INTRODUCTION TO CHRONOPHARMACOLOGY
Chronopharmacology is the science that deals with the optimizations of drug effect and the
minimizations of adverse effects of timing medications in relation to biological rhythm.
The science concerned with the biological rhythm dependencies of medications.
The two major disciplines of Chronopharmacology which are important in medical practice
nowadays include the Chrono therapeutics, which is the treatment in accordance with the
body's biological rhythms that aids in optimizing therapeutic outcomes and minimize side
effects.
Chrono pharmacokinetics, which is the study of the absorption, distribution, metabolism and
excretion of drugs according to the time of days or year.
Biological Rhythms
Any cyclic change in the level of a bodily chemical or function.
Biological rhythms can be: – Internal (endogenous) - controlled by the internal biological
clock e.g. body temperature cycle
– External (exogenous) - controlled by synchronizing internal cycles with external stimuli
e.g. sleep/wakefulness and day/night. These stimuli are called zeitgebers -- from the German
meaning “time givers”. These stimuli include environmental time cues such as sunlight, food,
noise, or social interaction. Zeitgebers help to reset the biological clock to a 24-hour day.
Circadian rhythms: endogenously generated rhythms with a period close to 24 hours.
Diurnal rhythms: a circadian rhythm that is synchronized with the day/night cycle.
Ultradian rhythms: biological rhythms (e.g. feeding cycles) with a period much shorter (i.e.,
frequency much higher) than that of a circadian rhythm.
Infradian rhythms: biological rhythms with a cycle of more than 24 hours (e.g. the human
menstrual cycle).
Circadian Rhythms
Circadian is derived from a Latin phrase meaning "about a day“ [about (circa) and a day
(dia)].
Circadian rhythms are physiological and behavioral rhythms and include: sleep/wakefulness
cycle, body temperature, patterns of hormone secretion, – blood pressure, digestive
secretions, levels of alertness and reaction times
Circadian rhythms have a period of approximately 24-25hrs.
When the rhythm is synchronized with the day/night cycle it is termed a diurnal rhythm.
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Circadian Clock
In humans (and other mammals), a circadian clock is located in the suprachiasmatic nuclei
(SCN).
The SCN is in the hypothalamus. It is a tiny cluster of about 10 thousand nerve cells.
This circadian clock is synchronized to the external cycles of light and darkness and social
contact. The synchronized rhythm is called the diurnal rhythm.
Disruption of the clock or its synchronization occurs during jet-lag, shift work and old-age.
Disruption of the clock detrimentally affects our well-being and mental and physical
performance.
Biological Clock and Melatonin
The circadian clock controls longer term cycles:
– seasonal rhythms in reproduction
– seasonal rhythms metabolism and appetite.
The pineal hormone melatonin, (a hormone that induces sleep) mediates this seasonality.
The SCN clock ensures that melatonin is secreted only at night. Melatonin secretion last
longer on the longer winter nights.
The duration of the circadian melatonin is used by the brain to orchestrate seasonal rhythms.
Circadian Regulation of Pharmacodynamics:
Circadian mechanisms regulate many factors which influence the efficacy of drugs aside
from their metabolism.
Rhythmic alterations in the expression of target receptors, transporters and enzymes,
intracellular signaling systems and gene transcription all have been reported and have the
potential to impact the efficacy of therapeutics.
Several of the neurotransmitter systems, including serotonergic, cholinergic and
dopaminergic nuclei plays critical role in the circadian rhythm.
The circadian gene also regulates metabolic processes like insulin secretion, gluconeogenesis
and fatty acid metabolism.
Cardiovascular System
Based on the influence of external stimuli and endogenous homoeostatic mechanisms, the
cardiac electrophysiological properties change diurnally and enable the cardiovascular system
to adapt accordingly with the rest-exercise cycles.
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For example, Blood Pressure peaks in the late afternoons, and gradually decreases in the
evening to attain lowest values in the night.
Myocardial infarction (MI) occurs more frequently in the morning as a result of the
concomitant unfavourable timing of several physiological parameters and/or biochemical
conditions.
Urinary System:
The urinary system which plays a pivotal role in the elimination of a drug has many instances
of circadian rhythms altering either the clearance or the urinary flow causing nephrotoxicity.
Gastrointestinal System:
The gastrointestinal motility, the intraluminal pH, blood flow to the stomach and enzymatic
action are not the only factors that influence the gastrointestinal absorption of the drug.
It even depends on the circadian rhythms and is influenced by the time of the day.
Most of the drugs we generally take are lipophilic and they are found to have more rate of
absorption in early mornings rather than any hour of the day.
Respiratory System:
The development of asthma symptoms and many types of bronchospastic attacks is clearly
more common from midnight to early morning from AM to 6AM.
Chronopharmacotherapy for asthma is aimed at getting maximal effect from bronchodilator
medications during the early morning hours.
SCOPE AND PROSPECTS
Ongoing research has begun to disclose the molecular mechanisms by which circadian genes
regulate pharmacokinetic and pharmacodynamic processes.
It is also becoming evidentthat drugs can influence the rhythmicity of circadian clocks, alter
physiology and perhaps with unintended consequences.
Chronopharmacology also grants new challenges for scientists and regulators.
According to US Food and Drug Administration (USFDA), Chronopharmacology clinical
studies need more additional parameters which are not applied for other clinical trials,
including drug administration time of the day; patient’s normal habits and sleep pattern;
biological factors which are time related likeseasonal disorder.
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