Autonomic Pharmacology

The autonomic nervous system (ANS) regulates involuntary functions of smooth muscle, cardiac muscle, and glands. Its two divisions — sympathetic and parasympathetic — exert opposing effects on most target organs, allowing precise homeostatic control.

ANS ANATOMY

The sympathetic (thoracolumbar) division originates from preganglionic neurons in the lateral horn of T1-L2 spinal segments. These short preganglionic fibres synapse in paravertebral (sympathetic chain) or prevertebral (coeliac, mesenteric) ganglia, from which long postganglionic fibres travel to target organs. The parasympathetic (craniosacral) division has long preganglionic fibres from cranial nerve nuclei (CN III — ciliary ganglion; CN VII — pterygopalatine and submandibular ganglia; CN IX — otic ganglion; CN X — ganglia near target organs) and sacral spinal cord (S2-S4); short postganglionic fibres then innervate the target organ.

CHOLINERGIC NEUROTRANSMISSION

Acetylcholine (ACh) is synthesised in the presynaptic terminal by choline acetyltransferase (ChAT) from choline and acetyl-CoA, stored in vesicles, and released by Ca2+-dependent exocytosis. ACh is rapidly hydrolysed in the synaptic cleft by acetylcholinesterase (AChE). ACh acts at two receptor classes: nicotinic (nAChR) — a ligand-gated Na+/K+ ion channel found at the neuromuscular junction and in autonomic ganglia (both sympathetic and parasympathetic) — and muscarinic (mAChR) — GPCRs with five subtypes. M1 mediates CNS effects and gastric acid secretion. M2 (cardiac, Gi-coupled) slows heart rate (negative chronotropy) and prolongs AV node conduction (negative dromotropy). M3 (smooth muscle/glands, Gq-coupled) causes bronchoconstriction, increased secretions (salivation, lacrimation, sweat), gastrointestinal motility, bladder contraction (detrusor), and pupil constriction (miosis), plus penile erection.

Muscarinic agonists: pilocarpine (M3 agonist for glaucoma — miosis and reduced intraocular pressure); bethanechol (M3 agonist for post-operative urinary retention and neurogenic bladder). Muscarinic antagonists: atropine — M1-M3 block causes tachycardia, bronchodilation, mydriasis, dry mouth, urinary retention, and reduced GI motility; ipratropium (inhaled, quaternary amine — M3 block in COPD/asthma); hyoscine (scopolamine — M1 block for motion sickness). AChE inhibitors increase synaptic ACh by blocking hydrolysis: neostigmine (does not cross BBB — reversal of neuromuscular blockade, post-operative ileus, myasthenia gravis); physostigmine (crosses BBB — glaucoma, anticholinergic toxicity reversal); donepezil (selective CNS AChE inhibitor — Alzheimer's disease); organophosphates cause the SLUDGE toxidrome (Salivation, Lacrimation, Urination, Defaecation, GI cramps, Emesis) plus bradycardia, miosis, and bronchospasm.

ADRENERGIC NEUROTRANSMISSION

Noradrenaline (NA) biosynthesis: tyrosine → DOPA (via tyrosine hydroxylase, the rate-limiting step) → dopamine (DOPA decarboxylase) → NA (dopamine beta-hydroxylase, in vesicle). NA is stored in vesicles via VMAT (vesicular monoamine transporter), released by Ca2+-dependent exocytosis, and removed primarily by neuronal reuptake via NET (noradrenaline transporter). Remaining NA is metabolised by MAO (monoamine oxidase) and COMT (catechol-O-methyltransferase).

Adrenoceptor subtypes: α1 (Gq → IP3/DAG → ↑Ca2+) — vasoconstriction, mydriasis (dilator pupillae), urethral sphincter contraction; α2 (Gi → ↓cAMP) — presynaptic inhibition of NA release (autoreceptors), clonidine (antihypertensive, α2 agonist) reduces sympathetic outflow; β1 (Gs → ↑cAMP) — increases heart rate (chronotropy) and contractility (inotropy), renin release; β2 (Gs → ↑cAMP) — bronchodilation, vasodilation in muscle, uterine relaxation (tocolysis), glycogenolysis; β3 (Gs → ↑cAMP) — lipolysis in adipose tissue.

Key adrenergic drugs: adrenaline (epinephrine) — non-selective α1+β1+β2 agonist, used in anaphylaxis, cardiac arrest; salbutamol — selective β2 agonist, first-line for acute asthma; propranolol — non-selective β1+β2 blocker, used in hypertension, arrhythmias, thyrotoxicosis, tremor; metoprolol — cardioselective β1 blocker, used in heart failure, hypertension, post-MI; prazosin — selective α1 blocker, used in benign prostatic hyperplasia (BPH) and hypertension.