Labetalol

ラベタロール;

• Molecular FormulaC₁₉H₂₄N₂O₃
• Average mass328.405 Da

Labetalol hydrochloride, AH-5158A, Sch-15719W, Amipress, Trandate, Normodyne

Labetalol was granted FDA approval on 1 August 1984

Presolol; (RS)-2-Hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl}benzamide; 5-[1-Hydroxy-2-[(1-methyl-3-phenyl propyl)amino]ethyl]salicylamide

A salicylamide derivative that is a non-cardioselective blocker of BETA-ADRENERGIC RECEPTORS and ALPHA-1 ADRENERGIC RECEPTORS.

Labetalol[Wiki]

labetolol

[32780-64-6]

[36894-69-6]

2948416[Beilstein]

2-Hydroxy-5-(1-hydroxy-2-((1-methyl-3-phenylpropyl)amino)ethyl)benzamide

• AH 5158
• Albetol
• EC 253-258-3
• EINECS 253-258-3
• HSDB 6537
• Ibidomide
• Labetalol
• Labetalolum
• Labetalolum [INN-Latin]
• Labetolol
• SCH 15719W
• UNII-R5H8897N95

Labetalol hydrochloride

• CAS Number 32780-64-6,
• Empirical Formula (Hill Notation) C₁₉H₂₄N₂O₃ · HCl,
• Molecular Weight 364.87

REF https://www.accessdata.fda.gov/drugsatfda_docs/anda/98/74787_Labetalol%20Hydrochloride_Chemr.pdf

RR

CAS 75659-07-3

• (R,R)-Labetalol
• Dilevalol
• Dilevalolum
• Dilevalolum [Latin]
• UNII-P6629XE33T

Labetalol is a racemic mixture of 2 diastereoisomers where dilevalol, the R,R’ stereoisomer, makes up 25% of the mixture.⁸ Labetalol is formulated as an injection or tablets to treat hypertension

Labetalol is a medication used to treat high blood pressure and in long term management of angina.^[1][2] This includes essential hypertension, hypertensive emergencies, and hypertension of pregnancy.^[2] In essential hypertension it is generally less preferred than a number of other blood pressure medications.^[1] It can be given by mouth or by injection into a vein.^[1]

Common side effects include low blood pressure with standing, dizziness, feeling tired, and nausea.^[1] Serious side effects may include low blood pressure, liver problems, heart failure, and bronchospasm.^[1] Use appears safe in the latter part of pregnancy and it is not expected to cause problems during breastfeeding.^[2][3] It works by blocking the activation of β-receptors and α-receptors.^[1]

Labetalol was patented in 1966 and came into medical use in 1977.^[4] It is available as a generic medication.^[2] A month supply in the United Kingdom costs the NHS about 8 £ as of 2019.^[2] In the United States the wholesale cost of this amount is about US$12.^[5] In 2016 it was the 233rd most prescribed medication in the United States with more than 2

Medical uses

Labetalol is effective in the management of hypertensive emergencies, postoperative hypertension, pheochromocytoma-associated hypertension, and rebound hypertension from beta blocker withdrawal. ^[7]

It has a particular indication in the treatment of pregnancy-induced hypertension which is commonly associated with pre-eclampsia. ^[8]

It is also used as an alternative in the treatment of severe hypertension.^[7]

Special populations

Pregnancy: studies in lab animals showed no harm to the baby. However, a comparable well-controlled study has not been performed in pregnant women.^[9]

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.^[9]

Pediatric: no studies have established safety or usefulness in this population.^[9]

Geriatric: the elderly are more likely to experience dizziness when taking labetalol. Labetalol should be dosed with caution in the elderly and counseled on this side effect.^[9]

Side effects

Common

• Neurologic: headache (2%), dizziness (11%) ^[9]
• Gastrointestinal: nausea (6%), dyspepsia (3%) ^[9]
• Cholinergic: nasal congestion (3%), ejaculation failure (2%) ^[9]
• Respiratory: dyspnea (2%) ^[9]
• Other: fatigue (5%), vertigo (2%), orthostatic hypotension ^[9]

Low blood pressure with standing is more severe and more common with IV formulation (58% vs 1%^[9]) and is often the reason larger doses of the oral formulation cannot be used.^[10]

