Autonomic Nervous System

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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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. 4 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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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.

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