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Labetalol

PubChem CID
3869
Structure
Labetalol_small.png
Labetalol_3D_Structure.png
Molecular Formula
Synonyms
  • labetalol
  • 36894-69-6
  • Labetolol
  • Ibidomide
  • Albetol
Molecular Weight
328.4 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Labetalol is a diastereoisomeric mixture of approximately equal amounts of all four possible stereoisomers ((R,S)-labetolol, (S,R)-labetolol, (S,S)-labetalol and (R,R)-labetalol). It is an adrenergic antagonist used to treat high blood pressure. It has a role as an antihypertensive agent, a sympatholytic agent, an alpha-adrenergic antagonist and a beta-adrenergic antagonist. It contains a (R,R)-labetalol, a (S,S)-labetalol, a (R,S)-labetolol and a (S,R)-labetolol.
Labetalol is a racemic mixture of 2 diastereoisomers where dilevalol, the R,R' stereoisomer, makes up 25% of the mixture. Labetalol is formulated as an injection or tablets to treat hypertension. Labetalol was granted FDA approval on 1 August 1984.
Labetalol is a beta-Adrenergic Blocker. The mechanism of action of labetalol is as an Adrenergic beta-Antagonist.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Labetalol.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-hydroxy-5-[1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl]benzamide
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 InChI

InChI=1S/C19H24N2O3/c1-13(7-8-14-5-3-2-4-6-14)21-12-18(23)15-9-10-17(22)16(11-15)19(20)24/h2-6,9-11,13,18,21-23H,7-8,12H2,1H3,(H2,20,24)
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

SGUAFYQXFOLMHL-UHFFFAOYSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

CC(CCC1=CC=CC=C1)NCC(C2=CC(=C(C=C2)O)C(=O)N)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C19H24N2O3
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

36894-69-6

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 PharmGKB ID

2.3.14 Pharos Ligand ID

2.3.15 RXCUI

2.3.16 Wikidata

2.3.17 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • AH 5158
  • AH-5158
  • AH5158
  • Albetol
  • Apo Labetalol
  • Apo-Labetalol
  • ApoLabetalol
  • Dilevalol
  • Hydrochloride, Labetalol
  • Labetalol
  • Labetalol Hydrochloride
  • Labetalol, (R,R)-Isomer
  • Labetolol
  • Normodyne
  • Presolol
  • R,R Labetalol
  • R,R-Labetalol
  • SCH 19927
  • SCH-19927
  • SCH19927
  • Trandate

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
328.4 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3
Property Value
3.1
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
8
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
328.17869263 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
328.17869263 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
95.6 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
24
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
385
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Boiling Point

3.2.3 Melting Point

188 °C
U.S. Patent 4,012,444.
195 - 196 °C

3.2.4 Solubility

5.78e-03 g/L

3.2.5 LogP

2.7

3.2.6 Stability / Shelf Life

Labetalol hydrochloride tablets should be stored in well closed containers at 2-30 °C; tablets 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/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1063
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% dextrose; 0.9% sodium chloride; 2.5% dextrose and 0.45% sodium chloride; 5% dextrose and 0.2, 0.33, or 0.9% sodium chloride; 5% dextrose and lactated Ringer's or Ringer's; lactated Ringer's; or 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 injection; labetalol 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/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1063

3.2.7 Dissociation Constants

Basic pKa
7.4
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
pKa
9.3
pKa = 9.3
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1063

3.2.8 Collision Cross Section

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

173.29 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

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

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

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111
178.1 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

3.2.9 Other Experimental Properties

White crystalline solid from ethanol-ethyl acetate; mp: 187-189 °C; sol in water, ethanol; insol in ether, chloroform. /Labetalol hydrochloride/
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 841

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Adrenergic Beta-Antagonists; Antiarrhythmics
Human drug -> Discontinued
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 GC-MS

1 of 4
View All
NIST Number
248725
Library
Main library
Total Peaks
115
m/z Top Peak
162
m/z 2nd Highest
91
m/z 3rd Highest
58
Thumbnail
Thumbnail
2 of 4
View All
NIST Number
120430
Library
Replicate library
Total Peaks
45
m/z Top Peak
58
m/z 2nd Highest
162
m/z 3rd Highest
91
Thumbnail
Thumbnail

