Journal of Internal Medicine Society
The article is part of the journal :
Nr.2 din luna 2011
Author Bălan Horia
Article titleCHRONOPHARMACOLOGY, A GOLDEN STANDARD FOR GOOD PRACTICE:
Keywordschronopharmacology, chronotherapy, chronobiology, circadian rhythm.
Article
Bălan Horia, Gabriela Angelescu, Elena Popescu
University of Medicine and Pharmacy „Carol Davila”, Bucharest
Medical Clinic, Clinical Emergency Hospital Ilfov County
Bucharest, Basarabia Bul. 49-51,
e-mail: balanhoria@yahoo.com
The first step in the existence of our Universe is considered to be the appearance of the planets, those in our system turning around the Sun. The second step can be considered the appearance of living creatures. As they appeared, the terrestrial forms of life adapted to the environmental rhythmicity. The temporal variations of the cardiovascular functions have been remarked since the II-nd century after Christ by Galen (quoted by 1), and the first remarks regarding the periodical changes of circadian kind appeared in the medical literature of the XIX-th century. In 1881 Zadek (quoted by 2) and after him Brush, Fayerweather and Janeway (quoted by 1) have confirmed by their studies, the existence of these ones.
The definition of the time formulated by NEWTON was: The knowledge of the order of the events.
The existence of a temporal structure of the organism, mainly the circadian rhythmicity, makes possible the prediction of the effects of the periodical environmental modifications, allowing a better adaptation, fundamentally different to the one due to the control by feed-back loops, in which the answers to the modifications produced at the environmental levels appears at different intervals after the event production. Such modifications, generated by the body “clock“, are independent of the external environment; on the other side, this signal of the “clock” of the body can modify the sensibility and the threshold of the different elements that compose a feed-back loop. Such an interconnexion allows to the organism to be prepared in face of the predictable environmental modifications (a very useful example is represented by the increases of the plasmatic concentrations of the epinephrine and respectively of the body temperature, which precede awakening, preparing thus the organism for the strains of the day - in diurnal species -, and in the evening they decrease before the beginning of the sleep, as preparation for relaxation), but to answer also to other strains, unexpected, unpredictable of this one.
The system that is generating the circadian rhythms is better known as the „internal clock”, a neuronal network that has in his center the suprachiamatic nucleus (SCN) composed by neurones with an electrical activity, secretory activity, gene expression activity with a reactivity of about 24 hours. Because of this „multilayered” structure, the external „zeitgebbers” have only a modulating influence on the „intenal clock”. The main environmental synchronizer is the photoperiod ( the night/day alternance), sustained by melatonine, neurohormone produced by the pineal gland, influenced by the retinohypothalamic tract of the photic system. The photic perception is also present in blind people, and animal models demonstrated that this system is functionally independent from the perceptive visual system(2).
Melatonin has also a central action: by an incompletely understood mechanism, on the „internal clock”
Pacemakers are primary oscillators, which show a genetically determined self-sustained oscillation, without external time cues, which provide timing signals to the organism that synchronize a multitude of rhythms in the same frequency range.
The first scientific approach of the importance of synchronization of the therapy with the “biological clocks” took place in 1814 and Julien – Joseph Virey (quoted by 3) was his author; he concluded that any drug (or food) is not equally indicated at any hour of the 24: “hypnotics, narcotics, opium, except some extreme conditions shouldn’t be administered in the morning, when all the faculties tend to awakening; but these remedies have a more intense action and having a more good action in the evening, because the forces of the organism incline to sleep and rest”, a fact that makes that also the desires effects as the undesired ones of the drugs are variable, function of the moment of the administration(4).
A first mention concerning a treatment administered on the basis of a temporal prospection is due to BALFOUR (1815 – quoted by 1), and SMITH, (1861 – quoted by 1) that have reported the greatest ethanol toxicity when this one is administered in the morning, underlining that his effects are dependent of the moment of administration, during all 24 hours. Real precursor of contemporary chronopharmacology, BALFOUR concluded: “the efficacy of the remedia will depend as much to the proper period of administration, as to his qualities”.
A large number of researches realized in animals and in humans have demonstrated that also the sensibility, as their resistance to the different substances tested – including drugs – are significantly influenced by the moment (the circadian cycle phase) of their administration (Bruguerole, 1994, quoted by 2)(5, 6).
The human body is not only organized in space, anatomically, but it is also organized in time, in terms of biological rhythms. Circadian rhythms, and their alteration could be important determinants of morbidity and mortality. They may also be very important in influencing the responses to various medications. The human circadian time structure can be represented as a clock-like diagram making reference to the sleep/activity cycle
Clearly, these data are compelling that human biochemistry and physiology are not constant; rather, they vary in a predictable manner during the 24-hour time period. It seems plausible that timing of certain medical conditions and life-threatening emergencies may parallel these physiochemical circadian variations (Figure 1).
There is an „evil crossing” of many unfavorable events early in the morning:
Hemodynamic factors: the following are increased: BP and heart rate, stroke volume and cardiac output, total peripheral resistance, vascular tone, plasma volume, pulmonary arterial pressure, platelet agregability, blood coagulability, blood viscosity, serum cholesterol; the following are decresed: coronary blood flow, forearm blood flow, renal flow, glomerular filtration rate, urinary flow, fibrinolysis.
Neuro-hormonal factors: the following are increased: autonomous tone, plasmatic concentrations of: norepinephrine, epinephrine, tyrosine, dopamine, prorenine, renine, angiotensin I, aldosterone, ACTH, cortisol, endogenous opioids; the following are decreased: serotonine, natriuretic peptid system, Na excretion, K excretion.
In the first morning hours the physical and mental activity are increased, so that the “shear stress” of vascular atheroma is also increased, of sufficient magnitude to cause initial disruption of a stable atherosclerotic plaque. The exposure of naked intimal collagen and tissue factors in turn serve as foci for platelet aggregation, inflammatory mediators accumulation, and resultant thrombus formation around the disrupted plaque. The mutual interaction of these unfavorable factors is creating what the actual president of the International Society of Chronobiology, prof. Portaluppi was calling: a cardio-vascular “Twin Peaks”.The temporal distribution of different diseases/disfunctions can be presented by the following figure imagined by Smolensky(12)(Figure 1).
Figure 1. Worst of Times
The term Chronopharmacology has been introduced by HALBERG(7) in the 60’s. The rhythmical functionality of the organism being evident is perfectly logical and demonstrated by the existence of a rhythmicity of his functions, as an exemple: parameters, that means of the normal values of the biological test, a fact that makes perfectly justified the desire that the administration of a drug to be as possible adequate to the evolution of the circadian rhythm determinants of the pathological processes(4, 8, 9).
The modern Chronopharmacology consists not only in the study of the temporal variations of the kinetics, of the activity, of the efficacy and the toxicity function of the moment of the administration of the medication, as in the study of the possible modifications in the temporal structure of the organism in which the drug is administered(8-22). We live, although, in an era where the conservatorism of teaching and of the classical medical practice determine the attitude to overlook the temporal structure of the organism, trying to answer to questions of this kind: “why”, “how”, “with what” and “in what dose”, neglecting the question: “when?”.
