Drugs used in the

Treatment of
Bronchial Asthma
AYESHA IDRISS
Outline
• Overview
• Causes
• Pathophysiology
• Diagnosis
• Treatment
• Medication
• Step-up approach

2
Overview
• Bronchial asthma (BA)
• Is a respiratory tract condition where there is an element of
chronic inflammatory process, with reversible narrowing of the
airways and an associated airway hyperresponsiveness

• Cardiac asthma (CA)

• Is a condition where there is either an acute left ventricular
failure or congestive cardiac failure

3
 Overview Differences between BA and CA
Bronchial Asthma
Pathophysiology Usually caused by immune
mediated mechanisms and/
direct contact with minute
particles.
Oedematus cells with mucus
plugs, secretion of mucus and
thickened basement
membranes.
Signs Lungs will have bilateral
wheezing sounds/rhonchi
SOB with wheezing
Management Use of oxygen and
bronchodilators like beta
agonists, with long term usage
of corticosteroids to retard the
chronic inflammatory process.
Cardiac Asthma
The hearts left side has
become damaged leading to
reduced capacity to pump the
blood out of the heart, leading
to build up of fluid in the
lungs.
Lungs will be bilateral basal
fine crepitations
SOB with or without
wheezing, increase in BP and
HR, and a feeling of
apprehension.
Based on oxygenation and
reducing the fluids in the lungs
with morphine, and reducing4
the overall load to the heart
with a loop diuretic like
furosemide, and controlling
Overview
• Bronchial Asthma:
• an inflammatory disease associated with:
• Bronchial hyperactivity
• Bronchospasm
• Mucus secretion
• Edema
• Cellular infiltration

• Asthmatic responses which normally last from 30 to 60 min are

associated with bronchospasm due to the actions of histamine and
leukotrienes released
5
Overview
• Obstruction in airflow
• Acute or sub-acute inflammation of the airways, precipitated by a
variety of factors that result in bronchial hyperreactivity
• Inflammation of the airways
• Varying degrees of severity and chronicity
• Hyperresponsiveness
• Coughing and wheezing

6
Overview
• Late asthmatic responses involve infiltration of eosinophils and
lymphocytes into airways, leading to bronchoconstriction and
inflammation with mucus plugging

• Management of asthma include bronchodilators to provide short-

term relief and antiinflammatory agents which reduce hyperactivity
and protect against cellular infiltration

7
Overview
• Overall aim of treatment is to reduce overall airway
inflammation and aborting acute (inflammatory) attacks with
a “rescue inhaler”

• Education of patients is vital, particularly if a certain stimulus

is noted

8
Epidemiology

• 7-10% worldwide
• 250000 deaths a year
• 9-13% in the US
• Preponderance in children
• Boys are affected more than girls but women are affected
more than men
• Blacks are affected more than whites

9
Causes
• Lumen gets smaller when smooth muscles contract
• Obstruction in small airways cause decrease in flow rate
• Inflammatory process stimulates cytokine cascade and causes
smooth muscle to constrict
• RESULT: lumens get smaller until there is wheezing, obstruction
and primarily, air can’t get out of the small airways

10
Causes
• Symptoms include:
• Shortness of breath
• Wheezing
• Increased respiratory rate
• History of allergies
• Nasal polyps
• Obstructive
• Accessory muscles to breath
• Decreased breath sounds
• Diaphoresis

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Causes
• Idiopathic
• Exercise
• Allergens (environmental)
• Mites
• animals
• Infections
• Rhinovirus
• Sinitus present in about 50% of cases
• GERD
• Aspirin
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Pathophysiology
• In asthma there is reversible airway inflammation

• Inflammation and constriction are stimulated by increased

Immunoglobulin E (IgE)

13
Determining Severity
• Two factors are considered:
I. Impairment
• How much the patient is affected in their daily lives
II. Risk
• How much severe attacks to warrant major therapy (systemic
corticosteroids)

