|Trade names||Afken, Estulic, Intuniv, Tenex|
|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 Paediatrics|
|Excretion||renal (80%; 50% [range: 40-75%] as unchanged drug)|
|Chemical and physical data|
|Molar mass||246.093 g/mol|
|3D model (JSmol)|
|(what is this?)|
Guanfacine (trade names Estulic, Tenex, and, in extended release form, Intuniv) is a sympatholytic drug used to treat hypertension and attention deficit hyperactivity disorder (ADHD). It is a selective α2A receptor agonist.
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, and medications that inhibit or induce those enzymes change the amount of guanfacine in circulation and thus its efficacy and adverse effects, and likewise guanfacine affects those medications. Because of its effects on the heart, it needs to be used with caution with other medications that may affect the heart; likewise, other medications that may cause sedation.
Guanfacine is a highly selective agonist of the α2A adrenergic receptor, with negligible affinity for any other receptor. However, it may also be a potent 5-HT2B receptor agonist, potentially (theoretically) contributing to valvulopathy.
Mechanism of action
Guanfacine works by activating α2A adrenoceptors in the central nervous system. This results in 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 thought to be due to drug stimulation of post-synaptic α2A adrenoceptors on dendritic spines, which inhibit cAMP-mediated opening of HCN and KCNQ channels and thus strengthen prefrontal cortical synaptic connectivity and enhance neuronal firing. The use of guanfacine for treating prefrontal disorders was developed by the Arnsten lab at Yale University based on understanding the needs of the prefrontal cortex.
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 being an epoxide. It is also shown that elimination in patients with impaired renal function does not differ significantly from those with normal 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.
Guanfacine has been studied as a treatment for posttraumatic stress disorder. 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 cortical self-control.
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