Bronchodilators

Bronchodilators and Other Bronchodilators and Other Respiratory AgentsRespiratory Agents

Drugs Affecting Drugs Affecting the Respiratory Systemthe Respiratory System

• BronchodilatorsBronchodilators

– Xanthine derivativesXanthine derivatives

– Beta-agonistsBeta-agonists

• AnticholinergicsAnticholinergics

• Antileukotriene agentsAntileukotriene agents

• CorticosteroidsCorticosteroids

• Mast cell stabilizersMast cell stabilizers

Bronchodilators: Xanthine DerivativesBronchodilators: Xanthine Derivatives

• Plant alkaloids: caffeine, theobromine, and Plant alkaloids: caffeine, theobromine, and theophyllinetheophylline

• Only theophylline is used as a bronchodilatorOnly theophylline is used as a bronchodilator

Examples:Examples: aminophyllineaminophyllinedyphilline dyphilline oxtriphyllineoxtriphyllinetheophylline (Bronkodyl, Slo-theophylline (Bronkodyl, Slo-

bid,bid,Theo-Dur,Uniphyl)Theo-Dur,Uniphyl)

Bronchodilators: Xanthine Derivatives Bronchodilators: Xanthine Derivatives Mechanism of ActionMechanism of Action

• Increase levels of energy-producing cAMP*Increase levels of energy-producing cAMP*

• This is done competitively inhibiting This is done competitively inhibiting phosphodiesterase (PDE), the enzyme that phosphodiesterase (PDE), the enzyme that breaks down cAMPbreaks down cAMP

• Result: decreased cAMP levels, smooth Result: decreased cAMP levels, smooth muscle relaxation, bronchodilation, and muscle relaxation, bronchodilation, and increased airflowincreased airflow

*cAMP = cyclic adenosine monophosphate*cAMP = cyclic adenosine monophosphate

Bronchodilators: Xanthine Derivatives Bronchodilators: Xanthine Derivatives Drug EffectsDrug Effects

• Cause bronchodilation by relaxing smooth muscles Cause bronchodilation by relaxing smooth muscles of the airways.of the airways.

• Result: relief of bronchospasm and greater airflow Result: relief of bronchospasm and greater airflow into and out of the lungs.into and out of the lungs.

• Also causes CNS stimulation.Also causes CNS stimulation.

• Also causes cardiovascular stimulation: increased Also causes cardiovascular stimulation: increased force of contraction and increased HR, resulting in force of contraction and increased HR, resulting in increased cardiac output and increased blood flow increased cardiac output and increased blood flow to the kidneys (diuretic effect).to the kidneys (diuretic effect).

Bronchodilators: Xanthine Derivatives Bronchodilators: Xanthine Derivatives Therapeutic UsesTherapeutic Uses

• Dilation of airways in asthmas, chronic Dilation of airways in asthmas, chronic bronchitis, and emphysemabronchitis, and emphysema

• Mild to moderate cases of asthmaMild to moderate cases of asthma

• Adjunct agent in the management of COPDAdjunct agent in the management of COPD

• Adjunct therapy for the relief of pulmonary Adjunct therapy for the relief of pulmonary edema and paroxysmal nocturnal edema in edema and paroxysmal nocturnal edema in left-sided heart failureleft-sided heart failure

Bronchodilators: Xanthine Derivatives Bronchodilators: Xanthine Derivatives Side EffectsSide Effects

• Nausea, vomiting, anorexiaNausea, vomiting, anorexia

• Gastroesophageal reflux during sleepGastroesophageal reflux during sleep

• Sinus tachycardia, extrasystole, palpitations, Sinus tachycardia, extrasystole, palpitations, ventricular dysrhythmiasventricular dysrhythmias

• Transient increased urinationTransient increased urination

Bronchodilators: Beta-AgonistsBronchodilators: Beta-Agonists

• Large group, sympathomimeticsLarge group, sympathomimetics

• Used during acute phase of asthmatic Used during acute phase of asthmatic attacksattacks

• Quickly reduce airway constriction and Quickly reduce airway constriction and restore normal airflowrestore normal airflow

• Stimulate betaStimulate beta22 adrenergic receptors adrenergic receptors throughout the lungsthroughout the lungs

Bronchodilators: Beta-Agonists Bronchodilators: Beta-Agonists Three typesThree types

• Nonselective adrenergicsNonselective adrenergics

– Stimulate alphaStimulate alpha11, beta, beta11 (cardiac), and beta (cardiac), and beta22 (respiratory) (respiratory) receptors.receptors.

Example: epinephrineExample: epinephrine

• Nonselective beta-adrenergicsNonselective beta-adrenergics

– Stimulate both betaStimulate both beta11 and beta and beta22 receptors. receptors.

