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Asthma Chapter 33. Chapter 28. Pharmacotherapy: A Pathophysiologic Approach The McGraw-Hill Companies. Abbreviations. Arg : arginine BHR: bronchial hyperresponsiveness CYP- cytochrome DPI: dry-powder inhaler FEV1: forced expiratory volume in 1 second FVC: forced vital capacity

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Asthma chapter 33

Asthma Chapter 33

Chapter 28

Pharmacotherapy: A Pathophysiologic Approach

The McGraw-Hill Companies


Abbreviations

Abbreviations

Arg: arginine

BHR: bronchial hyperresponsiveness

CYP- cytochrome

DPI: dry-powder inhaler

FEV1: forced expiratory volume in 1 second

FVC: forced vital capacity

ICS: inhaled corticosteroid

IgE: immunoglobulin E

LABA: long-acting β2-agonist

LTRA: leukotriene receptor antagonist

MDI: metered-dose inhaler

NAEPP: National Asthma Education and Prevention Program

PEF: peak expiratory flow

SABA: short-acting β2-agonist

VHC: valved holding chamber


Key concepts

Key Concepts

  • Asthma is a disease of increasing prevalence

    • caused by genetic & environmental factors

    • chronic inflammatory pulmonary disorder

  • No known cure or 1˚ prevention

  • Immunohistopathologic features include cell infiltration by eosinophils, neutrophils, T-helper type 2 lymphocytes, mast cells, epithelial cells


Key concepts1

Key Concepts

  • Intermittent or persistent airflow obstruction

    • inflammation & bronchial smooth muscle constriction

    • persistent changes in airway structure may occur

  • Inhaled corticosteroids have the greatest efficacy/safety profile for long-term management across all age groups

  • Bronchial smooth muscle constriction prevented/treated most effectively with inhaled β2-adrenergic receptor agonists


Key concepts2

Key Concepts

  • Variability in response to medications requires individualization of therapy

    • use lowest dose to maintain control

  • Ongoing patient education for a partnership in asthma care essential for optimal outcomes


Asthma

Asthma

  • Chronic inflammatory lung disease

    • reversible airflow obstruction

    • increase in bronchial hyperresponsiveness (BHR)

  • Recurrent symptoms

    • wheezing

    • breathlessness

    • chest tightness

    • coughing especially at night or early morning


Epidemiology

Epidemiology

  • Affects about 23 million Americans

    • most common childhood chronic disease

    • by early adulthood, 30 to 70% will markedly improve or be symptom-free

  • Higher prevalence in minorities

    • urbanization

    • poor access to care

American Lung Association. Lung Disease Data: 2008. http://www.lungusa.org. Accessed 5-24.09.


Epidemiology1

Epidemiology

  • Significant burden on healthcare system

    • 3rd leading cause of preventable hospitalization

    • > $19 billion direct & indirect costs

  • Can be life-threatening if not properly managed

    • nearly 4,000 asthma deaths per year

    • 80 to 90% preventable

    • education is key to prevention of death from asthma

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

American Lung Association. Lung Disease Data: 2008. http://www.lungusa.org


Etiology

Etiology

  • Genetic predisposition

    • atopy

    • linked with metalloproteinase genes

  • Environmental exposure

    • risk factors

      • socioeconomic status

      • family size

      • tobacco smoke

      • allergen exposure

      • urbanization

      • exposure to common childhood infectious agents

    • hygiene hypothesis


Asthma triggers

Asthma Triggers

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. http://www.accesspharmacy.com


Pathophysiology

Pathophysiology

  • Airway inflammation

  • BHR

  • Airflow obstruction

    • bronchospasm, edema, mucus hypersecretion

  • Airway remodeling

  • Mediated by eosinophils, T cells, mast cells, macrophages, epithelial cells, fibroblasts, bronchial smooth muscle cells


Pathology found in asthmatic bronchus compared to normal bronchus

Pathology Found in Asthmatic Bronchus Compared to Normal Bronchus


Pathophysiology1

Pathophysiology

  • Epithelial cells

    • release eicosanoids, peptidases, matrix proteins, cytokines, nitric oxide

    • epithelial shedding

  • Eosinophils

    • release inflammatory mediators

      • leukotrienes, granule proteins


Pathophysiology2

Pathophysiology

  • TH2 lymphocytes

    • produce cytokines that mediate allergic inflammation

    • TH1/TH2 imbalance

  • Mast cell degranulation

    • release histamine, leukotrienes, prostaglandins

  • Mucus plugs

    • epithelial & inflammatory cells

    • further airway obstruction


Asthma chapter 33

ECP: eosinophil cationic protein; GM-CSF: granulocyte-macrophage colony-stimulation factor; IAR: immediate asthmatic reaction; IFN: interferon; IL: interleukin ; LAR: late asthmatic response; LT: leukotriene; MBP: major basis protein; PAF: platelet-activating factor; PG:prostaglandin

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. http://www.accesspharmacy.com


