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4/20/2013
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Bronchial asthma
Dr. Ahmed A. Elberry, MBBCH, MSc, MDAssociate 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 asthmasymptoms.
• 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 irritants3. Exposure to environmental changes (eg.: weather
changes, cold)4. Exposure to viral respiratory tract infection
5. Exercise induced6. Emotional induced7. Drug induced
– NSAIDs– Antiadrenergic drugs (BB)– Cholinergic drugs (Bethanechol)– Preservatives or excipients in drugs
Allergens & Irritants
• Allergens:– Pollen,
– House dustmites,
– Householdpets,
– Molds
– Foods
• Irritants:– Smoking
– Chemicals &fumes
– Environmentalpollutants
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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 IgEattached to bronchial mast cells release ofinflammatory mediators from mast cells,macrophages, T lymphocytes & epithelial cellsThese mediators attract & activate otherinflammatory cells, especially eosinophils, to theairways.
– Eosinophils release biochemicals airway injury, including epithelialdamage, mucus hypersecretion, & increased reactivity of smoothmuscle.
– T lymphocytes (TH2) release cytokines (e.g., ILs) that control theactivation & 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 2hr.
– 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 (bothexpiratory & inspiratory)
– Tachypnea– Tachycardia– Cyanosis
asthma wheezing (sound) - YouTube.FLVBA 11.MP4
Diagnosis1. Clinical picture2. 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 revealmetabolic acidosis & a low Pa O2
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Severity classificationSymptoms/d Nocturnal
symptomsFEV1 FEV1/FVC
Step 1Mildintermittent
< 2 days/week ≤ 2 times/month
> 80%(normal)
Normal
Step 2Mildpersistent
>2 days/ week(but not daily)
3- 4 times/month
> 80%(normal)
Normal
Step 3Moderatepersistent
Daily > once weekly,but not nightly
> 60% to < 80% Reduced 5%
Step 4Severepersistent
Continual Often 7times/week
< 60% Reduced > 5%
- How be classified if different categosies????- Well controlled???
Management of Bronchial asthma
General
AvoidTreat
Pharmacological
- Bronchodilators- Antiinflammatory- Immunoglobiulinantagonists- Adjuvant drugs
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General1.Avoid:
1.Antigen exposure – smoking - stress – emotions - severe exercises2.the following drugs:
1. NSAIDs allow only paracetamol2. Non- elective βB allow only selective β1 blockers3. Parasympathomimetics Bronchospasm4. Parasympatholytic: Atropine Dry secretions allow onlyIpratropium.5. Histamine & histamine releasers6. 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 releaser9. Ether, thiopentone & cyclopropane general anesthesia allow onlyHalothane
3. ttt: Any chest infection - Immunotherapy (hyposensitization)
Antiasthmatic drugs1.Broncho – dilators:
1. Sympathomimetic: B2 agonist (SABA & LABA)2. Parasympatholytic (Anticholinergics): SAMA & LAMA3. 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. inhibitor2. 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 ofAntiasthmatic 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 AsthmaExacerbations: Home Treatment
Initial Treatment• Inhaled SABA: up to 2 times 20 min apart, 2–6 puffs by MDI or nebulizer.
Good ResponseNo wheezing, dyspneaor tachypnea. PEF≥80%.• Contact clinician for
further instructions .• May continue
inhaled SABA every3–4 hr for 24–48 hr.
Incomplete ResponsePersistent wheezing ,dyspnea or tachypnea.PEF 50–79%.• Add OCS• Continue inhaled
SABA.• Contact clinician
urgently (this day) forfurther instruction.
Poor ResponseMarked wheezing anddyspnea. PEF <50%.• Add OCS• Repeat inhaled
SABA immediately.• PROCEED TO ED
PFM.FLV
Management Of AsthmaExacerbations: 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 takeup to 20 minutes for onset & 1-4 hours for maximum effect afterinhalation.
• Side effects:– tachycardia- tremors- tolerance- nervous tension – Hypokalemia
(leg cramps)
Corticosteroids• Mechanism:1. Anti- inflammatory effect:
1. phospholipase A2 arachidonic acid PGs & LTs2. capillary permeability edema
2. Anti – allergic effect: antibody formation & antigen /antibody reaction
3. Potentiate the effect of B2 agonists as they cause upregulationof 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 60mg/day): to gain prompt control of inadequately controlledpersistent asthma not responding completely to initial inhaledSABA (every 20 min for 3-4 doses)..
• For long-term prevention of symptoms in severe persistentasthma.
– 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 ofdeath from asthma
Estimated Comparative Daily Dosesfor Inhaled Corticosteroids
Drug Low dose Med. dose High doseBeclomethasone (QVAR)42, 84 mcg/puff
168-504 mcg 504-840 mcg >840
Budesonide (Pulmicort) 200mcg/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 withhigh doses)– Adrenal insufficiency,
osteoporosis, growthsuppression
• NB.: Rinsing the mouth afterinhaler use & use of a spacerdevice can reduce both local &systemic SE
Methylxanthines• Mechanism of action:
1. [P.D.E] enz c.A.M.P1. Bronchodilatation2. bronchial secretion3. mast cell stabilization
2. competitive block of adenosine receptors1. Bronchodilatation2. release of histamine3. 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 variousenvironmental 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 tablets2. Aminophylline: Orally & IV
NB.: Theophylline is the preferredorally & aminophylline is the preferredIV
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Algorithm for theophyllinedosage
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 membranesand inhibits activation and release of mediatorsfrom eosinophils and epithelial cells. Blocks earlyand 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 serumIgE & 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 forinhaled medications
1. MDI
2. MDI with spacers
3. DPI
4. Nebulizers
mdi.FLV DPI.FLV nebulizer.FLV
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