Clonidine
Encyclopedia
Clonidine is a sympatholytic
medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder. It is a direct-acting α2
adrenergic agonist.
Action as an imidazoline receptor
agonist is controversial.
Guanidine
receptor agonist action is possible .
It has found new uses later, including treatment of some types of neuropathic pain
, opioid
detoxification, sleep hyperhidrosis
, and as veterinary anaesthetic drug.
Clonidine is used to treat anxiety and panic disorder. It is also FDA approved to treat ADHD. It is becoming a more accepted treatment for insomnia
, as well as for relief of menopausal symptoms.
Clonidine is increasingly used in conjunction with stimulants to treat attention-deficit hyperactivity disorder (ADHD), for which it is administered in late afternoon or evening for sleep, and because it sometimes helps moderate ADHD-associated impulsive and oppositional behavior, and may reduce tic
s, a problem in which a part of the body moves repeatedly and suddenly. Clonidine can be used in the treatment of Tourette syndrome
(specifically for tics). Clonidine along with Methylphenidate has been studied for treatment of ADHD. In 2010, the Food and Drug Administration
approved the use of clonidine either as an adjunct to traditional stimulant therapy or as a monotherapy in the treatment of attention deficit hyperactivity disorder (ADHD).
This medication may also be used to ease withdrawal symptoms associated with the long-term use of narcotic
s, alcohol
and nicotine
(smoking). In addition, clonidine has also been used for migraine
headaches and hot flushes associated with menopause.
Clonidine is regularly prescribed to help alleviate opiate
withdrawal symptoms. It is mainly used to combat the sympathetic nervous system
response to opiate withdrawal, namely tachycardia
and hypertension
, in the initial days of withdrawals. It helps take away the sweating, hot/cold flushes, and general restlessness. The sedation effect is also useful although its side effects can include insomnia, thus exacerbating an already common feature of opiate withdrawal.
Clonidine also has several off-label use
s, and has been prescribed to treat psychiatric disorders including stress
, sleep disorders, and hyperarousal caused by post-traumatic stress disorder
, borderline personality disorder
, and other anxiety
disorders. Clonidine is also a mild sedative
, and can be used as premedication
before surgery or procedures. Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively.
Clonidine has also been found to prolong the effects of analgesia when used together with a local anesthetic
such as ropivacaine
or levobupivacaine
.
in the brain, which decreases cardiac output
and peripheral vascular resistance, lowering blood pressure. It has specificity towards the presynaptic α2 receptors in the vasomotor
center in the brainstem. This binding decreases presynaptic calcium
levels, and inhibits the release of norepinephrine
(NE). The net effect is a decrease in sympathetic tone.
The antihypertensive effect of clonidine is due to agonism on the I1-receptor (imidazoline receptor
), which mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure.
Clonidine is typically available as tablet
s (Catapres, Dixarit), as a transdermal patch
(Catapres-TTS), or as an injectable
form to be given i.m., i.v. or epidural
ly - directly to the central nervous system
.
, jitters, and hypertension.
.
Clonidine also has peripheral alpha agonist activity which can lead to hypertension - especially when it is injected intravenously. This blood pressure increase is sometimes witnessed in cases of overdose in children. As the clonidine is eliminated by the body, the peripheral effects wear off and its basic hypotensive effect becomes evident.
Both the hypertensive and hypotensive effects can be harmful.
Pediatric doses of clonidine are calculated based on the child's body weight. Clonidine dosage for ADHD in children is 5 micrograms per kilogram of body weight per day orally in four divided doses. Children who require a daily dosage of 0.2 mg usually can use the 0.3 mg dermal patch. If ADHD is associated with sleep disturbances, low to moderate doses of clonidine can be taken at bedtime. Oral doses in children with Tourette's syndrome range from 3 to 6 micrograms per kilogram of body weight per day divided into two to four even doses.
Clonidine therapy should generally be gradually tapered off when discontinuing therapy to avoid rebound effects from occurring. Treatment of clonidine withdrawal hypertension depends on the severity of the condition. Reintroduction of clonidine for mild cases, alpha and beta blockers for more urgent situations. Beta blockers never should be used alone to treat clonidine withdrawal as alpha vasoconstriction would still continue.
