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

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

Chapter 7Chapter 7

Anticholinergic (Parasympatholytic) Anticholinergic (Parasympatholytic) BronchodilatorsBronchodilators

22Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.

Clinical Indications for UseClinical Indications for Use

Indication for anticholinergic bronchodilatorIndication for anticholinergic bronchodilator COPD maintenanceCOPD maintenance

Indication for combined anticholinergic and Indication for combined anticholinergic and

β-agonist bronchodilatorsβ-agonist bronchodilators COPD with airflow obstructionCOPD with airflow obstruction

Anticholinergic nasal sprayAnticholinergic nasal spray Allergic and nonallergic perennial rhinitis and the Allergic and nonallergic perennial rhinitis and the

common coldcommon cold


Specific Anticholinergic Specific Anticholinergic (Parasympatholytic) Agents(Parasympatholytic) Agents

Atropine sulfateAtropine sulfate Not recommended for inhalationNot recommended for inhalation

Ipratropium bromideIpratropium bromide Available as MDI, SVN solution, and nasal sprayAvailable as MDI, SVN solution, and nasal spray Quaternary ammonium derivative of atropineQuaternary ammonium derivative of atropine Distribution is limited to lung when inhaledDistribution is limited to lung when inhaled


Specific Anticholinergic Specific Anticholinergic (Parasympatholytic) Agents (Parasympatholytic) Agents (cont’d)(cont’d)

Ipratropium and albuterolIpratropium and albuterol Synergistic effect in COPDSynergistic effect in COPD

GlycopyrrolateGlycopyrrolate Used parenterally to reverse neuromuscular Used parenterally to reverse neuromuscular

blockadeblockade Currently not approved for inhalationCurrently not approved for inhalation

Tiotropium bromideTiotropium bromide Longer-acting (up to 24 hours) quaternary Longer-acting (up to 24 hours) quaternary

ammonium derivative of atropineammonium derivative of atropine


Clinical PharmacologyClinical Pharmacology

Structure-activity relationsStructure-activity relations Atropine and scopolamineAtropine and scopolamine

• Tertiary ammonium compoundsTertiary ammonium compounds

• Easily absorbed in the bloodstreamEasily absorbed in the bloodstream

• Cross the blood-brain barrierCross the blood-brain barrier

Quaternary forms Quaternary forms • Poorly absorbed in the bloodstream or central nervous Poorly absorbed in the bloodstream or central nervous

system system

• Better for inhalationBetter for inhalation


Pharmacological EffectsPharmacological Effects

Anticholinergic (antimuscarinic) agentsAnticholinergic (antimuscarinic) agents Tertiary ammonium compound effectsTertiary ammonium compound effects

• Respiratory tract Respiratory tract

• Central nervous system Central nervous system

• EyesEyes

• Cardiac Cardiac

• GastrointestinalGastrointestinal

• GenitourinaryGenitourinary


Pharmacological Effects Pharmacological Effects (cont’d)(cont’d)

Quaternary ammonium compound effectsQuaternary ammonium compound effects• Respiratory tractRespiratory tract

• Central nervous systemCentral nervous system

• EyesEyes

• CardiacCardiac

• GastrointestinalGastrointestinal

• GenitourinaryGenitourinary

Side effects are localized to the site of drug Side effects are localized to the site of drug exposureexposure


Mode of ActionMode of Action

Parasympathetic innervation causes basal Parasympathetic innervation causes basal level bronchomotor tone.level bronchomotor tone.

Parasympatholytic bronchodilators block this Parasympatholytic bronchodilators block this tone.tone.

Degree of bronchodilation depends on the Degree of bronchodilation depends on the amount of parasympathetic tone present.amount of parasympathetic tone present.


