STEPTRACKERPHARMACOLOGY + PHYSIOLOGY | AUTONOMIC | HIGH-YIELD REVIEW

Autonomic Receptors & Neurotransmission

Every autonomic drug acts at one step of a short chain — synthesis, storage, release, receptor or breakdown. Know the receptor map and the drugs fall into place.

FOCUS ON

All preganglionic neurons (sympathetic and parasympathetic) release ACh at nicotinic (Nn) receptors. Postganglionic parasympathetic → ACh at muscarinic. Postganglionic sympathetic → NE at α/β, except sweat glands (ACh at M3) and renal vessels (dopamine at D1). The adrenal medulla is a modified ganglion: preganglionic ACh → epinephrine into blood. Somatic motor → ACh at Nm (NMJ). Receptor G proteins: α1 (Gq) vasoconstriction, mydriasis, sphincter contraction; α2 (Gi) ↓ sympathetic outflow, ↓ insulin; β1 (Gs) ↑ HR, contractility, renin; β2 (Gs) bronchodilation, vasodilation, uterine relaxation, glycogenolysis, K⁺ into cells; M1 (Gq) CNS/enteric; M2 (Gi) ↓ HR; M3 (Gq) glands, bronchoconstriction, bladder detrusor, GI motility, miosis; D1 (Gs) renal vasodilation; D2 (Gi) CNS; H1 (Gq), H2 (Gs), V1 (Gq), V2 (Gs).

RECEPTOR · G PROTEIN

MAIN LOCATIONS

EFFECT WHEN STIMULATED

KEY DRUGS

α1 · Gq

Vascular smooth muscle, radial (dilator) muscle of iris, bladder neck, prostate

Vasoconstriction, mydriasis, urinary retention, ↑ BP

Agonists: phenylephrine, midodrine · blockers: prazosin, tamsulosin

α2 · Gi

Presynaptic sympathetic terminals, brainstem, pancreatic β cells, ciliary epithelium

↓ NE release, ↓ sympathetic outflow, ↓ insulin, ↓ aqueous humor

Clonidine, methyldopa, brimonidine · blocker: mirtazapine

β1 · Gs

Heart (SA, AV, myocardium), juxtaglomerular cells

↑ HR, ↑ contractility, ↑ AV conduction, ↑ renin

Dobutamine · blockers: metoprolol, atenolol

β2 · Gs

Bronchioles, arterioles of skeletal muscle, uterus, liver, ciliary body

Bronchodilation, vasodilation, tocolysis, glycogenolysis, K⁺ into cells, ↑ aqueous humor

Albuterol, salmeterol, terbutaline

β3 · Gs

Detrusor, adipose

Bladder relaxation, lipolysis

Mirabegron (overactive bladder)

M1 · Gq

CNS, enteric nervous system, gastric parietal-cell area

Cognition, GI secretion

Blocked by anticholinergics → confusion

M2 · Gi

Heart (SA, AV node)

↓ HR, ↓ AV conduction

Atropine blocks → tachycardia

M3 · Gq

Exocrine glands, bronchial and GI smooth muscle, detrusor, sphincter pupillae, ciliary muscle, endothelium (NO)

Secretions, bronchoconstriction, GI motility, voiding, miosis, accommodation

Bethanechol, pilocarpine · blockers: oxybutynin, ipratropium

Nn · Nm (ion channels)

Autonomic ganglia, adrenal medulla · NMJ

Depolarization (Na⁺/K⁺ channel)

Nicotine, varenicline · NM blockers act at Nm

D1 · D2

Renal, mesenteric vessels · CNS, pituitary, chemoreceptor trigger zone

Renal vasodilation · ↓ prolactin, movement, emesis

Fenoldopam (D1) · antipsychotics, metoclopramide block D2

Cholinergic synapse

Choline + acetyl-CoA → ACh (choline acetyltransferase) → vesicle (VAChT) → release (Ca²⁺, SNARE)

AChE breaks ACh into choline + acetate

Hemicholinium blocks choline uptake · vesamicol blocks storage · botulinum toxin blocks release

Noradrenergic synapse

Tyrosine → DOPA (tyrosine hydroxylase, rate-limiting) → dopamine → NE (in vesicle) → release

Reuptake (NET) ends action; MAO and COMT degrade

Metyrosine blocks synthesis · reserpine blocks VMAT · cocaine, TCAs block NET

Picture it — the autonomic wiring

Neurotransmitters and receptors at each stepEvery preganglionic fiber releases ACh onto nicotinic (Nn) receptors. Parasympathetic endings release ACh onto muscarinic receptors; sympathetic endings release NE onto α/β receptors — except sweat glands (ACh on M). The adrenal medulla acts as a ganglion and secretes epinephrine into blood; somatic motor nerves release ACh onto Nm at the NMJ.

Schematic diagrams, not to scale.

Mechanism — the adrenergic nerve ending

Tyrosine → DOPATyrosine hydroxylase (metyrosine blocks)

→

Dopamine into vesicleVMAT (reserpine blocks)

→

NE releasedCa²⁺-dependent (guanethidine, bretylium block)

→

Reuptake via NETCocaine, TCAs, amphetamine reverse it

Presynaptic α2 receptors provide negative feedback — clonidine exploits this to lower sympathetic tone.

Dual innervation — who wins at rest

ORGAN

SYMPATHETIC

PARASYMPATHETIC

Heart rate

↑ (β1)

↓ (M2) — dominant at rest

Pupil

Mydriasis (α1)

Miosis (M3)

Bronchi

Dilate (β2)

Constrict (M3)

Bladder

Retain (β2/β3 relax detrusor, α1 tighten sphincter)

Void (M3)

Vessels

Constrict (α1) — dominant tone

Little direct supply

How it's tested

COMMON CONFUSIONSweat glands are sympathetic but cholinergic (M3) — so anticholinergics cause dry, hot skin and β-blockers don't stop sweating.

THE TRAPBlocking ganglia removes whichever tone dominates: heart rate rises (vagal tone lost), BP falls (sympathetic vascular tone lost).

YOUR APPROACHName the effect → which receptor → which G protein → which drug activates or blocks it.

If you see… think…

Neurotransmitter at all autonomic ganglia → ACh at Nn

Sympathetic fibers releasing ACh → sweat glands (M3)

Adrenal medulla → modified sympathetic ganglion, releases epinephrine

Gq receptors → α1, M1, M3, H1, V1

Gi receptors → α2, M2, D2

Rate-limiting step in catecholamine synthesis → tyrosine hydroxylase

Reserpine → depletes vesicles (blocks VMAT)

Botulinum toxin → blocks ACh release (cleaves SNAREs)

Ganglionic blocker → tachycardia + hypotension

β2 stimulation and potassium → K⁺ shifts into cells