INTRODUCTION TO ANS

PHARMACOLOGY
OLORO JOSEPH
(DCM, BSc. MSc. Pharm, PhD Tox. Fellow)
0774606015/0704788731
.
 Introduction
• The nervous system is divided into two anatomical
divisions:
– The central nervous system (CNS), composed of the brain and
spinal cord, and
– The peripheral nervous system, includes neurons located
outside the brain and spinal cord—that is, any nerves that enter
or leave the CNS
• The peripheral nervous system is subdivided into
– The efferent division, the neurons of which carry signals away
from the brain and spinal cord to the peripheral tissues, and
– Afferent division, the neurons of which bring information from
the periphery to the CNS.
• Afferent neurons provide sensory input to modulate the
function of the efferent division through reflex arcs, or
neural pathways that mediate a reflex action
Important terms in pharmacology of ANS
 Anatomy of the ANS
• Efferent neurons: The ANS carries nerve impulses from the
CNS to the effector organs by way of two types of efferent
neurons
• The first nerve cell is called a preganglionic neuron, and its cell
body is located within the CNS, which emerge from the
brainstem or spinal cord and make a synaptic connection in
ganglia (an aggregation of nerve cell bodies located in the
peripheral nervous system).
• These ganglia function as relay stations between a
preganglionic neuron and a second nerve cell, the
postganglionic neuron.
• The latter neuron has a cell body originating in the ganglion.
• It is generally nonmyelinated and terminates on effector
organs, such as smooth muscles of the viscera, cardiac muscle,
and the exocrine glands.
Afferent neurons:
• The afferent neurons (fibers) of the ANS are
important in the reflex regulation of this
system (for example, by sensing pressure in
the carotid sinus and aortic arch) and
• In signaling the CNS to influence the efferent
branch of the system to respond.
Efferent neurons
• The efferent ANS is divided into the
sympathetic and the parasympathetic nervous
systems as well as the enteric nervous system
• Anatomically, the sympathetic and the
parasympathetic neurons originate in the CNS
and emerge from two different spinal cord
regions.
• Sympathetic neurons:
• The preganglionic neurons of the sympathetic system come from thoracic
and lumbar regions (T1 to L2) of the spinal cord, and
• They synapse in two cordlike chains of ganglia that run close to and in
parallel on each side of the spinal cord.
• The preganglionic neurons are short in comparison to the postganglionic
ones.
• Axons of the postganglionic neuron extend from these ganglia to the tissues
that they innervate and regulate
• The sympathetic nervous system is also called the thoracolumbar division
because of its origins.
• In most cases, the preganglionic nerve endings of the sympathetic nervous
system are highly branched, enabling one preganglionic neuron to interact
with many postganglionic neurons.
• This arrangement enables this division to activate numerous effector organs
at the same time.
• The adrenal medulla, like the sympathetic ganglia, receives preganglionic
fibers from the sympathetic system. Lacking axons, the adrenal medulla, in
response to stimulation by the ganglionic neurotransmitter acetylcholine,
influences other organs by secreting the hormone epinephrine, also known
as adrenaline, and lesser amounts of norepinephrine, into the blood.
Parasympathetic neurons:
• The PNS preganglionic fibers arise from cranial nerves III
(oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus)
and also sacral region (S2 to S4) of the spinal cord and synapse
in ganglia near or on the effector organs.
• [The vagus nerve accounts for 90% of preganglionic
parasympathetic fibers in the body.
• Postganglionic neurons from this nerve innervate most of the
organs in the thoracic and abdominal cavity.]
• PNS is also called the cranio-sacral division.
• Unlike the SNS, the preganglionic fibers are long, and the
postganglionic ones are short, with the ganglia close to or within
the organ innervated.
• In most instances there is a one-to-one connection btwn the
preganglionic and postganglionic neurons, enabling the discrete
response of this division.
• Enteric neurons: The enteric nervous system is the third division
of
• the ANS. It is a collection of nerve fi bers that innervate the
gastrointestinal
• (GI) tract, pancreas, and gallbladder, and it constitutes the
• “brain of the gut.” This system functions independently of the
CNS
• and controls the motility, exocrine and endocrine secretions, and
• microcirculation of the GI tract. It is modulated by both the
sympathetic
• and parasympathetic nervous systems.
Functions of the Parasympathetic &
sympathetic nervous system
AUTONOMIC TRANSMISSION
Synthesis, storage, release & termination of
effects of acetylcholine
• Synthesis and storage—
• Acetylcholine is synthesized in the nerve terminal by the enzyme
choline acetyltransferase (ChAT) from acetyl-CoA (produced in
mitochondria) and choline (transported across the cell membrane).
• The rate-limiting step is the transport of choline into the nerve
terminal.
• This transport can be inhibited by the research drug hemicholinium.
• Acetylcholine is actively transported into its vesicles for storage by
the vesicle-associated transporter, VAT.
• This process can be inhibited by another research drug, vesamicol.
• Release of acetylcholine—
• Release of transmitter stores from vesicles in the nerve ending requires the
entry of calcium through calcium channels and triggering of an interaction
between SNARE (soluble N-ethylmaleimide-sensitive-factor attachment
protein receptor) proteins.
• SNARE proteins include v-SNARES associated with the vesicles (VAMPs, vesicle
associated membrane proteins: synaptobrevin, synaptotagmin) and t-SNARE
proteins associated with the nerve terminal membrane (SNAPs, synaptosome-
associated proteins: SNAP25, syntaxin, and others).
• This interaction results in docking of the vesicle to the terminal membrane
and, with influx of calcium, fusion of the membranes of the vesicles with the
nerve-ending membranes, the opening of a pore to the extracellular space,
and the release of the stored transmitter.
• The several types of botulinum toxins enzymatically alter synaptobrevin or
one of the other docking or fusion proteins to prevent the release process.
• Termination of action of acetylcholine—The action
of acetylcholine in the synapse is normally
terminated by metabolism to acetate and choline
by the enzyme acetylcholinesterase in the synaptic
cleft.
• The products are not excreted but are recycled in
the body.
• Inhibition of acetylcholinesterase is an important
therapeutic (and potentially toxic) effect of several
drugs.
• Drug effects on synthesis, storage, release, and
termination of action of acetylcholine—
• Drugs that block the synthesis of acetylcholine (eg,
hemicholinium), its storage (eg, vesamicol), or its release
(eg, botulinum toxin) are not very useful for systemic
therapy because their effects are not sufficiently
selective (ie, PANS and SANS ganglia and somatic
neuromuscular junctions all may be blocked).

