Etiopathogenesis and pharmacotherapy of Asthma the pathophysiology of selected disease states and the rationale for drug therapy; b. the therapeutic approach to management of these diseases; c. the controversies in drug therapy; d. the importance of preparation of individualised therapeutic plans based on diagnosis; e. needs to identify the patient-specific parameters relevant in initiating drug therapy, and monitoring therapy (including alternatives, time-course of clinical and laboratory indices of therapeutic response and adverse effects); f. describe the pathophysiology of selected disease states and explain the rationale for drug therapy; g. summarise the therapeutic approach to management of these diseases including reference to the latest available evidence; h. discuss the controversies in drug therapy; i. discuss the preparation of individualised therapeutic plans based on diagnosis; and j. identify the patient-specific parameters relevant in initiating drug therapy, and monitoring therapy (including alternatives, time-course of clinical and laboratory indices of therapeutic response and adverse effects).

1. DOCTOR OF PHARMACY
II YEAR
ASTHMA
CHAPTER-2
RESPIRATORY SYSTEM
Dr. V. Chanukya (Pharm D)

2. History
• Asthma means ‘laboured breathing/ panting.’ in Greek and was first
described 3000 years ago.
• It is a broad term used to refer to a disorder of the respiratory system
that leads to episodic difficulty in breathing.
• Hippocrates used the word asthma to describe episodic shortness of
breath; however, the first detailed clinical description of the asthmatic
patient was made by Aretaeus in the second century

3. Introduction
• The national UK guidelines (BTS/SIGN, 2009) define asthma as ‘a
chronic inflammatory disorder of the airways which occurs in
susceptible individuals; inflammatory symptoms are usually
associated with widespread but variable airflow obstruction and an
increase in airway response to a variety of stimuli.
• According to National Institutes of Health, the National Asthma
Education and Prevention Program (NAEPP), 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.
• Obstruction is often reversible either spontaneously or with treatment’
and reversibility of airflow limitation may be incomplete in some
patients with asthma.

4. Epidemiology
• The exact prevalence of asthma remains uncertain because of the
differing ways in which airway restriction is reported, diagnostic
uncertainty (especially for children under 2 years) and the overlap
with other conditions such as chronic obstructive pulmonary disease
(COPD).
• 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.

5. • Over 5 million people in the UK have asthma (Asthma UK, 2001) and
around 300 million worldwide.
• Mortality from asthma is estimated at approximately 0.4 per 100,000
with around 1400 deaths per annum in the UK.
• Most deaths occur outside hospital; the most common reasons for
death are thought to be inadequate assessment of the severity of
airway obstruction by the patient and/or clinician and inadequate
therapy with inhaled or oral steroids.

6. • Ethnic minorities continue to share the burden of asthma
disproportionately.
• African Americans have a higher prevalence than whites, but this
appears to be a result of urbanization and not race or socioeconomic
status.
• African Americans are three times as likely to be hospitalized and
approximately 2.5 times more likely to die from asthma.
• These patterns are likely a result of poor access to care as Hispanics in
general have a lower prevalence than African Americans or whites.

7. Etiology
Genetic / Heriditary
• Genetic factors account for 35% to 70% of the susceptibility.
• Asthma represents a complex genetic disorder in that the asthma
phenotype is likely a result of polygenic inheritance or different
combinations of genes.
• Initial searches focused on establishing links between atopy
(genetically determined state of hypersensitivity to environmental
allergens) and asthma, but more recent genome-wide searches have
found linkages with genes for metalloproteinases (e.g., ADAM33).

8. • Thus, although genetic predisposition to atopy is a significant risk
factor for developing asthma, not all atopic individuals develop
asthma, nor do all asthmatics exhibit atopy.
• Environmental risk factors
• Environmental risk factors for the development of asthma include
socioeconomic status, family size, exposure to secondhand tobacco
smoke in infancy and in utero, allergen exposure, urbanization, and
increased exposure to common childhood infectious agent.

