Clonidine

266.5548

230.09

224-119-4

MN3L5RMN02

DTXSID6022846

C380

Crystals

C02AC01|C - Cardiovascular system|N - Nervous system|S - Sensory organs

2933290090

36.42000

1.41

Solid

1.5±0.1 g/cm3

130 °C

319.3±52.0 °C at 760 mmHg

9℃

1.671

4.80e-01 g/L

-20°C

1.87X10-5 mm Hg at 25 deg C (est)

Oral-Rat  LD50 67.3  mg/kg; Oral-Mouse LD50: 108 mg/kg

Open flame, heat, oxidant is combustible; burning emits toxic chloride and nitrogen oxide fumes

8.05(at 25 °C)

Henry's Law constant = 1.51X10-11 atm-cu m/mol at 25 °C (est)

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/

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

Hydroxyl radical reaction rate constant =1.41X10-10 cu cm/molecule-sec at 25 °C (est)

UN1230 - class 3 - PG 2 - Methanol, solution

1

11-23/24/25-39/23/24/25

16-36/37-45

F,T

The warehouse is ventilated, low temperature and dry; lightly loaded and unloaded, stored separately from oxidants and acids

STABLE IN LIGHT, AIR, & HEAT /HCL/

Missing Phrase - N15.00950417

H301

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.

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/

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P260, P262, P264, P270, P271, P280, P284, P301+P310, P302+P350, P304+P340, P310, P320, P321, P322, P330, P361, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 94 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

highly toxic

Oral LD50 is 126 mg/kg in rats. The TDLO is 70µg/kg in children, 126µg/kg in women, and 69µg/kg in men. Symptoms of overdose include hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased reflexes, weakness, irritability, and miosis. Severe overdoses can cause reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Induction of vomiting is not recommended due to CNS depression but gastric lavage or activated charcoal may be useful in recent ingestion. Dialysis is also unlikely to be beneficial. Overdose can be treated with supportive measures such as atropine sulfate for bradycardia, intravenous fluids or vasopressors for hypotension, vasodilators for hypertension, naloxone for respiratory depression, and blood pressure monitoring.

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.

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.

LD50 Rat oral 126 mg/kg /Clonidine hydrochloride/|LD50 Rat ip 100 mg/kg /Clonidine hydrochloride/|LD50 Rat iv 29 mg/kg /Clonidine hydrochloride/|LD50 Rat sc 77 mg/kg /Clonidine hydrochloride/|For more Non-Human Toxicity Values (Complete) data for CLONIDINE (9 total), please visit the HSDB record page.

The elderly may be more sensitive than younger adults to clonidine's hypotensive effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving clonidine.

Clonidine is 20-40% bound to plasma proteins, especially albumin.

Clonidine's production and use as medication(1) may result in its release to the environment through various waste streams(SRC).

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).

The rate constant for the vapor-phase reaction of clonidine with photochemically-produced hydroxyl radicals has been estimated as 1.4X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about one hour at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Clonidine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Clonidine does not contain chromophores that absorb at wavelengths >290 nm(2), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 5 was calculated in fish for clonidine(SRC), using a log Kow of 1.59(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

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).

The Henry's Law constant for clonidine is estimated as 1.5X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that clonidine is expected to be essentially nonvolatile from water and moist soil surfaces(2). Clonidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-5 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to clonidine were not located(SRC, 2011), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).

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.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 339 workers (170 of these were female) were potentially exposed to clonidine in the US(1). Occupational exposure to clonidine may occur through inhalation and dermal contact with this compound at workplaces where clonidine is produced or used. Exposure to clonidine among the general population may be limited to those administered the drug Catapres, an antihypertensive(SRC).

Clonidine tablets and transdermal systems are indicated for the treatment of hypertension alone or in combination with other medications. A clonidine injection is indicated for use with opiates in the treatment of severe cancer pain where opiates alone are insufficient. An extended release tablet of clonidine is indicated for the treatment of ADHD either alone or in combination with other medications. Clonidine is also used for the diagnosis of pheochromocytoma, treatment of nicotine dependance, and opiate withdrawal.|Treatment of painful diabetic neuropathy

Clonidine is a centrally active alpha-adrenergic agonist used predominantly as an antihypertensive agent, usually in combination with other agents. Despite wide scale use for many years, clonidine has not been linked definitively to either serum aminotransferase elevations or clinically apparent liver injury.

