CHAPTER 2-50: CLONIDINE AND RELATED DRUGS

INTRODUCTION

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.

MECHANISM OF TOXICITY

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).

TOXIC DOSE

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. ...