Clonidine

Clonidine, sold as the brand name Catapres among others, is a medication used to treat high blood pressure, attention deficit hyperactivity disorder, drug withdrawal (alcohol, opioids, or smoking), menopausal flushing, diarrhea, and certain pain conditions.[7] It is used by mouth, by injection, or as a skin patch.[7] Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.[7]

Clonidine
Clinical data
Pronunciation/ˈklɒnədiːn/
Trade namesCatapres, Kapvay, Nexiclon, others
AHFS/Drugs.comMonograph
MedlinePlusa682243
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    administration    		By mouth, epidural, IV, transdermal, topical
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability70–80% (oral),[1] 60–70% (transdermal)[2]
    Protein binding20–40%[3]
    MetabolismLiver to inactive metabolites,[3] 2/3 CYP2D6
    Onset of actionIR:30-60 minutes after an dose by mouth[4]
    Elimination half-lifeIR: 12–16 hours; 41 hours in kidney failure,[5][6] 48 hours for repeated dosing[2]
    ExcretionUrine (72%)[3]
    Identifiers
    CAS Number
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.021.928
    Chemical and physical data
    FormulaC9H9Cl2N3
    Molar mass230.09 g·mol−1
    3D model (JSmol)
      (verify)

    Common side effect include dry mouth, dizziness, headaches, and sleepiness.[7] Severe side effects may include seeing or hearing things that other people do not, heart arrhythmias, and confusion.[8] If rapidly stopped, withdrawal effects may occur.[7] Use during pregnancy or breastfeeding is not recommended.[8] Clonidine lowers blood pressure by stimulating α2 receptors in the brain, which results in relaxation of many arteries.[7]

    Clonidine was patented in 1961 and came into medical use in 1966.[9][10][11] It is available as a generic medication.[7] As of 2019 a month of medication costs the NHS about £8.[8] In the United States this amount costs about US$2.70 as of 2019.[12] In 2017, it was the 79th most commonly prescribed medication in the United States, with more than ten million prescriptions.[13][14]

    Medical uses
    Clonidine tablets and transdermal patch

    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.[7]

    Resistant hypertension

    Clonidine may be effective for lowering blood pressure in people with resistant hypertension.[15]

    Clonidine works by slowing the pulse rate and exert a reduction of serum concentrations of renin, aldosterone and catecholamines.[16]

    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.[17] In Australia, clonidine is an accepted but not approved use for ADHD by the TGA.[18] Clonidine along with methylphenidate has been studied for treatment of ADHD.[19][20][21] 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.[23] Some studies show clonidine more sedating than guanfacine, which may be better at bed time along with an arousing stimulant at morning.[24][25]

    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 (smoking).[26] 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.[27] It may also be helpful in aiding smokers to quit.[28] The sedation effect is also useful. However, its side effects can include insomnia, thus exacerbating an already common feature of opioid withdrawal.[29] Clonidine may also reduce severity of neonatal abstinence syndrome in infants born to mothers that are using certain drugs, particularly opioids.[30] In infants with neonatal withdrawal syndrome, clonidine may improve the neonatal intensive care unit Network Neurobehavioral Score.[31]

    Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.[32]

    Other

    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.[33][34][35][36][37][38][39][40] Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures.[41] Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively.[42] Clonidine can be used in restless legs syndrome.[43] It can also be used to treat facial flushing and redness associated with rosacea.[44] It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy.[45] Clonidine can also be used for migraine headaches and hot flashes associated with menopause.[46][47] 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.[48] Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).[49]

    Injection into the knee joint space of α2 receptor agonists, including clonidine, may reduce the severity of knee pain after arthroscopic knee surgery.[50]

    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 tumour, usually found in the adrenal medulla.[51] 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.[51]

    Pregnancy and breastfeeding

    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.[52] Clonidine appears in high concentration in breast milk and nursing infants have approximately 2/3 of serum clonidine concentrations as the mother.[53] Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.[54]

    Adverse effects

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

    By frequency[52][55]

    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

    While clonidine suppresses sympathetic outflow resulting in lower blood pressure, the sudden discontinuation can cause rebound hypertension due to a rebound in sympathetic outflow.[56]

    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.[57][58]

    Pharmacology

    Mechanism of action
    ReceptorKi (nM)[59]
    Alpha-1A adrenergic receptor316.23
    Alpha-1B adrenergic receptor316.23
    Alpha-1D adrenergic receptor125.89
    Alpha-2A adrenergic receptor42.92
    Alpha-2B adrenergic receptor106.31
    Alpha-2C adrenergic receptor233.1
    The Ki refers to a drug's affinity for a receptor. The smaller the Ki, the higher the affinity for that receptor.[60]

    Clonidine crosses the blood-brain barrier.[5]

    High blood pressure

    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, renin, and neuropeptide Y which if released would increase vascular resistance.[61]:201–203

    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, but this effect acts upstream of the central α2 agonist effect of clonidine.[61]:201–203[62]

    Clonidine also may cause bradycardia, probably 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.[63] This hypertensive effect is not usual when clonidine is given by mouth or by the transdermal route.[61]:201–203

    Plasma concentration of clonidine exceeding 2.0 ng/mL does not provide further blood pressure reduction.[64]

    Attention deficit hyperactivity disorder
    Structural comparison between the neurotransmitter norepinephrine and the drug clonidine. Both drugs bind to alpha-2 adrenergic receptors.[65] 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 alpha-2A adrenergic receptor, the subtype of the alpha-2 adrenergic receptor that is most principally found in the brain. Within the brain, the alpha-2A adrenergic receptors are found within the prefrontal cortex (PFC), among other areas. The alpha-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 alpha-2A adrenergic receptors in the PFC inhibits the action of downstream neurons by preventing the secretion of norepinephrine.[65]

    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 alpha-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.[65]

    Growth hormone test

    Clonidine stimulates release of growth hormone releasing hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone.[66] This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children.[67]

    Pharmacokinetics

    After being ingested, clonidine is absorbed into the blood stream rapidly and nearly completely, with peak concentrations in human plasma occurring within 60–90 minutes.[68] Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6;[69][68] 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.[70] 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.[68] About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces.[68] The half-life of clonidine varies widely, with estimates between 6 and 23 hours, and is greatly affected by and prolonged in the setting of poor kidney function.[68]

    History

    Clonidine was introduced in 1966.[71] It was first used as a hypertension treatment under the trade name of Catapres.[72]

    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.[73] It was marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso.[73]

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