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Circadian Rhythms

Chapter · January 2015

DOI: 10.1007/978-3-642-36172-2_287

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 Lemmer in: Encyclopedia Psychopharmacology,
Synonyms Springer 2015
Biological rhythms; Biological clock

Definition
Introduction: The Biological Clock
Living organisms are continuously influenced by external stimuli, many of which have rhythmic patterns.
Environmental rhythms in daily and seasonal patterns of light, food availability, and temperature are
predictable, and animals - including humans - have the ability to anticipate these environmental events
with periodically and predictably changing internal conditions. These rhythmic patterns of anticipation
have clear advantages and survival value. Thus, rhythmicity is the most ubiquitous feature of nature.
Rhythms are found from unicellular to complex multicellular organisms in plants, animals, and men. The
frequencies of rhythms in nature cover nearly every division of time. There are rhythms that oscillate once
per second (e.g., in the electroencephalogram), once per several seconds (respiratory rhythm, heart rate),
and up to once per year (circannual rhythm).

The most evident environmental change that results from the regular spin of the earth around its central
axis and in the alternation between day and night seems to have induced the predominant oscillation, the
circadian rhythm (the about-24-h rhythm; circa = about, dies = day, as proposed by Halberg (1959). There
is sound evidence that living systems including humans are not only organized in space but are also highly
organized in time.

Circadian rhythms have been documented throughout the plant and animal kingdoms at every level of
eukaryotic organization. Circadian rhythms by definition are endogenous in nature and driven by
oscillators or clocks (Aschoff 1965) and persist under free-running conditions. In various species
(Drosophila melanogaster, Neurospora, mouse, golden hamster), the genes controlling circadian rhythms
have been identified (genes: per, frq, clock, tau). In 1971, Konopka and Benzer (1971) were able to
identify on the X chromosome of Drosophila a region, which controlled the period in the eclosion rhythm
of three mutants (per clock gene). This data provided the first evidence that the biological clock is
genetically determined and can even be transplanted from one animal into another, thereby inducing the
rhythmicity of the donor into the recipient.

Circadian clocks are believed to have evolved in parallel with the geological history of the earth and have
undergone selection pressures imposed by cyclic factors in the environment. These clocks regulate a wide
variety of behavioral and metabolic processes in many life forms. They enhance the fitness of organisms
by improving their ability to efficiently anticipate periodic events in their external environments,
especially periodic changes in light, temperature, and humidity.

The mammalian circadian clock, located in the neurons of suprachiasmatic nuclei (SCN) in the brain and
in the cells of peripheral tissues, is driven by a self-sustained molecular oscillator, which generates
rhythmic gene expression with a periodicity of about 24 h. This molecular oscillator is composed of
interacting positive and negative transcription/translation feedback loops as well as clock-controlled
output genes. It is interesting to note that clock genes have been also found in single cells of human skin
and mucosa (Bjarnason et al. 2001); furthermore, it has been shown that about 8-10 % of all genes are
regulated in a circadian fashion.

In general, the human endogenous clock does not run at a frequency of exactly 24 h, but tends to be
somewhat slower. The rhythm in human body temperature, which is timed by the biological clock, has a
period of about 25 h under free-running conditions, i.e., without environmental time cues or zeitgebers
(e.g., light, temperature). The term "zeitgeber" introduced by Jürgen Aschoff (1954) is now part of the
international scientific language. Mammals such as rodents or humans can entrain their activity to regular
light cycles not shorter than 22 but not longer than 26 h. Zeitgebers entrain the circadian rhythm to a
precise 24-h period. Zeitgebers are, therefore, necessary to entrain a living subject to a "normal" period of
24 h!

In experimental animals and in humans, however, most rhythmic fluctuations still cannot be studied under
free-running conditions, leaving the answer open to what degree they are really "circadian." Purely
exogenous rhythms are better termed as "24-h" or "daily" rhythms. Thus, an overt 24-h rhythm in a given
parameter can be endogenous or predominately exogenous in nature. Within the published clinical
literature, however, the term "circadian" is not always used in the abovementioned correct sense (as used
by chronobiologists).

Circadian Rhythms in Man

It is a common paradigm in clinical pharmacology that pharmacokinetic parameters are considered not to
be influenced by the time of day of drug administration. Concerning drug concentrations-versus-time
profiles, the flatter, the better is also a common aim in drug targeting. However, there is convincing
evidence that this paradigm cannot be held any longer. The reason is that it is now well established that
nearly all functions of the body, including those influencing pharmacokinetic parameters, display
significant daily variations. Circadian or 24-h rhythms exist in heart rate, body temperature, blood
pressure, blood flow, stroke volume, peripheral resistance, parameters of ECG recordings, in the plasma
concentrations of hormones, neurotransmitters, second messengers (e.g., cortisol, melatonin, insulin,
prolactin, atrial natriuretic hormone, noradrenaline, cAMP), in the renin-angiotensin-aldosterone system,
in blood viscosity, aggregability and fibrinolytic activity, in the plasma concentrations of glucose,
electrolytes, plasma proteins, enzymes, in the number of circulating red and white blood cells and blood
platelets, etc. Moreover, various functions of the lung such as minute volume, peak flow, FEV1, and
dynamic compliance and functions of the liver (metabolism, estimated hepatic blood flow, first-pass
effect) and of the kidneys (glomerular filtration, renal plasma flow, pH, urine volume, electrolyte
excretion) vary with time of day. Also gastric acid secretion, gastrointestinal motility, gastric emptying
time, and GI tract perfusion exhibit pronounced circadian variation (see Lemmer 1989, 2005, 2006;
Reinberg and Smolensky 1983).

