Labetalol

Labetalol

Systematic (IUPAC) name
(RS)-2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}benzamide
Clinical data
Trade names	Trandate
AHFS/Drugs.com	monograph
MedlinePlus	a685034
Pregnancy cat.	C One of few drugs used for PIH
Legal status	℞ Prescription only
Routes	oral iv
Pharmacokinetic data
Bioavailability	90-100%
Protein binding	50%
Metabolism	hepatic pass metabolism,
Half-life	Tablet: 6-8 hours; IV: 5.5 hours
Excretion	Excreted in urine, not removed by hemodialysis
Identifiers
CAS number	36894-69-6 Y
ATC code	C07AG01
PubChem	CID 3869
DrugBank	APRD01062
ChemSpider	3734 Y
UNII	R5H8897N95 Y
KEGG	D08106 Y
ChEBI	CHEBI:6343 N
ChEMBL	CHEMBL429 Y
Chemical data
Formula	C19H24N2O3
Mol. mass	328.406 g/mol
SMILES	eMolecules & PubChem
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) Y Key:SGUAFYQXFOLMHL-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Labetalol (Normodyne, Trandate, fixed combination with hydrochlorothiazide: Normozyde) is a mixed alpha/beta adrenergic antagonist, which is used to treat high blood pressure.^[1]

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 (only 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. IV doses are usually started at 20 mg over 2 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:

• Drowsiness
• Fatigue
• Weakness
• Difficulty sleeping
• Diminished sexual function
• Scalp tingling which passes after time.
• Drug eruption similar to lichen planus^[4]
• A rare but potentially lethal side effect is respiratory distress.

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 therefore 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.

Labetolol 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]

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.

• H.C. Welch, DE 2032642  (1971).
• L.H.C. Lunts, D.T. Collin, U.S. Patent 4,012,444 (1977).
• 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. doi:10.1021/jm00348a013. PMID 6124636.  edit

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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1908821. 
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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1428931.