Clonidine and Related Imidazoline Derivatives

Case Scenario

A mother of a 5-year-old boy is called at 8:30 AM by school officials, saying her child is notably lethargic and that she needs to come and get him. Upon arrival at the Emergency Department, the child was lethargic but responsive with a heart rate of 80 bpm, BP of 90/50 mmHg, temp 98O, respirations of 20/min and O2 sat 96%. Pupils were 2mm and reactive. Upon questioning it was learned that the child's medications are clonidine 0.05mg qH.S. for ADHD. The medication was available as 0.1mg tablets broken in half. The mother is asked to return to the home and finds an open pill bottle in the child's room with pills strewn about and 8 half-tablets missing (0.4mg).
In the ED, the child remained obtunded and refused to drink the activated charcoal. Two administrations of naloxone failed to show any improvement in mental status. The child remained obtunded, limp and pale. He is admitted with a HR of 84 bpm, BP 74/72 mmHg and resp 20/min. Administration of intravenous bolus of normal saline results in a rise in systolic pressure to the mid 90's. Over the next 16 hours the child remains obtunded but arousable to stimuli and limp. He was discharged the following morning without sequelae.

Introduction

Poisoning is considered to be the third most common cause of accidental death in the home. An estimated 8 billion dollars are spent annually in the U.S. to treat the effects of human toxic exposures. Approximately 8 million intentional and unintentional poisonings occur each year. The average cost for a fatal poisoning is estimated at $372,691; the cost per patient admission is $17,631. ¹²

Pharmaceutical poisonings accounted for greater than half of all poisonings (~57%) reported to poison centers in 2004, an increase of about 10% from 1997.^11,22 Various reasons could have contributed to this increase, including an overall rise in poison center calls received due to public education advocating poison center usage. Nonetheless, it is important for poison centers to continually educate staff and healthcare professionals regarding commonly ingested pharmaceutical products to ensure that the most appropriate monitoring and treatment is provided following a poisoning.

This review will focus on a group of drugs with alpha agonist activity derived from the imidazoline chemical structure and the issues surrounding these medications in poisoning.

Alpha agonists are agents that stimulate alpha-adrenergic receptors located within the sympathetic portion of the autonomic nervous system. However, imidazolines differ markedly from most sympathomimetics in their central inhibition of sympathetic outflow. Their effects as central (pre-synaptic) alpha agonists are exerted on the alpha-2 receptors, thus exhibiting sympatholytic effects. The organs that can be affected by alpha agonist activity include the eyes, blood vessels, liver, smooth muscle of the gastrointestinal and genitourinary tracts, and the skin. The adverse effects of adrenoreceptor agonists are primarily extensions of their receptor effects in the cardiovascular and central nervous systems.

This review will discuss both the prescription and over-the-counter medications capable of central alpha agonist activity. Two prescription medications capable of central alpha stimulation are clonidine and tizanidine. This review will also include over-the-counter imidazoline-derived products with similar activity. Exposure to over-the-counter nose drops and eye drops containing imidazolines is frequent but those exposures tend to be less eventful.¹⁰ Malicious administration of these products has been reported.

Clonidine

Clonidine was initially developed as a topical nasal decongestant in 1962. Subsequently, it was found to have significant sympatholytic effects and was marketed as an anti-hypertensive. Clonidine is approved by the US Food and Drug Administration for essential hypertension and cancer pain, but has been used successfully in a variety of other conditions. Alternative uses in adults include detoxification of opiate dependence, alcohol withdrawal, alleviation of postmenopausal hot flashes and epidural anesthesia for cesarean section.^2,6 Off-label uses in children include the management of attention-deficit/hyperactivity disorder (ADHD) and Tourette syndrome. Clonidine exposure is responsible for more than 5000 poisonings per year and is notable for serious signs and symptoms following exposure.^22,23 Children are especially susceptible to the toxic effects of clonidine; as little as one 0.1-mg tablet has the potential to cause significant signs and symptoms.¹ Clonidine is being prescribed with increasing frequency for the treatment of ADHD in children. This medication is not available as a suspension; therefore, prescriptions for young children must be compounded. In a drug with a narrow therapeutic index, this process introduces an added opportunity for a medication error to occur.

Clonidine is available as an oral tablet (Catapres), a transdermal system (Catapress-TTS), and as a solution for injection (Duraclon).