Chronoepidemiology

In man, the organization in time can also be seen in certain states of disease in which the onset and
symptoms do not occur at random within 24 h of a day: Asthma attacks are more frequent at nightly hours
than at other times of day as already observed about 300 years ago by John Floyer (1698) when stating "I
have observed the fit always to happen after sleep in the night…."

Similarly, the occurrences of coronary infarction as well as of angina pectoris attacks and of pathologic
ECG recordings are unevenly distributed over the 24-h span of a day with a predominant peak in the early
morning hours. Moreover, subtypes of a disease entity such as forms of vasospastic and stable angina
pectoris or of primary and secondary hypertensions may exhibit pronouncedly different 24-h patterns in
their symptoms. The occurrence of stroke and fatal pulmonary embolism and the onset of gastrointestinal
bleeding also do not happen at random within the 24 h of a day.

Current Concepts and State of Knowledge

Chronopharmacology
Having in mind the organization in time of living systems including man, it is easy to conceive that not
only must the right amount of the right substance be at the right place but also this must occur at the right
time. This is even more important when an organism or individual itself has to act or react in favorable
biotic or environmental conditions, which by themselves are highly periodic. Thus, it is easy to
understand that exogenous compounds, including drugs, may differently challenge the individual
depending on the time of exposition.

Chronopharmacokinetics and Chronopharmacodynamics

In the last decade, numerous studies in animals as well as clinical studies have provided convincing
evidence that the pharmacokinetics (Lemmer and Bruguerolle 1994) and/or the drugs' effects/side effects
can be modified by the circadian time and/or the timing of drug application within 24 h of a day (see
Lemmer 1989, 2005, 2006; Redfern and Lemmer 1997; Reinberg and Smolensky 1983).

Functions involved in the pharmacokinetic steps - from drug absorption to drug elimination - can be
circadian phase dependent (Table 1). Thus, gastric emptying time of solids is faster in the morning than in
the afternoon. Also, the perfusion of the gastrointestinal tract varies with time of day, being more
pronounced at midnight and early morning hours than around noon and in the late afternoon. These
observations would nicely explain that - in general - drugs are more rapidly absorbed and more rapidly
reach the systemic perfusion when taken in the morning. Accordingly, clinical studies showed - mainly for
lipophilic drugs - that Tmax (time to peak drug concentration) can be shorter and/or Cmax (peak drug
concentration) can be higher after morning drug dosing than evening drug dosing.

Table 1

Biological rhythms and oral pharmacokinetics (Lemmer 2005)

Absorption GI Metabolism Elimination

Liberation Distribution
tract liver kidney

Perfusion Perfusion Perfusion Perfusion

Blood
Gastric pH First-pass effect Renal plasma flow
distribution

Peripheral Enzyme Glomerular

Acid secretion
resistance activity filtration rate
(Time-specified release,
programmable)
Transporter
Motility Blood cells Urine excretion
proteins

Gastric
Protein binding Urine pH
emptying

Rest-activity Rest-activity Electrolytes

In Tables 2 and 3, drugs are compiled for which the pharmacokinetics and pharmacodynamics were
studied "around the clock" in order to get information whether a circadian time-dependent effect is
present. This observation was corroborated for a number of compounds resulting in recommendations for
a time-specified drug dosing. These findings have greatly contributed to the fact that now time of day
plays an increasing role in drug treatment (see Lemmer 1989, 2006; Redfern and Lemmer 1997; Reinberg
and Smolensky 1983). Unfortunately, psychotropic drugs were only scarcely studied in this respect (see
Tables 2 and 3).

