Unlike other ADHD medications that work indirectly in the prefrontal cortex, guanfacine works directly as it binds specifically to the alpha-2A adrenergic cell receptors in the prefrontal cortex. The prefrontal cortex is the area of the brain associated with executive function, behavioral inhibition, regulation of attention, distractibility, impulsivity, and frustration tolerance. The selective alpha-2A agonist strengthens working memory and assists firing of the neurons in the prefrontal cortex. Guanfacine is not a controlled substance and does not appear to have a known mechanism for potential abuse of dependence.

Tenex, a formulation of guanfacine, is an orally administered centrally acting antihypertensive agent that may confer less of a risk of sedation and hypotensive effects than clonidine. Clinicians have been increasing their use of guanfacine in treating ADHD. It may be considered for children older that 7 years or adolescents with ADHD or other comorbid conditions after treatment with established medications such as stimulants or antidepressants.

In May 2008, Shire Pharmaceuticals announced findings from analyses of pivotal trials of INTUNIV, a once-daily formulation of guanfacine that provides a steady delivery of drug throughout the day and is designed to minimize the fluctuations between peak and trough concentrations as seen with immediate release guanfacine. In Phase III clinical trials all patients treated with INTUNIV showed significantly greater improvement on rating scales than the group receiving placebo. Safety data showed that adverse events reported were generally mild and moderate, with the most common complaint being the feeling of sedation.

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