Chronotherapeutics refers to treating patients based on their biological clocks to maximize health benefits and minimize adverse effects. Many diseases have circadian rhythms that can be targeted through timed drug delivery. For example, asthma symptoms peak in early morning, so antiasthmatics should be dosed higher in the evening. Cardiovascular risks are also higher in the morning, so drugs like aspirin have maximum effect then. Understanding biological rhythms allows optimizing drug therapy to decrease toxicity and increase effectiveness. New drug delivery technologies further enable chronotherapeutic approaches.

1. Chronotherapeutics

2. • Biological rhythm - one or more biological events or
functions that reoccur in time in a repeated order and
with a repeated interval between occurrences .
• Chronobiology - science concerned with the biological
mechanism of the diseases according to a time
structure.
• Chronopharmacology - science concerned with the
variations in the pharmacological actions of various
drugs over a period of time of the day.

3. • Circadian rhythms are driven by a group of genes called
clock genes.
• In mammals, the core clock genes consist of
• Bmal1 (Brain and muscle arylhydrocarbon receptor nuclear
translocator-like 1)
• CLOCK (Circadian Locomotor Output Cycles Kaput)
• Per (Period)- Per 1, Per 2, Per 3
• Cry (Cryptochrome)- Cry 1 and Cry 2

4. Circadian Pacemaker
Light
Suprachiasmatic
Nucleus
Output Rhythm

6. Uric acid
Melatonin

7. Peptic ulcer Disease
Congestive Heart Failure
Apnea
Prinzmetal Angina
Asthma
Migraine
Rheumatoid
Arthritis
Angina
MI
Stroke
Chronic Pain
Osteoarthritis
Hemorrhagic and
perforated ulcer
crisis

8. Chronopharmacology
Chronopharmacokinetics
Chronopharmacodynamics/
Chronoesthesy
Chronotherapeutics
Chronotoxicology
Chronergy

9. Chronotherapeutics
Chronotherapeutics refers to treating a
patient according to a person's daily, monthly,
seasonal, or yearly biological clock, in order
to maximize the health benefits and minimize
adverse effects.

10. INSULIN
Advantages
Stability
Prevents Overdosage
Appropriate usage of drugs
Reduce side effects

12. Asthma
• Symptoms of asthma occur 50 to 100 times more often
in early morning than during the day.
• Many circadian dependent factors appear to contribute
to the worsening of nocturnal asthmatic symptoms.
Histamine (a mediator of bronchoconstriction)
and other inflammatory mediators, their
concentrations peak at a level that coincided
with the greatest degree of
bronchoconstriction at 4:00 am.

13. Antiasthmatic drugs such as theophylline
and long acting beta sympathomimetics
may/ should be dosed higher in the
evening than during daytime when asthma
is predominantly nocturnal.
The theophylline concentration peak
height (Cmax) is greater and time to peak
(Tmax) shorter with dosing at 08:00 than at
20:00

14. •NSAIDs, e.g., indomethacin and
ketoprofen, have shown that they have
a greater rate and/or extent of
bioavailability when they are given in
the morning than when they are given
in the evening due to better morning
absorption.
•Greater blood flow of the
gastrointestinal tract in the morning
than in the evening explains this
phenomenon.
Pain and Arthritis

15. Patients with osteoarthritis tend to have less
pain in the morning and more at night while
those with rheumatoid arthritis, have pain
that usually peaks in the morning and
decreases throughout the day.
Chronotherapy for all forms of arthritis using
NSAID’s such as ibuprofen should be timed
to ensure that the highest blood levels of the
drug coincide with peak pain.

16. For osteoarthritis sufferers, the optimal
time for a nonsteroidal anti-inflammatory
drug such as ibuprofen would be around
noon or mid-afternoon.
The same drug would be more effective for
people with rheumatoid arthritis when
taken after the evening meal.

17. Myocardial infarction
Sudden cardiac death
Angina pectoris
Transient ischemic attacks / Stroke
Cardiovascular diseases
Capillary resistance and vascular reactivity are higher
in the morning and decrease later in the day.
Platelet aggregability is increased and fibrinolytic activity is
decreased in the morning, leading to a state of relative
hypercoagulability of the blood.

18. • Aspirin – maximum antiplatelet effect in the
morning.
• Thrombolytics and Heparin – ↓ benefit
during early morning hours.
• Atenolol – more effective during day time.
• Labetalol – more effective in early morning
hours.
• Enalapril -Peak effect in the afternoon after
morning dose, Early morning after evening
dose.

19. • BP is at its lowest during the sleep cycle and rises steeply
during the early morning awakening period.
• Most patients with essential hypertension have quite a
marked rise in blood pressure upon awakening - called 'the
morning surge' – that increase can be 3 mm Hg/hour
(systolic) and 2 mm Hg/hour (diastolic) for the first four to
six hours after waking up.
• This is due to high catecholamine concentration in the early
morning.
Hypertension

21. • Cardiovascular drugs such as nifedipine, oral nitrates
and propranolol
• Peak plasma concentration is twice as high and time to
reach peak concentration is shorter after morning
dosing compared with evening dosing.
• The underlying mechanisms of their
chronopharmacokinetic pattern involve a faster gastric
emptying time and a greater gastrointestinal perfusion
in the morning.

