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• Pharmacology of anti asthmatic drugs
Bronchial asthma is a chronic inflammatory disorder of the
airways associated with airway hyper responsiveness
• Chest tightness
• Nighttime or early morning cough
Airway obstruction is reversible
either spontaneously or with treatment.
• Bronchial asthma is a disease of the lungs in which
an obstructive ventilation disturbance of the
respiratory passages evokes a feeling of shortness of
• The cause is a sharply elevated resistance to airflow
in the airways.
• Despite its most strenuous efforts, the respiratory
musculature is unable to provide sufficient gas
• The result is a characteristic asthma attack, with
spasms of the bronchial musculature, edematous
swelling of the bronchial wall and increased mucus
WHO Definition of Asthma
• "A chronic inflammatory disorder of the airways in which
many cells play a role, in particular mast cells, eosinophils,
and T lymphocytes. In susceptible individuals this
inflammation causes recurrent episodes of wheezing,
breathlessness, chest tightness, and cough particularly at
night and/or in the early morning. These symptoms are
usually associated with widespread but variable airflow
limitation that is at least partly reversible either
spontaneously or with treatment. The inflammation also
causes an associated increase in airway responsiveness to a
variety of stimuli."
• 235-330 million affected individuals
• 1% -18% - global prevalence rate
• 2,50,000-3,45,000 people die per year from
• It is more common in developed than
• Common in both gender
Asthma Prevalence and Mortality
Source: Masoli M et al. Allergy 2004
Higher concordance in Monozygotic twins
↑ed incidence in primary relatives
• ADAM-33 1st gene identified as Asthma susceptibility gene
• 10 most common genes a/w Asthma
Innate immunity (CD-14,HLA DRB1,DQB1)
Th₂ cell signalling (IL-4,IL-13,IL-4Ra)
Cellular inflammation (TNF,FCEDR1B)
Lung development (ADAM33,ADRB2)
Genome-wide association studies (GWAS) : 17 q 21,11 p 14,5
q 23,Chr 18
Environment : Epigenetic modifications
Begins in childhood.
A positive family history of atopy is common,
Asthmatic attacks are often preceded by allergic
rhinitis, urticaria, or eczema.
The disease is triggered by environmental
antigens, such as dusts, pollen, animal dander, and
foods, but potentially any antigen is implicated.
A skin test with the offending antigen results in an
immediate wheal-and-flare reaction, a classic
example of the type I IgE-mediated
hypersensitivity reaction .
NON ATOPIC ASTHMA
• The mechanism of bronchial inflammation and hyper-
responsiveness is much less clear in individuals with non-atopic
• Viral infections of the respiratory tract (most common) and
inhaled air pollutants such as sulfur dioxide, ozone, and nitrogen
• In asthmatic subjects however, the bronchial response,
manifested as spasm, is much more severe and sustained.
• A positive family history is uncommon
• Serum IgE levels are normal
• There are no associated allergies
• Virus-induced inflammation of the respiratory mucosa lowers the
threshold of the subepithelial vagal receptors to irritants.
• The ultimate humoral and cellular mediators of airway
obstruction (e.g., eosinophils) are common to both atopic and
non-atopic variants of asthma. 10
Extrinsic (Allergic) Triggers:
Intrinsic (Non-Allergic) Triggers:
Infections (cold and flu)
Cold or humid air
Intense emotions (ex. Stress)
Fragrances and chemicals
Occupational irritants 11
Pathophysiology of Asthma
• Asthma is a disease characterized by airway
inflammation and episodic, reversible
– Two characteristic features:
1) Inflammatory changes in the airway;
2) Bronchial hyperreactivity to stimuli.
Pathophysiology of Asthma
• Antigens (pollen and house-dust mites) sensitize patients
by eliciting the production of IgE type of antibodies, which
remain either circulating in the blood or become attached to
the mast cells of nasal or bronchial tissues and basophils.
• On re-exposure the same antigen, the resulting antigen-
antibody reaction in the early phase causes degranulation
of the lung mast cells and releasing of the powerful
bronchoconstrictors: histamine, 5-HT, PGD2 and
cysteinyl leucotriens (LTB4, LTC4 and LTD4).
• Lung mast cells also release ILs (IL-4, IL-5 and IL-13).
In the late (delayed) phase of asthma, these mediators
activate additional inflammatory cells (eosinophils,
basophils, and alveolar macrophages) which also release
LTs and ILs.
• Other mediators of inflammation, in delayed phase,
are: adenosine (causing bronchconstriction), neuropeptides
( causing mucus secretion and increase in vascular
permeability; neurokinin A, causing bronchoconstriction),
•The normal tone of bronchial smooth muscle is influenced
by a balance between parasympathetic, sympathetic and
non-adrenergic–non-cholinergic (NANC) mediators
Aims of anti asthmatic drugs:
• To relieve acute episodic attacks of asthma
(bronchodilators, quick relief medications).
