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CLINICAL PHARMACOLOGY

SGD CASE 4: BRONCHIAL ASTHMA


LECTURE NOTES (Dr. Cesar Mendoza)

ASTHMA
Asthma is a heterogeneous disease, usually characterized by
chronic airway inflammation.

VARIABLE AIRFLOW LIMITATION

Confirm presence of airflow limitation

Document that FEV 1/FVC is reduced (at least


once, when FEV 1 is low)

FEV 1/ FVC ratio is normally >0.75 0.80 in


healthy adults, and
>0.90 in children

It is defined by the history of respiratory symptoms such as

wheeze, shortness of breath, chest tightness and cough


that vary over time and in intensity, together with variable
expiratory airflow limitation
A syndrome characterized by airflow obstruction that varies
markedly, both spontaneously and with treatment. It harbors a
special type of inflammation in the airways that makes them more
responsive than non-asthmatics to a wide range of triggers,
leading to excessive narrowing with consequent reduced airflow
and symptomatic wheezing and dyspnea. Narrowing of the
airways is usually reversible, but in some patients with chronic
asthma, there may be an element of irreversible airflow
obstruction.

Confirm variation in lung function is greater than in


healthy individuals

The greater the variation, or the more times


variation is seen, the greater probability that the
diagnosis is asthma

Excessive bronchodilator reversibility (adults:


increase in FEV 1 >12% and >200mL; children:
increase >12% predicted)

Excessive diurnal variability from 1-2 weeks


twice-daily PEF monitoring (daily amplitude x
100/daily mean, averaged)

Significant increase in FEV 1 or PEF after 4 weeks


of controller treatment

If initial testing is negative:

DIAGNOSIS OF ASTHMA

The diagnosis of asthma should be based on:

A history of characteristic symptom patterns


Evidence
of
variable
airflow
limitation,
from
bronchodilator reversibility testing or other tests
Asthma is usually characterized by airway inflammation
and airway hyperresponsiveness, but these are not
necessary or sufficient to make the diagnosis of asthma.

Repeat when patient is symptomatic,


or after withholding bronchodilators

Refer for additional tests (especially


children 5 years, or the elderly)

SYMPTOMS

probability that symptoms are due to asthma if:


o More than 1 type of symptom (wheeze, shortness of
breath, cough, chest tightness)
o Symptoms often worse at night or in the morning
o Symptoms vary over time and in intensity
o Symptoms are triggered by viral infections, exercise,
allergen exposure, changes in weather, laughter,
irritants such as car exhaust, fumes, smoke, or
strong smells

probability that symptoms are due to asthma if:


o Isolated cough with no other respiratory symptoms
o Chronic production of sputum
o Shortness of breath associated with dizziness, light headedness or peripheral tingling
o Chest pain
o Exercise-induced dyspnea with noisy
inspiration (stridor)

CLINICAL PHARMACOLOGY
SGD CASE 4: BRONCHIAL ASTHMA
LECTURE NOTES (Dr. Cesar Mendoza)

PHYSICAL EXAMINATION

Physical Examination in people with asthma


o Often normal
o The most frequent finding is wheezing on
auscultation, especially on forced expiration
Wheezing is also found in other conditions, for example:
o Respiratory infections
o COPD
o Upper airway dysfunction
o Endobronchial obstruction
o Inhaled foreign body
Wheezing may be absent during severe asthma
exacerbations silent chest
TYPES OF ASTHMA

Extrinsic (atopic) & Intrinsic (non-atopic)


Exercised induced
Occupational
Drug induced

ATOPY

is a major risk factor for asthma, and nonatopic

individuals have a very low risk of developing asthma. Asthmatics


commonly suffer from other atopic diseases, like allergic rhinitis,
which may be found in over 80% of asthmat ic patients, and atopic
dermatitis (eczema).
Atopy is due to the genetically determined production of specific
IgE antibody, with many patients showing a family history of
allergic diseases.