Clonidine use in pain control is secondary to reduced norepinephrine release. Clonidine use potentiates opiate analgesia in poorly responding patients and is beneficial for neuropathic or sympathetically maintained pain.

Tizanidine

Tizanidine was approved in 1996 by the U.S. Food and Drug Administration for adults with spasticity. This medication is available as 2 mg and 4 mg oral tablets (Zanaflex). Capsules are available in 2, 4, and 6 mg strengths. Despite its structural and biochemical similarity to clonidine, the cardiovascular properties of tizanidine at therapeutic doses are mild and transitory in relation to its activity as a muscle relaxant.⁴ Whereas clonidine shows equal affinity to both alpha-2 and imidazoline receptors, tizanidine binds with 20 times higher affinity to the imidazoline receptors than to the alpha-2 adrenoreceptors.^13,14 Spiller, et al, found that tizanidine overdose patients present similar to clonidine in overdose with alterations in mental status, bradycardia, and hypotension.¹⁸

Over the Counter Centeral Alpha Agonists

Oxymetazoline, tetrahydrozoline, naphazoline, and xylometazoline are also imidazoline derivatives available in a number of over-the-counter nasal sprays and eye drops. (See table 1) These agents are intended to be applied topically to the nasal or ocular membranes for the treatment of symptoms associated with allergic rhinitis, sinusitis or the common cold. When applied topically these chemicals cause peripheral alpha receptor stimulation responsible for their vasoconstrictive and decongestive actions. On the other hand, when improperly ingested they can have a stimulatory effect on the centrally located alpha-adrenergic receptors similar to those of their prescription counterparts (clonidine and tizanaidine).

Table 1

Examples of the common OTC imidazoline-derived products

Clinical Effects

In overdose, the sympatholytic effects of imidazolines predominate. Stimulation of the alpha-2 and imidazole receptors decreases production of cyclic AMP and therefore a decrease in neuron activity. Decreased norepinephrine release in the central nervous system is responsible for the clinical effects reported in overdose.

The end organs most commonly affected are the brain and the heart. Neurologic effects may include miosis, hypotonia, lethargy and coma with associated respiratory depression and apnea. ^20,23 Cardiac consequences include bradycardia and hypotension .The hypotensive effect of the imidazolines is exerted at alpha-2 adrenoceptors in the medulla (brain stem). Reduced sympathetic outflow causes reduced vascular resistance from vasodilation and increased vagal tone with subsequent bardycardia. In children, however, a paradoxical hypertension has been reported, which is assumed to secondary to stimulation of peripheral (vascular) alpha receptors causing vasoconstriction. Other notable clinical effects in overdose include pallor and hypothermia.

Signs of toxicity often appear within 1 hour of ingestion with peak onset in less than 4 hours. An observation period of 4 to 6 hours is considered appropriate for disposition decisions. Close observation of patients is suggested because of the potential for rapid decompensation. Normally, the duration of clinical effects in symptomatic patients following ingestion is less than 24 hours.

Imidazolines are not found on comprehensive toxicology screening evaluations and no specific laboratory findings exist. In general, patients will have signs similar to opiate intoxication, with a concomitant bradycardia and/or hypotension. They may improve after naloxone administration but have no identifiable opiate ingestion.

Death after clonidine overdose is rare, with only a single death reported in one study of more than 10,000 overdoses.⁸

Reasons for exposures may be: unintentional overdose in children, therapeutic error, compounding error, intentional abuse, suicide attempt or malicious use (munchausen's syndrome by proxy, chemical submission for sexual assault).

For cases of suspected malicious use, a history of deep sedation or coma in a particular victim's situation may be cause to look at this possibility more closely. Bradycardia and hypotension would be expected with possible respiratory depression if the victim presented in time to gather clinical evidence.

Treatment in Overdose

The treatment of imidazoline toxicity consists mainly of gastrointestinal decontamination, supportive care, and observation. Massive overdoses from 1000-fold dosing errors have had successful outcomes utilizing routine supportive measures. ¹⁶

Hemodynamic compromise in these poisonings may occur and usually manifests as bradycardia and hypotension. Cardiorespiratory resuscitation remains the mainstay of supportive care. Therefore, medical staff should be prepared for measures including tracheal intubation and mechanical ventilation when poisoned patients present with apneic episodes or hypoventilation.

