chronopharmacology, circadian rhythum,

1. CHRONOPHARMACOLOGY: New
Insights and Therapeutic
Implications
Gaurav Chhabra
M-Pharm II Sem.
(Pharmacology)
UIPS, Panjab University
Chandigarh

2. OUTLINE
• Introduction(Chronology and chronobiology)
• Biological rhythm
• Circadian rhythm
• Molecular fundamentals of circadian clocks
• Chronopharmacolgy
• Applied Chronopharmacolgy
• Conclusion

3. INTRODUCTION
• Chronology : The arrangement of events according to the time of occurrence.
• These events occur after particular time interval called Rhythm.
CHRONOBIOLOGY
• The science dealing with the phenomenon of rhythmicity in living organisms.
• In medicines three disciplines take into account with the influence of time:-
CHRONOPHYSIOLOGY
CHRONOPATHOLOGY
CHRONOPHARMACOLOGY

4. Biological rhythm - types

5. CIRCADIAN RHYTHM
CIRCA-AROUND DIAM- A DAY
• A circadian rhythm is a 24 hour cycle of physiological and biological processes of living
beings including plants, animals, fungi and cyanobacteria.
• Circadian rhythms are endogenously generated, although they can be modulated by external
factors such as sunlight and temperature.
• It also important in sleeping and feeding patterns of all animals, including human beings.
• Brain wave activity, hormone production, cell regeneration and other biological activities
linked to this daily cycle.
CONTI…….

6. • An internal biological clock is located in mammals, in the suprachiasmatic
nucleus of the hypothalamus (SCN), delivering its message of time throughout the
body i.e. is responsible for circadian rhythms.
• It is also known as the master clock of our body.
• 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.

7. SCN Cells contain a newly discovered protein (eg.
clock protein) that regulates gene function and
which shows 24-hr variations in cellular levels.
Anterior Portion of the Hypothalamus  (SCN)
Superior to optic chiasm, receives input from optic nerves
(RHT); this input synchronizes the “clock” in the SCN to
the exterior day-night cycle
Fig-:Saggittal section of brain
• When light falls on the eye, afferent nerves arising from the
retina of the eye transmit the light signals directly through
retinal hypothalamic tract to the paired suprachiasmatic
nuclei situated in the hypothalamus and pineal gland.
• Biological clock since found is represented by
suprachiasmatic nuclei , which creates biological rhythms
under control of clock genes

8. MOLECULAR FUNDAMENTALS OF CIRCADIAN CLOCKS
P
P
P P
Transcriptional-translational Feedback loop

9. MOLECULAR FUNDAMENTALS OF CIRCADIAN CLOCKS
CLOCK (circadian locomotor output cycles kaput)
BMAL1 (brain and muscle Arnt-like protein-1)
PARbZip(proline
and acidic amino acid–rich basic region/leucine
zipper protein)
PER (period)
POR(cytochrome P450 oxidoreductase)
ROR(retinoic acid receptor–related orphan
receptor)

10. CHRONOPHARMACOLOGY

11. • The study of rhythmic, predictable-in-time differences in the effects of
drugs both in experimental animals and in men.
• It investigates the effects/side effects of drugs upon temporal changes in
biological functions or symptoms of a disease as well as drug effects as
a function of biologic timing.
• It is defined as an investigative science concerned with the biological
rhythm dependencies of medication.
CONT….
Definition ????

12. • Chronopharmacolgy subdivided into 4 categories:-
 Chrono pharmacokinetics(ADME)
 Chronotoxicity (The toxic effect of drug on the organism, which is
undesirable and affects the rhythmic system.)
 Chronesthesy(doseing schedule of drugs according to the biological
rhythm/clock)
 Chronotherapy(whole therapy of particular disease depending upon
biological rhythum)

13. APPLIED CHRONOPHARMACOLOGY

14. CHRONOPHARMAKINETICS
• Chronopharmacokinetics 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.
• The main aim of chronokinetic studies is to control the time of
administration which can be responsible for variations of drug kinetics
but also may explain chronopharmacological effects observed with
certain drugs.

15. NEED OF CHRONOKINETIC STUDY
• When possible daily variations in pharmacokinetics may be responsible for time
dependent variations in drug effects (e.g. some antimicrobial agents are more
effective at a specific time of day),
• When drugs have a narrow therapeutic range .
• When symptoms of a disease are clearly circadian phase-dependent (e.g.
nocturnal asthma, angina pectoris, myocardial infarction, ulcer disease).
• When drug plasma concentrations are well correlated to the therapeutic effect in
case the latter is circadian phase dependant.

