Chronopharmacology introduction

Introduction to chronopharmacology

1. BY GURUBARATH M M.PHARM (PHARMACOLOGY) CHRONOPHARMACOLOGY INTRODUCTION JUN 2020 PSG College of Pharmacy 1

2. chronopharmacology The study of rhythmic, predictable-in-time differences in the effects and/or pharmacokinetics of drugs both in experimental animas and in men. Concerned with biological rhythm dependencies of medication The arrangement of events according to the time of occurrence CHRONOLOGY Objectives To optimize drug effects To minimize adverse effects To avoid multiple dose therapy JUN 2020 PSG College of Pharmacy 2

3. chronopharmacology Subdivided into: Chrono pharmacokinetics Study of the temporal changes in the pharmacokinetics of the drugs with responsive time Study of absorption , distribution , metabolism and excretion of drug according to time of the day or year Chron ethesy Rhythmic changes in susceptibility or sensitivity of a target system to a drug Chron ergy Rhythmic changes of both the desired (effectiveness) and undesired (toxicity, tolerance) effects on the organism as a whole Chrono Pharmaceutics Branch which designs and develops a drug delivery system in accordance with biological rhythm to optimize the treatment of disease JUN 2020 PSG College of Pharmacy 3

4. Chronokinetics Why study Chronopharmacokinetics ? Chronokinetic information can be used in choosing proper timing of drug administration to optimize drug therapy When Symptoms of disease are circadian phase dependent e.g. Nocturnal asthma, Angina pectoris, ulcer diseases, etc. Toxicity can be minimized or avoided by administering at particular time JUN 2020 PSG College of Pharmacy 4

5. Biological rhythm Self sustaining movement with duration of time between successive repetitions which are not varying under normal conditions. Types of rhythm Ultradian (20hr) (signaling between neurons, heart) Circadian (20-28hr) (Sleep wake cycle, Most biological functions) Infradian (>28hr) (Menstrual cycle) JUN 2020 PSG College of Pharmacy 5

6. Biological Rhythm - Spectrum Category of Rhythm Period of Rhythm Term used to Describe Rhythm Illustrative Examples Short periods ≤Sec High frequency oscillations Electroencephalogram Electrocardiogram Medium periods 30min to 20hr 20hr to 28hr 28hr to 6days Ultradian Circadian Infradian Sleep staging Pulsatile hormone secretion Most biologic functions Little studied thus far Long periods ≈ Week ≈ Month ≈Year Circaseptan Circamensual Circannual Work-rest routine Menstruation, Fertility Neuroendocrine functions Many biochemical, endocrine and Physiological parameters JUN 2020 PSG College of Pharmacy 6

7. Peak time functions HUMAN CIRCADIAN TIME STRUCTURE JUN 2020 PSG College of Pharmacy 7

8. Disease rhythm Ulcer crises Asthma attacks Rapid rise in Blood pressure Angina attacks Pain of Rheumatoid arthritis Nasal symptoms of Allergy Migraine Headaches Stroke due to Clot formation Overall ease of Breathing Perforated Peptic Ulcer Pain of Osteoarthritis Sensitivity to Allergy and skin tests Stroke due to Hemorrhage Intractable Pain Stomach acid production CIRCADIAN RHYTHM OF DISEASES JUN 2020 PSG College of Pharmacy 8

9. Circadian rhythm Circadian ( Circa – about; dies – day/about 24 hour ) Oscillations in the biological, physiological and behavioral functions of an organism with a periodicity of 24hrs Circadian clock in brain coordinates daily physiological cycles E.g., sleep-wake cycles Clock is daily reset by the environment CIRCADIAN CLOCKS Central Clock Peripheral Clock Located in suprachiasmatic nucleus (SCN) of the hypothalamus Present in other cells JUN 2020 PSG College of Pharmacy 9

10. biorhythms Basic units of circadian timekeeping Suprachiasmatic nucleus Clock genes ZEITGEBER Circadian rhythms are driven by endogenous processes, are self-sustaining, and rely upon circadian time cues ( Zeitgebers ) to remain appropriately oriented to the individual’s environment and desired routine 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 – Pineal Gland – melatonin SCN – ANS – Endocrine glands Time of light, duration, wavelength intensity – determine circadian patterns JUN 2020 PSG College of Pharmacy 10

11. Clock genes Circadian rhythms are driven by a group of genes called Clock genes Bmal1 (Brain and muscle aryl-hydrocarbon receptor nuclear translocator-like 1) CLOCK (Circadian Locomotor Output Cycles Kaput) Per (period) Cry (Cryptochrome) The clock genes consists of They form a tightly regulated system with interlocking feedback and feed-forward loops JUN 2020 PSG College of Pharmacy 11

