Circadian Variation in Efficacy of Medications

Abstract

Although much has been learned about circadian clocks and rhythms over the past few decades, translation of this foundational science underlying the temporal regulation of physiology and behavior to clinical applications has been slow. Indeed, acceptance of the modern study of circadian rhythms has been blunted because the phenomenology of cyclic changes had to counteract the 20th century dogma of homeostasis in the biological sciences and medicine. We are providing this review of clinical data to highlight the emerging awareness of circadian variation in efficacy of medications for physicians, clinicians, and pharmacists. We are suggesting that gold-standard double-blind clinical studies should be conducted to determine the best time of day for optimal effectiveness of medications; also, we suggest that time of day should be tracked and reported as an important biological variable in ongoing clinical studies hereafter. Furthermore, we emphasize that time of day is, and should be considered, a key biological variable in research design similar to sex. In common with biomedical research data that have been historically strongly skewed toward the male sex, most pharmaceutical data have been skewed toward morning dosing without strong evidence that this is the optimal time of efficacy.

Figure 1.. Circadian rhythms in physiology.

In humans, environmental light information is detected by specialized retinal ganglion cells in the eyes that project to the master circadian clock, the suprachiasmatic nuclei in the hypothalamus. In a top-down fashion, the master clock then transduces photic information to drive neural and hormonal signals, such as melatonin and cortisol, which in turn synchronize circadian cellular rhythms in the network of peripheral clocks which control and coordinate physiology and body function. Peak and nadir circadian timing of some of these and other physiological and bodily functions are depicted here (redrawn from [7]).

Figure 2.. Endogenous circadian rhythm of cortisol.

Cortisol, the primary glucocorticoid in humans, is produced by the adrenal glands and is regulated by one of the major neuroendocrine systems, namely, the hypothalamic-pituitary-adrenal (HPA) axis. Typical physiological cortisol concentrations function to regulate energy mobilization in the body and thus follows a circadian rhythm in which changes in circulating cortisol generally precede daily activity patterns; cortisol values rise sharply just prior to the onset of activity (prewaking) and then gradually decline across the day to reach nadir at the end of the active period (onset of sleep) (based on [74]). The HPA axis also functions to integrate physiological systems (e.g., immune, cardiovascular, reproductive, metabolism, central nervous system) to rapidly adapt to changes in the environment. Strong bidirectional feedback between the HPA axis and these systems place it as the fulcrum of typical physiology; thus, HPA axis dysregulation is implicated in many medical conditions.

Figure 3.. Chronotherapy for rheumatoid arthritis (RA).

Suggested optimal timing of various treatments for circadian RA symptoms (redrawn from [159]).