[Chronopharmacology. Time of day variations in the action of bupivacaine are not manifested in nerves].

UNLABELLED: To test the hypothesis that the efficacy of local anaesthetics to block nerve conduction is related the time of day (TOD) of drug application, we retrospectively analysed data from previous experiments on tachyphylaxis. During the course of these experiments, as a measure of drug efficacy we determined the minimal blocking concentration (c(m)) of bupivacaine in rabbit aortic nerves at several TODs. The special in situ preparation used permitted study of local anaesthetic pharmacodynamics without the influence of pharmacokinetics, making it possible to investigate the chronopharmacodynamics of these drugs by relating c(m)s to the respective TODs of their measurement.

METHODS

In 43 New Zealand rabbits anaesthetised with urethane, the aortic nerve was dissected and partly placed in a double-lumen perfusion chamber (Fig. 1A), which was continuously perfused with tyrode solution or bupivacaine. Spike activity was continuously recorded by bipolar platinum-iridium electrodes caudad to the chamber for control and cephalad for registration of blocking effects. As a measure of drug efficacy, by increasing the bupivacaine concentration stepwise we determined the smallest concentration that blocks spike activity i.e., c(m). After each determination bupivacaine was rinsed off to confirm intact nerve function (Fig. 18).

RESULTS

Forty-nine determinations of bupivacaine c(m) were performed between 12:25 p.m. and 2:35 a.m. Data were pooled into groups of 2 h (Fig. 2). There was no significant difference between groups (ANOVA). In particular, c(m) at 3:00 p.m. was not lower than at 11:00 p.m., times at which local anaesthetics have been found to be most and least effective, respectively.

CONCLUSIONS

The c(m) of bupivacaine, and thus its efficacy to block nerve conduction, does not depend on TOD of drug application. Therefore, it is suggested that chronopharmacodynamics does not play an important role in the well-known circadian rhythm of the action of bupivacaine and probably of local anaesthetics in general.