detail study on asthma for the medical student and for the pharmacologist

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INTRODUCTION TO ASTHMA
Asthma is a chronic inflammatory disorder of the
airways in which many cells & cellular elements
play a role (mast cells, eosinophils, T lymphocytes,
macrophages, neutrophils, & epithelial cells).
In susceptible individuals , inflammation causes
recurrent episodes of wheezing, breathlessness,
chest tightness, and coughing, particularly at
night/early morning. These episodes are associated
with variable airflow obstruction often reversible
spontaneously/treatment

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REASON OF ASTHMA
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INFLAMMATION
Airflow Limitation
SYMPTOMS
Cough Wheeze
Dyspnoea
TRIGGERS
Allergens, Exercise,
Cold Air, SO2 Particulates
Pathogenesis:(11)
Airway
Hyperresponsiveness
Genetic*
INDUCERS
Allergens,Chemical sensitisers,
Air pollutants, Virus infections

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DIFFERENCE BETWEEN NORMAL AND ASTHMATIC
PERSON
Airways narrow, caused
by:
• tightening of the
muscles that
surround the
airways
• swelling of the
inner lining, and/or
• increase in mucus
production

6. CAUSES
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•ENVIRONMENTAL
•GENETIC
•GENE-ENVIRONMENT INTERACTIONS
CD14-ENDOTOXIN REACTIONS
ALLERGENSPOLLUTION

7. TYPES OF ASTHMA
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In others, a variety of trigger factors (infection,
irritants, pollution exercise, exposure to cold air,
psychogenic) may
be involved:
Extrinsic asthma: it is mostly episodic, less
prone to status asthmaticus.
Intrinsic asthma: it is tends to be perennial(lasting for
an indefinitely long time), status asthmaticus is more common.

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TYPES OF ASTHMA
• Extrinsic (Allergic/Immune)
– Atopic - IgE
– Occupational – IgG
• Intrinsic (Non immune)
– Aspirin induced
– Infections induced

9. Pathophysiology
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Inflammation
Bronchial smooth muscle
Hypertrophy
+
Mucous glands
Hypertrophy
Thick mucous
Plugging of small airway
(bronchoconstriction)
Hyper responsiveness to triggers
Long period (chronicity)

10. PHARMACOLOGY

11. TRICKS TO COUNTER ASTHMA-
• DIAGNOSE- AT CORRECT TIME
• PREVENTION- FROM CAUSATIVE
AGENTS AND EVENTS
• TREATMENT- SELECTION OF BEST
SUITABLE COURSES
• EMRGENCY- OPT INHALATIONAL
QUICK RELIEF DRUGS
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• Asthma is a problem worldwide, with an
estimated 300 million affected individuals
• Prevalence increasing in many countries,
especially in children
• A cause of a significant number of
preventable deaths
EPIDEMIOLOGY

13. 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

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16. 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, protease,
PAF
edema
mucus hypersecretion, increase in bronchial
reactivity, smooth muscle contraction

17. 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

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CLASSIFICATION
I. Bronchodilators
A. β 2 Sympathomimetics:
-- Salbutamol, Terbutaline, Bambuterol, Salmeterol, Formoterol, Ephedrine.
B. Methylxanthines:
-- Theophylline (anhydrous), Aminophylline, Choline theophyllinate,
Hydroxyethyl theophylline, Theophylline ethanolate of piperazine, Doxophylline.
C. Anticholinergics:
--Ipratropium bromide, Tiotropium bromide.
II. Leukotriene antagonists :
--Montelukast, Zafirlukast.
III. Mast cell stabilizers:
--Sodium cromoglycate, Ketotifen.
IV. Corticosteroids
A.Systemic:
-- Hydrocortisone, Prednisolone and others.
B. Inhalational:
--Beclomethasone dipropionate, Budesonide, Fluticasone propionate, Flunisolide,
Ciclesonide.
V. Anti-IgE antibody : Omalizumab

19. 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

20. 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

21. 2. Methylxanthine drugs
a. caffeine
b. theophylline
c. theobromide
• Mechanism of action
- inhibit the enzyme phosphodiesterase
hydrolyses cyclic nucleotide result in high
concentration of cAMP smooth muscle relaxation
- inhibition of cell surface receptors for adenosine
- anti-inflammatory effect : inhibit the late response
of antigenic challenge

22. 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

23. 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

24. Adverse Effect
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25. Adverse effect
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27. 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

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29. 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

30. Side Effect
• Both montelukast and zafirlukast are very
Safe drugs;
• produce few side effects like headache
and rashes.
Eosinophilia and neuropathy are infrequent.
• Few cases of Churg-Strauss syndrome
(vasculitis with eosinophilia) have been reported.
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Churg–Strauss syndrome (CSS, also known as eosinophilic granulomatosis with polyangiitis [EGPA] or
allergic granulomatosis) is an autoimmune condition that causes inflammation of small and medium-sized blood
vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy).

31. 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 (inflammation and degeneration of muscle tissue.),
gastroenteritis, pulmonary infiltration with
eosinophils and anaphylaxis

32. 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

33. • Taken orally
• Have demonstrated an important role
for 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

34. 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
- Omalizumab (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

35. Possible Future Therapies
• Monoclonal antibodies directed against
cytokines
• Antagonist of cell adhesion molecules
• Protease inhibitors
• Immunomodulators

36. 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

37. 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

38. FUTURE SCOPE
The current 'gold standard' of asthma
therapy is a combination inhaler
containing a long-acting β2-agonist with a
corticosteroid – an improved form of
adrenal gland extract. Cromoglycate,
derived from a plant product and
theophylline, a dietary methyl xanthine,
has also been extensively used in the
therapy of asthma.
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SO WE SHOULD HOPE FOR A BETTER SCOPE

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