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Pathophysiology of Asthma
Pharmacology of • Airway inflammation
– Cytokines
Asthma • Bronchial hyper-responsiveness
– Hipersensitifity type 1
• Alergen
• Antibodi (IgE)
Tri Widyawati
• Mast cell
• Mediators (Histamin, Lekotrien, etc)
– Slow phase
• Airflow limitation

Pathologic Findings Etiology

• Bronchoconstriction • Genetic factors
• Hyperinflation of the
– Atopy
lungs
• Hyperplasia of the • Environmental
smooth muscle factors
surrounding the bronchial
and bronchiolar walls – Viruses
• Thickening of the – Allergens
basement membrane – Occupational
• Mucosal edema exposure

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

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Factors that Influence Asthma

Factors that Exacerbate Asthma
Development and Expression

Allergens
Host Factors Environmental Factors

Genetic
Indoor allergens
Respiratory infections
• Atopy
Outdoor allergens
Exercise and hyperventilation
• Airway
Occupational
hyperresponsiveness
sensitizers
Weather changes

Gender

Tobacco smoke
Sulfur dioxide

Obesity

Air Pollution

Respiratory Infections

Food, additives, drugs

Diet

Major Cells Implicated in

Inflammatory Processes
Inflammatory Response
• Mast cells • In the early stages of asthma, inflammatory processes, such as
infiltration of the airway wall with white blood cells, disruption of the
– an important cell type in the asthmatic lung.
epithelium and mucus plugging of the airway lumen, are thought to
– These cells produce numerous mediators that be potentially reversible with effective anti-inflammatory treatment
contribute to the development of asthma, • Chronic uncontrolled or poorly controlled asthma is associated with
including: a variety of structural changes in the airway wall, which in turn leads
• histamine, to a progressive reduction in the ‘reversibility’ of the airway
• cysteinyl leukotrienes, obstruction in response to a bronchodilator
• tryptase,
• Structural changes, such as thickening of the basement membrane,
• tumor necrosis factor-alpha,
hyperplasia of the mucus glands and hypertrophy of the airway
• prostaglandin D2, and
smooth muscle ultimately progress to the development of
• cytokines including IL4, IL-5 and IL-13
irreversible fibrosis (remodelling)
• Lymphocytes
• Eosinophils
• Neutrophils

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Inflammatory processes Chemicals Involved in

Inflammation
Desquamation of
epithelium
• IgE • Interleukins (IL-4, IL-5)
Hyperplasia of Mucus plug
Mucos glands • Histamine • Granulocyte-
• Tryptase macrophage colony
Basement
• Leukotrienes (LTC4) stimulating factor
Membrane • Platelet activating (GM-CSF)
thickening
factor (PAF) • Tumor Necrosis Factor
• Prostaglandins (TNF)
(PGD2) • Major Basic Proteases
Oedema (MBP)
Neutrophil and
Smooth muscle eosinophil infiltration • Eosinophil Cationic
Hypertrophy and contraction Protein (ECP)
Barnes PJ

Patho-physio-pharmacology of Asthma Patho-physio-pharmacology of Asthma

Allergen
• Regards it as a specific type of inflammatory condition, Macrophage/
involving, in particular, mast cells, eosinophils and T dendritic cell Mast cell

lymphocytes, which release a wide range of Th2 cell Neutrophil

inflammatory mediators
Eosinophil
• These mediators act on cells in the airway, leading to Mucus plug
Epithelial shedding
contraction of smooth muscle, oedema due to plasma Nerve activation

leakage and mucus plugging, all of which contribute to

Subepithelial
the narrowing of the airways fibrosis
Plasma leak
Sensory nerve
• Activation of the sensory nerves in the airway wall is Oedema activation
thought to be an important factor in triggering episodes Mucus
Vasodilatation Cholinergic
New vessels reflex
of coughing hypersecretion
Hyperplasia Bronchoconstriction
Hypertrophy / hyperplasia

Barnes PJ

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Asthma components
Healthy airway Asthmatic airway
Aveolar septum Mucus and plasma
Inflammation
and oedema exudation

Smooth Epithelium Smooth muscle Epithelial shedding /

muscle contraction damage

Barnes PJ

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Classification of Asthma Severity: General Goals of Asthma Therapy

