11 CHRONOPHARMACOLOGY

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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) Cock and Cyce!

Circadian Cock

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 ! hr cycles.

"early all body functions, including those influencing pharmacokinetics and pharmacodynamics

of a drug, display significant daily or circadian variations

#ite of circadian pacemaker in mammals is the #uprachiasmatic "ucleus (#$"). %ight signals

are detected by retinal photoreceptor cells and transmitted to the neurons in the #$" via theretinohypothalamic tract

Circadian cock i! co"#o!ed of$

&. 'nput pathway that adust the time

. $entral oscillator (or clock) generator

. *utput pathway that is manifested by circadian physiology and behavior

"*+ aily changes in light intensities are thought to be a maor environmental cue involved in

circadian entrainment

$ircadian rhythms, by definition are endogenous in nature and persist under free-runningconditions (i.e. without environmental time cues). +he endogenous clock in humans runs at a

period of / hr (slightly slower than ! hr)

'nherent rhythmicity allows organisms to more readily adapt and survive better under changing

environmental conditions during the ! hrs of a day

nvironmental time cues - aka synchroni0ers or 0eitgebers (daily light-dark cycle occurring in

conunction with the sleep-wake routine) - set the inherent pacemaker circadian time-keeping

system to ! hr each day


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C%ronot%era#y

iscipline that is concerned with the administration of drugs at times where they will have the

greatest efficacy and1or be best tolerated

Rationale for chronotherapy - there is a ! hr rhythm in the risk of certain diseases and a ! hr

rhythm of drug pharmacokinetics, pharmacodynamics and safety. +he therapeutic to toxicityration od a medication varies predictably according to chronobiological determinants

&%e ri!k and'or inten!ity of t%e !y"#to"! of di!ea!e ary #redictaby oer ti"e &%i! i!

%ig%y reeant for$

* Migraine %eadac%e!$most fre2uent in the morning after awakening

+ Aergic r%initi!$ symptoms are worst in morning after awakening

, R%eu"atoid art%riti!$ symptoms are worst when awakening from nighttime

- O!teoart%riti!$ 3orst later in the day

. Myocardia infarction$ morbidity and mortality are greatest during the initial daytime hours

/ Conge!tie %eart faiure$ symptomns are worse nocturnally

0 &%ro"botic1 %e"orr%agic !troke$ incidence is highest in the morning around the time of

beginning daily activities

2 Angina$most fre2uent during the middle to latter half of the nighttime hours

3 A!t%"a$ risk of attack is greatest during the nighttime

*4 5#ie#!y$ sei0ures are most common around sleep onset and offset in the morning

** Pe#tic ucer #ain and di!tre!!$worst late evening and early morning


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'nformation and 4igures from

rug 5etab 6harmacokinetics -&!, 7789 Annu Rev 6harmacol +oxicol !8/:-;

11 CHRONOPHARMACOLOGY

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