Autonomic Nervous System

Anatomy The autonomic nervous

system (ANS) is a division of the peripheral
nervous system that influences the function
ofinternal organs.[1] The autonomic nervous
system is a control system that acts largely
unconsciously and regulates bodily functions
such as the heart rate, digestion, respiratory
rate, pupillary response, urination, and sexual
arousal. This system is the primary mechanism
in control of the fight-or-flight response and the
freeze-and-dissociate response.
Within the brain, the autonomic nervous system is
regulated by the hypothalamus. Autonomic functions
include control of respiration, cardiac regulation (the
cardiac control center), vasomotor activity
(the vasomotor center), and certainreflex
actions such
as coughing, sneezing, swallowing and vomiting.
Those are then subdivided into other areas and are
also linked to ANS subsystems and nervous
systems external to the brain.
The autonomic nervous system (ANS) is a very
complex, multifaceted neural network that maintains
internal physiologic homeostasis. This network
includes cardiovascular, thermoregulatory,
gastrointestinal (GI), genitourinary (GU), and
ophthalmologic (pupillary) systems (see the
following image). Given the complex nature of this
system, a stepwise approach to autonomic disorders
is required for proper understanding.

Gross Anatomy
Central integration
The central autonomic network is a complex network
in the central nervous system (CNS) that integrates
and regulates autonomic function. The network
involves the cerebral cortex (the insular and medial
prefrontal regions), amygdala, stria terminalis,
hypothalamus, and brainstem centers
(periaqueductal gray, parabrachial pons, nucleus of
the tractus solitarius, and intermediate reticular zone
of the medulla).[1]

Afferent pathways
The afferent pathways have receptors residing in the
viscera and are sensitive to mechanical, chemical,
or thermal stimuli. They conduct along somatic and
autonomic nerves and enter the spinal cord through
the dorsal roots or the brainstem through cranial
nerves. Impulses initiate local, segmental, or rostral
reflexes.

Efferent pathways
The autonomic nervous system (ANS) consists of the sympathetic and parasympathetic nervous system. The sympathetic
nervous system (SNS) descends to the intermediolateral and intermediomedial cells in the thoracolumbar regions of the
spine, extending from TI to L2. Preganglionic axons exiting the spinal cord enter the white rami communicantes to join a
network of prevertebral and paravertebral ganglia. These preganglionic axons are relatively short, myelinated, and
cholinergic. Postganglionic axons exit the ganglia through the gray rami communicantes and extend with the peripheral
nerves and blood vessels to innervate their end organs. These postganglionic axons are long, unmyelinated, and primarily
adrenergic, except for the innervation of the sweat glands, which are cholinergic.

Adrenergic receptors are (1) alpha, which cause peripheral vasoconstriction; (2) beta 1, which increase heart rate and
contractility; or (3) beta 2, which cause relaxation of smooth muscle located in the peripheral vasculature, bronchi,
gastrointestinal (GI) tract, and genitourinary (GU) organs. The parasympathetic nervous system (PNS) exits the central
nervous system primarily with cranial nerves III, VII, IX, and X, as well as the sacral spinal roots. Preganglionic axons are
generally myelinated and have long peripheral projections before synapsing with postganglionic neurons in ganglia that are
located close to the end organs; preganglionic axons are also cholinergic. The postganglionic axons are short and
cholinergic; cholinergic receptors are also known as muscarinic receptors because of the pharmacology that defines them. [2]
Nerve fibers contributing to the superior hypogastric plexus and the hypogastric nerves are currently considered to comprise
an adrenergic part of the autonomic nervous system located between vertebrae T1 and L2, with cholinergic aspects
originating from sacral spinal segments S2-4. The illustrates the nature of the superior hypogastric plexus, which gives a
better understanding of the urinary and sexual dysfunctions after surgical injuries. [3]

