4. 54 dt2 ans intro
TRANSCRIPT
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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
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10
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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
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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
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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