Adrenergic Receptor

Aka: Adrenergic Receptor, Catecholamine, Sympathomimetic, Adrenergic Agonist, Dopaminergic Receptor

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II. Definitions

  1. Sympathetic Nervous System
    1. Part of Autonomic Nervous System with activity that typically counters the Parasympathetic Nervous System
    2. Energy expending (catabolic) system, activated in stressful situations (e.g. emergency fight or flight)
      1. Contrast with the Parasympathetic Nervous System, an energy conserving system activated at times of rest
  2. Catecholamines
    1. Catecholamines act as Sympathetic System neuromodulators, binding adrenergic and Dopaminergic Receptors
    2. Catecholamines contain a catechol (benzene ring with 2 hydroxyl groups) derived from the Amino AcidTyrosine
    3. Endogenous Catecholamines are synthesized in the Adrenal Gland and postganglionic sympathetic Neurons
    4. Catecholamines include Epinephrine, Norepinephrine and Dopamine
  3. Sympathomimetics (Adrenergic Agonist)
    1. Sympathomimetics are agents that mimic the activity of postganglionic sympathetic Neurons
    2. Sympathomimetics include exogenous Catecholamines, as well as other agents with sympathetic activity
    3. Direct Sympathomimetics bind specific Adrenergic Receptors (a1, a2, b1, b2, d1-5) to trigger sympathetic activity
    4. Indirect Sympathomimetics enter the presynaptic Neuron and displace Norepinephrine from their storage vessicles
    5. Mixed Sympathomimetics act both indirectly (Norepinephrine displacement) AND directly (Adrenergic Receptor binding)

III. Physiology: Images

  1. sympatheticNervousSystem.jpg
  2. AdrenalFunction.png
  3. autonomicSynapse.png

IV. Physiology: Receptor Types

  1. Alpha Adrenergic Receptor
    1. Alpha 1 Adrenergic Agonists Vasoconstrict, increase myocardial contractility, decrease Heart Rate, dilate pupil, constrict anal sphincter
    2. Peripheral Alpha 2 Adrenergic Agonists have mixed vessel effects, relaxe GI Smooth Muscle and stimulate fat cell lipolysis
    3. Central Alpha 2 Adrenergic Agonists vasodilate peripheral vessels
  2. Beta Adrenergic Receptor
    1. Beta 1 Adrenergic Agonists increase myocardial contractility and Heart Rate, and increases renin release and fat cell lipolysis
    2. Beta 2 Adrenergic Agonists vasodilate, bronchodilate, relax Bladder wall and stimulate liver Gluconeogenesis and glycogenolysis
  3. Dopaminergic Receptor
    1. Central Dopaminergic Agonists effect motion, cognition, emotion, motivation and nutritional intake
    2. Peripheral Dopaminergic Agonists increase cardiac contractility, vasodilation and diuresis

