PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRASPINAL DEXMEDETOMIDINE IN SHEEP

Introduction: Epidural and spinal injection of alpha(2)-adrenergic agonists causes analgesia and hypotension. For opioids, relative analgesic potency of epidural to intravenous administration decreases with increasing lipophilicity, but such pharmacodynamic studies have been performed with only one alpha(2)-adrenergic agonist, clonidine, of moderate lipophilicity. This study examines antinociception, transfer to cerebrospinal fluid (CSF), and CSF pharmacokinetics in sheep of the selective alpha(2)-adrenergic agonist dexmedetomidine, with lipophilicity 3.5 times greater than clonidine, and correlates CSF concentrations to hemodynamic effects. Methods: Six sheep with chronically implanted epidural, intrathecal, and vascular catheters received, on separate days, 100 mu g dexmedetomidine intravenously, epidurally, or intrathecally. Cerebrospinal fluid and blood were sampled at specified intervals for dexmedetomidine assay. Pharmacokinetics of dexmedetomidine in CSF were determined using a NONMEM approach. Hemodynamic effects were measured and correlated to CSF concentrations. A second group of four sheep received intrathecal dexmedetomidine to define its time course for antinociception. Results: Intrathecal dexmedetomidine decreased blood pressure within 1 min, with a maximum reduction of -22 +/- 3%. Epidural injection decreased blood pressure with a slower onset (11 min) and to a lesser degree (-14 +/- 4%), whereas intravenous injection did not affect blood pressure (-8 +/- 6%). Dexmedetomidine absorption in CSF after epidural injection was rapid (T-max = 5-20 min), although pharmacokinetic modeling suggested a biphasic absorption process. Only 22% of the injected dose was identified in the CSF. There was a delay of at least 30 min between peak CSF concentrations and time of maximal reduction in blood pressure. At times of identical CSF dexmedetomidine concentrations, blood pressure decreased more after epidural than after intrathecal administration. Intrathecal dexmedetomidine injection produced maximum antinociception within 20-30 min of injection. Conclusions: These data support a primary spinal site of action for decreased blood pressure after intraspinal dexmedetomidine injection. Dexmedetomidine appears rapidly in CSF after epidural administration and decreases blood pressure. The relationship between CSF dexmedetomidine concentrations and drug effect may require more complex modeling tools than those used to relate plasma drug concentrations to effects of systemically administered opioids or neuromuscular blockers.