CLINICAL PHARMACOLOGY
SGD CASE 4: BRONCHIAL ASTHMA
LECTURE NOTES (Dr. Cesar Mendoza)
Intrinsic asthma represents a small amount of all cases

It usually develops after the age of 30 and is not typically


associated with allergies
Women are more frequently affected and many cases
seem to follow a respiratory tract infection
The condition can be difficult to treat and symptoms are
often chronic and year-round

Exercise

Assess asthma severity after patient has been


on controller treatment for several months.
Severity is not static it may change over
months or years, or as different treatments
become available.

is a common trigger of asthma, particularly in

children. The mechanism is linked to hyperventilation, which


results in increased osmolality in airway lining fluid and triggers
mast cell mediator release, resulting in bronchoconstriction.

EIA

typically begins after exercise has ended and resolves

spontaneously within about 30min. EIA is worse in cold, dry


climates.
More common in sports activities such as cross-country running in
cold weather, overland skiing, and ice hockey than in swimming.

Occupational asthma

is characteristically associated with


symptoms at work with relief on weekends and holidays.
Several substances found in the workplace acting as sensitizing
agents that may trigger asthma symptoms.

PHARMACOLOGIC TREATMENT

o
o
o

SEVERAL DRUGS MAY TRIGGER ASTHMA

B-blockers commonly acutely worsen asthma, and their


use may be fatal
The mechanisms are not clear, but are likely mediated
through increased cholinergic bronchoconstriction.
All B blockers need to be avoided, and even selective B2
blockers or topical application may be dangerous
ACEI are theoretically detrimental as they inhibit
breakdown of kinins (bronchoconstrictors) however, they
rarely worsen asthma.
Aspirin may worsen asthma in some patients.

ASSESSING ASTHMA SEVERITY

How?
o

When?

Asthma severity is assessed retrospectively from


the level of treatment required to control
symptoms and exacerbations

Beta agonist
Anticholinergic
Theophyllines

Controllers
o
o
o

If removed from exposure within the first 6 months of symptoms,


there is usually complete recovery.
More persistent symptoms lead to irreversible airway changes.

Relievers (bronchodilators)

Corticosteroids
Antileukotrienes
C

CLASSIFICATION

Bronchodilators
o B sympathomimetics

Salbutamol, Terbutaline, Bambuterol,


Salmeterol, Formoterol, Ephedrine
o Methylxanthines

Theophylline (anhydrous),
Aminophylline, Choline, Theophyllinate,
Hydroxyethyl theophylline,
Theophylline ethanolate of piperazine,
Doxophylline
o Anticholinergics (muscarinic receptor
antagonist)

Ipratropium Br, Tiotropium Br


o Leukotriene Antagonists

Montelukast, Zafirilukast
o Mast cell stabilizers

Sodium Cromoglycate, Ketotifen


o Corticosteroids

CLINICAL PHARMACOLOGY
SGD CASE 4: BRONCHIAL ASTHMA
LECTURE NOTES (Dr. Cesar Mendoza)
Systemic: Hydrocortisone, Prednisolone
and others

Inhalational: Beclomethasone
dipropionate, Budesonide, Fluticasone
propionate, Flunisolide, Circlesonide
Anti-IgE antibody

Omalizumab

Concurrent use of inhaled glucocorticoid with


salmeterol is advised for patient with persistent
asthma
o COPD: equivalent to inhaled anticholinergics in
COPD. Reduce breathlessness by abolishing the
reversible component of airway obstruction.
FORMOTEROL
o Long acting selective B2 agonist which acts 12h
when inhaled
o Compare to salmeterol it has a faster onset of
action (within 10mins)
o

METHYXANTHINES

Theophylline and its derivatives are most commonly used


for the treatment of COPD and asthma
Caffeine, theophylline and t heobromine are naturally
occurring xanthine alkaloids which have qualitatively
similar actions

