The Cerebral Pharmacokinetics of Meperidine and Alfentanil in Conscious Sheep

Abstract

Background: Different opioids have different delays (hysteresis) between their concentrations in blood and their cerebral effects. Possible mechanisms include differences in their rate of penetration into the brain and differences in their distribution volume in the brain. There have been few in vivo studies of the cerebral kinetics of opioids to differentiate these mechanisms. Methods: The cerebral kinetics of meperidine and alfentanil were examined using conscious sheep that were fitted with long-term monitoring equipment to measure relative changes in cerebral blood flow and opioid concentration gradients across the brain through frequent sampling of arterial and sagittal sinus blood. The data were compared using hybrid physiologic modeling with membrane-limited (consistent with mechanism 1) and flow-limited (consistent with mechanism 2) models of cerebral kinetics. Results: Alfentanil had a variable effect on relative cerebral blood flow, whereas meperidine induced a transient increase. The arteriovenous concentration gradients were small after alfentanil but large after meperidine. The flow-limited model gave acceptable descriptions of observed sagittal sinus concentrations for alfentanil and meperidine, whereas the membrane-limited model collapsed to a flow-limited model. The half-lives of equilibrium between blood and brain were 6.3 and 0.8 min for meperidine and alfentanil, 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 accounted for the respective delays in their peak brain concentration relative to blood.