Guanfacine
Encyclopedia
Guanfacine is a sympatholytic
. It is an agonist
of the α2A
subtype of norepinephrine receptors. These receptors are concentrated heavily in the prefrontal cortex
and the locus coeruleus, with the potential to improve attention abilities via modulating post-synaptic α2A receptors in the prefrontal cortex. 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. Its side-effects are dose dependent, with practically no dryness of the mouth at doses of 2 mg and less.
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.
Guanfacine has also been approved by the FDA for the treatment of attention-deficit hyperactivity disorder
(ADHD) as an alternative to stimulant medications. 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 alpha-2A adrenergic receptors on prefrontal cortical neurons, which strengthen prefrontal cortical network connections.
Another psychiatric use of guanfacine is for treatment of anxiety
, such as generalized anxiety disorder and post-traumatic stress disorder
symptoms. Guanfacine and other alpha-2A agonist 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. 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. Guanfacine is also being investigated for treatment of withdrawal for opioid
s, alcohol
, and nicotine
.
, drowsiness, headache
, depression
, 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.
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
. 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.
Sympatholytic
A sympatholytic drug is a medication which inhibits the postganglionic functioning of the sympathetic nervous system . They are indicated for various functions, for example they may be used as antihypertensives...
. It is an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
of the α2A
Alpha-2A adrenergic receptor
The alpha-2A adrenergic receptor , also known as ADRA2A, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.-Role in Central Nervous System:...
subtype of norepinephrine receptors. These receptors are concentrated heavily in the prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
and the locus coeruleus, with the potential to improve attention abilities via modulating post-synaptic α2A receptors in the prefrontal cortex. Guanfacine lowers both systolic
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
and diastolic blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
by activating the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
α-2a norepinephrine autoreceptors, which results in reduced peripheral
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
sympathetic outflow and thus a reduction in peripheral sympathetic tone. Its side-effects are dose dependent, with practically no dryness of the mouth at doses of 2 mg and less.
Uses
Guanfacine is a sympatholytic. Sympatholytics are used for various reasons, such as lowering blood pressure, treating hyperactivity or treating anxiety or panic disorders. It reduces hypertensionHypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
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
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
(ADHD) as an alternative to stimulant medications. 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 alpha-2A adrenergic receptors on prefrontal cortical neurons, which strengthen prefrontal cortical network connections.
Another psychiatric use of guanfacine is for treatment of anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, such as generalized anxiety disorder and post-traumatic stress disorder
Post-traumatic stress disorder
Posttraumaticstress disorder is a severe anxiety disorder that can develop after exposure to any event that results in psychological trauma. This event may involve the threat of death to oneself or to someone else, or to one's own or someone else's physical, sexual, or psychological integrity,...
symptoms. Guanfacine and other alpha-2A agonist 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. 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
Clonidine
Clonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...
) are commonly the first choice for treatment. Guanfacine is also being investigated for treatment of withdrawal for opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
s, alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
, and nicotine
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
.
Side effects
Usual: dizzinessDizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, drowsiness, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, gas pains, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, loss of appetite, fatigue, and nasal congestion
Nasal congestion
Nasal congestion is the blockage of the nasal passages usually due to membranes lining the nose becoming swollen from inflamed blood vessels. It is also known as nasal blockage, nasal obstruction, blocked nose, stuffy nose, or stuffed up nose.Nasal congestion has many causes and can range from a...
may occur.
Rare: chest pain
Chest pain
Chest pain may be a symptom of a number of serious conditions and is generally considered a medical emergency. Even though it may be determined that the pain is non-cardiac in origin, this is often a diagnosis of exclusion made after ruling out more serious causes of the pain.-Differential...
, shortness of breath, skin rash, swelling
Swelling (medical)
In medical parlance, swelling is the transient enlargement or protuberance in the body and may include tumors. According to cause, it may be congenital, traumatic, inflammatory, neoplastic or miscellaneous....
of the hands or feet, blurred vision
Blurred vision
-Causes:There are many causes of blurred vision:* Use of atropine or other anticholinergics* Presbyopia -- Difficulty focusing on objects that are close. The elderly are common victims....
, 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.
Psychological indications
In animal models, guanfacine is seen to affect a number of cognitive factors, including working memory improvement, distractibility reduction, response inhibition improvement, and attention control. Performance increases in spatial working memory have also been observed in humans. Another study found no effect on healthy male adult's executive functions and working memory, and small decrements on 2 tasks relating to the sedative effect of guanfacine.Pharmacokinetics and metabolism
Guanfacine shows an absolute bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
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
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
is the 3-hydroxy derivative, with evidence of moderate biotransformation
Biotransformation
Biotransformation is the chemical modification made by an organism on a chemical compound. If this modification ends in mineral compounds like CO2, NH4+, or H2O, the biotransformation is called mineralisation....
, and the key intermediate being an epoxide
Epoxide
An epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...
. 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.