Guanfacine

Last updated

Guanfacine
Guanfacine.svg
Guanfacine molecule ball.png
Clinical data
Trade names Estulic, Intuniv, Tenex, others
AHFS/Drugs.com Monograph
MedlinePlus a601059
License data
Routes of
administration 		By mouth
Drug class Centrally acting α2A- adrenergic receptor agonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 80–100% (IR), 58% (XR) [5] [6]
Protein binding 70% [5] [6]
Metabolism CYP3A4 [5] [6]
Elimination half-life IR: 10–17 hours; XR: 17 hours (10–30) in adults & adolescents and 14 hours in children [5] [6] [7] [8]
Excretion Kidney (80%; 50% [range: 40–75%] as unchanged drug) [5] [6]
Identifiers
  • N-(Diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.044.933 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H9Cl2N3O
Molar mass 246.09 g·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) Yes check.svgY
  • Key:INJOMKTZOLKMBF-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Guanfacine, sold under the brand name Tenex (immediate-release) and Intuniv (extended-release) among others, is an oral alpha-2a agonist medication used to treat attention deficit hyperactivity disorder (ADHD) and high 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 as stimulants. [9] Guanfacine is also used off-label to treat tic disorders, anxiety disorders, and post-traumatic stress disorder (PTSD). [10]

Contents

Common side effects include sleepiness, constipation, and dry mouth. [9] Other side effects may include low blood pressure and 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 or breastfeeding. [12] [11] It appears to work by activating α2A-adrenergic receptors in the brain, thereby decreasing sympathetic nervous system activity. [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 a generic medication. [9] In 2021, it was the 231st most commonly prescribed medication in the United States, with more than 1 million prescriptions. [14] [15]

Medical uses

1 mg guanfacine tablets. Guanfacine tablets.jpg
1 mg guanfacine tablets.

Guanfacine is FDA-approved as monotherapy or augmentation with stimulants to treat attention deficit hyperactivity disorder (ADHD). [3] [16] [17] Unlike stimulant medications, guanfacine is regarded as having no abuse potential, and may even be used to reduce abuse of drugs including nicotine and cocaine. [18] It is also FDA approved to treat high blood pressure. [6] Guanfacine can offer a synergistic enhancement of stimulants such as amphetamines and methylphenidate for treating ADHD, and in many cases can also help control the side effect profile 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 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 (Hedges' g = -0.66). [20] [21] [22] 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. [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 other α2A-adrenergic receptor agonists have anxiolytic-like action, [25] thereby reducing the emotional responses of the amygdala, and strengthening prefrontal cortical regulation of emotion, action, and thought. [26] These actions arise from both inhibition of stress-induced catecholamine release, and from prominent, post-synaptic actions in the prefrontal cortex. [26] Due to its prolonged elimination half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients. [27] All of these actions likely contribute to the relief of the hyperarousal, re-experiencing of memory, and impulsivity associated with PTSD. [28] Guanfacine appears to be especially helpful in treating children who have been traumatized or abused. [26]

Adverse effects

Side effects of guanfacine are dose-dependent. [29]

Very common (>10% incidence) adverse effects include sleepiness, tiredness, headache, and stomach ache. [30]

Common (1–10% incidence) adverse effects include decreased appetite, nausea, dry mouth, urinary incontinence, and rashes. [30]

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. [31] [32]

Guanfacine may worsen sleep in children with ADHD, including reduced total sleep time. [31] [32]

A 2020 systematic review found side effects of guanfacine including abdominal pain, sedation, and QT prolongation. [33]

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. [30]

Pharmacology

Pharmacodynamics

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

Guanfacine is a highly selective agonist of the α2A-adrenergic receptor, with low affinity for other receptors. [34] However, it is also a serotonin 5-HT2B receptor agonist. [37] [38] [39] [40]

Guanfacine works by activating α2A-adrenoceptors [41] 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. [42]

