PHAR270 Module 02 Section 03

Sympathetic Nervous System

Introduction:
The sympathetic nervous system is a second division of the autonomic nervous system,
alongside the parasympathetic nervous system. Although both activation and inactivation are
important in terms of regulating the autonomic nervous system, in response to a perceived
threat the body specifically activates the sympathetic nervous system and prepares for fight or
flight.

General stimulation of the sympathetic nervous system results in the mobilization of resources
to prepare the body to meet emergencies. The mass sympathetic discharge results in increased
activity of many functions of the body, including increases in heart rate, blood pressure, blood
supply to the tissues, rate of cell metabolism, and blood glucose. The sum of these effects
permits the body to perform physical tasks that otherwise would not be possible.

Organization of the Sympathetic Nervous System:

The neurons of the sympathetic nervous system originate from the thoracic and lumbar regions
of the spinal cord. These two sections constitute the middle portions of the spinal cord.

The sympathetic nervous system is organized in a slightly different manner than the
parasympathetic. The sympathetic nervous system has short preganglionic neurons that
release acetylcholine at the ganglia. The acetylcholine binds to and activates NN receptors at
the sympathetic ganglia, conducting the signal to the long postganglionic neurons of the
sympathetic nervous system. The sympathetic postganglionic neurons predominantly release
norepinephrine at the target organ, which binds to alpha (α) or beta (β) receptors. Exceptions
to this rule are the sympathetic postganglionic neurons that innervate sweat glands and renal
vascular smooth muscle, as they release acetylcholine (binds to M receptors) and dopamine
(binds to D receptors) respectively. Axons of the sympathetic nervous system are highly
branched, and therefore influence many organs. Some of these organs influenced by the
sympathetic nervous system are shown in the figure.

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The Adrenal Medulla:

You will now learn about the adrenal medulla and its role in the sympathetic nervous system.
The adrenal medulla is a specialized organ that essentially functions as a sympathetic
autonomic ganglion. You may recall from previous anatomy or physiology courses that the
adrenal medulla is the centre portion of the adrenal gland, surrounded by the adrenal cortex. It
is innervated by sympathetic preganglionic fibres.

When these sympathetic preganglionic fibres are activated, they release acetylcholine, which
binds to NN receptors on the adrenal medulla. Activation of these NN receptors results in the
release of predominantly epinephrine (also known as adrenaline; 80%), but also norepinephrine
(20%) from the adrenal medulla. The released epinephrine and norepinephrine travel through
the blood and interact with α and β receptors throughout the body, causing varying effects.
Since the neurotransmitters released by the adrenal medulla act via the circulation at distant
sites, they are considered to act like hormones. Stress can stimulate the adrenal medulla,
releasing epinephrine and norepinephrine, leading to a prolonged sympathetic effect.

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Question:

Which one of the following effects listed is mediated by increased activity of the sympathetic
nervous system?

a) Inhibition of the adrenal glands

b) Increased digestion
c) Increased heart rate
d) Constriction of the pupils

Answer: c

Video: Sympathetic Nervous System

Watch the video for an overview of the sympathetic nervous system. As you watch, focus on
the neurotransmitters that function within the sympathetic nervous system to elicit a response.

Sympathetic Neurotransmitters and Receptors:

As indicated previously, the neurotransmitter released by the sympathetic preganglionic
neurons is acetylcholine, which binds to the NN receptors on the ganglia. The neurotransmitter
at the postganglionic sympathetic nerve ending is predominantly norepinephrine, which can
bind to α or β receptors. These receptors have been designated adrenergic receptors and are
typical G-protein coupled receptors, as you learned in Module 01. Multiple subtypes of
adrenergic receptors exist, however, this lesson will focus on two main subtypes of each of
alpha and beta receptors.

