Labetalol

Absorption

100mg and 200mg oral doses of labetalol have a Tmax of 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86% and may increase in older patients or when taken with food.

Toxicity

The oral LD50 in mice is 600mg/kg and in rats is >2g/kg. The intravenous LD50 in mice and rats is 50-60mg/kg.
Patients experiencing an overdose may present with excessive hypotension and bradycardia. Patients should be placed on their back with their legs raised to maintain perfusion of the brain. Oral overdoses may be treated with gastric lavage or emesis, bradycardia may be treated with atropine or epinephrine, cardiac failure may be treated with digitalis and a diuretic, hypotension may be treated with vasopressors, bronchospasms may be treated with epinephrine or a beta2 agonist, and seizures may be treated with diazepam.

Description

Labetalol is an α-adrenergic and α-1 blocking agent which caused contact dermatitis and a contact anaphylactoid reaction during patch testing in a nurse.

Originator

Trandate,Allen and Hanburys,UK,1977

The Uses of Labetalol

Labetalol is used to treat essential hypertension.

The Uses of Labetalol

Anti-adrenergic (α-receptor); anti-adrenergic (β-receptor).

Indications

Labetalol injections are indicated to control blood pressure in severe hypertension. Labetalol tablets are indicated alone or in combination with antihypertensives like thiazides and loop diuretics to manage hypertension.

Background

Labetalol is a racemic mixture of 2 diastereoisomers where dilevalol, the R,R' stereoisomer, makes up 25% of the mixture. Labetalol is formulated as an injection or tablets to treat hypertension.
Labetalol was granted FDA approval on 1 August 1984.

Definition

ChEBI: A secondary amino compound formally derived from ammonia by replacing two of the hydrogens by 2-(3-carbamoyl-4-hydroxyphenyl)-2-hydroxyethyl and 4-phenylbutan-2-yl groups. It is an adrenergic antagonist used to treat high blood pressure.

Manufacturing Process

(a) 5-Bromoacetylsalicylamide (2.6 g), N-benzyl-N-(1-methyl-3-phenylpropyl) amine (4.8 g) and methyl ethyl ketone (50 ml) were heated at reflux for 40 minutes. The solvent was removed and the residue was treated with benzene. The secondary amine hydrobromide was filtered off and discarded, and the filtrate was evaporated to dryness. The residue was treated with an excess of ethanolic hydrogen chloride when 5-[N-benzyl-N-(1-methyl-3-phenylpropyl)- glycyl]-salicylamide hydrochloride (1.15 g) crystallized out, MP 139°C to 141°C.
(b) 5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]-salicylamide hydrochloride (0.75 g), 10% mixture of PdO and PtO on carbon catalyst (0.1 g) and ethanol (20 ml) were shaken at room temperature and pressure with hydrogen until uptake ceased. The catalyst was filtered off and the filtrate evaporated to dryness. The residue was crystallized from ethanol to give 5-[1- hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamide hydrochloride as a white solid (0.40 g), MP 188°C.

brand name

Normodyne (Schering); Trandate (Promethus).

Therapeutic Function

Alpha-adrenergic blocker, Beta-adrenergic blocker

Biological Functions

Labetalol (Normodyne, Trandate) possesses both - blocking and β-blocking activity and is approximately one-third as potent as propranolol as a -blocker and one-tenth as potent as phentolamine as an -blocker. The ratio of β- to α-activity is about 3:1 when labetalol is administered orally and about 7: 1 when it is administered intravenously. Thus the drug can be most conveniently thought of as a β -blocker with some -blocking properties.

General Description

Labetalol is a phenylethanolamine derivative, is representative of a classof drugs that act as competitive blockers at α1-, β1-, andβ2-receptors. It is a more potent β-blocker than α-blocker.Because it has two asymmetric carbon atoms (1 and 1' ), it existsas a mixture of four isomers. It is this mixture that is usedclinically in treating hypertension. The different isomers,however, possess different α- and β-blocking activities. The -blocking activity resides solely in the (1R,1 'R) isomer,whereas the 1-blocking activity is seen in the (1S,1 R) and(1S,1'S) isomers, with the (1S,1'R) isomer possessing thegreater therapeutic activity.

