Chronobiology and anesthesia.

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CHRONOBIOLOGY investigates biologic rhythms that are involved in the organization of living organisms. Biologic rhythms consist of variations of biologic phenomena that are periodic and foreseeable in time. They are genetically determined as indicated by their persistence during constant conditions such as continuous light or darkness. Temporal variations in cycles of light– dark, rest–activity, fasting–eating, and other environmental conditions, defined as synchronizers, give the organism temporal markers and thus impose their period on these biologic rhythms. These rhythms can therefore be characterized by different periods, leading to the division of circadian (a period of approximately 24 h), ultradian (a cycle that is shorter than 1 day), and infradian (a cycle that may last weeks, months, or seasons). These clocks influence how our bodies change throughout the day, affecting blood pressure, activity of the immune system, blood coagulation, and gastric and renal functions. Almost all hormones are regulated by circadian rhythms. For example, cortisol naturally decreases to its lowest concentrations at bedtime and reaches its highest concentrations during the early waking hours. This variation may be fit to a sinusoidal function by the cosinor method, a linear method of least squares (fig. 1). This function is characterized by parameters such as the midline-estimating statistic of rhythm (MESOR), i.e., the mean level that is equal to the 24-h average), amplitude (half of the peak-to-trough difference of the fitted cosinus function), and acrophase (the crest time of rhythm given in degrees, where 360° corresponds to a 24-h cycle, or in hours and minutes). Other methods, such as Fourier transformation, may be used to detect the periodicity of the rhythm. Biologic rhythms are influenced by socioecologic factors, such as jet lag and shiftwork, as well as by illness and drugs. Available clinical data have shown that signs and symptoms are not constant over time and often have cyclic patterns. More strokes and heart attacks occur in the morning compared with any other time of day, and people with osteoarthritis tend to feel less pain in the morning than at night. Studies also suggest that chemotherapy and treatments for asthma and arthritis may be more effective and less toxic if drugs are administered at carefully selected times. Taking into account the circadian rhythms for medical treatment by choosing the time of day for drug administration is called chronotherapy. Drug effects can be optimized and side effects can be reduced by basing drug administration on the circadian patterns of a disease. Chronopharmacology is the study of the influence of the moment of administration of a drug (hour, month, and year) on its response according to the temporal structure of the organism receiving it. Chronopharmacology also studies the drug-induced alterations of biologic rhythms. Two aspects of chronopharmacology must be distinguished: the time of administration of a drug may determine a different response from a qualitative or a quantitative point of view (chronopharmacodynamics) and/or a different effective drug concentration (chronopharmacokinetics). Pharmacokinetic parameters are influenced by different physiologic functions displaying circadian rhythm. Temporal changes of drug kinetics have been reported in animals and humans for more than a hundred drugs, including anesthetics. It has been shown, for example, that despite a constant infusion rate of heparin, the risk of bleeding and the activated partial thromboplastin are higher at night. Chronopharmacokinetic data may partly explain chronopharmacodynamic phenomena. Knowledge of the influence of the time of administration on the drug kinetics could therefore have implications for its prescription by modulating the distribution of the total daily dose over a 24-h period. The aim of this review is to provide an update on the chronobiologic and chronopharmacologic findings that could have an impact on the daily practice of anesthesiology and/or research in this area.