4.1.2 MS-MS

1 of 8
View All
Spectra ID
Ionization Mode
Negative
Top 5 Peaks

157.0408 100

175.0513 37.22

131.0377 32.65

181.0381 13.70

163.0275 12.59

Thumbnail
Thumbnail
2 of 8
View All
Spectra ID
Ionization Mode
Negative
Top 5 Peaks

175.0513 100

157.0407 86.19

176.0591 59.27

131.0376 51.58

181.0381 36.78

Thumbnail
Thumbnail

4.1.3 LC-MS

1 of 33
View All
Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
10 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
5.594 min
Precursor m/z
329.186
Precursor Adduct
[M+H]+
Top 5 Peaks

329.1858 999

311.1756 537

330.1892 223

312.1783 107

331.1917 28

Thumbnail
Thumbnail
License
CC BY
2 of 33
View All
Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
5.626 min
Precursor m/z
329.186
Precursor Adduct
[M+H]+
Top 5 Peaks

311.1748 999

162.0536 326

294.148 279

207.1116 214

179.0802 190

Thumbnail
Thumbnail
License
CC BY

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Labetalol injections are indicated to control blood pressure in severe hypertension. Labetalol tablets are indicated alone or in combination with antihypertensives like thiazides and loop diuretics to manage hypertension.

7.2 LiverTox Summary

Labetalol is an antihypertensive agent with both alpha- and beta-adrenergic receptor blocking activity. Labetalol has been linked to several cases of clinically apparent drug induced liver disease, some of which have been severe and even fatal.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Adrenergic Beta-Antagonists; Antiarrhythmics
Beta-Adrenergic Receptor Antagonists

7.4 FDA National Drug Code Directory

7.5 Drug Labels

Drug and label
Active ingredient and drug

7.6 Clinical Trials

7.6.1 ClinicalTrials.gov

7.6.2 EU Clinical Trials Register

7.7 Therapeutic Uses

Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Sympatholytics
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Antihypertensive
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 841
Labetalol hydrochloride is an alpha and beta-adrenergic blocking agent. The drug is commercially available as a racemic mixture of its 4 stereoisomers. The RR isomer has about 2-4 times the beta-adrenergic blocking activity of the racemic mixture but has only minimal alpha1-adrenergic blocking activity; most of the alpha1-adrenergic blocking activity of the drug is attributable to the SR isomer. The RR isomer also appears to possess some beta2-agonist activity. /Labetalol hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1063
Labetalol hydrochloride is used in the management of hypertension. The drug has been used as monotherapy or in combination with other classes of antihypertensive agents. The drug is at least as effective as pure beta-adrenergic blocking agents, thiazide diuretics, methyldopa, or clonidine. ... Iv labetalol hydrochloride is used to control blood pressure in patients with severe hypertension or hypertensive emergencies. Unlike other currently available parenteral hypotensive agents, labetalol usually produces a prompt, but gradual reduction of blood pressure without substantial changes in heart rate or cardiac output. Iv labetalol appears to adequately reduce blood pressure in about 80-90% of patients with severe hypertension or hypertensive emergencies, irrespective of etiology, and may be useful even when other drugs have failed. /Labetalol hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1065
For more Therapeutic Uses (Complete) data for LABETALOL (9 total), please visit the HSDB record page.

7.8 Drug Warnings

Serious clinical effects of overdose involve primarily the cardiovascular system (bradycardia. hypotension, cardiogenic shock, pulmonary edema) and the central nervous system (coma, convulsions, apneal). In severe overdose, apnea and hemodynamic compromise may appear suddenly after ingestions of large beta-blocker doses. /Class II beta-blockers/
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 187
Adverse reations depend more on drug affinity for B1 and B2 receptors than overdose does. B1 Blockade (antagonist) activity causes decreased sinus rate, contractility, and conduction, decreased renin release, and decreased aqueous humor formation. B2 Blockade produces bronchiolar and arteriolar smooth muscle constriction, decreasd insulin secretion and decreased lipolysis and glucogenolysis resulting in decreased blood fatty acids and glucose. /Class II beta-Blockers/
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 191
Labetalol shares the toxic potentials of beta-adrenergic and postsynaptic alpha1-adrenergic blocking agents, and the usual precautions of these agents should be observed. When labetalol is used in fixed combination with hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with labetalol.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1066
Labetalol should be used with caution in patients with inadequate cardiac function, since congestive heart failure may be precipitated by blockade of beta-adrenergic stimulation when labetalol therapy is administered. In addition, in patients with latent cardiac insufficiency, prolonged beta-adrenergic blockade may lead to cardiac failure. Although beta-adrenergic blocking agents should be avoided in patients with overt congestive heart failure, labetalol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics). Patients receiving labetalol therapy should be instructed to consult their physician at the first sign or symptom of impending cardiac failure and should be adequately treated (e.g., with a cardiac glycoside and/or diuretic) and observed closely; if cardiac failure continues, labetalol should be discontinued, gradually if possible.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1066
For more Drug Warnings (Complete) data for LABETALOL (17 total), please visit the HSDB record page.