Since ADHD drugs like amphetamine and methylphenidate tend to stimulate the sympathetic nervous system, missed doses of clonidine while under ADHD stimulant therapy might entail increased risks of a more severe rebound hypertension. This has not been evaluated.
with more affinity for α2 than α1. It selectively stimulates receptors in the brain that monitor catecholamine
levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (epinephrine
, also known as adrenaline, and norepinephrine
) in the adrenal medulla
. By fooling the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure, with side effects of dry mouth and fatigue. If clonidine is suddenly withdrawn the sympathetic nervous system will revert to producing high levels of epinephrine and norepinephrine, higher even than before treatment, causing rebound hypertension. Rebound hypertension can be avoided by slowly withdrawing treatment.
, which is a catecholamine-synthesizing tumor, usually of the adrenal medulla. In a clonidine suppression test plasma catecholamines levels are measured before and 3 hours after a 0.3 mg oral test dose has been given to a patient. A positive test occurs if there is no decrease in plasma levels.
gives N-(2,6- dichlorophenyl)thiourea. Methylation
of this product, followed by the subsequent reaction with ethylene diamine
gives clonidine.
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...
medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder. It is a direct-acting α2
Alpha-2 adrenergic receptor
The alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
adrenergic agonist.
Action as an imidazoline receptor
Imidazoline receptor
Imidazoline receptors are receptors for clonidine and other imidazolines.-Classes:There are three classes of imidazoline receptors:* I1 receptor – mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure, * I2 receptor – an allosteric binding site of monoamine oxidase and is...
agonist is controversial.
Guanidine
Guanidine
Guanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. It is used in the manufacture of plastics and explosives. It is found in urine as a normal product of protein metabolism. The molecule was first synthesized in 1861 by the oxidative degradation of an...
receptor agonist action is possible .
Uses
Clonidine has been investigated and prescribed first as an antihypertensive drug in the 1950s.It has found new uses later, including treatment of some types of neuropathic pain
Neuralgia
Neuralgia is pain in one or more nerves that occurs without stimulation of pain receptor cells. Neuralgia pain is produced by a change in neurological structure or function rather than by the excitation of pain receptors that causes nociceptive pain. Neuralgia falls into two categories: central...
, 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...
detoxification, sleep hyperhidrosis
Sleep hyperhidrosis
Sleep hyperhidrosis, more commonly known as the night sweats, is the occurrence of excessive sweating during sleep. The sufferer may or may not also suffer from excessive perspiration while awake....
, and as veterinary anaesthetic drug.
Clonidine is used to treat anxiety and panic disorder. It is also FDA approved to treat ADHD. It is becoming a more accepted treatment for insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, as well as for relief of menopausal symptoms.
Clonidine is increasingly used in conjunction with stimulants to treat attention-deficit hyperactivity disorder (ADHD), for which it is administered in late afternoon or evening for sleep, and because it sometimes helps moderate ADHD-associated impulsive and oppositional behavior, and may reduce tic
Tic
A tic is a sudden, repetitive, nonrhythmic, stereotyped motor movement or vocalization involving discrete muscle groups. Tics can be invisible to the observer, such as abdominal tensing or toe crunching. Common motor and phonic tics are, respectively, eye blinking and throat clearing...
s, a problem in which a part of the body moves repeatedly and suddenly. Clonidine can be used in the treatment of Tourette syndrome
Tourette syndrome
Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...
(specifically for tics). Clonidine along with Methylphenidate has been studied for treatment of ADHD. In 2010, the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved the use of clonidine either as an adjunct to traditional stimulant therapy or as a monotherapy in the treatment of attention deficit hyperactivity disorder (ADHD).
This medication may also be used to ease withdrawal symptoms associated with the long-term use of narcotic
Narcotic
The term narcotic originally referred medically to any psychoactive compound with any sleep-inducing properties. In the United States of America it has since become associated with opioids, commonly morphine and heroin and their derivatives, such as hydrocodone. The term is, today, imprecisely...
s, alcohol
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
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...
