clonidine

Image:Clonidine pills and patch.jpg

Clonidine is used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD); drug withdrawal, including from (alcohol, opioids, and/or nicotine); menopausal flushing, diarrhea, and certain pain conditions. In addition, it also sees some use off-label for episodic insomnia, and tics (e.g. from Tourette Syndrome, restless legs syndrome, and anxiety, among others).

Clonidine may be effective for lowering blood pressure in people with resistant hypertension.{{cite journal |vauthors=Viera AJ |title=Hypertension Update: Resistant Hypertension |journal=FP Essent |volume=469 |pages=20–25 |date=June 2018 |pmid=29863319 }}

Clonidine works by slowing the pulse rate and exerts a reduction of serum concentrations of renin, aldosterone, and catecholamines.{{cite web | title=Catapres- clonidine hydrochloride tablet | website=DailyMed | date=6 September 2016 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7f569dc-6bed-42dc-9bec-940a9e6b090d | access-date=21 December 2019 | quote=Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise. Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804180055/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7f569dc-6bed-42dc-9bec-940a9e6b090d | url-status=live }}

Clonidine may improve symptoms of attention deficit hyperactivity disorder in some people but causes many adverse effects and the beneficial effect is modest.{{cite journal | vauthors = Connor DF, Fletcher KE, Swanson JM | title = A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 38 | issue = 12 | pages = 1551–1559 | date = December 1999 | pmid = 10596256 | doi = 10.1097/00004583-199912000-00017 }} In Australia, clonidine is an accepted but not approved use for ADHD by the TGA.{{cite book | editor = Rossi, S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }} Clonidine, along with methylphenidate, has been studied for treatment of ADHD.{{cite journal | vauthors = Palumbo DR, Sallee FR, Pelham WE, Bukstein OG, Daviss WB, McDERMOTT MP | title = Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 47 | issue = 2 | pages = 180–188 | date = February 2008 | pmid = 18182963 | doi = 10.1097/chi.0b013e31815d9af7 }}{{cite journal | vauthors = Daviss WB, Patel NC, Robb AS, McDERMOTT MP, Bukstein OG, Pelham WE, Palumbo D, Harris P, Sallee FR | title = Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 47 | issue = 2 | pages = 189–198 | date = February 2008 | pmid = 18182964 | doi = 10.1097/chi.0b013e31815d9ae4 }}{{cite journal | vauthors = Kornfield R, Watson S, Higashi AS, Conti RM, Dusetzina SB, Garfield CF, Dorsey ER, Huskamp HA, Alexander GC | title = Effects of FDA advisories on the pharmacologic treatment of ADHD, 2004-2008 | journal = Psychiatric Services | volume = 64 | issue = 4 | pages = 339–346 | date = April 2013 | pmid = 23318985 | pmc = 4023684 | doi = 10.1176/appi.ps.201200147 }} While not as effective as methylphenidate in treating ADHD, clonidine does offer some benefit; it can also be useful in combination with stimulant medications.{{cite journal | vauthors = Kollins SH, Jain R, Brams M, Segal S, Findling RL, Wigal SB, Khayrallah M | title = Clonidine extended-release tablets as add-on therapy to psychostimulants in children and adolescents with ADHD | journal = Pediatrics | volume = 127 | issue = 6 | pages = e1406–e1413 | date = June 2011 | pmid = 21555501 | pmc = 3387872 | doi = 10.1542/peds.2010-1260 }} Some studies show clonidine to be more sedating than guanfacine, which may be better at bedtime along with an arousing stimulant in the morning.{{cite journal | vauthors = Jäkälä P, Riekkinen M, Sirviö J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen P | title = Guanfacine, but not clonidine, improves planning and working memory performance in humans | journal = Neuropsychopharmacology | volume = 20 | issue = 5 | pages = 460–470 | date = May 1999 | pmid = 10192826 | doi = 10.1016/S0893-133X(98)00127-4 | doi-access = free }}{{Cite journal |url = http://cpnp.org/resource/mhc/2014/01/clonidine-and-guanfacine-ir-vs-er-old-drugs-new-formulations |title = Clonidine and Guanfacine IR vs ER: Old Drugs With "New" Formulations |access-date = 1 August 2014 |journal = Mental Health Clinician |year = 2014 |doi = 10.9740/mhc.n186955 |vauthors = Freeland K, Turner A, Gormley L |volume = 4 |pages = 22–26 |doi-access = free |archive-date = 9 August 2014 |archive-url = https://web.archive.org/web/20140809181310/http://cpnp.org/resource/mhc/2014/01/clonidine-and-guanfacine-ir-vs-er-old-drugs-new-formulations |url-status = live }} Clonidine has been used to reduce sleep disturbances in ADHD, including to help offset stimulant-associated insomnia.{{cite journal | vauthors = Nguyen M, Tharani S, Rahmani M, Shapiro M | title = A review of the use of clonidine as a sleep aid in the child and adolescent population | journal = Clinical Pediatrics | volume = 53 | issue = 3 | pages = 211–216 | date = March 2014 | pmid = 24027233 | doi = 10.1177/0009922813502123 | s2cid = 742140 }}{{cite journal | vauthors = Hoban TF | title = Assessment and treatment of disturbed sleep in attention deficit hyperactivity disorder | journal = Expert Review of Neurotherapeutics | volume = 4 | issue = 2 | pages = 307–316 | date = March 2004 | pmid = 15853572 | doi = 10.1586/14737175.4.2.307 | s2cid = 35000868 }}{{cite book | editor-first = | title = Handbook of Disruptive Behavior Disorders | vauthors = Schachar R, Ickowicz A | chapter = Pharmacological Treatment of Attention-Deficit/HyperactivityDisorder | date = 1999 | pages = 221–254 | publisher = Springer US | doi = 10.1007/978-1-4615-4881-2_10 | isbn = 978-1-4613-7214-1| url = }}{{cite journal | vauthors = Wilens TE, Biederman J, Spencer T | title = Clonidine for sleep disturbances associated with attention-deficit hyperactivity disorder | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 33 | issue = 3 | pages = 424–426 | date = 1994 | pmid = 8169189 | doi = 10.1097/00004583-199403000-00018 }} Unlike stimulant medications, clonidine is regarded as having no abuse potential, and may even be used to reduce abuse of drugs including nicotine and cocaine.{{cite journal | vauthors = Clemow DB, Walker DJ | title = The potential for misuse and abuse of medications in ADHD: a review | journal = Postgraduate Medicine | volume = 126 | issue = 5 | pages = 64–81 | date = September 2014 | pmid = 25295651 | doi = 10.3810/pgm.2014.09.2801 | s2cid = 207580823 }}

