ISWANDI DARWIS, MD

FACULTY OF MEDICINES LAMPUNG UNIVERSITY

DRUGS USED IN ASTHMA

BRONCHODILATORS ANTI-INFLAMMATORY AGENTS RELEASE INHIBITORS STEROIDS LEUKOTRIENE ANTAGONISTS AGONISTS MUSCARINIC ANTAGONISTS LIPOXYGENASE RECEPTOR INHIBITORS INHIBITORS ANTIBODIES

METHLYXANTHINES SLOW ANTIINFLAMMATORY DRUGS

BRONCHIAL ASTHMA
Airway inflammation Episodic, reversible bronchospasm Chronic inflammation that leads to marked bronchial hyperreactivity

BRONCHIAL ASTHMA

BRONCHIAL ASTHMA

AC Dilatation
CAMP

ATP

AMP

Bronchial Tone
Acetylcholine Leukotrienes

PDE

Adenosine

Constriction

BRONCHIAL ASTHMA
Release of several mediators from IgEsensitized mast cells and other cells involved in immunologic responses Mediators include
Leukotrienes Chemoattractants Cytokines Enzymes

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STRATEGIES OF ASTHMA THERAPY ACUTE ASTHMATIC ATTACKS
Treated promptly and effectively with

bronchodilators

2 agonist Muscarinic antagonists Theophylline and its derivatives

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STRATEGIES OF ASTHMA THERAPY CHRONIC ASTHMA
Long term preventive treatment Requires control of inflammatory process in

the airways

Corticosteroids Cromolyn

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BRONCHODILATORS
AGONISTS MUSCARINIC ANTAGONISTS ANTI-INFLAMMATORY LEUKOTRIENE AGENTS ANTAGONISTS LIPOXYGENASE RECEPTOR INHIBITORS INHIBITORS ANTIBODIES RELEASE INHIBITORS STEROIDS

METHLYXANTHINES SLOW ANTIINFLAMMATORY DRUGS

DRUGS USED IN ASTHMA

BETA-ADRENOCEPTOR AGONISTS Mechanism of action
Stimulate adenyl cyclase and increasing cAMP

in smooth muscle cells bronchodilatation

Relaxation
CAMP

ATP AMP

Bronchial Tone
Acetylcholine Leukotrienes

PDE

Adenosine

Constriction

DRUGS USED IN 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

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BETA-ADRENOCEPTOR AGONISTS Albuterol, terbutaline, metaproterenol
Short-acting Drug of choice for acute asthma

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BETA-ADRENOCEPTOR AGONISTS Salmeterol and formoterol
Long-acting
12 h or more Used for prophylaxis

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BETA-ADRENOCEPTOR AGONISTS Epinephrine and isoproterenol
Still used occasionally

Used for chronic obstructive pulmonary disease (COPD) patients

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BETA-ADRENOCEPTOR AGONISTS TOXICITY
Skeletal muscle tremor

Significant 1 effects (tachycardia) at high

clinical dosage Arrhythmias may occur when used excessively

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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 USED IN 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
Acetylcholine Leukotrienes

PDE

Adenosine

Constriction

DRUGS USED IN ASTHMA

METHYLXANTHINES Found in plants and provide the stimulant effect of 3 common beverages
Caffeine (coffee) Theophylline (tea) Theobromine (cocoa)

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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

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METHYLXANTHINES Clearance varies
Highest in young adolescents Higher in smokers Concurrent use of other drugs that inhibit or

induce hepatic enzyme

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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

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METHYLXANTHINES Eliminated by Cytochrome P450-drug metabolizing enzyme in the liver Pentoxifylline
Used for treatment of intermittent

claudication

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METHYLXANTHINES TOXICITY
Common adverse effects

GI distress Tremor Insomnia

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METHYLXANTHINES TOXICITY
Overdosage

Severe nausea and vomiting Hypotension Cardiac arrhythmias Convulsion

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MUSCARINIC ANTAGONISTS MOA
Competitively blocks muscarinic receptors in

the airways Prevents bronchoconstriction mediated by vagal discharge

Relaxation
CAMP

ATP AMP

Bronchial Tone
Acetylcholine Leukotrienes

PDE

Adenosine

Constriction

DRUGS USED IN 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 agonists

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MUSCARINIC ANTAGONISTS Atropine and other naturally-occurring belladona alkaloids were used for asthma