Antihypertensive Agents

Adrenergic alpha-Agonists; Antihypertensive Agents; Sympatholytics; Analgesics|Clonidine hydrochloride and transdermal clonidine are used alone or in combination with other classes of antihypertensive agents in the management of hypertension. /Included in US product labeling/|Clonidine hydrochloride administered by epidural infusion is used as adjunctive therapy in combination with opiates in the management of severe cancer pain that is not relieved by opiate analgesics alone. /Clonidine hydrochloride; Included in US product labeling/|Oral loading-dose regimens of clonidine hydrochloride have been effective in rapidly reducing blood pressure in patients with severe hypertension in whom reduction of blood pressure was considered urgent, but not requiring emergency treatment. Hypertensive urgencies are those situations in which it is desirable to reduce blood pressure within a few hours. Such situations include the upper levels of severe hypertension, hypertension with optic disk edema, progressive target organ complications, and severe perioperative hypertension. /Clonidine hydrochloride; NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for CLONIDINE (15 total), please visit the HSDB record page.

Abrupt withdrawal of clonidine therapy may result in a rapid increase of systolic and diastolic blood pressures with associated symptoms such as nervousness, agitation, confusion, restlessness, anxiety, insomnia, headache, sweating, palpitation, increased heart rate, tremor, hiccups, stomach pains, nausea, muscle pains, and increased salivation. The exact mechanism(s) of the withdrawal syndrome following discontinuance of alpha-adrenergic agonists has not been determined but may involve increased concentrations of circulating catecholamines, increased sensitivity of adrenergic receptors, enhanced renin-angiotensin system activity, decreased vagal function, failure of autoregulation of cerebral blood flow, and/or failure of central alpha2-adrenergic receptor mechanisms that regulate sympathetic outflow from the CNS and modulate baroreflex function.|Because of the risk of rebound hypertension, patients receiving clonidine preparations should be warned of the danger of missing doses or stopping the drug without consulting their physician. When discontinuing clonidine therapy, a rapid rise in blood pressure may be minimized or prevented by tapered withdrawal of the drug over 2-4 days. Tapered withdrawal of transdermal clonidine or initiation of a tapered regimen of oral clonidine also is recommended by some clinicians when the transdermal dosage form is discontinued, particularly in geriatric patients. If clonidine therapy is to be discontinued in patients receiving clonidine and a beta-adrenergic blocking agent concomitantly, the beta-adrenergic blocker should be discontinued several days before clonidine therapy is discontinued. It is recommended that clonidine therapy not be interrupted for surgery; transdermal therapy can be continued throughout the perioperative period and oral therapy should be continued to within 4 hours before surgery. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if necessary. If clonidine therapy must be interrupted for surgery, parenteral hypotensive therapy should be administered as necessary, and clonidine therapy should be resumed as soon as possible. If transdermal therapy is initiated during the perioperative period, it must be kept in mind that therapeutic plasma clonidine concentrations are not achieved until 2-3 days after initial application of the transdermal system.|Implantable epidural catheters are associated with a risk of infection, including meningitis and/or epidural abscess. The incidence of catheter-related infections is about 5-20%, and depends on several factors, including the clinical status of the patient, type of catheter used, catheter placement technique, quality of catheter care, and duration of catheter placement. The possibility of catheter-related infection should be considered in patients receiving epidural clonidine who develop a fever.|Fever, malaise, pallor, muscle or joint pain, and leg cramps have been reported in up to 0.5% of patients during postmarketing experience with transdermal clonidine.|For more Drug Warnings (Complete) data for CLONIDINE (22 total), please visit the HSDB record page.

...TOLERANCE TO ANTIHYPERTENSIVE EFFECT DEVELOPS MORE FREQUENTLY & RAPIDLY WHEN CLONIDINE IS GIVEN ALONE THAN WHEN IT IS COMBINED WITH THIAZIDE DIURETIC.

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.

