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Bronchial Asthma

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


Asthma — a global healthcare
problem
• Prevalence is increasing worldwide
• Causes significant morbidity and mortality
• Patients need continuous medical care
• Major healthcare cost burden
Asthma is a variable disease
Allergens & Cold weather
viral infection & exercise
Increased

Use of reliever
medication or
symptoms

Time

Asthma control

Decreased
Exacerbation Exacerbation
Cost of asthma

Direct Medical Care Indirect Costs


Hospital stay Social security
Intensive care Loss of work output
Emergency department Loss of school days
Primary care Impact on individual /
Medications
family / society

GINA Guidelines 1998


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
Asthma components
Healthy Airway Asthmatic Airway
Aveolar septum Mucus and plasma
Inflammation
and oedema exudation

Smooth muscle Epithelium Smooth muscle Epithelial shedding /


contraction damage

Barnes PJ
Inflammation in asthma
Acute
inflammation

Steroid
response

Chronic inflammation

Structural changes

Time

Barnes PJ
Inflammatory processes

Barnes PJ
Asthma - an inflammatory disease
Normal Asthma
Classification of asthma by stimuli

• Stimuli
Extrinsic, Intrinsic
• Frequency and severity of symptom
Intermittent
Chronic asthmatic
Seasonal or indeterminate asthmatic
Examples of trigger factors
which may cause asthma
• Allergens (e.g. Pollens, moulds, house dust mite,
animals’ dander, saliva and urine, bacteria
• Cold dry air
• Exercise
• Viral respiratory tract infections
• Psychological stimuli (e.g.stress, anxiety)
• Drugs (e.g. aspirin, ibuprofen and other PEG
synthetase inhibitors, β -blockers)
Examples of trigger factors
which may cause asthma
• Industrial chemicals (e.g. isocyanates,
epoxy resins, aluminium, hair sprays,
penicillins, cimetidine)
• Other industrial triggers (e.g. wood or grain
dust, colophony in solder, cotton dust, grain
weevils, mites)
Risk factors that lead to asthma
development
• Predisposing Factors • Contributing Factors
– atopy
– gender
– respiratory infections
• Causal Factors – small size at birth
– indoor allergens – diet
• dust ``mites

– air pollution
animal dander
• cockroach • outdoor
• fungi • indoor
– outdoor allergens – smoking
• pollens
• passive
• fungi
– occupational sensitizers • active

GINA Guidelines 1998


Factors that induce asthma
variability
• Allergens
• Cigarette smoke
• Respiratory infections
• Exercise and hyperventilation
• Weather changes
• Air pollutants, e.g. sulphur dioxide
• Food, additives, drugs
Common occupational agents
• Flour / grain dust (bakery)

• Paint, glue or plastic fumes

• Soldering flux

• Natural rubber latex

• Wood dust
INDUCERS
Allergens, Chemical sensitizers,
Air pollutants, Virus infections

INFLAMMATION

Airway
Hyperresponsiveness Airflow Limitation

TRIGGERS SYMPTOMS
Allergens, Cough Wheeze
Exercise Chest tightness
Cold Air, SO2 Dyspnoea
Particulates

Barnes PJ
Diagnosis and clinical findings
• Tightness in the chest
• Overinflation of the chest
• Wheezing, cough
• Decreased respiratory movement
• Dyspnea, orthopnea
• Thick viscous sputum
• Cyanosis, tachycardia
• Agitation, confusion
Pathogenesis of asthma
• The obstruction to airflow in asthma is due to
three processed:
• 1. Bronchial smooth muscle contraction.
• 2. Thickening of the mucous membrane lining
of the lung.
• 3. Plugging of the bronchi and bronchioles
with thick, tenacious mucus.
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
• Smoke
• Dust mites • Changes in temperature
• Pollen • Strong emotional
expression
• Fungi • Aerosol chemicals
• Drugs (NSAIDs, ß-
blockers)
Peak flow 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 measurement
Skin prick test
‘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

