Negative Chronotropic Effects of Fentanyl Attenuate Beneficial Effects of Dobutamine on Oxygen Metabolism: Hemodynamic and Pharmacokinetic Interactions

Abstract

Opioids are well known to cause cardiovascular depression. The aim of the present investigation was to determine whether an interaction of opioid derivatives with catecholamines might be involved in these hemodynamic alterations. Six comatose patients were enrolled into a prospective, nonrandomized pilot trial. All patients first received a continuous i.v. infusion of dobutamine (10 μg · kg⁻¹ · min⁻¹) paralleled by continuous administration of midazolam (0.4 mg · kg⁻¹ · h⁻¹); thereafter, fentanyl was added i.v. (4 μg · kg⁻¹ · h⁻¹). Hemodynamic parameters as well as dobutamine and endogenous catecholamines plasma levels were determined. The mean arterial blood pressure did not change significantly during the whole study period. The continuous administration of dobutamine (steady-state plasma concentrations: 217 ± 118 ng · ml⁻¹) increased the β₁-adrenergic receptor-mediated hemodynamic parameters such as heart rate, stroke volume index, cardiac index, and oxygen delivery index (p < .05). The concomitant administration of fentanyl decreased the heart rate-dependent hemodynamic parameters (p < .05), suggesting that fentanyl antagonizes the chronotropic effects of dobutamine. In parallel, dobutamine plasma levels increased significantly (275 ± 165 ng · ml⁻¹; p < .05). Noteworthy, after administration of fentanyl, oxygen delivery and consumption index returned to baseline values. Radioligand binding experiments on rat cardiac ventricular microsomes ruled out a direct interaction of fentanyl with β-adrenergic receptors and, more importantly, a fentanyl-induced inhibition of β-adrenergic receptor G protein coupling. Our observations suggest that fentanyl inhibits the frequency-related hemodynamic changes induced by dobutamine. The underlying mechanism is independent of β-adrenergic receptors, but is powerful enough to abolish the salutary effect of dobutamine on oxygen delivery and consumption.