Introduction to Autonomic Nervous System

What is the autonomic (involuntary, visceral) nervous

system?
This is the system that regulates functions which are
not under voluntary control, including:
• Cardiac muscle contractions (force "inotropy" and rate
"chronotropy").
• Smooth muscle contractions (visera, blood vessels,
respiratory tree).
• Exocrine gland secretions.
• Metabolism, body temperature and fluid/electrolyte
balance.
Divisions of the autonomic nervous system:
The autonomic nervous system is divided anatomically
into sympathetic and parasympathetic divisions. The
sympathetic nerve fibres originate from the thoracolumbar
regions (thoracic segments 1, 4, 5, 11, 12 and lumbar
segments 1, 3) while the parasympathetic nerve fibres
originate from the craniosacral regions of the CNS (cranial
nerve nuclei III, VII, IX, X and sacral segments 2, 3, 4).
Sympathetic nervous system is responsible for
accommodation to stressful conditions while
parasympathetic nervous system is responsible for
maintaining normal physiology. The two systems are known
to be physiological antagonists.
 Autonomic nerve fibres:
The efferent nerve fibres of the autonomic nervous
system, unlike somatic nerves, do not travel directly from
the CNS to the effector organ but rather travel as two
nerves separated by a synapse. The nerve fibre originating
from the CNS is called the preganglionic one while the next
one is the postganglionic.
In the sympathetic nervous system, the preganglionic
fibres are short and their synapses rely in the vertebral and
paravertebral ganglia. In the parasympathetic nervous
system, however, the synapses rely inside the effector
organ followed by a short postsynaptic fibre.
ympathetic and parasympathetic nerve fibres
Chemical transmission of the autonomic nervous system:
Neurotransmission in the autonomic nervous
system involves the following steps:
1) Biosynthesis of the transmitter. Acetylcholine is
synthesized from choline and acetyl-CoA by the
action of choline acetyl transferase enzyme.
Noradrenaline is synthesized from the amino acid
tryptophan as illustrated in the figure.
2) Storage in storage vesicles in the nerve ending.
3) Release from nerve ending after nerve depolarization (electric
transmission).
4) Action of the transmitter on the specific receptor in the effector organ or
gland.
5) Termination of action by reuptake or metabolism of the transmitter.
Acetylcholine is metabolized by the action of
acetylcholinesterase enzyme into choline and acetic acid.
Noradrenaline and adrenaline are metabolized by the action of
monoamine oxidase (MAO) and catechol-O- methyltransferase
(COMT) enzymes.
 Synthesis of
adrenaline and
noradrenaline
 Types of preganglionic and postganglionic
fibres:

Nerve fibres are named according to the neurotransmitter they

release. Nerves that release acetylcholine as the transmitter are called
cholinergic nerves while nerves that release noradrenaline are called
adrenergic nerves. The following is the main classification of nerve fibres:
• All somatic nerves are cholinergic.
• All preganglionic nerve fibres are cholinergic.
• All parasympathetic postganglionic fibres are cholinergic.
• Most sympathetic postganglionic fibres are adrenergic.
• Few sympathetic postganglionic fibres are cholinergic (supplying sweat
glands and piloerector muscles).
Types of autonomic receptors:
Acetylcholine acts on two main types of receptors:
• Nicotinic receptors that are found in the autonomic ganglia
(N1) as well as neuromuscular junction of skeletal muscles
(N2).

• Muscarinic receptors that are found in cardiac muscles,

smooth muscles and exocrine glands (M1 for secretions,
respiratory tract and CNS, M2 in the heart, M3 in bronchi
and blood vessels, M4 that regulates dynamics of
muscarinic receptors and M5 in the CNS).

• Noradrenaline and adrenaline act on five receptors, namely

α1, α2, β1, β2 and β3 receptors. These are listed below in
detail.
 Sympathetic Nervous System

• Sympathetic nervous system is activated all at once to prepare the

body to face dangers (fear, fright and flight).

