1 PCTH 300-305 AUTONOMIC NERVOUS SYSTEM (ANS) Please note: This is an extensive set of notes for a first exposure to pharmacology. Not all handouts will be so voluminous. The intent is to make you read, and think about pharmacology. Memorizing so many drug names in Pharmacology is intimating and it is not possible to know them all, but it is best to know those in bold type. Brief overview of anatomy and function of the ANS: The peripheral nervous system is outside the Central Nervous System (brain and spinal cord). It consists of the autonomic nervous system (ANS) and the motor (somatic) nervous system. The ultimate control of both systems lies within the CNS in ‘command and control’ centres. However, while the ANS has considerable autonomy, CNS imperatives drive the motor (skeletal muscle) nervous system. Thus one consciously walks, talks, etc. as a result of central commands from the CNS but digestion, heart rate, etc. are not so directly controlled. The ANS serves to regulate the internal organs and function of the body, while the motor system serves skeletal muscle (locomotion) functions. Basic anatomy of the autonomic nervous system (ANS) Anatomically the peripheral ANS is comprised of three (3) anatomic and functional divisions: sympathetic, parasympathetic and enteric. The basic pattern for both sympathetic(S) and parasympathetic sections (PS) of the ANS consists of pre-ganglionic neurons arising from the CNS (where there are ANS centres) that travel to peripheral ganglia from where postganglionic nerves innervate target organs. The peripheral parasympathetic CNS outflows are to: o Cranial nerves (cranial nerves III, VII, IX and X) o Sacral nerves Parasympathetic ganglia usually lie close to, or within, the target organ Sympathetic nerves leave the CNS via thoracic and lumbar spinal roots to synapse at sympathetic ganglia which form two (2) paravertebral chains, plus some midline ganglia The enteric nerves arise from neurons in the intramural plexi of the gastrointestinal tract. This enteric system receives input from both sympathetic and parasympathetic nerves, but can act autonomously to control motor and secretion functions of the intestine. The following diagrams outline the peripheral ANS – both structure and function. The two major systems (PS and S), to a degree, act as counterparts to each other. Thus, parasympathetic nerve activity slows heart rate while sympathetic activity increases heart rate. However, such simplification cannot be taken too far. For example, via effects on heart and blood vessels sympathetic nerve activity increases blood pressure whereas parasympathetic nerve activity has little or no effect on blood pressure. An accelerator/brake analogy has been used for the roles of the PS and S, but it overly simplistic. Each and every organ in the body has different degrees of sympathetic and parasympathetic innervation. The pharmacology of the ANS mainly concerns drugs acting on efferent side of the ANS since few drugs influence ANS afferent activity going to the CNS, or the ANS centres within the CNS. For the greater part, most ANS drugs either mimic, accentuate, or block responses to efferent ANS activity.
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PCTH 300-305 AUTONOMIC NERVOUS SYSTEM (ANS)
Please note: This is an extensive set of notes for a first exposure to pharmacology. Not all handouts will be so voluminous.
The intent is to make you read, and think about pharmacology. Memorizing so many drug names in Pharmacology is
intimating and it is not possible to know them all, but it is best to know those in bold type.
Brief overview of anatomy and function of the ANS:
The peripheral nervous system is outside the Central Nervous System (brain and spinal cord). It consists
of the autonomic nervous system (ANS) and the motor (somatic) nervous system. The ultimate control
of both systems lies within the CNS in ‘command and control’ centres. However, while the ANS has
considerable autonomy, CNS imperatives drive the motor (skeletal muscle) nervous system. Thus one
consciously walks, talks, etc. as a result of central commands from the CNS but digestion, heart rate, etc.
are not so directly controlled. The ANS serves to regulate the internal organs and function of the body,
while the motor system serves skeletal muscle (locomotion) functions.
Basic anatomy of the autonomic nervous system (ANS)
Anatomically the peripheral ANS is comprised of three (3) anatomic and functional divisions:
sympathetic, parasympathetic and enteric.
The basic pattern for both sympathetic(S) and parasympathetic sections (PS) of the ANS consists
of pre-ganglionic neurons arising from the CNS (where there are ANS centres) that travel to
peripheral ganglia from where postganglionic nerves innervate target organs.
The peripheral parasympathetic CNS outflows are to:
o Cranial nerves (cranial nerves III, VII, IX and X)
o Sacral nerves
Parasympathetic ganglia usually lie close to, or within, the target organ
Sympathetic nerves leave the CNS via thoracic and lumbar spinal roots to synapse at
sympathetic ganglia which form two (2) paravertebral chains, plus some midline ganglia
The enteric nerves arise from neurons in the intramural plexi of the gastrointestinal tract. This
enteric system receives input from both sympathetic and parasympathetic nerves, but can act
autonomously to control motor and secretion functions of the intestine.
