Pharmacology of

Asthma
AZL & YSP
Dept. Pharmacology & Therapeutic,
School of Medicine
Universitas Sumatera Utara
Mei 2008, KBK, Respirasi, FK USU, Medan

Pathophysiology of Asthma
Airway inflammation
Cytokines

Bronchial hyper-responsiveness
Hipersensitifity type 1

Alergen
Antibodi (IgE)
Mast cell
Mediators (Histamin, Lekotrien, etc)

Slow phase

Airflow limitation

Pathologic Findings
Bronchoconstriction
Hyperinflation of the
lungs
Hyperplasia of the
smooth muscle
surrounding the bronchial
and bronchiolar walls
Thickening of the
basement membrane
Mucosal edema

DesJardin, T, Burton, G: Clinical Manifestations and Assessment of Respiratory Disease. St. Louis, Mosby,
1995

Chemicals Involved in
Inflammation

IgE
Histamine
Tryptase
Leukotrienes (LTC4)
Platelet activating
factor (PAF)
Prostaglandins
(PGD2)

Interleukins (IL-4, IL-5)

Granulocyte-macrophage
colony stimulating factor
(GM-CSF)
Tumor Necrosis Factor
(TNF)
Major Basic Proteases
(MBP)
Eosinophil Cationic
Protein (ECP)

Patho-physio-pharmacology of Asthma
Allergen
Macrophage/
dendritic cell

Mast cell

Th2 cell

Neutrophil
Eosinophil

Mucus plug

Nerve activation

Epithelial shedding

Subepithelial
fibrosis
Plasma leak
Oedema
Mucus
hypersecretion
Hyperplasia
Barnes PJ

Vasodilatation
New vessels

Sensory nerve
activation
Cholinergic
reflex
Bronchoconstriction
Hypertrophy / hyperplasia

Asthma components
Healthy airway
Aveolar septum

Smooth
muscle
Barnes PJ

Epithelium

Asthmatic airway
Inflammation
and oedema

Smooth muscle
contraction

Mucus and plasma

exudation

Epithelial shedding /
damage

General Goals of Asthma Therapy

Relief airways tightening / bronchoconstriction
immediately.
Education of asthma management.
Prevent chronic symptoms and asthma
exacerbations during the day and night
Maintain normal activity levels
Have normal or near-normal lung function
Have no or minimal side effects while receiving
optimal medications

Intervention in Asthma
Avoidance
of allergens, infections

Inhaled
corticosteroids

2 agonist
bronchodilators

Inducers

Triggers

Inflammation
eosinophils
ECP

Airways
Hyper-responsiveness
Exercise induced asthma

Symptoms
Cough, chest tightness

Wheeze, dyspnea

Airways obstruction

General Pharmacologic Approach to

the Treatment of Asthma
Relievers

Short-acting bronchodilators

2-adrenergic agents
Anti-cholinergic (Parasympatholytic) agents

Controllers

Corticosteroids
Long-Acting bronchodilators
2-adrenergic agents
Methylxanthines

Cromolyn sodium
Leukotriene inhibitors
Anti-IgE monoclonal antibodies

Relievers

Historical Perspective

Datura stramonium (1802)

Epinephrine (1903)
Ephedrine (1926)
Isoproterenol (1940)
Isoetharine (1951)
Metaproterenol (1961)
Beta2-adrenergic agents via MDI (1973)
Ipratropium bromide (1987)
Salmeterol (1994)
Levalbuterol (1999)

Patho-Physio-Pharmacology of
Bronchodilators

Adrenergic Bronchodilators
Short-Acting Agents
Catecholamines
Epinephrine
Isoproterenol
Isoetharine

Resorcinol agents
Metaproterenol

Saligenin agents
Salbutamol

Pirbuterol
Bitolterol

-Agonists
Mechanism of Action -relax smooth muscle
within the airways, causing bronchodilation.
Short Acting

Salbutamol (Various Brands)

Levalbuterol (Xopenex)
Biltolterol (Tornalate)
Pirbuterol (Maxair)
Isoproternol (Medihaler-Iso)
Metaproternol (Alupent)
Terbutaline (Brethaire)

Long Acting
Salmeterol (Serevent)
Formoterol (Foradil)

