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- Clonidine
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/03/22 15:25:19」(JST)
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Not to be confused with clomifene, Klonopin, or clonazepam.
| Systematic (IUPAC) name | |
|---|---|
| N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine | |
| Clinical data | |
| Trade names | Catapres |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682243 |
| Pregnancy cat. | C (US) |
| Legal status | ℞ Prescription only |
| Routes | oral, transdermal |
| Pharmacokinetic data | |
| Bioavailability | 75-95% |
| Protein binding | 20-40% |
| Metabolism | Hepatic to inactive metabolites |
| Half-life | 12-33 hours |
| Excretion | urine (40-50%) |
| Identifiers | |
| CAS number | 4205-90-7 Y |
| ATC code | C02AC01 N02CX02, S01EA04 |
| PubChem | CID 2803 |
| IUPHAR ligand | 516 |
| DrugBank | DB00575 |
| ChemSpider | 2701 Y |
| UNII | MN3L5RMN02 Y |
| KEGG | D00281 Y |
| ChEBI | CHEBI:3757 Y |
| ChEMBL | CHEMBL134 Y |
| Chemical data | |
| Formula | C9H9Cl2N3 |
| Mol. mass | 230.093 g/mol |
|
SMILES
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InChI
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| Y (what is this?) (verify) |
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Clonidine (trade name Kapvay or Nexiclon) is a sympatholytic medication used to treat medical conditions, such as high blood pressure, ADHD, anxiety/panic disorder, and certain pain conditions. It is classified as a centrally acting α2 adrenergic agonist. An alternative hypothesis that has been proposed is that clonidine acts centrally as an imidazoline receptor agonist.
Contents
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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, 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 in an extended release form. 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 tics, a problem in which a part of the body moves repeatedly and suddenly.[1] Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).[2] Clonidine along with methylphenidate has been studied for treatment of ADHD. [3][4] 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).
Clonidine may be used to ease withdrawal symptoms associated with the long-term use of narcotics, alcohol and nicotine (smoking). It can alleviate opioid withdrawal symptoms by reducing the sympathetic nervous system response such as tachycardia and hypertension, as well as reducing sweating, hot and cold flushes, and general restlessness.[5] The sedation effect is also useful although its side effects can include insomnia, thus exacerbating an already common feature of opioid withdrawal.[6]
Clonidine can be used for migraine headaches and hot flushes associated with menopause.[7][8]
Clonidine also has several off-label uses, 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.[9][10][11][12][13][14][15][16][17] Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures. [18] Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively.[19] Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.[20]
Clonidine has also been found to prolong the effects of analgesia when used together with a local anesthetic such as ropivacaine or levobupivacaine.[citation needed]
Mechanism of action
Clonidine treats high blood pressure by stimulating α2 receptors 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.[21]
It has also been proposed that 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.[22]
Preparation and indications
Clonidine tablets and transdermal patch
Clonidine is typically available as tablets (Catapres, Dixarit), extended-release tablets (Kapvay), as a transdermal patch (Catapres-TTS), or as an injectable form to be given i.m., i.v. or epidurally - directly to the central nervous system.
Alternative uses
Clonidine can be used in Restless Legs Syndrome. It can also be used to treat facial flushing and redness associated with rosacea.[23]
Adverse effects
This drug may cause lightheadedness, dry mouth, dizziness and constipation. Clonidine may also cause hypotension.[24]
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.[25]
Pregnancy
Clonidine is classed by the FDA as pregnancy category C. It is not known whether clonidine is harmful to an unborn baby. Additionally, clonidine can pass into breast milk and may harm a nursing baby. Therefore, caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.[26]
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 1.5 mg[citation needed], 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.[27]
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.[28][29]
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 agonist 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.
Clonidine suppression test
Clonidine's effect on reducing circulating epinephrine by a central mechanism was used in the past as an investigatory test for pheochromocytoma,[30] 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 thiocyanate gives N-(2,6- dichlorophenyl)thiourea. Methylation of this product, followed by the subsequent reaction with ethylene diamine gives clonidine.
- K. Zeile, H. Staehle, K. H. Hauotman, DE 1303141 (1961).
- H. Stahle, K. Zeile, U.S. Patent 3,202,660 (1965).
- K. Zeile, K. H. Hauotman, H. Stahle, U.S. Patent 3,236,857 (1966).
- Boehringer Sohn Ingelheim, BE 653933 (1964).
- Boehringer Sohn Ingelheim, GB 1016514 (1962).
- Boehringer Ingelheim GmbH, GB 1034938 (1964).
US patent 3937717, Stahle, H.; Koppe, H.; Kummer, W.; Stockhaus, K., "2-Phenylamino-imidazolines-(2)", issued 1976-02-10, assigned to Boehringer Ingelheim GmbH
References
- ^ National Institute of Neurological Disorders and Stroke (2002). "Methylphenidate and Clonidine Help Children With ADHD and Tics".
