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INTRODUCTION TOAUTONOMIC PHARMACOLOGY

INTRODUCTION TOAUTONOMIC PHARMACOLOGY

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Brunton LL, Lazo JS, Paeker KL, eds. Goodman &

Gilmans The Pharmacological Basis of Therapeutics

Katzung BG. Basic & Clinical Pharmacology

Rang HP, Dale MM et al. Pharmacology

References:

References:

http://www.pharmacology2000.com/Autonomics/In

troduction/Introobj1.htm

E-Books:

Website:

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1. Anatomy of Autonomic Nervous System (ANS), review

2. Neurotransmitters of ANS

2.1 Cholinergic transmission

2.2 Adrenergic transmission

2.3 Presynaptic regulation2.4 Effects of drugs on autonomic transmission

3. Autonomic Receptors

3.1 Cholinoceptors

3.2 Adrenoceptors

4. Autonomic Functions

Objectives

Objectives

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Nervous System(NS)

Nervous System(NS)

Central

NS

Peripheral

NS Brain

Spinal cord

1. Anatomy of Autonomic Nervous System (ANS)Review

Autonomic

Somatic

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1. Autonomous (independent)

2. Necessary for life

3. Consist of 2 basic neurons

- pre-ganglionic neuron- post-ganglionic neuron

4. Divided into 2 types (opposite actions)- parasympathetic NS (rest & digest)

- sympathetic NS (fight or flight response)

Autonomic Nervous System (ANS)

2 N i (NT) & h i M d l i

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2.Neurotransmitters (NT) & their Modulation(: synthesis, storage, and release of NT)

1 = uptake of precursors2 = synthesis of transmitter

3 = storage of transmitter

4 = degradation of transmitter

5 = depolarization bypropagated action potential

6 = influx of Ca2+ in response to

depolarization

7 = release of transmitter byexocytosis

8 = diffusion to postsynaptic

membrane

9 = interaction withpostsynaptic receptors

10= inactivation of transmitter

11= reuptake of transmitter or

degradation products12= interaction with

presynaptic receptors

1

4

5

6

113

12

7

10

8

9

2

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2.1 Cholinergic Transmission2.1 Cholinergic Transmission

2 2. Storage:into synaptic vesicles

3

3. Release:by Ca2+-mediated exocytosis

4. Action:binds to cholinergic receptors

45

5. Degradation:

hydrolysed by AchE

1 1. ACh synthesis:CAT

choline + acetyl CoA --> ACh

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2.2 Adrenergic Transmission2.2 Adrenergic Transmission

2

2. Storage:

into synaptic vesicles

3

3. Release: exocytosis

(by Ca2+-mediated)

4

4. Action: binds toadrenergic receptors

1 1. NE synthesis:Tyrosine ->DOPA->Dopamine -> NE

55. Metabolism:

- re-uptake

- hydrolysis- diffusion

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Neurotransmitters of the ANS

Principal transmitters

Are acetylcholine (ACh) and noradrenaline (NA)

Pre-ganglionic neurons are cholinergic (ACh)

Post-ganglionic

- parasympathetic neurons are cholinergic (ACh)- sympathetic neurons, mainly noradrenergic (NA)

though a few are cholinergic (e.g. sweat glands)

Non noradrenaline none cholinergic (NANC transmitters)

: NO and VIP (parasympathetic), ATP and NPY (sympathetic)

Others, such as 5-HT, GABA and dopamine Co-transmission

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2.3 Presynaptic Regulation2.3 Presynaptic Regulation

Release of transmitter electrical activity in the nerve fiber&

substances that produce locally

There are 2 types of the regulation:

Heterotropic interactions: one NT affects the release of another.

Homotropic interactions: the NT affects the nerve terminals fromwhich it is being released.

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Ex: inhibitory and facilitory influences on noradrenalinerelease from sympathetic nerve endings

Ex: inhibitory and facilitory influences on noradrenalinerelease from sympathetic nerve endings

2 4 Eff t f D A t i T i i

2 4 Eff t f D A t i T i i

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Promote transmitterrelease

Adrenergic nerveterminals

Tyramine,amphetamine

Causes explosivetransmitter release

Cholinergic andadrenergic vesicles

-Latrotoxin5Prevents releaseCholinergic vesiclesBotulinum toxin

Reduces transmitterreleaseNerve terminal calciumchannels

-Conotoxin GVIA

4

Modulate releaseNerve terminal membranereceptors

Many3

Transmitter release

Prevents storage,depletes

Adrenergic terminalsvesicles

Reserpine

Prevents storage,depletes

Cholinergic terminalsvesicles

VesamicolTransmitter storage

Blocks synthesisAdrenergic nerveterminals and adrenalmedulla: cytoplasm

-Methyltyrosine(metyrosine)

