Introduction to chronopharmacology

1. BY
GURUBARATH M
M.PHARM
(PHARMACOLOGY)
CHRONOPHARMACOLOGY
INTRODUCTION
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2. CHRONOPHARMACOLOGY
The study of rhythmic, predictable-in-time differences in the effects and/or
pharmacokinetics of drugs both in experimental animas and in men.
Concerned with biological rhythm dependencies
of medication
The arrangement of events according to
the time of occurrence
CHRONOLOGY
Objectives
• To optimize drug effects
• To minimize adverse effects
• To avoid multiple dose therapy
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3. CHRONOPHARMACOLOGY
Subdivided into:
Chronopharmacokinetics
Study of the temporal changes in the
pharmacokinetics of the drugs with responsive time
Study of absorption, distribution, metabolism and excretion of
drug according to time of the day or year
Chronethesy 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
ChronoPharmaceutics Branch which designs and develops a drug delivery system in
accordance with biological rhythm to optimize the treatment of
disease
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4. CHRONOKINETICS
Why study Chronopharmacokinetics?
Chronokinetic information can be used in choosing proper timing of
drug administration to optimize drug therapy
When Symptoms of disease are circadian phase dependent
e.g. Nocturnal asthma, Angina pectoris, ulcer diseases, etc.
Toxicity can be minimized or avoided by administering at
particular time
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5. BIOLOGICAL RHYTHM
Self sustaining movement with duration of time between successive
repetitions which are not varying under normal conditions.
Types of rhythm
i) Ultradian (20hr)
(signaling between neurons, heart)
ii) Circadian (20-28hr)
(Sleep wake cycle, Most biological functions)
iii) Infradian (>28hr)
(Menstrual cycle)
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6. BIOLOGICAL RHYTHM - SPECTRUM
Category of Rhythm Period of Rhythm Term used to Describe
Rhythm
Illustrative Examples
Short periods ≤Sec High frequency
oscillations
Electroencephalogram
Electrocardiogram
Medium periods
30min to 20hr
20hr to 28hr
28hr to 6days
Ultradian
Circadian
Infradian
Sleep staging
Pulsatile hormone secretion
Most biologic functions
Little studied thus far
Long periods
≈ Week
≈ Month
≈Year
Circaseptan
Circamensual
Circannual
Work-rest routine
Menstruation, Fertility
Neuroendocrine functions
Many biochemical, endocrine and
Physiological parameters
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7. PEAK TIME FUNCTIONS
HUMAN CIRCADIAN TIME STRUCTURE
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8. DISEASE RHYTHM
Ulcer crises
Asthma attacks
Rapid rise in Blood pressure
Angina attacks
Pain of Rheumatoid arthritis
Nasal symptoms of Allergy
Migraine Headaches
Stroke due to Clot
formation
Overall ease of Breathing
Perforated Peptic Ulcer
Pain of Osteoarthritis
Sensitivity to Allergy and skin tests
Stroke due to Hemorrhage Intractable Pain
Stomach acid production
CIRCADIAN RHYTHM
OF DISEASES
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9. CIRCADIAN RHYTHM
Circadian (Circa – about; dies – day/about 24 hour)
Oscillations in the biological, physiological and behavioral functions of an
organism with a periodicity of 24hrs
Circadian clock in brain coordinates daily physiological cycles
E.g., sleep-wake cycles
Clock is daily reset by the environment
CIRCADIAN CLOCKS
Central Clock Peripheral Clock
Located in suprachiasmatic
nucleus (SCN) of the
hypothalamus
Present in other cells
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10. BIORHYTHMS
Basic units of circadian timekeeping
Suprachiasmatic 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
• Light falls on the eye
• Light signals transmitted by
afferent nerves arising from
the retina
• Retino hypothalamic tract
• Paired suprachiasmatic nuclei
in the hypothalamus
• SCN – Pineal Gland – melatonin
• SCN – ANS – Endocrine glands
• Time of light, duration, wavelength
intensity – determine circadian
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11. CLOCK GENES
Circadian rhythms are driven by a group of genes called Clock genes
Bmal1 (Brain and muscle aryl-hydrocarbon receptor nuclear
translocator-like 1)
CLOCK (Circadian Locomotor Output Cycles Kaput)
Per (period)
Cry (Cryptochrome)
The clock genes consists of
They form a tightly regulated system with interlocking
feedback and feed-forward loops
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12. HUMAN CIRCADIAN TIME STRUCTURE
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13. CIRCADIAN RHYTHM
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14. Circadian rhythms in various diseases
CIRCADIAN RHYTHM
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15. CHRONOPHARMACOTHERAPY
Medical treatment that involves the increase of efficiency and safety of
medications by proportioning their concentrations during the 24hours in
synchrony with biological rhythm determinants of disease
Advantages
 Prevents over dosing
 Appropriate usage of drugs
 Reduce side effects
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16. CHRONOPHARMACOTHERAPY
Osteoarthritis
