Guanfacine
Guanfacine, sold under the brand name Tenex and Intuniv among others, is an oral alpha-2a agonist medication used to treat attention deficit hyperactivity disorder and high blood pressure.
Common side effects include sleepiness, constipation, and dry mouth. Other side effects may include low blood pressure and urinary problems. It appears to work by activating α2A-adrenergic receptors in the brain, thereby decreasing sympathetic nervous system activity.
Guanfacine was first described in 1974 and was approved for medical use in the United States in 1986. It is available as a generic medication. In 2023, it was the 263rd most commonly prescribed medication in the United States, with more than 1million prescriptions. Guanfacine is approved in the US for monotherapy treatment of attention deficit hyperactivity disorder, as well as being used for augmentation of stimulant medications. Guanfacine is also used off-label to treat tic disorders, anxiety disorders, and post-traumatic stress disorder.
Medical uses
Guanfacine IR is FDA-approved for the management of hypertension.Guanfacine XR is indicated for the treatment of attention deficit hyperactivity disorder, primarily for hyperactive symptoms. It is used both as monotherapy and as adjunctive therapy to stimulant medications. In some cases, it can also help control the side effect profile of stimulant medications. Unlike stimulant medications, guanfacine is regarded as having no abuse potential. However, stimulant medications still remain the first-line treatment for ADHD, and guanfacine is typically only prescribed by itself in patients who cannot take stimulant medications.
For attention deficit hyperactivity disorder, it is claimed that guanfacine helps individuals better control behavior, inhibit inappropriate distractions and impulses, and inhibit inappropriate aggressive impulses. Systematic reviews and meta-analyses have found guanfacine to be effective in the treatment of ADHD in both children and adults, with a moderate effect size found in adults. A systematic review and meta-analysis also found that guanfacine reduced oppositional behavior in children and adolescents with ADHD who also had or did not also have oppositional defiant disorder, with a small-to-moderate effect size. In any case, guanfacine and other α2-adrenergic receptor agonists are considered to be less effective than stimulants in the treatment of ADHD, at least when compared on rating scales developed to assess stimulant efficacy.
Guanfacine is also used off-label to treat tic disorders, anxiety disorders such as generalized anxiety disorder, and PTSD. Guanfacine and other α2A-adrenergic receptor agonists have anxiolytic-like action, thereby reducing the emotional responses of the amygdala, and strengthening prefrontal cortical regulation of emotion, action, and thought. These actions arise from both inhibition of stress-induced catecholamine release, and from prominent, post-synaptic actions in the prefrontal cortex. Due to its prolonged elimination half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients. All of these actions likely contribute to the relief of the hyperarousal, re-experiencing of memory, and impulsivity associated with PTSD. Guanfacine appears to be especially helpful in treating children who have been traumatized or abused.
Other indications for guanfacine are drug withdrawals, migraine prophylaxis, and Fragile X Syndrome, among others.
Adverse effects
s of guanfacine are dose-dependent.Very common adverse effects include somnolence, fatigue, headache, and stomach ache.
Common adverse effects include decreased appetite, nausea, dry mouth, urinary incontinence, and rashes.
Guanfacine has been reported to cause high rates of somnolence in children with attention deficit hyperactivity disorder, for instance 73% with guanfacine versus 6% with placebo in one trial.
Guanfacine may worsen sleep in children with attention deficit hyperactivity disorder, including reduced total sleep time.
A 2020 systematic review found side effects of guanfacine including abdominal pain, sedation, and QT prolongation.
Interactions
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. Because of its impact on the heart, it should be used with caution with other cardioactive drugs. A similar concern is appropriate when it is used with sedating medications.Pharmacology
Pharmacodynamics
Guanfacine is a highly selective agonist of the α2A-adrenergic receptor, with low affinity for other receptors. However, it is also a serotonin 5-HT2B receptor agonist.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 is thought to work by strengthening the 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, and are not dependent on activation of pre-synaptic α2A-adrenoceptors. Cyclic adenosine monophosphate -mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing. In monkeys, guanfacine improves working memory, attention regulation, and behavioral inhibition, and these actions are independent of its sedative effects. The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University.Because sedation is a common side-effect of guanfacine, it is often best administered in the evening.
Guanfacine is much more selective for α2A-adrenergic receptors than clonidine, which binds to and activates not only the α2A-adrenergic receptor but also α2B- and α2C-adrenergic receptors and the imidazoline receptor. It is weaker than clonidine in producing hypotension and sedation, has weaker pre-synaptic actions on the α2A-adrenergic receptor than clonidine, and may have greater efficacy in activating post-synaptic α2A-adrenergic receptors.
Activation of the 5-HT2B receptor is a well-known antitarget and is associated with cardiac valvulopathy. However, not all 5-HT2B receptor agonists, for instance ropinirole, have this effect. Guanfacine has not been associated with cardiac valvulopathy despite a long history of use, perhaps due to modest potency as a 5-HT2B receptor agonist. In in vitro studies, guanfacine showed 100-fold lower affinity for the 5-HT2B receptor than for the α2A-adrenergic receptor, 30-fold lower affinity for the 5-HT2B receptor than serotonin, and 1,000-fold lower potency in activating the 5-HT2B receptor compared to serotonin. It was concluded that at clinically relevant concentrations, guanfacine would not be expected to show significant binding to or activation of 5-HT2B receptors, and that it is unlikely that guanfacine is a cardiac valvulopathogen in humans. In any case, different studies have reported different potencies of guanfacine as a 5-HT2B receptor agonist, and as of 2018, no clinical data on the risk of cardiac valvulopathy with guanfacine were available. As such, while the likelihood is thought to be low, guanfacine might still have a risk of cardiac valvulopathy.
Guanfacine has been found to act as a full agonist of the trace amine-associated receptor 1 with an and of 20nM and ≥85% respectively.
Pharmacokinetics
Guanfacine has an oral bioavailability of 80%. There is no clear evidence of any first-pass metabolism. Its elimination half-life is 17hours with the major elimination route being renal. The principal metabolite is the 3-hydroxylated derivative, with evidence of moderate biotransformation, and the key intermediate is an epoxide. Elimination is not impacted by impaired renal function. As such, metabolism by the liver is the assumption for those with impaired renal function, as supported by the increased frequency of known side effects of orthostatic hypotension and sedation.| Intuniv 1 mg QD | Tenex 1 mg QD | Unit | |
| Cmax | 1.0 ± 0.3 | 2.5 ± 0.6 | ng/mL |
| AUC∞ | 32 ± 9 | 56 ± 15 | ng*h/mL |
| T1/2 | 18 ± 4 | 16 ± 3 | h |
| Tmax | 6.0 | 3.0 | h |
| Bioavailability | 58% | 80 - 100% | unitless |