Chemistry:Guanfacine

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Short description: Medication used for high blood pressure and ADHD
Guanfacine
Guanfacine.svg
Guanfacine molecule ball.png
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)[3][4]
Protein binding70%[3][4]
MetabolismCYP3A4[3][4]
Elimination half-lifeIR: 10–17 hours; XR: 17 hours (10–30) in adults & adolescents and 14 hours in children[3][4][5][6]
ExcretionKidney (80%; 50% [range: 40–75%] as unchanged drug)[3][4]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC9H9Cl2N3O
Molar mass246.09 g·mol−1
3D model (JSmol)
 ☒N☑Y (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.[2][7] Guanfacine is FDA-approved for monotherapy treatment of ADHD,[2] as well as being used for augmentation of other treatments, such as stimulants.[7] Guanfacine is also used off-label to treat tic disorders, anxiety disorders, and post-traumatic stress disorder (PTSD).[8]

Common side effects include sleepiness, constipation, and dry mouth.[7] Other side effects may include low blood pressure and urinary problems.[9] 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.[10][9] It appears to work by activating α2A-adrenergic receptors in the brain, thereby decreasing sympathetic nervous system activity.[7]

Guanfacine was first described by 1974[11] and was approved for medical use in the United States in 1986.[7] It is available as a generic medication.[7] In 2020, it was the 300th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[12][13]

Medical uses

Red pills
1 mg guanfacine tablets.

Guanfacine is FDA-approved as monotherapy or augmentation with stimulants to treat attention deficit hyperactivity disorder (ADHD).[2][14][15] 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.[16] It is also FDA approved to treat high blood pressure.[4] 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.[7] For ADHD, it is claimed that guanfacine helps individuals better control behavior, inhibit inappropriate distractions and impulses, and inhibit inappropriate aggressive impulses.[17] 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).[18][19][20] 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.[21] In any case, guanfacine and other α2-adrenergic receptor agonists are considered to be less effective than stimulants in the treatment of ADHD.[21][22][20]

Guanfacine is also used off-label to treat tic disorders, anxiety disorders such as generalized anxiety disorder, and PTSD.[8] Guanfacine and other α2A-adrenergic receptor agonists have anxiolytic-like action,[23] thereby reducing the emotional responses of the amygdala, and strengthening prefrontal cortical regulation of emotion, action, and thought.[24] These actions arise from both inhibition of stress-induced catecholamine release, and from prominent, post-synaptic actions in the prefrontal cortex.[24] Due to its prolonged elimination half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients.[25] All of these actions likely contribute to the relief of the hyperarousal, re-experiencing of memory, and impulsivity associated with PTSD.[26] Guanfacine appears to be especially helpful in treating children who have been traumatized or abused.[24]

Adverse effects

Side effects of guanfacine are dose-dependent.[27]

Very common (>10% incidence) adverse effects include sleepiness, tiredness, headache, and stomach ache.[28]

Common (1–10% incidence) adverse effects include decreased appetite, nausea, dry mouth, urinary incontinence, and rashes.[28]

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.[29][30]

Guanfacine may worsen sleep in children with ADHD, including reduced total sleep time.[29][30]

A 2020 systematic review found side effects of guanfacine including abdominal pain, sedation, and QT prolongation.[31]

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.[28]

Pharmacology

Pharmacodynamics

Guanfacine[32]
Site Ki (nM) Species Ref
α2A 50.3 – 93.3 Human [33][34]
α2B 1,020 – 1,380 Human [33][34]
α2C 1,120 – 3,890 Human [33][34]
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.[32] However, it is also a 5-HT2B receptor agonist.[35][36][37][38]

Guanfacine works by activating α2A-adrenoceptors[39] 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.[40]

In ADHD, guanfacine is thought to work by strengthening the regulation of attention and behavior by the prefrontal cortex.[41][17] 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.[17] Cyclic adenosine monophosphate (cAMP)-mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing.[41][42] In monkeys, guanfacine improves working memory, attention regulation, and behavioral inhibition, and these actions are independent of its sedative effects.[17] The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University.[41][17]

