Clonidine

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Not to be confused with clomifene, clonazepam (Klonopin), or clozapine.
Clonidine
Clonidine2DACS3.svg
Clonidine3DanBS.gif
Systematic (IUPAC) name
N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine
Clinical data
Trade names Catapres, Kapvay, Nexiclon
AHFS/Drugs.com monograph
MedlinePlus a682243
Licence data US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes oral, epidural, IV, transdermal, topical
Pharmacokinetic data
Bioavailability 75-95% (oral), 60-70% (transdermal)[1]
Protein binding 20-40%[2]
Metabolism Hepatic to inactive metabolites[2]
Half-life 5.2-13 hours (average: 8 hours) for single dosing, 14 hours (repeated dosing)[1]
Excretion urine (72%)[2]
Identifiers
CAS number 4205-90-7 YesY
ATC code C02AC01 N02CX02, S01EA04
PubChem CID 2803
IUPHAR ligand 516
DrugBank DB00575
ChemSpider 2701 YesY
UNII MN3L5RMN02 YesY
KEGG D00281 YesY
ChEBI CHEBI:3757 YesY
ChEMBL CHEMBL134 YesY
Chemical data
Formula C9H9Cl2N3 
Mol. mass 230.093 g/mol
 YesY (what is this?)  (verify)

Clonidine (trade names Catapres, Kapvay, Nexiclon and others) is a sympatholytic medication used to treat high blood pressure, attention-deficit/hyperactivity disorder, anxiety disorders, withdrawal (from either alcohol, opioids or smoking), migraine, menopausal flushing, diarrhoea and certain pain conditions.[3] It is classified as a centrally acting α2 adrenergic agonist and imidazoline receptor agonist that has been in clinical use for over 40 years.[4]

Medical uses[edit]

Clonidine tablets and transdermal patch

Clonidine along with methylphenidate has been studied for treatment of ADHD.[5][6][7] In 2010, the Food and Drug Administration approved the use of clonidine either as an adjunct to traditional stimulant therapy or as a monotherapy in the treatment of ADHD.[2] In Australia, while ADHD is an accepted use for clonidine (which in Australia is only available in immediate release formulations) it has not been approved by the TGA for this indication.[8] Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).[9] Clonidine may be used to ease withdrawal symptoms associated with the long-term use of narcotics, alcohol and nicotine (smoking).[10] It can alleviate opioid withdrawal symptoms by reducing the sympathetic nervous system response such as tachycardia and hypertension, as well as reducing sweating, hot and cold flashes, and general restlessness.[11] It may also be helpful in aiding smokers to quit.[12] The sedation effect is also useful although its side effects can include insomnia, thus exacerbating an already common feature of opioid withdrawal.[13]

Clonidine also has several off-label uses, and has been prescribed to treat psychiatric disorders including stress, sleep disorders, and hyperarousal caused by post-traumatic stress disorder, borderline personality disorder, and other anxiety disorders.[14][15][16][17][18][19][20][21] Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures.[22] Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively.[23] Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.[24] Clonidine can be used in restless legs syndrome. It can also be used to treat facial flushing and redness associated with rosacea.[25] It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy.[26] Clonidine can also be used for migraine headaches and hot flashes associated with menopause.[27][28]

Clonidine suppression test[edit]

Clonidine's effect on reducing circulating epinephrine by a central mechanism was used in the past as an investigatory test for phaeochromocytoma, which is a catecholamine-synthesizing tumour, usually of the adrenal medulla.[29] In a clonidine suppression test plasma catecholamines levels are measured before and 3 hours after a 0.3 mg oral test dose has been given to somebody. A positive test occurs if there is no decrease in plasma levels.[29]

Pregnancy[edit]

Clonidine is classed by the FDA as pregnancy category C. It is classified by the TGA of Australia as pregnancy category B3, which means that it has shown some detrimental effects on foetal development in animal studies, although the relevance of this to human beings is unknown.[30] Additionally, clonidine can pass into breast milk and may harm a nursing baby. Therefore, caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.[31]

Adverse effects[edit]

The principle adverse effects of clonidine are dry mouth, dizziness, hypotension (low blood pressure) and drowsiness.[2]

Adverse effects by frequency[30][32][33]

Very common (>10% frequency):

Common (1-10% frequency):

  • Anxiety
  • Constipation
  • Sedation (dose-dependent)
  • Nausea/vomiting
  • Malaise
  • Abnormal LFTs
  • Rash
  • Weight gain/loss
  • Pain below the ear (from salivary gland)
  • Erectile Dysfunction

Uncommon (0.1-1% frequency):

Rare (<0.1% frequency):

Withdrawal[edit]

Clonidine suppresses sympathetic outflow resulting in lower blood pressure, but sudden discontinuation can cause rebound hypertension due to a rebound in sympathetic outflow.[3]

Clonidine therapy should generally be gradually tapered off when discontinuing therapy to avoid rebound effects from occurring. Treatment of clonidine withdrawal hypertension depends on the severity of the condition. Reintroduction of clonidine for mild cases, alpha and beta blockers for more urgent situations. Beta blockers never should be used alone to treat clonidine withdrawal as alpha vasoconstriction would still continue.[34][35]

Mechanism of action[edit]

Clonidine treats high blood pressure by stimulating α2-receptors in the brain, which decreases peripheral vascular resistance, lowering blood pressure. It has specificity towards the presynaptic α2-receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels, thus inhibiting the release of norepinephrine (NE). The net effect is a decrease in sympathetic tone.[36] It has also been proposed that the antihypertensive effect of clonidine is due to agonism on the I1-receptor (imidazoline receptor), which mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure.[37] Its mechanism of action in the treatment of ADHD is to increase noradrenergic tone in the prefrontal cortex (PFC) directly by binding to postsynaptic α2A adrenergic receptors and indirectly by increasing norepinephrine input from the locus coeruleus.[38]

Receptor Ki (nM)[39]
α1A 316.23
α1B 316.23
α1D 125.89
α2A 42.92
α2B 106.31
α2C 233.1

Synthesis[edit]

Clonidine, 2-(2,6-dichlorophenylamino)imidazoline, is synthesized from 2,6-dichloroaniline, the reaction of which with ammonium thiocyanate gives N-(2,6- dichlorophenyl)thiourea. Methylation of this product, followed by the subsequent reaction with ethylene diamine gives clonidine. Clonidine synthesis.png

Clonidine Synthesis.png

US patent 3937717, Stahle, H.; Koppe, H.; Kummer, W.; Stockhaus, K., "2-Phenylamino-imidazolines-(2)", issued 1976-02-10, assigned to Boehringer Ingelheim GmbH 

[40]

References[edit]

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  2. ^ a b c d e "clonidine (Rx) - Catapres, Catapres-TTS, more..". Medscape Reference. WebMD. Retrieved 10 November 2013. 
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External links[edit]