Mechanism of antihypertensive action of dilevalol compared with that of “cardioselective” beta-blocking agents

Strom, Joel A.; Vidt, Donald G.; Bugni, William J.; Atkins, James M.; Fouad‐Tarazi, Fetnat M.; Cubbon, Judith; Poland, Marcia

doi:10.1016/0002-9149(89)90125-2

Cited by 17 publications

(7 citation statements)

References 40 publications

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“…However, the decrease in TPR was of moderate intensity, since it was counteracted by the marked simultaneous increase in NE levels, due to presynaptic/32-adrenoceptor stimulation [25,26]. The results with dilevalol are consistent with those previously obtained after acute oral or intravenous administration both in healthy volunteers [5,27] and in hypertensive patients [6,7,28].…”

Section: Discussionsupporting

confidence: 78%

Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise

Annane

Thuillez

1994

Eur J Clin Pharmacol

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The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers. At rest, as compared to placebo, neither dilevalol nor propranolol significantly affected arterial pressure and heart rate but, whereas propranolol decreased cardiac output (-27% at 2 h) and tended to increase total peripheral resistance, dilevalol tended to increase cardiac output and decreased total peripheral resistance (-7% at 2 h). Neither dilevalol nor propranolol affected brachial artery diameter. Propranolol tended to decrease brachial artery flow (-20% at 2 h) and to increase brachial vascular resistance (+25% at 2 h), but dilevalol did not and the brachial irrigation ratios did not change. Neither of the drugs affected carotid haemodynamics or plasma atrial natriuretic factor. Both drugs tended to decrease plasma renin activity, and dilevalol (+82% at 2 h) increased norepinephrine more than propranolol (+19% at 2 h). After exercise, dilevalol and propranolol produced similar falls in the induced increases in arterial pressure, heart rate and cardiac output, and had the same effects on regional haemodynamics, plasma renin activity and atrial natriuretic factor. Finally, dilevalol greatly increased plasma norepinephrine. We conclude that the beta 2-adrenoceptor agonist activity of dilevalol was clearly expressed at rest, thus inducing vasodilation and counteracting the beta-adrenoceptor blockade-induced negative chronotropic and inotropic effects. However, during sub-maximal exercise, only the beta-adrenoceptor antagonist activity of dilevalol was apparent.

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Section: Discussionsupporting

confidence: 78%

Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise

Annane

Thuillez

1994

Eur J Clin Pharmacol

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“…Peripheral haemodynamics Dilevalol lowers blood pressure to a similar degree to metoprolol and propranolol (Materson et al, 1989;Schoenberger et al, 1989). This is achieved by an average 20% fall in systemic vascular resistance which correlates well with the hypotensive effect (Strom et al, 1989). There is no change in vascular resistance during exercise compared with pre-treatment values (Vidt, 1988), which contrasts with the rise after atenolol.…”

Section: Peripheral Haemodynamics Epanolol Behavesmentioning

confidence: 95%

“…Cardiac haemodynamics After both acute and chronic administration to hypertensive subjects, dilevalol reduced heart rate to a lesser extent than atenolol or metoprolol (Strom et al, 1989). However, the blunted rise in heart rate in response to exercise is reminiscent of a typical 1adrenoceptor blocker (Tsukiyama et al, 1987).…”

Section: Peripheral Haemodynamics Epanolol Behavesmentioning

confidence: 99%

Beta‐adrenoceptor partial agonists: a renaissance in cardiovascular therapy?

Waller

1990

Brit J Clinical Pharma

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“…In contrast, the blood pressure-lowering effect of dilevalol is due principally to the fall in peripheral vascular resistance (Strom et al 1989). Heart rate and cardiac output at rest are usually unchanged with dilevalol, and this is likely to be due to a reflex positive chronotropic effect in response to the fall in vascular resistance.…”

Section: Dilevalolmentioning

confidence: 98%

“…For example, in healthy volunteers, the former is twice as effective at the same dose in attenuating isoprenaline (isoproterenol)-induced increases in heart rate (EI-Ackad et al 1984). The haemodynamic profile of dilevalol is characterised by reductions in peripheral vascular resistance (Maclennan et al 1989) and blood pressure (Fogari et al 1988;Strom et al 1989) with little or no overall effect on heart rate Fujimura et al 1989a). The antihypertensive effect is sustained for 24h (Dahlof et al 1989;Kinhal et al 1989;Silagy et al 1990) and appears to be comparable with that of established treatments (Fogari et al 1988;McGrath et al 1990;Materson et al 1988;Rodriguez-Saavedra et al 1989).…”

Section: Dilevalolmentioning

confidence: 99%

Clinical Pharmacokinetics and Kinetic-Dynamic Relationships of Dilevalol and Labetalol

Donnelly

Macphee

1991

Clinical Pharmacokinetics

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Dilevalol and labetalol are examples of a growing number of new beta-blockers which combine nonselective beta-adrenoceptor antagonism with vasodilator activity. Dilevalol is one of the 4 stereoisomers of labetalol, and is estimated to form approximately 25% of the racemic drug. Labetalol itself is an alpha 1-antagonist but dilevalol, which has negligible affinity for alpha-receptors, exerts its vasodilator effect via beta 2-agonism. Both drugs are rapidly and completely absorbed in 60 to 90 min and subject to extensive first-pass hepatic metabolism; the average bioavailability after oral administration is around 20 to 35%, and there is wide interindividual variability in plasma drug concentrations and dosage requirements. The volume of distribution of dilevalol (17 to 25 L/kg) is higher than that reported for labetalol (3 to 16 L/kg), although both drugs are concentrated in the extravascular compartment. Correspondingly, the elimination half-life of dilevalol at steady-state is around 15h compared with 8h for labetalol. There is evidence that the pharmacokinetics of dilevalol change (a reduction in clearance) in translation from single-dose to long term therapy. There is no clinically significant effect of age on the steady-state disposition of either drug and the pharmacokinetics of labetalol appear to be unchanged during pregnancy. Although there is a linear relationship between dose and area under the concentration-time curve, early studies found no evidence of a simple relationship between dose or plasma drug concentration and the fall in blood pressure. However, an integrated pharmacokinetic-pharmacodynamic model has been used to correlate concentrations of both drugs with reductions in systolic and diastolic blood pressure in individuals. This approach derives a mathematical description of antihypertensive response which integrates pharmacokinetic and pharmacodynamic information and also takes account of placebo effects and changes in drug concentration and blood pressure during the dosage interval. The pharmacokinetic-pharmacodynamic relationships of labetalol are characterised by a linear model. For example, in a group of healthy volunteers, the 'responsiveness' to labetalol was -0.19mm Hg/micrograms/L. In contrast, the relationships of dilevalol are best described by a Langmuir maximum effect model, and so individual responses to short and long term treatment have been quantified by the concentration-effect parameters of maximum effect and drug concentration required to produce 50% of this.(ABSTRACT TRUNCATED AT 400 WORDS)

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Mechanism of antihypertensive action of dilevalol compared with that of “cardioselective” beta-blocking agents

Cited by 17 publications

References 40 publications

Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise

Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise

Beta‐adrenoceptor partial agonists: a renaissance in cardiovascular therapy?

Clinical Pharmacokinetics and Kinetic-Dynamic Relationships of Dilevalol and Labetalol

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