1. Alpha (α) receptors can be sub-divided into α1 and α2.

a. α1 receptors are located post-synaptically, predominantly on smooth muscle (e.g.
blood vessels, gastrointestinal muscle, and uterus). Activation of α1 receptors
predominantly leads to contraction of the muscle. Multiple subtypes of α1
receptors exist. The different subtypes are organ selective and drugs can be
designed to target a specific subclass of α1 receptors, allowing for drug
selectivity.
b. α2 receptors are located post-synaptically on smooth muscle as well as pre-
synaptically on the neuronal membrane. Those receptors located pre-
synaptically are considered auto-receptors. The effects listed for activation of α1
receptors also apply to activation of α2 receptors that are located post-
synaptically. Activation of α2 autoreceptors, however, leads to a decrease in the

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release of norepinephrine from the presynaptic nerve, thereby decreasing

sympathetic activation. These receptors are only targeted in specific situations.
As such, the remainder of this lesson will focus on the clinical applications of
targeting α1 receptors.

2. Beta (β) receptors can be sub-divided into β1 and β2.

a. β1 receptors are found predominantly in the heart and gastrointestinal muscle,
and when activated, increase the force and rate of contraction of the heart, and
relax gastrointestinal smooth muscle.
b. β2 receptors are found in the lungs, blood vessels, gastrointestinal muscle, and
uterus. Activation of these receptors leads to muscle relaxation.

The location of the different receptors and their responses are summarized in the table:

Receptor Primary Locations Responses

Alpha1 • Predominantly on smooth • Contracts smooth muscle in

muscle (e.g. blood vessels, the vessels and uterus
gastrointestinal muscle, uterus) • Decreases motility and tone in
the gastrointestinal tract

Alpha2 • Post-synaptic membrane • Same as alpha 1 (post-

• Pre-synaptic neuronal synaptic)
membrane • Decreases the release of
norepinephrine from the
presynaptic neuron (pre-
synaptic)

Beta1 • Heart • Increases heart rate and force

• Gastrointestinal muscle of contraction
• Relaxes gastrointestinal
smooth muscle

Beta2 • Lungs, blood vessels, • Relaxes smooth muscle

gastrointestinal muscle, and
uterus

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Questions:

1. Which receptor corresponds to the primary locations listed?

a) Pre-synpatic neuronal membrane

b) Heart and gastrointestinal muscle
c) Lungs, blood vessels, gastrointestinal muscle, and uterus

2. Which receptor corresponds to the responses listed?

a) Relaxes smooth muscle

b) Contracts smooth muscle in the vessels and uterus and decreases motility and tone in
the gastrointestinal tract
c) Increases heart rate and force of contraction
d) Decreases the release of norepinephrine from the presynaptic neuron

Answers:

Question 1 Question 2

a) Alpha 2 Beta 2

b) Beta 1 Alpha 1

c) Beta 2 Beta 1

d) n/a Alpha 2

Recall: Norepinephrine
Recall that the sympathetic postganglionic neurons predominantly release norepinephrine at
the target organ. Norepinephrine binds to α1 or β receptors in the postsynaptic membrane to
exert its action. The activity of norepinephrine is terminated by reuptake back into the
presynaptic neuron followed by enzyme degradation within the neuron.

The activity of norepinephrine is terminated by reuptake back into the presynaptic neuron
followed by enzyme degradation within the neuron.

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PHAR270 Module 02 Section 03

Activation of the Sympathetic Nervous System

Drugs acting directly or indirectly on the sympathetic nervous system can mimic the actions of
norepinephrine, thereby appearing to increase the activity of the sympathetic nervous system.
Three mechanisms are indicated:

1. Direct stimulation: The drug binds directly to the receptor and produces an effect. An
example is epinephrine, which works by directly binding to alpha and beta receptors.

2. Indirect stimulation: The drug increases the release of norepinephrine from the
presynaptic neuron. Amphetamines act in this way.

3. Combination of the two: The drug binds directly to the receptor AND increases release
of norepinephrine. Drugs can stimulate one or both of alpha and beta receptors. An
example is the drug ephedrine which is used as a decongestant.

Did you Know? Many drugs that activate the sympathetic nervous system target more than
one receptor subtype.

