Autonomic Nervous System Agents (1) – Let’s Learn About Adrenomimetics

Autonomic Nervous System Agents (1) – Let’s Learn About

Hello!
Today, we will take some time to study various drugs. We are going to begin learning about the types of drugs that act on the autonomic nervous system and their mechanisms of action.

First, let’s take a moment to learn about adrenomimetics.

1) Adrenomimetics

Definition

Adrenomimetics are drugs that mimic the action of neurotransmitters, stimulating the sympathetic nervous system and causing various physiological responses.
They are primarily used to treat cardiovascular, respiratory, and nervous system disorders, working by binding to alpha and beta adrenergic receptors.

Alpha Adrenomimetics

– **Alpha-1 receptor agonists**: These drugs constrict peripheral blood vessels, raising blood pressure. They are mainly used to treat hypotension. – **Alpha-2 receptor agonists**: These inhibit the sympathetic nervous system, regulating high blood pressure and providing sedation and analgesic effects.

Beta Adrenomimetics

– **Beta-1 receptor agonists**: These increase cardiac contractility and heart rate, enhancing heart function. They are used to treat heart failure and hypotension. – **Beta-2 receptor agonists**: These dilate the bronchi, aiding in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

Direct-acting agents: These bind directly to the receptors.
Indirect-acting agents: These increase the secretion of norepinephrine or decrease its reuptake, enhancing the activity of endogenous catecholamines (epinephrine, norepinephrine, dopamine).

Below is a description of commonly used agents in clinical practice.

(1) Endogenous Catecholamines

⓵ Epinephrine

  • Epinephrine is an endogenous catecholamine synthesized in the adrenal medulla that directly acts on all alpha and beta receptors.
  • **Beta-1 receptor stimulation**: Increases myocardial contractility, heart rate, and cardiac output.
  • **Beta-2 receptor action**: Relaxes smooth muscles in blood vessels and bronchi, dilating skeletal muscle blood vessels.
  • **Alpha-1 receptor action**: Constricts systemic blood vessels, reduces renal blood flow, increases renin secretion, and raises blood glucose levels.
  • Epinephrine is one of the most potent blood pressure-raising agents. In proportion to the dose administered, it raises blood pressure, increasing SBP more than DBP, thus widening the pulse pressure. However, in very low doses (0.1 µg/kg), its beta-2 receptor effects may outweigh alpha receptor effects, causing blood pressure to drop.
  • Epinephrine is the first-choice drug in life-threatening situations like cardiac arrest, ventricular fibrillation, and anaphylactic shock (0.05~1 mg IV).
  • It is added during regional anesthesia or local anesthesia to reduce systemic absorption or prolong the action of local anesthetics.
  • For bronchospasm treatment, 200 µg is recommended for subcutaneous injection.
  • Continuous IV infusion of 1–2 µg/min at low doses results in vasodilation and bronchodilation via beta-2 effects.
  • Doses of 2–10 µg/min increase heart contractility, heart rate, and atrioventricular nodal conduction via beta-1 and beta-2 effects.
  • Doses above 10 µg/min result in systemic vasoconstriction due to alpha-1 receptor stimulation.
  • When administered with inhaled anesthetics, the risk of cardiac arrhythmias increases due to epinephrine, so caution is needed.
  • **Epinephrine side effects**: cerebral hemorrhage, arrhythmia, angina.

 

⓶ Norepinephrine

  • Acts directly on alpha and beta receptors but has little effect on beta-2 receptors.
  • The increase in blood pressure is due to increased systemic vascular resistance, often accompanied by reflex bradycardia with little or no change in cardiac output.
  • It constricts blood vessels in the kidneys and intestines, potentially leading to ischemia.
  • Unlike epinephrine, it constricts skeletal muscle blood vessels.
  • It increases afterload, so it is not used for cardiogenic shock but is preferred for severe sepsis and septic shock.
  • Administer via continuous IV infusion at 2–20 µg/min.
  • If extravasation occurs, it can cause tissue necrosis, treated by infiltrating phentolamine.