That’s why, not rarely, absolutely automatically, one consider that the effect of the medication is optimal if the level of the drug is maintained constant during the 24 hours, because, absolutely wrong, one consider that a constant concentration of a drug determines a constancy of the effect of the drug. This fact explains why the great majority of the therapeutical schemes, of drugs administration, as of technologies of drug production have the homeostatic aim of their blood and tisular constancy.
But, knowing the temporal variability (ultradian, circadian, infradian, circaseptan, circatrigintan, circannual etc.) of the manifestations (for example, the intensity of the symptoms), the security of drug utilization constitutes the reason of a new approach of the therapy – chronotherapy.
Chronotherapy can be defined as a modality of optimization of the efficiency and security of the medications by temporal distribution of the drug administration on the 24 hours, so that to achieve an action of them synchron with the determinants – the biological rhythms of the pathologic processes and/or with the tolerance of the patient to the adverse effects associated with them. Such a chronotherapeutic approach has been imposed in the case of the predictable risk of some medical severe events or of the predictable variation of the intensity of the symptoms of some diseases.
Conventional medications can have a significant increase of the efficacy and security by concordant administration with the temporal structure.
The first mention to such an optimization of the therapeutic effect was made in the ‘60’s: the single morning administration of metilprednisolone reduces the risk of suppression of hypotalamo-hypophyseal-adrenal axis and, on the other hand, ameliorates the efficacy of his anti-inflammatory action.
Later, many clinical studies, on large groups, have proved similar effects, the largest and the most quickly recognized example being the vesperal administration (in single dose) of the H2-receptor blockers having an superior efficacy and necessitating smaller doses for counteracting the nocturnal increase of the acid gastric secretion.
Drug prescription must be realized with the aim of obtaining an optimal benefit/risk ratio (in principal), and secondary trying to realize the best cost/efficiency ratio, because it is now considered that in the third row, in the decreasing order of frequency, after the cardio-vascular diseases and the oncological ones are situated those secondary to medications, which affect almost 10% of the population.
Chronopharmacology is ment also to restaure the perturbated temporal structure of an organism – to resynchronize the biorhythms of this one by adequate therapeutical schedules. One can affirm that without an application of the chronotherapy principles one couldn’t obtain the practical realization of the definition (created by a group of WHO experts) of the drug: “any substance or product utilized or destinated to be utilized for modifying or the study of a physiological system or of a pathologic condition, in the interest of the subject to whom it is administered”.
Pharmacology includes pharmacodynamics (the study of the way by which a drug is working) and pharmacokinetics (the study of the evolution of the drugs is the organism). It’s obvious that the two domains overlap, the response of the receptor situs being dependent on one side of the drug concentration at this level, and on the other side of the drug fate (that includes the absorbtion, the distribution, the metabolization and the elimination of this one). As an example, the rate of the dissolution of pH-dependent formula can differ substantially in the case that the medication is administered in the morning, when the acid secretion is reduced, and the local environment is basic, in comparison to the vesperal administration, when the basal acid secretion is increased, and the local environment is acid.
Because at all these levels one can see the existence of a temporal variation, Reinberg(4), proposed 3 terms which implies their interdependence in chronopharmacology: chronoestesy, chronopharmacokinetics, chronoergy.
Chronoestesy represent the sum of the temporal modifications in the absorbtion, the metabolisation and elimination of a drug. She describes the influence of the moment of the administration of a drug on the parameters that describe these processes in the terms of the absorbtion rate, the peak concentration of the drug (C max), of the time passed till obtaining the maximal concentration of the drug (E max), of the surface under the curve concentration – time (AUC), of the half-time (T ½) etc(8-22).
Chronoergy – represent the rhythmical modification of the organism response to a drug (his total effect), according to his chronokinetics and chronoestesy. The final aim of chronopharmacology is to study the calitative and/or cantitative termporal modifications of the drugs efficacy, for the optimization of their utilizations. One has demonstrated that all the steps of pharmacokinetics: absorbtion, transport, tissular diffusion, metabolisation, drug elimination have all rhythmical variations, with the above-mentioned periodicities.
The rhythms associated to the free proportion of the drug, as the cellular functions from the sites of the drug action can have as result significant differences in the dependent of time efficacy of the therapy. It is also possible that the same active substance, contained in products of the different societies, can have different effects, in function of the moment of their administration, due to the their differences in the eliberation systems of this active substance, a fact that determine that the influences of the circadian rhythm on the kinetics and the effects of the individual forms of dosage and presentation are important to know(4, 6, 9, 10, 12-14, 17-20).
So, factors that influence the action of the drugs are:
a.) The drug and his characteristics: the chemical structure, dosage, the ratio between the distribution speed and the elimination and biotransformation speed, the distribution in the body and the fastening to tissues, the association with other drugs.
b.) The organism and his characteristics: species, kind of nervous system and metabolism, age, sex, the way to administer, weight physiological or pathological condition all realize interconditionnings/interconnexions that have the shape of sinusoidal curves with different periodicities.
For the therapeutic optimization it is mandatory to:
to clear up the mechanisms of action and to prove scientifically some therapeutical indications;
to indicate the optimal ways or respectively the optimal alternance of the ways of drug administration for obtaining the optimization of the therapeutic effect, concomitantly with:
- maximal reduction of the side and toxic effects
- the optimization of the rhythm of administration
- the choose the most appropriate drug associations
- to restore, by medication, the affected temporal structure of the organism.
Such a chronotherapeutic approach is especially necessary:
when the risk of disease or when the risk of apparition of some symptoms is known
when the “therapeutic window” for a given medication is very narrow, close to toxicity
when the toxicity of the drug is a factor of dose – limitation
when the kinetics or/and the effects are dependent of the moment of the administration
when the aim of the hormonal treatment administration is to simulate the temporal schemes observed in healthy subjects
when the effect of the drug can be obtained only by a time-modulated therapeutical modality.
Nearly all functions of living creatures including man exibit significant daily variations. There are also temporal changes in receptors drug binding or transductional effects, as well as pharmacokinetic variations in absobtion, distribution, metabolism and elimination according to the moment of administration. So, it isn’t surprising that the pharmacokinetics as well the effects and side-effects of drugs can vary significantly with the time of day as has been documented in many clinical studies. Thus „time-or-day” as to be regarded as an important factor to evaluate drug efficacy and the terapeutic window.
Nearly all functions of the body, including those influencing pharmacokinetic parameters such as drug absorbtion and distribution, drug metabolism and renal elimination, show significant daily variations: these include liver metabolism, hepatic blood flow and the first-pass effect; glomerular filtration, renal plasma flow and urine volume and pH, blood pressure, heart rate and organ perfusion rates, acid secretion in the gastro-intestinal tract gastric emptying time.
There is clear evidence that even dose/concentration-response relationships can be significantly modified by the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug’s pharmacokinetics and its effects or side-effects.
Circadian rhythms are now clearly demonstrated for the function of physiology and the pathophysiology of diseases. The efectivenesss and toxicity of many drugs vary depending on dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also by the pharmacokinetics of medications. The underlying mechanisms are associated with 24 h rhythms of biochemical physiological and behavioral processes under the control of circadian clock. Thus, the knowledge of 24 rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and sefety constitutes the rationale for pharmacotherapy.