Rare

• Fever ^[9]
• Muscle cramps ^[9]
• Dry eyes ^[9]
• Heart block ^[9]
• Hyperkalemia ^[9]
• Hepatotoxicity ^[9]
• Drug eruption similar to lichen planus^[11]
• Hypersensitivity – which may result in a lethal respiratory distress^[9]

Contraindications

Labetalol is contraindicated in people with overt cardiac failure, greater-than-first-degree heart block, severe bradycardia, cardiogenic shock, severe hypotension, anyone with a history of obstructive airway disease including asthma, and those with hypersensitivity to the drug.^[12]

Chemistry

The minimum requirement for adrenergic agents is a primary or secondary amine separated from a substituted benzene ring by one or two carbons.^[13] 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 have receptor affinity without intrinsic activity, and is, therefore, an antagonist.^[13] 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.^[14]

Labetalol has two chiral carbons and consequently exists as four stereoisomers.^[15] 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.^[14] Labetalol is typically given as a racemic mixture to achieve both alpha and beta receptor blocking activity.^[16]

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

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.^[17][18]

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.^[16][19]

Pharmacology

Mechanism of action

Labetalol’s dual alpha and beta adrenergic antagonism has different physiological effects in short- and long-term situations. In short-term, acute situations, labetalol decreases blood pressure by decreasing systemic vascular resistance with little effect on stroke volume, heart rate and cardiac output.^[20] During long-term use, labetalol can reduce heart rate during exercise while maintaining cardiac output by an increase in stroke volume.^[21]

Labetalol is a dual alpha (α1) and beta (β1/β2) adrenergic receptor blocker and competes with other Catecholamines for binding to these sites.^[22] Its action on these receptors are potent and reversible.^[12] Labetalol is highly selective for postsynaptic alpha1- adrenergic, and non-selective for beta-adrenergic receptors. It is about equipotent in blocking both beta1- and beta2- receptors.^[14]

The amount of alpha to beta blockade depends on whether labetalol is administered orally or intravenously (IV). Orally, the ratio of alpha to β blockade is 1:3. Intravenously, alpha to β blockade ratio is 1:7.^[14][12] Thus, the labetalol can be thought to be a beta-blocker with some alpha-blocking effects.^[12][22][23] By comparison, labetalol is a weaker β-blocker than propranolol, and has a weaker affinity for alpha-receptors compared to Phentolamine.^[14][22]

Labetalol possesses intrinsic sympathomimetic activity.^[23] In particular, it is a partial agonist at beta2- receptors located in the vascular smooth muscle. Labetalol relaxes vascular smooth muscle by a combination of this partial beta2- agonism and through alpha1- blockade.^[23][24] Overall, this vasodilatory effect can decrease blood pressure.^[25]

Similar to local anesthetics and sodium channel blocking antiarrhythmics, labetalol also has membrane stabilizing activity.^[23][26] By decreasing sodium entry, labetalol decreases action potential firing and thus has local anesthetic activity.^[27]

Physiological action

The physiological effects of labetalol when administered acutely (intravenously) are not predictable solely by their receptor blocking effect, i.e. blocking beta1- 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 alpha1-, beta1- and beta2- blocking mechanism.^[20][21] These effects are mainly seen when the person is in the upright position.^[25]

Long term labetalol use also has different effects from other beta-blocking drugs. Other beta-blockers, such as propranolol, 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 increases stroke volume. Thus, labetalol is able to reduce heart rate during exercise while maintaining cardiac output by the increase in stroke volume.^[21]

Pharmacokinetics

Labetalol, in animal models, was found to cross the blood-brain-barrier in only negligible amounts.^[28]

History

Labetalol was the first drug created that combined both alpha- and beta- 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 beta-receptors or tachycardia after blocking alpha 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 alpha- and beta- receptors could work together to decrease blood pressure.^[14][21]

Syn 1

Drugs Fut 1976,1(3),125

DE 1643224; FR 1557677; FR 8010M; GB 1200886; US 3642896; US 3644353; US 3705233

Condensation of 5-bromoacetylsalicylamide (I) with N-benzyl-N-(1-methyl-3-phenylpropyl)amine (II) in refluxing butanone to 5-(N-benzyl-N-(1-methyl-3-phenylpropyl) glycyl)salicylamide hydrochloride (III), m.p. 139-141 C, which is reduced with H2 over Pt-Pd/C in ethanol.