Example: isoproterenol (Isuprel)Example: isoproterenol (Isuprel)

• Selective betaSelective beta22 drugs drugs

– Stimulate only betaStimulate only beta22 receptors. receptors.

Example: albuterolExample: albuterol

Bronchodilators: Beta-Agonists Bronchodilators: Beta-Agonists Mechanism of ActionMechanism of Action

• Begins at the specific receptor stimulatedBegins at the specific receptor stimulated

• Ends with the dilation of the airwaysEnds with the dilation of the airways

Activation of betaActivation of beta22 receptors activate cAMP, which receptors activate cAMP, which relaxes smooth muscles of the airway and results relaxes smooth muscles of the airway and results in bronchial dilation and increased airflow.in bronchial dilation and increased airflow.

Bronchodilators: Beta-Agonists Bronchodilators: Beta-Agonists Therapeutic UsesTherapeutic Uses

• Relief of bronchospasm, bronchial asthma, Relief of bronchospasm, bronchial asthma, bronchitis, and other pulmonary disease.bronchitis, and other pulmonary disease.

• Useful in treatment of acute attacks as well Useful in treatment of acute attacks as well as prevention.as prevention.

• Used in hypotension and shock.Used in hypotension and shock.

• Used to produce uterine relaxation to prevent Used to produce uterine relaxation to prevent premature labor.premature labor.

• Hyperkalemia—stimulates potassium to shift Hyperkalemia—stimulates potassium to shift into the cell.into the cell.

Bronchodilators: Beta-Agonists Bronchodilators: Beta-Agonists Side EffectsSide Effects

Alpha-Beta Alpha-Beta BetaBeta11 and Beta and Beta22 BetaBeta22

(epinephrine)(epinephrine) (isoproterenol)(isoproterenol) (albuterol)(albuterol)

insomniainsomnia cardiac stimulationcardiac stimulation hypotensionhypotensionrestlessnessrestlessness tremortremor vascularvascular

headacheheadacheanorexiaanorexia anginal painanginal pain tremortremorcardiac stimulationcardiac stimulation vascular headachevascular headache tremortremorvascular headachevascular headache

Respiratory Agents: Respiratory Agents: General Nursing ImplicationsGeneral Nursing Implications

• Encourage patients to take measures that Encourage patients to take measures that promote a generally good state of health in promote a generally good state of health in order to prevent, relieve, or decrease order to prevent, relieve, or decrease symptoms of COPD.symptoms of COPD.

– Avoid exposure to conditions that precipitate Avoid exposure to conditions that precipitate bronchospasms (allergens, smoking, stress, air pollutants)bronchospasms (allergens, smoking, stress, air pollutants)

– Adequate fluid intakeAdequate fluid intake

– Compliance with medical treatmentCompliance with medical treatment

– Avoid excessive fatigue, heat, extremes in temperature, Avoid excessive fatigue, heat, extremes in temperature, caffeinecaffeine


• Encourage patients to get prompt treatment Encourage patients to get prompt treatment for flu or other illnesses, and to get for flu or other illnesses, and to get vaccinated against pneumonia or flu.vaccinated against pneumonia or flu.

• Encourage patients to always check with Encourage patients to always check with their physician before taking any other their physician before taking any other medication, including OTC.medication, including OTC.


• Perform a thorough assessment before Perform a thorough assessment before beginning therapy, including:beginning therapy, including:– Skin colorSkin color– Baseline vital signsBaseline vital signs– Respirations (should be <12 or >24 breaths/min)Respirations (should be <12 or >24 breaths/min)– Respiratory assessment, including PORespiratory assessment, including PO22

– Sputum productionSputum production– AllergiesAllergies– History of respiratory problemsHistory of respiratory problems– Other medications Other medications


• Teach patients to take bronchodilators Teach patients to take bronchodilators exactly as prescribed.exactly as prescribed.

• Ensure that patients know how to use Ensure that patients know how to use inhalers, MDIs, and have the patients inhalers, MDIs, and have the patients demonstrate use of devices.demonstrate use of devices.

• Monitor for side effects.Monitor for side effects.

Respiratory Agents: Respiratory Agents: Nursing ImplicationsNursing Implications

• Monitor for therapeutic effectsMonitor for therapeutic effects

– Decreased dyspneaDecreased dyspnea

– Decreased wheezing, restlessness, and anxietyDecreased wheezing, restlessness, and anxiety

– Improved respiratory patterns with return to Improved respiratory patterns with return to normal rate and qualitynormal rate and quality

– Improved activity toleranceImproved activity tolerance

• Decreased symptoms and increased Decreased symptoms and increased ease of breathingease of breathing

Bronchodilators: Nursing Implications Bronchodilators: Nursing Implications Xanthine DerivativesXanthine Derivatives

• Contraindications: history of PUD or Contraindications: history of PUD or GI disordersGI disorders

• Cautious use: cardiac diseaseCautious use: cardiac disease

• Timed-release preparations should not be Timed-release preparations should not be crushed or chewed (causes gastric irritation)crushed or chewed (causes gastric irritation)


• Report to physician:Report to physician:

PalpitationsPalpitations NauseaNausea VomitingVomiting

WeaknessWeakness DizzinessDizziness Chest painChest pain

ConvulsionsConvulsions


• Be aware of drug interactions with:Be aware of drug interactions with:cimetidine, oral contraceptives, allopurinolcimetidine, oral contraceptives, allopurinol

• Large amounts of caffeine can have Large amounts of caffeine can have deleterious effects.deleterious effects.

