Chronopharmacology and its application.pptx

Chronopharmacology

1. 1  CHRONOPHARMACOLOGY

2. Introduction Circadian clock defined as changes of mammalian physiology and behavior according to time- of-day, is called as “circadian” clock. Daily oscillations of proteins is necessary for either drug absorption or metabolism result 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. 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 , appetite, digestion Seasonal: Seasonal affective disorders. Like depression occur at the same time in a year

4. Definitions : Chronobiology The branch of science focusing on biological rhythms and their mechanisms. Chronos (time), Bios (life), Logos (study).

5. Chronopharmacology 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. The study of rhythmic, predictable-intime differences in the effects and/or pharmacokinetics of drugs both in experimental animals and in men Subdivided into Chronopharmacokinetics Chronotoxicity Chronesthesy Chronotherapy

6. Chronopharmacokinetics It deals with the study of the temporal changes in the pharmacokinetics of the drugs with respective time. Study of absorption, distribution, metabolism, and excretion of drug according to the time of the day or year.

7. 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 concept of matching timing of treatment with intrinsic timing of illness. Advantages Prevents over dosage Appropriate usage of drug Reduce side effects

8. ChronoPharmaceutics - Branch which designs and develops a drug delivery system in accordance with biological rhythm to optimize the treatment of disease.

9. Circadian rhythm The basic unit of circadian timekeeping is the… Supra chiasmatic nucleus Clock genes

10. 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.

11. Circadian clock Input Signal transduction - Retinohypothalamic tract (Photic Zeitgeber) Rhythm generator - Central clock in the suprachiasmatic nucleus (SCN) in the hypothalamus, and its peripheral tissues serve as the peripheral clock. Output signal transduction - to perform biochemical or physiological roles in a circadian manner.

12. Clock Genes : Circadian rhythms are driven by a group of genes called clock genes. In mammals, the core clock genes consist of Bmal1 (Brain and muscle aryl- hydrocarbon receptor nuclear translocator-like 1), CLOCK (Circadian Locomotor Output Cycles Kaput), Per (Period), and Cry (Cryptochrome). They form a tightly regulated system with interlocking feedback and feed- forward loops.

13. 13 Interlocking repressing and activating transcriptional and translational feedback loops culminate in the approximately 24-h rhythmic expression and activity of a set of core clock genes in each organ. CLOCK and BMAL1 increase transcription of period (PER1/2) and cryptochrome (CRY1/2) genes. As protein levels increase, PER and CRY associate and translocate into the nucleus, repressing CLOCK/BMAL1, thereby inhibiting their own transcription. Enzymatic degradation of PERIOD and CRYPTOCHROME proteins provides a delay mechanism prior to the onset of the next transcriptional cycle. The expression of positive factors , CLOCK and BMAL1, and negative factors , PER and CRY, are in antiphase to one another, providing circadian timing at the molecular level. The second loop regulates the transcription of Bmal1, which is inhibited by Reverb and activated by ROR Molecular Mechanism of circadian clock

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15. 15 The cell-autonomous molecular clock of the mammals consists of two transcription/translation feedback loops (TTFL) that interact with each other and generate strong 24-hour rhythms for gene expression. The core of TTFL is composed of four integral clock proteins: two activators (CLOCK and BMAL1) and two repressors (Period circadian protein homolog;PER1 and PER2 ). Their location and stability are regulated by kinases and phosphatases (kinases: CKI, phosphatases: PP1, PP5). CLOCK: BMAL1 is a type of transcription factor that stimulates the expression of the  Per  and  Cry  ( Cryptochrome ) repressor genes and other genes responsible for the clock-controlled output( CCGs ). The heterodimer formed in the cytoplasm between PER and CRY proteins is transported to the nucleus, so that it could inhibit further transcriptional activity via interacting by CLOCK: BMAL1. After about 24 hours, PER and CRY proteins are destructed through a ubiquitin-dependent processes, releasing the regulation of CLOCK: BMAL1. Molecular pathway of the circadian rhythm

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18. 19 Advantages of Chronotherapeutics: It prevents an overdosing of drug.
It makes the utilization of the drug more appropriate. It reduces unnecessary side effects of a drug and helps in caring out the treatment for only a particular or limited period of time. Need for Chronotherapeutics : It is required to observe therapy to limit the duration of therapy especially in cases where patients are already having renal, cardiac and hepatic other function of the body. Accumulation of drugs in these organs causes greater toxicity which may diminish function of the organ. Thus, the chronotherapeutics becomes a very important part of treatment of diseases particularly those effecting targeted body parts.

19. 20 Applications of chronotherapy in various diseases like Asthma Cardiovascular disease Diabetes

20. ASTHMA 21

21. Application of chronotherapy in asthma Asthma: worsening and Increased bronchoconstriction at night due to… ↑Parasympathetic tone ↓ Adrenaline ↓ Cortisol at midnight ↑Sensitivity to irritants and allergens at night  exacerbations of allergic rhinitis & asthma

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23. A s t h m a Main chronobiological features of asthma is the worsening of symptoms between midnight and early morning referred to as the morning drip. - more common between midnight and 6 am. Most of the drugs used for asthma administered once at night to prevent chronic inflammation and air way limitation. Rx - Theophylline and Beta 2 agonist is timed at evening

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25. 26 Plasma epinephrine shows a circadian rhythm with the lowest level at 4 am and the highest level at 4 pm in both healthy subjects and patients with asthma. Evening dosing was more advantageous because it improved Forced expiratory volume ( FEV 1)  throughout the 24 hours to a greater extent than morning dosing. Bronchodilators β2- adrenergic agonist medication

26. 27 β 2 -agonists (BAs) primarily cause relaxation of airway smooth muscle, to increase airway caliber and relieve bronchoconstriction .  Plasma epinephrine shows a circadian rhythm with the lowest level at 4 am and the highest level at 4 pm in both healthy subjects and patients with asthma. BAs are predominantly inhaled and can be short-acting BA (SABA) with a duration of around 4 hours, or LABA effective for 12–24 hours. SABAs are prescribed as “reliever” medications for immediate relief from bronchoconstriction. The majority of LABAs are inhaled as aerosols β 2 -adrenergic agonist medication

27. 28 Five milligrams was administered in the morning (8 am) when the lung function was beginning to improve to its best level in the afternoon. Ten milligrams was administered in the evening (8 pm) when lung function was beginning its decline to its worst level in the early hours of the morning. This Chrono therapeutic strategy significantly increased the 24-hour mean PEFR and FEV 1  and almost completely averted their characteristic nocturnal decline. Bambuterol is a prodrug of terbutaline and exerts a bronchodilator effect for 24 hours. A chronotherapeutic trial of bambuterol investigated once-daily dosing with 20 mg in the morning, versus the evening, versus placebo. Evening dosing resulted in a considerably higher morning FEV 1  and PEFR. Overall, evening dosing was more advantageous because it improved FEV 1  throughout the 24 hours to a greater extent than morning dosing . LABA tablet formulation

28. 29 Formoterol and salmeterol are aerosol LABA medications, with few adverse effects. Both medications have duration of action of about 12 hours. LABA inhaler medication

29. 30 Theophylline : Bronchodilator and also suppress airway inflammation. Sustained formulation of theophylline once daily evening administration observed better anti-asthmatic effect. Efficacy more Sustained serum drug concentration achieving peak concentration overnight/early morning when the drop in PEF is the greatest. Reduced side effect Avoid multiple dosing

30. 31 Airway Inflammation Circadian changes in airway inflammation in patients with asthma significantly more present at 4 am versus 4 pm . There is a circadian variation in the number of alveolar eosinophils (significantly more present at 4:00 am versus 4:00 pm) in subjects with nocturnal asthma compared to those with nonnocturnal asthma. In this patient population, bronchoalveolar lavage fluid contained increased numbers of macrophages, neutrophils, and CD4+ T lymphocytes at 4 am versus 4 pm.

31. 32 Anti-inflammatory agents Systemic corticosteroids Asthma is controlled on long-term “maintenance” of oral corticosteroids and will be affected by the many adverse side effects. Use of synthetic steroids must take into account the pronounced endogenous circadian variation in cortisol levels. Cortisol is highest in the morning and lowest during night . Suggesting that synthetic corticosteroids administered at 3 pm are more effective in nocturnal asthma and cause less disruption to endogenous circadian cortisol rhythm.

32. 33 Inhaled corticosteroids ICSs are the mainstay of asthma treatment and ICSs are very effective in controlling asthma symptoms in asthmatic patients of all ages and severity. Ciclesonide once daily in the morning or evening significantly improves peak expiratory flow ( PEF) and FEV1 without causing adrenocortical suppression; however, the evening dosing regimen best improved the morning PEF. Leukotriene receptor antagonists In a double-blind study showed that montelukast better improved FEV 1  when dosed in the evening than morning, and a second study confirmed this and also showed that even once-daily, low-dose (10 mg) evening montelukast dosing improves asthma.

33. Cardiovascular Disease 34

34. 35 The human cardiovascular system has different activity patterns with cycles of 24 h, including heart rate, blood pressure, circulating catecholamines, blood coagulation markers, vascular endothelial function, and autonomic nervous system . An apparent increase in the number of adverse cardiovascular events is observed during morning hours (06.00–12.00 h ), such as stroke, myocardial infarction, ventricular arrhythmias, and sudden cardiac arrest. Patients who had a heart attack during morning hours will mostly have a larger infarct size and worse prognosis, compared with patients having a myocardial infarction during the rest of the day Cardiovascular Disease and Circadian Rhythm

35. 36 Autonomic Nervous System and Circadian Rhythm The ANS plays a vital role in physiological and pathological responses of the cardiovascular system. The sympathetic system induces an increase in heart rate, myocardial contractility, and peripheral resistance. The parasympathetic system , on the other hand, has the opposite effect. The parasympathetic and sympathetic system both follow a circadian rhythm. Whereas, the parasympathetic activity is more pronounced during the nigh t , the sympathetic system has a peak in activity during the morning .

36. 37 Moreover, this early morning peak coincides with a high sensitivity of vascular receptors . This morning peak of the sympathetic nervous system and the increased activity of the renin-angiotensin-aldosterone axis along with the decreased parasympathetic system contribute to the rise in blood pressure and heart rate in the morning . These changes in the morning probably add to the increased incidence of CVD during the same time period.

37. 38 Blood pressure follows a 24 h rhythm. In the morning there is a rise, which reaches a plateau around 11 am. Then it gradually decreases, and around midnight it reaches its lowest value. Blood pressure usually is about 10 to 20% lower while sleeping than during daytime The change in blood pressure is related to the change in activity of the sympathetic nervous system running parallel to the normal sleep-wake cycle Night-time blood pressure is lower due to the reduction of sympathetic tone and the parallel increase in vagal activity during the sleep period. Blood Pressure and Circadian Rhythm

38. 39 The rise in blood pressure in the morning coincides with the increase in the number of cardiovascular events in the morning . Due to the rise in blood pressure in the morning, vulnerable plaques in arteries are more prone to rupture, which can lead to acute adverse cardiovascular events. The MAPEC study showed that, with the use of chronotherapy, nighttime blood pressure would be reduced, thereby diminishing the risk of CVD.

39. CVS- Night time dip

40. Morning rise

41. The effects of chronotherapy on HR 42 The effects of chronotherapy on HR are not as well investigated as with BP profiles, however, several studies have indicated a time-of-day influence of β-blockers on HR. ( 1) In healthy subjects, the β-blocker propanolol exhibits a significantly faster time to peak effect on HR if taken in the morning (8 A.M.) as compared to late at night (2 A.M). (2) The suppressive effect of propranolol on the rise in HR during exercise is significantly greater if the drug is taken in the morning versus at night (3 ) In patients with stable coronary disease, myocardial ischemic episodes associated with HR increases are more likely to occur during the day time than at night; propranolol reduces the proportion of these daily HR-related episodes. ( 4) In hypertensive patients, the β-blocker bisoprolol reduces the 24-h ambulatory HR if the drug is taken in the morning.

42. 43 The vascular endothelium has anti-atherosclerotic functions, plays a role in the aggregation of platelets and regulates the patency of vessels via excretion of nitrogen oxide . All of these factors influence the cardiovascular system, and therefore, dysfunction may lead to adverse cardiovascular events . The endothelium-dependent vasodilator function is normally reduced during morning hours , because of the lower production of nitrogen oxide . This vasodilating function of the endothelium protects against diseases such as hypertension, stroke, and myocardial infarction. The deterioration of this function might contribute to the morning peak of CVD. Vascular Endothelium and Circadian Rhythm

43. 44 Formation of clots in blood vessels can also lead to ischemic stroke, myocardial infarction, and sudden cardiac arrest. Coagulation is increased during morning hours , partly because platelet aggregation and platelet surface activation markers experience a peak in the morning between 06.00 and 12.00 h. In this same period, there is reduced thrombolysis which can partly be explained by a reduced concentration of plasmin. Secondly by an increased level of plasminogen activator inhibitor-1 (PAI-1). These phenomena lead to an increased risk of developing blood clots in the morning hours, possibly contributing to the peak of CVD in this period Blood Clotting and Circadian Rhythm

44. 45 Evening administration of low-dose aspirin reduces morning platelet reactivity, via COX-1 dependent pathways, as compared with taking aspirin upon awakening. acute cardiovascular events (e.g., MI) are most likely to occur in the early morning hours vs. other times of day or night and platelet reactivity likely contributes to this early morning peak. Thus it is postulated that aspirin chronotherapy taken at bedtime instead of on awakening, as a preventative measure in healthy subjects and by patients with cardiovascular disease, can reduce the incidence of adverse cardiac events during the high-risk morning hours. Aspirin Chronotherapy and Timing of Acute Cardiovascular Events

45. 46 In our recent pre-clinical study in mice, we showed that chronotherapy can have direct benefits on the heart in cardiovascular disease models. Mice with pressure-overload induced cardiac hypertrophy were administered the short-acting angiotensin converting enzyme inhibitor ( ACEi ) captopril at either sleep-time or wake-time. We found that only sleep-time administration improves cardiac function, and reduces cardiac remodeling , as compared to wake-time captopril and placebo-treated animals. Mechanistically , captopril given at sleep-time appears to target the peak in the renin-angiotensin-system gene profiles in the heart . The important clinical implications are that ACE is given at bedtime can benefit myocardial remodeling in hypertensive patients, or after MI, or in congestive heart failure. Chronotherapy Decreases Adverse Cardiovascular Remodeling

46. 47 Evening ingestion of cholesterol-lowering agents Eg. Statins HMG Co A reductase Inhibitor Morning glyceroltrinitrate therapy to protect at this time against greatest risk for effort-induced angina of variant( Prinzmetal )patients Dosing schedules of b-adrenoceptor antagonists to ensure enhanced concentration to protect against highest risk for myocardial ischemic, AP, MI, and SCD, that is, after awakening from sleep. Evening ingestion of low-dose acetylsalicylic acid to attenuate prominent morning peak of platelet aggregation . Upon-awakening ingestion of diuretics assumingly for pragmatic reason (avoidance of nocturia) to attenuate daytime blood pressure (BP) and/or manage pulmonary edema of congestive heart failure Chronotherapy of CVS

47. 48 New COER Verapamil (Controlled onset extended release) is used in hypertension. It is formulated such that when it is taken at bedtime and it dissolves slowly and exerts its peak effect between 5 am and noon. There is also no dip in blood pressure during night . Diltiazem once in the morning strong influence in the evng . ACEIs like Ramipril , more effective when given at bed time rather than morning. In addition… Anti hyperlipidemic drugs: Cholesterol synthesis takes place in the presence of hydroxyl methyl glutaryl Co enzyme A reductase (HMGCoA reductase). More cholesterol is synthesized in the evening than in the morning. Therefore anti hyperlipidemic drugs like HMGCoA reductase inhibitors should be administered in evening for increased efficacy except atorvastatin which has a longer half-life. .

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

49. 50 In one study , Nebivolol during the evening is the most optimized treatment compared to morning intake, which can prevent the distortion of circadian BP pattern.

50. 51 MARKETED TECHNOLOGIES OF PULSATILE DRUG DELIVERY : Technology Mechanism API Disease OROS Osmotic mechanism Verapamil HCL HYP CODOS Multiparticulate pH dependent system Verapamil HCL HYP DIFFUCAPS Multiparticulate system Verapamil HCL , Propranolol HCL HYP Pulsincap Rupturable system Dofetilide HYP

51. DIABETES 52

52. 53 Morning hyperglycemia is common in patients with diabetes mellitus. This can be explained by two phenomena a) Dawn phenomenon Recurring abnormally high glucose levels in the morning before breakfast is known as dawn phenomenon . It occurs mostly between 3 am to 5 am . This is due to increase in growth hormone secretion which has hyperglycemic properties during sleep . b) Somogyi phenomenon It is also called as rebound hyperglycemia phenomenon. Diabetes mellitus

53. 54 It refers to blood sugar being high in the morning, after having been low (hypoglycemia). Hyperglycemia after hypoglycemia is a result of the insulin-antagonistic action of some hormones, especially those belonging to the hypothalamic-pituitary-adrenal axis. It is mainly caused by too much or long acting insulin. Because of insulin the glucose levels will be low at night or bed time, but later because of increase in growth hormone, cortisol and catecholamine levels during bed time causing hyperglycemia. Therefore, controlled release insulin (insulin pumps) should be preferred or should be taken at the time when there are more chances of hyperglycemia. Care should be taken so that insulin should not peak at the wrong time or in the middle of the night.

54. 55 It has been known for nearly half a century that normal human subjects exhibit a diurnal cycle in glucose tolerance . The rise in plasma glucose concentrations is much lower in the evening than in the morning after ingesting glucose orally or receiving an intravenous infusion of glucose. The reasons behind impaired glucose tolerance include insulin resistance, high hepatic glucose production (HGP) from the liver, and impaired β-cell function. Patients with T2DM commonly experience the dawn phenomenon (hyperglycemia in the morning). The increased HGP in the morning before breakfast has been linked to both a circadian modulation counterregulatory hormones (such as cortisol, growth hormones, and norepinephrine) Circadian rhythm of glucose homeostasis: Diabetic vs healthy

55. 56 Therefore, controlled release insulin (insulin pumps) should be preferred or should be taken at the time when there are more chances of hyperglycemia. Care should be taken so that insulin should not peak at the wrong time or in the middle of the night.

56. GASTRIC ULCER 57

57. Gastrointestinal tract Acid secretion peaks between 10 pm and 2 am. Ulcer pain is worst at this time. Ulcer healing is directly related to acid secretion inhibition at night. Evening dosage of H 2 receptor antagonists or PPI.

58. 59 ARIGATO / THANK YOU !!!