This document discusses asthma, including its pathophysiology. It describes how asthma involves chronic airway inflammation with activated cells like eosinophils, T cells, mast cells, macrophages, and epithelial cells. These cells release inflammatory mediators that cause bronchospasm, mucus production, and airway remodeling. Histamine, leukotrienes, prostaglandins, and other mediators are involved in the inflammatory process and cause symptoms like wheezing, coughing, and shortness of breath. Overall, the document provides an overview of the inflammatory pathophysiology underlying asthma.

1. ASTHMA
Shaik Liakhat Ali
ASSISTANT PROFESSOR
NIRMALA COLLEGE OF PHARMACY

2.  The air within the lung at the end of a forced inspiration can be divided into four
compartments or lung volumes
 The volume of air exhaled during normal quiet breathing is the tidal volume(VT).
 The maximal volume of air inhaled above tidal volume is the inspiratory reserve
volume(IRV), and the maximal air exhaled below tidal volume is the expiratory reserve
volume(ERV).
 The residual volume(RV) is the amount of air remaining in the lungs after a maximal
exhalation.
 The combinations or sums of two or more lung volumes are termed capacities.

3. LUNG VOLUMES
 Vital capacity(VC) is the maximal amount of air that can be exhaled after a maximal inspiration. It is
equal to the sum of IRV, VT, and ERV.
When measured on a forced expiration, it is called the forced vital capacity(FVC). When measured
over an exhalation of at least 30 seconds, it is called the slow vital capacity(SVC). The VC is
approximately 75% of the total lung capacity(TLC), and when the SVC is within the normal range, a
significant restrictive disorder is unlikely.
 TLC is the volume of air in the lung after the maximal inspiration and is the sum of the four primary
lung volumes (IRV, VT, ERV, and RV).
 The functional residual capacity(FRC) is the volume of air remaining in the lungs at the end of a quiet
expiration. FRC is the normal resting position of the lung; it occurs when there is no contraction of
either inspiratory or expiratory muscles and normally is 40% of TLC.

5. OBSTRUCTIVE LUNG DISEASE
 Obstructive lung disease implies a reduced capacity to
get air
through the conducting airways and out of the lungs.
 This reduction in airflow may be caused by a decrease
in the diameter of the airways (bronchospasm), a loss of
their integrity (bronchomalacia), or a reduction in elastic
recoil (emphysema) with a resulting decrease in driving
pressure.
 The most common diseases associated with obstructive
pulmonary functions are asthma, emphysema, and
chronic bronchitis.
 The standard test used to evaluate airway obstruction is
the forced expiratory spirogram

6. AIRWAY HYPER REACTIVITY
 Airway hyperreactivity or hyperresponsivenessis defined as an exaggerated bronchoconstrictor
response to physical, chemical, or pharmacologic stimuli. Individuals with asthma, by definition, have
hyperresponsive airways. The Lung Health Study Group observed nonspecific hyperresponsiveness in
a significant number of patients with COPD. This group of patients with airway hyperreactivity
appears to have a worse prognosis and an accelerated rate of decline in FEV1
 Some patients with asthma (especially cough-variant asthma) present with no history of wheezing and
normal PFTs. The diagnosis of asthma still can be established by demonstrating hyperresponsiveness
to provocative agents.
 The two agents used most widely in clinical practice are methacholine and histamine. Other agents
used for bronchial provocation include distilled water, cold air, and exercise.
 During a typical bronchoprovocation test, baseline FEV 1 is measured after inhalation of isotonic
saline, then increasing doses of methacholine are given at set intervals.
 Hyperresponsiveness is defined as a decline in FEV1≥20% and reversibility of obstruction to
bronchodilators. The result can best be expressed as the provocative concentration needed to cause a
20% fall in FEV 1(PC 20 ). A test is considered positive if either methacholine or histamine demon-
strates a PC 20for FEV 1≤8 mg/mL or <60 to 80 cumulative breath

7. UPPER AIRWAY OBSTRUCTION
 Obstruction of airflow by abnormalities in the upper
airway often goes undiagnosed or misdiagnosed
because of improper interpretation of PFTs.
 Patients have obstructive physiology and often are
misclassified as having asthma or COPD.
 The shape of the flow– volume loop, which includes
inspiratory and expiratory flow– volume curves, and
the ratio of forced expiratory and inspiratory flow at
50% of vital capacity (FEF50%/FIF50%) may be
useful in the diagnosis of upper airway obstruction.

