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OVERVIEW OF ASTHMA
MANAGEMENT
ZESHAN HAIDER KAZMI
M.PHIL (PHARMACOLOGY)
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Asthma:epidemiology / pathology
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Epidemiology
Common disease
Prevalence of asthma :
Primary school children : 13.8%
Children aged 13-14 : 9.6%
Adults : 4.1%
Higher prevalence in rural (4.5%),compared to urban areas (4.0%)
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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 hyper responsiveness
Asthma definition
GINA Guidelines 1998
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Patho-physiology:chronicinflammation
Comparisons of asthma
Asthma CD 4+ lymphocytes
Eosinophils
Mast cells
Vary over time and inseverity
cough
wheeze chest tightness
breathlessness
Clinical
history:
symptoms
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Mucus
hypersecretion
Hyperplasia
Eosinophil
Mast cell
Allergen
Th2 cell
Vasodilatation
New vessels
Plasma leakOedema
Neutrophil
Mucus plug
Macrophage/dendritic cell
Bronchoconstriction
Hypertrophy / hyperplasia
Cholinergicreflex
Epithelial shedding
Subepithelial
fibrosis
Sensory nerveactivation
Nerve activ
ation
Modern view ofasthma
Barnes PJ
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Inflammatory processes
Barnes PJ Epidemiology / pathology
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AsthmaNormal
Asthma - an inflammatorydisease
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Risk factors that lead toasthma development
Predisposing Factorsatopy
Causal Factors indoor allergens
dust mites animal dander cockroach fungi
outdoor allergens pollens fungi
occupational sensitisers
Contributing Factors respiratory infectionssmall size at birthdiet
air pollution outdoor indoor
smoking passive
active
GINA Guidelines 1998
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flour / grain dust (bakery)
paint, glue or plastic fumes
soldering flux
natural rubber latex
wood dust
Common occupationalagents
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Asthma diagnosis
history and pattern of symptoms
physical examination
measurements of lung function
- reversibility test
- diurnal variability
evaluation of allergic status
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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
Is it asthma?
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Allergens
animal dander dust mites
pollen
fungi
Symptoms can occur or worsen in the presence of:
Others
exercise
viral infection
smoke
changes in temperature
strong emotional expression aerosol chemicals
drugs (NSAIDs, -blockers)
Ask about triggers
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Clinical classification of severity
Clinical features before treatment
Symptoms Night-timesymptoms
PEF
STEP 4
Severepersistent
STEP 3
Moderatepersistent
STEP 2
Mild persistent
STEP 1
Intermittent
Continuous
Limited physical
activityDaily
Use 2-agonist daily
Attacks affect activity
>1 time a week
but 2 times a month
60% - 30%
>80% predicted
Variability 20-30%
>80% predicted
Variability
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no chronic symptoms
no asthma attacks
no emergency visits
no need for quick relief (as needed) 2-agonist
normal physical activity including exercise
lung function as close to normal as possible no adverse effects from medicine
GINA Guidelines 1998
Treatment goal: takecontrol of asthma
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Pharmacological therapy
Controllers inhaled corticosteroids
inhaled long-acting 2-
agonists
inhaled cromones
oral anti-leukotrienes
oral theophyllines oral corticosteroids
Relievers inhaled fast-acting
2-agonists
inhaled anticholinergics
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RELIEVERS MEDICATION
Quick relief medicine or rescuemedicine.
Rapid acting bronchodilators that act to
relieve bronchoconstriction.
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ROUTE OF ADMINISTRATION
INHALATION Pressurized metered dose inhalers ( MDI) MDI-plus-spacer
Breath actuated MDI Dry powder inhalers Nebulised
ORAL
PARENTERAL
Cl f i
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Classes of 2-agonists
fast onset, long duration
inhaled terbutaline
inhaled salbutamol inhaled formoterol
oral terbutaline
oral salbutamol
oral formoterol
inhaled salmeterol
oral bambuterol
MAI
NTENAN
CE
RESCUE MEDICATIONSpeed of
onset
Duration
of action
fast
slow
longshort
Inhaled formoterol belongs to a new class of bronchodilator, in thatit has both a long duration and fast onset of effect.
