1. CHRONOKINETICS CHRONOTHERAPEUTICS ANDCHRONOMODULATED DRUG DELIVERY SYSTEM

2. Chronobiology is the science concerned with thebiological mechanism of the diseases according to a timestructure.Chronopharmacology is the science concerned with thevariations in the pharmacological actions of various drugsover a period of time of the day.A biological rhythm is one or more biological events orfunctions that reoccur in time in a repeated order and witha repeated interval between occurrences .The biological clock is the mechanism found within livingorganisms that coordinates the timing of physiologicalfunctions and behaviors to the natural day-night cycle. 3. The mammalian Circadian pacemaker resides in the pairedsuprachiasmatic nuclei (SCN).When light falls on the eye, afferent nerves arising from theretina of the eye transmit the light signals directly throughretino hypothalamic tract to the paired suprachiasmaticnuclei situated in the hypothalamus and pineal gland.Biological clock since found is represented bysuprachiasmatic nuclei , which creates biological rhythmsunder control of clock genes. 4. Clock genes control vast array of circadian rhythms inphysiology and behaviour.The rhythmic activities of Clock genes and cyclic secretionof melatonin from pineal gland comprise the centraltimekeeping mechanism.These generated biological rhythms deal with the control ofbiological functions including those of the autonomic nervesystem, endocrine system, and immune system, which arefundamental in homeostasis and in protection againstvarious diseases . 5. Types of biological rhythms:- Ultradian rhythms, shorter than a day .Eg: thousandths of a second (like the pulses in neurons)seconds (like the heartbeat)- Circadian rhythms, which last about one day.Circadian rhythms are self-sustaining and endogenousoscillations that occur with a periodicity of about 24 Hours.Eg: the sleep-waking rhythm, the body temperature,sensitivity to pain or alcohol, reaction time, levels ofhormones in the blood etc. 6. -Infradian rhythms, longer than a day.Eg: monthly rhythm - menstrual cycleYearly rhythm bird migration-Tidal rhythms, commonly observed in marine life, whichfollow the roughly 12-hour transition from high to low tideand back. 7. Circadian rhythm:Derived from the Latin circa, meaning "around," and dies,meaning "day. Circadian : around a day.Rhythm is the measured movement, recurrence of action orfunction at regular intervals.Circadian rhythm is the regular recurrence of certainphenomena in cycles of approximately 24 hours.The best-known circadian rhythms include bodytemperature , hormone secretion, metabolism, sleep or wakecycle . 8. The suprachiasmatic nucleus controls circadian rhythmsin response to hormonal variation in the body 9. Biological Clock in Human 10. The hormones that are secreted in the morning includecortisol, catecholamines, plasma renin, aldosterone, andangiotensin.In contrast, gastric acid, growth hormone, prolactin,melatonin, follicle-stimulating hormone, luteinizinghormone, and adreno-corticotrophic hormone (ACTH) peakin the evening or during sleep.For instance, the increase in catecholamines in the morningpromotes platelet aggregation. This is especially importantsincefibrinogen also increases, and the bodys ownendogenous t-PA decreases, promoting a procoagulant statewith increased blood viscosity.Cholesterol synthesis is more in the evening than in themorning. 11. Circadian Rhythms in Occurrence and Severity ofDiseaseSudden infant death, symptoms of allergic rhinitis, andrheumatoid arthritis are either most intense overnight or in themorning upon wakening.Migraine headache is typically triggered during rapid eyeballmovement (REM) episodes during night time sleep or in the earlymorning hours after awakening.Angina pectoris, ventricular arrhythmia, acute myocardialinfarction, sudden cardiac death, stroke, fatal pulmonaryembolism, and hypertensive crises, all are most frequent in themorning. 12. Perforated and bleeding ulcer is reported to be mostcommon in the afternoon.Some seizure disorders are triggered during specific sleepstages and / or by transitions between sleep andwakefulness.Symptoms of osteoarthritis worsen during the course ofdaily activity, being typically most intense in the lateafternoon and evening.Depression is most severe in the morning.Gout, gall bladder and peptic ulcer attacks are most frequentat night.Acute pulmonary edema, congestive heart failure, andasthma worsen nocturnally 13. Diseases known to display circadian Rhythm 14. CIRCADIAN RHYTHMS OF DISEASESPeak Time of Event/Variable 15. CHRONOKINETICSChronopharmacokinetics deals with the study of the temporalchanges in absorption, distribution, metabolism andelimination and thus takes into account the influence of time ofadministration on these different steps.All physiological functions oscillate rhythmically in time, theactivity, toxicity, and kinetics of a medication may depend on itsadministration time.The main aim of chronokinetic studies is to control the time ofadministration which can be responsible for variations of drugkinetics but also may explain chronopharmacological effectsobserved with certain drugs. 