8. Restrictive lung disease
 Restrictive lung disease is defined as an inability to get
air into the lungs and to maintain normal lung volumes.
Restrictive lung disease reduces all the subdivisions of
lung volumes (IRV, VT, ERV, and RV) without reducing
airflow. Patients have normal airway resis-tance and FEV
1 /FVC >75%.
 Althoughrestrictioncould be defined as a reduction in
vital capacity (VC or FVC) with normal FEV1 /FVC, poor
effort also will reduce FVC with normal FEV 1/FVC.
 A reduction in TLC is the most accurate measurement of
restrictive lung function.

9. DEFINITION
Asthma is a chronic inflammatory disorder of the airways in
which many cells and cellular elements play a role: in particular,
mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils,
and epithelial cells. In susceptible individuals, this inflammation
causes recurrent episodes of wheezing, breathlessness, chest tightness,
and coughing, particularly at night or in the early morning.
These episodes are usually associated with widespread but variable
airflow obstruction that is often reversible either spontaneously or
with treatment. The inflammation also causes an associated increase
in the existing bronchial hyperresponsiveness (BHR) to a variety of
stimuli. Reversibility of airflow limitation may be incomplete in
some patients with asthma

10. EPIDEMIOLOGY
An estimated 20.5 million persons in the United States have asthma (approximately 7% of the population).
Asthma is the most common chronic disease among children in the United States, with approximately 6.5
million children affected. The prevalence of asthma in the United States and worldwide has continued to
increase.
The prevalence rate is highest in children 5–17 years at 9.6%. 3 In the United States, as in other Western
industrialized countries, the prevalence of asthma has reached epidemic propor-tions. Asthma accounts
for 1.6% of all ambulatory care visits (13.7 million physician office visits and 1.0 million hospital
outpatient visits) and results in more than 497,000 hospitalizations and 1.8 million emergency department
visits per year.3 Although asthma is the third leading cause of preventable hospitalization in the United
States, hospitalizations for asthma have decreased only slightly over the past 10 years to 17 per 10,000
population.
Children younger than 15 years of age have the highest rate of hospitalization at 31 per 10,000 population.
Asthma accounts for more than 10 million missed school days per year.
The prevalence of disabling asthma in children has increased 232% over the past 20 years compared with a
113% increase from all other chronic conditions in childhood.
In young children (0 to 10 years of age), the risk of asthma is greater in boys than in girls, becomes about
equal during puberty, and then is greater in women than in men.

11. ETIOLOGY

12. Asthmatic bronchus T.S.

14. PATHOPHYSIOLOGY
 The major characteristics of asthma include a
variable degree of airflow obstruction (related to
bronchospasm, edema, and hyperse-cretion), BHR,
and airways inflammation

15. Hot TipASTHMA PATHOPHYSIOLOGY

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18.  CHRONIC INFLAMMATION
 Airways inflammation has been demonstrated in all forms of asthma, and an association between
the extent of inflammation and the clinical severity of asthma has been demonstrated in selected
studies.
 It is accepted that both central and peripheral airways are inflamed.
 In asthma, all cells of the airways are involved and become activated
 CELLS Included are eosinophils, T cells, mast cells, macrophages,
epithelial cells, fibroblasts, and bronchial smooth muscle cells. These
cells also regulate airway inflammation and initiate the process of
remodeling by the release of cytokines and growth factors.

19. Epithelial Cells
Bronchial epithelial cells traditionally have been considered as a
barrier, participating in mucociliary clearance and removal of nox-ious agents.
However, epithelial cells also participate in inflammation by the release of eicosanoids, peptidases, matrix proteins,
cytokines, and nitric oxide (NO).
Epithelial cells can be activated by IgE-dependent mechanisms, viruses, pollutants, or histamine.
In asthma, especially fatal asthma, extensive epithelial shedding occurs.
The functional consequences of epithelial shedding may include
heightened airways responsiveness, altered permeability of the air-way mucosa, depletion of epithelial-derived
relaxant factors, and
loss of enzymes responsible for degrading proinflammatory neu-ropeptides.
The integrity of airway epithelium may influence the sensitivity of the airways to various provocative stimuli.
Epithelial cells also may be important in the regulation of airway remodeling and fibrosis.

20. Eosinophils
 Eosinophils play an effector role in asthma by release of proinflammatory mediators,
cytotoxic mediators, and cytokines.
 Circulating eosinophils migrate to the airways by cell rolling, through interactions with
selectins, and eventually adhere to the endothelium through the binding of integrins to
adhesion proteins (vascular cell adhesion molecule 1 [VCAM-1] and intercellular
adhesion molecule 1 [ICAM-1]).
 As eosinophils enter the matrix of the membrane, their survival is
prolonged by interleukin (IL)-5 and granulocyte-macrophage col-ony-stimulating factor
(GM-CSF).
On activation, eosinophils release inflammatory mediators such as leukotrienes and
granule proteins to injure airway tissue.