• To reduce the frequency of attacks, and
nocturnal awakenings (anti-inflammatory
drugs, prophylactic or control therapy ).
Anti asthmatic drugs
(Quick relief medications)
treat acute episodic attack of
• Short acting 2-agonists
• Xanthine preparations
(control medications or
reduce the frequency of attacks
• Mast cell stabilizers
• Leukotrienes antagonists
• Anti-IgE monoclonal antibody
• Long acting ß2-agonists
Non selective -agonists.
• Potent bronchodilator
• rapid action (maximum effect within 15 min).
• S.C. or by inhalation (aerosol or nebulizer).
• Has short duration of action (60-90 min)
• Drug of choice for acute anaphylaxis
Not effective orally.
CVS side effects:
tachycardia, arrhythmia, hypertension
Skeletal muscle tremor
Not suitable for asthmatic patients with
hypertension or heart failure.
CVS patients, diabetic patients
Selective 2 –agonists
drugs of choice for acute attack of asthma
Are mainly given by inhalation (metered dose
inhaler or nebulizer).
Can be given orally, parenterally.
Short acting ß2 agonists
e.g. salbutamol, terbutaline
Long acting ß2 agonists
e.g. salmeterol, formeterol
• Beta agonists or adrenergic agents, can be thought of as
rescue medications because they provide rapid relief of
labored breathing during an asthma episode.
• All of the currently available beta agonists are superior
to both adrenaline and ephedrine for duration of action
and less-pronounced side effects.
• These potent , when inhaled, provide rapid relief of
bronchial obstruction. Duration of action varies from
four to six hours. An exception is salmeterol
(Serevent®) which works for up to twelve hours but has
a slower onset of action of about an hour.
• These agents are excellent for the prevention of
wheezing triggered by exercise or cold air if taken
before the activity or exposure.
• Individuals may prefer one agent to another for
reasons of taste, cost, or personal preference. Generic
agents are now available for albuterol.
• Users of generic substitutes should be aware of the
potential problem of dosage variability.Side effects
are mild affecting less than 10% of users.
Short acting ß2 agonists
Salbutamol, inhalation, orally, i.v.
Terbutaline, inhalation, orally, s.c.
Have rapid onset of action (15-30
short duration of action (4-6 hr)
used for symptomatic treatment of
episodic attack of asthma.
• Salmeterol is a bronchodilator. It works
by relaxing muscles in the airways to
• Salmeterol inhalation is used to prevent
asthma attacks. It will not treat an asthma
attack that has already begun.
Salmeterol inhalation is also used to treat
chronic obstructive pulmonary disease
(COPD) including emphysema and
LONG ACTING ß2 AGONIST
Adverse Reactions of β2 agonists:
1) Skeletal muscle tremor - which results from a
direct stimulation of 2-adrenoceptors in skeletal
• This effect is most notable on the initiation of
therapy and gradually improves on continued
2) Cardiac effect - 2-Agonists also cause tachycardia
and palpitations in some patients.
• When administered by inhalation, the 2-agonists
produce only minor side effects.
3) Metabolism disturbance - ketone bodies↑,
acidosis, [K+]o↓ 39
• Clinical Use:
1. Asthma: maintenance treatment
2. Chronic obstructive pulmonary disease (COPD)
3. Central sleep apnea (CSA)
• Adverse Reactions:
– Narrow margin of safety. Toxic effects are
related to its plasma concentrations.
– Gastrointestinal distress, tremor, and insomnia.
– Cardiac arrhythmias, convulsions → lethal.
• There are M1, M2, M3 receptor subtype in the airway.
• Selectively blocking M1, M3 receptor is resulted in
• Ipratropium bromide binds to all M-R subtypes (M1,
M2 and M3 ), and inhibits acetylcholine-mediated
• In the treatment of asthma, anticholinergic drugs are both old
and new. One hundred years ago, atropine, the parent drug of
this class, was smoked as a cigarette for asthma.
• Its usefulness was limited by unacceptable side effects of rapid
heart rate, hot skin, and dry mucous membranes. Excessive
doses could even provoke delusions and irrational behavior.
• Ipratropium (Atrovent®) preserves the bronchodilator effects
while eliminating these adverse effects.
• Atrovent® is not as potent as the sympathomimetics and is not
considered a first choice medication. It has an additive effect
when beta agonists are insufficient for symptom relief. It can
serve as an acceptable alternate when sympathomimetics
• Atrovent® should be inhaled four
times daily for maximum
• It's available in multidose inhaler
form and in unit dose ampoules for
• The only common side effect is dry
• Combivent® is a convenient,
combination product composed of
albuterol and ipratropium.
