5.4 Adrenergic Drugs (Sympathomimetics)
Adrenergic drugs mimic sympathetic nervous system activation by stimulating α and β adrenergic receptors, either directly or indirectly. They are essential for treating shock, heart failure, asthma, anaphylaxis, and nasal congestion.
Mechanisms of Action
Direct-Acting
Directly bind and activate α or β adrenergic receptors
Examples: Epinephrine, norepinephrine, phenylephrine, albuterol, dobutamine
Indirect-Acting
Increase NE release from nerve terminals or inhibit NE reuptake
Examples: Amphetamine, tyramine, cocaine, tricyclic antidepressants (TCAs)
Mixed-Acting
Both direct receptor activation and indirect NE release
Examples: Ephedrine, pseudoephedrine
Catecholamines (Direct-Acting)
Epinephrine (Adrenaline)
Receptors: α1, α2, β1, β2 (non-selective)
Cardiovascular: ↑ HR, ↑ contractility (β1), vasoconstriction (α1, high dose) or vasodilation (β2, low dose)
Respiratory: Bronchodilation (β2)
Metabolic: Hyperglycemia (β2 glycogenolysis, α2 ↓ insulin), lipolysis (β3)
Clinical uses:
- • Anaphylaxis: First-line (IM, 0.3-0.5 mg) - bronchodilation, ↓ mediator release, vasoconstriction
- • Cardiac arrest: IV/IO during CPR
- • Severe asthma: Bronchodilation (SC, rarely used now)
- • Local anesthesia adjunct: Vasoconstriction → prolonged duration, ↓ systemic absorption
Route: IV, IM, SC, inhaled, topical. Not oral (extensive first-pass metabolism by MAO/COMT)
Norepinephrine (Noradrenaline)
Receptors: α1, α2, β1 (minimal β2 activity)
Cardiovascular: Potent vasoconstriction (α1) → ↑ SVR, ↑ BP → reflex bradycardia (despite β1 stimulation)
Clinical uses:
- • Septic shock: First-line vasopressor (↑ BP via vasoconstriction)
- • Neurogenic shock: Vasopressor support
Route: IV infusion only. Caution: Extravasation → tissue necrosis (treat with phentolamine, α-blocker)
Dopamine
Receptors (dose-dependent):
- • Low (2-5 μg/kg/min): D1 receptors → renal/splanchnic vasodilation
- • Medium (5-10): β1 → ↑ HR, ↑ contractility
- • High (>10): α1 → vasoconstriction
Uses: Cardiogenic shock, heart failure (↑ CO), hypotension (less commonly used now; norepinephrine preferred)
Adverse: Tachyarrhythmias, tissue necrosis (extravasation)
Dobutamine
Receptors: β1 >> β2, α1 (β1-selective)
Effects: ↑ Contractility, ↑ HR (modest), mild vasodilation (β2) → ↑ CO, ↓ afterload
Uses: Acute decompensated heart failure (cardiogenic shock), stress echo (induces ischemia)
Advantage over dopamine: Less tachycardia, no peripheral vasoconstriction
Isoproterenol
Receptors: β1, β2 (pure β-agonist, no α activity)
Effects: ↑ HR, ↑ contractility, bronchodilation, vasodilation → ↑ SBP, ↓ DBP
Uses: AV block (rarely, until pacing available), bradycardia, torsades de pointes
Adverse: Severe tachycardia, ↑ myocardial O2 demand (can precipitate ischemia)
Selective α-Agonists
α1-Selective Agonists
Phenylephrine
Pure α1 agonist: Vasoconstriction → ↑ BP → reflex bradycardia
Uses: Hypotension (anesthesia, septic shock), nasal decongestant (topical), mydriasis (ophthalmic, no cycloplegia)
Route: IV, oral, topical (nasal, ophthalmic)
Midodrine
Prodrug: Converted to desglymidodrine (α1 agonist)
Use: Orthostatic hypotension (oral, increases standing BP)
Oxymetazoline
Use: Nasal decongestant (Afrin). Caution: Rebound congestion with prolonged use (>3-5 days)
α2-Selective Agonists
Clonidine
Central α2: ↓ Sympathetic outflow → ↓ BP, ↓ HR
Uses: Hypertension, opioid/alcohol withdrawal, ADHD, menopausal hot flashes
Adverse: Sedation, dry mouth, rebound hypertension (abrupt discontinuation)
Methyldopa
Prodrug: Converted to α-methylnorepinephrine (α2 agonist in CNS)
Use: Hypertension in pregnancy (safe, first-line)
Dexmedetomidine
Use: ICU sedation (no respiratory depression), procedural sedation. α2 agonist.
Brimonidine
Use: Glaucoma (topical, ↓ aqueous humor production via α2 in ciliary body)
Selective β-Agonists
β2-Selective Agonists (Bronchodilators)
Mechanism: β2 activation → Gs → cAMP → bronchial smooth muscle relaxation
Short-Acting β-Agonists (SABAs)
Albuterol (salbutamol), Levalbuterol: Onset 5 min, duration 4-6 hours
Uses: Asthma/COPD acute exacerbations (rescue inhaler), exercise-induced bronchospasm prophylaxis
Adverse: Tremor (β2 in skeletal muscle), tachycardia (β1 at high doses), hypokalemia
Long-Acting β-Agonists (LABAs)
Salmeterol, Formoterol: Duration 12 hours (BID dosing)
Indralaterol, Vilanterol: Duration 24 hours (once daily)
Uses: Asthma/COPD maintenance (MUST be combined with inhaled corticosteroid in asthma)
Warning: LABA monotherapy in asthma ↑ mortality (FDA black box warning)
β2-Agonists: Other Uses
Terbutaline
Use: Tocolysis (preterm labor, delays delivery). SC or IV. β2 → uterine relaxation. Caution: Maternal cardiovascular risks.
Ritodrine
Historic use: Tocolysis (no longer marketed in US). Replaced by nifedipine, indomethacin.
β3-Agonist
Mirabegron
Receptor: β3 in bladder detrusor muscle
Effect: Relaxation → ↑ bladder capacity
Use: Overactive bladder (alternative to antimuscarinics, fewer anticholinergic side effects)
Indirect and Mixed-Acting Sympathomimetics
Mixed-Acting
Ephedrine, Pseudoephedrine
Mechanism: Direct α/β activation + indirect NE release
Uses: Nasal decongestant (oral), hypotension (ephedrine IV), urinary incontinence (α1 urethral tone)
Adverse: Hypertension, tachycardia, CNS stimulation (insomnia, anxiety)
Indirect-Acting
Amphetamine, Methamphetamine
Mechanism: ↑ NE/dopamine release, ↓ reuptake, MAO inhibition
Medical uses: ADHD (amphetamine salts), narcolepsy, obesity (short-term)
Abuse potential: High (Schedule II). Tolerance, dependence, psychosis.
Cocaine
Mechanism: Blocks NE, dopamine, serotonin reuptake
Medical use: Topical anesthetic (nasal surgery) - vasoconstriction limits bleeding. Abuse: Highly addictive.
Tyramine
Source: Aged cheeses, wines. Normally metabolized by MAO. MAOI patients: Hypertensive crisis (avoid tyramine-rich foods).
Adverse Effects and Precautions
Cardiovascular
Hypertension, tachycardia, arrhythmias, myocardial ischemia (↑ O2 demand), stroke. Exaggerated in hyperthyroidism, CAD.
Metabolic
Hyperglycemia (β2 glycogenolysis, α2 ↓ insulin), hypokalemia (β2 ↑ cellular K⁺ uptake), hyperlactatemia
CNS
Anxiety, tremor, insomnia, headache, psychosis (amphetamines, high-dose β-agonists)
Contraindications
Angle-closure glaucoma (α1 mydriasis), MAOIs (hypertensive crisis with indirect agents), severe CAD (relative)