*Introduction to autonomic pharmacologyStudy Unit 3.1Compiled by Prof DP VenterAdapted by Dr M Viljoen (Room 121A G16)

*Pre Knowledge Class Test = 27 Feb2015Study Unit 3.1

*INTRODUCTIONReceptorsNeuro transmittersPharmacological effectsOrgansSynthesisMetabolismBind

CNSCNSSYMPATHETIC NERVOUS SYSTEMPARASYMPATHETIC Nervous systemSOMATIC Nervous system M AchNnNnAch AchNAAchCNSNM Skeletal musclesGanglionNerve end plateNerve end plateReceptorReseptorReceptorReceptorReceptor

*Outonome senuweestelseloverviewPeripheral Nervous System

*Review + Outcomes of the Peripheral Nervous SystemRelevant anatomySynthesis, storage, release and removal of transmittersReceptorsGeneral rules of innervation

*Nervous systemPeripheral nervous systemCentral nervous systemAutonomic nervous systemSomatic nervous systemParasympathetic nervous systemSympathetic nervous systemENS

*Schematic presentation of Autonomic Nervous SystemSkeletal muscleAdrenal medullaSmooth muscle, myocard, endocrine glands Acetylcholinecholinergic receptors Noradrenaline adrenergic receptorsNN, MNNNNMSkeletel muscle relaxantsganglionblockerspostganglionic sympathetic nerve-endingsSomaticSympatheticParasympatheticnoradrenaline adrenaline in bloodpreganglionic sympathetic nerve endingsadrenergic drugsmuskarinic drugs

*Important notes regarding the nervous systemDie outonome senuweestelsel is verantwoordelik vir die instandhouding van die interne omgewing van die liggaam (homeostase)In die outonome senuweesisteem is twee neurone nodig om die teiken orgaan te bereik: n preganglioniese neuron, en n postganglioniese neuronAlle preganglioniese neurone stel asetielcholien as hul oordragstof vry. Die asetielcholien bind aan die nikotiniese reseptore in die postganglioniese sel.All the parasympathetis postganglionic fibres release acetylcholine . In the target organ interacts acetylcholine with muscarinic receptors.The most sympathetic postganglionic fibres release noradrenaline . In the target organ noradrenaline interacts with a variety of receptors.Usually noradrenaline acts in the sympathetic nervous system. There are two exceptions:1) Acetylcholine acts in the Symp Nerv system on the sweat glands 2) Dopamine acts in the Symp Nerv system on the smooth muscle of the kidneysThe adrenal medulla, that releases adrenaline, is also seen as part of the sympathetic nervous system.

*Heart and smooth muscle endocrine glands Acetylcholine Noradrenaline DopamineExceptions on Sympathetic Innervation:

*NeurotransmittersThe synthesis, storage, release and removal of transmitters are important, since each of these steps act as a target for drugs

*Classification of neurotransmitters and - regulatorsAcetylcholine (ACh)Biogeniese amieneCatecolamine:Dopamine (DA) Noradrenaline (NA) Adrenaline (Adr) Serotonin (5-hydroxytryptamine, 5-HT) HistaminAmino-acids Exitatory amino acids Glutamate Inhibitory amino acids, Gamma-amino butiric acids (GABA)NeuropeptidesOpioids, -endorfphins & encephalinsDiversGas, NO Purines, Adenosine & ATP

*Neurotransmitters criteria for chemical agents to act as neurotransmittersSynthesis compounds are synthesised in the bodyStorage compounds are stored in vesiclesRelease are generally released by nerve impulsActivation of receptors activation gives rise to an effectTermination of action re-uptake and/or methabolism

*Cholinergic Neurotransmission:

*Cholinergic NeurotransmissionEffector cellnerve-endingMmitochondriaAChAChAChChAcCoAChATChAChacetate+AChCa2+Ca2++AChENMEksositoseCholinePostsynaptic Nicotinic receptorPresinaptiese Muskariniese reseptorAcetylcholine- esterasePostsynaptic Muscarinic receptorAcetylcholineNNMMMMAChAChVesikelAcCoAPDHActive transport

*Nor (Adrenergic) Neurotransmission:

