Autonomic nervous system
The two-neuron motor system that runs everything you do not think about — heart rate, vessel tone, pupils, sweat, gut, bladder — using essentially two transmitters, acetylcholine and noradrenaline, sorted into receptor subtypes that decide which organ responds to which drug.
What it normally does
Both halves run through two neurons in series with a ganglion between them. Sympathetic fibres leave the cord from T1 to L2 (thoracolumbar), the first neuron is short and the ganglion sits close to the spine in the sympathetic chain, so the second neuron is long. Parasympathetic fibres leave in cranial nerves III, VII, IX and X and from S2 to S4 (craniosacral), the first neuron is long and the ganglion sits in or near the target organ, so the second neuron is very short. Every first neuron in both systems releases acetylcholine onto nicotinic receptors in the ganglion (Nn). The adrenal medulla is the exception that proves the rule: its chromaffin cells are modified second neurons that never grew axons, so instead of a synapse they release catecholamines straight into the blood — roughly 80 per cent adrenaline, the rest noradrenaline.
the pathway to the eye is long and superficial and can be interrupted almost anywhere between the hypothalamus and the orbit, which is why Horner syndrome is a localising sign rather than a diagnosis. It also explains why anything acting at the ganglion knocks out both systems at once, and why the useful drugs act at the second synapse, on the organ, where the two systems finally differ.
The second synapse is where the receptor subtypes live, and they are the whole map. Sympathetic second neurons release noradrenaline onto alpha-1 (vascular smooth muscle, bladder neck and prostate, pupil dilator, the small Muller muscle that helps hold the upper lid up), alpha-2 (mostly on the nerve terminal itself as a brake on further release, and in the brainstem), beta-1 (SA node, AV node, ventricle, renin-releasing cells of the kidney), beta-2 (bronchial smooth muscle, skeletal muscle arterioles, uterus, liver) and beta-3 (bladder detrusor, fat). Parasympathetic second neurons release acetylcholine onto muscarinic receptors: M1 in stomach and brain, M2 on the SA and AV nodes and atria, M3 on glands and on smooth muscle everywhere — pupillary sphincter, ciliary muscle, bronchi, gut, detrusor. Sweat glands break the pattern: they are sympathetic but their nerves release acetylcholine onto muscarinic receptors.
there is no such thing as an autonomic side effect list. There is one receptor appearing in several tissues. Block M3 and you get a dry mouth, blurred near vision, a hot dry skin, constipation and a bladder that will not empty — the same receptor five times over. This one fact lets a student derive almost every adverse effect on this page instead of memorising it.
What each receptor does to the cell is fixed and short. Alpha-1 is Gq: it raises intracellular calcium and the smooth muscle contracts. Beta receptors are Gs: they raise cyclic AMP, which in cardiac muscle means faster and harder, and in smooth muscle means relax. M2 is Gi: it lowers cyclic AMP and opens potassium channels, so the SA node cell hyperpolarises, drifts to threshold more slowly and the heart slows, and AV conduction drags. M3 is Gq again: contraction and secretion.
selectivity, not signalling, is what separates the drugs. Salbutamol and a beta-1 agonist trigger the same second messenger; they differ in which cells carry their receptor, and the cell decides whether more cyclic AMP means contract harder or relax. When a beta-2 agonist causes tremor it is because skeletal muscle carries beta-2 as well as bronchus. Beta selectivity is always relative rather than absolute, which is the usual explanation offered for a beta-3 bladder drug nudging blood pressure and heart rate up, although the mechanism of that effect is not settled.
The system is tonically active and reflex-controlled. Stretch receptors in the carotid sinus and aortic arch report blood pressure up cranial nerves IX and X respectively to the brainstem (nucleus tractus solitarius). A high pressure increases vagal outflow and withdraws sympathetic outflow; a low pressure does the reverse. Stand up and roughly 500 to 800 mL of blood pools below the diaphragm within seconds; the baroreflex answers within a beat or two by constricting vessels through alpha-1 and lifting heart rate through beta-1. At rest the vagus dominates the SA node — cut all autonomic input and the intrinsic rate is about 100 beats per minute, not 70.
lying and standing blood pressure with the pulse beside it is an autonomic function test you can do at the bedside. A pressure that falls with a heart rate that rises means the reflex is working against a volume or vasodilation problem. A pressure that falls with a heart rate that does not move means the arc itself is broken — neuropathy, or a drug sitting on the receptors.