14
Determining Severity
• Impairment
• Daytime symptoms
• Awakenings
• SABA (short acting beta agonist)
• Daily interference
• Lung function (not commonly used)
• Risk
• Exacerbation
• Requiring systemic corticosteroids

15
 Determining Severity
Impairment
Factors intermittent Mild Moderate Severe

Daytime ≤ 2days/week > 2x/week Everyday Multiple x/day

symptoms

Awakenings ≤ 3-4x/month 1/week Many times

2nIghts/month

SABA ≤ 2x/week > 2days/week Everyday Many time

Daily None Few Some Extreme

interference

16
Lung function FEV1 FEV1 FEV1
= Normal FEV1 = Normal =< 5% => 5%
FVC FVC FVC FVC
Determining Severity
Risk

Source: NAEPP; US Department of Human services

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Pathophysiology
Immediate/ Early phase
 Immunoglobin E (IgE) uses mass cells and basophils to release histamine
which causes swelling

Late phase (4-12hrs)

 Inflammatory cell recriuitment
 Eosinophils
 Basophil
 Neutrophil
 Helper-T’s-IL-4, IL-5, IL-13

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Pathophysiology
• Airway remodelling
• Mucous gland hyperplasia, smooth muscle hypertrophy,
thickening, fibrosis, angiogenesis

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Clinical Pathophysiology
• Air

• Gastroosophageal Reflux Disease (GERD)

• Post- Nasal Drip (PND)

• Sentos Triad
• Aspirin (NSAIDs)

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Risk Factors
• Genetics
• Atrophy
• Wheezing with RSV
• Smoking exposure
• Antibiotic use
• Volatile organic compounds
• phthalates

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Precipitating Factors
• Dust
• Mold
• Smoke
• Allergens
• Viral infections
• Weather
• Perfumes

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Diagnosis
• Clinical diagnosis
• Chest tightness
• Wheezing
• Exercising
• Allergies
• Pulmonary Function Tests (PFTs)

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Diagnosis
PFTs
• Since asthma is reversible, PFTs can be either normal or
abnormal
• Normal
• Provokative test is done (methacholine challenge test)
• Abnormal =

FEV1
< 0.7
FVC
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Diagnosis
PFTs
• Stimulation of smooth muscle with choline causes constriction
• Methacholine is an analogue of muscarinic agonist

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Treatment
• Two types
• Non pharmacological

• Pharmacological

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Treatment
Non pharmacological
• Get rid of all precipitating factors or causes that can be
controlled with medication

• Smoking
• Pets
• Dust

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Treatment
Non pharmacological
• GERD
• Elevate patient during sleep
• No food before 3hrs to bedtime
• Avoid spicy food, caffeine, cigarette

• PND
• Intranasal corticorsteriods (ICS)

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 Treatment
Pharmacological
• Sympathomimetic drugs
• Adrenalin, Ephedrine, Isoproterenol, Albutrerol)
• Methylxanthine drugs
• Theophylline, Theobromine, Caffeine
• Antimuscarinic drugs
• Atropine
• Corticosteroids
• Fluticason, Budesonide, Triamcinolone, Mometasone
• Mast cell Stabilizers
• Cromlyn and Nedocromil

• Leukotriene receptor antagonists (LTRAs) 29

Mechanism of Action

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Drugs Used in The Treatment of
Asthma
Sympathomimetics
• Adrenoceptors relax airway smooth muscle and block the release of
bronchoconstricting mediators from mast cells

• May also block microvascular leakage and increase mucociliary

transport by increasing ciliary activity

• Generally, stimulation of Β2 receptors relaxes airway smooth

muscles, blocks mediator release, and causes tachycardia and
skeletal muscle tremor as side effects

• Best delivered by inhalation due to greatest local effect on airway 31

smooth muscle with least systemic toxicity
Drugs Used in The Treatment of
Asthma
β2 Agonists (Albuterol)
• Most widely use sympathomimetics presently