Bronchodilators: Nursing Implications Bronchodilators: Nursing Implications Beta-Agonist DerivativesBeta-Agonist Derivatives

• Albuterol, if used too frequently, loses its Albuterol, if used too frequently, loses its betabeta22-specific actions at larger doses.-specific actions at larger doses.

• As a result, betaAs a result, beta11 receptors are stimulated, receptors are stimulated, causing nausea, increased anxiety, causing nausea, increased anxiety, palpitations, tremors, and increased palpitations, tremors, and increased heart rate.heart rate.

Bronchodilators: Nursing ImplicationsBronchodilators: Nursing ImplicationsBeta-Agonist DerivativesBeta-Agonist Derivatives

• Patients should take medications exactly Patients should take medications exactly as prescribed, with no omissions or double as prescribed, with no omissions or double doses.doses.

• Patients should report insomnia, jitteriness, Patients should report insomnia, jitteriness, restlessness, palpitations, chest pain, or restlessness, palpitations, chest pain, or any change in symptoms.any change in symptoms.

Anticholinergics: Anticholinergics: Mechanism of ActionMechanism of Action

• Acetylcholine (ACh) causes bronchial Acetylcholine (ACh) causes bronchial constriction and narrowing of the airways.constriction and narrowing of the airways.

• Anticholinergics bind to the ACh receptors, Anticholinergics bind to the ACh receptors, preventing ACh from binding.preventing ACh from binding.

• Result: bronchoconstriction is prevented, Result: bronchoconstriction is prevented, airways dilate.airways dilate.

AnticholinergicsAnticholinergics

• Ipratropium bromide (Atrovent) is the only Ipratropium bromide (Atrovent) is the only anticholinergic used for respiratory disease.anticholinergic used for respiratory disease.

• Slow and prolonged actionSlow and prolonged action

• Used to Used to preventprevent bronchoconstriction bronchoconstriction

• NOT used for acute asthma exacerbations!NOT used for acute asthma exacerbations!

Anticholinergics: Side EffectsAnticholinergics: Side Effects

Dry mouth or throatDry mouth or throat Gastrointestinal Gastrointestinal distressdistress

HeadacheHeadache CoughingCoughing

AnxietyAnxiety

No known drug interactionsNo known drug interactions

AntileukotrienesAntileukotrienes

• Also called leukotriene receptor antagonists Also called leukotriene receptor antagonists (LRTAs)(LRTAs)

• New class of asthma medicationsNew class of asthma medications

• Three subcategories of agentsThree subcategories of agents

AntileukotrienesAntileukotrienes

Currently available agents:Currently available agents:

• montelukast (Singulair)montelukast (Singulair)

• zafirlukast (Accolate)zafirlukast (Accolate)

• zileuton (Zyflo)zileuton (Zyflo)

Antileukotrienes: Antileukotrienes: Mechanism of ActionMechanism of Action

• Leukotrienes are substances released when Leukotrienes are substances released when a trigger, such as cat hair or dust, starts a a trigger, such as cat hair or dust, starts a series of chemical reactions in the body.series of chemical reactions in the body.

• Leukotrienes cause inflammation, Leukotrienes cause inflammation, bronchoconstriction, and mucus production.bronchoconstriction, and mucus production.

• Result: coughing, wheezing, shortnessResult: coughing, wheezing, shortnessof breathof breath

Antileukotrienes: Antileukotrienes: Mechanism of ActionMechanism of Action

• Antileukotriene agents Antileukotriene agents preventprevent leukotrienes leukotrienes from attaching to receptors on cells in the from attaching to receptors on cells in the lungs and in circulation.lungs and in circulation.

• Inflammation in the lungs is Inflammation in the lungs is blockedblocked, and , and asthma symptoms are relieved.asthma symptoms are relieved.

