Adrenergic Agonists

Adrenergic agonists (sympathomimetics) are drugs that mimic the actions of the sympathetic nervous system by activating adrenoceptors. Mastering their receptor selectivity is the single highest-yield concept that unlocks shock management, anaphylaxis, bronchodilation and a huge slice of integrated pharmacology MCQs.

Definition & classification

A sympathomimetic is any agent that produces effects resembling those of adrenergic (sympathetic) nerve stimulation. They are classified by mechanism and by receptor selectivity.

By mechanism of action:

• Direct-acting — bind and activate the receptor directly (adrenaline, noradrenaline, dopamine, dobutamine, phenylephrine, salbutamol, clonidine).
• Indirect-acting — increase noradrenaline (NA) availability at the synapse by promoting release (tyramine, amphetamine) or blocking reuptake (cocaine).
• Mixed-acting — both displace stored NA and directly stimulate receptors (ephedrine, pseudoephedrine).

High-yield: Indirect-acting amines (tyramine, amphetamine) depend on intact NA stores. Their effect is abolished by reserpine (depletes vesicles) and by prior treatment with cocaine/TCAs only for tyramine (which needs uptake-1 to enter the nerve), but potentiated for those acting purely on the receptor. Reserpine + tyramine = no response is a classic stem.

Adrenoceptor subtypes — the master table

Receptor	G-protein / 2nd messenger	Key location	Principal effect
α1	Gq → ↑IP3/DAG → ↑Ca²⁺	Vascular smooth muscle, pupillary dilator, bladder trigone, prostate	Vasoconstriction, mydriasis, ↑BP, contraction
α2	Gi → ↓cAMP	Presynaptic nerve terminal (CNS), pancreatic β-cell, platelets	↓NA release, sedation, ↓insulin, platelet aggregation
β1	Gs → ↑cAMP	Heart (SA node, myocardium), JG apparatus	↑HR, ↑contractility, ↑renin
β2	Gs → ↑cAMP	Bronchi, uterus, skeletal muscle vessels, liver	Bronchodilation, tocolysis, vasodilation, glycogenolysis
β3	Gs → ↑cAMP	Adipose tissue, detrusor	Lipolysis, bladder relaxation (mirabegron target)
D1	Gs → ↑cAMP	Renal, mesenteric, coronary vasculature	Vasodilation (↑renal blood flow)
D2	Gi → ↓cAMP	Presynaptic, pituitary, CTZ	↓NA release, prolactin inhibition

High-yield: α1 = Gq (IP3/DAG); α2 = Gi; all β = Gs. "α1 raises calcium, β raises cAMP, α2 lowers cAMP." This single line answers most second-messenger MCQs.

Receptor selectivity of the key agents

This is the conceptual spine of the topic. Learn the relative affinities, not just "yes/no".

Drug	α1	α2	β1	β2	D	Net haemodynamic signature
Adrenaline	++	++	+++	++	–	Low dose β predominates (↓DBP, ↑HR); high dose α predominates (↑↑BP)
Noradrenaline	+++	+++	++	–	–	↑↑SVR, reflex bradycardia, little β2
Dopamine	dose-dependent		+	–	+++ (low dose)	Low: D1 (renal); mid: β1; high: α1
Dobutamine	–	–	+++	+	–	↑contractility, modest ↓afterload
Isoprenaline	–	–	+++	+++	–	Pure β: ↑HR, ↓DBP, bronchodilation
Phenylephrine	+++	–	–	–	–	Pure α1 vasoconstrictor, reflex bradycardia
Salbutamol	–	–	– (+)	+++	–	Bronchodilation, tocolysis
Clonidine	–	+++ (central)	–	–	–	Central α2 → ↓sympathetic outflow → ↓BP

High-yield: Noradrenaline has negligible β2 action → unopposed α1 vasoconstriction → reflex (vagal) bradycardia despite its β1 effect. Adrenaline, by contrast, has strong β2 → vasodilation in skeletal muscle beds.

Pharmacodynamics — the adrenaline biphasic response

Adrenaline is the most-tested drug because its effect reverses with dose and with prior α-blockade.

Low-dose adrenaline (β2 > α1 in vessels) → skeletal muscle vasodilation → ↓diastolic BP; β1 → ↑HR, ↑systolic BP. Net: mean BP roughly unchanged or slightly down, pulse pressure widens.

High-dose adrenaline (α1 dominates) → generalised vasoconstriction → ↑↑systolic and diastolic BP.

Adrenaline (vasomotor) reversal

If an α-blocker (e.g., phentolamine, phenoxybenzamine) is given first, then adrenaline:

α1 is blocked → only β2 vasodilation is expressed → BP falls instead of rising.

Flow: Adrenaline alone → ↑BP → add α-blocker → re-give adrenaline → ↓BP (reversal).