Contact allergens

This beta-adrenergic and alpha-1 blocking agent caused contact dermatitis and a contact anaphylactoid reaction during patch testing in a nurse.

Mechanism of action

Labetalol produces equilibrium-competitive antagonism at β-receptors but does not exhibit selectivity for β1- or β2-receptors. Like certain other β-blockers (e.g., pindolol and timolol), labetalol possesses some degree of intrinsic activity. This intrinsic activity, or partial agonism, especially at β2-receptors in the vasculature, has been suggested to contribute to the vasodilator effect of the drug. The membrane-stabilizing effect, or local anesthetic action, of propranolol and several other β-blockers, is also possessed by labetalol, and in fact the drug is a reasonably potent local anesthetic.
Labetalol appears to produce relaxation of vascular smooth muscle not only by α-blockade but also by a partial agonist effect at β2-receptors. In addition, labetalol may produce vascular relaxation by a direct non–receptor-mediated effect. Labetalol can block the neuronal uptake of norepinephrine and other catecholamines. This action, plus its slight intrinsic activity at α-receptors, may account for the seemingly paradoxical, although infrequent, increase in blood pressure seen on its initial administration.

Pharmacokinetics

Labetalol antagonizes various adrenergic receptors to decrease blood pressure. The duration of action is long as it is generally given twice daily, and the therapeutic window is wide as patients usually take 200-400mg twice daily. Patients susceptible to bronchospasms should not use labetalol unless they are unresponsive to or intolerant of other antihypertensives.

Pharmacokinetics

Labetalol is almost completely absorbed from the gastrointestinal tract. However, it is subject to considerable first-pass metabolism, which occurs in both the gastrointestinal tract and the liver, so that only about 25% of an administered dose reaches the systemic circulation. While traces of unchanged labetalol are recovered in the urine, most of the drug is metabolized to inactive glucuronide conjugates.The plasma half-life of labetalol is 6 to 8 hours, and the elimination kinetics are essentially unchanged in patients with impaired renal failure.

Clinical Use

Labetalol is a clinically usefulantihypertensive agent. The rationale for its use in themanagement of hypertension is that its α-receptor–blockingeffects produce vasodilation and its β-receptor–blockingeffects prevent the reflex tachycardia usually associated withvasodilation. Although labetalol is very well absorbed, it undergoesextensive first-pass metabolism.

Side Effects

There have been reports of excessive hypotension and paradoxical pressor effects following intravenous administration of labetalol. These latter effects may be due to a labetalol-induced blockade of neuronal amine uptake, which increases the concentrations of norepinephrine in the vicinity of its receptors.
Approximately 5% of the patients who receive labetalol complain of side effects typical of noradrenergic nervous system suppression. These include postural hypotension, gastrointestinal distress, tiredness, sexual dysfunction, and tingling of the scalp. Most of these effects are related to α-blockade, although the tingling of the scalp may be due to the drug’s intrinsic activity at α-receptors. Side effects associated with β-blockade, such as induction of bronchospasm and congestive heart failure, may also occur, but generally at a lower frequency than -receptor–associated effects.
Skin rashes have been reported, as has an increase in the titer of antinuclear antibodies. Despite the latter observation, the appearance of a systemic lupus syndrome is rare. Labetalol also has been reported to interfere with chemical measurements of catecholamines and metabolites.

Synthesis

Labetalol, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropanol)amino)] ethyl] benzamide (12.1.12) is synthesized by the N-alkylation of N-benzyl-N(4-phenyl-2- butyl)amine 5-bromacetylsalicylamide and forming aminoketone (12.1.11), which is further debenzylated by hydrogen using a palladium¨Cplatinum on carbon catalyst into labetalol (12.1.12) [28¨C30].

Metabolism

The metabolism of labetalol has not been fully described in the literature but studies in sheep show an N-dealkylation to 3-amino-1-phenyl butane. This metabolite may be further metabolized to benzylacetone and 3-amino-(4-hydroxyphenyl)butane. Labetalol in humans is mainly metabolized to glucuronide metabolites such as the O-phenyl-glucuronide and the N-glucuronide.