Department of Anaesthesia

University of Cape Town

Autonomic Nervous System

The autonomic nervous system (ANS) regulates the unconscious, involuntary control of automatic
bodily functions; as opposed to the somatic nervous system that is under voluntary control. There is
close integration between the ANS and the motor and sensory systems; ensuring that responses to
sensory stimuli elicit appropriate motor responses. The autonomic nervous system can be influenced
by higher centres, with some voluntary control over autonomic functions.

Origins
The autonomic nervous system is divided into two systems, the parasympathetic and the sympathetic.
The parasympathetic nervous system outflow is cranio-sacral. The sympathetic nervous system
outflow is thoraco-lumbar. Central control and integration between the systems is performed by the
hypothalamus. Both systems consist of ganglia situated outside the central nervous system with pre-
ganglionic fibres synapsing in the ganglia and sending signals onward via post-ganglionic fibres.

Sympathetic nervous system

The pre-ganglionic fibres of the sympathetic nervous
system arise from the lateral horn of the spinal cord
and frequently ascend or descend one or two
segments within the spinal cord before they emerge
along with the posterior segmental roots. These fibres
then synapse in the ganglia of the sympathetic chain
and give rise to long post-ganglionic neurons. The
head is supplied by superior, middle and inferior
(stellate) cervical ganglia, which are formed from pre-
ganglionic fibres emerging from the first three thoracic
segments. Sympathetic fibres frequently reach the end
organs via the arterial blood supply to those organs.
The adrenal medulla is a specialised sympathetic
ganglion, in which the post-ganglionic fibres are
modified into secretory cells rather than nerve fibres.
Consequently, the output of this gland is hormonal
rather than neuronal with noradrenaline being the
dominant hormone (70 %) and most of the remainder
adrenaline, with small amounts of dopamine. Figure 1. Sympathetic outflow from the
spinal cord with associated ganglia

Parasympathetic nervous system

The parasympathetic nerve fibres arise from a cranio-sacral outflow, with the cranial outflow emerging
with cranial nerves III, VII, IX, and X. Pre-ganglionic fibres arise from the brain stem, and these fibres
are very long, with the parasympathetic ganglia being found close to the effector organs.
Consequently, post-ganglionic fibres are usually short.
Functions of the ANS are often organised as reflex arcs with outflow and inflow of these reflexes
travelling along the same nerves.

Figure 2. Parasympathetic outflow from the cranial and sacral segments respectively, showing the
long pre-ganglionic and short post-ganglionic fibres.
 Autonomic nervous system

Neurotransmitters in the ANS

The only two transmitter substances of importance in the ANS are acetylcholine and noradrenaline.

Acetylcholine (ACh)
ACh is the neurotransmitter at all autonomic ganglia (nicotinic actions); at the post-ganglionic
synapses in the post-ganglionic parasympathetic nerve endings and only at 2 sites in the sympathetic
system: Apocrine sweat glands and vasodilatation in blood vessels of skeletal muscle (muscarinic
actions). This latter action is physiologically unimportant.
ACh is also the dominant neurotransmitter in the motor division of the somatic nervous system,
supplying the neuromuscular junction.
Nicotinic and muscarinic Receptors
The cholinergic receptors are named nicotinic or muscarinic because of the substances that stimulate
them in vivo i.e. nicotine and muscarine.
The major response in the ganglia is nicotinic.
Muscarinic transmission occurs at the post-ganglionic synapses of all parasympathetic nerve terminals
and the sympathetic fibres to the sweat glands and vasodilators of skeletal muscle (mentioned above).
Nicotinic receptors are also found in the somatic nervous system at the neuromuscular junction (NMJ).

Noradrenaline
This is the transmitter at most post-ganglionic sympathetic endings (excluding the exceptions
mentioned above) and is divided into the well known  and  classification. The -adrenergic
receptors are subdivided into 1 and 2 with the 2 receptors being mainly presynaptic and 1
receptors being on the arteriolar smooth muscle.  receptors are subdivided into 1 (heart) and 2
(lungs), both of which are postsynaptic.

Functions of the autonomic nervous system

The sympathetic nervous system
The sympathetic nervous system mainly mediates the “fight or flight” response and is important for
stress responses and bodily defence mechanisms.
What is the stress response?
This is a neuro-humeral mechanism aimed at optimising circulation and metabolism for short-term
survival and is a response designed to increase survival in the wild by optimising escape mechanisms.
It is not, as frequently stated in the textbooks, aimed at perfusion of vital organs. See notes in the
Fluid Chapter.
The response involves haemodynamic changes redirecting blood flow to the “fight or flight” organs
(heart, muscle and lungs) with sustained perfusion of the brain. Increased sympathetic tone
decreases blood flow in all -adrenergically mediated vessels in the gut, kidney, liver and skin; while
-agonist effects enhance blood flow in the coronaries and skeletal muscle and increase cardiac
output. The response also involves mechanisms that maintain circulating blood volume.
Redistribution of blood flow away from the kidneys decreases the glomerular filtration rate (GFR), but
there is redistribution of intra-renal blood flow resulting in greater perfusion of the juxtamedullary
nephrons which have long loops of Henlé and are specialised for salt and water retention. This leads
to decreased salt and water clearance. Non-sympathetic components of the defence of blood volume
include aldosterone release, enhancing sodium retention and antidiuretic hormone (ADH) release
leading to increased water retention. Metabolic responses are aimed at directing glucose to “fight or
flight” organs and involve the inhibition of insulin release through sympathetic mechanisms.