16. NEED OF CHRONOKINETIC STUDYWhen possible daily variations in pharmacokinetics may beresponsible for time dependent variations in drug effects(e.g. some antimicrobial agents are more effective at a specifictime of day),When drugs have a narrow therapeutic range .When symptoms of a disease are clearly circadian phase-dependent (e.g. nocturnal asthma, angina pectoris, myocardialinfarction, ulcer disease).When drug plasma concentrations are well correlated to thetherapeutic effect in case the latter is circadian phasedependant. 17. Drug Absorption :Several factors, such as the physico-chemical properties ofthe drug ( lipophilicity or hydrophilicity ), the area and thestructure of the biomembrane , gastric emptying, pH andmotility, and gastrointestinal blood flow, may influence theabsorption process after oral drug administration.Most lipophilic drugs seem to be absorbed faster when thedrug is taken in the morning compared with the eveningbecause of faster gastric emptying time and a higher GIperfusion in the morning.Such changes may contribute to the dosing time dependentdifference of drug absorption. 18. Drug Distribution:Blood flow depends on several regulatory factors, includingsympathetic and parasympathetic systems which activities areknown to be circadian time dependent with a predominantdiurnal effect of the sympathetic system..A diurnal increase and nocturnal decrease of blood flow andlocal tissue blood flows may explain a possible difference indrug distribution depending on the dosing time.Plasma proteins such as albumin or alpha 1 glycoprotein acidhave been documented to be circadian time dependent. Theplasma concentrations of albumin and alpha 1 glycoproteinacid show peak around noon. 19. Drug metabolism :Hepatic drug metabolism seems to depend on liver enzymeactivity and / or hepatic blood flow.Both factors show a circadian time-dependent difference.Enzyme activities show a circadian time-dependentdifference in many tissues such as brain, kidney, and liver.Conjugation, hydrolysis, and oxidation show a circadiantime-dependent difference. 20. Drug elimination:Renal physiological functions such as glomerular filtration,renal blood flow, urinary pH, and tubular resorption show acircadian time-dependent difference with higher values duringdaytime. 21. DRUGS UNDERGOING CHRONOKINETICS:1. Antibiotics :Important aspect of chronokinetics in antibiotics is that notonly the efficacy of the drug may increase but also the toxicityof certain drugs may decrease at different time of day.Aminoglycosides:Renal toxicity of aminoglycosides can be reduced by givingthe drug as a single daily injection when patients are active (atday time or in other words in the activity period)Eg: gentamycin, tobramycin, amikacin 22. 2. Antihypertensive drugs:Blood pressure, stroke volume, cardiac output, blood floware higher in morning and decrease later in the day. Cmax was higher and/or tmax shorter after morning thanevening dosing of the lipophilic drugs (nifedipine, oralnitrates, propranolol) .Atenolol (hydrophilic drug ) is not absorbed rapidly aftermorning administration.ACE inhibitors were found to be safe and effective whenadministered at bed time when compared to morning. 23. 3. Valproic acid(antiepileptic):Cmax tended to be higher, tmax was shorter and absorptionrate constant (ka) tended to be larger for VPA in the morningthan in evening.4. Anti-inflammatory drugs :They have greater rates and extents of bioavailability whenadministered in the morning than evening.Eg. Indomethacin, Ketoprofen 24. 5. AntiAsthmatic drugs :Asthma is attacked more frequently in night hours.Lungs are more sensitive to bronchoconstrictor substancessuch as Acetylcholine, Histamine, house mite dust, grasspropellers, at night time than day time. It is treated byantiasthmatic drugs.Ex:-Theophylline, beta sympathomimetics.Theophylline must be given in higher doses during the nighttime than day time.6. Antiulcer drugs :Gastric acid secretion is highest at early night or late afternoon.H2 blockers like Ranitidine ,cimetidine ,famotidine should betaken once a day in the late afternoon or early night when acidsecretion is more. 25. 7. Anticancer drugs :The blood flow to tumors and tumor growth rate are each upto three fold greater during each daily activity phase of thecircadian cycle than during the daily rest phase.Normal human bone marrow DNA synthesis peaks aroundnoon, DNA synthesis in malignant lymphoma cells peaks nearmidnight. By treatment at mid night, more tumor cell kill could beachieved with same dose of S-phase active cytotoxic therapyand with relatively little bone marrow damage. 26. The activity of dehydropyrimidine dehydrogenase in humanmononuclear cells increases by 40% around midnight. This enzyme brings about the intracellular catabolism of5-FU and contributes to improved tolerability of this drugbetween 00:00 and 04:00.One approach to increasing the efficiency of thepharmacotherapy is by administering drugs at times duringwhich they are best tolerated. 