Clonidin

Pharmaceuticals -> Antihypertensives

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

log Kow = 1.57

2.7

Insoluble in water

4.80e-01 g/L

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Adrenergic alpha-2 Receptor Agonists

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

130 °C

MP: 305 °C. Soluble in aboslute ethanol. One gram is soluble in 6 mLs water (60 °C); about 13 mLs water (20 °C); about 5.8 mLs methanol; about 25 mLs ethanol; about 5000 mLs chloroform. UV max (water): 213, 271, 302 nm (epsilon 8290.327, 713.074, 339.876) /Clonidine hydrochloride/

130 °C

8.05 (at 25 °C)

pKa = 8.05

Odorless, bitter tasting; pKa 8.2; does not exhibit polymorphism. White to off-white crystalline powder. 1 g in about 13 mL water at 20 °C; 1 g in about 25 mL alcohol; 1 g in about 5000 mL chloroform /Clonidine hydrochloride/

146.5 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID8044670]

144 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

142.2 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P260, P262, P264, P270, P271, P280, P284, P301+P316, P302+P352, P304+P340, P316, P320, P321, P330, P361+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 95 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clonidine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clonidine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Clonidine hydrochloride/

The commercially available transdermal system of clonidine should be stored at a temperature less than 30 °C. Clonidine hydrochloride tablets should be stored in tight, light-resistant containers at a controlled room temperature of 25 °C, but may be exposed to temperatures ranging from 15-30 °C. ... Commercially available clonidine hydrochloride injection should be stored at controlled room temperature of 25 °C, but may be exposed to temperatures ranging from 15-30 °C.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. (L1712)

Potential additive effects (eg, hypotension, bradycardia). If carvedilol is used concomitantly with clonidine, caution should be exercised, particularly when discontinuing therapy; carvedilol generally should be discontinued first, and clonidine continued for several days thereafter with gradual downward dosage titration.

Epidural clonidine may prolong the duration of the pharmacologic effects, including both sensory and motor blockade, of epidural local anesthetics.

Because beta-adrenergic blocking agents may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy, beta-adrenergic blocking agents should be discontinued several days before gradual withdrawal of clonidine when clonidine therapy is to be discontinued in patients receiving a beta-adrenergic blocking agent and clonidine concurrently. If clonidine therapy is to be replaced by a beta-adrenergic blocking agent, administration of the beta-adrenergic blocking agent should be delayed for several days after clonidine therapy has been discontinued

Because clonidine may produce bradycardia and atrioventricular (AV) block, the possibility of additive effects should be considered if it is given concomitantly with other drugs that affect sinus node function or AV nodal conduction (e.g., guanethidine), beta-adrenergic blocking agents (e.g., propranolol), calcium-channel blocking agents, or cardiac glycosides.

For more Interactions (Complete) data for CLONIDINE (15 total), please visit the HSDB record page.

