Presented by:
ASHUTOSH MISHRA
M. Pharm. [Pharmacology] 1st Yr.
KIET School Of Pharmacy
What is Chronopharmacology ?
It is the science concerned
with the variations in the
pharmacological actions of
various drugs over a
biological timings &
endogenous periodicities.
Pharmacology-
It is the science of drugs.
Phamacon - (Drug),
Logos – (study)
It deals with the interaction of administered
Chem. molecule (Drug) with living
systems.
But most importantly those that are
relevant to effective and safe use for
medicinal purposes.
Chronobiology-
Chronos (time),
Bios (life),
Logos (study).
The science dealing with the phenomenon of
rhythmicity in living organisms is called
CHRONOBIOLOGY.
Biological Rhythm
A determined rhythmic biological process or
function.
A biological rhythm is a self-sustaining
oscillation with the duration of time
between successive repetitions (i.e; the
period) being rather non-varying under
normal conditions.
Example-
CIRCADIAN RHYTHM:
Circadian (circa - about; dies, day, or about 24
hour)
Oscillations in the biological, physiological &
behavioral functions of an organism with a
periodicity of 24 hrs.
Continue…
Circadian rhythms are particularly important in
medicine.
A circadian clock in the brain coordinates 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
Types of Rhythm
Ultradian ( <20h): cycles shorter than
a day e.g. micro sec. for a neuron to fire.
Circadian (20< <28h):Lasting for
about 24 hrs. e.g. sleep and wake cycles.
Infradian (≥28 h): Cycles longer than
24 hrs e.g. menstrual cycle.
sleep-wake cycle
BIORHYTHMS
External cues which reset the circadian clock =
ZEITGEBERS = synchronizers
Defination-Endogenously generated, and can be
entrained by external factors, called zeitgebers.
LD- Light-Darkness
EF- Eating-Fasting
SI- Social Contact- Isolation
NQ- Noise-Quiet
Biological Clock
An internal biological clock, located, in mammals, in
the suprachiasmatic nucleus of the hypothalamus
(SCN), delivering its message of time throughout the
body.
It is responsible for circadian rhythms and annual /
seasonal rhythms.
The SCN uses its connections with the autonomic
nervous system for spreading its time-of-day
message, either by setting the sensitivity of endocrine
glands (i.e., thyroid, adrenal, ovary) or by directly
controlling an endocrine output of pineal gland
(i.e., melatonin synthesis).
Regulatory System-
In medicine 3 disciplines taken
account acc. To time-
- CHRONOPHYSIOLOGY
- CHRONOPATHOLOGY
- CHRONOPHARMACOLOGY
•Chronotherapeutics
•Chronokinetic
•Chronesthesy
•Chronergy
•Chronotoxicity
Chronotherepeutics-
New technology makes possible
CHRONOTHERAPY
(=CHRONOTHERAPEUTICS), that is, increase of
the efficiency and safety of medications by
proportioning their concentrations during the 24
hours in synchrony with biological rhythm
determinants of disease.
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.
Chronergy-
Rhythmic difference in effects of drug on the
organism as a whole which includes both desired
and undesired effects.
Chronotoxicity- The toxic effect of drug on
the organism, which is undesirable and affects the
rhythmic system. Specifically with antitumor agents
Irinotecan induced leucopenia is more pronounced.
Applications & Uses-
Chronotherapy found useful in:
Oncology,
Asthma therapy,
Hypertension,
Strokes,
Sleep apnea,
GI tract disorders,
Allergies.
Cancers-
Different biological rhythms for normal and tumor
cells
Appropriate timing.
Cancer Cells
1.Duration of the phase of cell cycle
2.Cell proliferation rate
TATO (theoretical analysis of treatment outcome)
Tumor: fast growing-2 am, slow growing-10 pm
Later half of the menstrual cycle have more clearance
rate then early half of the cycle.
Progesterone in the later half inhibit the enzymes
responsible for spread of cancer cells.
Cancer drug administered more in night
time, because cancer cells divide more in night time.
But not all, Treatment with 6-mercaptopurine and
methotrexate , evening dose is given to patient.
Colorectal cancer- Oxaliplatin is given in during
daytime & flurouracil at night.
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 :
•Exogenous factors-
Allergen exposure,
Dust and pollution,
temperature changes during the day,
position during sleep.
Endogenous factors- Small bronchi diameter
significantly increases during the day and decreases at
night b’coz-
Adrenergic blockade of ß-receptors,
Dominance of alpha-adrenergic pathways,
Cholinergic dominance,
Smallest conc. of Ig E and
Highest concentration of histamine around 04:00.
Treatment-
SR formulation of theophyline once daily
Increase efficacy
Avoid multiple dosing
Nocturnal vagus nerve hyperactivity
Relieved by cholinergic antagonist
eg. Ipratropium bromide
oxitropium bromide
Stroke-
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.
Reasons - ↑ physical activity (sudden)
- ↑ catecholamine levels
- ↑ platelet aggregation
- ↑ vascular tone
Graphical explanation-
Treatment-
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 5 am and noon & no mid-night dip in B.P is
seen.
Diltiazam- once in a morning strong influence in
evening.
Peptic Ulcer-
Pathogenesis- Helicobacter pylori and H+ ions
secretion by the stomach.
Acidity(H+) peak-evening.
Treatment-
Once daily given conventional H2blockers
(Ranitidine, Cemitidine, famotidine) are given at
evening time.
Allergic Rhinitis-
Rhinitis- worst in the morning and evening.
It is a Type-I (Anaphylactic) reaction, in which
antibodies (Ig E) are produced which get fixed to
the mast cells. On exposure to antigen, AG:AB
reaction takes place on mast cell surface releasing
Histamine, -HT, LTs, PGs etc.
Resulting in
urticaria, itching, bronchiospasm, rhinitis like
conditions.
Immediate Hypersensitivity.
Treatment-
Once-daily, non-sedating antihistamine (like;
Chlorpheniramine 10-20 mg) by giving it before
bedtime to control overnight exacerbations and
during sleep
Morning oral corticosteroid therapy for severe
allergic rhinitis.
Drug delivery systems-
1. Enteric-coated systems
2. Pulsatile drug dilivary systems
3. Membrane diffusion controlled
systems
4. Osmotic systems
5. Compression coated system
6. Layered system
Recent Advances-
Due to advances in
chronobiology, chronopharmacology, and global market
constraints, the traditional goal of pharmaceutics (e.g.
design drug delivery systems with a constant drug release
rate) is becoming obsolete.
However, the major bottleneck in the development of drug
delivery systems that match the circadian rhythm
(chronopharmaceutical drug delivery systems: ChrDDS)
may be the availability of appropriate technology.
Continue…
The last decade has witnessed the emergence of
ChrDDS against several diseases. The increasing
research interest surrounding ChrDDS may lead to the
creation of a new sub-discipline in pharmaceutics
known as chronopharmaceutics.
Futuristic Approach-
Future development in chronopharmaceutics may be
made at the interface of other emerging disciplines
such as-
System biology and
Nanomedicine
Such novel and more biological approaches to drug
delivery may lead to safer and more efficient disease
therapy in the future.
ThankX !!