9. The “hygiene hypothesis
• The “hygiene hypothesis” proposes that genetically susceptible
individuals develop allergies and asthma by allowing the allergic
immunologic system (T-helper cell type 2 [TH2]-lymphocytes) to
develop instead of the immunologic system used to fight infections (T-
helper cell type 1 [TH1]-lymphocytes), and is being used to explain
the increase of asthma in Western countries.
• The first 2 years of life appear to be most important for the exposures
to produce an alteration in the immune response system.

10. • Epidemics of severe asthma in cities have followed exposures to high
concentrations of aeroallergens.
• Viral respiratory tract infections remain the single most significant
precipitant of severe asthma in children, and are an important trigger
in adults as well.
• Other possible factors include air pollution, sinusitis, food
preservatives, and drugs.

11. MARCH -2019 170101 /Chapter-3 /S11
EDUCATION FOR PEACE & PROGRESS
COPY RIGHTS RESERVED
Santhiram College of Pharmacy, Nandyal

12. Pathophysiology
• The two main causes of asthma symptoms are airway
hyperresponsiveness and bronchoconstriction.
• Hyperresponsiveness is an increased tendency of the airway to react to
stimuli or triggers to cause an asthma attack.
• Bronchoconstriction is a narrowing of the airways that causes airflow
obstruction
• Asthma can be classified according to the underlying pattern of
airway inflammation with the presence or absence of eosinophils in
the airways (eosinophilic vs. non-eosinophilic).

13. • Traditionally patients are described as having ‘extrinsic asthma’
when an allergen is thought to be the cause of their asthma.
• This is more common in children with a history of atopy, where
triggers, such as dust mite, cause IgE production.
• Other environmental factors are also important, such as exposure to
rhinovirus during the first 3 years of life.
• ‘Intrinsic asthma’ develops in adulthood, with symptoms triggered
by non-allergenic factors such as a viral infection, irritants which
cause epithelial damage and mucosal inflammation, emotional
upset which mediates excess parasympathetic input or exercise
which causes water and heat loss from the airways, triggering
mediator release from mast cells.

14. • In practice, patients often have features of both types of asthma and
the classification is unhelpful and oversimplifies the pathogenesis of
asthma.
• Mast cell components are released as a result of an IgE antibody-
mediated reaction on the surface of the cell.
• Histamine and other mediators of inflammation are released from
mast cells, for example, leukotrienes, prostaglandins, bradykinin,
adenosine and prostaglandin-generating factor of anaphylaxis, as well
as various chemotactic agents that attract eosinophils and neutrophils.

15. • Macrophages release prostaglandins, thromboxane and platelet-
activating factor (PAF).
• PAF appears to maintain bronchial hyperreactivity and cause
respiratory capillaries to leak plasma, which increases mucosal
oedema.
• PAF also facilitates the accumulation of eosinophils within the
airways, a characteristic pathological feature of asthma.
• Eosinophils release various inflammatory mediators such as
leukotriene C4 (LTC4) and PAF.
• Epithelial damage results and thick viscous mucus is produced that
causes further deterioration in lung function.

16. • These cell-derived mediators also play a role in causing marked
hypertrophy and hyperplasia of bronchial smooth muscle (these
structural changes are described as ‘airway remodelling’), mucus
gland hypertrophy leading to excessive mucus production and airway
plugging, airway oedema, acute bronchoconstriction and impaired
mucociliary clearance.
• Mucus production is normally a defence mechanism, but in asthma
patients, there is an increase in the size of bronchial glands and goblet
cells that produce mucus.
• Mucus transport is dependent on its viscosity.

17. • If it is very thick, it plugs the airways, which also become blocked
with epithelial and inflammatory cell debris.
• Mucociliary clearance is also decreased due to inflammation of
epithelial cells.
• The environmental factors causing asthma are also thought to affect
the structure and function of the airway epithelium.
• The exact role of these cytokines, cellular mediators and the
interrelationships with each other and with the causative allergenic or
non-allergenic mechanisms has, however, yet to be fully determined
and may vary over time elisuated.