Anticholinergic AgentAnticholinergic Agent

Figure 7-2 Figure 7-2 Conceptual overview of the action of anticholinergic (parasympatholytic) Conceptual overview of the action of anticholinergic (parasympatholytic) bronchodilating agents in preventing cholinergic-induced bronchoconstriction. bronchodilating agents in preventing cholinergic-induced bronchoconstriction. Ach,Ach, Acetylcholine.Acetylcholine.


Mode of ActionMode of Action

Vagally mediated reflex bronchoconstrictionVagally mediated reflex bronchoconstriction Irritant aerosols, cold air, high airflow rates, Irritant aerosols, cold air, high airflow rates,

smoke, fumes, histamine releasesmoke, fumes, histamine release Afferent impulse to CNS Afferent impulse to CNS reflex cholinergic reflex cholinergic

efferent impulse efferent impulse constriction of airway smooth constriction of airway smooth muscle muscle mucus and cough mucus and cough

Can be blocked by competitive inhibitors of Can be blocked by competitive inhibitors of acetylcholineacetylcholine


Mechanism of ActionMechanism of Action

Figure 7-3 Figure 7-3 Mechanism of vagally mediated reflex bronchoconstriction induced Mechanism of vagally mediated reflex bronchoconstriction induced by nonspecific stimuli on sensory C-fibers. by nonspecific stimuli on sensory C-fibers. Ach,Ach, Acetylcholine; Acetylcholine; CNS,CNS, central central nervous system; nervous system; SP,SP, substance P. substance P.


Receptor SubtypesReceptor Subtypes

MuscarinicMuscarinic MM11

• Parasympathetic gangliaParasympathetic ganglia

• Facilitate neurotransmission and bronchoconstrictionFacilitate neurotransmission and bronchoconstriction

• Cause secretion and rhinitis in the noseCause secretion and rhinitis in the nose MM22

• Inhibit continued use of acetylcholineInhibit continued use of acetylcholine

• Blockade may enhance acetylcholine release, counteracting Blockade may enhance acetylcholine release, counteracting bronchodilation (tiotropium is selective for Mbronchodilation (tiotropium is selective for M11 and M and M33))

MM33

• Smooth airway muscle and submucosal glandsSmooth airway muscle and submucosal glands

• Cause bronchoconstrictionCause bronchoconstriction

• Cause secretion and rhinitis in the noseCause secretion and rhinitis in the nose


Muscarinic ReceptorsMuscarinic Receptors

Figure 7-4 Figure 7-4 Identification and location of muscarinic receptor subtypes MIdentification and location of muscarinic receptor subtypes M11, M, M

22, and M, and M33 in the in the

vagal nerve, submucosal gland, and bronchial smooth muscle in the airway, showing vagal nerve, submucosal gland, and bronchial smooth muscle in the airway, showing nonspecific blockade by anticholinergic drugs such as ipratropium. nonspecific blockade by anticholinergic drugs such as ipratropium. Ach,Ach, Acetylcholine. Acetylcholine.


Adverse EffectsAdverse Effects

Changes in BP, EKG, or HR not usually seenChanges in BP, EKG, or HR not usually seen No worsening of ventilation-perfusion No worsening of ventilation-perfusion

abnormalitiesabnormalities No tolerance/loss of protectionNo tolerance/loss of protection Side effects:Side effects:

Dry mouth (most common)Dry mouth (most common) CoughCough Mydriasis (eyes should be protected)Mydriasis (eyes should be protected) SVN: also pharyngitis, dyspnea, flulike symptoms, SVN: also pharyngitis, dyspnea, flulike symptoms,

bronchitis, upper respiratory infectionbronchitis, upper respiratory infection


Clinical ApplicationClinical Application

Use in COPDUse in COPD More potent bronchodilators than β-adrenergics in More potent bronchodilators than β-adrenergics in

emphysema/bronchitisemphysema/bronchitis FDA approved specifically for COPDFDA approved specifically for COPD Tiotropium maintains higher PFT levels than Tiotropium maintains higher PFT levels than

ipratropiumipratropium


Effect of Effect of ββ-Agonist-Agonist

Figure 7-6 Figure 7-6 Effect of the Effect of the ββ agonist metaproterenol and the anticholinergic ipratropium on forced agonist metaproterenol and the anticholinergic ipratropium on forced expiratory volume in 1 second expiratory volume in 1 second (FEV(FEV

