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Marc Imhotep Cray, M.D.

Learning Objectives
Treatment of Asthma and COPD
1. The indications, mechanism of action, adverse effects and contraindications for
the different anti-asthmatics including the preference for certain drugs in certain
situations.
2. The pharmacokinetics of anti-asthmatics and the rapidity of their onset of
action.
3. Describe the strategies of drug treatment of asthma and COPD.
4. List the major classes of drugs used in asthma and COPD.
5. Describe the mechanisms of action of these drug groups.
6. List the major adverse effects of the prototype drugs used in airways disease.

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Marc Imhotep Cray, M.D.
Learning Objective cont.
7. To provide a global overview of the drugs affecting the respiratory system
as a prerequisite to deeper layered discussions and case-based learning in
subsequent lectures, including:
 Classification and class prototype/s
 Mechanism of action
 Indications (therapeutic use)
 Side effects (adverse effects)
 Drug-drug interactions and contraindications
 Pharmacokinetic properties and drug-disease (patient) interactions
 Toxicities and antidotes (or) treatment

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Marc Imhotep Cray, M.D.
Learning Objectives cont.
8. Histamine and its Antagonists
 The physiological and pathophysiological role of histamine
 The pharmacology of histamine receptors
 The mechanisms of histamine release
 The indications, mechanism of action, adverse effects and contraindications
of histamine H1 and H2 receptor antagonists.

See: Histamine and Antihistamines in Autocoids, Ergots, Anti-inflammatory and
Immunosuppressive Agents Notes

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Marc Imhotep Cray, M.D.
Organization of the Nervous System
CENTRAL
BRAIN & SPINAL CORD NERVOUS
SYSTEM (CNS)

AFFERENT EFFERENT
(Sensory) (Motor)
NERVES NERVES
PERIPHERAL
NERVOUS
EXTEROCEPTORS INTEROCEPTORS SOMATIC AUTONOMIC SYSTEM (PNS)

SMOOTH MUSCLE,
EFFECTOR SKELETAL
CARDIAC MUSCLES
ORGANS MUSCLES
AND GLANDS

VOLUNTARY
INVOLUNTARY
Monosynaptic
Marc Imhotep Cray, M.D. Pre & Post Ganglionic Fiber
Classes of Chemical Messengers
1. Autocrine chemical messengers An autocrine chemical messenger
stimulates the cell that originally secreted it
 Examples are those secreted by white blood cells during an infection
o Several types WBCs can stimulate their own replication, so that
total number of white blood cells increases rapidly

2 Paracrine chemical messengers Paracrine chemical messengers act locally
on nearby cells
 These chemical messengers are secreted by one cell type into
extracellular fluid and affect surrounding cells
o An is histamine, released by certain white blood cells during
allergic reactions Histamine stimulates vasodilation in nearby
blood vessels

Marc Imhotep Cray, M.D.
Classes of Chemical Messengers (2)
3 Neurotransmitters Neurotransmitters are chemical messengers secreted by
neurons that activate an adjacent cell, whether it is another neuron, a muscle
cell, or a glandular cell
 NTs are secreted into a synaptic cleft, rather than into bloodstream
Therefore, in strictest sense NTs are paracrine agents, but for our
purposes it is most appropriate to consider them as a separate category

4 Endocrine chemical messengers Endocrine chemical messengers are secreted
into bloodstream by certain glands and cells, which together constitute
endocrine system
 These chemical messengers travel through general circulation to their
target cells

Marc Imhotep Cray, M.D.
Summary of drugs affecting the
respiratory system

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Marc Imhotep Cray, M.D.
Summary of drugs affecting the respiratory
system
MEDICATION INDICATION
SHORT-ACTING β2 ADRENERGIC AGONISTS
Albuterol PROAIR, PROVENTIL, VENTOLIN Asthma, COPD
Levalbuterol XOPENEX Asthma, COPD
LONG-ACTING β2 ADRENERGIC AGONISTS
Arformoterol BROVANA COPD
Formoterol FORADIL, PERFOROMIST Asthma, COPD
Indacaterol ARCAPTA COPD
Salmeterol SEREVENT Asthma, COPD

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Marc Imhotep Cray, M.D.
Summary of drugs affecting respiratory
system (2)
MEDICATION INDICATION
INHALED CORTICOSTEROIDS
Beclomethasone BECONASE AQ, QVAR Allergic rhinitis, Asthma, COPD
Budesonide PULMICORT, RHINOCORT Allergic rhinitis, Asthma, COPD
Ciclesonide ALVESCO, OMNARIS, ZETONNA Allergic rhinitis
Fluticasone FLONASE, FLOVENT Allergic rhinitis, Asthma, COPD
Mometasone ASMANEX, NASONEX Allergic rhinitis, Asthma
Triamcinolone NASACORT AQ Allergic rhinitis

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Marc Imhotep Cray, M.D.
Summary of drugs affecting respiratory
system (3)
MEDICATION INDICATION
LONG-ACTING β2 ADRENERGIC AGONIST
/CORTICOSTEROID COMBINATION
Formoterol/budesonide SYMBICORT Asthma, COPD
Formoterol/mometasone DULERA Asthma, COPD
Salmeterol/futicasone ADVAIR Asthma, COPD
Vilanterol/futicasone BREO ELLIPTA COPD
SHORT-ACTING ANTICHOLINERGIC
Ipratropium ATROVENT Allergic rhinitis, COPD
LONG-ACTING ANTICHOLINERGIC
Aclidinium bromide TUDORZA PRESSAIR COPD
Tiotropium SPIRIVA COPD

