chronopharmacology

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chronopharmacology

• Dr. Kartik doshi

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• Are u a morning then evening person?
• Does a pm shift assignment stretch your coping
  abilities?
• Have you ever wonder about rhythmic variation in
  serum analyte conc.?
• Have u ever noticed effectiveness of any drug on
  particular time of a day?

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• Chronopharmacology

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Overview

• History
• Biological clock
• Types of rhythm
• Impact
• Application in various disease
• Pulsatile drug delivery system
• Recent advances
• Bibliography
• summary

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History

• Jean-Jacques d'Ortous de Mairan
• description of circadian rhythms in plants in
  18th century

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• Franz Halberg
• who coined the word circadian, is widely
  considered the "father of American chronobiology

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Chronopharmacology
Effects of drug- biological timing Endogenous
periodicity
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Biological clock

• also termed as circadian rhythm

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Types of rhythm

• Ultradian (? lt20h)
• Circadian (20lt ? lt28h)
• Infradian (gt28 h)
• Circaseptan (? 7d)
• Circamensual (?30d) sleep-wake
  cycle
• Circannual (?1 yr)

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• Impact
• Particularly important in medicine
• biochemical, physiological or behavioural
  processes of living entities
• prevalence of disease symptoms, diagnostic test
  results and response of drug therapy

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Endogenously generated, and can be entrained by
external factors, called zeitgebers LD-
light-darkness EF-eating-fasting SI-social
contact-isolation NQ-noise-quiet
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Molecular oscillator of mammalian cells is
thought to be based on molecular feedback loops
Nuclear orphan receptor REV-ERBa
Negative oscillator limb (PER and CRY proteins)
Positive oscillator limb(CLOCK, BMAL1
Not yet certain whether the interactions are
indeed the rhythm-generating principle
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• In medicine 3 disciplines taken account acc. To
  time
• Chronophysiology
• Chronopathology
• chronopharmacology
• Chronotherapeutics
• Chronokinetic
• Chrnesthesy
• Chronergy
• chronotoxicity

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• 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

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• Chronergy
• Rhythmic difference in effects of drug on the
  organism as a whole which includes both desired
  and undesired

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As a diagnostic tool

• knowledge of early morning peak in plasma
  cortisol level is helpful in ruling out Addisons
  disease
• Diagnostic skin test for Allergic rhinitis show
  false negative in morning
• Alteration in the circadian rhythm of circulating
  lymphocytes- early event in HIV infection

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Disease and its circadian rhythm

• Diseases
• Allergic rhinitis
• Bronchial asthma
• Rheumatoid arthritis
• Osteoarthritis
• Angina pectoris
• MI
• Peptic ulcer disease
• stroke

• Circadian rhythm

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Allergic rhinitis

• Rhinitis- worst in the morning and evening
• once-daily, non-sedating antihistamine by giving
  it before bedtime to control overnight
  exacerbations and during sleep
• morning oral corticosteroid therapy for severe
  allergic rhinitis

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Asthma

• SR formulation of theophyline once daily
• Increase efficacy
• Decrease s/e
• Avoid multiple dosing
• Nocturnal vagus nerve hyperactivity
• Relieved by cholinergic antagonist
• eg.ipratropium bromide
• oxitropium bromide

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• Corticosteroids
• 8 am and 3 pm is more effective
• 3 pm and 8 pm is less effective
• single dose prednisolone 3pm is most
  effective
• leukotriene receptor antagonist zileuton
  nocturnal most effective
• LTB4 conc. max in night

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Arthritis

• Rheumatoid arthritis, ank. Spondylitis- morning
  more
• Osteoarthritis- evening more
• COX-2(Ibuprofen,
• indomethacin,tenoxicam, acetylsalicylic acid)
  
• Effectively relieve pain of RA when given at
  night, and better results in case of OA seen when
  these are given in morning.

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cvs

• B.P rises about 20 immediately after awakening
  least during sleep.
• 1st two hours after arising are the peak hrs.
  for MI, hemorrhagic stroke thrombotic
  infarcts.
• Reason - ? physical activity (sudden)
• - ? catecholamine levels
• - ? platelet aggregation
• - ? vascular tone
• - ? intrinsic thrombolytic activity

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• 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 5am and noon no mid-night dip
  in B.P is seen.
• b) Doxazosin, given at bedtime
• c) ACE-I when given at bedtime nocturnal dip in
  BP

