Clonidine

Clonidine
Clinical data
Pronunciation /ˈklɒnədiːn/
Trade names Catapres, Kapvay, Nexiclon, others
AHFS/Drugs.com Monograph
MedlinePlus a682243
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
    Bioavailability 75–95% (oral), 60–70% (transdermal)[1]
    Protein binding 20–40%[2]
    Metabolism Hepatic to inactive metabolites,[2] 2/3 CYP2D6
    Elimination half-life IR: 12–16 hours,[3] 48 hours for repeated dosing[1]
    Excretion Urine (72%)[2]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard 100.021.928 Edit this at Wikidata
    Chemical and physical data
    Formula C9H9Cl2N3
    Molar mass 230.093 g/mol
    3D model (JSmol)
      (verify)

    Clonidine is a medication that is used to treat high blood pressure, attention deficit hyperactivity disorder, anxiety disorders, tic disorders, withdrawal (from either alcohol, opioids, or smoking), migraine, menopausal flushing, diarrhea, and certain pain conditions.[4] It is marketed under many brand names.

    The adverse effects include sedation, dry mouth, and low blood pressure.[2]

    Clonidine treats high blood pressure by stimulating α2 receptors in the brain stem, which decreases peripheral vascular resistance, lowering blood pressure. Clonidine also may cause bradycardia, probably by increasing signaling through the vagus nerve. When given intravenously, clonidine temporarily increases blood pressure by stimulating postsynaptic α2 receptors in smooth muscle in the lining of blood vessels. This does not occur when clonidine is given by mouth or transdermally.[5]:201–203

    It has been in use as a medication since 1966.[6][7]

    Medical uses

    Clonidine tablets and transdermal patch

    Clonidine was introduced in 1966.[8] It was first used as a hypertension treatment under the trade name of Catapres.[9] The US Food and Drug Administration (FDA) has approved clonidine for the treatment of attention deficit hyperactivity disorder (ADHD), under the trade name of Kapvay alone or with stimulants in 2010, for pediatric patients aged 6–17 years.[2][10] It was later approved for adults. In Australia, clonidine is an accepted but not approved use for ADHD by the TGA.[11] Clonidine along with methylphenidate has been studied for treatment of ADHD.[12][13][14] While not as effective as methylphenidate in treating ADHD, Clonidine does offer some benefit;[15] it can also be useful in combination with stimulant medications.[16] Some studies show clonidine more sedating than guanfacine, which may be better at bed time along with an arousing stimulant at morning.[17][18] Clonidine can be used in the treatment of Tourette syndrome (specifically for tics).[19]

    Clonidine may be used to ease withdrawal symptoms associated with the long-term use of narcotics, alcohol, benzodiazepines and nicotine (smoking).[20] 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.[21] It may also be helpful in aiding smokers to quit.[22] The sedation effect is also useful. However, its side effects can include insomnia, thus exacerbating an already common feature of opioid withdrawal.[23]

    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.[24][25][26][27][28][29][30][31] Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures.[32] Its epidural use for pain during heart attack, postoperative and intractable pain has also been studied extensively.[33] Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.[34] Clonidine can be used in restless legs syndrome.[35] It can also be used to treat facial flushing and redness associated with rosacea.[36] It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy.[37] Clonidine can also be used for migraine headaches and hot flashes associated with menopause.[38][39] Clonidine has also been used to treat diarrhea associated with irritable bowel syndrome, fecal incontinence, diabetes, withdrawal-associated diarrhea, intestinal failure, neuroendocrine tumors and cholera.[40]

    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.[41] 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.[41]

    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.[42] 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.[43]

    Adverse effects

    The principal adverse effects of clonidine are sedation, dry mouth, and hypotension (low blood pressure).[2]

    Adverse effects by frequency[42][44]

    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

    Clonidine suppresses sympathetic outflow resulting in lower blood pressure, but sudden discontinuation can cause rebound hypertension due to a rebound in sympathetic outflow.[4]

    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.[45][46]

    Pharmacology

    Mechanism of action

    ReceptorKi (nM)[47]
    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.[48]

    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.[5]: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.[5]:201–203[49]

    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.[50] This hypertensive effect is not usual when clonidine is given by mouth or by the transdermal route.[5]:201–203

    Attention deficit hyperactivity disorder

    Structural comparison between the neurotransmitter norepinephrine and the drug clonidine. Both drugs bind to alpha-2 adrenergic receptors.[51] 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.[51]

    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 adreneric 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.[51]

    Growth hormone test

    Clonidine stimulates release of growth hormone releasing hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone.[52] This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children.[53]

    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.[54] Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6;[55][54] 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.[56] 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.[54] About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces.[54] 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.[54]

    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.[57] It was marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso.[57]

    References

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    35. ↑ "Treatment and Management of RLS". www.medscape.org. WebMD LLC. Retrieved 3 October 2018.
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    41. 1 2 Eisenhofer, G; Goldstein, DS; Walther, MM; et al. (2003). "Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results". Journal of Clinical Endocrinology & Metabolism. 88 (6): 2656–2666. doi:10.1210/jc.2002-030005. PMID 12788870.
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