The following diagrams outline the peripheral ANS – both structure and function. The two major
systems (PS and S), to a degree, act as counterparts to each other. Thus, parasympathetic nerve activity
slows heart rate while sympathetic activity increases heart rate. However, such simplification cannot be
taken too far. For example, via effects on heart and blood vessels sympathetic nerve activity increases
blood pressure whereas parasympathetic nerve activity has little or no effect on blood pressure. An
accelerator/brake analogy has been used for the roles of the PS and S, but it overly simplistic. Each and
every organ in the body has different degrees of sympathetic and parasympathetic innervation.
The pharmacology of the ANS mainly concerns drugs acting on efferent side of the ANS since few
drugs influence ANS afferent activity going to the CNS, or the ANS centres within the CNS. For the
greater part, most ANS drugs either mimic, accentuate, or block responses to efferent ANS activity.
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The role of the ANS is to maintain homeostasis and ensure that internal organs respond to the
requirements of the body. The following Diagrams (1-3) indicate which organs are innervated by the
ANS. For convenience in Diagram 1 para-sympathetic activity is on the left and sympathetic on the
right.
Diagram 1 An incomplete overview of the ANS
Diagram 2 provides more detail including the location of ganglia for both parasympathetic (left) and
sympathetic (right) pathways and more information as to organ responses to PS and S nerve activity.
Note: parasympathetic ganglia are located close to, on, or in, the organ they innervate, whereas the
sympathetic ganglia are mainly located in close proximity to the spinal column and, most importantly
communicate with each other particularly via the paravertebral sympathetic chain that lies just outside
the spinal column, but within the thorax. This anatomical pattern allows for an overall coordinated
activation of the sympathetic system, as opposed to the directed and localized activation of single organs
by parasympathetic nerves.
Diagram 2 ANS – more detail
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To complete the boredom quotient Diagram 3 further amplifies the anatomical and functional
differences between the PS and S sections of the ANS but, this time, with the parasympathetic section
on the right. Diagram 3 better illustrates the peripheral wiring of the ANS and the central role of the
parasympathtic vagus nerve in controlling internal organs. Note: the role of the cranial nerves in eye,
lacrymal and salivary glands in the head, and the sacral nerves in the lower part of gastrointestinal and
urinary organs. This diagram exemplifies the ‘wiring’ differences in the the two sections inasmuch that
most PS ganglia lie on or within the organ they innervate. On the otherhand, the diagram also shows the
important paravertebral sympathetic ganglion chain which forms a network with few ‘external way
stations’ such as the coeliac and superior and inferior mesenteric ganglia. The left side diagrams in
insets illustrate how sympathetic nerves innervate blood vessels and skin. Sweating is an important
function of the sympathetic nervous system as well as control of body hair and skin blood vessels.
When we are hot we sweat, body hair stands upright and skin flushes - all driven by sympathetic
activation BUT, as seen later, sweating in particular involves post ganglionic cholinergic activity.
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ANS:- Neurotransmitter Molecules
Acetylcholine (Ach) is the principal transmitter molecule at ganglia and at post-ganglionic
parasympathetic nerve endings.
Norepinephrine NA or NE (noradrenaline) is the principal neurotransmitter at post ganglionic
sympathetic nerve endings.
There are a few special exceptions to the above:
sympathetic nerves to sweat glands release ACh
the adrenal medulla (which is a sympathetic ganglion) releases mainly epinephrine (adrenaline).
Cholinergic refers to sites at which acetylcholine is the primary neurotransmitter.
Adrenergic refers to sites at which norepinephrine is the primary neurotransmitter.
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Overall summary of the physiological function of the ANS
The autonomic nervous system controls: smooth muscle (visceral and vascular) activity;
exocrine (and some endocrine) secretions; rate and force of the heart; certain metabolic processes
(e.g. glucose utilization)
Sympathetic and parasympathetic systems sometimes have opposing actions in certain situations
(e.g. control of the heart rate, gastrointestinal smooth muscle); but not in others (e.g. salivary
Others have some relative selectivity for M3 (HHSD) and M2 (AF-DX116)
Mamba toxins (from snakes) for M1 and M4
As an example of ANS pharmacology consider the pharmacology of the Eye The eye is mainly controlled by parasympathetic nerves and cholinergic innervation: sympathetic nerves have a
minor role. Thus, muscarinic antagonists can have marked actions in the eye - dilate the pupil and prevent
accommodation. By interfering with drainage of the eye such drugs can “cause” or exacerbate glaucoma.
