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PHARMACOLOGY OF
AUTONOMIC NERVOUS
SYSTEM
Prof.Dr. Cihat KKHSEYN
PHARMACOLOGY OF
AUTONOMIC NERVOUS SYSTEM
Vegetative Nervous System
Visceral Nervous System
Involuntary Nerve System
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Nervous system Central nervous system
Peripheral nervous system
Efferent nerves Afferent nerves
Somatic nerves (to striated muscles)
Autonomic nerves (to peripheral organs)
Parasympathetic
Sympathetic
(Enteric nervous system ?!)
AUTONOMIC NERVOUS SYSTEM
(From Greek)
Autos (self) + Nomos (law) =
Self governing
Independent
Functioning by its own law
Functioning unconsciously and freely
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Regulation and integration of
body functions by
1) Nervous system 2) Endocrine system
Common features
-High level integration in the brain
-Influence on processes at distant
regions in the body
-Usage of negative feed-backs
Differences in the transmission of information
-Transmission is rapid - Transmission is slow
-Carried electrically along the - Carried chemically by
nerve fibers blood-borne hormones
-Carried chemically by -Carried chemically by
neurotransmitters at by blood to effect organs
synapses or neuro
junctions blood to
Organization of autonomic
nerve system
CNS Synaps Neuro-effecter junction
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Organization of synapses or
neuro-effector junctions
Presinaptik alan
Post sinaptik alan
Stractural
elements
Conduction of biological signal
a) Along axon: electrical
b) Across synapses or neuro-effecter junctions:
chemical, by neurotransmitters
c) Historical background:
1869:-Muscarine mimics the effects of
parasympathetic nerve stimulation
-Atropine can antagonize both muscurine
and the effects of parasympathetic nerve
stimulation
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1877, Du Bois Reymond:
-Conduction along axon is electrical
-Transmission across synaptic junction is by
stimulatory secretion
1904, Elliot: Suggested adrenaline to be a transmitter in
the sympathetic nerve system
1906, Langley: Showed the effects of nicotine and
curare at the neuromuscular junction
1921, Otto Loewi: Elucidation that a neurotransmitter is
released from the autonomic nerve terminals for the
first time
P.symp
Symp
Straub
cannula
Frog heart
Symp
P. symp
Perfusate
P.symp nevre stimulation
Atropine P.symp nevre stimulation
Perfusate
Atropine Perfusate
Physostigmine P.symp nerve stimulation Symp nerve stimulation
Results of Otto Loewies
experiments:
1) Stimulation of
cardiac p.symp nerve:
release of Ach from nerve
terminal
2) Stimulation of
cardiac symp nerve:release
of adrenaline from nerve
terminal
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-1903, Dale; Showed ACh to be a transmitter at the neuromuscular
junction and in autonomic ganglia
-The effect of coronary sinus blood collected during cardic
parasympathetic nerve stimulation on several assay organs.
Cat blood
pressure
Frog
heart
Frog
Rectus
abdominis
R S R S
Physostigmine, a cholinesterase inhibitor
Leech
Dorsal
muscle
BASIC ANATOMY AND PHYSIOLOGY OF
AUTONOMIC NERVOUS SYSTEM I
Conveys all the involuntary outputs from CNS to the
periphery. Exception: skeletal muscle innervation which
mediate voluntary movements
Outside the influence of voluntary control
Regulates: 1) Contraction and relaxation of smooth
muscles
2) Secretions of exocrine and certain
endocrine glands
3) Heart beat and contractility
4) Certain steps of intermediary metabolism
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BASIC ANATOMY AND PHYSIOLOGY OF
AUTONOMIC NERVOUS SYSTEM II
Autonomic efferent pathway uses two neurons
arranged in series to integrate CNS to the peripheral
organs.
Somatic efferent pathway, however, uses a single
neuron for the integration of CNS to the skeletal
muscles
-1st Neuron -Pregang -2nd neuron -Postgang. -Effector
-Spinal chord n. Fiber -Autonomic gg n. Fiber organ or
-Pregang. neuron -Postgang. Neuron tissue
Sinaps
Neuroeffecter
junction
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Splancnic
nerves
gg. cervicale
superior, medium,
inferior
