Chrono Pharmaco L

CHRONOPHARMACOLOGY
- Dr Mangala Nischal
- 2nd yr PG
- M D pharmacology
Overview
• Introduction
• History
• Definitions
• Circadian rhythm & clock genes
• Applications of Chronopharmacology
• Chronopharmaceutics
• Conclusion
• References
Introduction :
- facets of mammalian physiology and behavior vary according to time-
• Most
of-day, thanks to an endogenous “circadian” clock.
• Daily oscillations of proteins is necessary for either drug absorption
or metabolism result in circadian pharmacokinetics; and oscillations in
the physiological systems targeted by these drugs result in circadian
pharmacodynamics.
• Circadian clocks influence all major organ systems, and this influence
translates directly into disease pathology that also varies with time of day.
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; dian-day,
or about 24 hour).
• Considered as one of the founders of
Modern Chronobiology.
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.
Biorhythm
s
Circa
Circa Circa
Ultra Cir Infra Circa Tri Circa
Di Vi
radian cadian radian Septan gintan Annual
Septan gintan
T<24 h T~24 h T>24 h

T = 7 T = 14 T = 21 T = 30 T = 1
d d d d y
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.
• Subdivided into
- Chronopharmacokinetics
- Chronotoxicity
- Chronesthesy
- Chronotherapy
Chronopharmacokinetics :
• It deals with the study of the temporal changes in the pharmacokinetics

of the drugs with respective time.
• Study of absorption, distribution, metabolism, and excretion of
drug according to the time of the day or year.
• Chronesthesy
• The rhythmic changes in susceptibility or sensitivity of a
target system to a drug.

• Chronergy
Rhythmic changes of both the desired [effectiveness] and undesired
[toxicity, tolerance] effects on the organism as a whole.

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.
• Refers to concept of matching timing of treatment with intrinsic timing of

illness.
Advantages
• Prevents over dosage
• Appropriate usage of drug
• Reduce side effects
• ChronoPharmaceutics
- Branch which designs and develops a drug delivery system in
accordance with biological rhythm to optimize the treatment of
disease.
Circadian rhythm
• The basic unit of circadian timekeeping
is the…
• Supra chiasmatic nucleus
• Clock genes
Zeitgeber
Circadian rhythms are driven by endogenous processes, are
self-sustaining, and rely upon circadian time cues (zeitgebers)
to remain appropriately oriented to the individual's
environment and desired routine.

Circadian clock
• Input Signal transduction - Retinohypothalamic tract (Photic
Zeitgeber)
• Rhythm generator - Central clock in the suprachiasmatic nucleus

(SCN) in the hypothalamus, and its peripheral tissues serve as the
peripheral clock.
• Output signal transduction - to perform biochemical or physiological

roles in a circadian manner.
Clock Genes :
• Circadian rhythms are driven by a group of genes called clock genes.
• In mammals, the core clock genes consist of Bmal1 (Brain and muscle aryl-
hydrocarbon receptor nuclear translocator-like 1), CLOCK (Circadian
Locomotor Output Cycles Kaput), Per (Period), and Cry (Cryptochrome).
• They form a tightly regulated system with interlocking feedback and feed-
forward loops.
Applications of
Chronopharmacology
Respiratory
system
Increased bronchoconstriction at night due to…
↑Parasympathetic tone
↓ Adrenaline
↓ Cortisol at midnight
↑Sensitivity to irritants and allergens at night
 exacerbations of allergic rhinitis & asthma

Asthma
• Acute attack of asthma

- more common between midnight and 6 am.
• Rx - Theophylline and Beta 2 agonist is timed at evening

CVS-
Night time dip
Morning rise
Cardiovascular Disorders
• Myocardial infarction
Sudden cardiac death
Angina pectoris
Transient ischemic
attacks / Stroke
High incidence
between 6am and
12 noon.
• ↑ Vascular tone
• ↑ Platelet
aggregation
Cardiovascular drugs
• 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.

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
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 or PPI.

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 - more effective.

Musculoskeletal
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.
Hypercholesterolemia
• Cholesterol synthesis more at night.
• Evening dose of HMG CoA reductase inhibitors is more effective.

