Basic Concepts

in
Chronopharmacology

DR.swanand s. pathak
MBBS, MD ( Pharmacology),DACM,IDCR
drswanandp@yahoo.co.in



Chrono -Pharmacology


Chronology : The arrangement of events according to
the time of occurrence .
Rhythm

CHRONOBIOLOGY
The science dealing with the phenomenon of
rhythmicity in living organisms


CHRONOPHYSIOLOGY

CHRONOPATHOLOGY

CHRONOPHARMACOLOGY
In medicine, 3 disciplines take into
account the influence of time:
The study of rhythmic, predictable-in-
time differences in the effects and/or
pharmacokinetics of drugs both in
experimental animals and in men. It
investigates the effects/side effects of
drugs upon temporal changes in
biological functions or symptoms of a
disease as well as drug effects as a
function of biologic timing.

Definition ????


Investigative science concerned with the
biological rhythm dependencies of
medications.




Chronopharmacology
Subdivided into


chronopharmacokinetics
chronotoxicity
chronesthesy
chronotherapy


same events occurring in the body of a
living being over a particular time interval

Flowers
Fruits

Human body
Biological rhythm ( biological clock)

Dhire dhire re mana
dhere sab kuch hoi
Mali siche
sau ghada
ritu aay phal hoi

--- KABIR
Biological rhythm - types
Blood Pressure Rhythm
Peak time functions
Disease rhythm
Advantage
Time the administration
of the drugs

Applied Chronopharmacology

Endocrine system
Corticosteroids

Once-daily morning dose dosing
minimizes risk of adrenal suppression
and other side effects.
Peak time functions
Applied Chronopharmacology
Applied Chronopharmacology
Applied Chronopharmacology

Endocrine system

Congenital adrenal hyperplasia

Bedtime corticosteroid dosing controls excessive hormone
secretion in

Applied Chronopharmacology

Endocrine system
Chronotherapy for Addisons disease

Asymmetrical morning high and late-afternoon low-dose
corticosteroid substitution best corrects fatigue and
abnormal circadian time structure.

Peak time functions
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:
Less insulin in body
Spurt in GH, cortisol.

Rise in blood sugar at night

Treatment:
Use enough dose.
Reduce bed time snack.


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 insulin

Long acting

Blood sugar drop at night
Hormones to rise blood sugar levels
Treatment:
Decrease pre-supper
intermediate insulin.
Change or start pre-bed snack.


Applied Chronopharmacology

Endocrine system


Bedtime ADH analogue dosing helps to alleviate
nocturnal bedwetting in children and nocturia in adults.
Applied Chronopharmacology

CVS
Myocardial infarction, acute cardiac
arrest , transient myocardial ischemia
Onset early morning 34% events

Reason release of catecholamines ,
cortisol , increase in platelet
aggregation , vascular tone ,
heart rate surge.
MORNING HOURS
INCREASED PLASMA
NOREPINEPHRINE ,
CORTISOL AND RENIN
ACTIVITY
INCREASED
SYMPATHETIC TONE
INCREASED PLATELET
AGGREGABILIGY AND
DECREASED
FIBRINOLYTIC
ACTIVITY
Applied Chronopharmacology

CVS
Objective
Deliver drug in high conc. During great
need
ACE inhibitors
Nifedipine
Amlodipine
Night
Applied Chronopharmacology

CVS
The first chronotherapeutic therapy for
hypertension and angina pectoris

Matches drug delivery to the circadian
patternof blood pressure and rhythm of
myocardialischemia.

Verapamil has been employed
Applied Chronopharmacology

CVS
When the 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors were first
introduced,


morning dosing was recommended.

Peak time functions
Applied Chronopharmacology

CVS

This strategy was re-evaluated after the discovery of
the circadian rhythm of cholesterol biosynthesis in
which higher rates of cholesterol intake and hepatic
cholesterogenesis occur during the evening hours,
even in the fasting state.

Except Atorvastatin all (HMG-CoA) reductase
inhibitors are administered between the evening
meals and sleep.

Applied Chronopharmacology

CVS
Bedtime (but not morning) aspirin


dosing best for preventing pregnancy-induced
hypertension and preeclampsia.
Applied Chronopharmacology

RS


Asthma the most common disease with the largest
circadian variation.

Because asthma has such a striking circadian variation,
several types of chronotherapy have been tried.

Peak time functions
Applied Chronopharmacology

RS
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.

Oral prednisone
has been shown to be much more effective in
improving several features of nocturnal asthma
[FEV1]and response to a standard dose of
inhaled beta2 agonist when administered at 3 pm
rather than 8 am
Applied Chronopharmacology

RS
Theo-24

Use of a timed-release formulation of theophylline achieved
therapeutic drug concentrations during the night and avoided toxic
levels during the day.
Applied Chronopharmacology

Autoimmune diseases


Arthritis

The new cyclooxygenase-2 inhibitors effectively relieve
osteoarthritis symptoms when taken in the evening;
better results are obtained in rheumatoid arthritis when
part of the dose is taken in the morning.
Disease rhythm
Applied Chronopharmacology

GIT
Histamine2 antagonists

In the past, were administered at regular intervals around
the clock, on the basis of pharmacokinetic properties.

Peak time functions
Applied Chronopharmacology

GIT


Maximal acid secretion, peptic ulcer disease pain, and
perforation of gastric and duodenal ulcers are more
common at night, administration of these drugs at bedtime
is more effective.

Nocturnal administration not only reduces acid secretion
more effectively but also promotes ulcer healing and
reduces ulcer recurrence
Applied Chronopharmacology

CNS
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.
Acknowledgements
Wikipedia
Google
Concepts of Chronopharmacology by N. Udupa
Lullmans atlas of pharmacology
Presented on
30-03-2011/national CME on personalized medicine / MGMC / Puducherry
23-07-2011/zonal CME for post graduates/ DR NTR University/ mamata medical college/
Vijaywada