Introduction to Introduction to Autonomic Nervous Autonomic Nervous

SystemSystem

Pawitra PulbutrM.Sc. In Pharm (Pharmacology)

ObjectivesObjectives

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Motor (Efferent) portion of Motor (Efferent) portion of nervous systemnervous system

Autonomic portion… Autonomic portion… Autonomic Nervous System Autonomic Nervous System (ANS)(ANS)

Involuntary controlCVS, GI, Iris, Genitourinary function

Somatic portionVoluntary controlCommanded by brain

Posture/ Movement >>> Skeletal Skeletal MuscleMuscle

Difference between ANS VS Somatic nervous Difference between ANS VS Somatic nervous systemsystem

Preganglionic Preganglionic neuronneuron

Postganglionic Postganglionic neuronneuron

Drugs acting on ANSDrugs acting on ANS

Act on receptor of NTsAgonistAntagonist

Interfere biosynthesis of NTsInhibit precursor uptakeInhibit enzyme for biosynthesis

Interfere degradation of NTsInhibit degradation enzymeInhibit NTs reuptake

Autonomic Nervous Autonomic Nervous System (ANS)System (ANS)

Sympathetic Nervous System (Thoracolumbar division)Parasympathetic Nervous System (Craniosacral division)Named after anatomy origin NOT after type of action or NTs !!

Basic plan of ANSBasic plan of ANS

Medullary

Cervical

Thoracic

Lumbar

Sacral

A highly simplified diagram of some of the circuitry A highly simplified diagram of some of the circuitry of the enteric nervous system (ENS)of the enteric nervous system (ENS)

Enteric Nervous System (ENS)Enteric Nervous System (ENS)

Neurotransmitters of Neurotransmitters of ANSANS

Major (Primary) NTs

Acetylcholine (ACh)Acetylcholine (ACh) “Cholinergic fiber”

Norepinephrine (NE)Norepinephrine (NE)”Noradrenergic or Adrenergic fiber”

Co-transmittersPeptide, etc.

Cholinergic fiberCholinergic fiber

Synthesis & release AChAChAll Pre-ganglionic autonomic fiber (both SNS & PNS)Somatic fiber (innervate skeletal M.)All ParasympatheticAll Parasympathetic postganglionic fiberSome sympatheticSome sympathetic postganglionic fiber (innervate eccrine sweat gland)

Adrenergic fiberAdrenergic fiber

Synthesis & release NENEMost Postganglionic sympathetic fiberAdrenal medulla = Modified Modified postganglionic sympathetic postganglionic sympathetic neuronneuron release both NE & Epinephrine (Epi)Epinephrine (Epi)

Cholinergic Cholinergic transmissiotransmissio

nnCholine acetyl transferase (ChAT)

AChEAChE

precursor

Hemicholiniums

vesamicol

Botulinum toxin

ACh receptor = Cholinergic receptor

Postsynaptic RC >>> Action

Presynaptic RC

AutoreceptorAutoreceptor

HeteroreceptoHeteroreceptorr

Action potenti

al

ACh ACh hydrolysis hydrolysis via AChEvia AChE

AcetylcholineAcetylcholine

Acetylated enzymeAcetylated enzyme

Free AChEFree AChE

Anionic Anionic sitesite

EsteratiEsteratic sitec siteAChE AChE

enzymeenzyme

AdrenergiAdrenergic c transmissitransmissionon

Tyrosine Tyrosine hydroxylasehydroxylase

MetyrosineReserpine

Cocaine / Tricyclic antidepressant (TCA)

Bretylium/ Guanethidine

Dopamine Dopamine --hydroxylasehydroxylase

Metabolism via Metabolism via MAO & COMTMAO & COMT

RLSRLS

Action Action PotentialPotential

TyrosineTyrosine

1

2

Degradation of NEDegradation of NE

LessLess are metabolized in synaptic cleft Major degradationSimple diffusionSimple diffusion away from synapse

Metabolize in plasma & liverUptake via uptakeUptake via uptake

Uptake 1 into presynaptic nerveUptake 2 into perisynaptic glia & smooth muscle

Drugs acting on adrenergic Drugs acting on adrenergic transmissiontransmission

Direct actingAdrenergic AgonistAdrenergic AgonistAdrenergic AntagonistAdrenergic Antagonist

Indirect acting… increase NE at synaptic cleft

Reuptake inhibitorsReuptake inhibitorsCocaine, TCACocaine, TCA

Increase NE release from Increase NE release from vesiclevesicle

Amphetamine, TyrosineAmphetamine, Tyrosine

Autonomic receptorAutonomic receptorAcetylcholine receptor Acetylcholine receptor (Cholinergic receptor)(Cholinergic receptor)

Nicotinic receptor (N receptor)NN, NM Ion channel linked receptor

Muscarinic receptor (M receptor)M1, M2, M3GPCR

Noradrenergic receptor Noradrenergic receptor (Adrenergic receptor)(Adrenergic receptor)

Alpha receptorAlpha1, Alpha2GPCR

Beta receptorBeta1, Beta2, Beta3GPCR

Direct effects of ANS Direct effects of ANS activity on some organ activity on some organ

systemssystemsOrgan Effect of

Sympathetic Activity Parasympathetic Activity

Action Receptor

Action Receptor

EyeEyeIrisIrisRadial muscleRadial muscleCircular Circular musclemuscleCiliary muscleCiliary muscle

ContractsContracts……..[Relaxes][Relaxes]

11……..