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Marc Imhotep Cray, M.D.
Summary of drugs affecting respiratory
system (4)
MEDICATION INDICATION
LEUKOTRIENE MODIFIERS
Montelukast SINGULAIR Asthma, Allergic rhinitis
Zafirlukast ACCOLATE Asthma
Zileuton ZYFLO CR Asthma
ANTIHISTAMINES (H1-RECEPTOR BLOCKERS)
Azelastine ASTELIN, ASTEPRO Allergic rhinitis
Cetirizine ZYRTEC Allergic rhinitis
Desloratadine CLARINEX Allergic rhinitis
Fexofenadine ALLEGRA Allergic rhinitis
Loratadine CLARITIN Allergic rhinitis

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Marc Imhotep Cray, M.D.
Summary of drugs affecting respiratory
system (5)
MEDICATION INDICATION
α-ADRENERGIC AGONISTS
Oxymetazoline AFRIN, DRISTAN Allergic rhinitis
Phenylephrine NEOSYNEPHRINE, SUDAFED PE Allergic rhinitis
Pseudoephedrine SUDAFED Allergic rhinitis
AGENTS FOR COUGH
Benzonatate TESSALON PERLES
Codeine (with guaifenesin) VARIOUS
Dextromethorphan VARIOUS
Dextromethorphan (with guaifenesin) VARIOUS
Guaifenesin VARIOUS

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Marc Imhotep Cray, M.D.
Summary of drugs affecting respiratory
system (6)
MEDICATION INDICATION
OTHER AGENTS
Cromolyn NASALCROM Asthma, Allergic rhinitis
Omalizumab XOLAIR Asthma
Roflumilast DALIRESP COPD
Theophylline ELIXOPHYLLIN, THEO-24, UNIPHYL Asthma

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Marc Imhotep Cray, M.D.
Overview
 Common respiratory diseases include:
 Asthma
 chronic obstructive pulmonary disease(COPD includes emphysema
and chronic bronchitis)
 acute bronchitis
 dyspnea(difficult breathing) and
 pneumonia
 Drugs for treating respiratory system are used primarily to open bronchial
tubes, either
 By reversing effects of histamines (which are released by body when
exposed to substances that cause allergic reactions) or
 By relaxing muscle bundles surrounding bronchial tubes

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Marc Imhotep Cray, M.D.
Overview (2)
 Asthma, which involves constriction of pulmonary passages and secretion
of excess mucus, is characterized by
 Dyspnea
 Coughing and
 wheezing
 Asthma is precipitated by triggers such as
 Allergens
 cold air
 viral infections
 bacterial infections and
 Exercise
 Anti-IgE antibodies, mast cell degranulation blockers, smooth muscle
relaxants, and antiinflammatory agents are major drug classes used for
asthma
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Marc Imhotep Cray, M.D.
Overview (3)
 Emphysema results from breakdown of alveolar walls, which leads to
reduced alveolar surface area and impaired cellular respiration and gas
exchange
 Acute bronchitis results from inflammation of bronchial passages and has
causes similar to those of asthma
 Chronic bronchitis is characterized by persistent production of excess
mucus in bronchial tubes
 Cough, shortness of breath, and lung damage are typical of chronic
bronchitis
 Medications for COPD include short-acting β2 agonists and other
bronchodilators
 Pneumonia is an acute lung inflammation that results in collapse of lung
tissue and can be treated with antibiotics only when cause is bacterial
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Marc Imhotep Cray, M.D.
Respiration: Introduction to
Physiology and Pathology

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Marc Imhotep Cray, M.D.
Respiration Overview
 Respiration means ventilation, or breathing
 2 phases of breathing are inspiration (inhalation) and expiration (exhalation)

 Primary functions of respiratory system are to provide oxygen to tissues
and to expel carbon dioxide from body
 Respiration is classified into 3 functional categories:
 external respiration exchange of gas between atmosphere and blood
 internal respiration exchange of gas between blood and cells, and
 cellular respiration process whereby cells use oxygen and convert energy into useful
forms

 Major waste product of cellular respiration= carbon dioxide diffuses
from cells into blood transported to lungs and expelled during expiration

 Pharmacologic intervention becomes necessary when respiratory system
functions improperly 19
Marc Imhotep Cray, M.D.
Respiratory Diseases
 Most common respiratory disorders are asthma, cough, COPD
(emphysema; chronic bronchitis), and pneumonia
 Less common disorders are hyperventilation (excessive inspiration and expiration);
apnea (temporary breathing cessation that may follow hyperventilation); and
rhinitis (nasal mucosa inflammation)
 Drugs used for these conditions normally given by inhalation (metered-
dose or nebulized inhaler) or by oral means
 Inhalation is preferred because of direct drug delivery to lungs,
avoidance of first-pass metabolism by liver and intestine, and
minimization of adverse effects of systemic distribution
 Certain drugs used to treat asthma (eg, theophylline, albuterol, terbutaline) can be
given orally
 Parenteral dosing (intravascular, subcutaneous, or intramuscular) may be
needed, especially when rapid onset of action is critical or drug
absorption from GI tract is poor controls dose delivered, but adverse
effects can result
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Marc Imhotep Cray, M.D.
Allergy
Allergic rhinitis affects approximately 20% of the American
population. It is characterized by itchy, watery eyes, runny nose,
and a nonproductive cough that can significantly decrease
quality of life.

