THE EFFECT OF HALOTHANE ON THE RECIRCULATORY PHARMACOKINETICS OF PHYSIOLOGICAL MARKERS

Background: The cardiovascular effects of halothane are well recognize d, but little is known of how this affects drug distribution, The effe ct of halothane anesthesia on physiologic factors that affect drug dis position from the moment of injection was investigated, Methods: The d ispositions of markers of intravascular space and blood flow (indocyan ine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and w hile anesthetized with 1%, 1.5%, and 2% halothane in a randomized orde r determined by a repeated measures Latin square experimental design, Marker dispositions were described by recirculatory pharmacokinetic mo dels based on frequent early and less frequent later arterial blood sa mples. These models characterize the role of cardiac output and its di stribution on drug disposition. Results: Halothane caused a significan t and dose-dependent decrease in cardiac output, The disposition of an tipyrine was most profoundly affected by halothane anesthesia, which i ncreased both nondistributive intercompartmental clearance and volume while decreasing fast and slow tissue clearances and elimination clear ance in a halothane dose-dependent manner, Conclusions: Halothane-indu ced changes in blood flow to the compartments of the antipyrine recirc ulatory model were not proportional to changes in cardiac output. Halo thane anesthesia significantly increased (to more than double) the are a under the drug concentration versus time curve due to an increase in the apparent peripheral blood flow not involved in drug distribution, despite a dose-dependent cardiac output decrease. Recirculatory pharm acokinetic models include the best aspects of traditional compartmenta l and physiologic pharmacokinetic models while offering advantages ove r both.