|Trade names||Estulic, Intuniv, Tenex, others|
|Bioavailability||80-100% (IR), 58% (XR)|
|Elimination half-life||IR: 10-17 hours; XR: 17 hours (10-30) in adults & adolescents and 14 hours in children|
|Excretion||Kidney (80%; 50% [range: 40-75%] as unchanged drug)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||246.09 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Guanfacine, sold under the brand name Tenex among others, is an oral medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure. It is not considered a first-line treatment for either indication.
Common side effects include sleepiness, constipation, dry mouth, sexual problems, and headaches. Other side effects may include anxiety, low blood pressure, depression, and urinary problems. Use is not recommended during pregnancy or breastfeeding. It appears to work by activating the α2A receptors in the brain thereby decreasing sympathetic nervous system activity.
Guanfacine was approved for medical use in the United States in 1986. It is available as a generic medication. In 2018, it was the 127th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Guanfacine is used alone or with stimulants to treat people with attention deficit hyperactivity disorder. It is also used to treat high blood pressure. It is a less preferred treatment for ADHD (after more established treatments such as methylphenidate and amphetamines) and for high blood pressure.
Side effects of guanfacine are dose-dependent.
Very common (>10% incidence) adverse effects include sleepiness, tiredness, headache, and stomach ache.
Common (1-10% incidence) adverse effects include decreased appetite, depressed mood, anxiety, irritability, mood changes, insomnia, nightmares, dizziness, lack of energy, slowed heart beat, low blood pressure, feeling faint when standing quickly, vomiting, nausea, diarrhea, constipation, dry mouth, urinary incontinence, and rashes.
Typical side effects such as fatigue, irritability and stomach upset can take a week or two to subside. Increases in dosage can have the same adjustment period.
Guanfacine availability is significantly affected by the CYP3A4 and CYP3A5 enzymes. Medications that inhibit or induce those enzymes change the amount of guanfacine in circulation and thus its efficacy and rate of adverse effects; likewise, guanfacine affects those medications. Because of its impact on the heart, it should be used with caution with other cardioactive drugs. Similar concern is appropriate when it is used with sedating medications.
Guanfacine is a highly selective agonist of the α2A adrenergic receptor, with low affinity for other receptors. However it may also be a potent 5-HT2B receptor agonist, potentially contributing to valvulopathy.
Mechanism of action
Guanfacine works by activating α2A adrenoceptors within the central nervous system. This leads to reduced peripheral sympathetic outflow and thus a reduction in peripheral sympathetic tone, which lowers both systolic and diastolic blood pressure.
In ADHD, guanfacine works by strengthening regulation of attention and behavior by the prefrontal cortex. These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α2A adrenoceptors on dendritic spines. cAMP-mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing. The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University.
Guanfacine has an oral bioavailability of 80%. There is no clear evidence of any first-pass metabolism. Elimination half-life is 17 hours with the major elimination route being renal. The principal metabolite is the 3-hydroxy-derivative, with evidence of moderate biotransformation, and the key intermediate is an epoxide. Elimination is not impacted with impaired renal function. As such, metabolism by liver is the assumption for those with impaired renal function, as supported by increased frequency of known side effects of orthostatic hypotension and sedation.
In 1986, guanfacine was approved by the FDA for the treatment of hypertension under the brand name Tenex (Drugs@FDA). In 2010, guanfacine was approved by the FDA for the treatment of attention deficit hyperactivity disorder for people 6–17 years old. It was approved for ADHD by the European Medicines Agency under the name Intuniv in 2015. It was added to the Australian Pharmaceutical Benefits Scheme for the treatment of ADHD in 2018.
Brand names include Tenex, Afken, Estulic, and Intuniv (an extended release formulation).
Guanfacine has been studied as a treatment for post-traumatic stress disorder (PTSD). Evidence of efficacy in adults is limited, but one study found positive results in children with comorbid ADHD. It may be also useful in adult PTSD patients who do not respond to SSRIs.
Guanfacine has been investigated for treatment of withdrawal for opioids, ethanol, and nicotine. Guanfacine has been shown to help reduce stress-induced craving of nicotine in smokers trying to quit, which may involve strengthening of prefrontal cortex meditated self-control.
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