Serum aminotransferase elevations during clonidine therapy are uncommon and rates of such elevations have not been reported in the large clinical trials, demonstrating its efficacy in hypertension. Despite many decades of use, clonidine has not been implicated in instances of clinically apparent acute liver injury.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 52(SRC), determined from a log Kow of 1.59(2) and a regression-derived equation(3), indicates that clonidine is expected to have high mobility in soil(SRC). The pKa of clonidine is 8.05(4), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization of Clonidine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.5X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(6). Clonidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 52(SRC), determined from a log Kow of 1.59(2) and a regression-derived equation(3), indicates that clonidine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 1.5X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 5(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2011).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), clonidine, which has an estimated vapor pressure of 1.9X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase clonidine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1 hour(SRC), calculated from its rate constant of 1.4X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase clonidine may be removed from the air by wet or dry deposition(SRC). Clonidine does not contain chromophores that absorb at wavelengths >290 nm(4), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Animal studies indicate that clonidine is widely distributed into body tissues; tissue concentrations of the drug are higher than plasma concentrations. The mean volume of distribution of clonidine is reported to be 2.1 L/kg. After oral administration, highest concentrations of the drug are found in the kidneys, liver, spleen, and GI tract. High concentrations of the drug also appear in the lacrimal and parotid glands. Clonidine is concentrated in the choroid of the eye and is also distributed into the heart, lungs, testes, adrenal glands, fat, and muscle. The lowest concentration occurs in the brain. Clonidine is distributed into CSF. Following epidural infusion, clonidine is rapidly and extensively distributed into CSF and readily partitions into the plasma via epidural veins. In vitro, clonidine is approximately 20-40% bound to plasma proteins, mainly albumin. Clonidine crosses the placenta1 and is distributed into milk. In one lactating woman who received approximately 0.04 mg of oral clonidine hydrochloride twice daily and 25 mg of oral dihydralazine 3 times daily, clonidine concentrations were 0.33 ng/mL in a plasma sample obtained 1 hour after a dose and 0.6 ng/mL in a milk sample obtained 2.5 hours after a dose; the drug was not detected in the plasma of the infant 1 hour after nursing.

Signs and Symptoms of Overdose

Clonidine acts as an agonist at presynaptic alpha(2)-receptors in the nucleus tractus solitarius of the medulla oblongata. Stimulation of these receptors results in the supression of efferent sympathetic pathways and the subsequent decrease in blood pressure and vascular tone in the heart, kidneys, and peripheral vasculature. Clonidine is also a partial agonist at presynaptic alpha(2)-adrenergic receptors of peripheral nerves in vascular smooth muscle.

The Koc of clonidine is estimated as 52(SRC), using a log Kow of 1.59(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that clonidine is expected to have high mobility in soil. The pKa of clonidine is 8.05(1), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/SIGNS AND SYMPTOMS/ The initial effect is usually mental status depression, which occurs within an hour of ingestion. Life-threatening signs of clonidine poisoning include apnea, coma, bradycardia, and hypotension. It also cause miosis and hypothermia. Cardiovascular effects usually follow central nervous system effects.

/SIGNS AND SYMPTOMS/ Hypotension is usually mild but may be more severe after large ingestion. The more direct and dangerous effects is hypoventilation and apnea from central respiratory failure. Coma and apnea are common effects after a large overdose. The mental status change is curious in that tactile stimulation has been noted to awaken the patient. For example, testing for a Babinski reflex may transiently awaken a formerly unresponsive patient.

/SIGNS AND SYMPTOMS/ Children may be more likely to experience CNS depression associated with clonidine overdosage. In children, signs of toxicity have occurred with oral clonidine doses as low as 0.1 mg. Rare cases of clonidine toxicity (many involving children) associated with accidental or deliberate mouthing or ingestion of clonidine transdermal systems have been reported.

/SIGNS AND SYMPTOMS/ Signs and symptoms of overdosage of clonidine include hypotension (which may be profound), transient hypertension, weakness, vomiting, irritability, diminished or absent reflexes, lethargy, somnolence, drowsiness, deep sedation, irritability, skin pallor, hypothermia, decreased or irregular heart rate, dryness of the mouth, constricted pupils with poor reaction to light, respiratory depression, and hypoventilation. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Signs and symptoms of clonidine overdosage usually occur within 30-120 minutes after ingestion.

For more Human Toxicity Excerpts (Complete) data for CLONIDINE (15 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clonidine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clonidine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Clonidine hydrochloride/

C02AC01

N - Nervous system

C - Cardiovascular system

S - Sensory organs

QN - Nervous system

QS - Sensory organs

Clonidine functions through agonism of alpha-2 adrenoceptors which have effects such as lowering blood pressure, sedation, and hyperpolarization of nerves. It has a long duration of action as it is given twice daily and the therapeutic window is between 0.1mg and 2.4mg daily.

