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MED II-B Level II Block V Module 1 – RESPIRATORY SYSTEM • Asthma is defined as a chronic inflammatory disease of airways that is characterized
by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli.
Case 2: “Wheezy Vanna”

1. What are the most probable causes of tachypnea/dyspnea in this patient?


• It is manifested physiologically by a widespread narrowing of the air passages, which
may be relieved spontaneously or as a result of therapy, and clinically by paroxysms
of dyspnea, cough, and wheezing.

• Asthma is an episodic disease, with acute exacerbations interspersed with symptom-


free periods.

• Typically, most attacks are short-lived, lasting minutes to hours, and clinically the
patient seems to recover completely after an attack. However, there can be a phase in
which the patient experiences some degree of airway obstruction daily.

• This phase can be mild, with or without superimposed severe episodes, or much more
serious, with severe obstruction persisting for days or weeks; the latter condition is
known as status asthmaticus.

• In unusual circumstances, acute episodes can cause death.

(Harrison’s Principles of Internal Medicine 16th Edition)

(Harrison’s Principles of Internal Medicine 16th Edition) • Asthma is a syndrome characterized by airflow obstruction that varies markedly, both
spontaneously and with treatment.
The most probable causes of tachypnea / dyspnea in Vanna’s situation are:
• Asthmatics harbor a special type of inflammation in the airways that makes them
• Asthma more responsive than nonasthmatics to a wide range of triggers, leading to excessive
• Exercise narrowing with consequent reduced airflow and symptomatic wheezing and dyspnea.
• Chest pain
• Metabolic acidosis • Narrowing of the airways is usually reversible, but in some patients with chronic
• Anxiety asthma there may be an element of irreversible airflow obstruction.

• The increasing global prevalence of asthma, the large burden it now imposes on
2. Define asthma. patients, and the high health care costs have led to extensive research into its
mechanisms and treatment.

• Asthma is a chronic inflammatory condition of the lung airways resulting in episodic


airflow obstruction. (Harrison’s Principles of Internal Medicine 17th Edition)

• This chronic inflammation heightens the “twitchiness” of the airways airways


hyperresponsiveness to provocative exposures. • Asthma is a chronic inflammatory disorder of the airways that causes recurrent
episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night
• Other associated histopathologic abnormalities of the airways characteristic of asthma and/or in the early morning.
include epithelial damage, subepithelial collagen deposition with basement membrane
thickening, and mucus gland and smooth muscle hypertrophy. • These symptoms are usually associated with widespread but variable
bronchoconstriction and airflow limitation that is at least partly reversible, either
spontaneously or with treatment. It is thought that inflammation causes an increase in
airway responsiveness (bronchospasm) to a variety of stimuli.
(Nelson’s Textbook of Pediatrics 17th Edition)
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• Some of these stimuli would have little or no effect on nonasthmatics with normal  The symptoms of asthma consist of a triad of dyspnea, cough, and wheezing, the
airways. Many cells play a role in the inflammatory response, in particular eosinophils, last often being regarded as the sine qua non.
mast cells, macrophages, T lymphocytes, neutrophils, and epithelial cells.
 In its most typical form, all three symptoms coexist.
• Patients with asthma experience disabling attacks of severe dyspnea, coughing, and
wheezing triggered by sudden episodes of bronchospasm.  At the onset of an attack, patients experience a sense of constriction in the chest,
often with a nonproductive cough.
• Rarely, a state of unremitting attacks, called status asthmaticus, proves fatal; usually,
such patients have had a long history of asthma.  Respiration becomes audibly harsh; wheezing in both phases of respiration
becomes prominent; expiration becomes prolonged; and patients frequently have
• Between the attacks, patients may be virtually asymptomatic. tachypnea, tachycardia, and mild systolic hypertension.

• In some cases, the attacks are triggered by exercise and cold or by exposure to an  The lungs rapidly become overinflated, and the anteroposterior diameter of the
allergen to which the patient has previously been sensitized, but often no trigger can thorax increases.
be identified. There has been a significant increase in the incidence of asthma in the
Western world in the past three decades.  If the attack is severe or prolonged, there may be a loss of adventitial breath
sounds, and wheezing becomes very high pitched.
• Asthma has such a wide spectrum of predisposing factors and clinical presentations
that there is no uniform classification.  Furthermore, the accessory muscles become visibly active, and a paradoxical
pulse often develops.
• Categorization into mild intermittent, mild, moderate, and severe persistent asthma,
based on the frequency and severity of symptoms, is useful as a guide to therapy.  These two signs are extremely valuable in indicating the severity of the
obstruction. In the presence of either, pulmonary function tends to be
• Other clinical categories include steroid-dependent, steroid-resistant, difficult, and significantly more impaired than in their absence.
brittle asthma.
 It is important to note that the development of a paradoxical pulse depends on
• Typically, asthma is categorized into extrinsic (initiated by a type I hypersensitivity the generation of large negative intrathoracic pressures.
reaction induced by exposure to an extrinsic antigen) and intrinsic (initiated by
diverse, nonimmune mechanisms, including ingestion of aspirin; pulmonary infections,  Thus, if the patient’s breathing is shallow, this sign and/or the use of accessory
especially viral; cold; inhaled irritants; stress; and exercise). muscles could be absent even though obstruction is quite severe.

• This distinction is useful from the point of pathophysiology; however, so many patients  The other signs and symptoms of asthma only imperfectly reflect the physiologic
manifest overlapping characteristics and have elevated IgE levels that this alterations that are present.
classification is no longer clinically applicable.
 Indeed, if the disappearance of subjective complaints or even of wheezing is used
• Other informal categories classify asthma according to the agents or events that as the end point at which therapy for an acute attack is terminated, an enormous
trigger bronchoconstriction. reservoir of residual disease will be missed.

• These include seasonal, exercise-induced, drug-induced, and occupational asthma and  The end of an episode is frequently marked by a cough that produces thick,
asthmatic bronchitis in smokers. stringy mucus, which often takes the form of casts of the distal airways
(Curschmann’s spirals)and, when examined microscopically, often shows
• Allergic bronchopulmonary aspergillosis, which may complicate asthma, is partly an eosinophils and Charcot-Leyden crystals.
allergic reaction to fungus that has colonized the bronchial mucosa.
 In extreme situations, wheezing may lessen markedly or even disappear, cough
• Patients with this disease have very high serum IgE levels, eosinophilia, and serum may become extremely ineffective, and the patient may begin a gasping type of
antibodies to Aspergillus. respiratory pattern.

 These findings imply extensive mucus plugging and impending suffocation.

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(Robbins and Cotran Pathologic Basis of Disease 7 Edition)  Ventilatory assistance by mechanical means may be required.

 Atelectasis due to inspissated secretions occasionally occurs with asthmatic


attacks.
2.1 What is the clinical hallmark of asthma?
 Spontaneous pneumothorax and/or pneumomediastinum occur but are rare.

 Less typically, a patient with asthma may complain of intermittent episodes of


nonproductive cough or exertional dyspnea.
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 Unlike other individuals with asthma, when these patients are examined during (Harrison’s Principles of Internal Medicine 17th Edition)
symptomatic periods, they tend to have normal breath sounds but may wheeze
after repeated forced exhalations and/or may show ventilatory impairments when
tested in the laboratory.
 The major etiologic factors of asthma are genetic predisposition to type I
 In the absence of both these signs, a bronchoprovocation test may be required to hypersensitivity ("atopy"), acute and chronic airway inflammation, and bronchial
make the diagnosis. hyperresponsiveness.

(Robbins and Cotran Pathologic Basis of Disease 7th Edition)  The inflammation involves many cell types and numerous inflammatory
mediators,but the precise relationship of specific inflammatory cells and the
mediators to airway hyperreactivity is not fully understood.

2.2 Describe the pathophysiology of asthma.


 Type 2 helper T (TH2) cells, a type of CD4+ helper T cell, are prominent
components of the bronchial inflammation.
Pathophysiology

 TH2 cells secrete interleukins that promote allergic inflammation and stimulate B
cells to produce IgE and other antibodies.

 Limitation of airflow is due mainly to bronchoconstriction, but airway edema,


 In contrast, type 1 helper T (TH1) cells, the other class of CD4+ T cells, produce
vascular congestion, and luminal occlusion with exudate may also contribute.
interferon-γ and interleukin-2, which initiate the killing of viruses and other
intracellular organisms by activating macrophages and cytotoxic T cells.
 This results in a reduction in forced expiratory volume in 1 s (FEV1), FEV1/forced
vital capacity (FVC) ratio, and peak expiratory flow (PEF), as well as an increase
in airway resistance.  These two subgroups of helper T cells arise in response to different immunogenic
stimuli and cytokines, and they constitute an immunoregulatory loop: cytokines
 Early closure of peripheral airway results in lung hyperinflation (air trapping), and from TH1 cells inhibit TH2 cells, and vice versa.
increased residual volume, particularly during acute exacerbations.
 An imbalance in this reciprocal arrangement may be the key to asthma:
 In more severe asthma, reduced ventilation and increased pulmonary blood flow
result in mismatching of ventilation and perfusion and in bronchial hyperemia.  There is credible evidence that, when freed from the restraining influence of
interferon-γ, TH2 cells can provoke airway inflammation.
 Ventilatory failure is very uncommon, even in patients with severe asthma, and
arterial PaCO2 tends to be low due to increased ventilation.  It appears that in patients with allergic asthma, T cell differentiation is skewed in
the direction of TH2. The molecular basis of such bias is not clear.

Airway Hyperresponsiveness
 Recent studies indicate that a transcription factor called T-bet is required for TH1
cell differentiation, and immunohistochemical studies on lung tissues from
asthmatics reveal absence of T-bet in lung lymphocytes.

 These studies suggest that therapeutic upregulation of T-bet might be an


 AHR is the characteristic physiologic abnormality of asthma, and describes the attractive molecular therapy for asthma.
excessive bronchoconstrictor response to multiple inhaled triggers that would
have no effect on normal airways.
 In addition to the inflammatory responses mediated by TH2 type cells, asthma is
 The increase in AHR is linked to the frequency of asthma symptoms; thus, an characterized by structural changes in the bronchial wall, referred to as "airway
important aim of therapy is to reduce AHR. remodelling”.

 Increased bronchoconstrictor responsiveness is seen with direct  These changes, described later in greater detail, include hypertrophy of bronchial
bronchoconstrictors, such as histamine and methacholine, which contract airway smooth muscles and deposition of subepithelial collagen.
smooth muscle, but it is characteristically also seen with many indirect stimuli,
which release bronchoconstrictors from mast cells or activate sensory neural  Until recently, these changes were considered secondary to chronic inflammation
reflexes. occurring late in the disease.

 Most of the triggers for asthma symptoms appear to act indirectly, including  However, this view has been challenged, since in some studies, airway
allergens, exercise, hyperventilation, fog (via mast cell activation), irritant dusts, remodeling has been seen several years before the onset of symptoms.
and sulfur dioxide (via cholinergic reflex).
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 According to some, therefore, an abnormal, perhaps genetically determined,  Subsequent IgE-mediated reaction to inhaled allergens elicits an acute response
microenvironment in the bronchial wall is an essential cofactor in the and a late-phase reaction.
pathogenesis of asthma.
 Recall that exposure of presensitized IgE-coated mast cells to the same or a
 This view has been bolstered by the recent linkage of the ADAM-33 gene to cross-reacting antigen stimulates cross-linking of IgE and the release of chemical
asthma. ADAM-33 belongs to a subfamily of metalloproteinases related to the mediators.
matrix metalloproteinases (MMPs) such as collagenases.
 In the case of airborne antigens, the reaction occurs first on sensitized mast cells
 Although the precise function of ADAM-33 remains to be elucidated, it is known on the mucosal surface; the resultant mediator release opens the mucosal
to be expressed by lung fibroblasts and bronchial smooth muscle cells intercellular tight junctions and enhances penetration of antigen to the more
numerous submucosal mast cells.
 It is speculated that ADAM-33 polymorphisms accelerate proliferation of bronchial
smooth muscle cells and fibroblasts, thus contributing to bronchial  In addition, direct stimulation of subepithelial vagal (parasympathetic) receptors
hyperreactivity and subepithelial fibrosis. provokes bronchoconstriction through both central and local reflexes (including
those mediated by unmyelinated sensory C fibers).
 Mast cells are also suspected to contribute to airway remodeling.
 This occurs within minutes after stimulation and is called the acute, or
 Bronchial biopsies of patients with asthma reveal heavy infiltration of smooth immediate, response, which consists of bronchoconstriction, edema (owing to
muscle cells by mast cells. increased vascular permeability), mucus secretion, and, in extreme instances,
hypotension. Mast cells also release cytokines that cause the influx of other
leukocytes, including neutrophils and monocytes, lymphocytes, basophils, and
 When mast cells are triggered by IgE or other stimuli, they not only release particularly eosinophils (IL-5).
vasoactive mediators and cytokines but also growth factors such as PDGF and
proteases that can trigger smooth muscle proliferation.
 These inflammatory cells set the stage for the late-phase reaction, which starts 4
to 8 hours later and may persist for 12 to 24 hours or more.
 In a reciprocal action, activated smooth muscle cells secrete stem cell factor,
which is a chemoattractant and growth factor for mast cells.
 The late-phase reaction, as was noted earlier, is mediated by the swarm of
leukocytes recruited by the chemotactic factors and cytokines derived from mast
cells during the acute-phase response.
Atopic Asthma
 However, mediators can also be produced by other cells in the affected bronchi,
including (1) inflammatory cells that are already present in asthmatics suffering a
recurrent attack, (2) vascular endothelium, or (3) airway epithelial cells.
 This most common type of asthma usually begins in childhood.
 Epithelial cells are now known to produce a large variety of cytokines in response
 The disease is triggered by environmental antigens, such as dusts, pollens, to infectious agents, drugs, and gases as well as to inflammatory mediators.
animal dander, and foods, but potentially any antigen is implicated.
 This second wave of mediators stimulates the late reaction.
 A positive family history of atopy is common, and asthmatic attacks are often
preceded by allergic rhinitis, urticaria, or eczema.  For example, eotaxin, produced by airway epithelial cells, is a potent
chemoattractant and activator of eosinophils.

 Candidate genes for predisposition to atopy and airway hyperresponsiveness are  The major basic protein of eosinophils, in turn, causes epithelial damage and
currently subjects of intensive search and include genes involved in antigen airway constriction.
presentation (the HLA complex), T-cell activation (T-cell receptor complex, γ-
interferon), regulation of cytokine production or function of relevant cytokines (IL-
4, IL-5, IL-13), and receptors for bronchodilators (β2-adrenergic receptors).  The presence of both immediate and delayed reactions in IgE-mediated events
helps to explain the prolonged manifestations of asthma.
 In any case, a skin test with the offending antigen in these patients results in an
immediate wheal-and-flare reaction, a classic example of type I IgE-mediated  Many mediators have been implicated in the asthmatic response, but the relative
hypersensitivity reaction, discussed in detail in. importance of each putative mediator in actual human asthma has been difficult
to establish.

