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Chronic Asthma

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					Chronic Asthma




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             Goals of Therapy
• Reduce impairment
  – prevent chronic, troublesome symptoms
  – require infrequent use (≤ 2 days a week) of
    inhaled SABA for quick relief of symptoms
  – maintain (near-) normal pulmonary function
  – maintain normal activity levels
  – meet patients’ & families’ expectations of and
    satisfaction with care


                                                     2
             Goals of Therapy
• Reduce risk
  – prevent recurrent exacerbations
  – minimize need for visits/hospitalizations
  – prevent loss of lung function
  – prevent reduced lung growth in children
  – minimal adverse effects of therapy




                                                3
   Nonpharmacologic Treatment
• Environmental control
• Manage comorbid conditions
• Self-management skills
  – written action plans
  – recognize early signs of deterioration
• Education
  – asthma, role of medications, inhalation technique,
    environmental control, how to use action plan
  – reinforce every visit

                                                     4
                        Pharmacologic Treatment
       • National Asthma Education Prevention
         Program (NAEPP) recommendations
         categorized by age
              – 0 to 4 years
              – 5 to 11 years
              – ≥12 years
       • Stepwise approach
              – initial therapy based on asthma severity
              – therapy adjusted based on asthma control
National Institutes of Health, National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program.   Full Report of
the Expert Panel: Guidelines for the diagnosis and management of asthma (EPR-3) 2007. http://www.nhlbi.nih.gov/guidelines/asthma 5
                       Treatment
• Quick relief: SABA for all patients
• Long-term control
   – preferred
      • ICS for persistent asthma
      • increased ICS dose or addition of long-acting β2-agonist
        (LABA) for further control
   – alternatives
      • no to minimal difference in efficacy between alternatives
      • cromolyn, nedocromil, leukotriene modifiers, theophylline
   – omalizumab: severe uncontrolled asthma & atopy
                                                                    6
              Classifying Asthma Severity for Patients Not Currently Taking Long-Term
                          Control Medications (Children 0-4 and 5-11 years)
                                                                                              Persistent
                Components               Intermittent
                                                                       Mild                    Moderate                     Severe
              Symptoms                   ≤2 days/week          >2 days/week but                   Daily               Throughout the
                                                                   not daily                                               day
              Nighttime awakenings           None               1-2 times/month            2-3 times/month            > Once a week
              (0-4 yr)
                                         ≤twice/month
 Impairment




              Nighttime awakenings                              3-4 times/month           > Once per week                    Often 7
              (5-11 yr)                                                                    but not nightly                 times/week
              SABA use for               ≤2 days/week          >2 days/week but                   Daily              Several times per
              symptom control                                      not daily                                               day
              Interference with              None               Minor limitation           Some limitation           Extremely limited
              normal activity
              Lung function (5-11 yr)     FEV1 >80%              FEV1 >80%                 FEV1 60-80%                 FEV1 <60%
                                        FEV1/FVC >85%          FEV1/FVC >80%             FEV1/FVC 75-80%             FEV1/FVC <75%
              Exacerbations              Intermittent                                         Persistent
 Risk




              (0-4 yr)                      0-1/year            ≥2 in 6 months or ≥4 wheezing episodes/1 yr lasting >1 day
              (5-11 yr)                     0-2/year          >2 in 1 year 
       Recommended step for                  Step 1                   Step 2                Step 3 and consider short course of
         initiating treatment                                                                  systemic oral corticosteroids

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:             7
http://www.accesspharmacy.com/
              Classifying Asthma Severity for Patients Not Currently Taking Long-Term
                               Control Medications (≥12 years old)
                                                                                               Persistent
                  Components               Intermittent
                                                                        Mild                  Moderate                      Severe
               Symptoms                   ≤2 days/week            >2 days/week                    Daily               Throughout the
                                                                   but not daily                                           day
               Nighttime awakenings        ≤twice/month          3-4 times/month          > Once per week                    Often 7
                                                                                           but not nightly                 times/week
               SABA use for symptom       ≤2 days/week            >2 days/week                    Daily              Several times per
 Impairment




               control                                            but not > once                                           day
                                                                     per day
               Interference with normal        None              Minor limitation          Some limitation           Extremely limited
               activity

