Bronchial Asthma

Dr. Layla Borham

 Objectives
By the end of the lecture you are able to:
• Describe the classification and strategies of drug treatment of
bronchial asthma.
• Discuss mechanism of action, therapeutic uses, adverse reactions,
treatment advantages, and drug interactions of:
• B-adrenergic agonists, Methylxanthines, Anticholinergics, Mast
cell stabilizers, Corticosteroids, Leukotriene pathway inhibitors,
Monoclonal antibodies
• Describe methylxanthine toxicity and factors affecting its blood
level
• Discuss the goals of asthma therapy
• Know the levels of asthma control.
• Describe rescue and preventive treatment
• Discuss Gina guidelines in management of bronchial asthma.
• List drugs contraindicated in bronchial asthma Dr. Layla Borham
 Clinical Case
• An 8-year-old boy is brought to your office because of a chronic
cough. His mother says that he coughs frequently throughout the
day and will have symptoms 2 or 3 nights a month as well. This has
been a problem on and off for approximately a year, but seems to be
worse in the spring and fall. He also coughs more when he is riding
his bike or playing soccer.
• He has been treated twice in the past year for “bronchitis” with
antibiotics and cough suppressants but he never seems to clear up
completely. His examination is normal except for his lungs, which
reveal expiratory wheezing. You diagnose him with asthma and
prescribe an albuterol inhaler.
• What is the mechanism of action of the albuterol?
• What are the most common side effects of the albuterol?
• What medications can be used to provide long-term control of the
asthma symptoms? Dr. Layla Borham
 4
Dr. Layla Borham
Drugs used in the treatment
of bronchial asthma

Dr. Layla Borham

 Asthma Medications

Controller medications Reliever medications

Long-term control Quick relief
1. Inhaled corticosteroids, Used to relieve acute asthma
2. Inhaled cromolyn or nedocromil, exacerbations and to prevent
3. Long-acting bronchodilators, exercise-induced asthma (EIA)
4. Theophylline, 1. Short-acting bronchodilators,
5. leukotriene modifiers, 2. Systemic corticosteroids,
6. Anti-immunoglobulin E (IgE) 3. Ipratropium
antibodies (omalizumab).
A) Bronchodilators

I- Beta-adrenergic agonists
II- Methylxanthines
III- Anticholinergics
Dr. Layla Borham
 I- Beta-adrenergic agonists
 These agents stimulate adenylyl cyclase, increasing cAMP
formation in airway tissue:

1. Relax airway smooth muscle.

2. Inhibit release of some mast cell bronchoconstrictive

mediators.

3. May inhibit microvascular leakage.

4. May increase mucociliary transport.

5. Prevent edema induced by histamine, etc. by preventing

increase in endothelial permeability.
Dr. Layla Borham
 ß2 receptor selective agonists
 Albuterol, terbutaline, formoterol , metaproterenol,
salmeterol

 Most effective drugs (by inhalation) for treatment of acute

bronchospasm and for prevention of exercise-induced
asthma.

 Route of administration:

1. Inhalation

2. Oral for albuterol, metaproterenol and, terbutaline.

3. Subcutaneous: terbutaline.
Dr. Layla Borham
 B- ß2 receptor selective agonists
 Longer acting ß2 receptor-selective agents (LABA):
Salmeterol:

1. Increased duration of action, 12 hours or more.

2. Potent, selective ß2 receptor-selective drug.

3. Mechanism for long duration: high lipid solubility

(creates a depot effect).

4. Routes of administration: Oral, inhalation (greatest airway

effect), and parenteral.