22. A new Controlled onset extended release (COER-V)
verapamil use in HT is designed so drug
concentrations rise sharply in the early morning to
coincide with the peak incidence of cardiovascular
events.
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.

23. Peptic Ulcer
In peptic ulcer patients, gastric acid secretion is highest during
the night.
Suppression of nocturnal acid is an important factor in peptic
ulcer healing.

24. H2-blockers (ranitidine, cimetidine, famotidine,
roxatidine, nizatidine) should be taken once a day in
the late afternoon or early night when acid secretion
is increasing.
Therefore, for active duodenal ulcer, once daily at bedtime is the
recommended dosage regimen for H2 antagonists.
At nighttime, when gastric motility and emptying are slower,
drug disintegration, dissolution, and absorption may be slower.

25. Hypercholesterolemia
Cholesterol synthesis is generally higher during the night
than during daylight, and diurnal synthesis may represent up
to 30%–40% of daily cholesterol synthesis.
Studies with HMG CoA reductase inhibitors have suggested that
evening dosing was more effective than morning dosing.
Free cholesterol levels are reported to be lowest at 2 pm to 6 pm and
peak at 6 am.

26. Highest secretion of cortisol early morning.
Lowest at midnight.
GH peaks during sleep.
Testosterone peaks early morning.
TSH peaks at mid night.
Corticosteroids given as single morning dose
cause less pituitary adrenal suppression
Endocrine system

27. In the middle of the night, there is a surge in the amount of growth
hormone the body releases, followed by a surge in cortisol, which
increases blood glucose production by the liver.
Normally, these processes are offset by increased insulin
secretion by the pancreas, so blood glucose levels remain
relatively stable.
However, Diabetes Mellitus patients whose livers may not respond to
insulin well enough to achieve euglycemia, the blood glucose levels rises
during sleep and can have a powerful effect on morning blood glucose
levels.
Diabetes Mellitus

28. INSULIN

29. Melatonin – secreted at night by
pineal gland.
• Function – synchronizes sleep wake cycle with
circadian rhythm.
Melatonin agonist[Ramelteon] –
hypnotic for sleep onset insomnia.
• Reduces Jet lag symptoms.
• Bedtime administration of hypnotics- more
effective.

30. Cancer
The rhythmic circadian changes in tumor
blood flow and cancer growth are relevant
both when tumors are small and growing
most rapidly and when they are larger and
growing more slowly.
The blood flow to tumors and tumor growth
rate are each up to threefold greater during
each daily activity phase of the circadian cycle
than during the daily rest phase.

31. Normal human bone marrow DNA
synthesis peaks around noon, DNA
synthesis in malignant lymphoma cells
peaks near midnight.
By treatment at mid night, more
tumor cell kill could be achieved with
same dose of S-phase active cytotoxic
therapy and with relatively little bone
marrow damage

33. CONTIN technology
Physico-chemical modification of the API
OROS technology
CODAS technology CE
FORM technology
DIFFUCAPS technology
Chronomodulating infusion pumps
TIMERx technology
Other CR erodible polymers
Controlled-release microchip
CHRONOTHERAPEUTIC DRUG DELIVERY
SYSTEM (CDDS)

34. • Effectiveness and toxicity of a drug are not constant
over 24 hr period.
• Understanding the biological rhythms can optimize
and individualize drug therapy to a great extent.
• Thus it can help to decrease the drug related toxicity
and enhance effectiveness.
Conclusion

36. Disadvantages
• It develops a non 24 hours sleep wake syndrome
after the treatment as the person sleeps or over
24 hours during the treatment.
• Person become less productive during
chronotherapy and staying awake till the other
schedule will be bit uncomfortable.
• Medical supervision is mandatory for this
therapy.
• Large number of process variables.
• Trained /skilled person is needed for
manufacturing.

37. Environmental times, termed
synchronizers or zeitgebers, the strongest
one being the daily light–dark cycle
occurring in conjunction with the wake–
sleep routine, set the inherited
pacemaker circadian timekeeping
systems to 24h each day.

42. Both insulin secretion by pancreatic cells and insulin sensitivity in the insulin target
organs exhibit daily rhythmicity, which may be involved in maintaining homeostasis
of glucose metabolism.
Because these rhythms are impaired in patients with diabetes, the correction of
these abnormalities is necessary for effective treatment.
At present, there are few studies showing chronotherapy of insulin
sensitizers (thiazolidinediones and biguanides).
However, for the treatment of impaired insulin secretion, including
glinides and rapid- and long-acting insulin analogs, also have the
merit of chronotherapeutic approach.

43. • In human bone marrow, skin, and oral and rectal mucosae, DNA
synthesis, a stage of the cell-division cycle associated with increased
susceptibility to Sphase-specific agents, decreases by 50% or more
between 00:00 and 04:00 compared with daytime.
• 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.
• In contrast, cisplatin are better tolerated between 16:00 and 20:00
than 12 h apart.
• The chronopharmacokinetic finding of cisplatin seems to contribute
to the decreased renal toxicity during evening administration

44. Diseases requiring Chronotherapeutic
drug delivery

45. Drugs developed or under
development as chronotherapies