Clonidine

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Clonidine
Systematic (IUPAC) name
N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine
Clinical data
Trade namesCatapres, Kapvay, Nexiclon
AHFS/Drugs.commonograph
MedlinePlusa682243
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routesoral, epidural, IV, transdermal, topical
Pharmacokinetic data
Bioavailability75-85% (IR), 89% (XR)[1]
Protein binding20-40%[1]
MetabolismHepatic to inactive metabolites[1]
Half-life12-16 hours[1]
Excretionurine (72%)[1]
Identifiers
CAS number4205-90-7 YesY
ATC codeC02AC01 N02CX02, S01EA04
PubChemCID 2803
IUPHAR ligand516
DrugBankDB00575
ChemSpider2701 YesY
UNIIMN3L5RMN02 YesY
KEGGD00281 YesY
ChEBICHEBI:3757 YesY
ChEMBLCHEMBL134 YesY
Chemical data
FormulaC9H9Cl2N3 
Mol. mass230.093 g/mol
 YesY (what is this?)  (verify)
 
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Clonidine
Systematic (IUPAC) name
N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine
Clinical data
Trade namesCatapres, Kapvay, Nexiclon
AHFS/Drugs.commonograph
MedlinePlusa682243
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routesoral, epidural, IV, transdermal, topical
Pharmacokinetic data
Bioavailability75-85% (IR), 89% (XR)[1]
Protein binding20-40%[1]
MetabolismHepatic to inactive metabolites[1]
Half-life12-16 hours[1]
Excretionurine (72%)[1]
Identifiers
CAS number4205-90-7 YesY
ATC codeC02AC01 N02CX02, S01EA04
PubChemCID 2803
IUPHAR ligand516
DrugBankDB00575
ChemSpider2701 YesY
UNIIMN3L5RMN02 YesY
KEGGD00281 YesY
ChEBICHEBI:3757 YesY
ChEMBLCHEMBL134 YesY
Chemical data
FormulaC9H9Cl2N3 
Mol. mass230.093 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, ADHD, anxiety/panic disorder, and certain pain conditions. It is classified as a centrally acting α2 adrenergic agonist. An alternative hypothesis that has been proposed is that clonidine acts centrally as an imidazoline receptor agonist.

Medical uses[edit]

Clonidine tablets and transdermal patch


Clonidine XR has been approved by the FDA for the treatment of ADHD.[1] 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.[2]

Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).[3] Clonidine along with methylphenidate has been studied for treatment of ADHD.[4][5] 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 attention deficit hyperactivity disorder (ADHD).

Clonidine may be used to ease withdrawal symptoms associated with the long-term use of narcotics, alcohol and nicotine (smoking). 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.[6] The sedation effect is also useful although its side effects can include insomnia, thus exacerbating an already common feature of opioid withdrawal.[7]

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.[8][9][10][11][12][13][14][15][16] Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures.[17] Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively.[18] Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.[19] Clonidine can be used in restless legs syndrome. It can also be used to treat facial flushing and redness associated with rosacea.[20] It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy.[21] Clonidine can also be used for migraine headaches and hot flashes associated with menopause.[22][23]

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 pheochromocytoma,[24] which is a catecholamine-synthesizing tumor, usually of the adrenal medulla. 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 a patient. A positive test occurs if there is no decrease in plasma levels.

Pregnancy[edit]

Clonidine is classed by the FDA as pregnancy category C. It is not known whether clonidine is harmful to an unborn baby. 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.[25]

Adverse effects[edit]

The principle adverse effects of clonidine are dry mouth, dizziness, hypotension (low blood pressure) and drowsiness.[1]

Adverse effects by incidence[26][27][28]

Very common (>10% incidence) adverse effects include:

Common (1-10% incidence) adverse effects include:

Uncommon (0.1-1% incidence) adverse effects include:

Rare (0.01-0.1% incidence) adverse effects include:

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.

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.[29][30]

Since ADHD drugs like amphetamine and methylphenidate tend to stimulate the sympathetic nervous system, missed doses of clonidine while under ADHD stimulant therapy might entail increased risks of a more severe rebound hypertension. This has not been evaluated.

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.[31]

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.[32]

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.[33]

ReceptorKi (nM)[34]
α1A316.2278
α1B316.2278
α1D125.8925
α2A42.92
α2B106.31
α2C233.1

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 

References[edit]

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External links[edit]