Guanfacine

Guanfacine (brand name Tenex, and the extended release Intuniv) is a sympatholytic. It is a selective α2A 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 α2A norepinephrine autoreceptors, which results in reduced peripheral sympathetic outflow and thus a reduction in peripheral sympathetic tone.

Hypertension
It 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.

Attention-deficit hyperactivity disorder
An extended-release formulation of guanfacine (Intuniv) has also been approved by the FDA for the treatment of attention-deficit hyperactivity disorder (ADHD) in people ages 6–17. 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, counter side effects, reduce rebound, and when taken at night, to induce sleep. Guanfacine is thought to improve regulation of behavior, attention, and emotion through actions at post-synaptic α2A 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 α2A-agonists reduce sympathetic arousal, weaken the emotional responses of the amygdala, and strengthen prefrontal cortical regulation of emotion, action and thought. All of these actions likely contribute to the relief of the hyperarousal, re-experiencing of memory, and impulsivity associated with PTSD. Due to its prolonged half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients. 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 α2A-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, alcohol, and nicotine.

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


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

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


 * Alopecia (hair loss)
 * Asthenia
 * Bradycardia (low heart rate)
 * Confusion
 * Decreased appetite
 * Depression
 * Dermatitis
 * Diaphoresis (sweating without a physiologic reason)
 * Dizziness
 * Dyspepsia (indigestion)
 * Dysphagia (being unable to swallow)
 * Dyspnoea (air hunger)
 * Hypokinesia
 * Hypotension
 * 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
 * Blurred vision
 * Chest pain
 * Confusion
 * Diarrhoea
 * Exfoliation
 * Exfoliative dermatitis
 * Hallucinations
 * Impotence
 * Leg pains
 * Malaise
 * Myalgia
 * Nervousness
 * Nocturia
 * Oedema
 * Orthostatic hypotension
 * Paresthesia
 * Rash
 * Tremor
 * Urinary frequency
 * Vertigo

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 fairly selective agonist of the α2A adrenergic receptor.

 Binding profile of guanfacine  Guanfacine is a fairly selective agonist of the α2A adrenergic receptor.

Guanfacine may be a potent 5-hydroxytryptamine2B (5-HT2B) receptor agonist, potentially contributing to valvulopathy.

 Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment