Chronopharmacology

1. CHRONOPHARMACOLOGY Presented by: ASHUTOSH MISHRA M. Pharm. [Pharmacology] 1 st Yr. KIET School Of Pharmacy

2. What is Chronopharmacology ? It is the science concerned with the variations in the pharmacological actions of various drugs over a biological timings & endogenous periodicities.

3. Pharmacology- It is the science of drugs. Phamacon - (Drug), Logos – (study) It deals with the interaction of administered Chem. molecule (Drug) with living systems. But most importantly those that are relevant to effective and safe use for medicinal purposes.

4. Chronobiology- Chronos (time), Bios (life), Logos (study). The science dealing with the phenomenon of rhythmicity in living organisms is called CHRONOBIOLOGY.

5. BIOLOGICAL RHYTHMS IN HUMANS

6. Biological Rhythm A determined rhythmic biological process or function. A biological rhythm is a self-sustaining oscillation with the duration of time between successive repetitions ( i.e ; the period) being rather non-varying under normal conditions.

7. Example- CIRCADIAN RHYTHM: Circadian (circa - about; dies, day, or about 24 hour) Oscillations in the biological, physiological & behavioral functions of an organism with a periodicity of 24 hrs.

8. Continue… Circadian rhythms are particularly important in medicine. A circadian clock in the brain coordinates daily physiological cycles. – sleep/wake - digestion – temperature - hormones Physiological day is about 24 hours . – Clock is reset daily by the environment . • day/night • social schedules

9. Types of Rhythm Ultradian (  <20h): cycles shorter than a day e.g. micro sec. for a neuron to fire. Circadian (20<  <28h): Lasting for about 24 hrs. e.g. sleep and wake cycles. Infradian (≥28 h): Cycles longer than 24 hrs e.g. menstrual cycle. sleep-wake cycle

10. BIORHYTHMS External cues which reset the circadian clock = ZEITGEBERS = synchronizers Defination - Endogenously generated, and can be entrained by external factors, called zeitgebers . LD- Light-Darkness EF- Eating-Fasting SI- Social Contact- Isolation NQ- Noise-Quiet

11. Biological Clock An internal biological clock, located, in mammals, in the suprachiasmatic nucleus of the hypothalamus (SCN), delivering its message of time throughout the body. It is responsible for circadian rhythms and annual / seasonal rhythms. The SCN uses its connections with the autonomic nervous system for spreading its time-of-day message, either by setting the sensitivity of endocrine glands (i.e., thyroid, adrenal, ovary) or by directly controlling an endocrine output of pineal gland (i.e., melatonin synthesis).

12. Regulatory System-

13. In medicine 3 disciplines taken account acc. To time- - CHRONOPHYSIOLOGY - CHRONOPATHOLOGY - CHRONOPHARMACOLOGY Chronotherapeutics Chronokinetic Chronesthesy Chronergy Chronotoxicity

14. Chronotherepeutics - New technology makes possible CHRONOTHERAPY (=CHRONOTHERAPEUTICS), that is, increase of the efficiency and safety of medications by proportioning their concentrations during the 24 hours in synchrony with biological rhythm determinants of disease.

15. Chronokinetic - Time dependent and predictable changes in PK parameter . Chronesthesy - Circadian or other systemic changes in the susceptibility and sensitivity of the target system to a drug.

16. Chronergy - Rhythmic difference in effects of drug on the organism as a whole which includes both desired and undesired effects. Chronotoxicity - T he toxic effect of drug on the organism, which is undesirable and affects the rhythmic system. Specifically with antitumor agents Irinotecan induced leucopenia is more pronounced.

17. Applications & Uses- Chronotherapy found useful in: Oncology, Asthma therapy, Hypertension, Strokes, Sleep apnea, GI tract disorders, Allergies.

