What are adrenergic receptors and how do they signal?
Adrenergic receptors (adrenoceptors) are the targets of noradrenaline released from sympathetic nerve endings and of adrenaline released from the adrenal medulla. They fall into two classes, alpha (α) and beta (β), subdivided into α1, α2, β1, β2 and β3. Both α1 and α2 have three further subtypes, but exams stop at the five main types.
All adrenoceptors are G-protein-coupled receptors. The G-protein decides the second messenger, and that single fact answers most mechanism questions:
| Receptor | G-protein | Second messenger | Net cell effect |
|---|---|---|---|
| α1 | Gq | Phospholipase C → IP3 + DAG → intracellular calcium rises | Smooth muscle contraction |
| α2 | Gi | Adenylate cyclase inhibited → cAMP falls | Mixed; presynaptic inhibition, central sympatholysis (clonidine) |
| β1 | Gs | Adenylate cyclase activated → cAMP rises | Heart rate and force up, renin release |
| β2 | Gs (also couples to Gi) | cAMP rises | Smooth muscle relaxation (bronchi, uterus, vessels) |
| β3 | Gs (also couples to Gi) | cAMP rises | Lipolysis; detrusor relaxation (basis of mirabegron) |
Where is each adrenergic receptor and what does it do?
| Receptor | Key locations | Effect of stimulation | Selective agonist (use) |
|---|---|---|---|
| α1 | Vascular smooth muscle, myocardium, radial (dilator) muscle of iris | Vasoconstriction → raised BP; positive inotropy; mydriasis | Phenylephrine (decongestant, vasopressor), oxymetazoline (decongestant) |
| α2 | CNS — nucleus tractus solitarii, medulla (site of clonidine action) | Mixed smooth muscle effects; central fall in sympathetic outflow → hypotension, bradycardia, sedation, dry mouth | Clonidine, methyldopa (hypertension), dexmedetomidine (ICU sedation) |
| β1 | Heart, kidney (juxtaglomerular apparatus), fat cells | Heart rate and contractility up; renin release; lipolysis | Dobutamine (cardiogenic shock, heart failure, stress echo) |
| β2 | Smooth muscle of airways, uterus, intestine and systemic vessels; skeletal muscle; liver | Bronchodilation, uterine relaxation, vasodilation; potassium shift into cells; glycogenolysis; tremor | Salbutamol (albuterol), salmeterol (asthma); terbutaline (tocolysis) |
| β3 | Adipose tissue, bladder detrusor | Lipolysis; detrusor relaxation | Mirabegron (overactive bladder) |
β2 effects explain the side-effect list of salbutamol: tremor, tachycardia, palpitations, hypokalaemia (β2 stimulates membrane Na⁺/K⁺-ATPase and pushes potassium into cells) and hyperglycaemia (glycogenolysis). The potassium shift is put to use — nebulised salbutamol is a rapid temporising treatment for hyperkalaemia. Terbutaline is used off-label as a short-term tocolytic, but prolonged use beyond 48–72 hours is not advised because of maternal cardiovascular risk.
How do adrenaline, noradrenaline, dopamine and dobutamine differ?
| Drug | Receptors | Haemodynamic signature | Main clinical use |
|---|---|---|---|
| Adrenaline (epinephrine) | All α and β receptors | Low dose: β effects (bronchodilation, ↑ cardiac output); high dose: α vasoconstriction | Anaphylaxis, cardiac arrest, croup |
| Noradrenaline (norepinephrine) | α1, α2, β1 (little β2) | Intense vasoconstriction, ↑ BP; reflex bradycardia may follow | First-line vasopressor in septic shock unresponsive to fluids |
| Dopamine | D1 + β1 + α1 (dose-dependent) | See dose table below | Hypotension, bradycardia (largely replaced by noradrenaline in shock) |
| Dobutamine | Selective β1 agonist (racemic mixture) | ↑ contractility and cardiac output | Cardiogenic shock, decompensated heart failure, pharmacological stress echo |
| Isoprenaline (isoproterenol) | Non-selective β | ↑ heart rate | Bradycardia and heart block |
Selectivity is dose-dependent: these drugs bind more receptor types at higher doses and lose selectivity. Adrenaline at low doses mainly activates β receptors; at higher doses α receptors take over and vascular tone rises. Noradrenaline is less likely than other pressors to cause arrhythmias, probably because it is relatively more α1- than β1-selective.
In shock, noradrenaline is the usual first agent to restore arterial pressure. If tissue perfusion remains low despite an adequate pressure, dobutamine can be added to raise cardiac output. The Society of Critical Care Medicine recommends noradrenaline over dopamine for children with septic shock.
What are the dose-dependent effects of dopamine?
| Infusion rate | Dominant receptor | Effect |
|---|---|---|
| Low: < 2 mcg/kg/min | Dopaminergic D1 | Renal and mesenteric vasodilation, diuresis — but no proven renal benefit |
| Moderate: 5–10 mcg/kg/min | β1 | ↑ heart rate and contractility → ↑ cardiac output |
| High: > 10 mcg/kg/min | α1 | Peripheral vasoconstriction → ↑ BP |
Dopamine receptors fall into a D1 class (D1, D5) that stimulates adenylyl cyclase and a D2 class (D2, D3, D4) that inhibits it. Activation of D1 receptors on smooth muscle and on the proximal tubule and cortical collecting duct promotes diuresis.