21. Lymphocytes
 Mucosal biopsy specimens from patients with asthma contain
lymphocytes, many of which express surface markers of inflam-mation.
There are two types of T-helper CD4+ cells. TH1cells produce IL-2 and
interferon-γ(INF-γ), both essential for cellular defense mechanisms.
 TH2 cells produce cytokines (IL-4, -5, and -13) that mediate allergic
inflammation. It is known that TH 1
 Cytokines inhibit the production of TH 2 cytokines, and vice versa. It is
hypothesized that allergic asthmatic inflammation results from a TH2-
mediated mechanism (an imbalance between TH 1and TH 2 cells).

22. Mast Cells
Mast cell degranulation is important in the initiation of immediate responses following exposure to allergens.
 Mast cells are found throughout the walls of the respiratory tract, and increased num-bers of these cells
(three- to fivefold) have been described in the airways of asthmatics with an allergic component.
 Once binding of allergen to cell-bound IgE occurs, mediators such as histamine;
eosinophil and neutrophil chemotactic factors; leukotrienes (LTs) C4, D 4, and E 4 ; prostaglandins; platelet-
activating factor; and others are released from mast cells . Histologic examination has revealed decreased
numbers of granulated mast cells in the airways of patients who have died from acute asthma attacks,
suggesting that mast cell degranulation is a contributing factor in the progression of the disease.
Sensitized mast cells also may be activated by osmotic stimuli to account for exercise-induced bron-
chospasm (EIB).

23. Alveolar Macrophages
 The primary function of alveolar macrophages in the normal airway is to serve as
“scavengers,” engulfing and digesting bacteria andother foreign materials.
 They are found in large and small airways, ideally located for affecting the
asthmatic response. A number of mediators produced and released by macrophages
have been iden-tified, including platelet-activating factor, LTB 4, LTC 4, and
LTD4.
 Additionally, alveolar macrophages are able to produce neutrophil chemotactic
factor and eosinophil chemotactic factor, which, inturn, amplify the inflammatory
process

24. Neutrophils
 The role of neutrophils in the pathogenesis of asthma remains somewhat unclear because
they normally may be present in the airways and usually do not infiltrate tissues showing
chronic allergic inflammation despite the potential to participate in late-phase inflammatory
reactions.
 However, high numbers of neutrophils have been reported to be present in the airways of
patients who died from sudden-onset fatal asthma and in those with severe disease.
 This suggests that neutrophils may play a pivotal role in the disease process, at least in some
patients with long-standing or corticoster-oid-dependent asthma.
 The neutrophil also can be a source for a variety of mediators, including platelet-activating
factor, prosta-glandins, thromboxanes, and leukotrienes, that contribute to BHRand airway
inflammation.

25. Fibroblasts and Myofibroblasts
 Fibroblasts are found frequently in connective tissue. Human lung
fibroblasts may behave as inflammatory cells on activation by IL-4
and IL-13. The myofibroblast may contribute to the regulation of
inflammation via the release of cytokines and to tissue remod-eling.
 In asthma, myofibroblasts are increased in numbers beneath the
reticular basement membrane, and there is an association between
their numbers and the thickness of the reticular basement
 membrane.

26.  Associated with asthma for many years, histamine is capable of inducing smooth muscle
constriction and bronchospasm and is thought to play a role in mucosal edema and mucus
secretion.
 Lung mast cells are an important source of histamine. The release of histamine can be stimulated
by exposure of the airways to a varietyof factors, including physical stimuli (such as exercise) and
relevant allergens.
 Histamine is involved in acute bronchospasm following allergen exposure; however, other
mediators, such as leukotrienes are also involved.
 Besides histamine release, mast cell degranulation releases inter-leukins, proteases, and other
enzymes that activate the production of other mediators of inflammation. Several classes of
important mediators, including arachidonic acid and its metabolites (i.e., prostaglandins, LTs, and
platelet-activating factor), are derived from cell membrane phospholipids.
 Once arachidonic acid is released, it can be metabolized by the enzyme cyclooxygenase to form
prostaglandins. Although prosta-glandin D 2 is a potent bronchoconstricting agent, it is unlikely to
produce sustained effects and its role in asthma remains to bedetermined.
 Similarly, prostaglandin F2α is a potent bronchocon-strictor in patients with asthma and can
enhance the effects of histamine. However, its pathophysiologic role in asthma is unclear.
Inflammatory Mediators

