The role of chronopharmacology in therapeutics drinjeti

Many drugs are still given without regard to the time of day

Identification of rhythmic marker for selecting dosing time will lead to progress of chronopharmacotherapy.

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 reduce their side effects .

To produce new rhythmicity by manipulating the conditions of living organs by using rhythmic administration of altered feeding schedules for several drugs appears to lead to a new concept of chronopharmacotherapy

1. ROLE OF CHRONOPHARMACOLOGY IN THERAPEUTICS Dr. Prabhakar Injeti Post Graduate 2/7/2015 1

2. Outline INTRODUCTION TYPES OF BIOLOGICAL RHYTHMS BIOLOGICAL CLOCK IN HUMAN CIRCADIAN RHYTHMS IN OCCURRENCE AND SEVERITY OF DISEASE CHRONOKINETICS DRUGS UNDERGOING CHRONOKINETICS CHRONODYNAMICS CHRONOTHERAPEUTICS CHRONOMODULATED DRUG DELIVERY SYSTEMS CONCLUSION 2/7/2015 2

3. Chronobiology is the scientific study of effect of time on living systems and biological rhythms. Chronopharmacology is the science concerned with the variations in the pharmacological actions of various drugs over a period of time of the day. A biological rhythm is one or more biological events or functions that reoccur in time in a repeated order and with a repeated interval between occurrences . The biological clock is the mechanism found within living organisms that coordinates the timing of physiological functions and behaviors to the natural day-night cycle. iNTRODUCTION 2/7/2015 3

4. The mammalian Circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). When light falls on the eye, afferent nerves arising from the retina of the eye transmit the light signals directly through retino hypothalamic tract to the paired suprachiasmatic nuclei situated in the hypothalamus and pineal gland. Biological clock since found is represented by suprachiasmatic nuclei , which creates biological rhythms under control of clock genes. 2/7/2015 4

5. The suprachiasmatic nucleus controls circadian rhythms in response to hormonal variation in the body 2/7/2015 5

6. Clock genes control vast array of circadian rhythms in physiology and behaviour . The rhythmic activities of Clock genes and cyclic secretion of melatonin from pineal gland comprise the central timekeeping mechanism. These generated biological rhythms deal with the control of biological functions including those of the autonomic nerve system , endocrine system, and immune system , which are fundamental in homeostasis and in protection against various diseases . 2/7/2015 6

7. Types of biological rhythms:       -   Ultradian rhythms , shorter than a day . Eg : thousandths of a second (like the pulses in neurons) seconds (like the heartbeat)     -   Circadian rhythms , which last about one day. Circadian rhythms are self-sustaining and endogenous oscillations that occur with a periodicity of about 24 Hours. Eg : the sleep-waking rhythm, the body temperature, sensitivity to pain or alcohol, reaction time, levels of hormones in the blood etc.    2/7/2015 7

8.   Infradian rhythms , longer than a day. Eg : monthly rhythm - menstrual cycle Yearly rhythm – bird migration - Tidal rhythms , commonly observed in marine life , which follow the roughly 12-hour transition from high to low tide and back. 2/7/2015 8

9. Circadian rhythm: Derived from the Latin circa , meaning "around," and dies , meaning "day”. Circadian : around a day. Rhythm is the measured movement, recurrence of action or function at regular intervals. Circadian rhythm is the regular recurrence of certain phenomena in cycles of approximately 24 hours. The best-known circadian rhythms include body temperature , hormone secretion, metabolism, sleep or wake cycle . 2/7/2015 9

10. Biological Clock in Human 2/7/2015 10

11. 2/7/2015 11

12. The hormones that are secreted in the morning include cortisol , catecholamines , plasma renin , aldosterone , and angiotensin . In contrast, gastric acid, growth hormone, prolactin , melatonin, follicle-stimulating hormone, luteinizing hormone, and adreno-corticotrophic hormone (ACTH) peak in the evening or during sleep. For instance, the increase in catecholamines in the morning promotes platelet aggregation. This is especially important since fibrinogen also increases, and the body’s own endogenous t-PA decreases, promoting a procoagulant state with increased blood viscosity. Cholesterol synthesis is more in the evening than in the morning. 2/7/2015 12

