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CHRONOPHARMACOLOGY
Dr. Ashutosh Tiwari
M.D. Pharmacology (1st year)
14/02/2014 SAIMS Indore
Overview
 History
 Biological clock
 Types of rhythm
 Physiological functions & diseases
exhibiting circadian rhythm
...
History
Jean-Jacques
d'Ortous de Mairan
description of
circadian rhythms in
plants in 18th century
Franz Halberg
coined th...
Chronopharmacology
science concerned with
the variations in the
pharmacological
actions of various
drugs over biological
t...
Biological Rhythm
 A determined rhythmic biological
process or function.
 Chronobiology
 Science that studies the biolo...
Types of rhythm
 Ultradian ( <20h)
 ECG, Sleep stages
 Circadian (20<  <28h)
 Sleep wake cycle
 Infradian (>28 h)
...
CIRCADIAN RHYTHM
 Circadian (circa = around & diem = day)
 Go over ~24hrs
 Oscillations in the biological, physiologica...
 Circadian rhythms are particularly
important in medicine
 A circadian clock in the brain coordinates
with daily physiol...
Zeitgeber
 from German: “synchronizer”
 Any exogenous (external) cue that
synchronizes an organism's endogenous
(interna...
Circadian Rythm
 Biological clock / Circadian pacemaker is
present in the Supra-chiasmatic nuclei
(SCN) in hypothalamus
...
Circadian rhythm
 SCN passes the information to Pineal
gland  Melatonin hormone
 SCN connections with the autonomic
ner...
The suprachiasmatic nucleus controls circadian
rhythms in response to hormonal variation in
the body
Consequences of disrupting biological rhythms
 If external cues
change there occurs
disruption of
biological rhythms
 Sh...
Physiological functions showing
circadian rhythm
Diseases known to display circadian Rhythm
 In medicine 3 disciplines are taken
account according to time
Chronophysiology
Chronopathology
chronopharmacology
Chrono...
Chronokinetics
Deals with study of temporal changes in
pharmakokinetic parameters – ADME, due to time
of administration
Ch...
Chronotherapeutics
Application of chrono-biological principles to the
treatment of diseases
Chronopharmaceutics
branch of ...
Pulsatile drug delivery system
 Now a days there is greater attention on
development of sustained, controlled, and
delaye...
Chronopharmacodynamics
Important factors in
Chronopharmacodynamics:
 Circadian Rhythm has been found for
 receptor numbe...
Why study Chronopharmacokinetics?
 PK-PD vary with time
 Gastric motility: is double in day time than in night
 Plasma ...
Chrono PK- Absorption
 Depends on pH, gastric emptying, motility and
gastrointestinal blood flow
 Lipophilic drugs are b...
Chrono PK- Distribution
• Blood flow depends on several regulatory factors,
including sympathetic and parasympathetic syst...
Chrono PK- Metabolism
 Depends on Liver enzyme activity & Hepatic
blood flow
 High extraction ratio: metabolism depends ...
Chrono PK- Elimination
 Renal physiological functions such as
glomerular filtration, renal blood flow, urinary
pH, and tu...
DRUGS UNDERGOING CHRONOKINETICS:
1. Antibiotics :
Aminoglycosides: gentamycin, tobramycin,
amikacin
•Renal toxicity of ami...
2. Antihypertensive drugs:
• Cmax was higher and/or tmax shorter after
morning than evening dosing of the lipophilic
drugs...
3. Valproic acid(antiepileptic):
•Cmax tended to be higher, tmax was shorter and
absorption rate constant (ka) tended to b...
5. Anti-Migraine drugs
•Sumatriptan is a drug of choice in migraine
treatment.
•The mean peak serum concentration was
sign...
7. Anti hyperlipidemic drugs
•More Cholesterol systhesis takes place in the evening
than in the morning with the involveme...
8. Opiod analgesics
•Stronger analgesic effects were observed when
tramadol and dihydrocodeine were given in the
evening t...
9. Heparin: even if given at a constant infusion
rate; aPTT and risk of bleeding varies with hour of
day and is higher at ...
11. General anesthetics
Barbiturates
• Higher brain pentobarbital or hexobarbital
concentrations occurred when injected du...
12. Antipsychotic drugs
 Chlorpromazine would be most effective in
producing sedative and antipsychotic
effects when admi...
