Chapter 6 Adrenergic Sympathomimetic Bronchodilators Copyright 2012 2008

Clinical Indications for Adrenergic Bronchodilators Relaxation of smooth airway muscle in the presence of reversible obstruction Asthma • Acute, chronic, exercise-induced Ø Bronchitis Ø Emphysema Ø Bronchiectasis Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 2

Asthma Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc.

Indication for Short-Acting Agents Acute reversible airflow obstruction Short-acting agents: Ø Ø Ø a. k. a. “rescue” agents Albuterol Levalbuterol Metaproterenol Pirbuterol Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 4

Indication for Long-Acting Agents Maintenance bronchodilation, control of bronchospasm, and control of nocturnal symptoms Salmeterol Ø Formoterol Ø Arformoterol Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 5

Indications for Racemic Epinephrine To control airway bleeding during endoscopy To reduce airway swelling Ø Ø Postextubation stridor Epiglottitis Croup Bronchiolitis Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 6

Specific Adrenergic Agents and Formulations Ultrashort acting Duration < 3 hours Ø Epinephrine and racemic epinephrine Ø Short acting Duration of 4 to 6 hours Ø Albuterol, levalbuterol, metaproterenol, pirbuterol Ø Long acting Duration of 12 hours Ø Salmeterol, formoterol, arformoterol Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 7

Catecholamines Sympathomimetic bronchodilators are either catecholamines or derivatives of catecholamines Catecholamines mimic epinephrine Ø Ø Ø Tachycardia Elevated BP Smooth muscle relaxation (bronchioles and skeletal muscle blood vessels) Glycogenolysis Skeletal muscle tremor CNS stimulation Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 8

Catecholamine Structure Figure 6 -1 Basic catecholamine structure, showing the catechol nucleus connected to an amine side chain. Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 9

Adrenergic Bronchodilators as Stereoisomers Nonsuperimposable molecular mirror images (R)-Isomer (right isomer) Ø (S)-Isomer (left isomer) Ø Similar physical and chemical properties Different physiological effects Example: levalbuterol Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 10

Epinephrine Structure Figure 6 -2 Structure of epinephrine, illustrating the (R)-isomer (levo, l, −) and (S)-isomer (dextro, d, ＋) as mirror images of each other, termed enantiomers. Natural epinephrine is (R)-epinephrine. Synthetic formulations for inhalation are racemic (50: 50) mixtures of (R)-isomers and (S)-isomers. Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 11

Epinephrine Potent catecholamine bronchodilator Stimulates both α- and β-receptors High prevalence of side effects Ø Ø Ø Tachycardia Increased BP Tremor Headache Insomnia Available as a synthetic racemic mixture Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 12

Isoproterenol Potent catecholamine bronchodilator Ø Stimulates both β 1 - and β 2 -receptors No longer manufactured as a nebulizer solution Available parenterally Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 13

Isoetharine One of first β 2 -specific adrenergic bronchodilators Short duration, rapid onset Minimal β 1 stimulation Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 14

Keyhole Theory of β 2 Specificity The larger the catecholamine side chain, the more β 2 specific Epinephrine • Equal α and β Ø Isoproterenol • Strong β, little α Ø Isoetharine • β 2 preferential Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 15

Metabolism of Catecholamines Rapidly inactivated by COMT Duration of action is limited Ø 1. 5 to 3 hours Ø Unsuitable for oral administration Ø Inactivated in gut and liver Also inactivated by: Heat Ø Light Ø Air Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 16

% of Change FEV 1 Figure 6 -7 Mean percent change in forced expiratory volume in 1 second (FEV 1) from baseline (week 0) to the end of treatment (week 4) with various doses of levalbuterol, racemic albuterol, and placebo (PBO). (From Nelson HS, Bensch G, Pleskow WW, et al: Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma, J Allergy Clin Immunol 102: 943, 1998. ) Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 17

% of Change FEV 1 Figure 6 -7 Mean percent change in forced expiratory volume in 1 second (FEV 1) from baseline (week 0) to the end of treatment (week 4) with various doses of levalbuterol, racemic albuterol, and placebo (PBO). (From Nelson HS, Bensch G, Pleskow WW, et al: Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma, J Allergy Clin Immunol 102: 943, 1998. ) Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 18

Resorcinol Agents Better for maintenance therapy Significantly longer duration of action Ø Slower peak effect Ø 4– 6 hours 30– 60 minutes Examples: Terbutaline Ø Metaproterenol Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 19

Saligenin Agents Example: Ø Albuterol Available as: Ø Ø MDI Syrup Nebulizer Extended-release tablets Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 20

Saligenin Agents (cont’d) Benefits: Ø Ø β 2 Preference Effective by mouth Peak effect in 30– 60 minutes Duration of up to 6 hours Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 21

Pirbuterol Noncatecholamine adrenergic agent Available as breath-actuated MDI Onset: 5 to 8 minutes Peak effect: At 30 minutes Duration of action: 5 hours Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 22

Levalbuterol: The (R)-Isomer of Albuterol Pure (R)-isomer of racemic albuterol Available as HFA MDI and nebulizer solution Available in four doses: Ø Ø 0. 31 mg/3 m. L 0. 63 mg/3 m. L 1. 25 mg/0. 5 m. L concentrate Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 23

