Link to [[Problems for Discussion- 2- Clonidine|Problems for Discussion]]
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[[toc]]
=Clonidine=

==DRUGS INCLUDED IN THIS CATEGORY==

* 2-(2,6-dichloroanilino)-2-imidazoline
* 2-(2,6-dichloroanilino)-1,3-diazacyclopentane-(2)
* 2-((2,6-dichlorophenyl)imino)-2-imidazoline
* 2,6-dichloro-n-2-imidazolidinyldenebenzeneamine
* Catapres
* Catapresan
* Catapress-TTS
* Clonistada
* Dixarit
* Ipotensium
* Isoglavcon
* ST-155
* ST-155-BS
* Tenso-Timelets
falsely previous


==OVERVIEW==

Clonidine is is a 2-imidazoline derivative originally used as an antihypertensive but now more frequently used in a number of others disorders including ADHD in children and as an adjunct in opioid withdrawal (these 2 patient groups are associated with most clonidine poisonings). There is a long list of other disorders where it is used.

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.

==MECHANISM OF TOXIC EFFECTS==

Clonidine is a central α2 -adrenoceptor agonist that stimulates post-synaptic α2 -adrenergic receptors in the vasomotor centre of the medulla, leading to a decreased sympathetic outflow. It also acts peripherally on receptors to cause a pressor response that is usually overshadowed by the central effects in therapeutic doses. Clonidine also binds to the imidazoline receptor. The drug is classified as a partial agonist of alpha-receptors because it also inhibits the effects of other alpha agonists.

Its major receptor effects can be summarised

**Alpha-adrenoceptor partial agonist**
* medulla of the brain (post-synaptic α2 -agonist effect)
* reduction in sympathetic outflow and an increase in parasympathetic tone, resulting in a lowering of blood pressure and bradycardia (postulated to be mediated by endogenous opiate release)
* arterioles (α 1-agonist effect) with hypertension (normally a transient early effect)
* peripheral pre-synaptic α2 -agonist effects causing reduced noradrenaline release from adrenergic nerve terminals (possible hypotensive effect)

==KINETICS IN OVERDOSE==

===Absorption===
Oral absorption is rapidly and almost complete 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.

===Distribution===
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%.

===Metabolism - Elimination===
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.

==CLINICAL EFFECTS==

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.

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
* Minimal < 10 microg/kg
* Bradycardia and hypotension 10 - 20 microg/kg
* Apnoea and respiratory depression > 20 microg/kg

Clonidine overdose is characterised by a classic triad of CNS clinical signs, and a biphasic haemodynamic response.
* CNS depression
* Respiratory depression
* Miosis

* Hypertensive phase
* Hypotensive and bradycardic phase

===Central nervous system effects===
CNS toxicity in clonidine overdose is similar to that seen in [[2.1.1.3 Opioids|opiates]] and [[Barbiturates|phenothiazines]]. The major features are: CNS depression (lethargy or coma), miosis and respiratory depression (or apnoea).

Other CNS signs and symptoms include
* Hypotonia or hyporeflexia (25%)
* [[Status Epilepticus and Treatment of Seizures|Seizures]] (< 10% in one study)
* Ataxia / dysarthria (7%)
* Weakness
* [[3.2.1.1.5 Hallucinations|Hallucinations]]
* Irritability

===Cardiac effects===
**Hypertension**
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 hypertension can be severe initially.

**Hypotension**
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 central sympathetic inhibition and vagal stimulation.

**Bradycardia**
Bradycardia also occurs. It is due mainly to increased vagal outflow.

**Heart block**
Less commonly, various degrees of heart block can occur - AV block (1st, 2nd or 3rd degree). SA conduction disturbances have also been reported.

**Supraventricular tachycardia**
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.

===Other effects===
**Hypothermia**
Clonidine suppresses spontaneous motor activity and lowers body. 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.

==INVESTIGATIONS==

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, and should not be relied on except to exclude other coingestants.

===Blood concentrations===
**Conversion factor**
* microg/L x 4.35 = nmol/L
* nmol/L x 0.230 = microg/L

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.