Typical Spirometric (FEV1) Tracings
2 3 4 5
Asthmatic (After Bronchodilator)
Asthmatic (Before Bronchodilator)
Note: Each FEV1 curve represents the highest of three repeat measurements
• Act at several points in this process. Cromolyn and nedocromil
stabilize mast cells and nerve endings preventing initiation of the
• Leukotriene antagonists block the production of leukotrienes, a
potent mast cell messenger chemical, or block the transmission of
their message to receptor cells.
• Corticosteroids stabilize blood vessels reducing vascular leakiness.
They also restore sensitivity of receptor cells to beta-agonists and
down-regulate the production and release of inflammatory
chemicals. This results in decreased numbers of eosinophils in the
airway walls. Corticosteroids have considerably greater anti-
inflammatory activity than any of the other drugs. The result is a
gradual resolution of the asthmatic condition.
• Since these drugs do not relax bronchial muscle, they
don’t provide the immediate relief characteristic of
• With regular and continued use of anti-inflammatory
agents however, the need for bronchodilators is
• Inhaled corticosteroids may trigger cough during an
acute asthma attack. Oral prednisone may be substituted
at such times.
• Mechanism of Action:
1. Broad anti-inflammatory efficacy
① Block the synthesis of arachidonic acid by
② Reduce bronchial reactivity.
2. Increase the responsiveness of β-adrenoceptors
in the airway.
• The anti-inflammatory actions of GCS are mediated by
stimulation of synthesis of lipocortin, which inhibits pathways
for production of PGs, LTs and PAF. These mediators
would normally contribute to increased vascular
permeability and subsequent changes including
oedema, leucocyte migration, fibrin deposition. 50
• Glucocorticosteroids provide long-term
stabilization of the symptoms due to their anti-inflammatory
effects. Inhaled GCS, along with beta-2-agonists are the
first choice drugs for chronic asthma.
• GCS inhibit the release of PGs and LTs and thus prevent
smooth muscle contraction, vascular permeability and
airway mucus secretion.
• GCS produce eosinopenia which prevents cytotoxic effects
of the mediators released from eosinophils.
• GCS enhance beta-2-adrenergic response by up-regulating
the beta-2-receptors in lung cells and leuckocytes.
•Several hours are required for DNA transcription and RNA
translation to occur after administering GCS.
Routes of administration
e.g. Budesonide & Fluticasone, beclometasone
– Given by inhalation, given by metered-dose
– Have first pass metabolism
– Best choice in asthma, less side effects
Orally: Prednisone, methyl prednisolone
Injection: Hydrocortisone, dexamethasone
Glucocorticoids in asthma
Are not bronchodilators
Reduce bronchial inflammation
Reduce bronchial hyper-reactivity to stimuli
Have delayed onset of action (effect usually
attained after 2-4 weeks).
Maximum action at 9-12 months.
Given as prophylactic medications, used alone or
combined with beta-agonists.
Effective in allergic, exercise, antigen and
Systemic corticosteroids are reserved for:
– Status asthmaticus (i.v.).
Inhaled steroids should be considered for adults,
children with any of the following features
• using inhaled β2 agonists three times/week
• symptomatic three times/ week or more;
• or waking one night/week.
• Cushing’s syndrome
• Tendency to hyperglycaemia
• Negative nitrogen balance
• Increased appetite
• Increased susceptibility
• Obesity etc.
Side effects due to systemic corticosteroids
– Adrenal suppression
– Growth retardation in children
– Fluid retention, weight gain, hypertension
– Susceptibility to infections
– Fat distribution, wasting of the muscles
Inhalation has very less side effects:
– Oropharyngeal candidiasis (thrush).
– Dysphonia (voice hoarseness).
– Abrupt stop of corticosteroids should be
avoided and dose should be tapered (adrenal
produced by the action of 5-lipoxygenase on
Synthesized by inflammatory cells found in the
airways (eosinophils, macrophages, mast cells).
Leukotriene B4: chemotaxis of neutrophils
Cysteinyl leukotrienes C4, D4 & E4:
– increase bronchial hyper-reactivity
– mucosal edema, mucus hyper-secretion
Leukotriene receptor antagonists
e.g. zafirlukast, montelukast, pranlukast
are selective, reversible antagonists of cysteinyl
leukotriene receptors (CysLT1receptors).
Have anti-inflammatory action
Less effective than inhaled corticosteroids
Have glucocorticoids sparing effect (potentiate
Uses of leukotriene receptor antagonists
Are not effective to relieve acute attack of
Prophylaxis of mild to moderate asthma.
Antigen and exercise-induced asthma
Can be combined with glucocorticoids (additive
effects, low dose of glucocorticoids can be
Elevation of liver enzymes, headache, dyspepsia
Mast cell stabilizers
e.g. Cromolyn (cromoglycate) - Nedocromil
act by stabilization of mast cell membrane.
given by inhalation (aerosol, microfine powder,
Have poor oral absorption (10%)
These are Not bronchodilators.
