Common side effect include dry mouth, dizziness, headaches, hypotension, and sleepiness. Severe side effects may include hallucinations, heart arrhythmias, and confusion. If rapidly stopped, withdrawal effects may occur. Use during pregnancy or breastfeeding is not recommended. Clonidine lowers blood pressure by stimulating α2 receptors in the brain, which results in relaxation of many arteries.
Clonidine was patented in 1961 and came into medical use in 1966. It is available as a generic medication. In 2018, it was the 75th most commonly prescribed medication in the United States, with more than 11million 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 to be more sedating than guanfacine, which may be better at bed time along with an arousing stimulant in the morning.
Clonidine has also been suggested as a treatment for rare instances of dexmedetomidine withdrawal.
Clonidine has some role in the treatment of spasticity, acting principally by inhibiting excessive sensory transmission below the level of injury. Its use, however, is mainly as a second or third line agent, due to side effects such as hypotension, bradycardia and drowsiness.
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).
Because clonidine suppresses sympathetic outflow, resulting in lower blood pressure, sudden discontinuation can result in acute hypertension due to a rebound in sympathetic outflow. In extreme cases, this can result in a hypertensive crisis, which is a medical emergency.
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.
Plasma concentration of clonidine exceeding 2.0 ng/mL does not provide further 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 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.
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, Lonid, 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.
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