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Guanfacine

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Guanfacine
Clinical data
Pregnancy
category
  • B
Routes of
administration		oral, intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability99.9%
Elimination half-life14.8–18.3 h
Excretionrenal
Identifiers
  • 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 Edit this at Wikidata
Chemical and physical data
FormulaC9H9Cl2N3O
Molar mass246.093 g/mol 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) checkY
  • Key:INJOMKTZOLKMBF-UHFFFAOYSA-N checkY
  (verify)

Guanfacine (brand name Tenex, and the extended release Intuniv) is an agonist of the α2A subtype of norepinephrine receptors. These receptors are concentrated heavily in the prefrontal cortex and the locus coeruleus, with the potential to improve attention abilities via modulating post-synaptic α2A receptors in the prefrontal cortex.[1] Guanfacine lowers both systolic and diastolic blood pressure by activating the central nervous system α-2a norepinephrine autoreceptors, which results in reduced peripheral sympathetic outflow and thus a reduction in peripheral sympathetic tone.[2] Its side-effects are dose dependent, with frequency and severity almost disappearing at doses of 2 mg and less.[3]

Uses

Guanfacine has the cardiovascular effect of lowering blood pressure.[4] It reduces hypertension not just in short-term, but also as shown in long-term studies with normalization of blood pressure of 54% treated over a year and 66% over two years.[5]

1 mg Guanfacine tablets.

Guanfacine has also been approved by the FDA for the treatment of attention-deficit hyperactivity disorder (ADHD) as an alternative to stimulant medications. Its beneficial actions are likely due to its ability to strengthen prefrontal cortical regulation of attention and behavior [6]. Guanfacine is also used in conjunction with stimulants to augment therapeutic actions, counter side effects, reduce rebound, and when taken at night, to induce sleep.[7] Guanfacine is thought to improve regulation of behavior, attention and emotion through actions at post-synaptic, alpha-2A adrenergic receptors on prefrontal cortical neurons, which strengthen prefrontal cortical network connections [8]. Another psychiatric use of guanfacine is for treatment of Anxiety, such as Generalized Anxiety Disorder and Post-traumatic Stress Disorder symptoms. Alpha-2A agonists such as guanfacine reduce sympathetic arousal, weaken the emotional responses of the amygdala, and strengthen prefrontal cortical regulation of emotion, action and thought. All of these actions likely contribute to the relief of the hyperarousal, re-experiencing, and impulsivity associated with PTSD.[9] Due to its prolonged half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients.[10] According to recent studies (Srour et al., 2008) there is controversy as to guanfacine’s usefulness in treating tics. There has been success when tic symptoms are co-morbid with ADHD, and as such, guanfacine and other alpha-2-adrenergic agonists (clonidine) are commonly the first choice for treatment. Guanfacine is also being investigated for treatment of withdrawal for opioids, alcohol, and nicotine.[11]

Side effects

Usual: dizziness, drowsiness, headache, depression, constipation, gas pains, diarrhea, loss of appetite, fatigue, and nasal congestion may occur.[12]

Rare: chest pain, shortness of breath, skin rash, swelling of the hands or feet, blurred vision, yellowing of the eyes or skin.

Others: mental/mood changes, tingling of the hands or feet, dry mouth, impotence, decreased sexual desire, vision changes, taste changes, ringing in the ears, leg cramps.

Cardiovascular side effects include orthostatic hypotension, dizziness, palpitations, and tachycardia upon standing, and possibly bradycardia. Rebound hypertension is a possibility with abrupt discontinuation, and as such a gradual discontinuation is recommended.[4][13]

Psychological indications

In animal models, guanfacine is seen to affect a number of cognitive factors, including working memory improvement, distractibility reduction, response inhibition improvement, and attention control[14]. Performance increases in spatial working memory have also been observed in humans[15].

