Circadian rhythms and their development in children: implications for pharmacokinetics and pharmacodynamics in anesthesia

Abstract

The influence of time-of-day on the action and toxicity of drugs may be an important factor in the design of pharmacokinetic (PK) and pharmacodynamic (PD) studies, and the interpretation of data resulting from these studies. Time-of-day can have a profound influence on the action of drugs. In some settings (e.g. cancer chemotherapy), the timing of drug administration has been utilized to maximize therapeutic effect and minimize toxicity. Time-of-day variation in the action of anesthetic drugs has been clearly demonstrated in adults. For example, local anesthetic action is longest during the afternoon, and neuromuscular blockade by rocuronium lasts one-third longer in the morning than the afternoon. Circadian rhythms develop over the first months and years of life. Robust rhythms in hormone production (e.g. melatonin and cortisol) are seen at approximately 3 months of age, but it remains unclear as to when daily rhythms in drug PK and PD first appear. Here, we review the evidence for time-of-day effects in anesthetic drugs in adults and children and outline the potential influence this has on pediatric anesthesia.