Guanfacine: Classification, Mechanism of Action, and Side Effects
Guanfacine is an alpha-2A adrenergic receptor agonist that works by enhancing noradrenergic neurotransmission in the prefrontal cortex, with primary side effects including dry mouth, somnolence, and hypotension. 1, 2
Classification
- Guanfacine belongs to the class of centrally acting alpha-2 adrenergic receptor agonists 1
- It has higher specificity for alpha-2A receptors compared to clonidine, which explains its different adverse effect profile (less sedation) 2
- Guanfacine is approximately ten times less potent than clonidine but has greater selectivity for alpha-2A receptors 1
- FDA-approved for attention-deficit/hyperactivity disorder (ADHD) and hypertension 3
Mechanism of Action
- Guanfacine stimulates alpha-2A adrenergic receptors in the brain 1, 2
- In the brain stem, alpha-2 agonism leads to a reduction in peripheral vascular resistance and consequently lower blood pressure 1
- In the prefrontal cortex, postsynaptic alpha-2A agonism enhances noradrenergic neurotransmission 1, 4
- This strengthens the regulatory role of the prefrontal cortex, which is responsible for top-down guidance of attention, thought, and working memory 1, 4
- Guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels, resulting in decreased peripheral vascular resistance and reduced heart rate 5
Pharmacokinetics
- Guanfacine is primarily metabolized via CYP3A4 and excreted predominantly through renal pathways 1, 2
- The absolute bioavailability after oral administration is approximately 81.1% 6
- Elimination half-life is approximately 13-14 hours 6
- Mean plasma protein binding is about 71.6% 6
- Renal clearance accounts for approximately 50% of total body clearance 6
Side Effects
The most common adverse effects of guanfacine include:
Cardiovascular Effects
Central Nervous System Effects
- Somnolence/sedation (up to 39% at higher doses) 2, 5
- Dizziness (up to 15% at higher doses) 5
- Headache 5
- Fatigue 5
- Asthenia (weakness) 5
- Insomnia 5
Gastrointestinal Effects
- Dry mouth (most common side effect, up to 54% at higher doses) 5
- Constipation (up to 15% at higher doses) 5
- Nausea 5
- Abdominal pain 5
Other Effects
- Impotence 5
- Discontinuation effects (medication should be tapered rather than suddenly discontinued) 2
- Skin rash with exfoliation (rare) 5
Clinical Considerations
- Dose-related side effects are common, with higher incidence at doses of 2-3 mg 5
- The therapeutic effects in ADHD typically take 2-4 weeks to become apparent, unlike stimulants which have a more rapid onset 2
- Guanfacine provides "around-the-clock" effects compared to stimulant medications 2
- Careful monitoring is particularly important during dose adjustments 7
- Warnings exist regarding hypotension/bradycardia, somnolence/sedation, discontinuation effects, and cardiac conduction abnormalities 2, 3
Important Distinctions from Clonidine
- Guanfacine has higher specificity for alpha-2A receptors compared to clonidine 1, 2
- Guanfacine is approximately ten times less potent than clonidine 1
- Guanfacine has less sedative effects compared to clonidine due to its greater selectivity for alpha-2A receptors 1, 8
- Guanfacine is primarily metabolized via CYP3A4, while clonidine is primarily metabolized via CYP2D6 1