Labetalol

LABETOLOL · Laβlol · ah5158 · albetol · LABEIM-B · LABETALOL · ibidomide · SeH-15719W

식별자 및 물리적 특성

CAS No.	36894-69-6
분자식	C19H24N2O3
평균 분자량	328.4 g/mol
단동위원소 질량	328.17869263 g/mol
SMILES	CC(CCc1ccccc1)NCC(O)c1ccc(O)c(C(N)=O)c1
InChIKey	SGUAFYQXFOLMHL-UHFFFAOYSA-N
PubChem CID	3869
ChEMBL	CHEMBL429
ChEBI	CHEBI:6343
EC No.	253-258-3
DTXSID	DTXSID2023191

화학 및 물리적 성질

XLogP	3.1
극성 표면적	95.6
수소 결합 공여자 수	4
수소 결합 수용자 수	4
회전 가능 결합 수	8
무거운 원자 수	24
형식 전하	0
복잡도	385
의약품	Pharmaceuticals -> Used in Switzerland
LogP(분배 계수)	2.71.89
용해도	5.78e-03 g/LDMSO : 125 mg/mL (380.62 mMNeed ultrasonic)
Human Drugs	Breast FeedingLactationMilk, HumanAntihypertensive AgentsAdrenergic Beta-AntagonistsAntiarrhythmicsPharmaceuticals
녹는점	195 - 196 °C188 °C
Physical Description	Solid
Stability/Shelf Life	Labetalol hydrochloride tablets should be stored in well closed containers at 2-30 °Ctablets in unit dose packages should be protected from excessive moisture. Labetalol hydrochloride injection should be stored at 2-30 °C and protected from light and freezing. Labetalol hydrochloride tablets and injection have an expiration date of 3 and 2 years, respectively, after the date of manufacture. /Labetalol hydrochloride/Labetalol hydrochloride is most stable in solutions having a pH of 2- 4. The drug is physically and chemically compatible with the following iv solutions: 5% dextrose0.9% sodium chloride2.5% dextrose and 0.45% sodium chloride5% dextrose and 0.2, 0.33, or 0.9% sodium chloride5% dextrose and lactated Ringer's or Ringer'slactated Ringer'sor Ringer's. Following dilution of labetalol hydrochloride injection with one of these iv solutions, solutions containing 1.25-3.75 mg/ml are stable for at least 24 hrs when refrigerated or stored at room temperature. In one study, these solutions were stable for at least 72 hrs at 4 or 25 °C. Appreciable changes in pH or osmolarity of these iv solutions did not occur following admixture of labetalol hydrochloride injection. The drug is physically and/or chemically incompatible with 5% sodium bicarbonate injectionlabetalol hydrochloride solutions containing 1.25-3.75 mg/ml in 5% sodium bicarbonate have a pH of 7.6-8 and form a white precipitate, probably the free base, within 6 hrs after admixture. /Labetalol hydrochloride/
Dissociation Constants	7.49.3pKa = 9.3
Collision Cross Section	175.2 Å² [M+H]+ [CCS Type: DTBuffer gas: N2Ionization: ESI+Dataset: TOXCASTSource Identifier: DTXSID0044654]176.41 Å² [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]178.1 Å² [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]
Other Experimental Properties	White crystalline solid from ethanol-ethyl acetatemp: 187-189 °Csol in water, ethanolinsol in ether, chloroform. /Labetalol hydrochloride/
끓는 점	552.7±50.0 °C(Predicted)
밀도	1.200±0.06 g/cm3(Predicted)
저장 조건	Store at -20°C
pKa(산도 계수)	pKa 7.41 ± 0.019.36± 0.01(H2O,t =25,I=0.15(KCl)，Ar)(Approximate)
물리적 상태	고체
색상	흰색에서 옅은 주황색까지
안정성	흡습성
NIST	Benzamide, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-(36894-69-6)

