INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Clonidine is a commonly used antihypertensive agent. Other reported clinical uses include treatment of opiate and alcohol withdrawal and control of atrial fibrillation with a rapid ventricular rate. It is also used as a pediatric preanesthetic, for pediatric postoperative pain management, treatment of migraine headaches, nicotine addiction, menopausal flushing, attention deficit disorder, Tourette syndrome, and 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 it 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.

Pathophysiology

Clonidine is an imidazole derivative and was first used as a nasal decongestant. Decongestants containing tetrahydrozoline, also an imidazole derivative, can result in signs and symptoms of 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 for 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 metabolized by the liver.

Mortality/Morbidity

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

While elucidating the amount and timing of the clonidine ingestion is helpful, in practice, signs and symptoms guide therapy. Always suspect other co-ingestants and screen appropriately.

• Children are particularly susceptible to toxic reaction from small doses (ie, normal adult therapeutic doses) of clonidine.
• The Catapres TTS patch appears similar to a small Band-Aid or sticker, and a child could pull the patch off a sleeping caretaker.
• • Several case reports document patches detaching spontaneously from a sleeping parent in a bed shared with a child and subsequently adhering to the child with resultant toxicity.
  • In cases of possible clonidine toxicity involving children, always question family, friends, and emergency medical services (EMS) as to whether a child may have had access to clonidine.
• Irritability

Physical

Symptoms develop rapidly (usually within 30-60 min) postingestion and may resemble a narcotic overdose with miosis, bradycardia, respiratory depression, and coma. From a differential standpoint, comatose-appearing children with clonidine toxicity may awaken and be intermittently lucid when subjected to vigorous stimuli (eg, physical, verbal), whereas patients with narcotic overdoses subjected to the same stimuli may awaken but are obtunded. Symptoms tend to be relatively more severe in pediatric patients. Toxic presentations also may include hypotension, hypertension, mydriasis, hypothermia, ileus, hypotonia, hyporeflexia, intermittent apnea, atrioventricular (AV) nodal heart block, and seizures.

• With significant ingestions, patients usually present with bradycardia.
• Associated hypotension may be severe and last up to 24 hours.
• Hypertension is less common and usually more transient.
• Hypothermia has been reported but is usually mild.
• Patients may present with CNS depression, which may range from mild drowsiness (common) to coma.
• Baseline mental status usually returns within 24-48 hours of ingestion.
• Hyporeflexia may develop.
• Seizures may occur.
• Dysrhythmias may occur and include AV nodal block, Wenckebach, and tachycardia.
• Pulmonary
• • Respiratory depression is common, especially in children, and may require endotracheal intubation.
  • Respiratory failure usually occurs within 1-2 hours of ingestion.
  • Ataxic breathing may be observed.
  • Patient may experience periods of apnea.
• Pallor and cool extremities have been reported.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Clonidine levels have not been shown to correlate with toxicity and should not be routinely drawn.
• Measure electrolyte and glucose levels to screen for anion gap acidosis or hypoglycemia.
• Toxicology screen may be useful if patient is not responding to standard measures, has significant symptoms and a co-ingestion is suspected, is comatose, or a specific drug level is desired.
• Test for pregnancy in women of childbearing age.

Imaging Studies

• Cranial CT scan (noncontrast): Obtain cranial CT scan if hemorrhagic bleeding, stroke, or head trauma is suspected.
• Consider an emergent MRI if concern exists over a brainstem infarct or a change in management may result.

Other Tests

• Perform a 12-lead electrocardiogram (ECG) in addition to continuous cardiac monitoring.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

• Provide aggressive supportive care because patients may rapidly decompensate. Address airway, breathing, and circulation (ABCs) as usual.
• Intravenous access with crystalloid and pressor support with dopamine may be necessary.
• Initiate standard naloxone therapy and blood glucose checks.
• Continuous ECG monitoring should carry over to the ED.
• Prehospital ipecac syrup administration is contraindicated.

Emergency Department Care

Focus initial treatment on ABCs. Clonidine toxicity can cause serious respiratory depression and apnea requiring immediate endotracheal intubation and mechanical ventilation. Once the airway is secure, place the patient on continuous ECG, blood pressure, and oxygen saturation monitoring. Place at least one large-bore IV line. Consider central venous pressure (CVP) monitoring in patients who are markedly hypotensive.

