Chronopharmacology is the science dealing with the optimization of drug effect and the minimization of adverse effects by timing medication in relation to biological rhythm. The molecular mechanisms that underlie the function of the biological clocks are universally present in all cells and consists of gene-protein-gene feedback loops in which proteins can downregulate their own transcription and stimulate the transcription of other clock proteins. Chronobiology – It is the branch of sciences dealing with the “Biological rhythm” and their mechanism in the living organism. Biological Rhythm – It is the determined rhythmic biological process or function within a defined time period. Chronotherapeutics – i.e. increase in efficacy and safety of medications by proportioning their concentrations during the 24 hrs in synchrony with biological rhythm determinants of disease. Chronokinetics – Time dependent and predictable changes in PK parameter. Eg; Cmax, tmax, AUC, T1/2 Chronesthesy – Circadian or other systemic changes in the susceptibility and sensitivity of the target system of the target system to a drug. Chronergy – Rhythmic differences in effects of drugs on the organisms as a whole includes both desired and undesired effects. Chronotoxicity – The toxic effect of drug on the organism, which is undesirable and affects the rhythmic system. Specifically with anti-tumor agents. The basic unit of circadian timekeeping is the cell. Even in very complex organisms, most cells contain autonomous circulatory for circadian oscillations. Generally speaking, this mechanism is comprised of negative feedback loops of transcription and translation: activation of a repressor gene results in its later repression by its own protein products, and the instability of this repressor ensures this repression is short lived, so that a new cycle can begin. In mammals, the principle activators within this system are the CLOCK and BMAL-1 proteins and their homolog, which dimerize and bind to certain elements to activate transcription of a large number of circadian genes.

2.  Chronopharmacology is the science dealing with the optimization of drug effect
and the minimization of adverse effects by timing medication in relation to
biological rhythm.
 The molecular mechanisms that underlie the function of the biological clocks are
universally present in all cells and consists of gene-protein-gene feedback loops in
which proteins can downregulate their own transcription and stimulate the
transcription of other clock proteins.

3.  Chronobiology –
It is the branch of sciences dealing with the “Biological rhythm” and their mechanism in
the living organism.
 Biological Rhythm –
It is the determined rhythmic biological process or function within a defined time period.

4.  Circadian –
“Sleep wake cycles”
Lasts for about 24 hours
 Infradian –
“menstural cycle”
Cycle longer than 24 hours
 Ultradian –
“Neuronal firing time”
Cycles shorter than a day
 Seasonal –
Seasonal affective disorders

5. External cues which reset the circadian clock = Zeitgebers
E.g:
 Photic zeitgeber –
Dark/Light cycle
 Non- Photic zeitgeber –
Sleep wake
Physical activity
Social time
Meals

7.  Chronotherapeutics –
i.e. increase in efficacy and safety of medications by proportioning their concentrations during the 24 hrs
in synchrony with biological rhythm determinants of disease.
 Chronokinetics –
Time dependent and predictable changes in PK parameter.
Eg; Cmax, tmax, AUC, T1/2
 Chronesthesy –
Circadian or other systemic changes in the susceptibility and sensitivity of the target system of the
target system to a drug.
 Chronergy –
Rhythmic differences in effects of drugs on the organisms as a whole includes both desired and undesired
effects.
 Chronotoxicity –
The toxic effect of drug on the organism, which is undesirable and affects the rhythmic system.
Specifically with anti-tumor agents.

8.  Allergic rhinitis – worse in early a.m./upon arising
 Bronchial asthma – Exacerbations more common during sleep
 Rheumatoid arthritis – symptoms are most intense on awakening
 Osteoarthritis – Symptoms worse in the middle/later portions of the day
 Angina Pectoris – Chest pain and ECG changes more common during the early a.m.
 Peptic Ulcer – Symptoms worse in the early (sleep) a.m.
 Stroke – Incidence greatest in the early a.m.

9. The basic unit of circadian timekeeping is the cell. Even in very complex organisms, most cells
contain autonomous circulatory for circadian oscillations.
Generally speaking, this mechanism is comprised of negative feedback loops of transcription and
translation: activation of a repressor gene results in its later repression by its own protein products,
and the instability of this repressor ensures this repression is short lived, so that a new cycle can
begin.
In mammals, the principle activators within this system are the CLOCK and BMAL-1 proteins and
their homolog, which dimerize and bind to certain elements to activate transcription of a large
number of circadian genes.

