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Guanfacine

Clinical data
Trade names	Tenex
AHFS/Drugs.com	Monograph
MedlinePlus	a601059
Pregnancy category	B
Routes of administration	oral, intravenous
ATC code	C02AC02 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	99.9%
Elimination half-life	14.8–18.3 h
Excretion	renal
Identifiers
IUPAC name N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
CAS Number	29110-47-2
PubChem CID	3519
IUPHAR/BPS	522
DrugBank	APRD00075
ChemSpider	3399
UNII	30OMY4G3MK
KEGG	D08031
ChEMBL	ChEMBL862
CompTox Dashboard (EPA)	DTXSID9046944
ECHA InfoCard	100.044.933
Chemical and physical data
Formula	C9H9Cl2N3O
Molar mass	246.093 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES Clc1cccc(Cl)c1CC(=O)\N=C(/N)N
InChI 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) Key:INJOMKTZOLKMBF-UHFFFAOYSA-N
(verify)

Guanfacine (brand name Tenex, and the extended release Intuniv) is a sympatholytic. It is an agonist of the α_2A 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 α_2A receptors in the prefrontal cortex. 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. Its side-effects are dose dependent, with frequency and severity almost disappearing at doses of 2 mg and less.

Uses

Guanfacine is a sympatholytic. Sympatholytics are used for various reasons, such as lowering blood pressure, treating hyperactivity or treating anxiety or panic disorders. 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.

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. 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. 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.

Another psychiatric use of guanfacine is for treatment of anxiety, such as generalized anxiety disorder and post-traumatic stress disorder symptoms. Guanfacine and other alpha-2A agonist 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 of memory, and impulsivity associated with PTSD. Due to its prolonged half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients. 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.

Side effects

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

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.

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. Performance increases in spatial working memory have also been observed in humans. Another study found no effect on healthy male adult's executive functions and working memory, and small decrements on 2 tasks relating to the sedative effect of guanfacine.

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. 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 animal models, guanfacine’s enhancing effects on the working-memory functions of the pre-frontal cortex are thought to be 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.

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, PMID 0 {{citation}}: Check |pmid= value (help); Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help).
3. 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, PMC 1430125, PMID 6994770.
4. ^ 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: Part I: 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), "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 {{citation}}: Explicit use of et al. in: |last4= (help)CS1 maint: unflagged free DOI (link)
8. Wang, M; Ramos, BP; Kratochvil, Christopher J; Fegert, Joerg M; Greenhill, Laurence L; Vijayraghavan, S; Brennan, A; Dudley, A; et al. (2007), "Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex", Cell, 129 (2): 397–410, doi:10.1186/1753-2000-2-24, PMID 17448997 {{citation}}: Explicit use of et al. in: |last4= (help)CS1 maint: unflagged free DOI (link)
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 ADHD with Respect to Physical Growth and Cardiovascular Function", 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. 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.
15. Müller, U; Clark, L; Lam, ML; Moore, RM; Murphy, CL; Richmond, NK; Sandhu, RS; Wilkins, IA; Menon, DK (2005), "Lack of effects of guanfacine on executive and memory functions in healthy male volunteers", Psychopharmacology, 182 (2): 205–13, doi:10.1007/s00213-005-0078-4, PMID 16078088.
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-adrenoceptor 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.

External links

• Guanfacine.com
• Intuniv

• Antihypertensive agents
• Guanidines
• Alpha-adrenergic agonists
• Acetamides
• Organochlorides