Clonidine

Clonidine, sold under the brand name Catapres among others, is an α_2A-adrenergic receptor agonist, hypotensive and anxiolytic agent<ref name="Goodman13">Template:Cite book</ref> used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD), drug withdrawal (e.g., alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and certain pain conditions.<ref name="AHFS2019">Template:Cite web</ref> The drug is often prescribed off-label for tics. It is used orally (by mouth), by injection, or as a transdermal skin patch.<ref name="AHFS2019" /> Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.<ref name="AHFS2019" /> Xylazine is a structural analog of clonidine.

Common side effects include dry mouth, dizziness, headaches, hypotension, and sleepiness.<ref name="AHFS2019" /> Severe side effects may include hallucinations, heart arrhythmias, and confusion.<ref name="BNF76">Template:Cite book</ref> If rapidly stopped, withdrawal effects may occur, such as a dangerous rise in blood pressure.<ref name="AHFS2019" /> Use during pregnancy or breastfeeding is not recommended.<ref name="BNF76" /> Clonidine lowers blood pressure by stimulating α₂-adrenergic receptors in the brain, which results in relaxation of many arteries.<ref name="AHFS2019" />

Clonidine was patented in 1961 and came into medical use in 1966.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=Fis2006>Template:Cite book</ref> It is available as a generic medication.<ref name=AHFS2019/> In 2023, it was the 82nd most commonly prescribed medication in the United States, with more than 8Template:Nbspmillion prescriptions.<ref name="Top300Drugs">Template:Cite web</ref><ref>Template:Cite web</ref> Template:TOC limit

Medical uses

File:Clonidine pills and patch.jpg

Clonidine tablets and transdermal patch

Clonidine is used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD); drug withdrawal, including from (alcohol, opioids, and/or nicotine); menopausal flushing, diarrhea, and certain pain conditions. In addition, it also sees some use off-label for episodic insomnia, and tics (e.g. from Tourette syndrome, restless legs syndrome, and anxiety, among others).<ref name=AHFS2019/>

Resistant hypertension

Clonidine may be effective for lowering blood pressure in people with resistant hypertension.<ref>Template:Cite journal</ref>

Clonidine works by slowing the pulse rate and exerts a reduction of serum concentrations of renin, aldosterone, and catecholamines.<ref name="DailyMed">Template:Cite web</ref>

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.<ref>Template:Cite journal</ref> In Australia, clonidine is an accepted but not approved use for ADHD by the Therapeutic Goods Administration.<ref name="AMH">Template:Cite book</ref> Clonidine, along with methylphenidate, has been studied for treatment of ADHD.<ref name="Clonidine for attention-deficit">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Effects">Template:Cite journal</ref> While not as effective as methylphenidate in treating ADHD, clonidine does offer some benefit;<ref name="Clonidine for attention-deficit" /> it can also be useful in combination with stimulant medications.<ref>Template:Cite journal</ref> Some studies show clonidine to be more sedating than guanfacine, which may be better at bedtime along with an arousing stimulant in the morning.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Clonidine has been used to reduce sleep disturbances in ADHD, including to help offset stimulant-associated insomnia.<ref name="pmid24027233">Template:Cite journal</ref><ref name="pmid15853572">Template:Cite journal</ref><ref name="SchacharIckowicz1999">Template:Cite book</ref><ref name="pmid8169189">Template:Cite journal</ref> 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.<ref name="Walker2014">Template:Cite journal</ref>

In the US, only the extended-release form of clonidine is approved for ADHD treatment.<ref name="FDA_PI">Template:Cite web</ref>

Borderline personality disorder

Clonidine has been studied off-label in borderline personality disorder (BPD) to address specific acute symptoms such as hyperarousal, inner tension, dissociation, self-injurious urges, and sleep disturbances.Template:Citation needed

A systematic review of psychopharmacology in BPD identified clonidine as a promising adjunctive therapy targeting noradrenergic dysregulation, especially in comorbid PTSD cases. However, it emphasized the limitations of small sample sizes and called for larger placebo-controlled trials.<ref>Stoffers, J. M., & Lieb, K. (2015). Pharmacotherapy for borderline personality disorder—symptom targeted and disorder specific treatment options. Current Pharmaceutical Design, 21(23), 3301–3311.</ref>

Clinicians often employ clonidine when BPD patients present with acute emotional dysregulation, intrusive dissociation, or insomnia. Clinical anecdotal reports and patient experiences have also highlighted its practical utility.Template:Citation needed

Drug withdrawal

Clonidine may be used to ease drug withdrawal symptoms associated with abruptly stopping the long-term use of opioids, alcohol, benzodiazepines, and nicotine.<ref>Template:Cite journal</ref> It can alleviate opioid withdrawal symptoms by reducing the sympathetic nervous system response such as tachycardia and hypertension, hyperhidrosis (excessive sweating), hot and cold flashes, and akathisia.<ref>Template:Cite book</ref> It may also be helpful in aiding smokers to quit.<ref>Template:Cite journal</ref> The sedation effect can also be useful. Clonidine may also reduce severity of neonatal abstinence syndrome in infants born to mothers that are using certain drugs, particularly opioids.<ref>Template:Cite journal</ref> In infants with neonatal withdrawal syndrome, clonidine may improve the neonatal intensive care unit Network Neurobehavioral Score.<ref>Template:Cite journal</ref>

Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.<ref>Template:Cite journal</ref>

Spasticity

Clonidine has some role in the treatment of spasticity caused by spinal cord injury, acting principally by inhibiting excessive sensory transmissionTemplate:Clarify span Its use, however, is mainly as a second or third line agent, due to side effects such as hypotension, bradycardia, and drowsiness.<ref>Template:Cite journal</ref> Clonidine can be administered intrathecally,<ref name="PMID18443642">Template:Cite journal</ref> which confers various benefits, including a reduction or prevention of the blood pressure lowering effects and increased effectiveness against spasticity.<ref name="PMID11723871">Template:Cite journal</ref> The effectiveness of intrathecal clonidine is comparable to that of intrathecal baclofen for spasticity.<ref name=PMID11723871/>

Clonidine suppression test

The reduction in circulating norepinephrine by clonidine was used in the past as an investigatory test for phaeochromocytoma, which is a catecholamine-synthesizing tumor, usually found in the adrenal medulla.<ref name="pmid12788870">Template:Cite journal</ref> 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.<ref name="pmid12788870"/>

Other uses

Clonidine also has several off-label uses, and has been prescribed to treat psychiatric disorders including stress, hyperarousal caused by post-traumatic stress disorder, borderline personality disorder, and other anxiety disorders.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures.<ref name=premed>Template:Cite journal</ref> It has also been studied as a way to calm acute manic episodes.<ref>Template:Cite journal</ref> Its epidural use for pain during heart attack, and postoperative and intractable pain has also been studied extensively.<ref>Template:Cite journal</ref> Clonidine can be used in restless legs syndrome.<ref name="RLS medscape">Template:Cite web</ref> It can also be used to treat facial flushing and redness associated with rosacea.<ref>Template:Cite journal</ref> It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy.<ref>Template:Cite journal</ref> Clonidine can also be used for migraine headaches and hot flashes associated with menopause.<ref name="Web MD">Template:Cite web</ref><ref>Template:Cite web</ref> Clonidine has also been used to treat refractory diarrhea associated with irritable bowel syndrome, fecal incontinence, diabetes, diarrhea associated with opioid withdrawal, intestinal failure, neuroendocrine tumors, and cholera.<ref>Template:Cite journal</ref> Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).<ref>Template:Cite journal</ref> Clonidine has also had some success in clinical trials for helping to remove or ameliorate the symptoms of hallucinogen persisting perception disorder (HPPD).<ref>Template:Cite journal</ref>

Injection of α₂-adrenergic receptor agonists into the knee joint space, including clonidine, may reduce the severity of knee pain after arthroscopic knee surgery.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Pregnancy and breastfeeding

It is classified by the Australian Therapeutic Goods Administration 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.<ref name = TGA>Template:Cite web</ref> Clonidine appears in high concentration in breast milk; a nursing infant's serum clonidine concentration is approximately 2/3 of the mother's.<ref>Template:Cite book</ref> Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.<ref>Template:Cite web</ref>

Adverse effects

The principal adverse effects of clonidine are sedation, dry mouth, and hypotension (low blood pressure).<ref name = MSR/>

Pharmacology

Clonidine<ref name="PDSP">Template:Cite web</ref>

Site	Ki (nM)	Species	Ref
Template:Abbrlink	>1,000	Human	<ref name="milan2000"/>
5-HT1B	>10,000	Rat	<ref>Template:Cite journal</ref>
5-HT2A	>10,000	Human	<ref name="PDSP"/>
α1A	316.23	Human	<ref name="milan2000">Template:Cite journal</ref>
α1B	316.23	Human	<ref name="milan2000"/>
α1D	125.89	Human	<ref name="milan2000"/>
α2A	35.48 – 61.65	Human	<ref name="milan2000"/><ref name="Jasper1998">Template:Cite journal</ref>
α2B	69.18 – 309.0	Human	<ref name="Jasper1998" /><ref name="milan2000" />
α2C	134.89 – 501.2	Human	<ref name="Jasper1998" /><ref name="milan2000" />
D1	> 10,000	Rat	<ref name="Neve1990">Template:Cite journal</ref>
I1	31.62	Bovine	<ref name="milan2000" />
I2 (cortex)	>1,000	Rat	<ref name="milan2000" />
MAO-A	>1,000	Rat	<ref name="milan2000" />
MAO-B	>1,000	Rat	<ref name="milan2000" />
σ	>10,000	Guinea Pig	<ref>Template:Cite journal</ref>
The Ki refers to a drug's affinity for a receptor. The smaller the Ki, the higher the affinity for that receptor.<ref name="Pharmacology 2009">Template:Cite book</ref> Reported imidazoline-2 binding is measured in the cortex — I2 receptor bindings measured in stomach membranes are much lower.<ref>Template:Cite journal</ref>

