Many drugs are still given without regard to the time of day Identification of rhythmic marker for selecting dosing time will lead to progress of chronopharmacotherapy. To monitor rhythmic markers such as clock genes it may be useful to choose the most appropriate time of day for administration of drugs that may increase their therapeutic effects and reduce their side effects . To produce new rhythmicity by manipulating the conditions of living organs by using rhythmic administration of altered feeding schedules for several drugs appears to lead to a new concept of chronopharmacotherapy

1. ROLE OF
CHRONOPHARMACOLOGY
IN THERAPEUTICS
Dr. Prabhakar Injeti
Post Graduate
2/7/2015
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2. OUTLINE
INTRODUCTION
TYPES OF BIOLOGICAL RHYTHMS
BIOLOGICAL CLOCK IN HUMAN
CIRCADIAN RHYTHMS IN OCCURRENCE AND
SEVERITY OF DISEASE
CHRONOKINETICS
DRUGS UNDERGOING CHRONOKINETICS
CHRONODYNAMICS
CHRONOTHERAPEUTICS
CHRONOMODULATED DRUG DELIVERY SYSTEMS
CONCLUSION
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3. • Chronobiology is the scientific study of effect of time on
living systems and biological rhythms.
• Chronopharmacology is the science concerned with the
variations in the pharmacological actions of various drugs
over a period of time of the day.
• A biological rhythm is one or more biological events or
functions that reoccur in time in a repeated order and with
a repeated interval between occurrences .
• The biological clock is the mechanism found within living
organisms that coordinates the timing of physiological
functions and behaviors to the natural day-night cycle.
INTRODUCTION
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4. • The mammalian Circadian pacemaker resides in the
paired suprachiasmatic nuclei (SCN).
• When light falls on the eye, afferent nerves arising from
the retina of the eye transmit the light signals directly
through retino hypothalamic tract to the paired
suprachiasmatic nuclei situated in the hypothalamus and
pineal gland.
• Biological clock since found is represented by
suprachiasmatic nuclei , which creates biological rhythms
under control of clock genes.
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5. The suprachiasmatic nucleus controls circadian rhythms
in response to hormonal variation in the body
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6. • Clock genes control vast array of circadian rhythms in
physiology and behaviour.
• The rhythmic activities of Clock genes and cyclic
secretion of melatonin from pineal gland comprise the
central timekeeping mechanism.
• These generated biological rhythms deal with the control
of biological functions including those of the autonomic
nerve system, endocrine system, and immune system,
which are fundamental in homeostasis and in protection
against various diseases .
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7. Types of biological rhythms:
- Ultradian rhythms, shorter than a day .
Eg: thousandths of a second (like the pulses in
neurons)
seconds (like the heartbeat)
- Circadian rhythms, which last about one day.
• Circadian rhythms are self-sustaining and endogenous
oscillations that occur with a periodicity of about 24
Hours.
Eg: the sleep-waking rhythm, the body temperature,
sensitivity to pain or alcohol, reaction time, levels of
hormones in the blood etc.
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8. -Infradian rhythms, longer than a day.
Eg: monthly rhythm - menstrual cycle
Yearly rhythm – bird migration
-Tidal rhythms, commonly observed in marine life, which
follow the roughly 12-hour transition from high to low tide
and back.
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9. Circadian rhythm:
• Derived from the Latin circa, meaning "around," and dies,
meaning "day”. Circadian : around a day.
• Rhythm is the measured movement, recurrence of action
or function at regular intervals.
• Circadian rhythm is the regular recurrence of certain
phenomena in cycles of approximately 24 hours.
• The best-known circadian rhythms include body
temperature , hormone secretion, metabolism, sleep or
wake cycle .
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10. BIOLOGICAL CLOCK IN HUMAN
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11. 2/7/2015
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12. • The hormones that are secreted in the morning include
cortisol, catecholamines, plasma renin, aldosterone, and
angiotensin.
• In contrast, gastric acid, growth hormone, prolactin,
melatonin, follicle-stimulating hormone, luteinizing
hormone, and adreno-corticotrophic hormone (ACTH)
peak in the evening or during sleep.
• For instance, the increase in catecholamines in the
morning promotes platelet aggregation. This is especially
important since fibrinogen also increases, and the body’s
own endogenous t-PA decreases, promoting a
procoagulant state with increased blood viscosity.
• Cholesterol synthesis is more in the evening than in the
morning.
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13. • Sudden infant death, symptoms of allergic rhinitis, and
rheumatoid arthritis are either most intense overnight or in the
morning upon wakening.
• Migraine headache is typically triggered during rapid eyeball
movement (REM) episodes during night time sleep or in the
early morning hours after awakening.
