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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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