LABETALOL HYDROCHLORIDE SOLUTION FOR INJECTION

Indications

• Hypertension
• Hypertensive emergencies
• Pregnancy-induced hypertension
• Chronic hypertension

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing information.

Adults: Refer to the BNF for specific adult dosing information.

Mechanism of action

Labetalol non-selectively antagonizes beta-adrenergic receptors and selectively antagonizes alpha-1-adrenergic receptors. This results in vasodilation and decreased vascular resistance, leading to a reduction in blood pressure. The beta-1 antagonism causes a slight decrease in heart rate, while the beta-2 antagonism can lead to side effects like bronchospasms. The drug has a greater beta-blocking ability compared to its alpha-blocking ability, especially after intravenous administration.

Pharmacodynamics

Labetalol effectively lowers blood pressure through its action on adrenergic receptors, with a long duration of action allowing for twice-daily dosing. Its therapeutic window is wide, and it generally does not significantly reduce cardiac output or stroke volume. Patients prone to bronchospasms should use labetalol cautiously, as it may exacerbate respiratory issues.

Pharmacokinetics

Labetalol exhibits good oral bioavailability and is extensively metabolized by the liver. It has a relatively long half-life, allowing for sustained antihypertensive effects. The pharmacokinetic profile supports its dosing regimen of 200-400 mg twice daily for most patients.

Contra-indications

• Asthma or other bronchospastic conditions
• Severe bradycardia
• Heart block greater than first degree
• Cardiogenic shock
• Decompensated heart failure

Adverse effects

• Hypotension
• Dizziness
• Fatigue
• Nausea
• Bronchospasm
• Heart block
• Elevated liver enzymes

Interactions

• Propafenone+labetalol: Unknown (increases risk of cardiovascular adverse effects)

Precautions

• Use with caution in patients with a history of asthma or bronchospastic disease
• Monitor heart rate and blood pressure regularly
• Caution in patients with hepatic impairment

Pregnancy

Labetalol is generally considered safe to use during pregnancy, but should be used under the guidance of a healthcare provider.

Breast-feeding

Labetalol is excreted in breast milk. Use with caution and monitor the infant for adverse effects.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets (e.g., 100 mg, 200 mg, 400 mg)
• Injectable solution

Indications

• Hypertension
• Hypertensive emergencies
• Controlled hypotension in anaesthesia
• Hypertension of pregnancy
• Hypertension following myocardial infarction

Dosage

Children: Refer to the BNF for Children for appropriate dosing in paediatric patients.

Adults: Initially, for intravenous infusion, 2 mg/minute until a satisfactory response is achieved, then discontinue. Usual dose 50–200 mg; for intravenous injection, 50 mg over at least 1 minute, then 50 mg every 5 minutes if required, maximum 200 mg per course.

Mechanism of action

Labetalol acts by competitively inhibiting beta-adrenergic receptors (primarily beta-1 and beta-2) and alpha-1 adrenergic receptors. This dual action leads to vasodilation and a decrease in heart rate, resulting in lowered blood pressure. The blocking of beta receptors helps reduce cardiac output and oxygen demand, while the alpha-1 blockade aids in vasodilation.

Pharmacodynamics

The pharmacodynamic effects of labetalol include a reduction in systemic vascular resistance, leading to decreased blood pressure without a significant reflex tachycardia. This is due to its balanced activity on both alpha and beta receptors, allowing for effective control of blood pressure while preserving some degree of cardiac output.

Pharmacokinetics

Labetalol is well-absorbed after oral administration, with a bioavailability of approximately 25% due to first-pass metabolism. Peak plasma concentrations are typically reached within 1-2 hours. It is extensively metabolized in the liver, and its elimination half-life ranges from 5 to 8 hours. The drug is primarily excreted in urine, with renal function affecting its clearance.

