**9. Current understandings and future directions in the chronopharmacology management of cardiovascular chronic diseases**

Circadian rhythms have tremendous importance in cardiovascular system functions in both healthy people and patients, being one of the first scientifically acknowledged physiopathologic areas interlinked by chronomodulatory mechanisms [25]. Heart rate and blood pressure (BP) rhythms are the most studied periodic functions in the circulatory system, but lately, new evidence suggests blood flow, cardiac output, stroke volume, or peripheral resistance can furthermore trigger relevant circadian changes [50, 51].

Hypertension, the high systemic blood pressure, represents the major risk factor for a series of acute or chronic pathologic events, from myocardial infarction and ischemic events to chronic kidney failure and sudden death. Chronic high blood pressure is a silent condition since it progresses primarily asymptomatically, but has a devastating effect, conducting to cardiovascular disruptive events and end-organ damage, which leads to a reduction in the quality of life or events of life expectancy. The simple association between high blood pressure and cardiovascular diseases, which is largely controlled by our social and nutritional behavior, is also influenced by a circadian pattern. As a consequence, circadian rhythm plays an important role in blood pressure management, which is the reason for chronobiological studies to comprise chronopharmacology and chrononutrition aspects in the same research field [24, 52, 53].

Blood pressure registers circadian variations due to internal and external modulatory factors. Endogenous regulatory performers such as hematological and renal inputs, endocrine signals perceived by the circulatory system, and the autonomic nervous system activity, interact with environmental parameters like temperature and humidity, nutrients intake, vasoactive xenobiotics as alcohol and caffeine, and nevertheless with the physical activity, emotional status, and the sleep pattern. Despite the overabundance of parameters that influence it, circadian variations of blood pressure in normotensive patients are characterized by a decrease in both systolic and diastolic blood pressure during the night, on average by 10–20% compared with diurnal values, defining the normal pressure physiological profile [20, 33].

### *Chronotherapy Advances in the Management of Chronic Neurological and Cardiovascular… DOI: http://dx.doi.org/10.5772/intechopen.106950*

The magnitude of the decrease in nocturnal BP values was mainly quantified by calculating the dipping index (relative nocturnal decrease in BP) which is defined as the percentage decrease in the value of the average night BP compared with the mean daily BP. This dipping index allowed the classification of the night profile of TA in dipper profile when the index is between 10 and 20%, non-dipper profile when the night decrease of TA is less than 10%, of extreme-dipper type when the decrease of nocturnal BP is over 20% of daytime values and riser profile when BP increases during sleep. The classification has acquired a great utility, especially from the point of view of the prognosis, especially since there are studies that demonstrate the reproducibility of the evolution of nocturnal values of BP, in the same individual, for several months [51].

The circadian rhythm of BP shows maximum values in the early hours of the morning, followed by a subsequent gradual decrease and with minimum nocturnal values, respectively. Explanations of this variability involve the influence of exogenous or environmental factors and endogenous factors.

The endogenous rhythm associated with the body's clock determines amplitudes ranging from 5 to 10 mmHg. Blood pressure increases adjacent to waking time are associated with increases in catecholamine plasma levels: both norepinephrine and epinephrine are at peak levels in the morning and low levels at night [33]. At the moment, there are many drug classes that are used in the management of hypertension, the majority of therapeutic schemes comprising a combination of them, as they have different mechanisms of action and sometimes variable sites of action, being complementary: α- and β-adrenoceptor blocking drugs, calcium channel blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, AT1-receptor blockers, etc. (**Figure 3**). Ambulatory blood pressure monitoring of hypertensive patients is of absolute importance as it can reveal abnormal variable patterns predicting super dipping and late-night angina crises [54, 55].

Furthermore, the pharmacokinetic profile, half-life, formulation, duration of pharmacological impact, and hence the dosing interval vary between antihypertensive medication classes and individual compounds.

The primary steps in the processes that regulate blood pressure are reliant on the circadian phase, indicating that β-adrenoceptor antagonists have no effect on, diminish, or even abolish the rhythmic pattern in BP. β-adrenoceptor antagonists, on the other hand, have the property to reduce daytime BP levels and have little effect on night-time values, being not effective in lowering the early morning spike in BP. Heart rate declines caused by β-adrenoceptor antagonists are consistently more evident during the daytime hours [24, 56].

Taking into account numerous studies conducted conventionally, β-adrenoceptor antagonists—β1-selective, nonselective, or with intrinsic sympathomimetic activity do not modify or lessen the rhythmic pattern in blood pressure. Generally, it is estimated that adrenoceptor antagonists lower daytime blood pressure levels while having little or no effect on nocturnal values and are less effective in reducing the early morning escalation in blood pressure levels [56].