 In the airways, the scene for the reaction is set in large part by initial  The long list of "suspects" in acute asthma can be subclassified by the clinical
sensitization to inhaled antigens (allergens), which stimulate induction of TH2- efficacy of pharmacologic intervention with inhibitors or antagonists of the
type cells that release cytokines such as IL-4 and IL-5. mediators.

 These cytokines, in turn, promote IgE production by B cells, growth of mast cells  The first (disappointingly small) group includes putative mediators whose role in
(IL-4), and growth and activation of eosinophils (IL-5). bronchospasm is clearly supported by efficacy of pharmacologic intervention: (1)
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leukotrienes C4, D4, and E4, extremely potent mediators that cause prolonged
bronchoconstriction as well as increased vascular permeability and increased
mucus secretion, and (2) acetylcholine, released from intrapulmonary motor  Several pharmacologic agents provoke asthma.
nerves, which can cause airway smooth muscle constriction by directly
stimulating muscarinic receptors.
 Aspirin-sensitive asthma is an uncommon yet fascinating type, occurring in
patients with recurrent rhinitis and nasal polyps.
 A second group includes agents present at the scene of the crime and with
potent asthma-like effects but whose actual clinical role in acute allergic asthma
appears relatively minor on the basis of lack of efficacy of potent antagonists or  These individuals are exquisitely sensitive to small doses of aspirin, and they
synthesis inhibitors: (1) histamine, a potent bronchoconstrictor; (2) prostaglandin experience not only asthmatic attacks but also urticaria. It is probable that
D2 (PGD2), which elicits bronchoconstriction and vasodilation; and (3) PAF, which aspirin triggers asthma in these patients by inhibiting the cyclooxygenase
causes aggregation of platelets and release of histamine and serotonin from their pathway of arachidonic acid metabolism without affecting the lipoxygenase
granules. These mediators might yet prove important in other types of chronic or route, thus tipping the balance toward elaboration of the bronchoconstrictor
nonallergic asthma. leukotrienes.

 Finally, a large third group comprises the suspects for whom specific antagonists
or inhibitors are not available or have been insufficiently studied as yet.
Occupational Asthma
 These include numerous cytokines, such as IL-1, TNF, and IL-6 (some of which
exist in a preformed state within the mast cell granules),37 chemokines (e.g.,
eotaxin), neuropeptides, nitric oxide, bradykinin, and endothelins.
 This form of asthma is stimulated by fumes (epoxy resins, plastics), organic and
 It is thus clear that multiple mediators contribute to the acute asthmatic chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals
response. Moreover, the composition of this mediator soup might differ among (formaldehyde, penicillin products).
different individuals or types of asthma.
 Minute quantities of chemicals are required to induce the attack, which usually
 The appreciation of the importance of inflammatory cells and mediators in occurs after repeated exposure.
asthma has led to greater emphasis on anti-inflammatory therapeutics in clinical
practice.  The underlying mechanisms vary according to stimulus and include type I
reactions, direct liberation of bronchoconstrictor substances, and hypersensitivity
responses of unknown origin.

Nonatopic Asthma

(Robbins and Cotran Pathologic Basis of Disease 7th Edition)

 The second large group is the nonatopic, or nonreaginic, variety of asthma, which
is most frequently triggered by respiratory tract infection.
2.3 Describe the histology changes seen in asthma.
 Viruses (e.g., rhinovirus, parainfluenza virus) rather than bacteria are the most
common provokers.

 A positive family history is uncommon, serum IgE levels are normal, and there  The morphologic changes in asthma have been described principally in patients
are no other associated allergies. dying of status asthmaticus, but it appears that the pathology in nonfatal cases is
similar.
 In these patients, skin test results are usually negative, and although
hypersensitivity to microbial antigens may play a role, present theories place  Grossly, the lungs are overdistended because of overinflation, and there may be
more stress on hyperirritability of the bronchial tree. small areas of atelectasis.

 It is thought that virus-induced inflammation of the respiratory mucosa lowers  The most striking macroscopic finding is occlusion of bronchi and bronchioles by
the threshold of the subepithelial vagal receptors to irritants. thick, tenacious mucous plugs.

 Inhaled air pollutants, such as sulfur dioxide, ozone, and nitrogen dioxide, may  Histologically, the mucous plugs contain whorls of shed epithelium, which give
also contribute to the chronic airway inflammation and hyperreactivity that are rise to the well-known Curschmann spirals.
present in some cases.
 Numerous eosinophils and Charcot-Leyden crystals are present; the latter are
collections of crystalloid made up of eosinophil membrane protein.

Drug-Induced Asthma
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o The other characteristic histologic findings of asthma, collectively called 4. Wood- or coal-burning smoke
"airway remodeling" include:
5. Endotoxin, mycotoxins
o Thickening of the basement membrane of the bronchial epithelium.
6. Dust
o Edema and an inflammatory infiltrate in the bronchial walls, with a
prominence of eosinophils and mast cells. E. Strong or noxious odors or fumes

o An increase in size of the submucosal glands. 1. Perfumes, hairsprays

o Hypertrophy of the bronchial wall muscle. 2. Cleaning agents

 While airflow obstruction is primarily attributed to muscular bronchoconstriction, F. Occupational exposures


the airway remodeling may contribute as well.
1. Farm and barn exposures

2. Formaldehydes, cedar, paint fumes


(Robbins and Cotran Pathologic Basis of Disease 7th Edition)
G. Cold air, dry air

H. Exercise
3. Identify the risk factors (triggers) of asthma.
I. Crying, laughter, hyperventilation

J. Co-morbid conditions
Asthma Triggers
1. Rhinitis
A. Common viral infections of the respiratory tract
2. Sinusitis
B. Aeroallergens in sensitized asthmatics
3. Gastroesophageal reflux
1. Animal dander

2. Indoor allergens:
(Nelson’s Textbook of Pediatrics 17th Edition)
a. Dust mites

b. Cockroaches
Risk Factors and Triggers Involved in Asthma
c. Molds

3. Seasonal aeroallergens:
Endogenous Factors
a. Pollens (trees, grasses, weeds)

b. Seasonal molds
1. Genetic predisposition
C. Environmental tobacco smoke
2. Atopy
D. Air pollutants
3. Airway hyperresponsiveness
1. Ozone
4. Gender
2. Sulfur dioxide
5. Ethnicity?
3. Particulate matter
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Environmental Factors Allergens

1. Indoor allergens • Inhaled allergens are able to activate mast cells with bound IgE directly leading to the
immediate release of bronchoconstrictor mediators, resulting in the early response
2. Outdoor allergens reversed by bronchodilators.

3. Occupational sensitizers • Often, experimental allergen challenge is followed by a late response when there is
airway edema and an acute inflammatory response with increased eosinophils and
4. Passive smoking neutrophils that is not very reversible with bronchodilators.

5. Respiratory infections • The most common allergen to trigger asthma is Dermatophagoides sp., and
environmental exposure leads to low-grade chronic symptoms that are perennial.
6. Obesity?
• Perennial allergens are derived from cats and other domestic pets, as well as
7. Early viral infections? cockroaches.

• Other allergens, including grass pollen, ragweed, tree pollen, and fungal spores, are
seasonal.
Triggers
• Pollens usually cause allergic rhinitis rather than asthma, but in thunderstorms the
pollen grains are disrupted, and the particles that may be released can trigger severe
asthma exacerbations (thunderstorm asthma).
1. Allergens

2. Upper respiratory tract viral infections


Virus Infections
3. Exercise and hyperventilation

4. Cold air
• Upper respiratory tract virus infections, such as rhinovirus, respiratory syncytial virus,
and coronavirus, are the commonest triggers of acute severe exacerbations.
5. Sulfur dioxide

• The mechanism whereby these viruses cause exacerbations is poorly understood, but
6. Drugs ( blockers, aspirin)
there is an increase in airway inflammation with increased numbers of eosinophils and
neutrophils.
7. Stress
• There is evidence for reduced production of type I interferons by epithelial cells from
8. Irritants (household sprays, paint fumes) asthmatic patients, resulting in increased susceptibility to these viral infections and a
greater inflammatory response.

(Harrison’s Principles of Internal Medicine 17th Edition)


Pharmacologic Agents

Asthma Triggers
• Several drugs may trigger asthma. -adrenergic blockers commonly worsen asthma,
and their use may be fatal.

• Several stimuli trigger airway narrowing, wheezing, and dyspnea in asthmatic • The mechanisms are not clear but are mediated through increased cholinergic
patients. bronchoconstriction.

• While the previous view held that these should be avoided, it is now seen as evidence
for poor control and an indicator of the need to increase controller therapy. • All β-blockers need to be avoided, and even selective 2 blocker or topical application
(e.g., timolol eye drops) may be dangerous.
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• Angiotensin-converting enzyme inhibitors are theoretically detrimental as they inhibit
There is little evidence that allergic reactions to food lead to increased asthma
symptoms, despite the belief of many patients that their symptoms are triggered by
breakdown of kinins, which are bronchoconstrictors; however, they rarely worsen particular food constituents.
asthma and the characteristic cough is no more frequent in asthmatics than
nonasthmatics.
• Exclusion diets are usually unsuccessful at reducing the frequency of episodes.
• Aspirin may worsen asthma in some patients (aspirin-sensitive asthma is discussed
below under "Special Considerations"). • Some foods, such as shellfish and nuts, may induce anaphylactic reactions that may
include wheezing.

• Patients with aspirin-induced asthma may benefit from a salicylate-free diet, but these
Exercise are difficult to maintain.

• Certain food additives may trigger asthma. Metabisulfite, which is used as a food
preservative, may trigger asthma through the release of sulfur dioxide gas in the
stomach.
• Exercise is a common trigger of asthma, particularly in children.
• Tartrazine, a food yellow-coloring agent, was believed to be a trigger for asthma, but
• The mechanism is linked to hyperventilation, which results in increased osmolality in there is little convincing evidence for this.
airway lining fluids and triggers mast cell mediator release, resulting in
bronchoconstriction.

• Exercise-induced asthma (EIA) typically begins after exercise has ended and recovers
Air Pollution
spontaneously within about 30 min.

• EIA is worse in cold, dry climates than in hot, humid conditions.

• Increased ambient levels of sulfur dioxide, ozone, and nitrogen oxides are associated
• It is therefore more common in sports such as cross-country running in cold weather, with increased asthma symptoms.
overland skiing, and ice hockey than in swimming.

• It may be prevented by prior administration of 2-agonists and antileukotrienes, but is


best prevented by regular treatment with inhaled glucocorticoids, which reduce the
Occupational Factors
population of surface mast cells required for this response.

Physical Factors • Several substances found in the workplace may act as sensitizing agents, as discussed
above, but may also act as triggers of asthma symptoms.

• Occupational asthma is characteristically associated with symptoms at work with relief


on weekends and holidays.
• Cold air and hyperventilation may trigger asthma through the same mechanisms as
exercise.
• If removed from exposure within the first 6 months of symptoms there is usually
complete recovery.
• Laughter may also be a trigger.

• More persistent symptoms lead to irreversible airway changes, and therefore early
• Many patients report worsening of asthma in hot weather and when the weather detection and avoidance are important.
changes.

• Some asthmatics become worse when exposed to strong smells or perfumes, but the
mechanism of this response is uncertain.
Hormonal Factors

Food
• Some women show premenstrual worsening of asthma, which can occasionally be
very severe.

• The mechanisms are not completely understood but are related to a fall in
progesterone and in severe cases may be improved by treatment with high doses of
progesterone or gonadotropin-releasing factors.
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• Thyrotoxicosis and hypothyroidism can both worsen asthma, although the PEFR or FEV1 (PEFR Variability): ≥80% (<20%)
mechanisms are uncertain.

Daily Medications to Maintain Long-Term Control


Gastroesophageal Reflux

• No daily medication needed.


• Gastroesophageal reflux is common in asthmatic patients as it is increased by
bronchodilators.
• Severe exacerbations may occur, separated by long periods of normal lung function
and no symptoms.
• While acid reflux might trigger reflex bronchoconstriction, it rarely causes asthma
symptoms, and anti-reflux therapy fails to reduce asthma symptoms in most patients.
• A course of systemic glucocorticoids is recommended.

Stress
Step 2: Mild persistent

• Many asthmatics report worsening of symptoms with stress.


Symptoms
• There is no doubt that psychological factors can induce bronchoconstriction through
cholinergic reflex pathways. Paradoxically, very severe stress, such as bereavement,
usually does not worsen, and may even improve, asthma symptoms.
Day: >2 days/week but <1 per day

Night: >2 nights/months


(Harrison’s Principles of Internal Medicine 17th Edition)
PEFR or FEV1 (PEFR Variability): ≥80% (20-30%)

4. Give the classification of asthma by level of control.


Daily Medications to Maintain Long-Term Control:

Stepwise Approach for Managing Asthma in Adults


• Low-dose inhaled glucocorticoids

Classify Severity: Clinical Features Before Treatment or Adequate Control • Alternative treatment (listed alphabetically): cromolyn, leukotriene modifier,
nedocromil, or sustained-release theophylline to serum concentration of 5–15 µg/mL.

Step 1: Mild intermittent


Step 3: Moderate persistent

Symptoms
Symptoms

Day: ≤2 days/week
Day: Daily
Night: ≤2 nights/month
Night: >1 night/week
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PEFR or FEV1 (PEFR Variability): >60%–<80% (>30%)


• Use of short-acting 2-agonists 2 times a week in intermittent asthma (daily, or
increasing use in persistent asthma) may indicate the need to initiate (increase)long-
term control therapy.

Daily Medications to Maintain Long-Term Control

(Harrison’s Principles of Internal Medicine 16th Edition)

• Low- to medium-dose inhaled glucocorticoids and long-acting inhaled β2-agonists.

5. What are the asthma-related chemical mediators and their significance?


• Alternative treatment: leukotriene modifier or theophylline instead of β2 agents

Inflammation
Step 4: Severe persistent

• There is inflammation in the respiratory mucosa from trachea to terminal bronchioles,


Symptoms but with a predominance in the bronchi (cartilaginous airways).

• Considerable research has identified the major cellular components of inflammation,


but it is still uncertain how inflammatory cells interact and how inflammation
Day: Continual translates into the symptoms of asthma.

Night: Frequent • There is good evidence that the specific pattern of airway inflammation in asthma is
associated with airway hyperresponsiveness (AHR), the physiologic abnormality of
PEFR or FEV1 (PEFR Variability): ≤60% (>30%) asthma that is correlated with variable airflow obstruction.

• The pattern of inflammation in asthma is characteristic of allergic diseases, with


similar inflammatory cells seen in the nasal mucosa in rhinitis.
Daily Medications to Maintain Long-Term Control
• However, an indistinguishable pattern of inflammation is found in intrinsic asthma,
although this may reflect local rather than systemic IgE production.

• Although most attention has focused on the acute inflammatory changes seen in
• High-dose inhaled glucocorticoids and Long-acting inhaled β2-agonists and, if needed, asthma, this is a chronic condition, with inflammation persisting over many years in
Glucocorticoid tablets or syrup long term (2mg/kg per day, generally do not exceed 60 most patients.
mg/d).
• The mechanisms involved in persistence of inflammation in asthma are still poorly
• Make repeat attempts to reduce systemic glucocorticoids and maintain control with understood. Superimposed on this chronic inflammatory state are acute inflammatory
high-dose inhaled glucocorticoids. episodes, which correspond to exacerbations of asthma.