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Marc Imhotep Cray, M.D.
Allergy
Term allergy, from Greek allos (altered state) and ergon
(reactivity), was first used to describe patients who had
reactions caused by effect of external factors, or allergens, on
body’s immune system
 Often defined as hypersensitive reactions of immune system
to substances (allergens) that are usually innocuous in most
people food, animal dander, pollen, bee stings, mold,
ragweed, and drugs

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Marc Imhotep Cray, M.D.
Allergy (2)
 Allergic person’s immune system recognizes something as foreign
mounts a specific reaction to identify allergen and destroy it via
inflammation
 Thus, a sensitivity to a material that causes a symptom is allergic only
if it has an identifiable mechanism

 Distinction between allergic and nonallergic disorders is important
because it determines evaluation and treatment
 Treatment of an allergy as if it were nonallergic will fail and vice versa

 In asthma, allergens increase sensitivity of bronchial smooth muscle,
thereby creating an allergic state

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Marc Imhotep Cray, M.D.
Mechanism of Type 1 (Immediate) Hypersensitivity

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Marc Imhotep Cray, M.D.
Leukocyte Function
 Humans have a special immune system to combat infectious and toxic
agents (eg, bacteria and viruses)
 Major cells involved in defense against foreign substances are leukocytes
(WBCs)
 Like all blood cells synthesized in bone marrow

 Leukocytes can be classified into 2 basic classes:
 granular store mediators in granules, and
 mononuclear or agranular have no granules

 Three types of granular leukocytes exist:
 neutrophils
 eosinophils and
 basophils
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Marc Imhotep Cray, M.D.
Leukocyte Function (2)
 Eosinophils, which phagocytize antigen-antibody complexes (antigen-IgE
complexes that initiate an asthmatic reaction), and
 Basophils, which release
 heparin (clotting)
 serotonin (clotting) and
 histamine (immune reaction) play primary roles in asthma
 Agranular cells are
 monocytes, which phagocytize foreign particles, and
 lymphocytes, which play a critical role in delayed asthmatic response
o T cells (a subtype of lymphocytes) synthesize cytokines (Interleukins)
o B cells (another subtype) synthesize IgE antibodies

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Marc Imhotep Cray, M.D.
Leukocyte Function (3)

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Marc Imhotep Cray, M.D.
Leukocyte Function (4)

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Marc Imhotep Cray, M.D.
Allergic Rhinitis
 Allergic rhinitis (hay fever), an inflammation or irritation of mucous
membranes lining nose initiated when allergens cause body to defend
itself by producing antibodies
 allergen-antibody combination prompts histamine release and allergic
response
 Symptoms are
o sneezing
o stuffy or runny nose
o itchy eyes
o noisy breathing
o chronic fatigue
o poor appetite and
o nausea
 seasonal disorder is caused by pollen and normally wanes during winter
 perennial disorder occurs year-round and is caused by indoor allergens(eg,
animal dander, mold spores, dust mites)
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Marc Imhotep Cray, M.D.
Allergic Rhinitis (2)
 Treatments are:
 Antihistamines (H1 antagonist) (Treatment of choice; blocks histamine
action but can cause drowsiness)
o Diphenhydramine (1st Gen.), Loratadine (2nd Gen.= less sedation)
o See: Histamine and Antihistamines in Autocoids, Ergots, Anti-inflammatory and
Immunosuppressive Agents Notes
 Nasal decongestants (relieve nasal stuffiness but can increase histamine
release and worsen congestion)
o Short-acting α-adrenergic agonists, such as phenylephrine, constrict dilated
arterioles in nasal mucosa and reduce airway resistance
o Longer-acting oxymetazoline
 corticosteroids (desensitize cellular response to histamine and
minimize allergic reaction) and
 cromolyn sodium (inhibits histamine release, which reduces or stops
allergic response)
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Marc Imhotep Cray, M.D.
General Management Principles for Allergic Rhinitis

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Marc Imhotep Cray, M.D.
Asthma
Asthma is a chronic disease characterized by hyperresponsive
airways, affecting over 25 million patients in U.S , and resulting in 2
million emergency room visits and 500,000 hospitalizations annually.

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Marc Imhotep Cray, M.D.
Introduction to Asthma
Bronchial asthma, known simply as asthma, is a chronic lung
disease characterized by inflammation and obstruction of lower
airways
 Affects approximately 10% of the US population, or 25 million
people
 Most common symptoms are
o acute constriction of bronchial smooth muscle
o cough
o chest tightness High-Yield Tip: Chronic cough in a young
o wheezing and adult, particularly a cough that worsens at
night and is associated with dyspnea and
o rapid breathing chest tightness, is classic for asthma.

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Marc Imhotep Cray, M.D.
Types of Asthma
 Older classification: Extrinsic and Intrinsic Asthma

 Newer (preferred) Classification
 Atopic (Extrinsic) : A type I hypersensitivity reaction with
strong familial tendencies
 Nonatopic (Intrinsic): Asthma associated with viral
infection (e.g. rhinovirus, parainfluenza virus) in patients
with no family history of allergies and who have normal
levels of IgE
 Drug-induced asthma
 Occupational asthma
 Cardiac asthma
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Marc Imhotep Cray, M.D.
Types of Asthma (2)
Alternative classification:
 Allergic asthma versus Nonallergic asthma
 Allergic asthma
o Epidemiology: Occurs more frequently in children
o Associated conditions: Patients may have hay fever or eczema
o Mechanism of allergic asthma: Type I hypersensitivity reaction
o Causes: Pollens, dust, drugs

 Nonallergic asthma
o Epidemiology: Occurs more frequently in adults
o Mechanism of nonallergic asthma: Not type I hypersensitivity
reaction; IgE levels are normal
o Causes: Exercise, cold air, drugs, gastroesophageal reflux, viral
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Marc Imhotep Cray, M.D.
Clinical presentation of asthma
Symptoms:
 Classic triad is persistent wheezing, chronic episodic dyspnea,
and chronic nonproductive cough
 Symptoms may be worse, or only present at night, due to
physiologic drop in cortisol secretion
 Night-time cough, which may be only symptom, is a classic
symptom of asthma
 Dark rings under the eyes (“allergic shiners”) and a dark
transverse crease on nose (“allergic salute”) are often seen,
especially in children
 Status asthmaticus is a prolonged asthmatic attack, which can be
fatal Otherwise deaths caused by asthma are infrequent
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Marc Imhotep Cray, M.D.
Clinical presentation of asthma (2)
Laboratory studies:
 Low peak expiratory flow (PEF)