In ADHD, guanfacine is thought to work by strengthening the regulation of attention and behavior by the prefrontal cortex. [43] [19] 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. [19] Cyclic adenosine monophosphate (cAMP)-mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing. [43] [44] In monkeys, guanfacine improves working memory, attention regulation, and behavioral 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 at Yale University. [43] [19]

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. [19] It is weaker than clonidine in producing hypotension and sedation, has weaker pre-synaptic actions on the α2A-adrenergic receptor than clonidine (10-fold less effective in decreasing locus coeruleus activity and norepinephrine 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). [19]

Activation of the 5-HT2B receptor is a well-known antitarget and is associated with cardiac valvulopathy. [37] [38] However, not all 5-HT2B receptor agonists, for instance ropinirole, have this effect. [37] [38] 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. [40] [45] [46] 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. [45] 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. [45] In any case, different studies have reported different potencies of guanfacine as a 5-HT2B receptor 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 a full agonist of the trace amine-associated receptor 1 (TAAR1) with an EC50 Tooltip half-maximal effective concentration and Emax Tooltip maximal efficacy of 20 nM and ≥85% respectively. [48] [49]

Pharmacokinetics

Comparison of Intuniv 1mg QD and Tenex 1mg QD at steady-state. Guanfacine Pharmokinetic Data.png
Comparison of Intuniv 1mg QD and Tenex 1mg QD at steady-state.

Guanfacine has an oral bioavailability of 80%. There is no clear evidence of any first-pass metabolism. Its elimination half-life is 17 hours 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. [51] 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. [52]

Pharmacokinetic Data [53] [54]
Intuniv 1mg QDTenex 1mg QDUnit
Cmax1.0 ± 0.32.5 ± 0.6ng/mL
AUC∞32 ± 956 ± 15ng*h/mL
T1/218 ± 416 ± 3h (hours)
Tmax6.0 (4.0 - 8.0)3.0 (1.5 - 4.0)h (hours)
Bioavailability58%80 - 100%unitless

Preparation

Guanfacine can be prepared from equal parts methyl 2,6-dichlorophenylacetate and guanidine: [55]

Guanfacine synthesis 2.svg

History

Guanfacine was first described in the literature by 1974. [13] [56] [57] [58] [59] In 1986, guanfacine was approved by the FDA for the treatment of hypertension under the brand name Tenex. [60] In 2010, guanfacine was approved by the FDA for the treatment of attention deficit hyperactivity disorder for people 6 to 17 years old. [16] It was approved for ADHD by the European Medicines Agency under the name Intuniv in 2015. [61] It was added to the Australian Pharmaceutical Benefits Scheme for the treatment of ADHD in 2018. [62]

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. [63] It may be also useful in adult PTSD patients who do not respond to selective serotonin reuptake inhibitors (SSRIs). [64]

Results of studies using guanfacine to treat Tourette's syndrome have been mixed. [65]

Guanfacine does not appear to be effective for improving sleep in children with ADHD and behavioral insomnia. [31] Instead, guanfacine worsened certain sleep parameters, for instance total sleep time, in one clinical trial. [31] [32]

Guanfacine has been investigated for treatment of withdrawal for opioids, ethanol, and nicotine. [66] 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. [67]

Guanfacine has been researched for treatment of a variety of conditions impacting prefrontal cortex function, including cognitive and attentional problems in people with traumatic brain injury, stroke, schizophreniform disorders, and the elderly. [19] [68]

Guanfacine is being studied for the possible treatment of long COVID. [69] [70] [71]

Related Research Articles

<span class="mw-page-title-main">Attention deficit hyperactivity disorder</span> Neurodevelopmental disorder

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by executive dysfunction occasioning symptoms of inattention, hyperactivity, impulsivity and emotional dysregulation that are excessive and pervasive, impairing in multiple contexts, and developmentally-inappropriate.

<span class="mw-page-title-main">Propranolol</span> Beta blocker drug

Propranolol is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, neuroleptic-induced akathisia, performance anxiety, and essential tremors, as well to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks. It can be taken orally or by intravenous injection. The formulation that is taken orally comes in short-acting and long-acting versions. Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken orally.