Antileukotrienes: Drug EffectsAntileukotrienes: Drug Effects

By blocking leukotrienes:By blocking leukotrienes:

• Prevent smooth muscle contraction of the Prevent smooth muscle contraction of the bronchial airwaysbronchial airways

• Decrease mucus secretionDecrease mucus secretion

• Prevent vascular permeabilityPrevent vascular permeability

• Decrease neutrophil and leukocyte infiltration Decrease neutrophil and leukocyte infiltration to the lungs, preventing inflammationto the lungs, preventing inflammation

Antileukotrienes: Therapeutic UsesAntileukotrienes: Therapeutic Uses

• Prophylaxis and chronic treatment of asthma Prophylaxis and chronic treatment of asthma in adults and children over age 12in adults and children over age 12

• NOT meant for management of acute NOT meant for management of acute asthmatic attacksasthmatic attacks

• Montelukast is approved for use in children Montelukast is approved for use in children age 2 and olderage 2 and older

Antileukotrienes: Side EffectsAntileukotrienes: Side Effects

zileutonzileuton zafirlukastzafirlukast

HeadacheHeadache HeadacheHeadache

DyspepsiaDyspepsia NauseaNausea

NauseaNausea DiarrheaDiarrhea

DizzinessDizziness Liver dysfunctionLiver dysfunction

InsomniaInsomnia

Liver dysfunctionLiver dysfunction

montelukast has fewer side effects montelukast has fewer side effects

Antileukotrienes: Antileukotrienes: Nursing ImplicationsNursing Implications

• Ensure that the drug is being used for Ensure that the drug is being used for chronic management of asthma, not chronic management of asthma, not acute asthma.acute asthma.

• Teach the patient the purpose of the therapy.Teach the patient the purpose of the therapy.

• Improvement should be seen in about Improvement should be seen in about 1 week.1 week.

Antileukotrienes: Antileukotrienes: Nursing ImplicationsNursing Implications

• Check with physician before taking any Check with physician before taking any OTC or prescribed medications—many OTC or prescribed medications—many drug interactions.drug interactions.

• Assess liver function before beginning Assess liver function before beginning therapy.therapy.

• Medications should be taken every night on Medications should be taken every night on a continuous schedule, even if symptoms a continuous schedule, even if symptoms improve.improve.

CorticosteroidsCorticosteroids

• Anti-inflammatoryAnti-inflammatory

• Used for CHRONIC asthmaUsed for CHRONIC asthma

• Do not relieve symptoms of acute Do not relieve symptoms of acute asthmatic attacksasthmatic attacks

• Oral or inhaled formsOral or inhaled forms

• Inhaled forms reduce systemic effectsInhaled forms reduce systemic effects

• May take several weeks before full May take several weeks before full effects are seeneffects are seen

Corticosteroids: Corticosteroids: Mechanism of ActionMechanism of Action

• Stabilize membranes of cells that release Stabilize membranes of cells that release harmful bronchoconstricting substances.harmful bronchoconstricting substances.

• These cells are leukocytes, or white These cells are leukocytes, or white blood cells.blood cells.

• Also increase responsiveness of bronchial Also increase responsiveness of bronchial smooth muscle to beta-adrenergic smooth muscle to beta-adrenergic stimulation.stimulation.

Inhaled CorticosteroidsInhaled Corticosteroids

• beclomethasone dipropionate beclomethasone dipropionate (Beclovent, Vanceril)(Beclovent, Vanceril)

• triamcinolone acetonide triamcinolone acetonide (Azmacort)(Azmacort)

• dexamethasone sodium phosphate dexamethasone sodium phosphate (Decadron Phosphate Respihaler)(Decadron Phosphate Respihaler)

• flunisolide (AeroBid)flunisolide (AeroBid)

Inhaled Corticosteroids: Inhaled Corticosteroids: Therapeutic UsesTherapeutic Uses

• Treatment of bronchospastic disorders Treatment of bronchospastic disorders that are not controlled by conventional that are not controlled by conventional bronchodilators.bronchodilators.

• NOT considered first-line agents for NOT considered first-line agents for management of acute asthmatic attacks management of acute asthmatic attacks or status asthmaticus.or status asthmaticus.

Inhaled Corticosteroids: Inhaled Corticosteroids: Side EffectsSide Effects

• Pharyngeal irritationPharyngeal irritation

• CoughingCoughing

• Dry mouthDry mouth

• Oral fungal infectionsOral fungal infections

Systemic effects are rare because of the low Systemic effects are rare because of the low doses used for inhalation therapy.doses used for inhalation therapy.

Inhaled Corticosteroids: Inhaled Corticosteroids: Nursing ImplicationsNursing Implications

• Contraindicated in patients with psychosis, Contraindicated in patients with psychosis, fungal infections, AIDS, TB.fungal infections, AIDS, TB.

• Cautious use in patients with diabetes, Cautious use in patients with diabetes, glaucoma, osteoporosis, PUD, renal glaucoma, osteoporosis, PUD, renal disease, CHF, edema.disease, CHF, edema.

• Teach patients to gargle and rinse the mouth Teach patients to gargle and rinse the mouth with water afterward to prevent the with water afterward to prevent the development of oral fungal infections.development of oral fungal infections.