*Nor(Adrenergic) transmissionl-Tl-Tl-DDANANAOksNANAMAOKOMTNAMe-R-E1-RDiffusion and metabolismCa2+Ca2+Effector cell2-RTHALASDDBHsenu-einde-EExocitosis1-R1-R-R-R+l-TyrosinePostsynaptic -receptorsPostsynaptic -receptorsPresynaptic -receptorsl-Tyrosinel-DopaDopaminel-Noradrenaline: Reuptake-1H1Reuptake-2H22-R2-RNATH: TirosienhidroksilaseALASD: Aromatiese l-aminosuurdekarboksilaseDBH: Dopamien--hidrosilaseMAO: Mono-amienoksidaseKOMT: Katesjol-O-metieltransferase3-Metoxi-NA

*Asetielcholien word vanaf asetielKoA en choline gesintetiseer. Die werking van asetielcholien word deur asetielcholienesterase getermineer.The effect of noradrenaline is terminated primarily by re-uptake in the neuron (nerve cell) from where it was released (reuptake-1; H1/NET). Reuptake2/Duffusion/EnzymesNeurotransmitters:

*Synthesis and metabolism of neurotransmittersThe synthesis and metabolism of acetylcholine and catecholamines

*Synthesis and metabolism of acetylcholineAcKoA: asetielkonsiem AChAT: cholienasetieltransferaseAChE: asetielcholienesterase

*Synthesis of (nor) adrenaline(synthesis of catecholamines)THALASDRate limiting step

*Synthesis of (nor) adrenaline(synthesis of catecholamines) DBHFEANMT

*Noradrenaline and AdrenalineStored in: sympathetic nerveStored in: adrenal medulla

*Treatment of Parkinsons diseaseALASDVitamin B6 is the coenzyme for aromatic l-amino acid decarboxlase

*Receptors for TransmittersClassification

*Cholinergic ReceptorsNicotinicMuscarinicGanglionicNeuronal NNSkeletal muscle NMNeuronal SSSM1M3M5M2M4M5M4M1, M3, M5: Gq-coupled, IP3 (inositol triphosphate) Ca2+-channel activityM2, M4: Gi -coupled, inhibition of AC (adeninyl cyclase) cAMP Ca2+ in sitosool Ach = neurotransmitter

*Adrenergic Receptors121A1B1D2A2B2C12341L NA/A = neurotransmitter

*2nd Messengers Receptors

Receptor

Mecha-nism

Effector

2nd messenger

Result

(1M1, M3,

Gq-coupled

PLC (

IP3 (DAG (

Ca2+(

(2,M2,D2

Gi-coupled

AC (

cAMP (

Cardiac K-channel opens:( heart rate (,Ca2+influx (Enzyme activity (

(,D1

Gs-coupled

AS (

cAMP (

Enzyme activity (

NNNM

Ionchannel

-

-

DepolarisesElicits action potential

*Innervations and general rules of innervationOrgans and Effects

*Autonomic Nervous systemParasimpatiese innerveringSimpatiese innerveringSpeekselklier Speekselklier HartHartRespiratoriese stelselRespiratoriese stelselMaag Maag Dunderm Dunderm Proksimale kolon KolonNiereNiere (dopamien)BlaasBlaasDistale kolonRektumRektumGenitalieGenitalieTraansakkie ?UrienleiersRadiale spier, irisBloedvate, kop en nekBloedvate, romp Sweetkliere (Ach) Lewer Milt BynierBloedvate laer ekstremiteiteKringspier, iris

*Many organs are innervated by both the parasympathetic and sympathetic nervous systems In most of these cases opposing effects are obtainedThe one exception to this rule of opposite effects is seen in the salivary glands. Both parasympathetic and sympathetic systems increase secretions. Important organs innervated both by parasympathetic and sympathetic systems are: hart, eye, bronchial smooth muscle (trachea), digestive system, smooth muscle of the urine system In the resting state (not in fight or flight situations) most of the dualistic innervated organs are controlled by the parasympathetic system Most of the vascular smooth muscle is innervated only by the sympathetic nervous system Blood pressure and peripheral resistance are controlled by the sympathetic nervous systemKontraction of the radial muscle (sympathetic) in the eye gives dilation, mydriasis, whilst contraction of the circular muscle (parasympathetic) gives miosis.The hart is the main area for 1-receptors As n geneesmiddel selektief is vir 1-reseptore, dan sal sy hoofeffek op die hart wees.Aktivtion of 2-receptors dilate smooth muscles This is a generalization, 2-receptors are evident in: blood vessels of skeletal muscles (causes vasodilation), gastrointestinal tract, trachea, bladder wall, and pregnant uterus.Activation of -receptors causes contraction or constriction. Activation of 1-receptors causes vasoconstriction.Important Remarks:

Fight or Flight vs. Rest & Digest"

*Effects of autonomic nervous system

Effector

organ

Receptortype

Sympatheticeffect

Parasympatheticeffect

Eye

Iris:radial muscle

(1

Contraction of radial muscle(mydriasis)

Iris:circular muscle (pupillary constrictor)

M3, M2

Contraction of the circular muscle(miosis)

Ciliarymuscle

(2M3, M2

Relaxation(lens flattens for far vision)

Contraction(lens becomes more convex for near vision)

Tear gland

(M3, M2

Secretion

Secretion

*Effects of autonomic nervous system

Effector organ

Receptor type

Sympathetic

effect

Parasympathetic effect

Heart

SA-node

(1 > (2M2 >> M3

( chronotropy

( chronotropy

Atria

(1 > (2M2 >> M3

( inotropy

( inotropy

AV-node

(1 > (2M2 >> M3

( conduction

rate

( conduction

rate

Ventricles

(1 > (2M2 >> M3

( inotropy

( inotropy

*Effects of autonomic nervous systemPost-synaptic 2-receptors,and thus 2-agonists, causes contraction Endothelium Ach + M3 releases epithelium-derived relaxing factors like NO

Effector organ

Receptor type

Sympathetic

effect

Parasympathetic effect

Blood vessels

Arteries(most)

(1 ((2)

Vasoconstriction

-

Skeletal muscle

(1(2

VasoconstrictionVasodilation

Veins(systemic)

(2 ((1)(2

VasoconstrictionVasodilation

Endothelium

M3

Vasodilation

*Effects of autonomic the nervous system

Effector

organ

Receptor

type

Sympathetic

effect

Parasympathetic effect

Lungs

Bronchialmuscle

(2M2 = M3

Broncho-dilation

Broncho-constriction

Bronchialglands

(1M3, M2

Inhibitssecretion

Stimulatessecretion

(

Stimulatessecretion

*Effects of autonomic the nervous system

Effector organ

Receptor type

Sympathetic

effect

Parasympathetic effect

Salivary glands

(1M3, M2

K+ and water secretion

K+ and water secretion

(

Amylase secretion

*Effects of autonomic nervous system

Effector organ

Receptor type

Sympathetic

effect

Parasympathetic effect

Bladder, Ureter en Kidneys

Bladder wall

(2M3 > M2

Relaxation

Contraction

Trigonus and sphincter

(1M3 > M2

Contraction

Relaxation

Ureter

(1M3

Contraction

Relaxation

Kidneys

Vascular smooth muscle

(1(1D1

Renin secretion Renin secretion

*Effects of autonomic nervous system

Effector organ

Receptor type

Sympathetic

effect

Parasympathetic effect

Gastro-intestinal tract

Motility

(1, (2, (1, (2M2 = M3

Increases(channel relaxes)

Increases

Sphincters

(1M3, M2

Contraction(usually)

Relaxation(usually)

Secretion: gastricacids

(2M1

Inhibition

Stimulation

*Effects of autonomic the nervous systemLocalised 1-receptors, located in sweat glands in hand palms and forehead, activated in during stressful situation

Effector organ

Receptor type

Sympathetic effect

Parasympathetic effect

Skin

Muscles that make hair stand on end (arrector pili muscles)

(1

Contraction

-

Sweat glands:localisedgeneral

(1M3, M2

Secretion

Secretion

*Effects of autonomic nervous system

Effector organ

Receptor type

Sympathetic

effect

Parasympathetic effect

Uterus

Pregnant

(1(2M

ContractionRelaxation

Varies

Non-pregnant

(2

Relaxation

*Effects of autonomic the nervous system

Effector organ

Receptor type

Sympathetic effect

Parasympathetic effect

Pancreas, Fat cells and Liver

Pancreas:insulin release

(2(2

((

-

Fat cells

(1, (1, (2, (3(2

LipolysisInhibits lipolysis

-

Liver: glucogenolysis and gluconeogenesis

(1, (2

(

-

***Metabotropic (via G-coupled proteins) vs Inotropic (Ligand-ion channel)

Simpathetic = Catabolic (No new energy is stored, energy is used, degraded processes, fight or flight mode ready)Parasimpathetic = Anabolic (builds up, calm resting situations, sleep , eat and moderate exercise are all building up processes*Inotropy = ContractilityChronotropy = heart rate Tachycardia = increased heart rate Bradycardia = reduced rateDromotropy = heart conduction*