• Many inflammatory cells are known to be involved in asthma, with no predominant key
cell
Quick relief for all patients

Mast Cells
• Short-acting bronchodilator: 2–4 puffs short-acting inhaled 2-agonists as needed for
symptoms.

• Mast cells are important in initiating the acute bronchoconstrictor responses to


• Intensity of treatment will depend on severity of exacerbation; up to 3 treatments at allergens and several other indirectly acting stimuli, such as exercise and
20-min intervals or a single nebulizer treatment as needed. hyperventilation (via osmolality or thermal changes), as well as fog. In biopsies from
asthmatic patients, mast cells are localized to the airway smooth muscle layer; they
• Course of systemic glucocorticoids may be needed. are not found in normal subjects or in patients with eosinophilic cough.
11

• Mast cells are activated by allergens through an IgE-dependent mechanism, and eosinophilic inflammation is also found in patients with chronic cough who do not have
binding of specific IgE to mast cells renders them more sensitive to activation. any clinical features of asthma or AHR.

• The importance of IgE in the pathophysiology of asthma has been highlighted by • Increasing evidence suggests that eosinophils may be more important in release of
clinical studies with humanized anti-IgE antibodies, which inhibit IgE-mediated effects, growth factors involved in airway remodeling than in AHR.
reduce asthma symptoms, and prevent exacerbations.

• There are, however, uncertainties about the role of mast cells in more chronic allergic
inflammatory events. Neutrophils

• Mast cells release several bronchoconstrictor mediators, including histamine and


cysteinyl-leukotrienes, but also several cytokines, chemokines, growth factors, and
neurotrophins. • Increased numbers of activated neutrophils are found in sputum and airways of some
patients with severe asthma and during exacerbations, although there is a proportion
of patients even with mild or moderate asthma that have a predominance of
neutrophils.
Macrophages and Dendritic Cells

• The role of neutrophils in asthma, which are resistant to the anti-inflammatory effects
• Macrophages, which are derived from blood monocytes, may traffic into the airways in of corticosteroids, is currently unknown.
asthma and may be activated by allergens via low-affinity IgE receptors (FcRII).

• Macrophages have the capacity to initiate a type of inflammatory response via the
release of a certain pattern of cytokines, but these cells also release anti-inflammatory T Lymphocytes
mediators, such as IL-10, and thus their role in asthma is uncertain.

• Dendritic cells are specialized macrophage-like cells in the airway epithelium, which
are the major antigen-presenting cells. • T lymphocytes play a very important role in coordinating the inflammatory response in
asthma through the release of specific patterns of cytokines, resulting in the
• Dendritic cells take up allergens, process them to peptides, and migrate to local lymph recruitment and survival of eosinophils and in the maintenance of a mast cell
nodes where they present the allergenic peptides to uncommitted T-lymphocytes to population in the airways.
program the production of allergen-specific T cells.
• The naïve immune system and the immune system of asthmatics are skewed to
• Immature dendritic cells in the respiratory tract promote TH2 cell differentiation and express the TH2 phenotype, whereas in normal airways TH1 cells predominate.
require cytokines, such as IL-12 and TNF-, to promote the normally preponderant TH1
response. • TH2 cells, through the release of IL-5, are associated with eosinophilic inflammation
and, through the release of IL-4 and IL-13, are associated with increased IgE
Eosinophils formation.

• Recently, bronchial biopsies have demonstrated a preponderance of natural killer


CD4+ T lymphocytes, which express high levels of IL-4.
• Eosinophil infiltration is a characteristic feature of asthmatic airways.
• Regulatory T cells play an important role in determining the expression of other T
• Allergen inhalation results in a marked increase in activated eosinophils in the airways cells, and there is evidence for a reduction in a certain subset of regulatory T cells
at the time of the late reaction. (CD4+CD25+) in asthma, which is associated with increased TH2 cells.

• Eosinophils are linked to the development of airway hyperresponsiveness through the


release of basic proteins and oxygen-derived free radicals.
Structural Cells
• Eosinophil recruitment involves adhesion of eosinophils to vascular endothelial cells in
the airway circulation due to interaction between adhesion molecules, migration into
the submucosa under the direction of chemokines, and their subsequent activation
and prolonged survival. • Structural cells of the airways, including epithelial cells, fibroblasts and airway smooth-
muscle cells, are also an important source of inflammatory mediators, such as
• Blocking antibodies to IL-5 cause a profound and prolonged reduction in circulating cytokines and lipid mediators, in asthma.
and sputum eosinophils, but they are not associated with reduced AHR or asthma
symptoms, thus questioning the pivotal role of eosinophils in asthma. Furthermore,
12

• Indeed, because structural cells far outnumber inflammatory cells, they may become • Eotaxin (CCL11) is selectively attractant to eosinophils via CCR3 and is expressed by
the major source of mediators driving chronic inflammation in asthmatic airways. epithelial cells of asthmatics, whereas CCL17 (TARC) and CCL22 (MDC) from epithelial
cells attract TH2 cells via CCR4.
• In addition, epithelial cells may have a key role in translating inhaled environmental
signals into an airway inflammatory response, and are probably a major target cell for
ICSs.
Oxidative Stress

Inflammatory Mediators
• There is increased oxidative stress in asthma as activated inflammatory cells, such as
macrophages and eosinophils, produce reactive oxygen species.

• Many different mediators have been implicated in asthma, and they may have a • Evidence for increased oxidative stress in asthma is provided by the increased
variety of effects on the airways that could account for the pathologic features of concentrations of 8-isoprostane (a product of oxidized arachidonic acid) in exhaled
asthma. breath condensates and increased ethane (a product of lipid peroxidation) in the
expired air of asthmatic patients.
• Mediators such as histamine, prostaglandins, and cysteinyl-leukotrienes contract
airway smooth muscle, increase microvascular leakage, increase airway mucus • Increased oxidative stress is related to disease severity, may amplify the inflammatory
secretion, and attract other inflammatory cells. response, and may reduce responsiveness to corticosteroids.

• Because each mediator has many effects, the role of individual mediators in the
pathophysiology of asthma is not yet clear.
Nitric Oxide
• Although the multiplicity of mediators makes it unlikely that preventing the synthesis
or action of a single mediator will have a major impact in clinical asthma, recent
clinical studies with antileukotrienes suggest that cysteinyl-leukotrienes have a
clinically important effect. • Nitric oxide (NO) is produced by several cells in the airway by NO synthases,
particularly airway epithelial cells and macrophages.

• The level of NO in the expired air of patients with asthma is higher than normal and is
Cytokines related to the eosinophilic inflammation.

• Increased NO may contribute to the bronchial vasodilation observed in asthma.

• Multiple cytokines regulate the chronic inflammation of asthma. • Exhaled NO is increasingly used in the diagnosis and monitoring of asthmatic
inflammation, although it is not used routinely in clinical practice.
• The TH2 cytokines IL-4, IL-5, and IL-13 mediate allergic inflammation, whereas
proinflammatory cytokines, such as tumor necrosis factor (TNF-) and IL-1, amplify the
inflammatory response and play a role in more severe disease.
Transcription Factors
• Thymic stromal lymphopoietin is an upstream cytokine released from epithelial cells of
asthmatics that orchestrates the release of chemokines, which selectively attract TH2
cells.
• Proinflammatory transcription factors, such as nuclear factor B (NFB) and activator
• Some cytokines, such as IL-10 and IL-12, are anti-inflammatory and may be deficient protein 1 (AP-1), are activated in asthmatic airways and orchestrate the expression of
in asthma. multiple inflammatory genes.

• More-specific transcription factors that are involved include nuclear factor of activated
T cells and GATA-3, which regulate the expression of TH2 cytokines in T cells.
Chemokines

(Harrison’s Principles of Internal Medicine 17th Edition)


• Chemokines are involved in attracting inflammatory cells from the bronchial
circulation into the airways.

6. List the laboratory tests useful in diagnosing asthma and their expected results.
13

• Asthmatic airways are hyperresponsive and therefore more sensitive to inhaled


methacholine, histamine, and cold or dry air.
Laboratory Findings
• The degree of airways hyperresponsiveness to these exposures correlates with
asthma severity and airways inflammation.

• Lung or pulmonary function tests including bronchoprovocation challenges are the • Although bronchoprovocation challenges are carefully dosed and monitored in an
basis of documenting the presence of asthma and the severity of acute exacerbations. investigational setting, their use is rarely practical in a general practice setting.

• Exercise challenges (i.e., aerobic exertion or “running” for 6-8min) can also help to
identify the child with exercise-induced bronchospasm. Although the airflow response
LUNG FUNCTION TESTING of nonasthmatics to exercise is to increase functional lung volumes and improve FEV1
slightly (5-10%), exercise typically induces airflow obstruction in untreated asthmatics.
Accordingly, in asthmatics, FEV1 typically decreases during or after exercise by more
than 15%.
• Measures of expiratory airflow are helpful in diagnosing and monitoring asthma and in
assessing efficacy of therapy.
• The onset of exercise-induced bronchospasm is usually within 15?min after a vigorous
exercise challenge and can spontaneously resolve within 60min.
• Lung function testing is particularly helpful in asthmatics who are poor perceivers of
airflow obstruction or when physical signs of asthma do not occur until airflow • Studies of U.S. school-age children using such exercise challenges typically identify
obstruction has become severe. about 10% with exercise-induced bronchospasm but previously undiagnosed asthma,
in addition to the known asthmatics with exercise-induced bronchospasm.
• Spirometry measures airflow and lung volumes during a forced expiratory maneuver
and is considered the gold standard measure of airflow in asthma. • Exercise challenges can induce 765 severe asthma exacerbations in at-risk patients;
therefore, careful patient selection for exercise challenges, and preparedness for
• Its helpfulness as an objective measure in the initial evaluation and management of severe asthma exacerbations, is required.
asthmatics has led to recommendations for its standard use in the U.S. National
Asthma Education and Prevention Program (NAEPP) guidelines sponsored by the U.S. • Peak expiratory flow (PEF) monitoring devices provide a simple and inexpensive home-
use tool to measure airflow and can be particularly helpful in many circumstances.
• National Institutes of Health. In asthma, airways blockage results in reduced airflow
• PEFs vary in their ability to detect airflow obstruction, and, in some patients, PEF
and smaller partial-expiratory lung volumes.
declines only when airflow obstruction is severe.

• Of these measures, normative values for FEV1 (forced expiratory volume in 1?sec)
have been standardized for children, based on height, gender, and ethnicity. • Therefore, PEF monitoring should be started by measuring morning and evening PEFs
(best of three consecutive attempts) for several weeks for patients to practice the
technique, to determine a “personal best,” and to correlate PEF values with symptoms
• The reductions in FEV1 as a percentage of predicted is one of four criteria used to (and ideally spirometry).
determine asthma severity in the NAEPP guidelines. Because asthmatics are typically
hyperinflated, often profoundly, FEV1 can be simply adjusted for full expiratory lung • PEF morning-to-evening variation greater than 20% is consistent with asthma.
volume, the forced vital capacity (FVC), with an FEV1 /FVC ratio. Generally, an FEV1
/FVC ratio less than 0.8 indicates significant airflow obstruction.

• Such measures of airflow alone, however, are not diagnostic of asthma, because RADIOLOGY
numerous other conditions can cause airflow reduction. Bronchodilator response to
inhaled ß-agonist medication (i.e., albuterol by nebulizer) is greater in asthmatics vs.
nonasthmatics, an improvement in FEV1 greater than 12% is consistent with asthma.
• Chest radiographs (posteroanterior and lateral views) in children with asthma often
• Importantly, valid spirometric measures are dependent on a patient's ability to appear to be normal, aside from subtle and nonspecific findings of hyperinflation (e.g.,
properly execute a full, forced, and prolonged expiratory maneuver, typically feasible flattening of the diaphragms) and peribronchial thickening.
in children older than 6 yr of age (with some younger exceptions).
• Chest radiographs are helpful in identifying abnormalities that are hallmarks of
• Reproducible spirometric efforts are an indicator of test validity. If, on three asthma masqueraders (e.g., aspiration pneumonitis, hyperlucent lung fields in
consecutive attempts, the FEV1 is within 5%, then the best FEV1 effort of the three is bronchiolitis obliterans), and complications during asthma exacerbations (e.g.,
used. atelectasis, pneumothorax).

• Bronchoprovocation challenges can be helpful in diagnosing asthma and optimizing • Some lung abnormalities can be better appreciated with high-resolution, thin-section
asthma management. chest CT scans.
14

• For example, bronchiectasis is sometimes difficult to appreciate on chest radiograph • Reversibility is demonstrated by a >12% or 200 mL increase in FEV1 15 min after an
but is clearly seen on CT scan and implicates asthma masqueraders such as cystic inhaled short-acting 2-agonist or, in some patients, by a 2- to 4-week trial of oral
fibrosis, allergic bronchopulmonary mycoses (e.g., aspergillosis), ciliary dyskinesias, or glucocorticoids (prednisone or prednisolone 30–40 mg daily).
immune deficiencies.
• Measurements of PEF twice daily may confirm the diurnal variations in airflow
obstruction.

(Nelson’s Textbook of Pediatrics 17th Edition) • Flow-volume loops show reduced peak flow and reduced maximum expiratory flow.

DIAGNOSIS • Further lung function tests are rarely necessary, but whole body plethysmography
shows increased airway resistance and may show increased total lung capacity and
residual volume.
• The diagnosis of asthma is established by demonstrating reversible airway
obstruction. • Gas diffusion is usually normal but there may be a small increase in gas transfer in
some patients.
• Reversibility is traditionally defined as a >15% increase in FEV1 after two puffs of a β-
Airway Responsiveness
adrenergic agonist.

• When the spirometry results are normal at presentation, the diagnosis can be made
by showing heightened airway responsiveness to challenges with histamine, • The increased AHR is normally measured by methacholine or histamine challenge with
methacholine, or isocapnic hyperventilation of cold air. calculation of the provocative concentration that reduces FEV1 by 20% (PC20).

• Once the diagnosis is confirmed, the course of the illness and the effectiveness of • This is rarely useful in clinical practice, but can be used in the differential diagnosis of
therapy can be followed by measuring PEFRs at home and/or the FEV1 in the office or chronic cough and when the diagnosis is in doubt in the setting of normal pulmonary
laboratory. function tests.

• Positive whealand-flare reactions to skin tests can be demonstrated to various • Occasionally exercise testing is done to demonstrate the post-exercise
allergens, but such findings do not necessarily correlate with the intrapulmonary bronchoconstriction if there is a predominant history of EIA.
events.
• Allergen challenge is rarely necessary, and should only be undertaken by a specialist if
• Sputum and blood eosinophilia and measurement of serum IgE levels are also helpful specific occupational agents are to be identified.
but are not specific for asthma. Chest roentgenograms showing hyperinflation are also
nondiagnostic.

(Harrison’s Principles of Internal Medicine 16th Edition)


Hematologic Tests

Diagnosis
• Blood tests are not usually helpful.