Clonidine is primarily an alpha-2 adrenoceptor agonist which causes central hypotensive and anti-arrhythmogenic effects. The alpha-2 adrenoceptor is coupled to the G-proteins G_o and G_i. G_i inhibits adenylyl cyclase and activates opening of a potassium channel that causes hyperpolarization. Clonidine binding to the alpha-2 adrenoceptor causes structural changes in the alpha subunit of the G-protein, reducing its affinity for GDP. Magnesium catalyzes the replacement of GDP with GTP. The alpha subunit dissociates from the other subunits and associates with an effector. The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the hypnotic effects of clonidine as this region of the brain helps regulate wakefulness. Clonidine can also decrease transmission of pain signals at the spine. Finally clonidine can affect regulators of blood pressure in the ventromedial and rostral-ventrolateral areas of the medulla.

Intravenous infusion of clonidine causes an acute rise in blood pressure, apparently because of activation of postsynaptic alpha2 receptors in vascular smooth muscle. The affinity of clonidine for these receptors is high, although the drug is a partial agonist with relatively low efficacy at these sites. The hypertensive response that follows parenteral administration of clonidine generally is not seen when the drug is given orally. However, even after intravenous administration, the transient vasoconstriction is followed by a more prolonged hypotensive response which results from decreased central outflow of impulses in the sympathetic nervous system. ... The effect appears to result from activation of alpha2 receptors in the lower brain stem region. This central action has been demonstrated by infusing small amounts of the drug into the vertebral arteries or by injecting it directly into the cisterna magna.

Clonidine decreases discharges in sympathetic preganglionic fibers in the splanchnic nerve as well as in postganglionic fibers of cardiac nerves. These effects are blocked by alpha2-selective antagonists ... Clonidine also stimulates parasympathetic outflow, and this may contribute to the slowing of heart rates as a consequence of increased vagal tone as well as diminished sympathetic drive.

THE SITES OF ACTION OF CLONIDINE INDUCED ADRENAL-SUPPRESSANT EFFECT WERE INVESTIGATED IN SPONTANEOUSLY HYPERTENSIVE RATS. FIVE TO 10 MINUTES AFTER IV ADMINISTRATION OF CLONIDINE (3-100 MG/KG), THERE WAS A DECREASE IN BOTH SYMPATHETIC ADRENAL NERVE ACTIVITY AND ADRENAL CATECHOLAMINE SECRETION RATES, ALONG WITH THE DECREASE IN ARTERIAL BLOOD PRESSURE AND HEART RATE. APPARENTLY, BOTH THE ADRENAL MEDULLA AND THE SPINAL AND SUPRASPINAL STRUCTURES ARE THE RESPONSIBLE SITES OF ACTION OF CLONIDINE-INDUCED ADRENAL SUPPRESSION. THE CENTRAL ACTION OF CLONIDINE APPEARS TO PREDOMINATE OVER THE PERIPHERAL ACTION IN THIS SUPPRESSION.

Clonidine appears to stimulate alpha2-adrenergic receptors in the CNS (mainly in the medulla oblongata), causing inhibition, but not blockade, of sympathetic vasomotor centers. Cardiovascular reflexes remain intact, and normal homeostatic mechanisms and hemodynamic responses to exercise are maintained. The central effects of the drug result in reduced peripheral sympathetic nervous system activity, reduced peripheral and renovascular resistance, reduction of systolic and diastolic blood pressure, and bradycardia. Peripheral venous pressure remains unchanged. It has been postulated that the hypotensive response to clonidine may result from reduced angiotensin II generation because of inhibition of renin release or from reduced stimulation of medullary vasomotor centers responsive to circulating angiotensin II; however, the exact relationship between the action of the drug in reducing renin activity and excretion of aldosterone and catecholamines and the hypotensive effect of the drug has not been fully elucidated.

The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h.

The elimination half-life of the drug ranges from 6 to 24 hours, with a mean of about 12 hours.

