IN-VIVO RELATIONSHIPS BETWEEN THE CEREBRAL PHARMACOKINETICS AND PHARMACODYNAMICS OF THIOPENTONE IN SHEEP AFTER SHORT-TERM ADMINISTRATION

The cerebral kinetics and dynamics of thiopentone after infusions of 2 50, 500, and 750 mg over 2 min were examined in chronically instrument ed sheep (6, 6, and 5 sheep per dose, respectively). The cerebral kine tics were studied by rapid sampling of arterial and dorsal sagittal si nus blood (afferent and efferent blood for the brain, respectively) fo r 40 min, and could be described by a single flow-limited compartment when arterial concentrations and cerebral blood flow were used as forc ing input functions. The half-lives of equilibration between blood and the brain were estimated to be 0.67 (SEM = 0.07), 0.57 (0.03) and 0.7 4 (0.05) min for the 250-, 500- and 750-mg doses, respectively, showin g that the cerebral concentrations of thiopentone rapidly equilibrate with the afferent blood concentration. Simultaneous pharmacodynamic me asurements included cerebral blood flow via a Doppler flowmeter on the sagittal sinus, and an index of the depth of anesthesia based on an a lgesimetry method. Thiopentone transiently reduced cerebral blood flow to 82 (SEM = 3), 80% (7), and 74% (10) of baseline for the 250-, 500- , and 750-mg doses, respectively, and failure to account for drug-indu ced changes in cerebral blood flow in the model over estimated the app arent volume of the brain by 12% for the 500-mg dose. For the 500-mg d ose, the changes in cerebral blood flow could be accounted for by an e ffect compartment with a half-life of 0.82 min for arterial blood and 0.00 min for sagittal sinus blood, showing the effluent brain concentr ations were in equilibrium with this drug effect. The time course of t he depth of anesthesia for the 250-mg dose could be accounted for by a n effect compartment with a half-life of 1.33 min for arterial blood a nd 0.41 min for sagittal sinus blood. Thus, the rate of equilibration between blood and brain could not account for all of this delay. It is concluded that after short-term administration thiopentone equilibrat ed rapidly with the brain, and that this is consistent with the observ ation that the magnitude of its clinically relevant effects closely fo llow the time course of the arterial blood concentrations.