CHRONOPHARMACOLOGY: AN OVERVIEW

 

ABOUT AUTHORS:
Pankaj Sharma*, Bhupendra Vyas, Yuvraj Singh Sarangdevot, Abhishek Sharma, Bhuvanesh Sharma
Department of Quality Assurance,
Bhupal Nobles’ College of Pharmacy,
Udaipur- 313002, Rajasthan, India
*pankajs.medicolite@gmail.com

ABSTRACT
Chronopharmacology involves both the investigation of drug effects as a function of biologic timing and the investigation of drug effects upon rhythm characteristics. Chronopharmacology certainly holds promise for the creation of the most favourable conditions for drug effects and safety and may therefore represent an important method of improving the treatment of many diseases. The goal of chronopharmacology is to optimize the therapeutic effect and control or reduce the adverse effects without altering the functioning of the drug in the body. Pharmacologic chronotherapy is a developing science that holds much hope for increasing the effectiveness of drug therapy and for reducing the incidence of toxic drug reaction. There is convincing scientific work to indicate that more attention should be given to the timing of drug administration. Most prescribers are currently more concerned with "what" to prescribe rather than "when" to prescribe it. Chronopharmacology certainly holds promise for the creation of the most favourable conditions for drug effects and safety and may therefore represent an important method of improving the treatment of many diseases.


REFERENCE ID: PHARMATUTOR-ART-1749

1. INTRODUCTION
Nearly all functions of the body, including those influencing pharmacokinetic parameters such as drug absorption and distribution, drug metabolism and renal elimination, show significant daily variations: these include liver metabolism, hepatic blood flow and the first-pass effect; glomerular filtration, renal plasma flow and urine volume and pH; blood pressure, heart rate and organ perfusion rates; acid secretion in the gastro-intestinal tract and gastric emptying time.

The onset and symptoms of diseases such as asthma attacks, coronary infarction, angina pectoris, stroke and ventricular tachycardia are circadian phase dependent. In humans, variations during the 24 h day in pharmacokinetics (chrono-pharmacokinetics) have been shown for cardiovascularly active drugs (propranolol, nifedipine, verapamil, enalapril, isosorbide 5-mononitrate and digoxin), anti-asthmatics (theophylline and terbutaline), anticancer drugs, psychotropics, analgesics, local anaesthetics and antibiotics, to mention but a few. Even more drugs have been shown to display significant variations in their effects throughout the day (chronopharmacodynamics and chronotoxicology) even after chronic application or constant infusion.

Moreover, there is clear evidence that even dose/concentration-response relationships can be significantly modified by the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug's pharmacokinetics and its effects or side-effects.

There is convincing scientific work to indicate that more attention should be given to the timing of drug administration. Most prescribers are currently more concerned with "what" to prescribe rather than "when" to prescribe it.

Chronotherapeutics certainly holds promise for the creation of the most favourable conditions for drug effects and safety and may therefore represent an important method of improving the treatment of many diseases. The goal of chronotherapeutics is to optimize the therapeutic effect and control or reduce the adverse effects without altering the functioning of the drug in the body.

Pharmacologic chronotherapy is a developing science that holds much hope for increasing the effectiveness of drug therapy and for reducing the incidence of toxic drug reaction.


Chronopharmacology:
It is the science dealing with the optimizations of drug effect and the minimizations of adverse effects by timing medications in relation to biological rhythm Goal is to improve our understand­ing of periodic and thus predictable changes in both desired effects and tolerance of medication. Chronopharmacologyis the investigative science concerned with the biological rhythm dependencies of medications.

Chronobiology:
It is the science dealing with the phenomenon of rhythmicity in living organisms is called Chronobiology. It is derived from chronos (time), bios (life), and logos (study of)--is the objective description of biological time structures and plays an important role in medicine. Circadian rhythms regulate the behavior, physiology and function of living organisms at many biochemical levels.

Aim of chronobiology is optimization of pharmacotherapeutics, taking into consideration-rhythm dependencies in kinetics and dynamics of medications, predictable in time variability in the manifestation and severity of diseases.

Circadian rhythm:
It is defined as oscillations in the biological, physi­ological and behavioral function of an organism with a periodicity of 24 hrs. The concepts of chronobiology and chronopharmacology have become more and more important in medical practice nowadays. Today, the circadian variation in blood pressure and heart rate as well as in the occurrence of acute cardiovascular disease is quite obvious (ischemia, infarction, stroke and sudden death). However, biological rhythms are also present in episodes of dyspnoea in nocturnal asthma, in hormonal pulses, in the organization of the immunological system and in the processes of cellular proliferation.

SuprachtAsmatic Nuclei (SCN) located in the anterior ventral hypothalamus has been identified as that centre. That generates circadian activity. Lesion of SCN produces loss of circadian rhythm- sleep-wake cycle activity- rest cycle, skin temperature and corticosteroidSecretion. Goals of Chronotherapy are to match the timing of treatment with the in­trinsic timing-of illness.

The introduction of chronopharmacology into pharmacokinetic theory leads to a clock time-dependent infusion rate. The infusion modulation depends both on type of chronophenomenon, chronopharmacokinetics or chronestesy, and plasma clearance rate of the drug. In the presence of chronestesy of a biosystem the pharmacologic effect can be maintained constant only when plasma drug clearance is fast enough to allow an adequate modulation of the plasma drug concentration.

Circadian (congruent to 24 h), circannual (congruent to 1 year) and other biological rhythms of endogenous origin, detectable at all levels of organization, constitute a temporal structure in all animal species, including man. Circadian, circannual and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical as well as chemical agents including medications and foods are rather common phenomena.

Chronergy:
It isrhythmic changes of both desired (effectiveness) and undesired (toxicity, tolerance) ef­fects on the organism as a whole.

On a 24 hour scale there are peaks and troughs of physiological vari­ables that are not randomly distrib­uted, but the controlled by a set pacemaker, so called biological clocks.

Chronokinetics:
It is study of absorp­tion, distribution, metabolism and excretion of drug according to the time of day, menstrual cycle or year.

Chronesthesy:
It is rhythmic changes in susceptibility or sensitivity of a target system to a drug, which can­not be explained by chronokinetic changes. In humans, target can be skin, bronchial tree, and stomach.

2. BIOLOGICAL RHYTHMS
Biological rhythms are innately determined rhythmic biological process or function and self-sustaining oscillation with the duration of time between successive repetitions (i.e., the period) being rather non varying under normal conditions.100 different, measurable parameters in human body exhibit rhythmic variability within 24 hours.

Circadian rhythms are particularly important in medicine. Circadian (circa about dies, day, or about 24 hour) Physiological day is about 25 hours Clock is reset daily by the environment night day social schedules. A circadian clock in the brain coordinates daily physiological cycles like sleep/wake, digestion, temperature, hormones. Biologic rhythms are endogenous nature of circadian. Lack of external synchronizers leads to free running rhythms. The period of free-running rhythms is longer or shorter than 24 hours and is characteristic for each species. Our internal clocks are genetically determined. An internal biological clock located in mammals, 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).

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