Blocks uptake ofcholine and slowssynthesis

Cholinergic nerveterminals: membrane

HemicholiniumTransmittersynthesis

Block sodiumchannels; blockconduction

Nerve axonsLocal anesthetics,tetrodotoxin,1

saxitoxin2

Action potentialpropagation

ActionSiteDrug ExampleProcess Affected

2.4 Effects of Drugs on Autonomic Transmission2.4 Effects of Drugs on Autonomic Transmission

1. Puffer fish,2. Red tide3. NE, DA, ACh,AgII,

PGs

4. Marine snail5. Black widow spider

Kat2007 T6-5 p 90

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Inhibits enzyme; increasesstored transmitter pool

Adrenergic nerve terminals(monoamine oxidase)

Tranylcypromine

Inhibits enzyme; prolongsand intensifies transmitteraction

Cholinergic synapses(acetylcholinesterase)

NeostigmineEnzymaticinactivationof transmitter

Binds muscarinic receptors;prevents activation

Receptors, parasympatheticeffector cells

Atropine

Binds and activatesmuscarinic receptors

Receptors, parasympatheticeffector cells (smooth muscle,glands)

Bethanechol

Prevents activationNeuromuscular end platesTubocurarine

Binds nicotinic receptors;opens ion channel inpostsynaptic membrane

Receptors at nicotiniccholinergic junctions(autonomic ganglion,

neuromuscular end plates)

Nicotine

Binds receptors;prevents activation

Receptors at adrenergicjunctions

Propranolol

Binds receptors;activates adenylyl cyclase

Receptors at adrenergicjunctions

Isoproterenol

Binds receptors;prevents activation

Receptors at adrenergicjunctions

Phentolamine

Binds receptors; causes

contraction

Receptors at adrenergic

junctions

NorepinephrineReceptor

activation orblockade

ActionSiteDrug ExampleProcessAffected

3 A t i R t

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3. Autonomic Receptors

Skeletal muscle neuromuscular endplatesNicotinic NM

Postganglionic neurons, some presynaptic cholinergic

terminals

Nicotinic NN

Vascular endothelium, especially cerebral vessels; CNSneurons

Muscarinic M5

CNS neurons; possibly vagal nerve endingsMuscarinic M4

Exocrine glands, Vessels (smooth muscle &endothelium); CNS neurons

Muscarinic M3(Granular type)

Myocardium, Smooth muscle,

Some presynaptic sites; CNS neurons

Muscarinic M2

(Cardiac type)

CNS neurons, Sympathetic postganglionic neurons,

Some presynaptic sites

Muscarinic M1

(Neural type)

3.1 CholinoceptorsTypical LocationsReceptor Name

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Postsynaptic effector cells, especially lipocytes; heartBeta3

Postsynaptic effector cells, especially smooth muscle

and cardiac muscle

Beta2

Postsynaptic effector cells, especially heart,

lipocytes, brain; presynaptic adrenergic and

cholinergic nerve terminals, juxtaglomerular

apparatus of renal tubules, ciliary body epithelium

Beta1

Presynaptic adrenergic nerve terminals, platelets,

lipocytes, smooth muscle

Alpha2

Postsynaptic effector cells, especially smooth muscleAlpha1

3.2 Adrenoceptors

Typical LocationsReceptor Name

T f R Eff Li k

T f R t Eff t Li k

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Type of Receptor-Effector Linkage, reviewType of Receptor-Effector Linkage, review

Li G d I Ch l

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Ligan-Gated Ion Channels: nACh, GABA A, 5-HT3

Composed of 5 subunits Ex:nicotinic receptor

ACh + Receptor (alpha site)

Open transmembrane ion channel

Na+ influx

Depolarization

Muscle contraction

G P t i C l d R t

G P t i C l d R t

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G-Protein-Coupled Receptor: muscarinic & adrenergic receptors

G-Protein-Coupled Receptor: muscarinic & adrenergic receptors

The main G protein subtypes and their functions

The main G protein subtypes and their functions

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The main G-protein subtypes and their functionsThe main G-protein subtypes and their functions

- adenylyl cyclase cAMP

Open cardiac K channelsHyperpolarization HR (ACh)

analgesic (opioids)

As for G subunits (see above). Also: activate potassium channels

inhibit voltage-gated Ca channels

activate GPCR kinases

activate mitogen-activated proteinkinase cascade.

