Guanabenz acetate

291.13

290.03400

245-534-7

443O19GK1A

C65826

White solid from acetonitrile|White to almost white powder

2928002500

114

white solid

227-229 °C (decomp)

405.7°C at 760 mmHg

199.1ºC

H2O: 11 mg/mL

Store at RT

Slight odor

pKa = 8.1

Solid; mp: 192.5 °C (decomposition); solubility at 25 °C (mg/ml): propylene glycol 100, chloroform 0.6, ethyl acetate 1 /Guanabenz monoacetate/

Ⅲ

6.1(b)

UN 2811 6.1/PG 3

3

22

22-36/37/39-45

MF0382000

Xn

Missing Phrase - N15.00950417

H301

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

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

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P264, P270, P301+P310, P321, P330, P405, and P501|Aggregated GHS information provided by 45 companies from 2 notifications to the ECHA C&L Inventory.

Additive CNS depression may occur when guanabenz is administered concomitantly with other CNS depressants including alcohol, phenothiazines, barbiturates, or benzodiazepines.|When guanabenz is administered with other hypotensive agents, including diuretics, the hypotensive effect of guanabenz may be increased.|Guanabenz, administered concurrently with antidiabetic agents (eg, insulin, chlorpropramide), does not appear to interfere with the control of blood glucose concentration.

LD50 Rat oral 126 mg/kg|LD50 Mouse oral 150 mg/kg

Adrenergic alpha-Agonists; Antihypertensive Agents; Sympatholytics|Guanabenz is used in the management of hypertension. The efficacy of guanabenz in hypertensive patients is similar to that of other adrenergic inhibitors such as clonidine, methyldopa, or beta-adrenergic blocking agents (eg, pindolol, propranolol).|Guanabenz may be particularly useful in hypertensive patients whose baseline catecholamine concentrations are markedly elevated and whose hypertension is characterized by increased sympathetic activity. The drug may also be useful in the treatment of hypertension that is predominantly of the systolic form, commonly occurring in patients 60 years of age and older. Because guanabenz does not appear to induce sodium retention, the drug is useful in patients who develop secondary renal or cardiac induced sodium retention during therapy with clonidine or methyldopa. Guanabenz has been used in diabetic hypertensive patients with no adverse effect on control or therapy of diabetes; the drug has also been effective in hypertensive patients with chronic obstructive pulmonary disease, including asthma, chronic bronchitis, or emphysema. As with other hypotensive agents, treatment with guanabenz is not curative; after withdrawal of the drug, blood pressure returns to pretreatment levels or greater.|Guanabenz has been used alone or in combination with naltrexone in the management of opiate withdrawal in patients physically dependent on opiates and undergoing detoxification. Guanabenz has also been used as an analgesic in a limited number of patients with chronic pain; use of the drug permitted a reduction in opiate dosage or discontinuance of opiate therapy in these patients, but additional study is necessary. /Use is not currently included in the labeling approved by the FDA/|For more Therapeutic Uses (Complete) data for GUANABENZ ACETATE (6 total), please visit the HSDB record page.

Because of the risk of rebound or "overshoot" hypertension, patients receiving guanabenz should be warned of the danger of missing doses or stopping the drug without consulting their physician. When guanabenz therapy must be interrupted for surgery, the drug should be discontinued slowly over several days, if possible, to avoid precipitating the withdrawal syndrome. If necessary, parenteral hypotensive therapy should be administered throughout the period that oral medication cannot be given; oral guanabenz should be resumed as soon as possible.|Guanabenz should be used with caution and blood pressure monitored carefully in patients with hepatic and/or renal impairment, since the pharmacokinetics of the drug may be altered in such patients. The drug also should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, and/or cerebrovascular disease. Guanabenz should also be used with caution in geriatric patients since they may be more sensitive to the hypotensive and sedative effects of the drug.|Because of the potential sedative effect of guanabenz, patients should be warned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (eg, operating machinery, driving a motor vehicle). Additive CNS depression may occur when guanabenz is administered concomitantly with other CNS depressants including alcohol, phenothiazines, barbiturates, or benzodiazepines, and patients should be warned that their tolerance for CNS depressants may be decreased.|Although guanabenz has been used in the management of hypertension in a limited number of children 12 yr of age and older, further study on the use of the drug in these patients is necessary. Safety and efficacy of guanabenz in children younger than 12 yr of age have not been established; therefore, the manufacturer does not recommend use of the drug in these children.|For more Drug Warnings (Complete) data for GUANABENZ ACETATE (12 total), please visit the HSDB record page.

