bronchial asthma & its treatment

1. 4/20/2013
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Bronchial asthma
Dr. Ahmed A. Elberry, MBBCH, MSc, MD
Associate Professor of Clinical Pharmacy
Faculty of pharmacy,
KAU
Bronchial Asthma
• Definition:
– Asthma is a chronic inflammatory disorder of the
airways associated with hyperresponsiveness &
remodeling leading to obstruction & episodic asthma
symptoms.
• Epidemiology
– 7 % of Americans have asthma.
– overall costs > $12 billion/year in USA.
– It is the leading cause of lost school days in children &
lost workdays in adults.

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Causes of BA
1. Exposure to allergens
– Usually associated with atopy mainly in children (childhood-onset
asthma) & may be also in adults (adulthood-onset asthma)
2. Exposure to irritants
3. Exposure to environmental changes (eg.: weather
changes, cold)
4. Exposure to viral respiratory tract infection
5. Exercise induced
6. Emotional induced
7. Drug induced
– NSAIDs
– Antiadrenergic drugs (BB)
– Cholinergic drugs (Bethanechol)
– Preservatives or excipients in drugs
Allergens & Irritants
• Allergens:
– Pollen,
– House dust
mites,
– Household
pets,
– Molds
– Foods
• Irritants:
– Smoking
– Chemicals &
fumes
– Environmental
pollutants

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Pathophysiology
• Inflammation:
• Hyperresponsiveness:
• Remodeling:
Pathophysiology
• Inflammation:
– interaction between inflammatory cells (e.g.
eosinophils, mast cells) & mediators (e.g.
interleukins, leukotrienes)
– exposure to asthma-triggers  binds to IgE
attached to bronchial mast cells  release of
inflammatory mediators from mast cells,
macrophages, T lymphocytes & epithelial cells 
These mediators attract & activate other
inflammatory cells, especially eosinophils, to the
airways.
– Eosinophils release biochemicals  airway injury, including epithelial
damage, mucus hypersecretion, & increased reactivity of smooth
muscle.
– T lymphocytes (TH2) release cytokines (e.g., ILs) that control the
activation & enhanced survival of eosinophils.

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Pathophysiology
• Hyperresponsiveness:
– exaggerated response of bronchial smooth muscles to
trigger stimuli
– caused by chronic inflammation
• Remodeling:
– Failure to control the inflammation  airway
remodeling.
Phases of BA
• Early-phase:
– within 30 min of trigger & resolves within 2
hr.
– Associated with hyperresponsiveness.
– respond to bronchodilators ; but not to
corticosteroids
• Late-phase:
– 4- 12 hours later. It is more severe, more
prolonged,
– Associated with influx of inflammatory cells
& mediators.
– Don’t respond to bronchodilators ; but
respond to corticosteroids

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Clinical symptoms of BA
• Episodes of triad: Cough – Dyspnea - Wheezes
• Between the attacks the pt. may be asymptomatic
• In acute exacerbation:
– Severe symptoms: cough, dysnea , wheezes (both
expiratory & inspiratory)
– Tachypnea
– Tachycardia
– Cyanosis
asthma wheezing (sound) - YouTube.FLVBA 11.MP4
Diagnosis
1. Clinical picture
2. Family history
3. Spirometry: FEV1/VC less than 80%
Normal FEV1/FVC:
– 8–19 years old: 85%,
– 20–39 years old: 80%,
– 40–59 years old: 75%,
– 60–80 years old: 70%.
4. Pulse oximetry: decreased arterial oxygen
& O2 saturations.
5. Arterial blood gases may reveal
metabolic acidosis & a low Pa O2

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Severity classification
Symptoms/d Nocturnal
symptoms
FEV1 FEV1/FVC
Step 1
Mild
intermittent
< 2 days/week ≤ 2 times/
month
> 80%
(normal)
Normal
Step 2
Mild
persistent
>2 days/ week
(but not daily)
3- 4 times/
month
> 80%
(normal)
Normal
Step 3
Moderate
persistent
Daily > once weekly,
but not nightly
> 60% to < 80% Reduced 5%
Step 4
Severe
persistent
Continual Often 7
times/week
< 60% Reduced > 5%
- How be classified if different categosies????
- Well controlled???
Management of Bronchial asthma
General
Avoid
Treat
Pharmacological
- Bronchodilators
- Antiinflammatory
- Immunoglobiulin
antagonists
- Adjuvant drugs