Hypotension can normally be managed with rapid intravascular volume expansion with normal saline or lactated Ringer's. Positive chronotropic drugs such as atropine are effective treatments for symptomatic bradycardia associated with episodes of hypotension. Dopamine, a vasopressor, is sometimes instituted according to ACLS guidelines.

Activated charcoal may be an effective binding agent for the imidazolines when orally administered shortly after ingestion. However, in cases where eye or nose drops are ingested, some authors contend that these agents are absorbed so quickly that GI decontamination is of little value.

Hypothermia is somewhat uncommon in these patients, but monitoring is necessary. The decreased sympathetic outflow may limit the appropriate thermoregulatory mechanisms needed to compensate for a decrease in core body temperature. The patient may require a warming blanket to maintain normal body temperature.

Toxicity from the central alpha-2 receptor agonists may present with features similar to opiod toxicity. Although interaction of these drugs with opiod receptors is unclear, naloxone has been reported to be effective in some cases. However it is not universally effective; supportive measures take precedence. In a retrospective review of tizanidine overdose naloxone therapy was associated with arousal in only one in seven cases. ¹⁸ The efficacy of naloxone in OTC imidazoline product overdose is not known.

Conclusion

With routine supportive measures the majority of imidazoline ingestions have favorable outcomes. Symptoms typically resolve within within 24 hours without lasting sequelae. The trend toward increasing numbers of exposures in children, especially with evidence of toxic effects in children receiving clonidine therapeutically, is cause for concern. Furthermore, pharmaceutical exposures in children will remain a problem in any class of medication and reason for us all to look at them more closely.

References

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3. Clinical Pharmacology Matters. Clonidine and tizanidine drug monographs. Accessed 3/2/2006. www.clinicalpharmacology.com
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8. Klein-Schwartz W. Trends and toxic effects from pediatric clonidine exposures. Arch Pediatr Adolesc Med 2002; 156:392-396.
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11. Litovitz TL, Klein-Schwartz W, Dyer KS, et al. 1997 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1998; 16:443-497.
12. Litovitz T, Manoguerra A. Comparison of pediatric poisoning hazards: an analysis of 3.8 million exposure incidents. Pediatrics 1992; 89:999-1006.
13. Luciani A, Brugioni L, Serra L, Graziina A. Sino-atrial and atrio-ventricular node dysfunction in a case of tizanidine overdose. Vet Hum Toxicol 1995; 37:556-557.
14. Muramatsu I, Kigoshi S. Tizanidine may discriminate between imidazoline receptors and alpha 2-adrenoceptors. Japanese Journal of Pharmacology 1992; 59:457-459.
15. Osterhoudt KC, Henretig FM. Letter to the Editor: Sinoatrial node arrest following tetrahydrozoline ingestion. Am J Emerg Med 2004; 27:313-315.
16. Romano MJ, Dinh A. A 1000-Fold overdose of clonidine caused by a compounding error in a 5-year-old with Attention-Deficit/Hyperactivity Disorder. Pediatrics 2001; 108:471-473.
17. Snopes, Rumor Has It. Urban Legends Reference Pages. Accessed 2/27/2006. http://www.snopes.com/medical/myths/visine.asp
18. Spiller HA, Bosse GM, Adamson LA. Retrospective review of tizanidine (Zanaflex®) overdose. Journal of Toxicology 2004; 42:593-596.
19. Spiller HA, Klein-Schwartz W, Colvin JM. Toxic clonidine ingestion in children. J Pediatr 2005; 146:263-266.
20. Stein B, Volans GN. Dixarit overdose: The problem of attractive tablets. BMJ 1978; 2:667-668.
21. Tobias JD. Central nervous system depression following accidental ingestion of Visine Eye Drops. Clin Pediatr 1996; 35:539-540.
22. Watson WA, Litovitz TL, Rodgers GC Jr., Klein-Schwartz W, et al. 2004 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2005; 23:589-666.
23. Wiley JF II, Wiley CC, Torrey SB, Henretig FM. Clonidine poisoning in young children. J Pediatr 1990; 116:654-658.

AUTHOR INFORMATION

Written by: Camille Shouse-Coke, Pharm.D, 2/2006

Reviewed by:
George M. Bosse, M.D. 5/2006
Henry A. Spiller M.S., D.ABAT 5/2006

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