University of California San Francisco, 500 Parnassus Avenue, MUE455, San Francisco, CA, 94143, USA.
University of Auckland, Private Bag 92024, Auckland, 1001, New Zealand.
Br J Clin Pharmacol. 2018 Jun;84(6):1364-1372. doi: 10.1111/bcp.13571. Epub 2018 Apr 2.
Alpha-2 agonists are direct peripheral vasoconstrictors, which achieve these effects by activating 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.
After local ethics committee approval, we studied 10 healthy volunteers. To study the peripheral vasoconstrictive effect of dexmedetomidine without concurrent sympatholytic effects, sympathetic fibres were blocked with a brachial plexus block. Volunteers received a 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 PK analysis. Peripheral vasoconstriction (PD) was assessed using finger photoelectric plethysmography. PK/PD analysis was carried out using nonlinear mixed-effect models.
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. A three-compartment model provided a better fit to the data than a two-compartment model.
We found that dexmedetomidine-induced vasoconstriction is concentration dependent over time. Dexmedetomidine PK were best estimated by a three-compartment model with allometric scaling. Our results may contribute to future modelling of dexmedetomidine-induced haemodynamic effects.
α-2 激动剂是直接的外周血管收缩剂，通过激活血管平滑肌 α-2 肾上腺素能受体来实现这些作用。在右美托咪定输注期间，这种反应的影响尚未得到充分量化。我们的目标是研究健康志愿者中计算机控制的右美托咪定输注的药代动力学（PK）和药效学（PD，血管收缩）效应。
在当地伦理委员会批准后，我们研究了 10 名健康志愿者。为了研究右美托咪定的外周血管收缩作用而不伴有同时的交感神经抑制作用，我们用臂丛神经阻滞来阻断交感神经纤维。志愿者接受右美托咪定目标控制输注 15 分钟，目标浓度为 0.3ng/ml。在右美托咪定输注期间和输注后 60 分钟内采集动脉血样进行 PK 分析。使用手指光电体积描记法评估外周血管收缩（PD）。使用非线性混合效应模型进行 PK/PD 分析。
我们发现，在 15 分钟的输注过程中，计算机控制的输注泵输送的平均浓度超过了 0.3ng/ml。外周血管收缩作用与输注期间和输注后的右美托咪定血浆浓度相关。三房室模型比二房室模型提供了更好的拟合数据。
我们发现，右美托咪定诱导的血管收缩随时间呈浓度依赖性。右美托咪定 PK 最好通过带有比例缩放的三房室模型进行估计。我们的结果可能有助于未来对右美托咪定引起的血液动力学效应的建模。