GINA Guidelines 1998


輕度持續支氣管哮喘之定義
1. 氣喘發作次數每週多於一次但並非
每天發作。
2. 發作時會影響日常生活及睡眠。
3. 夜晚發作次數每月多於二次。
4. 尖峰呼氣流速 (PFR) 或第一秒呼
氣量大於 80%; 預測值每日變化異
值為 20-30% 。
Etiology of asthma
• Bronchial asthma is a hetergenous disorder-
immunologically, physiologically and
biochemically.
• Its aetiology is multifactorial and the
rationale for the therapeutic approach
depends on the unravelling of the
underlying causes.
Drug induced asthma
• 2 to 5% of all asthmatics are hypersensitive to aspirin.
• A reaction may start within a few minites to several
hours after ingestion of the aspirin, but it usually
begin with 30 minites.
• The patient will often first notice a profuse, watery
rhinorrhea,followed by a scarlet flash of the head,
neck,upper chest, and extremities then wheezing and
cyanosis due to bronchoconstriction.
• The patient may go into shock and die.
Drug induced asthma
The mechanism of the reaction is due to
aspirin's effect on prostaglandins. Aspirin
and the related drugs mentioned below all
inhibit the biosynthesis of the E series of
prostaglandins,which have bronchodilating
activity, it is through that this allows the
bronchoconstricting effects of the F series of
prostaglandins to dominate.
Drugs usually precipitate attacks in
preexisting asthmatics
• Parasympathomimetics
• Anticholinesterase
• Histamine
• β -blocker
• F series of prostaglandins.
Goals of asthma therapy
• Prevent chronic and troublesome symptoms
• Prevent acute exacerbations
• Maintain normal activity levels
• Maintain (near) normal pulmonary function
• Avoid adverse effects from medications
Treatment of asthma
All therapy must include patient
education about prevention (including
environmental control where
appropriate) as well as control of
symptoms
Treatment of asthma
Because airway inflammation is
now proposed as a principal factor
in airway responsiveness,
therapeutic agents to prevent or
reverse this abnormality are
considered first-line therapy.
Summary on the principles of
the use of drugs (I)
• The minimum treatment necessary to maintain
control is the correct treatment.
• Bronchodilator side effects are not acceptable.
• When the asthma gets out of control, the patient
must quickly increase treatment, and then slowly
decrease it once control is achieved
• The appearance of new coughing or breathlessness
in an asthmatic is a sign to increase treatment.
Summary on the principles of
the use of drugs (II)
• Use of several drugs simultaneously is more
effective than single agents.
• Use of several agents in suboptimal doses often
gives good relief and leaves a therapeutic reserve
for exacerbation.
• Patients hospitalized for exacerbation of their
asthma should receive adrenocorticosteroids.
Drugs treatment of asthma
• Hyposensitization
• Bronchodilators
• Anticholinergics
• Hydration.
• Expectorants (and mucolytics)
• Corticosteroids
• Cromolyn
• Antileukotriene antagonist
Progression of asthma therapy

ICS treatment Salbutamol


High use of introduced introduced
short-acting 1972 1968
β 2-agonists
1975
Combination
1980 products
Increased use of introduced
ICS

1985
2000
1990 1995
Launch of
long-acting
β2 -agonists

Bronchospasm Inflammation Remodelling


Drug therapy in asthma

Preventive therapy
Inhaled steroids Oral methylxanthines
Inhaled cromones Oral leukotriene antagonists
Oral steroids Oral steroid-sparing agents
Reliever therapy
Inhaled β2-agonists Oral(or injected) β2-agonists
Inhaled anticholinergics Oral(or injected)
methylxanthines
Hyposensitization
The mechanism of hyposensitization is still
unclear, but it is thought that injections of very
small amounts of allergen (antigen) cause a
build up of IgG or " blocking" antibodies to
the antigen (levels of IgE will also increase,
but with continued treatment will decreased
often to levels less than those prior to initiation
to therapy).
Hyposensitization
• When the patient is exposed to
naturally occurring antigen, the IgG
will combine with it and prevent or
block it from reaction with the
"asthma-producing " IgE antibodies.
Therapeutics agents used in asthma
Bronchodilators Anti-inflammatory drugs
β -Agonist drugs Corticosteroids(inhaled,system)
Anticholinergic Sod. Cromoglycate(Cromolyn)
Methylxanthines Ketotifen
Bronchodilators
• Anticholinergic drugs
Ipratropium bromide
Tiotropium
• Sympathomimetic
Increase adenylcyclase
Alpha and Beta agonists
• Theophylline
Decrease Phosphodiesterase
Increase C’-AMP
Bronchodilators
1.Sympathomimetics
2. Methylxanthines
3. Anticholinergics
β -adrenergic agonist toxicity
• Skeletal muscle tremor
• Tachycardia
• Palpitations
• Certain degree of nervousness
Aminophylline
1. Loading dose : 6 mg/kg over 20 minutes
2. Standard maintenance dose --- 0.5 mg/kg/hr
Children --- 0.6 mg/kg/hr
Cigarette smokers --- 0.8 mg/kg/hr
Congestive heart failure --- 0.2 mg/kg/hr
Liver disease --- 0.2 mg/kg/hr
Severe airway obstruction --- 0.4mg/kg/hr
Aminophylline
Usual loading dose* 6mg/Kg
Maintenance dose
Young children 1.0 mg/kg per hour
Older children 0.8 mg/kg per hour
Smokers 0.8mg/kg per hour
Nonsmoking Adults 0.5mg/kg per hour
Elderly 0.3mg/kg per hour
Cor pulmonale 0.3mg/kg per hour
Congestive heart failure 0.1- 0.2mg/kg per hour
Liver disease 0.1 - 0.2mg/kg per hour
Each 0.5mg/kg of theophylline administered as a loading dose
will result in an approximately 1 ug/ml increase in serum level.
Theophylline toxicity
• Initiation of therapy
Caffeine-like CNS stimulation
• SDC above 20 ug/ml
Vomiting, headache, diarrhea, irritability
and insomnia
• SDC above 35 ug/ml
Hyperglycemia, hypotension, cardiac arrhythmia
seizure, permanent brain damage and death
Factors reported to affect Theophylline
clearance
• Increase clearance Decrease clearance
• Smoking Hepatic cirrhosis
• Phenobarbital Cor pulmonnale
• Hugh protein/low Congestive heart failure
carbohydrate diet Erythromycin
• Phenytoin Cimetidine
• Carbamazepine Allopurinol(>600mg/d)
• Rifampin Troleandomycin
Disease states which affect
theophylline clearance
Disease Factor
Smoking history 1.6
Congestive heaart failure 0.4
Acute pulmonary edema 0.5
Acute viral illness 0.5
Hepatic cirrhosis 0.5
Severe obstructive pulmonary disease 0.8
Obesity IBW
Pharmacokinetic of Theophylline