Clinical Indications for Adrenergic Drugs

Clinically, drugs that activate processes normally controlled by the sympathetic nervous system
are primarily used for their effects on the heart, blood pressure, bronchial tree, and nasal
passages. These drugs produce similar effects to the anticholinergics, but due to the receptor

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subtypes (α1, β1, β2), the actions of these drugs are more specific and predictable depending on
which receptor subtype is activated. Some common clinical indications for adrenergic drugs
are:

• Anaphylaxis: Anaphylaxis is a severe immune reaction affecting both respiratory and

cardiovascular systems. Hypersensitivity to food, drug, or other substances (e.g. bee
stings) can trigger anaphylaxis, which results in severe bronchospasm and mucous
membrane congestion, among other symptoms. The treatment for these severe
allergic reactions is epinephrine (e.g. EpiPen), which causes bronchodilation and
constriction of blood vessels, relieving the symptoms. Epinephrine will also increase
heart rate and the force of contraction of the heart, thereby increasing blood
pressure if the person happens to go into shock.

• Cardiac applications: Adrenergic drugs, such as epinephrine, increase heart rate and
the force of contraction of the heart by activating β receptors. As such, these drugs
can be used for temporary emergency management of complete heart block or
cardiac arrest.

• Nasal congestion: α1 agonists constrict blood vessels and are therefore useful in the
treatment of nasal congestion. Phenylephrine and pseudoephedrine are examples
of α1 agonists that are used as nasal decongestants.

• Ophthalmic: When given in the eye, α1 agonists such as phenylephrine dilate the
pupil, facilitating retinal examination.

• Pulmonary: β2-selective drugs, such as salbutamol, produce bronchodilation, which

is an effective treatment for someone suffering from asthma. Both short-acting and
long-acting β2 agonists are available. These drugs can also be used to treat chronic
obstructive pulmonary disease (COPD).

Question:

Which one of the conditions listed is the correct clinical indication for a beta 2 receptor
agonist?

a) Congestive heart failure

b) Asthma
c) Nasal congestion
d) Benign prostatic hyperplasia

Answer: B

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Adrenergic drugs, like all drugs, can result in adverse effects. Adverse effects are often the
result of stimulation of receptors in another area of the body. Some of the more common
adverse effects are:

• CNS: headache, restlessness, mild tremors, nervousness, dizziness, excitement,

insomnia, euphoria.

• Cardiovascular: palpitations, tachycardia, vasoconstriction, hypertension.

• Other: anorexia, dry mouth, nausea, vomiting, muscle cramps.

Remember: Whenever giving a drug to a patient, keep in mind the characteristics of the
patient. Patients who are elderly or very young will react differently to drugs based on their
ability to biotransform and excrete drugs. In addition, information such as drug allergies and
other illnesses, such as hypertension, cardiac dyshrythmias, or angina pectoris may change the
therapeutic management of a patient.

Clinical Indications of Antiadrenergic Drugs

Antiadrenergic drugs are used clinically for a variety of different indications. Drugs that inhibit
the function of the sympathetic nervous system produce characteristics of “rest and relaxation”
and have a wide therapeutic application. The most widely prescribed drugs that target the
autonomic nervous system are those drugs that block the sympathetic nervous system, called
antiadrenergic drugs. Antiadrenergic drugs can specifically block either α or β receptors, or
they can block both classes of receptors. Some common indications for antiadrenergic drugs
are discussed:

• Pheochromocytoma: Pheochromocytoma is a tumour of the adrenal medulla, the

organ responsible for secreting epinephrine and norepinephrine in response to stress.
The tumour secretes epinephrine and norepinephrine without the stimulus of stress,
resulting in unwanted increases in sympathetic activity. Symptoms include
intermittent or sustained high blood pressure, headache, palpitations, and increased
sweating. Surgical resection of the tumour is the first-line treatment for
pheochromocytoma, however an anti-adrenergic is first given to block the sympathetic
receptors to prevent intra-operative hypertension.