Dr. Layla Borham

 Side Effects of ß2 receptor agonists
 Due to extrapulmonary 2-receptor activation: dose-related and
unusual with inhalation.
1. Skeletal muscle tremor due to skeletal muscle -receptors
activation.
2. Tachycardia and palpitations due to reflex cardiac
stimulation secondary to peripheral vasodilatation, direct
stimulation of atrial 1 receptors, and possible direct stimulation
of myocardial 1 receptors.
3. Metabolic effects: increased FFA, glucose, lactate after large
systemic doses.
4. Hypokalemia (due to stimulation of K+ entry into skeletal
muscle).
5. Nervousness.
6. Asthmatics do not develop tolerance to 2-agonists as normal
subjects. Dr. Layla Borham
 II- Methylxanthines: Mechanism of Actions
1. Inhibition of phosphodiesterases. Increase intracellular
cAMP

2. Adenosine receptor antagonism. Adenosine causes

bronchoconstriction in asthmatics.

3. Other

  epinephrine secretion form adrenal medulla; small,

cannot account for the bronchodilatation.

 Antagonize some prostaglandins in smooth muscle.

4. Anti-inflammatory action.
Dr. Layla Borham
 II- Methylxanthines
Caffeine, Theophylline (Aminophylline)
 Central Nervous System Effects:

1. Increased alertness; reduced fatigue, caffeine 

nervousness/insomnia.

2. Very high methylxanthine doses: medullary stimulation,

convulsions.

 Cardiovascular Effects:

1. Direct positive inotropic and chronotropic.

Dr. Layla Borham

 II- Methylxanthines
 Increase secretion of gastric acid and digestive
enzymes.

 Weak diuretics, not therapeutically important.

1. Increased glomerular filtration.

2. Reduced tubular sodium reabsorption.

 Smooth muscle effects: Major therapeutic effect:

bronchodilatation.

 Enhanced skeletal muscle contraction.

Dr. Layla Borham
 II- Methylxanthines: Clinical Use
Theophylline (Aminophylline): bronchodilator
 Relieves airway obstruction:
1. In acute asthma: reduces symptoms severity.
2. In chronic asthma: reduces off-time from work or school in
chronic asthma.

Theophylline: Less effective bronchodilator compared to inhaled

β2-agonists
1. Slower onset of action.
2. Some modest anti-inflammatory effect.
3. Relatively limited usefulness in acute asthma compared other
drugs. Theophylline decreased frequency and severity of
symptoms in chronic asthma.
Dr. Layla Borham
 Toxicity of Theophylline
 Therapeutic/toxic effects: related to plasma concentration. Low
therapeutic index (narrow safety margin).
 Pulmonary function improvement: effective plasma
concentration range: 5-20 mg/L.
 At concentrations > 20 mg/L:
1. GIT: Anorexia, nausea, and vomiting.
2. CNS: Headache, insomnia, and nervousness.
3. CVS: Tachycardia and palpitation.
 Higher concentrations (> 40 mg/L) leads to:
1. Seizures, neuromuscular irritability, tremor.
2. Hypokalemia, hyperglycemia, vomiting.
3. Arrhythmias, tachycardia and palpitation.
• Rapid IV push  Velocity syndrome (seizures, tachycardia,
arrhythmia and cardiac arrest). Dr. Layla Borham
 Factors affecting theophylline administration/ blood levels
 Plasma clearance: wide variation:
Decreased liver function may cause toxic theophylline levels
(theophylline is hepatically metabolized).
Changes in hepatic function:
1. Reduced blood flow secondary to heart failure.
2. Attenuated function due to hepatic cirrhosis.
3. Large differences in clearance rates due to hepatic metabolism
by P450 system; factors affecting this include:
Increased clearance : (decreased level) induction of P450 by:
1. Rifampicin, phenobarbitone, phenytoin.
2. Smoking.
3. High protein, low carbohydrate.
Decreased clearance: (increased level) inhibition of P450 by:
1. Cimetidine, erythromycin, allopurinol.
2. Congestive heart failure. Dr. Layla Borham
 III- Anticholinergics (Muscarinic Antagonists)
 Effective bronchodilators, preferred route of administration:
inhalation (enhanced organ selectivity).
 Antimuscarinic with limited systemic adverse effects:
ipratropium bromide (Atrovent).
 Ipratropium bromide available in combination with albuterol
(Combivent).
Antimuscarinic drugs- Clinical Findings:
1. Valuable in patients intolerant of inhaled beta-agonist drugs.
2. May be slightly less effective than beta-agonist drugs in reversing
bronchospasm.
3. Block reflex bronchospasm but can not suppress allergic,
inflammatory reaction.
Dr. Layla Borham
III- Anticholinergics (Muscarinic Antagonists)
Role in acute severe asthma:
1. Enhances albuterol-mediated bronchodilatation if taken after it.
2. Ipratropium: especially effective in management of asthma in
the elderly.
3. Ipratropium: treatment of choice for beta-blocker-induced
bronchospasm.
Adverse Effects:
 Local: dry mouth; pharyngeal irritation.
 Systemic: (dependent on extent of absorption):
1. Urinary retention.
2. Loss of ocular accommodation.
3. Tachycardia.
4. Agitation. Dr. Layla Borham
5. May increase intraocular pressure in patients with glaucoma.
 20