7.9 Drug Idiosyncrasies

The FDA has received 11 reports of cases (three fatal) in the US in which hepatocellular damage was associated with labetalol. The temporal circumstances strongly implicate labetalol; the conditions of nine patients improved after cessation of labetalol therapy, and one patient had a recurrence after therapy was restarted. Follow up with each reporting physician failed to provide historic or laboratory evidence for other viral, toxic, or drug induced causes of hepatocellular damage, and the case series did not show the demographic and historic risk factors that would be expected if non-A, non-B hepatitis were the cause. Reports of microscopic liver examinations were available in the 5 cases in which they were done. The reported histologic changes were consistent with hepatocellular necrosis in four instances and chronic active hepatitis in one. The clinical presentation of the cases was most compatible with the mechanism of metabolic idiosyncracy, but other pathogenetic explanations could not be entirely excluded.
Clark JA et al; Ann Intern Med 113 (3): 210-3 (1990)

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Labetalol antagonizes various adrenergic receptors to decrease blood pressure. The duration of action is long as it is generally given twice daily, and the therapeutic window is wide as patients usually take 200-400mg twice daily. Patients susceptible to bronchospasms should not use labetalol unless they are unresponsive to or intolerant of other antihypertensives.

8.2 MeSH Pharmacological Classification

Antihypertensive Agents
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.)
Adrenergic alpha-1 Receptor Antagonists
Drugs that bind to and block the activation of ADRENERGIC ALPHA-1 RECEPTORS. (See all compounds classified as Adrenergic alpha-1 Receptor Antagonists.)
Adrenergic beta-Antagonists
Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. (See all compounds classified as Adrenergic beta-Antagonists.)
Sympathomimetics
Drugs that mimic the effects of stimulating postganglionic adrenergic sympathetic nerves. Included here are drugs that directly stimulate adrenergic receptors and drugs that act indirectly by provoking the release of adrenergic transmitters. (See all compounds classified as Sympathomimetics.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
R5H8897N95
Active Moiety
LABETALOL
Pharmacological Classes
Mechanisms of Action [MoA] - Adrenergic beta-Antagonists
Pharmacological Classes
Established Pharmacologic Class [EPC] - beta-Adrenergic Blocker
FDA Pharmacology Summary
Labetalol is a beta-Adrenergic Blocker. The mechanism of action of labetalol is as an Adrenergic beta-Antagonist.
2 of 2
Non-Proprietary Name
LABETALOL
Pharmacological Classes
beta-Adrenergic Blocker [EPC]; Adrenergic beta-Antagonists [MoA]

