NEW INSIGHTOF COPD

AIRFLOWLIMITATIONIN SMALL AIRWAYSDEFINITIONCOPDPROGRESSIVEIRREVERSIBLEPARTIALREVERSIBLE CHRONIC BRONCHITISEMPHYSEMATOUS LUNGMIXEDCHRONICINFLAMMATION12ALVEOLER STRUCTURE DAMAGED DECREASED ELASTIC RECOIL

INCREASE OF 51 % ACUTE EXACERBATIONIN HOSPITAL ADMISSION BETWEEN 1991 - 2000INCREASINGPROBLEMSOF COPDGOLD [ NHLBI WHO ]GUIDELINES MANAGEMENT STRATEGYOF COPDMORBIDITY& MORTALITYIV in USAWHO 2020MORTALITY3 million/year

HOSPITALMORTALITY10 %WORSENHEALTHSTATUSPREMATURE DEATH

LUNG INFLAMMATIONNOXIOUSPARTICLEGASESCOPDOXIDATIVE STRESSPROTEINASE IMBALANCEHOST FACTORSANTI OXIDANTS[ environmental ]ANTI OXIDANTSANTI PROTEINASES[ genetic ]REPAIRMECHANISMREPAIRMECHANISMPATHOGENESIS OF COPD

ANTI PROTEASE ENZYME1-Antitrypsin

MacrophagesNeutrophilsCD8+ LymphocytesEosinophilsEpithelial cellsFibroblastsCELLSIL-8, GRO-1MCP-1, MIP-1GM-CSFEndothelinSubstance PNeutrophil elastaseCathepsinProteinase-3MMPsPROTEINASESMEDIATORS

MUCUS HYPERSECRETION

FIBROSIS

ALVEOLAR WALLDESTRUCTIONEFFECTSCELLS & INFLAMMATORY MEDIATORS IN COPD PATHOGENESIS

INFLAMMATORYMEDIATORIN COPDTNF-NeutrophilchemoatractantIL-8Inflammatorymarker

LTB4Neutrophilchemoatractant

GM-CSFAcuteexacerbationMCP-1Alveolar macrophagerecruitmentSubstance PMukushypersecretionTGF-Airwayremodelling1234567

O2, H2O2OH, ONOO Antiproteinases SLPI 1-AT

ProteolysisANTIOXIDANTSGlutathione AnalogsVitamins C, EN-acetylsisteineNitrones [spin-trap] NF-KB

IL-8 TNF

NeutrophilrecruitmentISOPROSTANES Mucus secretion Plasma leakREACTIVE OXYGEN SPECIES IN COPD

Bronchoconstriction

SYMPTOMSCOUGHSPUTUMDYSPNEAEXPOSURE TORISK FACTORSTobacco SmokeOccupationIndoor / outdoorpollution12DIAGNOSISOF COPDSPIROMETRY3

COPDComplicationsSYSTEMICEFFECTOF COPDCARDIOVASCULARDISORDERHANDICAP / DISABILITYNUTRITIONALDISORDER

PSYCHOLOGICALFACTORANXIETY - DEPRESSIONSYSTEMICINFLAMMATORYRESPONSRESPIRATORYMUSCLEDISFUNCTION

GOALS OF COPD TREATMENTGLOBAL GOLDPREVENT DISEASE PROGRESSIVEREDUCE EXACERBATIONSIMPROVE QUALITY OF LIFEIMPROVE EXERCISE TOLERANCEREDUCE MORTALITYIMMEDIATE BENEFITSRELIEF OF SYMPTOMS[ BREATHLESSNESS ]LONG TERMGOALSSMOKINGCESSATIONSHORT TERM GOALS123

COPD MANAGEMENTPULMONARY REHABILITATIONPROGRAMMEESTABLISH DIAGNOSISASSESS SYMPTOMSSTOP SMOKINGHEALTHY LIFESTYLEIMMUNISATIONTREAT OBSTRUCTIONASSESS FOR HYPOXIABRONCHODILATORSLONG TERMOXYGEN THERAPY1234

COPDPHARMACOTHERAPYINHALED CORTICOSTEROIDSONLY FOR CONCOMITANTASTHMALONG TERMOXYGEN THERAPY[ SELECTED PATIENT ]ANTICHOLINERGICS[ TIOTROPIUM SOON AVAILABLE ]LABATHEOPHYLLINE[ ANTI INFLAMMATORY EFFECT ]BRONCHODILATORSNEW ANTIINFLAMMATORYTREATMENT NEEDEDTRIAL OF BUPROPIONNICOTINE REPLACEMENTSTOP SMOKING12345

