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PH2.{1,3} | PH2.{1,3} | Adrenergic Drugs and Emergency Sympathomimetic Use — SDL Guide — SDL Guide (Part 2)

Adrenergic Agonists — PK, PD, Uses, and Adverse Effects

Adrenergic agonists are among the most pharmacokinetically constrained drugs in the formulary: most catecholamines (adrenaline, noradrenaline, dopamine, dobutamine) are polar, cannot cross the blood-brain barrier, undergo extensive first-pass O-methylation (COMT) and oxidative deamination (MAO), and have plasma half-lives of 1–3 minutes. This mandates IV infusion for systemic emergency use. Exceptions: salbutamol is inhaled for local bronchial effect (oral bioavailability is limited); ephedrine and pseudoephedrine are orally effective (non-catecholamine structure, not MAO/COMT substrates).

Drug	Receptor profile	Key uses	Major ADRs	Key cautions
Adrenaline	α1, α2, β1, β2, β3 (all)	Anaphylaxis (IM), cardiac arrest (IV), severe asthma (IM/SC)	Palpitations, hypertension, arrhythmia, anxiety, tremor, ischaemia	Halothane anaesthesia (sensitises myocardium → VF); narrow-angle glaucoma
Noradrenaline	α1, α2, β1 (negligible β2)	Septic shock (IV infusion), vasodilatory shock	Peripheral ischaemia (gangrene at high doses), arrhythmia, reflex bradycardia via α1-mediated BP rise	Extravasation → tissue necrosis (phentolamine antidote); hypertension
Dopamine	D1/D2 (low), β1 (mid), α1 (high)	Cardiogenic/distributive shock, acute HF, dopamine renal-dose (historically, now controversial)	Tachyarrhythmias, nausea, vasoconstriction at high doses	Tachycardia limits use in AF; phaeochromocytoma (avoid)
Dobutamine	β1 selective	Acute decompensated HF, cardiogenic shock, cardiac stress test	Tachycardia, ectopics, angina (↑O₂ demand), hypotension (β2 at high doses)	Avoid in HOCM (↑outflow tract obstruction)
Phenylephrine	α1 selective	Vasopressor (spinal hypotension, adjunct in shock), nasal decongestant, eye drops (mydriasis)	Reflex bradycardia, hypertension, peripheral ischaemia	Low cardiac output states (↑afterload → worse)
Salbutamol	β2 selective	Asthma/COPD (inhaled), hyperkalaemia (IV), tocolysis (IV)	Tremor, palpitations, hypokalaemia (β2 → K⁺ into cells), headache	Cardiac disease (tachycardia)
Ephedrine	Mixed α + β (indirect + direct)	Spinal anaesthesia hypotension (IV), bronchospasm (oral, now restricted)	Insomnia, hypertension, tachycardia, urinary retention	MAO inhibitors (hypertensive crisis); repeated use → tachyphylaxis

Key PD principle: receptor selectivity is dose-dependent. Dopamine acts on D1 at 1–3 mcg/kg/min, β1 at 3–10 mcg/kg/min, and α1 at >10 mcg/kg/min. Even 'selective' agents lose selectivity at supratherapeutic doses — salbutamol at very high IV doses activates β1 (tachycardia).

Adrenergic Antagonists — Alpha and Beta Blockers

Adrenergic antagonists block catecholamine access to adrenoceptors. Their clinical utility derives from removing pathological sympathetic tone — in hypertension, ischaemic heart disease, heart failure, and phaeochromocytoma. Pharmacokinetically, beta-blockers as a class are well-absorbed orally, but vary in lipophilicity: lipophilic agents (propranolol, metoprolol) cross the blood-brain barrier (CNS effects — dreams, depression); hydrophilic agents (atenolol) do not. Beta-blockers are largely renally or hepatically cleared; dose adjustment is needed in renal failure for atenolol.

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Alpha-blockers in detail:
- Phenoxybenzamine: irreversible, non-competitive α-block (covalent alkylation). Duration 24–48 hours (requires new receptor synthesis to reverse). Used for pre-operative α-blockade in phaeochromocytoma (started 10–14 days before surgery). Major ADRs: postural hypotension (especially on first standing), reflex tachycardia, nasal stuffiness, miosis.
- Phentolamine: competitive, reversible, non-selective α-blocker. Short-acting IV drug used for phaeochromocytoma crisis (hypertensive emergency) and to reverse noradrenaline extravasation tissue necrosis (local injection). Causes reflex tachycardia (block α2 presynaptic → ↑NA release + direct β stimulation).
- Prazosin / terazosin / doxazosin: selective α1 blockade. No presynaptic α2 block → less reflex tachycardia. Uses: hypertension, benign prostatic hyperplasia (α1A in bladder neck/prostate). First-dose hypotension is a well-known class effect — always start with a low dose at bedtime.

Beta-blockers in detail:
- Propranolol: prototype non-selective β-blocker (β1 + β2). Uses: hypertension, angina, arrhythmias (supraventricular), essential tremor, portal hypertension (↓splanchnic flow), thyroid storm. Contraindicated in asthma/COPD (β2 blockade → bronchoconstriction). Also contraindicated in significant bradycardia, heart block, and decompensated HF (acute).
- Atenolol / metoprolol / bisoprolol: cardioselective β1-blockers (ISA absent in most). Preferred when beta-blockade is needed in patients with mild-to-moderate reactive airway disease (still use with caution — selectivity is relative, lost at high doses). Uses: hypertension, stable angina, post-MI, HF (bisoprolol — mortality benefit in HFrEF).
- Carvedilol: non-selective β + α1 blocker. Used in HFrEF (evidence-based: reduces all-cause mortality and hospitalisation in systolic HF — targets both β1-mediated adverse remodelling and α1-mediated vasoconstriction). Additional anti-oxidant properties. Dose must be titrated up slowly in HF (start low, go slow).
- Labetalol: α1 + β1 + β2 blocker (α:β ratio ~1:7 IV, ~1:3 oral). Used in hypertensive emergencies, particularly in pregnancy (safe profile; does not cause foetal bradycardia at standard doses unlike other beta-blockers).