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.)|Compounds that bind to and activate ADRENERGIC ALPHA-2 RECEPTORS. (See all compounds classified as Adrenergic alpha-2 Receptor Agonists.)

Guanabenz undergoes extensive first-pass hepatic metabolism. Its elimination half-life is 7-14 hr, and its renal clearance is 0.09-0.131 l/min. Less than 2% is excreted unchanged in the urine. About 80% of a dose is excreted in urine in the first 24 hr.|Following oral administration, at least 70-80% of a dose of guanabenz acetate is absorbed. The effect of food on the absorption of guanabenz acetate has not been determined. Following oral administration of the drug in fasting individuals, peak plasma guanabenz concentrations usually occur within 2-5 hr. Following a single 16 mg oral dose, peak plasma guanabenz concentrations average 2.4-2.7 ng/ml (range: 1.2-5.2 ng/ml) in fasting healthy individuals and 7.8 ng/ml (range: 3-16 ng/ml) in fasting individuals with hepatic impairment (chronic alcohol-induced liver disease). ... Such alterations in these patients may result from enhanced oral bioavailability (secondary to portosystemic shunting and/or decreased intrinsic clearance) and decreased hepatic clearance of guanabenz.|The hypotensive effect of guanabenz acetate begins within 1 hr after oral administration and peaks within 2-7 hr. The duration of hypotensive effect is variable; the manufacturer states that the hypotensive effect is substantially diminished within 6-8 hr and that blood pressure returns to baseline values within 12 hr; however, the hypotensive effect of a single dose can persist for 12 or more hr.|Information on the distribution of guanabenz is limited. Following iv administration in rats, guanabenz is rapidly and extensively distributed into the CNS; brain concentrations of the drug are 3-70 times higher than concurrent plasma concentrations. In humans, guanabenz appears to be extensively distributed. The apparent steady state volume of distribution of guanabenz averages approximately 93 and 147 l/kg after 16 and 32 mg oral doses, respectively. The apparent volume of distribution of guanabenz appears to be substantially decreased in patients with hepatic impairment.|For more Absorption, Distribution and Excretion (Complete) data for GUANABENZ ACETATE (7 total), please visit the HSDB record page.

Guanabenz is extensively metabolized. The site(s) of guanabenz metabolism has not been determined, but the drug probably undergoes extensive firstpass metabolism. Guanabenz is metabolized principally by hydroxylation to form (E)-p-hydroxyguanabenz (4-hydroxyguanabenz), which is largely conjugated with glucuronic acid. A small fraction of guanabenz is cleaved at the benzal carbon to form 2,6-dichlorobenzyl alcohol, which is apparently completely conjugated. A small fraction of guanabenz also apparently undergoes N-glucuronidation. Other minor metabolites include (Z)-guanabenz and possibly (Z)-p-hydroxyguanabenz (Z-isomer of 4-hydroxyguanabenz); these metabolites are apparently almost completely conjugated. Numerous other, unidentified metabolites are also formed. The (Z)-isomer of guanabenz appears to have about 25% of the hypotensive activity of the unchanged drug following oral administration. Animal studies indicate that (E)-p-hydroxyguanabenz is inactive following oral administration but produces a slight hypotensive effect following intraperitoneal administration of large doses. Other metabolites of guanabenz are inactive.|About 10% of an oral dose of guanabenz is excreted in urine as (E)-p-hydroxyguanabenz, 25% as the glucuronide conjugate of (E)-p-hydroxyguanabenz, 1% as unchanged guanabenz, 5% as guanabenz conjugates, 1% as (Z)-guanabenz, 1% as (Z)guanabenz conjugates, less than 1% possibly as (Z)-p-hydroxyguanabenz, 2% as (Z)-p-hydroxyguanabenz conjugates, 2% as 2,6-dichlorobenzyl alcohol conjugates, and the remainder as unidentified metabolites and their conjugates.

The elimination half-life of guanabenz following single oral doses of the drug in healthy adults has been variably reported to average 4-14 hr (range: 3.5-21 hr); In one well-designed study, the elimination half-life averaged 12-14 hr. In patients with hepatic impairment, the half-life of the drug is only slightly prolonged. The elimination half-life of guanabenz also may be prolonged in patients with renal impairment.

