Labetalol was patented in 1966 and came into medical use in 1977.[7] It is available as ageneric medication.[5] In 2023, it was the 232nd most commonly prescribed medication in the United States, with more than 1million prescriptions.[8][9]
It is also used as an alternative in the treatment of severe hypertension.[10]
Labetalol is useful in the treatment of acutecardiovasculartoxicity (e.g. inoverdose) caused bysympathomimetics likeamphetamine,methamphetamine,cocaine,ephedrine, andpseudoephedrine.[12][13] Other beta blockers are also used.[12][13] However, the controversial yet possible phenomenon of "unopposed α-stimulation" with administration of selective beta blockers to block non-selective sympathomimetics potentially makes dualalpha-1 and beta blockers like labetalol andcarvedilol more favorable for such purposes.[12][13] The rate of unopposed α-stimulation with selective beta blockers has been reported to be 0.4%,[12] whereas no cases of unopposed α-stimulation have been reported with dual alpha and beta blockers like labetalol.[13]
Pregnancy: studies in lab animals showed no harm to the baby. However, a comparable well-controlled study has not been performed in pregnant women.[1]
Nursing: breast milk has been shown to contain small amounts of labetalol (0.004% original dose). Prescribers should be cautious in the use of labetalol for nursing mothers.[1]
Pediatric: no studies have established safety or usefulness in this population.[1]
Geriatric: the elderly are more likely to experiencedizziness when taking labetalol. Labetalol should be dosed with caution in the elderly and counseled on this side effect.[1]
Low blood pressure with standing is more severe and more common with IV formulation (58% vs 1%[1]) and is often the reason larger doses of the oral formulation cannot be used.[15]
Labetalol is aboutequipotent in blocking β1- and β2-adrenergic receptors.[19] The amount of α to β blockade depends on whether labetalol is administered orally orintravenously (IV). Orally, the ratio of α to β blockade is 1:3.[20][21]Intravenously, α to β blockade ratio is 1:7.[19][14] Thus, labetalol can be thought to be a beta blocker with some α-blocking effects.[14][18][22] By comparison, labetalol is a weaker β-adrenergic receptor blocker thanpropranolol, and has a weaker affinity for α-adrenergic receptors compared tophentolamine.[19][18]
Labetalol's dual α- and β-adrenergic antagonism has different physiological effects in short- and long-term situations. In short-term, acute situations, labetalol decreases blood pressure by decreasingsystemic vascular resistance with little effect onstroke volume, heart rate and cardiac output.[23] During long-term use, labetalol can reduce heart rate during exercise while maintainingcardiac output by an increase instroke volume.[24]
Labetalol possesses significant intrinsic sympathomimetic activity (ISA).[2][22] In particular, it is apartial agonist at β2-adrenergic receptors located in thevascularsmooth muscle. Labetalol relaxes vascular smooth muscle by a combination of this partial β2-adrenergic receptor agonism and through α1-adrenergic receptor blockade.[22][25] Overall, thisvasodilatory effect can decrease blood pressure.[26] It was originally reported to lack ISA, but a slight degree of activity was subsequently characterized.[2]
The physiological effects of labetalol when administered acutely (intravenously) are not predictable solely by their receptor blocking effect, i.e. blocking β1-adrenergic receptors should decrease heart rate, but labetalol does not. When labetalol is given in acute situations, it decreases the peripheral vascular resistance and systemic blood pressure while having little effect on the heart rate, cardiac output and stroke volume, despite its α1-, β1- and β2-adrenergic receptor blocking mechanism.[23][24] These effects are mainly seen when the person is in the upright position.[26]
Long term labetalol use also has different effects from other beta blockers. Other beta blockers, such aspropranolol, persistently reduce cardiac output during exercise. The peripheral vascular resistance decreases when labetalol is first administered. Continuous labetalol use further decreases peripheral vascular resistance. However, during exercise, cardiac output remains the same due to a compensatory mechanism that increasesstroke volume. Thus, labetalol is able to reduce heart rate during exercise while maintaining cardiac output by the increase in stroke volume.[24]
Labetalol is often classified as a beta blocker with lowlipophilicity and hence lower potential for crossing theblood–brain barrier andblood–placenta barrier.[17][29][30] This in turn may result in fewer effects in thecentral nervous system as well as a lower risk ofneuropsychiatric side effects.[17] Paradoxically however, labetalol actually shows high lipophilicity.[31][3][32][33][34][2] In any case, labetalol, inanimals including rats, rabbits, and dogs, was found to cross into the brain in negligible amounts, probably for reasons other than low lipophilicity.[1][2][35] On the other hand, the drug has been shown to cross the blood–placenta barrier in humans.[1]
