Catecholamine GPCRs split into α-family (Gq-coupled vasoconstriction at α1; Gi-coupled presynaptic feedback inhibition at α2) and β-family (Gs-coupled cAMP elevation: β1 cardiac chronotropy + inotropy, β2 bronchodilation + vasodilation, β3 lipolysis + detrusor relaxation). Antagonists branch by subtype: non-selective β-blockers (propranolol, nadolol, sotalol) block β1+β2; β1-cardioselective (atenolol, metoprolol, bisoprolol) preserve bronchodilation at therapeutic doses; mixed α/β (carvedilol, labetalol) add vasodilation. α1-blockers (prazosin, doxazosin, tamsulosin) lower BP + relax urethra. α2-agonists (clonidine, guanfacine) suppress central sympathetic outflow. β2-agonists (albuterol, salmeterol) relax bronchial smooth muscle. Sympathomimetics (ephedrine, pseudoephedrine, phenylephrine, synephrine) activate α + β to varying degrees. NRI (atomoxetine) blocks NET, raising synaptic NE without the abuse potential of stimulants.
Organ Systems
cardiovascular
nervous
respiratory
Pathway Steps
norepinephrine → adrenergic-receptor-activation — via cross-link: catecholamine_synthesis pathway upstream (tyrosine → L-DOPA → dopamine → NE → epi). Norepinephrine (and epinephrine) activate adrenergic GPCRs whose subtype sets the response: α1 (Gq, vasoconstriction), α2 (Gi, presynaptic autoinhibition), β1 (Gs, cardiac stimulation), β2 (Gs, smooth-muscle relaxation), β3 (lipolysis/thermogenesis). This subtype diversity is the basis of selective adrenergic drugs (β-blockers, α-agonists).
adrenergic-receptor-activation → G-protein second-messenger response (β→Gs/cAMP, α1→Gq/Ca²⁺, α2→Gi) — via NET reuptake (atomoxetine target) — terminates synaptic NE; complements postsynaptic adrenoceptor antagonism. Adrenergic receptors are GPCRs whose downstream signal depends on subtype: β (Gs) raise cAMP/PKA, α1 (Gq) drive PLC→IP3/Ca²⁺, and α2 (Gi) lower cAMP. This subtype-to-G-protein coupling converts one transmitter into opposite tissue effects — and is exactly what subtype-selective agonists and blockers exploit.
norepinephrine → metanephrine — via COMT → MAO inactivation pathway (cross-link: monoamine_oxidase_metabolism). Norepinephrine is inactivated by reuptake (NET) and enzymatic metabolism: COMT and MAO convert it to normetanephrine and ultimately VMA. Plasma/urine metanephrines are the key biochemical test for pheochromocytoma — and blocking reuptake or metabolism (TCAs, MAO inhibitors) potentiates adrenergic signaling.
sotalol (inhibitor) — β1 + β2 (non-selective) + IKr block. class III antiarrhythmic by IKr block at higher doses; QT prolongation requires admission for initiation
labetalol (inhibitor) — β1 + β2 + α1 (mixed). mixed α/β; IV use in hypertensive emergencies + pregnancy HTN
prazosin (inhibitor) — α1. first-dose syncope; PTSD nightmare indication off-label; not a first-line HTN agent
doxazosin (inhibitor) — α1. BPH + HTN; ALLHAT showed worse HF outcomes vs thiazide — relegated to second-line
tamsulosin (inhibitor) — α1A (uroselective). BPH; uroselectivity minimizes BP effects but floppy-iris syndrome risk persists
clonidine (activator) — α2 (central). central sympatholysis lowers BP + heart rate; rebound HTN on abrupt discontinuation; also opioid-withdrawal symptom control
guanfacine (activator) — α2A (central). extended-release for ADHD (esp. impulsivity); sedation less than clonidine due to subtype selectivity
phenylephrine otc (activator) — α1. oral decongestant; 2023 FDA advisory committee found PO phenylephrine ineffective for nasal congestion (poor F)
pseudoephedrine (activator) — α1 + β1/β2 (mixed; releases NE). effective oral decongestant; behind-the-counter restrictions due to meth-precursor risk
ephedrine (activator) — α + β (mixed; releases NE). indirect sympathomimetic; ephedrine alkaloids banned from supplements 2004; IV pressor use persists
synephrine (activator) — α1 (selective in vitro). bitter orange supplement; weaker than ephedrine but flagged in dietary supplement safety reviews
salmeterol (activator) — β2 (long-acting). LABA; 12-hour duration via lipophilic membrane retention; never monotherapy in asthma (boxed warning)
albuterol (activator) — β2. SABA bronchodilator; rescue inhaler; tremor + hypokalemia at high doses
atomoxetine (inhibitor) — NET (norepinephrine transporter). non-stimulant ADHD; NRI raises NE + DA in PFC without abuse liability; CYP2D6 substrate (5× AUC in PM)
nebivolol (inhibitor) — β1 + NO release. highly selective β1 + endothelial NO release → vasodilation; HTN with favorable BP + erectile function profile
betaxolol (inhibitor) — β1 (cardioselective + ophthalmic for glaucoma). topical glaucoma; PO HTN; cross-link: aqueous_humor_iop_regulation
pindolol (inhibitor) — β1 + β2 with ISA (intrinsic sympathomimetic). non-selective β-blocker with partial agonist activity; less bradycardia than pure antagonists
esmolol (inhibitor) — β1 (ultra-short-acting IV). IV β-blocker; t½ ~9 min via RBC esterases; OR/ICU titration
salbutamol (activator) — β2 (SABA). salbutamol (UK term for albuterol); short-acting β2-agonist; asthma rescue
formoterol (activator) — β2 (LABA, fast onset). LABA with fast onset (1-3 min); component of ICS/LABA combos (Symbicort)