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.[17] 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).[17]

Activation of the 5-HT2B receptor is a well-known antitarget and is associated with cardiac valvulopathy.[35][36] However, not all 5-HT2B receptor agonists, for instance ropinirole, have this effect.[35][36] 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.[38][43][44] 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.[43] 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.[43] In any case, different studies have reported different potencies of guanfacine as a 5-HT2B receptor agonist,[37][38][43][44] and as of 2018, no clinical data on the risk of cardiac valvulopathy with guanfacine were available.[45] As such, while the likelihood is thought to be low, guanfacine might still have a risk of cardiac valvulopathy.[43]

Pharmacokinetics

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.[46] 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.[47]

History

Guanfacine was first described in the literature by 1974.[11][48][49][50][51] In 1986, guanfacine was approved by the FDA for the treatment of hypertension under the brand name Tenex.[52] In 2010, guanfacine was approved by the FDA for the treatment of attention deficit hyperactivity disorder for people 6 to 17 years old.[14] It was approved for ADHD by the European Medicines Agency under the name Intuniv in 2015.[53] It was added to the Australian Pharmaceutical Benefits Scheme for the treatment of ADHD in 2018.[54]

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.[55] It may be also useful in adult PTSD patients who do not respond to selective serotonin reuptake inhibitors (SSRIs).[56]

Results of studies using guanfacine to treat Tourette's syndrome have been mixed.[57]

Guanfacine does not appear to be effective for improving sleep in children with ADHD and behavioral insomnia.[29] Instead, guanfacine worsened certain sleep parameters, for instance total sleep time, in one clinical trial.[29][30]

Guanfacine has been investigated for treatment of withdrawal for opioids, ethanol, and nicotine.[58] 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.[59]

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.[17][60]

Guanfacine is being studied for the possible treatment of long COVID.[61][62][63]

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2017". 21 June 2022. https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017. 
  2. ↑ 2.0 2.1 2.2 2.3 "Intuniv- guanfacine tablet, extended release Intuniv- guanfacine kit". 26 January 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b972af81-3a37-40be-9fe1-3ddf59852528. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Guanfacine (guanfacine) Tablet [Genpharm Inc."]. Genpharm Inc.. March 2007. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9fc0bdc2-5ba2-48dd-aa87-7b0050a2d6ce. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "guanfacine (Rx) - Intuniv, Tenex". WebMD. http://reference.medscape.com/drug/intuniv-tenex-guanfacine-342384. 
  5. ↑ "New Treatment Options for Attention-Deficit/Hyperactivity Disorder (ADHD): Part II. Guanfacine". Pediatric Pharmacotherapy (14): 4. 2008. http://medscape.com/viewarticle/578747_4. Retrieved 30 July 2014. 
  6. ↑ "Guanfacine Extended-Release Tablets (Intuniv), a Nonstimulant Selective Alpha(2A)-Adrenergic Receptor Agonist For Attention-Deficit/Hyperactivity Disorder". P & T 35 (8): 448–451. August 2010. PMID 20844694. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 "Guanfacine Monograph for Professionals" (in en). American Society of Health-System Pharmacists. https://www.drugs.com/monograph/guanfacine.html. 
  8. ↑ 8.0 8.1 Kaplan & Sadock's Concise Textbook of Clinical Psychiatry (5th ed.). Philadelphia. 2023. pp. 1811–1812. ISBN 978-1-9751-6748-6. OCLC 1264172789. https://www.worldcat.org/oclc/1264172789. Retrieved 12 January 2023. 
  9. ↑ 9.0 9.1 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 349–350. ISBN 9780857113382. 
  10. ↑ "Patient Information. INTUNIV (in-TOO-niv) (guanfacine). Extended-Release Tablets". http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022037s002lbl.pdf. 
  11. ↑ 11.0 11.1 Turner, A. S. (1974). BS 100-141 in the treatment of arterial hypertension. Seventh World Congr. of Cardiol., Abstr, 336.
  12. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  13. ↑ "Guanfacine - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Guanfacine. 
  14. ↑ 14.0 14.1 "Effects of FDA advisories on the pharmacologic treatment of ADHD, 2004-2008". Psychiatric Services 64 (4): 339–346. April 2013. doi:10.1176/appi.ps.201200147. PMID 23318985. 
  15. ↑ "Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring". Child and Adolescent Psychiatry and Mental Health 2 (1): 24. September 2008. doi:10.1186/1753-2000-2-24. PMID 18793403. 
  16. ↑ Clemow, DB; Walker, DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review.". Postgraduate Medicine 126 (5): 64–81. doi:10.3810/pgm.2014.09.2801. PMID 25295651. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 "Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale". The Yale Journal of Biology and Medicine 85 (1): 45–58. March 2012. PMID 22461743. 
  18. ↑ "Nonstimulant Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) in Adults: Systematic Review and Meta-analysis". CNS Drugs 37 (5): 381–397. May 2023. doi:10.1007/s40263-023-01005-8. PMID 37166701. 
  19. ↑ "Guanfacine for the Treatment of Attention-Deficit Hyperactivity Disorder: An Updated Systematic Review and Meta-Analysis". J Child Adolesc Psychopharmacol 33 (2): 40–50. March 2023. doi:10.1089/cap.2022.0038. PMID 36944092. 
  20. ↑ 20.0 20.1 "The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials". PLOS ONE 12 (7): e0180355. 2017. doi:10.1371/journal.pone.0180355. PMID 28700715. Bibcode: 2017PLoSO..1280355C. 
  21. ↑ 21.0 21.1 "The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 1: psychostimulants, alpha-2 agonists, and atomoxetine". Can J Psychiatry 60 (2): 42–51. February 2015. doi:10.1177/070674371506000202. PMID 25886655. 
  22. ↑ "Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis". Eur Child Adolesc Psychiatry 27 (10): 1335–1345. October 2018. doi:10.1007/s00787-018-1125-0. PMID 29460165. 
  23. ↑ "Noradrenergic alpha-2 agonists have anxiolytic-like actions on stress-related behavior and mesoprefrontal dopamine biochemistry". Brain Research 1027 (1–2): 173–178. November 2004. doi:10.1016/j.brainres.2004.08.057. PMID 15494168. 
