Клонидин: применение, действие и побочные эффекты

Pharmaceutical drug

Clonidine, sold under the brand name Catapres among others, is an α2A adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal (alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and certain pain conditions. The drug is often prescribed off label for tics. It is used orally (by mouth), by injection, or as a transdermal skin patch. If rapidly stopped, withdrawal effects may occur. It is available as a generic medication.

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. It also sees some use off label for episodic insomnia, restless legs syndrome, and anxiety, among other uses. Clonidine works by slowing the pulse rate and exerts a reduction of serum concentrations of renin, aldosterone, and catecholamines.

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; Some studies show clonidine to be more sedating than guanfacine, which may be better at bedtime along with an arousing stimulant in the morning. Clonidine has been used to reduce sleep disturbances in ADHD, including to help offset stimulant associated insomnia. Unlike stimulant medications, clonidine is regarded as having no abuse potential, and may even be used to reduce abuse of drugs including nicotine and cocaine. In the US, only the extended release form of clonidine is approved for ADHD treatment.

Clonidine may be used to ease drug withdrawal symptoms associated with abruptly stopping the long term use of opioids, alcohol, benzodiazepines and nicotine. It can alleviate opioid withdrawal symptoms by reducing the sympathetic nervous system response such as tachycardia and hypertension, hyperhidrosis (excessive sweating), hot and cold flashes, and akathisia. It may also be helpful in aiding smokers to quit. The sedation effect can also be useful. 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.

Clonidine has some role in the treatment of spasticity, acting principally by inhibiting excessive sensory transmission Its use, however, is mainly as a second or third line agent, due to side effects such as hypotension, bradycardia, and drowsiness. Clonidine can be administered intrathecally, which confers various benefits, including a reduction or prevention of the blood pressure lowering effects and increased effectiveness against spasticity. The effectiveness of intrathecal clonidine is comparable to that of intrathecal baclofen for spasticity. 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. Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures. It has also been studied as a way to calm acute manic episodes. Its epidural use for pain during heart attack, and postoperative and intractable pain has also been studied extensively. Clonidine can be used in restless legs syndrome. It can also be used to treat facial flushing and redness associated with rosacea. It has also been successfully used topically in a clinical trial as a treatment for diabetic neuropathy. Clonidine can also be used for migraine headaches and hot flashes associated with menopause. 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. Clonidine can be used in the treatment of Tourette syndrome (specifically for tics). Clonidine has also had some success in clinical trials for helping to remove or ameliorate the symptoms of hallucinogen persisting perception disorder (HPPD). Injection of α2 receptor agonists into the knee joint space, including clonidine, may reduce the severity of knee pain after arthroscopic knee surgery. Light activated derivatives of clonidine (adrenoswitches) have been developed for research purposes and shown to control pupillary reflex with light in blind mice by topical application.

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. Caution is warranted in women who are pregnant, planning to become pregnant, or are breastfeeding.

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.

+ Clonidine Site Ki (nM) Species Ref >1,000 Human 5 HT2A >10,000 Human α1B 316.23 Human α2B 69.18 – 309.0 Human I1 31.62 Bovine The Ki refers to a drug's affinity for a receptor. The smaller the Ki, the higher the affinity for that receptor. Reported imidazoline 2 binding is measured in the cortex — I2 receptor bindings measured in stomach membranes are much lower.

Clonidine crosses the blood–brain barrier. Clonidine may also cause bradycardia, theoretically 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 orally or by the transdermal route.

[[File:Structural comparison of norepinephrine and clonidine. svg|thumb|325px|right|Structural comparison between the neurotransmitter norepinephrine and the drug clonidine. Both drugs bind to α2 adrenergic receptors. 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 α2A 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. 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 with an overall bioavailability around 70–80%. 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. Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6; 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. Measurements of the half life of clonidine vary widely, between 6 and 23 hours, with the half life being greatly affected by and prolonged in the setting of poor kidney function. while other work contradicts this. A similar N=5 study by Davies et al. (1977) found a narrower range of half lives, between 6.7 and 13 hours (average 8.6 hours),

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.