(smoking). In addition, clonidine has also been used for migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
headaches and hot flushes associated with menopause.
Clonidine is regularly prescribed to help alleviate opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
withdrawal symptoms. It is mainly used to combat the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
response to opiate withdrawal, namely tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
and hypertension
Hypertension
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...
, in the initial days of withdrawals. It helps take away the sweating, hot/cold flushes, and general restlessness. The sedation effect is also useful although its side effects can include insomnia, thus exacerbating an already common feature of opiate withdrawal.
Clonidine also has several off-label use
Off-label use
Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration...
s, and has been prescribed to treat psychiatric disorders including stress
Stress (biology)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
, sleep disorders, and hyperarousal caused by 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,...
, borderline personality disorder
Borderline personality disorder
Borderline personality disorder is a personality disorder described as a prolonged disturbance of personality function in a person , characterized by depth and variability of moods.The disorder typically involves unusual levels of instability in mood; black and white thinking, or splitting; the...
, and other 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,...
disorders. Clonidine is also a mild sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
, and can be used as premedication
Premedication
Premedication refer to a drug treatment given to a patient before a medical procedure. These drugs are typically sedative or analgesic....
before surgery or procedures. Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively.
Clonidine has also been found to prolong the effects of analgesia when used together with a local anesthetic
Local anesthetic
A local anesthetic is a drug that causes reversible local anesthesia, generally for the aim of having local analgesic effect, that is, inducing absence of pain sensation, although other local senses are often affected as well...
such as ropivacaine
Ropivacaine
Ropivacaine is a local anaesthetic drug belonging to the amino amide group. The name ropivacaine refers to both the racemate and the marketed S-enantiomer...
or levobupivacaine
Levobupivacaine
Levobupivacaine is a local anaesthetic drug belonging to the amino amide group. It is the S-enantiomer of bupivacaine. Levobupivacaine hydrochloride is commonly marketed by Abbott under the trade name Chirocaine.-Clinical use:...
.
Mechanism of action
Clonidine treats high blood pressure by stimulating α2 receptorsAlpha-2 adrenergic receptor
The alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
in the brain, which decreases cardiac output
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
and peripheral vascular resistance, lowering blood pressure. It has specificity towards the presynaptic α2 receptors in the vasomotor
Vasomotor
Vasomotor refers to actions upon a blood vessel which alter its diameter. More specifically, it can refer to vasodilator action and vasoconstrictor action....
center in the brainstem. This binding decreases presynaptic calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
levels, and inhibits the release of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(NE). The net effect is a decrease in sympathetic tone.
The antihypertensive effect of clonidine is due to agonism on the I1-receptor (imidazoline receptor
Imidazoline receptor
Imidazoline receptors are receptors for clonidine and other imidazolines.-Classes:There are three classes of imidazoline receptors:* I1 receptor – mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure, * I2 receptor – an allosteric binding site of monoamine oxidase and is...
), which mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure.
Preparation and indications
Clonidine is typically available as tablet
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...
s (Catapres, Dixarit), as a transdermal patch
Transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
(Catapres-TTS), or as an injectable
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
form to be given i.m., i.v. or epidural
Epidural
The term epidural is often short for epidural analgesia, a form of regional analgesia involving injection of drugs through a catheter placed into the epidural space...
ly - directly to 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...
.
Alternative uses
Used for opiate withdrawal to help with Restless Legs SyndromeRestless legs syndrome
Restless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...
, jitters, and hypertension.
Adverse effects
This drug may cause lightheadedness, dry mouth, dizziness and constipation. Clonidine may also cause hypotensionHypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
.
Clonidine also has peripheral alpha agonist activity which can lead to hypertension - especially when it is injected intravenously. This blood pressure increase is sometimes witnessed in cases of overdose in children. As the clonidine is eliminated by the body, the peripheral effects wear off and its basic hypotensive effect becomes evident.
Both the hypertensive and hypotensive effects can be harmful.
