Pharmacokinetics and Pharmacodynamics of Antiarrhythmic Drugs in Disease State

在设计给药方案时，患者对抗心律失常药物反应的差异性是一个重要的考虑因素，而药物反应的个体差异性机制的定义至关重要。影响心脏功能的各种疾病状态可能会引起抗心律失常药物作用动力学的显著变化。在本研究中，研究了疾病状态对抗心律失常药物的药代动力学和药代动力学的影响。用药代动力学-药代动力学联合模型分析了药动学药效与药效的关系，其中假想药效室与中央室的药效室浓度按一级过程相连。该模型可以估计静脉给药后的心电图变化。本实验观察了伊马林对麻醉大鼠缺血及再灌注性心律失常的影响。伊马林对再灌注性心律失常的保护作用与缺血心肌组织中的吲哚青碱浓度有关，且受给药时间的影响显着。Aimaline在甲亢大鼠中表现出比正常大鼠更强的负性促流活性。起搏频率与伊马林的变流作用呈正相关。由此可见，甲亢大鼠心率的增加主要是由于其对肾上腺皮质激素的亲水性增强。肾功能不全的大鼠显示口服依那林和心得安的利用度增加。肾功能障碍与小肠的吸收率增加有关。伊马林在肾功能障碍中的利用率较高，至少部分原因是肠道吸收速度的增加和肝脏的非线性提取。

Variability in the patients response to antiarrhythaics is a crucial consideration in designing dosage regimens, and the definition of the mechanisms of interindividual variability in drug response is of critical importance. Various .-kinds of disease states affecting the cardiac function may cause significant variations in the kinetics of antiarrhythmic drug action. In the present study, the effects of disease states on both the pharmacokinetics and the pharmacodynazibs of antiarrhythmic drugs were investigated.1. The relationship between the unbound drug concentration and the pharmacolgic effect was analyzed by a combined pharmacokinetic-pharjeacodyninic model, where the hypothetical effect compartment is connected to the unbound drug concentration in the central compartment by a first-order process. This model allows estimation of the ECG changes after intravenous administration of aimaline.2. Antiarrhythmic actions of aimaline against ischemia and subsequent reperfusion induced arrhythmias were investigated in anesthetized rats. The beneficial effect of aimaline against reperfusion-induced arrhythmias is related to the ischemic myocardial concentration of ainaline which is markedly affected by the time of drug administration.3. Aimaline exhibited an increased negative dromotropic activity in hyperthyroid rats compared with control rats. A positive correlation was found between the pacing rate and the dromotropic action of aimaline. Thus, the increased dronotropic activity of ainaline is mainly due to the increased heart rate in hyperthyroid rats.4. Rats with renal dysfunction showed an increased availability of orally administered ainaline and propranolol. Renal dysfunction was associated with an increased absorption rate from the small intestine. The higher availability of aimaline and in renal dysfunction could be explained at least in part by the increased absorption rate from the intestine and the non-linear extraction in the liver.