• β2 agonists target the bronchial smooth muscles

• Cause efflux of calcium out of the smooth muscle cell

• RESULT: Relaxation of bronchial smooth muscle cells

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Drugs Used in The Treatment of Asthma
β2 Agonists
• Short-acting beta agonist (SABA)
• Albuterol
• Levalbuterol (Zopanex)
• Meter dose inhalers (MDI) and nebulizers

• Long-acting beta agonist (high lipid solubility)

• Salmeterol
• Formeterol

• Two stages of asthma:

• Intermittent (2x or less/week)
• Persistent (2+/week) 33
Short term Medication
β2 agonists (SABA)
• All asthmatic patients

• Acute attacks

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Long term Medication
β2 agonists (LABA)
• Salmeterol is used in conjunction with inhaled glucorticosteroids (ICS)

• Duration of action is at least 12 hours, hence a twice daily

administration

• Lipophilic side-chain binds firmly to an exo-site that is adjacent to, but

distinct from, the β2–agonist binding site, resulting in Salmeterols
functions being almost irreversible agonist

• Due to its slow onset of action, salmeterol should not be used to treat
acute attacks of bronchospasm
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Drugs Used in The Treatment of
Asthma
Methylxanthine derivatives
• The major source of theophylline, theobromine and caffeine is
beverages (tea, cocoa and coffee respectively

• An important advantage of theophylline is due to its low cost

• Most commonly used theophylline preparation is aminophylline

(theophylline-ethylenediamine complex)

36
Mechanism of Action
Methylxanthine derivatives
• It is not entirely clear how methylxanthines produce bronchodilation.
Pharmacological actions include;

• Relaxation of airway smooth muscle and inhibition of mediator release (e.g.

from mast cells)
• Theophylline
• Raises intracellular cAMP by inhibiting phosphodiesterase
• However, this inhibition is modest at therapeutic concentrations of
theophylline

• Antagonism of adenosine (a potent bronchoconstrictor) at A2-receptors

• Anti-inflammatory activity on T-lymphocytes by reducing release of platelet- 37

activating factor (PAF)
Drug interactions
Methylxanthine derivatives
• Synergism between theophylline and agonists has been demonstrated
in vitro, however, clinically the effects of this combination is at best
additive

• Many drugs inhibit CYP1A2- mediated theophylline metabolism, e.g.

erythromycin, ciprofloxacin, interferon and cimetidine, thus
precipitating theophylline toxicity

• Theophylline metabolism is induced in the presence of hepatic

CYP450-inducing agents, such as rifampicin

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Drugs Used in The Treatment of Asthma
Muscarinic Antagonists
• Use of leaves from Datura stramonium to treat asthma in India led to the
discovery of atropine

• Potent atropine analog, poorly absorbed after aerosol administration and

hence relatively free of systemic atropine-like effects was thus developed

• Antagonists at M2 and M3 muscarinic receptors in the bronchi, causing

bronchodilatation

• Slow onset of long-lasting bronchodilatation (given 6-8 hourly), especially in

older patients

• Compliance is compromised due to its bitter taste 39

• Little systemic absorption with rare side effects

Mechanism of Action
Antimuscarinic Agonists
• Competitively inhibit the effect of acetylcholine at muscarinic
receptors in the airways

• Thus, they inhibit the contraction of airway smooth muscle

and the increase in secretion of mucus that occurs in response
to vagal activity

• Common pathway of acetylcholine also is vai membrane-

bound G-protein which when stimulated leads to a fall in
cAMP and increased intracellular calcium, with consequent
bronchoconstriction. This pathway is also inhibited by
antimuscarinics 40
 Mechanism of Action
Antimuscarinic Agonists
• In the doses given, antimuscarinic agents will only inhibit the
portion of response mediated by muscarinic receptors
• responses varies by stimulus and among individuals in response
to the same stimulus

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 Drugs Used in The Treatment of
Asthma