Pharmacokinetics and metabolism

Guanfacine shows an absolute bioavailability of nearly 100%. 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.[16] 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.[17] Guanfacine’s enhancing effects on the working-memory functions of the pre-frontal cortex is due to inhibition of cAMP-mediated signaling, which is effected by the Gi proteins that are generally coupled to the post-synaptic alpha-2a-adrenoceptors that guanfacine stimulates through binding.[18]

Notes and references

  1. ^ Kolar, Dusan; Keller, Amanda; Golfinopoulos, Maria; Cumyn, Lucy; Syer, Cassidy; Hechtman, Lily (2008), "Treatment of adults with attention-deficit/hyperactivity disorder", Neuropsychiatric Disease and Treatment, 4 (2): 389–403, PMC 2518387, PMID 18728745 {{citation}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help).
  2. ^ 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, PMC 1427667 {{citation}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help).
  3. ^ Jerie, P. (1980), "Clinical Experience with Guanfacine in Long-Term Treatment of Hypertension: Adverse Reactions to Guanfacine", British Journal of Clinical Pharmacology, 10 (Suppl 1): 157S–164S, PMC 1430125, PMID 6994770.
  4. ^ a b Vitiello, B. (2008), "Understanding the Risk of Using Medications for ADHD with Respect to Physical Growth and Cardiovascular Function", Child and Adolescent Psychiatric Clinics of North America, 17 (2): 459–xi, doi:10.1016/j.chc.2007.11.010, PMC 2408826, PMID 18295156.
  5. ^ Jerie, P. (1980), "Clinical Experience with Guanfacine in Long-Term Treatment of Hypertension: Efficacy and Dosage", British Journal of Clinical Pharmacology, 10 (Suppl 1): 37S–47S, PMC 1430120, PMID 6994777.
  6. ^ Arnsten AF. The use of alpha-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Rev Neurother. 10:1595-605, 2010
  7. ^ Zito, Julie M.; Derivan, Albert T.; Kratochvil, Christopher J.; Fegert, JM; Greenhill, LL; et al. (2008), "Child and Adolescent Psychiatry and Mental Health", Child and Adolescent Psychiatry and Mental Health, 2 (1): 24, doi:10.1186/1753-2000-2-24, PMC 2566553, PMID 18793403 {{citation}}: Explicit use of et al. in: |last4= (help)CS1 maint: unflagged free DOI (link).
  8. ^ Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397-410, 2007
  9. ^ Kaminer, D.; Seedat, S.; Stein, D. (2005), "Post-traumatic stress disorder in children", World Psychiatry, 4 (2): 121–125, PMC 1414752, PMID 16633528 {{citation}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help).
  10. ^ Kozarlc-Kovaclc, D. (2008), "Psychopharmacotherapy of Posttraumatic Stress Disorder", Croatian Medical Journal, 49 (4): 459–475, doi:10.3325/cmj.2008.4.459, PMC 2525822, PMID 18716993.
  11. ^ 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 2657197, PMID 18811678 {{citation}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help).
  12. ^ "Intuniv for ADHD: Efficacy, Side Effects". Health and Life.
  13. ^ Vitiello B (2008), "Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function" (PDF), Child Adolesc Psychiatr Clin N Am, 17 (2): 459–74, xi, doi:10.1016/j.chc.2007.11.010, PMC 2408826, PMID 18295156. {{citation}}: Unknown parameter |month= ignored (help)
  14. ^ Arnsten AF. The use of alpha-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Rev Neurother. 10:1595-605, 2010
  15. ^ Jäkälä P, Riekkinen M, Sirviö J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen P Jr. Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology. 20:460-70, 1999.
  16. ^ Kiechel, J. (1980), "Pharmacokinetics and Metabolism of Guanfacine in Man: A Review", British Journal of Clinical Pharmacology, 10 (Suppl 1): 25S–32S, PMC 1430131, PMID 6994775.
  17. ^ 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, PMC 1430110, PMID 6994776 {{citation}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help).
  18. ^ Ramos, Brian P.; Stark, David; Verduzco, Luis; van Dyck, Christopher H.; Arnsten, Amy F. T. (2006), "α2A-stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals", Learning & Memory, 13 (6): 770–776, doi:10.1101/lm.298006, PMC 1783631, PMID 17101879.
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