CHRONOTHERAPEUTICS :
•Chronotherapeutics refers to a treatment method in
which in vivo drug availability is timed to match...
Chronotherapeutics:
Chronotherapy found useful in:
1. Allergic rhinitis
2. Bronchial asthma
3. Peptic ulcer disease
4. Rhe...
Necessity of Chronotherapeutic approach
 When the “therapeutic window” for a
given medication is very narrow, close
to to...
Allergic rhinitis
 Rhinitis- worst in the
morning and evening
 once-daily, non-sedating
antihistamine by giving it
befor...
Bronchial Asthma-
 The risk of asthmatic attack is almost 70
times higher in patients at 04:00-05:00 in the
morning, comp...
Treatment
 SR formulation of theophyline at night
 Increase efficacy
 Decrease s/e
 Avoid multiple dosing
Nocturnal va...
Corticosteroids
 a single daily dose of inhaled corticosteroids,
when administered at 5:30 pm rather than 8
am, was nearl...
Peptic ulcer
 In the past, were administered at
regular intervals around the clock, on
the basis of pharmacokinetic
prope...
Arthritis
 The symptoms of
rheumatoid arthritis are
worse in the morning.
 People with osteoarthritis,
tend to have less...
cvs
B.P. rises about 20%
immediately after
awakening & least during
sleep.
1st two hours after arising
are the peak hrs. f...
CVS
Reason
- ↑ physical activity (sudden)
- ↑ catecholamine levels
- ↑ platelet aggregation
- ↑ vascular tone
- ↓ intrinsi...
 A new COER verapamil (Controlled Onset Extended
Release) used in Hypertension
 It is formulated as a pill with a shell ...
Endocrine system
 Once-daily morning dose dosing
minimizes risk of adrenal
suppression and other side effects.
 Bedtime ...
Diabetes Mellitus
 Morning hyperglycemia may be
observed in patients with diabetes
mellitus
 Dawn phenomenon
 Somogyi P...
Dawn Phenomenon
0
10
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cause:
During night increase in GH,...
Somogyi Phenomenon
0
10
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Cause:
too much / long acting in...
Oral contracetives
Prescribed as per
menstrual cycle
Cancer
 Different biological rhythms for normal and
tumor cells
 Tumor: fast growing-2 am,
slow growing:10pm
 Cancer Rx...
Cancer
 Cancer drug (s phase specific) administered more in night
time, because cancer cells divide more in night time &
...
Chronotoxicity
 Specifically with antitumor agents
 Irinotecan induced leucopenia is more
pronounced in late active phase
Recent advances
 Casein Kinase 1 (CK-1) inhibitor- potential
new drug
 Reset the circadian clock enzymes
 Use: jet lag,...
Summary:
 Chronopharmacology: science concerned
with the variations in the pharmacological
actions of various drugs over ...
Slowly slowly O mind,
everything in own pace happens
Gardner may water a hundred buckets,
fruit arrives only in its season...
Chronopharmacology
Chronopharmacology
Chronopharmacology
Chronopharmacology
Chronopharmacology
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Chronopharmacology

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Chronopharmacology

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Chronopharmacology

  1. 1. CHRONOPHARMACOLOGY Dr. Ashutosh Tiwari M.D. Pharmacology (1st year) 14/02/2014 SAIMS Indore
  2. 2. Overview  History  Biological clock  Types of rhythm  Physiological functions & diseases exhibiting circadian rhythm  Application in various disease  Pulsatile drug delivery system  Recent advances
  3. 3. History Jean-Jacques d'Ortous de Mairan description of circadian rhythms in plants in 18th century Franz Halberg coined the word circadian in 1960s considered as one of the founders of chronobiology
  4. 4. Chronopharmacology science concerned with the variations in the pharmacological actions of various drugs over biological timings & endogenous periodicities
  5. 5. Biological Rhythm  A determined rhythmic biological process or function.  Chronobiology  Science that studies the biological rhythms or the science dealing with the phenomenon of rhythmicity in living organisms
  6. 6. Types of rhythm  Ultradian ( <20h)  ECG, Sleep stages  Circadian (20<  <28h)  Sleep wake cycle  Infradian (>28 h)  Pre-menstrual syndrome  Circaseptan ( ~7d)  Work rest scheme  Circamensual (~30d)  Menstrual cycle  Circannual (~1 yr)  Hibernation period
  7. 7. CIRCADIAN RHYTHM  Circadian (circa = around & diem = day)  Go over ~24hrs  Oscillations in the biological, physiological & behavioral functions of an organism with a periodicity of 24 hrs.