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MUSCARINIC ANTAGONISTS Ipatropium
Quaternary antimuscarinic drug Delivered to the airways by pressurized aerosol Have little systemic action

Tiotropium
Newer longer-acting analog

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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

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CROMOLYN AND NEDOCROMIL No bronchodilator action but can prevent bronchoconstriction caused by a challenge with antigen to which the patient is allergic

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CROMOLYN AND NEDOCROMIL MOA
Decrease in the release of mediators

(leukotrienes and histamine) from mast cells Prevents both early and late responses to challenge

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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 USED IN ASTHMA

CROMOLYN AND NEDOCROMIL Food allergy
Given orally

Asthma in children
Most important use

Hay fever
Nasal and eyedrop formulations

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CROMOLYN AND NECRODOMIL TOXICITY
Cough and irritation of the airway when given

by aerosol Drug allergy is rare

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BRONCHODILATORS

ANTI-INFLAMMATORY LEUKOTRIENE AGENTS ANTAGONISTS

RELEASE INHIBITORS
STEROIDS

AGONISTS
MUSCARINIC ANTAGONISTS

LIPOXYGENASE RECEPTOR INHIBITORS INHIBITORS

ANTIBODIES

METHLYXANTHINES SLOW ANTIINFLAMMATORY DRUGS

DRUGS USED IN ASTHMA

CORTICOSTEROIDS MOA
Reduces the synthesis of arachidonic acid by

phospholipase A2 Inhibit the expression of COX-2 (antianflammatory action) Postulated that: this drugs increases the responsiveness of beta agonists in the airway

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Phospholipase Membrane A2

Lipid

Arachidonic acid

Lipooxygenase

Cyclooxygenase

Hydroxypeptidase

Endoperoxidase

Leukotrienes

Prostacycline

Prostaglandin

Thromboxane A2

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CORTICOSTEROIDS All are potentially beneficial in severe asthma Systemic (oral corticosteroids)
Used chronically only if other therapies fail

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CORTICOSTEROIDS Local aerosol administration of surface active corticosteroids are relatively safe
Beclomethasone Budesonide Dexamethasone

Flunisolide
Fluticasone Mometasone

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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 agonist

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CORTICOSTEROIDS Prednisolone and hydrocortisone
Intravenous For status asthmaticus

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CORTICOSTEROIDS Reduced activity of phospholipase A2 Leukotrienes that result from the synthesis of prostaglandins are potent bronchoconstrictors

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CORTICOSTEROIDS Early use may prevent the severe, progressive inflammatory changes of longstanding asthma

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CORTICOSTEROIDS TOXICITY
candidiasis For oral therapy

Changes on oropharyngeal flora result to

Adrenal suppression can be reduced by using alternate day therapy (give the drug in slightly higher dosage every other day)

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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 USED IN ASTHMA

BRONCHODILATORS ANTI-INFLAMMATORY AGENTS

LEUKOTRIENE
ANTAGONISTS

AGONISTS
MUSCARINIC ANTAGONISTS

RELEASE INHIBITORS
STEROIDS

LIPOXYGENASE RECEPTOR INHIBITORS INHIBITORS

ANTIBODIES

METHLYXANTHINES SLOW ANTIINFLAMMATORY DRUGS

DRUGS USED IN 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 USED IN ASTHMA

Arachidonic acid

Lipooxygenase

Cyclooxygenase

Hydroxypeptidase

Endoperoxidase

Leukotrienes

Prostacycline

Prostaglandin

Thromboxane A2

DRUGS USED IN ASTHMA

LEUKOTRIENE ANTAGONISTS Zileuton
Orally active Selectively inhibits 5-lipoxygenase,

a key enzyme in the conversion of arachidonic acid to leukotrienes

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LEUKOTRIENE ANTAGONISTS Zileuton
Effective in

Exercise- and antigen-induced bronchospasm Aspirin allergy Toxicity include occasional elevation of liver enzymes

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LEUKOTRIENE ANTAGONISTS Zafirlukast and montelukast
Antagonist at the LTD4 leukotriene receptor Orally active

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LEUKOTRIENE ANTAGONISTS Effective in preventing exercise-, antigen-and aspirin-induced bronchospastic attacks

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Anti-IgE antibody
Omalizumab

Humanized murine monoclonal antibody to human IgE Prophylactic management of asthma Given parenterally

DRUGS USED IN 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 . .