In the US, only the extended-release form of clonidine is approved for ADHD treatment.{{cite web |title=Highlights of Prescribing Information: Kapvay |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022331s014lbl.pdf |archive-url=https://web.archive.org/web/20160327193722/http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022331s014lbl.pdf |url-status=dead |archive-date=27 March 2016 |publisher=US FDA |access-date=31 March 2024}}

Clonidine may be used to ease drug withdrawal symptoms associated with abruptly stopping the long-term use of opioids, alcohol, benzodiazepines, and nicotine.{{cite journal | vauthors = Fitzgerald PJ | title = Elevated Norepinephrine may be a Unifying Etiological Factor in the Abuse of a Broad Range of Substances: Alcohol, Nicotine, Marijuana, Heroin, Cocaine, and Caffeine | journal = Substance Abuse | volume = 7 | pages = 171–183 | date = October 2013 | pmid = 24151426 | pmc = 3798293 | doi = 10.4137/SART.S13019 }} It can alleviate opioid withdrawal symptoms by reducing the sympathetic nervous system response such as tachycardia and hypertension, hyperhidrosis (excessive sweating), hot and cold flashes, and akathisia.{{ cite book | vauthors = Giannini AJ | title = Drugs of Abuse | edition = 2nd | location = Los Angeles | publisher = Practice Management Information | year = 1997 }} It may also be helpful in aiding smokers to quit.{{cite journal | vauthors = Gourlay SG, Stead LF, Benowitz NL | title = Clonidine for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 2008 | issue = 3 | pages = CD000058 | date = 2004 | pmid = 15266422 | pmc = 7038651 | doi = 10.1002/14651858.CD000058.pub2 }} The sedation effect can also be useful. Clonidine may also reduce severity of neonatal abstinence syndrome in infants born to mothers that are using certain drugs, particularly opioids.{{cite journal | vauthors = Streetz VN, Gildon BL, Thompson DF | title = Role of Clonidine in Neonatal Abstinence Syndrome: A Systematic Review | journal = The Annals of Pharmacotherapy | volume = 50 | issue = 4 | pages = 301–310 | date = April 2016 | pmid = 26783353 | doi = 10.1177/1060028015626438 | s2cid = 40652097 }} In infants with neonatal withdrawal syndrome, clonidine may improve the neonatal intensive care unit Network Neurobehavioral Score.{{cite journal | vauthors = Disher T, Gullickson C, Singh B, Cameron C, Boulos L, Beaubien L, Campbell-Yeo M | title = Pharmacological Treatments for Neonatal Abstinence Syndrome: A Systematic Review and Network Meta-analysis | journal = JAMA Pediatrics | volume = 173 | issue = 3 | pages = 234–243 | date = March 2019 | pmid = 30667476 | pmc = 6439896 | doi = 10.1001/jamapediatrics.2018.5044 }}

Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.{{cite journal | vauthors=Kukoyi A, Coker S, Lewis L, Nierenberg D | title = Two cases of acute dexmedetomidine withdrawal syndrome following prolonged infusion in the intensive care unit: Report of cases and review of the literature | journal = Human & Experimental Toxicology |date=January 2013 | volume = 32 |issue = 1 | pages = 107–110 | doi = 10.1177/0960327112454896 | pmid = 23111887 | s2cid = 31570614 }}