Mechanism of action

Clonidine crosses the blood–brain barrier.<ref name="DailyMed III"/>

High blood pressure

Clonidine treats high blood pressure by stimulating α₂ receptors in the brainstem, 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, renin, and neuropeptide Y which if released would increase vascular resistance.<ref name=Goodman13/>Template:Rp

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.<ref name=Goodman13/>Template:Rp<ref name=imidazoline>Template:Cite journal</ref>

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.<ref name=":0">Template:Cite journal</ref> This hypertensive effect is not usual when clonidine is given orally or by the transdermal route.<ref name="Goodman13"/>Template:Rp

Plasma concentration of clonidine exceeding 2.0 ng/mL does not provide further blood pressure reduction.<ref name="DailyMed IV">Template:Cite web</ref>

Attention deficit hyperactivity disorder

File:Structural comparison of norepinephrine and clonidine.svg

Structural comparison between the neurotransmitter norepinephrine and the drug clonidine. Both compounds bind to α₂ adrenergic receptors.<ref name="Cinnamon Review" /> Similarities between the two structures are shown highlighted in red.

In the setting of attention deficit hyperactivity disorder (ADHD), clonidine's molecular mechanism of action occurs due to its agonism at the α_2A adrenergic receptor, the subtype of the adrenergic receptor that is most principally found in the brain. Within the brain, the α_2A adrenergic receptors are found within the prefrontal cortex (PFC), among other areas. The α_2A 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 α_2A adrenergic receptors in the PFC inhibits the action of downstream neurons by preventing the secretion of norepinephrine.<ref name="Cinnamon Review">Template:Cite journal</ref>

This mechanism is similar to the brain's physiological inhibition of PFC neurons by the locus ceruleus (LC), which secretes norepinephrine into the PFC. Although norepinephrine can also bind to target adrenergic receptors on the downstream neuron (otherwise inducing a stimulatory effect), norepinephrine also binds to α_2A adrenergic receptors (akin to clonidine's mechanism of action), inhibiting the release of norepinephrine by that neuron and inducing an inhibitory effect. Because the PFC is required for working memory and attention, it is thought that clonidine's inhibition of PFC neurons helps to eliminate irrelevant attention (and subsequent behaviors), improving the person's focus and correcting deficits in attention.<ref name="Cinnamon Review" />

Growth hormone test

Clonidine stimulates release of GHRH hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone.<ref name="pmid1901390">Template:Cite journal</ref> This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children.<ref name="GH Test Cinci">Template:Cite web</ref>

Pharmacokinetics

After being ingested, clonidine is absorbed into the blood stream rapidly with an overall bioavailability around 70–80%.<ref name="davies">Template:Cite journal</ref> Peak concentrations in human plasma occur within 60–90 minutes for the "immediate release" (IR) version of the drug, which is shorter than the "extended release" (ER/XR) version.<ref name="Khan Review 1999">Template:Cite journal</ref> Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6;<ref name="Foye 2008">Template:Cite book</ref><ref name="Khan Review 1999" /> to compare, the optimal log P to allow a drug that is active in the human central nervous system to penetrate the blood brain barrier is 2.0.<ref name="Pajouhesh 2005">Template:Cite journal</ref> Less than half of the absorbed portion of an orally administered dose will be metabolized by the liver into inactive metabolites, with roughly the other half being excreted unchanged by the kidneys.<ref name="Khan Review 1999" /> About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces.<ref name="Khan Review 1999" /> Work with liver microsomes shows in the liver clonidine is primarily metabolized by CYP2D6 (66%), CYP1A2 (10–20%), and CYP3A (0–20%) with negligible contributions from the less abundant enzymes CYP3A5, CYP1A1, and CYP3A4.<ref name="cypmetabolism"/> 4-hydroxyclonidine, the main metabolite of clonidine, is also an α_2A agonist but is non lipophilic and is not believed to contribute to the effects of clonidine since it does not cross the blood–brain barrier.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="Khan Review 1999" /> Variations in half-life may be partially attributable to CYP2D6 genetics.<ref name="cypmetabolism"/> Some research has suggested the half-life of clonidine is dose dependent and approximately doubles upon chronic dosing,<ref name="halflife">Template:Cite journal</ref> while other work contradicts this.<ref name = clinp/> 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).<ref>Template:Cite journal</ref> A similar N=5 study by Davies et al. (1977) found a narrower range of half-lives, between 6.7 and 13 hours (mean 8.6),<ref name="davies"/> while an N=8 study by Keraäen et al. that included younger patients found a somewhat shorter mean half-life of 7.5 hours.<ref>Template:Cite journal</ref>

History

Clonidine was introduced in 1966.<ref name="history1">Template:Cite journal</ref> It was first used as a hypertension treatment under the trade name of Catapres.<ref>Template:Cite web</ref>

Society and culture

Brand names

As of June 2017, clonidine is 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.<ref name=brands>Template:Cite web</ref> It is marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso.<ref name=brands/>

External links

• Alpha-2 agonists in ADHD