chronopharmacology.pptx

chorono pharmacology m.pharm second sem

1. CHRONOPHARMACOLOGY BIOLOGICAL AND CIRCADIAN RHYTHM Presented by: Gifty Julia.I M.Pharm Department of Pharmacology 1 PSG COLLEGE OF PHARMACY

2. CONTENTS Introduction Chronopharmacology Types Biological rhythm & types Circadian clock Chronopharmacodynamics Chronopharmacokinetics Reference 2 PSG COLLEGE OF PHARMACY

3. Chronobiology Chronobiology is the branch of science which examines periodic phenomena in living organisms and their adaptation to biological rhythms . Chrono – relating to TIME In medicine 3 disciplines take into account the influence of time;  Chronophysiology  Chronopathology  Chronopharmacology   3 PSG COLLEGE OF PHARMACY

4. Chronophysiology Studies the timely organization of physiological processes. Chronophysiology deals with phenomenon of morning people and night owls and explain how biological systems and processes of organisms relate to each other with regard to timing. Chronopathology Deals with subject of disrupted timing in vital biological process. It describes different phenomena in abnormality of chronological sequences, as well as its characteristics, causes, prognostic and diagnostic significance and therapeutic implications.   4 PSG COLLEGE OF PHARMACY

5. Chronopharmacology It is concerned with effects of drug upon the timing of biological events and rhythms and the relation of biological timing and endogenous periodicities to the effect of drugs. When a drug is administered the pharmacological action of drug can be predicted based on body circadian rhythm. The maximum efficacy and minimum toxicity of a drug can be achieved if it is administered at appropriate time. “ Right drug in the right form at right dose at right time”. A circadian clock in the brain coordinates daily physiological cycle. 5 PSG COLLEGE OF PHARMACY

6. Chronopharmacology deals with 6 PSG COLLEGE OF PHARMACY

7. Chronotherapeutics : Knowledge of day-night and other prediction in time variations in the symptoms intensity and risk of acute exacerbation of disease coupled with evidence of circadian rhythms in the kinetics, effects and safety of medications constitutes the rationale for new pharmacologic approach to treatment. It deals with increase of the efficiency and safety of medications by proportioning their concentrations during the 24hrs in synchrony with biological rhythm determinants of disease. 7 PSG COLLEGE OF PHARMACY

8. Chronocokinetics It deals with the study of temporary changes in absorption (A), distribution (D), metabolism (M), excretion (E) and thus takes into account the influence of time of administration on these different steps. Temporal changes in drug absorption from GIT occurs due to circadian variations in gastric acid secretion and pH, motility, gastric emptying time, gastro intestinal blood flow, plasma protein binding and drug distribution Drug metabolism - temporal variations in enzyme activity, hepatic blood flow Renal drug excretion - due to variations in glomerular filtration, renal blood flow, urinary pH and tubular reabsorption 8 PSG COLLEGE OF PHARMACY

9. Chronesthesy : It deals with circadian or other systemic changes in the susceptibility and sensitivity of the target system to a drug. Chronergy : It deals with rhythmic difference in effects of drug on the organism as a whole which includes both desired and undesired effects Chrono toxicology : It is an aspect of chrono dynamics; it refers specifically to dosing time i.e rhythm – dependant differences in the manifestations and severity of adverse effects and thus intolerance of patients to medication. 9 PSG COLLEGE OF PHARMACY

10. Biological rhythm Biological rhythm are the repeating cycles of activity in living organisms. Eg;circadian rhythm . It is any cyclic change in level of bodily chemical or function Biological rhythm can be Internal (endogenous)-controlled by the internal biological clock e.g. body temperature cycle. External (exogenous)-controlled by synchronizing internal cycles with external stimuli eg . Sleep /wakefulness and day/light. 10 PSG COLLEGE OF PHARMACY

