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8/18/2019 Introduction to ANS Pharmacology
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Chapter 6
Intrduction to Autonomic Pharmacology
Hong-wei Yi
Department of Pharmacology
School of Basic Medical Science
Southeast University
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efferent nervous system (ENS)
• autonomic nervous system (ANS
vegetative nervous system)
• somatic motor nervous system
!he efferent portion of the nervous system can "e
divided into t#o ma$or su"divisions
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• !S is largely autonomous in that its
activities are not under direct conscious
control" #t is concerned primarily with visceral
functions such as cardiac output$ %lood flowto various organs$ and digestion$ which are
necessary for life"
• &he somatic division is largely concerned with
consciously controlled functions such asmovement$ respiration$ and posture"
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'omparison of somatic and autonomic
nervous systems
!S S(M' !S
#nnervation) heartsmooth muscle
glands - e*ocrine +endocrine
sense organss,eletal muscle
%ones + oints
'ontrol) not consciouslycontrolled
mostly conscious
.ffect) modify on-goingactivity initiate activity
'omposition) synapses outside'!S
synapses in '!S
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utonomic versus Somatic !S
• utonomic !S pathway is a / neurons pathway
• Somatic !S pathway only contains one neuron"
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Comparison of somatic and autonomic systems
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0unctional Divisions of the !S
• sympathetic nervous system 1S!S$ thoraco-
lum%ar division2 - response to stress 1fight-or-
flight2
• parasympathetic nervous system 1PS!S$cranial-sacral division2 - homeostatic function
• enteric nervous system 1.!S2 - regulation of
gastrointestinal function3 autonomous
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enteric nervous system$ 1 .!S2
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n important traditional classification of
autonomic nerves is %ased on the primary
transmitter molecules acetylcholine ornorepinephrine released from their
terminal %outons and varicosities"
• cholinergic fi%ers
• noradrenergic 1or 4adrenergic42 fi%ers
Classification of ANS according to
the released neurotransmitters
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Cholinergic nerve% Acetylcholine (ACh)
#nclude• all preganglionic efferent autonomic
fi%ers3
• the somatic motor fi%ers to s,eletalmuscle3
• most parasympathetic postganglionic
fi%ers3
• a few sympathetic postganglionic fi%ers"
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Noradrenergic nerve% Norepinephrine (NE)
&hey act %y releasing norepinephrine"
#nclude
Most postganglionic sympathetic fi%ers
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0ive ,ey features of neurotransmitter
function provide potential targets for
pharmacologic therapy) synthesis$
storage$ release$ and termination of action
of the transmitter$ and functions of the
receptor "
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Cholinergic Transmission
Synthesis cetylcholine is synthesi5ed in the
cytoplasm from acetyl-'o and choline
through the catalytic action of the en5ymecholine acetyltransferase 1'h&2"
cetyl-'o is synthesi5ed in mitochondria$ which are
present in large num%ers in the nerve ending" 'holine is
transported from the e*tracellular fluid into the neuron
terminal %y a sodium-dependent mem%rane choline
transporter "
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Storage (nce synthesi5ed$ acetylcholine is
transported from the cytoplasm into the
vesicles %y a vesicle-associatedtransporter "
Storage of acetylcholine is accomplished %y
the pac,aging of 46uanta4 of acetylcholine
molecules 1usually 7888-98$888
molecules in each vesicle2"
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:elease
:elease of 'h from the vesicles isdependent on e*tracellular calcium"
;hen an action potential reaches theterminal$ calcium ions influ* into the nerve
terminal < triggers fusion of the vesiclemem%rane with the terminal mem%raneand opening of a pore into the synapse"
&he opening of the pore results in e*ocytotice*pulsion in the case of somatic motornerves of several hundred 6uanta ofacetylcholine into the synaptic cleft"
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acetylcholine molecules may %ind to and
activate an acetylcholine receptor(cholinoceptor)
Termination
acetylcholinesterase 1'h.2 moleculevery efficiently splits acetylcholine intocholine and acetate$ neither of which hassignificant transmitter effect$ and there%yterminates the action of the 'h"
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Most cholinergic synapses are richly
supplied with acetylcholinesterase3 thehalf-life of acetylcholine in the synapse istherefore very short 1seconds2"
cetylcholinesterase is also found in other
tissues$ eg$ red %lood cells" nother cholinesterase with a lower
specificity for acetylcholine$pseudocholinesterase= %utyrylcholinesterase >$ is found in %loodplasma$ liver$ glia$ and many othertissues"2
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Adrenergic Transmission
drenergic neurons also transport aprecursor molecule into the nerve ending$then synthesi5e the catecholamine
transmitter$ and finally store it inmem%rane-%ound vesicles"
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&yrosine is transported into the
noradrenergic ending or varicosity %y asodium-dependent carrier 12"Synthesis&yrosine is converted to dopa %y tyrosine
hydro*ylase"Dopa is converted to dopamine %y dopa
decar%o*ylase" &hen dopamine istransported into the vesicle"
Dopamine is converted to !. in the vesicle%y dopamine-?-hydro*ylase"
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:elease
Physiologic release of transmitter occurswhen an action potential opens voltage-sensitive calcium channels and increasesintracellular calcium"
0usion of vesicles with the surface mem%raneresults in e*pulsion of norepinephrine"
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&ermination
!orepinephrine diffuses out of the cleft3
Be transported into the cytoplasm of theterminal %y the norepinephrine transporter
1!.&2$ or into postunctional orperiunctional cells"
!orepinephrine can %e meta%oli5ed %y
monoamine o*idase 1M(2 in themitochondria of the nerve terminal"
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However$ meta%olism is not the primary
mechanism for termination of action of
norepinephrine physiologically released
from noradrenergic nerves"
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&wo types of upta,e of !.
