Lecture Notes: Adrenergic Agonists

Introduction

• Adrenergic agonists: Drugs acting on adrenergic receptors
• Importance of understanding adrenergic neurons, synthesis and release of norepinephrine (NE), receptor types and functions
• Reminder to support through likes, comments, subscriptions, and to use provided illustrations and notes

Adrenergic Neurons

Synthesis and Release of Norepinephrine

• Source: Tyrosine (from diet) taken up by neurons
• Tyrosine converts to L-Dopa, then Dopamine (DA), and finally NE (in vesicles)
• Action Potential: Triggers voltage-gated calcium channels, leading to fusion and release of NE via exocytosis

Receptors and Effects

• Receptor Types:
  • Alpha receptors [α1, α2]
  • Beta receptors [β1, β2, β3]
• **Intracellular Mechanisms:
  • α1:** Phospholipase C pathway
  • α2: Inhibition of adenylate cyclase (decrease cAMP)
  • β1, β2, β3: Activation of adenylate cyclase (increase cAMP)
  • α vs. β: β1 (heart/kidneys) causes contraction, β2/β3 (smooth muscle) causes relaxation

Elimination

• Breakdown: By catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO)
• Reuptake: Via norepinephrine transporter (NET) back into neurons

Epinephrine vs. Norepinephrine

• NE and Epi: Both act on α and β receptors
• Source of Epi: Adrenal medulla (80% NE, 20% Epi)
• Mechanism Comparison: Similar structure but slight chemical difference

Types of Agonists

Direct Agonists

• Function: Bind directly to receptors and mimic NE/Epi
• Categories: Selective (specific to one type) vs. Non-selective (multiple receptors)

Indirect Agonists

• Function: Increase NE levels in synapses indirectly
• Examples: Cocaine, Amphetamines
• Mechanism: Inhibit NE breakdown/reuptake, increase NE vesicle release

Mixed Agonists

• Function: Combination of direct and indirect actions
• Examples: Ephedrine, Pseudoephedrine
• Uses: Decongestants, vasoconstriction

Clinical Uses and Effects

Alpha 1 Agonists

• Function: Contraction of smooth muscle (vascular, pupil, sphincters)
• Clinical Uses: Hypotension (Phenylephrine, Metaraminol), Nasal congestion (Phenylephrine, Oxymetazoline)
• Adverse Effects: Reflex bradycardia, rebound congestion

Alpha 2 Agonists

• Function: Inhibit NE release, sedation
• Clinical Uses: Hypertension, ADHD, Withdrawal symptoms (Clonidine)

Beta 1 Agonists

• Function: Increase heart rate (HR) and contractility
• Clinical Uses: Bradycardia, Acute heart failure, Cardiogenic shock (Dobutamine)
• Adverse Effects: Tachyarrhythmias, increased myocardial demand

Beta 2 Agonists

• Function: Relax smooth muscle (bronchodilation)
• Clinical Uses: Asthma, COPD (Albuterol, Salmeterol, Terbutaline)
• Adverse Effects: Tremors, Hypokalemia, Hyperglycemia

Beta 3 Agonists

• Function: Relaxation of detrusor muscle
• Clinical Uses: Overactive bladder (Mirabegron)

Alpha and Beta Mixed Agonists

• Common Examples: Norepinephrine, Epinephrine, Dopamine
• Effects:
  • Norepinephrine: Primarily vasoconstriction (α), cardiac effects (β at high doses)
  • Epinephrine: Cardiac stimulation (β1), vasodilation (β2 at low doses, α at high doses)
  • Dopamine: Dose-dependent effects (low doses: β1, high doses: α)
• Uses: Shock states, cardiac arrest, severe bradycardia

Graph Interpretation for Exams

• **Norepinephrine:

  • Reflex bradycardia
  • Increased systolic/diastolic BP
  • Neutral cardiac output

• Epinephrine:

  • Increased HR, systolic BP
  • Decreased diastolic BP
  • Increased cardiac output

• Isoproterenol:

  • Increased HR
  • Increased systolic BP
  • Decreased diastolic BP
  • Increased cardiac output
  • Drop in MAP due to decreased diastolic BP