안전 및 규제

GHS 분류	WarningH315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]P203, P261, P264, P264+P265, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
규제 정보	REACH registered substance: Labetalol (EC: 253-258-3)
기타 안전 정보	IMAP assessments - Benzamide, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-: Environment tier I assessment
FDA 요건	Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended21 U.S.C. 321-392).The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl labetalol hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /Labetalol hydrochloride/
Special Reports	Prichard BNBeta-blocking Agents with Vasodilating Action. J Cardiovasc Pharmacol 19 (Suppl 1): S1-4 (1992). Beta-blocking agents with vasodilating action are discussed. Drugs have been developed that in addition to blocking the beta-receptor have an important peripheral vasodilator activity. Labetalol was the first drug of this group to be developed.Donnelly R, Macphee GJClinical Pharmacokinetics and Kinetic-dynamic Relationships of Dilevalol and Labetalol. Clin Pharmacokinet 21 (2): 95-109 (1991). A review comparing the availability, metabolism, pharmacokinetics, efficacy and side effects of th vasodilatory beta-blockers labetalol and its stereoisomer, dilevalol, is presented. The effects of patient age and smoking habits on the response to hypertension therapy with these 2 drugs are included.Jackson CD, Fishbein LA Toxicological Review of Beta-adrenergic Blockers. Fundam Appl Toxicol 6 (3): 395-422 (1986). Eighteen beta-adrenergic blockers have been reviewed and the available literature pertaining to their potential carcinogenicity, mutagenicity, and teratogenicity has been summarized and compared.
Hazard Classes and Categories	Skin Irrit. 2 (100%)
상호 작용	Reproduction studies in rats or rabbits using combined oral labetalol hydrochloride and hydrochlorothiazide dosages up to about 15 and 80 times the maximum recommended human dosage, respectively, have not revealed evidence of teratogenicity, although combined oral dosages 3.5 and 20 times the maximum recommended human dosage, respectively, were maternotoxic with resultant fetotoxicity in rabbits. The combination appeared to be more toxic than either drug alone in rabbits. /Labetalol hydrochloride/When labetalol is administered with diuretics or other hypotensive drugs, the hypotensive effect may be increased. ... When beta-adrenergic blocking agents are administered with calcium-channel blocking agents, therapeutic as well as adverse effects may be additive.Concomitant administration of iv labetalol and halothane anesthesia results in asynergistic hypotensive effect, the degree and duration of which may be controlled by adjusting the halothane concentrationhowever, excessive hypotension can result in a large reduction in cardiac output and an increase in central venous pressure.Concomitant administration of oral cimetidine has been shown to substantially increase the absolute bioavailability of oral labetalol, possibly via enhanced absorption or decreased first pass hepatic metabolism of labetalol.For more Interactions (Complete) data for LABETALOL (10 total), please visit the HSDB record page.
Hepatotoxicity	Labetalol therapy has been associated with mild-to-moderate elevations of serum aminotransferase levels in up to 8% of patients, a rate far higher than with other beta-blockers. These elevations, however, are usually transient, not associated with symptoms, and can resolve even with continuation of therapy. Idiosyncratic, clinically apparent liver injury from labetalol is rare, but several instances have been reported as isolated case reports as well as in case series. The liver injury typically arises after 4 to 16 weeks of therapy and the pattern of serum enzyme elevations is usually hepatocellular with an acute hepatitis-like onset and course. Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. While most cases resolve rapidly once labetalol is stopped, there have been several instances of acute liver failure and death or need for emergency liver transplantation associated with labetalol use, particularly if there is a delay in its discontinuation. Labetalol is the beta-blocker with the highest apparent risk for causing clinically apparent liver injury.
유해 작용	Overall, labetalol is usually well tolerated. Most adverse effects are typically mild and transient. As previously described above, symptomatic postural hypotension is a potential occurrence if patients are tilted or allowed to change positions from the supine or seated position to standing too quickly. This is especially important in the post-operative period (PACU or the ward) when managing a hypertensive patient with labetalol who can otherwise ambulate to the bathroom. Increased sweating, as well as flushing, have been reported with the use of labetalol. It seems the incidence of adverse reactions after administering labetalol seems to be dose-dependent.
노출 경로	Oral, parenteral (intravenous injection). Completely absorbed (100%) from the gastrointestinal tract with peak plasma levels occurring 1 to 2 hours after oral administration. The absolute bioavailability of labetalol is increased when administered with food.