• Total serum IgE and specific IgE to inhaled allergens (RAST) may be measured in some
patients.
• The diagnosis of asthma is usually apparent from the symptoms of variable and
intermittent airways obstruction, but is usually confirmed by objective measurements
of lung function.

Imaging

Lung Function Tests

• Chest roentgenography is usually normal but may show hyperinflated lungs in more
severe patients.
• Simple spirometry confirms airflow limitation with a reduced FEV1, FEV1/FVC ratio,
and PEF. • In exacerbations, there may be evidence of a pneumothorax.

• Lung shadowing usually indicates pneumonia or eosinophilic infiltrates in patients with


bronchopulmonary aspergillosis.
15

• High-resolution CT may show areas of bronchiectasis in patients with severe asthma, • Continuous nebulization of B2-agonists has also been employed, but it is unclear if it is
and there may be thickening of the bronchial walls, but these changes are not materially better than the other forms of treatment. Ipratropium can be added to the
diagnostic of asthma. regimen in an attempt to speed resolution.

• The benefits on lung function are small, but the need for admission has decreased in
some studies.
Skin Tests
• There are no hard and fast rules as to who should be admitted. Acute episodes of
bronchial asthma are one of the most common respiratory emergencies, and it is
essential that the physician recognize which episodes of airway obstruction are life-
• Skin prick tests to common inhalant allergens are positive in allergic asthma and threatening and which patients demand what level of care.
negative in intrinsic asthma, but are not helpful in diagnosis.
• These distinctions can be made readily by assessing selected clinical parameters in
• Positive skin responses may be useful in persuading patients to undertake allergen combination with measures of expiratory flow and gas exchange.
avoidance measures.
• The presence of a paradoxical pulse, use of accessory muscles, and marked
hyperinflation of the thorax signify severe airways obstruction, and failure of these
signs to remit promptly after aggressive therapy mandates objective monitoring of the
patient with measurements of arterial blood gases and PEFR or FEV1.
(Harrison’s Principles of Internal Medicine 17th Edition)

• Although pulse and respiratory rates are commonly recorded, there is no relationship
between these variables and the severity of the obstruction or the outcome of
treatment. Patients with the most impairment typically require the most extensive
7. Describe the step-wise management of asthma based on the classification of asthma by therapy for resolution.
level of control.
• If the PEFR or FEV1 is <20% of predicted on presentation and does not double within
an hour of receiving the preceding therapy, the patient is likely to require extensive
treatment, including glucocorticoids, before the obstruction dissipates.
(please check the table on number 4)
• This group represents ~20% of all the patients who present for acute care.
Framework for Management in EMERGENCY SITUATIONS
• They generally require inpatient treatment before becoming asymptomatic.

• The most effective treatment for acute episodes of asthma requires a systematic • In such patients, if the clinical signs of a paradoxical pulse and accessory muscle use
approach based on the aggressive use of sympathomimetic agents and serial are diminishing and/or the PEFR is increasing, there is no need to change medications
objective monitoring of key indices of improvement. or doses, but the patient needs to be followed closely.

• Reliance on empiricism and subjective assessment is no longer acceptable. • However, if the PEFR falls by >20% of its previous value or if the magnitude of the
pulsus paradoxicus is increasing, serial measures of arterial blood gases are required,
• Multiple inhalations of a short-acting sympathomimetic, such as albuterol, are the as well as a reconsideration of the therapeutic modalities being employed.
cornerstone of most regimens.
• If the patient has hypocarbia, one can afford to continue the current approaches a
• These drugs provide three to four times more relief than does intravenous while longer.
aminophylline.
• On the other hand, if the PaCO is within the 2 normal range or is elevated, the patient
• Anticholinergic drugs are not first-line therapy because of their long lag time to onset should be monitored in an intensive care setting, and therapy should be intensified to
(30 to 40 min)and their relatively modest bronchodilator properties. reverse or arrest the patient’s respiratory failure.

• In emergency situations, B2-agonists can be given very 20 min by handheld nebulizer • Treatment with 70 to 80% helium (balance oxygen)may be beneficial in patients with
for 2 to 3 doses. severe airway obstruction.

• The optimum cumulative dose of albuterol appears to lie between 5 and 10 mg. It • This gas mixture reduces airway resistance and improves the effect of aerosolized
does not matter how the adrenergic agonists are inhaled. Treatment with albuterol bronchodilators.
administered by jet nebulizer, metered dose inhaler, or dry powder inhaler all provide
equal resolution in acute situations when the doses are matched. • This form of treatment should be considered in patients whose airway obstruction and
gas exchange are worsening despite aggressive therapy. However, there are no large-
scale clinical trials comparing this approach with other forms of treatment.
16

• The criteria for intubation and ventilatory support have not been standardized. • An upper limit has not yet been established, but side effects of glucocorticoid excess
begin to appear more frequently when the dose exceeds 2.0 mg/ kg per d.
• The decision to use this therapy should be made by physicians with the most
experience in caring for severely ill asthmatic patients. • Persistent asthma complaints can be treated with low- to medium-dose inhaled
glucocorticoids and long-acting inhaled B2-agonists.
Chronic Treatment
• Alternative treatments include leukotriene modifiers or sustained-release theophylline.

• The goal of chronic therapy is to achieve a stable, asymptomatic state with the best • In patients with recurrent or perennial symptoms and unstable lung function (step 4),
pulmonary function possible using the least amount of medication. the preferred treatment is high-dose inhaled glucocorticoids and long-acting inhaled
B2-agonists.
• The specific recommmendations from consensus guidelines are to promote a state of
health encompassing the following: • If needed, oral glucocorticoids in a single daily dose are added to the regimen.

1. Minimal or absent daytime or nocturnal chronic symptoms. • Acute symptoms are treated with short-acting rescue medications such as albuterol
alone or in combination with a parasympatholytic.
2. Minimal or absent exacerbations.
• Once control is reached and sustained for several weeks, a stepdown reduction in
therapy should be undertaken, beginning with the most toxic drug, to find the
3. No limitation on activities.
minimum amount of medication required to keep the patient well.

4. No absences from school or work.


• During this process, the PEFR should be monitored and medication adjustments should
be based on objective changes in lung function as well as on the patient’s symptoms.
5. Maintenance of normal or near-normal pulmonary functions.
• The recommendations in the step-down mode are that treatment be reviewed every 1
to 6 months. In many instances, shorter periods can be employed.
6. The minimal use of short-acting B2-agonists (<once per day, <1 canister/month).
• We have found that 2 to 4 weeks are a reasonable period.
7. Minimal or absent adverse effects from medications.
• When a patient’s asthma is destabilizing, frequent assessments are required. It is
• A primary step is to educate patients to function as partners in their management. important to gain control as quickly as possible and then step down to the least
medication necessary to maintain control.
• The severity of the illness needs to be assessed and monitored with objective
measures of lung function. • If there are difficulties in achieving this goal, then referral to an asthma specialist
should be considered.
• Asthma triggers should be avoided or controlled, and plans should be made for both
chronic management and treatment of exacerbations. Regular follow-up care is • Prior to increasing treatment, an important component is to review patients’ inhaler
mandatory. technique, their adherence to therapeutic recommendations, and environment control.

• The purpose of this schema is to assist and not replace the clinical decision-making (Harrison’s Principles of Internal Medicine 16th Edition)
required to meet individual patient needs.

• In general, the simplest approach works best.


7.1 What are the reliever drugs and what are controller drugs?

• Infrequent symptoms (step 1) require only the use of an inhaled sympathomimetic on  The available agents for treating asthma can be divided into two general
an “as-needed” basis. categories: drugs that inhibit smooth-muscle contraction, i.e., the so-called
“quick relief medications” (B-adrenergic agonists, methylxanthines, and
• When the disease worsens to a persistent state (step 2), as manifested by nocturnal
anticholinergics) and agents that prevent and/or reverse inflammation, i.e., the
“long-term control medications” (glucocorticoids, long-acting B2-agonists,
awakenings and daytime symptoms, inhaled steroids, mast cell-stabilizing agents, combined medications, mast cell–stabilizing agents, leukotriene modifiers, and
and/or leukotriene modifiers should be added. methylxanthines.

• Methylxanthines can also be employed. (Harrison’s Principles of Internal Medicine 16th Edition)

• If symptoms do not abate (step 3), the dose of inhaled steroids can be increased. (explanation of each drugs will be discussed below)

8. Enumerate the different bronchodilator drugs?


17

8.1 Discuss each drug as to: o Of particular interest, stimulation of β2 adrenergic receptors inhibits the
function of numerous inflammatory cells, including mast cells, basophils,
a. Route of administration eosinophils, neutrophils, and lymphocytes.

b. Pharmacodynamic properties
o In general, stimulating β2 adrenergic receptors in these cell types increases
c. Pharmacokinetic properties intracellular cyclic AMP, activating a signaling cascade that inhibits the
release of inflammatory mediators and cytokines.
d. Toxicology

Short-Acting b2 Adrenergic Receptor Agonists


β2 Adrenergic Receptor Agonists

o Drugs in this class include albuterol (PROVENTIL, VENTOLIN), levalbuterol,


the (R)-enantiomer of albuterol (XOPENEX), metaproterenol (ALUPENT),
Mechanism of Action and Use in Asthma terbutaline (BRETHAIRE), and pirbuterol (MAXAIR).

o These drugs are used for acute inhalation treatment of bronchospasm.

o The β adrenergic receptor agonists available for the treatment of asthma o Terbutaline (BRETHINE, BRICANYL), albuterol, and metaproterenol also are
are selective for the b2-receptor subtype. available in oral dosage form.

o With few exceptions, they are delivered directly to the airways via o Each of the inhaled drugs has an onset of action within 1 to 5 minutes and
produces bronchodilation that lasts for about 2 to 6 hours. When given in
inhalation.
oral dosage forms, the duration of action is somewhat longer (oral
terbutaline, for example, has a duration of action of 4 to 8 hours).
o The agonists can be classified as short- or long-acting.
o Although there are slight differences in the relative b2/b1-receptor potency
o This subclassification is useful from a pharmacological perspective: Short- ratios among the drugs, all of them are selective for the b2 subtype.
acting agonists are used only for symptomatic relief of asthma, whereas
long-acting agonists are used prophylactically in the treatment of the
o The most effective drugs in relaxing airway smooth muscle and reversing
disease.
bronchoconstriction are short-acting b2 adrenergic receptor agonists.

o The mechanism of the antiasthmatic action of β adrenergic receptor


o They are the preferred treatment for rapid symptomatic relief of dyspnea
agonists is undoubtedly linked to the direct relaxation of airway smooth
associated with asthmatic bronchoconstriction.
muscle and consequent bronchodilation.

o Although these drugs are prescribed on an as-needed basis, it is imperative


o Although human bronchial smooth muscle receives little or no sympathetic that guidelines be given to the patient so that reliance on relief of
innervation, it nevertheless contains large numbers of b2 adrenergic symptoms during times of deteriorating asthma does not occur.
receptors.
o When the asthma symptoms become persistent, the patient should be
o Stimulation of these receptors activates the Gs adenylyl cyclase-cyclic AMP reevaluated so that drugs aimed at controlling, in addition to reversing, the
pathway with a consequent reduction of in smooth muscle tone (Sylvester, disease can be prescribed.
2004).
Long-Acting β Adrenergic Receptor Agonists
o β2 Adrenergic receptor agonists also increase the conductance of large
Ca2+-sensitive K+ channels in airway smooth muscle, leading to membrane
hyperpolarization and relaxation.
o Salmeterol xinafoate (SEREVENT) and formoterol (FORADIL) are long-lasting
o This occurs at least partly by mechanisms independent of adenylyl cyclase adrenergic agents with very high selectivity for the b2-receptor subtype.
activity and cyclic AMP production and may involve the regulation of
capacitative Ca2+ entry by small G proteins.
o Inhalation of salmeterol provides persistent bronchodilation lasting over 12
hours.
o There are β2 adrenergic receptors on cell types in the airways other than
bronchial smooth muscle.
18

o The mechanism underlying the extended duration of action of salmeterol is


not yet fully understood.
Toxicity
o The extended side chain on salmeterol renders it 10,000 times more
lipophilic than albuterol.

o The lipophilicity regulates the diffusion rate away from the receptor by o Owing to their β2-receptor selectivity and topical delivery, inhaled b
determining the degree of partitioning in the lipid bilayer of the membrane. adrenergic receptor agonists at recommended doses have relatively few
side effects.
o Subsequent to binding the receptor, the less lipophilic, short-acting agonists
are removed rapidly from the receptor environment by diffusion in the o A portion of inhaled drug is inevitably absorbed into the systemic
aqueous phase. circulation.

o Unbound salmeterol, by contrast, persists in the membrane and only slowly o At higher doses, therefore, these drugs may lead to increased heart rate,
dissociates from the receptor environment. cardiac arrhythmias, and central nervous system (CNS) effects associated
with b adrenergic receptor activation.
o Long-acting β adrenergic receptor agonists relax airway smooth muscle and
cause bronchodilation by the same mechanisms as short-duration agonists. o This is of particular concern in patients with poorly controlled asthma, in
whom there may be excessive and inappropriate reliance on symptomatic
treatment with short-acting b receptor agonists.
o Chronic treatment with a receptor agonist often leads to receptor
desensitization and a diminution of effect.

o The rate and degree of β2 adrenergic receptor desensitization depend on Oral Therapy with b Adrenergic Receptor Agonists
the cell type.

o For example, the β2 receptors on human bronchial smooth muscle are


relatively resistant to desensitization, whereas receptors on mast cells and o The use of orally administered β adrenergic agonists for bronchodilation has
lymphocytes are desensitized rapidly following agonist exposure. not gained wide acceptance largely because of the greater risk of side
effects, especially tremulousness, muscle cramps, cardiac
o This may help to explain why there is little evidence that these drugs are tachyarrhythmias, and metabolic disturbances.
effective in inhibiting airway inflammation associated with asthma.
o There are two primary situations in which oral β adrenergic agonists are
o Several studies have evaluated the effect of adding a long-acting β2 used.
adrenergic agonist to inhaled glucocorticoid treatment in patients with
persistent asthma.
o First, brief courses of oral therapy (albuterol or metaproterenol syrups) are
well tolerated and effective in young children (<5 years old) who cannot
o Combinations examined include salmeterol-fluticasone and formoterol-
manipulate metered-dose inhalers yet have occasional wheezing with viral
budesonide.
upper respiratory infections.

o The data suggest that adding a long-acting b2 adrenergic agonist to the o Second, in some patients with severe asthma exacerbations, any aerosol,
inhaled steroid regimen is more effective than doubling the steroid dose. whether delivered via a metered-dose inhaler or a nebulizer, can worsen
cough and bronchospasm owing to local irritation.
o Thus, current management guidelines for asthma recommend that long-
acting β2 adrenergic agonists be added if symptoms persist in patients on o In this setting, oral therapy with β2 adrenergic agonists (e.g., albuterol,
low or medium doses of inhaled steroids. metaproterenol, or terbutaline tablets) can be effective. However, the
frequency of adverse systemic side effects with orally administered agents
is higher in adults than in children.
o Because chronic treatment with long-lasting inhaled β2 adrenergic agonists
does not decrease airway inflammation significantly, most experts do not
use them as sole agents for asthma treatment. o Even though stimulation of b adrenergic receptors inhibits the release of
inflammatory mediators from mast cells, long-term administration of β2-
agonists, either orally or by inhalation, does not reduce bronchial
o A convenient fixed-dosage combination of salmeterol and fluticasone
hyperresponsiveness.
(ADVAIR) is marketed in the United States, and a fixed dosage combination
of formoterol and budesonide is available in other countries.
19

o Thus, other approaches are preferred for the treatment of chronic o Suffice it to say that the mechanism of action of cromolyn and nedocromil in
asthma is not known.
symptoms. As discussed below under "Pharmacogenetics," polymorphisms
of the b2 adrenergic receptor may correlate with response to therapy and
adverse effects with b-agonists.