Chronotherapy is especially relevant, when the risk and/or the intensity of the symptoms of disease vary predictably over time as exemplified by alergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke and ulcer disease. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. To monitor the rhythmic marker such as clock genes it may be useful to choose the most appropriate time of day for administration of drugs that may increase their therapeutic effects and/or reduce their side effects. Furthermore, to produce new rhythmicity by monitoring the conditions of living organs by using rhythmic administration of altered feeding schedules of several drugs appears to lead to the new concept of chronopharmacotherapy.
Attention should be paid to the alteration of biological clock and consider it an adverse effect, when it leads to altered regulation of the circadian system whichis a serious problem affceting basic functioning of living organisms.
One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best tolerated. From a pharmaceutical point of views, the appplication of biological rhythm to pharmacotherapy may be accomplished by the appropriate timing of conventionally formulated tablets or capsules, or by using special drug delivery systems to synchronize drug concentrations to rhythms in disease activity.
New technologies for delivery medications precisely in a time-modulated fashion by bedside or ambulatory pumps is developing to manage human disease(23,24).
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 corner stone in the development or drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: Chr DDS) may be the availability to appropriate technology(6).
It worth underline the fact that the realization, in the last decade, of different forms of presentation for the same drug, made possible his administration orally, cutaneous, nasal, parenterally, etc., the permanently growing possibility to utilize scheduled, extracorporeal and implantable pumps constitute elements of great utility in the future, being essential elements, of material support in realizing these principles of chronotherapy.
It results, so, that the application of the therapeutical measures must have in mind on one part the temporal structure of the organism, the temporal susceptibility of this one to the drug, and on the other side to choose the optimal moment for the drug administration and his biodisponibility in conjunction to the one of the organism(25-33).
The following data represent a summary of the actual proven data regarding the results of chronotherapeutic studies, as presented in „Chronobiologie medicale, Chronotherapeutique” – Reinberg(4), but also with other data(2, 5-13, 17-20, 23, 24, 26-44).
Alergology
H1 receptor blockers (Mequitazine, Rimalan) – maximal efficacy for the whole daily dose in the evening (even in those suffering from allergic rhinitis, symptomatic in the morning.
Anesthesics
Bupivacaine, Lidocaine, Mepivacaine – administred at 15.00 have a 2-4 times longer duration of action as compared with the administration at 7.00 or 19.00
Oncology
Adriamicine (doxorubicine) and Cisplatin (Cis-DDP)
The best clinical and biological tolerance:
adriamicine – i.v. administred at 06.00;
cis-DDP – i.v. administred at 18.00
without significant benefits regarding the efficacy by chronotherapy.
5-Fluoro-uracile (5-FU)
In metastatic colo-recal cancer in perfusion by programmed pumps: the morning dose administred at 04.00 had an excellent tolerance for doses ranging from 5 to 8 g/m2/cycle; unchanged efficacy by chronotherapy
5-FU + Oxaliplatine (I-OHP) + folinic acid
In metastatic colo-rectal cancer, in perfusion by programmed pumps: the maximal dose of 5-FU and folinic acid being programmed at 04.00 and the maximal dose of I-OHP being programmed at 16.00 were follwed by:
excellent tolerability;
no need for hospital management;
significant amelioration of QOL ;
18% lesser financial value of the chronomodulated treatment.
6-Mercaptopurine – in acute lymphoid leukemia in children:
2 times increase of the number of survivals by evening administration, compared to morning treatment with the same product, in the same dosage ș a model of oncological chronotherapy optimisatin.
Cardiology
It’ mandatory that we don’t forget the morning „fatal crossing”
Beta-blockers:
Atenolol, Sotalol
with reduced lipophylicity
non-dependent effects regarding the temporal schedule of their administration
Metoprolol, Propranolol
effects influenced by the temporal schedule of their administration. They are relatively inactive during the night, even when using formulations with extended release.
Diuretics
by administering the thiazidic diuretics in the morning (before 09.00) the risk of hypokaliemia is significantly decreased.
Calcium antagonists: Nicardipine, Nitrendipine, Verapamil, Amlodipine, Diltiazem
must be administred in the evening (they do not excessively decrease BP values during the night).
Specially conceived systems (available in USA and canada: COER, CODAS: Covera-HS, Verelan-PM
Anti-anginal drugs
Diltiazem – greater efficacy by morning administration, compared to the 12.00 a.m. administration in Prinzmetal angina
Anticoagulants
Aspirine – recommended at bedtime (best effects, best tolerance.
We will make a special reference for hypertension.
Table 1. Time-Dependent Differences in the BP-Lowering Effect of Conventional Once-a-Day Drugs(17, 34)
Medication
(Authors)
Dose
(mg) Dosing Times
(Conditions)
Subjects
(No. and Type) Differential Administration
Time Effect on 24 BP Pattern
Benazepril
(Palatini et al., 1993) 10 mg
9 a.m. vs. 9 p.m.
(single dose) 10 EH
9 a.m. dose exerted greater BP-lowering effect. Duration of therapeutic effect shortened by 5h with 9 p.m. dosing.
Ramipril
(Myburgh et al., 1995) 2.5 mg
8 a.m. vs. 8 p.m.
(4 weeks) 33 EH
8 p.m. dosing improved nocturnal BP-lowering effect.
Enalapril
(Witte et al., 1993)
10 mg
7 a.m. vs. 7. p.m.
(single dose) 8 EH
7 a.m. dose significantly reduced daytime but not nighttime BP; 7 p.m. dose: stronger overnight and morning but no afternoon effect on BP.
Quinapril
(Palatini et al., 1992) 20 mg
8 a.m. vs. 10 p.m.
(4 weeks) 18 EH
No dosing-time difference on day-time BP; 10 p.m. dosing reduced nocturnal BP more than 8 a.m. dosing.
Perindopril
(Morgan et al, 1997) 4 mg
9 a.m. vs. 9 p.m.
(4 weeks)
18 EH
9 p.m. dosing markedly lowered BP (particularly SBP) during nocturnal sleep but was associated with ~33% shortening of SBP and
DBP-lowering effect during the 24h dosing interval.
Captopril + HTZ
(Middeke et al., 1991)
25/12.5 mg
7 – 8 a.m. vs. 6-8 p.m.
(3 weeks)
13 EH
Evening dosing resulted in attenuation of daytime BP-lowering. Evening dose reduced BP during daytime (6 a.m.– 6 p.m.) equal to that achieved by a q12h dosing schedule (equal to twice the
dose/24h) of the combination medication.
Diltiazem Retard
(Kohno et al., 1997) 100 – 200 mg 8 a.m. vs. 7 p.m.
(3 weeks )
7 EH
8 a.m. dosing better reduced BP during nighttime sleep; 8 p.m. dosing exerted greater daytime BP-lowering effect and inhibition of morning BP rise.
Isradipine
(Portaluppi et al., 1995) 5 mg
8 a.m. vs. 8 p.m.
(4 weeks) 16 RF
8 p.m. dosing best lowered both day and nighttime BP and normalized the non-dipping circadian BP pattern of renal patients.
Doxazosin
(Hermida, et al., 2004)
4 mg
Morning vs. Bedtime
(3 months)
91 EH
Morning dosing exerted little nocturnal BP- lowering and had only minor effect on 24h mean BP. Bedtime dosing exerted full 24h BP control and, compared to morning dosing, several-fold greater reduction in 24h mean BP.
Normalization of the circadian BP pattern is considered to be an important clinical goal of pharmacotherapy because it may slow the advance of renal injury and avert end-stage renal failure.
