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OVERVIEW OF ASTHMA

MANAGEMENT

ZESHAN HAIDER KAZMI


M.PHIL (PHARMACOLOGY)
Asthma:
epidemiology / pathology
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%)
Asthma definition
 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

GINA Guidelines 1998


Comparisons of asthma
Asthma
Patho-  CD 4+ lymphocytes
physiology:
chronic  Eosinophils
inflammation  Mast cells

Vary over time and in


Clinical severity
history:  cough
symptoms
 wheeze
 chest tightness
 breathlessness
Modern view of
asthma Allergen

Macrophage/
dendritic cell Mast cell

Th2 cell Neutrophil

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
Inflammatory processes

Barnes PJ Epidemiology / pathology


Asthma - an inflammatory
disease
Normal Asthma
Risk factors that lead to
asthma development
Predisposing Factors Contributing Factors
 atopy  respiratory infections
 small size at birth
 diet
Causal Factors
 air pollution
 indoor allergens – outdoor
– dust mites
– indoor
– animal dander
– cockroach  smoking
– fungi – passive
 outdoor allergens – active
– pollens
– fungi
 occupational sensitisers

GINA Guidelines 1998


Common occupational
agents
 flour / grain dust (bakery)

 paint, glue or plastic fumes

 soldering flux

 natural rubber latex

 wood dust
Asthma diagnosis

 history and pattern of symptoms


 physical examination
 measurements of lung function
- reversibility test
- diurnal variability
 evaluation of allergic status
Is it asthma?

 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
Ask about triggers
Symptoms can occur or worsen in the presence of:

Others
Allergens
 exercise
 animal dander
 viral infection
 dust mites  smoke

 pollen  changes in temperature

 fungi  strong emotional expression


 aerosol chemicals
 drugs (NSAIDs, ß-blockers)
‘Clinical’ classification of severity

Clinical features before treatment


Symptoms Night-time PEF
symptoms

STEP 4 Continuous <60% predicted


Severe Frequent
persistent
Limited physical Variability >30%
activity
STEP 3 Daily >60% - <80%
Moderate Use β2-agonist daily >1 time a week predicted
persistent
Attacks affect activity Variability >30%
STEP 2
>1 time a week >80% predicted
Mild persistent >2 times a month
but <1 time a day Variability 20-30%

STEP 1 <1 time a week


Intermittent >80% predicted
Asymptomatic and <2 times a month
normal PEF between Variability <20%
attacks

Asthma severity is graded, in the GINA guidelines, according to the frequency of symptoms,
occurrence of symptoms at night, and PEF measurement before treatment.
Treatment goal: take
control of asthma
 no chronic symptoms
 no asthma attacks
 no emergency visits
 no need for quick relief (as needed) ß2-agonist
 normal physical activity including exercise
 lung function as close to normal as possible
 no adverse effects from medicine

GINA Guidelines 1998


Treatment
strategy
 identify and avoid triggers that make asthma
worse
 achieve control by selecting appropriate
medication
 treat asthma attacks promptly and
effectively
 educate patients to manage their condition
 monitor and modify asthma care to maintain
effective long-term control

GINA Guidelines 1998


Pharmacological therapy

Relievers Controllers
 inhaled
fast-acting  inhaled corticosteroids
ß2-agonists  inhaled long-acting ß -
2
 inhaled anticholinergics agonists
 inhaled cromones

 oral anti-leukotrienes

 oral theophyllines

 oral corticosteroids
 RELIEVERS MEDICATION

 Quickrelief medicine or rescue


medicine.

 Rapid acting bronchodilators that act to


relieve bronchoconstriction.
ROUTE OF ADMINISTRATION
 INHALATION
 Pressurized metered dose inhalers ( MDI)
 MDI-plus-spacer
 Breath actuated MDI
 Dry powder inhalers
 Nebulised

 ORAL

 PARENTERAL
Classes of ß2-agonists
Speed of
onset RESCUE MEDICATION

fast onset, long duration M


inhaled terbutaline A
fast inhaled salbutamol inhaled formoterol I
N
T
E
N
oral terbutaline A
inhaled salmeterol N
slow oral salbutamol oral bambuterol C
oral formoterol E
Duration
short long of action
Inhaled formoterol belongs to a new class of bronchodilator, in that
it has both a long duration and fast onset of effect.
Short-acting inhaled B-agonist
 Use intermittently to control
episodes of bronchoconstriction
 Avoid regular scheduled use if
possible
 An increase use is an indication of
deteriorating control
LONG ACTING β2 AGONIST

