Chronopharmacology

1. Dr. Seema Bansal

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

3. Chronobiology-
 Chronos (time),
 Bios (life),
 Logos (study).
 The science dealing with the phenomenon of
rhythmicity in living organisms is called
CHRONOBIOLOGY.

5. 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.

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

7. 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

8. 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.
sleep-wake cycle

9. BIORHYTHMS
 External cues which reset the circadian clock =
ZEITGEBERS = synchronizers
 Definition-Endogenously generated, and can be
entrained by external factors, called zeitgebers.
 LD- Light-Darkness
 EF- Eating-Fasting
 SI- Social Contact- Isolation
 NQ- Noise-Quiet

10. 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).

11. Regulatory System-

12. In medicine 3 disciplines taken
account acc. To time-
 - CHRONOPHYSIOLOGY
 - CHRONOPATHOLOGY
 - CHRONOPHARMACOLOGY
•Chronotherapeutics
•Chronokinetic
•Chronesthesy
•Chronergy
•Chronotoxicity

13. Chronotherepeutics-
 New technology makes possible
CHRONOTHERAPY
(=CHRONOTHERAPEUTICS), that is, increase of
the efficiency and safety of medications by
proportioning their concentrations during the 24
hours in synchrony with biological rhythm
determinants of disease.

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

15. Chronergy-
Rhythmic difference in effects of drug on the
organism as a whole which 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 antitumor agents
 Irinotecan induced leucopenia is more pronounced.

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

17. 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.

18.  Progesterone in the later half inhibit the enzymes
responsible for spread of cancer cells.
 Cancer drug administered more in night time,
because cancer cells divide more in night time.
 But not all, Treatment with 6-mercaptopurine and
methotrexate , evening dose is given to patient.
 Colorectal cancer- Oxaliplatin is given in during
daytime & flurouracil at night.

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

20. 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 04:00.

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

22.  Stroke-
B.P rises about 20% immediately after awakening & 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

23.  Graphical explanation-

24. Treatment-
 A new COER verapamil use in HT
It is formulated as a pill with a shell that dissolves
slowly. Taken at bed-time, this exerts peak effects
btw 5 am and noon & no mid-night dip in B.P is
seen.
 Diltiazam- once in a morning strong influence in
evening.

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

26. 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.

27. Treatment-
 Once-daily, non-sedating antihistamine (like;
Chlorpheniramine 10-20 mg) by giving it before
bedtime to control overnight exacerbations and
during sleep
 Morning oral corticosteroid therapy for severe
allergic rhinitis.

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

29. 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.

30. 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.

31. 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.

33. ThankX !!