11. These stimuli are called ZEITGEBERS -from the German meaning “time givers”. Any exogenous (external) cue that synchronizes an organisms endogenous (internal) time-keeping system (clock) to the earth's 24hour cycles.Eg ; Light-darkness Warmth-cold Eating-fasting Social contact-isolation Noise-quiet 11 PSG COLLEGE OF PHARMACY

12. TYPES OF RHYTHM Ultradian -it is a recurrent period or cycle repeated throughout a 24hr day e.g. heart rate ,90 minutes sleep cycle Circadian (<28hrs)-“body clock” it is a cycle that tells our bodies when to sleep, rise, eat-regulating many physiological processes.E.g . sleeping and waking patterns. Infradian (>28hr) – rhythm with a period longer than the period of circadian rhythm eg . menstruation Circaseptan (approx.7days):work rest scheme Circamensual (appro.30days): menstrual cycle. Circannua l (appro.1yr)-occur at annual basis even in the absence of environmental cues.eg; animal migration. 12 PSG COLLEGE OF PHARMACY

13. CIRCADIAN RHYTHM Its derived from Latin phrase meaning “about a day”(about-circa, a day- dia ) Circadian rhythms are physiological and behavioural rhythm and include; Sleep/wakefulness cycle Body temperature Pattern of hormone secretion Blood pressure Digestive secretion Levels of alertness Reaction time Circadian rhythm have a period of 24-25hours When the rhythm is synchronized with the day/night it is termed a diurnal rhythm 13 PSG COLLEGE OF PHARMACY

14. CIRCADIAN CLOCK In humans circadian clock is located in the suprachiasmatic nuclei(SCN), in the hypothalamus. It is a tiny cluster of about 10000 nerve cells. Circadian clock controls longer term cycles The circadian clock is synchronised to the external cycles of light and darkness and social contact. The synchronized rhythm is called the diurnal rhythm . 14 PSG COLLEGE OF PHARMACY

15. Light falls on the eye  light signals transmitted by afferent nerves arising from the retina  retino hypothalamic tract  paired suprachiasmatic nuclei in the hypothalamus  SCN passes the information to pineal gland  melatonin hormone. The SCN clock ensures that melatonin is secreted only at night. Melatonin secretion last longer on the longer winter night. SCN connection with the autonomic nervous system  set the sensitivity of endocrine glands( ie , thyroid, adrenal, ovary) Time of light, duration, wavelength and intensity determine circadian pattern of body Disruption of the clock or its synchronization occurs during jet-lag, shift work, and old age Disruption of the clock detrimentally affects our well being and mental and physical performance. 15 PSG COLLEGE OF PHARMACY

16. BIOLOGICAL RHYTHMS OBSERVED IN VARIOUS BIOLOGICAL SYSTEMS 1.Urinary system Water and electrolyte excretion is significantly low during the sleep phase compared with active daytime in healthy individual. 2. Gastrointestinal system The rhythm of slow waves is controlled in various segments of the GIT: in the stomach (about 3 cycles per min), in the duodenum (12 cycles per min), in the jejunum and ileum (from 7 to 10 cycles per min), and in the colon (12 cycles per min). 16 PSG COLLEGE OF PHARMACY

17. 3. Hepatic system In normal humans, blood glucose and insulin levels in response to an oral glucose load vary over 24 h L ower glucose response and higher insulin levels occurrs in morning, regardless of fasting duration. This results in increased glucose tolerance in the morning compared to evening. 17 PSG COLLEGE OF PHARMACY

18. 4. Cardiovascular system Cardiovascular activities show circadian rhythm and cardiac electrophysiological properties change diurnally and enable the cardiovascular system adapt to rest, exercise cycles. Blood pressures are highest in afternoon and decrease in evening and attain lowest values at nights which are due to circadian rhythms in nervous and endocrine system. Myocardial infarction occurs frequently in morning as a result of several physiological and biochemical conditions.  18 PSG COLLEGE OF PHARMACY