Pharmacokinetics

Cromolyn Sodium and Nedocromil Sodium

o For asthma, cromolyn is given by inhalation using either solutions (delivered


by aerosol spray or nebulizer) or, in some countries but not in the United
History and Chemistry States, powdered drug (mixed with lactose and delivered by a special
turboinhaler).

o The pharmacological effects result from the topical deposition of the drug in
the lung, since only about 1% of an oral dose of cromolyn is absorbed.
o Cromolyn was synthesized in 1965 in an attempt to improve on the
bronchodilator activity of khellin.
o Once absorbed, the drug is excreted unchanged in the urine and bile in
about equal proportions.
o This chromone, derived from the plant Ammi visnaga, had been used by the
ancient Egyptians for its spasmolytic properties.
o Peak concentrations in plasma occur within 15 minutes of inhalation, and
excretion begins after some delay such that the biological half-life ranges
o Although devoid of the bronchodilating effect of the parent compound, from 45 to 100 minutes.
cromolyn was found to inhibit antigen-induced bronchospasm as well as the
release of histamine and other autacoids from sensitized rat mast cells.
o The terminal half-time of elimination following intravenous administration is
about 20 minutes.
o Cromolyn has been used in the United States for the treatment of asthma
since 1973.
o The pharmacokinetic properties of cromolyn have been reviewed.
o The initial clinical results were disappointing, in retrospect largely owing to a
misplaced hope that cromolyn would reduce or eliminate the need for
systemic glucocorticoids in the treatment of patients with relatively severe
asthma. Toxicity

o However, its therapeutic role has been reevaluated in recent years, and
cromolyn has emerged as one of the first-line agents in the treatment of
mild to moderate asthma.
o Cromolyn and nedocromil generally are well tolerated by patients.

o Nedocromil, a compound with similar chemical and biological properties,


o Adverse reactions are infrequent and minor and include bronchospasm,
became available in 1992.
cough or wheezing, laryngeal edema, joint swelling and pain, angioedema,
headache, rash, and nausea. Such reactions have been reported at a
frequency of less than 1 in 10,000 patients.

Mechanism of Action o Very rare instances of anaphylaxis also have been documented.

o Nedocromil and cromolyn can cause a bad taste.

o Cromolyn and nedocromil have a variety of activities that may relate to their
therapeutic efficacy in asthma.
Use in Asthma
o These include inhibiting mediator release from bronchial mast cells;
reversing increased functional activation in leukocytes obtained from the
blood of asthmatic patients; suppressing the activating effects of
chemotactic peptides on human neutrophils, eosinophils, and monocytes; o The main use of cromolyn (INTAL) and nedocromil (TILADE) is to prevent
inhibiting parasympathetic and cough reflexes and inhibiting leukocyte asthmatic attacks in individuals with mild to moderate bronchial asthma.
trafficking in asthmatic airways.
o These agents are ineffective in treating ongoing bronchoconstriction.
20

o When inhaled several times daily, cromolyn inhibits both the immediate and o The benefits reflect local action rather than systemic absorption; cromolyn
the late asthmatic responses to antigenic challenge or to exercise. is poorly absorbed, and only the gastrointestinal symptoms are improved in
the treated patients.
o With regular use for more than 2 to 3 months, bronchial hyperreactivity is
reduced, as measured by response to challenge with histamine or
Methacholine.
Theophylline
o Nedocromil generally is more effective than cromolyn in animal models and
human beings (Brogden and Sorkin, 1993). o Theophylline, a methylxanthine, is among the least expensive drugs used to
treat asthma, and consequently, it remains a commonly used drug for this
indication in many countries.
o Nedocromil is approved for use in asthmatic patients 12 years of age and
older; cromolyn is approved for all ages.
o In industrialized countries, the advent of inhaled glucocorticoids, β
o Cromolyn and nedocromil generally are less effective than inhaled adrenergic receptor agonists, and leukotriene-modifying drugs has
glucocorticoids in controlling asthma. diminished theophylline use significantly, and it has been relegated to a
third- or fourth-line treatment in patients whose asthma is otherwise difficult
to control.
o Cromolyn (2 mg inhaled four times daily) was less effective than 200 mg
twice daily of beclomethasone or 4 mg four times daily of nedocromil.

o Although necrodomil was roughly comparable with 200 mg beclomethasone Source and History
inhaled twice daily, nedocromil was not as effective in controlling
symptoms, reducing bronchodilator use, or improving bronchial o Theophylline, caffeine, and theobromine are three closely related plant
hyperreactivity.
alkaloids that are imbibed widely.

o In a second study, 4 mg nedocromil four times daily was as effective as 100 o At least half the population of the world consumes tea (containing caffeine
mg beclomethasone four times daily. and small amounts of theophylline and theobromine) prepared from the
leaves of Thea sinensis, a bush native to southern China and now cultivated
extensively in other countries.
o In a thorough review concluded that nedocromil is useful in patients with
mild to moderate asthma as added therapy, as an alternative to regularly
administered oral and inhaled b adrenergic agonists and oral o Cocoa and chocolate, from the seeds of Theobroma cacao, contain
methylxanthines, and possibly as an alternative to low-dose inhaled theobromine and some caffeine.
glucocorticoids.
o Coffee, the most popular source of caffeine in the American diet, is
o The addition of cromolyn to inhaled glucocorticoid therapy yields no extracted from the fruit of Coffea arabica and related species. Cola-flavored
additional benefit in moderately severe asthma. drinks usually contain considerable amounts of caffeine in part because of
their content of extracts of the nuts of Cola acuminata and in part because
caffeine is added during their production.
o Nedocromil may allow a reduction of steroids in patients receiving high
doses of inhaled steroids. o The basis for the popularity of all caffeine-containing beverages is the
ancient belief that they have stimulant and antisoporific actions that elevate
o These studies were short term; whether or not long-term reduction in mood, decrease fatigue, and increase capacity for work.
steroid dose is possible remains to be determined.
o Classical pharmacological studies principally of caffeine confirmed this belief
o In one study, the addition of nedocromil 4 mg four times daily for 8 weeks to and revealed that methylxanthines also possess other important
pharmacological properties.
high-dose inhaled glucocorticoid treatment resulted in modest
improvements in patients with moderately severe asthma.
o These properties were exploited in a variety of therapeutic applications, in
many of which caffeine now has been replaced by more effective agents.
o Because of its limited efficacy, the use of cromolyn for the treatment of
asthma in the United States is decreasing.
o However, in recent years, there has been a resurgence of interest in the
natural methylxanthines and their synthetic derivatives principally as a
o In patients with systemic mastocytosis who have gastrointestinal symptoms result of increased knowledge of their cellular basis of action.
owing to an excessive number of mast cells in the gastrointestinal mucosa,
an oral preparation of cromolyn (GASTROCROM) is effective in reducing
symptoms.
Mechanism of Action
21

o Therefore, inhibition of this function of adenosine may contribute to


theophylline-induced bronchodilation in some asthmatic subjects. Inhibition
o Theophylline inhibits cyclic nucleotide PDEs, thereby preventing breakdown of PDE4 and PDE5 effectively relaxes human isolated bronchial smooth
of cyclic AMP and cyclic GMP to 5¢-AMP and 5¢-GMP, respectively. muscle.

o Inhibition of PDEs will lead to an accumulation of cyclic AMP and cyclic GMP, o It thus seems likely that inhibition of PDEs also contributes to the
thereby increasing signal transduction through these pathways. The cyclic bronchodilating effect of theophylline.
nucleotide PDEs are members of a superfamily of genetically distinct
enzymes. o Studies with the related methylxanthine enprofylline (3-propylxanthine),
which has been investigated extensively for treatment of asthma in Europe,
o Theophylline and related methylxanthines are relatively nonselective in the also support a mechanistic role for PDE inhibition in the bronchodilator
PDE subtypes they inhibit. actions of theophylline.

o Cyclic nucleotide production is regulated by endogenous receptor-ligand o Enprofylline is more potent than theophylline as a bronchodilator but is
interactions leading to activation of adenylyl cyclase and guanylyl cyclase. much less potent in inhibiting most types of adenosine receptors.

o Inhibitors of PDEs therefore can be thought of as drugs that enhance the o The latter point, however, must be interpreted cautiously.
activity of endogenous autacoids, hormones, and neurotransmitters that
signal via cyclic nucleotide messengers.
o Activation of the A2B subtype of adenosine receptor causes several
o This may explain why the in vivo potency often exceeds that observed in proinflammatory effects, and both theophylline and enprofylline are potent
vitro. competitive antagonists of A2B adenosine receptors.

o Theophylline is a competitive antagonist at adenosine receptors. o Theophylline also inhibits synthesis and secretion of inflammatory mediators
from numerous cell types, including mast cells and basophils.
o Adenosine can act as an autacoid and transmitter with myriad biological
actions. o This effect of theophylline likely is due to PDE inhibition and can be
mimicked in large part with drugs that selectively inhibit PDE4 isozyme.
o Of particular relevance to asthma are the observations that adenosine can
cause bronchoconstriction in asthmatics and potentiate immunologically o At therapeutic concentrations, the antiinflammatory effect of theophylline
induced mediator release from human lung mast cells. may be more relevant to the drug's therapeutic actions than direct
bronchodilation, but this remains unproven.
o Inhibition of the actions of adenosine therefore also must be considered
when attempting to explain the mechanism of action of theophylline.

o Consistent with an important role of PDE4 in obstructive lung disease,


o Theophylline also may owe part of its antiinflammatory action to its ability selective PDE4 inhibitors have been evaluated in clinical trials for the
to activate histone deacetylases in the nucleus. treatment of asthma and chronic obstructive pulmonary disease (COPD).

o In theory, the deacetylation of histones could decrease the transcription of o In one study, cilomilast (ARIFLO; 15 mg twice daily for 10 weeks) decreased
several proinflammatory genes and potentiate the effect of corticosteroids. inflammatory cell infiltration significantly in bronchial biopsies of patients
with COPD.

o Further studies are needed to define the role of PDE4 inhibitors in asthma
Pulmonary System and COPD, but these drugs are promising candidates for new approaches to
asthma therapy.

o Theophylline effectively relaxes airway smooth muscle; this bronchodilation


likely contributes to its acute therapeutic efficacy in asthma. Absorption, Fate, and Excretion

o Both adenosine receptor antagonism and PDE inhibition are likely involved
in the bronchodilating effect of theophylline. Adenosine does not contract
isolated human bronchial smooth muscle directly, but when it is inhaled, it o The methylxanthines are absorbed readily after oral or parenteral
acts as a potent bronchoconstrictor in asthmatic subjects. administration.

o Absorption from rectal suppositories is slow and unreliable.


22

o Theophylline administered in liquids or uncoated tablets is absorbed rapidly o Caffeine has a half-life in plasma of 3 to 7 hours; this increases by about
and completely. twofold in women during the later stages of pregnancy or with long-term
use of oral contraceptives.
o Absorption also is complete from some, but not all, sustained-release
o In premature infants, the rate of elimination of both methylxanthines is
formulations.
quite slow; the average half-life for caffeine is more than 50 hours, whereas
the mean values for theophylline obtained in various studies range between
o In the absence of food, solutions or uncoated tablets of theophylline 20 and 36 hours.
produce maximal concentrations in plasma within 2 hours; caffeine is
absorbed more rapidly, and maximal plasma concentrations are achieved
within 1 hour. o However, the latter values include the extensive conversion of theophylline
to caffeine in these infants.
o Numerous sustained-release preparations of theophylline are available,
designed for dosing intervals of 8, 12, or 24 hours. o There is marked individual variation in the rate of elimination of theophylline
owing to both genetic and environmental factors; fourfold differences are
o There is marked interpatient variability with regard to the rate and extent of not uncommon.
absorption and especially the effect of food and time of administration on
these parameters. o The half-life averages about 3.5 hours in young children, whereas values of
8 or 9 hours are more typical in adults.
o Thus it is necessary to calibrate a given preparation in a given patient and
to avoid substituting one apparently similar product for another. o In most patients the drug obeys first-order elimination kinetics within the
therapeutic range.
o Food ordinarily slows the rate of absorption of theophylline but does not
limit its extent. o At higher concentrations, zero-order kinetics become evident because of
saturation of metabolic enzymes, prolonging the decline of theophylline
o With sustained-release preparations, food may decrease the bioavailability concentrations to nontoxic levels.
of theophylline with some products but may increase it with others.
o Methylxanthine metabolism also is influenced by other diseases or drugs.
o Recumbency or sleep also may reduce the rate or extent of absorption to an
important degree. o Hepatic cirrhosis, congestive heart failure, and acute pulmonary edema all
increase the half-life, as does concurrent therapy with cimetidine or
o These factors make it difficult to maintain relatively constant concentrations erythromycin.
of theophylline in plasma throughout the day. Concentrations required to
alleviate asthmatic symptoms do not remain constant, and the emphasis o In contrast, clearance is increased twofold by phenytoin or barbiturates,
has shifted toward designing dosing regimens that ensure peak whereas cigarette smoking, rifampin, and oral contraceptives induce smaller
concentrations in the early morning hours, when symptoms frequently changes.
worsen.
o Although scarcely detectable in adults, the conversion of theophylline to
o Methylxanthines are distributed into all body compartments; they cross the
caffeine is significant in preterm infants.
placenta and pass into breast milk.
o In this setting, caffeine accumulates in plasma to a concentration
o The apparent volumes of distribution for caffeine and theophylline are
approximately 25% that of theophylline.
between 0.4 and 0.6 L/kg.
o About 50% of the theophylline administered to such infants appears in the
o These values are considerably higher in premature infants.
urine unchanged; the excretion of 1,3-dimethyluric acid, 1-methyluric acid,
and caffeine derived from theophylline accounts for nearly all the
o Theophylline is bound to plasma proteins to a greater extent than is remainder.
caffeine, and the fraction bound declines as the concentration of
methylxanthine increases.

o At therapeutic concentrations, the protein binding of theophylline averages Toxicology


about 60%, but it is decreased to about 40% in newborn infants and in
adults with hepatic cirrhosis.

