilator
Morning
Day
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 Time (sec)
5
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
STEP 4 Severe persistent
STEP 3 Moderate persistent
STEP 2 Mild persistent
STEP 1 Intermittent
Continuous Limited physical activity Daily Use β2-agonist daily
Night-time symptoms
Frequent
>1 time a week
<60% predicted Variability >30% >60% - <80% predicted Variability >30%
Attacks affect activity >1 time a week but <1 time a day
PEF
>2 times a month
>80% predicted Variability 20-30%
<1 time a week Asymptomatic and normal PEF between attacks
<2 times a month
>80% predicted Variability <20%
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 ß2-agonists
inhaled
anticholinergics
inhaled corticosteroids inhaled long-acting ß 2 agonists inhaled cromones oral anti-leukotrienes oral theophyllines oral corticosteroids
RELIEVERS MEDICATION Quick
relief 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
fast
slow
inhaled terbutaline inhaled salbutamol
oral terbutaline oral salbutamol oral formoterol
short
inhaled formoterol
inhaled salmeterol oral bambuterol
long
Inhaled formoterol belongs to a new class of bronchodilator, in that it has both a long duration and fast onset of effect.
M A I N T E N A N C E Duration of action
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
Parenteral : Hydrocortisone Methylprednisolone
: Prednisolone Dexamethasone
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 CONTROLLER: daily multiple medications • Inhaled steroid • Long-acting bronchodilator • Oral steroid
RELIEVER • Inhaled ß2agonist p.r.n.
Step down when controlle d
Avoid or control triggers STEP 3: MODERATE PERSISTENT CONTROLLER: daily medications • Inhaled steroid and long-acting bronchodilator • Consider anti-leukotriene
RELIEVER • Inhaled ß2agonist p.r.n.
Avoid or control triggers STEP 2: MILD PERSISTENT CONTROLLER: daily medications • Inhaled steroid • Or possibly cromone, oral theophylline or anti-leukotriene
RELIEVER • Inhaled ß2agonist p.r.n.
• Patient education essential at every step • Reduce therapy if controlled for at least 3 months • Continue monitoring
Avoid or control triggers STEP 1: INTERMITTENT CONTROLLER: none
RELIEVER • Inhaled ß2agonist p.r.n.
Avoid or control triggers TREATMENT GINA Guidelines 1998
Step up if not controlled (after check on inhaler technique and compliance)
Step 1 Step 1: Intermittent asthma Reliever
Controller
None required
Inhaled β 2-agonist prn (not more than 3x a week) 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 Reliever
Controller Daily inhaled corticosteroid (200-500 µg), cromone, sustained release theophylline, or anti-leukotriene
Inhaled β2-agonist prn (but less than 3-4 times 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 > 500 µg Daily long-acting bronchodilator Consider anti-leukotriene
Inhaled β2-agonist prn (but less than 3-4 times per day)
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 800-2000 µg Daily long-acting bronchodilator Daily / alternate day oral corticosteroid
Inhaled β2-agonist prn (but less than 3-4 times per day)
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-tosevere 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 Increasing Pulmicort® dose: p <0.001
Exacerbations / patient / year
1
Adding Oxis®: p = 0.014 Pulmicort® 800 vs. Pulmicort® 200 + Oxis®: p = 0.031
0.5
0
Pulmicort® 100 µg bid
Pauwels et al, NEJM 1997
Pulmicort® 100 µg bid + Oxis® 9 µg bid
Pulmicort® 400 µg bid
Pulmicort® 400 µg bid + Oxis® 9 µg bid
% predicted
Adding formoterol to budesonide 90 improves FEV1 85 80 Pulmicort® 100 µg bid Pulmicort® 400 µg bid
75 70
-1
0
1
2
3
6 Months
Pauwels et al, NEJM 1997
Pulmicort® 100 µg bid + Oxis® 9 µg bid Pulmicort® 400 µg bid + Oxis® 9 µg bid
9
12
Adding formoterol to budesonide 30 improves morning PEF 20 L / min
10 0 -10 Pulmicort® 100 µg bid Pulmicort® 400 µg bid
-20 -30
0
1
Pauwels et al, NEJM 1997
2
3
Pulmicort® 100 µg bid + Oxis® 9 µg bid Pulmicort® 400 µg bid + Oxis® 9 µg bid
6
Months
9
12
Synergy between formoterol and budesonide
Why add formoterol to budesonide? Functional activity
Budesonide
Formoterol
Suppresses inflammation
+
ө
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 β2receptor.
Β2-agonists prime glucocorticoid receptors for
activation by corticosteroids, enhancing their antiinflammatory 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.