The effects of **β-adrenoceptor antagonists** on heart rate are consistently more evident during the daytime. Correspondingly, a fourfold crossover trial using propranolol in healthy adults revealed a more dramatic reduction in heart rate and blood pressure during the day than at night. Furthermore, it is demonstrated that the circadian phase can affect the dose–response relationship. Pindolol, a partial agonist, even raised the heart rate at night, which was a surprising finding [26, 34]. Thus, clinical evidence suggests that β-adrenoceptor-mediated blood pressure regulation is

### **Figure 3.**

*The biological mechanisms of blood pressure (BP) and the therapeutic approaches that are subjected to circadian modulation. α1 ADR.ANT, α1-adrenoreceptor antagonists; β ADR.ANT, β-adrenoreceptor antagonists; ACE. INH, ACE inhibitors; ALDO.ANT, aldosterone antagonists; AT1-REC.ANT, AT1-receptor antagonists; CAL. CH.BL, calcium channel blockers; DIUR, diuretics; REN.INH, renin inhibitors; RES, reserpine; VASODIL, vasodilators.*

more important during the day and less important at night and early in the morning. This is consistent with the circadian regularity in sympathetic tone, as evidenced by plasma noradrenaline and cAMP levels [56].

**Calcium channel blockers'** effects were also investigated, primarily by the assessment of blood pressure profiles. The administration of non-retard verapamil three times a day did not significantly modify the blood pressure profile in primary hypertensive patients, however, it was less effective at night. A single morning dose of sustained-release verapamil provided good 24-hour blood pressure management, while a sustained-release diltiazem formulation was less effective at night [26, 52]. Different pharmacokinetics of dihydropyridine derivatives appear to decrease blood pressure to wide-ranging degrees during the day and night, the specific drug formulation, and dose interval play a role [27].

In essential hypertensive patients (dippers), amlodipine, sustained-release isradipine and lacidipine, nifedipine gastrointestinal therapeutic system (GITS), and nisoldipine extended-release (ER), as well as in normotensives, immediate-release nifedipine had no impact on the 24-hour blood pressure profile after one dose taken in the morning and one in the evening, whereas, with nitrendipine, there was either no impact or a slight impact after the evening dose. Nifedipine, taken twice a day, reduced blood pressure over a 24-hour period in primary hypertension individuals. Most notably, isradipine only normalized the greatly disturbed blood pressure profile in secondary hypertensives (non-dippers) due to renal failure after the evening, but not the morning dosing. In contrast, amlodipine and nisoldipine ER normalized the disturbed blood pressure profile in non-dippers after both morning and evening dosing [20].

These studies clearly show that calcium channel blockers lower elevated blood pressure in both non-dippers and dippers without distorting the latter's normal blood pressure profile or causing super dipping and can convert non-dipping behavior into dipping behavior, the dose administered in the evening being more appropriate.

Several crossover studies, assessing morning versus evening dose, with **ACE inhibitors** in essential hypertensive patients, revealed that among dipper patients, the *Chronotherapy Advances in the Management of Chronic Neurological and Cardiovascular… DOI: http://dx.doi.org/10.5772/intechopen.106950*

evening dosing of benazepril, enalapril, and perindopril resulted in a more dramatic overnight decline than the morning dose, resulting in a super dipping blood pressure profile. Evening quinapril doses had a stronger effect than the morning ones, but the blood pressure pattern was not significantly altered [57].

After either dosing time, ramipril had no visible effect on the 24-hour blood pressure profile. An excessively severe nocturnal reduction in blood pressure, the super dipping pattern, following night-time dosage could be a possible risk factor for the development of ischemic events in individuals with hypertension, given their reduced cardiac reserve.

Other antihypertensive agents have been seldom explored in regard to probable circadian fluctuations. In essential hypertensive patients, once-daily morning doses of the diuretics xipamide and indapamide decreased blood pressure without affecting its 24-hour pattern [58].

Trials conducted on diuretics in salt-sensitive hypertensive patients (dippers and non-dippers), revealed that diuretics did not modify the circadian blood pressure profile in dippers, but did turn non-dippers into dippers [20, 27, 33].

The **α-adrenoceptor antagonists** indoramin and prazosin did not modify the blood pressure profile when administered twice daily. Throughout both day and night, a single night-time dose of the α-adrenoceptor antagonist doxazosin lowered equally systolic and diastolic blood pressure, however, the greatest decrease occurred in the morning hours. Recent research in dippers using doxazosin-gastrointestinal therapeutic system (GITS) as monotherapy demonstrated a slight but considerable reduction in blood pressure over the course of 24 hours without disrupting the normal blood pressure profile. These findings suggest the importance of α-adrenoceptor mediated BP regulation during the early morning hours because α-adrenoceptor blockade lowered peripheral resistance more efficiently during the early morning hours than at other times of the day.

