Chronopharmacology

Chronopharmacology

1. CHRONOPHARMACOLOGY Dr Rupendra K. Bharti MBBS MD

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

3. Pharmacology- It is the science of drugs. Phamacon - (Drug), Logos – (study) It deals with the interaction of administered 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. 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 Rhythms 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 Definition- 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 into account according 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(pharmacokinetic) parameters. 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 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 in all of the cases as in Treatment with 6-mercaptopurine and methotrexate , evening dose is given to the patient. Colorectal cancer- Oxaliplatin is given during daytime & flurouracil at night.

20. Disease rhythm

21. Advantage Time the administration of the drugs

22. Applied Chronopharmacology Endocrine system Corticosteroids Once-daily morning dose dosing minimizes risk of adrenal suppression and other side effects.

23. Applied Chronopharmacology Endocrine system Congenital adrenal hyperplasia Bedtime corticosteroid dosing controls excessive hormone secretion in CAH

24. Applied Chronopharmacology Endocrine system Chronotherapy for Addison’s disease Asymmetrical morning high and late-afternoon low-dose corticosteroid substitution best corrects fatigue and abnormal circadian time structure.

25. Applied Chronopharmacology Endocrine system Bedtime ADH analogue dosing helps to alleviate nocturnal bedwetting in children and nocturia in adults.

26. Applied Chronopharmacology CVS Myocardial infarction, acute cardiac arrest , transient ischaemic attack Onset – early morning – 34% events Reason – release of catecholamines , cortisol , increase in platelet aggregation , vascular tone , heart rate surge.

27. Applied Chronopharmacology CVS Objective Deliver drug in high concentration during great need ACE inhibitors Nifedipine Amlodipine Night

28. Applied Chronopharmacology CVS The first chronotherapeutic therapy for hypertension and angina pectoris Matches drug delivery to the circadian pattern of blood pressure and rhythm of myocardial ischemia. Verapamil has been employed

29. Applied Chronopharmacology CVS When the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were first introduced, morning dosing was recommended.

30. Applied Chronopharmacology CVS This strategy was re-evaluated after the discovery of the circadian rhythm of cholesterol biosynthesis in which higher rates of cholesterol intake and hepatic cholesterogenesis occur during the evening hours , even in the fasting state. Except Atorvastatin all (HMG-CoA) reductase inhibitors are administered between the evening meals and sleep.

31. Applied Chronopharmacology CVS Bedtime (but not morning) aspirin dosing best for preventing pregnancy-induced hypertension and preeclampsia.

32. 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,

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

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

35. Applied Chronopharmacology RS A single daily dose of inhaled corticosteroids , when administered at 5:30 pm rather than 8 am, was nearly as effective as four doses a day. Oral prednisone has been shown to be much more effective in improving several features of nocturnal asthma [FEV1]and response to a standard dose of inhaled beta2 agonist when administered at 3 pm rather than 8 am

36. Applied Chronopharmacology Autoimmune diseases Arthritis The new cyclooxygenase-2 inhibitors effectively relieve osteoarthritis symptoms when taken in the evening ; better results are obtained in rheumatoid arthritis when part of the dose is taken in the morning.

37. Applied Chronopharmacology GIT Histamine2 antagonists In the past, were administered at regular intervals round the clock, on the basis of pharmacokinetic properties.

38. Applied Chronopharmacology GIT Maximal acid secretion, peptic ulcer disease pain, and perforation of gastric and duodenal ulcers are more common at night, administration of these drugs at bedtime is more effective. Nocturnal administration not only reduces acid secretion more effectively but also promotes ulcer healing and reduces ulcer recurrence

39. Applied Chronopharmacology CNS Chlorpromazine would be most effective in producing sedative and antipsychotic effects when administered at midnight and immediately after rising, respectively. For haloperidol, administration in the evening would be best for obtaining either a sedative or antipsychotic effect.

40. 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, bronchospasm, rhinitis like conditions. Immediate Hypersensitivity.

41. 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.

42. 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 due to the nonavailability of appropriate technology.

43. 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 .