Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions

Abstract

Circadian rhythms are ubiquitous phenomena that recur daily in a self-sustaining, entrainable, and oscillatory manner, and orchestrate a wide range of molecular, physiological, and behavioral processes. Circadian clocks are comprised of a hierarchical network of central and peripheral clocks that generate, sustain, and synchronize the circadian rhythms. The functioning of the peripheral clock is regulated by signals from autonomic innervation (from the central clock), endocrine networks, feeding, and other external cues. The critical role played by circadian rhythms in maintaining both systemic and tissue-level homeostasis is well established, and disruption of the rhythm has direct consequence for human health, disorders, and diseases. Circadian oscillations in both pharmacokinetics and pharmacodynamic processes are known to affect efficacy and toxicity of several therapeutic agents. A variety of modeling approaches ranging from empirical to more complex systems modeling approaches have been applied to characterize circadian biology and its influence on drug actions, optimize time of dosing, and identify opportunities for pharmacological modulation of the clock mechanisms and their downstream effects. In this review, we summarize current understanding of circadian rhythms and its influence on physiology, pharmacology, and therapeutic interventions, and discuss the role of chronopharmacometrics in gaining new insights into circadian rhythms and its applications in chronopharmacology.

New and Emerging Approaches to Better Define Sleep Disruption and Its Consequences

“…Effects of circadian rhythms on respiratory control (Stephenson, 2003;Yamauchi et al, 2014) and hypoxia (von Allmen et al, 2018) have also been hypothesized and supported by recent evidence of circadian modulation of the key OSA endotypes (El-Chami et al, 2014Puri et al, 2020). Circadian rhythms also have an influential effect on metabolism, diabetes, cardiovascular disorders, obesity, and the efficacy of a range of pharmacological interventions; factors often applicable to sleep disorder cohorts (Guo and Stein, 2003;Frazier and Chang, 2020;Ayyar and Sukumaran, 2021). Therefore, strategies to better define sleep disruption that incorporate circadian rhythm assessments have significant potential to improve diagnostic and targeted therapy outcomes.…”

Chronopharmacology in Therapeutic Drug Monitoring—Dependencies between the Rhythmics of Pharmacokinetic Processes and Drug Concentration in Blood

“…Biological rhythms are characterized by such features as period (duration of one full cycle), mean value (mesor), amplitude (difference between the mesor and maximum value), acrophase (time of reaching the maximum value during one cycle), and nadir (the opposite of the acrophase-time of reaching the minimum value by the rhythm). Taking the period into consideration, we can differentiate the ultradian rhythms, with cycles of varying duration, shorter than 24 h, ranging from one second through several seconds (e.g., oscillations in electroencephalographic recordings, heart rate, respiratory rate) to several hours (e.g., the basic sleep stage change cycle); circadian ("circa"-around; "dies"-day) rhythms, with an approximate duration of 24 h, related mainly to photoperiodism (e.g., sleep-wake rhythm, changes in core body temperature, secretion of selected hormones, changes in arterial blood pressure, and efficiency of the immune system); and infradian rhythms, the cycle of which exceeds 24 h (e.g., weekly, monthly, annual, and even seasonal) [1][2][3]9,12]. Physiological and pathophysiological phenomena controlled by the circadian rhythm are particularly noticeable.…”

“…Melatonin receptors can be found in multiple peripheral tissues through which the hormone can exert its effect, modulating the physiological functions. Another important tract is the tract connecting the SCN with the periventricular nucleus of the hypothalamus, connecting the SCN with neurosecretory cells secreting corticoliberin (HPA tract-hypothalamus-pituitary gland-adrenal glands) and other cells controlling the endocrine glands [1][2][3]9,12].…”

“…The drugs should be administrated in the morning hours, e.g., beta-adrenoreceptor antagonists, since the morning dosing of the drugs is correlated with the morning peak of sympathetic activity [1,2,12,16] Hypertension Among patients with primary arterial hypertension, the population of "dippers" (patients showing a decrease in nighttime RR value) or "nondippers" (patients with no expected night decrease in RR value), as well as patients characterized by the phenomenon of "morning surge" (an excessive morning surge in the value of RR) can be distinguished "dippers"-antihypertensive drug administered in the morning "nondippers"-antihypertensive drug given in the evening or 2/3 of the dose in the evening and 1/3 in the morning "dippers" + "morning surge"-antihypertensive drug in the morning or 1/2 dose in the morning and 1/2 in the evening "nondippers" + "morning surge"-antihypertensive drug given in the evening or 2/3 of the dose in the evening and 1/3 in the morning [1,2,15,16] Respiratory system Bronchial asthma…”

Circadian Clock Core Component Bmal1 Dictates Cell Cycle Rhythm of Proliferating Hepatocytes during Liver Regeneration

“…The core component of the mammalian circadian clock is composed of Bmal1 and Clock. These two transcription factors form a heterodimer, operate a set of transcriptional/translational feedback loops, generate diurnal outputs of the cellular transcriptome, and ultimately govern various rhythmic biological processes (3,7) . Of note, the circadian clock interacts with the cell cycle to regulate tissue renewal and repair (30).…”