Pharmacokinetics and pharmacodynamics of dexmedetomidine-induced vasoconstriction in healthy volunteers

Abstract

Aims

Alpha-2 agonists are direct peripheral vasoconstrictors by activation of vascular smooth muscle alpha-2 adrenoceptors. The impact of this response during dexmedetomidine infusion remains poorly quantified. Our goal was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD, vasoconstriction) effects of a computer controlled dexmedetomidine infusion in healthy volunteers.

Methods

After local ethics committee approval, we studied 10 healthy volunteers. To study the peripheral vasoconstrictive effect of dexmedetomidine without concurrent sympatholytic effects, sympathetic fibers were blocked with a brachial plexus block. Volunteers received dexmedetomidine target controlled infusion for 15 min to a target concentration of 0.3 ng/ml. Arterial blood samples were collected during and for 60 min after dexmedetomidine infusion for pharmacokinetic analysis. Peripheral vasoconstriction (PD) was assessed using finger photoelectric plethysmography. PK/PD analysis was done using nonlinear mixed effect models.

Results

We found that the computer-controlled infusion pump delivered mean concentrations greater than 0.3 ng/ml over the 15 min infusion duration. The peripheral vasoconstrictive effect correlated with dexmedetomidine plasma concentrations during and after the infusion. This verifies that dexmedetomidine induced vasoconstriction is concentration dependent over time. A 3-compartment model provided a better fit to the data than a 2-compartment model.

Conclusions

We found that dexmedetomidine induced vasoconstriction is concentration dependent over time. Dexmedetomidine pharmacokinetics were best estimated by a 3-compartment model with allometric scaling. Our results will contribute to future modeling of dexmedetomidine induced hemodynamic effects.

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