<span class="mw-page-title-main">Methylphenidate</span> Central nervous system stimulant

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a first-line treatment for ADHD ; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines, alleviating the executive functioning deficits of sustained attention, inhibition, working memory, reaction time and emotional self-regulation.

<span class="mw-page-title-main">Aripiprazole</span> Atypical antipsychotic

Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder; other uses include as an add-on treatment in major depressive disorder and obsessive–compulsive disorder (OCD), tic disorders, and irritability associated with autism. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

Dextroamphetamine is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.

<span class="mw-page-title-main">Clonidine</span> Pharmaceutical drug

Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic receptor agonist medication used to treat high blood pressure, ADHD, drug withdrawal, menopausal flushing, diarrhea, spasticity, and certain pain conditions. The drug is often prescribed off-label for tics. It is used orally, by injection, or as a transdermal skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.

<span class="mw-page-title-main">Atomoxetine</span> Medication used to treat ADHD

Atomoxetine, sold under the brand name Strattera among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome (CDS). It may be used alone or along with stimulant medication. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time, and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.

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<span class="mw-page-title-main">Dexmethylphenidate</span> CNS Stimulant

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<span class="mw-page-title-main">Viloxazine</span> Medication used to treat ADHD

Viloxazine, sold under the brand name Qelbree among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken orally. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form, latterly with comparable effectiveness to atomoxetine and methylphenidate.

<span class="mw-page-title-main">Alpha-2 adrenergic receptor</span> Protein family

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<span class="mw-page-title-main">Molindone</span> Antipsychotic medication

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Attention deficit hyperactivity disorder management options are evidence-based practices with established treatment efficacy for ADHD. Approaches that have been evaluated in the management of ADHD symptoms include FDA-approved pharmacologic treatment and other pharmaceutical agents, psychological or behavioral approaches, combined pharmacological and behavioral approaches, cognitive training, neurofeedback, neurostimulation, physical exercise, nutrition and supplements, integrative medicine, parent support, and school interventions. Based on two 2024 systematic reviews of the literature, FDA-approved medications and to a lesser extent psychosocial interventions have been shown to improve core ADHD symptoms compared to control groups.

<span class="mw-page-title-main">Alpha-adrenergic agonist</span> Class of drugs

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<span class="mw-page-title-main">ABT-418</span> Chemical compound

ABT-418 is a drug developed by Abbott, that has nootropic, neuroprotective and anxiolytic effects, and has been researched for treatment of both Alzheimer's disease and ADHD. It acts as an agonist at neural nicotinic acetylcholine receptors, subtype-selective binding with high affinity to the α4β2, α7/5-HT3, and α2β2 nicotinic acetylcholine receptors but not α3β4 receptors ABT-418 was reasonably effective for both applications and fairly well tolerated, but produced some side effects, principally nausea, and it is unclear whether ABT-418 itself will proceed to clinical development or if another similar drug will be used instead.

<span class="mw-page-title-main">Brexpiprazole</span> Atypical antipsychotic

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.

<span class="mw-page-title-main">Hypofrontality</span> State of decreased cerebral blood flow

Hypofrontality is a state of decreased cerebral blood flow (CBF) in the prefrontal cortex of the brain. Hypofrontality is symptomatic of several neurological medical conditions, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and major depressive disorder. This condition was initially described by Ingvar and Franzén in 1974, through the use of xenon blood flow technique with 32 detectors to image the brains of patients with schizophrenia. This finding was confirmed in subsequent studies using the improved spatial resolution of positron emission tomography with the fluorodeoxyglucose (18F-FDG) tracer. Subsequent neuroimaging work has shown that the decreases in prefrontal CBF are localized to the medial, lateral, and orbital portions of the prefrontal cortex. Hypofrontality is thought to contribute to the negative symptoms of schizophrenia.

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