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Chapter: Modern Medical Toxicology: Cardiovascular Poisons: Diurets, Antihypertensives and Antiarrhythmics

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Clonidine - Sympatholytic Drug Cardiovascular Poison

Clonidine is an imidazoline compound with potent alpha2-adrenergic agonist effects.

Clonidine

Clonidine is an imidazoline compound with potent alpha2-adrenergic agonist effects. At high doses, it has been shown to act as a peripheral partial alpha-adrenergic receptor agonist, resulting in stimulation of the peripheral post-synaptic alpha2-receptors, thus temporarily increasing blood pressure and pulse rate.

Apart from its utility in hypertension, clonidine is also used in the treatment of attention deficit disorder, prophylaxis of migraine, and management of ethanol, opiate, and nicotine withdrawal. It is well absorbed orally and demonstrates peak effects at 2 to 3 hours. Excretion as unchanged drug is mostly via the kidneys. Apraclonidine is a related drug which is used as 0.5% or 1.0% ophthalmic solution in a sterile isotonic solution for topical application to the eye. Guanfacine and guanabenz are not popular in India, but share the same mode of action as clonidine.

Adverse Effects

·      Dry mouth, drowsiness, orthostatic hypotension, insomnia, agitation, myalgia, arrhythmias, and GI upset. Paralytic ileus occurs rarely.

·      Abrupt withdrawal of clonidine can be life-threatening. Withdrawal effects include agitation, tremor, palpitations, insomnia, severe hypertension, nausea, and vomiting. Even otherwise, rebound hypertension is common.

Clinical (Toxic) Features

·      Usual therapeutic plasma level of clonidine has been reported as less than or equal to 4 mcg/L. Toxic effects generally occur within 30 minutes to 4 hours after overdose and usually resolve within 24 to 72 hours.

·      Overdose results in bradycardia progressing to heart block, hypotension, hypothermia, CNS depression, miosis, and periodic apnoea. Sometimes there is paradoxical hyperten-sion. Clonidine poisoning is much more severe in children as compared to adults.

·      Central adrenergic inhibitory effects following clonidine overdose include impaired consciousness, hypotonia and hyporeflexia, miosis, bradycardia, hypotension, respiratory depression and apnoea, and hypothermia. Partial peripheral adrenergic stimulatory effects include mild to moderate hypertension and tachycardia, which is usually short-lived, and most often followed by hypotension and bradycardia.

·      Large overdoses may result in reversible cardiac conduction defects or arrhythmias.

·      Hypothermia may occur within 1 hour of the ingestion and may last as long as 48 hours, but is usually mild and resolves spontaneously within 6 to 8 hours.

·      Drowsiness, somnolence, ataxia, impaired consciousness and coma are frequently seen. Seizures may rarely occur following large overdoses.

·      Toxic effects following ingestion of apraclonidine ophthalmic drops are similar to those of clonidine overdose.

Treatment

·            Clonidine levels are not readily available or useful for guiding therapy.

·            No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise indicated.

·            Monitor for CNS and respiratory depression. Monitor vital signs, continuous ECG, and pulse oximetry in symptomatic patients.

·            Endotracheal intubation and ventilation may be indicated in the presence of apnoea, coma, depressed respirations, or hypotonia during the first 24 hours following ingestion of clonidine.

·              All patients with an altered mental status, bradycardia, hypo or hypertension require observation (frequent monitoring of vital signs and ECG) for a minimum of 6 to 12 hours or until the patient remains asymptomatic for a period of 4 hours.

·            Activated charcoal is beneficial if administered early. Induc-tion of vomiting and gastric lavage are contraindicated.

·            Naloxone reverses the deleterious effects on respiration and CVS function. Large doses may have to be admin-istered (upto 8 to 10 mg). Naloxone is most effective at reversing respiratory depression, somewhat helpful at lessening the “paradoxical hypertensive” effect, and least effective against hypotension. The most frequently recommended initial naloxone dose for opiate overdose is as follows: 0.4 to 2 mg intravenous bolus in both children and adults, and may be repeated at 2 to 3 minutes intervals according to desired patient response. Caution should be exercised when administering naloxone to the paediatric patient. Severe hypertension requiring management with phentolamine has followed the administration of naloxone in several paediatric clonidine overdoses.

·            Atropine counteracts bradycardia. Bradycardia and hypotension may respond to atropine alone in patients with heart rates below 60. Give 1 mg intravenously, and repeat in three to five minutes if asystolic cardiac arrest persists. Three milligrams (0.04 mg/kg) intravenously is a fully vagolytic dose in most adults.

·            For hypotension, infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position.If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy. Dopamine is effective for hypotension. Paradox-ical hypertension responds well to sodium nitroprusside (intravenous infusion at a rate between 0.5 and 10 mcg/ kg/min, and adjusted based on the patient’s response).

·            Cardiac arrhythmias should be treated with standard antiarrhythmic drugs, if necessary.

·            Alpha-adrenergic antagonists such as tolazoline may have antidotal action in clonidine poisoning. The recom-mended dose is 5 to 10 mg as IV infusion every 15 minutes (upto a maximum of 40 mg).

·            Yohimbine, a CNS alpha2-adrenergic antagonist, has been used for treatment of clonidine overdose.

·            Haemodialysis, haemoperfusion and forced diuresis are not likely to significantly enhance the elimination of this drug.

 

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