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. (See all compounds classified as Sympatholytics.)|Compounds that bind to and activate ADRENERGIC ALPHA-2 RECEPTORS. (See all compounds classified as Adrenergic alpha-2 Receptor Agonists.)|Compounds capable of relieving pain without the loss of CONSCIOUSNESS. (See all compounds classified as Analgesics.)|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. (See all compounds classified as Antihypertensive Agents.)

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 C_max 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.|THE PHARMACOKINETICS OF CLONIDINE WERE INVESTIGATED IN HEALTHY VOLUNTEERS OVER A TIME MORE THAN 3 TIMES LONGER THAN PREVIOUSLY REPORTED. APPROXIMATELY 62% OF A GIVEN DOSE WAS EXCRETED UNCHANGED IN URINE, INDEPENDENT OF THE QUANTITY ADMINISTERED, THE DRUG FORMULATION, OR THE MODE OF ADMINISTRATION. SINCE THE PHARMACOKINETICS OF THE DRUG WERE AFFECTED BY ENTEROHEPATIC CIRCULATION, IT CANNOT BE DESCRIBED BY A CONVENTIONAL, OPEN 1 OR 2 COMPARTMENT MODEL. THE TIME COURSES OF THE PLASMA CLONIDINE CONCENTRATION AND ITS DRUG EFFECTS RAN ASYNCHRONOUSLY.|CLONIDINE KINETICS WERE STUDIED IN 21 PATIENTS WITH ESSENTIAL HYPERTENSION WHO RECEIVED 2 BOLUS IV INJECTIONS (0.78-3.36 MCG/KG) AND ONE SINGLE ORAL DOSE (1.7-2.3 MCG/KG) ON SEPARATE OCCASIONS; KINETICS WERE STUDIED IN SOME PATIENTS AFTER MULTIPLE THERAPEUTIC ORAL DOSES (1.1 OR 1.9 MCG/KG TWICE DAILY) DURING A DOSAGE INTERVAL AFTER 6-12 MONTHS MONOTHERAPY WITH CLONIDINE. WITH INCREASING IV DOSES, THE RATE CONSTANTS DECREASED AND THE PLASMA CLEARANCE WAS REDUCED BY 74% (9.94-2.61 ML/MIN/KG) INDICATING DOSE-DEPENDENT KINETICS. THE VOLUME OF DISTRIBUTION DID NOT CHANGE WITH DOSE IN CONTRAST TO THE VOLUME OF THE PLASMA COMPARTMENT WHICH WAS INCREASED AT THE HIGHEST DOSES. THE SINGLE ORAL DOSE KINETICS AGREED WITH THE IV KINETICS AT COMPARABLE DOSE. THE BIOAVAILABILITY WAS 90%. DURING MULTIPLE ORAL DOSING THE ELIMINATION RATE CONSTANTS DECREASED COMPARED TO THE SINGLE DOSE. THE PLASMA CLEARANCE INCREASED (7.18 ML/MIN/KG) COMPARED TO THE CORRESPONDING SINGLE DOSE (4.17 ML/MIN/KG). THE LATTER CHANGE WAS PROBABLY CAUSED BY THE DECREASE IN BIOAVAILABILITY TO ABOUT 65%. IT WAS DETERMINED THAT THE PHARMACODYNAMIC PROPERTIES OF THE DRUG COULD EXPLAIN THE CHANGES IN PHARMACOKINETICS WITH INCREASED DOSE AND DURING MULTIPLE DOSES.|For more Absorption, Distribution and Excretion (Complete) data for CLONIDINE (8 total), please visit the HSDB record page.

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.

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.

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.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures: Protect the airway and assist ventilation if necessary. Treat coma, hypotension, and bradycardia if they occur. They usually resolve with supportive measures such as fluids, atropine, and dopamine. Hypertension is usually transient and does not require treatment. Treat lethargy and respiratory depression initially with intermittent tactile stimulation. Mechanical ventilation may be necessary in some patients.|For more Antidote and Emergency Treatment (Complete) data for CLONIDINE (7 total), please visit the HSDB record page.

/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.

Catapres

Table: Clonidine hydrochloride Preparations [Table#4366]|Table: Clonidine Preparations [Table#4367]

GLC METHOD USING ELECTRON-CAPTURE DETECTION.

GC (gas chromatography) determination in plasma.|RADIOIMMUNOASSAY IN SERUM.

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