Download The autonomic nervous system (ANS)

INTRODUCTION TO AUTONOMIC
NERVOUS SYSTEM
Peripheral NS: nerve fibers that carry information between CNS and other
parts of the body
Peripheral
nervous system
(PNS)Afferent (sensory)
Efferent (motor)
nervous system
From CNS to effector
organs
Autonomic
nervous
system
sympathetic
Somatic
efferent
system
parasympathetic
nerves
To CNS from
external
environment and
internal organs
The autonomic nervous system (ANS):



ANS: the involuntary branch of the peripheral efferent
division
not under direct conscious control- involuntary;
concerned primarily with visceral functions—cardiac
output, blood flow, digestion, etc—that are necessary
for life
Somatic division is :


largely nonautonomic
concerned with consciously controlled functions such
as movement, respiration, and posture.
ANATOMY OF THE ANS


Divided into the sympathetic (thoracolumbar)
division and the parasympathetic
(craniosacral) division
Both divisions originate in nuclei* within the
central nervous system (CNS) and give rise to
preganglionic efferent fibers that exit from the
brain stem or spinal cord and terminate in
motor ganglia.
*Nucleus: demarcated mass of cell bodies in the brain
The enteric nervous system (ENS)


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ENS: is a large and highly organized collection
of neurons located in the walls of the GIT
It is sometimes considered a 3rd division of the
ANS
Includes: the myenteric plexus (MP) and the
submucous plexus (SMP)
NEUROTRANSMITTER CHEMISTRY OF THE
ANS

Peripheral fibers that synthesize and release
Ach (acetylcholine) are termed cholinergic
fibers, ie, they act by releasing ACh. These
include:
1.
all preganglionic efferent autonomic fibers
somatic (nonautonomic) motor fibers to skeletal muscle
all parasympathetic postganglionic (some NO/ peptides)
a few sympathetic postganglionic fibers (e.g. sweat
glands and some blood vessels in the skeletal muscles)
Some neurons in the CNS
2.
3.
4.
5.
NEUROTRANSMITTER CHEMISTRY OF THE
ANS
Adrenergic neurons:

Most sympathetic postganglionic terminals
Adrenal medulla
Some neurons in the CNS

What is co-transmission?


Key features of neurotransmitter function that
represent potential targets of pharmacologic
therapy:
1.
2.
3.
4.
5.
Synthesis
Storage
Release
Activation of receptors
Termination of action of the transmitter
Cholinergic Transmission

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The terminals of cholinergic neurons contain
large numbers of vesicles that contain Ach in
high concentration and other molecules (eg,
peptides) (cotransmitters);
Ach is synthesized in the cytoplasm from
acetyl-CoA and choline through the action of
choline acetyltransferase (ChAT);
Acetyl-CoA is synthesized in mitochondria
botulinum toxin type a
<chemical> A neurotoxin produced by clostridium botulinum. When
consumed in contaminated food it can cause paralysis and death. In its
purified form, it has been used in the treatment of blepharospasm and
strabismus.
Pharmacological action: neuromuscular agents.
Adrenergic Transmission
The synthesis of the adrenergic transmitters is more
complex than that of acetylcholine.
 In the adrenal medulla and certain areas of the brain,
NE is further converted to epinephrine.
 Several important processes in the noradrenergic
nerve terminal are potential sites of drug action.
1. The conversion of tyrosine to dopa, is the rate-limiting
step in NE synthesis,

Adrenergic Transmission
How does indirect sympathomimetics (tyramine
and amphetamines) act?
1.
2.
They are taken up into noradrenergic nerve
endings by uptake 1 → may displace NE
from storage vesicles,
inhibit monoamine oxidase (MAO) → ↑ NE
activity in the synapse.
Adrenergic Transmission
1.
2.
3.
4.
Processes that terminate NE action:
Metabolism by MAO and COMT
simple diffusion away from the receptor site
(with eventual metabolism in the plasma or
liver)
reuptake into the nerve terminal (uptake 1)
or into perisynaptic glia or smooth muscle
cells (uptake 2)
Metabolism of
catecholamines
Brain Massage:

1.
2.
3.
4.
5.
What is the mechanism of action of the
following?
Botulinum toxins
Cocaine
Tricyclic antidepressants
Amphetamines
Tyramine
Tyramine-rich Foods
Red plums, figs,
raisins, avocados,
green bean pods,
pcikeled hearrings,
druy sausages,
canned meat, yogurt,
soup cubes,
commercial gravies,
chocolate and soy
sauce
AUTONOMIC RECEPTORS

The primary Ach receptor subtypes were
named after the alkaloids originally used in
their identification: muscarine and nicotine

The term cholinoceptor denotes receptors
(both muscarinic and nicotinic) that respond to
acetylcholine

