The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane

The plasma concentration vs. anesthetic effect relationships for ketamine are not well known. It is desirable to establish stable and predictable drug concentrations in plasma (and brain) in order to define such relationships. As a prelude to pharmacodynamic studies, we investigated ketamine pharmacokinetics in eight dogs anesthetized with enflurane and correlated ketamine concentration in plasma (KET) with its ability to reduce the enflurane concentration required for anesthesia (enflurane EC50: MAC--the end-tidal concentration at which half the dogs moved in response to clamping of the tail and half did not move). Four dogs (Group 1) received ketamine 10 mg/kg iv over 30 sec. Blood for determination of KET was collected repeatedly over the 5-h period following injection. Based on the pharmacokinetic parameters determined for Group 1, four dogs in Group 2 received ketamine as a continuous infusion of 300 micrograms.kg-1.min-1 for 5 hr accompanied by an initial loading dose (26 mg/kg administered over 20 min) designed to produce a stable KET of 20 micrograms/ml of plasma. Enflurane MAC and KET were determined regularly during the infusion and for 5 hr after discontinuation of the infusion. There were no significant differences in the following pharmacokinetic parameters determined for Group 1 vs. Group 2: t1/2 beta = 122 +/- 9 vs. 141 +/- 40 min (mean +/- SD) and CL = 18.1 +/- 5.9 vs. 13.9 +/- 2.5 ml.kg-1.min-1, respectively. When administered as a continuous infusion (Group 2), KET remained relatively stable at 22.1 +/- 4.6 micrograms/ml for 5 hr. The degree of MAC reduction remained relatively stable at 73% during the continuous infusion. Finally, the enflurane MAC reduction vs. KET was established over a wide range of plasma concentrations in 4 additional dogs (Group 3). This study determined that the pharmacokinetics of ketamine were consistent under two different experimental conditions and demonstrated the relationship between plasma concentration and anesthetic effect in the dog.