The minimum requirement foradrenergic agents is a primary or secondary amine separated from a substituted benzene ring by one or two carbons.[36] This configuration results in strong agonist activity. As the size of the substituent attached to the amine becomes greater, particularly with respect to a t-butyl group, then the molecule typically is found to havereceptor affinity without intrinsic activity, and is, therefore, an antagonist.[36] Labetalol, with its 1-methyl-3-phenylpropyl substituted amine, is greater in size relative to a t-butyl group and therefore acts predominantly as an antagonist. The overall structure of labetalol is very polar. This was created by substituting the isopropyl group in the standard beta blocker structure with an aralkyl group, including a carboxamide group on the meta position, and by adding a hydroxyl group on the para position.[19]
Labetalol has twochiral carbons and consequently exists as fourstereoisomers.[37] Two of these isomers, the (S,S)- and (R,S)-forms are inactive. The third, the (S,R)-isomer, is a powerfulα1-adrenergic receptor blocker. The fourth isomer, the (R,R)-isomer which is also known as dilevalol, is a mixed non-selective β-adrenergic receptor blocker and selective α1 blocker.[19] Labetalol is typically given as a racemic mixture to achieve both α- and β-adrenergic receptor blocking activity.[38]
Stereoisomers of labetalol
(R,R)-Labetalol CAS number: 75659-07-3
(S,S)-Labetalol CAS number: 83167-24-2
(R,S)-Labetalol CAS number: 83167-32-2
(S,R)-Labetalol CAS number: 83167-31-1
It is chemically designated in International Union of Pure and Applied Chemistry (IUPAC) nomenclature as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride.[38][39]
Labetalol was the first drug created that combined both α- and β-adrenergic receptor blocking properties. It was created to potentially fix the compensatory reflex issue that occurred when blocking a single receptor subtype, i.e. vasoconstriction after blocking β-adrenergic receptors or tachycardia after blocking α-adrenergic receptors. Because the reflex from blocking the single receptor subtypes acted to prevent the lowering of blood pressure, it was postulated that weak blocking of both α- and β-adrenergic receptors could work together to decrease blood pressure.[19][24]
^abWatson K, Watson B, Summers K, Michocki R (2013). "Chapter 21: Hypertensive Crises". In Koda-Kimble MA, Alldredge BK (eds.).Koda-Kimble and Young's Applied Therapeutic: The Clinical Use of Drugs. Philadelphia: Lippincott Williams & Wilkins. pp. 520–535.ISBN978-1-60913-713-7.
^Arulkumaran N, Lightstone L (December 2013). "Severe pre-eclampsia and hypertensive crises".Best Practice & Research. Clinical Obstetrics & Gynaecology.27 (6):877–884.doi:10.1016/j.bpobgyn.2013.07.003.PMID23962474.
^abcdRichards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ (May 2015). "Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review".Drug Alcohol Depend.150:1–13.doi:10.1016/j.drugalcdep.2015.01.040.PMID25724076.
^abcdRichards JR, Hollander JE, Ramoska EA, Fareed FN, Sand IC, Izquierdo Gómez MM, et al. (May 2017). "β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon".J Cardiovasc Pharmacol Ther.22 (3):239–249.doi:10.1177/1074248416681644.PMID28399647.
^Shiohara T, Kano Y (2007). "Lichen planus and lichenoid dermatoses". In Bolognia JL (ed.).Dermatology. St. Louis: Mosby. p. 161.ISBN978-1-4160-2999-1.
^abcRobertson D, Biaggioni I (2012). Katzung BG (ed.).Adrenoceptor Antagonist Drugs IN: Basic & Clinical Pharmacology (12th ed.). San Francisco: McGraw Hill Lange Medical. pp. 151–168.ISBN978-0-07-176401-8.
^abcdefLouis W, McNeill JJ, Drummer OH (1988). "Labetalol and other vasodilator/Beta-blocking drugs.". In Doyle AE (ed.).Handbook of Hypertension. Amsterdam, Netherlands: Elsevier Sciences Publishing Co. pp. 246–273.ISBN978-0-444-90469-0.
^Katzung BF (2006).Basic and clinical pharmacology. New York: McGraw-Hill Medical. p. 170.ISBN978-0-07-145153-6.
^Mottram AR, Erickson T (2009). Field J (ed.).Toxicology in Emergency Cardiovascular Care IN: The Textbook of Emergency Cardiovascular Care and CPR. Philadelphia, PA: Lippincott Williams & Wilkins. pp. 443–452B.ISBN978-0-7817-8899-1.
^Donnelly R, Macphee GJ (August 1991). "Clinical pharmacokinetics and kinetic-dynamic relationships of dilevalol and labetalol".Clin Pharmacokinet.21 (2):95–109.doi:10.2165/00003088-199121020-00002.PMID1884570.
^Peacock WF, Hilleman DE, Levy PD, Rhoney DH, Varon J (July 2012). "A systematic review of nicardipine vs labetalol for the management of hypertensive crises".Am J Emerg Med.30 (6):981–993.doi:10.1016/j.ajem.2011.06.040.PMID21908132.
^abWoods PB, Robinson ML (March 1981). "An investigation of the comparative liposolubilities of beta-adrenoceptor blocking agents".J Pharm Pharmacol.33 (3):172–173.doi:10.1111/j.2042-7158.1981.tb13743.x.PMID6116760.
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