Chapter 6

Intrduction to Autonomic Pharmacology

Hong-wei Yi
Department of Pharmacology
School of Basic Medical Science
Southeast University

efferent nervous system (ENS)

The efferent portion of the nervous system can be
divided into two major subdivisions

autonomic nervous system (ANS,

vegetative nervous system)
somatic motor nervous system

 ANS is largely autonomous in that its

activities are not under direct conscious
control. It is concerned primarily with visceral
functions such as cardiac output, blood flow
to various organs, and digestion, which are
necessary for life.
The somatic division is largely concerned with
consciously controlled functions such as
movement, respiration, and posture.

Comparison of somatic and autonomic

nervous systems
Innervation:

Control:
Effect:
Composition:

ANS

SOMATIC NS

heart
smooth muscle
glands - exocrine &
endocrine
not consciously
controlled
modify on-going
activity
synapses outside
CNS

sense organs
skeletal muscle
bones & joints
mostly conscious
initiate activity
synapses in CNS

Autonomic versus Somatic NS

Autonomic NS pathway is a 2 neurons pathway
Somatic NS pathway only contains one neuron.

Comparison of somatic and autonomic systems

Functional Divisions of the ANS

sympathetic nervous system (SNS, thoracolumbar division) - response to stress (fight-orflight)
parasympathetic nervous system (PSNS,
cranial-sacral division) - homeostatic function
enteric nervous system (ENS) - regulation of
gastrointestinal function; autonomous

enteric nervous system, ( ENS)

Classification of ANS according to

the released neurotransmitters
An important traditional classification of
autonomic nerves is based on the primary
transmitter molecules acetylcholine or
norepinephrine released from their
terminal boutons and varicosities.
cholinergic fibers
noradrenergic (or "adrenergic") fibers

Cholinergic nerve: Acetylcholine (ACh)

Include
all preganglionic efferent autonomic
fibers;
the somatic motor fibers to skeletal
muscle;
most parasympathetic postganglionic
fibers;
a few sympathetic postganglionic fibers.

Noradrenergic nerve: Norepinephrine (NE)

They act by releasing norepinephrine.
Include
Most postganglionic sympathetic fibers

Five key 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.

Cholinergic Transmission
Synthesis
Acetylcholine is synthesized in the
cytoplasm from acetyl-CoA and choline
through the catalytic action of the enzyme
choline acetyltransferase (ChAT).
Acetyl-CoA is synthesized in mitochondria, which are
present in large numbers in the nerve ending. Choline is
transported from the extracellular fluid into the neuron
terminal by a sodium-dependent membrane choline
transporter.

Storage
Once synthesized, acetylcholine is
transported from the cytoplasm into the
vesicles by a vesicle-associated
transporter.
Storage of acetylcholine is accomplished by
the packaging of "quanta" of acetylcholine
molecules (usually 1000-50,000
molecules in each vesicle).

Release
Release of ACh from the vesicles is
dependent on extracellular calcium.
When an action potential reaches the
terminal, calcium ions influx into the nerve
terminal triggers fusion of the vesicle
membrane with the terminal membrane
and opening of a pore into the synapse.
The opening of the pore results in exocytotic
expulsion in the case of somatic motor
nerves of several hundred quanta of
acetylcholine into the synaptic cleft.

acetylcholine molecules may bind to and

activate an acetylcholine receptor
(cholinoceptor)
Termination
acetylcholinesterase (AChE) molecule
very efficiently splits acetylcholine into
choline and acetate, neither of which has
significant transmitter effect, and thereby
terminates the action of the ACh.

Most cholinergic synapses are richly

supplied with acetylcholinesterase; the
half-life of acetylcholine in the synapse is
therefore very short (seconds).
Acetylcholinesterase is also found in other
tissues, eg, red blood cells.
Another cholinesterase with a lower
specificity for acetylcholine,
pseudocholinesterase
[ butyrylcholinesterase ], is found in blood
plasma, liver, glia, and many other
tissues.)

Adrenergic Transmission
Adrenergic neurons also transport a
precursor molecule into the nerve ending,
then synthesize the catecholamine
transmitter, and finally store it in
membrane-bound vesicles.

