|Trade names||Afken, Estulic, Intuniv, Tenex|
|Bioavailability||80-100% (IR), 58% (XR)|
|Elimination half-life||IR: 10-17 hours; XR: 17 hours (10-30) in adults & adolescents and 14 hours in Paediatrics|
|Excretion||renal (80%; 50% [range: 40-75%] as unchanged drug)|
|Chemical and physical data|
|Molar mass||246.093 g/mol|
|3D model (JSmol)|
|(what is this?)|
Guanfacine (trade names Estulic, Tenex, and, in extended release form, Intuniv) is a sympatholytic drug used to treat hypertension and attention deficit hyperactivity disorder (ADHD). It is a selective α2A receptor agonist.
Side effects of guanfacine are dose-dependent.
Very common (>10% incidence) adverse effects include sleepiness, tiredness, headache, and stomach ache.
Common (1-10% incidence) adverse effects include decreased appetite, depressed mood, anxiety, irritability, mood changes, insomnia, nightmares, dizziness, lack of energy, slowed heart beat, low blood pressure, feeling faint when standing quickly, vomiting, nausea, diarrhea, constipation, dry mouth, urinary incontinence, and rashes.
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.
Guanfacine availability is significantly affected by the CYP3A4 and CYP3A5 enzymes, and medications that inhibit or induce those enzymes change the amount of guanfacine in circulation and thus its efficacy and adverse effects, and likewise guanfacine affects those medications. Because of its effects on the heart, it needs to be used with caution with other medications that may affect the heart; likewise, other medications that may cause sedation.
Guanfacine is a highly selective agonist of the α2A adrenergic receptor, with negligible affinity for any other receptor. However, it may also be a potent 5-HT2B receptor agonist, potentially (theoretically) contributing to valvulopathy.
Mechanism of action
Guanfacine works by activating α2A adrenoceptors in the central nervous system. This results in reduced peripheral sympathetic outflow and thus a reduction in peripheral sympathetic tone, which lowers both systolic and diastolic blood pressure. In ADHD, guanfacine works by strengthening regulation of attention and behavior by the prefrontal cortex. These enhancing effects on prefrontal cortical functions are thought to be due to drug stimulation of post-synaptic α2A adrenoceptors on dendritic spines, which inhibit cAMP-mediated opening of HCN and KCNQ channels and thus strengthen prefrontal cortical synaptic connectivity and enhance neuronal firing. The use of guanfacine for treating prefrontal disorders was developed by the Arnsten lab at Yale University based on understanding the needs of the prefrontal cortex.
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 being an epoxide. It is also shown that elimination in patients with impaired renal function does not differ significantly from those with normal 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.
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. It was approved for ADHD by the European Medicines Agency under the name Intuniv in 2015. It was added to the Australian Pharmaceutical Benefits Scheme for the treatment of ADHD in 2018.
Guanfacine has been studied as a treatment for posttraumatic stress disorder. Evidence of efficacy in adults is limited, but one study found positive results in children with comorbid ADHD. It may be also useful in adult PTSD patients who do not respond to SSRIs.
Guanfacine has been investigated for treatment of withdrawal for opioids, ethanol, and nicotine. Guanfacine has been shown to help reduce stress-induced craving of nicotine in smokers trying to quit, which may involve strengthening of prefrontal cortical self-control.
- "Guanfacine (guanfacine) Tablet [Genpharm Inc.]". DailyMed. Genpharm Inc. March 2007. Retrieved 9 November 2013.
- "guanfacine (Rx) - Intuniv, Tenex". Medscape Reference. WebMD. Retrieved 9 November 2013.
- Hofer, Kristi N.; Buck, Marcia L. (2008). "New Treatment Options for Attention-Deficit/Hyperactivity Disorder (ADHD): Part II. Guanfacine". Pediatric Pharmacotherapy. Medscape (14): 4.