Clonidine has some role in the treatment of spasticity caused by spinal cord injury, acting principally by inhibiting excessive sensory transmission{{clarify span|below the level of injury.|date=March 2024}} Its use, however, is mainly as a second or third line agent, due to side effects such as hypotension, bradycardia, and drowsiness.{{cite journal | vauthors = Chang E, Ghosh N, Yanni D, Lee S, Alexandru D, Mozaffar T | title = A Review of Spasticity Treatments: Pharmacological and Interventional Approaches | journal = Critical Reviews in Physical and Rehabilitation Medicine | volume = 25 | issue = 1–2 | pages = 11–22 | date = 2013 | pmid = 25750484 | pmc = 4349402 | doi = 10.1615/CritRevPhysRehabilMed.2013007945 }} Clonidine can be administered intrathecally,{{cite journal | vauthors = Smith HS, Deer TR, Staats PS, Singh V, Sehgal N, Cordner H | title = Intrathecal drug delivery | journal = Pain Physician | volume = 11 | issue = 2 Suppl | pages = S89–S104 | date = March 2008 | doi = 10.36076/ppj.2008/11/S89 | pmid = 18443642 }} which confers various benefits, including a reduction or prevention of the blood pressure lowering effects and increased effectiveness against spasticity.{{cite journal | vauthors = Rémy-Néris O, Denys P, Bussel B | title = Intrathecal clonidine for controlling spastic hypertonia | journal = Physical Medicine and Rehabilitation Clinics of North America | volume = 12 | issue = 4 | pages = 939–51, ix | date = November 2001 | doi = 10.1016/S1047-9651(18)30040-8 | pmid = 11723871 }} The effectiveness of intrathecal clonidine is comparable to that of intrathecal baclofen for spasticity.

The reduction in circulating norepinephrine by clonidine was used in the past as an investigatory test for phaeochromocytoma, which is a catecholamine-synthesizing tumor, usually found in the adrenal medulla.{{cite journal | vauthors = Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JW, Keiser HR, Pacak K | title = Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 6 | pages = 2656–2666 | date = June 2003 | pmid = 12788870 | doi = 10.1210/jc.2002-030005 | doi-access = free }} In a clonidine suppression test, plasma catecholamine levels are measured before and 3 hours after a 0.3 mg oral test dose has been given to the patient. A positive test occurs if there is no decrease in plasma levels.

