Q1 LONG ANSWER 10M ★ High-yield

Describe the organisation of the autonomic nervous system. Explain cholinergic and adrenergic transmission with receptor types and classify autonomic drugs.

Pharmacology · 2nd Professional — Para-Clinical

Organisation of the Autonomic Nervous System

Feature	Sympathetic	Parasympathetic
Outflow	Thoracolumbar (T1–L2)	Craniosacral (III, VII, IX, X; S2–S4)
Ganglia	Near the spinal cord (paravertebral chain); short preganglionic, long postganglionic fibres	Near or within the effector organ; long preganglionic, short postganglionic
Preganglionic transmitter	Acetylcholine acting on nicotinic (NN) receptors	Acetylcholine acting on nicotinic receptors — the same for both
Postganglionic transmitter	Noradrenaline on adrenergic receptors (except sweat glands, which are cholinergic)	Acetylcholine on muscarinic receptors
Divergence	Wide — one preganglionic fibre supplies many postganglionic; diffuse, mass response	Limited — discrete, localised response
Overall role	"fight, flight and fright" — catabolic; mobilises resources	"rest and digest" — anabolic; conserves resources
Adrenal medulla	A modified sympathetic ganglion — innervated by a preganglionic fibre and secreting adrenaline (80%) and noradrenaline directly into the blood	—

CLINICAL PEARL

Every autonomic ganglion uses acetylcholine on nicotinic receptors, whichever division it belongs to. The divisions differ only at the postganglionic synapse. That is why ganglion blockers such as hexamethonium paralyse both systems indiscriminately and were abandoned — and why the effect of ganglion blockade on any organ is predicted by asking which division normally dominates there.

Cholinergic Transmission

Choline is taken into the nerve terminal by a carrier — the rate-limiting step, blocked by hemicholinium → Choline acetyltransferase combines it with acetyl-CoA → acetylcholine → Stored in vesicles by a vesicular transporter, blocked by vesamicol → The action potential opens voltage-gated calcium channels → Calcium-dependent exocytosis; blocked by botulinum toxin (which cleaves snare proteins) and by aminoglycosides; increased by black widow spider venom → Acetylcholine acts on muscarinic or nicotinic receptors → Rapidly hydrolysed by acetylcholinesterase to choline and acetate; choline is recaptured

Receptor	Type	Location	Effect
M1	GPCR — Gq	CNS, autonomic ganglia, gastric parietal cells	Gastric acid secretion; pirenzepine blocks it
M2	GPCR — Gi	Heart (SA and AV node, atria)	Bradycardia, reduced AV conduction and atrial contractility
M3	GPCR — Gq	Smooth muscle, glands, eye, vascular endothelium	Contraction of gut, bronchi and bladder detrusor; secretion; miosis and accommodation; endothelial nitric oxide release causing vasodilatation
NN (neuronal)	Ligand-gated ion channel	All autonomic ganglia, adrenal medulla, CNS	Ganglionic transmission; blocked by hexamethonium
NM (muscle)	Ligand-gated ion channel	Neuromuscular junction (motor end plate)	Skeletal muscle contraction; blocked by d-tubocurarine

Adrenergic Transmission

Tyrosine enters the neuron and is converted by tyrosine hydroxylase to dopa — the rate-limiting step, inhibited by metyrosine → dopa → dopamine by dopa decarboxylase (blocked by carbidopa) → Dopamine enters the vesicle by VMAT, blocked by reserpine → Inside the vesicle, dopamine beta-hydroxylase makes noradrenaline → (In the adrenal medulla only, PNMT converts it to adrenaline) → Release by calcium-dependent exocytosis; blocked by guanethidine, and inhibited by presynaptic alpha2 autoreceptors → Action terminated chiefly by reuptake-1 (net) into the neuron — blocked by cocaine, tricyclic antidepressants → Metabolised by MAO (neuronal, mitochondrial) and COMT (extraneuronal) to VMA

Reuptake, not enzymatic destruction, is what mainly terminates noradrenergic transmission — the opposite of acetylcholine, and the reason cocaine and tricyclics potentiate sympathetic effects so strongly
Indirectly acting sympathomimetics (tyramine, amphetamine, ephedrine) enter the neuron by the same reuptake carrier and displace stored noradrenaline — so they are blocked by cocaine and by reserpine, and show tachyphylaxis as stores are exhausted