19. 5. Hormone 19 PSG COLLEGE OF PHARMACY

20. CHRONOPHARMACODYNAMICS Biological rhythms at the cellular and subcellular level give rise to significant dosing-time differences in the pharmacodynamics of medications that are unrelated to their pharmacokinetics. Circadian rhythm has been found for Receptor number or Receptor conformation Second messenger 20 PSG COLLEGE OF PHARMACY

21. CHRONOPHARMACOKINETICS Pharmacokinetics- Pharmacodynamics 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 8am and metabolism to be reduced during the night. When symptoms of a disease are circadian phase dependent e.g. nocturnal asthma, angina pectoris, myocardial infraction, ulcer diseases Drug toxicity can be avoided/ minimized by administering at a particular time. 21 PSG COLLEGE OF PHARMACY

22. 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 higher GI perfusion in the morning. Valproic acid , Indomethacin , ketoprofen are better absorbed in the morning. Chrono PK distribution Blood flow depends on several regulatory factors, including sympathetic and parasympathetic systems with a predominant diurnal effect of the sympathetic system. A diurnal increase and nocturnal decrease of blood flow and local tissue blood flows shows difference in drug distribution depending on the dosing time. 22 PSG COLLEGE OF PHARMACY

23. Chrono PK metabolism Depends on liver enzyme activity and 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 reduced in night 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 day time. 23 PSG COLLEGE OF PHARMACY

24. DRUGS UNDERGOING CHRONOKINETICS Cephalosporins : the toxicity of ceftriaxone is decreased by administering it at night as its total clearance value is highest during night and lowest during day time . Anti-inflammatory drugs : Have greater rates and extents of bioavailability when administered in the morning than evening. E.g. indomethacin , ketoprofen   Anti hyperlipidemic drugs : More cholesterol synthesis takes place in evening than in morning with involvement of the enzyme HMG Co.A reductase (Inhibited by statins ) e.g. atorvastatin , fluvastatin.So statins should be administered at evening rather than at morning for increased efficacy. PSG COLLEGE OF PHARMACY 24

25. DISEASE AND THEIR CIRCADIAN RHYTMCITY Disease or syndrome Circadian Rhythmicity Allergic rhinitis Worse in early a.m./upon arising Bronchial asthma Exacerbations more common during sleep Rheumatoid arthritis Symptoms are most intense on awakening Osteoarthrtits Symptoms worse in the middle/latter portion of the day Angina pectoris Chest pain and ECG changes more common during the early a.m. Myocardial infraction Incidence greatest in the early a.m. Sudden cardiac death Incidence highest in ventricular tachycardia morning after awakening Peptic ulcer disease Symptoms worse in the early(sleep) a.m. Allergic rhinitis Worse in early a.m./upon arising Stroke Incidence greatest in the early a.m. 25 PSG COLLEGE OF PHARMACY

26. REFERENCE Amol A. Patil , Manohar D. Kengar , Suhas A. Mane, Sujit . Wagmare , Dnyaneshwar M. Nirmale1, Chronopharmacology : A Great Future for the Medicines ,February 2020 IJSDR | Volume 5, Issue 2 Sagar Singh Jough , Shashi Pratap Singh, YatendraSingh , Dakshina Gupta, Preeti Saxena , Saumya Gupta, Ankit Singh, Akash Srivastva, Chronopharmacology : Recent Advancements in the Treatment of Diabetes Mellitus through Chronotherapy , IJPPR,Human JournalsReview Article May 2017 Vol.:9, Issue:2 Bjorn Lemmer and Gaston Labrecquet , chronopharmacology & chronotherapeutics definitions & concepts, Chronobiolagv Inrernarional. Val 4. No. 3, pp. 319-329. 198 Chronopharmacology an overview https://www.pharmatutor.org /articles/ chronopharmacology -overview assessed on; 12-2-18. 26 PSG COLLEGE OF PHARMACY

27. THANK YOU PSG COLLEGE OF PHARMACY 27