12. Human circadian time structure JUN 2020 PSG College of Pharmacy 12

13. Circadian rhythm JUN 2020 PSG College of Pharmacy 13

14. Circadian rhythms in various diseases Circadian rhythm JUN 2020 PSG College of Pharmacy 14

15. Chronopharmacotherapy Medical treatment that involves the increase of efficiency and safety of medications by proportioning their concentrations during the 24hours in synchrony with biological rhythm determinants of disease Advantages Prevents over dosing Appropriate usage of drugs Reduce side effects JUN 2020 PSG College of Pharmacy 15

16. Chronopharmacotherapy Osteoarthritis Pain is maximum in the evening Analgesics like ibuprofen are administered in afternoon Rheumatoid arthritis Pain is maximum in the early morning Long-acting NSAIDs like flurbiprofen, ketoprofen, and indomethacin are administered at bedtime Acid peptic disease Basal gastric acid secretion peaks during the midnight H2 blockers are given before bedtime to inhibit basal acid secretion at midnight JUN 2020 PSG College of Pharmacy 16

17. Chronopharmacotherapy Bronchial asthma Precipitation of attacks during late night or at early morning hour ( 2-6a.m. ) due to increased bronchial hyperactivity during this period Inhaled salbutamol given early morning Evening dose of a sustained release preparation of theophylline produces peak drug concentrations in late night and early morning JUN 2020 PSG College of Pharmacy 17

18. Chronopharmacotherapy Hypertension Blood pressure increases briskly in the morning after awakening, decreases in the evening, and is lowest during sleep If given only as once daily early in the morning, many antihypertensive drugs do not reduce the early morning blood pressure Extended release formulation of L-type calcium channel blocker, verapamil is administered orally at bedtime JUN 2020 PSG College of Pharmacy 18

19. Chronopharmacotherapy Cardiovascular diseases including Stroke and Myocardial infarction Commonly occur during the initial hours of morning between 6 a.m. and 12 noon; a state of relative hypercoagulability of the blood prevails in morning Coronary blood flow decreases in the morning Increased Oxygen demand of the heart in early morning Evening or bedtime administration of angiotensin- converting enzyme inhibitors or Angiotensin receptor blockers or CCBs produce better reduction in BP Administration of beta-blockers prevents the morning increase in the incidence of angina, myocardial infarction, and sudden death JUN 2020 PSG College of Pharmacy 19

20. Chronopharmacotherapy Allergic rhinitis Symptoms are worst in the late night or early morning Anti-histamines are usually given once daily at bedtime Hypercholesterolemia HMG CoA reductase enzyme activity is maximum in the night, and thus cholesterol synthesis is usually greater during night time than during day Statins like simvastatin given in the evening or night are more effective JUN 2020 PSG College of Pharmacy 20

21. Chronopharmacotherapy Diseases where systemic steroids are given Endogenous secretion of adrenocorticotropic hormone (ACTH) and cortisol peaks in the early morning Prednisolone and other corticosteroids are given early morning to mimic the release from HPA axis Addison’s disease Asymmetrical morning high and late afternoon low dose corticosteroid substitution best corrects fatigue and abnormal circadian time structure JUN 2020 PSG College of Pharmacy 21

22. Chronopharmacotherapy Epilepsy Seizure attacks are common around the onset of sleep at night and the offset of sleep in the morning Patients in whom the evening dose was double that of the morning dose, without altering the total dose of medication, showed better seizure control Cancer Normal cells and cancer cells vary in their chronobiological rhythm. The DNA synthesis peaks in the normal human bone marrow at noon and in lymphoma cells at midnight S-phase active cytotoxic drugs are administered at late night , providing selective suppression of the lymphoma cells over normal bone marrow cells. JUN 2020 PSG College of Pharmacy 22

23. Chronotherapeutic - drug delivery systems Developed to circumvent the need for administering the drugs at odd timings Spheroidal oral drug absorption system (SODAS)  Controlled release beads which release the drugs according to the circadian rhythm. Chronotherapeutics oral drug absorption system (CODAS) Enteric release-controlling polymer applied to drug-loaded beads, drug release after a prolonged period of time after ingestion Container Technology TIMERx Technology (hydrophilic system) Semipermeable matrix technology with uniform porosity, releasing the drug in a controlled release manner A combination of Xanthan and Locust bean gums mixed with dextrose - forms a gel when in contact with water and aids in controlled drug release. JUN 2020 PSG College of Pharmacy 23

24. Limitations of chronopharmacology Interindividual variations make it difficult to design a common dosing regimen, and thus individual dosing regimen is required. Interspecies variations in diurnal cycle make it inappropriate to extrapolate the results of animal studies to humans. Increased cost of trials in which chronopharmacological studies are included because it will increase the duration, sample size, and cost of the trial Absence of a reliable marker of biorhythm to guide chronotherapy JUN 2020 PSG College of Pharmacy 24

25. References Introduction to Basics of Pharmacology and Toxicology; Gerard Marshall Raj Ramasamy Raveendran; page no.261-269 Maurya k.k et al. Chronopharmacology: A tool for therapy of diseases. IRJP 2012,3(5):128-132 JUN 2020 PSG College of Pharmacy 25