Inhaled Corticosteroids: Inhaled Corticosteroids: Nursing ImplicationsNursing Implications

• Abruptly discontinuing these medications Abruptly discontinuing these medications can lead to serious problems.can lead to serious problems.

• If discontinuing, should be weaned for a If discontinuing, should be weaned for a period of 1 to 2 weeks, and only if period of 1 to 2 weeks, and only if recommended by physician.recommended by physician.

• REPORT any weight gain of more than 5 REPORT any weight gain of more than 5 pounds a week or the occurrence of chest pounds a week or the occurrence of chest pain.pain.

Mast Cell StabilizersMast Cell Stabilizers

• cromolyn (Nasalcrom, Intal)cromolyn (Nasalcrom, Intal)

• nedocromil (Tilade)nedocromil (Tilade)

Mast Cell StabilizersMast Cell Stabilizers

• Indirect-acting agents that prevent the Indirect-acting agents that prevent the release of the various substances that release of the various substances that cause bronchospasmcause bronchospasm

• Stabilize the cell membranes of Stabilize the cell membranes of inflammatory cells (mast cells, monocytes, inflammatory cells (mast cells, monocytes, macrophages), thus preventing release of macrophages), thus preventing release of harmful cellular contentsharmful cellular contents

• No direct bronchodilator activityNo direct bronchodilator activity

• Used prophylacticallyUsed prophylactically

Mast Cell Stabilizers: Mast Cell Stabilizers: Therapeutic UsesTherapeutic Uses

• Adjuncts to the overall management Adjuncts to the overall management of COPDof COPD

• Used solely for prophylaxis, NOT for Used solely for prophylaxis, NOT for acute asthma attacksacute asthma attacks

• Used to prevent exercise-induced Used to prevent exercise-induced bronchospasmbronchospasm

• Used to prevent bronchospasm associated Used to prevent bronchospasm associated with exposure to known precipitating factors, with exposure to known precipitating factors, such as cold, dry air or allergenssuch as cold, dry air or allergens

Mast Cell Stabilizers: Side EffectsMast Cell Stabilizers: Side Effects

CoughingCoughing Taste changesTaste changes

Sore throatSore throat DizzinessDizziness

RhinitisRhinitis HeadacheHeadache

BronchospasmBronchospasm

Mast Cell Stabilizers: Mast Cell Stabilizers: Nursing ImplicationsNursing Implications

• For prophylactic use onlyFor prophylactic use only

• Contraindicated for acute exacerbationsContraindicated for acute exacerbations

• Not recommended for children under age 5Not recommended for children under age 5

• Therapeutic effects may not be seen for up Therapeutic effects may not be seen for up to 4 weeksto 4 weeks

• Teach patients to gargle and rinse the mouth Teach patients to gargle and rinse the mouth with water afterward to minimize irritation to with water afterward to minimize irritation to the throat and oral mucosathe throat and oral mucosa

LEARNING OBJECTIVESLEARNING OBJECTIVES

• To appreciate basic pathogenesis of and therapeutic strategies for To appreciate basic pathogenesis of and therapeutic strategies for the management of asthma and chronic obstructive pulmonary the management of asthma and chronic obstructive pulmonary disease (COPD)disease (COPD)

• To understand the mechanism of action of the To understand the mechanism of action of the three major classes of bronchodilatorsthree major classes of bronchodilators

• To appreciate prospects for new therapies for To appreciate prospects for new therapies for asthma and COPDasthma and COPD

Asthma and COPD are common disorders (affecting 10 and 30 million Americans, respectively) and show several similarities in their clinical features. The goal of this lecture and the lecture on anti-inflammatory agents will be to highlight the fundamental pharmacological basis to manage the pathological changes associated with these diseases and to restore normal functionality.

www.freelivedoctor.com

ASTHMAASTHMA

The clinical hallmarks of asthma are recurrent, The clinical hallmarks of asthma are recurrent, episodic bouts of coughing, shortness of breath, episodic bouts of coughing, shortness of breath, chest tightness, and wheezing. In mild asthma, chest tightness, and wheezing. In mild asthma, symptoms occur only occasionally but in more symptoms occur only occasionally but in more severe forms of asthma frequent attacks of severe forms of asthma frequent attacks of wheezing dyspnea occur, especially at night, and wheezing dyspnea occur, especially at night, and chronic activity limitation is common. chronic activity limitation is common.


Pathological Features of Pathological Features of AsthmaAsthma

• Asthma is characterized physiologically by Asthma is characterized physiologically by increased responsiveness of the trachea and increased responsiveness of the trachea and bronchi to various stimuli and by widespread bronchi to various stimuli and by widespread narrowing of the airways. narrowing of the airways.