Clonidine also has several off-label uses, and has been prescribed to treat psychiatric disorders including stress, hyperarousal caused by post-traumatic stress disorder, borderline personality disorder, and other anxiety disorders.{{cite journal | vauthors = van der Kolk BA | title = The drug treatment of post-traumatic stress disorder | journal = Journal of Affective Disorders | volume = 13 | issue = 2 | pages = 203–213 | date = September–October 1987 | pmid = 2960712 | doi = 10.1016/0165-0327(87)90024-3 }}{{cite journal | vauthors = Sutherland SM, Davidson JR | title = Pharmacotherapy for post-traumatic stress disorder | journal = The Psychiatric Clinics of North America | volume = 17 | issue = 2 | pages = 409–423 | date = June 1994 | pmid = 7937367 | doi = 10.1016/S0193-953X(18)30122-9 }}{{cite journal | vauthors = Southwick SM, Bremner JD, Rasmusson A, Morgan CA, Arnsten A, Charney DS | title = Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder | journal = Biological Psychiatry | volume = 46 | issue = 9 | pages = 1192–1204 | date = November 1999 | pmid = 10560025 | doi = 10.1016/S0006-3223(99)00219-X | s2cid = 32148292 | doi-access = free }}{{cite journal | vauthors = Strawn JR, Geracioti TD | title = Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder | journal = Depression and Anxiety | volume = 25 | issue = 3 | pages = 260–271 | date = 2008 | pmid = 17354267 | doi = 10.1002/da.20292 | s2cid = 33940152 | doi-access = free }}{{cite journal | vauthors = Boehnlein JK, Kinzie JD | title = Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin | journal = Journal of Psychiatric Practice | volume = 13 | issue = 2 | pages = 72–78 | date = March 2007 | pmid = 17414682 | doi = 10.1097/01.pra.0000265763.79753.c1 | s2cid = 1607064 }}{{cite journal | vauthors = Huffman JC, Stern TA | title = Neuropsychiatric consequences of cardiovascular medications | journal = Dialogues in Clinical Neuroscience | volume = 9 | issue = 1 | pages = 29–45 | date = 2007 | pmid = 17506224 | pmc = 3181843 | doi = 10.31887/DCNS.2007.9.1/jchuffman }}{{cite journal | vauthors = Najjar F, Weller RA, Weisbrot J, Weller EB | title = Post-traumatic stress disorder and its treatment in children and adolescents | journal = Current Psychiatry Reports | volume = 10 | issue = 2 | pages = 104–108 | date = April 2008 | pmid = 18474199 | doi = 10.1007/s11920-008-0019-0 | s2cid = 23494905 }}{{cite journal | vauthors = Ziegenhorn AA, Roepke S, Schommer NC, Merkl A, Danker-Hopfe H, Perschel FH, Heuser I, Anghelescu IG, Lammers CH | title = Clonidine improves hyperarousal in borderline personality disorder with or without comorbid posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial | journal = Journal of Clinical Psychopharmacology | volume = 29 | issue = 2 | pages = 170–173 | date = April 2009 | pmid = 19512980 | doi = 10.1097/JCP.0b013e31819a4bae | s2cid = 31292297 }} Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures.{{cite journal | vauthors = Fazi L, Jantzen EC, Rose JB, Kurth CD, Watcha MF | title = A comparison of oral clonidine and oral midazolam as preanesthetic medications in the pediatric tonsillectomy patient | journal = Anesthesia and Analgesia | volume = 92 | issue = 1 | pages = 56–61 | date = January 2001 | pmid = 11133600 | doi = 10.1097/00000539-200101000-00011 | s2cid = 18885497 | doi-access = free }} It has also been studied as a way to calm acute manic episodes.{{ cite journal | vauthors = Giannini AJ, Extein I, Gold MS, Pottash AL, Castellani S | title = Clonidine in mania | journal = Drug Development Research | volume = 3 | issue = 1 | pages = 101–105 | year = 1983 | doi = 10.1002/ddr.430030112 |s2cid=85093127 }} Its epidural use for pain during heart attack, and postoperative and intractable pain has also been studied extensively.{{cite journal | vauthors = Patel SS, Dunn CJ, Bryson HM | title = Epidural clonidine: a review of its pharmacology and efficacy in the management of pain during labour and postoperative and intractable pain | journal = CNS Drugs | year = 1996 | volume = 6 | issue = 6 | pages = 474–497 | doi = 10.2165/00023210-199606060-00007 |s2cid=72544106 }} Clonidine can be used in restless legs syndrome.{{cite web |title=Treatment and Management of RLS |url=https://www.medscape.org/viewarticle/522010_6 |website=www.medscape.org |publisher=WebMD LLC |access-date=3 October 2018 |archive-date=29 September 2017 |archive-url=https://web.archive.org/web/20170929042337/http://www.medscape.org/viewarticle/522010_6 |url-status=live }} It can also be used to treat facial flushing and redness associated with rosacea.{{cite journal | vauthors = Blount BW, Pelletier AL | title = Rosacea: a common, yet commonly overlooked, condition | journal = American Family Physician | volume = 66 | issue = 3 | pages = 435–440 | date = August 2002 | pmid = 12182520 | url = http://www.aafp.org/afp/2002/0801/p435.html | access-date = 12 February 2012 | archive-date = 26 July 2011 | archive-url = https://web.archive.org/web/20110726103851/http://www.aafp.org/afp/2002/0801/p435.html | url-status = live }} It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy.{{cite journal | vauthors = Campbell CM, Kipnes MS, Stouch BC, Brady KL, Kelly M, Schmidt WK, Petersen KL, Rowbotham MC, Campbell JN | title = Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy | journal = Pain | volume = 153 | issue = 9 | pages = 1815–1823 | date = September 2012 | pmid = 22683276 | pmc = 3413770 | doi = 10.1016/j.pain.2012.04.014 }} Clonidine can also be used for migraine headaches and hot flashes associated with menopause.{{cite web | title = Clonidine Oral Uses | url = http://www.webmd.com/drugs/drug-11754-Clonidine.aspx?drugid=11754&drugname=Clonidine | publisher = WebMD | access-date = 30 May 2007 | archive-date = 25 October 2007 | archive-url = https://web.archive.org/web/20071025030547/http://www.webmd.com/drugs/drug-11754-Clonidine.aspx?drugid=11754&drugname=Clonidine | url-status = live }}{{cite web | title = Clonidine | url = https://www.drugs.com/clonidine.html | publisher = Drugs.com | access-date = 25 May 2017 | archive-date = 14 April 2017 | archive-url = https://web.archive.org/web/20170414001745/https://www.drugs.com/clonidine.html | url-status = live }} Clonidine has also been used to treat refractory diarrhea associated with irritable bowel syndrome, fecal incontinence, diabetes, diarrhea associated with opioid withdrawal, intestinal failure, neuroendocrine tumors, and cholera.{{cite journal | vauthors = Fragkos KC, Zárate-Lopez N, Frangos CC | title = What about clonidine for diarrhoea? A systematic review and meta-analysis of its effect in humans | journal = Therapeutic Advances in Gastroenterology | volume = 9 | issue = 3 | pages = 282–301 | date = May 2016 | pmid = 27134659 | pmc = 4830099 | doi = 10.1177/1756283X15625586 }} Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).{{cite journal | vauthors = Egolf A, Coffey BJ | title = Current pharmacotherapeutic approaches for the treatment of Tourette syndrome | journal = Drugs of Today | volume = 50 | issue = 2 | pages = 159–179 | date = February 2014 | pmid = 24619591 | doi = 10.1358/dot.2014.50.2.2097801 }} Clonidine has also had some success in clinical trials for helping to remove or ameliorate the symptoms of hallucinogen persisting perception disorder (HPPD).{{cite journal | vauthors = Martinotti G, Santacroce R, Pettorruso M, Montemitro C, Spano MC, Lorusso M, di Giannantonio M, Lerner AG | title = Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives | journal = Brain Sciences | volume = 8 | issue = 3 | page = 47 | date = March 2018 | pmid = 29547576 | pmc = 5870365 | doi = 10.3390/brainsci8030047 | doi-access = free }}