18. Pathophysiology over view

20. Clinical presentations

21. Chronic asthma
• Classic asthma is characterized by episodic dyspnea associated with
wheezing, but the clinical presentation of asthma is diverse.
• Patients may also complain of episodes of dyspnea, chest tightness,
coughing (particularly at night), wheezing, or a whistling sound
when breathing.
• These often occur with exercise but may occur spontaneously or in
association with known allergens.
• Signs include expiratory wheezing on auscultation, dry hacking
cough, or signs of atopy (e.g., allergic rhinitis or eczema).

22. • Asthma can vary from chronic daily symptoms to only intermittent
symptoms.
• The intervals between symptoms may be days, weeks, months, or
years.
• The severity is determined by lung function, symptoms, night time
awakenings, and interference with normal activity prior to therapy.
• Patients can present with mild intermittent symptoms that require no
medications or only occasional use of short-acting inhaled β2-agonists
to severe chronic asthma symptoms despite receiving multiple
medications.

23. Severe acute asthma
• Uncontrolled asthma can progress to an acute state where
inflammation, airway edema, excessive mucus accumulation, and
severe bronchospasm result in profound airway narrowing that is
poorly responsive to usual bronchodilator therapy.
• Patients may be anxious in acute distress and complain of severe
dyspnea, shortness of breath, chest tightness, or burning.
• They may be able to say only a few words with each breath.
Symptoms are unresponsive to usual measures.

24. • Signs include expiratory and inspiratory wheezing on auscultation,
dry hacking cough, tachypnea, tachycardia, pallor or cyanosis, and
hyperinflated chest with intercostal and supraclavicular
retractions.
• Breath sounds may be diminished with very severe obstruction.

25. Investigations
CHRONIC ASTHMA
• The diagnosis of asthma is made primarily by a history of recurrent
episodes of coughing, wheezing, chest tightness, or shortness of
breath and confirmatory spirometry.
• The patient may have a family history of allergy or asthma or have
symptoms of allergic rhinitis.
• A history of exercise or cold air precipitating dyspnea or increased
symptoms during specific allergen seasons also suggests asthma.

26. • Spirometry demonstrates obstruction (forced expiratory volume
in 1 second [FEV1]/forced vital capacity less than 80%) with
reversibility after inhaled β2-agonist administration (at least a
12% improvement in FEV1).
• Failure of pulmonary function to improve acutely does not
necessarily rule out asthma.
• If baseline spirometry is normal, challenge testing with exercise,
histamine, or methacholine can be used to elicit BHR.

27. Acute severe asthma
• Peak expiratory flow (PEF) and FEV1 are less than 50% of normal
predicted values.
• Pulse oximetry reveals decreased arterial oxygen and O2 saturations.
• The best predictor of outcome is early response to treatment as
measured by improvement in FEV1 at 30 minutes after inhaled β2-
agonists.
• Arterial blood gases may reveal metabolic acidosis and a low PaO2.
• The history and physical examination should be obtained while initial
therapy is being provided.

28. • A history of previous asthma exacerbations (e.g., hospitalizations,
intubations) and complicating illnesses (e.g., cardiac disease,
diabetes) should be obtained.
• The patient should be examined to assess hydration status; use of
accessory muscles of respiration; and the presence of cyanosis,
pneumonia, pneumothorax, pneumomediastinum, and upper airway
obstruction.
• A complete blood count may be appropriate for patients with fever or
purulent sputum.

29. • Normal individuals can exhale at least 70% of their total capacity in 1
second.
• In obstructive lung disorders, such as asthma, the FEV1 is usually
decreased, the FVC normal or slightly reduced and the FEV1/FVC
ratio decreased, usually <0.7.

30. • A peak flow meter is a useful means of self-assessment for the patient.
• It gives slightly less reproducible results than the spirometer but has
the advantage that the patient can do regular tests at home with a
hand-held meter.
• The peak flow meter measures peak expiratory flow (PEF) rate, the
maximum flow rate that can be forced during expiration.
• The PEF can be used to assess the improvement or deterioration in the
disease as well as the effectiveness of treatment.

