Guanfacine (hydrochloride) promotes delay-related neuronal activity of dIPFC neurons essential for working memory at the cellular level [1][2]. Guanfacine improves PFC cognitive performance by reducing the generation of CAMP, blocking HCN channels and strengthening the PFC network [1][2].

Guanfacine (hydrochloride) improves impulse control in monkeys completing a delay discounting exercise and increases PFC working memory function in older monkeys [1][2]. When injected directly into the PFC of rats or monkeys, guanfacine enhances cognitive function [1][2]. Guanfacine dramatically reduces sustained neuronal activity, behavioral inhibition, and working memory in monkeys by blocking 2A receptors in the dIPFC [1][2].

Absorption, Distribution and Excretion
Guanfacine is 80% orally bioavailable. 1mg immediate release oral guanfacine reaches a Cmax of 2.5±0.6ng/mL with a Tmax of 3.0h and an AUC of 56±15ng\*h/mL. 1mg extended release oral guanfacine reaches a Cmax of 1.0±0.3ng/mL with a Tmax of 6.0h and an AUC of 32±9ng\*h/mL. In adults, a 4mg oral extended release dose reaches a Cmax of 3.58±1.39ng/mL with a Tmax of 5.5h; in children, a 2mg oral extended relsease dose reaches a Cmax of 2.6±1.03ng/mL with a Tmax of 4.98h; in adolescents, a 2mg oral extended release dose reaches a Cmax of 1.7±0.43ng/mL with a Tmax of 4.96h.
Guanfacine is 57.0±32.0% eliminated in the urine in patients with normal renal function. Patients with a glomerular filtration rate (GFR) of 10-30mL/min eliminate 14.0±9.0% of a dose in the urine, while patients with a GFR of <1mL/min eliminate 7.5±2.4% of a dose in the urine.
Guanfacine has a volume of distribution of 6.3L/kg.
Guanfacine has a total body cleraance of 360±262mL/min and a renal clearance of 233±245mL/min in patients with normal renal function. Patients with a glomerular filtration rate (GFR) of 10-30mL/min had a total body clearance of 308±274mL/min and a renal clearance of 34±22mL/min. Patients with a GFR of <1mL/min had a total body clearance of 257±187mL/min and a renal clearance of 18±15mL/min.

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Metabolism / Metabolites
Guanfacine is oxidized by CYP3A4 to it's main metabolite, 3-hydroxyguanfacine. 3-hydroxyguanfacine is then either glucuronidated or sulphated.

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Biological Half-Life
Guanfacine has a half life of 17 hours, but this may range from 10-30 hours. The half life is largely independant of renal function.

Hepatotoxicity
In the multiple clinical trials of guanfacine in adolescents and children with ADHD there were no reports of serum enzyme elevations or in instances of clinically apparent liver injury. Furthermore, despite widescale use of the agent for both hypertension and ADHD, there have been no reports of clinically apparent liver injury attributable to guanfacine. Thus, significant liver injury from guanfacine must be quite rare, if it exists at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of guanfacine during breastfeeding and its possible negative effects on lactation, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Published information on the effects of guanfacine on serum prolactin or on lactation in nursing mothers was not found as of the revision date. Guanfacine decreases basal serum prolactin in men and nonnursing women. Serum prolactin continues to decrease for at least 7 years during continuous use. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
◈ What is guanfacine?
Guanfacine is a medication approved to treat high blood pressure and attention deficit hyperactivity disorder (ADHD). It has also been used for Gilles de la Tourette's syndrome and opioid withdrawal. Some brand names for guanfacine are Intuniv® and Tenex®.Sometimes when people find out they are pregnant, they think about changing how they take their medication or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy. If you have been taking this medication regularly, you should not stop taking it suddenly. If you do plan to stop this medication, it should be stopped slowly under the care of your healthcare provider.
◈ I take guanfacine. Can it make it harder for me to get pregnant?
Studies have not been done to see if guanfacine could make it harder to get pregnant. Animal studies did not find that guanfacine affected fertility.
◈ Does taking guanfacine increase the chance for miscarriage?
Miscarriage can occur in any pregnancy. Studies have not been done to see if guanfacine could increase the chance for a miscarriage.
◈ Does taking guanfacine increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Guanfacine has not been well studied. Birth defects were not seen in a small study on 30 pregnancies exposed to guanfacine. Animal studies did not suggest that guanfacine would increase the chance of birth defects.
◈ Does taking guanfacine in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done to see if guanfacine increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth). One study looked at the pregnancies of 30 women who were given guanfacine to treat preeclampsia. Preeclampsia is a pregnancy-related condition that can cause symptoms such as high blood pressure or fluid retention. The study on guanfacine did not find changes in the baby’s heart rate during pregnancy.
◈ Does taking guanfacine in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if guanfacine can cause behavior or learning issues for the child after prenatal exposure.
◈ Breastfeeding while taking guanfacine:
Guanfacine has not been studied in breastfeeding. Since this medication has not been well studied, you might discuss medication options with your healthcare provider to see if there are better-studied medications that could be used to treat your medical condition while breastfeeding. If you suspect that the baby has symptoms (too sleepy, muscle weakness, or low blood pressure), contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes guanfacine, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects in a partner’s pregnancy?
Studies have not been done to see if guanfacine could affect male fertility or increase the chance of birth defects.In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherTobaby fact sheet Paternal Exposures at: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy.

