Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
J Cardiovasc Transl Res. 2012 Aug;5(4):535-40. doi: 10.1007/s12265-011-9315-x. Epub 2011 Aug 30.
Anti-arrhythmic drugs have narrow therapeutic ranges and typically can engender harmful side effects. The intrapericardial (IP) delivery of anti-arrhythmic agents proposes to achieve higher myocardial levels while minimizing plasma concentrations, thus diminishing systemic side effects. Furthermore, IP delivery enables concentrations at the target site to be more precisely controlled. Our study objective was to compare the relative cardiac effects of intrapericardial administration of metoprolol to standard intravenous (IV) delivery in a swine surgical model. In order to answer the question of how IP metoprolol affects sinus tachycardia, atrial electrophysiology, and pharmacokinetics compared with IV delivery, a medial sternotomy was performed on 21 swine that were divided into three groups: (1) After inducing sinus tachycardia, metoprolol boluses were delivered IP (n = 4) or IV (n = 4); (2) metoprolol was administered either IP (n = 3) or IV (n = 3) with saline controls (n = 3), and electrophysiologic data were collected; (3) metoprolol levels were tracked both in the blood (IV, n = 2) and pericardial (IP, n = 2) fluid. After either IP or IV delivery of metoprolol, heart rates were lowered significantly to 70% and 73% of control rate, respectively. The therapeutic effect of IV-administered metoprolol was considerably reduced after 1 h but was sustained longer in the IP group. Additionally, ventricular contractility and mean arterial pressure parameters were significantly lower in IV-treated animals but were nearly unaffected in IP-treated animals. With IP administration, the elimination half-life of metoprolol in pericardial fluid was 14.4 min with negligible accumulations in the plasma, whereas with IV delivery, the elimination half-life in plasma was 11.1 min with negligible amounts found in the pericardial fluid. The targeted intrapericardial delivery of metoprolol effectively lowers heart rates for sustained periods of time, with minimal effect on either ventricular contractility or mean arterial pressure. We did not observe dramatic changes in induced atrial fibrillation times or refractory periods using this model.
抗心律失常药物的治疗范围较窄，通常会产生有害的副作用。心包内（IP）给药可以在最小化血浆浓度的同时提高心肌内的药物浓度，从而减少全身副作用。此外，IP 给药还可以更精确地控制靶部位的浓度。我们的研究目的是比较心包内给予美托洛尔与标准静脉（IV）给药在猪手术模型中的相对心脏效应。为了回答心包内给予美托洛尔如何影响窦性心动过速、心房电生理和药代动力学与 IV 给药的问题，对 21 头猪进行了正中胸骨切开术，将其分为三组：（1）在诱导窦性心动过速后，通过心包内（n = 4）或静脉内（n = 4）给予美托洛尔推注；（2）通过心包内（n = 3）或静脉内（n = 3）给予美托洛尔，同时给予生理盐水对照（n = 3），并收集电生理数据；（3）在血液（IV，n = 2）和心包液（IP，n = 2）中追踪美托洛尔的水平。心包内或静脉内给予美托洛尔后，心率分别显著降低至对照心率的 70%和 73%。静脉内给予美托洛尔的治疗效果在 1 小时后显著降低，但在 IP 组持续时间更长。此外，静脉内治疗的动物心室收缩力和平均动脉压参数显著降低，但在 IP 治疗的动物中几乎不受影响。心包内给予美托洛尔时，其在心包液中的消除半衰期为 14.4 分钟，而在血浆中几乎没有蓄积，而静脉内给予美托洛尔时，其在血浆中的消除半衰期为 11.1 分钟，在心包液中几乎没有发现。经心包内靶向给药，美托洛尔可有效降低心率，持续时间较长，对心室收缩力或平均动脉压的影响最小。在这种模型中，我们没有观察到诱导的心房颤动时间或不应期发生显著变化。