Injection of α₂-adrenergic receptor agonists into the knee joint space, including clonidine, may reduce the severity of knee pain after arthroscopic knee surgery.{{cite journal |vauthors=Ryan TJ, Holyoak R, Vlok R, Melhuish T, Hodge A, Binks M, Hurtado G, White L |title=Intra-articular Alpha-2 Agonists as an Adjunct to Local Anesthetic in Knee Arthroscopy: A Systematic Review and Meta-Analysis |journal=J Knee Surg |volume=32 |issue=2 |pages=138–145 |date=February 2019 |pmid=29534270 |doi=10.1055/s-0038-1636909 |s2cid=3861878 }}

Light-activated derivatives of clonidine (adrenoswitches) have been developed for research purposes and shown to control pupillary reflex with light in blind mice by topical application.{{cite journal | vauthors = Prischich D, Gomila AM, Milla-Navarro S, Sangüesa G, Diez-Alarcia R, Preda B, Matera C, Batlle M, Ramírez L, Giralt E, Hernando J, Guasch E, Meana JJ, de la Villa P, Gorostiza P | title = Adrenergic Modulation With Photochromic Ligands | journal = Angewandte Chemie | volume = 60 | issue = 7 | pages = 3625–3631 | date = February 2021 | pmid = 33103317 | doi = 10.1002/anie.202010553 | publisher = Wiley | hdl-access = free | hdl = 2434/778579 }}

It is classified by the TGA of Australia as pregnancy category B3, which means that it has shown some detrimental effects on fetal development in animal studies, although the relevance of this to human beings is unknown. Clonidine appears in high concentration in breast milk; a nursing infant's serum clonidine concentration is approximately 2/3 of the mother's.{{cite book |title=Drugs and Lactation Database (LactMed) |date=2006 |publisher=National Library of Medicine (US) |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK501628/ |access-date=5 January 2019 |chapter=Clonidine |pmid=30000689 |archive-date=5 December 2020 |archive-url=https://web.archive.org/web/20201205111454/https://www.ncbi.nlm.nih.gov/books/NBK501628/ |url-status=live }} Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.{{cite web | url = http://drugsdb.eu/drug.php?d=Clonidine&m=Physicians%20Total%20Care,%20Inc.&id=b65742b7-5db5-41cf-bf69-41700cdd2c59.xml | title = Clonidine | work = Prescription Marketed Drugs | publisher = www.drugsdb.eu | access-date = 2 August 2011 | archive-date = 28 March 2012 | archive-url = https://web.archive.org/web/20120328060203/http://drugsdb.eu/drug.php?d=Clonidine&m=Physicians%20Total%20Care,%20Inc.&id=b65742b7-5db5-41cf-bf69-41700cdd2c59.xml | url-status = dead }}

The principal adverse effects of clonidine are sedation, dry mouth, and hypotension (low blood pressure).

By frequency{{cite web|title=Catapres 150 Tablets Catapres Ampoules|work=TGA eBusiness Services|publisher=Boehringer Ingelheim Pty Limited|date=28 February 2013|access-date=27 November 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02400-3|format=PDF|archive-date=16 January 2017|archive-url=https://web.archive.org/web/20170116171140/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02400-3|url-status=live}}{{cite web|title=Clonidine 25 mcg Tablets BP - Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Sandoz Limited|date=2 August 2012|access-date=27 November 2013|url=http://www.medicines.org.uk/emc/medicine/21711/SPC/Clonidine+25mcg+Tablets+BP/|archive-date=2 December 2013|archive-url=https://web.archive.org/web/20131202235526/http://www.medicines.org.uk/emc/medicine/21711/SPC/Clonidine+25mcg+Tablets+BP/|url-status=live}}

Very common (>10% frequency):

{{div col|colwidth=18em}}

• Dizziness
• Orthostatic hypotension
• Somnolence (dose-dependent)
• Dry mouth
• Headache (dose-dependent)
• Fatigue
• Skin reactions (if given transdermally)
• Hypotension

