introduction to ans pharmacology

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

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