27.  Another cyclooxygenase product, prostacyclin (prostaglandin I2), is known to be produced in the lung
and may contribute to inflamma-tion and edema owing to its effects as a vasodilator.
 Thromboxane A2 is produced by alveolar macrophages, fibro-blasts, epithelial cells, neutrophils, and
platelets within the lung.
 Indirect evidence from animal models suggests that thromboxane A2 may have several effects,
including bronchoconstriction, involve-ment in the late asthmatic response, and involvement in the
devel-opment of airway inflammation and BHR.
 The 5-lipoxygenase pathway of arachidonic acid metabolism is responsible for the production of the
cysteinyl leukotrienes.
 LTC4, LTD4, and LTE 4 are released during inflammatory processes in the lung.
 LTD 4and LTE4 share a common receptor (LTD 4 receptor) that, when stimulated, produces
bronchospasm, mucus secretion, microvascular permeability, and airway edema, whereas LTB4 is
involved with granulocyte chemotaxis.
 Thought to be produced by macrophages, eosinophils, and neu-trophils within the lung, platelet-
activating factor is involved in the mediation of bronchospasm, sustained induction of BHR, edema

28. Adhesion Molecules
 An important step in the inflammatory process is the adhesion of the various cells to each other and
the tissue matrix to facilitate infiltra-tion and migration of these cells to the site of inflammation.
 To promote this, cell membranes express a number of glycoproteins, or adhesion molecules.
 Adhesion molecules have additional functions involved in the inflammatory process aside from
promoting cell adhesion, including activation of cells and cell–cell communication, and promoting
cellular migration and infiltration.
 The many adhe-sion molecules are divided into families on the basis of their chemical structure.
 These families are the integrins, cadherins, immunoglobu-lin supergene family, selectins, vascular
adressins, and carbohydrate ligands.
 Those thought to be important in inflammation include the integrins, immunoglobulin supergene
family, selectins, and car-bohydrate ligands, including ICAM-1 and VCAM-1.
 Adhesion molecules are found on a variety of cells, such as neutrophils, monocytes, lymphocytes,
basophils, eosinophils, granulocytes, plate-lets, endothelial cells, and epithelial cells, and can be
expressed or activated by the many inflammatory mediators present in asthma.

29. CLINICAL CONSEQUENCES
 CHRONIC INFLAMMATION
 Chronic inflammation is associated with nonspecific BHR and increases the risk of asthma exacerbations.
Exacerbations are char-acterized by increased symptoms and worsening airways obstruction over a period of
days or even weeks, and rarely hours.
 Hyperresponsiveness of the airways to physical, chemical, and pharmacologic stimuli is a hallmark of asthma.
 BHR also occurs in some patients with chronic bronchitis and allergic rhinitis.
 Normal healthy subjects also may develop a transient BHR after viral respiratory infections or exposure to
ozone. However, the degree of BHR is quantitatively greater in asthmatic patients than in other groups.
 Bronchial responsiveness of the general population fits a unimodal distribution that is skewed toward increased
reactivity.
 Patients with clinical asthma represent the extreme end of the distribution. The degree of BHR within asthmatics
correlates with
 the clinical course of their disease and medication requirement necessary to control symptoms.
 Patients with mild symptoms or in remission demonstrate lower levels of responsiveness, although still greater
than the normal population.
 Our current understanding recognizes that the increased BHR seen in asthma is at least in part owing to an
inflammatory response
 within the airways. Early investigations found correlations with inflammatory cells in bronchoalveolar lavage
fluids and degree of BHR.
 Newer evidence suggests that airways remodeling, subepithe-lial fibrosis, or collagen deposition also correlates
with BHR.
 Although the precise link is unknown, BHR is in part related to the extent of inflammation in the airways

30. REMODELING OF THE AIRWAYS
 Acute inflammation is a beneficial, nonspecific response of tissues to injury and generally leads to repair and
restoration of the normal structure and function. In contrast, asthma represents a chronic inflammatory process
of the airways followed by healing.
 The end result may be an altered structure referred to as a remodeling of the airways.
 Repair involves replacement of injured tissue by paren-chymal cells of the same type and replacement by
connective tissue and its maturation into scar tissue. In asthma, the repair process can be followed by complete
or altered restitution of airways structure and function, presenting as fibrosis and an increase in smooth
 muscle and mucus gland mass.
 The precise mechanisms of remodeling of the airways are under intense study.
 Airways remodeling is of concern because it mayrepresent an irreversible process that can have more serious
sequelae such as the development of chronic obstructive pulmonary disease.
 Observations in children with asthma indicate that some loss of lung function may occur during the first 5 years
of life.
 Of greatest concern is that no current therapies have been shown to alter either early decreased lung growth or
later increased loss of lung function