  8. 8.  Circadian rhythms are particularly important in medicine  A circadian clock in the brain coordinates with 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. 9. Zeitgeber  from German: “synchronizer”  Any exogenous (external) cue that synchronizes an organism's endogenous (internal) time-keeping system (clock) to the earth's 24- hour cycle  Examples  Light-darkness  Warmth-cold  Eating-fasting  Social contact-isolation  Noise-quiet  Also: pharmacological manipulation 
  10. 10. Circadian Rythm  Biological clock / Circadian pacemaker is present in the Supra-chiasmatic nuclei (SCN) in hypothalamus  Light falls on the eye  light signals transmitted by afferent nerves arising from the retina  retino hypothalamic tract  paired suprachiasmatic nuclei in the hypothalamus
  11. 11. Circadian rhythm  SCN passes the information to Pineal gland  Melatonin hormone  SCN connections with the autonomic nervous system  set the sensitivity of endocrine glands (i.e., thyroid, adrenal, ovary)  Time of light, duration, wavelength & intensity determine circadian patterns of body
  12. 12. The suprachiasmatic nucleus controls circadian rhythms in response to hormonal variation in the body
  13. 13. Consequences of disrupting biological rhythms  If external cues change there occurs disruption of biological rhythms  Shift work  Jet lag we have to re-adjust our internal clock  Melatonin (useful in jet lag /sleep disorder)
  14. 14. Physiological functions showing circadian rhythm
  15. 15. Diseases known to display circadian Rhythm
  16. 16.  In medicine 3 disciplines are taken account according to time Chronophysiology Chronopathology chronopharmacology Chronokinetics Chronesthesy Chronergy Chronotoxicity Chronotherapeutics
  17. 17. Chronokinetics Deals with study of temporal changes in pharmakokinetic parameters – ADME, due to time of administration Chronesthesy Circadian or other systemic changes in the susceptibility and sensitivity of the target system to a drug Chronergy Rhythmic difference in effects of drug on the organism as a whole which includes both desired and undesired effects
  18. 18. Chronotherapeutics Application of chrono-biological principles to the treatment of diseases Chronopharmaceutics branch of pharmaceutics devoted to the design and evaluation of drug delivery systems that release a bioactive agent at a rhythm that ideally matches the biological requirement of a given disease therapy.
  19. 19. Pulsatile drug delivery system  Now a days there is 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  Therefore 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
  20. 20. Chronopharmacodynamics Important factors in Chronopharmacodynamics:  Circadian Rhythm has been found for  receptor number or  Receptor conformation  second messengers
  21. 21. Why study Chronopharmacokinetics?  PK-PD vary with time  Gastric motility: is double in day time than in night  Plasma protein concentrations are higher in day than in night  Hepatic blood flow has been shown to be greatest at 8 am and metabolism to be reduced during the night  When Symptoms of a disease are circadian phase dependent e.g. nocturnal asthma, angina pectoris, myocardial infarction, ulcer diseases  Drug toxicity can be avoided/ Minimized by administering at a particular time
  22. 22. Chrono PK- Absorption  Depends on pH, gastric emptying, motility and gastrointestinal blood flow  Lipophilic drugs are better absorbed in morning because of faster gastric emptying time and a higher GI perfusion in the morning  Valproic acid, Indomethacin, Ketoprofen are better absorbed in the morning  Skin penetration of lidocaine and prilocaine is better in evening
  23. 23. Chrono PK- Distribution • Blood flow depends on several regulatory factors, including sympathetic and parasympathetic systems whose activities are known to be circadian time dependent with a predominant diurnal effect of the sympathetic system. • A diurnal increase and nocturnal decrease of blood flow and local tissue blood flows may explain a possible difference in drug distribution depending on the dosing time.  plasma concentration of albumin and alpha 1 glycoprotein is circadian time dependent : show peak around noon. Therefore drugs bound to plasma proteins like valproic acid, carbamazepine, diazepam, prednisolone etc. show increase in free fraction at night
  24. 24. Chrono PK- Metabolism  Depends on Liver enzyme activity & Hepatic blood flow  High extraction ratio: metabolism depends on blood flow  Low extraction ratio: metabolism depends on enzyme activity  Hepatic blood flow high in morning  Metabolism reduces in night
  25. 25. Chrono PK- Elimination  Renal physiological functions such as glomerular filtration, renal blood flow, urinary pH, and tubular resorption show a circadian time-dependent difference with higher values during daytime.
