Mechanism of Action of Guanfacine
Guanfacine works primarily as a selective alpha-2A adrenergic receptor agonist that acts centrally to reduce sympathetic outflow, which affects cardiac function and lowers blood pressure. 1, 2, 3
Primary Mechanism
- Guanfacine selectively stimulates postsynaptic alpha-2A adrenergic receptors in the prefrontal cortex (PFC), enhancing working memory and attention 4
- By stimulating these receptors, 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 3
- Unlike stimulants which act presynaptically, guanfacine mimics noradrenaline stimulation of postsynaptic alpha-2A receptors in the PFC 4
- At the cellular level, guanfacine inhibits the production of cAMP and closes HCN channels, enhancing the effectiveness of signals in pyramidal neurons of the prefrontal cortex 4
Pharmacological Properties
- Guanfacine has higher specificity for alpha-2A receptors compared to clonidine, which explains its different adverse effect profile (less sedation) 1, 2
- Guanfacine is approximately ten times less potent than clonidine but has greater selectivity for alpha-2A receptors 1
- The drug is primarily metabolized via CYP3A4 and excreted predominantly through renal pathways 1
- Guanfacine is approximately 70% bound to plasma proteins, independent of drug concentration 3
- The elimination half-life averages approximately 17 hours (range 10-30 hours), with younger patients having shorter half-lives (13-14 hours) 3
Therapeutic Effects
- In ADHD treatment, guanfacine promotes growth and maturation of dendritic spines of pyramidal neurons in the medial PFC, associated with learning and memory functions 4
- The therapeutic effects of guanfacine in ADHD are not immediate and typically take 2-4 weeks to become apparent, unlike stimulants which have a more rapid onset 1
- Guanfacine provides "around-the-clock" effects compared to stimulant medications 1
- Extended-release formulations of guanfacine maintain effectiveness for up to 24 hours with once-daily dosing 3, 5
Cardiovascular Effects
- Guanfacine lowers blood pressure by decreasing peripheral vascular resistance 3
- It causes a slight reduction in heart rate (approximately 5 beats/min) 3
- Cardiac output under conditions of rest or exercise is not altered by guanfacine 3
- Guanfacine lowers elevated plasma renin activity and plasma catecholamine levels in hypertensive patients, though this does not correlate with individual blood pressure responses 3
Clinical Considerations
- Guanfacine is available in tablet form with doses of 1,2,3, and 4 mg, with dosing typically adjusted to body weight (0.1 mg/kg as a rule of thumb) 1, 6
- Evening administration is generally preferable due to the relatively frequent occurrence of somnolence/fatigue as an adverse effect 6
- Common adverse effects include somnolence, fatigue, bradycardia, and hypotension 2, 7
- Warnings exist regarding hypotension/bradycardia, somnolence/sedation, discontinuation effects, and cardiac conduction abnormalities 1, 2
- The medication should be tapered rather than suddenly discontinued to avoid withdrawal effects 2, 6
Comparison to Other ADHD Medications
- Guanfacine has a different mechanism of action compared to stimulants and atomoxetine, making it a valuable alternative treatment option 8, 4
- Effect sizes compared to placebo are generally in the medium range and smaller than those of stimulants 1
- Guanfacine has been shown to improve functional impairment and quality of life in ADHD patients 1
- It can be used as monotherapy or as adjunctive therapy to stimulant medications 7, 9