31. MUCUS PRODUCTION
 The mucociliary system is the lung’s primary defense mechanism against irritants and infectious agents. Mucus,
composed of 95% water and 5% glycoproteins, is produced by bronchial epithelial
 glands and goblet cells.
 The lining of the airways consists of a continuous aqueous layer controlled by active ion transport across the
epithelium in which water moves toward the lumen along the concentration gradient.
 Catecholamines and vagal stimulation enhance the ion transport and fluid movement.
 Mucus transport depends on the viscoelastic properties of the mucus. Mucus that is either too watery or too
viscous will not be transported optimally.
 The exudative inflammatory process and sloughing of epithelial cells into the airway lumen impair mucociliary
transport. The bronchial glands are increased in size and the goblet cells are increased in size and number in
asthma.
 Expectorated mucus from patients with asthma tends to have a high viscosity. The mucus plugs in the airways of
patients who died in status asthmaticus are tenacious and tend to be connected by mucous strands to the goblet
cells.
 Asthmatic airways also may become plugged with casts consisting of epithelial and inflammatory cells.
Although it is tempting to speculate that death from asthma attacks is a result of the mucus plugging resulting in
irreversible obstruction, there is no direct evidence for this.
 Autopsies of asthmatics who died from other causes have shown similar pathology.

32. AIRWAY SMOOTH MUSCLE
 The smooth muscle of the airways does not form a uniform coat around the airways but is wrapped around in a
connecting network best described as a spiral arrangement.
 The muscle contraction displays a sphincteric action that is capable of completely occluding the airway lumen.
 The airway smooth muscle extends from the trachea through the respiratory bronchioles. When expressed as a percentage
of wall thickness, the smooth muscle represents 5% of the large central airways and up to 20% of the wall thickness in
the bronchioles.
 Total smooth muscle mass decreases rapidly past the terminal bronchioles to the alveoli, so the contribution of smooth
muscle tone to airway diameter in this region is relatively small. In
 the large airways of asthmatics, smooth muscle may account for
 11% of the wall thickness.
 It is possible that the increased smooth muscle mass of the asthmatic airways is important in magnifying and maintaining
BHR in chronic asthma. However, it appears that the hypertrophy and hyperplasia are secondary processes caused by
chronic inflammation and are not the primary cause of BHR.

33. NEURAL CONTROL/NEUROGENIC
INFLAMMATION
 The airway is innervated by parasympathetic, sympathetic, and nonadrenergic inhibitory
nerves.
 Parasympathetic innervation of the smooth muscle consists of efferent motor fibers in the vagus
 nerves and sensory afferent fibers in the vagus and other nerves.
 The normal resting tone of human airway smooth muscle is main-tained by vagal efferent
activity. Maximum bronchoconstriction mediated by vagal stimulation occurs in the small
bronchi and is absent in the small bronchioles. The nonmyelinated C fibers of the afferent
system lie immediately beneath the tight junctions betweenepithelial cells lining the airway
lumen.
 These endings probably represent the irritant receptors of the airways. Stimulation of these
irritant receptors by mechanical stimulation, chemical and particu-late irritants, and
pharmacologic agents such as histamine produces reflex bronchoconstriction.
 The nonadrenergic noncholinergic (NANC) nervous system has been described in the trachea
and bronchi. Substance P, neurokinin A, neurokinin B, and vasoactive intestinal peptide are the
best-character-ized neurotransmitters in the NANC nervous system.
 Vasoactive intestinal peptide is an inhibitory neurotransmitter in the system.
 Inflammatory cells in asthma can release peptidases that can degrade vasoactive intestinal
peptide, producing exaggerated reflex cholinergic bronchoconstriction. NANC excitatory
neuropeptides such as sub-stance P and neurokinin A are released by stimulation of C-
fibersensory nerve endings.
 The NANC system may play an important role in amplifying inflammation in asthma by
releasing NO.

34. NITRIC OXIDE
 NO is produced by cells within the respiratory tract. It has been
thought to be a neurotransmitter of the NANC nervous system.
 Endogenous NO is generated from the amino acid L-arginine by the
enzyme NO synthase.
 There are three isoforms of NO synthase.
 One isoform is induced in response to proinflammatory cytokines,
inducible NO synthase, in airway epithelial cells and inflammatory
cells of asthmatic airways.
 NO produces smooth muscle relaxation in the vasculature and
bronchials; however, it appears to amplify the inflammatory process
and is unlikely to be of therapeutic benefit.
 Recent investigations measuring the fraction of exhaled NO (FeNO)
concentrations have suggested that it may be a useful measure of
ongoing lower airways inflammation in patients with asthma and
for guiding asthma therapy.