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Protein Binding
Guanfacine is approximately 70% protein bound in serum.

[1]. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012 Mar;85(1):45-58. Epub 2012 Mar 29.

[2]. The pharmacology of centrally acting antihypertensive drugs. Br J Clin Pharmacol. 1983; 15(Suppl 4): 455S–462S.

[3]. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007 Apr 20;129(2):397-410.

Guanfacine is a member of acetamides.
Guanfacine, or BS 100-141, is a selective alpha-A2 adrenergic receptor agonist initially indicated for the treatment of hypertension but is now indicated as an extended release tablet for the treatment of ADHD. Guanfacine was first described in the literature in 1974. Guanfacine was granted FDA approval on 27 October 1986.
Guanfacine is a Central alpha-2 Adrenergic Agonist. The mechanism of action of guanfacine is as an Adrenergic alpha2-Agonist.
Guanfacine is a selective alpha-adrenergic receptor agonist used for the treatment of hypertension and attention deficit hyperactivity disorder (ADHD) in adults and children. Guanfacine has not been linked to serum enzyme elevations during treatment or to cases of acute, clinically apparent liver injury.
Guanfacine is a centrally acting adrenergic agonist with non-stimulant and antihypertensive property. Guanfacine selectively stimulates alpha-2 adrenergic receptors in the central nervous system, thereby resulting in inhibition of sympathetic nervous system outflow. Used alone or in combination with other drugs, this agent causes reduction of peripheral and renal vascular resistance, and lowers both systolic and diastolic blood pressure and heart rate.
A centrally acting antihypertensive agent with specificity towards ADRENERGIC ALPHA-2 RECEPTORS.
See also: Guanfacine Hydrochloride (has salt form).

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Drug Indication
Guanfacine is indicated alone or as an adjunct with stimulants to treat ADHD.
Intuniv is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents 6 17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. , , Intuniv must be used as a part of a comprehensive ADHD treatment programme, typically including psychological, educational and social measures. ,

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Mechanism of Action
Guanfacine is a selective alpha-2A adrenergic receptor agonist, which reduces the effects of the sympathetic nervous system on the heart and circulatory system. The link between guanfacine’s molecular mechanism and it’s effect on the treatment of ADHD has not been determined.

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Pharmacodynamics
Guanfacine is a selective alpha-2A adrenergic receptor agonist but it is unclear how this translates to the treatment of ADHD. It has a long duration of action as it is given once daily and a wide therapeutic window as fatal overdoses have not been described in literature. Patients should be counselled regarding the risk of hypotension, bradycardia, and syncope.

C9H9CL2N3O

246.0933

280.988

29110-48-3

Guanfacine;29110-47-2;Guanfacine-d2 hydrochloride;1398065-88-7

3519

White to off-white solid powder

213 °C

3.538

2

1

2

15

256

0

INJOMKTZOLKMBF-UHFFFAOYSA-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)

N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 30 mg/mL (~106.18 mM)
H2O : ~20 mg/mL (~70.78 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.85 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.85 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)