Therapeutic plasma concentration 10-20mg/L


Bioavailability 100 %
Volume distribution 0.5L/Kg
Clearance 0.04L/hr/Kg
Half-life 8.3 hr
Pharmacokinetic of Theophylline

(Vd) (Cp)

Loading Dose =
(S) (F)
Pharmacokinetic of Theophylline
Patient: 80 Kg
Age : 50 year-old
Plasma theophylline conc 15 mg/L
Theophylline Vd = (0.5L/Kg)(Weight)
= (0.5 L/Kg) (80 Kg)
= 40 L
(Vd) (Cp) (40L) (15mg/L) 600mg
Loading Dose = = = = 750mg
(S) (F) (0.8 ) (1.0) 0.8
Pharmacokinetic of Theophylline

( Cl ) ( Cpss ave) (T)


Maintenance Dose =
(S)(F)
Pharmacokinetic of Theophylline
Theophylline clearance : 0.04L/hr/Kg

(Cl)(Cpss ave) (T) (3.2l/hr)(15mg/L)(1hr)


Maintenance Dose = =
(S) (F) ( 0.8 ) ( 1.0 )
48 mg
= = 60 mg Aminophylline
0.8
Pharmacokinetic of Theophylline
A patient has severe obstructive pulmonary
disease, congestive heart failure, and a greater-
than 1 pack/day smoking history. If none of the
factors known to alter theophylline clearance were
present, expected theophylline clearance would
3.2L/hr(0.04L/hr/Kg)
However, smoking, severe obstructive pulmonary
disease and congestive heart failure alter
theophylline clearance by a factor of 1.6, 0.8 and
0.4 respectively.
Pharmacokinetic of Theophylline
The product of these factors is 0.512
(1.6)(0.4)(0.8)=0.512
Theophylline clearance value should be multipled
by this factor of 0.512 to estimate the theophylline
clearance : (3.2L/hr/Kg)(0.512) = 1.64 L/hr.
Pharmacokinetic of Theophylline

(0.693) (Vd)
t1/2 =
Cl
Clearance : 1.64 L/hr
Vd : 40 L
(0.693) (40) 26.6 L
t1/2 = = = 16.9 hour
1.64 L/hr 1.64 L/hr
Corticosteroid
The proposed antiasthma mechanism:
1. Direct bronchial smooth muscle relaxation.
2. Suppression of the immune system.
3. Beneficial changes in the cyclic AMP:cyclic
GMP ratio.
4. Alteration in the synthesis and release of
the mediators of the attack.
5. Inhibition of prostaglandin synthesis.
Indication For Corticosteroid Therapy