• Actions of sympathetic nervous system stimulation can be

summarized as follows:
i) On CVS:
1-Blood vessels of skin and splanchic area are constricted
(α1-mediated), while those of skeletal muscles and
coronaries are dilated (β2- mediated).
2-Heart: Positive inotropic effect (increased force of
contraction), poitive chronotropic effect (increased heart
rate), increased cardiac output, cardiac muscle work
and oxygen consumption and altered rhythmic functions
of the heart leading to extrasystole (decreases the
refractory period).
3-Blood pressure: Increased rennin release (β1) from the
kidney increases blood pressure by activation of rennin-
angiotensin system.
ii) On Respiratory tract:
• β2-stimulation: bronchodilatation.
• α1-stimulation: pulmonary decongestion.

iii) On the eye:

Active mydriasis (by α1-stimulation of radial muscles), accomodation
of eye to far vision and increased production of aqueous humor (β2-
mediated, while α1-stimulation increases outflow).
• iv) On the spleen:
Increases the production of erythrocyte-rich blood in circulation (α1-
stimulation).
• v) On GIT:
Contraction of sphinctor muscles (α1), relaxation of wall muscles (α1 and
β2) and inhibition of movement (α1 and β2) and secretions (α2) of stomach
and intestine.
vi) On the urinary bladder:
Contraction of sphinctor and trigone (α1-mediated) and relaxation of
wall (β2-mediated)  urine retention.
vii) Exocrine glands:
Reduction of all body secretions, thick viscid salivary secretions (α2).
Sweating is the only secretion that is increased (Ach).

viii) On CNS:
Stimulation of CNS takes place. α2 stimulation decreases central
sympathetic outflow.
 ix) Metabolic effects:

β2-mediated increase in glcogenolysis in liver and skeletal muscles

 hyperglycaemia. α2 stimualtion decreases insulin secretion while β2
stimulation increases insulin secretion. β3-mediated ↑ in lipolysis  ↑
level of plasma free fatty acids. `
x) On the uterus:
Relaxation of uterus muscles and decreased uterine movement
(β2).
xi) Sympathetic nerve endings:
Presynaptic inhibition of noradrenaline release from nerve endings
(α2).
 Drugs affecting sympathetic nervous
system:
A) Sympathomimetics:

These are drugs that produce effects similar to those produced by

endogenous sympathetic stimulation. These include:
a) Direct acting sympathomimetics that act directly on sympathetic
receptors including:
* Adrenaline "epinephrine" (non-selective α and β agonist).
* Noradrenaline "norepinephrine" (non-selective α agonist).
* Phenylephrine (α1 agonist).
* Isoprenaline (non-selective β agonist).
* Dobutamine (β1 agonist).
* Salbutamol and terbutaline (β2 agonists).
b) Indirect acting sympathomimetics that act indirectly by stimulating
the release of neurotransmitters from adrenergic nerve endings. These
include tyramine and amphetamine.
c) Mixed action sympathomimetics that act both directly and indirectly. These
include ephedrine.
d) Inhibitors of transmitter metabolism, like monoamine oxidase inhibitors
(MAOI's), e.g. tranylcypromine.
B) Sympatholytics:

These are agents that depress sympathetic activity by one of the

following mechanisms:
a) Interference with the synthesis of neurotransmitters, e.g.
methyldopa.
b) Inhibition of the release of neurotransmitters, or adrenergic
neuron blockers, e.g. guanethidine.
c) Depletion of storage of the transmitter, e.g. reserpine.
d) Ganglionic blockers, that block both sympathetic and
parasympathetic nerves, e.g. hexamethonium.
e) Alpha-2 receptor (α2) agonists that inhibit central sympathetic
outflow, e.g. clonidine.
f) Adrenergic receptor blockers, including:
* Prazosin (reversible selective α1 blocker).
* Yohimbine (selective α2 blocker).
* Phentolamine (reversible non-selective α blocker).
* Phenoxybenzamine (irreversible non- selective α blocker).
* Atenolol (selective β1 blocker).
* Butoxamine (selective β2 blocker).
* Propranolol (non-selective β blocker).
 Selected sympathomimetics:
• Adrenaline:
Adrenaline gives all the actions of sympathetic stimulation but it is not
effective orally as it is inactivated by digestive enzymes and gastqic juice.
Additionally, it is metabolized in the liver as well as metabolizing enzymes in
the gut (MAO and COMT). Additionally, exogenous adrenaline has no CNS
stimulant effect at normal doses as it does not pass the blood brain barrier.
Adrenaline is administered by local or subcutaneous administration for the
following purposes:
* Decongestant and hemostatic for nasal congestion or bleeding.
* With local anaesthetics to increase the action and decrease toxicity.
* Bronchodilator for bronchial asthma.
* Cardiac arrest in hospitalized patients.
* For anaphylactic shock with an antihistaminic and a glucocorticoid.
 However, adrenaline use is associated with adverse effects like
hypertension, angina attacks, arrhythmia, constipation, urine
retention, hyperglycemia and dry mouth.
Isoprenaline:

This is a non-selective β agonist that increases heart rate, dilates

coronaries and skeletal muscle blood vessels, dilates bronchi and
increases glycogenolysis and lipolysis. It is used for the management
of bronchial asthma and heart block.
Dopamine:

It is an agonist on β1 receptors (so useful in cardiogenic shock),

α receptors (decreases blood flow to non-essential vascular bed) and
dopamine D1 receptors (vasodilation to blood vessels of coronaries,
mesentry and kidney so increases blood flow to vital organs).
Dobutamine:

It is a selective agonist on β1 receptors used to treat cardiogenic

shock. It causes less reflex tachycardia compared to non-selective
beta agonists.
Phenylephrine:

This is a selective α1 agonist that lacks catecholamine nucleus. It

is used as vasoconstrictor to decrease nasal congestion and
symptoms of common cold. It can also be used as mydriatic.
However, hypertension is a common side effect.
Methoxamine:
• It is similar to phenylephrine. It is used to treat hypotensive patients.

Xylometazoline and oxymetazoline:

• These agents are non-catecholamine alpha-agonists used mainly as
nasal decongestants. Prolonged use may cause atrophy of nasal mucosa and
loss of smell sensation.
Salbutamol and terbutaline:

These are selective agents on β2 receptors used as

bronchodilators to treat bronchial asthma. Additionally, these agents
can be used to prevent premature labor through decreasing uterine
contractions.
Ritodrine:

• It is a uterine relaxant through stimulation of β2 receptors. It is

used mainly to protect against premature labor.

Clonidine:
• This is a selective α2 agonist used to treat essential hypertension
by inhibition of central sympathetic outflow.
Amphetamine:

• An indirect sympathomimetic with marked CNS stimulant effect

and has the following uses:
• * Anorexigenic (appetite suppressant).
• * Treatment of narcolepsy.
• * In nocturnal enuresis.
• * Hyperactive children.
• * Mental and physical fatigue and depression.
Methamphetamine:
• It is very similar to amphetamine but with higher central to peripheral
effects.

Tyramine:
• An indirect sympathomimetic present in certain foods like old cheese
and causes severe hypertension when combined with MAOI's (cheese
reaction).
Ephedrine:

• A sympathomimetic that acts both directly and indirectly. This is

not a catecholamine and so it is a poor substrate to COMT and MAO
resulting in a long duration of action. It is used as a bronchodilator
and decongestant in addition to treatment of narcolepsy and
nocturnal enuresis.
Cocaine:

• It is a sympathomimetic agent with a local anaesthetic activity. It

causes euphoria, alertness, hypertension and addiction.
Selected sympatholytics:
Prazosin:
• A selective α1-blocker used for the treatment of
hypertension and peripheral vascular diseases (Raynauld's
disease). It is used also to treat phaeochromocytoma (a
tumor of adrenal medulla accompanied by increased levels
of adrenaline and noradrenaline, severe hypertension,
angina attacks and arrhythmia). It decreases pupillary
dilatation and adrenergic sweating. Alpha blockers decrease
smooth muscle contractions in enlarged prostate and
bladder base, so help in managing urine retention. Adverse
effects include reflex tachycardia, postural hypotension,
nasal congestion and inhibition of ejaculation.
 Propranolol:
• As with other beta blockers, it is well absorbed after oral administration. It is
a non-selective beta-blocker that has the following actions:

i) On the heart: Attenuates cardiac response to sympathetic stimulation, causing

negative chronotropy, negative inotropy and decreased cardiac output.
Therefore, it decreases cardiac work and myocardial oxygen consumption. It
prolongs the AV-nodal refractory period and has an antiarrhythmic and
quinidine-like action.
ii) On blood pressure: It reduces blood pressure by
four mechanisms. a) initially the fall in blood
pressure is due to the decrease in cardiac output.
After some time, the cardiac output returns to
normal, but the blood pressure remains low; b)
inhibition of renin-release by an action on β1-
receptors in the juxtaglomerular apparatus; c) CNS
effect, by a decrease in the central sympathetic
outflow; d) presynaptic β inhibition decreases NE
release.
• iii) On the respiratory system: It causes bronchospasm specially in
asthmatic patients.
• iv) On the eye: It decreases intraocular pressure without an effect on
accomodation or miosis.
v) On Metabolism: It causes inhibition of
glycogenolysis and impairs recovery from
hypoglycaemia caused by insulin. It also masks the
warning signs of hypoglycaemia caused by
adrenaline release. For these reasons, it should be
used with caution in diabetic patients. Inhibition of
lipolysis leads to increased level of plasma
triglycerides and LDL, so it should be used with
caution in atherosclerosis.
It is used for the following purposes:
1-Hypertension, specially if accompanied with high renin activity.
2-Angina pectoris and myocardial infarction.
3-Cardiac arrhythmia.
4-Symptomatic control of adrenergic signs of thyrotoxicosis.
5-Glucoma, by decreasing aqueous humor formation and increasing
outflow.
6-Migraine.
7-Antianxiety (central sedative).
Its side effects include:
• 1-Fatigue, cold extremities, intermittent claudication.
• 2-Heart failure, heart block if combined with Ca2+-channel blockers.
• 3-Bronchospasm, specially in asthmatics.
• 4-Bradycardia and hypotension.
• 5-Hypoglycemia and hypertriglyceridaemia.
• 6-Sudden withdrawal causes exacerbations of anginal attacks due to
receptor up- regulation during treatment.
Parasympathetic Nervous System

