notes on asthma disease

1. ASTHMA
Dr Michelle Munyoro
MBChB, MSc (UZ)

2. OVERVIEW
• Common chronic inflammatory condition of the airways consisting of
- Airflow limitation
- Airway hyper-responsiveness
- Inflammation of the bronchi

3. Epidemiology
• Affects 10 to 15% of general population
• More common in developed countries
• Genetic predisposition plus environmental interaction
• Extrinsic- with a definite external cause
• Intrinsic-when no causative agent can be found

4. Pathogenesis

5. Pathophysiology
• Inhaled allergens cause an early-phase allergic reaction characterized
by activation of cells bearing allergen-specific immunoglobulin E (IgE)
antibodies.
• There is rapid activation of airway mast cells and macrophages, which
release proinflammatory mediators such as histamine and
eicosanoids that induce contraction of airway smooth muscle, mucus
secretion, vasodilation, and exudation of plasma in the airways.
• Plasma protein leakage induces a thickened, engorged, edematous
airway wall and a narrowing of the airway lumen with reduced mucus
clearance

6. Pathophysiology
• The late-phase inflammatory reaction occurs 6 to 9 hours after allergen
provocation and involves recruitment and activation of eosinophils, T
lymphocytes, basophils, neutrophils, and macrophages.
• Eosinophils migrate to the airways and release inflammatory mediators
(leukotrienes and granule proteins), cytotoxic mediators, and cytokines.
• T-lymphocyte activation leads to release of cytokines from type 2 T-helper
(TH2) cells that mediate allergic inflammation (interleukin [IL]-4, IL-5, and
IL-13).
• Conversely, type 1 T-helper (TH1) cells produce IL-2 and interferon γ that
are essential for cellular defense mechanisms.
• Allergic asthmatic inflammation may result from an imbalance between
TH1 and TH2 cells.

7. Pathophysiology
• Mast cell degranulation in response to allergens results in release of
mediators such as histamine
• The 5-lipoxygenase pathway of arachidonic acid metabolism is
responsible for production of cysteinyl leukotrienes. Leukotrienes C4,
D4, and E4 are released during inflammatory processes in the lung
and produce bronchospasm, mucus secretion, microvascular
permeability, and airway edema
• 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

8. Pathophysiology
• The airway is innervated by parasympathetic, sympathetic, and
nonadrenergic inhibitory nerves.
• The normal resting tone of airway smooth muscle is maintained by
vagal efferent activity, and bronchoconstriction can be mediated by
vagal stimulation in the small bronchi.
• Airway smooth muscle contains noninnervated β 2-adrenergic
receptors that produce bronchodilation.

12. Clinical Presentation
• Classic asthma is characterized by episodic dyspnea associated with
wheezing
• chest tightness
• coughing (particularly at night),
• Wheezing
• 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).

13. Clinical features before treatment#
Symptoms¶ Night-time symptoms Lung function
Step 4: severe persistent Continual symptoms Frequent FEV1 or PEF ≤60% pred
Limited physical activity PEF variability >30%
Frequent exacerbations
Step 3: moderate
persistent
Daily symptoms More than once per week FEV1 or PEF >60 and ≤80% pred
Daily use of inhaled SABA PEF variability >30%
Exacerbations affect activity
Exacerbations more than twice
per week; may last days
Step 2: mild persistent Symptoms more than twice per
week but no more than once per
day
More than twice per month FEV1 or PEF ≥80% pred
Exacerbations may affect activity PEF variability 20–30%
Step 1: mild intermittent Symptoms no more than twice
per week
No more than twice per month FEV1 or PEF ≥80% pred
Asymptomatic and normal PEF
between exacerbations
PEF variability <20%
Exacerbations are brief (from a

14. LEVEL OF ASTHMA CONTROL (WHO)
Well Controlled Partially Controlled Poorly Controlled
Daytime symptoms in past 2–4
weeks
≤ 2 days/week but not more
than once daily
> 2 days/week or more than
once daily
Throughout the day
Limitation of activities in the
past 2–4 weeks
None Some limitation Extremely limited
Nocturnal
symptoms/awakenings in past
2–4 weeks
None ≤ 2 nights/week > 2 nights/week
Need for short-acting β2-
agonists in past 2–4 weeks
≤ 2 days/week > 2 days/week Several times a day
FEV1 or peak flow% predicted ≥ 80 60–79 < 60
Exacerbations annually requiring
oral or systemic corticosteroids
0–1 2 > 2