Metered-dose inhaler (MDI)

= spacers

Metered-dose inhaler (MDI)

valved holding chamber

Dr. Layla Borham

B) Anti-inflammatory Drugs

Dr. Layla Borham

 I- Mast cell stabilizer
 These agents used prophylactically by aerosol (metered-
dose inhalers). Not in acute attack.

 Cromolyn (disodium cromoglycate) and Nedocromil

inhibit:

• Antigen and exercise-induced asthma, and occupational

asthma.

• Bronchial reactivity.

 They have no direct effect on airway smooth muscle tone and

will not reverse asthmatic bronchospasm.
Dr. Layla Borham
 I- Mast cell stabilizer
Mechanism of Action
1. Alters function of delayed chloride channels (best
demonstrated for nedocromil) and inhibits cell
activation.

2. Chloride-mediated channel effects:

 Inhibition of cough.

 Mast cells specific. Inhibition of early response to

antigens (mast cells).

 Inhibition of late response to antigens (eosinophils).

 I- Mast cell stabilizer
Cromolyn Na: (Intal)
1. Poorly absorbed.
2. Administered by microfine powder inhalation or
aerosol.
3. Absorption: approximately 10%.
4. No bronchodilating activity.
Nedocromil: (Tilade)
1. Also poorly absorbed; low bioavailability.
2. Aerosol form only
Dr. Layla Borham
 Clinical Use: Cromolyn
1. Blocks bronchoconstriction due to antigen inhalation and
environmental agents.
2. Reduces bronchodilators medication requirements and
symptomatic severity in patients with asthma.
3. Cromolyn (chronic treatment) appears to decrease the bronchial
hyperreactivity.
4. Effective in reducing symptoms of allergic rhinitis and hay fever.
5. Prophylaxis of mild to moderate asthma, especially allergic
asthma. Often administered in conjunction with an inhaled ß2-
agonist; e.g. albuterol, to ensure better access of cromolyn to the
distal airways. Dr. Layla Borham
 Adverse/Side effects: Cromolyn

1. Throat irritation.

2. Cough.

3. Mouth dryness.

4. Wheezing.

5. Chest tightness.

Dr. Layla Borham

 II- Corticosteroids
Corticosteroid Effects

1. Diminish bronchial reactivity.

2. Increase airway diameter.

3. Reduced frequency of asthma attacks.

Dr. Layla Borham

Dr. Layla Borham
 II- Corticosteroids
Mechanisms of Action:

1. Primary: inhibition of eosinophil-mediated airway

mucosal inflammation pathway in asthmatic airways.

2. Mast cell stabilization and inhibits degranulation.

3. Inhibits prostaglandin and leukotriene synthesis by

inhibition of arachidonic acid production.

4. Principal anti-inflammatory action: Inhibition of cytokine

production.

5. Secondary: enhancement of -receptor agonist effects.

Dr. Layla Borham
 II- Corticosteroids
Aerosol Treatment:
• Beclometasone, Budesonide, Fluticasone, triamcinolone.

• Most appropriate way to decrease adverse systemic

corticosteroid effects.