Guanabenz is a central alpha 2-adrenoreceptor agonist. Its antihypertensive action appears to result from a decrease in sympathetic outflow from the brain to the peripheral circulatory system following stimulation of central alpha 2-adrenoreceptors. Peripherally it has a presynaptic alpha-receptor stimulant action and a guanethidinelike neuron-blocking action. There does not appear to be a physical dependence liability of the morphine type.|The affinity of guanabenz for the alpha2-adrenergic receptor is greater than that for the alpha1-adrenergic receptor. The central effects of the drug in the lower brain stem result in reduced peripheral sympathetic activity and a reduction in systolic and diastolic blood pressure. Following iv or oral administration of guanabenz in animals, an initial hypertensive response to the drug occurs and is caused by direct peripheral alpha2-adrenergic stimulated vasoconstriction; however, oral guanabenz usually does not produce an initial increase in blood pressure in hypertensive patients. Guanabenz induced bradycardia appears to result principally from central alpha2-agonist effects, although a peripheral alpha2-agonist effect on the heart may also be involved. In animals, guanabenz induced bradycardia results from inhibition of sympathetic nervous system activity and activation of cholinergic nervous system activity. Although guanabenz is not a true adrenergic blocking agent, the drug produces some postganglionic alpha (similar to guanethidine) and beta-adrenergic blockade and decreases the response to peripheral sympathetic nerve stimulation in animals. Cardiac output, left ventricular ejection fraction, and left ventricular stroke volume remain unchanged during long term therapy with the drug.

... A complete and uneventful recovery occurred within 12 hrs after treatment of acute guanabenz overdosage in several children 1-3 yr of age; treatment included gastric lavage and administration of an activated charcoal slurry, vasopressor, and fluids.|Given that tolazoline treatment is variably successful and that most physicians are unfamiliar with this agent, it cannot be recommended in the primary management strategy... . It should be considered only after tactile stimulation, naloxone, atropine, iv fluids, and dopamine have failed.|If the patient presents early or after a massive overdose, paradoxical hypertension may occur. It is typically self-limited and is routinely followed by profound hypotension. If severe or prolonged then treatment with a short-acting antihypertensive such as sodium nitroprusside is appropriate.|Appropriate therapy begins with particular focus on the patient's respiratory and hemodynamic status. Administration of activated charcoal is the primary mode of gastrointestinal decontamination. Emesis... is contraindicated. Lavage has limited utility... . All patients with CNS depression should be routinely evaluated for hypoxia and hypoglycemia. Respiratory compromise, including apnea, often responds well to simple auditory or tactile stimulation. ...Endotracheal intubation may be required.

/HUMAN EXPOSURE STUDIES/ If the patient presents early or after a massive overdose, paradoxical hypertension may occur. It is typically self-limited and is routinely followed by profound hypotension.|/HUMAN EXPOSURE STUDIES/ Signs and symptoms of guanabenz overdosage are similar to those following clonidine overdosage. Overdosage of guanabenz produces signs and symptoms that are mainly extensions of the usual pharmacologic and common adverse effects of the drug, including hypotension, respiratory depression, bradycardia, drowsiness, lethargy, irritability, miosis, and coma. Other effects occurring following overdosage of centrally active alpha2-adrenergic agonists include tachycardia, hypertension, hypotonia, hypothermia, pallor, and arrhythmias (eg, cardiac conduction defects).

2,6 Dichlorobenzylideneaminoguanidine

Oral Tablets, 4 mg (of guanabenz), Wytensin, Wyeth; 8 mg (of guanabenz), Wytensin (scored), Wyeth.|N-(2,6-Dichlorobenzylidene)-N'-amidinohydrazine|N-(2,6-dichlorobenzylidene)amino]guanidine|2-[(2,6-Dichlorophenyl)methylene]-hydrazinecarboximidamide

Analyte: guanabenz acetate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: guanabenz acetate; matrix: chemical purity; procedure: potentiometric titration with perchloric acid|Analyte: guanabenz acetate; matrix: pharmaceutical preparation (tablet); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)|Analyte: guanabenz acetate; matrix: pharmaceutical preparation (tablet); procedure: liquid chromatography with detection at 254 nm and comparison to standards (chemical purity)

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients