Clonidine

Not to be confused with clomifene, clonazepam (Klonopin), or clozapine.

Clonidine

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 category	AU: B3 US: C (Risk not ruled out)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	oral, epidural, IV, transdermal, topical
Pharmacokinetic data
Bioavailability	75-95% (oral), 60-70% (transdermal)
Protein binding	20-40%
Metabolism	Hepatic to inactive metabolites, 2/3 CYP2D6 [2]
Biological half-life	IR: 12-16 hours, 14 hours for repeated dosing
Excretion	urine (72%)
Identifiers
CAS Number	4205-90-7 Y
ATC code	C02AC01 (WHO) N02CX02, S01EA04
PubChem	CID: 2803
IUPHAR/BPS	516
DrugBank	DB00575 Y
ChemSpider	2701 Y
UNII	MN3L5RMN02 Y
KEGG	D00281 Y
ChEBI	CHEBI:3757 Y
ChEMBL	CHEMBL134 Y
Chemical data
Formula	C9H9Cl2N3
Molecular mass	230.093 g/mol
SMILES Clc1c(c(Cl)ccc1)N/C2=N/CCN2
InChI 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) Y Key:GJSURZIOUXUGAL-UHFFFAOYSA-N Y
(verify)

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

Medical uses

File:Clonidine pills and patch.jpg

Clonidine tablets and transdermal patch

The US Food and Drug Administration (FDA) has approved clonidine for the treatment of attention deficit hyperactivity disorder (ADHD), alone or with stimulants in 2010, for pediatric patients aged 6–17 years. It was later approved for adults. In Australia, clonidine is an accepted but not approved use for ADHD by the TGA. Clonidine along with methylphenidate has been studied for treatment of ADHD. Some studies show clonidine more sedating than guanfacine, which may be better at bed time along with an arousing stimulant at morning. Clonidine can be used in the treatment of Tourette syndrome (specifically for tics). Clonidine may be used to ease withdrawal symptoms associated with the long-term use of narcotics, alcohol, benzodiazepine 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. It may also be helpful in aiding smokers to quit. The sedation effect is also useful although its side effects can include insomnia, thus exacerbating an already common feature of opioid withdrawal.

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. Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures. Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively. Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal. Clonidine can be used in restless legs syndrome. It can also be used to treat facial flushing and redness associated with rosacea. It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy. Clonidine can also be used for migraine headaches and hot flashes associated with menopause.

Clonidine suppression test

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. 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.

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. 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.

Adverse effects

The principle adverse effects of clonidine are sedation, dry mouth, and hypotension (low blood pressure).

Adverse effects by frequency

Very common (>10% frequency):

• Dizziness
• Drops in blood pressure upon standing up
• Somnolence (drowsiness; dose-dependent)
• Dry mouth
• Headache (dose-dependent)
• Fatigue
• Skin reactions (if given transdermally)
• Low blood pressure

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):

• Delusional perception
• Hallucination
• Nightmare
• Paraesthesia
• Sinus bradycardia
• Raynaud's phenomenon
• Itchiness
• Hives

Rare (<0.1% frequency):

• Swelling of breast tissue in males
• Impaired ability to cry
• Atrioventricular block
• Nasal dryness
• Colonic pseudo-obstruction
• Alopecia (hair loss)
• High blood sugar

Withdrawal

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 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.

Mechanism of action

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. 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. Its mechanism of action in the treatment of ADHD is to increase noradrenergic tone in the prefrontal cortex (PFC) directly by binding to postsynaptic α_2A adrenergic receptors and indirectly by increasing norepinephrine input from the locus coeruleus.

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

External links

• U.S. National Library of Medicine: Drug Information Portal - Clonidine
• Alpha-2 agonists in ADHD