To aleviate/to abolish the morning surge is mandatory: there’s a „Twin peaks” period (PORTALUPPI) during the morning hours: silent myocardial ischemia, angina pectoris, unstable pectoris, acute myocardial infarction (AMI), coronary spasm, pulmonary thromboembolism, ectopic beats, ventricular tachycardia, atrial flutter and fibrillation, paroxysmal supraventricular tachycardia, aortic aneurism rupture, spontaneous aortic dissection are all much more frequent in the morning hours (Figure 2).
It’s now possible to use either time-coordinated schedules of conventional antihypertensive drugs administration (see below) or products specially conceived for chrontherapy.
Conventional antihypertensive drugs(35-44)
Any BETA-BLOCKER should be administered in the morning
CALCIUM-CHANNEL BLOCKERS WITH SUSTAINED RELEASE have a significant residual effect even after 24 hours: Amlodipine, Isoptin-RR, CALAN-SR, VERELAN-PM. When you administer them in the morning you can attenuate the morning peak, but, with the vesperal administration it is possible to induce a “dipper” profile: Isradipine, Verapamil-SR.
ACEI: it’s preferable to administer them in the evening:
- Ramipril (HOPE study) (To keep in mind: in the Heart Outcome Prevention Evaluation (HOPE) trial, the ACE inhibitor ramipril, which has an intermediate duration of action, was given at nighttime before sleep, this was found to be significantly associated with decreased cardiovascular morbidity and mortality inpatients at high risk for cardiovascular events). A HOPE substudy of 38 patients demonstrated significantly reduced 24-hr ABPM compared with office BP because of a more pronounced BP-lowering effect during nighttime. In addition, the night/day ratio was significantly reduced, raising the theory that some of cardiovascular benefits could be ascribed to the effects of nighttime and early-morning BP. HOPE study results: combined cardiovascular endpoint (cardiovascular mortality, MI, stroke) – a decrease of 22% (p <0,001); cardiovascular mortality - a decrease of 26% (p < 0,001); stroke – a decrease of 32% (p < 0,001);
- Benazepril
- Enalapril (when we use at least 20 mg).
It’s preferable to use in the morning:
Quinapril (it’s possible to have an excessive effect with a vesperal administration)
Perindopril (for an effect longer than 24 hours)
DIURETICS: Indapamide; Xipamide have both similar BP lowering effects in morning or evening administration
α-BLOCKERS: DOXAZOSIN – determine the higest BP reduction when is administered in the morning.
About ¾ of untreated patients with essential hypertension are “dippers”, about 20% are „non-dippers”. Non-dippers show a higher risk of target organ damage and worse cardiovascular outcomes than normal dippers, which suggests these could be a benefit to bringing down the nighttime blood pressure of non-dippers to a pattern more closely resembling normal dipping“. All three groups: dippers, non-dippers and excessive dippers seem to get some benefit from chronotherapeutic dosing”(45).
Drugs specially conceived for CHRONOTHERAPY (true chronotherapeutic agents impart a dynamic element to drug delivery by providing larger drug concentrations during the critical morning period and smaller amounts during the nighttime, thereby minimizing the risk of excessive nocturnal BP drops):
the vesperal administration offers an efficient 24 hours control, the highest reductions appearing in the critical hours of the morning
their action begins after 4 hours
maximal plasmatic levels around 10.00 a.m.
N.B. These kind of preparations must be swallowed whole and not chewed, crushed, or split, as this may damage the drug delivery system and cause dose dumping.
Chronotherapy of hypertension: special formulations marketed in USA: COVERA-HS; VERELAN-PM; CARDIZEM-LA; INNOPRAN-XL; and conventional medications dosed at bedtime versus upon awakening (FDA)(45).
Endocrinology
ACTH
indicated: morning administration, in phase with the morning peak of the ACTH secretion of the body: maximal stimulating effect in comparison with afternoon or evening administration.
Corticosteroids
Recommended: 2/3 of the dose in the morning, at awakening 07.00; 1/3 at 12.00 or 15.00 with the aim to restore the natural circadian rhythm of the corticosteroids.
hCG (human chorionic gonadotropine)
indicated in gonadal failure: the morning administration has the most powerful testicular answer, in comparison to afternoon or evening administration (the evening administration has no effects)
Gn-RH
in sterility due to hypothalamic failure a pulsatile administration, every 90 minutes, with programmed pumps is indicated;
in hormono-dependent cancers of the breast and of the prostate is recommended an administration with a constant rate.
Levo-thyroxine
the peak of the physiologic secreton is around 08.00 so it is recommended to be administered at this hour.
Testosterone
the peak of the physiologic secreton is around 08.00 so it is recommended to be administered at this hour, as a patch.
Gastro-Enterology
H2-receptro blockers: Cimetidine, Famotidine, Nizatidine, Ranitidine
a single bedtime administration is efficient in more than 80% of cases on 24 h.
it is demonstrated that the control of gastric pH by i.v. infucsion make mandatory hourly administration of H2 receptor blockers, with greater doses during the night.
Inhibitors of the proton pump: Lansoprazole, Omeprazole, Pantoprazole
a maximal dose of Omeprazole (40 mg) at awakening, before eating, can 99% inhibit the nocturnal gastric acidity. Other treatment schedules have worse results.
Pneumology
Nocturnal bronchial asthma
The chronotherapy has the following targets:
to increase te desired effects (a better control of te intensity of te frequency of the attacks)
to reduce the adverse effects, especially tose of corticosteroids.
Theophyllines with extended release
It is recommended to deliver in the evening the entire dosage or 2/3 of this, the other 1/3 being administered in the morning. The result is characterized by a better efficacy and tolerance.
Corticosteroids: 15.00 is the moment of administation characterized bya better efficacy and tolerance and the evening administration is poorly tolerated, with a diminished efficacy.
B2Agonists
Orciprenaline: best effcicacy is in the evening, during the night and early in the morning. During the day the efficacy is reduced.
Salbutamol, Terbutaline
Best results by administering 2/3 of the daily dose at 20.00, 1/3 at 08.00.
Rheumatology
„Ancient” AINS
the digestive tolerance is better in the evening
Recommended temporal schedule:
Indometacin – 20.00 h when the pain is worse in the morning;
in the morning or at noon when the pain is worse in the evening.
Ketoprofene
recommended adminstration: 20.00
Tenoxicam
recommended adminstration: in the morning or at noon.
And as final proofs we must remember many won „battles” by chronotherapy (2)
the morning administration of the corticosteroids
the asymmetrical dosage: a.m./p.m. of the corticosteroids in Addison’S disease
the vesperal administration of HMG-CoAs antagonists
the vesperal administration of theophylline with prolonged action and the asymmetric dosage a.m./p.m. of the beta-2-agonists in the treatment of bronchial asthma
utilization of the melatonine and of the exposure to powerful light for the treatment of the symptoms of jet lag and of the perturbations of the sleep rhythm
the vesperal administration of non-steroidal anti-inflamatory drugs in the treatment of rheumatoid poliartritis
the vesperat administration of aspirin in the treatment of pre-eclampsia
the vesperatl administration of ADH analogues for nicturia treatment
the vesperal dosage of the cortico-steroids in Cushing’s disease
the chronotherapy, before-mentioned, of HBP and of the ischemic heart disease.
the oncologic chronotherapy.