13. Sudden infant death, symptoms of allergic rhinitis, and rheumatoid arthritis are either most intense overnight or in the morning upon wakening. Migraine headache is typically triggered during rapid eyeball movement (REM) episodes during night time sleep or in the early morning hours after awakening.  Angina pectoris, ventricular arrhythmia, acute myocardial infarction, sudden cardiac death, stroke, fatal pulmonary embolism, and hypertensive crises, all are most frequent in the morning.  Circadian Rhythms in Occurrence and Severity of Disease  2/7/2015 13

14. Perforated and bleeding ulcer is reported to be most common in the afternoon.   Some seizure disorders are triggered during specific sleep stages and / or by transitions between sleep and wakefulness.  Symptoms of osteoarthritis worsen during the course of daily activity, being typically most intense in the late afternoon and evening.  Depression is most severe in the morning.  Gout, gall bladder and peptic ulcer attacks are most frequent at night. Acute pulmonary edema, congestive heart failure, and asthma worsen nocturnally 2/7/2015 14

15. more Noon 6 AM 6 PM Midnight Perforated peptic ulcer. Pain of Osteo arthtites Sensitivity to allergy skin test Gastric acid Production Stroke due to Hemorrhage Intractable pain Ulcer crises Asthma attacks Rapid raise in blood pressure Angina attack Pain of Rheumatoid arthritis Nasal symptoms of allergy Migraine attacks Stroke due to clot formation Overall ease of breathing CIRCADIAN RHYTHMS OF DISEASES Peak Time of Event/Variable 2/7/2015 15

16. CHRONOKINETICS Chronopharmacokinetics deals with the study of the temporal changes in absorption, distribution, metabolism and elimination and thus takes into account the influence of time of administration on these different steps. All physiological functions oscillate rhythmically in time, the activity, toxicity, and kinetics of a medication may depend on its administration time . The main aim of chronokinetic studies is to control the time of administration which can be responsible for variations of drug kinetics but also may explain chronopharmacological effects observed with certain drugs. 2/7/2015 16

17. NEED OF CHRONOKINETIC STUDY When possible daily variations in pharmacokinetics may be responsible for time dependent variations in drug effects (e.g. some antimicrobial agents are more effective at a specific time of day), When drugs have a narrow therapeutic range . When symptoms of a disease are clearly circadian phase-dependent (e.g. nocturnal asthma, angina pectoris, myocardial infarction, ulcer disease). When drug plasma concentrations are well correlated to the therapeutic effect in case the latter is circadian phase dependant. 2/7/2015 17

18. Drug Absorption : Several factors, such as the physico -chemical properties of the drug ( lipophilicity or hydrophilicity ), the area and the structure of the biomembrane , gastric emptying, pH and motility, and gastrointestinal blood flow , may influence the absorption process after oral drug administration. Most lipophilic drugs seem to be absorbed faster when the drug is taken in the morning compared with the evening because of faster gastric emptying time and a higher GI perfusion in the morning. Such changes may contribute to the dosing time dependent difference of drug absorption. 2/7/2015 18

19. Drug Distribution : Blood flow depends on several regulatory factors, including sympathetic and parasympathetic systems which activities are known to be circadian time dependent with a predominant diurnal effect of the sympathetic system. A diurnal increase and nocturnal decrease of blood flow and local tissue blood flows may explain a possible difference in drug distribution depending on the dosing time. Plasma proteins such as albumin or alpha 1 glycoprotein have been documented to be circadian time dependent . The plasma concentrations of albumin and alpha 1 glycoprotein acid show peak around noon. 2/7/2015 19

20. Drug metabolism : Hepatic drug metabolism seems to depend on liver enzyme activity and / or hepatic blood flow. Both factors show a circadian time-dependent difference. Enzyme activities show a circadian time-dependent difference in many tissues such as brain, kidney, and liver. Conjugation, hydrolysis, and oxidation show a circadian time-dependent difference. 2/7/2015 20

21. Drug 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 daytime.  2/7/2015 21

22. DRUGS UNDERGOING CHRONOKINETICS: 1. Antibiotics : Important aspect of chronokinetics in antibiotics is that not only the efficacy of the drug may increase but also the toxicity of certain drugs may decrease at different time of day. Aminoglycosides : Renal toxicity of aminoglycosides can be reduced by giving the drug as a single daily injection when patients are active (at day time or in other words in the activity period ) Eg : gentamycin , tobramycin , amikacin 2/7/2015 22

