Clonidine, sold under the brand nameCatapres andKapvay, among others, is anα2-adrenergic receptor agonist,hypotensive andanxiolytic agent used to treathigh blood pressure,attention deficit hyperactivity disorder,perioperative pain,drug withdrawal (e.g.,alcohol,opioids, ornicotine), andmenopausal flushing.[15][16][17] Clonidine is often prescribed off-label fortics. It is usedorally (by mouth), byinjection, or as atransdermal skin patch.[17] Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.[17]Xylazine is astructural analog ofclonidine.[18]
Common side effects includedry mouth,dizziness,headaches,hypotension, andsleepiness.[17] Severe side effects may includehallucinations,heart arrhythmias, andconfusion.[19] If rapidly stopped, withdrawal effects may occur, such asa dangerous rise in blood pressure.[17] Use duringpregnancy orbreastfeeding is not recommended.[19] Clonidine lowers blood pressure by stimulatingα2-adrenergic receptors andimidazoline receptors in the brain, which results in relaxation of many arteries.[15][17]
Clonidine was patented in 1961 and came into medical use in 1966.[20][21][22] It is available as ageneric medication.[17] In 2023, it was the 82nd most commonly prescribed medication in the United States, with more than 8 million prescriptions.[23][24]
Clonidine is used to treathigh blood pressure,attention deficit hyperactivity disorder (ADHD);drug withdrawal, including from (alcohol,opioids, and/ornicotine);menopausal flushing,diarrhea, and certain pain conditions.[6][10][8][17]
Hypertension is a chronic elevation ofarterial blood pressure that increases the risk ofcardiovascular disease and organ damage.[25] Many people with essential hypertension experience increasedsympathetic nervous system activity, in addition torenin–angiotensin–aldosterone system activation.[25] Clonidine is a non-selectiveα2 adrenoreceptor andimidazoline receptor agonist that reduces sympathetic nervous system output from the brainstem, which lowers peripheralvascular resistance,heart rate and plasmarenin activity, thereby reducing systolic and diastolic blood pressure as a consequence.[15]
Meta-analyses ofrandomized controlled trials in arterial hypertension have found that clonidine is an effective antihypertensive that leads to greater reductions in systolic and diastolic blood pressure than placebo.[26][27] A 2024 network meta-analysis ofimidazoline receptor agonists (i.e.,moxonidine and clonidine) reported that this drug class produced ambulatory blood pressure reductions that were close in magnitude to those of commonly used first-line antihypertensive drug classes, but with higher odds of adverse effects such as dry mouth and sedation, especially with clonidine.[27] Hypertension Canada's 2020 clinicalpractice guideline on resistant hypertension similarly notes that clonidine significantly lowers blood pressure in clinical trials, though it is considered asecond-line therapy due to its potential for side effects.[28] A 2025 review of randomized and observational studies ontransdermal clonidine reported that once-weekly patch formulations achieve blood pressure reductions similar tobeta blockers,calcium channel blockers anddiuretics, while reducing the risk ofwithdrawal-related rebound hypertension compared withoral clonidine.[29]
Clonidine is not considered a first-line treatment for hypertension due to its propensity to cause sedation andxerostomia compared with other antihypertensive medications (e.g.,angiotensin-converting enzyme inhibitors).[30] When used for blood pressure control, clonidine is typically reserved forhypertensive emergencies rather than routine management hypertension, but it is considered appropriate for treatingresistant hypertension.[30]
Clonidine is used as anon-stimulant pharmacological treatment forADHD and isUSFDA-approved in itsextended-release formulation as both amonotherapy and anadjunctive therapy topsychostimulants.[note 1][32][33] Clinical guidelines and comparative-efficacy reviews regard psychostimulant medications (i.e.,amphetamine andmethylphenidate) as first-linepharmacotherapy for ADHD, while non-stimulant agents such as clonidine are recommended as second-line options because their effect sizes are smaller than those of psychostimulants.[34][35][36] Non-stimulant medications, including clonidine, are typically used in individuals who do not respond adequately to psychostimulants, cannot tolerate psychostimulant adverse effects, have contraindications such as tic disorders or a high risk of psychostimulant misuse, or who have a preference for a non-stimulant treatment.