THE PHARMACOKINETICS OF CLONIDINE WERE INVESTIGATED IN HEALTHY VOLUNTEERS OVER A TIME MORE THAN 3 TIMES LONGER THAN PREVIOUSLY REPORTED. THE COMPLETE BIOAVAILABILITY OF CLONIDINE AND ITS ELIMINATION T/2 (20 TO 25.5 HOURS) REMAINED CONSTANT AFTER SINGLE AND MULTIPLE DOSES.

The plasma half-life of clonidine is 6-20 hours in patients with normal renal function. The half-life in patients with impaired renal function has been reported to range from 18-41 hours. The elimination half-life of the drug may be dose dependent, increasing with increasing dose.

The metabolism of clonidine is poorly understood. The main reaction in clonidine metabolism is the 4-hydroxylation of clonidine by CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5. Clonidine is <50% metabolized in the liver to inactive metabolites.

Clonidine hydrochloride is metabolized in the liver. In humans, 4 metabolites have been detected but only one, the inactive p-hydroxyclonidine, has been identified.

...Seventeen cDNA-expressed P450 enzymes, in addition to pooled human liver microsomes, were evaluated for clonidine 4-hydroxylation activity in vitro. Five P450 enzymes-CYP2D6, 1A2, 3A4, 1A1, and 3A5-catalyzed measurable formation of 4-hydroxyclonidine. Selective inhibition studies in human liver microsomes confirmed that these isoforms are jointly responsible for 4-hydroxylation of clonidine in vitro, and CYP2D6 accounted for approximately two-thirds of the activity. The major role of CYP2D6 in clonidine metabolism might explain the increase in its nonrenal clearance during pregnancy.

CLONIDINE SHOWS SPECIES DIFFERENCES IN THE EXTENT OF BIOTRANSFORMATION. THE FATE OF (14)C-CLONIDINE IN THE DOG HAS BEEN REPORTED AND SIX COMPONENTS WERE ISOLATED AND IDENTIFIED. UNCHANGED CLONIDINE AND ITS P-HYDROXYLATED DERIVATIVE WERE DETECTED. DICHLOROPHENYLGUANIDINE, WHICH HAS PREVIOUSLY BEEN REPORTED AS A METABOLITE IN DOGS, WAS ALSO IDENTIFIED. THREE METABOLITES NOT PREVIOUSLY DESCRIBED WERE ALSO ISOLATED FROM DOG URINE. THE MAJOR METABOLIC ROUTES FOR CLONIDINE ARE PHENYL RING HYDROXYLATION AND SPLITTING OF THE IMIDAZOLIDINE RING. COMPARATIVE STUDIES SHOWED THAT THE METABOLISM OF CLONIDINE IS RATHER SIMILAR IN RAT, DOG, AND MAN, BUT MAN EXCRETED MOST UNCHANGED DRUG AND DOG SHOWED THE MOST EXTENSIVE METABOLISM.

Hepatic. Metabolized via minor pathways. The major metabolite, <i>p</i>-hydroxyclonidine, is present in concentrations less than 10% of those of unchanged clonidine in urine. Four metabolites have been detected, but only <i>p</i>-hydroxyclonidine has been identified. Half Life: 6-20 hours; 40-60% is excreted in urine unchanged, 20% is excreted in feces. Less than 10% is excreted by <i>p</i>-hydroxyclonidine.

MN3L5RMN02

CLONIDINE

Mechanisms of Action [MoA] - Adrenergic alpha2-Agonists

Established Pharmacologic Class [EPC] - Central alpha-2 Adrenergic Agonist

Clonidine is a Central alpha-2 Adrenergic Agonist. The mechanism of action of clonidine is as an Adrenergic alpha2-Agonist.

