Clonidine Toxicity
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Clonidine is a central alpha-agonist that is used as an antihypertensive agent. Other reported clinical uses include treatment of opiate and alcohol withdrawal [1] and control of atrial fibrillation with a rapid ventricular rate. It is also used for the following:
Pediatric preanesthesia
Pediatric postoperative pain
Migraine headaches
Nicotine addiction
Menopausal flushing
Attention deficit disorder [2]
Tourette syndrome [3]
Pediatric panic and anxiety disorders
At therapeutic doses (0.2-0.9 mg/d), clonidine is commonly associated with adverse effects such as dry mouth, sedation, dizziness, and constipation. While generally safe, at toxic doses clonidine can cause serious cardiopulmonary instability and central nervous system (CNS) depression in children and adults.
Clonidine is available in a weekly transdermal patch (Catapres TTS: 0.1 mg, 0.2 mg, or 0.3 mg/d, with each patch containing 2.5 mg, 5 mg, and 7.5 mg of clonidine, respectively) and in tablet form (Catapres: 0.1 mg, 0.2 mg, and 0.3 mg; Combipres includes 15 mg of chlorthalidone diuretic). An ophthalmic solution is occasionally used in the treatment of glaucoma.
Clonidine is an imidazole derivative and was first used as a nasal decongestant. Decongestants containing tetrahydrozoline, also an imidazole derivative, can result in the same signs and symptoms as clonidine poisoning when ingested, especially in children.
Clonidine acts primarily as a presynaptic CNS alpha2-agonist, stimulating receptors in the nucleus tractus solitarii of the medulla oblongata. This inhibits sympathetic outflow, which results primarily in a reduction of sympathetically mediated vasoconstriction, cardiac inotropy, and chronotropy.
Clonidine also has peripheral alpha1-agonist activity, which may produce transient vasoconstriction and hypertension early in overdose when peripheral drug levels may be transiently higher than levels in the CNS.
Clonidine is rapidly absorbed from the gastrointestinal tract and has excellent CNS penetration because of lipid solubility. Peak plasma concentrations are reached 3-5 hours after a single oral dose. Dermal application may take several days to reach steady state levels. No known pharmacologically active metabolites exist. Plasma half-life is 12-16 hours, with the antihypertensive effects occurring within 30-60 minutes of ingestion. Clonidine is excreted unchanged in the urine and is metabolized by the liver.
United States
In the 2016 Annual Report of the American Association of Poison Control Centers’ National Poison Data System, 5351 single exposures to clonidine were reported. Of those, 3504 were unintentional toxicities and 106 were reported as an adverse reaction. [4]
Mortality is rare with a small number of reported deaths. Morbidity, in terms of cardiorespiratory and CNS dysfunction, generally tends to be more severe in young persons than in adults.
Of the 5351 reported toxic exposures to clonidine in 2016, 3858 were treated in a health care facility. Of this subset of patients, 972 had no significant outcome, 1192 had minor effects, 1748 had moderate morbidity, and 139 had major morbidity. No deaths were reported. [4]
Of the 5351 reported toxic exposures to clonidine in 2016, 1760 were in patients younger than 6 years, 2106 were in patients 6-19 years old, and 1315 were in patients 20 years of age and older. [4]
Gowing L, Farrell M, Ali R, White JM. Alpha₂-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2016 May 3. CD002024. [Medline].
Albertson TE, Chenoweth JA, Colby DK, Sutter ME. The Changing Drug Culture: Use and Misuse of Cognition-Enhancing Drugs. FP Essent. 2016 Feb. 441:25-9. [Medline].
Hollis C, Pennant M, Cuenca J, Glazebrook C, Kendall T, Whittington C, et al. Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis. Health Technol Assess. 2016 Jan. 20 (4):1-450, vii-viii. [Medline].
Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila). 2017 Dec. 55 (10):1072-1252. [Medline]. [Full Text].
Perruchoud C, Bovy M, Durrer A, Rosato M, Rutschmann B, Mustaki JP, et al. Severe hypertension following accidental clonidine overdose during the refilling of an implanted intrathecal drug delivery system. Neuromodulation. 2012 Jan-Feb. 15(1):31-4; discussion 34. [Medline].
Isbister GK, Heppell SP, Page CB, Ryan NM. Adult clonidine overdose: prolonged bradycardia and central nervous system depression, but not severe toxicity. Clin Toxicol (Phila). 2017 Mar. 55 (3):187-192. [Medline].
Ahmad SA, Scolnik D, Snehal V, Glatstein M. Use of naloxone for clonidine intoxication in the pediatric age group: case report and review of the literature. Am J Ther. 2015 Jan-Feb. 22 (1):e14-6. [Medline].
Wasserberger J, Ordog GJ. Naloxone-induced hypertension in patients on clonidine. Ann Emerg Med. 1988 May. 17 (5):557. [Medline].
Hegenbarth MA, American Academy of Pediatrics Committee on Drugs. Preparing for pediatric emergencies: drugs to consider. Pediatrics. 2008 Feb. 121(2):433-43. [Medline].
Roberge RJ, McGuire SP, Krenzelok EP. Yohimbine as an antidote for clonidine overdose. Am J Emerg Med. 1996 Nov. 14 (7):678-80. [Medline].
Malaty J, Malaty IA. Hypertensive urgency: an important aetiology of rebound hypertension. BMJ Case Rep. 2014 Oct 21. 2014:[Medline].
David Riley, MD, MSc, RDMS, RDCS, RVT, RMSK Assistant Clinical Professor of Medicine, Director of Emergency Ultrasonography and Ultrasound Research, Attending Physician, Department of Emergency Medicine, Columbia University Medical Center, New York Presbyterian Hospital
David Riley, MD, MSc, RDMS, RDCS, RVT, RMSK is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Institute of Ultrasound in Medicine, American Society of Echocardiography, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph’s Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.
John G Benitez, MD, MPH Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Undersea and Hyperbaric Medical Society, Wilderness Medical Society, American College of Occupational and Environmental Medicine
Disclosure: Nothing to disclose.
Michael A Miller, MD Clinical Professor of Emergency Medicine, Medical Toxicologist, Department of Emergency Medicine, Texas A&M Health Sciences Center; CHRISTUS Spohn Emergency Medicine Residency Program
Michael A Miller, MD is a member of the following medical societies: American College of Medical Toxicology
Disclosure: Nothing to disclose.
Edward A Michelson, MD Associate Professor, Program Director, Department of Emergency Medicine, University Hospital Health Systems of Cleveland
Edward A Michelson, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Clonidine Toxicity
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