Guanfacine

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%
Metabolism	?
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 α_2A subtype of norepinephrine receptors. These receptors are concentrated heavily in the prefrontal cortex and the locus ceruleus, 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]

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. Guanfacine is also used in conjunction with stimulants to reduce, rebound, as well as 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.[1]) 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. Further, treatment for co-morbidity between anti-social (and oppositional) behavior, such as Tourette’s, and ADHD includes guanfacine (or clonidine) as a part of the drug regimen, to counter the effects of psychostimulants. ^[4][12] While this use of guanfacine is becoming common, this antihypertensive drug is being prescribed off-label in these instances as there is no official indication for the treatment of ADHD.^[4] Guanfacine is also being investigated for treatment of withdrawal for opioids, alcohol, and nicotine.^[13]

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][14]

Psychological indications

In animal models, guanfacine is seen to effect a number of cognitive factors, including working memory improvement, distractibility reduction, response inhibition improvement, and attention control. Performance increases in spatial working memory has 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 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.^[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

External links

• Guanfacine.com
• Shoop SA (1998). "Is the use of Guanfacine effective in treatment of attention deficit/hyperactivity disorder?". U.S. Pharmacist 23 (5). http://www.uspharmacist.com/oldformat.asp?url=newlook/files/Drug/ACF2FD1.cfm&pub_id=8&article_id=113.