Labetalol

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Labetalol
Labetalol.svg
Systematic (IUPAC) name
(RS)-2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}benzamide
Clinical data
Trade names Normodyne, Trandate
AHFS/Drugs.com monograph
MedlinePlus a685034
Pregnancy
category
  • C
    One of few drugs used for PIH
Legal status
  • (Prescription only)
Routes of
administration
oral iv
Pharmacokinetic data
Bioavailability 25%
Protein binding 50%
Metabolism hepatic pass metabolism,
Biological half-life Tablet: 6-8 hours; IV: 5.5 hours
Excretion Excreted in urine, not removed by hemodialysis
Identifiers
CAS Registry Number 36894-69-6 YesY
ATC code C07AG01
PubChem CID: 3869
IUPHAR/BPS 7207
DrugBank DB00598 YesY
ChemSpider 3734 YesY
UNII R5H8897N95 YesY
KEGG D08106 YesY
ChEBI CHEBI:6343 YesY
ChEMBL CHEMBL429 YesY
Chemical data
Formula C19H24N2O3
Molecular mass 328.406 g/mol
 YesY (what is this?)  (verify)

Labetalol (INN) (/ləˈbɛtəlɔːl/) (trade names Normodyne and Trandate) is a mixed alpha/beta adrenergic antagonist that is used to treat high blood pressure.[1]

Indications[edit]

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[edit]

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[edit]

Side effects may include:

Contraindications[edit]

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

Chemistry[edit]

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 which is also known as dilevalol, 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[edit]

Labetalol synthesis:[8][9][10] stereoisomers:[11]

Synthesis begins with Friedel-Crafts acetylation of salicylamide (1). α-Bromination of the methylketone followed by displacement with N-benzyl-4-phenylbutan-2-amine 3 (in one of the texts a protecting group is not used) forming the aminoketone (4). The last step is a catalytic hydrogenation over a palladium–platinum on carbon catalyst which serves the dual purpose of debenzylation and reduction of the ketone to afford Labetalol (5).

Mechanism of action[edit]

Labetalol 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. The principal physiologic action of labetalol is to competitively block adrenergic stimulation of β-receptors within the myocardium (β1-receptors) and within bronchial and vascular smooth muscle (β2-receptors), and α1-receptors within vascular smooth muscle. This causes a 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 α- and β-adrenergic blocking activity.

Labetalol has local anesthetic activity.[12]

Labetalol, in animal models, was found to cross the blood-brain-barrier in only negligible amounts.[13]

See also[edit]

References[edit]

  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. 
  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. doi:10.1111/j.1476-5381.1991.tb12513.x. PMC 1908821. PMID 1687367. 
  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. doi:10.1111/j.1365-2125.1976.tb00637.x. PMC 1428931. PMID 9968. 
  8. ^ H.C. Welch, DE 2032642  (1971).
  9. ^ L.H.C. Lunts, D.T. Collin, U.S. Patent 4,012,444 (1977).
  10. ^ Clifton, J. E.; Collins, I.; Hallett, P.; Hartley, D.; Lunts, L. H. C.; Wicks, P. D. (1982). "Arylethanolamines derived from salicylamide with .alpha.- and .beta.-adrenoceptor blocking activities. Preparation of labetalol, its enantiomers and related salicylamides". Journal of Medicinal Chemistry 25 (6): 670–9. doi:10.1021/jm00348a013. PMID 6124636.  edit
  11. ^ doi:10.1021/jm00353a017
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  12. ^ Exam Zone (1 January 2009). Elsevier Comprehensive Guide. Elsevier India. pp. 449–. ISBN 978-81-312-1620-0. 
  13. ^ Detlev Ganten; Patrick J. Mulrow (6 December 2012). Pharmacology of Antihypertensive Therapeutics. Springer Science & Business Media. pp. 147–. ISBN 978-3-642-74209-5.