• Clonidine toxicity can cause serious respiratory depression and apnea requiring immediate endotracheal intubation and mechanical ventilation.
• Hypotension is very common with clonidine toxicity; initially treat patient with aggressive crystalloid infusion. If aggressive volume resuscitation fails to raise blood pressure, consider pressors such as dopamine and epinephrine. Maintain good urine output because clonidine is excreted at least 50% unchanged in the urine.
• Bradycardia, either sinoatrial (SA) nodal or AV nodal, has been reported with clonidine toxicity.
• • Atropine is the first-rate drug of choice. Consider dopamine if atropine fails with SA nodal, first-degree, or Mobitz I AV nodal block; however, in Mobitz II and third-degree AV nodal block, atropine is only temporizing until definitive pacing is initiated.
  • Transcutaneous pacing is quicker to initiate, yet it causes patient more discomfort than transvenous pacing. Consider transvenous pacing in patients with massive ingestions who have third-degree AV nodal block.
• Hypertension may occur initially from peripheral alpha1-agonist activity and vasoconstriction. This hypertension is usually transient and does not require treatment; however, in patients with sustained diastolic pressures above 130 mm Hg, consider a short acting, easily titratable intravenous agent such as sodium nitroprusside.
• Administer activated charcoal by mouth or nasogastric tube for clonidine toxicity in a 1-g/kg dose (standard for toxic ingestions). If significant CNS depression exists, intubate before administering activated charcoal to prevent aspiration. Lavage is controversial; yet consider if ingestion is significant and occurred less than an hour before arrival.
• Naloxone (Narcan) may treat clonidine toxicity. It improves the mental status of adults and children who have ingested toxic amounts of clonidine; this, however, has not been universal and naloxone can cause hypotensive and hypertensive responses. Narcan also has been reported to cause severe hypertension.
• American Academy of Pediatrics recommends a dose of 0.1 mg/kg for infants and children up to age 5 years or weighing 20 kg. Children older than 5 years or weighing more than 20 kg may be given 2 mg of Narcan. Adults may be given 2 mg doses of Narcan, titrated to effect.
• Provide symptomatic and supportive care, the main therapy for clonidine toxicity. Passively warm patients with hypothermia. Most comas resolve with supportive measures.
• Two case reports document yohimbine reversal of clonidine toxic states. Yohimbine is a central alpha2-adrenergic antagonist with effects that directly oppose clonidine, making it theoretically a useful antidotal agent. The dosage has been a single 5.4 mg tablet administered orally or via nasogastric tube; a parenteral form is not clinically available.

Consultations

Unless the treating physician has extensive experience with acute poisonings or if significant toxicity manifests, contacting a poison control center for advice and feedback is reasonable. A formal toxicology team may provide valuable input.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In general, treat with supportive care. Administer activated charcoal to all patients at risk for aspiration after intubation. Temporary support for symptomatic cardiovascular effects of clonidine also may be necessary.

Drug Category: Cardiovascular agents

Used to elevate blood pressure and heart rate in patients who already have been adequately volume resuscitated and remain in shock.

Drug Name	Atropine (Atropair)
Description	Vagolytic for patients with bradycardia (eg, SA or AV nodal block). Doses <0.5 mg can produce a paradoxical reaction.
Adult Dose	Hypotension: 0.5-1 mg IV repeated q5min until desired response Cardiac arrest: 1 mg IV repeated q3-5min; minimal dose is 0.5 mg IV; not to exceed 0.04 mg/kg or 3 mg IV
Pediatric Dose	Hypotension: 0.02 mg/kg IV; minimum dose is 0.1 mg IV Cardiac arrest: Not to exceed 0.5 mg in children and 1 mg IV in adolescents; may repeat above dose once, not to exceed 1 mg in children and 2 mg in adolescents
Contraindications	Documented hypersensitivity; thyrotoxicosis; narrow-angle glaucoma; tachycardia
Interactions	Coadministration with other anticholinergics have additive effects; pharmacologic effects of atenolol and digoxin may increase; antipsychotic effects of phenothiazines may decrease; tricyclic antidepressants with anticholinergic activity may increase effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid in Down syndrome and/or children with brain damage to prevent hyperreactive response; avoid in coronary heart disease, congestive heart failure, cardiac arrhythmias, and hypertension; caution in peritonitis, ulcerative colitis, hepatic disease, and hiatal hernia with reflux esophagitis; in prostatic hypertrophy, prostatism can have dysuria and may require catheterization

Drug Category: Antagonist

May improve level of consciousness.

Drug Category: GI decontaminant

Empirically used to minimize systemic absorption of the toxin. Most effective if administered within 4 h of ingestion.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit significantly symptomatic patients with clonidine toxicity to the intensive care unit (ICU).
• A ward admission on a monitor is probably reasonable for minimal symptoms if the patient has been observed for several hours with improvement or without worsening. Remember that patients demonstrating clonidine toxicity, secondary to transdermal exposure, may experience a prolonged period of symptoms from a prolonged half-life secondary to a "depot" effect in the subdermal tissues.

Further Outpatient Care

• Patients with suspected clonidine ingestion may be discharged if they remain asymptomatic for 4-6 hours and have normal vital signs.
• Obtain a psychiatric evaluation before discharge for patients with suspected intentional ingestion.

Transfer

• Transfer patients with clonidine toxicity if the potential benefits outweigh the risks.

Prognosis

• Prognosis is generally good for patients who present early and have had prompt and proper treatment.