• Effective lipid-soluble corticosteroids -- administered by

aerosol.

 budesonide (rapid effect after inhalation).

Dr. Layla Borham

 II- Corticosteroids
Clinical Use of Corticosteroids in Asthma:
• Oral/parenteral corticosteroids are used:
1. For management of acutely ill patients.
2. Patients not adequately maintained with bronchodilators.
3. Patients whose symptoms are worsening, despite
reasonable maintenance treatment.
4. Corticosteroids for urgent/emergent intervention.
• Systemic corticosteroid treatment: discontinued in 7-10
days.
• Nocturnal asthma: oral/inhaled corticosteroids in late afternoon.
Dr. Layla Borham
 II- Corticosteroids
Toxicities/Cautions/Problems:
1. Taper oral therapy slowly to avoid causing adrenal-
insufficiency.
2. Chronic use of inhaled steroids may cause adrenal suppression
at high dosages.
3. Inhaled topical corticosteroids: oropharyngeal candidiasis, risk
reduced by gargling with water and spitting after each
inhalation.
4. Hoarseness: local effect on vocal cords.
5. Decreased bone density.
6. Cataract formation.
7. Dysphoria.
8. High doses: dermal thinning, glaucoma Dr. Layla Borham
 II- Corticosteroids
Adverse effects of systemic steroids

Short term steroid use Long term steroid use

• Reversible increases in glucose • As those in short term use +
• Height and growth suppression
• Fluid retention with weight gain
• Suppression of immune system
• Hypertension
• Hypertension, cataracts
• Decreases potassium
• Hirsutism
• Mood alterations including rare psychosis

• Peptic ulcers

• Very rare allergic reactions

Dr. Layla Borham
 III- Leukotriene Pathway Inhibitors
• Leukotriene production: action of 5-lipoxygenase on
arachidonic acid.

• Leukotriene B4 (neutrophil chemoattractant), leukotriene C4,

and leukotriene D4 provoke symptoms consistent with those
seen in asthma:

1. Bronchoconstriction.

2. Mucosal edema.

3. Mucus hypersecretion.

4. Increase bronchial reactivity.

Dr. Layla Borham
 Interruption of leukotriene pathways
Inhibition of 5-lipoxygenase
Zileuton:

1. Prevents leukotriene synthesis (Inhibits 5-lipoxygenase).

2. Effective for maintenance treatment of asthma.

3. Requires monitoring for hepatic toxicity.

4. metabolized by cytochrome P450 1A2, 2C9, 3A4:

• Can decrease clearance; increasing concentration of:

theophylline, warfarin, propranolol.
Dr. Layla Borham
 Interruption of leukotriene pathways
Inhibition of leukotriene D4 receptor binding
Zafirlukast:

1. Effective for maintenance treatment in mild to

moderate asthmatics.

2. Less effective than inhaled beclomethasone.

3. Bioavailability decreases significantly with food.

4. Theophylline may also decrease its effect.

5. Zafirlukast: increases serum concentration of oral

anticoagulants (may provoke bleeding). Dr. Layla Borham
 Interruption of leukotriene pathways
Montelukast:

1. Leukotriene D4 receptor antagonist.

2. Effective for maintenance treatment of adults and children

with intermittent/persistent asthma.

3. Less effective than inhaled corticosteroids (addition to

montelukast may reduce corticosteroid dosage requirement).

4. Orally effective. Montelukast, added to oral/inhaled

corticosteroids, improves asthma patients with aspirin-
induced asthma.
Dr. Layla Borham
 Omalizumab
Xolair

• It is a monoclonal antibody.

• Used mainly in allergy-related asthma therapy, with the

purpose of reducing allergic hypersensitivity.

