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Guanfacine
Systematic (IUPAC) name
N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
Identifiers
CAS number 29110-47-2
ATC code C02AC02
PubChem 3519
DrugBank APRD00075
Chemical data
Formula C9H9Cl2N3O 
Mol. mass 246.093 g/mol
Pharmacokinetic data
Bioavailability 99.9%
Half life 14.8-18.3 h
Excretion renal
Therapeutic considerations
Pregnancy cat. B
Legal status Prescription only
Routes oral, intravenous
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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 α-2a 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] See the ‘Side Effects’ section for further information. Withdrawal syndrome contains confounds making it a subject for debate, and tolerance is not observed.[3]

Contents

Uses

Guanfacine has the cardiovascular effect of lowering blood pressure.[4] It does not affect heart rate[5] but significantly 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.[6]

1 mg Guanfacine tablets.

It is also effective in treating the symptoms of attention-deficit hyperactivity disorder (ADHD) as an alternative to stimulants.[1] Guanfacine is also used in conjunction with stimulants to reduce rebound, as well as to induce sleep.[7] (In August 2006, the makers of guanfacine applied to the FDA to use this drug to treat ADHD. In June 2007, the U.S. Food and Drug Administration (FDA) issued an approvable letter for guanfacine for the use of ADHD treatment.[2]) Another psychiatric use of guanfacine is for treatment of Post-traumatic Stress Disorder symptoms. As an adrenergic agent, guanfacine’s reduction of sympathetic arousal leads to relief on the hyperarousal, re-experiencing, and impulsivity associated with PTSD.[8] Due to its prolonged half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients.[9] However, a study showed no results for PTSD[10], while prazosin did [11]. 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.[12]

Side effects

Usual: Dizziness, drowsiness, headache, 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.[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.[citation needed] Performance increases in spatial working memory has also been observed in humans.[14]

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.[15] It is also shown that elimination in patients with impaired renal function do 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.[16] 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.[17]

Notes and references

  1. ^ Kolar, D. et al. (2008). Treatment of adults with attention-deficit/hyperactivity disorder. Neuropsychiatric Disease and Treatment 4(2) 389–403
  2. ^ Van Zwieten, P., Thoolen, M., & Timmermans, P. (1983). The Pharmacology of Centrally Acting Antihypertensive Drugs. British Journal of clinical Pharmacology. 15, 455S-462S.
  3. ^ a b Jerie, P. (1980). Clinical Experience with Guanfacine in Long-Term Treatment of Hypertension: Adverse Reactions to Guanfacine. British Journal of clinical Pharmacology. 10, 157S-164S.
  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. http://www.childpsych.theclinics.com/article/S1056-4993(07)00124-1/abstract
  5. ^ Philipp, E. (1980). Guanfacine in the Treatment of Hypertension due to Pre-eclamptic Toxaemia in Thirty Women. British Journal of clinical Pharmacology. 10, 137S-140S.
  6. ^ Jerie, P. (1980). Clinical Experience with Guanfacine in Long-Term Treatment of Hypertension: Efficacy and Dosage. British Journal of clinical Pharmacology. 10, 37S-47S.
  7. ^ Zito, J. et al. (2008). Child and Adolescent Psychiatry and Mental Health. Child and Adolescent Psychiatry and Mental Health. 2:24. http://www.capmh.com/content/2/1/24
  8. ^ Kaminer, D., Seedat, S., & Stein, D. (2005). Post-traumatic stress disorder in children. World Psychiatry. 4(2), 121-125.
  9. ^ Kozarlc-Kovaclc, D. (2008). Psychopharmacotherapy of Posttraumatic Stress Disorder. Croatian Medical Journal. 49, 459-75.
  10. ^ No Improvement of Posttraumatic Stress Disorder Symptoms With Guanfacine Treatment http://ajp.psychiatryonline.org/cgi/reprint/163/12/2186.pdf
  11. ^ Drug Helps PTSD Nightmares (prazosin) http://www.research.va.gov/news/press_releases/ptsd-033007.cfm
  12. ^ Sofuogul., M., & Sewell, A. (2009). Norepinephrine and Stimulant Addiction. Addiction Biology. 14(2), 119-129.
  13. ^ Vitiello B (April 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. PMID 18295156. PMC 2408826. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2408826&blobtype=pdf. 
  14. ^ Arnsten, A. & Dudley, A. (2005). Methylphenidate improves prefrontal cortical cognitive function through α2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behavioral and Brain Functions. 1:2. http://www.behavioralandbrainfunctions.com/content/1/1/2
  15. ^ Kiechel, J. (1980). Pharmacokinetics and Metabolism of Guanfacine in Man: A Review. British Journal of clinical Pharmacology. 10, 25S-32S.
  16. ^ Kirch, W., Kohler, H., & Braun, W. (1980). Elimination of Guanfacine in Patients with Normal and Impaired Renal Function. British Journal of clinical Pharmacology. 10, 33S-35S.
  17. ^ Ramos, B., et al. (2006). Alpha-2a-adrenoceptor stimulation improves pre-frontal cortical regulation of behavior through inhibition of camp signaling in aging animals. Learning & Memory. 13, 770-776.

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