Circadian rhythms exist in many physiological processes and influence disease symptoms and drug effects. Disrupting rhythms through shift work or jet lag can cause adverse consequences. Chronopharmacology aims to optimize drug therapy based on biological rhythms. Factors like food, induction, and inhibition impact drug levels over time, necessitating chronotherapeutic approaches. Diseases like asthma, arthritis, and diabetes exhibit circadian patterns, suggesting timing medications for peak symptoms. Biological clocks govern rhythms, so understanding chronopathology allows chronotherapy for maximizing drug effects.

1. Dr. R. S. Bagali
Professor & HOD-Pharmacology
Ashokrao Mane College of Pharmacy,
Peth Vadgaon

2. Contents:
• Introduction
• Regulation of circadian rhythms
• Consequences of disrupting biological rhythms
• Types of biological rhythm
• Chronopharmacology
– Divisions
– Reasons
– Necessity of Chronotherapeutic approach
• Biological clock-Its significance leading to chronotherapy
• Conclusion

3. Introduction
• As a result of living on a planet whose principal
source of light and heat is only periodically
present, organisms on earth rapidly adopts
physiological systems to exploit these variations
for maximum fitness. Collectively, these systems
are named Circadian clocks (circa diem -about a
day).
• In mammals, circadian clocks influence all major
organ systems, and this influence translates
directly into disease pathology that also varies
with time of day.

4. • Rhythmic physiology has long been recognized to
result in rhythmic disease symptoms.
• Circadian rhythms are self-sustaining,
endogenous oscillations that occur with a
periodicity of about 24 hours and persist under
free-running conditions.
Introduction contd…….

5. • Normally, circadian rhythms are synchronized
according to internal biologic clocks related to the
sleep-wake cycle. Our circadian rhythm is based
on sleep-activity cycle and is influenced by our
genetic makeup and thereby affects our body’s
function throughout day and night (24 hour
period)
Introduction contd…….

6. Circadian or 24-hour rhythms exist in
• heart rate
• Pulse
• body temperature
• blood pressure
• blood flow
• stroke volume
• Peripheral resistance
• parameters of electrocardiogram (ECG) recordings
Introduction contd…….

7. Circadian or 24-hour rhythms exist in
• in the plasma concentrations of hormones,
neurotransmitters
• second messengers (eg, cortisol, melatonin, insulin,
prolactin, atrial natriuretic hormone, noradrenaline,
cAMP [cyclic adenosine monophosphate])
• in the RAAS
• in blood viscosity, aggregability and fibrinolytic
activity
• in the plasma concentrations of glucose,
electrolytes, plasma proteins, enzymes
Introduction contd…….

8. Circadian or 24-hour rhythms exist in
• in the number of circulating red and white blood
cells and blood platelets.
• gastric acid secretion, gastro-intestinal motility and
gastric emptying time
Introduction contd…….

10. • A 24-h change in drug bioavailability has
therefore been established for hundreds of drugs.
– For example, acetaminophen and theophylline show
different pharmacokinetics in the morning compared
with the evening.
• These changes are the results of several time-
dependent modifications of physiological and
molecular processes that influence drug
absorption and distribution.
Introduction contd…….

11. • Circadian rhythms are governed by a network of
hierarchical master clocks present at various
locations in the brain and peripheral tissues.
• Of these clocks, the most important are the paired
Suprachiasmatic nuclei (SCN) located in the
hypothalamus, which coordinate the multitude of
these other clock networks via endocrine and neural
signals.
• Specialised cells in the retina convey the onset and
offset of daylight to the SCN & Pineal gland & form one
of the external environmental signals (Zeitgebers)
which keeps the circadian rhythms in pace.
Introduction contd…….

12. • This gives rise to rhythmic variations in the
physiological status of the body’s systems and even
influences the susceptibility of human beings to
morbid and mortality events.
• For example, the incidence of myocardial infarction
mostly occurs between 6:00 a.m. and 12:00 noon .
• Diseases, such as asthma, allergic rhinitis, cancer,
cardiovascular diseases, osteoarthritis and peptic
ulcers exhibit circadian rhythms in the occurrence or
intensity of symptoms.
Introduction contd…….