What goes wrong
- Diabetic autonomic neuropathy← from “The system is tonically active and reflex-cont…”
Chronic hyperglycaemia damages the small unmyelinated autonomic fibres in the same way it damages sensory ones — microvascular ischaemia of the vasa nervorum plus direct metabolic injury. The long vagal fibres tend to go first, so the picture starts as unopposed sympathetic tone (a resting tachycardia around 90 to 100 that does not vary with breathing), then the sympathetic efferent limb fails too and the baroreflex can no longer constrict vessels or lift the rate on standing. The same fibre loss hits the stomach (gastroparesis), the bladder (a large flaccid bladder emptying incompletely), the genital vasculature (erectile dysfunction, often an early complaint) and the sweat glands (feet dry, trunk and face sweating excessively, sometimes only while eating).
Orthostatic drop with a fixed heart rate points to autonomic failure rather than hypovolaemia. Look for gastroparesis, erectile dysfunction, hypoglycaemia unawareness and silent ischaemia in the same patient. Type 2 diabetes is roughly three to four times more prevalent among Aboriginal and Torres Strait Islander Australians and typically begins a decade or more earlier, so duration-dependent complications like this one land disproportionately and at younger ages.
You would find: Systolic blood pressure falling 20 mmHg or more, or diastolic 10 mmHg or more, within three minutes of standing, with a pulse that barely moves — that flat pulse is the finding. Add a resting tachycardia with no sinus arrhythmia, early satiety and vomiting of food eaten hours before, and loss of the adrenergic warning symptoms of hypoglycaemia so the patient goes straight to neuroglycopenia and confusion. Cardiac autonomic neuropathy also blunts anginal pain, which is one reason myocardial infarction presents late or silently in long-standing diabetes.
- Horner syndrome← from “Both halves run through two neurons in series …”
The sympathetic supply to the eye is three neurons long and takes an absurd route. Neuron one runs from the hypothalamus down the brainstem to the ciliospinal centre at C8 to T2. Neuron two leaves the cord there, arches over the apex of the lung and up the neck to the superior cervical ganglion. Neuron three climbs on the wall of the internal carotid artery through the cavernous sinus into the orbit, where it supplies the pupil dilator and the small smooth muscle of the upper lid (Muller muscle). Cut it anywhere and the dilator and lid muscle lose their alpha-1 drive: the pupil cannot dilate and the lid droops a little. The sudomotor fibres for the face leave the superior cervical ganglion and travel on the external carotid, so where the fibres are cut decides whether the face sweats.
Ptosis plus miosis, anisocoria worse in the dark, with anhidrosis when the lesion is central or preganglionic and often absent when it is on the carotid. Painful acute Horner equals carotid dissection until proven otherwise. Horner with hand wasting equals apical lung tumour. The ptosis is partial because Muller muscle is only an accessory lid elevator — levator palpebrae superioris is cranial nerve III and is unaffected.
You would find: A partial ptosis with a small pupil on the same side. The anisocoria is greater in the dark than in the light, because the problem is failure to dilate, and the affected pupil dilates slowly (dilation lag). Sweating helps localise: a first-order (central) lesion tends to give anhidrosis of the whole ipsilateral body, a second-order (preganglionic) lesion anhidrosis of the hemiface, and a third-order lesion on the carotid little or no sweating change beyond at most a small patch of medial forehead — so normal sweating does not exclude the diagnosis. The causes that matter are the ones you must not miss — a Pancoast tumour at the lung apex in a smoker with T1 arm pain and wasting of the small hand muscles, and internal carotid dissection, which is a painful Horner with neck pain or headache in a younger person and is a stroke waiting to happen, so it goes to imaging the same day.
