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Clonidine is a 2-imidazoline derivative originally used as an antihypertensive but now more frequently used in a number of other disorders, including ADHD in children and as an adjunct in opioid withdrawal (these 2 patient groups are associated with most clonidine poisonings). Other uses include treatment of migraine, chronic pain, menopausal symptoms, peri-anaesthetic emergence phenomena and psychiatric disorders such as anxiety or PTSD.
Death is rare but symptomatic patients often need prolonged observation.
Hypotension, bradycardia, respiratory depression, hypothermia, miosis, apnea, and coma have been noted following overdose. The hypotension may be preceded by hypertension. Signs and symptoms generally occur within 4 hours and generally resolve within 24 to 48 hours.
Clonidine and the other drugs in this class are central α2 -adrenoceptor agonists that stimulate post-synaptic α2 -adrenergic receptors in the vasomotor centre of the medulla, leading to enhanced activity of inhibitory neurons and subsequent decreased sympathetic outflow. Some may also act peripherally on α-receptors to cause a pressor response that is usually overshadowed by the central effects in therapeutic doses. Methyldopa is metabolised to alpha-methylnoradrenaline, which is thought to stimulate alpha2 adrenoceptors. It also appears to act as a false neurotransmitter, and have some inhibitory actions on plasma renin activity. Methyldopa reduces the tissue concentrations of dopamine, noradrenaline, adrenaline, and serotonin.
Clonidine, moxonidine and rilmenidine also bind to specific imidazoline receptors, but the significance of this is unclear. Clonidine is classified as a partial agonist of α-receptors because it also inhibits the effects of other α-agonists.
The major receptor effects can be summarised:
Alpha-adrenoceptor partial agonist:
Oral absorption is rapid with a bioavailability of 70-80%. Peak plasma concentrations occur 30-60 minutes after oral dosing, and peak antihypertensive effects after 1-4 hours (1.5 -2.5 h).
Intramuscular administration is effective within 5-10 minutes, with a maximal effect reached by 75 minutes, and a duration of action of about 5 hours.
Intravenous administration is effective within 5 minutes, has a maximum hypotensive effect within 20 - 30 minutes, and a duration of effect of several hours.
Clonidine transdermal patches
These patches contain 2.5, 5 and 7.5 mg of clonidine and are used for a 7-day period. They may contain up to 1.9 mg of active drug once they are disposed of and have lead to overdose in children, and in adults.
Vd = 3-6 L/kg. Clonidine is lipid-soluble and rapidly enters the brain from the circulation. Its antihypertensive effect is thus directly related to blood concentration. Plasma protein binding is 20-40%.
About 50% is excreted unchanged in urine, the remainder is metabolised to inactive metabolites by the liver. Metabolites are excreted about equally in urine and faeces. Elimination half-life is prolonged in patients with renal impairment.
Peak blood concentrations occur about 90 minutes after ingestion of clonidine, and symptoms of toxicity usually develop 30 - 60 minutes after ingestion. Death is rare.
Clonidine overdose is characterised by a classic triad of CNS clinical signs, and a biphasic haemodynamic response:
There does not appear to be a good correlation between the dose ingested and the clinical symptoms, however one study showed a dose-related response in 11 cases of paediatric clonidine poisoning:
Adult patients are more tolerant of the CNS and respiratory effects of clonidine in overdose, particularly if they are not naive to the drug. However, lethal coma can occur in adult patients, and haemodynamic effects can be evident for 1-2 days following large overdoses.
CNS toxicity in clonidine overdose is similar to that seen in opiates. The major features are: CNS depression (lethargy or coma), miosis and respiratory depression (or apnoea).
Other CNS signs and symptoms include:
There may be an initial transient pressor effect following overdose due to the peripheral a1-agonist effect. The hypertension occurs in about one third of patients. Although the hypertension is usually transient, it can last for up to 10–12 hours. In patients with renal disease the initial hypertension can be severe.
Hypotension usually develops after 2-4 hours, may be severe, and is not always preceded by hypertension. It is due to the α2-agonist effects of clonidine on the medulla causing inhibition of central sympathetic outflow and vagal stimulation.