 FEV1/FVC is often decreased as in other obstructive lung
diseases, and residual volume is increased

 Carbon dioxide is usually low in an acute asthma exacerbation
secondary to hyperventilation
 a rising carbon dioxide concentration in this setting often
precedes respiratory failure

 Eosinophilia may be present
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Marc Imhotep Cray, M.D.
Asthma Capsule

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Marc Imhotep Cray, M.D.
Extrinsic and Intrinsic Asthma
 Pharmacotherapy of asthma depends on understanding disease pathogenesis
 extrinsic (allergic, type I) or intrinsic (nonallergic, type II) asthma
 In immunologic, or antigen challenge, model IgE antibodies produced by
airway mucosa mast cells mediate asthma

 B lymphocytes synthesize IgE antibodies after exposure to an antigen

 IgE antibodies attach to mast cells  with re-exposure to antigen form
antigen-antibody complexes complexes trigger synthesis and release of
mediators from mast cells, including
 Histamine
 Leukotrienes (LTC4 and LTD4) and
 Prostaglandins
 Bronchoconstriction and vascular leakage result
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Marc Imhotep Cray, M.D.
Extrinsic and Intrinsic Asthma (2)
 Other substances (eg, cytokines) mediate late response (IgE release)

 Corticosteroids reduce bronchial responses by inhibiting cytokine
production

 In some asthmatic patients who are not hypersensitive to antigens
infections and non-antigenic stimuli can evoke symptoms (Intrinsic asthma)

 Intrinsic asthma develops later in life, has unclear causes, is associated with
a worse prognosis, and is less responsive to treatment than extrinsic asthma

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Marc Imhotep Cray, M.D.
Extrinsic Allergic Asthma:
Clinical Features
 Features common to both extrinsic
allergic and intrinsic asthma:
 respiratory distress
 dyspnea
 wheezing
 flushing
 cyanosis
 cough
 flaring of alae
 use of accessory respiratory muscles
 apprehension
 tachycardia
 perspiration
 hyperresonance
 distant breath sounds and rhonchi
 eosinophilia
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Marc Imhotep Cray, M.D.
Intrinsic Asthma:
Clinical Features
 Features common to both extrinsic
allergic and intrinsic asthma:
 respiratory distress
 dyspnea
 wheezing
 flushing
 cyanosis
 cough
 flaring of alae
 use of accessory respiratory muscles
 apprehension
 tachycardia
 perspiration
 hyperresonance
 distant breath sounds and rhonchi
 eosinophilia
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Marc Imhotep Cray, M.D.
Asthma Pharmacotherapy
Major classes of drugs for asthma:
I. Anti-lgE Antibodies
II. Mast Cell Degranulation Blockers
III. Bronchodilators
IV. Methylxanthine
V. β-Adrenergic Agonists:
o Nonselective
o Selective
VI. Antimuscurinic Antagonists
VII. Anti-inflammatory Agents:
o Corticosteroids
o Leukotriene Antagonists
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Marc Imhotep Cray, M.D.
Asthma
Pharmacotherapy
Capsule

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Marc Imhotep Cray, M.D.
Asthma Pharmacotherapy (2)
 When exposure to allergens cannot be avoided, drug therapy is needed
 Major goals being to reverse asthmatic symptoms and prevent recurrent
episodes by disrupting actions of endogenous agents that worsen
bronchospasm and inflammation

 Bronchodilators were first and most effective treatment, but a better
approach is prophylactic use of antiinflammatory agents to control bronchial
inflammation
 With these agents, patients with asthma are rarely hospitalized, seriously
ill, or in need of emergency treatment
 Patients can control their disease, and therapy is much less expensive
than previous emergency management

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Marc Imhotep Cray, M.D.
Asthma Pharmacotherapy (3)
 Now, antiinflammatory agents are first-line therapy [(Inhaled
corticosteroids (ICS)] for patients who have more than occasional
symptoms

 Bronchodilators are still used but only when antiinflammatory therapy is
inadequate, and then in smaller amounts
 SABA manage symptoms (rescue therapy) and does not address
underlying cause, which is airway inflammation
 LABA still useful as in prophylaxis /control therapy, particularly in
combination with ICS

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Marc Imhotep Cray, M.D.
Guidelines for Treatment of Asthma
Classification Bronchoconstrictive Results of Peak Flow Long-term Quick Relief of
Episodes or Spirometry Control Symptoms
Intermittent Less than 2 days per Near normal* No daily Short-acting β2
week medication agonist

Mild More than 2 days per Near normal* Low-dose ICS Short-acting β2
persistent week, not daily agonist
Moderate Daily 60% to 80% of normal Low-dose ICS + Short-acting β2
persistent LABA agonist
OR Med-dose
ICS
Severe Continual Less than 60% of Med-dose ICS + Short-acting β2
persistent normal LABA OR High- agonist
dose ICS + LABA
ICS = inhaled corticosteroid. LABA = long-acting β2 agonist. *Eighty percent or more of predicted function.
Redrawn from: Whalen K. Lippincott Illustrated Reviews: Pharmacology Sixth Ed., 2015.