35. CLINICAL PRESENTATION
 CHRONIC ASTHMA
 Classic asthma is characterized by episodic dyspnea associated with wheezing; however, the clinical
presentation of asthma is as diverse as the number of triggering events (see Clinical Presentation: Chronic
Ambulatory Asthma).
 Although wheezing is the characteris-tic symptom of asthma, the medical literature is replete with the warning
that “not all that wheezes is asthma.” A wheeze is a high-pitched, whistling sound created by turbulent airflow
through an obstructed airway, so any condition that produces significant obstruction can result in wheezing as a
symptom. In addition, “all of asthma does not wheeze” is an equally justifiable warning. Patients
 may present with a chronic persistent cough as their only symptom.

36. CLINICAL PRESENTATION: CHRONIC
AMBULATORY ASTHMA
General
 ■Asthma is a disease of exacerbation and remission, so the patient may not have any signs or symptoms at the
time of examination.
Symptoms
 ■The patient may complain of episodes of dyspnea, chest tightness, coughing (particularly at night), wheezing,
or a whistling sound when breathing. These often occur in associ-ation with exercise, but also occur
spontaneously or in associ-ation with known allergens.
Signs
 ■Expiratory wheezing on auscultation, dry hacking cough, or signs of atopy (allergic rhinitis and/or eczema)
may occur.
Laboratory
 ■Spirometry demonstrates obstruction (reduced FEV 1 /FVC) with reversibility following inhaled β2-agonist
administration(at least a 12% improvement in FEV1).
Other Diagnostic Tests
 ■A fall in FEV1 of at least 15% following 6 minutes of near maximal exercise. Elevated eosinophil count and
IgE concen-tration in blood. Elevated FeNO (greater than 20 parts per billion in children younger than 12 years
of age, and greater than 25 parts per billion in adults). Positive methacholine challenge (PC 20FEV1 less than
12.5 mg/mL)

37. CLINICAL PRESENTATION:
SEVERE ACUTE ASTHMA
General
 ■An episode can progress over several days or hours (usual scenario) or can progress rapidly over 1 to 2 hours.
Symptoms
 ■The patient is anxious in acute distress and complains of severe dyspnea, shortness of breath, chest tightness,
or burning. The patient is only able to say a few words with each breath.
 Symptoms are unresponsive to usual measures (inhaled short-actingβ2 -agonist administration).
Signs
 ■Signs include expiratory and inspiratory wheezing on ausculta-tion (breath sounds may be diminished with
very severeobstruction), dry hacking cough, tachypnea, tachycardia, paleor cyanotic skin, hyperinflated chest
with intercostal and supra-clavicular retractions, and hypoxic seizures if very severe.
 Laboratory
 ■PEF and/or FEV1less than 50% of normal predicted values.
 Decreased arterial oxygen (PaO2), and O 2 saturations by pulse oximetry (SaO2 less than 90% on room air is
severe).
 Decreased arterial or capillary CO2 if mild, but in the normal range or increased in moderate to severe
obstruction.
Other Diagnostic Tests
 ■Blood gases to assess metabolic acidosis (lactic acidosis) in severe obstruction. Complete blood count if there
are signs of infection (fever and purulent sputum). Serum electrolytes as therapy with β2-agonist and
corticosteroids can lower serum potassium and magnesium and increase glucose. Chest radio-graph if signs of
consolidation on auscultation.

38. EXERCISE-INDUCED BRONCHOSPASM
 During vigorous exercise, pulmonary functions (FEV1 and peak expiratory flow [PEF])
in patients with asthma increase during the first few minutes but then begin to decrease
after 6 to 8 minutes.
 EIB is defined as a drop in FEV1 of greater than 15% of baseline (preexercise value)
 Most studies suggest that many patients with persistent asthma experience EIB.
 The exact pathogenesis of EIB is unknown, but heat loss and/or water loss from the
central airwayappears to play an important role.
 EIB is provoked more easily in cold, dry air, and warm, humid air can blunt or block it.
 A number of studies have demonstrated increased plasma histamine, cysteinyl
leukotrienes, prostaglandins, and tryptase concentrations during EIB, suggesting a role
for mast cell degranulation. A refractory period following EIB lasts up to 3 hours after
exercise. During this period, repeat exercise of the same intensity produces either no
decrease in pulmonary function or a drop of less than 50% of the initial response.
 This refractory period is thought o be caused by an acute depletion of mast cell
mediators and time required for their repletion. Patients with known refractoriness to
exercise will still respond to histamine, so acute hyporesponsiveness of airway smooth
muscle does not appear to be a factor.