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Short-acting inhaled B-agonist
Use intermittently to controlepisodes of bronchoconstriction
Avoid regular scheduled use ifpossible
An increase use is an indication ofdeteriorating control
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LONG ACTING 2 AGONIST
Mechanism of action: Bronchodilator (They stimulate intracellular adenyl
cyclase, the enzyme that catalyzes the conversion ofadenosine triphosphate to cyclic-3',5'-adenosinemonophosphate (cAMP). Increased cAMP levels causerelaxation of bronchial smooth muscle and inhibition ofrelease of mediators of immediate hypersensitivity fromcells, especially from mast cells)
Enhance mucociliary clearance Modulate mediators release from mast cells and basophils
Example : Inhaled : Salmeterol (Seretide), formeterol
Oral : BambuterolSalbutamol (Ventolin)Terbutaline (Bricanyl)Clenbuterol
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LONG ACTING 2 AGONIST
Inhaled 2 Agonists have fewer side effects thanoral formulations.
Side-effects : tachycardia, palpitations, tremors,anxiety, headache and hypokalaemia.
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Differences between 2-agonists
chemical structure
pharmacological properties:
mode of action in the 2-receptor region
potency
efficacy (ie full / partial agonism)
selectivity
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CONTROLLER MEDICATIONS
Are medications taken daily on a long termbasis that are useful in getting and keepingpersistent asthma under control.
Prophylactic, preventive or maintenance
medications Include
Inhaled glucocorticosteroids Systemic glucocorticosteroids Theophylline Long acting inhaled 2 agonist Long acting oral 2 agonist Leukotriene modifiers
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GLUCOCORTICOSTEROIDS
Mechanisms of action :
Reduced airway inflammation (They are anti-inflammatory agents which inhibit the production ofcytokines, an effect which reduces eosinophil infiltration,
inhibits macrophage and eosinophil function, decreasesmediator cells in the epithelium, reduces vascular
permeability, and reduces the production of leukotrienes)
Efficacy in improving lung function, decreasing
airways hyperresponsiveness, reducingsymptoms, reducing frequency and severity ofexacerbations and improving quality of life.
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GLUCOCORTICOSTEROID
Inhaled : Beclomethasone (Becotide, Clenil A)
Budesonide
Fluticasone
Oral : Prednisolone
Dexamethasone
Parenteral : Hydrocortisone
Methylprednisolone
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Side effects
Local effects
oropharyngeal candidiasis, dysphonia, upper airway
irritation How to prevent ? Mouth washing after inhalation &
use of spacer
Systemic adverse effects depends on the dose and potency of
glucocrticosteroids , absorption in thegut, first pasteffect of liver.
Systemic adverse effects include : skin thinning,easy bruising, cataract, obesity, adrenalsuppression, hypertension, diabetes and myopathy.
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Laitinen LA et al, J Allergy Clin Immunol 1992J Allergy Clin Immunol 1992
maintenance therapy
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METHYLXANTHINES
Mechanism of action: Anti-inflammatoryeffects & bronchodilator (The proposedmechanism of action was inhibition ofphosphodiesterase, which results in anincrease in cAMP. However, this effect isnegligible at therapeutic concentrations)
Side effects : GIT Symptoms nausea, vomiting
CVS Symptoms tachycardia, arrhythmias Drug interaction : Erythromycin, cimetidine
and rifampicin
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Anti-cholinergics
Inhaled Ipratropium bromide (ATEM,spiriva)
Mechanism of action : Bronchodilator.
Efficacy : Bronchodilator actions are less
potent than those of inhaled 2-agonists,slower onset of action which peaks 30 60 min.
Side-effect : Dry mouth.
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LEUKOTRIENE MODULATORS
MECHANISM OF ACTION : Block the synthesis of all leukotrienes (The
leukotriene receptor antagonists are selective andcompetitive antagonists of the cysteinyl leukotriene(Cys LT1) receptor. Cysteinyl leukotriene (LTC4,LTD4 and LTE4) production and receptor occupationhave been correlated with the pathophysiology ofasthma, including airway edema, smooth muscleconstriction, and altered cellular activity associatedwith the inflammatory process. Zafirlukast is thefirst Cys LT1 receptor antagonist to be released)
Example : montelukast ( Singulair, Montiget,Montair ), Zafirlukast (Accolate)
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Adverse Effects
Headache
Gastritis
Rhinitis
Considerations:*Zafirlukast should be taken one hour before meals or two hours after mealsbecause food can decrease the bioavail-ability.