N.B. In all asthmatic patients, quick relief (“rescue” therapy) is provided by a SABA as needed for
symptoms.
Marc Imhotep Cray, M.D. 47
I. Anti-lgE Antibodies
 One of the more novel therapies is use of anti-IgE antibodies
 In theory, drugs acting as anti-IgE antibodies would prevent IgE binding to
mast cell surfaces

 Action reduces formation of activated antigen-IgE complexes and
suppress release of mediators that induce immediate
bronchoconstriction in early phase
 Mediators such as histamine, prostaglandins, and leukotrienes are unable
to cause sneezing, wheezing, itching, and coughing

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Marc Imhotep Cray, M.D.
Immunologic basis of anti-IgE antibodies MOA

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014. Figure 7-9
Anti-lgE Antibodies (2)
Most notable anti-IgE antibody, omalizumab, is a recombinant
humanized monoclonal antibody to human immunoglobulin E
(IgE)
 By binding to circulating IgE in blood, omalizumab blocks
release of inflammatory mediators by keeping IgE from binding
to mast cells and basophils
 Reduction in surface-bound IgE limits release of mediators of
allergic response
Indicated for treatment of moderate to severe persistent asthma
in patients who are poorly controlled with conventional therapy

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Marc Imhotep Cray, M.D.
Anti-lgE Antibodies (3)
 Rhumab-E25 (Omalizumab) blocks release of inflammatory mediators by
keeping IgE from binding to mast cells

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Marc Imhotep Cray, M.D.
Anti-lgE Antibodies (4)
Omalizumab use is limited by high cost, route of administration
(subcutaneous), and adverse effect profile
 Adverse effects include:
o serious immediate- or delayed-onset anaphylactic
reactions pose the greatest risk (rare)
o arthralgias
o fever, and rash
o secondary malignancies have been reported
High-Yield Pearl: Anaphylaxis or less severe untoward
immunologic reactions have been reported 24 hours or longer
post administration, so patient should have an epinephrine
autoinjector (self-injector) (prescribed by physician) handy for
at least several days after an omalizumab dose. 52
Marc Imhotep Cray, M.D.
II. Mast Cell Degranulation Blockers
(Chromones)
 Cromolyn block mast cell degranulation by suppressing release of
mediators of immediate bronchoconstriction (early response) and
reduce eosinophil recruitment that causes airway inflammation
 Does not directly alters smooth muscle tone or reverses
bronchospasm

 Inhaled as aerosols, can be used for intrinsic or extrinsic asthma

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Marc Imhotep Cray, M.D.
Mast Cell Degranulation Blockers (2)
 Poorly absorbed, so adverse effects are restricted to deposition
site
 Cromolyn (nasal spray) is preferred for young patients
 Cromolyn alter Cl− channel function, which
1) on airway neurons underlies cough inhibition
2) on mast cells delays antigen-evoked bronchoconstriction
and
3) on eosinophils prevents inflammatory responses to
antigens
NB: Cromolyn and related compounds do not
posses bronchodilator activity and are therefore
not useful in acute asthma attacks.
Neither cromolyn and nedocromil, is available in
Marc Imhotep Cray, M.D.
the USA. 54
Mast Cell
Degranulation
Blockers MOA

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014
III. Bronchodilators (smooth muscle relaxants)
 Drugs that expand pulmonary airways (bronchi)-bronchodilators-block
early response by inhibiting immediate bronchoconstriction

 Some agents, especially theophyline and β2-adrenergic agonists, inhibit
late response inflammation

 These drugs are usually used when a persistent cough and bronchial
constriction are present

 In addition to relaxing smooth muscles and reducing airway reactivity,
bronchodilators reduce coughing, wheezing, and shortness of breath

 Agents are usually given via inhalation, but some can be given orally or
parenterally (intravenous, intramuscular, or subcutaneous route)
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Marc Imhotep Cray, M.D.
Bronchodilators (2)
 Most drugs have a rapid onset of action (within minutes), but
effect usually wanes in 5 to 7 hours (short duration of action)

 Some agents, especially theophylline, inhibit delayed response
to antigen
 Most common bronchodilators are
1) methylxanthines (eg, theophylline, caffeine)
2) β-adrenergic agonists (eg, isoproterenol, albuterol,
epinephrine)
3) cholinergic antagonists (eg. ipratropium, tiotropium)

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Marc Imhotep Cray, M.D.
G protein linked 2nd messenger mechanism
(β2-Receptor)
Receptor G-Protein Class Major Function
Beta 2 Gs Vasodilation, Bronchodilation, Increase Heart Rate,
Increase Contractility, Increase Lipolysis, Increase
Insulin release, Decrease Uterine Muscle tone

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

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Marc Imhotep Cray, M.D.
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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
IV. Methylxanthines
 The methylxanthines theophylline, caffeine, and theobromine, found in
cola, tea, and coffee, are bronchodilators that reduce bronchial smooth
muscle activity by causing increase intracellular cAMP levels

 Mechanism of Action (MOA):
 Signal molecules (eg, transmitters, drugs) activate GPCRs on airway
smooth muscle cells and increase conversion rate of ATP to cAMP 
increased cAMP levels relax bronchial muscle and reduce airway
reactivity
 Phosphodiesterase stops cAMP effects and reduces cAMP levels by
catalyzing hydrolysis of cAMP to AMP
o Methylxanthines prevent cAMP hydrolysis (PDE Inhibitor)
o Or, theophylline may block cell surface receptor effects of
adenosine, which may induce bronchoconstriction and
inflammation
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Marc Imhotep Cray, M.D.
Methylxanthines (2)
 These drugs may also be antiinflammatory
 Theophylline, the most widely prescribed and of low cost,
comes as:
 short-acting tablets and syrups,
 sustained-release capsules and tablets, and
 intravenous doses
 Synthetic dyphylline may help patients who are unable to use
theophylline
 Previously the mainstay of asthma therapy, has been largely
replaced with β2 agonists and corticosteroids due to narrow
therapeutic window, adverse effect profile, and potential for
drug interactions
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Marc Imhotep Cray, M.D.
Methylxanthines