31. Treatment- Aims and goals
• CHRONIC ASTHMA
• The NAEPP provides the following goals for chronic asthma
management:
 Reducing impairment:
1. prevent chronic and troublesome symptoms (e.g., coughing or
breathlessness in the daytime, at night, or after exertion);
2. Require infrequent use ( ≤2 days/wk) of inhaled short-acting β2-
agonist for quick relief of symptoms (not including prevention of
exercise-induced bronchospasm

32. 3. Maintain (near-) normal pulmonary function;
4. Maintain normal activity levels (including exercise and attendance at
work or school)
5. Meet patients’ and families’ expectation of and satisfaction with care.
Reducing risk:
1. Prevent recurrent exacerbations and minimize the need for visits or
hospitalizations
2. Prevent loss of lung function; for children, prevent reduced lung
growth;
3. Minimal or no adverse effects of therapy.

33. Acute severe asthma
• The goals of treatment include:
1. Correction of significant hypoxemia;
2. Rapid reversal of airway obstruction (within minutes);
3. Reduction of the likelihood of recurrence of severe airflow
obstruction
4. Development of a written action plan in case of a future exacerbation.

34. Nonpharmacologic and ancillary therapy
• Infants and young children may be mildly dehydrated owing to
increased insensible loss, vomiting, and decreased waater intake.
• Unless dehydration has occurred, increased fluid therapy is not
indicated in acute asthma management because the capillary leak from
cytokines and increased negative intrathoracic pressures may promote
edema in the airways.
• Correction of significant dehydration is always indicated, and the
urine specific gravity may help to guide therapy in young children, in
whom the state of hydration may be difficult to determine.

35. • Chest physio therapy and mucolytics are not recommended in the
therapy of acute asthma.
• Sedatives should not be given because anxiety may be a sign of
hypoxemia, which could be worsened by central nervous system
depressants.
• Antibiotics also are not indicated routinely because viral respiratory
tract infections are the primary cause of asthma exacerbations.
• Antibiotics should be reserved for patients who have signs and
symptoms of pneumonia (e.g., fever, pulmonary consolidation, and
purulent sputum from polymorphonuclear leukocytes).

36. Pharmacotherapy
β2-Agonists
• The short-acting inhaled β2-agonists are the most effective
bronchodilators and the treatment of first choice for the management
of severe acute asthma.
• Up to 66% of adults presenting to an emergency department require
only three doses of 2.5-mg nebulized albuterol to be discharged.
• Aerosol administration enhances bronchoselectivity and provides a
more rapid response and greater protection against provocations that
induce bronchospasm (e.g., exercise, allergen challenges) than does
systemic administration.

37. • Systemic adverse effects, hypokalemia, hyperglycemia, tachycardia,
and cardiac dysrhythmias are more pronounced in patients receiving
systemic β2-agonist therapy.
• Children younger than 2 years of age achieve clinically significant
responses from nebulized albuterol.
• Effective doses of aerosolized β2-agonists can be delivered
successfully through mechanical ventilator circuits to infants,
children, and adults in respiratory failure secondary to severe airways
obstruction.

39. • Albuterol and other inhaled short-acting selective β2 -agonists are
indicated for treatment of intermittent episodes of bronchospasm and
are the first treatment of choice for acute severe asthma and EIB.
• Regular treatment (four times daily) does not improve symptom
control over as-needed use.
• Formoterol and salmeterol are inhaled long-acting β2-agonists
indicated as adjunctive long-term control for patients with symptoms
who are already on low to medium doses of inhaled corticosteroids
prior to advancing to medium- or high-dose inhaled corticosteroids.

40. • Short-acting β2 –agonists should be continued for acute
exacerbations.
• Long-acting agents are ineffective for acute severe asthma because it
can take up to 20 minutes for onset and 1 to 4 hours for maximum
bronchodilation after inhalation.
• In acute severe asthma, continuous nebulization of short-acting β 2-
agonists (e.g., albuterol) is recommended for patients having an
unsatisfactory response after three doses (every 20 minutes) of
aerosolized β 2 -agonists and potentially for patients presenting
initially with PEF or FEV1 values <30% of predicted normal.

