Chronopharmacology

1. CHRONOPHARMACOLOGY
Presented by
Dr. Sajeena Jose. C
Department of Pharmacology
Amala Institute of Medical Sciences

2. INTRODUCTION
• The physiological parameters shows a rhythmic
change, mostly synchronized with the periodic
changes in the environment. biological rhythm.
• They do not behave constantly in time, but varies
with changing external cues like day-night cycle.

3. BIOLOGICAL RHYTHMS
• Circadian: Lasting for about 24 hours. -Sleep wake
cycles
• Infradian: Cycles longer than 24 hours. -Menstrual
cycle
• Ultradian: Cycles shorter than a day. -Neuronal firing
time
• Seasonal: Seasonal affective disorders.

4. HISTORY
• Jean-Jaques d’Ortous de Mairan : described circadian
rhythms of plants in the 18th century.
• Franz Halberg coined the term ‘Circadian’ in 20th
century. (circa – about or approximately; dies-day, or
about 24 hour).
• Considered as one of the founders of Modern
Chronobiology.

5. DEFINITIONS
• Chronobiology - The branch of science focusing on
biological rhythms and their mechanisms. Chronos-
time, Bios- life, Logos -study.
• Chronopharmacology - Science dealing with
optimization of drug effects & minimization of
adverse effects by timing medications in relation to
biological rhythm. It is concerned with the effects of
drugs upon the timing of biological events and
rhythms.

6. THERAPEUTIC APPLICATIONS
RESPIRATORY SYSTEM
• Increased broncho constriction at night.
↑Parasympathetic tone
↓ Adrenaline
↓ Cortisol at midnight
↑Sensitivity to irritants and allergens at night
-exacerbations of allergic rhinitis & asthma

7. ASTHMA
• Acute attack of asthma - more common between midnight
and 6 am.
• Theophylline and Beta 2 agonist is timed at evening
• CONTIN- Complex formed between cellulose polymer
and non polar solid aliphatic alcohol which act as matrix

8. CARDIOVASCULAR SYSTEM
• BP peaks between 6am and 9am, and 6pm and 7 pm.
• BP dips at night, decreases slightly afternoon.
• Diastolic BP varies more than systolic

9. NIGHT TIME DIP

10. MORNING RISE

11. CARDIOVASCULAR DISORDERS
Myocardial infarction
Sudden cardiac death
Angina pectoris
Transient ischemic attacks / Stroke
• High incidence between 6am and 12 noon.
↑ Vascular tone
↑ Platelet aggregation
↓ Intrinsic thrombolytic activity.

12. • Aspirin – maximum antiplatelet effect in the
morning.
• Thrombolytics and Heparin – ↓ benefit during
early morning hours.
• Atenolol – more effective during day time.
• Labetalol – more effective in early morning hours.
• Enalapril- Peak effect in the afternoon after morning dose,
early morning after evening dose.

13. ENDOCRINE SYSTEM
• Highest secretion of cortisol early morning.
• Lowest at midnight.
• GH peaks during sleep.
• Testosterone peaks early morning.
• TSH peaks at mid night.
• Corticosteroids given as single morning dose cause less
pituitary adrenal suppression

14. DIABETES
• Insulin – regular pulses every 5 – 15 min.
• Non diabetics: ↓ glucose tolerance in the later part of
the day.
- ↓ utilization
-↓ insulin sensitivity
• T2 DM: progressive glucose tolerance from morning
to evening.
- higher dose of insulin in the morning.

15. GASTROINTESTINAL TRACT
• Acid secretion peaks between 10 pm and 2 am.
• Ulcer pain is worst at this time.
• Ulcer healing is directly related to acid secretion
inhibition at night.
• Evening dosage of H2 receptor antagonists

16. CNS
• 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.

17. MUSCULOSKELETEL SYSTEM
Rheumatoid Arthritis
• Symptoms more severe - 8am & 11am.
• Long acting NSAIDS at bed time
Osteoarthritis
• Pain more intense between 2 pm and 8 pm.
• Morning dose for afternoon worsening, evening dose
for night time worsening

18. CANCER
• 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.

19. COLORECTAL CANCER
• Continuous infusion over 24 hrs
• Oxaliplatin during day time, Folinic acid & Flurouracil at
night.(chronotherapy group )
• Statistically significant differences in complete and partial
remission rates between the constant-infusion group (29%)
and chronotherapy group (51%) were found.
• Doxorubicin – last stage of sleep / before normal waking time.
• Cisplatin: Maximum toxicity and kidney damage in the
morning.

20. SKIN DISORDERS
• Psoriasis: cell proliferation rate peaks between 9pm &
3am.
-Inflammatory activity highest at night, least in the
morning.
• Atopic dermatitis: sensitivity to histamine highest at
night.

21. • Lignocaine: Skin penetration at 11am twice that at
8am.
• Topical corticosteroids: activity in the afternoon
higher than that in the morning.

22. CHRONO DRUG DELIVERY SYSTEMS

23. Design and development of ChrDDS

24. Chronopharmaceutical Technologies
• CONTIN technology
• Physico-chemical modification of the API
• OROS technology
• CODAS technology
• CEFORM technology
• DIFFUCAPS technology
• Chronomodulating infusion pumps
• TIMERx technology
• Other CR erodible polymers
• Controlled-release microchip

25. Marketed Drugs
FDA approval
date
API Propriatory
name;
dosage form
Chronopharmac
eutical
technology
Indication
Sept. 01,1982 Theophylline Uniphy CONTIN ASTHMA
Oct. 15, 1986 Famotidine PepcidR; tablets Physico-chemical
modification of
API
ULCER
Dec. 23, 1991 Simvastatin ZocorR; Tablets Physico-chemical
modification of
API
HYPERCHOLES
TRELEMIA
Feb. 26,1996 Verapamil HCl Covera-HSR
Tablet
OROS HYPERTENSIO
N
Nov. 25, 1998 Verapamil HCl VerelanRPM;
Capsule
CODAS HYPERTENSIO
N
Feb. 06, 2003 Diltiazem HCl,
Verapamil HCl
CardizemR LA;
Tablet
CEFORM HYPERTENSIO
N

26. FUTURE DIRECTIONS
• One of the major challenges in Chronopharmacology
is the Identification of Circadian Oscillations at the
protein level.