Bradycardia is common. It is due mainly to unopposed vagal parasympathetic outflow.
Less commonly, various degrees of heart block can occur - AV block (1st, 2nd or 3rd degree). SA node conduction disturbances have also been reported.
SVT has been reported in a 22 year old with SLE and mild renal insufficiency after an accidental overdose of 18.8 mg. This was associated with AV block.
Clonidine suppresses spontaneous motor activity and lowers body temperature. Hypothermia usually develops after 1 hour and resolves within 8 hours, but can last up to 48 hours. Vomiting, diarrhoea, and pallor can also occur.
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.
The presence of clonidine can be confirmed by specific serum concentrations using HPLC, however these are not readily available and can take days to report. Serum concentrations do not correlate with toxicity very well.
Clonidine toxicity is similar to toxicity by a number of agents:
The treatment is predominantly general supportive care with haemodynamic monitoring, ECG, blood sugar, neurological and body temperature observations. The symptoms will usually resolve after 24-48 hours, so the blood pressure should be monitored carefully for 48 hours following the overdose. A later hypertensive phase may be associated with declining blood concentrations of clonidine, due to clonidine withdrawal syndrome.
Activated Charcoal: The risk of early CNS depression after clonidine overdose means that oral decontamination with activated charcoal is contraindicated.
Maintenance of a patent airway is of prime importance in management of a patient following clonidine overdose, and definitive protection with endotracheal intubation may be required.
Hypotension usually responds to volume expansion with intravenous fluids. Intravenous inotropic or chronotropic agents are not usually required to maintain adequate tissue perfusion. Low-dose peripheral dopamine may be a reasonable choice if central venous access is not available.
Bradycardia should be treated only in association with haemodynamic instability. Atropine has been used successfully to treat symptomatic bradycardia in clonidine overdose. Adrenaline and dopamine have also been reported to improve bradycardia.
Treatment of hypertension is not usually required unless there is life-threatening hypertension, or end-organ damage is evident. The agent of choice is sodium nitroprusside by IV infusion. Its rapid onset and short duration of action facilitate titration of dose.
Glyceryl trinitrate is an alternative short-acting intravenous vasodilator that can be used if hypertension is significant or prolonged.
Great care should be taken when treating hypertension, and long acting agents should not be used. Aggressive therapy of hypertension has resulted in profound and prolonged hypotension in a number of cases. Some authors advocate the use of phentolamine because it is short acting and blocks the peripheral alpha1-agonist effects of clonidine.
Treat with titrated doses of intravenous benzodiazepines. Underlying hypoglycaemia or hypoxia needs to be excluded.
Treatment is rarely required and consists of passive external rewarming.
There has been considerable controversy over the use naloxone in clonidine overdose. Clonidine's inhibition of central sympathetic outflow may be mediated by endogenous opioid release and this is the postulated reason for the effect of naloxone in clonidine overdose. There is variable effectiveness of naloxone in many different studies, with significant dose variations between the studies.
The greatest effect appears to be with reversal of CNS depression, with less effect on cardiovascular and respiratory depression. A trial of naloxone can certainly be justified, particularly in paediatric patients as a temporising measure if definitive airway protection (endotracheal intubation) cannot be provided.
Yohimbine is a selective α2 -adrenoceptor blocker that penetrates the CNS and causes an increase in BP, HR, and motor activity. It has only been studied in one report.
Idazoxan, another specific α2-adrenoceptor antagonist, has been shown to reverse clonidine-induced miosis in healthy adults, but it is currently investigational.
Sudden cessation of clonidine therapy is known to be associated in some instances with rebound hypertension, which can be severe. These symptoms may occur as early as 12 hours after the last dose.
The symptoms last for 5 to 7 days and consist of:
Ventricular arrhythmias, hypertensive encephalopathy, and death have been reported. Clonidine should be tapered over 3 to 5 days to prevent this withdrawal. Restarting clonidine is the most effective treatment. Nitroprusside may be required to treat hypertension. Clonidine withdrawal has not been reported with acute overdose alone, however it may occur in those taking clonidine regularly who take an overdose and then suddenly cease their clonidine.
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Moxonidine Aust Prescr 2006;29:25-7