Chronopharmacology and its aspects

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Chronopharmacology and its aspects
The richness of the Indian culture lies in its tradition, but most of us do not follow it, our grandparents insist us to do our activities in the orderly and timely fashion, have you ever wondered why it is so? Or why do they impose things on us and admit that it's only for our well being. There is science in every thing, though it is our dietary control or timing of food intake. In our pharmaceutical terms we call it as chronopharmacology, chrono means time and pharmacology is the study of the pharmacokinetics and dynamics of the drug in the body.
What is chronopharmacology?
A branch of chronobiology concerned with the effects of drugs upon the timing of biological events and rhythms, and the relation of biological timing to the effects of drugs (1).
When a drug is administered the pharmacological action of the drug can be predicted based on the body circadian rhythm.
In the present scenario, it is possible to explain all the functions of the body as a function of time. In the same way as sleep-wake, feed-hunger and joy-depression are regulated by the living clocks, the maximum efficacy and minimum toxicity of a drug can be achieved if it is administered at the appropriate time; i.e., right drug in the right form, at the right dose, at the right time. So the given drug can act synergistically with biological clock. For example, sleeping pill should be taken in the nighttime to produce good results.(2)

Thus the chronopharmacology is based on the Circadian rhythms
Circadian (circa, about; dies, day, or about 24 hour)-Physiological day is about 25 hours-Clock is reset daily by the environment day/night social schedules.
Hence circadian rhythms are particularly important in medicine.
A circadian clock in the brain coordinates daily physiological cycles-
* sleep/wake
* digestion-temperature
* hormones etc...

The internal biological clock will synchronize with the environmental conditions.
An internal biological clock, located, in mammals, is in the suprachiasmatic nucleus of the hypothalamus (SCN), delivering its message of time throughout the body, It is responsible for circadian rhythms and annual / seasonal rhythms. The SCN uses its connections with the autonomic nervous system for spreading its time-of-day message, either by setting the sensitivity of endocrine glands(i.e., thyroid, adrenal, ovary) or by directly controlling an endocrine output of pineal gland (i.e., melatonin synthesis).

In medicine, 3 disciplines take into account the influence of time:

* Chronophysiology
* Chronopathology
* chronopharmacology

Chronopharmacology is the investigative science concerned with the biological rhythm dependencies of medications.

It maybe subdivided into chronotherapy, chronopharmacokinetics and chronotoxicity.

CHRONOTHERAPEUTICS: Knowledge of day-night and other predictable-in-time variation in the symptom intensity and risk of acute exacerbations of disease coupled with evidence of circadian rhythms in the kinetics, effects, and safety of medications constitutes the rationale for a new pharmacologic approach to treatment-

A chronotherapeutic approach is indicated when the risk of severe medical events or the intensity of diseases and their symptoms is known to vary predictably during the24 hours and/or other time periods. Large-scale clinical trials have shown that the efficiency and safety of certain conventional(so-called homeostatically formulated medications can be improved by dosing them with reference to the circadian time structure.

This was first demonstrated during the1960s; once-daily morning as opposed to multiple-daily dosing of methylprednisolone tablets reduces the risk of hypothalamic-pituitary-adrenal suppression and improves the treatment of severe inflammatory conditions.

Chronopharmacokinetics: It deals with the study of the temporal changes in absorption, distribution, metabolism and elimination and thus takes into account the influence of time of administration on these different steps. Temporal changes can be involved at each step of the sequence of pharmacokinetic processes: temporal variations in drug absorption from the gastro-intestinal tract (due to circadian variations in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow), plasma protein binding and drug distribution, drug metabolism (temporal variations in 2 enzyme activity, hepatic blood flow) and in renal drug excretion (due to variation in glomerular filtration, renal blood flow, urinary pH and tubular resorption). Thus, the time of administration of a drug is an important source of variation which must be taken into account in kinetic studies and particular methodological aspects of chronokinetics are needed (4).

Chronotoxicology: is an aspect of chronodynamics; it refers specifically to dosing-time, i.e., rhythm-dependent, differences in the manifestation and severity of adverse effects and thus intolerance of patients to medications. Classes of medications that have high risk of adverse effects and relatively narrow therapeutic range, in particular, are likely to show significant dosing-time differences in safety (i.e., chronotoxicologies). Circadian rhythm experiments conducted more than 50 years ago clearly showed a major adverse effect -- adrenocortical suppression of potent synthetic anti-inflammatory glucocorticoid medications, such as ethylprednisolone, triamcinolone, and prednisolone, can be significantly attenuated, or even averted, if correctly timed to circadian rhythms.

Chronesthesy means medications and other chemical substances typically exhibit dose and/or concentration- response relationships. However, chronopharmacology studies sometimes reveal great differences in their effects with different biological times of application, even through the pharmacokinetics and concentration are the same. This phenomenon is termed chronesthesy. It is
another new concept in pharmacology, and it refers to rhythm-dependent differences in the sensitivity of target systems to medications that cannot be explained by corresponding administration-time differences in pharmacokinetic phenomena. Chronesthesies are demonstrable by the direct application of medications to their sites of action and by differences in the
blood/tissue concentration-biological response to medications when administered at different times during the 24 h. The mechanisms of chronesthesies have yet to be fully elucidated.(5)

Thus the chronopharmacology can be used as an powerful tool to modify the action of the drug and this promises to be a good tool in drug regimen, and therapeutics.

(4) Chronopharmacokinetics: The Circadian Rhythm of Drugs, by Haya M. Al-Malaq, Teaching Assistant-Clinical Pharmacy Department College of Pharmacy King Saud University December 25-2004.
(5) Pdf


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