- ^ Schapiro, NA (May-June 2002). "Dude, you don't have Tourette's". Pediatr. Nurs. 3 (28): 243–246, 249–253. PMID 12087644.
- ^ Daviss, W.; Patel, N.; Robb, A.; McDermott, M.; Bukstein, O.; Pelham Jr, W.; Palumbo, D.; Harris, P. et al. (2008). "Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis". Journal of the American Academy of Child and Adolescent Psychiatry 47 (2): 189–198. doi:10.1097/chi.0b013e31815d9ae4. PMID 18182964. edit
- ^ Palumbo, D.; Sallee, F.; Pelham Jr, W.; Bukstein, O.; Daviss, W.; McDermott, M. (2008). "Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes". Journal of the American Academy of Child and Adolescent Psychiatry 47 (2): 180–188. doi:10.1097/chi.0b013e31815d9af7. PMID 18182963. edit
- ^ AJ Giannini. Drugs of Abuse--Second Edition. Los Angeles, Practice Management Information Corporation,1997.
- ^ AJ Giannini, I. Extein, MS Gold, ALC Pottash, S. Castellani. Clonidine in mania. Drug Development Research. 3:101-105,1983.
- ^ "Clonidine Oral Uses". Web MD. http://www.webmd.com/drugs/drug-11754-Clonidine.aspx?drugid=11754&drugname=Clonidine.
- ^ "Clonidine". Drugs.com. http://www.drugs.com/clonidine.html.
- ^ Ziegenhorn, A.; Roepke, S.; Schommer, N.; Merkl, A.; Danker-Hopfe, H.; Perschel, F.; Heuser, I.; Anghelescu, I. et al. (2009). "Clonidine improves hyperarousal in borderline personality disorder with or without comorbid posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial". Journal of Clinical Psychopharmacology 29 (2): 170–173. doi:10.1097/JCP.0b013e31819a4bae. PMID 19512980. edit
- ^ Najjar, F.; Weller, R. A.; Weisbrot, J.; Weller, E. B. (2008). "Post-traumatic stress disorder and its treatment in children and adolescents". Current psychiatry reports 10 (2): 104–108. doi:10.1007/s11920-008-0019-0. PMID 18474199. edit
- ^ Huffman, J. C.; Stern, T. A. (2007). "Neuropsychiatric consequences of cardiovascular medications". Dialogues in clinical neuroscience 9 (1): 29–45. PMID 17506224. edit
- ^ Boehnlein, J.; Kinzie, J. (2007). "Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin". Journal of Psychiatric Practice 13 (2): 72–78. doi:10.1097/01.pra.0000265763.79753.c1. PMID 17414682. edit
- ^ Strawn, J.; Geracioti Jr, T. (2008). "Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder". Depression and anxiety 25 (3): 260–271. doi:10.1002/da.20292. PMID 17354267. edit
- ^ Southwick, S. M.; Bremner, J. D.; Rasmusson, A.; Morgan Ca, 3.; Arnsten, A.; Charney, D. S. (1999). "Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder". Biological Psychiatry 46 (9): 1192–1204. doi:10.1016/S0006-3223(99)00219-X. PMID 10560025. edit
- ^ Sutherland, S. M.; Davidson, J. R. (1994). "Pharmacotherapy for post-traumatic stress disorder". The Psychiatric clinics of North America 17 (2): 409–423. PMID 7937367. edit
- ^ Van Der Kolk, B. A. (1987). "The drug treatment of post-traumatic stress disorder". Journal of Affective Disorders 13 (2): 203–213. doi:10.1016/0165-0327(87)90024-3. PMID 2960712. edit
- ^ "Understanding Comorbid Depression and Anxiety". http://www.psychiatrictimes.com/anxiety/content/article/10168/53896?verify=0.
- ^ Fazi L. A comparison of oral clonidine and oral midazolam as preanesthetic medications in the pediatric tonsillectomy patient. Anesth Analg. 2001 Jan;92(1):56-61. PMID 11133600
- ^ Patel SS, Dunn CJ, Bryson HM (1996). "Epidural clonidine: a review of its pharmacology and efficacy in the management of pain during labour and postoperative and intractable pain". CNS Drugs 6 (6): 474–497.
- ^ Kukoyi, AT; Coker SA, Lewis LD, Nierenberg DW (January 2013). "Two cases of acute dexmedetomidine withdrawal syndrome following prolonged infusion in the intensive care unit: Report of cases and review of the literature". Human and Experimental Toxicology 32 (1): 107-110. doi:10.1177/0960327112454896. http://het.sagepub.com/content/32/1/107.full. Retrieved 1 March 2013.
- ^ Shen, Howard (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. pp. 12. ISBN 1-59541-101-1.
- ^ Reitz, DJ; Piletz, JE (1997). "The imidazoline receptor in control of blood pressure by clonidine and allied drugs". American Journal of Physiology 273 (5): R1569-R1571.