27. 8. Arthritis :Patients with osteoarthritis tend to have less pain in themorning and more at night; while those with rheumatoidarthritis, have pain that usually peaks in the morning anddecreases throughout the day.Chronotherapy for all forms of arthritis using NSAIDs such asibuprofen should be timed to ensure that the highest bloodlevels of the drug coincide with peak pain.For osteoarthritis sufferers, the optimal time for a non-steroidal anti-inflammatory drug such as ibuprofen would bearound noon or mid-afternoon.The same drug would be more effective for people withrheumatoid arthritis when taken after the evening meal. 28. 9. Anti hyperlipidemic drugsMore Cholesterol systhesis takes place in the evening than inthe morning.The enzyme HMG Co-A Reductase is required to reducehydroxy 3-methyl glutaryl Co-A to mevalonate in the synthesisof cholesterol.This enzyme is competitively inhibited by HMG Co-AReductase inhibitors (Statins)Hence statins should be administered at evening rather than atmorning for increased efficacy. 29. 10. Opiod analgesicsStronger analgesic effects were observed when tramadol anddihydrocodeine were applied in the evening to relieve painfulstimuli.Peak morphine use occurred at 9 a.m. and least use at 3 a.m.A recent study of meperidine reveals a circadian variation ofmeperidine-induced analgesia in sickle cell anemia patients,with maximal analgesic effect occurring with the morningdose. 30. 11. Anti-Migraine drugsSumatriptan is a drug of choice in migraine treatment.The mean peak serum concentration, AUC and AUMC weresignificantly higher following the 07:00 h administration thanafter the 19:00 h administration.12. ImmunosupressantsA slightly increased AUC and AUMC resulting fromdecreased apparent clearance during the resting (PM) versusactivity (AM) period were observed for cyclosporine. 31. 13. Local anestheticsThe duration of local anesthesia was longest when amide-type local anesthetic agents (lidocaine, ropivacaine,mepivacaine and betoxycaine) were applied around 3 p.m. Area under the lidocaine plasma concentration curves (AUC)was largest in the afternoon.The plasma levels of lidocaine were significantly higher in theevening than at any other time of day. 32. 14. General anestheticsBarbituratesHigher brain pentobarbital or hexobarbital concentrationsoccurred when injected during the dark phase. Postsynaptictype A GABAergic activity is increased during nocturnalhours, corresponding to the duration of the maximal efficacyof barbiturates.BenzodiazepinesThe elimination half-life of midazolam was found to be at itsshortest at 14:00 h and at its longest at 02:00 hKetamine, Etomidate, Propofol, and Halogenated AgentsAction longer during the night than during the day.HalothaneGreatest efficacy of halothane occurred between 24:00 and06:00 h. 33. CHRONOTHERAPEUTICS :Chronotherapeutics refers to a treatment method in which invivo drug availability is timed to match rhythms of disease inorder to optimize therapeutic outcomes and minimize theside effects.Chronotherapeutics is the discipline concerned with thedelivery of drugs according to inherent activities of a diseaseover a certain period of time.The chronotherapy of a medication may be accomplished bythe appropriate timing of conventionally formulated tabletsand capsules, and the special drug delivery system tosynchronize drug concentrations to rhythms in disease activity. 34. CHRONOMODULATED DRUG DELIVERY SYSTEMS1. The pulsatile drug delivery system Pulsatile drug release is a system where the drug is releasedsuddenly after a well-defined lag time or time gap accordingto the circadian rhythm of disease states. No drug is released from the device within this lag time. This delivery system is suitable in cases where drugsincluding proteins and peptides undergo great metabolicdegradation. In case of chronic treatment, the drug resistance may growand an adverse effect may be seen. Here chances are less because the desired concentration ofthe drug at a certain time point is available. 35. This method is good for drugs with extensive first passmetabolism and those targeted to specific sites in theintestinal tract. Therefore, by developing the pulsatile device for specificcolonic delivery, the plasma peak is obtained at an optimaltime, the number of doses per day can be reduced, it is withsaturable first pass metabolism, and tolerance developmentcan also be avoided. 36. AdvantagesPredictable, reproducible, and short gastric residence timeLess inter- and intra-subject variabilityImproves bioavailabilityReduced adverse effects and improved tolerabilityLimited risk of local irritationNo risk of dose dumpingFlexibility in designEase of combining pellets with different compositions orrelease patternsImproves stabilityImproves patient comfort and complianceAchieves a unique release patternExtends patent protection, globalizes the product, andovercomes competition 37. DisadvantagesLow drug loadingProportionally higher need for excipientsLack of manufacturing reproducibility and efficacyLarge number of process variablesMultiple formulation stepsHigher cost of productionNeed of advanced technologyTrained / skilled personnel needed for manufacturing 38. 