Lecture on Adrenergic Agonists

Introduction

• Adrenergic agonists: Drugs that mimic actions of norepinephrine and epinephrine
  • Norepinephrine is also known as noradrenaline
  • Epinephrine is also known as adrenaline
• Sympathomimetics: Agents that activate adrenergic receptors
• Sympatholytics: Agents that block adrenergic receptors

Neurotransmission in Adrenergic Neurons

1. Tyrosine Transport: Amino acid tyrosine transported into neuron
   • Converted to L-dopa by tyrosine hydroxylase
2. Dopamine Formation: L-dopa converted to dopamine by aromatic amino acid decarboxylase
3. Norepinephrine Formation: Dopamine transported into synaptic vesicle, converted to norepinephrine by dopamine beta hydroxylase
4. Action Potential: Triggers calcium influx, leading to norepinephrine release into synapse
5. Binding and Removal
   • Norepinephrine binds to postsynaptic receptors and triggers intracellular response
   • Removed by diffusion, inactivation by COMT, or reuptake by NET and broken down by MAO or recycled

Adrenergic Receptors

Alpha Receptors

• Alpha-1: Gq protein-coupled, stimulatory (increased intracellular calcium)
  • Locations & Effects:
    • Vascular smooth muscle: Vasoconstriction
    • Iris dilator muscle: Mydriasis (pupil dilation)
    • Urinary sphincters: Contraction, urinary retention
    • Liver: Glycogenolysis
    • Kidney: Inhibition of renin release
• Alpha-2: Gi protein-coupled, inhibitory
  • Locations & Effects:
    • Presynaptic nerve endings: Decreased norepinephrine release
    • Pancreatic islets: Decreased insulin secretion

Beta Receptors

• Beta-1: Gs protein-coupled
  • Locations & Effects:
    • Heart: Increased heart rate, contractility, AV node conduction
    • Juxtaglomerular cells (kidney): Increased renin release
• Beta-2: Gs protein-coupled
  • Locations & Effects:
    • Bronchial smooth muscle: Bronchodilation
    • Vascular smooth muscle (skeletal muscle arteries): Vasodilation
    • GI tract & uterus smooth muscle: Relaxation (↓motility & inhibition of labor)
    • Pancreas: Increased insulin secretion
• Beta-3: Gs protein-coupled
  • Locations & Effects:
    • Adipose tissue: Lipolysis
    • Urinary bladder: Relaxation, prevention of urination

Adrenergic Agonists

Chemical Classes

• Catecholamines: Benzene ring with hydroxyl groups, ineffective orally, short-acting, poor CNS penetration
• Noncatecholamines: Similar structure without hydroxyl groups, effective orally, long-acting, better CNS penetration

Types of Adrenergic Agonists

1. Direct Acting Agonists: Bind to alpha/beta receptors, e.g., Epinephrine, Norepinephrine, Dopamine

   • Epinephrine: Treats anaphylactic shock, cardiac arrest, respiratory conditions
   • Norepinephrine: Vasoconstriction, blood pressure increase, used in cardiac arrest and hypotensive shock
   • Dopamine: Acts dose-dependently on dopamine, beta-1, and alpha-1 receptors, treats heart failure and hypotensive shock

2. Selective Adrenergic Agonists

   • Alpha-1 Selective: Oxymetazoline (nasal congestion, eye redness), Phenylephrine (nasal congestion, hypotension)
   • Alpha-2 Selective: Clonidine (hypertension, ADHD, withdrawal)
   • Beta-1 Selective: Dobutamine (heart failure)
   • Beta-2 Selective: Albuterol, Terbutaline (acute asthma), Salmeterol, Formoterol (prevent asthma attacks)
   • Beta-3 Selective: Mirabegron (over-reactive bladder)

3. Indirect Acting Agonists: Inhibit reuptake or degradation of norepinephrine and dopamine, e.g., Cocaine, Amphetamine

4. Mixed Action Agonists: Both direct binding and release of stored norepinephrine, e.g., Ephedrine, Pseudoephedrine

   • Ephedrine: Rarely used, vasoconstriction, bronchodilation
   • Pseudoephedrine: Commonly used as nasal decongestant