Labetalol (INN) (/ləˈbÉ›tÉ™lÉ"Ël/) (trade names Normodyne and Trandate) is a mixed alpha/beta adrenergic antagonist that is used to treat high blood pressure.
Indications
It has a particular indication in the treatment of pregnancy-induced hypertension which is commonly associated with pre-eclampsia.
It is also used to treat chronic and acute hypertension of pheochromocytoma and hypertensive crisis.
Administration
Labetalol is available in 100, 200, and 300Â mg tablets and intravenously (available as Trandate) in 5Â mg/ml solution. Adults taking tablets usually start with 100Â 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 20Â mg over two minutes. Additional doses of 40Â mg, then 80Â mg may be administered every ten minutes as needed. Additional 80Â mg doses can be given to a total maximum dose of 300Â mg. Additionally, labetalol can be administered by IV infusion at a rate of 2Â mg/minute, with a maximum dose of 300Â mg.
Side effects
Side effects may include:
- Drowsiness
- Fatigue
- Weakness
- Difficulty sleeping
- Diminished sexual function
- Orthostatic hypotension (due to alpha receptor blockade)
- Scalp tingling
- Hyperkalemia
- Hepatotoxicity
- Drug eruption similar to lichen planus
- 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, hypotension 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. Labetalol has two chiral carbons and consequently exists as four stereoisomers. 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.
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 palladiumâ€"platinum on carbon catalyst into labetalol. Presumably the ketone is also reduced in this last step.
- H.C. Welch, DE 2032642Â (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): 670â€"9. doi:10.1021/jm00348a013. PMID 6124636.Â
Mechanism of action
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.