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Red lines:
Sympathetic
nerves
Dark lines:
Parasympa-
thetic nerves
Red lines:
Sympathetic
nerves
Dark lines:
Parasympa-
thetic nerves
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Red lines: Sympathetic nerves Dark lines: Parasympa-thetic nerves
I: CHOLINERGIC SUBDVSON
(Called cholinergic due to Ach)
Motor nerves to skeletal m.
All nerve fibers emerging from CNS
Parasympathetic
Preganglionic fibers in autonomic ganglia
Symp. Postganglionic fibers to sweat gland.
Preganglionic fibers to surrenal medulla
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CHOLINERGIC SUBDVSON
Main neurotransmitter: Acetylcholine (ACh)
Co-transmitters : ATP, neuropeptide, NO, PGs
Cholinergic nerve terminal
Synthesis of ACh
Storage of ACh
Release of ACh upon depolarization
Neuro-effecter junction
Acetate + Choline ACh Acetate+Choline
(Acetyl CoA) (uptake, Na+/H+)
(mitochondria)
ChAT AChE
(cholinacetytransferase ) (acetycholinesterase)
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ACETYCHOLINESTERASE
True AChE Pseudo AChE
(Butyrylcholinesterase)
Confined only to synapses, * Wide spread, found in
cholinergic neuro-effecter blood, liver, glia, tissues
junctions and erythrocytes * Main substrate: butyrylcholine
Basement membrane attached * ACh is also substrate
Main substrate: ACh * But, metacholine is not a
substrate
MW: 250.000, 4 major subunits * Other esters are also substrate, eg.
Methacholine is also substrate, benzoycholine, procaine,
But not other esters of ACh propanidid (short-acting anaesth.),
succinylcholine (succamethonium)
* Genetic polymorphism: the
enzyme is abnormal; ACh and
succinylcholine hydrolysis are slow
Parasympathetic system emerges from two separate
regions:
a) Cranial region: -n. Occulomotorious (3) to eye
-n. Facialis (7) to nasopharynx and
salivary glands
-n. Glossapharyngeous (9) to
nasopharynx and salivary glands
-n. Vagus (10) to thoracic and
abdominal viscera
b) Sacral region: As nervii erigentes (erection of
genitalia) Pelvic gg.
to: Pelvic and low abdominal viscera
(bladder, rectum, genitalia
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ACH is a neurotransmitter in:
All motor fibers leaving CNS
Autonomic ganglia (m, Ni)
Postganglionic parasympathetic fibers (m)
Postganglionic sympathetic cholinergic
fibers(m, sweat gland)
Surrenal medulla (Ni, analogue to ganglion
neurons)
Motor nerves running to striated muscles
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Transmitter release from nerve endings: -Exocytosis
-Endocytosis
Partial exocytosis, as schematized in the following figure, is
a rather complex process.
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It is triggered by Ca2+ entering the nerve ending upon depolarization.
Achieved by 4 successive processes upon phosphorylation of special
proteins by kinases:
1) Docking: -Attachment of vesicles to surface membrane of nerve ending.
-Carried out under the regulatory role of synaptotagmins by:
Synaptobrevin in the vesicular membrane
Rab3
Syntaxins in the cytoplasm of nerve ending
SNAPS-25 molecules
2) Priming: -Getting prepared for exocytosis
-Mediated by: - cytoplasm NSF-protein
(an ATPase sensitive to N- ethylmelamide)
- SNAPs (soluble NSF attachment proteins)
- Some other proteins
3) Ca2+-binding: Binding to Ca2+-receptor proteins like
synaptotagmin and CAPS
4) Fusion and pore formation:Mediated by: - Ca2+-binding
- synaptophysins
-vesicular content is flushed out with a jet speed
-Pore is closed and empty vesicle internalized by endocytosis and
refilled
-Vesicles are found as two pools:
a) Releasable pool: It is small
The balance in between
b) Spare pool: It is too big is achieved by Synaptin
I and II, phosphoproteins
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Classification of cholinergic receptors:
By sets of effects produced by ACh or cholinergic nerve
stimulation
By agonist and antagonist selectivity for cholinergic
receptors (natural or synthetic)
Muscarinic (due to the alkaloid muscarine): G-protein coupled
Nicotinic (due to the alkaloid nicotine) : Na-channel coupled
Clasification
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Nicotinic receptor subtypes
