Clonidine and the related centrally acting adrenergic inhibitors guanabenz, guanfacine, and methyldopa are commonly used for the treatment of hypertension. Clonidine has also been used to alleviate opioid and nicotine withdrawal symptoms. Clonidine overdose may occur after ingestion of pills or ingestion of the long-acting skin patches. Oxymetazoline, naphazoline, and tetrahydrozoline are nasal and conjunctival decongestants that may cause toxicity identical to that of clonidine. Tizanidine is a chemically related agent used for the treatment of muscle spasticity. Apraclonidine and brimonidine, ophthalmic preparations for the treatment of glaucoma and ocular hypertension, may cause poisoning from ingestion and from systemic absorption after topical administration.

All these agents decrease central sympathetic outflow by stimulating alpha₂-adrenergic presynaptic (inhibitory) receptors in the brain.

1. Clonidine, oxymetazoline, and tetrahydrozoline may also stimulate peripheral alpha₁ receptors, resulting in vasoconstriction and transient hypertension.
2. Guanabenz is structurally similar to guanethidine, a ganglionic blocker. Guanfacine is related closely to guanabenz and has more selective alpha₂ agonist activity than does clonidine.
3. Methyldopa may further decrease sympathetic outflow by metabolism to a false neurotransmitter (alpha-methylnorepinephrine) or by decreasing plasma renin activity.
4. Tizanidine is structurally related to clonidine but has low affinity for alpha₁ receptors.
5. Pharmacokinetics. The onset of effects is rapid (30 minutes) after oral administration of clonidine. Other than methyldopa, these drugs are widely distributed with large volumes of distribution (see also Table II-63).

1. Clonidine. As little as one 0.1-mg tablet of clonidine has produced toxic effects in children; however, 10 mg shared by twin 34-month-old girls was not lethal. Adults have survived acute ingestions with as much as 100 mg. No fatalities from acute overdoses have been reported, but a child had permanent neurologic damage after a respiratory arrest.
2. Guanabenz. Mild toxicity developed in adults who ingested 160-320 mg and in a 3-year-old child who ingested 12 mg. Severe toxicity developed in a 19-month-old child who ingested 28 mg. A 3-year-old child had moderate symptoms after ingesting 480 mg. All these children recovered by 24 hours.
3. Guanfacine. Severe toxicity developed in a 25-year-old woman who ingested 60 mg. A 2-year-old boy ingested 4 mg and became lethargic within 20 minutes, but the peak hypotensive effect occurred 20 hours later.
4. Methyldopa. More than 2 g in adults is considered a toxic dose, and death was reported in an adult after an ingestion of 25 g. However, survival was reported after ingestion of 45 g. The therapeutic dose of methyldopa for children is 10-65 mg/kg/d, and the higher dose is expected to cause mild symptoms.
5. Brimonidine and apraclonidine. Recurrent episodes of unresponsiveness, hypotension, hypotonia, hypothermia, and bradycardia occurred in a 1-month-old infant receiving therapeutic dosing of brimonidine. A 2-week-old infant had severe respiratory depression after one drop was instilled into each eye. Both children recovered with supportive care in less than 24 hours. Apraclonidine ingestion in a 6-year-old girl led to respiratory depression requiring short-term intubation with uneventful recovery.

Manifestations of intoxication result from generalized sympathetic depression and include pupillary constriction, lethargy, coma, apnea, bradycardia, hypotension, and hypothermia. Paradoxical hypertension caused by stimulation of peripheral alpha1 receptors may occur with clonidine, oxymetazoline, and tetrahydrozoline (and possibly guanabenz) and is usually transient. The onset of symptoms is usually within 30-60 minutes, although peak effects may occur more than 6-12 hours after ingestion. Full recovery is usual within 24 hours. In an unusual massive overdose, a 28-year-old man who accidentally ingested 100 mg of clonidine powder had a three-phase intoxication over 4 days: initial hypertension, followed by hypotension, and then a withdrawal reaction with hypertension.

Poisoning frequently mimics opioid overdose and should be suspected in patients with pinpoint pupils, respiratory depression, hypotension, and bradycardia.

1. Specific levels. Serum drug levels are not routinely available or clinically useful. These drugs are not usually detectable on comprehensive urine toxicology screening.
2. Other useful laboratory studies include electrolytes, glucose, and arterial blood gases or oximetry.

Patients usually recover within 24 hours with supportive care.

1. Emergency and supportive measures
   1. Protect the airway and assist ventilation if necessary.
   2. Treat coma, hypotension, and bradycardia if they occur. They usually resolve with supportive measures such as fluids, atropine, and dopamine. Hypertension is usually transient and does not require treatment. Treat lethargy and respiratory depression initially with intermittent tactile stimulation. Mechanical ventilation may be necessary in some patients.
2. Specific drugs and antidotes
   1. Naloxone has been reported to reverse signs and symptoms of clonidine overdose. In a retrospective review, the administration of high dose naloxone (up to 10 mg via intravenous bolus) reversed somnolence in 41 out of 50 pediatric patients with suspected clonidine toxicity. The mechanism may be related to competitive inhibition of endorphins and enkephalins. In addition, naloxone is indicated for suspected clonidine intoxication because co-ingestion of opioids cannot be excluded based on clinical presentation alone.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. Consider whole-bowel irrigation after ingestion of clonidine skin patches.
4. Enhanced elimination. There is no evidence that enhanced removal procedures are effective.