독성 요약	Supportive care and close monitoring are the staples of treatment for an overdose of beta-blockers with the addition of glucagon for severe refractory hypotension and bradycardia.Labetalol has two asymmetric centers and therefore, exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R,R' stereoisomer, makes up 25% of racemic labetalol. Labetalol HCl combines both selective, competitive, alpha-1-adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity in a single substance. In man, the ratios of alpha- to beta- blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous (IV) administration, respectively. Beta-2-agonist activity has been demonstrated in animals with minimal beta-1-agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta- adrenergic blockade, a membrane stabilizing effect has been demonstrated.
Signs and Symptoms	Side effects or adverse reactions include dizziness when standing up, very low blood pressure, severely slow heartbeat, weakness, diminished sexual function, fatigue
Human Toxicity Excerpts	In several studies in patients with hypertension and elevated plasma renin activity, long term oral administration of labetalol hydrochloride (150 mg to 2.4 g daily) has been reported to suppress plasma renin activity at rest and during exercise, and in the supine and standing positionsin most of the studies, the net suppressive effect on renin was generally proportional to basal plasma renin activity. In other studies, labetalol has been reported to have an inconsistent overall effect on resting plasma renin activity, but there was considerable interindividual variation in plasma renin activity in these studies. Following acute iv administration, labetalol has been reported to produce substantial reductions in plasma angiotensin II concentration, particularly in patients with high basal values. Although labetalol has been reported to have little, if any, effect on plasma aldosterone concentration following long term oral administration in several studies, there is some evidence that the drug may decrease plasma aldosterone concentration following oral or iv administration. Labetalol has also been reported to decrease urinary aldosterone excretion following oral administration in patients with hypertension. /Labetalol hydrochloride/Following iv administration in one preliminary study, labetalol caused a substantial increase in serum prolactin concentration which was more marked in females than in males.The most frequent adverse cardiovascular effect of labetalol is symptomatic orthostatic hypotension, which occurs in about 1-5% or 60% of patients following oral (alone or in fixed combination with hydrochlorothiazide) or iv administration of the drug, respectively. Orthostatic hypotension has been associated with loss of consciousness occasionally following iv administration and rarely following oral administration. Symptomatic orthostatic hypotension is likely to occur if supine patients are tilted upward or allowed to assume the upright position within 3 hr following iv administration of labetalol. Moderate hypotension occurs in about 1% of patients in the supine position who are receiving the drug iv. Following oral administration, orthostatic hypotension appears to occur more frequently during initiation of therapy, in patients receiving concomitant administration of a diuretic, and in those receiving higher dosages of the drug. ... Development or exacerbation of congestive heart failure has occurred in some patients receiving labetalol, although the drug appears to be less likely to precipitate congestive heart failure than pure beta-adrenergic blocking agents. At the first sign or symptom of impending cardiac failu re during labetalol therapy, patients should receive adequate treatment (eg, cardiac glycoside, diuretic) and should be observed closelyif cardiac failure continues, labetalol should be discontinued, gradually if possible. ... Ventricular arrhythmia (including ventricular premature contractions), edema or fluid retention, bradycardia, hypotension, syncope, chest pain, atrioventricular conduction delay, and atrioventricular block have occurred during therapy with labetalol.Adverse nervous system effects occur with variable frequency with labetalol and most of these effects appear to be dose related. At the usual labetalol hydrochloride dosage of 200-400 mg twice daily (alone or in fixed combination with hydrochlorothiazide), most adverse nervous system effects occur in 5% or less of patients. Adverse nervous system effects of the drug include drowsiness or tiredness, dizziness or lightheadedness (often posture related), headache, fatigue, lethargy, and nightmares or vivid dreams. Paresthesia, usually mild, transient tingling of the scalp or skin, may also occur following oral (alone or in fixed combination with hydrochlorothiazide) or iv administration of the drug, usually at the beginning of therapy. Hypoesthesia or numbness and circumoral paresthesia have also occurred. Mental depression, paroniria, vertigo, somnolence, yawning, tremor, asthenia, and insomnia have also been reported. Some adverse nervous system effects such as fatigue, mental depression, and sleep disorders may occur less frequently with labetalol than with pure beta-adrenergic blocking agents. Adverse nervous system effects of labetalol may be obviated by a reduction in dosage or alteration of dosage schedule.For more Human Toxicity Excerpts (Complete) data for LABETALOL (15 total), please visit the HSDB record page.