OTHER TREATMENTIN COPDANTILEUCOTRIENTSPROPHYLACTICANTIBIOTICSNO EVIDENCEN-ACETYLCYSTEINEANTI INFLAMMATORYDUGSINHALED CORTICOSTEROID ?ANTIOXIDANTSCARBOCYSTINEBROMHEXOLAMBROXOLMUCOLYTICS123

NONPHARMACOLOGICALMANAGEMENTEXERCISEPULMONARY REHABILITATIONAVOIDANCE OF POLLUTANTOBESITY&NUTRITIONALINTERVENTIONEDUCATIONSURGERYVACCINATIONPHYSIOTHERAPY12345768

BRONCHODILATORSFOR COPDIPRATROPIUM BROMIDEOXITROPIUM BROMIDETIOTROPIUM BROMIDEINHALEDANTICHOLINERGICSIPRATOPRIUM BROMIDE&SHORT ACTING INHALEDBETA 2 AGONISTSHORT ACTING INHALED BETA 2 AGONISTBETA 2AGONISTCOMBINATIONINHALER123THEOPHYLLINE4

BRONCHODILATORSIN COPDRELAXAIRWAY SMOOTHMUSCLEDECREASEDPLASMAEXUDATION ?DECREASEDINFLAMMATORYMEDIATORRELEASE ?IMPROVERESPIRATORYMUSCLEFATIGUE ?DECREASEDNEUROTRANSMITTERRELEASE ?12345

CONTROL OF THE AIRWAYS

SYMPATHETIC NERVE SYSTEMPARASYMPATHETIC NERVE SYSTEMCyclic GMPCyclic AMPGTP5AMPATP5GMPBRONCHOCONSTRICTIONBRONCHODILATATIONGUANILCYCLASEADENYLCYCLASEFOSFODIESTERASEANTICHOLINERGICBETA 2 AGONISTMETHYLXANTINCHOLINERGIC RECEPTORBETA ADRENERGIC RECEPTOR

BRONCHODILATORSEFFECT IN COPDINCREASEDFEV1, FVC,PEF[ < 10 % ]DECREASEDHYPERINFLATIONDECREASEDDYSPNOEAIMPROVEDEXERCISETOLERANCEIMPROVED RESPIRATORY MUSCLE STRENGTH ?123

INHALEDCORTICOSTEROIDSIN COPDTREAT ASSOCIATED ASTHMACLINICALLY IRRELEVANT EFFECTON EXACERBATIONSNO EFFECTONPROGRESSIONOF DISEASEHIGH RISKOF ADVERSESYSTEMICEFFECTSEXPENSIVESHOULD NOT BERECOMMENDEDNO SIGNIFICANTEFFECT ONINFLAMMATION

ACTION OFBETA2-AGONISTSIN COPDBRONCHODILATATIONINCREASEDMUCOCILIARYCLEARANCEDECREASEDNEUTROPHILFUNCTIONDECREASEDBACTERIALADHERENCEDECREASEDCHOLINERGICNEUROTRANSMISSIONDECREASEDPLASMAEXUDATION

ACTION OFMETHYLXANTHINEIN COPDTHEOPHYLLINEDECREASEDPLASMAEXUDATIONBRONCHODILATATIONIncl. Small airwaysDECREASEDMACROPHAGEFUNCTIONINCREASEDRESPIRATORYMUSCLESTRENGTHDECREASEDT CELLFUNCTIONINCREASEDMUCOCILIARYCLEARANCEDECREASEDNEUTROPHILFUNCTION

ANTICHOLINERGICS IN COPDNORMALCOPDVAGAL TONEThe main reversibleComponent in COPDAChACh

Vagusnerve ANTICHOLINERGICSResistance1/rANTICHOLINERGICS BLOCKSMUSCARINIC RECEPTORSTHEREBY REDUCTIONVAGAL TONECLEARANCEOF EXCESSMUCUSBRONCHODILATATION

AChN +M1 +M2 +M3 +

MUSCARINICRECEPTORM1 +M2 +M3 +MUSCARINIC RECEPTOR SUBTYPES IN AIRWAYSNICOTINIC RECEPTORAIRWAY SMOOTH MUSCLEANTICHOLINERGICCHOLINERGICEFFECTPOSTGANGLIONIC NERVEPARASYMPATHETICGANGLIONPREGANGLIONIC NERVE