1. Acute severe asthma.


2. Worsening chronic asthma.
3. Long term maintenance therapy.
4. Diagnostic trial of reversibility in a
patient with chronic airflow
obstruction.
Guidelines For Steroid Therapy
1. Start with high doses for exacerbation.
2. After control of symptoms, taper rapidly to baseline
steroid dose.
3. For chronic use, try to keep daily dose of prednisolone
below 10mg/day.
4. Give daily dose in the A.M.
5. Attempt alternate day steroid if more than 7.5 mg
prednisolone/day is required
6. Use 2-3 times daily dose for "on" day initially.
7. Use beclomethasone dipropionate aerosol to avoid need
for, or reduce dose of oral prednisone.
Cromolyn sodium
1. Cromolyn prevents degranulation of mast cells
and therefore, the release of the mediators of
asthma in both allergic and nonallergic asthmatics.
2. It has no bronchodilating or anti-inflammatory
effects.
3. It is strictly prophylactic and has no benefit in
acute attacks.
4. Clinically, it appears to be more effective in
extrinsic asthmatics and in those with exercise-
induced asthma.
Side Effects of Short-Term,
High-Dose Corticosteroids
• Hypokalemic alkalosis Cerebral edema
• Diabetes mellitus Proximal myopathy
• Hyperosmolar non-ketotic coma Glaucoma
• Hypertension Pancreatitis
• Sodium and water retension Mood disorders

• Peptic ulcer and G-I hemorrhage


Side effects of long-term
glucocorticoid administration
• Osteoporosis Centripetal obesity
• Aseptic necrosis of bone Growth failure
• Pseudotumor cerebri Secondary amenorrhea
• Mood disorders Suppresion of HPA axis
• Posterior subcapsular cataracts Impaired wound healing
• Hyperlipidemia Suppression of immune
• Increased prevalence of gallstone (?) response
Cromolyn sodium
• Cromolyn is not a first-line drug for
asthma.
• It is generally used if the bronchodilators
do not provide adequate relief. Some
patients who have been on steroids may be
able to reduce the dose when placed on
cromolyn.
Some fundamental benefits of
Cromolyn sodium
Appears to provide antiinflammatory activity.
Is free of the systemic side effects of
theophylline.
May be initiated with a tid-qid dosing
regimen
and sometimes reduced to bid therapy.
Nebulizeer solutions available for children
under 5 years of age who cannot master the
Hydration and Expectorants
1. Humidification of their homes.
2. Breathing in steam or cool water
vapor.
3. In oxygen therapy, the oxygen must
be humidified because gases can be
very drying.
Summary of drugs used in the treatment of asthma

Drug Mode of action Route of Recommended use


administrations
Cromoglycate Anti-inflammatory Inhaled Maintenance therapy
Corticosteoid Anti-inflammatory Inhaled Maintenance therapy in
Oral exacerbation or as mainten
maintenance therapy
in severe asthma
Ketotifen Anti-histamine Oral Maintenance therapy
B2-agonists Bronchodilator Parenteral Maintenance therapy in sever
short-acting inhaled/oral As required
Long-aacting inhaled/oral Maintenance therapy,especia

for nocturnal symptoms


Summary of drugs used in the treatment of asthma

Drug Mode of action Route of Recommended use


administrations

Anticholinergic Bronchodilator Inhaled As required or maintenance


therapy in acute exacerbation
Xanthines Bronchodilator,weak Oral maintenance therapy
anti-inflammatory
Parenteral In severe exacerbations
Antileukotriene Antagonist
• Zafirlukast (Accolate) Tab 20 mg
• Montelukast Sod (Singulair film tab10mg)
• (Singulair chewable Tab 5 mg)
Zafirlukast (Accolate) 之給付規定

1. 限用於成人輕度至中度持續性支氣管
哮喘疾患
2. 病歷上應詳細記載上個月發作次數頻
率及 PFR 值之變化
3. 每月最大量限六十粒
4. 本品項不得與 Cromoglycate 或
Ketotifen 併用
Montelukast Sod (Singulair ) 之給付
規定
• Singulair coated tab 10mg:
限用於成人輕度至中度持續性支氣管哮喘病

上應詳細記載上個月發作次數頻率及 PFR 值
之變化
• 每月最大量限三十粒
• 本品項不得與 Cromoglycate 或 Ketotifen 併用
• Chewable Tab 5mg 限六歲以上小兒使用
Spiral channels Symbicort®
Turbuhaler®
design

Dose counter

Air inlets Air inlets

Desiccant store Turning grip


Lung deposition with Turbuhaler®

Newman SP (1995)
未來藥物發展
 Combivent (Ipratropium / Albuterol)
 Seretide (Salmeterol / Fluticasone)
 Symbicort (Formoterol / Budesonide)
 Trinity (Tiotropium / Formoterol
/Budesonide)