BRONCHODILATORS

BRONCHODILATORS AND
AND OTHER
OTHER
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA

ISWANDI DARWIS, MD
FACULTY OF MEDICINES
LAMPUNG UNIVERSITY
 DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BRONCHODILATORS ANTI-INFLAMMATORY LEUKOTRIENE
AGENTS ANTAGONISTS

β RELEASE LIPOXYGENASE RECEPTOR

AGONISTS INHIBITORS INHIBITORS INHIBITORS

MUSCARINIC STEROIDS ANTIBODIES

ANTAGONISTS

METHLYXANTHINES SLOW ANTI-

INFLAMMATORY DRUGS
BRONCHIAL
BRONCHIAL ASTHMA
ASTHMA
Airway inflammation
Episodic, reversible bronchospasm
Chronic inflammation that leads to
marked bronchial hyperreactivity
BRONCHIAL
BRONCHIAL ASTHMA
ASTHMA
 ASTHMA
BRONCHIAL ASTHMA Dilatation
AC
ATP

CAMP AMP

Bronchial Tone PDE

Acetylcholine Leukotrienes
BRONCHIAL

Adenosine

Constriction
BRONCHIAL
BRONCHIAL ASTHMA
ASTHMA
Release of several mediators from IgE-
sensitized mast cells and other cells
involved in immunologic responses
Mediators include
Leukotrienes
Chemoattractants
Cytokines
Enzymes
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
STRATEGIES OF ASTHMA THERAPY
ACUTE ASTHMATIC ATTACKS
Treated promptly and effectively with
bronchodilators
β22 agonist


Muscarinic
 antagonists
Theophylline and its derivatives

DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
STRATEGIES OF ASTHMA THERAPY
CHRONIC ASTHMA
Long term preventive treatment
Requires control of inflammatory process in
the airways
Corticosteroids


Cromolyn

 DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BRONCHODILATORS ANTI-INFLAMMATORY LEUKOTRIENE
AGENTS ANTAGONISTS

β RELEASE LIPOXYGENASE RECEPTOR

AGONISTS INHIBITORS INHIBITORS INHIBITORS

MUSCARINIC STEROIDS ANTIBODIES

ANTAGONISTS

METHLYXANTHINES SLOW ANTI-

INFLAMMATORY DRUGS
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BETA-ADRENOCEPTOR AGONISTS
Mechanism of action
Stimulate adenyl cyclase and increasing cAMP
in smooth muscle cells  bronchodilatation
 Relaxation ATP

CAMP AMP

Bronchial Tone PDE

Acetylcholine Leukotrienes

BETA AGONIS Adenosine

Constriction
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BETA-ADRENOCEPTOR AGONISTS
Most important sympathomimetic used
to reverse asthmatic bronchoconstriction
Almost given exclusively by inhalation
Decreases the systemic dose and adverse
effects
Occasionally by nebulizer
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BETA-ADRENOCEPTOR AGONISTS
Albuterol, terbutaline, metaproterenol
Short-acting
Drug of choice for acute asthma
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BETA-ADRENOCEPTOR AGONISTS
Salmeterol and formoterol
Long-acting
12 h or more
Used for prophylaxis
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA

BETA-ADRENOCEPTOR AGONISTS
Epinephrine and isoproterenol
Still used occasionally
Used for chronic obstructive pulmonary
disease (COPD) patients
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BETA-ADRENOCEPTOR AGONISTS
TOXICITY
Skeletal muscle tremor
Significant β11 effects (tachycardia) at high
clinical dosage
Arrhythmias may occur when used excessively
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BETA-ADRENOCEPTOR AGONISTS
TOXICITY
Tolerance, tachyphylaxis (loss of
responsiveness) is an unwanted effect
COPD patients often with concurrent cardiac
disease may have arrhythmias at normal
dosage
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
METHYLXANTHINES
Purine derivatives
MOA
Inhibit phosphodiesterase (PDE), the enzyme
that degrades cAMP to AMP, thus increases
cAMP
Anti-PDE effect requires high concentration of
the drug
 Relaxation
ATP