16. Disease Rhythm

17. Peak time functions

18. DRUGS UNDERGOING CHRONOKINETICS:
Antibiotics :
• Important aspect of chronokinetics in antibiotics is that not only the efficacy of
the drug may increase but also the toxicity of certain drugs may decrease at
different time of day.
Aminoglycosides:
• Renal toxicity of aminoglycosides can be reduced by giving the drug as a single
daily injection when patients are active (at day time or in other words in the
activity period)
Eg: gentamycin, tobramycin, amikacin

19. CVS
Myocardial infarction,
acute cardiac arrest ,
transient myocardial
ischemia
Onset – early morning –
34% events
Reason – release of
catecholamines, cortisol,
increase in platelet
aggregation, vascular tone,
heart rate surge.
MORNING HOURS
INCREASED PLASMA
NOREPINEPHRINE ,
CORTISOL AND RENIN
ACTIVITY
INCREASED
SYMPATHETIC TONE
INCREASED PLATELET
AGGREGABILIGY AND
DECREASED
FIBRINOLYTIC
ACTIVITY

20. Objective- To deliver drug in high concentration when its great need
required.
ACE inhibitors
Nifedipine
Amlodipine
Night

21. Anti hyperlipidemic drugs
• More Cholesterol systhesis takes place in the evening than in the
morning.
• The enzyme HMG Co-A Reductase is required to reduce hydroxy 3-
methyl glutaryl Co-A to mevalonate in the synthesis of cholesterol.
• This enzyme is competitively inhibited by HMG Co-A Reductase
inhibitors (Statins)
• Hence statins should be administered at evening rather than at
morning for increased efficacy.

22. Antiasthmatic drugs :
• Asthma is attacked more frequently in night hours.
• Lungs are more sensitive to bronchoconstrictor substances such as
Acetylcholine, Histamine, house mite dust, grass propellers, at night time
than day time. It is treated by antiasthmatic drugs.
Ex:-Theophylline, beta sympathomimetics.
• Theophylline must be given in higher doses during the night time than day
time.
Antiulcer drugs :
• Gastric acid secretion is highest at early night or late afternoon.
• H2 blockers like Ranitidine ,cimetidine ,famotidine should be taken once a
day in the late afternoon or early night when acid secretion is more.

23. Applied Chronopharmacology
Endocrine system
Corticosteroids
Congenital adrenal
hyperplasia
Bedtime
corticosteroid
dosing controls
excessive hormone
secretion
Bedtime ADH analogue
dosing helps to alleviate
nocturnal bedwetting in
children and nocturia in
adults.

24.  Cancer cells are considered to have lost internal time keeping mechanism.
 Tumor cells and normal cells differ in their chronobiological cycles.
(The basis for the chronopharmacotherapy of cancers.)
 The DNA synthesis in the normal human bone marrow cells has a peak
around noon while the peak of DNA synthesis in lymphoma cells is near
midnight.
 So, an s-phase active cytotoxic therapy at late nights should be more
advantageous.
conti….

25.  A comparison study* included 118 children received maintenance chemotherapy
of mercaptopurine and methotrexate around the period from 1976 to 1984
 It was found that the risk of relapse was 2.56 times higher in children who
received chemotherapy in the morning than in those receiving in the evening.
*Circadian time dependent response of childhood lymphoblastic leukemia to chemotherapy: A long-term follow-up study of survival.
Chronobiology International, 10(3): 201-4.

26. NSAID’s & Arthritis
• Patients with osteoarthritis tend to have less pain in the morning and
more at night; while those with rheumatoid arthritis, have pain that usually
peaks in the morning and decreases throughout the day.
• Chronotherapy for all forms of arthritis using NSAID’s such as ibuprofen
should be timed to ensure that the highest blood levels of the drug
coincide with peak pain.
• For osteoarthritis sufferers, the optimal time for a non- steroidal anti-
inflammatory drug such as ibuprofen would be around noon or mid-
afternoon.
• The same drug would be more effective for people with rheumatoid
arthritis when taken after the evening meal.

27. Opiod analgesics
• Stronger analgesic effects were observed when tramadol and
dihydrocodeine were applied in the evening to relieve painful stimuli.
• Peak morphine use occurred at 9 a.m. and least use at 3 a.m.

28.  Melatonin – secreted at night by pineal gland.
 Function – synchronizes sleep wake cycle with circadian
rhythm.
 Melatonin agonist [Ramelteon] – hypnotic for sleep onset
insomnia.
 Reduces Jet lag symptoms.
 Bedtime administration of hypnotics- more
effective.

31.  Effectiveness and toxicity of a drug are not constant over 24 hr period.
 Understanding the biological rhythms can optimize and individualize drug
therapy to a great extent. Thus it can help to decrease the drug related toxicity
and enhance effectiveness.
 To monitor rhythmic markers such as clock genes it may be useful to choose
the most appropriate time of day for administration of drugs that may increase
their therapeutic effects and reduce their side effects.