Labetalol

Labetalol is an Antihypertensive agent belonging to alpha and beta-adrenergic antagonist.

Labetalol is used in the management of Hypertension (IV indicated for severe Hypertension only [eg, hypertensive emergencies]. It is also used in acute aortic syndromes/Acute aortic dissection; Acute ischemic stroke, BP management with reperfusion therapy; Hypertensive emergency in pregnancy or postpartum (including acute-onset severe Hypertension in preeclampsia/eclampsia); Intracerebral hemorrhage, acute, blood pressure management; Subarachnoid hemorrhage, blood pressure management.

It is absorbed readily from the GI tract. Its bioavailability is increased by food. It crosses the placenta, and enters breast milk. The volume of distribution is 3-16 L/kg and plasma protein binding: was approx 50%. It has extensive first-pass metabolism, primarily via glucuronide conjugation.It excreted Via urine (55-60% as glucuronide conjugates; <5% as unchanged drug). Elimination half-life: Approx 6-8 hr (oral); approx 5.5 hr (IV).

The common side effects are hives, severe stomach pain, difficult breathing, swelling in the face or throat or severe skin reaction (fever, sore throat , burning in eyes, skin pain, red or purple skin rash that spreads and causes blistering and peeling).

Labetalol is available in the form of a dosage forms such as Tablets, Solutions, Injection.

Labetalol is available in the USA, France, Spain, Canada, and India.

Labetalol competitively inhibits the adrenergic stimulation of β-receptors w/in the myocardium, bronchial and vascular smooth muscle, and α1-receptors w/in vascular smooth muscle. It also has some intrinsic β2-agonist and membrane-stabilizing activity.

Labetalol is available in the form of a dosage forms such as Tablets, Solutions, and Injection.

Labetalol comes as a tablet or oral to be taken by mouth. It is usually taken once or twice a day with or without food.

Labetalol Injection:- Dilute 100mg of Labetalol in 30mL of sodium chloride 0.9% and delivery through a syringe driver. Infuse via a dedicated peripheral or central lumen. Do not attach to a two-way infusion, as an inadvertent bolus may be delivered. Commence infusion at 10 mL/hour (20mg/hour).

Labetalol works by relaxing blood vessels and slowing heart rate to improve blood flow and decrease blood pressure. Labetalol leads to sustained vasodilation over the long term without a significant decrease in cardiac output or stroke volume and a minimal decrease in heart rate.

Labetalol is used in the management of Hypertension (IV indicated for severe Hypertension only [e.g., hypertensive emergencies]. It is also used for acute aortic syndromes/Acute aortic dissection; Acute ischemic stroke, BP management with reperfusion therapy; Hypertensive emergency in pregnancy or postpartum (including acute-onset severe Hypertension in preeclampsia/eclampsia); Intracerebral hemorrhage, acute, blood pressure management; Subarachnoid hemorrhage, blood pressure management.

It is indicated in the following conditions:-

• Hypertension: Management of Hypertension
• IV indicated for severe Hypertension only [e.g., hypertensive emergencies]

Although not approved, there have been certain label use documented for Labetalol, which includes:-

• Acute aortic syndromes/Acute aortic dissection;
• Acute ischemic stroke, BP management with reperfusion therapy;
• Hypertensive emergency in pregnancy or postpartum (including acute-onset severe Hypertension in preeclampsia/eclampsia);
• Intracerebral hemorrhage, acute blood pressure management;
• Subarachnoid hemorrhage, blood pressure management

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Labetalol is available in various dosage strengths:

For Injection:

5 mg/mL (4 mL, 20 mL, 40 mL); 100 mg/100 mL (1 mg/mL) with NaCl 0.72% (100 mL); 200 mg/200 mL (1 mg/mL) with NaCl 0.72% (200 mL); 200 mg/200 mL (1 mg/mL) with dextrose 5% (200 mL); 300 mg/300 mL (1 mg/mL) in NaCl 0.72% (300 mL)

For Tablets:

100 mg, 200 mg, 300 mg.

Labetalol is available in the form of dosage forms such as solutions, tablets, and injection

Dose Adjustment in Kidney Patients:

● IV, Oral:

● Altered kidney function:

Mild to severe impairment: No dosage adjustment necessary.

● Hemodialysis, intermittent (thrice weekly):

Poorly dialyzed; No supplemental dose or dosage adjustment necessary.

• Peritoneal dialysis:

Poorly dialyzed; No dosage adjustment necessary.

• CRRT: No dosage adjustment necessary.
• PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment is necessary.

Dose Adjustment in Hepatic Impairment Patient

No dosage adjustment is necessary.

Dose Adjustment in Pediatric Patients.

• Hypertension:

IV (intermittent bolus): Children and Adolescents: 0.2 to 1 mg/kg/dose; maximum dose: 40 mg/dose.

Continuous IV infusion: Infants, Children, and Adolescents: 0.25 to 3 mg/kg/hour; initiate at the lower end of the range and titrate up slowly to effect;

In one retrospective study in infants and children ≤24 months of age, reductions in blood pressure were observed at doses up to 0.59 mg/kg/hour, with little additional benefit at higher doses.

• Chronic Hypertension:

Children and Adolescents:

Oral: Initial: 1 to 3 mg/kg/day in 2 divided doses; maximum daily dose: 10 to 12 mg/kg/day, up to 1,200 mg/day .

