Pharmacology of the Autonomic Nervous System- overview and transmitter metabolismRichard D. Ye, MD, PhDTel. 312-996-5087 E-mail: [email protected] CMW 406ThoracolumbarCranialSacralCNS Pre-ganglionic Ganglion Post-ganglionicParasympatheticAchNAchNAchNAchNAchNEpiSympatheticSympatheticSympatheticSympathetic (adrenal medulla)Motor (somatic)AchAchMMNEα, βDD1AchNCardiac & smoothmuscles, gland cells,nerve terminalsCardiac & smoothmuscles, gland cells,nerve terminalsSweat glandsRenal vascularsmooth muscleReleased intobloodSkeletal muscleAch = acetylcholine NE = norepinephrineEpi = epinephrineD = dopamineM = muscarinic N = nicotinic α, β = (α,β) adrenergicEfferentnervoussystemAutonomic nervous system(vegetative, visceral, involuntary)Somatic motor nervous system(non-autonomic, voluntary)Sympathetic(thoracolumbar outflow)Parasympathetic(craniosacral outflow)Skeletal muscleHeart, blood vessels,glands, other visceralorgans, smooth muscleYE, ANS/transmitters, Page 1Differences between autonomic and somatic nerves:Autonomic: Synapses located in ganglions outside cerebrospinal axisExtensive peripheral plexusesPostganglionic nerves are not myelinatedSome level of spontaneous activity without intact innervationSomatic: No peripheral ganglions; synapses located entirely within cerebrospinal axisNo peripheral plexusesNerves are myelinatedFunction depends entirely on intact innervationNeurohumoral transmission (neurotransmission) occurs between nerve cells (acrosssynapses), and between nerve cells and effector cells (across neuroeffector junctions).Acetylcholine and norepinephrine (noradrenaline) are major neurotransmitters ofthe peripheral autonomic nervous system. ♦ 5 key steps in neurotransmission:• Synthesis of neurotransmitter• Storage of neurotransmitter• Release of neurotransmitter• Recognition of neurotransmitter• Metabolism of neurotransmitterPre-synapticnerve cellPost-synapticnerve cellSynapticcleftCa2+Na+Precursors(choline/tyrosine)♦ Synapse: A junctional connection between two neurons, across which a signal can passPrecursorNeurotransmitterStorageReleaseRecognitionby receptorsMetabolicdispositionYE, ANS/transmitters, Page 2Cholinergic TransmissionY Synthesis of acetylcholine (Ach):CoA-SH(CH3)3 N+–CH2–CH2–OH CoA–S–C–CH3O+(CH3)3 N+–CH2–CH2–O–C–CH3O+CATCAT = choline acetyltransferase (present in axonal terminals)Acetyl CoA: synthesized in mitochondria (present in large numbers in axonal terminals)Choline: transported from the plasma (rate-limiting step that requires a Na+-dependent carrier)Y Storage of Ach:Ach is transported into synaptic vesicles via a proton antiporter (inhibited by vesamicol)Y Release of Ach:Action potential triggers Ca2+ influx, causing release of vesicle content through exocytosisY Degradation of Ach:Through the action of acetylcholinesterase (AchE), present in cholinergic synapses. AchE rapidlyconverts Ach to choline and acetic acid with a turnover time of 150 microseconds (CH3)3 N+–CH2–CH2–O–C–CH3OH2O(-)(H)AchECH3COOH+• Binding of substrate• Formation of a transient intermediate involving the hydroxyl group of Serine 203 of AchE• Loss of choline and formation of acetylated enzyme• Deacylation of enzymeAnti-AchE agents may interact with AchE in a manner similar to Ach, but form more stable conjugates Steps involved in the hydrolysis of Ach by AchE:AchE(CH3)3 N+–CH2–CH2–OHTrp-86Glu-334His-447Ser-203YE, ANS/transmitters, Page 3HOHOCH2NHCH3OHCHEpinephrineHOHOCH2NH2OHCHNorepinephrineHOHOCH2NH2CH2DopamineHOHOHCNH2CH2DopaCOOHHOHCNH2CH2TyrosineCOOHHOHOCOOHOHCHDihydroxymandelic acid(DOMA)HOCH3OCOOHOHCH3-Methoxy-4-hydroxy-mandelic acid(VMA)CH3OHOCH2NHCH3OHCHMetanephrineHOCH2NH2OHCHNormetanephrine(NMN)CH3OHOHOCOOHCH2Dihydroxyphenylacetic acid(DOPAC)CH3OHOCH2NH2CH23-MethoxytyramineCH3OHOCOOHCH2Homovanillic acid(HVA)COMTCOMTCOMTCOMTCOMTMAOMAOMAOMAOMAOMAOTHDD (L-AAD)DBHPNMTSynthesis and Degradation of CatecholaminesCOMT = catechol-O-methyltransferase; DBH = dopamine β-hydroxylase; DD = dopa decarboxylase;L-AAD = L-amino acid decarboxylase; MAO = monoamine oxidase; PNMT = phenylethanolamine-N-methyl transferase; TH = tyrosine hydroxylaseAdrenalmedullaYE, ANS/transmitters, Page 4Norepinephrine Metabolism in the Adrenergic Nerve EndingTransporter that carries tyrosine to axoplasm in a sodium-dependent mannerTH: Tyrosine hydroxylase converts Tyr to dopa, a rate-limiting step inhibited by the Tyr analog metyrosineHigh-affinity carrier that transports dopamine into vesicles containing DBH (blocked by reserpine)NE: Norepinephrine. Conversion of dopamine to NE occurs in vesicles, through the action of DBHCa2+Influx of Ca2+ through voltage-gated channel induces exocytosis (blocked by bretylium, guanethidine)NE released to synaptic cleft. May be removed by diffusion, metabolism, or recaptureαRPost-synaptic α-adrenergic receptors stimulated by NE. Same for βR (β-adrenergic receptors)α2RPre-synaptic α2-adrenergic receptors. They deliver negative feedback for inhibition of exocytosisUptake-1, primarily responsible for recapture of released NE to presynaptic nerve ending (blocked by cocaine and tricyclic antidepressants such as imipramine). It does not recapture isopreterenol Uptake-2, low-affinity for NE but high-affinity for isopreterenol. Responsible for disposition of circulatingcatecholaminesPre-synaptic(axon)Post-synaptic(next nerve cell)SynapticcleftCa2+Na+TyrosineTyrosineDopaRecognitionby receptorsDiffusion, metabolismTHDDDopamine(DA)NEDBHATPNEDBHATPNENECa2+COMTNMNMAOαRβRα2RNE(-)YE, ANS/transmitters, Page 5Autonomic Nervous System: Receptor Location & Responsesalpha1, alpha2, beta1, beta2, beta3(G-protein-coupled receptors)Cholinergic receptors:Nicotinic receptors: NN, NM(sodium channels comprised of 5 subunits)Muscarinic receptors: M1, M2, M3(G-protein-coupled receptors)Adrenergic receptors:NICOTINICNALPHA1All blood vessels• vasoconstriction• increase TPRMucosa• decongestionEye radial muscle, iris• mydriasisSkin• contraction of pilomotor musclesHyperglycemiaALPHA2Presynaptic• reduce releaseCNS• reduce sympathetic outflowDA receptorSplanchnic area• vasodilationBETA2Blood vessels(pulmonary, coronary)• vasodilationBronchial muscle• bronchodilationUterus• relaxationHyperglycemiaLactic acidemiaBETA1Heart• increase rate• increase force of contraction• increase velocity of conductionBETA3Adipose tissue• thermogenesis• lipolysisAutonomic ganglia• depolarization &