Chronopharmacology

2. CHRONOPHARMACOLOGY
Dr. Ashutosh Tiwari
M.D. Pharmacology (1st year)
14/02/2014 SAIMS Indore

3. Overview
 History
 Biological clock
 Types of rhythm
 Physiological functions & diseases
exhibiting circadian rhythm
 Application in various disease
 Pulsatile drug delivery system
 Recent advances

4. History
Jean-Jacques
d'Ortous de Mairan
description of
circadian rhythms in
plants in 18th century
Franz Halberg
coined the word circadian
in 1960s
considered as one of the
founders of chronobiology

5. Chronopharmacology
science concerned with
the variations in the
pharmacological
actions of various
drugs over biological
timings & endogenous
periodicities

6. Biological Rhythm
 A determined rhythmic biological
process or function.
 Chronobiology
 Science that studies the biological rhythms
or the science dealing with the phenomenon
of rhythmicity in living organisms

7. Types of rhythm
 Ultradian ( <20h)
 ECG, Sleep stages
 Circadian (20<  <28h)
 Sleep wake cycle
 Infradian (>28 h)
 Pre-menstrual syndrome
 Circaseptan ( ~7d)
 Work rest scheme
 Circamensual (~30d)
 Menstrual cycle
 Circannual (~1 yr)
 Hibernation period

8. CIRCADIAN RHYTHM
 Circadian (circa = around & diem = day)
 Go over ~24hrs
 Oscillations in the biological, physiological &
behavioral functions of an organism with a
periodicity of 24 hrs.

9.  Circadian rhythms are particularly
important in medicine
 A circadian clock in the brain coordinates
with daily physiological cycles
 – sleep/wake - digestion
 – temperature - hormones
 Physiological day is about 24 hours .
– Clock is reset daily by the
environment .
• day/night
• social schedules

10. Zeitgeber
 from German: “synchronizer”
 Any exogenous (external) cue that
synchronizes an organism's endogenous
(internal) time-keeping system (clock) to
the earth's 24- hour cycle
 Examples
 Light-darkness
 Warmth-cold
 Eating-fasting
 Social contact-isolation
 Noise-quiet
 Also: pharmacological
manipulation


11. Circadian Rythm
 Biological clock / Circadian pacemaker is
present in the Supra-chiasmatic nuclei
(SCN) in hypothalamus
 Light falls on the eye  light signals
transmitted by afferent nerves arising from the
retina 
retino hypothalamic tract 
paired suprachiasmatic nuclei in the
hypothalamus

12. Circadian rhythm
 SCN passes the information to Pineal
gland  Melatonin hormone
 SCN connections with the autonomic
nervous system  set the sensitivity of
endocrine glands (i.e., thyroid, adrenal,
ovary)
 Time of light, duration, wavelength &
intensity determine circadian patterns of
body

13. The suprachiasmatic nucleus controls circadian
rhythms in response to hormonal variation in
the body

14. Consequences of disrupting biological rhythms
 If external cues
change there occurs
disruption of
biological rhythms
 Shift work
 Jet lag
we have to re-adjust
our internal clock
 Melatonin (useful in
jet lag /sleep
disorder)

15. Physiological functions showing
circadian rhythm

17. Diseases known to display circadian Rhythm

19.  In medicine 3 disciplines are taken
account according to time
Chronophysiology
Chronopathology
chronopharmacology
Chronokinetics
Chronesthesy
Chronergy
Chronotoxicity
Chronotherapeutics

20. Chronokinetics
Deals with study of temporal changes in
pharmakokinetic parameters – ADME, due to time
of administration
Chronesthesy
Circadian or other systemic changes in the
susceptibility and sensitivity of the target system
to a drug
Chronergy
Rhythmic difference in effects of drug on the
organism as a whole which includes both desired
and undesired effects

21. Chronotherapeutics
Application of chrono-biological principles to the
treatment of diseases
Chronopharmaceutics
branch of pharmaceutics devoted to the design and
evaluation of drug delivery systems that release a
bioactive agent at a rhythm that ideally matches the
biological requirement of a given disease therapy.

22. Pulsatile drug delivery system
 Now a days there is greater attention on
development of sustained, controlled, and
delayed release system
 Diseases have predictable cyclic rhythm and
timing of medication can improve the
outcome of desired effect
 Therefore condition demands release of a
drug as a pulse after a lag time and has to be
complete and rapid drug release after a lag
time

23. Chronopharmacodynamics
Important factors in
Chronopharmacodynamics:
 Circadian Rhythm has been found for
 receptor number or
 Receptor conformation
 second messengers

24. Why study Chronopharmacokinetics?
 PK-PD vary with time
 Gastric motility: is double in day time than in night
 Plasma protein concentrations are higher in day than in
night
 Hepatic blood flow has been shown to be greatest at 8 am
and metabolism to be reduced during the night
 When Symptoms of a disease are circadian phase dependent
e.g. nocturnal asthma, angina pectoris, myocardial infarction,
ulcer diseases
 Drug toxicity can be avoided/ Minimized by administering at
a particular time

25. Chrono PK- Absorption
 Depends on pH, gastric emptying, motility and
gastrointestinal blood flow
 Lipophilic drugs are better absorbed in
morning because of faster gastric emptying
time and a higher GI perfusion in the morning
 Valproic acid, Indomethacin, Ketoprofen are
better absorbed in the morning
 Skin penetration of lidocaine and prilocaine is
better in evening

26. Chrono PK- Distribution
• Blood flow depends on several regulatory factors,
including sympathetic and parasympathetic systems
whose 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 concentration of albumin and alpha 1 glycoprotein
is circadian time dependent : show peak around noon.
Therefore drugs bound to plasma proteins like
valproic acid, carbamazepine, diazepam, prednisolone etc.
show increase in free fraction at night

27. Chrono PK- Metabolism
 Depends on Liver enzyme activity & Hepatic
blood flow
 High extraction ratio: metabolism depends on
blood flow
 Low extraction ratio: metabolism depends on
enzyme activity
 Hepatic blood flow high in morning
 Metabolism reduces in night

28. Chrono PK- 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.

29. DRUGS UNDERGOING CHRONOKINETICS:
1. Antibiotics :
Aminoglycosides: gentamycin, tobramycin,
amikacin
•Renal toxicity of aminoglycosides can be reduced
by giving the drug as a single daily injection when
patients are active (at day time / in the activity
period)

30. 2. Antihypertensive drugs:
• 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.

31. 3. Valproic acid(antiepileptic):
•Cmax tended to be higher, tmax was shorter and
absorption rate constant (ka) tended to be larger in
the morning than in evening.
4. Anti-inflammatory drugs :
•Have greater rates and extents of bioavailability
when administered in the morning than evening.
Eg. Indomethacin, Ketoprofen

32. 5. Anti-Migraine drugs
•Sumatriptan is a drug of choice in migraine
treatment.
•The mean peak serum concentration was
significantly higher following the 07:00 h
administration than after the 19:00 h administration.
6. Anticancer drugs :
•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.

33. 7. Anti hyperlipidemic drugs
•More Cholesterol systhesis takes place in the evening
than in the morning with the involvement of the
enzyme HMG Co-A Reductase.
•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 with the
exception of Atorvastatin which has got longer half
life.

34. 8. Opiod analgesics
•Stronger analgesic effects were observed when
tramadol and dihydrocodeine were given 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.

35. 9. Heparin: even if given at a constant infusion
rate; aPTT and risk of bleeding varies with hour of
day and is higher at night.
10. Topical steroids: anti-inflammatory action is
maximum in afternoon
11. 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.
•The plasma levels of lidocaine were significantly
higher in the evening than at any other time of day.

36. 11. 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 14:00 h and at its longest at 02:00 h
Ketamine, Etomidate, Propofol, and Halogenated Agents
Action longer during the night than during the day.
Halothane
Greatest efficacy of halothane occurred between 24:00
and 06:00 h.

37. 12. Antipsychotic drugs
 Chlorpromazine would be most effective in
producing sedative and antipsychotic
effects when administered at midnight and
immediately after rising, respectively.
 For haloperidol, administration in the
evening would be best for obtaining either a
sedative or antipsychotic effect.

38. 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, and
the special drug delivery system to synchronize drug
concentrations to rhythms in disease activity.

39. Chronotherapeutics:
Chronotherapy found useful in:
1. Allergic rhinitis
2. Bronchial asthma
3. Peptic ulcer disease
4. Rheumatoid arthritis, Osteoarthritis
5. Angina pectoris
6. MI
7. Hypertension, stroke
8. Cancer

40. Necessity of Chronotherapeutic approach
 When the “therapeutic window” for a
given medication 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 efect of the drug can be
obtained only by a time-modulated
therapeutical modality.

