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Transcript
Bronchial Asthma
• A disease of the airways that is
characterized by hyperresponsiveness
of the tracheobronchial tree to a
multiplicity of stimuli
• Manifested physiologically by a
widespread narrowing of the air
passages and clinically by paroxysm of
dyspnea, cough, and wheezes
Pathogenesis
A.
Exposure to allergen
synthesis of IgE binds to
mast cells in the airway mucosa
Re-exposure to allergen/antigen
Ag-Ab
interaction on the surface of the mast cell triggers:
1) release of mediators of anaphylaxis: histamine,
tryptase, PGD2, leukotriene C4, PAF
provoke contraction of the airway
smooth muscle
2) Synthesis and release of other mediators or a
variety of cytokines:
interleukines 4 & 5, granulocyte-macrophage
colony stimulating factor, tumor necrosis factor,
tissue growth factor from T cells and mast cells
attract and activate eosinophils & neutrophils
eosinophil cationic proteins, MBP, protease,
PAF
edema
mucus hypersecretion, increase in bronchial
reactivity, smooth muscle contraction
B.
Inhaled irritants
afferent pathways in the
vagus nerves travel to the CNS
efferent
pathways from the CNS travel to efferent ganglia
postganglionic fibers release acetylcholine
binds to muscarinic receptors on airway smooth
muscle
broncho-constriction
C.
inhaled materials
stimulate afferent receptors
to initiate reflex bronchoconstiction or release of
tachynins (substance P)
directly stimulate
smooth muscle contraction
Basic Pharmacology
I.
-
Bronchodilators
1. Sympathomimetic Agents
Directly relax airway smooth muscle by
stimulating adenyl cyclase and increase the
formation of cAMP in the airway tissues that
results in bronchodilatation
-
Inhibit release of some bronchoconstricting
substances from the mast cells
-
Increase mucociliary transport
a. Beta-2 Selective Agonists
-
With large substitution on the amino group & in position of the
hydroxyl group on the aromatic ring
-
Given orally, by inhalation and parenterally
-
For short-acting: (terbutaline, albuterol, metaproterenol,
bitolterol, pirbuterol) - bronchodilation maximal in 30 minutes
lasting to 4 hours
-
For long acting:(salmeterol, bambuterol, formeterol) - 12 hours or
more
-
SE: skeletal muscle, tremor, nervousness and weakness
b. Non-selective Beta-Agonists:
- epinephrine, ephedrine, isoproterenol
2. Methylxanthine
drugs
a. caffeine
b. theophylline
c. theobromide
• Mechanism of action
- inhibit the enzyme phosphodiesterase
hydrolyses
cyclic nucleotide
result in high concentration of IC
cAMP
smooth muscle relaxation
- inhibition of cell surface receptors for adenosine
- anti-inflammatory effect : inhibit the late response of
antigenic challenge
Pharmacodynamics
• CNS : mild cortical arousal w/ increased alertness & deferral of
fatigue
- nervousness; insomnia
- in high doses: medullary stimulation and convulsions
- primary SE: nervousness and tremor
• CVS: have positive inotropic and chronotropic effects
- arrhythmia
- sinus tachycardia and increased cardiac output
- rises the PVR and BP slightly
- decrease blood viscosity and may improve blood flow –
pentoxifylline
• GIT: stimulate secretion of gastric acid and digestive enzymes
• Kidneys: weak diuretics
• Skeletal muscles: have potent effects in improving contractility
and in reversing fatigue of diaphragm in patient with COPD
• Smooth muscle: inhibit antigen-induced release of histamine
from lung tissue
Pharmacokinetics
-
Well absorbed from the GIT
Metabolized in the liver
Usual dose: 3-4mg/kg every 6 hours
SE: 15mg/L : anorexia, N/V, abdominal
discomfort, headache and anxiety
40mg/L: seizures or arrhythmia
Anti-Muscarinic Agent
• Competitively inhibits the effect of
acetylcholine at muscarinic receptors
effectively block the contraction of
the airway smooth muscle and increase
in secretion of mucus
• Ipratropium bromide – a quarternary
ammonium derivative of atropine
• Delivered by inhalation
• Slightly less effective than beta agonist
• Effective in COPD
II. Anti-inflammatory Agents
1.
-
-
Corticosteroids
Improving all indices of asthma: severity of
symptoms, tests of airway caliber, bronchial
reactivity, frequency of exacerbation and quality
of life
Inhibit production of inflammatory cytokines
Reduce bronchial reactivity
Increase airway caliber
SE: oral candidiasis
Preparations:
a. oral: prednisone
b. IV: methylprednisolone
c. aerosol: beclomethasone, flunisolide,
budesonide, triamcinolone, fluticasone,
mometasone
2. Cromolyn Sodium & Nedocromil
- Prevent mast cell degranulation
- Taken prophylactically
- Used as aerosol
- Effectively inhibit both antigen-and exerciseinduced asthma
- Also useful in reducing symptoms of allergic
rhinoconjunctivitis
- SE: throat irritation, cough, mouth dryness,
chest tightness and wheezing, reversible
dermatitis, myositis, gastroenteritis,
pulmonary infiltration with eosinophils and
anaphylaxis
III. Leukotriene Antagonists
• Block the action of leukotrienes by :
- inhibition of 5-lipoxygenase, thereby preventing
leukotriene synthesis
- inhibition of the binding of leukotriene D4 to its
receptor on target tissues, thereby preventing its
action
• Drug categories
a. Zileuton – a 5-lipoxygenase inhibitor
- 600 mg QID
- may cause hepatotoxicity
b. Zafirlukast – 20mg BID
Montelukast – 10mg OD
- are LTD4 antagonist
• Taken orally
• Have demonstrated an important role
fro leukotrienes in aspirin-induced
asthma
• Their effect on symptoms, airway
caliber, bronchial reactivity and airway
inflammation are less marked than the
effects of inhaled corticosteroids,
but they are almost equally effective
in reducing the frequency of
exacerbations
Other Drugs in the
Treatment of Asthma
1.
Anti-IgE Antibodies
- drugs that reduce the amount of IgE to mast cells
- inhibits synthesis of IgE by B-lymphocytes
- Omalizunab (anti-IgE Mab)
2. Calcium channel Blockers
- inhibit airway narrowing induced by variety of
stimuli
3. Nitric Oxide Donors
- relaxation of smooth muscle and vasculature
- very lipophilic drug, can be inhaled as a gas
- more useful in pulmonary hypertension
Possible Future Therapies
• Monoclonal antibodies directed
against cytokines
• Antagonist of cell adhesion molecules
• Protease inhibitors
• Immunomodulators
Other Respiratory Agents
A. Mucolytic Agents
1. Acetylcysteine (mucomyst)
- reduce the thickness and stickiness of purulent
and non-purulent pulmonary secretions
- antidote for paracetamol poisoning
2. Carbocysteine (SCMC)
- act by regulating and normalizing the viscosity of
secretion from the mucus cell of respiratory tract
- decrease the size and number of mucus
producing cells
3. Bromhexine
- depolymerization of mucopolysaccharides,
direct effect on bronchial glands
- liberation of lysosomal enzymes producing cells
which digest mucopolysaccharide fibers
B. Mucokinetic & Secretolytic
- increase respiratory tract secretions
- enhance pulmonary surfactant production
- stimulates cilia activity
C. Expectorant
1. Vagal stimulants: glyceryl guiacolate, salt
solution
2. Direct stimulants: KISS, bromhexine,
SCMC, ambroxol
D. Antitussives
1. Narcotic antitussives: heroin, codeine,
morphine
2. Non-narcotic antitussive:
Dextromethorphan