• Chronic pathological features:Chronic pathological features:

– contraction of airways smooth muscle, leading contraction of airways smooth muscle, leading to reversible airflow obstruction, to reversible airflow obstruction,

– mucosal thickening from edema and cellular mucosal thickening from edema and cellular infiltration with airway inflammation and infiltration with airway inflammation and persistent airway hyperreactivity, persistent airway hyperreactivity,

– airway remodeling. airway remodeling. www.freelivedoctor.com

Anatomy of AsthmaAnatomy of Asthma


Impact of Inflammation on Impact of Inflammation on Small AirwaysSmall Airways

Acute Fatal AsthmaNormal Chronic Severe Asthma

From the lecture tomorrow by A. Petrov, MDwww.freelivedoctor.com

Mechanisms of airway inflammation in Mechanisms of airway inflammation in asthmaasthma

Allergen exposure initiates a complex, self-amplifying process among cells, cytokines, and neurogenic components, resulting in chronic, symptomatic inflammation with bronchial hyperresponsiveness. Mast cells in the bronchial lumen & epithelium & within the bronchial wall become activated, releasing a mediators, which initiate an acute phase reaction (within min), including bronchospasm, resulting in airflow obstruction.


Cellular mediators and cytokines in Cellular mediators and cytokines in COPDCOPD


Current and Future Asthma Treatment Current and Future Asthma Treatment

The worldwide asthma market is The worldwide asthma market is estimated to exceed US $7 billion estimated to exceed US $7 billion and is increasing rapidly. and is increasing rapidly. Approximately 5% of asthmatic Approximately 5% of asthmatic patients remain poorly controlled. patients remain poorly controlled. Despite considerable effort by the Despite considerable effort by the pharmaceutical industry, it has pharmaceutical industry, it has proven very difficult to develop new proven very difficult to develop new classes of therapeutic agents for classes of therapeutic agents for asthmaasthma..


Chronic Obstructive Pulmonary Chronic Obstructive Pulmonary DiseaseDisease

• COPD is characterized by airflow limitation caused by COPD is characterized by airflow limitation caused by chronic bronchitis or emphysema often associated chronic bronchitis or emphysema often associated with long term tobacco smoking. This is usually a with long term tobacco smoking. This is usually a slowly progressive and largely irreversible process, slowly progressive and largely irreversible process, which consists of increased resistance to airflow, loss which consists of increased resistance to airflow, loss of elastic recoil, decreased expiratory flow rate, and of elastic recoil, decreased expiratory flow rate, and overinflation of the lung. overinflation of the lung.

• COPD is clinically defined by a low FEV1 value that COPD is clinically defined by a low FEV1 value that fails to respond acutely to bronchodilators, a fails to respond acutely to bronchodilators, a characteristic that differentiates it from asthma. characteristic that differentiates it from asthma.

• The degree of broncodilatory response at the time of The degree of broncodilatory response at the time of testing, however, does not predict the degree of testing, however, does not predict the degree of clinical benefit to the patient and thus bronchodilators clinical benefit to the patient and thus bronchodilators are given irrespective of the acute response obtained are given irrespective of the acute response obtained in the pulmonary function laboratory.in the pulmonary function laboratory.


ControlControl Severe COPDSevere COPD

Pathology of Small Airways i.e. less then 2mm in diameter

From Danielle Morse, MDwww.freelivedoctor.com

LungTopical effect~2-10%

LiverFirst passMetabolism(inactivation)

GI Tract

MouthDeposition~90% swallowed

LungPulmonary absorption

BLOOD STREAMDrug systemic effect + inactive metabolite

Schematic representation of the disposition of inhaled Schematic representation of the disposition of inhaled drugsdrugs


Aerosol & Spacer TechnologyAerosol & Spacer Technology


Aerosol Delivery of DrugsAerosol Delivery of Drugs

• The size of the particle is a critical delivery The size of the particle is a critical delivery determinant.determinant.

• Particles > 10 Particles > 10 m are deposited primarily in the m are deposited primarily in the mouth & oropharynx.mouth & oropharynx.

• Particles < 0.5 Particles < 0.5 m are inhaled to the alveoli and m are inhaled to the alveoli and exhaled without being deposited in the lungs.exhaled without being deposited in the lungs.

• The most effective particles have a diameter of The most effective particles have a diameter of 1-5 1-5 m.m.

• Other important factors for deposition are rate of Other important factors for deposition are rate of breathing and breathing-holding after inhalation.breathing and breathing-holding after inhalation.