Contra-indications

• Severe hepatic impairment
• Severe heart disease
• Ischaemic heart disease
• Diffuse vascular disease

Adverse effects

• Hypotension
• Bradycardia
• Nausea
• Dizziness
• Fatigue
• Visual impairment
• Heart failure
• Tremor
• Alopecia
• Raynaud's phenomenon
• Drug fever
• Ejaculation failure
• Urinary disorders
• Hypersensitivity reactions
• Liver damage
• Systemic lupus erythematosus
• Toxic myopathy
• Cyanosis
• Hyperhidrosis

Interactions

• Non-selective beta-blockers
• Other antihypertensives may enhance hypotensive effect
• Caution with drugs that may affect hepatic function

Precautions

• Monitor renal function during dose titration in patients with heart failure
• Caution in patients with diabetes as it may mask hypoglycemia
• Monitor for signs of liver dysfunction
• Use caution in patients with respiratory conditions such as asthma

Pregnancy

Labetalol is generally considered safe in pregnancy, except possibly during the first trimester. If used close to delivery, infants should be monitored for signs of alpha- and beta-blockade.

Breast-feeding

Labetalol is excreted in breast milk. Infants should be monitored for possible toxicity due to alpha- and beta-blockade.

Storage

Store at room temperature, away from moisture and light.

Formulations

• Oral tablet
• Intravenous injection
• Intravenous infusion

Mechanism of action

Labetalol non-selectively antagonizes beta-adrenergic receptors, and selectively antagonizes alpha-1-adrenergic receptors. Following oral administration, labetalol has 3 times the beta-blocking ability than alpha-blocking ability. This increases to 6.9 times following intravenous administration. Antagonism of alpha-1-adrenergic receptors leads to vasodilation and decreased vascular resistance. This leads to a decrease in blood pressure that is most pronounced while standing. Antagonism of beta-1-adrenergic receptors leads to a slight decrease in heart rate. Antagonism of beta-2-adrenergic receptors leads to some of the side effects of labetalol such as bronchospasms, however this may be slightly attenuated by alpha-1-adrenergic antagonism. 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. A specific competitive antagonist at both alpha- and beta-adrenergic receptor sites. Class II antiarrhythmic, beta-adrenoceptor-blocking agents are membrane depressant drugs that decrease the influx of sodium and calcium ions by reducing membrane bound adenylate cyclase and cAMP. The reduction in cation transport lengthens depolarization by decreasing the amplitude and slope of the transmembrane potential. Beta-adrenoceptor-blocking agents also reduce myocardial contractility by decreasing calcium release from the sarcoplasmic reticulum (the influx of calcium couples excitation and contraction by initiating the release of calcium from the sarcoplasmic reticulum). Membrane-stabilizing activity enhances the reduction in myocardial contractility in overdose with these drugs in addition to producing a quinidinelike effect of ORS widening. A direct myocardial effect also leads to myocardial depression independent of beta-adrenergic blockade and membrane stabilization. ... beta-Blockers are classified as cardioselective based on their ability to antagonize the cardiac (beta1) but not the peripheral (beta2) receptors. However, cardioselectivity is incomplete and dose dependent and disappears at high doses. /Class II beta-Blockers/ The principal physiologic action of labetalol is to competitively block adrenergic stimulation of beta-receptors within the myocardium (beta1-receptors) and within bronchial and vascular smooth muscle (beta2-receptors) and alpha1-receptors within vascular smooth muscle. In addition to inhibiting access of endogenous or exogenous catecholamines to beta-adrenergic receptors, labetalol has been shown to exhibit some intrinsic beta2-agonist activity in animals; however, the drug exerts little, if any, intrinsic beta1-agonist activity. Labetalol does not exhibit intrinsic alpha-adrenergic agonist activity. There is some evidence from animal studies suggesting that the drug may have a vasodilating effect, possibly resulting from a direct or beta2-agonist action. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, labetalol also has a membrane stabilizing effect on the heart which is similar to that of quinidine; however, this effect is unlikely to be clinically important since it occurs only at doses higher than those required for alpha- or beta-adrenergic blockade. The hemodynamic effects of labetalol are variable following oral or iv administration. Labetalol, unlike pure beta-adrenergic blocking agents, produces a dose dependent (at usual doses) decrease in systemic arterial blood pressure and systemic vascular resistance without a substantial reduction in resting heart rate, cardiac output, or stroke volume, apparently because of its combined alpha- and beta-adrenergic blocking activity. Labetalol effectively reduces blood pressure in the standing or supine position, but because of the drug's alpha1-adrenergic blocking activity, the effect on blood pressure is position dependent; labetalol induced decreases in blood pressure are greater in the standing than in the supine pos

Pharmacodynamics

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.