Clonidine
Clinical data | |
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Pronunciation | /ˈklɒnədiːn/ |
Trade names | Catapres, Kapvay, Nexiclon, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682243 |
License data | |
Pregnancy category |
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Routes of administration | Oral, epidural, intravenous (IV), transdermal, topical |
Drug class | Centrally acting α2A-agonist hypotensive agent |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 70–80% (oral),[2][3] 60–70% (transdermal)[4] |
Protein binding | 20–40%[5] |
Metabolism | Liver to inactive metabolites,[5] 2/3 CYP2D6[9] |
Onset of action | IR: 30–60 minutes after an oral dose[6] |
Elimination half-life | IR: 12–16 hours; 41 hours in kidney failure,[7][8] 48 hours for repeated dosing[4] |
Excretion | Urine (72%)[5] |
Identifiers | |
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Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic agonist[10] medication used to treat high blood pressure, ADHD, drug withdrawal (alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and certain pain conditions.[11] The drug is often prescribed off-label for tics. It is used orally (by mouth), by injection, or as a transdermal skin patch.[11] Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.[11]
Common side effects include dry mouth, dizziness, headaches, hypotension, and sleepiness.
Clonidine was patented in 1961 and came into medical use in 1966.
Medical uses
Clonidine is used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD), drug withdrawal (alcohol, opioids, or smoking), menopausal flushing, diarrhea, and certain pain conditions. It also sees some use off-label for episodic insomnia, restless-legs syndrome, and anxiety, among other uses.[11]
Resistant hypertension
Clonidine may be effective for lowering blood pressure in people with resistant hypertension.[18]
Clonidine works by slowing the
Attention deficit hyperactivity disorder
Clonidine may improve symptoms of attention deficit hyperactivity disorder in some people but causes many adverse effects and the beneficial effect is modest.[20] In Australia, clonidine is an accepted but not approved use for ADHD by the TGA.[21] Clonidine, along with methylphenidate, has been studied for treatment of ADHD.[22][23][24] While not as effective as methylphenidate in treating ADHD, clonidine does offer some benefit;[22] it can also be useful in combination with stimulant medications.[25] Some studies show clonidine to be more sedating than guanfacine, which may be better at bedtime along with an arousing stimulant in the morning.[26][27] Clonidine has been used to reduce sleep disturbances in ADHD, including to help offset stimulant-associated insomnia.[28][29][30][31] Unlike stimulant medications, clonidine is regarded as having no abuse potential, and may even be used to reduce abuse of drugs including nicotine and cocaine.[32]
In the US, only the extended-release form of clonidine is approved for ADHD treatment.[33]
Drug withdrawal
Clonidine may be used to ease drug withdrawal symptoms associated with abruptly stopping the long-term use of
Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.[39]
Spasticity
Clonidine has some role in the treatment of spasticity, acting principally by inhibiting excessive sensory transmission below the level of injury[
Clonidine suppression test
The reduction in circulating norepinephrine by clonidine was used in the past as an investigatory test for
Other uses
Clonidine also has several
Injection of α2 receptor agonists into the knee joint space, including clonidine, may reduce the severity of knee pain after arthroscopic knee surgery.[63]
Light-activated derivatives of clonidine (adrenoswitches) have been developed for research purposes and shown to control pupillary reflex with light in blind mice by topical application.[64]
Pregnancy and breastfeeding
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.[65] Clonidine appears in high concentration in breast milk; a nursing infant's serum clonidine concentration is approximately 2/3 of the mother's.[66] Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.[67]
Adverse effects
The principal adverse effects of clonidine are sedation, dry mouth, and hypotension (low blood pressure).[5]
Very common (>10% frequency):
- Dizziness
- Orthostatic hypotension
- Somnolence (dose-dependent)
- Dry mouth
- Headache (dose-dependent)
- Fatigue
- Skin reactions (if given transdermally)
- Hypotension
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
- Paresthesia
- Sinus bradycardia
- Raynaud's phenomenon
- Pruritus
- Urticaria
Rare (<0.1% frequency):
- Gynaecomastia
- Impaired ability to cry
