Guanfacine

Guanfacine, sold under the brand name Tenex among others, is an oral medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure.[1][6] Guanfacine is FDA-approved for monotherapy treatment of ADHD[1] as well as being used for augmentation of other treatments, such as stimulants.[6] Guanfacine is also used off-label to treat tic disorders, anxiety disorders and PTSD.[7]

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
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80–100% (IR), 58% (XR)[2][3]
Protein binding70%[2][3]
MetabolismCYP3A4[2][3]
Elimination half-lifeIR: 10-17 hours; XR: 17 hours (10-30) in adults & adolescents and 14 hours in children[2][3][4][5]
ExcretionKidney (80%; 50% [range: 40–75%] as unchanged drug)[2][3]
Identifiers
IUPAC name
  • N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.044.933
Chemical and physical data
FormulaC9H9Cl2N3O
Molar mass246.09 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) Y
  • Key:INJOMKTZOLKMBF-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Common side effects include sleepiness, constipation, and dry mouth.[6] Other side effects may include low blood pressure and urinary problems.[8] 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.[9][8] It appears to work by activating the α2A receptors in the brain thereby decreasing sympathetic nervous system activity.[6]

Guanfacine was approved for medical use in the United States in 1986.[6] It is available as a generic medication.[6] In 2020, it was the 300th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10][11]

Medical uses
1 mg guanfacine tablets.

Guanfacine is FDA approved as monotherapy or augmentation with stimulants to treat attention deficit hyperactivity disorder.[1][12][13] It is also FDA approved to treat high blood pressure.[3] It is FDA approved as monotherapy treatment for ADHD,[1] and it is also FDA approved to be used in augmentation with stimulant medications when stimulants medications are not fully effective (stimulants include medications such as amphetamines and methylphenidate). Guanfacine can offer a synergistic enhancement of stimulant treatment for ADHD, and in many cases can also help control the side effect profile of stimulant medications.[6] Guanfacine is also used off-label to treat Tic Disorders, Anxiety Disorders and PTSD.[14]

An off-label use of guanfacine is for treatment of anxiety, such as generalized anxiety disorder and post-traumatic stress disorder symptoms. Guanfacine and other α2A agonists have anxiolytic-like action,[15] thereby reducing the emotional responses of the amygdala, and strengthening prefrontal cortical regulation of emotion, action and thought.[16] These actions arise from both inhibition of stress-induced catecholamine release, and from prominent, post-synaptic actions in prefrontal cortex.[17] Due to its prolonged half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients.[18] All of these actions likely contribute to the relief of the hyperarousal, re-experiencing of memory, and impulsivity associated with PTSD.[19] Guanfacine appears to be especially helpful in treating children who have been traumatized or abused.[17]

Adverse effects

Side effects of guanfacine are dose-dependent.[20]

Very common (>10% incidence) adverse effects include sleepiness, tiredness, headache, and stomach ache.[21]

Common (1-10% incidence) adverse effects include decreased appetite, nausea, dry mouth, urinary incontinence, and rashes.[21]

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.

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. Similar concern is appropriate when it is used with sedating medications.[21]

Guanfacine is known to lower the user's tolerance for alcohol, heightening its effect, and alcohol use may prolong the effects of the medication.[22]

Pharmacology

Guanfacine is a highly selective agonist of the α2A adrenergic receptor, with low affinity for other receptors.[23] However it may also be a potent 5-HT2B receptor agonist, which can be associated with valvulopathy, although not all 5-HT2B agonists have this effect.[24]

Mechanism of action

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.[25]

In ADHD, guanfacine works by strengthening regulation of attention and behavior by the prefrontal cortex.[26] These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α2A adrenoceptors on dendritic spines. cAMP-mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing.[26][27] The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University.[26][28]

Pharmacokinetics

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 is an epoxide.[29] Elimination is not impacted with impaired 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.[30]

