Pharmacologic Treatment Of Asthma 1 د. ميريانا البيضة

There are both short-term and long-term therapeutic objectives for every asthmatic patient 2

short-term objectives are the control of immediate symptoms 3

Long-term objectives are those directed at disease prevention to avoid serious exacerbations 4

Reliever Medications Short-Acting inhaled β 2-Agonists(SABA) β 2-Agonists(SABA)Anticholinergics5

Controller Medications Controller Medications  Inhaled gluCocorticoSteroids (ICS)  Leukotriene Modifiers (LM)  Theophylline (THEO)  Long-Acting inhaled β 2-Agonists (LABA)  Systemic GlucoCorticoSteroids (SGCS) 6

7 Pharmacologic Therapy (Staging) Routine Monitoring (Symptoms & Lung Function) Prevention (Trigger factors co- morbid conditions) Patient education (create a partnership Between Clinician & patient) Successful Asthma Management

8 Pharmacologic Therapy (Staging) Routine Monitoring (Symptoms & Lung Function) Prevention (Trigger factors co- morbid conditions) Patient education (create a partnership Between Clinician & patient) Successful Asthma Management

9 Initial Evaluation to classify Asthma Severity Treating for 4-6 weeks to achieve control Total evaluation after treatment to identify the Level of Control Treatment Modification : Step up or Step down

Initial Evaluation to classify Asthma Severity 10

Assessment of asthma severity using symptoms and PEF in patients presenting for the First Time on No Treatment 11 Old calcification

Classification of Severity 12

13 CLASSIFY SEVERITY Clinical Features Before Treatment Symptoms NocturnalSymptoms FEV 1 or PEF STEP 4 Severe Persistent STEP 3 Moderate Persistent STEP 2 Mild Persistent STEP 1 Intermittent Continuous Limited physical activity Daily Attacks affect activity > 1 time a week but 1 time a week but < 1 time a day < 1 time a week Asymptomatic and normal PEF between attacks Frequent > 1 time week > 2 times a month 2 times a month 2 times a month 60% predicted Variability > 30% % predicted Variability > 30%  80% predicted Variability % 80% predicted Variability < 20%

Treating for 4-6 weeks to achieve control 14

Asthma Education Environmental Control As needed rapid-acting inhaled B2-agonist 15 TREATMENT STEPS REDUCEINCREASE STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

16 REDUCEINCREASE Treatment steps Step 1 Step 2 Step 3 Step 4 Step 5 Asthma education Environmental control As-needed rapid-acting B2- agonist Controller options Select one Add one or more Add one or both Low-dose inhaled ICS Leukotriene modifier Low-dose ICS plus long-acting B2-agonist Low-dose ICS plus long-acting B2-agonist Medium-or high-dose ICS Low-dose ICS plus leukotriene modifier Low-dose ICS plus sustained release theophylline Medium-or high- dose ICS plus long-acting B2- agonist Leukotrien e modifier Sustained release theophylline Oral glucocorticoste roid (lowest dose) Anti-IgE treatment

REDUCEINCREASE Asthma education Environmental control As-needed rapid-acting  2 -agonist Controller options Select one Add one or moreAdd one or both Low-dose inhaled ICS Low-dose ICS plus long-acting  2 -agonist Medium-or high-dose ICS plus long-acting  2 - agonist Oral glucocorticosteroid (lowest dose) Leukotriene modifier Medium-or high-dose ICS Leukotriene modifierAnti-IgE treatment Low-dose ICS plus leukotriene modifier Sustained release theophylline Low-dose ICS plus sustained release theophylline Treatment steps Step 1 Step 2 Step 3 Step 4 Step 5

As needed Short-acting inhaled B2-agonist (SABA) Indicated in all age groups18

19 Low-dose ICS Montelukast Preferred Alternative

20 Low-dose ICS LABA Montelukast SR-Theo Or Preferred + +

OR21 Medium- dose ICS High – dose ICS

children 0- 4 years of age22 Medium-dose ICS

23 Medium -dose ICS plus LABA High-dose ICS plus LABA Montelukast SR-Theo +/-

Step 4 Moderate & Severe Asthma children 0- 4 years of age children 0- 4 years of age 24 Medium-dose ICS Montelukast +