14. Time of day when physiological or biochemical functions are at peak
PEF-Peak expiratory flow, FEV-Forced expiratory volume

15. Peak time of
functions

16. Time of day when symptoms or events of diseases are most frequent

19. • Zeitgeber-
• from German: “time-giver”, “synchronizer”
• Any exogenous (external) cue that
synchronizes an organism's endogenous
(internal) time-keeping system (clock) to the
earth's 24- hour cycle
Introduction contd…….

20. Examples of zeitgebers
• Light-darkness
• Warmth-cold
• Eating-fasting
• Social contact-isolation
• Noise-quiet
Introduction contd…….

21. The center regulating circadian rhythms
• Suprachiasmatic nucleus (SCN) is the main
pacemaker for endogenous biological rhythms
– A small group of cells located in the area of the
brain called the hypothalamus
• It lies above the optic chiasma
– it can receive information directly from the eye
so the rhythm can be reset by the amount of
light entering the eye

25. Consequences of disrupting biological
rhythms
• If external cues change, we have to re-adjust our
internal clock
– Shift work
– Jet lag

26. Shift work
• Phase advance: rising early or retiring to bed
earlier than normal
• Phase delay:
– going to bed late or getting up late
• Delay/advance of our rhythms compromises the
ability to cope in the short term
– Usually, it takes ~3 days to adjust to a 12-hour
shift in time

27. Shift work
• Phase delay seems to be more beneficial than
phase advance
– Working a few hours longer is less tiring for the
organism than being woken up in the middle of
sleep

28. Shift work
• An example: usually you work from 8 AM to 4 PM
(8 hours – work, 16 hours - rest)
– Shift work 1 (delay): the next day you will work
from 4PM to 12AM – less tiring for the
organism, as you have 24 hours for rest
between shifts
– Shift work 2 (advance): the next day you will
work from 12 AM to 8AM – more tiring, as you
have only 8 hours for rest between shifts

30. Jet lag
• Its easier to adapt to jet lag when flying in a
westerly direction because the day of travel is
lengthen, whereas it is shortened when
travelling east
• As our endogenous cycle is about 25 hours,
we are more able to cope with phase delay
than phase advance
• We can stay up when we should be asleep but
we don’t like being woken if we want to sleep

31. Jet lag
• Only occurs when flying from East-West or from
West to East (the change of times zone)
– does not occur form North-South and vice versa
• An example: You fly from Scotland (UK) – Boston
(USA).
– you leave at 11am and arrive at 5pm British time
– but actually it is 12pm in Boston
– by 8pm Boston time you’ll be tired as it is 1am to
you normally

32. • Chronology : The arrangement of events
according to the time of occurrence .
• Rhythm
• CHRONOBIOLOGY
• Chronobiology is the study of biological
rhythms and their mechanisms.
• Chronos (Time),
• Bios(Life),
• Logus(Study)
Definations

33. Types of Biological Rhythm
• I. Ultrdian: Oscillation of shorter duration (more than one
cycle per 24 h).
– Eg. Electrocardiogram, Sleeping stages -light and deep sleep lasting
about 90 minutes
• II. Circadian: This word comes from Latin word “circa” means
about and “dies” means day.
• III. Infradian: Oscillations that are longer than 24 h (cycles with
period longer than 1day and shorter than 6 days)
• IV. Circaseptan (~7 days): e.g. workrest scheme
• V. Circamensual (~30 days): e.g. a woman's menstrual cycle

35. Chronopharmacology
• is the science concerned with the variations in
the pharmacological actions of various drugs
over biological timings & endogenous
periodicities.
• is the science that deals with the optimizations
of drug effect and the minimizations of adverse
effects of timing medications in relation to
biological rhythm.

36. Standard therapy
• It assumes that the need for medication by
patients is non varying throughout the 24 hours
• Constancy of drug level translates into constancy
in drug effect.

