chronopharmacology credit seminar by Pankaj.N.Kapgate

1. Presented by:
PANKAJ KAPGATE
M. V.Sc [Pharmacology] 2nd Yr.
NAGPUR VETERINARY COLLEGE
DEPARTMENT OF VETERINARY
PHARMACOLOGY AND TOXICOLOGY
WELCOMES
CREDIT SEMINAR
ON
Under the guidance of
DR. C.R. JANGDE

2. overview
Introduction
What Is Chonopharmacology
Chronobiology
Biologycal Rhythm
Types Of Rhythm
Biorythm
Biologycal Clock
Application And Uses
Drug Delivery System
Conclusion

3. What is Chronopharmacology ?
It is the science concerned with the
variations in the pharmacological actions of
various drugs over a biological timings &
endogenous periodicities.
Introduction

4. Pharmacology-
• It is the science of drugs.
Phamacon - (Drug),
Logos – (study)
• It deals with the interaction of administered Chem.
molecule (Drug) with living systems.
• But most importantly those that are relevant to
effective and safe use for medicinal purposes.

5. Chronobiology-
 Chronos (time),
 Bios (life),
 Logos (study).
 The science dealing with the phenomenon of
biological rhythmicity in living organisms is called
chronobiology (Halberg,1969).

6. Biological Rhythm-
 A determined rhythmic biological process or
function.
 A biological rhythm is a self-sustaining oscillation
with the duration of time between successive
repetitions (i.e; the period) being rather non-varying
under normal conditions.

7. Example-
CIRCADIAN RHYTHM:
 Circadian (circa – about or approximately; dies, day,
or about 24 hour).
 Oscillations in the biological, physiological &
behavioral functions of an organism with a
periodicity of 24 hrs.

8. Continue…
 Circadian rhythms are particularly important in
medicine.
 A circadian clock in the brain coordinates daily
physiological cycles.
– sleep/wake - digestion
– temperature - hormones
 Physiological day is about 24 hours .
– Clock is reset daily by the environment .
• day/night
• social schedules

9. Types of Rhythm-
Ultradian ( <20h): cycles shorter than
a day e.g. micro sec. for a neuron to fire.
Circadian (20<  <28h):Lasting for
about 24 hrs. e.g. sleep and wake cycles.
Infradian (≥28 h): Cycles longer than
24 hrs e.g. menstrual cycle, estrous
cycle.
sleep-wake cycle

10. Biorhythms-
 Defination- Endogenously generated, and can be entrained
by external factors called zeitgebers.
 ZEITGEBERS- reset the circadian clock
LD- Light-Darkness
EF- Eating-Fasting
SI- Social Contact- Isolation
NQ- Noise-Quiet

11. Biological Clock-
 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).

12. Biological Clock-

13. Regulatory System-

15. In medicine 3 disciplines are taken into
account according. to time-
1) - CHRONOPHYSIOLOGY
2) - CHRONOPATHOLOGY
3) - CHRONOPHARMACOLOGY
A. Chronotherapeutics
B. Chronokinetic
C. Chronesthesy
D. Chronergy
E. Chronotoxicity

16. A) Chronotherepeutics-
New technology makes possible CHRONOTHERAPY
(=CHRONOTHERAPEUTICS) -The efficiency and safety of
medications is increased by proportioning their
concentrations during the 24 hours in synchrony with
biological rhythm determinants of disease.

17. B) Chronokinetic-
Time dependent and predictable changes in PK parameter .
C) Chronesthesy-
Circadian or other systemic changes in the susceptibility and
sensitivity of the target system to a drug.

18. C) Chronergy-
Rhythmic difference in effects of drug on the organism as a
whole which includes both desired and undesired effects.
D) Chronotoxicity-
The toxic effect of drug on the organism, which is
undesirable and affects the rhythmic system. Specifically
with antitumor agents.

19. Chronotherapy found useful in:
 Oncology,
 Asthma therapy,
 Hypertension,
 Strokes,
 Sleep apnea,
 GI tract disorders,
 Allergies.
Applications & Uses-

20. Cancers-
 Different biological rhythms for normal and tumor cells.
 Appropriate timing.
 Cancer Cells
1.Duration of the phase of cell cycle.
2.Cell proliferation rate.
TATO (theoretical analysis of treatment outcome)
 Tumor: fast growing-2 am, slow growing-10 pm
 Later half of the menstrual cycle have more clearance rate then
early half of the cycle.

21.  Progesterone in the later half inhibit the enzymes responsible for
spread of cancer cells.
 As cancer cells divide more in night time therefore anticancer
drugs may be advised in night time.
 Treatment with 6-mercaptopurine and methotrexate drugs
should be administered in the evening.
 Colorectal cancer- Oxaliplatin is given during daytime &
5-flurouracil at night hours.

22. Asthma- The risk of asthmatic attack is almost 70 times
higher in patients at 04:00-05:00am in the morning, compared
with the afternoon.
Causes :
•Exogenous factors-
 Allergen exposure,
 Dust and pollution,
 temperature changes during the day,
 position during sleep.

23. Endogenous factors- Small bronchi diameter significantly
increases during the day and decreases at night b’coz-
 Adrenergic blockade of ß-receptors,
 Dominance of alpha-adrenergic pathways,
 Cholinergic dominance,
 Smallest conc. of Ig E and
 Highest concentration of histamine around 04:00am.