Table 2

Chronopharmacokinetic studies in man

Cardiovascular active drugs Antiasthmatic drugs

Beta-blockers Aminophylline, theophylline

Propranolol Terbutaline

Atenolol Prednisolone

Arotinolol (α-,β-blocker) Pranlukast

Calcium channel blockers NSAIDs, local anesthetics

Diltiazem Acetylsalicylic acid

Nifedipine Indomethacin

Verapamil Ketoprofen, diclofenac

Nitrendipine Pranoprofen, naproxen

Organic nitrates Phenacetin, paracetamol

Isosorbide dinitrate Lidocaine, bupivacaine

Isosorbide-5-mononitrate Sulindac, ibuprofen

ACE inhibitors Opioids

Enalapril Dihydrocodeine

Others Tramadol

Digoxin, methyldigoxin Anticancer drugs

Potassium chloride Cisplatin

Dipyridamole, tiracizine Doxorubicin, 5-fluorouracil

Psychotropic drugs Cyclosporine

Benzodiazepines Vindesine

Diazepam, lorazepam Methotrexate

Midazolam, temazepam Busulfan, mercaptopurine

Melatonin Antibacterial agents

Hexobarbitone Amikacin

Amitriptyline, nortriptyline Cefprozil

Lithium Ampicillin

Haloperidol Gentamicin

Carbamazepine Griseofulvin

Diphenylhydantoin Sulfamethazine

Valproic acid Sulfisomidine

Levodopa Vancomycin

Miscellaneous Gastroenterology

Ethanol, caffeine Cimetidine

Mequitazine Omeprazole

Dexamethasone Pravastatin

5-Methoxysporalene

Table 3

Chronopharmacodynamic studies in man

Cardiovascular active drugs Antiasthmatic drugs

Beta-blockers Theophylline, aminophylline

Acebutolol, metoprolol Orciprenaline

Atenolol, nadolol Terbutaline, bambuterol

Bevantolol, oxprenolol Methacholine

Bopindolol, pindolol Methylprednisolone

Labetalol, propranolol Dexamethasone, fluticasone

Mepindolol, sotalol Budesonide, ciclesonide

Bisoprolol, carvedilol Adrenaline, isoprenaline

Nebivolol, timolol (IOP) Terbutaline + budesonide

Beta-agonists Psychotropic drugs

Xamoterol, midodrine Diazepam

Terbutaline (IOP), adrenaline (IOP) Clomipramine

Calcium channel blockers Haloperidol

Amlodipine, nitrendipine Phenylpropanolamine

Nifedipine, verapamil Caffeine

Nisoldipine, lacidipine Desipramine

Diltiazem, isradipine H1-antihistamines

Nicardipine Clemastine, terfenadine

ACE inhibitors Cyproheptadine

Captopril, enalapril Mequitazine

Quinapril, lisinopril Ophthalmology

Perindopril, spirapril Terbutaline, timolol

Benazepril, delapril Adrenaline

Trandolapril Isoprenaline

AT 1 -receptor antagonists NSAIDs, general and local anesthetics, and opioids

Irbesartan, losartan Acetylsalicylic acid

Diuretics Flurbiprofen, ibuprofen

Hydrochlorothiazide Ketoprofen, indomethacin

Indapamide Metamizole, pranoprofen

Xipamide Paracetamol

Piretanide, torasemide Tenoxicam, piroxicam

Furosemide Mepivacaine

Organic nitrates Carticaine, lidocaine

Glyceryl trinitrate Halothane

Isosorbide dinitrate Morphine, fentanyl

Isosorbide-5-mononitrate Narcotic analgesics

Others Endocrinology/gastroenterology

Clonidine Prednisone ACTH

Prazosin Methylprednisolone

Phentolamine Insulin, tolbutamide

Indoramin Glucose

Potassium chloride Bezafibrate, clofibrate

Sodium nitroprusside Simvastatin

Anticancer drugs Proton pump inhibitors

Cisplatin, oxaliplatin Omeprazole, lansoprazole

THP FUDR H 2 -blockers

Folinic acid Cimetidine, famotidine

Doxorubicin, methotrexate Nizatidine, ranitidine

Busulfan combinations Roxatidine

Miscellaneous

Tuberculin, ethanol

Heparin, nadroparin

Placebo bright light

Conclusion
The chronopharmacological studies published in recent years gave evidence that both the
pharmacokinetics and the effects of drugs can be circadian phase dependent. In the light of the circadian
organization of the onset and 24-h pattern of various diseases, the knowledge about possible
chronokinetics and a circadian phase dependency in the dose response relationship are of utmost
importance for increasing drug efficacy and/or reducing side effects.

Cross-References
Analgesics

Anticonvulsants

Antidepressants

Antipsychotic Drugs

Barbiturates

Benzodiazepines

Beta-Adrenoceptor Antagonists
Caffeine

Drug Interactions

Histaminic Agonists and Antagonists

Hypnotics

Lithium

Opioids

Pharmacokinetics

Placebo Effect

References
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Aschoff J (1965) Circadian clocks. North-Holland, Amsterdam

Bjarnason GA, Jordan RC, Wood PA, Li Q, Lincoln DW, Sothern RB, Hrushesky WJ, Ben-David Y
(2001) Circadian expression of clock genes in human oral mucosa and skin: association with
specific cell cycle phases. Am J Pathol 158:1793-1801

Floyer J (1698) A treatise of the Asthma (eds: Wilkins R, Innis W). London

Halberg F (1959) Physiologic 24-hour periodicity: general and procedural considerations with
reference to the adrenal cycle. Z Vitam-Horm-Fermentforsch 10:225-296

Konopka RJ, Benzer S (1971) Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S
A 68:2112-2116

Lemmer B (1989) Chronopharmacology: cellular and biochemical interactions (cellular clocks).

Marcel Dekker, New York/Basel

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Lemmer B (2006) The importance of circadian rhythms on drug response in hypertension and
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