===Other investigations===
* ECG - sinus bradycardia and AV block
* Arterial blood gas

==DIFFERENTIAL DIAGNOSIS==

Clonidine toxicity is similar to toxicity by a number of agents:
* [[2.1.1.3 Opioids|Opiates]]
** CNS depression, miosis and respiratory depression
* [[3.4.3.4.2 Beta-blockers|Beta-blockers]]
** Bradycardia, hypotension, respiratory and CNS depression
* [[2.1.11.9.3 Antipsychotics|Phenothiazines]]
** Miosis, CNS depression and hypotension
* [[2.2.7.4.5 Organophosphates|Pesticides]]
** Miosis, CNS depression and bradycardia

==TREATMENT==

===Supportive===
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.

===GI Decontamination===
[[3.2.2.2.3 Activated charcoal| Activated Charcoal]]: Single dose activated charcoal is the recommended [[Gastrointestinal Decontamination |gastrointestinal decontamination]] procedure for presentations under 1-2 hours.

===Elimination enhancement===
There is no evidence of enhanced elimination with forced diuresis, [[Alkaline Diuresis and Ion Trapping|urinary pH manipulation]], [[3.2.3.1.1 Haemodialysis|haemodialysis]], or [[3.2.3.1.2 Charcoal Haemoperfusion|haemoperfusion]].

===Treatment of specific complications===
**Hypotension**
Hypotension usually responds to [[3.4.8 Fluid Resuscitation|intravenous fluids]] and volume expansion with colloid. Dopamine is the most commonly used agent in the literature when the patient remains hypotensive despite volume expansion. Any inotrope is probably reasonable to use.

Tolazoline, an alpha blocker (reversible, short acting, slightly alpha2-selective) has been used to treat unresponsive hypotension. Experimentally, tolazoline blocks the peripheral and central effects of clonidine. Significant complications have been reported with its use in other clinical settings: seizures, hypotension, GIT haemorrhage and death. It is not generally recommended for treatment.

**Bradycardia**
[[Heart rates| Bradycardia]] should be treated only in association with haemodynamic instability. Atropine has been used very successfully to treat bradycardia in clonidine overdose. Adrenaline, dopamine have also been reported to improve bradycardia.

**Hypertension**
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. Infusion is begun at 25 or 50 microg/minute with increments if required of 25 microg every 5-15 minutes to a maximum of 150 microg/minute. 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.

===Other complications===
**Seizures**
Treat with [[Benzodiazepines|diazepam]]. Underlying hypoglycaemia or hypoxia needs to be excluded.

**Hypothermia**
Treatment is rarely required and consists of passive external rewarming.

===Antidotes===
**Naloxone**
There has been considerable controversy over the use naloxone in clonidine overdose. Clonidine's inhibition of central sympathetic outflow is thought to be mediated by endogenous opiate release and this is the postulated reason for the effect of naloxone in clonidine overdose. There is a range of effectiveness of naloxone in many different studies. There is a lot of dose variation between the studies.

The greatest effect appears to be with reversal of CNS depression, with less effect on cardiovascular and respiratory depression. The initial dose needs to be 0.1 mg/kg or 2 - 4 mg in adults, if effective it should be followed by an infusion.

**Other agents**
**Yohimbine**
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**
Idazoxan, another specific α2 -adrenoceptor antagonist, has been shown to reverse clonidine-induced miosis in healthy adults, but it is currently investigational.

==LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP==

===Clonidine withdrawal===
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
* Anxiety
* Diaphoresis
* Headache
* Nausea and abdominal pain
* [[Heart rates|Tachycardia]]
* Hypertension

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.

==REFERENCES==

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[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1969468|Wiley JF 2d, Wiley CC, Torrey SB, Henretig FM.]] Clonidine poisoning in young children. J Pediatr 1990 Apr;116(4):654-658
[[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=382842|Conner CS, Watanabe AS]]. Clonidine overdose: a review. Am J Hosp Pharm 1979 Jul;36(7):906-911
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