Lipophilicity affects the pharmacokinetics and toxicity of local anaesthetic agents administered by caudal block

1. Drugs administered into the epidural space by caudal block are cleared by means of a process potentially affected by the lipophilic character of the compounds. 2. In the present study, we examined the relationship between the octanol-water partition coefficient (log P-oct) and the time to reach the maximum plasma drug concentration (t(max)) of lignocaine, bupivacaine and ropivacaine administered by caudal block in paediatric patients. We also examined the relationship between log P-oct and the toxicity of these local anaesthetic agents in experimental models. The t(max) and toxicity data were obtained from the literature. 3. Ropivacaine, with a log P-oct of 2.9, exhibited a t(max) of 61.6 min. The t(max) of lignocaine, with a log P-oct of 2.4, and bupivacaine, with a log P-oct of with 3.4, were approximately 50% shorter than ropivacaine. At log P-oct of approximately 3.0, the toxicity of these local anaesthetic agents was substantially increased. The relationship between log P-oct and the convulsive effect in dogs was similar to the relationship between log P-oct and the lethal dose in sheep. 4. With local anaesthetic agents, it appears that the relationship between log P-oct and drug transfer from the epidural space to the blood stream is parabolic, being the slowest rate of transference at log P-oct 3.0. Toxicity, due to plasma availability of these local anaesthetic agents, seems to be increased at log P-oct equal or higher than 3.0 secondary to the highest transfer from plasma into the central nervous system.