  24. ↑ 24.0 24.1 24.2 "The Effects of Stress Exposure on Prefrontal Cortex: Translating Basic Research into Successful Treatments for Post-Traumatic Stress Disorder". Neurobiology of Stress 1: 89–99. January 2015. doi:10.1016/j.ynstr.2014.10.002. PMID 25436222. 
  25. ↑ "Psychopharmacotherapy of posttraumatic stress disorder". Croatian Medical Journal 49 (4): 459–475. August 2008. doi:10.3325/cmj.2008.4.459. PMID 18716993. 
  26. ↑ "Post-traumatic stress disorder in children". World Psychiatry 4 (2): 121–125. June 2005. PMID 16633528. 
  27. ↑ "Clinical experience with guanfacine in long-term treatment of hypertension. Part II: adverse reactions to guanfacine". British Journal of Clinical Pharmacology 10 (Suppl 1): 157S–164S. 1980. doi:10.1111/j.1365-2125.1980.tb04924.x. PMID 6994770. 
  28. ↑ 28.0 28.1 28.2 "Intuniv 1 mg, 2 mg, 3 mg, 4 mg prolonged-release tablets - Summary of Product Characteristics". UK Electronic Medicines Compendium. June 2017. https://www.medicines.org.uk/emc/medicine/31294. 
  29. ↑ 29.0 29.1 29.2 29.3 "Safety, Tolerability and Efficacy of Drugs for Treating Behavioural Insomnia in Children with Attention-Deficit/Hyperactivity Disorder: A Systematic Review with Methodological Quality Assessment". Paediatr Drugs 19 (3): 235–250. June 2017. doi:10.1007/s40272-017-0224-6. PMID 28391425. https://eprints.soton.ac.uk/412343/1/Anand.docx. 
  30. ↑ 30.0 30.1 30.2 "Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release". J Atten Disord 22 (1): 14–24. January 2018. doi:10.1177/1087054714554932. PMID 25376194. 
  31. ↑ "Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects". World Psychiatry 19 (2): 214–232. June 2020. doi:10.1002/wps.20765. PMID 32394557. 
  32. ↑ 32.0 32.1 "PDSP Ki Database". University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. 12 January 2011. http://pdsp.med.unc.edu/pdsp.php. 
  33. ↑ 33.0 33.1 33.2 "Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding". Biochemical Pharmacology 55 (7): 1035–1043. April 1998. doi:10.1016/s0006-2952(97)00631-x. PMID 9605427. 
  34. ↑ 34.0 34.1 34.2 "The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors". The Journal of Pharmacology and Experimental Therapeutics 271 (3): 1558–1565. December 1994. PMID 7996470. 
  35. ↑ 35.0 35.1 35.2 "2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery". J Med Chem 66 (16): 11027–11039. August 2023. doi:10.1021/acs.jmedchem.3c01178. PMID 37584406. "These results strongly indicate substantial risks for treatments involving 5-HT2B agonists, and it has been recommended that all serotonergic drugs be screened for this functional profile.43,59 [...] Additionally, there are cases of marketed drugs that were only later determined to have 5-HT2B activity. Of particular note is guanfacine, an FDA-approved medication for the treatment of attention deficit hyperactivity disorder (ADHD) that possesses potent 5-HT2B agonist activity in functional readouts to a similar degree as known valvulopathogens.66". 
  36. ↑ 36.0 36.1 36.2 "Serotonin receptors and heart valve disease--it was meant 2B". Pharmacol Ther 132 (2): 146–57. November 2011. doi:10.1016/j.pharmthera.2011.03.008. PMID 21440001. 
  37. ↑ 37.0 37.1 "Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment". Molecular Pharmacology 76 (4): 710–722. October 2009. doi:10.1124/mol.109.058057. PMID 19570945. 
  38. ↑ 38.0 38.1 38.2 "Kinetics of 5-HT2B receptor signaling: profound agonist-dependent effects on signaling onset and duration". J Pharmacol Exp Ther 347 (3): 645–59. December 2013. doi:10.1124/jpet.113.207670. PMID 24049061. 
  39. ↑ Tardner, Paul (May 2023). "A Comprehensive Literature Review on Guanfacine as a Potential Treatment for Attention-Deficit/Hyperactivity Disorder (ADHD)". International Journal of Environmental Science and Technology. https://www.ijest.org/guanfacine-adhd-tardner-2023/. 
  40. ↑ "Centrally mediated hypotensive activity of B-HT 933 upon infusion via the cat's vertebral artery". Pharmacology 21 (5): 327–332. 1983. doi:10.1111/j.1365-2125.1983.tb00311.x. PMID 7433512. 
  41. ↑ 41.0 41.1 41.2 "The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder". Expert Review of Neurotherapeutics 10 (10): 1595–1605. October 2010. doi:10.1586/ern.10.133. PMID 20925474. 
