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Guanfacine

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Not to be confused withGuanine,Guanosine,Guanidine,Guaifenesin,orClonidine.

Guanfacine
Clinical data
Trade namesEstulic, Intuniv, Tenex, others
AHFS/DrugsMonograph
MedlinePlusa601059
License data
Routes of
administration		By mouth
Drug classCentrally acting α2A- adrenergic receptor agonist
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability80–100% (IR), 58% (XR)[5][6]
Protein binding70%[5][6]
MetabolismCYP3A4[5][6]
Eliminationhalf-lifeIR: 10–17 hours; XR: 17 hours (10–30) in adults & adolescents and 14 hours in children[5][6][7][8]
ExcretionKidney (80%; 50% [range: 40–75%] as unchanged drug)[5][6]
Identifiers
  • N-(Diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.044.933Edit this at Wikidata
Chemical and physical data
FormulaC9H9Cl2N3O
Molar mass246.09g·mol−1
3D model (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-NcheckY
☒NcheckY(what is this?)(verify)

Guanfacine,sold under the brand nameTenex(immediate-release) andIntuniv(extended-release) among others, is anoralAlpha -2a agonistmedication used to treatattention deficit hyperactivity disorder(ADHD) andhigh blood pressure.[3][9]Guanfacine is FDA-approved for monotherapy treatment of ADHD,[3]as well as being used for augmentation of other treatments, such asstimulants.[9]Guanfacine is also usedoff-labelto treattic disorders,anxiety disorders,andpost-traumatic stress disorder(PTSD).[10]

Commonside effectsincludesleepiness,constipation,anddry mouth.[9]Other side effects may includelow blood pressureand urinary problems.[11]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 orbreastfeeding.[12][11]It appears to work by activatingα2A-adrenergic receptorsin thebrain,thereby decreasingsympathetic nervous systemactivity.[9]

Guanfacine was first described by 1974[13]and was approved for medical use in the United States in 1986.[9]It is available as ageneric medication.[9]In 2021, it was the 231st most commonly prescribed medication in the United States, with more than 1million prescriptions.[14][15]

Medical uses

[edit]
Red pills
1 mg guanfacine tablets.

Guanfacine is FDA-approved as monotherapy or augmentation with stimulants to treatattention deficit hyperactivity disorder(ADHD).[3][16][17]Unlike stimulant medications, guanfacine is regarded as having noabuse potential,and may even be used to reduce abuse of drugs includingnicotineandcocaine.[18]It is also FDA approved to treathigh blood pressure.[6]Guanfacine can offer a synergistic enhancement of stimulants such asamphetaminesandmethylphenidatefor treating ADHD, and in many cases can also help control theside effectprofile of stimulant medications.[9]For ADHD, it is claimed that guanfacine helps individuals better control behavior, inhibit inappropriate distractions and impulses, and inhibit inappropriate aggressive impulses.[19]Systematic reviewsandmeta-analyseshave found guanfacine to be effective in the treatment of ADHD in both children and adults, with a moderateeffect sizefound in adults (Hedges' g= -0.66).[20][21][22]A systematic review and meta-analysis also found that guanfacine reducedoppositional behaviorin children and adolescents with ADHD who also had or did not also haveoppositional defiant disorder,with a small-to-moderate effect size.[23]In any case, guanfacine and other α2-adrenergic receptor agonists are considered to be less effective than stimulants in the treatment of ADHD.[23][24][22]

Guanfacine is also used off-label to treat tic disorders, anxiety disorders such as generalized anxiety disorder, and PTSD.[10]Guanfacine and otherα2A-adrenergic receptor agonistshaveanxiolytic-like action,[25]thereby reducing the emotional responses of theamygdala,and strengtheningprefrontal corticalregulation of emotion, action, and thought.[26]These actions arise from both inhibition ofstress-inducedcatecholaminerelease, and from prominent,post-synapticactions in the prefrontal cortex.[26]Due to its prolongedelimination half-life,it also has been seen to improve sleep interrupted bynightmaresin PTSD patients.[27]All of these actions likely contribute to the relief of thehyperarousal,re-experiencing ofmemory,andimpulsivityassociated with PTSD.[28]Guanfacine appears to be especially helpful in treating children who have beentraumatizedorabused.[26]

Adverse effects

[edit]

Side effectsof guanfacine aredose-dependent.[29]

Very common (>10% incidence) adverse effects includesleepiness,tiredness,headache,andstomach ache.[30]

Common (1–10% incidence) adverse effects includedecreased appetite,nausea,dry mouth,urinary incontinence,andrashes.[30]

Guanfacine has been reported to cause high rates ofsomnolencein children with ADHD, for instance 73% with guanfacine versus 6% with placebo in one trial.[31][32]

Guanfacine may worsensleepin children with ADHD, including reducedtotal sleep time.[31][32]

A 2020systematic reviewfound side effects of guanfacine includingabdominal pain,sedation,andQT prolongation.[33]

Interactions

[edit]

Guanfacine availability is significantly affected by theCYP3A4andCYP3A5enzymes.Medications thatinhibitorinducethose enzymes change the amount of guanfacine in circulation and thus its efficacy and rate of adverse effects. Because of its impact on theheart,it should be used with caution with othercardioactivedrugs. A similar concern is appropriate when it is used withsedatingmedications.[30]

Pharmacology

[edit]

Pharmacodynamics

[edit]
Guanfacine[34]
Site Ki(nM) Species Ref
α2A 50.3 – 93.3 Human [35][36]
α2B 1,020 – 1,380 Human [35][36]
α2C 1,120 – 3,890 Human [35][36]
The smaller the value, the more strongly the drug binds to the site.