o Methylxanthines are eliminated primarily by metabolism in the liver. Less


o Fatal intoxications with theophylline have been much more frequent than
than 15% and 5% of administered theophylline and caffeine, respectively, is
recovered in the urine unchanged. with caffeine.
23

o Rapid intravenous administration of therapeutic doses of aminophylline (500 o Even subjects with a history of light to moderate use of caffeine experience
mg) sometimes results in sudden death that is probably due to cardiac
tension, anxiety, and dysphoria after ingesting 400 mg or more of the drug.
arrhythmias, and the drug should be injected slowly over 20 to 40 minutes
to avoid severe toxic symptoms.
o In infants who have received treatment for apnea of prematurity (see
o These include headache, palpitation, dizziness, nausea, hypotension, and below), theophylline may produce persistent changes in sleep-wake
precordial pain. Additional symptoms of toxicity include tachycardia, severe patterns, but long-term effects on behavior or cognitive development have
restlessness, agitation, and emesis; these effects are associated with yet to be identified.
plasma concentrations of more than 20 mg/ml.
o There has been mounting concern that the treatment of asthmatic children
o Focal and generalized seizures also can occur, sometimes without prior with theophylline may produce depression, hyperactivity, or other
signs of toxicity. behavioral toxicity.

o Most toxicity results from repeated administration of theophylline by either o However, a study of academic performance of children treated or not with
oral or parenteral routes. theophylline showed equal academic performance in asthmatic and
nonasthmatic subjects.
o Although convulsions and death have occurred at plasma concentrations as
low as 25 mg/ml, seizures are relatively rare at concentrations below 40 o Even though it is difficult to factor out specific effects of theophylline from
mg/ml. those caused by the illness or by other features of the treatment regimen,
many investigators believe that most children will benefit from the use of
o Patients with long-term theophylline intoxication appear to be much more alternative means of controlling their symptoms.
prone to seizures than those who experience short-term overdoses.

o Such a dependence on the history of exposure to theophylline may


contribute to the difficulty in establishing a relationship between the Use in Asthma
severity of toxic symptoms and the concentration of the drug in plasma
(Aitken and Martin, 1987; Bertino and Walker, 1987), and greater caution is
advised in treating intoxicated patients who have been ingesting
theophylline regularly (see Paloucek and Rodvold, 1988). o Theophylline has proven efficacy as a bronchodilator in asthma and formerly
was considered first-line therapy.
o Treatment may include prophylactic administration of diazepam, perhaps in
combination with phenytoin or phenobarbital; phenytoin also may be a
useful alternative to lidocaine in the treatment of serious ventricular o It now is relegated to a far less prominent role primarily because of the
arrhythmias. modest benefits it affords, its narrow therapeutic window, and the required
monitoring of drug levels.

o Once seizures appear, they may be refractory to anticonvulsant therapy,


sometimes necessitating general anesthesia or other measures used to o Nocturnal asthma can be improved with slow-release theophylline
treat status epilepticus. preparations but other interventions such as inhaled glucocorticoids or
salmeterol probably are more effective.
o The widespread use of sustained-release preparations of theophylline has
renewed emphasis on measures to prevent continued absorption, o Therapy usually is initiated by the administration of 12 to 16 mg/kg per day
particularly the use of oral activated charcoal and sorbitol as a cathartic of theophylline (calculated as the free base) up to a maximum of 400
(Goldberg et al., 1987). mg/day for at least 3 days.

o However, when plasma concentrations exceed 100 mg/ml, invasive o Children younger than 1 year of age require considerably less; the dose in
measures usually are required, especially hemoperfusion through charcoal milligrams per kilogram per day may be calculated as 0.2 ´ (age in weeks) +
cartridges. 5.

o Starting with these low doses minimizes the early side effects of nausea,
vomiting, nervousness, and insomnia that often subside with continued
Behavioral Toxicity therapy and virtually eliminates the possibility of exceeding plasma
concentrations of 20 mg/ml in patients older than age 1 year who do not
have compromised hepatic or cardiac function.

o Thereafter, the dosage is increased in two successive stages to between 16


o Moderate doses of caffeine can provoke intense feelings of anxiety, fear, or
and 20 and, subsequently, 18 and 22 mg/kg per day (up to a maximum of
panic in some individuals. 800 mg/day) depending on the age and clinical response of the patient and
allowing at least 3 days between adjustments.
24

o The plasma concentration of theophylline is determined before a further o A large multicenter study showed that the asthmatic subjects with the worst
adjustment in dosage is made.
initial lung function benefited most from combination therapy.

o Although extended-release preparations of theophylline usually allow twice-


o Thus the combination of a selective b2 adrenergic agonist and ipratropium
daily dosing, variations in the rate and extent of absorption of such
should be considered in acute treatment of severe asthma exacerbations.
preparations require individualized calibration of dosing regimens for each
patient and preparation.
o Ipratropium is available in metered-dose inhalers and as a nebulizer
solution.
Anticholinergic Agents

o A metered-dose inhaler containing a mixture of ipratropium and albuterol


(COMBIVENT) also is available in the United States.
o There is a long history of the use of anticholinergic agents in the treatment
o In Europe, metered-dose inhalers containing a mixture of ipratropium and
of asthma.
fenoterol are available (DUOVENT, BERODUAL).
o With the advent of inhaled b adrenergic agonists, use of anticholinergic
agents declined. o Recently, tiotropium (SPIRIVA), a structural analogue of ipratropium, has
been approved for the treatment of COPD and emphysema. Like
o Renewed interest in anticholinergic agents paralleled the realization that ipratropium, tiotropium has high affinity for all muscarinic receptor
parasympathetic pathways are important in bronchospasm in some subtypes, but it dissociates from the receptors much more slowly that
asthmatics and the availability of ipratropium bromide (ATROVENT), a ipratropium.
quaternary muscarinic receptor antagonist that has better pharmacological
properties than prior drugs. o In particular, binding and functional studies indicate that tiotropium
dissociates from muscarinic M3 receptors more slowly than from muscarinic
M2 receptors.
o A particularly good response to ipratropium may be seen in the subgroup of
asthmatic patients who experience psychogenic exacerbations.
o The high affinity of tiotropium for muscarinic receptors, combined with its
very slow dissociation rate, permits once-daily dosing.
o The cholinergic receptor subtype responsible for bronchial smooth muscle
contraction is the muscarinic M3 receptor.
o The slow dissociation rate also provides a theoretical advantage in that it
limits the capacity of large concentrations of the endogenous agonist
o Although iprotropium and related compounds block all five muscarinic acetylcholine to surmount the receptor blockade.
receptor subtypes with similar affinity, it is likely that M3-receptor
antagonism alone accounts for the bronchodilating effect.
o Tiotropium is provided as a capsule containing a dry-powder formulation
that is intended only for oral inhalation using the HandiHaler inhalation
o The bronchodilation produced by ipratropium in asthmatic subjects develops device.
more slowly and usually is less intense than that produced by adrenergic
agonists.

o Some asthmatic patients may experience a useful response lasting up to 6


Pharmacogenetics and Variability of Response to Asthma Medications
hours.

o The variability in the response of asthmatic subjects to ipratropium


presumably reflects differences in the strength of parasympathetic tone and
in the degree to which reflex activation of cholinergic pathways participates o There is a wide degree of interindividual variability in the response of
in generating symptoms in individual patients. Hence the utility of asthmatic subjects to pharmacotherapy.
ipratropium must be assessed on an individual basis by a therapeutic trial.
o For example, some individuals benefit dramatically from treatment with
leukotriene modifiers, whereas many others are essentially resistant to
o The pharmacological properties and therapeutic uses of ipratropium have these treatments.
been reviewed.
o Although more rare, the "steroid resistant" asthmatic receives relatively
o Combined treatment with ipratropium and b2 adrenergic agonists results in little benefit from treatment with inhaled corticosteroids.
slightly greater and more prolonged bronchodilation than with either agent
alone in baseline asthma. o At present, it is impossible to predict who will benefit the most from a given
treatment.
o In acute bronchoconstriction, the combination of a b2 adrenergic agonist
o This unpredictability of response largely reflects our limited understanding
and ipratropium is more effective than either agent alone and more
of the underlying pathophysiology of asthma.
effective than simply giving more b2 adrenergic agonist.
25

o In addition, some component of this variability likely is explained by specific (Goodman and Gilman’s Pharmacological Basis of Therapeutics 11th Edition)
pharmacogenetic factors.

o Three functionally relevant mutations have been found in the promotor Bronchodilator Therapies
region of the gene encoding 5-lipoxygenase.

o These mutations lead to a small decrease in promotor activity and


leukotriene synthesis. o Bronchodilators act primarily on airway smooth muscle to reverse the
bronchoconstriction of asthma.
o About 35% of the population has at least one of these mutations in at least
one allele. o This gives rapid relief of symptoms but has little or no effect on the
underlying inflammatory process.
o In one placebo-controlled clinical trial it was noted that individuals with
mutations at both alleles responded less well to treatment with a 5- o Thus, bronchodilators are not sufficient to control asthma in patients with
lipoxygenase inhibitor than did those with two wild-type alleles. persistent symptoms.

o A variant of the b2 adrenergic receptor in which glycine replaces arginine at o There are three classes of bronchodilator in current use: 2-adrenergic
position 16 (Gly 16) shows an increased rate of down-regulation in response agonists, anticholinergics, and theophylline; of these, 2-agonists are by far
to agonist exposure. the most effective.

o This polymorphism occurs with equal frequency in asthmatic and


nonasthmatic populations.
β2-Agonists
o There is some evidence that asthmatics who are homozygous for Gly 16
receptors are less responsive to b-agonist therapy than wild-type controls
(Martinez et al., 1997; Tan et al., 1997). However, this was not noted in all
studies (Hancox et al., 1998).
o β2-Agonists activate 2-adrenergic receptors, which are widely expressed in
the airways.

o There are several relatively rare genetic variants in the gene encoding the o β2-Receptors are coupled through a stimulatory G protein to adenylyl
glucocorticoid receptor. cyclase, resulting in increased intracellular cyclic AMP, which relaxes
smooth-muscle cells and inhibits certain inflammatory cells.
o Some of these variants produce receptors with a diminished affinity for
glucocorticoid agonists.

o There is no evidence, however, that any glucocorticoid-receptor Mode of Action


polymorphism is strongly associated with clinically relevant steroid
resistance.

o Consequently, attention is shifting away from polymorphisms in the receptor o The primary action of β2-agonists is to relax airway smooth-muscle cells of
per se toward the numerous other candidate genes in the functional all airways, where they act as functional antagonists, reversing and
pathway of glucocorticoids as potential explanations for the preventing contraction of airway smooth-muscle cells by all known
unresponsiveness of some individuals to steroid therapy. bronchoconstrictors.

o The treatment of asthma is straightforward and the majority of patients are o This generalized action is likely to account for their great efficacy as
now managed by internists with effective and safe therapies. bronchodilators in asthma.

o Most emphasis has been placed on drug therapy, but several


nonpharmacologic approaches have also been used.
o There are also additional non-bronchodilator effects that may be clinically
useful, including inhibition of mast cell mediator release, reduction in
plasma exudation, and inhibition of sensory nerve activation.
o The main drugs for asthma can be divided into bronchodilators, which give
rapid relief of symptoms mainly through relaxation of airway smooth
muscle, and controllers, which inhibit the underlying inflammatory process. o Inflammatory cells express small numbers of β2-receptors, but these are
rapidly downregulated with β2-agonist activation so that, in contrast to
corticosteroids, there are no effects on inflammatory cells in the airways
and there is no reduction in AHR.
26

o Tolerance is a potential problem with any agonist given chronically, but


while there is downregulation of β2-receptors, this does not reduce the
Clinical Use bronchodilator response as there is a large receptor reserve in airway
smooth-muscle cells.

o By contrast, mast cells become rapidly tolerant, but their tolerance may be
o β2-Agonists are usually given by inhalation to reduce side effects. prevented by concomitant administration of ICS.

o Short-acting β2-agonists (SABAs), such as albuterol and terbutaline, have a


duration of action of 3-6 hours. Safety

o They have a rapid onset of bronchodilation and are therefore used as


needed for symptom relief. Increased use of SABAs indicates that asthma is
not controlled. o The safety of β2-agonists has been an important issue.

o They are also useful in preventing EIA if taken prior to exercise.


o There is an association between asthma mortality and the amount of SABA
o SABAs are used in high doses by nebulizer or via a metered dose inhaler used, but careful analysis demonstrates that the increased use of rescue
with a spacer. SABAs reflects poor asthma control, which is a risk factor for asthma death.

o The slight excess in mortality that has been associated with the use of
o Long-acting β2-agonists (LABAs) include salmeterol and formoterol, both of
LABAs is related to the lack of use of concomitant ICS, as the LABA therapy
which have a duration of action over 12 hours and are given twice daily. does not deal with the underlying inflammation.

o LABAs have replaced the regular use of SABAs, but LABAs should not be o This highlights the importance of always using an ICS when LABAs are
given in the absence of ICS therapy as they do not control the underlying given, which is most conveniently achieved by using a combination inhaler.
inflammation.

o They do, however, improve asthma control and reduce exacerbations when
added to ICS, which allows asthma to be controlled at lower doses of Anti-Cholinergics
corticosteroids.

o This observation has led to the widespread use of fixed combination inhalers
that contain a corticosteroid and a LABA, which have proved to be highly
effective in the control of asthma.
o Muscarinic receptor antagonists, such as ipratropium bromide, prevent
cholinergic nerve–induced bronchoconstriction and mucus secretion.
Side Effects
o They are much less effective than β2-agonists in asthma therapy as they
inhibit only the cholinergic reflex component of bronchoconstriction,
whereas β2-agonists prevent all bronchoconstrictor mechanisms.
o Adverse effects are not usually a problem with β2-agonists when given by
inhalation. o Anticholinergics are therefore only used as an additional bronchodilator in
patients with asthma that is not controlled on other inhaled medications.
o The most common side effects are muscle tremor and palpitations, which
are seen more commonly in elderly patients. o High doses may be given by nebulizer in treating acute severe asthma but
should only be given following β2-agonists since they have a slower onset of
o There is a small fall in plasma potassium due to increased uptake by bronchodilation.
skeletal muscle cells, but this effect does not usually cause a clinical
problem. o Side effects are not usually a problem as there is little or no systemic
absorption.

o The most common side effect is dry mouth; in elderly patients, urinary
Tolerance retention and glaucoma may also be observed.
27

Theophylline o Oral theophylline is well absorbed and is largely inactivated in the liver.

o Side effects are related to plasma concentrations; measurement of plasma


theophylline may be useful in determining the correct dose.
o Theophylline was widely prescribed as an oral bronchodilator several years
ago, especially as it was inexpensive. o The most common side effects—nausea, vomiting, and headaches—are due
to phosphodiesterase inhibition.
o It has now fallen out of favor as side effects are common and inhaled β2-
agonists are much more effective as bronchodilators. o Diuresis and palpitations may also occur, and at high concentrations cardiac
arrhythmias, epileptic seizures, and death may occur due to adenosine
receptor antagonism.
o The bronchodilator effect is due to inhibition of phosphodiesterases in
airway smooth-muscle cells, which increases cyclic AMP, but doses required o Theophylline side effects are related to plasma concentration and are rarely
for bronchodilation commonly cause side effects that are mediated mainly observed at plasma concentrations below 10 mg/L. Theophylline is
by phosphodiesterase inhibition. metabolized by CYP450 in the liver, and thus plasma concentrations may be
elevated by drugs that block CYP450, such as erythromycin and allopurinol.
o There is increasing evidence that theophylline at lower doses has anti-
inflammatory effects, and these are likely to be mediated through different o Other drugs may also reduce clearance by other mechanisms leading to
molecular mechanisms. increased plasma concentrations.

o There is evidence that theophylline activates the key nuclear enzyme


histone deacetylase-2, which is a critical mechanism for switching off
activated inflammatory genes. (Harrison’s Principles of Internal Medicine 17th Edition)

Clinical Use 9. What is the role of steroids is asthma?

o Oral theophylline is usually given as a slow-release preparation once or • Systemic glucocorticoids long have been used to treat severe chronic asthma or
twice daily as this gives more stable plasma concentrations than normal severe acute exacerbations of asthma.
theophylline tablets.
• The development of aerosol formulations significantly improved the safety of
o It may be used as an additional bronchodilator in patients with severe
glucocorticoid treatment, allowing it to be used for moderate asthma.
asthma when plasma concentrations of 10–20 mg/L are required, although
these concentrations are often associated with side effects.
• Asthmatic subjects who require inhaled b2 adrenergic agonists four or more times
weekly are viewed as candidates for inhaled glucocorticoids.
o Low doses of theophylline, giving plasma concentrations of 5–10 mg/L, have
additive effects to ICSs and are particularly useful in patients with severe
asthma.

o Indeed, withdrawal of theophylline from these patients may result in marked Mechanism of Glucocorticoid Action in Asthma
deterioration in asthma control.

o The drug is well tolerated at low doses.