 

⓷ Dopamine

  • Dopamine acts directly and indirectly as a catecholamine by acting on alpha and beta receptors and dopamine receptors, as well as by releasing norepinephrine.
  • In the central nervous system, it functions as a neurotransmitter involved in motor control.
  • It is not used for intermittent IV injections, usually administered via continuous IV infusion at 1–20 µg/kg/min.
  • Doses below 2 µg/kg/min stimulate DA1 receptors, dilating the renal and mesenteric blood vessels.
  • Doses of 2–10 µg/kg/min stimulate beta-1 receptors.
  • Doses above 10 µg/kg/min stimulate alpha receptors, with vasoconstriction predominating.

Next, let’s learn about synthetic catecholamines.

(2) Synthetic Catecholamines

⓵ Isoproterenol

  • A direct-acting non-selective beta agonist.
  • **Beta-1 receptor action**: Increases heart rate and myocardial contractility.
  • **Beta-2 receptor action**: Reduces systemic vascular resistance.
  • It increases cardiac output but increases blood flow to the skin and muscles more than to major organs, making it inappropriate for shock or cardiac arrest.
  • **Side effects**: tachycardia, arrhythmia.
  • Clinically used to treat bradycardia unresponsive to atropine and as a temporary solution for AV block until a pacemaker is implanted.
  • Useful for increasing heart rate in transplanted hearts.

 

⓶ Dobutamine

  • A synthetic catecholamine acting on beta-1, beta-2, and alpha-1 receptors.
  • Increases myocardial contractility and dilates peripheral blood vessels.
  • Useful in cases of low cardiac output, such as in myocardial infarction or cardiomyopathy.
  • Increases cardiac output and reduces systemic vascular resistance, with little effect on blood pressure or heart rate.
  • It also reduces pulmonary vascular resistance, making it useful in cases of right heart failure.

 

(3) Non-Catecholamines

  • Ephedrine is a non-catecholamine sympathomimetic.
  • It acts directly and indirectly on alpha and beta receptors.
  • It promotes the release of endogenous catecholamines like norepinephrine.
  • Increases blood pressure, heart rate, myocardial contractility, cardiac output, and bronchodilation.
  • Administer 5–10 mg via intermittent IV injections.
  • Repeated use may lead to rapid tolerance, reducing the effectiveness of ephedrine.

 

(4) Alpha Agonists

    1. Phenylephrine
      • Acts directly on alpha-1 receptors, increasing systemic vascular resistance and blood pressure, often leading to reflex bradycardia.
      • Useful in treating hypotension due to reduced peripheral vascular resistance.
      • It helps increase coronary perfusion pressure without inducing tachycardia, especially in patients with ischemic heart disease or aortic stenosis.
      • Administer 50–100 µg via IV bolus or 10–20 µg/min via continuous infusion.
      • It has a rapid onset of action, and its effects last for about 5–10 minutes.
  • Clonidine
    • Selectively acts on alpha-2 receptors, effectively treating severe hypertension by reducing sympathetic outflow.
    • Causes hypotension, bradycardia, and sedation.
    • Reduces the required dosage of anesthetics or opioids post-surgery.
    • When administered in the epidural or subarachnoid space, it provides analgesic effects proportional to the dosage.
    • Side effects: dry mouth.
  • Dexmedetomidine (Precedex)
    • Acts approximately 7 times more selectively on alpha-2 receptors compared to clonidine.
    • Provides sedation and analgesia, reducing heart rate and cardiac output proportionally to the dosage.
    • May reduce the dosage of anesthetics and analgesics.
    • Mild respiratory depression, with the advantage of easy arousal → widely used for sedation purposes.
    • When administered intravenously during spinal anesthesia, dexmedetomidine extends the duration of spinal anesthesia.
    • Administer 1 mcg/kg over 10 minutes, followed by continuous infusion at 0.3-0.7 mcg/kg.
    • Duration of action is less than 5 minutes, with maximum effect occurring around 15 minutes.
  • Fenoldopam
  • Selective DA1 receptor agonist.
  • Used as an antihypertensive agent → decreases blood pressure by reducing peripheral vascular resistance/increasing renal blood flow and promoting diuresis.
  • Administered as a continuous infusion at a dose of 0.1-0.8 mcg/kg/min, used in surgeries like aortic aneurysm repair that may cause renal impairment.
  • Start continuous infusion at 0.1 mcg/kg/min, increasing by 0.1 mcg/kg/min every 15-20 minutes.

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