Classification of agonists
Beta Agonists
Short acting
Generic name

Duration of action

2-selectivity

Salbutamol

4-6 h

+++

Levalbuterol

8h

+++

Metaproterenol

4-6 h

++

Isoproterenol

3-4 h

++

Epinephrine

2-3 h

Salmeterol

12+ h

+++

Formoterol

12+ h

+++

Long acting

2 agonists were developed through substitutions in the catecholamine structure of

norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and modification at
this site confers beta receptor selectivity; further substitutions have resulted in 2 selectivity. The
selectivity of 2 agonists is obviously dose dependent. Inhalation of the drug aids selectivity since
it delivers small doses to the airways and minimizes systemic exposure. agonists are generally
divided into short (4-6 h) and long (>12 h) acting agents.

Beta-2 Adrenergic Agonists

Short acting agents
Mode of administration
Inhaled/Parenteral

Modes of action
Relax airway smooth muscle
Enhance mucociliary clearance
Decrease vascular permeability
May modulate mediator release from mast
cells and basophils

Beta-2 Adrenergic Agonists

Short acting agents
Role in therapy
Medication of choice for treatment of acute
exacerbations of asthma and useful in the
pretreatment of exercise-induced
bronchospasm (EIB)
Used to control episodic bronchoconstriction
Increased used or even daily use of these agents
is a warning of deterioration of asthma and
indicates the need to institute or to intensify regular
anti-inflammatory therapy.

Beta-2 Adrenergic Agonists

Short acting agents
Side Effects

Tremor
Papitations and tachycardia
Headache
Insomnia
Rise in blood pressure
Nervousness
Dizziness
Nausea

Salbutamol
Mainstay of Therapy for Many Years
Characteristics
Dosing every 4-6 hours
Dosage Forms
MDI (HFA), Unit Dose Vials for Nebulizers, Oral
Solutions, Oral Tablets

Advantages- quick action, rescue therapy

Side Effects/Problems
The most common side effects are heart
palpitations, irregular, rapid heartbeat, anxiety, and
increased blood pressure.

Anticholinergic Bronchodilators
Tertiary Ammonium Compounds
Atropine sulfate
Scopalamine

Quaternary Ammonium Compounds

Ipratropium
Tiotropium

Anticholinergic Bronchodilators
Mode of administration
Inhaled

Mechanisms of action
Block the effects of acetylcholine released from
cholinergic nerves in the airways (i.e., reduce intrinsic
vagal cholinergic tone to the airways).
Block reflex bronchoconstriction caused by inhaled
irritants
They do not diminish the early and late allergic
reactions and have no effect on airway inflammation.
Less potent bronchodilators than inhaled beta-2
agonists, and in general, have a slower onset of
action (30-60 min to maximum action).

Anticholinergic Bronchodilators
Role in therapy
Additive effect when nebulized together with a
rapid-acting beta-2 agonist for exacerbations of
asthma
It is recognized that Ipratropium can be used
an alternative bronchodilator for patients who
experience adverse effects such as
tachycardia, arrhythmias, and tremors from
beta-2 agonists.

Side effects
Dryness of the mouth and bitter taste

Controllers

Controllers
Corticosteroids
Long-Acting bronchodilators
2-adrenergic agents
Methylxanthines

Cromolyn sodium/Nedrocromil
Leukotriene inhibitors
Anti-IgE monoclonal antibodies

Corticosteroids
Inhaled Glucocorticoids

Beclomethasone
Flunisolide
Fluticasone
Triamcinolone
Budesonide, and
Mometasone

Systemic Glucocorticoids

Prednisone
Methylprednisolone
Prednisolone
Dexamethasone

Inhaled Glucocorticoids
Mechanisms of action
Reduces pathologic signs of airway
inflammation mediated in part by inhibition of
production of inflammatory cytokines
Airway hyperresponsiveness continues to
improve with prolonged treatment

Role in therapy
Most effective anti-inflammatory medication
for the treatment of asthma

Inhaled Glucocorticoids
Side effects

Local adverse effects include oropharyngeal

candidiasis, dysphonia, and occasional coughing from
upper airway irritation.
Because there is some systemic absorption, the risks
of systemic adverse effects will depend on the dose
and potency of the Glucocorticoids as well as its
bioavailability, absorption in the gut, metabolism by
the liver, and the half-life of its systemically absorbed
fraction.