„The fields of chronobiology and chronopharmacology are not only a new and modern branch of science, but that it stands on the shoulders of wonderful and insightful observations and explanations made by our scientific forefathers” (29).
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Nr.2 din luna 2011
Bălan Horia, Gabriela Angelescu, Elena Popescu
University of Medicine and Pharmacy „Carol Davila”, Bucharest
Medical Clinic, Clinical Emergency Hospital Ilfov County
Bucharest, Basarabia Bul. 49-51,
e-mail: balanhoria@yahoo.com
The first step in the existence of our Universe is considered to be the appearance of the planets, those in our system turning around the Sun. The second step can be considered the appearance of living creatures. As they appeared, the terrestrial forms of life adapted to the environmental rhythmicity. The temporal variations of the cardiovascular functions have been remarked since the II-nd century after Christ by Galen (quoted by 1), and the first remarks regarding the periodical changes of circadian kind appeared in the medical literature of the XIX-th century. In 1881 Zadek (quoted by 2) and after him Brush, Fayerweather and Janeway (quoted by 1) have confirmed by their studies, the existence of these ones.
The definition of the time formulated by NEWTON was: The knowledge of the order of the events.
The existence of a temporal structure of the organism, mainly the circadian rhythmicity, makes possible the prediction of the effects of the periodical environmental modifications, allowing a better adaptation, fundamentally different to the one due to the control by feed-back loops, in which the answers to the modifications produced at the environmental levels appears at different intervals after the event production. Such modifications, generated by the body “clock“, are independent of the external environment; on the other side, this signal of the “clock” of the body can modify the sensibility and the threshold of the different elements that compose a feed-back loop. Such an interconnexion allows to the organism to be prepared in face of the predictable environmental modifications (a very useful example is represented by the increases of the plasmatic concentrations of the epinephrine and respectively of the body temperature, which precede awakening, preparing thus the organism for the strains of the day - in diurnal species -, and in the evening they decrease before the beginning of the sleep, as preparation for relaxation), but to answer also to other strains, unexpected, unpredictable of this one.
The system that is generating the circadian rhythms is better known as the „internal clock”, a neuronal network that has in his center the suprachiamatic nucleus (SCN) composed by neurones with an electrical activity, secretory activity, gene expression activity with a reactivity of about 24 hours. Because of this „multilayered” structure, the external „zeitgebbers” have only a modulating influence on the „intenal clock”. The main environmental synchronizer is the photoperiod ( the night/day alternance), sustained by melatonine, neurohormone produced by the pineal gland, influenced by the retinohypothalamic tract of the photic system. The photic perception is also present in blind people, and animal models demonstrated that this system is functionally independent from the perceptive visual system(2).
Melatonin has also a central action: by an incompletely understood mechanism, on the „internal clock”
Pacemakers are primary oscillators, which show a genetically determined self-sustained oscillation, without external time cues, which provide timing signals to the organism that synchronize a multitude of rhythms in the same frequency range.
The first scientific approach of the importance of synchronization of the therapy with the “biological clocks” took place in 1814 and Julien – Joseph Virey (quoted by 3) was his author; he concluded that any drug (or food) is not equally indicated at any hour of the 24: “hypnotics, narcotics, opium, except some extreme conditions shouldn’t be administered in the morning, when all the faculties tend to awakening; but these remedies have a more intense action and having a more good action in the evening, because the forces of the organism incline to sleep and rest”, a fact that makes that also the desires effects as the undesired ones of the drugs are variable, function of the moment of the administration(4).
A first mention concerning a treatment administered on the basis of a temporal prospection is due to BALFOUR (1815 – quoted by 1), and SMITH, (1861 – quoted by 1) that have reported the greatest ethanol toxicity when this one is administered in the morning, underlining that his effects are dependent of the moment of administration, during all 24 hours. Real precursor of contemporary chronopharmacology, BALFOUR concluded: “the efficacy of the remedia will depend as much to the proper period of administration, as to his qualities”.
A large number of researches realized in animals and in humans have demonstrated that also the sensibility, as their resistance to the different substances tested – including drugs – are significantly influenced by the moment (the circadian cycle phase) of their administration (Bruguerole, 1994, quoted by 2)(5, 6).
The human body is not only organized in space, anatomically, but it is also organized in time, in terms of biological rhythms. Circadian rhythms, and their alteration could be important determinants of morbidity and mortality. They may also be very important in influencing the responses to various medications. The human circadian time structure can be represented as a clock-like diagram making reference to the sleep/activity cycle
Clearly, these data are compelling that human biochemistry and physiology are not constant; rather, they vary in a predictable manner during the 24-hour time period. It seems plausible that timing of certain medical conditions and life-threatening emergencies may parallel these physiochemical circadian variations (Figure 1).
There is an „evil crossing” of many unfavorable events early in the morning:
Hemodynamic factors: the following are increased: BP and heart rate, stroke volume and cardiac output, total peripheral resistance, vascular tone, plasma volume, pulmonary arterial pressure, platelet agregability, blood coagulability, blood viscosity, serum cholesterol; the following are decresed: coronary blood flow, forearm blood flow, renal flow, glomerular filtration rate, urinary flow, fibrinolysis.
Neuro-hormonal factors: the following are increased: autonomous tone, plasmatic concentrations of: norepinephrine, epinephrine, tyrosine, dopamine, prorenine, renine, angiotensin I, aldosterone, ACTH, cortisol, endogenous opioids; the following are decreased: serotonine, natriuretic peptid system, Na excretion, K excretion.
In the first morning hours the physical and mental activity are increased, so that the “shear stress” of vascular atheroma is also increased, of sufficient magnitude to cause initial disruption of a stable atherosclerotic plaque. The exposure of naked intimal collagen and tissue factors in turn serve as foci for platelet aggregation, inflammatory mediators accumulation, and resultant thrombus formation around the disrupted plaque. The mutual interaction of these unfavorable factors is creating what the actual president of the International Society of Chronobiology, prof. Portaluppi was calling: a cardio-vascular “Twin Peaks”.The temporal distribution of different diseases/disfunctions can be presented by the following figure imagined by Smolensky(12)(Figure 1).
Figure 1. Worst of Times
The term Chronopharmacology has been introduced by HALBERG(7) in the 60’s. The rhythmical functionality of the organism being evident is perfectly logical and demonstrated by the existence of a rhythmicity of his functions, as an exemple: parameters, that means of the normal values of the biological test, a fact that makes perfectly justified the desire that the administration of a drug to be as possible adequate to the evolution of the circadian rhythm determinants of the pathological processes(4, 8, 9).
The modern Chronopharmacology consists not only in the study of the temporal variations of the kinetics, of the activity, of the efficacy and the toxicity function of the moment of the administration of the medication, as in the study of the possible modifications in the temporal structure of the organism in which the drug is administered(8-22). We live, although, in an era where the conservatorism of teaching and of the classical medical practice determine the attitude to overlook the temporal structure of the organism, trying to answer to questions of this kind: “why”, “how”, “with what” and “in what dose”, neglecting the question: “when?”.
That’s why, not rarely, absolutely automatically, one consider that the effect of the medication is optimal if the level of the drug is maintained constant during the 24 hours, because, absolutely wrong, one consider that a constant concentration of a drug determines a constancy of the effect of the drug. This fact explains why the great majority of the therapeutical schemes, of drugs administration, as of technologies of drug production have the homeostatic aim of their blood and tisular constancy.
