Basic Concepts and Parameters of Biological Rhythms
Chronopharmacology is based on the study of biological rhythms — periodic fluctuations in the intensity of biological processes.
To describe these rhythms, the following parameters are used:
- Mesor — the rhythm-adjusted 24-hour mean value.
- Amplitude — the measure of half of the extent of predictable variation (from the mesor to the peak or trough).
- Bathyphase — the time when the function reaches its minimum.
- Acrophase — the time point of the maximum value of the process.
- Period ($ au$) — the duration of one complete cycle.
Based on period length, biological rhythms are classified into ultradian (3–20 hours), circadian (about 24 hours, 20–28 hours), infradian (28–96 hours), circaseptan (about a week), and circatrigintan (about a month).
Core Branches of Chronopharmacology
The interaction between drugs and biological rhythms is examined through three key aspects:
- Chronopharmacokinetics (chronokinetics) — studies rhythmic fluctuations in absorption, distribution, biotransformation, and excretion. For example, the antifungal drug griseofulvin is best absorbed during the day (~12:00), whereas amphetamine is excreted by the kidneys most intensively in the early morning.
- Chronoesthesia — reflects daily changes in the sensitivity of the body or target tissues to a substance. This is related to fluctuations in receptor density, receptor affinity, and membrane permeability.
- Chronergy — an integrated parameter representing the combined result of chronokinetics and chronoesthesia, which determines the overall magnitude and duration of the drug's effect.
Diurnal and Seasonal Dynamics of Drug Effects
Therapeutic efficacy depends directly on the time of administration.
Examples of diurnal (circadian) dependence:
- Nitroglycerin relieves angina more effectively in the morning.
- The peak activity of endogenous glucocorticoids occurs around 8:00.
- The maximum analgesic effect of morphine is observed around 16:00.
- The nephrotoxicity of the antineoplastic drug cisplatin is minimal in the evening (18:00), although its peak concentration occurs in the morning (6:00).
Seasonal dependence (circannual rhythms): Drug efficacy can also vary throughout the year. A prominent example is plant-based adaptogens (e.g., Panax ginseng, Eleutherococcus senticosus). Their antihypoxic effect is maximal in January–March, whereas in spring and summer this effect completely disappears, and increasing the dose does not restore it.
Traditional Approach vs. Chronotherapy
Traditional dosing relies on rigid schedules (e.g., one tablet three times a day), ignoring physiological fluctuations.
The chronotherapeutic approach proposes using dynamic dosing to align with circadian rhythms.
Goals of chronotherapy:
- Achieve maximum therapeutic efficacy.
- Use the lowest possible effective doses.
- Reduce the frequency and severity of adverse drug reactions (such as decreasing the nephrotoxicity of cisplatin via evening administration).