Pregnancy
FDA pregnancy category C. It is not known whether clonidine is harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Clonidine can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.Recommended dosage
Dosages of 0.4–0.6 mg have been used for the treatment of alcohol withdrawal. Total daily dosage for the treatment of opiate withdrawal range between 0.5 and 1.4 mg, depending on the stage as well as the severity of withdrawal symptoms. If the clonidine patch is used to treat nicotine withdrawal symptoms, dosages that deliver 0.1–0.2 mg daily are used. For oral therapy (tablets), a total dosage of 0.2–0.4 mg daily is taken in divided doses.Pediatric doses of clonidine are calculated based on the child's body weight. Clonidine dosage for ADHD in children is 5 micrograms per kilogram of body weight per day orally in four divided doses. Children who require a daily dosage of 0.2 mg usually can use the 0.3 mg dermal patch. If ADHD is associated with sleep disturbances, low to moderate doses of clonidine can be taken at bedtime. Oral doses in children with Tourette's syndrome range from 3 to 6 micrograms per kilogram of body weight per day divided into two to four even doses.
Rebound hypertension on withdrawal
Clonidine suppresses sympathetic outflow resulting in lower blood pressure, but sudden discontinuation can cause rebound hypertension due to a rebound in sympathetic outflow.Clonidine therapy should generally be gradually tapered off when discontinuing therapy to avoid rebound effects from occurring. Treatment of clonidine withdrawal hypertension depends on the severity of the condition. Reintroduction of clonidine for mild cases, alpha and beta blockers for more urgent situations. Beta blockers never should be used alone to treat clonidine withdrawal as alpha vasoconstriction would still continue.
Since ADHD drugs like amphetamine and methylphenidate tend to stimulate the sympathetic nervous system, missed doses of clonidine while under ADHD stimulant therapy might entail increased risks of a more severe rebound hypertension. This has not been evaluated.
Pharmacodynamics
Clonidine is a centrally-acting α-adrenergic receptor agonistAlpha-adrenergic agonist
An adrenergic alpha-agonist is a drug that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α1 and α2.-Classes:...
with more affinity for α2 than α1. It selectively stimulates receptors in the brain that monitor catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, also known as adrenaline, and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
) in the adrenal medulla
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
. By fooling the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure, with side effects of dry mouth and fatigue. If clonidine is suddenly withdrawn the sympathetic nervous system will revert to producing high levels of epinephrine and norepinephrine, higher even than before treatment, causing rebound hypertension. Rebound hypertension can be avoided by slowly withdrawing treatment.
Clonidine suppression test
Clonidine's effect on reducing circulating epinephrine by a central mechanism was used in the past as an investigatory test for pheochromocytomaPheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
, which is a catecholamine-synthesizing tumor, usually of the adrenal medulla. In a clonidine suppression test plasma catecholamines levels are measured before and 3 hours after a 0.3 mg oral test dose has been given to a patient. A positive test occurs if there is no decrease in plasma levels.
Synthesis
Clonidine, 2-(2,6-dichlorophenylamino)imidazoline, is synthesized from 2,6-dichloroaniline, the reaction of which with ammonium thiocyanateAmmonium thiocyanate
Ammonium thiocyanate is an inorganic compound with the formula NH4SCN. It is the salt of the ammonium cation and the thiocyanate anion.-Uses:...
gives N-(2,6- dichlorophenyl)thiourea. Methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
of this product, followed by the subsequent reaction with ethylene diamine
Ethylene diamine
Ethylenediamine is the organic compound with the formula C2H42. This colorless liquid with an ammonia-like odor is a strongly basic amine. The liquid fumes upon contact with humid air...
gives clonidine.
- K. Zeile, H. Staehle, K. H. Hauotman, (1961).
- H. Stahle, K. Zeile, (1965).
- K. Zeile, K. H. Hauotman, H. Stahle, (1966).
- Boehringer Sohn Ingelheim, (1964).
- Boehringer Sohn Ingelheim, (1962).
- Boehringer Ingelheim GmbH, (1964).