THE CEREBRAL PHARMACOKINETICS OF MEPERIDINE AND ALFENTANIL IN CONSCIOUS SHEEP

Background: Different opioids have different delays (hysteresis) betwe en their concentrations in blood and their cerebral effects, Possible mechanisms include differences in their rate of penetration into the b rain and differences in their distribution volume in the brain. There have been few in vivo studies of the cerebral kinetics of opioids to d ifferentiate these mechanisms. Methods: The cerebral kinetics of meper idine and alfentanil were examined using conscious sheep that were fit ted with long-term monitoring equipment to measure relative changes in cerebral blood flow and opioid concentration gradients across the bra in through frequent sampling of arterial and sagittal sinus blood, The data were compared using hybrid physiologic modeling with membrane-li mited (consistent with mechanism 1) and flow-limited (consistent with mechanism 2) models of cerebral kinetics. Results: Alfentanil had a va riable effect on relative cerebral blood how, whereas meperidine induc ed a transient increase. The arteriovenous concentration gradients wer e small after alfentanil but large after meperidine. The flow-limited model gave acceptable descriptions of observed sagittal sinus concentr ations for alfentanil and meperidine, whereas the membrane-limited mod el collapsed to a flow-limited model. The half-lives of equilibrium be tween blood and brain were 6.3 and 0.8 min for meperidine and alfentan il, respectively. Conclusions: The rate of penetration of both opioids into the brain was rapid and not rate-limiting. Large differences in the cerebral distribution volume of meperidine and alfentanil accounte d for the respective delays in their peak brain concentration relative to blood.