Introduction to chronology, chronotherapy, and chronopharmacology. How chronopharmacology involved in asthma and helps to manage asthma?. Biological rhythms in bronchial asthma. Factors associated with nocturnal exacerbation of bronchial asthma. Introduction to asthma and their symptoms. Introduction to Antiasthmatic drugs like beta-blockers, leukotriene antagonists, steroids, etc. Chronopharmacology division & their examples. Advantages and disadvantages of chronopharmacology. Marketed preparation and their images along with the price in India.

1. SEMINAR ON
CHRONOPHARMACOLOGY
IN ASTHMA
Presented by
Moh. Uzair
M.Pharm(Pharmacology) IInd Semester Student
SPER, Jamia Hamdard New Delhi
1

2. CONTENTS
2
Title Slide Number
CHRONOLOGY 4
CHRONOBIOLOGY 5
CHRONOPHARMACOLOGY 7-8
CHRONOPHARMACOKINETIC 9
CHRONOTOXICITY 10
CHRONESTHESY 11
CHRONERGY 12

3. 3
Title Slide Number
CHRONOTHERAPY 13
BIOLOGICAL RHYTHM 14
TYPES OF BIOLOGICAL
RHYTHMS
15
ZEITGEBERS 16
PEAK TIME FUNCTIONS 17
DISEASE RHYTHM 18
APPLICATION OF
CHRONOPHARMACOLOGY
21
ASTHMA 22-35
Marketed Preparations 36-38
References 39-48

4. CHRONOLOGY
 Chronos (time), Logos (study).
 The arrangements of events
according to the
time of occurrence.
4

5. CHRONOBIOLOGY
 Chronos (time), bios (life),
logos (study).
 Also termed as—
The Science of Time.
 Chronobiology refers to the
day-night cycle that affects the
human organism when the earth
rotates.
5

6. IN MEDICINE, 3 DISCIPLINES
TAKE INTO ACCOUNT THE
INFLUENCE OF TIME
 CHRONOPHYSIOLOGY
 CHRONOPATHOLOGY
 CHRONOPHARMACOLOGY
6

7. CHRONOPHARMACOLOGY
 The Right Formulation At The Right Time.
 Study of how the effects of drugs vary with
biological timing and endogenous
periodicities.
 Chronopharmacology dealing with
optimization of drug effects and minimization
of adverse effects by timing medications in
relation to biological rhythm.
7

8. CHRONOPHARMACOLOGY
IS SUBDIVIDED INTO —
 1.Chronopharmacokinetics
 2.Chronotoxicity
 3.Chronesthesy
 4.Chronergy
 5.Chronotherapy
8

9. 1.CHRONOPHARMACOKINETIC
 Deals with study of temporal changes in
pharmacokinetic parameters – ADME,
due to time of administration.
 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.
9

10.  Pharmacokinetics of mainly lipophilic drugs can
be circadian phase dependant. The studies show
that after oral dosing, peak drug conc.(Cmax ) is
generally higher or time to peak (tmax), shorter
after morning compared with evening
administration.
 Thus, circadian variations in gastric acid
secretion and pH, motility, gastric emptying time,
gastrointestinal blood flow, drug protein binding,
liver enzyme activity and/or hepatic blood flow,
glomerular filtration, renal blood flow, urinary
pH and tubular resorption may play a role in such
kinetic variations.
10

11. 2.CHRONOTOXICITY
 Defined as the changes in an organism's
sensitivity to toxicants in relation to time.
 Specifically with antitumor drug like
Irinotecan.
 Irinotecan induced leukopenia.
 Leukopenia more serious in the late dark
and milder in the late light.
11

12. 3.CHRONESTHESY
 Indicates circadian or other systemic changes
in the susceptibility of target biosystems to an
agent and involves receptors, cells, tissues,
organs and organ systems.
 Emphasizes predictable(in- time) rather than,
randomly distributed, biologic time related
differences of target system.
 e.g. Beta-receptor blocking drugs (β-blockers)
consist of an important group of cardio-active
drugs like Atenolol,Propanolol etc.
12