Conditions affecting asthma severity

Conditions Affecting Asthma Severity

  • Viral respiratory infections

  • Environmental/occupational triggers

  • Psychosocial stressors

  • Rhinitis/sinusitis

  • Gastroesophageal Reflux Disease (GERD)


Clinical presentation

Clinical Presentation

  • No single test can diagnose asthma

    • careful patient history

    • spirometry demonstrates reversible airway obstruction

  • Symptoms

    • chronic asthma: dyspnea, chest tightness, coughing especially at night, wheezing

    • severe acute asthma: acute respiratory distress


Aerosol therapy

Aerosol Therapy


Devices

Devices

  • Must determine which device is best for each patient

  • Metered-dose inhaler (MDI)

    • spacers

      • valved holding chamber (VHC)

  • Dry-powder inhaler (DPI)

  • Nebulizers

    • jet

    • ultrasonic


Metered dose inhaler

Metered-Dose Inhaler


Factors determining lung deposition of aerosols

Factors Determining Lung Deposition of Aerosols

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. http://www.accesspharmacy.com


Patient education

Patient Education

  • Appropriate inhalation technique is vital for optimal drug delivery and therapeutic effect

    • up to 30% cannot master MDI technique

  • Rinse mouth after inhaled corticosteroids (ICS)

  • < 4 years old usually need to attach a face mask to the inhalation device


Steps for using your inhaler

Steps for Using Your Inhaler

  • Remove the cap and hold inhaler upright

  • Shake the inhaler

  • Tilt your head back slightly and breathe out slowly

  • Position the inhaler

    • A or B is optimal

    • C is acceptable for those who have difficulty with A or B; required for breath-activated inhalers

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. http://www.accesspharmacy.com


Steps for using your inhaler continued

Steps for Using Your Inhaler Continued

  • Press down on the inhaler to release medication as you start to breath in slowly

  • Breathe in slowly (3 to 5 seconds)

  • Hold your breath for 10 seconds to allow the medicine to reach deeply into your lungs

  • Repeat puff as directed. Waiting 1 minute between puffs may permit second puff to penetrate your lungs better

  • Spacers/holding chambers are useful for all patients. Recommended for young children and older adults and for use with corticosteroids.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. http://www.accesspharmacy.com


Steps for using your inhaler continued1

Steps for Using Your Inhaler Continued

  • Avoid common inhaler mistakes

    • breathe out before pressing your inhaler

    • inhale slowly

    • breathe in through your mouth, not your nose

    • press down on your inhaler at the start of inhalation (or within the first second of inhalation)

    • keep inhaling as you press down on inhaler

    • press your inhaler only once while you are inhaling (one breath for each puff)

    • make sure you breathe in evenly & deeply

  • Different type of inhalers require different techniques

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. http://www.accesspharmacy.com


Severe acute asthma

Severe Acute Asthma


Goals of therapy

Goals of Therapy

  • Correct significant hypoxemia

  • Rapid reversal of airflow obstruction

  • Reduce likelihood of relapse or future recurrence of severe obstruction

  • Develop written action plan


Treatment

Treatment

  • Early recognition of deterioration & aggressive treatment are vital

    • patient/family education

  • Primary therapy

    • short-acting β2-agonist (SABA)

  • Additional therapy depending on severity

    • systemic corticosteroids

    • inhaled anticholinergic

    • O2


Asthma chapter 33

Home Management of Acute Asthma Exacerbations


Asthma chapter 33

Hospital Care of Acute Asthma Exacerbations

Continued on next slide


Asthma chapter 33

Continued from previous slide

Hospital Care of Acute Asthma Exacerbations


Special populations

Special Populations

  • Children < 4 years old may have higher risk for respiratory failure

  • Require use of a face mask for aerosolized medication

    • appropriate size/fit

    • reduces drug delivery to lung by 50%

      • minimal dose is recommended vs weight based dose


2 agonists

β2-Agonists

  • Mechanism: bronchodilator

    • smooth muscle relaxation

    • skeletal muscle stimulation

  • Aerosol route more bronchoselective


Inhaled sabas

Inhaled SABAs

  • Treatment of choice

    • most effective bronchodilator for severe acute asthma

  • Frequent administration

    • inhalations every 20 minutes

    • continuous nebulization

      • young children

      • unsatisfactory response to initial 3 doses of inhaled SABA

      • PEF or FEV1 < 30% predicted or personal best


Inhaled corticosteroids

Inhaled Corticosteroids

  • Mechanism: antiinflammatory

    • reduce number of mast cells & eosinophils

    • increase number of β-adrenergic receptors, improve receptor responsiveness

    • reduce mucus production, hypersecretion

    • reduce BHR

    • reduce airway edema/exudation


Pharmacokinetics of inhaled corticosteroids

Pharmacokinetics of Inhaled Corticosteroids


Systemic corticosteroids

Systemic Corticosteroids

  • Use

    • incomplete response to initial inhaled SABA doses

  • Continue full dose until peak flow 70% of predicted or personal best

  • Adverse effects dependent on dose & duration

    • short “bursts” do not cause serious toxicities

    • adrenal suppression less common with shorter-acting corticosteroids (e.g. prednisone)


