For Mpharm Students Pharmacology

1. CHRONOPHARMACOLOGY
PRESENTED BY
NIDHI TIWARI
ASSISTANT PROFESSOR
PHARMACOLOGY
KSOP

2. Contents of the Lecture:
Introduction
History
Definitions
Circadian Rhythm
Chronopharmacology
Application of Chronopharmacology
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3. Introductio
Introduction
Medications used in best time for enhance their therapeutic value

4. History
Jean-Jaques d’Ortousde Mairan
described circadian rhythms of plants in the 18th century
Franz Halberg
He 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.

5. Definitions
Definitions
Chronobiology:
Chronos – Time; Bio-Life; Logos- Study
It is the branch of sciences dealing with the “Biological rhythm” and their
mechanism in the living organism is called Chronobiology
Biological Rhythm:
It is the determined rhythmic biological process or function within a defined
time period.

6. Definitions
Definition
s
Biological Rhythm:
A biological rhythm is a self-sustaining oscillation with the duration
of time between successive repetitions (i.e; the period) being rather non-
varying under normal conditions.
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.

7. Definitions
Definition
s
Chronopharmacology
Chronos – Time; Pharmacon- Drug; Logos- Study
It is the branch of sciences dealing with the pharmacological action of a drug in
relation to biological rhythm. It is concerned with the effects of drugs upon the
timing of biological events and rhythms.
Aim: Enhance the therapeutic efficacy, optimization of drug effects & minimization
of adverse effects by using timing medications in relation to biological rhythm.

8. Circadian Rhythm
Circadian Rhythm
Oscillations in the biological, physiological & behavioral functions of an
organism with a periodicity of 24 hrs
Circadian rhythms are particularly important in medical sciences
and right time use of a medicine. (E.g. statins in bed time)
A circadian clock (24 h clock) in the NS (nervous system)
coordinates daily physiological cycles.
sleep/wake
Digestion
temperature
Hormones
Cardiovascular activity

9. Circadian Rhythm
Circadian Rhythm
Regulation: External cues which reset the circadian clock = ZEITGEBERS
(German words-Timer)= synchronizers

10. Circadian Rhythm
Circadian Rhythm
In the mammals, an internal biological clock is located in the
suprachiasmatic nucleus (SCN) of the hypothalamus, delivering its message
of time throughout the body.
It is responsible for circadian rhythms and annual and seasonal rhythms.
SCN uses its connected ANS for spreading its time-of-day message,
either by setting the sensitivity of endocrine glands (i.e., thyroid, adrenal,
ovary) or by directly controlling an endocrine output of pineal gland (i.e.,
melatonin synthesis)

11. Circadian Rhythm
Circadian Rhythm

12. Chronopharmacolgy
Chronopharmacolgy
It is the branch of sciences dealing with the pharmacological action of a drug
in relation to biological rhythm
Chrophysiology—Chronopathophysiology—Chronopharmacology
Subdivision:
Chronotherapeutics
Chronokinetic
Chronotoxicity
Chronesthesy
Chronergy

13. Chronopharmacolgy
Chronopharmacolgy
Chronotherapeutics: Study of effective therapy relation to biological rhythm of a
disease
Chronokinetic: It deals with the study of the temporal changes in the
pharmacokinetics (ADME) of the drugs with respective time.
Chronotoxicity: it may be defined as the changes in an organism's sensitivity to
toxicants in relation to time.
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

14. Chronopharmacolgy
Chronopharmacolgy
of a disease
Chronotherapeutics (Chronotherapy)
Effective therapy relation to biological rhythm
(Chrono-pathophysiology)
It refers to treatment method in which drug availability is timed to match
rhythm of diseases in order to optimize the therapeutic outcomes and
minimize side effects
Advantages: Prevents over dosage; Appropriate usage of drug;
Reduce side effects

15. Chronopharmacolgy
Chronopharmacology

16. Chronopharmacolgy
Chronopharmacolgy
Chronopharmaceutics: Development of chrono drug delivery system
Drug
Chrono Pharmaceutical Products
Chronotropic Drug Delivery
System
• Functional Design
• Formulation Design
• Process design
• Packaging desing
Chrono Pharmaceutical Products
 Optimal dose timing
 Time control
 Site Control
Ideal Chronotherapy

