ROLE OF

CHRONOPHARMACOLOGY

IN THERAPEUTICS

Dr. Prabhakar Injeti

Post Graduate

2/7/2015

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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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• 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.

INTRODUCTION2/7/2015

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• 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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The suprachiasmatic nucleus controls circadian rhythms

in response to hormonal variation in the body

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• 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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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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-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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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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BIOLOGICAL CLOCK IN HUMAN2/7/2015

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• 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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• 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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• 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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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

DISEASESPeak Time of Event/Variable

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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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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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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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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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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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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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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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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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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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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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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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• 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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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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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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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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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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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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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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ChronodynamicsRhythm 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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• 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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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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CHRONOMODULATED DRUG

DELIVERY SYSTEMS

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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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• 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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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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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

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

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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

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THANK YOU

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