Guanfacine

Not to be confused with Guanine, Guanosine, Guanidine, Guaifenesin, or Clonidine.

Guanfacine

Systematic (IUPAC) name
N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
Clinical data
Trade names	Afken, Estulic, Intuniv, Tenex
AHFS/Drugs.com	monograph
MedlinePlus	a601059
Licence data	US Daily Med:link
Pregnancy category	US: B (No risk in non-human studies)
Legal status	US: ℞-only
Routes of administration	oral, intravenous
Pharmacokinetic data
Bioavailability	80-100% (IR), 58% (XR)
Protein binding	70%
Metabolism	CYP3A4
Biological half-life	IR: 10-17 hours; XR: 17 hours (10-30) in adults & adolescents and 14 hours in Paediatrics
Excretion	renal (80%; 50% [range: 40-75%] as unchanged drug)
Identifiers
CAS Number	29110-47-2 Y
ATC code	C02AC02 (WHO)
PubChem	CID: 3519
IUPHAR/BPS	522
DrugBank	DB01018 Y
ChemSpider	3399 Y
UNII	30OMY4G3MK Y
KEGG	D08031 N
ChEMBL	CHEMBL862 Y
Chemical data
Formula	C9H9Cl2N3O
Molecular mass	246.093 g/mol
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) Y Key:INJOMKTZOLKMBF-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Guanfacine (brand name Estulic, Tenex and the extended release Intuniv) is a sympatholytic drug used in the treatment of attention deficit hyperactivity disorder (ADHD) and hypertension (not to be confused with guaifenesin, an expectorant). It is a selective α_2A receptor agonist. These receptors are concentrated heavily in the prefrontal cortex and the locus coeruleus, with the potential to improve attention resulting from interaction with receptors in the former. 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.

Guanfacine is currently approved and marketed in the United States as Intuniv and has been filed and is under investigation by the European Medicines Agency for the treatment of ADHD in children and adolescents aged 6–18 years.

Medical uses

Hypertension

It has been shown to reduce hypertension not just in the short-term, but also in long-term studies to be able to achieve normalization in the blood pressure of 54% of patients treated over a year and 66% over two years. The average reduction in mean arterial pressure of all patients was 16% at the end of the first year and 17% at the end of the second year.

1 mg guanfacine tablets.

Attention deficit hyperactivity disorder

The US Food and Drug Administration (FDA) has approved guanfacine for the treatment of attention deficit hyperactivity disorder (ADHD), like clonidine, alone or with stimulants in 2010, for pediatric patients aged 6–17 years. 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, reduce rebound, and when taken at evening, to induce sleep. Guanfacine is thought to improve regulation of behavior, attention, and emotion through actions at post-synaptic α_2A adrenergic receptors on prefrontal cortical neurons, which strengthen prefrontal cortical network connections. In animal models, guanfacine is seen to affect a number of cognitive factors, including working memory improvement, distractibility reduction, response inhibition improvement, and enhanced attention and impulse control. Improvement is most evident in subjects with cognitive deficits; more subtle effects are seen in healthy young animals. Performance increases in spatial working memory have also been observed in humans. Another study found no effect on healthy male adults' executive functions and working memory, and small decrements on 2 tasks relating to the sedative effect of guanfacine. Recent studies suggest that guanfacine may help patients with a variety of prefrontal cortical disorders, including traumatic brain injury to the frontal lobe, strokes affecting higher cognitive function, and dysregulated emotional behavior, e.g. in children who have been traumatized.

Side effects of guanfacine are dose-dependent.

Anxiety

Another psychiatric use of guanfacine is for treatment of anxiety, such as generalized anxiety disorder and post-traumatic stress disorder symptoms. Guanfacine and other α_2A agonists have anxiolytic-like action, reducing sympathetic arousal in the emotional responses of the amygdala, and strengthen prefrontal cortical regulation of emotion, action and thought. Due to its prolonged half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients. All of these actions likely contribute to the relief of the hyperarousal, re-experiencing of memory, and impulsivity associated with PTSD. However, a recent study showed no benefit for patients suffering from PTSD.

Tics

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 α_2A-adrenergic agonists (clonidine) are commonly the first choice for treatment.

Treatment of withdrawal syndrome

Guanfacine is also being investigated for treatment of withdrawal for opioids, ethanol, and nicotine.

Adverse effects

Adverse effects incidence:
Very common (>10% incidence) adverse effects include:

• Xerostomia (dry mouth)
• Somnolence (sleepiness)
• Fatigue
• Dizziness
• Headache
• Constipation
• Abdominal pain

Common (1-10% incidence) adverse effects include:

• Alopecia (hair loss)
• Asthenia (weakness)
• Bradycardia (low heart rate)
• Confusion
• Increased appetite
• Depression
• Dermatitis
• Diaphoresis (sweating without a physiologic reason)
• Dizziness
• Dyspepsia (indigestion)
• Dysphagia (being unable to swallow)
• Dyspnoea (air hunger)
• Hypokinesia
• Hypotension (low blood pressure)
• Impotence
• Insomnia
• Irritability
• Leg cramps
• Lethargy
• Nausea
• Palpitations
• Pruritus (itching)
• Tachycardia (high heart rate)
• Weakness

Unknown frequency adverse effects include:

• Abnormal liver function tests
• Agitation
• Alterations in taste
• Anxiety
• Arthralgia (joint pain)
• Blurred vision
• Chest pain
• Confusion
• Diarrhoea
• Exfoliation
• Exfoliative dermatitis
• Hallucinations
• Impotence
• Leg pains
• Malaise
• Myalgia (muscle pain)
• Nervousness
• Nocturia (waking to urinate)
• Oedema (swelling)
• Orthostatic hypotension
• Paresthesia (pins and needles)
• Rash
• Tremor
• Urinary frequency
• Vertigo (dizziness)

Interactions

• CYP3A4/5 inhibitors — Use caution. Elevates plasma concentration of guanfacine.
• CYP3A4 inducers — Recommended increase in guanfacine dose.
• Valproic acid — Use caution. Elevates plasma concentration of valproic acid.
• Antihypertensive drugs — Use caution. Potential for additive pharmacodynamic effects (hypotension, syncope, etc.)
• CNS depressant drugs — Use caution. Potential for additive pharmacodynamic effects (sedation, somnolence, etc.)

Pharmacokinetics and metabolism

Guanfacine has an oral bioavailability of 80%. 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.

Pharmacology

Guanfacine is a highly selective agonist of the α_2A adrenergic receptor, with negligible affinity for any other receptor. However, it may also be a potent 5-HT_2B receptor agonist, potentially contributing to valvulopathy.

Receptor	Ki (nM)
α2A	71.8
α2B	1200.2
α2C	2505.2

See also

• Guanabenz
• Guaifenesin

External links

• Intuniv