CLONIDINE

Compounds capable of relieving pain without the loss of CONSCIOUSNESS.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Drugs that inhibit the actions of the sympathetic nervous system by any mechanism. The most common of these are the ADRENERGIC ANTAGONISTS and drugs that deplete norepinephrine or reduce the release of transmitters from adrenergic postganglionic terminals (see ADRENERGIC AGENTS). Drugs that act in the central nervous system to reduce sympathetic activity (e.g., centrally acting alpha-2 adrenergic agonists, see ADRENERGIC ALPHA-AGONISTS) are included here.

Compounds that bind to and activate ADRENERGIC ALPHA-2 RECEPTORS.

Clonidine reaches maximum concentration in 60-90 minutes after oral administration. Race and fasting status do not influence pharmacokinetics of clonidine. A 100µg oral clonidine tablet reaches a Cmax of 400.72pg/mL with an AUC of 5606.78h\*pg/mL and a bioavailability of 55-87%.

Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces.

The volume of distribution of clonidine has been reported as 1.7-2.5L/kg, 2.9L/kg, or 2.1±0.4L/kg depending on the source.

The clearance of clonidine is 1.9-4.3mL/min/kg.

Animal studies indicate that clonidine is widely distributed into body tissues; tissue concentrations of the drug are higher than plasma concentrations. The mean volume of distribution of clonidine is reported to be 2.1 L/kg. After oral administration, highest concentrations of the drug are found in the kidneys, liver, spleen, and GI tract. High concentrations of the drug also appear in the lacrimal and parotid glands. Clonidine is concentrated in the choroid of the eye and is also distributed into the heart, lungs, testes, adrenal glands, fat, and muscle. The lowest concentration occurs in the brain. Clonidine is distributed into CSF. Following epidural infusion, clonidine is rapidly and extensively distributed into CSF and readily partitions into the plasma via epidural veins. In vitro, clonidine is approximately 20-40% bound to plasma proteins, mainly albumin. Clonidine crosses the placenta1 and is distributed into milk. In one lactating woman who received approximately 0.04 mg of oral clonidine hydrochloride twice daily and 25 mg of oral dihydralazine 3 times daily, clonidine concentrations were 0.33 ng/mL in a plasma sample obtained 1 hour after a dose and 0.6 ng/mL in a milk sample obtained 2.5 hours after a dose; the drug was not detected in the plasma of the infant 1 hour after nursing.

...IN HEALTHY VOLUNTEERS... AFTER IV INFUSION OF 300 UG CLONIDINE IN 10 MINUTES, PLASMA LEVELS OF DRUG DECLINED BI-EXPONENTIALLY WITH RAPID AND SLOW HALF-LIFE VALUES OF 11 MINUTES AND 8.5 HOURS, RESPECTIVELY.

MEDICATION

Use (kg; approx.) in Germany (2009): >10

May be used as an adjunct in the treatment of hypertension, as an epidural infusion as an adjunct treatment in the management of severe cancer pain that is not relieved by opiate analgesics alone, for differential diagnosis of pheochromocytoma in hypertensive patients, prophylaxis of vascular migraine headaches, treatment of severe dysmenorrhea, management of vasomotor symptoms associated with menopause, rapid detoxification in the management of opiate withdrawal, treatment of alcohol withdrawal used in conjunction with benzodiazepines, management of nicotine dependence, topical use to reduce intraocular pressure in the treatment of open-angle and secondary glaucoma and hemorrhagic glaucoma associated with hypertension, and in the treatment of attention-deficit hyperactivity disorder (ADHD).

Ammonium thiocyanate converts 2,6-dichloroaniline to the thiourea, which is treated with methyl iodide to yield the S-methylthiouronium salt. The latter compound, with ethylenediamine, closes the imidazoline ring to afford the product. /Clonidine hydrochloride/

Zeile et al, US patent 3,202,660 (1965 to Boehringer Ing). ... In shaving soap formulations, Zeile et al, US patent 3,190,802 (1965 to Boehringer Ing).

Table: Clonidine hydrochloride Preparations [Table#4364]

Table: Clonidine Preparations [Table#4365]