8.4 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

C - Cardiovascular system

C07 - Beta blocking agents

C07A - Beta blocking agents

C07AG - Alpha and beta blocking agents

C07AG01 - Labetalol

8.5 Absorption, Distribution and Excretion

Absorption
100mg and 200mg oral doses of labetalol have a Tmax of 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86% and may increase in older patients or when taken with food.
Route of Elimination
Radiolabelled doses of labetalol are 55-60% recovered in the urine and 12-27% recovered in the feces.
Volume of Distribution
In normotensive patients, the volume of distribution is 805L. In hypertensive patients, the volume of distribution is between 188-747L with an average of 392L.
Clearance
Labetalol has a plasma clearance of approximately 1500mL/min and a whole blood clearance of 1100mL/min.
Cardioselective beta-blockers /including labetalol/ tend to be hydrophilic, whereas nonselective beta blockers tend to be lipophilic. The property of lipophilicity is an essential factor for the expression of nonselectivity. Lopophilic beta-blockers generally undergo hepatic elimination and distribute well into all body compartments, including the brain. Hydrophilic beta-blockers usually are excreted unchanged by the kidney and enter deep body compartments with difficulty. /From table/
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 189
Beta-blocker drugs are rapidly absorbed, with a bioavailability varying between 30% and 90% because of the large first-pass hepatic extraction. ... Most beta-blockers ... have apparent volumes of distribution greater than 1 l/kg /Class II beta-blockers/
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 190
Labetalol hydrochloride is rapidly and approximately 90-100% absorbed from the GI tract following oral administration, but the drug undergoes extensive first pass metabolism in the liver and/or GI mucosa. Only about 25% of an oral dose reaches systemic circulation unchanged in fasted adults. Although absolute bioavailability in one study reportedly ranged from 11-86% (mean: 33%) following oral administration of a single 100 mg dose in fasted adults, the considerable interindividual variability in this study may have resulted from use of a relatively insensitive spectrofluorometric assay. Food delays GI absorption of labetalol hydrochloride but increases absolute bioavailability of the drug, possibly by decreasing first pass metabolism and/or hepatic blood flow. Following oral administration of a single 200 mg dose in healthy adults in one study, absolute bioavailability of the drug averaged 26 and 36% in the fasted and nonfasted state, respectively. First pass metabolism may also be reduced and bioavailability substantially increased in geriatric patients and in patients with hepatic dysfunction. However, in one study in patients with hepatosplenic schistosomiasis, mean absolute bioavailability of the drug was reportedly decreased when compared with healthy individuals. Oral cimetidine increases, and glutethimide decreases, the bioavailability of labetalol. Concomitant oral administration of labetalol hydrochloride and hydrochlorothiazide does not affect the bioavailability of either drug.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1064
Following multiple dose oral administration of labetalol hydrochloride, peak plasma concentrations are generally achieved within 40 min to 2 hr. Peak plasma concentrations reportedly increase proportionately with oral dosage at dosages ranging from 100 mg to 3 g daily. In one study in hypertensive patients, peak plasma labetalol concentration following oral administration of 200 mg 3 times daily or 300 mg twice daily averaged 323 or 430 ng/ml, respectively, and the steady state plasma drug concentration averaged 149 or 145 ng/ml, respectively; based on pharmacokinetic and pharmacodynamic (ie, blood pressure response) evaluation, these dosage regimens were considered equivalent. Following iv injection over 1 min of a 1.5 mg/kg dose of labetalol hydrochloride in one study, a mean peak plasma concentration of about 5.7 ug/ml occurred 2 min after injection and plasma concentration had declined to an average of 575 ng/ml at 10.5 min after injection.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1064
For more Absorption, Distribution and Excretion (Complete) data for LABETALOL (14 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

The metabolism of labetalol has not been fully described in the literature but studies in sheep show an N-dealkylation to 3-amino-1-phenyl butane. This metabolite may be further metabolized to benzylacetone and 3-amino-(4-hydroxyphenyl)butane. Labetalol in humans is mainly metabolized to glucuronide metabolites such as the O-phenyl-glucuronide and the N-glucuronide.
Labetalol is extensively metabolized in the liver and possibly in the GI mucosa following oral administration, principally by conjugation with glucuronic acid. The major metabolite is the O-alkylglucuronide, with smaller amounts of the O-phenylglucuronide and N-glucuronide being formed. Following oral administration, labetalol undergoes extensive first pass metabolism in the liver and/or GI mucosa.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1064
Primarily hepatic, undergoes significant first pass metabolism Route of Elimination: These metabolites are present in plasma and are excreted in the urine, and via the bile, into the feces. Half Life: 6-8 hours

8.7 Biological Half-Life

Labetalol has a half life of 1.7-6.1 hours.
Plasma concentrations of labetalol appear to decline in a biphasic or possibly triphasic manner. In healthy adults and adults with hypertension, the half-life in the distribution phase has been reported to average 6-44 min and the half-life in the terminal elimination phase (t1/2beta) has been reported to average 2.5-8 hr. The variability in reported mean half-lives for the drug may have resulted in part from use of a relatively insensitive spectrofluorometric assay in some studies. The manufacturers state that the drug has a plasma elimination half-life of 5.5 or 6-8 hr following iv or oral administration, respectively. The elimination half-life of the drug appears to be unchanged in individuals with renal or hepatic impairment, but may be increased in patients with severe renal impairment (eg; creatinine clearance less than 10 ml/min) undergoing dialysis and slightly increased (but within the reported range) in geriatric individuals.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1064

8.8 Mechanism of Action

Labetalol non-selectively antagonizes beta-adrenergic receptors, and selectively antagonizes alpha-1-adrenergic receptors. Following oral administration, labetalol has 3 times the beta-blocking ability than alpha-blocking ability. This increases to 6.9 times following intravenous administration. Antagonism of alpha-1-adrenergic receptors leads to vasodilation and decreased vascular resistance. This leads to a decrease in blood pressure that is most pronounced while standing. Antagonism of beta-1-adrenergic receptors leads to a slight decrease in heart rate. Antagonism of beta-2-adrenergic receptors leads to some of the side effects of labetalol such as bronchospasms, however this may be slightly attenuated by alpha-1-adrenergic antagonism. Labetalol leads to sustained vasodilation over the long term without a significant decrease in cardiac output or stroke volume, and a minimal decrease in heart rate.
A specific competitive antagonist at both alpha- and beta-adrenergic receptor sites.
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 841
Class II antiarrhythmic, beta-adrenoceptor-blocking agents are membrane depressant drugs that decrease the influx of sodium and calcium ions by reducing membrane bound adenylate cyclase and cAMP. The reduction in cation transport lengthens depolarization by decreasing the amplitude and slope of the transmembrane potential. Beta-adrenoceptor-blocking agents also reduce myocardial contractility by decreasing calcium release from the sarcoplasmic reticulum (the influx of calcium couples excitation and contraction by initiating the release of calcium from the sarcoplasmic reticulum). Membrane-stabilizing activity enhances the reduction in myocardial contractility in overdose with these drugs in addition to producing a quinidinelike effect of ORS widening. A direct myocardial effect also leads to myocardial depression independent of beta-adrenergic blockade and membrane stabilization. ... beta-Blockers are classified as cardioselective based on their ability to antagonize the cardiac (beta1) but not the peripheral (beta2) receptors. However, cardioselectivity is incomplete and dose dependent and disappears at high doses. /Class II beta-Blockers/
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 191
The principal physiologic action of labetalol is to competitively block adrenergic stimulation of beta-receptors within the myocardium (beta1-receptors) and within bronchial and vascular smooth muscle (beta2-receptors) and alpha1-receptors within vascular smooth muscle. In addition to inhibiting access of endogenous or exogenous catecholamines to beta-adrenergic receptors, labetalol has been shown to exhibit some intrinsic beta2-agonist activity in animals; however, the drug exerts little, if any, intrinsic beta1-agonist activity. Labetalol does not exhibit intrinsic alpha-adrenergic agonist activity. There is some evidence from animal studies suggesting that the drug may have a vasodilating effect, possibly resulting from a direct or beta2-agonist action. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, labetalol also has a membrane stabilizing effect on the heart which is similar to that of quinidine; however, this effect is unlikely to be clinically important since it occurs only at doses higher than those required for alpha- or beta-adrenergic blockade.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1063
The hemodynamic effects of labetalol are variable following oral or iv administration. Labetalol, unlike pure beta-adrenergic blocking agents, produces a dose dependent (at usual doses) decrease in systemic arterial blood pressure and systemic vascular resistance without a substantial reduction in resting heart rate, cardiac output, or stroke volume, apparently because of its combined alpha- and beta-adrenergic blocking activity. Labetalol effectively reduces blood pressure in the standing or supine position, but because of the drug's alpha1-adrenergic blocking activity, the effect on blood pressure is position dependent; labetalol induced decreases in blood pressure are greater in the standing than in the supine position, and orthostatic hypotension can occur. The blunting of exercise induced increases in blood pressure by oral or iv labetalol is generally greater than that produced by pure beta-adrenergic blocking agents (eg; propranolol), but the blunting of exercise induced tachycardia produced by labetalol is generally less than that produced by pure beta-adrenergic blocking agents.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1063
The electrophysiologic effects of labetalol are variable and appear to be mediated via the drug's myocardial beta1-adrenergic blocking activity. Labetalol may decrease conduction velocity through the atrioventricular node and increase the atrial effective refractory period, but the drug appears to have inconsistent effects on sinoatrial conduction time and the atrioventricular nodal refractory period; the decrease in atrioventricular nodal conduction velocity produced by labetalol is less than that produced by pure beta-adrenergic blocking agents. In healthy individuals and in patients with cardiac disease (eg, coronary artery disease), labetalol generally has little effect on sinus rate, intraventricular conduction, the His-Purkinje system, or duration of the QRS complex. In one study in hypertensive patients, oral labetalol therapy was associated with a substantial reduction in ventricular premature contractions, and in another study in hypertensive patients, iv labetalol rapidly restored sinus rhythm in some patients with supraventricular or ventricular arrhythmias.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1063