• Benign prostatic hyperplasia (BPH): BPH is a non-cancerous growth of the prostate

gland that is common in older men. Symptoms include frequency, difficulty voiding,

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urgency, and voiding at night. Treatment includes α1 receptor antagonists, which work
by relaxing smooth muscle in the prostate and bladder, facilitating urination.

• Angina and congestive heart failure: Angina is chest pain due to poor oxygen supply to
the heart, while congestive heart failure is a condition where cardiac pumping is
impaired due to weakening or death of part of the heart muscle. Treatment for both
conditions can include selective β1 receptor antagonists. Blocking β1 receptors in the
heart reduces heart rate and the force of contraction of the heart, resulting in a
decrease in oxygen demand and blood pressure, thereby relieving the pain.

• Glaucoma: Recall from Section 01 that glaucoma is a disease of the eye, often
associated with increased intraocular pressure, which can damage the optic nerve and
lead to loss of vision. β-blocking drugs are also useful in the treatment of glaucoma.
Topical application of either non-selective or beta 1-selective beta blockers reduce the
production of the aqueous humor, which in turn reduces intraocular pressure.

• Neurological diseases: β-blockers are also useful in the treatment of a number of

neurological diseases. For example, β-blockers can reduce the frequency and intensity
of migraines, reduce tremors in Parkinson’s Disease, and reduce anxiety. They may
also benefit patients undergoing alcohol withdrawal.

Adverse effects also exist with the use of antiadrenergic drugs. For the purposes of this course,
you will earn about one common adverse effect of antiadrenergic drugs - orthostatic
hypotension. Orthostatic hypotension is the decrease in blood pressure that occurs when
moving from a laying or sitting position to a standing position. This is a common adverse effect,
as constriction of blood vessels is a normal process for maintaining blood pressure. With the
use of antiadrenergic drugs, the ability of blood vessels to constrict is impaired, as is the ability
of the heart to increase contractions, leading to decreased blood pressure.

Summary of Drugs that Target the ANS:

Since the transmission of messages in the synaptic junctions of the autonomic nervous system
is chemical in nature, these junctions can be targets for drug action. Many drugs modify these
systems, but they are often categorized into four general types:

1. Drugs that mimic the effects of the sympathetic system.

2. Drugs that block the effects of the sympathetic system.

3. Drugs that mimic the effects of the parasympathetic system.

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4. Drugs that block the effects of the parasympathetic system.

Because there is a balance between the parasympathetic and sympathetic nervous systems,
drugs that block the activity of one system can often "unmask" the activity of the other system.

Question:

You are provided with the mechanism of action for four drugs. Using the dropdown menu,
apply knowledge gained from this module to categorize the drugs according to the types of
drugs that target the ANS:

a) Epinephrine: activates alpha and beta receptors

b) Propranolol: blocks beta receptors in the heart
c) Methacholine: activates muscarinic receptors
d) Atropine: blocks muscarinic receptors

Answers:

a) Drugs that mimic the effects of the sympathetic system

b) Drugs that block the effects of the sympathetic system
c) Drugs that mimic the effects of the parasympathetic system
d) Drugs that block the effects of the parasympathetic system

Drugs Affecting the ANS through their Action on the Brain

The activity of the autonomic nervous system also can be modified by drugs acting on the brain.
Central stimulants (e.g. amphetamine) can increase sympathetic and parasympathetic activity
(excitation), and central depressants can decrease the activity of these two systems (inhibition).

End of Section Quiz

1. Which neurotransmitter and receptor are correctly matched?
a. Acetylcholine: alpha 1 receptors
b. Norepinephrine: beta 1 receptors
c. Dopamine: beta 2 receptors
d. Epinephrine: nicotinic receptors

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2. Which one of the statements regarding the sympathetic nervous system is correct?
a. Beta 1 receptors are predominantly found in the heart
b. The sympathetic nervous system has long preganglionic fibres
c. The adrenal medulla secretes epinephrine during relaxed states
d. Beta 2 receptors are found on pre-synaptic neuronal membranes

Answers:

1. B
2. A

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