Causes of ANS dysfunction

The etiology of autonomic dysfunction can be primary or idiopathic and secondary causes. Autonomic failure is seen in
multiple system atrophy, pure or progressive autonomic failure, Parkinson and other neurodegenerative diseases, metabolic
diseases such as Wernicke and cobalamin deficiency, diabetes mellitus, hyperlipidemia, trauma, vascular diseases,
neoplastic diseases, and multiple sclerosis. In addition, autonomic dysfunction is associated with various medications.
In addition to diabetes, autonomic dysfunction is associated with other neuropathies, including Guillain-Barr
syndrome, Lyme disease, human immunodeficiency virus (HIV) infection, leprosy, acute idiopathic
dysautonomia,amyloidosis, porphyria, uremia, and alcoholism. Besides nerve localization in the peripheral nervous system,
it occurs in diseases of the presynaptic neuromuscular junction such as botulism and myasthenic syndrome.
In addition to the acquired causes, inherited disorders like hereditary sensory-autonomic neuropathy (HSAN), familial
amyloid polyneuropathy (FAP), Tangier disease, and Fabry disease also exist.

Clinical presentation
Clinically, postural lightheadedness, dry mouth, dry eyes, impotence, loss of sweating or hyperthermia, nocturnal diarrhea,
gastroparesis, impaired accommodation, urinary or bowel incontinence, and small fiber neuropathy are some of the
presenting symptoms. Most peripheral neuropathies affect all fiber sizes. Few peripheral neuropathies are associated with
pure or predominantly small fiber involvement. A large proportion is associated with diabetes. Painful burning feet is caused
by a sensory neuropathy with small fiber involvement in more than 90% of cases. Patients with pure small fiber involvement
display normal large fiber function. Muscle bulk, strength, muscle stretch reflexes, and large fiber sensory function (ie,
vibration, proprioception) are normal.

Myelinated vs unmyelinated small fibers

Small fibers are both myelinated and unmyelinated. Small myelinated fibers transmit preganglionic autonomic efferents (B
fibers) and somatic afferents (A delta fibers). Unmyelinated (C) fibers transmit postganglionic autonomic efferents as well as
somatic and autonomic afferents. Both A delta and C fibers are widely distributed in skin and deep tissues.
The neurotransmitter for preganglionic sympathetic and parasympathetic nervous system (PNS) as well as postganglionic
parasympathetic nervous system is acetylcholine (ACh). The neurotransmitter for the postganglionic sympathetic nervous
system (innervating sweat glands) is also acetylcholine, whereas that for the remaining postganglionic sympathetic nervous
system is norepinephrine (NE).

Electromyography
Electromyography (EMG) plays a key role in the evaluation of most peripheral neuropathies and helps in assessing only
large myelinated fibers. Thus, pure small fiber neuropathies may be associated with normal findings on routine
electrophysiologic studies. Elderly patients who lack sural sensory responses can still be diagnosed with small fiber
neuropathy. Patients with symptoms other than neuropathic ones certainly need autonomic function testing for appropriate
diagnosis.

Regulation of Autonomic Nervous System Activity

The efferent nervous activity of the ANS is largely regulated by autonomic reflexes. In many of these
reflexes, sensory information is transmitted to homeostatic control centers, in particular, those located in the
hypothalamus and brainstem. Much of the sensory input from the thoracic and abdominal viscera is
transmitted to the brainstem by afferent fibers of cranial nerve X, the vagus nerve. Other cranial nerves also
contribute sensory input to the hypothalamus and the brainstem. This input is integrated and a response is
carried out by the transmission of nerve signals that modify the activity of preganglionic autonomic neurons.
Many important variables in the body are monitored and regulated in the hypothalamus and the brainstem
including heart rate, blood pressure, gastrointestinal peristalsis and glandular secretion, body temperature,