MECHANISM OF ACTION

SYMPATHOMIMETICS

SALBUTAMOL
o Selective B2 agonist with less cardiac side
effects
o Inhaled salbutamol produce bronchodilation
within 5 min and the action lasts for 2-4h
o Used for acute asthmatic attack. Not suitable for
prophylaxis
o Side effect: Palpitation, restlessness,
nervousness, throat irritation
o Metabolism: metabolized in gut; oral
bioavailability is 50%
o Duration of action: Oral salbutamol acts 4-6h
o Dose: 2-4mg/oral; 100-200ug/inhalation
TERBUTALINE
o Similar to salbutamol.; regular use dose not
reduce bronchial hyper-reactivity
o Dose: 5mg/oral; 0.25mg/ip or sc;
250ug/inhalation
SALMETEROL
o First long acting selective B2 agonists with slow
onset of action
o Twice daily for maintain therapy/nocturnal
asthma, but not for acute asthma

Methylxanthines inhibits cyclic nucleotide


phosphodiesterase (PDEs), thereby preventing
conversion of cAMP and cGMP to 5-AMP and 5-GMP
respectively. Inhibition of PDEs will lead to an
accumulation of intracellular cAMP and cGMP.
Bronchodilation, cardiac stimulation and vasodilation
occur when cAMP level rises in the concerned cells.
Theophylline and related methylxanthines are
relatively nonselective in the PDE subtypes inhibitor.
Theophylline is a competitive antagonist at
adenosine receptors. Adenosine can cause
bronchoconstriction in asthmatics and potentiate
immunologically induced mediator release from
human lung mast cells. Methylxanthines inhibits the
adenosine action thereby causing bronchodilation.

CLINICAL PHARMACOLOGY
SGD CASE 4: BRONCHIAL ASTHMA
LECTURE NOTES (Dr. Cesar Mendoza)
METHYXANTHINES THEOPHYLLINE

INTERACTIONS

Theophylline metabolism decreased by smoking,


phenytoin, rifampicin, phenobarbitone and charcoal
broiled meat meal which increases the parenthesis.
Erythromycin, ciprofloxacine, cimetidine, oral
contraceptives and allopurinol inhibits CYP1A2 and
increasing the theophylline plasma concentration; dose
should be reduced to 2/3.
Theophylline reduces the effects of phenytoin, lithium.
Theophylline enhances the effects of furosemide,
sympathomimetics, digitalis, oral anticoagulants and
hypoglycemics.

Corticosteroids are not bronchodilator; benefit by


reducing bronchial hypereactivity, mucosal edema and by
suppressing inflammatory.
Inhaled glucocorticoids are partially absorbed and
because of their systemic AEs oral glucocorticoids are
usually reserved for patients with severe persistent
asthma
Systemic steroid therapy
o Severe chronic asthma
o Status asthmaticus/acute asthma exacerbation
Inhaled steroids
o High topical and low systemic activity (due to
poor absorption/fast pass metabolism)

INDICATIONS

Primarily used to treat chronic obstructive lung


disorders and asthma
Also used to treat apnea

ANTICHOLINERGICS

Parasympathetic activation / release of Ach cause


bronchoconstriction and increase mucus secretion
Blocking the action of Ach by anticholinergic drugs
produce bronchodilation and also reduce the volume of
respiratory secretion.
Less effective than sympathomimetic
Inhaled ipratropium / tiotropium are choice of
bronchodilator choice in COPD
Tritropium produce longer duration of action than
ipratropium
ADR: Dry mouth, urinary tract discomfort

LEUKOTRIENE ANTAGONISTS (Montelukast, Zafirlukast)

Both are having similar action and clinical utility


Block the cys-leukotrienes C4, D4 and E4 (LTC4, LTD4,
LTE4)
Alternative for inhaled glucocorticoids
Prophylactic therapy for mild, moderate asthma, not used
for terminating asthma
Both are very safe drugs and ADRs are few (headache,
rashes); eosinophilia and neuropathy are infrequent. Few
cases Churg-strauss syndrome (vasculitis with
eosinophilia) have been reported.
Dose: Montelukast 10mg OD, Zafirlukast 20mg BD