8.9 Human Metabolite Information

8.9.1 Cellular Locations

Membrane

8.9.2 Metabolite Pathways

9 Use and Manufacturing

9.1 Uses

MEDICATION

Use (kg) in USA (2002): 1980

Consumption (g per capita) in the USA (2002): 0.00702

Excretion rate: 0.04

Calculated removal (%): 32.1

For the management of hypertension (alone or in combination with other classes of antihypertensive agents), as well as chronic stable angina pectoris and sympathetic overactivity syndrome associated with severe tetanus. Labetalol is used parenterally for immediate reduction in blood pressure in severe hypertension or in hypertensive crises when considered an emergency, for the control of blood pressure in patients with pheochromocytoma and pregnant women with preeclampsia, and to produce controlled hypotension during anesthesia to reduce bleeding resulting from surgical procedures.

9.1.1 Use Classification

Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Formulations / Preparations

Oral Tablets, film coated, 100 mg, Normodyne (with parabens, scored), Schering; Trandate (with parabens: scored), Allen & Hanburys; 200 mg, Normodyne (with parabens: scored), Schering; Trandate (with parabens; scored), Allen & Hanburys; 300 mg, Normodyne (with parabens), Schering; Trandate (with aprabens; scored), Allen & Hanburys. /Labetalol hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1069
Parenteral Injection, for IV use, 5 mg/ml, Normodyne (with anhydrous dextrose 15 mg/ml, edetate disodium, and parabens), Schering; Trandate (with anhydrous dextrosse 45 mg ml, edetate disodium and parabens), Allen & Hanburys. /Labetalol hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1069
Oral Tablets film coated, 100 mg with Hydrochlorothiazide 25 mg, Normozide 100/25 (with parabens), Schering; Trandate HCT 9 with parabens), Allen & Hanburys; 200 mg with Hydrochlorothiazide 25 mg, Normozide 200/25 (with parabens), Schering; Trandate HCT (with parabens), Allen & Hanburys; 300 mg withHydrochlorothiazide 25 mg, Normozide 300/25 (with parabens), Schering; Trandate HCT (with parabens), Allen & Hanburys. /Labetalol Hydrochloride Combinations/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1069

10 Identification

10.1 Analytic Laboratory Methods

Determination of labetalol using GC equipped with a FID. Nitrogen is used as the carrier gas at the flow rate of about 30 ml/min.
USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990., p. 749

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Irritant
Health Hazard
Environmental Hazard
Signal
Warning
GHS Hazard Statements

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (100%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

H411 (66.7%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

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

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

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.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Skin Irrit. 2 (100%)

Eye Irrit. 2 (100%)

STOT SE 3 (100%)

Repr. 2 (100%)

Aquatic Chronic 2 (66.7%)

11.2 Regulatory Information

REACH Registered Substance

11.2.1 FDA Requirements

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 amended; 21 U.S.C. 321-392).
21 CFR 200-299, 300-499, 820, and 860 (4/1/91)
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/
DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-167 (1992)

11.3 Other Safety Information

Chemical Assessment

IMAP assessments - Benzamide, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-: Environment tier I assessment

IMAP assessments - Benzamide, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-: Human health tier I assessment

11.3.1 Special Reports

Prichard BN; Beta-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 GJ; Clinical 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 L; A 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.

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

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.

12.1.2 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.

Likelihood score: C (probable although rare cause of clinically apparent liver injury).

12.1.3 Drug Induced Liver Injury

Compound
labetalol
DILI Annotation
Most-DILI-Concern
Severity Grade
8
Label Section
Warnings and precautions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.4 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

12.1.5 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Because of the low levels of labetalol in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in fullterm breastfed infants. No special precautions are required in most infants. However, other agents may be preferred while nursing a preterm infant. Labetalol may predispose nursing mothers to Raynaud’s phenomenon of the nipple.

◉ Effects in Breastfed Infants

One investigator reported that no adverse effects occurred in breastfed infants whose mothers were taking labetalol in doses of 330 to 800 mg daily.

