Noradrenergic Pharmacology
Norepinephrine pathways in the CNS and periphery, adrenergic receptor subtypes, and drugs modulating noradrenergic transmission.
## Norepinephrine Synthesis and Metabolism
Norepinephrine (NE) is synthesized from dopamine by dopamine beta-hydroxylase (DBH) within synaptic vesicles. The synthetic pathway is: tyrosine -> L-DOPA (TH) -> dopamine (AADC) -> norepinephrine (DBH). In the adrenal medulla, PNMT further converts NE to epinephrine.
NE is cleared from the synapse primarily by the norepinephrine transporter (NET, uptake-1). It is metabolized by MAO and COMT to normetanephrine and VMA.
## Central Noradrenergic Pathways
The locus coeruleus (LC) is the principal noradrenergic nucleus, projecting diffusely to the cortex, hippocampus, thalamus, and spinal cord. LC activity regulates arousal, attention, stress responses, and the sleep-wake cycle. LC dysfunction is implicated in PTSD, ADHD, and depression.
## Adrenergic Receptor Subtypes
| Receptor | Coupling | Location | Function |
|----------|----------|----------|----------|
| Alpha-1 | Gq | Vascular smooth muscle | Vasoconstriction |
| Alpha-2 | Gi | Presynaptic terminals, LC | Inhibits NE release (autoreceptor) |
| Beta-1 | Gs | Heart | Increases heart rate, contractility |
| Beta-2 | Gs | Bronchial smooth muscle | Bronchodilation |
| Beta-3 | Gs | Adipose tissue | Lipolysis, bladder relaxation |
## Key Drug Classes
- **SNRIs** -- venlafaxine, duloxetine block NET and SERT; used for depression, anxiety, neuropathic pain
- **NRIs** -- atomoxetine (selective NET inhibitor) for ADHD
- **Alpha-2 agonists** -- clonidine, guanfacine reduce central sympathetic outflow; used for hypertension, ADHD, opioid withdrawal
- **Alpha-1 blockers** -- prazosin for PTSD nightmares and BPH; doxazosin for hypertension
- **Beta-blockers** -- propranolol (nonselective), metoprolol (beta-1 selective); used for hypertension, heart failure, performance anxiety
- **Indirect sympathomimetics** -- amphetamine reverses NET to release NE and DA
## Key Takeaways
- The locus coeruleus is the brain's primary noradrenergic center, modulating arousal and attention
- NET is the target of SNRIs, NRIs, and indirect sympathomimetics
- Alpha-2 agonists reduce sympathetic outflow by activating presynaptic autoreceptors
- Adrenergic receptor subtype selectivity determines both therapeutic effects and side effect profiles