37. Chronopathology
• Periodic time-dependent changes in the incidence of
infectious diseases
• Morbidity and the mortality from infectious diseases
is greatest during the winter and least during the
summer
– Seasonal cycles in infectious diseases are
generally attributed to seasonal differences in
weather/atmospheric conditions, virulence or
prevalence of causal pathogens, and/or variations
in the behavior of the host

38. Divisions of Chronopharmacology
• Chronotherapy (Chronotherapeutics)
• Chronopharmacokinetcs
• Chronotoxicity
• Chronesthesy

39. Chronotherapy
• It is a discipline of medical treatment which allows
– the consideration of a patient’s biological rhythm
– changes in the severity of a disease state during
the day
– the synchronizing of dosing and delivery of a
particular drug to allow for the optimal efficacy in
the patient.
• Advantages
• Prevents over dosage
• Appropriate usage of drug
• Reduce side effects

40. Chronopharmacokinetics
• Study of the absorption, distribution,
metabolism and excretion of drugs according
to the time of days or year

41. • The toxic effect of a drug on a organism, which is
undesirable and affects the rhythmic system.
Specifically with antitumour agents
• Irinotecan induced leucopenia is more
pronounced
Chronotoxicity

42. Chronotoxicity

43. 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.

44. According to circadian variations in the
case of patients who tends to more
consideration of chronotherapy in clinical
trials is highly welcomed by the whole
medical community and nearly 75% of
the doctors are in favour of patient’s
circadian or daily rhythm oriented
treatment.

45. Reasons for Chronopharmacology
• Auto Induction: A repetitive dose of a drug
induces or increases enzymes responsible for its
elimination, thereby increasing its clearance.
– Ex. Carbamazepine
• Here either the oral bioavailability decreases or
clearance increases with time due to repetitive
oral administration .

46. • Auto Inhibition: The metabolites formed from
the drug initially increase in concentration and
further inhibit metabolism of the parent drug.
– Ex. Clarithromycin is an inhibitor of intestinal and
hepatic CYP3A4 activity and thus gradually inhibits
its own metabolism as well as that of co-
administered drugs
Reasons for Chronopharmacology

47. • Food Effects: Gastric emptying is slowed or delayed
by food, often resulting in a decrease in the peak
concentration and an increase in the time of its
occurrence following a single dose of drug.
• It is a major cause of circadian variations in the case
of patients who tends to eat more in the evening
than at breakfast. Usually when absorption is slowed
by food, the rate of input into the liver and
concentration of drug entering liver are lowered and
prolonged and thus metabolism is lowered
Reasons for Chronopharmacology

48. Necessity of Chronotherapeutic approach
• When the ‘therapeutic window’ for a given drug is very
narrow, close to toxicity
• When the toxicity of the drug is a factor of dose
limitation
• When the kinetics and or the effects are dependent on
the moment of the administration
• When the effect of the drug can be obtained only by
time-modulated therapeutic modality

49. Biological clock-Its significance leading
to chronotherapy
• Biological Rhythms in Common Diseases:
– The basic physiological process governing the
drug action, such absorption, distribution,
metabolism and excretion is controlled by
various organ systems of the body. Hence it is
important to know the circadian rhythms in
these systems and their effect on drug action.

50. Respiratory System
• Increased bronchoconstriction at night due to
↑ Parasympathetic tone
↓ Adrenaline
↓ cortisol at midnight
↑ Sensitivity to irritants and allergens at night
→worsening of allergic rhinitis and asthma

51. Asthma
• Chronopharmacological studies show that the
development of asthma symptoms and many
types of bronchospastic attacks is clearly more
common from midnight to early morning
• The risk of asthmatic attack is almost 70 times
higher at 04:00-05:00 AM, compared with the
afternoon

52. • Exogenous factors:
– allergen exposure
– temperature changes during the day
– night break in bronchodilator use
– supine position during sleep
– gastroesophageal reflux
Asthma

53. • Endogenous factors: small bronchi diameter
significantly increases during the day and
decreases at night:
• adrenergic blockade of beta-receptors
• cholinergic dominance
• lowest concentrations of cortisol and
• Ig E with highest concentration of histamine
around 4:00 AM
Asthma