CAMP AMP

Bronchial Tone PDE

Acetylcholine Leukotrienes

ANTAGONIS
Adenosine

Constriction
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
METHYLXANTHINES
Found in plants and provide the stimulant
effect of 3 common beverages
Caffeine (coffee)
Theophylline (tea)
Theobromine (cocoa)
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
METHYLXANTHINES
Theophylline and several analogs
Orally active
Available as salts and base
Slow-release theophylline
For control of nocturnal asthma
Most important in clinical use
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
METHYLXANTHINES
Clearance varies
Highest in young adolescents
Higher in smokers
Concurrent use of other drugs that inhibit or
induce hepatic enzyme
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
METHYLXANTHINES
Bronchodilation is the most important
therapeutic effect
CNS stimulation, cardiac stimulation,
vasodilation and slight increase in BP (due
to release of NE from adrenergic nerves
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
METHYLXANTHINES
Eliminated by Cytochrome P450-drug
metabolizing enzyme in the liver
Pentoxifylline
Used for treatment of intermittent
claudication
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
METHYLXANTHINES
TOXICITY
Common adverse effects
GI
 distress
Tremor


Insomnia

DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
METHYLXANTHINES
TOXICITY
Overdosage
Severe
 nausea and vomiting
Hypotension


Cardiac arrhythmias


Convulsion

DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
MUSCARINIC ANTAGONISTS
MOA
Competitively blocks muscarinic receptors in
the airways
Prevents bronchoconstriction mediated by
vagal discharge
 Relaxation ATP

CAMP AMP

Bronchial Tone PDE

Acetylcholine Leukotrienes

Adenosine
ANTAGONIS

Constriction
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
MUSCARINIC ANTAGONISTS
Reverses bronchoconstriction
Useful in 1/3 to 2/3 of asthmatic patients
(especially children)
No effect on the inflammatory aspects of
asthma
Useful in many COPD patients
More
 effective and less toxic than β
agonists
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
MUSCARINIC ANTAGONISTS
Atropine and other naturally-occurring
belladona alkaloids were used for asthma
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
MUSCARINIC ANTAGONISTS
Ipatropium
Quaternary antimuscarinic drug
Delivered to the airways by pressurized aerosol
Have little systemic action
Tiotropium
Newer longer-acting analog
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
MUSCARINIC ANTAGONISTS
TOXICITY
Delivered directly to the airway, minimally
absorbed
Systemic effects are small
In excessive dosage, minor atropine-like toxic
effects may occur
Does not cause tremor or arrhythmias
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CROMOLYN AND NEDOCROMIL
No bronchodilator action but can prevent
bronchoconstriction caused by a challenge
with antigen to which the patient is allergic
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CROMOLYN AND NEDOCROMIL
MOA
Decrease in the release of mediators
(leukotrienes and histamine) from mast cells
Prevents both early and late responses to
challenge
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CROMOLYN AND NEDOCROMIL
Cromolyn – prototype drug
Unusual chemicals
Extremely insoluble
Massive doses given orally or by
aerosol result in minimal systemic levels
(local effects)
Given by aerosol for asthma
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CROMOLYN AND NEDOCROMIL
Food allergy
Given orally
Asthma in children
Most important use
Hay fever
Nasal and eyedrop formulations
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CROMOLYN AND NECRODOMIL
TOXICITY
Cough and irritation of the airway when given
by aerosol
Drug allergy is rare
 DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BRONCHODILATORS ANTI-INFLAMMATORY LEUKOTRIENE
AGENTS ANTAGONISTS

