Chronopharmacology in asthma

Introduction to chronology, chronotherapy, and chronopharmacology.
How chronopharmacology involved in asthma and helps to manage asthma?.
Biological rhythms in bronchial asthma.
Factors associated with nocturnal exacerbation of bronchial asthma.
Introduction to asthma and their symptoms.
Introduction to Antiasthmatic drugs like beta-blockers, leukotriene antagonists, steroids, etc.
Chronopharmacology division & their examples.
Advantages and disadvantages of chronopharmacology.
Marketed preparation and their images along with the price in India.

1. SEMINAR ON CHRONOPHARMACOLOGY IN ASTHMA Presented by Moh. Uzair M.Pharm(Pharmacology) II nd Semester Student SPER, Jamia Hamdard New Delhi 1

2. CONTENTS 2 Title Slide Number CHRONOLOGY 4 CHRONOBIOLOGY 5 CHRONOPHARMACOLOGY 7-8 CHRONOPHARMACOKINETIC 9 CHRONOTOXICITY 10 CHRONESTHESY 11 CHRONERGY 12

3. 3 Title Slide Number CHRONOTHERAPY 13 BIOLOGICAL RHYTHM 14 TYPES OF BIOLOGICAL RHYTHMS 15 ZEITGEBERS 16 PEAK TIME FUNCTIONS 17 DISEASE RHYTHM 18 APPLICATION OF CHRONOPHARMACOLOGY 21 ASTHMA 22-35 Marketed Preparations 36-38 References 39-48

4. CHRONOLOGY Chronos (time), Logos (study). The arrangements of events according to the time of occurrence. 4

5. CHRONOBIOLOGY Chronos (time), bios (life), logos (study). Also termed as— The Science of Time. Chronobiology refers to the day-night cycle that affects the human organism when the earth rotates. 5

6. IN MEDICINE, 3 DISCIPLINES TAKE INTO ACCOUNT THE INFLUENCE OF TIME CHRONOPHYSIOLOGY CHRONOPATHOLOGY CHRONOPHARMACOLOGY 6

7. CHRONOPHARMACOLOGY The Right Formulation At The Right Time. Study of how the effects of drugs vary with biological timing and endogenous periodicities. Chronopharmacology dealing with optimization of drug effects and minimization of adverse effects by timing medications in relation to biological rhythm. 7

8. CHRONOPHARMACOLOGY IS SUBDIVIDED INTO — 1.Chronopharmacokinetics 2.Chronotoxicity 3.Chronesthesy 4.Chronergy 5.Chronotherapy 8

9. 1.CHRONOPHARMACOKINETIC Deals with study of temporal changes in pharmacokinetic parameters – ADME, due to time of administration. 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. 9

10.   Pharmacokinetics of mainly lipophilic drugs can be circadian phase dependant. The studies show that after oral dosing, peak drug conc.( Cmax ) is generally higher or time to peak ( tmax ), shorter after morning compared with evening administration. Thus, circadian variations in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow, drug protein binding, liver enzyme activity and/or hepatic blood flow, glomerular filtration, renal blood flow, urinary pH and tubular resorption may play a role in such kinetic variations. 10

11. 2.CHRONOTOXICITY Defined as the changes in an organism's sensitivity to toxicants in relation to time. Specifically with antitumor drug like Irinotecan. Irinotecan induced leukopenia. Leukopenia more serious in the late dark and milder in the late light. 11

12. 3.CHRONESTHESY   Indicates circadian or other systemic changes in the susceptibility of target biosystems to an agent and involves receptors, cells, tissues, organs and organ systems. Emphasizes predictable(in- time) rather than, randomly distributed, biologic time related differences of target system. e.g. Beta-receptor blocking drugs (β-blockers) consist of an important group of cardio-active drugs like Atenolol,Propanolol etc. 12

13. The peak concentration of propanolol was achieved in the application between 8 A.M. and 2 P.M.. However, when applied on 2 A.M., the heart rate can be slightly changed in the following 6 hours. Therefore, it can be stated that sympathetic tonus, which is demonstrated by the rhythm in plasma noradrenaline and cAMP levels, affects the pharmacodynamics of the particular drug and it can be concluded that propanolol should be applied in hours when sympathetic tonus is high. 13