The parasympathetic nervous system

The parasympathetic system manages the “vegetative” functions associated with digestion and
metabolism and include the “emptying” responses of the GIT (hence nausea and vomiting) and
urogenital systems.

It is thus the dominant system during periods of calm and rest or sleep. The sympathetic system only
dominates during periods of stress, arousal, emotion or perceived danger; the “fight or flight”
response.

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Organisation of the autonomic nervous system

The ANS is organised is such a way that most organs receive both a sympathetic and parasympathtic
supply. This means that the sympathetic post-ganglionic fibres are often very long (Figure 3).

Figure 3. Diagram of the autonomic nervous system.

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 Autonomic nervous system

The autonomic nerve supply from each system is usually balanced, with the overall effect depending
on the relative dominance of each system:

Sympathetic Parasympathetic
Dilate pupil Constrict pupil
The eye
Relax ciliary muscle Constrict ciliary muscle
Copious sweating No effect on sweating
Sweat and Salivary Glands
Inhibit secretions Copious GIT secretions
↓ peristalsis and tone ↑ peristalsis and tone
Stomach
↑ Sphincter tone Relax sphincters
Glucose released Slight ↑ glycogen synthesis
Liver and Gall Bladder
Gall bladder relaxed Constriction of biliary tree
Bronchi dilated Bronchi constricted
Lungs
Pulmonary vessel constriction
↑ rate ↓ rate
Heart ↑ force of contraction ↓ force of contraction
Coronaries dilated

The ANS and the heart

The intrinsic rate of the heart is 100 - 120 beats min-1. This is determined by the inherent activity of the
sino-atrial node. Changes in heart rate are a result of the balance between the sympathetic and
parasympathetic activity. At rest in adults, vagal inhibition outweighs sympathetic stimulation and the
normal heart rate is 70 - 80, whereas in children, the sympathetic system is dominant, resulting in a
higher heart rate. A heart that has been transplanted would have had the vagus innervation
completely transected during surgery; therefore patients with heart transplants have a HR of ± 110.

The ANS and peripheral vasculature

Blood vessels receive 1 receptor innervation and stimulation produces vasoconstriction through the
innervation of arteriolar smooth muscle. Vasoconstriction is predominantly mediated by noradrenaline.
Sympathetic “tone” is produced by intrinsic activity in these sympathetic nerves controlling the
diameter of the vessels and is the major determinant of peripheral vascular resistance.

Pharmacology of the autonomic nervous system

The effects of drugs can be specific, precise, receptor-driven; or generalised, mediated through non-
specific mechanisms affecting more global responses. The basic principal is that in organs innervated
by both systems a specific desired effect can be achieved by either stimulating one system or blocking
the other, e.g. heart rate is increased by either a sympathetic agonist or a parasympathetic antagonist.

Drugs acting at ganglia

The following examples illustrate some of the effects that drugs have on ganglionic activity. Ganglion
blocking drugs are usually competitive antagonists at the post-synaptic nicotinic receptors. The only
one in current use is trimetaphan camsilate (Arfonad®). This rarely used sulphonium compound is a
competitive antagonist of the nicotinic action of ACh in the ganglia and blocks ganglionic transmission.
Consequently, it has a direct vasodilator action on blood vessels, reducing arteriolar and venous tone.
It has a number of unwanted effects due to simultaneous inhibition of both the parasympathetic and
sympathetic nervous system. As vagal tone is the dominant factor on the heart, ganglion blockade
produces a reflex tachycardia; whereas in the lungs, sympathetic blockade dominates, so blockade
can lead to oedema and bronchospasm. In the gut and urinary tract, the parasympathetic usually
dominates, so ganglion blockade leads to paralytic ileus and urinary retention; impotence is also
frequent. Splanchnic and renal blood flows are reduced. Sympathetic blockade affects the eye,
resulting in long-lasting pupillary dilatation.
Interestingly, neostigmine, by causing a generalised increase in acetylcholine stimulates ganglionic
transmission, resulting in an increase in blood pressure (dominant sympathetic effect) and enhanced
gut peristalsis with increased nausea and vomiting (dominant parasympathetic). In the lungs, it will
lead to bronchoconstriction unless adequate muscarinic antagonism is provided.
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 Autonomic nervous system

Parasympathetic pharmacology
This is governed by the post-ganglionic muscarinic cholinergic receptors.
Two strategies are available for stimulating parasympathetic activity:
Muscarinic agonists
or Prolongation of the action of native acetyl choline by anti-cholinesterases.