25 Medium dose ICS plus LABA Montelukast SR-Theo +/- Oral Glucocorticosteroids low dose Anti-IgE High-dose ICS plus LABA + +

Total evaluation after treatment to identify the Level of Control 26

27 Total Asthma control Normal Lung Function Better Quality of life Non Exacerbation

28 Better Quality of life

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33 Levels of Asthma Control

Characteristic Controlled (All of the following) Partly controlled (Any present in any week) Uncontrolled Daytime symptoms None (2 or less / week) More than twice / week 3 or more features of partly controlled asthma present in any week Limitations of activities NoneAny Nocturnal symptoms / awakening NoneAny Need for rescue / “reliever” treatment None (2 or less / week) More than twice / week Lung function (PEF or FEV 1 ) Normal < 80% predicted or personal best (if known) on any day ExacerbationNoneOne or more / year1 in any week

35 Treatment Modification : Step up or Step down Step up or Step down

36 Step up after 4-6 weeks Of Treatment Step up after 4-6 weeks Of Treatment Step down After 3-6 months of Treatment Step down After 3-6 months of Treatment STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

Controlled Partly controlled Uncontrolled Exacerbation LEVEL OF CONTROL Maintain and find lowest controlling step Consider stepping up to gain control Step up until controlled Treat as exacerbation TREATMENT ACTION Treatment steps Step 1 Step 2 Step 3 Step 4 Step 5 REDUCEINCREASE

Stepping Down Treatment When Asthma Is Controlled

Regular use of treatment in practice: stepping down Low-dose ICS plus sustained release theophylline Sustained release theophylline Low-dose ICS plus leukotriene modifier Anti-IgE treatmentLeukotriene modifier Medium-or high-dose ICS Leukotriene modifier Oral glucocorticosteroid (lowest dose) Medium-or high-dose ICS plus long-acting  2 - agonist Low-dose ICS plus long-acting  2 -agonist Low-dose inhaled ICS Controller options Add one or bothAdd one or moreSelect one Treatment steps Step 1 Step 2 Step 3 Step 4 Step 5

LABA + ICS (M) LABA + ICS (L) Stop LABA / ICS (L) once daily LABA + ICS (H)

Controllers + ICS (M) Controllers + ICS (L) Stop Controllers / ICS (L) once daily Controllers (Leukotriene modifier or SR Theophylline) ICS ( H ) + +

Medications Airway Inflammation ICS Systemic Steroids Leukotriene modifiers Cromolyn and nedocromil Airway Obstruction LABASABA AnticholinergicTheophylline Airway Remodelling ICS

Corticosteroids Corticosteroids are the most useful antiinflammatory agents

Corticosteroids are available for Oral Parenteral and inhaled use

Inhaled gluCocorticoSteroids ( ICS ) Inhaled glucocorticosteroids are the most effective controller therapy in all ages Evidence A in Long Term asthma Management

ICS are safe and effective treatment for moderate- to- severe asthma The longterm use of ICS has been associated with a good safety profile

Side Effects High doses ICS (eg, 1,000 μg/d) Hypophyseal Pituitary adrenal axis suppression can usually be avoided by the use of a spacer or holding chamber and by rinsing the mouth after each use Local adverse effects Hoarseness Dysphonia Cough oral candidiasis

Oral preparations (prednisone) are useful for the treatment of acute exacerbations of asthma that are unresponsive to bronchodilator therapy Doses of 40 to 60 mg/d are administered until the patient responds and then the dosage can be slowly tapered down

IV corticosteroids (methylprednisolone, 60 to 80 mg every 6 to 8 h for 1 or 2 days) preventing further progression of the severe asthma exacerbation That requires hospitalization

Side Effects Osteoporosis Cataractsdiabetes mellitus depression of immunity to infection

Leukotriene Modifiers ( LM ) LT pathway modifiers (LPMs) are also medications that are considered to be asthma controllers Evidence A in Long Term asthma Management