               Lung function (Normal        FEV1 >80%              FEV1 >80%               FEV1 60-80%                  FEV1 <60%
               FEV1/FVC: age 8-19 y         FEV1/FVC               FEV1/FVC              FEV1/FVC reduced                FEV1/FVC
               85%; 20-39 y 80%; 40-          normal                 normal                    5%                      reduced > 5%
               59 y 75%; 60-80 y 70%)

                                           Intermittent                                        Persistent
 Risk




               Exacerbations                  0-2/year          >2 in 1 year 
              Recommended step for             Step 1                  Step 2                Step 3 and                    Step 4 or 5
                initiating treatment                                                       consider short
                                                                                         course of systemic
                                                                                         oral corticosteroids
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:             8
http://www.accesspharmacy.com/
Stepwise Approach for Asthma Management




                                          9
Stepwise Approach for Asthma Management




                                          10
Stepwise Approach for Asthma Management




                                          11
            Special Populations
• Young children, especially 0-4 years
  – many recommendations based on extrapolated data
  – studies of ICS show improvement
  – combination therapy inadequately studied
• Elderly
  – osteoporosis risk increased with high dose ICS
• Pregnancy
  – budesonide preferred ICS
  – albuterol preferred for quick relief
                                                      12
    Inhaled Corticosteroids (ICS)
• Use: cornerstone of chronic asthma therapy
  – improve lung function
  – reduce severe exacerbations
  – only therapy shown to reduce risk of asthma
    death
• Low systemic activity
• Response delayed for several weeks


                                                  13
       Inhaled Corticosteroids
• Products
  – beclomethasone dipropionate
  – budesonide
  – flunisolide
  – fluticasone propionate
  – mometasone furoate
  – triamcinolone acetonide
  – ciclesonide

                                  14
                                Inhaled Corticosteroids

        • Adverse effects dose dependent
                – systemic effects can occur at high doses
                – oropharyngeal candidiasis
                – dysphonia
        • Growth retardation may occur
                –    dose-dependent
                –    transient
                –    susceptible populations
                –    studies suggest reaching predicted adult height not
                     affected
National Institutes of Health, National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Full Report of the Expert Panel:
Guidelines for the diagnosis and management of asthma (EPR-3) 2007                                                                                 15
Kelly HW. Potential adverse effects of the inhaled corticosteroids. J Allergy Clin Immunol 2003;112:469–478.
                     LABAs
• Use: preferred adjunct/ICS combination
  – adults & most children
  – better control than increasing ICS dose alone
• Not for quick relief
• Provide long lasting bronchodilation (≥ 12
  hours)
• Products
  – formoterol
  – salmeterol
                                                    16
                                                               LABAs
       • Systemic side effects dose dependent
       • Not to be used as monotherapy
               – increased risk of severe, life threatening
                 exacerbation & asthma related death
               – preliminary data suggest concomitant ICS may
                 prevent/decrease risk




Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: A comparison of usual pharmacotherapy for
asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15–26.                                                                       17
Kelly HW. Risk versus benefit considerations for the 2-agonists. Pharmacotherapy 2006;26:164S–174S.
              Methylxanthines
• Mechanism: bronchodilation
  – nonselective phosphodiesterase inhibitor
     • isoenzyme III: airway smooth muscle
     • isoenzyme IV: inflammatory cell regulation
  – competitively inhibit adenosine
  – stimulate catecholamine release
• Use declined due to risk for toxicity
  – alternative/adjunct therapy

                                                    18
               Theophylline
• Routine serum concentration monitoring
  – significant bronchodilation by 5 mcg/mL
  – most will not have toxic symptoms when <15
    mcg/mL
• Much potential for interactions
  – CYP-450 1A2, 3A3 metabolism
  – age dependent clearance



