Adrenergic Drugs — Sympathomimetics and Sympatholytics

🟢 Lite — Quick Review (1h–1d)

Direct Adrenergic Agonists:

Drug	α	β1	β2	Clinical Use
Epinephrine	+++	++	++	Anaphylaxis, cardiac arrest, glaucoma
Norepinephrine	+++	++	0	Hypotensive shock, vasopressor
Isoproterenol	0	+++	+++	Bradycardia, heart block, bronchospasm
Dopamine	+	++	+	Shock, heart failure (dose-dependent)
Dobutamine	+	+++	+	Acute heart failure, cardiogenic shock
Phenylephrine	+++	0	0	Hypotension, nasal decongestion, mydriasis
Clonidine	α2 >> α1	0	0	Hypertension, ADHD, withdrawal states
Albuterol/Salbutamol	0	0	+++	Asthma, COPD (bronchodilator)
Terbutaline	0	0	+++	Asthma, preterm labor (tocolysis)
Midodrine	α1	0	0	Orthostatic hypotension

Indirect Adrenergic Agonists:

• Amphetamine — displaces NE from vesicles → ↑ catecholamine release
• Ephedrine — ↑ NE release + direct α/β agonism
• Tyramine — displaces NE from vesicles (found in aged cheese, wine; causes hypertensive crisis with MAO inhibitors)
• Cocaine — blocks NE reuptake (NET inhibition)

---

🟡 Standard — Regular Study (2d–2mo)

Catecholamine Pharmacokinetics:

• NOT effective orally (inactivated by COMT and MAO in gut/liver)
• Short duration of action (minutes)
• Administered: IV infusion, nebulization, intraocular
• Dobutamine — synthetic catecholamine; mixed α1 agonist + β1 agonist (net: ↑ contractility > ↑ afterload)
• Dopamine — endogenous catecholamine; dose-dependent receptors

Dopamine Receptors — Renal Protection:

• Low-dose dopamine (renal dose: 1-3 μg/kg/min) → D1 receptors → renal vasodilation → ↑ GFR → natriuresis
• Note: Landmark studies showed no renal protection in critically ill patients; low-dose dopamine no longer recommended

Shock — Vasopressor Choice:

Type of Shock	First-Line Vasopressor	Goal
Hypovolemic	Norepinephrine or dopamine	MAP > 65 mmHg
Cardiogenic	Norepinephrine	MAP > 65 mmHg, reduce inotropes
Septic (early/warm)	Norepinephrine	MAP > 65 mmHg
Neurogenic	Norepinephrine or phenylephrine	MAP > 65 mmHg
Anaphylactic	Epinephrine (IM)	Support circulation

α-Blockers:

Drug	Selectivity	Half-life	Clinical Use	Notes
Phenoxybenzamine	Non-competitive α1 = α2	Long (24h)	Pheochromocytoma (pre-op), frostbite	Irreversible (alkylation); causes reflex tachycardia
Phentolamine	Competitive α1 = α2	Short	Pheochromocytoma (intra-op), hypertensive crisis	Reversible; causes reflex tachycardia
Prazosin	α1 selective	3-4h	Hypertension, BPH (urinary symptoms)	“First-dose phenomenon” (orthostatic hypotension); less reflex tachycardia
Terazosin	α1 selective	12-24h	Hypertension, BPH	Long-acting; qDay dosing
Doxazosin	α1 selective	22h	Hypertension, BPH	qDay dosing; can cause floppy iris syndrome
Tamsulosin	α1A selective	12-15h	BPH (urinary symptoms)	Spares vascular α1B → minimal hypotension
Alfuzosin	α1A selective	10h	BPH	Less orthostatic hypotension
Silodosin	α1A selective	13-24h	BPH	Most uroselective α1A blocker

β-Blockers:

Drug	α1	β1	β2	ISA	MS	Notes
Propranolol	0	++	++	0	++	Non-selective; ↑ airway resistance; crosses BBB
Metoprolol	0	++	0	0	+	Cardioselective (β1 > β2 at low doses)
Atenolol	0	++	0	0	0	Cardioselective; hydrophilic (doesn’t cross BBB)
Bisoprolol	0	++	0	0	0	Cardioselective; COPD safer
Nebivolol	0	++	0	0	0	Cardioselective; + NO → vasodilation
Carvedilol	++	++	++	0	++	Non-selective; α1 + β blocker; used in heart failure
Labetalol	++	++	++	0	++	Non-selective; α1 + β blocker; IV for hypertensive emergency
Esmolol	0	++	0	0	0	Ultra-short acting; IV; titratable
Sotalol	0	++	++	0	++	Non-selective; class III + β blocker; QT prolongation

ISA (Intrinsic Sympathomimetic Activity): Partial agonist activity at β-receptors; less bradycardia, less CV depression

β-Blockers in Heart Failure:

• Carvedilol, Metoprolol succinate, Bisoprolol — mortality benefit (proven in trials)
• Start low dose, titrate slowly (↑ tolerance)
• Mechanism: ↓ HR → ↑ diastolic filling time, ↓ myocardial O₂ demand, anti-apoptotic, anti-remodeling

β-Blocker Toxicity/Withdrawal:

• Overdose: Bradycardia, hypotension, heart block, bronchospasm, hypoglycemia (masked), CNS depression
• Withdrawal syndrome: Tachycardia, hypertension, arrhythmias, angina — abrupt discontinuation contraindicated (especially in coronary artery disease)

---

🔴 Extended — Deep Study (3mo+)

Epinephrine — Complete Profile:

• Mechanism: Direct α1, α2, β1, β2 agonist
• Effects:
  • α1: Vasoconstriction → ↑ SBP and DBP, hemostasis
  • β1: ↑ HR, ↑ contractility, ↑ conduction → ↑ CO
  • β2: Bronchodilation, vasodilation (skeletal muscle)
• Dose-dependent response:
  • Low dose (1-2 μg/min): β > α → ↓ DBP (vasodilation), ↑ SBP
  • Medium dose (2-10 μg/min): α begins to predominate → ↑ SBP and DBP
  • High dose (10-50 μg/min): α predominates → marked vasoconstriction
• Clinical uses:
  • Anaphylaxis — IM 0.3-0.5 mg (1:1000) ASAP; can repeat q5-15min
  • Cardiac arrest — IV 1 mg (1:10,000) q3-5min
  • Glaucoma — topical (decreases aqueous humor production)
  • Hemostasis — topical for bleeding
• Contraindications: Angle-closure glaucoma, coronary artery disease (increases myocardial O₂ demand)

Norepinephrine:

• Mechanism: Direct α1 >> α2 > β1 agonist (minimal β2)
• Effect: ↑ SBP, ↑ DBP, ↑ TPR → ↑ MAP; reflex bradycardia (baroreceptor); minimal effect on β2
• Clinical use: Septic shock, cardiogenic shock (afterload reduction)
• Complication: Extravasation → tissue necrosis (use large IV line; avoid peripheral lines; treat extravasation with phentolamine or nitroglycerin)

Isoproterenol:

• Mechanism: Direct β1 = β2 agonist (no α activity)
• Effect: ↑ HR, ↑ contractility, bronchodilation, vasodilation → ↓ DBP
• Clinical use: Bradyarrhythmias, heart block (temporary pacing bridge), bronchospasm

Dobutamine:

• Mechanism: Synthetic catecholamine; mixture of (+) and (-) enantiomers; net: β1 > β2 > α1
• Effect: ↑ contractility (positive inotropy) → ↑ CO; mild β2 → vasodilation → ↓ afterload
• Clinical use: Acute decompensated heart failure, cardiogenic shock
• Note: Tachyphylaxis develops after 48-72h (β-receptor downregulation)

Milrinone:

• Mechanism: Phosphodiesterase-3 (PDE-3) inhibitor → ↑ cAMP → positive inotropy + vasodilation
• Effect: ↑ contractility, ↑ CO, ↓ PCWP, ↓ SVR
• Advantage over dobutamine: Does not increase myocardial O₂ demand as much; useful in β-blocker overdose
• Side effects: Arrhythmias, hypotension, thrombocytopenia (PDE-3 inhibition)

Levosimendan:

• Mechanism: Ca²⁺ sensitizer (binds troponin C) + PDE-3 inhibition → ↑ contractility without ↑ intracellular Ca²⁺
• Advantage: Does not increase myocardial O₂ demand; does not cause arrhythmias

