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Asthma definition
• Chronic inflammatory disorder of the airways
• Infiltration of mast cells, eosinophils and
lymphocytes
• Wheeze, cough, chest tightness and shortness of
breath
Use of reliever
medication or
symptoms
Time
Asthma control
Decreased
Exacerbation Exacerbation
Cost of asthma
Macrophage/
dendritic cell Mast cell
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
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
• Soldering flux
• 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
FEV1
Normal subject
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
1985
2000
1990 1995
Launch of
long-acting
β2 -agonists
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
(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
(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. 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
歷
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
Newman SP (1995)
未來藥物發展
Combivent (Ipratropium / Albuterol)
Seretide (Salmeterol / Fluticasone)
Symbicort (Formoterol / Budesonide)
Trinity (Tiotropium / Formoterol
/Budesonide)