These agents have been shown to be effective in preventing allergic rhinitis

Prevention of exercise - induced bronchospasm Adolescents 15 years and Adults: 10 mg at least 2 hours prior to exercise Additional doses should not be administered within 24 hours Adolescents 15 years and Adults: 10 mg at least 2 hours prior to exercise Additional doses should not be administered within 24 hours

Montelukast DOSING 6 months to 5 years4 mg/day6-14 years5 mg/day Adolescents >14 years and Adults 10 mg/day

Short - Acting inhaled β 2- Agonists ( SABA ) Evidence A Relief bronchospasm during acute exacerbations of asthma Pretreatment of exercise-induced bronchoconstriction

Short - Acting inhaled β 2- Agonists ( SABA ) Treatment should be taken as needed in controlled asthma Regular SABA Increased risk of: Exacerbation Hospital admission in children

Short - Acting inhaled β 2- Agonists ( SABA ) The need for regularly scheduled doses of SABAs should alert the physician to the need for more intense antiinflammatory medication

Long - Acting inhaled β 2- Agonists ( LABA ) Evidence A in Long Term asthma Management in children, adolescents and adults: Control of chronic symptoms Prevent nocturnal symptoms Exercise-induced bronchoconstriction

Long - Acting inhaled β 2- Agonists ( LABA ) The effect of (LABA) has not yet been adequately studied in infants 5 years and younger

Long-Acting inhaled β2-Agonists LABASalmeterol > 4 years old Inhalation 50 mcg / 12 hours Formoterol > 5 years old Inhalation 12 mcg / 12 hours

Formoterol (Pharmacodynamics) Onset Within 3 minutes Peak effect 80% of peak effect within 15 minutes Duration Improvement in FEV1 observed for 12 hours in most patients

ombination Strategy Rational Better control Better lung function Better QOL Synergy ICS + LABA

Anticholinergics produce bronchodilatation by reducing vagal tone

Anticholinergics In Acute Asthma Reliever medication but less effective than SABA substitute bronchodilator when side effects preclude the use of β2-agonist Not recommended for long-term management of asthma in children

Anticholinergics The combination between SABA & Anticholinergics Significant Improvement in pulmonary function Significantly reduces the risk of hospital admission

Medications Airway Inflammation ICS Systemic Steroids Leukotriene modifiers Cromolyn and nedocromil Airway Obstruction LABASABA AnticholinergicTheophylline Airway Remodelling ICS

Theophylline Theophylline is an effective bronchodilator and has antiinflammatory properties Evidence B in Long Term asthma Management in children, adolescents and adults

Theophylline The side effects are more pronounced 8 to 15 μg/Ml therapeutic 20 to 30 μg/mL GI side effects blood levels in excess of this range Serious cardiac arrhythmias and seizures

Anti-IgE therapy in Allergic Diseases

Omalizumab Xolair® is a: IgG monoclonal antibody (recombinant DNA-derived) IMMUNOMODULATORY AGENTS (Anti IgE )

Anti IgE inhibits the binding of IgE to mast cells by forming complexes with circulating free IgE down-regulation of basophil and mast-cell receptors and the subsequent release of inflammatory mediators IMMUNOMODULATORY AGENTS (Anti IgE )

Xolair® FDA approved for subcutaneous use in severe asthmatics incomplete symptom control with inhaled corticosteroid treatment

Subcutaneous injection under medical supervision 150 mg – 375 mg every 2- 4 weeks Subcutaneous injection under medical supervision 150 mg – 375 mg every 2- 4 weeks

Side Effects one in 1000 patients Anaphylaxis 1 % of patients urticarial skin rash occur in 44 % Mild injection site reactions

ANTI - IgE THERAPY IN OTHER DISEASES Allergic Rhinitis Atopic Dermatitis Food Allergy Chronic Urticaria Churg-strauss Syndrome Allergic Rhinitis Atopic Dermatitis Food Allergy Chronic Urticaria Churg-strauss Syndrome

Important limits of clinical use Individuals must be 12 years of age or older

 Exacerbations   Symptoms   On-demand medication   Steroid-sparing  Quality of life   Lung function (  )  Side effects  Omalizumab in allergic asthma