Mechanism of Action of Guanfacine Extended Release (Intuniv)
Guanfacine ER works primarily by selectively stimulating alpha-2A adrenergic receptors in the prefrontal cortex, inhibiting cAMP-PKA signaling pathways, which strengthens prefrontal cortical network connectivity and improves executive functioning. 1
Primary Mechanism
Guanfacine's mechanism of action involves several key processes:
- Selective Alpha-2A Receptor Activation: Unlike clonidine which acts on all alpha-2 subtypes (A, B, C), guanfacine selectively targets alpha-2A adrenergic receptors 2
- Prefrontal Cortex Enhancement: It acts on postsynaptic alpha-2A receptors located on dendritic spines in the prefrontal cortex 1
- Cellular Signaling Pathway: Guanfacine inhibits the cAMP-PKA-potassium channel signaling pathway, which:
- Strengthens network connectivity in the prefrontal cortex
- Enhances prefrontal neuronal firing
- Improves prefrontal cortical cognitive functions 1
Physiological Effects
The activation of alpha-2A receptors by guanfacine leads to several physiological effects:
- Reduced Sympathetic Outflow: Stimulation of central alpha-2A receptors reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels 3
- Hemodynamic Changes: This results in decreased peripheral vascular resistance and reduced heart rate 3
- Catecholamine Modulation: Chronic administration increases basal release of norepinephrine in the orbitofrontal cortex, ventral tegmental area, and reticular thalamic nucleus 4
- Enhanced Thalamocortical Transmission: Chronic guanfacine administration phasically enhances thalamocortical glutamatergic transmission 4
Comparison to Other Alpha-2 Agonists
Guanfacine differs from other alpha-2 agonists like clonidine in several important ways:
- Receptor Specificity: Guanfacine is alpha-2A selective, while clonidine acts on all alpha-2 subtypes 2
- Sedative Effects: Guanfacine has less pronounced sedative effects compared to clonidine 2
- Cardiovascular Profile: Guanfacine produces more stable blood pressure effects and reduced risk of rebound hypertension upon discontinuation 2
Clinical Relevance
Understanding guanfacine's mechanism of action explains its therapeutic benefits in:
- ADHD: FDA-approved for ADHD treatment, particularly effective for executive function deficits 5, 6
- Off-label Uses: Used in stress-related disorders, substance abuse, schizotypic cognitive deficits, and traumatic brain injury due to its effects on prefrontal cortex function 1
Dual Actions of Guanfacine
Research has revealed that guanfacine has dual actions on catecholaminergic transmission:
- Acute Effects: Initial attenuation of noradrenergic transmission
- Chronic Effects: Long-term enhancement of noradrenergic transmission and thalamocortical glutamatergic transmission 4
This dual mechanism likely contributes to guanfacine's clinical efficacy in treating ADHD and other prefrontal cortical disorders.