Role of beta agonists in asthma and Role of beta agonists in asthma and COPDCOPD

2 agonists have other beneficial effects including inhibition of mast cell-mediator release, prevention of microvascular leakage and airway edema, and enhanced mucocillary clearance. The inhibitor effects on mast cell actions suggest that 2 agonists may modify acute inflammation.www.freelivedoctor.c

om

Classes of BronchodilatorsClasses of Bronchodilators

AgonistsAgonistsAlbuterol, levalbuterol, metaproterenol, terbutaine, isoproterenol, & epinephrine

• PDE inhibitorsPDE inhibitorsTheophylline

• AnticholinergicsAnticholinergicsIpratropium & tiotropium


BronchodiliationPDE3

Signal Transduction Pathway for Signal Transduction Pathway for BronchodilationBronchodilation


Classification of Classification of agonistsagonistsTable 1. Beta Agonists

Short acting

Generic name Duration of action 2-selectivity

Albuterol 4-6 h +++

Levalbuterol 8 h +++

Metaproterenol 4-6 h ++

Isoproterenol 3-4 h ++

Epinephrine 2-3 h -

Long acting

Salmeterol 12+ h +++

Formoterol 12+ h +++

2 agonists were developed through substitutions in the catecholamine structure of norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and modification at this site confers beta receptor selectivity; further substitutions have resulted in 2 selectivity. The selectivity of 2 agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small doses to the airways and minimizes systemic exposure. agonists are generally divided into short (4-6 h) and long (>12 h) acting agents.


ChemicalsChemicals

HO

HN

C(CH3)3

OH

HO

Epinephrine Isoproterenol Albuterol

HN

CH3

HO

OH

HO

OHHN CH3

CH3HO

HO

Metaproterenol Salmeterol

HN CH3HO

OH

OH

CH3

HO

HO

OHHN

O

Fomoterol


Classification of Classification of agonistsagonistsTable 1. Beta Agonists

Short acting

Generic name Duration of action 2-selectivity

Albuterol 4-6 h +++

Levalbuterol 8 h +++

Metaproterenol 4-6 h ++

Isoproterenol 3-4 h ++

Epinephrine 2-3 h -

Long acting

Salmeterol 12+ h +++

Formoterol 12+ h +++

2 agonists were developed through substitutions in the catecholamine structure of norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and modification at this site confers beta receptor selectivity; further substitutions have resulted in 2 selectivity. The selectivity of 2 agonists is obviously dose dependent. Inhalation of the drug aids selectivity since it delivers small doses to the airways and minimizes systemic exposure. agonists are generally divided into short (4-6 h) and long (>12 h) acting agents.


Pulmonary and cardiac effectsPulmonary and cardiac effects ofof adrenergicadrenergic receptor agonistsreceptor agonists

Log dose

FE

V1(

% m

axim

al

incr

ease

)

100

0

100

0

Hea

rt r

ate

(%m

axim

al i

ncr

ease

)

Isoproterenol

Albuterol


Pharmacological Approaches to Pharmacological Approaches to Asthma ControlAsthma Control

Selective 2 agonist

ATP

cAMP

Theophyline

5’-AMP

Relaxation

Ach

Ipratopium

Vagus nervewww.freelivedoctor.com

TheophyllineTheophylline The methylxantine theophylline share a similar structure to

the dietary xanthine caff eine. Many salts of theophylline have been marketed, the most

common being aminophylline, which is the ethylenediamine salt.

Theophylline has been in clinical use since the 1930s. I t is a weak, non-selective inhibitor of phosphodiesterase (PDE).

There are at least 10 PDE family members, all of which catabolize cyclic nucleotides in the cell.

PDE inhibition results in an increased in cAMP and cGMP. Another hypothesize mechanism of action is adenosine

receptor inhibition, which may prevent the release of mediators f rom mast cells.


TheophyllineTheophylline


Pharmacology of TheophyllinePharmacology of Theophylline

ADME

• Absorption: oral. The dose of theophylline required to yield therapeutic concentrations varies among subjects, largely because of differences in clearance.

• Metabolism. Concurrent administration of phenobarbitol or phenytoin increases activity of cytochrome P-450 (CYP), which results in increased metabolic breakdown.

• Elimination. Increased clearance is seen in children and in cigarette and marijuana smokers. Reduced clearance is also seen with the common drugs that interfere with the CYP system, such as cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton, and zafirlukast. Viral infections and vaccinations may also reduce clearance.


Pharmacological Approaches to Pharmacological Approaches to Asthma ControlAsthma Control

Selective 2 agonist

ATP

cAMP

Theophyline

5’-AMP

Relaxation

Ach

Ipratopium

Vagus nervewww.freelivedoctor.com

Anticholinergic DrugsAnticholinergic Drugs

Human airways are innervated by a supply of efferent, cholinergic, parasympathetic autonomic nerves.

Motor nerves derived from the vagus form ganglia within and around the walls of the airways. This vagally derived innervation extends along the length of the bronchial tree, but predominates in the large and medium-sized airways.