Patient Education

• Children may be easily affected by relatively small doses of clonidine. Educating patients about the importance of keeping clonidine and all drugs out of children's reach is critical.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider the possibility of child abuse when children present with clonidine toxicity
• Failure to closely monitor patients, especially elderly patients, after administering naloxone
• Failure to avoid administering ipecac syrup for gastric decontamination (because of its increased risk for causing aspiration)
• Failure to treat the severe early hypertensive phase of clonidine toxicity
• Failure to consider clonidine toxicity when a patient presents with a narcotic toxidrome
• Failure to protect the compromised airway before administering activated charcoal

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• American Academy of Pediatrics. American Academy of Pediatrics Committee on Drugs: Naloxone dosage and route of administration for infants and children: addendum to emergency drug doses for infants and children. Pediatrics. Sep 1990;86(3):484-5. [Medline].
• Anderson RJ, Hart GR, Crumpler CP, et al. Clonidine overdose: report of six cases and review of the literature. Ann Emerg Med. Feb 1981;10(2):107-12. [Medline].
• Domino LE, Domino SE, Stockstill MS. Relationship between plasma concentrations of clonidine and mean arterial pressure during an accidental clonidine overdose. Br J Clin Pharmacol. Jan 1986;21(1):71-4. [Medline].
• Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Crit Care Med. Oct 1990;18(10):1124-8. [Medline].
• Glassman AH, Stetner F, Walsh BT, et al. Heavy smokers, smoking cessation, and clonidine. Results of a double- blind, randomized trial. JAMA. May 20 1988;259(19):2863-6. [Medline].
• Gold MS, Pottash AC, Sweeney DR, et al. Opiate withdrawal using clonidine. A safe, effective, and rapid nonopiate treatment. JAMA. Jan 25 1980;243(4):343-6. [Medline].
• Gulec S, Aydin Y, Uzuner K. Effects of clonidine pre-treatment on bupivacaine and ropivacaine cardiotoxicity in rats. Eur J Anaesthesiol. Mar 2004;21(3):205-9. [Medline].
• Killian CA, Roberge RJ, Krenzelok EP, et al. "Cloniderm" toxicity: another manifestation of clonidine overdose. Pediatr Emerg Care. Oct 1997;13(5):340-1. [Medline].
• Litovitz TL, Bailey KM, Schmitz BF, et al. 1990 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. Sep 1991;9(5):461-509. [Medline].
• Lowenthal DT, Matzek KM, MacGregor TR. Clinical pharmacokinetics of clonidine. Clin Pharmacokinet. May 1988;14(5):287-310. [Medline].
• Mikawa K, Maekawa N, Nishina K, et al. Efficacy of oral clonidine premedication in children. Anesthesiology. Nov 1993;79(5):926-31. [Medline].
• Moiseev VM, Edel'' IuP. Development of forensic medical expertise in Kharkov during the years of Soviet rule. Sud Med Ekspert. Jan-Mar 1989;32(1):54-5. [Medline].
• Nichols MH, King WD, James LP. Clonidine poisoning in Jefferson County, Alabama. Ann Emerg Med. Apr 1997;29(4):511-7. [Medline].
• Prisant LM, Elliott WJ. Drug delivery systems for treatment of systemic hypertension. Clin Pharmacokinet. 2003;42(11):931-40. [Medline].
• Roberge RJ, McGuire SP, Krenzelok EP. Yohimbine as an antidote for clonidine overdose. Am J Emerg Med. Nov 1996;14(7):678-80. [Medline].
• Roberge RJ, Kimball ET, Rossi J, et al. Clonidine and sleep apnea syndrome interaction: antagonism with yohimbine. J Emerg Med. Sep-Oct 1998;16(5):727-30. [Medline].
• Roberge RJ, Krenzelok EP, Mrvos R. Transdermal drug delivery system exposure outcomes. J Emerg Med. Feb 2000;18(2):147-51. [Medline].
• Roth A, Kaluski E, Felner S, et al. Clonidine for patients with rapid atrial fibrillation. Ann Intern Med. Mar 1 1992;116(5):388-90. [Medline].
• Sanklecha M, Jog A, Raghavan K. Clonidine casualty. Indian J Pediatr. Jul-Aug 1993;60(4):611-2. [Medline].
• Spies CD, Dubisz N, Neumann T, et al. Therapy of alcohol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial. Crit Care Med. Mar 1996;24(3):414-22. [Medline].
• Stieger DS, Cantieni R, Frutiger A. Acute colonic pseudoobstruction (Ogilvie''s syndrome) in two patients receiving high dose clonidine for delirium tremens. Intensive Care Med. Jul 1997;23(7):780-2. [Medline].
• Wasserberger J, Ordog GJ. Naloxone-induced hypertension in patients on clonidine. Ann Emerg Med. May 1988;17(5):557. [Medline].
• Williams PL, Krafcik JM, Potter BB, et al. Cardiac toxicity of clonidine. Chest. Dec 1977;72(6):784-5. [Medline].

Article Last Updated: Jan 8, 2007