The term adrenoceptor is used to describe
receptors that respond to catecholamines such
as NE.
Autonomic receptor types with documented or probable effects on
peripheral autonomic effector tissues.
Typical Locations
Receptor
Name
Result of Ligand Binding
Cholinoceptors
Muscarinic M1
CNS neurons, sympathetic
postganglionic neurons, some
presynaptic sites
Formation of IP3 and DAG,
increased intracellular
calcium
Muscarinic M2
Myocardium, smooth muscle,
some presynaptic sites
Opening of potassium
channels, inhibition of
adenylyl cyclase
Muscarinic M3
Exocrine glands, vessels
(smooth muscle and
endothelium)
Formation of IP3 and DAG,
increased intracellular
calcium
Nicotinic NN
Postganglionic neurons, some
presynaptic cholinergic
terminals
Opening of Na+, K+
channels, depolarization
Nicotinic NM
Skeletal muscle neuromuscular
endplates
Opening of Na+, K+
channels, depolarization
Adrenoceptors
Alpha1
Postsynaptic effector cells, especially
smooth muscle
Formation of IP3 and DAG,
increased intracellular
calcium
Alpha2
Presynaptic adrenergic nerve
terminals, platelets, lipocytes, smooth
muscle
Inhibition of adenylyl
cyclase, decreased cAMP
Beta1
•
Postsynaptic effector cells, especially
heart, lipocytes, brain,
• presynaptic adrenergic and
cholinergic nerve terminals
Stimulation of adenylyl
cyclase, increased cAMP
Beta2
Postsynaptic effector cells, especially
smooth muscle and cardiac muscle
Stimulation of adenylyl
cyclase and increased
cAMP
Beta3
Postsynaptic effector cells, especially
lipocytes
Stimulation of adenylyl
cyclase and increased
cAMP
Dopamine receptors
D1 (DA1), D5
Brain; effector tissues, especially
smooth muscle of the renal
vascular bed
Stimulation of
adenylyl cyclase and
increased cAMP
D2 (DA2)
Brain; effector tissues especially
smooth muscle; presynaptic nerve
terminals
Inhibition of adenylyl
cyclase; increased
potassium
conductance
D3
Brain
Inhibition of adenylyl
cyclase
D4
Brain, cardiovascular system
Inhibition of adenylyl
cyclase
Dopamine selectivity is dose-dependent
Dopamine Dosing
 1-5 mcg/kg/min IV (low dose): May increase urine output
and renal blood flow
 5-15 mcg/kg/min IV (medium dose): May increase renal
blood flow, cardiac output, heart rate, and cardiac
contractility
 20-50 mcg/kg/min IV (high dose): May increase blood
pressure and stimulate vasoconstriction; may not have
a beneficial effect in blood pressure; may increase risk of
tachyarrhythmias
 May increase infusion by 1-4 mcg/kg/min at 10-30 min
intervals until optimum response obtained
 Titrate to desired response
NONADRENERGIC, NONCHOLINERGIC
NEURONS
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Such fibers may be both motor and sensory
(eg, in the gut, airways, bladder).
Peptides are the most common transmitters.
Other transmitters: NO, purines, serotonin,
cholecystokinin, enkephalins
The enteric system in the gut wall is the most
extensively studied.
The ENS contains nonadrenergic,
noncholinergic, in addition to cholinergic and
adrenergic fibers
FUNCTIONAL ORGANIZATION OF
AUTONOMIC ACTIVITY
FUNCTIONAL ORGANIZATION OF
AUTONOMIC ACTIVITY
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parasympathetic system is trophotropic
(leading to growth) used to “rest and digest”
(eg, slowing of the heart and stimulation of
digestive activity)
sympathetic system is ergotropic (leading to
energy expenditure) that is activated for "fight
or flight." (eg, cardiac stimulation, ↑ blood
sugar, and cutaneous vasoconstriction)
FUNCTIONAL ORGANIZATION OF
AUTONOMIC ACTIVITY

cooperative interactions between the
parasympathetic and sympathetic systems:

eg, the sensory carotid sinus baroreceptor
fibers in the glossopharyngeal nerve (the ninth
cranial nerve) have a major influence on
sympathetic outflow from the vasomotor center
Direct effects of autonomic nerve activity on some organ systems.
Effect of
Organ
Sympathetic Activity
Parasymp. Activity
Action1
Action
Receptor
Eye
Iris
Radial muscle
Circular muscle
Ciliary muscle
Contracts
...
[Relaxes]
α1
Heart
Sinoatrial node
Ectopic pacemakers
Contractility
Accelerates
Accelerates
Increases
Contracts
Relaxes
[Contracts]
Relaxes
Blood vessels
Skin, splanchnic
vessels
Skeletal muscle vessels
Endothelium
Receptor
...
Contracts
Contracts
...
M3
M3
β1,β2
β1,β2
β1,β2
Decelerates
...
Decreases
(atria)
M2
α
β2
α
M3
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...
β
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Releases EDRF
...
M2
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.
M34
Effect of
Organ
Bronchiolar smooth
muscle
Gastrointestinal tract
Smooth muscle
Walls
Sphincters
Secretion
Myenteric plexus
Genitourinary smooth
muscle
Bladder wall
Sphincter
Uterus, pregnant
Penis, seminal vesicles
Sympathetic Activity
Parasymp. Activity
Action1
Action
Receptor
Receptor
Relaxes
β2
Contracts
M3
Relaxes
Contracts
...
α2,5 β2
α1
Contracts
Relaxes
Increases
Activates
M3
M3
M3
M1
Relaxes
Contracts
Relaxes
Contracts
β2
α1
β2
α
Contracts
Relaxes
...
Contracts
M3
M3
Ejaculation
α
Erection
...
...
M3
M
Effect of
Organ
Skin
Pilomotor smooth
muscle
Sweat glands
Thermoregulatory
Apocrine (stress)
Metabolic functions
Liver
Liver
Fat cells
Kidney
Autonomic nerve
endings
Sympathetic
Parasympathetic
NBVascular
Sympathetic Activity
Parasymp. Activity
Action1
Action
Receptor
Contracts
α
Increases
Increases
M
α
Gluconeogenesis
Glycogenolysis
Lipolysis
Renin release
β2,α
β2,α
β3
β1
...
...
Decreases ACh
release
α
Receptor
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Decreases
NE release
...
M6
...
smooth m. in skeletal m has sympathetic cholinergic dilator fibers.
The endothelium of most blood vessels releases EDRF which causes marked
vasodilation, in response to muscarinic stimuli. These muscarinic receptors are not
innervated and respond only to circulating muscarinic agonists.
Integration of Cardiovascular Function
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Changes in any variable contributing to MAP →
homeostatic responses to compensate for the
change.
Eg, NE is a powerful vasoconstrictor → ↑ peripheral
vascular resistance → ↑ mean arterial pressure.
In the absence of reflex control—in a patient who has
had a heart transplant—the drug's effect on the heart is
also stimulatory; ie, it ↑heart rate and contractile force.
Integration of Cardiovascular Function

In a subject with intact reflexes, the negative feedback
baroreceptor response to ↑ MAP → decreased
sympathetic outflow to the heart and ↑ in
parasympathetic (vagus nerve) discharge at the
cardiac pacemaker → the net effect of ordinary pressor
doses of NE is to produce a marked ↑ in peripheral
vascular resistance, a moderate ↑ in MAP, & ↓ HR
(heart rate) - the exact opposite of the drug's direct
action.
Presynaptic Regulation



α2 receptor located on noradrenergic nerve
terminals. This receptor is activated by NE
↓further release of NE from these nerve
endings
Conversely, a presynaptic β receptor appears
to facilitate the release of NE.
Presynaptic receptors that respond to the
transmitter substances released by the nerve
ending have been called autoreceptors.
Postsynaptic Regulation
1.
Up- and down-regulation occur in response to
↓ or ↑ activation, respectively, of the receptors.
(Eg, surgical denervation of skeletal muscle results in marked
proliferation of nicotinic cholinoceptors over all parts of the fiber)
Postsynaptic Regulation
2. Modulation of the primary transmitter-receptor event
by events evoked by the same or other transmitters
acting on different postsynaptic receptors.
PHARMACOLOGIC MODIFICATION OF
AUTONOMIC FUNCTION
Table 6-5: Not important
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Drugs that block action potential propagation (local
anesthetics) are very nonselective in their action,
Drugs that act on the biochemical processes involved
in transmitter synthesis and storage are more selective,
Activation or blockade of effector cell receptors offers
maximum flexibility and selectivity of effect.
Individual subgroups can often be selectively activated
or blocked within each major type.
Example: Pharmacology of the eye

The eye is a good example of an organ with
multiple ANS functions

Anterior chamber is the site of several tissues
controlled by ANS:
1.
3 muscles: pupillary dilator and constrictor, and ciliary
Secretory epithelium of the ciliary body
2.
Example: pharmacology of the eye

-
-
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Parasympathetic (muscarinic):
contraction of the circular muscles (miosis)
Contraction of ciliary muscle: (1)
accommodation (2) outflow of aqueous humour
Alpha-adrenopceptors  radial muscles 
(mydriasis)
Beta-adrenoceptors ciliary epithelium 
facilitate secretion of aqueous humour