Upta,e7 1neuronal upta,e 2 @9A-8A3
storage in vesiclesCM(
Upta,e/ 1non-neuronal upta,e23
meta%oli5ed %y catechol-(-methyl
transferase 1'(M&2 and M(
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uptake 1(7%~ !% )
uptake "
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A#T$N$%&C 'CT$'S
&he primary acetylcholine receptor
su%types were named after the al,aloids
originally used in their identification)
muscarine) muscarinic receptors* %-'
nicotine) nicotinic receptors* N-'
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Adrenoceptor is widely used to descri%e
receptors that respond to catecholamines
such as norepinephrine"
adrenergic 1or noradrenergic2 receptors
can %e further su%divided into)
&-adrenoceptor$
?-adrenoceptor$
dopamine-receptor
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'holinergic :eceptor &ypes
• %uscarinic cardiac$ smooth muscle$ glands$ganglia PS!S postganglionic synapses
S!S postganglionic synapses on sweat glands 1somespecies2$ s,eletal muscle %lood vessels
M7 - M9 3 meta%otropic$ /nd messengers adenylylcyclase or phospholipase '
• Nicotinic - ionotropic !! - neuronal 1ganglia$ '!S2
!M - s,eletal muscle
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+#NCT&$NA, $'AN&.AT&$N $+
A#T$N$%&C ACT&/&T0 M-R: muscarine
M1-R: ganglion, CNS
M2-R: heart, presynaptic sites (negativefeedac!"
M#-R: e$ocrine glands, smooth muscle,
endotheliumM% -R: e$ocrine glands, smooth muscle
M& -R: CNS
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drenergic :eceptor Su%types
• alpha 1α2
α7 1postsynaptic2 - %lood vessels$ eye$
sphincters$ genitals$ %ladder$ gut$ liver$ heart
=E further su%types> α/ 1presynaptic in peripheral !S for negative
feed%ac,3 pre- and postsynaptic in '!S23
also on %lood vessels$ pancreas$ platelets
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drenergic :eceptor Su%types
• %eta 1β2 - inhi%itory e*cept in the heart β7 - heart$ ,idney3 generally e*citatory
β/ - lungs$ vascular$ gastrointestinal$ genitourinarysmooth muscle$ liver$ s,eletal muscle1glycogenolysis$ FG upta,e23 generally inhi%itory
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&he %asic mechanisms of actions of !S
drugs
• 'irect action of receptors
agonist
antagonist ("loc*er)
• +lnfluence of neurotransmitters
release
transshipment and storage
conversion
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Possi%le drug sites 1to 'h2)
• %loc, 'h synthesis - hemicholinium$ %loc,s
choline entrance to cell
• %loc, 'h release - %otulinum to*in$ lead
• inhi%ition of 'h. - organophosphates$car%amates
• %loc, of 'h receptors - atropine$ curare
• direct receptor stimulation - %ethanechol$nicotine
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Possi%le drug sites 1to !.2)
• interference with synthesis - α-methyl-p-tyrosine$false transmitters 1α−methyl dopa2
• %loc, of !. active upta,e %y pre-synapticmem%rane - cocaine
• %loc, of !. active transport into vesicles - reserpine
• triggered release of !. from pre-synaptic terminalinto cleft - amphetamine
• triggered release of !. from vesicles -guanethedine
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Possi%le drug sites 1to !.2)
• %loc, of !. release from action potential - %retylium
• direct stimulation of receptors - isoproterenol$
phenylephrine
• %loc, of receptors propranolol 1β2$pheno*y%en5amine 1α2
• M( inhi%ition - tranylcypromine$ pargyline
• '(M& inhi%ition - none yet