Continuing Education Activity

Clonidine is a commonly prescribed biochemical derivative of imidazoline with a variety of clinical uses. It was originally developed as a nasal decongestant, but its main use has been an anti-hypertensive agent. In recent years it has gained popularity in pediatric patients for the treatment of attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, and sleep disturbances. It has also been shown to be useful in treating several different drug withdrawal syndromes. Clonidine’s effect on the body stems from its action on alpha-2 receptors, imidazoline receptors, and the functional overlap of alpha-2 receptors on mu receptors. Overdose results in a toxidrome not easily identified. This activity reviews the etiology, presentation, evaluation, and management/prevention of clonidine toxicity and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Describe the basic pathophysiology/toxicokinetics of clonidine toxicity.
• Summarize some of the various presenting signs and symptoms that would accompany clonidine toxicity.
• Review treatment and management strategies available for clonidine toxicity.
• Evaluate possible interprofessional team strategies for improving care coordination and communication to advance the evaluation and treatment of clonidine toxicity and improve outcomes.

Introduction

Clonidine is a commonly prescribed biochemical derivative of imidazoline with a variety of clinical uses. It was originally developed as a nasal decongestant, but its main use has been as an anti-hypertensive agent.[1] In recent years it has gained popularity in pediatric patients for the treatment of attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, and sleep disturbances. It has also been shown to be useful in treating several different drug withdrawal syndromes. Clonidine’s effect on the body stems from its action on alpha-2 receptors, imidazoline receptors, and the functional overlap of alpha-2 receptors on mu receptors. Overdose results in a toxidrome not easily identified.[2][3]

Even at therapeutic doses, clonidine has a number of anticholinergic side effects that include dry mouth, constipation, and sedation. However, at toxic doses, it can cause hemodynamic instability and depression.

Etiology

Clonidine toxicity may occur from over-placement of transdermal patches or accidental or deliberate overdose of the tablet form.[4]

Epidemiology

Over the past few decades, as more clinical indications for clonidine have been discovered, prescribing rates have increased. Consequently, misuse and accidental ingestion of clonidine have increased. According to an analysis looking at data from the National Poison Data System, the number of unintentional pediatric exposures to alpha-2 agonists increased 5.9% per year between 2000 and 2011. Clonidine was the most commonly reported culprit agent with the highest percentage of “moderate to major outcomes" compared to other commonly prescribed A-2 agonists, specifically, guanfacine and tizanidine.[5][6]

Pathophysiology

As mentioned, clonidine is an alpha-2 receptor and imidazoline-1 receptor agonist. These receptors have been found to work in tandem to produce the hypotensive effects of clonidine. By activating the presynaptic alpha-2 adrenergic receptors of the central nervous system, specifically in the rostral ventrolateral medulla and the nucleus tractus solitarii, the release of norepinephrine (NE) into neuronal synapses is inhibited. This inhibition then reduces sympathetic tone throughout the body, particularly decreasing the level of vasoconstriction, causing hypotension and bradycardia. A-2 receptors are also found in the locus coeruleus (LC), which plays a large role in autonomic function and states of arousal. Clonidine’s inhibitory effect on the LC causes disinhibition of the ventrolateral preoptic nucleus, which is responsible for the drug's sedative effect. The inhibition of the LC also contributes to the decrease in circulating norepinephrine and indirectly contributes to the hypotension and bradycardic effects.

In tandem with this, Imidazoline-1 receptors in the rostral ventrolateral medulla, which have a high affinity for clonidine, compound the inhibition of sympathetic neurotransmission when activated by clonidine. I-1 receptors are also found peripherally in the plasma membranes of the heart and kidneys and cause a decrease in peripheral vascular resistance, heart rate, and cardiac contractility. Clonidine’s effect on nitric oxide production in the endothelial cells and the subsequent vasodilation has also been discussed. Additionally, clonidine has been shown to affect GABA levels by several different mechanisms, which clearly play a role in sympathetic/parasympathetic regulation.[7][8]

Toxicokinetics

Clonidine is rapidly absorbed, with 100% bioavailability, when given by mouth. Its peak concentration in the blood occurs 2 to 4 hours post-ingestion, and its half-life is between 5 and 13 hours. Half the administered dose is excreted unchanged in the urine. Toxic exposure via clonidine transdermal patches, while less common, is more likely to produce significant symptoms in those exposed. Patches can contain up to 9 mg of clonidine and, if ingested, may have a prolonged release in the gastrointestinal (GI) tract.

History and Physical

Poisoning with clonidine classically presents with somnolence, respiratory depression, hypotension, bradycardia, and miosis. Alteration in the level of consciousness usually presents within the first one and a half hours, preceding any cardiovascular effects, which usually present within 4 hours. Of note, patients who ingest large amounts may initially have early hypertension, which then progresses to hypotension. This is poorly described in the literature, but it is likely related to peak serum concentrations and baseline sympathetic tone prior to clonidine administration. Hypothermia is also observed, which can help differentiate from opioid toxicity as this is not observed in those cases.