Guanfacine is a highlyselectiveagonistof theα2A-adrenergic receptor,with lowaffinityfor otherreceptors.[34]However, it is also a5-HT2Breceptoragonist.[37][38][39][40]

Guanfacine works by activating α2A-adrenoceptors[41]within thecentral nervous system.This leads to reducedperipheralsympatheticoutflow and thus a reduction in peripheralsympathetic tone,which lowers bothsystolicanddiastolicblood pressure.[42]

In ADHD, guanfacine is thought to work by strengthening the regulation of attention and behavior by theprefrontal cortex.[43][19]These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α2A-adrenoceptors ondendritic spines,and are not dependent on activation of pre-synaptic α2A-adrenoceptors.[19]Cyclic adenosine monophosphate(cAMP)-mediated opening ofHCNandKCNQ channelsis inhibited, which enhances prefrontal cortical synaptic connectivity andneuronal firing.[43][44]In monkeys, guanfacine improvesworking memory,attentionregulation, andbehavioral inhibition,and these actions are independent of its sedative effects.[19]The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab atYale University.[43][19]

Guanfacine is much more selective for α2A-adrenergic receptors thanclonidine,which binds to and activates not only the α2A-adrenergic receptor but alsoα2B-andα2C-adrenergic receptorsand theimidazoline receptor.[19]It is weaker than clonidine in producinghypotensionandsedation,has weakerpre-synapticactions on the α2A-adrenergic receptor than clonidine (10-fold less effective in decreasinglocus coeruleusactivity andnorepinephrinerelease), 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-relatedworking memoryin aged monkeys).[19]

Activation of the 5-HT2Breceptor is a well-knownantitargetand is associated withcardiac valvulopathy.[37][38]However, not all 5-HT2Breceptor agonists, for instanceropinirole,have this effect.[37][38]Guanfacine has not been associated with cardiac valvulopathy despite a long history of use, perhaps due to modestpotencyas a 5-HT2Breceptor agonist.[40][45][46]Inin vitrostudies, guanfacine showed 100-fold loweraffinityfor the 5-HT2Breceptor than for the α2A-adrenergic receptor, 30-fold lower affinity for the 5-HT2Breceptor thanserotonin,and 1,000-fold lower potency in activating the 5-HT2Breceptor compared to serotonin.[45]It was concluded that at clinically relevant concentrations, guanfacine would not be expected to show significant binding to or activation of 5-HT2Breceptors, and that it is unlikely that guanfacine is a cardiac valvulopathogen in humans.[45]In any case, different studies have reported different potencies of guanfacine as a 5-HT2Breceptor agonist,[39][40][45][46]and as of 2018, no clinical data on the risk of cardiac valvulopathy with guanfacine were available.[47]As such, while the likelihood is thought to be low, guanfacine might still have a risk of cardiac valvulopathy.[45]

Guanfacine has been found to act as an agonist of thetrace amine-associated receptor 1(TAAR1).[48]

Pharmacokinetics

[edit]

Guanfacine has anoralbioavailabilityof 80%. There is no clear evidence of anyfirst-pass metabolism.Itselimination half-lifeis 17hours with the majoreliminationroute beingrenal.The principalmetaboliteis the 3-hydroxylatedderivative,with evidence of moderatebiotransformation,and the key intermediate is anepoxide.[49]Elimination is not impacted by impairedrenalfunction. As such,metabolismby theliveris the assumption for those with impaired renal function, as supported by the increased frequency of known side effects oforthostatic hypotensionandsedation.[50]

Preparation

[edit]

Guanfacine can be prepared from equal parts methyl 2,6-dichlorophenylacetate andguanidine:[51]

History

[edit]

Guanfacine was first described in the literature by 1974.[13][52][53][54][55]In 1986, guanfacine was approved by the FDA for the treatment ofhypertensionunder the brand name Tenex.[56]In 2010, guanfacine was approved by the FDA for the treatment ofattention deficit hyperactivity disorderfor people 6 to 17 years old.[16]It was approved for ADHD by theEuropean Medicines Agencyunder the name Intuniv in 2015.[57]It was added to the AustralianPharmaceutical Benefits Schemefor the treatment of ADHD in 2018.[58]

Society and culture

[edit]

Brand names

[edit]

Brand names include Tenex, Afken, Estulic, and Intuniv (anextended releaseformulation).

Research

[edit]

Guanfacine has been studied as a treatment forpost-traumatic stress disorder(PTSD). Evidence of efficacy in adults is limited, but one study found positive results in children with comorbid ADHD.[59]It may be also useful in adult PTSD patients who do not respond toselective serotonin reuptake inhibitors(SSRIs).[60]

Results of studies using guanfacine to treatTourette's syndromehave been mixed.[61]

Guanfacine does not appear to be effective for improvingsleepin children with ADHD and behavioralinsomnia.[31]Instead, guanfacine worsened certain sleep parameters, for instancetotal sleep time,in one clinical trial.[31][32]

Guanfacine has been investigated for treatment ofwithdrawalforopioids,ethanol,andnicotine.[62]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.[63]

Guanfacine has been researched for treatment of a variety of conditions impactingprefrontal cortexfunction, including cognitive and attentional problems in people withtraumatic brain injury,stroke,schizophreniform disorders,and theelderly.[19][64]

Guanfacine is being studied for the possible treatment oflong COVID.[65][66][67]

References

[edit]
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