{{div col end}}

Common (1–10% frequency):

{{div col|colwidth=18em}}

• Anxiety
• Constipation
• Sedation (dose-dependent)
• Nausea/vomiting
• Malaise
• Abnormal LFTs
• Rash
• Weight gain/loss
• Pain below the ear (from salivary gland)
• Erectile dysfunction

{{div col end}}

Uncommon (0.1–1% frequency):

{{div col|colwidth=18em}}

• Delusional perception
• Hallucination
• Nightmare
• Paresthesia
• Sinus bradycardia
• Raynaud's phenomenon
• Pruritus
• Urticaria

{{div col end}}

Rare (<0.1% frequency):

{{div col|colwidth=18em}}

• Gynaecomastia
• Impaired ability to cry
• Atrioventricular block
• Nasal dryness
• Colonic pseudo-obstruction
• Alopecia
• Hyperglycemia

{{div col end}}

Because clonidine suppresses sympathetic outflow, resulting in lower blood pressure, sudden discontinuation can result in acute hypertension due to a rebound in sympathetic outflow. In extreme cases, this can result in a hypertensive crisis, which is a medical emergency.{{cite web|title=Clonidine|work=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=13 January 2014|access-date=28 June 2014|url=http://www.medicinescomplete.com/mc/martindale/current/ms-11308-l.htm|editor=Brayfield, A|location=London, UK|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828041402/https://about.medicinescomplete.com/wp-content/plugins/revslider/public/assets/js/extensions/revolution.extension.layeranimation.min.js?version=5.4.5|url-status=live}}

Clonidine therapy should generally be gradually tapered 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 should never be used alone to treat clonidine withdrawal as alpha vasoconstriction would still continue.{{cite book | vauthors = Parker K, Brunton L, Goodman LS, Lazo JS, Gilman A | title = Goodman & Gilman's - the pharmacological basis of therapeutics |url=https://archive.org/details/goodmangilmansph00brun_116 |url-access=limited | publisher = McGraw-Hill | location = New York | year = 2006 | pages = [https://archive.org/details/goodmangilmansph00brun_116/page/n879 854]–855 | isbn = 978-0-07-142280-2 }}{{cite journal | vauthors = Vitiello B | title = Understanding the Risk of Using Medications for ADHD with Respect to Physical Growth and Cardiovascular Function | journal = Child Adolesc Psychiatr Clin N Am | volume = 17 | issue = 2 | pages= 459–474, xi | year = 2008 | pmid = 18295156 | pmc = 2408826 | doi = 10.1016/j.chc.2007.11.010 }}

Clonidine crosses the blood–brain barrier.

Clonidine treats high blood pressure by stimulating α₂ receptors in the brainstem, which decreases peripheral vascular resistance, lowering blood pressure. It has specificity towards the presynaptic α₂ receptors in the vasomotor center in the brainstem. This binding has a sympatholytic effect, suppresses release of norepinephrine, ATP, renin, and neuropeptide Y which if released would increase vascular resistance.{{rp|201–203}}

Clonidine also acts as an agonist at imidazoline-1 (I₁) receptors in the brain, and it is hypothesized that this effect may contribute to reducing blood pressure by reducing signaling in the sympathetic nervous system; this effect acts upstream of the central α₂ agonist effect of clonidine.{{rp|201–203}}{{cite journal | vauthors = Reis DJ, Piletz JE | title = The imidazoline receptor in control of blood pressure by clonidine and drugs | journal = American Journal of Physiology | year = 1997 | volume = 273 | issue = 5 | pages = R1569–R1571 | pmid = 9374795 |doi=10.1152/ajpregu.1997.273.5.R1569 }}

Clonidine may also cause bradycardia, theoretically by increasing signaling through the vagus nerve. When given intravenously, clonidine can temporarily increase blood pressure by stimulating α₁ receptors in smooth muscles in blood vessels.{{cite journal | vauthors = Giovannitti JA, Thoms SM, Crawford JJ | title = Alpha-2 adrenergic receptor agonists: a review of current clinical applications | language = en-US | journal = Anesthesia Progress | volume = 62 | issue = 1 | pages = 31–39 | date = 2015 | pmid = 25849473 | pmc = 4389556 | doi = 10.2344/0003-3006-62.1.31 }} This hypertensive effect is not usual when clonidine is given orally or by the transdermal route.{{rp|201–203}}

Plasma concentration of clonidine exceeding 2.0 ng/mL does not provide further blood pressure reduction.{{cite web | title=Catapres- clonidine hydrochloride tablet | website=DailyMed | date=6 September 2016 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7f569dc-6bed-42dc-9bec-940a9e6b090d | access-date=21 December 2019 | quote=The antihypertensive effect is reached at plasma concentrations between about 0.2 and 2.0 ng/mL in patients with normal excretory function. A further rise in the plasma levels will not enhance the antihypertensive effect. | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804180055/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7f569dc-6bed-42dc-9bec-940a9e6b090d | url-status=live }}