Many sources report dose-dependent and age-dependent responses, although neither is well established. It is suggested that cardiovascular and respiratory effects are limited to ingestions of greater than 0.01 mg/kg to 0.02 mg/kg, while other sources document toxicity after ingestion of only 0.2 mg. One study done on adults showed the severity of bradycardia to be consistently dose-dependent, while hypotension was much more variable in severity, time of onset, and duration. Age affects the sensitivity of presynaptic A-2 receptors and decreases the reuptake of NE so that elderly patients will have an overall increase in NE concentration at baseline compared to younger patients. This can attenuate the effects of clonidine and the doses required to cause toxicity. A study done on pediatric overdoses shows the highest incidence of clinical effects in the 0 to 4 years age group compared to five to eight-year and nine to 12 year age groups.

Respiratory depression is most common in children and may require mechanical ventilation. Respiratory failure often occurs within a few hours of a toxic ingestion.

Evaluation

Clonidine levels do not correlate with toxicity, and blood should not be drawn routinely. Blood should be evaluated for electrolyte and glucose levels and to screen for anion gap acidosis or hypoglycemia.

Other studies to consider include:

• 12-lead electrocardiogram
• Pregnancy test
• Computed tomography (CT) scan
• Magnetic resonance imaging (MRI) scan
• Lumbar puncture

Treatment / Management

The majority of clonidine overdoses in adults and children have not been shown to cause significant symptoms requiring major intervention. Death or the need for invasive intervention such as intubation or use of vasopressors are rare and are reported only in extreme cases, for example, with a very young age or extremely large dose/patch ingestion. In a study done on adults, bradycardia was the most consistent finding, lasting about 24 to 48 hours post-ingestion.[3][4]

As severe toxicity requiring advanced resuscitation is rare, supportive care is the basis of managing clonidine overdoses. Hypotension should be addressed first with fluid resuscitation. In refractory cases, pressors are recommended. Dopamine and NE have both been cited as the agent of choice. However, there have been no studies to support the use of one over the other. Dopamine may also improve associated bradycardia. One case report demonstrated worsening hypotension with the prehospital administration of epinephrine. Rarely, intubation is needed for patients with severe respiratory depression. No specific recommendations for RSI medications are found.

The use of naloxone as an antidote to clonidine has been debated for many years. Its efficacy in this situation is thought to stem from the reversal of endogenous opioids released in the body secondary to clonidine toxicity. However, this depends on several factors, including the patient’s baseline blood pressure and sympathetic tone before ingestion. Several published studies and case reports show differing outcomes, highlighting the likely role of unknown cofactors. Despite its questionable utility, sources recommend judicious use of naloxone in cases where the patient is not protecting their airway, as the incidence of adverse effects is rare. Escalating doses of 0.1 mg to 10 mg is suggested.

Atropine for bradycardia has also been suggested, although it too has inconsistent results when studied. One study reported eight adults treated with atropine to have had transient improvement of heart rate of about an hour duration. In a bradycardic patient who becomes hemodynamically unstable, transcutaneous or transvenous pacing is suggested but unsubstantiated.

The consensus from multiple sources is that a patient who does not show any clinical signs of toxicity within several hours of ingestion may be discharged home following an observation period. Four to 8 hours has been suggested as the appropriate time frame. In adults without co-ingestion, intensive care unit (ICU) stay is not indicated as significant delayed effects are rare. Adults with isolated bradycardia may even be discharged in some situations. Pediatric ICU admission is recommended for pediatric patients with any cardiovascular or central nervous system symptoms.

Differential Diagnosis

• Alcohol toxicity
• Sedative drug overdose
• Electrolyte disturbances (hypercalcemia, hypernatremia)
• Meningitis
• Reye syndrome
• Stroke

Prognosis

Clonidine is a relatively safe drug, and even at toxic doses, mortality is rare. Most morbidity or mortality arises from airway problems instead of cardiovascular issues, and the medication can be associated with CNS morbidity (depression) and cardiorespiratory compromise.[1] Clonidine overdose generally results in good outcomes when properly addressed.

Complications

Clonidine toxicity can result in serious apnea and respiratory depression, requiring emergent endotracheal intubation and mechanical ventilation. Clonidine toxicity also commonly causes hypotension.[2] Bradycardia is also possible[3]

Deterrence and Patient Education

If the ingestion was intentional, then intervention from psychological professionals is necessary. For unintentional ingestion, the patient will require counsel on proper dosing and administration to prevent further events. If the overdose occurred in a child, it is often a case of the patient or parent needing to understand the importance of keeping the drug in a place not accessible by the child.

Enhancing Healthcare Team Outcomes

Clonidine toxicity can impact many organ systems, and it is important to have an interprofessional team looking after the patient. The majority of patients initially present to the emergency department. Hence, all interprofessional team members (clinicians, including PAs and NPs, nurses, and pharmacists) should be familiar with the drug toxicity symptoms. The triage nurse should quickly admit the patient and inform the emergency department physician. All unstable patients need monitoring in an ICU setting.

Stable patients can be discharged and need to be educated on how to store the medication away from the reach of children properly. For those with intentional overdose, a mental health consult is necessary before discharge.[9]

The pharmacist should educate the patient on drug safety and keep the medication away from the reach of children. The dose of the drug should not be altered by the patient. If drug dosage is altered by a team member, the entire team looking after the patient should be notified. Only with open communication with the team members can the outcomes be improved.

For the majority of patients with clonidine toxicity, the prognosis is good with treatment. However, those who delay seeking treatment may suffer adverse cardiac or neurological problems. Deaths from clonidine toxicity are very rare.[3]

The above points out the importance of an interprofessional team approach to clonidine toxicity to provide the best possible outcomes with a good prognosis. [Level 5]