Cocorticorsteroids
• Inhaled forms; Fluticason, Budesonide,Triancinolone,
mometasone
• Administered systemically (i.v./p.o.) in severe, acute and chronic
asthma (Hydrocortisone, prednisolone)
• Inhaled topically or nebulized in chronic asthma
• Mechanism is anti-inflammatory

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Mechanism of Action
Corticosteroids
• Gets directly into cell and decrease transcription

• Decreases the production of inflammatory mediators, hence

inflammation

• They inhibit lymphocytic, eosinophilic mucosal inflammation of

asthmatic airways

• They do not relax airway smooth muscle but directly but reduce
bronchial reactivity and reduce the frequency of asthmatic attacks if
taken regularly
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Drugs Used in The Treatment of Asthma
Mast-cell stabilizers
• Cromolyn and Nedocromil
• Inhibits the function of cells other than mast cells

• Both cromolyn sodium and nedocromil sodium are stable but

the salt forms are very insoluble

• Cromolyn, an inhaled powder, undergoes little systemic

absorption and nedocromil has similar systemic bioavailability

• They are only used prophylactically

44
 Mechanism of Action
Mast cell stabilizers
• Complete mechanism underlying their therapeutic efficacy is
uncertain

• Anti-inflammatory effect

• Both Cromolyn and Nedocromil inhibit mediator release from

sensitized mast cells in vitro, and so reduce firing of sensory C-
fibres in response to tachykinins (e.g. bradykinin)

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 Mechanism of Action
Mast cell stabilizers
• Alter the function of delayed chloride channels in the cell membrane
(best demonstrated by nedocromil) and blocks cell activation

• Chloride-mediated channel effects;

• Inhibition of cough
• On mast cells; for inhibition of early response to antigens
• Mast cell specific (cromolyn - little inhibitory effect on mediator release from
human basophils; inhibit mast cell degranulation in human and primate lung but
not skin)

• On eosinophil's; inhibition of late response to antigens

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Drugs Used in The Treatment of Asthma
Leukotriene Modulators
• Leukotrienes (LT) are fatty acid-derived mediators containing a
conjugated triene structure

• They are formed when arachidonic acid is liberated from the

cell membrane of cells, as a result of cell activation by allergic
or other noxious stimuli

• There are two classes;

• Leukotriene receptor antagonists (C4 and D4)
• 5’-lipoxygenases inhibitors

47
 Drugs Used in The Treatment of Asthma
Leukotriene Modulators
• 5’-lipoxygenase is the enzyme required for the synthesis of LTA4,
which is an unstable epoxide precursor of the two subgroups of
biologically important leukotrienes

• These are:
• Leukotriene B4 (LTB4) is a potent pro-inflammatory chemo-attractant
• Cysteinyl leukotrienes C4, D4, and E4 (LTC4, LTD4 and LTE4) these
collectively account for the activity that used to be referred to as ‘slow-
reacting substance of anaphylaxis’

• They all (but especially LTD4) bind to the Cys-LT1 receptor to cause
bronchoconstriction, attraction of eosinophils and production of
oedema 48
Mechanism of Action
Leukotriene Receptor Antagonist
• E.g. Montelukast, Zafirlukast

• Competitively blocks LTC4 and LTD4 at the Cys-LT1 receptor on

target tissues, thereby preventing their actions

• Efficacy in blocking airway responses to exercise and to

antigen challenge has been shown also

49
 Mechanism of Action
5’-lipoxygenases inhibitors

• E.g. Zileuton
• They competitively inhibit the enzyme 5’-lipoxygenases,
thereby preventing leukotriene synthesis
• Efficacy in blocking airway responses to exercise and to
antigen challenge has also been shown for this group of drugs

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Mechanism of Action
Other drugs
• Anti-IgE Monoclonal Antibodies
• Omalizumab is a recombinant humanized IgG1 monoclonal anti-
IgE antibody
• It blocks the binding of IgE to mast cells but does not activate IgE
already bound to these cells and therefore does mot provoke
mast cell degranulation
• It may also block IgE synthesis by B lymphocytes