- Atrioventricular block
- Nasal dryness
- Colonic pseudo-obstruction
- Alopecia
- Hyperglycemia
Withdrawal
Because clonidine suppresses sympathetic outflow, resulting in lower blood pressure, sudden discontinuation can result in acute hypertension due to a rebound in sympathetic outflow. In extreme cases, this can result in a hypertensive crisis, which is a medical emergency.[69]
Clonidine therapy should generally be gradually tapered when discontinuing therapy to avoid
Pharmacology
Site | Ki (nM) | Species | Ref |
---|---|---|---|
NET | >1,000 | Human | [73] |
5-HT1B | >10,000 | Rat | [74] |
5-HT2A | >10,000 | Human | [72] |
α1A | 316.23 | Human | [73] |
α1B | 316.23 | Human | [73] |
α1D | 125.89 | Human | [73] |
α2A | 35.48 – 61.65 | Human | [73][75] |
α2B | 69.18 – 309.0 | Human | [75][73] |
α2C | 134.89 – 501.2 | Human | [75][73] |
D1 |
> 10,000 | Rat | [76] |
I1 | 31.62 | Bovine | [73] |
I2 (cortex) | >1,000 | Rat | [73] |
MAO-A | >1,000 | Rat | [73] |
MAO-B | >1,000 | Rat | [73] |
σ | >10,000 | Guinea Pig | [77] |
The Ki refers to a drug's affinity for a receptor. The smaller the Ki, the higher the affinity for that receptor.[78] Reported imidazoline-2 binding is measured in the cortex — I2 receptor bindings measured in stomach membranes are much lower.[79] |
Mechanism of action
Clonidine crosses the blood–brain barrier.[7]
High blood pressure
Clonidine treats high blood pressure by stimulating
Clonidine also acts as an agonist at imidazoline-1 (I1) receptors in the brain, and it is hypothesized that this effect may contribute to reducing blood pressure by reducing signaling in the sympathetic nervous system; this effect acts upstream of the central α2 agonist effect of clonidine.[10]: 201–203 [80]
Clonidine may also cause bradycardia, theoretically by increasing signaling through the vagus nerve. When given intravenously, clonidine can temporarily increase blood pressure by stimulating α1 receptors in smooth muscles in blood vessels.[81] This hypertensive effect is not usual when clonidine is given orally or by the transdermal route.[10]: 201–203
Plasma concentration of clonidine exceeding 2.0 ng/mL does not provide further blood pressure reduction.[82]
Attention deficit hyperactivity disorder
In the setting of attention deficit hyperactivity disorder (ADHD), clonidine's molecular mechanism of action occurs due to its agonism at the α2A adrenergic receptor, the subtype of the adrenergic receptor that is most principally found in the brain. Within the brain, the α2A adrenergic receptors are found within the prefrontal cortex (PFC), among other areas. The α2A adrenergic receptors are found on the presynaptic cleft of a given neuron, and, when activated by an agonist, the effect on downstream neurons is inhibitory. The inhibition is accomplished by preventing the secretion of the neurotransmitter norepinephrine. Thus, clonidine's agonism on α2A adrenergic receptors in the PFC inhibits the action of downstream neurons by preventing the secretion of norepinephrine.[83]
This mechanism is similar to the brain's physiological inhibition of PFC neurons by the
Growth hormone test
Clonidine stimulates release of GHRH hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone.[84] This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children.[85]
Pharmacokinetics
After being ingested, clonidine is absorbed into the blood stream rapidly with an overall
Measurements of the half-life of clonidine vary widely, between 6 and 23 hours, with the half-life being greatly affected by and prolonged in the setting of poor kidney function.[86] Variations in half-life may be partially attributable to CYP2D6 genetics.[9] Some research has suggested the half-life of clonidine is dose dependent and approximately doubles upon chronic dosing,[91] while other work contradicts this.[4] Following a 0.3 mg oral dose, a small study of five patients by Dollery et al. (1976) found half-lives ranging between 6.3 and 23.4 hours (mean 12.7).[92] A similar N=5 study by Davies et al. (1977) found a narrower range of half-lives, between 6.7 and 13 hours (average 8.6 hours),[2] while an N=8 study by Keraäen et al. that included younger patients found a somewhat shorter average half-life of 7.5 hours.[93]
History
Clonidine was introduced in 1966.[94] It was first used as a hypertension treatment under the trade name of Catapres.[95]
Society and culture
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, Lonid, Melzin, Menograine, Normopresan, Paracefan, Pinsanidine, Run Rui, and Winpress.[96] It was marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso.[96]
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External links
- Alpha-2 agonists in ADHD