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Pharmacokinetics and Pharmacodynamics of Antiarrhythmic Drugs in Disease State

抗心律失常药物疾病状态下的药代动力学和药效学

基本信息

批准号：
62480431
负责人：
HORI Ryohei
金额：
$ 3.84万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1987
资助国家：
日本
起止时间：
1987 至 1989
项目状态：
已结题

项目摘要

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.

在设计给药方案时，患者对抗抑郁药反应的变异性是一个至关重要的考虑因素，并且药物反应个体间变异性机制的定义至关重要。各种各样。影响心脏功能的各种疾病状态可引起抗心律失常药物作用动力学的显著变化。本研究探讨了疾病状态对抗肿瘤药物的药代动力学和药效学的影响.通过药代动力学-药效学联合模型分析了未结合药物浓度与药效学效应之间的关系，其中假设效应室通过一级过程与中央室中的未结合药物浓度相连。该模型允许估计静脉内施用丙肾上腺素后的ECG变化。在麻醉大鼠上观察了异丙肾上腺素对缺血再灌注心律失常的抗心律失常作用。Aimaline抗再灌注心律失常的作用与缺血心肌中Aimaline浓度有关，且受给药时间的影响显著.与对照组大鼠相比，阿马林在甲亢大鼠中表现出增加的负变频活性。起搏频率与异丙肾上腺素的变频作用呈正相关。因此，甲状腺功能亢进大鼠的心率加快是其促甲状腺激素活性增强的主要原因.肾功能不全的大鼠表现出增加的可用性，口服给药的丙氨酸和普萘洛尔。肾功能不全与小肠吸收率增加有关。在肾功能不全的情况下，高可用性的阿马林至少可以部分地解释为肠吸收率的增加和肝脏中的非线性提取。