Enteric Nervous System
May be considerd as 3th subdivision of autonomic nevous system
A collection of highly organized neurons in the walls of gut
Includes:
1) myenteric plexus (the plexus of Auerbach)
2) Submucous plexus (the plexus of Meissner)
The neuronal networks receive:
1) Preganglionic fibers from P.sympathetic system
2) Preganglionic fibers from sympathetic system
3) Sensory inputs from within the wall of gut
Fibers from cell bodies in the plexus run to smooth muscle of the gut
to control motility.
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Longitudinal
muscle layer
Myenteric
plexus
Circular
Muscle layer
Summucousal
Plexus
II. SYMPATHETIC SUBDIVISION
Sympathetic nerve system:
= Adrenergic nerve system (due to A)
= Noradrenergic nerve system (due to NA)
Main neurotransmitter:
-Noradrenaline
-Adrenaline: in autonomic gg. and in certain regions of
CNS
-ACh: In sympathetic cholinerjik n. fibers to sweat
glands
Emerges from thoracic and lumbar regions of
spinal chord
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Vetral root Spinal nerve to Effector Perifery Organs
-1
sth
Neuron
-Spinal chord White ramus Gray ramus
-Intermedio-lateral communcans communicans
horn
-2
nd
Neuron
-Paired parvertebral
and unpaired
prevertebral gg (Celiac gg, gg Solare)
-Outside the spinal
chord To:- abdominal and
pelvic viscera
-Adrenal medulla chromaphin cells
(preganglionic)
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SYNTHESIS of Noradrenaline (Adrenaline, Dopamine) in
the sympathetic nerve terminals and in adrenal medulla
-Moment-to-moment
regul.
-Rate-limiting step
-End-product inhibition
-Main control point
-Negative feed-back
Enzymes involved in synthesis
1) Tyrosine hydroxylase: -Very selective
(cytoplasmic) -Rate-limiting step
-CoF: Tetrahydrobiopterin
2)Dopa decarboxylase: -Non-selective
(cytoplasmic) -Substrates:-L-Dopa
-L-histidine
-L-tryptophan
-CoF: Pyridoxalphosphate
3) Dopamine -hydroxylase: -Non-selective
(vesicle membrane-bound) -Found only in catecholamine
synthesizing cells
-CoF: Ascorbate
4) Phenyethanolamine: -Found in brain, autonomic gg. and
N-methyltransferase in adrenal medulla
-A-cell: after birth
(Stimulation by some -NA-cell: evolves later
cortical steroids) -CoF: S-Adenosylmethionine
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STORAGE of Noradrenaline (Adrenaline,
Dopamine) in the sympathetic nerve terminals
and in adrenal medulla
Varicosities
Neuro-effecter
junction
Symp. neuron in
sympathetic gg
Effecter
cells
-Terminals of symp. fibers show numerous swellings called varicosity
-Varicosities are sites of neuro-effecter junctions
-Varicosities contain vesicles for storage of NA called chromaphin
granules
-Diameter of granules= 0.05-0.2m
-Site of synthesis, storage and release of catecholamines (eg. NA, A, DA)
containing a catechol nucleus (dihydroxybenzene) in their structure
-Catechol
-Dihydroxybenzene
-Noradrenaline
-Adrenaline
-Dopamine
-Isoprenaline
HO
HO
By flouresance histo-chemistry, NA shown to locate in the
varicosities
In sympathetic nerve terminal, the catecholamine is 80-85% NA and 15-
20% A
In adrenal medulla, the catecholamine is 80-85% A and 15-20% NA
NA content in a tissue represents the density of sympathetic innervation
NA content is as high as 5 to 50M/g-tissue in spleen, vas deference
blood vessels
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-Contents of storage vesicles:- 1molecule NA(+)makes
complex with 4 molecules ATP(-)
As so: -NA is stable
-Resistant to metabolism
-Not releasable
-Osmolality of vesicle is reduced
-Na-chromogranin, a dye
RELEASE of Noradrenaline (Adrenaline,
Dopamine) in the sympathetic nerve terminals
and in adrenal medulla
Partial exocytosis, as discussed for ACh from cholinergic
nerve terminals
All the vesicular content is released into the neuro-
effecter junction
This includes: - NA
-ATP, neuromodulaters or co-transmitters
- Na-chromogranin
-Dopamine -hydroylase (blood level
represents symp. activity)
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METABOLISM of Noradrenaline (Adrenaline,
Dopamine) in the sympathetic nerve terminals
and in adrenal medulla
Dopamine Metabolism