[34][32][36] α2 adrenoreceptor agonists (i.e., clonidine andguanfacine) are one class of non-stimulant medications that treat ADHD by stimulating receptors expressed in theprefrontal cortex, thereby enhancingcognitive control of behavior.[32][36] Clonidine acts non-selectively atα2A,α2B andα2C receptor subtypes across the central nervous system, whereas guanfacine is selective for α2A adrenoreceptors in the prefrontal cortex, a difference that is believed to be partially responsible for clonidine's greater propensity for sedative and hypotensive side effects.[15][35][36]
Randomized controlled trials show that clonidine monotherapy reduces core ADHD symptoms, including inattention, hyperactivity, impulsivity and disruptive behavior, compared with placebo.[32][36][33] Medical reviews on the efficacy of non-stimulant medications for ADHD indicate that clonidine produces moderate effect sizes for core symptom reduction, which are smaller than the large effect sizes reported for psychostimulants.[35][36] In contrast to the rapid onset seen with psychostimulant medications, clinically significant symptom improvement may be delayed by a few weeks.[32][35] Reviews of alpha-2 agonists suggest that this drug class may be more effective for managing hyperactivity and impulsivity than for inattentive ADHD symptoms, and that long-term treatment efficacy has been documented more extensively forguanfacine than for clonidine.[35][36][37] Unlike psychostimulants, clonidine is regarded as having no abuse potential due in part to a lack ofdopaminergic activity along themesolimbic pathway.[38]
Clonidine is also used as an add-on to psychostimulant medications in individuals who have a partial response to psychostimulants, cannot tolerate higher psychostimulant doses, or experience notable early-morning or evening symptoms.[32][35][36] In a randomized controlled trial of ADHD children with an incomplete response to psychostimulants, the addition of clonidine extended-release produced greater reductions in ADHD symptom scores than continuing psychostimulant monotherapy.[32] α2 adrenoreceptor agonists may also improve symptoms incomorbidities of ADHD such astic disorders,oppositional or aggressive behavior, andinsomnia.[32][36][39]
Sleep disturbances are common in individuals with ADHD and may arise both from the disorder itself and as adverse effects of psychostimulant medications, which can cause delayed sleep onset and insomnia.[40] Whilst clonidine's sedative properties, particularly in its immediate-release formulation, can limit its acceptability as a monotherapy for core ADHD symptoms during the daytime, it has been used as asleep aid in ADHD individuals who are also treated with psychostimulants and experience insomnia.[35][36][39] Evidence suggests that immediate-release clonidine taken at bedtime can reduce sleep-onset difficulties and night-time awakenings, but its treatment effects do not persist into the following day and it is therefore not generally effective for daytime ADHD symptoms when used in this manner.[32][36][39]
Clonidine is sometimes used inperioperative medicine as anadjunctive therapy during theperioperative period, where it is administered alongside otheranalgesics to providesedation and pain-control.[41][42] Whilst clonidine itself has limited clinical utility as amonotherapy forpostoperative pain, its combination withopioid medications may allow adequate pain relief to be achieved at lower opioid doses, which may reduce the frequency and severity of opioid-related adverse effects.[42] Compared with other sedative and opioid medications used perioperatively, clonidine does not producerespiratory depression oranterograde amnesia.[42] Moreover, itshemodynamic-stabilising effects and ability to reduce postoperativeshivering are considered particularly useful in patients at high risk ofmyocardial ischaemia.[42] Clonidine also hasanxiolytic properties that may help reducepreoperative anxiety.[42] In perioperative settings, clonidine may beorally ingested during the preoperative stage or administeredintravenously orintramuscularly immediately before, during or shortly after surgery.[41] Clonidine can also be administered viaepidural orintrathecalcatheters as an adjuvant to local anesthetics to enhance perioperative and postoperativeneuraxial blockade.[43][41] Clonidine's analgesic effects are attributed in part to activation of α2 adrenoreceptors within thedorsal horn of the spinal cord, which inhibits the release ofpronociceptive neurotransmitters fromprimary afferent terminals andhyperpolarizesnociceptiveinterneurons.[43][15][42]