- Cruz, MP (Aug 2010). "Guanfacine Extended-Release Tablets (Intuniv), a Nonstimulant Selective Alpha(2A)-Adrenergic Receptor Agonist For Attention-Deficit/Hyperactivity Disorder". P & T : a peer-reviewed journal for formulary management. 35 (8): 448–51. PMC . PMID 20844694.
- "Intuniv 1 mg, 2 mg, 3 mg, 4 mg prolonged-release tablets - Summary of Product Characteristics". UK Electronic Medicines Compendium. June 2017.
- 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 . PMID 26322115.
- Kornfield R, Watson S, Higashi A, Dusetzina S, Conti R, Garfield R, Dorsey ER, Huskamp HA, Alexander GC (April 2013). "Impact of FDA Advisories on Pharmacologic Treatment of Attention Deficit Hyperactivity Disorder". Psychiatric Services. 64 (4): 339–46. doi:10.1176/appi.ps.201200147. PMC . PMID 23318985.
- Zito, Julie M.; Derivan, Albert T.; Kratochvil, Christopher J.; Safer, Daniel J.; Fegert, Joerg M.; Greenhill, Laurence L. (15 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 . PMID 18793403.
- Jerie, P. (1980). "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. doi:10.1111/j.1365-2125.1980.tb04924.x. PMC . PMID 6994770.
- Roth, BL; Driscol, J (12 January 2011), "PDSP Ki Database", Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill and the United States National Institute of Mental Health, archived from the original on 8 November 2013, retrieved 15 November 2013
- Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N.; Allen, John A.; Rogan, Sarah C.; Hanson, Bonnie J.; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L. (2009). "Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment". Molecular Pharmacology. 76 (4): 710–22. doi:10.1124/mol.109.058057. PMC . PMID 19570945.
- Van Zwieten, P.; Thoolen, M. & Timmermans, P. (1983). "The pharmacology of centrally acting antihypertensive drugs". British Journal of Clinical Pharmacology. 15 (Suppl 4): 455S–462S. doi:10.1111/j.1365-2125.1983.tb00311.x. PMC .
- Arnsten AF (October 2010), "The use of α2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder", Expert Review of Neurotherapeutics, 10 (10): 1595–605, doi:10.1586/ern.10.133, PMC , PMID 20925474
- Wang, m; et al. (2007). "Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex". Cell. 129 (2): 397–410.
- Arnsten&Jin (2012). "Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale". Yale J Biol Med. 85 (1): 45–58.
- Kiechel, J. (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 . PMID 6994775.
- Kirch, W.; Kohler, H. & Braun, W. (1980). "Elimination of guanfacine in patients with normal and impaired renal function". British Journal of Clinical Pharmacology. 10 (Suppl 1): 33S–35S. doi:10.1111/j.1365-2125.1980.tb04902.x. PMC . PMID 6994776.
- "European Medicines Agency: Intuniv". ema.europa.eu. October 2015.
- "New drugs listed on the PBS for rheumatoid arthritis, cystic fibrosis and ADHD". Royal Australian College of General Practitioners. Retrieved 11 September 2018.
- Connor, Daniel F.; Grasso, Damion J.; Slivinsky, Michelle D.; Pearson, Geraldine S.; Banga, Alok (May 2013). "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. doi:10.1089/cap.2012.0119. ISSN 1044-5463. PMC . PMID 23683139.
- Srour M, Lespérance P, Richer F, Chouinard S (2008). "Psychopharmacology of Tic Disorders". J Can Acad Child Adolesc Psychiatry. 17 (3): 150–159. PMC . PMID 18769586.
- Sofuogul, M. & Sewell, A. (2009), "Norepinephrine and Stimulant Addiction", Addiction Biology, 14 (2): 119–129, doi:10.1111/j.1369-1600.2008.00138.x, PMC , PMID 18811678
- McKee, SA; Potenza, MN; Kober, H; Sofuoglu, M; Arnsten, AF; Picciotto, MR; Weinberger, AH; Ashare, R; Sinha, R (Mar 2015). "A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation". J. Psychopharmacol. 29 (3): 300–311. doi:10.1177/0269881114562091. PMC . PMID 25516371.