Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Chapter 6 Adrenergic (Sympathomimetic) Bronchodilators

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

3 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Asthma

4 Indication for Short-Acting Agents  Acute reversible airflow obstruction  Short-acting agents:  a.k.a. “rescue” agents  Albuterol  Levalbuterol  Metaproterenol  Pirbuterol

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

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

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

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

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

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

11 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. 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.

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

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

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

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

16 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Metabolism of Catecholamines  Rapidly inactivated by COMT  Duration of action is limited  1.5 to 3 hours  Unsuitable for oral administration  Inactivated in gut and liver  Also inactivated by:  Heat  Light  Air

17 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. % 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.)

18 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. % 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.)

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

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

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

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

23 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Levalbuterol: The (R)-Isomer of Albuterol  Pure (R)-isomer of racemic albuterol  Available as HFA MDI and nebulizer solution  Available in four doses:  0.31 mg/3 mL  0.63 mg/3 mL  1.25 mg/3 mL  1.25 mg/0.5 mL concentrate

24 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. 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.

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

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

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

28 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. 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 +)  Exercise-induced bronchospasm (5 years +)  COPD

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

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

31 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. 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

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

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

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

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

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

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

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

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

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

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

42 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. 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  SQ terbutaline 0.25 mg  Should be used as a last resort and requires:  Infusion pump  Cardiac monitor  Close attention for systemic side effects

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

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

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

46 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. 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

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

48 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Respiratory Care Assessment of β-Agonist Therapy (cont’d)  For long-acting β-agonists  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