Description

AB-LOL is Labetalol HCl Tablet which is an adrenergic receptor blocking agent having both selective alpha1-adrenergic and nonselective beta-adrenergic receptor blocking actions in a single substance.

Pharmacology

Labetalol HCl combines both selective, competitive, alpha1-adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity in a single substance

Pharmacodynamics

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 HCl 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 to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration.

Labetalol HCl produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha- and beta-blocking effects. Hemodynamic effects are variable, with small, no significant 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 mildly to severely hypertensive patients with normal renal function. Due to the alpha1-receptor blocking activity of Labetalol HCl, 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.

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 HCl 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.

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 A-V block by preventing the necessary facilitating effects of sympathetic activity on conduction.

Pharmacokinetics and Metabolism

Labetalol HCl is completely absorbed from the gastrointestinal tract with peak plasma levels occurring 1 to 2 hours after oral administration. The relative bioavailability of Labetalol HCl tablets compared to an oral solution is 100%. The absolute bioavailability (fraction of drug reaching systemic circulation) of Labetalol when compared to an IV 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 3,000 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

Indications

  • Pregnancy-Induced Hypertension Which Is Commonly Associated With Pre-Eclampsia.
  • Chronic Hypertension of Pheochromocytoma
  • Hypertensive Emergency

Gestational hypertension or pregnancy-induced hypertension is defined as the development of new arterial hypertension in a pregnant woman after 20 weeks gestation Pre-eclampsia and eclampsia are sometimes treated as components of a common syndrome. Hypertension can arise before week 20 if the woman has multiple fetuses or a hydatidiform mole.

Pre-eclampsia is a medical condition where hypertension arises in pregnancy (pregnancy-induced hypertension) in association with significant amounts of protein in the urine. Because pre-eclampsia refers to a set of symptoms rather than any causative factor, it is established that there are many different causes for the syndrome. It also appears likely that there is a substance or substances from the placenta that may cause endothelial dysfunction in the maternal blood vessels of susceptible women. While blood pressure elevation is the most visible sign of the disease, it involves generalized damage to the maternal endothelium and kidneys and liver, with the release of vasopressive factors only secondary to the original damage.

Pre-eclampsia may develop from 20 weeks gestation (it is considered early onset before 32 weeks, which is associated with increased morbidity) and its progress differs among patients; most cases are diagnosed pre-term. Apart from Caesarean section, or induction of labor, and therefore delivery of the placenta, there is no known cure. It may also occur up to six weeks post-partum. It is the most common of the dangerous pregnancy complications; it may affect both the mother and the fetus.

Phaeochromocytoma (PCC) is a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines.

Usually adrenaline and noradrenaline. Extra-adrenal paragangliomas (often described as extra-adrenal pheochromocytomas) are closely related, though less common, tumors that originate in the ganglia of the sympathetic nervous system and are named based upon the primary anatomical site of origin.

Either surgical option requires prior treatment with the non-specific and irreversible alpha adrenoceptor blocker Phenoxybenzamine. Minimizing the likelihood of severe intraoperative hypertension (as might occur when the tumor is manipulated). Some authorities would recommend that a combined alpha/beta blocker such as Labetalol also be given in order to slow the heart rate. Regardless, a "pure" beta blocker such as atenolol must never be used in the presence of a pheochromocytoma due to the risk of such treatment leading to unopposed alpha agonism and, thus, severe and potentially refractory hypertension.

Hypertensive emergency is severe hypertension (high blood pressure) with acute impairment of an organ system (especially the central nervous system, cardiovascular system and/or the renal system) and the possibility of irreversible organ-damage. In case of a hypertensive emergency, the blood pressure should be lowered aggressively over minutes to hours with an antihypertensive agent.

Several classes of antihypertensive agents are recommended and the choice for the antihypertensive agent depends on the cause for the hypertensive crisis, the severity of elevated blood pressure and the patient's usual blood pressure before the hypertensive crisis. In most cases, the administration of an intravenous sodium nitroprusside injection which has an almost immediate antihypertensive effect is suitable but in many cases not readily available. In less urgent cases, oral agents like captopril, clonidine, Labetalol, prazosin, which all have a delayed onset of action by several minutes compared to sodium nitroprusside, can also be used.

It is also important that the blood pressure is lowered not too abruptly, but smoothly. The initial goal in hypertensive emergencies is to reduce the pressure by no more than 25% (within minutes to 1 or 2 hours) and then toward a level of 160/100 mm Hg within 26 hours. Excessive reductions in pressure may precipitate coronary, cerebral, or renal ischemia. The diagnosis of a hypertensive emergency is not only based on the absolute level of blood pressure, but also on the individual regular level of blood pressure before the hypertensive crisis. Individuals with a history of chronic hypertension may not tolerate a "normal" blood pressure.

Dosage and Administration

DOSAGE MUST BE INDIVIDUALIZED. The recommended initial dosage is 100 mg twice daily whether used alone or added to a diuretic regimen. After 2 or 3 days, using standing blood pressure as an indicator, dosage may be titrated in increments of 100 mg bid every 2 or 3 days. The usual maintenance dosage of Labetalol HCl is between 200 and 400 mg twice daily.

Since the full antihypertensive effect of Labetalol HCl is usually seen within the first 1 to 3 hours of the initial dose or dose increment, the assurance of a lack of an exaggerated hypotensive response can be clinically established in the office setting. The antihypertensive effects of continued dosing can be measured at subsequent visits, approximately 12 hours after a dose, to determine whether further titration is necessary. Patients with severe hypertension may require from 1,200 to 2,400 mg per day, with or without thiazide diuretics. Should side effects (principally nausea or dizziness) occur with these doses administered twice daily, the same total daily dose administered three times daily may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg twice daily.

Overdosage

Overdosage with Labetalol causes excessive hypotension that is posture sensitive and, sometimes, excessive bradycardia. Patients should be placed supine and their legs raised if necessary to improve the blood supply to the brain. If overdosage with Labetalol follows oral ingestion, gastric lavage or pharmacologically induced emesis (using syrup of ipecac) may be useful for removal of the drug shortly after ingestion. The following additional measures should be employed if necessary: Excessive bradycardia-administer atropine or epinephrine. Cardiac failure-administer a digitalis glycoside and a diuretic. Dopamine or dobutamine may also be useful. Hypotension-administer vasopressors, e.g., norepinephrine. There is pharmacologic evidence that norepinephrine may be the drug of choice. Bronchospasm-administer epinephrine and/or an aerosolized beta2-agonist. Seizures-administer diazepam.

In severe beta-blocker overdose resulting in hypotension and/or bradycardia, glucagon has been shown to be effective when administered in large doses (5 to 10 mg rapidly over 30 seconds, followed by continuous infusion of 5 mg per hour that can be reduced as the patient improves). Neither hemodialysis nor peritoneal dialysis removes a significant amount of Labetalol from the general circulation (<1%). The oral LD50 value of Labetalol HCl in the mouse is approximately 600 mg/kg and in the rat is >2 g/kg. The IV LD50 in these species is 50 to 60 mg/kg.

Side effects

  • Drowsiness
  • Fatigue
  • Weakness
  • Difficulty sleeping
  • Diminished sexual function
  • Scalp tingling which passes after time.
  • A rare but potentially lethal side effect is respiratory distress.

Contraindications

Labetalol has relative contraindications for use in patients with asthma, congestive heart failure, any degree of heart block, bradycardia, or those in cardiogenic shock.

Presentation

AB-LOL is available as Labetalol HCl 50 mg tablets supplied in aluminum foil blister strips of 10 tablets and 10 such strips in a box.