CH2

CH2


NH2
HO
HO
Dopamine
Dihydroxyphenyl
aceticacid

CH2

C=O

OH

HO


HO
CH
2
CH
2
NH
2
H
3
C
O
H
O
3-metyoxy tyramine
Homovalinic acid (HVA, mainly in the CNS)

CH2

C=O

OH

H3CO


HO
MAO
MAO
COMT
COMT
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Termination of noradrenergic
transmission
Reuptake into the nerve terminal by amine pump (uptake-I)
Uptake into the presynaptic glia or post-junctional effecter cells
(uptake-II)
Inactivation by MAO or COMT
Diffusion into the blood
MAO (monoamine oxydase):
Intracellular; bound to mitochondria surface
Abundant in adrenergic nerve terminal
But, also found in other tissues, eg. Live and intestinal epithelia
Can also oxydase other monoamines, eg. Dopamine, Serotonin
MAO
Catecholamine Aldehyde Carboxylic acid
Termination of noradrenergic
transmission
COMT (Catechol-O-methyltransferase):
A widespread enzyme (neuronal and non-neuronal tissues)
Mediates methylation of one catechol OH-group to yield
methoxy-metabolite
NA normethanephrine; A metanephrine
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Sympathetic and p.sympathetic systems
are not always physiologic opponents



Act synergistic: Exocrin secretions (eg. saliva)
Act antagonistic: Heart, pupil, gut, bladder, bronchi
Single innervation: Symp.: blood vessels, sweat glands;
P.symp.: ciliary body, lacrimal glands
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Regulation of autonomic activity
1) Reflex regulation:
Baroreceptors: blood pressure as cardiovascular variable
Chemoreceptors : pCO2 as cardiovascular variable
2) Pre-synaptic regulation:
by transmitter itself
by neuromodilators (ATP, adenosine, neuropeptides etc)
by cross-innervation
3) Post-synaptic regulation: up- and down-regulation,
temporarily occuring events such as ganglion
transmission
4) Pharmacologic modification
1) Reflex regulation
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Blood(+) (+)Baroreceptors (-)V.motor (-)Symp. nerve (-)Blood pressure
Pressure center activity center
(+) (+)Brain stem (+)P.symp. nerve (-)
P.symp. activity
Nuclei
Blood(+) Chemoreceptors (+)V.motor(+) Symp. Nerve (+)Blood
pH, pCO2 center activity pressure
(+) (-)
(+) Brain stem P.symp. nerve
P.symp. (+)activity (+) Rate of
nuclei breathing
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2) Pre-synaptic regulation
Some co-transmitters (neuro-modulators)
at peripheral autonomic junctions
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Main co-transmitters and their effects at
sympathetic and parasympathetic neuro-
effecter junctions
3) Post-synaptic regulation
Up-regulation of post-synaptic receptors
by receptor antagonists, eg. propranolol
for -adrenoceptors
Down-regulation of post-synaptic
receptors by receptor agonsts, eg.
isoproterenol for -adrenoceptors
Temporally occurring events, eg.
ganglionic transmission
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SIF-cell
SIF= small intensely fluorescent Adrenaline
(similar to chromaphin cells in adrenal medulla)
4)Pharmacologic modulation:
Autonomic targets for drug actions
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