Labetalol is used in the management of Hypertension.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

Labetalol may be contraindicated in the following:

Hypersensitivity to labetalol or any component of the formulation; severe bradycardia; heart block greater than first degree (except in patients with a functioning artificial pacemaker); cardiogenic shock; bronchial asthma or a history of obstructive airway disease; uncompensated cardiac failure; conditions associated with severe and prolonged hypotension

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Cardiac Failure

Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure. Beta-blockade carries a potential hazard of further depressing myocardial contractility and precipitating more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, labetalol HCl can be used with caution in patients with a history of heart failure who are well compensated. Congestive heart failure has been observed in patients receiving Labetalol HCl. Labetalol HCl does not abolish the inotropic action of digitalis on the heart muscle.

• In Patients Without a History of Cardiac Failure

In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response should be observed closely. If cardiac failure continues despite adequate digitalization and diuretic, therapy with Labetalol (Labetalol) Tablets should be withdrawn (gradually, if possible).

• Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal

Angina pectoris has not been reported upon labetalol HCl discontinuation. However, hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered Labetalol. Tablets, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored.

If angina markedly worsens or acute coronary insufficiency develops, therapy with Labetalol. Tablets should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with Labetalol. Tablets abruptly in patients being treated for Hypertension.

• Nonallergic Bronchospasm (e.g., Chronic Bronchitis and Emphysema):

Patients with bronchospastic disease should, in general, not receive beta-blockers. Labetalol (Labetalol) Tablets may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Labetalol Tablets are used, to use the smallest effective dose, so that inhibition of endogenous or exogenous beta-agonists is minimized.

• Pheochromocytoma

Labetalol HCl has been shown to be effective in lowering blood pressure and relieving symptoms in patients with pheochromocytoma. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol HCl to patients with pheochromocytoma.

• Diabetes Mellitus and Hypoglycemia

Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs.

Precautions

General

Impaired Hepatic Function

Labetalol Tablets should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (Labetalol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

Because of the low levels of Labetalol in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants. The relative infant dose (RID) of Labetalol and Labetalol at are <0.1% of the weight-adjusted maternal dose when calculated using the highest average breast milk concentration located and compared to a weight-adjusted maternal dose of 20 mg/day.In general, breastfeeding is considered acceptable when the RID of a medication is <10%.

Teratogenic Effects

Pregnancy Category C:

Teratogenic studies were performed with Labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with Labetalol in rabbits at IV doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol HCl for Hypertension during pregnancy. Oral administration of Labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.

Salt Substitutes: Those who are taking Labetalol should avoid sodium, calcium and magnesium-rich foods. The salts may reduce the blood-pressure lowering effect of Labetalol.

The adverse reactions related to molecule Labetalol can be categorized as

● Common Adverse effect: 

Cough ,headache, dizziness, drowsiness

● Less Common adverse effects:

Swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower, hoarseness, difficulty breathing or swallowing, light headedness, fainting, rash, yellowing of the skin or eyes, fever, sore throat, chills, and other signs of infection.

The clinically relevant drug interactions of Labetalol is briefly summarized here.

• Synergistic hypotensive effect w/ halothane.
• Increased absolute bioavailability w/ cimetidine.
• Decreased absolute bioavailability w/ glutethimide.
• Additive hypotensive effect w/ nitroglycerin.
• Increased incidence of tremor w/ TCAs.
• Increased risk of bradycardia and heart block w/ Ca channel blocker (e.g., verapamil, diltiazem).

Symptoms: Hypotension which may be associated with electrolyte disturbances and renal failure.

Management: Supportive treatment. If ingestion is recent, consider administration of activated charcoal; gastric decontamination (e.g., vomiting, gastric lavage) may be considered in the early period after ingestion. Monitor blood pressure and clinical symptoms. Ensure adequate hydration. Infuse 0.9% NaCl to treat marked hypotension and consider vasopressors (e.g., catecholamines) if necessary. Consider dialysis in patients with severe renal impairment.

Pharmacodynamics:

Labetalol competitively inhibits the adrenergic stimulation of β-receptors w/in the myocardium, bronchial and vascular smooth muscle, and α1-receptors w/in vascular smooth muscle. It also has some intrinsic β2-agonist and membrane-stabilizing activity.

Labetalol is an adrenergic receptor blocking agent that has both nonselective beta-adrenergic and Selective alpha1 adrenergic receptor blocking actions. As a nonselective beta blocking agent it slows sinoatrial (SA) discharge, AV conduction and lessens ventricular inotropy (force of muscle contraction). It also causes alpha blockade effects which result in vasodilatation and a diminishment in Peripheral resistance.

Pharmacokinetics:

• Absorption: Absorbed readily from the GI tract. Bioavailability increased by food. Time to peak plasma concentration: Approx 1-2 hr (oral); 5-15 min (IV).
• Distribution: Crosses the placenta, enters breast milk. Volume of distribution: 3-16 L/kg. Plasma protein binding: Approx 50%.
• Metabolism: Extensive first-pass metabolism primarily via glucuronide conjugation.
• Excretion: Via urine (55-60% as glucuronide conjugates; <5% as unchanged drug). Elimination half-life: Approx 6-8 hr (oral); approx 5.5 hr (IV).

1. https://go.drugbank.com/drugs/DB01118

2. https://pubmed.ncbi.nlm.nih.gov/11179527/

3. https://pubmed.ncbi.nlm.nih.gov/10666663/

4. https://pubmed.ncbi.nlm.nih.gov/1279278/

5. https://www.uptodate.com/contents/Labetalol -drug-

6. https://www.drugs.com/mtm/Labetalol .html