Clinical Features Before Treatment
• Relief airways tightening / bronchoconstriction
Days with Nights with PEF or immediately.
Severity
Symptoms Symptoms FEV1.0 • Education of asthma management.
Severe Continual Frequent ≤ 60%
Persistent • Prevent chronic symptoms and asthma
Moderate Daily ≥ 5/month > 60% exacerbations during the day and night
Persistent < 80% • Maintain normal activity levels
Mild 3-6/ week 3-4/month ≥ 80% • Have normal or near-normal lung function
Persistent • Have no or minimal side effects while receiving
Mild ≤ 2/week ≤ 2/month ≥ 80% optimal medications
Intermittent

General Pharmacologic Approach to

Intervention in Asthma the Treatment of Asthma
Avoidance
– “Relievers”
Inducers Triggers
of allergens, infections
• Short-acting bronchodilators
– β2-adrenergic agents
Inflammation
– Anti-cholinergic (Parasympatholytic) agents
Inhaled Airways
eosinophils Hyper-responsiveness
corticosteroids
ECP Exercise induced asthma
– “Controllers”
• Corticosteroids
ß2 agonist
• Long-Acting bronchodilators
bronchodilators
Symptoms – β2-adrenergic agents
– Methylxanthines
Cough, chest tightness Wheeze, dyspnea • Cromolyn sodium
• Leukotriene inhibitors
Airways obstruction
• Anti-IgE monoclonal antibodies

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Historical Perspective
• Datura stramonium (1802)
• Epinephrine (1903)
• Ephedrine (1926)
“Relievers” •
•
Isoproterenol (1940)
Isoetharine (1951)
• Metaproterenol (1961)
• Beta2-adrenergic agents via MDI (1973)
• Ipratropium bromide (1987)
• Salmeterol (1994)
• Levalbuterol (1999)

Patho-Physio-Pharmacology of Adrenergic Bronchodilators –

Bronchodilators Short-Acting Agents
• Catecholamines
– Epinephrine
– Isoproterenol
– Isoetharine
• Resorcinol agents
– Metaproterenol
• Saligenin agents
– Salbutamol
• Pirbuterol
• Bitolterol

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β-Agonists Classification of β−agonists

β−
• Mechanism of Action -relax smooth muscle Beta Agonists
Short acting
within the airways, causing bronchodilation. Generic name Duration of action β2-selectivity
• Short Acting Salbutamol 4-6 h +++
– Salbutamol (Various Brands) Levalbuterol 8h +++
– Levalbuterol (Xopenex) Metaproterenol 4-6 h ++
– Biltolterol (Tornalate) Isoproterenol 3-4 h ++
– Pirbuterol (Maxair) Epinephrine 2-3 h -

– Isoproternol (Medihaler-Iso) Long acting

Salmeterol 12+ h +++
– Metaproternol (Alupent)
Formoterol 12+ h +++
– Terbutaline (Brethaire)
β2 agonists were developed through substitutions in the catecholamine structure of norepinephrine
• Long Acting (NE). NE differs from epinephrine in the terminal amine group, and modification at this site confers
– Salmeterol (Serevent) beta receptor selectivity; further substitutions have resulted in β2 selectivity. The selectivity of β2
agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small
– Formoterol (Foradil) doses to the airways and minimizes systemic exposure. β agonists are generally divided into short
(4-6 h) and long (>12 h) acting agents.

Beta-2 Adrenergic Agonists – 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
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.

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Beta-2 Adrenergic Agonists –

Short acting agents
Salbutamol
Side Effects • Mainstay of Therapy for Many Years
• Tremor • Characteristics
• Papitations and tachycardia – Dosing –every 4-6 hours
• Headache – Dosage Forms
• MDI (HFA), Unit Dose Vials for Nebulizers, Oral
• Insomnia Solutions, Oral Tablets
• Rise in blood pressure – Advantages- quick action, “rescue therapy”
• Nervousness – Side Effects/Problems
• Dizziness • The most common side effects are heart
palpitations, irregular, rapid heartbeat, anxiety, and
• Nausea increased blood pressure.