Muscarinic stimulation
1) Muscarinic agonists
Muscarinic agonists are of two types: Esters of choline (methacholine, carbamic acid, carbacol,
bethanechol) and alkaloids based on muscarine (pilocarpine). Muscarinic agonists are mainly used in
ophthalmology for the management of closed angle glaucoma as they constrict the pupil opening the
flow of aqueous humour and reducing intra-ocular pressure (methacholine, carbacol and pilocarpine).
Bethanechol is used in GI and GU tract pathology to counteract atony of the bladder and increase
intestinal motility.
2) The anticholinesterases
Acetyl cholinesterase is an enzyme present in high concentrations in cholinergic synapses. It
hydrolyses acetylcholine to choline and acetyl co-A. Anticholinesterase drugs are used for treating
myasthenia gravis and to reverse the competitive non-depolarising neuromuscular blockers.
They include the short-acting agent, edrophonium, and the carbamates, of which neostigmine is the
one commonly used for reversal. The organophosphates are also anticholinesterases, and produce
their toxic effects through cholinergic activation and a weak depolarising muscle relaxant activity.

Muscarinic inhibition
Muscarinic antagonists (anti-muscarinics)
These agents, which block the action of ACh at muscarinic nerve endings, include atropine,
glycopyrrolate, hyoscine, and homatropine. Originally, these agents were derived from the plant
Atropa belladonna, (Deadly Nightshade). They are absorbed from the GI tract and some through skin.
Atropine crosses the blood-brain barrier (BBB) and may elicit central effects. Atropine is a partial
agonist and stimulation of parasympathetic central vagal centres by a small dose of atropine can
produce a transient paradoxical bradycardia before the anti-muscarinic tachycardia is seen.
Glycopyrrolate (Robinul®), the preferred anti-muscarinic in anaesthesia, does not cross the BBB and
will not elicit these effects.
Peripherally, these drugs exhibit non-selective competitive antagonism at muscarinic receptors, but
they have no agonist action in the absence of parasympathetic tone.
 CNS: In the CNS, atropine is a mild stimulant
 CVS: Atropine causes a tachycardia, which is solely due to vagal blockade allowing unopposed
sympathetic drive. Giving atropine if a bradycardia is due to non-vagal causes, e.g. hypoxia, will
not increase the heart rate. Atropine can also prolong the P-R interval
 Respiratory: Atropine reduces secretions and is a bronchodilator
 GIT: Atropine is an anti-sialogogue which means it decreases salivation; it also reduces gastrin
secretion, with reduction in secretion of gastric acid. GI motility is reduced but not abolished

Sympathetic pharmacology

Sympathetic stimulation (sympathomimetics)

These are drugs that mimic the actions of endogenous adrenaline and noradrenaline. They can be
grouped into those agents that stimulate adrenergic receptors directly, and indirectly acting agents that
either release noradrenaline or prevent its re-uptake.
1) Directly-acting drugs
The catecholamines, adrenaline (β-adrenergic at low doses with increasing α-agonist action at higher
doses) and noradrenaline (predominantly α-adrenergic, but with significant β effects) are used for
their inotropic and vasoconstrictor (vasopressor) effects. β2-receptors in the coronary arteries and
skeletal muscles are stimulated by adrenaline. This causes dilatation of the blood vessels and a fall in
systemic vascular resistance (SVR). Noradrenaline is less potent at the β2-receptor and more potent
at the α1-receptor causing a rise in SVR, systolic and diastolic pressure.

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 Autonomic nervous system

Isoprenaline is a potent β-receptor agonist with very little α-effects. It is chronotropic, inotropic and a
potent vasodilator. It produces an increase in cardiac output with a fall in diastolic and mean arterial
pressure. It was widely used in asthma as it is a potent bronchodilator, but its use is limited by its
dysrhythmogenic tendency which was frequently associated with fatalities in severe asthma.
It is currently not available in South Africa.
Dobutamine and dopamine act at dopamine (DA) receptors at low doses and adrenergic receptors at
higher doses. Dopamine acts at β2-receptors at low doses and both α1 and β2 at high doses.
Dobutamine is relatively selective for β1-receptors, with some weak β2- and α1- stimulating properties,
resulting in no change- or a slight decrease- in SVR; but producing a shift in perfusion from the gut to
cardiac and skeletal muscle. Nevertheless, the overall effect is improved splanchnic perfusion.
Both dobutamine and dopamine have short half-lives.