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...
Lymphoma
• 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
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.
• Topical corticosteroids: activity in the afternoon higher than that in

the morning.
ChronoPharmaceutics
Design and development of Chrono drug delivery
system :
Chrono Drug Delivery Systems (Chrono-
DDS)
OROS, CODAS, CEFORM, TIMERx, POLYMERS,

MICROCHIPS, DIFFUCAPS
Chronopharmaceutical technologies:
• Parenteral routes in chronotherapy include
-Chronomodulating infusion pumps (i.e. Melodie™, Panomat™
V5, Synchromed™, Rhythmic™)
- Controlled-release microchips
• Oral administration include
-Contin™, Chronset™, Codas™, Ceform™, Diffucaps™,
TIMERx®, Chronotopic™, Egalet™, GeoClock™, Port™, Three-
dimensional printing (3DP)™
- methods involve physico-chemical modification of the active
pharmaceutical ingredient and/or the use of controlled-release erodible
polymer .
• Pulsatile drug delivery systems: Here a targeted drug is deliverd
at specific site due to induction of certain physiochemical stimuli at
target site.
• Release of certain enzymes, hormones, antibodies, pH of the site,
temperature of the site, presence of certain cells, and concentration
of biomolecules (glucose, neurotransmitters, inflammatory
mediators) act as stimuli to trigger the release of drug from these
types of drug delivery systems.
• Recently, a novel floating pulsatile system - high internal phase

emulsion based porous material.
Marketed technologies of pulsatile drug delivery
Conclusion
• 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.
References :
• Maurya K.K et al. Chronopharmacology: A tool for therapy of
diseases.IRJP 2012,3(5):128-132
• Youan B-BC. Chronopharmaceutical Drug Delivery Systems: Hurdles,
Hype or Hope? Advanced drug delivery reviews. 2010;62(9-10):898-
903. doi:10.1016/j.addr.2010.04.010.
• Chen L and Yang G (2015) Recent advances in circadian rhythms in
cardiovascular system. Front. Pharmacol. 6:71. doi:
10.3389/fphar.2015.00071
• V S Chopra et al. Chronotherapy: A Novel Concept In Drug Delivery
Der Pharmacia Lettre, 2010, 2(3): 136-153.
Thank you

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CHRONOPHARMACOLOGY

• Jean-Jaques d’Ortous de Mairan

• Franz Halberg coined the term ‘Circadian’

• Infradian: Cycles longer than 24 hours.

• Ultradian: Cycles shorter than a day.

• Seasonal: Seasonal affective

T<24 h T~24 h T>24 h

• It deals with the study of the temporal changes in the pharmacokinetics

• The rhythmic changes in susceptibility or sensitivity of a

target system to a drug.

Rhythmic changes of both the desired [effectiveness] and undesired

[toxicity, tolerance] effects on the organism as a whole.

• Refers to concept of matching timing of treatment with intrinsic timing of

- Branch which designs and develops a drug delivery system in

accordance with biological rhythm to optimize the treatment of

• The basic unit of circadian timekeeping

• Supra chiasmatic nucleus

Circadian rhythms are driven by endogenous processes, are

self-sustaining, and rely upon circadian time cues (zeitgebers)

to remain appropriately oriented to the individual's

environment and desired routine.

• Rhythm generator - Central clock in the suprachiasmatic nucleus

• Output signal transduction - to perform biochemical or physiological

↑Sensitivity to irritants and allergens at night

 exacerbations of allergic rhinitis & asthma

• Acute attack of asthma

• Rx - Theophylline and Beta 2 agonist is timed at evening

• 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.

• Ulcer pain is worst at this time.

• Ulcer healing is directly related to acid secretion inhibition at night.

• Evening dosage of H2 receptor antagonists or PPI.

• Melatonin – secreted at night by pineal gland.

• Function – synchronizes sleep wake cycle with circadian rhythm.

• Melatonin agonist [Ramelteon] – hypnotic for sleep onset insomnia &

• Bedtime administration - more effective.

• Symptoms more severe - 8am &

• Long acting NSAIDS at bed time

• Pain more intense between 2 pm and 8 pm.

• Cholesterol synthesis more at night.

• Evening dose of HMG CoA reductase inhibitors is more effective.

• Cancer cells are considered to have lost internal time keeping

• Tumor cells and normal cells differ in their chronobiological

• So, an s-phase active cytotoxic therapy at late nights should be more

-Inflammatory activity highest at night, least in the morning.

• Atopic dermatitis: sensitivity to histamine highest at night.

• Topical corticosteroids: activity in the afternoon higher than that in

OROS, CODAS, CEFORM, TIMERx, POLYMERS,

• Recently, a novel floating pulsatile system - high internal phase

• Understanding the biological rhythms can optimize and individualize

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