Guanfacine

Absorption

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.

Toxicity

The oral LD50 in rats is 142mg/kg and 15.3mg/kg in mice. The subcutaneous LD50 in rats is 114mg/kg and 46mg/kg in mice.
Patients experiencing and overdose may present with hypotension, drowsiness, lethargy, and bradycardia. Overdose should be managed by first calling local poison control. Patients may require intravenous saline to maintain blood pressure.

Chemical properties

White Solid

Originator

Estulic,Sandoz,Switz.,1980

The Uses of Guanfacine

Centrally acting α-adrenoceptor agonist. Antihypertensive.

The Uses of Guanfacine

Guanfacine centrally acting α-adrenoceptor agonist. Guanfacine is an antihypertensive.

Indications

Guanfacine is indicated alone or as an adjunct with stimulants to treat ADHD.

Background

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.

Definition

ChEBI: Guanfacine is a member of acetamides.

Manufacturing Process

2,6-Dichlorophenyl-acetyl-guanidine: A solution of 3.245 g (0.055 mol) of guanidine in isopropanol is added to a solution of 11.7 g (0.05 mol) of 2,6- dichlorophenyl-acetic acid ethyl ester (BP 142°C to 143°C/12 mm of Hg) in 20cc of isopropanol. The reaction mixture is allowed to stand overnight and is subsequently concentrated by evaporation. After recrystallizing the residue from methanol/ether 2,6-dichlorophenyl-acetyl-guanidine is obtained in the form of white grains having a MP of 225°C to 227°C.
2,6-Dichlorophenyl-acetyl-guanidine hydrochloride: A solution of 5.6 g (0.025 mol) of 2,-dichlorophenylacetic acid chloride (BP 137°C to 138°C/12 mm of Hg) in 10 cc of toluene is added dropwise to a mixture of 4.5 g (0.076 mol) of guanidine and 60 cc of toluene. The reaction mixture is allowed to stand at room temperature for 20 minutes, is then heated on a steam bath for 2 hours and is subsequently cooled. The resulting precipitate is filtered off and washed twice with 25 cc amounts of water in order to separate the guanidine hydrochloride. The residue (2,6-dichlorophenyl-acetyl-guanidine) is washed with chloroform for further purification and is then dissolved in 50 cc of isopropanol. The pH-value of the solution is adjusted to 6 with ethanolic hydrochloric acid and the solution is cooled. The resulting white needles are again washed with chloroform. The resulting 2.6-dichlorophenyl-acetylguanidine hydrochloride has a MP of 213°C to 216°C.

brand name

Tenex (Dr. Reddy’s).

Therapeutic Function

Antihypertensive

General Description

Guanfacine is more selective for 2-receptors than isclonidine. Their mechanism of action is the same as that ofclonidine. Differences between clonidine and its twoanalogs are seen in their elimination half-life values and intheir metabolism and urinary excretion patterns. The eliminationhalf-life of clonidine ranges from 20 to 25 hours,whereas that for guanfacine is about 17 hours. Guanabenzhas the shortest DOA of these three agents, with a half-lifeof about 6 hours. Clonidine and guanfacine are excretedunchanged in the urine to the extent of 60% and 50%,respectively. Very little of guanabenz is excreted unchangedin the urine.

Pharmacokinetics

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.

Synthesis

Guanfacin, N-amidino-2-(2,6-dichlorophenyl)acetamide (22.3.2), is also synthesized in a very easy synthesis of reacting the acid chloride or ester of 2,6- dichlorophenylacetic acid with guanidine.

Metabolism

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