2. Enteric-coated systems :Enteric coatings have traditionally been used to prevent therelease of a drug in the stomach .Enteric coatings are pH sensitive and drug is released when pHis raised above 5 in the intestinal fluid. These formulations canbe utilised in time-controlled drug administration when a lagtime is needed.The system contains a core which is film coated with twopolymers, first with HPMC and then with a gastro-resistantpolymer (Eudragit L30D). In this system the duration of the lag phase in absorption canbe controlled by the thickness of the HPMC layer. 39. Schematic representation of enteric coated systemDisadvantage :Because of the unpredictability of gastric residence, suchsystems cannot be the first choice when a time-controlledrelease is required 40. 3. Osmotic systemsIn the case of the osmotic system, osmotic pressure acts as adriving force for the pulsatile drug release. The system consistsof application of a semipermeable membrane around the coreof an osmotically active drug or a drug combined with anosmotic agent. The delivery orifice is drilled in to the system by lasertechnique or a high speed mechanical drill.When the system comes in contact with fluid, due to thedifferences in the osmotic pressure, the drug inside the systemis pumped out at controlled rate. 41. A lag time of 1-10 hr can be achieved depending on thethickness, orifice diameter and concentration of an osmoticagent. e.g. Port system.This system consists of a capsule coated with a semipermeable membrane.The capsule acts as a reservoir of the drug and osmoticagent.Water enters into the system through the semi permeablemembrane and leads to the development of osmotic pressureand expulsion of the drug after a desired lag time. 42. 4. Swelling and erodible systemsIn this system the drug reservoir is surrounded by a polymericbarrier layer that swells and gets dissolved when it is in contactof dissolution media and drug is released after the lag time.The coating layer is made up of various hydrophilic polymers.In addition to this enteric coating can be applied outside toovercome the gastric pH effect on the drug. The lag time of thesystem can be controlled by thickness of the polymeric coat andthe viscosity grade of the polymer used. 43. 5. Press-coated systemsPress-coating, also known as compression coating, isrelatively simple and cheap, and may involve directcompression of both the core and the coat, obviating the needfor a separate coating process and the use of coating solutions.The limitation of the system is that central position of thecore layer cannot be assured.The system can be two or three component, that is two orthree layered tablet.One layer provides the initial dose of the drug while otherlayers are formulated with the components that are insolublein gastric media but dissolves in intestine. The tablet can becoated with a semi permeable polymeric coating layer thatcontrols drug release. 44. 6 . PulsincapIt is a single unit system comprised of a water insoluble capsulebody enclosing the drug reservoir.The capsule body is closed at one end with a swellable hydrogelplug.Various hydrogels such as hydroxypropylmethyl cellulose,hydroxypropyl, polyvinylpyrrolidone are used as plug materials.Enzymatically controlled erodible polymers such as pectin canalso be used as plugging material. When the capsule comes in contact with water it absorbs waterand swells. 45. After a lag time the plug gets pushed out and the drug getsrelease rapidly in the form of a pulse. The total length of the plug, its position of the insertioninto the capsule and the polymer used for making the plugcontrols the lag time of the system. Rapid release of the drug can be ensured by the inclusionof effervescent agents, super disintegratnts and osmoticagents. 46. 7. Ultrasound drug delivery systemsUltrasound is an enhancer for improvement of drugpenetration through biological barriers such as skin, bloodvessels etc.The ultrasound effect enhances degradation of the polymerin which the drug molecules are incorporated.The drug can be released by repeated ultrasound exposure.Pulse delivery is achieved by on off application of ultrasound. 47. 8. Multiparticulate systemsMore reliable gastric emptying pattern is observed formultiparticulate systems and is based on changes inmembrane permeability and rupture of the coating.The drug is coated on non-peril sugar beads followed bycoating with swellable polymeric layer.The swelling agents include super disintegrants, effervescentagents and osmotic agents.Upon ingress of water, the swellable layer expands resultingin rupture of the film and rapid drug release. 48. 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