41. Allergic rhinitis
 Rhinitis- worst in the
morning and evening
 once-daily, non-sedating
antihistamine by giving it
before bedtime to control
overnight exacerbations and
during sleep
 morning oral corticosteroid
therapy for severe allergic
rhinitis

42. Bronchial Asthma-
 The risk of asthmatic attack is almost 70
times higher in patients at 04:00-05:00 in the
morning, compared with the afternoon.
Causes :
Small bronchi diameter significantly increases during the day and
decreases at night because of :
 Adrenergic blockade of ß-receptors,
 Dominance of alpha-adrenergic pathways,
 Cholinergic dominance,
 Lowest concentrations of cortisol
 Ig E with highest concentration of histamine around 04:00 AM

43. Treatment
 SR formulation of theophyline at night
 Increase efficacy
 Decrease s/e
 Avoid multiple dosing
Nocturnal vagus nerve hyperactivity
Relieved by cholinergic antagonist
eg. ipratropium bromide

44. Corticosteroids
 a single daily dose of inhaled corticosteroids,
when administered at 5:30 pm rather than 8
am, was nearly as effective as four doses a
day.
 single dose oral prednisolone at 3pm is most
effective
Leukotriene receptor antagonist
zileuton at night is most effective as LTB4
conc. max in night

45. Peptic ulcer
 In the past, were administered at
regular intervals around the clock, on
the basis of pharmacokinetic
properties.
 Maximal acid secretion, peptic ulcer
disease pain, and perforation of gastric
and duodenal ulcers are more common
at night
 H2blockers(Ranitidine, Cemitidine,
famotidine) are given at evening time

46. Arthritis
 The symptoms of
rheumatoid arthritis are
worse in the morning.
 People with osteoarthritis,
tend to have less pain in the
morning and more at night
 NSAIDs (flubiprofen,
ketoprofen and
indomethacin)
 Effectively relieve pain of RA
when given at night, and
better results in case of OA
seen when these are given
in morning.

47. cvs
B.P. rises about 20%
immediately after
awakening & least during
sleep.
1st two hours after arising
are the peak hrs. for MI,
hemorrhagic stroke &
thrombotic infarcts.

48. CVS
Reason
- ↑ physical activity (sudden)
- ↑ catecholamine levels
- ↑ platelet aggregation
- ↑ vascular tone
- ↓ intrinsic thrombolytic activity

50.  A new COER verapamil (Controlled Onset Extended
Release) used in Hypertension
 It is formulated as a pill with a shell that dissolves slowly.
 Taken at bed-time, this exerts peak effects between 5
am and noon & no mid-night dip in B.P is seen.
 ACE-I (Ramipril) & Doxazosin, given at bedtime

51. Endocrine system
 Once-daily morning dose dosing
minimizes risk of adrenal
suppression and other side effects.
 Bedtime ADH analogue dosing
helps to alleviate nocturnal
bedwetting in children and
nocturia in adults.

52. Diabetes Mellitus
 Morning hyperglycemia may be
observed in patients with diabetes
mellitus
 Dawn phenomenon
 Somogyi Phenomenon

53. Dawn Phenomenon
0
10
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cause:
During night increase in GH, cortisol, catecholamines
+ decreasing levels of bedtime insulin

Rise in blood sugar in morning

54. Somogyi Phenomenon
0
10
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cause:
too much / long acting insulin or decreased bedtime snacks  hypoglycemia at
night 
increase in GH, cortisol, catecholamines 
Rise in blood sugar in morning

55. Oral contracetives
Prescribed as per
menstrual cycle

56. Cancer
 Different biological rhythms for normal and
tumor cells
 Tumor: fast growing-2 am,
slow growing:10pm
 Cancer Rx
1.duration of the phase of cell cycle
2.cell proliferation rate

57. Cancer
 Cancer drug (s phase specific) administered more in night
time, because cancer cells divide more in night time &
Host cells in morning
 But in treatment with 6-mercaptopurine and methotrexate
, evening dose is given to patient.
 Colorectal cancer- Oxaliplatin is given in during daytime &
flurouracil at night.
 Breast cancer: Surgery during later half of the menstrual
cycle - more clearance rate then early half
 Progesterone in the later half inhibit the enzymes
responsible for spread of cancer cells

58. Chronotoxicity
 Specifically with antitumor agents
 Irinotecan induced leucopenia is more
pronounced in late active phase

59. Recent advances
 Casein Kinase 1 (CK-1) inhibitor- potential
new drug
 Reset the circadian clock enzymes
 Use: jet lag, sleep disorder, bipolar disorder
 Animals trials completed.
 Human trials awaited
New Discovery May Allow People to Hit “Snooze” Button on
Internal Clock

60. Summary:
 Chronopharmacology: science concerned
with the variations in the pharmacological
actions of various drugs over biological
timings & endogenous periodicities
 Various physiological functions as well as
diseases exhibit circadian rhythm
 Also there are various drugs which follow
chronokinetics
 Therefore application of chronotherapeutics
in such diseases can maximise the efficacy
& minimize the adverse effects associated
with the drugs resulting in improved
therapeutic outcome.

62. Slowly slowly O mind,
everything in own pace happens
Gardner may water a hundred buckets,
fruit arrives only in its season
Sant Kabir