A 2017 systematic review and meta-analysis of 57 randomized controlled trials (RCTs) found that clonidine improved postoperative pain control.[41] In a subset of trials reporting detailed postoperative analgesia outcomes, clonidine delayed the time until patients required additional pain medication and reduced cumulative postoperative analgesic consumption over the first 24 hours by ~24%.[41] The same review reported that clonidine reduced the incidence of postoperative nausea and vomiting compared with placebo.[41] Meta-analyses of α2 adrenoreceptor agonists (i.e., clonidine anddexmedetomidine) likewise report small to moderate reductions in postoperative pain intensity and opioid consumption during the first postoperative day, consistent with an opioid-sparing effect, but are limited by substantialstatistical heterogeneity.[44][45] In one meta-analysis of clonidine RCTs, overall adverse event rates did not differsignificantly between clonidine and placebo.[41] However, that same paper noted that a large included trial reported a higher incidence of hypotension and non-fatal cardiac arrest with clonidine, and that the available data were insufficient to rule out uncommon but serious hemodynamic complications.[41]
Clonidine may be used to ease drug withdrawal symptoms associated with abruptly stopping the long-term use ofopioids,alcohol,benzodiazepines, andnicotine.[46] It can alleviateopioid withdrawal symptoms by reducing thesympathetic nervous system response such astachycardia andhypertension,hyperhidrosis (excessive sweating), hot and cold flashes, andakathisia.[47] It may also be helpful in aiding smokers to quit.[48] The sedation effect can also be useful. Clonidine may also reduce severity ofneonatal abstinence syndrome in infants born to mothers that are using certain drugs, particularly opioids.[49] In infants with neonatal withdrawal syndrome, clonidine may improve theneonatal intensive care unit Network Neurobehavioral Score.[50]
Clonidine has also been suggested as a treatment for rare instances ofdexmedetomidine withdrawal.[51]
The reduction in circulating norepinephrine by clonidine was used in the past as an investigatory test forphaeochromocytoma, which is acatecholamine-synthesizing tumor, usually found in theadrenal medulla.[52] 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.[52]
Clonidine also has severaloff-label uses, and has been prescribed to treatpsychiatric disorders includingstress,hyperarousal caused bypost-traumatic stress disorder,borderline personality disorder, and otheranxiety disorders.[53][54][55][56][57][58][59] It has also been studied as a way to calm acutemanic episodes.[60] Clonidine can be used inrestless legs syndrome.[61] It can also be used to treat facial flushing and redness associated withrosacea.[62] It has also been successfully used topically in a clinical trial as a treatment fordiabetic neuropathy.[63] Clonidine can also be used formigraine headaches andhot flashes associated withmenopause.[64][65] Clonidine has also been used to treat refractorydiarrhea associated withirritable bowel syndrome,fecal incontinence, diabetes, diarrhea associated with opioid withdrawal,intestinal failure,neuroendocrine tumors, andcholera.[66] Clonidine can be used in the treatment ofTourette syndrome (specifically fortics).[67] Clonidine has also had some success in clinical trials for helping to remove or ameliorate the symptoms ofhallucinogen persisting perception disorder (HPPD).[68]
The most commonadverse side effects of clonidine aredry mouth andsedation.[69][70][39][42] Many side effects are dose-related and tend to diminish withtolerance that develops from continued use.[69][70] For the same reason that clonidine has efficacy for treating hypertension,hypotension andbradycardia arepredictable dose-dependent effects.[42] However, with overdose in children, the degree of central nervous system depression does not clearly correlate with the ingested dose.[71]
