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| Pronunciation | /ləˈbɛtəlɔːl/ |
| Trade names | Normodyne, Trandate, others |
| Other names | Ibidomide; AH-5158; SCH-19927 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a685034 |
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| Routes of administration | By mouth,intravenous |
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| Bioavailability | 25% (11–86%)[1][2][3] |
| Protein binding | 50%[1][3] |
| Metabolism | Mainlyconjugation viaglucuronidation[1][2][3] |
| Metabolites | •Glucuronideconjugates[2] |
| Eliminationhalf-life | Oral: 6–8 hours[1][2][3] IVTooltip Intravenous infusion: 5.52 hours[2] |
| Duration of action | 8–12 hours[1] |
| Excretion | Urine (55–60% as conjugates or unchanged within 24 hours)[1] |
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| ECHA InfoCard | 100.048.401 |
| Chemical and physical data | |
| Formula | C19H24N2O3 |
| Molar mass | 328.412 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
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Labetalol is a medication used to treathigh blood pressure and in long term management ofangina.[4][5] This includesessential hypertension,hypertensive emergencies, andhypertension of pregnancy.[5] In essential hypertension it is generally less preferred than a number of otherblood pressure medications.[4] It can be givenby mouth or byinjection into a vein.[4]
Common side effects includelow blood pressure with standing, dizziness, feeling tired, and nausea.[4] Serious side effects may includelow blood pressure,liver problems,heart failure, andbronchospasm.[4] Use appears safe in the latter part ofpregnancy and it is not expected to cause problems duringbreastfeeding.[5][6] It works by blocking the activation ofβ- andα-adrenergic receptors.[4]
Labetalol was patented in 1966 and came into medical use in 1977.[7] It is available as ageneric medication.[5] In 2022, it was the 215th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[8][9]
Labetalol is effective in the management ofhypertensive emergencies, postoperative hypertension,pheochromocytoma-associated hypertension, andrebound hypertension frombeta blocker withdrawal.[10]
It has a particular indication in the treatment ofpregnancy-induced hypertension which is commonly associated withpre-eclampsia.[11]
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.[14]
Labetalol iscontraindicated in people with overtcardiac failure, greater-than-first-degreeheart block, severebradycardia,cardiogenic shock, severehypotension, anyone with a history ofobstructive airway disease includingasthma, and those withhypersensitivity to the drug.[16]
Labetalol is abeta blocker, or anantagonist of theβ-adrenergic receptors. It is specifically anon-selective antagonist of theβ1- andβ2-adrenergic receptors.[17] Labetalol hasintrinsic sympathomimetic activity.[17] It is also an antagonist of theα1-adrenergic receptor, and hence is additionally analpha blocker. The antagonism of the adrenergic receptors by labetalol iscompetitive against othercatecholamines[18] and its actions on the receptors arepotent andreversible.[16] Labetalol acts by blocking α- and β-adrenergic receptors, resulting in decreasedperipheral vascular resistance without significant alteration ofheart rate orcardiac output.
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][16] Thus, the labetalol can be thought to be a beta blocker with some α-blocking effects.[16][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]
Similar tolocal anesthetics andsodium channel blockingantiarrhythmics, labetalol also hasmembrane stabilizing activity.[2][22][27] By decreasing sodium entry, labetalol decreasesaction potential firing and thus haslocal anesthetic activity.[28]
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 | |
|---|---|
-Labetalol_Structural_Formula_V1.svg) (R,R)-Labetalol CAS number: 75659-07-3 | -Labetalol_Structural_Formula_V1.svg) (S,S)-Labetalol CAS number: 83167-24-2 |
-Labetalol_Structural_Formula_V1.svg) (R,S)-Labetalol CAS number: 83167-32-2 | -Labetalol_Structural_Formula_V1.svg) (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]
The experimentallog P of labetalol is 2.7 to 3.1 and its predicted log P ranges from 1.73 to 3.1.[31][3][32][33] Hence, it has relatively highlipophilicity.[31][3][32][33][34]
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]