 Mechanism of action:
 Bronchodilator (They stimulate intracellular adenyl
cyclase, the enzyme that catalyzes the conversion of
adenosine triphosphate to cyclic-3',5'-adenosine
monophosphate (cAMP). Increased cAMP levels cause
relaxation of bronchial smooth muscle and inhibition of
release of mediators of immediate hypersensitivity from
cells, especially from mast cells)
 Enhance mucociliary clearance
 Modulate mediators release from mast cells and basophils

 Example : Inhaled : Salmeterol (Seretide), formeterol


Oral : Bambuterol
Salbutamol (Ventolin)
Terbutaline (Bricanyl)
Clenbuterol
LONG ACTING β2 AGONIST

 Inhaled β2 Agonists have fewer side effects than


oral formulations.

 Side-effects : tachycardia, palpitations, tremors,


anxiety, headache and hypokalaemia.
Differences between ß2-agonists

 chemical structure

 pharmacological properties:
 mode of action in the ß2-receptor region
 potency
 efficacy (ie full / partial agonism)
 selectivity
CONTROLLER MEDICATIONS

 Are medications taken daily on a long term


basis that are useful in getting and keeping
persistent asthma under control.
 Prophylactic, preventive or maintenance
medications
 Include
 Inhaled glucocorticosteroids
 Systemic glucocorticosteroids
 Theophylline
 Long acting inhaled β2 agonist
 Long acting oral β2 agonist
 Leukotriene modifiers
GLUCOCORTICOSTEROIDS
 Mechanisms of action :
 Reduced airway inflammation (They are anti-
inflammatory agents which inhibit the production of
cytokines, an effect which reduces eosinophil infiltration,
inhibits macrophage and eosinophil function, decreases
mediator cells in the epithelium, reduces vascular
permeability, and reduces the production of leukotrienes)

 Efficacy in improving lung function, decreasing


airways hyperresponsiveness, reducing
symptoms, reducing frequency and severity of
exacerbations and improving quality of life.
GLUCOCORTICOSTEROID

 Inhaled : Beclomethasone (Becotide, Clenil A)


Budesonide
Fluticasone

 Oral : Prednisolone
Dexamethasone

 Parenteral : Hydrocortisone
Methylprednisolone
 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 the gut, first past
effect of liver.
 Systemic adverse effects include : skin thinning,

easy bruising, cataract, obesity, adrenal


suppression, hypertension, diabetes and myopathy.
Inhaled steroids are first line
maintenance therapy

Laitinen LA et al, J Allergy Clin Immunol 1992


METHYLXANTHINES

 Mechanism of action: Anti-inflammatory


effects & bronchodilator (The proposed
mechanism of action was inhibition of
phosphodiesterase, which results in an
increase in cAMP. However, this effect is
negligible at therapeutic concentrations)
 Side effects :
 GIT Symptoms – nausea, vomiting
 CVS Symptoms – tachycardia, arrhythmias
 Drug interaction : Erythromycin, cimetidine
and rifampicin
Anti-cholinergics
 Inhaled Ipratropium bromide (ATEM,
spiriva)

 Mechanism of action : Bronchodilator.

 Efficacy : Bronchodilator actions are less


potent than those of inhaled ß2-agonists,
slower onset of action which peaks 30 –
60 min.

 Side-effect : Dry mouth.


LEUKOTRIENE MODULATORS

 MECHANISM OF ACTION :
 Block the synthesis of all leukotrienes (The
leukotriene receptor antagonists are selective and
competitive antagonists of the cysteinyl leukotriene
(Cys LT1) receptor. Cysteinyl leukotriene (LTC4,
LTD4 and LTE4) production and receptor occupation
have been correlated with the pathophysiology of
asthma, including airway edema, smooth muscle
constriction, and altered cellular activity associated
with the inflammatory process. Zafirlukast is the
first Cys LT1 receptor antagonist to be released)

