CHRONOPHARMACOLOGY

Definition - branch of pharmacology that examines the effect that the time of day has on the
pharmacodynamic and pharmacokinetic profile of a drug
Background about Circadian (about a day) Clock and Cycles
Circadian Clock
Regarded as one of the most indispensable biological functions
Acts a multifunctional timer to regulate homeostatic systems (e.g. sleep, activity, appetite,
hormones levels) with 24 hr cycles.
Nearly all body functions, including those influencing pharmacokinetics and pharmacodynamics
of a drug, display significant daily or circadian variations
Site of circadian pacemaker in mammals is the Suprachiasmatic Nucleus (SCN). Light signals
are detected by retinal photoreceptor cells and transmitted to the neurons in the SCN via the
retinohypothalamic tract
Circadian clock is composed of:
1. Input pathway that adjust the time
2. Central oscillator (or clock) generator
3. Output pathway that is manifested by circadian physiology and behavior
NOTE: Daily changes in light intensities are thought to be a major environmental cue involved in
circadian entrainment
Circadian rhythms, by definition are endogenous in nature and persist under free-running
conditions (i.e. without environmental time cues). The endogenous clock in humans runs at a
period of 25 hr (slightly slower than 24 hr)
Inherent rhythmicity allows organisms to more readily adapt and survive better under changing
environmental conditions during the 24 hrs of a day
Environmental time cues - aka synchronizers or zeitgebers (daily light-dark cycle occurring in
conjunction with the sleep-wake routine) - set the inherent pacemaker circadian time-keeping
system to 24 hr each day

Chronotherapy
Discipline that is concerned with the administration of drugs at times where they will have the
greatest efficacy and/or be best tolerated
Rationale for chronotherapy - there is a 24 hr rhythm in the risk of certain diseases and a 24 hr
rhythm of drug pharmacokinetics, pharmacodynamics and safety. The therapeutic to toxicity
ration od a medication varies predictably according to chronobiological determinants
The risk and/or intensity of the symptoms of disease vary predictably over time. This is
highly relevant for:
1. Migraine headaches: most frequent in the morning after awakening
2. Allergic rhinitis: symptoms are worst in morning after awakening
3. Rheumatoid arthritis: symptoms are worst when awakening from nighttime
4. Osteoarthritis: Worst later in the day
5. Myocardial infarction: morbidity and mortality are greatest during the initial daytime hours
6. Congestive heart failure: symptomns are worse nocturnally
7. Thrombotic, hemorrhagic stroke: incidence is highest in the morning around the time of
beginning daily activities
8. Angina: most frequent during the middle to latter half of the nighttime hours
9. Asthma: risk of attack is greatest during the nighttime
10. Epilepsy: seizures are most common around sleep onset and offset in the morning
11. Peptic ulcer pain and distress: worst late evening and early morning

Information and Figures from:

Drug Metab Pharmacokinetics 22:3-14, 2007; Annu Rev Pharmacol Toxicol 47:593-628, 2007;
Pharmacological Reviews 33:107-115, 1996; J Pharmaceutical Sci 1-10, 2007 (DOI
10.1002/jps.21044