39.  Exercise-induced bronchospasm is believed to be a reflection of the
increased BHR of asthmatics. A correlation, though not perfect, exists
between EIB and reactivity to histamine and methacholine.
 Other patient groups with BHR (e.g., after viral infection, cystic
fibrosis, allergic rhinitis) show bronchoconstriction after exercise to a
lesser degree (5% to 10% drop) than patients with asthma (20% to 40%
drops).
 Patients will not always demonstrate the same sensitivity.
 During periods of remission, they often have a decreased sensitivity to
the same degree of exercise. Finally, a number of children and adults
with EIB are otherwise normal, without symptoms or abnormal
pulmonary function except in association with exercise.
 Elite athletes have a higher prevalence of EIB than the general
population

40. DRUG TREATMENT
 The available agents for treating asthma can be divided into two general categories: drugs
that inhibit smooth-muscle contraction, i.e., the so-called “quick relief medications”
adrenergic agonists, methylxanthines, and anticholinergics) and agents that prevent
and/or reverse inflammation, i.e., the “long-term control medications” (glucocorticoids,
long-acting 2-agonists, combined medications, mast cell–stabilizing agents, leukotriene
modifiers, and methylxanthines.
 Quick Relief MedicationsADRENERGIC STIMULANTS The drugs in this category consist
of the catecholamines, resorcinols, and saligenins. These agents produce airway dilation
through stimulation of-adrenergic receptors and activation of G proteins with the
resultant formation of cyclic adenosine monophosphate (AMP). They also decrease
release of mediators and improve mucociliary transport.

42.  The catecholamines(epinephrine, isoproterenol, and isoetharine) are short-acting (30 to 90 min) and are
effective only when administered by inhalational or par-enteral routes. Their use has been superceded by
the longer acting selective beta-2 -agonists terbutaline, fenoterol (a resorsinol), and albuterol (a
saligenin). The resorsinols and saligenins are highly selective for the respiratory tract and are virtually
devoid of significant cardiac ef-fects except at high doses.
 Their major side effect is tremor. They are active by all routes of administration and are relatively long-
lasting (4 to 6 h). Inhalation is the preferred route because it allows maximal bronchodilation with fewer
side effects. In treating episodes of severe asthma, intravenous administration offers no advantages over
the inhaled route. Very long lasting compounds (salmeterol and formoterol)are available and provide
sustained effects for 9 to 12 h .
 They are particularly helpful for conditions such as nocturnal and exercise-induced asthma. Salmeterol is
not recommended for the treatment of acute epi-sodes because of its relatively slow onset of action (30
min), nor is it intended as a rescue drug for breakthrough symptoms. In addition, its long half-life means
that administration of extra doses can cause cumulative side effects.
 The limits to the use of formoterol are not yet fully established. These compounds are now thought of as
long-term controller medications by some, presumably because of their anti-inflammatory activities

43. METHYLXANTHINES
 Theophylline and its various salts are medium-potency bronchodilators with questionable anti-inflammatory properties.
The therapeutic plasma concentrations of theophylline lie between 5 and 15g/mL. The dose required to achieve the
desired level varies widely from patient t patient owing to differences in the metabolism of the drug.
 Clearance falls with age and the concurrent use of erythromycin and other ma-crolide antibiotics, the quinolone
antibiotics, and troleandomycin, al-lopurinol, cimetidine, and propranolol. It rises with use of cigarettes, marijuana,
phenobarbital, phenytoin, or any other drug that is capable of inducing hepatic microsomal enzymes.
 For maintenance therapy, long-acting theophylline compounds are available and are usually given once or twice daily.
The dose is ad-justed on the basis of the clinical response with the aid of serum the-ophylline measurements.
 Single-dose administration in the evening reduces nocturnal symptoms and helps keep the patient complaint-free during
the day. However, the methylxanthines can disrupt sleep ar-chitecture. They are now considered second-line therapy, and
as such they are rarely used in acute situations and infrequently in chronic ones.
 There is minimal evidence for additional benefit when used with optimal doses of-adrenergics. There are some data that
the meth-ylxanthines can decrease inflammation, but as with the long-acting2 -agonists, the effect is not large and its
clinical impact is undefined.
 Nonetheless, some authorities now place these compounds in the “controller” class
 The most common side effects are nerv-ousness, nausea, vomiting, anorexia, and headache. At plasma levels 30g/mL
there is a risk of seizures and cardiac arrhythmias.