Cardiovascular side effects can include hypotension (includingorthostatic hypotension) and bradycardia;atrioventricular block and otherbradyarrhythmias have also been reported.[42]Raynaud's phenomenon andsyncope may also occur.[39][42] Because clonidine can cause bradycardia and hypotension, precautions are advised in people withsinoatrial node dysfunction (e.g.,sick sinus syndrome) oratrioventricular block, and in those with severecoronary artery disease,cerebrovascular disease, orchronic kidney failure.[72]
Gastrointestinal side effects can includexerostomia,constipation,nausea, andvomiting.[39][42]Colonic pseudo-obstruction has been described as a rare side effect.[70]
Other reported physical side effects includeheadache,fatigue orweakness and, less commonly,urinary retention and transientedema.[39][42] In addition to dry mouth, clonidine has been reported to reducetear production (i.e.,dry eyes), a rare side effect that may be more noticeable in people who wearcontact lenses.[42]
Skin reactions appear to occur uniquely with transdermal formulations of clonidine;[69]contact dermatitis at the transdermal patch application site has been reported in about 15% to 20% of users.[69]
Common psychological side effects from clonidine include sedation,drowsiness, anddizziness.[70][39][42] The sedative effect of intravenous clonidine is dose-dependent and attributed in part to α2B adrenoceptor activation in thethalamus.[15]Sleep disturbance anddepressed mood have been reported, and theAustralian Medicines Handbook advises caution in people with a history of depression.[39][72][42] Less common neuropsychiatric reactions reported with clonidine (i.e., <1%) include disturbed mental state,nightmares,confusion,hallucinations, anddelusions.[70][39][42]
Physical dependence can develop with long-term clonidine use, and abrupt discontinuation can cause awithdrawal syndrome marked by a pronounced rebound increase in blood pressure.[72][42] Symptoms of clonidine withdrawal include a marked rise in blood pressure with symptoms such as headache,sweating,insomnia,agitation,tremor,palpitations,nervousness], andnausea.[72][42] Among dependent individuals, the severity of drug withdrawal appears to be significantly more pronounced in people with pre-existing hypertension and after prolonged treatment at higher doses (i.e., >900 mcg/day), and severe cases (hypertensive encephalopathy,stroke, anddeath) have been reported albeit rarely.[72][42] The severity of withdrawal symptoms is attenuated by tapering the dose.[72][42]
Clonidine is classified by the AustralianTherapeutic 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.[73] Clonidine appears in high concentration in breast milk; a nursing infant's serum clonidine concentration is approximately 2/3 of the mother's.[74] Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.[75]
| Site | Ki (nM) | Species | Ref |
|---|---|---|---|
| NETTooltip Norepinephrine transporter | >1,000 | Human | [77] |
| 5-HT1B | >10,000 | Rat | [78] |
| 5-HT2A | >10,000 | Human | [76] |
| α1A | 316.23 | Human | [77] |
| α1B | 316.23 | Human | [77] |
| α1D | 125.89 | Human | [77] |
| α2A | 35.48 – 61.65 | Human | [77][79] |
| α2B | 69.18 – 309.0 | Human | [79][77] |
| α2C | 134.89 – 501.2 | Human | [79][77] |
| D1 | > 10,000 | Rat | [80] |
| I1 | 31.62 | Bovine | [77] |
| I2 (cortex) | >1,000 | Rat | [77] |
| MAO-A | >1,000 | Rat | [77] |
| MAO-B | >1,000 | Rat | [77] |
| σ | >10,000 | Guinea Pig | [81] |
| TheKi refers to a drug's affinity for a receptor. The smaller the Ki, the higher the affinity for that receptor.[82] Reported imidazoline-2 binding is measured in the cortex — I2 receptor bindings measured in stomach membranes are much lower.[83] | |||
Clonidine produces most of itspharmacodynamic effects by acting as a non-selectivepartial agonist atα2 adrenoceptors (α2A, α2B, and α2C), where it can mimic the actions ofendogenousnorepinephrine at these receptors in thecentral nervous system and thesympathetic nervous system.[15] Clonidine can also bindimidazoline I1 receptors inbrainstem regions involved incardiovascular responses.[15] Through these actions clonidine lowersarterial blood pressure,heart rate, and totalperipheral resistance.[69][70] α2 adrenoceptor activation decreases noradrenergic arousal signaling in theascending reticular activating system, can modifyprefrontal cortical network activity relevant to attention, and suppressesnociceptive signaling in thedorsal horn of the spinal cord.[84][85][70]