23. 2. Antihypertensive drugs: Blood pressure, stroke volume, cardiac output, blood flow are higher in morning and decrease later in the day. Cmax was higher and/or tmax shorter after morning than evening dosing of the lipophilic drugs ( nifedipine , oral nitrates, propranolol ) . Atenolol (hydrophilic drug ) is not absorbed rapidly after morning administration. ACE inhibitors were found to be safe and effective when administered at bed time when compared to morning. 2/7/2015 23

24. 3. Valproic acid(antiepileptic): Cmax tended to be higher, tmax was shorter and absorption rate constant tended to be larger for VPA in the morning than in evening. 4. Anti-inflammatory drugs : They have greater rates and extents of bioavailability when administered in the morning than evening. Eg . Indomethacin , Ketoprofen 2/7/2015 24

25. 5. AntiAsthmatic drugs : Asthma is attacked more frequently in night hours . Lungs are more sensitive to bronchoconstrictor substances such as Acetylcholine, Histamine, house mite dust, grass propellers, at night time than day time. It is treated by antiasthmatic drugs. Ex :- Theophylline , beta sympathomimetics . Theophylline must be given in higher doses during the night time than day time. 6. Antiulcer drugs : Gastric acid secretion is highest at early night or late afternoon. H2 blockers like Ranitidine , cimetidine , famotidine should be taken once a day in the late afternoon or early night when acid secretion is more. 2/7/2015 25

26. 7. Anticancer drugs : The blood flow to tumors and tumor growth rate are each up to three fold greater during each daily activity phase of the circadian cycle than during the daily rest phase. Normal human bone marrow DNA synthesis peaks around noon , DNA synthesis in malignant lymphoma cells peaks near midnight. By treatment at mid night , more tumor cell kill could be achieved with same dose of S-phase active cytotoxic therapy and with relatively little bone marrow damage. 2/7/2015 26

27. The activity of dehydropyrimidine dehydrogenase in human mononuclear cells increases by 40% around midnight . This enzyme brings about the intracellular catabolism of 5-FU and contributes to improved tolerability of this drug between 00:00 and 04:00 . One approach to increasing the efficiency of the pharmacotherapy is by administering drugs at times during which they are best tolerated. 2/7/2015 27

28. 8. NSAID’s & Arthritis : Patients with osteoarthritis tend to have less pain in the morning and more at night; while those with rheumatoid arthritis, have pain that usually peaks in the morning and decreases throughout the day. Chronotherapy for all forms of arthritis using NSAID’s such as ibuprofen should be timed to ensure that the highest blood levels of the drug coincide with peak pain. For osteoarthritis sufferers, the optimal time for a non- steroidal anti-inflammatory drug such as ibuprofen would be around noon or mid-afternoon . The same drug would be more effective for people with rheumatoid arthritis when taken after the evening meal . 2/7/2015 28

29. 9. Anti hyperlipidemic drugs More Cholesterol systhesis takes place in the evening than in the morning. The enzyme HMG Co-A Reductase is required to reduce hydroxy 3-methyl glutaryl Co-A to mevalonate in the synthesis of cholesterol. This enzyme is competitively inhibited by HMG Co-A Reductase inhibitors ( Statins ) Hence statins should be administered at evening rather than at morning for increased efficacy. 2/7/2015 29

30. 10. Opiod analgesics Stronger analgesic effects were observed when tramadol and dihydrocodeine were applied in the evening to relieve painful stimuli. Peak morphine use occurred at 9 a.m . and least use at 3 a.m. A recent study of meperidine reveals a circadian variation of meperidine-induced analgesia in sickle cell anemia patients, with maximal analgesic effect occurring with the morning dose . 2/7/2015 30

31. 11. Anti-Migraine drugs Sumatriptan is a drug of choice in migraine treatment. The mean peak serum concentration, were significantly higher following the 07:00 am administration than after the 7:00 pm administration. 12. Immunosupressants A slightly increased concentration resulting from decreased apparent clearance during the resting (PM) versus activity (AM) period were observed for cyclosporine . 2/7/2015 31

32. 13. Local anesthetics The duration of local anesthesia was longest when amide-type local anesthetic agents ( lidocaine , ropivacaine , mepivacaine and betoxycaine ) were applied around 3 p.m . Area under the lidocaine plasma concentration curves (AUC) was largest in the afternoon. The plasma levels of lidocaine were significantly higher in the evening than at any other time of day . 2/7/2015 32

33. 14. General anesthetics Barbiturates Higher brain pentobarbital or hexobarbital concentrations occurred when injected during the dark phase . Postsynaptic type A GABAergic activity is increased during nocturnal hours, corresponding to the duration of the maximal efficacy of barbiturates. Benzodiazepines The elimination half-life of midazolam was found to be at its shortest at 2:00 pm and at its longest at 02:00 am Ketamine , Etomidate , Propofol , and Halogenated Agents Action longer during the night than during the day . Halothane Greatest efficacy of halothane occurred between 12:00 am and 06:00 am. 2/7/2015 33

34. Chronodynamics Rhythm in receptor number or conformation , second messengers , metabolic pathway , and/or free-to-bound fraction of medications help to explain this phenomenon. Examples: Antitumour effect of IFN- β and the antiviral effect lymphocyte stimulating effect of INF- α in mice are more excient during the early rest phase than during the early active phrase . Cell division in many mammalian tissues is associated with specific times of day . In the regenerating liver of mice,the circadian clock controls the expression of cell cycle related genes that in turn modulate that expression of activity Cyclin B1-Cdc2 kinase , a key regulator of mitosis. 2/7/2015 34

35. Angiogenesis is important for tumour growth and metastasis. Hypoxia-induced expression of vascular endothelial growth factor (VEGF) plays an important role in tumour -induced angiogenesis . The level of VEGF mRNA in tumour cells implanted in mice rise substantially in response to hypoxia , but the levels show a 24 hr rhythm. Methionine aminopeptidase 2 ( MetAP2 ) plays an important role in growth of endothelial cells during the tumour angiogenesis stage . MetAPs show a 24 hr rhythm in implanted tumour masses . 2/7/2015 35

36. CHRONOTHERAPEUTICS : Chronotherapeutics refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize the side effects. The chronotherapy of a medication may be accomplished by the appropriate timing of conventionally formulated tablets and capsules. The special drug delivery system to synchronize drug concentrations to rhythms in disease activity. 2/7/2015 36

37. CHRONOMODULATED DRUG DELIVERY SYSTEMS 2/7/2015 37

38. 1. The pulsatile drug delivery system Pulsatile drug release is a system where the drug is released suddenly after a well-defined lag time or time gap according to the circadian rhythm of disease states.   No drug is released from the device within this lag time. This delivery system is suitable in cases where drugs including proteins and peptides undergo great metabolic degradation. In case of chronic treatment, the drug resistance may grow and an adverse effect may be seen. Here chances are less because the desired concentration of the drug at a certain time point is available.  2/7/2015 38

39. This method is good for drugs with extensive first pass metabolism and those targeted to specific sites in the intestinal tract. Therefore, by developing the pulsatile device for specific colonic delivery, the plasma peak is obtained at an optimal time, the number of doses per day can be reduced, it is with saturable first pass metabolism, and tolerance development can also be avoided. 2/7/2015 39

40. Advantages Predictable, reproducible, and short gastric residence time Less inter- and intra-subject variability Improves bioavailability Reduced adverse effects and improved tolerability Limited risk of local irritation No risk of dose dumping Flexibility in design Ease of combining pellets with different compositions or release patterns Improves stability Improves patient comfort and compliance Achieves a unique release pattern Extends patent protection, globalizes the product, and overcomes competition 2/7/2015 40

41. Disadvantages Low drug loading Proportionally higher need for excipients Lack of manufacturing reproducibility and efficacy Large number of process variables Multiple formulation steps Higher cost of production Need of advanced technology Trained / skilled personnel needed for manufacturing 2/7/2015 41

42. 2/7/2015 42 Enteric-coated systems Osmotic systems Swelling and erodible systems Press-coated systems Pulsincap systems Ultrasound drug delivery systems Multiparticulate systems OTHER CHRONOMODULATED DRUG DELIVERY SYSTEMS

43. Conclusion Many drugs are still given without regard to the time of day Identification of rhythmic marker for selecting dosing time will lead to progress of chronopharmacotherapy . 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 reduce their side effects . To produce new rhythmicity by manipulating the conditions of living organs by using rhythmic administration of altered feeding schedules for several drugs appears to lead to a new concept of chronopharmacotherapy 2/7/2015 43

44. References Contemporary perspectives on Clinical Pharmacotherapeutics , - Kamalesh Kohli & Mathur Guptha Post Graduate Topics in Pharmacology, - Rithuparna Maiti Chronopharmacology and its Aspects, www.pharmainfo.net 2/7/2015 44

45. THANK YOU 2/7/2015 45

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