2) Unselective sympathomimetics
Ephedrine is used parenterally (IV preferred) as a vasopressor agent with a dual mode of action; its
primary action is to release noradrenaline from sympathetic terminals, and its secondary effect is a
direct effect on both α and β receptors, resulting in vasoconstriction and increased cardiac output.
Usual doses in adult patients: 2,5 - 10 mg as a bolus, the onset of effect occurs within 1 minute and it
can be given repeatedly, titrated to effect. The ampoules in South Africa are 50 mg in 1 ml. This
should be diluted into 10 ml so the concentration in 5 mg ml-1.

3) Receptor-specific adrenergic receptor agonists

Alpha receptor agonists:
Phenylephrine and methoxamine (not available in SA) are both relatively selective for α1-receptors.
These agents are almost entirely vasoconstrictors and are used to raise the SVR.
Clonidine and dexmedetomidine have an α2 action. Clonidine is not highly selective and has mixed
α1 and α2 actions, although the α2 effects predominate. This results in sedation, due to the central α2
effects and a decrease in SVR. Dexmedetomidine is much more selective for the α2-receptors. In
addition to its sedative and anxiolytic effects, it is also a very potent analgesic without the side
effects of respiratory depression as with the opiates. Dexmedetomidine has been newly released in
South Africa within the last few years for use as an IV infusion for sedation and analgesia. It is widely
used (but expensive) for procedures being performed under conscious sedation; and for sedation and
analgesia during GA and in the ICU.

Beta receptor agonists:

These have been widely used for their positive inotropic effects (adrenaline, dobutamine, isoprenaline
and dopamine), but pure β-agonists have the disadvantage of excessive tachydysrhythmias and a
reduction in SVR. Selective β2 receptor agonists have been developed for the management of
asthma and include salbutamol, terbutaline, fenoterol, reproterol and rimiterol.

Sympathetic inhibition (sympatholytics)

Adrenergic receptor antagonists
1) Alpha antagonists (α-blockers)
These drugs are occasionally used to lower blood pressure, but they are limited by their propensity to
cause a reflex tachycardia. They are the drugs of first choice in the control of hypertension in the
management of phaeochromocytoma. Examples:
Phentolamine is a competitive antagonist at both α1 and α2 receptors. It is also a serotonin
antagonist, and an agonist at histamine (H1 and H2) receptors resulting in many unwanted effects. It is
an IV drug, but not available in SA.
Phenoxybenzamine is more selective for α1 receptors and is a non-competitive alpha antagonist that
binds covalently with the receptor, permanently destroying the receptor. As it is non-competitive, it is
particularly effective against sudden catecholamine surges, but produces a high incidence of side
effects, particularly postural hypotension and nasal congestion. It is an IV drug given as an infusion.
It is very useful in the treatment of the BP swings during phaeochromocytoma surgery, but
unfortunately also not available in SA.
Prazosin is one of the most selective oral α1 antagonists and thus causes less tachycardia. It is,
however, quite short acting with a half-life of 3 - 4 hours, requiring a four times daily dosage schedule.
Doxazosin has largely replaced prazosin, as it is much longer acting and is widely used as an
antihypertensive, as well as in the pre-operative management of phaeochromocytoma.

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2) Mixed receptor antagonists

Labetalol has both α and β blocking properties. It is predominantly a beta-blocker with 7 x more
affinity for β- than α- receptors when given orally and 10 times greater β effect intravenously. It is the
only parenteral β-blocker readily available in SA.

3) Beta receptor antagonists (β-blockers)

These are all competitive antagonists with varying degrees of specificity for β1 and β2 receptors.
Some are also partial agonists (lisinopril). Some have local anaesthetic membrane stabilising effects
and they are effective antidysrhythmics. They are all well absorbed orally, but have a high 1st pass
metabolism resulting in a much higher oral than intravenous dose requirement. These drugs lower
blood pressure via actions on heart, blood vessels and renin angiotensin system. Some have a
central action, producing sedative and “calming” effects (propanolol). They reduce myocardial
work and prevent tachydysrhythmias. They may be effective in decreasing mortality after
myocardial infarction and may have a similar protective effect against adverse myocardial events in
high-risk surgery.
The major disadvantage of non-selective β antagonists is the effect of β2 antagonism in the lungs,
increasing airways resistance in asthmatics. The risk of increased airway resistance in patients
with chronic obstructive lung disease (COAD / COPD) has been overstated. None of the currently
available drugs are truly selective, and all must be used with caution in the presence of reactive
airways disease.
β antagonists inhibit lipolysis and have a complex effect on carbohydrate metabolism. They increase
the risk of hypoglycaemia partly because they inhibit gluconeogenesis in the liver. Previous concerns
in their use in diabetes mellitus are probably not justified, as the advantages in hypertension control
and myocardial ischaemia protection (both common in diabetes) generally outweigh these risks.