High-yield: "Adrenaline reversal" is seen ONLY with adrenaline (has β2), NOT with noradrenaline or phenylephrine (no meaningful β2 to unmask). A classic single-best-answer trap.

High-yield: Dale's vasomotor reversal phenomenon is the historical eponym for adrenaline reversal.

Clinical applications — drug of choice by scenario

1. Anaphylaxis — adrenaline IM is the unequivocal DOC

• Route/dose: 0.5 mg IM (0.5 mL of 1:1000) into the anterolateral thigh (vastus lateralis); repeat every 5–15 min. Paediatric: 0.01 mg/kg.
• Why adrenaline? It is the only drug hitting every pathophysiological arm at once:
  • α1 → reverses vasodilation/hypotension and mucosal oedema.
  • β1 → inotropy/chronotropy.
  • β2 → bronchodilation + stabilises mast cells (↓mediator release).

High-yield: IM (not subcutaneous, not first-line IV) is preferred — faster, more reliable absorption, lower arrhythmia risk. IV adrenaline is reserved for refractory shock/arrest under monitoring.

2. Cardiac arrest

Adrenaline 1 mg IV every 3–5 minutes (the α1 effect raising aortic diastolic pressure improves coronary perfusion — the main benefit, more than the β effect).

3. Shock — vasopressor & inotrope selection

Shock type	First-line agent	Rationale
Septic / distributive	Noradrenaline	Restores SVR via α1; less tachyarrhythmia than dopamine
Cardiogenic	Dobutamine (± noradrenaline if hypotensive)	β1 inotropy, ↓afterload, improves CO
Anaphylactic	Adrenaline	Covers all arms (above)
Refractory septic (vasopressin sparing)	add vasopressin / adrenaline	second-line catecholamine

High-yield: Noradrenaline is the first-line vasopressor in septic shock (SCC / Surviving Sepsis). Dopamine is no longer preferred — it causes more arrhythmias and showed no mortality benefit (SOAP II trial).

4. Acute decompensated heart failure / low-output states

Dobutamine — selective β1 agonist → ↑contractility with mild β2 afterload reduction; raises cardiac output without large rises in SVR. Useful for short-term support.

5. Bronchospasm / asthma & COPD

• SABA: salbutamol (albuterol), terbutaline — acute relief, β2-selective.
• LABA: salmeterol, formoterol — maintenance, always with ICS in asthma.
• Ultra-LABA: indacaterol, vilanterol (once daily, COPD).

High-yield: β2 agonist adverse effects to recognise: fine tremor (most common), tachycardia, hypokalaemia (β2 drives K⁺ intracellularly — exploited to treat hyperkalaemia), hyperglycaemia, lactic acidosis at high dose.

6. Other targeted uses

• Phenylephrine / oxymetazoline — nasal decongestant, mydriatic without cycloplegia, treats SVT-associated hypotension (reflex bradycardia terminates SVT).
• Clonidine, methyldopa, dexmedetomidine — central α2 agonists → ↓sympathetic outflow → antihypertensive; dexmedetomidine for ICU sedation (no respiratory depression). Clonidine also for opioid withdrawal and ADHD.
• Terbutaline / ritodrine — β2 tocolytics in preterm labour.
• Mirabegron — β3 agonist for overactive bladder.
• Dopamine (low "renal" dose 1–3 µg/kg/min) — historically for renal protection; now discredited (no benefit on renal outcomes).
• Fenoldopam — selective D1 agonist for hypertensive emergency with renal impairment.

Dose-dependent pharmacology of dopamine — must-know ladder

1–3 µg/kg/min → D1 (renal/mesenteric vasodilation, natriuresis) → 3–10 µg/kg/min → β1 (↑contractility, ↑HR, ↑CO) → >10 µg/kg/min → α1 (vasoconstriction, ↑SVR, ↑BP)

High-yield: This dose ladder (D1 → β1 → α1 as dose climbs) is a perennial favourite. Remember "Dopamine Dilates, then Drives, then Constricts."

Pharmacokinetics & administration pearls

• Catecholamines (adrenaline, NA, dopamine, dobutamine, isoprenaline) are inactivated by COMT and MAO, are not orally active, do not cross the blood–brain barrier well, and have a short plasma half-life (~2 min) → given by IV infusion.
• The catechol ring (3,4-dihydroxy) confers COMT susceptibility; removing one hydroxyl (e.g., in salbutamol, ephedrine) → longer acting and orally active.
• A large N-substituent increases β selectivity (isoprenaline = isopropyl → pure β); a small/absent one favours α (NA, phenylephrine).
• Extravasation of NA/adrenaline → local ischaemic necrosis; antidote is local phentolamine (α-blocker) infiltration.