Pain is maximum in the evening
Analgesics like ibuprofen are administered in
afternoon
Rheumatoid arthritis
Pain is maximum in the early morning
Long-acting NSAIDs like flurbiprofen, ketoprofen,
and indomethacin are administered at bedtime
Acid peptic disease
Basal gastric acid secretion peaks during the midnight
H2 blockers are given before bedtime to inhibit basal acid
secretion at midnight
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17. CHRONOPHARMACOTHERAPY
Bronchial asthma
Precipitation of attacks during late night or at early morning hour
(2-6a.m.) due to increased bronchial hyperactivity during this
period
Inhaled salbutamol given early morning
Evening dose of a sustained release preparation of theophylline
produces peak drug concentrations in late night and early morning
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18. CHRONOPHARMACOTHERAPY
Hypertension
Blood pressure increases briskly in the morning after awakening,
decreases in the evening, and is lowest during sleep
If given only as once daily early in the morning, many antihypertensive
drugs do not reduce the early morning blood pressure
Extended release formulation of L-type calcium channel
blocker, verapamil is administered orally at bedtime
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19. CHRONOPHARMACOTHERAPY
Cardiovascular diseases including Stroke and Myocardial infarction
Commonly occur during the initial hours of morning between 6 a.m. and 12 noon;
a state of relative hypercoagulability of the blood prevails in morning
Coronary blood flow decreases in the morning
Increased Oxygen demand of the heart in early morning
Evening or bedtime administration of angiotensin- converting enzyme
inhibitors or Angiotensin receptor blockers or CCBs produce better reduction
in BP
Administration of beta-blockers prevents the morning increase in
the incidence of angina, myocardial infarction, and sudden death
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20. CHRONOPHARMACOTHERAPY
Allergic rhinitis
Symptoms are worst in the late night or early morning
Anti-histamines are usually given once daily at
bedtime
Hypercholesterolemia
HMG CoA reductase enzyme activity is maximum in the night,
and thus cholesterol synthesis is usually greater during night time
than during day
Statins like simvastatin given in the evening or night are
more effective
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21. CHRONOPHARMACOTHERAPY
Diseases where systemic steroids are given
Endogenous secretion of adrenocorticotropic hormone (ACTH)
and cortisol peaks in the early morning
Prednisolone and other corticosteroids are given early morning to mimic
the release from HPA axis
Addison’s disease
Asymmetrical morning high and late afternoon low dose corticosteroid substitution
best corrects fatigue and abnormal circadian time structure
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22. CHRONOPHARMACOTHERAPY
Epilepsy
Seizure attacks are common around the onset of sleep at night
and the offset of sleep in the morning
Patients in whom the evening dose was double that of the morning dose,
without altering the total dose of medication, showed better seizure
control
Cancer
Normal cells and cancer cells vary in their chronobiological rhythm.
The DNA synthesis peaks in the normal human bone marrow at noon and in
lymphoma cells at midnight
S-phase active cytotoxic drugs are administered at late night, providing selective
suppression of the lymphoma cells over normal bone marrow cells.
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23. CHRONOTHERAPEUTIC - DRUG DELIVERY SYSTEMS
Developed to circumvent the need for administering the drugs at odd timings
Spheroidal oral drug absorption system (SODAS)
Controlled release beads which release the drugs according to the circadian rhythm.
Chronotherapeutics oral drug absorption system (CODAS)
Enteric release-controlling polymer applied to drug-loaded beads, drug release
after a prolonged period of time after ingestion
Container Technology
TIMERx Technology (hydrophilic system)
Semipermeable matrix technology with uniform porosity, releasing the
drug in a controlled release manner
A combination of Xanthan and Locust bean gums mixed with dextrose - forms a gel
when in contact with water and aids in controlled drug release.
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24. LIMITATIONS OF CHRONOPHARMACOLOGY
Interindividual variations make it difficult to design a common dosing
regimen, and thus individual dosing regimen is required.
Interspecies variations in diurnal cycle make it inappropriate to
extrapolate the results of animal studies to humans.
Increased cost of trials in which chronopharmacological studies are
included because it will increase the duration, sample size, and cost
of the trial
Absence of a reliable marker of biorhythm to guide
chronotherapy
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25. REFERENCES
Introduction to Basics of Pharmacology and Toxicology;
Gerard Marshall Raj Ramasamy Raveendran; page no.261-269
Maurya k.k et al. Chronopharmacology: A tool for therapy of
diseases. IRJP 2012,3(5):128-132
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