CONTROL OF THE AIRWAYS

ADRENERGIC & CHOLINERGIC ( MUSCARINIC ) RECEPTORSADRENERGICRECEPTORSCHOLINERGICRECEPTORS

ADRENERGICRECEPTORSRECEPTORSADRENERGICNEUROTRANSMITTERNORADRENALINESUB-TYPES OFRECEPTORALPHA [a1&a2]BETA [b1&b2]RESULT OFSTIMULATIONIN THE LUNGSAirways dilated &Reduced airflowObstruction[bronchodilatation]

CHOLINERGICRECEPTORSRECEPTORSCHOLINERGICNEUROTRANSMITTERSUB-TYPES OFRECEPTORRESULT OFSTIMULATIONIN THE LUNGSACETYLCHOLINEMUSCARINICM1-M2-M3Airways constricted& increased airflowObstruction[bronchoconstriction]

CHOLINERGICRECEPTORSM1-RECEPTORS ENHANCETHE CHOLINERGIC REFLEXM2-RECEPTORS INHIBITACETYLCHOLINE RELEASEM3-RECEPTORS MEDIATEBRONCHOCONSTRICTIONAND MUCUS SECRETIONM4 & M5-RECEPTORSNOT DETECTED INTHE LUNG

NEW DRUGFOR COPDPROTEASEINHIBITORSNEW BRONCHODILATORSMEDIATORANTAGONISTSALVEOLARREPAIRDRUGSNEW ANTIINFLAMMATORYDRUGS1245TRIOTROPIUM3

TIOTROPIUMBROMIDESIGNIFICANTREDUCTIONINEXACERBATIONSSIGNIFICANTIMPROVEMENTIN LUNG FUNCTIONSUSTAINEDOVER 12 MONTHSSTATISTICALLYSIGNIFICANTIMPROVEMENTINBREATHLESSNESSSCORESTATISTICALLY SIGNIFICANTIMPROVEMENT IN HEALTH-RELATEDQUALITY OR LIFE SCORELONG ACTING ANTICHOLINERGIC

TIOTROPIUMBROMIDEPROLONGEDBLOCKADE OFM3 RECEPTORSUBTYPESIGNIFICANTLYREDUCES THE USEOF SHORT ACTINGBETA AGONISTSNO OTHERANTICHOLINERGICEFFENTSGREATER THANIPRATOPRIUMSAFE & WELL TOLERATED IN CLINICAL STUDYONLY SIGNIFICANT ADVERSE EVENT ISDRY MOUTHLONG ACTING ANTICHOLINERGICSAFETY

Why are exacerbations important?Exacerbations are important because they may provide the only contact a patient has with a GP or hospital doctor.The costs of treating COPD are already vast and will increase in the future with increasing prevalence: exacerbations consume a lot of resources and have a major influence on the costs of treating COPD.Exacerbations are a major factor in winter bed crises, when there is already pressure on beds from patients needing hospitalisation for influenza, flu-like illnesses and respiratory conditions such as bronchitis and asthma.Exacerbations can have adverse effects on a patients health status and may lead to progression of the disease.

BronchodilatorsEitherAct as agonists at beta receptorsorAct as antagonists at muscarinic receptorsBronchodilatorsEitherAct as agonists at beta receptorsorAct as antagonists at muscarinic receptorsControl of the airwaysThe ANS controls the rate of breathing and the diameter of the bronchioles, regulating airflow rate. The SNS causes the smooth muscles of the bronchi and bronchioles to relax, allowing them to dilate (bronchodilatation).The PNS causes smooth muscle to contract, which constricts the airways (bronchoconstriction).Under normal circumstances, with a constant low level of PNS stimulation, the bronchi are kept in a constant state of tension known as cholinergic, vagal or bronchomotor tone.Prolonged and extensive exposure of the lungs to irritants, such as cigarette smoke, can lead to chronic pulmonary diseases. One effect of such exposure is increased cholinergic or bronchomotor tone. This decreases the patency of the airways, adding to the airway obstruction seen in COPD.

BronchodilatorsEitherAct as agonists at beta receptorsorAct as antagonists at muscarinic receptorsControl of the airwaysThe ANS controls the rate of breathing and the diameter of the bronchioles, regulating airflow rate. The SNS causes the smooth muscles of the bronchi and bronchioles to relax, allowing them to dilate (bronchodilatation).The PNS causes smooth muscle to contract, which constricts the airways (bronchoconstriction).Under normal circumstances, with a constant low level of PNS stimulation, the bronchi are kept in a constant state of tension known as cholinergic, vagal or bronchomotor tone.Prolonged and extensive exposure of the lungs to irritants, such as cigarette smoke, can lead to chronic pulmonary diseases. One effect of such exposure is increased cholinergic or bronchomotor tone. This decreases the patency of the airways, adding to the airway obstruction seen in COPD.

