Selected topics: toxicology
Are one or two dangerous? Clonidine and topical imidazolines exposure in toddlers

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Abstract

Clonidine and the imidazolines, commonly found in topical ophthalmic and nasal decongestants, are chemically related drugs that have been responsible for many pediatric poisonings. These medications can cause significant morbidity in small doses. A review of the available literature reveals that young children have exhibited severe signs and symptoms after ingesting as little as one to two clonidine tablets or 2.5 ml of a topical imidazoline product. Central nervous system depression, respiratory depression, and cardiovascular instability are the most common features of poisoning. Signs and symptoms develop rapidly, within 4–6 h. Care is supportive. Death is rare, but many poisoned patients require monitoring in an intensive care setting.

Introduction

Clonidine is an imidazoline derivative initially developed in the 1960s as a nasal decongestant. During clinical testing, clonidine caused hypotension and bradycardia, which led to its use as an antihypertensive agent (1). The therapeutic applications of clonidine more recently have expanded to narcotic and alcohol withdrawal, tobacco cessation and peri-menopausal hot flashes 2, 3, 4, 5. Clonidine also has been used in children for behavioral problems such as attention-deficit hyperactivity disorder (ADHD) and Tourette's syndrome (6).

Clonidine poisoning in young children is a significant problem in the United States. The American Association of Poison Control Centers Toxic Exposure Surveillance System (AAPCC TESS) documented 1438 clonidine exposures in children less than 6 years of age in 2001 (7). The number of clonidine poisonings appears to be increasing in frequency. Klein-Schwartz reports a 2-fold increase in the number of clonidine exposures reported to Poison Control Centers over the period from 1993 to 1999 (8).

Expanded therapeutic applications of clonidine among children (e.g., ADHD) may have changed the epidemiology of pediatric clonidine poisoning. In 1990, Bamshad described a series of pediatric clonidine intoxications in which the medication belonged to a grandparent in 13 of 15 cases (9). In contrast, eight years later in 1998, Kappagoda et al. found that only 2 of 16 exposures involved medication belonging to an older relative, whereas the remaining 14 cases involved medications prescribed for children (10). In the largest series to date, Klein-Schwartz reviewed 10,600 pediatric clonidine exposure cases occurring between 1993 and 1999. In that period, the proportion of poisoning cases due to a child's own medication rose from 2.6% to 13.1% for children under 6 years old (8).

Clonidine is available in the United States in tablets in 0.1 mg, 0.2 mg, and 0.3 mg strengths and in a transdermal patch (Catapress TTS®). The clonidine patch is applied to the skin and changed every 7 days. The patches contain either 2.5, 5, or 7.5 mg of clonidine and are designed to release 0.1, 0.2, or 0.3 mg of clonidine per day (11).

The topical imidazolines are found in many over-the-counter topical eye and nose decongestants. They can produce toxic effects similar to clonidine. Products with imidazoline components are numerous and include: Visine® (tetrahydrozoline), Naphcon® (naphazoline), Afrin Nasal Spray/Pump® (oxymetazoline), and Otrivin Pediatric Nasal® (xylometazoline).

As reported in the AAPCC TESS data, there were 891 children under 6 years old with exposures to ophthalmic tetrahydrozoline in 2001 (7). The number of cases may be so high because these products are accessible to children. Many of these products are available without prescription and most are not packaged with childproof safety caps (12). Furthermore, parents and caregivers may not perceive the potential harm of these products and may not store them safely.

Section snippets

Pathophysiology

The exact mechanism behind the hypotensive effect of clonidine is not completely understood. In fact, clonidine can cause a transient rise in blood pressure by activating alpha 2 receptors on peripheral vascular smooth muscle. However, this is usually followed by a decrease in blood pressure and heart rate due to the activation of alpha 2 receptors in the brainstem. This causes decreased sympathetic nervous system output, decreased plasma concentrations of norepinepherine, and decreased

Clinical manifestations

There is no established minimum toxic dose of clonidine. Significant side effects have been reported after ingestions of one to two tablets. Clonidine toxicity is manifested as central nervous system depression, respiratory depression, and cardiovascular compromise. Clonidine toxicity may be confused with opiate intoxication because lethargy, miosis, and respiratory depression are prominent features. Frequently reported signs include altered mental status, miosis, hypothermia, respiratory

Treatment

The majority of studies referenced here are either case studies or case series. Consequently, therapeutic recommendations are based on the authors' evaluation of the published data with strength of evidence less than that provided by randomized clinical trials, case control studies, and meta-analyses.

All children with suspected clonidine ingestion above the therapeutic dose (0.002–0.005 mg/kg) should be evaluated by a physician, preferably in a setting where hemodynamic monitoring is available

Conclusions

Clonidine and the topical imidazolines can cause serious toxicity in young children in doses as small as 1–2 tablets of clonidine and 2.5–5 ml of topical imidazoline. The expanded therapeutic application of clonidine, particularly among children, may lead to increased numbers of pediatric poisonings. Topical imidazolines are available in over-the-counter eye and nose preparations without childproof safety caps; this may give adults the impression that they are harmless, and makes these products

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