 Example : montelukast ( Singulair, Montiget,


Montair ), Zafirlukast (Accolate)
Adverse Effects
 Headache
 Gastritis
 Rhinitis

Considerations:
*Zafirlukast should be taken one hour before meals or two hours after meals
because food can decrease the bioavail-ability.
*Montelukast should be taken in the evening
and may be taken without regard to food.
Cromolyn Sodium And Nedocromil
 Mechanism of Action: Cromolyn and
nedocromil are mast-cell stabilizers. They
prevent the release of the mediators of
type I allergic reactions, including
histamine and slow-reacting substance of
anaphylaxis, from sensitized mast cells.
They also inhibit type III reactions to a
lesser extent. It has been suggested that
the drugs may block calcium channels in
mast cell membranes. The specific
mechanism(s) of action of the drug on
mast cells remains to be established
Cromolyn Sodium And Nedocromil
 Use: Cromolyn or  Adverse Effects:
nedocromil is 2. Dryness of throat
recommended for
prophylaxis of 3. Bad Taste
exercise induced 4. wheezing
bronchospasm or 5. nausea
exposure to a known
allergen. They are
also recommended as
anti-inflammatory
long-term control
medications in
patients with mild
persistent asthma.
*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.
R-DNA derived Monoclonal Antibodies
 Mechanism: These bind to human IgE selectively,
this leads to decrease binding of IgE to the high
affinity IgE receptor on the surface of mast cells and
basophiles
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
STEP 4: SEVERE PERSISTENT Step
CONTROLLER: daily multiple down
medications RELIEVER when
• Inhaled steroid
• Long-acting bronchodilator • Inhaled ß2- controlle
• Oral steroid agonist p.r.n. d
Avoid or control triggers
STEP 3: MODERATE PERSISTENT • Patient
CONTROLLER: daily education
medications RELIEVER
• Inhaled steroid and long-acting essential at
bronchodilator • Inhaled ß2- every step
• Consider anti-leukotriene agonist p.r.n. • Reduce
Avoid or control triggers therapy if
controlled for
STEP 2: MILD PERSISTENT at least
CONTROLLER: daily 3 months
medications RELIEVER • Continue
• Inhaled steroid • Inhaled ß2-
• Or possibly cromone, oral monitoring
theophylline or anti-leukotriene agonist p.r.n.
Avoid or control triggers
STEP 1: INTERMITTENT

RELIEVER Step up
CONTROLLER: none
• Inhaled ß2- if not controlled
agonist p.r.n. (after check on
inhaler technique
Avoid or control triggers and compliance)
TREATMENT
GINA Guidelines 1998
Step 1

Step 1: Intermittent asthma


Controller Reliever
 Inhaled β 2-agonist prn
(not more than 3x a week)
None required
 Inhaled β 2-agonist or
cromone prior to exercise
or allergen exposure

Avoid or control triggers


ICS should be prescribed
to asthmatic patients
requiring daily B-agonist use
If asthma symptoms are intermittent, then reliever therapy
alone is sufficient.
Step 2

Step 2: Mild persistent asthma


Controller Reliever
 Daily inhaled corticosteroid  Inhaled β2-agonist prn
(200-500 µg), cromone, (but less than 3-4 times
sustained release theophylline,
or anti-leukotriene per day)

If still not controlled, particularly
nocturnal symptoms, increase
inhaled steroid (500-800 µg) or
add long-acting bronchodilator

Avoid or control triggers

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 3

Step 3: Moderate persistent asthma


Controller Reliever
 Daily inhaled corticosteroid  Inhaled β2-agonist prn
> 500 µg (but less than 3-4 times
 Daily long-acting per day)
bronchodilator
 Consider anti-leukotriene

Avoid or control triggers

A long-acting inhaled β2-agonist is the first choice add on therapy to


inhaled steroids
Step 4

Step 4: Severe persistent asthma


Controller Reliever
 Daily inhaled corticosteroid  Inhaled β2-agonist prn
800-2000 µg (but less than 3-4 times
 Daily long-acting per day)
bronchodilator
 Daily / alternate day oral
corticosteroid

Avoid or control triggers

Patients with severe persistent asthma are often poorly controlled


despite using combinations of all available controller medications.
Summary of GINA
guidelines 1998
 gain control

 step up if control is not achieved and sustained

 step down if control is sustained for at least 3


months

 review treatment every 3-6 months

Future?
stepping up and down should involve both LAßA and ICS
Conclusion

 There is a synergistic effect on


treatment 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 constituents
separately.
Management of Asthma in Pregnancy.

 Management of asthma during


pregnancy should be aggressive.

 Cooperation between the resp.


physician and obstetrcian
throughout pregnancy for women
with severe asthma.
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 in
pregnant women.
Theophyllines.
 May aggravate the nausea and gastroesophageal
reflux.
 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 in
pregnant women.
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 during


pregnancy and lactation and the benefits outweigh
any potential risks to the foetus and baby.