hunger, thirst, plasma volume, and plasma osmolarity. An example of this type of autonomic reflex is the
baroreceptor reflex. Baroreceptors located in some of the major systemic arteries are sensory receptors that
monitor blood pressure. If blood pressure decreases, the number of sensory impulses transmitted from the
baroreceptors to the vasomotor center in the brainstem also decreases. As a result of this change in
baroreceptor stimulation and sensory input to the brainstem, ANS activity to the heart and blood vessels is
adjusted to increase heart rate and vascular resistance so that blood pressure increases to its normal value.
These neural control centers in the hypothalamus and the brainstem may also be influenced by higher
brain areas. Specifically, the cerebral cortex and the limbic system influence ANS activities associated
with emotional responses by way of hypothalamic-brainstem pathways. For example, blushing during an
embarrassing moment, a response most likely originating in the frontal association cortex, involves
vasodilation of blood vessels to the face. Other emotional responses influenced by these higher brain
areas include fainting, breaking out in a cold sweat, and a racing heart rate.
Some autonomic reflexes may be processed at the level of the spinal cord. These include the micturition
reflex (urination) and the defecation reflex. Although these reflexes are subject to influence from higher
nervous centers, they may occur without input from the brain.
Efferent Pathways of the Autonomic Nervous System

The efferent pathways of the ANS consist of 2 neurons that transmit impulses from the CNS to
the effector tissue. The preganglionic neuron originates in the CNS with its cell body in the
lateral horn of the gray matter of the spinal cord or in the brainstem. The axon of this
neuron travels to an autonomic ganglion located outside the CNS, where it synapses with
a postganglionic neuron. This neuron innervates the effector tissue.
Divisions of the Autonomic Nervous System

The ANS is composed of 2 anatomically and functionally distinct divisions, the sympathetic system and
the parasympathetic system. Both systems are tonically active. In other words, they provide
some degree of nervous input to a given tissue at all times. Therefore, the frequency of
discharge of neurons in both systems can either increase or decrease.
As a result, tissue activity may be either enhanced or inhibited. This characteristic of the ANS improves its
ability to more precisely regulate a tissue's function. Without tonic activity, nervous input to a tissue could
only increase. Several distinguishing features of these 2 divisions of the ANS are summarized in Table

Each system is dominant under certain conditions. The sympathetic system predominates during emergency
fight-or-flight reactions and during exercise. The overall effect of the sympathetic system under these
conditions is to prepare the body for strenuous physical activity. More specifically, sympathetic nervous
activity will increase the flow of blood that is well-oxygenated and rich in nutrients to the tissues that need
it, in particular, the working skeletal muscles. The parasympathetic system predominates during quiet,
resting conditions. The overall effect of the parasympathetic system under these conditions is to conserve
and store energy and to regulate basic body functions such as digestion and urination.
Sympathetic Division

The preganglionic neurons of the sympathetic system arise from the thoracic and lumbar
regions of the spinal cord (segments T1 through L2). Most of these preganglionic axons are
short and synapse with postganglionic neurons within ganglia found in the sympathetic
ganglion chains. These ganglion chains, which run parallel immediately along either side
of the spinal cord, each consist of 22 ganglia.
The preganglionic neuron may exit the spinal cord and synapse with a postganglionic neuron in a ganglion
at the same spinal cord level from which it arises. The preganglionic neuron may also travel more rostrally
or caudally (upward or downward) in the ganglion chain to synapse with postganglionic neurons in ganglia
at other levels. In fact, a single preganglionic neuron may synapse with several

postganglionic neurons in many different ganglia. Overall, the ratio of preganglionic

fibers to postganglionic fibers is about 1:20. The long postganglionic neurons originating
in the ganglion chain then travel outward and terminate on the effector tissues.
This divergence of the preganglionic neuron results in coordinated sympathetic
stimulation to tissues throughout the body. The concurrent stimulation of many organs
and tissues in the body is referred to as a mass sympathetic discharge.
Other preganglionic neurons exit the spinal cord and pass through the ganglion chain without synapsing with
a postganglionic neuron. Instead, the axons of these neurons travel more peripherally and synapse with
postganglionic neurons in one of the sympathetic collateral ganglia. These ganglia are located about halfway
between the CNS and the effector tissue.
Finally, the preganglionic neuron may travel to the adrenal medulla and synapse directly