14. 4.CHRONERGY Designates time-dependent effects on the organism as a whole which include both desired and undesired effects. Depends both upon the chronesthesy of target biosystems and the chronokinetics of drugs. The term chronergy thus was preferred to chronoeffectiveness. Chronoeffectiveness refers to temporal change in the desired therapeutic effects of drugs. 14

15. Example Induced sleepiness may be desired effect for a sleeping pill but the nondesired effect for a tranquilizer or an antihistamine agents. 15

16. 5.CHRONOTHERAPY Also called chronotherapeutics. Refers to a treatment method in which drug availability is timed to matched rhythms of disease in order to optimize therapeutic outcomes and minimize the side effects. 16

17. BIOLOGICAL RHYTHM Biological rhythms are the natural cycle of change in our body’s chemicals or functions. It’s like an internal master “clock” that coordinates the other clocks in your body. The “clock” is located in the brain, right above the nerves where the eyes cross. It’s made up of thousands of nerve cells that help sync your body’s functions and activities. 17

18. TYPES OF BIOLOGICAL RHYTHMS 1.Circadian rhythms : The 24-hour cycle that includes physiological and behavioral rhythms like sleeping. 2.Diurnal rhythms : The circadian rhythm synced with day and night like   release of microfilariae of loa loa into the peripheral blood predominantly at daytime. Loa loa  is the filarial nematode (roundworm) species that causes  Loa loa filariasis .  Loa loa  actually means "worm worm", but is commonly known as the "eye worm", as it localizes  to  the conjunctiva of the eye.  Loa loa  is commonly found in Africa. 18

19. 3.Ultradian rhythms : Biological rhythms with a shorter period and higher frequency than circadian rhythms like cellular processes, respiraton, circulation, heartbeat & REM. 4.Infradian rhythms : Biological rhythms that last more than 24 hours, such as a menstrual cycle. 19

20. ZEITGEBERS It is any external or environmental cue that provides the stimulus or resetting a biological clock. It helps to regulate the biological clock in an organism. e.g — Light, Darkness, Warmth, Cold, Eating, Fasting etc. 20

21. PEAK TIME FUNCTIONS 21

22. DISEASE RHYTHM 22

23. ADVANTAGE Prevent over dosage. Appropriate usage of drug. Reduce side effects. When a person sleeps for several hours then the chronotherapy is more effective. Prediction of Chronotherapy is easy because it possess beginning, middle and end stage. Gives a new schedule to the patients of getting up and sleeping early but it provides them a period to adjust psychologically. 23

24. DISADVANTAGES Need of consulting the doctor and sleep specialists regularly to avoid side effects . Unusual feeling of hot or cold when the person is undergoing therapy. Patient incompliance as he has to keep himself awake till the next sleep schedule. Sometimes the patient may also be sleep deprived. 24

25. APPLICATION OF CHRONOPHARMACOLOGY RESPIRATORY SYSTEM Increased Bronchoconstriction at Night ↑ Parasympathetic tone ↓ Adrenaline ↓ Cortisol at midnight ↑ Sensitivity to irritants & allergens at night -exacerbations of allergic rhinitis & asthma. 25

26. ASTHMA Bronchial asthma is characterized by chronic airways inflammation and reversible airflow limitation . When treatment is inadequate, however, airway remodeling can occur and reversibility of obstruction becomes incomplete. 26

27. Chronic inflammation of the airways is associated with infiltration of eosinophils, T lymphocytes, mast cells and other inflammatory cells, as well as with production of various humoral factors. Persistent inflammation may lead to airway obstruction or airway hyperreactivity. 27

28. SYMPTOMS Paroxysmal dyspnea Chest tightness Wheezing Cough Hypoxia during acute attacks 28

29. FACTORS ASSOCIATED WITH NOCTURNAL EXACERBATION OF BRONCHIAL ASTHMA 29

30. CHRONOBIOLOGICAL ASPECT IN ASTHMA Main chronobiological features of asthma is the worsening of symptoms between midnight and early morning, referred to as the morning dip. 30

31. Most of the drugs currently used for chronotherapy of asthma are administered once at night – TO prevent chronic airway inflammation or the onset of airflow limitation. 31

