Guanfacine

Source: Wikipedia, the free encyclopedia.
Not to be confused with Guanine, Guanosine, Guanidine, Guaifenesin, or Clonidine.

Guanfacine
Clinical data
Trade namesEstulic, Intuniv, Tenex, others
AHFS/Drugs.comMonograph
MedlinePlusa601059
License data
Routes of
administration		By mouth
Drug classCentrally acting α2A- adrenergic receptor agonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80–100% (IR), 58% (XR)[4][5]
Protein binding70%[4][5]
MetabolismCYP3A4[4][5]
Elimination half-lifeIR: 10–17 hours; XR: 17 hours (10–30) in adults & adolescents and 14 hours in children[4][5][6][7]
ExcretionKidney (80%; 50% [range: 40–75%] as unchanged drug)[4][5]
Identifiers
  • N-(Diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
JSmol)
  • Clc1cccc(Cl)c1CC(=O)\N=C(/N)N
  • InChI=1S/C9H9Cl2N3O/c10-6-2-1-3-7(11)5(6)4-8(15)14-9(12)13/h1-3H,4H2,(H4,12,13,14,15) checkY
  • Key:INJOMKTZOLKMBF-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Guanfacine, sold under the brand name Tenex (

high blood pressure.[3][8] Guanfacine is FDA-approved for monotherapy treatment of ADHD,[3] as well as being used for augmentation of other treatments, such as stimulants.[8] Guanfacine is also used off-label to treat tic disorders, anxiety disorders, and post-traumatic stress disorder (PTSD).[9]

Common

low blood pressure and urinary problems.[10] The FDA has categorized Guanfacine as "Category B" in pregnancy, which means animal-reproduction studies have not demonstrated a fetal risk or an adverse effect during pregnancy or breastfeeding.[11][10] It appears to work by activating α2A-adrenergic receptors in the brain, thereby decreasing sympathetic nervous system activity.[8]

Guanfacine was first described by 1974

generic medication.[8] In 2021, it was the 231st most commonly prescribed medication in the United States, with more than 1 million prescriptions.[13][14]

Medical uses

Red pills
1 mg guanfacine tablets.

Guanfacine is FDA-approved as monotherapy or augmentation with stimulants to treat

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.[22] In any case, guanfacine and other α2-adrenergic receptor agonists are considered to be less effective than stimulants in the treatment of ADHD.[22][23][21]

Guanfacine is also used off-label to treat tic disorders, anxiety disorders such as generalized anxiety disorder, and PTSD.

hyperarousal, re-experiencing of memory, and impulsivity associated with PTSD.[27] Guanfacine appears to be especially helpful in treating children who have been traumatized or abused.[25]

Adverse effects

dose-dependent.[28]

Very common (>10% incidence) adverse effects include

stomach ache.[29]

Common (1–10% incidence) adverse effects include

dry mouth, urinary incontinence, and rashes.[29]

Guanfacine has been reported to cause high rates of somnolence in children with ADHD, for instance 73% with guanfacine versus 6% with placebo in one trial.[30][31]

Guanfacine may worsen

total sleep time.[30][31]

A 2020

QT prolongation.[32]

Interactions

Guanfacine availability is significantly affected by the

cardioactive drugs. A similar concern is appropriate when it is used with sedating medications.[29]

Pharmacology

Pharmacodynamics

Guanfacine[33]
Site Ki (nM) Species Ref
α2A 50.3 – 93.3 Human [34][35]
α2B 1,020 – 1,380 Human [34][35]
α2C 1,120 – 3,890 Human [34][35]
The smaller the value, the more strongly the drug binds to the site.

Guanfacine is a highly

affinity for other receptors.[33] However, it is also a 5-HT2B receptor agonist.[36][37][38][39]

Guanfacine works by activating α2A-adrenoceptors

diastolic blood pressure.[41]

In ADHD, guanfacine is thought to work by strengthening the regulation of attention and behavior by the

behavioral inhibition, and these actions are independent of its sedative effects.[18] The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University.[42][18]

Guanfacine is much more selective for α2A-adrenergic receptors than

release), and may have greater efficacy in activating post-synaptic α2A-adrenergic receptors (as suggested by guanfacine being more potent than clonidine in enhancing prefrontal cortex-related working memory in aged monkeys).[18]

Activation of the 5-HT2B receptor is a well-known

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.[44] 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.[44] In any case, different studies have reported different potencies of guanfacine as a 5-HT2B receptor agonist,[38][39][44][45] and as of 2018, no clinical data on the risk of cardiac valvulopathy with guanfacine were available.[46] As such, while the likelihood is thought to be low, guanfacine might still have a risk of cardiac valvulopathy.[44]

Pharmacokinetics

Guanfacine has an

derivative, with evidence of moderate biotransformation, and the key intermediate is an epoxide.[47] 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.[48]

Preparation

Guanfacine can be prepared from equal parts methyl 2,6-dichlorophenylacetate and guanidine:[49]

History

Guanfacine was first described in the literature by 1974.[12][50][51][52][53] In 1986, guanfacine was approved by the FDA for the treatment of hypertension under the brand name Tenex.[54] In 2010, guanfacine was approved by the FDA for the treatment of attention deficit hyperactivity disorder for people 6 to 17 years old.[15] It was approved for ADHD by the European Medicines Agency under the name Intuniv in 2015.[55] It was added to the Australian Pharmaceutical Benefits Scheme for the treatment of ADHD in 2018.[56]

Society and culture

Brand names

Brand names include Tenex, Afken, Estulic, and Intuniv (an

extended release
formulation).

Research

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.[57] It may be also useful in adult PTSD patients who do not respond to selective serotonin reuptake inhibitors (SSRIs).[58]

Results of studies using guanfacine to treat

Tourette's syndrome have been mixed.[59]

Guanfacine does not appear to be effective for improving

total sleep time, in one clinical trial.[30][31]

Guanfacine has been investigated for treatment of withdrawal for opioids, ethanol, and nicotine.[60] Guanfacine has been shown to help reduce stress-induced craving of nicotine in smokers trying to quit, which may involve strengthening of prefrontal cortex-mediated self-control.[61]

Guanfacine has been researched for treatment of a variety of conditions impacting

elderly.[18][62]

Guanfacine is being studied for the possible treatment of long COVID.[63][64][65]

References

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  6. ^ Hofer KN, Buck ML (2008). "New Treatment Options for Attention-Deficit/Hyperactivity Disorder (ADHD): Part II. Guanfacine". Pediatric Pharmacotherapy (14): 4. Archived from the original on 31 October 2015. Retrieved 30 July 2014.
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