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Therapeutic Uses

52
 Therapeutic uses
Methylxanthine derivatives
• Aminophylline (theophylline, 80%; ethylene diamine, 20%) is
occasionally used intravenously in patients with severe refractory
bronchospasm

• Oral theophylline may be used for less severe symptoms or to

reduce noctural asthma symptoms

• For IV aminophylline, a loading dose given slowly (20-30 mins) is

followed by a maintenance infusion

• Oral theophylline sustained-releases preparation can provide 53

effective therapeutic concentration for up to 12 hours following a
single dose
 Therapeutic uses
Antimuscarinic Antagonists
• Antimuscarinic agents are effective bronchodilators

• Atropine causes bronchodilation at a lower dose than that needed to

cause an increase in HR

• Selectivity of atropine’s effect can be increased further by administrating

it by inhalation or by use of a more selective quaternary ammonium
derivative of atropine, ipratropium bromide

• Used in patients who are intolerant of β–agonist agents

54
 Therapeutic uses
Muscarinic Antagonists
• Maintenance therapy and treatment of acute severe attacks of Asthma
and chronic bronchitis:
• Ipratropium is given from a metered-dose inhaler or nebulizer 3-4 times daily
• Inhaled muscarinic antagonists are most effective in older patients with COPD
• rate of onset of bronchodilation are less than those of slabutamol, but
duration of response is longer

• Tiotropium is a long-acting antimuscarinic bronchodilator administered

by inhalation in the management of COPD patients

• It is not used to treat acute bronchospasm

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Therapeutic uses
Corticorsteroids
• Effective in improving all indices of asthma control (severity of
symptoms, tests of airway caliber and bronchial reactivity,
frequency of exacerbations, and quality of life)
• Slow onset of action hence not used in emergencies, but
rather over a long period of time
• Dose is increased according to the severity (low, medium and
high dose)

56
Therapeutic uses
Mast cell stabilizers
• Cromolyn, Nedocromil

• Prophylaxis for allergic asthma in children

(largely supersided by ICS)
• Sodium cromoglicate may be used to prevent
exercise-induced asthma
• Used as a nasal spray for perennial and allergic
rhin-itus
• Eye drops in allergic conjunctivitis

• No benefit of Cromolyn during acute asthmatic attack and 57

nedocromil is an alternative to Cromolyn
Therapeutic uses
Leukotriene Modulators
• Leukotriene receptor antagonists (Montelukast, Zafirlukast)
• Used as an alternative to β-agonists, e.g. on CHF
patients who are on β-antagonists
• Zileuton
• More recent
• They’ve all been shown to improve asthma
control and to reduce the frequency of
asthma exacerbations in outpatient clinical
trials
Taken orally (principal advantage) 58
 Therapeutic uses
Leukotriene Modulators
• Leukotriene receptor antagonists (Montelukast, Zafirlukast)
• Used as an alternative to β-agonists, e.g. on CHF patients who are on β-
antagonists
• Zileuton
• More recent, used in asthma therapy, although this has declined considerably with
the efficacy of leukotriene receptor antagonists

• Useful in the prophylaxis of exercise-or antigen-induced asthma

• Motelukast has anti-inflammatory properties and is a mild, slow-onset

bronchodilator

• Taken orally (principal advantage) 59

Therapeutic uses
Anti-IgE Monoclonal Antibodies
• Used as an addition therapy in patients with severe persistent
allergic asthma

• Can be used in children, but very expensive therapy

• Lessens asthma severity and reduces the corticorsteroid

requirement in patients with moderate to severe disease

• Reduces the frquency of exacerbatons, even while enabling a

reduction in corticorsteroid requirements

60
Side Effects

61
Side effects
Methylxanthine derivatives
• GI: nausea, vomiting, anorexia

• Cardiovascular:
• Dilitation of vascular smooth muscles-headache, flushing and hypotension
• Tachycardia and cardiac dysrhythmias (atrial and ventricular)