13.  The peak concentration of propanolol was
achieved in the application between 8 A.M.
and 2 P.M.. However, when applied on 2 A.M.,
the heart rate can be slightly changed in the
following 6 hours.
 Therefore, it can be stated that sympathetic
tonus, which is demonstrated by the rhythm in
plasma noradrenaline and cAMP levels, affects
the pharmacodynamics of the particular drug
and it can be concluded that propanolol should
be applied in hours when sympathetic tonus is
high.
13

14. 4.CHRONERGY
 Designates time-dependent effects on the
organism as a whole which include both
desired and undesired effects.
 Depends both upon the chronesthesy of target
biosystems and the chronokinetics of drugs.
 The term chronergy thus was preferred to
chronoeffectiveness.
 Chronoeffectiveness refers to temporal change
in the desired therapeutic effects of drugs.
14

15. Example
 Induced sleepiness may be desired effect for
a sleeping pill but the nondesired effect for a
tranquilizer or an antihistamine agents.
15

16. 5.CHRONOTHERAPY
 Also called chronotherapeutics.
 Refers to a treatment method in which
drug availability is timed to matched
rhythms of disease in order to optimize
therapeutic outcomes and minimize the
side effects.
16

17. BIOLOGICAL RHYTHM
 Biological rhythms are the natural cycle of
change in our body’s chemicals or functions.
It’s like an internal master “clock” that
coordinates the other clocks in your body.
 The “clock” is located in the brain, right
above the nerves where the eyes cross. It’s
made up of thousands of nerve cells that
help sync your body’s functions and
activities.
17

18. TYPES OF BIOLOGICAL RHYTHMS
 1.Circadian rhythms: The 24-hour cycle that
includes physiological and behavioral rhythms
like sleeping.
 2.Diurnal rhythms: The circadian rhythm
synced with day and night like release of
microfilariae of loa loa into the peripheral
blood predominantly at daytime.
Loa loa is the filarial nematode (roundworm) species
that causes Loa loa filariasis. Loa loa actually
means "worm worm", but is commonly known as the
"eye worm", as it localizes to the conjunctiva of the
eye. Loa loa is commonly found in Africa.
18

19.  3.Ultradian rhythms: Biological
rhythms with a shorter period and higher
frequency than circadian rhythms like
cellular processes, respiraton, circulation,
heartbeat & REM.
 4.Infradian rhythms: Biological
rhythms that last more than 24 hours,
such as a menstrual cycle.
19

20. ZEITGEBERS
 It is any external or environmental cue that
provides the stimulus or resetting a
biological clock.
 It helps to regulate the biological clock in an
organism.
 e.g— Light, Darkness, Warmth, Cold,
Eating, Fasting etc.
20

21. PEAK TIME FUNCTIONS
21

22. DISEASE RHYTHM
22

23. 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.
23

24. 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.
24

25. 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.
25

26. 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.
26

27.  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.
 Persistent inflammation may lead to
airway obstruction or airway
hyperreactivity.
27

28. SYMPTOMS
 Paroxysmal dyspnea
 Chest tightness
 Wheezing
 Cough
 Hypoxia during acute attacks
28

29. FACTORS ASSOCIATED WITH
NOCTURNAL EXACERBATION
OF BRONCHIAL ASTHMA
29

30. 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.
30

31.  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.
31

32. CHRONOTHERAPY
 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
32

33.  Glucocorticoids —
Suppress systemic & local inflammation.
Once daily dose of inhaled corticosteroids in
evening(5:30 pm) administration—
. Nearly as effective as 4 doses a day
. Strong local anti-inflammatory action
on the airways without systemic
adverse effects.
e.g. Ciclesonide (ciclohale)
33

34.  Single oral dose of Prednisolon at 3 pm is
most effective.
 Nocturnal Vagus Nerve Hyperactivity
.Relieved by Cholinergic antagonist
e.g. Ipratropium bromide, Oxitropium bromide
34