Central α2-Agonists — Detailed:

Drug	Lipophilicity	Half-life	Clinical Use	Notes
Clonidine	Moderate	6-12h	Hypertension (centrally acting), ADHD, opioid withdrawal, menopausal hot flashes, spasticity	Patch available; rebound hypertension on abrupt withdrawal
Methyldopa	Moderate	2h (but effect ~12h)	Hypertension in pregnancy (safe in pregnancy)	Pro-drug; converted to α-methyl NE → false neurotransmitter → ↓ sympathetic outflow
Guanfacine	High	17h	ADHD (children), hypertension	Once daily; less sedation than clonidine
Tizanidine	Moderate	1.5h	Spasticity (MS, spinal cord injury)	Similar to clonidine but shorter acting
Dexmedetomidine	Very high	3-5h	ICU sedation (mechanically ventilated)	α2A selective; provides “cooperative sedation”

α2-Agonist Withdrawal:

• Rebound sympathetic hyperactivity → severe hypertension, tachycardia, anxiety
• Treatment: Reinstitute α2-agonist; nitroprusside or phentolamine for hypertensive crisis

Reserpine — Mechanism:

• Irreversibly inhibits VMAT (vesicular monoamine transporter) → catecholamines cannot be stored in vesicles → depleted over days
• Formerly used for hypertension; causes depression, parkinsonism

Guanethidine:

• Inhibits NE release from nerve terminals (blocks vesicle exocytosis)
• Formerly used for hypertension; causes orthostatic hypotension, diarrhea

Bretylium:

• Blocks NE release from nerve terminals (class III antiarrhythmic)
• Formerly used for ventricular arrhythmias

Imidazoline Receptors:

• Clonidine also acts on imidazoline I1 receptors in CNS → reduces sympathetic outflow
• Moxonidine, Rilmenidine — more selective for I1 receptors

Drug Interactions with β-Blockers:

Interaction	Mechanism	Effect
β-Blocker + Verapamil/Diltiazem	Negative inotropy + chronotropy	Severe bradycardia, heart failure, AV block
β-Blocker + Clonidine	Both ↓ sympathetic tone	Bradycardia, sedation; rebound HTN if clonidine stopped
β-Blocker + Digoxin	Additive bradycardia	Severe bradycardia, heart block
β-Blocker + Insulin/Sulfonylureas	Mask symptoms of hypoglycemia (except sweating)	Hypoglycemia awareness reduced
Non-selective β-blocker + β2-agonist (albuterol)	Bronchospasm	Worsened bronchospasm
β-Blocker withdrawal + OCPs	↑ β-receptor sensitivity	Hypertension, arrhythmias

Key NEET-PG Clinical Pearls:

• Hypertensive emergency + aortic dissection — treat with IV esmolol or labetalol (↓ HR + ↓ BP)
• Hypertensive emergency + pheochromocytoma — phentolamine (α-blocker) FIRST; never give β-blocker alone (unopposed α → severe HTN)
• Anaphylaxis — IM epinephrine BEFORE anything else; antihistamine and steroids are adjuncts (not first-line)
• Asthma/COPD + hypertension — avoid non-selective β-blockers; use cardioselective β1 blockers with caution; avoid propranolol
• Propranolol + thyroid storm — β-blockers control symptoms (tachycardia, tremor); prevent peripheral conversion of T4→T3
• Carvedilol in heart failure — unique α1 + β blockade + antioxidant effect; mortality benefit proven
• Nebivolol + hypertension — NO-mediated vasodilation; neutral on glucose/lipids; improves endothelial function
• Clonidine + opioid withdrawal — reduces autonomic symptoms of withdrawal; not analgesic
• Dexmedetomidine — ideal ICU sedation; patient arousable and cooperative; no respiratory depression; causes bradycardia
• First-dose phenomenon with prazosin — orthostatic hypotension with first dose; take at bedtime; less with subsequent doses
• Tamsulosin — most uroselective α1A blocker; minimal effect on blood pressure; causes intraoperative floppy iris syndrome (stop before cataract surgery)

---

Content adapted based on your selected roadmap duration. Switch tiers using the selector above.