Clinical Pearls & Morning Reports
Published May 24, 2023
Guanfacine and clonidine are both centrally acting α2-adrenergic agonists that were initially developed as antihypertensive medications but are increasingly being used for the treatment of behavioral disorders, especially attention deficit–hyperactivity disorder. Read the NEJM Case Records of the Massachusetts General Hospital here.
Q: Are cases of guanfacine poisoning on the rise?
A: Guanfacine can cause clinically significant toxic effects, particularly in children. From 2000 to 2016, more than 11,000 cases of guanfacine exposure in children were reported to poison centers in the United States. There was a sharp increase after 2009, particularly among children 6 to 12 years of age.
Q: What class of drugs does guanfacine belong to?
A: Guanfacine is an imidazoline drug. Guanfacine is more selective for α2-adrenergic receptors than clonidine (by a factor of 12 to 25). Stimulation of α2-adrenergic receptors ultimately reduces sympathetic outflow, thereby decreasing norepinephrine release. Imidazoline receptors, which function upstream from presynaptic α2-adrenergic receptors, are also stimulated. Stimulation of the I2 receptor mediates the release of β-endorphins that act on opioid receptors, producing opioid-like effects.
A: Guanfacine is readily absorbed. The peak concentration occurs 3 to 5 hours after the ingestion of an immediate-release dose. The volume of distribution is large, with 70% protein binding. Half the drug is metabolized in the liver by cytochrome P450 3A4, and the other half is excreted from the kidneys in its parent compound. The half-life is reported to be 17 hours, but a more important metric in treating toxic effects is the duration of action, which is at least 24 hours and can be longer with an extended-release formulation. The onset of toxic effects is expected to occur 30 to 90 minutes after the ingestion of an immediate-release formulation but can be delayed with the use of an extended-release formulation. Hypotension and bradycardia are the primary, and most worrisome, effects of poisoning.
A: Treatment is largely supportive, with the goal of maintaining ventilation and perfusion until the toxic effects resolve. The use of activated charcoal can be considered in patients with a recent ingestion and a patent airway. Fluids are administered for the treatment of hypotension. In addition, a vasopressor such as norepinephrine may be used as a first-line agent for hypotension because it has strong α-adrenergic agonist properties. Atropine can be considered for the treatment of symptomatic bradycardia; temporary transcutaneous pacing is occasionally used for the treatment of refractory bradycardia. Because an overdose of guanfacine (and other imidazoline derivatives) produces opioid-like effects, naloxone can be used in an attempt to reverse the effects. Naloxone may lead to a beneficial response resulting from alteration of the CNS sympathetic outflow by endogenous opioids. High doses are used, additional doses may be necessary, and the treatment is not always effective.