Clonidine was patented in 1961 and came into medical use in 1966. It is available as a generic medication. As of 2019 a month of medication costs the NHS about £8. In the United States this amount costs about US$2.70 as of 2019. In 2016 it was the 76th most prescribed medication in the United States with more than 10 million prescriptions.
Clonidine may improve symptoms of attention deficit hyperactivity disorder in some people but causes many adverse effects and the beneficial effect is modest. In Australia, clonidine is an accepted but not approved use for ADHD by the TGA. Clonidine along with methylphenidate has been studied for treatment of ADHD. While not as effective as methylphenidate in treating ADHD, clonidine does offer some benefit; it can also be useful in combination with stimulant medications. Some studies show clonidine more sedating than guanfacine, which may be better at bed time along with an arousing stimulant at morning.
Clonidine may be used to ease drug withdrawal symptoms associated with abruptly stopping the long-term use of opioids, alcohol, benzodiazepines and nicotine (smoking). 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. It may also be helpful in aiding smokers to quit. The sedation effect is also useful. However, its side effects can include insomnia, thus exacerbating an already common feature of opioid withdrawal. Clonidine may also reduce severity of neonatal abstinence syndrome in infants born to mothers that are using certain drugs, particularly opioids. In infants with neonatal withdrawal syndrome, clonidine may improve the neonatal intensive care unit Network Neurobehavioral Score.
Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.
Injection into the knee joint space of α2 receptor agonists, including clonidine, may reduces the severity of knee pain after arthroscopic knee surgery.
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. 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.
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. Clonidine appears in high concentration in breast milk and nursing infants have approximately 2/3 of serum clonidine concentrations as the mother. Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.
The principal adverse effects of clonidine are sedation, dry mouth, and hypotension (low blood pressure).
Clonidine suppresses sympathetic outflow resulting in lower blood pressure, but sudden discontinuation can cause rebound hypertension due to a rebound in sympathetic outflow.
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.
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. This hypertensive effect is not usual when clonidine is given by mouth or by the transdermal route.:201–203
Plasma concentration of clonidine exceeding 2.0 ng/mL will not confer further efficacy in blood pressure reduction.
Attention deficit hyperactivity disorder
Structural comparison between the neurotransmitter norepinephrine and the drug clonidine. Both drugs bind to alpha-2 adrenergic receptors. 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.
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.
Growth hormone test
Clonidine stimulates release of growth hormone releasing hormone from the hypothalamus, which in turn stimulates pituitary release of growth hormone. This effect has been used as part of a "growth hormone test," which can assist with diagnosing growth hormone deficiency in children.
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. Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6; 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. 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. About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces. 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.
Clonidine was introduced in 1966. It was first used as a hypertension treatment under the trade name of Catapres.
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. It was marketed as a combination drug with chlortalidone as Arkamin-H, Bemplas, Catapres-DIU, and Clorpres, and in combination with bendroflumethiazide as Pertenso.
^"CATAPRES- clonidine hydrochloride tablet". DailyMed. 2016-09-06. Retrieved 2019-12-21. The pharmacokinetics of clonidine is dose-proportional in the range of 100 to 600 µg.The absolute bioavailability of clonidine on oral administration is 70% to 80%. Peak plasma clonidine levels are attained in approximately 1 to 3 hours.
^"CATAPRES- clonidine hydrochloride tablet". DailyMed. 2016-09-06. Retrieved 2019-12-21. CATAPRES tablets act relatively rapidly. The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours.
^ ab"CATAPRES- clonidine hydrochloride tablet". DailyMed. 2016-09-06. Retrieved 2019-12-21. Following intravenous administration, clonidine displays biphasic disposition with a distribution half-life of about 20 minutes and an elimination half-life ranging from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Clonidine crosses the placental barrier. It has been shown to cross the blood-brain barrier in rats.
^"CATAPRES- clonidine hydrochloride tablet". DailyMed. 2016-09-06. Retrieved 2019-12-21. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise. Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines.
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^"CATAPRES- clonidine hydrochloride tablet". DailyMed. 2016-09-06. Retrieved 2019-12-21. The antihypertensive effect is reached at plasma concentrations between about 0.2 and 2.0 ng/mL in patients with normal excretory function. A further rise in the plasma levels will not enhance the antihypertensive effect.