17. ADVANTAGE
• Prevent over dosage.
• Appropriate usage of drug.
• Reduce side effects.
• When a person sleeps for several hours then the chronotherapy
is more effective.
• Prediction of Chronotherapy is easy because it possess
beginning, middle and end stage.
• Gives a new schedule to the patients of getting up and
sleeping early but it provides them a period to adjust
psychologically.
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18. DISADVANTAGES
• Need of consulting the doctor and sleep specialists regularly
to avoid side effects.
• Unusual feeling of hot or cold when the person is undergoing
therapy.
• Patient incompliance as he has to keep himself awake till the
next sleep schedule.
• Sometimes the patient may also be sleep deprived.
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19. Chronopharmacolgy
Chronopharmacolgy
Chrono drug delivery system
SODAS-Spheroidal oral drug absorption system
CODAS- Chronotherapeutics oral drug absorption system
Chronomodulating infusion pumps
TIMERx
CONTINR

20. Chronopharmacolgy
Chronopharmacology
Application of Chronopharmacology:
Asthma therapy
Hypertension
Oncology
Strokes
Sleep apnea
GI tract disorders
Allergies

21. DISEASE RHYTHM

22. APPLICATION OF
CHRONOPHARMACOLOGY
• RESPIRATORY SYSTEM
Increased Bronchoconstriction at Night
↑ Parasympathetic tone
↓ Adrenaline
↓ Cortisol at midnight
↑ Sensitivity to irritants & allergens at night -
exacerbations of allergic rhinitis & asthma.
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23. ASTHMA
• Bronchial asthma is characterized by chronic airways
inflammation and reversible airflow limitation.
• When treatment is inadequate, however, airway remodeling can
occur and reversibility of obstruction becomes incomplete.

24. • Chronic inflammation of the airways is associated with
infiltration of eosinophils, T lymphocytes, mast cells and other
inflammatory cells, as well as with production of various
humoral factors (endothelin-II & Angiotensin-II).
• Persistent inflammation may lead to airway obstruction or
airway hyperreactivity.

25. SYMPTOMS
• Paroxysmal dyspnea
• Chest tightness
• Wheezing
• Cough
• Hypoxia during acute attacks

26. FACTORS ASSOCIATED WITH NOCTURNAL
EXACERBATION OF BRONCHIAL ASTHMA

27. CHRONOBIOLOGICAL ASPECT IN
ASTHMA
Main chronobiological features of asthma is the worsening of
symptoms between midnight and early morning, referred to as
the morning dip.
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28. • Most of the drugs currently used for chronotherapy of asthma
are administered once at night –
To prevent chronic airway inflammation or the onset of airflow
limitation.
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29. CHRONOTHERAPY
• Asthmatic attack is more common between 2 AM to 6 AM
•The risk of asthmatic attack is almost 70 times higher in patients at
04:00-05:00 AM in the morning, compared with the afternoon
• Theophylline is a bronchodilator and also suppress airway inflammation.
• Sustained Release Formulation of Theophylline —
Once-daily evening administration
. Efficacy
. Serum Concentration
. Side Effects
. Avoid Multiple Dosing
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30. Chronopharmacolgy
Chronopharmacology
Asthma Therapy:
Chronopharmacotherapy for asthma is aim to getting maximum beneficial
effect from bronchodilators during the early morning
E.g., Sustained release long acting theophylline taken once a day in the evening
causes theophylline blood levels to reach their peak and improve lung
function during the difficult early morning.

31. CardiovascularTherapy
• The differences in patterns of illness between day and night for cardiovascular disorders such as
hypertension, angina, heart attack, sudden cardiac death and stroke have been documented .
• Medications have been formulated, and dosing schedules established, in an attempt to provide
appropriate concentration of a drug in the target area of the body when the drug is most needed.
• For example, it has often been found that the blood pressure of a hypertensive patient increases rapidly
in the morning after awakening, typically peaks in the middle to late time of the day, decreases in the
evening, and is lowest while the patient sleeps at night.
• It may also be important to recognize that the risk of heart attack appears to be greatest during the
early morning hours after awakening.

32. Chronopharmacolgy
Chronopharmacolgy
Hypertension Therapy: Blood pressure pattern in a day
Morning Rise
Night dip

33. • Currently, there are antihypertensive products in the market that are chronotherapeutic
medications with novel drug delivery systems, releasing drug during the vulnerable
period of 6 am to noon upon administration of medications at 10 pm.
• Some of these are listed in Table 1.
A new COER (Controlled onset extended release
system) verapamil use in HTN. It is formulated as a
pill with a shell that dissolves slowly. Taken at bed-
time, this exerts peak effects btw 5 am and noon &
no mid-night dip in B.P is seen.

34. THANK YOU