This document provides an overview of chronopharmacology, which studies the effects of drugs on biological rhythms. It discusses circadian rhythms and zeitgebers that modulate them. The molecular basis, modulators, and physiological variations related to circadian changes are examined. Disease patterns due to circadian disruptions and divisions of chronopharmacology involving pharmacokinetics, pharmacodynamics, therapeutics, and toxicity are summarized. Applied areas like asthma treatment and delivery systems are reviewed. The conclusions emphasize that circadian biology influences pharmacology and identifying rhythmic markers can improve drug effects and reduce side effects.

1. Chrono
Pharmacology
Dr. Anirudha Potey

2. Flow of the seminar
• Definition
• Biorhythms
• The Biological Clock
• Circadian Rhythm
• Zeitgebers
• Molecular Basis
• Modulators
• Physiologic Variations
• Disease pattern
• Divisions of Chronopharmacology
• ChronoPharmacokinetics
• ChronoPharmacodynamics/
Chronesthesy
• ChronoTherapeutics
• ChronoToxicity
• Chrono Drug Delivery Systems
• Applied Chronopharmacology
• Chronopharmacology in Ayurveda
• Conclusion

4. Definition
The investigative science concerned with the effects of drugs upon the
timing of biological events and rhythms.
It also links effects of drugs due to variations in the biological rhythms.

5. Ultra
radian
Cir
cadian
Infra
radian
Circa
Septan
Circa
Di
Septan
Circa
Vi
gintan
Circa
Tri
gintan
Circa
Annual
Biorhythms
T<20 h 20h<T<28 h T = 7 dT>28 h T = 1 yT = 30 dT = 21 dT = 14 d

6. The Biological Clock/ Circadian Rhythm

7. SCN Input Light
SCN Output Sleep/Wakefulness
Feeding and Energy
Expenditure
Glucose Homeostasis
Hormonal Regulation
Blood Pressure &
Respiratory changes
Peripheral Clocks
Input
Feeding/ Fasting
Signals from SCN
Peripheral Clocks
Output
Lipogenesis
Insulin Secretion
Glucose Clearance
Food Absorption
Fat Accumulation

8. Zeitgeber

9. Zeitgeber
Light – Darkness
Warmth – Cold
Eating – Fasting
Social Contact – Isolation
Noise – Quiet
Pharmacological Manipulation

10. Shift Work Jet Lag

11. Molecular Basis of Circadian Rhythm

13. E Box
PER 1
PER 3
PER 2
CRY 1
CRY 2
REVERB
WD40
NONO
CK1
WDR5

15. Circadian rhythm modulators
• REVERB agonists – SR9009
• CK1 inhibitor – Longdaysin, LH846
• GSK3b inhibitor – Indirubin

16. Physiologic variations in relation to Circadian
changes

19. Disease pattern due to circadian changes

21. ChronoPharmacokinetics
Subdivision of chronopharmacology which deals with the study of the
temporal changes in the pharmacokinetics of the drugs with respective
time.

22. Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics

23. Factors affecting pharmacokinetic variations
Gastric acid secretions and pH
Gastric motility
g.i blood flow
Drug protein binding
Liver enzyme activity
Hepatic blood flow
Glomerular Filtration Rate
Renal Blood Flow
Urinary pH
Tubular resorption

24. Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics
Diazepam
Acetaminophen
Theophylline
Digoxin
Propanolol
Nitrates
Nifedipine
Amitriptyline

25. Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics

26. Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics

27. Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics

28. Serum Concentration

29. Clearance

30. ChronoPharmacodynamics
Chronesthesy
Biological rhythms at the cellular and subcellular level can give rise to
significant dosing-time differences in the pharmacodynamics of
medications that are unrelated to their pharmacokinetics.

31. ChronoPharmacodynamics

32. ChronoTherapeutics
Discipline of medical treatment which allows for the consideration of a
patient’s biological rhythm, changes in the severity of a disease state
during the day, and the synchronizing of dosing and delivery of a
particular drug to allow for the optimal efficacy in the patient.

33. ChronoToxicity
Predictable- in-time variation in patient vulnerability to the side effects
of medications due to biological rhythm determinants.
Eg. irinotecan hydrochloride.

34. Chrono Drug Delivery Systems (Chrono-DDS)
OROS, CODAS, CEFORM, TIMERx, POLYMERS, MICROCHIPS

35. Applied Chronopharmacology

36. Asthma

39. Euphylong UniphylTheophylline SR

40. Allergic Rhinitis

44. Arthritis

45. Peptic Ulcer

47. Metabolic Disturbances

48. Myocardial Infarction

49. Hypertension

50. Valsartan

52. Antidepressants

53. Anticancer Drugs

55. Chronopharmacology in Ayurveda
Abhakta Drugs in morning absorption is maximum and more efficient
Pragbhakta Just before food. For diseases of apana vayu – for strengthening and
preventing the disease of lower half of body and treating obesity.
Madhyabhakta In between foods. For diseases of samana vayu, disease of koshtas and
for paittic diseases.
Sanya
Pscadbhakta
In evenings after food. For diseases of udana vayu.
Muhurmuhuh Drugs given repeatedly for treating swasa (dyspnoea), kasa (cough),
hikka (hiccoughs), chardi (vomitting), visa (poisoning) and pipasa
(Thirst).
Samudga Before and after light food in hikka, akepsa(convulsions) and in diseases
of head and neck.
Sabhakta Drugs as appetizers with food, in children with weak constitution.

56. Conclusions
• Circadian biology influences nearly every aspect of physiology and
pharmacology.
• Ongoing research has begun to unveil the molecular mechanisms by which
circadian clock genes regulate pharmacokinetic and pharmacodynamic
processes.
• Many drugs are still given without regard to the time of day.

57. Conclusions
• Identification of rhythmic markers for selecting dosing time and further
research in the field of chronopharmaceuticals will lead to improved
progress and diffusion of chronotherapeutics.
• 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/or reduce their side effects.

58. Conclusions
• To produce new rhythmicity by manipulating the conditions of living organs
by using rhythmic administration of altered feeding schedules or several
drugs appears to lead to a new concept of chronopharmacotherapy.
• One approach to increasing the efficiency of pharmacotherapy is
administering drugs at times during which they are most effective.