Tyrosine is transported into the

noradrenergic ending or varicosity by a
sodium-dependent carrier (A).
Synthesis
Tyrosine is converted to dopa by tyrosine
hydroxylase.
Dopa is converted to dopamine by dopa
decarboxylase. Then dopamine is
transported into the vesicle.
Dopamine is converted to NE in the vesicle
by dopamine--hydroxylase.

Release
Physiologic release of transmitter occurs
when an action potential opens voltagesensitive calcium channels and increases
intracellular calcium.
Fusion of vesicles with the surface membrane
results in expulsion of norepinephrine.

Termination
Norepinephrine diffuses out of the cleft;
Be transported into the cytoplasm of the
terminal by the norepinephrine transporter
(NET), or into postjunctional or
perijunctional cells.
Norepinephrine can be metabolized by
monoamine oxidase (MAO) in the
mitochondria of the nerve terminal.

However, metabolism is not the primary

mechanism for termination of action of
norepinephrine physiologically released
from noradrenergic nerves.

Two types of uptake of NE

Uptake1 (neuronal uptake ) 75%-90%;
storage in vesicles/MAO
Uptake2 (non-neuronal uptake);
metabolized by catechol-O-methyl
transferase (COMT) and MAO

uptake 1
(75 95 )

uptake 2

AUTONOMIC RECEPTORS
The primary acetylcholine receptor
subtypes were named after the alkaloids
originally used in their identification:
muscarine: muscarinic receptors; M-R
nicotine: nicotinic receptors; N-R

Adrenoceptor is widely used to describe

receptors that respond to catecholamines
such as norepinephrine.
adrenergic (or noradrenergic) receptors
can be further subdivided into:
-adrenoceptor,
-adrenoceptor,
dopamine-receptor

Cholinergic Receptor Types

Muscarinic cardiac, smooth muscle, glands,
ganglia
PSNS postganglionic synapses
SNS postganglionic synapses on sweat glands (some
species), skeletal muscle blood vessels
M1 - M5 ; metabotropic, 2nd messengers adenylyl
cyclase or phospholipase C

Nicotinic - ionotropic
NN - neuronal (ganglia, CNS)
NM - skeletal muscle

FUNCTIONAL ORGANIZATION OF
AUTONOMIC ACTIVITY
M-R: muscarine
M1-R: ganglion, CNS
M2-R: heart, presynaptic sites (negative
feedback)
M3-R: exocrine glands, smooth muscle,
endothelium
M4 -R: exocrine glands, smooth muscle
M5 -R: CNS

Adrenergic Receptor Subtypes

alpha ()

1 (postsynaptic) - blood vessels, eye,

sphincters, genitals, bladder, gut, liver, heart
[3 further subtypes]
2 (presynaptic in peripheral NS for negative
feedback; pre- and postsynaptic in CNS);
also on blood vessels, pancreas, platelets

Adrenergic Receptor Subtypes

beta () - inhibitory except in the heart
1 - heart, kidney; generally excitatory
2 - lungs, vascular, gastrointestinal, genitourinary
smooth muscle, liver, skeletal muscle
(glycogenolysis, K+ uptake); generally inhibitory

The basic mechanisms of actions of ANS

drugs
1.Direct action of receptors
agonist
antagonist (blocker)
2.lnfluence of neurotransmitters
release
transshipment and storage
conversion

Possible drug sites (to ACh):

block ACh synthesis - hemicholinium, blocks
choline entrance to cell
block ACh release - botulinum toxin, lead
inhibition of AChE - organophosphates,
carbamates
block of ACh receptors - atropine, curare
direct receptor stimulation - bethanechol,
nicotine

Possible drug sites (to NE):

interference with synthesis - -methyl-p-tyrosine,
false transmitters (methyl dopa)
block of NE active uptake by pre-synaptic
membrane - cocaine
block of NE active transport into vesicles - reserpine
triggered release of NE from pre-synaptic terminal
into cleft - amphetamine
triggered release of NE from vesicles guanethedine

Possible drug sites (to NE):

block of NE release from action potential - bretylium
direct stimulation of receptors - isoproterenol,
phenylephrine
block of receptors propranolol (),
phenoxybenzamine ()
MAO inhibition - tranylcypromine, pargyline
COMT inhibition - none yet