SYN 2

Reductocondensation of 5-(N,N-dibenzylglycyl)salicylamide (IV) and benzylace-tone (V) with H2 over Pd-Pt/C in methanol – acetic acid.

SYN 3

Reaction of methyl 5-(2-amino-1-hydroxyethyl)salicylate hydrochloride (VI) with NH3 to 5-(2-amino-1-hydroxyethyl)salicylamide hydrochloride (VII), m.p. >360 C, which is finally condensed with benzylacetone (V) and reduced with H2 over Pd-Pt/C in methanol.

SYN 4

SYN 5

2-hydroxy-5-(1-hydroxy-2-((1-methyl-3-phenylpropyl)amino)ethyl)-, monohydrochloride, could be produced through many synthetic methods.

Following is one of the synthesis routes: 5-Bromoacetylsalicylamide (I) with N-benzyl-N-(1-methyl-3-phenylpropyl)amine (II) is condensed in the presence of refluxing butanone to produce 5-(N-benzyl-N-(1-methyl-3-phenylpropyl) glycyl)salicylamide hydrochloride (III), m.p. 139-141 C, and next the yielding compound is reduced with H₂ over Pt-Pd/C in ethanol.

SYN 6

https://patents.google.com/patent/WO2017098520A1/en

aration of Labetaiol Hydrochloride of

Scheme -I illustrates the process for preparation of Labetaiol Hydrochloride of formula (I).

30% NaOH

Step – Sodium borohydride

Pure Labetaiol Hydrochloride (I)

aration of Labetaiol Hydrochloride of

Scheme -I illustrates the process for preparation of Labetaiol Hydrochloride of formula (I).

30% NaOH

Step – Sodium borohydride

Pure Labetaiol Hydrochloride (I)

SYN

https://patents.google.com/patent/EP0009702A1/en

• The substance labetalol is known from British patent specification 1,266,058 and U.S.P. 4,012,444. Its pharmacological properties are discussed by Farmer et. al. in British Journal of Pharmacology, 45: 660-675 (1972), who designate it AH5158; it is shown to block a- and β-adrenergic receptors, suggesting that it would be useful in the treatment of arrhythmia, hypertension and angina pectoris.
• [0003]
  The unique pharmacological properties of labetalol and its use as an antihypertensive agent are said to be largely a function of the exquisite balance of its a- and a-blocking activities. The file history of U.S.P. 4,012,444 indeed indicates that slight changes in the chemical structure of labetalol deleteriously affect this balance, and, even in the few analogous compounds where the balance is retained, the absolute potencies of these compounds are shown to be too low for them to be useful antihypertensive agents. Therefore, in the treatment of hypertension, labetalol is the compound of choice among those disclosed in British patent specification 1,266,058 and U.S.P. 4,012,444.
• [0004]
  Labetalol has two asymmetrically substituted carbon atoms and therefore can exist as two diastereoisomers and four optical isomers. Indeed, British patent specification 1,266,058 and U.S.P. 4,012,444 disclose that compounds such as labetalol have optically active forms, but give no example of an optically active form. These patent specifications .teach that “the racemic mixtures may be resolved by conventional methods, for example by salt formation with an optically active acid, followed by fractional crystallization”, but give no method of resolution. Example 14 of each specifi_– cation does indeed describe the separation of labetalol into two diastereoisomers “1” and “2”, using benzoic acid, but this is not an optical resolution. In British patent specifications 1,541,932 and 1,541,933, “isomer 1” is designated “diastereoisomer A” and is characterised as that diastereoisomer whose hydrochloride salt has the higher melting point. These two British patent specifications also disclose that diastereoisomer A is a valuable antiarrhythmic agent since it has strongly reduced β-adrenergic blocking activity and is therefore useful in the treatment of people who have suffered myocardial infarction.
• [0005]
  We have now discovered that diastereoisomer A is composed of the (S,R) and (R,S) optical isomers of labetalol, whereas diastereoisomer B is composed of the (S,S) and (R,R) optical isomers. We have also-surprisingly found that the novel (R,R) optical isomer of labetalol exhibits, in comparison with labetalol itself, both an unexpectedly high increase in β-adrenergic blocking potency and a decrease in a-adrenergic blocking potency. Thus, when the (R,R) optical isomer is compared with labetalol, the ratio of the β-adrenergic blocking potency to the a-adrenergic blocking potency is found to be greatly and unexpectedly increased. In particular, animal tests have indicated that the (R,R) optical isomer has about twelve times the β-blocking potency of labetalol, but only about one third of the a-blocking potency of labetalol. These. properties could in no way have been predicted theoretically, especially as the β-blocking potency of diastereoisomer B is not significantly different from that of labetalol and the a-blocking potency of diastereoisomer B is half that of labetalol. Indeed, it is clear, when the activities of the four optical isomers of labetalol are compared, that the activities of the diastereoisomers A and B and indeed of labetalol itself cannot be calculated from the activities of their components. One can put this the other way around by saying that the α-and β-blocking activities of the four optical isomers of labetalol do not merely average to give the a- and β-blocking activites of labetalol and of its diastereoisomers A and B. Some of the activities are much greater than could ever have been expected on a simple basis of mathematical proportions, in particular the high β-blocking activity of the (R,R) optical isomer: this activity is much higher than the β-blocking activity of diastereoisomer B so that antagonism evidently exists between the (S,S) and (R,R) optical isomers with respect to the β-blocking activity. This degree of antagonism could in no way have been foreseen. In the absence of this antagonism, the (R,R) optical isomer shows a balance of properties that make it the optical isomer of choice in the treatment of hypertension. In particular, the (R,R) optical isomer possesses potent antihypertensive activity and rapid onset of activity while substantially lacking the undesirable side-effects usually associated with a-blockade, e.g. postural hypotension.