A 26-week premature infant weighing 640 grams developed sinus bradycardia (80 to 90 bpm) and isolated atrial premature beats after nasogastric feeding with mother's pumped breastmilk began on day 8 of life. The mother was taking labetalol 300 mg twice daily by mouth for hypertension. Bradycardia and premature beats resolved within 24 hours of substitution of formula for breastmilk. No other causes for bradycardia could be identified. One untimed sample of the mother's breastmilk contained 710 mcg/L of labetalol. Although the authors estimated the infant's dose to be 100 mg/kg daily, a recalculation using their data indicates that the infant's dose was only 100 mcg/kg daily.

A 2-month-old infant was being breastfed exclusively by a mother taking labetalol 100 mg twice daily. The infants electrocardiogram had a regular heart rate, but borderline prolonged QT. The infant was started on propranolol 1 mg/kg daily for infantile hemangioma. One month later, the infant had a normal QT interval. A second infant was exclusively breastfed by a mother taking labetalol 150 mg twice daily and nifedipine 60 mg daily. The infant was started on propranolol 0.6 mg/kg daily for infantile hemangioma. The propranolol dose was increased over 2 weeks to 3.4 mg/kg daily. The infant had some sleeping difficulties with the higher propranolol dose, but no other symptoms.

A prospective study of pregnant patients taking a beta-blocker asked mothers to complete a questionnaire about postpartum breastfeeding and any side effects in their breastfed infants. One mother reported taking labetalol in an unreported dosage while breastfeeding. She reported weak sucking in her infant.

◉ Effects on Lactation and Breastmilk

Intravenous labetalol can increase serum prolactin in men and non-nursing women, although the increase is greater in women. Oral labetalol does not increase serum prolactin. The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed.

A woman with a history of symptoms of Raynaud's phenomenon developed Raynaud's phenomenon of the nipples when treated for pregnancy-induced hypertension with labetalol 100 mg twice daily. She breastfed for 5 weeks, but nursing caused pain in her nipples. In a subsequent pregnancy, similar symptoms occurred during treatment with labetalol 100 mg twice daily. Discontinuing labetalol eliminated the nipple pain in both instances.

A pregnant woman was treated on two occasions with intravenous labetalol for pre-eclampsia. On each occasion, she reported a burning sensation of the nipples. While continuing on labetalol, sustained-release nifedipine was added to her regimen and the burning of the nipple did not return.

◈ What is labetalol?

Labetalol is a medication that has been used to treat high blood pressure and chest pain. It works by slowing the heart rate and opening blood vessels to improve blood flow and lower blood pressure. Labetalol is part of a group of medications called beta-blockers. Some brand names are Trandate®, Normodyne®, or Labrocol®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.

◈ I take labetalol. Can it make it harder for me to get pregnant?

It is not known if labetalol can make it harder to get pregnant.

◈ Does taking labetalol increase the chance for miscarriage?

Miscarriage is common and can occur in any pregnancy for many different reasons. Based on the studies reviewed, it is not known if labetalol can increase the chance for miscarriage.

◈ Does taking labetalol increase the chance of birth defects?

Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Information on the use of labetalol in pregnancy is limited. Available information does not suggest the use of labetalol in pregnancy increases the chance of birth defects.

◈ Does taking labetalol in pregnancy increase the chance of other pregnancy-related problems?

Most studies do not suggest that labetalol increases the chance of other pregnancy-related problems, such as preterm delivery (birth before week 37), low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth), or stillbirth.There have been a few reports of temporary symptoms of beta-blockade that appeared shortly after birth in infants who were exposed to labetalol in late pregnancy. Symptoms can include slowed heart rate, low blood pressure, and low blood sugar. If these symptoms occur, they are expected to pass within 3 days.There have been cases where the effects of beta-blocker exposure occurred a week after birth. The symptoms were more severe and life-threatening. Symptoms reported included abnormal breathing, sepsis (blood infection), and seizures. It has been suggested that preterm infants that were exposed to labetalol over for a long period of time during pregnancy should be carefully monitored during the first week after birth.

◈ Does taking labetalol in pregnancy affect future behavior or learning for the child?