  26. 26. DRUGS UNDERGOING CHRONOKINETICS: 1. Antibiotics : Aminoglycosides: gentamycin, tobramycin, amikacin •Renal toxicity of aminoglycosides can be reduced by giving the drug as a single daily injection when patients are active (at day time / in the activity period)
  27. 27. 2. Antihypertensive drugs: • Cmax was higher and/or tmax shorter after morning than evening dosing of the lipophilic drugs (nifedipine, oral nitrates, propranolol). •Atenolol (hydrophilic drug) is not absorbed rapidly after morning administration. •ACE inhibitors were found to be safe and effective when administered at bed time when compared to morning.
  28. 28. 3. Valproic acid(antiepileptic): •Cmax tended to be higher, tmax was shorter and absorption rate constant (ka) tended to be larger in the morning than in evening. 4. Anti-inflammatory drugs : •Have greater rates and extents of bioavailability when administered in the morning than evening. Eg. Indomethacin, Ketoprofen
  29. 29. 5. Anti-Migraine drugs •Sumatriptan is a drug of choice in migraine treatment. •The mean peak serum concentration was significantly higher following the 07:00 h administration than after the 19:00 h administration. 6. Anticancer drugs : •The activity of dehydropyrimidine dehydrogenase in human mononuclear cells increases by 40% around midnight. • This enzyme brings about the intracellular catabolism of 5-FU and contributes to improved tolerability of this drug between 00:00 and 04:00.
  30. 30. 7. Anti hyperlipidemic drugs •More Cholesterol systhesis takes place in the evening than in the morning with the involvement of the enzyme HMG Co-A Reductase. •This enzyme is competitively inhibited by HMG Co-A Reductase inhibitors (Statins) •Hence statins should be administered at evening rather than at morning for increased efficacy with the exception of Atorvastatin which has got longer half life.
  31. 31. 8. Opiod analgesics •Stronger analgesic effects were observed when tramadol and dihydrocodeine were given in the evening to relieve painful stimuli. •Peak morphine use occurred at 9 a.m. and least use at 3 a.m. •A recent study of meperidine reveals a circadian variation of meperidine-induced analgesia in sickle cell anemia patients, with maximal analgesic effect occurring with the morning dose.
  32. 32. 9. Heparin: even if given at a constant infusion rate; aPTT and risk of bleeding varies with hour of day and is higher at night. 10. Topical steroids: anti-inflammatory action is maximum in afternoon 11. Local anesthetics •The duration of local anesthesia was longest when amide-type local anesthetic agents (lidocaine, ropivacaine, mepivacaine and betoxycaine) were applied around 3 p.m. •The plasma levels of lidocaine were significantly higher in the evening than at any other time of day.
  33. 33. 11. General anesthetics Barbiturates • Higher brain pentobarbital or hexobarbital concentrations occurred when injected during the dark phase. • Postsynaptic type A GABAergic activity is increased during nocturnal hours, corresponding to the duration of the maximal efficacy of barbiturates. Benzodiazepines The elimination half-life of midazolam was found to be at its shortest at 14:00 h and at its longest at 02:00 h Ketamine, Etomidate, Propofol, and Halogenated Agents Action longer during the night than during the day. Halothane Greatest efficacy of halothane occurred between 24:00 and 06:00 h.
  34. 34. 12. Antipsychotic drugs  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.
  35. 35. CHRONOTHERAPEUTICS : •Chronotherapeutics refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize the side effects. •The chronotherapy of a medication may be accomplished by the appropriate timing of conventionally formulated tablets and capsules, and the special drug delivery system to synchronize drug concentrations to rhythms in disease activity.
  36. 36. Chronotherapeutics: Chronotherapy found useful in: 1. Allergic rhinitis 2. Bronchial asthma 3. Peptic ulcer disease 4. Rheumatoid arthritis, Osteoarthritis 5. Angina pectoris 6. MI 7. Hypertension, stroke 8. Cancer
  37. 37. Necessity of Chronotherapeutic approach  When the “therapeutic window” for a given medication is very narrow, close to toxicity  When the toxicity of the drug is a factor of dose limitation  When the kinetics and or the effects are dependent on the moment of the administration  when the efect of the drug can be obtained only by a time-modulated therapeutical modality.