Contraindication:

hypersensitivity, nasal infection and haemorrhage,

candidiasis orofaring, and patient with recurrent
epistaxis.

Inhaled Glucocorticoids
Beclomethasone dipropionate
Dosage: 200-1000g

Budesonide
Dosage: 200-800g

Flunisolide
500-2000g

Fluticasone
100-500g

Triamcinolone acetonide
400-2000g

Systemic Glucocorticoids
Mode of administration
Oral
Parenteral

Mechanisms of action

Same as for inhaled Glucocorticoids however

systemic Glucocorticoids may reach different
target cells than inhaled drugs

Role in therapy

Long-term oral Glucocorticoids therapy (daily

or alternate-day) may be required to control
severe persistent asthma.

Systemic Glucocorticoids
side effects

Osteoporosis
Arterial hypertension
Diabetes
Hypothalamic-pituitary
axis suppression
Cataracts
Glaucoma

Obesity
Skin thinning leading
to cutaneous striae
Easy bruising
Muscle weakness
Fatal herpes virus
infections have been
reported among
patients who are
exposed to these
viruses when they are
taking systemic
Glucocorticoids

Adrenergic Bronchodilators
Long-Acting Agents
Sustainedreleased
salbutamol
Salmeterol
Formoterol

Adrenergic Bronchodilators
Long-Acting Agents
Modes of administration
Inhaled
Oral

Mechanisms of action
Same as short-acting beta-2 agonists
Effects persists for at least 12 hours

Adrenergic Bronchodilators
Long-Acting Agents
Role in therapy
Long-acting inhaled beta-2 agonists should be
considered when standard introductory doses of
inhaled Glucocorticoids fail to achieve control of asthma
before raising the dose of inhaled Glucocorticoids.
Because long-term treatment with these agents does
not appear to influence the persistent inflammatory
changes in asthma, this therapy should be combined
with inhaled Glucocorticoids
Fluticosone propionate salmeterol and bedesonideformoterol inhalers (Advair)

Adrenergic Bronchodilators
Long-Acting Agents
Side effects
Inhaled beta-2 agonists cause fewer systemic
adverse effect (e.g., cardiovascular
stimulation, skeletal muscle tremors, and
hypokalemia) than oral therapy particularly if
the oral regimen includes theophylline.

Salmeterol
Dosing - every 12 hours
Dosage Forms
MDI, Discus (powder), combination with steroid

Advantages
long acting, less tolerance to effects than
salbutamol- decreases need to increase
corticosteroid dose

Side Effects/Problems
Slow onset of effect
Headache, tremor, palpitations, and nervousness
are the most frequent side effects.

Formoterol
Dosing every 12 hours
Dosage Forms aerosolized powder
Similar to Spinhaler (drug in gelatin capsule)

Advantages
has both a rapid-onset bronchodilator is longacting but not as a rescue medicine

Side Effects/Problems
The most common side effects are headache,
palpitations, and tremor.
Less common side effects include agitation,
restlessness, sleep disturbance, muscle
cramps, and increased heart rate

Xanthine Agents
Naturally Occurring Agents
Caffeine (Coffee and kola beans; tea leaves)
Theophylline (Tea leaves)
Theobromine (Cocoa seeds or beans)

Synthetic Derivatives
Dyphylline
Proxyphylline
Enprophylline

Methylxanthines
Mode of administration
Oral or Parenteral
Mechanisms of action
The bronchodilator effect may be related to phosphodiesterase
inhibition (>10mg/L);
anti-inflammatory effect is due to an unknown mechanism and
may occur at lower concentrations (5-10mg/L).
This latter mechanism may involve the inhibition of cell surface
receptors for adenosine, which modulate adenylyl cyclase activity
(contraction of isolated smooth muscle and to provoke histamine
release from mast cells.