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General
1.Avoid:
1.Antigen exposure – smoking - stress – emotions - severe exercises
2.the following drugs:
1. NSAIDs allow only paracetamol
2. Non- elective βB allow only selective β1 blockers
3. Parasympathomimetics  Bronchospasm
4. Parasympatholytic: Atropine  Dry secretions allow only
Ipratropium.
5. Histamine & histamine releasers
6. Anti histaminics (1st generation as they have atropine like effect)
7. Brabiturates   Respiratory center (R.C)
8. Morphine   R.C,  cough center & it is a histamine releaser
9. Ether, thiopentone & cyclopropane general anesthesia allow only
Halothane
3. ttt: Any chest infection - Immunotherapy (hyposensitization)
Antiasthmatic drugs
1. Broncho – dilators:
1. Sympathomimetic: B2 agonist (SABA & LABA)
2. Parasympatholytic (Anticholinergics): SAMA & LAMA
3. Methylxanthines: Aminophylline
2. Anti- inflammatory:
1. Mast cell stabilizers:
• Cromoglycate (Cromolyn [ntal] & Nedocromil)
• Ketotifen
2. Cocticosteroids.
3. Anti leukotriene drugs:
1. Zileluten  5- lipo – oxygenase enz. inhibitor
2. Zafirlukast & montelukast  leukotriene [LTD4] receptor antagonist
3. Immunoglobulin antagonists:
Anti- IgE monocolonal antibodies Omalizumab (Xolair)
4. Adjuvant drugs:
Mucolytic, Expectorants & O2 - Heliox & IV Mg

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Clinical classification of
Antiasthmatic drugs
• Quick-relief (rescue)
medications:
– SABA
– Systemic steroids
– Anticholinergics
– Aminophylline
• Long-term (controller)
medications:
– LABA
– Long acting methylxanthines
– Antiinflammatory drugs
– Anti- IgE
Stepwise management

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Management Of Asthma
Exacerbations: Home Treatment
Initial Treatment
• Inhaled SABA: up to 2 times 20 min apart, 2–6 puffs by MDI or nebulizer.
Good Response
No wheezing, dyspnea
or tachypnea. PEF
≥80%.
• Contact clinician for
further instructions .
• May continue
inhaled SABA every
3–4 hr for 24–48 hr.
Incomplete Response
Persistent wheezing ,
dyspnea or tachypnea.
PEF 50–79%.
• Add OCS
• Continue inhaled
SABA.
• Contact clinician
urgently (this day) for
further instruction.
Poor Response
Marked wheezing and
dyspnea. PEF <50%.
• Add OCS
• Repeat inhaled
SABA immediately.
• PROCEED TO ED
PFM.FLV
Management Of Asthma
Exacerbations: Hospital Treatment
• O2
• Inhaled SABA + Ipratropium
• OCS
• IV corticosteroids
• Consider adjunctive therapy: (IV magnesium or heliox)

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β2-Agonists
• Classification:
– SABA (albuterol , levalbuterol , pirbuterol )
– LABA: Formoterol & salmeterol
• Indications:
– SABA: ttt of acute exacerbations & prophylaxis for EIB.
– LABA: as adjunctive long-term control for patients with
symptoms who are already on low to medium doses ICS.
NB.: LABA are ineffective for acute exacerbations because it take
up to 20 minutes for onset & 1-4 hours for maximum effect after
inhalation.
• Side effects:
– tachycardia- tremors- tolerance- nervous tension – Hypokalemia
(leg cramps)
Corticosteroids
• Mechanism:
1. Anti- inflammatory effect:
1.  phospholipase A2   arachidonic acid   PGs & LTs
2.  capillary permeability   edema
2. Anti – allergic effect:  antibody formation &  antigen /
antibody reaction
3. Potentiate the effect of B2 agonists as they cause upregulation
of B2 receptors.
• Preparations:
– oral : Prednisone - Prednisolone
– I.V : Hydrocortisone – Methylprednisolone
– Inhaled - Beclomethasone - Budesonide (Pulmicort)
- Fluticasone - Flunisolide
-Triamcinolone (azmacort) - mometasone (Asmanex) .

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Corticosteroids
• Indications:
– ICS:
• 1st - line antiinflammatory therapy for mild to severe persistent
asthma in both adults & children.
– Oral corticosteroids
• For short-term (3–10 days) “burst”, 1-2 mg/kg/day (up to 60
mg/day): to gain prompt control of inadequately controlled
persistent asthma not responding completely to initial inhaled
SABA (every 20 min for 3-4 doses)..
• For long-term prevention of symptoms in severe persistent
asthma.
– IV corticosteroids:
• patients who are unable to take oral medications in severe
exacerbations (e.g. methylprednisolone 60 mg or 125 mg int IV).
• NB.: they are the ONLY therapy shown to reduce the risk of
death from asthma
Estimated Comparative Daily Doses
for Inhaled Corticosteroids
Drug Low dose Med. dose High dose
Beclomethasone (QVAR)
42, 84 mcg/puff
168-504 mcg 504-840 mcg >840
Budesonide (Pulmicort) 200
mcg/dose
200-400 mcg 400-800 mcg >800 mcg
Fluticasone (Flovent)
44,110,220 mcg
88-264 mcg 264-660 mcg >660 mcg
Flunisolide (AeroBid)
250 mcg/puff
500-1000 mcg 1000-2000 mcg >2000 mcg
Triamcinolone (Azmacort)
100 mcg/puff
400-1000 mcg 1000-2000 mcg >2000 mcg
Mometasone (Asmanex)
100,200 mcg/puff
200 mcg 400 mcg > 400 mcg
NB.: formoterol /budesonide (Symbicort) and fluticasone/salmeterol (Advair)

