Labetalol Hydrochloride

LABETALOL HYDROCHLORIDE — labetalol hydrochloride tablet, film coated
Physicians Total Care, Inc.

Labetalol HCl USP is an adrenergic receptor blocking agent that has both selective alpha 1 -and non-selective beta-adrenergic receptor blocking actions in a single substance.

Labetalol HCl USP is a racemate, chemically designated as 5-[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl] salicylamide monohydrochloride, and has the following structural formula:

image of chemical structure
(click image for full-size original)

C 19 H24 N2 O3 •HCl M.W. 364.87

Labetalol HCl USP has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R,R’ stereoisomer, makes up 25% of racemic labetalol.

Labetalol HCl USP is a white or off-white crystalline powder, soluble in water.

Each tablet, for oral administration, contains 100 mg, 200 mg, or 300 mg of labetalol hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and colorants (100 mg: D&C yellow #10 aluminum lake and FD&C yellow #6 aluminum lake; and 300 mg: D&C yellow #10 aluminum lake, FD&C yellow #6 aluminum lake and FD&C blue #1 aluminum lake).

CLINICAL PHARMACOLOGY

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 administration, respectively. Beta2 — agonist activity has been demonstrated in animals with minimal beta1 -agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, a membrane-stabilizing effect has been demonstrated.

Pharmacodynamics

The capacity of labetalol to block alpha receptors in man has been demonstrated by attenuation of the pressor effect of phenylephrine and by a significant reduction of the pressor response caused by immersing the hand in ice-cold water (“cold-pressor test”). Labetalol’s beta 1 -receptor blockade in man was demonstrated by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. Beta2 -receptor blockade was demonstrated by inhibition of the isoproterenol-induced fall in diastolic blood pressure. Both the alpha- and beta-blocking actions of orally administered labetalol HCl contribute to a decrease in blood pressure in hypertensive patients. Labetalol consistently, in dose-related fashion, blunted increases in exercise-induced blood pressure and heart rate, and in their double product. The pulmonary circulation during exercise was not affected by labetalol HCl dosing.

Single oral doses of labetalol HCl administered in patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The AV conduction time was modestly prolonged in 2 of 7 patients. In another study, intravenous labetalol slightly prolonged AV nodal conduction time and atrial effective refractory period with only small changes in heart rate. The effects on AV nodal refractoriness were inconsistent.

Labetalol produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha-blocking and beta-blocking effects. Hemodynamic effects are variable with small nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced.

Doses of labetalol HCl that controlled hypertension did not affect renal function in mild to severe hypertensive patients with normal renal function.

Due to the alpha 1 -receptor blocking activity of labetalol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (2%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed (see DOSAGE AND ADMINISTRATION). Symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose.

The peak effects of single oral doses of labetalol HCl occur within 2 to 4 hours. The duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. The maximum, steady-state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours.

The antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise-induced tachycardia occurring at 2 hours after oral administration of labetalol HCl and the logarithm of the plasma concentration.

About 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg, with suggestion that about 40% remains at 8 hours.

The anti-anginal efficacy of labetalol has not been studied. In 37 patients with hypertension and coronary artery disease, labetalol did not increase the incidence or severity of angina attacks.

Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.

Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta 2 -adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.

Pharmacokinetics and Metabolism

Labetalol is completely absorbed from the gastrointestinal tract with peak plasma levels occurring 1 to 2 hours after oral administration. The relative bioavailability of labetalol tablets compared to an oral solution is 100%. The absolute bioavailability (fraction of drug reaching systemic circulation) of labetalol when compared to an intravenous infusion is 25%; this is due to extensive “first-pass” metabolism. Despite “first-pass” metabolism there is a linear relationship between oral doses of 100 to 3000 mg and peak plasma levels. The absolute bioavailability of labetalol is increased when administered with food.

The plasma half-life of labetalol following oral administration is about 6 to 8 hours. Steady-state plasma levels of labetalol during repetitive dosing are reached by about the third day of dosing. In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased “first-pass” metabolism.

The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. These metabolites are present in plasma and are excreted in the urine, and via the bile, into the feces. Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing.

Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol from the general circulation (less than 1%).

Labetalol Hydrochloride Indications and Usage

Labetalol HCl tablets are indicated in the management of hypertension. Labetalol HCl tablets may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics.

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