• However, because botulinum toxin is a very large

molecule and diffuses very slowly, it can be used by
injection for relatively selective local effects.
 Adrenergic Transmission
• Synthesis and storage—The synthesis of dopamine and
norepinephrine requires several steps.
• After transport across the cell membrane, tyrosine is
hydroxylated by tyrosine hydroxylase (the rate-limiting
step) to DOPA (dihydroxyphenylalanine), decarboxylated to
dopamine, and (inside the vesicle) hydroxylated to
norepinephrine.
• Tyrosinehydroxylase can be inhibited by metyrosine.
• Norepinephrine and dopamine are transported into
vesicles by the vesicular monoamine transporter (VMAT)
and are stored there.
Release and termination of action—
• Dopamine and norepinephrine are released from their nerve endings
by the same calcium-dependent mechanism responsible for
acetylcholine release (see prior discussion).
• Termination of action, however, is quite different. Metabolism is not
responsible for termination of action of the catecholamine
transmitters, norepinephrine and dopamine.
• Rather, diffusion and reuptake (especially uptake-1, by the
norepinephrine transporter, NET, or the dopamine transporter, DAT)
reduce their concentration in the synaptic cleft and stop their action.
• Outside the cleft, these transmitters can be metabolized—by MAO
and catechol-O-methyltransferase (COMT)—and the products of
these enzymatic reactions are excreted.
• Determination of the 24-h excretion of metanephrine,
normetanephrine, 3-methoxy-4-hydroxymandelic acid (VMA), and
other metabolites provides a measure of the total body production
of catecholamines,.
• useful in diagnosing conditions such as pheochromocytoma
• Drug effects on adrenergic transmission—Drugs
that.
• block norepinephrine synthesis (eg, metyrosine) or
catecholamine storage (eg, reserpine) or release
(eg, uanethidine) were used in treatment of several
diseases (eg, hypertension)
• Because they block sympathetic but not
parasympathetic functions.
• Other drugs promote catecholamine release (eg,
the amphetamine-like agents) and predictably
cause sympathomimetic effects.
 Co-transmitters
• Almost all autonomic nerves have transmitter vesicles that
contain other transmitter molecules in addition to the
primary agents (acetylcholine or norepinephrine) previously
described.
• These cotransmitters may be localized in the same vesicles
as the primary transmitter or in a separate population of
vesicles.
• Substances recognized to date as cotransmitters include ATP
(adenosine triphosphate), enkephalins, vasoactive
intestinal peptide, neuropeptide Y, substance P,
neurotensin, somatostatin, and others.
• Their main role in autonomic function appears to involve
modulation of synaptic transmission.
• They also function as primary transmitters in other synapses.
 RECEPTOR CHARACTERISTICS
• Cholinoceptors

• Adrenoceptors
Muscarinic receptors and major actions
 SITES OF AUTONOMIC DRUG ACTION
• Because of the number of steps in the transmission of
autonomic commands from the CNS to the effector
cells, there are many sites at which autonomic drugs
may act.
• These sites include the CNS centers; the ganglia; the
postganglionic nerve terminals; the effector cell
receptors; and the mechanisms responsible for
transmitter synthesis, storage, release, and termination
of action.
• The most selective effect is achieved by drugs acting at
receptors that mediate very selective actions
Integration of ANS and Hormonal
mechanism in CVS control
THANKS