History

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.[12] It was approved for ADHD by the European Medicines Agency under the name Intuniv in 2015.[31] It was added to the Australian Pharmaceutical Benefits Scheme for the treatment of ADHD in 2018.[32]

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.[33] It may be also useful in adult PTSD patients who do not respond to SSRIs.[34]

Results of studies using guanfacine to treat Tourette's have been mixed.[35]

Guanfacine has been investigated for treatment of withdrawal for opioids, ethanol, and nicotine.[36] Guanfacine has been shown to help reduce stress-induced craving of nicotine in smokers trying to quit, which may involve strengthening of prefrontal cortex meditated self-control.[37]

References
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  2. "Guanfacine (guanfacine) Tablet [Genpharm Inc.]". DailyMed. Genpharm Inc. March 2007. Retrieved 9 November 2013.
  3. "guanfacine (Rx) - Intuniv, Tenex". Medscape Reference. WebMD. Retrieved 9 November 2013.
  4. Hofer KN, Buck ML (2008). "New Treatment Options for Attention-Deficit/Hyperactivity Disorder (ADHD): Part II. Guanfacine". Pediatric Pharmacotherapy (14): 4.
  5. Cruz MP (August 2010). "Guanfacine Extended-Release Tablets (Intuniv), a Nonstimulant Selective Alpha(2A)-Adrenergic Receptor Agonist For Attention-Deficit/Hyperactivity Disorder". P & T. 35 (8): 448–451. PMC 2935643. PMID 20844694.
  6. "Guanfacine Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 4 January 2018. Retrieved 18 March 2019.
  7. Kaplan and Sadock Textbook of Clinical Psychiatry Fifth Edition. Pages 1811–1812
  8. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 349–350. ISBN 9780857113382.
  9. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022037s002lbl.pdf
  10. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
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  13. Zito JM, Derivan AT, Kratochvil CJ, Safer DJ, Fegert JM, Greenhill LL (September 2008). "Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring". Child and Adolescent Psychiatry and Mental Health. 2 (1): 24. doi:10.1186/1753-2000-2-24. PMC 2566553. PMID 18793403.
  14. Kaplan and Sadock Textbook of Clinical Psychiatry Fifth Edition. Page 1811–1812
  15. Morrow BA, George TP, Roth RH Noradrenergic alpha-2 agonists have anxiolytic-like actions on stress-related behavior and mesoprefrontal dopamine biochemistry. Brain Res. 2004 Nov 19;1027(1-2):173-8. PMID 15494168
  16. Arnsten AF, Raskind MA, Taylor FB, Connor DF The effects of stress exposure on prefrontal cortex: Translating basic research into successful treatments for Post-Traumatic Stress Disorder. Neurobio. Stress 2015 Jan 1;1(1):89-99. PMID 25436222>
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  21. "Intuniv 1 mg, 2 mg, 3 mg, 4 mg prolonged-release tablets - Summary of Product Characteristics". UK Electronic Medicines Compendium. June 2017.
  22. "Guanfacine | Side Effects, Dosage, Uses, and More". 11 November 2017.
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  29. Kiechel JR (1980). "Pharmacokinetics and metabolism of guanfacine in man: a review". British Journal of Clinical Pharmacology. 10 (Suppl 1): 25S–32S. doi:10.1111/j.1365-2125.1980.tb04901.x. PMC 1430131. PMID 6994775.
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  31. "European Medicines Agency: Intuniv". ema.europa.eu. October 2015.
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  34. Belkin MR, Schwartz TL (2015). "Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder". Drugs in Context. 4: 212286. doi:10.7573/dic.212286. PMC 4544272. PMID 26322115.
  35. Srour M, Lespérance P, Richer F, Chouinard S (August 2008). "Psychopharmacology of tic disorders". Journal of the Canadian Academy of Child and Adolescent Psychiatry. 17 (3): 150–159. PMC 2527768. PMID 18769586.
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  • "Guanfacine". Drug Information Portal. U.S. National Library of Medicine.
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