File:Structural comparison of norepinephrine and clonidine.svg

In the setting of attention deficit hyperactivity disorder (ADHD), clonidine's molecular mechanism of action occurs due to its agonism at the α_2A adrenergic receptor, the subtype of the adrenergic receptor that is most principally found in the brain. Within the brain, the α_2A adrenergic receptors are found within the prefrontal cortex (PFC), among other areas. The α_2A adrenergic receptors are found on the presynaptic cleft of a given neuron, and, when activated by an agonist, the effect on downstream neurons is inhibitory. The inhibition is accomplished by preventing the secretion of the neurotransmitter norepinephrine. Thus, clonidine's agonism on α_2A adrenergic receptors in the PFC inhibits the action of downstream neurons by preventing the secretion of norepinephrine.{{cite journal | vauthors = Cinnamon Bidwell L, Dew RE, Kollins SH | title = Alpha-2 adrenergic receptors and attention-deficit/hyperactivity disorder | journal = Current Psychiatry Reports | volume = 12 | issue = 5 | pages = 366–373 | date = October 2010 | pmid = 20652773 | pmc = 3676929 | doi = 10.1007/s11920-010-0136-4 }}

This mechanism is similar to the brain's physiological inhibition of PFC neurons by the locus ceruleus (LC), which secretes norepinephrine into the PFC. Although norepinephrine can also bind to target adrenergic receptors on the downstream neuron (otherwise inducing a stimulatory effect), norepinephrine also binds to α_2A adrenergic receptors (akin to clonidine's mechanism of action), inhibiting the release of norepinephrine by that neuron and inducing an inhibitory effect. Because the PFC is required for working memory and attention, it is thought that clonidine's inhibition of PFC neurons helps to eliminate irrelevant attention (and subsequent behaviors), improving the person's focus and correcting deficits in attention.

Clonidine stimulates release of GHRH hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone.{{cite journal | vauthors = Low LC | title = Growth hormone-releasing hormone: clinical studies and therapeutic aspects | journal = Neuroendocrinology | volume = 53 | issue = Suppl 1 | pages = 37–40 | year = 1991 | pmid = 1901390 | doi = 10.1159/000125793 }} This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children.{{cite web |title=Growth Hormone Test |url=https://www.cincinnatichildrens.org/health/g/growth-hormone |website=www.cincinnatichildrens.org |publisher=Cincinnati Children's Hospital Medical Center |access-date=13 October 2018 |archive-date=14 October 2018 |archive-url=https://web.archive.org/web/20181014010221/https://www.cincinnatichildrens.org/health/g/growth-hormone |url-status=live }}

After being ingested, clonidine is absorbed into the blood stream rapidly with an overall bioavailability around 70–80%.{{cite journal | vauthors = Davies DS, Wing AM, Reid JL, Neill DM, Tippett P, Dollery CT | title = Pharmacokinetics and concentration-effect relationships of intervenous and oral clonidine | journal = Clinical Pharmacology and Therapeutics | volume = 21 | issue = 5 | pages = 593–601 | date = May 1977 | pmid = 870272 | doi = 10.1002/cpt1977215593 | s2cid = 5566079 }} Peak concentrations in human plasma occur within 60–90 minutes for the "immediate release" (IR) version of the drug, which is shorter than the "extended release" (ER/XR) version.{{cite journal | vauthors = Khan ZP, Ferguson CN, Jones RM | title = alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role | journal = Anaesthesia | volume = 54 | issue = 2 | pages = 146–165 | date = February 1999 | pmid = 10215710 | doi = 10.1046/j.1365-2044.1999.00659.x | s2cid = 28405271 | doi-access = }} Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6;{{cite book |title=Foye's principles of medicinal chemistry |url=https://archive.org/details/foyesprinciplesm00lemk |url-access=limited |date=2008 |publisher=Lippincott Williams & Wilkins |location=Philadelphia |isbn=9780781768795 |page=[https://archive.org/details/foyesprinciplesm00lemk/page/n2265 403] |edition= 6th }} to compare, the optimal log P to allow a drug that is active in the human central nervous system to penetrate the blood brain barrier is 2.0.{{cite journal | vauthors = Pajouhesh H, Lenz GR | title = Medicinal chemical properties of successful central nervous system drugs | journal = NeuroRx | volume = 2 | issue = 4 | pages = 541–553 | date = October 2005 | pmid = 16489364 | pmc = 1201314 | doi = 10.1602/neurorx.2.4.541 }} Less than half of the absorbed portion of an orally administered dose will be metabolized by the liver into inactive metabolites, with roughly the other half being excreted unchanged by the kidneys. About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces. Work with liver microsomes shows in the liver clonidine is primarily metabolized by CYP2D6 (66%), CYP1A2 (10–20%), and CYP3A (0–20%) with negligible contributions from the less abundant enzymes CYP3A5, CYP1A1, and CYP3A4. 4-hydroxyclonidine, the main metabolite of clonidine, is also an α_2A agonist but is non lipophilic and is not believed to contribute to the effects of clonidine since it does not cross the blood–brain barrier.{{cite journal | vauthors = Skingle M, Hayes AG, Tyers MB | title = Antinociceptive activity of clonidine in the mouse, rat and dog | journal = Life Sciences | volume = 31 | issue = 11 | pages = 1123–1132 | date = September 1982 | pmid = 6128647 | doi = 10.1016/0024-3205(82)90086-8 }}{{cite journal | vauthors = Curtis AL, Marwah J | title = Alpha adrenoceptor modulation of the jaw-opening reflex | journal = Neuropharmacology | volume = 26 | issue = 7A | pages = 649–655 | date = July 1987 | pmid = 2819761 | doi = 10.1016/0028-3908(87)90224-3 | s2cid = 41743285 }}