Based on the studies reviewed, it is not known if labetalol increases the chance for behavior or learning issues. One study of 32 children between the ages of 3-7 years old who were exposed to labetalol during pregnancy found no differences on formal testing of learning and behavior compared to children who were not exposed to labetalol. Another study found a higher chance for attention deficit hyperactivity disorder (ADHD) in children who were exposed to labetalol or a different type of high blood pressure medication during pregnancy.Breastfeeding while taking labetalol:Labetalol gets into breastmilk in small amounts and is not expected to cause problems in full-term breastfed infants. Be sure to talk to your healthcare provider about all of your breastfeeding questions.

◈ If a male takes labetalol, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?

There have been case reports of sexual dysfunction (trouble with ejaculation) in males while taking labetalol. This can make it harder to conceive a pregnancy. Studies have not been done to see if labetalol could increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

12.1.6 Exposure Routes

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.

12.1.7 Symptoms

Side effects or adverse reactions include dizziness when standing up, very low blood pressure, severely slow heartbeat, weakness, diminished sexual function, fatigue

12.1.8 Acute Effects

12.1.9 Toxicity Data

LD50 = 66 mg/kg (Rat, parental-intravenous)

12.1.10 Interactions

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/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1067
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.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1068
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 concentration; however, excessive hypotension can result in a large reduction in cardiac output and an increase in central venous pressure.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1068
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.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1068
For more Interactions (Complete) data for LABETALOL (10 total), please visit the HSDB record page.

12.1.11 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/
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 192
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 used; dopamine 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.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1067

12.1.12 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 positions; in 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/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1063
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.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1064
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 closely; if 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.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1066
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.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1066
For more Human Toxicity Excerpts (Complete) data for LABETALOL (15 total), please visit the HSDB record page.

12.1.13 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.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1067
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/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1067
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 malformation; however, 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/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1067

12.1.14 Non-Human Toxicity Values

LD50 Mouse oral approx 0.6 g/kg /Labetolol hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1067
LD50 Rat oral > 2 g/kg /Labetalol hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1067
LD50 Dog oral > 1 g/kg /Labetolol hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1067

12.1.15 Protein Binding

Labetalol is approximately 50% protein bound in serum.

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Chemical Co-Occurrences in Literature

14.6 Chemical-Gene Co-Occurrences in Literature

14.7 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

16.3 Drug-Food Interactions

Take with or without food. The absorption is unaffected by food.

16.4 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: ATC

18.5 KEGG: Target-based Classification of Drugs

18.6 KEGG: Drug Groups

18.7 WHO ATC Classification System

18.8 FDA Pharm Classes

18.9 ChemIDplus

18.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.11 ChEMBL Target Tree

18.12 UN GHS Classification

18.13 NORMAN Suspect List Exchange Classification

18.14 CCSBase Classification

18.15 EPA DSSTox Classification

18.16 EPA Substance Registry Services Tree

18.17 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    Benzamide, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  3. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  5. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  6. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  7. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  8. Hazardous Substances Data Bank (HSDB)
  9. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  10. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
    2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide
    https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=25758
  11. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  12. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  13. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  14. Toxin and Toxin Target Database (T3DB)
    LICENSE
    T3DB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (T3DB) and the original publication.
    http://www.t3db.ca/downloads
  15. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  16. ChEBI
  17. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  18. LiverTox
  19. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  20. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  21. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  22. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  23. Therapeutic Target Database (TTD)
  24. DailyMed
  25. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  26. Drugs and Lactation Database (LactMed)
  27. Mother To Baby Fact Sheets
    LICENSE
    Copyright by OTIS. This work is available under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license (CC BY-NC-ND 3.0).
    https://www.ncbi.nlm.nih.gov/books/about/copyright/
  28. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  29. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    LABETALOL
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  30. EU Clinical Trials Register
  31. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  32. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  33. Japan Chemical Substance Dictionary (Nikkaji)
  34. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  35. MassBank Europe
  36. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  37. Metabolomics Workbench
  38. SpectraBase
    2-Hydroxy-5-(1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl)benzamide
    https://spectrabase.com/spectrum/7Jz6JBjkdVf
  39. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  40. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  41. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  42. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  43. Springer Nature
  44. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  45. Wikidata
  46. Wikipedia
  47. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
    Adrenergic alpha-1 Receptor Antagonists
    https://www.ncbi.nlm.nih.gov/mesh/68058668
  48. PubChem
  49. GHS Classification (UNECE)
  50. EPA Substance Registry Services
  51. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  52. PATENTSCOPE (WIPO)
  53. NCBI
CONTENTS