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
Methylxanthine: Adverse Effects
 Methylxanthine doses and bld levels must be closely watched
Low therapeutic index Serum concentration monitoring should be
performed when theophylline is used chronically
 Low doses have little effect, if any, whereas high doses can affect central
nervous (seizures), cardiovascular (arrhythmias), skeletal muscle, GI, and
renal system
 Theophylline is most selective at sm. mm.; caffeine induces most marked CNS
effects
 Even at low to moderate doses, they enhance cortical arousal & alertness &
defer fatigue
 In hypersensitive patients, insomnia and nervousness may occur

 Methylxanthines reduce blood viscosity increase blood flow increase
cardiac output & induce tachycardia in healthy subjects
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Marc Imhotep Cray, M.D.
Methylxanthine: Adverse Effects(2)
In sensitive persons, cardiac arrhythmias are common

These drugs strengthen contractions of isolated skeletal muscles
in vitro and improve contractility & reverse fatigue of diaphragm
in pts with COPD accounts for their usefulness in COPD

 Although methylxanthines enhance gastric acid and digestive
enzyme secretion in GI tract and induce a slight diuresis, these
effects are minor

Note: metabolism of theophylline depends on age; the
half-life of drug in children is much shorter than in adults
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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014. 65
V. β-Adrenergic Agonists
 Another class of drugs that enhance sympathetic discharge, β-adrenergic
agonists, are used to relieve a sudden asthma attack or block exercise-
induced asthma
 relax bronchial smooth muscle, inhibit mediator release, increase
transport of mucus, and alter composition of mucus by stimulating β
adrenoceptors
 Bronchodilation is mediated by β2 adrenoceptors located on smooth
muscle cells in human airways
 Nonselective β-adrenoceptor agonists (eg, epinephrine, ephedrine,
isoproterenol) stimulate all β adrenoceptors (β1 and β2 classes)
 These nonselective actions often produce adverse effects, particularly in CNS and
cardiovascular system
 Selective drugs activate only β2 receptors (eg, albuterol, terbutaline,
salmeterol) are most commonly prescribed sympathomimetic agents
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Marc Imhotep Cray, M.D.
Nonselective β-Adrenergic Agonists
 Agents that activate both β1 and β2 adrenoceptors have long been used
to treat asthma

 These drugs are potent, rapidly acting bronchodilators, but their
stimulation of cardiac system is a serious drawback

 Major agents are epinephrine, ephedrine, and isoproterenol

 Epinephrine is either inhaled or given subcutaneously and is active agent
in many over-the-counter (OTC) preparations
 Maximal bronchodilation is achieved 15 minutes after injection and lasts
approximately 90 minutes
 Because this drug stimulates cardiac output, increases heart rate, and exacerbates
angina, physicians rarely prescribe it
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Marc Imhotep Cray, M.D.
Nonselective β-Adrenergic Agonists
 Ephedrine, used in China more than 2000 years ago, has longest history of
use of any antiasthmatic

 It has a longer duration of action, lower potency, and greater oral activity
than epinephrine
 However, has marked adverse effects, particularly in CNS, and is
rarely administered

 Isoproterenol is characterized by a rapid onset of action, with peak
bronchodilation occurring within 15 minutes of injection

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Marc Imhotep Cray, M.D.
β-Adrenergic Agonists MOA

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
Selective β-Adrenergic Agonists
 Selective β2-adrenoceptor activators are most widely prescribed
sympathomimetic drugs because of their…
 β2 selectivity
 oral activity
 rapid onset and long duration of action (4 hours)

 Major drugs: metaproterenol, terbutaline, albuterol, salmeterol, and
formoterol  have minimal β1-mediated effects on nervous and cardiac
systems

 Inhalation route allows greatest local effects with fewest adverse effects
 Inhaled agents cause bronchodilation equal to isoproterenol and
persists for 4 hours (metaproterenol, terbutaline, albuterol)

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Marc Imhotep Cray, M.D.
Selective β-Adrenergic Agonists (2)
 Terbutaline, metaproterenol, and albuterol can be given orally as tablets

 Terbutaline, the only drug that can be used subcutaneously, is given for
severe asthma attacks or if insensitivity to inhaled agents exists

 Two newest drugs, salmeterol and formoterol, have a long duration of
action and high lipid solubility
 Both drugs at high concentrations move slowly into airway smooth
muscle so effects can last up to 12 hours
 Both also enhance antiasthmatic actions of corticosteroids

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Marc Imhotep Cray, M.D.
Catecholamine Action on α and β Receptors
of Heart and Bronchial Tree

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
VI. Antimuscarinic Agents (Muscarinic Antagonists)
 Acetylcholine mediates its physiologic effects via 2 types of
receptors:
 muscarinic and nicotinic
 Muscarinic receptors are GPCRs that are densely expressed in
airways
 When stimulated AChM receptors cause muscle contraction
leads to narrowing of airways bronchoconstriction
 Muscarinic antagonists, or anticholinergics, prevent
acetylcholine from producing smooth muscle contractions &
excess mucus in bronchi

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Marc Imhotep Cray, M.D.
Antimuscarinic Agents (2)
 Ipratropium bromide and atropine are most commonly used

 Antimuscarinic agents are less effective than β2-adrenergic
activators
 However, these drugs enhance bronchodilation induced by
β2-adrenoceptor agonists, so patients often take both
anticholinergics and β2 agonists

 Major adverse effects = dry mouth, bitter taste, scratchy throat,
and headache

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Marc Imhotep Cray, M.D.
Antimuscarinic Agents
MOA

Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

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Marc Imhotep Cray, M.D.
Leukotriene Modulators (LTMs)
 Leukotrienes (LTs) are potent
inflammatory mediators
generated from metabolism of
arachidonic acid through the 5-
lipoxygenase (5-LOX) pathway

 These compounds, along with
prostaglandins and related
compounds, belong to a group
of substances termed the Wecker L etal. Brady's Human Pharmacology, Molecular to
eicosanoids Clinical, 5th Ed. Philadelphia: Mosby, 2010
76
Marc Imhotep Cray, M.D.
Inflammatory mediators

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

See Eicosanoids in Autocoids, Ergots, Anti-inflammatory and Immunosuppressive Agents Notes 77
Marc Imhotep Cray, M.D.
VII. Anti-inflammatory Agents: Corticosteroids
 Corticosteroids are antiinflammatory drugs similar to natural corticosteroid
hormones produced by the adrenal cortex

 Tx with these agents improves symptoms of asthma, allergic rhinitis,
eczema, and rheumatoid arthritis

 Corticosteroids inhibit late phase allergic reactions (including late asthmatic
response to antigen challenge) by various mechanisms, eg., reduced
1) number of mast cells lining surfaces of airway mucosal cells;
2) chemotaxis and activation of eosinophils; and
3) cytokine production by eosinophils, monocytes, mast cells, and
lymphocytes

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Marc Imhotep Cray, M.D.
Corticosteroids (2)
 Corticosteroids taken regularly have the following effects:
 reduce bronchial reactivity
 enhance airway quality
 decrease severity & frequency of asthma attacks
o However, corticosteroids do not directly relax smooth muscle
o They would be only agents needed to treat asthma if their adverse
effects were not so pronounced

 Commonly used agents prednisone, methylprednisone, beclomethasone,
flunisolide, budesonide, and mometasone

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Marc Imhotep Cray, M.D.
Corticosteroids: Clinical Uses
 Corticosteroids have marked adverse effects on nonrespiratory systems,
so inhalation (maintenance therapy in asthma, via inhaler) or intranasal (in
allergy, as nasal spray) route is preferred
 Intranasal corticosteroids relieve stuffy nose, nasal irritation, and other
discomforts
 Corticosteroids inhaled by mouth effectively prevent asthma attacks
 Regular doses of aerosol agents are smaller than doses used in pill form
 Smaller, regular doses reduce side effect risk and may eliminate a need for oral
steroids
 Oral prednisone or IV methylprednisone is used only when pts are
insensitive to inhaled drugs or need urgent treatment for severe asthma
attacks

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Marc Imhotep Cray, M.D.
Corticosteroids:
Clinical Uses (2)
 Spacers (chambers) can be
attached to metered-dose
inhalers to reduce velocity &
particle size of drug amount
of drug reaching lungs
maximized,  quantity of drug
deposited in mouth is
minimized

 Spacers are crucial for Tx with
corticosteroids, which have
many adverse effects
Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.

Marc Imhotep Cray, M.D.
Corticosteroid
Actions in
Bronchial
Asthma

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
Corticosteroids: Adverse Effects
 Taking corticosteroids orally (prednisone) and intravenously
(methylprednisone) can cause unwanted side effects

 Short-term use (days) of prednisone can lead to
 increased appetite
 weight gain
 diarrhea
 headache
 mood changes & insomnia
 possibly hyperglycemia & hypertension
o Cessation of short term corticosteroid use or taking
smaller doses usually minimizes or eliminates effects
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Marc Imhotep Cray, M.D.
Corticosteroids: Adverse Effects (2)
 Adverse effects that accompany long-term (months to years)
oral and IV therapy are:
 suppressed immune system
 increased cholesterol levels
 rapid weight gain
 May also promote osteoporosis, cataracts, and thinning of skin

 Efforts to develop safer corticosteroids with antiinflammatory
properties but lacking adverse effects are ongoing
 Lipophilic inhaled steroids, such as beclomethasone, flunisolide,
budesonide, and mometasone, have a strong safety profile and are
almost devoid of orally precipitated systemic effects
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Marc Imhotep Cray, M.D.
Corticosteroids:
Adverse Effects

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
Leukotrienes
 Leukotrienes are arachidonic acid derivatives involved in inflammatory
processes including asthma and anaphylaxis

 The enzyme 5-lipoxygenase catalyzes synthesis of arachidonic acid into
unstable intermediates which are converted into leukotrienes

 A number of airway cells (including mast cells, macrophages, eosinophils,
and basophils) synthesize, store, & secrete several subtypes of
proinflammatory leukotrienes
 Leukotriene B4 (LTB4) attracts additional leukocytes, and LTC4 and LTD4 increase
bronchial reactivity, bronchoconstriction, and secretion of mucus

See Eicosanoids in Autocoids, Ergots, Anti-inflammatory Agents, and Immunosuppressive Agents Notes

86
Marc Imhotep Cray, M.D.
Leukotriene (2)
Evidence that inhaled leukotrienes increase bronchial reactivity
and that antigen challenge in sensitized airways augments
leukotriene synthesis supports a role for these mediators in
asthma and a rationale for development of drugs that block
leukotriene or 5-lipoxygenase action

87
Marc Imhotep Cray, M.D.
Newly generated lipid mast cell mediators
depicting sites of action of LTMs
Inhibitory actions of LTMs are shown in red

Zileuton inhibits 5-lipoxygenase,
thereby inhibiting synthesis of
leukotrienes

Zafirlukast and Montelukast are
antagonists at CysLT1 receptor

Wecker L etal. Brady's Human Pharmacology, Molecular to
88
Marc Imhotep Cray, M.D. Clinical, 5th Ed. Philadelphia: Mosby, 2010
Leukotrienes
Synthesis

