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: 3115241
• 负责人: DONALD R STANSKI
• 金额: $ 16.78万
• 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 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3115241
• 关键词: aging; anesthetics; animal old age; biological transport; cardiac output; catheterization; computer simulation; disease /disorder model; dosage; drug metabolism; electroencephalography; endogenous opioid; 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.

人老化会改变生理功能和药理反应。 用于用于静脉注射的催眠和阿片类药物 麻醉，药物分布到组织对照的速率和程度 麻醉作用的发作和耗散。我们以前的研究已经 表明，随着人类的年龄，催眠药的分布 依托妥象），但不改变阿片类药物（芬太尼，阿芬太尼）。变更 反过来，分布会影响患者的麻醉剂量需求。 年龄对某些麻醉分布的选择性影响 药物可能是由与年龄相关的心脏变化的组合引起的 输出，区域血流，组织组成和药物 - 溶解度 组织。我们的研究将确定与年龄相关的身体变化 灌注，组织的大小和成分会影响重新分布 FL杂化大鼠中的硫代硫代，芬太尼和阿尔芬太尼。这些 选择麻醉剂是因为其临床意义，因为 组织分布的速率和程度，脂质溶解度和速率 人类和大鼠的消除明显不同。对于每种药物，四种类型 研究将在老鼠和老鼠中进行。研究1将确定 剂量需求，血浆药代动力学和脑电图效应。在研究2中 长时间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 输出和区域血流。研究4将测量药物的冲洗 随着时间的流逝，各种组织。三种药物的药代动力学 各种组织将被估算并与药物诱导的 区域血流的变化。由此产生的药代动力学数据 单个组织将被“重新组装”以形成完整的动物，因此 然后，详细的计算机模拟可以估计 改变心输出量改变的区域血流 麻醉剂量需求，血浆药代动力学和脑电图反应。我们 然后将在年轻的FL中创建这种程度的心血管改变 杂交大鼠并前瞻性估计药理学后果。我们的 数据将为确定适当剂量的科学依据 对于提供SC药理作用的药物， 重新分布是随着年龄相关的心血管功能的变化而发生的。 这项研究将定义血液动力学的程度和程度 与衰老相关的变化改变了麻醉药物的重新分布。