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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
exercise-induced 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 D 4
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 aspirininduced 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

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