Critical class effect: rebound hypertension on abrupt beta-blocker withdrawal — receptor upregulation during chronic blockade means sudden cessation causes exaggerated sympathetic response. Always taper.

Emergency Use of Sympathomimetic and Parasympatholytic Drugs: Case-Based Decision Making

Emergency pharmacology demands rapid, protocol-driven decision-making grounded in receptor pharmacology. The five high-yield emergency scenarios below each follow a structured decision logic: identify the physiological defect → match the receptor target → select the drug → specify dose/route/monitoring.

Scenario 1 — Anaphylaxis
Physiology: IgE-mediated mast-cell degranulation → histamine + prostaglandins → vasodilation (↓SVR → hypotension) + bronchoconstriction + urticaria/angioedema.
Drug of choice: Adrenaline (epinephrine).
- Route: intramuscular (IM), lateral thigh (vastus lateralis). IM provides faster, more reliable absorption than SC; IV only in cardiac arrest or unresponsive to IM.
- Dose: 0.5 mg (500 mcg) IM of 1:1000 solution (1 mg/mL) for adults. Children: 0.01 mg/kg IM (max 0.5 mg).
- Rationale: α1 → vasoconstriction → restores BP + reduces urticaria/angioedema; β2 → bronchodilation; β1 → ↑HR and inotropy.
- Repeat in 5–15 min if no improvement. Adjuncts: IV fluid, antihistamine, corticosteroid (slower onset, prevent biphasic).

Scenario 2 — Septic Shock
Physiology: cytokine-driven vasodilation → ↓SVR → distributive hypotension, often with preserved/elevated CO early.
First-line vasopressor: Noradrenaline (norepinephrine).
- Dose: 0.01–3 mcg/kg/min IV infusion (central line preferred; titrate to MAP ≥65 mmHg).
- Rationale: strong α1 (vasoconstriction → ↑SVR → ↑MAP) + β1 (maintains CO) with less tachyarrhythmia than adrenaline.
- Dopamine is an alternative (especially with bradycardia) but meta-analyses (SOAP-II trial) show higher arrhythmia rates; guideline recommendation is noradrenaline as first-line.

Scenario 3 — Cardiac Arrest
Protocol: adrenaline 1 mg IV (1:10,000 solution = 0.1 mg/mL) every 3–5 minutes during CPR.
Rationale: α1-mediated vasoconstriction → ↑coronary + cerebral perfusion pressure during CPR. Note: the PARAMEDIC2 RCT showed adrenaline improved return of spontaneous circulation (ROSC) but NOT survival with favourable neurological outcome at 30 days (the benefit is haemodynamic; neurological outcome depends on CPR quality and time to defibrillation).

Scenario 4 — Acute Decompensated Heart Failure (Cardiogenic Shock)
Physiology: reduced LV contractility → ↓CO → hypotension despite normal/elevated filling pressures.
Drug: Dobutamine 2.5–20 mcg/kg/min IV infusion.
Rationale: selective β1 agonism → ↑contractility → ↑CO. Some β2-mediated vasodilation at higher doses reduces afterload (beneficial). Avoid in hypovolaemia (need adequate preload). Monitor for tachycardia and ventricular ectopy.

Scenario 5 — Bradycardia and Organophosphate (OPC) Poisoning: Atropine
Atropine is a competitive muscarinic antagonist (parasympatholytic, not adrenergic), but PH2.3 explicitly requires its emergency demonstration because it antagonises the excessive cholinergic state seen in OPC poisoning and in vagally mediated bradycardia.
- Bradycardia (symptomatic sinus bradycardia / AV block): atropine 0.5–1 mg IV bolus, repeat up to 3 mg total. Mechanism: blocks M2 receptors at SA node → removes vagal brake → ↑HR.
- OPC/organophosphate poisoning: atropine 2–4 mg IV (repeated large doses — up to 20 mg or more in severe poisoning) to dry secretions and restore HR. Titrate to secretions (salivation, bronchospasm) not to tachycardia. Pair with pralidoxime (oxime to reactivate AChE — give before ageing).

Emergency	Drug	Dose	Route	Monitoring
Anaphylaxis	Adrenaline	0.5 mg (adult)	IM — lateral thigh	BP, SpO2, HR, symptoms
Septic shock	Noradrenaline	0.01–3 mcg/kg/min	IV infusion (central)	MAP ≥65, urine output, lactate
Cardiac arrest	Adrenaline	1 mg every 3–5 min	IV bolus	ROSC, rhythm
Acute HF/cardiogenic shock	Dobutamine	2.5–20 mcg/kg/min	IV infusion	CO/CI, BP, HR, arrhythmia
Bradycardia	Atropine	0.5–1 mg (up to 3 mg)	IV bolus	HR, AV conduction
OPC poisoning	Atropine	2–4 mg (repeat)	IV bolus	Secretions dry, bronchospasm

Emergency Adrenergic Drug Selection Flowchart