54. • Chronopharmacotherapy
– aimed at getting maximal effect from bronchodilator
medications during the early morning hours.
• Inhaled corticosteroids: single daily dose administered
at 5:30 PM rather than 8 AM is nearly as effective as 4
doses per day
• Oral Prednisone: much more effective in improving
several features of nocturnal asthma and response to
inhaled β-2 agonists when administered at 3 PM rather
than 8 AM
Asthma

55. Allergic rhinitis
• The symptoms of allergic rhinitis and even
the skin testing results, can vary according
to the time of day
• The major symptoms are usually worst in the
morning and evening
• Chronotherapy:
• Antihistamine once-daily before bedtime to
control overnight exacerbations and during
sleep
• morning oral corticosteroid therapy for
severe allergic rhinitis

56. Blood Pressure

57. • B.P. rises about 20 % immediately after awakening & least during sleep
Blood Pressure

58. • ↑Physical activity (Sudden)
• ↑ Catecholamine levels

59. COMMON ONSET TIME OF CVS DISEASES
Disease Common Onset time
Atrial fibrillation Morning/ night
Ventricular
tachycardia/fibrillation
Morning
Acute coronary
syndrome
Early morning
Pulmonary embolism Early morning
Cerebral infraction Morning

61. • Bedtime ADH analogue dosing help to alleviate nocturnal bedwetting in
children and nocturia in adults

62. Peptic ulcer
• Pathogenesis of stomach ulcers is associated with
Helicobacter pylori and H+ secretion by the
stomach.
• Acidity (H+) reaches its peak in the evening
between 10 pm and 2 am in both the healthy
and patients affected by gastric ulcers.
• Ulcer pain is worst at this time
• Ulcer healing is directly related to acid secretion
inhibition at night
• Evening administration of H2 receptor
antagonists or PPI is justified from the point of
view of chronopharmacology.

65. Antipsychotic drugs

66. Musculoskeletal System
-Arthritis
• Chronobiological patterns have been
observed with arthritis pain
– The symptoms of rheumatoid
arthritis are always worse in the
morning between 8 am and 11 am
– Taking long-acting NSAIDs like
flubiprofen, ketoprofen and
indomethacin at bedtime
optimizes their therapeutic effect
and minimizes or averts their side
effects

67. • People with osteoarthritis, the most
common form of the disease, tend
to have less pain in the morning
and more intense between 2 pm
and 8 pm
• For osteoarthritis sufferers, the
optimal time for a NSAID-
Ibuprofen in morning for afternoon
worsening and evening dose for
night time worsening
Musculoskeletal System
-Arthritis

68. Hypercholesterolemia
• More Cholesterol synthesis takes place in the
evening than in the morning with the involvement of
the enzyme HMG-CoA reductase
• Inhibition by HMG-CoA reductase inhibitors (Statins)
• Hence, Evening dose of HMG-CoA reductase
inhibitors is more effective with the exception of
Atorvastatin which has got longer half life

69. Diabetes
• Early morning increase in blood sugar level:
– The dawn phenomenon: release of hormones
(between 3 a.m. and 8 a.m.) which signal the
liver to release glucose. As the bedtime
insuline level decreased, the sugar level rises.
– The Somogyi effect: “rebound hyperglycemia”;
high morning sugars preceded by an episode of
low blood sugar; occurs if the blood sugar
dropped to low in the night (for example
because of overabundance of insulin)

71. Diabetes
• Treatment:
– long-acting insulin in the evening so its peak
action happens when blood sugars start rising
– extra insulin overnight if blood sugar goes up
during the night
– insulin pump, which can be programmed to
release more medication in the morning
– use of appropriate types of insulin in
appropriate amounts

72. Aminoglycoside Antibiotics
• Renal toxicity of Aminoglycoside Antibiotics
(gentamycin, tobramycin & amikacin) can be
reduced by giving the drug as a single daily
injection when the patients are active (at day
time / in the activity period)

73. Analgesics
• Stronger analgesic effects were observed when
tramadol and dihydrocodeine were given in the
evening to relieve painful stimuli.

78. Conclusion
• Effectiveness and toxicity of a drug are not
constant over 24 hr period.
• Understanding the biological rhythms can
optimize and individualize drug therapy to a great
extent.
• Thus it can help to decrease the drug related
toxicity and enhance effectiveness.