Carcinogen Classification	No indication of carcinogenicity to humans (not listed by IARC).
Drug Induced Liver Injury	Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)labetalolTrandate®Beta blockers8most-DILI-concern
Non-Human Toxicity Excerpts	No evidence of labetalol induced mutagenesis was seen with the modified Ames test or in studies in mice and rats using dominant lethal assays.No evidence of carcinogenesis was seen in mice receiving oral labetalol hydrochloride dosages up to 200 mg/kg daily for 18 mo or in rats receiving oral dosages up to 225 mg/kg daily for up to 113 wk in females and up to 116 wks in males. /Labetalol hydrochloride/Reproduction studies in rats and rabbits using oral labetalol hydrochloride dosages up to about 6 and 4 times the maximum recommended human dosage, respectively, have not revealed reproducible evidence of fetal malformationhowever, oral dosages approximating the maximum recommended human dosage were associated with an increased incidence of fetal resorption in both species. There was no evidence of drug related fetotoxicity in rabbits receiving iv dosages of the drug up to 1.7 times the maximum recommended human dosage. In rats, oral administration of labetalol hydrochloride at dosages 2-4 times the maximum recommended human dosage during the period of late gestation through weaning was associated with decreased neonatal survival. /Labetalol hydrochloride/
Antidote and Emergency Treatment	Apnea and cardiovasular collapse may appear suddenly. Hence cardiac monitoring and iv lines should be established immediately. ... Dopamine and isoproterenol are the initial drugs of choice for hypotension, and atropine for bradycardia, but these agents may not be effective. Beta-blockers may saturate beta receptors, and cardioselectivity does not influence the decision about which inotropic agent to use. ... The usual measures of decontamination are emesis/lavage, activated charcoal, and cathartics for patients who present several hr after ingestion. Patients with severe overdoses may develop severe apnea and/or seizures, and this fact indicates that the use of syrup of ipecac in this setting is dangerous. Activated charcoal and/or lavage are safer procedures in severe overdoses. ... /Isoproterenol/ is a non-selective beta-adrenergic agonist in beta-blocker overdose. ... /Glucagon/ enhances cardiac contractility. /Class II beta-Blockers/Treatment of labetalol overdosage generally involves symptomatic and supportive care. Following acute ingestion of the drug, the stomach should be emptied immediately by inducing emesis or by gastric lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Administration of activated charcoal after emesis or gastric lavage may be useful in preventing absorption of labetalol, although specific data are not available. Patients should be placed in a supine position and their legs elevated if necessary to improve blood supply to the brain. For symptomatic bradycardia, atropine or epinephrine may be given. A vasopressor (eg, norepinephrine, dopamine) may be given for severe hypotension. For heart failure, a cardiac glycoside and diuretic may be useddopamine or dobutamine may also be useful. Glucagon may also be useful for the management of myocardial depression and hypotension. A beta-adrenergic agonist and/or a theophylline derivative may be used for bronchospasm. For seizures, diazepam may be used. Labetalol is not appreciably removed (less than 1% of a dose) by hemodialysis or peritoneal dialysis.
Effects During Pregnancy and Lactation	◉ Summary of Use during Lactation◈ What is labetalol?
유해 물질 데이터	36894-69-6(Hazardous Substances Data)

용도

개요

Labetalol is an α-adrenergic and α-1 blocking agent which caused contact dermatitis and a contact anaphylactoid reaction during patch testing in a nurse.

용도

Labetalol is used to treat essential hypertension.

일반 설명

Labetalol is a phenylethanolamine derivative, is representative of a classof drugs that act as competitive blockers at α1-, β1-, andβ2-receptors. It is a more potent β-blocker than α-blocker.Because it has two asymmetric carbon atoms (1 and 1' ), it existsas a mixture of four isomers. It is this mixture that is usedclinically in treating hypertension. The different isomers,however, possess different α- and β-blocking activities. The -blocking activity resides solely in the (1R,1 'R) isomer,whereas the 1-blocking activity is seen in the (1S,1 R) and(1S,1'S) isomers, with the (1S,1'R) isomer possessing thegreater therapeutic activity.