V. Preparations: Sympathetic Agents

  1. Catecholamines: Medical and endogenous agents with Direct Sympathetic Activity
    1. Background: Catecholamines with Direct Sympathetic Activity
      1. Catecholamines, on binding alpha and beta receptors, stimulate specific Neuron second messenger release (e.g. cAMP, Inositol)
      2. These second messengers exert inta-Neuron effects associated with the receptor stimulated (a1, a2, b1, b2, d1-d5)
      3. Catecholamines are rapidly metabolized by the enzymes COMT and MAO, and have a relatively short duration of action
    2. Alpha Adrenergic Agonists (also have beta effects as well)
      1. Epinephrine
        1. First line agent in ACLS (VT/VFib, PEA, Symptomatic Bradycardia), Anaphylaxis, Status Asthmaticus
        2. Vasoconstriction (a1), Tachycardia and increased contractility (b1) and bronchodilation (b2)
        3. Increased Serum Glucose via glycogenolysis and Gluconeogenesis (b2) and fat breakdown (b1)
      2. Norepinephrine
        1. First line Vasopressor in fluid refractory Hypotension (esp. Septic Shock)
        2. Strong Vasoconstriction and increased arterial pressure (a1) and reflex Bradycardia
        3. Unlike Epinephrine, only small effects on contractility and NO beta effect (no bronchodilation or metabolic effects)
    3. Beta Adrenergic Agonists
      1. Isoproterenol
        1. Pure Beta activity, with strong vasodilation, increased Heart Rate and contractility, and bronchodilation
        2. Increased Serum Glucose via glycogenolysis and Gluconeogenesis (b2) and fat breakdown (b1)
      2. Dobutamine
        1. Synthetic Dopamine derivative
        2. Primarily B1 activity with increased cardiac contractility, and minimal increase in Heart Rate
        3. Only weak B2 (no bronchodilation), and minimal alpha activity (no significant change in vascular resistance)
    4. Dopaminergic Agonists
      1. Dopamine
        1. Dopaminergic and B1 activity
        2. Has largely been replaced by Norepinephrine as a Vasopressor in adult shock (but still used in pediatric shock)
        3. Increases cardiac contractility, systolic Blood Pressure and to a lesser extent Heart Rate
        4. Dose related effects
          1. Low dose (renal dose Dopamine): Arteriole constriction in sites other than brain and Kidney, increasing GFR
          2. High dose: Diffuse Vasoconstriction with decreased renal perfusion and decreased GFR
  2. Non-Catecholamines: Medical agents with Direct Sympathetic Activity
    1. Background: Non-Catecholamines with Direct Sympathetic Activity
      1. Similar activity to Catecholamines by acting as direct Agonists, binding alpha and beta receptors
      2. However, non-Catecholamines have longer duration of action, as they are not metabolized by COMT and MAO
    2. Alpha Adrenergic Agonists
      1. Phenylephrine
        1. Frequent use as a Push Dose Pressor in Anesthesia for Hypotension
        2. Strong Vasopressor with increased systolic Blood Pressure and reflex Bradycardia
        3. Also used as a nasal Decongestant (neosynephrine)
    3. Beta 2 Adrenergic Agonists
      1. Bronchodilators (e.g. Albuterol, Terbutaline, Salmeterol, Pirbuterol)
        1. Primarily B2 activity with bronchodilation, but mild B1 activity results in Tachycardia
  3. Non-Catecholamines: Illicit and non-medical agents with Indirect Sympathetic Activity
    1. Background: Indirect Sympathomimetics
      1. Unlike direct sympathetic Agonists, these agents do not bind Adrenergic Receptors
      2. Indirect Sympathomimetics enter presynaptic Neuron and displace Norepinephrine from their storage vessicles
    2. Indirect Sympathomimetics
      1. Cocaine
        1. Blocks Monoamine Reuptake at nerve terminal
        2. Effects include Tachycardia, Hypertension, hyperthermia, Mydriasis, Seizures
      2. Amphetamines (MDMA or Ecstasy, Methamphetamine)
        1. Vasoconstriction, Hypertension, increased cardiac contractility, Tachycardia (or reflex decrease in Heart Rate)
        2. Amphetamines are used medically in Narcolepsy and Attention Deficit Disorder
      3. Caffeine
        1. Nonselective, Competitive Inhibition of Adenosine receptors
        2. Increases diastolic Blood Pressure and Epinephrine levels
  4. Non-Catecholamines: Illicit and non-medical agents with Mixed Sympathetic Activity
    1. Background: Mixed Sympathomimetics
      1. Mixed Sympathomimetics act both indirectly (Norepinephrine displacement) AND directly (Adrenergic Receptor binding)
    2. Mixed Sympathomimetics
      1. Synthetic Cathinones (Psychoactive Bath Salts)
        1. Inhibits Norepinephrine, Serotonin and Dopamine reuptake, resulting in increased Neurotransmitter levels
        2. Results in Sympathomimetic and Hallucinogenic effects (similar to Amphetamines)
      2. Ephedrine (Ephedra)
        1. Vasoconstriction, increased Blood Pressure, and cardiac contractility, no Heart Rate effect (indirect NE release)
        2. Bronchodilation (direct Sympathomimetic effect)
      3. Nicotine
        1. Acts at acetylcholine Nicotinic Receptors on peripheral postganglionic Sympathetic Nerves
        2. Stimulates Catecholamine release from Adrenal Medulla
        3. Sympathomimetic effects include Vasoconstriction, increased contractility and Heart Rate

VI. Preparations: Sympathetic Antagonists

  1. Central Adrenergic Agonist (presynaptic, Antagonize Sympathetic System, Antihypertensive agents)
    1. Clonidine
    2. Guanfacine
    3. Methyldopa (Aldomet)
  2. Peripheral Presynaptic Adrenergic Antagonist (Antihypertensive)
    1. Guanethidine
    2. Reserpine
  3. Postsynaptic Alpha Adrenergic Antagonist
    1. Selective Alpha-1a Antagonists: Prostate specific agents (e.g. Tamsulosin)
    2. Non-Selective Agents: Antihypertensives: (e.g. Terazosin, Doxazosin, Prazosin)
  4. Beta Adrenergic Antagonist (Beta Blocker)
    1. Beta-1 Selective Adrenergic Blockade (e.g. Metoprolol, Atenolol)
    2. Beta-1 and Beta-2 Adrenergic Blockade (e.g. Propranolol, Nadolol, Sotalol)
    3. Combined Alpha-1, Beta-1 and Beta-2 Adrenergic Blockade (e.g. Labetalol, Carvedilol)

VII. References

  1. Olson (2020) Clinical Pharmacology, Medmasters, Miami, p. 13-33
  2. Goldstein (2010) Clin Auton Res 20(6):331-52 +PMID: 20623313 [PubMed]

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