Chronotherapy

Complete pharmacology of chronotherapy

1. CHRONOTHERAPY
RVS Chaitanya
Koppala

2. CONCEPTS AND PRINCIPLES:
Biological rhythm is a self sustaining oscillation with the duration of
time between normal conditions and successive repetitions.
Rhythms are particularly important in medicine, body temperature
and heart rate are some circadian rhythms having relatively low
amplitude.
While plasma cortical and adrenalin having quite high amplitude.
The phasing and period of the peak through times of rhythms are
coordinated by endogenous genetically inherited pacemaker clocks
located at various levels of biological organization.

3. THE BIOLOGICAL RHYTHMS
Types:
Ultradian: This cycle is shorter than a day. Sleep cycles
within 90 minutes.
Circadian: These are the cycles which lasts for over 24 hours.
Examples are waking and sleeping pattern.
Infradian: These cycles are longer than 24 hours. Example:
monthly menstruation.
Seasonal: These cycles changes with the seasons. Example:
seasonal affective disorder causes depression during the short days
of winter.

5. ADVANTAGES OF
CHRONOTHERAPY:
When a person sleeps for several hours then the chronotherapy is
more effective.
Chronotherapy requires no drug.
While using chronotherapy a patient often fall asleep which improves
their condition and confidence.
Prediction of Chronotherapy is easy because it possess beginning,
middle and end stage.
Chronotherapy gives a new schedule to the patients of getting up and
sleeping early but it provides them a period to adjust psychologically.

6. DISADVANTAGES:
Need of consulting the doctor and sleep specialists
regularly to avoid side effects.
Unusual feeling of hot or cold when the person is
undergoing therapy.
Patient incompliance as he has to keep himself awake till
the next sleep schedule.
Sometimes the patient may also be sleep deprived.
The degree of risk is not known.

7. TREATMENT OF
CHRONOTHERAPY:
The treatment of biological rhythms coordination is
known as chronotherapy.
It is also known as Chronobiology.
Every person’s body has its own rhythms which are
governed by the environment changes or genetically.
A person can increase or decrease the dose of drug
thereby avoiding the unwanted effect of the particular
drug for determining these biological rhythms.

9. Chronotherapy can be used in the treatment of
various diseases given below:
Hypertension
Bronchial asthma
Peptic ulcer
Myocardial infarction
Arthritis
Cerebrovascular accidents
Hypercholesterolemia.

10. HYPER TENSION:
It is the physiological condition described as morning surge.
In hypertension the systolic bloods pressure rises up to
3mmHg/hour for 4-6 hours after getting up which is called as post-
awakening and the diastolic blood pressure also rises up to
2mmHg/hours .
Blood pressure and heart rate will be high at the time of walking in
the morning and it will begin to decrease in the afternoon and
reaches minimum at mid night.

11. Myocardial Infarction:
Platelet aggregation and the vascular tone is high in the morning
when the release of the catecholamine and cortisol is high.
The main regions for the outburst of the myocardial infarction in the
morning with 34% events taking place from 6 a.m. till noon.
Cyclooxygenase inhibitor-2 will relieve the pain effectively when
taken in the morning .
Peptic Ulcer Disease:
Histamine antagonist given at night shows the better result unlike
when given at the regular intervals around the clock.
But more pain and more acid secretion thus formation of gastric and
duodenal ulcers are more subjective at night time then day time.

12. Hyper Cholesterolemia:
Cholesterol intake and its biosynthesis is more in the evening
hour.
Therefore after the discovery of circadian rhythms the first
HMG co-A inhibitor was reevaluated and evening doses were
recommended inspite of the morning doses.
Bronchial Athma:
Asthma disease has more circadian variation then the other
diseases.
Intake of time released theophyllin at 3 P.M. achieves
therapeutic dose at night and toxic levels during the day are
avoided .

13. Cerebrovascular Accidents:
In the morning hours between 10 A.M to 12 Noon, the
cerebrovascular accidents are more common.
It decreases considerably from noon to midnight.
Chonotherapy is done for this condition to deliver the drug in higher
doses in the morning and little doses at the noon and in midnight.
Atenolol, Nifedipine and Amlodipine are the various ACE inhibitors
that are more effective when administered during the night.
Arthritis:
In accordance with the chronotherapeutic study, more desirable
results have been achieved for rheumatoid arthritis when the dose
was given in the evening time.
Cyclooxygenase inhibitor-2 taken in the morning time relieves the
pain effectively.

14. Diabetes:
The circadian rhythms of insulin and its action are of physiological
interest.
Insulin can show cylic rhythms for 8-30 mins. to show its
optimal action.
The modulators of insulin release and its action are secreted in a
circardian pattern and therefore insulin effects are altered .
Cancer:
The rhythmic circadian changes in cancer growth and tumour blood
flow are relevant when the tumours are small and growing rapidly.
The blood flow to tumours is threefold greater during each daily
activity phase of circadian cycle then during the daily rest phase.
More tumour cells are killed by treatment at mid night and with the
same dose of active cytotoxic therapy with little bone marrow
damage [25].

15. Duodenal Ulcer:
In duodenal and peptic ulcer, gastric acid secretion is highest
during the night.
Therefore a daily dose at bedtime is recommended for H2
antagonists.
At night time gastric motility, drug disintegration, dissolution
and absorption may be slower and thus the relieve in peptic
ulcer is efficient.

16. GENETIC BASIS:
Along an approximate 24-hour time cycle of Circardian rhythm
the Biological functions of most living organisms are organized
and fixed.
In microorganisms such as Neurospora crassaor, cyanobacterias the
endogenicity of the circadian rhythms has been demonstrated.
In plants and in all type of animal species such as mice, flies, rats
and humans circadian rhythms govern daily events such as activity,
sleep, hormonal secretion, cellular proliferation and metabolism.

17. CHRONOPHARMACOKINETICS OF
DRUGS
Antiasthmatic Drugs:
Beta sympathomimetics and Theophyllin should be dosed higher in
the evening than during day time when asthma is predominantly
nocturnal.
Local Anaesthetics:
The longest duration of Local Anaesthetic like Lidocane,
Ropivacane, Mepivacine, Betoxycaine was observed when these
amide type Local Anaesthetic agents were applied at around 3 P.M.
Lidocaine area under plasma concentration curves was largest in
the afternoon
The plasma levels of Lidocaine were significantly higher in the
evening than at any other time of the day.

19. CLINICAL MANIFESTATION
WITH CIRCADIAN RHYTHM

20. LIST OF DRUGS IN
CHRONOTHERAPY

21. CONCLUSION
Drug efficacy is related to the rhythmcity of the biochemical,
physiological and behavioural processes.
These processes are dependant on the circadian and the
biological clock of the body.
Therefore in an attempt to increase the effectiveness of the
therapy, chronotherapeutics is an emerging field these days.
Medications provided in accordance with chronotherapeutics in the
right time, in right amount, in right place improves the treatment
efficacy and also reduces the associated adverse effects.
Therefore many researches are undergoing these days in the field
of chronotherapeutics.