Learning Objective
Describe the steps involved in the synthesis, storage, release, and termination of norepinephrine (NE) at the adrenergic neuroeffector junction and identify drug classes that act at each step.
NE Synthesis
- Tyrosine uptake into the nerve terminal (active transport).
- Tyrosine → DOPA via tyrosine hydroxylase
- Rate-limiting step
- DOPA → Dopamine (DA) via DOPA decarboxylase
- DA is transported into vesicles
- DA → NE via dopamine β-hydroxylase
Drug modifiers:
- MAO inhibitors (MAO-A inhibitors) ↑ NE in the prejunctional mobile pool, but not in the vesicles.
NE Release
- An action potential depolarizes the presynaptic terminal
- Voltage-gated Ca²⁺ channels open
- Ca²⁺ influx → vesicle fusion with presynaptic membrane
- Exocytosis of NE into the synaptic cleft
- NE binds postsynaptic α₁, β₁, or other adrenergic receptors → physiologic response
Drug modifiers:
- Releasers (e.g., amphetamine, tyramine)
- α₂ agonists (clonidine) ↓ NE release
- α₂ antagonists (yohimbine) ↑ NE release
NE Clearance / Termination
Primary mechanism → Reuptake into nerve terminal (Reuptake-1)
- Via Na⁺/Cl⁻-dependent NE reuptake transporter
- Driven by Na⁺ gradient maintained by Na⁺/K⁺ ATPase
Other mechanisms:
- COMT in the synaptic cleft
- MAO-A in the presynaptic terminal
Drug modifiers:
- Reuptake blockers (e.g., cocaine, TCAs)
- COMT inhibitors (entacapone)
- MAO-A inhibitors (phenelzine)
Activity
Drug Interaction Key
| Step | Drugs Acting |
|---|---|
| 1 — Synthesis | Tyrosine hydroxylase inhibitors, MAO inhibitors |
| 2 — Release | Amphetamine (releaser), α₂ agonists/antagonists |
| 3 — Reuptake | Cocaine, TCAs |
| 4 — Metabolism | MAO inhibitors, COMT inhibitors |
Classic Notes
- Rate-limiting step: Tyrosine → DOPA
- Major termination: Reuptake (NOT metabolism)
- α₂ autoreceptors provide negative feedback
- Releasers + MAOI + reuptake blockers → dangerous ↑↑ NE → hypertensive crisis