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COER-verapamil
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• Once per day-evening ingestion of isradipine,
  normalize disturbed circadian rhythm in non
  dialysis CRF pt.
• Ramipril, quinapril- morning once per day dose
  evening time- BP low excessively(sp. With
  quinapril)
• Diltiazam- once in a morning strong influence in
  evening
• evening dose- more effect on the morning BP

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Diltiazam
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Oral contracetives

• Prescribed as per menstrual cycle

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Cancers

• Different biological rhythms for normal and tumor
  cells
• Appropriate timing.
• Cancer Rx
• 1.duration of the phase of cell cycle
• 2.cell proliferation rate
• TATO (theoretical analysis of treatment outcome)
• Tumor fast growing-2 am, slow growing10pm

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Cancer surgery

• Breast cancer later half of the menstrual cycle
  more clearence rate then early half
• Progesterone in the later half inhibit the
  enzymes responsible for spread of cancer cells
• Cancer drugs s phase specific , more in night
  time, because cancer cells divide more in night
  time
• Host cells in morning

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• ALL - treatment-6 mercaptopurine and
  methotrexate
• evening dose given
• colorectal cancer-oxaliplatin during daytime
  flurouracil and folinic acid at night

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Peptic ulcer

• Pathogenesis- Helicobacter pylori and H
  secretion by the stomach.
• Acidity(H) peak-evening
• H2blockers(Ranitidine, Cemitidine,famotidine
  are given at evening time

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• Drugs
• Corticosteroids
• Theophyline
• B agonist
• Melatonin
• H2 rec. blockers
• H1 rec. blockers
• Hmg co-a reductase inh.

• Dose time
• Morning
• Othe all bed time

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Circadian rhythm of drugs

• Heparin even if given at a constant infusion
  rate aPTT and risk of bleeding varies with hour
  of day and are higher at night.
• Nicotine penetrates skin faster around 4am.
• Topical steroids anti-inflammatory action is
  maximum in afternoon.
• Lidocaine twice as much is absorbed by skin
  when applied at 4pm than at 8am

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Chronotoxicity

• Specifically with antitumor agents
• Irinotecan induced leucopenia is more pronounced
  in late active phase

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Pulsatile drug delivery system

• Now a days greater attention on development of
  sustained, controlled, and delayed release system
• Diseases have predictable cyclic rhythm and
  timing of medication can improve the outcome of
  desired effect
• Condition demands release of a drug as a pulse
  after a lag time and has to be complete and rapid
  drug release after a lag time

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• 1. Enteric-coated systems
• 2. Pulsincap systems
• 3. Membrane diffusion controlled systems
• 4. Osmotic systems
• 5. Diffucaps
• 6.Compression coated system
• 7. Layered system

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Enteric coated system
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Pulsincap system
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Membrane diffusion coupled method
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Osmotic system
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Diffucaps
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Jet lag

• Travelling east
• Age
• Inherent susceptibility
• Morning peoplegtowl
• pathophysiology
• prevention and treatment
• Light therapy
• Melatonin
• (useful in sleep disorder)

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Melatonin and jet lag

• Use
• Jet lag, more then 5 eastern zone cross.
• M/A Realign circadian rhythm
• Late afternoon-phase advance
• Early morning-phase delay
• Given at wrong time-delays adaptation
• Doses between 0.5mg and 5mg
• Melatonin and warferin- may have
• Fatal interaction
• Cost12.99

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Recent advances

• CK-1 inh.-potential new drug
• Reset the circadian clock enzymes
• Use jet lag, sleep disorder, bipolar disorder
• Animals trials completed.
• Human trials awaited
• New Discovery May Allow People to Hit Snooze
  Button on Internal Clock
• Compound controlling c amp can decrease the
• cell cycle length

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Bibliography

• Review articlechronopharmacology focused on
  biological clock. Ohdo S. Drug metab.
  Pharmacokinet.22(1)3-14(2007)
• Chronopharmacokineticimplication for drug
  treatment. Lemmer B. journal of pharmacy and
  pharmacology.vol. 51 issue 8 pages 887-90.august
  1999.
• CONVINCE trial. JAMA april 23-30, 2003. vol. 289,
  no. 16
• Cover story Its about timea chronobiological
  approach to healthcare. Miller, Sharon M.
• the free library of farelex, 1996

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• jet lag. Pub med. Herxheimer A., 2008
• Sleepdexnew discovery may allow people to hit
  snooze button on internal clock
• Review of chronopharmacologyMishra K. Mriyala N.
  IJPRT online journal 2009
• Newsreuters body clock mouse study suggests new
  drug potential Mon. Aug. 23, 2010 by Kete Kelland

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Summary
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Thank you