CORTICOSTEROIDS
MAST CELL STABILIZERS (Sodium Cromoglycate, Ketotifen)

CLINICAL PHARMACOLOGY
SGD CASE 4: BRONCHIAL ASTHMA
LECTURE NOTES (Dr. Cesar Mendoza)

Inhibits degranulation of mast cell by trigger stimuli and


prevent the release of histamine, LTs, PAF, interleukins
etc. from mast cells. Inhibition of mediator release by
cromolyn is through blockade of calcium influx in mast
cells.
Long time therapy reduces cellular inflammatory
response.
It is not histamine antagonist / bronchodilator
ineffective in asthmatic attack
Pharmacokinetic
o Not absorbed orally. It is administered as an
aerosol through metered dose inhaler delivering
1mg per dose, 2 puffs 4 times a day
o Not popular, production of cough and
bronchospasm because of particulate nature of
the inhalation
o Small fraction of the inhaled drug is absorbed
systemically and excreted unchanged form in
urine and bile.

ANTI-IgE antibody: Omalizumab

Recombinant DNA derived monoclonal antibody


Selectively binds to human immunoglobulin E (IgE) and
decrease binding affinity of IgE to the high affinity IgE
receptor on the surface of mast cells and basophils,
reduce allergic response
Omalizumab may be part icularly useful for treatment of
moderate to severe allergic asthma in patients who are
poorly controlled with conventional therapy.
Due to the high cost of the drug, limitations on dosage,
and limited clinical trial data, it is not currently used as
first line therapy.

MDIs are devices used to administer aerosolized drugs that emit


a fixed dose of medication with each pulse. They have a metallic
chamber containing a suspension or solution of the drug with a
liquid propellant that at room temperature and at mospheric
pressure, turns to its gaseous phase. A key piece in this system is
the dosage valve, which releases at each pulse a controlled,
reproducible dose of medication. The drug is released at a high
speed (at more than 30m/s through the mouth piece) and in the
form of particles with an MMAD of between 2 and 4um.

USING AN MDI WITH A VALVED HOLDING CHAMBER


1.
2.
3.
4.
5.
6.
7.
8.

Remove the cap from the MDI and chamber


Shake well for 5 seconds
Insert the MDI into the open end of the chamber
(opposite the mouth piece).
Breather out all the way
Keep your chin up
Place the mouthpiece of the chamber between your teeth
and seal your lips tightly around it
Press the canister once
Breathe in slowly through your mouth to completely fill
your lungs. If you hear a horn-like: sound, you are
breathing too quickly and need to slow down

CLINICAL PHARMACOLOGY
SGD CASE 4: BRONCHIAL ASTHMA
LECTURE NOTES (Dr. Cesar Mendoza)
9.

Hold your breath for 10 seconds (count to 10 slowly) to


allow the medication to reach the airways of the lung.
10. Repeat steps 2-8 each puff ordered by your doctor. Wait
about 1 minute in between puffs.
11. Replace the cap on your MDI when finished.
12. If you are using a corticosteroid MDI, rinse your mouth
and gargle using water or mouthwash after each use.
You should always use a chamber with a steroid MDI

deposited in the lungs. The large droplets are deposited in the


oropharynx, while the droplets that are too small are expelled
during expiration.

TABLE 2. Advantages of the Inhalation Route of Administration


with Aerosolized Drugs in Treating Pulmonary Diseases
Aerosol doses are generally smaller than systemic doses. For
example, the oral dose of albuterol is 2-4mg, whereas the inhaled
dose is 0.2mg (via MDI) to 2.5mg (via SVN).
More than 90% of the B receptors are located in the alveolar
walls, and specifically there is a high density of B2 receptors
located in the epithelium of the airway between the main bronchi
and the terminal bronchioles. Salbutamol should be deposited
more peripherally (in the middle and small airways) to produce an
adequate therapeutic effect.

Onset of effect is faster with inhalation than with oral


administration. For example, the onset of effect with oral albuterol
is about 30mins. Whereas inhaled albuterol takes effect within
about 5mins.
The drug is delivered directly to the target organ (lungs), with
minimized systemic exposure.