with this glandular tissue. The cells of the adrenal medulla have the same embryonic
origin as neural tissue and, in fact, function as modified postganglionic neurons. Instead
of the release of neurotransmitter directly at the synapse with an effector tissue, the
secretory products of the adrenal medulla are picked up by the blood and travel
throughout the body to all of the effector tissues of the sympathetic system.
An important feature of this system, which is quite distinct from the parasympathetic
system, is that the postganglionic neurons of the sympathetic system travel within each of
the 31 pairs of spinal nerves. Interestingly, 8% of the fibers that constitute a spinal nerve
are sympathetic fibers. This allows for the distribution of sympathetic nerve fibers to the
effectors of the skin including blood vessels and sweat glands. In fact, most innervated
blood vessels in the entire body, primarily arterioles and veins, receive only sympathetic
nerve fibers. Therefore, vascular smooth muscle tone and sweating are regulated by the
sympathetic system only. In addition, the sympathetic system innervates structures of the
head (eye, salivary glands, mucus membranes of the nasal cavity), thoracic viscera (heart,

lungs) and viscera of the abdominal and pelvic cavities (eg, stomach, intestines, pancreas,
spleen, adrenal medulla, urinary bladder).
Parasympathetic Division

The preganglionic neurons of the parasympathetic system arise from several nuclei of the brainstem and
from the sacral region of the spinal cord (segments S2-S4). The axons of the preganglionic neurons are quite
long compared to those of the sympathetic system and synapse with postganglionic neurons within terminal
ganglia which are close to or embedded within the effector tissues. The axons of the postganglionic neurons,
which are very short, then provide input to the cells of that effector tissue.
The preganglionic neurons that arise from the brainstem exit the CNS through the cranial nerves. The
occulomotor nerve (III) innervates the eyes; the facial nerve (VII) innervates the lacrimal gland, the salivary
glands and the mucus membranes of the nasal cavity; the glossopharyngeal nerve (IX) innervates the parotid
(salivary) gland; and the vagus nerve (X) innervates the viscera of the thorax and the abdomen (eg, heart,
lungs, stomach, pancreas, small intestine, upper half of the large intestine, and liver). The physiological
significance of this nerve in terms of the influence of the parasympathetic system is clearly illustrated by its
widespread distribution and the fact that 75% of all parasympathetic fibers are in the vagus nerve. The
preganglionic neurons that arise from the sacral region of the spinal cord exit the CNS and join together to
form the pelvic nerves. These nerves innervate the viscera of the pelvic cavity (eg, lower half of the large
intestine and organs of the renal and reproductive systems).
Because the terminal ganglia are located within the innervated tissue, there is typically little divergence in
the parasympathetic system compared to the sympathetic system. In many organs, there is a 1:1 ratio of
preganglionic fibers to postganglionic fibers. Therefore, the effects of the parasympathetic system tend to be
more discrete and localized, with only specific tissues being stimulated at any given moment, compared to
the sympathetic system where a more diffuse discharge is possible.
Neurotransmitters of the Autonomic Nervous System

The 2 most common neurotransmitters released by neurons of the ANS are acetylcholine and
norepinephrine. Neurotransmitters are synthesized in the axon varicosities and stored in vesicles for
subsequent release. Several distinguishing features of these neurotransmitters are summarized in Table
Table2.2. Nerve fibers that release acetylcholine are referred to as cholinergic fibers. These include all
preganglionic fibers of the ANS, both sympathetic and parasympathetic systems; all postganglionic fibers of
the parasympathetic system; and sympathetic postganglionic fibers innervating sweat glands. Nerve fibers
that release norepinephrine are referred to as adrenergic fibers. Most sympathetic postganglionic fibers
release norepinephrine.