  38. 38. 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
  39. 39. Bronchial 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 : Small bronchi diameter significantly increases during the day and decreases at night because of :  Adrenergic blockade of ß-receptors,  Dominance of alpha-adrenergic pathways,  Cholinergic dominance,  Lowest concentrations of cortisol  Ig E with highest concentration of histamine around 04:00 AM
  40. 40. Treatment  SR formulation of theophyline at night  Increase efficacy  Decrease s/e  Avoid multiple dosing Nocturnal vagus nerve hyperactivity Relieved by cholinergic antagonist eg. ipratropium bromide
  41. 41. Corticosteroids  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.  single dose oral prednisolone at 3pm is most effective Leukotriene receptor antagonist zileuton at night is most effective as LTB4 conc. max in night
  42. 42. Peptic ulcer  In the past, were administered at regular intervals around the clock, on the basis of pharmacokinetic properties.  Maximal acid secretion, peptic ulcer disease pain, and perforation of gastric and duodenal ulcers are more common at night  H2blockers(Ranitidine, Cemitidine, famotidine) are given at evening time
  43. 43. Arthritis  The symptoms of rheumatoid arthritis are worse in the morning.  People with osteoarthritis, tend to have less pain in the morning and more at night  NSAIDs (flubiprofen, ketoprofen and indomethacin)  Effectively relieve pain of RA when given at night, and better results in case of OA seen when these are given in morning.
  44. 44. 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.
  45. 45. CVS Reason - ↑ physical activity (sudden) - ↑ catecholamine levels - ↑ platelet aggregation - ↑ vascular tone - ↓ intrinsic thrombolytic activity
  46. 46.  A new COER verapamil (Controlled Onset Extended Release) used in Hypertension  It is formulated as a pill with a shell that dissolves slowly.  Taken at bed-time, this exerts peak effects between 5 am and noon & no mid-night dip in B.P is seen.  ACE-I (Ramipril) & Doxazosin, given at bedtime
  47. 47. Endocrine system  Once-daily morning dose dosing minimizes risk of adrenal suppression and other side effects.  Bedtime ADH analogue dosing helps to alleviate nocturnal bedwetting in children and nocturia in adults.
  48. 48. Diabetes Mellitus  Morning hyperglycemia may be observed in patients with diabetes mellitus  Dawn phenomenon  Somogyi Phenomenon
  49. 49. Dawn Phenomenon 0 10 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Cause: During night increase in GH, cortisol, catecholamines + decreasing levels of bedtime insulin  Rise in blood sugar in morning
  50. 50. Somogyi Phenomenon 0 10 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Cause: too much / long acting insulin or decreased bedtime snacks  hypoglycemia at night  increase in GH, cortisol, catecholamines  Rise in blood sugar in morning
  51. 51. Oral contracetives Prescribed as per menstrual cycle
  52. 52. Cancer  Different biological rhythms for normal and tumor cells  Tumor: fast growing-2 am, slow growing:10pm  Cancer Rx 1.duration of the phase of cell cycle 2.cell proliferation rate
  53. 53. Cancer  Cancer drug (s phase specific) administered more in night time, because cancer cells divide more in night time & Host cells in morning  But in treatment with 6-mercaptopurine and methotrexate , evening dose is given to patient.  Colorectal cancer- Oxaliplatin is given in during daytime & flurouracil at night.  Breast cancer: Surgery during later half of the menstrual cycle - more clearance rate then early half  Progesterone in the later half inhibit the enzymes responsible for spread of cancer cells
  54. 54. Chronotoxicity  Specifically with antitumor agents  Irinotecan induced leucopenia is more pronounced in late active phase
  55. 55. Recent advances  Casein Kinase 1 (CK-1) inhibitor- 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
  56. 56. Summary:  Chronopharmacology: science concerned with the variations in the pharmacological actions of various drugs over biological timings & endogenous periodicities  Various physiological functions as well as diseases exhibit circadian rhythm  Also there are various drugs which follow chronokinetics  Therefore application of chronotherapeutics in such diseases can maximise the efficacy & minimize the adverse effects associated with the drugs resulting in improved therapeutic outcome.
  57. 57. Slowly slowly O mind, everything in own pace happens Gardner may water a hundred buckets, fruit arrives only in its season Sant Kabir

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