chronopharmacology
TRANSCRIPT
ChronoPharmacology
Dr. Anirudha Potey
Flow of the seminar
• Definition
• Biorhythms
• The Biological Clock
• Circadian Rhythm
• Zeitgebers
• Molecular Basis
• Modulators
• Physiologic Variations
• Disease pattern
• Divisions of Chronopharmacology
• ChronoPharmacokinetics
• ChronoPharmacodynamics/Chronesthesy
• ChronoTherapeutics
• ChronoToxicity
• Chrono Drug Delivery Systems
• Applied Chronopharmacology
• Chronopharmacology in Ayurveda
• Conclusion
Definition
The investigative science concerned with the effects of drugs upon the
timing of biological events and rhythms.
It also links effects of drugs due to variations in the biological rhythms.
Ultra
radian
Cir
cadian
Infra
radian
Circa
Septan
Circa
Di
Septan
Circa
Vi
gintan
Circa
Tri
gintan
Circa
Annual
Biorhythms
T<20 h 20h<T<28 h T = 7 dT>28 h T = 1 yT = 30 dT = 21 dT = 14 d
The Biological Clock/ Circadian Rhythm
SCN Input Light
SCN Output Sleep/WakefulnessFeeding and Energy ExpenditureGlucose HomeostasisHormonal RegulationBlood Pressure & Respiratory changes
Peripheral Clocks Input
Feeding/ FastingSignals from SCN
Peripheral Clocks Output
LipogenesisInsulin SecretionGlucose ClearanceFood AbsorptionFat Accumulation
Zeitgeber
Zeitgeber
Light – Darkness
Warmth – Cold
Eating – Fasting
Social Contact – Isolation
Noise – Quiet
Pharmacological Manipulation
Shift Work Jet Lag
Molecular Basis of Circadian Rhythm
E Box
PER 1
PER 3
PER 2
CRY 1
CRY 2
REVERBWD40
NONO
CK1
WDR5
Circadian rhythm modulators
• REVERB agonists – SR9009
• CK1 inhibitor – Longdaysin, LH846
• GSK3b inhibitor – Indirubin
Physiologic variations in relation to Circadian changes
Disease pattern due to circadian changes
ChronoPharmacokinetics
Subdivision of chronopharmacology which deals with the study of the
temporal changes in the pharmacokinetics of the drugs with respective
time.
Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics
Factors affecting pharmacokinetic variations
Gastric acid secretions and pH
Gastric motility
g.i blood flow
Drug protein binding
Liver enzyme activity
Hepatic blood flow
Glomerular Filtration Rate
Renal Blood Flow
Urinary pH
Tubular resorption
Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics
Diazepam
Acetaminophen
Theophylline
Digoxin
Propanolol
Nitrates
Nifedipine
Amitriptyline
Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics
Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics
Absorption
Distribution
Metabolism
Excretion
ChronoPharmacokinetics
Serum Concentration
Clearance
ChronoPharmacodynamics
Chronesthesy
Biological rhythms at the cellular and subcellular level can give rise to
significant dosing-time differences in the pharmacodynamics of
medications that are unrelated to their pharmacokinetics.
ChronoPharmacodynamics
ChronoTherapeutics
Discipline of medical treatment which allows for the consideration of a
patient’s biological rhythm, changes in the severity of a disease state
during the day, and the synchronizing of dosing and delivery of a
particular drug to allow for the optimal efficacy in the patient.
ChronoToxicity
Predictable- in-time variation in patient vulnerability to the side effects
of medications due to biological rhythm determinants.
Eg. irinotecan hydrochloride.
Chrono Drug Delivery Systems (Chrono-DDS)
OROS, CODAS, CEFORM, TIMERx, POLYMERS, MICROCHIPS
Applied Chronopharmacology
Asthma
Euphylong UniphylTheophylline SR
Allergic Rhinitis
Arthritis
Peptic Ulcer
Metabolic Disturbances
Myocardial Infarction
Hypertension
Valsartan
Antidepressants
Anticancer Drugs
Chronopharmacology in AyurvedaAbhakta Drugs in morning absorption is maximum and more efficient
Pragbhakta Just before food. For diseases of apana vayu – for strengthening and
preventing the disease of lower half of body and treating obesity.
Madhyabhakta In between foods. For diseases of samana vayu, disease of koshtas and
for paittic diseases.
Sanya
Pscadbhakta
In evenings after food. For diseases of udana vayu.
Muhurmuhuh Drugs given repeatedly for treating swasa (dyspnoea), kasa (cough),
hikka (hiccoughs), chardi (vomitting), visa (poisoning) and pipasa
(Thirst).
Samudga Before and after light food in hikka, akepsa(convulsions) and in diseases
of head and neck.
Sabhakta Drugs as appetizers with food, in children with weak constitution.
Conclusions
• Circadian biology influences nearly every aspect of physiology and
pharmacology.
• Ongoing research has begun to unveil the molecular mechanisms by which
circadian clock genes regulate pharmacokinetic and pharmacodynamic
processes.
• Many drugs are still given without regard to the time of day.
Conclusions
• Identification of rhythmic markers for selecting dosing time and further
research in the field of chronopharmaceuticals will lead to improved
progress and diffusion of chronotherapeutics.
• To monitor rhythmic markers such as clock genes it may be useful to
choose the most appropriate time of day for administration of drugs that
may increase their therapeutic effects and/or reduce their side effects.
Conclusions
• To produce new rhythmicity by manipulating the conditions of living organs
by using rhythmic administration of altered feeding schedules or several
drugs appears to lead to a new concept of chronopharmacotherapy.
• One approach to increasing the efficiency of pharmacotherapy is
administering drugs at times during which they are most effective.