Anticholinergics

Anticholinergics

  • Mechanism: bronchodilator

    • competitively inhibit muscarinic receptors

    • no effect on BHR

  • Less effective bronchodilator than β2-agonists

  • Not FDA approved for asthma

  • Available inhaled anticholinergics

    • ipratropium

    • tiotropium: studies inconclusive for use in asthma


Ipratropium

Ipratropium

  • Use

    • adjunct when incomplete response to SABA alone

  • Duration of action

    • 4 to 8 hours

    • duration/intensity of action dose dependent

  • Negligible systemic effects


Clinical controversy

Clinical Controversy

  • Emergency department

    • unresponsive to standard doses of inhaled β2-agonists

    • treat with IV magnesium sulfate?

  • Magnesium sulfate

    • moderately potent bronchodilator

    • adverse effects include hypotension

      • some require dopamine to treat hypotension


Clinical controversy1

Clinical Controversy

  • Severe obstruction

    • response improves with ipratropium & continuous SABA nebulization

  • Subset analyses of 2 studies

    • less hospitalizations for magnesium versus placebo in patients with severe obstruction

  • Large randomized study did not find less hospitalizations even in severe subset

Rowe BH, Bretzlaff JA, Bourdon C, et al. Intravenous magnesium sulfate treatment for acute asthma in the emergency department: A systematic review of the literature. Ann Emerg Med 2000;36:181-190.


Clinical controversy2

Clinical Controversy

  • Guideline recommendations

    • may consider IV magnesium sulfate in patients with severe exacerbations & poor response to initial inhaled β2-agonists


Clinical controversy3

Clinical Controversy

  • Inhaled β2-agonists administration

    • MDI plus VHC versus jet nebulization

      • treatment outcomes similar

    • is MDI plus VHC more cost effective?

      • no studies

  • Current practice should be based on comfort level of clinic staff

Dolovich MB, Ahrens RC, Hess DR, et al. Device selection & outcomes of aerosol therapy: Evidence-based guidelines. Chest 2005;127:335–371.

Dolovich MA, MacIntyre NR, Dhand R, et al. Consensus conference on aerosols and delivery devices.

Respir Care 2000; 45:588–776


Monitoring

Monitoring

  • Frequency dependent on exacerbation severity

    • lung function

      • spirometry

      • peak flow

    • O2 saturation


Education

Education

  • Self management plan

    • written action plan

    • peak flow monitoring

  • Asthma education

    • signs, symptoms of exacerbation

    • removal, avoidance of triggers


Chronic asthma

Chronic Asthma


Goals of therapy1

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


Goals of therapy2

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


Nonpharmacologic treatment

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


Pharmacologic treatment

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


Treatment1

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


Asthma chapter 33

Classifying Asthma Severity for Patients Not Currently Taking Long-Term Control Medications (Children 0-4 and 5-11 years)

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


Asthma chapter 33

Classifying Asthma Severity for Patients Not Currently Taking Long-Term Control Medications (≥12 years old)

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


Stepwise approach for asthma management

Stepwise Approach for Asthma Management


Stepwise approach for asthma management1

Stepwise Approach for Asthma Management


Stepwise approach for asthma management2

Stepwise Approach for Asthma Management


Special populations1

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


Inhaled corticosteroids ics

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


Inhaled corticosteroids1

Inhaled Corticosteroids

  • Products

    • beclomethasone dipropionate

    • budesonide

    • flunisolide

    • fluticasone propionate

    • mometasone furoate

    • triamcinolone acetonide

    • ciclesonide


Inhaled corticosteroids2

Inhaled Corticosteroids

  • Adverse effects dose dependent

    • systemic effects can occur at high doses

    • oropharyngealcandidiasis

    • 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

Kelly HW. Potential adverse effects of the inhaled corticosteroids. J Allergy Clin Immunol 2003;112:469–478.


Labas

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


Labas1

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. 

Kelly HW. Risk versus benefit considerations for the 2-agonists. Pharmacotherapy 2006;26:164S–174S.


Methylxanthines

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


Theophylline

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


Factors affecting theophylline clearance

Factors Affecting Theophylline Clearance

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: http://www.accesspharmacy.com/


Algorithm for theophylline titration

Algorithm for Theophylline Titration


Theophylline1

Theophylline

  • Signs of toxicity

    • nausea/vomiting

    • tachycardia

    • jitteriness

    • difficulty sleeping

    • tachyarrhythmias

    • seizures


Mast cell stabilizer

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


Leukotriene modifiers

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


Anti ige omalizumab

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


Omalizumab

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


Clinical controversy4

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

Kelly HW. Risk versus benefit considerations for the β2-agonists. Pharmacotherapy 2006;26:164S–174S


Clinical controversy5

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

Kelly HW. Risk versus benefit considerations for the β2-agonists. Pharmacotherapy 2006;26:164S–174S


Monitoring therapy

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


Acknowledgements

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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