Guanfacine, sold under the brand name Tenex among others, is an oral medication used to treat

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...

(ADHD) and

high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

. Guanfacine is FDA-approved for monotherapy treatment of ADHD as well as being used for augmentation of other treatments, such as

stimulants Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...

. Guanfacine is also used off-label to treat tic disorders, anxiety disorders and

PTSD Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on ...

.Boland, Robert and Verduin, Marcia (2022) ''Kaplan & Sadock's Concise Textbook of Clinical Psychiatry''. 5th ed. pp. 1811–1812. Common side effects include sleepiness, constipation, and dry mouth. Other side effects may include

low blood pressure Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

and urinary problems. The FDA has categorized Guanfacine as "Category B" in pregnancy which means animal-reproduction studies have not demonstrated a fetal risk or an adverse effect during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

. It appears to work by activating the α_2A receptors in the brain thereby decreasing

sympathetic nervous system The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of t ...

activity. Guanfacine was approved for medical use in the United States in 1986. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ...

. In 2020, it was the 300th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Guanfacine is FDA approved as monotherapy or augmentation with stimulants to treat

. It is also FDA approved to treat

. It is FDA approved as monotherapy treatment for ADHD, and it is also FDA approved to be used in augmentation with stimulant medications when stimulants medications are not fully effective (stimulants include medications such as

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

s and

methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...

). Guanfacine can offer a synergistic enhancement of stimulant treatment for ADHD, and in many cases can also help control the

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

profile of stimulant medications. Guanfacine is also used off-label to treat Tic Disorders, Anxiety Disorders and PTSD. An off-label use of guanfacine is for treatment of anxiety, such as generalized anxiety disorder and post-traumatic stress disorder symptoms. Guanfacine and other α2A agonists have anxiolytic-like action, thereby reducing the emotional responses of the amygdala, and strengthening prefrontal cortical regulation of emotion, action and thought. These actions arise from both inhibition of stress-induced catecholamine release, and from prominent, post-synaptic actions in prefrontal cortex. 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. Guanfacine appears to be especially helpful in treating children who have been traumatized or abused.

Adverse effects

Side effects of guanfacine are dose-dependent. Very common (>10% incidence) adverse effects include sleepiness, tiredness, headache, and stomach ache. Common (1-10% incidence) adverse effects include decreased appetite, nausea, dry mouth, urinary incontinence, and rashes. Typical side effects such as fatigue, irritability and stomach upset can take a week or two to subside. Increases in dosage can have the same adjustment period.

Interactions

Guanfacine availability is significantly affected by the

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

and CYP3A5 enzymes. Medications that inhibit or induce those enzymes change the amount of guanfacine in circulation and thus its efficacy and rate of adverse effects. Because of its impact on the heart, it should be used with caution with other cardioactive drugs. Similar concern is appropriate when it is used with sedating medications. Guanfacine is known to lower the user's tolerance for

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

, heightening its effect, and alcohol use may prolong the effects of the medication.

Pharmacology

Guanfacine is a highly selective

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

of the α_2A adrenergic receptor, with low affinity for other receptors. However it may also be a potent 5-HT_2B receptor agonist, which can be associated with valvulopathy, although not all 5-HT_2B agonists have this effect.

Mechanism of action

Guanfacine works by activating α_2A adrenoceptors within the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. This leads to reduced

peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by the ...

sympathetic outflow and thus a reduction in peripheral

sympathetic tone The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...

, which lowers both systolic and diastolic

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure ...

. In ADHD, guanfacine works by strengthening regulation of attention and behavior by the

prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA ...

. These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α_2A adrenoceptors on dendritic spines. cAMP-mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing. The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University.

Pharmacokinetics

Guanfacine has an oral

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of 80%. There is no clear evidence of any

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...

Elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the b ...

is 17 hours with the major elimination route being

renal The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

. The principal

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

is the 3-hydroxy-derivative, with evidence of moderate

biotransformation Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected w ...

, and the key intermediate is an

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

. Elimination is not impacted with impaired 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.

History

In 1986, guanfacine was approved by the FDA for the treatment of

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...

under the brand name Tenex
Drugs@FDA
. In 2010, guanfacine was approved by the FDA for the treatment of

for people 6–17 years old. It was approved for ADHD by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

under the name Intuniv in 2015. It was added to the Australian

Pharmaceutical Benefits Scheme The Pharmaceutical Benefits Scheme (PBS) is a program of the Australian Government that subsidises prescription medication for Australian citizens and permanent residents, as well as international visitors covered by a reciprocal health care ag ...

for the treatment of ADHD in 2018.

Brand names

Brand names include Tenex, Afken, Estulic, and Intuniv (an extended release formulation).

Research

Guanfacine has been studied as a treatment for

post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats o ...

(PTSD). Evidence of efficacy in adults is limited, but one study found positive results in children with comorbid ADHD. It may be also useful in adult PTSD patients who do not respond to

SSRIs Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellu ...

. Results of studies using guanfacine to treat

Tourette's Tourette syndrome or Tourette's syndrome (abbreviated as TS or Tourette's) is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) ...

have been mixed. Guanfacine has been investigated for treatment of withdrawal for

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

, and

nicotine Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and '' Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is use ...

. Guanfacine has been shown to help reduce stress-induced craving of nicotine in smokers trying to quit, which may involve strengthening of prefrontal cortex meditated self-control.

References

External links

* {{Serotonin receptor modulators 5-HT2B agonists Acetamides Acylguanidines Alpha-2 adrenergic receptor agonists Antihypertensive agents Attention deficit hyperactivity disorder management Chloroarenes Takeda Pharmaceutical Company brands Wikipedia medicine articles ready to translate