As previously mentioned, the cells of the adrenal medulla are considered modified sympathetic
postganglionic neurons. Instead of a neurotransmitter, these cells release hormones into the blood.
Approximately 20% of the hormonal output of the adrenal medulla is norepinephrine. The remaining 80% is
epinephrine. Unlike true postganglionic neurons in the sympathetic system, the adrenal medulla contains an
enzyme that methylates norepinephrine to form epinephrine. The synthesis of epinephrine, also known as
adrenaline, is enhanced under conditions of stress. These 2 hormones released by the adrenal medulla are
collectively referred to as the catecholamines.
Termination of Neurotransmitter Activity

For any substance to serve effectively as a neurotransmitter, it must be rapidly inactivated or removed from
the synapse or, in this case, the neuroeffector junction. This is necessary in order to allow new signals to get
through and influence effector tissue function.
The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase
hydrolyzes acetylcholine to its component choline and acetate. It is one of the fastest acting enzymes in the
body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for the removal
of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the
sympathetic nerve that released it. Norepinephrine may then be metabolized intraneuronally by monoamine
oxidase (MAO). The circulating catecholamines, epinephrine and norepinephrine, are inactivated by
catechol-O-methyltransferase (COMT) in the liver.
Receptors for Autonomic Neurotransmitters

As discussed in the previous section, all of the effects of the ANS in tissues and organs throughout the body,
including smooth muscle contraction or relaxation, alteration of myocardial activity, and increased or
decreased glandular secretion, are carried out by only 3 substances, acetylcholine, norepinephrine, and
epinephrine. Furthermore, each of these substances may stimulate activity in some tissues and inhibit
activity in others. How can this wide variety of effects on many different tissues be carried out by so few
neurotransmitters or hormones? The effect caused by any of these substances is determined by the receptor
distribution in a particular tissue and the biochemical properties of the cells in that tissue, specifically, the
second messenger and enzyme systems present within the cell.
The neurotransmitters of the ANS and the circulating catecholamines bind to specific receptors on the cell
membranes of the effector tissue. All adrenergic receptors and muscarinic receptors are coupled to G

proteins which are also embedded within the plasma membrane. Receptor stimulation causes activation of
the G protein and the formation of an intracellular chemical, the second messenger. (The neurotransmitter
molecule, which cannot enter the cell itself, is the first messenger.) The function of the intracellular second
messenger molecules is to elicit tissue-specific biochemical events within the cell which alter the cell's
activity. In this way, a given neurotransmitter may stimulate the same type of receptor on 2 different types of
tissue and cause 2 different responses due to the presence of different biochemical pathways within each
tissue.
Acetylcholine binds to 2 types of cholinergic receptors. Nicotinic receptors are found on the cell bodies of
all postganglionic neurons, both sympathetic and parasympathetic, in the ganglia of the ANS. Acetylcholine
released from the preganglionic neurons binds to these nicotinic receptors and causes a rapid increase in the
cellular permeability to Na+ ions and Ca++ ions. The resulting influx of these 2 cations causes depolarization
and excitation of the postganglionic neurons the ANS pathways.
Muscarinic receptors are found on the cell membranes of the effector tissues and are linked to G proteins
and second messenger systems which carry out the intracellular effects. Acetylcholine released from all
parasympathetic postganglionic neurons and some sympathetic postganglionic neurons traveling to sweat
glands binds to these receptors. Muscarinic receptors may be either inhibitory or excitatory, depending on
the tissue upon which they are found. For example, muscarinic receptor stimulation in the myocardium is
inhibitory and decreases heart rate while stimulation of these receptors in the lungs is excitatory, causing
contraction of airway smooth muscle and bronchoconstriction.
There are 2 classes of adrenergic receptors for norepinephrine and epinephrine, alpha () and beta ().
Furthermore, there are at least 2 subtypes of receptors in each class: 1, 2, 1 and 2. All of these receptors
are linked to G proteins and second messenger systems which carry out the intracellular effects.
Alpha receptors are the more abundant of the adrenergic receptors. Of the 2 subtypes, 1 receptors are more
widely distributed on the effector tissues. Alpha one receptor stimulation leads to an increase in intracellular
calcium. As a result, these receptors tend to be excitatory. For example, stimulation of 1 receptors causes
contraction of vascular smooth muscle resulting in vasoconstriction and increased glandular secretion by
way of exocytosis.
Pharmacy Application: Alpha One Adrenergic Receptor Antagonists.
Hypertension, or a chronic elevation in blood pressure, is a major risk factor for coronary artery disease,
congestive heart failure, stroke, kidney failure, and retinopathy. An important cause of hypertension is
excessive vascular smooth muscle tone or vasoconstriction. Prazosin, an 1-adrenergic receptor antagonist, is
very effective in the management of hypertension. Because 1-receptor stimulation causes vasoconstriction,
drugs that block these receptors result in vasodilation and a decrease in blood pressure.
Compared to 1 receptors, 2 receptors have only moderate distribution on the effector tissues. Alpha 2
receptor stimulation causes a decrease in cAMP and, therefore, inhibitory effects such as smooth muscle
relaxation and decreased glandular secretion. However, 2 receptors have important presynaptic effects.
Where 1 receptors are found on the effector tissue cells at the neuroeffector junction, the 2 receptors are
found on the varicosities of the postganglionic neuron. Norepinephrine released from this neuron binds to
not only the 1 receptors on the effector tissue to cause some physiological effect; it also binds to the
2 receptors on the neuron itself. Alpha 2 receptor stimulation results in presynaptic inhibition or in a
decrease in the release of norepinephrine. In this way, norepinephrine inhibits its own release from the
sympathetic postganglionic neuron and controls its own activity. Both 1 and 2 receptors have equal affinity