- Anticholinergic (antimuscarinic) effects and anticholinergic burden← from “The second synapse is where the receptor subty…”
Many drugs block muscarinic receptors as a side occupation: tricyclic antidepressants, older antihistamines such as promethazine, antipsychotics, benztropine, oxybutynin, hyoscine hydrobromide. Each blocks the same M receptors the parasympathetic system uses, in every tissue the drug reaches. Peripherally that is M3 on glands and smooth muscle and M2 on the SA node; centrally it is M1 in cortex and hippocampus, where acetylcholine underwrites attention and memory. The effects add up across drugs, so three weakly anticholinergic medicines produce a strongly anticholinergic patient — and an older brain has fewer cholinergic neurons to spare.
Any side effect list reading dry mouth, blurred vision, constipation, urinary retention and confusion is muscarinic blockade, whatever the drug was sold to do. Tertiary amines cross the blood-brain barrier and cause the delirium; quaternary ones such as ipratropium and hyoscine butylbromide largely do not. Anticholinergic burden is a modifiable cause of falls and delirium in Australian residential aged care.
You would find: Blind as a bat (two separate M3 effects in the eye — the ciliary muscle is paralysed so near vision blurs, and the pupillary sphincter is blocked so the pupil is dilated and poorly reactive), dry as a bone, hot as a hare (no sweating, so heat cannot be lost — remember sweat glands are sympathetic but muscarinic) and red as a beet (cutaneous vasodilation, a compensatory attempt to dump that heat rather than a direct receptor effect), mad as a hatter, plus a tachycardia and a palpable bladder that will not empty. In practice you meet it as an older person brought in after a fall or with new delirium and constipation, on amitriptyline for sleep and oxybutynin for urgency. Ask what is on the list before ordering a scan.
- Vasovagal (reflex) syncope← from “The system is tonically active and reflex-cont…”
A normal reflex arc misfires. Prolonged standing, heat, pain or fright triggers an abrupt withdrawal of sympathetic tone to the vessels and a simultaneous surge of vagal output to the heart. Alpha-1 mediated vasoconstriction disappears, so systemic vascular resistance collapses, and M2 stimulation at the SA and AV nodes slows or briefly stops the heart. Cerebral perfusion fails for a few seconds and the patient drops; lying flat restores venous return and the reflex resets, which is why recovery is fast.
Prodrome plus a trigger plus rapid full recovery equals reflex syncope. Both limbs fire: vasodepressor (loss of alpha-1 tone) and cardioinhibitory (M2 vagal bradycardia). Management is education, counter-pressure manoeuvres, salt and fluid, and avoiding triggers — drug treatment is weak and second line.
You would find: A warm crowded room or a blood test, then a prodrome the patient can describe — nausea, sweating, a sense of warmth, vision greying at the edges, hearing tunnelling. Bystanders report pallor. A few jerks are common and do not make it a seizure; what separates them is the absence of a true post-ictal period, with orientation back within a minute or so. Commonest cause of transient loss of consciousness in young people presenting to Australian emergency departments. The distinction that matters is syncope with no prodrome, on exertion, or when seated, which points at a cardiac cause and needs an ECG.
- Organophosphate poisoning (cholinergic crisis)← from “The second synapse is where the receptor subty…”
Organophosphate insecticides phosphorylate acetylcholinesterase and inactivate it, so acetylcholine is not cleared from any cholinergic synapse. It accumulates at muscarinic receptors on glands, smooth muscle and the heart, at nicotinic receptors in autonomic ganglia and at the neuromuscular junction, and in the brain. The enzyme-poison bond then loses an alkyl group and becomes permanent (ageing), after which no reactivator can free the enzyme and recovery waits on new enzyme being made. How fast that happens depends on the compound — a few hours for dimethyl agents, considerably longer for diethyl ones.