15. Goals of Therapy
• Reducing impairment
— Prevent chronic and troublesome symptoms (e.g., coughing or breathlessness in the
daytime, in the night, or after exertion)
— Require infrequent use (≤2 days a week) of SABA for quick relief of symptoms
— Maintain (near) normal pulmonary function
— Maintain normal activity levels (including exercise and other physical activity and
attendance at work or school)
— Meet patients' and families' expectations of and satisfaction with asthma care
• Reducing risk
— Prevent recurrent exacerbations of asthma, and minimize the need for ED visits or
hospitalizations
— Prevent progressive loss of lung function; for youths, prevent reduced lung growth
— Provide optimal pharmacotherapy with minimal or no adverse effects

17. Beta 2 agonists
• are the most effective bronchodilators
a) Short -acting β-agonists (albuterol , levalbuterol , pirbuterol ,
metaproterenol ) are best reserved for worsening symptoms, treatment
of acute exacerbations, and prophylaxis for EIB
b) Long-acting β2 -agonists (salmeterol , formoterol , arformterol ) for
maintenance treatment of moderate and severe persistent asthma in
combination with inhaled corticosteroids,
c) The use of a LABA, combined with an ICS, is a mainstay of treatment
for patients with moderate to severe asthma
d) Long-acting β-agonists should be used only in combination with ICSs

18. Mechanism of action
• β2 -Agonists stimulate β2 - receptors, activating adenyl cyclase,
which increases intracellular production of cyclic adenosine
monophosphate (cAMP) .
• Increased intracellular cAMP and activation of cAMP result in smooth
muscle relaxation(bronchodilation), improved mucociliary clearance
and reduced inflammatory cell mediator release due to mast cell
membrane stabilization.

19. • Aerosol administration enhances bronchoselectivity
• provides a more rapid response and greater protection against
provocations that induce bronchospasm (e.g., exercise, allergen
challenges) than does systemic administration

20. Side effects
• Common adverse effects of β-agonists include tremor , palpitation,
tachycardia, nervousness, headache, leg cramps may occur with high
doses
• Nonselective β-agonists (e.g. isoproterenol ) may induce myocardial
ischemia, myocardial necrosis, and arrhythmias
• Tachyphylaxis
• Hypokalemia
• Paradoxical bronchoconstriction

21. 2. Corticosteroids
a) are by far the most effective controllers of the underlying
inflammatory process in the airways
b) Mechanism of action.
• bind to glucocorticoid receptors on the cytoplasm of cells.
The activated receptor regulates transcription of target
genes.
• Corticosteroids reduce inflammation via:
(a) Inhibition of transcription and release of inflammatory
genes
(b) Increased transcription of anti- inflammatory genes that
produce proteins that participate in or suppress the
inflammatory process

22. Corticosteroids cont…
Clinical effects include
(a) Reduced production of inflammatory mediators
(b) Enhanced β-adrenergic receptor expression ( thus making the β2 -
agonist work better )
(c) Decreased mucus production
(d) Prevention of endothelial and vascular leakage
(e) Partial reversal of tissue- remodeling
• route of administration is determined by the condition of the patient

23. Corticosteroids
• Inhaled corticosteroids
-Beclomethasone dipropionate (BDP)
-Budesonide
-Flunisolide (FLU)
-Fluticasone propionate (FP)
-Mometasone furoate (MF)
-Triamcinolone acetonide (TAA)

24. Systemic Corticosteroids
• Hydrocortisone
• Prednisone
• Methylprednisolone
• Dexamethasone

25. Side effects
• Hyperglycemia
• Hypertension
• adrenal suppression
• congestive heart failure ( fluid retention owing to mineralocorticoid effects)
• peptic ulcer disease
• Candidiasis
• dysphonia
• Immunosuppression
• osteoporosis, cataracts,
• glaucoma, myasthenia gravis, and psychiatric diseases (e.g. , depression,
psychosis)

26. Ciclesonide
• Ciclesonide (Alvesco) is a new inhaled corticosteroids licensed for the
prophylactic treatment of persistent asthma in adults
• delivered via a hydrofluoroalkane metered-dose inhaler (HFA MDI) in
40, 80 and 160 mcg formulations.
• Oral bioavailability of < 1% and 99% protein bound

27. 3. Leukotriene modifiers
• Have anti- inflammatory and bronchodilator activity.
• They may allow reduction in corticosteroid doses in some patients.
• Leukotriene antagonists (LTRA) are effective for first-line or add-on
therapy.
• In children, for whom administration of inhaled drugs is challenging,
oral leukotriene receptor antagonists may be particularly useful .