11) in patients with chronic obstructive pulmonary disease ) in patients with chronic obstructive pulmonary disease

(COPD) after 90 days of treatment (*(COPD) after 90 days of treatment (*PP less than 0.01; less than 0.01; ††PP less than 0.05). (From Tashkin DP, less than 0.05). (From Tashkin DP, Ashutosh K, Bleecker ER, et al: Comparison of the anticholinergic bronchodilator ipratropium 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 bromide with metaproterenol in chronic obstructive pulmonary disease: a 90-day multi-center study, study, Am J Med Am J Med 81(suppl 5A):59, 1986. From Excerpta Medica, Inc.)81(suppl 5A):59, 1986. From Excerpta Medica, Inc.)


Clinical ApplicationClinical Application

Use in asthmaUse in asthma No label indication for asthma in the United StatesNo label indication for asthma in the United States Antimuscarinics not clearly superior to β-agonists for Antimuscarinics not clearly superior to β-agonists for

asthmaasthma May be useful in:May be useful in:

• Nocturnal asthmaNocturnal asthma

• Psychogenic asthmaPsychogenic asthma

• Asthmatics being treated for another condition with β-blockersAsthmatics being treated for another condition with β-blockers

• An alternative to theophyllineAn alternative to theophylline

• In acute/severe episodes not responding to β-agonistIn acute/severe episodes not responding to β-agonist


Combination TherapyCombination Therapy

β-Adrenergic and anticholinergic agents in β-Adrenergic and anticholinergic agents in COPDCOPD Complementarily sites of action Complementarily sites of action Mechanisms of action: separate and Mechanisms of action: separate and

complementarycomplementary• Additive effect of β-agonists and anticholinergicsAdditive effect of β-agonists and anticholinergics

Mean peak increases:Mean peak increases:– 31 to 33% for combined drugs31 to 33% for combined drugs– 24 to 25% for ipratropium alone24 to 25% for ipratropium alone– 24 to 27% for albuterol alone24 to 27% for albuterol alone


AdministrationAdministration

Sequence of administrationSequence of administration No data to support either drug being No data to support either drug being

administered firstadministered first Not an issue when using CombiventNot an issue when using Combivent β-Agonist may be given first becauseβ-Agonist may be given first because

• More rapid onsetMore rapid onset

• Distributed in large and small airwaysDistributed in large and small airways


Respiratory Care AssessmentRespiratory Care Assessment

Anticholinergic bronchodilator therapyAnticholinergic bronchodilator therapy Assess effectiveness based on indication for use Assess effectiveness based on indication for use Monitor flow ratesMonitor flow rates Perform respiratory assessmentPerform respiratory assessment Breath sounds, auscultation, respiratory rate Breath sounds, auscultation, respiratory rate

(pre- and posttreatment)(pre- and posttreatment) Assess pulseAssess pulse Subjective reactionSubjective reaction


Respiratory Care Assessment Respiratory Care Assessment (cont’d)(cont’d)

Anticholinergic bronchodilator therapy Anticholinergic bronchodilator therapy (cont’d)(cont’d) Arterial blood gases/SpOArterial blood gases/SpO22

Long term: PFTsLong term: PFTs Instruct/verify correct use of delivery deviceInstruct/verify correct use of delivery device For long-acting drugs:For long-acting drugs:

• Ongoing lung function over time Ongoing lung function over time

• Concomitant β-agonist use/nocturnal symptomsConcomitant β-agonist use/nocturnal symptoms

• Exacerbations/hospitalizationsExacerbations/hospitalizations

• Absences from work/schoolAbsences from work/school

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

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