Chronobiology and PK/PD Modeling in Anesthesia

Björn Lemmer

Institute of Pharmacology and Toxicology,

Ruprecht-Karls-University of Heidelberg, Germany

e-mail: bjoern.lemmer@urz.uni-heidelberg.de

Chronobiological Background: Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukariotic organization. Circadian rhythms by definition are endogenous in nature, driven by oscillators or clocks, and persist under free-running conditions. In various species (Drosophila melongaster, Neurospora, Mouse, Golden hamster) the genes controlling circadian rhythms have been identified (genes: per, frq, clock, tau). Recently, clock genes were identified even in human tissues such as the skin and the mucosa. In general, the endogenous clock in man does not exactly runs at a frequency of 24 hours but somewhat slower. The rhythm in human body temperature which is timed by the biological clock has an about 25-hour period under free-running conditions i.e. without environmental time-cues or Zeitgebers (Fig. 1; e.g. light, temperature). Zeitgebers entrain the circadian rhythm to a precise 24-hour period. Zeitgebers are necessary to entrain a living subject to a „normal“ period of 24 hours! Most important to note that endogenous biological rhythms are anticipatory in nature! Thus, rhythmicity inherent to all living systems, allows them to adapt more easily and to better survive under changing environmental conditions during the 24 hours of a day as well as during varying conditions of the changing seasons.

Fig. 1. Input and Output Mechanisms of the Biological Clock

Chronokinetics - Chronodynamics: It is still a common paradigm in clinical pharmacology that pharmacokinetic parameters as well as drug effects are considered not to be influenced by the time of day of drug administration. However, this paradigm can not be hold any longer since it is now well established that nearly all functions of the body, including those influencing pharmacokinetic parameters, display significant daily variations (Tab.1). In man the organization in time can also be seen in certain states of disease in which the onset and symptoms do not occur at random within 24 hours of a day, e.g. asthma attacks, symptoms and pain perception in coronary infarction and angina pectoris, pain perception in rheumatic disease and in osteoarthritis, postoperative pain and tooth pain.

There are data in experimental animals and in man demonstrating that drugs of different classes used for pain treatment – local anesthetics, NSAIDs, opioids, and placebo – cannot only display significant variations in their pharmacokinetis but also in the analgesic effects. In rodents, even the concentrations of endogenous opioids such as endorphins and enkephalins, were shown to be rhythmic.

Absorption, GI-tract	Distribution	Metabolism, liver	Excretion, kidney
perfusion, pH, acid secretion, motility, gastric emptying, rest-activity	perfusion, blood distribution, per. resistance, serum proteins/binding	perfusion, first-pass effect, (enzyme activity)	perfusion, plasma flow, filtration, excretion, pH, electrolytes

Tab. 1. Background for Chronopharmacokinetics

Having in mind the organization in time of living systems including man it is easy to conceive that not only must the right amount of the right substance be at the right place, but also this must occur at the right time. This is the more important when an organism or individual itself has to act or react in favorable biotic or environmental conditions which by themselves are highly periodic. Thus, it is easy to understand that exogenous compounds including drugs may differently challenge the individual depending on the time of exposition.

Conclusions: Over the last years numerous clinical studies in various disease entities including perception and treatment of pains have demonstrated that the pharmacokinetics and/or the effects of drugs can greatly depend on the time of day / circadian dosing time leading to a circadian phase-dependency in the dose response relationship. This can result in a dissociation between a drug's pharmacokinetic and pharmacodynamic profiles, PK/PD-modelling has to take into account this circadian phase dependency.