28. Mechanism of action
• The leukotriene receptor antagonists are selective cysteinyl leukotriene 1
(cys-LT-1) receptor antagonists; therefore, they prevent leukotrienes from
interacting with their receptors.
• This reduces the proinflammatory (increased microvascular permeability
and airway edema) and bronchoconstriction effects of leukotriene D4.
• However, they are less effective than low-dose inhaled corticosteroids.
• They are not used to treat acute exacerbations and must be taken on a
regular basis, even during symptom-free periods
• Montelukast 10mg daily
• Zafirlukast 20mg bd

29. Side effects
• Adverse reactions to montelukast are uncommon and include
headache, dizziness, and dyspepsia.
• Adverse reactions associated with zafirlukast include headache,
dizziness, nausea, and diarrhea
• An idiosyncratic syndrome similar to the Churg-Strauss syndrome,
with marked circulating eosinophilia, heart failure, and associated
eosinophilic vasculitis is rare.

30. 4. Mast Cell Stabilizers
• Cromolyn sodium and Nedocromil sodium are nonsteroidal drugs
with anti - inflammatory properties.
• excellent safety profile
(1) When used prophylactically, cromolyn sodium and nedocromil
sodium prevent the early and late response of asthma.
(2) When used as maintenance therapy for asthma, these medications
suppress nonspecific airway reactivity.

31. Mechanism of action.
• Cromolyn sodium and nedocromil sodium are believed to act locally
by stabilizing mast cells and thereby inhibiting mast cell degranulation
• They inhibit the response to allergen challenge as well as EIB but do
not cause bronchodilation.
• not effective during an acute asthma exacerbation.

32. Side effects
• Generally Well tolerated
• paradoxical bronchospasm
• wheezing
• Coughing
• nasal congestion
• irritation or dryness of the throat may occur

33. Indications
• Cromolyn and nedocromil are indicated for the prophylaxis of mild
persistent asthma in children and adults regardless of etiology.
• Their effectiveness is comparable to theophylline or leukotriene
antagonists for persistent asthma.
• Neither agent is as effective as inhaled corticosteroids for controlling
persistent asthma.
• Neither is as effective as the inhaled β 2agonists for preventing EIB,
but they can be used in conjunction for patients not responding
completely to inhaled β 2-agonists.
• Most patients experience improvement in 1 to 2 weeks

34. Methylxanthines
• Considered if β-agonists and corticosteroids fail to
control an acute asthma exacerbation.
• an alternative to long-acting β-agonists in the
treatment of persistent asthma.
• Theophylline is most beneficial as an adjuvant to
inhaled corticosteroids in patients with nocturnal or
early morning symptoms.

35. Therapeutic effects
• (1) Theophylline compounds produce bronchodilation to a
lesser extent than β-agonists.
• (2) Nonbronchodilator effects include reduced mucus
secretion, enhanced mucociliary transport , improved
diaphragmatic contractility, and possibly reduced
fatigability.
• (3) There may also be notable degree of anti -
inflammatory activity

36. Mechanism of action.
Theophylline- induced phosphodiesterase inhibition results in
increased levels of cAMP, which may also result in antiinflammatory
and other nonbronchodilator activity through :
1. decreased mast cell mediator release
2. decreased eosinophil basic protein release
3. decreased T-lymphocyte proliferation
4. decreased T-cell cytokine release
5. decreased plasma exudation

37. Side effects
• nausea, vomiting, diarrhea
• Anorexia
• Palpitations
• Dizziness
• restlessness
• nervousness
• Insomnia
• Seizures
• reduced lower esophageal sphincter tone, and reduced control of
gastroesophageal reflux disease

38. • 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.
• IV theophylline is also available

39. • Sustained-release theophylline is less effective than inhaled
corticosteroids and no more effective than oral sustained-release β 2-
agonists, cromolyn, or leukotriene antagonists.
• The addition of theophylline to optimal inhaled corticosteroids is
similar to doubling the dose of the inhaled corticosteroid
• less effective overall than the long-acting β 2-agonists as adjunctive
therapy.
• Metabolised by CYP450 – clinically significant drug interactions

40. 6. 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 β 2-
agonists.
• They attenuate, but do not block, allergen- or exercise-induced asthma in a
dose-dependent fashion
• Inhaled ipratropium bromide is only indicated as adjunctive therapy in
severe acute asthma not completely responsive to β 2-agonists alone
because it does not improve outcomes in chronic asthma

41. Omalizumab
• Omalizumab, a humanized anti-IgE monoclonal antibody
• specifically binds free IgE and interrupts the allergic cascade by
preventing binding of IgE with its high-affinity FcεRI receptors on mast
cells
• A recent update of National Institute for Health and Care Excellence
(NICE) guidance in 2013 recommends omalizumab for use as add-on
therapy in adults and children over six years of age with inadequately
controlled severe persistent allergic IgE-mediated asthma who require
continuous or frequent treatment with oral corticosteroids
• Quilizumab, mepolizumab