24. Treatment advise -
SR formulation of theophyline once daily
 Increase efficacy
 Avoid multiple dosing
Nocturnal vagus nerve hyperactivity
Relieved by cholinergic antagonist
eg. Ipratropium bromide
oxitropium bromide

25. Stroke-
B.P rises about 20% immediately after awakening and is least
during sleep.
1st two hours after arising are the peak hrs. for MI,
hemorrhagic stroke & thrombotic infarcts.
Reasons - ↑ physical activity (sudden)
- ↑ catecholamine levels
- ↑ platelet aggregation
- ↑ vascular tone

26. Graphical explanation-

27. Treatment advise-
 A new formulation of verapamil is in
use for hypertension.
It is formulated as a pill with a shell that
dissolves slowly. Taken at bed-time, this
exerts peak effects between 5 am and
noon & no mid-night dip in B.P is seen.
 Diltiazam- Once in a morning influences
strongly in evening.

28. Peptic Ulcer-
 Pathogenesis- Helicobacter pylori
and H+ ions secretion by the
stomach.
 Acidity(H+) peak-evening.
 Treatment-
 H2blockers (Ranitidine, Cemitidine,
famotidine) Once daily given in the
evening.

29. Allergic Rhinitis-
 Rhinitis- worst in the morning and
evening.
 It is a Type-I (Anaphylactic) reaction,
in which antibodies (Ig E) are
produced which get fixed to the mast
cells. On exposure to antigen, AG:AB
reaction takes place on mast cell
surface releasing Histamine, -HT, LTs,
PGs etc.
 Resulting in urticaria, itching,
bronchiospasm, rhinitis like conditions.
 Immediate Hypersensitivity.

30. Treatment advise-
 As per chronopharmacology drug should be prescribed
Once-daily, non-sedating antihistaminic (like;
Chlorpheniramine 10-20 mg) be given before bedtime to
control overnight exacerbations and during sleep.
 Oral corticosteroid therapy for severe allergic rhinitis should
be prescribed in morning .

31. Drug delivery systems-
1. Enteric-coated systems
2. Pulsatile drug dilivary systems
3. Membrane diffusion controlled systems
4. Osmotic systems
5. Compression coated system
6. Layered system

32. Recent Advances-
 Due to advances in chronobiology, chronopharmacology, and
global market constraints, the traditional goal of pharmaceutics
(e.g. design drug delivery systems with a constant drug release
rate) is becoming obsolete.
 However, the major bottleneck in the development of drug
delivery systems that match the circadian rhythm
(chronopharmaceutical drug delivery systems: ChrDDS) may be
the availability of appropriate technology.

33. Continue…
 The last decade has witnessed the emergence of ChrDDS against
several diseases. The increasing research interest surrounding
ChrDDS may lead to the creation of a new sub-discipline in
pharmaceutics known as chronopharmaceutics.

34. Conclusion
Chronotherapy will certainly improve treatment outcome and
optimize disease management in the future.
Selection of the appropriate chronopharmaceutical technology
should take into considerations the application range (e.g.
targeted drugs of different physico-chemical properties), the ease
of manufacturing, the cost-effectiveness, and the flexibility in the
pharmacokinetic profile.

35. Cont…
 Ideal ChrDDS should be
1)Self regulating
2)Can be taken any time of the day and
3) Should take environmental factors into account (e.g. awake–
sleep, light–dark, activity–rest status).

36. Futuristic Approach-
 Future development in chronopharmaceutics may be made at the
interface of other emerging disciplines such as-System biology
and Nanomedicine.
 Such novel and more biological approaches to drug delivery may
lead to safer and more efficient disease therapy in the future.

37. Bibliography
Bi-Botti C. Youan,(2010) Chronopharmaceutical drug delivery
systems: Hurdles, hype or hope? Advanced Drug Delivery
Reviews 62. pp.898–903.
CONVINCE trial. JAMA april 23-30, 2003. vol. 289, no. 16.
Halberg.F,(1969) Chronobiology. Ann Rev Physio 31:pp.675-725.
Lemmer B. (1999) “Chronopharmacokinetic:implication for drug
treatment”. journal of pharmacy and pharmacology.vol. 51
issue 8 pages 887-90.
Maurya.K.K.,Semwal.B.C.,Neelam.S.,Shrivastava.V.,Ruqsana.K.
(2012)“Chronopharmacology:A Tool For Therapy Of
Disease.International Research Journal Of Pharmacy.IRJP
2012,3(5)

38. Ohdo S. (2007) “chronopharmacology focused on biological
clock”. Drug metab. Pharmacokinet.22(1):3-14
Ohdo.S,(2010) “Chronotherapeutic strategy: Rhythm monitoring,
manipulation and disruption”. Advanced Drug Delivery
Reviews 62. pp.859–875.
Sattwa.A., Mandal, Biswas.N., Kazi.M.K., Guha.A.,
Chatterjee.S.,Behera.M., Kuotsu.k,(2010) “Drug delivery
system based on chronobiology—A review”. Journal of
Controlled Release 147. pp.314–325.
Sharon M. Miller, (1996) “Cover story: Its about time:a
chronobiological approach to healthcare”. the free library of
farelex.

39. QUISTIONS

40. ThankX !!