IVMS-ANS Pharmacology -Intro to the Autonomic Nervous System

ANS PharmacologyIntroduction to the Autonomic Nervous SystemPresenter: Marc Imhotep Cray, M.D.Professor Basic Medical SciencesRecommended Reading:Autonomic IntroductionFormative AssessmentPractice Question Set #1Clinical:E-Medicine ArticleEpilepsy and the Autonomic Nervous System9/30/20092HomeostasisThe physiologic process of maintaining an internal environment compatible with normal healthAutonomic reflexes maintain setpoints and modulate organ system functions in pursuit of homeostasisSee: Human homeostasishttp://en.wikipedia.org/wiki/Human_homeostasis9/30/20093Schematic From:Organization of the Nervous Systemhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/PNS.html9/30/20094Autonomic ReflexesAfferent fibers from periphery to CNSCNS integrationCortexThalamusHypothalamusMedullaSpinal cordEfferent fibers from CNS to periphery9/30/20095NeurotransmittersChemicals synthesized and stored in neuronsLiberated from axon terminus in response to action potentialsInteract with specialized receptorsEvoke responses in the innervated tissuesSee: http://en.wikipedia.org/wiki/Neurotransmitter9/30/20096Efferent Autonomic NervesInnervation of smooth muscle, cardiac muscle, and glandsPreganglionic neuronPeripheral ganglion -axodendritic synapsePostganglionic neuron(s)Effector organ(s)PreGanglionPostEffectororgan9/30/20097Anatomic Divisions of the ANSParasympatheticPreganglionic axons originate in the brain, and sacral spinal cordPeripheral ganglia are near, often within, the effector organsRatio of postganglionic-to-preganglionic axons is small, resulting in discrete responsesSympatheticPreganglionic axons originate in the thoracolumbar cordPeripheral ganglia are distant from the effector organsRatio of post-to-preganglionic axons is large, resulting in widely distributed responses9/30/20098Schematized Anatomic ComparisonPreGanglionEffectororgansPostThoracic or lumbarcordPreGanglionEffectororganPostCranial or sacral cordParasympatheticSympathetic9/30/20099Somatic Nervous SystemEfferent innervation of skeletal muscleNo peripheral gangliaRapid transmission, discrete control of motor unitsAny spinalsegmentMotor neuronStriated muscle9/30/200910Neurochemical Transmission in the Peripheral Nervous SystemCholinergic nervesAcetylcholineis the neurotransmitterLocationsPreganglionic neurons to all gangliaPostganglionic, parasympathetic neurons“Preganglionic” fibers to adrenal medullaPostganglionic, sympathetic neurons to sweat glands in most speciesSomatic motor neurons9/30/200911CholinergicNeurotransmissionPreGanglionEffectororgansPostThoracic or lumbarcordPreGanglionEffectororganPostCranial or sacral cordParasympatheticSympatheticDenotes AChDenotes ACh9/30/200912NeurochemicalTransmission in the PNSAdrenergic nervesNorepinephrineis the neurotransmitterLocationsPostganglionic, sympathetic axonsPreGanglionEffectororgansPostThoracic or lumbarcordSympatheticDenotes NorepinephrineDenotes ACh9/30/200913Adrenal MedullaPresynaptic nerves are cholinergicMedullary cells synthesize and release two, related catecholamines into the systemic circulationEpinephrine (adrenaline)NorepinephrineEpi and NE stimulate adrenergic sites9/30/200914Adrenal Medulla(2)Cholinergic neuronAdrenal medullaEpi and NE releasedinto systemic circulationDenotes ACh9/30/200915AChSynthesis, Release, and FateSynthesized from cholineand acetyl-CoAReleased in response to neuronal depolarization (action potential)Calcium enters the nerve cellTransmitter vesicles fuse with cell membraneAChreleased by exocytosisInactivated by acetylcholinesterase(AChE)AChSynthesis, Release, and Fate (2)9/30/200916Source: http://www.neurophysiology.ws/autonomicns.htmSynthesis and fate of synaptically released acetylcholine at cholinergic synapse.9/30/200917NE Synthesis, Release, and FateCatecholamine-synthesized in a multistep pathway starting with tyrosineReleased by exocytosis in response to axonal depolarizationDuration of activity primarily limited by neuronal reuptakeMinor metabolism by synaptic monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)NE Synthesis, Release, and Fate (2)9/30/200918Source: http://www.neurophysiology.ws/autonomicns.htmSynthesis and fate of synaptically released norepinephrine at adrenergic