There is a high density of M3 receptors in the submucosal glands


and lung lymph nodes. The location of these receptors in the lung Systemic adverse effects are less severe and less frequent with
suggests that ipratropium bromide should be deposited in the inhalation than with systemic drug delivery (injection or oral) (eg.
Less muscle tremor and tachycardia with B2 agonists; less
conducting airways in order to reach a greater effectiveness.
hypothalamic-pituitary-adrenal suppression with corticosteroids).
In the case of inhaled corticoids, the treatment seems to be more
beneficial when more of the drug is dispersed throughout the Inhaled drug therapy is painless and relatively comfortable.
lungs, as inflammatory cells such as eosinophils, lymphocytes and
macrophages are present throughout the respiratory tract and MDI metered dose inhaler
alveoli in asthma patients.
SVN small volume nebulizer

NEBULIZERS

can administer high doses of medications in

patients who are not able to coordinate or cooperate and they are
able to administer several substances mixed together in one same
solution. The minimal inspiratory flow needed for the aerosol
produced by a nebulizer to reach the lungs is 6-81/min. However,
there are high amounts of drug lost as much of the medication is
retained in the nebulizer dead-space, or it is lost in the room air
during expiration. It has been estimated that only 10% of the
dose that is initially placed in the nebulizer will be effectively

COPD chronic obstructive pulmonary disease

CLINICAL PHARMACOLOGY
SGD CASE 4: BRONCHIAL ASTHMA
LECTURE NOTES (Dr. Cesar Mendoza)

DEFINITION AND TERMINOLOGY

A flare-up or exacerbation is an acute or sub-acute


worsening of symptoms and lung function compared with
the patients usual status
TERMINOLOGY
o Flare-up is the preferred term for discussion
with patients
o Exacerbation is a difficult term for patients
o Attack has highly variable meanings for
patients and clinicians
o Episode does not convey clinical urgency

BRONCHODILATORS

Consider management of worsening asthma as a


continuum
o Self management with a written asthma action
plan
o Management in primary care
o Management in the emergency department and
hospital
o Follow -up after any exacerbation

B agonist
o Salbutamol

Ventolin, Asmalin, Asmacaire, Ventar

Combivent, Duavent, Multivent,


Pulmodual
o Terbutaline

Bricanyl, Pulmoxcel
o Procaterol

Meptin
o Procaterol

Meptin
o Salmeterol

Seretide, Adeflo, Airflusal, Combiwave,


Salmed, Salmeflo
o Formoterol

Symbicort, Foster, Flutiform, Foradil


o Indacaterol

Onbrez

CLINICAL PHARMACOLOGY
SGD CASE 4: BRONCHIAL ASTHMA
LECTURE NOTES (Dr. Cesar Mendoza)

CORTICOSTEROIDS

Prednisone
o Pred, Prolix
Methylprednisolone
o Medrol, Medcort, Medixon
Hydrocortisone
o Solucortef, Pharmacort, Hycortil, Hydrovex
Fluticasone
o Seretide, Adeflo, Combiwave, Salmed, Salmeflo,
Flutiform
Budesonide
o Symbicort, Budecort, Obucort
Beclomethasone
o Foster

NON PHARMACOLOGICAL INTERVENTIONS

Avoidance of tobacco smoke exposure


o Provide advice and resources at every visit;
advise against exposure of children to
environmental tobacco smoke (house, car)
Physical Activity
o Encouraged because of its general health
benefits. Provide advice about exercise -induced
bronchoconstriction
Occupational asthma
o Ask patients with adult -onset asthma about
work history. Remove sensitizers as soon as
possible. Refer for expert advice, if available.
Avoid medications that may worsen asthma
o Always ask about asthma before prescribing
NSAIDs or beta-blockers
(Allergen Avoidance)
o Not recommended as a general strategy for
asthma
See GINA Box 3-9 and online appendix for details