• Asthma is associated with airway inflammation, airway hyperreactivity, and acute
o Intravenous aminophylline (a soluble salt of theophylline) was used for the bronchoconstriction.
treatment of severe asthma but has now been largely supplemented by
inhaled SABAs, which are more effective and have fewer side effects. • Glucocorticoids do not directly relax airway smooth muscle and thus have little effect
on acute bronchoconstriction.
o Aminophylline is occasionally used (via slow intravenous infusion) in
patients with severe exacerbations that are refractory to high-dose SABAs. • By contrast, these agents are singularly effective in inhibiting airway inflammation.

• Very few mechanisms of inflammation escape the inhibitory effects of these drugs.

Side Effects • The antiinflammatory effects of glucocorticoids in asthma include modulation of


cytokine and chemokine production; inhibition of eicosanoid synthesis; marked
28

inhibition of accumulation of basophils, eosinophils, and other leukocytes in lung  Important variables that influence the effective dose include the severity of
tissue; and decreased vascular permeability. disease, the particular steroid used, and the device used for drug delivery, which
determines the actual quantity of drug delivered to the lungs.
• The profound and generalized antiinflammatory action of this class of drugs explains
why they are currently the most effective drugs used in the treatment of asthma.  When determining the optimal dose, keep in mind that maximal improvement in
lung function may not occur until after several weeks of treatment.

 Asthmatic patients maintained on inhaled glucocorticoids show improvement in


(Goodman and Gilman’s The Pharmacologic Basis of Therapeutics 11th Edition) symptoms and lowered requirements for "rescue" with b2 adrenergic agonists.

 Beneficial effects may be seen within 1 week; however, improvement, in terms of


reduced bronchial hyperreactivity, may continue for several months.
9.1 What are the routes of administration of steroids?
 Inhaled glucocorticoids are superior to inhaled β2-agonists for symptom control.

Inhaled Glucocorticoids  In one study, improved bronchial hyperreactivity persisted throughout 2 years of
treatment with inhaled budesonide (600 mg twice daily), and most patients were
able to reduce their dose to 200 mg twice daily thereafter without worsened
symptoms.
 Although glucocorticoids are very effective in controlling asthma, treatment with
systemic glucocorticoids comes at the cost of considerable adverse effects.  Complete discontinuation of budesonide generally was associated with increased
bronchial hyperreactivity and worsened symptoms, although symptoms did not
 A major advance in asthma therapy was the development of inhaled worsen in a third of patients.
glucocorticoids that targeted the drug directly to the relevant site of
inflammation.  Thus a trial discontinuation of inhaled glucocorticoids should be considered in
patients who are extremely well controlled.
 These formulations greatly enhance the therapeutic index of the drugs,
substantially diminishing the number and degree of side effects without
sacrificing clinical utility.
Systemic Glucocorticoids
 There are currently five glucocorticoids available in the United States for
inhalation therapy: beclomethasone dipropionate (BECLOVENT, VANCERIL),
triamcinolone acetonide (AZMACORT), flunisolide (AEROBID), budesonide
(PULMICORT), and fluticasone propionate (FLOVENT). While they differ markedly  Systemic glucocorticoids are used for acute asthma exacerbations and chronic
in their affinities for the glucocorticoid receptor, with fluticasone and budesonide severe asthma.
having much higher affinities than beclomethasone, they are all effective in
controlling asthma at the appropriate doses.
 Substantial doses of glucocorticoids (e.g., 40 to 60 mg prednisone or equivalent
daily for 5 days; 1 to 2 mg/kg per day for children) often are used to treat acute
 Few studies have directly assessed the relative therapeutic index of the various exacerbations of asthma.
formulations of inhaled steroids in the treatment of asthma, but available data
indicate that none has a clearly superior therapeutic index.
 Although an additional week at somewhat reduced dosage may be required, the
steroids can be withdrawn abruptly once control of the symptoms by other
 Inhaled glucocorticoids are used prophylactically to control asthma rather than medications has been restored; any suppression of adrenal function dissipates
acutely to reverse asthma symptoms. within 1 to 2 weeks.

 As with all prophylactic therapies, compliance is a significant concern. Issues  More protracted bouts of severe asthma may require longer treatment and
relating to drug compliance, therefore, become relevant when choosing among slower tapering of the dose to avoid exacerbating asthma symptoms and
the various steroid formulations. suppressing pituitary/adrenal function.

 The newer, highly potent drugs (e.g., fluticasone, flunisolide, and budesonide)  Previously, alternate-day therapy with oral prednisone was employed commonly
can be effective with as little as one or two puffs administered twice or even once in persistent asthma. Now most patients with asthma are better treated with
daily. inhaled glucocorticoids.

 This more convenient dosage regimen may be preferred by patients, providing


improved compliance and better asthma control.
(Goodman and Gilman’s The Pharmacologic Basis of Therapeutics 11th Edition)
 The appropriate dose of steroid must be determined empirically.
29

 Corticosteroids compete with each other for binding sites on CBG. CBG has
relatively high affinity for cortisol and most of its synthetic congeners and low
9.2 Give the pharmacodynamic and pharmacokinetic properties of steroids. affinity for aldosterone and glucuronide-conjugated steroid metabolites; thus,
greater percentages of these latter steroids are found in the free form.

 A special state of physiological hypercorticism occurs during pregnancy.


Absorption
 The elevated circulating estrogen levels induce CBG production, and CBG and
total plasma cortisol increase severalfold.

 Hydrocortisone and numerous congeners, including the synthetic analogs, are  The physiological significance of these changes remains to be established.
orally effective.
 All of the biologically active adrenocortical steroids and their synthetic congeners
 Certain water-soluble esters of hydrocortisone and its synthetic congeners are have a double bond in the 4,5 position and a ketone group at C 3.
administered intravenously to achieve high concentrations of drug rapidly in
body fluids.  As a general rule, the metabolism of steroid hormones involves sequential
additions of oxygen or hydrogen atoms, followed by conjugation to form water-
 More prolonged effects are obtained by intramuscular injection of suspensions of soluble derivatives.
hydrocortisone, its esters, and congeners.
 Reduction of the 4,5 double bond occurs at both hepatic and extrahepatic sites,
 Minor changes in chemical structure may markedly alter the rate of absorption, yielding inactive compounds.
time of onset of effect, and duration of action.
 Subsequent reduction of the 3-ketone substituent to the 3-hydroxyl derivative,
 Glucocorticoids also are absorbed systemically from sites of local administration, forming tetrahydrocortisol, occurs only in the liver.
such as synovial spaces, the conjunctival sac, skin, and respiratory tract.
 Most of these A ring-reduced steroids are conjugated through the 3-hydroxyl
 When administration is prolonged, when the site of application is covered with an group with sulfate or glucuronide by enzymatic reactions that take place in the
occlusive dressing, or when large areas of skin are involved, the absorption may liver, and to a lesser extent in the kidney.
be sufficient to cause systemic effects, including suppression of the HPA axis.
 The resultant sulfate esters and glucuronides are water-soluble and are the
predominant forms excreted in urine. Neither biliary nor fecal excretion is of
quantitative importance in humans.
Transport, Metabolism, and Excretion
 Synthetic steroids with an 11-keto substituent, such as cortisone and prednisone,
must be enzymatically reduced to the corresponding 11b-hydroxy derivative
before they are biologically active.
 After absorption, 90% or more of cortisol in plasma is reversibly bound to protein
under normal circumstances.  The type 1 isozyme of 11b-hydroxysteroid dehydrogenase catalyzes this
reduction, predominantly in the liver, but also in specialized sites such as
adipocytes, bone, eye, and skin.
 Only the fraction of corticosteroid that is unbound can enter cells to mediate
corticosteroid effects.
 In settings in which this enzymatic activity is impaired, it is prudent to use
steroids that do not require enzymatic activation (e.g., hydrocortisone and
 Two plasma proteins account for almost all of the steroid-binding capacity: prednisolone rather than cortisone or prednisone).
corticosteroid-binding globulin (CBG; also called transcortin), and albumin.

 Such settings include severe hepatic failure and patients with the rare condition
 CBG is an a-globulin secreted by the liver that has high affinity (estimated of cortisone reductase deficiency, who are unable to activate the 11-keto steroids
association constant of approximately 7.6 ´ 107 M-1) for steroids but relatively
because of a partial loss of 11bHSD1 activity and a relative deficiency in the
low total binding capacity, whereas albumin, also produced by the liver, has low enzyme hexose-6-phosphate dehydrogenase, which supplies reducing
affinity (estimated association constant of 1 ´ 103 M-1) but relatively large
equivalents to the 11b-hydroxysteroid dehydrogenase.
binding capacity.

 At normal or low concentrations of corticosteroids, most of the hormone is


protein-bound.
(Goodman and Gilman’s The Pharmacologic Basis of Therapeutics 11th Edition)

 At higher steroid concentrations, the capacity of protein binding is exceeded, and


a greater fraction of the steroid exists in the free state.

9.3 Toxicology of steroids.


30

 The most common adverse effects during a brief course are mood disturbances,
increased appetite, impaired glucose control in diabetics, and candidiasis.
Inhaled Glucocorticoids

(Goodman and Gilman’s The Pharmacologic Basis of Therapeutics 11th Edition)


 While there is a great deal of enthusiasm for inhaled glucocorticoids in asthma,
local and systemic adverse effects remain a concern. Some portion of any
inhaled drug is swallowed.

 Therefore, inhaled drugs can reach the circulation by direct absorption from the
10. What are the mast cell-stabilizing agents and what are their indications?
lung or by absorption from the gastrointestinal tract.
MAST CELL–STABILIZING AGENTS
 The newer glucocorticoids have extremely low oral bioavailability owing to
extensive first-pass metabolism by the liver and reach the circulation almost
exclusively by absorption from the lung.
• Cromolyn sodium and nedocromil sodium do not infuence airway tone.
 In contrast to the beneficial effects on asthma, which plateau at about 1600 • Their major therapeutic effect is to inhibit the degranulation of mast cells, thereby
mg/day, the probability of adverse effects continues to increase at higher doses. preventing the release of the chemical mediators of anaphylaxis.
• Cromolyn sodium and nedocromil sodium, like the inhaled steroids, improve lung
function, reduce symptoms, and lower airway reactivity in persons with asthma.
 Oropharyngeal candidiasis and, more frequently, dysphonia can be encountered.
• They are most effective in atopic patients who have either seasonal disease or
perennial airway stimulation.
 The incidence of candidiasis can be reduced substantially by rinsing the mouth
and throat with water after each use and by employing spacer or reservoir
devices attached to the dispenser to decrease drug deposition in the oral cavity.
Comparative Daily Doses for Inhaled Steroids

 Appreciable suppression of the hypothalamic-pituitary-adrenal axis is difficult to


document at doses below 800 mg/day and probably is rarely of physiologic
importance even at doses up to 1600 mg/day.
• A therapeutic trial of two puffs four times daily for 4 to 6 weeks is frequently
necessary before the bene.cial effects of the drug appear.
 Modest but statistically significant decreases in bone mineral density do occur in
• Unlike steroids, nedocromil and cromolyn sodium, when given prophylactically, block
female asthmatics receiving inhaled steroids, even when doses as low as 500
the acute obstructive effects of exposure to antigen, industrial chemicals, exercise, or
mg/day are employed.
cold air.
• With antigen, the late response is also abolished.
 Others have shown increases in markers for bone mineral turnover (serum • Therefore, a patient who has intermittent exposure to either antigenic or nonantigenic
osteocalcin and urine hydroxyproline levels) during treatment with inhaled stimuli that provoke acute episodes of asthma need not use these drugs continuously
glucocorticoids. but instead can obtain protection by taking the drug only 15 to 20 min before contact
with the precipitant.
 While the clinical relevance of these bone metabolism findings remains to be
determined, it is argued that inhaled glucocorticoid treatment should be reserved
for moderate or severe asthma because such treatment is likely to last for many (Harrison’s Principles of Internal Medicine 16th Edition)
years.

 Nonetheless, it has been suggested that the small risk of adverse effects at high
doses of inhaled glucocorticoids is outweighed by the risks of inadequately 11. What are leukotrienne modifiers? Give their therapeutic indication/s?
controlling severe asthma.
LEUKOTRIENE MODIFIERS

Systemic Glucocorticoids

• The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) produce many of the critical
elements of asthma, and drugs have been developed that either reduce the synthesis
 The adverse effects of systemic administration of glucocorticoids are well known, of all of the leukotrienes by inhibiting 5-lipoxygenase (5-LO), the enzyme involved in
but treatment for brief periods (5 to 10 days) causes relatively little dose-related their production, or competitively antagonize the principal moiety (LTD4).
toxicity. • Zileuton is the only 5-LO synthesis inhibitor that is available in the United States.
• It is a modest bronchodilator that reduces asthma morbidity, provides protection
against exercise-induced asthma, and diminishes nocturnal symptoms, but it has
limited effectiveness against allergens.
31

• Hepatic enzyme levels can be elevated after its use, and there are signi.cant CONTROL OF FACTORS CONTRIBUTING TO ASTHMA SEVERITY
interactions with other drugs metabolized in the liver.
• The LTD4 receptor antagonists (zafirlukast and montelukast)have therapeutic and
toxicologic profiles similar to that of zileuton but are long acting and permit twice- to
once-daily dose schedules. Controllable factors that can significantly worsen asthma can be generally grouped as:
• This class of drugs does not appear to be uniformly effective in all patients with
asthma. 1. Environmental exposures
• Although precise figures are lacking, most authorities put the number of positive 2. Co-morbid conditions.
responders at <50%.
• As yet, there is no way of determining prospectively who will benfit, so clinical trials
are required.
Control of Factors Contributing to Asthma Severity
• Typically, if there is no improvement after 1 month, treatment can be discontinued.
• The leukotriene blockers have been associated with uncovering of Churg-Strauss
syndrome.