But, knowing the temporal variability (ultradian, circadian, infradian, circaseptan, circatrigintan, circannual etc.) of the manifestations (for example, the intensity of the symptoms), the security of drug utilization constitutes the reason of a new approach of the therapy – chronotherapy.
Chronotherapy can be defined as a modality of optimization of the efficiency and security of the medications by temporal distribution of the drug administration on the 24 hours, so that to achieve an action of them synchron with the determinants – the biological rhythms of the pathologic processes and/or with the tolerance of the patient to the adverse effects associated with them. Such a chronotherapeutic approach has been imposed in the case of the predictable risk of some medical severe events or of the predictable variation of the intensity of the symptoms of some diseases.
Conventional medications can have a significant increase of the efficacy and security by concordant administration with the temporal structure.
The first mention to such an optimization of the therapeutic effect was made in the ‘60’s: the single morning administration of metilprednisolone reduces the risk of suppression of hypotalamo-hypophyseal-adrenal axis and, on the other hand, ameliorates the efficacy of his anti-inflammatory action.
Later, many clinical studies, on large groups, have proved similar effects, the largest and the most quickly recognized example being the vesperal administration (in single dose) of the H2-receptor blockers having an superior efficacy and necessitating smaller doses for counteracting the nocturnal increase of the acid gastric secretion.
Drug prescription must be realized with the aim of obtaining an optimal benefit/risk ratio (in principal), and secondary trying to realize the best cost/efficiency ratio, because it is now considered that in the third row, in the decreasing order of frequency, after the cardio-vascular diseases and the oncological ones are situated those secondary to medications, which affect almost 10% of the population.
Chronopharmacology is ment also to restaure the perturbated temporal structure of an organism – to resynchronize the biorhythms of this one by adequate therapeutical schedules. One can affirm that without an application of the chronotherapy principles one couldn’t obtain the practical realization of the definition (created by a group of WHO experts) of the drug: “any substance or product utilized or destinated to be utilized for modifying or the study of a physiological system or of a pathologic condition, in the interest of the subject to whom it is administered”.
Pharmacology includes pharmacodynamics (the study of the way by which a drug is working) and pharmacokinetics (the study of the evolution of the drugs is the organism). It’s obvious that the two domains overlap, the response of the receptor situs being dependent on one side of the drug concentration at this level, and on the other side of the drug fate (that includes the absorbtion, the distribution, the metabolization and the elimination of this one). As an example, the rate of the dissolution of pH-dependent formula can differ substantially in the case that the medication is administered in the morning, when the acid secretion is reduced, and the local environment is basic, in comparison to the vesperal administration, when the basal acid secretion is increased, and the local environment is acid.
Because at all these levels one can see the existence of a temporal variation, Reinberg(4), proposed 3 terms which implies their interdependence in chronopharmacology: chronoestesy, chronopharmacokinetics, chronoergy.
Chronoestesy represent the sum of the temporal modifications in the absorbtion, the metabolisation and elimination of a drug. She describes the influence of the moment of the administration of a drug on the parameters that describe these processes in the terms of the absorbtion rate, the peak concentration of the drug (C max), of the time passed till obtaining the maximal concentration of the drug (E max), of the surface under the curve concentration – time (AUC), of the half-time (T ½) etc(8-22).
Chronoergy – represent the rhythmical modification of the organism response to a drug (his total effect), according to his chronokinetics and chronoestesy. The final aim of chronopharmacology is to study the calitative and/or cantitative termporal modifications of the drugs efficacy, for the optimization of their utilizations. One has demonstrated that all the steps of pharmacokinetics: absorbtion, transport, tissular diffusion, metabolisation, drug elimination have all rhythmical variations, with the above-mentioned periodicities.
The rhythms associated to the free proportion of the drug, as the cellular functions from the sites of the drug action can have as result significant differences in the dependent of time efficacy of the therapy. It is also possible that the same active substance, contained in products of the different societies, can have different effects, in function of the moment of their administration, due to the their differences in the eliberation systems of this active substance, a fact that determine that the influences of the circadian rhythm on the kinetics and the effects of the individual forms of dosage and presentation are important to know(4, 6, 9, 10, 12-14, 17-20).
So, factors that influence the action of the drugs are:
a.) The drug and his characteristics: the chemical structure, dosage, the ratio between the distribution speed and the elimination and biotransformation speed, the distribution in the body and the fastening to tissues, the association with other drugs.
b.) The organism and his characteristics: species, kind of nervous system and metabolism, age, sex, the way to administer, weight physiological or pathological condition all realize interconditionnings/interconnexions that have the shape of sinusoidal curves with different periodicities.
For the therapeutic optimization it is mandatory to:
to clear up the mechanisms of action and to prove scientifically some therapeutical indications;
to indicate the optimal ways or respectively the optimal alternance of the ways of drug administration for obtaining the optimization of the therapeutic effect, concomitantly with:
- maximal reduction of the side and toxic effects
- the optimization of the rhythm of administration
- the choose the most appropriate drug associations
- to restore, by medication, the affected temporal structure of the organism.
Such a chronotherapeutic approach is especially necessary:
when the risk of disease or when the risk of apparition of some symptoms is known
when the “therapeutic window” for a given medication is very narrow, close to toxicity
when the toxicity of the drug is a factor of dose – limitation
when the kinetics or/and the effects are dependent of the moment of the administration
when the aim of the hormonal treatment administration is to simulate the temporal schemes observed in healthy subjects
when the effect of the drug can be obtained only by a time-modulated therapeutical modality.
Nearly all functions of living creatures including man exibit significant daily variations. There are also temporal changes in receptors drug binding or transductional effects, as well as pharmacokinetic variations in absobtion, distribution, metabolism and elimination according to the moment of administration. So, it isn’t surprising that the pharmacokinetics as well the effects and side-effects of drugs can vary significantly with the time of day as has been documented in many clinical studies. Thus „time-or-day” as to be regarded as an important factor to evaluate drug efficacy and the terapeutic window.
Nearly all functions of the body, including those influencing pharmacokinetic parameters such as drug absorbtion and distribution, drug metabolism and renal elimination, show significant daily variations: these include liver metabolism, hepatic blood flow and the first-pass effect; glomerular filtration, renal plasma flow and urine volume and pH, blood pressure, heart rate and organ perfusion rates, acid secretion in the gastro-intestinal tract gastric emptying time.
There is clear evidence that even dose/concentration-response relationships can be significantly modified by the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug’s pharmacokinetics and its effects or side-effects.
Circadian rhythms are now clearly demonstrated for the function of physiology and the pathophysiology of diseases. The efectivenesss and toxicity of many drugs vary depending on dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also by the pharmacokinetics of medications. The underlying mechanisms are associated with 24 h rhythms of biochemical physiological and behavioral processes under the control of circadian clock. Thus, the knowledge of 24 rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and sefety constitutes the rationale for pharmacotherapy.
Chronotherapy is especially relevant, when the risk and/or the intensity of the symptoms of disease vary predictably over time as exemplified by alergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke and ulcer disease. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. To monitor the rhythmic marker such as clock genes it may be useful to choose the most appropriate time of day for administration of drugs that may increase their therapeutic effects and/or reduce their side effects. Furthermore, to produce new rhythmicity by monitoring the conditions of living organs by using rhythmic administration of altered feeding schedules of several drugs appears to lead to the new concept of chronopharmacotherapy.