• Angina pectoris, ventricular arrhythmia, acute myocardial
infarction, sudden cardiac death, stroke, fatal pulmonary
embolism, and hypertensive crises, all are most frequent in
the morning.
Circadian Rhythms in Occurrence and
Severity of Disease
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14. • Perforated and bleeding ulcer is reported to be most
common in the afternoon.
• Some seizure disorders are triggered during specific
sleep stages and / or by transitions between sleep and
wakefulness.
• Symptoms of osteoarthritis worsen during the course of
daily activity, being typically most intense in the late
afternoon and evening.
• Depression is most severe in the morning.
• Gout, gall bladder and peptic ulcer attacks are most
frequent at night.
• Acute pulmonary edema, congestive heart failure, and
asthma worsen nocturnally
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15. more
Noon
6 AM
6 PM
Midnight
Perforated peptic ulcer.
Pain of Osteo arthtites
Sensitivity to allergy skin test
Gastric acid Production
Stroke due to Hemorrhage
Intractable pain
Ulcer crises
Asthma attacks
Rapid raise in blood pressure
Angina attack
Pain of Rheumatoid arthritis
Nasal symptoms of allergy
Migraine attacks
Stroke due to clot formation
Overall ease of breathing
CIRCADIAN RHYTHMS
OF
DISEASES
Peak Time of Event/Variable
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16. CHRONOKINETICS
• Chronopharmacokinetics deals with the study of the
temporal changes in absorption, distribution, metabolism
and elimination and thus takes into account the influence of
time of administration on these different steps.
• All physiological functions oscillate rhythmically in time, the
activity, toxicity, and kinetics of a medication may depend
on its administration time.
• The main aim of chronokinetic studies is to control the time
of administration which can be responsible for variations of
drug kinetics but also may explain chronopharmacological
effects observed with certain drugs.
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17. NEED OF CHRONOKINETIC STUDY
• When possible daily variations in pharmacokinetics may
be responsible for time dependent variations in drug
effects (e.g. some antimicrobial agents are more effective
at a specific time of day),
• When drugs have a narrow therapeutic range .
• When symptoms of a disease are clearly circadian phase-
dependent (e.g. nocturnal asthma, angina pectoris,
myocardial infarction, ulcer disease).
• When drug plasma concentrations are well correlated to
the therapeutic effect in case the latter is circadian phase
dependant.
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18. Drug Absorption :
• Several factors, such as the physico-chemical properties
of the drug ( lipophilicity or hydrophilicity ), the area and
the structure of the biomembrane , gastric emptying, pH
and motility, and gastrointestinal blood flow, may influence
the absorption process after oral drug administration.
• Most lipophilic drugs seem to be absorbed faster when
the drug is taken in the morning compared with the
evening because of faster gastric emptying time and a
higher GI perfusion in the morning.
• Such changes may contribute to the dosing time
dependent difference of drug absorption.
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19. Drug Distribution:
• Blood flow depends on several regulatory factors,
including sympathetic and parasympathetic systems which
activities are known to be circadian time dependent with a
predominant diurnal effect of the sympathetic system.
• A diurnal increase and nocturnal decrease of blood flow
and local tissue blood flows may explain a possible
difference in drug distribution depending on the dosing
time.
• Plasma proteins such as albumin or alpha 1 glycoprotein
have been documented to be circadian time dependent.
The plasma concentrations of albumin and alpha 1
glycoprotein acid show peak around noon.
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20. Drug metabolism :
• Hepatic drug metabolism seems to depend on liver
enzyme activity and / or hepatic blood flow.
• Both factors show a circadian time-dependent
difference. Enzyme activities show a circadian time-
dependent difference in many tissues such as brain,
kidney, and liver.
• Conjugation, hydrolysis, and oxidation show a circadian
time-dependent difference.
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21. Drug elimination:
• Renal physiological functions such as glomerular filtration,
renal blood flow, urinary pH, and tubular resorption show
a circadian time-dependent difference with higher values
during daytime.
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22. DRUGS UNDERGOING CHRONOKINETICS:
1. Antibiotics :
• Important aspect of chronokinetics in antibiotics is that
not only the efficacy of the drug may increase but also
the toxicity of certain drugs may decrease at different
time of day.
Aminoglycosides:
• Renal toxicity of aminoglycosides can be reduced by
giving the drug as a single daily injection when patients
are active (at day time or in other words in the activity
period)
Eg: gentamycin, tobramycin, amikacin
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23. 2. Antihypertensive drugs:
• Blood pressure, stroke volume, cardiac output, blood
flow are higher in morning and decrease later in the
day.