Albuterol Isomers Figure 6 -6 The (R)-isomer and (S)-isomer of racemic albuterol. Levalbuterol is the single, (R)-isomer form of racemic albuterol and contains no (S)-isomer. Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 24

Long-Acting β-Adrenergic Agents Offer less frequent dosing and nocturnal protection Ø Ø Extended-release albuterol Salmeterol Formoterol Arformoterol Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 25

Extended-Release Albuterol Available as Vospire ER 4 -mg or 8 -mg oral tablet Activity time, 8– 12 hours Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 26

Salmeterol Available as DPI (Diskus inhaler) Bronchodilator effect Slower onset than albuterol Ø Time to peak bronchodilating effect, 3– 5 hours Ø Duration, 12 hours Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 27

Formoterol β 2 -Selective agonist Short time to bronchodilatory effect (3 minutes) Duration of up to 12 hours Available as DPI Used for: Asthma (5 years +) Ø Exercise-induced bronchospasm (5 years +) Ø COPD Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 28

Antiinflammatory Effects Salmeterol and formoterol inhibit mast cell activation In vitro results only; not clinically proven Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 29

Arformoterol β 2 -Selective agonist Single isomer of formoterol Duration of up to 12 hours Available as nebulizer solution Approved for: Ø COPD Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 30

Clinical Use Maintenance therapy of asthma not controlled by inhaled corticosteroids COPD needing daily bronchodilator Not recommended for rescue therapy Not recommended for treatment of breakthrough symptoms Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 31

Mode of Action α-Receptor stimulation Ø β 1 -Receptor stimulation Ø Vasoconstriction effect Increased HR and contractile force β 2 -Receptor stimulation Ø Relaxation of bronchial smooth muscle Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 32

β- and α-Receptor Activation β-Receptor Ø Binds to β-receptor, ultimately causing increased synthesis of c. AMP α-Receptor Inhibits release of neurotransmitter from the presynaptic neuron Ø But may also lower the synthesis of intracellular c. AMP Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 33

α 1 -Receptor Activation Agonists such as: Phenylephrine Ø Epinephrine Ø Results in vasoconstriction of peripheral blood vessels Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 34

Salmeterol, Formoterol, and Arformoterol: Mechanism of Action Salmeterol Lipophilic Ø Approaches β-receptor laterally Ø Formoterol Also lipophilic Ø Can also approach the receptor from the aqueous phase Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 35

Routes of Administration Inhalation MDI Ø DPI Ø Nebulized Ø Orally Tablets Ø Syrup Ø Parenterally Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 36

Inhalation Route Catecholamines are ineffective orally Ø Benefits of inhalation: • Rapid onset • Smaller doses • Reduced side effects • Drug delivered directly to the target organ • Relatively safe and painless Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 37

Inhalation Route (cont’d) Limitations: Time Ø Public embarrassment Ø Difficult to use correctly Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 38

Continuous Nebulization Used for management of asthma Reduces need for frequent therapist attendance Generally 10 to 15 mg/hour for adult Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 39

Continuous Nebulization (cont’d) Delivery methods Refilling SVN Ø Volumetric infusion pump Ø Large-volume nebulizer Ø Toxicity and monitoring Ø Potential complications • Cardiac arrhythmias, hypokalemia, hyperglycemia, tremor Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 40

Oral Route Advantages Easy to use Ø Short administration time Ø Reproducibility and controlled dosage Ø Disadvantages Longer onset of action Ø More systemic side effects Ø Loss due to first pass through the liver Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 41

Parenteral Route Used in emergency management of acute asthma Thought to be useful when obstruction prevents penetration of aerosol to lung periphery SQ epinephrine 0. 3 mg Ø SQ terbutaline 0. 25 mg Ø Should be used as a last resort and requires: Infusion pump Ø Cardiac monitor Ø Close attention for systemic side effects Ø Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 42

Adverse Side Effects Side effect: Any effect other than the intended therapeutic effect Ø Ø Ø Ø Ø Tremor Cardiac effects Tolerance to bronchodilator effect Loss of bronchoprotection CNS effects Fall in Pa. O 2 Metabolic disturbances Propellant toxicity and paradoxical bronchospasm Sensitivity to additives Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 43

β-Agonist Controversy Asthma paradox: Increasing evidence of asthma mortality and morbidity despite advances in treatment Ø Ø Lack of steroid use? Loss of bronchodilator effect? Increase in bronchial hyperreactivity? Exposure to triggers with no immediate symptoms? Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 44

β-Agonist Controversy (cont’d) Ø Ø Temporary relief leads to delay in seeking medical help? Poor patient compliance/education? Accumulation of (S)-isomer? Environmental pollution and lifestyle changes? Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 45

Respiratory Care Assessment of β-Agonist Therapy Assess effectiveness of drug based on indications for use Monitor peak flow rates Perform physical assessment before/after treatment Monitor HR for 20% increase Subjective reactions Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 46

Respiratory Care Assessment of β-Agonist Therapy (cont’d) ABGs Monitor glucose/K+ PFTs Provide patient education Instruct/verify correct use of devices Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 47

Respiratory Care Assessment of β-Agonist Therapy (cont’d) For long-acting β-agonists Ø Ø Ø Assess ongoing lung function Assess the use of rescue drug and nocturnal symptoms Assess the number of exacerbations Assess the days absent from work/school Assess the ability to reduce the dose of inhaled corticosteroids Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc. , an affiliate of Elsevier Inc. 48