for norepinephrine released directly from sympathetic neurons as well as circulating epinephrine released
from the adrenal medulla.
Stimulation of each type of receptor leads to an increase in intracellular cAMP. Whether this results in an
excitatory or an inhibitory response depends upon the specific cell type. As with receptors, receptors are
also unevenly distributed with 2 receptors, the more common subtype on the effector tissues. Beta 2
receptors tend to be inhibitory. For example, 2 receptor stimulation causes relaxation of vascular smooth
muscle and airway smooth muscle resulting in vasodilation and bronchodilation, respectively. Beta 2
receptors have a significantly greater affinity for epinephrine than for norepinephrine. Furthermore,
terminations of sympathetic pathways are not found near these receptors. Therefore, 2 receptors are
stimulated only indirectly by circulating epinephrine instead of by direct sympathetic nervous activity.
Beta 1 receptors are the primary adrenergic receptor on the heart (a small percentage of the adrenergic
receptors on the myocardium are 2). Both subtypes of receptors on the heart are excitatory and stimulation
leads to an increase in cardiac activity. Beta 1 receptors are also found on certain cells in the kidney.
Epinephrine and norepinephrine have equal affinity for 1 receptors.
Beta three (3) receptors are found primarily in adipose tissue. Stimulation of these receptors, which have a
stronger affinity for norepinephrine, causes lipolysis.
Pharmacy Application: Sympathomimetic Drugs.
Sympathomimetic drugs are those that produce effects in a tissue resembling those caused from stimulation
by the sympathetic nervous system. An important use for these drugs is in the treatment of bronchial asthma
which is characterized by bronchospasm. As discussed, bronchodilation occurs following 2-adrenergic
receptor stimulation. Non-selective receptor agonists, such as epinephrine and isoproterenol, are capable of
causing bronchodilation. However, a potential problem with these drugs is that they stimulate all -receptors
including 1 receptors on the heart. Therefore, in patients with bronchospasm, an undesirable side effect of
treatment with these non-selective agents is an increase in heart rate. Instead, 2-selective drugs, such as
albuterol, are chosen for this therapy. They are equally effective in causing bronchodilation with a much
lower risk of adverse cardiovascular effects.
Functions of the Autonomic Nervous System