Attention should be paid to the alteration of biological clock and consider it an adverse effect, when it leads to altered regulation of the circadian system whichis a serious problem affceting basic functioning of living organisms.
One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best tolerated. From a pharmaceutical point of views, the appplication of biological rhythm to pharmacotherapy may be accomplished by the appropriate timing of conventionally formulated tablets or capsules, or by using special drug delivery systems to synchronize drug concentrations to rhythms in disease activity.
New technologies for delivery medications precisely in a time-modulated fashion by bedside or ambulatory pumps is developing to manage human disease(23,24).
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 corner stone in the development or drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: Chr DDS) may be the availability to appropriate technology(6).
It worth underline the fact that the realization, in the last decade, of different forms of presentation for the same drug, made possible his administration orally, cutaneous, nasal, parenterally, etc., the permanently growing possibility to utilize scheduled, extracorporeal and implantable pumps constitute elements of great utility in the future, being essential elements, of material support in realizing these principles of chronotherapy.
It results, so, that the application of the therapeutical measures must have in mind on one part the temporal structure of the organism, the temporal susceptibility of this one to the drug, and on the other side to choose the optimal moment for the drug administration and his biodisponibility in conjunction to the one of the organism(25-33).
The following data represent a summary of the actual proven data regarding the results of chronotherapeutic studies, as presented in „Chronobiologie medicale, Chronotherapeutique” – Reinberg(4), but also with other data(2, 5-13, 17-20, 23, 24, 26-44).
Alergology
H1 receptor blockers (Mequitazine, Rimalan) – maximal efficacy for the whole daily dose in the evening (even in those suffering from allergic rhinitis, symptomatic in the morning.
Anesthesics
Bupivacaine, Lidocaine, Mepivacaine – administred at 15.00 have a 2-4 times longer duration of action as compared with the administration at 7.00 or 19.00
Oncology
Adriamicine (doxorubicine) and Cisplatin (Cis-DDP)
The best clinical and biological tolerance:
adriamicine – i.v. administred at 06.00;
cis-DDP – i.v. administred at 18.00
without significant benefits regarding the efficacy by chronotherapy.
5-Fluoro-uracile (5-FU)
In metastatic colo-recal cancer in perfusion by programmed pumps: the morning dose administred at 04.00 had an excellent tolerance for doses ranging from 5 to 8 g/m2/cycle; unchanged efficacy by chronotherapy
5-FU + Oxaliplatine (I-OHP) + folinic acid
In metastatic colo-rectal cancer, in perfusion by programmed pumps: the maximal dose of 5-FU and folinic acid being programmed at 04.00 and the maximal dose of I-OHP being programmed at 16.00 were follwed by:
excellent tolerability;
no need for hospital management;
significant amelioration of QOL ;
18% lesser financial value of the chronomodulated treatment.
6-Mercaptopurine – in acute lymphoid leukemia in children:
2 times increase of the number of survivals by evening administration, compared to morning treatment with the same product, in the same dosage ș a model of oncological chronotherapy optimisatin.
Cardiology
It’ mandatory that we don’t forget the morning „fatal crossing”
Beta-blockers:
Atenolol, Sotalol
with reduced lipophylicity
non-dependent effects regarding the temporal schedule of their administration
Metoprolol, Propranolol
effects influenced by the temporal schedule of their administration. They are relatively inactive during the night, even when using formulations with extended release.
Diuretics
by administering the thiazidic diuretics in the morning (before 09.00) the risk of hypokaliemia is significantly decreased.
Calcium antagonists: Nicardipine, Nitrendipine, Verapamil, Amlodipine, Diltiazem
must be administred in the evening (they do not excessively decrease BP values during the night).
Specially conceived systems (available in USA and canada: COER, CODAS: Covera-HS, Verelan-PM
Anti-anginal drugs
Diltiazem – greater efficacy by morning administration, compared to the 12.00 a.m. administration in Prinzmetal angina
Anticoagulants
Aspirine – recommended at bedtime (best effects, best tolerance.
We will make a special reference for hypertension.
Table 1. Time-Dependent Differences in the BP-Lowering Effect of Conventional Once-a-Day Drugs(17, 34)
Medication
(Authors)
Dose
(mg) Dosing Times
(Conditions)
Subjects
(No. and Type) Differential Administration
Time Effect on 24 BP Pattern
Benazepril
(Palatini et al., 1993) 10 mg
9 a.m. vs. 9 p.m.
(single dose) 10 EH
9 a.m. dose exerted greater BP-lowering effect. Duration of therapeutic effect shortened by 5h with 9 p.m. dosing.
Ramipril
(Myburgh et al., 1995) 2.5 mg
8 a.m. vs. 8 p.m.
(4 weeks) 33 EH
8 p.m. dosing improved nocturnal BP-lowering effect.
Enalapril
(Witte et al., 1993)
10 mg
7 a.m. vs. 7. p.m.
(single dose) 8 EH
7 a.m. dose significantly reduced daytime but not nighttime BP; 7 p.m. dose: stronger overnight and morning but no afternoon effect on BP.
Quinapril
(Palatini et al., 1992) 20 mg
8 a.m. vs. 10 p.m.
(4 weeks) 18 EH
No dosing-time difference on day-time BP; 10 p.m. dosing reduced nocturnal BP more than 8 a.m. dosing.
Perindopril
(Morgan et al, 1997) 4 mg
9 a.m. vs. 9 p.m.
(4 weeks)
18 EH
9 p.m. dosing markedly lowered BP (particularly SBP) during nocturnal sleep but was associated with ~33% shortening of SBP and
DBP-lowering effect during the 24h dosing interval.
Captopril + HTZ
(Middeke et al., 1991)
25/12.5 mg
7 – 8 a.m. vs. 6-8 p.m.
(3 weeks)
13 EH
Evening dosing resulted in attenuation of daytime BP-lowering. Evening dose reduced BP during daytime (6 a.m.– 6 p.m.) equal to that achieved by a q12h dosing schedule (equal to twice the
dose/24h) of the combination medication.
Diltiazem Retard
(Kohno et al., 1997) 100 – 200 mg 8 a.m. vs. 7 p.m.
(3 weeks )
7 EH
8 a.m. dosing better reduced BP during nighttime sleep; 8 p.m. dosing exerted greater daytime BP-lowering effect and inhibition of morning BP rise.
Isradipine
(Portaluppi et al., 1995) 5 mg
8 a.m. vs. 8 p.m.
(4 weeks) 16 RF
8 p.m. dosing best lowered both day and nighttime BP and normalized the non-dipping circadian BP pattern of renal patients.
Doxazosin
(Hermida, et al., 2004)
4 mg
Morning vs. Bedtime
(3 months)
91 EH
Morning dosing exerted little nocturnal BP- lowering and had only minor effect on 24h mean BP. Bedtime dosing exerted full 24h BP control and, compared to morning dosing, several-fold greater reduction in 24h mean BP.
Normalization of the circadian BP pattern is considered to be an important clinical goal of pharmacotherapy because it may slow the advance of renal injury and avert end-stage renal failure.
