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
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
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)
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
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.
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
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
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.
61.
62. Slowly slowly O mind,
everything in own pace happens
Gardner may water a hundred buckets,
fruit arrives only in its season
Sant Kabir
Editor's Notes
The results indicate that in the unicellular green alga Acetabularia a rhythm of about 7 days (circaseptan) exists and that removal of the nucleus results in a circaseptan frequency multiplication
Ultradian-sleep cycle 90 min.
Infradian….circaannual-SAD. Treatment light therapy