The 2 divisions of the ANS are dominant under different conditions. As stated previously, the sympathetic
system is activated during emergency fight-or-flight reactions and during exercise. The parasympathetic
system is predominant during quiet conditions (rest and digest). As such, the physiological effects caused
by each system are quite predictable. In other words, all of the changes in organ and tissue function induced
by the sympathetic system work together to support strenuous physical activity and the changes induced by
the parasympathetic system are appropriate for when the body is resting.
The fight-or-flight reaction elicited by the sympathetic system is essentially a whole body response.
Changes in organ and tissue function throughout the body are coordinated so that there is an increase in the
delivery of well-oxygenated, nutrient-rich blood to the working skeletal muscles. Both heart rate and
myocardial contractility are increased so that the heart pumps more blood per minute. Sympathetic
stimulation of vascular smooth muscle causes widespread vasoconstriction, particularly in the organs of the
gastrointestinal system and in the kidneys. This vasoconstriction serves to redirect or redistribute the blood
away from these metabolically inactive tissues and toward the contracting muscles. Bronchodilation in the
lungs facilitates the movement of air in and out of the lungs so that the uptake of oxygen from the
atmosphere and the elimination of carbon dioxide from the body are maximized. An enhanced rate of

glycogenolysis (breakdown of glycogen into its component glucose molecules) and gluconeogenesis
(formation of new glucose from noncarbohydrate sources) in the liver increases the concentration of glucose
molecules in the blood. This is necessary for the brain as glucose is the only nutrient molecule that it can
utilize to form metabolic energy. An enhanced rate of lipolysis in adipose tissue increases the concentration
of fatty acid molecules in the blood. Skeletal muscles then utilize these fatty acids to form metabolic energy
for contraction. Generalized sweating elicited by the sympathetic system enables the individual to
thermoregulate during these conditions of increased physical activity and heat production. Finally, the eye is
adjusted such that the pupil dilates letting more light in toward the retina (mydriasis) and the lens adapts for
distance vision.
The parasympathetic system decreases heart rate which helps to conserve energy under resting conditions.
Salivary secretion is enhanced to facilitate the swallowing of food. Gastric motility and secretion are
stimulated to begin the processing of ingested food. Intestinal motility and secretion are also stimulated to
continue the processing and to facilitate the absorption of these nutrients. Both exocrine and endocrine
secretion from the pancreas is promoted. Enzymes released from the exocrine glands of the pancreas
contribute to the chemical breakdown of the food in the intestine and insulin released from the pancreatic
islets promotes the storage of nutrient molecules within the tissues once they are absorbed into the body.
Another bodily maintenance type of function caused by the parasympathetic system is contraction of the
urinary bladder which results in urination. Finally, the eye is adjusted such that the pupil contracts (miosis)
and the lens adapts for near vision.
Pharmacy application: cholinomimetic drugs.
Cholinomimetic drugs are those that produce effects in a tissue resembling those caused from stimulation by
the parasympathetic nervous system. These drugs have many important uses including the treatment of
gastrointestinal and urinary tract disorders that involve depressed smooth muscle activity without
obstruction. For example, postoperative ileus is characterized by a loss of tone or paralysis of the stomach or
bowel following surgical manipulation. Urinary retention may also occur postoperatively or it may be
secondary to spinal cord injury or disease (neurogenic bladder). Normally, parasympathetic stimulation of
the smooth muscle in each of these organ systems causes contraction to maintain gastrointestinal motility as
well as urination. There are 2 different approaches in the pharmacotherapy of these disorders. One type of
agent would be a muscarinic receptor agonist which would mimic the effect of the parasympathetic
neurotransmitter, acetylcholine, and stimulate smooth muscle contraction. One of the more commonly used
agents in this category is bethanechol which can be given subcutaneously. Another approach is to increase
the concentration and, therefore, activity of endogenously produced acetylcholine in the neuroeffector
junction. Administration of an acetylcholinesterase inhibitor prevents the degradation and removal of
neuronally-released acetylcholine. In this case, neostigmine is the most widely used agent. Neostigmine may
be given intramuscularly, subcutaneously, or orally.
Pharmacy application: muscarinic receptor antagonists.
Inspection of the retina during an ophthalmoscopic examination is greatly facilitated by mydriasis, or the
dilation of the pupil. Parasympathetic stimulation of the circular muscle layer in the iris causes contraction
and a decrease in the diameter of the pupil. Administration of a muscarinic receptor antagonist, such as
atropine or scopolamine, prevents this smooth muscle contraction. As a result, sympathetic stimulation of
the radial muscle layer is unopposed. This causes an increase in the diameter of the pupil. These agents are
given in the form of eye drops which act locally and limit the possibility of systemic side effects.
Adrenal Medulla