The extraocular skeletal muscle fibres that control movement of the eye are skeletal muscles but, very unusually,
have multiple skeletal motor nerve innervation on each muscle fibre.
Glaucoma (increased intraocular pressure that can destroy the eye’s function) is a mismatch of secretion of
ocular fluids, and their drainage. Drugs for glaucoma can increase drainage, or reduce formation of fluid.
Drugs and Glaucoma
Muscarinic antagonists can exacerbate glaucoma. Muscarinic agonists and anticholinesterases can alleviate,
glaucoma. Various other drugs can be useful in glaucoma, including beta blockers which appear to decrease
secretion, as well as prostaglandins.
Nicotinic Cholinergic Transmission
There are various types of nicotinic receptors in the periphery and the CNS. There are two main
families: nicotinic skeletal muscle and nicotinic ganglionic cholinoceptors (see Google for the
biochemical characteristics of nicotinic receptors, location, etc.) Nicotinic receptors (NAChR) are found on the:
Post junctional membranes of the skeletal neuromuscular endplate on a 1:1 relationship with
acetylcholinesterase enzyme.
Skeletal muscle spindle (afferent physiological receptor in skeletal muscle-extrafusal fibres).
At the ganglion of the sympathetic, parasympathetic and enteric ANS
Within CNS at various synaptic sites - both pre and post synaptic
Functionally there are at least two main peripheral types of nicotinic receptors (NAChR): skeletal muscle
and ganglionic (with at least two different CNS types).
NAChR is a ligand-gated ion channel where 2 molecules of the neurotransmitter ACh bind so as to open the
channel. NAChR receptors in skeletal muscle are generally "protected" from overstimulation with ACh by
adjacent AChE molecules. In the neuromuscular junction ACh released from the nerve generally only binds once
to a NAChR before it is hydrolyzed by acetylcholine into choline and acetate.
Structure of NAChR (Nicotinic receptor): Transmembrane spanning proteins (ligand-gated channel) are "gated"
by ACh to open to allow trans-membrane movement of ions - Na+ (Inwards) and K+ (Outwards) resulting in
depolarization of the post-synaptic end plate membrane.
Different subtypes of AChR nicotinic receptor are composed of alpha and beta components in various
proportions. In the skeletal muscle form of the nicotinic receptor 2 (two) ACh molecules have to bind to two
recognition sites in order to open the channel (co-operativity).
Ganglionic nicotinic receptors Agonists: ACh, CCh, nicotine (after which the receptor is named), lobeline and DMPP
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All "agonize" receptor but high and continuous occupancy desensitizes the receptor to the action of further ACh – this results in so-called desensitizing block. Nicotine first activates receptor, and then blocks it. This type of block also occurs in the
Therapeutic Uses: Nowadays rarely, if ever, used. For an understanding of the effects of nicotinic ganglionic blockade (and incidentally which aspects of the autonomic nervous system are functional important in normal life) see "hexamethonium man" as described by Paton . W. D. M. Paton, Pharm. Rev. 6, 59 (1954) Hexamethonium man: is a pink complexioned person, except when he has stood for a long time, when he may get pale and faint. His handshake is warm and dry. He is a placid and relaxed companion; for instance he may laugh, but he can’t cry because the tears cannot come. Your rudest story will not make him blush, and the most unpleasant circumstances will fail to make him pale. His socks and his shirt stay very clean and sweet. He wears corsets(!!) and may, if you meet him out, be rather fidgety (corsets to compress his splanchnic vascular pool, fidgety to keep the venous return going from his legs). He dislikes speaking much unless helped with something to moisten his dry mouth and throat. He is long-sighted and easily blinded by bright light. The redness of his eyeballs may suggest irregular habits and in fact his head is rather weak. But he always behaves as a gentlemen and never belches or hiccups. He tends to get cold, and keeps well wrapped up. But his health is good; he does not have chilblains and those diseases of modern civilization, hypertension and peptic ulcers, pass him by. He is thin because his appetite is modest; he never feels hunger pains and his stomach never rumbles. He gets rather constipated so his intake of liquid paraffin is high. As old age comes on he will suffer from retention of urine and impotence, but frequency, precipitancy, and strangury will not worry him. One is uncertain how he will end, but perhaps if he is not careful, by eating less and less and getting colder and colder, he will sink into a symptomless, hypoglycemic coma and die, as was proposed for the universe, a sort of entropy death.