All GPCRsGsubunits

+ PLC second messengers

inositol trisphosphate (IP3)

and diacylglycerol (DAG)

ACh (muscarinic), serotonin,

etc.

Gq

Not yet clearNeurotransmitters in brainGo

-Adrenergic amines, ACh

(muscarinic), opioids, serotonin,etc.

Gi

+ adenylyl cyclase cAMP-Adrenergic amines,glucagon,histamine, serotonin, etc.

Gs

Main effectorsAssociated receptorsTypes

G-protein and 2nd messenger control of cellular effector systems

G-protein and 2nd messenger control of cellular effector systems

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G-protein and 2nd messenger control of cellular effector systemsG-protein and 2 messenger control of cellular effector systems

Structure of Phosphatidylinositol Bisphosphate (PIP2)

Structure of Phosphatidylinositol Bisphosphate (PIP2)

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Structure of Phosphatidylinositol Bisphosphate (PIP2)Showing sites of cleavage by different phospholipases

Structure of Phosphatidylinositol Bisphosphate (PIP2)Showing sites of cleavage by different phospholipases

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Ex: Regulation of energy metabolism by cAMP

Ex: Regulation of energy metabolism by cAMP

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g gy yg gy y

Figure shows cAMP production in response to -adrenoceptor activation affectsenzymes involved in glycogen and fat metabolism in liver, fat & muscle cells

4 Autonomic Functions

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Control specific organs

- smooth muscle

- exocrine secretion

- heart (rate and force)

- certain metabolic processes

4. Autonomic Functions

Nicotinic receptor (N)Cholinergic: AChGanglion & NMJ

Adrenergic receptors ( & )Adrenergic: NESympathetic

Muscarinic receptors (M)Cholinergic: AChParasympathetic

ReceptorNeurotransmitter

The Main Effects of ANSR&D2003 Table 9-1p127

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Secretion-No effectGlands

M3

Constriction2

No sympathetic innervation,but dilated by circulatingadrenaline

Smooth muscle

Bronchi

Viscera

-No effect2

Dilatation

-No effectConstrictionVeins

M3

(via NO)DilatationConstrictionSalivary gland

M3

(via NO)DilatationConstrictionErectile tissue

-No effectConstrictionViscera, skin, brain-No effect2DilatationMuscle

-No effectConstrictionCoronary

Arterioles

Blood vessels

M2

No effect

1Automaticity

Force Ventricular muscle

M2

M2

Conduction velocity AV block

1

Automaticity AV nodeM

2Force

1Force Atrial muscle

M2

Rate 1

Rate SA node

Heart

Cholinergicreceptor typea

Parasympathetic effectAdrenergicreceptor typea

Sympathetic effectOrgan

R&D2003 Table 9 1p127

Cholinergicreceptor typea

Parasympathetic effectAdrenergicreceptor typea

Sympathetic effectOrgan

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26No effect, 2GlycogenolysisGluconeogenesis

Liver

-No effect1Renin secretionKidney

M3

Secretion-No effectLacrimal glands

M3

Secretion, SecretionSalivary glands

-No effectPiloerectionPilomotor

No effect-Secretion (mainly

cholinergic via M3receptors)

Sweat glands

Skin

M3

ContractionRelaxation (slight)Ciliary muscle

M3

ConstrictionDilatationPupil

Eye

M3

ErectionEjaculationMale sex organs

2

RelaxationNon-pregnant

-VariableContractionPregnantUterus

M3

Sphincter relaxation1

Sphincter contraction

M3

Contraction2

RelaxationBladder

M3

M3

SecretionGastric acid secretion

-No effectGlandsM3Dilatation2, 2ConstrictionSphincters

M3

Motility 1,

2,

2Motility Smooth muscle

Gastrointestinal tract

receptor typereceptor type

: ANS

: ANS

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1. System that regulates physiologic processes. automatically

2. Divided into 2 major divisions: sympathetic & parasympathetic

3. Physiology of ANS

1. Activates fight-or-flight responses.

2. Increases the following: HR and contractility

Bronchodilation

Hepatic glycogenolysis &

glucose release

2. Causes sweaty palms

3. Controls ejaculation

: ANS: ANS

http://www.merck.com/mmpe/sec16/ch208/ch208a.html

1. Conserves and restores

2. Stimulates GI secretionsand motility

3. Slows HR

4. Reduces BP

5. Controls erection

Parasympathetic (anabolic)Sympathetic (catabolic)

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QuestionsQuestions