18. Cancers- Different biological rhythms for normal and tumor cells Appropriate timing. Cancer Cells 1.Duration of the phase of cell cycle 2.Cell proliferation rate TATO (theoretical analysis of treatment outcome) Tumor: fast growing-2 am , slow growing- 10 pm Later half of the menstrual cycle have more clearance rate then early half of the cycle.

19. Progesterone in the later half inhibit the enzymes responsible for spread of cancer cells. Cancer drug administered more in night time, because cancer cells divide more in night time. But not all, Treatment with 6-mercaptopurine and methotrexate , evening dose is given to patient. Colorectal cancer- Oxaliplatin is given in during daytime & flurouracil at night.

20. Asthma- The risk of asthmatic attack is almost 70 times higher in patients at 04:00-05:00 in the morning, compared with the afternoon. Causes : •Exogenous factors- Allergen exposure, Dust and pollution, temperature changes during the day, position during sleep.

21. Endogenous factors- Small bronchi diameter significantly increases during the day and decreases at night b’coz - Adrenergic blockade of ß-receptors, Dominance of alpha-adrenergic pathways, Cholinergic dominance, Smallest conc. of Ig E and Highest concentration of histamine around 04:00.

22. Treatment- SR formulation of theophyline once daily Increase efficacy Avoid multiple dosing Nocturnal vagus nerve hyperactivity Relieved by cholinergic antagonist eg . Ipratropium bromide oxitropium bromide

23. Stroke- B.P rises about 20% immediately after awakening & least during sleep. 1 st two hours after arising are the peak hrs. for MI, hemorrhagic stroke & thrombotic infarcts. Reasons - ↑ physical activity (sudden) - ↑ catecholamine levels - ↑ platelet aggregation - ↑ vascular tone

24. Graphical explanation-

25. Treatment- A new COER verapamil use in HT It is formulated as a pill with a shell that dissolves slowly. Taken at bed-time , this exerts peak effects btw 5 am and noon & no mid-night dip in B.P is seen. Diltiazam - once in a morning strong influence in evening.

26. Peptic Ulcer- Pathogenesis- Helicobacter pylori and H+ ions secretion by the stomach. Acidity(H+) peak-evening. Treatment- Once daily given conventional H 2 blockers ( Ranitidine, Cemitidine , famotidine ) are given at evening time.

27. Allergic Rhinitis- Rhinitis- worst in the morning and evening. It is a Type-I (Anaphylactic) reaction, in which antibodies ( Ig E) are produced which get fixed to the mast cells. On exposure to antigen, AG:AB reaction takes place on mast cell surface releasing Histamine, -HT, LTs, PGs etc. Resulting in urticaria, itching, bronchiospasm, rhinitis like conditions. Immediate Hypersensitivity.

28. Treatment- Once-daily, non-sedating antihistamine (like; Chlorpheniramine 10-20 mg) by giving it before bedtime to control overnight exacerbations and during sleep Morning oral corticosteroid therapy for severe allergic rhinitis.

29. Drug delivery systems- Enteric-coated systems Pulsatile drug dilivary systems Membrane diffusion controlled systems Osmotic systems Compression coated system Layered system

30. Recent Advances- Due to advances in chronobiology , chronopharmacology , and global market constraints, the traditional goal of pharmaceutics (e.g. design drug delivery systems with a constant drug release rate) is becoming obsolete. However, the major bottleneck in the development of drug delivery systems that match the circadian rhythm ( chronopharmaceutical drug delivery systems: ChrDDS ) may be the availability of appropriate technology.

31. Continue… The last decade has witnessed the emergence of ChrDDS against several diseases. The increasing research interest surrounding ChrDDS may lead to the creation of a new sub-discipline in pharmaceutics known as chronopharmaceutics .

32. Futuristic Approach- Future development in chronopharmaceutics may be made at the interface of other emerging disciplines such as- System biology and Nanomedicine Such novel and more biological approaches to drug delivery may lead to safer and more efficient disease therapy in the future.

33. ThankX !!