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
Anti-inflammatory Agents: Leukotriene
Antagonists
 Efforts to develop drugs that disrupt proinflammatory actions of
leukotrienes produced 2 types of drugs:
1) 5-lipoxygenase inhibitors and
2) leukotriene antagonists

 Zileuton reduces leukotriene synthesis rate by blocking 5-lipoxygenase
 can cause increases in hepatic enzymes and altered liver function It decreases rate
of heparin metabolism, leaving patients prone to easy bruising

 Zafirlukast and montelukast, LTD4 antagonists, block leukotriene receptors
and prevent these mediators from causing an asthmatic response
 taken orally, easy to administer and are used more regularly than inhaled
corticosteroids in USA (especially in children ) because of concerns over possible long-
term toxicity of systemic absorption of ICSs
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Marc Imhotep Cray, M.D.
Leukotriene Antagonists (2)
 When taken regularly, these drugs work as well as inhaled corticosteroids
in reducing frequency of asthma attacks
 However, leukotriene antagonists are less successful for relieving
symptoms, reducing bronchial reactivity, and improving airway quality

 These drugs are effective and safe when taken orally, an advantage
compared with inhaled corticosteroids

 Strong safety profile and excellent oral activity account for popularity of
leukotriene antagonists for children

 Leukotriene antagonists also reduce responses in aspirin-induced asthma,
a disorder affecting nearly 10% of patients with asthma
91
Marc Imhotep Cray, M.D.
Leukotriene
Antagonists
MOA

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
Question
A woman who has asthma and is recovering from a myocardial infarction is on
several medications including a baby aspirin a day. She complains of large
bruises on her arms and legs and some fatigue. A standard blood panel reveals
markedly elevated alanine aminotransferase (ALT). Which of the following is
most likely responsible for the increase in liver enzymes?
(A)Heparin
(B)Zileuton
(C)Zafirlukast
(D)Albuterol
(E)Aspirin

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Marc Imhotep Cray, M.D.
Management of Acute Asthmatic Attack

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Marc Imhotep Cray, M.D. Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Saunders, 2014.
The National Asthma Education and
Prevention Program 1997 Guidelines (Updated)
RECOMMENDATIONS FOR PHARMACOLOGIC MANAGEMENT OF ASTHMA IN ADULTS AND CHILDREN
OLDER THAN 5
Asthma Severity Symptom Medications
Frequency
Mild intermittent <2 days/week, No regular therapy; short-acting β2 –agonists as needed for
<2 nights/month symptom relief
Mild persistent >2 per week but Low-dose inhaled glucocorticoids. Alternate: cromolyn,
<once per day nedocromil, leukotriene modifier, or sustained release
>2 nights/month theophylline
Moderate Daily, Low- to medium-dose glucocorticoids and long-acting inhaled
persistent >1 night/week β2 -agonists. Alternate: leukotriene modifier or theophylline
Severe persistent Continual during High-dose glucocorticoids and long-acting inhaled β2 -agonist
day, frequent at and (if needed) systemic glucocorticoids. Consider
night omalizumab for allergy sufferers

Ressel GW, Centers for Disease Control and Prevention, National Asthma Education and Prevention Program. NAEPP
updates guidelines for the diagnosis and management of asthma. Am Fam Physician . 2003;68:169–70.
95
Marc Imhotep Cray, M.D.
Respiratory Drugs Summary
Short-Acting β2-Adrenoceptor Agonists
Albuterol Levalbuterol Metaproterenol
Long-Acting β2-Adrenoceptor Agonists
Salmeterol Formoterol Terbutaline
Other Adrenoceptor Agonists for Asthma
Epinephrine Isoproterenol Ephedrine
Methylxanthines
Theophylline
Muscarinic Antagonists
Ipratropium bromide Tiotropium Atropine
Chromones
Cromolyn sodium Nedocromil sodium
Inhaled Glucocorticoids
Beclomethasone Triamcinolone acetate Budesonide Flunisolide Fluticasone
propionate
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Marc Imhotep Cray, M.D.
Respiratory Drug Summary cont.
Leukotriene Inhibitors
Zafirlukast Montelukast Zileuton
Enzyme Inhibitors
α1-Proteinase inhibitor
Anti-IgE Antibody
Omalizumab
Antihistamines (selected H1-receptor antagonists
Diphenhydramine Loratadine Chlorpheniramine Brompheniramine
α-Adrenoceptor Agonists (selected)
Oxymetazoline Phenylephrine Pseudoephedrine
Antitussives
Codeine Hydrocodone Hydromorphone Dextromethorphan Benzonatate
Expectorants
Guaifenesin
Mucolytics
Acetylcysteine
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Marc Imhotep Cray, M.D.
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Marc Imhotep Cray, M.D.
Further study:
eLearning:
 Unit 7: Drugs Used In Disorders Of The Respiratory System. In: Digital Guidebook 2015
Integrated Scientific and Clinical Pharmacology
 IVMS MedPharm Cloud Folder

Notes:
 Drugs Used In Disorders Of The Respiratory System Notes
 Autacoids, Ergots, Anti-inflammatory Agents, and Immunosuppressive Agents Notes
o Histamine and its Antagonists
o Eicosanoids

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Marc Imhotep Cray, M.D.
e-Medicine (Medscape) Articles
Obstructive Airway Diseases
 Alpha1-Antitrypsin Deficiency
 Asthma
 Bronchiectasis
 Bronchiolitis
 Bronchitis
 Chronic Bronchitis
 Chronic Obstructive Pulmonary Disease
 Emphysema
 Status Asthmaticus

100
Marc Imhotep Cray, M.D.