• CNS: insomnia, anxiety, agitation, hyperventilation, headache and fits

62
Side effects
Muscarinic Antagonists
• Bitter taste

• Acute urinary rentention (in patients with prostatic hypertrophy)

• Acute glaucoma has been precipitated when nebulized doses are

given via a face mask

• Paradoxical bronchoconstriction due to sensitivity to benzalkonium

chloride, which is the preservative in the nebulizer solution

63
Side effects
Corticorsteroids
• Candidiasis of the pharynx or larynx occurs in 10-15% of
patients
• A hoarse may develop due to a laryngeal myopathy at high
doses
• Bruising and skin atropy occur at high doses
• Inhibition of long bone growth during prolonged high dose
treatment in children
• Posterior subcapsular cataracts may develop following
prolonged use

64
Side effects
Mast cell stabilizers
• Cromolyn is virtually non-toxic. The powder can produce
bronchospasm or hoarseness (very rarely)
• Headache, cough
• Nausea, vomiting (rare)
• Nedocromil has a bitter taste

65
Side effects
Leukotriene Receptor Antagonists
• Montelukast is generally well tolerated
• Side effects include
• Gatro-intestinal upsets
• Asthenia and drowsiness
• Rash, fever, arthralgias
• Elevation of serum transaminases

• Zileuton
• Occasional liver toxicity

66
Side effects
Anti-IgE Monoclonal Antibodies
• Rashes
• Urticaria
• Pruritus
• Sinusitis
• Gastro-intestinal upsets
• Injection sites reactions
• Possibly secondary haematologic malignancies

67
Pharmacotherapy
Step-Up Approach
• 1 – Intermittent
• SABA

• 2 – Mild Intermittent
• SABA
• ICS (low dose)

68
Pharmacotherapy
Step-Up Approach
• 3 – Moderate Intermittent
• SABA
• ICS (low-medium dose)
• LABA

• 4 – Mild Persistent
• SABA
• ICS (medium dose)/LABA
• LTRA (Leukotriene Receptor Antagonist)

69
Pharmacotherapy
Step-Up Approach
• 5– Moderate Persistent
• SABA
• ICS (high dose)
• LABA
• IgE (Omalizumab)

• 6– severe Persistent
• ICS (high dose)
• LABA
• Oral corticosteroids (Predinisol)

70
Pharmacotherapy
Step-Up Approach
SABA ICS LABA Systemic
corticosteroids
(PO)
e.g. Albuterol e.g. Fluticason e.g. Formoterol e.g. Predinisol
mometasone Salmeterol
Step 6 Yes High dose Yes Yes

Step 5 Yes High dose Yes No

Step 4 Yes Medium dose Yes No

Step 3 Yes Low or medium Yes No

dose
71
Step 2 Yes Low dose No No
Step 1 Yes None No No
Side effects
• SABA
• Tachycardia
• ICS
• Osteoporosis
• Pneumonia
• Fungal infection on tongue
• LABA
• Cardiac deaths without ICS

72
Side effects
• Omalizumab
• Risk of cancer
• Perdinol
• Given orally, so high risk of side effects

73
Emergency Management of Acute
Attack
• Normally presented with:
• Wheezing
• SOB
• Classic dyspnea
• Prolonged expiration

• Used in situations when patients are presented with:

• Intercostal retraction
• Diminished breath sounds
• Use of accessory muscles
• Fatigue
• Perspiration 74
Emergency Management of Acute
Attack
• Best initial step is a short-acting beta agonist. Can be given as
an inhaler or in a nebulizer
• Supplementary management is mandatory

• Routine labs should be drawn, including ABGs as soon as

possible
• Patient is usually in respiratory alkalosis in the early stages and
will shift to acidosis without treatment

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Emergency Management of Acute
Attack
• Beta agonists? CHF patient
• Minor attack and is relatively stable, anticholinergic (ipratropium,
tiotropium). These drugs take longer
• Sever attack, beta agonists as they are faster
• Resistant, an IV beta agonist (terbutaline) may be administered
• If still resistant, admit patient

76