Adrenergic and muscarinic (cholinergic) receptorsAdrenergic receptorsThe a- and b-adrenergic receptor subtypes are found in different locations around the body.The a1-receptors are found mainly in the nerve/muscle junctions in the skin and smooth muscle. The a2-receptors are found mainly in pre- and post-synaptic nerve endings in skin and smooth muscle.The b1-receptors are found mainly in the heart muscle. The b2-receptors are found mainly in bronchial smooth muscle. Stimulation of a1-receptors causes vasoconstriction. Stimulation of of a2-receptors reduces the excitability of post-synaptic neurones.Stimulation of the b1-receptors increases heart rate and contractilityIn the respiratory system, stimulation of the b2-receptors on bronchial smooth muscle causes smooth muscle relaxation, resulting in bronchodilation. This is the point of action of the b2-agonist medications that stimulate b2-receptors, causing bronchodilatation.

Muscarinic (cholinergic) receptorsDifferent types of muscarinic receptors have been identified, of which three subtypes (M1, M2 and M3) are present in the bronchial airways of humans.The different subtypes have different regulatory functions.M1-receptors:Facilitate ganglionic transmission and enhance the cholinergic reflex.Located in the heart, parasympathetic ganglia, submucosal glands and alveolar walls.M2-receptors:Found on postganglionic cholinergic nerves.Inhibit acetylcholine release.Located in the postganglionic parasympathetic nerves.M3-receptors:Mediate bronchoconstriction and a mucus secretory response to acetylcholine and cholinergic nerve stimulation.Located in the smooth muscle of the airways, submucosal glands, endothelial cells and epithelium.

Adrenergic receptorsThe a- and b-adrenergic receptor subtypes are found in different locations around the body.The a1-receptors are found mainly in the nerve/muscle junctions in the skin and smooth muscle. The a2-receptors are found mainly in pre- and post-synaptic nerve endings in skin and smooth muscle.The b1-receptors are found mainly in the heart muscle. The b2-receptors are found mainly in bronchial smooth muscle. Stimulation of a1-receptors causes vasoconstriction. Stimulation of of a2-receptors reduces the excitability of post-synaptic neurones.Stimulation of the b1-receptors increases heart rate and contractilityIn the respiratory system, stimulation of the b2-receptors on bronchial smooth muscle causes smooth muscle relaxation, resulting in bronchodilation. This is the point of action of the b2-agonist medications that stimulate b2-receptors, causing bronchodilatation.

Muscarinic (cholinergic) receptorsDifferent types of muscarinic receptors have been identified, of which three subtypes (M1, M2 and M3) are present in the bronchial airways of humans.The different subtypes have different regulatory functions.M1-receptors:Facilitate ganglionic transmission and enhance the cholinergic reflex.Located in the heart, parasympathetic ganglia, submucosal glands and alveolar walls.M2-receptors:Found on postganglionic cholinergic nerves.Inhibit acetylcholine release.Located in the postganglionic parasympathetic nerves.M3-receptors:Mediate bronchoconstriction and a mucus secretory response to acetylcholine and cholinergic nerve stimulation.Located in the smooth muscle of the airways, submucosal glands, endothelial cells and epithelium.

Muscarinic (cholinergic) receptorsDifferent types of muscarinic receptors have been identified, of which three subtypes (M1, M2 and M3) are present in the bronchial airways of humans.The different subtypes have different regulatory functions.M1-receptors:Facilitate ganglionic transmission and enhance the cholinergic reflex and bronchoconstrictionLocated in the heart, parasympathetic ganglia, submucosal glands and alveolar walls.M2-receptors:Found on postganglionic cholinergic nerves.Inhibit acetylcholine release.Located in the postganglionic parasympathetic nerves.M3-receptors:Mediate bronchoconstriction and a mucus secretory response to acetylcholine and cholinergic nerve stimulation.Located in the smooth muscle of the airways, submucosal glands, endothelial cells and epithelium.M4 and M5-receptors are not detected in the lung

Under normal circumstances, with a constant low level of PNS stimulation, the bronchi are kept in a constant state of tension known as cholinergic, vagal or bronchomotor tone.Prolonged and extensive exposure of the lungs to irritants, such as cigarette smoke, can lead to chronic pulmonary diseases. One effect of such exposure is increased cholinergic or bronchomotor tone. This decreases the patency of the airways, adding to the airway obstruction seen in COPD.