Parasympathetic nervous system is the physiological antagonist of

sympathetic nervous system. This system works on separate organs and
tissues towards normal physiology.
 Actions of parasympathetic nervous system stimulation can be
summarized as follows:
i) On CVS: Negative chronotropic and inotropic effects as well as
increased refractory period. Vasodilation of arteries and veins is
mediated by nitric oxide (NO) release.
• ii) On the eye: Contraction of circular muscles (miosis, ↓ intraocular
pressure) and conraction of ciliary muscles (accomodation to near vision).
• iii) On GIT: Increased motility and secretions and relaxation of sphinctors.
• iv) On urinary bladder: Relaxation of sphinctor and trigone and
contraction of detrusor and wall muscles.
• v) On the respiratory tract:
Bronchospasm and increased secretions.
• vi) On secretions:
Increases salivary, lacrimal, nasopharyngeal and sweat secretions.
There are five types of muscarinic receptors, namely M1, M2, M3, M4
and M5. All of these receptors are blocked by atropine. M1 receptors
(responsible for vagally-induced gastric acid secretion) are blocked by
pirenzepine. M2 receptors are blocked by gallamine.
Drugs affecting parasympathetic
nervous system:
A) Parasympathomimetics:
•These are drugs that produce effects similar
to those produced by endogenous
parasympathetic stimulation.
a) Direct acting parasympathomimetics that act directly on parasympathetic
receptors including choline esters (acetylcholine, methacholine,
bethanechol and carbachol) and cholinomimetic alkaloids (muscarinic
agonists like pilocarpine and muscarine, and nicotinic agonists like nicotine
and lobeline).
b) Indirect-acting parasympathomimetics including anticholinesterases
that inhibit acetylcholine degradation thus increase its effect. These
may be reversible (including alcohols like edrophonium as well as
carbamates like neostigmine, pyridostigmine and physostigmine) or
irreversible (organophosphate insecticides that are toxic).
Selected parasympathomimetics:
Physostigmine:
This is an indirect acting parasympathomimetic agent that
increases the action of acetylcholine on both nicotinic and
muscarinic receptors by inactivating cholinesterase enzyme
responsible for conversion of acetylcholine into choline and acetic
acid.
This leads to the following effects:
i) On CNS: Central stimulation of cholinergic receptors
causes tremors, anxiety and restlessness.
ii) On skeletal muscles: It stimulates nicotinic receptors
at the neuromuscular junction (NMJ). This prolongs the
end plate potential and strengthen the muscle. The
effect is clear when transmission is greatly decreased
as in Myasthenia gravis (MG), or during recovery from
neuromuscular blockers.
iii) On the CVS, eye, GIT, urinary bladder, respiratory
tract and secretions: As mentioned before under
effects of parasympathetic nervous system.
This drug is used for the following purposes:
a) Myotonic to enhance neuromuscular transmission in severe
muscle atony as in MG and after recovery from neuromuscular
blockers after surgery; b) In severe paralytic constipation; c) in
poisoning with antimuscarinics, e.g. atropine.
Adverse effects include:

• 1- Excessive secretions of saliva and nasopharyngeal secretions and

hyperhydrosis.
• 2- Diarrhea, activation of peptic ulcer and abdominal cramps.
• 3- Miosis.
• 4- Bronchospasm.
• 5- Hypotension.
• 6- Trmors, anxiety and restlessness.
 General clinical uses of
cholinomimetics:
1-Treating glaucoma by increasing outflow of aqueous
humor. This can be performed by direct-acting agents
(pilocarpine, methacholine and carbachol) and indirect-
acting agents (physostigmine and echothiophate).
2-Gastrointestinal disorders related to paralysis without
obstruction, e.g. post-operative paralytic ileus (paralysis
of stomach or bowel following surgery). Drugs of choice
include choline esters (bethanechol) and
anticholinesterases (neostigmine).
3-Decreased tone of lower esophageal sphincter associated with reflux
esophagitis.
4-Urinary tract disorders, for example urinary retention due to surgical operations,
labor or spinal injury (bethanechol and neostigmine).
5-Myasthenia graevis (an auto-immune disease associated with decreased number
of nicotinic receptors due to destruction by auto-antibodies).
6-Treatment of supra-ventricular tachycardia (e.g. edrophonium).
7-Treatment of anti-muscarinic drug intoxication, e.g. toxicity of atropine.
Selected parasympatholytics:

• Atropine:
This is a blocker of muscarinic receptors. It reverses the actions
of acetylcholine on muscarinic receptors. This leads to tachycardia,
dry mouth, blurred vision, mydriasis, constipation and urine
retention (these effects are called together atropine-like side effects
when produced by other antimuscarinics).
 Atropine is used for the following
purposes:
• A pre-anaesthetic medication (bronchodilator,
decreases bronchial and salivary secretions and
protects the heart from excessive vagal
stimulation).
• Antispasmodic for renal and intestinal colic.
• Peptic ulcer.
• Nocturnal enuresis.
• Bronchial asthma.
• Antidote for anticholinesterase poisoning.
Atropine substitutes:

These are antimuscarinic agents used specifically for the

treatment of certain conditions that require blocking of muscarinic
receptors, including:
• Ipratropium for bronchial asthma.
• Benzatropine for parkinsonism.
• Pirenzepine for peptic ulcer.
• Hyoscine-N-butyl bromide for colic.
• Cyclopentolate as mydriatic.