44. ANTICHOLINERGICS
 Anticholinergic drugs such as ipratropium bromide have been found to be both
effective and free of untoward effects.
 They may be of particular benefit for patients with coexistent heart disease, in whom
the use of methylxanthines and-adrenergic stim-ulants may be dangerous.
 The major disadvantages of the anticholin-ergics are that they are slow to act (60 to 90
min may be required before peak bronchodilation is achieved)and they are of only
modest potency.

45. Long-Term Controller Medications
 GLUCOCORTICOIDS
 Glucocorticoids are the most potent and most effective anti-inflammatory medications
available. Systemic or oral steroids are most beneficial in acute illness, when severe
airway obstruction is not resolving or is worsening despite intense optimal
bronchodilator therapy, and in chronic disease, when there has been failure of a
previously optimal regimen with frequent recurrences of symptoms of increasing
severity.
 Inhaled glucocorticoids are used in the long-term control of asthma

47.  Inhaled Glucocorticoids
 These drugs are indicated in patients with persistent symptoms.
 These drugs share the ability to control inflammation, facilitate the long-term pre-vention of symptoms, reduce
the need for oral glucocorticoids, mini-mize acute occurrences, and prevent hospitalizations.
 There is no fixed dose of inhaled steroid that works for all patients.
 Requirements are dictated by the response of the individual and wax and wane in concert with progression of the
disease. Generally, the worse the patient’s condition, the more inhaled steroid is needed to gain control.
 Once achieved, however, remission can often be main-tained with quantities as low as one or two puffs/day.
Inhaled steroids can take up to a week or more to produce improvements; consequently, in rapidly deteriorating
situations, it is best to prescribe oral prepara-tions and initiate inhaled drugs as the dose of the former is reduced.
 In less emergent circumstances, the quantity of inhaled drug can be increased up to 2 to 2.5 times the
recommended starting doses.
 The side effects increase in proportion to the dose-time product. In addition to thrush and dysphonia, the
increased systemic absorption that ac-companies larger doses of inhaled steroids has been reported to pro-duce
adrenal suppression, cataract formation, decreased growth in children, interference with bone metabolism, and
purpura.
 As is the case with oral agents, suppression of inflammation, per se, cannot be relied upon to provide optimal
results. It is essential to continue adrenergic or methylxanthine bronchodilators if the patient’s disease is
unstable.
 The combination of a long acting-agonist and inhaled ster-oid seems particularly efficacious in patients with
mild to moderate disease

48. MAST CELL–STABILIZING AGENTS
 Cromolyn sodium and nedocromil sodium do not influence airway tone. Their major therapeutic effect is
to inhibit the degranulation of mast cells, thereby preventing the re-lease of the chemical mediators of
anaphylaxis.
 Cromolyn sodium and nedocromil sodium, like the inhaled ster-oids, improve lung function, reduce
symptoms, and lower airway re-activity in persons with asthma. They are most effective in atopic
patients who have either seasonal disease or perennial airway stimu-lation.
 A therapeutic trial of two puffs four times daily for 4 to 6 weeks is frequently necessary be-fore the
beneficial effects of the drug appear. Unlike steroids, nedocromil and cromolyn sodium, when given
prophylactically, block the acute obstructive ef-fects of exposure to antigen, in-dustrial chemicals,
exercise, or cold air. With antigen, the late response is also abolished. There-fore, a patient who has
intermit-tent exposure to either antigenic or nonantigenic stimuli that pro-voke acute episodes of asthma
need not use these drugs contin-uously but instead can obtain pro-tection by taking the drug only 15 to 20
min before contact with the precipitant.

49. LEUKOTRIENE MODIFIERS
 As mentioned earlier, the cysteinyl leukotrienes (LTC 4, LTD 4, and LTE 4 )produce many of the critical elements of
asthma, and drugs have been developed that either reduce the synthesis of all of the leukotrienes by inhibiting 5-
lipoxygenase (5-LO), the enzyme involved in their production, or competitively antagonize the principal moiety (LTD4 ).
 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-in-duced asthma, and diminishes nocturnal symptoms, but
it has limited effectiveness against allergens. Hepatic enzyme levels can be elevated after its use, and there are significant
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.
 This class of drugs does not appear to be uniformly effective in all patients with asthma. Although precise figures are
lacking, most au-thorities put the number of positive responders at50%.
 As yet, there is no way of determining prospectively who will benefit, so clinical trials are required.
 Typically, if there is no improvement after 1month, treatment can be discontinued. The leukotriene blockers have been
associated with uncovering of Churg-Strauss syndrome .