Adrenergic Agonists Lecture Notes

Introduction to Adrenergic Agonists

• Adrenergic agonists mimic actions of norepinephrine (noradrenaline) and epinephrine (adrenaline).
• Terminology:
  • Agents activating adrenergic receptors = Sympathomimetics
  • Agents blocking adrenergic receptors = Sympatholytics

Neurotransmission Process in Adrenergic Neurons

1. Tyrosine Transport: Tyrosine enters neuron via sodium-dependent transporter.
2. Conversion to L-DOPA: Tyrosine is hydroxylated to L-DOPA by enzyme tyrosine hydroxylase.
3. Dopamine Formation: L-DOPA is converted to dopamine by aromatic amino acid decarboxylase.
4. Norepinephrine Production: Dopamine transported into vesicles and converted to norepinephrine by dopamine beta-hydroxylase.
5. Release and Reuptake:
   • Action potential opens calcium channels, releasing norepinephrine into the synapse.
   • Norepinephrine binds to postsynaptic receptors, triggering intracellular responses.
   • Removal from synaptic space by diffusion and enzymatic inactivation (COMT, MAO) or reuptake via NET.

Adrenergic Receptors

• Receptors activated by norepinephrine, epinephrine, and adrenergic drugs.
• Sympathetic preganglionic neurons release acetylcholine, binding to nicotinic receptors on postganglionic neurons.
• Norepinephrine (20%) and epinephrine (80%) released from adrenal gland.
• Bound to Alpha and Beta receptors.

Alpha Receptors

• Alpha-1 Receptors:

  • GQ protein-coupled, causes stimulatory responses via increased intracellular calcium.
  • Functions:
    • Vasoconstriction in blood vessels.
    • Mydriasis (pupil dilation).
    • Urinary retention via sphincter contraction.
    • Glycogenolysis in the liver.
    • Inhibition of renin release in kidneys.

• Alpha-2 Receptors:

  • GI protein-coupled, decrease cAMP production, inhibiting norepinephrine release.
  • Found on presynaptic nerve endings and pancreatic islets (inhibit insulin secretion).

Beta Receptors

• Beta-1 Receptors:

  • GS protein-coupled, located in the heart.
  • Increase heart rate, contractility, and AV node conduction.
  • Located in juxtaglomerular cells (increase renin release).

• Beta-2 Receptors:

  • GS protein-coupled, located in lungs and vascular smooth muscle.
  • Functions:
    • Bronchodilation in lungs.
    • Vasodilation in skeletal muscles.
    • Smooth muscle relaxation in GI tract and uterus.

• Beta-3 Receptors:

  • Found in adipose tissue (increase lipolysis) and urinary bladder (relaxation).

Chemical Classes of Adrenergic Agonists

• Catecholamines:

  • Organic compounds with specific structure (benzene ring with hydroxyl groups).
  • Not orally usable, short duration, poor CNS penetration.
  • Examples: epinephrine, norepinephrine, dopamine.

• Non-Catecholamines:

  • Similar structure but lack catechol hydroxyl groups, better for oral use.
  • Examples: selective adrenergic agonists.

Types of Adrenergic Agonists

1. Direct Acting Agonists: Bind to adrenergic receptors (e.g., epinephrine, norepinephrine, dopamine).

   • Epinephrine: Treatment for anaphylactic shock, cardiac arrest, and respiratory emergencies.
   • Norepinephrine: Primarily stimulates alpha-1 receptors, used in hypotensive shock and cardiac arrest.
   • Dopamine: Dose-dependent effects on dopamine and adrenergic receptors; used in acute heart failure.

2. Selective Agonists:

   • Alpha-1 Selective: Oxymetazoline, phenylephrine (nasal congestion treatment).
   • Alpha-2 Selective: Clonidine (hypertension, ADHD).
   • Beta-1 Selective: Dobutamine (acute heart failure).
   • Beta-2 Selective: Albuterol (short-acting, asthma relief), Salmeterol (long-acting, asthma prevention).
   • Beta-3 Selective: Mirabegron (overactive bladder).

3. Indirect Acting Agonists: Enhance effects of norepinephrine (e.g., cocaine, amphetamines).

   • Block reuptake and stimulate adrenergic receptors.

4. Mixed Action Agonists:

   • Ephedrine and Pseudoephedrine: Activate adrenergic receptors through direct binding and norepinephrine release; used as decongestants.

Conclusion

• Overview of adrenergic agonists, their mechanisms, types, and clinical applications.