                                                 19
        Factors Affecting Theophylline Clearance
       Decreased Clearance                     % Decrease                 Increased Clearance                       % Increase
       Cimetidine                                 -25 to -60              Rifampin                                         +53
       Macrolides                                 -25 to -50              Carbamazepine                                    +50
       Allopurinol                                     -20                Phenobarbital                                    +34
       Propranolol                                     -30                Phenytoin                                        +70
       Quinolones                                 -20 to -50              Charcoal-broiled meal                            +30
       Interferon                                      -50                High-protein diet                                +25
       Thiabendazole                                   -65                Smoking                                          +40
       Ticlopidine                                     -25                Sulfinpyrazone                                   +22
       Zileuton                                        -35                Moricizine                                       +50
       Systemic viral illness                     -10 to -50              Aminoglutethimide                                +50
       Clinically significant interactions occur with ≥ 20% inhibition or ≥ 50% induction


DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:         20
http://www.accesspharmacy.com/
Algorithm for Theophylline Titration




                                  21
                 Theophylline
• Signs of toxicity
  – nausea/vomiting
  – tachycardia
  – jitteriness
  – difficulty sleeping
  – tachyarrhythmias
  – seizures



                                22
           Mast Cell Stabilizer
• Mechanism
  – no bronchodilatory effect
  – inhibit neurally mediated bronchoconstriction
• Improvement in 1 to 2 weeks
• Alternative to initial ICS therapy but not as
  effective
• Cromolyn
  – MDI or nebulizer

                                                    23
          Leukotriene Modifiers
 Leukotriene receptor antagonists (LTRA)
   zafirlukast
   montelukast
 5-lipoxygenase inhibitor
   zileuton
 Use: alternative/adjunct therapy
   less effective than ICS
   oral dosage form
 Adverse effects
   hepatic dysfunction

                                            24
          Anti-IgE: omalizumab
• Mechanism: recombinant anti-IgE antibody
  – prevents binding of IgE to mast cells & basophils
     • decreases release of mediators following allergen
       exposure
• Use
  – allergic asthma not well controlled by
    corticosteroids
  – ≥ 12 years old
  – severe persistent asthma
                                                           25
                  Omalizumab
• Dosage/administration
  – subcutaneous every 2 to 4 weeks
  – dosage based on serum IgE level & weight
• Adverse effect
  – anaphylaxis
     • 70% occur within 2 hours
     • may occur up to 24 hours after injection




                                                  26
                                   Clinical Controversy
       • Inhaled β2-agonists worsen asthma?
       • SABAs
              – regular administration did not worsen asthma
              – patients with β-receptor genotyped as
                homozygous Arg-16
                     • ~16% of population
                     • predisposed to worsening (lower PEFs)
                     • does not occur with as needed SABA use


                                                                                                      27
Kelly HW. Risk versus benefit considerations for the β2-agonists. Pharmacotherapy 2006;26:164S–174S
                                   Clinical Controversy
       • Do LABAs produce the same effect?
              – unknown
              – retrospective data has not shown worsening or
                whether concurrent ICS is protective
              – patients do respond to acute use of β2-agonists
       • Only use SABA as needed



                                                                                                      28
Kelly HW. Risk versus benefit considerations for the β2-agonists. Pharmacotherapy 2006;26:164S–174S
             Monitoring Therapy
• Regular follow up
  – 1 to 6 month intervals depending on control
  – 3 month interval if step down anticipated
• Evaluate asthma control
  –   symptoms
  –   lung function
  –   validated questionnaires
  –   medication adverse effects
  –   adherence, environmental control, comorbid
      condition

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            Acknowledgements

          Prepared By: Michelle Nguyen, Pharm.D.

          Series Editor: April Casselman, Pharm.D.

Editor-in-Chief: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA

         Chapter Authors: H. William Kelly, Pharm.D.
              Christine A. Sorkness, Pharm.D.

Section Editor: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA

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Description: astma chronic