The capacity of the night/day ratio of systolic BP to predict the risk of cardiovascular events is more accurate than BP recorded once, according to studies conducted in recent years. Given that nocturnal blood pressures are most consistently associated with cardiovascular risk, they require closer monitoring for patient safety [53]. The circadian rhythm plays an important role in the regulation of blood pressure, and research conclusions suggest that time is one of the most important factors influencing cardiovascular risk management. As a result, chronopharmacotherapy is required for circadian disorders including hypertension.

It is obvious that circadian rhythms have a significant impact on cardiovascular disorders. Metabolic pathways, signal transduction cascades, transcriptional networks, protein turnover, and other processes are all timed to promote optimal cellular and organ functioning.

The disruption of the circadian governance almost always triggers pathology. In addition, it is more and more obvious that the persistence and augmentation of circadian rhythms might cause and aggravate CVD in vulnerable individuals. For that purpose, it is important to identify all the details regarding the mechanisms implied by the entrainment of the cardiovascular system, using the pattern of cell-to-cell synchronization, and the particular points where the phase misalignment is transformed into pathological events (**Figure 4**).

By gathering as much chronobiologic data as possible for a single patient, it is conceivable to develop therapeutic strategies that specifically target circadian clock components and downstream mediators for the effective treatment and prevention of cardiovascular diseases, to adjust some significant lifestyle behaviors, as the timing of eating, of performing exercise and environmental conditions, as the exposure to light and certain temperatures, that work in synchrony with circadian governance of cellular processes [2, 53].

Food and Drug Administration recommends that the vast majority of long-acting formulations are preferable to be administered in the evening, at bedtime. Exceptions are represented beta-blockers that are not specifically designed for chronotherapy or do not have a similar 24-hour effect from the point of view of heart rate reduction making sense to administer them in the morning when the sympathetic drive is predominant, diuretics have the same effect over 24 hours, but the discomfort from frequent night-time awakenings should be avoided. In addition, quinapril at doses of 30–40 mg may register an excessive effect and doxazosin may provide an excessive decrease when administered in the evening. There are indications for the administration of antihypertensive drugs early in the morning, for the dipper patients, and for the non-dippers, it is necessary to add an evening dose or to switch to a single evening dose, in order to acquire a reduction in the blood pressure levels and a normalization of the 24-hour profile that is profoundly disturbed in these patients [33]. As cardiovascular drugs have vulnerable pharmacokinetic profiles that can be easily influenced by the circadian phase, it is of great importance to consider the half-life of the active components and the exact parameters of the employed pharmaceutical formulation, in order to emit a sustainable conclusion regarding the best dosage time within 24 hours [15, 26].

All the data converge to show that for the "non-dipper" type of patients and for "extreme dippers" the cardiovascular prognosis is rather poor. However, the only way

### **Figure 4.**

*The circadian imprint upon physiologic endocrine and metabolic parameters often reflected in the pathologic scenery of the human organism.*

### *Chronotherapy Advances in the Management of Chronic Neurological and Cardiovascular… DOI: http://dx.doi.org/10.5772/intechopen.106950*

to positively influence these unfavorable types of circadian variability of BP values can only be achieved by chronotherapy. It offers a way to personalize the treatment of hypertension considering each patient's distinct circadian profile, providing a better perspective on optimal blood pressure control and decreasing the associated cardiovascular risk.

It must be acknowledged that the development of antihypertensive therapy provides an effective arsenal in the sense of chronotherapy: the evolution from short-acting drugs to drugs that release the active substance slowly, allowing them to be administered in such a way as to achieve maximum effectiveness, both in terms of ideal day-time blood pressure values and by inducing a dipper-like profile of circadian variability during night-time.

### **10. Conclusions**

In essence, food intake performs a strong entrainable role in regard to human circadian rhythms. In addition, this entrainment modulates the timing of food digestion and metabolism by controlling clock-regulated output genes in the peripheral tissues, having tremendous effects on drug bioavailability and metabolism.

Understanding the mechanisms of food entrainment in the circadian system and the complexity of nutritional signals will contribute to chrono-nutritional therapy guidelines concerning the joint functionality of food and nutrition.

In the next period of time, further research will completely elucidate the interactions along the remarkable time–nutrition–drug axis within the framework of chrononutrition modulated chronopharmacotherapy, becoming an essential tool for chronic pathologies management, by individualizing the chrono-pharmaco-therapeutic approach for every single patient.
