WikiTox

Common agents: Clonidine, guanfacine and moxonidine.

Clonidine is a 2-imidazoline derivative that was originally used as an antihypertensive but is now more frequently used for ADHD and as an adjunct in opioid withdrawal. Guanfacine is less frequently used but is gaining in popularity, it acts similarly to clonidine but has a longer duration of action.

Overdose leads to sedation and bradycardia, with most cases requiring supportive care only.

Action is via central α2- receptor stimulation in the vasomotor centre of the medulla, leading to enhanced activity of inhibitory neurons and subsequent decrease in sympathetic outflow.

Transient hypertension may be seen early due to action of peripheral α receptors, but this is often overshadowed by the central effects.

Clonidine also binds to specific imidazoline receptors, but the significance of this in clinical terms in unclear.

Ingestions of greater than 10mcg/kg of clonidine can cause significant effects in children.

Toxic dose in adults is unclear and depends on several factors, in particular tolerance.

Absorption

Oral absorption of clonidine is rapid with bioavailability of 70-80%. Peak plasma concentrations occur 30-60mins after ingestion with peak antihypertensive effects seen after 1-4hours.

Volume of distribution is 3-6L/kg with rapid distribution to the CNS. Protein binding is 20-40%.

Approximately 50% is excreted unchanged in the urine, with the remainder being metabolised into inactive metabolites by the liver. Elimination half-life is prolonged in renal failure.

Due to rapid absorption clinical effects usually appear early with onset typically 30-60mins post ingestion.

CNS:

• Miosis
• CNS depression (mild sedation to coma, hypotnonia)
• Respiratory depression
• Seizures (rarely)

CVS:

• Early transient hypertension, secondary to peripheral α1-agnoist effect, is seen in up to a third of patients and can be severe in those with renal disease.
• Bradycardia is common (higher degrees of heart block can be seen but are rare) and sometimes associated with hypotension.

Other effects:

• Hypothermia

Besides the standard investigations, there are no specific laboratory tests that are useful in clonidine overdose. Normal urine toxicology screens are not useful for detecting clonidine.

• ECG – sinus bradycardia or heart block

Opioid toxicity: CNS depression, miosis, respiratory depression.

Beta-blocker toxicity: Bradycardia, hypotension.

Organophosphates: CNS depression, miosis, bradycardia, hypothermia.

Sedation severe enough to compromise airway or breathing following overdose is rare. If either are compromised, then the patient should be intubated.

Use of suxamethonium for paralysis can precipitate profound bradycardia in this group. Either use an alternative paralytic or pre-medicate with atropine.

Bradycardia is normally tolerated well. If hypotension is present this normally responds to IV crystalloid bolus.

Offer 50g (1g/kg in children) activated charcoal to cooperative patients who are able to protect their airway who present within 2 hours of ingestion.

There is no role for enhanced elimination.

Atropine:

In patients with hypotension associated with bradycardia, that does not respond to IV fluids, atropine will normally reverse the bradycardia and improve the bloods pressure. This effect is however transient and may require repeat once the effects wear off.

• Atropine 0.6mg (child:0.02mg/kg up to 0.6mg) IV, repeat after 15 minutes if required.

Naloxone:

The use of naloxone as an antidote for clonidine toxicity is controversial. It is postulated that clonidine’s inhibition of central sympathetic outflow may be mediated by endogenous opioid release, which naloxone may reverse. Studies looking at naloxone’s effectiveness show variable response and a wide variation in require dosage.

Whilst the evidence of its effectiveness is questionable in the unlikely event that a child is severely sedated to the point of requiring intubation after a clonidine ingestion then a trial of naloxone would be warranted.

Symptomatic patients should be admitted for observation until they are alert and able to mobilise safely. Bradycardia often persists longer than the sedation (24-48hrs) but should not preclude discharge if patient has otherwise normal observations and no postural drop.

Patients who are asymptomatic 6 hours post ingestion can be medically cleared.

1. Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Crit Care Med 1990;18(10):1124–8. PDF
2. 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;55(3):187–92. PDF
3. Toce MS, FreimanE, O’Donnell KA, Burns MM. Clinical effects of pediatric clonidine exposure: a retrospective cohort study at a single tertiary center. J Emerg Med 2021; 60(1): 58-66. PDF
4. Seger DL, Loden JK. Naloxone reversal of clonidine toxicity: dose, dose, dose. Clin Toxicol 2018; 56(10): 872-879. PDF