Basic Concepts and Parameters of Biorhythms
Chronopharmacology is based on the study of biorhythms—periodic changes in the intensity of biological processes.
The following characteristics are used to describe these rhythms:
- Mesor is the 24-hour mean value of the parameter.
- Amplitude is the magnitude of fluctuation from the mesor to the maximum or minimum.
- Bathyphase is the time when the function reaches its minimum.
- Acrophase is the point of the maximum value of the process.
- Period ($ au$) is the time of one complete cycle.
According to the duration of the period, biorhythms are divided into ultradian (3–20 hours), circadian (near-24-hour, 20–28 hours), infradian (28–96 hours), circaseptan, and circamoan rhythms.
Basic Sections of Chronopharmacology
The interaction between drugs and biorhythms is viewed 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), while amphetamine is excreted most intensively by the kidneys in the early morning.
- Chronoesthesia reflects circadian changes in the body's sensitivity to a substance. This is associated with changes in receptor count, receptor sensitivity, and membrane permeability.
- Chronergy is an integral indicator. It is the combined result of chronokinetics and chronoesthesia that determines the final potency and duration of a drug's action.
Daily and Seasonal Dynamics of Effects
Therapeutic efficacy directly depends on the time of administration.
Examples of daily dependence:
- Nitroglycerin relieves angina pectoris more effectively in the morning.
- The peak activity of glucocorticoids occurs at 8:00.
- The maximum effect of morphine is observed around 16:00.
- The nephrotoxicity of the antineoplastic agent cisplatin is minimal in the evening (18:00), although its peak concentration is observed in the morning (6:00).
Seasonal dependence (circannual rhythms): Drug efficacy can also change throughout the year. A striking example is herbal adaptogens (ginseng, Eleutherococcus). 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 uses rigid regimens (e.g., one tablet three times a day), ignoring physiological fluctuations.
The chronotherapeutic approach suggests using dynamic doses, adapting to circadian rhythms.
Goals of chronotherapy:
- To achieve maximum therapeutic effect.
- To use the minimum effective doses possible.
- To reduce the frequency and severity of side effects (as in the case of reducing cisplatin nephrotoxicity with evening administration).
Briefly: answers to topical questions
Which physiological parameters of the gastrointestinal tract that affect drug absorption exhibit a circadian rhythm?
Sources indicate the following circadian changes in GI functions:
- GI secretion and motility; their daily periodicity is regulated by melatonin;
- Bile secretion: most intensive in the first half of the day.
As an example of the temporal dependence of absorption, it is noted that griseofulvin is best absorbed around 12:00.
For which major groups of medicinal products has the necessity of chronotherapy been clinically proven?
Sources provide examples of time-dependent action or pharmacokinetics for the following drugs and groups:
- NSAIDs — acetylsalicylic acid and indomethacin;
- theophylline and propranolol — in the section on drugs affecting the cardiovascular and respiratory systems;
- the antibacterial agent erythromycin;
- the antineoplastic agent cisplatin.
The dependence of the effect on the time of day is also indicated for nitroglycerin, glucocorticoids, and morphine. Accounting for the time of day maximizes the therapeutic effect and/or reduces toxicity; cisplatin nephrotoxicity is minimal when administered at 18:00.
Chronokinetics is the movement (kinetics) of a drug in time. Chronoesthesia is the feeling (esthesia), the sensitivity of tissues in time. Chronergy is energy (ergia), the final potency of the effect.
Class and exam questions
What are acrophase and bathyphase?
Acrophase is the time when a biological process reaches its peak (maximum). Bathyphase is the time when the process is at its minimum (trough).
Why is it necessary to prescribe drugs by time rather than simply in equal doses?
To synchronize administration with receptor sensitivity peaks or safe metabolism phases. This enhances the effect and reduces toxicity while using smaller doses.
What else to study on this topic
- Graphical representation of biorhythms (sine wave, mesor, amplitude)
- Detailed hourly pharmacokinetics of NSAIDs (acetylsalicylic acid, indomethacin)
- Circadian dynamics of cardiovascular drugs (theophylline, propranolol)
- Experimental models of daily sensitivity using strychnine as an example
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