ELIMINATE OR REDUCE PROBLEMATIC ENVIRONMENTAL EXPOSURES


Miscellaneous Agents

• Environmental tobacco smoke elimination or reduction


• It has been suggested that steroid-dependent patients might benefit from the use of  In home and automobiles
immunosuppressant agents such as methotrexate, gold salts, or colchicine. • Allergen exposure elimination or reduction in sensitized asthmatics
• The effects of these agents on steroid dosage and disease activity are minor, and side  Animal danders
effects can be considerable. o Pets (cats, dogs, rodents, birds)
• Opiates, sedatives, and tranquilizers should be absolutely avoided in the acutely ill o Pests (mice, rats)
patient with asthma because the risk of depressing alveolar ventilation is great, and  Dust mites
respiratory arrest has been reported to occur shortly after their use.  Cockroaches
Molds
• Admittedly, most individuals are anxious and frightened, but experience has shown


Other airway irritants
that they can be calmed equally well by the physician’s presence and reassurances.
 Wood- or coal-burning smoke
• β-Adrenergic blockers and parasympathetic agonists are contraindicated because they  Strong chemical odors and perfumes (e.g., household cleaners)
can cause marked deterioration in lung function.  Dusts
• Expectorants and mucolytic agents have enjoyed great vogue in the past, but they do
not add significantly to the treatment of the acute or chronic phases of this disease.
• The use of intravenous fluids in the treatment of acute asthma has also been Eliminate or Reduce Problematic Environmental Exposures
advocated.
• There is little evidence that this adjunct hastens recovery.
• Nonstandard bronchodilators, such as intravenous magnesium sulfate, for the
treatment of acute asthma attacks are not yet warranted in clinical practice because • The majority of children with asthma have an allergic component to their disease.
of the controversy surrounding their efficacy. Because of this, steps should be taken to investigate and minimize allergen exposures
in sensitized asthmatics.
• Several studies have shown that, in sensitized asthmatics, reduced exposure to
Special Instructions allergens can decrease asthma symptoms, the need for medications, and airways
hyperresponsiveness.
• Asthmatic children who are sensitized to indoor allergens in particular can experience
greater asthma severity due to year-round exposure and can benefit from measures
to minimize allergen exposure in the home.
• The treatment of patients with asthma who have coexisting conditions such as heart • Common perennial allergen exposures include furred or feathered animals as pets or
disease or pregnancy does not differ materially from that outlined above. as pests and occult indoor allergens such as dust mites, molds, and cockroaches.
• Therapy with inhaled β2-selective and anti-in.ammatory agents is the mainstay. • Although some sensitized children may report an increase in asthma symptoms on
• The lowest doses of adrenergics that produce the desired effects should be used. exposure to the allergen source, improvement from allergen avoidance may not
become apparent without a sustained period of days to weeks away from the
offending exposure.
• Tobacco, wood, and coal smoke, dusts, and strong or noxious odors and fumes can all
(Harrison’s Principles of Internal Medicine 16th Edition)
aggravate asthma.
• At the very least, these airways irritants should be eliminated or reduced from the
homes and automobiles used by asthmatic children.
• School classrooms and daycare centers can also be sites of asthma-worsening
12. Basing on the risk factors or triggers of asthma, how do you reduce exposure to these risk environmental exposures.
factors of asthma?
32

• Eliminating or minimizing these exposures can reduce asthma symptoms, disease


severity, and the amount of medication needed to achieve good asthma control.
• Common viral infections of the respiratory tract are difficult to avoid; annual influenza • Provide a two-part care plan
vaccination is recommended for all asthmatic children (except for those with egg
allergy).
• Daily management

• Action plan for asthma exacerbations


(Nelson’s Textbook of Pediatrics 17th Edition)

13. How do you manage asthma exacerbation?

(Nelson’s Textbook of Pediatrics 17th Edition)

ASTHMA EXACERBATION MANAGEMENT


Four Components of Optimal Asthma Management

REGULAR ASSESSMENT AND MONITORING • Asthma exacerbations are acute or subacute episodes of progressively worsening
symptoms associated with expiratory airflow obstruction.

• It is important to consider asthma severity based on the frequency and severity of


• Asthma check-ups previous asthma exacerbations and to identify asthmatics at increased risk for life-
threatening exacerbations.
 Every 2–4 wk until good control is achieved
• Asthma exacerbation severity can be quantified by the number of emergency
 2–4 per year to maintain good control department visits, hospitalizations, and systemic glucocorticoid courses for asthma
exacerbations.
• Lung function monitoring
• Previous severe asthma exacerbations, resulting in respiratory distress, hypoxia, or
respiratory failure are probably the best predictors of a future life-threatening
exacerbation or fatal asthma episode.

CONTROL OF FACTORS CONTRIBUTING TO ASTHMA SEVERITY


• Biologic, environmental, economic, and psychosocial risk factors for increased asthma
morbidity and mortality have been identified.

• Eliminate or reduce problematic environmental exposures


Home Management of Asthma Exacerbations
• Treat co-morbid conditions: rhinitis, sinusitis, gastroesophageal reflux

• All asthmatics should have a written action plan that can help guide them in
ASTHMA PHARMACOTHERAPY recognizing and assessing their overall asthma control and the severity of acute
asthma exacerbations.

• Recognizing symptoms early and intensifying treatment soon after symptoms worsen
• Long-term-control versus quick-relief medications can often prevent further worsening and can keep exacerbations from becoming
severe.
• Classification of asthma severity for anti-inflammatory pharmacotherapy
• One study found that having a written home action plan was associated with a 70%
• Step-up, step-down approach reduction in the risk of asthma death associated with an acute exacerbation.

• Asthma exacerbation management • Clinical signs and symptoms characteristic of an acute episode include cough,
shortness of breath, wheezing, chest tightness, use of accessory muscles, and
suprasternal retractions.

PATIENT EDUCATION • The NAEPP guidelines recommend immediate treatment with “rescue” medication
(i.e., inhaled short-acting ß-agonist, up to three treatments in 1hr).
33

• A good response is characterized by resolution of symptoms within an hour, no further • For patients with a moderate to severe asthma exacerbation that does not
symptoms over the next 4hr, and improvement in PEF of 80% predicted or personal significantly improve within 1–2hr after the initial treatment, associated with PEFs less
best. than 70% or oxygen saturations less than 90–92%, admission to the hospital is
warranted.
• The child's physician should be contacted for follow-up, especially if bronchodilators
are required repeatedly over the next 24–48hr. • Other indications for hospital admission include prolonged symptoms before the
emergency department visit, inadequate access to medical care and medications,
difficult psychosocial conditions, or difficulty in obtaining transportation to the hospital
• If the child has an incomplete response to initial treatment with rescue medication in event of further deterioration. Admission to an intensive care unit is indicated for
(i.e., persistent symptoms and/or a PEF of 60–80% of predicted or personal best), a patients with poor response to therapy, persistent severe respiratory distress, or
short course of oral glucocorticoid therapy (e.g., prednisone 1–2mg/kg/24hr for 4 days) evidence of impending respiratory arrest.
in addition to inhaled ß-agonist therapy should be instituted.
• Supplemental oxygen, frequently administered inhaled ß-agonists, and systemic
• The physician should also be contacted for further instructions. Immediate medical glucocorticoid therapy are the treatments of choice for children admitted to the
attention should be sought for severe exacerbations, persistent signs of respiratory hospital for acute asthma.
distress, lack of expected response or sustained improvement after initial treatment,
further deterioration, or presence of risk factors for asthma morbidity or mortality. • Supplemental oxygen is administered because many children hospitalized with acute
asthma will have hypoxemia, especially at night.
• Patients should have medications such as inhaled short-acting ß-agonists, oral
glucocorticoids, and equipment for treating exacerbations at home. • Short-acting ß-agonists can be delivered frequently and, if needed, continuously.

• When administered continuously, significant systemic absorption of ß-agonist occurs


and, as a result, continuous nebulization can obviate the need for intravenous ß-
Emergency Department Management of Asthma Exacerbations agonist therapy.

• Adverse effects of frequently administered ß-agonist therapy include tremor,


irritability, tachycardia, and hypokalemia.
• The primary goals of asthma management in the emergency department setting
include correction of hypoxemia, rapid improvement of airflow obstruction, and • Patients requiring frequent or continuous nebulized ß-agonist therapy should have
prevention of progression or recurrence of symptoms. continuous cardiac monitoring.

• Treatment is based on clinical severity on arrival, response to initial therapy, and • Because frequent ß-agonist therapy can cause ventilation-perfusion mismatch and
presence of risk factors that are associated with asthma death. Initial treatment precipitate hypoxemia, oximetry is indicated with supplemental oxygen.
includes close monitoring of clinical status, treatment with supplemental oxygen,
inhaled ß-agonist every 20min for 1hr, and if necessary, systemic glucocorticoids (2? • Ipratropium is often added to albuterol every 6hr, although there is little evidence to
mg/kg/day) given either orally or intravenously. support its use in hospitalized children receiving aggressive inhaled ß-agonist therapy
and systemic glucocorticoids.
• Inhaled ipratropium may be added to the ß-agonist treatment if no significant
response is seen with the first inhaled ß-agonist treatment. • Patients with persistent severe dyspnea and high-flow oxygen requirements will often
require intravenously administered fluids. In this situation, administration of fluids at
• A subcutaneous injection of epinephrine or other ß-agonist may be administered in or slightly below maintenance fluid requirements is recommended, owing to increased
severe cases. antidiuretic hormone (ADH) secretion associated with status asthmaticus.

• Despite intensive therapy, some asthmatic children will remain critically ill and at risk
• The patient may be discharged to home if there is sustained improvement in for intubation and mechanical ventilation.
symptoms, normal physical findings, PEF greater than 70% of predicted or personal
best, and an oxygen saturation greater than 92% on room air for 4hr.
• Complications related to asthma exacerbations increase with intubation and assisted
ventilation; therefore, every effort should be made to relieve bronchospasm and
• Discharge medications include administration of an inhaled ß-agonist up to every 3– prevent respiratory failure.
4hr plus a 3–7 day course of oral glucocorticoids.
• Several therapies, including intravenous ß-agonists, intravenous theophylline, heliox,
and intravenous magnesium sulfate have some demonstrated benefit as adjunctive
therapies in severe status asthmaticus.
Hospital Management of Asthma Exacerbations

(Nelson’s Textbook of Pediatrics 17th Edition)


34

Management of Chronic Asthma

• Patients with asthma need to understand how to use their medications and the
difference between reliever and controller therapies.
• It is important to establish the diagnosis objectively using spirometry or PEF
measurements at home. • Education may improve compliance, particularly with ICSs.

• Triggers that worsen asthma control, such as allergens or occupational agents, should • All patients should be taught how to use their inhalers correctly.
be avoided, whereas triggers such as exercise and fog, which result in transient
symptoms, provide an indication that more controller therapy is needed. • In particular, they need to understand how to recognize worsening of asthma and how
to step up therapy.

• Written action plans have been shown to reduce hospital admissions and morbidity in
Stepwise Therapy adults and children and are recommended particularly in patients with unstable
disease who have frequent exacerbations.

• For patients with mild, intermittent asthma, a short-acting 2-agonist is all that is
Acute Severe Asthma
required.

• However, use of a reliever medication more than three times a week indicates the
need for regular controller therapy.
• Exacerbations of asthma are feared by patients and may be life-threatening.
• The treatment of choice for all patients is an ICS given twice daily.
• One of the main aims of controller therapy is to prevent exacerbations; in this respect,
ICS and combination inhalers are very effective.
• It is usual to start with an intermediate dose [e.g., 200 g bid of beclomethasone
dipropionate (BDP) or equivalent] and to decrease the dose if symptoms are controlled
after 3 months.

• If symptoms are not controlled, an LABA should be added, most conveniently by Clinical Features
switching to a combination inhaler.

• The dose of controller should be adjusted accordingly, as judged by the need for a
rescue inhaler. • Patients are aware of increasing chest tightness, wheezing, and dyspnea that are
often not or poorly relieved by their usual reliever inhaler.
• Low doses of theophylline or an antileukotriene may also be considered as an add-on
therapy, but these are less effective than LABAs. • In severe exacerbations patients may be so breathless that they are unable to
complete sentences and may become cyanotic.
• In patients with severe asthma, low-dose oral theophylline is also helpful, and when
there is irreversible airway narrowing, the long-acting anticholinergic tiotropium
• Examination usually shows increased ventilation, hyperinflation, and tachycardia.
bromide may be tried.

• Pulsus paradoxus may be present, but this is rarely a useful clinical sign.
• If asthma is not controlled despite the maximal recommended dose of inhaled
therapy, it is important to check compliance and inhaler technique. In these patients,
maintenance treatment with an oral corticosteroid may be needed, and the lowest • There is a marked fall in spirometric values and PEF.
dose that maintains control should be used.
• Arterial blood gases on air show hypoxia and PaCO2 is usually low due to
• Occasionally omalizumab may be tried in steroid-dependent asthmatics who are not hyperventilation.
well controlled.
• A normal or rising PaCO2 is an indication of impending respiratory failure and requires
• Once asthma is controlled, it is important to slowly decrease therapy in order to find immediate monitoring and therapy.
the optimal dose to control symptoms.
• A chest roentgenogram is not usually informative, but may show pneumonia or
pneumothorax.

Education
35

Acute Severe Asthma: Treatment have normal or near-normal lung function but intermittent, severe (sometimes life-
threatening) exacerbations.

(Harrison’s Principles of Internal Medicine 17th Edition)


• A high concentration of oxygen should be given by face mask to achieve oxygen
saturation of >90%.

• The mainstay of treatment is high doses of short-acting inhaled β2-agonists that are
given either by nebulizer or via a metered dose inhaler with a spacer.

• In severely ill patients with impending respiratory failure, intravenous β2-agonists may
be given.

• An inhaled anti-cholinergic may be added if there is not a satisfactory response to β2-


agonists alone, as there are additive effects.

• In patients who are refractory to inhaled therapies, a slow infusion of aminophylline


may be effective, but it is important to monitor blood levels especially if patients have
already been treated with oral theophylline.

• Magnesium sulfate given intravenously or by nebulizer has also been shown to be


effective when added to inhaled β2-agonists, and is relatively well tolerated but is not
routinely recommended.

• Prophylactic intubation may be indicated for impending respiratory failure, when the
PaCO2 is normal or rises.

• For patients with respiratory failure, it is necessary to intubate and institute


ventilation.

• These patients may benefit from an anesthetic, such as halothane, if they have not
responded to conventional bronchodilators.

• Sedatives should never be given as they may depress ventilation.

• Antibiotics should not be used routinely unless there are signs of pneumonia.

Refractory Asthma

• Although most patients with asthma are easily controlled with appropriate medication,
a small proportion of patients (approximately 5% of asthmatics) are difficult to control
despite maximal inhaled therapy.

• Some of these patients will require maintenance treatment with oral corticosteroids.

• In managing these patients, it is important to investigate and correct any mechanisms


that may be aggravating asthma.

• There are two major patterns of difficult asthma: some patients have persistent
symptoms and poor lung function, despite appropriate therapy, whereas others may