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ICS: Side Effects
• Local:
– Oral candidiasis, dysphonia,
cough
• Systemic: (observed with
high doses)
– Adrenal insufficiency,
osteoporosis, growth
suppression
• NB.: Rinsing the mouth after
inhaler use & use of a spacer
device can reduce both local &
systemic SE
Methylxanthines
• Mechanism of action:
1. [P.D.E] enz  c.A.M.P 
1. Bronchodilatation
2.  bronchial secretion
3. mast cell stabilization
2. competitive block of adenosine receptors 
1. Bronchodilatation
2.  release of histamine
3. release of catecholamines: [due to block of presynaptic
receptor]
3. improve diaphragmatic contractions.
• Indications:
– Long-term control in mild persistent asthma
– Adjunctive with ICS, in moderate or persistent asthma.
NB.: The addition of theophylline to optimal ICS is:
- similar to doubling the dose of the ICS and
- less effective than the LABA as adjunctive therapy.

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Methylxanthines (contin.)
Side effects:
1. Narrow safety margin & large interpatient variability in
clearance:
– Therapeutic plasma level  5-15 μg / ml & toxic level  >20 μg/
ml
– Routine monitoring is essential
– Observe for drug interaction: It is eliminated primarily by CYP-
P450  susceptible to induction & inhibition by various
environmental factors & drugs (inducers & inhibitors)
2. G.I.T
– anorexia – nausia – vomiting
– proctitis in childern when used rectally
3. C.V.S
– Tachycardia – Arrhythmia- Hypotension – Arrest
4. C.N.S
– Nervousness – Insomnia – Headache – Convulsions
Methylxanthines (contin.)
• Preparations:
1. Theophylline: SR oral tablets
2. Aminophylline: Orally & IV
NB.: Theophylline is the preferred
orally & aminophylline is the preferred
IV

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Algorithm for theophylline
dosage
Anticholinergics
• Preparations:
- SAMA: Ipratropium
- LAMA: Tiotropium
• Indication:
– Ipratropium is used with SABA in acute asthma (but are not as
potent as SABA & has delayed onset, 30-60 min)
– Tiotropium is currently studied in chronic asthma
• Side effects:
– Dry mouth,
– increased wheezing (???),
– blurred vision if sprayed in eyes.
– Tachycardia (less than SABAs).

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Mast Cell Stabilizers
(Cromolyn Sodium [Intal] & Ketotifen
[Zaditen])
• Mechanism:
– Anti-inflammatory. Stabilizes mast cell membranes
and inhibits activation and release of mediators
from eosinophils and epithelial cells. Blocks early
and late reaction to allergen
• Indications:
– Long-term prevention of symptoms in mild
persistent asthma.
– Preventive treatment prior to exposure to exercise
or known allergen.
• Side effects:
– Cough and irritation.
– Unpleasant taste from nedocromil.
Leukotriene Modifiers
(Montelukast - Zafirlukast -Zileuton)
• Indications:
– Long-term control in mild persistent asthma.
– With ICS as combination therapy in moderate
persistent asthma.
• NB.:
– Montelukast : for patients ≥1 year
– Zafirlucast: for patients ≥7 years of age
– Ziluten for patients ≥12 years of age
• Side effects:
– Montelukast: Churg–Strauss syndrome
– Zafirlukast –Zileuton: Hepatitis & Elevation of liver
enzymes
– NB: Zafirlukast -Zileuton are HMEI

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Omalizumab (Xolair)
• Anti-IgE antibody.
• Dose:
– The dosage is determined by the patient’s baseline serum
IgE & body weight (150-375 mg SC/2-4 w).
• Indication:
– Patients ((≥ 12 years) who have severe persistent asthma
that is inadequately controlled with the combination of high-
dose ICS . (high coast)
• Side effects:
– Anaphylaxis esp. in the 1st 2 hours
– Pain & bruising at injection sites
Drug delivery options for
inhaled medications
1. MDI
2. MDI with spacers
3. DPI
4. Nebulizers
mdi.FLV DPI.FLV nebulizer.FLV

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