• Cmax was higher and/or tmax shorter after morning
than evening dosing of the lipophilic drugs (nifedipine,
oral nitrates, propranolol) .
• Atenolol (hydrophilic drug ) is not absorbed rapidly
after morning administration.
• ACE inhibitors were found to be safe and effective
when administered at bed time when compared to
morning.
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24. 3. Valproic acid(antiepileptic):
• Cmax tended to be higher, tmax was shorter and
absorption rate constant tended to be larger for VPA in the
morning than in evening.
4. Anti-inflammatory drugs :
• They have greater rates and extents of bioavailability
when administered in the morning than evening.
Eg. Indomethacin, Ketoprofen
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25. 5. AntiAsthmatic drugs :
• Asthma is attacked more frequently in night hours.
• Lungs are more sensitive to bronchoconstrictor substances
such as Acetylcholine, Histamine, house mite dust, grass
propellers, at night time than day time. It is treated by
antiasthmatic drugs.
Ex:-Theophylline, beta sympathomimetics.
• Theophylline must be given in higher doses during the night
time than day time.
6. Antiulcer drugs :
• Gastric acid secretion is highest at early night or late
afternoon.
• H2 blockers like Ranitidine ,cimetidine ,famotidine should
be taken once a day in the late afternoon or early night
when acid secretion is more.
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26. 7. Anticancer drugs :
• The blood flow to tumors and tumor growth rate are each
up to three fold greater during each daily activity phase of
the circadian cycle than during the daily rest phase.
• Normal human bone marrow DNA synthesis peaks around
noon, DNA synthesis in malignant lymphoma cells peaks
near midnight.
• By treatment at mid night, more tumor cell kill could be
achieved with same dose of S-phase active cytotoxic
therapy and with relatively little bone marrow damage.
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27. • The activity of dehydropyrimidine dehydrogenase in
human mononuclear cells increases by 40% around
midnight.
• This enzyme brings about the intracellular catabolism of
5-FU and contributes to improved tolerability of this drug
between 00:00 and 04:00.
• One approach to increasing the efficiency of the
pharmacotherapy is by administering drugs at times
during which they are best tolerated.
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28. 8. NSAID’s & Arthritis :
• Patients with osteoarthritis tend to have less pain in the
morning and more at night; while those with rheumatoid
arthritis, have pain that usually peaks in the morning and
decreases throughout the day.
• Chronotherapy for all forms of arthritis using NSAID’s such as
ibuprofen should be timed to ensure that the highest blood
levels of the drug coincide with peak pain.
• For osteoarthritis sufferers, the optimal time for a non-
steroidal anti-inflammatory drug such as ibuprofen would be
around noon or mid-afternoon.
• The same drug would be more effective for people with
rheumatoid arthritis when taken after the evening meal.
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29. 9. Anti hyperlipidemic drugs
• More Cholesterol systhesis takes place in the evening
than in the morning.
• The enzyme HMG Co-A Reductase is required to reduce
hydroxy 3-methyl glutaryl Co-A to mevalonate in the
synthesis of cholesterol.
• This enzyme is competitively inhibited by HMG Co-A
Reductase inhibitors (Statins)
• Hence statins should be administered at evening rather
than at morning for increased efficacy.
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30. 10. Opiod analgesics
• Stronger analgesic effects were observed when tramadol
and dihydrocodeine were applied in the evening to relieve
painful stimuli.
• Peak morphine use occurred at 9 a.m. and least use at 3
a.m.
• A recent study of meperidine reveals a circadian variation
of meperidine-induced analgesia in sickle cell anemia
patients, with maximal analgesic effect occurring with the
morning dose.
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31. 11. Anti-Migraine drugs
• Sumatriptan is a drug of choice in migraine treatment.
• The mean peak serum concentration, were significantly
higher following the 07:00 am administration than after
the 7:00 pm administration.
12. Immunosupressants
• A slightly increased concentration resulting from
decreased apparent clearance during the resting (PM)
versus activity (AM) period were observed for
cyclosporine.
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32. 13. Local anesthetics
• The duration of local anesthesia was longest when
amide-type local anesthetic agents (lidocaine,
ropivacaine, mepivacaine and betoxycaine) were applied
around 3 p.m.
• Area under the lidocaine plasma concentration curves
(AUC) was largest in the afternoon.
• The plasma levels of lidocaine were significantly higher in
the evening than at any other time of day.
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33. 14. General anesthetics
Barbiturates
Higher brain pentobarbital or hexobarbital concentrations
occurred when injected during the dark phase. Postsynaptic
type A GABAergic activity is increased during nocturnal
hours, corresponding to the duration of the maximal efficacy
of barbiturates.