Postganglionic fibers derived from the vagal ganglia supply the smooth muscle and submucosal glands of the airways as well as the vascular structures. Release of acetylcholine (ACh) at these sites results in stimulation of muscarinic receptors and subsequent airway smooth muscle contraction and release of secretions from the submucosal airway glands.


Anticholinergic Drugs (cont)Anticholinergic Drugs (cont)

• Three pharmacologically distinct subtypes of muscarinic receptors exist within the airways: M1, M2 and M3 receptors.

• M1 receptors are present on peribronchial ganglion cells where the preganglionic nerves transmit to the postganglionic nerves. M2 receptors are present on the postganglionic nerves; they are activated by the release of acetylcholine and promote its reuptake into the nerve terminal. M3 receptors are present on smooth muscle.

• Muscarinic receptor activation of these M3 receptors leads to a decrease in intracellular cAMP levels, resulting in contraction of airway smooth muscle and bronchoconstriction.


Anticholinergic Drugs (cont)Anticholinergic Drugs (cont)• Atropine is the prototype anticholinergic

bronchodilator.

• Ipratropium is a quaternary amine, which is poorly absorbed across biologic membranes.

• Atropine and ipratropium antagonize the actions of Ach at parasympathetic, postganglionic, effector cell junctions by competing with Ach for M3 receptor sites.

• This antagonism of Ach results in airway smooth muscle relaxation and bronchodilation.


Anticholinergic Drugs (cont)Anticholinergic Drugs (cont)• Ipratropium is given exclusively by inhalation from a metered-dose

inhaler or a nebulizer. Inhaled ipratropium has a slow onset ( ~30 min) and a relatively long duration of action ( ~6 h).

• Tiotropium, a structural analog of ipratropiem, has been approved for treatment of COPD. Like iprotropiem, tiotropiem has high affinity for all muscarinic receptor subtypes but it dissociates from the receptors much more slowly than ipratropium, esp. M3 receptors. This permits once a day dosing. It is formulated for use with an oral inhalator.

• Clinical trials of anticholinergic therapy have generally failed to show significant benefit in asthma. This relative lack of efficacy in asthma contrasts with COPD, in which anticholinergic agents are among the most effective therapies.

N

O

O

OH

CH3

CH3

H3C

Br

IpratopiumN

O

CH3H3C

O

O

S

S

OH

Br

Tiotropium

N

CH3

O

OHO

Atropinewww.freelivedoctor.com

Approved in US February 2004


Future Pharmacological Agents for Asthma & Future Pharmacological Agents for Asthma & COPDCOPD

Vasoactive intestinal peptide (VIP) analogs. VIP is a potent relaxant of constricted human airways in vitro but it is degraded too quickly in the airway epithelium to be effective. A more stable cyclic analog of VIP (Ro-25-1553) has a prolonged effect in asthmatic patients by inhalation.

Prostaglandin E2. PGE agonists that are selective for lung receptors subtypes are being considered for exploration as bronchodilators/anti-inflammatory drugs. Atrial natriuretic peptides (ANP). Intravenous infusion of ANP produces a significant bronchodilator response and protect against bronchoconstriction induced by inhaled broncoconstrictors such as methacholine. ANP, however, is a peptide and subject to rapid enzymatic degradation. A related peptide, urodilatin, is less susceptible to degradation and has a longer duration of action. It is as potent as salbutamol when given iv.

Phosphodiesterase 4 (PDE4) inhibitors. Because of theophylline, other PDE4 inhibitors are being tested. The PDE4 inhibitor cilomilast has been clinically tested for COPD but the drug causes emesis, a common side effect with this class (this could be due to inhibition of PDE4D). There is hope that selective inhibitors of PDE4B might have more therapeutic potential.


PDE4 InhibitorsPDE4 Inhibitors


Future Pharmacological Agents for Asthma & Future Pharmacological Agents for Asthma & COPDCOPD

Pharmacogenomics. Current data suggest that the 16th amino acid position of the 2 adrenergic receptor is associated with a major, clinically significant pharmacogenomic effect, namely down regulation of the receptor and responsiveness of patients using -agonists. Investigations of the effect of this and other polymorphisms on the response to long-acting -agonists are currently being conducted.


ConclusionsConclusions

• Aerosol delivery of drugs is effective for Aerosol delivery of drugs is effective for asthma.asthma.

• Some key drugs classes for acute treatmentSome key drugs classes for acute treatment AgonistsAgonists

Albuterol, levalbuterol, metaproterenol, terbuta;ine, isoproterenol, & epinephrine

– PDE inhibitorsPDE inhibitorsTheophylline

– AnticholinergicsAnticholinergicsIpratropium & tiotropium

• New agents are coming!New agents are coming!


Bronchodilators

Documents

mast cell

delivers small

terminal amine

general nursing

nursing implicationsxanthine

minimizes

future pharmacological

oral fungal