Everything wet, pupils pinpoint, muscles twitching. Muscarinic excess is reversed by atropine, titrated to a dry chest; nicotinic weakness is not, and the answer to it is airway control and mechanical ventilation. An oxime (pralidoxime) is used in some protocols to reactivate the enzyme before ageing, but trial evidence of benefit is weak and it never substitutes for atropine and ventilation. Decontaminate and wear gloves and a gown — these compounds are lipid soluble and absorbed through skin.
You would find: A soaking wet patient: salivation, lacrimation, urination, defecation, vomiting, bronchorrhoea and bronchospasm, with pinpoint pupils and often a bradycardia. Death is respiratory — secretions plus bronchoconstriction plus weakness of the diaphragm from nicotinic overstimulation. Nicotinic features give the game away when muscarinic ones are confusing: fasciculations, weakness, and a tachycardia rather than a bradycardia. A garlic or solvent smell on the clothes and a rural or agricultural setting are the context, and in Australia this is seen with farm chemical exposure and in deliberate self-poisoning; ring the Poisons Information Centre on 13 11 26 early.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- M1 to M5 muscarinic receptors, competitively and without subtype selectivity
- Which does
- Acetylcholine is displaced from the receptor. At the SA and AV node the M2 Gi signal stops, so cyclic AMP rises again and the potassium conductance falls and the node fires faster. On glands and smooth muscle the M3 Gq signal stops, so secretion and contraction fall away.
- So you see
- Secretions dry up, bronchospasm eases, the chest becomes clear enough to ventilate, and the heart rate climbs. In poisoning, atropine is titrated against drying of the chest and adequate oxygenation, not against the pupils.
- And the same mechanism causes
- Once an antimuscarinic is absorbed systemically you cannot block M3 in one tissue and spare it in another, so the therapeutic effect and the toxic effect are the same effect in different organs: a dry mouth, blurred near vision from a paralysed ciliary muscle, a dilated poorly reactive pupil, a bladder that will not empty, and — because sweat glands are sympathetic but muscarinic — a hot dry skin that cannot lose heat. Central M1 blockade adds agitation and delirium. An inhaled quaternary agent such as ipratropium reaches little of this because so little is absorbed.
- Handling
- Atropine is a tertiary amine and crosses into the brain, which is why it causes confusion; ipratropium and hyoscine butylbromide are quaternary and stay largely outside it, which is why an inhaled or antispasmodic antimuscarinic is far better tolerated cognitively.
Catches people out: Atropine will not touch the nicotinic features. Fasciculations, weakness and respiratory muscle failure persist no matter how much atropine is given, so a patient can look dry and pink and still stop breathing — airway and ventilation are the priority. It can also precipitate acute angle-closure glaucoma in a susceptible eye by widening the pupil so the peripheral iris crowds the drainage angle, and can tip an older man with prostatic enlargement into acute urinary retention.
- Binds
- Alpha-1 adrenoceptors on vascular smooth muscle (midodrine is a prodrug, active as desglymidodrine)
- Which does
- Gq signalling raises intracellular calcium and the smooth muscle contracts. Arterioles narrow, raising systemic vascular resistance, and veins constrict, pushing pooled blood back to the heart.
- So you see
- Standing blood pressure rises and the patient can stay upright without greying out. It does not restore the reflex, so the heart rate still does not respond; it just holds the pressure up mechanically.
- And the same mechanism causes
- The drug cannot tell standing from lying, so the same vasoconstriction that fixes upright pressure produces supine hypertension when the patient goes to bed — which is why it is dosed during the day and not close to lying down. Alpha-1 receptors on the pilomotor muscles cause the characteristic scalp tingling and goosebumps, alpha-1 at the bladder neck can cause urinary retention, and the rise in pressure can provoke a baroreflex bradycardia in anyone whose reflex still works.
- Handling
- Desglymidodrine is hydrophilic and does not cross into the brain, so it lacks central effects — the trade-off is that it does nothing for the neuropathy itself.
Catches people out: Check the lying blood pressure, not just the standing one. Fludrocortisone is the other common option and works by a completely different route — mineralocorticoid receptor, sodium and water retention, expanding plasma volume — with hypokalaemia, oedema and its own supine hypertension following from that mechanism.