10.  Clinically, asthma exacerbations frequently occur in the early hours of the morning, around 4:00 a.m.
 Dyspnea-induced nighttime awakening occurs in more than 75% of respondents in a large survey of individuals
with asthma .
 70% of asthma-related deaths occurred between 12:00 a.m. and 6:0 a.m.
 Physiologically, airway caliber and inflammation also follow circadian patterns.
 Airway obstruction worsens during the night, with patients with asthma having a 51% larger change in PEF (peak
expiratory flow) during nighttime than control patients.
 Chronopharmacology of asthma is aimed at getting maximal effect from bronchodilators medication during the
early morning hours.
 Eg. Uniphyl (bronchodilator), a long-acting theophylline taken once a day in the evening causes theophylline blood
levels to reach their peak and improve lung function during the difficult early morning hours.

11. For example-Methyl prednisolone causes no suppression during a day(If given between 8:00 – 16:00) as shown
in below figure.

12.  Over the course of the day, the heart must contend with two major behavioral cycles;
Sleep-wake cycles
Fasting-feeding cycles
 These cycles are associated with profound fluctuations in energetic demand, neural stimulation,
hormones, nutrients, oxygen tension, body temperature, and shear stress.
 Consistent with its transcriptional nature, circadian clocks often govern cellular functions
through modulation of genes that are not clock components (termed clock output genes, CCG’s)
 Metabolic flux analysis reveals that the cardiomyocyte clock promotes oxidative metabolism at
the sleep wake transition (in anticipation of increased energetic demand upon awakening),
augments nutrient storage towards the end of the awake period (in anticipation of the upcoming
fast during the sleep period), and increases cellular constituent turnover at the beginning of the
sleep period (facilitating repair/renewal of the myocardium prior to awakening).

13.  Moreover, the myocardium exhibits clock-dependent rhythms in responsiveness to various
stimuli/stresses, including adrenergic stimulation, insulin, and fatty acids.
 At a functional level, both time-of day-dependent oscillations in heart rate and contractility
are attenuated in mice following genetic disruption of the cardiomyocyte circadian clock;
underscoring the importance of this mechanism in orchestrating critical processes in the
heart, these mice develop an age-onset dilated cardiomyopathy and exhibit reduced lifespan.

14.  Diabetes is a disease that occurs when your blood glucose, also called blood sugar, is too high.
 Disturbed circadian rhythms;
Caused by exposure to light at night. Associated with lower nocturnal melatonin. In turn affects
to glucose metabolism. Increase insulin resistance and decrease pancreatic function.
Gene clock polymorphism or altered expression of clock gene. Play role in development of obesity
and diabetes in human.
 Human glucose tolerance is reduced during evening than day and night because of circadian
rhythm.
 The genetic pathway an internal body clock takes to dictate how and when our pancreas must
produce insulin and control blood sugar.

15.  The body’s circadian clocks co-ordinate behaviors like eating and sleeping, as well as
physiological activity like metabolism, with the earth’s 24-hour light-dark cycle
 There’s a master clock in the brain as well as peripheral clocks located in individual organs.
 When genetics, environment or behavior disrupt the synchrony of these clocks, metabolic
disorders can develop.
 Dawn Phenomenon – Liver releases large amount of glucose into the blood stream just before
dawn. That can cause problems in diabetic patients.
 Hence, diabetics are advised not to eat high carb meals late at night, as this often causes higher
blood glucose levels than the same foods would cause at other times of the day.

16.  The medications which are used for the treatment of impaired insulin secretion, including
glinides and rapid and short acting insulin analogs, have the merit of chronotherapeutics
approach.
 These medications are useful not only for improving glycemic control but for the risk
reduction of prolonged hypoglycemia and body weight gain.

17.  Ulcer is caused by eradication of the stomach mucosa. In duodenal ulcer, acid secretion
is high in about half of the patients, reduction of acid secretion which is the main
approach to ulcer treatment.
 The rate of basal acid secretion is highest between 9 p.m. and midnight.
 Increase in acid secretion, meals are generally associated with a transient elevation in
the gastric pH due to the buffering effect of the meal.
 Thus, during the daytime hours, intragastric pH fluctuates, especially at mealtimes.
 During the nighttime hours, in absence of food, intragastric pH remains low.

18.  It is seen that gut motility and gastric exhausting is slower around evening time.
 In this way, for dynamic mending of peptic ulcer it is imperative to smother the
night-time acid.
 Eg. When 400 mg of cimetidine was given to DU patients with breakfast their
mean acid discharge was diminished till the following portion which was to be
given at night, at which the acid emission was restrained for 8 hr in night until
the following morning.