*Montelukast should be taken in the eveningand may be taken without regard to food.
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Cromolyn Sodium And Nedocromil
Mechanism of Action: Cromolyn andnedocromil are mast-cell stabilizers. Theyprevent the release of the mediators oftype I allergic reactions, including
histamine and slow-reacting substance ofanaphylaxis, from sensitized mast cells.They also inhibit type III reactions to alesser extent. It has been suggested thatthe drugs may block calcium channels in
mast cell membranes. The specificmechanism(s) of action of the drug onmast cells remains to be established
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Cromolyn Sodium And Nedocromil
Use: Cromolyn ornedocromil isrecommended forprophylaxis ofexercise induced
bronchospasm orexposure to a knownallergen. They arealso recommended asanti-inflammatorylong-term control
medications inpatients with mildpersistent asthma.
Adverse Effects:2. Dryness of throat3. Bad Taste4. wheezing
5. nausea
*The therapeutic response may occur within the first two weeks of therapy,but may take up to six weeks to determine the maximum benefit.The primary advantage of these agents is safety.
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R-DNA derived Monoclonal Antibodies
Mechanism: These bind to human IgE selectively,this leads to decrease binding of IgE to the highaffinity IgE receptor on the surface of mast cells andbasophiles
Reduction in surface binding of IgE limits the degree of
release of mediators of the allergic response
Omalizumab useful for treatment of
moderate to severe allergic asthma
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Step 1
Step 1: Intermittent asthma
Controller
None required
Reliever
Inhaled 2-agonist prn(not more than 3x a week)
Inhaled 2-agonist orcromone prior to exerciseor allergen exposure
Avoid or control triggers
If asthma symptoms are intermittent, then reliever therapy
alone is sufficient.
ICS should be prescribedto asthmatic patients
requiring daily B-agonist use
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Step 2
It is often best to initiate an inhaled steroid early and at a high dose to
establish rapid control and then reduce the dose.
Step 2: Mild persistent asthma
Avoid or control triggers
Controller
Daily inhaled corticosteroid
(200-500 g), cromone,sustained release theophylline,or anti-leukotriene
Reliever
Inhaled 2-agonist prn
(but less than 3-4 timesper day)
If still not controlled, particularlynocturnal symptoms, increase
inhaled steroid (500-800g) oradd long-acting bronchodilator
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Step 3
A long-acting inhaled 2-agonist is the first choice add on therapy to
inhaled steroids
Step 3: Moderate persistent asthma
Avoid or control triggers
Reliever
Inhaled 2-agonist prn
(but less than 3-4 timesper day)
Controller
Daily inhaled corticosteroid
> 500 g Daily long-acting
bronchodilator
Consider anti-leukotriene
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Summary of GINAguidelines 1998
gain control
step up if control is not achieved and sustained
step down if control is sustained for at least 3months
review treatment every 3-6 months
Future?stepping up and down should involve both LAA and ICS
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Conclusion
There is a synergistic effect ontreatment when these agents are combined.
The combination of these agents also
makes the treatment simpler for the patient,
which may improve compliance.
Co-formulated products are generally less
expensive than giving the two constituentsseparately.
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Management of Asthma in Pregnancy.
Management of asthma duringpregnancy should be aggressive.
Cooperation between the resp.physician and obstetrcianthroughout pregnancy for women
with severe asthma.
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Beta2 agonists.
There is no evidence of a teratogenic risk.
Ipratopium bromide / Sodium cromoglycate. Safe for use during pregnancy.
Salmeterol/formoterol.
Have not been tested extensively inpregnant women.
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Theophyllines.
May aggravate the nausea and gastroesophagealreflux.
May cause transient neonatal tachycardia and
irritability.
Inhaled corticosteroids.
Has good safety profile in pregnancy.
Experience with fluticasone in pregnancy is limited.
Anti-leukotrienes.
No data is available on the use of this agent inpregnant women.
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Oral corticosteroids. Sometimes necessary for severe asthma but usually
only for short periods. An increased risk of cleft palate has been reported in
animals given huge doses.
Breastfeeding. Should be continued in women with asthma.
In general, asthma medications are safe duringpregnancy and lactation and the benefits outweighany potential risks to the foetus and baby.
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