Labetalol

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Labetalol
Systematic (IUPAC) name
(RS)-2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}benzamide
Clinical data
Trade namesTrandate
AHFS/Drugs.commonograph
MedlinePlusa685034
Pregnancy cat.C
One of few drugs used for PIH
Legal status Prescription only
Routesoral iv
Pharmacokinetic data
Bioavailability25%
Protein binding50%
Metabolismhepatic pass metabolism,
Half-lifeTablet: 6-8 hours; IV: 5.5 hours
ExcretionExcreted in urine, not removed by hemodialysis
Identifiers
CAS number36894-69-6 YesY
ATC codeC07AG01
PubChemCID 3869
DrugBankDB00598
ChemSpider3734 YesY
UNIIR5H8897N95 YesY
KEGGD08106 YesY
ChEBICHEBI:6343 YesY
ChEMBLCHEMBL429 YesY
Chemical data
FormulaC19H24N2O3 
Mol. mass328.406 g/mol
 YesY (what is this?)  (verify)
 
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Labetalol
Systematic (IUPAC) name
(RS)-2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}benzamide
Clinical data
Trade namesTrandate
AHFS/Drugs.commonograph
MedlinePlusa685034
Pregnancy cat.C
One of few drugs used for PIH
Legal status Prescription only
Routesoral iv
Pharmacokinetic data
Bioavailability25%
Protein binding50%
Metabolismhepatic pass metabolism,
Half-lifeTablet: 6-8 hours; IV: 5.5 hours
ExcretionExcreted in urine, not removed by hemodialysis
Identifiers
CAS number36894-69-6 YesY
ATC codeC07AG01
PubChemCID 3869
DrugBankDB00598
ChemSpider3734 YesY
UNIIR5H8897N95 YesY
KEGGD08106 YesY
ChEBICHEBI:6343 YesY
ChEMBLCHEMBL429 YesY
Chemical data
FormulaC19H24N2O3 
Mol. mass328.406 g/mol
 YesY (what is this?)  (verify)

Labetalol (Normodyne, Trandate) is a mixed alpha/beta adrenergic antagonist, which is used to treat high blood pressure.[1]

Contents

Indications

It has a particular indication in the treatment of pregnancy-induced hypertension which is commonly associated with pre-eclampsia.[2]

It is also used to treat chronic and acute hypertension of pheochromocytoma and hypertensive crisis.[3]

Administration

Labetalol is available in 100, 200, and 300 mg tablets and intravenously (available as Trandate) in 5 mg/ml solution. Adults taking tablets usually start with 100 mg twice daily, with a maximum of 2.4 g/day. In cases of emergency, dosage might be higher. Intravenous (IV) doses are usually started at 20 mg over two minutes. Additional doses of 40 mg, then 80 mg may be administered every ten minutes as needed. Additional 80 mg doses can be given to a total maximum dose of 300 mg. Additionally, labetalol can be administered by IV infusion at a rate of 2 mg/minute, with a maximum dose of 300 mg.

Side effects

Side effects may include:

Contraindications

Labetalol has relative contraindications for use in patients with asthma, congestive heart failure, any degree of heart block, bradycardia, or those in cardiogenic shock.

Chemistry

For adrenergic agents, when the substituent on the amine nitrogen is greater in size than a t-butyl group, then the molecule typically is found to have receptor affinity without intrinsic activity, and is therefore an antagonist.[5] Labetalol has two chiral carbons and consequently exists as four stereoisomers.[6] Two of these isomers, the (S,S)- and (R,S)- forms are inactive. The third, the (S,R)-isomer, is a powerful α1 blocker. The fourth isomer, the (R,R)-isomer, is a mixed nonselective β blocker and selective α1 blocker.

Labetalol acts by blocking alpha and beta adrenergic receptors, resulting in decreased peripheral vascular resistance without significant alteration of heart rate or cardiac output. The β:α antagonism of labetalol is approximately 3:1.[3][7]

Synthesis

Labetalol, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropanol)amino)]ethyl] benzamide is synthesized by the N-alkylation of N-benzyl-N(4-phenyl-2-butyl)amine 5-bromacetylsalicylamide and forming the aminoketone, which is further debenzylated by hydrogen using a palladium–platinum on carbon catalyst into labetalol. Presumably the ketone is also reduced in this last step.

Labetalol synthesis.png

References

  1. ^ Fahed S, Grum DF, Papadimos TJ (2008). "Labetalol infusion for refractory hypertension causing severe hypotension and bradycardia: an issue of patient safety". Patient Saf Surg 2: 13. doi:10.1186/1754-9493-2-13. PMC 2429901. PMID 18505576. http://www.pssjournal.com/content/2//13.
  2. ^ http://www.bnf.org/bnf/bnf/56/2488.htm?q=%22labetalol%22
  3. ^ a b Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical. p. 170. ISBN 0-07-145153-6.
  4. ^ Shiohara T, Kano Y (2007). "Lichen planus and lichenoid dermatoses". In Bolognia JL. Dermatology. St. Louis: Mosby. p. 161. ISBN 1-4160-2999-0.
  5. ^ Medicinal Chemistry of Adrenergics and Cholinergics
  6. ^ Riva E, Mennini T, Latini R (December 1991). "The alpha- and beta-adrenoceptor blocking activities of labetalol and its RR-SR (50:50) stereoisomers". Br. J. Pharmacol. 104 (4): 823–8. PMC 1908821. PMID 1687367. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1908821/.
  7. ^ D A Richards, J Tuckman, and B N Prichard (October 1976). "Assessment of alpha- and beta-adrenoceptor blocking actions of labetalol". Br J Clin Pharmacol 3 (5): 849–855. PMC 1428931. PMID 9968. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1428931/.