Receptor	G protein	Main locations	Effects
Alpha1	Gq	Vascular smooth muscle, radial muscle of iris, bladder trigone and prostate	Vasoconstriction and raised blood pressure; mydriasis; urinary retention
Alpha2	Gi	Presynaptic nerve terminals, CNS, platelets, pancreatic beta cells	Inhibits noradrenaline release (autoreceptor); central sympathetic outflow reduced (clonidine); platelet aggregation; reduced insulin release
Beta1	Gs	Heart; juxtaglomerular cells	Increased rate, force, conduction and automaticity; renin release. "1 heart"
Beta2	Gs	Bronchi, uterus, skeletal muscle vessels, liver	Bronchodilatation, uterine relaxation, vasodilatation, glycogenolysis, tremor, hypokalaemia. "2 lungs"
Beta3	Gs	Adipose tissue; bladder detrusor	Lipolysis; detrusor relaxation (mirabegron)
D1	Gs	Renal, mesenteric and coronary vessels	Vasodilatation — the basis of low-dose dopamine

Dual Innervation and Predominant Tone

Organ	Sympathetic effect	Parasympathetic effect	Dominant tone
Heart rate	Increased (beta1)	Decreased (M2)	Parasympathetic — hence atropine causes tachycardia
Arterioles	Constriction (alpha1)	No innervation in most beds	Sympathetic
Bronchi	Dilatation (beta2, mainly by circulating adrenaline)	Constriction (M3)	Parasympathetic
Pupil	Mydriasis (alpha1, radial muscle)	Miosis (M3, circular muscle)	Parasympathetic
Gut	Reduced motility; sphincters contract	Increased motility; sphincters relax	Parasympathetic
Bladder	Detrusor relaxes (beta3); sphincter contracts (alpha1) — retention	Detrusor contracts (M3) — voiding	Parasympathetic
Sweat glands	Secretion — but by cholinergic sympathetic fibres on muscarinic receptors; the great exception	None	Sympathetic (cholinergic)

CLINICAL PEARL

Knowing which division holds the resting tone predicts what a blocker will do. The heart is under parasympathetic tone at rest, so blocking it with atropine produces tachycardia. Arterioles have almost no parasympathetic supply, so atropine barely changes blood pressure. One fact about resting tone replaces a list of drug effects.

Classification of Autonomic Drugs

Group	Examples
Cholinergic agonists (parasympathomimetic)	Direct — acetylcholine, bethanechol, pilocarpine, carbachol. Indirect (anticholinesterases) — neostigmine, physostigmine, organophosphates
Cholinergic antagonists	Muscarinic — atropine, hyoscine, ipratropium, glycopyrrolate. Ganglionic — hexamethonium. Neuromuscular — d-tubocurarine, succinylcholine
Adrenergic agonists (sympathomimetic)	Direct — adrenaline, noradrenaline, phenylephrine, salbutamol, dobutamine. Indirect — amphetamine, tyramine. Mixed — ephedrine
Adrenergic antagonists	Alpha — phentolamine, phenoxybenzamine, prazosin. Beta — propranolol, atenolol, metoprolol, carvedilol
Drugs acting on synthesis, storage or release	Metyrosine, reserpine, guanethidine, clonidine (alpha2 agonist)

Applied Aspects

Atropine is the antidote in organophosphorus poisoning, which is common in rural India; it reverses the muscarinic effects (bronchial secretion, bradycardia, miosis) but not the nicotinic ones, so muscle weakness and respiratory failure persist and require pralidoxime and ventilation
Titrate atropine against drying of bronchial secretions, not against pupil size or heart rate — secretions are what kill
Beta-blockers are relatively contraindicated in asthma (beta2 blockade) and mask the warning signs of hypoglycaemia in diabetics, except sweating
Sweat glands are sympathetic but cholinergic, which is why anticholinergics cause dry skin and hyperthermia, and why atropine poisoning gives a patient who is "hot as a hare, dry as a bone, red as a beet, blind as a bat and mad as a hatter"
Alpha1 blockade relieves prostatic obstruction by relaxing smooth muscle in the prostate and bladder neck — tamsulosin is relatively uroselective
Never give a beta-blocker before alpha-blockade in phaeochromocytoma, as unopposed alpha stimulation precipitates a hypertensive crisis
Cocaine and tricyclic antidepressants block reuptake-1, so they potentiate directly acting sympathomimetics and block indirectly acting ones — a distinction that is regularly examined
Reserpine depletes vesicular stores and so abolishes the effect of tyramine and amphetamine while leaving adrenaline effective
Denervation supersensitivity — after sympathetic denervation, receptors up-regulate and the tissue becomes far more sensitive to circulating catecholamines; relevant in Horner syndrome testing
Autonomic neuropathy in diabetes causes postural hypotension, gastroparesis, impotence and silent myocardial infarction, and alters the response to many autonomic drugs

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