35.  β2 Adrenoceptor Agonists
. β2 adrenergic receptors are widely
distributed in the lungs.
. β2 agonist are effective as
bronchodilators in the treatment of
asthma.
. Administration of sustained release
β2-agonists directly improves
bronchoconstriction in the early morning.
35

36. . A transdermal β2-agonist preparation has been
developed in Japan
(Hokunalin® tape, Abbott Japan Co., Ltd.) —
To provide slow release of the drug for
chronotherapy of nocturnal asthma when
applied at night.
36

37. . The transdermal preparation of this β2-
agonist is designed —
To avoid a rapid increase of the serum
concentration.
To decrease adverse effects.
e.g. Tulobuterol(Tuloplast)
37

38. Classification of β2 Agonist
β2 Agonist
Long actingShort acting
38
• Salbutamol
• Terbutaline
• Levalbuterol
• Pirbuterol
• Isoetharine
• Bitolterol
• Fenoterol
• Procaterol
• Salmeterol
• Formoterol
• Arformoterol
• Carmoterol
• Olodaterol
• Indacterol

39.  Leukotriene Receptor Antagonist
. Leukotrienes are the potent constrictors of
human airway smooth muscle, and also
cause —
Tissue edema eosinophil migration,
which can stimulate the production of
airway secretions and airway smooth
muscle proliferation.
39

40. . Leukotriene receptor antagonists are used
as an on-add therapy to improve the
symptoms of asthma patients.
Once daily dose—
e.g. Montelukast (Monticope)
40

41. Marketed Preparations
41
Brand
Name
Composition Company Packaging MRP Rs.
DERIPHYL-
-LIN
RETARD
300 tab
Theophylline
69mg,
etophylline
231mg
GERMAN
REMEDIES
10 6.78
DELTACORT
-IL tab
Prednisolone
5mg
PFIZER 20 18.00
DUOLIN
INHALER
Ipratropium
20mcg
CIPLA 200md
INHALER
281.93
CICLOHALE Ciclesonide 80
mcg
CIPLA 120md
INHALER
359.00
MONTAIR
Tab
Montelukast
4mg
CIPLA 10 59.00
TULOPLAST
T.PATCH
Tulobuterol
0.5mg
ZUVENTUS
H.CARE
2.5 cm PATCH
14
43.95

42. 42

43. 43

44. REFERENCES
 https://www.chronobiology.com/about-
chronobiology/
 https://www.healthline.com/health/biological-
rhythms
 Johnson, C. (2004). Chronobiology: Biological
Timekeeping. Sunderland, Massachusetts,
USA: Sinauer Associates, Inc. pp. 67–105
 Ohdo S, Koyanagi S, Matsunaga N, Hamdan
A. Molecular basis of chronopharmaceutics. J
Pharm Sci. 2011;100:3560–76.
44

45.  Ohdo S, Makinosumi T, Ishizaki T, Yukawa
E, Higuchi S, Nakano S, Ogawa N . (1997).
Cell cycle-dependent chronotoxicity of
irinotecan hydrochloride in mice. Journal of
Pharmacology and Experimental
Therapeutics, 283(3):1383-8.
 N. Burioka et al. (2010) .
Asthma: Chronopharmacotherapy and the
molecular clock. Advanced Drug Delivery
Reviews Elsevier, 62: 946-955.
45

46.  N. MOHAMMED EESA
L. K. CUTKOMP (1995) PESTICIDE
CHRONOTOXICITY TO INSECTS AND
MITES: Journal of Islamic Academy of
Sciences 8:1, 21-28.
 https://www.sciencedirect.com/topics/me
dicine-and-dentistry/loa-loa
 https://link.springer.com/chapter/10.1007
/978-3-662-06085-8_17
46

47.  Essentials Of Medical Pharmacology by
KD Tripathi 8th edition, Jaypee Brothers
Medical Publishers(P).Ltd. Page No. 242-
243
47

48. 48