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.
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