41. • Inhaled β2 -agonists agents are the treatment of choice for EIB.
• Shortacting agents provide complete protection for at least 2 hours
after inhalation; long-acting agents provide significant protection for 8
to 12 hours initially, but the duration decreases with chronic regular
use.
• In nocturnal asthma, long-acting inhaled β2-agonists are preferred
over oral sustained-release β2 -agonists or sustained-release
theophylline.
• However, nocturnal asthma may be an indicator of inadequate
antiinflammatory treatment.

42. Corticosteroids
• Corticosteroids increase the number of β2 -adrenergic receptors and
improve receptor responsiveness to β 2 -adrenergic stimulation,
thereby reducing mucus production and hypersecretion, reducing
BHR, and reducing airway edema and exudation.
• Inhaled corticosteroids are the preferred long-term control therapy for
persistent asthma in all patients because of their potency and
consistent effectiveness; they are also the only therapy shown to
reduce the risk of death from asthma.
• Most patients with moderate disease can be controlled with twice-
daily dosing; some products have once-daily dosing indications.

43. • Patients with more severe disease require multiple daily dosing.
• Because the inflammatory response of asthma inhibits steroid
receptor binding, patients should be started on higher and more
frequent doses and then tapered down once control has been
achieved.
• The response to inhaled corticosteroids is delayed; symptoms
improve in most patients within the first 1 to 2 weeks and reach
maximum improvement in 4 to 8 weeks.
• Maximum improvement in FEV1 and PEF rates may require 3 to 6
weeks.

45. • Prednisone, 1 to 2 mg/kg/day (up to 40 to 60 mg/day), is
administered orally in two divided doses for 3 to 10 days.
• Because short-term (1 to 2 weeks), high-dose systemic steroids do
not produce serious toxicities, the ideal method is to use a short
burst and then maintain the patient on appropriate long-term control
therapy with inhaled corticosteroids.
• In patients who require chronic systemic corticosteroids for asthma
control, the lowest possible dose should be used.
• Toxicities may be decreased by alternate-day therapy or high-dose
inhaled corticosteroids.

46. Methylxanthines
• Theophylline appears to produce bronchodilation by inhibiting
phosphodiesterases, which may also result in antiinflammatory and
other nonbronchodilator activity through decreased mast cell
mediator release, decreased eosinophil basic protein release,
decreased T-lymphocyte proliferation, decreased T-cell cytokine
release, and decreased plasma exudation.
• Methylxanthines are ineffective by aerosol and must be taken
systemically (orally or IV).
• Sustained-release theophylline is the preferred oral preparation,
whereas its complex with ethylenediamine (aminophylline) is the
preferred parenteral product due to increased solubility.

47. • Theophylline is eliminated primarily by metabolism via hepatic
cytochrome P450 mixed-function oxidase microsomal enzymes
(primarily CYP1A2 and CYP3A4) with 10% or less excreted
unchanged in the kidney.
• Because of large interpatient variability in theophylline clearance,
routine monitoring of serum theophylline concentrations is essential
for safe and effective use.
• A steady-state range of 5 to 15 mcg/mL is effective and safe for most
patients.
• Adverse effects include nausea, vomiting, tachycardia, jitteriness, and
difficulty sleeping; more severe toxicities include cardiac
tachyarrhythmias and seizures.

48. Anticholinergics
• Ipratropium bromide and tiotropium bromide are competitive
inhibitors of muscarinic receptors; they produce bronchodilation only
in cholinergic mediated bronchoconstriction.
• Anticholinergics are effective bronchodilators but are not as potent as
β2-agonists.
• They decrease, but do not block, allergen- or exercise-induced asthma
in a dose-dependent fashion.
• The time to reach maximum bronchodilation from aerosolized
ipratropium is longer than from aerosolized short-acting β2-agonists
(30 to 60 minutes vs. 5 to 10 minutes).