To aleviate/to abolish the morning surge is mandatory: there’s a „Twin peaks” period (PORTALUPPI) during the morning hours: silent myocardial ischemia, angina pectoris, unstable pectoris, acute myocardial infarction (AMI), coronary spasm, pulmonary thromboembolism, ectopic beats, ventricular tachycardia, atrial flutter and fibrillation, paroxysmal supraventricular tachycardia, aortic aneurism rupture, spontaneous aortic dissection are all much more frequent in the morning hours (Figure 2).
It’s now possible to use either time-coordinated schedules of conventional antihypertensive drugs administration (see below) or products specially conceived for chrontherapy.
Conventional antihypertensive drugs(35-44)
Any BETA-BLOCKER should be administered in the morning
CALCIUM-CHANNEL BLOCKERS WITH SUSTAINED RELEASE have a significant residual effect even after 24 hours: Amlodipine, Isoptin-RR, CALAN-SR, VERELAN-PM. When you administer them in the morning you can attenuate the morning peak, but, with the vesperal administration it is possible to induce a “dipper” profile: Isradipine, Verapamil-SR.
ACEI: it’s preferable to administer them in the evening:
- Ramipril (HOPE study) (To keep in mind: in the Heart Outcome Prevention Evaluation (HOPE) trial, the ACE inhibitor ramipril, which has an intermediate duration of action, was given at nighttime before sleep, this was found to be significantly associated with decreased cardiovascular morbidity and mortality inpatients at high risk for cardiovascular events). A HOPE substudy of 38 patients demonstrated significantly reduced 24-hr ABPM compared with office BP because of a more pronounced BP-lowering effect during nighttime. In addition, the night/day ratio was significantly reduced, raising the theory that some of cardiovascular benefits could be ascribed to the effects of nighttime and early-morning BP. HOPE study results: combined cardiovascular endpoint (cardiovascular mortality, MI, stroke) – a decrease of 22% (p <0,001); cardiovascular mortality - a decrease of 26% (p < 0,001); stroke – a decrease of 32% (p < 0,001);
- Benazepril
- Enalapril (when we use at least 20 mg).
It’s preferable to use in the morning:
Quinapril (it’s possible to have an excessive effect with a vesperal administration)
Perindopril (for an effect longer than 24 hours)
DIURETICS: Indapamide; Xipamide have both similar BP lowering effects in morning or evening administration
α-BLOCKERS: DOXAZOSIN – determine the higest BP reduction when is administered in the morning.
About ¾ of untreated patients with essential hypertension are “dippers”, about 20% are „non-dippers”. Non-dippers show a higher risk of target organ damage and worse cardiovascular outcomes than normal dippers, which suggests these could be a benefit to bringing down the nighttime blood pressure of non-dippers to a pattern more closely resembling normal dipping“. All three groups: dippers, non-dippers and excessive dippers seem to get some benefit from chronotherapeutic dosing”(45).
Drugs specially conceived for CHRONOTHERAPY (true chronotherapeutic agents impart a dynamic element to drug delivery by providing larger drug concentrations during the critical morning period and smaller amounts during the nighttime, thereby minimizing the risk of excessive nocturnal BP drops):
the vesperal administration offers an efficient 24 hours control, the highest reductions appearing in the critical hours of the morning
their action begins after 4 hours
maximal plasmatic levels around 10.00 a.m.
N.B. These kind of preparations must be swallowed whole and not chewed, crushed, or split, as this may damage the drug delivery system and cause dose dumping.
Chronotherapy of hypertension: special formulations marketed in USA: COVERA-HS; VERELAN-PM; CARDIZEM-LA; INNOPRAN-XL; and conventional medications dosed at bedtime versus upon awakening (FDA)(45).
Endocrinology
ACTH
indicated: morning administration, in phase with the morning peak of the ACTH secretion of the body: maximal stimulating effect in comparison with afternoon or evening administration.
Corticosteroids
Recommended: 2/3 of the dose in the morning, at awakening 07.00; 1/3 at 12.00 or 15.00 with the aim to restore the natural circadian rhythm of the corticosteroids.
hCG (human chorionic gonadotropine)
indicated in gonadal failure: the morning administration has the most powerful testicular answer, in comparison to afternoon or evening administration (the evening administration has no effects)
Gn-RH
in sterility due to hypothalamic failure a pulsatile administration, every 90 minutes, with programmed pumps is indicated;
in hormono-dependent cancers of the breast and of the prostate is recommended an administration with a constant rate.
Levo-thyroxine
the peak of the physiologic secreton is around 08.00 so it is recommended to be administered at this hour.
Testosterone
the peak of the physiologic secreton is around 08.00 so it is recommended to be administered at this hour, as a patch.
Gastro-Enterology
H2-receptro blockers: Cimetidine, Famotidine, Nizatidine, Ranitidine
a single bedtime administration is efficient in more than 80% of cases on 24 h.
it is demonstrated that the control of gastric pH by i.v. infucsion make mandatory hourly administration of H2 receptor blockers, with greater doses during the night.
Inhibitors of the proton pump: Lansoprazole, Omeprazole, Pantoprazole
a maximal dose of Omeprazole (40 mg) at awakening, before eating, can 99% inhibit the nocturnal gastric acidity. Other treatment schedules have worse results.
Pneumology
Nocturnal bronchial asthma
The chronotherapy has the following targets:
to increase te desired effects (a better control of te intensity of te frequency of the attacks)
to reduce the adverse effects, especially tose of corticosteroids.
Theophyllines with extended release
It is recommended to deliver in the evening the entire dosage or 2/3 of this, the other 1/3 being administered in the morning. The result is characterized by a better efficacy and tolerance.
Corticosteroids: 15.00 is the moment of administation characterized bya better efficacy and tolerance and the evening administration is poorly tolerated, with a diminished efficacy.
B2Agonists
Orciprenaline: best effcicacy is in the evening, during the night and early in the morning. During the day the efficacy is reduced.
Salbutamol, Terbutaline
Best results by administering 2/3 of the daily dose at 20.00, 1/3 at 08.00.
Rheumatology
„Ancient” AINS
the digestive tolerance is better in the evening
Recommended temporal schedule:
Indometacin – 20.00 h when the pain is worse in the morning;
in the morning or at noon when the pain is worse in the evening.
Ketoprofene
recommended adminstration: 20.00
Tenoxicam
recommended adminstration: in the morning or at noon.
And as final proofs we must remember many won „battles” by chronotherapy (2)
the morning administration of the corticosteroids
the asymmetrical dosage: a.m./p.m. of the corticosteroids in Addison’S disease
the vesperal administration of HMG-CoAs antagonists
the vesperal administration of theophylline with prolonged action and the asymmetric dosage a.m./p.m. of the beta-2-agonists in the treatment of bronchial asthma
utilization of the melatonine and of the exposure to powerful light for the treatment of the symptoms of jet lag and of the perturbations of the sleep rhythm
the vesperal administration of non-steroidal anti-inflamatory drugs in the treatment of rheumatoid poliartritis
the vesperat administration of aspirin in the treatment of pre-eclampsia
the vesperatl administration of ADH analogues for nicturia treatment
the vesperal dosage of the cortico-steroids in Cushing’s disease
the chronotherapy, before-mentioned, of HBP and of the ischemic heart disease.
the oncologic chronotherapy.
„The fields of chronobiology and chronopharmacology are not only a new and modern branch of science, but that it stands on the shoulders of wonderful and insightful observations and explanations made by our scientific forefathers” (29).
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