guanfacine (extended-release, for ADHD)
Brand: Intuniv
Prototype: clonidine
Drug Class: alpha-2A adrenergic agonist
Drug Family: antihypertensive
Subclass: non-stimulant ADHD medication
Organ Systems: cns
Mechanism of Action
Selectively stimulates postsynaptic alpha-2A adrenergic receptors in the prefrontal cortex, strengthening PFC network connections that regulate attention, impulsivity, and working memory. Unlike clonidine (which acts on alpha-2B and alpha-2C as well), guanfacine's selectivity for alpha-2A may produce less sedation and more targeted cognitive effects.
alpha-2A adrenergic receptor (postsynaptic)
Indications
- ADHD (monotherapy or adjunct to stimulants in children 6-17 years)
- off-label: ADHD in adults
- off-label: Tourette syndrome
- off-label: PTSD-related hyperarousal and nightmares
Contraindications
- hypersensitivity to guanfacine
Adverse Effects
Common
- somnolence
- headache
- fatigue
- upper abdominal pain
- nausea
- hypotension
- bradycardia
Serious
- severe hypotension (especially with CYP3A4 inhibitors)
- rebound hypertension on abrupt discontinuation
- syncope
Pharmacokinetics (ADME)
| Absorption | well absorbed; food increases Cmax by ~75% with high-fat meal — administer consistently with or without food |
| Distribution | protein binding ~70%; Vd ~6.3 L/kg |
| Metabolism | primarily CYP3A4; 3-hydroxy-guanfacine is main metabolite |
| Excretion | renal (80%) |
| Half-life | 17-24 hours |
| Onset | therapeutic effect 2-4 weeks |
| Peak | 5 hours |
| Duration | 24 hours |
| Protein Binding | 70% |
| Vd | 6.3 L/kg |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| CYP3A4 inhibitors (ketoconazole, valproic acid) | increase guanfacine levels; reduce dose | major |
| CYP3A4 inducers (rifampin) | decrease guanfacine levels; increase dose | major |
| antihypertensives | additive hypotension | moderate |
Nursing Considerations
- Monitor blood pressure and heart rate before and after dose changes; guanfacine can cause significant hypotension — hold dose and notify prescriber if BP is low.
- Taper to discontinue; abrupt withdrawal can cause rebound hypertension and agitation; reduce dose every 3-7 days over 1-2 weeks.
- Do not crush or chew extended-release tablet — this destroys the ER mechanism; a 20% higher Cmax occurs if crushed.
- Administer consistently with respect to high-fat meals to ensure consistent drug levels.
Clinical Pearls
- Guanfacine's mechanism targets the same alpha-2A receptors that naturally modulate PFC function during stress; in animal models, mild stress impairs PFC-mediated cognition through norepinephrine-mediated alpha-2A receptor internalization, and guanfacine reverses this effect.
- The combination of guanfacine with a stimulant (methylphenidate or amphetamine) addresses different neurobiological circuits and is FDA-approved for pediatric ADHD, providing complementary mechanisms for complex cases.
Safety Profile
Pregnancy use-with-caution
Lactation use-with-caution
Renal Adjustment Required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.