Anticholinergic Bronchodilators Anticholinergic Bronchodilators

• Mode of administration
• Tertiary Ammonium Compounds – Inhaled
– Atropine sulfate • Mechanisms of action
– Scopalamine – Block the effects of acetylcholine released from
cholinergic nerves in the airways (i.e., reduce intrinsic
• Quaternary Ammonium Compounds vagal cholinergic tone to the airways).
– Ipratropium – Block reflex bronchoconstriction caused by inhaled
irritants
– Tiotropium – 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).

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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 “Controllers”
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 Corticosteroids
• Corticosteroids Inhaled Glucocorticoids
• Beclomethasone
• Long-Acting bronchodilators • Flunisolide
– β2-adrenergic agents • Fluticasone
• Triamcinolone
– Methylxanthines • Budesonide, and
• Cromolyn sodium/Nedrocromil • Mometasone
Systemic Glucocorticoids
• Leukotriene inhibitors • Prednisone
• Anti-IgE monoclonal antibodies • Methylprednisolone
• Prednisolone
• Dexamethasone

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Inhaled Glucocorticoids 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
• 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 Systemic Glucocorticoids

• Beclomethasone dipropionate • Mode of administration
– Dosage: 200-1000µg – Oral
• Budesonide – Parenteral
– Dosage: 200-800µg • Mechanisms of action
• Flunisolide – Same as for inhaled Glucocorticoids however
systemic Glucocorticoids may reach different
– 500-2000µg target cells than inhaled drugs
• Fluticasone • Role in therapy
– 100-500µg – Long-term oral Glucocorticoids therapy (daily
• Triamcinolone acetonide or alternate-day) may be required to control
– 400-2000µg severe persistent asthma.

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Systemic Glucocorticoids Adrenergic Bronchodilators –

side effects Long-Acting Agents
– Osteoporosis – Obesity
– Arterial hypertension – Skin thinning leading • Sustained-
– Diabetes to cutaneous striae
– Easy bruising
released
– Hypothalamic-pituitary
axis suppression – Muscle weakness salbutamol
– Cataracts – Fatal herpes virus
– Glaucoma infections have been
• Salmeterol
reported among • Formoterol
patients who are
exposed to these
viruses when they are
taking systemic
Glucocorticoids

Adrenergic Bronchodilators – Adrenergic Bronchodilators –

Long-Acting Agents Long-Acting Agents
• Modes of administration • Role in therapy
– Inhaled – Long-acting inhaled beta-2 agonists should be
considered when standard introductory doses of
– Oral inhaled Glucocorticoids fail to achieve control of
• Mechanisms of action asthma before raising the dose of inhaled
Glucocorticoids.
– Same as short-acting beta-2 agonists
– Because long-term treatment with these agents does
– Effects persists for at least 12 hours not appear to influence the persistent inflammatory
changes in asthma, this therapy should be combined
with inhaled Glucocorticoids
• Fluticosone propionate – salmeterol and bedesonide-
formoterol inhalers (Advair®)

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Adrenergic Bronchodilators –
Salmeterol
Long-Acting Agents
• Side effects • Dosing - every 12 hours
– Inhaled beta-2 agonists cause fewer systemic
• Dosage Forms
– MDI, Discus (powder), combination with steroid
adverse effect (e.g., cardiovascular
stimulation, skeletal muscle tremors, and • Advantages
hypokalemia) than oral therapy particularly if – long acting, less tolerance to effects than
the oral regimen includes theophylline. 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 Xanthine Agents

• Dosing every 12 hours • Naturally Occurring Agents
• Dosage Forms –aerosolized powder – Caffeine (Coffee and kola beans; tea leaves)
– Similar to Spinhaler (drug in gelatin capsule) – Theophylline (Tea leaves)
• Advantages – Theobromine (Cocoa seeds or beans)
– has both a rapid-onset bronchodilator is long- • Synthetic Derivatives
acting but not as a rescue medicine
– Dyphylline
• Side Effects/Problems
– Proxyphylline
– The most common side effects are headache,
palpitations, and tremor. – Enprophylline
– Less common side effects include agitation,
restlessness, sleep disturbance, muscle
cramps, and increased heart rate