What is adrenaline reversal (vasomotor reversal)?
Adrenaline normally raises blood pressure because its α1 vasoconstriction outweighs its β2 vasodilation. If the α receptors are first blocked, the β2 vasodilator action is unmasked, and the same dose of adrenaline now lowers blood pressure. This is adrenaline (vasomotor) reversal.
- Normal: adrenaline → α1 (constriction) > β2 (dilation) → BP rises.
- After an α-blocker (phenoxybenzamine, phentolamine, or a drug with α-blocking action such as chlorpromazine): only β2 dilation remains → BP falls, with tachycardia.
- After α-blocker plus β-blocker: neither effect remains; the hypotension is abolished.
- Noradrenaline shows no reversal, because it has little β2 action — α blockade simply blunts its pressor effect.
An animal study in Anesthesia Progress (2014) showed this directly: in rats pretreated with chlorpromazine, adrenaline caused significant dose-dependent hypotension and tachycardia; when propranolol was added to chlorpromazine, adrenaline caused modest hypertension instead, confirming that the hypotension is β-receptor mediated. StatPearls likewise lists α-blockers among drugs that antagonise the pressor effect of adrenaline.
How is adrenaline used in anaphylaxis and cardiac arrest?
| Situation | Dose | Route and strength | Repeat |
|---|---|---|---|
| Anaphylaxis — adult (≥ 30 kg) | 0.3–0.5 mg | IM, 1:1000 (1 mg/mL), anterolateral thigh | Every 5–10 min as needed |
| Anaphylaxis — child | 0.01 mg/kg (or 0.15 mg auto-injector) | IM | Every 5–10 min |
| Cardiac arrest — adult | 1 mg | IV/IO, 0.1 mg/mL (1:10,000) | Every 3–5 min until ROSC |
| Cardiac arrest — child | 0.01 mg/kg (max 1 mg) | IV/IO, 0.1 mg/mL | Every 3–5 min |
| Cardiac arrest — no IV/IO | 2–2.5 mg | Endotracheal | Every 3–5 min |
- IM beats SC and IV in anaphylaxis: faster delivery and better outcomes. The thigh is preferred to the deltoid.
- IV adrenaline needs the 1:10,000 strength and carries a much higher risk of cardiovascular complications — reserve it for refractory cases, ideally as an infusion.
- Biphasic reactions occur in up to 20% of cases (clinically significant in 4–5%), so patients are observed after recovery.
- Patients on β-blockers may respond poorly and are at risk of unopposed α effects — monitor BP closely.
- Serum tryptase stays raised for several hours and can confirm anaphylaxis, but its sensitivity is low.
What are the adverse effects, interactions and contraindications?
| Receptor stimulated | Typical adverse effects | Caution / relative contraindication |
|---|---|---|
| α1 | Hypertension, reflex bradycardia (phenylephrine) | Hypertension, bradycardia, prostatic hyperplasia |
| α2 | Hypotension, dry mouth, sedation; respiratory depression at high doses | Low BP; elderly (falls) |
| β1 | Tachycardia, palpitations, tachyarrhythmias, anxiety | Arrhythmias |
| β2 | Tremor, tachycardia, palpitations, hypokalaemia, hyperglycaemia | Hypokalaemia |
| Non-selective (adrenaline, noradrenaline) | Tachycardia, hypertension, arrhythmias | Halothane anaesthesia; angle-closure glaucoma (adrenaline) |
- Halothane and cyclopropane sensitise the myocardium — adrenaline and noradrenaline then provoke dangerous arrhythmias.
- Adrenaline is contraindicated in angle-closure glaucoma (it dilates the pupil).
- Potentiate adrenaline: β-blockers, tricyclic antidepressants, MAO and COMT inhibitors, other sympathomimetics.
- Antagonise its pressor effect: α-blockers, nitrates and other vasodilators, diuretics.
- Beta-blockers can be used to treat tachycardia and hypertension from vasopressor excess.
What are the commonly tested traps on adrenergic drugs?
- Dobutamine is the classic selective β1 agonist; the question 'inotrope for cardiogenic shock' or 'pharmacological stress echo' → dobutamine (stress dose starts at 5 mcg/kg/min, rising by 10 every 3–5 min).
- Dexmedetomidine (α2) sedates without respiratory depression and leaves the patient arousable — useful in awake craniotomy and deep brain stimulator implantation.
- Clonidine and methyldopa are α2 agonists; methyldopa is used for gestational hypertension. Clonidine acts centrally to cut sympathetic outflow, causes dry mouth and sedation, must be tapered to avoid rebound hypertension, and has been misused with opioids.
- Mirabegron is a β3 agonist for overactive bladder — not an antimuscarinic.
- Phenylephrine (α1) gives mydriasis without cycloplegia and causes reflex bradycardia when given IV.
- Prolonged continuous salbutamol in paediatric status asthmaticus can cause hypokalaemia and raised liver enzymes.