  42. ↑ "Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex". Cell 129 (2): 397–410. April 2007. doi:10.1016/j.cell.2007.03.015. PMID 17448997. 
  43. ↑ 43.0 43.1 43.2 43.3 43.4 Therapeutic Goods Administration (May 2018). "Australian Public Assessment Report for Guanfacine (as hydrochloride)". https://www.tga.gov.au/sites/default/files/auspar-guanfacine-180503.pdf. 
  44. ↑ 44.0 44.1 Roihuvuo, E. (2022). Classical psychedelics and NBOMes as serotonin 2B receptor agonists: Valvulopathogenic signaling pathways and cardiac safety concerns (Master's thesis, Itä-Suomen yliopisto). http://urn.fi/urn:nbn:fi:uef-20220118
  45. ↑ "Comprehensive review of cardiovascular toxicity of drugs and related agents". Med Res Rev 38 (4): 1332–1403. July 2018. doi:10.1002/med.21476. PMID 29315692. "The list of valvulopathic drugs is short and can be seen in Table 7. According to a recent analysis, other drugs, in particular guanfacine, might possess some risk, but clinical data are yet not available.368–370". 
  46. ↑ "Pharmacokinetics and metabolism of guanfacine in man: a review". British Journal of Clinical Pharmacology 10 (Suppl 1): 25S–32S. 1980. doi:10.1111/j.1365-2125.1980.tb04901.x. PMID 6994775. 
  47. ↑ "Elimination of guanfacine in patients with normal and impaired renal function". British Journal of Clinical Pharmacology 10 (Suppl 1): 33S–35S. 1980. doi:10.1111/j.1365-2125.1980.tb04902.x. PMID 6994776. 
  48. ↑ "Proceedings: Inhibition of effects of accelerator nerve stimulation in cats and rabbits by BS 100-141 and guanabenz". Naunyn Schmiedebergs Arch Pharmacol 282 (Suppl): suppl 282:R86. 1974. PMID 4276642. 
  49. ↑ "Substituted phenylacetylguanidines: a new class of antihypertensive agents". Arzneimittelforschung 25 (10): 1477–82. October 1975. PMID 1243024. 
  50. ↑ "Pharmacology of BS 100-141, a centrally acting antihypertensive drug". Clin Exp Pharmacol Physiol Suppl 2: 207–12. 1975. PMID 241524. 
  51. ↑ "A new centrally action antihypertensive agent guanfacine (BS 100-141)". Arzneimittelforschung 27 (3): 674–6. 1977. PMID 326262. 
  52. ↑ "Drugs@FDA: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=019032. 
  53. ↑ "European Medicines Agency: Intuniv". Europa (web portal). October 2015. http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F003759%2Fhuman_med_001910.jsp&mid=WC0b01ac058001d124. 
  54. ↑ "New drugs listed on the PBS for rheumatoid arthritis, cystic fibrosis and ADHD". Royal Australian College of General Practitioners. https://www.racgp.org.au/newsGP/Clinical/New-drugs-listed-on-the-PBS-for-rheumatoid-arthrit. 
  55. ↑ "An open-label study of guanfacine extended release for traumatic stress related symptoms in children and adolescents". Journal of Child and Adolescent Psychopharmacology 23 (4): 244–251. May 2013. doi:10.1089/cap.2012.0119. PMID 23683139. 
  56. ↑ "Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder". Drugs in Context 4: 212286. 2015. doi:10.7573/dic.212286. PMID 26322115. 
  57. ↑ "Psychopharmacology of tic disorders". Journal of the Canadian Academy of Child and Adolescent Psychiatry 17 (3): 150–159. August 2008. PMID 18769586. 
  58. ↑ "Norepinephrine and stimulant addiction". Addiction Biology 14 (2): 119–129. April 2009. doi:10.1111/j.1369-1600.2008.00138.x. PMID 18811678. 
  59. ↑ "A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation". Journal of Psychopharmacology 29 (3): 300–311. March 2015. doi:10.1177/0269881114562091. PMID 25516371. 
  60. ↑ "Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species". Neurobiol Learn Mem 176: 107327. December 2020. doi:10.1016/j.nlm.2020.107327. PMID 33075480. 
  61. ↑ "Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID". Neurol Int 15 (2): 725–742. May 2023. doi:10.3390/neurolint15020045. PMID 37368329. 
  62. ↑ "Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders". Mol Psychiatry: 1–13. April 2023. doi:10.1038/s41380-023-02057-4. PMID 37029295. 
  63. ↑ Fesharaki-Zadeh, Arman; Lowe, Naomi; Arnsten, Amy F.T. (2023). "Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in "Long-COVID19"". Neuroimmunology Reports 3: 100154. doi:10.1016/j.nerep.2022.100154. 



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