_Chronopharmacology.pptx

Variations in the pharmacological actions of various drugs over a biological timing

1. Chronopharmacology Paul Mathew Post graduate Department of Pharmacology SJMC

2. History Jean – Jacques d’Ortous de Mairan – circadian rhythms in 18th century Franz Halberg – founders of chronobiology Chronopharmacology - scientific domain - early 1970’s. Purpose Of chronopharmacology solve the problem of drug optimization Enhance desired efficiency or to reduce its undesired effects

3. Definition Chronobiology – science that studies the biological rhythms Chronopharmacology - variations in the pharmacological actions of various drugs over a biological timings endogenous periodicities to the effect of drugs Maximum efficacy and minimum toxicity – drug administered at appropriate time Biological Rhythm - Periodic fluctuations in organisms corresponding to & in response to periodic environmental changes

4. Types of rhythm Ultradian - < 20 hrs  sleep stages Circadian – 20 – 28 hrs  sleep wake cycle Infradian - > 28 hrs  pre menstrual syndrome Circaseptan – 7 days  work rest scheme Circamensual – 30 days  menstrual cycle Circannual – 1 year  hibernation period

5. Circadian rhythms Latin word – circa means about & dian means day Most important type of biological rhythm Play an important role Maintaining body temperature, HR, BP Organ blood flow, pulmonary and kidney function Concentration of NT, hormones, enzymes, electrolytes, glucose Regulation – Superchiasmatic nucleus in hypothalamus Above optic chiasma  regulated by amount of light entering the eye

6. Consequences of disrupting biological rhythm Shift work Delay / advances of our rhythm 3hrs to adjust to a 12 hrs shift in time Jet Lag Flying from west to east or east to west More when travelling west to east Not able to cope up with phase delay

7. Terminologies In Chronopharmacology Chronokinetics : Rhythm-dependent , differences in absorption, distribution, metabolism & elimination of medications. Chronodynamics : Rhythm-dependent , differences in effects of medication. Chronesthesy : Rhythm-dependent, differences in sensitivity of target systems to medications Cannot be explained by chronokinetic changes.

8. Terminologies In Chronopharmacology Chronergy : - Rhythmic changes produced by drug either desired or undesired - Depends on both chronokinetics & chronesthesy Chronotoxicology: - Rhythm-dependent ,differences in manifestation & severity of adverse effects - Intolerance of patients to medication Chronotherapeutics : − In-vivo drug availability, timed to match circadian rhythms − To create maximum benefit & minimum harm

9. Ohdo , S.: Changes in toxicity and effectiveness with timing of drug administration: Implications for drug safety. Drug Safety, 26: 999–1010 (2003). Chronokinetics

10. Chronokinetics Circadian rhythms in absorption GA secretion, gastric motility, gastric emptying time & GI blood flow lipophilic drugs – morning -  blood supply to the GI tract and  gastric emptying time Circadian rhythms in distribution Blood flow -  daytime - predominant sympathetic activity Albumin and globulin -  day time

11. Chronokinetics Circadian rhythms in metabolism Activity of metabolizing enzymes and hepatic blood flow Circadian variation - hepatic blood flow - metabolism of propranolol. Oxidative microsomal reactions -  activity during the day Sulfate conjugation reactions - during night than during the day Circadian rhythms in excretion Renal BF, GFR, tubular secretion, and urinary pH GFR- maximum during midday and minimum in the night Urinary pH is acidic in the evening and alkaline in the morning

12. Diseases And Their Circadian Rhythm Allergic Rhinitis Bronchial Asthma Arthritis Cancers Cardiovascular Diseases Peptic ulcer disease Hypercholesterolemia

13. Ohdo , S.: Changes in toxicity and effectiveness with timing of drug administration: Implications for drug safety. Drug Safety, 26: 999–1010 (2003). Diseases And Their Circadian Rhythm

14. Allergic Rhinitis Reaction – interaction of immune and inflammatory responses Adrenocortical function & steroid release with high amplitude daily rhythms Symptoms worse in morning (after awakening) & evening. Non-sedating anti-histamine before bed time - overnight exacerbation. Morning oral corticosteroid : severe allergic rhinitis

15. Bronchial Asthma Symptoms - worse at night and early morning 70 times higher – 04 : 00 – 05 : 00 am Due to Exogenous factors – temperature changes , night break in bronchodilator, gastroesophageal reflux Endogenous factors – Bronchi diameter  at night Lowest cortisol levels at night Histamine  in early morning

16. Bronchial Asthma OD evening dose SR-Theophylline Elevated Theophylline conc at night & early morning LA inhaled β 2 agonist: Salmeterol & Formeterol Corticosteroids : 8:00AM &3:00 PM - controlling nocturnal asthma.

17. Title Timing of Prednisone and Alterations of Airways Inflammation in Nocturnal Asthma Journal, year American journal of respiratory and critical care medicine (21.405) April 1983 Objective s Effectiveness of corticosteroid with respect to circadian changes. Methods Randomized, Double-blind, Placebo controlled, crossover study. Results Mean reductions (95% credible intervals) in IOP in mmHg at 3 months (ordered from most to least effective drugs): bimatoprost 5·61 (4·94; 6·29), latanoprost 4·85 (4·24; 5·46), travoprost 4·83 (4·12; 5·54) timolol 3·7 (3·16; 4·24), brimonidine 3·59 (2·89; 4·29), carteolol 3·44 (2·42; 4·46) levobetaxolol 2·56 (1·52; 3·62), apraclonidine 2·52 (0·94; 4·11), dorzolamide 2·49 (1·85; 3·13), brinzolamide 2·42 (1·62; 3·23), betaxolol 2·24 (1·59; 2·88 Conclusion All active 1 st line drugs are effective compared to placebo in  IOP at 3 months Bimatoprost , latanoprost, and travoprost are the most efficacious drugs All factors, including AEs, patient preferences, and cost should be considered in selecting a drug for a given patient

18. Arthritis Rheumatoid arthritis Pain – worse in the morning Nocturnal cortisol secretion – less to suppress inflammation NSAIDS – bed time Osteoarthritis Pain – less in the morning more at night NSAIDS – noon or mid afternoon

19. Cancers Tumor cells and normal cells differ in their chronobiological cycles Normal bone marrow cells DNA synthesis peaks around noon Lymphoma cells DNA synthesis peaks near midnight S-phase active cytotoxic therapy at night is beneficial

20. ` Title Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer Journal, year The Lancet (September 6, 1997) ( IF – 79.321) Objective s Chronotherapy increased the objective response rate by 20% as compared with constant-infusion rate Methods Randomised multicentre trial 93 patients - chronotherapy 93 - constant-rate infusion Results Response - 47 (51%) of the chronotherapy group, 27 (29%) of the constant rate group Difference 21·5% [95% CI 13·7–31·2], p=0·003). Chronotherapy  5-fold the rate of severe mucosal toxicity (14% vs 76%, p<0·01) Conclusion Chronotherapy was less toxic and more effective than constant-rate infusion The results support the concept of temporal selectivity of cancer chemotherapy

21. Cardioavascular Diseases Diseases Severity Of Symptoms 1) HTN ↑ rapidly in morning after awakening peaks in noon ↓ in evening and is lowest in the night 2) Angina, MI Morning 3) Thrombotic events and Stroke Morning

22. Cardioavascular Diseases Chronobiology and Chronotherapy of Hypertension – A Review. International Journal of Health Research, September 2010; 3(3): 121-131

23. Cardiovascular Diseases Reasons: − ↑Physical activity − ↑Catecholamines levels − ↑Platelet aggregation − ↑Vascular tone − ↓Fibrinolytic activity Drug Dose timing Ramipril Night Valsartan Night COER-Verapamil Night

24. Peptic ulcer disease Pathogenesis H.pylori H+ secretion – peak in the evening Administration of H2 antagonist at bed-time  acid secretion  ulcer healing and prevents ulcer recurrence.