• The following Table shows the relationships between labetalol, its diastereoisomersA and B and the four pure optical isomers; below each compound are given its potencies as an a-blocking and then as a β-blocking agent, all relative to the values for labetalol (assigned values 1.0 for each blocking activity):

  This table clearly shows the unexpectedly high β-blocking activity and ratio of β-:α-blocking activities possessed by the (R,R)-optical isomer. Additionally, the (R,R)–optical isomer has been found to possess greater direct peripheral vasodilation activity than labetalol, and this also contributes to its anti-hypertensive activity. Moreover, the (R,R)-optical isomer is substantially non-toxic at therapeutic doses.

• [0007]
  According to the invention therefore we provide the (R,R)-optical isomer of labetalol, namely 5- {(R)–1-hydroxy-2-[(R)-(1-methyl-3-phenylpropyl)amino]ethyl} salicylamide, which can be characterised by means of its hydrochloride salt which is dimorphic with m.pts. of about 133-134°C. and about 192-193.5°C. and an [α]_D ²⁶ of about -30.6° (conc. 1 mg./ml., ethanol), said (R,R) optical isomer being substantially free of the corresponding (R,S), (S,R) and (S,S) optical isomers

reaction scheme:

Dilevalol

Synonyms:(R,R)-Labetalol

ATC:C02CB

Labetalol

Clinical data
Pronunciation	/ləˈbɛtəlɔːl/
Trade names	Normodyne, Trandate, others
AHFS/Drugs.com	Monograph
MedlinePlus	a685034
Pregnancy category	C One of few drugs used for PIH
Routes of administration	By mouth, intravenous
ATC code	C07AG01 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	25%
Protein binding	50%
Metabolism	Liver pass metabolism,
Elimination half-life	Tablet: 6-8 hours; IV: 5.5 hours
Excretion	Excreted in urine, not removed by hemodialysis
Identifiers
IUPAC name[show]
CAS Number	36894-69-6
PubChem CID	3869
IUPHAR/BPS	7207
DrugBank	DB00598
ChemSpider	3734
UNII	R5H8897N95
KEGG	D08106
ChEBI	CHEBI:6343
ChEMBL	ChEMBL429
CompTox Dashboard (EPA)	DTXSID2023191
ECHA InfoCard	100.048.401
Chemical and physical data
Formula	C19H24N2O3
Molar mass	328.412 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES[hide] O=C(c1cc(ccc1O)C(O)CNC(C)CCc2ccccc2)N
InChI[hide] 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)  Key:SGUAFYQXFOLMHL-UHFFFAOYSA-N

References

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External links

• Drug information by the NIH