Adrenergic receptors & sympathomimetics — concise study notes

Quick overview

• The sympathetic (adrenergic) system works via α (alpha) and β (beta) receptors that use distinct G-protein signaling to change smooth muscle tone, cardiac function, metabolism, and neurotransmitter release.
• Clinically important drugs are classified as direct (bind receptors) or indirect (promote endogenous monoamine release/uptake inhibition).

Receptor types: signaling, locations, and key effects

Alpha-1 (α1)

• Signaling: Gq → increases IP3 / DAG → raises intracellular Ca2+ causing contraction.
• Primary locations: Mainly postsynaptic on vascular smooth muscle (skin/mucosa), also sphincters and pupillary dilator.
• Key actions: Vasoconstriction (skin/mucosa), mydriasis (dilator pupillae), sphincter contraction, and hepatic glycogenolysis.

Alpha-2 (α2)

• Signaling: Gi → decreases cAMP.
• Locations: Presynaptic (autoreceptors), some postsynaptic sites, and CNS.
• Key actions: Decreases sympathetic outflow and NE release, reduces insulin and renin secretion, lowers lipolysis, and increases platelet aggregation.

Beta-1 (β1)

• Signaling: Gs → increases cAMP.
• Locations: Predominantly heart and juxtaglomerular cells.
• Cardiac effects: Positive inotropy, chronotropy, dromotropy, and excitability (all increase cardiac performance).
• Other: Increases renin release and lipolysis.

Beta-2 (β2)

• Signaling: Gs → increases cAMP.
• Smooth muscle effects: Relaxation of bronchi, GI wall, bladder detrusor, and uterus.
• Vascular: Vasodilation in coronary and skeletal muscle beds.
• Metabolic: Increases glycogenolysis and insulin release; promotes K+ uptake into cells (can cause hypokalemia and tremor).

Beta-3 (β3)

• Primary action: Relaxes bladder detrusor (used in overactive bladder). Promotes lipolysis in adipose tissue (clinically less emphasized here).

Direct vs. Indirect sympathomimetics

• Direct agonists: Bind adrenergic receptors directly (e.g., adrenaline, phenylephrine).
• Indirect agonists: Cause release of stored norepinephrine or block uptake/metabolism (e.g., amphetamine, tyramine).
• Clinical note: Indirect agents show tachyphylaxis due to depletion of neurotransmitter stores.

Catecholamines vs. Non‑catecholamines

• Catecholamines (e.g., adrenaline, noradrenaline): Poor oral bioavailability because of COMT/MAO metabolism and limited BBB penetration.
• Non‑catecholamines (e.g., amphetamine, some oral sympathomimetics): Better oral bioavailability and cross the BBB more readily, producing stronger CNS effects.

Key drugs and clinical pearls

Adrenaline (epinephrine)

• Receptor profile: Nonselective: α1, α2, β1, β2.
• Major uses: 1) Anaphylactic shock (drug of choice), 2) Cardiac arrest, 3) Acute severe asthma, 4) Local hemostasis (epistaxis), 5) Combined with local anesthetics to prolong duration.
• Contraindications for injection in end-artery areas: Avoid fingers, toes, ears, nose, penis — intense α1 vasoconstriction may cause ischemia and gangrene.
• Adrenaline reversal: If given after an α‑blocker, α1-mediated vasoconstriction is blocked and β2 vasodilation predominates, causing a paradoxical fall in blood pressure.

Noradrenaline (norepinephrine)

• Receptor profile: Strong α1 and α2 activity, weak β1.
• Clinical use: Potent vasoconstrictor for severe hypotension/shock (less β2-mediated vasodilation than adrenaline).

Isoprenaline (isoproterenol)

• Receptor profile: Pure β1 and β2 agonist; no α activity.
• Effects: Powerful cardiac stimulant and bronchodilator with vasodilatory β2 effects.

Dopamine — dose-dependent receptor effects

• Low dose: \(2\)–\(5\ \mu g\) → D1 receptor predominant → renal and mesenteric vasodilation.
• Moderate dose: \(5\)–\(10\ \mu g\) → β1 effects → increases cardiac output.
• High dose: \(>10\ \mu g\) → α1 effects → vasoconstriction and increased blood pressure.

Dobutamine

• Selectivity: Relatively selective β1 agonist.
• Primary indication: Acute heart failure and cardiogenic shock to increase cardiac contractility.

Amphetamine (and related stimulants)

• Mechanism: Indirectly promotes release of norepinephrine and dopamine.
• Clinical uses: Narcolepsy, ADHD (e.g., methylphenidate), short-term obesity treatment (selected cases).

MAO inhibitors and the 'Cheese reaction'

• Mechanism: MAO inhibitors prevent breakdown of dietary tyramine; tyramine causes massive NE release leading to hypertensive crisis.
• Clinical relevance: Avoid tyramine‑rich foods (aged cheese, cured meats) while on MAO inhibitors.

Phenylephrine

• Selectivity: α1 agonist.
• Uses: Nasal decongestant (topical or systemic), mydriatic agent, and vasopressor.
• Side effect: Rebound nasal congestion (rhinitis medicamentosa) with overuse of topical formulations.

β2-selective drugs (examples)

• Ritodrine: Tocolysis (to relax uterus).
• Isoxsuprine: Peripheral vasodilator (used in peripheral vascular disease).
• Salbutamol (albuterol): Bronchodilation for asthma/COPD.

Mirabegron

• Selectivity/use: β3 agonist used in overactive bladder to relax detrusor muscle and reduce urgency/frequency.

Comparisons at a glance

Clinical tips & safety reminders

• For anaphylaxis, always choose adrenaline intramuscularly as first-line therapy.
• Avoid injecting adrenaline into end-artery structures to prevent ischemia.
• Expect tachyphylaxis with indirect sympathomimetics; do not rely on them when stores are depleted.
• Be cautious of hypertensive crises with MAO inhibitors and tyramine-containing foods.
• Use dopamine dose ranges to target renal perfusion vs. cardiac output vs. vasoconstriction.

High-yield summary (one-line takeaways)

• α1: vasoconstriction and smooth-muscle contraction; α2: presynaptic inhibition of NE; β1: cardiac stimulation; β2: smooth-muscle relaxation and metabolic effects; direct vs indirect drugs differ by receptor binding vs release of endogenous catecholamines.