Not effective in acute attack of asthma.
Prophylactic anti-inflammatory drug.
Reduce bronchial hyper-reactivity.
Effective in exercise, antigen and irritant-induced
Children respond better than adults.
Prophylactic therapy in asthma especially in
minor upper respiratory tract irritation (burning
sensation, nasal congestion)
is a monoclonal antibody directed against
prevents IgE binding with its receptors on
mast cells & basophiles.
↓ release of allergic mediators.
used for treatment of allergic asthma.
Expensive-not first line therapy.
Medications to Treat Asthma:
How to Use a Spray Inhaler
technique at each visit.
Source: “What You and Your Family Can Do About Asthma” by the Global Initiative for Asthma Created
and funded by NIH/NHLBI
Used by some (usually
moderate or severe)
asthma patients to
monitor ongoing lung
function to detect changes
Also known as a
“spacer” or valved holding
Delivery of medication
over 100% more effective
Medications to Treat Asthma:
Inhalers and Spacers
Spacers can help
patients who have
difficulty with inhaler
use and can reduce
potential for adverse
Medications to Treat Asthma:
• Machine produces a mist
of the medication
• Used for small children or
for severe asthma
• No evidence that it is
more effective than an
inhaler used with a
Establishing the diagnosis
Not all that wheezes is asthma
• The medical history!
• Pulmonary function testing with
– Reversibility: 12% AND 200 cc change in FEV1
– Obstructive physiology on pulmonary function test (FEV1
reduced much more than FVC)
• Bronchoprovocation testing
– Methacholine, histamine, exercise
• Exhaled nitric oxide (NO)
Methods of investigation
• Objectively: Tachypnoe with prolonged expiration,
wheezing, dry rales
• Sputum analysis: eosinophils, Kurshman spirals
(mucus from small bronchi), Sharko-Leiden crystals
(enzymes of eosinophils)
• General blood analysis: mild leucocytosis,
• Spyrometry: decreased FVC, FEV1, FEV1/FVC,
increased daily variability
Test lung function when diagnosing asthma
• Exhaled nitric oxide is a biological marker
that correlates with eosinophilic
inflammation in asthma.
• Exhaled NO measurement can provide
diagnostic and predictive value for a
• More longitudinal studies are required
to clarify the clinical significance of
exhaled NO in asthma.
Kim et al, Curr Opin Allergy Clin Immunol 2014,14:49–5483
Indicators of Severe Asthma
Anxious and diaphoretic appearance, upright position
Breathlessness at rest and inability to speak in full sentences
Tachycardia (HR>120) and Tachypnoea (RR>30)
Pulse oximetry <91% (on room air)
PaCO2 normal or increased
PEFR <150 L/min or <50% predicted
LEVEL OF CONTROL
maintain and find lowest controlling
consider stepping up to
step up until controlled
treat as exacerbation
TREATMENT OF ACTION
Step-wise approach to the treatment of asthma according to recent guidelines. LTRA, leukotriene
receptor antagonist; SR, slow release. The dose of inhaled corticosteroids refers to
• Patient awareness/education
Efficacy of patient education and parental awareness has also been shown to be
effective in individual studies from India
(Singh et al. 2002; Gupta et al. 1998; Ghosh et al. 1998; Lal et al. 1995).
• Lifestyle Modifications: Regular balanced diet and avoidance of obesity.
Short acting beta-2 agonists should be used prior to anticipated exercise, in a
patient with exercise-induced Asthma, to alleviate symptoms
(Consensus on Guidelines of Management of Clinical Asthma 2005).
• Alternative System of Medicine:
Yogic breathing exercise technique, Pranayama, was been shown to reduce in
(Singh et al. 1990).
Avoidance of precipitating factors
Avoid dusting when subject is around
Avoid using carpets, stuffed toys, open bookshelves, smoking,
chemical sprays in house. Prefer mosquito nets to repellants
Food containing allergen to be avoided
Maintain record of daily symptoms
*Involves avoidance of allergens and nonspecific triggers when
Asthma is established.
(Custovic et al. 1998; Strachan and Cook 1998; Chalmers et al. 2002; Jindal et al.
• Asthma is not yet curable *
• Under diagnosis & Under management
• Therapy is still evolving
• Better understanding of Pathology
• New line of Promising Drugs.
• Proper management normal life.
• Goodman & Gilman’s - pharmacological basis of
therapeutics 11th edition
• Katzung - Basic & Clinical pharmacology 12th edition
• K D Tripathi – Essentials of medical pharmacology
• Lippincott – modern pharmacology with clinical
• Harrison’s principles of internal medicine 18th edition
• GINA guidelines 2014