Most studies show little or no effect on airway

hyperresponsiveness

Role in therapy
Sustained release theophylline is effective in controlling asthma
symptoms and improving lung function (i.e., nocturnal symptoms;
may be used as an add-on therapy to low or high doses of
glucocorticoids)

Methylxanthines
Side effects (serum concentrations > 15g/mL)*
Gastrointestinal symptoms nausea, vomiting
CNS Seizures
Cardiovascular tachycardia, arrhythmias
Pulmonary stimulation of the respiratory
center
*Monitoring theophylline levels is advised when high-dose
therapy (>10mg/kg body weight is used or when a
patient develops an adverse effect on the usual dosage

Mast Cell Stabilizing Agents

Mechanism of Action:
inhibit the activation of mast cells within the airway, thereby
preventing release of mediators that provoke asthma symptoms.
alter the function of delayed chloride channels in the cell membrane
considered by some as a type of NSAID.

Used for preventing asthma attack

Advantages:
As the prophylaxis of asthma attack caused by allergen, exercise,
aspirin, and working.
Used for long term medication

Disadvantages:

Using dosage four times a day

Expensive
Less effectivity than inhaled corticosteroid
side effects: throat iritation, cough, dry mouth, and bad taste of
tongue.

Cromolyn & Nedocromil

Dosing QID
Dosage Forms MDI or
Nebulized solution (Cromolyn)
Advantages - alternative to
steroids/-agonists
Side Effects/Problems
Daily dosing required (works
prophylactically)
Cromolyn (throat irritation or
dryness, wheezing, nausea,
coughing, and a bad taste in the
mouth).
Nedocromil (bad taste, nausea,
abdominal pain, and vomiting).

Leukotriene modifiers
Zafirlukast, Montelukast, and Zileuton

A relatively new class of

anti-asthma drugs that
include
cysteinyl leukotriene 1
(CysL T1) receptor
antagonists
(montelukast, zafirlukast)
and

5-lipoxeygenase inhibitor
(zileuton)

Leukotriene modifiers
Mode of administration
Oral
Using dosage four times a day (Zileuton)

Mechanism of action
Receptor antagonists block the CysLT1
receptors on airway smooth muscle and thus
inhibit the effects of cysteinyl leukotrienes that
are release from mast cells and eosinophils
5-lipoxygenase inhibitors block synthesis of
leukotrienes.

Leukotriene modifiers
Role in therapy
These agents have a small and variable
bronchodilator effect, reduce symptoms, improve
lung function, and reduce asthma exacerbations.
Effect of these drugs is less than that of lowdoses of inhaled glucocorticoids. There is
evidence that the use of these drugs as an addon may reduce the dose of inhaled glucocorticoid
required by patients with moderate to severe
asthma.
Note that leukotriene modifiers are less effective than long-acting
inhaled beta-2 agonists as an add-on therapy.

Leukotriene modifiers
Side effects
These drugs are usually well tolerated, and few
if any class-related effects have been
recognized.
Zileuton has been associated with liver toxicity and
monitoring liver test is recommended
There are several reports of Churg-Strauss
syndrome associated with the leukotriene modifier
therapy (typically associated with a reduction of
systemic glucocorticoids)

Contraindication:
patients with coronary heart disease, and cardiac
arrhythmias.

IgE Antibody
Omalizumab
Used as intravenous or intramuscular anti-asthma.
diminishing the production of IgE through effects on
interleukin 4 or on IgE itself have been evaluated

Soluble recombinant IL-4 receptor that can be delivered by

aerosol
Recombinant human monoclonal antibody that forms
complexes with free IgE (rhuMAb or omalizumab blocks the
interaction of IgE with mast cells and basophils.
Attenuates the early-phase and late phase airway obstruction
response to allergen and suppressed the accumulation of
eosinophils in the airways

Advantages:

- Decreasing the degrees of asthma

- Reducing the used of corticosteroid
- Repaired nasal symptoms for patients
with allergic rhinitis.
Disadvantage:
very expensive

Routes of Administration
Inhaled
Metered dose inhalers (MDI)
Spacers

Dry powder inhalers (DPI)

Nebulized (wet) aerosols

Oral
Parenteral
Subcutaneous
Intramuscular
Intravenous

Pharmacokinetics of anti-asthma
Oral

Inhaler

Sub-cutane

Vena
portae

Membrane
mucous

Blood
flow

Excretion

Urine

Is there an advantage to
using a nebulizer, as
opposed to an MDI, for
delivery of medications
for the treatment of
asthma?