49. • Ipratropium bromide has a duration of action of 4 to 8 hours;
tiotropium bromide has a duration of 24 hours.
• Inhaled ipratropium bromide is only indicated as adjunctive therapy in
severe acute asthma not completely responsive to β2-agonists alone
because it does not improve outcomes in chronic asthma.
• Tiotropium bromide has not been studied in asthma.
• Adverse effects of Ipratropium bromide includes occasionally dry
mouth, precipitation of acute glaucoma with nebulised therapy,
possibly worsened by co-administration of salbutamol.
• A mouthpiece should be used to minimise the exposure of the eyes to
the nebulised drug
• Rarely: systemic anticholinergic effects such as urinary retention and
constipation

50. Mast cell stabilizers
• Cromolyn sodium and nedocromil sodium have beneficial effects
that are believed to result from stabilization of mast cell membranes.
• They inhibit the response to allergen challenge as well as EIB but do
not cause bronchodilation.
• These agents are effective only by inhalation and are available as
metereddose inhalers; cromolyn also comes as a nebulizer solution.
• Cough and wheezing have been reported after inhalation of each
agent, and bad taste and headache after nedocromil.
• Cromolyn and nedocromil are indicated for the prophylaxis of mild
persistent asthma in children and adults regardless of etiology.

51. Leukotriene Modifiers
• Zafirlukast and montelukast are oral leukotriene receptor
antagonists that reduce the proinflammatory (increased microvascular
permeability and airway edema) and bronchoconstriction effects of
leukotriene D4.
• In adults and children with persistent asthma, they improve pulmonary
function tests, decrease nocturnal awakenings and β2-agonist use, and
improve asthma symptoms.
• However, they are less effective in asthma than low-dose inhaled
corticosteroids.

52. • They are not used to treat acute exacerbations and must be taken on a
regular basis, even during symptom-free periods.
• The adult dose of zafirlukast is 20 mg twice daily, taken at least 1
hour before or 2 hours after meals; the dose for children aged 5
through 11 years is 10 mg twice daily.
• For montelukast, the adult dose is 10 mg once daily, taken in the
evening without regard to food; the dose for children aged 6 to 14
years is one 5-mg chewable tablet daily in the evening.
• Adverse effects include Abdominal pain, headache, diarrhoea,
dizziness, upper respiratory tract infections.
• Rarely: acute hepatitis (associated with zafirlukast), Churg–Strauss
syndrome.

53. Anti-IgE antibody
• Omalizumab is an anti-IgE antibody approved for the treatment of
allergic asthma not well controlled by oral or inhaled corticosteroids.
• The dosage is determined by the patient’s baseline total serum IgE
(international units/mL) and body weight (kg). Doses range from 150
to 375 mg given subcutaneously at either 2- or 4-week intervals.
• Because of its high cost, it is only indicated as step 5 or 6 care for
patients who have allergies and severe persistent asthma that is
inadequately controlled with the combination of high-dose inhaled
corticosteroids and long-acting β2-agonists.

54. • Because it is associated with a 0.1% incidence of
anaphylaxis, patients should remain in the physician’s
office for a reasonable period after the injection because
70% of reactions occur within 2 hours.
• Some reactions have occurred up to 24 hours after
injection.

55. Combination Controller Therapy
• The addition of a second long-term control medication to inhaled
corticosteroid therapy is one recommended treatment option in
moderate to severe persistent asthma.
• Single-inhaler combination products containing fluticasone propionate
and salmeterol (Advair) or budesonide and formoterol (Symbicort) are
currently available.
• The inhalers contain varied doses of the inhaled corticosteroid with a
fixed dose of the long-acting β2-agonist.
• The addition of a long-acting β2-agonist allows a 50% reduction in
inhaled corticosteroid dosage in most patients with persistent asthma..

56. • Combination therapy is more effective than higher-dose inhaled
corticosteroids alone in reducing asthma exacerbations in patients
with persistent asthma.
• Leukotriene receptor antagonists also are successful as additive
therapy in patients inadequately controlled on inhaled corticosteroids
alone and as corticosteroid-sparing therapy.
• However, the magnitude of these benefits is less than that reported
with the addition of long-acting β2-agonists.

57. Summary of stepwise management in adults

58. Summary of stepwise management in adults