Measurements of the half-life of clonidine vary widely, between 6 and 23 hours, with the half-life being greatly affected by and prolonged in the setting of poor kidney function. Variations in half-life may be partially attributable to CYP2D6 genetics. Some research has suggested the half-life of clonidine is dose dependent and approximately doubles upon chronic dosing,{{cite journal | vauthors = Frisk-Holmberg M, Paalzow L, Edlund PO | title = Clonidine kinetics in man--evidence for dose dependency and changed pharmacokinetics during chronic therapy | journal = British Journal of Clinical Pharmacology | volume = 12 | issue = 5 | pages = 653–658 | date = November 1981 | pmid = 7332729 | doi = 10.1111/j.1365-2125.1981.tb01284.x | pmc = 1401969 }} while other work contradicts this. Following a 0.3 mg oral dose, a small study of five patients by Dollery et al. (1976) found half-lives ranging between 6.3 and 23.4 hours (mean 12.7).{{cite journal | vauthors = Dollery CT, Davies DS, Draffan GH, Dargie HJ, Dean CR, Reid JL, Clare RA, Murray S | title = Clinical pharmacology and pharmacokinetics of clonidine | journal = Clinical Pharmacology and Therapeutics | volume = 19 | issue = 1 | pages = 11–17 | date = January 1976 | pmid = 1245090 | doi = 10.1002/cpt197619111 | s2cid = 39473828 }} A similar N=5 study by Davies et al. (1977) found a narrower range of half-lives, between 6.7 and 13 hours (mean 8.6), while an N=8 study by Keraäen et al. that included younger patients found a somewhat shorter mean half-life of 7.5 hours.{{cite journal | vauthors = Keränen A, Nykänen S, Taskinen J | title = Pharmacokinetics and side-effects of clonidine | journal = European Journal of Clinical Pharmacology | volume = 13 | issue = 2 | pages = 97–101 | date = May 1978 | pmid = 658114 | doi = 10.1007/BF00609752 | s2cid = 24702183 }}

Clonidine was introduced in 1966.{{cite journal | vauthors = Stähle H | title = A historical perspective: development of clonidine | journal = Best Practice & Research Clinical Anaesthesiology | date = June 2000 | volume = 14 | issue = 2 | pages = 237–246 | doi = 10.1053/bean.2000.0079 }} It was first used as a hypertension treatment under the trade name of Catapres.{{Cite web|url=https://www.drugs.com/clonidine.html|title=Clonidine: Drug Uses, Dosage & Side Effects - Drugs.com|work=Drugs.com|access-date=10 December 2017|archive-date=14 April 2017|archive-url=https://web.archive.org/web/20170414001745/https://www.drugs.com/clonidine.html|url-status=live}}

As of June 2017, clonidine is marketed under many brand names worldwide: Arkamin, Aruclonin, Atensina, Catapin, Catapres, Catapresan, Catapressan, Chianda, Chlofazoline, Chlophazolin, Clonid-Ophtal, Clonidin, Clonidina, Clonidinã, Clonidine, Clonidine hydrochloride, Clonidinhydrochlorid, Clonidini, Clonidinum, Clonigen, Clonistada, Clonnirit, Clophelinum, Dixarit, Duraclon, Edolglau, Haemiton, Hypodine, Hypolax, Iporel, Isoglaucon, Jenloga, Kapvay, Klofelino, Kochaniin, Lonid, Melzin, Menograine, Normopresan, Paracefan, Pinsanidine, Run Rui, and Winpress.{{cite web|title=Clonidine brand names|url=https://www.drugs.com/international/clonidine.html|publisher=Drugs.com|access-date=16 June 2017|archive-date=6 August 2017|archive-url=https://web.archive.org/web/20170806101340/https://www.drugs.com/international/clonidine.html|url-status=live}} It is marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso.

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