Drug interactions worth memorising

• MAO inhibitors + tyramine-rich food (cheese, wine) → hypertensive crisis ("cheese reaction") — tyramine accumulates and massively releases NA.
• Non-selective β-blockers + adrenaline → unopposed α1 → severe hypertension + reflex bradycardia (important in anaphylaxis on a patient taking propranolol — may need glucagon).
• β2 agonists + thiazide/loop diuretics → additive hypokalaemia.
• Cocaine / TCAs potentiate direct sympathomimetics (block uptake-1) but blunt tyramine's effect.

Complications & adverse effects

• Cardiac: tachyarrhythmias, palpitations, angina, hypertensive crisis (especially with α agonists or in phaeochromocytoma).
• CNS: anxiety, tremor, headache, restlessness, insomnia (more with CNS-penetrant agents).
• Metabolic: hyperglycaemia, hypokalaemia, lactic acidosis (β2).
• Local: tissue necrosis on extravasation (α), reactive nasal congestion / rhinitis medicamentosa with prolonged topical decongestants.
• Tolerance/tachyphylaxis with indirect-acting amines (NA store depletion).

Key differentials & "which agent" reasoning

Clinical clue	Pick this agonist
Anaphylaxis with stridor + hypotension	Adrenaline IM
Septic shock, fluid-refractory	Noradrenaline
Cardiogenic shock, normotensive low CO	Dobutamine
Acute severe asthma	Nebulised salbutamol
SVT with hypotension (raise BP, terminate via reflex bradycardia)	Phenylephrine
Hypertensive emergency + renal impairment	Fenoldopam (D1)
ICU sedation without respiratory depression	Dexmedetomidine (α2)
Preterm labour	Terbutaline / ritodrine (β2)
Overactive bladder	Mirabegron (β3)

High-yield: Distinguish isoprenaline (pure β, both β1 + β2 → ↓DBP, reflex tachycardia) from dobutamine (β1 selective) and adrenaline (α + β). The isoprenaline triad: marked ↑HR, ↓diastolic BP, bronchodilation.

Mnemonics

• "QISS QIQ" for G-proteins: α1 = Q(Gq), α2 = I(Gi), β1 = S(Gs), β2 = S, β3 = S, then D1 = S, D2 = I → reads Q-I-S-S, S-S-I.
• β1 = 1 heart; β2 = 2 lungs ("you have one heart and two lungs").
• Dopamine ladder: "Dopamine Dilates, Drives, then Constricts."
• Adrenaline in anaphylaxis covers "ABC" — Airway (β2 bronchodilation), Blood pressure (α1), Cardiac output (β1).

Recently asked / exam angle

• Receptor–second-messenger matching: α1→Gq/IP3, β→Gs/cAMP, α2/D2→Gi (repeatedly tested).
• First-line vasopressor in septic shock = noradrenaline (post-SOAP II shift away from dopamine) — high-frequency clinical pharmacology stem.
• Adrenaline reversal phenomenon and why it does not occur with noradrenaline.
• Route of adrenaline in anaphylaxis = IM anterolateral thigh — guideline-based MCQ.
• β2 agonist used to treat hyperkalaemia (drives K⁺ into cells) — integration with medicine.
• Dopamine dose ladder and the obsolete "renal-dose dopamine".
• Dexmedetomidine / clonidine = α2 agonists, mechanism via ↓central sympathetic outflow.
• Tyramine–MAOI cheese reaction; reserpine abolishing tyramine response.
• Selectivity sorting: identify the "pure α1" (phenylephrine) vs "pure β" (isoprenaline) vs "β1-selective inotrope" (dobutamine).
• Mirabegron = β3 (overactive bladder); fenoldopam = D1 (hypertensive emergency).

Rapid revision

1. α1 = Gq (↑IP3/DAG/Ca²⁺); α2 = Gi (↓cAMP, ↓NA release); all β = Gs (↑cAMP).
2. β1 → heart (1 heart); β2 → bronchi + uterus (2 lungs); β3 → fat + bladder.
3. Adrenaline: low dose β predominates (↓DBP), high dose α predominates (↑↑BP) — biphasic.
4. Adrenaline reversal happens because β2 is unmasked after α-blockade; does NOT occur with noradrenaline.
5. Noradrenaline → α1 ↑↑SVR + reflex bradycardia; minimal β2.
6. Anaphylaxis DOC = adrenaline 0.5 mg IM anterolateral thigh, repeat q5–15 min.
7. Septic shock first-line vasopressor = noradrenaline (not dopamine — SOAP II).
8. Cardiogenic shock with low CO = dobutamine (β1 inotrope).
9. Dopamine dose ladder: D1 (low) → β1 (mid) → α1 (high); renal-dose dopamine is obsolete.
10. β2 agonists cause tremor, tachycardia, hypokalaemia (used to treat hyperkalaemia), hyperglycaemia.
11. Clonidine/methyldopa/dexmedetomidine = central α2 agonists → ↓sympathetic outflow → ↓BP.
12. Catecholamines are degraded by COMT + MAO, not orally active, very short t½ → IV infusion; extravasation antidote = local phentolamine.