- Binds
- M3 muscarinic receptors on detrusor smooth muscle (oxybutynin, solifenacin); beta-3 adrenoceptors on the same muscle (mirabegron)
- Which does
- Blocking M3 removes the Gq calcium signal, so involuntary detrusor contractions during filling are damped. Stimulating beta-3 raises cyclic AMP in the same cell and relaxes it directly, without touching any muscarinic receptor.
- So you see
- Fewer urgency episodes and less urge incontinence, with a bladder that fills to a larger volume before it complains. The size of the benefit is modest for both classes.
- And the same mechanism causes
- The antimuscarinic effect is not confined to the bladder, so the patient predictably gets a dry mouth, constipation and blurred near vision, and because oxybutynin is a lipid-soluble tertiary amine that enters the brain, confusion and falls in older people. Mirabegron avoids the muscarinic effects entirely, and instead raises blood pressure and heart rate in some patients — usually explained by beta selectivity being relative rather than absolute, with spill onto cardiac beta-1, though the mechanism is not firmly established.
- Handling
- Choose by which receptor the patient can least afford to have hit — a frail cognitively impaired patient should not be given a brain-penetrant antimuscarinic; mirabegron should be avoided in severe uncontrolled hypertension, and blood pressure checked before starting and during treatment.
Catches people out: Exclude a large post-void residual before treating urgency. In the diabetic patient with autonomic neuropathy the bladder is often underactive rather than overactive, and an antimuscarinic will tip it into retention.
- Binds
- Mainly alpha-2 adrenoceptors, with weak alpha-1 activity
- Which does
- In a normal eye the weak alpha-1 effect is negligible and the alpha-2 effect slightly constricts the pupil by reducing noradrenaline release. In the Horner eye the denervated dilator carries far more alpha-1 receptors than normal, so that same weak alpha-1 stimulus produces a real contraction of the dilator.
- So you see
- The affected pupil dilates and the ptosis lifts, while the normal pupil constricts a little — the anisocoria reverses. That reversal is the positive test.
- And the same mechanism causes
- Alpha-2 agonism is also a central sedative and sympatholytic action (the same mechanism clonidine and dexmedetomidine use), and in infants enough is absorbed to cause bradycardia, hypotension and drowsiness, so it is avoided in babies and young children.
- Handling
- Supersensitivity takes days to develop, so the test can be falsely negative in a Horner syndrome that started that morning — exactly the acute painful presentation you most want to catch. Never delay imaging to wait for it.
Catches people out: A positive test confirms the syndrome and tells you nothing about the cause. Localisation still comes from the sweating pattern and the associated signs, and imaging is chosen accordingly — the whole sympathetic path from hypothalamus to orbit, with urgent carotid imaging if there is pain.
Two questions answer nearly every autonomic item: which receptor, and which tissue. Once you know the drug hits M3, the adverse effects write themselves in salivary gland, ciliary muscle and iris sphincter, gut, bladder and sweat gland, because it is one receptor visiting several organs — and whether the patient also gets delirium depends on whether the molecule is tertiary (crosses into the brain) or quaternary (does not). Two exceptions carry more exam marks than anything else here: sweat glands are sympathetic but cholinergic, which is why atropine gives a hot dry skin and why a central or preganglionic Horner syndrome causes anhidrosis while a carotid one often does not; and the adrenal medulla is a modified sympathetic ganglion whose second neurons never grew axons, releasing mostly adrenaline into blood. Notice too that the drugs on this page mostly do not repair the autonomic lesion. Midodrine replaces a signal downstream of a dead nerve, atropine blocks a receptor while an oxime targets the poisoned enzyme, and apraclonidine only exploits denervation supersensitivity to support a diagnosis. Finally, the cheapest autonomic test in medicine is lying and standing blood pressure with the pulse recorded beside it — a falling pressure with a rising pulse is a volume or vasodilation problem, a falling pressure with a flat pulse is the reflex arc itself.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.