Chronopharmacology

CHRONOPHARMACOLOGY

1. BY DR RAMESH KRISHNAN FINAL YEAR MD PHARMACOLOGY CHRONOPHARMACOLOGY

2. Introduction :- • Most facets of mammalian physiology and behavior vary according to time of- day, thanks to an endogenous “circadian” clock. • Daily oscillations of proteins is necessary for either drug absorption or metabolism results in circadian pharmacokinetics; and oscillations in the physiological systems targeted by these drugs result in circadian pharmacodynamics . • Circadian clocks influence all major organ systems, and this influence translates directly into disease pathology that also varies with time of day

3. TYPES OF BIOLOGICAL RHYTHMS • Circadian: Lasting for about 24 hours. -Sleep wake cycles • Infradian : Cycles longer than 24 hours. -Menstrual cycle • Ultradian : Cycles shorter than a day. -Neuronal firing time • Seasonal: Seasonal affective disorders.

4. WHAT IS CHRONOBIOLOGY ? The branch of science focusing on biological rhythms and their mechanisms.

5. > Science dealing with optimization of drug effects & minimization of adverse effects by timing medications in relation to biological rhythm. > It is concerned with the effects of drugs upon the timing of biological events and rhythms. • Subdivided into - Chronopharmacokinetics - Chronotoxicity - Chronesthesy - Chronotherapy WHAT IS CHRONOPHARMACOLOGY ?

6. • It deals with the study of the temporal changes in the pharmacokinetics of the drugs with respect to time. • Study of absorption, distribution, metabolism, and excretion of drugs according to the time of the day or year. WHAT IS CHORONOPHARMACOKINETICS ?

7. The rhythmic changes in susceptibility or sensitivity of a target system to a drug. WHAT IS CHRONESTHESY ?

8. Rhythmic changes of both the desired[effectiveness] and undesired [toxicity, tolerance] effects on the organism . WHAT IS CHRONERGY ?

9. WHAT IS 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. Refers to the concept of matching timing of treatment with intrinsic timing of illness.

10. It prevents an overdosing of any class of drug. It makes the utilization of the drug more appropriate and thus the value of a drug is increased. It reduces the unnecessary side effects of a drug and helps in caring out the treatment for only a particular or limited period of time WHAT ARE THE ADVANTAGES OF CHRONOTHERAPEUTICS ?

11. Branch which designs and develops a drug delivery system in accordance with biological rhythm to optimize the treatment of disease. WHAT IS CHRONOPHARMACEUTICS ?

12. Circadian rhythm Biological processes, including the sleep-wake cycle is controlled by pacemaker present in the suprachiasmatic nuclei ( SCN) . Due to alterations in biological activity many diseases like allergic rhinitis ,arthritis, asthma, cardiovascular diseases, peptic ulcer disease, etc. shows exacerbation of symptoms. Circadian rhythms, physiology, and behavior of mammalian bodies are controlled by clock genes namely Per1, Per2 and Per3, which are rhythmically expressed in the SCN.

13. Applications of Chronopharmacology

14. WHY IS ACUTE ATTACK OF ASTHMA MORE COMMON DURING NIGHT ?

15. Because of Increased bronchoconstriction at night due to… ↑Parasympathetic tone ↓ Adrenaline ↓ Cortisol at midnight ↑Sensitivity to irritants and allergens at night leads to exacerbations of allergic rhinitis & asthma Rx - Theophylline and Beta 2 agonist are timed at evening .

16. Because between 6am and 12 noon there is • ↑ Vascular tone • ↑ Platelet aggregation • ↓ Intrinsic thrombolytic activity. WHY THERE IS HIGHER INCIDENCE OF MI, SUDDEN CARDIAC DEATH ,ANGINA PECTORIS & STROKE BETWEEN 6 AM & 12 NOON ?

17. Why there is faster reduction in BP with morning dose of antihypertensives ?

18. Heart rate and blood pressure are increased in the early morning hours (morning or A.M. surge). The blood pressure declines form mid afternoon and is minimum at midnight In most hypertensive patients, there is marked rise in blood pressure upon awakening that is called the morning or "a.m." surge.

19. Cardiovascular drugs • Aspirin – maximum antiplatelet effect in the morning. • Thrombolytics and Heparin – ↓ benefit during early morning hours. • Labetalol – more effective in early morning hours. • Enalapril - Peak effect in the afternoon after morning dose.

20. Why is Corticosteroids given as single morning dose causes less pituitary adrenal suppression ? Because there is highest secretion of cortisol in early morning & Lowest at midnight.

21. because acid secretion, pain and perforation of gastric and duodenal ulcers are more at night rather than in day time . Why is Administration of H2 receptors antagonists or PPI drugs at bedtime is more effective in reducing acid secretion and promoting peptic ulcer healing?

22. Because of higher rates of cholesterol intake and hepatic Cholesterogenesis occur during the evening hours, even in the fasting state. why is Evening dose of HMG CoA reductase inhibitors more effective ?

23. Because Melatonin is secreted at night by pineal gland and it synchronizes sleep wake cycle with circadian rhythm. Why is Bedtime administration of Melatonin agonist [ Ramelteon ] as hypnotic for sleep onset insomnia & jet lag symptoms is more effective ?

24. Why is s-phase active cytotoxic therapy at late night is more advantageous for lymphoma treatment ? Because DNA synthesis in the normal human bone marrow cells has a peak around noon while the peak of DNA synthesis in lymphoma cells are near midnight.

25. ChronoPharmaceutics

26. Chronotherapeutic Drug Delivery Systems

27. Controlled release formulations Controlled release formulations can be divided into rate-controlled release, delayed-release and pulsed-release formulations. Delayed-release formulations Time-controlled release and site-specific dosages forms. When constant drug plasma levels need to be avoided, as in chronotherapy , time-controlled or pulsed-release formulations are preferable. By timing drug administration, plasma peak is obtained at an optimal time and the number of doses per day can be reduced.

28. Pulsatile drug delivery systems Here a targeted drug is deliverd at specific site due to induction of certain physiochemical stimuli at target site. > Release of certain enzymes, hormones, antibodies, pH of the site, temperature of the site, presence of certain cells, and concentration of biomolecules (glucose, neurotransmitters, inflammatory mediators) acts as stimuli to trigger the release of drug from these types of drug delivery systems.

29. THANK YOU