Benzodiazepines
The elimination half-life of midazolam was found to be at its
shortest at 2:00 pm and at its longest at 02:00 am
Ketamine, Etomidate, Propofol, and Halogenated Agents
Action longer during the night than during the day.
Halothane
Greatest efficacy of halothane occurred between 12:00 am
and 06:00 am.
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34. Chronodynamics
Rhythm in receptor number or conformation , second
messengers , metabolic pathway , and/or free-to-bound
fraction of medications help to explain this phenomenon.
Examples:
• Antitumour effect of IFN-β and the antiviral effect
lymphocyte stimulating effect of INF-α in mice are more
excient during the early rest phase than during the early
active phrase .
• Cell division in many mammalian tissues is associated
with specific times of day . In the regenerating liver of
mice,the circadian clock controls the expression of cell
cycle related genes that in turn modulate that expression
of activity Cyclin B1-Cdc2 kinase , a key regulator of
mitosis.
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35. • Angiogenesis is important for tumour growth and
metastasis. Hypoxia-induced expression of vascular
endothelial growth factor (VEGF) plays an important role
in tumour-induced angiogenesis . The level of VEGF
mRNA in tumour cells implanted in mice rise substantially
in response to hypoxia , but the levels show a 24 hr
rhythm.
• Methionine aminopeptidase 2 (MetAP2) plays an
important role in growth of endothelial cells during the
tumour angiogenesis stage . MetAPs show a 24 hr rhythm
in implanted tumour masses .
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36. CHRONOTHERAPEUTICS :
• Chronotherapeutics refers to a treatment method in which
in vivo drug availability is timed to match rhythms of
disease in order to optimize therapeutic outcomes and
minimize the side effects.
• The chronotherapy of a medication may be accomplished
by the appropriate timing of conventionally formulated
tablets and capsules.
• The special drug delivery system to synchronize drug
concentrations to rhythms in disease activity.
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37. CHRONOMODULATED DRUG
DELIVERY SYSTEMS
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38. 1. The pulsatile drug delivery system
• Pulsatile drug release is a system where the drug is
released suddenly after a well-defined lag time or time gap
according to the circadian rhythm of disease states.
•
• No drug is released from the device within this lag time.
• This delivery system is suitable in cases where drugs
including proteins and peptides undergo great metabolic
degradation.
• In case of chronic treatment, the drug resistance may grow
and an adverse effect may be seen.
• Here chances are less because the desired concentration
of the drug at a certain time point is available.
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39. • This method is good for drugs with extensive first pass
metabolism and those targeted to specific sites in the
intestinal tract.
• Therefore, by developing the pulsatile device for specific
colonic delivery, the plasma peak is obtained at an optimal
time, the number of doses per day can be reduced, it is
with saturable first pass metabolism, and tolerance
development can also be avoided.
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40. Advantages
• Predictable, reproducible, and short gastric residence time
• Less inter- and intra-subject variability
• Improves bioavailability
• Reduced adverse effects and improved tolerability
• Limited risk of local irritation
• No risk of dose dumping
• Flexibility in design
• Ease of combining pellets with different compositions or
release patterns
• Improves stability
• Improves patient comfort and compliance
• Achieves a unique release pattern
• Extends patent protection, globalizes the product, and
overcomes competition
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41. Disadvantages
• Low drug loading
• Proportionally higher need for excipients
• Lack of manufacturing reproducibility and efficacy
• Large number of process variables
• Multiple formulation steps
• Higher cost of production
• Need of advanced technology
• Trained / skilled personnel needed for manufacturing
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2. Enteric-coated systems
3. Osmotic systems
4. Swelling and erodible systems
5. Press-coated systems
6. Pulsincap systems
7. Ultrasound drug delivery systems
8. Multiparticulate systems
OTHER CHRONOMODULATED
DRUG DELIVERY SYSTEMS

43. Conclusion
• Many drugs are still given without regard to the time of day
• Identification of rhythmic marker for selecting dosing time
will lead to progress of chronopharmacotherapy.
• To monitor rhythmic markers such as clock genes it may be
useful to choose the most appropriate time of day for
administration of drugs that may increase their therapeutic
effects and reduce their side effects .
• To produce new rhythmicity by manipulating the conditions
of living organs by using rhythmic administration of altered
feeding schedules for several drugs appears to lead to a
new concept of chronopharmacotherapy
2/7/2015
43

44. References
1. Contemporary perspectives on Clinical
Pharmacotherapeutics, - Kamalesh Kohli & Mathur
Guptha
2. Post Graduate Topics in Pharmacology, - Rithuparna
Maiti
3. Chronopharmacology and its Aspects,
www.pharmainfo.net
2/7/2015
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45. THANK YOU
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