……..ContractsContractsContractsContracts

……..M3M3M3M3

HeartHeartSinoatrial nodeSinoatrial nodeEctopic Ectopic pacemakerspacemakersContractilityContractility

AccelerateAcceleratessAccelerateAcceleratess

IncreasesIncreases

1,1,221,1,22

1,1,22

DeceleratDecelerateses……..

Decreases Decreases(atria)(atria)

M2M2……..

M2M2

Organ Effect of

Sympathetic Activity Parasympathetic Activity

Action Receptor Action Receptor

Blood vesselsBlood vesselsSkin, Skin,

splanchnic splanchnic vesselsvessels

Skeletal Skeletal muscle muscle vesselsvessels

EndotheliumEndothelium

ContracContractsts

RelaxesRelaxes[contra[contra

ct]ct]RelaxesRelaxes

22M*M*

……..……..……..……..

ReleaseRelease EDRFEDRF

……..……..……..……..

M3**M3**

Bronchiolar Bronchiolar smooth smooth musclemuscle

RelaxesRelaxes 22 ContracContractsts

M3M3

GI tractGI tractSmooth Smooth

muscle muscle WallsWalls SphincterSphincterSecretionSecretionMyenteric Myenteric

plexusplexus

RelaxesRelaxesContracContrac

tsts……..

2#, 2#, 2211……..

ContracContractsts

RelaxesRelaxesIncreasIncreas

esesActivateActivate

ss

M3M3M3M3M3M3M1M1

Organ Effect of

Sympathetic Activity Parasympathetic Activity

Action Receptor Action Receptor

Genitourinary Genitourinary smooth musclesmooth muscleBladder wallBladder wallSphincterSphincterUterus, Uterus, pregnantpregnant

Penis, Seminal Penis, Seminal vesiclevesicle

RelaxesRelaxesContractContractssRelaxesRelaxesContractContractssEjaculatnEjaculatn

221122

ContractContractssRelaxesRelaxes……ContractContractssErectionErection

M3M3M3M3……..M3M3MM

SkinSkinPilomotorsmooPilomotorsmooth muscleth muscleSweat glandsSweat glandsThermoregulatThermoregulatoryory Apocrine Apocrine (stress)(stress)

ContractContractss

IncreaseIncreasessIncreaseIncreasess

MM

………………

………………

Metabolic Metabolic functionsfunctionsLiverLiverLiverLiverFat cellsFat cellsKidneyKidney

GluconeogeneGluconeogenesissisGlycogenolysiGlycogenolysissLipolysisLipolysisRenin releaseRenin release

2,2,2,2,3311

……………………

……………………

Autonomic Autonomic nerve endingsnerve endingsSympatheticSympathetic

ParasympathParasympatheticetic

……

Decrease ACh Decrease AChreleaserelease

……

Decrease Decrease NE releas NE releas

ee……

##M##M

……

Organ Effect of

Sympathetic Activity Parasympathetic Activity

Action RC Action Receptor

Baroreceptor Reflex Baroreceptor Reflex ChartChartStand up quickly

BP falls in upper body

Aortic Arch Carotid Sinus

Medulla Oblongat

a

Nucleus Tractus SolitariusNeutral Integration

EffectorsEffectors

Veins & Arterioles

Heart Muscle SA node

VasoconstrictionVasoconstriction Increased SVIncreased SV Increased HRIncreased HR

Increased TPRIncreased TPR Increased COIncreased CO

Increased BP = CO x Increased BP = CO x TPRTPR

Autonomic and Hormonal Control of CVS Autonomic and Hormonal Control of CVS functionfunction

BP = TPR * COBP = TPR * CO

CO = HR * SVCO = HR * SV

SV = Contractility force * Venous returnSV = Contractility force * Venous return

Venous return = Venous tone * Blood Venous return = Venous tone * Blood volumevolume

Blood volume = Aldosterone regulationBlood volume = Aldosterone regulation

Presynaptic regulationPresynaptic regulationNegative feedback control““Autoreceptor”Autoreceptor”

Receptor of their own secreted Receptor of their own secreted NTsNTsAlpha 2-receptor at presynaptic nerveInhibit NE release from presynaptic

““Heteroreceptor”Heteroreceptor”Receptor of other NTsReceptor of other NTsCholinergic receptor at sympathetic nerveInhibit NE release from presynaptic

Postsynaptic regulationPostsynaptic regulation

Receptor dynamicReceptor dynamic

Receptor upregulationReceptor upregulationSurgical denervation… increase No. of RCIncrease response … “denervation “denervation supersensitivity”supersensitivity”Pharmacologic denervation supersensitivity … drug that decrease NTs >>> reserpine

Receptor downregulationReceptor downregulation

Receptor desensitizationReceptor desensitization

Main process Main process of transmittersof transmitters

1.1. uptake of precursorsuptake of precursors

2.2. synthesis of synthesis of transmitterstransmitters

3.3. storage in vesiclestorage in vesicle

4.4. degradation of surplusdegradation of surplus

5.5. depolarizationdepolarization

6.6. CaCa++++ influx influx

7.7. exocytosisexocytosis

8.8. diffusion to postsynp diffusion to postsynp RCRC

9.9. activation of postsynp activation of postsynp RCRC

10.10. inactivation of inactivation of transmitterstransmitters

11.11. reuptake or reuptake or degradationdegradation

12.12. interact with presynp interact with presynp RCRC