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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
In medicine, 3 disciplines take into
account the influence of time:


  CHRONOPHYSIOLOGY

  CHRONOPATHOLOGY

  CHRONOPHARMACOLOGY
Definition ????

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.
Chronopharmacology

  Investigative science concerned with the
  biological rhythm dependencies of
  medications.

Subdivided into

      chronopharmacokinetics
      chronotoxicity
      chronesthesy
      chronotherapy
Biological rhythm ( biological clock)

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

Flowers
Fruits

Human body
“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 Addison’s disease

Asymmetrical morning high and late-afternoon low-dose
corticosteroid substitution best corrects fatigue and
abnormal circadian time structure.
Peak time functions
Dawn Phenomenon
20




10




  0
      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:                                                        Treatment:
Less insulin in body                                           Use enough dose.
Spurt in GH, cortisol.                                         Reduce bed time snack.


Rise in blood sugar at night
Somogyi Phenomenon
 20




 10




   0
       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:                                                      Treatment:
too much insulin                                                  Decrease        pre-supper
                                                            intermediate insulin.
Long acting                                                 Change or start pre-bed snack.


Blood sugar drop at night
Hormones           to   rise        blood    sugar
levels
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.
Applied Chronopharmacology

                 CVS
Objective
Deliver drug in high conc. During great
need
ACE inhibitors
Nifedipine             Night
Amlodipine
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
•   Lullman’s 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

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Chronopharmacology basic concepts

  • 1. Basic Concepts in Chronopharmacology DR.swanand s. pathak MBBS, MD ( Pharmacology),DACM,IDCR drswanandp@yahoo.co.in
  • 2. 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
  • 3. In medicine, 3 disciplines take into account the influence of time: CHRONOPHYSIOLOGY CHRONOPATHOLOGY CHRONOPHARMACOLOGY
  • 4. Definition ???? 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.
  • 5. Chronopharmacology Investigative science concerned with the biological rhythm dependencies of medications. Subdivided into chronopharmacokinetics chronotoxicity chronesthesy chronotherapy
  • 6. Biological rhythm ( biological clock) same events occurring in the body of a living being over a particular time interval Flowers Fruits Human body
  • 7. “Dhire dhire re mana dhere sab kuch hoi Mali siche sau ghada ritu aay phal hoi” --- KABIR
  • 8.
  • 14. Applied Chronopharmacology Endocrine system Corticosteroids Once-daily morning dose dosing minimizes risk of adrenal suppression and other side effects.
  • 18. Applied Chronopharmacology Endocrine system Congenital adrenal hyperplasia Bedtime corticosteroid dosing controls excessive hormone secretion in
  • 19. Applied Chronopharmacology Endocrine system Chronotherapy for Addison’s disease Asymmetrical morning high and late-afternoon low-dose corticosteroid substitution best corrects fatigue and abnormal circadian time structure.
  • 21. Dawn Phenomenon 20 10 0 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: Treatment: Less insulin in body Use enough dose. Spurt in GH, cortisol. Reduce bed time snack. Rise in blood sugar at night
  • 22. Somogyi Phenomenon 20 10 0 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: Treatment: too much insulin Decrease pre-supper intermediate insulin. Long acting Change or start pre-bed snack. Blood sugar drop at night Hormones to rise blood sugar levels
  • 23. Applied Chronopharmacology Endocrine system Bedtime ADH analogue dosing helps to alleviate nocturnal bedwetting in children and nocturia in adults.
  • 24. 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.
  • 25.
  • 26. Applied Chronopharmacology CVS Objective Deliver drug in high conc. During great need ACE inhibitors Nifedipine Night Amlodipine
  • 27. 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
  • 28. Applied Chronopharmacology CVS When the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were first introduced, morning dosing was recommended.
  • 30. 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.
  • 31. Applied Chronopharmacology CVS Bedtime (but not morning) aspirin dosing best for preventing pregnancy-induced hypertension and preeclampsia.
  • 32. 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.
  • 33.
  • 34.
  • 36. 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
  • 37. 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.
  • 38. 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.
  • 40. Applied Chronopharmacology GIT Histamine2 antagonists In the past, were administered at regular intervals around the clock, on the basis of pharmacokinetic properties.
  • 42. 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
  • 43. 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.
  • 44.
  • 45.
  • 46. Acknowledgements • Wikipedia • Google • Concepts of Chronopharmacology by N. Udupa • Lullman’s atlas of pharmacology
  • 47.
  • 48. 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