- ^ Blount, BW; Pelletier AL. (Aug 2002). "Rosacea: A Common, Yet Commonly Overlooked, Condition". Am Fam Physician 66 (3): 435–41. http://www.aafp.org/afp/2002/0801/p435.html.
- ^ Hossmann V; Maling TJ, Hamilton CA, Reid JL, Dollery CT. (August 1980). "Sedative and cardiovascular effects of clonidine and nitrazepam". Clin Pharmacol Ther. 28 (2): 167–76. doi:10.1038/clpt.1980.146. PMID 7398184.
- ^ "Toxicity, Clonidine". http://emedicine.medscape.com/article/819776-overview.
- ^ "Clonidine, Prescription Marketed Drugs, www.drugsdb.eu". http://drugsdb.eu/drug.php?d=Clonidine&m=Physicians%20Total%20Care,%20Inc.&id=b65742b7-5db5-41cf-bf69-41700cdd2c59.xml.
- ^ "Clonidine". Encyclopedia of Mental Disorders. http://www.minddisorders.com/Br-Del/Clonidine.html.
- ^ Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred (2006). Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill. pp. 854–855. ISBN 0-07-142280-3.
- ^ Vitiello B (April 2008). "Understanding the Risk of Using Medications for ADHD with Respect to Physical Growth and Cardiovascular Function". Child Adolesc Psychiatr Clin N Am 17 (2): 459–74, xi. doi:10.1016/j.chc.2007.11.010. PMC 2408826. PMID 18295156. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2408826/.
- ^ Eisenhofer G, Goldstein DS, Walther MM, et al. (June 2003). "Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results". J. Clin. Endocrinol. Metab. 88 (6): 2656–66. doi:10.1210/jc.2002-030005. PMID 12788870. http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=12788870.
External links
- Clonidine Side Effects
- U.S. National Library of Medicine: Drug Information Portal - Clonidine
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UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
- 1. クロニジンおよびイミダゾリンによる中毒 clonidine and related imidazoline poisoning
- 2. Cannabis (marijuana): Acute intoxication
- 3. オピオイド中毒治療中の医師監督下の離脱 medically supervised opioid withdrawal during treatment for addiction
- 4. 思春期におけるオピオイド離脱 opioid withdrawal in adolescents
- 5. 成人における複合性局所疼痛症候群の予防およびマネージメント prevention and management of complex regional pain syndrome in adults
English Journal
- Stimulation of postsynapse adrenergic α2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder.
- Kawaura K1, Karasawa J1, Chaki S1, Hikichi H2.
- Behavioural brain research.Behav Brain Res.2014 Aug 15;270:349-56. doi: 10.1016/j.bbr.2014.05.044. Epub 2014 May 29.
- A 5-trial inhibitory avoidance test using spontaneously hypertensive rat (SHR) pups has been used as an animal model of attention deficit hyperactivity disorder (ADHD). However, the roles of noradrenergic systems, which are involved in the pathophysiology of ADHD, have not been investigated in this
- PMID 24882610
- Anesthesia in neurologic and psychiatric diseases: is there a 'best anesthesia' for certain diseases?
- Hachenberg T1, Schneemilch C.
- Current opinion in anaesthesiology.Curr Opin Anaesthesiol.2014 Aug;27(4):394-402. doi: 10.1097/ACO.0000000000000098.
- PURPOSE OF REVIEW: Patients with diseases affecting the central nervous system present a wide range of clinical manifestations increasing the perioperative risk. The following review focused on recommendations for anaesthesiological management in patients with both neurologic and psychiatric disease
- PMID 24979067
- A double-blind, placebo-controlled trial of dextromethorphan combined with clonidine in the treatment of heroin withdrawal.
- Lin SK1, Pan CH, Chen CH.
- Journal of clinical psychopharmacology.J Clin Psychopharmacol.2014 Aug;34(4):508-12. doi: 10.1097/JCP.0000000000000144.
- Dextromethorphan has been reported to ameliorate opioid withdrawal symptoms in both animal and human subjects. In the present study, we investigated the efficacy of dextromethorphan as an add-on medication in heroin detoxification treatment in a double-blind, placebo-controlled design. Sixty-five he
- PMID 24875077
Japanese Journal
- In Vitro and in Vivo Characterization of a Newly Developed Clonidine Transdermal Patch for Treatment of Attention Deficit Hyperactivity Disorder in Children(Biopharmacy)
- Biological & pharmaceutical bulletin 28(2), 305-310, 2005-02-01
- NAID 10016660113
- Electroencephalographic and psychometric assessment of the CNS effects of single doses of guanfacine hydrochloride (Estulic) and clonidine (Catapres)
- Neuropsychobiology 14, 97-107, 1985
- NAID 10009554839
- 一側椎骨動脈狭窄家兎の前庭眼反射に及ぼす血圧の影響について
- 耳鼻咽喉科臨床 75(11special), 2491-2496, 1982
- NAID 130001814121
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