25. Hypercholesterolemia  Cholesterol intake & Hepatic cholesterogenesis - evening hours. HMG-Co A Reductase inhibitor  serum cholesterol  CV end-points . HMG-COA Reductase inhibitors - evening meals & bedtime Atrovastatin - long elimination half life. Primary prevention – CVS risk factors evening administration

26. Drugs undergoing chronokinetics Antibiotics Temporal variation - PK in 24hr cycle Aminoglycosides – Renal toxicity  – OD – day time Cephalosporins – Toxicity  – night –total clearance value highest during night Floroquinolones – Elimination – more at morning

27. Anti hypertensive drugs PK – varies with time of the day Drug given in morning – Cmax higher and tmax shorter Ex – nifedipine, propranolol, verapamil ACEIs – safe at night

28. Drugs undergoing chronokinetics Drugs Chronokinetics Anti epileptic drug Valproic acid – Cmax higher in the morning Anti inflammatory drugs Indomethacin, ketoprofen -  BA in morning Anti – migraine drugs Sumatriptan -  Cmax in morning Anti cancer drugs Cisplastin – renal toxicity  - eve 5-Fluorouracil - cataboloised by dehydropyrimidine dehydrogenase Activity  40 % - midnight – administer b/w 00:00 – 04:00 hrs Opioid analgesics Tramadol -  analgesic effect – eve Anti coagulants Heparin – night Topical steroids  Anti inflammatory action – afternoon LA Amide type – lidocaine, ropivacaine, mepivacaine – 3:00 pm GA Barbiturates pentobarbital -  GABAergic activity – night BZD etomidate, ketamine – elimination half life – shortest at 2 pm, longest at 2 am Effective during night Anti psychotic drugs Chlorpromazine –  sedative effect midnight,  anti-psychotic effect awakening Haloperidol -  sedative, anti-psychotic effect - eve

29. Chronotoxicology  Study of the adverse effects of chemicals on living organisms in relation to their circadian rhythms Walker CA, Soliman MR, Soliman KF. Chronopharmacology and chronotoxicology of CNS drugs: interrelationships with neuromodulators. Journal of the American College of Toxicology. 1983 Nov;2(6):359-70.

30. Chronotoxicology Mechanisms of the chronotoxicity of aminoglycosides - Gentamycin Daily variation in aminoglycoside PK Food intake -  aminoglycoside toxicity - food intake is minimal

31. Chronotherapeutic Drug Delivery Systems Pulsincap systems - Capsule based systems Lag time - plug, pushed away by swelling or erosion Drug is released as a “Pulse” from the insoluble capsule body Chronotherapeutic requirements - lag time adjustment Content of gelforming polymer (HPMC) and the erodible plug weight.

32. Chronotherapeutic Drug Delivery Systems Capsular system based on Osmosis Capsule - semipermeable membrane. Inside the capsule - osmotically active agent & drug formulation Capsule - dissolution fluid - entry of water Pressure to develop and the insoluble plug expelled after a lag time. methylphenidate - treatment of ADHD as the pulsatile port system. Avoided second time dosing - school children during daytime

33. Chronotherapeutic Drug Delivery Systems The chronotropic system Drug-containing core - hydrophilic swellable hydroxypropylmethyl cellulose (HPMC) - lag phase colon-specific release Lag time - thickness and the viscosity grades of HPMC.

34. Chronotherapeutic Drug Delivery Systems Diffucaps Variations in pH in GI tract - solubility and absorption drugs. pH dependency - developing a sustained or controlled release formula. Diffucaps  - multiparticulate bead system Multiple layers of drug, excipients and release-controlling polymers. Beads - organic acid or alkaline buffer Control the solubility - optimal pH microenvironment

35. Limitations of  Chronopharmacology Interindividual variation - difficult to design a common regimen Interspecies variations in diurnal cycle - extrapolate the results of animal studies  cost of trials Absence of a reliable marker of biorhythm

36. Recent Advances Triple-negative breast cancer (TNBC). Cancer stem cells - high aldehyde dehydrogenase (ALDH) activity Animal study - ALDH-positive cells in a mouse 4T1 breast tumor model - circadian alterations