β RELEASE LIPOXYGENASE RECEPTOR

AGONISTS INHIBITORS INHIBITORS INHIBITORS

MUSCARINIC STEROIDS ANTIBODIES

ANTAGONISTS

METHLYXANTHINES SLOW ANTI-

INFLAMMATORY DRUGS
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
MOA
Reduces the synthesis of arachidonic acid by
phospholipase A22
Inhibit the expression of COX-2 (anti-
anflammatory action)
Postulated that: this drugs increases the
responsiveness of beta agonists in the airway
 DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
Phospholipase
Membrane A2
Lipid Arachidonic acid

Steroid

Lipooxygenase Cyclooxygenase

Hydroxypeptidase Endoperoxidase

Leukotrienes Prostacycline Prostaglandin

Thromboxane A2
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
All are potentially beneficial in severe
asthma
Systemic (oral corticosteroids)
Used chronically only if other therapies fail
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
Local aerosol administration of surface
active corticosteroids are relatively safe
Beclomethasone
Budesonide
Dexamethasone
Flunisolide
Fluticasone
Mometasone
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
Inhaled corticosteroids
Common first-line therapy for moderate to
severe asthma
Appropriate (even in children) in cases of
moderate asthma that does not fully respond to
aerosol β agonist
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
Prednisolone and hydrocortisone
Intravenous
For status asthmaticus
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
Reduced activity of phospholipase
A22
Leukotrienes that result from the
synthesis of prostaglandins are potent
bronchoconstrictors
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
Early use may prevent the severe,
progressive inflammatory changes of long-
standing asthma
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
TOXICITY
Changes on oropharyngeal flora result to
candidiasis
For oral therapy
Adrenal
 suppression can be reduced by
using alternate day therapy (give the
drug in slightly higher dosage every
other day)
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
CORTICOSTEROIDS
TOXICITY
Systemic toxicities
Occur
 if treatment is required for more
than 2 weeks
Regular use of inhaled steroids cause

mild growth retardation in children
 DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
BRONCHODILATORS ANTI-INFLAMMATORY LEUKOTRIENE
AGENTS ANTAGONISTS

β RELEASE LIPOXYGENASE RECEPTOR

AGONISTS INHIBITORS INHIBITORS INHIBITORS

MUSCARINIC STEROIDS ANTIBODIES

ANTAGONISTS

METHLYXANTHINES SLOW ANTI-

INFLAMMATORY DRUGS
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
LEUKOTRIENE ANTAGONISTS
Interfere with the synthesis or action
of leukotrienes
Not as effective as corticosteroids in
severe asthma
Not recommended for acute asthma
Low toxicity
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
S
Arachidonic acid
NI
O
G
TA
AN

Lipooxygenase Cyclooxygenase

Hydroxypeptidase Endoperoxidase

Leukotrienes Prostacycline Prostaglandin

Thromboxane A2
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
LEUKOTRIENE ANTAGONISTS
Zileuton
Orally active
Selectively inhibits 5-lipoxygenase,
a key enzyme in the conversion of
arachidonic acid to leukotrienes
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
LEUKOTRIENE ANTAGONISTS
Zileuton
Effective in
Exercise-
 and antigen-induced
bronchospasm
Aspirin allergy


Toxicity include occasional elevation of


liver enzymes
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
LEUKOTRIENE ANTAGONISTS
Zafirlukast and montelukast
Antagonist at the LTD44 leukotriene receptor
Orally active
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
LEUKOTRIENE ANTAGONISTS
Effective in preventing exercise-,
antigen-and aspirin-induced
bronchospastic attacks
DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
Anti-IgE antibody
Omalizumab
Humanized
 murine monoclonal
antibody to human IgE
Prophylactic management of asthma


Given parenterally

DRUGS
DRUGS USED
USED IN
IN ASTHMA
ASTHMA
Anti-IgE antibody
Binds to IgE on sensitized mast cells
Prevents activation by asthma triggers
Subsequent release of inflammatory
mediators
 HANUPIS 
NANYA ? SOK ATUH . .