Alpha-adrenoceptor blockade by labetalol during long-term dosing

Area of Science:

• Pharmacology
• Cardiovascular Medicine

Background:

• Labetalol, an alpha- and beta-adrenoceptor blocker, exhibits a greater hypotensive effect in the orthostatic position short-term.
• This effect is attributed to alpha-adrenoceptor blockade, but orthostatic hypotension disappears with prolonged use.

Purpose of the Study:

• To investigate if the loss of orthostatic hypotension during prolonged labetalol use is due to reduced alpha-blocking activity.
• To assess changes in both alpha- and beta-adrenoceptor blockade over time with continuous labetalol treatment.

Main Methods:

• Six subjects with mild essential hypertension received oral labetalol (200 mg three times daily).
• Phenylephrine-induced blood pressure increases were measured before and after 3 days, 6 days, 1 month, and 6 months of treatment.
• Isoproterenol-induced tachycardia was monitored at the same intervals to assess beta-blockade.

Main Results:

• After 3 days, phenylephrine required 1.7 times the dose for a 20% systolic pressure increase, indicating reduced alpha-blockade.
• This reduced alpha-blocking effect progressively declined, returning to baseline by 6 months.
• Beta-blockade, assessed by isoproterenol-induced tachycardia, remained consistently elevated (2-3 times the baseline dose) throughout the 6-month treatment period.

Conclusions:

• Oral labetalol demonstrates a decline in alpha-adrenoceptor blockade during prolonged therapy.
• This reduction in alpha-blocking activity correlates with the disappearance of orthostatic hypotension early in treatment.
• The sustained beta-adrenoceptor blockade suggests that the decrease in antihypertensive efficacy observed with long-term labetalol use may be linked to diminishing alpha-blockade.