α2 adrenoceptors areGi/Go-coupledG protein-coupled receptors that signal through heterotrimeric G proteins made up of a Gαi/osubunit protein and a paired Gβγ subunit complex (i.e., the β and γ subunits).[69][84] After receptor activation, Gαi/o and Gβγ can separate, and both components contribute to inhibition of neuronal activity and neurotransmitter release.[84][69] Gαi/o inhibitsadenylyl cyclase, which decreases the expression ofcyclic adenosine monophosphate (cAMP) and ceasesprotein kinase A (PKA)-dependentphosphorylation ofamino acid residues involved inneuronal excitability and synaptic signaling.[69][84] In parallel, Gβγ can increaseK+ conductance throughG protein-coupled inwardly rectifying potassium channels (GIRKs), an effect that reduces neuronal firing through membranehyperpolarization.[69][84]
In noradrenergic presynaptic neurons in the sympathetic nervous system, α2 adrenoceptors act as inhibitoryautoreceptors that inhibit action potential-evoked neurotransmitter release.[84][69] After presynaptic α2 adrenoceptor activation by clonidine, the released Gβγ dimer can inhibitvoltage-gated Ca2+ channels (including P/Q-type and N-type channels), which reducesCa2+ entry during presynapticdepolarization and lowers vesicular neurotransmitter release.[84] Gβγ signaling can also increase K+ conductance (including via GIRKs) to oppose presynaptic depolarization and further limit voltage-gated Ca2+ channel activation.[84][69] In addition, Gβγ can bind proteins within theSNARE complex (e.g.,SNAP-25), which can suppress synapticvesicle fusion downstream of Ca2+ entry.[84] These mechanisms reduce the release of norepinephrine and other neurotransmitters from affected nerve terminals.[84][69]
Clonidine lowers arterial blood pressure primarily by reducing sympathetic nervous system activity and increasingvagus nerve activity to theheart.[69][70] In themedulla oblongata, activation of α2 adrenoceptors reduces the firing of neurons that are responsible for sympathetic nerve signaling to the heart,kidneys, and peripheralvasculature and can slow heart rate by increasingvagal tone.[69][70] Atpostganglionic nerve fibers, presynaptic α2 adrenoceptors function as inhibitory autoreceptors that suppress nerve-evoked release of norepinephrine and other signaling compounds (includingadenosine triphosphate andneuropeptide Y).[69] These central and peripheral actions are associated with decreased plasma norepinephrine and reduced urinarycatecholamine excretion, and with reductions in plasmarenin and urinaryaldosterone reported alongside decreases in total peripheral resistance and heart rate.[69][70] With intravenous administration, clonidine may cause a short-lived increase in blood pressure attributed to α2 adrenoceptor-mediatedvasoconstriction in vascular smooth muscle, followed by a more sustained hypotensive response once clonidine crosses the blood brain barrier and binds to its receptor sites in the medulla oblongata; this biphasic pattern is generally less evident with oral or transdermal routes of administration due to dilution of the drug before reaching circulation.[69]
In the prefrontal cortex, α2A is the predominant α2 adrenoceptor subtype, and clonidine'sattention- andworking memory-related effects are attributed to postsynaptic α2A activation.[35][85] Across the brain more generally, α2A and α2C adrenoceptors are widely distributed, while α2B is primarily expressed in thethalamus.[36][15][85] α2A adrenoceptors ondendritic spines of prefrontalpyramidal neurons can closehyperpolarization-activated cyclic nucleotide-gated channels (HCNs) to promote attentional control and working memory.[85] The mechanism behind this behavioral effect has been described as the consequence of improvedsignal-to-noise ratio in the prefrontal cortex, which can facilitate focused attention on relevant stimuli and improved cognitive control of behavior.[35][85]
Sedation is attributed to clonidine's activity on noradrenergic neurons of the locus coeruleus and thalamus.[36][15]Somatodendritic α2 adrenoceptors reduce locus coeruleus firing, and presynaptic α2 adrenoceptors reduce norepinephrine release alongnoradrenergic pathways, in turn lowering noradrenergic modulation ofarousal in theascending reticular activating system.[84] α2 adrenoceptors are also expressed onaxon terminals that release several other neurotransmitters (i.e.,serotonin,dopamine,acetylcholine,GABA, andglutamate), and their activation can suppress release at these synapses as well.[84]
