Chronotherapeutics and Its Role in the Treatment of Hypertension and Cardiovascular Disease

Domenic A. Sica, MD; William White, MD; Division of Clinical Pharmacology and Hypertension, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA; Section of Hypertension and Pharmacology, University of Connecticut School of Medicine, Farmington, CT.

In This Article

Chronotherapeutics for Cardiovascular Disease

A major objective of a chronotherapy for cardiovascular diseases would be to deliver the drug in higher concentrations during time of greatest need (e.g., the early morning post-awakening period) and in lesser concentrations when the need is less (e.g., during the middle of the sleep cycle). At present, there are not enough data to know whether altering the dosing time of a conventional antihypertensive or anti-anginal therapy would achieve these objectives. Recently, the effects of the timing of the dose of a conventional antihypertensive agent on circadian blood pressure patterns, for example, morning vs. evening dosing of a once-daily agent have been evaluated in only a few studies with somewhat inconsistent results.[55,56,57,58]

In a study examining chronopharmacology, an ACE inhibitor was dosed either in the early morning or at bedtime in 18 moderately hypertensive patients.[55] Palatini et al[59] demonstrated that nocturnal dosing of the drug resulted in a substantially greater effect on nocturnal pressure than morning dosing. There was no significant difference in daytime blood pressure between the two groups. Measurement of ACE activity showed that nocturnal dosing induced a more sustained decline in plasma ACE. A recent review of the effects of ACE inhibitors on circadian rhythm of blood pressure discusses this subject in detail.[59] The greater decline in nocturnal pressures (i.e., an increase in "dipping"), although not formally proven as such, may be detrimental in the elderly or in subjects who have already had a cerebrovascular event.[50,51]

In contrast to the study of the ACE inhibitor quinapril, studies with ß blocker atenolol,[56] the dihydropyridine calcium channel blockers nifedipine-GITS[57] or amlodipine,[58] showed no differential effects on blood pressure when these drugs were dosed in the morning vs. the evening. Blood pressures were controlled for the better part of the 24-hour time interval after medication dosing. Like many studies in this area, relatively small sample sizes were studied; thus, these studies were underpowered for their designated task, that is, to demonstrate equivalence of the effect of dosing times on 24-hour, awake, or sleep blood pressure. Lemmer[60] recently provided a review on the impact of dosing time on the response to antihypertensive therapy in which he observed that circadian patterns were generally unchanged when comparing morning vs. evening administration of a variety of antihypertensive agents. In this review, as expected, nocturnal medication dosing generally reduced asleep blood pressure more than morning dosing of the same medication. Similarly, nocturnal medication dosing was accompanied by a waning of effect at the end of the dosing interval. In reviewing this issue it is obvious that drug class, formulation, and dose amount have an important influence on the observed findings.

The first chronotherapeutic therapy for hypertension[61,62] and angina pectoris[63] has recently been developed and marketed. This mode of therapy matches drug delivery to both the circadian pattern of blood pressure as well as conforming to the rhythm of myocardial ischemia.[64] The cardiovascular drug verapamil has been employed in this delivery system that has a delay in release for approximately 4-5 hours after dosing and then has an extended release for approximately 18 hours. When taken at bedtime, the delivery system provides optimal drug concentrations between 4 a.m. and noon, a period of time when both blood pressure and heart rate rise in association with awakening and increased physical activity. Thus, hemodynamic parameters, such as blood pressure and heart rate, are modified during the early morning hours. This delivery system allows the drug to remain clinically effective during the daytime, whereas when asleep -- a time when blood pressure naturally is lower and cardiovascular demands are less so -- the drug is minimally active. Although this mode of drug delivery is novel it is not unique in its ability to control morning blood pressure. Other long acting medications, administered in the morning, such as long acting ß blockers or calcium channel blockers, have been shown to have a relevant residual effect 18-24 hours out after dosing. The impact of nocturnally administered medication in reducing asleep blood pressure is very much formulation-dependent. For example, antihypertensive medications -- such as ß blockers or calcium channel blockers -- with convetional delivery systems, can increase nighttime ischemic episodes when given to patients exhibiting so-called nocturnal "extreme dipping."[65] Alternatively, doxazosin, which has a slow rate of absorption, does not excessively reduce asleep blood pressures when administered at bedtime while still controlling early morning peak values.[66]

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