A mass sympathetic discharge, which typically occurs during the fight-or-flight response and during
exercise, involves the simultaneous stimulation of organs and tissues throughout the body. Included among
these tissues are the adrenal medullae which release epinephrine and norepinephrine into the blood. In large
part, the indirect effects of these catecholamines are similar to and, therefore, reinforce those of direct
sympathetic stimulation. However, there are some important differences in the effects of the circulating
catecholamines and those of norepinephrine released from sympathetic nerves.
The duration of activity of the catecholamines is significantly longer than that of neuronally released
norepinephrine. Therefore, the effects on the tissues are more prolonged. This difference has to do with the
mechanism of inactivation of these substances. Norepinephrine is immediately removed from the
neuroeffector synapse by way of reuptake into the postganglionic neuron. This rapid removal limits the
duration of the effect of this neurotransmitter. In contrast, there are no enzymes in the blood to degrade the
catecholamines. Instead, the catecholamines are inactivated by COMT in the liver. As one might expect, the
hepatic clearance of these hormones from the blood would require several passes through the circulation.
Therefore, the catecholamines are available to cause their effects for a comparatively longer period of time
(up to 1-2 minutes as opposed to milliseconds).
Because they travel in the blood, organs and tissues throughout the body are exposed to the catecholamines.
Therefore, they are capable of stimulating tissues that are not directly innervated by sympathetic nerve
fibers: airway smooth muscle, hepatocytes, and adipose tissue, in particular. As a result, the catecholamines
have a much wider breadth of activity compared to norepinephrine released from sympathetic nerves.
The third important feature that distinguishes the catecholamines from neuronally released norepinephrine
involves epinephrine's affinity for 2 receptors. Norepinephrine has a very limited affinity for these
receptors. Therefore, circulating epinephrine causes effects that differ from those of direct sympathetic
innervation including a greater stimulatory effect on the heart and relaxation of smooth muscle (vascular,
bronchial, gastrointestinal, and genitourinary).
Epinephrine and norepinephrine have equal affinity for 1 receptors, the predominant adrenergic receptor on
the heart. However, the human heart also contains a small percentage of 2 receptors which, like 1 receptors
are excitatory. Therefore, epinephrine is capable of stimulating a greater number of receptors and of causing
a greater stimulatory effect on the myocardium.
Beta two adrenergic receptors are also found on smooth muscle in several organ systems. These receptors
tend to be inhibitory and cause relaxation of the smooth muscle. Vascular smooth muscle in skeletal muscle
contains both 1 and 2 receptors. Norepinephrine, which stimulates only the excitatory 1 receptors, causes
strong vasoconstriction. However, epinephrine, which stimulates both types of receptors, causes only weak
vasoconstriction. The vasodilation resulting from 2 receptor stimulation opposes and, therefore, weakens
the vasoconstriction resulting from 1 receptor stimulation. Given that skeletal muscle may account for 40%
of an adult's body weight, the potential difference in vasoconstriction, blood pressure, and the distribution of
blood flow could be quite significant.
Another noteworthy example of the relaxation of smooth muscle by way of 2 receptor stimulation involves
the airways. Bronchodilation, or the opening of the airways, facilitates airflow in the lungs. Any direct
sympathetic innervation to the lungs is irrelevant in this respect, as only circulating epinephrine is capable of
stimulating these receptors on airway smooth muscle.