What is the mechanism of action of guanfacine (Intuniv) in treating Attention Deficit Hyperactivity Disorder (ADHD)?

Mechanism of Action of Guanfacine for ADHD

Guanfacine works by selectively stimulating postsynaptic alpha-2A adrenergic receptors in the prefrontal cortex, enhancing working memory and attention by improving prefrontal cortical network connections that regulate attention, emotion, and behavior. 1

Specific Mechanism of Action

Guanfacine's therapeutic effects in ADHD are primarily mediated through its action as a selective alpha-2A adrenergic receptor agonist. This mechanism differs significantly from stimulants and other non-stimulant medications like atomoxetine. Key aspects of its mechanism include:

• Postsynaptic action: Unlike stimulants or atomoxetine that primarily work on presynaptic mechanisms, guanfacine acts at the postsynaptic level 1

• Cellular effects:

  • Inhibits the production of cyclic adenosine monophosphate (cAMP)
  • Closes hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
  • These actions enhance signal effectiveness in prefrontal cortex (PFC) pyramidal neurons 1

• Neuroplastic effects: Stimulation of alpha-2A receptors promotes growth and maturation of dendritic spines on pyramidal neurons in the medial PFC, which are associated with learning and memory functions 1

Pharmacological Properties

Guanfacine has several important pharmacological characteristics:

• It is approximately 15-20 times less potent than clonidine (another alpha-2 agonist) 2
• Higher specificity for alpha-2A receptors compared to clonidine, which may explain its different side effect profile (notably less sedation) 2
• Primarily metabolized via CYP3A4 and excreted predominantly through the kidneys 2
• Available in extended-release formulation (GXR) for once-daily administration 2, 3

Clinical Efficacy

Guanfacine has demonstrated efficacy in treating ADHD:

• Meta-analysis shows guanfacine is significantly more effective than placebo in treating ADHD (Risk Ratio 1.78) 4
• Effect size of approximately 0.7 compared to 1.0 for stimulants 5
• Provides all-day symptom coverage with a single morning dose 5
• Treatment effects typically observed within 2-4 weeks after initiation 2

Dosing Considerations

• Available in tablet form with doses of 1,2,3, and 4 mg 2
• Recommended dosing regimen is adjusted to body weight (approximately 0.1 mg/kg as a rule of thumb) 2
• Once-daily administration is standard for the extended-release formulation 2

Side Effects and Safety Profile

Common adverse effects include:

• Somnolence (38.6%), headaches (20.5%), and fatigue (15.2%) 4
• Other potential effects: irritability, insomnia, and nightmares 2
• Cardiovascular effects: hypotension and bradycardia (requires monitoring) 2

Clinical Implications

• Guanfacine is generally considered a second-line treatment after stimulants due to its medium effect size compared to the larger effect sizes of stimulants 2
• Particularly useful when:
  • Stimulants are not suitable, not tolerated, or ineffective 2
  • Comorbid tics or Tourette's syndrome are present 5
  • Sleep disturbances are prominent 5
  • As adjunctive therapy with stimulants 5

Important Distinctions

• Unlike stimulants, guanfacine has no abuse potential, making it suitable for patients with substance use concerns 5
• Its mechanism mimics noradrenaline stimulation of postsynaptic alpha-2A receptors in the PFC, rather than increasing catecholamine levels like stimulants do 1
• Guanfacine may reduce tics in patients with tic disorders, while many stimulants can worsen them 5

Understanding guanfacine's unique mechanism of action helps explain both its therapeutic effects in ADHD and its distinct side effect profile compared to other ADHD medications.