Clonidine produces analgesic effects in part through α2 adrenoceptors in thedorsal horn of the spinal cord.[70][84] In primary nociceptive neurons, α2A and α2C adrenoceptors are present on axon terminals and can be co-localized withneuropeptides involved in nociceptive signaling (e.g.,substance P andcalcitonin gene-related peptide), and clonidine inhibits their release in preclinical models.[84] Activation of α2 adrenoceptors in the spinal cord reduces excitatory input to dorsal horn neurons and decreases dorsal horn neuron firing, thereby inhibiting nociceptive signaling.[70][84]
The discovery of imidazoline receptors has prompted investigation of I1 receptor contributions to Clonidine's cardiovascular effects.[15][69] I1 receptors are widely distributed, including in the central nervous system, and I1 activation has been implicated in clonidine'ssympatholytic effect.[15][69] One proposed model is that I1 receptor activation in the brainstem facilitates endogenous catecholamine signaling that then activates α2 adrenoceptors to reduce sympathetic activity and blood pressure, but themagnitude of I1 receptors in clonidine's hypotensive effects remains unsettled.[69]
Clonidine stimulates release ofGHRH hormone from the hypothalamus, which in turn stimulates pituitary release ofgrowth hormone.[86] This effect has been used as part of a "growth hormone test," which can assist with diagnosinggrowth hormone deficiency in children.[87]
After being ingested, clonidine is absorbed into the blood stream rapidly with an overallbioavailability around 70–80%.[11]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.[88] Clonidine is fairly lipid soluble with thelogarithm of its partition coefficient (log P) equal to 1.6;[89][88] to compare, the optimal log P to allow a drug that is active in the humancentral nervous system to penetrate theblood brain barrier is 2.0.[90] Less than half of the absorbed portion of an orally administered dose will be metabolized by theliver into inactivemetabolites, with roughly the other half being excreted unchanged by thekidneys.[88] About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces.[88] Work with liver microsomes shows in the liver clonidine is primarily metabolized byCYP2D6 (66%),CYP1A2 (10–20%), andCYP3A (0–20%) with negligible contributions from the less abundant enzymesCYP3A5,CYP1A1, andCYP3A4.[14] 4-hydroxyclonidine, the main metabolite of clonidine, is also an α2A 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.[91][92]
Measurements of thehalf-life of clonidine vary widely, between 6 and 23 hours, with the half-life being greatly affected by and prolonged in the setting ofpoor kidney function.[88] Variations in half-life may be partially attributable toCYP2D6 genetics.[14] Some research has suggested the half-life of clonidine is dose dependent and approximately doubles upon chronic dosing,[93] while other work contradicts this.[12] 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).[94] 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),[11] while an N=8 study by Keraäen et al. that included younger patients found a somewhat shorter mean half-life of 7.5 hours.[95]
Clonidine was introduced in 1966.[96] It was first used as a hypertension treatment under the trade name of Catapres.[97]
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.[98] It is marketed as acombination drug withchlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination withbendroflumethiazide as Pertenso.[98]
A systematic review of psychopharmacology in borderline personality disorder 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.[99]
Clonidine is a relatively nonselective agonist at α2 receptors, with actions on α2A, α2B, and α2C receptors. In addition, clonidine has actions on imidazoline receptors, thought to be responsible for some of clonidine's sedating and hypotensive actions. Although the actions of clonidine at α2A receptors exhibit therapeutic potential for ADHD, its actions at other receptors may increase side effects. Clonidine is approved for the treatment of hypertension, but only the controlled release version of clonidine is approved for treatment of ADHD. ... Unlike clonidine, guanfacine is 15–60 times more selective for α2A receptors than for α2B and α2C receptors. Additionally, guanfacine is 10 times weaker than clonidine at inducing sedation and lowering blood pressure, yet it is 25 times more potent in enhancing prefrontal cortical function.