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 Pathophysiology: chronic inflammation Clinical history: symptoms
Asthma
COPD
CD 4+ lymphocytes
CD 8+ lymphocytes
eosinophils
macrophages
mast cells
neutrophils
Vary over time and in severity
Persistent and progressive over time
cough
cough
wheeze
sputum
chest tightness
breathlessness
breathlessness
wheeze
Asthma and COPD
Asthma population
COPD population
10% of patients have both conditions
Modern view of asthma
Allergen
Macrophage/ dendritic cell
Mast cell
Th2 cell
Neutrophil Eosinophil
Mucus plug
Nerve activation
Plasma leak Oedema
Mucus hypersecretion Hyperplasia
Barnes PJ
Vasodilatation New vessels
Epithelial shedding
Subepithelial fibrosis Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy / hyperplasia
Inflammatory processes
Barnes PJ
Epidemiology / pathology
Asthma - an inflammatory disease Normal
Asthma
Height-adjusted FEV1 (L)
Increased loss of FEV1 in asthma 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
Causal Factors indoor – – – –
allergens
dust mites animal dander cockroach fungi
outdoor – –
allergens
pollens fungi
occupational GINA Guidelines 1998
sensitisers
infections small size at birth diet air pollution – –
outdoor indoor
smoking – –
passive active
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
Variability of airways’ obstruction
increased PEF >15% 15-20 minutes after inhaling ß2agonist
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 (L / min)
PEF curves
Before bronchodilator After bronchodilator
Morning
Day
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 Time (sec)
5
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
STEP 4 Severe persistent
STEP 3 Moderate persistent
STEP 2 Mild persistent
STEP 1 Intermittent
Continuous Limited physical activity Daily Use β2-agonist daily
Night-time symptoms
Frequent
>1 time a week
<60% predicted Variability >30% >60% - <80% predicted Variability >30%
Attacks affect activity >1 time a week but <1 time a day
PEF
>2 times a month
>80% predicted Variability 20-30%
<1 time a week Asymptomatic and normal PEF between attacks
<2 times a month
>80% predicted Variability <20%
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 ß2-agonists
inhaled
anticholinergics
inhaled corticosteroids inhaled long-acting ß 2 agonists inhaled cromones oral anti-leukotrienes oral theophyllines oral corticosteroids
RELIEVERS MEDICATION Quick
relief 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
fast
slow
inhaled terbutaline inhaled salbutamol
oral terbutaline oral salbutamol oral formoterol
short
inhaled formoterol
inhaled salmeterol oral bambuterol
long
Inhaled formoterol belongs to a new class of bronchodilator, in that it has both a long duration and fast onset of effect.
M A I N T E N A N C E Duration of action
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
Parenteral : Hydrocortisone Methylprednisolone
: Prednisolone Dexamethasone
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 CONTROLLER: daily multiple medications • Inhaled steroid • Long-acting bronchodilator • Oral steroid
RELIEVER • Inhaled ß2agonist p.r.n.
Step down when controlle d
Avoid or control triggers STEP 3: MODERATE PERSISTENT CONTROLLER: daily medications • Inhaled steroid and long-acting bronchodilator • Consider anti-leukotriene
RELIEVER • Inhaled ß2agonist p.r.n.
Avoid or control triggers STEP 2: MILD PERSISTENT CONTROLLER: daily medications • Inhaled steroid • Or possibly cromone, oral theophylline or anti-leukotriene
RELIEVER • Inhaled ß2agonist p.r.n.
• Patient education essential at every step • Reduce therapy if controlled for at least 3 months • Continue monitoring
Avoid or control triggers STEP 1: INTERMITTENT CONTROLLER: none
RELIEVER • Inhaled ß2agonist p.r.n.
Avoid or control triggers TREATMENT GINA Guidelines 1998
Step up if not controlled (after check on inhaler technique and compliance)
Step 1 Step 1: Intermittent asthma Reliever
Controller
None required
Inhaled β 2-agonist prn (not more than 3x a week) 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 Reliever
Controller Daily inhaled corticosteroid (200-500 µg), cromone, sustained release theophylline, or anti-leukotriene
Inhaled β2-agonist prn (but less than 3-4 times 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 > 500 µg Daily long-acting bronchodilator Consider anti-leukotriene
Inhaled β2-agonist prn (but less than 3-4 times per day)
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 800-2000 µg Daily long-acting bronchodilator Daily / alternate day oral corticosteroid
Inhaled β2-agonist prn (but less than 3-4 times per day)
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-tosevere 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 Increasing Pulmicort® dose: p <0.001
Exacerbations / patient / year
1
Adding Oxis®: p = 0.014 Pulmicort® 800 vs. Pulmicort® 200 + Oxis®: p = 0.031
0.5
0
Pulmicort® 100 µg bid
Pauwels et al, NEJM 1997
Pulmicort® 100 µg bid + Oxis® 9 µg bid
Pulmicort® 400 µg bid
Pulmicort® 400 µg bid + Oxis® 9 µg bid
% predicted
Adding formoterol to budesonide 90 improves FEV1 85 80 Pulmicort® 100 µg bid Pulmicort® 400 µg bid
75 70
-1
0
1
2
3
6 Months
Pauwels et al, NEJM 1997
Pulmicort® 100 µg bid + Oxis® 9 µg bid Pulmicort® 400 µg bid + Oxis® 9 µg bid
9
12
Adding formoterol to budesonide 30 improves morning PEF 20 L / min
10 0 -10 Pulmicort® 100 µg bid Pulmicort® 400 µg bid
-20 -30
0
1
Pauwels et al, NEJM 1997
2
3
Pulmicort® 100 µg bid + Oxis® 9 µg bid Pulmicort® 400 µg bid + Oxis® 9 µg bid
6
Months
9
12
Synergy between formoterol and budesonide
Why add formoterol to budesonide? Functional activity
Budesonide
Formoterol
Suppresses inflammation
+
ө
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 β2receptor.
Β2-agonists prime glucocorticoid receptors for
activation by corticosteroids, enhancing their antiinflammatory 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.
