Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Chapter 7 Anticholinergic (Parasympatholytic) Bronchodilators

2 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Indications for Use  Indication for anticholinergic bronchodilator  COPD maintenance  Indication for combined anticholinergic and β-agonist bronchodilators  COPD with airflow obstruction  Anticholinergic nasal spray  Allergic and nonallergic perennial rhinitis and the common cold

3 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Specific Anticholinergic (Parasympatholytic) Agents  Atropine sulfate  Not recommended for inhalation  Ipratropium bromide  Available as MDI, SVN solution, and nasal spray  Quaternary ammonium derivative of atropine  Distribution is limited to lung when inhaled

4 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Specific Anticholinergic (Parasympatholytic) Agents (cont’d)  Ipratropium and albuterol  Synergistic effect in COPD  Glycopyrrolate  Used parenterally to reverse neuromuscular blockade  Currently not approved for inhalation  Tiotropium bromide  Longer-acting (up to 24 hours) quaternary ammonium derivative of atropine

5 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Pharmacology  Structure-activity relations  Atropine and scopolamine Tertiary ammonium compounds Tertiary ammonium compounds Easily absorbed in the bloodstream Easily absorbed in the bloodstream Cross the blood-brain barrier Cross the blood-brain barrier  Quaternary forms Poorly absorbed in the bloodstream or central nervous system Poorly absorbed in the bloodstream or central nervous system Better for inhalation Better for inhalation

6 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Pharmacological Effects  Anticholinergic (antimuscarinic) agents  Tertiary ammonium compound effects Respiratory tract Respiratory tract Central nervous system Central nervous system Eyes Eyes Cardiac Cardiac Gastrointestinal Gastrointestinal Genitourinary Genitourinary

7 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Pharmacological Effects (cont’d)  Quaternary ammonium compound effects Respiratory tract Respiratory tract Central nervous system Central nervous system Eyes Eyes Cardiac Cardiac Gastrointestinal Gastrointestinal Genitourinary Genitourinary  Side effects are localized to the site of drug exposure

8 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Mode of Action  Parasympathetic innervation causes basal level bronchomotor tone.  Parasympatholytic bronchodilators block this tone.  Degree of bronchodilation depends on the amount of parasympathetic tone present.

9 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Anticholinergic Agent Figure 7-2 Conceptual overview of the action of anticholinergic (parasympatholytic) bronchodilating agents in preventing cholinergic-induced bronchoconstriction. Ach, Acetylcholine.

10 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Mode of Action  Vagally mediated reflex bronchoconstriction  Irritant aerosols, cold air, high airflow rates, smoke, fumes, histamine release  Afferent impulse to CNS  reflex cholinergic efferent impulse  constriction of airway smooth muscle  mucus and cough  Can be blocked by competitive inhibitors of acetylcholine

11 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Mechanism of Action Figure 7-3 Mechanism of vagally mediated reflex bronchoconstriction induced by nonspecific stimuli on sensory C-fibers. Ach, Acetylcholine; CNS, central nervous system; SP, substance P.

12 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Receptor Subtypes  Muscarinic  M 1 Parasympathetic ganglia Parasympathetic ganglia Facilitate neurotransmission and bronchoconstriction Facilitate neurotransmission and bronchoconstriction Cause secretion and rhinitis in the nose Cause secretion and rhinitis in the nose  M 2 Inhibit continued use of acetylcholine Inhibit continued use of acetylcholine Blockade may enhance acetylcholine release, counteracting bronchodilation (tiotropium is selective for M 1 and M 3 ) Blockade may enhance acetylcholine release, counteracting bronchodilation (tiotropium is selective for M 1 and M 3 )  M 3 Smooth airway muscle and submucosal glands Smooth airway muscle and submucosal glands Cause bronchoconstriction Cause bronchoconstriction Cause secretion and rhinitis in the nose Cause secretion and rhinitis in the nose

13 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Muscarinic Receptors Figure 7-4 Identification and location of muscarinic receptor subtypes M 1, M 2, and M 3 in the vagal nerve, submucosal gland, and bronchial smooth muscle in the airway, showing nonspecific blockade by anticholinergic drugs such as ipratropium. Ach, Acetylcholine.

14 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Adverse Effects  Changes in BP, EKG, or HR not usually seen  No worsening of ventilation-perfusion abnormalities  No tolerance/loss of protection  Side effects:  Dry mouth (most common)  Cough  Mydriasis (eyes should be protected)  SVN: also pharyngitis, dyspnea, flulike symptoms, bronchitis, upper respiratory infection

15 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Application  Use in COPD  More potent bronchodilators than β-adrenergics in emphysema/bronchitis  FDA approved specifically for COPD  Tiotropium maintains higher PFT levels than ipratropium

16 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Effect of β-Agonist Figure 7-6 Effect of the β agonist metaproterenol and the anticholinergic ipratropium on forced expiratory volume in 1 second (FEV 1 ) in patients with chronic obstructive pulmonary disease (COPD) after 90 days of treatment (*P less than 0.01; † P less than 0.05). (From Tashkin DP, Ashutosh K, Bleecker ER, et al: Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease: a 90-day multi-center study, Am J Med 81(suppl 5A):59, From Excerpta Medica, Inc.)

17 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Application  Use in asthma  No label indication for asthma in the United States  Antimuscarinics not clearly superior to β-agonists for asthma  May be useful in: Nocturnal asthma Nocturnal asthma Psychogenic asthma Psychogenic asthma Asthmatics being treated for another condition with β- blockers Asthmatics being treated for another condition with β- blockers An alternative to theophylline An alternative to theophylline In acute/severe episodes not responding to β-agonist In acute/severe episodes not responding to β-agonist

18 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Combination Therapy  β-Adrenergic and anticholinergic agents in COPD  Complementarily sites of action  Mechanisms of action: separate and complementary Additive effect of β-agonists and anticholinergics Additive effect of β-agonists and anticholinergics  Mean peak increases: –31 to 33% for combined drugs –24 to 25% for ipratropium alone –24 to 27% for albuterol alone

19 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Administration  Sequence of administration  No data to support either drug being administered first  Not an issue when using Combivent  β-Agonist may be given first because More rapid onset More rapid onset Distributed in large and small airways Distributed in large and small airways

20 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Respiratory Care Assessment  Anticholinergic bronchodilator therapy  Assess effectiveness based on indication for use  Monitor flow rates  Perform respiratory assessment  Breath sounds, auscultation, respiratory rate (pre- and posttreatment)  Assess pulse  Subjective reaction

21 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Respiratory Care Assessment (cont’d)  Anticholinergic bronchodilator therapy (cont’d)  Arterial blood gases/SpO 2  Long term: PFTs  Instruct/verify correct use of delivery device  For long-acting drugs: Ongoing lung function over time Ongoing lung function over time Concomitant β-agonist use/nocturnal symptoms Concomitant β-agonist use/nocturnal symptoms Exacerbations/hospitalizations Exacerbations/hospitalizations Absences from work/school Absences from work/school