Compared with placebo/sham, a significant reduction in office sBP could also be accomplished with clonidine
In summary, both imidazoline receptor agonists, clonidine and moxonidine, were significantly more effective than placebo in all cases.
These agents attenuate noradrenaline release centrally (brainstem) reducing the output of vasoconstrictor signals to the peripheral SNS leading to hypotension and bradycardia. The classical example in this class is clonidine. This class of agents are used only in exceptional clinical cases and circumstances, mainly due to the limiting side effects of sedation, dry mouth, rebound effects after stopping, and depression. ... Clonidine may be used in resistant hypertension and hypertensive crisis particularly in patients in intensive care with concomitant agitation.
The psychostimulants, cocaine, amphetamine, and methylphenidate, are indirect DA agonists that interact with DA transporters. ... Cognitive control is impaired in several disorders, including attention deficit hyperactivity disorder (ADHD), which is treated with psychostimulants, a term used to describe indirect DA agonists such as methylphenidate and amphetamines that block DAT or cause reverse transport of DA.
Clonidine IR may be given at bedtime to help with sleep, but this will not help with ADHD symptoms during the day. Therefore, clonidine ER is preferred to clonidine IR for treating ADHD. ... Adding clonidine ER to a stimulant as an augmentation strategy has been shown to significantly improve ADHD symptoms for children who had only a partial response to stimulants.
In the prefrontal cortex, postsynaptic alpha-2 agonism leads to enhanced noradrenergic neurotransmission. This, in turn, strengthens the regulatory role of the prefrontal cortex, which is responsible for top-down guidance of attention, thought and working memory. ... While sharing the same mechanism of action, clonidine and guanfacine differ regarding their potency, with guanfacine being approximately ten times less potent than clonidine. The documented higher specificity of guanfacine to alpha-2A receptors may mediate differences between the two agents regarding the adverse effects profile, e.g., less sedative effects of guanfacine ... When sleep disturbances are present, clonidine and guanfacine may be considered.
Clonidine stimulates Alpha-2A, Alpha-2B, and Alpha2C, whereas guanfacine stimulates the Alpha-2A receptors in the prefrontal cortex. ... The most prominent side effect of both drugs is sedation and orthostatic hypotension. Sudden discontinuation of these drugs could also result in rebound hypertension. However, it has milder side effects than clonidine due to the longer duration of action of guanfacine. ... Although Clonidine has efficacy in reducing ADHD symptomatology, it is not favored for long-term treatment due to the risk of hypotension and a less favorable pharmacokinetic profile [40]. Switching patients from Clonidine IR to Guanfacine XR is one option for managing ADHD symptomatology
Historically, the α2-AR agonist, clonidine, was tested in ADHD, where it was thought that the powerful sedative effects of this nonselective agonist were helping to make patients less active (Hunt, Capper, & O'Connell, 1990). It is now known that the therapeutic effects are independent of, and indeed in spite of, these sedative side effects, with the development of guanfacine's use in ADHD based on understanding its prefrontal enhancement in monkeys (Arnsten and Contant, 1992, Arnsten et al., 1996), and the recognition that ADHD is a PFC disorder.
The reinforcing effects of cocaine and amphetamines require an intact mesolimbic dopamine system. ... Dopamine levels are increased in the NAc during self-administration of cocaine or amphetamines, as mentioned previously, and blockade of dopaminergic transmission in the NAc—for example, in response to intra-NAc injections of dopamine receptor antagonists or of the toxin 6-hydroxydopamine (Chapter 6)—dramatically reduces drug reinforcement. ... While physical dependence and withdrawal occur dramatically with some drugs of abuse (opiates, ethanol), these phenomena are not useful in the diagnosis of an addiction because they do not occur as robustly with other drugs of abuse (cocaine, amphetamine) and can occur with many drugs that are not abused (propranolol, clonidine).
Clonidine is the most common adjunctive drug for single-injection caudal blocks. Various mechanisms have been proposed to account for its favourable effect. Chief among them is presumably that clonidine binds to alpha-2 receptors in the dorsal horn of the spinal cord.
