IV ANESTHETIC DISPOSITION IN THE AGED HEMODYNAMIC STATE

IV 老年血流动力学状态下的麻醉处置

• 批准号: 3115234
• 负责人: DONALD R STANSKI
• 金额: $ 17.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-01-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3115234
• 关键词: aging; anesthetics; animal old age; biological transport; cardiac output; catheterization; computer simulation; disease /disorder model; dosage; drug metabolism; electroencephalography; fentanyl; hemodynamics; intravenous administration; juvenile animal; laboratory rat; mathematical model; model design /development; pharmacokinetics; thiopental; tissue /cell culture

Human aging alters both physiologic function and pharmacologic response. For intravenously-administered hypnotic and opioid drugs used in anesthesia, the rate and extent of drug distribution into tissues control the onset and dissipation of anesthetic effect. our previous research has shown that, as humans age, the distribution of hypnotic drugs (thiopental, etomidate) but not opioids (fentanyl, alfentanil) change. Changes in distribution, in turn, affect the patient's anesthetic dose requirement. This selective influence of age on the distribution of some anesthetic drugs may be caused by a combination of age-related changes in cardiac output, regional blood flow, tissue composition, and drug-solubility in tissues. Our research will determine how age-related changes in body perfusion and tissue size and composition affect the redistribution of thiopental, fentanyl, and alfentanil in the Fl Hybrid rat. These anesthetics were chosen for their clinical relevance, and because their rate and extent of tissue distribution, lipid solubility, and rate of elimination differ markedly in humans and rats. For each drug, four types of studies will be performed in young and old rats. Study 1 will determine dose requirements, plasma pharmacokinetics, and EEG effects. In Study 2, prolonged infusions will estimate steady-state blood:tissue partitioning (solubility). Study 3 will quantitate drug-induced changes in cardiac output and regional blood flow. Study 4 will measure the washout of drug from various tissues over time. The pharmacokinetics of the three drugs in various tissues will be estimated and integrated with the drug-induced changes in regional blood flow. The resulting pharmacokinetic data for individual tissues will be "reassembled" to create the intact animal, so that detailed computer simulations can then estimate the type and degree of change in cardiac output a regional blood flow necessary to alter anesthetic dose requirement, plasma pharmacokinetics, and EEG response. We will then create this degree of cardiovascular alteration in young Fl Hybrid rats and prospectively estimate the pharmacologic consequences. Our data will provide a scientific basis for determining the appropriate dosage for drugs whose provide a sC pharmacologic effects are terminated by redistribution as age-related changes in cardiovascular function occur. This research will define the degree and extent to which hemodynamic changes associated with aging alter the redistribution of anesthetic drugs.

人类衰老改变生理功能和药理学反应。 对于静脉给药的催眠药和阿片类药物， 麻醉，药物分布到组织中的速率和程度控制 麻醉效果的开始和消失。我们之前的研究 显示，随着人类年龄的增长，催眠药物（硫喷妥钠， 依托咪酯），但阿片类药物（芬太尼、阿芬太尼）无变化。变化 分布又影响患者的麻醉剂剂量需求。 年龄对某些麻醉剂分布的选择性影响 药物可能是由年龄相关的心脏变化的组合引起的， 输出量、局部血流量、组织成分和药物溶解度， 组织中我们的研究将确定年龄相关的身体变化 灌注和组织的大小和组成影响的再分布， 硫喷妥钠、芬太尼和阿芬太尼。这些 选择麻醉剂是因为它们的临床相关性， 组织分布的速率和程度、脂溶性和 消除在人类和大鼠中显著不同。对于每种药物，四种类型 将在年轻和老年大鼠中进行研究。研究1将确定 剂量要求、血浆药代动力学和EEG效应。在研究2中， 延长输注将估计稳态血液：组织分配 （溶解度）。研究3将定量药物诱导的心脏变化， 输出和局部血流。研究4将测量药物的洗脱 从各种组织中分离出来三种药物的药代动力学 将评估各种组织并与药物诱导的 局部血流的变化。所得的药代动力学数据 个体组织将被“重新组装”以产生完整的动物， 详细的计算机模拟可以估计出 心输出量的变化是改变心功能所必需的局部血流量 麻醉剂量要求、血浆药代动力学和EEG反应。我们 将在年轻的Fl中产生这种程度的心血管改变， 杂交大鼠并前瞻性估计药理学结果。我们 数据将为确定适当的剂量提供科学依据 对于提供sC药理作用的药物， 随着年龄的增长，心血管功能发生变化。 这项研究将确定血流动力学 与衰老相关的变化改变了麻醉药物的再分布。