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Clonidine

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Not to be confused with clomifene, clonazepam (Klonopin), clozapine, or guanfacine.
Clonidine
Clinical data
Pronunciation/ˈklɒnədiːn/
Trade namesCatapres, Kapvay, Nexiclon, others
AHFS/Drugs.comMonograph
MedlinePlusa682243
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth, epidural, IV, transdermal, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability75–95% (oral), 60–70% (transdermal)[2]
Protein binding20–40%[3]
MetabolismHepatic to inactive metabolites,[3] 2/3 CYP2D6 [2]
Elimination half-lifeIR: 12–16 hours,[4] 48 hours for repeated dosing[2]
ExcretionUrine (72%)[3]
Identifiers
  • N-(2,6-Dichlorophenyl)-4,5--1H-imidazol-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.021.928 Edit this at Wikidata
Chemical and physical data
FormulaC9H9Cl2N3
Molar mass230.093 g/mol g·mol−1
3D model (JSmol)
  • Clc1c(c(Cl)ccc1)N/C2=N/CCN2
  • InChI=1S/C9H9Cl2N3/c10-6-2-1-3-7(11)8(6)14-9-12-4-5-13-9/h1-3H,4-5H2,(H2,12,13,14) checkY
  • Key:GJSURZIOUXUGAL-UHFFFAOYSA-N checkY
  (verify)

Clonidine is a medication marketed under many brand names that is used to treat high blood pressure, attention deficit hyperactivity disorder, anxiety disorders, tic disorders, withdrawal (from either alcohol, opioids, or smoking), migraine, menopausal flushing, diarrhea, and certain pain conditions.[5]

The adverse effects include sedation, dry mouth, and low blood pressure.[3]

Clonidine treats high blood pressure by stimulating α2 receptors in the brain stem, which decreases peripheral vascular resistance, lowering blood pressure. Clonidine also may cause bradycardia, probably due to a temporary increase in vascular resistance caused by clonidine stimulating α2 receptors in smooth muscles in blood vessels. This blood pressure raising effect is seen when the drug is given intravenously, and is not usual when clonidine is given by mouth or by the transdermal route.[6]: 201–203 

It has been in clinical use since 1966.[7][8]

Medical uses

Clonidine tablets and transdermal patch

Clonidine was introduced in 1966.[9] It was first used as a hypertension treatment under the trade name of Catapres.[10] The US Food and Drug Administration (FDA) has approved clonidine for the treatment of attention deficit hyperactivity disorder (ADHD), under the trade name of Kapvay alone or with stimulants in 2010, for pediatric patients aged 6–17 years.[3][11] It was later approved for adults. In Australia, clonidine is an accepted but not approved use for ADHD by the TGA.[12] Clonidine along with methylphenidate has been studied for treatment of ADHD.[13][14][15] While not as effective as methylphenidate in treating ADHD, Clonidine does offer some benefit;[16] it can also be useful in combination with stimulant medications.[17] Some studies show clonidine more sedating than guanfacine, which may be better at bed time along with an arousing stimulant at morning.[18][19] Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).[20]

Clonidine may be used to ease withdrawal symptoms associated with the long-term use of narcotics, alcohol, benzodiazepines and nicotine (smoking).[21] 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.[22] It may also be helpful in aiding smokers to quit.[23] The sedation effect is also useful. However, its side effects can include insomnia, thus exacerbating an already common feature of opioid withdrawal.[24]

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.[25][26][27][28][29][30][31][32] Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures.[33] Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively.[34] Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.[35] Clonidine can be used in restless legs syndrome. It can also be used to treat facial flushing and redness associated with rosacea.[36] It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy.[37] Clonidine can also be used for migraine headaches and hot flashes associated with menopause.[38][39] Clonidine has also been used to treat diarrhea associated with irritable bowel syndrome, fecal incontinence, diabetes, withdrawal-associated diarrhea, intestinal failure, neuroendocrine tumors and cholera.[40]

Clonidine suppression test

Clonidine's effect on reducing circulating norepinephrine 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.[41] In a clonidine suppression test plasma catecholamine levels are measured before and 3 hours after a 0.3 mg oral test dose has been given to the patient. A positive test occurs if there is no decrease in plasma levels.[41]

Pregnancy

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 fetal development in animal studies, although the relevance of this to human beings is unknown.[42] Clonidine can pass into breast milk and may harm a nursing baby; caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.[43]

Adverse effects

The principal adverse effects of clonidine are sedation, dry mouth, and hypotension (low blood pressure).[3]

Adverse effects by frequency[42][44]

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

Clonidine suppresses sympathetic outflow resulting in lower blood pressure, but sudden discontinuation can cause rebound hypertension due to a rebound in sympathetic outflow.[5]

Clonidine therapy should generally be gradually tapered 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.[45][46]

Mechanism of action

Clonidine treats high blood pressure by stimulating α2 receptors in the brain stem, 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 has a sympatholytic effect, suppresses release of norepinephrine, ATP, and neuropeptide Y which if released would increase vascular resistance.[6]: 201–203 

Clonidine also acts as an agonist at imidazoline 1receptors in the brain, and it is hypothesized that this effect may contribute to reducing blood pressure by reducing signaling in the sympathetic nervous system, but this effect acts upstream of the central α2 agonist effect of clonidine.[6]: 201–203 [47]

Clonidine also may cause bradycardia, probably due to a temporary increase in vascular resistance caused by clonidine stimulating α2 receptors in smooth muscles in blood vessels. This blood pressure raising effect is seen when the drug is given intravenously, and is not usual when clonidine is given by mouth or by the transdermal route.[6]: 201–203 

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.[48]

Receptor Ki (nM)[49]
α1A 316.23
α1B 316.23
α1D 125.89
α2A 42.92
α2B 106.31
α2C 233.1

Brand names

As of June 2017 clonidine was marketed under many brand names worldwide: Arkamin, Aruclonin, Atensina, Catapin, Catapres, Catapresan, Catapressan, Chianda, Chlofazoline, Chlophazolin, Clonid-Ophtal, Clonidin, Clonidina, Clonidinã, Clonidine, Clonidine hydrochloride, Clonidinhydrochlorid, Clonidini, Clonidinum, Clonigen, Clonistada, Clonnirit, Clophelinum, Dixarit, Duraclon, Edolglau, Haemiton, Hypodine, Hypolax, Iporel, Isoglaucon, Jenloga, Kapvay, Klofelino, Kochaniin, Melzin, Menograine, Normopresan, Paracefan, Pinsanidine, Run Rui, and Winpress.[50] It was marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso.[50]

References

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