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Clonidine
Systematic (IUPAC) name
N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine
Identifiers
CAS number 4205-90-7
ATC code C02AC01 N02CX02, S01EA04
PubChem 2803
DrugBank APRD00174
ChemSpider 2701
Chemical data
Formula C9H9Cl2N3 
Mol. mass 230.093 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 75-95%
Protein binding 20-40%
Metabolism Hepatic to inactive metabolites
Half life 12-33 hours
Excretion urine (40-50%)
Therapeutic considerations
Pregnancy cat. C(US)
Legal status Prescription only
Routes oral, transdermal
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Clonidine is a medication used to treat several medical conditions. It is a direct-acting α2 adrenergic agonist.

Contents

Uses

It has been prescribed historically as an antihypertensive agent. It has found new uses, including treatment of some types of neuropathic pain, opioid detoxification, sleep hyperhidrosis, anaesthetic use, and off-label, to counter the side effects of stimulant medications such as methylphenidate or amphetamine. 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.[1] Clonidine can be used in the treatment of Tourette syndrome.[2] Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures. [3]

Mechanism

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.[4]

Indications & preparations

Clonidine tablets and transdermal patch


Clonidine is typically available as tablets (Catapres, Dixarit), as a transdermal patch (Catapres-TTS), or as an injectable form to be given epidurally, directly to the central nervous system.

FDA approved uses

This medication may also be used to ease withdrawal symptoms associated with the long-term use of narcotics, alcohol and nicotine (smoking). In addition, clonidine has also been used for migraine headaches, hot flashes associated with menopause, and attention deficit hyperactivity disorder.[5][6]

Clonidine is regularly prescribed to opiate addicts to help alleviate their 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.[7] It helps take away the sweating, hot/cold flashes, 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.[8]

Off-Label Uses

Clonidine is used off-label to treat psychiatric disorders including stress, sleep disturbances, 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 along with Methylphenidate has been studied for treatment of ADHD.[18][19]

An extended-release version of clonidine named Clonicel is also being studied for treatment of ADHD[20][21][22][23].

Adverse effects

This drug may cause lightheadedness, dry mouth, dizziness, or constipation. Clonidine may also cause hypotension[24]

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.[25][26]

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,[27] 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 µg/kg oral test dose has been given to a patient. A positive test occurs if there is no decrease in plasma levels.

References

  1. ^ National Institute of Neurological Disorders and Stroke (2002). "Methylphenidate and Clonidine Help Children With ADHD and Tics".
  2. ^ Schapiro NA. "Dude, you don't have Tourette's": Tourette's syndrome, beyond the tics. Pediatr Nurs. 2002 May-Jun;28(3):243-6, 249-53. PMID 12087644
  3. ^ 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
  4. ^ Shen, Howard (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. pp. 12. ISBN 1-59541-101-1. 
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  6. ^ "Clonidine". Drugs.com. http://www.drugs.com/clonidine.html. 
  7. ^ . AJ Giannini. Drugs of Abuse--Second Edition. Los Angeles, Practice Management Information Corporation,1997.
  8. ^ AJ Giannini, I. Extein,MS Gold, ALC Pottash, S. Castellani. Clonidine in mania. Drug Development Research. 3:101-105,1983.
  9. ^ 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
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  12. ^ 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
  13. ^ 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
  14. ^ Southwick, SM; Bremner, JD; Rasmusson, A; Morgan Ca, 3rd; Arnsten, A; Charney, DS (1999). "Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder". Biological psychiatry 46 (9): 1192–204. doi:10.1016/S0006-3223(99)00219-X. PMID 10560025.  edit
  15. ^ Sutherland, SM; Davidson, JR (1994). "Pharmacotherapy for post-traumatic stress disorder". The Psychiatric clinics of North America 17 (2): 409–23. PMID 7937367.  edit
  16. ^ Van Der Kolk, BA (1987). "The drug treatment of post-traumatic stress disorder". Journal of affective disorders 13 (2): 203–13. doi:10.1016/0165-0327(87)90024-3. PMID 2960712.  edit
  17. ^ "Understanding Comorbid Depression and Anxiety". http://www.psychiatrictimes.com/anxiety/content/article/10168/53896?verify=0. 
  18. ^ 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
  19. ^ 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
  20. ^ "Clinical Trials For Clonicel". http://clinicaltrials.gov/ct2/show/NCT00641329. 
  21. ^ "Clonicel Press Release". http://www.drugs.com/nda/clonicel_091002.html. 
  22. ^ "Addrenex's Clonicel Product Data". http://www.addrenex.com/Addrenex-Clonicel-10-01-2009.pdf. 
  23. ^ May, D.; Kratochvil, C. (2010). "Attention-deficit hyperactivity disorder: recent advances in paediatric pharmacotherapy". Drugs 70 (1): 15–40. doi:10.2165/11530540-000000000-00000. PMID 20030423.  edit
  24. ^ 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. PMID 7398184. 
  25. ^ 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. 
  26. ^ Vitiello B (April 2008). "Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function" (PDF). Child Adolesc Psychiatr Clin N Am 17 (2): 459–74, xi. doi:10.1016/j.chc.2007.11.010. PMID 18295156.& PMC 2408826. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2408826&blobtype=pdf. 
  27. ^ 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. 







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