Adrenergic Agonists Lecture Notes

Introduction

• Discussion on adrenergic agonists and their effects on adrenergic neurons and receptors.
• Importance of understanding norepinephrine synthesis, release, and receptor interaction.

Norepinephrine Synthesis and Release

• Synthesis:
  • Derived from amino acid tyrosine.
  • Tyrosine converted to L-DOPA, then dopamine, and finally norepinephrine.
  • Involves specific co-transporters and enzymes.
• Release:
  • Triggered by action potentials and voltage-gated calcium channels.
  • Leads to exocytosis of norepinephrine into synapses.

Adrenergic Receptors

• Types:
  • Alpha receptors (α1, α2) and Beta receptors (β1, β2, β3).
• Intracellular Mechanisms:
  • α1: Phospholipase C pathway, increases calcium and induces smooth muscle contraction.
  • α2: Adenylate cyclase pathway, decreases cyclic AMP, inhibiting release of neurotransmitters/hormones.
  • β1, β2, β3: Increase cyclic AMP, affecting cardiac muscle contraction and smooth muscle relaxation.

Norepinephrine Metabolism

• Enzymes involved:
  • Catechol-O-methyltransferase (COMT) and Monoamine Oxidases (MAO).
  • Norepinephrine can be metabolized or recycled via transporters.

Other Adrenergic Neurotransmitters

• Epinephrine:
  • Released from adrenal medulla.
  • Similar structure to norepinephrine.
  • Can exert effects on adrenergic receptors similar to norepinephrine.

Adrenergic Agonists

• Types:
  • Direct Agonists: Bind directly to receptors, mimicking norepinephrine/epinephrine.
  • Indirect Agonists: Increase norepinephrine in synapses, e.g., cocaine, amphetamines.
  • Mixed Agonists: Combine direct and indirect actions, e.g., pseudoephedrine.

Effects of Norepinephrine on Receptors

• α1 Receptors: Constrict blood vessels, increase BP, inhibit defecation/urination, cause pupil dilation.
• α2 Receptors: Inhibit norepinephrine release, decrease insulin secretion.
• β1 Receptors: Increase heart rate and contractility, stimulate renin release.
• β2 Receptors: Relax smooth muscle, bronchodilation, increase glucose production.
• β3 Receptors: Inhibit detrusor muscle contraction, aiding in overactive bladder treatment.

Clinical Usages of Adrenergic Agonists

• α1 Agonists: Treat hypotension, cause pupil dilation, and reduce nasal congestion.
  • Drugs: Phenylephrine, Midodrine.
• α2 Agonists: Used in hypertension management, ADHD, and withdrawal symptoms.
  • Drugs: Clonidine, Alpha-methyl DOPA.
• β1 Agonists: Utilized in bradycardia, acute heart failure, cardiogenic shock.
  • Drug: Dobutamine.
• β2 Agonists: Treat asthma, COPD, and inhibit uterine contractions.
  • Drugs: Albuterol, Terbutaline.
• β3 Agonists: Overactive bladder management.
  • Drug: Myrabegron.

Mixed Alpha and Beta Agonists

• Norepinephrine: Primarily α1 activity, used in shock states.
• Epinephrine: Prefers beta over alpha, used in asthma, anaphylaxis, cardiac arrest.
• Dopamine: Similar to epinephrine, used in shock and heart failure.

Hemodynamic Effects and Graph Interpretation

• Norepinephrine: Increases diastolic and systolic BP, can cause reflex bradycardia.
• Epinephrine and Dopamine: Increase heart rate and contractility; vasodilation at low doses.
• Isoproteranol: Significant increase in heart rate, decrease in diastolic BP and systemic vascular resistance.

Conclusion

• Summary of adrenergic agonists' mechanisms and clinical implications.

Key Points

• Understand adrenergic receptor types and their systemic effects.
• Differentiate between direct, indirect, and mixed adrenergic agonists.
• Recognize clinical uses based on receptor activity and patient conditions.