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Methylxanthines Methylxanthines
• Mode of administration
– Oral or Parenteral • Side effects (serum concentrations > 15µg/mL)*
• Mechanisms of action – Gastrointestinal symptoms – nausea, vomiting
– The bronchodilator effect may be related to phosphodiesterase
inhibition (>10mg/L); – CNS – Seizures
– anti-inflammatory effect is due to an unknown mechanism and
may occur at lower concentrations (5-10mg/L). – Cardiovascular – tachycardia, arrhythmias
• This latter mechanism may involve the inhibition of cell surface – Pulmonary – stimulation of the respiratory
receptors for adenosine, which modulate adenylyl cyclase activity
(contraction of isolated smooth muscle and to provoke histamine
release from mast cells.
center
– Most studies show little or no effect on airway
hyperresponsiveness *Monitoring theophylline levels is advised when high-dose
• Role in therapy therapy (>10mg/kg body weight is used or when a
– Sustained release theophylline is effective in controlling asthma patient develops an adverse effect on the usual dosage
symptoms and improving lung function (i.e., nocturnal symptoms;
may be used as an add-on therapy to low or high doses of
glucocorticoids)

Mast Cell Stabilizing Agents Cromolyn & Nedocromil

• Mechanism of Action: –Dosing QID
– inhibit the activation of mast cells within the airway, thereby
preventing release of mediators that provoke asthma symptoms. –Dosage Forms – MDI or
– alter the function of delayed chloride channels in the cell Nebulized solution (Cromolyn)
membrane
–Advantages - alternative to
– considered by some as a type of NSAID.
steroids/β-agonists
• Used for preventing asthma attack
• Advantages: –Side Effects/Problems
– As the prophylaxis of asthma attack caused by allergen, • Daily dosing required (works
exercise, aspirin, and working. prophylactically)
– Used for long term medication • Cromolyn (throat irritation or
• Disadvantages: dryness, wheezing, nausea,
– Using dosage four times a day coughing, and a bad taste in the
– Expensive mouth).
– Less effectivity than inhaled corticosteroid • Nedocromil (bad taste, nausea,
– side effects: throat iritation, cough, dry mouth, and bad taste of abdominal pain, and vomiting).
tongue.

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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)
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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 low-
doses of inhaled glucocorticoids. There is
evidence that the use of these drugs as an
add-on 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.
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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
IgE Antibodies
• 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 Busse, WW, Lemanske, RF: NEJM 344:350-362, 2001

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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 Membrane Blood

portae mucous flow

Excretion

Urine

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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 (MDI+ spacer) vs Nebulizer

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.

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

• Effectiveness of H1 antagonists in
adults with “seasonal” asthma
Are antihistamines useful in
the prophylaxis and/or
treatment of asthma?

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

• Conclusions of Analyses
• Short-acting beta2-agonists: Therapy of choice
• severe persistent asthma for relief of acute symptoms and prevention of EIB.
– no significant clinical effect • Anticholinergics:
• moderate persistent asthma - May provide some additive benefit to inhaled beta2-
– clinical benefits of H1 antagonists are apparent but agonists in severe exacerbations.
require higher-than-usual doses and are not worth the -May be an alternative for patients who do not tolerate
risk to patient inhaled beta2-agonists.
• mild seasonal asthma and allergic rhinitis • Systemic corticosteroids: Used for moderate-to-
coexistant severe exacerbations to speed and prevent recurrence
– significant improvement in asthma symptoms at usual of exacerbations.
dosing

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Key Points Key Points

• Corticosteroids: Most potent and effective anti- • Long-acting beta2-agonists: typically used
inflammatory medication currently available concurrently with anti-inflammatory medications for long-
• Cromolyn sodium and nedrocromil: Mild-to- term control of symptoms, especially nocturnal
moderate anti-inflammatory medication. symptoms.

• Leukotriene inhibitors: May be considered an • Methylxanthines: Sustained release theophylline is

a mild-to-moderate bronchodilator used principally as an
alternative therapy to low dose inhaled:
adjuvant to inhaled corticosteroids for prevention of
- corticosteroids or
nocturnal asthma symptoms.
- cromolyn sodium or
- nedrocromil for patients >12 years of age with mild
persistent asthma.

Treatment Protocols

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