32. CHRONOTHERAPY Theophylline is a bronchodilator and also suppress airway inflammation. Sustained Release Formulation of Theophylline — Once-daily evening administration . Efficacy . Serum Concentration . Side Effects . Avoid Multiple Dosing 32

33. Glucocorticoids — Suppress systemic & local inflammation. Once daily dose of inhaled corticosteroids in evening(5:30 pm) administration— . Nearly as effective as 4 doses a day . Strong local anti-inflammatory action on the airways without systemic adverse effects. e.g . Ciclesonide (ciclohale) 33

34. Single oral dose of Prednisolon at 3 pm is most effective. Nocturnal Vagus Nerve Hyperactivity . Relieved by Cholinergic antagonist e.g . Ipratropium bromide, Oxitropium bromide 34

35. β 2 Adrenoceptor Agonists . β 2 adrenergic receptors are widely distributed in the lungs. . β 2 agonist are effective as bronchodilators in the treatment of asthma. . Administration of sustained release β2-agonists directly improves bronchoconstriction in the early morning. 35

36. . A transdermal β 2 -agonist preparation has been developed in Japan (Hokunalin® tape, Abbott Japan Co., Ltd.) — To provide slow release of the drug for chronotherapy of nocturnal asthma when applied at night. 36

37. . The transdermal preparation of this β 2 -agonist is designed — To avoid a rapid increase of the serum concentration. To decrease adverse effects. e.g . Tulobuterol(Tuloplast) 37

38. Classification of β 2 Agonist 38 • Salbutamol • Terbutaline • Levalbuterol • Pirbuterol • Isoetharine • Bitolterol • Fenoterol • Procaterol • Salmeterol • Formoterol • Arformoterol • Carmoterol • Olodaterol • Indacterol

39. Leukotriene Receptor Antagonist . Leukotrienes are the potent constrictors of human airway smooth muscle, and also cause — Tissue edema eosinophil migration, which can stimulate the production of airway secretions and airway smooth muscle proliferation. 39

40. . Leukotriene receptor antagonists are used as an on-add therapy to improve the symptoms of asthma patients. Once daily dose— e.g . Montelukast (Monticope) 40

41. Marketed Preparations 41 Brand Name Composition Company Packaging MRP Rs. DERIPHYL- - LIN RETARD 300  tab Theophylline 69mg, etophylline 231mg GERMAN REMEDIES 10 6.78 DELTACORT-IL   tab Prednisolone 5mg PFIZER 20 18.00 DUOLIN INHALER Ipratropium 20mcg CIPLA 200md INHALER 281.93 CICLOHALE C iclesonide 80 mcg CIPLA 120md INHALER 359.00 MONTAIR  Tab Montelukast 4mg CIPLA 10 59.00 TULOPLAST T.PATCH Tulobuterol 0.5mg ZUVENTUS H.CARE 2.5 cm PATCH 14 43.95

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44. REFERENCES https://www.chronobiology.com/about-chronobiology/ https://www.healthline.com/health/biological-rhythms Johnson, C. (2004). Chronobiology: Biological Timekeeping. Sunderland, Massachusetts, USA: Sinauer Associates, Inc. pp. 67–105   Ohdo S, Koyanagi S, Matsunaga N, Hamdan A. Molecular basis of chronopharmaceutics . J Pharm Sci. 2011;100:3560–76. 44

45. Ohdo S, Makinosumi T, Ishizaki T, Yukawa E, Higuchi S, Nakano S, Ogawa N . (1997). Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice. Journal of Pharmacology and Experimental Therapeutics, 283(3):1383-8. N. Burioka et al. (2010) . Asthma: Chronopharmacotherapy and the molecular clock. Advanced Drug Delivery Reviews Elsevier, 62: 946-955. 45

46. N. MOHAMMED EESA L. K. CUTKOMP ( 1995 ) PESTICIDE CHRONOTOXICITY TO INSECTS AND MITES: Journal of Islamic Academy of Sciences 8:1, 21-28. https://www.sciencedirect.com/topics/medicine-and-dentistry/loa-loa https://link.springer.com/chapter/10.1007/978-3-662-06085-8_17 46

47. Essentials Of Medical Pharmacology by KD Tripathi 8 th edition, Jaypee Brothers Medical Publishers(P).Ltd. Page No. 242-243 47

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