Studies comparing Nebulizers

to MDIs with Spacers
Chou KJ, et al. Metered-Dose Inhalers with
Spacers vs Nebulizers for Pediatric Asthma. Arch
Ped Adol Med 149:201-5,1995.
Nebulized beta-agonist therapy had been the
standard of care for patients with acute asthma
exacerbations. Several studies in adults,
however, have found metered dose inhaler (MDI)
administration to be as effective.
Use of the MDI instead of nebulizer
administration would be economically
beneficial and easier for both patients and
clinicians.

(MDI+ spacer) vs Nebulizer

Are antihistamines useful in

the prophylaxis and/or
treatment of asthma?

Clin Exp Allergy. 29 Suppl 3:98-104,1999.

Effectiveness of H1 antagonists in
adults with seasonal asthma

Clin Exp Allergy. 29 Suppl 3:98-104,1999.

Conclusions of Analyses
severe persistent asthma
no significant clinical effect

moderate persistent asthma

clinical benefits of H1 antagonists are apparent but
require higher-than-usual doses and are not worth the
risk to patient

mild seasonal asthma and allergic rhinitis

coexistant
significant improvement in asthma symptoms at usual
dosing

Key Points
Short-acting beta2-agonists: Therapy of choice for
relief of acute symptoms and prevention of EIB.
Anticholinergics: May provide some additive
benefit to inhaled beta2-agonists in severe
exacerbations. May be an alternative for patients
who do not tolerate inhaled beta 2-agonists.
Systemic corticosteroids: Used for moderate-tosevere exacerbations to speed and prevent
recurrence of exacerbations.

Key Points
Corticosteroids: Most potent and effective antiinflammatory medication currently available
Cromolyn sodium and nedrocromil: Mild-tomoderate anti-inflammatory medication.
Leukotriene inhibitors: May be considered an
alternative therapy to low dose inhaled
corticosteroids or cromolyn sodium or
nedrocromil for patients >12 years of age with
mild persistent asthma.

Key Points
Long-acting beta2-agonists: These drugs are
typically used concurrently with antiinflammatory medications for long-term control
of symptoms, especially nocturnal symptoms.
Methylxanthines: Sustained release
theophylline is a mild-to-moderate
bronchodilator used principally as an adjuvant
to inhaled corticosteroids for prevention of
nocturnal asthma symptoms.

Treatment Protocols

Etiology
Genetic factors
Atopy

Environmental
factors
Viruses
Allergens
Occupational
exposure

Factors that Influence Asthma

Development and Expression
Host Factors
Genetic
Atopy
Airway
hyperresponsiveness

Gender
Obesity

Environmental Factors
Indoor allergens
Outdoor allergens
Occupational
sensitizers
Tobacco smoke
Air Pollution
Respiratory Infections
Diet

Factors that Exacerbate Asthma

Allergens
Respiratory infections
Exercise and hyperventilation
Weather changes
Sulfur dioxide
Food, additives, drugs

Major Cells Implicated in

Inflammatory Response
Mast cells
an important cell type in the asthmatic lung.
These cells produce numerous mediators that
contribute to the development of asthma,
including:

histamine,
cysteinyl leukotrienes,
tryptase,
tumor necrosis factor-alpha,
prostaglandin D2, and
cytokines including IL4, IL-5 and IL-13

Lymphocytes
Eosinophils
Neutrophils

Inflammatory processes
Desquamation of
epithelium
Hyperplasia of
Mucos glands

Mucus plug

Basement
Membrane
thickening

Oedema
Smooth muscle
Hypertrophy and contraction
Barnes PJ

Neutrophil and
eosinophil infiltration

Classification of Asthma Severity:

Clinical Features Before Treatment
Severity

Days with
Symptoms

Nights with
Symptoms

PEF or
FEV1.0

Severe
Persistent

Continual

Frequent

60%

Moderate
Persistent

Daily

5/month

> 60%
< 80%

Mild
Persistent

3-6/ week

3-4/month

80%

Mild
Intermittent

2/week

2/month

80%

IgE Antibodies

Busse, WW, Lemanske, RF: NEJM 344:350-362, 2001