synapse.9/30/200919ReceptorsSpecialized proteins that are binding sites for neurotransmitters and hormonesPostsynaptic cell membranes (neurotransmitters)Cell nucleus (steroid hormones)Linked to one of many signal transduction mechanisms9/30/200920Ligand-Receptor InteractionsComplementary conformations in 3 dimensionsSimilar to enzyme-substrate interactionsPhysiologic interactions are weak attractionsH-bonding, van der Waal’s forcesDrug mechanismsAgonists-bind and activate receptorsAntagonists-bind but DO NOT activate receptors9/30/200921Cholinergic ReceptorsActivated by ACh and cholinergic drugsAnatomic distributionPostganglionic, parasympathetic neuroeffector junctionsAll autonomic ganglia, whethe parasympathetic or sympatheticSomatic neuromuscular junctions9/30/200922CholinergicReceptor LocationsPreGanglionEffectororgansPostThoracic or lumbarcordPreGanglionEffectororganPostCranial or sacral cordParasympatheticSympatheticDenotes ACh receptorsDenotes ACh receptors9/30/200923Cholinergic Receptor SubtypesPostganglionic, parasympathetic, neuroeffectorjunctionsDistinction of two different subtypesGanglia -or type GNeuromuscular junctions -or type M9/30/200924Cholinergic Receptor Subtype LocationsPreGanglionEffectororgansPostThoracic or lumbarcordPreGanglionEffectororganPostCranial or sacral cordParasympatheticSympatheticN1MN19/30/200925Adrenergic ReceptorsActivated by NE, Epi, and adrenergic drugsAnatomic distributionPostganglionic, sympathetic, neuroeffector junctionsSubtypesAlpha-1, 2; Beta-1, 2, 39/30/200926Adrenergic Receptor LocationsSympatheticPreGanglionEffectororgansPostThoracic or lumbarcordAlpha or Betaadrenergic receptors9/30/200927Functional Significance of the Autonomic Nervous SystemOrgan system integrationParasympatheticDiscrete innervationEnergy conservationSympatheticHighly distributed innervation, global responsesEnergy expenditureFight or flight responses9/30/200928Functional Significance of the Autonomic Nervous System (2)Dual innervatonOrgan responses moderated by both parasympathetic and sympathetic influencesParasympathetic dominant at restBalance of opposing neurologic influences determines physiologic responses9/30/200929Introduction to Autonomic and Somatic PharmacologySome drugs evoke effects by interacting with receptorsAffinityEfficacy or (synonym) Intrinsic activityAgonistsMimic physiologic activationHave both high affinity and efficacyAntagonistsBlock actions of neurotransmitters or agonistsHave high affinity, but no efficacyOften used as pharmacologic reversal agents9/30/200930Alpha-1 Adrenergic ReceptorVascular smooth muscle contractionArterioles, veinsIncreased arterial resistanceDecreased venous capacitanceAgonists support systemic blood pressureIncreased resistanceRedistribution of blood toward heart, increased cardiac outputAntagonists decrease blood pressureIrisPupillarydilation (mydriasis)9/30/200931Alpha-2 Adrenergic ReceptorVasoconstrictionModulation of NE releasePresynaptic receptors on axon terminousSpinal alpha-2 receptors mediate analgesiaAgonists used clinically as epidural and spinal analgesicsSedation9/30/200932Beta-1 Adrenergic ReceptorExclusive to myocardiumAgonistsIncrease HR, contractility, and impulse conduction speedMay be arrhythmogenicAntagonistsDecrease HR, contractility, and impulse conduction speedUsed clinically as antiarrhythmics9/30/200933Beta-2 Adrenergic ReceptorVascular smooth muscle in skeletal muscleAgonists evoke active vasodilation, increased blood flowBronchial smooth muscleAgonists evoke bronchodilation, decreased airway resistance9/30/200934MuscarinicCholinergic ReceptorMyocardiumAgonists decrease HR and AV conduction velocityAntagonists used clinically to increase HR and facilitate AV conduction in heart blockIris sphincter muscleAgoinists evoke pupillary constriction (miosis)Antagoinists evoke mydriasisGastrointestinal tractAgonists increase peristalsis and relax sphinctersUrinary bladderAgonists evoke urinationDetrusor muscle (bladder) contractionTrigone (sphincter) relaxation9/30/200935Modified from: http://www.neurophysiology.ws/autonomicns.htmTHE END, THANK YOU FOR YOUR ATTENTION9/30/200936Recommended Reading:Autonomic IntroductionFormative AssessmentPractice Question Set #1Clinical:E-Medicine ArticleEpilepsy and the Autonomic Nervous System