• It is a recombinant DNA-derived humanized IgG

monoclonal antibody that selectively binds to human
immunoglobulin E (IgE). IgE is commonly involved
with allergies when present in high amounts in the
body.
Dr. Layla Borham
 Goals of Therapy: Asthma Control

1. Minimal or no chronic symptoms day or night

2. Minimal or no exacerbations

3. No limitations on activities; no school/work missed

4. Maintain (near) normal pulmonary function

5. Minimal use of short-acting inhaled beta2-agonist

6. Minimal or no adverse effects from medications

Dr. Layla Borham

Clinical Pharmacology
Treatment of bronchial
asthma

Dr. Layla Borham

G lobal
INitiative for
A sthma
© Global Initiative for Asthma 2014
 The control-based asthma management
cycle

NEW!

GINA 2014, Box 3-2 © Global Initiative for Asthma

 Level of Asthma Control

• Patients often move from one classification to another,

and the treatment is adjusted accordingly.
• Characteristics for classifying patients are given below:
 Controlled,
 Partly Controlled
 Uncontrolled

Dr. Layla Borham

Dr. Layla Borham
 Stepwise approach to control asthma symptoms
and reduce risk

NEW!

GINA 2014, Box 3-5 © Global Initiative for Asthma

 Stepwise management - pharmacotherapy

*For children 6-11 years,

theophylline is not
recommended, and
preferred Step 3 is medium
dose ICS
**For patients prescribed
BDP/formoterol or BUD/
formoterol maintenance
and reliever therapy

GINA 2014, Box 3-5 (upper part) © Global Initiative for Asthma
 Stepwise management – additional
components

GINA 2014, Box 3-5 (lower part) © Global Initiative for Asthma
 Step 1 – as-needed inhaled short-acting
beta2-agonist (SABA)
BDP: Beclomethasone dipropionate
BUD: budesonide

*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy

GINA 2014, Box 3-5, Step 1 © Global Initiative for Asthma

 Step 2 – low-dose controller + as-needed
inhaled SABA
BDP: Beclomethasone dipropionate
BUD: budesonide

*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy

GINA 2014, Box 3-5, Step 2 © Global Initiative for Asthma

 Step 3 – one or two controllers + as-needed
inhaled reliever
BDP: Beclomethasone dipropionate
BUD: budesonide

*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy

GINA 2014, Box 3-5, Step 3 © Global Initiative for Asthma

 Step 4 – two or more controllers + as-needed
inhaled reliever
BDP: Beclomethasone dipropionate
BUD: budesonide

*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy

GINA 2014, Box 3-5, Step 4 © Global Initiative for Asthma

 Step 5 – higher level care and/or add-on
treatment
BDP: Beclomethasone dipropionate
BUD: Budesonide
OCS: Oral corticosteroids

*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy

GINA 2014, Box 3-5, Step 5 © Global Initiative for Asthma

 Guidelines
- The roles in therapy of several medications have evolved:
 Due to increased risk of asthma-related death associated
with the use of long-acting 2-agonists in a small group of
individuals so that long-acting 2-agonists should not be
used as monotherapy in asthma, and must only be used in
combination with an appropriate dose of inhaled
corticosteroids.

 Leukotriene modifiers now have a more prominent role

as controller treatment in asthma, particularly in adults.
Dr. Layla Borham
 Monotherapy with cromolynes is no longer given as an
alternative to monotherapy with a low dose of inhaled
glucocorticoids in adults.

 The announced update of the GINA guidelines (2011)

provides supportive statements for a new management
approach to asthma, Symbicort, e.g. 'Combination inhalers
containing formoterol and budesonide may be used for both
rescue and maintenance.

Dr. Layla Borham

 Drugs contraindicated in bronchial
asthma
1. Histamine and histamine liberators (d-
tubocurarine, trimetaphane).

2. Parasympathomimetics.

3. Non-selective  blockers.

4. Morphine, and barbiturates.

5. Aspirin and other NSAIDs.

Dr. Layla Borham
 Refresh Your Information
-A 21-year-old woman with partially
controlled asthma on three-drug treatment
has elevated liver function tests thought to
be caused by one of her medications.
- What is this medication?
 10/19/2014

Dr. Layla Borham

 Step 1 – as-needed reliever inhaler
1. Preferred option: as-needed inhaled short-acting beta2-
agonist (SABA)
• SABAs are highly effective for relief of asthma
symptoms
• However …. there is insufficient evidence about the
safety of treating asthma with SABA alone
• This option should be reserved for patients with
infrequent symptoms (less than twice a month) of short
duration, and with no risk factors for exacerbations
2. Other options
• Consider adding regular low dose inhaled
corticosteroid (ICS) for patients at risk of exacerbations
GINA 2014
 Step 2 – Low dose controller + as-needed SABA
 Preferred option: regular low dose ICS with as-needed inhaled SABA
• Low dose ICS reduces symptoms and reduces risk of exacerbations
and asthma-related hospitalization and death
 Other options
• Leukotriene receptor antagonists (LTRA) with as-needed SABA
– Less effective than low dose ICS
– May be used for some patients with both asthma and allergic
rhinitis, or if patient will not use ICS
• Combination low dose ICS/long-acting beta2-agonist (LABA)
with as-needed SABA
– Reduces symptoms and increases lung function compared with
ICS
– More expensive, and does not further reduce exacerbations
• Intermittent ICS with as-needed SABA for purely seasonal allergic
asthma with no interval symptoms
– Start ICS immediately symptoms commence, and continue for
GINA 2014
 Step 3 – one or two controllers + as-
needed inhaled reliever
 Before considering step-up
• Check inhaler technique and adherence, confirm diagnosis
 Adults/adolescents: preferred options are either combination low dose
ICS/LABA maintenance with as-needed SABA, OR combination low
dose ICS/formoterol maintenance and reliever regimen*
• Adding LABA reduces symptoms and exacerbations and increases FEV1,
while allowing lower dose of ICS
• In at-risk patients, maintenance and reliever regimen significantly reduces
exacerbations with similar level of symptom control and lower ICS doses
compared with other regimens
 Children 6-11 years: preferred option is medium dose ICS with
as-needed SABA
 Other options
• Adults/adolescents: Increase ICS dose or add LTRA or theophylline (less
effective than ICS/LABA)
• Children 6-11 years – add LABA (similar effect as increasing ICS)
*Approved only for low dose beclometasone/formoterol and low dose budesonide/formoterol
GINA 2014
 Step 4 – two or more controllers + as-
needed inhaled reliever
 Before considering step-up
• Check inhaler technique and adherence
 Adults or adolescents: preferred option is combination low dose
ICS/formoterol as maintenance and reliever regimen*, OR
combination medium dose ICS/LABA with as-needed SABA
 Children 6–11 years: preferred option is to refer for expert advice
 Other options (adults or adolescents)
• Trial of high dose combination ICS/LABA, but little extra
benefit and increased risk of side-effects
• Increase dosing frequency (for budesonide-containing
inhalers)
• Add-on LTRA or low dose theophylline
*Approved only for low dose beclometasone/formoterol and low dose budesonide/formoterol
GINA 2014
Management of severe asthma
 Optimize dose of ICS/LABA
• Complete resistance to ICS is rare
• Consider therapeutic trial of higher dose
 Consider low dose maintenance oral corticosteroids
• Monitor for and manage side-effects, including osteoporosis
 Add-on treatments without phenotyping
• Theophylline, LTRA – limited benefit
• Tiotropium – not yet approved for asthma by a major regulator
 Phenotype-guided treatment
• Sputum-guided treatment to reduce exacerbations and/or steroid dose
• Severe allergic asthma: suggest add-on anti-IgE treatment (omalizumab)
• Aspirin-exacerbated respiratory disease: consider add-on LTRA
 Non-pharmacological interventions
• Consider bronchial thermoplasty for selected patients
• Comprehensive adherence-promoting program
 For detailed guidelines, see Chung et al, ERJ 2014
GINA 2014, Box 3-14 (2/2)
Dr. Layla Borham

The Global Initiative for Asthma (GINA) Scientific

The GlobalCommittee
Initiative(2010)
for Asthma (GINA) (2010)